Ligand design for Rh(iii)-catalyzed C–H activation: an unsymmetrical cyclopentadienyl group enables a regioselective synthesis of dihydroisoquinolones

We report the regioselective synthesis of dihydroisoquinolones from aliphatic alkenes and O-pivaloyl benzhydroxamic acids mediated by a Rh(iii) precatalyst bearing sterically bulky substituents. While the prototypical Cp* ligand provides product with low selectivity, sterically bulky Cp^t affords product with excellent regioselectivity for a range of benzhydroxamic acids and alkenes. Crystallographic evidence offers insight as to the source of the increased regioselectivity.C–H activation mediated processes have provided a unique retrosynthetic approach to access a variety of substituted heterocycles.¹ One tactic that has received increased attention is the coupling of π-components with heteroatom containing molecules.² A variety of transition metals are capable of catalyzing this type of transformation, providing access to dozens of heterocyclic motifs.^1–3 A challenge for these methods is controlling the regioselectivity of migratory insertion across alkenes and alkynes after the metallacycle forming C–H activation (eqn 1).Steric and electronic effects are understood to control migratory insertion of unsymmetrical alkynes in Rh(iii) catalyzed isoquinolone syntheses (eqn 1). When the substituents are electronically similar, the larger group resides β- to Rh in the metallacycle to avoid unfavorable steric interactions (selectivity is generally >10 : 1).⁴ When the substituents are electronically different, the more electron-donating group prefers being α- to rhodium in the metallacycle, presumably to stabilize the electron poor metal.^5,6 The type of C–H bond being activated also plays an important role in the regioselectivity of migratory insertion; aromatic substrates typically provide synthetically useful regioselectivities when electronically different alkynes are used (>10 : 1) but alkenyl C–H activation leads to products with lower regioselectivities, presumably due to minimal steric interactions during migratory insertion.^7,8 We found that sterically bulky di-tert-butylcyclopentadienyl ligand (Cp^t) enhances the regioselectivity of the alkyne migratory insertion event in these cases, delivering regioselectivities (>10 : 1) modestly above those achievable by Cp* ligated Rh complexes (<6 : 1). However, when the alkyne migratory insertion was poorly selective with RhCp* (<3 : 1), RhCp^t complex was ineffective at providing synthetically useful levels of selectivity. Furthermore, the Cp^t ligand was only effective with aryl substituted alkynes, presumably because of strong steric interactions between the ligand and alkyne in the insertion event. Migratory insertion of alkenes to access heterocycles using C–H activation chemistry is still relatively rare, with seminal studies by Glorius and Fagnou reporting the synthesis of dihydroisoquinolones.^9–11 Similar to alkynes, alkenyl electron-donating groups favor the position adjacent to the metal in the metallacycle delivering high regioselectivity. In contrast to alkynes, aliphatic alkenes afford product with poor regioselectivity (2 : 1) (eqn 2).^5h,12 We hypothesized competing steric and electronic effects cause the low regioselectivity, with steric effects favoring the formation of a 4-substituted product and electronics favoring the formation of a 3-substituted product.¹³ As a temporary solution to this problem, our group and others have employed tethering strategies to increase the regioselectivity of the migratory insertion event (eqn 3).^14,15 Of course, regioselectivity controlled by the ligand on Rh would be the optimal solution to the selectivity problem (eqn 4).¹⁶ Consequently, we focused our attention toward developing an intermolecular variant of this reaction that would provide product with improved regioselectivity.As a model system, we explored the impact ligands have on the coupling of O-pivaloyl-benzhydroxamic acid 1a with 1-decene 2a to provide dihydroisoquinolones 3a and 3a′. When Cp* is used as a ligand, the desired products are isolated in excellent yield but poor selectivity (2.4 : 1 3a : 3a′) ( a

Ligand-promoted palladium-catalyzed β-methylene C–H arylation of primary aldehydes

The transient directing group (TDG) strategy allowed long awaited access to the direct β-C(sp³)–H functionalization of unmasked aliphatic aldehydes via palladium catalysis. However, the current techniques are restricted to terminal methyl functionalization, limiting their structural scopes and applicability. Herein, we report the development of a direct Pd-catalyzed methylene β-C–H arylation of linear unmasked aldehydes by using 3-amino-3-methylbutanoic acid as a TDG and 2-pyridone as an external ligand. Density functional theory calculations provided insights into the reaction mechanism and shed light on the roles of the external and transient directing ligands in the catalytic transformation.

Aliphatic aldehydes are among the most common structural units in organic and medicinal chemistry research. Direct C–H functionalization has enabled efficient and site-selective derivatization of aliphatic aldehydes.

Simple aliphatic functional groups enrich the skeletal backbones of many natural products, pharmaceuticals, and other industrial materials, influencing the utility and applications of these substances and dictating their reactivity and synthetic modification pathways. Aliphatic aldehydes are some of the most ubiquitous structural units in organic materials.¹ Their relevance in nature and industry alike, combined with their reactivity and synthetic versatility, attracted much attention from the synthetic organic and medicinal chemistry communities over the years (Fig. 1).² Efficient means to the functionalization of these molecules have always been highly sought after.Open in a separate windowFig. 1Select aliphatic aldehyde-containing medicines and biologically active molecules.Traditionally, scientists have utilized the high reactivity of the aldehyde moiety in derivatizing a variety of functional groups by the means of red-ox and nucleophilic addition reactions. The resourceful moiety was also notoriously used to install functional groups at the α-position via condensation and substitution pathways.³ Although β-functionalization is just as robust, it has generally been more restrictive as it often requires the use of α,β-unsaturated aldehydes.^4,5 Hence, transition metal catalysis emerged as a powerful tool to access β-functionalization in saturated aldehydes.⁶ Most original examples of metal-catalyzed β-C–H functionalization of aliphatic aldehydes required the masking of aldehydes into better metal coordinating units since free unmasked aldehydes could not form stable intermediates with metals like palladium on their own.⁷ Although the masking of the aldehyde moiety into an oxime, for example, enabled the formation of stable 5-membered palladacycles, affording β-functionalized products, this system requires the installation of the directing group prior to the functionalization, as well as the subsequent unmasking upon the reaction completion, compromising the step economy and atom efficiency of the overall process.⁸ Besides, some masking and unmasking protocols might not be compatible with select substrates, especially ones rich in functional groups. As a result, the development of a one-step direct approach to the β-C–H functionalization of free aliphatic aldehydes was a demanding target for synthetic chemists.α-Amino acids have been demonstrated as effective transient directing groups (TDGs) in the remote functionalization of o-alkyl benzaldehydes and aliphatic ketones by the Yu group in 2016.⁹ Shortly after, our group disclosed the first report on the direct β-C–H arylation of aliphatic aldehydes using 3-aminopropanoic acid or 3-amino-3-methylbutanoic acid as a TDG.¹⁰ The TDG was found to play a similar role to that of the oxime directing group by binding to the substrate via reversible imine formation, upon which, it assists in the assembly of a stable palladacycle, effectively functionalizing the β-position.¹¹ Since the binding of the TDG is reversible and temporary, it is automatically removed upon functionalization, yielding an efficient and step-economic transformation. This work was succeeded by many other reports that expanded the reaction and the TDG scopes.^12–14 However, this system suffers from a significant restriction that demanded resolution; only substitution of methyl C–H bonds of linear aldehydes was made possible via this approach (Scheme 1a–e). The steric limitations caused by incorporating additional groups at the β-carbon proved to compromise the formation of the palladacycle intermediate, rendering the subsequent functionalization a difficult task.¹²Open in a separate windowScheme 1Pd-catalyzed β-C–H bond functionalization of aliphatic aldehydes enabled by transient directing groups.Encouraged by the recent surge in use of 2-pyridone ligands to stabilize palladacycle intermediates,^15,16 we have successfully developed the first example of TDG-enabled Pd-catalyzed methylene β-C–H arylation in primary aldehydes via the assistance of 2-pyridones as external ligands (Scheme 1f). The incorporation of 2-pyridones proved to lower the activation energy of the C–H bond cleavage, promoting the formation of the intermediate palladacycles even in the presence of relatively bulky β-substituents.¹⁷ This key advancement significantly broadens the structural scopes and applications of this process and promises future asymmetric possibilities, perhaps via the use of a chiral TDG or external ligand or both. Notably, a closely related work from Yu''s group was published at almost the same time.¹⁸We commenced our investigation of the reaction parameters by employing n-pentanal (1a) as an unbiased linear aldehyde and 4-iodoanisole (2a) in the presence of catalytic Pd(OAc)₂ and stoichiometric AgTFA, alongside 3-amino-3-methylbutanoic acid (TDG1) and 3-(trifluoromethyl)-5-nitropyridin-2-ol (L1) at 100 °C (ii) sources proved Pd(OAc)₂ to be the optimal catalyst, while Pd(TFA)₂, PdCl₂ and PdBr₂ provided only moderate yields (entries 10–12). Notably, a significantly lower yield was observed in the absence of the 2-pyridone ligand, and no desired product was isolated altogether in the absence of the TDG (entries 13 and 14). The incorporation of 15 mol% Pd catalyst was deemed necessary after only 55% yield of 3a was obtained when 10 mol% loading of Pd(OAc)₂ was instead used (entry 15).Optimization of reaction conditions^a

Entry	Pd source	L (mol%)	TDG1 (mol%)	Solvent (v/v, mL)	Yield (%)
1	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP	30
2	Pd(OAc)2	L1 (30)	TDG1 (40)	AcOH	<5
3	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP/AcOH (1 : 1)	28
4	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP/AcOH (9 : 1)	47
5	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP/AcOH (1 : 9)	<5
6	Pd(OAc)2	L1 (30)	TDG1 (60)	HFIP/AcOH (9 : 1)	50
7	Pd(OAc)2	L1 (30)	TDG1 (80)	HFIP/AcOH (9 : 1)	25
8	Pd(OAc)2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	70(68)b
9	Pd(OAc)2	L1 (75)	TDG1 (60)	HFIP/AcOH (9 : 1)	51
10	Pd(TFA)2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	60
11	PdCl2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	52
12	PdBr2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	54
13	Pd(OAc)2	—	TDG1 (60)	HFIP/AcOH (9 : 1)	9
14	Pd(OAc)2	L1 (60)	—	HFIP/AcOH (9 : 1)	0
15c	Pd(OAc)2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	55

Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd source (15 mol%), AgTFA (0.3 mmol), L1, TDG1, solvent (2.0 mL), 100 °C, 12 h. Yields are based on 1a, determined by ¹H-NMR using dibromomethane as an internal standard.^bIsolated yield.^cPd(OAc)₂ (10 mol%).To advance our optimization of the reaction conditions, a variety of 2-pyridones and TDGs were tested (Scheme 2). Originally, pyridine-2(1H)-one (L2) was examined as the external ligand, but it only yielded the product (3a) in 7% NMR yield. Similarly, other mono- and di-substituted 2-pyridone ligands (L3–L10) also produced low yields, fixating L1 as the optimal external ligand. Next, various α- and β-amino acids (TDG1–10) were evaluated, yet TDG1 persisted as the optimal transient directing group. These amino acid screening results also suggest that a [5,6]-bicyclic palladium species is likely the key intermediate in this protocol since only β-amino acids were found to provide appreciable yields, whereas α-amino acids failed to yield more than trace amounts of the product. The supremacy of TDG1 when compared to other β-amino acids is presumably due to the Thorpe–Ingold effect that perhaps helps facilitate the C–H bond cleavage and stabilize the [5,6]-bicyclic intermediate further.Open in a separate windowScheme 2Optimization of 2-pyridone ligands and transient directing groups.With the optimized reaction conditions in hand, substrate scope study of primary aliphatic aldehydes was subsequently carried out (Scheme 3). A variety of linear primary aliphatic aldehydes bearing different chain lengths provided the corresponding products 3a–e in good yields. Notably, relatively sterically hindered methylene C–H bonds were also functionalized effectively (3f and 3g). Additionally, 4-phenylbutanal gave rise to the desired product 3h in a highly site-selective manner, suggesting that functionalization of the methylene β-C–H bond is predominantly favored over the more labile benzylic C–H bond. It is noteworthy that the amide group was also well-tolerated and the desired product 3j was isolated in 60% yield. As expected, with n-propanal as the substrate, β-mono- (3k1) and β,β-disubstituted products (3k2) were isolated in 22% and 21% yields respectively. However, in the absence of the key external 2-pyridone ligand, β-monosubstituted product (3k1) was obtained exclusively, albeit with a low yield, indicating preference for functionalizing the β-C(sp³)–H bond of the methyl group over the benzylic methylene group.Open in a separate windowScheme 3Scope of primary aliphatic aldehydes. Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)₂ (15 mol%), AgTFA (0.3 mmol), L1 (60 mol%), TDG1 (60 mol%), HFIP (1.8 mL), HOAc (0.2 mL), 100 °C, 12 h. Isolated yields. ^aL1 (60 mol%) was absent and yields are given in parentheses.Next, substrate scope study on aryl iodides was surveyed (Scheme 4). Iodobenzenes bearing either an electron-donating or electron-withdrawing group at the para-, meta-, or ortho-position were all found compatible with our catalytic system (3l–3ah). Surprisingly, ortho-methyl- and fluoro-substituted aryl iodides afforded the products in only trace amounts. However, aryl iodide with ortho-methoxy group provided the desired product 3ac in a moderate yield. Notably, a distinctive electronic effect pattern was not observed in the process. It should be mentioned that arylated products bearing halogen, ester, and cyano groups could be readily converted to other molecules, which significantly improves the synthetic applicability of the process. Delightfully, aryl iodide-containing natural products like ketoprofen, fenchol and menthol were proven compatible, supplying the corresponding products in moderate yields. Unfortunately, (hetero)aryl iodides including 2-iodopyridine, 3-iodopyridine, 4-iodopyridine and 4-iodo-2-chloropyridine failed to produce the corresponding products. Although our protocol provides a novel and direct pathway to construct β-arylated primary aliphatic aldehydes, the yields of most examples are modest. The leading reasons for this compromise are the following: (1) aliphatic aldehydes are easily decomposed or oxidized to acids; (2) some of the prepared β-arylated aldehyde products may be further transformed into the corresponding α,β-unsaturated aldehydes.Open in a separate windowScheme 4Scope of aryl iodides. Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Pd(OAc)₂ (15 mol%), AgTFA (0.3 mmol), L1 (60 mol%), TDG1 (60 mol%), HFIP (1.8 mL), HOAc (0.2 mL), 100 °C, 12 h. Isolated yields.Density functional theory (DFT) calculations were performed to help investigate the reaction mechanism and to elucidate the role of the ligand in improving the reactivity (Fig. 2). The condensation of the aliphatic aldehyde 1a with the TDG to form imine-1a was found thermodynamically neutral (ΔG° = −0.1 kcal mol⁻¹). As a result, it was permissible to use imine-1a directly in the calculations. According to the calculations results, the precatalyst [Pd(OAc)₂]₃, a trimeric complex, initially experiences dissociation and ligand metathesis with imine-1a to generate the Pd(ii) intermediate IM1, which is thermodynamically favorable by 21.9 kcal mol⁻¹. Consequently, the deprotonated imine-1a couples to the bidentate ligand to form the stable six-membered chelate complex IM1. Therefore, IM1 is indeed the catalyst resting state and serves as the zero point to the energy profile. We have identified two competitive pathways for the Pd(ii)-catalyzed C–H activation starting from IM1, one of which incorporates L1 and another which does not. On the one hand, an acetate ligand substitutes one imine-1a chelator in IM1 to facilitate the subsequent C–H activation leading to IM2, which undergoes C(sp³)–H activation through concerted metalation-deprotonation (CMD) viaTS1 (ΔG^‡ = 37.4 kcal mol⁻¹). However, this kinetic barrier is thought to be too high to account for the catalytic activity at 100 °C. On the other hand, the chelate imine-1a could be replaced by two N-coordinated ligands (L1) leading to the Pd(ii) complex IM3. This process is endergonic by 6.4 kcal mol⁻¹. To allow the ensuing C–H activation, IM3 dissociates one ligand (L1) producing the active species IM4, which undergoes TS2 to cleave the β-C(sp³)–H bond and form the [5,6]-bicyclic Pd(ii) intermediate IM5. Although this step features an energy barrier of 31.2 kcal mol⁻¹, it is thought to be feasible under the experimental conditions (100 °C). Possessing similar coordination ability to that of pyridine, the ligand (L1) effectively stabilizes the Pd(ii) center in the C–H activation process, indicating that this step most likely involves a manageable kinetic barrier. This result explicates the origin of the ligand-enabled reactivity (TS2vs.TS1). Additionally, we considered the γ-C(sp³)–H activation pathway viaTS2′ which was found to have a barrier of 35.5 kcal mol⁻¹. The higher energy barrier of TS2′ compared to that of TS2 is attributed to its larger ring strain in the [6,6]-bicyclic Pd(ii) transition state, which reveals the motive for the site-selectivity. Reverting back to the supposed pathway, upon the formation of the bicyclic intermediate IM5, it undergoes ligand/substrate replacement to afford intermediate IM6, at which the Ar–I coordinates to the Pd(ii) center to enable oxidative addition viaTS3 (ΔG^‡ = 27.4 kcal mol⁻¹) leading to the five-coordinate Pd(iv) complex IM7. Undergoing direct C–C reductive elimination in IM7 would entail a barrier of 29.6 kcal mol⁻¹ (TS4). Alternatively, iodine abstraction by the silver(i) salt in IM7 is thermodynamically favorable and irreversible, yielding the Pd(iv) intermediate IM8 coordinated to a TFA ligand. Subsequently, C–C reductive coupling viaTS5 generates the Pd(ii) complex IM9 and concludes the arylation process. This step was found both kinetically facile (6.1 kcal mol⁻¹) and thermodynamically favorable (30.7 kcal mol⁻¹). Finally, IM9 reacts with imine-1avia metathesis to regenerate the palladium catalyst IM1 and release imine-3a in a highly exergonic step (21.0 kcal mol⁻¹). Ultimately, imine-3a undergoes hydrolysis to yield the aldehyde product 3a and to release the TDG.Open in a separate windowFig. 2Free energy profiles for the ligand-promoted Pd(ii)-catalyzed site-selective C–H activation and C–C bond formation, alongside the optimized structures of the C–H activation transition states TS1 and TS2 (selected bond distances are labelled in Å). Energies are relative to the complex IM1 and are mass-balanced.     

Polycyclic heteroaromatics via hydrazine-catalyzed ring-closing carbonyl–olefin metathesis

The use of hydrazine-catalyzed ring-closing carbonyl–olefin metathesis (RCCOM) to synthesize polycyclic heteroaromatic (PHA) compounds is described. In particular, substrates bearing Lewis basic functionalities such as pyridine rings and amines, which strongly inhibit acid catalyzed RCCOM reactions, are shown to be compatible with this reaction. Using 5 mol% catalyst loadings, a variety of PHA structures can be synthesized from biaryl alkenyl aldehydes, which themselves are readily prepared by cross-coupling.

Hydrazine catalysis enables the ring-closing carbonyl–olefin metathesis (RCCOM) to form polycyclic heteroaromatics, especially those with basic functionality.

Polycyclic heteroaromatic (PHA) structures comprise the core framework of many valuable compounds with a diverse range of applications (Fig. 1A).¹ For example, polycyclic azines (e.g. quinolines) are embedded in many alkaloid natural products, including diplamine² and eupolauramine³ to name just a few. These types of structures are also of interest for their biological activity, such as with the inhibitor of the Src-SH3 protein–protein interaction shown in Fig. 1A.⁴ Many nitrogenous PHAs are also useful as ligands for transition metal catalysis, as exemplified by the widely used ligand 1,10-phenanthroline.⁵ Meanwhile, chalcogenoarenes⁶ such as dinaphthofuran⁷ and benzodithiophene⁸ have attracted high interest for both their medicinal properties⁹ and especially for their potential use as organic light-emitting diodes (OLEDs), organic photovoltaics (OPVs), and organic field-effect transistors (OFETs).¹⁰ These and numerous other examples have inspired the development of a wide variety of strategies to construct PHAs.^1,11–14 Although these approaches are as varied as the structures they target, the wide range of molecular configurations within PHA chemical space and the challenges inherent in exerting control over heteroatom position and global structure make novel syntheses of these structures a topic of continuing interest.Open in a separate windowFig. 1(A) Examples of PHAs. (B) RCCOM strategy for PHA synthesis. (C) Lewis base inhibition for Lewis acid vs. hydrazine catalyzed RCCOM. (D) Hydrazine-catalyzed RCCOM for PHA synthesis.One potentially advantageous strategy for PHA synthesis is the use of ring-closing carbonyl–olefin metathesis¹⁵ (RCCOM) to forge one of the PHA rings, starting from a suitably disposed alkenyl aldehyde precursor 2 that can be easily assembled by cross-coupling (Fig. 1B). In related work, the application of RCCOM to form polycyclic aromatic hydrocarbons (PAHs) was reported by Schindler in 2017.¹⁶ In this case, 5 mol% FeCl₃ catalyzed the metathesis of substrates to form phenanthrenes and related compounds in high yields at room temperature. This method was highly attractive for its efficiency, its use of an earth-abundant metal catalyst, and the production of benign acetone as the only by-product. Nevertheless, one obvious drawback to the use of Lewis acid activation is that the presence of any functionality that is significantly more Lewis basic than the carbonyl group can be expected to strongly inhibit these reactions (Fig. 1C). Such a limitation thus renders this method incompatible with a wide swath of complex molecules, especially PHAs comprised of azine rings. This logic argues for a mechanistically orthogonal RCCOM approach that allows for the synthesis of PHA products with a broader range of ring systems and functional groups.We have developed an alternative approach to catalytic carbonyl–olefin metathesis that makes use of the condensation of 1,2-dialkylhydrazines 5 with aldehydes to form hydrazonium ions 6 as the key catalyst–substrate association step.^17–19 This interaction has a much broader chemoorthogonality profile than Lewis acid–base interactions and should thus be much less prone to substrate inhibition than acid-catalyzed approaches. In this Communication, we demonstrate that hydrazine-catalyzed RCCOM enables the rapid assembly of PHAs bearing basic functionality (Fig. 1D).For our optimization studies, we chose biaryl pyridine aldehyde 7 as the substrate (20 salt 11 was also productive (entry 2), albeit somewhat less so. Notably, iron(iii) chloride generated no conversion at either ambient or elevated temperatures (entries 3 and 4). Trifluoroacetic acid (TFA) was similarly ineffective (entry 5). Meanwhile, a screen of various solvents revealed that, while the transformation could occur in a range of media (entries 6–9), THF was optimal. Finally, by raising the temperature to 90 °C (entry 10) or 100 °C (entry 11), up to 96% NMR yield (85% isolated yield) of adduct 8 could be obtained in the same time period.Optimization studies^a

Non-directed Pd-catalysed electrooxidative olefination of arenes

The Fujiwara–Moritani reaction is a powerful tool for the olefination of arenes by Pd-catalysed C–H activation. However, the need for superstoichiometric amounts of toxic chemical oxidants makes the reaction unattractive from an environmental and atom-economical view. Herein, we report the first non-directed and regioselective olefination of simple arenes via an electrooxidative Fujiwara–Moritani reaction. The versatility of this operator-friendly approach was demonstrated by a broad substrate scope which includes arenes, heteroarenes and a variety of olefins. Electroanalytical studies suggest the involvement of a Pd(ii)/Pd(iv) catalytic cycle via a Pd(iii) intermediate.

The Fujiwara–Moritani reaction using electric current is a powerful tool for the olefination of arenes by Pd-catalysed C–H activation.

Transition metal-catalysed C–H functionalisation reactions have increasingly gained importance over the last few decades since they allow direct and rapid installation of functionality. Regardless of the undeniable synthetic value of such transformations, the need for superstoichiometric quantities of expensive and hazardous oxidants (e.g., silver and copper salts) remains a major drawback from a sustainable chemistry perspective.^1,2 Additionally, chemical oxidants often lead to the formation of by-products, hindering purification and decreasing atom economy. Nevertheless, very few reports were also reported in the literature wherein mild oxidant such as molecular oxygen can also serve as the oxidising agent.^2j To make chemical processes and transformations intrinsically sustainable, organic chemists re-discovered synthetic electrochemistry as an environmentally friendly approach.^3–6 In the domain of synthetic electrochemistry, the Lei group achieved a significant milestone and installed C–C bonds through a different cross-coupling strategy.^1k,2f–h Electroorganic synthesis utilizes electric current to realize redox processes and thereby avoids the use of dangerous, expensive, and polluting chemical oxidising or reducing agents. Precise control of electrochemical reaction parameters often leads to commendable reactivity and chemoselectivity and hence to an improved atom economy. In addition, electrochemical processes fulfil the expectations of sustainability since electricity can be generated from renewable energy sources, such as wind, sunlight or biomass. Recent efforts in the field of electrochemical C–H activation resulted in significant progress towards efficient C–C and C–heteroatom bond formations.^7–10 Hence, the utilization of electric current as an alternative oxidant in Pd-catalysed C–H functionalisations is emerging as an attractive alternative to stoichiometric reagents.^11–13The Fujiwara–Moritani reaction is one of the earliest known examples of Pd-catalysed oxidative C–H functionalisations for C–C bond formation.¹⁴ This extraordinary C(sp²)-H alkenylation reaction avoids the use of prefunctionalised starting materials; however, it suffers from the drawbacks of regioselectivity, reactivity and use of excess arenes.¹⁵ Since its development, a number of modified strategies have been reported by different research groups to address the issue of reactivity and selectivity.^16–21 In recent times, the ligand assisted oxidative C–H alkenylation of arenes without directing substituents has been established as one of the major strategies to overcome the reactivity issue and to elaborate the substrate scope.However, regioselectivity for most of the sterically and electronically unbiased arenes is still not up to the mark. The most recent studies on the non-directed oxidative C–H olefination of arenes were reported independently by Yu and van Gemmeren (Scheme 1). The Yu group employed electron-deficient 2-pyridone as an X-type ligand for the olefination of both electron-rich and electron-poor arenes including heteroarenes as the limiting reagent (Scheme 1a).¹⁸ The pyridone ligand improves the selectivity in a non-directed approach as compared to the directed C–H olefination reaction by enhancing the influence of steric effects. On the other hand, the van Gemmeren group utilizes two complementary ligands N-Ac–Gly–OH and a 6-methylpyridine derivative in a 1 : 1 ratio to accomplish the non-directed olefination reaction of arenes (Scheme 1b).²⁰ Despite the indisputable advances made by these research groups in the area of non-directed oxidative C–H olefination of arenes, the use of superstoichiometric amounts of toxic and waste-generating oxidants (Ag salts) deciphers into a strong call for an environmentally responsive and atom-economic protocol. To address these shortcomings, we recently introduced Pd-photoredox catalysed olefination of non-directed arenes with excellent site selectivity under oxidant free conditions.²¹Open in a separate windowScheme 1Recent approaches to sustainable C–H alkenylation reactions.In 2007, Jutand reported the directing group assisted Pd-electracatalysed ortho-olefination of acetyl protected aniline in a divided cell by utilizing catalytic amounts of benzoquinone as a redox mediator (Scheme 1c).^22a A Rh-catalysed ortho-C–H olefination of benzamide was developed through an electrooxidative pathway by the Ackermann group (Scheme 1d).^22b Simple arenes that bear no directing groups are cheap, easily available and very desirable starting materials. However, the use of such arenes is significantly more challenging for selective functionalisation as transformations often result in the formation of complex product mixtures. With no report of an electrooxidative Pd-catalysed C(sp²)-H alkenylation of simple arenes present, we wish to present such a variant of the Fujiwara–Moritani reaction (Scheme 1e). The developed method proceeds through a non-directed pathway and is controlled by stereoelectronic factors. This protocol does not require additional chemical oxidizing agents and is executed using an operator-friendly undivided cell setup.To start our study, naphthalene was chosen as a challenging substrate because of its ability to form α- and β-products. We examined various reaction conditions for the desired Pd-catalysed electrooxidative C–H alkenylation in a simple undivided cell setup (†) with n-butyl acrylate as the coupling partner. After rigorous optimisation, we found that naphthalene reacts with n-butyl acrylate in dichloroethane (DCE) in the presence of Pd(OAc)₂ (10 mol%), ligand L1 (20 mol%), and the electrolyte tetra-n-butylammonium hexafluorophosphate (TBAPF₆, 0.5 equiv.) while employing a graphite felt anode and a platinum cathode maintaining constant current electrolytic conditions (j = 2.5 mA cm⁻², EntryAlteration from standard conditionsYield of 1^b (%)Selectivity (β : α)1None70>25 : 12Co(OAc)₂·4H₂O instead of Pd(OAc)₂91 : 13[Ru(p-cymene)Cl₂]₂ instead of Pd(OAc)₂NR4Pd(OAc)₂·(5 mol%)51>25 : 15Pd(OAc)₂·(20 mol%)71>25 : 16L2 instead of L1458 : 17L3 instead of L15920 : 18L4 instead of L1195 : 19L5 instead of L181 : 110Benzoquinone (10 mol%)68>25 : 111PivOH (1.0 equiv.)6120 : 112Ni foam instead of Pt64>25 : 113GF instead of Pt4915 : 114Steel instead of Pt3113 : 1156 mA cm⁻² instead of 2.5 mA cm⁻²2711 : 11624 h reaction time4720 : 11712 h reaction time5621 : 118No electricityNR—19No Pd(OAc)₂NR— Open in a separate window^aStandard reaction conditions: undivided cell, GF anode, Pt cathode, j = 2.5 mA cm⁻², naphthalene (0.2 mmol), n-butyl acrylate (0.5 mmol), Pd(OAc)₂ (10 mol%), L1 (20 mol%), TBAPF₆ (0.5 equiv.), DCE (3 mL), 15 h, under air.^bYield determined by ¹H-NMR of crude reaction mixture. NR = no reaction; TBAPF₆ = tetra-n-butylammonium hexafluorophosphate. GF = graphite felt. Surface area of electrodes dipped in solution = 0.7 cm × 0.7 cm, current = 1.225 mA and current density = 2.5 mA cm⁻² (electrochemical surface area = 1.23 cm²).Notably, in the present transformation the ligand has a major influence on the reactivity and selectivity aspects (see the ESI, Table S4^†). After studying a series of 2-pyridone, pyridine and amino acid-based ligands L2–L5 it was found that L1 is the optimal ligand since it provided superior yield and selectivity (entries 6–9). Addition of catalytic amounts of p-benzoquinone as a redox mediator (entry 10) or pivalic acid as an additive (entry 11, Scheme 2). Following the olefination of naphthalene (68%, >25 : 1 β : α selectivity), 1,2,3,4-tetrahydronaphthalene was successfully reacted (52%, 11 : 1 β : α-selectivity). Next, we applied our standard reaction conditions to benzene and found them not to be equally effective as only 25% of the olefinated product 3 was obtained. As a result, further optimizations of electric current density and solvent were carried out to enhance the yield (see the ESI, Table S9^†). To our satisfaction, the yield of product 3 increased to 63% when the electrolysis was carried out with an electric current density of j = 1.5 mA cm⁻² and in a solvent mixture of DCE/HFIP (5 : 1). These modified reaction conditions were applied to the electrosynthesis of all other olefinated products 4–26 (Scheme 2). The olefination of 1,3,5-trimethoxybenzene and mesitylene with n-butyl acrylate proceeded smoothly under the revised reaction conditions to afford products 4–5 in up to 65% yield. The regioselectivity issue was more prominent for arenes bearing two or more electronically similar C–H bonds (e.g., electron-rich arenes: ortho vs. para). Dimethoxy benzene gives β-selective olefinated product 6 (β : α; 7 : 1). While toluene was converted with para-selectivity (7 : 1) to 7, phenol afforded olefinated product 8 with ortho-selectivity (o : others; 9 : 1, Scheme 2). On the other hand, subjecting TBDMS (tert-butyldimethylsilyl) protected phenol to the established protocol furnished 9 with 8 : 1 para-selectivity (Scheme 2). The TBDPS (tert-butyldiphenylsilyl) protected phenol afforded exclusively the para-olefinated product 10 which might be due to the steric repulsion caused by the bulky protecting group. Conversion of 2,6-diiso-propylphenol provided olefinated product 11 as a single para-olefinated isomer with 67% yield. Anisole and ethoxybenzene both reacted smoothly to produce 12 (72%, 15 : 1) and 13 (70%, 10 : 1) with ortho-selectivity (Scheme 2). The compatibility of the present transformation was further showcased by the olefination of N,N-dimethyl aniline in 70% yield (14) and 8 : 1 ortho-selectivity. Similarly, methyl ferrocene carboxylate and biologically active caffeine reacted smoothly with n-butyl acrylate to produce olefinated products 15 and 16 in good yields (Scheme 2). Moderately electron-withdrawing arenes such as a phenyl acetic acid derivative (17, 51%, o : others = 7 : 1), a homoveratric acid derivative (18, 48%, o : others = 15 : 1) or 4-methoxy acetophenone (19, 59%, m : others = 7 : 1) gave the corresponding products in satisfactory yields. The coupling of unsubstituted thiophene and furan with n-butyl acrylate afforded the olefinated products 20 and 21 (64% and 68%) with synthetically useful C2-selectivity, respectively (C2 : others; 18 : 1 and C2 : others; 19 : 1, Scheme 2). In contrast, thiophenes bearing a substituent at the C2 position such as 2-phenylthiophene and 1-(4-(thien-2-yl)phenyl)ethan-1-one reacted with high C5-selectivity (>20 : 1) to afford the arylated α,β-unsaturated esters 22 and 23 (76% and 73% yield). Conversion of 2-(2-nitrophenyl)thiophene delivered the desired product 24 in 64% yield with exclusive C5-selectivity. A C3-substituted thiophene also reacted with the acrylate to afford 25 in 72% yield (C5 : others; 6 : 1 selectivity). Heteroarenes bearing electron-withdrawing substituents such as 2-acetyl thiophene (26) afforded the C5-olefinated product in moderate yield and selectivity (60%, C5 : others = 8 : 1). However, aromatic rings bearing strong electron-withdrawing groups (–NO₂, –CHO, –CF₃, –F etc.) are not compatible under our present reaction conditions (see details in the ESI, Section 4.3^†).Open in a separate windowScheme 2Evaluation of simple arenes and heteroarenes in the electrochemical olefination.^a Reaction conditions: undivided cell, GF anode, Pt cathode, j = 2.5 mA cm⁻² or j = 1.5 mA cm⁻², corresponding arenes or heteroarenes (0.2 mmol), n-butyl acrylate (0.5 mmol), Pd(OAc)₂ (10 mol%), L1 (20 mol%), TBAPF₆ (0.5 equiv.), DCE (3 mL) or 5 : 1 ration of dichloroethane (DCE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), 15 h, under air. ^bYields of isolated products are reported.Next, we investigated the applicability of other olefins by reacting them with simple arenes (Scheme 3). In addition to other acrylates (methyl 27, ethyl 28 and tert-butyl 29), acrylic acid was successfully converted with naphthalene to its arylated product 30. Moderate yields (54–60%) and moderate to high β : α selectivities (up to >25 : 1) were obtained for all reactions. Coupling of methyl acrylate with benzene under adjusted electrochemical conditions (j = 1.5 mA cm²; DCE/HFIP mixtures) gave 62% of olefinated product 31. Other activated olefins such as methyl vinyl sulfone, and acrylonitrile were also amenable to the present olefination protocol. Subjecting these substrates in combination with different arenes to our protocol led to a variety of arylated products 32–35 in good yields and regioselectivities. α,β-Unsaturated ester derivatives of bioactive molecules such as δ-tocopherol and cholesterol were efficiently reacted with naphthalene to the olefinated products 36–37 in moderate yields. To further elaborate the scope of present protocol, un-activated olefins such as aliphatic olefins and styrene derivatives were tested. However, none of them afford olefinated products under our reaction conditions (see details in the ESI, Section 4.3^†). To monitor the scalability of the present transformation, two reactions were performed with the model reaction at scales of 0.504 g (46%, β : α = 7 : 1) and 1.08 g (41%, β : α = 7 : 1; see ESISection 4.2^†).Open in a separate windowScheme 3Evaluation of other α,β-unsaturated systems in the electrochemical olefination of arenes. ^aReaction conditions: undivided cell, GF anode, Pt cathode, j = 2.5 mA cm⁻² or j = 1.5 mA cm⁻², corresponding arenes or heteroarenes (0.2 mmol), activated olefins (0.5 mmol), Pd(OAc)₂ (10 mol%), L1 (20 mol%), TBAPF₆ (0.5 equiv.), DCE (3 mL) or 5 : 1 ratio of dichloroethane (DCE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), 15 h, under air. ^bYields of isolated products are reported.To gain insights into the catalytic mode of action, electrochemical and spectroelectrochemical experiments were performed. Cyclic voltammetry (CV) of Pd(OAc)₂ in DCE revealed two oxidation waves at +1.42 V vs. NHE (Normal Hydrogen Electrode) and at +2.47 V vs. NHE (Fig. 1a) which might refer to the redox conversion of Pd(ii/iii) and Pd(iii/iv).²³Fig. 1b shows the CVs of naphthalene (substrate), ligand L1, n-butyl acrylate, and Pd(OAc)₂. In comparison to the Pd(ii/iii) redox pair, a significantly higher oxidation potential (+2.16 V vs. NHE) was observed for naphthalene, which suggests that substrate activation is potentially induced by a Pd species with an oxidation state greater than +II (Fig. 1b). The CVs of other substrates followed the same pattern (see the ESI, Fig. S2^†). According to an electrochemical study on approximate ranges of standard redox potentials for Pd intermediates in catalytic reactions, the oxidation of Pd(ii) to Pd(iv) is usually observed in the range of +1.00–2.00 V (vs. Fc/Fc⁺ = ferrocene) or 1.63–2.63 V (vs. NHE).²³ The CV profile of Pd(OAc)₂ in the negative scan revealed two reduction waves at −0.23 V and at −1.06 V vs. NHE (Fig. S6^†) which might refer to the redox conversion of Pd(ii/i) and Pd(i/0). Taking these results into account, involvement of a Pd(ii/iv) catalytic cycle during the present transformation appears to be likely as the negative scan rules out a Pd(ii/0) cycle.^23d,eOpen in a separate windowFig. 1(a) Cyclic voltammograms of Pd(OAc)₂ and L1-Pd(OAc)₂ (1 mM, 100 mV s⁻¹ scan rate, glassy carbon, potential vs. NHE, 0.1 M TBAPF₆ in DCE); (b) cyclic voltammogram of reactants (1 mM, 100 mV s⁻¹ scan rate, glassy carbon, potential vs. NHE, 0.1 M TBAPF₆ in DCE); (c) in situ UV-Vis spectroelectrochemical spectra of the reaction mixture during bulk electrolysis at +2.61 V vs. NHE; (d) in situ UV-Vis spectroelectrochemical spectra of the Pd-ligand complex during bulk electrolysis at +2.61 V vs. NHE.In order to obtain further evidence for this hypothesis, we examined the reaction mixture at a constant potential of +2.61 V (vs. NHE) spectroelectrochemically (SEC) to check any changes in optical features during the reaction. This in situ UV-visible analysis of the reaction mixture revealed the gradual decrease of an absorption band at 379 nm and a new peak (∼350 nm) appeared over time (Fig. 1c). Similar behaviour was observed for the Pd-ligand complex as a blue shift of optical bands was found from 368 nm to 352 nm at the same potential of +2.61 V (vs. NHE, Fig. 1d). The differences in the observed UV-Vis peak positions are presumably due to a change in the geometry of the Pd-complex upon oxidation in the analysed reaction mixtures.To further consolidate this hypothesis, the same SEC experiment was repeated with only Pd(OAc)₂ which showed an absorption peak at 404 nm (Fig. S3^†). Electrolysis of Pd(OAc)₂ at +2.61 V (vs. NHE) also resulted in a blue shift with a new peak appearing at almost the same wavelength of 349 nm (Fig. S4^†). All these results led us to postulate that the new peak was associated with a change in the oxidation state of the Pd(ii) center. Moreover understand the nature of intermediates involved in the catalytic cycle, a series of electron paramagnetic resonance (EPR) experiments of the reaction mixture were conducted at different time intervals employing optimised reaction conditions. The EPR spectra (273 K) after 1 h showed a strong peak at g = 2.005 which was presumably due to the formation of an organic radical (Fig. 2a), however no naphthalene homo-coupled product was detected after different time intervals or under different conditions. At longer time intervals (4 h and 7 h), weak peaks at g_x = 2.139, g_y = 2.081 and g_z = 2.055 arose due to the asymmetry of the electronic distribution. The appearance of rhombic signals suggested the formation of a Pd(iii) intermediate having a d⁷ center (Fig. 2a).²⁴ An enlarged version of the spectra for Pd(iii) after 7 h is shown with simulated data in Fig. 2b. Time-dependent EPR spectra highlight that the build-up of Pd(iii) was concomitant with the decreased formation of an organic radical (Pd^III–R to Pd^IIR^.) as the corresponding peak diminished. This implied that the catalytically active Pd(iii) species got accumulated as the reaction approached towards completion. Furthermore, the EPR data in the absence of n-butyl acrylate (after 2 h) also revealed a very strong peak at g = 2.005; hence the formation of a radical species from the olefin was ruled out (Fig. S5^†).Open in a separate windowFig. 2(a) EPR spectrum of the reaction mixture under the standard reaction conditions at different time intervals (273 K); (b) enlarged EPR spectra of Pd(iii) after 7 h of experiment at 273 K (experimental vs. simulated).Additionally, radical quenching experiments with TEMPO did not show any effects under the standard reaction conditions. Furthermore, electrochemical arene oxidation to generate organic radicals has been well reported in the literature.^5f All these control experiments suggest that a phenoxy radical from L1 (C′) might be formed from intermediate C (Scheme 4).Open in a separate windowScheme 4Proposed catalytic cycle for the electrooxidative olefination of arenes.All of the performed experiments give a strong indication that a Pd(ii)/Pd(iv) cycle is involved in this electrochemical variant of the Fujiwara–Moritani reaction. Also, a palladium complex Pd^II(L1)₄ was synthesised and characterised by X-ray crystallography (Fig. 3). This Pd^II(L1)₄ complex was found to be a competent intermediate for the Pd-catalysed electrooxidative olefination of arenes.Open in a separate windowFig. 3Single X-ray crystal structure of Pd-complex [Pd(L1)₄].²⁵Based on these results and literature precedence,²³ a plausible Pd(ii/iv)-catalytic cycle is proposed for the electro-oxidative olefination of simple arenes (Scheme 4). The catalytic cycle starts with the anodic oxidation of the Pd(ii) catalyst A to form a Pd(iii) intermediate B. Arene C (sp²)–H bond activation delivers the organopalladium complex C which is converted to the Pd(iv) species D by anodic oxidation. Next, olefin coordination to form E followed by migratory insertion results in the formation of another organopalladium intermediate F. Finally, β-hydride elimination followed by reduction of Pd furnishes the olefinated product 1 and the Pd(ii) catalyst A is regenerated.     

Lithium achieves sequence selective ring-opening terpolymerisation (ROTERP) of ternary monomer mixtures

Heteroatom-containing degradable polymers have strong potential as sustainable replacements for petrochemically derived materials. However, to accelerate and broaden their uptake greater structural diversity and new synthetic methodologies are required. Here we report a sequence selective ring-opening terpolymerisation (ROTERP), in which three monomers (A, B, C) are selectively enchained into an (ABA′C)_n sequence by a simple lithium catalyst. Degradable poly(ester-alt-ester-alt-trithiocarbonate)s are obtained in a M_n range from 2.35 to 111.20 kDa which are not easily accessible via other polymerisation methodologies. The choice of alkali metal is key to achieve high activity and to control the terpolymer sequence. ROTERP is mechanistically compatible with ring-opening polymerisation (ROP) allowing switchable catalysis for blockpolymer synthesis. The ROTERP demonstrated in this study could be the first example of an entirely new family of sequence selective terpolymerisations.

A sequence selective ring-opening terpolymerisation of epoxides with CS₂ and phthalic thioanhydride yielding poly(ester-alt-ester-alt-trithiocarbonates) is reported.

Synthetic polymers are now more in demand than ever before and looking at their annually increasing production, a polymer free society is at best a vague memory rather than a vision for the future.¹ As most commodity polymers are based on chemically inert aliphatic –C–C– backbones, most polymer waste shows unappreciable degradation with respect to the polymer''s time in application.^2,3 In answer to the ever-increasing amount of plastic pollution, much effort focuses on the exploration of new heteroatom containing polymers which, because of their more polar bonds making up the backbone, are more susceptible to degradation via physical, chemical and biochemical pathways and even facilitate new chemical recycling methods.^4–8 Besides, there is also a constant demand for entirely new materials to enable technological innovation making new methodologies to synthesise heteroatom containing polymers necessary.Arguably one of the most popular methods to make such polymers is the ring-opening polymerisation (ROP) of a heterocycle A.^9–11 These polymerise under release of their associated ring strain energy to make polymers (A)_n such as poly(thio)ethers, poly(thio)ester and poly(thio)carbonates, only to name a few. Early on it has been realised that in some cases the ROP of three or four-membered heterocycles A can be coupled to the insertion of typically heteroallenes or cyclic anhydrides B to generate alternating copolymers (AB)_n.^12–14 The underlying requirements for (AB)_n polymerisations are a combination of kinetic factors, i.e. monomer A inserting orders of magnitude faster into the active catalyst growing chain-bond than monomer B, and chemoselectivities, i.e. insertion of monomer A resulting in type A active catalyst growing chain-bond that does not show appreciable reactivity with A but only with B (and vice versa). Prominent examples of this alternating (AB)_n ring-opening copolymerisation (ROCOP) include CO₂/epoxide ROCOP yielding polycarbonates and cyclic anhydride/epoxide ROCOP yielding polyesters.^15–17 Sulfur analogous are also accessible such as polythiocarbonate from CS₂/(epoxide or thiirane) and polythioesters from thioanhydride/(epoxide or thiirane) ROCOP.^18–31 Such sulfur rich polymers are attractive high-refractive index materials that can show improved crystallinity and degradability over their all-oxygen analogues and in some cases enable chemical polymer to monomer recycling.^32–39Most relevant to this study is a report by Werner and coworkers on lithium alkoxide catalysed CS₂/epoxide ROCOP yielding poly(monothio-alt-trithiocarbonate)s featuring R–O–C( S)–O–R and R–S–C( S)–S–R links (Fig. 1).^40,41 Such a polymer sequence is unexpected, as the formal product of alternating insertion would be a poly(dithiocarbonate) with R–O–C( S)–S–R links. Furthermore, the polymer shows an unusual “head-to-head-alt-tail-to-tail” selectivity meaning that the R–O–C( S)–O–R links sit adjacent to the tertiary CHR₃ positions of the ring opened epoxide (i.e. “head” position) and that the R–S–C( S)–S–R links sit adjacent to the secondary CH₂R₂ position of the ring opened epoxide (i.e. “tail” position). This sequence let the authors postulate a mechanism involving tail-selective epoxide ring-opening by a dithiocarbonate chain end which is formed by CS₂ insertion into an alkoxide intermediate. The resulting alkoxide intermediate was proposed to backbite into the adjacent dithiocarbonate link which after a rearrangement process resulted in an O/S exchange of the chain end. The rearrangement transforms the alkoxide into a thiolate chain end and the adjacent dithiocarbonate R–O–C( S)–S–R into a monothiocarbonate R–O–C( S)–O–R. CS₂ insertion of the thiolate generates a trithiocarbonate R–S–C( S)–S–R which after epoxide insertion regenerates the alkoxides. In contrast to alkoxides sitting adjacent to R–O–C( S)–S–R links, alkoxides next to R–S–C( S)–S–R links were not proposed to undergo backbiting and O/S exchange. Importantly the initial regioselectivity of the epoxide ring-opening was preserved throughout the rearrangement which explained the “head-to-head-alt-tail-to-tail” selectivity. Interestingly lithium appeared to be crucial as other alkali metal alkoxides failed to catalyse this ROCOP, while more sophisticated catalysts result in much more uncontrolled polymer sequences. Hence it appears that the Li controls which alkoxide intermediate precisely undergoes O/S exchange and to which degree this rearrangement occurs, but the reasons behind the special role of Li remains to be explored. Relatedly the ROCOP of thioanhydrides with epoxides has also been reported and similar exchange processes have been proposed as side reactions.²³ Although not directly proven, this mechanism seemed reasonable and let us hypothesise that lithium catalysts could grant a general access to control the O/S exchange process in ROCOP and even in the polymerisation of ternary monomer mixtures. Furthermore, we reasoned that the two distinct chain ends formed via O/S exchange, i.e. alkoxide and thiolate (type A vide supra), could enable discrimination between two different type B monomers and enable sequence selective terpolymerisations. It should be noted that reports exist in which mixtures of A, B and C (e.g. epoxide A, cyclic anhydride B and CO₂ C) either yield random terpolymers, (AB)_n-ran-(AC)_m poly(esters-ran-carbonate), or block-terpolymers, (AB)_n-b-(AC)_m, polyester-b-polycarbonate. In this case the monomer sequence depends on catalyst selection and reaction conditions, but sequence selective terpolymers, e.g. (ABC)_n or (ABAC)_n, are unknown.^42–48 The hypothesis of O/S exchange here led us to discover a new type of polymerisation, sequence selective ring-opening terpolymerisation (ROTERP) that we report in this contribution. ROTERP produces poly(ester-alt-ester-alt-trithiocarbonates), i.e. (ABA′C)_n sequences, from a mixture of the monosubstituted epoxides propylene oxide (PO) or butylene oxide (BO) A, phthalic thioanhydride (PTA) B and CS₂ C, employing simple lithium salts as the catalyst. Furthermore, model reactions proof the previously postulated O/S rearrangement that enable ROTERP and elucidate the role of the lithium catalyst. Finally, we employed ROTERP in so-called switchable catalysis, in which the onset of ROTERP stops the occurrence of ROP, for the construction of blockpolymers.Open in a separate windowFig. 1(Top) CS₂/epoxide ROCOP and postulated mechanism involving a central O/S exchange reaction, (middle) phthalic thioanhydride (PTA)/epoxide ROCOP and (bottom) PTA/CS₂/epoxide ROTERP reported in this study. R = Me, Et; [R_n] = polymer chain.ROTERP of mixtures of PTA, PO and CS₂ at loadings typically employed in ROCOP catalysis with lithium hexamethyldisilazide (LiHDMS) or lithium benzyloxide (LiOBn) as the catalyst at loadings in the range of 1 eq. LiX : (6.25–500 eq.) PTA : (31.25–2500 eq.) PO : (62.5–5000 eq.) CS₂ yield polymeric materials in 95% selectivity at 80 °C (see 40,47 Spectroscopic analysis of the isolated polymer reveals surprisingly clean NMR spectra given the potential for statistical terpolymerisation of these three monomers. The ¹H NMR spectrum (Fig. 2) shows two main aryl resonances for a symmetrically substituted terephthalate unit from ring opened PTA (δ = 7.72 and 7.56 ppm) as well as one main resonance for the CHMe (δ = 5.42 ppm; head position of the ring-opened epoxide) and CH₂ (δ = 3.90–3.40 ppm; tail position of the ring opened epoxide) groups respectively stemming from the ring opened PO. Correspondingly the ¹³C{¹H} NMR spectrum (ESI Fig. S1^†) reveals the almost exclusive presence of trithiocarbonate R–S–C( S)–S–R (δ = 222.8 ppm) and arylester R–C( O)–O–R (δ ∼166.6 ppm) resonances (94–98%) alongside minor thioester R–C( O)–S–R (δ = 192.7 ppm) resonances (2–6%). ¹H and 2D NMR spectra (ESI Fig. S3^†) show that trithiocarbonate units are positioned adjacent to CH₂ groups while arylesters are connected to the tertiary CHMe groups. The spectra remain unchanged after multiple precipitations from DCM : MeOH or THF : pentane and DOSY NMR shows that all ¹H NMR resonances diffuse at the same rate confirming that these are part of the same species. Furthermore, no other type of thiocarbonate R–(O/S)–C( O/S)–(O/S)–R are part of the polymer. Linkage identity was further substantiated by the ATR-IR spectrum (ESI Fig. S5^†) of these polymers showing an arylester C O stretch at = 1716 cm⁻¹ as well as a thiocarbonate C S stretch at = 1062 cm⁻¹ (ESI Fig. S5^†). Accordingly, the polymers are obtained as yellow solids due the presence of the C S chromophore (λ_abs = 435 nm, ESI Fig. S6^†). MALDI-TOF analysis unfortunately only led to decomposition of the materials and no signals could be identified as previously reported for sulfur-rich polymers.^26,38 Nevertheless ¹H NMR allows some conclusions regarding the topology as both for LiHMDS or LiOBn initiation, resonances for the HMDS and OBn groups can be identified to be part of the purified polymers. Insertion of alkalimetal alkoxides and amides into CS₂ yielding alkali dithiocarbonates and dithiocarbamates have been previously reported.^40,79 This makes initiation via CS₂ insertion likely which defines one end of the polymer and hence indicates that chains are linear rather than cyclic. As ROTERP is followed by CS₂/epoxide coupling once all PTA is consumed (vide infra) we infer that chains are terminated by CS₂ because heteroallene insertion products are generally established to be the resting states of heteroallene/heterocycle coupling reactions.¹²Data showing PTA/CS₂/epoxide ROTERP under different conditions

Ligand-dependent,palladium-catalyzed stereodivergent synthesis of chiral tetrahydroquinolines

The most fundamental tasks in asymmetric synthesis are the development of fully stereodivergent strategies to access the full complement of stereoisomers of products bearing multiple stereocenters. Although great progress has been made in the past few decades, developing general and practical strategies that allow selective generation of any diastereomer of a reaction product bearing multiple stereocentres through switching distinct chiral catalysts is a significant challenge. Here, attaining precise switching of the product stereochemistry, we develop a novel P-chirogenic ligand, i.e.YuePhos, which can be easily derived from inexpensive and commercially available starting materials in four chemical operations. Through switching of three chiral ligands, an unprecedented ligand-dependent diastereodivergent Pd-catalyzed asymmetric intermolecular [4 + 2] cycloaddition reaction of vinyl benzoxazinanone with α-arylidene succinimides was developed. This novel method provides an efficient route for the stereodivergent synthesis of six stereoisomers of pyrrolidines bearing up to three adjacent stereocenters (one quaternary center). Despite the anticipated challenges associated with controlling stereoselectivity in such a complex system, the products are obtained in enantiomeric excesses ranging up to 98% ee. In addition, the synthetic utilities of optically active hexahydrocarbazoles are also shown.

An unprecedented ligand-dependent stereodivergent Pd-catalyzed asymmetric intermolecular [4 + 2] cycloaddition reaction of vinyl benzoxazinanone with α-aryliene succinimides was developed.

The chirality of a biologically active molecule can alter its physiological properties. Therefore, highly efficient access to and fully characterizing all possible stereoisomers of a chiral molecule is one of the fundamental challenges in organic synthesis, drug discovery and development processes. However, most asymmetric catalytic transformations afford products enantioselectively and diastereoselectively and only form one of the stereoisomers containing multiple stereocenters. Stereodivergent access to all possible stereoisomers of the products is incredibly difficult because diastereochemical preference is largely dominated by the inherent structural and stereoelectronic characteristics of substrates, while absolute conformation can be dictated by the choice of the chiral catalyst.¹ In 2013, Carreira and co-workers addressed this limitation by introducing the concept of stereodivergent dual-catalytic synthesis, reporting the allylation of aldehydes in a diastereodivergent fashion by the synergistic reactivity of iridium and amine catalysts under acidic conditions.² Soon after, Carreira,³ Zhang,⁴ Hartwig,⁵ Dong,⁶ Wang,⁷ Zi,⁸ Lee,⁹ and other groups¹⁰ reported using an appropriate combination of dual chiral catalysts in a series of elegant studies (Scheme 1A). Recently, chemists found, in some cases, that tuning non-chiral parameters, including solvents or additives, also controlled the stereochemical outcomes through subtle perturbation of the key diastereomeric transition states.¹¹ In 2018, You and co-workers reported a solvent-controlled palladium-catalyzed enantioselective dearomative formal [3 + 2] cycloaddition, affording stereodivergent synthesis of two diastereomeric tetrahydrofuroindoles.¹² However, a rapid and predictable way to access complete stereoisomers of products bearing multiple stereocentres (for example, three contiguous stereocentres) remains an unsolved challenge through switching of ligands. To the best of our knowledge, only two successful examples were reported by Buchwald and Zhang, in which eight stereoisomers were obtained through tuning catalysts and reactive substrates (Scheme 1B).^4a,13Open in a separate windowScheme 1Strategy for stereodivergent synthesis of different stereoisomers.In metal-catalyzed reactions, ligands can manipulate the reactivity and selectivity by affecting the steric and electronic properties of metal catalysts. Therefore, the design and development of new ligands to improve the utility, activity and selectivity of their related metal catalysts are greatly desired by organic chemists. Recently, our groups have synthesized a new and promising class of P-chiral ligands ZD-Phos (including Ganphos and Jiaphos), and their conformational rigidity and chemical robustness have endowed the structure and its variants with outstanding activity and selectivity as well as excellent stereocontrol features essential to asymmetric cycloaddition reactions.¹⁴ Inspired by these advances, we are interested in continuing the development of P-chiral ligands with new structural motifs in the search for new reactivity and selectivity to tackle current synthetic challenges. More recently, Sadphos has emerged as another superior chiral skeleton, owing to the pioneering contributions by Zhang.¹⁵ Thus its aminophosphine scaffold is envisaged to be introduced into our 1-phosphanorbornene framework (ZD-Phos).¹⁶ We aim to combine the advantages of the aforementioned two types of chiral motifs, thus developing a novel P,P-bidentate ligand. Thus the novel P-chiral ligands, called Yuephos, may show unique stereoselectivity in a metal-catalyzed asymmetric cycloaddition reaction (Fig. 1).Open in a separate windowFig. 1Design of the Yuephos framework.Tetrahydroquinolines are important molecular skeletons that widely occur in natural molecules, pharmaceuticals, and functional materials. For this reason, realizing stereodivergent synthesis of all stereoisomers of fully substituted tetrahydroquinolines has been an important and challenging task in organic synthesis. However, to date, full control of absolute and relative stereochemical configuration of these molecules has remained an unmet synthetic challenge. Considering the potentiality of fully substituted chiral tetrahydroquinolines in drug discovery and stereodivergent synthesis,¹⁷ we envisioned that using our new palladium/ZD-Phos catalytic system may offer an efficient strategy for overcoming the challenges related to regio-, enantio-, and diastereo-selectivity. Herein, we report our studies on the unexplored stereodivergent synthesis of fully substituted tetrahydroquinolines through ligand-controlled, metal-catalyzed asymmetric annulation. Six possible stereoisomers bearing two tertiary and one quaternary stereocenters were easily synthesized in good yields with high enantio- and diastereo-selectivities from the same starting materials (Scheme 1C).The new bisphosphorus ligands we report herein can be easily synthesized by a two-pot method with good yields (Scheme 2). Starting from the corresponding aldehyde¹⁸ and commercially available chiral amine, one-pot sequential reaction gave diastereomers Y1 and Y1′ with 1 : 1 dr, which could be straightforwardly separated by column chromatography. The subsequent reduction using Raney Ni produced the final Yuephos in good yields. The absolute configuration of Yue-1′ was established by single crystal X-ray diffraction.¹⁹ Importantly, the ligands Yuephos can remain stable in air and moisture for more than one year.Open in a separate windowScheme 2Synthesis of Yuephos ligands.With new Yuephos ligands in hand, we began our study by choosing vinyl benzoxazinanone 1a with α-phenylidene succinimide 2a as the model substrate, combined with the Pd₂dba₃·CHCl₃/L complex as the catalyst. Details of [Pd] source and solvent screening can be found in the ESI (Table S1 and S2^†). Notably, using Pd₂dba₃·CHCl₃/Yuephos as the catalyst in ethyl acetate, the reaction proceeded smoothly, affording the desired product 3a in 69% yield with 96% ee and >20 : 1 dr (entry 1). It should be noted that Yuephos ligands were found to be efficient for this reaction, and the product 3a was obtained in good enantioselectivity with seemingly irregular yields and diastereoselectivities (entries 2–6). Trost''s ligand (L1) and chiral diphosphine ligand (L2) promoted the reaction with good diastereoselectivity but in a low yield and poor enantioselectivity (entries 7–8). However, (R)-SegPhos (L3) failed to afford the desired product (entry 9). To our surprise, when the phosphoramidite ligand (L4) was used, the diastereoselectivity was reversed compared to that in Yuephos (entry 10). Thus, a diastereodivergent phenomenon induced by the chiral ligand was discovered. To further improve the yield and selectivity, various solvents and [Pd] sources were screened (Table S3 and S4 in the ESI^†), and an obvious improvement in the enantioselectivity and diastereoselectivity was observed when using DCM as the solvent (entries 10 vs. 11). The reaction enantioselectivity was further increased to 92% with good yield (85%) when the reaction temperature was reduced to −20 °C (entries 12–14).With the optimal conditions established for (S, R, S)-3a (20Optimization of reaction conditions^a

Direct synthesis of pentasubstituted pyrroles and hexasubstituted pyrrolines from propargyl sulfonylamides and allenamides

Multisubstituted pyrroles are important fragments that appear in many bioactive small molecule scaffolds. Efficient synthesis of multisubstituted pyrroles with different substituents from easily accessible starting materials is challenging. Herein, we describe a metal-free method for the preparation of pentasubstituted pyrroles and hexasubstituted pyrrolines with different substituents and a free amino group by a base-promoted cascade addition–cyclization of propargylamides or allenamides with trimethylsilyl cyanide. This method would complement previous methods and support expansion of the toolbox for the synthesis of valuable, but previously inaccessible, highly substituted pyrroles and pyrrolines. Mechanistic studies to elucidate the reaction pathway have been conducted.

This method is a toolbox for the synthesis of valuable, but previously inaccessible, highly substituted pyrroles and pyrrolines.

Pyrroles are molecules of great interest in a variety of compounds including pharmaceuticals, natural products and other materials. Pyrrole fragments for example are key motifs in bioactive natural molecules, forming the subunit of heme, chlorophyll and bile pigments, and are also found in many clinical drugs, including those in Fig. 1a.¹ Although many classical methods of pyrrole synthesis, including the Paal–Knorr condensation,² the Knorr reaction,³ the Hantzsch reaction,⁴ transition metal-catalyzed reactions,⁵ and multicomponent coupling reactions,⁶ have been developed over many years, the efficient synthesis of multisubstituted pyrroles is still challenging. In condensation syntheses of pyrroles, the major problems lie in the extended syntheses of complex precursors and limited substitution patterns that are allowed. Multicomponent reactions are superior when building pyrrole core structures with more substituents. Among these, the [2+2+1] cycloaddition reaction of alkynes and primary amines is attractive because of the readily available alkyne and amine substrates and the ability to construct fully substituted pyrroles.⁷ However, with the exception of some rare examples,⁸ most [2+2+1] cycloaddition reactions afford pyrroles with two or more identical substituents. The synthesis of multisubstituted pyrroles with all different substituents from simple starting materials therefore remains a major challenge.Open in a separate windowFig. 1Previous reports and this work on propargylamides transformation.Easily accessible propargylamides are classical, privileged building blocks broadly utilized for the synthesis of a large variety of heterocyclic molecules such as pyrroles, pyridines, thiazoles, oxazoles and other relevant organic frameworks.⁹ For example, Looper¹⁰et al. reported the synthesis of 2-aminoimidazoles from propargyl cyanamides and Eycken¹¹ reported a method starting from propargyl guanidines which undergo a 5-exo-dig heterocyclization as shown in Fig. 1b. Subsequently, Wan¹²et al. revealed the cyclization of N-alkenyl propargyl sulfonamides into pyrroles via sulfonyl migration. Inspired by these transformations and multi-substituted pyrrole synthesis, we report herein a direct synthesis of pentasubstituted pyrroles and hexasubstituted pyrrolines with all different substituents from propargyl sulfonylamides and allenamides.Previously, Zhu,¹³ Ji¹⁴ and Qiu^13b,15 reported efficient syntheses of 2-aminopyrroles from isocyanides. Ye¹⁶ and Huang¹⁷ independently developed gold-catalyzed syntheses of 2-amino-pentasubstituted pyrroles with ynamides. Despite the many advantages of these methods, they all afford protected amines, rather than free amines. The deprotection of these amines may cause problems in further transformations of the products. Our method delivers pyrroles with an unprotected free amino group and are often complementary to the previously well-developed classical methods.Initially, the cyclization reaction of N-(1,3-diphenylprop-2-yn-1-yl)-N-ethylbenzenesulfonamide (1a) with trimethylsilyl cyanide (TMSCN) was carried out with Ni(PPh₃)₂Cl₂ as a catalyst, a base (Cs₂CO₃) and DMF as a solvent. Different metal catalysts, such as Ni(PPh₃)₂Cl₂, Pd(OAc)₂, Cu(OAc)₂, and Co(OAc)₂ provided the desired product with similar yields ( EntryCat.BaseSolventYield1Ni(PPh₃)₂Cl₂Cs₂CO₃DMF67%2Pd(OAc)₂Cs₂CO₃DMF65%3Cu(OAc)₂Cs₂CO₃DMF65%4Co(OAc)₂Cs₂CO₃DMF63%5Cs₂CO₃DMF65%6KFDMFTrace7K₃PO₄DMFTrace8K₂CO₃DMF48%9KOHDMF52%10KO^tBuDMF46%11Et₃NDMFTrace12Cs₂CO₃CH₃CN18%13Cs₂CO₃DME23%14Cs₂CO₃TolueneTrace15Cs₂CO₃DCETrace16Cs₂CO₃DioxaneTraceOpen in a separate window^aReaction conditions: 1a (0.1 mmol, 1 equiv.), TMSCN (0.3 mmol, 3 equiv.), cat. (0 or 10 mol%), base (0.3 mmol, 3 equiv.) and solvent (1 mL), at 80 °C for 10 h; isolated yield.With the optimal reaction conditions in hand, we investigated the scope of this reaction. As shown in Fig. 2, the transformation tolerates a broad variety of substituted propargylamides (1). The R¹ group could be an aryl group containing either electron-donating groups or electron-withdrawing groups, and the corresponding products (2b–2h) were obtained in yields of 62–80%. The substituent R¹ could also be an alkyl group such as 1-hexyl in which case the reaction provided the corresponding pyrrole (2i) in 53% yield. Exploration of the R² substituent was also conducted. Electron-rich and electron-deficient substituents in the aromatic ring of R² gave the desired products (2j–2o) with yields of 70–81%. The product bearing a furyl group (2p) can be produced in 61% yield. However, when R² group is an aliphatic group, the reaction failed to provide the desired product. Substituent groups R³, such as benzyl (2q) or 3,4-dimethoxyphenylethyl (2r) were also compatible in the reaction, providing the corresponding products in moderate yields. Significantly, this method has the potential to produce core structures (for example 2s) similar to that in Atorvastatin. Interestingly, when alkynyl substituted isoquinolines (1t–1v) were used as the substrates, the reactions smoothly afforded fused pyrrolo[2,1-α]isoquinoline derivatives (2t–2v), members of a class of compounds that are found widely in marine alkaloids and exhibit anticancer and antiviral activity.¹⁸Open in a separate windowFig. 2Substrate scope of propargylamides. Reaction conditions: 1 (0.20 mmol, 1 equiv.), TMSCN (0.60 mmol, 3 equiv.), Cs₂CO₃ (0.60 mmol, 3 equiv.) and DMF (2 mL), at 80 °C for 10 h; isolated yield.Allenes are key intermediates in the synthesis of many complex molecules.¹⁹ As a subtype of allenes, allenamines are also useful as reaction intermediates.²⁰ Although the transformation of allenamides to multisubstituted pyrroles has not been previously recorded, this reaction probably goes through the allenamide intermediates which can be derived from propargyl sulfonamides under basic conditions. To verify this hypothesis, the trisubstituted allenamide (3) was synthesized and subjected to the standard reaction conditions. A pyrrole (2a) was isolated in 82% yield from this reaction (Fig. 3). This result confirmed our assumption and raised a new question: is it possible to build hexasubstituted pyrrolines from tetrasubstituted allenamides? A range of tetrasubstituted allenamides²¹ was tested under the standard reaction conditions, and the hexasubstituted pyrrolines were obtained as is shown in Fig. 4. The R¹ group could be an aryl substituent or an alkyl chain, and the corresponding products (5a–5e) were obtained with good yields. Various aryl groups with either electron-donating groups or electron-withdrawing groups in the aromatic ring of R² provided the desired products (5f–5k) in 62–83% yields. In addition, the difluoromethyl group can also be replaced by a phenyl group, and the reaction provided the corresponding product 5l in 82% yield. It is worth noting that these pyrroline products are not easily accessible from other methods.Open in a separate windowFig. 3Synthesis of substituted pyrroles from allenes.Open in a separate windowFig. 4Substrate scope of tetrasubstituted allenamides. Reaction conditions: 4 (0.10 mmol, 1 equiv.), TMSCN (0.30 mmol, 3 equiv.), K₂CO₃ (0.30 mmol, 3 equiv.) and DMF (1 mL), at 80 °C for 10 h, isolated yield.Some synthetic applications of this method are shown in Fig. 5. The amide is a naturally occurring and ubiquitous functional group. When using benzoyl chloride to protect the free amino group of the fully-substituted pyrrole (2a), a bis-dibenzoyl amide (6) was obtained in the presence of a base, triethylamine while the monobenzoyl protected amide (7) was obtained in the presence of pyridine as the base (Fig. 5a). This method also provides a straightforward approach to pyrrole fused lactam structures (Fig. 5b). For examples, a five-membered lactam and a six-membered lactam were generated separately in a one pot reaction, directly from, (8 and 10), respectively. Taking advantage of this method, an analogue of the drug Atorvastatin was synthesized in 5 steps (Fig. 5c), demonstrating the synthetic value of the reaction.Open in a separate windowFig. 5Synthetic applications.Mechanistic experiments were performed (Fig. 6) to explore the mechanism of the reaction. When 3 equivalents of TEMPO were added, the reaction was not inhibited and the desired product (2a) was formed in 62% yield (Fig. 6a). This result suggested that the reaction might not involve a radical process. To probe the reaction further, a kinetic study was conducted (Fig. 6b). According to this study, the propargylamide (1a) was completely converted to an allenamide (3a) in 10 min under the standard conditions. The multi-substituted pyrrole (2a) was then gradually produced from the intermediate allenamide and no other reaction intermediates were observed or identified. On the other hand, DFT calculations of substrates 3b and 4a were carried out at the B3LYP-D3(SMD)/Def2-TZVP//B3LYP-D3/Def2-SVP level of theory to identify the natural bond orbital (NBO) charges on the carbons of the allene moieties. NBO charges on the internal carbon in both 3b and 4a are 0.11 and 0.18, respectively (Fig. 6c) indicating that the nucleophilic addition of cyanide anion onto the internal carbon should be reasonable as opposed to its addition onto the terminal carbon. Pathways of the cyano addition to 3b were also calculated (Fig. 6d). The transition state of cyano addition on the internal carbon (TS1), is indeed much lower than addition on the terminal carbon (TS2). The intermediate of internal carbon addition int1, is more stable than int2, implying that the internal carbon addition pathway is not only kinetically but also thermodynamically favoured.Open in a separate windowFig. 6Mechanistic studies and proposed mechanism.Based on the results of these mechanistic studies, a plausible reaction mechanism for the synthesis of pentasubstituted pyrroles and hexasubstituted pyrrolines is proposed and is shown in Fig. 6e. First, under basic conditions, the propargylamide isomerizes to an intermediate allenamide (A), which can be attacked nucleophilically by the cyanide anion to afford an intermediate imine (B) with release of the sulfonyl group. Then, the second cyanide anion attacks the imine to form an intermediate (C), which can undergo cyclization and protonation to afford the fully substituted pyrrole (2). Similarly, the hexasubstituted pyrroline product (5) can be obtained from double nucleophilic attack of the intermediate (A) by the cyanide ion.     

Correction: Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery

Correction for ‘Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery’ by Christine N. Morrison et al., Chem. Sci., 2020, 11, 1216–1225, https://doi.org/10.1039/C9SC05586J.

The authors regret that in the original article, inhibitory values reported for some metallofragments were incorrect. Unfortunately, DMSO stock solutions of reportedly active ferrocene-based metallofragments were found to decompose in the presence of light, which resulted in inaccurate inhibition values. The authors maintain that the core conclusions of the paper are accurate and the utility of three-dimensional metal complexes for fragment-based drug discovery has merit.In the original article, ‘class A’ metallofragments are comprised of ferrocene derivatives (Fig. 1). Some of these ferrocene fragments (specifically those containing carbonyl groups) are reported as broadly inhibiting several protein targets. It was noted in our original report that the ferrocene scaffold was likely promiscuous due to its lipophilicity and potential redox activity, but that it might still serve as a useful metallofragment for fragment-based drug discovery (FBDD) campaigns. However, re-evaluation of these compounds against the influenza endonuclease (PA_N) failed to reproduce our original inhibition results for the class A metallofragments using freshly prepared stocks, indicating a problem with the materials used in the original study.Open in a separate windowFig. 1Chemical structures of class A metallofragments.Several compounds from class A were originally reported as having near complete (100%) inhibition against PA_N endonuclease at an inhibitor concentration of 200 μM (​and2).2). However, when re-evaluated under identical conditions, using freshly prepared DMSO stock solutions, inhibition was only observed with one fragment of this class (A22, Fig. 1), with the previously reported highly active fragments (A4, A7–A21, CompoundA1A2A3A4A5A7A8A9A10A11Reported12 ± 6<1<145 ± 148 ± 7103 ± 5103 ± 453 ± 546 ± 790 ± 5Corrected3 ± 10n.d.18 ± 36 ± 321 ± 59 ± 310 ± 54 ± 216 ± 410 ± 7Open in a separate window^an.d. = not determined.

Redox-neutral manganese-catalyzed synthesis of 1-pyrrolines

This report describes a manganese-catalyzed radical [3 + 2] cyclization of cyclopropanols and oxime ethers, leading to valuable multi-functional 1-pyrrolines. In this redox-neutral process, the oxime ethers function as internal oxidants and H-donors. The reaction involves sequential rupture of C–C, C–H and N–O bonds and proceeds under mild conditions. This intermolecular protocol provides an efficient approach for the synthesis of structurally diverse 1-pyrrolines.

Described herein is a novel manganese-catalyzed radical [3 + 2] cyclization of cyclopropanols and oxime ethers, leading to valuable multi-functionalized 1-pyrrolines.

Pyrroline and its derivatives appear frequently as the core of the structure of natural products and biologically active molecules (Fig. 1A).¹ Such compounds also serve as versatile feedstocks in various transformations, such as 1,3-dipolar cyclization, ring opening, reduction and oxidation, leading to diverse and valuable compounds.^2–4 Over the past few decades, great effort has been devoted to the preparation of pyrrolines. This has resulted in several elegant approaches that rely on photoredox catalysis (Fig. 1B).⁵ The groups of Studer,^5a,b Leonori,^5c and Loh^5d–f disclosed intramolecular addition of the intermediate iminyl radical to alkenes to construct pyrrolines. Generally, the synthetic value of a method can be further improved by using an intermolecular reaction pattern. For example, Alemán et al. recently reported a radical-polar cascade reaction involving the addition to ketimines of alkyl radicals formed in hydrogen atom transfer (HAT) reactions.^5g That the existence of benzylic C–H bonds in the substrates is requisite for the HAT, compromises the substrate scope. Despite the appealing photochemical processes, development of new redox approaches to enrich the product diversity of pyrrolines, especially with inexpensive transition-metal catalysts, is still in demand.Open in a separate windowFig. 1(A) Importance of pyrrolines, and (B and C) synthetic approaches to pyrrolines.Prompted by extensive applications of cyclopropanols in synthesis⁶ and our achievements in manganese-catalyzed ring-opening reactions,⁷ we conceived a radical [3 + 2] cyclization using cyclopropanol as a C3 synthon and oxime ethers as a nitrogen source (Fig. 1C). Hypothetically, single-electron oxidation of cyclopropanol by Mnⁿ generates the β-keto radical (I), which undergoes a radical [3 + 2] cascade reaction with an oxime ether to give the alkoxy radical species (II). Conversion of II to the intermediate (III), the pyrroline precursor, requires an extra H-donor to support a HAT process and an oxidant for recovery of Mnⁿ to perpetuate the catalytic cycle. In this scenario, the strategic inclusion of oxime ether is crucial to the overall transformation. The oxime ether is not only an internal oxidant and H-donor, but should also be subject to in situ deprotection by cleaving the N–O bond during the reaction. The choice of a proper Mnⁿ/Mnⁿ⁻¹ pair with suitable redox potentials is also vital to the catalytic cycle.Herein, we provide proof-of-principle studies for this hypothesis. The desired radical [3 + 2] cyclization of cyclopropanols and O-benzyl oxime ethers is accomplished with manganese catalysis. This redox-neutral process involves sequential rupture of C–C, C–H, and N–O bonds under mild conditions. The intermolecular protocol provides an ingenious approach to the synthesis of multi-functionalized 1-pyrrolines.With these considerations in mind, phenylcyclopropanol (1a) and oxime ether (2a) were initially chosen as model substrates to evaluate reaction parameters in the presence of manganese salt ( N bond of 2a (entry 2). The optimization of organic solvents was then conducted (entries 3–8), and it was found that the use of fluorinated alcohols, such as trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP) as solvents provided excellent yields (entries 7 and 8). Decreasing the amount of Mn(acac)₃ to 1.2 equiv. gave a comparable yield (entry 9), but further reducing the amount compromised the yield (entry 10). Replacing Mn(acac)₃ with Mn(OAc)₃ or MnCl₂ significantly decreased the reaction yield (entries 11 and 12). However, the use of Mn(acac)₂ gave a similar yield to Mn(acac)₃ (entries 13 vs. 9). The above results prompted us to think over the counteranion effect that the acetylacetone (acac) anion may be requisite to the reaction. Indeed, the synergistic use of stoichiometric MnCl₂ and acetylacetone led to a good yield of the desired product (entry 14). More importantly, a comparable yield was obtained with only 0.2 equiv. of MnCl₂ and added acetylacetone, realizing this reaction under a catalytic amount of Mn salts (entry 15). Given that the low solubility of the Mn salt may lead to poor efficiency, a reaction with 0.067 M concentration was carried out and gave a 89% yield (entry 16). Further reducing the amount of acetylacetone to 1.0 equiv. had no influence on the outcome of the reaction (entry 17), but the reaction efficiency slightly decreased when 0.6 equiv. of acetylacetone was used as the additive (entry 18). Use of a decreased amount (1.0 equiv.) of acetic acid led to the best yield (91%, entry 19), whereas the reaction in the presence of 0.5 equiv. acetic acid (entry 20) or without acetic acid (entry 21) also gave high yields. It is noted that acetic acid is not crucial to the reaction using MnCl₂ as catalyst, as the reaction could generate cat. HCl in situ. The reaction with substoichiometric amount (0.6 equiv.) of acac gave a decreased but also good yield (entry 22). Reducing the catalytic loading of MnCl₂ to 10 mol% slightly compromised the yield (entry 23).Optimization of the synthesis of 1-pyrrolines

Entrya	Mn salt (equiv.)	Additive (equiv.)	Solvent	Yield (%)
1	Mn(acac)3 (1.7)	None	CH3CN	33
2b	Mn(acac)3 (1.7)	None	CH3CN	Trace
3	Mn(acac)3 (1.7)	None	DCM	31
4	Mn(acac)3 (1.7)	None	Acetone	25
5	Mn(acac)3 (1.7)	None	DMSO	Trace
6	Mn(acac)3 (1.7)	None	DMF	Trace
7	Mn(acac)3 (1.7)	None	TFE	80
8	Mn(acac)3 (1.7)	None	HFIP	82
9	Mn(acac)3 (1.2)	None	HFIP	83
10	Mn(acac)3 (0.9)	None	HFIP	55
11	Mn(OAc)3·2H2O (1.2)	None	HFIP	36
12	MnCl2 (1.2)	None	HFIP	Trace
13	Mn(acac)2 (1.2)	None	HFIP	88
14	MnCl2 (1.2)	acac (3.6)	HFIP	80
15	MnCl2 (0.2)	acac (3.6)	HFIP	81
16c	MnCl2 (0.2)	acac (3.6)	HFIP	89
17c	MnCl2 (0.2)	acac (1.0)	HFIP	89
18c	MnCl2 (0.2)	acac (0.6)	HFIP	83
19c,d	MnCl2 (0.2)	acac (1.0)	HFIP	91
20c,e	MnCl2 (0.2)	acac (1.0)	HFIP	83
21c,b	MnCl2 (0.2)	acac (1.0)	HFIP	80
22c,d	MnCl2 (0.2)	acac (0.6)	HFIP	82
23c,d	MnCl2 (0.1)	acac (1.0)	HFIP	81

Open in a separate window^aReaction conditions: 1a (0.45 mmol), 2a (0.3 mmol), AcOH (2.0 equiv.), and Mn salt (as shown) in solvent (2.0 mL), at room temperature (rt) under N₂, for 16 h.^bWithout AcOH.^c0.067 M reaction.^d1.0 equiv. AcOH.^e0.5 equiv. AcOH. acac = acetylacetone.With the optimized conditions in hand for the synthesis of 1-pyrrolines, the compatibility of various cyclopropanols was inspected (Scheme 1). Common functional groups on the phenyl ring, including halides (3b–3d), ester (3f), ether (3j), were compatible under the reaction conditions. Regardless of the presence of electron-withdrawing or -donating substituents at the para-position of this phenyl ring, the reactions readily proceeded with generally high yields (3b–3j). The cyclopropanol (1k) with an ortho-methyl substituent underwent a cyclization reaction with excellent yield, demonstrating that steric effects had little effect on product of the reaction (3k). By replacing the phenyl group with a naphthyl or thienyl group, the corresponding products (3l and 3m) were produced with slightly lower yields. When 2-substituted cyclopropanols were utilized, these reactions gave rise to a portfolio of trisubstituted 1-pyrrolines (3n–3u).The relative configuration of 3u was determined by comparison with a reported structure.⁸ Remarkably, this protocol provided a convenient method for the construction of an N-containing spiro skeleton (3t). The reaction with alkyl cyclopropanols could also furnish the desired products (3v–3x) smoothly and with good yields.Open in a separate windowScheme 1Scope of cyclopropanols. Reaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), AcOH (0.2 mmol), MnCl₂ (0.04 mmol), and acac (0.2 mmol) in HFIP (3.0 mL), at rt under N₂. The d.r. values were determined by ¹H NMR analysis with crude reaction mixture, and major isomers are shown with relative configurations. ^aThe reaction is scaled up for 10 times.Next, we studied the scope of oxime ethers (Scheme 2). Steric hindrance from the ester moiety in the oxime ethers appeared not to influence the reaction outcome. Oxime ethers bearing various esters, such as phenyl (3y), biphenyl (3z and 3ab), 2-naphthyl (3aa), 2,4-di-tert-butylphenyl (3ac and 3ad), and 2,6-dimethylphenyl (3ae) esters all reacted smoothly. In addition, the substrate with tert-butyl ester also readily underwent cyclization to afford the desired product 3af with excellent yield. Remarkably, the trifluoromethyl-substituted pyrroline (3ag) was afforded almost quantitatively from the corresponding ketoxime ether. However, if the trifluoromethyl group was replaced by a methyl or phenyl group, the reaction failed to give rise to the desired product (3ah or 3ai), and this might be attributed to poorer electrophilic nature of the methyl or phenyl substituted substrate.Open in a separate windowScheme 2Scope of oxime ethers. Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), AcOH (0.2 mmol), MnCl₂ (0.04 mmol), and acac (0.2 mmol) in HFIP (3.0 mL), at rt under N₂. The d.r. values were determined by ¹H NMR analysis with crude reaction mixture, and major isomers are shown with relative configurations.To illustrate the utility of this protocol, we carried out a set of synthetic applications using 1-pyrroline (3a) (Scheme 3). Upon treatment with acetyl chloride and pyridine at 42 °C, 1-pyrroline (3a) could be readily converted into the acyclic amino acid derivative (4). The reaction between 3a and LiAlH₄ gave rise smoothly to the corresponding alcohol (5). In the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquin-4-one (DDQ) and triethylamine, the 2,5-disubstituted pyrrole (6) was obtained. Moreover, treatment of 3a with MeOTf and NaBH₄ delivered the N-methyl proline derivative (7).⁹Open in a separate windowScheme 3Synthetic applications. Reaction conditions: (a) AcCl, pyridine, dry DCE, 42 °C, 63% yield; (b) LiAlH₄, THF, reflux, 90% yield; (c) DDQ, Et₃N, DCM, rt, 53% yield; (d) MeOTf, DCM, and then NaBH₄, THF, 40% yield, cis : trans = 6.6 : 1.To probe the mechanistic pathways, we performed a radical trapping experiment in the presence of 2.0 equiv. of radical scavenger TEMPO. The radical trapping product (8) was detected by high-resolution mass spectrometry (HRMS) (Scheme 4A, top). In addition, the reaction was obviously suppressed when 1,1-diphenylethylene was added under standard condition (Scheme 4A, bottom). These results suggested that this process engaged in a radical pathway. Kinetic studies illustrated that the reaction immediately started with 20 mol% Mn(acac)₂ but an approximate 15 min of induction period was appeared by using Mn(acac)₃, which probably indicated that the reaction was initiated with Mn(ii) rather than Mn(iii), and the Mn(ii)/Mn(i) cycle might be involved in the transformation (Scheme 4B, for details see ESI^†).Open in a separate windowScheme 4(A and B) Mechanistic studies, and (C) proposed mechanism.On the basis of these results, a plausible mechanism for this radical process was proposed in Scheme 4C. Initially, the interaction between cyclopropanol (1a) and Mn(ii) salt gives rise to the alkoxy manganese species (I), which undergoes a ligand-to-metal charge transfer (LMCT) process, leading to the alkoxy radical (II).^5f Subsequent ring-opening of the alkoxyl radical (II) provides the alkyl radical (III). The addition of intermediate (III) to the oxime ether, possibly activated by HFIP or HOAc, furnishes the N-centered radical (IV), which intramolecularly attacks the ketone to afford a new alkoxy radical (V).¹⁰ The subsequent 1,5-hydrogen atom transfer (HAT) process delivers the alkyl radical (VI) at the α-position adjacent to the O atom, thus driving N–O bond cleavage to generate the N-centered radical (VII),^5b,11 and benzaldehyde which was detected by TLC. This radical intermediate (VII) undergoes a single electron transfer (SET) mediated by the reduced-state Mn(i) species, and protonation to yield the cyclic pyrrolidine (VIII). Finally, dehydration of this intermediate produces 1-pyrroline (3a).     

Radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters enabled by a carbon shift from an all-carbon quaternary center

Herein, we report an intermolecular, radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters to achieve the goal of building molecular complexity via the one-pot multifunctionalization of alkenes. This reaction allows the expansion of the carbon ring by a carbon shift from an all-carbon quaternary center, and enables further C–C bond formation on the tertiary carbon intermediate with the aim of reconstructing a new all-carbon quaternary center. The good functional group compatibility ensures diverse synthetic transformations of this method. Experimental and theoretical studies reveal that the excellent diastereoselectivity should be attributed to the hydrogen bonding between the substrates and solvent.

Herein, we report an intermolecular, radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters to achieve the goal of building molecular complexity via the one-pot multifunctionalization of alkenes.

A leading motive for the impressive achievements in the area of assembling molecular complexity is the transformation of simple feedstock chemicals into complex molecular skeletons with superior bioactive properties. In this respect, the direct functionalization of alkenes has been demonstrated as one of the most effective and simple strategies to meet this criterion at a high level. While the difunctionalization of alkenes in a one-pot process is the major theme of considerable interest in this field,¹ the multifunctionalization of alkenes,² for example, a 1,2,3-trifunctionalization of alkenes, has the power to simultaneously incorporate multifunctional groups. Therefore, this multifunctionalization reaction model can be regarded as an efficient and novel strategy to afford molecules with high structural diversity and complexity. However, such methods are elusive.During the last decades, radical alkene functionalizations have been revealed to be a powerful tool for building complex molecular frameworks by employing a radical initiator, a transition metal catalyst, or a photocatalyst.^1f–i However, only several successful methods for the radical multifunctionalization of alkenes have been achieved. For example, the Studer group reported an elegant 1,2-boryl shift-enabled radical 1,2,3-trifunctionalization of allylboronic esters using AIBN as the radical initiator (Fig. 1a).³ Shi et al. disclosed an excellent photocatalytic perfluoroalkylation of a vinyl-substituted all-carbon quaternary center through 1,2-aryl migration (Fig. 1b).⁴ Herein, we report a new one-pot protocol to realize an intermolecular, radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters through a cascade process of deconstruction–reconstruction of the all-carbon quaternary center (Fig. 1c).⁵Open in a separate windowFig. 1Radical 1,2,3-trifunctionalization of alkenes. (a) Studer''s work; (b) Shi''s work; (c) This work.The direct incorporation of a fluorine atom or fluorinated moieties into organic compounds has been extensively investigated and proved to be an significant synthetic strategy in the field of discovering new pharmaceuticals.⁶ Recently, we are interested in the radical functionalization of alkenes with fluoroalkyl groups,⁷ and we envisioned that, different from the typical Dowd–Beckwith⁸ ring expansion reaction,⁹ the addition of a fluoroalkyl radical to the C C double bond would generate an adduct radical species I, which will transform into the radical intermediate II upon ring expansion (Fig. 1c). Finally, the cascade C–C coupling affords the product with a reconstructed all-carbon quaternary center. However, there are several challenging issues that need to be addressed: (1) the carbon shift from an all-carbon quaternary center to afford a tertiary carbon center which is bulkier than the tertiary carbon center formed in a typical Dowd–Beckwith ring expansion reaction; (2) the reconstruction of all-carbon quaternary center from tertiary carbon radical II will meet the associated conformational restriction and steric congestion; (3) side reactions, such as 1,2-radical addition to the alkenyl group, homolytic couplings of the carbon radical intermediates I and II, and direct H-atom abstraction;¹⁰ (4) how to control the diastereomeric ratio of the products. To meet these challenges, we developed a novel method for the 1,2,3-trifunctionalization of alkenes using alkynyl triflones as both the CF₃ (ref. 6) and alkynyl sources, providing the ring-expanded cyclic β-ketoesters with excellent diastereoselectivity and functional group diversity. In addition, good functional group compatibility of this method was observed, which ensures the diverse synthetic transformations. Moreover, hydrogen bonding between the substrates and 2,2,2-trifluoroethanol solvent was revealed to be the key factor for the excellent diastereoselectivity obtained in this reaction, and this result was confirmed by both experimental and theoretical studies.This study began by surveying radical initiators for 1,2,3-tricarbofunctionalizing α-vinyl-β-ketoester 1a with alkynyl triflone 2a¹¹ (12 (13 dramatically increased the diastereoselectivity and (±)-3a could be obtained in an identical yield with an even higher dr value (dr > 20 : 1) (14 Without the addition of a radical initiator, a reaction did not happen ( EntrySolventYield^b (%)1EA60 (dr = 13 : 1)^c2EA55 (dr = 11 : 1)^d3EA63 (dr = 12 : 1)4MTBE45 (dr = 10 : 1)5DCE63 (dr = 15 : 1)6TolueneTrace7DMFTrace8MeOHTrace9TFE63 (dr > 20 : 1)10^eTFE60 (dr > 20 : 1)11^fTFE56 (dr > 20 : 1)12^gTFE70 (dr > 20 : 1)13^hTFE76 (65)ⁱ (dr > 20 : 1)14^jTFE71 (dr > 20 : 1)15TFETraceOpen in a separate window^aReaction conditions: alkene 1a (0.2 mmol, 1 equiv.), 2a (0.6 mmol, 3.0 equiv.), and AIBN (0.3 equiv.) in 3 mL of solvent at 85 °C for 18 h in a sealed tube under a nitrogen atmosphere.^bCrude yield and crude diastereomeric ratio were determined by ¹⁹F NMR.^cLPO was used as the initiator.^dBPO was used as the initiator.^eThe reaction was performed at 100 °C.^fThe reaction was performed at 120 °C.^gAIBN (60 mol%) was used.^h2a (3.0 equiv.) and AIBN (60 mol%) were added as two equal portions with an interval of 9 h.ⁱIsolated yield in parentheses.^j2a (3.0 equiv.) and AIBN (60 mol%) were added as three equal portions with an interval of 6 h.Under optimal conditions, a diverse array of α-vinyl-β-ketoesters serve as substrates in this metal-free deconstruction–construction of all-carbon quaternary centers for the synthesis of carbon-ring expanded cyclic β-ketoesters (Fig. 2). In most of the cases, excellent diastereoselectivities (dr > 20 : 1) were observed by crude ¹⁹F NMR analysis. Substrates with the substituents at the 5- or 6-position of the α-vinyl-β-ketoesters generally produced the corresponding product (±)-3 in higher yields than those with the substituents at the 4-position. Apart from the carbonyl group and the ester group, functional groups such as chloride ((±)-3b and (±)-3f), fluoride ((±)-3c), a methoxyl group ((±)-3d and (±)-3h), a methyl group ((±)-3e and (±)-3g) and a phenyl group ((±)-3i) can be tolerated under the reaction conditions. Notably, the phenyl ring of the core structure with two substituents reacted smoothly to afford the corresponding products ((±)-3j and (±)-3k). When substrate 1l that lacks the fused benzene ring was used for this carbon-ring expansion reaction, a dramatical loss of diastereoselectivity was detected, presumably because of the feasible interconversion of the boat and chair conformations of the intermediate. Substrates with an ethyl ester or a benzyl ester group, as opposed to a methyl ester group, delivered the corresponding products ((±)-3m and (±)-3n) with moderate yields and excellent diastereoselectivity. When the CH₂ unit of the six membered-ring was replaced by a CMe₂ group, only a trace amount of the desired product (±)-3o was detected. A reaction with the purpose of realizing an extension from the six-membered ring was also carried out and (±)-3p was obtained, although with a low yield and low diastereoselectivity. Notably, the diastereochemistries of products (±)-3e and (±)-3h have been confirmed by X-ray crystallography.Open in a separate windowFig. 2Substrate scope of α-vinyl-β-ketoesters. ^aThe reaction was performed with 1p and 2b.The scope with respect to the alkynyl triflones was also investigated and the results are summarized in Fig. 3. Generally, substituents on the phenyl ring of the arylethynyl moiety have little impact on the yields of the corresponding products. The functional groups at the para-, meta-, or ortho-position of the phenyl ring produced the desired products ((±)-4a–(±)-4k) with excellent diastereoselectivities. Furthermore, the method is compatible with alkynyl triflones that have a thienyl group or a perfluorobutyl group and the reactions afforded the product ((±)-4l or (±)-4m) with an excellent dr value, respectively. However, when the arylethynyl moiety was replaced by an alkylethynyl or a silylethynyl part, the reaction failed to produce the targeted tricarbofunctionalization product ((±)-4n or (±)-4o).¹⁵ Moreover, when triflic azide or (Z)-TolCH CHSO₂CF₃ was used in place of the alkynyl triflone, the desired product was not obtained and most of the starting material was recovered. Notably, the diastereochemistry of product (±)-4a has been confirmed by X-ray crystallography.Open in a separate windowFig. 3Substrate scope of alkynyl triflones.This 1,2,3-trifunctionalization reaction not only allows the deconstruction and reconstruction of all-carbon quaternary centers, but features good functional group tolerance and excellent diastereoselectivity. Regarding the diverse reactivities of these functional groups, many valuable synthetic transformations have been successfully achieved (Fig. 4). For example, the C–C triple bond of (±)-4a can be completely reduced to a CH₂CH₂ unit ((±)-5) in the presence of hydrogen and a Pd/C catalyst,¹⁶ while the selective reduction of (±)-4a gives rise to a Z-alkene (±)-6 when quinoline is added as an additive for the Lindlar reduction.¹⁷ The diastereochemistry of (±)-6 has been confirmed by X-ray crystallography. The selective reducing methods afford formal approaches for radical 1,3-trifluoromethylalkylation and 1,3-trifluoromethylalkenylation of α-vinyl-β-ketoesters, respectively, to produce the corresponding products which are otherwise difficult to obtain. In addition, the C–C triple bond can be oxidized under oxidative conditions with RuCl₃/NaIO₄, and (±)-4a can be smoothly transformed into the trifluoromethylated triketone (±)-7 in 65% yield.¹⁸ With a large excess amount of reducing agent LiAlH₄, the carbonyl group and the ester group, together with the C–C triple bond, can be unexpectedly reduced simultaneously, affording the alkenyl diol (±)-8 in excellent regioselectivity. The hydrolysis process under basic conditions provided a reliable method for access to a free carboxylic acid (±)-9. Interestingly, when the reaction was performed under milder conditions compared to those for the synthesis of (±)-8, (±)-4a was successfully converted into an alkynyl diol (±)-10, which can be cyclized into a spiro compound (±)-11 (ref. 19) and an endocyclic compound (±)-12,²⁰ respectively. Notably, in the majority of these cases, the excellent diastereoselectivity was reserved. These synthetic applications can demonstrate the significant value of this method.Open in a separate windowFig. 4Synthetic transformations.In order to gain some mechanistic insights into this radical cascade reaction, subsequent efforts have been made (Fig. 5). First, the detection of trifluoromethylated toluene (with toluene as the solvent, Fig. 5a, see ESI^† for details). Second, we were curious about the excellent diastereoselectivity associated with the use of TFE as the solvent. As can be seen in Fig. 5b, ¹H NMR titration of 1a with increasing amounts of TFE showed a chemical shift of the resonance signal corresponding to protons. The 2D NOESY spectrum indicates the existence of an interaction between 1a and TFE (Fig. 5c). Moreover, Job plot studies by both ¹H NMR and ¹⁹F NMR imply a 1 : 1.5 stoichiometry of the complex adduct resulting from 1a and TFE (Fig. 5d). These mechanistic studies strongly suggest that the excellent diastereoselectivity of this reaction might be attributed to the hydrogen bonding between TFE and the α-vinyl-β-ketoester.Open in a separate windowFig. 5Mechanism studies. (a) Radical probe; (b) ¹H NMR titration; (c) 2D NOESY; (d) Job plot studies.On the other hand, density functional theory (DFT) calculations have also been performed at the B3LYP-D3(SMD)/Def2-TZVP//B3LYP-D3(SMD)/Def2-SVP level of theory in the TFE solvent model to further investigate the reaction pathways (Fig. 6). On the basis of the experimental results, herein, the radical pathway was considered. Initially, the CF₃ radical addition onto 1a was calculated, and a transition state, TS1, was located with a free energy barrier of 10.9 kcal mol⁻¹ to deliver the radical intermediate int1 with an exergonicity of 20.5 kcal mol⁻¹. Then, a bicyclic transition state, TS2,²¹ with a barrier of 11.0 kcal mol⁻¹ through a concerted 1,2-shift route was found to be the lower barrier TS for int2 formation than that of the addition to 2b for the byproduct (see Fig. S5 in ESI^†), which is consistent with the experimental results of the mainly hexacyclic products. Moreover, the intrinsic reaction coordinate (IRC) calculations and the root mean square (RMS) gradient of the potential energy surface from TS2 suggested that no transition state for the formation of the previously proposed strained alkoxyl radical was found. Next, the radical intermediate int2 attacking 2b was calculated. To understand the diastereoselectivity of this step, the transition states of the addition of 2b onto the Re and Si faces of C3 in int2 were located with barriers of 12.5 and 17.4 kcal mol⁻¹ (TS3 and TS3′), respectively. It is noteworthy that the torsion angle of C1–C2–C3–C4 in TS3′ is −62.3°, larger than that of −40.9° in int2 and −49.0° in TS3, indicating that the distortion factor in TS3′ is large due to the steric effect from the trifluoroethyl group in int2 and, therefore, increases the barrier. The transition states of 2b addition were also optimized in solvents DCE and EA, and the free energy barrier differences between TS3 and TS3′ [ΔG^‡ = G^‡(TS3′) − G^‡(TS3)] are 3.6 and 3.0 kcal mol⁻¹, respectively, in agreement with the experimental observations. Finally, dissociation of a SO₂ molecule with a CF₃ radical from int3 to deliver the product was conducted, and a transition state TS4 with a much lower barrier of only 7.1 kcal mol⁻¹ was located, which led to the major product (±)-4a with a relative free enthalpy of −51.6 kcal mol⁻¹.Open in a separate windowFig. 6Gibbs free energy profile for the synthesis of 4a in the TFE solvent model.     

Organocatalytic asymmetric formal oxidative coupling for the construction of all-aryl quaternary stereocenters

A new catalytic asymmetric formal cross dehydrogenative coupling process for the construction of all-aryl quaternary stereocenters is disclosed, which provides access to rarely explored chiral tetraarylmethanes with excellent enantioselectivity. The suitable oxidation conditions and the hydrogen-bond-based organocatalysis have enabled efficient intermolecular C–C bond formation in an overwhelmingly crowded environment under mild conditions. para-Quinone methides bearing an ortho-directing group serve as the key intermediate. The precise loading of DDQ is critical to the high enantioselectivity. The chiral products have also been demonstrated as promising antiviral agents.

A one-pot oxidation of racemic triarylmethanes to form para-quinone methides followed by enantioselective construction of all-aryl quaternary stereocenters has been developed.

Cross dehydrogenative coupling (CDC) is a powerful tool to forge intermolecular C–C bonds from two C–H bonds without prefunctionalization.¹ Specifically, the benzylic C–H bond is relatively prone to oxidation and thus it has evolved into a versatile arena for the implementation of this reaction, leading to efficient construction of various benzylic stereogenic centers. As a result, CDC has proved to be useful for the establishment of a wide range of 1,1-diaryl stereocenters (Scheme 1a).² Recently, Liu and coworkers reported a elegant synthesis of enantioenriched triarylacetonitriles via in situ oxidation of α-diarylacetonitriles to para-quinone methides (p-QMs) followed by asymmetric nucleophilic addition with stereocontrol induced by a chiral phosphoric acid catalyst. This represents a rare example of formal CDC for the synthesis of 1,1,1-triarylalkanes (Scheme 1b).³ However, the establishment of tetraaryl-substituted carbon stereocenters by this approach remains unknown (Scheme 1c).Open in a separate windowScheme 1Catalytic asymmetric synthesis of chiral tetraarylmethanes.Distinct from the asymmetric synthesis of triaryl-substituted stereocenters,⁴ substantial steric hindrance in establishing tetraaryl-substituted quaternary stereocenters poses significant synthetic challenges.^5–8 Indeed, even racemic or achiral syntheses of tetraarylmethanes have been an elusive topic of investigation in organic synthesis.⁶ In this context and in continuation of our effort in the studies of asymmetric reactions of para-quinone methides (p-QMs)^9,10 as well as the synthesis of chiral tetraarylmethanes,⁸ we envisioned that suitable oxidation of racemic triarylmethane 1 is expected to generate triarylmethyl cation IM1 (Scheme 1c). With one aryl group as para-hydroxyphenyl, this cation could be stabilized in the form of p-QM IM2. Subsequent asymmetric nucleophilic addition by another electron-rich arene to the p-QM intermediate is expected to generate chiral tetraarylmethanes 2. The challenges associated with this one-pot process mainly include the compatibility problem between the oxidative condition and the catalytic asymmetric system in order to achieve both high efficiency and enantioselectivity.We commenced our study with racemic triarylmethane 1a as the model substrate. The initial study was directed to the search for a suitable oxidant to mildly generate the p-QM intermediate (11 At room temperature, the use of superstoichiometric amounts of Ag₂O or benzoquinone was completely ineffective (entries 1 and 2). Similarly, the reaction did not proceed using oxygen as the oxidant in combination with catalyst Mn(acac)₃ (entry 3). Subsequently, considerable efforts were devoted to screening many other oxidation systems, almost all of which were completely incapable for this oxidation (entries 4–8). However, eventually we were delighted to identify DDQ as the superior oxidant, leading to complete and clean conversion to the desired QM at room temperature (entry 9). In contrast, a combination of catalytic DDQ with 5 equivalents of MnO₂ gave only 60% conversion (entry 10).Evaluation of oxidants

Hydroxy-directed fluorination of remote unactivated C(sp3)–H bonds: a new age of diastereoselective radical fluorination

We report a photochemically induced, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity in this burgeoning field. Numerous simple and complex motifs showcase a spectrum of regio- and stereochemical outcomes based on the configuration of the hydroxy group. Notable examples include a long-sought switch in the selectivity of the refractory sclareolide core, an override of benzylic fluorination, and a rare case of 3,3′-difluorination. Furthermore, calculations illuminate a low barrier transition state for fluorination, supporting our notion that alcohols are engaged in coordinated reagent direction. A hydrogen bonding interaction between the innate hydroxy directing group and fluorine is also highlighted for several substrates with ¹⁹F–¹H HOESY experiments, calculations, and more.

We report a photochemical, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity. Numerous motifs showcase a range of regio- and stereochemical outcomes based on the configuration of the hydroxy group.

The hydroxy (OH) group is treasured and versatile in chemistry and biology.¹ Its ubiquity in nature and broad spectrum of chemical properties make it an attractive source as a potential directing group.² The exploitation of the mild Lewis basicity exhibited by alcohols has afforded several elegant pathways for selective functionalization (e.g., Sharpless epoxidation,³ homogeneous hydrogenation,⁴ cross-coupling reactions,⁵ among others⁶). Recently, we reported a photochemically promoted carbonyl-directed aliphatic fluorination, and most notably, established the key role that C–H⋯O hydrogen bonds play in the success of the reaction.⁷ Our detailed mechanistic investigations prompt us to postulate that other Lewis basic functional groups (such as –OH) can direct fluorination in highly complementary ways.⁸ In this communication, we report a hydroxy-directed aliphatic fluorination method that exhibits unique directing properties and greatly expands the domain of radical fluorination into the less established realm governing high diastereoselectivity.⁹Our first inclination that functional groups other than carbonyls may influence fluorination regiochemical outcomes was obtained while screening substrates for our published ketone-directed radical-based method (Scheme 1).^8a In this example, we surmised that oxidation of the tertiary hydroxy group on substrate 1 cannot occur and would demonstrate functional group tolerance (directing to C11, compound 2). Surprisingly, the two major regioisomers (products 3 and 4) are derivatized by Selectfluor (SF) on C12 and C16 – indicative of the freely rotating hydroxyl directing fluorination. Without an obvious explanation of how these groups could be involved in dictating regiochemistry, we continued the mechanistic study of carbonyl-directed fluorination (Scheme 2A). We established that the regioselective coordinated hydrogen atom abstraction occurs by hydrogen bonding between a strategically placed carbonyl and Selectfluor radical dication (SRD).⁷ However, we noted that the subsequent radical fluorination is not diastereoselective due to the locally planar nature of carbonyl groups. Thus, we posed the question: are there other directing groups that can provide both regio- and diastereoselectivity? Such a group would optimally be attached to a sp³ hybridized carbon; thus the “three dimensional” hydroxy carbon logically comes to mind as an attractive choice, and Scheme 1 illustrates the first positive hint.Open in a separate windowScheme 1Observed products for the fluorination of compound 1.Open in a separate windowScheme 2(A) Proposed mechanism, (B) β-caryophyllene alcohol hypochlorite derivative synthetic probe, (C) isodesmic relation of transition states showing the general importance of the hydroxy group to reactivity (ωB97xd/6-31+G*), and (D) ¹H NMR experiment with Selectfluor and various additives at different concentrations.We began our detailed study with a simple substrate that contains a tertiary hydroxyl group. Alcohol 5 was synthesized stereoselectively by the reaction of 3-methylcyclohexanone, FeCl₃, and 4-chlorophenylmagnesium bromide;¹⁰ the 4-chlorophenyl substituent allows for an uncomplicated product identification and isolation (aromatic chromophore). We sought to determine optimal reaction conditions by examination of numerous photosensitizers, bases, solvents, and light sources (7 Although we utilize cool blue LEDs (sharp cutoff ca. 400 nm), CFLs (small amount of UVB (280–315 nm) and UVA (315–400 nm)) are useable as well.¹¹ A mild base additive was also found to neutralize adventitious HF and improve yields in the substrates indicated ( EntrySensitizer ¹⁹F yield1None0% 2 Benzil 83% 3Benzil, no base63%4Benzil, K₂CO₃68%5Benzil, CFL light source75%65-Dibenzosuberenone15%74,4′-Difluorobenzil63%89,10-Phenantherenequinone71%9Perylene8%10Methyl benzoylformate42%Open in a separate window^aUnless stated otherwise: substrate (0.25 mmol, 1.0 equiv.), Selectfluor (0.50 mmol, 2.0 equiv.), NaHCO₃ (0.25 mmol, 1.0 equiv.), and sensitizer (0.025 mmol, 10 mol%) were dissolved in MeCN (4.0 mL) and irradiated with cool white LEDs for 14 h.Substrate scope^a

Dirhodium(ii)-catalysed cycloisomerization of azaenyne: rapid assembly of centrally and axially chiral isoindazole frameworks

Described herein is a dirhodium(ii)-catalyzed asymmetric cycloisomerization reaction of azaenyne through a cap-tether synergistic modulation strategy, which represents the first catalytic asymmetric cycloisomerization of azaenyne. This reaction is highly challenging because of its inherent strong background reaction leading to racemate formation and the high capability of coordination of the nitrogen atom resulting in catalyst deactivation. Varieties of centrally chiral isoindazole derivatives could be prepared in up to 99 : 1 d.r., 99 : 1 er and 99% yield and diverse enantiomerically enriched atropisomers bearing two five-membered heteroaryls have been accessed by using an oxidative central-to-axial chirality transfer strategy. The tethered nitrogen atom incorporated into the starting materials enabled easy late-modifications of the centrally and axially chiral products via C–H functionalizations, which further demonstrated the appealing synthetic utilities of this powerful asymmetric cyclization.

Rh(ii)-catalyzed asymmetric cycloisomerization of azaenyne through a cap-tether synergistic modulation strategy was described. Diverse centrally and axially chiral isoindazoles were prepared and directed C–H late-stage modifications were developed.

Known as one of the most significant and reliable access methods to chiral heterocycles, asymmetric cycloisomerization of conjugated enyne has caught extensive attention and interest for its wide applications in synthetic route design and mechanistic investigation.¹ Specifically, asymmetric cyclization of conjugated enynone (X = C, Z = O) has been successfully developed and applied to the rapid construction of various chiral furan-containing skeletons with high efficiency in an extremely operationally simple manner (Scheme 1a).² However, compared to the fruitful research with enynone, it is surprising that the analogous asymmetric version of azaenyne (Z = N–R) still remains underdeveloped.³ In fact, no successful example of catalytic asymmetric cyclization of azaenyne has been reported in the literature despite the apparent significance of nitrogen-containing five-membered heterocycles in the synthetic and pharmaceutical community.⁴ In 2004, Haley and Herges reported a detailed experimental and theoretical study of the cyclization reaction of (2-ethynylphenyl)-phenyldiazene, which is a unique azaenyne.⁵ According to the DFT calculations, very close and low activation barriers for 5-exo-dig and 6-endo-dig cyclization pathways under catalyst-free conditions were found, which shed light on the inherent challenges of the asymmetric reaction of azaenyne (Scheme 1b). For instance, there was usually a regioselectivity issue (5-exo and 6-endo) in the cyclization reaction of azaenyne because of their close reaction barriers where the competitive 6-endo-dig cyclization^3a,6 may lead to troublesome side-product formation. In addition, the low activation barrier deriving from the strong N-nucleophilicity of azaenyne may easily lead to self-cyclization which will cause severe background reactions to interfere with the asymmetric process. More troublingly, this transformation might suffer from catalyst deactivation arising from the high coordinating capability of the nitrogen atom in both starting materials and products, which might give more opportunities to the propagation of detrimental background reactions. In some cases, even a super-stoichiometric amount of transition metal has to be used to ensure effective conversion.^3a,7 Therefore, although many nonchiral approaches have been reported,^3,5 catalytic asymmetric cyclization of azaenyne still remains elusive due to the inherent obstacles aforementioned. With our continuous interest in alkyne chemistry,^2a,8 herein we designed a cap-tether synergistic modulation strategy to tackle these challenges, envisioning that modulation of the tethered atom and protecting cap of nitrogen in the azaenyne would intrinsically perturb and alter the reactivity of the starting material, and therefore the azaenyne motif could be effectively harnessed as a promising synthon for asymmetric transformations (Scheme 1c). It should be noted that the obtained centrally chiral product produced from intramolecular C–H insertion of donor-type metal carbene⁹ might be potentially converted into the axially chiral molecule via a central-to-axial chirality conversion strategy.Open in a separate windowScheme 1Development of the asymmetric cyclization reaction of conjugated azaenyne.With this design in mind, different types of azaenynes bearing typical tethering atoms and capping groups were chosen to test our hypothesis and representative results are shown in Scheme 2. First, tBu-capping imine (X = C, R = tBu) was selected as a substrate to test our hypothesis.^6a It was found that the imine exhibited low reactivity and the reaction temperature has to be elevated to 100 °C to initiate the transformation with or without catalyst. Unfortunately, the desired 5-exo-dig cyclization product was not detected, but isoquinoline from 6-endo-dig cyclization was obtained instead (Scheme 2a). To further regulate and control the regioselectivity and reactivity, triazene (X = N, R = N-piperidyl) was then investigated. Similarly, this substrate also showed low reactivity and it is still required to be heated at 100 °C for conversion. In the absence of a metal catalyst, an unexpected alkyne, deriving from the fragmentation of the triazene moiety, was produced in 41% yield. When 2 mol% Rh₂(OPiv)₄ was added as a catalyst, the side reaction could be efficiently suppressed and the reaction selectivity was apparently reversed. In this case, the target C–H insertion dihydrofuran was furnished as the major product in 30% yield but still accompanied by concomitant formation of 12% yield of undesired alkyne (Scheme 2b). The above investigations showed neither the imine nor triazene was an ideal substrate for the asymmetric reaction. Thus, we moved our attention to the diazene substrate (X = N, R = aryl). As demonstrated by Haley''s and Herges'' pioneering work, ortho-alkynyl diazene, compared with imine and triazene, was more unstable and tended to self-cyclization even at room temperature.^5a As shown in Scheme 2c, the ortho-alkynyl diazene degrades and 5-exo-dig cyclization products could be observed even in DCE solvent without any catalyst at room temperature. When the phenyl capping group was installed in the substrate, the reaction furnished 10% yield of isoindazole derivative. The uncatalyzed self-cyclization reaction was obviously accelerated when an electron-rich capping group (4-MeO–C₆H₄–) was introduced, affording the corresponding product in 20% yield. Inspired by these findings, we assumed that installation of an electron deficient group on the capping phenyl would reduce the nucleophilicity of the nitrogen atom and thus the troublesome self-cyclization reaction might be effectively inhibited. To our delight, when a bromo-substituent was introduced onto the phenyl cap, the undesired self-cyclization was almost suppressed. When Rh₂(OPiv)₄ was added as a catalyst, the desired carbene-involved C–H insertion product was furnished in 90% yield at room temperature. Worthy of note was the total absence of any cinnoline formation from 6-endo-dig cyclization.^3a,6b In short, the synthetic challenges associated with regioselectivity (5-exo-dig and 6-endo-dig), strong background reaction and catalyst deactivation could be successfully regulated and controlled via a tether-cap synergistic modulation strategy.Open in a separate windowScheme 2Typical substrate investigation.Encouraged by the above findings, ortho-alkynyl bromodiazene 1a was chosen as a model substrate and different types of chiral dirhodium catalysts¹⁰ were screened in DCE at room temperature for 48 h. As shown in EntryRh(ii)*SolventYield^b [%]er^c1Rh₂(R-DOSP)₄DCE5629 : 712Rh₂(5S-MEPY)₄DCE1750 : 503Rh₂(S-BTPCP)₄DCE618 : 924Rh₂(S-PTPA)₄DCE9191 : 95Rh₂(S-PTTL)₄DCE8697 : 36Rh₂(S-PTAD)₄DCE9394 : 67Rh₂(S-NTTL)₄DCE9296 : 48Rh₂(S-TCPTTL)₄DCE9598 : 2 9 Rh ₂ (S-TFPTTL) ₄ DCE 98 ^d 98 : 210Rh₂(S-TFPTTL)₄DCM8898 : 211Rh₂(S-TFPTTL)₄Toluene9298 : 212Rh₂(S-TFPTTL)₄MeCN1692 : 813Rh₂(S-TFPTTL)₄ n-Hexane9698 : 214^eRh₂(S-TFPTTL)₄DCE65^f96 : 4 Open in a separate window^aUnless otherwise noted, reactions were performed at 0.1 M in DCE using 0.20 mmol substrate and catalyst (2 mol%) under a N₂ atmosphere.^bDetermined by ¹H NMR spectroscopy.^cThe er value of 2a was determined by HPLC using a chiral stationary phase.^dIsolated yields.^e1 mol% catalyst was used.^f25% starting material was recovered.With the optimized reaction conditions in hand (Scheme 3, the catalytic process could be successfully applied to azaenynes 1 bearing different ether side chains. For example, in addition to 1a, various azaenyne derivatives containing benzylic ethers could be efficiently converted into the desired products 2b–i with excellent diastereoselectivities and enantioselectivities (>99 : 1 d.r., 97:3–99 : 1 er). The yields were typically higher than 90% for most substrates. Satisfyingly, the substrates with bulkier aryl groups were well-tolerated to afford the isoindazole products 2j–m in good yields with excellent diastereo- and enantiocontrol (>97 : 3 d.r., > 95 : 5 er). In addition to azaenynes with arylmethyl ether, this protocol was also successfully applied to substrates with allylic ether, propargyl ether and even aliphatic ether to furnish the cyclization products 2n–u in good yields with decent diastereo- and enantioselectivities (>93 : 7 d.r., > 90 : 10 er). In the cases of allylic and propargyl ether, only C–H insertion products (2n–p) were observed though cyclopropanation or cyclopropenation often took place competitively when using the allylic or propargyl substrate to trap the carbene intermediate.¹¹ It was noted that the azaenynes with aliphatic ether, which represent challenging substrates^2a in the asymmetric carbene transfer reactions, also showed good reactivities to afford the corresponding chiral dihydrobenzofurans (2q–u) with excellent diastereoselectivities (>93 : 7 d.r.) and enantioselectivities (>98 : 2 er). Interestingly, when phenyl and methoxyphenyl capping azaenynes, which potentially suffered from the undesired background reactions, were subjected to the standard conditions, chiral products (2v–w) could be obtained with high optical purity (>99 : 1 d.r., > 96 : 4 er) as well. These results might be attributed to the high catalytic activity of Rh₂(S-TFPTTL)₄ in the asymmetric cyclization process, which eventually led to complete suppression of the uncatalyzed self-cyclization. The scopes with respect to the group R¹ on the fused phenyl ring were further investigated. Both electron-rich and -deficient substituents R¹ were well accommodated, with the product yields ranging from 80% to 99%, enantiomeric ratios ranging from 95 : 5 to 97 : 3 and diastereomeric ratios higher than 99 : 1 (2x–z). In addition, azaenyne substituted with an alkyl side chain at the alkynyl carbon atom was also tested, giving tetrahydrofuran (2aa) with excellent diastereoselectivity (>99 : 1 d.r.), good enantioselectivity (90 : 10 er) and moderate yield (43%). In addition to the side chain of ether, this asymmetric protocol could even be extended to the more challenging nitrogen- and thio-tethered analogues, albeit with somewhat lower reactivities (46–65% yields) but good stereoselectivities (93 : 7 er and 84 : 16 d.r. for 2ab; 81 : 19 er and >99 : 1 d.r. for 2ac). Structures of the resulting products were confirmed by X-ray crystallographic analysis of their analogue 2h.Open in a separate windowScheme 3 ^aUnless otherwise noted, the reactions were performed under standard conditions for 48 h or monitored by TLC until the starting material disappeared. ^b5 mol% catalyst was used. ^cReactions were performed in n-hexane, using 2 mol% Rh₂(S-TCPTTL)₄ as the catalyst.The successful preparation of centrally chiral isoindazole through the asymmetric cyclization reaction prompted us to explore the further applications of this protocol. Axially chiral biaryl skeletons are undoubtedly regarded as one of the most prominent structural motifs for their ubiquity in natural products, pharmaceuticals and useful chiral ligands in asymmetric catalysis.¹² Due to the lower rotational barrier, there are only limited examples of the enantioselective synthesis of axially chiral atropisomers featuring a five-membered ring, especially those bearing two pentatomic aromatics.¹³ Compared with the furan analogue, the extending cap in the isoindazole scaffold provides additional ortho steric hindrance making these molecules possible candidates for the preparation of five-five-membered biaryl atropisomers. Considering the unique chiral skeleton of dihydrofuranyl isoindazole 2, we began to explore their potential application in chiral atropisomer synthesis via a central-to-axial chirality transfer strategy. As shown in Scheme 4, oxidative aromatization of representative dihydrofuran candidate 2m furnished two configurationally unstable atropisomers, which might be attributed to their relatively low rotational barriers as five-membered atropisomers especially when the furan ring was incorporated (see ESI^† for details). Therefore, it was hypothesized that extending the fused phenyl to naphthyl might afford stable atropisomers by enhancing the ortho steric hindrance (Scheme 4b).Open in a separate windowScheme 4Investigation of central-to-axial chirality transfer.To our delight, as shown in Scheme 5, naphthyl-fused dihydrofurans 4 could be easily accessed through the above established dirhodium-catalyzed cyclization process and configurationally stable atropisomers 5 could be generated via further oxidative dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as the oxidant (see ESI^† for the proposed mechanism). For example, asymmetric cyclization reactions proceeded smoothly to give the centrally chiral compounds 4 in good yields (54–99%) with excellent diastereoselectivities (92 : 8–99 : 1 d.r.) and enantioselectivities (95 : 5–99 : 1 er) under slightly modified reaction conditions. This reaction was compatible with a variety of arylmethyl side chains in azaenynes and well-accommodated with various functional groups (F, Cl, Br, OMe, and –CO₂Me). Additionally, oxidative dehydrogenation of chiral candidates 4 with DDQ smoothly resulted in the formation of axially chiral atropisomers 5 in 90–99% yields with only slight loss of chiral integrity (90 : 10–97 : 3 er). An enantiomerically pure atropisomer could be obtained through a simple recrystallization procedure as exemplified by compound 5g. The structure and absolute configuration of isoindazole 4g and atropisomer 5g were confirmed by their single-crystal X-ray diffraction analysis.Open in a separate windowScheme 5 ^aConditions for cyclization of azaenyne: Rh₂(S-TCPTTL)₄ (2 mol%), n-hexane, rt for 48 h or monitored by TLC until the starting material disappeared; conditions for oxidative chirality transfer: DDQ (2 equiv.), DCE, −20 °C for 48 h or monitored by TLC until the starting material disappeared. ^b45 °C. ^cDDQ (5 equiv.). ^dRoom temperature. ^eAfter one recrystallization.With centrally and axial chiral molecules in hand, further transformations of these compounds were also explored. The tethered nitrogen atom in azaenynes not only showed a synergetic effect with the capping group on promoting asymmetric cyclization but also served as an innate directing group for late-stage modifications via C–H functionalization. As shown in Scheme 6, a variety of functional groups could be directly introduced onto the capping aromatic rings, allowing for rapid build-up of molecular complexity. For example, synthetically valuable alkenyl,¹⁴ allyl¹⁵ and alkynyl¹⁶ groups could be easily incorporated into the final structures, which had wide potential applications in organic synthesis (6a–c). Furthermore, C–H alkylation,¹⁷ amidation¹⁸ and selenylation¹⁹ were performed smoothly to afford the desired products 6d–g. It is noteworthy that unique chiral chelation backbones were constructed by amidation and selenylation of the isoindazole moiety (6e–g). In addition to centrally chiral compounds, axial chiral atropisomers 5 themselves could be efficiently converted to their functionalized scaffolds as well (6h–i) through a similar directed C–H functionalization process.Open in a separate windowScheme 6Late-stage modification of chiral isoindazoles. Reaction conditions: ^a4-octyne, [Rh(Cp*Cl₂)]₂, AgSbF₆, Cu(OAc)₂, DCE, 80 °C. ^bAllyl carbonate, [Rh(Cp*Cl₂)]₂, AgSbF₆, PivOH, PhCl, 40 °C. ^cHypervalent iodine-alkyne, [Rh(Cp*Cl₂)]₂, Zn(OTf)₂, DCE, 80 °C. ^dAlkene, [Rh(Cp*Cl₂)]₂, AgSbF₆, AcOH, 1,4-dioxane, 50 °C. ^e3-Phenyl-1,4,2-dioxazol-5-one, [Cp*Co(MeCN)₃](SbF₆)₂, DCE, 80 °C. ^fPhSeCl, [Rh(Cp*Cl₂)]₂, AgSbF₆, THF, 60 °C.     

Direct electrochemical hydrodefluorination of trifluoromethylketones enabled by non-protic conditions

CF₂H groups are unique due to the combination of their lipophilic and hydrogen bonding properties. The strength of H-bonding is determined by the group to which it is appended. Several functional groups have been explored in this context including O, S, SO and SO₂ to tune the intermolecular interaction. Difluoromethyl ketones are under-studied in this context, without a broadly accessible method for their preparation. Herein, we describe the development of an electrochemical hydrodefluorination of readily accessible trifluoromethylketones. The single-step reaction at deeply reductive potentials is uniquely amenable to challenging electron-rich substrates and reductively sensitive functionality. Key to this success is the use of non-protic conditions enabled by an ammonium salt that serves as a reductively stable, masked proton source. Analysis of their H-bonding has revealed difluoromethyl ketones to be potentially highly useful dual H-bond donor/acceptor moieties.

The electrochemical hydrodefluorination of trifluoromethylketones under non-protic conditions make this single-step reaction at deeply reductive potentials uniquely amenable to challenging electron-rich substrates and reductively sensitive functionalities.

The difluoromethyl group (CF₂H) has attracted significant recent attention in medicinal chemistry,^1,2 which complements the well-documented importance and growing use of fluorine in small molecule pharmaceuticals.^3–6 The CF₂H group is an H-bond donor^7,8 that is also lipophilic,^9,10 a unique combination that positions it as an increasingly valuable tool within drug-discovery.¹¹ CF₂H has been used as a bioisostere of OH and SH in serine and cystine moieties, respectively, as well as NH₂ groups, where greater lipophilicity and rigidity provide advantages to pharmacokinetics and potency.^12–14The hydrogen-bond acidity of CF₂H groups is exceptionally dependent on the atom or group to which it is appended (Fig. 1A).^1,2 The H-bond acidity of alkyl-CF₂H groups is half that of O–CF₂H and even a quarter of SO₂–CF₂H groups.¹ This mode of control allows the H-bonding strength and, therefore its function, to be finely tuned. While much research has focused on the synthesis, behaviour and use of XCF₂H groups, where X = O, S, SO, SO₂, Ar, it is surprising that the corresponding carbonyl containing moiety (X = CO) has remained relatively elusive in these contexts. Not only would difluoromethyl ketones (DFMK) be expected to provide a relatively strong H-bond, but the carbonyl unit provides a complementary, yet proximal mode of intermolecular interaction (Fig. 1B). Indeed, the dual action of neighbouring H-bond donor and acceptor functionalities provides the fundamental basis for many biological systems, including in the secondary structure assembly mechanisms for proteins and DNA/RNA nucleobase pairing, as well as in enzyme/substrate complexes. Indeed, the DFMK functionality has demonstrated important utility in biological applications, including anti-malarial and -coronaviral properties.¹⁵ Finally, the carbonyl provides a useful synthetic handle for further derivatization.Open in a separate windowFig. 1H-Bonding in DFMKs and their synthesis via hydrodefluorination.While some progress has been made on the synthesis of DFMKs,¹⁶ there still remains a need for a general and more broadly accessible route to their preparation. Current strategies for DFMK preparation require multi-step processes, expensive reagents, installation of activating groups, or are inherently low yielding.^15a,16–25 The hydrodefluorination of trifluoromethyl ketones (1) potentially represents the most accessible strategy, as the starting materials are most readily prepared through a high-yielding trifluoroacetylation of C–H or C–X bonds.^26–29 In 2001, Prakash demonstrated the viability of this approach using 2 equivalents of magnesium metal as stoichiometric reductant to drive the defluorination, with a second hydrolysis step (HCl (3–5 M) or fluoride, overnight stirring) to reveal the product.³⁰ The scope in this 2-step process (6 substrates) reflects the limitations of using a reductant, such as Mg, that has a fixed reduction potential, as well as incompatibilities arising from Mg/halide exchange with aryl halides. Similar limitations with the use of electron-rich substrates were revealed in related contributions from Uneyama.³¹In order to access more electron-rich and reductively challenging substrates, such as those containing medicinally relevant heterocycles, we postulated that electrochemical reduction could be employed (Fig. 1C). Electrosynthesis is becoming an increasingly valuable enabling technology and has seen a recent resurgence due to the precise control, unique selectivity, and the potential scalability and sustainability benefits that it offers.^32–36 This strategy would avoid the undesirable use of stoichiometric metals and the ‘deep-reduction’ potentials required are readily accessed by simply selecting the applied potential. Pioneering early work from Uneyama on the cathodic formation of silylenol ether intermediate 2, suggested this approach could be viable.^37,38 The fundamental challenge in designing a practical, single-step process under highly reducing potentials (<−2.0 V vs. Fc/Fc⁺), is to avoid the reduction of the proton source, which would otherwise compete to generate H₂ gas and leave the starting material untouched. Uneyama does not demonstrate hydrodefluorination, presumably due to this problem. Additional challenges posed by ‘deep-reduction’ include a lack of tolerance for reduction-sensitive functionality (alkene, C–X bonds etc.), low mass balance due to substrate decomposition and the undesirable use of sacrificial metal anodes.³⁹ Solving these problems should provide generally applicable, safe and scalable conditions for the hydrodefluorination of readily accessible trifluoromethyl ketones (1).Given the electron-rich nature of indoles, their ubiquity in bioactive compounds, and their ease of functionalisation, we chose indole 1a as the model substrate for optimisation. The highly reductive potentials required will render it a challenging substrate, which should lead to more general conditions suitable for other important substrate classes. Indeed, when we applied the Mg conditions of Prakash to this substrate, no silyl enol ether intermediate (2a) was observed, nor product 3a, and the starting material remained completely untouched ( EntryConditions different from aboveReductantProton source 1a ^a/%(2a) 3a^a/%1 Mg ⁰, THF, no electricity (Prakash conditions for3)Mg⁰—100(0) n/a2^bUndivided cell, TBAPF₆Sacrificial Mg anode—100(0) n/a3^bPb:C (cath:an), 0 ^oC, 30 mA (Uneyama conditions for2)TBABr (4 eq.)—33(32) 04^b—TBABr (2 eq.)(a) Acetic acid; (b) oxalic acid.51; 1000; 05^b—TBABr (2 eq.)Dimethylurea8206^b—TBABr (2 eq.)TEAPF₆ (4 eq.)49457TMSCl (0 eq.)TBABr (2 eq.)TEAPF₆ (4 eq.)8308^bTMSCl (6 eq.)TBABr (2 eq.)TEAPF₆ (4 eq.)49499^c TMSCl (3 + 3 eq.) TBABr (2 eq.) TEAPF ₆ (4 eq.) 0 97 10^cEntry 9, but Pt:Gr (cath:An)TBABr (2 eq.)TEAPF₆ (4 eq.)09411^cEntry 9, but Ni:Pt (cath:An)TBABr (2 eq.)TEAPF₆ (4 eq.)08312^cEntry 9, but Stainless Steel:Pt (cath:An)TBABr (2 eq.)TEAPF₆ (4 eq.)08513^cEntry 9, but Gr:Pt (cath:An)TBABr (2 eq.)TEAPF₆ (4 eq.)018Open in a separate window^{a 19}F NMR yields.^bTMSCl only added to cathodic chamber.^cTMSCl added to both cathodic and anodic chambers.The electrochemical conditions of Uneyama for preparing silylenol ethers (2) were applied to our indole 1a (entry 3). Unsurprisingly, no hydrodefluorinated product was observed, however intermediate 2a was formed in a 32% yield. In an effort to improve this yield we explored several solvents, reductants, additives and electrode materials, all of which were conducted in a divided cell at constant current and ambient temperature.⁴⁰ In addition, as we were keen to develop a single-step protocol, by avoiding the second hydrolysis step that can readily form homo-coupled aldol side products,³⁸ we surveyed a range of added proton sources for in situ delivery of 3a. The addition of carboxylic acids, such as acetic or oxalic acid (entry 4), gave no desired product, as the competing reduction of protons to H₂ gas dominated. Dimethylurea was recently used as a proton source in an electrochemical ‘deep-reduction’,⁴¹ but it returned no trace of intermediate 2a or product 3a (entry 5). We hypothesized that increasing the conductivity of the system, with additional tetraalkylammonium salts (from 2 to 4 eq.), the formation of intermediate 2a may be facilitated by avoiding large cell potentials. While this change did facilitate a lower cell potential, we discovered these salts behaved as reductively stable yet competent masked proton donors: 4 eq. NEt₄PF₆ gave 45% yield of product 3a, with no sign of intermediate 2a (entry 6). The detection of triethylamine in solution suggests donation through a Hoffmann elimination.⁴² With the exception of NMe₄⁺, other tetraalkylammonium salts were also competent proton donors (NEt₄⁺ > NBu₄⁺ > NPr₄⁺).A critical improvement to the yield was observed when the use of the radical anion trapping agent, TMSCl, was optimised. With no TMSCl, 3a was not observed (entry 7), and a loading of 6 equivalents saw little improvement over 3 equivalents (entry 8 vs. 6). Experiments hitherto described were conducted with TMSCl added only to the cathodic chamber (entries 2–8). Only when the 6 equivalents was split between both chambers was a drastic improvement observed (entry 9), giving an optimised yield of 97%. Notably, the increase in conversion still occurred with only 2 F, implying that a lower steady-state concentration may be important in the cathode chamber. To test this hypothesis, TMSCl was slowly added to the catholyte by syringe-pump addition over the course of the reaction, which gave a similar yield of 94%.⁴⁰ Although intermediate 2a is transient and was never observed, the importance of TMSCl to trap and stabilise reduced 1a was revealed by DFT (B3LYP/6-311+g(d)) calculations,⁴⁰ which suggested a thermodynamically highly challenging reaction in its absence.The oxidation of bromide to tribromide occurs on the anode, which is an ideal counter-electrode process: not only is bromide an inexpensive and metal-free sacrificial reductant, but as the produced Br₃⁻ is anionic, it does not rapidly migrate to the cathodic chamber, preventing unwanted side reactions.⁴³ The generated Br₃⁻ can even be used in follow-up bromination reactions.⁴⁴ An increase in the applied cell potential during the reaction signifies the consumption of Br⁻, and the oxidation of Br₃⁻ to Br₂ (Fig. 2).⁴⁵ Despite needing 3 equivalents of Br⁻ to form 2 equivalents of Br₃⁻ after 2 F, the loading of Br⁻ could be reduced to 2 equivalents without affecting yield. No over-reduction of 3a to the monofluoromethyl ketone was observed, which is significant considering the small difference in reduction potentials.⁴⁰ This emphasises the importance of a flat chronopotentiometry trace that is achieved with Br⁻ oxidation. Other reductants were found to be sub-optimal, including diisopropylamine and oxalic acid.⁴⁰Open in a separate windowFig. 2Reaction of 1a to 3a with 3 different Br⁻ concentrations.A graphite anode performed equally well as platinum for the counter electrode reaction (entry 10). Only marginally reduced yields were observed with nickel and stainless-steel cathodes (entries 11 and 12), however, a drastic decrease in the yield was observed with a graphite cathode (entry 13), possibly due to substrate grafting.³⁹We proceeded to explore the substrate scope with our optimized conditions, Fig. 3. As expected, our electrochemical conditions were suitable for the hydrodefluorination of electron-poor acetophenone derivatives (1b, 1c). However, unlike with the use of Mg,³⁰ substrates containing electron donating substituents are now well tolerated (1d–k). In addition, no hydrodebromination was observed for 1b, highlighting the selectivity and orthogonality granted by the use of our Mg-free, non-protic conditions. A selection of extended π-systems was tolerated, producing pyridyl 3l, biphenyl 3m, benzothiophene 3n, primary amine 3o, and pyrimidines 3p and 3q and in moderate to excellent yields. Chromoionophore dye 1r and stilbene 1s and were transformed in excellent yield, demonstrating tolerance to reductively sensitive alkenes, which would otherwise hydrogenate under protic electrochemical conditions.⁴⁶ Anthracenyl 1t and naphthyl substrates 1u and 1v all transformed efficiently in good to excellent yields, the latter of which underwent direct double hydrodefluorination. 4.5% over-reduction was observed in the double defluorination product, 3v, which was the only instance where this side-product was observed in greater than 1% quantities.⁴⁰ The good mass-balance and faradaic efficiency is notable considering the delocalization of charge around extended π-systems increases the likelihood of grafting.⁴⁷Open in a separate windowFig. 3Isolated yields of DFMKs tested under the reaction conditions at 0.5 mmol scale. NMR yields in parentheses. ^aReaction run at 10 mA; ^breaction run in IKA Divided ProSyn: quantitative yield based on RSM; ^c5 mmol scale, Ni foil:Gr (cath:an); ^disolated as the corresponding ketone following purification on silica.⁴⁹The model indole substrate 1a gave an excellent yield of DFMK at 0.5 mmol scale, which gave equally high yields when scaled up 10-fold (5 mmol), thereby demonstrating the robustness and practicality of the technique. We were also able to successfully prepare 3a in a commercially available divided cell set-up.⁴⁰ Alternative groups on nitrogen, including Boc, perfluoropyridyl and benzyl (3w–y), as well as the free indole 3z, were well tolerated and gave moderate to good yields of 3. Tosyl and acetyl groups on nitrogen were less well tolerated.⁴⁰ As with the acetophenones, indoles with electron donating (1aa) and withdrawing (1ab) groups proceeded to product. Methoxy demethylation of 3aa should lead to the corresponding phenol,⁴⁸ which is difficult to prepare using other methodologies due to competing side-reactions. Halide substitution also successfully yielded DFMKs (3ac–ag). The inclusion of the aryl-iodide functionality is especially notable due to its facile reduction; when a silver cathode was used to convert 1ag, hydrodeiodination was observed, but which was absent under our non-protic conditions with a Pt cathode. Increased steric bulk around the reacting center in thiophenyl and phenyl-substituted substrates 1ah and 1ai had no negative influence and gave good yields of product.Heterocyclic trifluoromethylketones were successfully hydrodefluorinated under the standard conditions, including indole 3aj, carbazole 3ak, pyrrole 3al, pyridine 3am, and pyrazoles 3an and 3ao, the latter of which leads to a compound with anti-malarial activity.^15a Alkyl trifluoromethylketones are more difficult to reduce compared to aromatic trifluoromethylketones, and are therefore challenging substrates to hydrodefluorinate, and impossible to convert using other methods. Nevertheless, oleyl 1ap, cyclohexyl 1aq and ethyl 1ar substrates were all amenable to the conditions, although the smaller alkyl products were cumbersome to isolate due to their volatility. The non-protic optimized conditions ensured no loss of mass-balance at these enhanced reduction potentials (|E_cell| = ca. 3.4–3.7 V for alkyl substrates vs. ca. 2.3–2.7 V for acetophenones and indoles). Finally, we tested the conditions on trifluoroacetamide 1as, thioester 1at and imines 1au and 1av. For each of these, the corresponding product was returned in moderate to good yields. Despite some complications in their isolation, these results are notable considering their difference in structure and lack of precedent. Unsuccessful substrates included a nitro-substituted indole, which was insoluble in the reaction medium, and hydrated TFMKs.⁴⁰We tested a variety of substrates with the Mg-mediated conditions reported by Prakash to gauge the level of complementary between the methods.³⁰ While acetophenone derivatives 1k and 1am were amenable to reduction with Mg, bromide substitution in 1b was unsurprisingly not tolerated with Grignard formation dominating. Indoles – 1a, 1ai, pyrazole – 1an, alkyl – 1aq, 1ar and anilide – 1as based trifluoromethylketones were untouched by Mg in all cases, with starting materials recovered only.To explore the value of the DFMK moiety in synthesis, we derivatized it in a variety of ways, Fig. 4. Resubjecting the product 3a to our non-protic hydrodefluorination conditions led to monofluorinated product 4, providing an alternative to the use of electrophilic fluorine sources.⁵⁰ Reduction of the ketone in 3ae to the methyl ether and alcohol successfully gave products, 5 and 6, respectively. The dithiane of 3a, which is a useful synthetic intermediate, was formed in excellent yield (7). A Corey–Chaykovsky methenylation gave epoxide 8 in good yield. A Horner–Wadsworth–Emmons reaction transformed the carbonyl to give alkene 9. Nucleophilic attack of the ketone was demonstrated with a trifluoromethylation reaction to give highly fluorinated alcohol 10. Orthogonal reactivity was also demonstrated with a Suzuki–Miyaura cross-coupling that gave biaryl 11. Interestingly, deuterium was not exchanged into 3a when stirred in a mixture of D₂O and MeCN, providing evidence for a less favourable enolization.Open in a separate windowFig. 4[A] Derivatization of DFMKs. X = H (3a) for 4, 7, and 8, X = Br (3ae) for others; [B] H-bond strength (A-value) correlated to σ_m Hammett parameter; [C] intermolecular H-bond revealed in X-ray crystal structure of 3ae; [D] DFT calculated (B3LYP/6-311+g(d)) relative energies of conformers with rotation around HC–CO bond. Brown arrows indicate direction of dipole.The H-bond strength (A-value) was measured for a series of phenyl substituted X–CF₂H derivatives using the NMR method from Abraham, Fig. 4B.^51–53 These experiments confirmed the sensitivity of the H-bonding ability to the identity of X. DFMK 3g and sulfoxide–CF₂H were found to be comparable H-bond donors, which were only marginally less than the sulfone–CF₂H. The H-bond strength correlated best with the σ_m parameter, reflecting the strong influence of inductive effects. Multiple regression analysis showed that any contribution of σ_p was statistically insignificant (P value = 0.33).Analysis of the X-ray crystal structure of 3ae, showed an inter-molecular H-bond between the CF₂H and a carbonyl from a neighbouring molecule (Fig. 4C). DFT was used to calculate the relative conformer energy with rotation about the (O)C–CF₂H dihedral bond (Fig. 4D). The lowest energy conformer eclipsed the H with the carbonyl, implying the possibility of an energy lowering intra-molecular H-bond. However, analysis of the other derivatives in the set (C(O)CH₃, C(O)CFH₂ and C(O)CF₃) revealed that the alignment of dipoles was the dominant effect (brown arrows, Fig. 4D).⁴⁰ The absence of an unusually low or even negative A-value also provides evidence against an intramolecular H-bond.⁵¹ Interestingly, in the solid-state structure (Fig. 4C), the highest energy conformer (with dipoles aligned) is adopted, highlighting the stronger propensity of this moiety to engage in H-bonding interactions.In conclusion, we have developed a mono-selective hydrodefluorination to access a broad scope of DFMKs, enabled by non-protic electrochemical conditions at deeply reducing potentials. These moieties have been studied and diversified and reveal themselves to be potentially useful dual H-bond donor/acceptor moieties. This is especially interesting considering the structurally related trifluoromethylketones are known reversible protease inhibitors;^54,55 thus, the additional H-bonding moiety could enhance interaction within enzymatic active sites.¹⁵     

Simplifying and expanding the scope of boron imidazolate framework (BIF) synthesis using mechanochemistry

Mechanochemistry enables rapid access to boron imidazolate frameworks (BIFs), including ultralight materials based on Li and Cu(i) nodes, as well as new, previously unexplored systems based on Ag(i) nodes. Compared to solution methods, mechanochemistry is faster, provides materials with improved porosity, and replaces harsh reactants (e.g. n-butylithium) with simpler and safer oxides, carbonates or hydroxides. Periodic density-functional theory (DFT) calculations on polymorphic pairs of BIFs based on Li⁺, Cu⁺ and Ag⁺ nodes reveals that heavy-atom nodes increase the stability of the open SOD-framework relative to the non-porous dia-polymorph.

Mechanochemistry enables rapid access to boron imidazolate frameworks (BIFs), including ultralight materials based on Li and Cu(i) nodes, as well as new, previously unexplored systems based on Ag(i) nodes.

Mechanochemistry^1–7 has emerged as a versatile methodology for the synthesis and discovery of advanced materials, including nanoparticle systems^8–10 and metal–organic frameworks (MOFs),^11–15 giving rise to materials that are challenging to obtain using conventional solution-based techniques.^16–18 Mechanochemical techniques such as ball milling, twin screw extrusion¹⁹ and acoustic mixing^20,21 have simplified and advanced the synthesis of a wide range of MOFs, permitting the use of simple starting materials such as metal oxides, hydroxides or carbonates,^22,23 at room temperature and without bulk solvents, yielding products of comparable stability and, after activation, higher surface areas than solution-generated counterparts.^24–29 The efficiency of mechanochemistry in MOF synthesis was recently highlighted by accessing zeolitic imidazolate frameworks (ZIFs)^30,31 that were theoretically predicted, but not accessible under conventional solution-based conditions.¹⁷The advantages of mechanochemistry in MOF chemistry led us to address the possibility of synthesizing boron imidazolate frameworks (BIFs),^32–34 an intriguing but poorly developed class of microporous materials analogous to ZIFs, comprising equimolar combinations of tetrahedrally coordinated boron(iii) and monovalent Li⁺ or Cu⁺ cations as nodes (Fig. 1A–C). Although BIFs offer an attractive opportunity to access microporous MOFs with lower molecular weights, particularly in the case of “ultralight” systems based on Li⁺ and B(iii) centers, this family of materials has remained largely unexplored – potentially due to the need for harsh synthetic conditions, including the use of n-butyllithium in a solvothermal environment.^32–34Open in a separate windowFig. 1Structures of previously reported BIFs with: (A) zni-, (B) dia-, or (C) SOD-topology (M = Li, Cu); (D) tetrakis(imidazolyl)boric acids used herein for mechanochemical BIF synthesis; and (E) schematic representation of the herein developed mechanosynthesis of dia- and SOD BIF polymorphs based on Li, Cu or Ag metal nodes.We now show how switching to the mechanochemical environment enables lithium- and copper(i)-based BIFs to be prepared rapidly (i.e., within 60–90 minutes), without elevated temperatures or bulk solvents, and from readily accessible solid reactants, such as hydroxides and oxides (Fig. 1D and E). While the mechanochemically-prepared BIFs exhibit significantly higher surface areas than the solvothermally-prepared counterparts, mechanochemistry allows for expanding this class of materials towards previously not reported Ag⁺ nodes. The introduction of BIFs isostructural with those based on Li⁺ or Cu⁺ but comprising of Ag⁺ ions, enables a periodic density-functional theory (DFT) evaluation of their stability. This reveals that switching to heavier elements as tetrahedral nodes improves the stability of sodalite topology (SOD) open BIFs with respect to close-packed diamondoid (dia) topology polymorphs.As a first attempt at mechanochemically synthesis of BIFs, we targeted the synthesis of previously reported zni-topology LiB(Im)₄ and CuB(Im)₄ frameworks (Li-BIF-1 and Cu-BIF-1, respectively, Fig. 1A) using a salt exchange reaction between LiCl or CuCl with commercially available sodium tetrakis(imidazolyl)borate (Na[B(Im)₄]) (Fig. 2A). Milling of LiCl and Na[B(Im)₄] in a 1 : 1 stoichiometric ratio for up to 60 minutes led to the appearance of Bragg reflections consistent with the target Li-BIF-1 (CSD MOXJEP) and the anticipated NaCl byproduct. The reaction was, however, incomplete, as seen by X-ray reflections of Na[B(Im)₄] starting material. In order to improve reactant conversion, we explored liquid-assisted grinding (LAG), i.e. milling in the presence of a small amount of a liquid phase (measured by the liquid-to-solid ratio η³⁵ in the range of ca. 0–2 μL mg⁻¹). Using LAG conditions with acetonitrile (MeCN, 120 μL, η = 0.5 μL mg⁻¹) led to the complete disappearance of reactant X-ray reflections, concomitant with the formation of Li-BIF-1 alongside NaCl within 60 minutes.Open in a separate windowFig. 2(A) Reaction scheme for the mechanochemical synthesis of Li-BIF-1 by a salt metathesis strategy. Selected PXRD patterns for: (B) Na[B(Im)₄] (C) LiCl, (D) simulated Li-BIF-1 (CSD MOXJPEP) and (E) synthesized BIF-1-Li by LAG for 60 minutes with MeCN (η = 0.5 μL mg⁻¹), (F) CuCl, (G) simulated Cu-BIF-1 (CSD MOXJIT), and (H) synthesized BIF-1-Cu by LAG for 60 minutes with MeOH (η = 0.50 μL mg⁻¹). Asterisks denote NaCl, a byproduct of the metathesis reaction. (Fig. 2B–E, also see ESI^†). The copper-based zni-CuB(Im)₄ (Cu-BIF-1) was readily obtained from CuCl within 60 minutes using similar LAG conditions. We also explored LAG with methanol (MeOH), revealing that the exchange reaction to form NaCl took place with both LiCl and CuCl starting materials. With LiCl, however, the PXRD pattern of the product could not be matched to known phases involving Li⁺ and B(Im)₄⁻ (see ESI^†). With CuCl as a reactant, LAG with MeOH (η = 0.5 μL mg⁻¹) cleanly produced Cu-BIF-1 alongside NaCl (see ESI^†).Next, we explored an alternative synthesis approach, analogous to that previously used to form ZIFs and other MOFs: an acid–base reaction between a metal oxide or hydroxide and the acid form of the linker: tetrakis(imidazolato)boric acid, HB(Im)₄ (Fig. 3A).^36–40 Neat milling LiOH with one equivalent of HB(Im)₄ in a stainless steel milling assembly led to the partial formation of Li-BIF-1, as evidenced by PXRD analysis (see ESI^†). Complete conversion of reactants into Li-BIF-1 was achieved in 60 minutes by LAG with MeCN (η = 0.25 μL mg⁻¹), as indicated by PXRD analysis (Fig. 3B–E), Fourier transform infrared attenuated total reflectance spectroscopy (FTIR-ATR), thermogravimetric analysis (TGA) in air, and analysis of metal content by inductively-coupled plasma mass spectrometry (ICP-MS) (see ESI^†).Open in a separate windowFig. 3(A) Reaction scheme for the mechanochemical synthesis of Li-BIF-1 using the acid–base strategy. Selected PXRD patterns for: (B) H[B(Im)₄] (C) LiOH, (D) simulated Li-BIF-1 (CSD MOXJPEP), (E) synthesized BIF-1-Li by LAG for 60 minutes with MeCN (η = 0.25 μL mg⁻¹), (F) Cu₂O, (G) simulated Cu-BIF-1 (CSD MOXJIT), and (H) synthesized Cu-BIF-1 by ILAG for 60 minutes with MeOH (η = 0.50 μL mg⁻¹) and NH₄NO₃ additive (5% by weight).Neat milling of HB(Im)₄ with Cu₂O under similar conditions gave a largely non-crystalline material, as evidenced by PXRD (see ESI^†). Switching to the ion- and liquid-assisted grinding (ILAG) methodology, in which the reactivity of a metal oxide is enhanced by a small amount of a weakly acidic ammonium salt, and which was introduced to prepare zinc and cadmium ZIFs from respective oxides,^37–40 enabled the synthesis of Cu-BIF-1 from Cu₂O. Specifically, PXRD analysis revealed complete disappearance of the oxide in samples obtained by ILAG with either MeOH or MeCN (η = 0.5 μL mg⁻¹) in the presence of NH₄NO₃ additive (5% by weight, see ESI^†). Notably, achieving complete disappearance of Cu₂O reactant signals also required switching from stainless steel to a zirconia-based milling assembly, presumably due to more efficient energy delivery.⁴¹ After washing with MeOH, the material was characterized by FTIR-ATR, TGA in air, and analysis of metal content by ICP-MS (see ESI^†).Whereas both the metathesis and acid–base approaches can be used to mechanochemically generate Li- and Cu-BIF-1, the latter approach has a clear advantage of circumventing the formation of the NaCl byproduct. Consequently, in order to further the development of mechanochemical routes to other BIFs, we focused on the acid–base strategy. As next targets, we turned to MOFs based on tetrakis(2-methylimidazole)boric acid H[B(Meim)₄],³⁶ previously reported³² to adopt either a non-porous diamondoid (dia) topology (BIF-2) or a microporous sodalite (SOD) topology (BIF-3) with either Li⁺ or Cu⁺ as nodes (Fig. 4). Attempts to selectively synthesize either Li-BIF-2 or Li-BIF-3 by neat milling or LAG (using MeOH or MeCN as liquid additives) with LiOH and a stoichiometric amount of HB(Meim)₄ were not successful. Exploration of different milling times and η-values produced only mixtures of residual reactants with Li-BIF-2, Li-BIF-3, and/or not yet identified phases (see ESI^†). Consequently, we explored milling in the presence of 2-aminobutanol (amb), which is a ubiquitous component of solvent systems used in the solvothermal syntheses of BIFs.^32,33 Gratifyingly, using a mixture of amb and MeCN in a 1 : 3 ratio by volume as the milling liquid led to an effective strategy for the selective synthesis of both the dia-topology Li-BIF-2 (CSD code MOXKUG), and the SOD-topology Li-BIF-3 (CSD code MUCLOM).^‡ The selective formation of phase-pure samples of Li-BIF-2 and Li-BIF-3 was confirmed by PXRD analysis, which revealed an excellent match to diffractograms simulated based on the previously reported structures (Fig. 4B–G). Systematic exploration of reaction conditions, including time (between 15 and 60 minutes) and η value (between 0.25 and 1 μL mg⁻¹) revealed that the open framework Li-BIF-3 is readily obtained at η either 0.75 or 1 μL mg⁻¹ after milling for 45 minutes or longer (Fig. 4B–G, also see ESI^†).^§ Lower η-values of 0.25 and 0.5 μL mg⁻¹ preferred the formation of the dia-topology Li-BIF-2, which was obtained as a phase-pure material upon 60 minutes milling at η = 0.5 μL mg⁻¹, following the initial appearance of a yet unidentified intermediate. The preferred formation of Li-BIF-2 at lower η-values is consistent with our previous observations that lower amounts of liquid promote mechanochemical formation of denser MOF polymorphs.³⁷Open in a separate windowFig. 4(A) Reaction scheme for the mechanochemical synthesis of Li-BIF-3. Comparison of selected PXRD patterns for the synthesis of Li-BIF-2 and Li-BIF-3: (B) H[B(Meim)₄] reactant; (C) LiOH reactant; (D) simulated for Li-BIF-3 (CSD MUCLOM); (E) simulated for Li-BIF-2 (CSD MOXKUG); (F) Li-BIF-3 mechanochemically synthesized by LAG for 60 minutes with a 1 : 3 by volume mixture of amb and MeCN (η = 1 μL mg⁻¹); and (G) Li-BIF-2 mechanochemically synthesized by LAG for 60 minutes with a 1 : 3 by volume mixture of amb and MeCN (η = 0.5 μL mg⁻¹). Comparison of selected PXRD patterns for the synthesis of Cu-BIF-2 and Li-BIF-3: (H) Cu₂O; (I) Cu-BIF-3 (CSD MOXJOZ); (J) Cu-BIF-2 (CSD MUCLIG); (K) Cu-BIF-3 mechanochemically synthesised by ILAG for 60 minutes using NH₄NO₃ ionic additive (5% by weight) and MeOH (η = 1 μL mg⁻¹); and (L) mechanochemically synthesised Cu-BIF-2 by ILAG for 90 minutes using NH₄NO₃ ionic additive (5% by weight) and MeOH (η = 0.5 μL mg⁻¹).Samples of both Li-BIF-2 and Li-BIF-3 after washing with MeCN were further characterized by FTIR-ATR, TGA in air, and analysis of metal content by ICP-MS (see ESI^†). Nitrogen sorption measurement on the mechanochemically obtained Li-BIF-3, after washing with MeCN and evacuation at 85 °C, revealed a highly microporous material with a Brunauer–Emmett–Teller (BET) surface area of 1010 m² g⁻¹ (Fig. 5A), which is close to the value expected from the crystal structure of the material (1200 m² g⁻¹, 32 For direct comparison with previous work,³² we also calculated the Langmuir surface area, revealing an almost 40% increase (1060 m² g⁻¹) compared to samples made solvothermally (762.5 m² g⁻¹) (Fig. 5A, inset).Experimental Brunauer–Emmett–Teller (BET) and Langmuir surface area (in m² g⁻¹) of mechanochemically synthesized SOD-topology BIFs, compared to previously measured and theoretically calculated values, along with average particle sizes (in nm) established by SEM and calculated energies (in eV) for all Li-, Cu-, and Ag-BIF polymorphs. The difference between calculated energies for SOD- and dia-polymorphs in each system is given as ΔE (in kJ mol⁻¹)

Organocatalytic discrimination of non-directing aryl and heteroaryl groups: enantioselective synthesis of bioactive indole-containing triarylmethanes

Despite the enormous developments in asymmetric catalysis, the basis for asymmetric induction is largely limited to the spatial interaction between the substrate and catalyst. Consequently, asymmetric discrimination between two sterically similar groups remains a challenge. This is particularly formidable for enantiodifferentiation between two aryl groups without a directing group or electronic manipulation. Here we address this challenge by using a robust organocatalytic system leading to excellent enantioselection between aryl and heteroaryl groups. With versatile 2-indole imine methide as the platform, an excellent combination of a superb chiral phosphoric acid and the optimal hydride source provided efficient access to a range of highly enantioenriched indole-containing triarylmethanes. Control experiments and kinetic studies provided important insights into the mechanism. DFT calculations also indicated that while hydrogen bonding is important for activation, the key interaction for discrimination of the two aryl groups is mainly π–π stacking. Preliminary biological studies also demonstrated the great potential of these triarylmethanes for anticancer and antiviral drug development.

Excellent enantiodiscrimination between aryl and heteroaryl groups without a directing group has been achieved with organocatalysis. The highly enantioenriched triarylmethane products exhibit anticancer and antiviral activities.

Asymmetric catalysis has evolved arguably into the most powerful method for the synthesis of enantioenriched molecules.¹ It features high efficiency and atom-economy in principle as compared to other approaches such as chiral resolution and auxiliary-based asymmetric synthesis, thereby enabling increasing applications in industrial synthesis.² In the past few decades, a wide range of chiral catalytic systems with diverse activation modes have been developed. However, the fundamental basis for enantiocontrol remains essentially unchanged, i.e., spatial interaction between the substrate and catalyst.^1,2 For example, in the construction of a tetrahedral C(sp³)-chiral center from a prochiral C(sp²)-based planar substrate (e.g., carbocation, radical, carbonyl, and olefin), a chiral catalyst typically provides enantiodifferentiation by blocking one face of the plane and directing the reaction partner (Y) to approach towards the other face (Scheme 1a). To achieve this, the catalyst must be able to effectively discriminate between the two substituents (R¹ and R²) on the prochiral carbon. Obviously, the larger the difference of these two substituents is, the better enantioselectivity will be expected. Consequently, it has been well-established to achieve high enantioselectivity for cases bearing two sterically different groups (e.g., alkyl/aryl vs. H and large alkyl vs. small alkyl). In contrast, for cases bearing two substituents of a similar size, it remains challenging.¹Open in a separate windowScheme 1Introduction to asymmetric differentiation in C(sp²)-prochiral centers.1,1-Diarylmethinyl stereocenters are a widely prevalent structural motif in various natural products and biologically important molecules.³ Asymmetric addition to the 1,1-diaryl C C and C = X (X = heteroatom) bonds represents one of the most direct approaches for the construction of this unit.^4–8 However, this requires effective discrimination between two (often) sterically similar aryl groups, which represents a notable challenge in asymmetric catalysis (Scheme 1b).⁴ So far, success has mainly relied on the use of a directing group in one aryl group to allow catalyst recognition (e.g., by coordination) or electronic difference by incorporating electron-donating/withdrawing groups.^6,7 Notably, the effective enantiodifferentiation between aryl and heteroaryl groups still remains challenging, particularly in the absence of a directing group.⁸ Moreover, despite the above-mentioned important progress, it is worth noting that almost all these examples relied on metal catalysis, and little success has been achieved by organocatalysis.^4–8 In this context, here we describe organocatalytic discrimination of non-directing aryl and heteroaryl groups, providing access to highly enantioenriched triarylmethanes, and in view of the general diverse biological activities of triarylmethanes,⁹ we have also investigated the anticancer and antiviral activities of these products.Indole imine methides (IIMs) have recently emerged as versatile intermediates for the asymmetric synthesis of enantioenriched indole derivatives, a family of useful units in medicinal chemistry.^10–12 In particular, those with the methide motif adorned in the 2-position of indole are particularly useful to construct indole-fused polyheterocycles via asymmetric annulation processes, as pioneered by Shi and co-workers.^10,11 In continuation of our interest in IIMs,¹² we envisioned that these types of intermediates would be a good platform to study the power of organocatalysis for the challenging discrimination between aryl and heteroaryl groups lacking a directing group (Scheme 1c). However, additional challenges should be expected since this intermediate II is likely generated as a Z/E mixture, typically in equilibrium with carbocation I. Therefore, the equilibrium should be made in synergy with the nucleophilic addition step to allow dynamic asymmetric control in order to achieve high enantioselectivity.To test our hypothesis, we employed racemic tertiary alcohol 1a as the model precursor to the 2-indole imine methide intermediate. Notably, no directing group is incorporated in the two aryl groups (phenyl and thienyl) to be discriminated by the catalyst. Despite the above-mentioned substantial challenges in this asymmetric control, considerable efforts were devoted to condition optimization and ultimately led to excellent reaction efficiency and enantiocontrol (13 With benzothiazoline 2a as the hydride source,¹⁴ the asymmetric reduction proceeded smoothly to form indole-containing triarylmethane 3a under mild conditions in essentially quantitative yield and 95% ee (entry 1, 15 gave drastically low enantiocontrol (entry 8). Other solvents did not provide a better result either (entries 9–11). The reaction was very sensitive to coordinating solvents, such as ether and ethyl acetate, which completely shut down the reaction, presumably due to competing binding with the acid catalyst. Decreasing the reaction temperature to 0 °C maintained high enantioselectivity, but moderately affected the reaction rate (entry 12). Finally, at a higher concentration, slightly lower enantioselectivity was observed (entry 13).Evaluation of the reaction conditions^a

Hypervalent iodine-mediated β-difluoroalkylboron synthesis via an unusual 1,2-hydrogen shift enabled by boron substitution

β-Difluoroalkylborons, featuring functionally important CF₂ moiety and synthetically valuable boron group, have great synthetic potential while remaining synthetically challenging. Herein we report a hypervalent iodine-mediated oxidative gem-difluorination strategy to realize the construction of gem-difluorinated alkylborons via an unusual 1,2-hydrogen migration event, in which the (N-methyliminodiacetyl) boronate (BMIDA) motif is responsible for the high regio- and chemoselectivity. The protocol provides facile access to a broad range of β-difluoroalkylborons under rather mild conditions. The value of these products was demonstrated by further transformations of the boryl group into other valuable functional groups, providing a wide range of difluorine-containing molecules.

A hypervalent iodine-mediated gem-difluorination allows the facile synthesis of β-difluoroalkylborons. An unusual 1,2-hydrogen migration, triggered by boron substitution, is involved.

Organofluorine compounds have been widely applied in medicinal chemistry and materials science.^1a–d In particular, the gem-difluoro moiety featuring unique steric and electronic properties can act as a chemically inert isostere of a variety of polar functional groups.^2a–c Therefore, the construction of gem-difluoro-containing compounds has received considerable attention in recent years. Efficient methods including deoxyfluorination of carbonyl compounds,^3a,b photoredox difluorination,⁴ radical difluorination,⁵ and cross-coupling reactions with suitable CF₂ carriers^6a–f are well developed. Alternatively, iodoarene-mediated oxidative difluorination reactions provide valuable access to these motifs by using simple alkenes as starting materials.^7a–i Previously, these reactions were generally associated with a 1,2-aryl or 1,2-alkyl migration (Scheme 1a).^7a–f Recent developments also allowed the use of heteroatoms as migrating groups, thereby furnishing gem-difluoro compounds equipped with easily transformable functional groups (Scheme 1b). In this regard, Bi and coworkers reported an elegant 1,2-azide migrative gem-difluorination of α-vinyl azides, enabling the synthesis of a broad range of novel β-difluorinated alkyl azides.^7g Jacobsen developed an iodoarene-catalyzed synthesis of gem-difluorinated aliphatic bromides featuring 1,2-bromo migration with high enantioselectivity.^7h Almost at the same time, research work from our group demonstrated that not only bromo, but also chloro and iodo could serve as viable migrating groups.⁷ⁱOpen in a separate windowScheme 1Hypervalent iodine-mediated β-difluoroalkylboron synthesis.We have been devoted to developing new methodologies for the assembly of boron-containing building blocks by using easily accessible and stable MIDA (N-methyliminodiacetyl) boronates^8a–c as starting materials.^9a–e Recently, we realized a hypervalent iodine-mediated oxidative difluorination of aryl-substituted alkenyl MIDA boronates.^9d Depending on the substitution patterns, the reaction could lead to the synthesis of either α- or β-difluoroalkylborons via 1,2-aryl migration (Scheme 1c). Recently, with alkyl-substituted branched alkenyl MIDA boronates, Szabó and Himo observed an interesting bora-Wagner–Meerwein rearrangement, furnishing β-difluorinated alkylboronates with broader product diversity (Scheme 1d).¹⁰ While extending the scope of our previous work,^9d we found that the use of linear alkyl-substituted alkenyl MIDA boronates also delivers β-difluoroalkylboron products. Intriguingly, instead of an alkyl- or boryl-migration, an unusual 1,2-hydrogen shift takes place. It should be noted that internal inactivated alkenes typically deliver the 1,2-difluorinated products, with no rearrangement taking place.^11a–d Herein, we disclose our detailed study of our second generation of β-difluoroalkylborons synthesis (Scheme 1e). The starting linear 1,2-disubstituted alkyl-substituted alkenyl MIDA boronates, unlike the branched ones,¹⁰ could be readily prepared via a two-step sequence consisting of hydroborylation of the terminal alkyne and a subsequent ligand exchange with N-methyliminodiacetic acid. This intriguing 1,2-H shift was found to be closely related to the boron substitution, probably driven thermodynamically by the formation of the β-carbon cation stabilized by a σ(C–B) bond via hyperconjugation.^12a–dTo start, we employed benzyl-substituted alkenyl MIDA boronate 1a as a model substrate (9d the use of F sources such as CsF, AgF and Et₃N·HF in association with PhI(OAc)₂ (PIDA) as the oxidant and DCM as the solvent led to no reaction (entries 1 to 3). The use of Py·HF (20 equiv) successfully provided β-difluorinated alkylboronate 2a, derived from an unusual 1,2-hydrogen migration, in 39% yield (entry 4). By simply increasing the loading of Py·HF to 40 equivalents, a higher conversion and thus an improved yield of 61% was obtained (entry 5). No further improvement was observed by using a large excess of Py·HF (100 equiv) (entry 6). Other hypervalent iodine oxidants such as PhIO or PIFA were also effective but resulted in reduced yields (entries 7 and 8). A brief survey of other solvents revealed that the original DCM was the optimal one (entries 9 and 10).Optimization of reaction conditions

HydroFlipper membrane tension probes: imaging membrane hydration and mechanical compression simultaneously in living cells

HydroFlippers are introduced as the first fluorescent membrane tension probes that report simultaneously on membrane compression and hydration. The probe design is centered around a sensing cycle that couples the mechanical planarization of twisted push–pull fluorophores with the dynamic covalent hydration of their exocyclic acceptor. In FLIM images of living cells, tension-induced deplanarization is reported as a decrease in fluorescence lifetime of the dehydrated mechanophore. Membrane hydration is reported as the ratio of the photon counts associated to the hydrated and dehydrated mechanophores in reconvoluted lifetime frequency histograms. Trends for tension-induced decompression and hydration of cellular membranes of interest (MOIs) covering plasma membrane, lysosomes, mitochondria, ER, and Golgi are found not to be the same. Tension-induced changes in mechanical compression are rather independent of the nature of the MOI, while the responsiveness to changes in hydration are highly dependent on the intrinsic order of the MOI. These results confirm the mechanical planarization of push–pull probes in the ground state as most robust mechanism to routinely image membrane tension in living cells, while the availability of simultaneous information on membrane hydration will open new perspectives in mechanobiology.

HydroFlippers respond to membrane compression and hydration in the same fluorescence lifetime imaging microscopy histogram: the responses do not correlate.

The detection and study of membrane mechanics in living cells is a topic of current concern.^1–14 To enable this research, appropriate chemistry tools, that is small-molecule fluorescent probes that allow imaging of membrane tension, are needed.¹⁵ With the direct imaging of physical forces being intrinsically impossible, design strategies toward such probes have to focus on the suprastructural changes caused by changes in membrane tension.¹⁵ These suprastructural changes are divers, often interconnected, and vary with the composition of the membrane.^15–25 Beyond the fundamental lipid compression and decompression, they include changes in membrane curvature, from rippling, buckling and budding to tubules extending from the membrane and excess lipid being ejected. Of similar importance are changes in membrane organization, particularly tension-induced phase separation and mixing, i.e. assembly and disassembly of microdomains. Consequences of these suprastructural changes include microdomain strengthening and softening and changes in membrane hydration and viscosity.^16–25The currently most developed fluorescent flipper probes have been introduced^26,27 to image membrane tension by responding to a combination of mechanical compression and microdomain assembly in equilibrium in the ground state.¹⁵ Extensive studies, including computational simulations,²⁸ have shown that flipper probes align non-invasively along the lipid tails of one leaflet and report changes in membrane order and tension as changes in fluorescent lifetimes and shifts of excitation maxima.¹⁵ Among other candidates, solvatochromic probes respond off-equilibrium in the excited state to changes in membrane hydration and have very recently been considered for the imaging of membrane tension in living cells.^29–36 So far not considered to image tension, ESIPT probes also report off equilibrium in the excited state on membrane hydration, but for different reasons.^37,38 Mechanosensitive molecular rotors respond off equilibrium in the excited state to changes in microviscosity.^{17,30,32,39–53} The same principle holds for the planarization of bent, papillon or flapping fluorophores.^54–57 The response of all possible probes to tension can further include less desired changes in positioning and partitioning between different domains, not to speak of more catastrophic probe aggregation, precipitation, disturbance of the surrounding membrane structure, and so on. Although the imaging of membrane tension is conceivable in principle with most of above approaches, the complex combination of parameters that has to be in place can thus far only be identified empirically, followed by much optimization.¹⁵The force-induced suprastructural changes are accompanied by the alteration in several unrelated physical properties of membranes. It is, for instance, well documented that membrane hydration increases with membrane disorder, from solid-ordered (S_o) to liquid-disordered (L_d) phases.^29,58 Increasing cholesterol content decreases membrane hydration in solid- and liquid-ordered membranes.⁵⁹ However, studies in model membranes also indicate that membrane hydration and membrane fluidity do not necessarily correlate.⁵⁹ The dissection of the individual parameters contributing to the response of fluorescent membrane tension probes would be important for probe design and understanding of their responses, but it remains a daunting challenge. In this study, we introduce fluorescent flipper probes that simultaneously report on mechanical membrane compression and membrane hydration at equilibrium in the ground state. Changes of both in response to changes in membrane tension and membrane composition are determined in various organelles in living cells.The dual hydration and membrane tension probes are referred to as HydroFlippers to highlight the newly added responsiveness to membrane hydration. The mechanosensing of lipid compression in bilayer membranes by flipper probes has been explored extensively.¹⁵ Fluorescent flippers²⁷ like 1 are designed as bioinspired⁶⁰ planarizable push–pull probes²⁶ (Fig. 1). They are constructed from two dithienothiophene fluorophores that are twisted out of co-planarity by repulsion of methyls and σ holes on sulfurs^61,62 next to the twistable bond. The push–pull system is constructed first from formal sulfide and sulfone redox bridges in the two twisted dithienothiophenes. These endocyclic donors and acceptors are supported by exocyclic ones, here a trifluoroketone acceptor and a triazole donor.⁶³ To assure stability, these endo- and exocyclic donors are turned off in the twisted ground state because of chalcogen bonding and repulsion, respectively.⁶²Open in a separate windowFig. 1The dual sensing cycle of HydroFlippers 1–5, made to target the indicated MOIs in living cells and responding to membrane compression by planarization and to membrane hydration by dynamic covalent ketone hydration. With indication of excitation maxima (ref. 63) and fluorescence lifetimes (this study).Mechanical planarization of the flipper probe establishes conjugation along the push–pull systems, electrons flow from endocyclic donors to acceptors, which turns on the exocyclic donors and acceptors to finalize the push–pull system.⁶² This elaborate, chalcogen-bonding cascade switch has been described elsewhere in detail, including high-level computational simulations.⁶² The planar high-energy conformer 1dp excels with red shifted excitation and increased quantum yield and lifetime compared to the twisted conformer 1dt because the less twisted Franck-Condon state favors emission through planar intramolecular charge transfer (PICT) over non-radiative decay through twisted ICT, or conical intersections.¹⁵Flipper probe 1 was considered for dual responsiveness to membrane tension and hydration because of the trifluoroketone acceptor.⁶³ Dynamic covalent hydration of 1dt yields hydrate 1ht.^64–76 Blue-shifted excitation and short lifetime of 1ht are not expected to improve much upon planarization because the hydrate is a poor acceptor and thus, the push–pull system in 1hp is weak. The dynamic covalent chemistry of the trifluoroketone acceptor has been characterized in detail in solution and in lipid bilayer membranes.⁶³To explore dual responsiveness to membrane tension in any membrane of interest (MOI) in living cells, HydroFlippers 2–5 were synthesized. While HydroFlipper 1 targets the plasma membrane (PM), HydroFlippers 2–4 were equipped with empirical targeting motifs.⁷⁷ HydroFlipper 5 terminates with a chloroalkane to react with the self-labeling HaloTag protein, which can be expressed in essentially any MOI.⁷⁸ Their substantial multistep synthesis was realized by adapting reported procedures (Schemes S1–S4^†).The MOIs labeling selectivity of HydroFlippers was determined in HeLa Kyoto (HK) cells by confocal laser scanning microscopy. Co-localization experiments of flippers 1–4 with the corresponding trackers gave Pearson correlation coefficients (PCCs) >0.80 for the targeting of mitochondria, lysosomes and the endoplasmic reticulum (ER, Fig. S4–S6^†). HydroFlipper 5 was first tested with stable HGM cells, which express both HaloTag and GFP on mitochondria (referred to as 5_M).^78,79 The well-established chloroalkane penetration assay demonstrated the efficient labeling of HaloTag protein by 5 as previously reported HaloFlippers (Fig. S3^†).⁷⁸ By transient transfection, HydroFlippers 5 were also directed to lysosomes (5_L), Golgi apparatus (GA, 5_G)⁸⁰ and peroxisomes (5_P) with HaloTag and GFP expressed on their surface.⁷⁸ PCCs >0.80 for co-localization of flipper and GFP emission confirmed that MOI labeling with genetically engineered cells was as efficient as with empirical trackers (Fig. S7–S11^†).Dual imaging of membrane compression and hydration was envisioned by analysis of fluorescence lifetime imaging microscopy (FLIM) images using a triexponential model (Fig. 2).⁸¹ FLIM images of ER HydroFlipper 4 in iso-osmotic HK cells were selected to illustrate the concept (Fig. 3a). Contrary to classical flipper probes, the fluorescence decay curve of the total FLIM image (Fig. 2a, grey) showed a poor fit to a biexponential model (Fig. 2a, cyan, b). Consistent with their expected dual sensing mode, a triexponential fit was excellent (Fig. 2a, dark blue, c). Lifetimes τ_1i = 4.3 ns (†) were obtained besides background. This three-component model was then applied to every pixel of FLIM images (Fig. 3c). The resulting reconvoluted FLIM histogram revealed three clearly separated populations for τ₁ (red), τ₂ (green), and background (τ₃, blue, Fig. 2d). Maxima of these three clear peaks were at the lifetimes estimated by triexponential fit of the global decay curve, thus demonstrating the validity of the methodology at necessarily small photon counts. Irreproducible fitting would give randomly scattered data without separated peaks.Open in a separate windowFig. 2(a) Fluorescence decay curve (grey, corresponding to the total image, not to a single pixel) with biexponential (cyan) and triexponential fit (dark blue). (b, c) Residual plots for bi- (b) and triexponential fit (c). (d) Histogram with the intensities associated with the τ₁ (red), τ₂ (green), and τ₃ (blue, background) components obtained by triexponential fit of the fluorescence decay curve of each pixel of the FLIM image, fit to Gaussian function (black solid curves).Open in a separate windowFig. 3FLIM images of HK cells labelled with ER flipper 4 before (a, c) and after (b, d) hyper-osmotic shock, showing average lifetimes τ_av (a, b) and τ₁ (c, d) from triexponential reconvolution; scale bars = 10 μm. (e) Distribution of the photon counts associated with the τ₁ component of 4 in HK cells after triexponential reconvolution of FLIM images before (c, τ_1i) and after (d, τ_1h) hyper-osmotic shock, showing decreasing lifetimes for τ₁ (4d). (f) The dehydration factor dh_i defined as total integrated photon counts for τ₁ (Στ₁) divided by Στ₂ (i.e., dh_i = area Στ_1i/area Στ_2i) for 4 in strongly hydrated ER (dh_i < 2, turquoise) and 1 in weakly hydrated plasma membrane (dh_i > 6, purple) of HK Kyoto cells under iso-osmotic conditions.Dual response of HydroFlippers to changes in membrane tension^a

Difluorination of α-(bromomethyl)styrenes via I(I)/I(III) catalysis: facile access to electrophilic linchpins for drug discovery

Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis. This inexpensive main group catalysis strategy employs p-TolI as an effective organocatalyst when combined with Selectfluor® and simple amine·HF complexes. Modulating Brønsted acidity enables simultaneous geminal and vicinal difluorination to occur, thereby providing a platform to generate multiply fluorinated scaffolds for further downstream derivatization. The method facilitates access to a tetrafluorinated API candidate for the treatment of amyotrophic lateral sclerosis. Preliminary validation of an enantioselective process is disclosed to access α-phenyl-β-difluoro-γ-bromo/chloro esters.

Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis.

Structural editing with fluorine enables geometric and electronic variation to be explored in functional small molecules whilst mitigating steric drawbacks.¹ This expansive approach to manipulate structure–function interplay continues to manifest itself in bio-organic and medicinal chemistry.² Of the plenum of fluorinated motifs commonly employed, the geminal difluoromethylene group³ has a venerable history.⁴ This is grounded in the structural as well as electronic ramifications of CH₂ → CF₂ substitution, as is evident from a comparison of propane and 2,2-difluoropropane (Fig. 1, upper). Salient features include localized charge inversion (C–H^δ+ to C–F^δ−) and a widening of the internal angle from 112° to 115.4°.⁵ Consequently, geminal difluoromethylene groups feature prominently in the drug discovery repertoire⁶ to mitigate oxidation and modulate physicochemical parameters. Catalysis-based routes to generate electrophilic linchpins that contain the geminal difluoromethylene unit have thus been intensively pursued, particularly in the realm of main group catalysis.^7–9 Motivated by the potential of this motif in contemporary medicinal chemistry, it was envisaged that an I(I)/I(III) catalysis platform could be leveraged to convert simple α-(bromomethyl)styrenes to gem-difluorinated linchpins: the primary C(sp³)–Br motif would facilitate downstream synthetic manipulations (Fig. 1, lower). To that end, p-TolI would function as a catalyst to generate p-TolIF₂in situ in the presence of an external oxidant¹⁰ and an amine·HF complex. Alkene activation (I) with subsequent bromonium ion formation (II)¹¹ would provide a pre-text for the first C–F bond forming process (III) with regeneration of the catalyst. A subsequent phenonium ion rearrangement¹²/fluorination sequence (III and IV) would furnish the geminal difluoromethylene group and liberate the desired electrophilic building block.Open in a separate windowFig. 1The geminal difluoromethylene group: bioisosterism, and catalysis-based access from α-(bromomethyl)styrenes via I(I)/I(III) catalysis.To validate this conceptual framework, a short process of reaction optimization (1a → 2a) was conducted to assess the influence of solvent, amine·HF ratio (Brønsted acidity)¹³ and catalyst loading (Table 1). Initial reactions were performed with p-TolI (20 mol%), Selectfluor® (1.5 equiv.) as an oxidant, and CHCl₃ as the reaction medium. Variation of the amine : HF ratio was conducted to explore the influence of Brønsted acidity on catalysis efficiency (entries 1–4). An optimal ratio of 1 : 6 was observed enabling the product 2a to be generated in >95% NMR-yield. Although reducing the catalyst loading to 10 and 5 mol% (entries 5 and 6, respectively) led to high levels of efficiency (79% yield with 5 mol%), the remainder of the study was performed with 20 mol% p-TolI. Notably, catalytic vicinal difluorination was not observed at any point during this optimization, in contrast with previous studies from our laboratory.^9d,i A solvent screen revealed the importance of chlorinated solvents (entries 7 and 8): in contrast, performing the reaction in ethyl trifluoroacetate (ETFA) and acetonitrile resulted in a reduction in yield (9 and 10). Finally, a control reaction in the absence of p-TolI confirmed that an I(I)/I(III) manifold was operational (entry 11). An expanded optimization table is provided in the ESI.^†Reaction optimization^a