Asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative. The [6,6]-bicyclic decalin B–C ring and the all-carbon quaternary stereocenter at C-6 were prepared via a desymmetric intramolecular Michael reaction with up to 97% ee. The naphthalene diol D–E ring was constructed through a sequence of Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder, dehydration, and aromatization reactions. This asymmetric strategy provides a scalable route to prepare target molecules and their derivatives for further biological studies.

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative.

Various halenaquinone-type natural products with promising biological activity have been isolated from marine sponges of the genus Xestospongia¹ from the Pacific Ocean. (+)-Halenaquinone (1),^2,3 (+)-xestoquinone (2), and (+)-adociaquinones A (3) and B (4)^4,5 bearing a naphtha[1,8-bc]furan core (Fig. 1) are the most typical representatives of this family. Naturally occurring (−)-xestosaprol N (5) and O (6)^6,7 have the same structure as 3 and 4 except for a furan ring, while a naphtha[1,8-bc]furan core can also be found in fungus-isolated furanosteroids (−)-viridin (7) and (+)-nodulisporiviridin E (8)^8,9 (Fig. 1). Halenaquinone (1) was first isolated from the tropical marine sponge Xestospongia exigua² and it shows antibiotic activity against Staphylococcus aureus and Bacillus subtilis. Xestoquinone (2) and adociaquinones A (3) and B (4) were firstly isolated, respectively, from the Okinawan marine sponge Xestospongia sp.^4a and the Truk Lagoon sponge Adocia sp.,^4b and they show cardiotonic,^4a,c cytotoxic,^4b,i antifungal,⁴ⁱ antimalarial,^4j and antitumor^4l activities. These compounds inhibit the activity of pp60v-src protein tyrosine kinase,^4d topoisomerases I^4e and II,^4f myosin Ca²⁺ ATPase,^4c,g and phosphatases Cdc25B, MKP-1, and MKP-3.^4h,kOpen in a separate windowFig. 1Structure of halenaquinone-type natural products and viridin-type furanosteroids.Owing to their diverse bioactivities, the synthesis of this family of natural compounds has been extensively studied, with published pathways making use of Diels–Alder,^{3a,d,e,5a–c,e,g} furan ring transfer,^5b Heck,^{3b,c,5f,7,9b,d} palladium-catalyzed polyene cyclization,^5d Pd-catalyzed oxidative cyclization,^3f and hydrogen atom transfer (HAT) radical cyclization^9c reactions. In this study, we report the asymmetric total synthesis of (+)-xestoquinone (2), (−)-xestoquinone (2′), and (+)-adociaquinones A (3) and B (4) (Fig. 1).The construction of the fused tetracyclic B–C–D–E skeleton and the all carbon quaternary stereocenter at C-6 is a major challenge towards the total synthesis of xestoquinone (2) and adociaquinones A (3) and B (4). Based on our retrosynthetic analysis (Scheme 1), the all-carbon quaternary carbon center at C-6 of cis-decalin 12 could first be prepared stereoselectively from the achiral aldehyde 13via an organocatalytic desymmetric intramolecular Michael reaction.^10,11 The tetracyclic framework 10 could then be formed via a Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder (PEDA) reaction^12–16 of 11 and enone 12. Acid-mediated cyclization of 10 followed by oxidation state adjustment could be subsequently applied to form the furan ring A of xestoquinone (2). Finally, based on the biosynthetic pathway of (+)-xestoquinone (2)^4b,5c and our previous studies,⁷ the heterocyclic ring F of adociaquinones A (3) and B (4) could be prepared from 2via a late-stage cyclization with hypotaurine (9).Open in a separate windowScheme 1Retrosynthetic analysis of (+)-xestoquinone and (+)-adociaquinones A and B.The catalytic enantioselective desymmetrization of meso compounds has been used as a powerful strategy to generate enantioenriched molecules bearing all-carbon quaternary stereocenters.^10,11 For instance, two types of asymmetric intramolecular Michael reactions were developed using a cysteine-derived chiral amine as an organocatalyst by Hayashi and co-workers,^11a,b while a desymmetrizing secondary amine-catalyzed asymmetric intramolecular Michael addition was later reported by Gaunt and co-workers to produce enantioenriched decalin structures.^11c Prompted by these pioneering studies and following the suggested retrosynthetic pathway (Scheme 1), we first screened conditions for organocatalytic desymmetric intramolecular Michael addition of meso-cyclohexadienone 13 (Table 1) in order to form the desired quaternary stereocenter at C-6. Compound 13 was easily prepared on a gram scale via a four-step process (see details in the ESI^†).Attempts of organocatalytic desymmetric intramolecular Michael addition^a

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

Palladium/GF-Phos-catalyzed asymmetric carbenylative amination to access chiral pyrrolidines and piperidines

The cross-coupling of N-tosylhydrazones has emerged as a powerful method for the construction of structurally diverse molecules, but the development of catalytic enantioselective versions still poses considerable challenges and only very limited examples have been reported. We herein report an asymmetric palladium/GF-Phos-catalyzed carbenylative amination reaction of N-tosylhydrazones and (E)-vinyl iodides pendent with amine, which allows facile access to a range of chiral pyrrolidines and piperidines in good yields (45–93%) with up to 96.5 : 3.5 er. Moreover, mild conditions, general substrate scope, scaled-up preparation, as well as the efficient synthesis of natural product (−)-norruspoline are practical features of this method.

An efficient asymmetric palladium/GF-Phos-catalyzed carbenylative amination reaction to access structurally diverse chiral pyrrolidines and piperidines in good yields with high chemo-, regio- and enantioselectivities has been developed.

N-tosylhydrazones, readily prepared from aldehydes or ketones, served as a safe source of carbene precursors and have attracted much attention of chemists.¹N-tosylhydrazone-mediated applications have been continuously developed, such as cyclopropanation or cyclopropenation, X–H insertion, ylide formation, cycloaddition, aza-Wacker-type cyclization, asymmetric allylic substitution, etc.² Among them, transition-metal-catalyzed cross-coupling is one of the powerful protocols for C–X or C C bond formation in organic synthesis involving versatile intermediates, of which in situ generation of diazo compounds and carbene migratory insertion are considered key steps.^3–5 Over the past decades, considerable progress has been made in the asymmetric cross-coupling reactions of N-tosylhydrazones with various coupling partners, including cyclobutanols, terminal alkynes, silacyclobutanes and so on.⁴ Relatively, only a few examples focus on the cross-coupling reactions of aryl halides with N-tosylhydrazones involving benzyl metal intermediates [Scheme 1A, eqn. (a)].⁶ For example, Gu,^6a Wu,^6b Lassaletta^6c and coworkers have developed a palladium-catalyzed asymmetric synthesis of axial chiral compounds from aryl bromides and N-tosylhydrazones, ending with β-H elimination. Very recently, we realized palladium/GF-Phos catalyzed asymmetric three component cross-coupling reactions of aryl halides, N-tosylhydrazones, with terminal alkynes.^6f In contrast, much less progress has been made in N-tosylhydrazone-based carbenylative insertions from vinyl halides, which would generate a π-allylic metal intermediate followed by nucleophile attack, providing a unique approach for building C–X bonds, especially for N-heterocyclic compounds [Scheme 1A, eqn. (b)].⁷N-heterocycles are important structural motifs for the development of various types of valuable chemicals and materials.⁸ Importantly, optically active 2-substituted pyrrolidine and piperidine derivatives are privileged scaffolds in many natural products and pharmaceuticals with a wide range of biological activities,⁹ as well as the backbone of organocatalysts in asymmetric catalysis (Fig. 1).¹⁰Open in a separate windowScheme 1Asymmetric transition-metal-catalyzed carbenylative cross-coupling reactions.Open in a separate windowFig. 1Selected natural products and pharmaceuticals containing chiral 2-substituted pyrrolidine and piperidine units.Notably, Van Vranken and coworkers reported an elegant palladium-catalyzed carbenylative amination reaction of N-tosylhydrazones and (E)-vinyl iodides pendent with amine, providing facile access to pyrrolidine and piperidine ring systems that are common to alkaloid natural products (Scheme 1B).¹¹ Unfortunately, only up to 58.5 : 41.5 er was obtained after they made a lot of efforts to screen a series of chiral phosphine ligands, indicating that this asymmetric reaction indeed poses considerable challenges in addition to competitive side reactions such as the dimerization of vinyl iodides,¹² the formation of diene via the palladatropic rearrangement/β-H elimination or allene via β-H elimination from C_sp²,¹³ and the π-allylpalladium intermediate trapped by the byproduct sulfinic acid salt.¹⁴ Given the significance of chiral pyrrolidines and piperidines as core structures in alkaloid natural products, the development of an asymmetric version of this elegant carbenylative amination reaction is highly desirable. In recent years, our group has developed a series of chiral sulfinamide phosphine ligands (so-called Sadphos), which showed unique potential in asymmetric transition-metal catalysis,^6f,15 so we wondered whether Sadphos could address this challenging asymmetric carbenylative amination reaction (Scheme 1C).Initially, our study began with (E)-vinyl iodide 1a and N-tosylhydrazone 2a in the presence of Pd₂(dba)₃, t-BuOLi, Et₃N, and triethylbenzylammonium chloride (TEBAC) in THF at 30 °C. A series of commercially available chiral ligands were first screened (Fig. 2). Only (R, R)-DIOP (L1), (R)-DTBM-SegPhos (L3) and (R)-MOP (L4) provided the desired product 3aa with poor enantioselectivity and other ligands such as (R, R)-Ph-BPE (L2), (R, S)-Josiphos (L5) and (S, S)-ⁱPr-FOXAP (L6) showed low reactivity. We next turned to systematically investigate Sadphos, such as Wei-Phos,¹⁶ Xiao-Phos,^15d,17 Ming-Phos,^15a,18 Xu-Phos,^15b,19 Xiang-Phos²⁰ and PC-Phos^15c,21 (Fig. 2). To our delight, PC1 delivered 3aa in 32% yield and 85.5 : 14.5 er. Inspired by this result, we further screened PC2–PC5 which vary in the substituent of phenyl, but unfortunately none of them showed better results. Surprisingly, the reactivity of this reaction could be greatly improved with our recently developed GF-Phos GF1, delivering 71% yield. When steric hindered tert-butyl groups were introduced on the phenyl group (GF2), the product 3aa was obtained in 77% yield with 91.5 : 8.5 er. After screening different palladium catalysts and solvents (Open in a separate windowFig. 2Screened chiral ligands.Optimization of reaction conditions^a

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

Reductive radical-initiated 1,2-C migration assisted by an azidyl group

We report here a novel reductive radical-polar crossover reaction that is a reductive radical-initiated 1,2-C migration of 2-azido allyl alcohols enabled by an azidyl group. The reaction tolerates diverse migrating groups, such as alkyl, alkenyl, and aryl groups, allowing access to n+1 ring expansion of small to large rings. The possibility of directly using propargyl alcohols in one-pot is also described. Mechanistic studies indicated that an azidyl group is a good leaving group and provides a driving force for the 1,2-C migration.

We report here a novel reductive radical-polar crossover reaction that is a reductive radical-initiated 1,2-C migration of 2-azido allyl alcohols enabled by an azidyl group.

Since the groups of Ryu and Sonoda described the reductive radical-polar crossover (RRPCO) concept in the 1990s,¹ it has attracted considerable attention in modern organic synthesis.² By using this concept, a variety of complex molecules could be assembled in a fast step-economic fashion which is not possible using either radical or polar chemistry alone. However, only two RRPCO reaction modes are known to date: nucleophilic addition and nucleophilic substitution (Fig. 1A). The first RRPCO reaction is the nucleophilic addition of organometallic species, which is generated in situ from the reduction of a strong reducing metal with a carbon-centered radical intermediate and cations (E⁺ = H⁺, I⁺, Br⁺, path 1).³ However, the necessity for a large amount of harmful and strong reducing metals has greatly limited the scope and functional group tolerance of the reaction. Recently, photoredox catalysis has not only successfully overcome the shortcomings of using toxic strong reducing metals in the RRPCO reaction,⁴ but also enabled the development of several new RRPCO reaction types, including the nucleophilic addition with carbonyl compounds or carbon dioxide (path 2),⁵ the cyclization of alkyl halides/tosylates (path 3),⁶ and β-fluorine elimination (path 4).⁷ Although the RRPCO reaction has been greatly advanced by photoredox catalysis, it is still in its infancy, and the development of a novel RRPCO reaction is of great importance.Open in a separate windowFig. 1(A) Reductive radical-polar crossover reactions; (B) this work: reductive radical-initiated 1,2-C migration assisted by an azidyl group.Herein, we wish to report a new type of reductive radical-polar crossover cascade reaction that is the reductive radical-initiated 1,2-C migration under metal-free conditions (Fig. 1B). The development of this approach is not only to further expand the application of the RRPCO reaction, but also to solve the problems associated with the oxidative radical-initiated 1,2-C migration, such as the necessity for an oxidant and/or transition metal for the oxidative termination of the radicals, and also required sufficient ring strain to avoid the generation of epoxy byproducts.⁸ To realize this reaction, a driving force is needed to drive the 1,2-C migration after reductive termination, to avoid the otherwise inevitable protonation of the generated anion.⁹ Inspired by the leaving group-induced semipinacol rearrangement,¹⁰ we envisaged that 2-azidoallyl alcohols¹¹ might be the ideal substrates for the reductive radical-initiated 1,2-C migration because these compounds contain both an allylic alcohol motif, which is vital for the radical-initiated 1,2-C migration, and an azidyl group, a good leaving group,¹² which may facilitate the 1,2-C migration after the reductive termination of the radicals.With the optimal conditions established (ESI, Table S1^†), we then explored the scope of this radical-initiated 1,2-migration. As shown in Table 1, a series of naphthenic allylic alcohols could undergo n+1 ring expansion with minimal impact on the product yield (Table 1, 3aa–aq). Notably, only the alkyl groups were migrated when using benzonaphthenic allylic alcohols in the reaction. These results might be attributed to the aryl group possessing greater steric resistance. The structure of 3an was further verified by single-crystal diffraction. Interestingly, the vinyl azide derived from a pharmaceutical ethisterone was also a viable substrate, affording the migration product 3aq in 57% yield, which highlighted the applicability of this strategy in the late-stage modification of pharmaceuticals. Moreover, the acyclic allylic alcohol with an alkyl chain also successfully delivered the migration product 3ar in 64% yield.Substrate scope of 2-azidoallyl alcohols^ab

Development of an active site titration reagent for α-amylases

α-Amylases are among the most widely used classes of enzymes in industry and considerable effort has gone into optimising their activities. Efforts to find better amylase mutants, such as through high-throughput screening, would be greatly aided by access to precise and robust active site titrating agents for quantitation of active mutants in crude cell lysates. While active site titration reagents designed for retaining β-glycosidases quantify these enzymes down to nanomolar levels, convenient titrants for α-glycosidases are not available. We designed such a reagent by incorporating a highly reactive fluorogenic leaving group onto unsaturated cyclitol ethers, which have been recently shown to act as slow substrates for retaining glycosidases that operate via a covalent ‘glycosyl’-enzyme intermediate. By appending this warhead onto the appropriate oligosaccharide, we developed efficient active site titration reagents for α-amylases that effect quantitation down to low nanomolar levels.

α-Amylases are among the most widely used classes of enzymes in industry and considerable effort has gone into optimising their activities.

Amylases are among the most common classes of enzymes employed in industrial settings, being used in detergents, bread, beer, biofuel, and many other sectors. Accordingly, α-amylases account for 25% of the world''s multi-billion dollar enzyme market.^1,2 α-Amylases are endo-acting enzymes that cleave starch into malto-oligosaccharides, which are further degraded by exo-acting α-glucosidases, glucoamylases, β-amylases and α-glucan phosphorylases and lyases. They are found in CAZy GH families 13, 57, 119 and 126, with the vast majority in the large GH13 family.³ GH13 enzymes adopt a (β/α)₈ fold with three highly conserved active site carboxylic acids.^4–6 They employ a classical double-displacement mechanism⁷ in which one of the glutamic acids provides acid catalytic assistance to the leaving group departure while an aspartate attacks the anomeric centre, forming a covalent glycosyl enzyme intermediate. In a second step, water attacks the anomeric centre with base assistance from the glutamate residue (Fig. 1A and B).Open in a separate windowFig. 1Koshland mechanism of retaining β- and α-glycosidases (A & B). The same mechanism has been observed for the hydrolysis of “β”-valienols (C), and for “α”-valienols (D).Given their industrial importance, a huge amount of attention has been given to the discovery and improvement of α-amylases to attain optimal performance for particular applications. These approaches typically require high-throughput analysis of large numbers of gene products or mutants thereof.^8–10 Identification of the best candidates then ideally requires high-throughput assay coupled with a method for determining the enzyme concentration in each sample. This can be a challenging task in the absence of purification, as would be the case for truly high-throughput approaches. The “gold standard” method to quantify active enzyme concentration is active site titration.¹¹ Active site titrants react stoichiometrically with their target enzymes and release one equivalent of a quantifiable agent, which is typically either a chromophore or fluorophore. For enzymes that operate via a covalent intermediate, such as retaining glycosidases, the active site titrants are usually chromogenic or fluorogenic substrates that form this intermediate with a rate constant (k_on) that is much greater than that for its hydrolysis (k_off) – ideally with k_off approaching zero.Our lab has previously developed active site titration reagents for several retaining β-glycosidases^12,13 and neuraminidases.^14,15 By replacing the substituent on the position adjacent to the anomeric centre of the sugar (the hydroxyl at C-2 for many monosaccharides) with a fluorine atom, both the formation and the hydrolysis of the glycosyl-enzyme intermediate are slowed, largely through inductive destabilisation of the transition state. Further incorporation of a reactive fluorogenic leaving group generates a reagent that, upon covalently inactivating the glycosidase, releases a stoichiometric and quantifiable amount of fluorophore. The fluorogenic response is then measured to determine the amount of active glycosidase that is present in solution.Unfortunately, this same strategy does not work for retaining α-glycosidases. In those cases, k_off remains greater than k_on, likely due to the inherently greater reactivity of the β-glycosyl-enzyme intermediate,^16,17 and the compounds are simply substrates with low turnover numbers. By use of 2,2-dihalosugars with yet more reactive leaving groups, this problem could be solved in some cases, but their synthesis is challenging, and inactivation rates were low, or non-existent in some cases.^18,19 Alternative approaches were called for.Recently, a new class of glycosidase substrates was reported in which the sugar moiety is replaced by an equivalently hydroxylated cyclohexene.^20–23 Hydrolysis of these enol ethers likely occurs via an allylic cation of almost identical reactivity to that of the equivalent oxocarbenium ion. Glycosidases cleave these substrates via the classical Koshland mechanism⁷ (Fig. 1C and D), but considerably more slowly than their natural substrates. However, incorporation of a good leaving group will accelerate, relatively, the first step such that, in some cases, they act as mechanism-based inactivators making them candidates for development of an active site titrant for α-amylases.Since α-amylases are endo-acting enzymes that do not usually cleave monosaccharide glycosides, an ‘extended” oligosaccharide version containing a total of 2 or 3 sugar/pseudosugar moieties would be needed. Substrates longer than this would be prone to internal glycoside cleavage. Since 2-chloro-4-nitrophenyl maltotrioside (CNP-G3) functions as a substrate for most amylases, we focused on addition of a maltosyl unit to a valienol moiety containing a 6,8-difluorocoumarin (F₂MU) leaving group at its “anomeric centre”. The low pK_a of this coumarin, 4.7,¹⁴ results in a greater reactivity of the reagent and also ensures the coumarin will be deprotonated and thus fluorescent, upon release at neutral pH.Synthesis of partially protected alcohol 2 from gluconolactone 1via literature methods²⁴ was followed by attachment of F₂MU via a Mitsunobu reaction and subsequent removal of the protecting groups under acidic conditions, generating known pseudo-glycoside 3.²³ To check this concept before we synthesized the longer version, we tested compound 3 as a titrant of a simple α-glucosidase and found that it did indeed titrate the enzyme (Fig. S5^†). Since elongation of this pseudosugar via classical organic synthesis would require substantial protecting group chemistry, we elected instead to employ an enzymatic coupling strategy using the GH13 cyclodextrin transglycosidase, CGTase. This enzyme can use glycosyl fluorides, such as α-maltosyl fluoride, to effect glycosyl transfer onto suitable acceptors. However, a significant competing reaction would involve self-condensation of glycosyl fluorides ultimately forming cyclodextrins. To avoid this problem, we employed a maltosyl fluoride donor (4), in which the 4′-hydroxyl had been capped with a methyl group.^25,26 Incorporation of 4′-methoxy groups does not alter the reaction with α-amylases, as this site in the normal substrate is occupied by additional sugar residues. Thus CGTase-catalysed glycosylation between known glycosyl fluoride 4 and pseudo-glycoside 3, gave the pseudo-trisaccharide 5 in 64% isolated yield (Scheme 1).Open in a separate windowScheme 1Synthesis of titration reagent 5.With this reagent in hand, we proceeded to screen its ability to inactivate a small panel of α-amylases. As shown in Fig. 2, time-dependent inactivation was observed for all enzymes tested, with the most industrially relevant enzymes, Effusibacillus pohliae amylase (EPA) and Aspergillus oryzae amylase (AOA), being inactivated the fastest.Open in a separate windowFig. 2Time-dependent inactivation of a small panel of amylases, showing remaining % activity versus time. Red box with X: AOA (91 nM); blue square: EPA (66.7 nM); purple cross: PPA (500 nM); green triangle: HPA (125 nM). AOA = A. oryzae amylase; EPA = E. pohliae amylase; HPA = human pancreatic amylase; PPA = porcine pancreatic amylase.Kinetic parameters for inactivation were then determined by directly monitoring the release of F₂MU by UV-Vis (Table 1). To determine k_on and k_off (Scheme 2), we monitored chromophore (F₂MU) release by absorbance at 370 or 380 nm (dependent on the concentration of 5 in the measurements of each enzyme). After mixing 5 with each enzyme individually, a burst phase followed by a steady-state phase was observed. For each enzyme, this was then repeated with varying concentrations of 5. Initial rates of F₂MU release versus concentration of 5 were fit to a Michaelis–Menten equation to provide k_on. The rate constant of cyclitol release, k_off, was determined by measuring rates of the steady-state region at a saturating concentration (5× K_i). We found that several amylases: Effusibacillus pohliae amylase (EPA), Aspergillus oryzae amylase (AOA), Rhizomucor pusillus amylase (RPA) and porcine pancreatic amylase (PPA), inactivated quickly (highest k_on, lowest k_off, and greatest k_on/K_i), and are therefore ideal candidates for titration with compound 5. Human pancreatic amylase (HPA), on the other hand, while inactivating rapidly, binds the reagent relatively poorly.Open in a separate windowScheme 2Kinetic parameters for the hydrolysis of 5 by several amylases (at 25 °C for EPA, AOA, and RPA and 30 °C for human pancreatic amylase [HPA] and porcine pancreatic amylase [PPA])

3-Aminooxetanes: versatile 1,3-amphoteric molecules for intermolecular annulation reactions

Despite the versatility of amphoteric molecules, stable and easily accessible ones are still limitedly known. As a result, the discovery of new amphoteric reactivity remains highly desirable. Herein we introduce 3-aminooxetanes as a new family of stable and readily available 1,3-amphoteric molecules and systematically demonstrated their amphoteric reactivity toward polarized π-systems in a diverse range of intermolecular [3 + 2] annulations. These reactions not only enrich the reactivity of oxetanes, but also provide convergent access to valuable heterocycles.

Despite the versatility of amphoteric molecules, stable and easily accessible ones are still limitedly known.

Amphoteric molecules, which bear both nucleophilic and electrophilic sites with orthogonal reactivity, represent an attractive platform for the development of chemoselective transformations.¹ For example, isocyanides are well-established 1,1-amphoteric molecules, with the terminal carbon being both nucleophilic and electrophilic, and this feature has enabled their exceptional reactivity in numerous multi-component reactions.² In the past few decades, substantial effort has been devoted to the search for new amphoteric molecules.^1–5 Among them, 1,3-amphoteric molecules proved to be versatile. The Yudin and Beauchemin laboratories have independently developed two types of such molecules, α-aziridine aldehydes and amino isocyanates, respectively.^4,5 With an electrophilic carbon and a nucleophilic nitrogen in relative 1,3-positions, these molecules are particularly useful for the chemoselective synthesis of heterocycles with high bond-forming efficiency without protective groups (Fig. 1). However, such elegant amphoteric systems still remain scarce. Therefore, the development of new stable amphoteric molecules with easy access remains highly desirable.Open in a separate windowFig. 1Representative [1,3]-amphoteric molecules versus 3-aminooxetanes.In this context, herein we introduce 3-aminooxetanes as a new type of 1,3-amphoteric molecules and systematically demonstrate their reactivity in a range of [3 + 2] annulations, providing rapid access to diverse heterocycles. Notably, 3-aminooxetanes are bench-stable and either commercially available or easily accessible. However, their amphoteric reactivity has not been appreciated previously.Oxetane is a useful functional group in both drug discovery and organic synthesis.^6–9 Owing to the ring strain, it is prone to nucleophilic ring-opening, in which it serves as an electrophile (Scheme 1A).^6–8 We envisioned that, if a nucleophilic group is installed in the 3-position (e.g., amino group), such molecules should exhibit 1,3-amphoteric reactivity due to the presence of both nucleophilic and electrophilic sites (Scheme 1B). Importantly, the 1,3-relative position is crucial for inhibiting self-destructive intra- or intermolecular ring-opening (i.e. the 3-nucleophilic site attack on oxetane itself) due to high barriers. Thus, such orthogonality is beneficial to their stability. In contrast, the nucleophilic site is expected to react with an external polarized π bond (e.g., X = Y, Scheme 1B), which enables a better-positioned nucleophile (Y) to attack the oxetane and cyclize. Thus, a formal [3 + 2] annulation should be expected. Unlike the well-known S_N2 reactivity of oxetanes with simple bond formation, this amphoteric reactivity would greatly enrich the chemistry of oxetanes with multiple bond formations and provide expedient access to various heterocycles. In contrast to the conventional approaches that require presynthesis of advanced intermediates (e.g., intramolecular ring-opening),⁸ the exploitation of such amphoteric reactivity in an intermolecular convergent manner from simple substrates would be more practically useful. Moreover, more activation modes could be envisioned in addition to oxetane activation. In 2015, Kleij and coworkers reported an example of cyclization between 3-aminooxetane and CO₂ in 55% yield, which provided a pioneering precedent.¹⁰ However, a systematic study to fully reveal such amphoteric reactivity in a broad context remains unknown in the literature.Open in a separate windowScheme 1Typical oxetane reactivity and the new amphoteric reactivity.To test our hypothesis, we began with the commercially available 3-aminooxetanes 1a and 1b as the model substrates. Phenyl thioisocyanate 2a and CS₂ were initially employed as reaction partners, as they both have a polarized C S bond as well as a relatively strong sulfur nucleophilic motif. Moreover, the resulting desired products, iminothiazolidines and mercaptothiazolidines, are both heterocycles with important biological applications (Fig. 2).¹¹ To our delight, simple mixing these two types of reactants in DCM resulted in spontaneous reactions at room temperature without any catalyst. The corresponding [3 + 2] annulation products iminothiazolidine 3a and mercaptothiazolidine 4a were both formed with excellent efficiency (Scheme 2). It is worth mentioning that catalyst-free ring-opening of an oxetane ring is rarely known, particularly for intermolecular reactions.^6–9 In this case, the high efficiency is likely attributed to the suitable choice and perfect position of the in situ generated sulfur nucleophile.Open in a separate windowFig. 2Selected bioactive molecules containing iminothiazolidine and mercaptothiazolidine motifs.Open in a separate windowScheme 2Initial results between 3-aminooxetanes and thiocarbonyl compounds.The catalyst-free annulation protocol is general with respect to various 3-aminooxetanes and isothiocyanates. A range of iminothiazolidines and mercaptothiazolidines were synthesized with high efficiency under mild conditions (Scheme 3). Many of them were obtained in quantitative yield. Quaternary carbon centers could also be generated from 3-substituted 3-aminooxetanes (e.g., 3j). The structure of product 3b was unambiguously confirmed by X-ray crystallography.Open in a separate windowScheme 3Formal [3 + 2] annulation with isothiocyanates and CS₂. Reaction conditions: 1 (0.3–0.4 mmol), 2 (1.1 equiv.) or CS₂ (1.5 equiv.), DCM (2 mL), RT, 3 h for 3 and 36 h for 4. Yields are for the isolated products.With the initial success of thiocarbonyl partners, we next turned our attention to isocyanates, in which the carbonyl group serves as the [3 + 2] annulation motif. Compared with sulfur as the nucleophilic site in the above cases, the oxygen atom is less nucleophilic. As expected, initial tests of the reactivity by mixing 1b and 5a resulted in no desired annulation product 6a in the absence of a catalyst (Table 1, entry 1). Next, Brønsted acids, including TsOH and the super acid HNTf₂, were examined as catalysts, but with no success (entries 2 and 3). We then resorted to various Lewis acids, particularly those oxophilic ones, in hope of activating the oxetane unit. Unfortunately, many of them still remained ineffective (e.g., ZnCl₂, AuCl, and FeCl₃). However, to our delight, further screening of stronger Lewis acids helped identify Sc(OTf)₃, Zn(OTf)₂, and In(OTf)₃ to be effective at room temperature, leading to the desired iminooxazolidine product 6a in good yield (entries 7–9). Its structure was confirmed by X-ray crystallography. Nevertheless, aiming to search for a cheaper catalyst, we continued to optimize this reaction at a higher temperature using previous ineffective catalysts. Indeed, FeCl₃ was found to be effective at 80 °C (61% yield, entry 10), while Brønsted acid TsOH remained ineffective at this temperature (entry 11). Notably, decreasing the loading of FeCl₃ to 1 mol% led to a higher yield (89% yield, entry 12). However, further decreasing to 0.5 mol% resulted in slightly diminished efficiency (entry 13).Reaction conditions for annulation with isocyanates^a

Rh(iii)-catalyzed tandem annulative redox-neutral arylation/amidation of aromatic tethered alkenes

Transition-metal-catalyzed directed C–H functionalization has emerged as a powerful and straightforward tool to construct C–C bonds and C–N bonds. Among these processes, the intramolecular annulative alkene hydroarylation reaction has received much attention because this intramolecular annulation can produce more complex and high value-added structural motifs found in numerous natural products and bioactive molecules. Despite remarkable progress, these annulative protocols developed to date remain limited to hydroarylation and functionalization of one side of alkenes, thus largely limiting the structural diversity and complexity. Herein, we developed a rhodium(iii)-catalyzed tandem annulative arylation/amidation reaction of aromatic tethered alkenes to deliver a variety of 2,3-dihydro-3-benzofuranmethanamine derivatives bearing an all-carbon quaternary stereo center by employing 3-substituted 1,4,2-dioxazol-5-ones as an amidating reagent to capture the transient C(sp³)–Rh intermediate. Notably, by simply changing the directing group, a second, unsymmetrical ortho C–H amidation/annulation can be achieved to provide tricyclic dihydrofuro[3,2-f]quinazolinones in good yields.

A rhodium(iii)-catalyzed tandem annulative arylation/amidation reaction of aromatic tethered alkenes was developed to deliver a variety of 2,3-dihydro-3-benzofuranmethanamine derivatives.

Transition-metal-catalyzed C–H functionalization for the direct conversion of C–H bonds to C–C bonds and C–N bonds has evolved into a widespread and effective strategy for fine chemical production.¹ Among these processes, the hydroarylation of C–C double bonds via a C–H addition has been well-established and become an effective strategy to access synthetically useful structural motifs.¹ Recently, this alkene hydroarylation reaction has received much attention in an intramolecular fashion² (Scheme 1a) because this intramolecular annulation can produce more complex and high value-added structural motifs found in numerous natural products and bioactive molecules (Fig. 1).³ Despite remarkable progress in this area, most of the annulative protocols developed to date remain limited to one-component intramolecular alkene hydroarylation and functionalization of one side of alkenes. More challenging C–H arylation of intramolecular alkenes followed by a tandem coupling with a different coupling partner have unfortunately proven elusive thus far, thus largely limiting the structural diversity and complexity.Open in a separate windowFig. 1Representative bioactive 2,3-dihydrobenzofurans.Open in a separate windowScheme 1Transition-metal-catalyzed C–H functionalization to construct the C–C and C–N bonds.On the other hand, nitrogen-containing molecules have gained great attention due to their widespread presence in natural products and widespread use in pharmaceutical science.⁴ During the last two decades, transition-metal-catalyzed direct C(sp²)–H amination/amidation assisted by chelating directing group is a well-established strategy.⁵ Recently, several examples of C(sp³)–H amination/amidation have also been reported for the efficient installation of C–N bonds.^6,7 Mechanistically, the reaction is initiated by a chelation-assisted C–H metalation to form a C(sp³)–M species, which is then coupled with amination reagents to construct the C–N bonds.In this context, we wondered if a catalytic annulative C–H arylation of a O-bearing olefin-tethered arenes might be possible, thus leading to a C(sp³)–M intermediate, which upon capture with a amidation reagent to construct a new C–N bond and provide bioactive 2,3-dihydro-3-benzofuranmethanamine derivatives. Inherently, the tandem annulative 1,2-arylation/amidation of alkenes has several challenges. First, the resulting C(alkyl)–M intermediate is liable to undergo protonation to provide the alkene hydroarylation products.^1,2 Moreover, a potential competing β-H elimination of the resulting C(alkyl)–M intermediate also required to be suppressed. In addition, compared with the C(sp²)–M species, the resulting C(alkyl)–M species is relatively unstable and also has a low reactivity.To address these challenges and with our continuing interest in the Rh(iii)-catalyzed C–H functionalization,⁸ we introduced a Weinreb amide as a directing group and 3-substituted 1,4,2-dioxazol-5-ones as the amide sources⁹ to trigger a new tandem annulative 1,2-arylation/amidation of alkenes via a Rh(iii)-catalyzed C–H activation,¹⁰ providing a variety of synthetically challenging 2,3-dihydro-3-benzofuranmethanamine derivatives bearing an all-carbon quaternary stereo center (Scheme 1b). More importantly, through simply changing the directing group, a second, unsymmetrical ortho C–H amidation/annulation could be realized to provide tricyclic dihydrofuro[3,2-f]quinazolinone derivatives. This protocol provides a good complement to previously reported carboamination reactions.¹¹To begin our studies, Weinreb amide 1a was reacted with methyl dioxazolone 3a in the presence of various catalyst and AgSbF₆ at 70 °C in DCE (Table 1, entries 1–4). The use of [Cp*RhCl₂]₂ as the catalyst was found to be crucial to give the desired tandem annulative product 4a, with other catalysts, such as [Ru(p-cymene)Cl₂]₂, [Cp*IrCl₂]₂, and Cp*Co(CO)I₂, resulting in no desired product. Attempt to increase or lower the reaction temperature led to a slightly low yield (entries 5 and 6). Interestingly, when employing a NH–OMe amide 2a as the substrate and using 3 equivalent of 3a, a second, unsymmetrical ortho C–H amidation/annulation was achieved to provide the tricyclic dihydrofuro[3,2-f]quinazolinone 5a in 50% yield (entry 7). A screen of additives (entries 8–10) identified LiOAc as the optimal additive, affording the desired product 5a in 93% yield (entry 10). The Rh(iii) catalyst was found to be crucial for this tandem annulative arylation/amidation reaction, with no reactivity in its absence (entries 11 and 12).Optimization of reaction conditions^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.     

Electrophilic fluoroalkylthiolation induced diastereoselective and stereospecific 1,2-metalate migration of alkenylboronate complexes

A transition metal free process for conjunctive functionalization of alkenylboron ate-complexes with electrophilic fluoroalkylthiolating reagents is described, affording β-trifluoroalkylthiolated and difluoroalkylthiolated boronic esters in good yield and excellent diastereoselectivity. The potential applicability of the method was demonstrated by the preparation of a difluoromethylthiolated mimic 12 of a potential drug molecule PF-4191834 for the treatment of asthma.

A transition metal free process for conjunctive functionalization of alkenylboron ate-complexes with electrophilic fluoroalkylthiolating reagents affords β-tri- and difluoroalkylthiolated boronic esters in good yield and diastereoselectivity.

An electrophile-induced 1,2-metalate migration of an alkenylboron “ate” complex and subsequent base-promoted β-elimination to form a functionalized cis-alkene, now the so-called Zweifel reaction, was first reported by Zweifel and co-workers in 1967 (Fig. 1A).^1–3 The reaction was proposed to proceed via an initial attack of the π electron of the alkene moiety to iodine to generate a zwitterionic iodonium ion, which then undergoes a stereospecific 1,2-metalate to afford a β-iodoboronic ester, followed by anti-elimination upon treatment with a base to afford a cis-olefin. Thus, if the iodine is replaced by an alternative electrophilic reagent and the use of a base is omitted, an interrupted-Zweifel reaction for the preparation of a stereospecific β-functionalized boronic ester could be realized. Toward this end, Aggarwal reported the first example of such a reaction by employing PhSeCl as the electrophilic reagent.⁴ It was proposed that PhSeCl first reacts with an alkenylboronate complex to form a zwitterionic seleniranium ion. Subsequent diastereospecific 1,2-metalate migration affords the stereospecific β-seleno-alkylboronate (Fig. 1B). Likewise, shortly after, Denmark and co-workers reported an analogous Lewis-base catalysed enantioselective and diastereoselective carbosulfenylation of an alkenylboronate complex using N-arylthiosaccharin as the electrophile (Fig. 1C).⁵Open in a separate windowFig. 1The interrupted Zweifel reaction.In light of these discoveries and our recent success in the development of a toolbox of electrophilic fluoroalkylthiolating reagents including three trifluoromethylthiolating reagents α-cumyltrifluoromethane sulfenate,⁶N-trifluoromethylthio-saccharin⁷ and N-trifluoromethylthiodibenzenesulfonimide,⁸ and two difluoromethylthiolating reagents N-difluoromethylthiophthalimide⁹ and S-(difluoromethyl)benzenesulfonothioate,¹⁰ we wondered whether these electrophilic fluoroalkylthiolating reagents could also trigger the proposed stereospecific 1,2-metalatation of the alkenylboronate complex to afford β-fluoroalkylthiolated borane derivatives (Fig. 1D). The trifluoromethylthio (–SCF₃) and the difluoromethylthio (–SCF₂H) groups have gained great attention recently, partially because of their high and tuneable lipophilicity¹¹ that might improve the drug candidate''s cell membrane permeability and consequently, its overall pharmacokinetics.¹² Thus, the development of new efficient reactions for the incorporation of the trifluoromethylthio¹³ or difluoromethylthio groups¹⁴ would be of vital importance in facilitating medicinal chemists'' endeavours in new drug discovery. Herein, we report that by employing electrophilic difluoromethylthiolating reagent PhSO₂SCF₂H 2a as the electrophile, the proposed difluoromethylthiolating induced stereospecific 1,2-metalate migration of alkenyl boronate complexes occurred smoothly to afford β-difluoromethylthiolated boronic esters in good yields and excellent diastereoselectivity. Likewise, when electrophilic trifluoromethylthiolating reagent N-trifluoromethylthiosaccharin 7 was used, an analogous reaction for the diastereoselective formation of β-trifluoromethylthiolated boronic esters was successfully achieved.We began our study by examining the reaction of the electrophilic difluoromethylthiolating reagent 2a with the alkenylboronate complex which was generated in situ by mixing 1a and PhLi in diethyl ether. It was found that the reaction in CH₃CN occurred in full conversion after 12 hours at room temperature, affording the corresponding product 3a in 53% yield (Table 1, entry 1). When the amount of PhLi was increased to 1.3 equivalents, the yield was increased to 76%, while the yield decreased to 66% when 2.0 equivalents of PhLi were used, likely due to the decomposition of the product under strong basic conditions (Table 1, entries 1–5). We then further investigated the effect of the reaction temperature and the solvent. It was found that the temperature did not affect the reaction significantly since the yields of the desired products were decreased slightly to 72% and 70%, respectively, when the reactions were conducted at 0 °C or −15 °C (Table 1, entries 6 and 7). Likewise, the reaction was not sensitive to the polarity of the solvent since reactions conducted in less polar solvents such as THF or CH₂Cl₂ or nonpolar solvents like toluene occurred in slightly lower 60–73% yields (Table 1, entries 9–11). We also found that reaction using N-difluoromethylthiophthalimide as the electrophilic difluoromethylthiolating reagent gave the same product in a slightly lower yield (Table 1, entry 8).Optimization of conditions for the reaction of the alkenyl boronate complex with PhSO₂SCF₂H^a

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).     

C(sp3)–C(sp3) coupling of non-activated alkyl-iodides with electron-deficient alkenes via visible-light/silane-mediated alkyl-radical formation

Here, we present a remarkably mild and general initiation protocol for alkyl-radical generation from non-activated alkyl-iodides. An interaction between a silane and an alkyl iodide is excited by irradiation with visible light to trigger carbon–iodide bond homolysis and form the alkyl radical. We show how this method can be developed into an operationally simple and general Giese addition reaction that can tolerate a range of sensitive functionalities not normally explored in established approaches to this strategically important transformation. The new method requires no photocatalyst or other additives and uses only commerical tris(trimethylsilyl)silane and visible light to effectively combine a broad range of alkyl halides with activated alkenes to form C(sp³)–C(sp³) bonds embedded within complex frameworks.

Here, we present a remarkably mild and general initiation protocol for alkyl-radical generation from non-activated alkyl-iodides.

The efficient and straightforward construction of C(sp³)–C(sp³) bonds is a crucial process in organic synthesis. Over the past 80 years, the polar conjugate addition reaction has become a powerful method to forge a variety of C(sp³)–C(sp³) bonds.¹ Alongside two-electron nucleophiles, alkyl-radicals – neutral yet nucleophilic species – have emerged as alternatives to organometallic reagents for additions to electron deficient alkenes.² Since the 1960s, a variety of methods have been reported for the formation of alkyl-radicals; early examples include the decomposition of in situ generated organomercurial hydrides, the fragmentation of xanthate or Barton esters, or the UV-mediated homolysis of alkyl halides, amongst many others.³ Although these strategies tolerate a broad range of functionalities, the initiation processes can be complicated by the need for aggressive reaction conditions and frequently require toxic reagents such as tributyltin hydride, with notable exceptions.^4,5The emergence of photoredox catalysis has obviated many of the potential drawbacks to the generation and use of alkyl-radicals. The exploitation of the multifaceted reactivity of visible light excited transition metal or organic-photocatalysts, whose properties can be tuned through modification of the ligand, metal and/or scaffold, facilitates optimization of the single electron transfer event towards alkyl-radical generation from a wide range of functionalized alkyl groups.⁶ In addition, the reactivity of electron donor–acceptor (EDA) complexes has also provided a straightforward means to form alkyl-radicals from a variety of precursors.⁷ As such, a plethora of methods have been developed for the generation of C(sp³)-centred radicals from a variety of commercially available native functionalities, which dramatically expand the scope of alkyl-radical chemistry^†. In this context, the single electron reduction of non-activated alkyl halides provides a useful means to generate alkyl radicals.⁸ As an example, Leonori and co-workers recently developed a method wherein halogen atom abstraction pathways were leveraged using radical species forged through photocatalyst-mediated oxidation event leading to a general alkyl-radical generation.⁹ Related to the current study, Jørgensen and co-workers published a visible-light mediated reduction of alkyl halides under very mild conditions. Accordingly, there remains a need for further innovation towards orthogonal, general and benign methods of alkyl-radical generation that tolerate a broad range of functionalities, thereby enabling the construction of a greater variety of C(sp³)–C(sp³) bonds.¹⁰Recently, we reported a general reaction to form tertiary alkylamines via the addition of alkyl-radicals (generated from non-activated alkyl-iodides) to in situ-generated all-alkyl iminium ions.^11a This carbonyl alkylative amination (CAA) reaction was promoted by the action of blue LEDs and tris(trimethylsilyl)silane ((Me₃Si)₃Si–H). No photoredox catalyst is required. We believe that the alkyl-radical formation step, devoid of traditional initiating reagents, proceeds through the visible-light excitation of a transient ternary EDA complex, which stimulates homolysis of the carbon–iodide bond that would be otherwise stable under such irradiation conditions (Fig. 1B). The presence of an enamine was important to the initiation pathway, as revealed by an absorption band in the UV/vis spectrum of its mixture with an alkyl-iodide and (Me₃Si)₃Si–H.^11a Gouverneur and co-workers have also reported an elegant example of visible-light mediated addition of more functionalized alkyl halides, such as iodofluoromethane, to electron deficient alkenes.¹² They proposed that light mediated homolytic cleavage of iodofluoromethane was responsible for radical initiation prior to a classical chain process.Open in a separate windowFig. 1(A) Selected visible-light mediated methods for the generation of alkyl-radicals; (B) previous work – a method for tertiary amine formation exploiting a visible-light activation of a ternary EDA complex to promote alkyl-radical formation. (C) Previous work from Gouverneur & Gaunt labs on radical fluoromethylation. (D) This work – alkyl-radical formation promoted solely by visible light and tris-trimethylsilyl silane demonstrated through a remarkably practical and straightforward Giese reaction.Gouverneur et al. also showed methyl iodide was only efficient as a radical source under these conditions when an organic photocatalyst was present and the reaction of other simple non-activated alkyl iodides was only demonstrated in the presence of iodofluoromethane, which was presumably responsible for the initiation pathway (vide supra). Our prior work in this area also identified iodofluoromethane as a visible-light activated source of fluoromethyl radical and its addition to iminium ions and electron deficient alkenes (Fig. 1C).^11b Taken together, these works reveal that the use of visible light and (Me₃Si)₃Si–H to initiate radical formation from non-activated alkyl halides has not been achieved in an unbiased transformation without the requirement of an initiation process via of the reaction components or a photocatalyst. Accordingly, we questioned whether a pathway mediated by visible-light and (Me₃Si)₃Si–H alone might facilitate alternative modes of radical initiation from non-activated alkyl halides, and therefore enable the general coupling of unbiased alkyl fragments with a wider range of acceptors under practical, straightforward reaction conditions.Herein, we report the successful realization of this idea through the development of a remarkably straightforward visible-light mediated method for alkyl-radical generation from non-activated alkyl iodides using only non-toxic tris(trimethylsilyl)silane as a reagent (Fig. 1D). While we are not certain of the precise pathway for the radical initiation, it seems likely that excitation of a species resulting from the interaction of tris(trimethylsilyl)silane and the alkyl iodide, leading to carbon–iodide bond homolysis. The utility of this activation mode is demonstrated through a broad and chemoselective Giese addition to electron deficient alkenes and is notable by its tolerance to a range of synthetically valuable functionalities in both alkyl iodide and alkene components. In comparison to other methods for Giese-addition,^2,3,8,9,12 the conditions are mild and do not require expensive catalysts or cocktails of additives.Our studies were stimulated from an observation arising from the development of the visible light mediated carbonyl alkylative amination (shown in Fig. 1B). High yields of the tertiary amine product, arising from the union of alkyl-radical, aldehyde and secondary amine were maintained when using a 455 nm long-pass filter, which discounted UV-mediated carbon–iodide bond homolysis as the initiation pathway for alkyl-radical formation.^11a To explore the formation of an alkyl-radical independently from the enamine component, the reaction conditions were simplified to comprise a representative alkyl halide and (Me₃Si)₃Si–H, which allowed us to first assess any impact solvent might have on the radical forming process. As shown in 13 However, 47% of 5 was still obtained after visible-light irradiation of a reaction mixture from which air had been rigorously excluded (entry 10), suggesting an alternative initiation pathway excluding oxygen could also operate.¹⁴ A reaction at 80 °C in the absence of light showed no conversion to 5. This data shows the nature of the solvent is not relevant for the initiation step and suggests a straightforward radical initiation process that results from visible-light excitation of an intermediate arising from an interaction between the alkyl halide and (Me₃Si)₃Si–H.Effect of different parameters on radical initiation^a

An unusual formal migrative cycloaddition of aurone-derived azadienes: synthesis of benzofuran-fused nitrogen heterocycles

Aurone-derived azadienes are well-known four-atom synthons for direct [4 + n] cycloadditions owing to their s-cis conformation as well as the thermodynamically favored aromatization nature of these processes. However, distinct from this common reactivity, herein we report an unusual formal migrative annulation with siloxy alkynes initiated by [2 + 2] cycloaddition. Unexpectedly, this process generates benzofuran-fused nitrogen heterocyclic products with formal substituent migration. This observation is rationalized by less common [2 + 2] cycloaddition followed by 4π and 6π electrocyclic events. DFT calculations provided support to the proposed mechanism.

A HNTf₂-catalyzed formal migrative cycloaddition of aurone-derived azadienes with siloxy alkynes has been developed to provide access to benzofuran-fused dihydropyridines.

Benzofuran is an important scaffold in biologically important natural molecules and therapeutic agents.¹ Among them, benzofuran-fused nitrogen heterocycles are particularly noteworthy owing to their broad spectrum of bioactivities for the treatment of various diseases (Fig. 1).² Consequently, the development of efficient methods for their assembly has been a topic receiving enthusiastic attention from synthetic chemists.³ Notably, aurone-derived azadienes (e.g., 1) have been extensively employed as precursors toward these skeletons owing to their easy availability and versatile reactivity (Scheme 1a).³ The polarized conjugation system, combined with the preexisting s-cis conformation, has enabled them to serve as ideal annulation partners for the synthesis of nitrogen heterocycles of variable ring sizes. Moreover, the aromatization nature of these processes by forming a benzofuran ring provides additional driving force for them to behave as a perfect four-atom synthon for [4 + n] cycloaddition.³ In contrast, the use of such species as a two-atom partner for [2 + n] cycloaddition has been less developed.^3c,k,4 Herein, we report a new migrative annulation leading to benzofuran-fused dihydropyridines of unexpected topology (Scheme 1b, with formal R² migration), which is initiated by the less common [2 + 2] cycloaddition.Open in a separate windowFig. 1Benzofuran-fused N-heterocyclic natural and bioactive molecules.Open in a separate windowScheme 1Synthesis of benzofuran-fused nitrogen heterocycles.Siloxy alkynes are another important family of building blocks in organic synthesis.^5–8 The presence of a highly polarized C–C triple bond enables such molecules to serve as versatile two-carbon cycloaddition partners in various annulation reactions.^5–7 In the above context and in continuation of our interest in the study of such electron-rich alkynes,⁷ we envisioned that the reaction between aurone-derived azadienes 1 and siloxy alkynes 2 should lead to facile electron-inversed [4 + 2] cycloaddition to form benzofuran-fused dihydropyridine products (Scheme 1b). Interestingly, the expected product 3′ from direct [4 + 2] cycloaddition was not observed. Instead, a dihydropyridine product 3 with formal R² migration was observed. Careful analysis of the mechanism suggested that a [2 + 2] cycloaddition followed by 4π and 6π electrocyclic steps might be responsible for this unexpected product topology (vide infra).We began our investigation with the model substrates 1a and 2a, which were easily prepared in one step from aurone and 1-hexyne, respectively.⁸ Various Lewis acids were initially examined as potential catalysts for this cycloaddition (Table 1). Unfortunately, common Lewis acids (e.g., TiCl₄, BF₃·OEt₂, Sc(OTf)₃, In(OTf)₃, and AgOTf) were all ineffective (entries 1–5). Substrate decomposition into an unidentifiable mixture was typically observed. However, further screening indicated that AgNTf₂ served as an effective catalyst, leading to benzofuran-fused dihydropyridine 3a in 44% yield (entry 6). Careful analysis by X-ray crystallography confirmed that it was not formed by simple [4 + 2] cycloaddition, as the positions of the phenyl and the siloxy groups were switched (vs. the expected topology). The distinct catalytic performance of AgNTf₂ (vs. AgOTf) suggested that the triflimide counter anion Tf₂N⁻ might be important. However, further screening of various metal triflimide salts did not improve the reaction efficiency (entry 7). Instead, we were delighted to find that the corresponding Brønsted acid HNTf₂ served as a better catalyst (57% yield, entry 8). However, triflic acid (TfOH) led to no desired product in spite of complete conversion (entry 9). After considerable efforts in the optimization of other reaction parameters, an improved yield of 75% was obtained with 2.5 mol% of HNTf₂ and 2.5 equivalents of 2a at 60 °C (entry 10). Solvent screening indicated that the reaction proceeded faster in DCE with comparable yield (entry 11). However, other solvents were all inferior (entries 12–15). Finally, with a reversed order of addition of the two reactants, the yield was slightly improved (entry 16). We believe that this might be related to the relative decomposition rates of the substrates.Reaction conditions^a

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     

Regioselective B(3,4)–H arylation of o-carboranes by weak amide coordination at room temperature

Palladium-catalyzed regioselective di- or mono-arylation of o-carboranes was achieved using weakly coordinating amides at room temperature. Therefore, a series of B(3,4)-diarylated and B(3)-monoarylated o-carboranes anchored with valuable functional groups were accessed for the first time. This strategy provided an efficient approach for the selective activation of B(3,4)–H bonds for regioselective functionalizations of o-carboranes.

B–H: site-selective B(3,4)–H arylations were accomplished at room temperature by versatile palladium catalysis enabled by weakly coordinating amides.

o-Carboranes, icosahedral carboranes – three-dimensional arene analogues – represent an important class of carbon–boron molecular clusters.¹ The regioselective functionalization of o-carboranes has attracted growing interest due to its potential applications in supramolecular design,² medicine,³ optoelectronics,⁴ nanomaterials,⁵ boron neutron capture therapy agents⁶ and organometallic/coordination chemistry.⁷ In recent years, transition metal-catalyzed cage B–H activation for the regioselective boron functionalization of o-carboranes has emerged as a powerful tool for molecular syntheses. However, the 10 B–H bonds of o-carboranes are not equal, and the unique structural motif renders their selective functionalization difficult, since the charge differences are very small and the electrophilic reactivity in unfunctionalized o-carboranes reduces in the following order: B(9,12) > B(8,10) > B(4,5,7,11) > B(3,6).⁸ Therefore, efficient and selective boron substitution of o-carboranes continues to be a major challenge.Recently, transition metal-catalyzed carboxylic acid or formyl-directed B(4,5)–H functionalization of o-carboranes has drawn increasing interest, since it provides an efficient approach for direct regioselective boron–carbon and boron–heteroatom bond formations (Scheme 1a),⁹ with major contributions by the groups of Xie,¹⁰ and Yan,¹¹ among others.¹² Likewise, pyridyl-directed B(3,6)–H acyloxylations (Scheme 1b),¹³ and amide-assisted B(4,7,8)–H arylations¹⁴ (Scheme 1c) have been enabled by rhodium or palladium catalysis, respectively.^15,16 Despite indisputable progress, efficient approaches for complementary site-selective functionalizations of o-carboranes are hence in high demand.¹⁷ Hence, metal-catalyzed position-selective B(3,4)–H functionalizations of o-carboranes have thus far not been reported.Open in a separate windowScheme 1Chelation-assisted transition metal-catalyzed cage B–H activation of o-carboranes.Arylated compounds represent key structural motifs in inter alia functional materials, biologically active compounds, and natural products.¹⁸ In recent years, transition metal-catalyzed chelation-assisted arylations have received significant attention as environmentally benign and economically superior alternatives to traditional cross-coupling reactions.¹⁹ Within our program on sustainable C–H activation,²⁰ we have now devised a protocol for unprecedented cage B–H arylations of o-carboranes with weak amide assistance, on which we report herein. Notable features of our findings include (a) transition metal-catalyzed room temperature B–H functionalization, (b) high levels of positional control, delivering B(3,4)-diarylated and B(3)-monoarylated o-carboranes, and (c) mechanistic insights from DFT computation providing strong support for selective B–H arylation (Scheme 1d).We initiated our studies by probing various reaction conditions for the envisioned palladium-catalyzed B–H arylation of o-carborane amide 1a with 1-iodo-4-methylbenzene (2a) at room temperature (Tables 1 and S1^†). We were delighted to observe that the unexpected B(3,4)-di-arylated product 3aa was obtained in 59% yield in the presence of 10 mol% Pd(OAc)₂ and 2 equiv. of AgTFA, when HFIP was employed as the solvent, which proved to be the optimal choice (entries 1–5).²¹ Control experiments confirmed the essential role of the palladium catalyst and silver additive (entries 6–7). Further optimization revealed that AgOAc, Ag₂O, K₂HPO₄, and Na₂CO₃ failed to show any beneficial effect (entries 8–11). Increasing the reaction temperature fell short in improving the performance (entries 12 and 13). The replacement of the amide group in substrate 1a with a carboxylic acid, aldehyde, ketone, or ester group failed to afford the desired arylation product (see the ESI^†). We were pleased to find that the use of 1.0 equiv. of trifluoroacetic acid (TFA) as an additive improved the yield to 71% (entry 14). To our delight, replacing the silver additive with Ag₂CO₃ resulted in the formation of B(3)–H mono-arylation product 4aa as the major product (entries 15–16).Optimization of reaction conditions^a

Ruthenium-catalyzed formal sp3 C–H activation of allylsilanes/esters with olefins: efficient access to functionalized 1,3-dienes

Ru-catalysed oxidative coupling of allylsilanes and allyl esters with activated olefins has been developed via isomerization followed by C(allyl)–H activation providing efficient access to stereodefined 1,3-dienes in excellent yields. Mild reaction conditions, less expensive catalysts, and excellent regio- and diastereoselectivity ensure universality of the reaction. In addition, the unique power of this reaction was illustrated by performing the Diels–Alder reaction, and enantioselective synthesis of highly functionalized cyclohexenone and piperidine and finally synthetic utility was further demonstrated by the efficient synthesis of norpyrenophorin, an antifungal agent.

Ru-catalysed oxidative coupling of allylsilanes and allyl esters with activated olefins has been developed via isomerization followed by C(allyl)–H activation providing efficient access to stereodefined 1,3-dienes in excellent yields.

1,3-Dienes not only are widespread structural motifs in biologically pertinent molecules but also feature as a foundation for a broad range of chemical transformations.^1–14 Indeed, these conjugated dienes serve as substrates in many fundamental synthetic methodologies such as cycloaddition, metathesis, ene reactions, oxidoreduction, or reductive aldolization. It is well-understood that the geometry of olefins often influences the stereochemical outcome and the reactivity of reactions involving 1,3-dienes.¹⁵ Hence, a plethora of synthetic methods have been developed for the stereoselective construction of substituted 1,3-dienes.^16–24 The past decade has witnessed a huge advancement in the field of metal-catalyzed C–H activation/functionalization.^25–27 Although, a significant amount of work in the field of C(alkyl)–H and C(aryl)–H activation has been reported; C(alkenyl)–H activation has not been explored conspicuously, probably due to the complications caused by competitive reactivity of the alkene moiety, which can make chemoselectivity a significant challenge. Over the past few years, several different palladium-based protocols have been developed for C(alkenyl)–H functionalization, but the reactions are generally limited to employing conjugated alkenes, such as styrenes,^28–31 acrylates/acrylamides,^32–36 enamides,³⁷ and enol esters/ethers.^38,39 To date, only a few reports have appeared in the literature for expanding this reactivity towards non-conjugated olefins, which can be exemplified by camphene dimerization,⁴⁰ and carboxylate-directed C(alkenyl)–H alkenylation of 1,4-cyclohexadienes.⁴¹ In 2009, Trost et al. reported a ruthenium-catalyzed stereoselective alkene–alkyne coupling method for the synthesis of 1,3-dienes.⁴² The same group also reported alkene–alkyne coupling for the stereoselective synthesis of trisubstituted ene carbamates.⁴³ A palladium catalyzed chelation control method for the synthesis of dienes via alkenyl sp² C–H bond functionalization was described by Loh et al.⁴⁴ Recently, Engle and coworkers reported an elegant approach for synthesis of highly substituted 1,3-dienes from two different alkenes using an 8-aminoquinoline directed, palladium(ii)-mediated C(alkenyl)–H activation strategy.⁴⁵ Allyl and vinyl silanes are known as indispensable nucleophiles in synthetic chemistry.⁴⁶ Alder ene reactions of allyl silanes with alkynes are reported for the synthesis of 1,4-dienes.⁴⁷ Innumerable methods are known for the preparation of both allyl and vinyl silanes^48–52 but limitations are associated with many of the current protocols, which impedes the synthesis of unsaturated organosilanes in an efficient manner. Silicon-functionalized building blocks are used as coupling partners in the Hiyama reaction⁵³ and are easily converted into iodo-functionalized derivatives (precursor for the Suzuki cross-coupling reaction), but there is little attention given for the synthesis of functionalized vinyl silanes. Herein, we report a general approach for the stereoselective synthesis of trisubstituted 1,3-dienes by the Ru-catalyzed C(sp³)–H functionalization reaction of allylsilanes (Scheme 1).Open in a separate windowScheme 1Highly stereoselective construction of 1,3-dienes.In 1993, Trost and coworkers reported an elegant method for highly chemoselective ruthenium-catalyzed redox isomerization of allyl alcohols without affecting the primary and secondary alcohols and isolated double bonds.^54,55 Inspired by the potential of ruthenium for such isomerization of double bonds in allyl alcohols, we sought to identify a ruthenium-based catalytic system that can promote isomerization of olefins in allylsilanes followed by in situ oxidative coupling with an activated olefin to form substituted 1,3-dienes. We initiated our studies by choosing trimethylallylsilane 1a and acrylate 2a by using a commercially available [RuCl₂(p-cymene)]₂ catalyst in the presence of AgSbF₆ as an additive and co-oxidant Cu(OAc)₂ in 1,2-DCE at 100 °C. Interestingly, it resulted into direct formation of (2E,4Z)-1,3-diene 3aa as a single isomer in 55% yield. It is likely that this reaction occurs by C(allyl)–H activation of the π-allyl ruthenium complex followed by oxidative coupling with the acrylate and leaving the silyl group intact (Table 1). π-Allyl ruthenium complex formation may be highly favorable due to the α-silyl effect which stabilizes the carbanion forming in situ in the reaction.⁵⁶ Next, the regioselective C–H insertion of vinyl silanes could be controlled by stabilization of the carbon–metal (C–M) bond in the α-position to silicon. This stability arises due to the overlapping of the filled carbon–metal orbital with the d orbitals on silicon or the antibonding orbitals of the methyl–silicon (Me–Si) bond.⁵⁷ The stereochemistry of the diene was established by 1D and 2D spectroscopic analysis of the compound 3aa. To quantify the C–H activation mediated coupling efficiency, an extensive optimization study was conducted (allylsilanes followed by in situ oxidative coupling with an activated olefin to form substituted 1,3-dienes). The change of solvents from 1,2-DCE to t-AmOH, DMF, dioxane, THF or MeCN did not give any satisfactory result, rather a very sluggish reaction rate or decomposition of starting materials was observed in each case (entry 2–6).Optimization 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.     

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