Electrooxidative o-carborane chalcogenations without directing groups: cage activation by copper catalysis at room temperature

Copper-catalyzed electrochemical direct chalcogenations of o-carboranes was established at room temperature. Thereby, a series of cage C-sulfenylated and C-selenylated o-carboranes anchored with valuable functional groups was accessed with high levels of position- and chemo-selectivity control. The cupraelectrocatalysis provided efficient means to activate otherwise inert cage C–H bonds for the late-stage diversification of o-carboranes.

Copper-catalyzed electrochemical cage C–H chalcogenation of o-carboranes has been realized to enable the synthesis of various cage C-sulfenylated and C-selenylated o-carboranes.

Carboranes are polyhedral molecular boron–carbon clusters, which display unique properties, such as a boron enriched content, icosahedron geometry and three-dimensional electronic delocalization.¹ These features render carboranes as valuable building blocks for applications to optoelectronics,² as nanomaterials, in supramolecular design,³ organometallic coordination chemistry,⁴ and boron neutron capture therapy (BNCT) agents.⁵ As a consequence, considerable progress has been witnessed in transition metal-catalyzed regioselective cage B–H functionalization of o-carboranes⁶ and different functional motifs have been incorporated into the cage boron vertices.^7–10 However, progress in this research arena continues to be considerably limited by the shortage of robust and efficient methods to access carborane-functionalized molecules. While C–S bonds are important structural motifs in various biologically active molecules and functional materials,¹¹ strategies for the assembly of chalcogen-substituted carboranes continue to be scarce. A major challenge is hence represented by the strong coordination abilities of thiols to most transition metals, which often lead to catalyst deactivation.¹² While copper-catalyzed B(4,5)–H disulfenylation of o-carboranes was achieved,^7e elevated reaction temperature was required, and 8-aminoquinoline was necessary as bidentate directing group. The bidentate directing group¹³ needs to be installed and removed, which jeopardizes the overall efficacy. Likewise, an organometallic strategy was recently devised for cysteine borylation with a stoichiometric platinum(ii)-based carboranes.¹⁴ Meanwhile, oxidative cage B/C–H functionalizations largely call for noble transition metal catalysts¹⁵ and stoichiometric amounts of chemical oxidants, such as expensive silver(i) salts.¹⁶In recent years, electricity has been identified as an increasingly viable, sustainable redox equivalent for environmentally-benign molecular synthesis.^17,18 While significant advances have been realized by the merger of electrocatalysis with organometallic bond activation,¹⁹ electrochemical carborane functionalizations continue unfortunately to be underdevelopment. In sharp contrast, we have now devised a strategy for unprecedented copper-catalyzed electrochemical cage C–H chalcogenations of o-carboranes in a dehydrogenative manner, assembling a variety of C-sulfenylated and C-selenylated o-carboranes (Fig. 1a). It is noteworthy that our electrochemical cage C–S/Se modification approach is devoid of chemical oxidants, and does not need any directing groups, operative at room temperature.Open in a separate windowFig. 1Electrochemical diversification of o-carboranes and optimization of reaction conditions. ^aReaction conditions: procedure A: 1a (0.10 mmol), 2a (0.3 mmol), CuOAc (15 mol%), 2-PhPy (15 mol%), LiOtBu (0.2 mmol), TBAI (2.0 equiv.), solvent (3 mL), platinum cathode (10 mm × 15 mm × 0.25 mm), graphite felt (GF) anode (10 mm × 15 mm × 6 mm), 2 mA, under air, r.t., 16 h. ^bYield was determined by ¹H NMR with CH₂Br₂ as the internal standard. ^cIsolated yields in parenthesis. ^dKI (1.0 equiv.) as additive. ^eProcedure B: 2 (0.3 mmol), LiOtBu (0.2 mmol), TBAI (2.0 equiv.), solvent (3.0 mL), 2 mA, r.t., 3 h, then adding 1a (0.10 mmol), 2-PhPy (15 mol%), CuOAc (15 mol%), 2 mA, rt, 16 h. ^f2b (0.3 mmol), LiOtBu (0.2 mmol), KI (1.0 equiv.), TBAI (2.0 equiv.), solvent (3.0 mL), 2 mA, r.t., 3 h, then adding 1a (0.10 mmol), 2-PhPy (15 mol%), CuOAc (15 mol%), r.t., 16 h. TBAI = tetrabutylammonium iodide, TBAPF₆ = tetrabutylammonium hexafluorophosphate. DCE = 1,2-dichloroethane, THF = tetrahydrofuran.We commenced our studies by probing various reaction conditions for the envisioned copper-catalyzed cage C–H thiolation of o-carborane in an operationally simple undivided cell setup equipped with a GF (graphite felt) anode and a Pt cathode (Fig. 1b and Table S1^†). After extensive experimentation, we observed that the thiolation of substrate 1 proceeded efficiently with catalytic amounts of CuOAc and 2-phenylpyridine, albeit in the presence of 2 equivalents LiOtBu as the base, and 2 equivalents n-Bu₄NI as the electrolyte at room temperature under a constant current of 2 mA (entry 1). The yield was reduced when other copper sources or additives were used (entries 2–5). Surprisingly, n-Bu₄NPF₆ as the electrolyte failed to facilitate the carborane modification, indicating that n-Bu₄NI operates not only as electrolyte, but also as a redox mediator (entry 6). Altering the stoichiometry of the electrolyte or using KI did not improve the performance (entries 7–8). Product formation was not observed, when the reaction was conducted with DCE as the solvent, while CH₃CN resulted in a drop of the catalytic performance (entries 9–10). Control experiments confirmed the essential role of the electricity and the catalyst (entries 11–12), while a sequential procedure was found to be beneficial (entries 13–15).With the optimized reaction conditions in hand, we explored the versatility of the cage C–H thiolation of o-carborane 1a with different thiols 2 (Scheme 1). Electron-rich as well as electron-deficient substituents on the arenes were found to be amenable to the electrocatalyzed C–H activation, providing the corresponding thiolation products 3aa–3ao in good to excellent yields. Thereby, a variety of synthetically useful functional groups, such as fluoro (3ae, 3am), chloro (3af, 3ak, 3an) and bromo (3ag, 3al), were fully tolerated, which should prove instrumental for further late-stage manipulations. Various disubstituted aromatic and heterocyclic thiols afforded the corresponding cage C–S modified products 3ap–3as. Notably, aliphatic thiols efficiently underwent the electrochemical transformation to provide the corresponding cage alkylthiolated products 3at–3au. Notably, the halogen-containing thiols (2e–2f, 2k–2n and 2q) reacted selectively with o-carboranes to deliver the desired products without halide coupling byproducts being observed. The connectivity of the products 3aa, 3am and 3ao was unambiguously verified by X-ray single crystal diffraction analysis.²²Open in a separate windowScheme 1Electrochemical C–H thiolation of o-carborane 1a. (a) Procedure B. (b) KI (1 equiv.). (c) Cul as the catalyst.Encouraged by the efficiency of the cupraelectro-oxidative cage C–H thiolation, we became intrigued to explore the chalcogenantion of differently-decorated o-carboranes 1 (Scheme 2). Electronically diverse carboranes 1 served as competent coupling partners, giving the corresponding thiolation products 4bo–4do with high levels of efficacy in position-selective manner. The strategy was not restricted to phenyl-substituted o-carboranes. Indeed, substrates bearing benzyl and even alkyl groups also performed well to deliver the desired products 4eo–4ga. It is noteworthy that the C–H activation approach was also compatible with selenols to give the o-carboranes 4av–4fv. The molecular structures of the carborane 4br and 4av were unambiguously verified by single-crystal X-ray diffraction.²²Open in a separate windowScheme 2Electrochemical cage C–H chalcogenation of o-carboranes. (a) Procedure B. (b) KI (1 equiv.).Scaffold functionalization of the thus obtained carborane 3ag provided the alkynylated derivative 5a and amine 5b (Scheme 3), giving access to carborane-based host materials of relevant to phosphorescent organic light-emitting diodes.²⁰Open in a separate windowScheme 3Late-stage diversification.Next, we became attracted to delineating the mode of the cupraelectro-catalyzed cage C–H chalcogenation. To this end, control experiments were performed (Scheme 4a). First, electrocatalysis in the presence of TEMPO or Ph₂C CH₂ gave the desired product 3aa. EPR studies of thiol 2a, LiOtBu and THF under the electrochemical conditions showed a small radical signal, which might be attributed to a thiol radical.²¹ Second, the cupraelectrocatalysis occurred efficiently in the dark. Third, detailed cyclovoltammetric analysis of the thiol and iodide mediator (Scheme 4b and ESI^†)²¹ revealed an irreversible oxidation of the thiol anion at E_p = −0.62 V vs. Ag/Ag⁺ and two oxidation events for the iodide, including an irreversible oxidation at E_p = 0.12 V vs. Ag/Ag⁺ and a reversible oxidation at E_p = 0.44 V vs. Ag/Ag⁺, which is in good agreement with the literature reported iodide oxidation potentials,^18c,d and is suggestive of the preferential oxidation of the iodide as a redox mediator. In this context, the use of n-Bu₄NI as a redox mediator to achieve copper-catalyzed electrochemical arene C–H aminations had been documented.^18d Furthermore, we calculated the redox potential of complex C by means of DFT calculations at the PW6B95-D4/def2-TZVP + SMD(MeCN)//TPSS-D3BJ/def2-SVP level of theory.²¹ These studies revealed a calculated oxidation half-wave potential for complex C is E^o,calc_1/2 = −0.08 V vs. SCE. Hence, iodide is a competent redox mediator to achieve the transformation from complex C to complex D. Analysis of non-covalent interactions²¹ in complex C (Fig. 2) show the presence of a weak stabilization interaction between the chalcogen''s anisole group and the 2-phenylpyridine. In contrast, in complex D these interactions were found more relevant between the o-carborane phenyl group and the chalcogen aromatic motif.Open in a separate windowFig. 2Non-covalent interaction plots for the complexes C and D. Strong attractive interactions are shown in blue, weak attractive interactions are given in green, while red corresponds to repulsive interactions. Ar = 4-MeOC₆H₄.Open in a separate windowScheme 4Control experiments and cyclic voltammograms.On the basis of the aforementioned findings,¹⁸ a plausible reaction mechanism is proposed in Scheme 5, which commences with an anodic single electron-transfer (SET) oxidation of the thiol anion E to form the sulfur-centered radical F. Subsequently, the copper(i) species A reacts with the sulfur radical F to deliver copper(ii) complex B, which next reacts with o-carborane 1 in the presence of LiOtBu to generate a copper(ii)-o-carborane complex C. Thereafter, the complex C is oxidized by the anodically generated redox mediator I₂ to furnish the copper(iii) species D,^18d which subsequently undergoes reductive elimination, affording the final product and regenerating the catalytically active complex A. Alternatively, the direct oxidation of copper(ii) complex C by electricity to generate copper(iii) species D can not be excluded at this stage.^18a,bOpen in a separate windowScheme 5Proposed reaction mechanism.In conclusion, a sustainable electrocatalytic C–H chalcogenation of o-carboranes with thiols and selenols was realized at room temperature by earth abundant copper catalysis. The C–H activation was characterized by mild reaction conditions and high functional group tolerance, leading to the facile assembly of various o-carboranes. Thereby, a transformative platform for the design of cage C–S and C–Se o-carboranes was established that avoids chemical oxidants by environmentally-sound electricity in the absence of directing groups. A plausible mechanism of paired electrolysis was established by detailed mechanistic studies.     

Catalytic enantioselective synthesis of benzocyclobutenols and cyclobutanols via a sequential reduction/C–H functionalization

We report here a sequential enantioselective reduction/C–H functionalization to install contiguous stereogenic carbon centers of benzocyclobutenols and cyclobutanols. This strategy features a practical enantioselective reduction of a ketone and a diastereospecific iridium-catalyzed C–H silylation. Further transformations have been explored, including controllable regioselective ring-opening reactions. In addition, this strategy has been utilized for the synthesis of three natural products, phyllostoxin (proposed structure), grandisol and fragranol.

We report here a sequential enantioselective reduction/C–H functionalization to install contiguous stereogenic carbon centers of benzocyclobutenols and cyclobutanols.

Molecules with inherent ring strain have gained considerable interest in the synthetic community.¹ Among them, four-membered ring molecules have been recognized as powerful building blocks in organic synthesis.² Driven by ring strain releasing, the reactions of carbon–carbon bond cleavage have been extensively studied in recent years.³ Meanwhile, cyclobutane motifs represent important structural units in natural product and bioactive molecules as well (Scheme 1).⁴ Therefore, a general and robust method to constitute four-membered ring derivatives is of great value, especially in an enantiomerically pure form.⁵Open in a separate windowScheme 1Representative cyclobutane-containing bioactive molecules.[2 + 2]-Cycloaddition⁶ and the skeleton rearrangement reaction⁷ are two primary methods to prepare chiral cyclobutane derivatives. Recently, the precision modification of four-membered ring skeletons to access enantioenriched cyclobutane derivatives has attracted emerging attention. Several strategies have been developed, including allylic alkylation,⁸ α-functionalization,⁹ conjugate addition¹⁰ and C–H functionalization¹¹ of prochiral or racemic cyclobutane derivatives (Scheme 2a).¹² However, the enantioselective synthesis of chiral benzocyclobutene derivatives is still underdeveloped.¹³ Although two efficient palladium-catalyzed C–H activation strategies have been developed by Baudoin¹⁴ and Martin¹⁵ groups via similar intermediate five-membered palladacycles, no enantioenriched benzocyclobutene derivative has been prepared by employing the above two methods. In 2017, Kawabata reported an elegant example of asymmetric intermolecular α-arylation of enantioenriched amino acid derivatives to afford benzocyclobutenones with tetrasubstituted carbon via memory of chirality (Scheme 2b).¹⁶ In 2018, Zhang reported an iridium-catalyzed asymmetric hydrogenation of α-alkylidene benzocyclobutenones in good enantioselectivities (3 examples, 83–88% ee).^12c To the best of our knowledge, there is no report on enantioselective synthesis of benzocyclobutene derivatives with all-carbon quaternary centers.Open in a separate windowScheme 2Asymmetric synthesis of cyclobutanes and their derivatives. (a) Enantioselective functionalization of four-membered ring substrates. (b) Synthesis of chiral benzocyclobutenone via memory of chirality. (c) This work: sequential enantioselective reduction/C–H functionalization.In line with our continued interest in precision modification of four-membered ring skeletons,^9d,10c,12a we initiated our studies on the synthesis of chiral benzocyclobutenes via enantioselective functionalization of highly strained benzocyclobutenones. It is well known that benzocyclobutene derivatives are labile to undergo a ring-opening reaction to release their inherent ring strains.¹⁷ Therefore, it is a challenging task to modify the benzocyclobutenone and preserve the four-membered ring skeleton at the same time. We envisioned that a carbonyl group directed C–H functionalization¹⁸ of the gem-dimethyl group could furnish enantioenriched α-quaternary benzocyclobutenones (Scheme 2c). This could be viewed as an alternative approach to achieve the alkylation of benzocyclobutenone, which was otherwise directly inaccessible using enolate chemistry through the unstable anti-aromatic intermediate.¹⁹ In addition, a highly regioselective C–H activation would be required to functionalize the methyl group instead of the aryl ring. Here we report our work on sequential enantioselective reduction and intramolecular C–H silylation to provide enantioenriched benzocyclobutenols and cyclobutanols with all-carbon quaternary centers. The excellent diastereoselectivity and regioselectivity of silylation were attributed to rigid structural organization of the 4/5 fused ring. Furthermore, this strategy has been utilized to accomplish the total synthesis of natural products phyllostoxin (proposed structure), grandisol and fragranol.We commenced our studies with enantioselective reduction of readily prepared dimethylbenzocyclobutenone 1a (Scheme 3).^15,20 Surprisingly, enantioselective reduction of the carbonyl group of cyclobutanone derivatives received little attention. The first reduction of parent benzocyclobutenone was studied in 1996 by Kündig using chlorodiisopinocamphenylborane²¹ or chiral oxazaborolidines (CBS reduction),²² and only moderate enantioselectivity (44–68% ee) was obtained.²³ Although copper-catalyzed asymmetric hydrosilylation of benzocyclobutenone 1a using CuCl/(R)-BINAP gave the benzocyclobutenol ent-2a in 88% ee, optimization of ligands gave no further improvement (Scheme 3a, see Tables S1–S4^† for details).²⁴ Gladly, excellent enantioselective reduction could be achieved in 94% yield and 97% ee under Noyori''s asymmetric transfer hydrogenation conditions (Scheme 3b, conditions A, RuCl[(S,S)-Tsdpen](p-cymene)).²⁵ The product 2a showed remarkable stability and no ring-opening byproduct 2a′ was observed. The reduction of parent benzocyclobutenone was examined under conditions A, and benzocyclobutenol was obtained in 90% yield and 81% ee. Apparently, the steric influence imposed by the α-dimethyl group enhanced the enantioselectivity of the reduction. Similarly, the CBS reduction ((S)-B–Me) of benzocyclobutenone 1a gave better results compared with parent benzocyclobutenone, affording the product 2a in 86% yield and 92% ee (Scheme 3c).Open in a separate windowScheme 3Enantioselective reduction of benzocyclobutenone 1a. (a) Copper hydride reduction. (b) Ru-catalyzed asymmetric transfer hydrogenation. (c) CBS reduction.We then examined the substrate scope of the reduction reaction (26 was chosen to improve the yield and enantioselectivity. Besides, benzocyclobutenol 2g with nitro substitution could be obtained in 96% yield and 93% ee. Treatment of pyrrolidinyl substituted benzocycobutenone 1h with catalyst (S,S)-Ts-DENEB afforded desired product 2h in 49% yield and 89% ee, together with ring-opening product 2h′ (18%).Enantioselective reduction of benzocyclobutenones^a

Construction of vicinal 4°/3°-carbons via reductive Cope rearrangement

Herein reported is a strategy for constructing vicinal 4°/3° carbons via reductive Cope rearrangement. Substrates have been designed which exhibit Cope rearrangement kinetic barriers of ∼23 kcal mol⁻¹ with isoenergetic favorability (ΔG ∼ 0). These fluxional/shape-shifting molecules can be driven forward by chemoselective reduction to useful polyfunctionalized building blocks.

Herein reported is a strategy for constructing vicinal 4°/3° carbons via reductive Cope rearrangement.

Constructing sterically congested vicinal quaternary–tertiary carbons (4°/3° carbons) via Cope rearrangement is currently quite limited with only a handful of papers on the subject published over the past 40 years. This stands in stark contrast to the plethora of other methods for establishing sterically congested vicinal carbons.^1–5 Central to the challenge are kinetic and thermodynamic issues associated with the transformation. In the simplest sense, Cope rearrangements proceed in the direction that results in highest alkene substitution (Fig. 1).^6,7 To forge 4°/3° motifs by Cope rearrangement, additional driving forces must be introduced to reverse the [3,3] directionality and compensate for the energetic penalty associated with the steric and torsional strain of the targeted vicinal 4°/3° motif. With limited reports in all cases, oxy-Cope substrates (Scheme 1, eqn (1)),^8–14 divinylcyclopropanes (Scheme 1, eqn (2)),^15–20 and vinylidenecyclopropane-based 1,5-dienes²¹ (Scheme 1, eqn (3)) have demonstrated favourability for constructing vicinal 4°/3° carbons. Malachowski et al. put forth a series of studies on the construction of quaternary centers via Cope rearrangement driven forward by a conjugation event (Scheme 1, eqn (4)).^22–25 In their work, a single example related to the construction of vicinal 4°/3° centers was disclosed, though kinetic (180 °C) and thermodynamic (equilibrium mixtures) challenges are also observed.²³ And of particular relevance to this work, Wigfield et al. demonstrated that 3,3-dicyano-1,5-dienes with the potential to generate vicinal 4°/3° carbons instead react via an ionic mechanism yielding the less congested products (Scheme 1, eqn (5)).²⁶Open in a separate windowFig. 1Cope equilibrium of 1,1,6-trisubstituted 1,5-dienes.Open in a separate windowScheme 1(A) Cope rearrangements for constructing vicinal 4°/3°-centers (B) this report.Our group has been examining strategies to decrease kinetic barriers and increase the thermodynamic favourability of 3,3-dicyano-1,5-diene-based Cope substrates.^27–31 Beyond the simplest, unsubstituted variants, this class of 1,5-diene is not particularly reactive in both a kinetic and thermodynamic sense (e.g.Scheme 1, eqn (5)).^26,32 Reactivity issues aside, these substrates are attractive building blocks for two main reasons: (1) they have straightforward accessibility from alkylidenemalononitriles and allylic electrophiles by deconjugative allylic alkylation.³³ (2) The 1,5-diene termini are substantially different (malononitrile vs. simple alkene) thus allowing for orthogonal functional group interconversion facilitating target and analogue synthesis.³⁴ Herein we report that a combination of 1,5-diene structural engineering^28,31 and reductive conditions (the reductive Cope rearrangement^29,30) can result in the synthesis of building blocks containing vicinal gem-dimethyl 4°/3° carbons along with orthogonal malononitrile and styrene functional groups for interconversion (Scheme 1B). On this line, malononitrile can be directly converted to amides³⁴ yielding functionally dense β-gem-dimethylamides, important pharmaceutical scaffolds.³⁵This project began during the Covid-19 pandemic lockdown (ca. March–May 2020). As such, we were not permitted to use our laboratory out of an abundance of caution. We took this opportunity to first computationally investigate a Cope rearrangement that could result in vicinal 4°/3° carbons (Scheme 2). Then, when permitted to safely return to the lab, we would experimentally validate our findings (vide infra). From our previous work, it is known that by adding either a 4-aromatic group²⁸ or a 4-methyl group³¹ to a 3,3-dicyano-1,5-diene, low barrier (rt – 80 °C) diastereoselective Cope rearrangements can occur. Notably, the 4-substituent was found to destabilize the starting material (weaken the C3–C4 bond, conformationally bias the substrate for [3,3]), and stabilize the product side of the equilibrium via resonance (phenyl group) or hyperconjugation (methyl group). In this study, we modelled substrates 1, 3, and 5 that have variable 4-substitution and would result in vicinal gem-dimethyl- and phenyl-containing 4°/3° carbons upon Cope rearrangement to 2, 4, or 6, respectively. We chose to target this motif due to likely synthetic accessibility from simple starting materials but also because of the important and profound impact that gem-dimethyl groups impart on pharmaceuticals.³⁵ Substrate 1 lacking 4-substitution had an extremely unfavourable kinetic and thermodynamic profile (ΔG^‡ = 31.6; ΔG = +5.3 kcal mol⁻¹). When a 4-methyl group was added, the kinetic barrier (ΔG^‡) dropped appreciably to 28.2 kcal mol; however, the thermodynamics were still quite endergonic (ΔG = +4.4 kcal mol⁻¹). Most excitingly, it was uncovered that the 4-phenyl group dramatically impacted the kinetics and thermodynamics: the [3,3] has a barrier of 22.9 kcal mol⁻¹ (ΔG^‡) and is ∼isoenergetic (ΔG = +0.17 kcal mol⁻¹). Thus, the reaction appears to be fluxional/shape-shifting at room temperature.^36–40 For this substrate, we also modelled the dissociative pathway (Scheme 2D). It was found that bond breakage to two allylic radical intermediates is a higher energy process than the concerted transition state (Scheme 2Cvs.Scheme 2D). Specifically, the dissociative pathway was found to be kinetically less favourable (ΔG^‡ ∼ 27.6 kcal mol; ΔG = 26.2 kcal mol⁻¹) than the concerted process (ΔG^‡ = 22.9 kcal mol⁻¹). While the dissociative pathway is less favourable than the concerted transformation, we surmised that the two-step process becomes accessible at elevated temperature (vide infra). Finally, the ionic pathway was calculated to be significantly higher for this substrate (see the ESI^†).Open in a separate windowScheme 2Computational analysis of 3,3-dicyano-1,5-diene that in theory could result in vicinal 4°/3° carbons. (A) 4-Unsubstituted 3,3-dicyano-1,5-diene. (B) 4-Methyl 3,3-dicyano-1,5-diene. (C) 4-Phenyl 3,3-dicyano-1,5-diene. (D) The dissociative mechanism for substrate 5 is higher than the closed transition state. (E) visualization of the kinetic- and thermodynamic differences of transformations (A–D).The class of substrate uncovered from our computational investigation could be accessed from γ,γ-dimethyl-alkylidenemalononitrile (7a) and 1,3-diarylallyl electrophiles (such as 8a) by Pd-catalyzed deconjugative allylic alkylation (Scheme 3A).³³ As such, model 1,5-diene 5a was prepared to verify the computational results. It was found that upon synthesis of 5a, an inseparable 21 : 79 mixture of 1,5-diene 5a and the 1,5-diene 6a was observed. The predicted ratio of 5a to 6a was 57 : 43 (Scheme 2C). These two results are within the error of the calculations (predicted; slightly endergonic, observed; slightly exergonic). To determine whether the transformation was progressing through the predicted concerted pathway (Scheme 2C) over the dissociative pathway (Scheme 2D), substrate 5b was prepared by an analogous deconjugative allylic alkylation reaction. Similarly, two Cope equilibrium isomers 5b and 6b are observed at room temperature in a 12 : 88 ratio. Upon heating at 100 °C for 3 h, the 1,5-dienes “scramble” (e.g. iso-6b is observed; 0.2 : 1.0 : 1.5 ratio of 5b : 6b : iso-6b) indicating that the dissociative pathway is only accessible at elevated temperature. This is all in good agreement with the calculated kinetics and thermodynamics of this system (Scheme 2).Open in a separate windowScheme 3(A) Observation of fluxional [3,3] and confirmation of calculated predictions. (B) Optimization of a reductive Cope rearrangement protocol for constructing vicinal 4°/3° centers. (C) The Pd-catalyzed deconjugative allylic alkylation must be regioselective.With respect to the synthetic methodology, we aimed to increase the overall efficiency and applicability of the sequence (Scheme 3B). Specifically, we wanted to avoid [3,3] equilibrium mixtures and sensitive/unstable substates and intermediates. It was found that the direct coupling of 7a with diphenylallyl alcohol 9a could take place in the presence of DMAP, Ac₂O, and Pd(PPh₃)₄. When the coupling was complete, methanol and NaBH₄ were added to drive the Cope equilibrium forward, yielding the reduced Cope rearrangement product 10a in 76% isolated yield. In terms of practicality and efficiency, this method utilizes diphenylallyl alcohols, which are more stable and synthetically accessible than their respective acetates, and the [3,3] equilibrium mixture can be directly converted dynamically to a single reduced product.With an efficient protocol in hand for constructing malononitrile–styrene-tethered building blocks featuring central vicinal 4°/3° carbons, we next examined the scope of the transformation (Scheme 4). We chose diarylallyl alcohols with the propensity to react regioselectively via an electronic bias (Scheme 3C).^41,42 The combination of p-nitrophenyl and phenyl (10b) or p-methoxyphenyl (10c) yielded regioselective outcomes with the electron-deficient arene at the allylic position. This is consistent with the expected regiochemical outcome where the nucleophile reacts preferentially at the α-position and the electrophile reacts at the allylic position bearing the donor-arene (Scheme 3C).^41,42 Then, reductive Cope rearrangement occurs to position the electron-deficient arene adjacent to the gem-dimethyl quaternary center. This is an exciting outcome as many pharmaceutically relevant (hetero)arenes are electron deficient. Thus, fluorinated arenes were installed at the allylic position of products 10d–10k. While the phenyl group resulted in poor regioselectivity (1 : 1–3 : 1), the p-methoxyphenyl group enhanced the regiomeric ratios in all cases (3 : 1–15 : 1). The degree of selectivity is correlated with the number and position of fluorine atoms. N-Heterocycles could be incorporated with excellent regioselectivity, generally speaking (10l–10q). For example, 3-chloro-4-pyridyl (10l/10m) groups were installed at the allylic position with >20 : 1 rr. 4-Chloro-3-pyridyl was poorly regioselective (10n), but the combination of 4-trifluomethyl-3-pyridyl/p-methoxyphenyl (10o) gave good regioselectivity of 11 : 1. 2-Pyridyl/p-methoxyphenyl (10q) was also a regioselective combination. We also examined a few other heterocycles including quinoline (10s) and thiazole (10t and 10u) with excellent and modest regioselectivity observed, respectively. As a general trend, when the arenes on the allylic electrophile become less polarized, poor regioselectivity is observed in the Pd-catalyzed allylic alkylation. For example, the combination of p-chlorophenyl and p-methoxyphenyl (10v) or phenyl (10w) yields regioisomeric mixtures of products. This can be circumvented by utilizing symmetric electrophiles (to 10x).Open in a separate windowScheme 4Scope of the 4°/3°-center-generating reductive Cope rearrangement.The phenyl or the p-methoxyphenyl group is necessary to achieve the 4°/3° carbon-generating Cope rearrangement: it functions as an “activator” by lowering the kinetic barrier and increasing thermodynamic favourability. These activating groups can be removed through alkene C C cleavage reactions (e.g. metathesis (Scheme 5) and ozonolysis (Scheme 6B)). In this regard, highly substituted cycloheptenes 11 were prepared by allylation and metathesis (Scheme 4).^28,43 The yields were modest to excellent over this two-step sequence. In many cases, where 10 exists as a mixture of regioisomers, the major allylation/RCM products 11 could be chromatographically separated from their minor constituents. As shown in Scheme 6A, the malononitrile can be transformed via oxidative amidation³⁴ to products 12 containing a dense array of pharmaceutically relevant functionalities (amides, gem-dimethyl, fluoroaromatics, and heteroaromatics). Following this transformation, ozonolysis terminated with a NaBH₄ quench installs an alcohol moiety on small molecule 13a.Open in a separate windowScheme 5Removal of the “activating group” by ring-closing metathesis.Open in a separate windowScheme 6(A) oxidative amidation of malononitrile. (B) Removal of “activating group” by ozonolysis.These first computational and experimental studies utilizing 3,3-dicyano-1,5-dienes as substrates for constructing vicinal 4°/3° centers sets the stage for much further examination and application. For example, while we focused our efforts on gem-dimethyl-based quaternary carbons, it is likely that other functionality can be installed at this position. For example, while unoptimized, it appears the protocol is reasonably effective at incorporating a piperidine moiety in addition to heteroarenes from the allylic electrophile (7b + 9f → 14a; Scheme 7A). Similar functional group interconversion chemistry as described in Schemes 5 and ​and66 can thus yield functionally dense building blocks 15 and 16 in good yields.Open in a separate windowScheme 7(A) The construction of 4/3° centres on piperidines. (B) Promoting endergonic [3,3] rearrangements is possible, assuming the [3,3] kinetic barrier is sufficiently low.While the 4,6-diaryl-3,3-dicyano-1,5-dienes offered the most attractive energetic profile (low kinetic barrier, isoenergetic [3,3] equillibrium; Scheme 2C), the 4-methyl analogue is also intriguing to consider as a viable substrate class for reductive Cope rearrangement (Scheme 2B). The challenge here is that the kinetics and thermodynamics are quite unfavourable (not observable by NMR), but potentially not prohibitively so. It is extremely exciting to find that Cope equilibria that are significantly endergonic in the desired, forward direction (e.g.3a to 4a) can be promoted by a related reductive protocol (Scheme 7B). While unoptimized, we were able to isolate product 17 in xx% yield by heating at 90 °C in the presence of Hantzsch ester in DMF.     

Electrochemically selective double C(sp2)–X (X = S/Se,N) bond formation of isocyanides

The construction of C(sp²)–X (X = B, N, O, Si, P, S, Se, etc.) bonds has drawn growing attention since heteroatomic compounds play a prominent role from biological to pharmaceutical sciences. The current study demonstrates the C(sp²)–S/Se and C(sp²)–N bond formation of one carbon of isocyanides with thiophenols or disulfides or diselenides and azazoles simultaneously. The reported findings could provide access to novel multiple isothioureas, especially hitherto rarely reported selenoureas. The protocol showed good atom-economy and step-economy with only hydrogen evolution and theoretical calculations accounted for the stereoselectivity of the products. Importantly, the electrochemical reaction could exclusively occur at the isocyano part regardless of the presence of susceptible radical acceptors, such as a broad range of arenes and alkynyl moieties, even alkenyl moieties.

We have developed an efficient and sustainable electrochemical strategy for the double C(sp²)–X (S/Se, N) bond formation of isocyanides simultaneously. A series of novel isothio/selenoureas were obtained via a three-component cross-coupling.

The construction of C(sp²)–X (X = B, N, O, Si, P, S, Se, etc.) bonds has drawn increased attention from researchers since heteroatomic compounds play a prominent role in various fields.¹ Traditionally, the transition-metal-catalyzed cross-coupling of a nucleophile and an electrophile is an important method for the formation of C(sp²)–X bonds.² Obviously, the direct cross-coupling of C(sp²)–H/X–H is a time-, effort-, and resource-economical process to construct C(sp²)–X bonds as it avoids the pre-functionalization of substrates.³ Alternatively, radical chemistry provides greener and more mild strategies for the formation of C(sp²)–X bonds, and a variety of high added-value compounds can be afforded successfully.⁴ Despite the numerous advances, these reported reactions are limited as they involve only single C(sp²)–X bond formation. Access to double C(sp²)–X bonds formation of one carbon remains still a room for improvement stimultaneously.As an ideal connector, isocyanides could be inserted into metal–carbon and metal–heteroatom bonds to construct double C(sp²)–X bonds.⁵ On the other hand, isocyanides could transform into heteroatomic molecules with electrophiles, nucleophiles and radicals.⁶ Although many elegant studies have been reported, the above methods are largely limited by the pre-functionalization of the substrate, the toxicity of metals or tedious synthesis steps. From the point of synthetic efficiency and economy, exploiting a novel, efficient, and diverse radical strategy to access double C(sp²)–X bonds under mild conditions and with broad functional group tolerance is of paramount importance and in urgent demand.Radical transformation processes are ubiquitous throughout synthesis chemistry and provide new ideas for forging new bonds and novel molecules, especially valuable product motifs.⁷ As a complementary strategy to conventional radical-based reactions, electrochemistry, effectively transferring electrons from the electrode surface to the substance, has been developed into a powerful synthetic technique toward radical chemistry.⁸ This electrochemical strategy further stimulated a resurgence of interest in radical chemistry with good atom-economy and step-economy.⁹ Myriad electrochemical-induced radical reactions have been reported via single-electron oxidation/reduction with a plethora of radicals and radical acceptors. As reported, alkenes, alkynes, and cyano and aromatic compounds could be considered to be favorable radical acceptors in diverse transformations, such as cross-coupling, cyclization and difunctionalization reactions.¹⁰ However, the application of isocyanides as radical acceptors is limited in utility due to electrochemical tandem cyclization.¹¹ Therefore, on the basis of our research on electrochemical oxidative functionalization of isocyanides,¹² we continued to explore the properties of isocyanides as radical acceptors under electrochemical conditions.Initially, we commenced our investigations by using abundant and inexpensive phenyl disulfide (1), ethyl 2-isocyanoacetate (2) and 1H-benzo[d][1,2,3]triazole (3) as model substrates in a single operation via a three-component cross-coupling. After systematic optimization, the isothiourea 21 could been obtained in 90% isolated yield. To gain insights into the reaction process, we continued to carry out a series of control experiments as shown in Scheme 1. The control experiment demonstrated that electricity is indispensable. Under standard conditions, addition of 2.0 equivalents of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) showed no traces of product. Similarly, the reaction was suppressed in the presence of butylated hydroxytoluene (BHT). The P(OEt)₃-trapping product could be detected by gas chromatography mass spectrometry (GCMS). Simultaneously, a S-centred radical signal (g = 2.0070, AN = 13.40 G, AH = 14.88 G) was quickly trapped by 5,5-dimethyl-1-pyrroline N-oxide (DMPO) via electron paramagnetic resonance (EPR) experiments. The reported results revealed that this reaction might proceed via S-radical pathways.Open in a separate windowScheme 1Control experiments.For deeper research of the priority of interaction for isocyanides vs. other radical acceptors with radicals, we sought to conduct robustness screening of a wide range of radical acceptors as shown in Scheme 2.¹³ The addition of an aryl olefin led to the complete shutdown of product formation (21) and the products of difunctionalization of alkenes were also not detected. To our delight, the alkenyl moiety did not affect the reaction efficiency under the electrochemical conditions. Unlike the aryl olefin, the addition of phenylacetylene did not inhibit product formation (21), delivering a yield of 93%. Similarly, ethyl 2-isocyanoacetate could be transformed into product (21) smoothly with 1-heptyne. The addition of mesitylene preserved the yield, while the yield decreased slightly with anisole. With the addition of furan and thiophene, an excellent yield of product (21) could still be obtained. Beside electron-donating arenes, we continued to add electron-withdrawing arenes to the reaction system. As expected, a satisfactory yield was obtained with 4-cyanopyridine. The results revealed that the electrochemical reaction exclusively occurred at the isocyano part regardless of the presence of electron-withdrawing arenes, electron-donating arenes and the alkynyl moiety, even the alkenyl moiety, which are also susceptible to radical conditions.Open in a separate windowScheme 2Competitive experiments of isocyanides vs. other radical acceptors with radicals. Conditions: 1 (0.15 mmol), 2 (0.6 mmol), 3 (0.5 mmol), R. A. = radical acceptors (0.6 mmol), ⁿBu₄NBF₄ (0.5 mmol), MeCN (6 mL), cloth anode, Pt cathode, undivided cell, constant current = 10 mA, room temperature, N₂, 2.25 h. ¹HNMR yield, dibromomethane as an internal standard.In order to further investigate the compatibility, we firstly examined the substrate scope of alkyl disulfides for the synthesis of isothioureas with ethyl 2-isocyanoacetate (2) and 1H-benzo[d][1,2,3]triazole (3) as shown in Scheme 3. To our delight, the yields did not decrease significantly with the increase of the carbon chain from methyl to decyl in this transformation (4–7). Isopropyl, isobutyl, cyclopentyl and cyclohexyl were well tolerated with good to excellent yields (8–11). Substances, containing sensitive benzylic C–H bonds, were tolerated to access novel isothioureas in this electrochemical induced-radical process (12–14, 34). Afterwards, we continued to explore the applicability from alkyl disulfides to thiophenol and a series of molecule isothioureas were obtained successfully with satisfactory yield. Thiophenol, containing electron-neutral (F, Cl, Br, H), electron-withdrawing (OCF₃, CF₃, and CO₂Me) and electron-donating (Me, Et, ^tBu, OMe, and SMe) groups, could smoothly transform to realize this process with high stereoselectivity under mild conditions (15–26). The structure of Z-conformer (16) was confirmed by X-ray crystallographic analysis. In addition, this protocol was successfully applied to thiophenols bearing diverse groups at different positions with good yields, indicating that steric hindrance has no obvious effect (20, 27–31). With curiosity, we tried to evaluate the tolerance of diselenides to construct novel Se–C–N bonds simultaneously. Unexpectedly, regardless of alkyl diselenides (32–33), benzyl diselenide (34) or aryl diselenide (35), all were well tolerated under electrochemical conditions, providing a series of unprecedented isoselenoureas, which were inaccessible by conventional methods. The compatibility of sensitive functional groups provides an opportunity for further molecular modification. The sensitive functional architectures including but not limited to ester (36), benzyloxy (37), allyl and allyloxy as well as endene (38, 41–44), labile alkyl chloride (39) and alkyl bromide (40), propargyl (44), and thiophene (45), all remained intact, enriching the diversity of heteroatom compounds. The merit of this methodology was further demonstrated by elaboration of a wide gamut of functional molecules and drug molecules to diverse isothioureas. Natural products including l-menthol and geraniol (46–47), food additives including isopulegol and furfuryl alcohol (48–49), and pharmaceuticals including ibuprofen (50) were apt to give rise to the corresponding isothioureas in 50–78% yields.Open in a separate windowScheme 3Scope of thiophenols/disulfides/diselenides. Conditions: ^a disulfides/diselenides (0.15 mmol) or ^b thiophenols (0.3 mmol), isocyanides (0.6 mmol), 1H-benzotriazole (0.5 mmol), ⁿBu₄NBF₄ (0.5 mmol), MeCN (6 mL), cloth anode, Pt cathode, undivided cell, constant current = 10 mA, room temperature, N₂, 2.25 h. Isolated yield.After defining the scope of thiophenols and disulfides, we turned our attention to explore the substrate scope with respect to nucleophiles in Scheme 4. Benzotriazole, with mono-substitution or multi-substitution, could be efficiently converted to the corresponding skeletons in 55–75% yields (51–54). Under standard conditions, pyrazole also showed great reactivity with phenyl disulfide or ethyl disulfide (55–56). The introduction of a halogen group in pyrazolylcycle, especially a subtle C–I bond, was compatible with satisfactory results (57–59, 64–65). 4-Methyl-1H-pyrazole as a coupling partner also realized the aminosulfenylation of isocyanide, albeit less efficiently (62). Of note is that the yield was increased to 70% from 40% by replacing methyl with phenyl (63). In addition to benzotriazole and pyrazole derivatives, other triazoles and tetrazole were proved to be viable coupling partners as well, enabling access to the target products in synthetically useful yields (66–70). Subsequently, with this established-optimized condition, we set out to investigate substrates for isocyanide coupling partners. With methyl isocyanoacetate (71), a similar effect was observed in an electrochemical difunctionalization reaction. As expected, both tosylmethyl isocyanide and benzyl isocyanide were demonstrated to be competent substrates (72–73). Cyclohexyl isocyanide, as a representative of secondary isocyanides, converted into the corresponding product (74). Gratifyingly, isocyanides, regardless of the steric effect, could engage with thiophenols to give the corresponding adducts in good yields (75–76). Aryl isocyanides however afforded the desired products in low yields under standard reaction conditions (77–78).Open in a separate windowScheme 4Scope of azazoles. Conditions: ^a disulfides/diselenides (0.15 mmol) or ^b thiophenols (0.3 mmol), isocyanides (0.6 mmol), azazoles (0.5 mmol), ⁿBu₄NBF₄ (0.5 mmol), MeCN (6 mL), cloth anode, Pt cathode, undivided cell, constant current = 10 mA, room temperature, N₂, 2.25 h. Isolated yield.To evaluate the feasibility of this electrochemical protocol, we monitored the reaction on a 4.5 mmol scale as shown in Scheme 5. Under similar conditions, by prolonging the reaction time to 34 h, a good isolated yield of 72% was obtained, which provided an opportunity for further synthetic manipulations.Open in a separate windowScheme 5Gram-scale synthesis.In order to account for the stereoselectivity of products, theoretical calculations were performed. The result demonstrated that the free energy of the Z-conformer of the product 16 is 2.3 kcal mol⁻¹ smaller than that of the E-conformer.Based on a previously reported mechanistic study¹⁴ and these above observations, a synthetically possible mechanism for the electrochemical intermolecular difunctionalization reaction is depicted in Scheme 6. A sulfur radical was formed via single-electron-transfer (SET) reduction of the disulfide or SET oxidation of the thiophenol. Subsequently, the exclusive capture of the S-radical by the isocyano part yields the imine C-radical I. Further SET oxidation of this radical intermediate to the corresponding imine carbocation II, followed by nucleophilic trapping intermolecularly, affords the final isothioureas.Open in a separate windowScheme 6Proposed reaction mechanism.     

Solvent coordination to palladium can invert the selectivity of oxidative addition

Reaction solvent was previously shown to influence the selectivity of Pd/P^tBu₃-catalyzed Suzuki–Miyaura cross-couplings of chloroaryl triflates. The role of solvents has been hypothesized to relate to their polarity, whereby polar solvents stabilize anionic transition states involving [Pd(P^tBu₃)(X)]⁻ (X = anionic ligand) and nonpolar solvents do not. However, here we report detailed studies that reveal a more complicated mechanistic picture. In particular, these results suggest that the selectivity change observed in certain solvents is primarily due to solvent coordination to palladium. Polar coordinating and polar noncoordinating solvents lead to dramatically different selectivity. In coordinating solvents, preferential reaction at triflate is likely catalyzed by Pd(P^tBu₃)(solv), whereas noncoordinating solvents lead to reaction at chloride through monoligated Pd(P^tBu₃). The role of solvent coordination is supported by stoichiometric oxidative addition experiments, density functional theory (DFT) calculations, and catalytic cross-coupling studies. Additional results suggest that anionic [Pd(P^tBu₃)(X)]⁻ is also relevant to triflate selectivity in certain scenarios, particularly when halide anions are available in high concentrations.

In the presence of the bulky monophosphine P^tBu₃, palladium usually prefers to react with Ar–Cl over Ar–OTf bonds. However, strongly coordinating solvents can bind to palladium, inducing a reversal of selectivity.

Oxidative addition is a key elementary step in diverse transformations catalyzed by transition metals.¹ For instance, this step is common to traditional cross-coupling reactions, which are among the most widely used methods for small molecule synthesis. During the oxidative addition step of cross-coupling reactions, a low valent metal [usually Pd(0)] inserts into a C–X bond with concomitant oxidation of the metal by two electrons. The “X” group of the C–X bond is commonly a halogen or triflate. Despite a wealth of research into this step,^2–5 uncertainties remain about its mechanistic nuances. The mechanistic details are especially pertinent to issues of selectivity that arise when substrates contain more than one potentially reactive C–X bond.⁶One of the best-studied examples of divergent selectivity at the oxidative addition step is the case of Pd-catalyzed Suzuki couplings of chloroaryl triflates. In 2000, Fu reported that a combination of Pd(0) and P^tBu₃ in tetrahydrofuran (THF) effects selective coupling of 1 with o-tolylB(OH)₂via C–Cl cleavage, resulting in retention of the triflate substituent in the final product 2a (Scheme 1A).⁷ In contrast, the use of PCy₃ (ref. 7) or most other phosphines⁸ provides complementary selectivity (product 2b) under similar conditions. The unique selectivity imparted by P^tBu₃ was later attributed to this ligand''s ability to promote a monoligated oxidative addition transition state on account of its bulkiness.^5,8 Smaller ligands, on the other hand, favor bisligated palladium, which prefers to react at triflate. The relationship between palladium''s ligation state and chemoselectivity has been rationalized by Schoenebeck and Houk through a distortion/interaction analysis.⁵ In brief, the selectivity preference of PdL₂ is dominated by a strong interaction between the electron-rich Pd and the more electrophilic site (C–OTf). On the other hand, PdL is less electron-rich and its selectivity preference mainly relates to minimizing unfavorable distortion energy by reacting at the more easily-distorted C–Cl bond.Open in a separate windowScheme 1Seminal reports on the effects of (A) ligands and (B) solvents on the selectivity of cross-coupling of a chloroaryl triflate.^5,7,9Proutiere and Schoenebeck later discovered that replacing THF with dimethylformamide (DMF, Scheme 1B, entry 1) or acetonitrile caused a change in selectivity for the Pd/P^tBu₃ system.^9,10 In these two polar solvents, preferential reaction at triflate was observed, and P^tBu₃ no longer displayed its unique chloride selectivity. The possibility of solvent coordination to Pd was considered, as bisligated Pd(P^tBu₃)(solv) would be expected to favor reaction at triflate. However, solvent coordination was ruled out on the basis of two intriguing studies. First, DFT calculations using the functional B3LYP suggested that solvent-coordinated transition states are prohibitively high in free energy (about 16 kcal mol⁻¹ higher than the lowest-energy monoligated transition structure). Second, the same solvent effect was not observed in a Pd/P^tBu₃-catalyzed base-free Stille coupling in DMF (Scheme 1B, entry 2). Instead, the Stille coupling was reported to favor reaction at chloride despite the use of a polar solvent. This result appears inconsistent with the possibility that solvent coordination induces triflate-selectivity, as coordination of DMF to Pd should be possible in both the Stille and Suzuki conditions, if it happens at all. Instead, it was proposed that the key difference between the Suzuki and Stille conditions was the absence of coordinating anions in the latter (unlike traditional Suzuki couplings, Stille couplings do not necessarily require basic additives such as KF to promote transmetalation). Indeed, when KF or CsF was added to the Stille reaction in DMF, selectivity shifted to favor reaction at triflate (Scheme 1B, entry 3), thereby displaying the same behavior as the Suzuki coupling in this solvent. On the basis of this and the DFT studies, it was proposed that polar solvents induce a switch in chemoselectivity if coordinating anions like fluoride are available by stabilizing anionic bisligated transition structures (Scheme 1B, right).However, our recent extended solvent effect studies produced confounding results.¹¹ In a Pd/P^tBu₃-catalyzed Suzuki cross-coupling of chloroaryl triflate 1, we observed no correlation between solvent polarity and chemoselectivity (Scheme 2). Although some polar solvents such as MeCN, DMF, and dimethylsulfoxide (DMSO) favor reaction at triflate, a number of other polar solvents provide the same results as nonpolar solvents by favoring reaction at chloride. For example, cross-coupling primarily takes place through C–Cl cleavage when the reaction is conducted in highly polar solvents like methanol, water, acetone, and propylene carbonate. In fact, the only solvents that promote reaction at triflate are ones that are commonly thought of as “coordinating” in the context of late transition metal chemistry.¹² These are solvents containing nitrogen, sulfur, or electron-rich oxygen lone pairs (nitriles, DMSO, and amides). The observed solvent effects were upheld for a variety of chloroaryl triflates and aryl boronic acids.¹¹Open in a separate windowScheme 2Expanded solvent effect studies in the Pd/P^tBu₃-catalyzed Suzuki coupling.¹¹We have sought to reconcile these observations with the earlier evidence⁹ against solvent coordination. Herein we report detailed mechanistic studies indicating that coordinating solvents alone are sufficient to induce the observed selectivity switch. In solvents like DMF and MeCN, stoichiometric oxidative addition is favored at C–OTf even in the absence of anionic additives. The apparent contradiction between our observations and the previously-reported DFT calculations and base-free Stille couplings is reconciled by a reevaluation of those studies. In particular, when dispersion is considered in DFT calculations, neutral solvent-coordinated transition structures involving Pd(P^tBu₃)(solv) become energetically feasible. Furthermore, we find that the selectivity analysis in the Stille couplings is convoluted by low yields, the formation of side products, and temperature effects. When these factors are disentangled, the Stille coupling in DMF displays selectivity similar to the Suzuki coupling in the same coordinating solvent. In light of these new results, anionic bisligated [Pd(P^tBu₃)(X)]⁻ does not appear to be the dominant active catalyst in nonpolar or polar solvents unless special measures are taken to increase the concentration of free halide, such as adding tetraalkylammonium halide salts or crown ethers.     

Assembly of multicyclic isoquinoline scaffolds from pyridines: formal total synthesis of fredericamycin A

The construction of an isoquinoline skeleton typically starts with benzene derivatives as substrates with the assistance of acids or transition metals. Disclosed here is a concise approach to prepare isoquinoline analogues by starting with pyridines to react with β-ethoxy α,β-unsaturated carbonyl compounds under basic conditions. Multiple substitution patterns and a relatively large number of functional groups (including those sensitive to acidic conditions) can be tolerated in our method. In particular, our protocol allows for efficient access to tricyclic isoquinolines found in hundreds of natural products with interesting bioactivities. The efficiency and operational simplicity of introducing structural complexity into the isoquinoline frameworks can likely enable the collective synthesis of a large set of natural products. Here we show that fredericamycin A could be obtained via a short route by using our isoquinoline synthesis as a key step.

A concise approach for rapid assembly of multicyclic isoquinoline scaffolds from pyridines and β-ethoxy α,β-unsaturated carbonyl compounds was developed, which enabled the formal total synthesis of fredericamycin A.

Isoquinolines and their derivatives are common structural motifs in numerous natural products. Among them, the analogues of isoquinolines fused with rings from the benzene side such as 8-hydroxyisoquinolin-1[2H]-one (Fig. 1a) have been found in hundreds of natural products with interesting bioactivities.¹ For example, fredericamycin A and the related family members, isolated from Streptomyces griseus, show both antimicrobial and anti-tumor activities.² Ericamycin is a natural product isolated in the culture of Streptomyces varius n. sp. with anti-staphylococcal activities.³ Due to the widespread presence of isoquinolines in both natural and synthetic molecules, numerous approaches have been developed to assemble this class of scaffolds.⁴ The dominated strategies reported to date focus on forming the new pyridine ring of isoquinolines (Fig. 1b, left part). Classic methods include Bischler–Napieralski isoquinoline synthesis,^4a,b Pictet–Gams isoquinoline synthesis,^4a and Pomeranz–Fritsch reaction.^4a These reactions, proven to be useful since as early as 1893,⁵ have their own merits and limitations. For instance, high reaction temperature (e.g. reflux in toluene) and strong acids are typically required and thus functional group tolerance can become challenging. On the other side, the introduction of structural complexities and substitution patterns is constrained as the substrates have to be pre-settled to favor the formation of pyridine moieties. Here we report a new approach to prepare isoquinoline scaffolds by constructing a new benzene ring (Fig. 1b, right part).⁶ Our method starts with pyridine derivatives as the substrates to react with readily available β-ethoxy α,β-unsaturated carbonyl compounds. The reaction cascade involves five main plausible mechanistic processes (Michael addition, Dieckmann condensation, elimination, aromatization and in situ methylation) to furnish isoquinoline-based products with medium to good yields. The tricyclic isoquinoline-containing products might serve as formal common starting points for rapid total synthesis of a large number of natural products, such as those exemplified in Fig. 1a. In the present study, we demonstrate that starting from the tricyclic isoquinoline adduct 6a prepared using our method, fredericamycin A can be synthesized in 8 steps (Fig. 1c). Our strategy for isoquinoline assembly offers complementary and in certain cases better solutions not readily provided by the classic methods. We expect our method to find impressive applications in concise modular synthesis of complex natural products and molecular libraries, especially those bearing isoquinoline units fused with additional cyclic structures.Open in a separate windowFig. 1Isoquinoline analogues and their synthesis.Our design and initial studies are illustrated in Scheme 1.⁷ We first used pyridine 1a to react with α-substituted cycloenones (2a–2d), in the hope of obtaining isoquinoline 3a as the target product (Scheme 1a). The use of 2a and 2b was inspired by studies from Tamura, in which α-Br in 1,4-naphthoquinone was used as a leaving group to form an aromatic ring.⁸ Unfortunately, no product was formed and most of the starting materials were recovered. When SPh (2c) or SOPh (2d) was incorporated at the α site of the cycloenone, side products 4a and 4b were isolated respectively in moderate yields. The Michael products 4a and 4b could not be further transformed into our desired cyclic product 3a under various conditions. We then studied the use of β-substituted cycloenones (2e–2g) to react with 1a (Scheme 1b). No reactions were observed when 2e or 2f was used. To our delight, when the halogen of 2e/2f was replaced with a methoxy unit (OCH₃, substrate 2g), an encouraging amount of annulation product 3a was detected (10% yield). A side product 5a was also obtained (5% yield) in this initial study and it couldn''t be further transformed into the annulation product 3a under various alkaline conditions. It is noteworthy that, while β-alkoxy cycloenones (specifically, only β-alkoxy cyclohexenones) have been used in Staunton–Weinreb annulation⁹ to prepare fused aromatic compounds, no examples for those containing a heterocyclic aromatic ring were reported.¹⁰ Even for the construction of an aromatic ring without any heteroatom, low yields (mostly ranging from 0 to 30%) often occurred for this type of annulation starting with β-alkoxy cycloenones,⁹ which severely hampered its usage in Staunton–Weinreb annulation for the total synthesis of natural products. Our initial results showcased the possibility of direct assembly of isoquinoline scaffolds from β-methoxy cyclopentenone for the first time, though also in a low yield of 10%.Open in a separate windowScheme 1Proposed routes and initial studies for isoquinoline synthesis.With the initial results in hand, we performed additional condition optimization (11 The β-methoxy cyclopentenone 2g could also react to give 6a in a lower yield of 65% (entry 3). Other bases [such as triethylenediamine (DABCO), diazabicyclo[5.4.0]undec-7-ene (DBU), 4-dimethylaminopyridine (DMAP), lithium bis(trimethylsilyl)amide (LiHMDS) and potassium bis(trimethylsilyl)amide (KHMDS)] gave poorer results with yields ranging from 0 to 42% (entry 4). When THF was changed to other solvents, lower yields (<41%) were obtained (entry 5). Revising the ratio of 1a to 2h from 1 : 1.5 to 1.5 : 1 delivered 6a in 39% to 54% yields (entries 6–8). Lower reaction temperature (e.g. −78 °C) could not improve the outcome of this cascade transformation, but gave 23% yield of 6a together with 16% yield of recovered starting material 2h (entry 9). Long exposure to low temperature in step 1 could also lead to a considerable amount of the undesired elimination product 5a (ca. 29% yield), which was decomposed under the following methylation conditions (step 2). No product was observed in the absence of the methoxy group in 1a as it could stabilize the transition state via the formation of a metallate complex (entry 10).Screening of conditions^a

Three-component 1,2-carboamination of vinyl boronic esters via amidyl radical induced 1,2-migration

Three-component 1,2-carboamination of vinyl boronic esters with alkyl/aryl lithium reagents and N-chloro-carbamates/carboxamides is presented. Vinylboron ate complexes generated in situ from the boronic ester and an organo lithium reagent are shown to react with readily available N-chloro-carbamates/carboxamides to give valuable 1,2-aminoboronic esters. These cascades proceed in the absence of any catalyst upon simple visible light irradiation. Amidyl radicals add to the vinylboron ate complexes followed by oxidation and 1,2-alkyl/aryl migration from boron to carbon to give the corresponding carboamination products. These practical cascades show high functional group tolerance and accordingly exhibit broad substrate scope. Gram-scale reaction and diverse follow-up transformations convincingly demonstrate the synthetic potential of this method.

Three-component 1,2-carboamination of vinyl boronic esters with alkyl/aryl lithium reagents and N-chloro-carbamates/carboxamides is presented.

Alkenes are important and versatile building blocks in organic synthesis. 1,2-Difunctionalization of alkenes offers a highly valuable synthetic strategy to access 1,2-difunctionalized alkanes by sequentially forming two vicinal σ-bonds.^1a–h Among these vicinal difunctionalizations, the 1,2-carboamination of alkenes, in which a C–N and a C–C bond are formed, provides an attractive route for the straightforward preparation of structurally diverse amine derivatives (Scheme 1a).^2a–c Along these lines, transition-metal-catalyzed or radical 1,2-carboaminations of activated and unactivated alkenes have been reported.^3a–p However, the 1,2-carboamination of vinylboron reagents, a privileged class of olefins,^4a–h to form valuable 1,2-aminoboron compounds which can be readily used in diverse downstream functionalizations,^{5a–c,6a–d} has been rarely investigated. To the best of our knowledge, there are only two reported examples, as shown in Schemes 1b and c. In 2013, Molander disclosed a Rh-catalyzed 1,2-aminoarylation of potassium vinyltrifluoroborate with benzhydroxamates via C–H activation (Scheme 1b).⁷ Thus, the 1,2-carboamination of vinylboron reagents is still underexplored but highly desirable.Open in a separate windowScheme 1Intermolecular 1,2-carboamination of alkenes.1,2-Alkyl/aryl migrations induced by β-addition to vinylboron ate complexes have been shown to be highly reliable for 1,2-difunctionalization of vinylboron reagents (Scheme 1c).^4d–h In 1967, Zweifel''s group developed 1,2-alkyl/aryl migrations of vinylboron ate complexes induced by an electrophilic halogenation.⁸ In 2016, the Morken group reported the electrophilic palladation-induced 1,2-alkyl/aryl migration of vinylboron ate complexes.^9a–k Shortly thereafter, we,^10a–c Aggarwal,^11a–c and Renaud¹² developed alkyl radical induced 1,2-alkyl/aryl migrations of vinylboron ate complexes. In these recent examples, the migration is induced by a C-based radical/electrophile, halogen and chalcogen electrophiles.^13a,bIn contrast, N-reagent-induced migration of vinylboron ate complexes proceeding via β-amination is not well investigated. To our knowledge, as the only example the Aggarwal laboratory described the reaction of a vinylboron ate complex with an aryldiazonium salt as the electrophile, but the desired β-aminated rearrangement product was formed in only 9% NMR yield (Scheme 1c).^13a No doubt, β-amino alkylboronic esters would be valuable intermediates in organic synthesis. Encouraged by our continuous work on amidyl radicals^14a–i and 1,2-migrations of boron ate complexes,^{10a–c,15a–f} we therefore decided to study the amidyl radical-induced carboamination of vinyl boronic esters for the preparation of 1,2-aminoboronic esters. N-chloroamides were chosen as N-radical precursors,^16a–c as these N-chloro compounds can be easily prepared from the corresponding N–H analogues.¹⁷ Herein, we present a catalyst-free three-component 1,2-carboamination of vinyl boronic esters with N-chloroamides and readily available alkyl/aryl lithium reagents (Scheme 1d).We commenced our study by exploring the reaction of the vinylboron ate complex 2a with tert-butyl chloro(methyl)carbamate 3a applying photoredox catalysis. Complex 2a was generated in situ by addition of n-butyllithium to the boronic ester 1a in diethyl ether at 0 °C. After solvent removal, the photocatalyst fac-Ir(ppy)₃ (1 mol%) and THF were added followed by the addition of 3a. Upon blue LED light irradiation, the mixture was stirred at room temperature for 16 hours. To our delight, the desired 1,2-aminoboronic ester 4a was obtained, albeit with low yield (26%, EntryPhotocatalystSolventT (°C)Yield^b (%)1 fac-Ir(ppy)₃THFrt262 fac-Ir(ppy)₃DMSOrt23 fac-Ir(ppy)₃MeCNrt564Ru(bpy)₃Cl₂·6H₂OMeCNrt695Na₂Eosin YMeCNrt696^cNa₂Eosin YMeCNrt707^cNoneMeCNrt458^cNoneMeCN0789^cNoneMeCN−2088 (85)10^c,dNoneMeCN−202Open in a separate window^aReaction conditions: 1a (0.20 mmol), ⁿBuLi (0.22 mmol), in Et₂O (2 mL), 0 °C to rt, 1 h, under Ar. After vinylboron ate complex formation, solvent exchange to the selected solvent (2 mL) was performed.^bGC yield using n-C₁₄H₃₀ as an internal standard; yield of isolated product is given in parentheses.^c4 mL MeCN was used.^dReaction carried out in the dark.With optimal conditions in hand, we then investigated the scope of this new 1,2-carboamination protocol keeping 2a as the N-radical acceptor (Scheme 2). This transformation turned out to be compatible with various primary amine reaction partners bearing carbamate (4a, 4b and 4d–4g) or acyl protecting groups (4c) (20–85%). Notably, N-chlorolactams can be used as N-radical precursors, as shown by the successful preparation of 4h (71%). Moreover, Boc-protected ammonia was also tolerated, delivering 4i in an acceptable yield (55%).Open in a separate windowScheme 21,2-Carboamination of 1a with various amidyl radical precursors. Reaction conditions: 1a (0.20 mmol, 1.0 equiv.), ⁿBuLi (0.22 mmol, 1.1 equiv.), in Et₂O (2 mL), 0 °C to rt, 1 h, under Ar; then [N]-Cl (0.24 mmol, 1.2 equiv.), −20 °C, 16 h, in MeCN (4 mL). Yields given correspond to yields of isolated products. ^aA solution of [N]-Cl (0.30 mmol, 1.5 equiv.) in MeCN (1 mL) was used. See the ESI^† for experimental details.We continued the studies by testing a range of vinylboron ate complexes (Scheme 3). To this end, various vinylboron ate complexes were generated by reacting the vinyl boronic ester 1a with methyllithium, n-hexyllithium, isopropyllithium and tert-butyllithium. For the n-alkyl-substituted vinylboron ate complexes, the 1,2-carboamination worked smoothly to afford 4j and 4k in good yields. However, the vinylboron ate complex derived from isopropyllithium addition provided the desired products in much lower yield (4l, 18% yield). When tert-butyllithium was employed, only a trace of the targeted product was detected (see ESI^†). As expected, cascades comprising a 1,2-aryl migration from boron to carbon worked well. Thus, by using PhLi for vinylboron ate complex formation, the 1,2-aminoboronic esters 4m–4o were obtained in 69–73% yields with the Boc (t-BuOCONClMe), ethoxycarbonyl-(EtOCONClMe) and methoxycarbonyl (Moc)-(MeOCONClMe) protected N-chloromethylamines (for the structures of 3, see ESI^†) as radical amination reagents. Keeping 3b as the N-donor, other aryllithiums bearing various functional groups at the para position of the aryl moiety, such as methoxy (4p), trimethylsilyl (4q), methyl (4r), phenyl (4s), trifluoromethoxy (4t), trifluoromethyl (4u), and halides (4v–4x) all reacted well in this transformation. Aryl groups bearing meta substituents are also tolerated, as documented by the preparation of 4y (81%). To our delight, a boron ate complex generated with a 3-pyridyl lithium reagent engaged in the cascade and the carboamination product 4z was isolated in high yield (82%).Open in a separate windowScheme 3Scope of vinylboron ate complexes. Reaction conditions: 1 (0.20 mmol, 1.0 equiv.), R_MLi (0.22 mmol, 1.1 or 1.3 equiv.), Et₂O or THF, under Ar; then [N]-Cl (0.30 mmol, 1.5 equiv.), −20 °C, 16 h, in MeCN. Yields given correspond to yields for isolated products. See the ESI^† for experimental details.The reason for the dramatic reduction in yield when α-branched alkyllithium or electron-rich aryllithium reagents were used might be that the corresponding vinylboron ate complexes could be oxidized by N-chloroamides via a single-electron oxidation process.^18a–e Furthermore, the α-unsubstituted vinyl boronic ester and vinyl boronic ester bearing various α-substituents are suitable N-radical acceptors and the corresponding products 4aa–4ac were obtained in 48–70% yield.To gain insights into the mechanism of this 1,2-carboamination, a control experiment was conducted. The reaction could be nearly fully suppressed when the reaction was carried out in the presence of a typical radical scavenger (2,2-6,6-tetramethyl piperidine-N-oxyl, TEMPO), indicating a radical mechanism (Scheme 4a). Further, considering an ionic process, the N-chloroamides would react as Cl⁺-donors that would lead to Zweifel-type products, which were not observed under the applied conditions. The proposed mechanism is shown in Scheme 4b. As chloroamides have been recently proposed to undergo homolysis under visible light irradiation,^19a,b we propose that initiation proceeds via homolytic N–Cl cleavage generating the electrophilic amidyl radical A, which then adds to the electron-rich vinylboron ate complex 2a to give the adduct boronate radical B. The radical anion B then undergoes single electron transfer (SET) oxidation with 3a in an electron-catalyzed process^20a,b or chloride atom transfer with 3a to provide C or D along with the amidyl radical A, thereby sustaining the radical chain. Intermediates C or D can then react via a boronate 1,2-migration^10c,11c,21 to eventually give the isolated product 4a.Open in a separate windowScheme 4Control experiment and proposed mechanism.To document the synthetic utility of the method, a larger-scale reaction and various follow-up transformations were conducted. Gram-scale reaction of 2a with 3a afforded the desired product 4a in good yield, demonstrating the practicality of this transformation (Scheme 5a). Oxidation of 4a with NaBO₃ provided the β-amino alcohol 5 in 89% yield (Scheme 5b). The N-Boc homoallylic amine 6 was obtained by Zweifel-olefination with a commercially available vinyl Grignard reagent and elemental iodine in good yield (79%).²² Heteroarylation of the C–B bond in 4a was realized by oxidative coupling of 4a with 2-thienyl lithium to provide 7.²³Open in a separate windowScheme 5Gram-scale reaction and follow-up chemistry.In summary, we have described an efficient method for the preparation of 1,2-aminoboronic esters from vinyl boronic esters via catalyst-free three-component radical 1,2-carboamination. Readily available N-chloro-carbamates/carboxamides, which are used as the N-radical precursors, react efficiently with in situ generated vinylboron ate complexes to afford the corresponding valuable 1,2-aminoboronic esters in good yields. The reaction features broad substrate scope and high functional group tolerance. The value of the introduced method was documented by Gram-scale reaction and successful follow-up transformations.     

Chelation-assisted C–C bond activation of biphenylene by gold(i) halides

A chelation-assisted oxidative addition of gold(i) into the C–C bond of biphenylene is reported here. The presence of a coordinating group (pyridine, phosphine) in the biphenylene unit enabled the use of readily available gold(i) halide precursors providing a new, straightforward entry towards cyclometalated (N^C^C)- and (P^C)-gold(iii) complexes. Our study, combining spectroscopic and crystallographic data with DFT calculations, showcases the importance of neighboring, weakly coordinating groups towards the successful activation of strained C–C bonds by gold.

Pyridine and phosphine directing groups promote the C–C activation of biphenylene by readily available gold(i) halides rendering a new entry to (N^C^C)- and (P^C)-gold(iii) species.

Activation of C–C bonds by transition metals is challenging given their inertness and ubiquitous presence alongside competing C–H bonds.¹ Both the intrinsic steric hindrance as well as the highly directional character of the p orbitals involved in the σ_C–C bond impose a high kinetic barrier for this type of processes.^2,3 Biphenylene, a stable antiaromatic system featuring two benzene rings connected via a four-membered cycle, has found widespread application in the study of C–C bond activation. Since the seminal report from Eisch et al. on the oxidative addition of a nickel(0) complex into the C–C bond of biphenylene,⁴ several other late transition metals have been successfully applied in this context.⁵ Interestingly, despite the general reluctance of gold(i) to undergo oxidative addition,⁶ its oxidative insertion into the C–C bond of biphenylene was demonstrated in two consecutive reports by the groups of Toste^7a and Bourissou,^7b respectively. The high energy barrier associated with the oxidation of gold could be overcome by the utilization of gold(i) precursors bearing ligands that exhibit either a strongly electron-donating character (e.g. IPr = [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene])^7a or small bite angles (e.g. DPCb = diphosphino-carborane).^7b,8 In line with these two approaches, more sophisticated bidentate (N^C)- and (P^N)-ligated gold(i) complexes have also been shown to aid the activation of biphenylene at ambient temperature (Scheme 1a).^7c,dOpen in a separate windowScheme 1(a) Previous reports on oxidative addition of ligated gold(i) precursors onto biphenylene. (b) This work: pyridine- and phosphine-directed C–C bond activation of biphenylene by commercially available gold(i) halides.In this context, we hypothesized that the oxidative insertion of gold(i) into the C–C bond of biphenylene could be facilitated by the presence of a neighboring chelating group.⁹ This approach would not only circumvent the need for gold(i) precursors featuring strong σ-donor or highly tailored bidentate ligands but also offer a de novo entry towards interesting, less explored ligand templates. However, recent work by Breher and co-workers showcased the difficulty of achieving such a transformation.¹⁰Herein, we report the oxidative insertion of readily available gold(i) halide precursors into the C–C bond of biphenylene. The appendage of both pyridine and phosphine donors in close proximity to the σ_C–C bond bridging the two aromatic rings provides additional stabilization to the metal center and results in a de novo entry to cyclometalated (N^C^C)- and (P^C)gold(iii) complexes (Scheme 1b).Our study commenced with the preparation of 5-chloro-1-pyridino-biphenylene system 2via Pd-catalyzed Suzuki cross coupling reaction between 2-bromo-3-methylpyridine and 2-(5-chlorobiphenylen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1 (Scheme 2).¹¹ To our delight, the reaction of 2 with gold(i) iodide in toluene at 130 °C furnished complex κ³-(N^C^C)Au(iii)–I 3 in 60% yield.^12,13 Complex 3 was isolated as yellow plate-type crystals from the reaction mixture and its molecular structure was unambiguously assigned by NMR spectroscopy, high-resolution mass spectrometry (HR-MS) and crystallographic analysis. Complex 3 exhibits the expected square-planar geometry around the metal center, with a Au–I bond length of 2.6558(3) Å.¹⁴ The choice of a neutral weakly bound gold(i)-iodide precursor is key for a successful reaction outcome: similar reactions in the presence of [(NHC)AuCl + AgSbF₆] failed to deliver the desired biscyclometalation adducts, as reported by Breher et al. in ref. 10. The oxidative insertion of gold(i) iodide into the four-membered ring of pyridino-substituted biphenylene provides a novel and synthetically efficient entry to κ³-(N^C^C)gold(iii) halides. These species have recently found widespread application as precursors for the characterization of highly labile, catalytically relevant gold(iii) intermediates,^15a–d as well as for the preparation of highly efficient emitters in OLEDs.^15e–g Previous synthetic routes towards these attractive biscyclometalated gold(iii) systems involved microwave-assisted double C–H functionalization reactions that typically proceed with low to moderate yields.^15aOpen in a separate windowScheme 2Synthesis of complex 3via oxidative addition of Au(i) into the C–C bond of pyridine-substituted biphenylene. X-ray structures of complex 3 with atoms drawn using 50% probability ellipsoids. Hydrogen atoms have been omitted for clarity. Additional selected bond distances [Å]: N–Au = 2.126(2), C1–Au = 1.973(2), C2–Au = 2.025(2), Au–I = 2.6558(3) and bond angles [deg]: N–Au–I = 99.25(6), N–Au–C1 = 79.82(9), C1–Au–C2 = 81.2(1), C2–Au–I = 99.73(8). For experimental details, see ESI.^†Encouraged by the successful results obtained with the pyridine-substituted biphenylene and considering the prominent use of phosphines in gold chemistry,^6,16 we wondered whether the same reactivity would be observed for a P-containing system. To this end, both adamantyl- and tert-butyl-substituted phosphines were appended in C1 position of the biphenylene motif. Starting from 5-chlorobiphenylene-1-carbaldehyde 4, phosphine-substituted biphenylenes 5a and 5b could be accessed in 3 steps (aldehyde reduction to the corresponding alcohol, Appel reaction and nucleophilic displacement of the corresponding benzylic halide) in 64 and 57% overall yields, respectively.¹³ The reactions of 5a and 5b with commercially available gold(i) halides (Me₂SAuCl and AuI) furnished the corresponding mononuclear complexes 7a–b and 8a–b, respectively (Scheme 3).¹³ All these complexes were fully characterized and the structures of 7a, 7b and 8a were unambiguously characterized by X-ray diffraction analysis.¹³ Interestingly, the nature of the halide has a clear effect on the chemical shift of the phosphine ligand so that a Δδ of ca. 5 ppm can be observed in the ³¹P NMR spectra of 7a–b (Au–Cl) compared to 8a–b (Au–I), the latter being the more deshielded. The Au–X bond length is also impacted, with a longer Au–I distance (2.5608(1) Å for 8a) compared to that measured in the Au–Cl analogue (2.2941(7) Å for 7a) (Δd = 0.27 Å).¹³Open in a separate windowScheme 3Synthesis and reactivity of complexes 7a–b, 8a–b, 9 and 10. X-ray structure of complexes 11b, 12 and 14 with atoms drawn using 50% probability ellipsoids. Hydrogen atoms have been omitted for clarity. For experimental details and X-ray structures see ESI.^†Despite numerous attempts to promote the C–C activation in these complexes,^10,13 all reactions resulted in the formation of highly stable cationic species 11a–b and 12, which could be easily isolated from the reaction media. In the case of cationic mononuclear-gold(i) complexes 11, a ligand scrambling reaction in which the chloride ligand is replaced by a phosphine in the absence of a scavenger, a process previously described for gold(i) species, can be used to justify the reaction outcome.¹⁷ The formation of dinuclear gold complex 12 can be ascribed to the combination of a strong aurophilic interaction between the two gold centers (Au–Au = 2.8874(4) Å) and the stabilizing η²-coordination of the metal center to the aromatic ring of biphenylene. Similar η²-coordinated gold(i) complexes have been reported but, to the best of our knowledge, only as mononuclear species.¹⁸Taking into consideration the observed geometry of complexes 7a–b in the solid state,¹³ the facile formation of stable cationic species 11 and 12 and the lack of reactivity of the gold(i) iodides 8a–b, we hypothesized that the free rotation around the C–P bond was probably restricted, placing the gold(i) center away from the biphenylene system and thus preventing the desired oxidative insertion reaction. To overcome this problem, we set out to elongate the arm bearing the phosphine unit with an additional methylene group, introduced via a Wittig reaction from compound 4 to yield ligand 6, prepared in 4 steps in 27% overall yield. Coordination with Me₂SAuCl and AuI resulted in gold(i) complexes 9 and 10, respectively (Scheme 3). The structure of 9 was unambiguously assigned by X-ray diffraction analysis and a similar environment around the metal center to that determined for complex 7a was observed for this complex.¹³With complexes 9 and 10 in hand, we explored their reactivity towards C–C activation of the four-membered ring of biphenylene.¹⁹ After chloride abstraction and upon heating at 100 °C for 5 hours, ring opening of the biphenylene system was observed for complex 9. Interestingly, formation of mono-cyclometalated adduct 13 was exclusively observed (the structure of 13 was confirmed by ¹H, ¹³C, ³¹P, ¹⁹F, ¹¹B and 2D NMR spectroscopy and HR-MS).¹³ The solvent appears to play a major role in this process, as performing the reaction in non-chlorinated solvents resulted in stable cationic complexes similar to 11.^13,20,21 The presence of adventitious water is likely responsible for the formation of the monocyclometalated (P^C)gold(iii) complex 13 as when the reaction was carried out in C₂H₄Cl₂ previously treated with D₂O, the corresponding deuterated adduct 13-d could be detected in the reaction media. These results showcase the difficulties associated with the biscyclometalation for P-based complexes as well as the labile nature of the expected biscyclometalated adducts. Interestingly though, these processes can be seen as a de novo entry towards relatively underexplored (P^C)gold(iii) species.²²The C–C activation was further confirmed by X-ray diffraction analysis of the phosphonium salt 14, which arise from the reductive elimination at the gold(iii) center in 13 upon exchange of the BF₄⁻ counter-anion with the weakly coordinating sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBAr^F).^13,23 The phosphorus atom is four-coordinate, with weak bonding observed to the distant counter-anion and a distorted tetrahedral geometry (C1–P–C2 = 95.05(17), C2–P–C3 = 112.1(1), C3–P–C4 = 116.6(1), C4–P–C1 = 107.4(2) deg). These results represent the third example in which the C(sp²)–P bond reductive elimination at gold(iii) has been reported.²⁴Further, it is important to note that, in contrast to the reactivity observed for the pyridine-substituted biphenylene, neither P-coordinated gold(i) iodo complexes 8a, 8b nor 10 reacted to give cyclometalated products despite prolonged heating, which highlights the need for highly reactive cationized gold(i) species to undergo oxidative addition when phosphine ligands are flanking the C–C bond.¹³To get a deeper understanding on the observed differences in reactivity for the N- vs. P-based directing groups, ground- and transition-state structures for the oxidative insertion of gold(i) halides in C1-substituted biphenylenes were computed by DFT calculations. The reactions of Py-substituted 2 with AuI to give 3 (I) and those of P-substituted 7a (II) and 9 (III) featuring the cationization of the gold(i) species were chosen as models for comparative purposes with the experimental conditions (Fig. 1 and S1–S10 in the ESI^†).^25–27 The computed activation energies for the three processes are in good agreement with the experimental data. The pyridine-substituted biphenylene I exhibits the lowest activation barrier for the oxidative insertion process (ΔG^‡ = 34.4 kcal mol⁻¹). The reaction on the phosphine-substituted derivatives II and III proved to be, after cationization of the corresponding gold(i) halide complexes (II-BF₄, III-BF₄) higher in energy (ΔG^‡ = 39.6 and 46.3 kcal mol⁻¹ respectively), although the obtained values do not rule out the feasibility of the C–C activation process. The transition state between I and I′ exhibits several interesting geometrical features: (a) the biphenylene is significantly bent, (b) the cleavage of the C–C bond is well advanced (d_C–C = 1.898 Å in TSIvs. d_C–C = 1.504 Å in I), and (c) the two C and the I atoms form a Y-shape around gold with minimal coordination from the pyridine (d_N–Au = 2.742 Å in TSIvs. d_N–Au = 2.093 Å in I and 2.157 Å in I′, respectively). The transition-state structures found for the P-based ligands (TSII and TSIII) also show an elongation of the C–C bond and display a bent biphenylene. However, much shorter P–Au distances (d_P–Au = 2.330 Å for TSII and 2.314 Å for TSIII) can be observed compared to the pyridine-based system, as expected due to the steric and electronic differences between these two coordinating groups. Analogously, longer C–Au distances were also found for the P-based systems (d_C1–Au = 2.152 Å for TSIvs. 2.235 Å and 2.204 Å for TSII and TSIII; d_C2–Au = 2.143 Å for TSIvs. 2.219 Å and 2.162 Å for TSII and TSIII), with a larger deviation of square planarity for Au in TSIII compared to TSII.^28,29 These results suggest that, provided the appropriate distance to the C–C bond is in place, the strong coordination of phosphorous to the gold(i) center does not prevent the C–C activation of biphenylene but other reactions (i.e. formation of diphosphine gold(i) cationic species, protodemetalation) can outcompete the expected biscyclometalation process. In contrast, a weaker donor such as pyridine offers a suitable balance bringing the gold in close proximity to the C–C bond and enables both the oxidative cleavage as well as the formation of the double metalation product.Open in a separate windowFig. 1Energy profile (ΔG and ΔG^‡ in kcal mol⁻¹), optimized structures, transition states computed at the IEFPCM (toluene/1,2-dichloroethane)-B3PW91/DEF2QZVPP(Au,I)/6-31++G(d,p)(other atoms) level of theory for the C–C activation of biphenylene with gold(i) iodide from I and gold(i) cationic from II and III. Computed structures of the transition states (TSI, TSII and TSIII) and table summarizing relevant distances.     

Pyridylphosphonium salts as alternatives to cyanopyridines in radical–radical coupling reactions

Radical couplings of cyanopyridine radical anions represent a valuable technology for functionalizing pyridines, which are prevalent throughout pharmaceuticals, agrochemicals, and materials. Installing the cyano group, which facilitates the necessary radical anion formation and stabilization, is challenging and limits the use of this chemistry to simple cyanopyridines. We discovered that pyridylphosphonium salts, installed directly and regioselectively from C–H precursors, are useful alternatives to cyanopyridines in radical–radical coupling reactions, expanding the scope of this reaction manifold to complex pyridines. Methods for both alkylation and amination of pyridines mediated by photoredox catalysis are described. Additionally, we demonstrate late-stage functionalization of pharmaceuticals, highlighting an advantage of pyridylphosphonium salts over cyanopyridines.

Cyanopyridines form dearomatized radical anions upon single-electron reduction and participate in photoredox coupling reactions. Pyridylphosphonium salts replicate that reactivity with a broader scope and increase the utility of these processes.

Modern photoredox catalysis and electrochemistry have enabled new synthetic methods that proceed via open-shell intermediates.¹ Under this regime, pyridine functionalization strategies have been developed where 4-cyanopyridines undergo single-electron reduction to form dearomatized radical species that couple with other stabilized radicals (Scheme 1A).² The cyano group is critical for efficient reactivity via pyridyl radical anions; alternatives such as 4-halopyridines more readily undergo elimination to pyridyl radicals after single-electron reduction resulting in a distinct set of coupling processes.³ We aimed to show that pyridylphosphonium salts could replicate the reactivity of cyanopyridines and allow a broader set of inputs into dearomatized pyridyl radical coupling reactions.⁴Open in a separate windowScheme 1Expansion of radical coupling reactions to complex pyridines.Cyanopyridines have facilitated pyridine alkylation, allylation, and alkenylation reactions providing access to valuable building blocks for medicinal and agrochemical programs.⁵ The cyano group is essential for these methods, but a problem arises when applying this chemistry to complex pyridines, such as those found in pharmaceutical and agrochemical candidates. These structures are often devoid of pre-installed functional groups, and it is often challenging to install a cyano group from C–H precursors regioselectively.⁶ We envisioned pyridylphosphonium salts, regioselectively constructed from the C–H bonds of a diverse set of pyridines, could serve as alternatives to cyanopyridines.⁷ Herein, we report couplings between alkyl BF₃K salts and preliminary studies of carboxylic acids and amines with pyridylphosphonium salts, including late-stage functionalization of complex pyridine-containing pharmaceuticals using this strategy.Recently, we reported a radical coupling reaction between a boryl-stabilized cyanopyridyl radical and a boryl-stabilized pyridylphosphonium radical.^7a The intermediate radicals arose via an unusual inner-sphere process that would be difficult to extend to other coupling reactions. A significant advance would be to show that pyridylphosphonium salts could function more generally as radical anion precursors and mimic the reactivity of cyano-pyridines. In particular, showing their viability in photoredox and electrochemical processes would translate to numerous synthetic transformations. To demonstrate this principle, we envisioned a redox-neutral alkylation reaction (Scheme 1B) via a radical coupling between radical zwitterion I, formed through single-electron reduction of a pyridylphosphonium salt (E^red_p/2 = −1.51 V vs. SCE) and benzyl radical II, resulting from single-electron oxidation of a BF₃K salt (E^red = +1.10 V vs. SCE for a primary benzylic salt).⁸ Loss of triphenylphosphine from dearomatized intermediate (III) would furnish the alkylated pyridine product. Notably, the redox events could invert, where the photocatalyst oxidizes the BF₃K salt first and reduces the pyridylphosphonium salt second, broadening the scope of amenable photocatalysts.We began our investigation by examining a series of photocatalysts for the coupling reaction of phosphonium salt 1a, formed with complete regioselectivity for the 4-position from 2-phenylpyridine, and benzylic BF₃K salt 2a under irradiation from a 455 nm Kessil light (Scheme 1B are potentially interchangeable.^1b The Adachi-type photocatalyst 3DPAFIPN improved the yield to 77% with a further increase to 82% after increasing the reaction concentration (entries 3 and 4). Adding 2,6-lutidine, previously shown as an effective additive for photoredox cross-coupling reactions of BF₃K salts by the Molander group,⁹ had no impact on the yield of 2-phenylpyridine salt 1a (entry 5) and the [Ir(ppy)₂(dtbbpy)]PF₆ catalyst was marginally less efficient under the same conditions (entry 6). We observed that 2,6-lutidine did substantially improve the yield when isomeric 3-Ph salt 1b was employed (entries 7 and 8); without 2,6-lutidine, the crude ¹H NMR indicates significant amounts of decomposition occurred, including 3-phenylpyridine, and the 4- vs. 2-position product ratio was 3 : 1. This outcome suggests that protiodephosphination and non-selective Minisci-type pathways can occur under these conditions. With 2,6-lutidine, the crude reaction pathway is cleaner, and the 4- vs. 2-position ratio improved to 8 : 1. At this point, we have not established the role of 2,6-lutidine, although it is conceivable that it reacts with BF₃ produced as the reaction progresses. In 2-substituted systems, steric hindrance around the pyridine N-atom of the salt would deter BF₃-coordination, whereas, in 3-substituted systems, such as salt 1b, coordination is more likely and may have a deleterious effect on the reaction (vide infra). Given the structural variation of pyridines that we anticipated applying to this process and how those structures could impact boron speciation during the reaction, we elected to use 2,6-lutidine as an additive in all subsequent reactions.¹⁰Optimization of pyridine alkylation, photocatalyst data and effect of BF₃·OEt₂ as an additive^a

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

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

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

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

Oxindole synthesis via polar–radical crossover of ketene-derived amide enolates in a formal [3 + 2] cycloaddition

Herein we introduce a simple, efficient and transition-metal free method for the preparation of valuable and sterically hindered 3,3-disubstituted oxindoles via polar–radical crossover of ketene derived amide enolates. Various easily accessible N-alkyl and N-arylanilines are added to disubstituted ketenes and the resulting amide enolates undergo upon single electron transfer oxidation a homolytic aromatic substitution (HAS) to provide 3,3-disubstituted oxindoles in good to excellent yields. A variety of substituted anilines and a 3-amino pyridine engage in this oxidative formal [3 + 2] cycloaddition and cyclic ketenes provide spirooxindoles. Both substrates and reagents are readily available and tolerance to functional groups is broad.

Herein we introduce a simple, efficient and transition-metal free method for the preparation of valuable and sterically hindered 3,3-disubstituted oxindoles via polar–radical crossover of ketene derived amide enolates.

Oxindoles, in particular the 3,3-disubstituted congeners, are highly valuable substructures in medicinal chemistry. The oxindole core can be found in various biologically active compounds, that are for example used in the treatment of cancer or as antibacterial agents.¹ In addition, the oxindole moiety also occurs in several complex natural products.² The first oxindole synthesis was reported by Baeyer and Knop in 1866.³ That time, isatin was converted by sodium amalgam reduction to the corresponding oxindole. Since then, many methods for the preparation of 3,3-disubstituted oxindoles have been developed that proceed via functionalization of a pre-existing oxindole core.⁴ In addition, methods for the construction of 3,3-disubstituted oxindoles starting from acyclic precursors have also been introduced.^5,6 Along these lines, transition metal-mediated reactions^5,7 or homolytic aromatic substitutions (HAS)^8–14 have found to be highly efficient for the construction of the oxindole core. Focusing on the latter approach, the intramolecular HAS proceeds via α-carbonyl radicals derived from radical addition to N-arylacrylamides,⁸ reduction of α-haloarylamides⁹ or oxidation of the corresponding enolates^10–14 (Scheme 1a).Open in a separate windowScheme 1Selected strategies for the synthesis of oxindoles.In 2017, the group of Taylor developed a transition metal-free enolate oxidation-HAS-approach towards oxindoles at low temperature using elemental iodine as the oxidant and malonic acid derived N-aryl amides as substrates which are readily deprotonated.¹⁴The unique reactivity of ketenes¹⁵ has been explored extensively,¹⁶ especially in [2 + 2]-cycloadditions.¹⁷ Moreover, Staudinger,¹⁸ Lippman¹⁹ and Taylor²⁰ showed that ketenes react with aryl nitrones in a tandem [3 + 2]-cycloaddition-[3,3]-sigmatropic-rearrangement cascade²¹ followed by hydrolysis to provide oxindoles (Scheme 1b). The use of chiral nitrones leads to chirality transfer and enantiomerically enriched oxindoles can be obtained via this approach.^21,22 In contrast to the examples discussed in Scheme 1a, two σ-bonds are formed and the overall sequence can be regarded as a formal [3 + 2] cycloaddition. Despite good yields and high enantiomeric excess, nitrones have to be used as precursors and an aldehyde is formed as the byproduct diminishing reaction economy of these elegant cascades.To address these drawbacks, we decided to use the nucleophilic addition^23–26 of deprotonated anilines to ketenes for the generation of the corresponding amide enolates that should then be oxidized in a single electron transfer process to α-amide radicals which can undergo a homolytic aromatic substitution providing direct access to sterically challenging 3,3-disubstituted oxindoles in a straightforward one-pot sequence (Scheme 1c). This polar–radical crossover reaction shows high atom economy and as the reaction with the nitrones can also be regarded as a formal [3 + 2] cycloaddition.We initiated the optimization study with N-methylaniline 1a and ethyl phenyl ketene 2a, which was prepared in an easy and scalable one-pot protocol starting from the corresponding carboxylic acid, as model substrates. Deprotonation of 1a with n-BuLi in THF and subsequent addition to the ketene 2a led to desired Li-enolate which was confirmed by protonation with water and isolation of the amide 4aa (56%). Pleasingly, addition of ferrocenium hexafluorophosphate (FcPF₆, 2.2 equiv.) at room temperature to the Li-enolate afforded the desired oxindole 3aa in 29% yield (14 Light does not appear to play a crucial role in this transformation, as performing the reaction in the dark does not have a significant effect on the reaction outcome ( EntryBaseConc. (M)Oxidant (equiv.)Yield 3aa (%)^b1 n-BuLi0.1FcPF₆ (2.2)29 (18)^c2^d n-BuLi0.1CuCl₂ (2.2)34^c3 n-BuLi0.1I₂ (2.2)41^c4EtMgBr0.1I₂ (2.2)44^c5EtMgBr0.02I₂ (2.2)78 6 EtMgBr 0.01 I ₂ (2.2) 90 (82) ^c 7EtMgBr0.01I₂ (1.2)258EtMgBr0.01NIS^e (2.2)399EtMgBr0.01I₂ (1.2)^f8010EtMgBr0.01I₂ (2.2)^g8211EtMgBr0.01I₂ (2.2)^h7412EtMgBr0.01I₂ (2.2)ⁱ93Open in a separate window^aReactions (0.20 mmol) were conducted under argon atmosphere.^{b 1}H NMR yield using 1,3,5-trimethoxybenzene as internal standard.^cIsolated yield.^dStep 1 and 2 were conducted at 0 °C.^e N-Iodosuccinimide.^fIodine addition at −78 °C, then slowly allowed to warm to room temperature.^14gIn the dark.^hIrradiation with blue LED (40 W, 467 nm, rt, 8 h).ⁱRefluxing THF for step 3, reaction completed within 2 h.With the optimized reaction conditions in hand, we investigated the scope by first varying the R¹-substituent at the N-atom using the ketene 2a as the reaction partner (Scheme 2). In general, increasing the steric bulk at the nitrogen leads to diminished yields of the targeted oxindoles. The lower yields go along with the formation of a larger amount of the corresponding α,β-unsaturated amide side product 5. Thus, as compared to the parent N-methyl derivative, all other N-alkyl derivatives were formed in lower yields (49%, 3ab; 35%, 3ac; 49%, 3ad). The N-benzyl protected oxindole 3af and the N-phenyl oxindole 3ae were isolated in 54% and 56% yield, respectively. Next, a diastereoselective oxindole synthesis was attempted using chiral anilines 1g and 1h. Surprisingly, despite the bulkiness of these nucleophiles containing styryl-type N-substituents, good yields were obtained for the oxindoles 3ag and 3ah (73–79%). Unfortunately, diastereocontrol was low in both cases (1.9 : 1 d.r. and 1.5 : 1 d.r.). Of note, addition of Mg-1g and Mg-1h to ketene 2a was rather slow under the standard reaction condition and a significant amount of unreacted aniline was recovered. That problem could be solved by prolonging the reaction time of both step 1 (deprotonation) and also step 2 (Mg-enolate formation).Open in a separate windowScheme 2Substrate scope – variation of substituents at the nitrogen. Reactions (0.20 mmol) were conducted under argon atmosphere. ^a For step 1 and 2 reaction time was 1 h.Next, the substrate scope was investigated by using different anilines in combination with the ketene 2a (Scheme 3). N-Methyl-p-toluidine 1i and N-methyl-p-haloanilines 1j–m could be successfully transformed to the corresponding oxindoles 3al–am in moderate to good yields (53–87%). Electron-withdrawing and also electron-donating substituents are tolerated and oxindoles derived from p-cyano- (3an, 92%), p-acetyl- (3ao, 30%), p-methoxycarbonyl- (3ap, 82%) and p-methoxy- (3aq, 71%) anilines were isolated in moderate to excellent yields documenting a high functional group tolerance of this reaction. The meta-methyl aniline afforded oxindole 3ar in 76% yield as a 1.8 : 1 mixture of the two regioisomers (only the major isomer drawn). For the pyridyl derivative 3as, a lower yield was obtained (39%), but reaction occurred with complete regiocontrol. Of note, ortho-methyl N-methylaniline provided the corresponding oxindole only in trace amounts (not shown).Open in a separate windowScheme 3Substrate Scope – variation of anilines and ketenes. Reactions (0.20 mmol) were conducted under argon atmosphere. ^a Isolated as an inseparable mixture (1 : 1.4) with the protonated enolate 4fa (56% combined yield).The ketene component was also varied using N-methylaniline 1a as the reaction partner. The transformation of methyl phenyl ketene 2b provided the oxindole 3ba in 58% yield. p-Bromophenyl ethyl ketene 2c and p-iodophenyl ethyl ketene 2d afforded the oxindoles 3ca and 3da in good yields (70% and 76%). For the ibuprofene-derived ketene 2e a lower yield was obtained (3ea, 40%) and the bulkier phenyl isopropyl congener 3fa was isolated in 27% yield as an inseparable mixture with the protonated enolate 4fa (56% combined yield). In the latter case, increasing the reaction time did neither lead to a higher yield of 3fa nor to a suppression of the formation of 4fa. The lower yield is likely caused by steric effects. Surprisingly, diphenyl ketene 2g delivered the targeted oxindole 3ga in acceptable 55% yield despite the steric demand of the two phenyl groups and the high stability of the corresponding α-amide radical. Spirocyclic oxindoles are of great interest due to their high pharmaceutical potential.²⁷ We were pleased to find that our method also works for the preparation of such spiro compounds as documented by the successful synthesis of 3ha (26%).Mechanistically, we propose initial formation of the enolate A by nucleophilic attack of the deprotonated aniline to the ketene 2, which is then oxidized by elemental iodine to the α-amide radical B (pathway b). The radical nature of the transformation is supported by the fact that electronic effects on the arene show no influence on the efficiency of the cyclization, as would be shown by a conceivable polar aromatic substitution. Radical B readily cyclizes onto the aniline ring to generate the cyclohexadienyl radical D which is oxidatively rearomatized via cationic intermediate E to finally give the oxindole 3 (Scheme 4).^10–14 Alternatively, enolate A can be iodinated with I₂ to give the unstable iodide C which then undergoes C–I bond homolysis to generate the radical B (pathway a). Indeed, Taylor and coworkers¹⁴ observed under similar reaction conditions the decay of α-iodinated compounds of type Cvia C–I homolysis^14,28 to give radicals of type B. Usually, we observed α,β-unsaturated amides analogous to 5aa as by-products. However, the corresponding protonated enolates were detected only in tiny amounts in most of these cases. This strongly suggests that those amides are not formed via disproportionation of radical B. HI-elimination seems more likely, pointing towards the presence of the iodinated species C and thus the contribution of pathway b to product formation. In addition, dimerization of radical B was also not observed.Open in a separate windowScheme 4Suggested mechanism.To further support pathway b, isolation of the iodinated intermediate C was attempted at low temperature. Upon addition of iodine (1.2 equiv.) to the preformed Mg-enolate A derived from aniline 1a and ketene 2a at −78 °C,¹⁴ TLC analysis showed a clean conversion to a single new compound, which was analyzed by rapid ESI-MS analysis and provided evidence for the formation of the iodinated intermediate C (Scheme 5). However, isolation of this highly unstable compound was not possible due to rapid HI-elimination to the amide 5aa. Note that oxindole formation worked well upon I₂-addition at −78 °C and subsequent warming to room temperature (see Scheme 5). This is consistent with the observation from our optimization studies that irradiation with blue light does not contribute to the yield of oxindole 3aa (Open in a separate windowScheme 5Mechanistic experiments. (a) (1) EtMgBr (1.1 equiv.), rt, 30 min, (2) 2a (1.5 equiv.), −78 °C, 30 min, (3) I₂ (1.2 equiv.), −78 °C, 15 min in THF (0.01 M). (b) Warm to room temperature in THF (0.01 M), 18 h. (c) NaI (1.2 equiv.) in acetone (0.77 M), rt, 18 h. (d) Irradiation with blue LED (40 W, 467 nm) in THF (0.01 M), rt, 8 h.     

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

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

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

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

A Paal–Knorr agent for chemoproteomic profiling of targets of isoketals in cells

Natural systems produce various γ-dicarbonyl-bearing compounds that can covalently modify lysine in protein targets via the classic Paal–Knorr reaction. Among them is a unique class of lipid-derived electrophiles – isoketals that exhibit high chemical reactivity and critical biological functions. However, their target selectivity and profiles in complex proteomes remain unknown. Here we report a Paal–Knorr agent, 4-oxonon-8-ynal (herein termed ONAyne), for surveying the reactivity and selectivity of the γ-dicarbonyl warhead in biological systems. Using an unbiased open-search strategy, we demonstrated the lysine specificity of ONAyne on a proteome-wide scale and characterized six probe-derived modifications, including the initial pyrrole adduct and its oxidative products (i.e., lactam and hydroxylactam adducts), an enlactam adduct from dehydration of hydroxylactam, and two chemotypes formed in the presence of endogenous formaldehyde (i.e., fulvene and aldehyde adducts). Furthermore, combined with quantitative chemoproteomics in a competitive format, ONAyne permitted global, in situ, and site-specific profiling of targeted lysine residues of two specific isomers of isoketals, levuglandin (LG) D2 and E2. The functional analyses reveal that LG-derived adduction drives inhibition of malate dehydrogenase MDH2 and exhibits a crosstalk with two epigenetic marks on histone H2B in macrophages. Our approach should be broadly useful for target profiling of bioactive γ-dicarbonyls in diverse biological contexts.

Natural systems produce various γ-dicarbonyl-bearing compounds that can covalently modify lysine in protein targets via the classic Paal–Knorr reaction.

Synthetic chemistry methods have been increasingly underscored by their potential to be repurposed as biocompatible methods for both chemical biology and drug discovery. The most-known examples of such a repurposing approach include the Staudinger ligation¹ and the Huisgen-based click chemistry.² Moreover, bioconjugation of cysteine and lysine can be built upon facile chemical processes,³ while chemoselective labelling of other polar residues (e.g., histidine,⁴ methionine,⁵ tyrosine,⁶ aspartic and glutamic acids^7,8) requires more elaborate chemistry, thereby offering a powerful means to study the structure and function of proteins, even at a proteome-wide scale.The classical Paal–Knorr reaction has been reported for a single-step pyrrole synthesis in 1884.^9,10 The reaction involves the condensation of γ-dicarbonyl with a primary amine under mild conditions (e.g., room temperature, mild acid) to give pyrrole through the intermediary hemiaminals followed by rapid dehydration of highly unstable pyrrolidine adducts (Fig. S1^†).Interestingly, we and others have recently demonstrated that the Paal–Knorr reaction can also readily take place in native biological systems.^11–13 More importantly, the Paal–Knorr precursor γ-dicarbonyl resides on many endogenous metabolites and bioactive natural products.¹⁴ Among them of particular interest are isoketals¹⁵ (IsoKs, also known as γ-ketoaldehydes) which are a unique class of lipid derived electrophiles (LDEs) formed from lipid peroxidation (Fig. S2^†)¹⁶ that has emerged as an important mechanism for cells to regulate redox signalling and inflammatory responses,¹⁷ and drive ferroptosis,¹⁸ and this field has exponentially grown over the past few years. It has been well documented that the γ-dicarbonyl group of IsoKs can rapidly and predominantly react with lysine via the Paal–Knorr reaction to form a pyrrole adduct in vitro (Fig. 1).¹⁵ Further, the pyrrole formed by IsoKs can be easily oxidized to yield lactam and hydroxylactam products in the presence of molecular oxygen (Fig. 1). These rapid reactions are essentially irreversible. Hence, IsoKs react with protein approximately two orders of magnitude faster than the most-studied LDE 4-hydoxynonenal (4-HNE) that contains α,β-unsaturated carbonyl to generally adduct protein cysteines by Michael addition (Fig. S3^†).¹⁵ Due to this unique adduction chemistry and rapid reactivity, IsoKs exhibit intriguing biological activities, including inhibition of the nucleosome complex formation,¹⁹ high-density lipoprotein function,²⁰ mitochondrial respiration and calcium homeostasis,²¹ as well as activation of hepatic stellate cells.²² Furthermore, increases in IsoK-protein adducts have been identified in many major diseases,²³ such as atherosclerosis, Alzheimer''s disease, hypertension and so on.Open in a separate windowFig. 1The Paal–Knorr precursor γ-dicarbonyl reacts with the lysine residue on proteins to form diverse chemotypes via two pathways. The red arrow shows the oxidation pathway, while the blue one shows the formaldehyde pathway.Despite the chemical uniqueness, biological significance, and pathophysiological relevance of IsoKs, their residue selectivity and target profiles in complex proteomes remain unknown, hampering the studies of their mechanisms of action (MoAs). Pioneered by the Cravatt group, the competitive ABPP (activity-based protein profiling) has been the method of choice to analyse the molecular interactions between electrophiles (e.g., LDEs,²⁴ oncometabolites,²⁵ natural products,^26,27 covalent ligands and drugs^28–30) and nucleophilic amino acids across complex proteomes. In this regard, many residue-specific chemistry methods and probes have been developed for such studies. For example, several lysine-specific probes based on the activated ester warheads (e.g., sulfotetrafluorophenyl, STP;³¹N-hydroxysuccinimide, NHS³²) have recently been developed to analyse electrophile–lysine interactions at a proteome-wide scale in human tumour cells, which provides rich resources of ligandable sites for covalent probes and potential therapeutics. Although these approaches can also be presumably leveraged to globally and site-specifically profile lysine-specific targets IsoKs, the reaction kinetics and target preference of activated ester-based probes likely differ from those of γ-dicarbonyls, possibly resulting in misinterpretation of ABPP competition results. Ideally, a lysine profiling probe used for a competitive ABPP analysis of IsoKs should therefore possess the same, or at least a similar, warhead moiety. Furthermore, due to the lack of reactive carbonyl groups on IsoK-derived protein adducts, several recently developed carbonyl-directed ligation probes for studying LDE-adductions are also not suitable for target profiling of IsoKs.^33,34Towards this end, we sought to design a “clickable” γ-dicarbonyl probe for profiling lysine residues and, in combination with the competitive ABPP strategy, for analysing IsoK adductions in native proteomes. Considering that the diversity of various regio- and stereo- IsoK isomers¹⁵ (a total of 64, Fig. S2^†) in chemical reactivity and bioactivities is likely attributed to the substitution of γ-dicarbonyls at positions 2 and 3, the “clickable” alkyne handle needs to be rationally implemented onto the 4-methyl group in order to minimize the biases when competing with IsoKs in target engagement. Interestingly, we reasoned that 4-oxonon-8-ynal, a previously reported Paal–Knorr agent used as an intermediate for synthesizing fatty acid probes³⁵ or oxa-tricyclic compounds,³⁶ could be repurposed for the γ-dicarbonyl-directed ABPP application. With this chemical in hand (herein termed ONAyne, Fig. 2A), we first used western blotting to detect its utility in labelling proteins, allowing visualization of a dose-dependent labelling of the proteome in situ (Fig. S4^†). Next, we set up to incorporate this probe into a well-established chemoproteomic workflow for site-specific lysine profiling in situ (Fig. 2A). Specifically, intact cells were labelled with ONAyne in situ (200 μM, 2 h, 37 °C, a condition showing little cytotoxicity, Fig. S5^†), and the probe-labelled proteome was harvested and processed into tryptic peptides. The resulting probe-labelled peptides were conjugated with both light and heavy azido-UV-cleavable-biotin reagents (1 : 1) via Cu^I-catalyzed azide–alkyne cycloaddition reaction (CuAAC, also known as click chemistry). The biotinylated peptides were enriched with streptavidin beads and photoreleased for LC-MS/MS-based proteomics. The ONAyne-labelled peptides covalently conjugated with light and heavy tags would yield an isotopic signature. We considered only those modified peptide assignments whose MS1 data reflected a light/heavy ratio close to 1.0, thereby increasing the accuracy of these peptide identifications. Using this criterium, we applied a targeted database search to profile three expected probe-derived modifications (PDMs), including 13 pyrrole peptide adducts (Δ273.15), 77 lactam peptide adducts (Δ289.14), and 557 hydroxylactam peptide adducts (Δ305.14), comprising 585 lysine residues on 299 proteins (Fig. S6 and S7^†). Among them, the hydroxylactam adducts were present predominately, since the pyrrole formed by this probe, the same as IsoKs, can be easily oxidized when being exposed to O₂. This finding was in accordance with a previous report where the pyrrole adducts formed by the reaction between IsoK and free lysine could not be detected, but rather their oxidized forms.³⁷ Regardless, all three types of adducts were found in one lysine site of EF1A1 (K387, Fig. S8^†), further confirming the intrinsic relationship among those adductions in situ.Open in a separate windowFig. 2Adduct profile and proteome-wide selectivity of the γ-dicarbonyl probe ONAyne. (A) Chemical structure of ONAyne and schematic workflow for identifying ONAyne-adducted sites across the proteome. (B) Bar chart showing the distribution of six types of ONAyne-derived modifications formed in situ and in vitro (note: before probe labelling, small molecules in cell lysates were filtered out through desalting columns).State-of-the-art blind search can offer an opportunity to explore unexpected chemotypes (i.e., modifications) derived from a chemical probe and to unbiasedly assess its proteome-wide residue selectivity.^38,39 We therefore sought to use one of such tools termed pChem³⁸ to re-analyse the MS data (see Methods, ESI^†). Surprisingly, the pChem search identified three new and abundant PDMs (Fig. 1 and Table S1^†), which dramatically expand the ONAyne-profiled lysinome (2305 sites versus 585 sites). Overall, these newly identified PDMs accounted for 74.6% of all identifications (Fig. 2B and Table S2^†). Among them, the PDM of Δ287.13 (Fig. 1 and S7^†) might be an enlactam product via dehydration of the probe-derived hydroxylactam adduct. The other two might be explained by the plausible mechanism as follows (Fig. 1). The endogenous formaldehyde (FA, produced in substantial quantities in biological systems) reacts with the probe-derived pyrrole adduct via nucleophilic addition to form a carbinol intermediate, followed by rapid dehydration to a fulvene (Δ285.15, Fig. S7^†) and immediate oxidation to an aldehyde (Δ301.14, Fig. S7^†). In line with this mechanism, the amount of FA-derived PDMs was largely eliminated when the in vitro ONAyne labelling was performed in the FA-less cell lysates (Fig. 2B and Table S3^†). Undoubtedly, the detailed mechanisms underlying the formation of these unexpected PDMs require further investigation, and so does the reaction kinetics. Regardless, all main PDMs from ONAyne predominantly target the lysine residue with an average localization probability of 0.77, demonstrating their proteome-wide selectivity (Fig. S9^†).Next, we adapted an ABPP approach to globally and site-specifically quantify the reactivity of lysine towards the γ-dicarbonyl warhead through a dose-dependent labelling strategy (Fig. 3A) that has been proved to be successful for other lysine-specific probes (e.g., STP alkyne).³¹ Specifically, MDA-MB-231 cell lysates were treated with low versus high concentrations of ONAyne (1 mM versus 0.1 mM) for 1 h. Probe-labelled proteomes were digested into tryptic peptides that were then conjugated to isotopically labelled biotin tags via CuAAC for enrichment, identification and quantification. In principle, hyperreactive lysine would saturate labelling at the low probe concentration, whereas less reactive ones would show concentration-dependent increases in labelling. For fair comparison, the STP alkyne-based lysine profiling data were generated by using the same chemoproteomic workflow. Although 77.5% (3207) ONAyne-adducted lysine sites can also be profiled by STP alkyne-based analysis, the former indeed has its distinct target-profile with 930 lysine sites newly identified (Fig. S10 and Table S4^†). Interestingly, sequence motif analysis with pLogo⁴⁰ revealed a significant difference in consensus motifs between ONAyne- and STP alkyne-targeting lysines (Fig. S11^†).Open in a separate windowFig. 3ONAyne-based quantitative reactivity profiling of proteomic lysines. (A) Schematic workflow for quantitative profiling of ONAyne–lysine reactions using the dose-dependent ABPP strategy (B) Box plots showing the distribution of R_10:1 values quantified in ONAyne- and STP alkyne-based ABPP analyses, respectively. Red lines showing the median values. ***p ≤ 0.001 two-tailed Student''s t-test. (C) Representative extracted ion chromatograms (XICs) showing changes in the EF1A1 peptide bearing K273 that is adducted as indicated, with the profiles for light and heavy-labelled peptides in blue and red, respectively.Moreover, we quantified the ratio (R_{1 mM:0.1 mM}) for a total of 2439 ONAyne-tagged lysines (on 922 proteins) and 17904 STP alkyne-tagged lysines (on 4447 proteins) across three biological replicates (Fig. S12 and Table S5^†). Strikingly, only 26.7% (651) of quantified sites exhibited nearly dose-dependent increases (R_{1 mM:0.1 mM} > 5.0) in reactivity with ONAyne, an indicative of dose saturation (Fig. 3B and C). In contrast, such dose-dependent labelling events accounted for >69.1% of all quantified lysine sites in the STP alkyne-based ABPP analysis.³¹ This finding is in accordance with the extremely fast kinetics of reaction between lysine and γ-dicarbonyls (prone to saturation). Nonetheless, by applying 10-fold lower probe concentrations, overall 1628 (80.2%) detected lysines could be labelled in a fully concentration-dependent manner with the median R_10:1 value of 8.1 (Fig. 3B, C, S12 and Table S5^†). Next, we asked whether the dose-depending quantitation data (100 μM versus 10 μM) can be harnessed to predict functionality. By retrieving the functional information for all quantified lysines from the UniProt Knowledgebase, we found that those hyper-reactive lysines could not be significantly over-represented with annotation (Fig. S12^†). Nonetheless, among all quantified lysines, 509 (25.1%) possess functional annotations, while merely 2.5% of the human lysinome can be annotated. Moreover, 381 (74.8%) ONAyne-labelled sites are known targets of various enzymatic post-translational modifications (PTMs), such as acetylation, succinylation, methylation and so on (Fig. S13^†). In contrast, all known PTM sites accounted for only 59.6% of the annotated human lysinome. These findings therefore highlight the intrinsic reactivity of ONAyne towards the ‘hot spots’ of endogenous lysine PTMs.The aforementioned results validate ONAyne as a fit-for-purpose lysine-specific chemoproteomic probe for competitive isoTOP-ABPP application of γ-dicarbonyl target profiling. Inspired by this, we next applied ONAyne-based chemoproteomics in an in situ competitive format (Fig. 4A) to globally profile lysine sites targeted by a mixture of levuglandin (LG) D₂ and E₂, two specific isomers of IsoKs that can be synthesized conveniently from prostaglandin H₂ (ref. 41) (Fig. S2^†). Specifically, mouse macrophage RAW264.7 cells (a well-established model cell line to study LDE-induced inflammatory effects) were treated with 2 μM LGs or vehicle (DMSO) for 2 h, followed by ONAyne labelling for an additional 2 h. The probe-labelled proteomes were processed as mentioned above. For each lysine detected in this analysis, we calculated a control/treatment ratio (R_C/T). Adduction of a lysine site by LGs would reduce its accessibility to the ONAyne probe, and thus a higher R_C/T indicates increased adduction. In total, we quantified 2000 lysine sites on 834 proteins across five biological replicates. Among them, 102 (5.1%) sites exhibited decreases of reactivity towards LGs treatment (P < 0.05, Table S6^†), thereby being considered as potential targets of LGs. Notably, we found that different lysines on the same proteins showed varying sensitivity towards LGs (e.g., LGs targeted K3 of thioredoxin but not K8, K85 and K94, Table S6^†), an indicative of changes in reactivity, though we could not formally exclude the effects of changes in protein expression on the quantified competition ratios. Regardless, to the best of our knowledge, the proteome-wide identification of potential protein targets by IsoKs/LGs has not been possible until this work.Open in a separate windowFig. 4ONAyne-based in situ competitive ABPP uncovers functional targets of LGs in macrophages. (A) Schematic workflow for profiling LGs–lysine interactions using ONAyne-based in situ competitive ABPP. (B) Volcano plot showing the log₂ values of the ratio between the control (heavy) and LGs-treated (light) channels and the −log₁₀(P) of the statistical significance in a two-sample t-test for all quantified lysines. Potential targets of LGs are shown in blue (R_C/T>1.2, P < 0.05), with the validated ones in red. (C) Bar chart showing the inhibitory effect of 2 μM LGs on the cellular enzymatic activity of MDH2. Data represent means ± standard deviation (n = 3). Statistical significance was calculated with two-tailed Student''s t-tests. (D) Pretreatment of LGs dose-dependently blocked ONAyne-labelling of MDH2 in RAW264.7 cells, as measured by western blotting-based ABPP. (E and F) LGs dose-dependently decreased the H2BK5 acetylation level in RAW 264.7 cells, as measured either by western blotting (E) or by immunofluorescence imaging (F). n = 3. For G, nuclei were visualized using DAPI (blue).We initially evaluated MDH2 (malate dehydrogenase, mitochondrial, also known as MDHM), an important metabolic enzyme that possesses four previously uncharacterized liganded lysine sites (K157, K239, K301 and K329, Fig. 4B) that are far from the active site (Fig. S14^†). We found that LGs dramatically reduced the catalytic activity of MDH2 in RAW264.7 cells (Fig. 4C), suggesting a potentially allosteric effect. We next turned our attention to the targeted sites residing on histone proteins, which happen to be modified by functionally important acetylation, including H2BK5ac (Fig. 4B) that can regulate both stemness and epithelial–mesenchymal transition of trophoblast stem cells.⁴² We therefore hypothesized that rapid adduction by LGs competes with the enzymatic formation of this epigenetic mark. Immunoblotting-based competitive ABPP confirmed that LGs dose-dependently blocked probe labelling of H2B (Fig. 4D). Further, both western blots and immunofluorescence assays revealed that LG treatment decreased the level of acetylation of H2BK5 (average R_C/T = 1.3, P = 0.007) in a concentration-dependent manner (Fig. 4E and F). Likewise, a similar competitive crosstalk was observed between acetylation and LG-adduction on H2BK20 (average R_C/T = 1.2, P = 0.01) that is required for chromatin assembly⁴³ and/or gene regulation⁴⁴ (Fig. 4B and S15^†). Notably, these findings, together with several previous reports by us and others about histone lysine ketoamide adduction by another important LDE, 4-oxo-2-noenal,^11,45,46 highlight again the potentially important link between lipid peroxidation and epigenetic regulation. In addition to the targets validated as above, many other leads also merit functional studies considering diverse biological or physiologic effects of LGs in macrophages.     

Allylic alcohol synthesis by Ni-catalyzed direct and selective coupling of alkynes and methanol

Methanol is an abundant and renewable chemical raw material, but its use as a C1 source in C–C bond coupling reactions still constitutes a big challenge, and the known methods are limited to the use of expensive and noble metal catalysts such as Ru, Rh and Ir. We herein report nickel-catalyzed direct coupling of alkynes and methanol, providing direct access to valuable allylic alcohols in good yields and excellent chemo- and regioselectivity. The approach features a broad substrate scope and high atom-, step- and redox-economy. Moreover, this method was successfully extended to the synthesis of [5,6]-bicyclic hemiacetals through a cascade cyclization reaction of alkynones and methanol.

Methanol is an abundant and renewable chemical raw material, but its use as a C1 source in C–C bond coupling reactions still constitutes a big challenge, and the known methods are limited to the use of expensive and noble metal catalysts such as Ru, Rh and Ir.

To address the sustainability issues in the production of new chemicals, the development of new catalytic processes that are free of by-products and using abundant renewable feedstocks is one of the most important challenges facing chemists today. The simplest alcohol, methanol, is very abundant, with a total annual production capacity of approximately 110 million metric tons per year,¹ and is an important C1-feedstock in the chemical industry. Beller² and Milstein³ made fundamental developments in catalytic dehydrogenation reactions of methanol.⁴ Krische and coworkers pioneered the study of Ir-catalyzed direct C–C coupling of methanol with reactive π-unsaturated reactants (1,3-dienes, 1,3-enynes and allenes).⁵ The groups of Glorius,⁶ Donohoe,⁷ Obora,⁸ Andersson⁹ and others¹⁰ demonstrated the direct methylation of ketones or amines using methanol. Despite these achievements, the catalytic C–C bond coupling reactions with methanol are still extremely rare and are limited to the use of precious and noble metal-catalysts such as Ru, Rh or Ir.¹¹ The development and use of cheap and abundant metal catalysts for methanol activation is uphill and remains an important field that urgently needs to be developed.On the other hand, allylic alcohols are highly versatile building blocks in organic synthesis and the pharmaceutical industry, and much effort has been devoted to their synthesis. Among them, nickel-catalyzed reductive coupling of alkynes and aldehydes represents an effective and powerful method. However, this method generally requires the use of stoichiometric reducing reagents that are air-sensitive, metallic or pyrophoric (e.g. ZnR₂, BEt₃, and R₃SiH, Scheme 1a).¹² The direct cross-coupling of alcohols and alkynes to synthesize allylic alcohols without the use of any reductant or oxidant represents a significant advancement (Scheme 1b).¹³ However, this approach still poses many limitations that will require considerable effort to overcome. (1) Alkynes are limited to dialkyl alkynes, and poor regioselectivities were observed for unsymmetrical alkynes, which greatly limits the scope of application of the reaction. (2) Alcohols are restricted to active benzyl alcohols and higher alcohols. The direct cross-coupling of alkynes with methanol has not yet been reported.Open in a separate windowScheme 1Synthesis of allylic alcohols by Ni-catalyzed coupling reaction with alkynes.Although the alkyne–paraformaldehyde reductive coupling has been developed,¹⁴ the paraformaldehyde was itself prepared from synthesis gas (through methanol). Therefore, the development of a new strategy for the direct coupling of alkynes and methanol without the use of any reductant or oxidant is still of great value, but also extremely challenging: (1) alkynes are reactive and could rapidly dimerize to 1,3-dienes¹⁵ or cyclotrimerize to aromatic ring derivatives in the interaction with nickel.¹⁶ (2) Unsymmetric alkynes could result in a mixture of regioisomers that are difficult to separate. (3) The activation energy of methanol in the dehydrogenation process (ΔH = +84 kJ mol⁻¹) is significantly higher than that of higher alcohols or even ethanol (ΔH = +68 kJ mol⁻¹).¹⁷Herein we report the nickel-catalyzed direct and regioselective hydrohydroxymethylation of alkynes for the first time using methanol as a C1-feedstock, providing a broad and efficient approach for the synthesis of high added-value allylic alcohols in a high atom-, step- and redox-economic manner. In addition, a cascade cyclization reaction of alkynones and methanol has also been developed for the synthesis of [5,6]-bicyclic hemiacetals in good yields and excellent regio- and diastereoselectivity (Scheme 1c).In our initial experiments, we chose unsymmetrical internal alkyne 1a as a model substrate to optimize the reaction conditions (13a Even if the reaction temperature was increased to 100 °C, only a trace amount of allylic alcohol product 2a was observed (entry 2), which indicates that the use of methanol in the catalytic C–C coupling reactions is indeed a big challenge. Various N-heterocyclic carbene ligands (L2–L6) were investigated (entries 3–9). We found that the selectivity of allylic alcohol 2a is challenged by a number of side reactions, such as the hydrogenation (3a), dimerization (4a) and trimerization (5a) of alkyne 1a. L4 is the most effective, providing 2a with the highest yield (40%) and excellent regioselectivity (14/1), but an appreciable quantity of dimerization and trimerization by-products 4a and 5a was still obtained (entry 5). Krische¹⁴ reported that PCy₃ could promote the reductive coupling of alkynes and paraformaldehyde, but we found that it is not effective for alkyne–methanol coupling (entry 8).Optimization of reaction conditions^a

Ruthenium pincer complex-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides: substrate keeps the catalyst active

The electron pair of the heteroatom in heterocycles will coordinate with metal catalysts and decrease or even inhibit their catalytic activity consequently. In this work, a pincer ruthenium-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides has been developed. Benefitting from the pincer ligand, a variety of heterocycles, such as thiophenes, morpholine, unprotected indoles, pyrrole, pyridine, pyrimidine, furan, thiazole, pyrazole, benzothiadiazole, and triazole, are compatible here.

A pincer ruthenium-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides has been developed.

Since the pioneering work on the catalytic alkoxycarbonylation of unactivated alkyl halides reported by Heck and Breslow in 1963,¹ this transformation has attracted a great deal of interest due to its modularity and the direct employment of CO as a cheap and abundant C1 feedstock.² However, compared with aryl halides, the development of alkoxycarbonylation of alkyl halides has been much more gradual.^2,3 This situation is due to both the slow oxidative addition of C(sp³)–X bonds to the metal center and the easy β-hydride elimination of the alkyl-metal intermediate, particularly in the presence of carbon monoxide.⁴ Several catalytic systems for this process have been successfully developed in recent years (Scheme 1A), such as pure radical-based systems,⁵ palladium-based systems,⁶hν/palladium-based systems,⁷ rhodium-based systems,⁸ copper-based systems,⁹ and other metal carbonyl complex-based systems.¹⁰ Very recently, Neumann, Skrydstrup, and co-workers reported a nickel pincer-mediated alkoxycarbonylation for complete carbon isotope replacement, and this approach provided a procedure for generating carbon-labeled versions of potential simple carboxylate prodrug derivatives (Scheme 1B).¹¹ Besides their advantages, in these cases the heterocycles, particularly those containing multiple N atoms or NH groups, are hardly compatible, which is considered as a remaining challenge. We attribute this to the Lewis-basic atoms in heterocyclic motifs being particularly detrimental to catalyst activity and potentially quenching the radical intermediates.¹² Indeed, the development of heterocycle compatible catalytic systems remains an exciting task in the field of alkoxycarbonylation.Open in a separate windowScheme 1Approaches to alkoxycarbonylation of alkyl halides.On the other hand, heterocycles constitute important structural components of biologically active compounds and are ubiquitous in agrochemical and pharmaceutical industries.¹³ In a recent survey, 88% of small molecule drugs approved by the FDA between 2015 and June 2020 were found to contain at least one N-heterocycle.¹⁴ Specifically, heterocyclic subunits can modify the solubility, lipophilicity, polarity and hydrogen bonding ability of biologically active agents, thereby optimizing the corresponding ADME/Tox (absorption, distribution, metabolism, excretion, and toxicity) properties of drugs or drug candidates.¹⁵ Under this premise, the pursuit of new synthetic methods with good heterocycle compatibility is a worthwhile endeavor.Herein we report a heterocycle compatible catalytic system for alkoxycarbonylation of alkyl iodides. With a ruthenium pincer complex as the catalyst, the tight coordination of the pincer ligand can effectively prevent the ruthenium from deactivation by heterocycle coordination (Scheme 1C). To the best of our knowledge, this is the first example of a ruthenium pincer complex-catalyzed carbonylation reaction.¹⁶ This new catalytic system might lead to novel synthetic routes toward heterocyclic carbonyl-containing compounds.Pincer complexes of ruthenium are among the most effective catalysts for hydrogen transfer reactions between alcohols and unsaturated compounds.¹⁷ We initially used it to attempt the carbonylative coupling of acetophenone with iodobutane, as shown in eqn (1). Although we did not get the desired product I, the ester II could be obtained in 22% yield. By literature survey, we found there was no example showing that alkyl halides could be activated by ruthenium in previous reports on carbonylation reactions.^3,16,18 We thus envisioned that the ruthenium pincer complex played a key role in this transformation.^11,191With this discovery in mind, we started the investigation of this ruthenium-catalyzed alkoxycarbonylation of alkyl halides by examining the reaction of (3-iodopropyl)benzene (1) with isopropanol (2) at 100 °C under a CO atmosphere (10 bar) in the presence of a catalytic amount of various readily available ruthenium pincer complexes (†). The improved yield of the desired product 3 was obtained when utilizing Milstein''s catalyst Ru-2²⁰ (21 were applied in the reaction; however, the selectivity obtained was unsatisfactory (eqn (2), when we removed isopropanol from the reaction, byproduct 2 which was produced by carbonylative homocoupling of the alkyl halide could be obtained in 71% yield.²² However, the reduced conversion and the absence of byproduct 3 implied that the alcohol plays more than a nucleophile role in this reaction. It is important to mention that the addition of water had no effect on the yield of byproduct 2. Concerning the effects from bases, organic bases, such as NEt₃ and DBU, were tested, but no desired ester could be detected. Inorganic bases, including K₂CO₃ and K₃PO₄, were also tested, but very low yield of the ester was obtained. Notably, comparable yield of ester 3 can be obtained when LiO^tBu was used as the base.2Optimization of the alkoxycarbonylation of 1^a