Palladium-catalysed transannular C-H functionalization of alicyclic amines.

Discovering pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. C-H bonds are present in almost all pharmaceutical agents. Consequently, the development of selective, rapid and efficient methods for converting these bonds into new chemical entities has the potential to streamline pharmaceutical development. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, such as treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukaemia (alvocidib), schizophrenia (risperidone, belaperidone), malaria (mefloquine) and nicotine addiction (cytisine, varenicline). However, existing methods for the C-H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited. Here we report a transannular approach to selectively manipulate the C-H bonds of alicyclic amines at sites remote to nitrogen. Our reaction uses the boat conformation of the substrates to achieve palladium-catalysed amine-directed conversion of C-H bonds to C-C bonds on various alicyclic amine scaffolds. We demonstrate this approach by synthesizing new derivatives of several bioactive molecules, including varenicline.

Enantioselective Nickel-Catalyzed Alkyne-Azide Cycloaddition by Dynamic Kinetic Resolution.

The triazole heterocycle has been widely adopted as an isostere for the amide bond. Many native amides are α-chiral, being derived from amino acids. This makes α-N-chiral triazoles attractive building blocks. This report describes the first enantioselective triazole synthesis that proceeds via nickel-catalyzed alkyne-azide cycloaddition (NiAAC). This dynamic kinetic resolution is enabled by a spontaneous [3,3]-sigmatropic rearrangement of the allylic azide. The 1,4,5-trisubstituted triazole products, derived from internal alkynes, are complementary to those commonly obtained by the related CuAAC reaction. Initial mechanistic experiments indicate that the NiAAC reaction proceeds through a monometallic Ni complex, which is distinct from the CuAAC manifold.

Combined Experimental and Computational Mechanistic Investigation of the Palladium-Catalyzed Decarboxylative Cross-Coupling of Sodium Benzoates with Chloroarenes.

Reported herein is a mechanistic investigation into the palladium-catalyzed decarboxylative cross-coupling of sodium benzoates and chloroarenes. The reaction was found to be first-order in Pd. A minimal substituent effect was observed with respect to chloroarene, and the reaction was zero-order with respect to chloroarene. Palladium-mediated decarboxylation was assigned as the turnover-limiting step based on an Eyring plot and density functional theory computations. Catalyst performance was found to vary based on the electrophile, which is best explained by catalyst decomposition at Pd(0). The 1,5-cyclooctadiene (COD) ligand contained in the precatalyst CODPd(CH2TMS)2 (Pd1) was shown to be a beneficial additive. The bench-stable Buchwald complex XPhosPdG2 could be used with exogenous COD and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) instead of complex Pd1. Adding exogenous XPhos significantly increased the catalyst turnover number and enhanced reproducibility.

A cascade reaction of cinnamyl azides with vinyl sulfones directly generates dihydro-pyrrolo-pyrazole heterocycles.

This report describes the direct synthesis of dihydro-pyrrolo-pyrazole heterocycles from allylic azides and methyl vinyl sulfone. The product results from a complex cascade reaction that is operationally straightforward, with aromatization being the result of a concomitant elimination step. A variety of azides could participate in this reaction (12 examples) and the isolated yields of the desired product ranged from 51%-72%. Lastly the ethylene sulfone group could be removed by heating the product in pyrrolidine.

Gold Catalyzed Decarboxylative Cross-Coupling of Iodoarenes.

This report details a decarboxylative cross-coupling of (hetero)aryl carboxylates with iodoarenes in the presence of a gold catalyst (>25 examples, up to 96% yield). This reaction is site specific, which overcomes prior limitations associated with gold catalyzed oxidative coupling reactions. The reactivity of the (hetero)aryl carboxylate correlates qualitatively to the field effect parameter (Fortho). Reactions with isolated gold complexes and DFT calculations support a mechanism proceeding through oxidative addition at a gold(I) cation with decarboxylation being viable at either a gold(I) or a silver(I) species.

Gram-Scale Synthesis of 2,5-Difluoro-7,7,8,8-tetracyanoquinodimethane (F2-TCNQ).

The molecule 2,5-difluoro-7,7,8,8-tetracyanoquinodimethane (F2-TCNQ) is an organic semiconductor with many promising properties, including high charge mobility (µ). However, an efficient gram-scale synthesis of F2-TCNQ has not been fully documented. Herein, we report a synthesis of F2-TCNQ via a three-step sequence that affords F2-TCNQ in 58% cumulative yield. This synthesis was used to prepare more than 1 g of F2-TCNQ.

A Cascade Reaction of Cinnamyl Azides with Acrylates Directly Generates Tetrahydro-Pyrrolo-Pyrazole Heterocycles.

Developing reactions to generate complex and modular building blocks in a concise and direct fashion remains a contemporary synthetic challenge. This work describes a stereoselective cascade reaction between allylic azides and acrylates that directly generates tetrahydro-pyrrolo-pyrazole ring systems. These products contain up to four contiguous stereocenters, two of which may be tetrasubstituted carbon atoms attached to a nitrogen atom. Over 30 examples are provided with an average isolated yield of 71% (ranging from 40% to 94%). The reaction was easily scaled to use more than one gram of starting material, and the products can be readily diversified.

Divergent Mechanisms of the Banert Cascade with Propargyl Azides.

Triazoles are privileged heterocycles for a variety of applications. The synthesis of 1H-triazoles can be accomplished by the Banert cascade from propargylic azides. Depending on the substrate and conditions, the Banert cascade can proceed by either a sigmatropic or prototropic mechanism. This report describes the first detailed kinetic analysis of the Banert cascade proceeding by both pathways including substituent effects and KIE. The analysis identified the inflection point in the divergent pathways, allowing future work to predict which Banert products are accessible.

Enantioselective Copper Catalyzed Alkyne-Azide Cycloaddition by Dynamic Kinetic Resolution.

The copper(I) catalyzed alkyne-azide cycloaddition (CuAAC), a click reaction, is one of the most powerful catalytic reactions developed during the last two decades. Conducting CuAAC enantioselectively would add a third dimension to this reaction and would enable the direct synthesis of α-chiral triazoles. Doing so is demanding because the two precursors have linear geometries, and the triazole product is a flat heterocycle. Designing a chiral catalyst is further complicated by the complex mechanism of CuAAC. We report an enantioselective CuAAC (E-CuAAC), enabled by dynamic kinetic resolution (DKR). The E-CuAAC is high yielding and affords up to 99:1 er. The E-CuAAC can directly generate α-chiral triazoles in a complex molecular environment.

Palladium-catalyzed salt-free double decarboxylative aryl allylation.

This report describes a palladium-catalyzed decarboxylative aryl allylation between unactivated benzoic acids and allylic carbonates. This transformation successfully couples a variety of carbonates and benzoic acids in good yield (up to 94%) using 1 mol% palladium. This salt free allyl-arylation proceeds without added base, copper, or silver. The only stoichiometric byproducts are carbon dioxide and tert-butanol.

Allylic azides: synthesis, reactivity, and the Winstein rearrangement.

Organic azides are useful synthetic intermediates, which demonstrate broad reactivity. Unlike most organic azides, allylic azides can spontaneously rearrange to form a mixture of isomers. This rearrangement has been named the Winstein rearrangement. Using allylic azides can result in low yields and azide racemization in some synthetic contexts due to the Winstein rearrangement. Effort has been made to understand the mechanism of the Winstein rearrangement and to take advantage of this process. Several guiding principles can be used to identify which azides will produce a mixture of isomers and which will resist rearrangement. Selective reaction conditions can be used to differentiate the azide isomers in a dynamic manner. This review covers all aspects of allylic azides including their synthesis, their reactivity, the mechanism of the Winstein rearrangement, and reactions that can selectively elaborate an azide isomer. This review covers the literature from Winstein's initial report to early 2019.

Stereoselective Dynamic Cyclization of Allylic Azides: Synthesis of Tetralins, Chromanes, and Tetrahydroquinolines.

This report describes the stereoselective synthesis of 3-azido-tetralins, -chromanes, and -tetrahydroquinolines via a tandem allylic azide rearrangement/Friedel-Crafts alkylation. Exposure of allylic azides with a pendant trichloroacetimidate to catalytic quantities of AgSbF6 proved optimal for this transformation. This cascade successfully differentiates the equilibrating azide isomers, providing products in excellent yield and selectivity (>25 examples, up to 94% yield and >25:1 dr). In many cases, the reactive isomer is only a trace fraction of the equilibrium mixture, keenly illustrating the dynamic nature of these systems. We demonstrate the utility of this process via a synthesis of hasubanan.

Evidence for a Sigmatropic and an Ionic Pathway in the Winstein Rearrangement.

The spontaneous rearrangement of allylic azides is thought to be a sigmatropic reaction. Presented herein is a detailed investigation into the rearrangement of several allylic azides. A combination of experiments including equilibrium studies, kinetic analysis, density functional theory calculations, and selective 15N-isotopic labeling are included. We conclude that the Winstein rearrangement occurs by the assumed sigmatropic pathway under most conditions. However, racemization was observed for some cyclic allylic azides. A kinetic analysis of this process is provided, which supports a previously undescribed ionic pathway.

Dynamic Kinetic Resolution of Allylic Azides via Asymmetric Dihydroxylation.

The catalytic enantioselective preparation of densely functionalized amines is a fundamental synthetic challenge. To address this challenge, we report for the first time that the Winstein rearrangement can be enlisted as the racemization pathway in a dynamic kinetic resolution of allylic azides. Alkene functionalization by Sharpless dihydroxylation affords tertiary azides in excellent enantioselectivity (up to 99:1 er). This approach establishes the chirality of the tertiary azide, obviates the need to directly forge either a congested C-N or C-C bond at the new nitrogenous stereocenter, and establishes additional functionality. Several examples demonstrate further elaboration of this functionality.

Iridium-Catalyzed Enantioselective Fluorination of Racemic, Secondary Allylic Trichloroacetimidates.

The Ir-catalyzed enantioselective fluorination of racemic, branched allylic trichloroacetimidates with Et3N·3HF is a mild and efficient route for selective incorporation of fluoride ion into allylic systems. We herein describe the asymmetric fluorination of racemic, secondary allylic electrophiles with Et3N·3HF using a chiral-diene-ligated Ir complex. The methodology enables the formation of acyclic fluorine-containing compounds in good yields with excellent levels of asymmetric induction and overcomes the limitations previously associated with the enantioselective construction of secondary allylic fluorides bearing α-linear substituents.

Reversible inhibition of human acetylcholinesterase by methoxypyridinium species.

The irreversible inhibition of acetylcholinesterase (AChE) by organophosphorous chemical warfare agents necessitates that antidotes be administered for effective treatment. Currently no antidote is known that resurrects the phosphyl-AChE complex once aging has occurred. This report characterizes the affinities of over 30 new AChE inhibitors which could act as resurrecting agents for the aged AChE-OP adduct.

Electrophilic aromatic prenylation via cascade cyclization.

To gain access to prenylated hexahydroxanthenes, tandem cascade cyclization-electrophilic aromatic substitution reactions have been studied on substrates bearing allylic and propargylic substituents. Both BF3·OEt2 and TMSOTf can be used to initiate this reaction sequence, resulting in different ratios of the C-2 and C-6 substitution products. Even though allylic transposition is observed in some cases, the results of a crossover experiment are consistent with an intramolecular reaction sequence. Taken together, these studies now allow preparation of either the C-2 or C-6 prenylated hexahydroxanthene products.

Iridium-catalyzed allylic fluorination of trichloroacetimidates.

A rapid allylic fluorination method utilizing trichloroacetimidates in conjunction with an iridium catalyst has been developed. The reaction is conducted at room temperature under ambient air and relies on Et(3)N·3HF reagent to provide branched allylic fluorides with complete regioselectivity. This high-yielding reaction can be conducted on a multigram scale and shows considerable functional group tolerance. The use of [(18)F]KF·Kryptofix allowed (18)F(-) incorporation in 10 min.

Exploration of cascade cyclizations terminated by tandem aromatic substitution: total synthesis of (+)-schweinfurthin A.

The termination of epoxide-initiated cascade cyclizations with a range of "protected" phenols is described. When the protecting group can be lost as a stabilized electrophile, the cascade process continues beyond ring closure to afford products which have undergone a tandem electrophilic aromatic substitution. A number of groups have proven viable in this process and the regiochemistry of their substitution reactions has been studied. Application of this methodology in the first total synthesis of (+)-schweinfurthin A, a potent antiproliferative agent, has been achieved.