Kiran Matcha

Metal-free cross-dehydrogenative coupling of heterocycles with aldehydes.

The direct transformation of nonfunctionalized C H bonds into C C bonds is a fundamental challenge in organic chemistry and offers substantial benefits. The synthetic method to generate C C bonds directly from two different C H bonds under oxidative conditions, termed cross-dehydrogenative coupling (CDC), represents the state-of-art in C C bond-forming reactions. 2] Such a coupling allows the use of simple nonfunctionalized substrates, thus making syntheses shorter and more efficient. Two issues with CDC methods are low reactivity and selectivity, owing to the highenergy of dissociation and the ubiquity of C H bonds in organic molecules, respectively. The development of new and efficient CDC reactions is a fundamental and important challenge in organic synthesis. Nitrogen-containing heterocycles are abundant in nature and have extensive applications in chemistry and biology. Numerous methods for the de novo synthesis of electrondeficient heterocycles have been described, but their functionalization by cross-dehydrogenative coupling is far less studied. In contrast to the acylation of electron-rich aromatic compounds (Friedel–Crafts reaction), very few methods are available for the acylation of electron-deficient heterocycles. Among these methods, the addition of nucleophilic acyl radicals to electron-deficient heterocyclic aromatic bases, that is, the Minisci reaction, is a commonly used approach. But, this reaction has been underutilized because of harsh reaction conditions, such as heating in the presence of peroxy compounds and metals. Additional reported issues include low site selectivity, incomplete conversion of starting materials, limited substrate scope, and the use of metals in up to stoichiometric amounts. Direct acylation of heterocycles with aldehydes is difficult owing to the electron-deficient nature of both partners, and because the products of radical acylation can be more susceptible to radical attack than the starting material. Based on previous reported acylations, we hypothesized that the generation of nucleophilic acyl radicals under mild reaction conditions could be key to eliminating the difficulties in direct acylations. 5] Herein, we describe an unprecedented metal-free, cross-dehydrogenative coupling of heterocycles with aldehydes at ambient temperature. Furthermore, this method was used for the synthesis of natural products in one step. In connection to our continued interest in developing efficient metal-free C H functionalization strategies, we decided to investigate the use of hypervalent iodine reagents for the direct acylation of N-heterocycles with aldehydes. Initially, we evaluated numerous reaction conditions for the direct coupling of isoquinoline (1a) and benzaldehyde (2a). To our delight, the cross-coupling occurred in presence of (bis(trifluoroacetoxy)iodo)benzene (PhI(OCOCF3)2) and sodium azide at ambient temperature in ethylacetate to form product 3 a in 47 % yield (Table 1, entry 1). Notably, functionalization of isoquinoline (1a) occurred selectively at the C1-position to give only one regioisomer of 3a. Product 3a was not formed in the absence of either PhI(OCOCF3)2 or NaN3. A variety of polar and nonpolar solvents were successfully employed (Table 1, entries 1-4 and the Supporting Information). The best yield (52 % of 3a) was achieved for the reaction with benzene as the solvent. Next, we examined the influence of various oxidants in the cross-dehydrogenative coupling (Table 1, entries 4–11). A number of other hypervalent iodine based oxidants were screened, and only the use of Koser s reagent and (bis(trifluoroacetoxy)iodo)pentafluorobenzene (Table 1, entries 7 and 8) provided product 3a, although in lower yield than with PhI(OCOCF3)2. Other oxidizing agents, such as tBuOOH and mCPBA, did not promote the desired transformation (Table 1, entries 9–11, and Supporting Information). With PhI(OCOCF3)2 as the obvious choice of oxidant, we tested different additives. Changing the additive from NaN3 to TMSN3 resulted in a dramatic rise of the yield to 90% (Table 1, entry 12). The use of other sources of azide and iodine did not lead to formation of the product (Table 1, entries 13–15). With the optimized oxidant and additive established, we looked into the relative ratio of reactants (Table 1, entries 16–21 and Supporting Information). Decreasing the amount of aldehyde from 4 equivalents to 3 and 1.5 equivalents led to a drop in yield to 70% and 26 %, respectively, and lowering the amount of oxidant and/or additive to 1 equivalent did not prove beneficial. Equipped with a set of optimized conditions (Table 1, entry 16), we explored the scope of this cross-coupling reaction by investigating the reaction between isoquinoline (1a) and various aldehydes (Scheme 1). The scope turned out to be very broad, and various aliphatic, aromatic and heteroaromatic aldehydes, including those with electron[*] Dr. K. Matcha, Dr. A. P. Antonchick Max-Planck-Institut f r Molekulare Physiologie Abteilung Chemische Biologie Otto-Hahn-Strasse 11, 44227 Dortmund (Germany) E-mail: andrey.antonchick@mpi-dortmund.mpg.de

Metal-Free Oxidative C-C Bond Formation through C-H Bond Functionalization.

The formation of C-C bonds embodies the core of organic chemistry because of its fundamental application in generation of molecular diversity and complexity. C-C bond-forming reactions are well-known challenges. To achieve this goal through direct functionalization of C-H bonds in both of the coupling partners represents the state-of-the-art in organic synthesis. Oxidative C-C bond formation obviates the need for prefunctionalization of both substrates. This Minireview is dedicated to the field of C-C bond-forming reactions through direct C-H bond functionalization under completely metal-free oxidative conditions. Selected important developments in this area have been summarized with representative examples and discussions on their reaction mechanisms.

Metal‐Free Annulation of Arenes with 2‐Aminopyridine Derivatives: The Methyl Group as a Traceless Non‐Chelating Directing Group

A novel annulation reaction between 2-aminopyridine derivatives and arenes under metal-free conditions is described. The presented intermolecular transformation provided straightforward access to the important pyrido[1,2-a]benzimidazole scaffold under mild reaction conditions. The unprecedented application of the methyl group of methylbenzenes as a traceless, non-chelating, and highly regioselective directing group is reported.

Palladium-catalyzed asymmetric quaternary stereocenter formation

An efficient palladium catalyst is presented for the formation of benzylic quaternary stereocenters by conjugate addition of arylboronic acids to a variety of β,β-disubstituted carbocyclic, heterocyclic, and acyclic enones. The catalyst is readily prepared from PdCl(2), PhBOX, and AgSbF(6), and provides products in up to 99% enantiomeric excess, with good yields. Based on this strategy, (-)-α-cuparenone has been prepared in only two steps.

Cascade Multicomponent Synthesis of Indoles, Pyrazoles, and Pyridazinones by Functionalization of Alkenes

The development of multicomponent reactions for indole synthesis is demanding and has hardly been explored. The present study describes the development of a novel multicomponent, cascade approach for indole synthesis. Various substituted indole derivatives were obtained from simple reagents, such as unfunctionalized alkenes, diazonium salts, and sodium triflinate, by using an established straightforward and regioselective method. The method is based on the radical trifluoromethylation of alkenes as an entry into Fischer indole synthesis. Besides indole synthesis, the application of the multicomponent cascade reaction to the synthesis of pyrazoles and pyridazinones is described.

Total synthesis of (-)-doliculide, structure-activity relationship studies and its binding to F-actin.

Actin, an abundant protein in most eukaryotic cells, is one of the targets in cancer research. Recently, a great deal of attention has been paid to the synthesis and function of actin‐targeting compounds and their use as effective molecular probes in chemical biology. In this study, we have developed an efficient synthesis of (−)‐doliculide, a very potent actin binder with a higher cell‐membrane permeability than phalloidin. Actin polymerization assays with (−)‐doliculide and two analogues on HeLa and BSC‐1 cells, together with a prediction of their binding mode to F‐actin by unbiased computational docking, show that doliculide stabilizes F‐actin in a similar way to jasplakinolide and chondramide C.