Vladimir Gevorgyan

Transition Metal-Mediated Synthesis of Monocyclic Aromatic Heterocycles

Heterocycles constitute the largest and the most diverse family of organic compounds. Among them, aromatic heterocycles represent structural motifs found in a great number of biologically active natural and synthetic compounds, drugs, and agrochemicals. Moreover, aromatic heterocycles are widely used for synthesis of dyes and polymeric materials of high value. 1 There are numerous reports on employment of aromatic heterocycles as intermediates in organic synthesis. 2 Although, a variety of highly efficient methodologies for synthesis of aromatic heterocycles and their derivatives have been reported in the past, the development of novel methodologies is in cuntinious demand. Particlularly, development of new synthetic approaches toward heterocycles, aiming at achieving greater levels of molecular complexity and better functional group compatibilities in a convergent and atom economical fashions from readily accessible starting materials and under mild reaction conditions, is one of a major research endeavor in modern synthetic organic chemistry. Transition metal-catalyzed transformations, which often help to meet the above criteria, are among the most attractive synthetic tools. Several excellent reviews dealing with transition metal-catalyzed synthesis of heterocyclic compounds have been published in literature during recent years. Many of them highlighted the use of a particular transition metal, such as gold,3 silver,4 palladium,5 copper,6 cobalt,7 ruthenium,8 iron,9 mercury,10 rare-earth metals,11 and others. Another array of reviews described the use of a specific kind of transformation, for instance, intramolecular nucleophilic attack of heteroatom at multiple C–C bonds,12 Sonogashira reaction,13 cycloaddition reactions,14 cycloisomerization reactions,15 C–H bond activation processes,16 metathesis reactions,17 etc. Reviews devoted to an application of a particular type of starting materials have also been published. Thus, for example, applications of isocyanides,18 diazocompounds,19 or azides20 have been discussed. In addition, a significant attention was given to transition metal-catalyzed multicomponent syntheses of heterocycles.21 Finally, syntheses of heterocycles featuring formation of intermediates, such as nitrenes,22 vinylidenes,23 carbenes, and carbenoids24 have also been reviewed. The main focus of the present review is a transition metal-catalyzed synthesis of aromatic monocyclic heterocycles. The organization of the review is rather classical and is based on a heterocycle, categorized in the following order: (a) ring size of heterocycle, (b) number of heteroatoms, (c) type of heterocycle, and (d) a class of transformation involved. A brief mechanistic discussion is given to provide information about a possible reaction pathway when necessary. The review mostly discusses recent literature, starting from 200425 until the end of 2011, however, some earlier parent transformations are discussed when needed.

Rhodium-Catalyzed Transannulation of 1,2,3-Triazoles with Nitriles

Stable and readily available 1-sulfonyl triazoles are converted to the corresponding imidazoles in good to excellent yields via a rhodium(II)-catalyzed reaction with nitriles. Rhodium iminocarbenoids are proposed intermediates.

Transition‐Metal‐Catalyzed Denitrogenative Transannulation: Converting Triazoles into Other Heterocyclic Systems

Transition metal catalyzed denitrogenative transannulation of a triazole ring has recently received considerable attention as a new concept for the construction of diverse nitrogen-containing heterocyclic cores. This method allows a single-step synthesis of complex nitrogen heterocycles from easily available and cheap triazole precursors. In this Minireview, recent progress of the transition metal catalyzed denitrogenative transannulation of a triazole ring, which was discovered in 2007, is discussed.

General and Efficient Copper‐Catalyzed Three‐Component Coupling Reaction towards Imidazoheterocycles: One‐Pot Synthesis of Alpidem and Zolpidem

Imidazopyridine is an important pharmacophore widely found in many biologically active compounds.[i] Particularly, imidazo[1,2-a]pyridine is an essential fragment present in pharmacologically important molecules, including several anxyolytic drugs,[ii] such as alpidem (A),[iia,b] necopidem (C), and saripidem (D), and insomnia treatment drug zolpidem (B).[iic,d] Although a variety of synthetic methods for the synthesis of these important cores have been developed,[iii] most of them are limited in scope and require multistep preparation of starting materials.[iv] Accordingly, development of straightforward and general method for the synthesis of imidazo[1,2-a]pyridines from easily available precursors is highly warranted. Herein we wish to report general and efficient synthesis of imidazopyridines 5 via the Cu-catalyzed three component coupling (TCC) reaction of 2-aminopyridines 1 with arylaldehydes 2 and alkynes 3 (Scheme 1).

Formal inverse Sonogashira reaction: direct alkynylation of arenes and heterocycles with alkynyl halides.

Functionalized aryl and heteroaryl alkynes are highly valuable classes of compounds widely used in contemporary organic synthesis and materials science. Such compounds are commonly formed by a Sonogashira cross-coupling reaction between a hetero(aryl) halide and a terminal alkyne. However, there has been growing interest in the development of a complementary strategy, an “inverse Sonogashira coupling” involving the direct alkynylation of unreactive C–H bonds with readily available alkynyl halides. A historical outline of the development of this transformation promoted or catalyzed by various main-group and transition metals is depicted in Scheme 1. Scheme 1 Development of the direct alkynylation of (hetero)arenes. The first practical example of this type of alkynylation of an aromatic heterocycle, the sydnone derivative 1, was disclosed by Kalinin et al. in 1992.[1] This formal direct alkynylation involved the use of a stoichiometric amount of CuI to generate the organocopper intermediate 2, which underwent palladium(0)-catalyzed cross-coupling with alkynyl bromides 3 to give alkynyl sydnones 4 [Eq. (1)]. Later, Trofimov and co-workers, who introduced the term “inverse Sonogashira coupling”, reported that a variety of (1) pyrroles and indoles 5 underwent alkynylation promoted by greater than stoichiometric amounts of Al2O3 to give C2-alkynylated pyrroles and C3-alkynylated indoles in good yields [Eq. (2)].[2] This reaction is specific to electron-deficient alkynyl ketones and esters 6, as it features the trans addition of nucleophilic heterocycles 5 to Michael acceptors 6, followed by a subsequent dehydrobromination to form 8. Besides Al2O3, other main-group metal oxide active surfaces, such as BaO and ZnO,[2b] and K2CO3 efficiently promoted this transformation. (2) In 2002, Yamaguchi and co-workers reported the first example of a catalytic direct alkynylation of aromatic compounds: phenols 9 (X = O) were coupled with the chloroalkyne 10 in the presence of a catalytic amount of the main-group-metal salt GaCl3 and the bases nBuLi and 2,6-di(tert-butyl)-4-methylpyridine (DtBMP) [Eq. (3); Bn = benzyl].[3a] A variety of alkynyl phenols 12 (X = O), including halosubstituted derivatives, were accessed in this way with exclusive ortho selectivity. The authors proposed that this reaction occurs via the vinyl–gallium intermediate 11 generated upon the carbogallation of 10 with gallium phenoxide; a subsequent β elimination yielded 12. Later, the same group adopted this chemistry for a direct alkynylation of N-benzylanilines 9 (X = NBn).[3b] (3) This field did not experience major growth, however, until 2007, when the first example of a transition-metal-catalyzed direct alkynylation of electron-rich N-fused heterocycles was reported by our research group (Scheme 2).[4] We showed that in the presence of a palladium catalyst, indolizine, pyrroloquinoline, pyrroloisoquinoline, and pyrrolooxazole cores 13 were highly efficiently and regioselectively alkynylated with bromoalkynes 3 containing a broad range of substituents. The crucial conceptual advance was the recognition that the reactivity of the alkynyl–palladium intermediate 15, generated through the oxidative addition of Pd0 into the C–Br bond of 3, resembled that of the aryl–palladium species 15′, which is known to participate in the arylation of indolizines through an electrophilic mechanism[5] (of the type 13→16→17; Scheme 2). Scheme 2 Palladium-catalyzed alkynylation of N-fused heterocycles. TMS = trimethylsilyl. Subsequently, Gu and Wang applied this chemistry to the direct palladium-catalyzed regioselective C3 alkynylation of indoles 18 with various aryl- and alkenyl-substituted alkynyl bromides 3 [Eq. (4)].[6] An electrophilic mechanism was also suggested in this case by the authors for the alkynylation reaction. Further benefits of the use of transition metals were revealed by Chatani and co-workers in an alkynylation of anilides that is complementary to the transformation described by Yamaguchi and co-workers[3b] (Scheme 3).[7] Thus, a variety of anilides 20 underwent the palladium(II)-catalyzed (4) directed ortho alkynylation to furnish aryl alkynes 22 in moderate to high yields. The authors proposed that the reaction proceeded by the ortho palladation of 20 with an electrophilic palladium catalyst to give palladacycle 23; the palladation was enhanced by the requisite addition of a silver salt. Next, two possibilities were envisioned. The first, similar to the proposal of Yamaguchi and co-workers,[3] involved carbopalladation (→25), followed by trans β elimination. An alternative path featured the PdII/PdIV cycle: the oxidative addition of 21 to 23 was followed by reductive elimination from 24. Importantly, since no Pd0 species was involved in the catalytic cycle, halogen substituents (Cl, Br) could be present. Thus, subsequent elaboration of the products by standard cross-coupling reactions is possible. Scheme 3 Direct alkynylation of anilides. Tf = trifluoromethanesulfonyl, TIPS = triisopropylsilyl. Recently, nickel(0)- and copper(I)-catalyzed variations of the inverse Sonogashira reaction of azoles 26 with different alkynyl bromides 3 were reported by Miura and co-workers[8] and Besselievre and Piguel[9] [Eq. (5); cod =1,5-cyclooctadiene, dppbz =1,2-bis(diphenylphosphanyl)benzene, dpephos = bis(2-(diphenylphosphanyl)phenyl) ether]. These reactions proceeded in moderate to high yields with an array of azole cores [see Eq. (5)]. Mechanistically, the direct alkynylation developed by Miura and co-workers proceeds through a catalytic version of the formal cross-coupling reaction described by Kalinin et al. [see Eq. (1)]. The alkynyl–nickel intermediate formed by the oxidative addition of the Ni0 catalyst to 3 undergoes a transmetalation/reductive elimination sequence with a heteroaryl copper or lithium species I,[1a] which is generated in situ through the metalation of 26. Independently, Besselievre and Piguel[9] postulated the same heteroaryl–copper intermediate I, the subsequent transformation of which was proposed to involve a CuI/CuIII cycle resembling the PdII/PdIV cycle proposed by Chatani and coworkers.[7] Gold is a recent addition by Waser and co-workers to the arsenal of transition-metal catalysts employed in the inverse Sonogashira reaction.[10] Unprecedented functional-group tolerance and mild reaction conditions were demonstrated (5) in the gold(I)-catalyzed alkynylation of indole (C3) and pyrrole (C2) cores 28 with the recyclable hypervalent alkynyl iodine reagent 29 [Eq. (6)]. The observed regioselectivity of alkynylation could be overruled by blocking the C3 (C2) position of the indole (pyrrole), or by the introduction of a bulky triisopropylsilyl (TIPS) group at the pyrrole N atom. Several mechanistic hypotheses featuring trans addition/elimination and AuI/AuIII catalytic cycles were suggested by the authors for this reaction. (6) In summary, recent findings in the field of direct alkynylation reactions open up new exciting opportunities for the functionalization of C–H bonds. Although the development of more general and efficient catalytic systems and the expansion of the scope of this reaction are still highly wanted, the current advances augur the continuing growing interest in and broad application of this method in synthesis.

Metal-Catalyzed 1,2-Shift of Diverse Migrating Groups in Allenyl Systems as a New Paradigm toward Densely Functionalized Heterocycles

A general, mild, and efficient 1,2-migration/cycloisomerization methodology toward multisubstituted 3-thio-, seleno-, halo-, aryl-, and alkyl-furans and pyrroles, as well as fused heterocycles, valuable building blocks for synthetic chemistry, has been developed. Moreover, regiodivergent conditions have been identified for C-4 bromo- and thio-substituted allenones and alkynones for the assembly of regioisomeric 2-hetero substituted furans selectively. It was demonstrated that, depending on reaction conditions, ambident substrates can be selectively transformed into furan products, as well as undergo selective 6-exo-dig or Nazarov cyclizations. Our mechanistic investigations have revealed that the transformation proceeds via allenylcarbonyl or allenylimine intermediates followed by 1,2-group migration to the allenyl sp carbon during cycloisomerization. It was found that 1,2-migration of chalcogens and halogens predominantly proceeds via formation of irenium intermediates. Analogous intermediate can also be proposed for 1,2-aryl shift. Furthermore, it was shown that the cycloisomerization cascade can be catalyzed by Brønsted acids, albeit less efficiently, and commonly observed reactivity of Lewis acid catalysts cannot be attributed to the eventual formation of proton. Undoubtedly, thermally induced or Lewis acid-catalyzed transformations proceed via intramolecular Michael addition or activation of the enone moiety pathways, whereas certain carbophilic metals trigger carbenoid/oxonium type pathway. However, a facile cycloisomerization in the presence of cationic complexes, as well as observed migratory aptitude in the cycloisomerization of unsymmetrically disubstituted aryl- and alkylallenes, strongly supports electrophilic nature for this transformation. Full mechanistic details, as well as the scope of this transformation, are discussed.

Versatile Reactivity of Rhodium–Iminocarbenes Derived from N-Sulfonyl Triazoles

Rhodium-stabilized carbenes possess diverse reactivity in a variety of organic transformations, such as addition to C–C and C–heteroatom multiple bonds, insertion into C–H and C–heteroatom bonds, as well as ylide formation.[1] However, this powerful chemistry is mostly limited to rhodium carbenes derived from the corresponding diazo compounds. Obviously, development of new and efficient methods to access Rh carbenoids from alternative and stable precursors could expand the scope of this chemistry. It is known that the stability of the 1,2,3-triazole ring is affected by the substituents at the N1, C4, and C5 atoms of the heterocycle.[2] For example, triazoles 1 that bear a sulfonyl group at the N1 atom exist in equilibrium with diazoimine tautomer 2.[3] Gevorgyan and Fokin took advantage of this process by trapping diazoimine 2 with a RhII catalyst to produce the putative RhII–iminocarbene 3 (Scheme 1).[4] This intermediate possessed reactivity inherent for RhII carbenoids. For example, it reacted with alkenes to form cyclopropane derivatives 4.[4] Later, this process was performed by Fokin and co-workers in a highly enantioselective manner.[5] On the other hand, the presence of the imino group at the α-position of 3 opens opportunities for novel heterocyclizations. Thus, the transannulation[6] reaction of N-sulfonyl triazoles with nitriles produced imidazoles 5,[4] whereas the reaction with alkynes[7a] led to pyrroles 6.[7b] As shown by Fokin and co-workers, Rh–iminocarbene 3 could also undergo insertion into a secondary or tertiary C–H bond of alkanes (as a solvent) to produce valuable β-chiral amines 7 in high yields and enantioselectivities.[8a] In 2012, Murakami reported an efficient RhII-catalyzed hydration of triazoles 1 to form α-aminoketones 8, proceeding through insertion of the RhII–iminocarbene intermediate into the O–H bond of water.[8b] Shortly after, Fokin and co-workers disclosed the RhII-catalyzed reaction of N-sulfonyl triazoles 1 with arylboronic acids, thus stereoselectively furnishing enamines 9.[8c] Note-worthy, the N-sulfonyl triazole precursors are easily available by Cu-catalyzed alkyne–azide cycloaddition (CuAAc) reaction,[9] which makes this approach to Rh-stabilized carbenes attractive for the synthesis of valuable carbo- and heterocyclic molecules (Scheme 1). Scheme 1 Use of N-sulfonyl triazole to form Rh–iminocarbene. Very recently, the groups of Murakami[10] and Fokin[11] independently reported the RhII-catalyzed denitrogenative rearrangement of 1-(N-sulfonyl-triazol-4-yl)alkanols 10, proceeding through migration of different groups to the Rh–carbene center of 12. The subsequent elimination of rhodium from the 12 produces iminoenol 14, which is converted to Z-substituted enaminone 11 upon facile proton transfer (Scheme 2). Scheme 2 The RhII-catalyzed rearrangement of triazolyl alcohols. Conditions A (Miura and Murakami[10]): CHCl3, 140°C, microwave, 15 min. Conditions B (Fokin[11]): CHCl3, 70°C, 5–60 min. Oct=octanoate, Ts=4-toluenesulfonyl. In general, the migratory aptitude of different groups to the Rh–carbene center derived from a diazo compound follows the common tendency: hydride > phenyl > primary alkyl > secondary alkyl groups.[12] Likewise, in the transformation 12→13, the 1,2-migration of hydride is favored over the 1,2-shift of alkyl and phenyl groups (Table 1, entries 1 and 2, respectively). The phenyl group, in turn, migrates more easily than the methyl group (entry 3), whereas the methyl group migrates more easily than the isopropyl group (entry 4). Furthermore, cyclic 1-triazolylalkanols 10 f underwent efficient ring expansion to produce the corresponding cyclic enaminones 11 f (entries 7 and 8). The reaction of fluorenol derivative 10g led almost quantitatively to the corresponding hydroxyphenanthrene derivative 11 g (entries 9 and 10). In most cases, a predominant formation of the Z-stereoisomer was observed, which can be attributed to the concerted transformation 14→11 (kinetic control), and to the higher stability of the Z-stereoisomer as a result of an additional stabilization through intramolecular hydrogen bonding (thermodynamic control). Table 1 Migrations of different groups to the metal–carbene center of RhII–iminocarbenes (see Scheme 2). Interestingly, protection of the hydroxy group as acetate enabled its selective migration to the carbene center to form products 16 (entry 11). It was also shown that 4-cyclohexyl and 4-tert-butyl triazoles gave the products of hydride and methyl group migration (18a and 18b, respectively) under these reaction conditions (entries 12 and 13). Moreover, Fokin and co-workers reported the first example of amine migration to the RhII carbenoid center. Thus, the reaction of 4-alkylamino triazole 17c produced the corresponding enamine 18c in good yields (entry 14).[11] In conclusion, the RhII–iminocarbenes, derived from the corresponding N-sulfonyl 1,2,3-triazoles, could be used in several transformations inherent for metal carbenoids. Thus, cyclopropanation of alkenes, reactions with alkynes, nitriles, and boronic acids, as well as insertion into C–H and O–H bonds were impressively developed. In addition, the recent reports also disclosed migrations of different groups to the RhII–carbene center of imino carbenoids. The N-sulfonyl 1,2,3-triazole precursors are easily available by CuAAc reaction of alkynes with azides, which makes this approach very useful for straightforward generation of RhII carbenoids. Some transformations could even be efficiently performed in a one-pot manner starting from alkynes and sulfonyl azides. Therefore, the reactivity of RhII–iminocarbenes can be tuned easily by variation of substituents in the parent triazole through the simple CuAAc approach. Moreover, a natural low concentration of diazoimine, which exists in equilibrium with triazoles, maintains a low concentration of the reactive RhII carbenoid, which obviates the necessity of slow-addition techniques that are often required in the reactions of diazo compounds.

Mechanistic Insights into the Gold-Catalyzed Cycloisomerization of Bromoallenyl Ketones: Ligand-Controlled Regioselectivity

Through computational and experimental studies, the mechanisms of gold-catalyzed cycloisomerization of bromoallenyl ketones in toluene have been elucidated. The divergent 1,2-migrations for the Au(I)- and Au(III)-catalyzed reactions have been investigated, and the results confirmed that the regiochemistry is ligand-dependent in cases of Au(PR3)L (L = Cl, OTf, BF4, and SbF6) catalysts.

Silanol: A Traceless Directing Group for Pd-Catalyzed o-Alkenylation of Phenols

A silanol-directed, Pd(II)-catalyzed C-H alkenylation of phenols is reported. This work features silanol, as a novel traceless directing group, and a directed o-C-H alkenylation of phenols. This new method allows for efficient synthesis of diverse alkenylated phenols, including an estrone derivative.

Computation-Guided Development of Au-Catalyzed Cycloisomerizations Proceeding via 1,2-Si or 1,2-H Migrations: Regiodivergent Synthesis of Silylfurans

A novel highly efficient regiodivergent Au-catalyzed cycloisomerization of allenyl and homopropargylic ketones into synthetically valuable 2- and 3-silylfurans has been designed with the aid of DFT calculations. This cascade transformation features 1,2-Si or 1,2-H migrations in a common Au-carbene intermediate. Both experimental and computational results clearly indicate that the 1,2-Si migration is kinetically favored over the 1,2-shifts of H, alkyl, and aryl groups in the beta-Si-substituted Au-carbenes. In addition, experimental results on the Au(I)-catalyzed cycloisomerization of homopropargylic ketones demonstrated that counterion and solvent effects could reverse the above migratory preference. The DFT calculations provided a rationale for this 1,2-migration regiodivergency. Thus, in the case of Ph(3)PAuSbF(6), DFT-simulated reaction proceeds through the initial propargyl-allenyl isomerization followed by the cyclization into the Au-carbene intermediate with the exclusive formation of 1,2-Si migration products and solvent effects cannot affect this regioselectivity. However, in the case of a TfO(-) counterion, reaction occurs via the initial 5-endo-dig cyclization to give a cyclic furyl-Au intermediate. In the case of nonpolar solvents, subsequent ipso-protiodeauration of the latter is kinetically more favorable than the generation of the common Au-carbene intermediate and leads to the formation of formal 1,2-H migration products. In contrast, when polar solvent is employed in this DFT-simulated reaction, beta-to-Au protonation of the furyl-Au species to give a Au-carbene intermediate competes with the ipso-protiodeauration. Subsequent dissociation of the triflate ligand in this carbene in polar media due to efficient solvation of charged intermediates facilitates formation of the 1,2-Si shift products. The above results of the DFT calculations were validated by the experimental data. The present study demonstrates that DFT calculations could efficiently support experimental results, providing guidance for rational design of new catalytic transformations.