Alexander S. Dudnik

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.

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.

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.

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.

PyDipSi: A General and Easily Modifiable/Traceless Si-Tethered Directing Group for C−H Acyloxylation of Arenes

A new general and easily installable silicon-tethered pyridyl-containing directing group (PyDipSi) that allows for highly efficient and regioselective Pd-catalyzed ortho C-H acyloxylation of arenes has been developed. It has also been demonstrated that this directing group can efficiently be removed as well as converted into a variety of other valuable functional groups. In addition, the installation of the PyDipSi directing group along with pivaloxylation and quantitative conversion of the PyDipSi group into a halogen functionality represents a formal three-step ortho oxygenation of haloarenes.

Nickel-Catalyzed Coupling Reactions of Alkyl Electrophiles, Including Unactivated Tertiary Halides, to Generate Carbon–Boron Bonds

Through the use of a catalyst formed in situ from NiBr(2)·diglyme and a pybox ligand (both of which are commercially available), we have achieved our first examples of coupling reactions of unactivated tertiary alkyl electrophiles, as well as our first success with nickel-catalyzed couplings that generate bonds other than C-C bonds. Specifically, we have determined that this catalyst accomplishes Miyaura-type borylations of unactivated tertiary, secondary, and primary alkyl halides with diboron reagents to furnish alkylboronates, a family of compounds with substantial (and expanding) utility, under mild conditions; indeed, the umpolung borylation of a tertiary alkyl bromide can be achieved at a temperature as low as -10 °C. The method exhibits good functional-group compatibility and is regiospecific, both of which can be issues with traditional approaches to the synthesis of alkylboronates. In contrast to seemingly related nickel-catalyzed C-C bond-forming processes, tertiary halides are more reactive than secondary or primary halides in this nickel-catalyzed C-B bond-forming reaction; this divergence is particularly noteworthy in view of the likelihood that both transformations follow an inner-sphere electron-transfer pathway for oxidative addition.

Gold-catalyzed double migration-benzannulation cascade toward naphthalenes.

A novel gold(I)-catalyzed cycloisomerization of propargylic esters leading to unsymmetrically substituted naphthalenes has been developed. This cascade reaction involves an unprecedented tandem sequence of 1,3- and 1,2-migration of two different migrating groups. It is believed that this transformation likely proceeds via the formation of 1,3-diene intermediate or its precursor, which upon cyclization and aromatization steps transforms into the naphthalene core.

Atom-efficient regioselective 1,2-dearomatization of functionalized pyridines by an earth-abundant organolanthanide catalyst

Developing earth-abundant, non-platinum metal catalysts for high-value chemical transformations is a critical challenge to contemporary chemical synthesis. Dearomatization of pyridine derivatives is an important transformation to access a wide range of valuable nitrogenous natural products, pharmaceuticals and materials. Here, we report an efficient 1,2-regioselective organolanthanide-catalysed pyridine dearomatization process using pinacolborane, which is compatible with a broad range of pyridines and functional groups and employs equimolar reagent stoichiometry. Regarding the mechanism, derivation of the rate law from NMR spectroscopic and kinetic measurements suggests first order in catalyst concentration, fractional order in pyridine concentration and inverse first order in pinacolborane concentration, with C=N insertion into the La–H bond as turnover-determining. An energetic span analysis affords a more detailed understanding of experimental activity trends and the unusual kinetic behaviour, and proposes the catalyst ‘resting’ state and potential deactivation pathways. Selective pyridine dearomatization processes traditionally use precious metal catalysts with reagents in stoichiometric excess, and are not well-understood mechanistically. Now, efficient 1,2-regioselective pyridine dearomatization is achieved using equimolar pinacolborane and an earth-abundant lanthanide catalyst. Mechanistic and theoretical studies elucidate the reaction mechanism and explain observed reactivity trends.

A General Strategy Toward Aromatic 1,2‐Ambiphilic Synthons: Palladium‐Catalyzed ortho‐Halogenation of PyDipSi‐Arenes

Ambiphilic aromatic synthons—compounds possessing both electrophilic and nucleophilic centers in the same molecule—are important building blocks that are widely used for a modular construction of complex molecules in organic synthesis, medicinal chemistry, and materials science.[1] Traditionally, they are accessed through multistep syntheses. One of the most efficient strategies toward 1,2-ambiphilic structures involves directed ortho-metalation (DOM) approach.[2] Our research group has recently developed the palladium-catalyzed directed ortho-acyloxylation of pyridyldiisopropylsilyl (PyDipSi) arenes B[3] [Eq. (1)] based on a C–H activation process.[4] Most importantly, we have shown that the PyDipSi directing group[5] could efficiently participate in a variety of reactions as a nucleophilic entity. Because the acyloxy group is known to serve as an electrophilic coupling partner,[6] the o-acyloxylated PyDipSi-arenes can be formally considered as 1,2-ambiphiles. Taking into account the immense synthetic potential of aryl halides as electrophilic reagents, we aimed at the development of a general strategy for the synthesis of ortho-halogenated aryl silanes C, which are much more powerful 1,2-ambiphiles. Herein, we report the palladium-catalyzed ortho-halogenation reaction of easily accessible PyDipSi-arenes B into 1,2-ambiphiles C and their further transformations to a variety of valuable building blocks.