Natalia Chernyak

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.

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).

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.

Exclusive 5-exo-dig Hydroarylation of o-Alkynyl Biaryls Proceeding via C-H Activation Pathway

The first example of the palladium-catalyzed exclusive 5-exo-dig hydroarylation of o-alkynyl biaryls has been demonstrated. In contrast to the reported earlier carbocyclizations proceeding via the Friedel-Crafts mechanism, this hydroarylation efficiently proceeds with electron-neutral and electron-deficient arenes, producing fluorene frameworks with defined stereochemistry of the double bond. On the basis of the high reactivity of electron-deficient arenes toward cyclization, high values of inter- and intramolecular kinetic isotope effects, and the exclusive cis-selectivity of cyclization, a mechanism involving a C-H activation motif has been proposed for this transformation.

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.

The Pyridyldiisopropylsilyl Group: A Masked Functionality and Directing Group for Monoselective ortho-Acyloxylation and ortho-Halogenation Reactions of Arenes

A novel, easily removable and modifiable silicon-tethered pyridyldiisopropylsilyl directing group for C-H functionalizations of arenes has been developed. The installation of the pyridyldiisopropylsilyl group can efficiently be achieved via two complementary routes using easily available 2-(diisopropylsilyl)pyridine (5). The first strategy features a nucleophilic hydride substitution at the silicon atom in 5 with aryllithium reagents generated in situ from the corresponding aryl bromides or iodides. The second milder route exploits a highly efficient room-temperature rhodium(I)-catalyzed cross-coupling reaction between 5 and aryl iodides. The latter approach can be applied to the preparation of a wide range of pyridyldiisopropylsilyl-substituted arenes possessing a variety of functional groups, including those incompatible with organometallic reagents. The pyridyldiisopropylsilyl directing group allows for a highly efficient, regioselective palladium(II)-catalyzed mono-ortho-acyloxylation and ortho-halogenation of various aromatic compounds. Most impor-tantly, the silicon-tethered directing group in both acyloxylated and halogenated products can easily be removed or efficiently converted into an array of other valuable functionalities. These transformations include protio-, deuterio-, halo-, boro-, and alkynyldesilylations, as well as a conversion of the directing group into the hydroxy functionality. In addition, the construction of aryl-aryl bonds via the Hiyama-Denmark cross-coupling reaction is feasible for the acetoxylated products. Moreover, the ortho-halogenated pyridyldiisopropylsilylarenes, bearing both nucleophilic pyridyldiisopropylsilyl and electrophilic aryl halide moieties, represent synthetically attractive 1,2-ambiphiles. A unique reactivity of these ambiphiles has been demonstrated in efficient syntheses of arylenediyne and benzosilole derivatives, as well as in a facile generation of benzyne. In addition, preliminary mechanistic studies of the acyloxylation and halogenation reactions have been performed. A trinuclear palladacycle intermediate has been isolated from a stoichiometric reaction between diisopropyl-(phenyl)pyrid-2-ylsilane (3a) and palladium acetate. Furthermore, both C-H functionalization reactions exhibited equally high values of the intramolecular primary kinetic isotope effect (kH/kD = 6.7). Based on these observations, a general mechanism involving the formation of a palladacycle via a C-H activation process as the rate-determining step has been proposed.

Palladium-catalyzed carbocyclization of alkynyl ketones proceeding through a carbopalladation pathway

Carbopalladation across carbon–carbon multiple bonds is a powerful strategy for inter- and intramolecular C–C bond formation.[1] Generally, these processes are well-studied for catalytic cascade transformations involving aryl palladium or vinylpalladium species.[2] In contrast, carbopalladations of Pd enolates, which represent another important class of reactive Pd intermediates widely used in organic synthesis,[3] are exceedingly rare. To date, only a few examples of stoichiometric Pd carbopalladation reactions of carbon–carbon double bonds with Pd enolates have been reported [Eq. (1)].[4] To our knowledge, there are no reports on a catalytic version of this reaction. Herein, we report the Pd-catalyzed cascade transformation featuring the catalytic generation of the Pd enolate by a C–H functionalization strategy, coupled with carbopalladation across the C–C triple bond [Eq. (2)]. (1) (2) Recently, we reported a hydroarylation reaction of o-alkynyl biaryls A to produce fluorenes B.[5] It was proposed that this reaction proceeds by exclusive 5-exo-dig carbopalladation of a triple bond (to give IV) in aryl palladium intermediate I, which is formed from A by aromatic ortho C–H bond activation in the adjacent arene ring (Scheme 1). We hypothesized that the coordination of palladium to a triple bond and a ketone moiety of 1 would eventually lead to the palladium enolate intermediate II, which upon intramolecular carbopalladation would lead to vinylpalladium species III. Subsequent protiodepalladation of the latter should lead to indanone 2 and regenerate the palladium catalyst. To this end, we examined cyclization of 1-(2-(phenylethynyl)phenyl)ethanone (1a) in the presence of several palladium catalysts. [(Ph3P)2PdCl2] and [(MeCN)2PdCl2] were tested first. However, no desired product 2a was formed under these reaction conditions (Table 1, entries 1 and 2). Next, employment of the Pd(OAc)2 catalyst, widely used in C–H activation reactions, in THF resulted in complete decomposition of 1a. Switching to less polar toluene as solvent prevented the decomposition of the starting material, but it did not support the cyclization reaction even at elevated temperatures (Table 1, entry 4). Further optimizations revealed that the employment of the Pd(OAc)2 catalyst in combination with Ph3P ligand enabled the exclusive 5-exo-dig carbocyclization of 1a, producing 2a in 20 % yield, as a single regio-[6] and stereoisomer (Table 1, entry 5), albeit with unexpected E-geometry of the double bond! Employment of BINAP resulted in a slight improvement of the reaction yield (Table 1, entry 6). Use of 1,1′-bis(diphenylphosphino)ferrocene (dppf) led to further improvement of the reaction yield (Table 1, entry 7). Switching to electron-rich 1,1′-bis(diisopropylphosphino)ferrocene (d-i-prpf) resulted in the dramatic improvement of the reaction outcome (Table 1, entry 8).[5] Finally, employment of 6 mol% d-i-prpf allowed us to obtain 2a in 95 % yield (Table 1, entry 9). Scheme 1 Proposed route for the catalytic formation of Pd enolate. Table 1 Optimization of the reaction conditions.[a] Next, the scope of this Pd-catalyzed cyclization was examined (Table 2). We found that this reaction was efficient for a wide range of alkynyl ketones 1, providing the alkylidene indanones 2a–l as single E isomers in good to excellent yields (Table 2). Various functional groups, such as F (Table 2, entries 4, 9), OMe (Table 2, entries 3, 7, 14), Cl (Table 2, entry 6), and CN (Table 2, entry 7) were perfectly tolerated under the reaction conditions. Cyclization of pyridine derivatives of o-alkynyl ketones occurred uneventfully as well, producing 2k (Table 2, entry 11) and 2l (Table 2, entry 12) in 86 % and 52% yield, respectively. Notably, the Pd-catalyzed cyclization of o-alkynyl aryl ketones possessing aryl substituents α to the carbonyl group (R1 = Ar) resulted in formation of isomeric indenone structures 2m (Table 2, entry 13) and 2n (Table 2, entry 14) in good yields. The cyclization of a substrate possessing a fluorine substituent ortho to the carbonyl function was effective as well, providing indanone 2o in 75% yield (Table 2, entry 15). Table 2 Pd-catalyzed 5-exo-dig carbocyclization of 1. Naturally, we were intrigued by the unexpected E-geometry of the double bond in the product 2. Different potential reaction pathways could account for the formation of E-alkylidene indanone 2 from 1 in this Pd-catalyzed cyclization reaction (Scheme 2). The first scenario (path A) features a well-known π-philic activation of the triple bond in 1 with PdII catalyst (3)[2a,7] and subsequent intramolecular 5-exo-dig carbocyclization of the enol tautomer 4 to produce trans-addition intermediate 5. Protiodepalladation of the latter furnishes E-alkylidene indanone 2 directly. Alternatively, the reaction may occur by the initial coordination of the palladium catalyst to the carbonyl group in alkynyl ketone 1 to form 6, which upon deprotonation would produce a Pd enolate species 7 (path B). The subsequent coordination of Pd in 7 to the triple bond would form the alkyne-coordinated Pd enolate 8. This species, upon intramolecular carbopalladation of the triple bond, would lead to a vinylpalladium species 9. The subsequent E–Z isomerization of the double bond[8] would furnish isomeric vinylpalladium intermediate 5, which upon protiodepalladation would produce E isomer 2. Scheme 2 Plausible reaction pathways for carbocyclization of 1. To verify the possibility of the electrophilic mechanism for this transformation (Scheme 2, path A), the carbocyclization of alkynyl ketone 1a was tested in the presence of several π-philic metal salts, including AuCl, AuCl3, PtCl2, electrophilic [Ph3PAuOTf], and Cu(OTf)2,[9] known to mediate cyclizations by π-philic activation of the alkyne moiety. However, no formation of the desired product 2a under these reaction conditions was observed.[10] This observation, together with the shown earlier low efficiency of Pd(OAc)2[9f] alone to catalyzed this transformation, did not support the possibility of the electrophilic path A for this transformation. To further shed light on the possible reaction mechanism of the Pd-catalyzed cyclization of o-alkynyl ketones, density functional theory (DFT) calculations of the possible reaction pathways A and B were performed (Scheme 3).[11] Accordingly, pathway A was ruled out owing to the high free energy (49.3 kcal mol−1) of the corresponding transition state from 4 to 5.[12] In contrast, pathway B, having the lower energy profile and consisting of two major steps with nearly equivalent energy barriers (TS-1 and TS-2), was found to be the most probable pathway for this transformation.[12] Thus, reaction starts with the formation of a complex 6 upon slightly endothermic coordination of compound 1 with the palladium catalyst. The subsequent intramolecular deprotonation of the methyl group of the ketone by the acetate ligand of the PdII catalyst, via transition state TS-1 (ΔG⧧ = 31.2 kcalmol−1), produces 10 (28.6 kcalmol−1), which, upon loss of the AcOH molecule, easily converts into palladium π complex 7 (11.0 kcal mol−1). Notably, this process is quite different from the concerted metalation–deprotonation (CMD) step in the PdII-catalyzed coupling reactions, in which proton transfer to the base and Pd–C bond formation occurs at the same time.[14] Next, the reaction intermediate 7 transforms into the key alkyne-coordinated Pd enolate 8. The subsequent rate-limiting carbopalladation of the triple bond (TS-2, ΔG⧧ = 31.6 kcal mol−1) produces vinyl palladium species 9, which upon E–Z isomerization (TS-3, ΔG⧧ = 9.6 kcalmol−1) transforms into the isomer 5 (ΔG = −5.4 kcalmol−1). Protiodepalladation of the latter leads to the E product 2a (ΔG = −28.6 kcalmol−1; Scheme 3). Scheme 3 Gibbs free energies for the Pd-catalyzed carboyclization of 1 a (L = PMe3).[13] In conclusion, we have developed the Pd-catalyzed regio- and stereoselective carbocyclization of o-alkynyl ketones, featuring the carbopalladation of the triple bond with Pd enolate species. This methodology allows for the synthesis of a variety of alkylidene indanones as single E stereoisomers in good to excellent yields. DFT calculations of the reaction mechanism revealed that the formation of the Pd enolate intermediate occurs by deprotonation assisted by the PdII acetate ligand. It was also demonstrated that the intramolecular carbopalladation of the alkyne with Pd enolate produces E-vinylpalladium species, which upon Z–E isomerization of the double bond transforms into thermodynamically more favorable Z isomer. Protiodepalladation from the latter produces indanones with unexpected E geometry of the methylene double bond.

Dual role of alkynyl halides in one-step synthesis of alkynyl epoxides

It was demonstrated that alkynyl halides could serve as a source of Br+ and acetylide ions in the same transformation. This allowed for the efficient one-step preparation of alkynyl epoxides, important organic building blocks, from readily available starting materials.