Novel Organosulfur Building Blocks for Heterocycle Synthesis

Dedicated to Professor Brindaban Chandra Ranu on the occasion of his 75th birthday.

Abstract

The present article provides a personalized account of our recent work on the synthesis of substituted and fused five-membered heterocycles using various organosulfur building blocks, derived primarily through base-mediated condensation of active methylene compounds with (het)aryl/alkyl dithioesters, which have not been previously explored. We initially describe the ring-opening transformations of 4-[(methylthio)-(het)aryl-methylene]-2-phenyl-5-oxazolones, leading to the synthesis of functionalized oxazoles, thiazoles, and bisoxazoles. We then go on to focus on the synthesis of substituted benzothiophenes, indoles, and benzofurans, as well as their hetero-fused analogs. These compounds are synthesized via transition-metal-catalyzed intramolecular C–heteroatom (C–S, C–N, C–O) bond formation (via cross-coupling or C–H bond functionalization) of various reactive organosulfur intermediates, derived from base-mediated condensation of 2-bromo(het)arylacetonitriles, acetates, or desoxybenzoins or the corresponding 2-unsubstituted precursors. Finally, we highlight the synthetic applications of a new class of previously unexplored organosulfur building blocks, namely, unsymmetrically substituted 1,3-bis(het)aryl-1,3-monothioketones, derived via base-mediated condensation of ketones with (het)aryl/alkyl dithioesters, for the regioselective synthesis of substituted pyrazoles, isoxazoles, thiophenes, imidazoles, and benzothiophenes.

1 Introduction

2 4-[(Methylthio)-het(aryl)-methylene]-2-phenyl/2-(2-thienyl)-5-oxazolones: Versatile Templates for the Synthesis of Oxazoles, Thiazoles, and Bisoxazoles

3 Synthesis of Benzothiophenes, Indoles, and Benzofurans via Transition-Metal-Catalyzed Intramolecular C–Heteroatom Bond Formation

4 1,3-Bis(het)arylmonothio-1,3-diketones and 1,3-Bis(Het)aryl-3-(methylthio)-2-propenones: Versatile Intermediates for the Regioselective Synthesis of Five-Membered Heterocycles

5 Conclusion

Biographical Sketches

Hiriyakkanavar Ila received her Ph.D. from IIT Kanpur (1968). After a postdoctoral stay with Prof. R. L. Whistler at Purdue University, USA (1969), she joined the Central Drug Research Institute, Lucknow (1970) as a research scientist. In 1977, together with her husband, Prof. H. Junjappa, also a chemistry professor, she moved to North Eastern Hill University, Shillong to establish a School of Chemistry there. She became a professor in 1986, and joined the Department of Chemistry at IIT Kanpur, her alma mater, in 1995. After her superannuation (2007), she moved to Bangalore and joined Jubilant Biosys as a ‘Principal Advisor, medicinal chemistry’ (2007–2009). In January 2010, she moved to the New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bangalore, as an INSA Senior Scientist (2010–2014), where she is currently the ‘Hindustan Lever Research Professor’ (2015 onward). Prof. Ila was elected as a Fellow of the Indian Academy of Science, Bangalore (FASc) in 1990 and the Indian National Science Academy (FNA) in 2001. She was awarded the Chemical Research Society of India, Lifetime Achievement Award Gold Medal in 2019 and Silver Medal in 2001, the AV Ramarao Foundation Prize in Chemistry, and the Indian Chemical Society Medal. She has been an Alexander von Humboldt Fellow (1984–1985, with Prof. R. Gompper, Munich; 1998, 2000, 2001, 2003, and 2016 with Prof. L. F. Tietze, Gottingen; 2004, 2005, 2010, 2011, and 2015 with Prof. Paul Knochel, LMU, Munich), a Marie Curie Visiting Fellow at the University of Cambridge, UK (1995), an INSA exchange visitor to the UK and France (1993 and 1996), a visiting professor at Sevilla, Spain (1999), USC, Los Angeles (2002), and the University of Sendai, Japan (2012). She has delivered several plenary and invited lectures at several international conferences as well as national conferences. She has co-authored more than 265 research publications in international journals, and her research activities revolve around the design and development of efficient new synthetic methods for biologically important molecules, especially heterocycles. Her biography was published in ‘Lilawati’s Daughters’, a book published by the Indian Academy of Science, Bangalore (2008) on Indian Women Scientists, and recently in ‘Vigyan Vidushi’, a book published by Vigyan Prasar DST (2023), New Delhi on Indian women scientists to celebrate ‘Azadi ka Amrut Mahotsav’.

Saravanan Peruncheralathan was born in 1976 in Salem, India, and began his academic journey in 1998 when he joined Prof. H. Ila’s research group as a junior research fellow at the Department of Chemistry at the Indian Institute of Technology (IIT) Kanpur. He earned his Ph.D. in 2004 and continued working with Prof. Ila as a research associate at IIT Kanpur. In 2006, he moved to Germany to join Prof. C. Schneider’s group at the Institute für Organische Chemie, Universität Leipzig, where he conducted postdoctoral research. During this time, he was honored with a prestigious Alexander von Humboldt Fellowship. In 2010, he joined the School of Chemical Sciences at the National Institute of Science Education and Research (NISER) in Bhubaneswar as an assistant professor. He was promoted to Reader-F in 2012 and subsequently to an associate professor in 2019. He currently serves in this position at NISER Bhubaneswar. His research interests include the selective functionalization of C–X and C–H bonds, asymmetric synthesis, domino reactions, and the synthesis of small molecules for therapeutic applications. He was the first Ph.D. co-worker in Prof. Ila’s group who initiated the dithioester chemistry.

Introduction

Five- and six-membered substituted and fused heterocycles constitute more than 50% of existing chemicals and form the basic skeletons of several FDA-approved drugs, especially those containing nitrogen heterocycles. They also find applications in materials science, optoelectronics, agrochemicals, and are present in naturally occurring compounds, nucleic acids, proteins, enzymes, vitamins, and dyes. The increasing demand for heterocycles, especially in drug discovery research, has necessitated the design and development of new synthetic methods, particularly examples utilizing easily accessible starting materials, that generate a large and diverse set of heterocyclic compounds for lead discovery.

Having started my research career at the Central Drug Research Institute, Lucknow, a drug discovery research laboratory, I have been continuously focused on designing and discovering new classes of reactive intermediates for the synthesis of five- and six-membered heterocycles.[1] During this period, our research team along with my husband Prof Junjappa have successfully developed polarized ketene dithioacetals 1, a class of stable organosulfur intermediates that are readily accessible from a broad range of active methylene compounds displaying large functional group diversity (Scheme [1]).[1] [2]

These intermediates not only display a variety of functional groups and skeletal diversity but also can be easily generated from readily available precursors. Among them, the corresponding α-oxoketene dithioacetals 2 (derived from active methylene ketones) and other reactive intermediates derived by replacing the alkylthio groups of 1 or 2 with various nucleophiles, especially amines (polarized ketene N,S-acetals), have emerged as versatile intermediates for the synthesis of heterocyclic compounds, providing an increasing wealth of information and are the subject of several reviews.[3] [4] Meanwhile, we initially investigated other organosulfur intermediates, such as β-ketodithioesters 3, which have subsequently been explored extensively by other research groups (Scheme [1]).[5]

In continuation of our interest in the design and discovery of potentially useful novel organosulfur intermediates, we have recently explored simple (het)aryl/alkyl dithioesters of the general structure 4, and the intermediates derived from them, for their application in heterocycle synthesis. Although alkyl and aryl esters constitute the backbone of C–C bond formation in synthetic organic chemistry, the related (het)aryl/alkyl dithioesters have not been explored for their synthetic applications, despite their syntheses being reported in the literature.[6] [7]

The present account highlights some of our research work in the last few years (2011–2016), conducted at Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bangalore, based on the synthetic applications of (het)aryl/alkyl dithioesters 4 and the intermediates derived from them. The various (het)aryl and alkyl dithioesters 4 employed in our present work have been synthesized mainly by two procedures reported in the literature: (a) by reactions of (het)aryl/alkyl Grignard reagents with carbon disulfide, followed by alkylation of the intermediate dithioate salts with alkyl halides, mainly methyl iodide (Method A),[6] and (b) by reactions of (het)aryl halides with n-butyllithium, generating the corresponding (het)aryl lithium salts, which were subjected to successive treatment with carbon disulfide and methyl iodide, yielding dithioesters 4 in good yields (Method B),[6] as shown in the Scheme [2]. The structures of most of the known and newly prepared dithioesters employed in our study are shown in the Scheme [2]. The corresponding 3-(N-methylindolyl)dithioester 4v was prepared by a different route, by treatment of thioimidium salt 7 (obtained by S-methylation of thioamide 6) with H₂S in pyridine (Scheme [3]).[7] Similarly, the related 2-, 3-, and 4-pyridyl dithioesters 4w–y were also prepared differently, from the corresponding sulfones 9 (prepared by treatment of the corresponding pyridylmethyl chlorides 8 with sodium phenyl sulfonate according to the reported procedure).[8] The sulfones 9 were reacted with sulfur in the presence of potassium t-butoxide at room temperature, followed by alkylation with methyl iodide to give products 4w–y in good yields (Scheme [3]).[8]

4-[(Methylthio)-(het)aryl-methylene]-2-phenyl/(2-thienyl)-5-oxazolones: Versatile Templates for the Synthesis of Substituted Oxazoles, Thiazoles, and Bisoxazoles

Nucleophilic Ring Opening of 4-[(Methylthio)-(het)aryl-methylene]-2-phenyl-5-oxazolones: Synthesis of 2-Phenyl-4,5-Substituted Oxazoles by Copper-Catalyzed Intramolecular Cyclization of Functionalized Enamides

In a previous paper, we had explored the synthetic transformation of 4-bis(methylthio)methylene-2-phenyl-5-oxazolone for the synthesis of 2-phenyl-5-(methylthio)-4-functionalized oxazoles.[9] Subsequently, we sought to explore an alternative similar strategy for the synthesis of 4-functionalized 2-phenyl-5-(het)aryl oxazoles by installing a (het)aryl group at the 5-position of oxazoles (Schemes 4–6).[10] The overall process involves the sequential nucleophilic ring opening of newly synthesized 4-[(methylthio)-(het)aryl-methylene]-2-phenyl-5-oxazolones 12 by nucleophiles such as alkoxides, amines and Grignard reagents, followed by copper-catalyzed intramolecular cyclization of the resulting highly functionalized enamide intermediates 13, 17, and 19 (Schemes 4–6). The desired 2-phenyl 4-[(methylthio)-(het)aryl-methylene]-5-oxazolones 12 were synthesized in good yields by reacting 2-phenyl-5-oxazolone 10 with various (het)aryl dithioesters 4 in the presence of sodium hydride in DMF, followed by alkylation of the resulting thioenolate salts 11 with methyl iodide (Scheme [4]).

The oxazolones 12 were first subjected to nucleophilic ring opening in the presence of various alkoxides to afford α-[(methylthio)-(het)aryl-methylene]-N-benzoylglycinates 13 in excellent yields. These intermediates 13 underwent facile intramolecular cyclization in the presence of a copper catalyst (CuI), 1,10-phenanthroline as a ligand, and cesium carbonate as a base in DMF, to afford various substituted alkyl 2-phenyl-5-(het)aryloxazole-4-carboxylates 14 in excellent yields (Scheme [4]).[10]

We also undertook the synthesis of a few naturally occurring oxazoles, such as texamine (16a) (isolated from Amyris texana), uguenenazole (16b) (recently isolated from Vepris uguenensis), and the corresponding 5-(3-indolyl) analog 16c via thermal decarboxylation of the corresponding carboxylic acids 15, obtained by hydrolysis of the oxazole 5-carboxylates 14 in the presence of ethanolic NaOH. Thermal decarboxylation of 15a–c in H₂O/DMF afforded products 16a–c in good yields (Scheme [4]).[10]

Nucleophilic ring opening of oxazolones 12 with various primary and secondary amines and a few amino acid esters was next investigated. Under optimal reaction conditions, this process afforded the open-chain enamide adducts 17, bearing amide functionalities, in excellent yields (Scheme [5]). Subsequent copper-catalyzed intramolecular cyclization of these enamide adducts 17 under identical conditions (see above) furnished a diverse range of novel 2-phenyl-5-(het)aryloxazole-4-carboxamides 18 in high yields (Scheme [5]). Similarly, the open-chain adducts derived from the ring opening of 12 with various amino acid esters furnished the corresponding novel oxazoles 18e–g possessing peptidomimetic motifs.[10]

Finally, after the successful implementation of this two-step protocol for the introduction of 4-carboxylate and 4-carboxamide functionalities on the trisubstituted oxazoles 14 and 18 (Schemes 4 and 5), the ring opening of oxazolones 12 with alkyl/aryl Grignard reagents was next explored (Scheme [6]). Thus, treatment of several oxazolones 12 with alkyl/aryl Grignard reagents afforded highly functionalized α-acylenamides 19 in good yields, in a highly regioselective manner, with no trace of conjugate addition–elimination products. These enamides 19 underwent facile copper-catalyzed cyclization under optimized reaction conditions, affording the corresponding 2-phenyl-5-(het)aryl-4-acyl/aroyloxazoles 20a–e in high yields (Scheme [6]). Overall, this nucleophilic ring-opening–cyclization protocol of oxazolone precursors 12 is found to be versatile for the installation of various functionalities at the 4-position of oxazoles.[10]

Synthesis of 2,4,5-Trisubstituted Thiazoles via Lawesson’s Reagent Mediated Chemoselective Thionation–Cyclization of Functionalized Enamides

We further envisaged utilizing enamide precursors 13 and 17, obtained by ring opening of oxazolones 12 with alkoxides and amines respectively, to develop a new chemoselective route for 2,4,5-trisubstituted thiazoles 22 and 23 via thionation–cyclization of these intermediates in the presence of Lawesson’s reagent (Scheme [7]).[11] Thus, when enamides 13 (obtained by nucleophilic ring opening of oxazolones 12 with alkoxides) were refluxed with two equivalents of Lawesson’s reagent in toluene for 2–12 hours, the corresponding 2,5-bis(het)arylthiazole-4-carboxylates 22 were obtained in high yields through spontaneous intramolecular cyclization of in situ generated thioenamide intermediates 21A. The reaction was found to be equally successful for the synthesis of thiazole 4-carboxylates with various alkyl groups such as ethyl (22b,d,e), t-butyl (22a) and n-butyl (22c) functionalities. The protocol could also be elaborated for the synthesis of the corresponding thiazole-4-carboxamides 23 from enamides 17, obtained by nucleophilic ring opening of oxazolones with primary aliphatic and aromatic amines and amino acid esters (Scheme [7]). However, due to the insolubility of enamides 17 in toluene, the reaction with Lawesson’s reagent was performed in refluxing THF, furnishing the corresponding thiazole 4-carboxamides 23 in good yields via thioenamides 21B (Scheme [7]). The reaction showed broad diversity, and thiazole-4-carboxamides 23 derived from primary aliphatic and aromatic amines as well as amino acid side chains were all obtained in high yields. However, the reaction was not successful with enamides derived from secondary amines.[11]

Copper-Catalyzed Domino Reactions of Activated Methylene Isocyanides with 2-Phenyl/(2-thienyl)-4-[(methylthio)-(het)aryl-methylene)]-5-oxazolones 12: Synthesis of 2,5-Bis(het)aryl 4′-Substituted-4,5′-Bisoxazoles

After successfully synthesizing substituted oxazoles and thiazoles via nucleophilic ring opening of 4-(het)aryl-methylene-5-oxazolones 12 with various nucleophiles and subsequent ring closure of the resulting enamide intermediates (see Schemes 4–7), we next explored the ring-opening–cyclization of oxazolones 12 with activated methylene isocyanide pronucleophiles 24, anticipating that it would bring about a different kind of rearrangement–cyclization process (Scheme [8]). In recent years, activated methylene isocyanides have emerged as versatile intermediates, participating in various types of base-mediated co-cyclization reactions with multiple bonds and other reactive species, leading to a diverse class of nitrogen heterocycles.[12] We have previously reported the efficient synthesis of 2,3,4-trisubstituted pyrroles[13a] and imidazo[1,5-a]quinoxalines[13b] by formal cycloaddition of activated methylene isocyanide carbanions to polarized ketene dithioacetals and 2,3-disubstituted quinoxalines, respectively. We had also reported reactions of cyclic α-oxoketene dithioacetals with activated methylene isocyanides, leading to the synthesis of pyrrolo-fused heterocycles via an interesting ring enlargement–pyrrole annulation domino protocol.[13c] In continuation of these studies, we further speculated that the nucleophilic ring opening–cyclization of oxazolones 12 by activated methylene isocyanide pronucleophiles would first give acyclic oxazole intermediate 25 bearing an enamide side chain, which could be further manipulated to undergo intramolecular cyclization to provide bisoxazoles 26 (Scheme [8]).[14] In fact, we have successfully achieved this domino transformation under copper-catalyzed conditions, providing a straightforward and direct route to a wide range of 2,5,4′-trisubstituted 4,5′-bisoxazoles 26 (Scheme [8]).

Thus, the ring opening of oxazolones 12 with ethyl isocyanatoacetate 24a (X = CO₂Et) in the presence of different bases such as DBU, NaH, potassium t-butoxide, or Cs₂CO₃ at low temperatures mostly afforded a mixture of adduct 25 and bisoxazole 26 (X = CO₂Et) in varying yields (Scheme [8]). Complete conversion of adducts 25 into bisoxazoles 26 required higher temperatures (120 °C), yielding products 26 in moderate to good yields. However, when the reaction was carried out in the presence of a copper catalyst (CuI, 10 mol%) and cesium carbonate as the base in DMF at 90 °C, bisoxazoles 26 were obtained as the only products in excellent yields. The reaction was successful with a variety of acceptor-substituted activated methylene isocyanides 24a–e, yielding bisoxazoles 26, with a broad diversity of substituents at the 4′ and 5 positions, in excellent yields under optimized reaction conditions in the presence of the copper catalyst (Scheme [8]).[14]

Based on experimental studies, a plausible mechanism for the formation of bisoxazoles 26 from oxazolones 12 and activated methylene isocyanides 24 under copper catalysis has been suggested, as shown in Scheme [9]. Nucleophilic ring opening of the lactone ring of oxazolone 12 by the α-cuprioisocyanide complex A, formed by reaction of the activated methylene isocyanide with Cu(I), generates acyclic α-acylisonitrile intermediate B, which exists in equilibrium with the copper enolate C under basic conditions. The intermediate C undergoes facile intramolecular cyclization by attack on the isonitrile carbon to furnish the oxazolocopper intermediate D. The C–Cu bond in intermediate D is protonated by isocyanide 24, furnishing the initially formed oxazole-containing acyclic product 25 at low temperature with regeneration of the copper intermediate A or A′, thus completing the catalytic cycle for the formation of the initial adduct 25. Subsequently, coordination of the amide functionality of 25 with a cuprous ion forms the chelated intermediate E, which undergoes intramolecular nucleophilic substitution at the electrophilic double bond through the transition-state intermediate F. This is followed by Cs₂CO₃-assisted elimination of MeSH and decomposition of the resulting bisoxazole-Cu complex, furnishing bisoxazole 26 along with the regenerated Cu(I) catalyst.[14]

Synthesis of Benzothiophenes, Indoles, and Benzo[b]furans via Transition-Metal-Catalyzed Intramolecular C–Heteroatom Bond Formation

In another project, we planned to develop synthetic routes for benzothiophenes, indoles, and benzofurans via transition-metal-catalyzed intramolecular C–heteroatom bond formation through cross-coupling or C–H functionalization of reactive intermediates. These intermediates are generated by base-mediated condensation of the corresponding active methylene compounds, such as 2-bromoarylacetonitriles, 2-bromoaryl acetates, and 2-bromodesoxybenzoins (or the corresponding 2-unsubstituted analogs), with dithioesters 4. The resulting intermediates are then subjected to various transformations, which are discussed in the following section (Schemes 10–24).

Synthesis of Benzothiophenes and their Hetero-Fused Analogs via Copper-Catalyzed Intramolecular Cross-Coupling of in situ Generated Enethiolates and Pd-Catalyzed Intramolecular C–H Functionalization–Arylthiolation

We have previously reported the synthesis of 2,3-disubstituted benzothiophenes and their hetero-fused analogs via radical-mediated intramolecular cyclization of 2-bromo-(het)aryl-3-(methylthio)-3-(het)arylacrylonitriles.[15] In continuation of these studies, we have developed an efficient one-pot direct synthesis of benzothiophenes and their hetero-fused analogs by trapping the corresponding enethiolate intermediates 28 derived from base-mediated condensation of o-bromoarylacetonitriles 27 with dithioesters 4, and subjecting them to copper-catalyzed intramolecular C–S cross-coupling, involving formation of the C(2)–C(3) and S(1)–C(7a) bonds of benzothiophenes 29 in a tandem fashion (Scheme [10]).[16] Thus, under optimized reaction conditions, 2-bromo(het)arylacetonitriles 27 were reacted with (het)aryl dithioesters 4 or other thiocarbonyl compounds, such as dimethyl trithiocarbonates, S-methyl xanthates, methyl-N-imidazolyl dithioates, and aryl isothiocyanates, in the presence of sodium hydride in DMF to give enethiolates 28. These were subsequently subjected to in situ intramolecular arylthiolation in the presence of 10 mol% of CuI and l-proline (20 mol%), with heating of the reaction mixture at 90 °C for 3 to 6 hours, to give the corresponding 2-cyano-3-(het)aryl-substituted benzothiophenes 29 in high yields (Scheme [10]).

Both electron-donating and electron-withdrawing groups on the aromatic ring were tolerated (29a–c), and other substituents like alkyl, O-alkoxy, and NH-aryl functionalities could also be installed at the 2-position of the benzothiophenes (29d–f), depending on the choice of (het)aryl dithioester 4 and thiocarbonyl compound (Scheme [10]). The reaction was equally facile for the synthesis of hetero-fused thiophenes 30, such as 2,3-disubstituted thieno[2,3-b]thiophenes 30a,b, thieno[2,3-b]indoles 30c,d, thieno[2,3-b]pyridines 30e,f, and thieno[3,2-c]pyrazole 30g, bearing a diverse range of (het)aryl groups, by subjecting the corresponding 2-bromo-substituted thienyl-, indolyl-, pyrazolyl-, or pyridylacetonitriles to a two-step base-mediated condensation/Cu-catalyzed intramolecular thiolation process with various dithioesters under optimized conditions (Scheme [10]). This new methodology allows direct access to a broad range of benzo/hetero-fused thiophenes with various substitution patterns, making it a useful process for structure–activity relationship studies.[16]

During the course of this work, we became intrigued by the idea of whether benzothiophenes could be synthesized by an alternative strategy, involving direct catalytic oxidative intramolecular C–H bond functionalization–arylthiolation of thioenolate precursors such as 32 without any o-bromo substituents (derived from 31), thus eliminating the requirement of an o-bromo substituent and opening up much more readily accessible precursors for benzothiophene synthesis (Schemes 11–13). We therefore developed a novel one-pot, two-step, diversity-oriented synthesis of highly functionalized benzothiophenes and their hetero-fused analogs by palladium-catalyzed oxidative intramolecular C–H bond functionalization–arylthiolation of thioenolates 32, generated in situ from substrates 31 (Scheme [11]).[17] Thus, enethioates 32, obtained from arylacetonitriles, aryl acetates, and desoxybenzoins 31 (EWG = CN, CO₂Et, COAr) and dithioesters 4 in the presence of sodium hydride in DMF, underwent smooth in situ intramolecular C–H bond functionalization/C–S bond formation in the presence of palladium acetate (20 mol%), cupric acetate (1 equiv) as an oxidant, and Bu₄NBr as an additive in DMF at 90 °C within 4–6 hours to give benzothiophenes 29 (EWG = CN) and 33 (EWG = CO₂Et, COAr) in high yields (Method A). In some cases, the yields of the benzothiophenes were better using a two-step process by isolating the corresponding enethiols 34 as substrates (Method B). In a few examples, Pd(OAc)₂ as the catalyst in the presence of oxygen was found to be more efficient than cupric acetate as a reoxidant (Method C), furnishing benzothiophenes in improved yields by avoiding the formation of side products.[17]

The method is compatible with a diverse range of heteroaromatic substituents as well as with various substituents on the aromatic ring (29h,i); besides ester and aroyl substituents could also be introduced at the 3-position of benzothiophenes (33a–d). Interestingly, when an electron-withdrawing group, such as a cyano or a fluoro substituent, was present para to the site of cyclization in 31, the corresponding benzothiophenes 29j,k were not obtained (Scheme [11]).

The versatility of this method was further demonstrated by extending it to the synthesis of thieno-fused heterocycles such as thieno[2,3-b]thiophenes, thieno[2,3-b]indoles, thieno[3,2-c]pyrazoles, and thieno[2,3-b]pyridines with cyano (35a–d), carboethoxy(35e,f) and (het)aroyl substituents (35g,h) (Scheme [12]). The protocol could also be extended to the synthesis of compound 38, a precursor of raloxifene (39), a selective estrogen receptor modulator,[15b] in a good yield (Scheme [13]).

Based on experimental studies, a possible mechanistic pathway for the formation of benzothiophenes 29 and 33 from the corresponding thioenolate 32 or thioenol 34 was proposed (Scheme [14]). Thus, the reaction of thioenolate 32 with Pd(OAc)₂ leads to the formation of the Pd–S adduct 32A. Subsequent intramolecular attack of the aryl ring on the sulfur atom in 32A, similar to electrophilic substitution, furnishes benzothiophenes 29 and 33, with concurrent release of the reduced Pd species followed by rearomatization (Path A). Alternatively, the aromatic ring attacks the palladium center in 32A to afford the palladacycle intermediate 32B, followed by reductive elimination leading to benzothiophenes 29 and 33 and the reduced Pd(0) species (Path B), which is reoxidized in the presence of cupric acetate or oxygen.[17] This electrophilic substitution mechanism also supports the failure of arylacetonitriles bearing electron-withdrawing groups para to the site of cyclization to afford benzothiophenes 29j and 29k (see Scheme [11]), because of reduced electron density at the site of cyclization.

In subsequent studies, we extended this methodology to the synthesis of 2-amino-substituted benzothiophenes 41 and their hetero-fused analogs 42. This was achieved by employing palladium-catalyzed intramolecular oxidative C–H functionalization/arylthiolation of in situ generated N-(alkyl/aryl)thioamides 40, obtained by base-mediated condensation of readily available (heteroaryl)acetonitriles 31 and alkyl/aryl isothiocyanates (Scheme [15]). This protocol was further elaborated for the synthesis of a few amino-substituted benzothieno[2,3-b]quinolines 43 by employing a triflic acid mediated cyclocondensation of the newly prepared 2-arylamino-3-cyanobenzothiophenes 41 (Scheme [15]).[18]

In a further extension of this work, we also developed a metal-free one-pot synthesis of 2-substituted-3-cyanobenzothiophenes 29 by iodine-mediated intramolecular cyclization of enethiolate intermediates 32 (Scheme [16]). Thus, under optimized reaction conditions, the enethiolates 32 were generated from arylacetonitriles 31 and dithioesters 4 in the presence of potassium t-butoxide as the base and 1,4-dioxane as the solvent. Subsequent iodine-mediated intramolecular arylthiolation of enethiolates 32 at 90 °C for 8–10 hours afforded the substituted benzothiophenes 29 and their hetero analogs 35 in good yields.[19] Interestingly, in this case also, the enethiolates 32 derived from arylacetonitriles bearing electron-withdrawing substituents such as fluoro or cyano groups (31, R = m-F or m-CN) did not furnish even a trace of the corresponding benzothiophenes. Based on experimental studies, a probable mechanism involving intramolecular electrophilic cyclization of the sulfenyl iodide intermediate 44, formed by nucleophilic displacement of thioenolate 32 with iodine, was suggested (Scheme [16]).[19]

Synthesis of 1,2,3-Trisubstituted Indoles via Copper-Catalyzed Intramolecular Cross-Coupling and Palladium-Catalyzed Oxidative Intramolecular C–H Functionalization/C–N Bond Formation

We next explored the synthesis of substituted indoles via copper-catalyzed intramolecular cross-coupling/N-arylation of in situ generated 2-[2-bromo(het)aryl-3-(het)aryl/alkyl-3-(arylamino)-2-enenitriles 46 (Scheme [17]). These enaminonitriles 46 were generated in situ by base-mediated 1,4-addition–elimination of (het)arylamines of the corresponding 2-(2-bromoaryl)-3-(het)aryl-3-(methylthio)acrylonitriles 45,[15] [20] prepared by S-alkylation of thioenolates 28 with methyl iodide. Under optimized reaction conditions, the in situ generated enaminonitriles 46 underwent facile intramolecular cross-coupling/N-arylation in the presence of cuprous iodide (10 mol%) as the catalyst and l-proline (20 mol%) as the ligand in DMF at high temperature (120 °C, 8–10 h), yielding 2,3-disubstituted N-arylindoles 47 in high yields (Scheme [17]).[21]

The reaction was equally facile with both electron-donating and electron-withdrawing groups on both arylamines, as well as on the benzene ring of the 2-bromoarylacetonitriles 27, yielding indoles 47a,b in high yields (Scheme [17]). The corresponding 2-alkyl- and 1-N-alkyl-3-cyanoindoles 47c–e could also be synthesized from the appropriate enamines by slightly different routes in moderate to good yields (Scheme [17]).[21] Depending on the choice of dithioester 4, a number of (het)aryl substituents like 2-thienyl, 2-(N-methyl-3-indolyl), and 2-(3-pyridyl) groups could be introduced at the 2-position of indoles (47e–g) (Scheme [17]).[21]

This methodology could be further extended to the synthesis of hetero-fused pyrroles 48–50 when the corresponding enaminonitrile precursors 46, derived from 2-bromo-het(aryl)acetonitriles, were subjected to the one-pot N-arylation/Cu-catalyzed intramolecular C–N bond formation under identical conditions (Figure [1]). Thus, previously unreported 4-cyano-5,6-bis(het)aryl-thieno[2,3-b]pyrroles 48a–c, 3-cyano-2-(het)arylpyrrolo[2,3-b]indoles 49a–c, and 1,3-bis(het)aryl-pyrrolo[3,2-c]pyrazoles 50a–c bearing a large variety of (het)aryl groups at the 4,5-positions could be synthesized in good yields (Figure [1]).[21] These hetero-fused pyrroles exhibit optoelectronic properties and a broad range of biological activities.

Interestingly, the attempted synthesis of N-acylindoles 52 via Cu-catalyzed intramolecular cross-coupling of in situ generated N-acylenaminonitriles 51 (formed by reacting compounds 45 with amides in the presence of NaH) yielded only N-unsubstituted indoles 53 in good yields, which appear to be formed by in situ hydrolysis of N-acylindoles 52 (Scheme [18]). Thus, it was also possible to synthesize N-unsubstituted indoles 53 by following this procedure.[21]

In continuation of this work, we next envisaged developing an alternative direct route for the synthesis of N-aryl-2,3-substituted indoles 47 via palladium-catalyzed intramolecular oxidative C–H functionalization–amination of readily available simpler intermediates such as 2,3-bis[(het)aryl]-3-N-aryl/acylenaminonitriles 55 (EWG = CN, CO₂Et, ArCO), thus avoiding the necessity of introducing an o-bromo substituent (Scheme [17] vs Scheme [19]). Thus, when in situ generated 2-unsubstituted enaminonitriles 55 [obtained by nucleophilic displacement of aromatic amines on the corresponding 3-(methylthio) precursors 54] were reacted with palladium acetate (20 mol%) in the presence of cupric acetate (1 equiv) as an oxidant in DMSO under an oxygen atmosphere at 120 °C, 3-cyano-2-(het)arylindoles 47 were obtained in good yields (Method A, Scheme [19]).[22] Alternatively, when palladium acetate (20 mol%) was employed as the catalyst along with Ag₂CO₃ (1.0 equiv) as a reoxidant (instead of cupric acetate) and pivalic acid (1 equiv) as an additive in DMSO under identical conditions, which were found to be equally efficient, the indoles 47 were obtained in comparable yields (Method B) (Scheme [19]). The reaction was amenable to both electron-donating and electron-withdrawing substituents on the aryl ring of enaminonitriles 55, furnishing the substituted indoles 47h,i in high yields. The 2-alkylindoles 47j,k could also be obtained in good yields from the corresponding enaminonitriles 55 under identical conditions.

Further, a range of commercially available anilines bearing electron-withdrawing, electron-donating, sterically constrained substituents and 3-N-pyridyl moiety could also be installed in N-arylindoles (e.g., 47h, 47i, 47l–o). Notably, unlike benzothiophene synthesis (see Scheme [11]), substituted indoles such as 47l,m, bearing electron-withdrawing substituents (i.e., F and CN) at the 5-position of the aromatic ring, could also be obtained in good yields (Scheme [19]). These results are contrary to our earlier observations during palladium-catalyzed intramolecular C–H functionalization–arylthiolation of the corresponding enethiolates 32 bearing electron-withdrawing groups at the 3-position, which failed to furnish benzothiophenes 29j,k under the optimized conditions (Scheme [11] vs Scheme [19]).[22] These results suggest a different mechanism for the synthesis of indoles via Pd-catalyzed intramolecular C–H N-arylation. The scope and utility of the method were further demonstrated by installing other electron-withdrawing groups at the 3-position of the indole ring. Thus, intramolecular cyclization of enaminones 55 (EWG = ArCO) also proceeded efficiently under the optimized conditions, affording the substituted 3-aroylindoles 47p,q in good yields (Scheme [19]).[22]

This palladium-catalyzed intramolecular C–H functionalization–N-arylation protocol was found to be equally facile for the synthesis of thieno- and indolo-fused pyrroles, i.e., thieno[2,3-b]pyrroles 48d,e, pyrrolo[2,3-b]indoles 49d,e, and pyrrolo[2,3-b]pyridines 56a,b, bearing cyano as well as aroyl and other functionalities (Figure [2]), thus avoiding the synthesis of the corresponding halo precursors, as observed in the Cu-catalyzed intramolecular cross-coupling of intermediates 46 (Scheme [17] and Figure [1]).[22] It should be noted that examples of transition-metal-catalyzed C–H heterocyclizations of five- and six-membered heterocycles furnishing fused heterocycles are not known in the literature.

A few N-acyl enamides 51A were synthesized by base-mediated conjugate addition–elimination of β-(methylthio)acrylonitrile intermediates 54 with primary amides (Scheme [20]). As observed in our previous study (see Scheme [18]), these N-acylenamides 51A, when subjected to palladium-catalyzed intramolecular C–H N-arylation under standard conditions, yielded N-unsubstituted indoles 53 in good yields (Scheme [20]). These experiments confirm the intermediacy of N-acylenamides 51A during the formation of N-unsubstituted indoles 53. The N-unsubstituted hetero-fused indoles 57a,b could also be synthesized by this procedure (Scheme [20]). It should be noted that N-unsubstituted indoles have not been synthesized previously by direct intramolecular C–H functionalization of the corresponding N-unsubstituted enamide precursors.[22]

Based on experimental studies, a probable mechanism for the formation of indoles 47 from enaminonitriles 55 in the presence of a palladium catalyst via intramolecular C–H N-arylation is shown in Scheme [21]. Thus, the arylamino moiety in 55 can readily coordinate with the Pd(II) catalyst to form the Pd(II)-aminoaryl complex 55A with concomitant release of acetic acid. The initially formed coordinated species 55A can undergo intramolecular cyclization through insertion into the arene to give either intermediates 55B1 (Heck type) or 55B2 (Wacker type), which would undergo β-hydrogen elimination to give indole 47. Alternatively, the reaction can proceed via σ-bond metathesis through an irreversible ligand-assisted ‘concerted metalation–deprotonation’ (CMD) mechanism involving intermediate 55C. Subsequent reductive elimination gives the product indole 47 through palladacycle intermediate 55D, with concurrent formation of Pd(0), which is then oxidized by cupric acetate (or oxygen) to regenerate the Pd(II) species. In view of the observation that the reaction proceeds efficiently in the presence of pivalic acid as an additive, wherein an anionic pivalate (or acetate)-Pd bond ligand aids in proton abstraction, a σ-bond metathesis pathway through the CMD mechanism is more likely preferred in this process.

A Serendipitous Synthesis of Substituted Benzofurans via Copper-Catalyzed Intramolecular Cross-Coupling

During the course of our ongoing indole syntheses (Schemes 17–21), we planned to react the β-(methylthio)acrylonitrile intermediate 45a with benzyl carbamate (58) under basic conditions, followed by copper-catalyzed intramolecular cross-coupling of the resulting (N-benzyloxycarbonyl)enaminonitrile 59a to afford the corresponding N-benzyloxyindole 60a (Scheme [22]). However, to our surprise, work-up of the reaction did not give the expected indole 60a or the corresponding N-unsubstituted indole 60b, but instead, the product isolated in good yield was found to be 3-cyano-2-(4-methoxyphenyl)benzofuran 62a, obtained in 83% yield.[23]

Further experimental studies revealed that the initial product formed by the reaction of 45a with benzyl carbamate (58) at a high temperature in the presence of NaH was not the expected enaminonitrile 59a, but was characterized as α-aroyl-(2-bromoaryl)acetonitrile 61a (Scheme [22]). Apparently, the benzofuran 62a is formed by copper-catalyzed intramolecular cross-coupling of the ketone 61a. The ketone 61a could be isolated in 84% yield when the substrate 45a was reacted with benzyl carbamate in the presence of NaH in DMF at 90 °C for 6 hours. Subsequent intramolecular cyclization of 61a in the presence of CuI (10 mol%) and l-proline as the ligand provided benzofuran 62a in 83% yield, thus confirming the intermediacy of ketone 61a in this unexpected, serendipitous synthesis of a benzofuran.

The reaction was found to be general, and a series of substituted 3-cyano-2-(het)aryl/alkyl benzofurans 62, bearing a broad range of substituents at the 2-position of the aromatic ring, could be synthesized in good yields from 45 following this general procedure (Scheme [23]).[23] The reaction could also be extended to the synthesis of hetero-fused benzofurans such as furo[2,3-b]pyridines 62k,l in good yields.

Mechanistic studies revealed that benzyl carbamate (58) undergoes cleavage to give a benzyloxy anion under basic conditions, which undergoes conjugate addition–elimination with β-methylthio-(2-bromophenyl)acrylonitrile 45 to form an unstable β-benzyloxyacrylonitrile intermediate 63. This intermediate undergoes O–CH₂Ph bond cleavage in the presence of the nucleophilic methylthio anion to afford the ketone 61 (Scheme [24]).[23] This reaction provides a useful synthesis of 2-aryl-3-cyanobenzofurans 62 from readily available precursors, which are important compounds for hepatitis virus inhibitors, and some of these compounds are also found to be efficient blue-light-emitting fluorophores.

1,3-Bis(Het)arylmonothio-1,3-diketones and 1,3-Bis(Het)aryl-3-(methylthio)-2-propenones: Versatile Intermediates for the Regioselective Synthesis of Five-Membered Heterocycles

During the course of our continued interest in the design and development of new organosulfur synthons as precursors for the diversity-oriented synthesis of novel heterocycles, we became interested in unsymmetrically substituted 1,3-bis(het)arylmonothio-1,3-diketones of the general structure 64 as potentially useful 3-carbon-1,3-biselectrophilic synthons for the regiospecific construction of five- and six-membered heterocycles (Scheme [25]). One of the most popular, oldest, and frequently used methods for the synthesis of 1,3,5-trisubstituted pyrazoles is the classical cyclocondensation of monosubstituted hydrazines with 1,3-dicarbonyl compounds (the Knorr synthesis) or their surrogates. However, the appealing generality of this method is somewhat vitiated due to the frequent formation of regioisomeric mixtures of unsymmetrically substituted pyrazoles in these reactions, since the regioselectivity of the reaction relies on the differential reactivity of the two carbonyl groups of the 1,3-diketones. It was anticipated that cyclocondensation of monothio-1,3-diketones 64 with various unsymmetrical heterobinucleophiles (monosubstituted hydrazines, hydroxylamines, etc.) would be intrinsically more regioselective due to the significant difference in the reactivity and electronic properties of the carbonyl and thiocarbonyl groups.

Our literature survey at this stage revealed that 1,3-bis(het)arylmonothio-1,3-diketones 64 have been known for a long time,[24] and these intermediates have attracted considerable attention in the past as chelating agents with promising applications, especially in analytical chemistry.[25] However, the synthetic potential of these compounds as useful precursors for the regiospecific synthesis of five- and six-membered heterocycles has been virtually unexplored. We therefore, undertook a systematic investigation of these intermediates with a view to developing new regioselective methods for heterocycle synthesis.

These 1,3-monothioketones 64 and their cyclic analogs were prepared in excellent yields via modification of a reported procedure,[26] which involved thioacylation of various active methylene (het)aryl/alkylmethyl ketones with (het)aryldithioesters 4 in the presence of sodium hydride in DMF (Scheme [25]). The ¹H NMR spectra of all these newly synthesized unsymmetrical 1,3-monothioketones 64 showed that they exist in the intramolecular H-bonded thioenol tautomeric form 64B, as evidenced by the presence of a low-field signal at δ 12.02–16.2 due to the intramolecular H-bonded enolic hydrogen, as reported earlier.[26] Some of the 1,3-monothioketones 64a–i synthesized from various aryl, heteroaryl, and cyclic active methylene ketones and employed in our research group are shown in Scheme [25].

Reactions of 1,3-Bis(Het)arylmonothio-1,3-diketones with Arylhydrazines: Synthesis of Unsymmetrically Substituted 1-Aryl-3,5-bis(het)arylpyrazoles with Complementary Regioselectivity

We initially explored the potential for developing a regioselective synthesis of both regioisomers of unsymmetrically substituted 1-aryl-1,3-bis(het)arylpyrazoles 65 and 66 through the cyclocondensation of 1,3-monothioketones 64 with arylhydrazines under varied reaction conditions (Scheme [26]).[27] Thus, after optimization of the reaction conditions, when (het)aryl-1,3-monothioketones 64 were reacted with equimolar amounts of arylhydrazines in refluxing ethanol, analysis of the reaction mixture revealed the exclusive formation of only one product in excellent yields. These compounds were identified as unsymmetrically substituted 1-aryl-3,5-bis(het)arylpyrazoles 65, which are apparently formed via regioselective nucleophilic addition of the NH₂ group of the arylhydrazines to the thiocarbonyl functionality, accompanied by concurrent elimination of H₂S and subsequent cyclization through attack of the NH-aryl functionality of the arylhydrazine on the carbonyl group of 64 (Scheme [27]).[28] The regiochemistry of these pyrazoles was confirmed through X-ray diffraction data. This reaction proved compatible with monothioketones 64 bearing both electron-withdrawing and electron-donating groups, as well as with various (het)aryl substituents such as 2-thienyl, 2-furyl, 2-(1-N-methylpyrrolyl), 3-(N-methylindolyl), and 3-pyridyl groups.[28]

We then attempted the synthesis of pyrazoles 66 with complementary regioselectivity by reacting 1,3-monothioketones 64 with arylhydrazines under a variety of reaction conditions, but without success. The reactions yielded only mixtures of both regioisomers 65 and 66 in varying proportions. Subsequently, monothioketones 64 were transformed into 3-(methylthio)-1,3-bis(het)aryl-2-propenones 67 by alkylation of the corresponding thioenolate anion 68 with methyl iodide in the presence of sodium hydride. When these intermediates 67 were subjected to cyclocondensation with various arylhydrazines under basic conditions, analysis of the reaction mixtures revealed the exclusive formation of one product, identified as the regioisomeric pyrazoles 66 (Scheme [26]).[28]

This reaction showed a reversal of regioselectivity, where the anionic nitrogen derived from the NHAr group of the arylhydrazine undergoes conjugate addition–elimination at the β-carbon of 67, followed by subsequent cyclocondensation of the NH₂ group of the arylhydrazine with the carbonyl group of 67 to yield pyrazoles 66 (Scheme [27]). In an alternative approach, we developed a one-pot, three-step method, wherein β-(methylthio)-1,3-bis(het)aryl-2-propenones 67 were generated in situ via base-mediated thioacylation of active methylene ketones with dithioesters 4 followed by in situ S-methylation of thioenolate 68 and subsequent in situ reaction of the resulting intermediate 67 with various arylhydrazines under basic conditions. This method furnished pyrazoles 66 exclusively in high yields (Scheme [26]). Thus, we have developed the synthesis of both regioisomers of pyrazoles 65 and 66 from the same precursors 64 (Scheme [26] and Figure [3]).[28]

Cyclocondensation of Hydroxylamine with 1,3-Bis(het)arylmonothio-1,3-diketones 64 and 1,3-Bis(het)aryl-3-(methylthio)-2-propenones 67: Synthesis of 1,3-Bis(het)arylisoxazoles with Complementary Regioselectivity

Encouraged by the regioselective synthesis of trisubstituted pyrazoles 65 and 66 from 64, as described above in Scheme [26], we further explored the cyclocondensation of hydroxylamine, an unsymmetrical bifunctional bisnucleophile, with 1,3-monothioketones 64 and the corresponding β-(methylthio)-2-propenones 67, with a view to develop regioselective syntheses of unsymmetrically substituted 3,5-bis(het)arylisoxazoles 69 and 70 (Scheme [28]).[29] Under optimized reaction conditions, when unsymmetrically substituted monothio-1,3-diketones 64 were reacted with hydroxylamine hydrochloride in the presence of sodium acetate in a mixture of acetic acid, benzene, ethanol, and water (1:1:0.5:0.1; pH = 2.2) at reflux for 3 to 4 hours, the reaction yielded exclusively single products identified as 3,5-bis(het)arylisoxazoles 69. Here, the amino group of hydroxylamine reacted with the thiocarbonyl group of 64, and the oxygen of hydroxylamine underwent cyclocondensation with the carbonyl group of 64 (Scheme [29]). This reaction was found to be general with various unsymmetrically substituted 1,3-monothioketones 64 bearing both electron-withdrawing and electron-donating groups, as well as various (het)aryl groups (Scheme [28]).[29] Additionally, the corresponding isoxazole 69e with a methyl group at the 3-position could be obtained from the respective 1,3-monothioketone 64 in a good yield (Scheme [28]). The regiochemistry of these isoxazoles was confirmed by X-ray diffraction data.

Having established a completely regioselective synthesis of 3,5-bis(het)arylisoxazoles 69 from the corresponding 1,3-monothioketones 64, we then aimed to obtain the corresponding regioisomeric unsymmetrically substituted isoxazoles 70. However, attempts to synthesize these compounds by reacting unsymmetrically substituted 1,3-monothioketones 64 with hydroxylamine under different reaction conditions were unsuccessful. Alternatively, when the corresponding 1,3-bis(het)aryl-β-(methylthio)-2-propenones 67 (obtained via base-mediated alkylation of 1,3-monothioketones 64 with methyl iodide) were subjected to cyclocondensation with hydroxylamine in the presence of barium hydroxide in refluxing ethanol, the corresponding regioisomeric 1,3-bis(het)arylisoxazoles 70 were obtained exclusively in good yields (Scheme [28]).[29]

This reaction demonstrated a reversal of reactivity with hydroxylamine, forming 1,3-bis(het)arylisoxazoles 70 as exclusive products (Scheme [29]). The generality of the reaction was established by varying the aryl and hetaryl groups on 3-(methylthio)-1,3-bis(het)arylenones 67, consistently yielding only one regioisomer of isoxazoles 70 with no trace of isoxazoles 69. The formation of isoxazoles 70 likely occurs via cyclocondensation of hydroxylamine, where its amino group attacks the carbonyl group of enone 67 and the oxygen at the β-(methylthio)-substituted carbon in a conjugate fashion (Scheme [29]).[29]

Under acidic conditions, the monothioketone 64 exists in its enol form and initially undergoes attack at the thiocarbonyl group by the amino group of hydroxylamine, yielding isoxazoles 69 after subsequent intramolecular cyclocondensation of intermediate 69A. Conversely, under basic conditions, β-(methylthio)propenones 67 undergo initial conjugate addition of the hydroxylamine anion at the β-carbon, followed by cyclocondensation of intermediate 70A to yield isoxazoles 70 exclusively (Scheme [29]).[29]

Sequential One-Pot Synthesis of Tri- and Tetrasubstituted Thiophenes and Fluorescent Push–Pull Thiophene 5-Acrylates

In continuation of the above studies, exploring the synthetic applications of 1,3-bis(het)aryl-1,3-monothioketones 64 (Schemes 25–28), we further conceived of developing an efficient synthesis of multisubstituted thiophenes 74 via base-mediated S-alkylation of the thioenolate 71 (derived from 1,3-monothioketones 64) with activated methylene halides 72, followed by subsequent in situ base-induced intramolecular cyclocondensation of the resulting S-alkylated intermediates 73 (Scheme [30]).

Initially, a few thiophenes were obtained in good yields using this strategy. Subsequently, we developed a one-pot, three-component synthesis of tri- and tetrasubstituted thiophenes by the in situ generation of enethiolate salts 71 of 1,3-monothioketones 64 by reacting various active methylene ketones with (het)aryl dithioesters 4 in the presence of sodium hydride (Scheme [30]). This was followed by in situ S-alkylation of thioenolate intermediates 71 with activated methylene halides 72 and intramolecular cyclocondensation of the resulting the alkylated intermediates 73 to yield thiophenes 74 in high yields.[30] Indeed, this one-pot, three-component method worked well, and we were able to develop a general diversity-oriented synthesis of highly functionalized polysubstituted thiophenes 74 in high yields (Scheme [30]).[30]

Depending on the choice of active methylene ketone and their α-(het)aryl analogs, along with various (het)aryl dithioesters 4, a variety of substituents could be installed at the 2-, 3-, and 4-positions of thiophenes 74 (Scheme [30]). Similarly, by employing a large variety of activated methylene halides 72 (EWG = ArCO, CHO, CO₂Et, CN, CONH₂, CONHR, etc.), a diverse range of electron-withdrawing groups could be introduced at the 5-position of thiophenes 74.[30] The methodology could also be extended for the synthesis of condensed thiophenes, such as 74j,k, by using cyclic active methylene ketones.

We next extended our newly developed methodology for the synthesis of push–pull thiophenes such as 75, with extended π-conjugation, which may serve as useful fluorophores in optoelectronic devices. Thus, sequential treatment of a few selected active methylene ketones with various aryl dithioesters 4, bearing electron-donating groups, and ethyl bromocrotonate under the above-described one-pot conditions, afforded the corresponding thiophene-5-acrylates 75 bearing an electron-donating (het)aryl group at the 2-position in overall high yields (Scheme [31]).[30] All of these newly synthesized thiophenes 75 displayed pronounced yellow to green or yellow to red fluorescence.[30]

One-Pot Synthesis of 2,4,5-Trisubstituted Imidazoles via [2+2+1] Cycloannulation of 1,3-Bis(Het)arylmonothio-1,3-diketones, α-Substituted Methylamines and Sodium Nitrite

We have shown in the previous discussion that 1,3-bis(het)arylmonothio-1,3-diketones 64 can be considered as 1,3-diketone surrogates, displaying significantly different reactivity and electronic properties at carbonyl and thiocarbonyl groups, which overcome shortcomings associated with 1,3-diketones in terms of regioselective nucleophilic addition with various heteronucleophiles. We therefore examined the nucleophilic addition of aliphatic amines, especially benzylamines (R = Ar), to 1,3-monothioketones 64, and found that these amines react with 64 very efficiently at room temperature and regioselectively at the thiocarbonyl group, yielding enaminoketones 76 in high yields (Scheme [32]). Therefore, we exploited this highly efficient and regiospecific nucleophilic addition of (het)arylmethyl amines to 1,3-monothioketones 64 for the further transformation of enaminoketones 76, leading to a one-pot multicomponent synthesis of 2,4,5-trisubstituted imidazoles 78 (Scheme [32]).[31]

(Het)arylmethylamines, allylamine, ethyl glycinate and propargylamine were selected for this study. Thus, nucleophilic addition of these amines to 1,3-monothioketones 64 proceeded efficiently at room temperature, yielding enaminoketones 76 in excellent yields. These enaminoketones 76 were subsequently subjected to α-nitrosation with sodium nitrite and acetic acid in acetonitrile, affording the corresponding nitrosoenaminones 77 in high yields, which were shown to exist in intramolecularly H-bonded hydroxyiminoimine tautomeric forms 77A and 77B (Scheme [32]). The intramolecular cyclodehydration of these nitrosoenaminones 77 was next investigated with a view to synthesizing imidazoles 78. Thus nitrosoenaminones 77 underwent facile cyclodehydration in the presence of potassium carbonate in acetonitrile at 80 °C, yielding 2,3-bis(het)aryl-5-aroylimidazoles 78 in good yields. These imidazoles 78 were shown to exist in tautomeric forms 78A and 78B in varying ratios, however, methylation of 78 with methyl iodide in the presence of potassium carbonate at room temperature afforded 1-N-methyl-2,5-bis(het)aryl-4-aroylimidazoles 79, exclusively, in highly a regioselective manner.

Subsequently, we developed a sequential, three-step, one-pot protocol for the synthesis of imidazoles 78 by performing enaminone 76 formation, in situ nitrosation to 77, followed by intramolecular cyclodehydration in the presence of potassium carbonate to yield imidazoles 78 in comparable yields (Scheme [32]).[31] These optimized one-pot reaction conditions were used for the synthesis of a diverse range of substituted imidazoles 78 and their N-methyl derivatives 79. Depending on the choice of α-substituted methylamine, such as (het)arylmethyl amines, allyl amine, ethyl glycinate and propargyl amine, a variety of substituents could be introduced at the 2-position of the imidazole (e.g., 79a–h). Similarly, by appropriate choice of the 1,3-(het)arylmonothioketone, various substituents could be introduced at the 4- and 5-positions of the imidazoles, including an alkyl group at the 5-position (79c) and an acyl group at the 4-position (79d). The present methodology could also be extended for the synthesis of 4(5)-(2-hydroxyphenyl)-substituted imidazoles such as 81a–c, which are known to act as good coordinating ligands for various metal ions. Thus, the corresponding 4(5)-2-(4-methoxybenzyloxy)phenyl-substituted imidazoles 80a–c, obtained from the corresponding 1,3-monothioketones 64 by the above procedure, were subjected to O-benzyl cleavage in the presence of TFA, affording the desired imidazoles 81a–c in good yields (Scheme [32]).[31] This novel three-step, one-pot protocol for imidazole synthesis involves the formation of three new carbon–nitrogen bonds in a contiguous fashion.

Sequential Copper-Catalyzed C–S Bond Formation and Palladium-Catalyzed Intramolecular Arene–Alkene Coupling of Bis(het)aryl/alkyl-1,3-monothioketones with o-Bromoiodoarenes: A New Regiospecific Route to Substituted Benzo[b]thiophenes

Taking advantage of the differential reactivity of carbonyl and thiocarbonyl groups in 1,3-monothio-diketones 64, we have recently developed a novel convergent approach for 2,3-disubstituted benzothiophenes 84 via the sequential one-pot copper-catalyzed intermolecular Ullman-type C–S coupling of 1,3-monothiodiketones 64 and 2-bromoiodoarenes 82, followed by subsequent palladium-catalyzed intramolecular Heck-type coupling of the resulting β-(2-bromoarylthio)enones 83 (Scheme [33]).[32] Thus when 1,3-monothioketones 64 were subjected to copper-catalyzed intermolecular C–S coupling with 2-bromoiodoarenes 82 in the presence of 10 mol% of CuI and Cs₂CO₃ as the base in DMF at 100 °C for 3 hours, followed by in situ palladium-catalyzed intramolecular cyclization via arene–alkene coupling of the resulting β-(2-bromoarylthio)enones 83 in the presence of palladium acetate (10 mol%) in DMF at 100 °C for 8-10 hours in a two-step, one-pot protocol, the corresponding 2-(het)aryl-3-(het)aroyl benzothiophenes 84 were obtained in moderate to excellent yields.[32] These optimized one-pot reaction conditions were effective with an array of substituted o-bromoiodoarenes 82 bearing electron-withdrawing or electron-donating groups, and with 1,3-monothioketones with diverse (het)aryl substituents, including alkyl groups adjacent to either the carbonyl or thiocarbonyl moieties, thus affording the corresponding 2-(het)aryl/alkyl-3-(het)aroylbenzothiophenes 84a–h in excellent yields. Similarly, the 2-(N-morpholino)-substituted benzothiophene 84i was also synthesized in a moderate yield when the corresponding β-acylthioamide 64 (R² = N-morpholino) was used as the coupling partner.

Also, by employing two equivalents of a 1,3-monothioketone and 1,4-dibromo-2,5-diiodobenzene, the linear benzo(bis)thiophene 84j could be synthesized in a moderate 52% yield under one-pot conditions (Scheme [34]).[32]

Interestingly, when 1,3-monothioketones 64 bearing either a 2-thienyl or 2-furyl group adjacent to the thiocarbonyl moiety (i.e., 64A) and 2-bromoiodoarenes 82 were subjected to sequential copper and palladium-catalyzed coupling under standard reaction conditions, the expected 2-(2-thienyl)/(2-furyl)benzothiophenes 84A were not obtained, and only β-(arylthiol)enones 83A were isolated in varying yields (Scheme [35]). Therefore, we attempted to cyclize the thiovinylketones 83A under modified reaction conditions by treatment with palladium acetate (10 mol%) in the presence of tetrabutylammonium iodide (1 equiv) in DMF at 100 °C, however, analysis of the reaction mixtures showed the formation of unexpected products obtained in high yields, which were characterized as 2-[(het)aroylethylidene]thieno/furo[2,3-c]thiochromenes 85.[32] This novel transformation, which apparently involves palladium-catalyzed direct C–H arylation of the thiophene or furyl ring in thioenones 83 (via conformation 83B), was found to be general with other 1,3-monothioketones bearing 2-thienyl or 2-furyl moieties, furnishing the corresponding thieno- or furo-fused 2-[(het)aroylethylidene]thiochromenes 85a–e in good overall yields (Scheme [35]).[32]

The probable mechanism for the formation of benzothiophenes 84 and thiochromenes 85 via palladium-catalyzed arene–alkene coupling of β-(o-bromoaryl)thiovinylketones 83 is shown in Scheme [36]. Thus, the insertion intermediate 83C, obtained by oxidative addition of Pd(0) into (2-bromoarylthio)enone 83, could be transformed into resonance-stabilized cationic intermediate 83D, formed by intramolecular attack of the electron-rich thiovinyl group on the electrophilic metal center. Subsequent deprotonation of the acidic proton in intermediate 83D would lead to palladacycle 83E, which on reductive elimination affords the benzothiophenes 84 (Route A). Alternatively, the palladacycle 83E could be transformed into intermediates 83F and 83F′ via an alkene insertion process, followed by subsequent β-hydride elimination to give benzothiophenes 84. On the other hand, insertion complex 83C, in conformation 83G with either 2-thienyl or 2-furyl groups, may undergo palladium-catalyzed intramolecular C–H arylation yielding thieno/furo-fused thiochromenes 85 (Scheme [36]).[32] It should be noted that such a disconnection approach for the construction of benzothiophene rings involving concurrent copper-catalyzed C–S bond formation and palladium-catalyzed intramolecular C–C bond formation in a one-pot reaction has not been reported in literature.

Reactions of 1,3-Bis(het)arylmonothio-1,3-diketones with Sodium Azide: Regioselective Synthesis of 3,5-Bis(het)arylisoxazoles via Intramolecular N–O Bond Formation

In continuation of our research program directed towards exploring synthetic applications and reactivity of newly synthesized 1,3-bis(het)arylmonothio-1,3-diketones 64, we further conceived of examining the reactions of these monothioketones with sodium azide, with a view to synthesizing 1,2,3-triazoles. However, when compounds 64 were reacted with two equivalents of sodium azide in DMF at room temperature, analysis of the reaction mixture unexpectedly showed the formation of 3,5-bis(het)arylisoxazoles 86 in moderate yields. On further optimization of the reaction conditions, when 1,3-monothioketones 64 were reacted with sodium azide in the presence of a catalytic amount of IBX (10 mol%), isoxazoles 86 were obtained in excellent yields (Scheme [37]).[33] The generality of the reaction was established by the synthesis of various 3,5-bis(aryl)isoxazoles, such as 86a–e, bearing both electron-donating as well as electron-withdrawing substituents. Besides, a series 3,5-bis(het)aryl isoxazoles 86 having various heterocyclic substituents, such as 2-thienyl, 2-furyl, 2-N-methylpyrrolyl, 2-thiazolyl, 3- or 4-pyridyl, and 3-N-methylindolyl (86e–i), could be obtained in high yields following this procedure.

The methodology could also be extended to the synthesis of 5-methyl-3-(het)arylisoxazoles 86j,k, representing an important subunit present in many marketed drugs such as valdecoxib, parecoxib, oxacillin, cloxacillin and flucloxacillin, a group of β-lactamase-resistant antibiotics widely used clinically to treat infections caused by penicillin-resistant Staphylococcus aureus.[32] However, the trisubstituted isoxazoles 86l,m and the cyclic isoxazole 86n could not be obtained following this general procedure from the corresponding monothioketones 64 derived from butyrophenone, desoxybenzoin and α-tetralone, respectively, yielding only complex mixtures of products (Scheme [37]). A few 3-(het)aryl-5-styrylisoxazoles 88a–c and their higher homolog 88d were also synthesized in good yields from different precursors such as 1-(het)aryl-1-(methylthio)-4-(het)arylidene-but-1-en-3-ones 87, as the corresponding 1,3-monothioketones could not be synthesized from the appropriate precursors (Scheme [38]).[33]

In continuation of our research, we became interested in exploring the reaction of sodium azide with other thiocarbonyl compounds like β-ketodithioesters 89 under identical conditions. However, in this case, the products isolated were not the expected 3-(methylthio)-5-(het)arylisoxazoles 90, but instead were characterized as α-aroylacetonitriles 91 (Scheme [39]).[33]

A probable mechanism for the formation of isoxazoles 86 from compounds 64 is shown in Scheme [40]. Nucleophilic attack of the thiocarbonyl group of 64 on IBX results in the formation of intermediate 92A, which undergoes conjugate addition–elimination with sodium azide to furnish β-azidoenone intermediate 92C via 92B. Subsequent intramolecular electrocyclization of 92C, with concurrent N–O bond formation and extrusion of nitrogen, provides isoxazoles 86 in high yields. The present synthesis provides a new set of disconnections for isoxazole synthesis involving tandem intramolecular C–N and N–O bond formation, which is not well-documented in the literature.

Conclusion

The research work presented in this account makes a substantial contribution to the field of heterocyclic chemistry, particularly in developing new synthetic routes for substituted and fused heterocycles. By utilizing novel organosulfur intermediates, specifically (het)aryl/alkyl dithioesters, and the intermediates derived from them, our work has pioneered a systematic exploration of these compounds, which have been largely unexplored in synthetic organic chemistry until now.

Over the course of our studies conducted between 2011 and 2016, we have developed several innovative methodologies that enable the efficient and regioselective synthesis of a wide variety of heterocycles, including oxazoles, thiazoles, bisoxazoles, benzothiophenes, indoles, benzofurans, pyrazoles, isoxazoles, thiophenes, and imidazoles, that display broad functional group and skeletal diversity. These methods often involve critical steps such as base-mediated condensations, copper- and palladium-catalyzed intramolecular cross-coupling, C–H functionalization leading to C–heteroatom bond formation, and functional group transformations, providing access to complex molecular frameworks. Besides many of these transformations involve one-pot, multicomponent reactions, thus avoiding multistep syntheses of these target heterocycles. In addition, several of these transformations are mechanistically intriguing.

Overall, the research highlighted in this account significantly expands the synthetic toolkit for constructing heterocycles, offering new pathways that are both versatile and highly efficient. The methodologies developed here hold great promise for future applications in pharmaceutical and materials science, particularly for the synthesis of complex molecules with precise functionalization. This account not only highlights the utility of organosulfur building blocks but also lays the groundwork for further innovations in the field, which will be explored in a forthcoming Part II of this account.

Conflict of Interest

The authors declare no conflict of interest.

• References

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  Crossref
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For analytical applications of 1,3-monothioketones, see:
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• 25b Richardson MF, Sievers RE. Inorg. Chem. 1971; 10: 498
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• 26b Duus F. J. Org. Chem. 2002; 42: 3123
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• 26c Duus F. Synthesis 1985; 672
  Thieme Connect

For our previous regioselective synthesis of pyrazoles, see:
• 27a Peruncheralathan S, Yadav AK, Ila H, Junjappa H. J. Org. Chem. 2005; 70: 9644
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Corresponding Author

Publication History

Received: 15 August 2024

Accepted: 10 September 2024

Accepted Manuscript online:
10 September 2024

Article published online:
09 October 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 For an earlier account, see: Ila H, Junjappa H. Chimia 2013; 67: 17
  CrossrefPubMedSearch in Google Scholar

For reviews on polarized ketene dithioacetals, see:
• 2a Wang L, He W, Yu Z. Chem. Soc. Rev. 2013; 42: 599
  CrossrefPubMedSearch in Google Scholar
• 2b Pan L, Bi X, Liu Q. Chem. Soc. Rev. 2013; 42: 1251
  CrossrefPubMedSearch in Google Scholar
• 2c Ila H, Junjappa H, Barun O. J. Organomet. Chem. 2001; 624: 34
  CrossrefSearch in Google Scholar
• 2d Kolb M. Synthesis 1990; 171
  Thieme Connect
• 2e Junjappa H, Ila H, Asokan CV. Tetrahedron 1990; 46: 5423
  CrossrefSearch in Google Scholar
• 2f Dieter RK. Tetrahedron 1986; 42: 3029
  CrossrefSearch in Google Scholar

For ketene N,S-acetal reviews, see:
• 3a Wang KM, Yan SJ, Lin J. Eur. J. Org. Chem. 2013; 1129
• 3b Huang ZT, Wang MX. Heterocycles 1994; 37: 1233
  CrossrefSearch in Google Scholar
• 3c Rajappa S. Tetrahedron 1981; 37: 1453
  CrossrefSearch in Google Scholar
• 4 Zhang L, Dong J, Xu X, Liu Q. Chem. Rev. 2016; 116: 287
  CrossrefPubMedSearch in Google Scholar
• 5a Singh MS, Nandi GC, Chanda T. RSC Adv. 2013; 3: 14183
  CrossrefSearch in Google Scholar
• 5b Roy A, Nandi S, Ila H, Junjappa H. Org. Lett. 2001; 3: 229
  CrossrefPubMedSearch in Google Scholar
• 5c Singh G, Bhattacharjee SS, Ila H, Junjappa H. Synthesis 1982; 693
  Thieme Connect
• 6a Verkruijsse HD, Brandsma L. J. Organomet. Chem. 1987; 332: 95
  CrossrefSearch in Google Scholar
• 6b Ramadas SR, Srinivasan PS, Ramachandran J, Sastry VV. S. K. Synthesis 1983; 605
  Thieme Connect
• 7 Harris RL. N. Aust. J. Chem. 1974; 27: 2635
  CrossrefSearch in Google Scholar
• 8 Masson S, Abrunhosa I, Gulea M. Synthesis 2004; 928
  Thieme Connect
• 9a Amareshwar V, Mishra NC, Ila H. Org. Biomol. Chem. 2011; 9: 5793
  CrossrefPubMedSearch in Google Scholar
• 9b Misra NC, Ila H. J. Org. Chem. 2010; 75: 5195
  CrossrefPubMedSearch in Google Scholar
• 10 Vijay Kumar S, Saraiah B, Misra NC, Ila H. J. Org. Chem. 2012; 77: 10752
  CrossrefPubMedSearch in Google Scholar
• 11 Vijay Kumar S, Parameshwarappa G, Ila H. J. Org. Chem. 2013; 78: 7362
  CrossrefPubMedSearch in Google Scholar

For recent reviews, see:
• 12a Lygin AV, de Meijere A. Angew. Chem. Int. Ed. 2010; 49: 9094
  CrossrefPubMedSearch in Google Scholar
• 12b Gulevich AV, Zhdanko AG, Orru RV, Nenajdenko VG. Chem. Rev. 2010; 110: 5235
  CrossrefPubMedSearch in Google Scholar
• 13a Misra NC, Panda K, Ila H, Junjappa H. J. Org. Chem. 2007; 72: 1246
  CrossrefPubMedSearch in Google Scholar
• 13b Sundaram GS, Singh B, Venkatesh C, Ila H, Junjappa H. J. Org. Chem. 2007; 72: 5020
  CrossrefPubMedSearch in Google Scholar
• 13c Yugandar S, Misra NC, Parameshwarappa G, Panda K, Ila H. Org. Lett. 2013; 15: 5250
  CrossrefPubMedSearch in Google Scholar
• 14 Yugandar S, Acharya A, Ila H. J. Org. Chem. 2013; 78: 3948
  CrossrefPubMedSearch in Google Scholar
• 15a Singh PP, Yadav AK, Ila H, Junjappa H. Eur. J. Org. Chem. 2011; 4001
  Crossref
• 15b Singh PP, Yadav AK, Ila H, Junjappa H. J. Org. Chem. 2009; 74: 5496
  CrossrefPubMedSearch in Google Scholar
• 16 Acharya A, Vijay Kumar S, Saraiah B, Ila H. J. Org. Chem. 2015; 80: 2884
  CrossrefPubMedSearch in Google Scholar
• 17 Acharya A, Vijay Kumar S, Ila H. Chem. Eur. J. 2015; 21: 17116
  CrossrefPubMedSearch in Google Scholar
• 18 Saraiah B, Gautam V, Acharya A, Pasha MA, Hiriyakkanavar I. Eur. J. Org. Chem. 2017; 5679
  Crossref
• 19 Bonagiri S, Acharya A, Pasha MA, Hiriyakkanavar I. Tetrahedron Lett. 2017; 58: 4577
  CrossrefSearch in Google Scholar

For previous transformations of 2-(2-bromoaryl)-3-(methylthio)-3-(het)arylacrylonitriles, see:
• 20a Yadav AK, Ila H, Junjappa H. Eur. J. Org. Chem. 2010; 338
  Crossref
• 20b Kumar S, Peruncheralathan S, Ila H, Junjappa H. Org. Lett. 2008; 10: 965
  CrossrefPubMedSearch in Google Scholar
• 21 Vijay Kumar S, Saraiah B, Parameshwarappa G, Ila H, Verma GK. J. Org. Chem. 2014; 79: 7961
  CrossrefPubMedSearch in Google Scholar
• 22 Yugandar S, Konda S, Ila H. J. Org. Chem. 2016; 81: 2035
  CrossrefPubMedSearch in Google Scholar
• 23 Saraiah B, Gautam V, Acharya A, Pasha MA, Ila H. ACS Omega 2018; 3: 8355
  CrossrefPubMedSearch in Google Scholar
• 24a Chaston SH. H, Livingstone SE, Lockyer TN. Aust. J. Chem. 1966; 19: 1401
  CrossrefSearch in Google Scholar
• 24b Chaston SH. H, Livingstone SE, Lockyer TN, Pickles VA, Shannon JS. Aust. J. Chem. 1965; 18: 673
  CrossrefSearch in Google Scholar

For analytical applications of 1,3-monothioketones, see:
• 25a Honjyo T, Kiba T. Bull Chem. Soc. Jpn. 1972; 45: 185
  CrossrefSearch in Google Scholar
• 25b Richardson MF, Sievers RE. Inorg. Chem. 1971; 10: 498
  CrossrefSearch in Google Scholar
• 25c Bayer E, Mueller HP, Sievers R. Anal. Chem. 2002; 43: 2012
  CrossrefSearch in Google Scholar
• 26a Carlsen L, Duus F. Synthesis 1977; 256
  Thieme Connect
• 26b Duus F. J. Org. Chem. 2002; 42: 3123
  CrossrefSearch in Google Scholar
• 26c Duus F. Synthesis 1985; 672
  Thieme Connect

For our previous regioselective synthesis of pyrazoles, see:
• 27a Peruncheralathan S, Yadav AK, Ila H, Junjappa H. J. Org. Chem. 2005; 70: 9644
  CrossrefPubMedSearch in Google Scholar
• 27b Peruncheralathan S, Khan TA, Ila H, Junjappa H. J. Org. Chem. 2005; 70: 10030
  CrossrefPubMedSearch in Google Scholar
• 28 Kumar SV, Yadav SK, Raghava B, Saraiah B, Ila H, Rangappa KS, Hazra A. J. Org. Chem. 2013; 78: 4960
  CrossrefPubMedSearch in Google Scholar
• 29 Raghava B, Parameshwarappa G, Acharya A, Swaroop TR, Rangappa KS, Ila H. Eur. J. Org. Chem. 2014; 1882
  Crossref
• 30 Acharya A, Parameshwarappa G, Saraiah B, Ila H. J. Org. Chem. 2015; 80: 414
  CrossrefPubMedSearch in Google Scholar
• 31 Yugandar S, Konda S, Parameshwarappa G, Ila H. J. Org. Chem. 2016; 81: 5606
  CrossrefPubMedSearch in Google Scholar
• 32 Yugandar S, Konda S, Ila H. Org. Lett. 2017; 19: 1512
  CrossrefPubMedSearch in Google Scholar
• 33 Antony PM, Balaji GL, Iniyavan P, Ila H. J. Org. Chem. 2020; 85: 15422
  CrossrefPubMedSearch in Google Scholar