Categories: Synthesis of N-Heterocyles >
Related: benzo-fused O-Heterocyles, benzo-fused S-Heterocycles, N-substitution

Synthesis of benzo-fused N-Heterocycles and similar compounds

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Recent Literature

An operationally simple and efficient AgOTf-promoted tandem olefin isomerization/intramolecular hydroamination of 1,1-disubstituted alkenyl amines provides diverse 2-alkyl-substituted 1,3-X,N-heterocycles in very good yields through chemo- and regioselective C(sp³)-N bond formation with high atom economy. The reaction offers high functional group tolerance and broad substrate scope.
Y. H. Kim, D. B. Kim, S. W. Youn, J. Org. Chem., 2022, 87, 11919-11924.

In the presence of CuCl, a three-component reaction of o-iodoanilines and K₂S with TosMIC proceeded smoothly to yield the corresponding benzothiazolethiones in very good yields. Notably, isocyanide served as a carbon source and K₂S functioned as a sulfur source.
P. Dang, W. Zeng, Y. Liang, Org. Lett., 2015, 17, 34-37.

An efficient synthesis of 2-substituted 3-thioxoisoindolin-1-one derivatives is based on the solvent-free reaction of 2-carboxybenzaldehyde with aliphatic amines and sulfur at 100°C. This reaction enables a facile synthesis of asymmetric thioxoisoindolin-1-one derivatives with phthalimide backbones.
F. Gholami, A. Moazzam, S. Bahadorikhalili, M. Adib, S. Hosseini, B. Larijani, M. Mahdavi, Synlett, 2022, 33, 1729-1732.

A carbonylative cyclization of 2-iodosulfonamides using a Pd(OAc)₂/Xantphos catalyst system and phenyl formate as a CO source provides various saccharin derivatives under milder reaction conditions.
S. P. Chavan, Adithyaraj. K., B. M. Bhanage, Synlett, 2017, 28, 2000-2003.

A molecular iodine-catalyzed oxidative cyclization of 2-aminopyridine/amidine and isothiocyanate via N-S bond formation enables the synthesis of N-fused and 3,4-disubstituted 5-imino-1,2,4-thiadiazole derivatives at ambient temperature. This transition-metal-free protocol provides a facile and highly efficient regiospecific synthesis of various 1,2,4-thiadiazole derivatives with good to excellent yields using inexpensive I₂ as a catalyst.
N. Tumula, N. Jatangi, R. K. Palakodety, S. Balasubramanian, M. Nakka, J. Org. Chem., 2017, 82, 5310-5316.

A broad range of substituted benzisoxazolines have been synthesized by a mild [3 + 2] cycloaddition of nitrones and arynes. The process tolerates various functional groups.
C. Lu, A. V. Dubrovskiy, R. C. Larock, J. Org. Chem., 2012, 77, 2279-2284.

Rhodium(II) perfluorobutyrate-mediated decomposition of vinyl azides allows rapid access to a variety of complex, functionalized N-heterocycles in two steps from commercially available starting materials.
B. J. Stokes, H. Dong, B. E. Leslie, A. L. Pumphrey, T. G. Driver, J. Am. Chem. Soc., 2007, 129, 7500-7501.

Sequential coupling-imination-annulation reactions of ortho-bromoarylaldehydes and terminal alkynes with ammonium acetate in the presence of a palladium catalyst under microwave irradiation gives various substituted isoquinolines, furopyridines, and thienopyridines in good yields.
D. Yang, S. Burugupalli, D. Daniel, Y. Chen, J. Org. Chem., 2012, 77, 4466-4472.

A palladium(II)-catalyzed C(sp)-C(sp²) coupling of phenylboronic acids and readily synthesized 2-carbonyl- or 2-formylpyrroloacetonitriles followed by intramolecular cyclization provide multisubstituted pyrrolo[1,2-a]pyrazines in very good yields.
C. He, Z. Wang, Y. Chen, G. Zhang, Y. Yu, Synthesis, 2021, 53, 2051-2056.

Commercially available pyrazoles were alkylated and formylated in a regiocontrolled manner to give pyrazole-5-aldehydes bearing 2,2-dialkoxyethyl substitution on N-1. Subsequent deprotection and cyclization of these intermediates allowed access to pyrazolo[1,5-a]pyrazines with multiple substitution patterns, whereas a deprotection and double-reductive amination sequence provides 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazines.
P. J. Lindsay-Scott, N. G. Charlesworth, A. Grozavu, J. Org. Chem., 2017, 82, 11295-11303.

A tandem oxidative cyclization/1,2-carbon migration of a broad scope of hydrazides enables the synthesis of otherwise inaccessible hindered or enantiopure triazolopyridinones with retention of configuration. This protocol can be easily scaled up by continuous flow synthesis under mild conditions.
Z. Ye, H. Zhang, N. Chen, Y. Wu, F. Zhang, Org. Lett., 2020, 22, 6464-6467.

A Pd-catalyzed amide coupling reaction enables a facile synthesis of imidazo[4,5-b]pyridines and -pyrazines. This reaction provides quick access to various substituted products. A model system relevant to the natural product pentosidine has been demonstrated, as well as the total synthesis of the mutagen 1-Me-5-PhIP.
A. J. Rosenberg, J. Zhao, D. A. Clark, Org. Lett., 2012, 14, 1761-1767.

Pharmaceutically important azolo[1,5-a]pyrimidines can be synthesized from widely available 3- or 5-aminoazoles, aldehydes, and triethylamine. The key is the in situ generation of an acyclic enamine followed by an annulation reaction. This strategy is capable of constructing a range of 5,6-unsubstituted pyrazolo[1,5-a]pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines.
Q. Gao, Z. Sun, Q. Xia, R. Li, W. Wang, S. Ma, Y. Chai, M. Wu, W. Hu, P. Ábrányi-Baloghm G. M. Keserű, X. Han, Org. Lett., 2021, 23, 2621-2625.

Pyridinium N-(heteroaryl)aminides are robust and practical synthetic equivalents of nucleophilic 1,3-N,N-dipoles in a Au-catalyzed formal cycloaddition onto electron-rich alkynes. Convergent and regioselective access to five types of imidazo-fused heteroaromatics is provided from the appropriate aminide. The efficient transformation tolerates significant structural variation.
M. Garzón, P. W. Davies, Org. Lett., 2014, 16, 4850-4853.

The reaction of β,γ-unsaturated γ-alkoxy-α-keto esters with 5-aminopyrazoles proceeds with high regioselectivity to yield new pyrazolo[1,5-a]pyrimidines bearing an ester function in the 7-position. The obtained drug-like compounds have a great potential for medicinal chemistry as they closely resemble the structure of several marketed pharmaceuticals.
O. O. Stepaniuk, V. O. Matviienko, I. S. Kontratov, I. V. Vitruk, A. O. Tolmachev, Synthesis, 2013, 45, 925-930.

A set of benzimidazoles, 3H-imidazo[4,5-b]pyridines, purines, xanthines and benzothiazoles was readily prepared from (hetero)aromatic ortho-diamines or ortho-aminothiophenol and aldehydes using chlorotrimethylsilane in DMF as a promoter and water-acceptor agent, followed by oxidation with air oxygen.
S. V. Ryabukhin, A. S. Plaskon, D. M. Volochnyuk, A. A. Tolmachev, Synthesis, 2006, 3715-3726.

A highly efficient and versatile method for the synthesis of a series of 2-substituted N-H, N-alkyl, and N-aryl benzimidazoles containing a wide range of functional groups was achieved in one step via the Na₂S₂O₄ reduction of o-nitroanilines in the presence of aldehydes.
D. Yang, D. Fokas, J. Li, L. Yu, C. M. Baldino, Synthesis, 2005, 47-56.

The 3-Aminoimidazo[1,2-a]pyrazine scaffold is rapidly accessible through a Groebke-Blackburn-Bienaymé cyclisation starting from an aminopyrazine, an aldehyde and an isocyanide. A scale-up process of this multicomponent reaction has been achieved in high yield and with excellent purity.
M. Baenziger, E. Durantie, C. Mathes, Synthesis, 2017, 49, 2266-2274.

In a regioselective and high-yielding Groebke-Blackburn-Bienaymé reaction, glyoxylic acid is used as formaldehyde equivalent leading to a regioselective, mild, convenient, and effective synthesis of 3-aminoalkyl imidazoazines.
A. Sharma, H.-y. Li, Synlett, 2011, 1407-1412.

In a regioselective and high-yielding Groebke-Blackburn-Bienaymé reaction, glyoxylic acid is used as formaldehyde equivalent leading to a regioselective, mild, convenient, and effective synthesis of 3-aminoalkyl imidazoazines.
A. Sharma, H.-y. Li, Synlett, 2011, 1407-1412.

An Au-catalyzed synthesis of fused pyrroloheterocycles from diverse propargyl-substituted heterocycles proceeds via alkyne-vinylidene isomerization with concomitant 1,2-shift of hydrogen, silyl, and stannyl groups. This method allows for mild and efficient synthesis of diverse C-2 substituted N-heterocycles.
I. V. Seregin, V. Gevorgyan, J. Am. Chem. Soc., 2006, 128, 12050-12051.

In a copper-catalyzed synthesis of benzo[d]isothiazol-3(2H)-ones and N-acyl-benzothiazetidine by intramolecular dehydrogenative cyclization, a new nitrogen-sulfur bond is formed by N-H/S-H coupling. The present reaction tolerates various functional groups and gives products in gram scale.
Z. Wang, Y. Kuninobu, M. Kanai, J. Org. Chem., 2013, 78, 7337-7342.

The use of N,N′-bis(2,6-diisopropylphenyl)dihydroimidazol-2-ylidene (SIPr) as a ligand and tBuONa as the base for sequential palladium-catalyzed intra- followed by intermolecular aryl amination enables the synthesis of N-arylated five-, six- and seven-membered nitrogen heterocycles.
R. Omar-Amrani, R. Schneider, Y. Fort, Synthesis, 2004, 2257-2534.

Phenols react with nitriles and dimethyl sulfoxide (DMSO) in the presence of a catalytic amount of (COCl)₂ in CH₃CN or chloroform to afford the corresponding N-acylbenzoxazines in good yields. DMSO acts as a source of HCHO, which is generated in situ.
H. Wang, Z. Xi, S. Huang, R. Ding, Y. Gao, Y. Liu, B. Sun, H. Tian, S. Liang, J. Org. Chem., 2021, 86, 4932-4943.

An effient tandem process consisting of palladium-catalyzed double-bond isomerization of long-chain olefins followed by intramolecular cyclization promoted by B₂(OH)₂ provides benzo-fused oxazaheterocycles. This strategy also provides rapid access to pyrido[3,4-b]indoles, trans-2-olefins, and enamides with high regio- and stereoselectivity.
L. Ding, Y.-N. Niu, X.-F. Xia, J. Org. Chem., 2021, 86, 10032-10042.

With the proper choice of palladium catalyst, ligand, and base, five-, six-, and seven-membered rings are formed efficiently from secondary amide or secondary carbamate precursors.
B. H. Yang, S. L. Buchwald, Org. Lett., 1999, 1, 35-37.

An addition-cyclization of α-chiral imines with substituted aromatic Grignard reagents in the presence of 2,2'-bipyridine provides isoquinolone products with excellent yields and outstanding diastereoselectivities. Moreover, N-methylmorpholine (NMM) was found to be an effective additive for the formation of 3-substituted isoindolin-1-ones using a one-pot addition-cyclization-deprotection sequence.
W. Zhou, Y.-X. Zhang, X.-D. Nie, C.-M. Si, X. Sun, G.-G. Wei, J. Org. Chem., 2018, 83, 9879-9889.

A convenient rearrangement of indazolium salts provides 1,2-dihydroquinazolines. The rearrangement passes through cleavage of a N-N bond after basic deprotonation of the 2-benzyl group.
Q. Chen, Z. Mao, K. Gao, F. Guo, L. Sheng, Z. Chen, J. Org. Chem., 2018, 83, 8750-8758.

A convenient copper-catalyzed oxidative cross-dehydrogenative [4 + 2]-cyclization of glycine derivatives with anthranils enables an efficient and atom-economical synthesis of various 3,4-dihydroquinazolines. The reaction offers high efficiency and wide substrate tolerance.
J. Ren, C. Pi, Y. Wu, X. Cui, Org. Lett., 2019, 21, 4067-4071.

A gold(I)-catalyzed heteroannulation of salicylic amides with alkynes provides a broad range of variously substituted benzoxazinones containing quaternary carbon centers. The method offers a high functional group tolerance and excellent atom economy.
M. Abe, M. Kawamoto, M. Inoue, T. Kimachi, K. Inamoto, Org. Lett., 2022, 24, 5684-5687.

A unique cyclization of benzamide derivatives that contain a propargyl ether by a Pd(0)/dialkyl(biaryl)phosphine catalytic system efficiently provides various six-membered N-heterocyclic compounds that contain a fully substituted carbon center. Mechanistic studies suggest that this unprecedented cyclization starts with the cleavage of a propargylic C-O bond, and a 1,3-diene has been identified as a key intermediate.
Y. Ogiwara, Y. Suzuki, K. Sato, N. Sakai, Org. Lett., 2018, 20, 6965-6969..

An Inverse Electron Demand Azo-Diels-Alder Reaction of o-Quinone Methides and Imino Ethers: Synthesis of Benzocondensed 1,3-Oxazines
D. V. Osipov, V. A. Osyanin, G. D. Khaysanova, E. R. Masterova, P. E. Krasnikov, Y. N. Klimochkin, J. Org. Chem., 2018, 83, 4775-4785.

Treatment of various 2-amino-arylalkyl alcohols with isothiocyanates afforded thiourea intermediates, which were reacted in situ with molecular iodine in the presence of triethylamine to give 2-amino-4H-1,3-benzoxazines. The reaction of the thiourea intermediates with T3P as mild cyclodehydrating reagent and triethylamine as the base provides 2-amino-4H-1,3-benzothiazines.
V. P. R. K. Putta, N. Vodnala, R. Gujjarappa, U. Tyagi, A. Garg, S. Gupta, P. P. Pujar, C. C. Malakar, J. Org. Chem., 2020, 85, 380-396.

Copper catalyzes a mild and operationally simple N-arylation of isatoic anhydrides with aryl(TMP)iodonium trifluoroacetates in good yields at room temperature. Alternative one-pot approaches for biologically relevant fenamic acid derivatives and N,N'-diarylindazol-3-ones are reported too.
R. A. Saikia, K. Talukdar, D. Pathak, B. Sarma, A. J. Thakur, J. Org. Chem., 2023, 88, 3567-3581.

A Rh(III)-catalyzed, N-amino (hydrazine)-directed C-H functionalization with α-diazo-β-ketoesters provides a simple and efficient access to the cinnoline scaffold via successive C-H activation/C-C coupling/intramolecular dehydration.
C. Song, C. Yang, F. Zhang, J. Wang, J. Zhu, Org. Lett., 2016, 18, 4510-4513.

A regioselective deoxygenative C-H functionalization of readily available quinoline-N-oxides with thiourea upon activation with triflic anhydride enable the synthesis of quinoline-2-thiones in very good yields.
D. I. Bugaenko, O. A. Tikhanova, A. V. Karchava, J. Org. Chem., 2023, 88, 1018-1023.

An efficient Cu(I)/DMAP/air system enables a one-pot synthesis of 4-oxo-4H-cinnolin-2-ium-1-ides from substituted 2-alkynylanilines and nitrosoarenes. The use of an inexpensive copper catalyst and molecular oxygen as the oxygen source and the oxidant make this an attractive green protocol.
X. Fang, J. Cao, W. Ding, H. Jin, X. Yu, S. Wang, Org. Lett., 2021, 23, 1228-1233.

Rh(III) catalyzes a synthesis of bicyclic [1,3,5]triazinones from a diverse array of imines with ethyl (pivaloyloxy)carbamate. The preparation of [5,6]- and [6,6]-bicyclic heterocycles substituted with aryl, alkyl, and alkoxy groups demonstrated a broad reaction scope. The development of a three-component variant featuring in situ imine formation is also reported.
D. N. Confair, N. S. Greenwood, B. Q. Mercado, J. A. Ellman, Org. Lett., 2020, 22, 8993-8997.

A water-gas shift reaction (WGSR) employing sodium 2-nitrobenzenesulfinates and α-bromo ketones enables a facile domino approach to benzothiazine 1,1-dioxides. This strategy is cost-effective and environmentally beneficial. The optimized reaction conditions demonstrated remarkable chemical tolerance to a wide range of electrically and sterically varied substituents on both coupling partners.
Y. Sharma, G. P. Pawar, V. D. Chaudhari, J. Org. Chem., 2023, 88, 701-710.

A one-pot method for the Sonogashira coupling and cyclization of 2-bromobenzenesulfonamides and terminal alkynes allows access to various substituted benzosultams regioselectively in excellent yields.
S. Debnath, S. Mondal, J. Org. Chem., 2015, 80, 3940-3948.

A copper-catalyzed three-component tandem reaction enables a convenient and practical synthesis of 1,4-benzothiazines from terminal alkynes, 2-iodophenyl isothiocyanates, and aqueous ammonia.
J.-J. Chu, B.-L. Hu, Z.-Y. Liao, X.-G. Zhang, J. Org. Chem., 2016, 81, 8647-8652.

A regioselective one-pot synthesis of 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines under microwave heating starts from commercially available 2-aminophenols. Base-mediated regioselective O-alkylation with 2-bromoalkanoates gives acyclic intermediates. A subsequent intramolecular amidation reaction furnishes the desired products in good yields.
W.-M. Dai, X. Wang, C. Ma, Tetrahedron, 2005, 61, 6879-6885.

A highly atom-efficient PIDA-mediated intramolecular iminoenol tautomer trapping reaction, followed by Et₃N-promoted aerobic oxidative ring construction enables the synthesis of multisubstituted 2-hydroxy-benzo[b][1,4]oxazins from N-(2-hydroxylaryl)enaminones at room temperature under air. O₂ serves as the oxygen source of the hydroxyl group.
H. Zhang, J. Shen, G. Cheng, Y. Feng, X. Cui, Org. Lett., 2018, 20, 664-667.

The reaction of o-haloaniline derivatives and carbon disulfide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene at 80-140˚C provides the corresponding 1,3-benzothiazole-2(3H)-thione derivatives in good yields.
Y. Fu, X. Hu, Y. Chen, Y. Yang, H. Hou, Y. Hu, Synthesis, 2012, 44, 1477-1480.

A H₂SO₄-mediated intramolecular cyclization enables the preparation of biologically important tetrahydro-1-benzazepines from N-arylated homoallylamines. This solvent- and metal-free, atom- and step-economical transformation offers mild reaction conditions, experimental simplicity, and the use of a readily available, cheap, and nontoxic mediator.
H.-S. Gao, F. Dou, A.-L. Zhang, R. Sun, L.-M. Zhao, Synthesis, 2017, 49, 1597-1602.

A low-temperature, protecting-group-free oxidation of 2-substituted anilines with PIFA in the presence of an acid generates an electrophilic N-aryl nitrenoid intermediate that can engage in C-NAr bond formation to construct functionalized N-heterocycles, such as spirocyclic- or bicyclic 3H-indoles or benzazepinones.
T. Deng, W. Mazumdar, R. L. Ford, N. Jana, R. Izar, D. J. Wink, T. G. Driver, J. Am. Chem. Soc., 2020, 142, 4456-4463.

An isothiourea-catalyzed enantioselective formal [4+3] cycloaddition of various α,β-unsaturated carboxylic acid derivatives with 2-aminothiophenols proceeds via a reversible sulfa-Michael addition to α,β-unsaturated acylammonium intermediates, followed by an enantioselective formation of a seven-membered ring. This method enables a facile and divergent synthesis of optically active 2- and 3-substituted 1,5-benzothiazepines.
Y. Fukata, K. Yao, R. Miyaiji, K. Asano, S. Matsubara, J. Org. Chem., 2017, 82, 12655-12668.

N-heterocyclic carbene/copper-cocatalyzed [4 + 3] annulations of salicylaldehydes with aziridines provide the corresponding 1,4-benzoxazepinones in good yields with exclusive regioselectivity.
Y.-F. Han, Z.-H. Gao, C.-L. Zhang, S. Ye, Org. Lett., 2020, 22, 8396-8400.

An atom-economic, efficient, rapid, and highly regioselective one-pot click reaction allows the synthesis of benzo[e][1,4]oxazepin-5-ones in excellent yields. The method involves epoxide ring-opening-ring-closing cascade with anthranilic acids using neat grinding at room temperature in the presence of lithium bromide as a mild catalyst. Pure products are obtained simply by washing the reaction mixture with warm water.
A. K. Singh, R. Chawla, L. D. S. Yadav, Synthesis, 2012, 44, 2353-2358.

Benzo-fused sulfamate-derived imines readily react with glycine aldimino esters in the presence of an amine base to furnish 1,3-benzoxazepine frameworks in good yields.
M. K. Reddy, V. Bhajammanavar, M. Baidya, Org. Lett., 2021, 23, 3868-3872.

A catalyst-free [4+3]-cycloaddition reaction of N-aryl sulfilimines with cyclobutenones provides 1,5-dihydro-2H-benzo[b]azepin-2-ones under mild reaction conditions. This reaction offers a broad substrate scope and good functional group tolerance and does not require additives. Using a N-pyridinyl sulfilimine as the substrate, a series of pyridoazepinones have also been prepared.
X. Xie, J. Sun, Org. Lett., 2021, 23, 8921-8925.

uthenium-catalyzed enyne metathesis of enynes connected with catechol, o-amino phenol, or o-phenylenediamine in DCM at room temperature overnight provides eight-membered ring compounds in high yield. In a similar manner, monocyclic 1,4-diaza- or 1-oxa-4-azacyclooctene can be synthesized.
M. Mori, T. Kitamura, N. Sakakibara, Y. Sato, Org. Lett., 2000, 2, 543-545.

Phthalic anhydride mediates a reaction of hydrazine hydrate and cyclic/linear iodonium compounds to provide benzo[c]cinnolines/azobenzenes in one pot. The reaction proceeds through diacylation, N,N'-diarylation, and deacylation/oxidation.
R. Xie, Y. Xiao, Y. Wang, Z.-W. Xu, N. Tian, S. Li, M.-H. Zeng, Org. Lett., 2023, 25, 2415-2419.

tert-Butyl hydroperoxide promotes an oxidative annulation reaction of isatins with 2-(trimethylsilyl)aryl triflates for the convenient synthesis of acridone derivatives. The reaction may proceed via consecutive Baeyer-Villiger-type rearrangement followed by an intermolecular cyclization. This convenient method offers broad substrate scope and good functional group tolerance.
M. Luo, N. Dong, M. Zhu, Y. Wang, C. Xu, G. Yin, J. Org. Chem., 2023, 88, 9419-9423.

An N- and S-arylation sequence of o-sulfanylanilines enables an efficient synthesis of various N-arylphenothiazines under transition-metal-free conditions.
T. Matsuzawa, T. Hosoya, S. Yoshida, Org. Lett., 2021, 23, 2347-2352.