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

Synthesis of
Indoles	Indolenines	Indolines
Oxindoles	3-Oxindoles	Isatins
Azaindoles	Carbazoles
Isoindoles	Isoindolines	Isoindolinones	Phthalimides
Benzimidazoles	Benzimidazolones
Indazoles	2H-Indazoles	Indazolones
Benzoxazoles	Benzoxazolones	Benzothiazoles
Benzisoxazoles		Benzisothiazoles
Benzotriazoles	2H-Benzotriazoles
Indolizines	Indolizinones
Imidazo[1,2-a]pyridines	Imidazo[1,5-a]pyridines	Pyrazolo[1,5-a]pyridines
1,2,3-Triazolo[1,5-a]pyridines	1,2,4-Triazolo[1,5-a]pyridines	1,2,4-Triazolo[4,3-a]pyridines	Tetrazolo[1,5-a]pyridines
Quinolines	Tetrahydro- quinolines	1,2- Dihydroquinolines
Isoquinolines and rel. comp.	3,4-dihydroisoquinolines	Tetrahydroisoquinolines	Phthalazines
1,8- Naphthyridines	Quinazolines	Quinoxalines	Tetrahydro- quinoxalines
1,2,4-benzotriazines
Dihydroquinolinones	2,3-Dihydroquinolin-4-ones
4-Quinolones	2-Quinolones	Isoquinolones	Isoquinolin-3-ones
Quinazolinones	Quinoxalinones
2,3-Dihydroquinazolinones	Quinazolinediones
1,2,3-benzotriazine-4(3H)-ones	Benzoxazinones

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Recent Literature

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.

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.

Iron(II) bromide catalyzes the transformation of aryl and vinyl azides with ketone or methyl oxime substituents into 2,1-benzisoxazoles, indazoles, or pyrazoles through the formation of an N-O or N-N bond. This transformation tolerates various functional groups and facilitates access to a range of benzisoxazoles or indazoles.
B. J. Stokes, C. V. Vogel, L. K. Urnezis, M. Pan, T. G. Driver, Org. Lett., 2010, 12, 2884-2887.

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.

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 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.

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.

Asymmetric C-H functionalization in the presence of cobalt(III)-complexes equipped with trisubstituted chiral cyclopentadienyl ligands enables the synthesis of dihydroisoquinolones from N-chlorobenzamides with a broad range of alkenes. The transformation proceeds with excellent enantioselectivities and high regioselectivities.
K. Ozols, Y.-S. Jang, N. Cramer, J. Am. Chem. Soc., 2019, 141, 5675-5680.

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.

A palladium-catalyzed [4+2] annulation of aryl and alkenyl carboxamides with 1,3-dienes provides 3,4-dihydroisoquinolones and 5,6-dihydropyridinones in very good yields in the presence of air as the terminal oxidant. The method demonstrates good functional group tolerance.
M. Sun, J. Li, W. Chen, H. Wu, J. Yang, Z. Wang, Synthesis, 2020, 52, 1253-1265.

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.

An efficient synthesis of 3,4-dihydro-1,4-benzoxazine derivatives in excellent enantio- and diastereospecificity (ee > 99%, de > 99%) proceeds via Lewis acid-catalyzed S_N2-type ring opening of activated aziridines with 2-halophenols followed by Cu(I)-catalyzed intramolecular C-N cyclization in a stepwise fashion.
A. Mal, I. A. Wani, G. Goswami, M. K. Ghorai, J. Org. Chem., 2018, 83, 7907-7918.

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.

A palladium-catalyzed cross-coupling reaction of aryl halides with isoquinoline-1,3(2H,4H)-diones enables the synthesis of 4-aryl isoquinoline-1,3(2H,4H)-diones. The products could be conveniently transformed to 4-aryl tetrahydroisoquinolines.
Y. Yang, Y. Li, C. Cheng, G. Yang, J. Zhang, Y. Zhang, Y. Zhao, L. Zhang, C. Li, L. Tang, J. Org. Chem., 2018, 83, 3348-3353.

A copper-catalyzed asymmetric formal [4 + 2]-cycloaddition of copper-allenylidenes and hexahydro-1,3,5-triazines provides chiral tetrahydroquinazolines in good yields and with high enantioselectivities for most cases.
D. Ji, C. Wang, J. Sun, Org. Lett., 2018, 20, 3710-3713.

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.

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.

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 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.

Whereas the cyclocondensation of 2-aminothiophenols with 1,2-biselectrophiles such as ethyl glyoxalate and diethyl oxalate in aqueous medium leads to the formation of benzothiazole-2-carboxylates via a 5-endo-trig process contrary to Baldwin’s rule, the reaction of 2-aminophenols/anilines produced the corresponding benzazine-3-ones or benzazine-2,3-diones via a 6-exo-trig process in compliance with Baldwin’s rule.
T. M. Dhameliya, S. S. Chourasiya, E. Mishra, P. S: Hadhavar, P. V. Bharatam, A. K. Chakraborti, J. Org. Chem., 2017, 82, 10077-10091.

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.

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.

Synthesis of Eight-Membered Ring Compounds Using Enyne Metathesis
M. Mori, T. Kitamura, N. Sakakibara, Y. Sato, Org. Lett., 2000, 2, 543-545.