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
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.
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.
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.
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.
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.
In a constant-potential electrolysis (CPE) for the synthesis of
phenanthridinones, TBAI plays a dual role as both a redox catalyst and a
supporting electrolyte. This metal and oxidant free reaction proceeds with 100%
current efficiency via an intramolecular C-H activation under mild reaction
conditions and with a short reaction time.
K. Subramanian, S. L. Yedage, K. Sethi, B. M. Bhanage, Synlett, 2021,
32,
999-1003.
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.