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
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 SN2-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.