Synthesis of N-Heterocycles
| Synthesis of | ||||||
 Cyclic amines |
 Lactams |
 Sultams |
||||
 Imidazolidones |
 Oxazolidinones and Derivatives |
 Hydantoins |
 Urazoles |
 Oxazolidines |
 Isoxazolidines and Benzisox. |
 Pyrazolidines |
 2H-Azirines |
 3-Pyrrolines |
 2-Pyrrolines |
 1-Pyrrolines |
 Maleimides |
||
 2-Isoxazolines |
 2-Oxazolines |
 3-Oxazolines |
 2-Imidazolines |
 Pyrazolines |
||
 Pyrroles |
 Imidazoles Benzimidazoles |
 Pyrazoles Indazoles |
 1,2,3-Triazoles Benzotriazoles |
 1,2,4-Triazoles |
 Tetrazoles |
|
 Imidazol-2-ones Benzimidazol-2-ones |
 Imidazol-5-ones |
 2-Oxazolones |
||||
 Oxazoles Benzoxazoles |
 Isoxazoles Benzisoxazoles |
 Thiazoles Benzothiazoles |
 1,3,4- Oxadiazoles |
 1,2,4- Oxadiazoles |
 1,3,4- Thiadiazoles |
Related: |
 Indoles |
 Oxindoles |
 Indolines |
 Carbazoles |
|||
 Azaindoles |
 Isoindoles |
 Indolizines |
 Indolizinones |
|||
 Pyridines, and rel. comp. |
 Dihydro- pyridines |
 2-Pyridones |
 Pyrazines |
 Pyrimidines |
 1,3,5- Triazines |
|
 Quinolines and rel. comp. |
 Tetrahydro- quinolines |
 1,2- Dihydroquinolines |
 Isoquinolines and rel. comp. |
 3,4-dihydroisoquinolines |
 Tetrahydroisoquinolines |
|
 1,8- Naphthyridines |
 Quinazolines |
 Quinoxalines |
 Tetrahydro- quinoxalines |
|||
 2,3-dihydro- 4-pyridones |
 4-Quinolones |
 Quinazolinones |
 Azepines |
|||
Name Reactions
Recent Literature
A high-yielding, asymmetric synthesis of novel 4-formyl-1-(2- and
3-haloalkyl)azetidin-2-ones was developed as valuable starting materials for the
synthesis of different enantiomerically enriched bicyclic azetidin-2-ones, such
as piperazine, morpholine, and 1,4-diazepane annulated β-lactam derivatives.
W. Van Brabandt, M. Vanwalleghem, M. D'hooghe, N. De Kimpe, J. Org. Chem., 2006, 71, 7083-7086.
Bisphosphine-catalyzed mixed double-Michael reactions between amino-acid-derived
pronucleophiles as Michael donors and electron-deficient acetylenes as acceptors
afford β-amino carbonyl derivatives of oxazolidines, thiozolidines, and
pyrrolidines in excellent yields and with high diastereoselectivities under
operationally simple and mild conditions.
V. Sriramurthy, G. A. Barcan, O. Kwon, J. Am. Chem. Soc., 2007,
129, 12928-12929.
A simple, commercially available iridium catalyst allows the use of sulfoxonium
ylides as a carbene source for various intra- and intermolecular X-H bond
insertions, including a practical ring-expansion strategy for lactams. The
safety and stability of sulfoxonium ylides recommend them as preferable
surrogates to traditional diazo ketones and esters.
I. K. Mangion, I. K. Nwamba, M. Shevlin, M. A. Huffman, Org. Lett., 2009,
11, 3566-3569.
[RuCl2(CO)3]2/dppp is a highly effective
catalyst system for the intramolecular oxidative amination of various
aminoalkenes in presence of K2CO3 and allyl acetate in
N-methylpiperidine to give the corresponding cyclic imines and
indoles in excellent yields.
T. Kondo, T. Okada, T.-A. Mitsudo, J. Am. Chem. Soc., 2002, 124,
186-187.
An efficient chiral Lewis acid-catalyzed inverse-electron-demand Diels-Alder
reaction of N-sulfonyl 1-aza-1,3-dienes is based on the combination of
Ni(II)-DBFOX complex as catalyst and the use of a metal-coordinating
(8-quinolyl)sulfonyl moiety. The reaction provides highly functionalized
piperidine derivatives in good yields with excellent endo-selectivity, and good
enantioselectivities.
J. Esquivias, R. G. Arrays, J. C. Carretero, J. Am. Chem. Soc., 2007,
129, 1480-1481.
A wide screening of substrates in ring-closing metathesis reactions reveals the
great efficiency of phosphabicyclononane (phoban)-containing ruthenium-based
pre-catalysts. Comparison of the catalytic activities with Grubbs'
first-generation pre-catalyst illustrates the key role of the Phoban ligand.
F. Boeda, H. Clavier, M. Jordaan, W. H. Meyer, S. P. Nolan, J. Org. Chem., 2008,
73, 259-263.
Aminocarbonyl Group Containing Hoveyda-Grubbs-Type Complexes: Synthesis and
Activity in Olefin Metathesis Transformations
D. Rix, F. Caijo, I. Laurent, F. Boeda, H. Clavier, S. P. Nolan, M. Mauduit, J. Org. Chem., 2008,
73, 4225-4228.
Δ3-Aryl/heteroaryl substituted heterocycles via sequential Pd-catalysed
termolecular cascade/ring closing metathesis (RCM)
H. A. Dondas, B. Clique, B. Cetinkaya, R. Grigg, C. Kilner, J. Morris, V.
Sridharan, Tetrahedron, 2005,
61, 10652-10666.
Organic phosphine-catalyzed [4
+ 2] annulation of
ethyl 2-(substituted-methyl)-2,3-butadienoates as 1,4-dipole synthons with N-tosylimines
gave ethyl
2,6-cis-disubstituted-1-(4-tosyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylates
in excellent yields with complete regioselectivity and high diastereoselectivity.
X.-F. Zhu, J. Lan, O. Kwon, J. Am. Chem. Soc., 2003, 125, 4716-4717.
Fully substituted 4-aminopyrrolones are easily accessed starting from imines,
ketones, or α-bromophenyl acetonitriles. Imines are reacted with KCN/NH4Cl,
whereas ketones are transformed to the desired α-amino nitriles using a modified
Strecker reaction. Reaction with a suitable acyl halide produces the
corresponding amides. Ttreatment of these amides with ethanolic KOH gives
4-amino-1H-pyrrol-2(5H)-one derivatives in good yields.
H. Zali-Boeini, M. Mobin, K. Hajibabaei, M. Ghani, J. Org. Chem., 2012,
77, 5808-5812.
Pentafluorophenyl anion and trifluoromethyl anion as leaving groups enable a new
synthesis of 1,2,4-oxadiazol-5-ones from amidoximes using pentafluorobenzoyl
chloride or trifluoroacetic anhydride (TFAA) as a double acylating agent.
T. Gerfaud, H.-L. Wei, L. Neuville, J. Zhu, Org. Lett., 2011,
13, 6172-6175.
A reaction between N-benzylideneanilines and Danishefsky's diene proceeds
smoothly in acidic aqueous medium in the presence of a catalytic amount of
copper(II) triflate and sodium dodecyl sulfate to afford the corresponding
1,2-diphenyl-2,3-dihydro-4-pyridones in excellent yields. The aqueous solution
containing the catalyst can be recovered and reused without any loss in
efficiency.
D. Lanari, O. Piermatti, F. Pizzo, L. Vaccaro, Synthesis, 2012,
2181-2184.
Ring-closing olefin metathesis (RCM)/elimination and RCM/oxidation/deprotection
of nitrogen-containing dienes are the key processes of new synthetic routes to
substituted 3-hydroxypyridines. An application of RCM/oxidation/deprotection
allows the synthesis of 3-aminopyridine derivatives.
K. Yoshida, F. Kawagoe, K. Hayashi, S. Horiuchi, T. Imamoto, A. Yanagisawa, Org. Lett., 2009,
11, 515-518.
Acid-catalysed intramolecular hydroamination of 2-alkenylarylethylamine
derivatives gives smoothly isoindolines via benzylic carbenium ion generation.
L. Henderson, D. W. Knight, A. C. Williams, Synlett, 2012,
1667-1669.
Various N-substituted isoindolinones can be synthesized in
excellent yields through the reductive C-N coupling and intramolecular amidation
of 2-carboxybenzaldehyde with amines in the presence of ultrathin Pt nanowires
as catalysts under 1 bar of hydrogen. These unsupported catalysts can also be
used for the synthesis of phthalazinones in high yield when hydrazine or phenyl
hydrazine is used instead of amines.
L. Shi, L. Hu, J. Wang, X. Cao, H. Gu, Org. Lett., 2012,
14, 1876-1879.
A one-pot strategy allows the synthesis of phthalazines and pyridazino-aromatics
starting from aromatic aldehydes. A variety of substituents ranging from
electron withdrawing to donating is tolerated furnishing the desired 1,2-diazine
in good to excellent yields. A subsequent bidentate Lewis acid catalyzed inverse
electron-demand Diels-Alder (IEDDA) reaction opens a novel two-step entry into
substituted naphthalenes, such as Naproxen.
S. N. Kessler, H. A. Wegner, Org. Lett., 2012,
14, 3268-3271.
Iodine-mediated intramolecular cyclization of enamines leads to a various 3H-indole
derivatives bearing multifunctional groups in good to high yields under
transition metal-free reaction conditions.
Z. He, H. Li, Z. Li, J. Org. Chem., 2010,
75, 4296-4299.
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.
Fused bicyclic imidazole rings have been prepared in good yields by a
sequence of the van Leusen three-component reaction and the ring-closing
metathesis reaction.
V. Gracias, A. F. Gasiecki, S. W. Djuric, Org. Lett., 2005, 7, 3183-3186.
An efficient and convenient synthesis of [1,2,4]triazolo[4,3-a]pyridines
involves a palladium-catalyzed addition of hydrazides to 2-chloropyridine, which
occurs chemoselectively at the terminal nitrogen atom of the hydrazide, followed
by dehydration in acetic acid under microwave irradiation.
A. Reichelt, J. R. Falsey, R. M. Rzasa, O. R. Thiel, M. M. Achmatowicz, R. D.
Larsen, D. Zhang, Org. Lett., 2010,
12, 792-795.
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.
A rhodium-catalyzed cycloisomerization converts various acyclic enynes to
their cyclic diene isomers with endoselectivity. Two different catalyst
systems have been developed, which are effective in promoting the C-C
bond-forming cyclization of enynes to furnish carbo- and heterocycles in
good to excellent yield. The mechanism is discussed.
H. Kim, C. Lee, J. Am. Chem. Soc.,
2005, 127, 10180-10181.
A solvent- and metal-free regioselective cyclization affords 1,4-oxazine and
1,4-oxazepine derivatives as exo-dig products. Substrates for the
cyclization step can be produced in a highly diastereomeric fashion by Grignard
reaction as key synthetic step following Cram’s rule.
J. K. Vandavasi, W.-P. Hu, H.-Y. Chen, G. C. Senadi, C.-Y. Chen, J.-J. Wang, Org. Lett., 2012,
14, 3134-3137.
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.
[1,2,4]Triazolo[1,5-a]pyridines have been prepared in good yields
from 2-aminopyridines by cyclization of N-(pyrid-2-yl)formamidoximes
under mild reaction conditions with trifluoroacetic anhydride.
E. Huntsman, J. Balsells, Eur. J. Org. Chem., 2005,
3761-3765.
Pyridine N-oxides were converted to tetrazolo[1,5-a]pyridines in good
yield in the presence of sulfonyl or phosphoryl azides and pyridine by
heating in the absence of solvent. Diphenyl phosphorazidate (DPPA) was the
most convenient reagent.
J. M. Keith, J. Org. Chem., 2006,
71, 9540-9543.
An efficient three-component coupling reaction of substituted picolinaldehydes,
amines, and formaldehyde produces imidazo[1,5-a]pyridinium ions in high
yields under mild conditions, allowing the incorporation of diverse
functionality and chiral substituents. Higher order condensations are also
described that provide access to multidentate NHC ligands useful for a variety
of applications.
J. T. Hutt, Z. D. Aron, Org. Lett., 2011,
13, 5256-5259.
Starting from readily available o-mercaptoacylphenones, a mild S-nitrosation
and a subsequent intramolecular aza-Wittig reaction lead to the construction of
3-substituted benzisothiazoles.
N. O. Devarie-Baez, M. Xian, Org. Lett., 2010,
12, 752-754.
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.
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.
The use of a readily available Sc(III)-inda-pybox as the catalyst enabled an
enantioselective synthesis of 2,3-dihydroquinazolinones (DHQZs) via a metal
catalyzed asymmetric intramolecular amidation of an imine.
M. Prakash, V. Kesavan, Org. Lett., 2012,
14, 1896-1899.
The use of cationic silver (AgSbF4) as a catalyst for intra- and
intermolecular alkyne-carbonyl coupling is described.
J. U. Rhee, M. J. Krische, Org. Lett., 2005, 7, 2493-2495.
An effective route to novel 5-hydroxy-1,5-dihydro-2H-pyrrol-2-one is
described which involves the reaction of an enamine, derived from addition
of a secondary amine to dibenzoylacetylene, with an arylsulfonyl isocyanate.
A. Alizadeh, F. Movahedi, H. Masrouri, L.-G. Zhu, Synthesis, 2006, 3431-3436.
Trialkylsilyl triflates effect cyclization of ester-imides and diesters.
Trapping of the in situ generated, nucleophilic ketene acetal is a key
aspect of the transformation. In many instances the levels of
diastereoselectivity are very high. Mechanistic points are inferred from
spectroscopic observations.
T. R. Hoye, V. Dvornikovs, E. Sizova, Org. Lett., 2006, 8, 5089-5091.
A tandem palladium-catalyzed arylation-ester amidation sequence allows the
synthesis of various quinazolinedione products by reaction of o-halo
benzoates with monoalkyl ureas. The reactions are regioselective for the
formation of 3-N-alkyl isomers.
M. C. Willis, R. H. Snell, A. J. Fletcher, R. L. Woodward, Org. Lett., 2006, 8, 5089-5091.
A convenient environmentally friendly method for the cyclization of
2-aminochalcones to 2-aryl-2,3-dihydroquinolin-4(1H)-ones on the surface
of silica gel impregnated with indium(III) chloride under microwave irradiation
without any solvent has been reported.
K. H. Kumar, D. Muralidharan, P. T. Perumal, Synthesis, 2004,
63-68.
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,
1477-1480.
A three-component condensation gave
2-amino-4H-1,3-oxazines or 2-amino-4H-1,3-thiazines from alkynes, urea or
thiourea, and aldehydes.
S. Huang, Y. Pan, Y. Zhu, A. Wu, Org. Lett., 2005, 7, 3797-3799.
tert-Butyl hypoiodite is a mild and powerful reagent for the cyclization
of N-alkenylamides leading to various N-heterocycles.
N-alkenylsulfonamides gave three- to six-membered saturated N-heterocycles
in good yields, whereas alkenylbenzamide derivatives afforded
N-, O- or N-, S-heterocycles.
S. Minakata, Y. Morino, Y. Oderaotoshi, M. Komatsu, Org. Lett.,
2006, 8, 3335-3337.
S. Huang, Y. Pan, Y. Zhu, A. Wu, Org. Lett., 2005, 7, 3797-3799.
