Synthesis of N-Heterocycles

Synthesis of
Cyclic amines	Lactams	Sultams
Imidazolidones	Oxazolidinones and Derivatives	Hydantoins	Urazoles	Isoxazolidines
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: Substituted N-Heterocycles
Indoles		Oxindoles		Indolines		Carbazoles
Azaindoles		Isoindoles		Indolizines		Indolizinones
Pyridines, and rel. comp.	Dihydro- pyridines	2-Pyridones		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
4-Quinolones

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Name Reactions

Biginelli Reaction

Hetero-Diels-Alder Reaction

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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 catalyst composed of Pd(OAc)₂ and S-Phos allows the conversion of aryl chlorides as electrophiles in Pd-catalyzed alkene carboamination and carboetherification, minimizes N-arylation, and prevents formation of regiosisomieric mixtures. Various heterocycles, including pyrrolidines, isoxazolidines, tetrahydrofurans, and pyrazolidines, are efficiently generated with this method.
B. R. Rosen, J. E. Ney, J. P. Wolfe, J. Org. Chem., 2010, 75, 2756-2759.

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.

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.

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.

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.

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.

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 aza Diels-Alder reaction of an in situ generated novel iododiene works well with aryl- and benzyl-N-substituted imines. Moderate diastereoselectivities can be obtained using simple α-methylbenzyl chiral imines.
C. Timmons, A. Kattuboina, L. McPherson, J. Mills, G. Li, Tetrahedron, 2005, 61, 11837-11842.

Imidazolinium salts are capable of catalysing an aza-Diels-Alder reaction with a range of imines and Danishefsky's diene, leading to the desired products in good to excellent yields.
V. Jurcik, R. Wilhelm, Org. Biomol. Chem., 2005, 3, 239-244.

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.

A mild ICl-induced cyclization of heteroatom-substituted alkynones provides a simple, highly efficient approach to various 3-iodochromones, iodothiochromenones, iodoquinolinones and analogues in good to excellent yields. Subsequent palladium-catalyzed transformations afford a rapid increase in molecular complexity.
C. Zhou, A. V. Dubrovsky, R. C. Larock, J. Org. Chem., 2006, 71, 1728-1731.

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.

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.

Stereocontrolled Construction of N-Heterocycles Preparation of Heteraromatics Asymmetric Hetero-Diels-Alder Reactions N-Heterocycle Construction by Alkene Metathesis Diastereoselective and Enantioselective Construction of Aza-Heterocycles New Routes to Heterocycles