Synthesis of N-Heterocycles
| Synthesis of | |||
 benzo-fused N-Heterocycles |
Related: Substituted N-Heterocycles |
||
 Cyclic amines |
 Lactams |
 Sultams |
 Oxaziridines |
 Imidazolidones |
 Oxazolidinones |
 Hydantoins |
|
 Succinimides |
 Urazoles |
||
 Oxazolidines |
 Imidazolidines |
 Isoxazolidines |
 Pyrazolidines |
 2H-Azirines |
 2-Azetines |
||
 3-Pyrrolines |
 2-Pyrrolines |
 1-Pyrrolines |
 Maleimides |
 3-Pyrrolin-2-ones |
|||
 2-Isoxazolines |
 3-Isoxazolines |
 4-Isoxazolines |
|
 2-Oxazolines |
 3-Oxazolines |
 2-Imidazolines |
 Thiazolines |
 Pyrazolines |
 3-Pyrazolines |
||
 Pyrroles |
 Imidazoles |
 Pyrazoles |
 3H-Pyrazoles |
 1,2,3-Triazoles |
 1,2,4-Triazoles |
 Tetrazoles |
|
 Imidazol-2-ones |
 Imidazol-5-ones |
 2-Oxazolones |
|
 Oxazoles |
 Isoxazoles |
 1,3,4- Oxadiazoles |
 1,2,4- Oxadiazoles |
 Thiazoles |
 Isothiazoles |
 1,3,4- Thiadiazoles |
 1,2,4- Thiadiazoles |
 Pyridines |
 Dihydro- pyridines |
 2,3-Dihydropyridines |
 2-Pyridones |
 Pyrazines |
 Pyrimidines |
 Pyridazines |
|
 1,3,5-Triazines |
 1,2,4-Triazines |
||
 2,3-dihydro- 4-pyridones |
 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.
In situ generated aza-oxyallyl cation intermediates react with a variety of
carbonyl compounds via an efficient (3 + 2) cycloaddition to provide
4-oxazolidinones with good yields and diastereoselectivities.
A. Acharya, K. Montes, C. S. Jeffrey, Org. Lett.,
2016, 18, 6083-6085.
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.
Silver nitrate catalyzes a reaction of primary amines with methyl
α,α-disubstituted α-isocyanoacetates to provide 3,5,5-trisubstituted
imidazolones in very good yields via Ag-catalyzed insertion of the isocyano
group into the N-H bond of the amine followed by in situ lactamization. The
catalytic system also converts methyl 2-isocyanobenzoate and amines into
quinazolin-4-ones in excellent yields.
A. Clemenceau, Q. Wang, J. Zhu, Org. Lett.,
2017, 19, 4872-4875.
A one-pot sequential N-acylation/dehydrative cyclization between ethyl
carbazate and N-acylbenzotriazoles in the presence of Ph3P-I2
as a dehydrating agent enables a convenient synthesis of 5-substituted-2-ethoxy-1,3,4-oxadiazoles. Subsequent treatment with a
stoichiometric amount of alkyl halides provides 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-ones in
very good
yields.
S. Wet-osot, W. Phakhodee, M. Pattawarapan, J. Org. Chem.,
2017, 82, 9923-9929.
In a gold-catalyzed synthesis of bicyclic imidazoles, a highly electrophilic
α-imino gold carbene intermediate can react with a weakly nucleophilic nitrile,
which is used as the reaction solvent, to deliver the desired product rapidly in
an overall bimolecular [2 + 2 + 1] cycloaddition and in good yield. The
competing intramolecular azide-alkyne click reaction, although likely also
catalyzed by gold, is minimized by using AuCl3 as the catalyst.
Y. Xiao, L. Zhang, Org. Lett., 2012,
14, 4662-4665.
An iron-catalyzed [3 + 2] annulation from readily available oxime acetates with
vinyl azides enables the synthesis of 2,4-substituted 2H-imidazoles via
N-O/N-N bond cleavages and two C-N bond formations. This green reaction
involving oxime acetate as internal oxidant, acetic acid, and nitrogen as
byproducts can be performed under mild reaction conditions and needs no
additives or ligands.
Z. Zhu, X. Tang, J. Li, X. Li, W. Wu, G. Deng, H. Jiang, Org. Lett.,
2017, 19, 1370-1373.
A palladium-catalyzed highly 6-endo-selective alkyl-Heck reaction of
unactivated alkyl iodides provides efficient access to various
5-phenyl-1,2,3,6-tetrahydropyridine derivatives, which are important structural
motifs for bioactive molecules. Mechanistic investigations reveal a hybrid
palladium-radical process.
X. Dong, Y. Han, F. Yan, Q. Liu, P. Wang, K. Chen, Y. Li, Z. Zhao, Y. Dong, H.
Liu, Org. Lett.,
2016, 18, 3758-3761.
A palladium-catalyzed cyclization-Heck reaction of allenamides enables an
efficient one-pot construction of functionalized
3-methylene-5-aryl-1,2,3,4-tetrahydropyridines. These compounds feature a
nonconjugated diene, including one endo-enamine and one exocyclic double
bond, which could be used for further transformation.
F. Yan, H. Liang, J. Song, J. Cui, Q. Liu, S. Liu, P. Wang, Y. Dong, H. Liu, Org. Lett.,
2017, 19, 86-89.
A Pd-catalyzed α,β-desaturation of N-protected lactams provides
conjugated unsaturated counterparts under mildly acidic conditions at room
temperature. The reaction tolerates a wide range of functional groups and shows
reactivity complementary to that of prior desaturation methods. Lactams with
various ring sizes and substituents at different positions all reacted smoothly.
M. Chen. G. Dong, J. Am. Chem. Soc., 2017,
139, 7757-7760.
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.
Palladium-catalyzed alkene carboamination reactions between acyclic N-allyl
guanidines and aryl or alkenyl halides provide substituted 5-membered cyclic
guanidines in good yield. This method allows access to a number of different
cyclic guanidine derivatives in only two steps from readily available allylic
amines.
B. P. Zavesky, N. R. Babij, J. A. Fritz, J. P. Wolfe, Org. Lett., 2013,
15, 5420-5423.
A silver-catalyzed hydroamination of tosyl-protected N-allylguanidines
provides substituted cyclic guanidines in high yields. The reactions can be used
for construction of quaternary stereocenters as well as both monocyclic and
bicyclic guanidine products.
Z. J. Garlets, M. Silvi, J. P. Wolfe, Org. Lett.,
2016, 18, 2331-2334.
An intramolecular transition-metal-free base-mediated hydroamination of
propargylamine with isothiocyanates enables an atom-economical, regioselective
synthesis of diversely substituted imidazole-2-thiones and spiro-cyclic
imidazolidine-2-thiones in good yields via intramolecular 5-exo-dig
cycloisomerization.
A. Ranjan, R. Yerande, P. B. Wakchaure, S. G Yerande, D. H. Dethe, Org. Lett.,
2014,
16, 5788-5791.
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.
Formation of iminophosphoranes in a Staudinger reaction and condensation with
carbon disulfide followed by condensation with α-amino esters provides
N-3-substituted 2-thiohydantoins.
S. Gosling, C. El Amri, A. Tatibouët, Synthesis, 2014, 46,
1079-1084.
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.
In situ derived acyclic and cyclic 1,2-diaza-1,3-dienes (DDs) undergo an
interceptive [4 + 1] annulation with diazo esters (DEs) in the presence of
inexpensive copper(II) chloride to yield mono-, bi-, and tricyclic
4,5-dihydropyrazole-5-carboxylic acid derivatives.
O. A. Attanasi, L. De Crescentini, G. Favi, F. Mantellini, S. Mantenuto, S.
Nicolini, J. Org. Chem., 2014,
79, 8311-8338.
A novel palladium-catalyzed oxidative, intramolecular cyclocarbonylation
provides an efficient and direct approach for the construction of valuable
1,3,4-oxadiazole-2(3H)-ones and their derivatives.
F. Ji, X. Li, W. Guo, W. Wu, H. Jiang, J. Org. Chem.,
2015,
80, 5713-5718.
An unprecedented intermolecular cyclizative capture of the cyanamide anion and
several nitrile oxides enables the synthesis of 1,2,4-oxadiazol-5(4H)-imines.
Treatment of the imine products with concd. HCl furnishes 1,2,4-oxadiazol-5(4H)-ones.
S. V. Bhat, D. Robinson, J. E. Moses, P. Sharma, Org. Lett., 2016, 18,
1100-1103.
[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.
In situ transformation of a metathesis active Ru-carbene into an isomerization
active Ru-hydride catalyst by addition of hydroxide as a chemical trigger
enables the conversion of N-Allyl-N-homoallylamines in one step
into cyclic enamides via a tandem catalytic ring-closing
metathesis-isomerization sequence.
B. Schmidt, S. Hauke, N. Mühlenberg, Synthesis, 2014, 46,
1648-1658.
A highly efficient ruthenium-catalyzed stereospecific N-demethylative
rearrangement of isoxazolidines gives synthetically useful N-H-1,3-oxazinanes.
1,3-Oxazinanes are useful building blocks, which can be converted to
N-H-1,3-aminoalcohols in a subsequent step.
C.-Z. Yao, Z.-F. Xiao, X.-S. Ning, J. Liu, X.-W. Zhang, Y.-B. Kang, Org. Lett.,
2014,
16, 5824-5826.
A palladium-catalyzed cyclization reaction for the modular synthesis of highly
substituted piperazines and related bis-nitrogen heterocycles couples two of the
carbons of a propargyl unit with various diamine components to provide products
in very good yields with high regio- and stereochemical control.
T. D. Montgomery, V. H. Rawal, Org. Lett., 2016, 18,
740-743.
A cyclization of N-alkenylamides catalyzed by iodoarenes under oxidative
conditions enables the preparation of five-, six-, and seven-membered rings with
a range of substitutions. Preliminary data from the use of chiral iodoarenes as
precatalysts show that enantiocontrol is feasible.
A. Alhalib, S. Kamouka, W. J. Moran, Org. Lett.,
2015,
17, 1453-1456.
Regioselective ring closing ene-yne metathesis provided an efficient access to
different substituted 1-benzazepine scaffolds. Five- and six-membered lactams
were efficiently prepared by ring-closing metathesis affording highly
functionalizable compounds.
E. Benedetti, M. Lomazzi, F. Tibiletti, J.-P. Goddard, L. Fensterbank, M.
Malacria, G. Palmisano, A. Penoni, Synthesis, 2012, 44,
3523-3533.
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.
An N-heterocyclic carbene catalyzes a highly enantioselective [3 + 3] annulation
reaction of N-hydroxyphthalimide (NHPI) 3,3-disubstituted acrylates and
N-Ts ketimines, providing the desired chiral dihydropyridinone products bearing
an all carbon quaternary stereogenic center in good yields with excellent
enantioselectivities. The reaction demonstrates that NHPI acrylates are
excellent substrates in NHC-catalysis.
Z. Zhang, X. Zeng, D. Xie, D. Chen, L. Ding, A. Wang, L. Yang, G. Zhong, Org. Lett.,
2015,
17, 5052-5055.
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.
An efficient enantioselective hydrazination/cyclization cascade reaction of
α-substituted isocyanoacetates to azodicarboxylates is catalyzed by a squaramide
catalyst derived from Cinchona alkaloid. The reaction affords optically
active 1,2,4-triazolines in excellent yields and very good enantioselectivities
under mild conditions.
M-X. Zhao, H.-L. Bi, H. Zhou, H. Yang, M. Shi, J. Org. Chem., 2013,
78, 9377-9382.
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.
A facile and practical TBAI-catalyzed reaction between N-tosyl hydrazones
and sulfur provides 1,2,3-thiadiazoles in good yields under metal-free
conditions. This procedure serves as an improvement for the Hurd-Mori reaction.
J. Chen, Y. Jiang, J.-T. Yu, J. Cheng, J. Org. Chem.,
2016,
81, 271-275.
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, 44,
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.
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.
Ring-opening of cyclic sulfamidates with propargylic sulfonamides yielded
substrates for a gold-catalyzed cyclization to yield tetrahydropyrazines.
Subsequent reduction or multicomponent reactions of the tetrahydropyrazines gave
various piperazine scaffolds, that have a certain value in the synthesis of
novel screening compounds with lead-like molecular properties.
T. James, I. Simpson, J. Grant, V. Sridharan, A. Nelson, Org. Lett., 2013,
15, 6094-6097.
A Brønsted acid accelerated oxidative radical annulation of sulfonyl
hydrazones with simple olefins provides six-membered
heterocycles. The method offers a rapid and efficient approach to tetrahydropyridazines
which are key structural motifs in pharmaceutically active compounds.
X. Zhong, J. Lv, S. Luo, Org. Lett.,
2016, 18, 3150-3153.
A mild and highly efficient AgOTf catalyzed [3,3] sigmatropic rearrangement/1,3-H
shift/6π aza-electrocyclization cascade reaction of N-propargylic
hydrazones provides arious polysubstituted 1,6-dihydropyridazines with high
selectivity.
Z.-C. Ding, L-C. Ju, Y. Yang, X.-M. An, Y.-B. Zhou, R.-H. Li, H.-T. Tang, C.-K.
Ding, Z.-P. Zhan, J. Org. Chem.,
2016,
81, 3936-3941.
The combination of palladium and photoredox catalysis enables an aerobic
intramolecular oxidative carbonylation of enamides. The dual catalytic system
provides a mild and environmentally friendly method for the synthesis of
1,3-oxazin-6-ones without the use of a stoichiometric amount of hypervalent
metal salts.
K. Liu, M. Zou, A. Lei, J. Org. Chem.,
2016, 81, 7088-7092.
In a cascade β-C-H bond trifluoromethylation/C(sp3)-F bond activation/hydrolysis
reaction of enamides with Togni’s reagent, the CF3 group acts as a CO
surrogate to provide 1,3-oxazin-6-ones in good yields, including synthetically
or pharmaceutically important compounds, which are difficult to access by known
methods.
P. Song, P. Yu, J.-S. Lin, Y. Li, N.-Y. Yang, X.-Y. Liu, Org. Lett.,
2017, 19, 1330-1333.
Under very mild conditions employing BBr3 as a Lewis acid catalyst
and P2O5 as an additive, tertiary enamides that contain a
formyl group underwent highly efficient and scalable intramolecular cyclic
condensation to afford diverse 2,3-dihydro-1H-azepine and 1H-azepin-2(3H)-one
derivatives in very good yields.
W. Zhu, L. Zhao, M.-X. Wang, J. Org. Chem.,
2015,
80, 12047-12057.
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 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.
