Synthesis of N-Heterocycles
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.
A [2 + 1 + 1] radical tandem cycloaddition of styrenes, arylamines, and tert-butyl hydroperoxide enables a regioselective synthesis of polysubstituted 1,2-oxazetidines. TBHP was employed in this conversion not only as the oxidant but also as the oxygen source.
W. Liu, C. Chen, P. Zhou, H. Tan, Org. Lett., 2017, 19, 5830-5832.
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 base-promoted [3 + 2] cycloaddition reaction of azaoxyallyl cations with hexahydro-1,3,5-triazines provides 4-imidazolidinones in good yields under mild reaction conditions.
D. Ji, J. Sun, Org. Lett., 2018, 20, 2745-2748.
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.
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.
A selective, formal, 1,3-dipolar cycloaddition of organo-cyanamide ions with nitrile imine dipoles provides 1,2,4-triazol-3-imines. Hydrolysis of the 1,2,4-triazol-3-imines yields the corresponding 1,2,4-triazol-5-ones.
P. Sharma, S. B. Bhat, M. R. R. Prabhath, A. Molino, E. Nauha, D. J. D. Wilson, J. E. Moses, Org. Lett., 2018, 20, 4263-4266.
A visible light-promoted three-component tandem annulation of α-bromoesters, amines, and aryl/alkyl isothiocyanates provides 2-iminothiazolidin-4-ones at room temperature in the absence of metal and photocatalyst. This [1 + 2 + 2] cyclization strategy offers broad substrate scope, excellent functional group tolerance, mild reaction conditions, step-economy, and simple operation.
W. Guo, M. Zhao, W. Tan, L. Zheng, K. Tao, L. Liu, X. Wang, D. Chen, X. Fan, J. Org. Chem., 2018, 83, 1402-1413.
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.
The ion-paired Lewis acid [FeCl2]+[FeCl4]- generated by the in situ disproportionation of FeCl3 catalyzes an aza-Diels-Alder reaction of nonactivated dienes and imines.
R. Tomifuji, J. Maeda, T. Takahashi, T. Kurahashi, S. Matsubara, Org. Lett., 2018, 20, 7474-7477.
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.
An oxidative relay Heck arylation reaction enables the construction of chiral α,β-unsaturated δ-lactams, widely used as pharmacophores, in high yields and excellent enantioselectivities. This strategy also allows facile access to 7-substituted α,β-unsaturated ε-lactam products and δ-lactams.
Q. Yuan, M. S. Sigman, J. Am. Chem. Soc., 2018, 140, 6527-6530.
An N-heterocyclic carbene-catalyzed oxidative LUMO activation of the β-cabons of saturated carboxylic esters enables an efficient asymmetric access to lactams and lactones. The method introduces functional groups at the typically inert β-sp3 carbons of saturated esters. The use of HOBt as an additive improves both yields and enantioselectivities of the reactions.
B. Liu, W. Wang, R. Huang, J. Yan, J. Wu, W. Xue, S. Yang, Z. Jin, Y. R. Chi, Org. Lett., 2018, 20, 260-263.
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.
A copper-promoted 6-endo-trig cyclization of readily available β,γ-unsaturated hydrazones enables an efficient synthesis of a series of 1,6-dihydropyridazines with good yields, high functional group tolerance, and remarkable regioselectivity under mild conditions. Importantly, the 1,6-dihydropyridazines can be efficiently converted to biologically important pyridazines in the presence of NaOH.
Y.-Q. Guo, M.-N. Zhao, Z.-H. Ren, Z.-H. Guan, Org. Lett., 2018, 20, 3337-3340.
Cu(II)-catalyzed aerobic 6-endo-trig cyclizations provide 1,6-dihydropyridazines and pyridazines via the judicious choice of reaction solvent. Whereas 1,6-dihydropyridazines were obtained in good yields with MeCN as the reaction solvent, employment of AcOH directly afforded pyridazines in good yields.
Z. Fan, Z. Pan, L. Huang, J. Cheng, J. Org. Chem., 2019, 84, 4236-4245.
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.
The use of cheap and innocuous reagents, such as NaClO2, NaOCl, and catalytic amounts of TEMPO enables an environmentally friendly C(sp3)-H oxidation of piperazines and morpholines to 2,3-diketopiperazines and 3-morpholinones, respectively. In addition, by using a stoichiometric amount of TEMPO, 2-alkoxyamino-3-morpholinones can be prepared from morpholine derivatives.
D. Chamorro-Arenas, U. Osorio-Nieto, L. Quintero, L. Hernández-García, F. Sartillo-Piscil, J. Org. Chem., 2018, 83, 15333-15346.
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 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.
A photochemical rearrangement of N-vinylpyrrolidinones provides azepin-4-ones in good yields. This transformation allows for the conversion of readily available pyrrolidinones and aldehydes to densely functionalized azepane derivatives in a facile two-step procedure.
S. M. Thullen, D. M. Rubush, T. Rovis, Synlett, 2017, 28, 2755-2758.
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.
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 formal [3 + 3] cycloaddition reaction between azides and in situ formed azaoxyallyl cations provides 1,2,3,4-tetrazines in good yields under mild conditions.
X. Xu, K. Zhang, P. Li, H. Yao, A. Lin, Org. Lett., 2018, 20, 1781-1784.
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.
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.