Categories: C-N Bond Formation >
Synthesis of urea derivatives
A direct and convenient reaction of primary amides with phenyliodine diacetate in the presence of an ammonia source (NH3 or ammonium carbamate) provides N-substituted ureas. This transformation involves a nucleophilic addition of ammonia to an isocyanate intermediate generated in situ by a Hofmann rearrangement of the starting amide.
N. S. Rosa, T. Glachet, Q. Ibert, J.-F. Lohier, X. Franck, V. Reboul, Synthesis, 2020, 52, 2099-2105.
A facile and efficient Pd/C-catalyzed carbonylation of both aliphatic and aromatic azides in the presence of amines under CO atmosphere provides functionalized unsymmetrical ureas with N2 as the only byproduct.
J. Zhao, Z. Li, S. Yan, S. Xu, M.-A. Wang, B. Fu, Z. Zhang, Org. Lett., 2016, 18, 1736-1739.
General procedures allow the carbonylation of aliphatic amines by employing S,S-dimethyl dithiocarbonate (DMDTC) as a phosgene substitute to yield N-alkylureas, N,N′-dialkylureas (both symmetrical and unsymmetrical), and N,N,N′-trialkylureas. All reactions were carried out in water.
E. Artuso, I. Degani, R. Fochi, C. Magistris, Synthesis, 2007, 3497-3506.
Commercially available diiodosilane is a particularly useful reagent for isocyanate formation under mild reaction conditions, particularly from N-Boc systems.
S. Gastaldi, S. M. Weinreb, D. Stien, J. Org. Chem., 2000, 65, 3239-3240.
Lanthanum triflate catalyzes a direct conversion of N-benzyloxycarbonyl-, N-allyloxycarbonyl-, and N-trichloroethoxycarbonyl-protected amines into nonsymmetric ureas in high yields. A variety of protected aromatic and aliphatic carbamates reacted readily with various amines in the presence of lanthanum triflate to generate the desired ureas.
T. T. Bui, H.-K. Kim, Synlett, 2020, 31, 997-1002.
A ruthenium-based pincer complex catalyzed acceptorless dehydrogenative coupling reactions of readily available formamide precursors for a selective access to a broad range of ureas, carbamates, and heterocycles. This highly atom-efficient approach avoids the use of hazardous isocyanates.
J. Bruffaerts, N. von Wolff, Y. Diskin-Posner, Y. Ben-David, D. Milstein, J. Am. Chem. Soc., 2019, 141, 16486-16493.
A one pot reaction of carbonylimidazolide in water with a nucleophile provides an efficient and general method for the preparation of urea, carbamates and thiocarbamates without an inert atmosphere. Products precipitate out from the reaction mixture and can be obtained in high purity by filtration.
K. J. Padiya, S. Gavade, B. Kardile, M. Tiwari, S. Bajare, M. Mane, V. Gaware, S. Varghese, D. Harel, S. Kurhade, Org. Lett., 2012, 14, 2814-2817.
With ambient pressure of carbon monoxide and oxygen at room temperature, N,N-dialkyl-N′-arylureas were selectively accessible from secondary amines, aromatic amines, and sulfur in very good yields.
T. Mizuno, T. Nakai, M. Mihara, Synthesis, 2009, 2492-2496.
In a mild and metal-free synthesis of aryl isocyanates from arylamines, a carbamic acid intermediate, derived from the arylamine starting material and CO2 in the presence of DBU, is dehydrated by activated sulfonium reagents to generate the corresponding isocyanate. The latter can be trapped by various amines and alcohols to make unsymmetrical ureas and carbamates, respectively.
Y. Ren, S. A. L. Rousseaux, J. Org. Chem., 2018, 83, 913-920.
The good leaving group ability of the benzotriazole moiety in N-acylbenzotriazoles enables a mild, metal-free synthesis of symmetric, unsymmetric, N-acyl, and cyclic ureas in good yields by treatment with TMSN3/Et3N in the presence of various amines in short reaction time. In many cases, no column chromatography is required for the purification.
A. S. Singh, A. K. Agrahari, S. K. Singh, M. S. Yadav, V. K. Tiwari, Synthesis, 2019, 51, 3443-3450.
Commercially available ruthenium pincer complexes as catalysts enable an urea synthesis directly from methanol and amine without additive, such as a base, oxidant, or hydrogen acceptor. The reaction is highly atom-economical, producing hydrogen as the sole byproduct. Furthermore, unsymmetrical urea derivatives were successfully obtained via a one-pot, two-step reaction.
S. H. Kim, S. H. Hong, Org. Lett., 2016, 18, 212-215.
Hydroxamic acids were synthesized from carboxylic acids and hydroxylamine hydrochloride in the presence of ethyl 2-cyano-2-(4-nitrophenylsulfonyloxyimino)acetate (4-NBsOXY). 4-NBsOXY also promotes the Lossen rearrangement of hydroxamic acids in the presence of amines to yield ureas. The reactions are compatible with common N- and O-protecting groups and prevent racemization.
K. Thalluri, S. R. Manne, D. Dev, B. Mandal, J. Org. Chem., 2014, 79, 3765-3775.
In a practical one-pot synthesis of ureas, Boc-protected amines are transformed into nonsymmetrical and symmetrical disubstituted and trisubstituted ureas via in situ generation of isocyanates utilizing 2-chloropyridine and trifluoromethanesulfonyl anhydride. A variety of amines can be employed successfully, leading to high yields of isolated ureas.
C. Spyropoulos, C. G. Kokotos, J. Org. Chem., 2014, 79, 4477-4483.
An efficient method for palladium-catalyzed cross-coupling of aryl chlorides and triflates with sodium cyanate allows the synthesis of unsymmetrical N,N′-di- and N,N,N′-trisubstituted ureas in one pot and is tolerant of a wide range of functional groups. Insight into the mechanism of aryl isocyanate formation was gleaned through studies of the transmetalation and reductive elimination steps of the reaction.
E. V. Vinogradova, B. P. Fors, S. L. Buchwald, J. Am. Chem. Soc., 2012, 134, 11132-11135.
1-Propanephosphonic acid cyclic anhydride (T3P) promotes the synthesis of hydroxamic acids from carboxylic acids. Application of ultrasonication accelerates this conversion. Further, T3P has also been employed to activate the hydroxamates, leading to isocyanates via Lossen rearrangement. Trapping with suitable nucleophiles affords the corresponding ureas and carbamates.
B. Vasantha, H. P. Hemantha, V. V. Sureshbabu, Synthesis, 2010, 2990-2996.
Carbonyldiimidazole mediates the Lossen rearrangement of various hydroxamic acids to isocyanates. This process is experimentally simple and mild, with imidazole and CO2 being the sole stoichiometric byproduct. The method avoids the use of hazardous reagents and thus represents a green alternative to standard processing conditions for the Curtius and Hofmann rearrangements.
P. Dubé, N. F. F. Nathel, M. Vetelino, M. Couturier, C. L. Abossafy, S. Pichette, M. L. Jorgensen, M. Hardink, Org. Lett., 2009, 11, 5622-5625.
A smooth and efficient oxidation of isonitriles to isocyanates by DMSO as the oxidant is catalyzed by trifluoroacetic anhydride. The process is complete in a few minutes, forming dimethyl sulfide as the only byproduct. The newly formed isocyanates may be used directly or isolated in high purity by solvent evaporation.
H. V. Le, B. Ganem, Org. Lett., 2011, 13, 2584-2585.
Zirconium(IV)-catalyzed exchange processes of dialkyl carbonates and carbamates in the presence of amines gave carbamates and ureas using 2-hydroxypyridine (HYP) and 4-methyl-2-hydroxyquinoline (MeHYQ) as catalytic additives, respectively. A microwave acceleration effect was observed in Zr(IV)-catalyzed carbamate-urea exchange.
C. Han, J. A. Porco, Jr, Org. Lett., 2007, 9, 1517-1520.
Selective and convenient syntheses of carbamates, symmetric ureas, and unsymmetrical ureas have been accomplished by the reaction of amines with phenyl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylate as a carbonyl source under mild conditions.
H.-G. Lee, M.-J. Kim, S.-E. Park, J.-J. Kim, S.-G. Lee, Y.-J. Yoon, Synlett, 2009, 2809-2814.
A facile one-pot procedure for the synthesis of urea-linked peptidomimetics and neoglycopeptides under Curtius rearrangement conditions employing Deoxo-Fluor and TMSN3 is efficient and circumvents the isolation of acyl azide and isocyanate intermediates. The reaction was carried out under ultrasonication.
H. P. Hemantha, G. Chennakrishnareddy, T. M. Vishwanatha, V. V. Sureshbabu, Synlett, 2009, 407-410.
The reaction of di-tert-butyl dicarbonate or a chloroformate and sodium azide with an aromatic carboxylic acid produces the corresponding acyl azide. The acyl azide undergoes a Curtius rearrangement to form an isocyanate derivative which is trapped either by an alkoxide or by an amine to form the aromatic carbamate or urea.
H. Lebel, O. Leogane, Org. Lett., 2006, 8, 5717-5720.
Readily prepared carbamoylimidazolium salts act as efficient N,N-disubstituted carbamoylating reagents, as a result of the ‘imidazolium’ effect. The salts react with amines, thiols, phenols/alcohols, and carboxylic acids in high yields, without the need for subsequent chromatographic purification of the products, producing ureas, thiocarbamates, carbamates, and amides, respectively.
J. A. Grzyb, M. Shen, C. Yoshina-Ishii, W. Chi, R. S. Brown, R. A. Batey, Tetrahedron, 2005, 61, 7153-7175.
Acyl isocyanates generated by the reaction of primary amides with oxalyl chloride react with a wide range of amides, hydrazides, amines, alcohols, carbazate, and sulfonate to provide symmetrical and unsymmetrical diacyl urea derivatives, acyl ureas/carbamates/thiocarbamates, and related compounds. This convenient one-pot, two-step synthesis uses cheap and commercially available starting reagents.
A. G. Hernandez, G. M. Grooms, A. T. El-Alfy, J. Stec, Synthesis, 2017, 49, 2163-2176.
A simple Pd-catalyzed carbonylation reaction of acyl azides provides facile access to acyl ureas with broad substrate scope, high efficiency, and simple operation under mild conditions.
Z. Li, S. Xu, B. Huang, C. Yuan, W. Chang, B. Fu, L. Jiao, P. Wang, Z. Zhang, J. Org. Chem., 2019, 84, 9497-9508.
A simple and highly efficient synthesis of ω-substituted arylbiurets in a one-pot reaction from readily available starting materials offers an easy work-up procedure and good yields. ω-Substituted arylbiurets can be selectively prepared with an excess of potassium cyanate (KOCN), while an excess of glacial acetic acid (AcOH) switches the reaction towards the formation of N-monosubstituted urea.
X. Min, J. Liu, Y. Dong, M. Hussain, Synthesis, 2018, 50, 341-348.
A broadly applicable procedure for an aza-Lossen rearrangement converts amines into complex hydrazine derivatives in two steps under safe, mild conditions. This method allows the chemoselective formation of N-N bonds, resulting in the synthesis of cyclic and acyclic products while avoiding side reactions of the amphoteric (ambident) nitrogen-substituted isocyanate intermediate.
D. E. Polat, D. D. Brzezinski, A. M. Beauchemin, Org. Lett., 2019, 21, 4849-4852.
High-yielding reductive alkylation of electron-deficient o-haloarylamines followed by treatment with inexpensive N-chlorosulfonyl isocyanate afforded primary ureas in good overall yields. A Pd-catalyzed urea cyclization reaction furnished imidazopyridinones and benzoimidazolones in excellent yields.
M. McLaughlin, M. Palucki, I. W. Davies, Org. Lett., 2006, 8, 3311-3314.
Imidazolidin-2-ones are prepared in two steps from readily available N-allylamines. Addition of the amine starting materials to isocyanates affords N-allylureas, which are converted to imidazolidin-2-ones with generation of two bonds and up to two stereocenters in the presence of aryl bromides, a catalytic amount of Pd2(dba)3/Xantphos and NaOtBu.
J. A. Fritz, J. S. Nakhla, J. P. Wolfe, Org. Lett., 2006, 8, 2531-2534.
Aliphatic and aromatic aldehydes can be converted to acyl azides by treatment with iodine azide. If the reaction is performed at reflux, Curtius rearrangement occurs and carbamoyl azides are obtained directly from the aldehyde in good yield.
L. Marinescu, J. Thinggaard, I. B. Thomsen, M. Bols, J. Org. Chem., 2003, 68, 9453-9455.
The reaction of carbamoyl azides with hydroxylamine leads to N-hydroxyureas, whereas the reaction of carbamoyl cyanides with hydroxylamine gives carbamoyl amidoxime derivatives. The latter type of compound represents an interesting precursor for heterocyclic structures.
J. Paz, C. Pérez-Balado, B. Iglesias, L. Muñoz, J. Org. Chem., 2010, 75, 8039-8047.
Carbamates can be converted into ureas using aluminum amide complexes. Bi-, tri- and tetra-substituted ureas were prepared from carbamate-protected primary or secondary amines by reaction with primary or secondary amines in the presence of stoichiometric quantities of trimethylaluminum.
S.-H. Lee, H. Matsushita, B. Clapham, K. D. Janda, Tetrahedron, 2004, 60, 3439-3443.