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Synthesis of hydroxamates (Weinreb amides)
Weinreb amides can be prepared directly from carboxylic acids and N,O-dimethylhydroxylamine in the presence of phosphorus trichloride at 60°C in toluene without separation of the moisture and air sensitive intermediate P[NMe(OMe)]3. Various functional groups are tolerated and even sterically hindered carboxylic acids give the corresponding Weinreb amides in excellent yields. The method is suitable for large-scale production.
T. Niu, K.-H. Wang, D. Huang, C. Xu, Y, Su, Y. Hu, Y. Fu, Synthesis, 2014, 46, 320-330.
P[NCH3(OCH3)]3 is a powerful reagent for conversion of aromatic and aliphatic carboxylic acids, including sterically hindered substrates, directly to Weinreb amides in excellent yields in toluene as solvent.
T. Niu, W. Zhang, D. Huang, C. Xu, H. Wang, Y. Hu, Org. Lett., 2009, 11, 4474-4477.
A reaction of unactivated carboxylic acids with masked O-substituted isocyanates provides hydroxamates. This method offers broad functional group tolerance.
J. S. Derasp, E. A. Barbera, N. R. Séguin, D. D. Brzezinski, A. M. Beauchemin, Org. Lett., 2020, 22, 7403-7407.
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.
The coupling reagent ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino)acetate (o-NosylOXY) produces only byproducts that can be easily recovered and reused for the synthesis of the same reagent, making coupling reactions to yield amides, hydroxamates, peptides, and esters more environmentally friendly and cost-effective.
D. Dev, N. B. Palakurthy, K. Thalluri, J. Chandra, B. Mandal, J. Org. Chem., 2014, 79, 5420-5431.
A continuous flow tubing reactor can be used to readily transform methyl or ethyl carboxylic esters into the corresponding hydroxamic acids. Flow rate, reactor volume, and temperature were optimized for increased reaction rate and higher product purity.
E. Riva, S. Gagliardi, C. Mazzoni, D. Passarella, A. Rencurosi, D. Vigo, M. Martinelli, J. Org. Chem., 2009, 74, 3540-3543.
The reaction of esters with hydroxylamine in the presence of a base under microwave activation provides hydroxamic acids in good yields and purity. The method has been successfully applied to enantiomerically pure esters without loss of stereochemical integrity.
A. Massaro, A. Mordini, G. Reginato, F. Russo, M. Taddei, Synthesis, 2007, 3201-3204.
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.
The use of tert-butyl hydroperoxide as an oxidant and an inexpensive and air stable copper catalyst enables a simple and efficient protocol for the oxidative amidation of commercially affordable alcohols to Weinreb amides in very good yields. The reaction tolerates various functional groups.
S. L. Yedage, B. M. Bhanage, Synthesis, 2015, 47, 526-532.
NHC-catalyzed direct amidation of a variety of aryl, alkyl, alkenyl, and heterocyclic aldehydes with nitroso compounds is a powerful method for the synthesis of N-arylhydroxamic acids in excellent yields. This chemistry was also extended to a three-component reaction for the synthesis of N-arylaziridines.
F. T. Wong, P. K. Patra, J. Seayad, Y. Zhang, J. Y. Ying, Org. Lett., 2008, 10, 2333-2336.
Imidazole carbamates and ureas are chemoselective esterification and amidation reagents. A simple synthetic procedure allows the conversion of a wide variety of carboxylic acids to ester or amide analogues in high yields.
S. T. Heller, R. Sarpong, Org. Lett., 2010, 12, 4572-4575.
A convenient and simple one-flask method for the preparation of Weinreb amides, hydroxamates and hydroxamic acids even in large scale is described.
L. De Luca, G. Giacomelli, M. Taddei, J. Org. Chem., 2001, 66, 2534-2537.
Deoxo-Fluor is a versatile and mild reagent for acyl fluoride generation and subsequent one-flask amide coupling. The conversion of acids to amides and Weinreb amides and the use of Deoxo-Fluor as peptide-coupling reagent have been explored. Products were isolated after facile purification in good yields.
J. M. White, A. R. Tunoori, B. J. Turunen, G. I. Georg, J. Org. Chem., 2004, 69, 2573-2576.
Carboxylic acids were conveniently converted into unsubstituted, N-alkyl-, O-alkyl-, and O,N-dialkylhydroxamic acids via acylbenzotriazole intermediates. The ready availability of the reagents, mild conditions, and easy handling of the intermediates are advantageous.
A. R. Katritzky, N. Kirichenko, B. V. Rogovoy, Synthesis, 2003, 2777-2780.
A simple and high-yielding one-step method for the synthesis of hydroxamates from various unactivated esters (including enolizable esters and chiral α-amino acid esters and peptides) has been developed.
A. Gissot, A. Volonterio, M. Zanda, J. Org. Chem., 2005, 70, 6925-6928.
Sterically hindered carboxylic acids can be efficiently converted to N-methoxy-N-methyl amides with 1.1 equiv of methanesulfonyl chloride, 3 equiv of triethylamine, and 1.1 equiv of N-methoxy-N-methylamine in good yields. The major byproduct in these reactions, N-methoxy-N-methylmethanesulfonamide, can be removed under vacuum for 14-24 h.
J. C. S. Woo, E. Fenster, G. R. Dake, J. Org. Chem., 2004, 69, 8984-8986.
A Pd-catalyzed aminocarbonylation of aryl bromides into the corresponding Weinreb amides at atmospheric pressure efficiently transforms eletron-deficient, - neutral, and -rich aryl bromides.
J. R. Martinelli, D. M. M. Freckmann, S. L. Buchwald, Org. Lett., 2006, 8, 4795-4797.
A one-pot method allows the synthesis of α-siloxy-Weinreb amides from aldehydes using N,O-dimethylhydroxylamine and a masked acyl cyanide reagent bearing a tert-butyldimethylsilyl group. The TBS group avoids the competitive reaction toward N-methoxy-N-methyl-2-amino-1-siloxymalononitrile.
H. Nemoto, R. Ma, H. Moriguchi, T. Kawamura, M. Kamiya, M. Shibuya, J. Org. Chem., 2007, 72, 9850-9853.