One-Pot Curtius Rearrangement Processes from Carboxylic Acids

Abstract

An efficient and practical synthesis of amine derivatives from carboxylic acids is described using new one-pot Curtius rearrangement processes. The preparation of carbamate-protected amines and anilines, as well as ureas was achieved in good to excellent yields on a multigram scale.

Key words

Curtius rearrangement - acyl azides - carbamates - protected amino acids - anilines - ureas

References

• 1a Buchner E. Curtius T. Ber. Dtsch. Chem. Ges.  1885,  18:  2371 
• 1b Curtius T. J. Prakt. Chem.  1894,  50:  275 
• 2a Smith PAS. Org. React.  1946,  3:  337 
• 2b Shioiri T. In Comprehensive Organic Synthesis   Vol. 6:  Trost BM. Fleming I. Pergamon Press; Oxford: 1991.  p.795 
• 2c Scriven EF. Turnbull K. Chem. Rev.  1988,  88:  297 
• 3a Shioiri T. Ninomiya K. Yamada S. J. Am. Chem. Soc.  1972,  94:  6203 
• 3b Ninomiya K. Shioiri T. Yamada S. Tetrahedron  1974,  30:  2151 
• 3c Murato K. Shioiri T. Yamada S. Chem. Pharm. Bull.  1975,  23:  1738 
• 3d Capson TL. Poulter CD. Tetrahedron Lett.  1984,  25:  3515 
• 3e Wolff O. Waldvogel SR. Synthesis  2004,  1303 
• For recent examples, see:
• 4a Gomez-Sanchez E. Marco-Contelles J. Tetrahedron  2005,  61:  1207 
• 4b Kanakubo A. Gray D. Innocent N. Wonnacott S. Gallagher T. Bioorg. Med. Chem. Lett.  2006,  16:  4648 
• 4c Jewett JC. Rawal VH. Angew. Chem. Int. Ed.  2007,  46:  6502 
• 5a Lebel H. Leogane O. Org. Lett.  2005,  7:  4107 
• 5b Lebel H. Leogane O. Huard K. Lectard S. Pure Appl. Chem.  2006,  78:  363 
• 5c Leogane O. Lebel H. Org. Synth.  2009,  86:  113 
• 6 Duggan ME. Imagire JS. Synthesis  1989,  131 
• 7 Lebel H. Leogane O. Org. Lett.  2006,  8:  5717 
• 10a Bretherick L. Handbook of Reactive Chemical Hazards   4th ed.:  Butterworths; London: 1990.  p.1360 
• 10b Armour M.-A. Waste Disposal in Academic Institutions   Kaufman JA. Lewis; Chelsea MI: 1990.  p.122 
• 13a Cacchi S. Fabrizi G. Chem. Rev.  2005,  105:  2873 
• 13b Humphrey GR. Kuethe JT. Chem. Rev.  2006,  106:  2875 
• 14 A novel one-pot procedure that allows the direct synthesis of 2,3-disubstituted and 3-substituted indoles starting from readily available 2-iodobenzoic acid was also developed, see: Leogane O. Lebel HC. Angew. Chem. Int. Ed.  2008,  47:  350 

8

When the reaction was run at 66 ˚C, the yields for compounds 9 and 13 decreased to 48% and 40%, respectively. The remaining product was the corresponding tert-butyl ester.

9

Lower yields (15-40%) were obtained with other solvents, such as Et₂O, dioxane, DMSO, and CH₂Cl₂. This process is not compatible with protic solvents.

11

79% of unsubstituted Boc-aniline was obtained under these reaction conditions. However, functional groups such as methyl ether, thiomethyl ether, nitro, and halides were not tolerated, and the corresponding anilines were isolated in less than 25% yield.

12

A control experiment was run with chloroformate, NaN₃, and carboxylic acid at r.t., which showed the formation of acyl azide, suggesting that the base is not essential for the formation of this intermediate. The base is probably involved in the formation of the carbamate from the isocyanate, by trapping the proton of the nucleophile.

15

The chloroformate reagent must be stored in a refrigerator prior to use.