Metal-Free Amidation of Acids with Formamides and T3P^®

This paper is dedicated to the memory of the inspirational late Professor Vincenzo Caia.

Abstract

A new, simple and metal-free method for the direct formation of dialkylamides from carboxylic acids employing N,N-dialkylform­amides as amine source is described. The one-pot reaction is promoted by propylphosphonic anhydride (T3P^®) in the presence of 0.5 equivalents of HCl.

Key words

formamides - propylphosphonic anhydride - amidation - carboxylic acids - metal-free

• References

• 1 For a review on amide bond formation, see: Valeur E, Bradley M. Chem. Soc. Rev. 2009; 38: 606
• 2 Ding S, Jiao N. Angew. Chem. Int. Ed. 2012; 51: 9226
• 3a SOCl₂: Kumagai T, Anki T, Ebi T, Konishi A, Matsumoto K, Kurata H, Kubo T, Katsumoto K, Kitamura C, Kawase T. Tetrahedron 2010; 66: 8968
• 3b P₂O₅: Schindlbauer H. Monatsh. Chem. 1968; 99: 1799
• 3c P₂O₅: Ciszek JW, Keane ZK, Cheng L, Stewart MP, Yu LH, Natelson D, Tour JM. J. Am. Chem. Soc. 2006; 128: 3179
• 3d 1,1-Carbonyldimidazole with N,N-dimethylacetamide: Aavula SK, Chikkulapally A, Hanumanthappa N, Jyothi I, Kumar CH. V, Manjunatha SG, Sythana SK. J. Chem. Res. 2013; 155
• 4a Santhosh Kumar P, Sathish Kumar G, Arun Kumar R, Veera Reddy N, Rajender Reddy K. Eur. J. Org. Chem. 2013; 1218
• 4b Priyadarshini S, Amal Joseph PJ, Lakshmi Kantam M. RSC Adv. 2013; 3: 18283
• 4c Xie Y.-X, Song R.-J, Yang X.-H, Xiang J.-N, Li J.-H. Eur. J. Org. Chem. 2013; 5737
• 4d Liu HQ, Liu J, Zhang Y.-H, Shao C.-D, Yu J.-X. Chin. Chem. Lett. 2015; 26: 11
• 4e From cinnamic acids: Yan H, Yang H, Lu L, Liu D, Rong G, Mao J. Tetrahedron 2013; 69: 7258
• 4f From cinnamic acids: Li H, Pan C, Cheng Y, Zhu C. Tetrahedron Lett. 2013; 54: 6679
• 4g From α-oxocarboxylic acids: Wang H, Guo L.-N, Duan X.-H. Org. Biomol. Chem. 2013; 11: 4573
• 4h From α-oxocarboxylic acids: Li D, Wang M, Liu J, Zhao Q, Wang L. Chem. Commun. 2013; 49: 3640
• 4i From aldehydes: Liu Z, Zhang J, Chen S, Shi E, Xu Y, Wan X. Angew. Chem. Int. Ed. 2012; 51: 3231
• 4j From alcohols: Xu K, Hu Y, Zhang S, Zha Z, Wang Z. Chem. Eur. J. 2012; 18: 9793
• 5a Dunetz JR, Xiang Y, Baldwin A, Ringling J. Org. Lett. 2011; 13: 5048
• 5b Millbanks C In e-EROS Encyclopedia of Reagents for Organic Synthesis [Online]. Wiley & Sons; New York: 2001
• 5c Koch P, Vedder C, Schaffer T. Chim. Oggi 2008; 26: 6

For additional applications of T3P^® see:
• 5d Review: Augustine JK, Vairaperumal V, Narasimhan S, Alagarsamy P, Radharkrishnan A. Tetrahedron 2009; 65: 9989
• 5e Review: Vishwanatha BT. M, Panguluri NR, Sureshbabu VV. Synthesis 2013; 45: 1569
• 5f Augustine JK, Bombrun A, Mandal AB, Alagarsamy P, Atta RN, Selvam P. Synthesis 2011; 1477

T3P^® is also used as dehydrating agent to form nitriles. For representative examples, see:
• 6a Herold P, Mah R, Tschinke V, Stajanovic A, Behnke D, Marti C, Stutz S, Jelakovic S. EP1958634A2, 2008
• 6b Meudt A, Scherer S, Nerdinger S. WO2005/070879A1, 2005
• 6c Augustine JK, Atta RN, Ramappa BK, Boodappa C. Synlett 2009; 3378
• 6d The exact role of Et₄NCl is unclear; however, it can be postulated that it acts as a weak acid that could enhance DMF cleavage, therefore promoting the reaction.
• 7 Pure TfOH, TsOH, and TFA were employed; for HBr and H₂SO₄, aqueous concentrated solutions were used.
• 8 An efficient method for the synthesis of sterically hindered secondary amides has been reported, see: Schäfer G, Matthey C, Bode JW. Angew. Chem. Int. Ed. 2012; 51: 9173

N,N-Diethyl-2-phenylacetamide (DEPA):
• 9a Martensson O, Nilsson E. Acta Chem. Scand. 1960; 14: 1129
• 9b Hougard J.-M, Pennetier C. US2007/122437 A1, 2007
• 9c Von Deyn W, Bastiaans HM. M, Pohlman M, Rack M, Baumann E, Puhl M, Hofmann M, Tedeschi L, Kordes M, Koradin C, Anspaugh DD, Culbertson DL, Cotter HV. T, Oloumi-Sadeghi H. (BASF Aktiengesellschaft) WO2006/56433A2, 2006

N,N-Diethylbenzamide (DEB):
• 10a Jang DO, Park DJ, Kim J. Tetrahedron Lett. 1999; 40: 5323
• 10b Gruenewald H.-W, Axt A. US2008/319015 A1, 2008

N,N-Diethyl-3-methylbenzamide (DEET):
• 11a Fradin MS, Day JF. N. Engl. J. Med. 2002; 347: 13
• 11b http://www.deet.com/.

N,N-Diethylnicotinamide (Coramine):
• 12a Fricker K. DE653873C, 1934
• 12b Martindale: The Extra Pharmacopoeia . 30th ed.; Reynolds JE. F. The Pharmaceutical Press; London: 1993: 1229
• 13 http://www.stepan.com/products/Surfactants/STEPOSOL%C2%AE/STEPOSOL%C2%AE-MET-10U.aspx; accessed March 31, 2016.
• 14 Manning PT, Misko TP. WO2005/025620A2, 2005
• 15a Chang P. Drugs Future 1989; 14: 138
• 15b Baker BR, Ashton WT. J. Med. Chem. 1973; 16: 209 ; and references cited therein
• 16 Intermediates 1a (n = 1–3) have been observed (but not isolated) by LC/MS and the structure was assigned on the basis of m/z values.
• 17 Muzart J. Tetrahedron 2009; 65: 8313
• 18a Carbon monoxide was observed in the off-gas during the course of the reaction by analysis with a Dräger Pac^® 5500 gas detector.
• 18b The formation of this species was not proven, despite several measurements by ³¹P NMR spectroscopy of control reaction mixtures.
• 19 Baba H, Moriyama K, Togo H. Synlett 2012; 23: 1175
• 20a Keck GE, McLaws MD, Wager TT. Tetrahedron 2000; 56: 9875
• 20b Allais A, Meier J, Mathieu J, Nomine G, Peterfalvi M, Deraedt R, Chifflot L, Benzoni J, Fournex R. Eur. J. Med. Chem. 1975; 10: 187
• 21 Schiemenz GP, Stein G. Tetrahedron 1970; 26: 2007
• 22 Houlihan WJ, Gogerty JH, Ryan EA, Schmitt G. J. Med. Chem. 1985; 28: 28
• 23 Yamada S, Morita C. Chem. Lett. 2001; 1034
• 24a Zanatta N, Alves SH, Coelho HS, Borchhardt DM, Machado P, Flores KM, da Silva FM, Spader TB, Santurio JM, Bonacorso HG, Martins MA. P. Bioorg. Med. Chem. 2007; 15: 1947
• 24b Kinoshita T, Icbinari D, Sinya J. J. Heterocycl. Chem. 1996; 33: 1313 ; (melting point)
• 25 Tang D.-TD, Collins KD, Ernst JB, Glorius F. Angew. Chem. Int. Ed. 2014; 53: 1809
• 26 Sunada Y, Kawakami H, Imaoka T, Motoyama Y, Nagashima H. Angew. Chem. Int. Ed. 2009; 48: 9511
• 27 Xie P, Xia C, Huang H. Org. Lett. 2013; 15: 3370
• 28 http://www.sigmaaldrich.com/spectra/fnmr/FNMR009877.PDF; accessed March 31, 2016.
• 29 Luo Q.-L, Lv L, Li Y, Tan J.-P, Nan W, Hui Q. Eur. J. Org. Chem. 2011; 6919
• 30 http://www.sigmaaldrich.com/spectra/fnmr/FNMR010347.PDF; accessed March 31, 2016.
• 31 Yun JI, Kim HR, Kim SK, Kim D, Lee J. Tetrahedron 2012; 68: 1177