Improved Procedure for the Bimolecular Oxidative Amidation of Phenols Huan Liang and Marco A. Ciufolini* Department of Chemistry, The UniVersity of British Columbia, 2036 Main Mall, VancouVer, BC V6T 1Z1, Canada ciufi@chem.ubc.ca ReceiVed February 1, 2008 Trifluoroacetic acid (TFA) is an effective promoter of the bimolecular Ritter-like oxidative amidation of 4-substituted phenols induced by PhI(OAc) 2 in MeCN. This suppresses the need for fluoroalcohol cosolvents, increases the yields, and facilitates isolation/purification procedures. The oxidative amidation of phenols offers interesting op- portunities in the synthesis of nitrogenous substances. 1 This appears to be especially true of the bimolecular variant of the process, which converts 4-substituted phenols 1 into dienones 2 (Scheme 1). 2 In its original form, the reaction entails attack of the phenol with PhI(OAc) 2 (DIB) in a mixture of MeCN and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). Products 2 emerge in 40-70% yield, at least on a small scale. Research focusing on the application of this reaction to current synthetic problems has required substantial scaling-up of the original procedure. Reactions run on larger scales afford products contaminated with much polymeric matter, imposing the need for impractical, costly chromatographic purifications. Also, the cost of HFIP 3 becomes a significant issue during scale- up. The need for this cosolvent derives from the fact that the reaction of phenolic substrates with DIB proceeds poorly in an aprotic milieu such as plain MeCN, 4 whereas nucleophilic protic solvents such as alcohols or water (S-H in Scheme 2) promote clean conversion to products 9 (Z ) OMe, OH, etc.), possibly by the mechanism of Scheme 2. Pioneering work by Kita 5 showed that solvolysis of (presumed) species 8 can be avoided by operating poorly nucleophilic fluoroalcohol media. This enables capture with various nucleophiles, both in an intra- and in an intermolecular mode. 6 Fluoroalcohol solvents have since become a standard feature of many such reactions. In accord with Wood, 7 we observed that the use of the more reactive PhI(OCOCF 3 ) 2 (PIFA) in lieu of DIB eliminates the need for HFIP. However, the formation of polymeric materials remains a serious problem; furthermore, PIFA is expensive. 8 We thus sought a method to induce DIB to react in the absence of HFIP and in such a manner as to minimize polymer formation. A solution emerged as detailed herein. Protic solvents are likely to favor heterolysis of hypervalent iodine complexes, either by hydrogen bonding (cf. 3, 6) or by reversible protonation, thereby behaving as acidic promoters. Indeed, other acidic adjuvants capable of favoring dissociation of hypervalent iodine species, such as heteropolyacids or TMS- Br, 9 do induce DIB oxidations in nonprotic media. This suggested that HFIP might be replaceable with a suitable Lewis or Brønsted acid. On the other hand, polymeric byproducts are (1) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D. Synthesis 2007, 3759. (2) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005, 7, 175. (3) About $1000 for 500 g (Sigma-Aldrich). (4) This is true also for other polar, aprotic solvents such as MeNO 2 , CH 2 Cl 2 , etc. See ref 1 and literature cited therein. (5) (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987, 52, 3927. (b) Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura, T. J. Org. Chem. 1991, 56, 435. (c) Kita, Y.; Takada, T.; Tohma, H. Pure Appl. Chem. 1996, 68, 627. (d) Dohi, T.; Ito, M.; Morimoto, K.; Minamitsuji, Y.; Takenaga, N.; Kita, Y. Chem. Commun. 2007, 4152. (6) Oxygen nucleophiles; cf. ref 5 as well as (a) Rodrı ´guez, S.; Wipf, P. Synthesis 2004, 2767. (b) Wipf, P.; Jung, J.-K. Chem. ReV. 1999, 99, 1469. (c) Li, C.; Danishefsky, S. J. Tetrahedron Lett. 2006, 47, 385. Nitrogen nucleophiles: cf. refs 1, 2 as well as (d) Scheffler, G.; Seike, H.; Sorensen, E. J. Angew. Chem., Int. Ed. 2000, 39, 4593. (e) Mizutani, H.; Takayama, J.; Soeda, Y.; Honda, T. Tetrahedron Lett. 2002, 43, 2411. (f) Braun, N. A.; Ousmer, M.; Bray, J. D.; Bouchu, D.; Peters, K.; Peters, E.-M.; Ciufolini, M. A. J. Org. Chem. 2000, 65, 4397. (g) Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123, 7534. (h) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Angew. Chem., Int. Ed. 2004, 43, 4336. Carbon nucleophiles: leading reviews of the massive volume of literature in this area: (i) Arisawa, M.; Toma, H.; Kita, Y. Yakugaku Zasshi 2000, 120, 1061. (j) Tohma, H.; Kita, Y. Top. Curr. Chem. 2003, 224. Recent developments: (k) Berard, D.; Jean, A.; Canesi, S. Tetrahedron Lett. 2007, 48, 8238. (l) Jean, A.; Cantat, J.; Berard, D.; Bouchu, D.; Canesi, S. Org. Lett. 2007, 9, 2553. (7) Drutu, I.; Njardarson, J. T.; Wood, J. L. Org. Lett. 2002, 4, 493. (8) Gram per gram, PIFA is about 3 times as costly as DIB, and more than 4 times as expensive on a molar basis. SCHEME 1. Bimolecular Oxidative Amidation of Phenols SCHEME 2. Possible Oxidative Amidation Mechanism 10.1021/jo800267q CCC: $40.75  2008 American Chemical Society J. Org. Chem. 2008, 73, 4299–4301 4299 Published on Web 05/01/2008