Discussion Addendum for: Trifluoromethylation at the -Position of, -Unsaturated Ketones: 4-Phenyl-3-Trifluoromethyl-2-Butanone

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1 DI: /orgsyn Discussion Addendum for: Trifluoromethylation at the -Position of, -Unsaturated Ketones: 4-Phenyl-3-Trifluoromethyl-2-Butanone C 3 Ph hcl(pph 3 ) 3 C 3 I C 3 Ph T C 3 Prepared by Kazuyuki Sato, Atsushi Tarui, Masaaki mote, Itsumaro Kumadaki and Akira Ando.* 1 riginal article: Sato, K.; mote, M.; Ando, A.; Kumadaki, I. rg. Synth. 2006, 83, 177. Trifluoromethylated (C 3 ) compounds are one of the most important classes of fluorine compounds, but the reactions for introducing a C 3 group at the -position of carbonyl compounds were rarely reported until recently. The reductive -trifluoromethylation of, -unsaturated ketones using the combination of hcl(pph 3 ) 3 -, based on the eformatsky-onda reaction of non-fluorinated -bromoacetate, became one of the breakthrough reactions in this field. The birth and advances of this -trifluoromethylation and related reactions will be summarized here. -luoroalkylation Using eformatsky-onda eaction Condition ormerly, we applied the so-called eformatsky-onda reaction, using hcl(pph 3 ) 3 -, 2 to the reaction of 2-cyclohexen-1-one with ethyl bromodifluoroacetate (BrC 2 CEt), and found that the reaction afforded either the -(ethoxycarbonyl)difluoromethyl ketone or the usual eformatsky-type product selectively only by changing the solvent (igure 1). 3 The former was a new type of product; thus, we tried to expand this reaction to the synthesis of -fluoroalkyl compounds, especially -C 3 compounds. After many efforts, we succeeded in the synthesis of -C 3 and other fluoroalkyl ( f ) ketones from, -unsaturated ketones, 4,5 and showed through the use of -d 10 that a h- complex played an important role (igure 2). 5 urthermore, based on this mechanism, we developed a new 374 rg. Synth. 2012, 89, Published on the Web 2/20/ rganic Syntheses, Inc.

2 methodology for synthesis of - f ketones from silyl enol ethers of ketones in the absence of, although this reaction required high temperature. 6 The addition of allowed the reaction to proceed at lower temperature, improved the yield 7, and extended its application to various fluoroalkyl halides (igure 3). 8 ormation of the h(i)et complex appears to promte the oxidative addition of C 3 I at lower temperature. Br C 2 CEt hcl(pph 3 ) 3 0 C in T in C 3 C C 2 CEt C 2 CEt igure 1. Solvent effect of h-catalyzed reaction of BrC 2 CEt with 2- cyclohexen-1-one. f f h(i)l n ' hcl(pph 3 ) 3 h(iii)l n f f ' f = C 3, C 4 9, C 2 CEt, etc. ' (or D) ' (or D) (or D) ' ' L n h(i) (or D) L n h(i) f ethylene L n h(i) C 2 C 3 (or Et-d 5 ) (or -d 10 ) rg. Synth. 2012, 89, ZnEt (or Et-d 5 ) igure 2. h-catalyzed reductive -fluoroalkylation and its mechanism. Y TMS ' TMS ' f f hcl(pph 3 ) 3 1,4-dioxane reflux hcl(pph 3 ) 3 DME, 0 C Y f f ' f = C 3, C 4 9, C 2 C 6 5, etc. ' f = C 3, C 4 9, C 2 C 6 5, etc. Y = alkyl, alkoxy, amino, sulfanyl igure 3. Synthesis of various -fluoroalkylated carbonyl compounds.

3 The eformatsky-onda eaction of BrC 2 CEt with Imines This eformatsky-onda reaction of BrC 2 CEt has been applied to imines. Interestingly, we succeeded in selective syntheses of difluoro- lactams and 3-amino-2,2-difluorocarboxylic esters (igure 4), depending upon the presence or absence of MgS MgS serves as a convenient source of 2. Addition of 2 also provided the ester, but the yield was lower. urthermore, highly stereoselective syntheses of difluoro- -lactams have also been accomplished using chiral auxiliaries. 10 hcl(pph 3 ) 3 Bn Bn Br C 2 CEt T, 0 C hcl(pph 3 ) 3 C 2 Cl 2, 0 C MgS Bn C 2 CEt Ph Br C 2 CEt hcl(pph 3 ) 3 T, 10 C Ph d.e. > 99% PMB PMB hcl(pph 3 ) 3 Br C2C T, 10 C e.e % igure 4. eformatsky-onda reaction of BrC 2 CEt with imines. eductive eformatsky-onda eaction The mechanistic studies of -fluoroalkylation of, -unsaturated ketone led to another new discovery. The most recent advance has been a synthesis of 1,3-diketones by reductive -acylation of, -unsaturated ketones under the eformatsky-onda reaction conditions that easily generate a h- complex (igure 5). 11, -Unsaturated esters can be utilized with various electrophiles besides acid chlorides to give reductive substitution products such as aldol-type and Mannich-type products rg. Synth. 2012, 89,

4 ' " Cl hcl(pph 3 ) 3 T, 0 C ' " Electrophile ' hcl(pph 3 ) 3 T, 0 C E ' Electrophile = acid chlorides, acid anhydrides, aldehydes, ketones, imines, etc. igure 5. eductive eformatsky-onda reaction with acid chlorides and various electrophiles. 1. aculty of Pharmaceutical Sciences, Setsunan University, 45-1, agaotoge-cho, irakata, saka , Japan. aando@pharm.setsunan.ac.jp 2. (a) Kanai, K.; Wakabayashi,.; onda, T. rg. Lett. 2000, 2, (b) onda, T.; Wakabayashi,.; Kanai, K. Chem. Pharm. Bull. 2002, 50, (c) Kanai, K.; Wakabayashi,.; onda, T. eterocycles 2002, 58, Sato, K.; Tarui, A.; Kita, T.; Ishida, Y.; Tamura,.; mote, M.; Ando, A.; Kumadaki, I. Tetrahedron Lett. 2004, 45, Sato, K.; mote, M.; Ando, A.; Kumadaki, I. rg. Lett. 2004, 6, Sato, K.; Ishida, Y.; Murata, E.; ida, Y.; Mori, Y.; kawa, M.; Iwase, K.; Tarui, A.; mote, M.; Kumadaki, I.; Ando, A. Tetrahedron 2007, 63, Sato, K.; igashinagata, M.; Yuki, T.; Tarui, A.; mote, M.; Kumadaki, I.; Ando, A. J. luorine Chem. 2008, 129, (a) Sato, K.; Yuki, T.; Tarui, A.; mote, M.; Kumadaki, I.; Ando, A. Tetrahedron Lett. 2008, 49, (b) Sato, K.; Yuki, T.; Yamaguchi,.; amano, T.; Tarui, A.; mote, M.; Kumadaki, I.; Ando, A. J. rg. Chem. 2009, 74, Sato, K.; Yamazoe, S.; Akashi, Y.; amano, T.; Miyamoto, A.; Sugiyama, S.; Tarui, A.; mote, M.; Kumadaki, I.; Ando, A. J. luorine Chem. 2010, 131, Sato, K.; Tarui, A.; Matsuda, S.; mote, M.; Ando, A.; Kumadaki, I. Tetrahedron Lett. 2005, 46, rg. Synth. 2012, 89,

5 10. (a) Tarui, A.; Kondo, K.; Taira,.; Sato, K.; mote, M.; Kumadaki, I.; Ando, A. eterocycles 2007, 73, (b) Tarui, A.; zaki, D.; akajima,.; Yokota, Y.; Sokeirik, Y. S.; Sato, K.; mote, M.; Kumadaki, I.; Ando, A. Tetrahedron Lett. 2008, 49, Sato, K.; Yamazoe, S.; Yamamoto,.; hata, S.; Tarui, A.; mote, M.; Kumadaki, I.; Ando, A. rg. Lett. 2008, 10, Sato, K.; Isoda, M.; hata, S.; Morita, S.; Tarui, A.; mote, M.; Kumadaki, I.; Ando, A. Adv. Synth. Catal. 2011, Kazuyuki Sato studied organofluorine chemistry at aculty of Pharmaceutical Sciences, Setsunan University. e received Ph.D. degree from Setsunan University on the study of synthesis of fluorine compounds using cupper-mediated reactions of ethyl bromodifluoroacetate under the guidance of Prof. Itsumaro Kumadaki in Since 1999, he is working as a research associate at Setsunan University. is main interest is rhodium-catalyzed synthesis of fluorine compounds. e received two awards from the Pharmaceutical Society of Japan and the Society of Synthetic rganic Chemistry, Japan. Atsushi Tarui was born in 1981 in Wakayama (Japan). e received Ph.D. degree from Setsunan University on the research of synthesis of, -difluoro- -lactam using rhodiumcatalyzed reaction of bromodifluoroacetate with imines and related reactions under supervision of Prof. Akira Ando in Since 2006, he is working there as a research associate under the guidance of Prof. A. Ando. is research interest is synthesis of fluorinated -lactams and -amino acids. 378 rg. Synth. 2012, 89,

6 Masaaki mote received his Ph.D. from aculty of Pharmaceutical Sciences, Setsunan University under the supervision of Prof. Itsumaro Kumadaki in 1997, and he became research associate of Setsunan University. In 2004, he spent a year as a postdoctoral research associate in State University of ew York (Albany, ew York) under the supervision of Prof. John T. Welch. In 2010 he promoted to associate professor of Setsunan University. is research interest is syntheses of fluorous and partially fluorinated chiral ligands useful for enantioselective synthesis of non-fluorinated compounds. Itsumaro Kumadaki received Ph.D. degree from Kyushu University on the study of reaction of heteroaromatic amine - oxides under the supervision of Prof. Masatomo amana in e joined Prof. Yoshiro Kobayashi of Tokyo College of Pharmacy in 1967 and started the studies on organic fluorine chemistry. e moved to Setsunan University in 1983 as a professor of aculty of Pharmaceutical Sciences, and retired in is interests are still new reactions for synthesis of organofluorine compounds, new reactions of organofluorine compounds, and chemical and biological effects of fluorine substituents on organic compounds. Akira Ando was born in 1951 in Tokyo (Japan), and obtained Ph.D. degree from Tokyo College of Pharmacy on the study of the synthesis and reactions of valence-bond isomers of tetrakis(trifluoromethyl)pyrroles under supervision of Prof. Yoshiro Kobayashi in After working as a research assistant at Tokyo College of Pharmaceutical Sciences and a research fellow at Sagami Chemical esearch Center, he joined Prof. Kumadaki s group of fluorine chemistry at Setsunan University in 1985, and since 2004 he is a full professor there. is interest is to develop new methodologies for synthesis of organofluorine compounds. rg. Synth. 2012, 89,