Abnormal and Direct para-Trifluoroacetylation of Branched Alkyl Phenyl Ketones by Magnesium-Promoted Reductive Aromatic Substitution

Abstract

Magnesium-promoted reduction of branched alkyl phenyl ketones in the presence of ethyl trifluoroacetate and chlorotri­methylsilane in N,N-dimethylformamide (DMF), followed by air oxidation, and the subsequent treatment of tetrabutylammonium fluoride brought about selective and efficient formation of the corresponding aromatic para-substituted diketones possessing a tri­fluoroacetyl group in good yields through abnormal addition toward the para positions of the aromatic ketones in good yields.

Key words

trifluoroacetylation - cross-coupling - electron transfer - magnesium - reduction

References and Notes

• 1 Moilliet JS. J. Fluorine Chem.  2001,  109:  13 
• 2 Umemoto T. Fukami S. Tomizawa G. Harasawa K. Kawada K. Tomioka K. J. Am. Chem. Soc.  1990,  112:  8563 
• 3 Singh RP. Shreeve JM. Synthesis  2002,  2561 
• 4 Hayashi M. Hashimoto S. Noyori R. Chem. Lett.  1984,  1747 
• 5 Yoneda N. Fukuhara T. Yamagishi K. Suzuki A. Chem. Lett.  1987,  1675 
• 6 Munyemana F. Frisque-Hesbain A.-M. Devos A. Ghosez L. Tetrahedron Lett.  1989,  30:  3077 
• 7 Itoh Y. Mikami K. J. Fluorine Chem.  2006,  127:  539 
• 8 Mizuta S. Shibata N. Hibino M. Nagano S. Nakamura S. Toru T. Tetrahedron  2007,  63:  8521 
• 9 Kawai H. Kusuda A. Mizuta S. Nakamura S. Funahashi Y. Masuda H. Shibata N. J. Fluorine Chem.  2009,  130:  762 
• 10 Keumi T. Shimada M. Takahashi M. Kitajima H. Chem. Lett.  1990,  783 
• 11 Mo J. Xu L. Xiao J. J. Am. Chem. Soc.  2005,  127:  751 
• 12 Creary X. J. Org. Chem.  1987,  52:  5026 
• 13 Zhu L. Miao Z. Sheng C. Yao J. Zhuang C. Zhang W. J. Fluorine Chem.  2010,  131:  800 
• 14 Kiselyov AS. Harvey RG. Tetrahedron Lett.  1995,  36:  4005 
• 15 Ruiz J. Astruc D. Gilbert L. Tetrahedron Lett.  1996,  37:  4511 
• 16 Salazar J. López SE. Rebollo O. J. Fluorine Chem.  2003,  124:  111 
• 17 López SE. Pérez Y. Restrepo J. Salazar J. Charris J. J. Fluorine Chem.  2007,  128:  566 
• 18 Prashad M. Hu B. Har D. Repic O. Blacklock TJ. Tetrahedron Lett.  2000,  41:  9957 
• 19 Ohtaka J. Sakamoto T. Kikugawa Y. Tetrahedron Lett.  2009,  50:  1681 
• 20 Gassman PG. O’Reilly NJ. J. Org. Chem.  1987,  52:  2481 
• 21 Peláez WJ. Burgos Paci MA. Argüello GA. Tetrahedron Lett.  2009,  50:  1934 
• 22 Kim J. Jang DO. Tetrahedron Lett.  2010,  51:  683 
• 23 Ohno T. Sakai M. Ishino Y. Shibata T. Maekawa H. Nishiguchi I. Org. Lett.  2001,  3:  3439 
• 24 Maekawa H. Ozaki T. Nishiguchi I. Tetrahedron Lett.  2010,  51:  796 
• 27 Mandell L. Johnston JC. Day RA. J. Org. Chem.  1978,  43:  1616 
• 28 Brieger G. Nestrick TJ. Fu TH. J. Org. Chem.  1979,  44:  1876 
• 29 Aulenta F. Hölemann A. Reißig H.-U. Eur. J. Org. Chem.  2006,  1733 
• 30 Prabhu UDG. Eapen KC. Tamboraki C. J. Org. Chem.  1984,  49:  2792 
• 31 Marsilje TH. Hedrick MP. Desharnais J. Tavassoli A. Zhang Y. Wilson IA. Benkovic SJ. Boger DL. Bioorg. Med. Chem.  2003,  11:  4487 

25

Aprotic polar solvent is required for this coupling reaction. Use of DMF as a solvent gave better yield of coupling compounds than that of NMP.

26

Only para-substituted compounds were isolated while ortho-substituted ones can not be detected by gas chromatography. The reason is not clear, but it may be attributed to steric effects between the acyl group on the benzene ring and the acetal of trifluoroacetyl group.

32

1-[4-(1-Ethoxy-2,2,2-trifluoro-1-trimethylsiloxyethyl)-phenyl]-2-methylpropan-1-one (4e); Typical Procedure for the Coupling Reaction of Isobutyrophenone and Ethyl Trifluoroacetate
A mixture of TMSCl (20 mmol), ethyl trifluoroacetate (50 mmol), magnesium turnings (15 mmol) for the Grignard reagent with no pretreatment, and anhyd DMF (10 mL) was placed in a 100 mL four-necked flask and after activation of magnesium for 30 min, a solution of isobutyrophenone (5 mmol) in anhyd DMF (20 mL) was added dropwise at r.t. The reaction mixture was stirred for 6 h. Then, 1 M HCl (50 mL) was added to the flask, and the mixture was stirred for 30 min. The reaction mixture was extracted with EtOAc. Usual workup, subsequent silica gel column chromatography gave 1-[4-(1-ethoxy-2,2,2-trifluoro-1-trimethylsiloxyethyl)phenyl]-2-methylpropan-1-one (4e) in 63% yield.
^¹H NMR (400 MHz, CDCl₃): δ = 0.26 (9 H, s), 1.23 (6 H, d, J = 8.0 Hz), 1.24 (3 H, t, J = 8.0 Hz), 3.35 (1 H, sept, J = 8.0 Hz), 3.49-3.59 (2 H, m), 7.70 (2 H, d, J = 8.3 Hz), 7.97 (2 H, d, J = 8.3 Hz) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 1.08, 14.72, 19.03, 35.54, 58.56, 97.65 (q, ^² J _CF = 31.3 Hz), 122.38 (q, ^¹ J _CF = 287.5 Hz), 127.91, 128.46, 136.97, 140.83, 204.05 ppm. ^¹9F NMR (376 MHz, CDCl₃): δ = -81.63 ppm. IR (neat): 3063, 2978, 1687, 1384, 847 cm^-¹. LRMS (EI): m/z = 362 [M⁺]. HRMS (EI): m/z calcd for C₁₇H₂₅O₃F₃Si: 362.1525; found: 362.1573.
2-Methyl-1-(4-trifluoroacetylphenyl)propan-1-one (5e); Typical Procedure for the Desilylation of Acetal 4e
To a solution of 4e (2.5 mmol) in anhyd THF (10 mL) is added dropwise 1 M TBAF (1 mL) at -15 ˚C, and the reaction mixture was stirred for 30 min. Then the reaction mixture was added to 100 mL of H₂O and ice, and stirring was continued for 30 min. The product was extracted with EtOAc. Usual workup and subsequent silica gel column chromatography gave 2-methyl-1-(4-trifluoroacetylphenyl)-propan-1-one (5e) in 62% yield. ^¹H NMR (400 MHz, CDCl₃): δ = 1.24 (6 H, d, J = 6.6 Hz), 3.56 (1 H, sept, J = 6.6 Hz), 8.08 (2 H, d, J = 8.4 Hz), 8.16 (2 H, d, J = 8.4 Hz) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 18.77, 36.05, 116.42 (q, ^¹ J _CF = 291.0 Hz), 128.68, 130.35 (q, ^³ J _CF = 1.8 Hz), 132.60, 141.29, 180.56 (q, ^² J _CF = 36.0 Hz), 203.47 ppm. ^¹9F NMR (376 MHz, CDCl₃): δ = -72.05 ppm. IR (neat): 3023, 2977, 1726, 1689, 1214, 857, 759 cm^-¹. LRMS (EI): m/z = 244 [M⁺]. HRMS (EI): m/z calcd for C₁₂H₁₁O₂F₃: 244.0711; found: m/z = 244.0696.