The use of trifluoroacetaldehyde ethyl hemiacetal or hydrate in a simple and practical regioselective synthesis of β-hydroxy-β-trifluoromethyl ketones from enamines and imines

Article abstract of DOI:10.1021/jo026697j

The reaction of trifluoroacetaldehyde ethyl hemiacetal or hydrate with an equimolar amount of enamines, derived from various methyl ketones, smoothly proceeded to give the corresponding β-hydroxy-β-trifluoromethyl ketones in high yields. An equimolar amou

Full text of DOI:10.1021/jo026697j

Th e Use of Tr iflu or oa ceta ld eh yd e Eth yl Hem ia ceta l or Hyd r a te in
a Sim p le a n d P r a ctica l Regioselective Syn th esis of
â-Hyd r oxy-â-tr iflu or om eth yl Keton es fr om En a m in es a n d Im in es
Kazumasa Funabiki,* Kei Matsunaga, Miwa Nojiri, Wataru Hashimoto, Hitoshi Yamamoto,
Katsuyoshi Shibata, and Masaki Matsui*
Department of Materials Science and Technology, Faculty of Engineering, Gifu University, 1-1 Yanagido,
Gifu 501-1193, J apan
kfunabik@apchem.gifu-u.ac.jp
Received November 12, 2002
The reaction of trifluoroacetaldehyde ethyl hemiacetal or hydrate with an equimolar amount of
enamines, derived from various methyl ketones, smoothly proceeded to give the corresponding
â-hydroxy-â-trifluoromethyl ketones in high yields. An equimolar amount of imines derived from
various methyl ketones with aliphatic, aromatic, and heteroaromatic substituents also readily
reacted with trifluoroacetaldehyde ethyl hemiacetal or hydrate to afford the corresponding
â-hydroxy-â-trifluoromethyl ketones in good to excellent yields. Difluoroacetaldehyde ethyl hemi-
acetal as well as pentafluoropropionaldehyde also participated in the reaction, affording good yields
of the corresponding â-hydroxy-â-difluoromethyl or â-pentafluoropropyl ketones.
4
,5,6
In tr od u ction
blocks such as trifluoroacetaldehyde (CF
3
CHO),
its
derivatives,7 and R-trifluoromethyl ketones as the
,8
9
Much attention has been addressed to the effective
introduction of fluorine and the trifluoromethyl group in
both academia and industry, since the replacement of
hydrogen by the fluorine atom sometimes brings about
a dramatic change in the physical properties and bioac-
tivity of the compounds arising due to the special proper-
ties of the fluorine atom, such as the highest electrone-
gativity of fluorine and high carbon-fluorine bond energy.1
R-Trifluoromethylated alcohols are some of the most
valuable compounds in organofluorine synthesis, and
several types of syntheses of such compounds have been
(
4) For the reaction with boron enolates, see: (a) Iseki, K.; Koba-
yashi, Y. Chem. Pharm. Bull. 1996, 44, 2003. (b) Iseki, K.; Oishi, S.;
Kobayashi, Y. Tetrahedron 1996, 52, 71. (c) Makino, Y.; Iseki, K. Oishi,
S.; Hirano, T.; Kobayashi, Y. Tetrahedron Lett. 1995, 36, 6527. For
the reaction with a lithium enolate, see: (d) Qian, C.-P.; Liu, Y.-Z.;
Tomooka, K.; Nakai, T. Organic Synthesis 1999, 76, 151. (e) Qian, C.
P.; Nakai, T.; Dixon, D. A.; Smart, B. E. J . Am. Chem. Soc. 1990, 112,
4602. (f) Patel, D. V.; Rielley-Gauvin, K.; Ryono, D. E.; Free, C. A.;
Smith, S. A.; Petrillo, E. W. J . Med. Chem. 1993, 36, 2413. (g) Patel,
D. V.; Rielley-Gauvin, K.; Ryono, D. E. Tetrahedron Lett. 1988, 29,
4
665. (h) Seebach, D.; J uaristi, E.; Miller, D. D.; Schickli, C.; Weber,
T. Helv. Chem. Acta 1987, 70, 237. (i) Yamazaki, T.; Takita, K.;
Ishikawa, N. Nippon Kagaku Kaishi 1985, 2131. (j) Tius, M. A.;
Savariar, S. Tetrahedron Lett. 1985, 26, 3635. For the reaction with a
zinc enolate, see: (k) Watanabe, S.; Sakai, Y.; Kitazume, T.; Yamazaki,
T. J . Fluorine Chem. 1994, 68, 59. (l) Kitazume, T. Ultrasonics 1990,
2
developed over the last two decades because they can
serve as the useful core system of liquid crystals imparted
by a trifluoromethyl group.3 Most syntheses of these
2
8, 322. For the reaction with a nickel enolate, see: (m) Soloshonok,
compounds utilize the R-trifluoromethylated building
V. A.; Kukhar, V. P.; Galushko, S. V.; Svistunova, N. Y.; Avilov, D. V.;
Kuz’mina, N. A,; Raevski, N. I.; Struchkov, Y. T.; Pysarevsky, A. P.;
Belokon, Y. N. J . Chem. Soc., Perkin Trans. 1 1993, 3143. For the
reaction with ketene silyl acetal, see: (n) Mikami, K.; Yajima, T.;
Takasaki, T.; Matsukawa, S.; Terada, M.; Uchimaru, T.; Maruta, M.
Tetrahedron 1996, 52, 85. For the reaction with enol silyl ether, see:
(o) Ishii, A.; Kojima, J .; Mikami, K. Org. Lett. 1999, 1, 2013. For the
reaction with vinyl ether, see: (p) Ishii, K.; Mikami, K. J . Fluorine
Chem. 1999, 97, 51. For the reaction with enamines, see: (q) Molines,
H.; Wakselman, C. J . Fluorine Chem. 1980, 16, 97.
(5) For the reaction with sodium cyanide, see: (a) Kitazume, T. J .
Fluorine Chem. 1987, 35, 287. For the reaction with active methylene
compounds, see: (b) Hager, C.; Miethchen, R.; Reinke, H. J . Fluorine
Chem. 2000, 104, 135. (c) Uneyama, K.; Itano, N. Denki Kagaku 1994,
62, 1151. (d) Cen, W.; Dai, X.; Shen, Y. J . Fluorine Chem. 1993, 65,
49. (e) Ogoshi, H.; Mizushima, H.; Toi, H.; Aoyama, Y. J . Org. Chem.
1986, 51, 2366. For the reaction with lithium or zinc reagents, see: (f)
Tomoyasu, T.; Tomooka, K.; Nakai, T. Synlett 1998, 1147. (g) Obrecht,
D.; Gerber, F.; Sprenger, D.; Masqelin, T. F. Helv. Chem. Acta 1997,
80, 531. (h) Kitazume, T.; Lin, J . T.; Yamazaki, T. J . Fluorine Chem.
1989, 43, 177. (i) Hanzawa, Y.; Ishizawa, S.; Kobayashi, Y. Chem.
Pharm. Bull. 1988, 36, 4209. (j) Ishikawa, N.; Koh, M. G.; Kitazume,
T. J . Fluorine Chem. 1984, 24, 419. For the reaction with vinyl
aluminum reagents, see: (k) Ramachandran, P. V.; Reddy, M. V. R.;
Rudd, M. T.; De Alaniz, J . R. Tetrahedron Lett. 1998, 39, 8791. (l)
Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T. Chem. Commun.
1999, 1979.
(1) (a) Welch, J . T., Eswarakrishnan, S., Eds. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991. (b) Filler, R., Kobayashi, Y.,
Yagupolskii, L. M., Eds. Organofluorine Compounds in Medicinal
Chemistry and Biomedical Applications; Elsevier: Amsterdam, 1993.
(
c) Banks, R. E., Smarts, B. E., Tatlow, J . C., Eds. Organofluorine
Chemistry: Principles and Commercial Applications; Plenum: New
York, 1994. (d) Ojima, I., McCarthy, J . R., Welch. J . T., Eds. Biomedical
Frontiers of Fluorine Chemistry; American Chemical Society: Wash-
ington, DC, 1996. (e) Hiyama, T., Ed. Organofluorine Compounds:
Chemistry and Applications; Springer-Verlag: Berlin, 2000.
(2) For recent reviews, see: (a) Ramachandran, P. V.; Brown, H. C.
In Asymmetric Fluoroorganic Chemistry; Ramachandran, P. V., Ed.;
American Chemical Society: Washington, DC, 2000; p 22. (b) Ishii,
A.; Mikami, K. In ref 2a, p 60. (c) Abouabdellah, A.; Begue, J . P.;
Bonnet-Delpon, D.; Kornilov, A.; Rodrigues, I.; Nga, T. T. T. In ref 2a,
p 84. (d) Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T. In ref 2a,
p 117. (e) Hiyama, T.; Kusumoto, T.; Matsutani, H. In ref 2a, p 226.
(
f) Mikami, K. In ref 2a, p 255. (g) Iseki, K. In Enantiocontrolled
Synthesis of Fluoro-organic Compounds; Soloshonok, V. A., Ed.; J ohn
Wiley & Sons: Chichester, 1999; p 33. (h) Bravo, P.; Zanda, M. In ref
2
g, p 107. (i) Bravo, P.; Zanda, M. In ref 2g, p 105. (j) Katagiri, T. In
ref 2g, p 161. (k) Ramachandran, P. V.; Brown H. C. In ref 2g, p 179.
l) Soloshonok, V. A. In ref 2g, p 229. (m) Fujisawa, T.; Shimizu, M. In
ref 2g, p 307. (n) Mikami, K.; Yajima, T. In ref 2g, p 557.
3) For recent reviews, see: ref 2e,f,n.
(
(
1
0.1021/jo026697j CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/12/2003
J . Org. Chem. 2003, 68, 2853-2860
2853

Funabiki et al.
starting substrates. Among them, CF
3
CHO is especially
with enamines or imines, demonstrating an expedient
access to â-trifluoromethylated aldol units. The present
reaction will provide a new, promising, effective, and
practical synthetic method for the â-hydroxy-â-trifluo-
romethyl ketones because it has some significant advan-
tages such as no need of an excess amount of strong acid
the most attractive compound like fluorine-free aldehydes
for the construction of â-trifluoromethylated aldol units.
However, it normally exists as a hydrate or hemiacetal
form due to the strong electron-withdrawing properties
of the trifluoromethyl group.10 Therefore, before the use
of CF
protocols, which rely on not only using a large amount
of concentrated H SO or P but also utilizing a high
reaction temperature. Furthermore, the boiling point
-18 °C) as well as the high hygroscopicity of CF CHO
3
CHO, the aldehyde must be generated by the early
for the generation of CF
3
CHO, the use of only an
equimolar amount of CF CHO ethyl hemiacetal or hy-
3
2
4
1
2
O
5
drate, a high generality of the reaction, high yields of the
products, and no serious handling problems.
1
13,14
(
3
seems to cause handling problems at room temperature.
Although there are some reports about the efficient
Resu lts a n d Discu ssion
generation of CF
3
CHO and the reaction with various
Rea ction w ith En a m in es. The treatment of hemi-
acetal 1a with an equimolar amount of enamine 2a ,
prepared between morpholine and acetophenone, at room
temperature in hexane for 1 h gave the â-hydroxy-â-
trifluoromethyl ketone 3a in 88% yield (Table 1, entry
1).
nucleophiles to give functionalized R-trifluoromethylated
alcohols,12 it is highly desirable to develop a more
environmentally friendly, convenient, and efficient meth-
odology for the generation of CF
carbon-carbon bond forming reactions. Herein, we report
a novel reaction of CF CHO ethyl hemiacetal or hydrate
3
CHO and successive
3
3
The reactions of the CF CHO ethyl hemiacetal 1a or
hydrate 1b with enamines 2 under various conditions are
summarized in Table 1. Other solvents, such as 1,2-
dichloroethane, tetrahydrofuran (THF), toluene, and
acetonitrile, were also used for the reaction (entries 2-5).
Noteworthy is that the presence of a small amount of
water did not have a significant influence on the yield of
the product (entry 6). The use of the enamine 2b having
a piperazino group instead of the morpholino one gave a
similar yield of 3a (entry 7). Other aromatic- or het-
eroaromatic-substituted enamines 2c,d ,e,g,h partici-
pated nicely in the reaction to afford the corresponding
â-hydroxy-â-trifluoromethyl ketone 3b,c,d ,e,g in good
yields, respectively (entries 8, 9, 10, 13, and 14). Enamine
(
6) For the Morita-Baylis-Hillman Reaction, see: (a) Reddy, M.
V. R.; Rudd, M. T.; Ramachandran, P. V. J . Org. Chem. 2002, 67, 5382.
For the Friedel-Crafts reaction, see: (b) Shermolovich, Y. G.; Yemets,
S. V. J . Fluorine Chem. 2000, 101, 111. For the asymmetric Friedel-
Crafts reaction, see: (c) Ishii, A.; Soloshonok, A. V.; Mikami, K. J . Org.
Chem. 2000, 65, 1597. For the ene reaction, see: (d) Hayashi, E.;
Takahashi, Y.; Itoh, H.; Yoneda, N. Bull. Chem. Soc. J pn. 1994, 67,
040. (e) Ogawa, K.; Nagai, T.; Nonomura, M.; Takagi, T.; Koyama,
M.; Ando, A.; Miki, T.; Kumadaki, I. Chem. Pharm. Bull. 1991, 39,
707. (f) Pautrat, R.; Marteau, J .; Cheritat, R. Bull. Soc. Chim. Fr.
968, 1182. For the asymmetric ene reaction with alkenes, see ref 4x,
and with vinyl sulfides, see: (g) Mikami, K. Yajima, T.; Siree, N.;
Terada, M.; Suzuki, Y.; Kobayashi, I. Synlett 1996, 837. For the hetero-
Diels-Alder reaction, see: (h) Leveque, L.; Le Blanc, M.; Pastor, R.
Tetrahedron Lett. 1997, 38, 6001. (i) J eong, I. H.; Kim, Y. S.; Cho, K.
Y.; Kim, K. J . Bull. Korean Chem. Soc. 1991, 12, 125. For the
asymmetric hetero-Diels-Alder reaction, see: (j) Mikami, K.; Yajima,
T.; Matsukawa, S.; Terada, M. 72nd National Meeting of the Chemical
Society of J apan, Tokyo, March 1997, Abstr. No. 4H332.
3
1
1
2
f with a nitro substituent on the phenyl group did not
react smoothly, providing only 13% of the product 3e, due
to the low solubility of the enamine 2f (entry 11). The
yield of 3e could be improved by carrying out the reaction
in toluene (entry 12). The reaction of the hemiacetal 1a
with the mixture of aliphatic enamines, such as 2i and
(7) For trifluoroacetaldehyde hemiacetal or hydrate, see: (a) Fern a´ n-
dez, R.; Mart ´ı n-Zamora, E.; Pareja, C.; Alcarazo, M.; Mart ´ı n, J .;
Lassaletta, J . M. Synlett 2001, 1158. (b) Gong, Y.; Kato, K.; Kimoto,
H. J . Heterocycl. Chem. 2001, 38, 25. (c) Shirai, K.; Onomura, O.; Maki,
T.; Matsumura, Y. Tetrahedron Lett. 2000, 41, 5873. (d) Kuwano, R.;
Miyazaki, H.; Ito, Y. J . Organomet. Chem. 2000, 603, 18. (e) Gong, Y.;
Kato, K.; Kimoto, H. Bull. Chem. Soc. J pn. 2000, 73, 249. (f) Loh, T.-
P.; Li, X.-R. Tetrahedron 1999, 55, 5611. (g) Sakumo, K.; Kuki, N.;
Kuno, T.; Takagi, T.; Koyama, M.; Ando, A.; Kumadaki, I. J . Fluorine
Chem. 1999, 93, 165. (h) Gong, Y. F.; Kato, K.; Kimoto, H. Synlett 1999,
403. (i) Loh, T.-P.; Xu, K. C.; Ho, D. S. C.; Sim, K. Y. Synlett 1998,
69. (j) Omote, M.; Ando, A.; Takagi, T.; Koyama, M.; Kumadaki, I.
Tetrahedron 1996, 52, 13961. (k) Ishihara, T.; Hayashi, H.; Yamanaka,
H. Tetrahedron Lett. 1993, 34, 5777. (l) Kubota, T.; Iijima, M.; Tanaka,
T. Tetrahedron Lett. 1992, 33, 1351. (m) Guy, A.; Lobgeois, M. J .
Fluorine Chem. 1986, 32, 361.
4
-(3-methybut-1-en-2-yl)morpholine (29:71), gave 3h in
25% yield, and there is no detectable amount of the
product, which reacts with the 4-(3-methybut-2-en-2-yl)-
morpholine, in the crude reaction mixture (entry 15).
1
3
The CF
reaction. The reaction of the hydrate 1b with the enamine
a under the various reaction conditions as well as with
various enamines 2c-f,h ,i are also summarized in Table
. Among the solvents examined at room or reflux
3
CHO monohydrate 1b can also be used for the
2
(
8) For trifluoroacetaldehyde derivatives, see: (a) Matsutani, H.;
1
Poras, H.; Kusumoto, T.; Hiyama, T. Chem. Commun. 1998, 1259. (b)
Matsutani, H.; Poras, H.; Kusumoto, T.; Hiyama, T. Synlett 1998, 1353.
c) Matsutani, H.; Kusumoto, T.; Hiyama, T. Chem. Lett. 1999, 529.
d) Xu, Y.; Dolbier, W. R., J r. Tetrahedron Lett. 1998, 39, 9151.
temperature (entries 16, 18-26), using toluene at reflux
gave the best yield of 3a (entry 25). The addition of MS
(
(
3
A to the reaction mixture at room temperature was not
(9) For recent examples, see: (a) Chu-Moyer, M. Y.; Ballinger, W.
very effective, giving 3a in 43% yield (entry 17). The
reaction of 1b with various other aromatic or heteroaro-
matic enamines smoothly occurred to provide the corre-
sponding â-hydroxy-â-trifluoromethyl ketones 3 in good
yields (entries 27-31). When a mixture of enamines 2i
E.; Beebe, D. A.; Berger, R.; Coutcher, J . B.; Day, W. W.; Li, J .; Mylari,
B. L.; Oates, P. J .; Weekly, R. M. J . Med. Chem. 2002, 45, 511. (b)
Bertau, M.; Burli, M.; Hungerbuhler, E.; Wagner, P. Tetrahedron:
Asymmetry 2001, 12, 2103. (c) Omote, M.; Ando, A.; Sato, K.; Ku-
madaki, I. Tetrahedron 2001, 57, 8085. (d) Kuroki, Y.; Sakamaki, Y.;
Iseki, K. Org. Lett. 2001, 3, 457. (e) Kato, K.; Gong, Y.; Saito, T.;
Kimoto, H. Enantiomer 2000, 5, 521.
(
10) Trifluoroacetaldehyde ethyl hemiacetal exists as an equilibrium
mixture of ethyl hemiacetal, diethylacetal, and hydrate; see: Guthrie,
J . P. Can. J . Chem. 1975, 53, 898.
(13) A part of this work was reported preliminarily, see: (a)
Funabiki, K.; Nojiri, M.; Matsui, M.; Shibata, K. Chem. Commum.
1998, 2051. (b) Funabiki, K.; Matsunaga, K.; Matsui, M.; Shibata, K.
Synlett 1999, 1477.
(11) (a) Ishii, A.; Terada, Y. J . Syn. Org. Chem. J pn. 1999, 57, 898.
(
b) Baraid, M.; Isersone, H.; Lawlore, F. E. J . Am. Chem. Soc. 1954,
7
1
7
6, 4027. (c) Henne, A. L.; Pelley, R. L.; Alm, R. M. J . Am. Chem. Soc.
950, 72, 3370. (d) Shechter, H.; Conrad, F. J . Am. Chem. Soc. 1950,
2, 3371.
(14) For the reaction of trifluoromethy ketones with enamines or
imines, see: (a) Funabiki, K.; Isomura, A.; Yamaguchi, Y.; Hashimoto,
W.; Matsunaga, K.; Shibata, K.; Matsui, M. J . Chem. Soc., Perkin
Trans. 1 2001, 2578. (b) Barten, J . A.; Funabiki, K.; R o¨ schenthaler,
G.-V. J . Fluorine Chem. 2002, 113, 105.
(12) For excellent examples, see ref 7a,c and: Shen, Y.; Qi, M. J .
Chem. Soc., Perkin Trans. 1, 1994, 1179.
2
854 J . Org. Chem., Vol. 68, No. 7, 2003

Synthesis of â-Hydroxy-â-trifluoromethyl Ketones
TABLE 1. Rea ction of Tr iflu or oa ceta ld eh yd e Eth yl Hem ia ceta l or Hyd r a te w ith Va r iou s En a m in esa
l
2
R3
b
entry
1
enamine
R , R
solvent
hexane
ClCH2CH2Cl
THF
toluene
CH3CN
hexane-H2O (40:1)
hexane
hexane
hexane
hexane
hexane
toluene
hexane
hexane
hexane
hexane
T
product
yield (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)5-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
Ph
Ph
Ph
Ph
Ph
Ph
Ph
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3e
3f
88
78
73
88
75
68
86
87
72
86
13
52
87
75
25
46
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
4-NO2C6H4
2-MeC6H4
2-thienyl
i-Prc
1
1
1
1
1
1
1
0
1
2
3
4
5
6
2f
2g
2h
2i
3g
3h
3a
2a
Ph
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
7d
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2c
2d
2e
2f
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
hexane
THF
rt
rt
rt
rt
rt
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3g
3h
43
20
66
77
39
54
77
65
84
56
80
80
78
72
77
18
CH2Cl2
toluene
CH3CH2CN
hexane
THF
CH2Cl2
toluene
CH3CH2CN
toluene
toluene
toluene
toluene
toluene
toluene
Ph
Ph
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
2-thienyl
i-Pre
2h
2i
a
All reactions were carried out as decsribed in the Experimental Section. b Isolated yields of analytical pure products. c A mixture of
2
i and 4-(3-methylbut-2-en-2-yl)morpholine (29:71) was used. d MS 3A (0.5 g) was added. e A mixture of 2i and 4-(3-methylbut-2-en-2-
yl)morpholine (30:70) was used.
SCHEME 1
and 4-(3-methylbut-2-en-2-yl)morpholine (30:70) (1 equiv)
was used for the reaction of the hydrate 1b, the corre-
sponding â-hydroxy-â-trifluoromethyl ketone 3h was only
obtained in 18% yield and the product derived from the
major enamine was not detected in the reaction mixture
(entry 32).
Treating the hemiacetal 1a with a 1.5 equimolar
amount of BuLi exclusively gave the lithium alkoxide A′,
which did not react with the enamine 2a at all under
the same conditions, and neither a trace amount of the
â-hydroxy-â-trifluoromethyl ketone 3a nor a detectable
amount of 1,1,1-trifluoro-2-hexanol was obtained in
this reaction with quantitative recovered acetophenone
(
Scheme 1).
potent electron-withdrawing properties of the trifluoro-
methyl group.
In a previous paper,15 the difluoroacetaldehyde ethyl
hemiacetal smoothly reacted with various Grignard
reagents or organolithiums affording good yields of the
R-difluoromethylaled alcohols, but the CF CHO ethyl
3
hemiacetal 1a did not react at all with any organome-
tallics. These results are attributed to the much higher
stability of the intermediate trifluoromethylated lithium
alkoxide A than the difluoromethylated one due to the
3
Furthermore, as shown in Scheme 2, after the CF CHO
hemiacetal reacted with an equimolar amount of the
enamine 2a at reflux temperature for 1 h, an equimolar
amount of another enamine 2e was added to the reaction
mixture and stirred at room temperature for 1 h, followed
by hydrolysis with 10% HCl to give the product 3a (81%)
with a trace amount of 3d . On the other hand, succesive
reaction with another enamine 2e at reflux temperature
gave a mixture of 3a and 3d in 50% and 36% yields,
respectively.
(
15) Kaneko, S.; Yamazaki, T.; Kitazume, T. J . Org. Chem. 1993,
5
8, 2302.
J . Org. Chem, Vol. 68, No. 7, 2003 2855

Funabiki et al.
TABLE 2. Rea ction of Tr iflu or oa ceta ld eh yd e Eth yl Hem ia ceta l or Hyd r a te w ith Va r iou s Im in esa
b
entry
1
1
imine
R4
R3
solvent
hexane
hexane
hexane
CH2Cl2
THF
benzene
hexane-H2O (4:1)
hexane-H2O (2:1)
hexane-H2O (1:1)
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
CH2Cl2
THF
toluene
CH3CH2CN
hexane
hexane
hexane
hexane
hexane
hexane
T
product
yield (%)
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
n-Hex
Ph
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
rt
rt
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3i
49
64
91
76
83
83
70
59
35
89
51
88
94
89
79
83
78
65
93
61
90
92
77
87
94
83
83
75
77
69
83
55
77
48
b
2
3
4
5
6
7
8
9
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
4-EtOCOC6H4
2-thienyl
i-Pr
4g
4h
4i
3g
3h
3j
4j
4k
41
4a
4a
4a
4a
4a
4d
4e
4f
4g
4h
4i
4j
4k
41
c-Hex
t-Bu
Ph
Ph
Ph
Ph
Ph
3k
3a
3a
3a
3a
3a
3b
3c
3d
3e
3i
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
4-EtOCOC6H4
2-thienyl
i-Pr
3g
3h
3j
hexane
hexane
hexane
c-Hex
t-Bu
3k
a
All reactions were carried out as decsribed in the Experimental Section. b Performed for 3 h. c Isolated yields of analytical pure products.
SCHEME 2
1a or hydrate 1b will proceed by the reaction of 1a ,b with
enamines 2 to give the ammonium alkoxide, followed by
elimination of the ethoxide or hydroxide leading to the
in situ generation of CF
3
CHO in the equilibrium. The in
situ generated CF CHO reacts with the regenerated
3
enamines 2 to provide the intermediates, which are
hydrolyzed leading to the corresponding â-hydroxy-â-
trifluoromethyl ketones 3.
Rea ction w ith Im in es. When the hemiacetal 1a was
subjected to the reaction with an equimolar amount of
the imine 4a , derived from acetophenone and c-hexy-
lamine, in hexane at room temperature, the correspond-
ing â-hydroxy-â-trifluoromethyl ketone 3a was produced
in 49-64% yields (Table 2, entries 1 and 2).
3
The reactions of the CF CHO ethyl hemiacetal 1a or
hydrate 1b with the imines 4 under various conditions
are summarized in Table 2. An elevated temperature
resulted in an extreme increase in the yield (entry 3).
Out of the solvents employed, such as hexane, dichlo-
romethane, THF, and benzene (entries 3-6), the best
result was obtained for the reaction in hexane (entry 3).
It should be noted that the reaction even in the presence
of a significant amount of water smoothly proceeds to give
3a in moderate to good yields (entries 7-9). The imine
4b with the n-hexyl group on the nitrogen atom also can
Unfortunately, 19F NMR could not detect the existence
of CF
3
CHO in the reaction mixture, even if the use of an
CHO hemiacetal. Therefore, we
excess amount of CF
3
cannot describe the exact reaction mechanism. As only
one possibility of the reaction mechanism, a plausible
reaction mechanism between 1a ,b and the enamines may
be described as follows. Deprotonation of the hemiacetal
2
856 J . Org. Chem., Vol. 68, No. 7, 2003

Synthesis of â-Hydroxy-â-trifluoromethyl Ketones
SCHEME 3
TABLE 3. Rea ction of Diflu or oa ceta ld eh yd e Eth yl
Hem ia ceta l or P en ta flu or op r op ion a ld eh yd e Hyd r a te
w ith Va r iou s En a m in es or Im in esa
enamine
or imine
b
SCHEME 4
entry
1
R1
T
product yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1d
1d
1d
1d
2a
2c
2d
2e
2f
2h
4a
4e
4f
4g
2a
2c
2e
4a
Ph
4-MeC6H4
4-MeOC6H4 rt
4-ClC6H4 rt
4-NO2C6H4 rt
2-thienyl
Ph
4-MeOC6H4 reflux
4-ClC6H4 reflux
4-NO2C6H4 reflux
rt
rt
5a
5b
5c
5d
5e
5f
5a
5c
5d
5e
6a
6b
6c
6a
65
70
73
69
32
52
67
84
70
50
78
83
85
70
rt
reflux
1
1
1
1
1
Ph
rt
rt
rt
reflux
4-MeC6H4
4-ClC6H4
Ph
a
All reactions were carried out as decsribed in the Experimental
Section. b Isolated yields of analytical pure products.
be used, affording 3a in 89% yield (entry 10). However,
the reaction between 1a and the imine 4c, prepared from
aniline, gave a lower yield (51%) (entry 11).
droxy-â-trifluoromethyl ketones 3a and 3c in 48% and
Other imines 4d -i with various aromatic or heteroaro-
matic substituents smoothly reacted to furnish the cor-
responding â-hydroxy-â-trifluoromethyl ketones 3b-e,g,i
in good to excellent yields (entries 12-17). More signifi-
cant imines, prepared from aliphatic methyl ketones,
participated well in the reaction to give the â-hydroxy-
â-trifluoromethyl ketones 3h ,j,k in moderate to excellent
yields (entries 18-20). For the imines with an isopropyl
3
5% yields, respectively.
The formation of 3 from the imines may be explained
by the mechanism, which is very similar to that of the
enamines, and imines 4 probably react with 1a ,b via the
enamines, which are in tautomeric equilibrium with the
imines 4.
17
Rea ction of Diflu or oa ceta ld eh yd e Eth yl Hem i-
a ceta l a n d P en ta flu or op r op ion a ld eh yd e Hyd r a te.
These methods can be successfully utilized for the
synthesis of â-hydroxy-â-difluoromethyl or â-pentafluo-
ropropyl ketones. The results of the reaction of the
difluoroacetaldehyde ethyl hemiacetal 1c as well as the
pentafluoropropionaldehyde hydrate 1d are summarized
in Table 3.
The difluoroacetaldehyde ethyl hemiacetal 1c reacted
well with various aromatic enamines (entries 1-6) or
imines (entries 7-10) affording the â-hydroxy-â-difluo-
romethyl ketones 5a -f in good yields. The reaction of
the pentafluoropropionaldehyde hydrate 1d with the
enamines (entries 11-13) or imines (entry 14) also
smoothly proceeded to give the corresponding â-hydroxy-
â-pentafluoropropyl ketones 5a -f in good yields.
3
or cyclohexyl group as a R , although there are two kinds
of tautomeric enamines in an equilibrium, the reaction
of the imines 4j,k with CF CHO proceeded regioselec-
3
tively at the sterically less hindered R-position of the
kinetic enamines to furnish the corresponding â-hydroxy-
â-trifluoromethyl aliphatic ketones 3h ,j in good yields
(
Scheme 3).16 No products 3h ′,j′ derived from the more
highly substituted enamines were observed in the reac-
tion mixture.
The hydrate 1b also reacted with various imines
3
carrying a variety of substituents R , including aromatic
(entries 21-30), heteroaromatic (entry 31), and alkyl
groups (entries 32-34) using various reaction solvents,
such as hexane, dichloromethane, THF, toluene, and
propionitrile, to afford the corresponding â-hydroxy-â-
trifluoromethyl ketones 3 in good to excellent yields.
As shown in Scheme 4, interestingly, the reaction was
performed with an equimolar amount of imine 4a in
hexane at reflux temperature for 1 h, followed by further
addition of an equimolar amount of the other imine 4e,
heating at reflux temperature for 1 h, and hydrolysis
under acidic conditions, to give a mixture of the â-hy-
Con clu sion s
In summary, we have described a new expedient
method for the simple and practical regioselective syn-
thesis of â-hydroxy-â-trifluoromethyl ketones by the
reaction of trifluoroacetaldehyde ethyl hemiacetal or
(
17) (a) J abin, I.; Revial, G.; Monnier-Benoit, N.; Netchita ¨ı lo, P. J .
(
16) For similar results, see: Arend, M.; Risch, N. Angew. Chem.,
Org. Chem. 2001, 66, 256. (b) Pfau, M.; Revaial, G.; Guingant, A.;
d’Angelo, J . J . Am. Chem. Soc. 1985, 107, 273 and ref 15.
Int. Ed. Engl. 1995, 34, 2639 and references sited therein.
J . Org. Chem, Vol. 68, No. 7, 2003 2857

Funabiki et al.
(34.8); HRMS (EI) found m/z 232.0710, calcd for C11
M, 232.0711. Anal. Calcd: C, 56.90; H, 4.77. Found: C, 56.83;
H, 4.72.
hydrate with enamines or imines. Diastereoselective and/
or enantioselective versions of this reaction are currently
investigated and will be reported in due course.
11 3 2
H F O
4
,4,4-Tr iflu or o-3-h yd r oxy-1-(4-m et h oxyp h en yl)-1-b u -
2
0,21
ta n on e 3c:
R 0.10 (benzene); mp 104.5-105.1 °C (hexane/
f
Exp er im en ta l Section
-1
1
ethyl acetate); IR (KBr) 1677.1 (CdO), 3379.3 (OH) cm ; H
NMR (CDCl ) δ 3.27 (dd, J ) 17.81, 4.15 Hz, 1H), 3.32 (dd, J
17.81, 8.05 Hz, 1H), 3.65 (d, J ) 4.39 Hz, 1H), 3.90 (s, 3H),
.62-4.71 (m, 1H), 6.97 and 7.95 (AB quartet, J ) 8.79 Hz,
H); 13C NMR (CDCl
) δ 37.64 (s), 55.58 (s), 67.18 (q, J ) 31.98
Gen er a l Meth od s. H (400 MHz) or 13C (100 MHz) NMR
1
3
)
4
4
spectra were measured with a J EOL R-400 FT-NMR spec-
trometer in deuteriocholoroform (CDCl
ramethylsilane (Me Si) as the internal standard. F NMR (376
MHz) spectra were recorded on a J EOL R-400 FT-NMR in
CDCl solutions using trifluoroacetic acid as the external
3
) solutions with tet-
1
9
3
4
Hz), 114.04 (s), 124.80 (q, J ) 280.37 Hz), 129.05 (s), 130.61
s), 164.34 (s), 196.13 (s); 19F NMR (CDCl
) δ -1.42 (d, J )
.87 Hz, 3F); MS (EI) m/z (rel intensity) 248 (M , 16.8), 230
37.4), 150 (5.6), 136 (11.9), 135 (100.0), 107 (9.4), 92 (11.9),
7 (13.7); HRMS (EI) found m/z 248.0663, calcd for C11
(
6
3
3
+
standard. Tetrahydrofuran (THF) was freshly distilled from
sodium benzophenone ketyl. Hexane, benzene, 1,2-dichloro-
ethane, dichloromethane (CH Cl ), toluene, acetonitrile (MeCN),
2 2
(
7
11 3 3
H F O
M, 248.0660. Anal. Calcd: C, 53.23; H, 4.47. Found: C, 53.11;
H, 4.44.
1-(4-Ch lor op h e n yl)-4,4,4-t r iflu or o-3-h yd r oxy-1-b u -
and propionitrile (EtCN) were distilled over calcium hydride
under argon. Enamines or imines were prepared according to
1
8
the previous reports.
ta n on e 3d :20
R 0.25 (benzene); mp 109.3-110.0 °C (hexane/
f
Typ ica l P r oced u r e for th e Rea ction of Tr iflu or oa cet-
a ld eh yd e Eth yl Hem ia ceta l w ith En a m in es. To a solution
of trifluoroacetaldehyde ethyl hemiacetal 1a (0.144 g, 1 mmol)
in hexane (4 mL) was added enamine 2a (0.189 g, 1 mmol) at
room temperature. After being stirred at room temperature
for 1 h, the reaction mixture was quenched with a saturated
-
1 1
ethyl acetate); IR (KBr) 1688.3 (CdO), 3383.7 (OH) cm ; H
NMR (CDCl ) δ 3.27 (dd, J ) 17.63, 2.56 Hz, 1H), 3.37 (dd, J
17.63, 9.27 Hz, 1H), 3.40 (d, J ) 4.63 Hz, 1H), 4.65-4.74
3
)
1
3
(
m, 1H), 7.49 and 7.92 (AB quartet, J ) 8.79 Hz, 4H); C NMR
CDCl ) δ 38.28 (s), 66.90 (q, J ) 33.08 Hz), 124.70 (q, J )
81.19 Hz), 129.24 (s), 129.60 (s), 134.29 (s), 140.76 (s), 196.18
s); 19F NMR (CDCl
) δ -1.50 (d, J ) 6.86 Hz, 3F); MS (EI)
(
2
(
3
NH
at room temperature for 3 h, followed by extraction with
SO , and concentra-
4
Cl solution (50 mL) or hydrolyzed with 10% HCl (4 mL)
3
+
+
m/z (rel intensity) 254 (M + 2, 1.3), 252 (M , 4.0), 236 (13.0),
diethyl ether (30 mL × 3), drying over Na
2
4
2
35 (3.7), 234 (34.2), 232 (7.8), 142 (3.3), 141 (40.6), 140 (10.0),
39 (100.0), 123 (4.5), 113 (14.8), 112 (4.4), 111 (33.8), 76 (4.1),
5 (14.0), 74 (3.7); HRMS (EI) found m/z 254.0138, calcd for
tion under vacuum. The residue was chromatographed on
silica gel successive using benzene and hexanes-ethyl acetate,
giving 4,4,4-trifluoro-3-hydroxy-1-phenyl-1-butanone (3a) (0.191
g, 88%).
1
7
3
3
7
5
C
C
10
H
H
8
ClF
ClF
3
O
O
2
M, 254.0135, found m/z 252.0162, calcd for
10
8
3
2
M, 252.0165. Anal. Calcd: C, 47.55; H, 3.19.
Typ ica l P r oced u r e for th e Rea ction of Tr iflu or oa cet-
a ld eh yd e Eth yl Hem ia ceta l w ith Im in es. Imine 4a (0.201
g, 1 mmol) was added to a solution of trifluoroacetaldehyde
ethyl hemiacetal 1a (0.144 g, 1 mmol) in hexane (4 mL) at
room temperature. The mixture was stirred at reflux temper-
ature for 1 h. After being cooled to the room temperature, the
Found: C, 47.54; H, 3.30.
4
,4,4-T r iflu o r o -3-h y d r o x y -1-(4-n it r o p h e n y l)-1-b u -
2
0,21
ta n on e 3e:
R 0.11 (benzene); mp 104.5-105.0 °C (hexane/
f
-
1 1
ethyl acetate); IR (KBr) 1698.0 (CdO), 3429.7 (OH) cm ; H
NMR (CDCl
3
) δ 3.15 (d, J ) 4.88 Hz, 1H), 3.32 (dd, J ) 17.69,
.44 Hz, 1H), 3.47 (dd, J ) 17.69, 9.51 Hz, 1H), 4.70-4.79 (m,
2
1
(
(
(
4
reaction mixture was quenched with a saturated NH Cl (50
mL) or hydrolyzed with 10% HCl (4 mL) at room temperature
1
3
H), 8.15 and 8.36 (AB quartet, J ) 9.27 Hz, 4H); C NMR
) δ 39.01 (s), 66.72 (q, J ) 32.26 Hz), 124.09 (s), 124.59
q, J ) 281.19 Hz), 129.29 (s), 140.28 (s), 150.85 (s), 195.52
s); 19F NMR (CDCl
) δ -1.53 (d, J ) 6.87 Hz, 3F); MS (EI)
CDCl
3
for 3 h, followed by extraction with diethyl ether (30 mL × 3),
2 4
drying over Na SO , and concentration under vacuum. Column
3
chromatography of the residue on silica gel successive using
benzene and hexanes-ethyl acetate gave 4,4,4-trifluoro-3-
hydroxy-1-phenyl-1-butanone (3a ) (0.198 g, 91%).
+
m/z (rel intensity) 263 (M , 5.1), 247 (6.7), 246 (13.3), 245
(
(
23.8), 244 (10.6), 243 (83.9), 229 (3.3), 215 (3.8), 194 (4.8), 165
9.6), 151 (46.7), 150 (100.0), 123 (12.8), 120 (26.8), 105 (7.1),
4
,4,4-Tr iflu or o-3-h yd r oxy-1-p h en yl-1-bu ta n on e 3a :19
R
f
1
04 (84.3), 92 (29.1), 76 (35.0), 75 (14.9); HRMS (EI) found
0
(
3
.17 (benzene); mp 79.4-79.8 °C (hexane/ethyl acetate); IR
m/z 263.0403, calcd for C10 NO M, 263.0405. Anal.
H
8
F
3
4
KBr) 1686.5 (CdO), 3390.3 (OH) cm- ; H NMR (CDCl
.33 (dd, J ) 17.93, 3.17 Hz, 1H), 3.39 (dd, J ) 17.93, 8.79
Hz, 1H), 3.47 (d, J ) 2.92 Hz, 1H), 4.65-4.74 (m, 1H), 7.49-
1 1
) δ
3
Calcd: C, 45.64; H, 3.06; N, 5.32. Found: C, 45.68; H, 3.13;
N, 5.41.
4,4,4-Tr iflu or o-3-h yd r oxy-1-(2-m e t h ylp h e n yl)-1-b u -
.53 (m, 2H), 7.62-7.66 (m, 1H), 7.97-7.99 (m, 2H); 13C NMR
CDCl ) δ 38.22 (s), 67.03 (q, J ) 31.98 Hz), 124.69 (q, J )
80.37 Hz), 128.21 (s), 128.88 (s), 134.18 (s), 135.96 (s), 197.56
7
(
2
ta n on e 3f: R
acetate); IR (KBr) 1685.2 (CdO), 3408.5 (OH) cm ; H NMR
(CDCl ) δ 2.54 (s, 3H), 3.26 (dd, J ) 17.69, 3.05 Hz, 1H), 3.33
f
0.20 (benzene); mp 81.1-81.6 °C (hexane/ethyl
3
-
1 1
1
9
3
(
s); F NMR (CDCl
m/z (rel intensity) 218 (M , 11.7), 200 (4.0), 198 (12.2), 162
3.8), 106 (7.9), 105 (100.0), 78 (4.1), 77 (38.9); HRMS (EI)
found m/ z 218.0553, calcd for C10 M, 218.0555. Anal.
Calcd: C, 55.05; H, 4.16. Found: C, 54.99; H, 4.21.
3
) δ -1.80 (d, J ) 6.87 Hz, 3F); MS (EI)
+
(dd, J ) 17.69, 8.91 Hz, 1H), 3.55 (d, J ) 4.64 Hz, 1H), 4.62-
4
7
.71 (m, 1H), 7.28-7.33 (m, 2H), 7.42-7.46 (m, 1H), 7.70-
(
.72 (m, 1H); 13C NMR (CDCl
) δ 21.63 (s), 40.49 (s), 67.26 (q,
3
9 3 2
H F O
J ) 31.97 Hz), 124.77 (q, J ) 280.64 Hz), 125.97 (s), 129.09
1
9
(s), 132.39 (s), 132.48 (s), 136.17 (s), 139.18 (s), 200.77 (s);
F
4
,4,4-Tr iflu or o-3-h yd r oxy-1-(4-m e t h ylp h e n yl)-1-b u -
NMR (CDCl ) δ -1.42 (d, J ) 6.87 Hz, 3F); MS (EI) m/z (rel
3
2
0
ta n on e 3b:
R 0.19 (benzene); mp 108.4-108.8 °C (hexane/
f
+
intensity) 232 (M , 34.9), 214 (22.5), 194 (16.6), 167 (13.6), 145
100.0), 127 (17.6), 117 (11.6), 91 (61.1); HRMS (EI) found m/z
-
1 1
ethyl acetate); IR (KBr) 1685.0 (CdO), 3378.9 (OH) cm ; H
NMR (CDCl ) δ 2.44 (s, 3H), 3.30 (dd, J ) 16.83, 3.17 Hz, 1H),
.36 (dd, J ) 16.83, 7.57 Hz, 1H), 3.55 (d, J ) 3.90 Hz, 1H),
.62-4.72 (m, 1H), 7.30 and 7.87 (AB quartet, J ) 8.05 Hz,
H); C NMR (CDCl ) δ 21.73 (s), 38.00 (s), 67.08 (q, J ) 31.99
Hz), 124.78 (q, J ) 281.19 Hz), 128.34 (s), 129.54 (s), 133.52
s), 145.25 (s), 197.25 (s); F NMR (CDCl
.87 Hz, 3F); MS (EI) m/z (rel intensity) 232 (M , 9.8), 214
24.3), 195 (1.6), 145 (2.7), 134 (4.0), 120 (9.1), 119 (100.0), 91
(
3
2
5
11 3 2
32.0710, calcd for C11H F O M, 232.0711. Anal. Calcd: C,
6.90; H, 4.77. Found: C, 56.94; H, 4.77.
3
4
4
1
3
4,4,4-Tr iflu or o-3-h yd r oxy-1-(2-th ien yl)-1-bu ta n on e 3g:
R 0.18 (benzene); mp 71.3-71.7 °C (hexane/ethyl acetate);
f
3
2
2
1
9
(
6
(
3
) δ -1.43 (d, J )
+
(19) Lin, J . T.; Yamazaki, T.; Kitazume, T. J . Org. Chem. 1987, 52,
211.
20) Pashkevich, K. I.; Ratner, V. G.; Khomutov, O. G.; Korolev, V.
3
(
B.; Filyakova, V. I. Izv. Akad. Nauk, Ser. Khim. 1996, 1493.
(21) Kim, B.-H.; Kim, S.-W. Bull. Korean Chem. Soc. 1994, 15, 807.
(22) Forni, A.; Moretti, I.; Prati, F.; Torre, G. Tetrahedron 1994, 50,
11995.
(
18) (a) Carlson, R.; Nilsson, Å. Acta Chem. Scand. Ser. B 1984, B38,
4
9. (b) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovics, J .;
Terrell, R. J . Am. Chem. Soc. 1963, 85, 207.
2
858 J . Org. Chem., Vol. 68, No. 7, 2003

Synthesis of â-Hydroxy-â-trifluoromethyl Ketones
IR (KBr) 1663.7 (CdO), 3385.6 (OH) cm-1; 1H NMR (CDCl
) δ
(t, J ) 24.81 Hz), 115.50 (t, J ) 243.15 Hz), 128.16 (s), 128.77
(s), 133.92 (s), 136.24 (s), 198.79 (s); 19F NMR (CDCl
) δ -50.93
3
3
.26 (dd, J ) 17.20, 2.93 Hz, 1H), 3.33 (dd, J ) 17.20, 9.03
Hz, 1H), 3.50 (d, J ) 4.88 Hz, 1H), 4.61-4.72 (m, 1H), 7.18
dd, J ) 5.13, 3.67 Hz, 1H), 7.74 (dd, J ) 5.13, 1.23 Hz, 1H),
3
(ddd, J ) 287.92, 55.87, 9.73 Hz, 1F), -53.75 (ddd, J ) 287.92,
+
(
55.87, 14.12 Hz, 1F); MS (EI) m/z (rel intensity) 200 (M ; 14.2),
7
6
1
.78 (dd, J ) 3.67, 1.23 Hz, 1H); 13C NMR (CDCl
6.93 (q, J ) 31.98 Hz), 124.64 (q, J ) 280.64 Hz), 128.45 (s),
33.21 (s), 135.20 (s), 143.01 (s), 190.01 (s); 19F NMR (CDCl
3
) δ 38.73 (s),
180 (80.8), 136 (11.9), 149 (47.1), 120 (33.5), 105 (100.0), 91
(17.2), 77 (89.8); HRMS (EI) found m/z 200.0620, calcd for
3
)
C
10
H
10
F
2
O
2
M, 200.0649.
,4-D iflu o r o -3-h y d r o x y -1-(4-m e t h y lp h e n y l)-1-b u -
ta n on e 5b: R 0.06 (benzene); mp 42.5-43.5 °C (hexane/ethyl
acetate); IR (KBr) 1680.2 (CdO), 3501.2 (OH) cm ; H NMR
δ -1.51 (d, J ) 6.86 Hz, 3F); MS (EI) m/z (rel intensity) 224
4
+
(
M , 9.9), 207 (4.3), 206 (44.4), 205 (7.3), 204 (8.0), 159 (3.2),
50 (3.2), 126 (5.1), 112 (8.2), 111 (100.0), 83 (6.0); HRMS (EI)
found m/z 224.0121, calcd for C S M, 224.0119. Anal.
Calcd: C, 42.86; H, 3.15. Found: C, 43.00; H, 3.22.
,6,6-Tr iflu or o-5-h yd r oxy-2-m eth yl-3-h exa n on e 3h :23
.12 (benzene); mp 33.5-34.2 °C (hexane/ethyl acetate); IR
f
1
-1 1
8
7 3 2
H F O
(
3
CDCl ) δ 2.43 (s, 3H), 3.25 (dd, J ) 18.05, 8.29 Hz, 1H), 3.31
(
dd, J ) 17.81, 4.15 Hz, 1H), 3.50 (d, J ) 4.88 Hz, 1H), 4.38-
6
R
f
4.49 (m, 1H), 5.89 (dt, J ) 55.86, 3.41 Hz, 1H), 7.29 and 7.87
(AB quartet, J ) 8.30 Hz, 4H); 13C NMR (CDCl ) δ 21.71 (s),
0
3
1
1
(
KBr) 1709.6 (CdO), 3397.0 (OH) cm- ; H NMR (CDCl
.15 (d, J ) 6.83 Hz, 6H), 2.65 (septet, J ) 6.83 Hz, 1H), 2.79
dd, J ) 17.93, 2.92 Hz, 1H), 2.87 (dd, J ) 17.93, 9.03 Hz,
H), 3.41 (d, J ) 4.39 Hz, 1H), 4.44-4.55 (m, 1H); 13C NMR
CDCl ) δ 17.77 (s), 39.52 (s), 41.62 (s), 66.75 (q, J ) 31.98
Hz), 124.70 (q, J ) 280.64 Hz), 212.63 (s); F NMR (CDCl
1.69 (d, J ) 6.86 Hz, 3F); MS (EI) m/z (rel intensity) 184
3
) δ
37.46 (s), 67.88 (t, J ) 24.81 Hz), 115.50 (t, J ) 243.98 Hz),
1
9
1
(
1
(
128.29 (s), 129.49 (s), 133.75 (s), 145.02 (s), 198.58 (s); F NMR
(CDCl ) δ -50.87 (ddd, J ) 287.73, 55.86, 9.92 Hz, 1F), -53.67
3
(ddd, J ) 287.73, 55.86, 14.31 Hz, 1F); MS (EI) m/z (rel
+
3
intensity) 214 (M , 1.1), 196 (2.2), 145 (0.9), 134 (1.9), 120
1
9
3
) δ
(10.2), 119 (100.0), 91 (40.6), 77 (2.7), 65 (15.2). Anal. Calcd:
C, 61.68; H, 5.65. Found: C, 61.72; H, 5.47.
-
+
(
M , 1.9), 166 (4.4), 164 (3.7), 141 (100.0), 138 (22.7), 123 (42.9),
4
,4-Diflu or o-3-h yd r oxy-1-(4-m e t h oxyp h e n yl)-1-b u -
ta n on e 5c: R 0.04 (benzene); mp 43.0-44.0 °C (hexane/ethyl
acetate); IR (KBr) 1680.2 (CdO), 3503.2 (OH) cm ; H NMR
CDCl
1
1
4
13 (16.9), 95 (8.5), 71 (37.0), 69 (6.3); HRMS (EI) found m/z
84.0716, calcd for C M, 184.0711. Anal. Calcd: C,
5.65; H, 6.02. Found: C, 45.47; H, 5.80.
-(4-Eth oxyca r bon ylp h en yl)-4,4,4-tr iflu or o-3-h yd r oxy-
-bu ta n on e 3i: R 0.08 (benzene); mp 124.2-124.7 °C (hex-
f
H
11
F
3
O
2
-1 1
7
(
3
) δ 3.22 (dd, J ) 17.56, 4.15 Hz, 1H), 3.28 (dd, J ) 17.56,
1
7.81 Hz, 1H), 3.68 (d, J ) 3.91 Hz, 1H), 3.88 (s, 3H), 4.37-
1
f
4.48 (m, 1H), 5.89 (dt, J ) 55.87, 3.41 Hz, 1H), 6.95 and 7.93
(AB quartet, J ) 8.79 Hz, 4H); 13C NMR (CDCl ) δ 37.15 (s),
ane/ethyl acetate); IR (KBr) 1688.3 (CdO), 1717.0 (CdO),
3
-
1
1
3
3
1
2
412.3 (OH) cm ; H NMR (CDCl
3
) δ 1.43 (t, J ) 7.32 Hz,
55.49 (s), 67.87 (t, J ) 24.81 Hz), 113.91 (s), 115.54 (t, J )
1
9
H), 3.33 (dd, J ) 17.68, 2.44 Hz, 1H), 3.33 (d, J ) 4.88 Hz,
H), 3.43 (dd, J ) 17.68, 9.52 Hz, 1H), 4.42 (q, J ) 7.32 Hz,
H), 4.68-4.77 (m, 1H), 8.03 and 8.17 (AB quartet, J ) 8.78
243.15 Hz), 129.26 (s), 130.51 (s), 164.13 (s), 197.35 (s);
F
NMR (CDCl ) δ -50.84 (ddd, J ) 287.23, 55.87, 9.92 Hz, 1F),
3
-53.56 (ddd, J ) 287.23, 55.87, 14.12 Hz, 1F); MS (EI) m/z
1
3
+
Hz, 4H); C NMR (CDCl
3
) δ 14.23 (s), 38.74 (s), 61.65 (s), 66.81
q, J ) 32.53 Hz), 124.73 (q, J ) 280.64 Hz), 128.07 (s), 129.99
s), 135.10 (s), 139.00 (s), 165.52 (s), 196.79 (s); 19F NMR
CDCl ) δ -1.81 (d, J ) 6.86 Hz, 3F); MS (EI) m/z (rel intensity)
(rel intensity) 230 (M ; 6.9), 213 (1.3), 212 (5.4), 150 (3.1), 136
(
(
(
(9.6), 135 (100.0), 107 (10.0), 92 (12.5), 77 (18.2). Anal. Calcd
for C, 57.39; H, 5.25. Found: C, 57.60; H, 5.25.
3
1
-(4-C h lo r o p h e n y l)-4,4-d iflu o r o -3-h y d r o x y -1-b u -
ta n on e 5d : R 0.09 (benzene); mp 91.5-92.5 °C (hexane/ethyl
acetate); IR (KBr) 1693.7 (CdO), 3426.0 (OH) cm ; H NMR
CDCl
+
2
90 (M , 3.4), 270 (6.3), 245 (27.1), 227 (18.1), 218 (9.3), 217
11.0), 178 (22.7), 177 (100.0), 149 (56.9), 147 (13.9), 121 (15.9),
04 (19.4), 103 (10.1), 77 (7.9), 76 (20.8), 65 (15.5). Anal. Calcd
for C, 53.80; H, 4.51. Found: C, 53.84; H, 4.49.
-Cycloh e xyl-4,4,4-t r iflu or o-3-h yd r oxy-1-b u t a n on e
j: R 0.16 (benzene); mp 40.9-41.6 °C (hexane/ethyl acetate);
IR (KBr) 1707.3 (CdO), 3400.5 (OH) cm ; H NMR (CDCl
.14-1.94 (m, 10H), 2.39 (tt, J ) 11.45, 3.42 Hz, 1H), 2.78
dd, J ) 17.81, 3.42 Hz, 1H), 2.85 (dd, J ) 17.81, 8.79 Hz,
H), 3.44 (d, J ) 4.39 Hz, 1H), 4.43-4.52 (m, 1H); 13C NMR
CDCl ) δ 25.38 (s), 25.61 (s), 28.05 (s), 39.62 (s), 51.33 (s), 66.86
q, J ) 31.98 Hz), 124.60 (q, J ) 281.19 Hz), 212.00 (s); 19
) δ -1.96 (d, J ) 6.87 Hz, 3F); MS (EI) m/z (rel
f
(
1
-1 1
(
6
5
3
) δ 3.25 (dd, J ) 18.05, 5.13 Hz, 1H), 3.29 (dd, J ) 18.05,
.59 Hz, 1H), 3.45 (d, J ) 4.88 Hz, 1H), 4.40-4.51 (m, 1H),
.90 (dt, J ) 55.74, 3.41 Hz, 1H), 7.46 and 7.90 (AB quartet,
1
3
f
13
J ) 8.78 Hz, 4H); C NMR (CDCl
2
1
3
) δ 37.74 (s), 67.60 (t, J )
-
1 1
3
) δ
4.81 Hz), 115.38 (t, J ) 243.98 Hz), 129.13 (s), 129.56 (s),
1
(
1
(
(
19
34.49 (s), 140.50 (s), 197.46 (s); F NMR (CDCl ) δ -50.83
3
(
ddd, J ) 287.92, 55.74, 9.92 Hz, 1F), -53.71 (ddd, J ) 287.92,
5.74, 14.31 Hz, 1F); MS (EI) m/z (rel intensity) 234 (1.9), 141
34.7), 139 (100.0), 113 (7.4), 111 (24.3). Anal. Calcd: C, 51.19;
H, 3.87. Found: C, 51.31; H, 3.98.
,4-Diflu or o-3-h yd r oxy-1-(4-n it r op h en yl)-1-b u t a n on e
e: R 0.04 (benzene); mp 88.0-89.0 °C (hexane/ethyl acetate);
IR (KBr) 1691.8 (CdO), 3445.3 (OH) cm ; H NMR (CDCl
5
(
3
F
NMR (CDCl
intensity) 224 (M , 3.7), 206 (0.5), 169 (15.2), 141 (12.1), 123
3
4
+
5
f
(
(
3.4), 113 (5.0), 111 (22.7), 95 (2.2), 83 (100.0), 68 (11.6), 67
12.2). Anal. Calcd: C, 53.57; H, 6.74. Found: C, 53.54; H, 6.64.
-1 1
3
) δ
.12 (d, J ) 4.87 Hz, 1H), 3.33 (dd, J ) 18.05, 4.39 Hz, 1H),
.39 (dd, J ) 18.05, 7.81 Hz, 1H), 4.45-4.56 (m, 1H), 5.92 (dt,
3
3
6
,6,6-Tr iflu or o-5-h yd r oxy-2,2-d im e t h yl-3-h e xa n on e
3
k : R 0.17 (benzene); mp 44.4-44.8 °C (hexane/ethyl acetate);
f
J ) 55.62, 3.41 Hz, 1H), 8.15 and 8.35 (AB quartet, J ) 9.27
Hz, 4H); C NMR (CDCl
-
1 1
IR (KBr) 1708.9 (CdO), 3518.7 (OH) cm ; H NMR (CDCl
3
) δ
.18 (s, 9H), 2.80 (dd, J ) 17.81, 2.69 Hz, 1H), 2.91 (dd, J )
7.81, 9.03 Hz, 1H), 3.42 (d, J ) 4.39 Hz, 1H), 4.42-4.53 (m,
13
3
) δ 38.48 (s), 67.50 (t, J ) 24.81 Hz),
15.22 (t, J ) 243.98 Hz), 124.04 (s), 129.26 (s), 140.51 (s),
1
1
1
1
1
2
1
1
19
50.75 (s), 196.95 (s); F NMR (CDCl
3
) δ -50.76 (ddd, J )
1
3
H); C NMR (CDCl ) δ 26.01 (s), 36.34 (s), 44.52 (s), 66.92
19
3
88.78, 55.62, 9.54 Hz, 1F), -53.75 (ddd, J ) 288.78, 55.62,
(
q, J ) 31.98 Hz), 124.80 (q, J ) 280.64 Hz), 214.23 (s);
F
+
4.12 Hz, 1F); MS (EI) m/z (rel intensity) 227 (M - H
2
O; 19.7),
NMR (CDCl ) δ -1.59 (d, J ) 6.86 Hz, 3F); MS (EI) m/z (rel
3
76 (17.5), 151 (12.3), 150 (100.0), 149 (6.9), 134 (7.8), 133
+
intensity) 198 (M , 0.8), 141 (9.3), 87 (12.2), 85 (73.3), 84 (10.4),
3 (100.0), 82 (39.6), 71 (4.5). Anal. Calcd: C, 48.48; H, 6.61.
Found: C, 48.33; H, 6.42.
,4-Diflu or o-3-h yd r oxy-1-p h en yl-1-bu ta n on e 5a :1
R
f
(14.4), 120 (16.5), 105 (33.6), 104 (36.9), 103 (6.4), 102 (5.1),
8
9
2 (19.1), 83 (11.3), 77 (24.4), 76 (29.6), 75 (16.7), 74 (12.1).
Anal. Calcd: C, 48.99; H, 3.70; N, 5.71. Found: C, 49.00; H,
3.76; 5.66.
5
4
-
1 1
0
.08 (benzene); IR (KBr) 1684.1 (CdO), 3508.2 (OH) cm ; H
NMR (CDCl ) δ 3.29 (dd, J ) 17.93, 7.81 Hz, 1H), 3.34 (dd, J
17.93, 4.15 Hz, 1H), 3.43 (br s, 1H), 4.41-4.50 (m, 1H), 5.91
dt, J ) 55.87, 3.42 Hz, 1H), 7.48-7.52 (m, 2H), 7.60-7.65
4
,4,4-Diflu or o-3-h yd r oxy-1-(2-t h ien yl)-1-b u t a n on e 5f:
3
-1
R
f
0.05 (benzene); IR (neat) 1650.9 (CdO), 3442.2 (OH) cm
H NMR (CDCl ) δ 3.23 (dd, J ) 17.57, 5.86 Hz, 1H), 3.27 (dd,
J ) 17.81, 6.11 Hz, 1H), 3.49 (d, J ) 4.88 Hz, 1H), 4.38-4.49
;
)
1
3
(
(
1
3
m, 1H), 7.96-7.99 (m, 2H); C NMR (CDCl ) δ 37.77 (s), 67.74
3
(
3
3
m, 1H), 5.88 (dt, J ) 55.87, 3.42 Hz, 1H), 7.17 (dd, J ) 4.88,
.90 Hz, 1H), 7.72 (dd, J ) 4.88, 0.98 Hz, 1H), 7.78 (dd, J )
.90, 0.98 Hz, 1H); 13C NMR (CDCl
) δ 38.23 (s), 67.81 (t, J )
(
23) Kiehlmann, E.; Menon, B. C.; McGillivray, N. Can. J . Chem.
973, 51, 3177.
3
1
25.64 Hz), 115.36 (t, J ) 243.15 Hz), 128.40 (s), 133.06 (s),
J . Org. Chem, Vol. 68, No. 7, 2003 2859

Funabiki et al.
1
34.94 (s), 143.28 (s), 191.36 (s); 19F NMR (CDCl
3
) δ -50.80
ethyl acetate); IR (KBr) 1686.0 (CdO), 3410.6 (OH) cm-1; 1H
(ddd, J ) 288.63, 55.87, 9.54 Hz, 1F), -53.65 (ddd, J ) 287.63,
NMR (CDCl
4.74-4.87 (m, 1H), 7.48 and 7.92 (AB quartet, J ) 8.78 Hz,
4H); 13C NMR (CDCl
3
) δ 3.29-3.43 (m, 2H), 3.48 (d, J ) 4.88 Hz, 1H),
+
5
1
8
5.87, 13.74 Hz, 1F); MS (EI) m/z (rel intensity) 206 (M , 2.7),
88 (10.1), 186 (4.5), 155 (4.2), 126 (8.1), 111 (100.0), 110 (15.3),
3 (10.4); HRMS (EI) found m/z 206.0246, calcd for C
3
) δ 37.55 (s), 66.01 (dd, J ) 29.25, 22.91
8
H
8
F
2
O
2
S
Hz), 113.50 (ddq, J ) 260.33, 253.26 and 36.22 Hz), 118.91
M, 206.0213.
P e n t a flu o r o -3-h y d r o x y -4,4,5,5,5-1-p h e n y l-1-p e n -
ta n on e 6a : R 0.23 (benzene); mp 98.0-99.0 °C (hexane/ethyl
acetate); IR (KBr) 1684.1 (CdO), 3350.8 (OH) cm ; H NMR
CDCl ) δ 3.35-3.46 (m, 2H), 3.57 (d, J ) 4.39 Hz, 1H), 4.74-
.88 (m, 1H), 7.49-7.53 (m, 2H), 7.62-7.66 (m, 1H), 7.97-
(qt, J ) 285.84, 35.35 Hz), 129.17 (s), 129.57 (s), 134.27 (s),
140.77 (s), 196.65 (s); 19F NMR (CDCl
) δ -3.84 (s, 3F), -44.31
3
f
(dd, J ) 276.57, 4.96 Hz, 1F), -52.90 (dd, J ) 276.57, 18.70
-
1
1
+
Hz, 1F); MS (EI) m/z (rel intensity) 302 (M , 0.7), 141 (63.7),
(
3
140 (16.8), 139 (100.0), 113 (17.9), 111 (53.9), 76 (9.2), 75 (29.1),
69 (6.0). Anal. Calcd for C, 43.66; H, 2.66. Found: C, 43.55;
H, 2.38.
4
7
2
1
1
3
.99 (m, 2H); C NMR (CDCl ) δ 37.49 (s), 66.26 (dd, J ) 29.25,
3
2.92 Hz), 113.68 (ddq, J ) 260.69, 253.13 and 36.01 Hz),
19.00 (qt, J ) 286.00, 35.59 Hz), 128.25 (s), 128.89 (s), 134.23
Ack n ow led gm en t. We thank Professors H. Ya-
manaka and T. Ishihara as well as Dr. T. Konno of the
Kyoto Institute of Technology for the HRMS measure-
ments of 3a -h and 5a . We thank Professor T. Kitazume
and Dr. T. Yamazaki of the Tokyo Institute of Technol-
ogy for the elemental analysis of 5b-e and 6a -c. We
are also grateful to Dr. H. Muramatsu for his valuable
discussions. We thank the Central Glass Co., Ltd., for
the gift of trifluoroacetaldehyde ethyl hemiacetal and
hydrate. This work was partially supported by a Grant-
in-Aid for Encouragement of Young Scientists (B) (Grant
No.14750665) from the Ministry of Education, Culture,
Sports, Science and Technology of J apan.
(
s), 136.00 (s), 198.06 (s); 19F NMR (CDCl
3
) δ -3.84 (s, 3F),
-
1
44.36 (dd, J ) 276.57, 5.72 Hz, 1F), -52.96 (dd, J ) 276.57,
8.70 Hz, 1F); MS (EI) m/z (rel intensity) 268 (M , 1.3), 248
+
(
7.6), 149 (3.8), 106 (30.4), 105 (100.0), 78 (18.4) 77 (10.0). Anal.
Calcd: C, 49.26; H, 3.38. Found: C, 49.25; H, 3.35.
,4,5,5,5-P en ta flu or o-3-h yd r oxy-1-(4-m eth ylp h en yl)-1-
p en ta n on e 6b: R 0.25 (benzene); mp 91.5-92.5 °C (hexane/
ethyl acetate); IR (KBr) 1662.8 (CdO), 3481.9 (OH) cm ; H
NMR (CDCl ) δ 2.44 (s), 3.32-3.42 (m, 2H), 3.65 (d, J ) 3.42
Hz, 1H), 4.72-4.88 (m, 1H), 7.30 and 7.87 (AB quartet, J )
4
f
-
1 1
3
1
3
7
(
3
.81 Hz, 4H); C NMR (CDCl
dd, J ) 29.01, 22.68 Hz), 113.75 (ddq, J ) 260.20, 253.14,
6.20 Hz), 119.04 (qt, J ) 286.49, 35.58 Hz), 128.38 (s), 129.54
3
) δ 21.65 (s), 37.31 (s), 66.25
1
9
(
(
2
1
3
s), 133.58 (s), 145.33 (s), 197.70 (s); F NMR (CDCl ) δ -3.88
s, 3F), -44.41 (dd, J ) 276.76, 5.34 Hz, 1F), -53.03 (dd, J )
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 5a ,f. This material is available free of charge via
the Internet at http://pubs.acs.org.
+
76.76, 18.69 Hz, 1F); MS (EI) m/z (rel intensity) 282 (M , 1.7),
20 (10.5), 119 (100.0), 91 (33.8), 83 (4.6), 77 (2.2), 65 (11.8).
Anal. Calcd for C, 51.07; H, 3.93. Found: C, 51.13; H, 3.78.
,4,5,5,5-P en ta flu or o-1-(4-ch lor op h en yl)-3-h yd r oxy-1-
p en ta n on e 6c: R 0.30 (benzene); mp 93.0-94.0 °C (hexane/
4
f
J O026697J
2
860 J . Org. Chem., Vol. 68, No. 7, 2003