Reversal of diastereoselectivity in reactions of the trifluoroacetaldehyde ethyl hemiacetal with enamines and imines: Metal-free, complementary anti-and syn-selective synthesis of 4,4,4-trifluoro-1-aryl-3-hydroxy-2-methyl-1-butanones

Article abstract of DOI:10.1021/jo101733j

A complete reversal of diastereoselectivity was observed for reactions of the trifluoroacetaldehyde ethyl hemiacetal with enamines and imines, derived from propiophenones, that produce 4,4,4-trifluoro-1-aryl-3-hydroxy-2-methyl-1- butanones. This process s

Full text of DOI:10.1021/jo101733j

pubs.acs.org/joc
interest, the substrates are limited to some aliphatic ketones2
Reversal of Diastereoselectivity in Reactions of the
Trifluoroacetaldehyde Ethyl Hemiacetal with
Enamines and Imines: Metal-Free, Complementary
anti- and syn-Selective Synthesis of 4,4,4-Trifluoro-
1-aryl-3-hydroxy-2-methyl-1-butanones
or aldehydes,3 and there is no example that involves aromatic
ethyl ketones.4
In recent investigations, we have explored reactions of the
ethyl hemiacetal of trifluoroacetaldehyde (CF3CHO) with
various enamines and imines derived from methyl ketones as
part of a regio-5,6 and enantio-controlled7 asymmetric meth-
ods for the synthesis of 1-aryl- and 1-alkyl-4,4,4-trifluoro-3-
hydroxy-1-butanones. Furtheremore, recently, we reported
the L-proline-catalyzed complementary syn- and anti-selective
synthesis of 2-(2,2,2-trifluoro-1-hydroxyethyl)cycloalkanones
via the direct aldol reaction of CF3CHO hemiacetal with
aliphatic cyclic ketones.8 Below, we describe the first metal-
free, complementary anti- and syn-selective method to pre-
pare 4,4,4-trifluoro-1-aryl-3-hydroxy-2-methyl-1-butanones
by the reactions of CF3CHO hemiacetal with enamines or
imines, derived from aromatic ethyl ketones, which should
have a significant impact and basic information for the organo-
catalytic direct diastereoselective aldol reaction of aro-
matic ethyl ketones, leading to R-methylated aldol products
(Scheme 1).
Kazumasa Funabiki,* Kei Matsunaga, Hiroshi Gonda,
Hitoshi Yamamoto, Takao Arima, Yasuhiro Kubota, and
Masaki Matsui
Department of Materials Science and Technology, Faculty of
Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193,
Japan
funabiki@gifu-u.ac.jp
Received September 3, 2010
SCHEME 1. Complementary anti- or syn-Selective Synthesis of
4,4,4-Trifluoro- and 4,4-Difluoro-1-aryl-3-hydroxy-2-methyl-1-
butanones (4, 5)
A complete reversal of diastereoselectivity was observed
for reactions of the trifluoroacetaldehyde ethyl hemiacetal
with enamines and imines, derived from propiophenones,
that produce 4,4,4-trifluoro-1-aryl-3-hydroxy-2-methyl-
1-butanones. This process serves as the first reliable,
metal-free, complementary anti- and syn-selective method
to prepare 4,4,4-trifluoro-1-aryl-3-hydroxy-2-methyl-1-
butanones.
The development of diastereo- and enantioselective meth-
ods for the synthesis of β-hydroxy-R-methylated aldol prod-
ucts based on aldol reactions continues to be of crucial
importance in organic syntheses, since these units appear in
many natural products such as macrolide antibiotics. For
this purpose, many complementary anti- and syn-selective
aldol reactions that use metal-enolates to give the β-hydroxy-
R-alkylated ketones, esters, and amides have been well studied.1
Although metal-free or organocatalytic complementary dia-
stereoselective direct aldol reactions are also of increasing
(3) For recent examples of R-alkylated aldehydes, syn-adducts, see: (a) Li, J.;
Fu, N.; Li, X.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2010, 75, 4501. For anti-
adductts, see: (b) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan,
D. W. C. Angew. Chem., Int. Ed. 2004, 43, 2152.
(4) For organocatalytic asymmetric direct aldol reaction of aromatic
methyl ketones, see: (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983. (b) Mei, K.; Zhang, S.;
He, S.; Li, P.; Jin, M.; Xue, F.; Luo, G.; Zhang, H.; Song, L.; Duan, W.;
Wang, W. Tetrahedron Lett. 2008, 49, 2681. (c) Carpenter, R. D.; Fettinger,
J. C.; Lam, K. S.; Kurth, M. J. Angew. Chem., Int. Ed. 2008, 47, 6407.
(5) For methyl ketones, see: (a) Funabiki, K.; Nojiri, M.; Matsui, M.;
Shibata, K. Chem. Commun. 1998, 2051. (b) Funabiki, K.; Matsunaga., K.;
Matsui, M.; Shibata, K. Synlett 1999, 1477. (c) Funabiki, K.; Matsunaga, K.;
Nojiri, M.; Hashimoto, W.; Yamamoto, H.; Matsui, M.; Shibata, K. J. Org.
Chem. 2003, 68, 2853. For aldehydes, see: (d) Funabiki, K.; Furuno, K.;
Sato, F.; Gonda, H.; Kubota, Y.; Matsui, M. Chem. Lett. 2010, 39, 410.
(6) Funabiki, K. In Fluorine-Containing Synthons; Soloshonok, V., Ed.;
ACS Symposium Series 911; Oxford University Press/American Chemical
Society: Washington, DC, 2005; p 342.
(1) A recent book, see: Modern Aldol Reactions;Mahrwald, R., Ed.;
Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2004.
(2) For recent examples of R-methyl-, chloro-, and fluoro- alkoxy-, hydroxy-
aliphatic ketones, syn-adducts, see: (a) Xu, X.-Y.; Wang, Y.-Z.; Gong, L.-Z.
Org. Lett. 2007, 9, 4247. (b) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.;
Barbas, C. F., III J. Am. Chem. Soc. 2007, 129, 288. (c) Ramasastry, S. S. V.;
Albertshofer, K.; Utsumi, N.; Tanaka, F.; Barbas, C. F., III Angew. Chem., Int.
Engl. 2007, 46, 5572. (d) Utsumi, N.; Imai, M.; Tanaka, F.; Ramasastry, S. S. V.;
Barbas, C. F., III Org. Lett. 2007, 9, 3445. (e) Teo, Y.-C.; Chua, G.-L.; Ong
C.-Y.; Poh, C.-Y. Tetrahedron Lett. 2009, 50, 4854. For anti-products, see:
(f) Enders, D.; Grondal, C. Angew. Chem., Int. Ed. 2005, 44, 1210. (g) Suri, J. T.;
Ramachary, D. B.; Barbas, C. F., III Org. Lett. 2005, 7, 1383. (h) Ibrahem, I.;
Cordova, A. Tetrahedron Lett. 2005, 46, 3363.
(7) Funabiki, K.; Hashimoto, W.; Matsui, M. Chem. Commun. 2004,
2056.
(8) (a) Funabiki, K.; Yamamoto, H.; Nagaya, H.; Matsui, M. Tetra-
hedron Lett.2006, 47, 5507. (b) Funabiki, K.; Matsui, M. Current Fluoroorganic
Chemistry; Soloshonok,V., Mikami, K., Yamazaki, T., Welch, J. T., Honek, J. F.,
Eds.; ACS Symposium Series 949; Oxford University Press/American Chemical
Society: Washington, DC, 2007; p 141. Saito and Yamamoto also reported the
same results of chloral with cycloalkanones; see ref 4a.
DOI: 10.1021/jo101733j
r
Published on Web 12/03/2010
J. Org. Chem. 2011, 76, 285–288 285
2010 American Chemical Society

Funabiki et al.
JOCNote
TABLE 1. Optimization of the Reaction Conditions for anti-Selective
TABLE 2. anti-Selective Synthesis of 4,4,4-Trifluoro- and 4,4-Di-
Synthesis of 4aa
fluoro-1-aryl-3-hydroxy-2-methyl-1-butanones 4, 5a
entry
1
2
solvent temp (°C), time (h) yield (%)b (syn:anti)c
1
2
3
4
1a 2a hexane
1a 2a hexane
1a 2a hexane
1a 2a hexane
1a 2a toluene
1a 2a CH2Cl2
1a 2a CH2Cl2
1a 2a CH2Cl2
1a 2bg CH2Cl2
rt, 24
0, 48
63
39
27
21
43
63
70
71
13
17
24
18:82
11:89
9:91
-15, 120
-78 to rtd
-78 to rtd
-78 to rtd
-78 to rtd
-15, 72
10:90
19:81
6:94e
10:90e
4:96e
17:83
4:96e
4:96e
5
yield of
4, 5 (%)b
6
entry
1
2
condition
Ar
(syn:anti)c
7f
8f
9
1
2
3
4
5
6
7
8
9
1a 2a
1a 2a
1a 2c
1a 2d
1a 2e
1a 2f
1a 2gd
1a 2he
1a 2if
A
B
A
A
A
A
B
B
B
A
A
Ph
Ph
4a: 71 4:96 (>98% de)
4a: 70 10:90 (>98% de)
-78 to rtd
-78 to rtd
-15, 72
10f 1b 2a CH2Cl2
4-MeC6H4
4-MeOC6H4 4c: 87
4b: 67
5:95 (>98% de)
7:93 (>98% de)
7:93 (>98% de)
6:94 (>98% de)
10:90 (>98% de)
11
1b 2a CH2Cl2
4-ClC6H4
4-FC6H4
3-ClC6H4
2-FC6H4
4-PhC6H4
2-thienyl
Ph
4d: 86
4e: 64
4f: 72
aConditions: CF3CHO ethyl hemiacetal 1a or hydrate 1b (1 mmol),
enamine 2 (1 mmol, E/Z = 98/2), solvent (4 mL). bYields of isolated
products. cDetermined by 19F NMR analysis of the crude reaction
mixture. dOvernight. eAfter column chromatography, the de of 4a was
>98%. f1a (3 equiv) was used. gE/Z = 89/11.
4g: 76 10:90 (>98% de)
8:92 (>98% de)
7:93 (>98% de)
4h: 63
4i: 74
5a: 73 12:88
10 1a 2jg
11 1c 2a
aConditions: ethyl hemiacetal 1a,c (3 mmol), enamine 2 (1 mmol,
E/Z = 98/2), CH2Cl2 (4 mL). bCombined yields of isolated anti- and syn-
products. cDetermined by 19F NMR analysis of the crude reaction
mixture. Values in parentheses are the de of 4 after column chromatog-
raphy. dE/Z = 97/3. eE/Z = 97/3. fE/Z = 99/1. gE/Z = 96/4.
Initially, upon treatment of CF3CHO ethyl hemiacetal 1a
with 1 equiv of enamine 2a (E:Z = 98:2), prepared from
propiophenone with morpholine, in hexane at room tem-
perature for 24 h, followed by hydrolysis with 10% HCl aq at
room temperature, 4,4,4-trifluoro-3-hydroxy-2-methyl-1-
phenyl-1-butanone (4a) was obtained in 63% yield with
anti-selectivity9 (syn:anti = 18:82) (Table 1, entry 1). The
results of the reaction of hemiacetal 1a with enamines 2a under
various reaction conditions are summarized in Table 1. When
reaction of CF3CHO ethyl hemiacetal 1a with the propio-
phenone enamine 2a is performed at 0 and -15 °C for long
time periods (48 and 120 h), the aldol product 4a is generated
in respective yields of 39% and 27% and with syn:anti dia-
stereomer ratios of 11:89 and 9:91, respectively (entries 2 and 3).
In addition, when hexane is used as solvent for this reaction
carried out from -78 °C to room temperature overnight, 4a
is formed in yields and diastereoselectivities that are similar
to those resulting from use of the shortest reaction time
(entry 4). Among the solvents examined (hexane, toluene,
and CH2Cl2), the use of CH2Cl2 for reaction of 1a with
enamines 2a leads to formation of 4a in a satisfactory yield
(63%) and a high anti-selectivity (syn:anti = 6:94, entry 6).
For the reaction in toluene, the aldol product 4a is produced
in 43% yield with a lower anti-selectivity than seen when
either hexane or CH2Cl2 is employed as solvent (entry 5).
When the amount of hemiacetal 1a is increased to 3 equiv, the
efficiencies for formation of fluorinated phenones 4a are
increased (entry 7). Importantly, reaction of enamine 2a with
3 equiv of 1a at -15 °C for 72 h gives 4a in 71% yield with
the highest observed diastereoselectivity (entry 8). Enamine
2b carrying a diethylamino group in place of morpholino-
substituted 2a was not suitable for the reaction, because of
decreasing diastereoselectivity (entry 9). Reactions of the hydrate
of CF3CHO 1b with enamine 2a under the optimized conditions
produce 4a in low yields (17-24%) but with high diastereo-
selectivities. The reason for the significant decrease in yield seen in
reactions of the hydrate 1b is not yet clear (entries 10 and 11).
The results of reactions between hemiacetal 1a,c and various
enamines 2 run under optimized conditions are summarized in
Table 2.
Reactions of hemiacetal 1a with various enamines 2a,c,d
derived from phenones containing phenyl, 4-methylphenyl,
and 4-methoxyphenyl groups proceed smoothly to give the
corresponding 4,4,4-trifluoro-3-hydroxy-2-methyl-1-aryl-1-
butanones 4a,b,c in 67-87% yields with high anti-selectiv-
ities under the optimized reaction conditions (entries 1-4).
Other enamines, carrying 4-chlorophenyl, 4-fluorophenyl,
3-chlorophenyl, 2-fluorophenyl, and biphenyl groups also
participated well in the reaction of 1a to produce the
corresponding 4,4,4-trifluoro-3-hydroxy-2-methyl-1-aryl-1-
butanones 4d,e,f,g,h in 63-86% yields with high anti-selec-
tivities under either of the optimized reaction conditions
(entries 5-9). The reactions of 1a with enamine 2i having a
heteroaromatic group, such as a 2-thienyl substituent, at -15 °C
for 72 h proceed smoothly to give the corresponding products
4i in 74% yield and with high anti-selectivity (entry 10).
Notably, in all cases of 4, good to excellent anti-selectivities are
observed, and the major diastereomers (>98% de) can be
readily separated by using silica gel column chromatography.
Finally, reaction of difluoroacetaldehyde (CHF2CHO)
ethyl hemiacetal 1c with enamine 1a generates the corre-
sponding difluoromethyl-aldol product 5a in 73% yield
with slightly lower diastereoselectivity (syn:anti = 12:88)
than is observed with the trifluoro-substituted analogue,
due to the lower bulkiness of the difluoromethyl group com-
pared with trifluoromethyl group (entry 11).10 Unfortunately,
(9) The relative configurations were determined by NMR, according to
the literature: (a) Ishii, A.; Kojima, J.; Mikami, K. Org. Lett. 1999, 1, 2013.
(b) Ishii, A.; Mikami, K. J. Fluorine Chem. 1999, 97, 51.
286 J. Org. Chem. Vol. 76, No. 1, 2011

Funabiki et al.
JOCNote
TABLE 3. Optimization of the Reaction Conditions for syn-Selective
TABLE 4. syn-Selective Synthesis of 4,4,4-Trifluoro- and 4,4-Difluoro-
Synthesis of 4aa
1-aryl-3-hydroxy-2-methyl-1-butanones 4, 5a
entry
1
3
solvent temp (°C), time (h) yield (%)b (syn:anti)c
1
2
3
4
5
6
7
8
9
1a 3a hexane
1a 3a hexane
1a 3a hexane
1a 3a hexane
1a 3b hexane
1a 3c hexane
1a 3c toluene
1a 3c CH2Cl2
1b 3c toluene
rt, 24
0, 48
75
27
tr
45
30
63
68
62
62
80:20
84:16
yield of
4, 5 (%)b
entry
1
3
condition
Ar
(syn:anti)c
-15, 120
-78 to rtd
-78 to rtd
-78 to rtd
-78 to rtd
-78 to rtd
-78 to rtd
1
2
3
4
5
6
7
8
9
1a 3c
1a 3d
1a 3e
1a 3f
1a 3g
1a 3h
1a 3i
1a 3j
1a 3k
C
C
C
C
C
D
D
D
D
C
Ph
4a: 68
4b: 60
4c: 63
4d: 64
4e: 61
4f: 52
4g: 64
4h: 31
4i: 58
5a: 56
90:10 (>98% de)
90:10 (>98% de)
91:9 (>98% de)
82:18 (>98% de)
80:20 (>98% de)
79:21 (>98% de)
86:14 (>98% de)
70:30 (>98% de)
80:20 (>98% de)
65:35
84:16
72:28
88:12
90:10e
85:15e
92:8e
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
3-ClC6H4
2-FC6H4
4-PhC6H4
2-thienyl
Ph
aConditions: CF3CHO ethyl hemiacetal 1a (1 mmol), imine 3a
(1 mmol), solvent (4 mL). bYields of isolated products. cDetermined
by 19F NMR analysis of the crude reaction mixture. dOvernight. eAfter
column chromatography, the de of 4a was >98%.
10 1c 3c
aConditions: ethyl hemiacetal 1a,c, imine 3 (1 mmol), toluene (4 mL).
bCombined yields of isolated anti- and syn-products. cDetermined by 19
NMR analysis of the crude reaction mixture. Values in parentheses are
the de of 4 after column chromatography.
F
the diastereomers of difluoro-substituted 5a cannot be separated
by using flash chromatography.
Next, treatment of CF3CHO ethyl hemiacetal 1a with 1
equiv of imine 3a, prepared by the reaction of propiophe-
none with cyclohexylamine in hexane at room temperature
for 24 h, followed by hydrolysis with 10% HCl aq at room
temperature, gives rise to 4a in 75% yield in a syn:anti ratio of
80:20 (Table 3, entry 1).
When lower reaction temperatures (0 or -15 °C) and
longer reaction times (48 and 120 h) are employed, 4a is
formed in dramatically reduced yields and only slightly
higher diastereoselectivity (syn:anti = 84:16, entries 2 and 3).
When this reaction is performed using hexane as solvent
from -78 °C to room temperature (overnight), the aldol product
4a isgeneratedin45%yieldwithasyn:anti diastereoselectivity of
84:16 (entry 4). The findings of this effort show that substituents
on the imine nitrogen strongly influence both the yields and
isomer ratios seen in these processes (entries 4, 5, and 6). For
example, imine 3b that possesses a n-butyl group on nitrogen
reacts with a decreased efficiency and a low diastereoselectivity
(entry 5). In addition, reaction of hemiacetal 1a with imine 3c,
carrying a N-tert-butyl group, gives product 4a in 63% yield and
with better diastereoselectivity (syn:anti = 88:12, entry 6).
Finally, the effect of solvent on this reaction was examined.
The use of toluene led to both the highest yield and diastereo-
selectivity (syn:anti = 90:10, entry 7). In contrast, reaction in
CH2Cl2 was not effective since a slightly lower yield and a much
lower diastereoselectivity (syn:anti = 85:15) were observed
(entry 8). The CF3CHO hydrate 1b also reacts with imine 3c
to produce 4a in 62% yield with the same high syn-selectivity
(syn:anti = 92:8).
FIGURE 1. Proposed transition states.
overnight. These processes produce aldol products 4b,c
in 60-63% yields and with high syn-diastereoselectivities
(syn:anti = 90:10-91:9) (entries 2 and 3). 4-Chlorophenyl
and 4-fluorophenyl containing imines 3f,g react with hemi-
acetal 1a under the same conditions to give the correspond-
ing products 4d,e in similar good yields and lower syn-
diastereoselectivities (entries 4 and 5). The reaction of imines
3 h,i,j,k carrying the 3-chlorophenyl, 2-fluorophenyl, biphe-
nyl, and 2-thienyl groups was achieved by the use of an excess
amount (5 equiv) of hemiacetal 1a to give the corresponding
products 4f,g in 31-64% yields with lower syn-diastereo-
selectivities (entries 6-9). Finally, reaction of CHF2CHO
ethyl hemiacetal 1c with the imine 3c also proceeds smoothly
to give the corresponding difluoromethyl-aldol product 5a in
56% yield, but with a lower diastereoselectivity (syn:anti =
65:35, entry 10).
For the reversal of diastereoselectivity in the reaction of
hemiacetal 1a with enamines 2 or imines 3, it could be
realized by the explanation that in situ generated CF3CHO5
reacts with enamine 2 or 30 (MeCHdC(Ar)NHt-Bu), which
is a tautomer of imine 3, through the open transition state
(T1 or T2), as shown in Figure 1. According to the literature
of not only the aldol reaction of CF3CHO11 but also chiral
pyrrolidines or primary amines-catalyzed anti- or syn-selec-
tive asymmetric direct aldol reaction of fluorine-free alde-
hydes,2,3 the trifluoromethyl group is situated in antiperiplanar
The results of reactions of hemiacetal of CF3CHO or
CHF2CHO 1a,c with various imines 3 under optimized
conditions are also given in Table 4.
Imines 3d,e, containing 4-methylphenyl and 4-methoxy-
phenyl substituents, participate in smooth reactions with 1
equiv of 1a in toluene from -78 °C to room temperature
(10) Tafts, K. W., Jr Steric Effects in Organic Chemistry; Newman, M. S.,
Ed.; John Wiley & Sons: New York, 1956; p 556.
(11) Makino, M.; Iseki, K.; Fujii, K.; Oishi, S.; Hirano, T.; Kobayashi, Y.
Tetrahedron Lett. 1995, 36, 6527.
J. Org. Chem. Vol. 76, No. 1, 2011 287

Funabiki et al.
JOCNote
asymmetric complementary direct aldol reaction with aromatic
ethyl ketones are currently being investigated.
Experimental Section
Typical Procedure (Condition A) for the Synthesis of anti-
4,4,4-Trifluoro-3-hydroxy-2-methyl-1-aryl-1-butanones. To a so-
lution of CF3CHO ethyl hemiacetal 1a (3 mmol, 0.432 g) in
CH2Cl2 (4 mL) was added enamine 2a (1 mmol, 0.203 g) at -15 °C
under an argon atmosphere. After being stirred at -15 °C for 72 h,
the mixture was hydrolyzed with 10% HCl aq (4 mL) at room
temperature for 24 h, extracted with Et2O (30 mL ꢀ 3), dried over
Na2SO4, and concentrated under vacuum. After the distribution of
the diastereomers was determined by 19F NMR, the residue was
subjected to chromatography on silica gel using hexane-EtOAc
(10:1) give 4,4,4-trifluoro-3-hydroxy-2-methyl-1-phenyl-1-butanone
(4a) (0.165 g, 71%). anti-4,4,4-Trifluoro-3-hydroxy-2-methyl-1-phe-
FIGURE 2. Synthesis of both diastereomers of the trifluoromethyl-
ated analogue of Muguesia.
of the carbon-carbon double bond of enamine 2, because of
electrostatic interaction of the trifluoromethyl group in T1 and
T2, which minimizes the gauche interaction between the tri-
fluoromethyl and the methyl group on the forming bond. In T2,
not only the steric interaction between the aryl and the methyl
groups2a,3a but also hydrogen bonding between the oxygen atom
and amino group are also important for syn-selectivities.
Unfortunately, 4-nitrobenzaldehyde as a fluorine-free al-
dehyde did not react with enamine 2a or imine 3a under the
same conditions. The reaction of ethyl glyoxalate with enamine
2h in toluene under the same conditions (condition B) occurred
to give ethyl 4-(2-fluorophenyl)-2-hydroxy-3-methyl-4-oxobu-
tanoate in 69% yield (syn:anti = 33:67). However, the reaction
of imine 3i with ethyl glyoxalate (condition D) gave ca. 40%
yield of intermediate, followed by the hydrolysis to give a trace
amount of the aldol product, since the retro-aldol reaction
should occurr during the hydrolysis. These results indicate that
the potent electron-withdrawing property and bulkiness of the
trifluoromethyl group accelerates the metal-free carbon-carbon
bond formation reaction with high diastereoselectivities.
Finally, synthesis of both diastereomers of trifluoromethyl-
ated analogue 6a of Muguesia,12 which is a kind of odorant, was
carried out (Figure 2). Reductive decarbonylation of thus-
obtained anti- and syn-4a in the presence of a catalytic amount
(5 mol %) of Pd (10 wt %) on carbon with hydrogen (1 atm) in
ethanol at room temperature for 1 h smoothly occurred without
epimerization to give anti- and syn-1,1,1-trifluoro-3-methyl-4-
phenylbutan-2-ol (6a) in 76-79% yields. Odor evaluation of
racemic 6a was not carried out at the present time.
In conclusion, a complete reversal of the diastereoselec-
tivity has been observed for the carbon-carbon bond for-
mation reactions of the ethyl hemiacetal of CF3CHO with either
enamines and imines, derived from propiophenones. These
reactions, which produce 4,4,4-trifluoro-3-hydroxy-2-methyl-
1-aryl-1-butanones, serve as the first reliable, metal-free, com-
plementary anti- and syn-selective routes for the preparation
of the aldol products. The extension of this method to the
nylbutan-1-one (anti-4a): IR (neat) 1682 (CdO), 3441 (OH) cm-1
;
1H NMR (CDCl3) δ 1.43 (d, J = 7.32 Hz, 3H), 3.89 (dq, J = 7.32,
4.29 Hz, 1H), 4.20 (dquin, J = 7.64, 4.29 Hz, 1H), 4.73 (d, J =
8.29 Hz, 1H), 7.49-7.53 (m, 2H), 7.61-7.65 (m, 1H), 7.94-7.96
(m, 2H); 13C NMR (CDCl3) δ 15.9 (s), 37.9 (s), 73.8 (q, J =
30.3 Hz), 125.0 (q, J= 283.4 Hz), 128.4 (s), 128.9 (s), 134.2 (s), 135.4
(s), 204.5 (s); 19F NMR (CDCl3, TFA) δ 0.99 (d, J = 7.64 Hz, 3F);
HRMS (CI-FAB) found m/z 233.0788, calcd for C11H12F3O2
(M þ H) 233.0790.
Typical Procedure (Condition C) for the Synthesis of syn-4. To
a solution of 1a (1 mmol, 0.144 g) in toluene (4 mL) was added
imine 3c (1 mmol, 0.189 g) at -78 °C under an argon atmo-
sphere. After being stirred overnight from -78 °C to room
temperature, the mixture was hydrolyzed with 10% HCl aq
(4 mL) at room temperature for 48 h, extracted with Et2O
(30 mL ꢀ 3), dried over Na2SO4, and concentrated under
vacuum. After the distribution of the diastereomers was deter-
mined by 19F NMR, the residue was subjected to chromatogra-
phy on silica gel using hexane-EtOAc (10:1) to give 4a (0.158 g,
68%). syn-4a: IR (neat) 1684 (CdO), 3448 (OH) cm-1; 1H NMR
(CDCl3) δ 1.32 (d, J = 7.28 Hz, 3H), 3.40 (br s, 1H), 3.77 (dq, J =
7.28, 3.54 Hz, 1H), 4.47 (dq, J = 6.83, 3.54 Hz, 1H), 7.40-7.46
(m, 2H), 7.53-7.58 (m, 1H), 7.84-7.91 (m, 2H); 13C NMR
(CDCl3) δ 11.8 (s), 40.0 (s), 70.1 (q, J = 30.9 Hz), 124.7 (q, J =
281.2 Hz), 128.6 (s), 129.0 (s), 134.0 (s), 134.7 (s), 203.0 (s); 19F
NMR (CDCl3, TFA) δ 1.32 (d, J = 6.83 Hz, 3F); HRMS (CI)
found m/z 233.0788, calcd for C11H12F3O2 (M þ H) 233.0789.
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research (C) (19550104) and
Young Scientists (B) (14750665) of the Japan Society for
the Promotion of Science (JSPS). We are grateful to Central
Glass Co., Ltd., for the gift of CF3CHO hemiacetal as well as
for financial support. We thank not only Professors T. Ishihara
and T. Konno of the Kyoto Institute of Technology but also
Dr. Tomoko Yajima of Ochanomizu University for the HRMS
measurements.
Supporting Information Available: Detailed procedures and
1
characterization of all of the compounds; H and 13C NMR
spectra for 4, 5, and 6. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) Abate, A.; Brenna, E.; Fuganti, C.; Gatti, F. G.; Giovenzana, T.;
Malpezzi, L.; Serra, S. J. Org. Chem. 2005, 70, 1281.
288 J. Org. Chem. Vol. 76, No. 1, 2011