Solvent free synthesis of trifluoromethyl tertiary alcohols by cross Aldol reaction

Article abstract of DOI:10.1016/j.cclet.2015.04.015

Abstract Exceedingly fast preparation of trifluoromethyl tertiary alcohols has been accomplished from methyl ketones and trifluoromethyl ketones under solvent free conditions by cross Aldol reaction. The reaction was achieved in the presence of common ino

Full text of DOI:10.1016/j.cclet.2015.04.015

G Model
CCLET 3282 1–4
Chinese Chemical Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
Solvent free synthesis of trifluoromethyl tertiary alcohols by cross
Aldol reaction
*
Q1 Rui Tao, Xue-Jiao Yin, Ke-Hu Wang , Yu-Zhuo Niu, Ya-Lin Wang, Dan-Feng Huang,
5
6
*
Ying-Peng Su, Jin-Xian Wang, Yu-Lai Hu , Ying Fu, Zheng-Yin Du
7
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Exceedingly fast preparation of trifluoromethyl tertiary alcohols has been accomplished from methyl
ketones and trifluoromethyl ketones under solvent free conditions by cross Aldol reaction. The reaction
was achieved in the presence of common inorganic base by grinding method at ambient temperature to
Received 10 January 2015
Received in revised form 13 March 2015
Accepted 24 March 2015
Available online xxx
give
b-trifluoromethyl-b-hydroxyl ketones in high yields (up to 95%).
ß 2015 Ke-Hu Wang and Yu-Lai Hu. Published by Elsevier B.V. on behalf of Chinese Chemical Society and
Institute of Materia Medica, Chinese Academy of Medical Sciences. All rights reserved.
Keywords:
Cross Aldol reaction
Grinding
Solvent free
Trifluoromethyl tertiary alcohols
8
9
1. Introduction
solvent free organic reactions were reported to afford high 31
conversions and yields in short reaction time at ambient 32
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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29
30
Organic trifluoromethyl compounds are of increasing impor-
tance as pharmaceuticals, agrochemicals and functional materials
[1]. Introduction of trifluoromethyl group into organic compounds
usually induces dramatic consequences on their physical, chemical
and biological properties [1,2]. Among trifluoromethylated com-
pounds, trifluoromethyl tertiary alcohols are important inter-
mediates or trifluoromethyl group building blocks in organic
synthesis [3] and are desirable starting materials for preparing
liquid crystals [4] and drugs such as Efavirenz (anti-HIV) [5].
Many methods for preparation of trifluoromethyl tertiary
alcohols have been developed. Higashiyama’s group reported
the direct catalytic Aldol reaction of trifluoromethyl ketones with
ketones to prepare trifluoromethyl tertiary alcohols using diethyl-
zinc secondary amine complex as catalysts [6]. Organocatalytic
Aldol addition of methyl ketones to aryl trifluoromethyl ketones
temperature [8].
33
Our research group is engaged in green chemistry [9] and 34
fluorine chemistry [10] for many years. Herein, we will report 35
exceedingly fast preparation of trifluoromethyl tertiary alcohols 36
from Aldol reaction between methyl ketones and trifluoromethyl 37
ketones in high yields under solvent free conditions.
38
2. Experimental
39
All reactions were conducted in a 30 mL pear-shaped flask. 40
Reagents were obtained from commercial suppliers and used 41
without further purification unless otherwise noted. Flash column 42
chromatography was carried out using Qingdao silica gel (230– 43
400 mesh). Analytical thin layer chromatography (TLC) was done 44
using Qingdao silica gel (silica gel GF254). TLC plates were 45
analyzed by an exposure to ultraviolet (UV) light and/or in I2. 1
NMR, 13C NMR and 19F NMR spectra were recorded at 400 MHz 47
and 100 MHz on Varian Mercury 400 plus instrument, respec- 48
afforded
b-trifluoromethyl-b-hydroxyl ketones in good to excel-
H
46
lent yield [7]. Although the above methods provided easy access to
trifluoromethyl tertiary alcohols, it is still necessary to find more
environment benign methods.
Solvent free organic reactions have attracted much research
interest from the point of green chemistry in recent years. Many of
tively. Chemical shifts are reported as
d values (ppm) relative to 49
tetramethylsilane (TMS) for 1H NMR and chloroform for 13C NMR. 50
Coupling constants (J) are reported in Hertz (Hz). Melting points 51
were uncorrected. Infrared spectra were recorded on an IR 52
spectrometer (Perkin Elmer BX FT-IR), and absorption frequencies 53
were reported in reciprocal centimeters (cmꢀ1). The HRMS 54
data were measured on MALDI-TOF type of instrument for the 55
*
Corresponding authors.
E-mail addresses: wangkh@nwnu.edu.cn (K.-H. Wang), huyl@nwnu.edu.cn
(Y.-L. Hu).
high-resolution mass spectra.
56
http://dx.doi.org/10.1016/j.cclet.2015.04.015
1001-8417/ß 2015 Ke-Hu Wang and Yu-Lai Hu. Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical
Sciences. All rights reserved.
Please cite this article in press as: R. Tao, et al., Solvent free synthesis of trifluoromethyl tertiary alcohols by cross Aldol reaction, Chin.
Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.04.015

G Model
CCLET 3282 1–4
2
R. Tao et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
57
2.1. Synthesis of
b
-trifluoromethyl-
b
-hydroxyl ketones 3
(s, 3H). 13C NMR (100 MHz, DMSO-d6):
129.2, 128.2, 127.8, 127.7, 126.5, 125.4 (q, J = 285.1 Hz), 75.2 (q,
J = 27.3 Hz), 41.1, 21.1. 19F NMR (376 MHz, DMSO-d6):
4,4,4-Trifluoro-3-hydroxy-1-(4-methoxyphenyl)-3-phenylbu-
tan-1-one (3h) [6]: White solid, mp: 90–91 8C. 1H NMR (400 MHz,
DMSO-d6): d 7.92 (d, 2H, J = 7.6 Hz), 7.58 (d, 2H, J = 6.8 Hz), 7.28–
7.34 (m, 3H), 7.00 (d, 2H, J = 7.6 Hz), 6.56 (s, 1H), 4.15 (d, 1H,
J = 17.2 Hz), 3.81 (s, 3H), 3.70 (d, 1H, J = 17.2 Hz). 13C NMR
d
194.9, 143.8, 138.0, 134.5,
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
The mixture of trifluoroacetophenone (34.8 mg, 0.2 mmol) and
acetophenone (24.0 mg, 0.2 mmol) was put into oven-dried, 30 mL
pear-shaped flask at room temperature, and then lithium
hydroxide powder (5.3 mg, 0.22 mmol) was added. The mixture
was grinded and stirred in the flask at room temperature for
5–16 min, and then dissolved in water (5 mL) and ethyl acetate
(5 mL). The organic phase was separated. Aqueous phase was
extracted with ethyl acetate (3ꢁ 5 mL). The organic layer was
combined, dried over anhydrous MgSO4, and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography with petroleum ether and ethyl acetate
as eluent to give the pure 3a. Other target products were obtained
in the same procedure.
d
ꢀ79.53.
(100 MHz, DMSO-d6):
127.7, 126.5, 125.4 (q, J = 285.2 Hz), 113.8, 75.3 (q, J = 27.3 Hz),
55.6, 40.7. 19F NMR (376 MHz, DMSO-d6):
d 194.1, 163.4, 138.1, 130.6, 129.9, 127.8,
d
ꢀ74.74.
4,4,4-Trifluoro-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylbu-
tan-1-one (3i) [11]: White solid, mp: 112–113 8C. 1H NMR
(400 MHz, DMSO-d6): d 11.40 (s, 1H), 7.84 (d, 1H, J = 8.0 Hz),
7.61 (d, 2H, J = 6.8 Hz), 7.49 (t, 1H, J = 7.6 Hz), 7.30–7.35 (m, 3H),
6.94 (d, 2H, J = 7.2 Hz), 6.65 (s, 1H), 4.31 (d, 1H, J = 17.6 Hz), 3.86 (d,
1H, J = 17.6 Hz). 13C NMR (100 MHz, DMSO-d6):
d 200.0, 160.2,
138.1, 136.1, 131.0, 128.1, 128.0, 126.7, 125.6 (q, J = 285.5 Hz),
122.0, 119.4, 117.8, 75.3 (q, J = 27.0 Hz), 43.1. 19F NMR (376 MHz,
4,4,4-Trifluoro-3-hydroxy-1,3-diphenylbutan-1-one (3a) [6]:
White solid, mp: 42–43 8C. 1H NMR (400 MHz, DMSO-d6):
d
7.95
(d, 2H, J = 7.6 Hz), 7.61–7.65 (m, 3H), 7.51 (t, 2H, J = 7.2 Hz), 7.28–
7.37 (m, 3H), 6.62 (s, 1H), 4.27 (d, 1H, J = 17.2 Hz), 3.83 (d, 1H,
J = 17.2 Hz). 13C NMR (100 MHz, DMSO-d6):
d
200.2, 143.1, 142.1,
138.4, 133.7, 133.1, 132.9, 132.8, 131.6, 130.5 (q, J = 285.0 Hz), 80.2
(q, J = 27.2 Hz), 46.5. 19F NMR (376 MHz, CDCl3):
ꢀ77.01.
1-(2-Bromophenyl)-4,4,4-trifluoro-3-hydroxy-3-phenylbutan-
1-one (3b) [7d]: Colorless oil. 1H NMR (400 MHz, CDCl3):
7.58–
DMSO-d6):
d
ꢀ77.01.
1-([1,10-Biphenyl]-4-yl)-4,4,4-trifluoro-3-hydroxy-3-phenyl-
d
butan-1-one (3j): White solid, mp: 51–52 8C. 1H NMR (400 MHz,
DMSO-d6): d 8.02 (d, 2H, J = 8.0 Hz), 7.79 (d, 2H, J = 8.0 Hz), 7.72
d
(d, 2H, J = 7.2 Hz), 7.63 (d, 2H, J = 7.2 Hz), 7.49 (t, 2H, J = 7.2 Hz),
7.40–7.43 (m, 1H), 7.29–7.36 (m, 3H), 6.64 (s, 1H), 4.27 (d, 1H,
J = 17.2 Hz), 3.83 (d, 1H, J = 17.2 Hz). 13C NMR (100 MHz, DMSO-
7.62 (m, 3H), 7.26–7.35 (m, 5H), 7.18–7.19 (m, 1H), 5.36 (s, 1H),
3.96 (d, 1H, J = 17.2 Hz), 3.74 (d, 1H, J = 17.2 Hz). 13C NMR
(100 MHz, CDCl3):
128.8, 128.4, 127.6, 126.4, 124.4 (q, J = 283.5 Hz), 118.8, 76.6 (q,
J = 29.1 Hz), 45.1. 19F NMR (376 MHz, CDCl3):
ꢀ80.50.
1-(3-Bromophenyl)-4,4,4-trifluoro-3-hydroxy-3-phenylbutan-
1-one (3c): Colorless oil. 1H NMR (400 MHz, DMSO-d6):
8.07 (s,
1H), 7.91 (d, 1H, J = 7.2 Hz), 7.83 (d, 1H, J = 7.6 Hz), 7.61 (d, 2H,
J = 6.8 Hz), 7.46 (t, 1H, J = 7.6 Hz), 7.41–7.23 (m, 3H), 6.64 (s, 1H),
4.28 (d, 1H, J = 17.6 Hz), 3.80 (d, 1H, J = 17.6 Hz). 13C NMR
(100 MHz, DMSO-d6):
133.0, 132.9, 132.2, 131.7, 130.5 (q, J = 285.2 Hz), 127.2, 80.2 (q,
J = 27.4 Hz), 47.1. 19F NMR (376 MHz, CDCl3):
Calcd. for C16H12BrF3O2 (M + Na): 394.9865, Found: 394.9870.
1-(4-Bromophenyl)-4,4,4-trifluoro-3-hydroxy-3-phenylbutan-
1-one (3d) [3]: White solid, mp: 109–110 8C. 1H NMR (400 MHz,
d
203.4, 140.5, 137.1, 133.9, 132.6, 129.0,
d6):
132.8, 132.1, 131.9, 131.6, 130.5 (q, J = 285.3 Hz), 80.3 (q,
J = 27.3 Hz), 46.5. 19F NMR (376 MHz, DMSO-d6):
d 199.9, 149.8, 143.9, 143.1, 140.9, 134.2, 133.9, 133.5, 132.9,
d
d
ꢀ79.46.
HRMS (ESI) Calcd. for C22H17F3O2 (M + Na): 393.1073, Found:
393.1078.
d
4,4,4-Trifluoro-3-hydroxy-1-(5-methylfuran-2-yl)-3-phenyl-
butan-1-one (3k): Colorless oil. 1H NMR (400 MHz, DMSO-d6):
d
7.61 (d, 2H, J = 6.4 Hz), 7.51 (s, 1H), 7.34 (d, 3H, J = 7.6 Hz), 6.67 (s,
1H), 6.36 (s, 1H), 3.88 (d, 1H, J = 16.0 Hz), 3.51 (d, 1H, J = 16.0 Hz),
90
91
92
93
94
95
96
97
d 199.1, 144.2, 143.0, 141.0, 136.0, 135.8,
2.33 (s, 3H). 13C NMR (100 MHz, DMSO-d6):
d
182.6, 158.2, 150.9,
137.5, 128.0, 127.7, 126.5, 125.2 (q, J = 284.8 Hz), 121.5, 109.4, 75.2
(q, J = 27.5 Hz), 40.7, 13.5. 19F NMR (376 MHz, DMSO-d6):
d
ꢀ80.62. HRMS (ESI)
d
ꢀ79.34.
HRMS (ESI) Calcd. for C15H13F3O3 (M + Na): 321.0709, Found:
321.0714.
DMSO-d6):
d
7.87 (d, 2H, J = 7.6 Hz), 7.72 (d, 2H, J = 7.2 Hz), 7.61
4,4,4-Trifluoro-3-hydroxy-3-phenyl-1-(pyridin-3-yl)butan-1-
one (3l): Colorless oil. 1H NMR (400 MHz, DMSO-d6):
d 9.05 (s, 1H),
8.75 (d, 1H, J = 4.0 Hz), 8.22 (d, 1H, J = 7.2 Hz), 7.59 (d, 2H,
J = 6.8 Hz), 7.48–7.52 (m, 1H), 7.28–7.32 (m, 3H), 6.67 (s, 1H), 4.25
(d, 1H, J = 17.2 Hz), 3.83 (d, 1H, J = 17.2 Hz). 13C NMR (100 MHz,
(d, 2H, J = 6.8 Hz), 7.30–7.36 (m, 3H), 6.62 (s, 1H), 4.24 (d, 1H,
J = 17.6 Hz), 3.79 (d, 1H, J = 17.6 Hz). 13C NMR (100 MHz, DMSO-
98
99
d6):
130.5 (q, J = 285.0 Hz), 80.2 (q, J = 27.3 Hz), 46.7. 19F NMR
(376 MHz, DMSO-d6):
ꢀ79.54.
1-(2-Chlorophenyl)-4,4,4-trifluoro-3-hydroxy-3-phenylbutan-
d 199.4, 143.0, 141.2, 136.8, 135.3, 133.0, 132.9, 132.5, 131.6,
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
d
DMSO-d6):
131.6, 130.5 (q, J = 285.2 Hz), 128.8, 80.2 (q, J = 27.3 Hz), 47.3. 19F
NMR (376 MHz, DMSO-d6):
ꢀ79.36. HRMS (ESI) Calcd. for
15H12F3NO2 (M + H): 296.0893, Found: 296.0898.
1-(2,5-Dimethylthiophen-3-yl)-4,4,4-trifluoro-3-hydroxy-3-
phenylbutan-1-one (3m): Colorless oil. 1H NMR (400 MHz, DMSO-
d6): 7.59 (d, 2H, J = 7.2 Hz), 7.32–7.37 (m, 4H), 6.54 (s, 1H), 4.01 (d,
1H, J = 17.2 Hz), 3.57 (d, 1H, J = 17.2 Hz), 2.43 (s, 3H), 2.39 (s, 3H).
13C NMR (100 MHz, DMSO-d6):
196.5, 151.5, 143.1, 141.0, 139.9,
132.9, 132.8, 131.9, 131.6, 130.4 (q, J = 285.5 Hz), 80.3 (q,
J = 26.7 Hz), 49.0, 20.6, 19.7. 19F NMR (376 MHz, DMSO-d6):
d 199.7, 158.5, 154.4, 142.9, 140.7, 137.5, 133.0, 132.9,
1-one (3e) [7d]: Colorless oil. 1H NMR (400 MHz, DMSO-d6):
7.50–7.56 (m, 3H), 7.42 (s, 2H), 7.29–7.36 (m, 4H), 6.82 (s, 1H), 4.09
(d, 1H, J = 16.8 Hz), 3.65 (d, 1H, J = 16.8 Hz). 13C NMR (100 MHz,
d
d
C
DMSO-d6):
127.7, 127.0, 126.5, 125.2 (q, J = 285.4 Hz), 75.0 (q, J = 27.4 Hz),
45.9. 19F NMR (376 MHz, DMSO-d6):
ꢀ79.49.
4,4,4-Trifluoro-3-hydroxy-1-(3-nitrophenyl)-3-phenylbutan-
1-one (3f): Colorless oil. 1H NMR (400 MHz, DMSO-d6):
8.59 (s,
d 197.0, 138.7, 136.9, 132.0, 130.1, 129.4, 129.2, 127.9,
d
d
d
d
1H), 8.43 (d, 1H, J = 7.8 Hz), 8.33 (d, 1H, J = 7.2 Hz), 7.78 (t, 1H,
J = 8.0 Hz), 7.61 (d, 2H, J = 6.8 Hz), 7.23–7.40 (m, 3H), 6.72 (s, 1H),
4.36 (d, 1H, J = 17.2 Hz), 3.88 (d, 1H, J = 17.2 Hz). 13C NMR
(100 MHz, DMSO-d6):
133.1, 132.9, 132.5, 131.7, 130.6 (q, J = 284.8 Hz), 127.7, 80.2 (q,
J = 27.7 Hz), 47.6. 19F NMR (376 MHz, DMSO-d6):
(ESI) Calcd. for C16H12F3NO4 (M + Na): 362.0611, Found: 362.0617.
4,4,4-Trifluoro-3-hydroxy-3-phenyl-1-(p-tolyl)butan-1-one
(3g) [6]: White solid, mp: 72–73 8C. 1H NMR (400 MHz, DMSO-d6):
d
ꢀ74.87. HRMS (ESI) Calcd. for C16H15F3O2S (M + H): 329.0818,
Found: 329.0824.
d
198.8, 153.1, 143.5, 142.8, 139.5, 135.6,
4,4,4-Trifluoro-3-hydroxy-3-(4-nitrophenyl)-1-phenylbutan-
1-one (3n): Colorless oil. 1H NMR (400 MHz, DMSO-d6):
d 8.20 (d,
d
ꢀ79.40. HRMS
2H, J = 8.0 Hz), 7.90–7.92 (m, 4H), 7.60–7.62 (m, 1H), 7.48–7.51 (m,
2H), 7.02 (s, 1H), 4.41 (d, 1H, J = 18.0 Hz), 3.94 (d, 1H, J = 18.0 Hz).
13C NMR (100 MHz, DMSO-d6):
d
199.1, 152.2, 151.0, 141.7, 138.5,
133.7, 133.1, 130.2 (q, J = 285.4 Hz), 127.9, 79.9 (q, J = 27.2 Hz),
46.8. 19F NMR (376 MHz, DMSO-d6):
ꢀ79.40. HRMS (ESI) Calcd.
for C16H12F3NO4 (M + H): 340.0791, Found: 340.0796.
d
7.83 (d, 2H, J = 7.2 Hz), 7.59 (d, 2H, J = 6.8 Hz), 7.28–7.32 (m, 5H),
d
6.56 (s, 1H), 4.20 (d, 1H, J = 17.2 Hz,), 3.74 (d, 1H, J = 17.2 Hz,), 2.35
Please cite this article in press as: R. Tao, et al., Solvent free synthesis of trifluoromethyl tertiary alcohols by cross Aldol reaction, Chin.
Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.04.015

G Model
CCLET 3282 1–4
R. Tao et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
3
Table 1
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
3-(3-Bromophenyl)-4,4,4-trifluoro-3-hydroxy-1-phenylbutan-
1-one (3o) [7d]: Colorless oil. 1H NMR (400 MHz, DMSO-d6):
7.92
Optimization of reaction conditions for the synthesis of 3a.a
d
(d, 2H, J = 7.6 Hz), 7.82 (s, 1H), 7.61 (d, 2H, J = 5.6 Hz), 7.49–7.51
(m, 3H), 7.27–7.31 (m, 1H), 6.79 (s, 1H), 4.31 (d, 1H, J = 17.6 Hz),
3.83 (d, 1H, J = 17.6 Hz). 13C NMR (100 MHz, DMSO-d6):
d 194.4,
140.8, 136.8, 133.3, 130.6, 129.8, 129.3, 128.5, 128.0, 125.5, 125.1
(q, J = 285.2 Hz), 121.3, 74.5 (q, J = 27.3 Hz), 41.3. 19F NMR
.
Entry
Base
Temp. (8C)
Time (min)
Yield (%)b
(376 MHz, DMSO-d6):
3-(4-Chlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-phenylbutan-
1-one (3p) [6]: White solid, mp: 71–73 8C. 1H NMR (400 MHz,
d
ꢀ79.70.
1
2
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
LiOH
r.t.
0
5
30
5
80
77
3
40
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
46
DMSO-d6):
d 7.94 (d, 2H, J = 7.2 Hz), 7.64–7.66 (m, 3H), 7.50–7.53
4
7
79
(m, 2H), 7.42 (d, 2H, J = 7.2 Hz), 6.78 (s, 1H), 4.30 (d, 1H,
J = 17.6 Hz), 3.86 (d, 1H, J = 17.6 Hz). 13C NMR (100 MHz, DMSO-
5
12
15
8
78
6
78
d6):
125.2 (q, J = 285.3 Hz), 74.6 (q, J = 27.8 Hz), 41.2. 19F NMR
(376 MHz, DMSO-d6):
d
194.5, 137.1, 136.8, 133.3, 132.6, 128.5, 128.4, 127.9, 127.6,
7
89
8
KOH
4
65
9
Cs2CO3
K2CO3
Na2CO3
NaOCH3
NEt3
10
20
20
5
86
d
ꢀ79.82.
10
11
12
13
14
56
4,4,4-Trifluoro-3-hydroxy-3-(4-methoxyphenyl)-1-phenylbu-
tan-1-one (3q) [6]: White solid, mp: 71–72 8C. 1H NMR (400 MHz,
Trace
23
20
6
Trace
76
DMSO-d6):
d 7.93 (d, 2H, J = 7.2 Hz,), 7.60–7.61 (m, 1H), 7.49–7.51
DBU
(m, 4H), 6.88 (d, 2H, J = 8.4 Hz), 6.51 (s, 1H), 4.18 (d, 1H,
J = 17.2 Hz), 3.75 (d, 1H, J = 17.2 Hz), 3.72 (s, 3H). 13C NMR
a
Reaction conditions: a mixture of 1a (0.2 mmol), 2a (0.2 mmol), and base
(0.22 mmol) was grinded under solvent free conditions.
(100 MHz, DMSO-d6):
128.0, 127.8, 125.4 (q, J = 284.8 Hz), 113.1, 74.9 (q, J = 27.5 Hz),
55.0, 41.2. 19F NMR (376 MHz, DMSO-d6):
ꢀ79.84.
4,4,4-Trifluoro-3-hydroxy-1-phenyl-3-(p-tolyl)butan-1-one
(3r) [6]: Colorless oil. 1H NMR (400 MHz, DMSO-d6):
7.94 (d, 2H,
d 195.4, 158.8, 137.0, 133.3, 129.7, 128.6,
b
Yield of isolated product.
d
prolong the reaction time (Table 1, entry 2). However, the yield of 3a 252
was only 46% with the appearance of ethanol-insoluble solid when 253
the reaction temperature was increased to 40 8C (Table 1, entry 3). 254
The effects of reaction time were examined next. The results 255
demonstrated that 5 min was enough for completion of the reaction 256
(Table 1, entries 4–6). When the reaction time was prolonged, the 257
yield of 3a will not change too much. The choice of base was crucial 258
to obtain good yields (Table 1, entries 7–14). A series of bases were 259
tested, it was found that LiOH was the best base (Table 1, entry 7). 260
Thus, the best result was achieved in the presence of LiOH at room 261
d
J = 6.8 Hz), 7.62–7.63 (m, 1H), 7.50 (s, 4H), 7.14 (d, 2H, J = 7.2 Hz),
6.54 (s, 1H), 4.23 (d, 1H, J = 17.2 Hz), 3.77 (d, 1H, J = 17.2 Hz), 2.28
(s, 3H). 13C NMR (100 MHz, DMSO-d6):
d
195.2, 137.0, 134.9, 133.3,
128.6, 128.3, 128.0, 126.4, 125.4 (q, J = 285.0 Hz), 75.0 (q,
J = 27.0 Hz), 41.2, 20.5. 19F NMR (376 MHz, DMSO-d6):
d
ꢀ79.73.
4,4,4-Trifluoro-3-hydroxy-3-(naphthalen-1-yl)-1-phenylbu-
tan-1-one (3s) [7d]: White solid, mp: 80–81 8C. 1H NMR (400 MHz,
DMSO-d6): d 9.16 (s, 1H), 8.07 (d, 2H, J = 7.6 Hz), 7.97–8.02 (m, 2H),
7.74–7.75 (m, 2H), 7.66–7.52 (m, 4H), 7.46–7.48 (m, 1H), 6.99 (s,
1H), 4.88 (d, 1H, J = 18.4 Hz), 4.00 (d, 1H, J = 18.4 Hz). 13C NMR
temperature under solvent free conditions (Table 1, entry 7).
In order to demonstrate the efficiency and the applicability of 263
the method, the reactions were performed with various methyl 264
262
(100 MHz, DMSO-d6):
d 194.9, 136.8, 134.3, 133.4, 133.1, 131.9,
129.5, 128.6, 128.5, 127.9, 127.6, 126.7, 126.0 (q, J = 286.2 Hz),
125.3, 125.1, 124.4, 78.4 (q, J = 28.9 Hz), 43.2. 19F NMR (376 MHz,
Table 2
DMSO-d6):
d
ꢀ78.07.
Solvent free synthesis of
methyl ketones.a
b-trifluoromethyl-b-hydroxyl ketones from various
228
3. Results and discussion
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
Although many methods for preparation of trifluoromethyl
organic compounds have been developed by using trifluoromethy-
lation reagents, such as Togni reagent, Umemoto reagent, and
Ruppert-Prakash reagent, trifluoromethyl group-containing build-
ing blocksstill play important rolesinpreparation oftrifluoromethyl
compounds because of their easy commercial availability, low cost
and stability [12]. The Aldol reaction using trifluoromethyl ketones
were apparently a convergent method for preparation of trifluor-
omethyl tertiary alcohols. Thus, we firstly tried the Aldol reaction
between trifluoroacetophenone 1a and acetophenone 2a in the
presence of NaOH without any catalyst at room temperature under
.
Entry
R
Products
Time (min)
Yield (%)b
1
2
C6H5
3a
3b
3c
3d
3e
3f
8
89
2-BrC6H4
3-BrC6H4
4-BrC6H4
2-ClC6H4
3-NO2C6H4
4-MeC6H4
4-MeOC6H4
2-OHC6H4
4-PhC6H4
8
91
3
8
84
4
10/20
8
79/73c
95
5
6
16
8
Trace/70c
87
7
3g
3h
3i
8
10
6
71
solvent free conditions to get
b-trifluoromethyl-b-hydroxyl
9
Trace/86c
Trace/67c
87
ketones. Thereaction proceededsmoothlyto generate Aldol product
4,4,4-trifluoro-3-hydroxy-1,3-diphenylbutan-1-one 3a with the
yield of 80%. However, if the ethanol was used as solvent, there
was no reaction occurred. It was found that the reaction was
exothermic under grinding condition with liquification of the
reaction mixture, and then solidification of the product 3a [13].
In order to improve the yields of the products, the reaction
temperature was firstly examined. It was found that the tempera-
ture had great influence on the reaction. When the reaction was
carried out at room temperature, the product 3a could be obtained
in 80% yield (Table 1, entry 1). Lowering reaction temperature would
10
11
12
13
3j
10
8
2-(5-Methyl-furanyl)
3-Pyridinyl
3k
3l
16
16
84
3-(2,5-Dimethyl-
thiophthyl)
3m
63
14
15
C2H5
10
8
NDd
NDd
Cyclohexanone
a
Reaction conditions:
a mixture of 1 (0.2 mmol), 2 (0.2 mmol), and LiOH
(0.22 mmol) was grinded at room temperature under solvent free conditions.
b
Yield of isolated product.
c
DBU (0.22 mmol) was used as base instead of LiOH.
d
No detected.
Please cite this article in press as: R. Tao, et al., Solvent free synthesis of trifluoromethyl tertiary alcohols by cross Aldol reaction, Chin.
Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.04.015

G Model
CCLET 3282 1–4
4
R. Tao et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
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306
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325
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365
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379
380
381
382
383
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386
387
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390
Table 3
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heterocycles by utilizing gem-difluorocyclopropyl tosylate, Chin. Chem. Lett. 25
(2014) 24–28.
Solvent free synthesis of
trifluoromethyl ketones.a
b-trifluoromethyl-b-hydroxyl ketones from various
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intuition, Science 317 (2007) 1881–1886;
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chemistry, Chem. Soc. Rev. 37 (2008) 320–330;
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Chem. 51 (2008) 4359–4369.
.
Entry
R
Products
Time (min)
Yield (%)b
1
2
3
4
5
6
4-NO2C6H4
3-BrC6H4
3n
3o
3p
3q
3r
10
16
16
8
Trace/83c
[3] H. Kawai, S. Okusu, E. Tokunaga, N. Shibata, Enantioselective synthesis of 5-tri-
fluoromethyl-2-isoxazolines and their N-oxides by [hydroxy(tosyloxy)iodo] ben-
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and Future Directions, ACS, Washington, 1999, pp. 255–269.
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74
76
88
80
71
4-ClC6H4
4-MeOC6H4
4-MeC6H4
1-Naphthyl
16
8
3s
a
Reaction conditions:
a
mixture of
1
(0.2 mmol),
2
(0.2 mmol), and LiOH
(0.22 mmol) was grinded at room temperature under solvent free conditions.
b
Yield of isolated products.
c
DBU (0.22 mmol) was used as base instead of LiOH.
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
ketones and trifluoromethyl ketones under the optimized condi-
tions. The results are summarized in Tables 2 and 3.
It showed that aromatic methyl ketones and trifluoromethyl
ketones reacted smoothly affording the corresponding
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ketones, Chem. Commun. 48 (2012) 4308–4310.
b-trifluor-
omethyl- -hydroxyl ketones in good to excellent yields (63–95%).
b
Aliphatic methyl ketones failed to give the desired products
(Table 2, entries 14 and 15). This is due to the cross condensations
between aliphatic methyl ketones to make the products very
complex. The reactions of heterocyclic ketones with trifluoroace-
tophenone proceeded smoothly to furnish the products in good
yields (Table 2, entries 11–13). The other trifluoromethyl ketones
could also be converted to the corresponding products (Table 3).
No obvious electronic effects of the ketones were observed.
In the course of the experiment, we found that when both
methyl ketones and trifluoromethyl ketones were liquid, the solid
base LiOH was the best suitable base to obtain the corresponding
products 3 in excellent yields. For example, 1-(4-bromopheny-
l)ethanone reacted with trifluoroacetophenone smoothly to afford
the corresponding compound 3d with the yield of 79% when LiOH
was used as base. Liquid organic base such as DBU could also been
used in the reaction to obtain reasonable yield of 3d (73%, Table 2,
entry 4). If methyl ketones or trifluoromethyl ketones were solid,
liquid base such as DBU must be used in order to obtain good yields
(Table 2, entries 6, 9, and 10; Table 3, entry 1).
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heterocyclic synthesis, Chem. Rev. 109 (2009) 4140–4182;
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addition, Green Chem. 13 (2011) 276–282;
(c) A. Kumar, S. Sharma, A grinding-induced catalyst- and solvent-free synthesis
of highly functionalized 1,4-dihydropyridines via a domino multicomponent
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(d) D. Wang, J. Li, N. Li, T. Gao, S. Hou, B. Chen, An efficient approach to
homocoupling of terminal alkynes: solvent-free synthesis of 1,3-diynes using
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(f) J. Yang, N. Li, S. Li, W. Wang, L. Li, A. Wang, X. Wang, Synthesis of diesel and jet
fuel range alkanes with furfural and ketones from lignocellulose under solvent
free conditions, Green Chem. 16 (2014) 4879–4884;
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highly substituted bicyclic pyridines containing a ring-junction nitrogen, Green
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289
4. Conclusion
290
291
292
293
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295
296
In conclusion, b-trifluoromethyl-b-hydroxyl ketones were
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successfully synthesized from cross Aldol reaction of methyl
ketones and trifluoromethyl ketones under solvent free conditions.
The reaction could be achieved smoothly with various aromatic
methyl ketones, even with some heterocyclic and aliphatic ketone.
The features of this procedure are mild conditions, high yields,
operational simplicity, and the environmental friendliness.
(b) X.Q. Men, T.J. Meng, J.X. Wang, L. Xin, Pd(II) catalyzed addition reaction of
benzylzinc bromides or allylzinc iodines with aromatic aldehydes, Chin. J. Org.
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centers featuring a trifluoromethyl group from prochiral trifluoromethylated
substrates, Chem. Rev. 111 (2011) 455–529.
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297
Acknowledgments
298 Q3
299
300
301
302
We are thankful for the financial support from the National
Natural Science Foundation of China (No. 21262031), Bioactive
Product Engineering Research Center for Gansu Distinctive Plants,
and State Key Laboratory of Applied Organic Chemistry, Lanzhou
University.
ˇˇ ´
(b) T. Friscic, W. Jones, Recent advances in understanding the mechanism of
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Please cite this article in press as: R. Tao, et al., Solvent free synthesis of trifluoromethyl tertiary alcohols by cross Aldol reaction, Chin.
Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.04.015