Organocatalytic domino Michael-aldol reaction of ketones and α,β-unsaturated trifluoromethyl ketones

Article abstract of DOI:10.1055/s-0028-1083255

Pyrrolidine-catalyzed domino Michael-aldol reaction of α,β- unsaturated trifluoromethyl ketones and ketones was achieved under mild conditions; β-hydroxy-β-trifluoromethyl cyclohexanones were obtained in high yields with good diastereoselectivities. Georg

Full text of DOI:10.1055/s-0028-1083255

PAPER
3967
Organocatalytic Domino Michael–Aldol Reaction of Ketones and
a,b-Unsaturated Trifluoromethyl Ketones
Organocatalytic
D
i
omino
a
o
ldol
R
eaction
-
s
Jin Wang, Yan Zhao, Jin-Tao Liu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: jtliu@mail.sioc.ac.cn
Received 4 August 2008; revised 8 September 2008
catalyzed asymmetric aldol reaction between methyl ke-
tones and aryl trifluoromethyl ketones was realized by
Zhang and co-workers, although only moderate enantio-
selectivities were obtained.7a During the course of our
studies on the reaction of trifluoromethyl substituted ke-
tones, it was found that the regioselectivity of the reaction
of ketones and a,b-unsaturated trifluoromethyl ketones
could be controlled by choosing an appropriate organocat-
alyst; unsaturated a-trifluoromethyl tertiary alcohols were
synthesized with good enantioselectivities from the aldol
reaction of methyl ketones and a,b-unsaturated trifluo-
romethyl ketones under the catalysis of proline-derived N-
sulfonylamide (Scheme 1, equation 1).7b When pyrroli-
dine was used as the catalyst, however, 3-hydroxy-3-(tri-
fluoromethyl)cyclohexanones were obtained through an
organocatalyzed Michael–aldol reaction (Scheme 1,
equation 2). A few methods could be found in the litera-
ture concerning access to this kind of structure. The reac-
tion of fluoroalkyl-containing 1,3-dicarbonyl compounds
with enones suffered from low yields.8a,b The Michael–
aldol reaction of cyclic enamines with a,b-unsaturated
trifluoromethyl ketones affording hydroxy- and trifluoro-
methyl-containing bicyclic ketones was reported recently,
but only cyclic enamines worked well in such cases and
the preformation of enamines was not atom-economic.8c,d
Herein we report the detailed results of pyrrolidine-cata-
lyzed domino Michael–aldol reaction of ketones and a,b-
unsaturated trifluoromethyl ketones, which provides a
practical method for the synthesis of b-hydroxy-b-tri-
fluoromethyl cyclohexanones.
Abstract: Pyrrolidine-catalyzed domino Michael–aldol reaction of
a,b-unsaturated trifluoromethyl ketones and ketones was achieved
under mild conditions; b-hydroxy-b-trifluoromethyl cyclohex-
anones were obtained in high yields with good diastereoselectivi-
ties.
Key words: bicyclic compounds, cyclizations, domino reactions,
organocatalytic, trifluoromethyl
The importance of fluorine-containing compounds in the
fields of agricultural, medicinal and material chemistry is
well known.1 Among various organofluorine compounds,
a-trifluoromethyl tertiary alcohols have attracted much at-
tention recently because they could serve as liquid
crystals2a and drugs such as Efavirenz (anti-HIV).2b,c On
the other hand, since cyclic compounds form the back-
bone of many bioactive compounds, the development of
synthetic methods for cyclic a-trifluoromethyl tertiary al-
cohols would be very valuable in the field of pharmaceu-
tical research.3
Except for the direct trifluoromethylation of ketones,4
most methods for the synthesis of a-trifluoromethyl tertia-
ry alcohols utilize a-trifluoromethyl ketones as precursors
and the aldol reaction of such ketones takes an important
place in those synthetic methodologies.5 However, pre-
formed enol or enolate derivatives are involved in those
reactions, which is not atom efficient. Recently, a direct
organocatalytic aldol reaction pioneered by List, Barbas
and co-workers has achieved great success.6 The proline-
O
O
O
S
N
H
Ph
O
CF3
O
O
O
N
HO
H
R2
(1)
(2)
R2
+
+
R1
R1
CF3
TFA
76–99%, ee up to 95%
O
pyrrolidine
(20 mol%)
O
OH
R
CF3
acetone, r.t.
R
CF3
2
1
Scheme 1
SYNTHESIS 2008, No. 24, pp 3967–3973
x
x.
x
x
.
2
0
0
8
Advanced online publication: 01.12.2008
DOI: 10.1055/s-0028-1083255; Art ID: F17708SS
© Georg Thieme Verlag Stuttgart · New York

3968
X.-J. Wang et al.
PAPER
To some extent, the domino reaction9 reported herein is
similar to the proline-catalyzed Robinson annulation pio-
neered by Hajos, Eder and co-workers thirty years ago,9a,b
and the domino Michael–aldol reaction of acyclic b-keto
esters and unsaturated ketones recently reported by
Jørgensen et al.9d,e However, instead of simple ketones,
reactive ketones such as 1,3-diketones and b-keto esters
were necessary in both cases. Recently, Tang and co-
workers also reported an annulation reaction of cyclic ke-
tones with enone esters,9h but only acetone gave the aldol
product in their reaction.
In our case, acetone and a,b-unsaturated trifluoromethyl
ketones underwent a domino Michael–aldol reaction
smoothly to give the corresponding b-hydroxy-b-trifluo-
romethyl cyclohexanones in good yields and with high
diastereoselectivities using pyrrolidine as the catalyst.
The results are summarized in Table 1. The reaction
showed a wide scope for the structural variation of unsat-
urated ketone 1. Good yields were obtained not only with
aryl unsaturated ketones (Table 1, entries 1–6), but alky-
nyl-, alkenyl- and alkyl-substituted unsaturated ketones
were also found to be suitable substrates (Table 1, entries
7–9).
Figure 1 ORTEP representation of the crystal structure of 2a
To investigate the potential for a catalytic asymmetric
process, we tried the reaction with various chiral second-
ary amine catalysts. Unfortunately, the asymmetric reac-
tion suffered from poor reactivity and enantioselectivity.
The best result was obtained with the catalysis of 2-
(diphenylmethyl)pyrrolidine (Scheme 2).
Taking acetone as an example, a possible mechanism for
the above domino Michael–aldol reaction was proposed
as shown in Scheme 3 referring to the reaction of en-
amines with unsaturated ketones 1.8c,d The addition of the
enamine, formed from the reaction of pyrrolidine and ac-
etone, to 1 gave an iminium intermediate, which subse-
quently tautomerized to the corresponding enamine 3. The
intramolecular aldol reaction may proceed via the chair
transition-state to give the final product 2 after hydrolytic
release of the catalyst.
Table 1 Domino Michael–Aldol Reaction of Acetone and a,b-Un-
saturated Trifluoromethyl Ketonesa
O
pyrrolidine
O
O
(20 mol%)
+
OH
R
CF3
acetone, r.t.
R
CF3
2
1
Entry
1
R
Time
(h)
Product d.r.b
Yield
(%)c
Like the reported reaction of cyclic enamines and unsatur-
ated trifluoromethyl ketones, cyclic ketones could also
undergo the domino Michael–aldol reaction with 1 under
the catalysis of pyrrolidine. As shown in Table 2, various
six-membered cyclic ketones reacted well with 1 and gave
only one bicyclic hydroxy ketone isomer with good yields
(Entries 1–3). The electronic properties of the substituent
had little effect on the reaction (Entries 3, 4 and 5). How-
ever, the orientation of the substituents in the bicyclic
products was different from that found in the cyclohex-
anones obtained from acetone. Based on X-ray diffraction
analysis of 2m, the phenyl substituent is in the axial posi-
tion, whereas the trifluoromethyl group is equatorial
(Figure 2).10
1
2
3
4
5
6
7
8
9
1a
1b
1d
1e
1f
Ph
6
5
2a
2b
2d
2e
2f
>95:5
72
87
67
75
72
71
71
61
71
4-ClC6H4
4-MeOC6H4
4-MeC6H4
1-naphthyl
2-furyl
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
10
10
10
5
1g
1h
1i
2g
2h
2i
PhC≡C
10
4
PhCH=CH
n-C8H17
1k
5
2k
a Reaction conditions: Unsaturated ketone 1 (0.5 mmol), pyrrolidine
(20 mol%), acetone (5 mL), stirring.
b Determined by 1H NMR analysis of crude product.
c Isolated yield.
Ph
O
N
O
H
Ph
O
(20 mol%)
CF3
+
OH
The relative stereochemistry of cyclohexanones 2 was
determined by X-ray crystallographic analysis of 2a
(Figure 1).10 The bulky phenyl and trifluoromethyl groups
were found to be in equatorial positions.
0 °C, 5 d
Ph
CF3
1a
2a
79%, 58% ee
Scheme 2
Synthesis 2008, No. 24, 3967–3973 © Thieme Stuttgart · New York

PAPER
Organocatalytic Domino Michael–Aldol Reactions
3969
O
O
O
O
pyrrolidine
OH
R
CF3
(20 mol%)
H2O
CF3
Ph
+
1
CH2Cl2, r.t.
12 h
F3C
N
O
75%, dr > 95:5
2r
H
O
N
Scheme 4
CF3
R
N
H
O
H
O
N
OH
CF3
CF3
R
R
H
O
2
N
3
H2O
CF3
R
Scheme 3
Figure 3 ORTEP representation of the crystal structure of 2r
Table 2 Domino Michael–Aldol Reaction of a,b-Unsaturated Tri-
fluoromethyl Ketones and Cycloketonesa
O
R
O
pyrrolidine
(20 mol%)
O
OH
In contrast, the configuration of bicyclic product 2r from
the reaction of 1a and cyclopentanone, differs with that of
2m (Scheme 4, Figure 3).10 Both phenyl and trifluoro-
methyl groups are in equatorial positions as indicated by
its X-ray crystallographic analysis.
+
R
CF3
CH2Cl2, r.t.
X
F3C
X
2
1
Entry
R
X
Time d.r.b
(h)
Product Yield
(%)c
The different stereochemical outcomes for the reactions
of cyclohexanone and cyclopentanone might be caused by
steric effects in the Michael addition step. Two possible
transition states have been proposed as shown in
Figure 4.8c,d In the case of cyclohexanone, the addition
might proceed through transition state A in order to mini-
mize steric interaction between the cyclohexenyl and the
phenyl groups. The reaction is kinetically controlled and
gives the less energetically favored addition product with
the phenyl substituent in the axial position. When cyclo-
pentanone is used as reactant, the less bulky cyclopente-
nyl group makes it possible to adopt transition state B,
which affords the more stable addition product with the
phenyl group in the equatorial position. Different reaction
stereochemistry for cyclopentanone and cylcohexanone
has also been observed in the organocatalytic Michael ad-
dition reaction of cycloketones with chalcones.11 The high
diastereoselectivity for cyclohexanone (d.r. >50:1) is in
sharp contrast to the low diastereomeric ratio (3:1) for cy-
clopentanone.
1
2
3
4
5
Ph
Ph
Ph
CH2
10
14
36
10
10
>95:5
>95:5
>95:5
>95:5
>95:5
2m
2n
2o
70
87
96
80
83
N(Me)
O
4-MeOC6H4 CH2
4-ClC6H4 CH2
2p
2q
a Reaction conditions: Unsaturated ketone 1 (0.25 mmol), cyclo-
ketone (2.5 mmol), pyrrolidine (20 mol%), CH2Cl2 (5 mL), stirring.
b Determined by 1H NMR analysis of crude product.
c Isolated yield.
In addition, similar results have also been reported for a
number of oganocatalytic reactions proceeding via enam-
ine intermediates,12 especially in the proline-derived tetra-
zole-catalyzed aldol reaction of chloral and ketones, in
which the syn-selectivity (80% de) for cyclopentanone
was changed to anti-selectivity (92% de) for cyclohex-
anone.12a The reason for this change is still unknown and
has not been addressed in the literature.
Figure 2 ORTEP representation of the crystal structure of 2m
In summary, we have developed a facile method for the
preparation of b-hydroxy-b-trifluoromethyl cyclohexan-
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3970
X.-J. Wang et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 7.39–7.25 (m, 5 H), 3.49 (tt,
J1 = 12.9, 3.9 Hz, 1 H), 2.81–2.44 (m, 5 H), 2.30–2.04 (m, 2 H).
19F NMR (282 MHz, CDCl3): d = –84.1 (s, 3 F).
13C NMR (75 MHz, acetone-d6): d = 36.2, 37.6, 45.0, 47.3, 75.1 (q,
J = 28.6 Hz), 125.8 (q, J = 283.4 Hz), 126.9, 127.0, 128.8, 143.5,
205.0.
N
O
N
CF3
CF3
H
O
H
H
MS (70 eV): m/z (%) = 258 (37.65) [M+], 104 (100).
H
B
A
Anal. Calcd for C13H13F3O2: C, 60.46; H, 5.07. Found: C, 60.73; H,
5.28.
Compound 2a was also prepared through an asymmetric domino
Michael–aldol reaction as follows: Unsaturated ketone 1a (48 mg,
0.24 mmol) and (S)-2-(diphenylmethyl)pyrrolidine (11 mg, 0.048
mmol) were added to a mixture of acetone (0.2 mL) and Et2O (5
mL) at 0 °C. The reaction mixture was stirred for 5 d at 0 °C. After
removal of the solvent, the crude reaction product was directly
charged onto the chromatography column and purified on silica gel
(PE–EtOAc, 10:1) to afford compound 2a.
N
F3C
O
O–
Ph
CF3
H
H
N+
20
Yield: 49 mg (79%); [a]D +7.7 (c = 0.52, CHCl3); chiral HPLC
A'
(chiralpak OD column; detected at 214 nm; n-hexane–i-PrOH,
70:30) retention times: 7.8 min (major), 11.2 min (minor).
F3C
5-(4-Chlorophenyl)-3-hydroxy-3-(trifluoromethyl)cyclohex-
anone (2b)
White solid; mp 158–159 °C.
O–
H
N
Ph
CF3
IR (film): 3332, 1727, 1168 cm–1.
1H NMR (300 MHz, acetone-d6): d = 7.46–7.36 (m, 4 H), 3.48 (tt,
J = 12.9, 3.9 Hz, 1 H), 2.91–2.79 (m, 2 H), 2.58–2.18 (m, 4 H).
O
N+
H
H
B'
19F NMR (282 MHz, acetone-d6): d = –84.0 (s, 3 F).
13C NMR (75 MHz, acetone-d6): d = 36.0, 37.0, 44.9, 47.0, 75.0 (q,
J = 29.7 Hz), 125.8 (q, J = 282.8 Hz), 128.7, 128.8, 132.1, 142.5,
204.4.
Figure 4
ones. Using pyrrolidine as the catalyst, domino Michael–
aldol reaction between a,b-unsaturated trifluoromethyl
ketones and ketones took place readily under mild condi-
tions to give the corresponding addition products in high
yields and diastereoselectivities.
MS (70 eV): m/z (%) = 292 (10.53) [M+], 44 (100).
Anal. Calcd for C13H12F3O2: C, 53.35; H, 4.13. Found: C, 53.31; H,
4.33.
3-Hydroxy-5-(4-methoxyphenyl)-3-(trifluoromethyl)cyclohex-
anone (2d)
White solid; mp 147–148 °C.
IR (film): 3337, 1725, 1260, 1162 cm–1.
1H NMR (300 MHz, acetone-d6): d = 7.31 (d, J = 8.4 Hz, 2 H), 6.91
(d, J = 8.1 Hz, 2 H), 3.40 (tt, J = 12.9, 3.9 Hz, 1 H), 3.28 (s, 3 H),
2.82 (dd, J = 13.5 Hz, 2 H), 2.56–2.41 (m, 2 H), 2.28–2.15 (m, 2 H).
19F NMR (282 MHz, acetone-d6): d = –84.0 (s, 3 F).
13C NMR (75 MHz, acetone-d6): d = 36.4, 36.8, 43.1, 47.6, 54.6,
75.0 (q, J = 28.8 Hz), 114.0, 125.8 (q, J = 282.9 Hz), 127.8, 135.5,
158.7, 204.8.
Unless otherwise mentioned, solvents and reagents were purchased
from commercial sources and used as received. Acetone was dis-
tilled from K2CO3 before use. Melting points are uncorrected. H
1
and 13C NMR spectra were recorded on a Bruker AM-300 spec-
trometer. 19F NMR spectra were taken on a Bruker AM-300 (282
MHz) spectrometer using CFCl3 as external standard. IR spectra
were obtained with a Nicolet AV-360 spectrophotometer. Mass
spectra and high-resolution mass spectra (HRMS) were obtained on
a Finnigan GC-MS 4021 and a Finnigan MAT-8430 spectrometer,
respectively. Petroleum ether (PE), used for column chromatogra-
phy on silica gel (300–400 mesh), was the fraction boiling in the
range 60–90 °C.
MS (70 eV): m/z (%) = 288 (78.59) [M+], 134 (100).
Anal. Calcd for C14H15F3O2: C, 58.33; H, 5.24. Found: C, 58.44; H,
5.35.
Domino Michael–Aldol Reaction of Unsaturated Ketone 1 and
Acetone; General Procedure
Unsaturated ketone 1 (1 mmol) and pyrrolidine (14 mg, 0.2 mmol)
were added to acetone (5 mL). The reaction mixture was stirred at
r.t. for the time indicated in Table 1. After removal of the solvent,
the crude reaction product was directly charged onto the chromatog-
raphy column and purified on silica gel (PE–EtOAc, 5:1) to afford
compound 2.
3-Hydroxy-5-(4-methylphenyl)-3-(trifluoromethyl)cyclohex-
anone (2e)
White solid; mp 116–117 °C.
IR (film): 3369, 1721, 1168 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.19–7.11 (m, 4 H), 3.44 (tt,
J = 12.9, 3.9 Hz, 1 H), 2.79–2.43 (m, 5 H), 2.34 (s, 3 H), 2.30–2.03
(m, 2 H).
3-Hydroxy-5-phenyl-3-(trifluoromethyl)cyclohexanone (2a)
White solid; mp 140–141 °C.
IR (film): 3290, 1720, 1192, 1170 cm–1.
19F NMR (282 MHz, CDCl3): d = –84.0 (s, 3 F).
Synthesis 2008, No. 24, 3967–3973 © Thieme Stuttgart · New York

PAPER
Organocatalytic Domino Michael–Aldol Reactions
3971
13C NMR (100 MHz, CDCl3): d = 20.9, 36.4, 37.3, 45.8, 48.1, 76.0
(q, J = 29.6 Hz), 125.0 (q, J = 282.9 Hz), 126.6, 129.6, 136.9, 139.4,
206.9.
19F NMR (282 MHz, CDCl3): d = –84.0 (s, 3 F).
13C NMR (100 MHz, CDCl3): d = 35.0, 35.4, 45.8, 46.5, 75.6 (q,
J = 29.8 Hz), 125.0 (q, J = 282.7 Hz), 126.2, 127.7, 128.6, 130.3,
131.0, 136.6, 206.2.
MS (70 eV): m/z (%) = 272 (17.02) [M+], 43 (100).
Anal. Calcd for C14H15F3O2: C, 61.76; H, 5.55. Found: C, 61.97; H,
5.61.
MS (70 eV): m/z (%) = 284 (10.79) [M+], 91 (100).
Anal. Calcd for C15H15F3O2: C, 63.38; H, 5.32. Found: C, 63.40; H,
5.17.
3-Hydroxy-5-(naphthalen-1-yl)-3-(trifluoromethyl)cyclohex-
anone (2f)
White solid; mp 173–174 °C.
IR (film): 3343, 1712, 1178 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.08 (d, J = 8.4 Hz, 1 H), 7.88 (d,
J = 7.8 Hz, 1 H), 7.79 (d, J = 8.1 Hz, 1 H), 7.59–7.40 (m, 4 H), 4.37
(tt, J = 12.9, 3.9 Hz, 1 H), 2.89–2.68 (m, 5 H), 2.47–2.22 (m, 2 H).
19F NMR (282 MHz, CDCl3): d = –83.9 (s, 3 F).
13C NMR (100 MHz, CDCl3): d = 32.3, 36.2, 46.3, 47.5, 75.9 (q,
J = 29.7 Hz), 122.4, 122.5, 125.0 (q, J = 282.3 Hz), 125.9, 126.6,
127.7, 127.9, 129.1, 130.9, 134.1, 138.1, 206.2.
3-Hydroxy-5-octyl-3-(trifluoromethyl)cyclohexanone (2k)
White solid; mp 86–87 °C.
IR (film): 3332, 2921, 1720, 1134 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.66–2.51 (m, 3 H), 2.20–1.96 (m,
4 H), 1.64 (t, J = 13.2 Hz, 1 H), 1.39–1.27 (m, 14 H), 0.88 (t, J = 6.6
Hz, 3 H).
19F NMR (282 MHz, CDCl3): d = –84.2 (s, 3 F).
13C NMR (75 MHz, acetone-d6): d = 13.5, 22.4, 26.3, 29.1, 29.3,
31.7, 31.8, 34.89, 34.91, 36.2, 45.2, 45.5, 75.1 (q, J = 29.5 Hz),
125.9 (q, J = 282.3 Hz), 205.2.
MS (70 eV): m/z (%) = 308 (88.59) [M+], 153 (100).
MS (70 eV): m/z (%) = 294 (2.04) [M+], 43 (100).
Anal. Calcd for C17H15F3O2: C, 66.23; H, 4.90. Found: C, 66.27; H,
4.94.
Anal. Calcd for C15H25F3O2: C, 61.21; H, 8.56. Found: C, 61.12; H,
8.64.
5-(Furan-2-yl)-3-hydroxy-3-(trifluoromethyl)cyclohexanone
(2g)
White solid; mp 104–105 °C.
IR (film): 3325, 1722, 1267, 1184 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35 (s, 1 H), 6.33–6.31 (m, 1 H),
6.09 (d, J = 2.7 Hz, 1 H), 3.58 (tt, J = 12.9, 4.5 Hz, 1 H), 2.80–2.58
(m, 4 H), 2.40–2.35 (m, 1 H), 2.22–2.12 (m, 2 H).
19F NMR (282 MHz, CDCl3): d = –84.1 (s, 3 F).
Domino Michael–Aldol Reaction of Unsaturated Ketone 1 and
Cyclic Ketones; General Procedure
Unsaturated ketone 1 (0.25 mmol), cyclic ketones (2.5 mmol) and
pyrrolidine (3 mg, 0.05 mmol) were added to CH2Cl2 (5 mL). The
reaction mixture was stirred at r.t. for the time indicated in Table 2.
After removal of the solvent, the crude reaction product was directly
charged onto the chromatography column and purified on silica gel
(PE–EtOAc, 5:1) to afford compound 2.
13C NMR (75 MHz, CDCl3): d = 31.6, 33.8, 45.1, 45.8, 75.0 (q,
J = 29.7 Hz), 104.8, 110.2, 124.9 (q, J = 282.7 Hz), 141.8, 155.5,
206.3.
2-Hydroxy-4-phenyl-2-trifluoromethylbicyclo[3.3.1]nonan-9-
one (2m)
White solid; mp 184–186 °C.
IR (film): 3310, 1705, 1283, 1165, 758 cm–1.
MS (70 eV): m/z (%) = 248 (29.67) [M+], 94 (100).
1H NMR (300 MHz, CDCl3): d = 1.65–1.69 (m, 1 H), 1.86 (s, 1 H),
2.03–2.40 (m, 6 H), 2.74 (s, 1 H), 3.02–3.11 (m, 2 H), 3.62 (d,
J = 7.8 Hz, 1 H), 7.18–7.29 (m, 5 H).
Anal. Calcd for C11H11F3O3: C, 53.23; H, 4.47. Found: C, 53.22; H,
4.33.
19F NMR (282 MHz, CDCl3): d = –80.81 (s, 3 F).
13C NMR (75 MHz, acetone-d6): d = 18.7, 30.4, 34.1, 37.3, 45.7,
50.7, 52.3, 79.6 (q, J = 27.3 Hz), 125.7, 127.1, 127.6 (q, J = 284.9
Hz), 127.9, 147.5, 213.8.
3-Hydroxy-5-(2-phenylethynyl)-3-(trifluoromethyl)cyclohex-
anone (2h)
White solid; mp 102–103 °C.
IR (film): 3337, 1720, 1195, 1168, 1115 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.28 (m, 5 H), 3.40 (tt,
J = 12.6, 4.2 Hz, 1 H), 2.85–2.42 (m, 6 H), 2.16 (t, J = 13.2 Hz,
1 H).
19F NMR (282 MHz, CDCl3): d = –84.0 (s, 3 F).
MS (70 eV): m/z (%) = 298 (9.76) [M+], 98 (100.00).
Anal. Calcd for C16H17F3O2: C, 64.42; H, 5.74. Found: C, 64.25; H,
5.89.
13C NMR (100 MHz, CDCl3): d = 24.8, 35.1, 45.7, 46.1, 75.0 (q,
J = 30.1 Hz), 82.7, 89.2, 122.8, 124.7 (q, J = 282.4 Hz), 128.28,
128.32, 131.3, 204.3.
6-Hydroxy-3-methyl-8-phenyl-6-trifluoromethyl-3-azabicy-
clo[3.3.1]nonan-9-one (2n)
White solid; mp 145–147 °C.
IR (film): 3338, 2951, 1714, 1177, 697 cm–1.
MS (70 eV): m/z (%) = 282 (29.85) [M+], 128 (100).
1H NMR (300 MHz, CDCl3): d = 1.77 (s, 1 H), 2.06 (d, J = 13.8 Hz,
1 H), 2.29 (s, 3 H), 2.46 (d, J = 11.4 Hz, 1 H), 2.66 (dd, J = 10.8, 3
Hz, 2 H), 2.94 (s, 1 H), 3.28 (tt, J = 13.2, 2.7 Hz, 2 H), 3.81 (m,
2 H), 7.15–7.31 (m, 5 H).
19F NMR (282 MHz, CDCl3): d = –80.73 (s, 3 F).
13C NMR (75 MHz, CDCl3): d = 35.68, 44.39, 46.02, 51.02, 52.75,
58.13, 65.04, 80.13 (q, J = 28.1 Hz), 126.32, 126.66 (q, J = 284.4
Hz), 127.56, 128.54, 145.94, 213.12.
Anal. Calcd for C15H13F3O2: C, 63.83; H, 4.64. Found: C, 63.97; H,
4.62.
3-Hydroxy-5-styryl-3-(trifluoromethyl)cyclohexanone (2i)
White solid; mp 122–123 °C.
IR (film): 3333, 1719, 1191, 1142 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.37–7.22 (m, 5 H), 6.47 (d,
J = 15.9 Hz, 1 H), 6.14 (dd, J = 15.9, 7.2 Hz, 1 H), 3.13–3.05 (m,
1 H), 2.93 (s, 1 H), 2.72–2.58 (m, 3 H), 2.36–2.20 (m, 2 H), 1.92 (t,
J = 12.9 Hz, 1 H).
MS (70 eV): m/z (%) = 313 (21.42) [M+], 58 (100.00).
Synthesis 2008, No. 24, 3967–3973 © Thieme Stuttgart · New York

3972
X.-J. Wang et al.
PAPER
Anal. Calcd for C16H18F3NO2: C, 61.33; H, 5.79; N, 4.47. Found: C,
61.36; H, 5.89; N, 4.20.
13C NMR (CDCl3, 75 MHz): d = 16.86, 19.54, 27.70, 42.67, 49.02,
50.37, 78.70 (q, J = 28.7 Hz), 123.32 (q, J = 284.0 Hz), 127.16,
127.45, 140.18, 213.81.
6-Hydroxy-8-phenyl-6-trifluoromethyl-3-oxabicy-
clo[3.3.1]nonan-9-one (2o)
White solid; mp 168–169 °C.
19F NMR (CDCl3, 282 MHz): d = –79.66 (s, 3 F).
MS (EI, 70 eV): m/z (%) = 284 (9.56) [M+], 55 (100.00).
IR (film): 3327, 1716, 1170, 1008, 699 cm–1.
Anal. Calcd for C15H15F3O2: C, 63.38; H, 5.32. Found: C, 63.32; H,
5.32.
1H NMR (500 MHz, CDCl3): d = 2.25 (d, J = 14.4 Hz, 1 H), 2.70 (s,
1 H), 2.84 (s, 1 H), 3.28 (dd, J = 14.4, 8.9 Hz, 1 H), 3.76 (d, J = 12.2
Hz, 1 H), 3.89 (d, J = 8.9 Hz, 1 H), 3.92 (dd, J = 11.2, 2 Hz, 1 H),
4.41–4.47 (m, 2 H), 5.07 (s, 1 H), 7.13 (t, J = 7.3 Hz, 1 H), 7.22 (t,
J = 7.4 Hz, 2 H), 7.33 (t, J = 7.6 Hz, 2 H).
Acknowledgment
Financial support from the National Natural Science Foundation of
China (No. 20572124) is gratefully acknowledged.
19F NMR (282 MHz, CDCl3): d = –80.46 (s, 3 F).
13C NMR (125 MHz, acetone-d6): d = 34.95, 46.26, 54.53, 56.18,
71.30, 78.29, 80.14 (q, J = 27.4 Hz), 126.27 (q, J = 285.0 Hz),
126.53, 128.66, 128.85, 147.02, 209.78.
Reference
(1) (a) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine
Chemistry, Principle, and Commercial Applications;
Plenum Press: New York, 1994. (b) Hiyama, T.
MS (70 eV): m/z (%) = 300 (68.31) [M+], 55 (100.00).
Anal. Calcd for C15H15F3O3: C, 60.00; H, 5.04. Found: C, 59.83; H,
5.13.
Organofluorine Compounds, Chemistry and Application;
Springer: Berlin, 2000. (c) Filler, R.; Kobayashi, Y.;
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2-Hydroxy-4-(4-methoxyphenyl)-2-trifluoromethylbicy-
clo[3.3.1]nonan-9-one (2p)
White solid; mp 131–133 °C.
IR (film): 3306, 2942, 1708, 1516, 1160, 830 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.62 (s, 1 H), 2.01–2.33 (m, 7 H),
2.72 (d, J = 1.8 Hz, 1 H), 2.97–3.06 (m, 2 H), 3.56 (d, J = 9 Hz,
1 H), 3.75 (s, 3 H), 6.80 (d, J = 9.0 Hz, 2 H), 7.20 (d, J = 9.0 Hz,
2 H).
19F NMR (282 MHz, CDCl3): d = –80.65 (s, 3 F).
13C NMR (75 MHz, CDCl3): d = 18.81, 30.49, 35.14, 37.41, 44.96,
50.27, 52.26, 55.23, 80.11 (q, J = 28.1 Hz), 113.84, 126.73 (q,
J = 284.7 Hz), 128.64, 138.62, 157.91, 216.11.
Ramachandran, P. V., Ed.; American Chemical Society:
Washington DC, 1999, 255–269. (b) Ren, J.; Milton, J.;
Weaver, K. L.; Short, S. A.; Stuart, D. I.; Stammers, D. K.
Structure 2000, 8, 1089. (c) Pedersen, O. S.; Pedersen, E. B.
Synthesis 2000, 479.
(3) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635.
(4) (a) Prakash, G. K. S.; Hu, J. In Fluorine-Containing
Synthons; Soloshonok, V. A., Ed.; American Chemical
Society: Washington DC, 2005, 16–56. (b) Langlois, B. R.;
Billard, T. In Fluorine-Containing Synthons; Soloshonok,
V. A., Ed.; American Chemical Society: Washington DC,
2005, 57–86. For reviews on enantiomeric synthesis of
trifluoromethyl tertiary alcohols by trifluoromethylation
reaction, see: (c) Ma, J.-A.; Cahard, D. Chem. Rev. 2004,
104, 6119. (d) Billard, T.; Langlois, B. R. Eur. J. Org.
Chem. 2007, 891.
MS (70 eV): m/z (%) = 328 (17.18) [M+], 231 (100.00).
Anal. Calcd for C17H19F3O3: C, 62.19; H, 5.83. Found: C, 62.05; H,
5.84.
2-Hydroxy-4-(4-chlorophenyl)-2-trifluoromethylbicy-
clo[3.3.1]nonan-9-one (2q)
White solid; mp 194–195 °C.
IR (film): 3325, 1705, 1283, 1172, 1106 cm–1.
(5) (a) Sosnovskikh, V. Y.; Ovsyannikov, I. S.; Aleksandrova, I.
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Kacharov, A. D.; Avilov, D. V.; Ishikawa, K.; Nagashima,
N.; Hayashi, T. J. Org. Chem. 1997, 62, 3470. (d)Funabiki,
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Matsunaga, K.; Shibata, K.; Matsui, M. J. Chem. Soc.,
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Roschenthaler, G. V. J. Fluorine Chem. 2002, 113, 105.
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alcohols from trifluoromethyl ketones, see: (f) Pierce, M.
E.; Parsons, R. L. Jr.; Radesca, L. A.; Lo, Y. S.; Silverman,
S.; Moore, J. R.; Islam, Q.; Choudhury, A.; Fortunak, J. M.
D.; Nguyen, D.; Morgan, C.; Luo, S. J.; Davis, W. P.;
Confalone, P. N.; Chen, C.-Y.; Tillyer, R. D.; Frey, L.; Tan,
L.; Xu, F.; Zhao, D.; Thompson, A. S.; Corley, E. G.;
Grabowski, E. J. J.; Reamer, R.; Reider, P. J. J. Org. Chem.
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1H NMR (300 MHz, CDCl3): d = 1.65–1.69 (m, 1 H), 1.99–2.39 (m,
7 H), 2.72 (br s, 1 H), 2.94–3.06 (m, 2 H), 3.58 (d, J = 9 Hz, 1 H),
7.23 (d, J = 2.1 Hz, 4 H).
19F NMR (282 MHz, CDCl3): d = –80.79 (s, 3 F).
13C NMR (75 MHz, acetone-d6): d = 18.66, 30.36, 34.03, 37.14,
44.99, 50.49, 52.10, 79.40 (q, J = 27.5 Hz), 127.46 (q, J = 285.5
Hz), 127.82, 129.62, 130.96, 146.46, 213.83.
MS (70 eV): m/z (%) = 332 (27.03) [M+], 98 (100.00).
Anal. Calcd for C16H16ClF3O2: C, 57.75; H, 4.85. Found: C, 57.90;
H, 4.58.
2-Hydroxy-4-phenyl-2-trifluoromethylbicyclo[3.2.1]octan-8-
one (2r)
White solid; mp 114–115 °C.
IR (film): 3340, 1746, 1164, 1093, 705 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.70–2.15 (m, 5 H), 2.35 (t,
J = 13.2 Hz, 1 H), 2.53 (d, J = 6 Hz, 1 H), 2.60 (d, J = 6.3, 1 H),
3.65–3.72 (m, 1 H), 3.75 (s, 1 H), 7.23–7.38 (m, 5 H).
Synthesis 2008, No. 24, 3967–3973 © Thieme Stuttgart · New York

PAPER
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Synthesis 2008, No. 24, 3967–3973 © Thieme Stuttgart · New York