Reduction of 2,2,2-trifluoro-1-arylethanones with alkyl phosphines

Article abstract of DOI:10.1016/j.tet.2007.09.084

In the presence of alkyl phosphines, reduction of 2,2,2-trifluoro-1-arylethanones proceeded smoothly to give the corresponding reduction products in moderate to high yields at room temperature. The possible mechanism was discussed on the basis of deuteriu

Full text of DOI:10.1016/j.tet.2007.09.084

Tetrahedron 63 (2007) 12731–12734
Reduction of 2,2,2-trifluoro-1-arylethanones
with alkyl phosphines
a
b
b
Min Shi,a,b, Xu-Guang Liu, Ying-Wen Guo and Wen Zhang
*
aSchool of Chemistry and Molecular Engineering, East China University of Science and Technology,
130 Mei Long Road, Shanghai 200237, China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Science, 354 Fenglin Road, Shanghai 200032, China
Received 18 August 2007; revised 28 September 2007; accepted 29 September 2007
Available online 6 October 2007
Abstract—In the presence of alkyl phosphines, reduction of 2,2,2-trifluoro-1-arylethanones proceeded smoothly to give the corresponding
reduction products in moderate to high yields at room temperature. The possible mechanism was discussed on the basis of deuterium labeling
and control experiments, indicating that one hydrogen transfer took place from alkyl phosphine to the carbonyl group activated by a strongly
electron-withdrawing trifluoromethyl group.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Previously, we reported the reduction of activated carbonyl
groups such as a-keto esters, benzils, 1,2-cyclohexanedione,
and a-ketophosphonates by alkyl phosphines to afford the
corresponding a-hydroxy esters or ketones in good to excel-
lent yields in THF at room temperature as well as the reduc-
tive coupling of acyl cyanides promoted by alkyl phosphines
to give the substituted cyanohydrins in moderate to high
yields by using trimethylphosphine or tributylphosphine as
a promoter under mild reaction conditions.1 More recently,
organocatalysts, metal-free organic compounds, which ex-
hibit catalytic abilities in organic reactions, have received
much attention because of their advantages from an environ-
mental as well as a resource standpoint.2 On the basis of
these backgrounds, we attempted to further develop such
reduction of other substrates using alkyl phosphines. We
envisioned that the carbonyl group in 2,2,2-trifluoro-1-aryl-
ethanone could be also reduced with various alkyl phosphines
since its carbonyl group is connected with a strongly
electron-withdrawing trifluoromethyl group. Namely, this
carbonyl group is quite activated and it could be reduced
by alkyl phosphines. Herein we wish to describe the details
on the reduction of 2,2,2-trifluoro-1-arylethanones with
alkyl phosphines along with a mechanistic investigation.
Initial examinations using 2,2,2-trifluoro-1-phenylethanone
1a as the substrate in the presence of various alkyl phos-
phines, such as PMe3, PPh2Me, PPhMe2, and PBu3 were
aimed at determining the optimal conditions for the reduction
of 1a. The results are summarized in Table 1. As can be seen
from Table 1, 1a could be reduced with PMe3 (1.0 equiv) in
avariety of solvents to give the corresponding 2,2,2-trifluoro-
1-phenyl-ethanol 2a in 20–58% yields within 24–48 h (Table
1, entries 1–6). A prolonged reaction time slightly improved
the yield of 2a (Table 1, entry 2). Using PPh2Me and PPhMe2
as the reducing reagents, 2a was obtained in 30% and 33%
yields in THF, respectively (Table 1, entries 7 and 8). To
our delight, we found that using PBu3 as a reducing reagent,
2a could be obtained in 98% yield in toluene after 48 h under
the standard conditions (Table 1, entries 9–13). In the pres-
ence of methyl diphenylphosphinite (1.0 equiv), 2,2,2-tri-
fluoro-1-o-tolyl-ethanone was also produced in 21% yield
under identical conditions (Table 1, entry 14).
With the optimized reaction conditions in hand, we next ex-
amined the scope and limitations of this interesting reduc-
tion reaction. The results are summarized in Table 2. A
variety of 2,2,2-trifluoro-1-arylethanones 1b–h were tested
under the standard conditions. For 1b and 1c bearing an elec-
tron-withdrawing group on the benzene ring, the corre-
sponding reduction products 2b and 2c were obtained in
good yields (Table 2, entries 1 and 2). For electron-rich
2,2,2-trifluoro-1-arylethanones 1d–g, the corresponding re-
duction products 2d–g were obtained in moderate to good
Keywords: 2,2,2-Trifluoro-1-arylethanone; Alkyl phosphine; Hydrogen
transfer; Deuterium labeling experiment.
* Corresponding author. Tel.: +86 21 54925137; fax: +86 21 64166128;
e-mail: mshi@mail.sioc.ac.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.084

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M. Shi et al. / Tetrahedron 63 (2007) 12731–12734
Table 1. Reduction of 2,2,2-trifluoro-1-phenylethanone by various phos-
OH
O
phines in a variety of solventsa
D
THF, rt
CF3
CF3
OH
CF3
O
P(CD3)3
PR3 (1.0 equiv)
rt, solvent
CF3
1a
2a-d(C): 60% yield, D content 68%
2a
1a
Scheme 1. Reduction of 2,2,2-trifluoro-1-phenylethanone with trimethyl-
phosphine-d9 in THF and the isotopic labeling experiment.
Entry
PR3
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PPh2Me
PPhMe2
PBu3
PBu3
PBu3
PBu3
PBu3
PPh2(OMe)
THF
THF
DCM
Toluene
MeOH
CH3CN
THF
THF
THF
CH3CN
Toluene
Toluene
DCM
24
48
24
24
24
24
24
36
24
24
24
48
24
24
58
61
28
31
20
56
30
33
49
57
55
98
19
21
Bu
Bu
O
O
P
O
:P(Bu)3
CF3
Ar
Ar
P(Bu)3
Ar
Pr
H
B
CF3
CF3
A
H
Bu
O P
9
Bu
Pr
OH
H
10
11
12
13
14c
H2O
+
O=P(Bu)3
Ar
Ar
H
H
CF3
CF3
C
Toluene
Scheme 2. A proposed reaction mechanism.
a
2,2,2-Trifluoro-1-phenylethanone (0.3 mmol), phosphine (0.3 mmol), and
solvent (0.3 mL) were used.
Isolated yields.
b
c
reduction of 2,2,2-trifluoro-1-arylethanone 1 was proposed
in Scheme 2. Initially, the addition of phosphorus atom of
tributylphosphine to the carbonyl group in 1 takes place to
give intermediate A. This process is beneficial from the
strongly electron-withdrawing trifluoromethyl group on
the basis of previous investigations and computational
calculation.5 The rearrangement of intermediate A pro-
vides intermediate B from which intramolecular hydrogen
transfer from the butyl group of tributylphosphine to
the corresponding carbonyl group activated by a strongly
electron-withdrawing trifluoromethyl group produces in-
termediate C, which subsequently undergoes O–P bond
hydrolytic cleavage by ambient moisture or during work-
up to generate 2 and the corresponding phosphine oxide.
It should be noted that the carbonyl groups activated by
a strongly electron-withdrawing trifluoromethyl group are
essential for this reduction because no reaction occurred
if phenylethanone was used as the substrate under the
standard conditions.6 Concerning the reduction of 2,2,2-
trifluoro-1-o-tolyl-ethanone with Ph2P(OMe) indicated in
entry 14 of Table 1, the hydrogen transfer can also take
place from the MeO group in phosphite, although this pro-
cess is not as effective as alkyl phoshines under the same
conditions.7
2,2,2-Trifluoro-1-o-tolyl-ethanone was used.
Table 2. Reduction of 2,2,2-trifluoro-1-phenylethanone under optimized
conditionsa
OH
CF3
O
PBu3 (1.0 equiv)
toluene, rt, 48 h
R
R
CF3
2
1
Entry
R
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
4-ClC6H4 (1b)
4-BrC6H4 (1c)
48
48
48
48
48
48
48
2b, 99
2c, 91
2d, 68
2e, 71
2f, 50
2g, 40
2h, 68
4-CH3C6H4 (1d)
2-CH3C6H4 (1e)
2,4-(CH3)2C6H3 (1f)
4-CH3OC6H4 (1g)
1-Naphthyl (1h)
a
The reactions were conducted with PBu3 (1.0 equiv), 2,2,2-trifluoro-
1-phenylethanone (0.5 mmol) in toluene (0.5 mL) for 48 h at rt.
Isolated yields.
b
yields (Table 2, entries 3–6). Naphthyl derivative 1h also can
be reduced in good yield under the standard conditions
(Table 2, entry 7).
The reaction mechanism is the most interesting issue in this
context. In order to clarify the reaction mechanism, a deute-
rium labeling experiment was carried out with trimethyl-
phosphine-d9, prepared from the reaction of CD3MgI with
tri-o-tolyl phosphite,3 under the standard conditions. The cor-
responding product of 2a-d(C) was produced in 60% isolated
yield with 68% D incorporation at the C1 position (Scheme
2).4 This result suggests that one hydrogen is directly trans-
ferred from trimethylphosphine to product 2a, and an addi-
tional equivalent of water is required for the release of the
phosphorus atom through formation of the phosphine oxide
during work-up (Scheme 1 and also see Scheme 2).
According to the proposed reaction mechanism mentioned
above, when the alkyl phosphine was replaced by a chiral al-
kyl phosphine, an asymmetric reduction might be realized.
Therefore, we selected [2-(2-methoxynaphthalen-1-yl)-3-
methyl-1-methylene-hexa-2,4-dienyl]dimethylphosphane38
as a chiral alkyl phosphine in this reaction to examine the
achieved enantioselectivity of the reduced product. It was
found that the corresponding product 1-(4-chlorophenyl)-
2,2,2-trifluoroethanol was obtained in 5% ee and 33% yield
in toluene as well as 4% ee and 29% yield in THF after 15
days under the standard conditions (Scheme 3). The reaction
is sluggish and the achieved ee is low, suggesting that
a sterically bulky chiral back skeleton affects the reactivity.
In any sense, although the achieved ee is low, this prelimi-
nary result implied that the reaction mechanism shown in
Scheme 2 is reasonable.
According to the relative control experiments and our
previous investigations1 as well as the in situ 1H, 31P,
and 19F NMR monitoring, a plausible mechanism for the

M. Shi et al. / Tetrahedron 63 (2007) 12731–12734
12733
4.2. Typical reaction procedure for the
preparation of 2
OMe
PMe2
A mixture of 2,2,2-trifluoro-1-phenylethanone (0.5 mmol)
and PBu3 (0.5 mmol) in solvent was stirred under argon
atmosphere at room temperature for the required time
indicated in the tables. After the reaction solution was
concentrated under reduced pressure, the residue was puri-
fied by flash chromatography on silica gel (eluent: EtOAc/
petroleum¼1:20) to afford pure product 2.
OH
CF3
O
3 (1.0 equiv)
toluene, rt, 15 d
CF3
Cl
Cl
yield: 33%, ee: 5%
OMe
PMe2
4.3. Typical reaction procedure for the
asymmetric reduction of 1b
OH
O
A mixture of 1-(4-chlorophenyl)-2,2,2-trifluoroethanone
(1b) (20.8 mg, 0.1 mmol) and axially chiral phosphine
(34.4 mg, 0.1 mmol) in toluene was stirred under argon at-
mosphere at room temperature for 15 days. After the reac-
tion solution was concentrated under reduced pressure, the
residue was purified by flash chromatography on silica gel
(eluent: EtOAc/petroleum¼1:20) to afford pure product
2b. Yield 33%, 7.0 mg; [a]2D0 ꢀ3.0 (c 0.30, CHCl3);
HPLC: OD column; l¼254 nm; eluent: hexane/isopro-
CF3
3 (1.0 equiv)
THF, rt, 15 d
CF3
Cl
Cl
yield: 29%, ee: 4%
Scheme 3. Reduction of 1-(4-chlorophenyl)-2,2,2-trifluoroethanone by
a chiral phosphine.
3. Conclusion
panol¼95:5; flow rate: 0.7 mL/min; tmajor¼9.13 min, tminor
¼
11.18 min; ee¼5%.
In summary, we disclosed an efficient reductive process of
2,2,2-trifluoro-1-arylethanones to form the corresponding
reduction products with alkyl phosphine under mild condi-
tions. These reactions could take place at room temperature
in the presence of alkyl phosphines such as trimethylphos-
phine and tributylphosphine in various solvents within 36
or 48 h to give the corresponding reduction products in
good yields. We confirmed that this process involved with
a hydrogen transfer from alkyl phosphine to the carbonyl
group. Efforts are underway to elucidate the mechanistic
details of this reductive system and to extend the scope of
substrates in this interesting reduction reaction.
4.3.1. The in situ 1H, 31P, and 19F NMR monitoring of this
reduction. In a NMR tube, 1-(4-chlorophenyl)-2,2,2-tri-
fluoroethanone (1.0 equiv) was added to Ph2PMe
(20.02 mg, 0.1 mmol) in C6D6 (3.0 mL) under argon atmo-
1
sphere. Then, H, 19F, and 31P NMR measurements were
performed in different required time.
4.3.2. 2,2,2-Trifluoro-1-(2,4-dimethylphenyl)ethanol (2f)
(a unknown compound). 1H NMR (CDCl3, 300 MHz,
TMS): d 2.32 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.82 (s, 1H,
OH), 5.27 (q, 1H, J¼6.6 Hz, CH), 7.02 (s, 1H, Ar), 7.09
(d, 1H, J¼8.4 Hz, Ar), 7.48 (d, 1H, J¼8.4 Hz, Ar);
13C NMR (CDCl3, 75 MHz): d 19.2, 21.1, 68.6 (q,
J¼31.6 Hz), 124.8 (q, J¼280.1 Hz), 126.9 (q, J¼1.3 Hz),
127.2, 129.7 (q, J¼1.1 Hz), 131.3, 136.3, 139.1; 19F NMR
(CDCl3, 282 MHz, CFCl3): d ꢀ78.23 (d, J¼7.6 Hz). IR
(film) 3400, 2960, 2926, 2853, 1708, 1617, 1506, 1379,
1217, 1166, 1135, 1117, 1064, 1039, 862, 833, 810, 733,
694, 594. MS (EI) m/z (%): 204 (25.4) [M+], 135 (100),
107 (83.5), 105 (30.2), 91 (69.0), 79 (25.1), 77 (28.8);
HRMS (EI) calcd for C10H11F3O 204.0762, found 204.0769.
4. Experimental section
4.1. General remarks
Melting points were obtained with a Yanagimoto micro
melting point apparatus and are uncorrected. 1H NMR
and 13C NMR spectra were recorded for a solution in
CDCl3 with tetramethylsilane (TMS) as internal standard.
J-values are in Hertz. Mass spectra were recorded with
a HP-5989 instrument and HRMS was measured by a
Finnigan MA+ mass spectrometer. The solid compounds
reported in this paper gave satisfactory CHN microanaly-
ses with a Carlo-Erba 1106 analyzer. Commercially
obtained reagents were used without further purification.
All reactions were monitored by TLC with Huanghai
GF254 silica gel coated plates. Flash column chromato-
graphy was carried out using 300–400 mesh silica gel at
increased pressure. Reaction experiments were performed
under argon condition. The starting materials 1a–h were
synthesized according to the previous literature.9 Since
these alkyl phosphines are lachrymatory and sometimes
spontaneously flammable in air, these reactions must be
carried out under argon atmosphere in an efficient fume
hood.
Acknowledgements
We thank the Shanghai Municipal Committee of Science and
Technology (04JC14083, 06XD14005), and the National
Natural Science Foundation of China (20472096,
203900502, and 20672127, 20732008) for financial support.
Supplementary data
The spectroscopic charts (1H, 13C NMR spectra data),
HRMS, analytic data of the compounds shown in Tables 1
and 2 and Scheme 1, HPLC analysis, in situ 31P and 19F
NMR monitoring of this reduction are included in the

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M. Shi et al. / Tetrahedron 63 (2007) 12731–12734
3. Li, R. T.; Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem.
Soc. 1994, 116, 10032–10040. CD3MgI was prepared from CD3I
(D content >90%) with magnesium.
supplementary data. Supplementary data associated with
this article can be found in the online version, at
doi:10.1016/j.tet.2007.09.084.
4. The D content of 2f-d(C) was determined by 1H NMR spectrum.
5. (a) Niecke, E.; Gudat, D.; Schoeller, W. W.; Rademacher, P.
J. Chem. Soc., Chem. Commun. 1985, 1050–1051; (b) Seifert,
F. U.; Roeschenthaler, G. V. Z. Naturforsch., B. 1993, 48,
1089–1093; (c) Roeschenthaler, G. V. Chem. Ber. 1978, 111,
3105–3111; (d) Kukhtin, V. A.; Orekhova, K. M. Cine-Photo
Res. Insti., Kazan, Zhutnal Obeshchei Khimii 1960, 30, 1208–
1216.
6. We greatly appreciate one of the reviewers for his kind revision
on the reaction mechanism.
7. Olah, G. A.; Wu, A.-H. Synlett 1990, 54–56.
8. This chiral phosphine was synthesized according to the previous
literature: Shi, M.; Li, C. Q. Tetrahedron: Asymmetry 2005, 16,
1385–1391.
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