Direct aldol condensation reaction of ethyl diazoacetate with trifluoromethyl ketones

Article abstract of DOI:10.1016/j.tet.2011.09.009

An efficient and direct aldol-type condensation of ethyl diazoacetate with trifluoromethyl ketones was developed in the presence of dialkyl zinc. A series of trifluoromethylated products were obtained in good to excellent yields (60-95%). A preliminary ex

Full text of DOI:10.1016/j.tet.2011.09.009

Tetrahedron 67 (2011) 8470e8476
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Direct aldol condensation reaction of ethyl diazoacetate with trifluoromethyl
ketones
*
Han-Feng Cui, Lian Wang, Li-Jun Yang, Jing Nie, Yan Zheng, Jun-An Ma
Department of Chemistry, Tianjin University, Tianjin 300072, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 June 2011
Received in revised form 25 August 2011
Accepted 6 September 2011
Available online 10 September 2011
An efficient and direct aldol-type condensation of ethyl diazoacetate with trifluoromethyl ketones was
developed in the presence of dialkyl zinc. A series of trifluoromethylated products were obtained in good
to excellent yields (60e95%). A preliminary extension to a catalytic enantioselective aldol reaction of
ethyl diazoacetate to trifluoromethyl ketones (up to 72% ee) is also described.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aldol condensation
Trifluoromethyl ketone
Enantioselectivity
Ethyl diazoacetate
1. Introduction
carbon-nucleophiles in direct aldol-type condensation reactions.5
Although much progress has been made in the development of
The trifluoromethyl group is a bulky and highly electron-
withdrawing group (electronegativity of 3.5 on the Pauling scale)
that strongly affects the reactivity of the adjacent functional groups.
Incorporation of a trifluoromethyl group into organic molecules
generally increases their chemical stability owing to the high bond
strength that can induce increased resistance to metabolic de-
composition. Thus, over the past decades trifluoromethylated
compounds have attracted considerable attention in organic syn-
thesis, medicinal and agrochemical chemistry, and materials sci-
ences.1 Direct transformation of trifluoromethyl-containing
building blocks is a very appealing strategy for the construction
of trifluoromethylated molecules.2 For example, 1,2-addition of
various nucleophiles to trifluoromethyl ketones has been proved
a particularly attractive target, due largely to (a) the ready avail-
ability and high reactivity of trifluoromethyl ketones, and (b) the
high biological and medicinal utility of trifluoromethyl-substituted
tertiary alcohols. However, to the best of our knowledge, no direct
aldol condensation reactions of diazoacetates with trifluoromethyl
ketones have been reported.3
direct aldol reactions of aldehydes and aldimines, successful aldol
reactions of
a
-diazoacetates and derivatives with ketones are rare.6
The direct aldol reaction between ethyl diazoacetate and tri-
fluoromethyl ketones represents an attractive and an atom eco-
nomical method toward fluorinated products (Scheme 1).
O
H
O
O
O
O
R1
Rf
Base
H
Rf
R
O
R
O
R
O
R1
H
N2
N2
N2
Scheme 1. Aldol reaction between diazoacetate and trifluoromethyl ketone in the
presence of base.
Development of new organic transformations for the synthesis of
fluorine-containing functionalized compounds has been our in-
terest and research objective.7 As part of our ongoing studies, herein
we report an efficient and direct aldol-type condensation of ethyl
diazoacetate with trifluoromethyl ketones in the presence of dialkyl
zinc. Such studies would be of immense benefit for expanding the
scope of application of these aldol reactions in organic synthesis.
a
-Diazoacetates and derivatives are readily available C2 syn-
thons in organic chemistry as a result of their diverse reactivities.4
In addition to serving as metalecarbene precursors, -diazo-
The aldol reaction of a-diazoacetates and derivatives with al-
a
dehydes has been studied extensively with a variety of bases in-
cluding a number of strong bases. However, the reactions are not
feasible for trifluoromethyl ketones. Efficient, clean, and direct al-
dol reaction using trifluoromethyl ketones is difficult in the pres-
ence of common bases, such as 1,8-diazabicyclo[5.4.0] undec-7-ene
(DBU), potassium hydroxide, or sodium hydride (Table 1, entries
acetates and derivatives have in recent years been employed as
* Corresponding author. Tel.: þ86 22 27402903; fax: þ86 22 27403475; e-mail
address: majun_an68@tju.edu.cn (J.-A. Ma).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.009

H.-F. Cui et al. / Tetrahedron 67 (2011) 8470e8476
8471
Table 1
Optimization of the conditions for the aldol reaction of diazoacetate with trifluoroacetophenone (1a)a
Entry
Base
Solvent
Yieldb (%)
1
2
DBU
KOH
THF
THF
0
0
3
NaH
n-BuLi
LDA
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Me2Zn
THF
THF
THF
THF
15
39
50
61
56
20
80
90
85
95
4c
5c
6
7
8
9
10
11
12
Et2O
CH3CN
Toluene
CH2Cl2
ClCH2CH2Cl
CH2Cl2
a
Unless otherwise noted, the reaction was carried out with diazoacetate ester (0.3 mmol) and trifluoroacetophenone (0.2 mmol) in solvent with base (0.4 mmol) for 24 h.
Isolated yield (all data are the average of three experiments).
Reaction temperature: ꢀ78 ꢁC to 0 ꢁC.
b
c
1e3). We found that the reaction of ethyl
a
-diazoacetate with 1,1,1-
substantial change of the temperature did not have a significant
effect on the reactivity. It is noteworthy that the yield was further
improved to 95% in the replace of diethyl zinc with dimethyl zinc
(entry 12). It is well known that dimethyl zinc is significantly less
reactive than diethyl zinc in the 1,2-addition to aldehydes and ke-
tones in the presence of the amino alcohol ligand.8 Thus, the use of
dimethyl zinc could be more favorable for the current aldol
condensation.
With these optimized conditions in hand, the general scope of
trifluoromethyl ketones was examined in the aldol reaction in the
presence of Me2Zn (Table 2). It was found when aromatic tri-
fluoromethyl ketones with electron-neutral or -withdrawing
groups on aromatic rings were used, the aldol reactions proceeded
smoothly to give 2aee in 86e95% yield (entries 1e5). Furthermore,
the aldol reactions worked well with biphenyl, 1- and 2-naphthyl
trifluoromethyl ketones under our current conditions to afford
trifluoroacetophenone 1a in tetrahydrofuran (THF) with n-butyl
lithium or lithium diisopropylamide (LDA) as base gave the aldol
product 2a in moderate yield (entries 4 and 5). These results in-
dicated the need of the proper base, which plays the key role for the
success of the aldol reaction of fluorinated ketones. Therefore, we
performed this aldol reaction by using diethyl zinc as base. The
reaction is found to be clean and simple, and the aldol product 2a
was formed in 61% yield. In addition, the aldol condensation was
conducted in different solvents (entries 7e11). Tetrahydrofuran,
ether, and acetonitrile are not suitable for the Et2Zn-promoted di-
rect aldol reaction possibly due to their interaction with zinc. The
use of toluene and chlorinated alkanes minimizes such interaction,
resulting in enhanced yield and providing a suitable environment
for the reaction. Dichloromethane was found to be the best with
respect to reaction activity, and 2a was isolated in 90% yield. A
Table 2
Substrate scope for the aldol reactiona
Entry
1
Time (h)
24
Product 2
Yieldb (%)
95
2a
2
3
24
24
86
2b
85
2c
(continued on next page)

8472
H.-F. Cui et al. / Tetrahedron 67 (2011) 8470e8476
Product 2
Table 2 (continued )
Entry
Time (h)
24
Yieldb (%)
4
90
2d
5
6
24
24
86
82
2e
2f
7
24
88
2g
8
9
48
60
82
80
2h
2i
10
11
60
96
75
60
2j
2k
12
60
89
2l
13
14
48
48
76
74
2m
2n
15c
48
88
2o
a
Unless otherwise noted, the reaction was carried out with diazoacetate ester (0.3 mmol) and trifluoroacetophenone (0.2 mmol) in CH2Cl2 with Me2Zn (0.4 mmol).
b
c
Isolated yield (all data are the average of three experiments).
Reaction temperature: 0 ꢁC.

H.-F. Cui et al. / Tetrahedron 67 (2011) 8470e8476
8473
Ph
Ph
OH
the aldol products 2feh in good yields (entries 6e8). However, the
presence of electron-donating substituents on aromatic rings de-
creased the reaction rate, and relatively lower yields were obtained
(products 2iel, entries 9e12). Both heteroaromatic trifluoromethyl
ketone and 1,1-difluoroacetophenone also provide the normal ad-
ducts 2men in good yields (entries 13 and 14). Encouraged by these
results, we extended our methodology to aliphatic fluorinated ke-
tones. We found that 1,1,1-trifluoroacetone also reacts smoothly
N
H
O
O
OH
F3C
Ar
O
H
O
Ia
20 mol % ligand
OEt
O
*
OEt
Ar
CF3
N2
2
Me2Zn (2.0 equiv)
toluene, 0 oC, 48 h
N2
1
O
CF3
OH
CF3
F3C
HO
HO
OEt
OEt
*
OEt
*
with ethyl a-diazoacetate under mild conditions to give the cor-
*
N2
N2
N2
responding fluorinated product 2o in 88% yield (Table 2, entry 15).
As a successive study, the enantioselective version of the de-
scribed aldol condensation reaction using chiral ligands was also
disclosed. In order to obtain good ees, it is suitable to use a high
loading amount of the chiral ligand (20 mol %). Systemic optimi-
zation on the other reaction conditions (including chiral ligands
IeVIII, solvent, and temperature, Table 3) led to the discovery that
the best results were obtained when toluene was used as the sol-
vent and the reactions run at 0 ꢁC in the presence of (S)-diphe-
nylprolinol Ia (83% yield, 72% ee, entry 20). Several aldol products
were obtained in respectable yields with moderate to good enan-
tioselectivities (Scheme 2). It should be noted that even increasing
Cl
Br
75%, 34% ee
72%, 32% ee
90%, 32% ee
O
O
CF3
HO
CF3
N2
HO
OEt
*
OEt
*
N2
MeO
83%, 72% ee
85%, 30% ee
Scheme 2. The catalytic enantioselective aldol reaction of ethyl diazoacetate with
trifluoromethyl ketones.
Table 3
Optimization of the conditions for the enantioselective aldol reaction of diazoacetate with the substrate 1g
Entry
Ligand (mol %)
Solvent
Temperature (ꢁC)
Yield (%)a
eeb (%)
1
2
3
4
5
6
7
8
Ia (20)
Ib (20)
Ic (20)
Id (20)
II (20)
III (20)
IV (20)
V (20)
VIa (20)
VIb (20)
VIc (20)
VId (20)
VII (20)
VIII (20)
Ia (30)
Ia (20)
Ia (20)
Ia (20)
Ia (20)
Ia (20)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
Et2O
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
85
90
85
96
85
88
92
55
80
65
40
38
75
90
90
85
59
95
47
83
59
6
54
56
23 (d)
0
0
50 (d)
13 (d)
7
14 (d)
9
0
9
10
11
12
13
14
15
16
17
18
19
20
7
65
70
62
57
52
72
ꢀ20
0
0
0
Toluene
a
Isolated yield.
b
ee was determined by HPLC analysis on a chiral stationary phase.

8474
H.-F. Cui et al. / Tetrahedron 67 (2011) 8470e8476
of the amount of chiral ligand or lowering of the temperature did
not improve the enantioselectivity of the products.
which was purified by silica gel flash column chromatography
(petroleum ether/AcOEt: 8:1) to give the slightly yellow oil
(54.7 mg).
These aldol products 2 are versatile synthetic intermediates
and can be readily transformed into trifluoromethylated tertiary
alcohols. For example, direct hydrogenation of 2g in the presence
of Pd/C catalyst gave rise to 3 in good yield. Furthermore, hydro-
genation of the optically active compound 2g provided the cor-
responding product 3 without detectable loss of enantioselectivity
(Scheme 3).
2.2.1. Ethyl 4,4,4-trifluoro-3-hydroxy-3-phenyl-2-diazobutanoate
(2a). Slightly yellow oil, 95% yield, 19F NMR (376 MHz, CDCl3)
d
ꢀ77.1 (s, 3F); 1H NMR (400 MHz, CDCl3)
d
1.32 (t, J¼7.2 Hz, 3H),
4.32 (q, J¼6.8 Hz, 2H), 6.47 (br s, 1H), 7.45e7.49 (m, 3H), 7.69e7.71
(m, 2H); 13C NMR (100 MHz, CDCl3)
d 167.0, 134.8, 129.6, 128.7,
126.4, 125.1 (q, 1JCeF¼285.7 Hz), 75.6 (q, 2JCeF¼30.9 Hz), 62.9, 59.3
(d, J¼4.8 Hz), 14.2; MS (ESI): m/z 288.47 [M]þ, 259.16 [MꢀN2ꢀH]
þ
,
226.87 [MꢀOHꢀOEt]; IR (KBr)
n 2110, 1670, 1311, 1158,
O
CF3
N2
O
HO
CF3
712 cmꢀ1
.
HO
Pd/C, H2
EtOAc
OEt
*
OEt
*
2.2.2. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(4-fluorophenyl)-2-
diazobutanoate (2b). Slightly yellow oil, 86% yield; 19F NMR
2g
72% ee
3
(376 MHz, CDCl3)
CDCl3)
d
ꢀ77.4 (s, 3F), ꢀ111.6 (s, 1F); 1H NMR (400 MHz,
74% yield, 71% ee
d
1.32 (t, J¼7.0 Hz, 3H), 4.28e4.36 (m, 2H), 6.46 (br s, 1H),
Scheme 3. Synthetic transformation of 2g to the product 3.
7.14 (t, J¼8.8 Hz, 2H), 7.68 (dd, J¼8.4 and 5.2 Hz, 2H); 13C NMR
1
(100 MHz, CDCl3)
d
166.9, 163.3 (d, JCeF¼248.1 Hz), 130.7 (d,
4JCeF¼3.2 Hz), 128.6 (d, JCeF¼7.6 Hz), 125.0 (q, JCeF¼285.7 Hz),
115.7 (d, 2JCeF¼21.7 Hz), 75.4 (q, 2JCeF¼30.9 Hz), 62.0, 59.1, 14.2; MS
(ESI): m/z 306.06 [M]þ, 277.17 [MꢀN2ꢀH] þ, 226.87 [MꢀOHꢀOEt];
3
1
In summary, we have developed a direct and efficient aldol
condensation reaction of diazoacetate with trifluoromethyl ketones
in the presence of dialkyl zinc. Me2Zn simultaneously provide the
best base and Lewis acidity required for this successful reaction. A
series of fluorinated products were obtained in good to excellent
yields. In a preliminary experiment, a moderate to good enantio-
selectivity was obtained. Further tailored reagents and reaction
conditions in order to improve stereoselectivity of this trans-
formation as well as additional mechanistic studies are ongoing in
our laboratory and will be reported in due course.
IR (KBr)
n .
2105, 1675, 1311, 1163, 1107, 721 cmꢀ1
2.2.3. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(4-chlorophenyl)-2-
diazobutanoate (2c). Slightly yellow oil, 85% yield; 19F NMR
(376 MHz, CDCl3)
d
ꢀ77.4 (s, 3F); 1H NMR (400 MHz, CDCl3)
d 1.32 (t,
J¼7.0 Hz, 3H), 4.28e4.35 (m, 2H), 6.46 (br s, 1H), 7.43 (d, J¼8.4 Hz,
2H), 7.63 (d, J¼8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 166.9,
1
135.8, 133.5, 128.9, 128.0, 124.8 (q, JCeF¼285.7 Hz), 75.4 (q,
2JCeF¼31.1 Hz), 62.1, 59.0, 14.2; MS (ESI): m/z 322.32 [M]þ; IR (KBr)
n
2105, 1680, 1311, 1199, 1091 cmꢀ1
.
2. Experimental section
2.1. General details
2.2.4. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(4-bromophenyl)-2-
diazobutanoate (2d). Slightly yellow oil, 90% yield; 19F NMR
(376 MHz, CDCl3)
d
ꢀ77.3 (s, 3F); 1H NMR (400 MHz, CDCl3)
d 1.32 (t,
NMR was recorded on Varian Mercury Plus 500 instruments at
400 MHz (1H NMR), 100 MHz (13C NMR) and 376 MHz (19F NMR).
Chemical shifts were reported in parts per million down field from
internal Me4Si. MS were recorded on a VG-7070E or VG ZAB-HS
spectrometer with the ESI resource. Optical rotations were de-
termined using an Autopol IV-T. IR spectra were recorded on an
AVATAR 360 FT-IR spectrometer. HPLC analyses were carried out on
a Hewlett Packard Model HP 1200 instrument. Tetrahydrofuran,
diethyl ether, and toluene were distilled from sodium/benzophe-
none prior to use; Dichloromethane, dichloroethane, and acetoni-
trile were distilled from CaH2. All other purchased reagents were
used without further purification. Ethyl diazoacetate,9 ligand I,10
and VIII11 were prepared according to the literature procedures.
All of the reactions were carried out under an argon atmosphere
with the exclusion of moisture.
J¼7.2 Hz, 3H), 4.28e4.34 (m, 2H), 6.45 (br s, 1H), 7.57 (dd, J¼14.4
and 8.4 Hz, 4H); 13C NMR (100 MHz, CDCl3)
d 166.8, 134.0, 131.9,
128.3, 124.8 (q, 1JCeF¼285.7 Hz), 123.4, 75.5 (q, 2JCeF¼31.1 Hz), 62.1,
58.9, 14.2; MS (ESI): m/z 226.83 [MꢀOHꢀOEtꢀBr]; IR (KBr)
n 2105,
1670, 1317, 1158, 1009 cmꢀ1
.
2.2.5. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(3,4,5-trifluorophenyl)-2-
diazobutanoate (2e). Slightly yellow oil, 86% yield; 19F NMR
(376 MHz, CDCl3)
d
ꢀ77.6 (s, 3F), ꢀ131.9 (d, J¼20.3 Hz, 2F), ꢀ157.5 (t,
J¼20.5 Hz, 1F); 1H NMR (400 MHz, CDCl3)
d
1.34 (t, J¼7.2 Hz, 3H),
4.30e4.36 (m, 2H), 6.52 (br s, 1H), 7.35 (t, J¼7.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3)
d
166.7, 151.1 (ddd, JCeF¼250.0 and 10.1 and
3.8 Hz), 140.4 (dt, JCeF¼254.1 and 15.0 Hz), 131.5 (dd, JCeF¼11.4 and
1
6.7 Hz), 124.3 (q, JCeF¼285.4 Hz), 111.7e111.5 (m), 75.0 (q,
2JCeF¼31.9 Hz), 62.3, 58.4, 14.2; MS (ESI): m/z 342.25 [M]þ; IR (KBr)
2.2. Representative procedure for the aldol condensation
n .
2100, 1690, 1531, 1440, 1311, 1265, 1189, 1040, 1020 cmꢀ1
reaction of ethyl diazoacetate with trifluoromethyl ketone
2.2.6. Ethyl 4,4,4-trifluoro-3-hydroxy-3-biphenyl-2-diazobutanoate
(2f). Yellow oil, 82% yield; 19F NMR (376 MHz, CDCl3)
ꢀ77.1 (s,
3F); 1H NMR (400 MHz, CDCl3)
Dimethyl zinc (0.36 mL,1.1 M in hexane, 0.4 mmol) was added to
d
a solution of ethyl diazoacetate (30
methane (2.0 mL) under argon at room temperature. After the
resulting mixture was stirred for 10 min, 1,1,1-
mL, 0.3 mmol) in dichloro-
d
1.35 (t, J¼7.2 Hz, 3H), 4.35 (q,
J¼7.2 Hz, 2H), 6.53 (br s, 1H), 7.42 (t, J¼7.4 Hz, 1H), 7.50 (t, J¼7.6 Hz,
2H), 7.65 (d, J¼7.2 Hz, 2H), 7.70 (d, J¼8.4 Hz, 2H), 7.78 (d, J¼8.4 Hz,
trifluoroacetophenone 1a (34.8 mg, 0.2 mmol) was added into
the solution. The mixture was stirred at the same temperature until
the completion of the reaction with monitoring by TLC. Then, the
reaction solution was quenched with saturated NH4Cl solution
(10 mL), and extracted with AcOEt (10 mLꢂ3). The combined or-
ganic layers were washed with brine (10 mLꢂ3), dried over MgSO4,
and the solvent was removed in vacuum to yield the crude product,
2H); 13C NMR (100 MHz, CDCl3)
d 167.1, 142.4, 140.0, 133.7, 128.9,
1
127.8, 127.3, 127.2, 127.0, 125.2 (q, JCeF¼285.8 Hz), 75.6 (q,
2JCeF¼31.0 Hz), 62.0, 59.3, 14.3; MS (ESI): m/z 363.10 [MꢀH]ꢀ; IR
(KBr)
n .
2100, 1670, 1312, 1168, 1086, 738, 657 cmꢀ1
2.2.7. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(naphthalen-1-yl)-2-
diazobutanoate (2g). Light yellow viscous liquid, 88% yield; 19F

H.-F. Cui et al. / Tetrahedron 67 (2011) 8470e8476
8475
2
NMR (376 MHz, CDCl3)
d
ꢀ76.1 (s, 3F); 1H NMR (400 MHz, CDCl3)
1JCeF¼285.8 Hz), 74.3 (q, JCeF¼32.7 Hz), 62.1, 59.2, 14.2; MS (ESI):
d
1.35 (t, J¼7.0 Hz, 3H), 4.36e4.42 (m, 2H), 6.73 (br s, 1H), 7.45 (d,
m/z 294.33 [M]þ; IR (KBr)
n 2115, 1670, 1311, 1193, 1163, 1101,
J¼8.0 Hz, 1H), 7.54e7.61 (m, 2H), 7.74 (br s, 1H), 7.94 (t, J¼8.8 Hz,
707 cmꢀ1
.
2H), 8.63 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 167.1, 134.9,
1
131.5, 130.9, 129.4, 128.5, 126.8, 126.0, 125.9 (q, JCeF¼286.6 Hz),
2.2.14. Ethyl 4,4-difluoro-3-hydroxy-3-phenyl-2-diazobutanoate
(2n). Slightly yellow oil, 74% yield; 19F NMR (376 MHz, CDCl3)
3
2
125.8 (q, JCeF¼3.9 Hz), 125.2, 124.1, 77.4 (q, JCeF¼30.3 Hz), 61.9,
59.2, 14.2; MS (ESI): m/z 312.20 [MꢀN2], 226.79 [MꢀN2CCO2Et]; IR
d
ꢀ127.5 (dd, J¼294.1 Hz and 276.4 Hz, 2F); 1H NMR (400 MHz,
(KBr)
n
2105, 1669, 1311, 1259, 1157, 773 cmꢀ1
.
CDCl3)
d
1.31 (t, J¼7.0 Hz, 3H), 4.25e4.33 (m, 2H), 5.20 (br s, 1H),
6.16 (t, J¼55.4 Hz, 1H), 7.40e7.47 (m, 3H), 7.65 (d, J¼7.2 Hz, 2H); 13C
2.2.8. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(naphthalen-2-yl)-2-
diazobutanoate (2h). Light yellow viscous liquid, 82% yield; 19F
NMR (376 MHz, CDCl3)
NMR (100 MHz, CDCl3) d 167.2, 136.6, 129.3, 128.7, 126.5, 115.5 (t,
2
1JCeF¼249.6 Hz), 75.3 (t, JCeF¼22.8 Hz), 61.6, 60.0, 14.3; MS (ESI):
d
ꢀ76.8 (s, 3F); 1H NMR (400 MHz, CDCl3)
m/z 271.16 [MþH]þ; IR (KBr)
n .
2110, 1685, 1306, 1117, 1081 cmꢀ1
d
1.33 (t, J¼7.0 Hz, 3H), 4.31e4.37 (m, 2H), 6.61 (br s, 1H), 7.55e7.61
(m, 2H), 7.79 (d, J¼8.8 Hz, 1H), 7.89e7.96 (m, 3H), 8.21 (s, 1H); 13C
2.2.15. Ethyl 4,4,4-trifluoro-3-hydroxy-3-methyl-2-diazobutanoate
(2o). Slightly yellow oil, 88% yield; 19F NMR (376 MHz, CDCl3)
NMR (100 MHz, CDCl3) d 167.0,133.5,132.7,132.1,128.8, 128.7,127.6,
1
127.3, 126.7, 126.4, 125.5 (q, JCeF¼285.8 Hz), 123.5, 75.9 (q,
d
ꢀ83.4 (s, 3F); 1H NMR (400 MHz, CDCl3)
d
1.31 (t, J¼7.2 Hz, 3H),
2JCeF¼30.8 Hz), 62.0, 59.4, 14.3; MS (ESI): m/z 312.26 [MꢀN2],
1.58 (s, 3H), 4.29 (q, J¼7.2 Hz, 2H), 5.90 (br s, 1H); 13C NMR
1
226.80 [MꢀN2CCO2Et]; IR (KBr)
n
2105, 1675, 1301, 1188, 1153,
(100 MHz, CDCl3)
d
166.7, 125.7 (q, JCeF¼285.3 Hz), 71.0 (q,
748 cmꢀ1
.
2JCeF¼31.7 Hz), 61.7, 60.8, 19.7, 14.2; IR (KBr)
1307, 1249, 1035; MS (ESI) m/z: 226.16 [M]þ.
n
(cmꢀ1): 2106, 1682,
2.2.9. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(4-methoxylphenyl)-2-
diazobutanoate (2i). Yellow oil, 80% yield; 19F NMR (376 MHz,
2.3. Representative enantioselective version of the aldol
condensation procedure, ethyl 4,4,4-trifluoro-3-hydroxy-3-
phenyl-2-diazobutanoate (2a)
CDCl3)
d
ꢀ77.3 (s, 3F); 1H NMR (400 MHz, CDCl3)
1.32 (t, J¼7.2 Hz,
d
3H), 3.84 (s, 3H), 4.31 (q, J¼7.2 Hz, 2H), 6.40 (br s, 1H), 6.96 (d,
J¼8.8 Hz, 2H), 7.61 (d, J¼8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
167.0, 160.3, 127.9, 126.7, 125.2 (q, 1JCeF¼285.7 Hz), 114.0, 75.5 (q,
To a solution of (S)-diphenylprolinol 3 (10 mg, 0.04 mmol) in
toluene (3.0 mL) was added dimethyl zinc (0.36 mL,1.1 M in hexane,
0.4 mmol) under argon at 0 ꢁC and the resulting solution was
2JCeF¼30.9 Hz), 61.9, 59.5, 55.2 (d, J¼5.5 Hz), 14.2; MS (ESI): m/z
318.54 [M]þ; IR (KBr)
n 2105, 1670, 1516, 1312, 1260, 1168,
1030 cmꢀ1
.
stirred for 10 min. Ethyl diazoacetate (30 mL, 0.3 mmol) was added
into the solution. After stirring for 30 min, 1,1,1-trifluoro-
acetophenone 1a (34.8 mg, 0.2 mmol) was added into the above
solution. The mixture was stirred at the same temperature for the
stated time. Then, the reaction solution was quenched with satu-
rated NH4Cl solution (10 mL), and extracted with AcOEt (10 mLꢂ3).
The combined organic layers were washed with brine (10 mLꢂ3),
dried over MgSO4, and the solvent was removed in vacuum to yield
the crude product, which was purified by silica gel flash column
chromatography (petroleum ether/AcOEt: 8:1) to give the slightly
2.2.10. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(4-methylphenyl)-2-
diazobutanoate (2j). Slightly yellow oil, 75% yield; 19F NMR
(376 MHz, CDCl3)
d
ꢀ77.2 (s, 3F); 1H NMR (400 MHz, CDCl3)
d 1.33
(t, J¼7.2 Hz, 3H), 2.40 (s, 3H), 4.32 (q, J¼7.2 Hz, 2H), 6.43 (br s, 1H),
7.27 (d, J¼8.0 Hz, 2H), 7.58 (d, J¼8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3)
d
167.0, 139.6, 131.8, 129.4, 126.3, 125.2 (q, 1JCeF¼285.7 Hz),
2
75.6 (q, JCeF¼30.9 Hz), 61.9, 59.4, 21.1 (d, J¼4.4 Hz), 14.2; MS
(ESI): m/z 302.65 [M]þ; IR (KBr)
922 cmꢀ1
n 2105, 1680, 1306, 1158, 1020,
.
yellow oil (43.2 mg). 75% yield, ½a D20
þ6.5 (c 1.0, CH2Cl2), 34% ee,
ꢃ
Daicel Chiralcel AS-H, hexane/i-PrOH¼99.5/0.5, 0.8 mL/min,
254 nm, tR (major)¼7.5 min, tR (minor)¼8.1 min.
2.2.11. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(2-methylphenyl)-2-
diazobutanoate (2k). Slightly yellow oil, 60% yield; 19F NMR
(376 MHz, CDCl3)
d
ꢀ76.1 (s, 3F); 1H NMR (400 MHz, CDCl3)
d
1.34 (t,
2.3.1. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(4-chlorophenyl)-2-
J¼7.2 Hz, 3H), 2.58 (s, 3H), 4.35 (q, J¼7.2 Hz, 2H), 6.42 (br s, 1H), 7.22
diazobutanoate (2c). Yield 72%, ½a D20
þ11.3 (c 1.0, CH2Cl2), 32% ee,
ꢃ
(t, J¼8.0 Hz, 1H), 7.29e7.35 (m, 2H), 7.49 (d, J¼7.6 Hz, 1H); 13C NMR
Daicel Chiralcel AD-H, hexane/i-PrOH¼99.5/0.5, 0.8 mL/min,
254 nm, tR (major)¼9.7 min, tR (minor)¼10.4 min.
(100 MHz, CDCl3)
d 167.1, 138.7, 133.4, 131.7, 129.7, 126.9 (d,
3JCeF¼3.8 Hz), 125.7, 125.7 (q, JCeF¼286.4 Hz), 76.9 (q,
1
2JCeF¼30.0 Hz), 61.9, 57.9, 21.1 (d, J¼4.1 Hz), 14.3; MS (ESI): m/z
2.3.2. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(4-bromophenyl)-2-
302.05 [M]þ; IR (KBr)
n
2100, 1670, 1306, 1260, 1153, 922, 743,
diazobutanoate (2d). Yield 90%, ½a D20
þ9.0 (c 1.0, CH2Cl2), 32% ee
ꢃ
723 cmꢀ1
.
Daicel Chiralcel AD-H, hexane/i-PrOH¼99.5/0.5, 0.8 mL/min,
254 nm, tR (major)¼10.6 min, tR (minor)¼11.4 min.
2.2.12. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(3,5-dimethylphenyl)-2-
diazobutanoate (2l). Slightly yellow oil, 89% yield; 19F NMR
2.3.3. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(naphthalen-1-yl)-2-
(376 MHz, CDCl3)
d
ꢀ77.0 (s, 3F); 1H NMR (400 MHz, CDCl3)
d
1.33 (t,
diazobutanoate (2g). Yield 83%, ½a D20
þ60.8 (c 1.0, CH2Cl2), 72% ee,
ꢃ
J¼7.2 Hz, 3H), 2.38 (s, 6H), 4.30e4.35 (m, 2H), 6.44 (br s, 1H), 7.08 (s,
Daicel Chiralcel OJ-H, hexane/i-PrOH¼99.5/0.5, 1.0 mL/min,
254 nm, tR (major)¼18.4 min, tR (minor)¼27.4 min.
1H), 7.30 (s, 2H); 13C NMR (100 MHz, CDCl3)
d 167.1, 138.3, 134.6,
131.2, 125.2 (q, 1JCeF¼285.7 Hz), 124.1, 75.6 (q, 2JCeF¼30.7 Hz), 61.9,
59.4, 21.4, 14.2; MS (ESI): m/z 317.76 [MþH]þ; IR (KBr)
n
2100, 1675,
2.3.4. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(4-methoxylphenyl)-2-
1312, 1260, 1152, 1086, 1024 cmꢀ1
.
diazobutanoate (2i). Yield 85%, ½a D20
þ8.7 (c 1.0, CH2Cl2), 30% ee,
ꢃ
Daicel Chiralcel AS-H, hexane/i-PrOH¼99.5/0.5, 0.8 mL/min,
254 nm, tR (major)¼10.8min, tR (minor)¼12.3 min.
2.2.13. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(thiophen-2-yl)-2-
diazobutanoate (2m). Slightly yellow oil, 76% yield; 19F NMR
(376 MHz, CDCl3)
d
ꢀ79.8 (s, 3F); 1H NMR (400 MHz, CDCl3)
d
1.34
2.3.5. Ethyl 4,4,4-trifluoro-3-hydroxy-3-(naphthalen-1-yl)butanoate
3. A suspension of Pd/C (100 mg, 10% Pd) and 2g (101.4 mg,
0.3 mmol) in ethyl acetate (5 mL) under an atmosphere of hydrogen
(1 atm) was stirred for 3 h at room temperature. The reaction was
(t, J¼7.0 Hz, 3H), 4.34 (q, J¼7.2 Hz, 2H), 7.01 (br s, 1H), 7.05 (t,
J¼4.4 Hz, 1H), 7.16 (br s, 1H), 7.44 (d, J¼5.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d 166.9, 138.3, 127.3, 127.1, 125.7, 124.9 (q,

8476
H.-F. Cui et al. / Tetrahedron 67 (2011) 8470e8476
3. (a) Qiu, L.-H.; Shen, Z.-X.; Shi, C.-Q.; Liu, Y.-H.; Zhang, Y.-W. Chin. J. Chem. 2005,
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2007, 9, 1013; (c) Song, J. J.; Tan, Z.; Reeves, J. T.; Fandrick, D. R.; Yee, N. K.;
Senanayake, C. H. Org. Lett. 2008, 10, 877.
filtered through Celite and concentrated. Silica gel chromatography
using diethyl ether/hexanes gave final product as a white solid
(69.3 mg, 74% yield). ½a D25
þ25.4 (c 1.0, CH2Cl2); HPLC (Chiralpak OJ-
ꢃ
4. Selected reviews, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Cat-
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H, i-PrOH/hexane¼10/90, flow rate¼0.8 mL/min,
l
¼254 nm):
tmajor¼25.6 min, tminor¼37.0 min, ee¼71%. 1H NMR (400 MHz,
CDCl3)
d
1.21 (t, J¼7.2 Hz, 3H), 2.30 (dd, J¼26.8, 16.0 Hz, 2H);
3.69e3.84 (m, 2H), 5.38 (s, 1H), 7.30e7.39 (m, 3H), 7.76e7.90 (m,
3H), 8.10e8.22 (m, 1H); 13C NMR (125 MHz, CDCl3)
d 161.5, 134.6,
€
5. (a) Burkoth, T. L. Tetrahedron Lett. 1969, 57, 5049; (b) Schollkopf, U.; Frasnelli,
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1
132.1, 131.2, 129.7, 129.0, 126.4, 126.0, 125.3 (q, JCeF¼283.6 Hz),
3
2
124.3, 119.1 (d, JCeF¼1.3 Hz), 74.5 (q, JCeF¼30.5 Hz), 60.4, 38.5,
13.1; 19F NMR (376 MHz, CDCl3)
d
ꢀ77.3 (s, 3F); IR (KBr): 3406, 2990,
2938, 2906, 1687, 1584, 1544, 1369, 1305, 1274, 1212, 1176,
1060 cmꢀ1; MS (ESI): m/z 310.9 ([MꢀH]þ).
Acknowledgements
This work was supported financially by the National Natural
Science Foundation of China (No. 20972110 and 21002068).
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.09.009.
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