Resolution of secondary alcohols using 2-acyl-3-phenyl-l-menthopyrazoles as enantioselective acylating agents

Article abstract of DOI:10.1016/S0957-4166(02)00472-X

The chelation of AlCl₃ with N-acylpyrazoles leads to structural fixation of the acyl moiety and an acceleration in the rate of acylation of secondary alcohols. The chiral environment of the fixed acyl moiety of 2-acyl-3-phenyl-l-menthopyrazole 2 causes diastereofacial selectivity in the reaction with secondary alcohols, and thus 2 behaves as an enantioselective acylating agent. By the use of 2.4 molar equivalents of racemic 1-phenylethanol 3a, 2-acetyl-3-phenyl-l-menthopyrazole 2a afforded (S)-1-phenylethyl acetate (S)-4aa enantioselectively and unreacted 3a was recovered with (R)-configuration. Furthermore, the inverse configurational preferences were observed to give (R)-4aa and (S)-3a by the addition of strongly basic amines, which sometimes behaved as catalysts for enolate formation from 2 and AlCl₃. These dramatic changes in stereoselective preference should be useful properties of 2-acyl-3-phenyl-l-menthopyrazole 2 as an enantioselective acylating agent.

Full text of DOI:10.1016/S0957-4166(02)00472-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1713–1719
Resolution of secondary alcohols using
2-acyl-3-phenyl-l-menthopyrazoles as enantioselective acylating
agents
Choji Kashima,* Saori Mizuhara, Yohei Miwa and Yukihiro Yokoyama
Department of Chemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
Received 10 May 2002; accepted 29 July 2002
Abstract—The chelation of AlCl3 with N-acylpyrazoles leads to structural fixation of the acyl moiety and an acceleration in the
rate of acylation of secondary alcohols. The chiral environment of the fixed acyl moiety of 2-acyl-3-phenyl-l-menthopyrazole 2 causes
diastereofacial selectivity in the reaction with secondary alcohols, and thus 2 behaves as an enantioselective acylating agent. By
the use of 2.4 molar equivalents of racemic 1-phenylethanol 3a, 2-acetyl-3-phenyl-l-menthopyrazole 2a afforded (S)-1-phenylethyl
acetate (S)-4aa enantioselectively and unreacted 3a was recovered with (R)-configuration. Furthermore, the inverse configurational
preferences were observed to give (R)-4aa and (S)-3a by the addition of strongly basic amines, which sometimes behaved as catalysts
for enolate formation from 2 and AlCl3. These dramatic changes in stereoselective preference should be useful properties of
2-acyl-3-phenyl-l-menthopyrazole 2 as an enantioselective acylating agent. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
bonded to a nitrogen atom of the heteroaromatic pyra-
zole ring in a chiral environment. The steric hindrance
of 1 is especially relaxed by twisting of the benzene
ring, which overlaps on one side of the terminal nitro-
gen atom.4 These structural features cause a diastereo-
facial effect in the reactions of the substrate moiety.
Moreover, the lone pair of electrons on the adjacent
nitrogen acts as a Lewis base, causing the chelation of
N···LiꢀO in the lithium enolate derived from N-
acylpyrazoles. These chelations freeze the bond rotation
of the acyl group, fixing it in a syn-configuration. As a
result, the chirality of the (4R)-methyl group of 1
causes a high level of asymmetric induction at the
a-position of the acyl group of 2-acyl-3-phenyl-l-men-
thopyrazoles in their reactions with alkyl halides,6
diphenyldisulfide,7 acyl chloride,8 aldehydes,9 and CꢁN
compounds.10 A similar chelation of N···Mg···OꢁC,
which is observed with N-acylpyrazoles and
MgBr2·OEt2,11 induces the asymmetric Michael addi-
tion of Grignard reagents,12 Diels–Alder cycloaddi-
tions,13 and 1,3-dipolar cycloadditions14 with
N-(a,b-unsaturated acyl)pyrazoles.
The resolution of secondary alcohols has been investi-
gated for a long time by enantioselective acylation
using enzymes such as esterases, and this method has
extended to the practical preparation of optically active
alcohols and esters.1 However, enzymatic reactions
often have insufficient generality, and limitations in the
substrates and the enantiopreference of the reaction
often occur due to the high specificity of the enzyme.
For example, secondary alcohols were preferentially
acylated by a lipase to afford (R)-esters and the unre-
acted (S)-alcohols, but enantioselective acylation with
the opposite enantiopreference is very difficult under
enzymatic reaction conditions. In the mean time, some
non-enzymatic resolutions by enantioselective acylation
of secondary alcohols have appeared in the literature
using artificial auxiliaries.2 Also, alcohols and amines
were enantioselectively acylated by acyl chlorides in the
presence of a chiral catalyst.3
We have recently developed a method for the prepara-
tion for 3-phenyl-l-menthopyrazole 1 as a new chiral
auxiliary,4 which has a unique structure and properties,
relative to other auxiliaries.5 The most important char-
acteristics of this auxiliary are that the substrate is
N-Acylimidazoles are utilized as the activated acyl moi-
ety in a wide variety of organic syntheses.15 As ana-
logues of these N-acylheteroaromatics, N-acylpyrazoles
act as acyl donors on reaction with nucleophiles such as
alcohols,16 amines,17 Grignard reagents,18 and organo-
* Corresponding author. E-mail: kashima@chac.tsukuba.ac.jp
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00472-X

1714
C. Kashima et al. / Tetrahedron: Asymmetry 13 (2002) 1713–1719
zinc compounds19 under basic or acidic conditions. As
a further extension of the utility of 1 as a new chiral
auxiliary, we report herein the reaction of 2-acyl-3-
phenyl-l-menthopyrazoles 2 with racemic secondary
alcohols, where diastereoselective attack of the sec-
ondary alcohol on the activated acyl carbonyl group
was expected. Subsequently the resolution of racemic
secondary alcohols should be possible by enantioselec-
tive acylation using 2.
consumption of 5a was traced by HPLC monitoring in
the presence of various Lewis acids. The data in Table
1 showed that the reaction was accelerated more than
30 times by TiCl4, FeCl3 and AlCl3, which usually
behave as higher coordination number elements. These
Lewis acids should enable acylation of secondary alco-
hols under mild conditions, and to freeze the CꢀN bond
rotation between the acyl group and the pyrazole ring.
Further, the amount of AlCl3 was optimized in the
reaction of 5a with 3a, as summarized in Table 2. The
acylated product was obtained in moderate yields even
in the presence of less than 50 mol% of AlCl3 (run 2),
while reaction did not occur at all in the absence of
AlCl3 (run 1). Excess AlCl3 inhibited the acylation and
caused a Friedel–Crafts type side reaction, to form 6
and 7 (run 7). When the mixture of 3a and AlCl3 was
treated with 5a, no acylated product was obtained and
5a was recovered (run 10). In the case of 1-benzoyl-3,5-
dimethylpyrazole 5d, the acylation also proceeded to
give the corresponding benzoate ester 4da in good yield.
This shows that the intermediate from 5 and AlCl3 was
not the aluminum enolate but the chelated complex. By
the treatment of an equimolar mixture of 5a and AlCl3
with 20 molar equiv. of 3a at −5°C, half of 5a was
consumed in 15 min. In the case of 2.4 molar equiv. of
3a, the half-life of 5a was about 2 h, which suggests
that the rate-determining step of this reaction was the
attack of the alcohol on the acylpyrazole–AlCl3
chelated species.
2. Results and discussion
The phenyl group at the 3-position causes the chiral
environment on the acyl moiety of 2-acyl-3-phenyl-l-
menthopyrazoles 2, and leads to diastereofacial attack
of reagents on the a-position of the acyl moiety. These
diastereofacial attacks might be allowed on the car-
bonyl carbon, which is much closer to the stereogenic
center of 2. Thus, we first attempted the reaction of
2-acetyl-3-phenyl-l-menthopyrazole 2a with racemic 1-
phenylethanol 3a in the presence of BF3·OEt2. When
the reaction was carried out at 60°C for 48 h, 1-
phenylethyl acetate 4aa was obtained in 58% yield with
1% ee, as shown in Scheme 1. The low enantioselectiv-
ity of this reaction was thought to result from the
drastic acylation conditions. Although BF3·OEt2 acted
as a Lewis acid on the pyrazole nitrogen atom to
activate the carbonyl group toward nucleophiles, the
chelating bond between BꢀO could not be formed and
the rotation of the bond between the acyl group and the
pyrazole ring could not be frozen. These properties of
BF3·OEt2 also caused the low selectivity of this
reaction.
Table 1. The effect of Lewis acid on the reaction of 5a
with 3a
From the previous observations,10,12 rotation about the
bond between the acyl group and the pyrazole ring is
known to be frozen by the chelation of acylpyrazoles
with Lewis acids having high coordination number
(Scheme 2) By using 3a with 1-acetyl-3,5-dimethylpyra-
zole 5a, which is the most convenient N-acylpyrazole,
we optimized the acylation reaction in the presence of
various kinds of Lewis acids having higher coordina-
tion number. In order to reveal the reaction profiles, the
Lewis acid
Half life of 5a (min)
p-TsOH
BF3·OEt2
ZnCl2
CuBr2
TiCl4
384
191
188
88
13
7
FeCl3
AlCl3
6
Scheme 1.
Scheme 2.

C. Kashima et al. / Tetrahedron: Asymmetry 13 (2002) 1713–1719
Table 2. Catalytic effect of AlCl3 in the reaction of 5a with 3a
1715
Run
3a (equiv.)
AlCl3 (equiv.)
Yield (%)c
5a
4aa
3a
6
7
1
2
3
4
5
6
7
8
2.4
2.4
2.4
2.4
2.4
2.4
2.4
0
0
100
0
0
0
87
79
68
4
0
0
–
84
0
60
35
38
32
0
0
0
0
23
0
0
0
0
3
19
12
0
0
0
0
0
0
0
1.0
1.9
2.7
3.7
4.7
6.9
2.5
2.5
2.3
0
7
100
72
41
–
0
58
39
72
84
84
5
9a
10b
2.4
2.4
76
a Compound 3a (1.2 equiv.) was treated with 5a and AlCl3 for 30 min, and then further 3a (1.2 equiv.) was added to the mixture.
b 5a was added to the mixture of 3a and AlCl3 and stirred.
c The yields of 5a and 4aa were determined by GC based on 5a and those of 3a, 6 and 7 were determined based on 3a.
From these basic experiments, a catalytic amount of
Lewis acid such as AlCl3 was revealed to promote the
acylation of secondary alcohols with N-acylpyrazoles
even under mild conditions. Moreover, the results indi-
cated that reaction of secondary alcohols with the
chelated complex derived from 2 and AlCl3 is the rate
determining step and diastereofacial attack occurs due
to the chiral environment around the carbonyl carbon.
By the use of 2.4 molar equiv. of racemic 3a under
optimal conditions, (S)-4aa was obtained in 99% yield
with 66% ee. In this reaction, unreacted (R)-3a was
recovered in 93% yield with 46% ee as well as the chiral
auxiliary 1 in 64% yield. Similarly some secondary
alcohols were enantioselectively acetylated by the use of
2a in good yields, as summarized in Table 4. Also
(S)-1-phenylethyl propanoate 4ba was obtained by the
use of 2-propanoyl-3-phenyl-l-menthopyrazole 2b.
However, bulky acyl substituted 3-phenyl-l-menthopyr-
azoles 2c and 2d did not give the corresponding esters
and were hydrolyzed to 1 during workup. These results
show that the structure of the acyl moiety of 2 strongly
affects the approach of the alcohol molecule.
When 2a was treated with 20 molar equiv. of 3a in the
presence of equimolar AlCl3 at room temperature for 3
h, (S)-4aa was obtained in 87% yield with 48% ee. The
reaction was completed practically at −5°C for 17 h,
but the reaction was too slow at −20°C, affording 4aa
in only 50% yield after 17 h. After optimization of the
reaction in various solvents with a number of Lewis
acids, as summarized in Table 3, (S)-4aa was predomi-
nantly obtained in 94% yield with 71% ee in a toluene–
hexane mixture at −5°C. The selectivity factor(s) under
various conditions are also listed in Table 3. Here, the
enantioselective acylation of 3a was accomplished by
the use of 2a in the presence of AlCl3 (Scheme 3).
We have previously reported that magnesium enolates
of N-acylpyrazoles were formed by treatment with
MgBr2 in the presence of diisopropylethylamine.11 Oth-
erwise, N-acylpyrazoles reacted readily with primary
and secondary amines to afford the corresponding
amides.17 Since the nucleophilic attack of amines is
mainly seen with sterically unhindered amines such as
Table 3. Enantioselective acetylation of 3a with 2a
Run
Solvent
Lewis acid
Time (h)
Temp. (°C)
Product (4aa)
Yield (%)a
Ee (%)b
Conf.
sc
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Et2O
AlCl3
AlCl3
AlCl3
FeCl3
TiCl4
CuBr2
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
3
17
17
17
17
17
17
17
17
17
17
17
17
20
−5
−20
−5
−5
−5
−5
−5
−5
−5
−5
−5
−5
87
91
50
21
63
13
3
57
87
94
90
64
67
48
51
31
19
32
41
10
52
67
71
65
51
37
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
2.8
3.1
1.9
1.5
1.9
2.4
1.2
3.2
5.1
5.9
4.7
3.1
2.2
9
Toluene
10
11
12
13
Toluene–hexane (3:1)
Toluene–hexane (1:1)
Toluene–hexane (1:3)
Hexane
a Yields were determined by GC.
b Enantiomeric ratios were determined by chiral GC (Chirasil-DEX CB).
c Selectivity factor.

1716
C. Kashima et al. / Tetrahedron: Asymmetry 13 (2002) 1713–1719
Scheme 3.
4ef-d1 and 4ef-d2 were exclusively formed in the ratio of
65:35 in the presence of diisopropylethylamine. These
results using MeOD showed that the reaction pro-
ceeded through the enolate in the presence of strongly
basic bulky amines (Scheme 4).
methylamine and pyrrolidine, the formation of the alu-
minum enolate (rather than the formation of amides)
from N-acylpyrazoles and AlCl3 could be effected by
the use of bulky amines. Thus, the structural change
caused by the formation of the aluminum enolate of 2
perhaps leads to different steric effects toward the
attack of the alcohol. When 1-phenylacetyl-3,5-
dimethylpyrazole 5e was treated with MeOD in the
presence of AlCl3, product ratio of undeuterated 4ef-d0,
mono- 4ef-d1 and dideuterated methyl phenylacetates
4ef-d2 was shown to be 25:49:26. A similar ratio of
26:45:29 was observed in the reaction of 5e with MeOD
in the presence of AlCl3 and pyridine. On the contrary,
The reaction of 2a with 3a was performed by the
addition of various amines in the presence of AlCl3, as
summarized in Table 5. When strongly basic amines
were added, the configuration of 4aa was dramatically
changed (runs 4–6). On the other hand, the reaction
profile using pyridine (run 9) was similar to that seen in
the reaction of 2a with 3a in the absence of amine (run
Table 4. Resolution of 3 by enantioselective acylation with 2 in toluene–hexane (3:1)
Run
2
rac-3
Product (S)-4
Yield (%)a
Unreacted (R)-3
Yield (%)c Ee (%)b
1
R1
R2
R3
Ee (%)b
Yield (%)a
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2a
2a
2a
2a
Me
Et
t-Bu
Ph
Me
Me
Me
Me
3a
3a
3a
3a
3b
3c
3d
3e
H
H
H
H
p-Cl
p-Me
o-Me
H
Me
Me
Me
Me
Me
Me
Me
Et
4aa
4ba
4ca
4da
4ab
4ac
4ad
4ae
99
54
3
66
66
1
64
40
58
22d
81
24
58
65
46
57
1
93
88
51
95
86
83
37
90
Traced
85
–
–
60
53
69
66
30
13
16
42
79
29
89
a Yields were determined by GC.
b Enantiomeric ratios were determined by chiral GC (Chirasil-DEX CB).
c Yields were determined by HPLC.
d Yields were determined by NMR.
Scheme 4.

C. Kashima et al. / Tetrahedron: Asymmetry 13 (2002) 1713–1719
1717
Table 5. Resolution of 3a with 2a in the presence of AlCl3 and amines in toluene
Run
Amine
equiv.a
Temp. (°C)
Product 4aa
Unreacted 3a
1
Yieldb
Eec
Conf.
Yieldb
Eec
Conf.
Yieldd
1
2
3
4
5
6
7
8
Nonee
0
1.0
0
−5
40
40
40
40
40
40
40
40
99
8
66
12
13
15
18
38
6
6
4
0
0
(S)
(R)
(S)
(R)
(R)
(R)
(S)
(R)
(S)
64
26
31
56
72
31
65
57
75
69
73
58
70
60
76
77
58
79
85
46
5
7
7
8
11
4
3
2
0
0
30
9
41
23
38
24
0
(R)
(S)
(R)
(S)
(S)
(S)
(R)
(S)
(R)
93
16
84
87
91
32
91
93
86
9
i-Pr2NEte
None
77
99
100
26
33
58
100
5
i-Pr2NH
BnNH2
i-Pr2NEt
Pyrrolidine
t-BuNH2
Pyridine
DMAP
DBU
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0
0.5
1.0
1.2
1.5
2.0
1.0
1.0
9
10
11
12
13
14
15
16
17
18
19
40
40
5
8
None
−5
−5
−5
−5
−5
−5
−5
−5
90
98
89
69
100
82
69
68
49
5
(S)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(S)
(S)
94
89
83
67
82
58
64
70
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
BnNH2
i-PrNH2
64
61
64
61
2
65
26
(S)
a Amount of amine against 2a and AlCl3.
b Yields (%) were determined by GC.
c Enantiomeric excesses (%) were determined by chiral GC (Chirasil-DEX CB).
d Yields (%) were determined by HPLC.
e The solvent was a toluene–hexane mixture (3:1).
3), where no evidence of an enolate intermediate was
observed in the reaction of 5e with MeOD. Because of
the quantitative formation of 4aa, the reaction of 2a
with 3a was optimized in the cases of benzylamine and
diisopropylamine. When 2a was treated with 3a in the
presence of equimolar amounts of AlCl3 and diiso-
propylamine in toluene at −5°C, (R)-4aa was optimally
obtained in 89% yield with 64% ee, and unreacted
(S)-3a was recovered in 60% yield with 41% ee.
(R)-configuration. Furthermore, the inverse configura-
tional preferences were observed to give (R)-4aa and
(S)-3a by the addition of strongly basic amines, which
sometimes performed as catalysts for enolate formation
from 2 and AlCl3. These dramatic changes in enantio-
preference show 2-acyl-3-phenyl-l-menthopyrazole 2 to
be a very useful enantioselective acylating agent.
Finally the effect of diisopropylamine as an additive
was demonstrated by changing the amount added to
the reaction, as summarized in Table 5 (runs 13–17),
compared to the reaction without additive (run 12).
Increasing the amount of additive depressed the enan-
tioselectivity of the product, and the enantiopreference
was changed to the inverse configuration to give (R)-
4aa on addition of an equimolar amount of
diisopropylamine.
3. Experimental
1H NMR data were collected on a JEOL NMR JNM-
EX270 (270 MHz) spectrometer or a Varian NMR
Gemini-200 (200 MHz) spectrometer in deuteriochloro-
form with tetramethylsilane used as an internal stan-
dard. The yields of 3 and 4 were evaluated from their
chromatogram of GL-Science GC353 Gas Chro-
matograph through capillary column (0.25 mm f×25
m) coated with Silicon oil (TC-1) using naphthalene as
an internal standard. The enantiomer ratios of 3 and 4
were obtained from the peak intensities of gas-chro-
matogram using Shimadzu GC14A gas chromatograph
through CHROMPACK capillary (0.25 mm f×25 m)
column coated with Chirasil DEX-CB. For the determi-
nation of the contents of 1 and 2, HPLC analysis was
carried out by SIL-C18 column on a JASCO BIP-I
chromatograph using an aqueous methanol solvent.
Optical rotations were observed using a JASCO DIP-
370 digital polarimeter at 21°C. The melting points are
uncorrected.
In summary, the chelation of AlCl3 with an N-
acylpyrazole brings about the structural fixation of the
acyl moiety and an acceleration in the rate of acylation
of secondary alcohols with N-acylpyrazoles. The chiral
environment of the fixed acyl moiety of 2-acyl-3-
phenyl-l-menthopyrazole
2 leads to diastereofacial
selectivity in the attack of secondary alcohols, and thus
2 behaves as an enantioselective acylating agent. By the
use of 2.4 molar equiv. of racemic 3a, 2-acetyl-3-
phenyl-l-menthopyrazole 2a afforded (S)-4aa enan-
tioselectively, and unreacted 3a was recovered with

1718
C. Kashima et al. / Tetrahedron: Asymmetry 13 (2002) 1713–1719
3.1. Materials
(C), 177.4 (C). Anal. calcd for C22H30N2O: C, 78.06;
H, 8.93; N, 8.28; found: C, 78.02; H, 8.96; N, 8.26%.
Toluene and diisopropylamine were distilled over cal-
cium hydride under an argon atmosphere. Hexane and
CH2Cl2 were dried over calcium chloride under an
argon atmosphere. AlCl3 and another Lewis acids
were commercially available from Wako Pure Chemi-
3.1.4. 2-Benzoyl-3-phenyl-l-menthopyrazole, 2d. Mp
110–111°C (from hexane); yield 75%; [h]D −225.3 (c
1
0.35, CHCl3); H NMR: l 0.80 (3H, d, J=7 Hz), 0.89
(3H, d, J=7 Hz), 1.04 (3H, d, J=7 Hz), 1.35–1.18
(1H, m), 1.52–1.60 (1H, m), 1.87–2.01 (2H, m), 2.34–
2.41 (1H, m), 2.66 (1H, quint, J=5 Hz), 2.79–2.86
(1H, m), 7.36–7.56 (8H, m), 7.97–8.01 (2H, m); 13C
NMR: l 18.3 (CH3), 20.4 (CH3), 22.8 (CH2), 27.5
(CH2), 29.9 (CH), 32.3 (CH), 41.3 (CH), 125.8 (C),
127.5 (C), 127.6 (CH), 127.9 (CH), 128.1 (CH), 129.3
(CH), 131.7 (CH), 132.3 (CH), 133.3 (C), 142.1 (C),
155.9 (C), 167.4 (C). Anal. calcd for C24H26N2O: C,
80.41; H, 7.31; N, 7.81. Found: C, 80.22; H, 7.39; N,
7.88%.
cal
Industries,
Ltd.
1-Phenylpropanol,
1-(o-
methylphenyl)-, 1-(p-methylphenyl)- and 1-(p-chloro-
phenyl)ethanol were prepared by the NaBH4
reduction of the corresponding ketones. (S)-1-Phenyl-
ethanol ((S)-3a) was commercially available from
Tokyo Chemical Industry Co. Ltd., and was derived
into the corresponding ester ((S)-4aa) by the treat-
ment with acetyl chloride in the presence of Et3N. By
the gas chromatographic comparison with these
authentic samples, the absolute configuration of the
products was determined. According to the method
described previously,6 2-acyl-3-phenyl-l-menthopyra-
zoles (2) and 1-acyl-3,5-dimethylpyrazole (5) were pre-
pared from the corresponding acyl chloride and
pyrazoles in the presence of Et3N, and purified by
column chromatography on silica gel using benzene/
hexane mixture.
3.2. The reaction of 2a with 3a in the presence of
BF3·OEt2
A mixture of 2a (30 mg, 0.1 mmol), 3a (249 mg, 2.0
mmol) and BF3·OEt2 (0.015 mL) in THF (2 mL) was
heated at 60°C for 48 h under an argon atmosphere.
The reaction mixture was quenched with dil. hydro-
chloric acid and extracted with ether. The organic
layer was washed with aq. NaHCO3 and aq. NaCl,
and dried over anhydrous MgSO4. After the addition
of biphenyl as an internal standard, the yield of 4aa
was found to be 58% by GC. The ether solution was
concentrated and 4aa was distilled by cold finger dis-
tillator. From the GC of the distillate on chiral
column, 4aa was found have ee of <1%.
3.1.1. 2-Acetyl-3-phenyl-l-menthopyrazole, 2a. Yield:
1
62%; [h]D −268.5 (c 0.46, CHCl3); H NMR: l 0.69
(3H, d, J=7 Hz), 0.94 (3H, d, J=7 Hz), 1.09 (3H, d,
J=7 Hz), 1.18–1.31 (1H, m), 1.46–1.55 (1H, m), 1.83–
2.00 (2H, m), 2.36–2.44 (1H, m), 2.59–2.79 (2H, m),
2.63 (3H, s), 7.27–7.41 (5H, m); 13C NMR: l 18.6
(CH3), 20.2 (CH3), 20.4 (CH3), 23.0 (CH2), 23.6 (CH2),
27.3 (CH), 30.0 (CH), 32.1 (CH), 41.3 (CH3), 126.2
(C), 127.9 (CH), 128.1 (CH), 129.3 (CH), 132.6 (C),
140.8 (C), 155.9 (C), 170.5 (C). Anal. calcd for
C19H24N2O: C, 76.99; H, 8.16; N, 9.45; found: C,
76.75; H, 8.07; N, 9.42%.
3.3. Evaluation of the catalytic effect of Lewis acids
To the powdered Lewis acid (0.01 mmol), a mixture of
5a (138 mg, 0.1 mmol) and 3a (244 mg, 2.0 mmol) in
CH2Cl2 (2.0 mL) was added at room temperature
under an argon atmosphere. At regular intervals, a
small portion of the reaction mixture was taken and
quenched with dil. hydrochloric acid. The resulting
solution was monitored for content of 5a by GC anal-
ysis to allow the evaluation of catalytic effect of Lewis
acid (as summarized in Table 1).
3.1.2. 2-Propanoyl-3-phenyl-l-menthopyrazole, 2b. Yield
1
83%; [h]D −243.3 (c 0.48, CHCl3); H NMR: l 0.69
(3H, d, J=7 Hz), 0.94 (3H, d, J=7 Hz), 1.08 (3H, d,
J=7 Hz), 1.16 (3H, t, J=7 Hz), 1.20–1.31 (1H, m),
1.36–1.65 (1H, m), 1.76–2.06 (2H, m), 2.20–2.48 (1H,
m), 2.54–2.68 (1H, m), 2.70–2.83 (1H, m), 3.04–3.24
(2H, m), 7.25–7.46 (5H, m); 13C NMR: l 8.52 (CH3),
18.61 (CH3), 20.27 (CH3), 20.44 (CH3), 23.07 (CH2),
27.40 (CH2), 28.92 (CH), 30.05 (CH), 32.23 (CH),
41.40 (CH2), 126.06 (C), 128.25 (CH), 128.48 (CH),
129.40 (CH), 132.93 (C), 155.92 (C), 174.12 (C). Anal.
calcd for C20H26N2O: C, 77.38; H, 8.44; N, 9.02;
found: C, 77.43; H, 8.40; N, 9.10%.
3.4. Optimization of conditions for the reaction 2a with
3a
To the appropriate Lewis acid (0.1 mmol), a solution
(2 mL) of 2a (30 mg, 0.1 mmol) and 3a (244 mg, 2.0
mmol) was added under an argon atmosphere. After
stirring, the reaction mixture was quenched with dil.
hydrochloric acid and extracted with ether. The
organic layer was washed with aq. NaHCO3 and aq.
NaCl, and dried over anhydrous MgSO4. After addi-
tion of biphenyl as an internal standard, the yield of
4aa was evaluated by means of GC. The ether solu-
tion was concentrated and 4aa was distilled by cold
finger distillator, and the enantiomer ratios of 4aa
were obtained from the GC of the distillate on chiral
column. The results are summarized in Table 3.
3.1.3. 2-Pivaloyl-3-phenyl-l-menthopyrazole, 2c. Bp
160–170°C/5 mmHg; yield 99%; [h]D −244.9 (c 0.39,
1
CHCl3); H NMR: l 0.67 (3H, d, J=7 Hz), 0.96 (3H,
d, J=7 Hz), 1.09 (3H, d, J=7 Hz), 1.18–1.34 (1H, m),
1.41–1.56 (1H, m), 1.46 (9H, s), 1.85–1.98 (2H, m),
2.38–2.45 (1H, m), 2.59–2.77 (2H, m), 7.26–7.42 (5H,
m); 13C NMR: l 18.6 (CH3), 20.2 (CH3), 20.3 (CH3),
23.5 (CH2), 27.4 (CH2), 28.1 (CH3), 30.0 (CH), 32.6
(CH), 41.6 (CH), 42.2 (C), 124.7 (C), 127.8 (CH),
127.9 (CH), 129.0 (CH), 133.5 (C), 141.8 (C), 154.5

C. Kashima et al. / Tetrahedron: Asymmetry 13 (2002) 1713–1719
1719
3.5. General procedure for enantioselective acylation for
the resolution
2. (a) Evans, D. A.; Anderson, J. C.; Taylor, M. K. Tet-
rahedron Lett. 1993, 34, 5563; (b) Weidert, P. J.; Geyer,
E.; Horner, L. Liebigs Ann. Chem. 1989, 533.
3. (a) Oriyama, T.; Hori, Y.; Imai, K.; Sasai, R. Tetra-
hedron Lett. 1996, 37, 8543; (b) Ie, Y.; Fu, G. C.
Chem. Commun. 2000, 119; (c) Arai, S.; Bellemin-
Laponnaz, S.; Fu, G. C. Angew. Chem., Int. Ed. 2001,
40, 234; (d) Vedejs, E.; Daugulis, O.; MacKay, J. A.;
Rozners, E. Synlett 2001, 1499 and references cited
therein.
3.5.1. In the absence of amines. To the freshly powdered
AlCl3 (0.5 mmol), a mixture of 2 (0.5 mmol) and 3 (1.2
mmol) in toluene (3 mL) and hexane (1 mL) was added
at −5°C under an argon atmosphere. After stirring was
continued for 17 h at −5°C, the subsequent mixture was
quenched with dil. hydrochloric acid and extracted with
two portions of ether. The organic layer was washed
with aq. NaCl, and dried over anhydrous MgSO4. After
the addition of biphenyl as an internal standard, the
yields of 4 and unreacted 3 were evaluated by means of
GC. The ether solution was concentrated. Compounds
3 and 4 were roughly purified by cold finger distillation
of the residue. The enantiomeric ratios of 4 and unre-
acted 3 were obtained by means of GC analysis on a
chiral column. The results are summarized in Table 4.
4. Kashima, C.; Fukuchi, I.; Takahashi, K.; Hosomi, A.
Tetrahedron Lett. 1993, 34, 8305.
5. For recent reviews, see: (a) Asymmetric Synthesis, Mor-
rison, J. D., Ed.; Academic Press Inc.: New York,
1983–1985; Vols. 1–5; (b) Kim, B. H.; Curran, D. P.
Tetrahedron 1993, 49, 298; (c) Gant, T. G.; Meyers, A.
I. Tetrahedron 1994, 50, 2297.
6. Kashima, C.; Fukuchi, I.; Hosomi, A. J. Org. Chem.
1994, 59, 7821.
3.5.2. In the presence of amines. To freshly powdered
AlCl3 (0.5 mmol), a solution of the appropriate amine
(0.5 mmol) in toluene (2 mL) was added. A mixture of
2a (150 mg, 0.5 mmol) and 3a (146 mg, 1.2 mmol) in
toluene (3 mL) was added at −5°C under an argon
atmosphere. After stirring was continued at −5°C for 17
h, the mixture was quenched with dil. hydrochloric acid
and extracted with two portions of ether. The organic
layer was worked up as the method described above,
and the results are summarized in Table 5.
7. Kashima, C.; Takahashi, K.; Hosomi, A. Heterocycles
1996, 42, 241.
8. Kashima, C.; Fukuchi, I.; Takahashi, K.; Hosomi, A.
Tetrahedron 1996, 52, 10335.
9. Kashima, C.; Fukuchi, I.; Takahashi, K.; Fukusaka,
K.; Hosomi, A. Heterocycles 1998, 47, 357.
10. Kashima, C.; Fukusaka, K.; Takahashi, K. J. Hetero-
cycl. Chem. 1997, 34, 1559.
11. Kashima, C.; Takahashi, K.; Fukusaka, K. J. Hetero-
cycl. Chem. 1995, 32, 1775.
12. Kashima, C.; Takahashi, K.; Fukusaka, K.; Hosomi,
A. J. Heterocycl. Chem. 1998, 35, 503.
13. Kashima, C.; Fukusaka, K.; Takahashi, K.; Yokoyama,
Y. J. Org. Chem. 1999, 64, 1108.
14. Kashima, C.; Takahashi, K.; Fukuchi, I.; Fukusaka, K.
Heterocycles 1997, 44, 289.
15. (a) Staab, H. A. Angew. Chem. 1962, 74, 407; (b)
Kamijo, T.; Harada, H.; Iizuka, K. Chem. Pharm. Bull.
1984, 32, 5044; (c) Kitagawa, T.; Kawaguchi, M.;
Inoue, S.; Katayama, S. Chem. Pharm. Bull. 1991, 39,
3030.
16. Kashima, C.; Harada, H.; Kita, I.; Fukuchi, I.;
Hosomi, A. Synthesis 1994, 61.
17. Kashima, C.; Fukuchi, I.; Takahashi, K.; Hosomi, A.
Heterocycles 1994, 38, 1407.
Acknowledgements
The authors are grateful to the Chemical Analysis
Center, University of Tsukuba, for the measurement of
the NMR spectra, and the elemental analyses.
References
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