Asymmetric borane reduction of ketones promoted by menthopyrazole-ZnCl2 complex

Article abstract of DOI:10.1002/jhet.5570380308

The enantioselective reduction of ketones was accomplished by borane in the presence of pyrazole derivatives, particularly 2-methoxymethyl-3-phenyl-l-menthopyrazole (8). The catalysis of zinc chloride makes it possible to lower the reaction temperature be

Full text of DOI:10.1002/jhet.5570380308

May-Jun 2001
Asymmetric Borane Reduction of Ketones
601
Promoted by Menthopyrazole-ZnCl Complex
2
Choji Kashima*, Yoshihiro Tsukamoto, Yohei Miwa and Kohei Higashide
Department of Chemistry, University of Tsukuba, Ten-nodai, Tsukuba, Ibaraki 305-8571, Japan
Received September 19, 2000
The enantioselective reduction of ketones was accomplished by borane in the presence of pyrazole
derivatives, particularly 2-methoxymethyl-3-phenyl-l-menthopyrazole (8). The catalysis of zinc chloride
makes it possible to lower the reaction temperature below 0 °C, and to promote enantioselectivity.
J. Heterocyclic Chem., 38, 601 (2001).
Recently we developed the preparation and the utilities of
asymmetric borane reduction of ketones catalyzed by
N-hydroxyalkyl-3-phenyl-l-menthopyrazoles [17]. This
borane reduction however required long heating at 70 °C,
which was rather drastic conditions for the stereo
controlled reaction. Therefore milder reaction conditions
are desired for the higher selective reactions. In serial
study of the enantioselective synthesis of alcohols, we will
report here the effects of N-alkyl-3-phenyl-l-mentho-
pyrazoles and the co-effect of Lewis acids in the
asymmetric borane reduction of ketones.
3-phenyl-l-menthopyrazole (1) as a new chiral auxiliary [1],
which has unique structure and properties different from
conventional chiral auxiliaries [2]. The most important char-
acteristics of this auxiliary are that the acyl substrate termi-
nates to the nitrogen atom of heteroaromatic pyrazole ring,
and that the substrate is surrounded by a chiral atmosphere.
This structural feature causes the diastereofacial attack on
the acyl moiety in reactions with alkyl halides [3],
diphenyldisulfide [4], acyl chlorides [5], aldehydes [6], and
C=N compounds [7]. Moreover, the asymmetric additions
of Grignard reagents [8], dienes [9] and 1,3-dipolar
compounds [10] on 2-(α,β-unsaturated)acyl-3-phenyl-l-
menthopyrazoles have been reported. Otherwise,
N-acylheteroaromatics such as N-acylimidazoles are
utilized as the activated acyl moiety in a wide variety of
organic syntheses [11]. As an analogue of these
N-acylheteroaromatics, N-acylpyrazoles are easily
converted into acyl derivatives by the action of nucleophiles
such as alcohols [12], amines [13], Grignard reagents [14],
or organozinc compounds [15] under basic or acidic condi-
tions. As a part of these investigations, our goal was to
develop a catalytic use for pyrazole derivatives in synthetic
reactions, and particularly in asymmetric reactions.
Results and Discussion.
11
In a previous paper [17], a B-NMR study revealed that
the diastereoselection is not caused by the formation of boric
ester, but is regulated by chelation of the borane with the
pyrazole nitrogen atom. This fact suggested that N-alkyl-3-
phenyl-l-menthopyrazoles would satisfy the structural
requirements necessary for a chiral catalyst in the borane
reduction of ketones. As the typical N-substituted-3-phenyl-
l-menthopyrazoles, N-methyl- (2 and 3), N-benzyl- (4 and 5),
N-methoxymethyl- (7 and 8), N-ethoxymethyl- (9 and 10),
and N-benzyloxymethyl-3-phenyl-l-pyrazoles (11 and 12)
were provided by the alkylation of N-unsubstituted-3-
phenyl-l-menthopyrazole (1). 2,3-Diphenyl-l-menthopyra-
zole (6) was prepared by the treatment of phenylhydrazine
with benzoylmenthone. 2-(2'-Methoxyethyl)- (14) and (2'S)-
2-(2'-phenyl-2'-methoxyethyl)-3-phenyl-l-menthopyrazoles
(16) were prepared from the corresponding 2'-hydroxyethyl-
derivatives (13 and 15).
In the literature, there are some papers of chiral amino
alcohols, which are utilized as asymmetric catalysts for
borane reduction of ketones. The hydroxyl moiety of these
amino alcohols reacts with borane to form a boric esters,
and the amino moiety takes the role of a Lewis base.
Subsequently the rigid structure of the borane complex,
such as oxazaborolidine, sterically regulates the reduction
of ketones [16]. On these background, we examined the
The catalytic effects of these N-substituted-3-phenyl-l-
menthopyrazoles were compared with that of 2-(2'-
hydroxyethyl)-3-phenyl-l-menthopyrazole (13) in the
Table 1
Borane Reduction of p-Methylacetophenone (18a) Catalyzed by N-Substituted 3-Phenyl-l-menthopyrazoles
Entry
Catalyst
R
Solvent [a]
Alcohols
Yield (%)
Recovery [b]
(%)
Ee (%)
1
2
3
4
5
2
4
8
6
13
1-Me
1-Bn
Hexane
Hexane
Hexane
61
82
81
69
67
23(S)
4(S)
1(R)
13(R)
30(S)
92
73
87
84
89
2-CH OMe
2
2-Ph
Hexane-Toluene
Hexane
2-CH CH OH
2 2
[a] Borane reduction was carried out at 80°C for 24 hours; [b] Recovery of N-substituted-3-phenyl-l-menthopyrazoles.

602
C. Kashima, Y. Tsukamoto, Y. Miwa and K. Higashide
Vol. 38
Table 2
Borane Reduction Rates of
p-Methylacetophenone (18a) with 17 and ZnCl at -5 °C
2
Entry
BH •THF
(eq.)
17
(eq.)
ZnCl •Et O
Rate
(l·mol ·s )
3
2
2
-1 -1
(eq.)
-3
1
2
3
4
5
6
7
8
9
10
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0
1.0
0
1.0
0.5
1.3
1.5
2.0
2.0
1.0
0
0
5.1 x 10
7.0 x 10
9.5 x 10
1.8 x 10
4.6 x 10
1.7 x 10
4.8 x 10
2.7 x 10
-6
-5
1.0
1.0
0.5
1.3
1.5
2.0
1.0
2.0
-3
-3
-3
-4
-4
-4
2.9 x 10
3.7 x 10
-4
Table 3
Borane Reduction of p-Methylacetophenone (18a) in the Presence of 8
and Lewis Acids
Entry
Lewis Acid
Temp Yield Ee (conf.) Recovery of 8
(eq.) [a] (°C)
(%)
(%)
(%)
1
2
3
4
5
6
7
8
none
80
30
-5
-90
-5
-5
-5
-5
-5
81
80
54
74
34
99
68
67
3
1 (R)
22 (S)
46 (S)
34 (S)
47 (S)
16 (S)
19 (S)
35 (S)
6 (S)
87
78
79
76
96
85
69
84
70
60
76
69
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
1.0
1.0
1.0
2.0
0.1
1.0
1.0
1.0
1.0
2
2
2
2
2
BF ·OEt
3
2
CuBr
2
9
MgBr
2
borane reduction of ketones, and that drastic conditions
with prolonged heating at 80 °C were required for the
preparation of alcohols. Also the presence of excess
amount of either 17 or zinc chloride depressed the reaction
(entry 9 and 10), while the equimolar mixture of 17 and
zinc chloride retained the reactivity of borane (entry 4-8).
When taking into account the chiral catalytic effect, it was
found that the use of equimolar amounts of the pyrazole
derivative complex with zinc chloride resulted in the
optimum conditions for the borane reduction (entry 4).
10
11
12
AlEt Cl
-5
-5
-5
64
64
33
19 (S)
18 (S)
18 (S)
2
Al(i-PrO) 1.0
3
TiCl
1.0
4
[a] The ratio of the equimolar mixture of 8 and Lewis acid versus borane.
asymmetric borane reduction of p-methylacetophenone
11
(18a). As expected from B-NMR, the data in Table 1
show the applicability of N-substituted-3-phenyl-l-
menthopyrazoles for use as chiral catalysts in borane
reduction reactions.
In the meantime, milder reaction conditions were
desired in order to improve the borane reduction of
ketones. Our experience has shown that derivatives of
pyrazole such as N-acylpyrazoles exhibit a strong affinity
with zinc salts [9]. Moreover borane reductions are
accelerated by the addition of a Lewis acid [18]. Therefore
the additive effects of Lewis acids were studied on the
borane reduction catalyzed by N-substituted-3-phenyl-l-
menthopyrazoles, particularly the effect of zinc chloride.
For the experimental convenience, the reduction of
p-methylacetophenone (18a) with borane was firstly
surveyed in the presence of various amounts of
1-methoxymethyl-3,5-dimethylpyrazole (17) and zinc
chloride. The data in Table 2 show that the addition of
either 17 (entry 2) or zinc chloride (entry 3) retarded the

May-Jun 2001
Asymmetric Borane Reduction of Ketones
603
Table 4
Chiral Catalytic Effects of 2-Substituted 3-Phenyl-l-menthopyrazole on Borane Reduction of p-Methylacetophenone (18a) at -5 °C
Entry
2-Substituted
3-Phenyl-l-menthopyrazole
ZnCl •OEt
Yield
(%)
Ee (Conf.)
(%)
Pyrazole
(Recovery)
(%)
2
2
1
R
Eq [a]
1
2
3
4
5
6
7
8
13
13
8
CH CH OH
0
1.0
0
1.0
1.0
1.0
1.0
1.0
1.0
0
73
53
81
54
55
70
40
61
48
84
62
30 (S)
27 (S)
1 (R)
46 (S)
36 (S)
36 (S)
23 (S)
37 (S)
8 (S)
89
73
87
79
76
95
65
83
89
84
96
2
2
CH CH OH
2
2
CH OMe
2
8
CH OMe
2
10
12
14
15
16
6
CH OEt
2
CH OBn
2
CH CH OMe
2 2
(2'S)-CH CH(Ph)OH
2
9
10
11
(2'S)-CH CH(Ph)OMe
2
Ph
Ph
13 (S)
13 (R)
6
1.0
[a] Amount of ZnCl •OEt was used versus amount of 2-substituted-3-phenyl-l-menthopyrazoles.
2
2
Table 5
Enantioselective Borane Reduction of Ketones (18) in the Presence of 8 and ZnCl •OEt at -5 °C
2
2
Entry
Ketones (18)
Product (19)
Recovery of 8
2
3
R
R
Yield (%)
Ee (Conf.)(%)
(%)
1
2
3
4
5
6
7
8
9
18b
18c
18a
18d
18e
18f
18g
18h
18i
Ph
4-Cl-C H
Me
Me
Me
Me
Me
Et
19b
19c
19a
19d
19e
19f
19g
19h
19i
48
74
54
51
61
40
77
59
66
36 (S)
39 (S)
46 (S)
12 (S)
46 (S)
40 (S)
4 (S)
98
78
79
92
99
91
73
99
91
6
4
4-Me-C H
6
4
4
2-Me-C H
6
4-MeO-C H
6
4
Ph
Ph
1-Naphth
CH Br
2
Me
3 (R)
12 (R)
2-C H -(CH )
6
4
2 3
EXPERIMENTAL
Since the chilled reaction conditions generally brought a
good stereo regulation, the borane reduction of 18a was
carried out in the presence of 8 under various
temperatures, summarized in Table 3. The additive effects
of various Lewis acids are also given in the Table 3.
Moreover, the effects of N-substituted-3-phenyl-l-
menthopyrazoles are shown in Table 4. These data show
that the optimal conditions for the borane reduction of 8 is
in the presence of an equimolar amount of zinc chloride at
-5 °C. Under these optimal conditions, various ketones
were reduced by borane THF complex in the presence of 8
and zinc chloride, and the results are listed in Table 5. In
these reductions, the pyrazole derivative catalysts were
recovered in high yield and reused.
In conclusion, the enantioselective reduction of ketones
was accomplished by borane in the presence of pyrazole
derivatives, particularly 2-methoxymethyl-3-phenyl-l-
menthopyrazole (8). The addition of zinc chloride acceler-
ated the borane reduction, and made it possible to obtain
enantioselectivity at a low reaction temperature.
1
13
Melting points are uncorrected. H NMR and C NMR
spectra were obtained on JEOL JNM-EX270 (270 MHz) or
Varian GEMINI 2000 (200 MHz) spectrometers in deutero-
chloroform with tetramethylsilane as an internal standard. The
enantiomer ratios were evaluated from the peak ratios of gas
chromatography on SHIMADZU GC-14A gas chromatograph
using Chrompack Chirasil DEX-CB capillary column (0.25 mm
x 25 m). The yields of the products were evaluated by GL
Science GC-353 gas chromatograph using dimethylsiloxane type
capillary column (0.25 mm x 30 m) of GL Science TC-1.
General Procedure for N-Alkylation of Pyrazole
To a solution of 3-phenyl-l-menthopyrazole (or 3,5-
dimethylpyrazole) (2.0 mmol) in THF (2 ml) was added a hexane
solution (1.6 M) of butyllithium (1.25 ml, 2.0 mmol) at -5 °C.
After stirring for 30 minutes, alkyl halide (2.2 mmol) was added
to the mixture which was stirred for another 1.5 hours at room
temperature. The mixture was quenched with water, and
extracted with ether. The ether layer was washed with saturated

604
C. Kashima, Y. Tsukamoto, Y. Miwa and K. Higashide
Vol. 38
sodium hydrogen carbonate and sodium chloride solution, dried
over anhydrous magnesium sulfate, and concentrated. The
residue was chromatographed on silica gel column eluting with
hexane-ethyl acetate mixture (v/v 7 : 1).
Anal. Calcd. for C H N O: C, 76.47; H, 8.78; N, 9.39.
19 26 2
Found: C, 76.11; H, 8.78; N, 9.27.
2-Methoxymethyl-3-phenyl-l-menthopyrazole (8).
1
Compound 8 has bp 225-235 °C/ 5 mmHg; yield 61%; H
NMR: δ 0.79 (3H, d, J = 6.6 Hz), 0.89 (3H, d, J = 6.8 Hz), 1.09
(3H, d, J = 7.0 Hz), 1.23-1.35 (1H, m), 1.44-1.61 (1H, m),
1.81-2.05 (2H, m), 2.44-2.60 (1H, m), 2.66-2.77 (1H, m),
2.80-2.91 (1H, m), 3.34 (3H, s), 5.21 (2H, AB-q, J = 10.6, 27.2
Hz), 7.42 (5H, s).
1-Methyl-3-phenyl-l-menthopyrazole (2).
1
Compound 2 was obtained in 21% yield; H NMR: δ 0.92 (3H,
d, J = 6.8 Hz), 0.97 (3H, d, J = 6.8 Hz), 1.02 (3H, d, J = 6.8 Hz),
1.37-1.47 (1H, m), 1.73-1.88 (2H, m), 1.97-2.16 (2H, m),
2.54-2.62 (1H, m), 3.19-3.28 (1H, m), 3.81 (3H, s), 7.23-7.42
13
(3H, m), 7.72 (2H, d, J = 6.8 Hz); C NMR: δ 19.6 (CH ), 20.5
Anal. Calcd. for C
H N O: C, 76.47; H, 8.78; N, 9.39.
3
19 26 2
(CH ), 21.4 (CH ), 21.4 (CH ), 26.0 (CH ), 27.9 (CH), 31.1
Found: C, 76.27; H, 8.56; N, 9.43.
2
3
3
2
(CH), 37.1 (CH), 37.6 (CH ), 119.0 (C), 126.9 (CH), 127.0 (CH),
3
1-Ethoxymethyl-3-phenyl-l-menthopyrazole (9).
128.2 (CH), 135.0 (C), 142.1 (C), 147.4 (C).
1
Anal. Calcd. for C
Found: C, 80.01; H, 8.90; N, 10.33.
H N : C, 80.55; H, 9.01; N, 10.44.
Compound 9 has Bp 120 °C/ 8 mmHg; yield 22; H NMR: δ
0.86 (3H, d, J = 6.8 Hz), 0.96 (3H, d, J = 6.8 Hz), 1.04 (3H, d, J =
6.8 Hz), 1.15 (3H, t, J = 6.8 Hz), 1.33-1.46 (1H, m), 1.75-1.91
(2H, m), 1.96-2.10 (1H, m), 2.13-2.39 (1H, m), 2.75-2.83
(1H, m), 3.14 (1H, m), 3.60 (2H, quint, J = 7.0 Hz), 5.45 (2H,
AB-q, J = 11.0, 23.0 Hz), 7.26-7.42 (3H, m), 7.70-7.74 (2H, m);
18 24 2
2-Methyl-3-phenyl-l-menthopyrazole (3).
1
Compound 3 was obtained in 83% yield; H NMR: δ 0.74 (3H,
d, J = 6.60 Hz), 0.88 (3H, d, J = 6.6 Hz), 1.08 (3H, d, J = 6.9 Hz),
1.18-1.29 (1H, m), 1.45-1.54 (1H, m), 1.82-2.12 (2H, m),
13
C NMR: δ 14.9 (CH ), 17.8 (CH ), 20.6 (CH ), 20.7 (CH ),
22.6 (CH ), 27.5 (CH ), 29.7 (CH), 29.8 (CH), 32.6 (CH), 40.9
(CH ), 64.0 (CH ), 121.5 (C), 127.9 (CH), 128.2 (CH), 128.3
(CH), 129.8 (CH), 131.5 (C), 140.2 (C), 151.8 (C).
Anal. Calcd. for C N O: C, 76.88; H, 9.03; N, 8.97.
3
3
3
3
2.41-2.50 (1H, m), 2.63-2.70 (1H, m), 2.77-2.85 (1H, m), 3.68
2
2
13
(3H, s), 7.27-7.46 (5H, m); C NMR: δ 17.9 (CH ), 20.8 (CH ),
3
3
2 2
22.7 (CH ), 27.5 (CH ), 29.8 (CH), 32.7 (CH), 36.7 (CH), 40.9
2
2
(CH ), 120.2 (C), 128.1 (CH), 128.4 (CH), 129.7 (CH), 132.1
3
H
20 28
2
(C), 139.5 (C), 150.7 (C).
Anal. Calcd. for C
Found: C, 79.95; H, 9.09; N, 10.36.
Found: C, 76.71; H, 8.81; N, 9.18.
H N : C, 80.55; H, 9.01; N, 10.44.
18 24 2
2-Ethoxymethyl-3-phenyl-l-menthopyrazole (10).
1
Compound 10 was obtained in 54% yield; H NMR: δ 0.77
1-Benzyl-3-phenyl-l-menthopyrazole (4).
(3H, d, J = 6.6 Hz), 0.87 (3H, d, J = 6.8 Hz), 1.07 (3H, d, J =
7.0 Hz), 1.13 (3H, t, J = 7.2 Hz), 1.21-1.25 (1H, m), 1.27-1.43
(1H, m), 1.49-1.60 (1H, m), 1.80-2.03 (2H, m), 2.42-2.58
(1H, m), 2.64-2.75 (1H, m), 2.79-2.90 (1H, m), 3.54 (2H,
quint, J = 7.0 Hz), 5.24 (2H, quint, J = 10.6, 30.4 Hz),
7.36-7.44 (5H, m).
1
Compound 4 was obtained in 65% yield; H NMR: δ 0.81 (3H,
d, J = 6.8 Hz), 0.97 (3H, d, J = 6.8 Hz), 1.00 (3H, d, J = 6.8 Hz),
1.21-1.63 (1H, m), 1.65-1.86 (1H, m), 1.89-2.23 (2H, m),
2.46-2.53 (1H, m), 2.67-2.80 (1H, m), 3.18-3.30 (1H, m), 5.35
(2H, AB-q, J = 16.6, 19.2 Hz), 6.86-7.41 (8H, m), 7.75-7.80
13
(2H, m); C NMR: δ 19.3 (CH ), 19.9 (CH ), 21.3 (CH ), 21.5
(CH ), 26.1 (CH ), 28.1 (CH), 31.1 (CH), 37.2 (CH), 53.4 (CH ),
120.2 (C), 126.4 (CH), 127.0 (CH), 127.2 (CH), 128.2 (CH),
3
2
3
Anal. Calcd. for C
H N O: C, 76.88; H, 9.03; N, 8.97.
20 28 2
3
2
2
Found: C, 76.75; H, 9.29; N, 8.96.
128.5 (CH), 135.0 (C), 137.9 (C), 142.3 (C), 148.4 (C).
1-Benzyloxymethyl-3-phenyl-l-menthopyrazole (11).
Anal. Calcd. for C H N : C, 83.68; H, 8.19; N, 8.13. Found:
C, 83.60; H, 8.41; N, 7.95.
24 28
2
1
Compound 11 was obtained in 20% yield; H NMR: δ 0.85
(3H, d, J = 6.8 Hz), 0.96 (3H, d, J = 8.0 Hz), 1.00 (3H, d, J =
7.0 Hz), 1.27-1.45 (1H, m), 1.77-1.88 (2H, m), 1.99-2.13
(1H, m), 2.22-2.35 (1H, m), 2.71-2.79 (1H, m), 3.11-3.23
(1H, m), 4.61 (2H, AB-q, J = 12.0, 17.4 Hz), 5.53 (2H, AB-q, J =
2-Benzyl-3-phenyl-l-menthopyrazole (5).
1
Compound 5 was obtained in 31% yield; H NMR: δ 0.75 (3H,
d, J = 6.6 Hz), 0.87 (3H, d, J = 6.8 Hz), 1.06 (3H, d, J = 7.0 Hz),
1.21-1.63 (1H, m), 1.65-1.86 (1H, m), 1.89-2.23 (2H, m),
2.46-2.53 (1H, m), 2.67-2.80 (1H, m), 3.18-3.30 (1H, m), 5.16
11.0, 24.2 Hz), 7.23-7.44 (8H, m), 7.73 7 7 (2H, m).
- .7
Anal. Calcd. for C
H N O: C, 80.17; H, 8.07; N, 7.48.
25 30 2
Found: C, 80.00; H, 8.08; N, 7.44.
13
(2H, broad ), 6.86-7.41 (10H, m); C NMR: δ 17.8 (CH ), 20.6
3
(CH ), 20.9 (CH ), 22.7 (CH ), 27.5 (CH ), 29.9 (CH), 32.7
3
3
2
2
2-Benzyloxymethyl-3-phenyl-l-menthopyrazole (12).
(CH), 40.9 (CH), 52.7 (CH ), 120.9 (C), 126.8 (CH), 127.0 (CH),
2
Compound 12 was obtained in 51% yield; 1H NMR: δ 0.78
(3H, d, J = 6.6 Hz), 0.91 (3H, d, J = 6.6 Hz), 1.10 (3H, d, J =
7.0 Hz), 1.22-1.34 (1H, m), 1.44-1.63 (1H, m), 1.81-2.02
(1H, m), 2.44-2.59 (1H, m), 2.65-2.75 (1H, m), 2.80-2.90
(1H, m), 4.57 (2H, AB-q, J = 12.2, 16.6 Hz), 5.32 (2H, AB-q,
128.1 (CH), 128.2 (CH), 128.3 (CH), 129.8 (CH), 132.0 (C),
138.3 (C), 140.0 (C), 151.3 (C).
Anal. Calcd. for C H N : C, 83.68; H, 8.19; N, 8.13. Found:
24 28
2
C, 83.15; H, 8.15; N, 8.19.
1-Methoxymethyl-3-phenyl-l-menthopyrazole (7).
13
J = 10.8, 30.2 Hz), 7.20-7.41 (10H, m); C NMR: δ 18.0 (CH ),
3
1
20.6 (CH ), 20.7 (CH ), 22.8 (CH ), 27.6 (CH ), 29.9 (CH), 32.7
Compound 7 has bp 225-235 °C/ 5 mmHg; yield 25%; H
NMR: δ 0.87 (3H, d, J = 7.0 Hz), 0.96 (3H, d, J = 7.0 Hz), 1.03
(3H, d, J = 7.0 Hz), 1.36-1.47 (1H, m), 1.75-1.84 (2H, m),
1.97-2.10 (1H, m), 2.21-2.31 (1H, m), 2.73-2.80 (1H, m),
3.15-3.23 (1H, m), 3.37 (3H, s), 5.40 (2H, AB-q, J = 10.8,
22.4 Hz), 7.25-7.43 (3H, m), 7.71-7.76 (2H, m).
3
3
2
2
(CH), 41.0 (CH ), 70.3 (CH ), 121.8 (C), 127.6 (CH), 127.9
2
2
(CH), 128.3 (CH), 128.3 (CH), 129.8 (CH), 131.4 (C), 137.7 (C),
140.3 (C), 152.0 (C).
Anal. Calcd. for C
H N O: C, 80.17; H, 8.07; N, 7.48.
25 30 2
Found: C, 80.08; H, 8.07; N, 7.47.

May-Jun 2001
Asymmetric Borane Reduction of Ketones
605
1-Methoxymethyl-3,5-dimethylpyrazole (17).
ABX, J = 13.6, 5.2 Hz), 4.15 (1H, ABX, J = 8.2,13.6 Hz), 4.67
13
(1H, ABX, J = 8.0, 5.4 Hz), 7.07-7.37 (10H, m); C NMR; δ
1
Compound 17 has bp 75-85 °C/ 5 mmHg; yield 87%; H
NMR: δ 2.22 (3H, s), 2.29 (3H, d, J = 0.6 Hz), 2.29 (3H, d, J =
0.6 Hz), 3.31 (3H, s), 5.28 (2H, s), 5.87 (1H, s); MS (m/e,% Int.);
140 (11.3), 110 (71.0), 109 (100), 95 (10), 82 (12.9), 68 (30.6).
17.9 (CH ), 20.6 (CH ), 21.1 (CH ), 22.5 (CH ), 27.3 (CH ),
3
3
3
2
2
30.2 (CH), 32.4 (CH), 40.6 (CH), 54.8 (CH ), 57.2 (CH ), 82.4
3
2
(CH), 120.2 (C), 126.7 (CH), 127.8 (CH), 127.9 (CH), 128.1
(CH), 128.3 (CH), 130.1 (CH), 132.0 (C), 139.5 (C), 140.7 (C),
151.1 (C).
Anal. Calcd for C H N O: C, 59.98; H, 8.63; N, 19.98.
7
12 2
Found: C, 59.78; H, 8.58; N, 19.85.
Anal. Calcd for C H N O: C, 80.37; H, 8.3; N, 7.21. Found:
26 32
2
C, 79.99; H, 8.48; N, 7.06.
2,3-Diphenyl-l-menthopyrazole (6).
Borane Reduction of Ketone (18) using N-Substituted-3-Phenyl-
l-menthopyrazoles.
A toluene (5 ml) solution of phenylhydrazine (254 mg,
2.4 mmol), p-toluenesulfonic acid (76 mg, 0.4 mmol) and
benzoylmenthone (536 mg, 2.1 mmol), which was prepared from
benzoyl chloride and l-menthone according to the previously
reported method [3], was refluxed for 18 hours. The reaction
mixture was washed with saturated sodium hydrogen carbonate
and sodium chloride solution, dried over anhydrous magnesium
sulfate, and concentrated. The reaction residue was purified by
recrystallization from benzene-hexane; mp 111-112 °C; yield
Under argon atmosphere, Lewis acid (0.3 mmol) was stirred
with N-substituted 3-phenyl-l-menthopyrazoles (0.3 mmol) in
ether (3 ml) for 30 minutes at -5 °C. After the addition of borane
THF solution (1.0 M, 0.3 ml, 0.3 mmol) with 30 minutes stirring,
ketone (18, 0.3 mmol) was added at -5 °C and the mixture was
stirred for 24 hours at -5 °C. The mixture was quenched with
water and extracted with ether. The organic layer was washed
with dilute hydrochloric acid, water, saturated sodium hydrogen
carbonate, and saturated sodium chloride, and dried over
anhydrous magnesium sulfate. After removal of the solvent, the
yields of the products were evaluated by gas chromatography. By
silica gel column chromatography of the residue, the fraction of
the corresponding alcohol (19) was collected and the enantiomer
ratio were measured by the gas chromatography using a chiral
column. The absolute configuration of the product was deduced
by comparison of the optical rotation with authentic data [19].
1
43%; H NMR: δ 0.80 (3H, d, J = 6.6 Hz), 0.89 (3H, d, J = 6.9
Hz), 1.09 (3 Hz, d, J = 6.9 Hz), 1.24-1.37 (1H, m), 1.52-1.65 (1H,
m), 1.85-2.06 (2H, m), 2.46-2.53 (1H, m), 2.55-2.77 (1H, m),
13
2.90-2.97 (1H, m), 7.15-7.31 (5H, m); C NMR: δ 18.1 (CH ),
3
20.8 (CH ), 22.6 (CH ), 27.5 (CH ), 30.0 (CH), 32.5 (CH), 40.6
3
2
2
(CH), 122.0 (C), 125.0 (CH), 126.3 (CH), 127.8 (CH), 128.2
(CH), 128.5 (CH), 130.0 (CH), 132.2 (C), 138.9 (C), 140.6 (C),
152.7 (C).
Anal. Calcd. for C H N : C, 83.59; H, 7.93; N, 8.48. Found:
23 26
2
C, 83.31; H, 7.98; N, 8.46.
Borane Reduction Rates of p-Methylacetophenone (18a) in the
Presence of Zinc Chloride and 17.
General Procedure for Alkylation of 13 and 15.
To a dispersion (60%) of sodium hydride (54 mg, 1.4 mmol) in
mineral oil was added a tetrahydrofuran (THF) solution (1 ml) of
13 (or 15) (0.6 mmol) and stirred for 30 minutes. Methyl iodide
(0.06 ml, 1.0 mmol) was added to the mixture, which was stirred
for another 1 hour at room temperature. The mixture was
quenched with water, and extracted with ether. The ether layer
was washed with saturated sodium hydrogen carbonate and
sodium chloride solution, dried over anhydrous magnesium
sulfate, and concentrated. The residue was purified by silica gel
column chromatography eluting with hexane-ethyl acetate
mixture.
Under argon atmosphere, zinc chloride etherate (1.0 M, 0.3 ml,
0.3 mmol) was added to a ether solution (3 ml) of
1-methoxymethyl-3,5-dimethylpyrazole (17, 42 mg, 0.30 mmol)
with 30 minutes stirring at -5 °C, and then borane THF solution
(1.0 M, 0.3 ml, 0.3 mmol) was added and stirred at -5 °C. After
30 minutes, p-methylacetophenone (18a, 0.04 ml, 0.31 mmol)
was added to the mixture. Small portions of the solution were
sucked each hour, quenched with hydrochloric acid, and diluted
with dichloromethane. The contents of 18a mixture was
monitored by HPLC and the evaluated reaction rates are
summarized in Table 2.
2-(2'-Methoxyethyl)-3-phenyl-l-menthopyrazole (14).
Acknowledgement.
1
Compound 14 was obtained in 51% yield; H NMR: δ 0.73
The authors are grateful to the Chemical Analysis Center,
University of Tsukuba, for the measurement of various kinds of
spectra and the elemental analyses.
(3H, d, J = 6.6 Hz), 0.87 (3H, d, J = 6.6 Hz), 1.07 (3H, d, J = 6.9
Hz), 1.17-1.30 (1H, m), 1.42-1.57 (1H, m), 1.80-1.86 (1H, m),
1.89-1.97 (1H, m), 2.39-2.51 (1H, m), 2.64-2.69 (1H, m),
2.73-2.83 (1H, m), 3.18 (3H, s), 3.59-3.73 (2H, m), 4.06-4.11
13
REFERENCES AND NOTES
(2H, m), 7.34-7.44 (5H, m); C NMR: δ 18.2 (CH ), 20.9 (CH ),
3
3
21.2 (CH ), 23.0 (CH ), 27.7 (CH ), 30.2 (CH), 32.9 (CH), 41.1
3
2
2
(CH), 48.5 (CH ), 59.0 (CH ), 71.8 (CH ), 120.4 (C), 128.4
(CH), 128.6 (CH), 130.2 (CH), 132.3 (C), 140.4 (C), 151.5 (C).
[*] E-Mail: kashima@chac.tsukuba.ac.jp
[1] C. Kashima, I. Fukuchi, K. Takahashi, and A. Hosomi,
Tetrahedron Lett., 34, 8305 (1993).
[2] For recent reviews, see: [a] 'Asymmetric Synthesis', Vol. 1-5,
ed. by D. J. Morrison, Academic Press Inc., New York, 1983-1985; [b] B.
H. Kim and D. P. Curran, Tetrahedron, 49, 294 (1993); [c] L. Deloux and
M. Srebnik, Chem. Rev., 93, 763 (1993); [d] T. G. Gant and A. I. Meyers,
Tetrahedron, 50, 2297 (1994).
[3] C. Kashima, I. Fukuchi, and A. Hosomi, J. Org. Chem., 59,
7821 (1994).
[4] C. Kashima, K. Takahashi, and A. Hosomi, Heterocycles, 42,
241 (1996).
3
2
2
Anal. Calcd. for C N O: C, 76.88; H, 9.03; N, 8.97.
H
20 28
2
Found: C, 76.03; H, 9.10; N, 8.90.
(2'S)-2-(2'-Phenyl-2'-methoxyethyl)-3-phenyl-l-menthopyra-
zole (16).
1
Compound 16 was obtained in 66% yield; H NMR: δ 0.72
(3H, d, J = 6.6 Hz), 0.85 (3H, d, J = 6.8 Hz), 1.06 (3H, d, J = 6.8
Hz), 1.16-1.39 (1H, m), 1.42-1.61 (1H, m), 1.80-1.96 (2H, m),
2.40-2.49 (1H, m), 2.66-2.81 (2H, m), 3.09 (3H, s), 3.98 (1H,

606
C. Kashima, Y. Tsukamoto, Y. Miwa and K. Higashide
Vol. 38
[5] C. Kashima, I. Fukuchi, K. Takahashi, and A. Hosomi,
Tetrahedron, 52, 10335 (1996).
[12] C. Kashima, H. Harada, I. Kita, I. Fukuchi, and A. Hosomi,
Synthesis, 61 (1994).
[6] C. Kashima, I. Fukuchi, K. Takahashi, K. Fukusaka, and A.
Hosomi, Heterocycles, 47, 357 (1998).
[7] C. Kashima, K. Fukusaka, and K. Takahashi, J. Heterocyclic
Chem., 34, 1559 (1997).
[8] C. Kashima, K. Takahashi, K. Fukusaka, and A. Hosomi, J.
Heterocyclic Chem., 35, 503 (1998).
[9] C. Kashima, K. Fukusaka, K. Takahashi, and Y. Yokoyama, J.
Org. Chem., 64, 1108 (1999).
[10] C. Kashima, K. Takahashi, I. Fukuchi, and K. Fukusaka,
Heterocycles, 44, 289 (1997).
[11a] H. A. Staab, Angew. Chem., 74, 407 (1962); [b] T. Kamijo, H.
Harada, and K. Iizuka, Chem. Pharm. Bull., 32, 5044 (1984); [c] T.
Kitagawa, M. Kawaguchi, S. Inoue, and S. Katayama, Chem. Pharm.
Bull., 39, 3030 (1991).
[13] C. Kashima, I. Fukuchi, K. Takahashi, and A. Hosomi,
Heterocycles, 38, 1407 (1994).
[14] C. Kashima, I. Kita, K. Takahashi, and A. Hosomi, J.
Heterocyclic Chem., 32, 25 (1995).
[15] C. Kashima, I. Kita, K. Takahashi, and A. Hosomi, J.
Heterocyclic Chem., 32, 723 (1995).
[16] E. J. Corey and C. J. Helal, Angew. Chem. Int. Ed., 37, 1986
(1998).
[17] C. Kashima, Y. Tsukamoto, and K. Higashide, J. Heterocyclic
Chem., in press.
[18] W. M. Jones, J. Am. Chem. Soc., 82, 2528 (1960).
[19] K. Naemura, M. Murata, R. Tanaka, M. Yano, K. Hirose, and
Y. Tobe, Tetrahedron Asym., 7, 3285 (1996).