Asymmetric reaction of diethylzinc with aldehydes catalyzed by l-menthopyrazole derivatives

Article abstract of DOI:10.1002/jhet.5570390511

N-Hydroxyalkyl-1-menthopyrazoles acted as a chiral catalyst for the diethylzinc (1) addition to aromatic aldehydes, and 1-aryl-1-propanols were afforded enantioselectively. These reactions were carried out optimally in toluene at 40°C in the presence of 3

Full text of DOI:10.1002/jhet.5570390511

Sep-Oct 2002
Asymmetric Reaction of Diethylzinc with Aldehydes
Catalyzed by l-Menthopyrazole Derivatives
917
Choji Kashima,* Kohei Higashide, Yohei Miwa and Yoshihiro Tsukamoto
Department of Chemistry, University of Tsukuba, Ten-nodai, Tsukuba, Ibaraki 305-8571, Japan
E-Mail: kashima@chac.tsukuba.ac.jp
Received December 4, 2001
N-Hydroxyalkyl-l-menthopyrazoles acted as a chiral catalyst for the diethylzinc (1) addition to aromatic
aldehydes, and 1-aryl-1-propanols were afforded enantioselectively. These reactions were carried out opti-
mally in toluene at 40 °C in the presence of 30 mol% of (2'S)-2-(2-phenyl-2-hydroxyethyl)-3-phenyl-l-men-
thopyrazole ((S)-16d) to afford optically active 1-aryl-1-propanols up to 70% ee (S).
J. Heterocyclic Chem., 39, 917(2002).
Recently we have developed the preparation and the
papers using various amino alcohols followed to give sim-
ilar enantioselective addition of dialkylzinc toward aldehy-
des [18]. With the background, we wish to report the reac-
tion of diethylzinc with aldehydes catalyzed by l-men-
thopyrazoles having the hydroxylalkyl group.
utilities of 3-phenyl-l-menthopyrazole as a new chiral aux-
iliary [1], which has a unique structure and properties rela-
tive to the conventional chiral auxiliaries [2]. The most
important characteristics of this auxiliary are that the sub-
strate terminates at a nitrogen atom of the heteroaromatic
pyrazole ring, and that the substrate is surrounded by the
chiral environment. These structural features cause the
diastereofacial attack on the substrate moiety in the reac-
tions with alkyl halides [3], diphenyldisulfide [4], acyl
chloride [5], aldehydes [6], and C=N compounds [7].
Moreover, the asymmetric additions of Grignard reagents
Results and Discussion
N-(1-Hydroxyalkyl)pyrazoles were previously reported
to be prepared by the action of aldehydes toward N-unsub-
stituted pyrazoles [16a]. From these facts, the Lewis acid
complex of N-(1-hydroxyalkyl)pyrazoles with dialkylzinc
should be formed in situ by aldehydes with pyrazoles.
Moreover, this complex was expected to act as a self-cata-
lyst in the addition reaction of dialkylzinc to aldehydes.
Actually 1-(4-methylphenyl)-1-propanol (3a) was
obtained by the action of diethylzinc (1) toward 4-methyl-
benzaldehyde (2a) in the presence of 3,5-dimethylpyrazole
[
8], dienes [9] and 1,3-dipolar compounds [10] on 2-(a,b -
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 varieties of organic syntheses [11]. As an ana-
logue 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 conditions.
(4). This catalytic effect was observed with less than 30
mol% of 4. These results indicated the catalytic effect of
N-unsubstituted pyrazole for the addition reaction of
dialkylzinc to aldehydes through the formation of Lewis
acid complex.
Many reports of chiral amino alcohols relating to enan-
tioselective synthesis have appeared in the literature. The
chiral amino alcohols behave as a ligand for a metal atom
to form a complex, which takes the role of an optically
active Lewis acid. Since l-menthopyrazole derivatives
exhibit both the characteristic of Lewis basicity and asym-
metric structure, the introduction of a hydroxyl group was
expected to exploit the utilities of l-menthopyrazoles as a
ligand for an optically active Lewis acid. On this strategy,
the utility of l-menthopyrazole derivatives having an
hydroxyalkyl group was investigated as an optically active
catalyst for the borane reduction of ketones [16]. As a part
of these investigations been hoped to extend the catalytic
use of pyrazole derivatives in synthetic reactions espe-
cially in asymmetric reactions.
Next, the catalytic effect of 3-phenyl-l-menthopyrzole
(5a), which was recently designed as an optically active
pyrazole, was studied in the addition reaction of dialkylz-
inc to aldehydes. In the meanwhile, isomenthopyrazole
[(4R,7R)-4-methyl-7-isopropyl-4,5,6,7-tetrahydro-inda-
zole], (5b) was designed at an optically active pyrazole
[19]. Therefore the catalytic effects of 5b were also exam-
ined. In the various solvents, a mixture of 1.3 mmol of 2a
Recently, Soai and his co-workers focused their atten-
tion on the addition reaction of dialkylzinc toward alde-
hydes in the presence of chiral amino alcohols, and eluci-
dated their enantioselective reaction mechanism, catalyzed
by an optically active Lewis acid [17]. Since then, some

9
18
C. Kashima, K. Higashide, Y. Miwa and Y. Tsukamoto
Vol. 39
was treated with 2 mmol of 1 at 40 °C in the presence of 0.3
mmol of5. The data in Table 1 indicate that a non-polar sol-
vent was preferable, and that optically active 3a was
obtained in a moderate yield with an enantioselectivity of
about 20% ee. The low enantioselectivity of this reaction
was perhaps caused by the mixed formation of 4 isomers of
N -h ydroxymethylpyrazoles, which consisted of 2 diastere-
omers in each of 2 regioisomers, 6 and 7. Although the cat-
alyst in this reaction was easily formed in situ from 2 a, 5
and 1, the regioselective and diastereoselective formation
of these catalyst was difficult to control because of the
labile properties of N -h y d r o x y m e t h y l p y r a z o l e s .
Previously the reactions of N-acylpyrazoles with
organometallic substances such as lithium aluminum
hydride [20], Grignard reagents [14] and Reformatsky
reagents [15], were revealed to give carbonyl compounds,
where the reaction intermediate was explained to be N-
hydroxymethylpyrazoles. Since N-acyl-3-phenyl-l-men-
thopyrazoles (8 and 9) could be prepared regioselectively,
the regioselective formation of zinc complex of N-(1-
hydroxyalkyl)pyrazoles (6 or 7) was expected in situ by
the reaction of N-acylpyrazoles with dialkylzinc. The cat-
alytic effect of 8 and 9 in the addition reaction of 1 to 2a is
summarized in Table 1. As another attempt toward the
regioselective formation of catalysts such as 10 and 11,
another Lewis base center consisting of hydroxyl or
methoxy groups was introduced on pyrazole derivatives
(5d, 5e, and 5g). However, the data in Table 1 illustrate
that these attempts gave unsatisfactory results, and such
Table 1
Addition of 1 toward 2a Catalyzed by Menthopyrazoles
Run
Catalyst
R
Solvent
Yield
(%)
Ee
(%)
R1
3
R4
Mol %
_
_
_
1
2
3
4
5
6
7
8
9
None
0
Toluene
Toluene
Hexane
DMF
0
4
4
3,5-Dimethylpyrazole
3,5-Dimethylpyrazole
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
51
58
6
27
34
51
47
23
9
19
10
31
32
35
38
19
22
23
5a
5a
5a
5a
5b
5c
5d
5e
5f
5g
8h
9h
8i
Ph
Ph
Ph
Ph
H
1-H
1-H
1-H
1-H
1-H
1-H
1-H
1-H
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(R)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
(S)-i-Pr
9 (S)
24 (S)
23 (S)
11 (S)
3 (S)
22 (S)
14 (S)
3 (S)
THF
Toluene
Hexane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
2-MeO-C H4
2-HO-C H4
6
10
11
12
13
14
15
16
17
18
19
6
CH OH
2
Ph
1-Me
1-Me
1-Ac
7 (S)
2-HO-C H4
32 (S)
14 (S)
13 (S)
11 (S)
18 (S)
11 (S)
14 (S)
6
Ph
Ph
Ph
Ph
Ph
Ph
2-Ac
1-CO-i-Pr
2-CO-i-Pr
1-CO-Ph
2-CO-Ph
9i
8j
9j

Sep-Oct 2002
Asymmetric Reaction of Diethylzinc with Aldehydes
919
Also N-(2-hydroxyethyl)pyrazoles were prepared by the
hydride reduction of pyrazolylacetates (1 3 ,g 1 3 h, 1 4 ga n d
1
4 h) or aroylmethylpyrazoles (1 3 d -a fn d 1 4 d )- , fa nd were
easily isolated regio- and diastereoselectively as stable sub-
stances [16]. The catalytic effect of N-( 2 - h y d r o x y e t h- y l ) p y r a
zoles was optimized by the reaction of 2 awith 1 in the pres-
ence of 1-(2-hydroxyethyl)-3,5-dimethylpyrazole (1 2) under
various reaction conditions. The data in Table 2 exhibit that
30 mol% of 1 2catalyzed sufficiently the addition reaction of
dialkylzinc to aldehydes at 40 °C in toluene.
Table 2
Addition of 1 to 2a Catalyzed by 1-(2-Hydroxyethyl)-
3
,5-dimethylpyrazole (12)
Run
12
1
2a
Time
(h)
Temp. Yield of 3a
Lewis basic centers do not affect the promotion of enan-
tioselectivity in the addition reaction of dialkylzinc to
aldehydes. From these facts, the formation of a chiral cat-
alyst of N-(a -hydroxylalkyl)-l-menthopyrazoles was pre-
pared in situ with ease, but the satisfactory results in enan-
tioselectivity of dialkylzinc addition could not be obtained
by less diastereoselective formation of these catalyst.
On the other hand, N -( 2-hydroxyethyl)pyrazoles were pre-
pared by the direct alkylation of the corresponding pyrazoles.
(mol %) (mmol) (mmol)
(°C)
(%)
1
2
3
4
5
6
7
8
9
0
15
30
30
45
100
30
30
30
30
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
6.0
4.5
4.0
6.0
4.0
2.5
6.0
2.0
8.0
4.0
40
40
40
40
40
40
0
80
40
40
0
45
72
71
70
70
20
88
2
1
0
5
Table 3
Enantioselective Diethylzinc Addition to 2a Catalyzed by
N-(2-Hydroxyethyl)-menthopyrazole Derivatives
Run
Catalyst
R
Yield of 3a
Ee of 3a
(%)
1
R2
4
R
(%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
15a
16a
15b
16b
Ph
Ph
H
H
H
H
H
H
H
(S)-Ph
(R)-Ph
(S)-Ph
(R)-Ph
(S)-Ph
(R)-Ph
(S)-i-Pr 85
(S)-i-Pr 75
(R)-i-Pr 85
(R)-i-Pr 79
(R)-i-Pr 46
(R)-i-Pr 65
(S)-i-Pr 59
(S)-i-Pr 74
(S)-i-Pr 81
(S)-i-Pr 21
20 (R)
7 (S)
18 (R)
12 (S)
63 (S)
33 (R)
28 (S)
65 (R)
70 (S)
55(R)
25 (S)
43 (R)
72 (S)
24 (R)
56 (S)
44 (R)
70 (S)
39 (R)
(S)-16c
(R)-16c
(S)-15d
(R)-15d
(S)-16d
(R)-16d
(S)-15e
(R)-15e
(S)-16e
(R)-16e
(S)-15f
(R)-15f
(S)-16f
(R)-16f
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1
1
1
1
1
1
1
1
1
(S)-4-Me-C H (S)-i-Pr 17
(R)-4-Me-C H (S)-i-Pr 99
(S)-4-Me-C H (S)-i-Pr 83
(R)-4-Me-C H (S)-i-Pr 71
6
4
6
4
6
4
6
4
(S)-1-Naph
(S)-i-Pr 37
(S)-i-Pr 63
(S)-i-Pr 78
(S)-i-Pr 54
(R)-1-Naph
(S)-1-Naph
(R)-1-Naph
When various 1-(2-hydroxyethyl)- (1 5) and 2-(2-hydrox-
y e t h y- ll m-) enthopyrazole derivatives (1 6) were used as the
chiral catalyst, 1 reacted with 2a in an enantioselective
manner and the results are summarized in Table 3. The
stereo structures of menthopyrazole moiety in 1 5and 1 6
were affected to the formation of (R) -3 aand (S) -3 ar e s p -e c
t i v e,lb yu t their effects were rather small. The enantioselec-
tive control of the product was governed mainly by the

9
20
C. Kashima, K. Higashide, Y. Miwa and Y. Tsukamoto
Vol. 39
Table 4
Enantioselective Diethylzinc Addition to Aldehydes Catalyzed by (S) -1 d
0.99 (3H, d,J=7 Hz), 1.43-1.51 (1H, m), 1.76-1.83 (2H, m), 2.00-
2
.19 (2H, m), 2.73 (3H, s), 3.17-3.22 (1H, m), 3.37-3.42 (1H, m),
.35-7.47 (3H, m), 7.75-7.80 (2H, m); 13C nmr: d 19.6 (CH2),
7
Run
Aldehydes
Ar
Yield of 3
(%)
Ee of 3 Recovery of (S)-16d
19.7 (CH ), 20.7 (CH ), 21.2 (CH ), 23.9 (CH ), 25.7 (CH), 27.1
(CH ), 31.4 (CH), 37.9 (CH), 124.6 (C), 127.6 (CH), 128.5 (CH),
2
3 3 3 3
(%)
(%)
1
33.3 (C), 145.8 (C), 152.2 (C), 171.4 (C).
Anal. Calcd. for C19H24N O: C, 76.99; H, 8.16; N, 9.45;
1
3
2
3
4
2a
2b
4-Me-C H4
81
79
65
53
67
70 (S)
36 (S)
66 (S)
20 (S)
41 (S)
77
77
62
99
84
6
2
Ph
Found: C, 77.17; H, 8.23; N, 9.46.
2c 2- MeO-C H4
2d 4-MeO-C H4
2e
6
6
2-Acetyl-3-phenyl-l-menthopyrazole (9h).
This compound was obtained as a colorless oil in 62% yield;
4-Cl-C H4
6
1
H nmr: d 0.69 (3H, d, J= 7 Hz), 0.94 (3H, d, J=7 Hz), 1.09 (3H,
substituent group adjacent to the hydroxyl group, where the
d, J= 7 Hz), 1.18-1.31 (1H, m), 1.46-1.55 (1H, m), 1.83-2.00 (2H,
substituent group with (S)-configuration on the b- c a r b o n m), 2.36-2.44 (1H, m), 2.59-2.79 (2H, m), 2.63 (3H, s), 7.27-7.41
1
3
(
(
5H, m); C nmr: d 18.6 (CH ), 20.2 (CH ), 20.4 (CH ), 23.0
preferably gave (S) -3 a. In the case of (2 ' )S - 2 - ( 2 - p h e n y l - 2 -
3 3 3
CH ), 23.6 (CH ), 27.3 (CH), 30.0 (CH), 32.1 (CH), 41.3 (CH ),
2 2 3
hydroxyethyl)-3-phenyl-l-menthopyrazole ((S)-16d), the
structures of menthopyrazole moiety and side chain were
complementarily affected to the formation of (S)-3a.
Furthermore, the addition reaction of 1 with some aromatic
aldehydes (2) afforded the corresponding alcohols (3) enan-
t i o s e l e c t, ia vs se u lm ymarized in Table 4.
1
26.2 (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 C19H24N O: C, 76.99; H, 8.16; N, 9.45;
2
Found: C, 76.75; H, 8.07; N, 9.42.
1
-Isobutyryl-3-phenyl-l-menthopyrazole (8i).
N-Hydroxyalkyl-l-menthopyrazoles acted as a chiral
catalyst for the diethylzinc (1) addition to 4-methylben-
zaldehyde (2a), and 1-(4-methylphenyl)-1-proparnol (3a)
was afforded enantioselectively. These reactions were car-
ried out optimally in toluene at 40 °C in the presence of 30
mol% of (S)-16d to afford optically active 1-aryl-1-
propanols up to 70% ee (S).
This compound was obtained in 85% yield; bp 155-65°C/ 5
mmHg; 1H nmr: d 0.88 (3H, d, J=7 Hz), 0.96 (3H, d, J=7 Hz),
0.97 (3H, d, J=7 Hz), 1.28 (3H, d, J=7 Hz), 1.29 (3H, d, J=7 Hz),
1.43-1.50 (1H, m), 1.76-1.83 (2H, m), 2.02-2.14 (2H, m), 3.17-
3
(
1
2
.22 (1H, m), 3.41-3.46 (1H, m), 4.03-4.13 (1H, m), 7.34-7.46
3H, m), 7.77-7.80 (2H, m); 13C nmr: d 18.9 (CH ), 19.5 (CH ),
3
3
9.8 (CH ), 19.8 (CH ), 20.7 (CH ), 21.2 (CH ), 25.8 (CH ),
3 3 3 2 2
7.2 (CH), 31.6 (CH), 33.2 (CH), 38.1 (CH), 124.6 (C), 127.6
(
CH), 128.4 (CH), 128.5 (CH), 133.5 (C), 145.8 (C), 151.9 (C),
EXPERIMENTAL
178.3 (C).
Anal. Calcd. for C21H28N O: C, 77.74; H, 8.70; N, 8.63;
2
Melting points are uncorrected. 1H nmr and 13C nmr spectra
Found: C, 77.86; H, 8.77; N, 8.63.
were obtained on JEOL JNM-EX270 (270 MHz) or Varian
GEMINI 2000 (200 MHz) spectrometers in deuterochloroform
with tetramethylsilane as an internal standard. The IR spectra
were measured by Shimadzu IR-460 spectrophotometer.
Specific rotations were measured on JASCO DIP-370 digital
polarimeter. The enantiomer ratios were evaluated from the peak
ratios of gas chromatography on SHIMADZU GC-14A gas chro-
matograph using Chrompack Chirasil DEX-CB capillary column
2
-Isobutyryl-3-phenyl-l-menthopyrazole (9i).
This compound was obtained in 95% yield; bp 160-170 °C/ 5
1
mmHg; H nmr: d 0.70 (3H, d, J=7 Hz), 0.95 (3H, d, J=7 Hz),
1
1
2
.09 (3H, d, J=7 Hz), 1.20 (3H, d, J=7 Hz), 1.24 (3H, d, J=7 Hz),
.18-1.33 (1H, m), 1.45-1.58 (1H, m), 1.84-2.00 (2H, m), 2.37-
.45 (1H, m), 2.60-2.79 (2H, m), 3.88-3.99 (1H, m), 7.27-7.40
(
(
(
5H, m); 13C nmr: d 18.6 (CH ), 19.0 (CH ), 19.4 (CH ), 20.2
3 3 3
CH ), 20.4 (CH ), 23.2 (CH ), 27.4 (CH ), 30.0 (CH), 32.3
(
0.25 mm x 25 m). The yields of the products were evaluated by
3
3
2
2
CH), 33.2 (CH), 41.4 (CH), 126.0 (C), 127.9 (CH), 128.0 (CH),
29.2 (CH), 132.9 (C), 141.0 (C), 155.6 (C), 177.1 (C).
Anal. Calcd. for C21H28N O: C, 77.74; H, 8.70; N, 8.63;
GL Science GC-353 gas chromatograph using dimethylsiloxane
type capillary column (0.25 mm x 30 m) of GL Science TC-1.
1
2
Materials.
Found: C, 77.49; H, 8.78; N, 8.62.
Ether and THF were dried over ketyl radical generated from
sodium and benzophenone. Toluene was dried over calcium
hydride with refluxing. Diethylzinc hexane solution (1 mol/L)
was commercially available from Kanto Chemical CO.
Compounds 5c, 5d, 5f, 12, 13h and 14h were prepared according
to previously described method [16]. Isomenthopyrazole (5b)
was prepared by the method of Bovens [19]. N-Acyl-3-phenyl-l-
menthopyrazoles (8 and 9) were directly acylated with the corre-
sponding acyl chloride from 5a [3].
1
-Benzoyl-3-phenyl-l-menthopyrazole (8j).
This compound was obtained as a colorless oil in 25% yield;
1
H nmr: d 0.89 (3H, d, J=6.9 Hz), 1.01 (3H, d, J=6.9 Hz), 1.03
(3H, d, J=6.6 Hz), 1.47-1.55 (1H, m), 1.78-1.97 (2H, m), 2.03-
2.18 (2H, m), 3.18-3.25 (1H, m), 3.54-3.60 (1H, m), 7.34-7.58
(6H, m), 7.73 (2H, d-d, J=7.3, 1.3 Hz), 8.03 (2H, d, J=6.9 Hz);
13
C nmr: d 19.4 (CH3), 19.8 (CH3), 20.9 (CH3), 21.1 (CH2), 26.2
(CH2), 27.8 (CH), 31.4 (CH), 38.1 (CH), 124.9 (C), 127.7 (CH),
1
1
27.8 (CH), 128.4 (CH), 128.4 (CH), 131.5 (CH), 132.3 (CH),
33.4 (C), 133.7 (C), 146.8 (C), 152.1 (C), 169.0 (C).
1
-Acetyl-3-phenyl-l-menthopyrazole (8h).
This compound was obtained in 80% yield; bp 150 °C/ 5
mmHg; H nmr: d 0.88 (3H, d, J=7 Hz), 0.96 (3H, d, J=7 Hz),
Anal. Calcd. for C24H26N O: C, 80.41; H, 7.31; N, 7.81.
Found: C, 80.19; H, 7.34; N, 7.91.
2
1

Sep-Oct 2002
Asymmetric Reaction of Diethylzinc with Aldehydes
921
2
-Benzoyl-3-phenyl-l-menthopyrazole (9j).
hours under an argon atmosphere. The reaction mixture was
quenched with water, and the organic layer was washed with
aqueous sodium hydroxide and saturated sodium chloride. After
removal of the solvent, regioisomers of N-aroylmethyl-l-men-
thopyrazoles were purified by silica gel column chromatography
with hexane-ethyl acetate mixture.
This compound was obtained as colorless needles in 75% yield;
1
mp 11 0 -1 11 °C (from Hexane); H nmr: d 0.80 (3H, d, J=6.6 Hz),
0
1
.89 (3H, d,J=6.6 Hz), 1.04 (3H, d, J=6.9 Hz), 1.35-1.18 (1H, m),
.52-1.60 (1H, m), 1.87-2.01 (2H, m), 2.34-2.41 (1H, m), 2.66
(
8
2
1H, quint,J=4.9 Hz), 2.79-2.86 (1H, m), 7.36-7.56 (8H, m), 7.97-
.01 (2H, m); 1 3C nmr: d 18.3 (CH ), 20.4 (CH ), 22.8 (CH ) ,
3
3
2
2-Benzoylmethyl-isomenthopyrazole (14c).
7.5 (CH ), 29.9 (CH), 32.3 (CH), 41.3 (CH), 125.8 (C), 127.5
2
This compound was obtained as a colorless oil in 67% yield;
H nmr: d 0.86 (3H, d, J=6.9 Hz), 1.03 (3H, d, J=6.9 Hz), 1.17
(
(
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).
1
(
(
(
3H, d, J=6.9 Hz), 1.43-1.52 (1H, m), 1.63-1.83 (3H, m), 2.21
1H, sex, J=5.6 Hz), 2.58-2.65 (1H, m), 2.77-2.85 (1H, m), 5.50
2H, AB-q, J=6.6 Hz), 7.20 (1H, s), 7.47 (2H, t, J=7.3 Hz), 7.56-
Anal. Calcd. for C24H26N O: C, 80.41; H, 7.31; N, 7.81.
2
Found: C, 80.22; H, 7.39; N, 7.88.
3
-Hydroxymethyl-l-menthopyrazole (5e).
7.63 (1H, m), 7.97 (2H, d, J=7.3 Hz); 13C nmr: d 16.6 (CH ),
3
1
8.8 (CH ), 19.5 (CH ), 20.6 (CH ), 24.4 (CH ), 27.7 (CH), 28.8
Ethyl l-menthopyrazole-3-carboxylate (252 mg), which was
3 3 2 2
(
CH), 37.6 (CH), 55.7 (CH ), 121.7 (C), 125.2 (CH), 126.1 (CH),
prepared from l-menthone and diethyl oxalate, was reduced by
lithium aluminum hydride (75 mg) in anhydrous ether (5 ml) at
room temperature for 2 hours. The mixture was quenched with
water, and the organic layer was washed with dilute hydrochloric
acid, saturated sodium hydrogen carbonate, and sodium chloride.
After removal of the solvent, the residue was chromatographed
2
1
26.7 (CH), 131.7 (CH), 132.7 (C), 150.0 (C), 191.1 (C).
Anal. Calcd. for C19H24N O: C, 76.99; H, 8.16; N, 9.45.
2
Found: C, 76.88; H, 7.89; N, 9.53.
1
-[2-Oxo-2-(1-naphthyl)ethyl]-3-phenyl-l-menthopyrazole
(13f).
on silica gel with benzene-ethyl acetate mixture; yield 53%; mp
1
This compound was obtained as a colorless oil in 20% yield;
1
1
63-164°C (from Hexane); H nmr: d 0.76 (3H, d, J=6.9 Hz),
.00 (3H, d, J=6.6 Hz), 1.18 (3H, d, J=6.9 Hz), 1.20-2.19 (5H,
1
H nmr: d 0.86 (3H, d, J=6.6 Hz), 0.88 (3H, d, J=6.3 Hz), 1.00
(
2
3H, d, J=6.9 Hz), 1.30-1.39 (1H, m), 1.58-1.80 (2H, m), 1.94-
.08 (2H, m), 2.50-2.57 (1H, m), 3.14-3.21 (1H, m), 5.55 (2H,
m), 2.59-2.65 (1H, m), 2.68-2.77 (1H, m), 4.69 (2H, s), 0.80 (3H,
d, J=6.9 Hz), 1.01 (3H, d, J=6.6 Hz), 1.14 (3H, d, J=6.9 Hz),
AB-q, J=17.8 Hz), 7.23-7.67 (9H, m), 7.85 (2H, d-d, J=7.3, 1.0
Hz), 7.98 (1H, d, J=8.2 Hz), 8.60 (1H, d, J=8.2 Hz); 1 C nmr: d
1
(
(
(
.20-2.19 (5H, m), 2.59-2.65 (1H, m), 2.80-2.90 (1H, m), 4.64
3
2H, s); 1 C nmr: d 18.0 (CH ), 18.0 (CH ), 19.3 (CH ), 20.4
3
3
3
3
1
2
9.2 (CH ), 20.1 (CH ), 21.2 (CH ), 21.3 (CH ), 26.1 (CH ),
3 3 3 2 2
CH ), 20.5 (CH ), 21.2 (CH ), 21.8 (CH ), 22.4 (CH ), 25.0
3
3
3
2
2
8.1 (CH), 31.1 (CH), 37.8 (CH), 58.7 (CH ), 120.3 (C), 124.1
CH ), 27.0 (CH ), 30.0 (CH), 30.1 (CH), 32.1 (CH), 39.4 (CH),
2
2
2
(
1
(
CH), 125.4 (CH), 126.6 (C), 127.1 (CH), 127.3 (C), 127.3 (C),
28.2 (CH), 128.5 (CH), 130.2 (C), 133.0 (C), 133.2 (CH), 133.9
C), 134.8 (C), 143.2 (C), 148.9 (C), 197.3 (C).
Anal. Calcd. for C29H30N O: C, 82.43; H, 7.16; N, 6.63.
3
9.5 (CH), 57.1 (CH ), 57.7 (CH ), 118.4 (C), 119.1 (C).
2 2
Anal. Calcd. for C H N O: C, 69.19; H, 9.68; N, 13.45.
1
2 20 2
Found: C, 69.46; H, 9.82; N, 13.48.
-Methyl-3-(2-hydroxyphenyl)-l-menthopyrazole (5g).
-(2-Hydroxyphenyl)-l-menthopyrazole (5e, 145 mg, 0.54
2
1
Found: C, 82.58; H, 6.91; N, 6.63.
3
2
-[2-Oxo-2-(1-naphthyl)ethyl]-3-phenyl-l-menthopyrazole
mmol) in dry THF (3 ml) was treated with butyllithium hexane
solution (1.5 M, 0.7 ml) at 0 °C for 30 minutes. Methyl iodide
148 mg) in THF (2 ml) was added to the mixture, and stirred for
7 hours at room temperature. The reaction mixture was
(14f).
This compound was obtained as colorless needles in 19%
(
1
1
yield; mp 119-120 °C (from hexane); H nmr: d 0.76 (6H, d,
J=6.6 Hz), 1.02 (3H, d, J=6.9 Hz), 1.25 (1H, q, J=12.5 Hz), 1.50
extracted with ether, and the organic layer was washed with
dilute hydrochloric acid, saturated sodium hydrogen carbonate
and sodium chloride. After drying over anhydrous magnesium
sulfate, the solvent was removed. By silica gel chromatography
of the residue with hexane-ethyl acetate mixture, 5g was isolated;
(
2
1H, q, J=12.2 Hz), 1.80-1.97 (2H, m), 2.38-2.45 (1H, m), 2.68-
.83 (2H, m), 5.40 (2H, s), 7.25-7.63 (9H, m), 7.81 (1H, d-d,
J=5.9, 3.6 Hz), 7.93 (1H, d, J=8.3 Hz), 8.30 (1H, d-d, J=6.3, 3.6
13
Hz); C nmr: d 17.6 (CH ), 20.5 (CH ), 20.8 (CH ), 22.6 (CH ),
27.6 (CH ), 29.8 (CH), 32.7 (CH), 40.8 (CH), 57.9 (CH ), 121.1
3
3
3
2
1
yield 56%; mp 85-86.5 °C (from hexane); H nmr: d 0.93 (3H, d,
2
2
(
(
C), 124.0 (CH), 125.7 (CH), 126.5 (CH), 127.2 (CH), 127.9
CH), 128.2 (C), 128.5 (CH), 128.5 (CH), 129.8 (CH), 130.2 (C),
J=6.8 Hz), 1.01 (3H, d, J=7.0 Hz), 1.11 (3H, d, J=6.8 Hz), 1.48-
.56 (1H, m), 1.75-1.89 (2H, m), 1.93-2.12 (2H, m), 2.53-2.61
1
(
7
(
3
1
1
31.6 (C), 133.0 (CH), 133.1 (C), 133.8 (C), 140.6 (C), 152.1
1H, m), 3.33-3.38 (1H, m), 3.79 (3H, s), 6.85-7.26 (3H, m),
1
3
(C), 197.4 (C).
.66-7.70 (1H, m); C nmr: d 19.8 (CH ), 20.1 (CH ), 21.1
3 3
CH ), 21.4 (CH ), 26.3 (CH ), 27.0 (CH), 31.6 (CH), 37.0 (CH),
Anal. Calcd. for C29H30N2O: C, 82.43; H, 7.16; N, 6.63.
Found: C, 82.69; H, 7.23; N, 6.66.
3
2
2
7.1 (CH ), 116.9 (CH), 118.7 (CH), 119.2 (C), 126.8 (CH),
3
28.2 (CH), 128.6 (C), 142.0 (C), 146.0 (C), 156.2 (C).
Preparation of Ethyl Isomenthopyrazole-N-acetate.
Anal. Calcd. for C18H24N O: C, 76.02; H, 8.51; N, 9.85.
2
Found: C, 75.60; H, 8.39; N, 10.19.
After stirring a mixture of 5b (514 mg) and sodium hydride
(
40% in oil, 151 mg) in THF (8 ml) for 15 minutes, ethyl bro-
N-Aroylmethyl Menthopyrazoles from Phenacyl Bromide
Analogues.
moacetate (534 mg) in THF (2 ml) was added and continued stir-
ring for 6 hours at room temperature. The reaction mixture was
quenched with water and extracted with ether. The organic layer
was washed with water and saturated sodium chloride, dried over
anhydrous magnesium sulfate, and concentrated. By chromatog-
The mixture of menthopyrazoles (5a or 5b, 2 mmol), phenacyl
bromide analogues (2.1 mmol) and anhydrous potassium carbon-
ate (350 mg, 2.5 mmol) in toluene (7 ml) was refluxed for 23

9
22
C. Kashima, K. Higashide, Y. Miwa and Y. Tsukamoto
Vol. 39
raphy on silica gel with hexane-ethyl acetate, the regioisomers
were separated.
(3H, d, J=6.8 Hz), 1.20-1.59 (2H, m), 1.82-2.02 (2H, m), 2.32-
2.47 (1H, m), 2.60-2.86 (2H, m), 3.75-4.11 (4H, m), 7.27-7.38
(
2H, m), 7.41-7.46 (3H, m); 13C nmr: d 18.3 (CH ), 20.6 (CH ),
3 3
Ethyl Isomenthopyrazole-1-acetate (13g).
2
0.8 (CH ), 23.2 (CH ), 27.4 (CH ), 29.9 (CH), 32.8 (CH), 41.0
3 2 2
This compound was obtained as a colorless oil in 33% yield;
H nmr: d 0.85 (3H, d, J=6.6 Hz), 1.03 (3H, d, J=6.9 Hz), 1.17
(CH ), 50.0 (CH ), 62.4 (CH ), 120.3 (C), 127.0 (C), 128.4 (CH),
2 2 2
1
128.5 (CH), 129.8 (CH), 131.5 (C), 151.4 (C).
(
1
3H, d, J=7.3 Hz), 1.27 (3H, t, J=6.9 Hz), 1.46-1.49 (1H, m),
.64-1.82 (4H, m), 2.20 (1H, sex, J=6.3 Hz), 2.60 (1H, q, J=5.6
Hz), 2.65-2.80 (1H, m), 4.21 (2H, q, J=6.9 Hz), 4.82 (2H, AB-q,
Anal. Calcd. for C19H26N O: C, 76.47; H, 8.78; N, 9.39.
2
Found: C, 76.11; H, 8.71; N, 9.32.
1
3
1-(2-Hydroxyethyl)-isomenthopyrazole (15b).
This compound was obtained as a colorless oil in 87% yield;
J=17.0 Hz), 7.26 (1H, s); C nmr: d 14.1 (CH ), 18.6 (CH ),
3
3
2
0.9 (CH ), 21.5 (CH ), 22.6 (CH ), 26.4 (CH ), 29.7 (CH), 30.8
3 3 2 2
(
CH), 39.6 (CH), 53.0 (CH ), 61.5 (CH ), 123.6 (C), 127.0 (CH),
1
2
2
H nmr: d 0.86 (3H, d, J=6.9 Hz), 1.02 (3H, d, J=6.9 Hz), 1.15
1
52.3 (C), 168.4 (C).
(
3H, d, J=6.9 Hz), 1.45-1.50 (1H, m), 1.62-1.81 (3H, m), 2.17
Anal. Calcd. for C H N O : C, 68.15; H, 9.15; N, 10.60.
1
5
24
2
2
(1H, sex, 5.6 Hz), 2.50-2.60 (1H, q, J=5.9 Hz), 2.76 (1H, q, J=5.3
Hz), 3.92 (2H, t, J=4.6 Hz), 4.14 (2H, t, J=5.6 Hz), 7.13 (1H, s);
Found: C, 67.82; H, 8.99; N, 10.15.
13
C nmr: d 18.9 (CH ), 20.8 (CH ), 21.7 (CH ), 22.7 (CH ), 26.2
Ethyl Isomenthopyrazole-2-acetate (14g).
3
3
3
2
(
CH ), 29.7 (CH), 30.7 (CH), 39.7 (CH), 53.2 (CH ), 62.1 (CH ),
2
2
2
This compound was obtained as a colorless oil in 37% yield;
H nmr: d 0.86 (3H, d, J=6.9 Hz), 1.01 (3H, d, J=6.9 Hz), 1.21
1
22.4 (C), 126.6 (CH), 151.8 (C).
1
Anal. Calcd. for C13H22N O: C, 70.23; H, 9.97; N, 12.6.
2
(
3H, d, J=6.9 Hz), 1.26 (3H, t, J=7.3 Hz), 1.37-1.46 (1H, m),
Found: C, 69.95; H, 9.79; N, 12.62.
1
.58-1.82 (2H, m), 1.91-2.00 (2H, m), 2.54-2.60 (1H, m), 2.67-
2
.76 (1H, m), 4.22 (2H, q, J=6.9 Hz), 4.82 (2H, AB-q, J=17.5
2-(2-Hydroxyethyl)-isomenthopyrazole (16b).
This compound was obtained as colorless needles in 86%
yield; mp 98-99 °C (from Hexane) ; H nmr: d 0.87 (3H, d, J=6.9
Hz), 1.00 (3H, d, J=6.9 Hz), 1.21 (3H, d, J=6.9 Hz), 1.35-1.46
1
3
Hz), 7.40 (1H, s); C nmr: d 14.1 (CH ), 19.4 (CH ), 21.3
3
3
(
CH ), 21.7 (CH ), 23.4 (CH ), 27.0 (CH ), 29.1 (CH), 31.4
3 3 2 2
1
(
CH), 37.1 (CH), 51.3 (C), 61.6 (CH ), 122.8 (C), 137.6 (CH),
2
1
41.6 (C), 168.3 (C).
(
1H, m), 1.55-1.68 (1H, m), 1.72-1.83 (1H, m), 1.94-2.05 (2H,
Anal. Calcd. for C15H N O : C, 68.15; H, 9.15; N, 10.6.
24
2
2
13
m), 2.57-2.72 (2H, m), 3.88-4.19 (4H, m), 7.34 (1H, s); C nmr:
Found: C, 67.99; H, 9.04; N, 10.76.
d 19.7 (CH ), 21.4 (CH ), 21.7 (CH ), 23.9 (CH ), 27.0 (CH ),
3
3
3
2
2
Preparation of N-(2-Hydroxyethyl)-menthopyrazoles.
29.0 (CH), 31.6 (CH), 36.9 (CH), 50.7 (CH2), 61.9 (CH2), 121.9
C), 136.3 (CH), 141.2 (C).
Anal. Calcd. for C13H22N O: C, 70.23; H, 9.97; N, 12.6.
(
Menthopyrazole-N-acetates (1.5 mmol) was reduced by treat-
ment with lithium aluminum hydride (65 mg, 1.7 mmol) in anhy-
drous ether (5 ml) for 1.5 hour at room temperature. Similarly,
N-aroylmethyl menthopyrazoles (0.5 mmol) were reduced with
lithium aluminum hydride (60 mg, 1.6 mmol) in anhydrous ether
2
Found: C, 70.10; H, 10.08; N, 12.81.
(2'S)-2-(2-Phenyl-2-hydroxyethyl)-isomenthopyrazole (S)-
(16c).
(
4 ml) for 1.5 hour at room temperature. After the mixture was
1
This compound was obtained as colorless oil in 36% yield; H
quenched with water, the mixture was filtered. The organic layer
was washed with saturated sodium chloride, dried over anhy-
drous magnesium sulfate, and concentrated. The residue was
purified by silica gel column chromatography with hexane-ethyl
acetate mixture. N-(2-hydroxyethyl)-menthopyrazoles were also
prepared by the alkylation of menthopyrazole (5a and 5b) under
high pressure conditions according to a previously described
method [16].
nmr: d 0.91 (3H, d, J=6.9 Hz), 1.06 (3H, d, J=6.9 Hz), 1.10 (3H,
d, J=6.9 Hz), 1.43-1.50 (1H, m), 1.61-1.81 (3H, m), 2.24 (1H,
sex, J=5.3 Hz), 2.60 (1H, q, J=5.3 Hz), 2.70-2.78 (1H, m), 4.07-
4
.29 (2H, m), 5.04-5.08 (2H, m), 6.96 (1H, s), 7.24-7.38 (5H, m);
1
3
C nmr: d 18.9 (CH ), 20.8 (CH ), 21.6 (CH ), 22.7 (CH ), 26.1
3
3
3
2
(
CH ), 29.8 (CH), 30.8 (CH), 39.8 (CH), 58.4 (CH ), 73.8 (CH ),
2
2
2
1
1
22.5 (C), 125.9 (CH), 127.2 (CH), 127.7 (CH), 128.3 (CH),
28.4 (CH), 140.9 (C), 152.3 (C).
1-(2-Hydroxyethyl)-3-phenyl-l-menthopyrazole (15a).
Anal. Calcd. for C19H26N O: C, 76.47; H, 8.78; N, 9.39.
2
This compound was obtained as a colorless oil in 92% yield;
Found: C, 75.85; H, 8.59; N, 9.33.
1
H nmr: d 0.92 (3H, d, J=6.8 Hz), 0.99 (3H, d, J=6.4 Hz), 1.01
3H, d, J=6.4 Hz), 1.42-1.49 (1H, m), 1.747-1.83 (2H, m), 2.05
2H, m), 2.59 (1H, q, J=5.0 Hz), 4.04 (2H, s), 4.09-4.22 (2H,
(2'R)-2-(2-Phenyl-2-hydroxyethyl)-isomenthopyrazole (R)-
16c).
(
(
(
m), 4.63 (1H, m), 7.26-7.43 (3H, m), 7.73 (2H, d, J=8.0 Hz);
This compound was obtained as a colorless oil in 16% yield;
1H nmr: d 0.89 (3H, d, J=6.9 Hz), 1.04 (3H, d, J=6.9 Hz), 1.14
1
3
C nmr: d 19.7 (CH ), 20.3 (CH ), 21.4 (CH ), 21.4 (CH ),
3
3
3
2
2
5.9 (CH ), 27.7 (CH), 31.5 (CH), 37.2 (CH), 50.6 (CH ), 62.1
(3H, d, J=6.9 Hz), 1.43-1.52 (1H, m), 1.63-1.82 (3H, m), 2.21
(1H, sex, J=5.6 Hz), 2.59 (1H, q, J=5.6 Hz), 2.70-2.76 (1H, m),
4.06-4.219 (1H, m), 4.95-5.04 (2H, m), 6.95 (1H, s), 7.24-7.38
(5H, m); 13C nmr: d 18.9 (CH3), 20.8 (CH3), 21.7 (CH3), 22.6
(CH2), 26.2 (CH2), 29.7 (CH), 30.8 (CH), 39.7 (CH), 58.5 (CH2),
2
2
(
(
CH ), 118.8 (C), 127.0 (CH), 127.3 (CH), 128.4 (CH), 134.5
C), 142.7 (C).
2
Anal. Calcd. for C19H26N O: C, 76.47; H, 8.78; N, 9.39.
2
Found: C, 76.47; H, 8.78; N, 9.39.
7
3.7 (CH ), 122.5 (C), 126.0 (CH), 127.1 (CH), 127.8 (CH),
2
2
-(2-Hydroxyethyl)-3-phenyl-l-menthopyrazole (16a).
1
28.4 (CH), 140.8 (C), 152.2 (C).
This compound was obtained as a colorless oil in 50% yield;
H nmr: d 0.74 (3H, d, J=6.8 Hz), 0.88 (3H, d, J=6.8 Hz), 1.06
Anal. Calcd. for C19H26N O: C, 76.47; H, 8.78; N, 9.39.
Found: C, 75.85; H, 8.69; N, 9.22.
2
1

Sep-Oct 2002
Asymmetric Reaction of Diethylzinc with Aldehydes
923
(
(
2'S)-1-(2-Phenyl-2-hydroxyethyl)-3-phenyl-l-menthopyrazole
S)-(15d).
Hz), 0.93 (3H, d, J=6.9 Hz), 0.96 (3H, 6.9, J= Hz), 1.26-1.45
(2H, m), 1.53-1.71 (2H, m), 1.87-2.25 (2H, m), 2.32 (3H, s),
3
.20-3.26 (1H, m), 4.08 (1H, ABX, J=6.6, 13.9 Hz), 4.34 (1H,
This compound was obtained as colorless needles in 25% yield;
mp 46-47 °C (from Hexane); H nmr: d 0.79 (3H, d, J=6.8 Hz),
.89 (3H, d,J=6.8 Hz), 0.97 (3H, d, J=7.0 Hz), 1.23-2.09 (5H, m),
.26-2.34 (1H, m), 3.17-3.29 (1H, m), 4.10 (1H, ABX, J=4.4, 13.4
ABX, J=2.3,13.9 Hz), 5.18-5.29 (1H, m), 5.62 (1H, s), 7.10 (4H,
s), 7.29-7.45 (3H, m), 7.78 (2H, d, J=7.3 Hz); 13C nmr: d 20.0
1
0
2
(
CH ), 21.0 (CH ), 21.4 (CH ), 21.5 (CH ), 25.8 (CH ), 27.1
3 3 3 3 2
(
CH ), 31.6 (CH ), 37.0 (CH), 55.7 (C), 73.5 (CH), 118.9 (CH),
Hz), 4.22 (3H, ABX, J=7.8, 13.8 Hz), 5.14 (1H, ABX, J=4.4, 7.8
2
2
1
3
125.6 (CH), 127.00 (CH), 127.4 (C), 128.4 (CH), 129.0 (CH),
Hz), 7.12-7.57 (7H, m), 7.73-7.79 (2H, m);
C nmr: d 1 9 . 6
1
37.3 (CH), 138.3 (CH).
(
(
1
CH ), 20.1 (CH ), 21.3 (CH ), 21.5 (CH ), 25.9 (CH ), 27.5
3
3
3
2
2
Anal. Calcd. for C26H32N O: C, 80.37; H, 8.30; N, 7.21.
CH), 31.5 (CH), 37.1 (CH), 56.2 (CH ), 73.7 (CH), 119.1 (C),
2
2
Found: C, 79.84; H, 8.39; N, 6.84.
26.2 (CH), 127.1 (CH), 127.4 (CH), 127.9 (CH), 128.4 (CH),
28.5 (CH), 134.3 (C), 141.0 (C), 142.8 (C), 147.8 (C).
1
(2'R)-1-[2-(4- Methylphenyl)-2-hydroxyethyl]-3-phenyl-l-men-
Anal. Calcd. for C25H30N O: C, 80.17; H, 8.07; N, 7.48.
2
thopyrazole (R)-(15e).
Found: C, 79.53; H, 8.26; N, 8.69.
This compound was obtained as colorless needles in 32%
(
(
2'R)-1-(2-Phenyl-2-hydroxyethyl)-3-phenyl-l-menthopyrazole
R)-(15d).
1
yield; mp 50 °C (from MeOH); H nmr: d 0.82 (3H, d, J=6.9
Hz), 0.91 (3H, d, J=6.9 Hz), 0.99 (3H, d, J=6.9 Hz), 1.39-1.47
(1H, m), 1.65-2.06 (4H, m), 2.36 (3H, s), 2.41-2.47 (1H, m),
3.22-3.28 (1H, m), 4.09 (1H, ABX, J=1.6, 11.2 Hz), 4.17 (1H,
ABX, J=5.3 Hz), 5.09 (1H, dd, J=4.3, 7.6 Hz), 5.67 (1H, s), 7.25
(4H, AB, J=8.2, 6.3 Hz), 7.30-7.43 (3H, m), 7.77 (2H, d, J=8.0
This compound was obtained as a colorless oil in 38% yield;
H nmr: d 0.80 (3H, d, J=6.8 Hz), 0.96 (3H, d, J=7 Hz), 0.99
3H, d, J=7 Hz), 1.21-1.48 (1H, m), 1.51-1.64 (1H, m), 1.75-1.84
1H, m), 1.85-2.21 (2H, m), 2.53-2.62 (1H, m), 3.04-3.14 (1H,
1
(
(
13
m), 4.10-4.28 (4H, m),5.55-6.05 (1H, m), 7.24-7.63 (10H, m).
Hz); C nmr: d 19.5 (CH ), 20.0 (CH ), 21.0 (CH ), 21.2 (CH ),
3 3 3 3
Anal. Calcd. for C25H30N O: C, 80.17; H, 8.07; N, 7.48.
21.2 (CH ), 21.3 (CH ), 25.8 (CH ), 27.4 (CH ), 31.3 (CH ),
3 2 2 2 2
2
Found: C, 79.77; H, 8.21; N, 7.13.
37.0 (CH), 56 (CH), 73.4 (CH), 118.9 (CH), 126.0 (CH), 126.9
(
(
CH), 127.3 (CH), 128.2 (CH), 129.0 (CH), 134.2 (CH), 127.5
CH), 127.9 (CH), 142.6 (CH).
(
(
2'S)-2-(2-Phenyl-2-hydroxyethyl)-3-phenyl-l-menthopyrazole
S)-(16d).
Anal. Calcd. for C26H32N O: C, 80.37; H, 8.30; N, 7.21.
2
This compound was obtained as a colorless oil in 39% yield;
Found: C, 80.82; H, 8.09; N, 6.84.
1
H nmr: d 0.69 (3H, d, J=6.9 Hz), 0.94 (3H, d, J=6.9 Hz), 1.10
3H, d, J=6.9 Hz), 1.19-2.03 (4H, m), 2.39-2.55 (1H, m), 2.66-
.79 (2H, m), 3.97 (1H, ABX, J=6.9, 13.9 Hz), 4.21 (1H, ABX,
(
2'S)-2-[2-(4-Methylphenyl)-2-hydroxyethyl]-3-phenyl-l-men-
(
2
thopyrazole (S)-(16e).
J=2.6, 13.9 Hz), 5.06 (1H, d-d, J=2.6, 6.9 Hz), 5.7-5.9 (1H,
This compound was obtained as a colorless oil in 43% yield;
H nmr: d 0.70 (3H, d, J=6.8 Hz), 0.93 (3H, d, J=6.8 Hz), 1.10
(3H, d, J=7.0 Hz), 1.22 (1H, q, J=10 Hz), 1.51 (1H, q, J=10 Hz),
1.83-1.99 (2H, m), 2.31 (3H, s), 2.38-2.50 (1H, m), 2.63-2.77
(2H, m), 3.94 (1H, ABX, J=7.2, 14.0 Hz), 4.17 (1H, ABX, J=2.6,
broad), 6.98-7.02 (2H, m), 7.11-7.14 (2H, m), 7.20- 7.28 (3H, m),
1
1
3
7
.32-7.41 (3H, m); C nmr: d 18.5 (CH ), 20.8 (CH ), 20.9
3 3
(
CH ), 23.2 (CH ), 27.5 (CH ), 30.2 (CH), 33.0 (CH), 41.0 (CH),
3 2 2
5
4.6 (CH ), 73.8 (CH), 120.4 (C), 125.9 (CH), 127.5 (CH), 128.3
2
(
1
CH), 128.5 (CH), 129.9 (CH), 131.3 (C), 140.8 (C), 141.3 (C),
51.7 (C).
Anal. Calcd. for C25H30N O: C, 80.17; H, 8.07; N, 7.48.
1
7
2
4.0 Hz), 5.04 (1H, d, J=6.8 Hz), 5.65 (1H, s), 7.04 (5H, s), 7.33-
.36 (4H, m); 13C nmr: d 18.3 (CH ), 20.6 (CH ), 20.8 (CH ),
3
3
3
2
1.0 (CH ), 23.1 (CH ), 27.4 (CH ), 30.9 (CH), 32.8 (CH), 40.0
3
2
2
Found: C, 80.05; H, 8.12; N, 7.42.
(
CH), 54.6 (CH ), 73.5 (CH), 120.3 (CH), 125.7 (CH), 128.2
2
(
(
2'R)-2-(2-Phenyl-2-hydroxyethyl)-3-phenyl-l-menthopyrazole
R)-(16d).
(CH), 128.8 (CH), 129.7 (CH), 129.9 (CH), 131.2 (CH), 137.0
(CH), 138.0 (CH), 140.6 (C), 151.5 (C).
Anal. Calcd. for C26H32N O: C, 80.37; H, 8.30; N, 7.21.
Found: C, 80.12; H, 7.93; N, 7.31.
2
This compound was obtained as a colorless oil in 25% yield;
1
H nmr: d 0.72 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.9 Hz), 1.10
3H, d, J=6.9 Hz), 1.22-2.03 (5H, m), 2.41-2.50 (1H, m), 2.66-
.85 (2H, m), 3.98 (1H, ABX, J=8.3, 13.9 Hz), 4.09 (1H, ABX,
(
2
(
2'R)-2-[2-(4-Methylphenyl)-2-hydroxyethyl]-3-phenyl-l-men-
thopyrazole (R)-(16e).
J=3.0, 13.9 Hz), 4.83 (1H, d-d, J=3.0, 8.3 Hz), 5.63-5.70 (1H,
This compound was obtained as a colorless oil in 11% yield;
H nmr: d 6.94 (3H, d, J=6.9 Hz), 0.93 (3H, d, J=6.6 Hz), 1.09
3H, d, J=6.9 Hz), 1.22-1.32 (1H, m), 1.50-1.57 (1H, m), 1.85-
.01 (2H, m), 2.31 (3H, s), 2.42-2.49 (1H, m), 2.66-2.82 (2H, m),
.97 (1H, ABX, J=8.0, 13.9 Hz),4.06 (1H, ABX, J=3.0, 13.9 Hz),
.79 (1H, dd, J=3.0, 8.6 Hz), 5.55 (1H, s), 7.09 (4H, c, J= Hz),
.13-7.19 (2H, m), 7.35-7.40 (3H, m); 13C nmr: d 18.4 (CH3),
broad), 7.10-7.16 (2H, m), 7.17-7.20 (2H, m), 7.23-7.32 (3H, m),
1
1
3
7
2
(
(
1
.33-7.42 (3H, m); C nmr: d 18.3 (CH ), 20.6 (C), 20.8 (CH ),
3 3
(
3.1 (CH ), 27.4 (CH ), 30.0 (CH), 32.7 (CH), 41.0 (CH), 55.3
2
2
2
3
4
7
2
(
1
1
CH ), 73.9 (CH), 120.7 (C), 126.0 (CH), 127.7 (CH), 128.3
2
CH), 128.5 (C), 129.7 (C), 131.1 (C), 140.4 (C), 140.9 (C),
51.7 (C).
Anal. Calcd. for C25H30N O: C, 80.17; H, 8.07; N, 7.48.
2
0.6 (CH ), 21.1 (CH ), 23.2 (CH ), 27l4 (CH ), 30.0 (CH), 32.7
Found: C, 79.66; H, 8.05; N, 7.33.
3
3
2
2
CH), 41.0 (CH), 53.4 (C), 55.4 (CH), 73.8 (CH), 120.7 (CH),
(
2'S)-1-[2-(4- Methylphenyl)-2-hydroxyethyl]-3-phenyl-l-men-
thopyrazole (S)-(15e).
26.0 (CH), 128.4 (CH), 128.5 (CH), 129.0 (CH), 129.8 (CH),
31.2 (CH), 137.4 (CH), 138.0 (CH), 140.4 (C), 151.7 (C).
Anal. Calcd. for C26H32N2O: C, 80.37; H, 8.30; N, 7.21.
This compound was obtained as colorless needles in 18%
1
yield; mp 105 °C (from MeOH); H nmr: d 0.89 (3H, d, J=6.6
Found: C, 79.98; H, 8.54; N, 6.63.

9
24
C. Kashima, K. Higashide, Y. Miwa and Y. Tsukamoto
Vol. 39
(
2'S)-1-[2-(1-Naphthyl)-2-hydroxyethyl]-3-phenyl-l-menthopy-
(CH), 128.0 (CH), 128.6 (CH), 128.8 (CH), 128.8 (CH), 129.8
(CH), 129.9 (C), 133.5 (C).
razole (S)-(15f).
Anal. Calcd. for C29H32N O: C, 82.04; H, 7.60; N, 6.60.
Found: C, 81.56; H, 7.58; N, 6.57.
2
This compound was obtained as a colorless oil in 28% yield;
H nmr: d 0.69 (3H, d, J=6.9 Hz), 0.75 (3H, d, J=6.9 Hz), 0.86
1
(
1
3H, d, J=6.6 Hz), 0.92-1.02 (1H, m),1.18-1.37 (3H, m), 1.69-
.86 (2H, m), 3.11-3.17 (1H, m), 4.50 (2H, ABX, J=13.9, 5.0, 2.3
Hz), 5.76 (1H, d, J=5.9 Hz), 5.97 (1H, m), 7.28-7.60 (7H, m),
Diethylzinc Addition Reaction on Aromatic Aldehyde.
With N-Unsubstituted Pyrazoles.
1
3
7
(
(
1
1
1
.72-7.90 (4H, m), 8.06 (1H, d, J=8.6 Hz); C nmr: d 19.6
To the mixture of N-unsubstituted pyrazole(0.3 mmol), aro-
matic aldehyde (1.3 mmol) in toluene (4 ml) was added diethyl
zinc hexane solution (1 mol/l, 2.0 ml) under argon atmosphere.
The mixture was stirred for several hours at 40 °C. The small
portion of reaction mixture was quenched with hydrochloric acid
in some intervals, and was monitored by gas chromatography
using naphthalene as the internal standard. The reaction mixture
was quenched with dilute hydrochloric acid and the organic layer
was washed with water, dilute sodium hydroxide and saturated
sodium chloride. After drying over anhydrous magnesium sul-
fate, the solvent was evaporated, and the desired 1-aryl-1-
propanol was distilled using a cold finger apparatus. The ee of
distillate was evaluated by gas chromatography through a chiral
phase column. From the residue of the distillation, pyrazole
compounds were isolated by silica gel column chromatography.
CH ), 19.7 (CH ), 21.2 (CH ), 21.4 (CH ), 25.8 (CH ), 27.0
3
3
3
2
2
CH), 31.4 (CH), 36.4 (CH), 54.3 (CH ), 70.3 (CH), 118.9 (C),
2
22.0 (CH), 123.3 (CH), 125.5 (CH), 125.6 (CH), 126.3 (CH),
27.0 (CH), 127.4 (CH), 127.9 (CH), 128.5 (CH), 129.1 (CH),
29.9 (C), 133.6 (C), 134.3 (C), 136.6 (C), 143.9 (C), 148.7 (C).
Anal. Calcd. for C29H32N O: C, 82.04; H, 7.60; N, 6.60.
2
Found: C, 81.79; H, 7.64; N, 6.54.
(
2'R)-1-[2-(1-Naphthyl)-2-hydroxyethyl]-3-phenyl-l-menthopy-
razole (R)-(15f).
This compound was obtained as colorless needles in 53%
1
yield; mp 72-73 °C (from MeOH); H nmr: d 0.69 (3H, d, J=6.6
Hz), 0.79 (3H, d, J=6.9 Hz), 0.97 (3H, d, J=6.9 Hz), 1.36-1.43
(
1H, m), 1.62-1.82 (3H, m), 1.94-2.02 (1H, m), 2.36-2.42 (1H,
m), 3.20-3.27 (1H, m), 4.35 (2H, ABX, J=13.9, 8.3, 3.0 Hz),
With N-Acylpyrazoles.
5
8
2
.90-5.94 (2H, m), 7.30-7.56 (6H, m), 7.79-7.92 (5H, m), 8.02-
.06 (1H, m); 13C nmr: d 19.4 (CH ), 20.0 (CH ), 21.2 (CH ),
To a mixture of N-acylpyrazole(0.3 mmol), aromatic aldehyde
3
3
3
(
1.3 mmol) in toluene (4 ml) was added diethylzinc hexane solu-
1.4 (CH ), 25.9 (CH ), 27.7 (CH), 31.4 (CH), 37.0 (CH), 55.4
2
2
tion (1 mol/l, 2.0 ml) under argon atmosphere. The mixture was
stirred for several hours at 40 °C. The reaction mixture was
worked up described above.
(
CH ), 70.5 (CH), 119.2 (C), 122.4 (CH), 124.2 (CH), 125.5
2
(
CH), 125.7 (CH), 126.2 (CH), 127.1 (CH), 127.4 (CH), 128.3
(
1
CH), 128.4 (CH), 129.1 (CH), 130.4 (C), 133.7 (C), 134.4 (C),
36.4 (C), 142.7 (C), 147.9 (C).
Anal. Calcd. for C29H32N O: C, 82.04; H, 7.60; N, 6.60.
With N-(2-Hydroxyethyl)-pyrazoles.
2
To the mixture of N-(2-hydroxyethyl)-pyrazole (0.3 mmol),
aromatic aldehyde (1.0 mmol) in toluene (4 ml) was added
diethylzinc hexane solution (1 mol/l, 2.0 ml) under argon atmos-
phere. The mixture was stirred for several hours at 40 °C. The
reaction mixture was worked up described above.
Found: C, 81.69; H, 7.29; N, 6.56.
(2'S)-2-[2-(1-Naphthyl)-2'-hydroxyethyl]-3-phenyl-l-menthopy-
razole (S)-(16f).
This compound was obtained as colorless needles in 38%
1
yield; mp 133-134 °C (from MeOH); H nmr: d 0.69 (3H, d,
Acknowledgement.
J=6.6 Hz), 1.01 (3H, d, J=6.9 Hz), 1.14 (3H, d, J=6.9 Hz), 1.23
The authors are grateful to the Chemical Analysis Center,
University of Tsukuba, for the measurement of various kinds of
spectra and the elemental analyses.
(
1H, q, J=11.9 Hz), 1.53 (1H, q, J=11.9 Hz), 1.83-1.95 (2H, m),
2
5
7
2
.50-2.77 (3H, m), 4.25 (1H, ABX, J=14.2, 6.6, 2.3 Hz), 5.78-
.86 (2H, m), 6.83 (2H, d, J=6.3 Hz), 7.07-7.42 (6H, m), 7.55-
.81 (4H, m); 13C nmr: d 18.4 (CH ), 20.7 (CH ), 20.9 (CH ),
3
3
3
REFERENCES AND NOTES
3.1 (CH ), 27.5 (CH ), 30 (CH), 32.8 (CH), 41.0 (CH), 53.6
2
2
(
(
(
CH), 70.4 (CH), 122.0 (CH), 123.6 (CH), 125. (CH), 125.4
CH), 125.8 (CH), 127.9 (CH), 128.0 (CH), 128.1 (CH), 128.8
CH), 129.5 (CH), 151.0 (C).
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[
2] For recent reviews, see: [a] 'Asymmetric Synthesis', Vol.
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2
1
1
-5, ed. by D. J. Morrison, Academic Press Inc., New York, 1983-
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[
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5
4
9, 7821 (1994).
1
[
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3H, d, J=6.9 Hz), 1.26 (1H, q, J=12.5 Hz), 1.57 (1H, q, J=12.2
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.25 (2H, ABX, J=14.2, 8.9, 2.0 Hz), 5.30 (1H, s), 5.41 (1H, d,
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(
(
(
3H, m); 13C nmr: d 18.3 (CH ), 20.6 (CH ), 20.8 (CH ), 23.2
3 3 3
CH ), 27.5 (CH ), 29.9 (CH), 32.8 (CH), 41.15 (CH ), 71.0
2
2
2
CH), 121.8 (C), 123.5 (CH), 125.2 (CH), 125.6 (CH), 125.9

Sep-Oct 2002
Asymmetric Reaction of Diethylzinc with Aldehydes
925
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