Asymmetric conjugate addition reaction using pyrazole derivatives as a chiral catalyst

Article abstract of DOI:10.1002/jhet.5570400426

The conjugate addition of Grignard reagent (2) onto 1-(α,β -unsaturated)acyl 3,5-dimethylpyrazole (1) was enantioselectively catalyzed by the copper complex from cuprous compounds and 3-phenyl-l-menthopyrazole (3).

Full text of DOI:10.1002/jhet.5570400426

Jul-Aug 2003
Asymmetric Conjugate Addition Reaction
717
Using Pyrazole Derivatives as a Chiral Catalyst
Choji Kashima*, Hiroyo Yokoyama, Saori Shibata,
Kiyoshi Fujisawa and Takehiko Nishio
Department of Chemistry, University of Tsukuba,
Ten-nodai, Tsukuba, Ibaraki 305-8571, Japan
(
E-Mail: Choji.kashima@nifty.ne.jp)
The conjugate addition of Grignard reagent (2) onto 1-(a,b -unsaturated)acyl 3,5-dimethylpyrazole (1)
was enantioselectively catalyzed by the copper complex from cuprous compounds and 3-phenyl-l-mentho-
pyrazole (3).
J. Heterocyclic Chem., 40, 717(2003).
Recently we have reported the preparation and the utili-
iodide and magnesium bromide acted as the effective cata-
lyst. Under these situation, the extensive utilities of the
pyrazole derivatives as a chiral catalyst were investigated
in the enantioselective conjugate addition of Grignard
reagents on N-(a,b -unsaturated)acyl pyrazoles.
ties of the optically active pyrazoles as a new chiral auxil-
iary [1,2], which has unique structure and properties differ-
ent from the conventional chiral auxiliaries [3]. The most
important characteristics of this auxiliary are that the acyl
substrate terminates to nitrogen atom of heteroaromatic
pyrazole ring, and the substrate is surrounded by a chiral
atmosphere [4]. This structural feature causes the diastere-
ofacial attack on the enolate of N-acylpyrazoles in the
reactions with alkyl halides [5], phenyldisulfide [6], acyl
chlorides [7], aldehydes [8], and C=N compounds [9].
Moreover, the asymmetric cycloadditions of dienes [10]
and 1,3-dipolar compounds [11] on N-(a,b -unsaturated)-
acyl substituted pyrazoles have been reported. Subsequent
N-acylpyrazoles are easily converted into acyl derivatives
by the action of nucleophiles such as alcohols [12], amines
Results and Discussion
Previous paper [21] reported that the treatment of 1-cin-
namoyl-3,5-dimethylpyrazole (1a) with methylmagnesium
iodide (2b) afforded 1-(3-phenyl)butanoyl-3,5-dimethyl-
pyrazole (4ab) and 3-methyl-1-phenyl-1,3-butadiene
(5ab). The addition of cuprous iodide depressed the for-
mation of 5ab, and the yield of desired 4ab was increased.
By the addition of cuprous chloride and 3-phenyl-l-men-
thopyrazole (3), the reaction of 1a with 2b afforded 4ab
enantioselectively in good yield. For the confirmation of
the stereostructure of the conjugate adduct, 4ab was
hydrolyzed into the corresponding carboxylic acid (6ab)
by treatment with aqueous sodium hydroxide. By the
HPLC of subsequent carboxylic acid, the stereostructure of
the conjugate adduct was found to be 3'S-4ab by the com-
parison with authentic sample [21].
[
[
13], Grignard reagents [14], or organozinc compounds
15] under basic or acidic conditions [16].
The optically active pyrazoles are also expected to show
the effective chiral catalytic activities for various enantios-
elective syntheses. We have already exhibited the chiral
catalytic activities of these optically active pyrazoles in the
borane reduction and the dialkylzinc addition on the
prochiral carbonyl compounds [17]. Furthermore, we
have strongly desired to develop an effective catalyst of
optically active pyrazole derivatives in the wide variety of
synthetic reactions.
When 1a was treated with 2b in the presence of merely
3
, 4ab was obtained in poor yield without any enantiose-
lectivity. Even though cuprous chloride and 3 were added
in catalytic amounts, enantioselective formation of 4ab
was observed in good yield. Further, 1a was treated with
2
b after the formation of copper complex with 3 in situ.
Recently, pyrazoles have been paid a great deal of atten-
tion because they are good ligands for various Lewis acids
[
18]. The complex formation of 3,5-Diphenylpyrazole
Scheme 1
with cuprous hydroxide was reported having 1 : 1 metal/
pyrazole ratio [19]. We also revealed the complex forma-
tion of sodium salt of 3,5-diisopropylpyrazole with
cuprous, silver and gold ions [20]. From the X-ray analy-
sis, the structures of these complexes were found to be the
cyclic trimer consisted of 3 pyrazoles and 3 cuprous ions
or analogous tetramer. Otherwise, cuprous salts were
widely applicable catalysts for the conjugate addition reac-
tion. Previously we reported the diastereoselective conju-
gate addition of Grignard reagent on 2-(a,b -unsaturated)-
acyl 3-phenyl-l-menthopyrazole [21], where cuprous

7
18
C. Kashima, H. Yokoyama, S.i Shibata, K. Fujisawa and T. Nishio
Vol. 40
Scheme 2
As a result, the enantioselectivity of the conjugate adduct
increased up to 33 % ee. From these facts, the copper
complex with optically active pyrazole catalyzed the con-
jugate addition of Grignard reagent onto 1, as summarized
in the Table.
Since Grignard reagents were labile onto 1, the conju-
gate addition was completed during 1 h, and the lower
reaction temperature was preferred for the higher enan-
tioselectivity. From the attempts using various cuprous
salts as the Lewis acid, the yields and the enantioselectivi-
ties of these conjugate additions were independent of the
kinds of cuprous salt, shown in Table.
N-Cu-N chelate bond independent from the structure of
the substituent group on pyrazole ring. By the treatment
with Grignard reagent, the copper atom was deformed into
trigonal planar shape. The subsequent cuprate complex
acted as the Lewis acid onto a,b -unsaturated carbonyl
group to form the tetrahedral copper complex intermedi-
ate, and the conjugate addition proceeded intramolecu-
larly. When the optically active pyrazole was provided for
these reactions, the diastereofacial attack of a,b -unsatu-
rated carbonyl compound occurred on the cuprate com-
plex. Namely the Si-facial attack of 2b was performed in
the conjugate addition onto 1a.
Table 1
Chiral Catalytic Effects of Cu Complex of 3 in the Conjugate Addition
Run
3
eq
Cu Salt
Base
R2MgX
Temp
°C
Yield
%
Ee (Conf.)
%
eq
eq
eq
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1.0
0.1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.0
1.0
1.0
1.0
1.0
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
0.0
0.05
0.1
0.2
0.6
0.5
0.5
0.5
1.0
0.5
0.6
1.0
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
BuLi
MeMgI
MeMgI
MeMgI
PhMgBr
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
1.0
0.08
0.1
0.2
0.6
0.6
0.6
0.8
1.0
1.1
1.7
0.5
0.5
0.4
0.6
0.5
0.6
0.5
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
PhMgBr
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
MeMgI
2.5
2.1
2.3
2.6
2.6
2.8
2.9
2.9
2.1
2.8
2.3
2.8
2.4
2.0
2.9
2.5
2.5
2.9
-28
-28
-28
-28
-5
33
92
43
52
22
60
11
31
62
85
83
25
34
67
91
51
38
16
1
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
?
12
17
15
7
33
3
5
2
11
13
9
8
7
16
24
18
[a]
-28
-90
-28
-28
-28
-28
-28
-28
-28
-28
-28
-28
-28
0
1
2
3
4
5
6
7
8
CuCl+MgBr2 0.6
CuBr 1.0
CuBr(DMSO) 0.5
CuI
Cu(OTf)2
ZnCl2
0.5
0.5
0.5
[
a] Enantiomer ratio could not be measured.
The reaction mechanism of these stereo controlled con-
jugate additions onto 1 is illustrated in Scheme 2. From
the previous discussions [19,20], the structure of 1:1
cuprous complex with pyrazolato anion was found to be a
triangle trimer or a square tetramer, having the straight
If the substituent group on g-position of1 was exchanged
for the group of Grignard reagent (2), the product should
have the reverse stereo structure. However, the conjugate
addition of phenylmagnesium bromide (2a) onto
1-crotonoyl-3,5-dimethylpyrazole (1 b) afforded preferably

Jul-Aug 2003
Asymmetric Conjugate Addition Reaction Using Pyrazole Derivatives
719
3
S' -4 a bwith different diastereoselection. Previously such
HPLC for determining the enantiomer ratio of the conjugate
adduct.
an inverse diastereoselectivity was observed in the conju-
gate addition of Grignard reagent onto 2-(a,b -unsatu-
rated)acyl 3-phenyl-l-menthopyrazole due to the geometric
structural change of the N-acyl moiety [21].
After all, the conjugate addition of Grignard reagent (2)
onto 1-(a,b -unsaturated)acyl 3,5-dimethylpyrazole (1)
was enantioselectively catalyzed by the copper complex
from cuprous chloride and 3-phenyl-l-menthopyrazole (3).
Acknowledgement.
The authors are grateful to the Chemical Analysis Center,
University of Tsukuba, for the measurement of various kinds of
spectra and the elemental analyses.
REFERENCES AND NOTES
[
1] C. Kashima, I. Fukuchi, K. Takahashi, and A. Hosomi,
Tetrahedron Lett., 34, 8305 (1993).
2a] C. Kashima, Y. Miwa, S. Shibata, and H. Nakazono,
EXPERIMENTAL
[
J. Heterocyclic Chem., 39, 1235 (2002); [b] C. Kashima, Y. Miwa,
T.Yokawa, and S. Shibata, Heterocycles, 59, 225 (2003).
Melting points are uncorrected. 1H NMR and 13C NMR spec-
tra were obtained on JEOL JNM-EX270 (270 MHz) spectrome-
ter in deuterochloroform with tetramethylsilane as an internal
standard. The enantiomer ratios of 3-phenylbutanoic acid were
evaluated from the peak ratios of HPLC by CHIRALCEL OD-R
[
3] 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); [e] ‘Catalytic Asymmetric Synthesis’, 2nd
Ed., ed. By I. Ojima, Wiley-VCH, New York, 2000.
(
Daicel Chemical Industries) column on JASCO GULLIVER
chromatograph series using acetonitrile-perchlorate buffer (pH
.0, 0.5 M) mixture (v/v 3:7). The yields of the products were
3
[4] C. Kashima, Heterocycles, 60, 959 (2003).
[5] C. Kashima, I. Fukuchi, and A. Hosomi, J. Org. Chem., 59,
evaluated by GL Science GC-353 gas chromatograph using
dimethylsiloxane type capillary column (0.25 mm x 30 m) of GL
Science TC-1.
7
2
821 (1994).
[
6] C. Kashima, K. Takahashi, and A. Hosomi, Heterocycles, 42,
41 (1996).
Materials
[
7] C. Kashima, I. Fukuchi, K. Takahashi, and A. Hosomi,
Tetrahedron, 52, 10335 (1996).
8] C. Kashima, I. Fukuchi, K. Takahashi, K. Fukusaka, and A.
Hosomi, Heterocycles, 47, 357 (1998).
9] C. Kashima, K. Fukusaka, and K. Takahashi, J. Heterocyclic
Chem., 34, 1559 (1997).
10] C. Kashima, K. Fukusaka, K. Takahashi, and Y. Yokoyama,
J.Org. Chem., 64, 1108 (1999).
11] C. Kashima, K. Takahashi, I. Fukuchi, and K. Fukusaka,
1
-(a,b -Unsaturated)acyl 3,5-dimethylpyrazoles (1) were
[
prepared from 3,5-dimethylpyrazole and (a,b -unsaturated)acyl
chlorides in the presence of triethylamine according to the method
of the previous paper [11], and purified by silica gel column chro-
matography and distillation. 3-Phenyl-l-menthopyrazole (3) was
prepared from l-menthone according to the previous paper [1,2].
Cuprous salts were commercially available from Wako Pure
Chemical Industries Ltd., and purified cuprous chloride was
prepared by washing with acetic acid and with ethanol, and then
heating in the casserole until acetic acid was not detected, and
stored under nitrogen atmosphere. THF and ether were dried over
benzophenone ketyl radical prepared in situ from sodium metal
and benzophenone, and freshly distilled just before use.
[
[
[
Heterocycles, 44, 289 (1997).
[12a] C. Kashima, H. Harada, I. Kita, I. Fukuchi, and A. Hosomi,
Synthesis, 61 (1994); [b] C. Kashima, S. Mizuhara, Y. Miwa, and
Y.Yokoyama, Tetrahedron Asymm ., 13, 1713 (2002).
[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] C. Kashima, Heterocycles, 60, 437 (2003).
17a] C. Kashima, Y. Tsukamoto, K. Higashide, and H. Nakazono,
General Procedure of Asymmetric Conjugate Addition.
[
To the mixture of cuprous salt (0.08 mmol), 3 (0.16 mmol) and
biphenyl (internal standarad, ca 20 mg) in THF (1 ml) was added
Grignard reagent (ca 1 M, 0.16 mmol), and stirred for 20 min at
room temperature. The THF (2 ml) solution of 1-(a,b -unsatu-
rated)acyl 3,5-dimethylpyrazole (1) (0.16 mmol) was added to
the subsequent mixture at room temperature and stirred another
[
[
J. Heterocyclic Chem., 37, 983 (2000); [b] C. Kashima, Y. Tsukamoto,
Y. Miwa, and K. Higashide, J. Heterocyclic Chem., 38, 601 (2001); [c] C.
Kashima, K. Higashide, Y. Miwa, and Y. Tsukamoto, J. Heterocyclic
Chem., 39, 917 (2002).
2
0min. After the mixture was chilled at –28 °C, the Grignard
solution(ca 2M, 0.35 mmol) was again added and stirred for 1 h.
The reaction mixture was quenched with acetic acid, and diluted
with water. By the GC measurement of the ether extract, the
yields of the conjugate adduct were evaluated. Aqueous sodium
hydroxide (3M, 0.5 ml) and methanol (4 ml) was added to this
ether extract, and refluxed for 1 h. The subsequent mixture was
washed with ether, and the aqueous layer was directly injected to
[
[
18] R. Mukherjee, Coord. Chem. Rev., 203 151 (2000).
19] M. K. Ehlert, S. J. Rettig, S. Storr, R. C. Thompson, and
J.Trotter, Can. J. Chem., 68, 1444 (1990).
[20] K. Fujisawa, Y. Ishikawa, Y. Miyashita, and K. Okamoto,
manuscript in preparation.
[21] C. Kashima, K. Takahashi, K. Fukusaka, and A. Hosomi,
J.Heterocyclic Chem., 35, 503 (1998).