Development of bis-thiourea-type organocatalyst for asymmetric Baylis-Hillman reaction

Article abstract of DOI:10.1016/j.tetlet.2004.05.137

A new chiral bis-thiourea-type organocatalyst 2 developed for the Baylis-Hillman reaction provided a drastic rate enhancement. Allylic alcohols were obtained with up to 90% ee in the case of cyclohexanecarboxaldehyde (4i).

Full text of DOI:10.1016/j.tetlet.2004.05.137

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5589–5592
Development of bis-thiourea-type organocatalyst for
asymmetric Baylis–Hillman reaction
q
Yoshihiro Sohtome, Aya Tanatani, Yuichi Hashimoto and Kazuo Nagasawa*
Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Received 1 May 2004; revised 25 May 2004; accepted 27 May 2004
Abstract—A new chiral bis-thiourea-type organocatalyst 2 developed for the Baylis–Hillman reaction provided a drastic rate
enhancement. Allylic alcohols were obtained with up to 90% ee in the case of cyclohexanecarboxaldehyde (4i).
Ó 2004 Elsevier Ltd. All rights reserved.
8
The Baylis–Hillman reaction is a superior carbon–
carbon bond-forming reaction since it gives synthetically
useful chiral building blocks, that is, allylic alcohols,
from simple aldehydes and electron-deficient alkenes
dently found the urea/thiourea compounds 1 having
3,5-bis-trifluoromethylphenyl groups activated the car-
bonyl compounds through hydrogen-bonding interac-
tions, and drastically accelerated the hetero-Michael
1
7e
without generating by-products. This atoms economi-
cally superior reaction, however, is well known to be
sluggish, and controlling the newly generated chirality in
reaction of d-lactone with pyrrolidine. These findings
prompted us to apply the urea/thiourea catalyst 1 to the
Baylis–Hillman reaction with the aim of enhancing the
reaction between the ammonium enolate and the alde-
hyde, the rate-determining step, through promoting the
enolate formation, as well as activating the aldehyde
2
the product is also an issue. To address these problems,
various approaches, especially focusing on Lewis acid
3–5
3
4
catalysts and/or chiral tertiary amine catalysts, have
been investigated. Herein, we report a novel approach to
enhance the reaction rate, together with an asymmetric
version of the Baylis–Hillman reaction of cyclohexenone
with aldehydes, using a chiral bis-thiourea-type organo-
catalyst.
9
reactivity. Asymmetric induction of the product was
also expected as a result of the chirality in 1 (Chart 1).
First, the reactions of cyclohexenone (3) and benzalde-
hyde (4a) with DABCO in the presence of 1a and 1b as
organocatalysts were examined without using solvent
(Table 1). The allylic alcohol 5a was obtained in 52%
and 60% yields, respectively, which are more than 50-
fold higher than the yield of the uncatalyzed reaction.
An organocatalyst, that is, an organic compound, which
6
exhibits catalytic activities, does not contain heavy
metal, and so is advantageous from an environmental as
well as a resource standpoint. The easy reproducibility
and flexible design of such a catalyst are additional
advantages. During our recent studies focusing on the
1
H NMR experiments showed that the thiourea 1b
interacted with both the enone 3 and aldehyde 4a,
10
7
development of efficient organocatalysts, we indepen-
CF3
CF3
CF3
X
S
2
Keywords: Baylis–Hillman reaction; Organocatalyst; Bis-thiourea;
Asymmetric reaction.
F3C
N
H
N
H
CF3
N
H
N
H
CF3
NH
NH
q
S
Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.05.137
1a : X = O
b : X = S
F3C
1
*
Corresponding author at present address: Department of Biotech-
nology and Life Science, Graduate School of Technology, Tokyo
University of Agriculture and Technology, 2-24-16 Naka-cho, Kog-
anei, Tokyo 184-8588, Japan. Tel.: +81-358417848; fax: +81-35841-
CF3
8495; e-mail: nagasawa@iam.u-tokyo.ac.jp
Chart 1. Structure of urea/thiourea and bis-thiourea compounds.
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.137

5
590
Y. Sohtome et al. / Tetrahedron Letters 45 (2004) 5589–5592
Table 2. Reaction of 3 and 4a with various amines and phosphines
Table 1. Baylis–Hillman reaction catalyzed by 1 and 2
O
O
O
OH O
OH
O
cyclohexenone (3) (1.2 eq)
(0.2 eq)
1
or 2 (0.2 eq)
2
H
DABCO (0.25 eq)
R
H
R
+
amines or
phosphines (0.25 eq)
no solvent, rt, 24 h
no solvent, rt, 24 h
4
a
5
a
4
a
3
5a
(
1 eq)
Base
DMAP
(
1 eq)
(1.2 eq)
a
a
Entry
Yield (%)
Ee (%)
Entry
Catalyst
Yield (%)
Ee (%)
1
2
3
4
5
6
7
8
9022
49
1
2
3
4
None
1a
1b
1
52
––
––
Et
3
N
30
29
1-Methyl pyrrolidine
Imidazole
43
60––
72
b
1061
1047
9
2
33 (R)
N-Methylimidazole
1,4-Dimethylpiperazine
a
The enantiomeric excess of 5a was determined by HPLC analysis
using a chiral column.
31
––
––
5e
Ph
3
P
n-Bu
Trace
Trace
b
Absolute stereochemistry was determined by comparison of the ½aŠ
3
P
D
5
e
value with that of reported by McDougal and Schaus.
a
The enantiomeric excess of 5a was determined by HPLC analysis
using a chiral column.
5e
which indicated that 1b is involved in at least two steps
of the Baylis–Hillman reaction, that is, (1) hetero-Mi-
chael reaction of the enone and tertiary amine, and (2)
aldol reaction (Fig. 1). Based on these observations, we
anticipated that compounds in which two urea/thiourea
groups are connected with an appropriate spacer would
accelerate the reaction by holding the two reaction
components in a suitable position to react. The hypo-
thetical structure of the complex further implies that
chirality in the spacer might cause asymmetric induction
5
e
was found to be 33%, favoring ‘R ’ configuration.
Under these conditions, the reactions of various tertiary
amines and phosphines were examined, and the results
are summarized in Table 2.
In the case of DMAP, the reaction proceeded more
effectively than with DABCO to give 5a in 90% yield.
Triethylamine and 1-methylpyrrolidine afforded mod-
erate reaction enhancement and 5a was obtained in 49%
and 43% yields, respectively. In these cases, the enan-
tiomeric excess was 22–30%. Interestingly, in the case of
imidazole, the enantiomeric excess of 5a was increased
to 61%, though the yield was low. With these results in
hand, we examined the feasibility of an asymmetric
version of the Baylis–Hillman reaction of cyclohexenone
(3) with various aldehydes 4 to investigate the utility and
limitations of this bis-thiourea catalyst 2 (Table 3).
11
of the product. Therefore, we designed a bis-thiourea-
functionalized chiral catalyst 2 to accommodate an en-
one and an aldehyde in a spatially restricted orientation.
The bis-thiourea catalyst 2 was prepared from isothio-
cyanate and diaminocyclohexane simply by mixing
12
them, and purified by recrystallization. Using the bis-
thiourea catalyst 2, coupling reaction of cyclohexenone
(
3) and benzaldehyde (4a) was examined under the same
conditions as used for entries 1–3 in Table 1. In the
presence of the bis-thiourea catalyst 2, the yield of the
allylic alcohol 5a was increased to 72%, which indicates
great effectiveness (72-fold versus the uncatalyzed reac-
tion) of the bis-functionalized catalyst, as expected
The Baylis–Hillman reaction with cyclohexenone (3)
(2 equiv) and aldehydes 4 (1 equiv) was examined, using
0.4 equiv of base and bis-thiourea 2 in the absence of
solvent. In the case of benzaldehyde (4a) with DMAP,
5a was obtained in 33% ee with 88% yield. Changing the
base to imidazole increased the ee value to 57% even
13
(
Table 1). In this case, the enantiomeric excess of 5a
CF3
CF3
S
F3C
N
H
N
H
CF3
1
b
O
a
CF3
CF3
CF3
CF3
Ph
4
H
S
S
F3C
N
H
N
CF3
F3C
N
H
N
H
CF3
H
1b
5
a
O
O
O
Aldol reaction
H
R3N + 1b
Ph
R3N
3
R3N
Hetero-Michael reaction
Figure 1. Baylis–Hillman reaction promoted by bis-thiourea catalyst.

Y. Sohtome et al. / Tetrahedron Letters 45 (2004) 5589–5592
Table 3. Reaction of 3 with various aldehydes in the presence of 2
5591
O
cyclohexenone (3) (2 eq)
(0.4 eq)
OH O
2
R
H
R
R
amine (0.4 eq)
no solvent
4
a-i
5
a-5i
(
1 eq)
a
Entry
1
4
Base
Temp (°C)
Time (h)
Yield (%)
88
Ee (%)
33
O
H
H
DMAP
)5
rt
72
4a
Imidazole
12040 57
CF3
O
2
3
DMAP
DMAP
)5
)5
72
72
38
88
30
4b
O
F3C
H
H
19
33
4c
O
DMAP
Imidazole
)5
4
72
12095
99
44
4
4d
F3C
O
5
6
DMAP
DMAP
)5
)5
72
72
33
63
59
60
Ph
Me
H
4e
O
H
4f
O
Me
7
8
H
DMAP
DMAP
)5
)5
72
72
67
55
60
86
Me
O
4g
H
4h
O
9
H
DMAP
)5
72
72
90
4i
a
5e;14
The enantiomeric excess of 5 was determined by HPLC analysis using a chiral column.
though the reaction was conducted at room tempera-
ture. ortho-, meta-, and para-substituted benzaldehyde
derivatives reacted to give 5b–d in 30%, 20%, and 33%
ee, respectively (runs 3–5). The chemical yields of
aromatic aldehydes were quite high, except for ortho-
substituted derivatives. The ortho-substituent presum-
ably disturbs the coordination of the carbonyl group in
3
O
H
N
R3N
S
H
N
Ar
OH
R R
O
Ar
N
O
N
2
S
H
H
H
4
b to the thiourea moiety. Although asymmetric
5
induction with aromatic aldehydes was low, the ali-
phatic aldehydes 4e, 4f, and branched aldehyde 4g gave
the corresponding allylic alcohols 5e–g with 60% ee.
More excitingly, five- and six-membered cyclic aliphatic
aldehyde 4h and 4i, gave the alcohols 5h and 5i with very
high enantiomeric excess, that is, 86% and 90% ee,
respectively.
R
4
Figure 2. Proposed transition state of the bis-thiourea-catalyzed
Baylis–Hillman reaction.
which interacts with the enone, and these two compo-
nents interact to form the new carbon–carbon bond.
This would afford (R)-5 as the major coupling product.
Since the newly generated stereochemistry of the alcohol
in 5 is ‘R ’,
5e;14
the transition state of this Baylis–Hillman
reaction can be considered to be as shown in Figure 2.
The aldehyde 4 and the enone 3 coordinate to the
thiourea groups in 2 through hydrogen-bonding inter-
actions, such that the ‘R’ group in the aldehyde is lo-
cated on the opposite side from the thiourea group,
In summary, we have developed the new bis-thiourea-
type catalyst 2 for the Baylis–Hillman reaction. This
catalyst drastically improved the reaction rate. Further,
the produced allylic alcohol 5 showed induction of

5592
Y. Sohtome et al. / Tetrahedron Letters 45 (2004) 5589–5592
chirality up to 90% ee in the case of cyclohexanecar-
boxaldehyde (4i). It should be noted that the bis-thio-
urea catalyst 2 can be easily recovered quantitatively by
silica-gel column chromatography. This catalyst could
also be easily modified by introducing an appropriate
chiral spacer, which might improve the asymmetric
induction with a variety of substrates. Further efforts to
improve the catalyst are in progress.
(c) Kita, T.; Georgieva, A.; Hashimoto, Y.; Nakata, T.;
Nagasawa, K. Angew. Chem., Int. Ed. 2002, 41, 2832; (d)
Nagasawa, K.; Hashimoto, Y. Chem. Rec. 2003, 3, 201; (e)
Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Chem. Pharm. Bull. 2004, 52, 477.
8
9
. (a) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217;
(
b) Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9,
07; (c) Okino, T.; Hoashi, Y.; Takemoto, Y. Tetrahedron
Lett. 2003, 44, 2817.
4
. Maher and Connon recently reported 1 as an efficient
catalyst for the Baylis–Hillman reaction: Maher, D. J.;
Connon, S. J. Tetrahedron Lett. 2004, 45, 1301.
1
1
0. The H NMR spectrum of a 1:1 mixture of the thiourea 1b
and enone 3 showed a downfield shift of N-H in 1b from
References and notes
7
.90to 8.73 ppm. In the case of a 1:1 mixture of 1b and 4a,
1
2
. (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc.
Jpn. 1968, 41, 2815; (b) Baylis, A. B.; Hillman, M. E. D.
German Patent 2155113, 1972; Chem Abstr. 1972, 77,
a downfield shift of N-H in 1b was also observed from 7.90
to 8.30ppm.
1
1. Bifunctional catalysts, see: (a) Shibuguchi, T.; Fukuta, Y.;
Akachi, Y.; Sekine, A.; Ohshima, T.; Shibasaki, M.
Tetrahedron Lett. 2002, 43, 9539; (b) Okino, T.; Hoashi,
Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 2672; (c)
Okino, T.; Nakamura, S.; Fukuzawa, T.; Takemoto, Y.
Org. Lett. 2004, 6, 625.
34174q.
. For recent reviews, see: (a) Ciganek, E. In Organic
Reactions; Paquette, L. A., Ed.; Wiley: New York, 1977;
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Langer, P. Angew. Chem., Int. Ed. 2000, 9, 3049; (e)
Basavaih, D.; Dharma Rao, P.; Suguna Hyma, R.
Tetrahedron 1996, 52, 8001.
1
2. The bis-thiourea catalyst 2 was prepared as follows: To a
solution of (1R,2R)-())-1,2-diaminocyclohexane (866 mg,
7
methyl)phenyl isothiocyanate (2.77 mL, 15.2 mmol) at
0
warming to room temperature, the reaction mixture was
stirred for 22 h and concentrated in vacuo. The residue
was recrystallized from ethyl acetate–hexane to give 2
.58 mmol) in THF (10mL) was added 3,5-bis(trifluoro-
3
4
. (a) Aggarwal, V. K.; Tarver, G. J.; MacCauge, R. J.
Chem. Soc., Chem. Commun. 1996, 2713; (b) Aggarwal, V.
K.; Mereu, A.; Tarver, G. J.; McCauge, R. J. Org. Chem.
°C, and the mixture was stirred for 10min. After
1998, 63, 7183; (c) Yang, K.-S.; Lee, W.-D.; Pan, J.-F.;
Chen, K. J. Org. Chem. 2003, 68, 915.
(
4.68 g, 94%) as a white solid. Mp ¼ 132–133 °C (decom-
. (a) Oishi, T.; Oguri, H.; Hirama, M. Tetrahedron: Asym-
metry 1995, 6, 1241; (b) Marko, I. E.; Giles, P. R.;
Hindley, N. J. Tetrahedron 1997, 53, 1015; (c) Barrett, A.
G. M.; Cook, A. S.; Kamimura, A. Chem. Commun. 1998,
2
5
position). ½aŠ )60.6 (c 1, CHCl
3
). IR (KBr) 3357, 3280,
D
065, 2950, 1688, 1573, 1473, 1389, 1279, 1189, 1124 cm
ꢀ1
3
.
1
H NMR (500 MHz, CDCl
3
) d 8.12 (br s, 2H), 7.81 (s,
H), 7.69 (s, 2H), 7.07 (br s, 2H), 4.38 (br s, 2H), 2.20 (br s,
4
2
2533; (d) Iwabuchi, Y.; Sugihara, T.; Esumi, T.; Hatake-
yama, S. J. Am. Chem. Soc. 1999, 121, 10219.
1
3
H), 1.81 (br s, 2H), 1.35 (br s, 4H). C NMR (125 MHz,
) d 180.54, 138.59, 132.78 (JCF ¼ 33:1 Hz), 124.08
CDCl
br), 122.71 (JCF ¼ 273:1 Hz), 119.67 (br), 59.45, 31.74,
3
5
. Alternative approaches for asymmetric Baylis–Hillman
reactions, see: (a) Brzezinski, L. J.; Rafel, S.; Leahy, J. W.
J. Am. Chem. Soc. 1997, 119, 4317; (b) Yang, K.-S.; Chen,
K. Org. Lett. 2000, 2, 729; (c) Hayase, T.; Shibata, T.;
Soai, K.; Wakatsuki, Y. Chem. Commun. 1998, 1271; (d)
Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000,
(
2
6
4.39. HRMS (FAB, M+H) calcd for C24
57.1016, found 657.1031.
21 12 4 2
H F N S
1
1a
1
3. When 1c was used as catalyst, 5a was obtained in 20%
yield. This result clearly indicates the importance of the
bis-functionality of catalyst 2.
41, 2165; (e) McDougal, N. T.; Schaus, S. E. J. Am. Chem.
Soc. 2003, 125, 12094; (f) Imbriglio, J. E.; Vasbinder,
M. M.; Miller, S. J. Org. Lett. 2003, 5, 3741.
. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001,
CF3
6
7
S
4
5
0, 3726; (b) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002,
8, 2481.
N
H
N
H
CF3
1
c
. (a) Nagasawa, K.; Georgieva, A.; Takahashi, H.; Nakata,
T. Tetrahedron 2000, 56, 187; (b) Nagasawa, K.; Georgieva,
A.; Takahashi, H.; Nakata, T. Tetrahedron 2001, 57, 8959;
14. The absolute stereochemistries of 5b–d, 5f, 5h and 5i are
e
determined by Sharpless epoxidation method.
5