Asymmetric Michael addition of arylthiols to α,β-unsaturated carbonyl compounds catalyzed by bifunctional organocatalysts

Article abstract of DOI:10.1055/s-2005-863710

Bifunctional chiral organocatalysts comprising thiourea and tertiary amine groups were synthesized. They act as efficient catalysts for asymmetric Michael addition of arylthiols to α,β-unsaturated carbonyl compounds. Enantioselectivity up to 85% has been achieved. Asymmetric α-protonation reaction (up to 60% ee) can be obtained in the presence of the bifunctional catalyst.

Full text of DOI:10.1055/s-2005-863710

LETTER
603
Asymmetric Michael Addition of Arylthiols to a,b-Unsaturated Carbonyl
Compounds Catalyzed by Bifunctional Organocatalysts
A
a
symmetric Mich
a
ael
A
dditi
n
on of
A
rylthi
g
ols to
a
,
b
-U
n
-
saturate
J
d Carbony
i
l
Com
n
pound g Li,b Lin Jiang,a Min Liu,a Ying-Chun Chen,*a Li-Sheng Ding,b Yong Wua
Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. China
Fax +86(28)85502609; E-mail: ycchenhuaxi@yahoo.com.cn
b
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. China
Received 10 December 2004
Michael addition of phenylthiol to a,b-unsaturated imide
7a11 were tested. We envisage that the thiourea would ac-
tivate the carbonyl electrophile through double hydrogen
bonding,12 in connect with tertiary amine activating the
Abstract: Bifunctional chiral organocatalysts comprising thiourea
and tertiary amine groups were synthesized. They act as efficient
catalysts for asymmetric Michael addition of arylthiols to a,b-un-
saturated carbonyl compounds. Enantioselectivity up to 85% has
been achieved. Asymmetric a-protonation reaction (up to 60% ee) nucleophile. High catalytic activity was observed at 10
can be obtained in the presence of the bifunctional catalyst.
mol% catalyst loading in CH2Cl2. Unfortunately, only
poor enantioselectivity was obtained for both catalysts
with almost quantitative yields (Table 1, entries 1 and 2),
probably owing to the improper positions of two function-
al groups. On the other hand, bifunctional catalyst 1c,
prepared6,13 smoothly from (R,R)-1,2-diphenylethylenedi-
amine in 45% overall yield (Scheme 1), showed better
enantioselectivity (entry 3). More satisfactory results
were achieved by (S,S)-1,2-cyclohexanediamine-derived
1d (Scheme 1, Takemoto’s catalyst,6 entry 4, 60% ee). It
seems that the more rigid skeleton of chiral 1,2-cyclohex-
anediamine is vital to give better enantioselectivity, the
Takemoto’s catalyst 1d was further modified in consider-
ation of the electronic and steric reasons.14 It was found
that both catalytic activity and enantioselectivity were de-
creased when 1e was used probably due to the lower elec-
tron-withdrawing ability of 4-trifluomethylphenyl group
(entry 5). In addition, lower enantioselectivity was also
observed when bulky catalyst 1f was applied (entries 6).
Nevertheless, slightly better ee was obtained using cata-
lyst 1g with a strong electron-withdrawing group, while
reactivity was decreased probably owing to the bulky
structure (entry 7, 62% ee). It should be noted that better
and more reproducible results could be achieved in the
presence of freshly dried 4Å MS. Furthermore, almost ra-
cemic product was obtained when 10% (v/v) methanol
was added to the CH2Cl2 solution (entry 8). The findings
indicated that the hydrogen-bonding activation of carbon-
yl group by thiourea moiety was significant for the control
of enantioselectivity since trace water or proton solvent
would affect the weak interaction.
Key words: bifunctional organocatalyst, thiourea, hydrogen bond-
ing, asymmetric Michael addition, asymmetric protonation
Hydrogen bonding as a force for promoting chemical re-
actions has attracted increasing attention, and the develop-
ment of hydrogen bonding activated asymmetric catalysis
has been a rapidly growing area in synthetic organic
chemistry over the past few years.1 Apart from proline and
proline-derived organocatalysts-catalyzed direct aldol,
Mannich, amination and aminoxylation reactions,2 more
and more organocatalysts in connect with hydrogen bond-
ing activation have been reported.3 In the domain of urea
and thiourea catalysts,4 remarkable advances were made
by Jacobsen in a serials of asymmetric reactions promoted
by urea or thiourea containing Schiff base catalysts.5
More recently, Takemoto developed an excellent bifunc-
tional organocatalyst comprising tertiary amine and thio-
urea moiety for the enantioselective 1,4- or 1,2-addition
reactions through hydrogen bonding interaction with nitro
group.6 However, the asymmetric catalysis involving hy-
drogen bonding between carbonyl compounds and thio-
urea (urea) has largely been left unexplored.7 Here we
would like to report the synthesis of thiourea and tertiary
amine-based chiral organocatalysts and the application in
the asymmetric Michael addition of arylthiols to a,b-un-
saturated carbonyl compounds.8
Natural cinchona alkaloids and their derivatives have
been widely used in the asymmetric organocatalysis.9 The
bulky tertiary amine unit plays a very important role by
activating nucleophilic agent. Therefore, a thiourea moi-
ety bearing a 3,5-bis(trifluoromethyl)phenyl group was
introduced in the 9-position10 of cinchonidine 2a or cin-
chonine 2b to give the novel bifunctional catalysts 1a or
1b in two steps, respectively, in over 60% yields
(Scheme 1). Their catalytic activities in the asymmetric
While screened out the best bifunctional organocatalyst
1d for the Michael addition, more reaction conditions
were investigated in order to improve the enantioselectiv-
ity. Solvent was found to have dramatic effects on the
catalytic performance. Similar results were obtained using
toluene as the solvent (Table 1, entry 9). However, very
poor enantioselectivity was observed when THF was used
(entry 10). Product with reversed configuration was ob-
tained in MeOH solution while with low enantioselectivi-
ty (entry 11). No beneficial effect in enantioselectivity
was observed when 20 mol% catalyst loading was applied
SYNLETT 2005, No. 4, pp 0603–0606
0
4.
0
3.
2
0
0
5
Advanced online publication: 22.02.2005
DOI: 10.1055/s-2005-863710; Art ID: U34104ST
© Georg Thieme Verlag Stuttgart · New York

604
B.-J. Li et al.
LETTER
(entry 12). On the other hand, better enantioselectivity
could be achieved when the reaction was conducted at
lower temperature (entry 13, 0 °C, 67% ee), and up to 75%
ee was obtained at –40 °C while the reaction time should
be extended (entry 14). However, almost no reaction
happened when the temperature was further decreased to
–78 °C.
CF3
i) HN3, DEAD,PPh3
HO
H
F3C
NH
S
N
N
F3C
N
ii)
NCS
F3C
N
N
(8R,9R)-2a
(8R,9S)-2b
(8R,9S)-1a
(8R,9R)-1b
With the optimized reaction conditions in hand, the scope
and limitations of the bifunctional thiourea-tertiary amine
catalyst 1d promoted Michael addition were investigat-
ed.15 A series of a,b-unsaturated imides 7 were reacted
with phenylthiol catalyzed by 10 mol% 1d at –40 °C. The
results were summarized in Table 2. It was found that the
reactions were not very sensitive to substitution patterns
of acceptors. Similar enantioselectivity was obtained in
the reactions of phenylthiol with a,b-unsaturated imides
bearing various aryl or alkyl substitutions. In general over
70% ee was obtained except a t-butyl group was sub-
stituted at b-position (Table 2, entry 5, 55% ee). The best
result was achieved when a linear alkyl substitution was
introduced (entry 6, 77% ee). However, lower enantio-
selectivity was observed while 2-naphthylthiol was used
(entry 7).
m
R
R
N
R
R
R
R
R
R
O
O
i
ii
iii
N
H2N
N
H2N
NH2
N
NH2
O
O
5
6
4
3
(R,R)-1c: R = Ph, Ar = 3,5-(CF3)2C6H3
(S,S)-1d: R = R = C4H8, Ar = 3,5-(CF3)2C6H3
(S,S)-1e: R = R = C4H8, Ar = 4-CF3C6H4
(S,S)-1f: R = R = C4H8, Ar = 3,5-(3',5'-F2C6H3)2C6H3
(S,S)-1g: R = R = C4H8, Ar = 3,5-[3',5'-(CF3)2C6H3]2C6H3
R
R
S
iv
N
HN
Ar
NH
Scheme 1 Conditions: (i) phthalic anhydride, TsOH, toluene;
(ii) HCOOH, HCHO; (iii) N2H4·H2O, EtOH; (iv) ArNCS, toluene.
Table 1 Optimization of Reaction Conditions for Michael Addition
of Phenylthiol to Unsaturated Imide 7aa
O
Ph
O
cat. (0.1 equiv)
4Å MS
S
O
O
PhSH
Table 2 Michael Addition of Thiol to Unsaturated Imide Catalyzed
by 1da
Ph
N
Ph
Ph
N
Ph
H
H
8a
7a
O
SPh
O
O
O
1d (0.1 equiv)
PhSH
Entry Catalyst Solvent
Temp
(°C)
Time
(h)
Yield
(%)b
ee
R
N
Ph
4Å MS
R
N
Ph
(%)c,d
H
H
8
7
1
2
3
4
5
6
7
8e
9
1a
1b
1c
1d
1e
1g
1h
1d
1d
1d
1d
1d
1d
1d
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
20
20
20
20
20
20
20
20
20
20
20
20
0
2
99
99
99
98
98
97
97
96
98
98
97
98
98
95
7
Entry
R
Time (h)
72
Yield (%)b ee (%)c
2
17
39
60
56
53
62
6
1
2
3
4
5
6
7d
C6H5
98
97
96
92
90
95
96
75
70
73
72
55
77
67
2
p-MeO-C6H4
Cyclohexyl
CH(CH3)2
C(CH3)3
72
4
72
5
84
12
10
12
4
84
(CH2)2CH3
(CH2)2CH3
72
72
59
4
a Reactions were carried out at 0.1 mmol scale in 0.5 mL CH2Cl2
at –40 °C and 20 mg 4Å MS were added.
10
12
12
3
b Isolated yield.
c The ee was determined by HPLC analysis on chiral column.
d 2-Naphthylthiol as the Michael addition donor.
11
12g
13
14
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
25f
60
67
75
12
72
Since the single carbonyl group of ketone or aldehyde can
also form double hydrogen bonding to thiourea moiety,16
the asymmetric Michael additions between cyclic enones
and thiols were also investigated in the presence of cata-
lyst 1d. The results were summarized in Table 3. In the
model reaction of phenylthiol and cyclohenxen-2-one,
better enantioselectivity (80% ee) was obtained compared
with the above reactions of acyclic unsaturated imides
(Table 3, entry 1). The enantioselectivity could be raised
to 85% at 0 °C (entry 2). But the ee lowered down when
–40
a Reactions were carried out at 0.1 mmol scale in 0.5 mL solvent and
20 mg 4Å MS were added.
b Isolated yield.
c The ee was determined by HPLC analysis on chiral column.
d The absolute configuration was determined to be R by the rotation
after conversion to ethyl ester.8g
e 10% (v/v) MeOH was added.
f S-configuration was obtained.
g 20 mol% catalyst was used.
Synlett 2005, No. 4, 603–606 © Thieme Stuttgart · New York

LETTER
Asymmetric Michael Addition of Arylthiols to a,b-Unsaturated Carbonyl Compounds
605
Table 3 Michael Addition of Arylthiol to Enone Catalyzed by 1da
CF3
CF3
S
S
O
O
N
H
N
H
N
H
N
H
1d (0.1 equiv)
+ ArSH
N
N
Ar
4Å MS
H
O
O
H
O
O
CF3
n
S
CF3
n
ArS
Ph
ArS
10
9
N
H
Ph
N
H
Ph
Entry ArSH
Enone
Temp Time Yield ee
A
Ph
B
(°C)
(h)
(%)b (%)c
CF3
S
O
80d
85d
81d
Ph
O
1
2
3
PhSH
20
0
–35
4
12
40
99
97
95
N
H
N
O
S
N
Ph
N
H
H
H
O
O
CF3
Ph
(R)-8a
4
0
8
98
71
SH
Ph
S
N
H
Ph
O
O
C
5
0
8
99
77
SH
MeO
SPh
O
O
O
O
1d (0.1 equiv)
PhSH
N
H
Ph
DCM, –78 °C
4Å MS, 72 h
97% yield
N
H
Ph
6
7
PhSH
PhSH
0
0
12
10
95
97
76
68
O
(S)-12
60 % ee
11
O
O
Scheme 2
8
9
0
0
12
12
96
98
63
74
SH
drogen bonding interaction (complex C). Further protona-
SH
MeO
tion study is in progress in our group.
O
In conclusion, we report that chiral organocatalysts bear-
ing tertiary amine and thiourea moiety can efficiently cat-
alyze the asymmetric Michael addition of thiols to a,b-
unsaturated carbonyl compounds in a concerted double
activation way. The reactions showed good substrate
scope and up to 85% ee was obtained. Moreover, we dem-
onstrated for the first time that this type of bifunctional
organocatalysts6 could serve as chiral proton catalysts and
asymmetric a-protonation (up to 60% ee) has been ob-
tained. Further study in asymmetric protonation reaction
and application of the bifunctional catalysts in other
asymmetric reactions are actively under investigation.
a Reactions were carried out at 0.1 mmol scale in 0.5 mL CH2Cl2 and
20 mg 4Å MS were added.
b Isolated yield.
c The ee was determined by HPLC analysis on chiral column.
d The absolute configuration was determined to be S by the rotation.8f
the reaction temperature was further decreased (entry 3).
Thus, the reaction scope was studied at 0 °C. In general,
slightly lower enantioselectivity was observed for other
substrates. Over 70% ee was obtained for the Michael ad-
dition of arylthiols to six-membered cyclic enones (entries
4–6). On the other hand, moderate enantioselectivity (63–
74% ee) was gained when cyclopenten-2-one was used as
the substrate (entries 7–9).
Acknowledgment
We are grateful for the financial support from Sichuan University
Like the catalytic model of malonates with nitroolefins6 in (No. 0082204127058).
the presence of bifunctional catalyst 1d, the plausible
mechanism for the Michael addition of arylthiols to a,b-
unsaturated carbonyl compounds is proposed (Scheme 2,
References
(1) For recent reviews on organocatalysis involving hydrogen
complexes A and B). The formation of double hydrogen
bonding between thiourea moiety and imide,11 in addition
to the concerted activation of thiol by the tertiary amine,
is essential for the enantioselective discrimination. On the
basis of the configuration of 8a, the reaction would pro-
ceed through complex B to give the R-product. We also
found that the asymmetric protonation could be achieved
in the reaction of phenylthiol and a-prochiral imide 11
(Scheme 2).17 Up to 60% ee was obtained on a-carbon
center of 12 with S-configuration18 when the reaction was
conducted at –78 °C. We speculate that the ammonium
group may act as the proton source after the conjugate
addition of thiol anion to the b-carbon, while the thiourea
moiety stabilizes the more stable Z-enolate through hy-
bonding, see: (a) Pihko, P. M. Angew. Chem. Int. Ed. 2004,
43, 2062. (b) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed.
2004, 43, 5138.
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M. J. Am. Chem. Soc. 2004, 126, 11804; and references
therein.
Synlett 2005, No. 4, 603–606 © Thieme Stuttgart · New York

606
B.-J. Li et al.
LETTER
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(11) (a) Goodman, S. N.; Jacobsen, E. N. Adv. Synth. Catal. 2002,
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unsaturated imide, see: Sammis, G. M.; Danjo, H.; Jacobsen,
E. N. J. Am. Chem. Soc. 2004, 126, 9928; and references
therein. (c) We failed to get the desired Michael addition
product using cinnamoyl-2-oxazolidinone as the receptor.
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Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. J. Am.
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modified cinchona alkaloids, see: Tian, S.-K.; Chen, Y.;
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(14) HRMS data of new organocatalysts: 1a, 564.1770 (calcd
564.1782); 1b, 564.1781 (calcd 564.1782); 1f, 501.1853
(calcd 501.1861); 1g, 701.1728 (calcd 701.1734).
(15) General Experimental Procedure for (S,S)-1d-Catalyzed
Asymmetric Michael Addition. Phenylthiol (12 mL, 0.11
mmol) was added to the stirred solution of a,b-unsaturated
imide 7a (25.1 mg, 0.1 mmol) and 1d (4.2 mg, 0.01 mmol)
in 0.5 mL CH2Cl2 at –40 °C. The reaction was stirred for 72
h. Flash chromatography eluting with petroleum ether–
EtOAc (10:1) gave the product as a white solid (35.3 mg,
98%). 1H NMR (400 MHz, CDCl3): d = 9.47 (s, NH), 7.78–
7.76 (m, 2 H), 7.62–7.59 (m, 1 H), 7.51–7.47 (m, 2 H), 7.36–
7.32 (m, 4 H), 7.29–7.19 (m, 6 H), 4.85 (dd, J = 1.6, 8.4 Hz,
1 H), 3.77 (dd, J = 8.4, 15.6 Hz, 1 H), 3.62 (dd, J = 8.4, 15.6
Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 173.3, 165.6,
140.8, 133.9, 133.3, 133.1, 132.4, 128.9, 128.8, 128.4,
127.8, 127.7, 127.6, 127.4, 48.2, 43.8. ESI-MS: m/z = 360.1
[M – H]–; ee was determined by HPLC on Daicel Chiralcel
OD (20% 2-propanol in hexane, 0.5 mL/min, tS = 10.8 min,
tR = 12.1 min, 75% ee).
(16) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. Tetrahedron Lett.
2003, 44, 2817. (b) Wittkopp, A.; Shreiner, P. R. Chem.–
Eur. J. 2003, 9, 407.
(17) For catalytic asymmetric protonation in Michael additions of
thiols, see: (a) Pracejus, V. H.; Wilcke, F.-W.; Hanemann,
K. J. Prakt. Chem. 1977, 319, 219. (b) Kumar, A.;
Salunkhe, R. V.; Rane, R. A.; Dike, S. Y. J. Chem. Soc.,
Chem. Commun. 1991, 485; also see ref. 7c. (c) For
catalytic protonation of enolate, see: Ishihara, K.;
Nakashima, D.; Hiraiwa, Y.; Yamamoto, H. J. Am. Chem.
Soc. 2003, 125, 24; and references therein. (d) Hamashima,
Y.; Somei, H.; Shimura, Y.; Tamura, T.; Sodeoka, M. Org.
Lett. 2004, 6, 1861.
(18) The absolute configuration was determined by the rotation
(10) Brunner, H.; Bügler, J.; Nuber, B. Tetrahedron: Asymmetry
1995, 6, 1699.
after conversion to ethyl ester.8c
Synlett 2005, No. 4, 603–606 © Thieme Stuttgart · New York