Organocatalytic asymmetric thio-Michael addition of arylmethyl mercaptans to cyclic enones by a primary amino acid

Article abstract of DOI:10.1016/j.tetlet.2010.07.089

A simple primary amino acid was found to be an efficient catalyst for thio-Michael addition of benzyl mercaptan to cyclic enones.

Full text of DOI:10.1016/j.tetlet.2010.07.089

Tetrahedron Letters 51 (2010) 5134–5136
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic asymmetric thio-Michael addition of arylmethyl mercaptans
to cyclic enones by a primary amino acid
*
Masanori Yoshida , Yasunobu Ohno, Shoji Hara
Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, 8, Kita 13-jo Nishi, Kita-ku, Sapporo, Hokkaido 060-8628, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple primary amino acid was found to be an efficient catalyst for thio-Michael addition of benzyl
mercaptan to cyclic enones.
Received 24 June 2010
Revised 13 July 2010
Accepted 16 July 2010
Available online 25 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Thio-Michael addition of mercaptans to
a
,b-unsaturated car-
O-triphenylmethyl
L-serine (1d) gave the Michael adduct 3a with
bonylcompoundsis a useful methodology to introducea sulfurfunc-
tionality into the b-position of the carbonyl group and many
asymmetric processes have been developed.1,2 From a synthetic
point of view, benzyl mercaptan is an attractive Michael donor
because the benzyl group can be removed easily to give a thiol.3 Cat-
alytic asymmetric thio-Michael addition of benzyl mercaptan to
enones or enals has been achieved by both organometallic and or-
ganic catalyses; however, there are only a few reports regarding
the thio-Michael addition of benzyl mercaptan to cyclic enones by
organocatalysis and it is very difficult to carry out the reaction with
high enantioselectivity.4–6 Indeed, to the best of our knowledge, the
highest enantioselectivity which has been obtained from the reac-
tion of benzyl mercaptan with 2-cyclohexen-1-one by organocatal-
ysisis 21%eeasreportedbyDeng’sgroupin2002,6a while90%ee was
achieved by organometallic catalysis as reported by Shibasaki’s
group in 1998.4e Therefore, it is still a challenging subject to investi-
gate an organocatalytic asymmetric thio-Michael addition of benzyl
mercaptan to cyclic enones.
only 3% ee, S-triphenylmethyl
L
-cysteine (1f) improved the selectiv-
ity to 45% ee (Table 1, entries 2 and 4). A secondary amino acid 1g
was also examined as a catalyst; however, poor enantioselectivity
was observed (Table 1, entry 5). Thus, we chose 1f as a catalyst for
further investigations.
We then carried out a solvent screen for the thio-Michael addi-
tion using 1f (Table 2). It was found that the reaction smoothly
proceeded in a high-polarity solvent, DMSO or MeOH; however,
the product 3a was obtained as a racemate (Table 2, entries 1
and 2). After further solvent screening, dichloromethane was found
CO2M
NH2
CO2H
1e
RO
NH2
CO2H
TBDPSO
Ph3CS
TBDPSO
1a, R = TBDPS
M = Li
1b, R = TBDPS
M = H
1f
NH2
Recently, we reported that O-TBDPS L-serine lithium salt (1a)
1c, R = TIPS
M = H
progressed the Michael addition of malonates to cyclic enones effec-
tively to give 3-substituted cyclic ketones in good yields with high
enantioselectivity (Fig. 1).7,8 In this context, we attempted the
thio-Michael addition of benzyl mercaptan with 2-cyclohexen-
1-one (2a) in the presence of the catalyst 1a (Scheme 1). The reaction
slowly proceeded to give the desired Michael adduct, 3-(phenylm-
ethylthio)cyclohexanone (3a); however, the enantioselectivity was
quite low (7% ee). Encouragingly, it was found that the use of amino
acid 1b as a catalyst raised the enantioselectivity dramatically to
38% ee. To find a more selective catalyst, we carried out a catalyst
screen for the thio-Michael addition of benzyl mercaptan with 2a
CO2H
1d, R = Ph3C
N
H
1g
M = H
TBDPS = tert-Butyldiphenylsilyl
TIPS = Triisopropylsilyl
Figure 1. Catalysts used in the thio-Michael addition of mercaptans to enones.
O
O
Cat.
(20 mol%)
+ PhCH2SH
as shown in Table 1.9 It was found that the use of O-TIPS
(1c) or O-TBDPS -tyrosine (1e) as a catalyst resulted in a lower
L-serine
CH2Cl2
25 °C, 24 h
SCH2Ph
L
2a
3a
enantioselectivity than that of 1b (Table 1, entries 1 and 3). While
Cat. = 1a, 27%, 7% ee
1b, 46%, 38% ee
* Corresponding author. Tel./fax: +81 11 706 6557.
E-mail address: myoshida@eng.hokudai.ac.jp (M. Yoshida).
Scheme 1. Thio-Michael addition of benzyl mercaptan with 2a using 1a or 1b.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.089

M. Yoshida et al. / Tetrahedron Letters 51 (2010) 5134–5136
5135
Table 1
Table 3
Catalyst screen for thio-Michael addition of benzyl mercaptan with 2aa
Optimization of the reaction conditions using 1fa
1 (20 mol%)
1f
+ PhCH2SH
+ PhCH2SH
2a
3a
2a
3a
CH2Cl2
25 °C, 24 h
CH2Cl2, Additive
25 °C, 24 h
Entry
Catalyst
Yieldb (%)
eec (%)
Entry
1f (mol %)
Additive (mol %)
Yieldb (%)
eec (%)
1
2
3
4
5
1c
1d
1e
1f
11
50
10
17
53
23
3
30
45
6
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
20
20
20
10
3
DMSO (100)
28
24
25
27
15
90
23
20
53
83
85
61
56
55
38
47
51
4
59
60
60
55
55
55
Diphenylsulfoxide (100)
Dimethylsulfone (100)
MeOH (100)
H2O (100)
Triethylamine (100)
DMSO (50)
DMSO (20)
DMSO (50)
DMSO (50)
DMSO (50)
1g
a
The reaction was carried out with 2a (0.5 mmol), benzyl mercaptan
(0.55 mmol), and 1 (0.1 mmol) in dichloromethane (1 mL) at 25 °C for 24 h.
b
9d
10d,e
11d,e
12d,e
Isolated yield based on 2a.
Determined by chiral HPLC analysis.
c
DMSO (50)
to be a suitable solvent to obtain the best enantioselectivity (45%
ee), although the reaction was very slow (Table 2, entry 10). The
reaction rate could be improved by adding a small amount of
DMSO to dichloromethane without any loss of enantioselectivity
(Table 2, entries 11–14).10
a
Unless otherwise mentioned, the reaction was carried out with 2a (0.5 mmol),
benzyl mercaptan (0.55 mmol), 1f, and an additive in dichloromethane (1 mL) at
25 °C for 24 h.
b
Isolated yield based 2a.
Determined by chiral HPLC analysis.
The reaction was carried out for 72 h.
The reaction was carried out at 37 °C.
c
d
Encouraged by these results, we carried out a detailed screening
of additives for the thio-Michael addition of benzyl mercaptan to
2a using catalyst 1f in dichloromethane (Table 3). Interestingly,
when the amount of DMSO was reduced to 1 equivalent to 2a,
the enantioselectivity was improved to 56% ee (Table 3, entry1).
The addition of diphenylsulfoxide gave a result similar to that of
DMSO, while a lower enantioselectivity was obtained by the addi-
tion of dimethylsulfone (Table 3, entries 2 and 3). MeOH and H2O
did not greatly affect the yield and enantioselectivity, though tri-
ethylamine reduced the selectivity (Table 3, entries 4–6). We then
performed optimization of the reaction conditions using DMSO as
an additive. The most effective amount of DMSO added was deter-
mined to be 50 mol % (Table 3, entry 7). Although the thio-Michael
addition was very slow at 25 °C, the reaction was completed within
72 h by carrying out the reaction at 37 °C (Table 3, entries 9 and
10). The amount of catalyst 1f could be reduced to 10 mol % with-
out considerable loss of yield and selectivity (Table 3, entry 11).
Under the reaction conditions, the Michael adduct 3a was obtained
in 85% yield with 55% ee.
e
Then the thio-Michael addition of various arylmethyl mercap-
tans to cyclic enones was carried out in the presence of catalyst
1f (Table 4). By carrying out the reaction of 2a with benzyl mercap-
tan at 25 °C for seven days, the Michael adduct 3a was obtained in
75% yield with a slightly better selectivity (58% ee) (Table 4, entry
2). 2-Cyclohepten-1-one (2b) provided a Michael adduct 3b in
good yields (81–82%), although a relatively lower enantioselectiv-
ity was observed (23–30% ee) (Table 4, entries 3 and 4). Unfortu-
nately, the reaction of 2-cyclopenten-1-one (2c) was very slow
even at 37 °C (Table 4, entry 5).7,9 As for a Michael donor, it was
found that an electron-deficient mercaptan gave lower enantiose-
lectivity. For example, the reaction of 2a with 4-chlorophenyl-
methyl mercaptan afforded a Michael adduct 3d with 27% ee,
while 4-methoxyphenylmethyl mercaptan afforded 3e with 50%
ee (Table 4, entries 6 and 7). Likewise, diphenylmethyl mercaptan
showed lower enantioselectivity than that of benzyl mercaptan
Table 4
Substrate scopea
Table 2
Solvent screen for thio-Michael addition of benzyl mercaptan with 2aa
O
O
1f (20 mol%)
1f (10 mol%)
+ PhCH2SH
2a
3a
+ RSH
Solvent
25 °C, 24 h
*
CH2Cl2, DMSO
37 °C, 72 h
( )n
2
( )n
SR
3
Entry
Solvent
Yieldb (%)
eec (%)
Entry
Substrate
R
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DMSO
MeOH
AcOEt
MeCN
THF
1,4-Dioxane
Et2O
Toluene
H2O
85
75
37
37
53
44
11
Trace
71
17
83
82
69
59
0
0
1
2a, n = 1
2a
2b, n = 2
2b
2c, n = 0
2a
2a
PhCH2
PhCH2
PhCH2
PhCH2
3a, 85
3a, 75
3b, 81
3b, 82
3c, 44
3d, 81
3e, 81
3f, 86
3g, 69
55, (S)
58, (S)
23, (S)
30, (S)
24, (S)
27
50
39
8
2e
3
14
35
33
34
3
4e
5
PhCH2
6
7
8
9
4-ClC6H4CH2
4-MeOC6H4CH2
Ph2CH
-
7
2a
2a
Ph3C
CH2Cl2
45
11
17
35
47
CH2Cl2/DMSO (1:1)
CH2Cl2/DMSO (2:1)
CH2Cl2/DMSO (4:1)
CH2Cl2/DMSO (9:1)
a
Unless otherwise mentioned, the reaction was carried out with 2 (0.5 mmol),
mercaptan (0.55 mmol), DMSO (0.25 mmol), and 1f (0.05 mmol) in dichlorometh-
ane (1 mL) at 37 °C for 72 h.
b
Isolated yield based on 2.
Determined by chiral HPLC analysis.
c
a
The reaction was carried out with 2a (0.5 mmol), benzyl mercaptan
(0.55 mmol), and 1f (0.1 mmol) in a solvent (1 mL) at 25 °C for 24 h.
d
The absolute configuration of 3a–c was determined by comparison of the
optical rotation with that of the literature.4d,4e
b
Isolated yield based on 2a.
Determined by chiral HPLC analysis.
e
c
The reaction was carried out at 25 °C for 7 days.

5136
M. Yoshida et al. / Tetrahedron Letters 51 (2010) 5134–5136
Science) from the Ministry of Education, Culture, Sports, Science
O
and technology, Japan.
H2O
O
H
Supplementary data
2a
O
S
H
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.089.
CO2H
NH2
N
Ph3CS
1f
O
References and notes
1. Review on asymmetric thio-Michael addition: Enders, D.; Lüttgen, K.; Narine, A.
A. Synthesis 2007, 959.
SCH2Ph
PhCH2SH
3a
2. Pineering works on thio-Michael addition using an amine catalyst: (a) Helder,
R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg, H. Tetrahedron Lett. 1977, 25,
2181; (b) Pracejus, H.; Wilcke, F.-W.; Hanemann, K. J. Prakt. Chem. 1977, 319,
219; (c) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417.
3. Greene’s Protective Groups in Organic Synthesis; Wuts, P. G. M., Greene, T. W.,
Eds., 4th ed.; Wiley-Interscience: New Jersey, 2007.
O
H
O
H2O
S
H
N
4. Asymmetric thio-Michael addition of benzyl mercaptan to cyclic enones with
an organometallic catalyst: (a) Ba˘doiu, A.; Bernardinelli, G.; Besnard, C.;
Kündig, E. P. Org. Biomol. Chem. 2010, 8, 193; (b) Prabagaran, N.; Abraham, S.;
Sundararajan, G. ARKIVOC 2002, vii, 212; (c) Sundararajan, G.; Prabagaran, N.
Org. Lett. 2001, 3, 389; (d) Saito, M.; Nakajima, M.; Hashimoto, S. Tetrahedron
2000, 56, 9589; (e) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc.
1998, 120, 4043.
SCH2Ph
Scheme 2. Plausible reaction mechanism.
5. Asymmetric thio-Michael addition of benzyl mercaptan to acyclic enones or
enals with an organic catalyst: (a) Liu, Y.; Sun, B.; Wang, B.; Wakem, M.; Deng,
L. J. Am. Chem. Soc. 2009, 131, 418; (b) Scafato, P.; Colangelo, A.; Rosini, C.
Chirality 2009, 21, 176; (c) Ricci, P.; Carlone, A.; Bartoli, G.; Bosco, M.; Sambri,
L.; Melchiorre, P. Adv. Synth. Catal. 2008, 350, 49; (d) Ishino, T.; Oriyama, T.
Chem. Lett. 2007, 36, 550; (e) Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K. A.
and better selectivity than that of triphenylmethyl mercaptan
(Table 4, entries 8 and 9).
A plausible reaction mechanism for the thio-Michael addition of
benzyl mercaptan with 2a using the catalyst 1f is depicted in
Scheme 2.7,11 The primary amino acid catalyst 1f reacted with 2a
_
J. Am. Chem. Soc. 2005, 127, 15710; (f) Skarzewski, J.; Zielin´ ska-Błajet, M.;
Turowska-Tyrk, I. Tetrahedron: Asymmetry 2001, 12, 1923.
6. Asymmetric thio-Michael addition of benzyl mercaptan to cyclic enones with
an organic catalyst: (a) McDaid, P.; Chen, Y.; Deng, L. Angew. Chem., Int. Ed.
2002, 41, 338; (b) Shirakawa, S.; Kimura, T.; Murata, S.; Shimizu, S. J. Org. Chem.
2009, 74, 1289; (c) Suzuki, K.; Ikegawa, A.; Mukaiyama, T. Bull. Chem. Soc. Jpn.
1982, 55, 3277.
to give an a,b-unsaturated imine. Although (E)- and (Z)-stereoiso-
mers can be formed, a relatively bulky methylene group comes to
the less-hindered side rather than the vinyl group. The carboxyl
group coordinates with the nitrogen atom of imine by hydrogen
bonding to reduce the electron density of the b-carbon and to hold
the side chain of the amino acid on the Re-face of the imine. There-
fore, benzyl mercaptan attacks from the Si-face of the imine to give
(S)-Michael adduct 3a predominantly.
7. Yoshida, M.; Narita, M.; Hirama, K.; Hara, S. Tetrahedron Lett. 2009, 50, 7297.
8. The catalytic use of amino acid alkaline metal salts was first reported by
Yamaguchi’s group: (a) Yamaguchi, M.; Yokota, N.; Minami, T. J. Chem. Soc.,
Chem. Commun. 1991, 1088; (b) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org.
Chem. 1996, 61, 3520; (c) Yamaguchi, M.; Shiraishi, T.; Hirama, M. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1176; (d) Li, P.; Yamamoto, H. Chem. Commun.
2009, 5412; (e) Xiong, Y.; Wen, Y.; Wang, F.; Gao, B.; Liu, X.; Huang, X.; Feng, X.
Adv. Synth. Catal. 2007, 349, 2156; (f) Renzi, P.; Overgaard, J.; Bella, M. Org.
Biomol. Chem. 2010, 8, 980; (g) Sato, A.; Yoshida, M.; Hara, S. Chem. Commun.
2008, 6242; (h) Yoshida, M.; Sato, A.; Hara, S. Org. Biomol. Chem. 2010, 8, 3031.
9. TLC tracing of the reaction indicated that the thio-Michael addition using
catalyst 1 proceeded cleanly to give the desired Michael adduct 3 and no major
by-products were produced.
10. DMSO will act as a weak Lewis base to dissolve an amino acid in the reaction
media and to activate a mercaptan moderately. The use of a sulfoxide as a
Lewis base was well studied by Kobayashi et al.: Kobayashi, S.; Ogawa, C.;
Konishi, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 6610.
11. For reviews on organocatalysis using a primary amines, see: (a) Xu, L.-W.; Luo,
J.; Lu, Y. Chem. Commun. 2009, 1807; (b) Xu, L.-W.; Lu, Y. Org. Biomol. Chem.
2008, 6, 2047; (c) Chen, Y.-C. Synlett 2008, 1919.
In summary, we found that a simple and commercially available
primary amino acid, S-triphenylmethyl L-cysteine (1f), promoted
the thio-Michael addition of arylmethyl mercaptans to cyclic enon-
es with fair to high enantioselectivity. To the best of our knowl-
edge, this is the most successful report among the reported
organocatalytic asymmetric thio-Michael additions of benzyl mer-
captan to cyclic enones.
Acknowledgment
This work was partly supported by the Global COE Program
(Project No. B01: Catalysis as the Basis for Innovation in Materials