Asymmetric Michael addition of thiols to β-nitrostyrenes using a novel phenylpyrrolidine-based urea catalyst

Article abstract of DOI:10.1016/j.tetlet.2014.11.116

The catalyst 1-[(3R,4S)-1-benzyl-4-phenyl-pyrrolidin-3-yl]-3-[3,5-bis(trifluoromethyl)phenyl]urea (8) designed based on 1-[(3R)-1-benzylpyrrolidin-3-yl]-3-[3,5-bis(trifluoromethyl)phenyl]thiourea (4) and 1,3-bis[(3R,4S)-1-benzyl-4-phenylpyrrolidin-3-yl]urea (7) exhibited potent catalytic activity for the asymmetric Michael addition of thiols to β-nitrostyrenes. A mere 2 mol % of the catalyst afforded 2-nitro-1-phenylethylsulfides in high yields of up to 93% ee.

Full text of DOI:10.1016/j.tetlet.2014.11.116

Accepted Manuscript
Asymmetric Michael addition of thiols to β-nitrostyrenes using a novel phenyl-
pyrrolidine-based urea catalyst
Souichirou Kawazoe, Kazuki Yoshida, Yuichi Shimazaki, Takeshi Oriyama
PII:
S0040-4039(14)02030-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.116
TETL 45500
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
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17 November 2014
25 November 2014
Please cite this article as: Kawazoe, S., Yoshida, K., Shimazaki, Y., Oriyama, T., Asymmetric Michael addition of
thiols to β-nitrostyrenes using a novel phenylpyrrolidine-based urea catalyst, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.11.116
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Asymmetric Michael addition of thiols to β-
nitrostyrenes using a novel
phenylpyrrolidine-based urea catalyst
Souichirou Kawazoe,* Kazuki Yoshida, Yuichi Shimazaki, Takeshi Oriyama*
SR2
catalyst
HSR2
R1
R1
catalyst

1
Tetrahedron Letters
journal homepage: www.els evier.com
Asymmetric Michael addition of thiols to β-nitrostyrenes using a novel
phenylpyrrolidine-based urea catalyst
Souichirou Kawazoe,* Kazuki Yoshida, Yuichi Shimazaki, Takeshi Oriyama∗
Department of Chemistry, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito, Ibaraki 310-8512, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The catalyst 1-[(3R,4S)-1-benzyl-4-phenyl-pyrrolidin-3-yl]-3-[3,5-bis(trifluoromethyl)phenyl]-
urea (8) designed base on 1-[(3R)-1-benzylpyrrolidin-3-yl]-3-[3,5-bis(trifluoromethyl)phenyl]-
thiourea (4) and 1,3-bis[(3R,4S)-1-benzyl-4-phenylpyrrolidin-3-yl]urea (7) exhibited potent
catalytic activity for the asymmetric Michael addition of thiols to β-nitrostyrenes. A mere 2
mol% of the catalyst afforded 2-nitro-1-phenylethylsulfides in high yields of up to 93% ee.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Sulfa-Michael addition
Nitrostyrene
Urea catalyst
Benzyl thiol
2-Nitro-1-phenylethylsulfides
The treatment of sulfur sources with β-nitrostyrenes is a
known methodology for the synthesis of 2-nitro-1-phenylethyl
sulfides.1 The derivatives of 2-nitro-1-phenylethyl sulfide are
potential intermediate bioactive compounds, such as the dual
decrease side reactions caused by the nucleophilicity of thio urea.
The symmetric urea catalyst 6 exhibited a 47% ee (Entry 3). The
organocatalyst 7, which introduced a phenyl group into
compound 6 at the trans position of urea on the pyrrolidine ring,
increased the catalytic activity (Entry 4). From the viewpoint of
synthesis, symmetrical urea can be prepared by a very simple
method, however, asymmetric urea remains challenging.
2
antagonist of thromboxane A2 and leukotriene D4 , as well as
Sulconazole3 which has a broad spectrum antifungal activity.
Asymmetric sulfa-Michael addition (SMA) has been
developed in which several bifunctional organocatalysts play an
important role.4 Recently, SMA of thiols and nitroolefins has
been reported by Connon5 and Kowalczyk6. Connon’s catalyst
showed SMA between benzyl thiols and β-nitrostyrenes using a
10−20 mol% catalyst loading, with good yields of up to 96% ee,
while Kowalczyk’s catalyst 4 exhibited good yields with up to
87% ee (Scheme 1). Although these two works were impressive,
there remains some potential for improving the reaction with
regard to the loading amount, reaction yield, and
enantioselectivity.
Therefore, we designed
bis(trifluoromethyl)phenyl urea group and a phenyl group on the
trans side against the urea of the pyrrolidine ring.
a urea catalyst 8 with a 3,5-
SR2
catalyst
HSR2
R1
R1
1
2
3
Scheme 1. SMA of thiols to β-nitrostyrenes
As such, we investigated the activity of a symmetric urea
organocatalyst 7; however, the results were not sufficient for the
asymmetric Michael addition of thiols to β-nitrostyrenes because
of a moderate enantioselectivity (~80% ee).7 On the other hand,
we obtained the structure-activity relationship of the catalyst,
such as the ring size of amino moieties, substituents on the ring,
and so on. The structures and results of catalyst 4−7 are shown in
Table 1 and Figure 1. The catalytic activity was maintained,
which resulted in a change of Kowalczyk’s thio urea 4 to
corresponding urea catalyst 5 (Entries 1−2). However, avoidance
of the sulfur atom in urea may expand the substrate scope and
———
The synthesis of catalyst 8 is shown in Scheme 2.8 The
transformation
of
(3R,4S)-1-benzyl-4-phenylpyrrolidine-3-
carboxylic acid (9)9a was conducted via a Curtius rearrangement9b
[3,5-bis(tri-fluoromethyl)aniline (10) (1.38 mL, 8.91 mmol),
DPPA (0.42 mL, 1.95 mmol), DMF (2.5 mL), 100 °C, 5 h] to
give catalyst 8 in a 40% yield. The structure of 8 was determined
by X-ray crystal structure analysis with HBr salt, as shown in
Figure 2.10 The results indicated that the stereochemistry between
the phenyl group and the urea nitrogen on the pyrrolidine ring
∗ Corresponding author. Tel.: +81-29-228-8368; fax: +81-29-228-8403; e-mail: 13nd501@vc.ibaraki.ac.jp (S. Kawazoe), tor@mx.ibaraki.ac.jp
(T. Oriyama)

2
Tetrahedron Letters
was in a trans configuration. The absolute configuration of
Table 1. Based on Connon’s report, the absolute configuration
was determined by high-performance liquid chromatography
(HPLC) analysis.5 Treatment of catalyst 8 in a standard
condition, based on our previous results, showed an 88% isolated
yield and the enantioselectivity of (S)-3b was 93% ee (Entry 6).
In contrast, treatment of catalyst 7 resulted in a 78% ee (Entry 5).
carboxylic acid 9 is reflected from that of optically active styrene
oxide. This makes possible to prepare the catalyst with different
absolute configurations.
The activity of catalyst 8 was evaluated for the asymmetric
Michael addition of 4-tert-butylbenzyl thiol (2a) to β-nitrostyrene
(1a) using our general procedure.11 The results are shown in
.
S → O
urea
46
5
hybrid
8
trans
-phenyl
6
7
Figure 1. Design of organocatalyst 8.
CF3
H2N
H
N
H
N
COOH
10
CF3
CF3
DPPA, DMF,100 °C, 5 h
O
N
N
CF3
9
8
Scheme 2. Synthesis of catalyst 8.
Figure 2. ORTEP view of 8 HBr salt at 50% probability.
Table 1
Asymmetric addition of thiol to β-nitrostyrene
catalyst (X mol %)
tert
2a
4- -butylbenzyl thiol
(Y eq)
CH2Cl2, - 80 °C, 48 h, MS 4A (50 mg)
S
(
)
0.15 mmol
1a
3a
Entry
1c
Catalyst (X mol %)
2a (Y equiv.)
Yield (%)a
[76]
Ee (%)b
4, 2.5 mol %
1.05
[87 (S)]
2
3
4
5, 2.5 mol %
6, 2.5 mol %
7, 2.5 mol %
1.05
1.05
1.05
72
80
80
84 (R)
47 (R)
80 (S)
5
6
7, 2.0 mol %
8, 2.0 mol %
1.5
1.5
88
88
78 (S)
93 (S)
a Isolated yield.
b Determined by chiral-HPLC analysis.
c Kowalczyk’s paper.

3
alone may be confused with the benzyl thiol 2a in the hydrogen
bonding system that expresses enantioselectivity. 1-Naphthyl
derivative 3t decreased enantioselectivity to 69% ee, while 2-
naphthyl derivative 3u maintained an 86% ee. The 2-furyl
compound 3v, 2-thienyl compound 3w and 3-pyridinyl
compound 3x, which had hetero-cycles instead of the phenyl
group, showed 91% ee, 92% ee and 61% ee, respectively (Entries
11−13). The 1-methyl-3-indolyl compound 3y and phenetyl
compound 3z having linkers between nitroolefin and benzene
ring decreased enantioselectivity to 31% ee and 56% ee,
respectively (Entries 14−15). These results indicate possibilities
of widely application to not only nitrostyrenes but also
nitroolefins.
Table 2
Asymmentric addition of various thiols to β-nitrostyrene
cat. 8 (2 mol %)
RSH 2b-k (1.5 eq)
CH2Cl2(1.5 ml), - 80 °C
0.15 mmol
48 h, MS 4A (50 mg)
3b-k
1a
Yield
(%)a
Ee
Entry
R
Product
(%)b
1
2
3
4
5
6
7
Ph (2b)
PhCH2 (2c)
PhCH2CH2 (2d)
PhCH2CH2CH2 (2e)
cyclohexyl (2f)
t-Bu (2g)
3b
3c
3d
3e
3f
94
89
100
91
82
11
6
89
35
29
4
Table 3
Asymmentric addition of thiol to various nitroolefins
3g
3h
racemi
88
4-MeOC6H4CH2 (2h)
89
8
9
10
4-MeO2CC6H4CH2 (2i)
4-ClC6H4CH2 (2j)
2-ClC6H4CH2 (2k)
3i
3j
95
92
100
56
66
90
3k
cat. 8 (2 mol %)
4-tert-butylbenzyl thiol 2a (1.50 eq)
a Isolated yield.
b Determined by chiral-HPLC analysis.
0.15 mmol
1l-z
CH2Cl2(1.5 ml), - 80 °C
48 h, MS 4A (50 mg)
We tried several thiols 2b−2e with β-nitrostyrene 1a (Table
−1
2). The reaction of compounds 1b e afforded the corresponding
3l-z
products 31−3e in good yields (Entries 1−4). The thiophenol
derivative 3b showed little enantioselectivity (Entry 1). The
benzyl thiol 2c gave compound 3c in 89% yield with 89% ee
(Entry 2). The phenethyl derivative 3d showed 35% ee and
quantitative yield (Entry 3). The 3-phenylpropan thiol 2e gave
compound 3e in 91% yield with 29% ee. Depending on the
methylene chain length (CH2n, n: 0 − 3), enantioselectivities had
been changed. The cyclohexyl derivative 3f afforded a good
isolated yield (82%) but only a 4% ee (Entry 5). The tert-butyl
thiol gave a lower yield of 3g due to the slower conversion rate at
low reaction temperature13, and 3g did not exhibit any
enantioselectivity (Entry 6). The primary and secondary thiols
gave Michael adducts in good yields; however, the reaction of
tertiary thiol was less favorable. The benzyl thiol tended to
induce enantioselectivity among the thiols. Then the benzyl thiols
were screened. The thiols 2h−2k afforded the corresponding
products 3h−3k in good yields (Entries 7−12). The 4-
methoxybenzyl derivative 3h gave high enantioselectivity of
88% ee (Entry 7). The compound 3i, having a 4-methoxy-
carbonyl group on the 4-position of the benzene ring, resulted in
a smaller enantioselectivity of 56% ee (Entry 8). The Cl atom on
the 4-position and 2-position of benzyl thiol gave 3j (66% ee)
and 3k (90% ee), respectively (Entries 9−10). Compound 3a
showed the highest ee.
Yield
(%)a
100
100
99
Ee
(%)b
76
85
91
Entry
R
Product
1
2
3
4
5
6c
7
8d
9
10
11
12
13c
14
15
2-MeC6H4 (1l)
3-MeC6H4 (1m)
4-MeC6H4 (1n)
4-ClC6H4 (1o)
4-MeOC6H4 (1p)
4-NO2C6H4 (1q)
3-BrC6H4 (1r)
3-HOCH2C6H4 (1s)
1-naphthyl (1t)
2-naphthyl (1u)
2-furyl (1v)
3l
3m
3n
3o
93
89
3p
3q
3r
3s
3t
99
94
99
87
98
95
85
98
99
60
83
83
66
89
48
69
86
91
92
61
31
56
3u
3v
3w
3x
3y
3z
2-thienyl (1w)
3-pyridinyl (1x)
1-methyl-3-indolyl (1y)
phenethyl (1z)
a Isolated yield.
b Determined by chiral-HPLC analysis.
c 5.5 ml of CH2Cl2 were used.
d 2.5 ml of CH2Cl2 were used.
In the case of an intermediate sulconazol which is an
antifungal agent,3,6 4-chlorobenzyl thiol (2j) and 2,4-dichloro-1-
(2-nitrovinyl)benzene (1aa) were treated with SMA condition to
give corresponding product, 4-chlorobenzyl[1-(2,4-dichloro-
phenyl)-2-nitroethyl] sulfide (3aa), in 95% yield with 49% ee
(Scheme 3). Finally, we evaluated the asymmetric Michael
addition between β-nitrostyrene 1s and benzyl thiol 2i (Scheme
4). We obtained the intermediate of the dual antagonist of
thromboxane A2 and leukotriene D4, (S)-Methyl 4-{[(3-hydroxy-
methylphenyl)-2-nitro-ethyl]thiomethyl}benzoate (3ab), with
83% yield and 27% ee. We could enrich ee of 3ab which was
treated as racemate.1a
Next we evaluated the Michael addition between 4-tert-
butylbenzyl thiol (2a) and several β-nitroorefins 1l−z(Table 3).12
The reaction of compounds 1l−1s afforded the corresponding
products 3l−3s in good yields (Entries 1−8). Compound 3l (2-
Me), 3m (3-Me), and 3n (4-Me) showed 76% ee, 85% ee, and
91% ee, respectively (Entries 1−3). Compound 3o (4-Cl) showed
89% ee (Entry 4), while the electron-donating 4-MeO derivative
3p maintained an 83% ee (Entry 5). On the other hand, the
electron-withdrawing 4-nitro derivative 3q exhibited a low 66%
ee (Entry 6). 3-Br derivative 3r showed 89% ee (Entry 7). The 3-
hydroxymethyl derivative 3s presented an inadequate
enantioselectivity of 48% ee. Enantioselectivity can be
considered to be dependent on the hydrogen bond between the
catalyst and the substrate. The 3-hydroxymethyl benzene of 3s

4
Tetrahedron Letters
3. Fromtling, R. A. Clin Microbiol Rev. 1988; 1, 187–217.
4. For the reviews, see (a) Siau, W. Y.; Wang, J.; Catal. Sci. Technol. 2011,
1, 1298–1310. (b) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A.
Chem. Eur. J. 2011, 17, 6890–6899. (c) Connon, S. J. Chem. Commun.
2008, 2499–2510. (d) Enders, D.; Lüttgen, K.; Narine, A. A. Synthesis
2007, 7, 959–980.
5. Palacio, C.; Connon, S. J. Chem. Commun. 2012, 48, 2849–2851.
6. Kowalczyk, R.; Nowak, A. E.; Skarżewski, J. Tetrahedron: Asymmetry
2013, 24, 505–514.
2j
8
catalyst ( 2.0 mol % )
7. Kawazoe, S.; Yoshida, K.; Shimazaki, Y.; Oriyama, T. Chem. Lett. 2014,
48, 1659–1661.
CH2Cl2, -80 °C
48 h, MS 4A
8. Synthesis of catalyst 89: The mixture of (3R,4S)-1-benzyl-4-
phenylpyrrolidine-3-carboxylic acid (9) (0.50 g, 1.78 mmol), DPPA (0.42
mL, 1.95 mmol)，3,5-bis(trifluoromethyl)aniline (10) (1.38 mL, 8.91
mmol), and DMF 2.5 mL was heated to 100°C. After stirring for 5 h, the
mixture was cooled to r.t., then added with 5M NaOHaq 1.07 mL and
water 10 mL. Organic layer (lower) was separated. Water layer was
extracted with EtOAc 2 mL. Organic layers were collected then diluted
with water 15 mL and EtOAc 15 mL then organic layer was separated.
The solvents were concentrated under reduced pressure. The residue was
purified by column chromaotgraphy (n-heptane/EtOAc = 3/1 → 1/1) to
afford 1-[(3R,4S)-1-benzyl-4-phenylpyrrolidin-3-yl]-3-[3,5-bis(trifluoro-
methyl)phenyl]urea (8) 361 mg (0711 mmol, y. 40%) as a pale yellow
foam.
1aa
3aa
(95%, 49% ee)
Scheme 3. Synthesis of 3aa
2i
catalyst ( 2.0 mol % )
8
9. (a) Ohigashi, A.; Kikuchi, T.; Goto, S. Org. Process Res. Dev. 2010, 14,
127–132. (b) Kinoyama, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974,
30, 2151–2157.
CH2Cl2, -80 °C
48 h, MS 4A
10. 8 HBr was crystallized from MeOH/H2O. Crystal system
＝
1s
(83%, 27% ee)
3ab
orthorhombic, a = 5.8181(4) Å, b = 16.7744(11) Å, c = 26.5596(18) Å, V
= 2592.1(3) Å3, space group = P212121, Z = 4, µ = 1.658 cm1, T = 133 K,
Scheme 4. Synthesis of 3ab
R[F2 > 2σ(F2)] = 0.0400, wR2 = 0.1233, GOF = 0.871, Refl/param. =
5838/334. Complete crystallo- graphic data for compound 8 HBr have
been deposited with the Cambridge Crystallographic Data Center as
supplementary publication No. CCDC 1022570. Copies of the data
can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: 0044 1223 336 033, via
www.ccdc.cam.ac.uk/data_request/cif.
In summary, we rationally designed a new organocatalyst 8
for SMA between thiols and β-nitrostyrenes. In comparison to
symmetric urea 5, catalyst 8 showed a higher enantioselectivity
despite only one pyrrolidine unit. This result was very effective
with regard to furthering pyrrolidine catalyst design and synthesis.
For the common target compound 3a, a mere 2 mol% of the
catalyst afforded 2-nitro-1-phenylethylsulfides in high yields
with up to 93% ee. This enantioselectivity was more than
competitive with the 10 mol% loading of Connon’s catalyst. In
addition, catalyst 8 showed the same or slightly better catalytic
activity than that of Kowalczyk’s catalyst 4 in several cases.
Thus, we determined that urea 8 was effective for use in SMA,
and that benzyl thiols were particularly appropriate for the
reaction.
11. General procedure: To MS 4A (50 mg) heated and dried under reduced
pressure for 10 min in a two-necked round bottom flask (30 mL) were
added β-nitrostyrene (1a) (22.4 mg, 0.15 mmol), catalyst 8 (0.003 mmol),
and CH2Cl2 (1 mL) at room temperature. After stirring for 20 min, the
mixture was cooled to −80 °C. To the mixture was added the solution of
4-tert-butylbenzyl thiol (2a) (40.6 mg, 0.225 mmol) in CH2Cl2 (0.5 mL)
during 10 min at −80 °C. After stirring for 48 h, the mixture was filtered
and the solution was separated on TLC (n-hexane/EtOAc = 24/1) to give
(4-tert-butylbenzyl)(2-nitro-1-phenylethyl)sulfide (3a) 42 mg [88%,
93%ee, [α]20D + 177 (c 0.428, CH2Cl2)] as a oil.
12. Synthesis of β-nitrostyrenes (a) Jakubec, P.; Cockfield, D. M.; Hynes, P.
S.; Cleator, E.; Dixon. D. J. Tetrahedron: Asymmetry 2011, 22, 1147-
1155. (b) Trost, B. M.; Muller, C. J. Am. Chem. Soc. 2008, 130, 2438-
2439. (c) Mahmood, S. Y.; Lallemand, M.-C.; Sader-Bakaouni, L.;
Charton, O.; Vérité, P.; François, H. D. Tetrahedron, 2004, 60, 5105-
5110. (d) Atokinson, D.; Meredith, P. Synlett 2003, 12, 1853–1855. (e)
Liu, J.-T.; Yao, C.-F. Tetrahedron Lett. 2001, 42, 6147–6150. (f) Kuster,
G. J. T.; Steeghs, R. H. J.; Scheeren, H. W. Eur. J. Org. Chem. 2001, 3,
553-560. (g) Canoira, L., Rodriguez, J. G.; Subirats, J. B.; Escario, J.-A.,
Jimenez, I.; Martinez-Fernandez A. R. Eur. J. Med. Chem. 1989, 24, 39-
42. (h) Worrall, D. E. Org. Synth. 1929, 9, 66–68.
References and notes
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13. Racemic standards were prepared at room temperature.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at
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Ararkida, Y.; Takeuchi, M. Chem. Pharm. Bull. 2006, 54, 603–610.