Organocatalytic asymmetric sulfa-Michael addition of thiols to trans-3,3,3-trifluoropropenyl phenyl sulfone

Article abstract of DOI:10.1016/j.tetlet.2013.06.059

The first asymmetric sulfa-Michael addition of thiols to trans-3,3,3-trifluoropropenyl phenyl sulfone for the construction of a unique stereogenic center bearing a trifluoromethyl group and a sulfur atom has been achieved in high yields and moderate to go

Full text of DOI:10.1016/j.tetlet.2013.06.059

Tetrahedron Letters 54 (2013) 4509–4511
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Tetrahedron Letters
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Organocatalytic asymmetric sulfa-Michael addition of thiols
to trans-3,3,3-trifluoropropenyl phenyl sulfone
Xin Fang a, Xiu-Qin Dong a, Yuan-Yuan Liu a, Chun-Jiang Wang a,b,
⇑
a College of Chemistry and Molecular Sciences, Wuhan University, Hubei Province 430072, China
b State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjing 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first asymmetric sulfa-Michael addition of thiols to trans-3,3,3-trifluoropropenyl phenyl sulfone for
the construction of a unique stereogenic center bearing a trifluoromethyl group and a sulfur atom has
been achieved in high yields and moderate to good enantioselectivities with 1 mol % bifunctional
amine–thiourea catalyst.
Received 22 April 2013
Revised 28 May 2013
Accepted 13 June 2013
Available online 20 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Amine–thiourea catalyst
Asymmetric catalysis
Sulfa-Michael addition
trans-3,3,3-Trifluoropropenyl phenyl sulfone
Trifluoromethyl group
Incorporation of fluorine atoms into a stereogenic carbon center
has attracted considerable attention mainly owing to the outstand-
ing applications of chiral fluorinated organic compounds in various
fields, including pharmaceuticals, agrochemicals, and materials.1
Among organofluorine molecules, the trifluoromethyl group is fre-
quently encountered in a lot of biologically active medicinal and
agricultural compounds presumptively due to its intrinsic proper-
ties.2 It always leads to tremendous changes in physical, chemical,
and/or biological properties compared with non-fluorinated com-
pounds, such as increasing lipophilicity, metabolic stability, and
biological activity.3 Sulfones are valuable intermediates in organic
synthesis,4 meanwhile, enantiomerically enriched sulfones bearing
b-stereocenter are the key skeletons of complex natural or biolog-
ically important molecules.5 Most recently, we have developed the
first sulfa-Michael addition of thiols to cis-ethyl 4,4,4-trifluorocrot-
onate6 and trans-4,4,4-trifluorocrotonoyl-pyrazole7 catalyzed by a
bifunctional amine–thiourea catalyst, which provided a straight-
forward and effective synthetic route to chiral building blocks
bearing the trifluoromethyl group and sulfur atom at the stereo-
genic center. We envisioned that the sulfa-Michael addition of
thiols to trans-3,3,3-trifluoropropenyl phenyl sulfone could pro-
vide a general method to afford chiral sulfones bearing a unique
trifluoromethyl group. To the best of our knowledge, there was
no example of the asymmetric sulfa-Michael addition of thiols to
trans-3,3,3-trifluoropropenyl phenyl sulfone so far.8 Herein, we re-
ported the first catalytic asymmetric sulfa-Michael addition of thi-
ols to trans-3,3,3-trifluoropropenyl phenyl sulfone catalyzed by a
bifunctional amine–thiourea in high yields with moderate to good
enantioselectivities (up to 84% ee).
Our initial investigation began with the sulfa-Michael addition
of thiophenol 1a to trans-3,3,3-trifluoropropenyl phenyl sulfone 2
in dichloromethane at room temperature in the presence of
10 mol % bifunctional amine–thiourea catalysts (Fig. 1), and the
results are summarized in Table 1. In general, the reactions were
efficiently completed in less than 10 min yielding the desired ad-
duct 3a in good to high yields. The fine-tunable amine–thiourea
catalysts I and II bearing multiple hydrogen bonding donors devel-
oped in this lab9 were screened in this reaction (Table 1, entries
1–8). To our delight, catalyst II-c exhibited the best results and
the adduct 3a was obtained in 90% yield and 50% ee (entry 7).
Other commonly used chiral bifunctional amine–thiourea catalysts
derived from 1,2-diaminocyclohexane10 or cinchona alkaloids11
were also tested in this transformation, producing the adduct with
little lower enantioselectivities (entries 9–13).
The effects of solvent, reaction temperature, and catalyst load-
ing were also investigated. The reaction displayed much lower
enantiomeric excesses in polar solvents such as THF, MeCN, and
MeOH (Table 2, entries 4, 7, and 8). On the contrary, the reaction
was promoted efficiently in non-polar or less polar solvents, such
as CH2Cl2, CHCl3, Et2O, and PhMe, delivering the Michael adduct
with higher enantioselectivities (entries 1–3 and 6), and CH2Cl2
was the best solvent of choice. Reducing the reaction temperature
⇑
Corresponding author. Tel.: +86 27 68754067; fax: +86 27 65241880.
E-mail address: cjwang@whu.edu.cn (C.-J. Wang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.059

4510
X. Fang et al. / Tetrahedron Letters 54 (2013) 4509–4511
Table 2
S
Ph
*
Screening studies of sulfa-Michael addition of thiophenol 1a to trans-3,3,3-trifluo-
ropropenyl phenyl sulfone 2 catalyzed by catalyst II-c in various solventsa
*
Ph
*
*
1
N
H
N
H
1'
2'
N2
NR1R2
SPh
(1R,2R,1'S,2'S)-I-a: R1 = H, R2 = Ts
II-c (X mol %)
SO2Ph
SO2Ph
1
R = H, R2 = Ts
PhSH
+
F3C
-I-b:
(1R,2R,1'R,2'R)
F3C
solvent
(1R,2R,1'R,2'R)-I-c: R1 = H, R2 = Ms
1a
2
3a
1
-I-d:
(1R,2R,1'R,2'R)
R = H, R2 = 3,5-(CF3)2C6H3SO2
S
Ph
*
CF3
Entry
X mol %
T (°C)
Solvent
Time (min)
Yieldb (%)
eec (%)
*
Ph
1'
2'
1
2
3
4
5
6
7
8
9
10
11
12
13
14d
10
10
10
10
10
10
10
10
10
10
10
10
5
rt
rt
rt
rt
rt
rt
rt
rt
CH2Cl2
CHCl3
Et2O
10
10
10
10
10
10
10
10
50
100
150
300
100
100
90
95
84
66
76
79
67
81
89
95
92
90
92
95
50
49
32
12
22
42
3
*
*
1
N
H
N
H
S
N2
OH
N
H
N
H
CF3
(1R,2R,1'S,2'S)-II-a
(1R,2R,1'R,2'R)-II-b
(1R,2R,1'S,2'R)-II-c
N
THF
EtOAc
PhMe
MeCN
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
IV
-II-d
(1R,2R,1'R,2'S)
0
0
56
64
60
58
64
65
À20
À50
À78
À20
À20
N
N
H
N
H
N
H
H
N
CF3 F3C
N
H
H
R
S
S
R
1
a
CF3
CF3
Unless otherwise noted, the reaction was carried out with 0.12 mmol of 1a and
N
N
0.10 mmol of 2 in 0.5 mL of solvent.
III-a: R = H
III-b:
III-c: R = H
b
Isolated yield.
Determined by chiral HPLC analysis.
Carried out on a 0.25 mmol scale.
III-d:
R = MeO
R = MeO
c
d
Figure 1. Screened bifunctional amine–thiourea organocatalysts (I–IV).
with different substitution patterns on the aromatic ring reacted
smoothly with trans-3,3,3-trifluoropropenyl phenyl sulfone 2 to
afford the adducts (3a–3l) in high yields (82–99%) with moderate
to good enantioselectivities (44–84% ee) (Table 3, entries 1–12).
Comparable results were still achieved for the sterically hindered
ortho-methyl and ortho-fluoro substituted thiols 1b and 1h in terms
of enantioselectivity and reactivity (entries 2 and 8). Among the
tested nucleophiles, ortho-methoxy substituted thiol 1e afforded
the product with up to 84% ee (entry 5). Remarkably, the
challenging and less reactive alkyl thiol 1m also worked in this
reaction and gave the desired adduct in good yield and morderate
enantioselectivity (entry 13). The absolute configuration of the
Table 1
Screening studies of sulfa-Michael addition of thiophenol 1a to trans-3,3,3-trifluo-
ropropenyl phenyl sulfone 2 catalyzed by bifunctional amine–thiourea catalystsa
SPh
catal. (10 mol %)
CH2Cl2, rt, < 10 min
SO2Ph
SO2Ph
PhSH
+ F3C
F3C
1a
2
3a
Entry
Catal.
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
I-a
I-b
I-c
I-d
II-a
II-b
II-c
II-d
III-a
III-b
III-c
III-d
IV
86
90
86
88
86
83
90
79
79
85
82
89
96
14
À22
À15
À25
11
1
50
Table 3
Asymmetric sulfa-Michael addition of thiols 1 to trans-3,3,3-trifluoropropenyl phenyl
sulfone 2 with organocatalyst II-ca
À3
SR
6
II-c (1 mol %)
CH2Cl2, -20 oC, < 2 h
À10
À12
6
SO2Ph
SO2Ph
RSH +
F3C
F3C
1
2
3
26
a
Unless otherwise noted, the reaction was carried out with 0.12 mmol of 1a and
Entry
R
3
Yieldb (%)
eec (%)
0.10 mmol of 2 in 0.5 mL of CH2Cl2.
b
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph (1a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
95
87
82
93
94
99
99
83
85
89
83
90
82
65
64
57
48
84
49
53
64
44
47
49
56
36
Isolated yield.
Determined by chiral HPLC analysis.
c
o-Me–C6H4 (1b)
m-Me–C6H4 (1c)
p-Me–C6H4 (1d)
o-MeO–C6H4 (1e)
m-MeO–C6H4 (1f)
p-MeO–C6H4 (1g)
o-F–C6H4 (1h)
m-F–C6H4 (1i)
p-F–C6H4 (1j)
from room temperature to 0 °C and À20 °C improved the enanti-
oselectivity to 56% and 64% ee, respectively (entries 9 and 10). Fur-
ther reducing the reaction temperature could not lead to better
enantioselectivity (entries 11 and 12). Decreasing the catalyst
loading from 10 to 1 mol % did not result in the loss of either the
yield or enantioselectivity (entries 13 and 14).
Encouraged by this result, we turned our attention to the scope
and generality of this new asymmetric sulfa-Michael addition of
thiols 1 to trans-3,3,3-trifluoropropenyl phenyl sulfone 2 under
the optimized reaction conditions. As shown in Table 3, various
electron-rich, electron-neutral, and electron-deficient aryl thiols
3j
3k
3l
2-Naphthyl (1k)
4-tBu–C6H4 (1l)
Bn (1m)
3m
a
Unless otherwise noted, the reaction was carried out with 0.30 mmol of 1 and
0.25 mmol of 2 in 0.5 mL of CH2Cl2 at À20 °C.
b
Isolated yield.
c
Determined by chiral HPLC analysis.

X. Fang et al. / Tetrahedron Letters 54 (2013) 4509–4511
4511
Acknowledgments
This work is supported by the NSFC (20972117), NCET-10-0649,
IRT1030, and 973 Program (2011CB808600). We thank Professor
Hua Li in Wuhan University for solving the crystal structure.
Supplementary data
Supplementary data (spectroscopic data of the compounds
3a–3m) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2013.06.059.
References and notes
Figure 2. X-ray crystallographic structure of (S)-3g.
1. (a) Hudlicky, M.; Pavlath, A. E. Chemistry of Organic Fluorine Compounds II. ACS
Monograph; American Chemical Society: Washington, DC, 1995. Vol. 187; (b)
Young, S. D.; Britcher, S. F.; Tran, L. O.; Linda, L. S.; Lumma, W. C.; Lyle, T. A.;
Hyff, J. R.; Anderson, P. S.; Olsen, D. B.; Carrol, S. S.; Pettibone, Z. D.; Obrien, J. A.;
Ball, R. G.; Balani, S. K.; Lin, J. H.; Chen, I. W.; Schleif, W. A.; Sardana, V. V.; Long,
W. J.; Brynes, V. W.; Emini, E. A. Antimicrob. Agents Chemother. 1995, 39, 2602;
(c) Pierce, M. E.; Parsons, R. L., Jr.; Radesca, L. A.; Lo, Y. S.; Silverman, S.; Moore,
J. R.; Islam, Q.; Choudhury, A.; Fortunak, J. M. D.; Nguyen, D.; Luo, C.; Mogan, S.
J.; Davis, W. P.; Confalone, P. N.; Chen, C.; Tillyer, R. D.; Frey, L.; Tan, L.; Xu, F.;
Zhao, D.; Thompson, A. S.; Corley, E. G.; Grabowski, E. J. J.; Reamer, R.; Reider, P.
J. J. Org. Chem. 1998, 63, 8536; (d) Hiyama, T. Organofluorine Compounds;
Springer: New York, NY, 2000; (e) Sculptoreanu, A.; Yoshimura, N.; de Grout,
W. C. J. Pharmacol. Exp. Ther. 2004, 310, 159; (f) Chambers, R. D. Fluorine in
Organic Chemistry; Blackwell: Oxford, 2004; (g) Uneyama, K. Organofluorine
Chemistry; Blackwell: Oxford, 2006; (h)Fluorine in Medicinal Chemistry and
Chemical Biology; Ojima, I., Ed.; Wiley-Blackwell, 2009.
Ph
O
Ph
H
H
S
N
H
N
H
H
SPh
O
O
SO2Ph
F3C
S
H
N
Ph
H
(S)-3a
F3C
S
2. Hanamoto, T.; Anno, R.; Yamada, K.; Ryu, K.; Maeda, R.; Aoi, K.; Furuno, H.
Tetrahedron 2009, 65, 2757.
3. (a)Fluorine Containing Amino Acids-Synthesis and Properties; Kukhar, V. P.,
Soloshonok, V. A., Eds.; Wiley: Chichester, 1995; (b) Uneyama, K.
Enantiocontrolled Synthesis of Fluoro-Organic Compounds In Soloshonok, V.
A., Ed.; Wiley: Chichester, 1999; (c) Georgii, G. F. Fluorine-Containing
Heterocycles. Part I. Synthesis by Intramolecular Cyclization. In Advances in
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Elsevier: Amsterdam, 2004; (d)
Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320; (e) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1; (f) Smits, R.; Cadicamo,
C. D.; Burger, K.; Koksch, B. Chem. Soc. Rev. 2008, 37, 1727; (g) Nie, J.; Guo, H.-C.;
Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111, 455; (h) For a recent special issue on
organofluorine chemistry, see: Togni, A. Adv. Synth. Catal. 2010, 352, 2677.
4. (a) Comasseto, J. V.; Petragnani, N. J. Organomet. Chem. 1978, 152, 295; (b)
Comasseto, J. V. J. Organomet. Chem. 1983, 253, 131; (c) Simpkins, N. S.
Sulphones in Organic Synthesis; Pergamon Press: Oxford, 1993.
Figure 3. Proposed transition state model leading to (S)-adduct.
sulfa-Michael adduct 3g was determined unambiguously to be S by
single X-ray crystallographic analysis ( Fig. 2).12 Those of other
adducts were tentatively proposed on the basis of these results.
Based on the absolute configuration of (S)-3g, a plausible dual
activation model accounting for the observed stereoselectivity of
the addition of thiols to trans-3,3,3-trifluoropropenyl phenyl
sulfone is shown in Figure 3, in which the thiourea and hydroxy
moieties interact through hydrogen bonding with trans-3,3,3-triflu-
oropropenyl phenyl sulfone and enhances their reactivity toward
nucleophilic attack, while the neighboring tertiary amine serves
as a general base to enhance the nucleophilicity of thiols simulta-
neously. The attack of the thiol to the Si-face of trans-3,3,3-trifluo-
ropropenyl phenyl sulfone affords the corresponding (S)-adduct,
which is compatible with the experimental results.
5. Prilezhaeva, E. N. Russ. Chem. Rev. 2000, 69, 367.
6. Dong, X.-Q.; Fang, X.; Wang, C.-J. Org. Lett. 2011, 13, 4426.
7. Dong, X.-Q.; Fang, X.; Tao, H.-Y.; Zhou, X.; Wang, C.-J. Adv. Synth. Catal. 2012,
354, 1141.
8. Highly reactive trans-3,3,3-trifluoropropenyl phenyl sulfone (2) was employed
in the 1,3-dipolar cycloaddition reaction, see: (a) Tsuge, H.; Okano, T.; Eguchi, S.
J. Chem. Soc., Perkin Trans. 1 1995, 2761; (b) Llamas, T.; Arrayás, R. G.; Carretero,
J. C. Synthesis 2007, 950.
9. (a) Wang, C.-J.; Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-J. Chem. Commun. 2008, 1431;
(b) Zhang, Z.-H.; Dong, X.-Q.; Chen, D.; Wang, C.-J. Chem. Eur. J. 2008, 14, 8780;
(c) Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.; Teng, H.-L. J. Am. Chem. Soc.
2008, 130, 8606; (d) Dong, X.-Q.; Teng, H.-L.; Wang, C.-J. Org. Lett. 2009, 11,
1265; (e) Dong, X.-Q.; Teng, H.-L.; Tong, M.-C.; Huang, H.; Tao, H.-Y.; Wang, C.-J.
Chem. Commun. 2010, 6840.
10. (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672; (b)
Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005,
127, 119.
In conclusion, we have developed the first asymmetric sulfa-Mi-
chael addition of thiols to trans-3,3,3-trifluoropropenyl phenyl
sulfone catalyzed by
a bifunctional amine–thiourea catalyst
bearing multiple hydrogen bonding donors. This catalytic system
performed well over a broad scope of substrates and provided
the desired sulfones bearing a unique trifluoromethyl group at
the stereogenic center in high yields (82–99%) with moderate to
good enantioselectivities (36–84% ee). Further investigations of
the scope and synthetic applications of this methodology are ongo-
ing, and the results will be reported in due course.
11. (a) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett. 1967, 2005, 7; (b)
Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45,
7496; (c) Connon, S. J. Chem. Commun. 2008, 2499.
12. CCDC 934845 (3g) contains the supplementary crystallographic data for this
paper.