Highly efficient catalytic asymmetric Sulfa-Michael addition of thiols to trans-4,4,4-trifluorocrotonoylpyrazole

Article abstract of DOI:10.1002/adsc.201100899

A new protocol for the efficient construction of chiral trifluoromethylated building blocks was developed via organocatalyzed sulfa-Michael addition of thiols to the cost-efficient trans-trifluorocrotonamide. Introducing the pyrazole moiety is crucial to providing H-bond acceptor sites for better activation and hence affording comparable asymmetric induction with that obtained when employing the expensive cis-4,4,4-trifluorocrotonate as the Michael acceptor. Copyright

Full text of DOI:10.1002/adsc.201100899

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DOI: 10.1002/adsc.201100899
Highly Efficient Catalytic Asymmetric Sulfa-Michael Addition of
Thiols to trans-4,4,4-Trifluorocrotonoylpyrazole
Xiu-Qin Dong,a Xin Fang,a Hai-Yan Tao,a Xiang Zhou,a and Chun-Jiang Wanga,b,*
a
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, Peopleꢀs Republic of China
Fax : (+86)-27-6875-4067; e-mail: cjwang@whu.edu.cn
State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic of China
b
Received: November 19, 2011; Revised: January 1, 2012; Published online: April 12, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100899.
Abstract: A new protocol for the efficient construc- tion with that obtained when employing the expen-
tion of chiral trifluoromethylated building blocks was sive cis-4,4,4-trifluorocrotonate as the Michael ac-
developed via organocatalyzed sulfa-Michael addi- ceptor.
tion of thiols to the cost-efficient trans-trifluorocroto-
namide. Introducing the pyrazole moiety is crucial to Keywords: amine-thiourea catalysts; asymmetric·ca-
providing H-bond acceptor sites for better activation talysis; pyrazoles; sulfa-Michael addition; 4,4,4-tri-
and hence affording comparable asymmetric induc- fluorocrotonamide; trifluoromethyl group
Introduction
direct construction of chiral building blocks bearing
a unique trifluoromethyl group and a sulfur atom at
Fluorinated organic compounds play a unique and the stereogenic center, including the key intermediate
significant role in the pharmaceutical, agrochemical, of the potent inhibitor of MMP-3, (R)-g-trifluoro-
and material sciences.[1] Chiral trifluoromethylated methyl g-sulfone hydroxamate[1a,8a] (Figure 1 and
compounds have attracted considerable attention, Scheme 1). However, there is one limitation in that
mainly due to the fact that the trifluoromethyl group catalytic system regarding the synthetic difficulty of
often brings remarkably changes in the physical, accessing the Michael acceptor, ethyl cis-4,4,4-tri-
chemical, and biological properties of the parent mol-
fluorocrotonate.[10] Although the cost-efficient trans-
ACHTUNGTRENNUNG
ecules, such as enhanced binding selectivity, higher trifluorocrotonate[11] could be easily prepared from
lipophilicity, and increased metabolic stability.[2] Opti- the commercially available 4,4,4-trifluoroacetoacetate,
cally active, chiral sulfur-containing compounds also however, only moderate enantioselectivity was
have important applications in many areas of chemis- achieved.[9]
try and biology, for example, serving as antibiotics, li-
Considering that various activated unsaturated
gands for metal-based catalysts, as catalysts them- ester surrogates such as unsaturated imides, 2-acylimi-
selves, and as chiral auxiliaries.[3] In sharp contrast to dazoles, acyl phosphonates, styrylisoxazoles, or N-
the well-documented approaches to access either opti- acylpyrazoles, have been successfully employed in the
cally active chiral trifluoromethylated compounds[1,2] tremendous asymmetric catalysis,[12] we envisioned
or chiral sulfur-containing compounds,[4–7] the devel- that a change of the ester motif in trans-ethyl 4,4,4-tri-
opment of effective methods for the construction of fluorocrotonate to the easily introduced N-acylpyra-
stereogenic carbon centers bearing a unique trifluoro- zole motif might improve its reactivity and stereose-
methyl group and a sulfur atom remains not only a ne-
cessity for biochemists and medicinal chemists, but
also a challenge for synthetic organic chemists, and
has met with little success.[8]
Recently, we have developed the first asymmetric
sulfa-Michael addition of thiols to cis-ethyl 4,4,4-tri-
fluorocrotonate catalyzed by a bifunctional amine-
Figure 1. The potent inhibitor of MMP-3 (stromelysin-1):
thiourea,[9] which serves as a general method for the (R)-g-trifluoromethyl g-sulfone hydroxamate.
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Scheme 2. Synthesis of N-pyrazole-derived 4,4,4-trifluoro-
AHCTUNGTREGUNcNN rotonamide.
Scheme 1. Organocatalyzed asymmetric sulfa-Michael addi-
tion to construct a stereogenic center featuring a trifluoro-
methyl group.
lectivity control toward nucleophilic attack of thiols
through the enhanced the hydrogen bonding interac-
tions between the Michael acceptor and a bifunctional
organocatalyst,[13] and thereby realize this challenging
sulfa-Michael addition with excellent enantioselectivi-
ty using the easily available trans-4,4,4-trifluorocroto-
namide. Herein, we report our investigations in the
use of N-acylpyrroles as H-bond accepters in the or-
ganocatalyzed asymmetric sulfa-Michael addition of
thiols to trans-4,4,4-trifluorocrotonamide. This new
approach permits an easy and more practical route to
the chiral building blocks bearing a trifluoromethyl
group and a sulfur atom at the stereogenic carbon
center. Moreover, another key feature of the present
method is that the optical purity of the products can
be increased by simple recrystallization.
Figure 2. Screened bifunctional amine-thiourea catalysts.
thiourea catalysts derived from 1,2-diaminocyclohex-
ane or Cinchona alkaloids[15] (Figure 2).
Results and Discussion
The results showed that all of catalysts exhibited
high activity, and the reaction finished remarkably in
A convenient and efficient route to 4,4,4-trifluorocro- less than 10 min with high yields for the desired sulfa-
tonoylpyrazoles 1a–1d was developed starting from Michael adducts in all cases (Table 1, entries 1–9),
commercially available ethyl 4,4,4-trifluoroacetonace- which indicated that pyrazole-derived trans-4,4,4-tri-
tate 2 according to a modification of a procedure re- fluorocrotonamides could be applied in the sulfa-Mi-
ported in the literature[11,14] (Scheme 2). Ester 2 was chael addition as Michael acceptors for the efficient
first converted to (E)-ethyl 4,4,4-trifluorocrotonate 3 construction of chiral building blocks containing a tri-
by treatment with sodium borohydride, followed by fluoromethyl group and a sulfur atom at the stereo-
dehydration with phosphorus pentoxide. Hydrolysis genic center. Compared with the previous work em-
of the ester 3 in 1N NaOH proceeded smoothly, af- ploying expensive cis-4,4,4-trifluorocrotonate as the
fording 4,4,4-trifluorocrotonic acid 4 in quantitative Michael acceptor,[9] another interesting finding was
yield. Reaction of pyrazoles with thionyl chloride fol- that the Michael adduct 6aa was produced as an
lowed by the addition of compound 4 gave the corre- easily crystallized solid due to the incorporation of
sponding N-pyrazole-derived 4,4,4-trifluorocroton- the N-acylpyrazole moiety into the starting material.
A
This contrasts with the previously reported catalytic
We began our investigation by evaluating the reac- system with trans- or cis-trifluorocrotonate as the Mi-
tion of trans-4,4,4-trifluorocrotoylpyrazole 1a with thi- chael acceptor which afforded the corresponding ad-
ophenol 5a in dichlioromethane (DCM) at room tem- ducts as oils which could not be crystallized.[9] Among
perature with the commonly used bifunctional amine- the tested bifunctional amine-thioureas, I-d[16] devel-
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Highly Efficient Catalytic Asymmetric Sulfa-Michael Addition of Thiols
Table 1. Screening studies of asymmetric sulfa-Michael addi-
tion of thiophenol 5a and (E)-4,4,4-trifluorocrotonoylpyra-
zoles 1 catalyzed by bifunctional catalysts.[a]
Table 2. Asymmetric sulfa-Michael addition of various thiols
2 to (E)-4,4,4-trifluorocrotonoylpyrazole 1a with I-d as cata-
lyst.[a]
[a]
All reactions were carried out with 0.22 mmol of 1a,
0.20 mmol of 5 in 0.5 mL of solvent.
Isolated yield.
Determined by HPLC analysis.
Data in parentheses were achieved after one recrystalli-
[b]
[c]
[d]
[a]
All reactions were carried out with 0.22 mmol of 1,
0.20 mmol of 5a in 0.5 mL of solvent.
Isolated yield.
The ee was determined by HPLC analysis.
zation.
[e]
Data in parentheses were achieved after two recrystalli-
zations, and 86% ee was achieved for the first crystalliza-
tion.
[b]
[c]
[d]
[f]
Carried out at 08C.
1 mol% catalyst loading.
oped in this laboratory recently has the most favoura- chemical yield, but in the case of MeOH, the racemic
ble characteristics in terms of yield (93%) and enan- Michael adduct was obtained, probably due to the
tioselectivity (91%) and was chosen for further inves- competitive activation of 4,4,4-trifluorocrotonamide
tigation (entry 4). Subsequently, the effect of the pyr- between the catalyst and the protic solvent. Reducing
azole moieties in the trans-4,4,4-trifluorocrotonamide the reaction temperature to 08C did not improve the
was investigated for this transformation. Although no enantioselectivity (entry 19).
obvious differentiation of reactivity was observed
Under the optimal reaction conditions, various
when the amide functional group switched from 3,5- thiols were tested to examine the generality of this re-
dimethylpyrazole to 4-halogenated 3,5-dimethylpyra- action, and the results are summarized in Table 2. In
zole or 3,5-diphenylpyrazole, a bulky amide group most cases, the desired products were obtained in
had a detrimental effect on the enantioselectivity (en- high yields and excellent enantioselectivities (up to
tries 10–12). Solvent screening revealed that non- 97% ee), which was comparable with the results ob-
polar solvents were more suitable for this organocata- tained in the previously reported sulfa-Michael addi-
lyzed sulfa-Michael addition (entries 4 and 13–18), tion reaction employing the expensive cis-4,4,4-tri-
and toluene was the solvent of choice leading to 94% fluorocrotonate as the Michael acceptor.[9] In general,
yield and 93% ee. Reaction in MeCN led to a signifi- the electronic property of the substituents on the
cant drop in enantioselectivity albeit without loss of phenyl ring of thiols slightly influenced the enantiose-
Adv. Synth. Catal. 2012, 354, 1141 – 1147
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Table 3. Control experiments to evaluate the role of the pyr-
azole motif and the electron-withdrawing CF3 group.[a]
Scheme 3. Scale-up reaction with 1 mol% of I-d as the cata-
lyst.
lectivities, and aryl thiols bearing electron-neutral
(entries 1, 2 and 16) and electron-donating groups
(entries 3–9) exhibited slightly higher enantioselectivi-
ties than those bearing electron-withdrawing groups
(entries 10–15). The substitution pattern of the phenyl
ring had little effect on the enantioselectivity. It is
noteworthy that comparable results were still
[a]
All reactions were carried out with 0.22 mmol of 1,
0.20 mmol of 5a in 0.5 mL PhMe.
Isolated yield.
The ee was determined by HPLC analysis.
[b]
[c]
achieved for the sterically hindered ortho-methyl- and tonamide plays a significant role in providing H-bond
ortho-methoxy-substituted thiols 5b and 5e in terms acceptor sites for better chelation and hence higher
of enantioselectivity and reactivity (entries 3 and 6). enantioselectivity; meanwhile, higher reactivity was
The less reactive alkyl thiol – benzyl mercaptan 5m – also endowed by the s-electron-withdrawing CF3
was also evaluated for this reaction and it was found group.[18]
that the reaction took place in moderate enantioselec-
The absolute configuration of 6ag was assigned to S
tivity[17] and good yield (entries 17 and 18). Remarka- through efficient hydrolysis and then optical rotation
bly, the high yield and enantioselectivity and fast reac- comparison of the obtained acid 7ag with the data re-
tion rate remained when the reaction was performed ported in the literature (Scheme 4).[8a] Those of the-
with a low catalyst (1 mol%) loading (entries 2, 9, 11, other adducts were tentatively proposed on the basis
14 and 18). Another attractive feature of this method- of these results.
ology is all the sulfa-Michael adducts are solid, and
The synthetically useful thiochroman-4-ones (S)-8
the enantioenriched compounds could be easily ob- were easily attained by one-pot intramolecular Frie-
tained by simple crystallization of the crude products del–Crafts reaction without loss of enantiomeric
in petroleum ether (entries 1, 8 and 17).
excess. The carbonyl groups of (S)-8aa and 8ag were
Additionally, we tested the application of the cur- efficiently reduced to afford the corresponding syn-
rent catalytic system to prepare (S)-6ag on a large (2S,4S)-2-trifluoromethyl-thiochroman-4-ols 9aa and
scale (Scheme 3). With 1 mol% of bifunctional orga-
nocatalyst I-d, the reaction was completed in less than
30 min and the adduct was obtained in high yield and
93% ee.
In order to evaluate the roles that the pyrazole and
CF3 motifs played in this sulfa-Michael addition reac-
tion, control experiments were carried out with thio-
phenol as the Michael donor, trans-b-substituted ethyl
acrylates or acrylamides as the Michael acceptors
under the optimized reaction conditions (Table 3): re-
placing the ester group in trans-4,4,4-trifluorocroto-
nate with an amide group in the N-acylpyrazole not
only afforded a superior level of reactivity but also
led to much higher enantioselectivity with the same
sense of asymmetric induction (entry 1). On the con-
trary, without the pyrazole and/or electron-withdraw-
ing CF3 group, the reactivity and asymmetic induction
of the corresponding transformation dropped signifi-
cantly (entries 2–6). This indicated that introducing
the pyrazole moiety into the trans-4,4,4-trufluorocro- synthetic transformation.
Scheme 4. Determination of the absolute configuration and
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Adv. Synth. Catal. 2012, 354, 1141 – 1147

Highly Efficient Catalytic Asymmetric Sulfa-Michael Addition of Thiols
methyl group and a sulfur atom at the stereogenic
center. The ready availability of the starting materials,
easy crystallization of the Michael adducts and the
great importance of the chiral trifluoromethyl com-
pounds make the current methodology particularly in-
teresting in synthetic chemistry.
Experimental Section
General Procedure for the Asymmetric Sulfa-Michael
Addition of Thiols to (E)-4,4,4-Trifluorocrotonoyl-
pyrazoles Catalyzed by Organocatalysts (I-d)
To a vial containing thiol (0.22 mmol) and (E)-4,4,4-tri-
AHCTUNGTREGfNNNU luorocrotonoylpyrazole (0.20 mmol) in toluene (0.5 mL)
Figure 3. A plausible transition state model leading to (S)-
adduct.
was added the catalyst I-d (6.7 mg, 0.01 mmol) at the room
temperature. TLC analysis indicated completion of the reac-
tion after about 5 min. Then the reaction mixture was con-
centrated under vacuum and the crude product was purified
by flash chromatography on silica gel column with petrole-
um ether/ethyl acetate. The enantiomeric excess of the prod-
uct was determined by HPLC analysis with chiral column
(see Supporting Information).
9ag in high yield with excellent enantioselectivity and
remarkably high diastereoselectivity (>99:1 dr).[19]
Based on the absolute configuration of (S)-6ag and
previous studies,[20] a plausible dual acitivation model
accounting for the obsevered stereoselectivity of the
addition of thiols to trans-4,4,4-Trifluorocrotonoyl-
pyrazole is shown in Figure 3, in which the thiourea
and sulfonamide moiety interact through hydrogen
bonding with trans-4,4,4-trifluorocrotonamides and
this enhances their reactivity toward nucleophilic
attack while the neighbouring tertiary amine serves as
a general base to enhance the nucleophilicity of the
thiols simultaneously. The attack of the thiol to the
Re-face of trans-4,4,4-trifluorocrotonamide was re-
stricted by the cyclohexyl scaffold of the bifunctional
catalyst I-d. As a consequence, the Si-face of the
trans-4,4,4-trifluorocrotonamide was predominantly
approached by the thiol anion from upside during the
sulfa-Michael addition, affording the corresponding
(S)-adduct. This is compatible with the experimental
results. Nevertheless, the real catalytic mechanism still
needs further investigation.
Acknowledgements
This work is supported by the National Natural Science
Foundation of China (20972117, 21172176), the Program for
New Century Excellent Talents in University (NCET-10-
0649), the Program for Changjiang Scholars and Innovative
Research Team in University of the Ministry of Education
(IRT1030), 973 program (2011CB808600), the Fundamental
Research Funds for the Central Universities, and Large-scale
Instrument And Equipment Sharing Foundation of Wuhan
University.
References
[1] a) Fluorine in Medicinal Chemistry and Chemical Biol-
ogy, (Ed.: I. Ojima), Wiley-Blackwell, New York, 2009;
b) J.-P. Bꢂguꢂ, D. Bonnet-Delpon, Bioorganic and Me-
dicinal Chemistry of Fluorine, John Wiley & Sons, Inc.,
New York, 2008; c) A. Tressaud, G. Haufe, Fluorine
and Health-Molecular Imaging, Biomedical Materials
and Pharmaceuticals, Elsevier, Amsterdam, 2008;
d) A. M. Thayer, Chem. Eng. News 2006, 84, 15.
[2] a) Fluorine Containing Amino Acids – Synthesis and
Properties, (Eds.: V. P. Kukhar, V. A. Soloshonok),
Wiley, Chichester, 1995; b) K. Uneyama, in: Enantio-
controlled Synthesis of Fluoro-Organic Compounds,
(Ed.: V. A. Soloshonok), Wiley, Chichester, 1999,
Chapter 12; c) S. Purser, P. R. Moore, S. Swallow, V.
Gouverneur, Chem. Soc. Rev. 2008, 37, 320; d) J.-A.
Ma, D. Cahard, Chem. Rev. 2008, 108, PR1; e) R.
Smits, C. D. Cadicamo, K. Burger, B. Koksch, Chem.
Soc. Rev. 2008, 37, 1727; f) J. Nie, H.-C. Guo, D.
Cahard, J.-A. Ma, Chem. Rev. 2011; 111, 455; g) G. F.
Conclusions
In summary, we have developed a new protocol for
the organocatalytic asymmetric sulfa-Michael addition
of thiols to the easily available trans-4,4,4-trifluoroc-
rotonamide in excellent yields and good to excellent
enantioselectivities. The pyrazole moiety of the trans-
4,4,4-trifluorocrotonamide was revealed to play a key
role in providing H-bond acceptor sites for better che-
lation and hence affording a comparable asymmetric
induction with that obtained when employing the ex-
pensive cis-4,4,4-trifluorocrotonate as the Michael ac-
ceptor. This methodology presented herein could
open up new prospects for stereoselectively construct-
ing valuable chiral building blocks bearing a trifluoro-
Adv. Synth. Catal. 2012, 354, 1141 – 1147
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1145

Xiu-Qin Dong et al.
FULL PAPERS
Georgii, Fluorine-Containing Heterocycles. Part I. Syn-
thesis by Intramolecular Cyclization, in: Advances in
Heterocyclic Chemistry, (Ed.: A. R. Katritzky), Elsevi-
er, Amsterdam, 2004; for a recent special issue on or-
ganofluorine chemistry, see: h) Adv. Synth. Catal. 2010,
352, 2677.
[7] For examples of organocatalytic tandem reactions of
thiols, see: a) M. Marigo, T. Schulte, J. Franzꢂn, K. A.
Jørgensen, J. Am. Chem. Soc. 2005, 127, 15710; b) S.
Brandau, E. Maerten, K. A. Jøgensen, J. Am. Chem.
Soc. 2006, 128, 14986; c) W. Wang, H. Li, J. Wang, L.-S.
Zu, J. Am. Chem. Soc. 2006, 128, 10354; d) L.-S. Zu, J.
Wang, H. Li, H.-X. Xie, W. Jiang, W. Wang, J. Am.
Chem. Soc. 2007, 129, 1036; e) L.-S. Zu, H.-X. Xie, H
Li, J. Wang, W. Jiang, W. Wang, Adv. Synth. Catal.
2007, 349, 1882; f) G.-L. Zhao, J. Vesely, R. Rios, I.
Ibrahem, H. Sundꢂn, A. Cꢄrdova, Adv. Synth. Catal.
2008, 350, 237; g) R. Dodda, J. J. Goldman, T. Mandal,
C.-G. Zhao, G. A. Broker, E. R. T. Tiekink, Adv. Synth.
Catal. 2008, 350, 537.
[8] a) M. Sani, G. Candiani, F. Pecker, L. Malpezzi, M.
Zanda, Tetrahedron Lett. 2005, 46, 2393; b) D. Enders,
Z.-X. Chen, Lett. Org. Chem. 2005, 2, 156; c) N. M.
Karimova, A. A. Glazkov, A. V. Ignatenko, A. F. Kolo-
miets, Russ. Chem. Bull. Int. Ed. 2003, 52, 1621; d) T.
Kitazume, K. Murata, J. Fluorine Chem. 1988, 39, 75.
[9] X.-Q. Dong, X. Fang, C.-J. Wang, Org. Lett. 2011, 13,
4426.
[3] a) A. Nudelman, The Chemistry of Optically Active
Sulfur Compounds, Gordon and Breach, New York,
1984; b) Sulphur-Containing Drugs and Related Organ-
ic Compounds, (Ed.: L. A. Damani), Wiley, New York,
1989; c) Organosulfur Chemistry in Asymmetric Synthe-
sis, (Eds.:T. Toru, C. Bolm), Wiley-VCH, Weinheim,
Germany, 2008; d) Chiral Sulfur Ligands: Asymmetric
Catalysis, (Ed.: H. Pellissier), Cambridge, U.K, 2009;
e) J. Clayden, P. MacLellan, Beilstein J. Org. Chem.
2011, 7, 582.
[4] For a comprehensive review on asymmetric sulfa-Mi-
chael additions, see: D. Enders, K. Lꢃttgen, A. A.
Narine, Synthesis 2007, 959.
[5] For examples of organometallic-catalyzed Michael ad-
dition of thiols, see: a) K. Nishimura, M. Ono, Y. Na-
gaoka, K. Tomioka, J. Am. Chem. Soc. 1997, 119,
12974; b) E. Emori, T. Arai, H. Sasai, M. Shibasaki, J.
Am. Chem. Soc. 1998, 120, 4043; c) S. Kanemasa, Y.
Oderaotoshi, E. Wada, J. Am. Chem. Soc. 1999, 121,
8675; d) E. Emori, T. Iida, M. Shibasaki, J. Org. Chem.
1999, 64, 5318; e) S. Kobayashi, C. Ogawa, M. Kawa-
mura, M. Sugiura, Synlett 2001, 983; f) K. Matsumoto,
A. Watanabe, T. Uchida, K. Ogi, T. Katsuki, Tetrahe-
dron Lett. 2004, 45, 2385; g) A. M. M. Abe, S. J. K. Sau-
erland, A. M. P. Koskinen, J. Org. Chem. 2007, 72,
5411; h) M. Kawatsura, Y. Komatsu, M. Yamamoto, S.
Hayase, T. Itoh, Tetrahedron 2008, 64, 3488; i) A.
[10] a) J. Leroy, N. Fischer, C. Wakselman, J. Chem. Soc.
Perkin Trans. 1 1990, 1281; b) B. C. Hamper, Org.
Synth. 1998, 49, 1430.
[11] B.-L. Wang, F. Yu, X.-L. Qiu, Z. Jiang, F.-L. Qing, J.
Fluorine Chem. 2006, 127, 580.
[12] For selected examples, see; a) D. A. Evans, K. R. Fan-
drick, H.-J. Song, K. A. Scheidt, R. Xu, J. Am. Chem.
Soc. 2007, 129, 10029; b) M. P. Sibi, K. Itoh, J. Am.
Chem. Soc. 2007, 129, 8064; c) S. Matsunaga, T. Kinosh-
ita, S. Okada, S. Harada, M. Shibasaki, J. Am. Chem.
Soc. 2004, 126, 7559; d) J. K. Myers, E. N. Jacobsen, J.
Am. Chem. Soc. 1999, 121, 8959; e) A. Baschieri, L.
Bernardi, A. Ricci, S. Suresh, M. P. A. Adamo, Angew.
Chem. 2009, 121, 9506; Angew. Chem. Int. Ed. 2009, 48,
9342; f) D. A. Evans, J. S. Johnson, J. Am. Chem. Soc.
1998, 120, 4895; g) D. A. Evans, K. R. Fandrick, H.-J.
Song, J. Am. Chem. Soc. 2005, 127, 8942.
[13] For reviews on bifunctional organocatalysis, see:
a) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701; b) Y.
Takemoto, Org. Biomol. Chem. 2005, 3, 4299; c) T.
Marcelli, J. H. V. Maarseveen, H. Hiemstra, Angew.
Chem. 2006, 118, 7658; Angew. Chem. Int. Ed. 2006, 45,
7496; d) S. J. Connon, Chem. Eur. J. 2006, 12, 5418;
e) A.-G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107,
5713; f) H. Miyabe, Y. Takemoto, Bull. Chem. Soc. Jpn.
2008, 81, 785.
ˇ
Badoiu, G. Bernardinelli, C. Besnard, E. P. Kꢃndig,
Org. Biomol. Chem. 2010, 8, 193.
[6] For examples of organocatalyzed asymmetric sulfa-Mi-
chael addition, see: a) H. Hiemstra, H. Wynberg, J.
Am. Chem. Soc. 1981, 103, 417; b) P. McDaid, Y. G.
Chen, L. Deng, Angew. Chem. 2002, 114, 348; Angew.
Chem. Int. Ed. 2002, 41, 338; c) T. C. Wabnitz, J. B.
Spencer, Org. Lett. 2003, 5, 2141; d) B.-J. Li, L. Jiang,
M. Liu, Y.-C. Chen, L.-S. Ding, Y. Wu, Synlett 2005,
603; e) H. Li, J. Wang, L.-S. Zu, W. Wang, Tetrahedron
Lett. 2006, 47, 2585; f) Y. Liu, B.-F. Sun, B.-M. Wang,
M. Wakem, L. Deng, J. Am. Chem. Soc. 2009, 131, 418;
g) K. Kimmel, M. T. Robak, J. A. Ellman, J. Am.
Chem. Soc. 2009, 131, 8754; h) N. K. Rana, S. Selvaku-
mar, V. K. Singh, J. Org. Chem. 2010, 75, 2089; i) D.
Enders, K. Hoffman, Eur. J. Org. Chem. 2009, 1665;
j) J. Sun, G. C. Fu, J. Am. Chem. Soc. 2010, 132, 4568;
k) D. Leow, S. Lin, S. K. Chittimlla, X. Fu, C.-H. Tan,
Angew. Chem. 2008, 120, 5723; Angew. Chem. Int. Ed.
2008, 47, 5641; l) Y.-H. Hui, J. Jiang, W.-T. Wang, W.-L.
Chen, Y.-F. Cai, L.-L. Lin, X.-H. Liu, X.-M. Feng,
Angew. Chem. 2010, 122, 4386; Angew. Chem. Int. Ed.
2010, 49, 4290; m) X.-F. Wang, Q.-L. Hua, Y. Cheng,
X.-L. An, Q.-Q. Yang, J.-R. Chen, W.-J. Xiao, Angew.
Chem. 2010, 122, 8557; Angew. Chem. Int. Ed. 2010, 49,
8379; n) X. Tian, C. Cassani, Y. Liu, A. Moran, A. Ura-
kawa, P. Galzerano, E. Arceo, P. Melchiorre, J. Am.
Chem. Soc. 2011, 133, 17934.
[14] C. Kashima, H. Harada, I. Kita, I. Fukuchi, A. Hosomi,
Synthesis 1994, 61.
[15] a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem.
Soc. 2003, 125, 12672; b) T. Okino, Y. Hoashi, T. Furu-
kawa, X. Xu, Y. Takemoto, J. Am. Chem. Soc. 2005,
127, 119; c) B. Vakulya, S. Varga, A. Csꢅmpai, T. Soꢄs,
Org. Lett. 2005, 7, 1967; d) T. Marcelli, J. H. van Maar-
seveen, H. Hiemstra, Angew. Chem. 2006, 118, 7658;
Angew. Chem. Int. Ed. 2006, 45, 7496; e) S. J. Connon,
Chem. Commun. 2008, 2499.
[16] a) C.-J. Wang, Z.-H. Zhang, X.-Q. Dong, X.-J. Wu,
Chem. Commun. 2008, 1431; b) Z.-H. Zhang, X.-Q.
Dong, D. Chen, C.-J. Wang, Chem. Eur. J. 2008, 14,
8780; c) C.-J. Wang, X.-Q. Dong, Z.-H. Zhang, Z.-Y.
1146
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1141 – 1147

Highly Efficient Catalytic Asymmetric Sulfa-Michael Addition of Thiols
Xue, H.-L. Teng, J. Am. Chem. Soc. 2008, 130, 8606;
d) X.-Q. Dong, H.-L. Teng, C.-J. Wang, Org. Lett. 2009,
11, 1265; e) X.-Q. Dong, H.-L. Teng, M.-C. Tong, H.
Huang, H.-Y. Tao, C.-J. Wang, Chem. Commun. 2010,
46, 6840.
reogenic center was assigned as the S configuration,
see: B. I. Usachev, M. A. Shafeev, V. Y. Sosnovskikh,
Russ. Chem. Bull. Int. Ed. 2006, 55, 523.
[20] a) A. Hamza, G. Schubert, T. Soꢄs, I. Pꢅpai, J. Am.
Chem. Soc. 2006, 128, 13151; b) T.-Y. Liu, J. Long, B.-J.
Li, L. Jiang, R. Li, Y. Wu, L.-S. Ding, Y.-C. Chen, Org.
Biomol. Chem. 2006, 4, 2097; c) F.-Z. Peng, Z.-H. Shao,
B.-M. Fan, H. Song, G.-P. Li, H.-B. Zhang, J. Org.
Chem, 2008, 73, 5202; d) A.-D. Lu, P. Gao, Y. Wu, Y.-
M. Wang, Z.-H. Zhou, C.-C. Tang, Org. Biomol. Chem.
2009, 7, 3141; e) X.-X. Jiang, G. Zhang, D. Fu, Y.-M.
Cao, F.-F. Shen, R. Wang, Org. Lett. 2010, 12, 1544.
[17] No racemization or retro-Michael addition occurred
under the optimal reaction conditions, which implied
the moderate ee for benzyl mercaptan was caused by
the poor stereoselectivity of alkyl thiol.
[18] F. Zhang, Z.-J. Liu, J.-T. Liu, Tetrahedron 2010, 66,
6864.
[19] Racemic syn-2-trifluoromethylthiochroman-4-ol 9aa is
a known compound, hence the second generated ste-
Adv. Synth. Catal. 2012, 354, 1141 – 1147
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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