Enantioselective sulfonation of enones with sulfonyl imines by cooperative N-heterocyclic-carbene/thiourea/tertiary-amine multicatalysis

Article abstract of DOI:10.1002/anie.201305023

Many hands make light work: In an organocatalytic asymmetric sulfonation of enones, the activation of a sulfonyl imine by an N-heterocyclic carbene (NHC) catalyst led to the release of a sulfinic anion, which underwent nucleophilic addition to the enone. The enantioselectivity of the process was controlled by a chiral thiourea/amine co-catalyst through anion recognition and hydrogen-bonding interactions. Tol=p-tolyl. Copyright

Full text of DOI:10.1002/anie.201305023

Angewandte
Chemie
DOI: 10.1002/anie.201305023
Asymmetric Synthesis
Enantioselective Sulfonation of Enones with Sulfonyl Imines by
Cooperative N-Heterocyclic-Carbene/Thiourea/Tertiary-Amine
Multicatalysis**
Zhichao Jin, Jianfeng Xu, Song Yang,* Bao-An Song, and Yonggui Robin Chi*
Sulfones are applied widely as versatile synthetic building
blocks[1] and as biologically active agents for drugs.[2] Achiral
and racemic sulfones can be synthesized by a number of
methods, including the oxidation of sulfides or sulfoxides,[3]
nucleophilic displacement by a sulfinic acid or its salt,[4] and
reactions of sulfonyl halides with activated nucleophiles, such
as organolithium species and Grignard reagents.[5] In contrast
to the relatively well studied synthesis of achiral/racemic
sulfones, asymmetric catalytic approaches for direct access to
optically enriched sulfones are much less developed. Success
in this area has mainly come from the sulfonation of allylic
compounds in the presence of Pd(Ir) catalysts with chiral
ligands.[6] Herein we report the first organocatalytic enantio-
Scheme 1. Enantioselective catalytic sulfonation of enones. Tol=
p-tolyl.
selective sulfonation of a,b-unsaturated ketones (Scheme 1).
In this reaction, two organic catalysts containing three
catalytic moieties [an N-heterocyclic carbene (NHC),[7]
a thiourea, and a tertiary amine] operate in a cooperative
combinations of these additives led to no detectable forma-
tion of product 3a (Table 1, entry 1). We then accidentally
found that under the catalysis of the NHC precatalyst A1 and
DABCO as a base, benzaldehyde N-tosylimine (1a) could be
converted into the sulfonation product 3a in 14% yield
(Table 1, entry 2). No formation of the product was observed
in the presence of only A1 or DABCO (Table 1, entry 3). Hou
and co-workers previously observed the generation of sulfinic
anions from tosylimines under NHC catalysis.[10] In further
studies, we found that the chiral NHC catalyst A2 was more
effective and gave 3a in acceptable 66% yield (Table 1,
entry 4). Under various conditions studied, (e.g., with differ-
ent solvents), chiral NHC catalysts, such as A2, promoted the
transformation with no enantioselectivity (Table 1, entry 4;
see the Supporting Information for more examples).
manner.[8] Specifically, the NHC-catalyzed activation of
[10]
a sulfonylimine[9] with N S bond cleavage
generates
À
a sulfinic anion intermediate as a nucleophile. Through
noncovalent interactions and anion recognition by the
chiral thiourea[11]/tertiary amine cocatalyst, the sulfinic
anion is delivered to enones in an enantioselective manner
(Scheme 1).
We started by identifying sulfonation reagents and
catalysts for the racemic sulfonation of enone 2a under mild
conditions. The use of p-toluenesulfinic acid sodium salt
under various conditions in the presence of a tertiary amine,
an NHC, a thiourea/tertiary-amine bifunctional catalyst, or
[*] Z. Jin, Dr. J. Xu, Prof. Dr. Y. R. Chi
The absence of enantioselectivity with chiral NHC
catalysts suggests that the NHC is not covalently bonded to
the substrates when the Michael addition of the sulfinic-anion
equivalent to the enone occurs. In other words, the sulfinic
anion is probably released from the imine substrate before its
addition to the enone (Scheme 1). Mechanistically, the direct
deprotonation of the imine by a base (such as DABCO or
NHC) to release the sulfinic anion (Scheme 2a) is unlikely, as:
1) in the absence of an NHC, none of the product 3a was
obtained when a variety of bases were used; and 2) the acidity
of the imine hydrogen atom is much weaker than that of the
hydrogen atom on the triazolium ring of the NHC precatalyst,
as evidenced by H/D-exchange experiments in the presence
of D2O (see the Supporting Information). Deprotonation of
a “weak acid” (the imine) by a weak base (the free carbene) is
unfavorable. A reasonable pathway (Scheme 2b) is a multi-
step process involving an analogous Breslow intermediate
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: robinchi@ntu.edu.sg
Prof. Dr. S. Yang, Prof. Dr. B.-A. Song
State Key Laboratory Breeding Base of Green Pesticide and
Agricultural Bioengineering, Key Laboratory of Green Pesticide and
Agricultural Bioengineering, Ministry of Education, Guizhou Uni-
versity, Huaxi District, Guiyang 550025 (China)
E-mail: jhzx.msm@gmail.com
[**] This research was supported by the Singapore National Research
Foundation, the Singapore Economic Development Board (EDB),
GlaxoSmithKline (GSK), and Nanyang Technological University. S.Y.
and B.-A.S. gratefully acknowledge the financial support of the
National Key Program for Basic Research (No. 2010CB 126105) and
the National Natural Science Foundation of China (No. 21132003).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305023.
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Table 1: Optimization of the reaction conditions.[a]
formed between the imine and the NHC[12] to eventually
generate the sulfinic anion and release an equivalent of
phenyl nitrile (PhCN, isolated experimentally). NHC–imine
adducts similar to I (Scheme 2b) were previously observed in
NHC-catalyzed reactions studied by the research groups of
Rovis and Ye.[12a,b] Our attempts to detect intermediate I were
unsuccessful, which suggests that the process to release the
sulfinic anion and PhCN from I is facile.
Entry
Conditions
Yield [%][b]
e.r.[c]
1
2
p-TolSO2Na (no 1a), various conditions
A1, DABCO
0
14
–
–
Our failure to control the enantioselectivity of the
reaction with NHC catalysts prompted us to explore other
catalytic approaches for asymmetric induction. Hypotheti-
cally, it would be possible to control the enantioselectivity
through interactions with the enone and/or the catalytically
generated sulfinic anion. Thioureas are known for ion
recognition of anions and for noncovalent interactions with
electrophiles (such as imines and ketones), as pioneered by
Jacobsen and Sigman as well as others.[11,13] Since our reaction
involves both an anionic nucleophile and an a,b-unsaturated
ketone electrophile, thiourea cocatalysts were chosen for
further studies. Additionally, in our NHC-catalyzed step,
a base catalyst is needed to deprotonate the triazolium NHC
precatalyst. Therefore, a tertiary amine was incorporated as
a basic moiety into the thiourea cocatalyst to generate
a thiourea/tertiary-amine bifunctional catalyst.
3
4
5
6
7
8
9
10
11
12
13
only A1 or DABCO
A2, DABCO
A1, B1
A2, B1
A2, quinine (9-epi-B2)
A2, B3
0
66
18
45
36
38
79
68
–
50:50
55:45
52:48
42:58
70:30
73:27
88:12
96:4
95:5
57:43
A2, B4
A2, B5 (40 mol%)
A2, B5 (10 mol%), 08C, 72 h[d]
ent-A2,[e] B5 (10 mol%), 08C, 72 h[d]
achiral A1, B5 (40 mol%), RT, 12 h
67
65
ca. 5
[a] General conditions (unless otherwise specified): 1a (0.10 mmol), 2a
(0.05 mmol), NHC (20 mol%), base (40 mol%), toluene (0.5 mL), room
temperature (248C), 12 h. [b] Yield of the isolated product. [c] The
enantiomeric ratio was determined by HPLC on a chiral phase. [d] The
reaction was carried out with 2 mL of toluene (0.025m). [e] The
enantiomer of A2 was used. DABCO=1,4-diazabicyclo[2.2.2]octane.
When we used the cinchona-alkaloid-type compound B1
as a chiral base with the achiral NHC precatalyst A1, the
reaction gave product 3a with a low but encouraging
enantiomeric ratio of 55:45 (Table 1, entry 5). This result
suggested that the conjugate acid of B1 (formed by the
deprotonation of A1 to give the free carbene) might interact
with enone 2a and/or the sulfinic anion to cause asymmetric
induction. Since the reaction yields were low with achiral
NHC catalysts such as A1 (e.g., 18% yield, Table 1, entry 5),
we used A2 for further studies (Table 1, entries 6–12). With
the chiral base B1, the reaction gave 3a in 45% yield with e.r.
52:48 (Table 1, entry 6). The use of quinine (9-epi-B2) led to
3a in 36% yield with e.r. 42:58 (Table 1, entry 7). When
a thiourea moiety was introduced into the chiral base to give
the thiourea/tertiary-amine bifunctional cocatalyst B3, the
corresponding catalytic reaction afforded 3a in similar yield
(38%) but with a significantly higher enantiomeric ratio
(70:30; Table 1, entry 8). This result clearly showed the
beneficial effect of the use of thiourea/tertiary-amine coca-
talysts. By the further introduction of an additional tertiary
amino group into the thiourea-based catalyst (e.g. to give B4
and B5), both the yield and the enantioselectivity of the
reaction could be improved (Table 1, entries 9 and 10). Of
several promising thiourea/tertiary-amine catalysts (see the
Supporting Information), B5 was finally found to be the most
efficient: this cocatalyst mediated the formation of 3a in 67%
yield with e.r. 96:4 (Table 1, entry 11). The use of the opposite
enantiomer of the NHC precatalyst A2 under otherwise
identical conditions led to a similar result (65% yield, e.r.
95:5; Table 1, entry 12), which again confirms that the
chirality of the NHC has no apparent influence on the
enantioselectivity of the reaction.
Although the chiral NHC catalyst alone showed no
asymmetric induction, the structure of the NHC influenced
the enantioselectivity induced by the chiral thiourea/tertiary-
Scheme 2. Postulated pathways for the NHC-mediated generation of
a sulfinic anion from an imine.
2
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amine cocatalyst. For example, with the thiourea cocatalyst
B5, the use of NHC precatalyst A1 gave 3a with an
enantiomeric ratio of just 57:43 (Table 1, entry 13), whereas
an enantiomeric ratio of 88:12 was found when the NHC A2
was used under otherwise identical conditions (Table 1,
entry 10; see the Supporting Information for more examples).
These results suggested that the nucleophilic sulfinic anion
was not delivered to enones as an isolated species. Instead,
electrostatic interactions between the negatively charged
sulfinic anion and the positively charged triazolium NHC
precatalyst[14] also played a role in the asymmetric induction.
We next examined the scope of the reaction under the
optimized conditions (Table 2). Chalcone-type enones with
different aromatic substituents reacted smoothly to afford the
corresponding g-ketosulfones in good yields with excellent
under the standard conditions (Table 2, entries 18–20). We
finally found that the combined use of the NHC catalyst A3
and the bifunctional cocatalyst B6 in chloroform provided
acceptable results (Scheme 3). Much improved enantioselec-
tivity was observed for the alkyl-substituted enones with these
Table 2: Examples of the sulfonation reaction.[a]
Entry
1
R1
R2
3
Yield [%] e.r.
1[b]
2[c]
3
4
5
6
7
8
1a Ph
1a 4-MeOC6H4 Ph
Ph
3a
3b
3c
3d
3e
3 f
69
60
76
49
54
84
64
79
77
57
52
63
96:4
90:10
89:11
95:5
94:6
>99:1
97:3
97:3
>99:1
91:9
99:1
95:5
1a 3-NO2C6H4
1a 4-ClC6H4
1a 4-MeC6H4
1a 4-NO2C6H4
1a Ph
1a Ph
1a Ph
1a Ph
1a 4-ClC6H4
1a Ph
1b Ph
1c Ph
1d Ph
1e Ph
1a COOEt
1a Ph
1a nBu
Ph
Ph
Ph
Ph
4-MeOC6H4 3g
4-ClC6H4
4-BrC6H4
2-naphthyl
4-ClC6H4
2-furyl
Ph
Ph
Ph
Ph
Ph
3h
3i
3j
3k
3l
3m 52
3n
3o
3p
3q
3r
9[b]
10
11
12
13
14
15
16[c]
17
18[c]
19
20
96:4
92:8
67
44
13
50
30
58
86
73:27
93:7
50:50
77:23
60:40
50:50
Me
Me
Ph
Scheme 3. Examples of the sulfonation of aliphatic enones (see the
Supporting Information for detailed reaction conditions). [a] Yields and
enantiomeric ratios given in the parenthesis are for reactions carried
out under the conditions described in Table 1, entry 11. [b] The
reaction was carried out without molecular sieves (MS). Ts=
p-toluenesulfonyl.
3s
4a
1a Me
[a] General conditions (unless otherwise specified): as in Table 1,
entry 11. [b] The reaction was carried out on a 0.5 mmol scale (with
respect to 2). [c] The reaction was carried out at room temperature
(248C) for 24 h.
new catalysts and reaction conditions (e.g., for product 4a, e.r.
83:17, as opposed to e.r. 50:50 under the earlier conditions).
When enone substrates with alkyl substituents on both the b
and the carbonyl carbon atom were used, no product
formation was observed. The use of such alkyl enones in
many asymmetric catalytic reactions remains a challenge yet
to be addressed.[15]
enantioselectivity (Table 2, entries 1–14). When the tolyl
group of N-tosylimine 1a was replaced with an electron-
withdrawing 4-NO2C6H4 group (Table 2, entry 16), the reac-
tion of this substrate 1e proceeded in low yield even at room
temperature. The sterically smaller N-mesylimine 1d could
also be used as a substrate to give the corresponding product
3o in 44% yield with e.r. 73:27 (Table 2, entry 15). Race-
mization was clearly observed when the R1 group at the
b position of the enone was an ester group (Table 2, entry 17).
When the R1 and/or R2 group on the enone was an
aliphatic substituent, the corresponding product was obtained
in moderate to good yield but with lower enantioselectivity
The ketone moiety of the chiral g-ketosulfone 3a[16] could
be reduced stereoselectively with minimal erosion of the
optical purity (Scheme 4).[17] The resulting alcohol 5a was
transformed into cyclopropane 6a in good yield and with
good enantioselectivity.[17] The cyclopropane is a common
motif in pharmaceuticals and natural products.[18]
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Scheme 4. Further transformations of the chiral sulfone 3a. Ms=
methanesulfonyl, TEA=triethylamine.
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In summary, we have developed the first organocatalytic
enantioselective synthesis of b-sulfonyl ketones. The sulfinic
anion was generated from sulfonyl imines under NHC
catalysis. The enantioselectivity of the transformations was
controlled by the use of noncovalent thiourea/tertiary-amine
cocatalysts. We expect that this use of noncovalent cocatalysts
to control stereoselectivity can be extended to other NHC-
catalyzed reactions. Evaluation of the chiral sulfone products
for biological activity and further mechanistic investigations
are in progress.
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Received: June 11, 2013
Revised: August 30, 2013
Published online: && &&, &&&&
Keywords: enantioselective sulfonation · Michael addition ·
.
À
N S bond cleavage · organocatalysis · a,b-unsaturated ketones
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Sayed, M. S. Wadia, J. Chem. Res. Synop. 2001, 362.
´
´
[17] J. Skarz˙ewski, R. Siedlecka, E. Wojaczynska, M. Zielinska-
Błajet, Tetrahedron: Asymmetry 2002, 13, 2105.
[18] a) C. J. Thibodeaux, W. Chang, H. Liu, Chem. Rev. 2012, 112,
1681; b) A. K. Kumar, Int. J. Pharm. Pharm. Sci. 2013, 5, 467.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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Angewandte
Communications
Communications
Asymmetric Synthesis
Z. Jin, J. Xu, S. Yang,* B.-A. Song,
Y. R. Chi*
&&&& — &&&&
Enantioselective Sulfonation of Enones
with Sulfonyl Imines by Cooperative N-
Heterocyclic-Carbene/Thiourea/Tertiary-
Amine Multicatalysis
Many hands make light work: In an
organocatalytic asymmetric sulfonation
of enones, the activation of a sulfonyl
imine by an N-heterocyclic carbene
(NHC) catalyst led to the release of
a sulfinic anion, which underwent nucle-
ophilic addition to the enone. The enan-
tioselectivity of the process was con-
trolled by a chiral thiourea/amine coca-
talyst through anion recognition and
hydrogen-bonding interactions. Tol=p-
tolyl.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!