Organocatalytic asymmetric domino sulfa-Michael-aldol reactions of 2-mercaptobenzaldehyde with α,β-unsaturated N-acylpyrazoles for the construction of thiochromane

Article abstract of DOI:10.1039/c2cc31891a

An efficient protocol for the direct construction of bioactive thiochromanes was developed via a catalytic asymmetric cascade sulfa-Michael-aldol reaction of 2-mercaptobenzaldehyde with α,β- unsaturated N-acyl imides. The key to the present methodology is introducing a pyrazole moiety as H-bond acceptor, which allowed for better organization and activation and hence higher enantioselectivity.

Full text of DOI:10.1039/c2cc31891a

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Chemical Communications
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Volume 48 | Number 58 | 25 July 2012 | Pages 7221–7320
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Chun-Jiang Wang et al.
Organocatalytic asymmetric domino sulfa-Michael–aldol reactions of 2-mercaptobenzaldehyde with
α,β-unsaturated N-acylpyrazoles for the construction of thiochromane

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Cite this: Chem. Commun., 2012, 48, 7238–7240
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Organocatalytic asymmetric domino sulfa-Michael–aldol reactions of
2-mercaptobenzaldehyde with a,b-unsaturated N-acylpyrazoles for the
construction of thiochromanew
a
a
Xiu-Qin Dong,z Xin Fang,z Hai-Yan Tao,a Xiang Zhoua and Chun-Jiang Wang*ab
Received 15th March 2012, Accepted 17th April 2012
DOI: 10.1039/c2cc31891a
An efficient protocol for the direct construction of bioactive
thiochromanes was developed via a catalytic asymmetric cascade
sulfa-Michael–aldol reaction of 2-mercaptobenzaldehyde with
a,b-unsaturated N-acyl imides. The key to the present methodology is
introducing a pyrazole moiety as H-bond acceptor, which allowed for
better organization and activation and hence higher enantioselectivity.
Owing to their biological relevance, several asymmetric methods
have been developed for the facile access to such compounds.7
Recently, Wang and co-workers reported an elegant approach
to the highly functionalized thiochromane derivatives with
excellent diastereoselectivity and enantioselectivity control
via an organocatalyzed cascade Michael–aldol reaction of
2-mercaptobenzaldehydes with a,b-unsaturated oxazolidineones.7b
In spite of the considerable advancements, the electron-
deficient alkene substrates are limited to b-aryl substituted
a,b-unsaturated oxazolidineones. Most recently, we have
developed a new and efficient protocol for the organocatalytic
asymmetric sulfa-Michael addition of thiols to easily-available
(E)-4,4,4-trifluoro-crotonoyl-pyrazole,8 which overcomes the
drawback of our previous work employing expensive (Z)-ethyl
4,4,4-trifluoro-crotonate as the Michael acceptor,9 in which
the pyrazole moiety10 was revealed to play a key role in
providing H-bond acceptor sites for better chelation and hence
accelerating reactions and improving enantioselectivities.
Encouraged by these achievements and stimulated by the
biological significance of the thiochromane derivatives,2 we
envisioned that switching the amide motif of unsaturated
N-acylimide from oxazolidineone to pyrazole might improve
its stereoselectivity control for the above-mentioned cascade
sulfa-Michael–aldol reaction. Herein, we report our investigations
on the use of N-acyl pyrazoles as H-bond accepters, providing
diverse thiochromanes with excellent stereoselectivities for both
b-aryl and b-alkyl substituted a,b-unsaturated N-acylimides.
To explore the feasibility of the enhanced synergistic activation
endowed by the pyrazole moiety, the cascade sulfa-Michael-aldol
reaction of 2-mercaptobenzaldehyde (1) with the easily-available
N-pyrazole crotonamide (2a) bearing a methyl group at the
b-position was performed in DCM with bifunctional amine–
thiourea catalysts11,12 (Fig. 2), and the representative results
are summarized in Table 1. Amine–thioureas I developed in
this lab9,13 were revealed to be highly efficient for this trans-
formation, and the reaction went to completion at room
temperature in less than 1 h (entries 1–4). However, the desired
adduct 3a was formed in unsatisfied diastereoselectivity with
moderate to good enantioselectivity for the major diastereomer.
Some other commonly used amine–thiourea catalysts were then
evaluated to further improve the stereoselectivities of this
process. To our delight, amine–thioureas III–VI derived from
cinchona alkaloids were revealed as the best catalysts in terms
Optically active chiral sulfur-containing compounds have impor-
tant applications in many areas of chemistry and biology, for
example, serving as antibiotics, as ligands or catalysts, and as
chiral auxiliaries.1 Highly functionalized thiochromanes, the sulfur
analogues of chromanes, are common structural motifs in many
pharmaceutical molecules and have been reported to possess
important biological activities.2 Some representative examples
are shown in Fig. 1. Thiochromane derivative A displays high
clinical efficacy in tamoxifen and fulvestrant resistant ER-positive
breast cancer patients.3 Compound B exhibited potent anti-HIV
activity.4 Compound C showed a mixed binding affinity to
dopamine D2, D3 and 5HTA1 receptors,5 whereas tertatolol D
and its analogue E were revealed to be 5HT1A receptor agonists
for use in depression, schizophrenia and Parkinson’s disease.6
Fig. 1 Examples of biologically active thiochromane derivatives.
a College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan 430072, China. E-mail: cjwang@whu.edu.cn;
Fax: +86-27-68754067
b State Key Laboratory of Elemento-organic Chemistry,
Nankai University, Tianjin, China 300071, China
w Electronic supplementary information (ESI) available: Experimental
section. CCDC 861217. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc31891a
z X.-Q. Dong and X. Fang contributed equally to this work.
c
7238 Chem. Commun., 2012, 48, 7238–7240
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Table 2 Asymmetric cascade sulfa-Michael–aldol reaction of 1 with
b-alkyl substituted a,b-unsaturated N-pyrazole-derived amide 2a
Entry
Alkyl
4
Yieldb (%)
drc
eec (%)
1
2
3
4
Me (2a)
Et (2b)
Pr (2c)
i-Pr (2d)
n-Pentyl (2e)
Cy (2f)
n-C8H17 (2g)
PhCH2CH2 (2h)
3a
3b
3c
3d
3e
3f
88
85
72
80
88
65
90
70
98 : 2
97 : 3
97 : 3
93 : 7
96 : 4
96 : 4
98 : 2
94 : 6
98
96
97
91
97
93
98
98
5
6d
7d
8
Fig. 2 Screened bifunctional amine–thiourea organocatalysts.
3g
3h
Table 1 Screening studies of cascade sulfa-Michael addition–aldol
reaction of 2-mercaptobenzaldehyde 1 with N-pyrazole crotonamide 2aa
a
All the reactions were carried out with 0.3 mmol of 1, 0.33 mmol of
b
2 in 1.0 mL of solvent. Isolated yield. Determined by HPLC
c
d
analysis. Carried out with 5 mol% catalyst at ꢀ10 1C.
at the b-position of the a,b-unsaturated N-acyl pyrazole all
have afforded high diastereoselectivity and excellent enantio-
selectivity (entries 1–3 and 5). The decreased reactivity for
a,b-unsaturated N-acylimide 2g with longer carbon chain
n-C8H17 at the b-position could be improved through increasing
the catalyst loading to 5 mol%, and the stereoselectivity is
maintained at a similar level (entry 7). To further probe the
steric effects of the substituent on this catalytic system, several
substrates with branched and sterically bulky substituents at
the b-position such as iso-propyl and cyclohexyl were employed,
and a slight decrease in the enantioselectivity was observed,
which was probably caused by the unfavored steric congestion
(entries 4 and 6).
Entry Catalyst
Solvent Time/h Yieldb (%) drc
eec (%)
1
I–a (10 mol%) DCM
1
1
1
1
1
1
1
1
1
4
7
4
4
4
4
4
88
85
79
90
88
90
89
86
83
89
90
90
90
91
89
90
75 : 25 73
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
I–b (10 mol%) DCM
I–c (10 mol%) DCM
I–d (10 mol%) DCM
II (10 mol%) DCM
III (10 mol%) DCM
IV (10 mol%) DCM
V (10 mol%) DCM
VI (10 mol%) DCM
III (1 mol%) DCM
III (0.5 mol%) DCM
III (1 mol%) Et2O
III (1 mol%) THF
III (1 mol%) EtOAc
III (1 mol%) PhMe
74 : 26 95
77 : 23 94
89 : 11 97
83 : 17 94
96 : 4
98
88 : 12 ꢀ92
92 : 8 ꢀ95
93 : 7
94 : 6
93 : 7
98 : 2
96 : 4
94 : 6
93 : 7
96
97
97
98
97
94
95
Encouraged by the excellent results for the challenging
b-alkyl substituted a,b-unsaturated N-acylimide, we then
investigated the cascade reaction of b-aryl substituted N-acyl
pyrazole to further investigate the generality of this methodology.
As shown in Table 3, a,b-unsaturated N-acylpyrazoles bearing
electron-rich (entries 2–5), electron-neutral (entries 1 and 10), and
electron-deficient groups (entries 6–9) on the aryl rings reacted
with 2-mercapto-benzaldehyde 1 smoothly, affording the
corresponding thiochromanes (3i–3s) in good yields
(85–94%), excellent diastereoselectivities (95 : 5–99 : 1) and
good enantioselectivities (95–99%) at 0 1C in ether within
4–7 h. The substitution pattern and electronic property of
the phenyl ring have little effect on the enantioselectivity.
It is noteworthy that comparable results were still achieved
for the sterically hindered ortho-substituted N-acylimide 2j
and 2n in terms of diastereo-/enantioselectivity and reacti-
vity (entries 2 and 6). Additionally, the heteroaromatic sub-
stituted N-acylpyrazole 2s was also a viable substrate as
2-naphthylaldehyde derived N-acylpyrazole 2r, affording
the corresponding product with 95 : 5 dr and 95% ee
(entries 10–11).
V (1 mol%)
Et2O
95 : 5 ꢀ93
a
All the reactions were carried out with 0.3 mmol of 1, 0.33 mmol of 2a
b
in 1.0 mL of solvent. Isolated yield. Determined by HPLC analysis.
c
of yields and stereoselectivities (entries 6–9). Subsequently,
catalyst III was chosen for further optimization of the reaction
conditions. A comparable result was still achieved when
catalyst loading was reduced to 1 mol% (entry 10). Further
reducing the catalyst loading to 0.5 mol% showed that high
yield and enantioselectivity remained albeit with a little longer
reaction time (entry 11). A study of the reaction with 1 mol%
catalyst III in various solvents identified that ether was the
best solvent (entry 12). Of note is that cinchonine-derived
thiourea III and cinchonidine-derived thiourea V as catalysts
provided access to the opposite enantiomer of the cycloadduct
with excellent diastereoselectivity and enantioselectivity (entry 16).
In the presence of 1 mol% of catalyst III in ether at 0 1C, the
cascade sulfa-Michael–aldol reaction of 2-mercaptobenzaldehyde
with various b-alkyl substituted a,b-unsaturated N-acyl
pyrazoles was carried out to test the generality of the reaction.
As shown in Table 2, substrates with a primary n-alkyl substituent
such as methyl, ethyl, n-propyl, n-pentyl, or a phenethyl group
The optically active adducts containing three tertiary stereo-
genic centers can be readily transformed into a synthetically
useful compound as exemplified in Scheme 1. The corre-
sponding chiral b-hydroxyl carboxylic acid derivative 4a
can be easily obtained through cleavage of the pyrazole
c
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Table 3 Asymmetric cascade sulfa-Michael–aldol reaction of 1 with
b-aryl substituted a,b-unsaturated N-pyrazole-derived amide (2)a
various a,b-unsaturated N-acylimide bearing pyrazole moieties,
which provided H-bond acceptor sites for better chelation and
asymmetric induction, leading to excellent diastereoselectivity and
enantioselectivity for both b-aryl and b-alkyl a,b-unsaturated
N-acylimide.
This work was supported by NSFC (20972117, 21172176),
IRT1030, NCET-10-0649, the Fundamental Research Funds
for the Central Universities, 973 (2011CB808600), and Large-
scale instrument and equipment sharing foundation of Wuhan
University.
Entry
Ar
4
Yieldb (%)
drc
eec,d (%)
1
2
3
4
5
6
7
8
Ph (2i)
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
87
85
88
89
86
90
92
90
94
87
91
99 : 1
98 : 2
97 : 3
98 : 2
97 : 3
97 : 3
95 : 5
98 : 2
98 : 2
97 : 3
95 : 5
99
99
99
98
97
97
98
99
97
99
95
o-Me-Ph (2j)
m-Me-Ph (2k)
p-Me-Ph (2l)
p-MeO-Ph (2m)
o-Cl-Ph (2n)
m-Cl-Ph (2o)
p-Cl-Ph (2p)
p-Br-Ph (2q)
2-Naphthyl (2r)
2-Furyl (2s)
Notes and references
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Scheme 2 Control experiments to evaluate the role of the amide moiety
under the optimized reaction conditions (pyrazole vs. oxazolidineone).
moiety14 and then esterification without loss of diastereo/
enantiomeric excess.
In order to evaluate the role of the pyrazole motif played in
this domino sulfa-Michael–aldol reaction, control experiments
were carried out under the optimized reaction conditions
(Scheme 2): for a,b-unsaturated N-acylimide bearing methyl
at the b-position, replacing the oxazolidineone group with the
pyrazole group led to a superior level of enantioselectivity and
diastereoselectivity with the same sense of diastereoselectivity,
which demonstrated that introducing the pyrazole moiety into
the crotonamide plays a significant role in providing H-bond
acceptor sites for better organization and chelation and hence
delivering higher enantioselectivity compared with that of
employing oxazolidineone as the corresponding amide moiety.
In summary, we have developed an efficient protocol for the
direct construction of highly substituted and biologically active
thiochromanes via an organocatalyzed asymmetric cascade
sulfa-Michael–aldol reaction of 2-mercaptobenzaldehyde with
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c
7240 Chem. Commun., 2012, 48, 7238–7240
This journal is The Royal Society of Chemistry 2012