Hydrogen-bond-mediated cascade reaction involving chalcones: Facile synthesis of enantioenriched trisubstituted tetrahydrothiophenes

Article abstract of DOI:10.1021/ol2034959

A bifunctional squaramide catalyzed sulfa-Michael/aldol cascade reaction between 1,4-dithiane-2,5-diol and chalcones with a low catalyst loading has been developed. Trisubstituted tetrahydrothiophenes with three contiguous stereogenic centers are obtained

Full text of DOI:10.1021/ol2034959

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1090–1093
Hydrogen-Bond-Mediated Cascade
Reaction Involving Chalcones: Facile
Synthesis of Enantioenriched
Trisubstituted Tetrahydrothiophenes
Jun-Bing Ling, Yu Su, Hai-Liang Zhu, Guan-Yu Wang, and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry and College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou, 730000, P. R. China
xupf@lzu.edu.cn
Received December 31, 2011
ABSTRACT
A bifunctional squaramide catalyzed sulfa-Michael/aldol cascade reaction between 1,4-dithiane-2,5-diol and chalcones with a low catalyst loading
has been developed. Trisubstituted tetrahydrothiophenes with three contiguous stereogenic centers are obtained in a highly stereocontrolled
manner. Additionally, a remarkable temperature effect on reaction efficiency was observed and a synthetically potential gram-synthesis was also
conducted.
The development of organocatalyzed cascade reactions1
attracted continuing efforts owing to their ability toward
facile and stereoselective assembly of complex and diverse
molecules as well as their operational simplicity and en-
vironmental friendliness. Based on the covalent enamine
or iminium ion intermediate2 generated in situ from car-
bonyl compounds and chiral amines, substantial progress
has been made in the realm of amine-catalyzed cascade
transformations. Meanwhile, by means of the H-bonding
interaction between the chiral catalyst and H-bond ac-
ceptors such as activated alkenes and imines, H-bond-
mediated cascade reactions are also extensively explored.3
Nevertheless, to our knowledge, there is no precedent for
noncovalent interaction mediated cascade reactions of
chalcones4 despite the fact that chalcones have been widely
used as Michael acceptors in H-bond-mediated single-step
transformations.5 Therefore, the design and development
of H-bond-mediated cascade reactions involving chal-
cones will largely extend the scope of current organocas-
cade reactions and holds great potential in the synthesis of
structurally diverse molecules (Scheme 1).
(2) For reviews, see: (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.;
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Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (d)
MacMillan, D. W. C. Nature 2008, 455, 304. For selected papers of
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r
10.1021/ol2034959
Published on Web 02/07/2012
2012 American Chemical Society

regarding their potential toward further synthetically and
biologically useful elaboration. Surprisingly, practical and
efficient approaches, especially catalytic asymmetric var-
iants to assemble this useful architecture, are rare.7 In view
of the importance of this class of molecules as well as the
lack of generality and efficiency to access these important
synthetic targets, the development of a new catalytic asym-
metric synthesis of polysubstituted tetrahydrothiophenes
is still in demand. As our group is working on the devel-
opment of novel and practical asymmetric cascade reac-
tions8 and inspired by the previous achievements in
H-bonding activation of chalcones toward nucleophilic
addition, herein we propose that the trisubstituted tetra-
hydrothiophenes 4 could be directly constructed from
commercially available 1,4-dithiane-2,5-diol 2 and chal-
cones 3 via a sulfa-Michael9/aldol cascade reaction with
suitable H-bond donor catalyst 1.
Scheme 1. Development of Hydrogen-Bond-Mediated Asym-
metric Cascade Reaction of Chalcones
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Figure 1. Bifunctional catalysts screened in this study.
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the same conditions in hopes of enhancing the enantioin-
duction, and the results are outlined in Table 1. To our
surprise, Deng’s catalyst 1b10 gave a nearly racemic pro-
duct (Table 1, entry 2) . Switching from 1b to bifunctional
thiourea 1c,11 1d,12 and 1eꢀ1f13 also led to poor stereo-
chemical induction (Table 1, entries 3ꢀ6). Inspired by a
recent success in squaramide catalysis,14 squaramide ter-
tiaryꢀamine bifunctional catalysts 1gꢀ1h were tested
(Table 1, entries 7ꢀ9). Gratifyingly, improved results in
terms of reactivity and selectivity were obtained and
quinine-derived catalyst 1h was identified as the best
catalyst among those screened. Subsequently, a brief
survey of solvents revealed that toluene was better than
other solvents tested (Table 1, entries 10ꢀ15). Improv-
ing the catalyst loading to 20 mol % did not influence the
selectivity evidently (Table 1, entry 16). Lowering the
reaction temperature to 15 °C led to a slight decrease of
enantioselectivity, yet a longer reaction time was re-
quired (Table 1, entry 17). To enhance the reaction
efficiency, we conducted the reaction at elevated tem-
perature (40 °C) (Table 1, entries 18ꢀ20). An improve-
ment of selectivity of 88% ee was obtained at this
temperature when 5 mol % catalyst was used. Further
reducing the catalyst loading to 1 mol % gave 89% ee
while in this case the reaction cannot be completed in a
12 h period. The best result was obtained with the
reaction was performed at 60 °C and the catalyst loading
was maintained at 1 mol % (81% yield, >20:1 dr, 89% ee)
(Table 1, entry 21).
The scope of a current sulfa-Michael/aldol cascade
reaction between 1,4-dithiane-2,5-diol 2 and vaious chal-
cones 3 was next explored under the established condi-
tions. As summarized in Table 2, in all the cases, the
reaction proceeded smoothly affording the correspond-
ing trisubstituted tetrahydrothiophenes in generally
good yield and high levels of diastereo- and enantios-
electivity. The nature and the position of the substituents
of the phenyl ring of chalcones have no obvious influ-
ence on the enantioinduction, yet a little effect on the
yield (Table 2, entries 1ꢀ13). However, when the halo-
gented chalcones were used, the products were obtained
with decreased diastereoselectivity, possibly owing to a
retro-aldol process (Table 2, entries 4, 7ꢀ8, 11ꢀ12).
Notably, satisfying results are also achieved with the
chalcones bearing heteroaromatic rings (Table 2, entries
14ꢀ15).
Table 1. Optimization of the Reaction Conditions
a Unless otherwise noted, the reaction was carried out with 2
(0.3 mmol), 3a (0.2 mmol), and 1 (0.02 mmol) in dry toluene (1 mL) at rt.
b Isolated yield. c Determined by 1H NMR or HPLC analysis. d Deter-
mined by HPLC analysis. e 20 mol % catalyst was used. f The reaction
was conducted at 15 °C. g The reaction was conducted at 40 °C. h 5 mol %
catalyst was used. i 1 mol % catalyst was used. j The reaction was
conducted at 60 °C.
We were pleased to find that the model reaction of 1,4-
dithiane-2,5-diol 2 with chalcone 3a with 10 mol % quinine
1a (Figure 1) in toluene at 25 °C for 48 h proceeded as
anticipated furnishing the cyclic product 4a in satisfying
yield and diastereoselectivity, albeit low enantioselectivity
was observed (Table 1, entry 1). Then the effects of various
bifunctional H-bond donor catalysts were probed under
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In addition, cinnamaldehyde-derived dienone 5 can also
be utilized as a suitable reaction partner in the cascade
sulfa-Michale/aldol reaction to furnish the desired product
6 with high diastereo- and enantioselectivity while a 1,6
adduct was not observed. To demonstrate the potential
utility of this methodology, a gram-synthesis of 4c was
performed (Scheme 2). The reaction proceeded smoothly
affording the corresponding product in comparable yield
and slightly decreased stereoselectivity.
A plausible catalytic cycle of the current cascade reac-
tion is outlined in Scheme 3. The reaction could be initiated
via synergistic activation of both mercaptoacetaldehyde
and enone 3d by bifunctional squaramide to form
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S.-X.; Chem, F.-E. Adv. Synth. Catal. 2010, 352, 2137. (k) Hara, N.;
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1092
Org. Lett., Vol. 14, No. 4, 2012

Table 2. Scope of Sulfa-Michael/Aldol Cascade Reaction
Scheme 3. Proposed Catalytic Cycle for the Sulfa-Michael/
Aldol Cascade Reaction toward 4d
In summary, we have disclosed a chalcone-involved
sulfa-Michael/aldol cascade reaction furnishing tetrahy-
drothiophenes with three contiguous chiral centers in
generally good yield and high diastereo- and enantioselec-
tivity. Salient features of the present protocol include the
utilization of chalcones in the cascade reaction, effective
stereocontrol in multistereogenic formation, a relatively
low catalyst loading, and a remarkable temperature effect
upon reaction efficiency. The synthetic potential of this
chemistry was demonstrated by the functional diversity of
the products and a gram-scale synthesis. From a synthetic
standpoint, this study extends the scope of current
H-bond-mediated cascade reactions.
a Unless otherwise noted, the reaction was carried out with 2
(0.3 mmol), 3 (0.2 mmol), and 1h (0.002 mmol) in dry toluene (1 mL)
at 60 °C. b Isolated yield. c Determined by 1H NMR or HPLC analysis.
d Determined by HPLC analysis.
Scheme 2. Further Investigation of the Potential of the Reaction
Acknowledgment. We are grateful for the NSFC
(21032005, 20972058, 21172097), the National Basic Re-
search Program of China (No. 2010CB833203), and the
“111” program from MOE of P. R. China.
Supporting Information Available. Complete experi-
mental procedures and characterization of novel com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
intermediate I, which undergoes the intramolecular sulfa-
Michael addition to provide the intermediate II. Subse-
quent intramolecular aldol reaction closed the catalytic
cycle delivering the product 4d and regenerating the bi-
functional catalyst 1h. The absolute configuration of the
product was determined as (2R, 3S, 4S) by using X-ray
crystallographic analysis of 4d (Scheme 3).15
(15) CCDC 859341 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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