A catalytic Michael/Horner-Wadsworth-Emmons cascade reaction for enantioselective synthesis of thiochromenes

Article abstract of DOI:10.1002/adsc.201300281

A catalytic enantioselective sulfa-Michael/Horner-Wadsworth-Emmons reaction cascade has been developed, taking advantage of phosphonate as an electrophilic activator and a traceless binding site. Using a chiral bifunctional urea derivative as the catalyst, a variety of aryl and heteroaryl substituted thiochromenes was obtained in excellent yield with a high level of enantioselectivity. Copyright

Full text of DOI:10.1002/adsc.201300281

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DOI: 10.1002/adsc.201300281
A Catalytic Michael/Horner–Wadsworth–Emmons Cascade
Reaction for Enantioselective Synthesis of Thiochromenes
Abhijnan Ray Choudhurya and Santanu Mukherjeea,*
a
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Fax : (+91)-80-2360-0529; phone: (+91)-80-2293-2850; e-mail: sm@orgchem.iisc.ernet.in
Received: April 4, 2013; Revised: June 5, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300281.
Abstract: A catalytic enantioselective sulfa-Mi-
chael/Horner–Wadsworth–Emmons reaction cas-
cade has been developed, taking advantage of phos-
phonate as an electrophilic activator and a traceless
binding site. Using a chiral bifunctional urea deriva-
tive as the catalyst, a variety of aryl and heteroaryl
substituted thiochromenes was obtained in excellent
yield with a high level of enantioselectivity.
eral, for asymmetric transformation remains a promi-
nent limitation of organocatalysis.
In 2009, during their brilliant synthesis of oseltami-
vir, Hayashi and co-workers employed vinylphospho-
nate as a key three-carbon building block in a domino
Michael/Horner–Wadsworth–Emmons (HWE) reac-
tion for the construction of the desired six-membered
carbocycle.[7] The same reaction was once again em-
ployed by Hayashi for the synthesis of the DPP4-se-
lective inhibitor ABT-341.[8] However, in both these
cases, the stereochemistry of the newly formed chiral
center is governed by the adjacent pre-existing stereo-
genic center, as the reactions were conducted using
achiral reagents.[9] A catalytic asymmetric version of
this type of reaction cascade remains unknown even
today.[10]
Keywords: asymmetric catalysis; bifunctional catal-
ysis; cascade reactions; Horner–Wadsworth–
Emmons reaction; sulfa-Michael addition; thiochro-
menes
We envisioned a catalytic enantioselective synthesis
The synthetic organic chemistsꢀ version of natureꢀs ex- of chiral thiochromene derivatives by a sulfa-Michael/
traordinarily selective sequential transformations, HWE cascade reaction of a trisubstituted vinyl-
often termed as cascade or domino reactions, repre- phosphonate with 2-mercaptoaldehyde (Scheme 1).
sents an extremely powerful device for the rapid con- We realized that, with vinylphosphonates containing
struction of complex architecture in a stereocontrolled an ester at the a-position, the phosphonate moiety
fashion.[1] Particularly, with the advent of well-defined can act as a traceless binding site for the catalyst.
organocatalytic concepts, cascade reactions became Consequently, a catalyst-controlled enantioselective
an obvious component of the synthetic toolbox.[2] Not sulfa-Michael addition[11] followed by an HWE reac-
surprisingly, numerous reports of organocatalytic tion between the ensuing a-phosphonato ester (or its
asymmetric cascade reactions have appeared in the enolate equivalent) and the neighboring aldehyde
literature during the past decade.[3] Hetero-Michael- would lead to 2-substituted thiochromenes. At the
initiated cascade reactions occupy a special niche in
this category. In 2006, Wang et al. reported the first
sulfa-Michael-initiated catalytic enantioselective cas-
cade reaction for the synthesis of chiral thiochromene
derivatives.[4] Since this initial breakthrough, numer-
ous examples of enantioselective hetero-Michael-initi-
ated cascade reactions involving a,b-unsaturated alde-
hydes and ketones have been reported.[5] However,
similar reactions of the corresponding ester equiva-
lents have remained relatively underexplored and
almost always require an additional binding site.[6] In
fact, activation of ester-containing substrates, in gen-
Scheme 1. Synthetic strategy towards chiral thiochromenes.
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Table 1. Catalyst screening and optimization of reaction conditions.[a]
Entry
Catalyst
Solvent
T [8C]
t [h]
Yield[b] [%]
er[c]
1
2
3
4
5
6
7
8
I
II
II
II
II
II
II
II
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCH3
PhCF3
CHCl3
PhCl
TBME
n-hexane
DCE
CH2Cl2
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
25
25
0
5
9
10
17
8
5
5
7
10
11
8
4
4
5
5
4
8
8
6
5.5
7
9
7.5
3.5
6
9
6
82
84
86
91
93
92
88
86
82
81
84
82
92
72
83
94
84
93
85
89
79
82
82
88
89
84
93
92:8
93.5:6.5
92.5:7.5
92.5:7.5
92.5:7.5
92:8
92.5:7.5
94:6
91:9
87:13
93:7
87:13
82:18
78:22
92:8
93.5:6.5
93.5:6.5
91:9
-20
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
9
II
II
II
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25[d]
26[e]
27[f]
III
IV
V
VI
VII
VIII
IX
X
XI
XII
XIII
XIV
XV
II
92:8
91:9
80:20
84:16
92:8
87:13
92:8
PhCl
PhCl
CH2Cl2
PhCl
PhCl
II
II
94:6
94.5:5.5
PhCl
[a]
Reaction conditions: 1a (1.0 equiv.), 2a (1.0 equiv.), catalyst (10 mol%).
Yields of isolated pure products after column chromatography.
Determined by HPLC analysis using a stationary phase chiral column.
Reaction was run at 0.5M concentration.
Reaction was run at 0.05M concentration.
1.2 equiv. of 2a were used.
[b]
[c]
[d]
[e]
[f]
outset, we were aware of the challenges associated to yield the expected thiochromene derivative 3aa, ir-
with this transformation: (i) the potential enantiodi- respective of their steric and electronic environment
vergent nature of the sulfa-Michael step, depending (see the Supporting Information for the initial catalyst
on the geometry of vinylphosphonate and (ii) the epi- screening). However, the catalyst structure and partic-
merizable proton at the benzylic position could lead ularly the size of the substituents on the Brønsted
to racemization in the presence of the Brønsted basic basic tertiary amine center were found to have a tre-
catalyst (Scheme 1).
mendous influence on the stereochemical outcome of
To validate the feasibility of our hypothesis, the re- the reaction.
action between 2-mercaptobenzaldehyde 1a and di-
In the presence of the well-established Takemoto
ethyl vinylphosphonate derivative 2a was identified catalyst I,[13] the reaction was found to be complete
(Table 1). The absence of any practically detectable within 5 h and 3aa was obtained in 82% yield with
uncatalyzed reaction at room temperature assisted reasonably good enantioselectivity (er 92:8) when
our catalyst optimization process. A variety of bifunc- conducted in CH2Cl2 at 258C (Table 1, entry 1). We
tional (thio)urea derivatives was initially tested were pleased to find that the product racemization in
(Scheme 2).[12] In general, the reaction was found to the presence of this catalyst is not of significant con-
be efficiently catalyzed by a number of such catalysts cern and could easily be avoided by rapid chromato-
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A Catalytic Michael/Horner–Wadsworth–Emmons Cascade Reaction for Enantioselective Synthesis
poorly enantioselective catalyst for our cascade reac-
tion (entry 24). The reaction was found to work rea-
sonably well within a range of concentrations (0.05 to
0.5M) without much influence on the outcome (en-
tries 25 and 26). Finally the use of a slight excess of
2a (1.2 equiv.) led to a small improvement in enantio-
selectivity (entry 27).
Having established the optimized conditions for
our sulfa-Michael/HWE cascade reaction (Table 1,
entry 27), we went on to explore the scope of our pro-
tocol for the synthesis of different thiochromene de-
rivatives.
As evident from Table 2, a number of aromatic and
heteroaromatic substituted diethyl vinylphosphonates
2a–m were suitable substrates for this cascade reac-
tion and the products were obtained uniformly in ex-
cellent yield. In the case of aryl-substituted vinyl-
phosphonates, para-, meta- and ortho-substituents
were well tolerated and the corresponding thiochro-
menes were obtained in high enantioselectivity. The
cascade reaction worked well in the case of heteroar-
omatic substrates as well although the products were
obtained with somewhat reduced enantioselectivity. 2-
Mercapto-5-methylbenzaldehyde 1b also participated
Scheme 2. Bifunctional organocatalysts screened for the
sulfa-Michael/HWE cascade reaction.
graphic purification immediately after the completion in the cascade reaction as anticipated, generating the
of the reaction. However, prolonged exposure of the thiochromene products in excellent yield with good
product to the catalyst[14] or the reaction mixture to enantioselectivity. However, the same protocol could
silica gel[15] results in a small erosion of the er.
not be extended to vinylphosphonates containing an
A similar urea derivative containing a bulkier pyr- aliphatic substituent: one such attempt (with cyclo-
rolidine at the Brønsted basic site (II)[16] afforded the hexyl as the substituent) failed to deliver any desired
product with improved enantioselectivity (entry 2). product (3an). This seems to be a prominent limita-
Lowering the reaction temperature proved futile tion of our protocol at this moment.
since a product with lower er was obtained after
Substituents other than ethyl on the carboxylate
longer reaction times (entries 3 and 4). At this point, can also be used, as evident from methyl and isopro-
careful solvent screening at room temperature (en- pyl esters 2o and 2p, respectively (Scheme 3). In both
tries 5–11) revealed chlorobenzene as the optimal sol- the cases, products were obtained with comparable
vent for this cascade reaction, furnishing the product enantioselectivity, even though only modest yield
in 86% yield with er 94:6 within 7 h (entry 8). Bifunc- could be achieved for isopropyl ester. The low yield
tional (thio)urea derivatives with unsymmetrically obtained in the latter case is most likely due either to
substituted tertiary amines III–IV[17] turned out to be a poor E/Z ratio of 2p (5:1) or hindered substrate
very active catalysts; however, in both the cases, the binding to the catalyst (see Scheme 5) because of the
product was obtained with considerably inferior enan- bulky isopropyl ester group or both.
tioselectivity (entries 12 and 13). It is hardly surpris-
With the medicinal importance of 3-subsituted thio-
ing that the product with poor er was obtained when chromanes in mind,[20] we carried out synthetic modi-
primary amine-thiourea bifunctional compound V fications of the thiochromene derivatives (Scheme 4).
was employed as the catalyst (entry 14). (Thio)urea The ester group of product 3aa was reduced to pri-
derivatives containing other cyclic tertiary amine VI– mary alcohol 4 under mild conditions followed by
IX also failed to improve the enantioselectivity (en- controlled oxidation to aldehyde 5. Horner–Wittig
tries 15–18), hence proving the superiority of the pyr- olefination then furnished the thiochromene 6, with
rolidine moiety in catalyst II. After screening an a,b-unsaturated ester at the 3-position, exclusively
a number of pyrrolidinyl catalysts (X–XIV) contain- as a single diastereomer. It is noteworthy that the ste-
ing various electronically tuned aromatic and aliphatic reochemical integrity of each of these intermediates
substituents on the thiourea nitrogen (entries 19–23), was conserved during these synthetic manipulations.
catalyst II containing the privileged 3,5-bis(trifluoro-
The stereochemical outcome of the thiochromene
methyl)phenyl moiety[18] emerged as the optimum. product could be rationalized by considering the bi-
Squaramide-derived bifunctional catalyst XV, intro- functional nature of the catalysts employed for our
duced by Rawal,[19] turned out to be a very active but study (Scheme 5). Dual H-bonding from the Brønsted
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Table 2. Substrate scope of the sulfa-Michael/HWE cascade reaction.[a–d]
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[a]
[b]
[c]
All reactions were carried out with 0.22 mmol of 1.
Yields given are of pure products after column chromatography.
Enantiomeric ratios (er) were determined by HPLC analysis on a chiral sta-
tionary phase.
The absolute configuration of 3ae was established by X-ray crystallography
(vide infra) and absolute configurations of all others products were assigned
by analogy.
[d]
acidic urea NHs to both carboxylate and phosphonate phosphonate. General base catalysis from the Brønst-
oxygen atoms not only leads to electrophilic activa- ed basic tertiary amine enhances the nucleophilicity
tion, but also renders rigidity to vinylphosphonate. of thiol and steers it for a Re-face selective Michael
Such rigidification is extremely important for effective addition to establish the stereocenter. The subsequent
discrimination between the enantiofaces of the vinyl- HWE reaction delivers the (R)-enantiomer of the thi-
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A Catalytic Michael/Horner–Wadsworth–Emmons Cascade Reaction for Enantioselective Synthesis
Scheme 3. Substrate scope with respect to carboxylate.
Scheme 6. Attempted reaction of 2-mercaptobenzaldehyde
1a with ethyl cinnamate 7 and vinylphosphonate 8.
2-mercaptobenzaldehyde 1a and ethyl cinnamate 7
under our optimized reaction conditions (Scheme 6).
No product formation was observed even after 24 h.
This experiment clearly provides evidence that the
phosphonate moiety (i) enhances the electrophilicity
of the enoate by virtue of its electron-withdrawing
ability, and (ii) provides an additional binding site for
the catalyst. However, the phosphonate moiety alone
is not enough to activate the olefin for Michael addi-
tion as apparent from the inertness of vinylphospho-
nate 8 towards 1a. To the best of our knowledge, this
is the first time that the phosphonate functionality has
been used as a traceless binding site in a catalytic
enantioselective transformation.
Scheme 4. Synthetic modification of the cascade product
3aa.
To summarize, we have described a catalytic
enantioselective sulfa-Michael/Horner–Wadsworth–
EmACTHUNRTGNEUNGmons reaction cascade providing an easy access to
enantioenriched 2,3-disubstituted thiochromene deriv-
atives. This cascade sequence is initiated by a sulfa-
Michael addition to a vinylphosphonate catalyzed by
a chiral bifunctional urea derivative. Several aryl- and
heteroaryl-substituted thiochromenes were obtained
in excellent yield with a high level of enantioselectivi-
ty. Our report represents the first example of the use
of phosphonate as a traceless binding site in a catalytic
asymmetric transformation. The synthetic utility of
the products is demonstrated and a model is proposed
to rationalize the stereochemical outcome of the reac-
tion.
Experimental Section
General Procedure for the Catalytic Enantioselective
Sulfa-Michael/HWE Cascade Reaction
Scheme 5. Proposed stereochemical model for the sulfa-Mi-
chael/HWE cascade reaction and the X-ray structure of the
product 3ae.
In an oven-dried reaction tube, vinylphosphonate
2
(0.264 mmol, 1.2 equiv.) and catalyst II (9.3 mg, 0.022 mmol,
0.1 equiv.) were taken up in chlorobenzene (1.2 mL) under
a positive argon pressure. To this mixture, a solution of thio-
aldehyde 1 (0.220 mmol, 1 equiv,) in 1 mL chlorobenzene
was added and the resulting solution was stirred at 258C
under an argon atmosphere until the reaction was found to
ochromene, as supported by the X-ray structure of
3ae (Scheme 5).[21]
To further corroborate the dual role of phospho-
nate functionality, we attempted a reaction between be complete (TLC monitoring). The product was purified by
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Acknowledgements
Generous financial support from Indian Institute of Science,
Bangalore, in the form of start-up grant is gratefully acknowl-
edged. We thank the Department of Science and Technology
(DST), New Delhi (Grant No. SR/FT/CS-90/2010) and the
Council of Scientific and Industrial Research (CSIR), New
Delhi (Grant No. 01ACTHNUTRGNEUNG(2505)/11/EMR-II) for funding this re-
search program. A.R.C. thanks CSIR for the Shyama Prasad
Mukherjee Fellowship. We wish to thank Mr. Dipak Samanta
(Department of Inorganic and Physical Chemistry, IISc, Ban-
galore) for his help with the X-ray diffraction analysis.
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[14] Upon exposure of 3aa with 10 mol% catalyst II for
40 h at 258C, the er dropped from 94.5:5.5 to 92:8.
[15] After completion of the reaction, stirring the reaction
mixture with silica gel for 3 h afforded 3aa with an er
of 87:13 (compared to er 94.5:5.5; see Table 2).
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8 A Catalytic Michael/Horner–Wadsworth–Emmons Cascade
Reaction for Enantioselective Synthesis of Thiochromenes
Adv. Synth. Catal. 2013, 355, 1 – 8
Abhijnan Ray Choudhury, Santanu Mukherjee*
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