Chiral amine thiourea-promoted enantioselective domino Michael-aldol reactions between 2-mercaptobenzaldehydes and maleimides

Article abstract of DOI:10.1002/adsc.200700158

An organocatalytic, enantioselective domino Michael-aldol reaction of 2-mercaptobenz-aldehydes with maleimides has been developed. The process, catalyzed by a bifunctional chiral amine thiourea via a hydrogen-bonding mediated activation mechanism using as

Full text of DOI:10.1002/adsc.200700158

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DOI: 10.1002/adsc.200700158
Chiral Amine Thiourea-Promoted Enantioselective Domino
Michael-Aldol Reactions between 2-Mercaptobenzaldehydes
and Maleimides
Liansuo Zu,a Hexin Xie,a Hao Li,a Jian Wang,a Wei Jiang,a and Wei Wanga,*
a
Department of Chemistry and Chemical Biology, University of New Mexico, MSC03 2060, Albuquerque, NM 87131-0001,
USA
Fax : (+1)-505-277-2609; e-mail: wwang@unm.edu
Received: March 28, 2007; Revised: June 25, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An organocatalytic, enantioselective
domino Michael-aldol reaction of 2-mercaptobenz-
aldehydes with maleimides has been developed.
The process, catalyzed by a bifunctional chiral
amine thiourea via a hydrogen-bonding mediated
activation mechanism using as low as 1 mol% cata-
lyst loading, affords versatile succinimide-contain-
ing benzothiopyrans with the generation of 3 ste-
reogenic centers in one single operation.
Recently, we have described highly enantioselec-
tive, Cinchona alkaloid thiourea-promoted domino
Michael-aldol reactions of reactions of 2-mercapto-
benzaldehydes (1) with a,b-unsaturated oxazolidi-
nones [Scheme 1, Eq. (1)].[5–9] In this case, a, b-unsa-
turated oxazolidinones serve as Michael acceptor. We
envisioned that the switch of the a,b-unsaturated oxa-
zolidinones to maleimides (2) would generate a new
efficient cascade process for the incorporation of suc-
cinimides into the complex benzothiopyrans
[Scheme 1, Eq. (2)]. It should be pointed out that, to
date, the electrophiles employed in organocatalyzed
conjugate addition processes have been limited to
enones,[10] nitroolefins,[11] unsaturated imides[12] and
Keywords: asymmetric catalysis; asymmetric syn-
thesis; Michael addition; organic catalysis
The development of efficient synthetic methodologies,
which allow for the incorporation of important phar-
macophores into biologically interesting molecular ar-
chitectures, is of considerable significance from the
standpoint of the medicinal and organic chemistry.
Succinimides are such moieties, found in numerous
biologically interesting molecules and pharmaceuti-
cals.[1,2] Therefore, they are often used as phramaco-
phores in drug discovery. In this communication, we
describe a novel cycloaddition reactions of 2-mercap-
tobenzaldehydes with maleimides for the facile as-
sembly of succinimide motifs into complex biological-
ly and medicinally significant benzothiopyrans.[3] The
process is efficiently catalyzed by a robust, bifunction-
al amine-thiourea of low toxicity in high yields (83–
96%) and good to high levels of diastereoselectivity
(up to 20:1 dr) and enantioselectivity (74–94% ee).
In addition, several features of the process are worthy
of mention here: 1) pure hydrogen bonding as activa-
tion mode,[4] which is considered biomimetic; 2) uti-
lization of as low as 1 mol% of catalyst; and 3) crea-
tion of 3 new stereogenic centers in one-pot transfor-
mation.
Scheme 1. Organocatalytic, asymmetric domino Michael-
aldol reactions.
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Domino Michael-Aldol Reactions between 2-Mercaptobenzaldehydes and Maleimides
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smoothly to yield the desired benzothiopyran 3a in
high yields (75–94%) with moderate dr (5:3 to 4:1,
Table 1). However, the enantioselectivities varied
greatly depending on the organocatalyst used. Take-
motoꢁs catalyst II exhibited the most promising results
in terms of ee (70%), dr (4:1) and yield (94%)
(Table 1, entry 2). This prompted us to select this cat-
alyst for further optimization of the reaction condi-
tions. It is noted that in our cascade Michael-aldol re-
actions of 2-mercaptobenzaldehydes (1) with a, b-un-
saturated oxazolidinones [Scheme 1, Eq. (1)], Cincho-
na alkaloid thiourea III is the best promoter.[5a]
In an effort to seek the optimal conditions for the
II-catalyzed domino Michael-aldol reaction, we first
investigated the effect of the reaction medium on the
process. The studies showed that the reaction pro-
ceeded smoothly in non-polar, aprotic solvents
(Table 2, entries 1–7) and poor results were obtained
for polar solvents (entry 9). This is expected since
non-polar, aprotic solvents can minimize the disrup-
tion of the hydrogen-bonding interactions between
catalyst and substrates; and thus high catalytic activity
and stereoselectivity toward the reaction are generally
Figure 1. Structures of chiral organocatalysts.
sulfones.[13] In contrast, maleimides as electrophiles[14] observed. Among the non-polar, aprotic solvents
have been much less explored. probed, the process carried out in xylenes afforded
To probe the feasibility of the proposed organoca- the most encouraging results (entry 4). When the cat-
talytic domino Michael-aldol process, a model reac- alyst loading was reduced from 10% to 1 mol%, a
tion between 2-mercaptobenzaldehyde (1a) and N- comparable result was obtained (entry 5). Lowering
phenylmaleimide (2a) in 1,2-dichloroethane at room the reaction temperature to 08C led to improvement
temperature in the presence of a chiral bifunctional of both enantioselectivity and diastereoselectivity
organocatalyst including amine thioureas I–IV and (entry 6).
the Cinchona alkaloids V and VI was evaluated
(Figure 1).[4] The results of the investigation, summar-
ized in Table 1, revealed that the reaction proceeded
Table 2. Optimization of reaction conditions of II-catalyzed
domino Michael-aldol reaction of 2-mercaptobenzaldehyde
(1a) with N-phenylmaleimide (2a).[a]
Table 1. Organocatalytic enantioselective domino Michael-
aldol reaction of 2-mercaptobenzaldehyde (1a) with N-phe-
nylmaleimide (2a).[a]
Entry
Solvent
Cl(CH2)2Cl
t [h]
Yield [%][b]
% ee[c]
dr[d]
1
2
3
4
G
5
5
5
5
5
7
5
5
5
94
93
90
95
92
90
85
85
70
70
72
80
81
81
84
79
20
56
4:1
3:1
5:1
6:1
6:1
10:1
5:1
5:2
1:1
CH2Cl2
toluene
xylenes
xylenes
xylenes
p-cymene
THF
Entry
Catalyst
t [h]
Yield [%][b]
% ee[c]
dr[d]
1
2
3
4
5
6
I
II
III
IV
V
8
5
5
5
5
5
75
94
82
85
90
90
rac.[e]
70
À42
À33
À47
À23
3:1
4:1
5:2]
5:2
3:1
5:3
5[e]
6[f]
7
8
9
i-PrOH
VI
[a]
Unless specified, see Experimental Section.
Isolated yields.
[a]
[b]
[c]
[d]
[e]
[f]
Reaction conditions: see Experimental Section.
Isolated yields.
Determined by chiral HPLC analysis (Chiralcel OD-H).
Determined by 1H NMR.
Racemic.
[b]
[c]
[d]
[e]
Determined by chiral HPLC analysis (Chiralcel OD-H).
1
Determined by H NMR.
1 mol% catalyst used.
1 mol% catalyst used and reaction performed at 08C.
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Table 3. Catalyst II promoted domino Michael-aldol reac-
tions of 2-mercaptobenzaldehydes (2) with maleimides (3).[a]
Entry Product 3
Yield [%][b] % ee[c] dr[d]
1
90
95
92
95
83
96
90
88
84
92
84
83
83
78
94
86
75
74
83
80
10:1
8:1
Figure 2. X-ray crystal structure of 3e.
2
3
4
5
6
7
8
9
thiochromanes 3 containing 3 chiral centers in good
to high enantiomeric excesses (74–94% ee) and re-
spected levels of diastereoselectivities (3:1 to 20:1)
(Table 3). The II-promoted domino Michael-aldol
process took place with a variety of 2-mercaptoben-
zaldehydes, which possess neutral (entries 1 and 6–
10), electron-donating (entries 2 and 3), electron-with-
drawing (entry 4), and aromatic (entry 5) substituents.
Moreover, experimentation revealed that the elec-
tronic nature of the maleimides (2) has limited impact
on efficiency, enantioselectivity and diastereoselectiv-
ity of the domino reaction (entries 6–9). In each case,
the process proceeded rapidly (7 h) in high yields
(84–96%) and with good ees (74–86%). N-Alkylma-
leimides also efficiently participated in the reaction
7:1
8:1
20:1
5.5:1
10:1
3:1
albeit with
(entry 10).
a slight drop in diastereoselectivity
The stereoconfiguration of the products from the
domino Michael-aldol process was determined by X-
ray crystallography based on compound 3e (Figure 2,
Table 2, entry 5).[15] It was found that cis stereochem-
istry with (2S, 3S) configuration was formed
(Figure 3). Two possible reaction pathways were pro-
posed for the observation. In the cascade Michael-
aldol reaction (Pathway 1), a transition state A was
proposed based on the recent theoretical studies of
the bifunctional amine thiourea catalyst catalyzed Mi-
chael addition reactions.[16] The orientation of the
maleimide by the thiourea moiety of the catalyst
allows the thiol group in 2-mercaptobenzaldehyde,
which is activated and directed by the amine function-
ality of the catalyst, for si face attack to form the 2S
configuration. The observed cis (2S,3S) stereochemis-
try could result from cis-cyclic maleimide 2a. This is
in contrast to the observation from the H-bonding-
mediated domino Michael-aldol reactions or cascade
Michael-aldol reaction of trans-a,b-unsaturated alde-
hydes with 2-mercaptobenzaldehyde 1a that give rise
to trans products.[5a] The second possible reaction
mechanism, responsible for the formation of cis-prod-
11.5:1
3:1
10
[a]
Unless specified, see Experimental Section for reaction
conditions.
Isolated yields after flash chromatography.
Determined by chiral HPLC analysis (Chiralcel OD-H
and Chiralpak AD, AS-H or OJ-H).
[b]
[c]
[d]
1
Determined by H NMR.
The new methodology proves to be a general ap- ucts of the process, could be a Diels–Alder process
proach to the preparation of a range of substituted (Pathway 2). The tautomer 1a’ from 2-mercapto-ben-
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Domino Michael-Aldol Reactions between 2-Mercaptobenzaldehydes and Maleimides
COMMUNICATIONS
Experimental Section
Typical Procedure (Table 3, entry 1)
A mixture of 2-mercaptobenaldehyde 1 (21 mg, 0.15 mmol),
1-phenylpyrrole-2,5-dione 2a (17 mg, 0.1 mmol) and the cat-
alyst II (0.414 mg, 0.001 mmol) in xylenes (0.5 mL) was
stirred at 08C for 7 h. The crude product was purified direct-
ly by column chromatography on silica gel, eluted by
hexane/EtOAc=2:1 to give the desired product 3a; yield:
28 mg (90%) with 84% ee, determined by HPLC (Chiralcel
OD-H, i-PrOH/hexane=30/70, flow rate=0.5 mLminÀ1, l=
254 nm): tminor =32.80 min, tmajor =43.32 min, ee=84%, dr=
10:1; [a]2D3: +183.3 (c 1.0, CHCl3).
Acknowledgements
The financial support for this research by the Department of
Chemistry and the Research Allocation Committee, Universi-
ty of New Mexico, the National Science Foundation (CHE-
0704015) and the American Chemical Society-PRF (G1 type)
is gratefully acknowledged.
Figure 3. Proposed transition states.
zaldehyde 1a could serve as a diene for the Diels-
aldol reaction with cis-cyclic maleimide 2a. Such reac-
tion also could afford product 3a’ with cis stereoconfi-
guration, but with an opposite absolute (2R,3R,4S)
stereochemistry. As shown in proposed transition
state B, in contrast to the transition state A, the
amine moiety in the catalyst directs the enol moiety
of 1a’ rather than thiolphenol of 1a via an H-bond for
the Diels–Alder reaction. The transition state would
lead to a (2R,3R,4S) outcome. Based on the experi-
mental results, the Diels–Alder pathway could be
ruled out. The detailed mechanistic study is underway
in our laboratory.
In summary, we have developed an efficient, enan-
tioselective and diastereoselective organocatalytic
domino Michael-aldol process for the preparation of
synthetically useful and medicinally important chiral
succinimide-containing thiochromanes. The new one-
pot process, starting with simple substances, is pro-
moted by using as low as 1 mol% of a robust amine
thiourea II. The activity of the catalyst derives from
non-covalent hydrogen-bonding interactions between
the bifunctional amine-thiourea unit in II which syn-
ergistically activate both the nucleophiles and electro-
philes. This strategy closely mimics that is often used
by many enzyme catalysts. It is found that the process
might undergo a Michael-aldol reaction. Future stud-
ies of the reaction are aimed at investigating its full
scope, mechanism, and application to the synthesis of
biologically important targets.
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Adv. Synth. Catal. 2007, 349, 1882 – 1886