Synthesis of 2,3,4-trisubstituted thiochromanes using an organocatalytic enantioselective tandem michael-henry reaction

Article abstract of DOI:10.1002/adsc.200700331

Enantioenriched 2,3,4-trisubstituted thiochromanes have been synthesized by using a cupreine-catalyzed tandem Michael addition-Henry reaction between 2-mercaptobenzaldehydes and β-nitrostyrenes. Good diastereoselectivities and enantioselectivities were obtained for the title compounds, which may be further improved through a single recrystallization (up to 98% de and > 99% ee).

Full text of DOI:10.1002/adsc.200700331

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DOI: 10.1002/adsc.200700331
Synthesis of 2,3,4-Trisubstituted Thiochromanes using an Organo-
catalytic Enantioselective TandemMichael–Henry Reaction
Rajasekhar Dodda,a Joshua J. Goldman,a Tanmay Mandal,a Cong-Gui Zhao,a,*
Grant A. Broker,a and Edward R. T. Tiekinka
a
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249-0698, USA
Fax : (+1)-210-458-7428; e-mail: cong.zhao@utsa.edu
Received: July 6, 2007; Revised: January 22, 2008; Published online: February 26, 2008
Dedicated to Professor Rong-Yu Zhang on the occasion of his 73th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Enantioenriched 2,3,4-trisubstituted thio-
chromanes have been synthesized by using a cu-
preine-catalyzed tandem Michael addition–Henry
reaction between 2-mercaptobenzaldehydes and b-
nitrostyrenes. Good diastereoselectivities and enan-
tioselectivities were obtained for the title com-
pounds, which may be further improved through a
single recrystallization (up to 98% de and>99%
ee).
Keywords: Henry reaction; 2-mercaptobenzalde-
hyde; Michael addition; b-nitrostyrene; organoca-
talysis; tandem reaction
Figure 1. Some biologically active thiochromane derivatives.
and co-workers reported an enantioselective tandem
Chromanes are an important class of compounds that Michael–aldol reaction for the synthesis of thiochro-
are found in many biologically active natural prod- menes catalyzed by a proline derivative.[6] Most re-
ucts.[1] Thiochromanes, the sulfur analogues of chro- cently, the same group also reported a quinine thio-
manes, have also been reported to possess important
ACHTREuUNG rea-catalyzed tandem Michael–aldol reaction for
biological activities.[2] There are also reports that the synthesis of thiochromanes.[7] Nonetheless, even with
replacement of the oxygen atom in chromanes with a these progresses, an enantioselective method for the
sulfur atom results in enhanced bioactivities.[2d,f] Some synthesis of 3-amino-4-hydroxythiochromanes (such
representative examples are collected in Figure 1. Ter- as 2) is still lacking.
tatolol (1) has been shown to have affinity to 5HTA1
Recently, as part of our continued interest in enan-
receptors in human and rat brains.[2a,b] Thiochromane tioselective organocatalysis,[8] we reported a highly
derivative 2 also displays a mixed binding affinity to enantioselective Henry reaction[9] for the synthesis of
dopamine D2, D3 and 5HTA1 receptors,[2d] whereas a-hydroxyphosphonates by using cupreine derivatives
thiochromane derivative 3 shows potent anti-HIV ac- as the catalysts.[10] During this study, we envisioned
tivity.[2e]
that a tandem[11] Michael–Henry reaction may be
Owing to their biological activities, several asym- achieved if the starting material has both a nucleo-
metric methods have been developed for the synthesis philic and an electrophilic site, such as 2-mercapto-
of these compounds, which include asymmetric reduc- benzaldehyde. Although tandem Michael–Henry reac-
tion of thiochroman-4-ones,[3] enzymatic resolution of tions are known in the literature,[12] only very recently
racemic 4-hydroxythiochromanes or 4-acyloxythio- have Hayashi and co-workers reported a catalytic
chromanes,[4] and enantioselective alkylation of thio- enantioselective method.[13] Moreover, the synthesis
chromanes via conjugate addition.[5] Last year Wang of thiochromanes by using this tandem reaction has
Adv. Synth. Catal. 2008, 350, 537 – 541
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537

Rajasekhar Dodda et al.
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never been studied.[14] Herein, we report an organoca-
talytic, enantioselective tandem Michael–Henry reac-
tion for the direct synthesis of 2-aryl-3-nitro-4-hy-
ACHTREUNG
styrene (9) as the model compounds, we initially stud-
ied the tandem Michael–Henry reaction using 5
mol% of DABCO as the catalyst at room tempera-
ture (entry 1, Table 1). We were pleased to find that
the reaction was completed in just 5 min and only two
diastereomers of the expected 2-phenyl-3-nitro-4-hy-
droxythiochromane (10a) were obtained in a ratio of
Figure 2. Catalysts screened for the tandem Michael-Henry
reaction.
1
70:30, according to the H NMR analysis of the crude
product. Encouraged by this result, we further
screened some readily available alkaloid catalysts 4–7
(Figure 2) in an effort to develop an enantioselective
reaction, and the results are summarized in Table 1.
As shown in Table 1, with 5 mol% loading of qui-
nine (4) in diethyl ether, the reaction of 8 and 9 pro-
ceeds smoothly, and complete conversion was
achieved in just 5 min (entry 2). The same two diaste-
reomers were formed in a ratio of 75:25. However,
the ee value of the major diastereomer was only 8%
for the enantiomer of 10a [i.e., the (2S,3R,4S)-stereo-
isomer]. Catalyst 5 (9-O-benzylcupreine) also produ-
ces a similar diastereoselectivity (67:33) with a
modest ee value of 29%, but with 10a as the major
product of the major diastereomer (entry 3). In con-
trast, cupreine (6) proved to be a good catalyst for
this reaction, and an ee value of 75% for 10a was ob-
tained under similar conditions (entry 4). As expect-
ed, catalyst 7, the diastereomer of 6, yielded 10a in
similar diasteroselectivity and enantioselectivity as 6,
except that the enantiomer of 10a was obtained
(entry 5). The reaction conditions were further opti-
mized for 6. Screening of some common organic sol-
vents (toluene, CHCl3, and EtOAc, entries 6–8) re-
vealed that ether (entry 4) is the best one in terms of
both diastereoselectivity and enantioselectivity.
It was also found that the reaction temperature has
subtle effects on the reaction (entries 9–11): the high-
est enantioselectivity of 86% was obtained by carry-
ing out the reaction at À108C (entry 10), whereas
higher (entries 5 and 9) or lower temperatures
(entry 11) all led to inferior ee values. In contrast, the
diastereoselectivity of this reaction is essentially not
affected by the reaction temperature (entries 5, 9, and
11). Since the reaction proceeds very quickly under
Table 1. Catalyst screening and reaction condition optimiza-
tions.[a]
Entry Catalyst Solvent Conversion
[%][b]
dr[b]
ee
[%][c]
1
2
3
4
5
6
7
8
DABCO Et2O
100
100
100
100
100
70:30
75:25
67:33
70:30
70:30
65:35
60:40
56:44
70:30
70:30
68:32
70:30
-
4
5
6
7
6
6
6
6
6
6
6
Et2O
Et2O
Et2O
Et2O
toluene 100
CHCl3 100
EtOAc 100
Et2O
Et2O
Et2O
Et2O
8[d]
29
75
75[d]
56
42
72
80
86
82
9[e]
10[f]
11 g]
12[f,h,i]
100
100
100
100(50)
ACHRTUNEG(94:6) 86ACHTRE(UGN >99)
[a]
Unless otherwise specified, all reactions were conducted at
room temperature with 0.22 mmol of 8, 0.20 mmol of 9 and
the catalyst (5 mol%) in anhydrous diethyl ether (10 mL)
for 5 min.
[b]
1
Determined by H NMR spectroscopy on the crude product;
yield of isolated product after flash column chromatography the optimized conditions (À108C in ether), 5 mol%
was over 95% based on conversion.
of catalyst loading seems unnecessary. Indeed, the re-
action with only 2 mol% loading gave similar results
(entries 12 and 10). It should be pointed out that the
major diastereomer is a crystalline compound and the
diastereoselectivity and enantioselectivity may be
easily improved by recrystallization from hexane/
EtOAc. For example, the diastereoselectivity and
enantioselectivity of compound 10a were improved to
94:6 and >99% ee, respectively, after a single recrys-
tallization (entry 12, values in parentheses).
[c]
[d]
Enantiomeric excess of major isomer as determined by
HPLC analysis on a Chiralpak AD-H column.
The other enantiomer was obtained as the major product in
this case.
[e]
[f]
[g]
[h]
[i]
Reaction was performed at 08C.
Reaction was performed at À108C.
Reaction was performed at À258C.
With 2 mol% of catalyst loading.
Values in parantheses are the results of yield, dr, and ee of
the major product after a single recrystallization.
538
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Adv. Synth. Catal. 2008, 350, 537 – 541

Synthesis of 2,3,4-Trisubstituted Thiochromanes
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To test the substrate scope of this new tandem reac- trostyrene (entry 10) and 4-bromo-b-nitrostyrene
tion, the reaction of various 2-mercaptobenzalde- (entry 11) both give similar diastereoselectivities (ca.
hydes[15] and b-nitrostyrenes was studied under the 70:30) and enantioselectivities (ca. 80% ee). These re-
optimized conditions using 2 mol% of cupreine (6) as sults are comparable with those of 2-mercaptobenzal-
the catalyst. The results are collected in Table 2.
dehyde (entry 1). Similar results were also observed
As shown in Table 2, the reaction of 2-mercapto- when 4-methyl-2-mercaptobenzaldehyde (entry 12)
benzaldehyde with various b-nitrostyrenes all give ex- and 4-chloro-2-mercaptobenzaldehyde (entry 13) and
cellent yields of the desired products (ꢀ94%, en- b-nitrostyrene were used; except that the yields (ca.
tries 2–9). According to NMR analyses of the crude 85%) and ee values (ca. 75%) were slightly lower. As
products, only two diastereomers were formed, even with compound 10a (entry 1), all these diastereomeric
though three stereogenic centers were generated. The mixtures cannot be separated by column chromatog-
diastereoselectivities were in the range of 68:32 to raphy; however, they may be readily separated by re-
77:23, and the ee values of the major enantiomers crystallization. As shown in Table 2 (data in parenthe-
were from 72 to 86%. b-Nitrostyrenes with electron- ses), after a single recrystallization using hexane/
withdrawing substituents on the ortho, meta or para EtOAc, the major diastereomers of thiochromanes
positions afford thiochromanes with slightly inferior 10a–m may be obtained in very good diastereomeric
enantioselectivities (entries 3–6), except for the 2- purity (drꢀ87:13) and high optical purity (>99% ee
bromo substrate (entry 2), for which the product was in several cases).
obtained in 85% ee. Besides the prototype 2-mercap-
The absolute configuration of major diastereomer
tobenzaldehyde, substituted 2-mercaptobenzaldehydes was assigned on the basis of the X-ray crystallograph-
also react with b-nitrostyrenes. For example, the reac- ic analysis on compound 10b (CCDC deposition
tion of 2-mercapto-4-methoxybenzaldehyde and b-ni- number: 647961). The stereochemistry of the major
Table 2. Enantioselective tandem Michael–Henry reaction of 2-mercaptobenzaldehydes (8) with various b-nitrostyrenes
(9).[a]
Entry
R1
R2
10, Yield [%][b]
dr[c,d]
ee [%][d,e]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
a, 95 (50)
b, 97 (60)
c, 95 (50)
d, 96 (42)
e, 97 (46)
f, 95 (51)
g, 94 (52)
h, 96 (51)
i, 94 (48)
j, 95 (50)
k, 96 (62)
l, 84 (29)
m, 85 (32)
70:30 (94:6)
77:23 (93:7)
74:26 (92:8)
65:35 (92:8)
73:27 (96:4)
75:25 (99:1)
78:22 (93:7)
68:32 (93:7)
71:29 (92:8)
70:30 (91:9)
72:28 (94:6)
70:30 (87:13)
70:30 (93:7)
86 (>99)
85 (>99)
76 (99)
78 (>99)
72 (97)
2-Br
4-Br
3-Cl
4-Cl
2-NO2
2-OMe
4-OMe
4-Me
H
78 (90)
80 (>99)
85 (>99)
80 (>99)
82 (98)
80 (85)
72 (95)
9
H
10
11
12
13
4-OMe
4-OMe
4-Me
4-Cl
4-Br
H
H
75 (97)
[a]
Unless otherwise specified, all reactions were conducted at À108C with the substituted b-nitrostyrene (0.2 mmol), the
substituted 2-mercaptobenzaldehyde (0.22 mmol) and cupreine (6, 2 mol%) in anhydrous diethyl ether (10 mL) for
5 min. The absolute configuration of the major isomer 10b was determined by X-ray crystallography and the rest were as-
signed on the basis of the reaction mechanism.
[b]
Yields of nonseparable diastereomeric mixture after chromatography; values in parentheses are those after a single re-
crystallization.
[c]
[d]
[e]
1
Determined by H NMR analyses on the crude products or the recrystallized products.
Values in parantheses are those of the recrystallized products.
Values of enantiomeric excess of the major isomers as determined by HPLC analyses on a Chiralpak AD-H column (en-
tries 1-12) or a Chiralcel OD-H column (entry 13).
Adv. Synth. Catal. 2008, 350, 537 – 541
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539

Rajasekhar Dodda et al.
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trans,trans-isomer is 2R,3S,4R.[16] A mechanism as thesized with enantioselectivities up to 86% and dia-
shown in Scheme 1 is proposed to explain the ob- stereomeric ratios up to 78:22. A single recrystalliza-
served results. The mercapto group of the mercaptoal- tion of the diastereomeric mixture from hexane/
dehyde is deprotonated by the catalyst and the newly EtOAc enhances both the enantioselectivities (up to
>99% ee) and diastereoselectivities (up to 98% de).
These products are useful for the synthesis of biologi-
cally active thiochromane derivatives, such as com-
pound 2.
Experimental Section
General Experimental Procedure
A solution of b-nitrostyrene (9, 0.2 mmol) and cupreine (6,
1.25 mg, 0.004 mmol) in anhydrous diethyl ether (5.0 mL)
was stirred at À108C for 2 min. After which, a precooled so-
lution (À108C) of 2-mercaptobenzaldehyde (8, 0.22 mmol)
in anhydrous diethyl ether (5.0 mL) was added over a
period of 1 min. The reaction mixture was then stirred at
the same temperature for 5 min. The solvent was removed
at 08C under reduced pressure. The crude mixture was sub-
jected to flash column chromatography over silica gel
(eluted with 9:1 hexane/EtOAc and then EtOAc) to furnish
a mixture of two diastereomers, which was further recrystal-
lized using a mixture of hexane and ethyl acetate to afford
2,3,4-trisubstituted thiochromanes 10a–m as colorless crys-
tals. The compounds were fully characterized by 1H,
13C NMR, microanalysis and optical rotation data.
Scheme 1. Proposed transition states.
formed anion is associated with the catalyst through
charge interactions. When b-nitrostyrene approaches
this complex, the nitro group will form hydrogen
bonds with the two hydroxy groups of the curpreine.
Among the two possible orientations of the alkene
substrate (Scheme 1), the re face approach is favored
(left structure), as the unfavourable steric interaction
between the phenyl group and the catalyst backbone
is avoided. The attack of the sulfide anion onto the re
face of the b-nitrostyrene leads to the observed major
enantiomer of the product.
To show the utility of this method in the prepara-
tion of enantioenriched 3-amino-4-hydroxythiochro-
manes,[2d] the nitro compound 10a obtained in this
study was reduced with hydrogen gas under the catal-
ysis of palladium/carbon. As shown in Eq. (1), the re-
action leads to the desired amino derivative 11 in
good yield and with complete retention of the stereo-
chemistry.
Supporting Information
Detailed experimental procedure, NMR spectra for new
compounds, HPLC analysis and X-ray data are available as
Supporting Information
Acknowledgements
Generous financial support of this project from the Welch
foundation (grant no. AX-1593) and the NIH-MBRS pro-
gram (grant no. S06 08194) is gratefully acknowledged.
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Synthesis of 2,3,4-Trisubstituted Thiochromanes
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