L-proline-catalyzed three-component domino [3+2+1] annulation for the regio- and diastereoselective synthesis of highly substituted thienothiopyrans containing three or four stereocenters

Article abstract of DOI:10.1021/jo9021327

(Chemical Equation Presented) L-Proline-catalyzed three-component reactions of ethyl 2-[(2-oxo-2-arylethyl)sulfonyl]acetate or ethyl 2-[(2-ethoxy-2- oxoethyl)sulfonyl]acetate, aromatic aldehydes, and 5-aryltetrahydro-3- thiophenone furnished a variety of highly substituted thieno[3,2-c]thiopyran derivatives. This facile transformation presumably occurs via a one-pot domino sequence of enamine formation/aldol condensation/Michael addition/6-exo-trig cyclization/elimination and involves the creation in a single operation of three C-C bonds and the generation of three new stereocenters with complete diastereoselectivity in all cases and a fourth one in ca. 7:3 diastereomeric ratio when starting from a 5-substituted tetrahydro-3-thiophenone derivative.

Full text of DOI:10.1021/jo9021327

pubs.acs.org/joc
of synthetic targets.2 Members of the thienothiopyran class
L-Proline-Catalyzed Three-Component Domino
[3þ2þ1] Annulation for the Regio- and
Diastereoselective Synthesis of Highly Substituted
Thienothiopyrans Containing Three or Four
Stereocenters
have attracted much interest since they were reported to
possess antiglaucoma activity.3 In fact, Trusopt (dorzol-
amide hydrochloride) is one of the most popular topically
active carbonic anhydrase inhibitors (CAI), which causes a
decrease in the aqueous humor secretion and therefore
reduction of the intraocular pressure.4 Furthermore, com-
pounds with thiophene substructures have found remarkable
applications as electroactive and light-emitting materials in a
variety of opto-electronic devices and optical transducers in
biosensors as well as fluorescent markers for biopolymers.5
The biological importance of thienothiopyrans, in con-
junction with our interest in novel domino processes in
organic synthesis,6 led us to study the synthesis of thienothio-
pyrans 4-17 employing L-proline as a catalyst. This choice
was prompted by the fact that L-proline is an abundant and
inexpensive amino acid capable of catalyzing diverse organic
transformations, in both enantio- and nonenantioselective
fashions, including aldol,7 Mannich,8 Michael,9 and unsym-
metric Biginelli10 reactions as well as Diels-Alder/Knoeve-
nagel11 and other domino processes.12 The efficacy of
L-proline in diverse organic transformations is ascribable
to multiple catalytic roles it can play, such as an acid or a base
or both simultaneously, as a nucleophile and its ability to
form enamine/iminium intermediates upon reaction with
carbonyl/R,β-unsaturated carbonyl compounds.
Sethuraman Indumathi,† Subbu Perumal,*,† and
,‡
ꢀ
J. Carlos Menendez*
†Department of Organic Chemistry, School of Chemistry,
Madurai Kamaraj University, Madurai 625021, India and
‡
´
ꢀ
ꢀ
Departamento de Quımica Organica y Farmaceutica,
Facultad de Farmacia, Universidad Complutense,
28040 Madrid, Spain
subbu.perum@gmail.com, josecm@farm.ucm.es
Received October 4, 2009
Stirring at room temperature for 24 h a solution of ethyl
2-[(2-oxo-2-arylethyl)sulfonyl]acetate or ethyl 2-[(2-ethoxy-
2-oxoethyl)sulfonyl]acetate 1, a 5-aryltetrahydro-3-thiophe-
none derivative 2 (R2 = Ar),13 and an aromatic aldehyde 3 in
an equimolar ratio in the presence of L-proline (50 mol %) in
methanol furnished the thieno[3,2-c]thiopyran derivatives
L-Proline-catalyzed three-component reactions of ethyl 2-
[(2-oxo-2-arylethyl)sulfonyl]acetate or ethyl 2-[(2-ethoxy-
2-oxoethyl)sulfonyl]acetate, aromatic aldehydes, and 5-
aryltetrahydro-3-thiophenone furnished a variety of highly
substituted thieno[3,2-c]thiopyran derivatives. This facile
transformation presumably occurs via a one-pot domino
sequence of enamine formation/aldol condensation/Mi-
chael addition/6-exo-trig cyclization/elimination and in-
volves the creation in a single operation of three C-C
bonds and the generation of three new stereocenters with
complete diastereoselectivity in all cases and a fourth one in
ca. 7:3 diastereomeric ratio when starting from a 5-sub-
stituted tetrahydro-3-thiophenone derivative.
(3) Baldwin, J. J.; Ponticello, G. S.; Anderson, P. S.; Christy, M. E.;
Murcko, M. A.; Randall, W. C.; Schwam, H.; Sugrue, M. F.; Springer, J. P.;
Gautheron, P.; Grove, J.; Mallorga, P.; Viader, M. P.; McKeever, B. M.;
Navia, M. A. J. Med. Chem. 1989, 32, 2510.
(4) (a) Ponticello, G. S.; Freedman, M. B.; Habecker, C. N.; Lyle, P. A.;
Schwam, H.; Varga, S. L.; Christy, M. E.; Randall, W. C.; Baldwin, J. J.
J. Med. Chem. 1987, 30, 591. (b) Ponticello, G. S.; Freedman, M. B.;
Habecker, C. N.; Holloway, M. K.; Amato, J. S.; Conn, R. S.; Baldwin,
J. J. J. Org. Chem. 1988, 53, 9.
(5) Barbarella, G.; Melucci, M.; Sotgiu, G. Adv. Mater. 2005, 17, 1581.
(6) (a) Alex Raja, V. P.; Perumal, S. Tetrahedron 2006, 62, 4892.
(b) Savitha Devi, N.; Perumal, S. Tetrahedron 2006, 62, 5931. (c) Srinivasan,
M.; Perumal, S. Tetrahedron 2006, 62, 7726. (d) Indumathi, S.; Ranjith
Kumar, R.; Perumal, S. Tetrahedron 2007, 63, 1411. (e) Kamal Nasar,
M.; Ranjith Kumar, R.; Perumal, S. Tetrahedron Lett. 2007, 48, 2155.
~
ꢀ
(f) Sridharan, V.; Perumal, P. T.; Avendano, C.; Menendez, J. C. Tetrahedron
2007, 63, 4407. (g) Sridharan, V.; Perumal, P. T.; Avendano, C.; Menendez,
~
ꢀ
ꢀ
J. C. Org. Biomol. Chem. 2007, 5, 1351. (h) Sridharan, V.; Menendez, J. C.
ꢀ
Org. Lett. 2008, 10, 4303. (i) Sridharan, V.; Maiti, S.; Menendez, J. C.
Chem.;Eur. J. 2009, 15, 4565.
(7) Alcaide, B.; Almendros, P.; Luna, A.; Torres, M. R. J. Org. Chem.
2006, 71, 4818.
(8) Janey, J. M.; Hsiao, Y.; Armstrong, J. D. III J. Org. Chem. 2006, 71,
390.
(9) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975.
(10) (a) Yadav, J. S.; Kumar, S. P.; Kondaji, G.; Rao, R. S.; Nagaiah, K.
Chem. Lett. 2004, 33, 1168. (b) Mabry, J.; Ganem, B. Tetrahedron Lett. 2006,
47, 55.
(11) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F. III Angew. Chem.
2003, 115, 4365.
Cyclic sulfides are useful templates to facilitate and con-
trol various chemical transformations.1 In particular, thio-
pyran derived scaffolds have been used to construct a variety
(1) (a) Vedejs, E.; Krafft, G. A. Tetrahedron 1982, 38, 2857. (b) Ingall,
A. H. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Eds.; Pergamon: Oxford, UK, 1984; Vol. 3, p 885.
(2) (a) Hachem, A.; Toupet, L.; Gree, R. Tetrahedron Lett. 1995, 36, 1849.
(b) Ward, D. E.; Gai, Y. Synlett 1995, 261. (c) Ward, D. E.; Man, C. C.; Guo,
C. Tetrahedron Lett. 1997, 38, 2201.
(12) Srinivasan, M.; Perumal, S. Tetrahedron 2007, 63, 2865.
(13) Reinhoudt, D. N.; Trompenaars, W. P.; Geevers, J. Synthesis 1978,
368.
472 J. Org. Chem. 2010, 75, 472–475
Published on Web 12/16/2009
DOI: 10.1021/jo9021327
r
2009 American Chemical Society

Indumathi et al.
JOCNote
SCHEME 1. Synthesis of Thienothiopyrans
TABLE 2. Base-Mediated Product Selectivity and Solvent Effect on the
Three-Component Domino Reactions
entry
base (50 mol %)
solvent
product
yield, %
1
2
3
4
5
6
7
8
9
10
pyrrolidine
Et3N
DBU
pyridine
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
methanol
methanol
methanol
methanol
methanol
ethanol
DMF
DMSO
CH3CN
THF
18
19
72
48
19
no reaction
4
no reaction
4
4
4
4
56
no reaction
65
no reaction
35
38
50
45
TABLE 1. Scope, Yields, and Diastereomeric Excesses in the Synthesis
of Thienothiopyrans 4-17
SCHEME 2. Influence of the Basic Catalyst on the Results of
R1
R2
Ar1
yield, %
dra
the Three-Component Domino Reactiona
compd
4
5
6
7
8
9
10
11
12
13
14
15
16
17
p-ClC6H4 p-H3CC6H4 p-H3CC6H4
p-ClC6H4 p-H3CC6H4 p-ClC6H4
65
60
52
51
49
76
79
63
58
75
62
65
64
71
69/31
68/32
71/29
68/32
73/27
70/30
68/32
76/24
78/22
69/31
100/0
100/0
100/0
100/0
p-ClC6H4 C6H5
p-ClC6H4 C6H5
p-ClC6H4 p-ClC6H4
m-FC6H4
p-H3COC6H4
p-H3CC6H4
OEt
OEt
OEt
OEt
p-H3CC6H4 p-ClC6H4
C6H5
C6H5
p-ClC6H4
p-ClC6H4
H
H
H
H
p-FC6H4
o-H3CC6H4
C6H5
p-O2NC6H4
C6H5
OEt
p-ClC6H4
p-ClC6H4
OEt
o-H3CC6H4
o-BrC6H4
p-H3CC6H4
OEt
aThe major diastereomer of compounds 4-13 had the structure a.
4-13, bearing four stereocenters, in 49-79% yields as
mixtures of two diastereomers in ca. 7/3 ratio (Scheme 1,
Table 1). Remarkably, although thienothiopyrans 4-13
have four stereocenters and hence eight diastereomers would
be possible in principle, only two diastereomers, 4a-13a and
4b-13b, have been obtained, the former being highly pre-
dominating. These diastereomers (compounds 4a-13a and
4b-13b) could be separated in pure form by flash column
chromatography. As expected, those reactions involving the
use of tetrahydro-3-thiophenone 2 (R2 = H) afforded the
corresponding compounds 14-17 as single diastereomers in
62-71% yield (Scheme 1). Chiral HPLC analysis of thie-
nothiopyran 4a proved that this compound was almost
racemic, the enantiomeric ratio being 50.7:49.3, and this
showed that the reaction takes place essentially in a none-
nantioselective way.
aReagents and conditions: (i) pyrrolidine, CH3OH, rt; (ii) Et3N, or
DBU, CH3OH, rt; (iii) L-Pro, CH3OH, rt.
TABLE 3. Base-Mediated Product Selectivity of the Three-Component
Domino Reaction
entry
base (50 mol %)
product
yield, %
1
2
3
4
5
pyrrolidine
Et3N
DBU
L-proline
pyridine
18
19
72
48
56
65
19
4
no reaction
no reaction
The reaction was very sensitive to the nature of the solvent
employed as shown for the preparation of 4 (Table 2). Thus,
it proceeded most efficiently in methanol, while it did not
occur at all in ethanol. Thienothiopyrans were also obtained
when DMF, DMSO, THF, and CH3CN were employed as
solvents, albeit in lower yields in methanol. Interestingly, the
choice of basic catalyst also proved to be critical for the
success of the reaction. As shown in Scheme 2 and Table 2,
thienothiopyrans 4 were obtained only from the proline-
catalyzed reactions. When pyrrolidine was used instead, the
only product, isolated in 72% yield, was compound 18,14
arising from a double aldol condensation of compounds 2
and 3, while triethylamine or DBU led to the formation of
1-(4-chlorophenyl)-2-(methylsulfonyl)-1-ethanone 19 and
pyridine failed to catalyze any reaction (Table 3).
The structure of thienothiopyrans 4 was deduced from
one- and two-dimensional NMR spectroscopic data of 4a,
4b, and 14 and confirmed by single crystal X-ray diffraction
studies of 4a and 9a (see the Supporting Information).
The mechanism proposed for the formation of thienothio-
pyrans 4-17 (Scheme 3) is in agreement with the fact that
only L-proline catalyzes the domino reactions affording the
thienothiopyrans, while the other bases led to either 18 or 19.
This may be taken as indirect evidence for the involvement of
iminium intermediate 20, which is presumably endowed with
enhanced reactivity arising from (i) polarization of the CdC
bond by the positively charged nitrogen of the iminium
functionality and (ii) the probable hydrogen bonding be-
tween the carboxyl hydrogen and sulfonyl/carbonyl oxy-
gens. This hydrogen bonding facilitates the Michael addition
(14) Karthikeyan, S. V.; Perumal, S. Tetrahedron Lett. 2007, 48, 2261.
J. Org. Chem. Vol. 75, No. 2, 2010 473

Indumathi et al.
JOCNote
SCHEME 3. Mechanistic Proposal for the Formation of 4-17
reaction and creates three carbon-carbon bonds with com-
plete regioselectivity. Furthermore, this transformation gen-
erates three stereocenters that are completely controlled
when starting from tetrahydro-3-thiophenone and a fourth
one in ca. 7:3 diastereomeric ratio starting from a 5-sub-
stituted tetrahydro-3-thiophenone derivative. Finally, the
synthetic process described here is attractive from an envi-
ronmental point of view, as it requires only simple and readily
available starting materials and an inexpensive and nontoxic
catalyst (L-proline), and has water as the only side product.
Experimental Section
Synthesis of Thienothiopyrans: General Procedure. A mix-
ture of ethyl 2-[(2-oxo-2-arylethyl)sulfonyl]acetate/ethyl 2-
[(2-ethoxy-2-oxoethyl)sulfonyl]acetate (1.6 mmol), aromatic
aldehyde (1.6 mmol), 5-aryltetrahydro-3-thiophenone (1.6
mmol), and L-proline (50 mol %) in methanol was stirred at
room temperature for 24 h. Then the reaction mixture was
extracted with CH2Cl2 (35 mL). The combined organic
extracts were washed successively with water (25 mL), dried
over anhydrous Na2SO4, and concentrated under vacuum.
The diastereomers were separated and isolated in pure form
by flash chromatography on siliga gel with petroleum
ether-ethyl acetate mixture (47:3 v/v) as eluent. Data for
two representative examples are given below. Full character-
ization data for all compounds can be found in the Support-
ing Information.
by bringing the aldol product closer to compound 1; this
assistance is obviously absent in the pyrrolidine-catalyzed
reaction, which leads simply to the double aldol product 18.
Also, this hypothesis provides an explanation for the ob-
served regioselectivity in favor of the Michael attack from
the less acidic position in compound 1, which can be
accounted for by assuming that 1 approaches 20 so that its
less hindered end is close to the Ar1 substituent. When
tertiary amines (triethylamine, DBU) are employed as bases,
these enamine-initiated processes are not possible, and the
only observed product is 19 arising from hydrolysis/decar-
boxylation of the ester group in compound 1, probably by
hydroxide anion generated from the bases and traces of
water in the reaction media.
(2R*,4R*,6R*,7R*)-Ethyl 4-(4-chlorobenzoyl)-2,7-di(4-
methylphenyl)-5,5-dioxo-3,4,5,6,7-tetrahydro-2H-thieno[3,2-
c]thiopyran-6-carboxylate (4a): isolated as a colorless solid
(0.430 g, 45%); mp 186 °C; IR νmax (KBr) 1730, 1647, 1339,
1120 cm-1; 1H NMR (300 MHz, CDCl3) δH 1.11 (3H, t, J =
7.1 Hz, COOCH2CH3), 2.33 (3H, s, CH3), 2.37 (3H, s, CH3),
2.86 (1H, ddd, J = 15.9, 5.3, 3 Hz, 3-CH2), 3.26 (1H, ddd,
J=15.9, 9.6, 3 Hz, 3-CH2), 4.05-4.19 (2H, m, COOCH2-
CH3), 4.60-4.65 (2H, m, 2-CH and 7-CH), 4.81 (1H, d, J =
11.4 Hz, 6-CH), 5.51 (1H, s, 4-CH), 7.12 (2H, d, J = 8.1 Hz,
Ar), 7.19-7.24 (4H, m, Ar), 7.35 (2H, d, J = 8.1 Hz, Ar),
7.55 (2H, d, J = 8.1 Hz, Ar), 8.04 (2H, d, J = 8.7 Hz, Ar); 13
C
NMR (75 MHz, CDCl3) δC 13.8, 21.0, 21.2, 46.5, 48.5, 49.4,
62.9, 65.0, 66.2, 116.3, 126.5, 128.6, 129.5, 129.6, 130.8,
133.7, 134.1, 137.6, 138.5, 139.6, 140.3, 141.8, 162.2, 189.4;
ee 1.4% determined by HPLC [CHIRALCEL OD-H col-
umn; hexane:2-propanol [95:5 (v/v)]; flow rate 0.5 mL/min;
λ=254 nm; tR(major)=48.98 min; tR(minor) = 65.34 min].
Anal. Calcd for C31H29ClO5S2: C, 64.07; H, 5.03. Found: C,
64.12; H, 4.97.
(2S*,4R*,6R*,7R*)-Ethyl 4-(4-chlorobenzoyl)-2,7-di(4-
methylphenyl)-5,5-dioxo-3,4,5,6,7-tetrahydro-2H-thieno[3,2-
c]thiopyran-6-carboxylate (4b): isolated as an oily liquid
(0.191 g, 20%); IR νmax (CH2Cl2) 1732, 1680, 1277, 1121
cm-1; 1H NMR (300 MHz, CDCl3) δH 1.08 (3H, t, J=7.1
Hz, COOCH2CH3), 2.28 (3H, s, CH3), 2.33 (3H, s, CH3),
2.87-3.07 (2H, m, 3-CH2), 4.00-4.21 (2H, m, COOCH2-
CH3), 4.46-4.55 (1H, m, 7-CH), 4.78 (1H, d, J = 11.1 Hz, 6-
CH), 4.92 (1H, t, J = 9.3 Hz, 2-CH), 5.56 (1H, s, 4-CH), 7.06
(2H, d, J = 8.1 Hz, Ar), 7.15-7.21 (4H, m, Ar), 7.33 (2H, d,
J=7.8 Hz, Ar), 7.53 (2H, d, J = 8.7 Hz, Ar), 8.03 (2H, d,
J=8.7 Hz, Ar); 13C NMR (75 MHz, CDCl3) δC 13.8, 21.0,
21.2, 46.5, 48.0, 51.0, 62.9, 65.2, 66.3, 116.7, 127.0, 128.7,
129.3, 129.5, 129.6, 130.8, 133.5, 134.2, 137.5, 137.7, 138.4,
Presumably, the observed products are favored on ther-
modynamic grounds since they are more stable than other
possible diastereoisomers because (i) the aryl ring at C-7 and
the ester group at C-6 are in a trans-relationship and (ii) the
aroyl group at C-4 and the ester group at C-6 are also in a
trans-relationship to minimize interactions. Furthermore, in
compounds 4a-13a the aryl ring at C-2 and the proximate
aroyl/aryl at C-4 and C-7 respectively are also in a trans-
relationship, while in the minor diastereomers 4b-13b this
relationship is cis. However, semiempirical (AM1) calcula-
tions (MacSpartan 04) indicate that compound 9a is only
0.27 kcal mol-1 more stable than 9b, and this similar
3
stability explains the relatively modest a/b diastereoselecti-
vity that we have encountered.
In conclusion, the present study reports a unique one-pot,
three-component diastereoselective synthesis of thieno[3,2-
c]thiopyrans, structurally related to pharmaceutically rele-
vant compounds via a formal [3þ2þ1]annulation. This
novel transformation involves a domino process comprising
up to nine individual steps that include an aldol conden-
sation, a Michael addition, and a 6-exo-trig ring-closing
474 J. Org. Chem. Vol. 75, No. 2, 2010

Indumathi et al.
JOCNote
140.8, 141.8, 162.1, 189.2. Anal. Calcd for C31H29ClO5S2: C,
64.07; H, 5.03. Found: C, 64.13; H, 4.96.
IRHPA program for funds for the purchase of a high-
resolution NMR spectrometer and (ii) the FIST program
and the University Grants Commission, New Delhi, for
funds under the DRS and ASIST programs. S.I. thanks
the Council of Scientific and Industrial Research,
New Delhi, for the award of a Senior Research Fellowship.
J.C.M. gratefully acknowledges financial support from
MCINN (grants CTQ2006-10930-BQU and CTQ2009-
(4R*,6R*,7R*)-Ethyl 4-(4-chlorobenzoyl)-5,5-dioxo-
7-phenyl-2,3,4,5,6,7-hexahydro-5-thieno[3,2-c]thiopyran-6-car-
boxylate (14): isolated as a pale yellow solid (0.487 g, 62%);
mp 164 °C; IR νmax (KBr) 1739, 1679, 1315, 1150 cm-1; 1H
NMR (300 MHz, CDCl3) δH 1.03 (3H, t, J = 7.1 Hz,
COOCH2CH3), 2.72-2.79 (2H, m, 3-CH2), 3.03-3.11 (1H,
m, 2-CH2), 3.16-3.26 (1H, m, 2-CH2), 4.04-4.11 (2H, m,
COOCH2CH3), 4.52 (1H, d, J=11.3 Hz, 7-CH), 4.74 (1H, d,
J=11.3 Hz, 6-CH), 5.55 (1H, s, 4-CH), 7.35-7.44 (5H, m,
Ar), 7.54 (2H, d, J = 8.7 Hz, Ar), 8.03 (2H, d, J=8.7 Hz, Ar);
13C NMR (75 MHz, CDCl3) δC 13.8, 30.0, 39.8, 46.8, 62.8,
64.8, 66.2, 118.6, 128.6, 128.8, 128.9, 129.5, 130.8, 134.1,
136.8, 140.6, 141.8, 162.2, 189.3. Anal. Calcd for C23H21-
ClO5S2: C, 57.91; H, 4.44. Found: C, 57.86; H, 4.51.
ꢀ
12320-BQU) and UCM (Grupos de Investigacion, grant
920234). Both S.M. and J.C.M. thank MCINN for funding
a joint proposal under the ACI-Colabora Scheme (grant
ACI2009-0956).
Supporting Information Available: Experimental proce-
dures, analytical data, structural study of compounds 4a, 4b,
and 14 by NMR, X-ray crystallographic determination of
compounds 4a and 9a, copies of chiral chromatogram of 4a,
and 1H, 13C, and 2D NMR spectra of new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. S.P. thanks the Department of Science
and Technology, New Delhi, for funding for a major research
project (No. SR/S1/OC-70/2006) and for funds under (i) the
J. Org. Chem. Vol. 75, No. 2, 2010 475