A mild and efficient stereoselective synthesis of (Z)- and (E)-allyl sulfides and potent antifungal agent, (Z)-3-(4-methoxybenzylidene)thiochroman-4- one from Morita-Baylis-Hillman acetates

Article abstract of DOI:10.1248/cpb.55.1274

A facile stereoselective synthesis of (Z)- and (E)-allyl sulfides has been accomplished from Morita-Baylis-Hillman acetates in one-pot by treatment with benzene thiol in the presence of catalytic amounts of 15% aqueous NaOH and TBAI in DMSO at room temper

Full text of DOI:10.1248/cpb.55.1274

1274
Notes
Chem. Pharm. Bull. 55(8) 1274—1276 (2007)
Vol. 55, No. 8
A Mild and Efficient Stereoselective Synthesis of (Z)- and
(E)-Allyl Sulfides and Potent Antifungal Agent,
(Z)-3-(4-Methoxybenzylidene)thiochroman-4-one from
Morita–Baylis–Hillman Acetates1)
Biswanath DAS,* Nikhil CHOWDHURY, Kongara DAMODAR, and Joydeep BANERJEE
Organic Chemistry Division–I, Indian Institute of Chemical Technology; Hyderabad–500 007, India.
Received March 27, 2007; accepted May 16, 2007
A facile stereoselective synthesis of (Z)- and (E)-allyl sulfides has been accomplished from Morita–
Baylis–Hillman acetates in one-pot by treatment with benzene thiol in the presence of catalytic amounts of 15%
aqueous NaOH and TBAI in DMSO at room temperature. The method has been applied for the synthesis of
(Z)-3-(4-methoxybenzylidene)thiochroman-4-one, a potent antifungal compound.
Key words Morita–Baylis–Hillman acetate; benzene thiol; (Z)-allyl sulfide; (E)-allyl sulfide; (Z)-3-(4-methoxybenzylidene)-
thiochroman-4-one; antifungal compound
Allyl sulfides have gained significant importance as a class (Chart 1, Table 1). Thus, 3-acetoxy-2-methylene alkanoates 1
of useful scaffold in organic synthesis.2—4) They are used as (Morita–Baylis–Hillman acetates derived from acrylate es-
valuable synthons for the various organic transformations5—7) ters) on similar treatment afforded the corresponding (Z)-
including imidation and subsequent sigmatropic rearrange- allyl phenyl sulfides 3 while 3-acetoxy-2-methylene alkanen-
ments8) and thio-Claisen rearrangement.9) They also served itriles 2 (Morita–Baylis–Hillman acetates derived from ac-
as important synthetic intermediates in agricultural and phar-
maceutical chemistry.10,11) Hence, the development of effi-
cient methodology for their synthesis is highly essential.
Here the Morita–Baylis–Hillman chemistry12—14) has been
applied for the synthesis of these compounds.
Table 1. Stereoselective Synthesis of (Z)-Allylphenyl Sulfides 3a) and (E)-
Allylphenyl Sulfides 4a) from Baylis–Hillman Acetates
Entry Baylis–Hillman acetates
Productsb)
Isolated yields (%)
92
The Morita–Baylis–Hillman reaction is a versatile C–C
bond forming reaction which provides functionalized
adducts.12—14) These adducts and their derivatives have
widely been explored for the stereoselective synthesis of
trisubstituted alkenes and biologically active natural prod-
ucts.15—20) Nucleophilic displacement of the Morita–Baylis–
Hillman acetates is an important protocol for the synthesis of
trisubstituted alkenes in organic chemistry. Although there
exist several methods for the nucleophilic displacement
of Morita–Baylis–Hillman acetates with various reagents
such as metal halides,21) metal hydrides,22,23) amide,24,25)
cyanide,26,27) amine28,29) and azide26,27,30) those afford a vari-
ety of trisubstituted alkenes, displacement with sulfur nucle-
ophiles is limited.31,32)
In connection with our ongoing research to develop the
new synthetic routes for the preparation of trisubstituted
alkenes33—43) using Morita–Baylis–Hillman adducts, herein
we wish to report a one-pot stereoselective synthesis of
trisubstituted (Z)- and (E)-allyl sulfides from Baylis–Hillman
acetates by treatment with benzene thiol in the presence of
catalytic amounts of 15% aqueous NaOH and TBAI (tetra-
butylammonium iodide) in DMSO at room temperature
3a
3b
3c
3d
3e
86
89
79
82
75
3f
73
80
3g
4a
4b
77
74
71
4c
4d
a) All the products were characterized from their IR, 1H- and 13C-NMR, and MS
spectral data. b) E/Z ratio was determined by the 1H-NMR spectra of the crude prod-
ucts. The other regiomers of the products 4a—d were obtained in ca. 5% yields.
Chart 1
∗ To whom correspondence should be addressed. e-mail: biswanathdas@yahoo.com
© 2007 Pharmaceutical Society of Japan

August 2007
1275
rylonitrile) afforded (E)-allyl phenyl sulfides 4.
of the prepared allyl sulfides (3, 4). The stereochemistry of 3
Initially the conversion of 1a (RꢀPh, EWGꢀCOOMe) and 4 can possibly be explained16,42,43) by considering the
with PhSH was carried out with only aqueous NaOH solu- transition state models A, B and C (Fig. 1). Transition state
tion of different concentrations. The yield of the desired A is more favored than B when EWG is an ester and (Z)-
product was low. The reaction was next attempted with the products are formed exclusively. On the other hand, model C
addition of a Phase transfer catalyst (such as TBAF, TBAB or is more favored than A when the EWG is a nitrile as –CN is
TBAI) and using a solvent (such as DMF, DMSO or THF). linear and hence the (E)-products are formed predominantly.
Considering the yield and the reaction time the best result
The present method has been applied for the synthesis of
was obtained by using catalytic amount of the combination the antifungal compound, (Z)-3-(4-methoxybenzylidene)-
of 15% aqueous NaOH and TBAI in DMSO. By the addition thiochroman-4-one (5). The compound was found to be
of the phase transfer catalyst (TBAI) the yield of the product significantly active in vitro against the pathogenic fungi,
was increased due to an increased solubility of nucleophile Candida albicans (MICꢀ6 mg/ml) and Torulopsis glabrata
into organic phase. Subsequently utilizing these reagents and (MICꢀ6 mg/ml).51) The allyl sulfide 3c was utilized for the
DMSO, a series of (Z)- and (E)-allyl phenyl sulfides (3, 4) synthesis of 5. The ester group of 3c was hydrolyzed with
were prepared from various Morita–Baylis–Hillman acetates aqueous KOH to produce the corresponding acid 3c1. This
(1, 2). Alkyl, halogen, ether and ester remained intact. The acid 3c1 was next cyclized with TFAA in anhydrous CH2Cl2
Morita–Baylis–Hillman acetates 1 and 2 underwent the con- under reflux to form 5 in high yield (Chart 2). The spectral
version with equal ease. However, the conversions of those (IR, 1H- and 13C-NMR and MS) data of the compound
derived from aliphatic aldehydes (entry 3f, 3g, 4d) were clearly established its structure.
somewhat low. Moreover, the preparation of allyl sulfides
from 1 and 2 generated from aromatic aldehydes required only protocol for stereoselective one-pot synthesis of (Z)- and (E)-
0.5 h while generated from aliphatic aldehydes required 1 h. allyl phenyl sulfides from Morita–Baylis–Hillman acetates
In conclusion, we have developed a new, mild and simple
The present conversion is highly stereoselective. Adduct 1 by treatment with benzene thiol in the presence of catalytic
afforded allyl phenyl sulfides solely with (Z)-stereoselectivity amount of the combination of 15% aqueous NaOH and TBAI
while 2 afforded allyl phenyl sulfides with (E)-stereoselectiv- in DMSO as a solvent. The prepared compounds can be uti-
ity. The structures and stereochemistry of the products were lized for synthesis of useful heterocycles by thio-Claisen
1
confirmed from their spectral IR, H- and 13C-NMR and MS rearrangement and other methods. The present protocol has
data. The (Z)- and (E)-stereochemistry of the allyl sulfides been applied for the synthesis of the potent antifungal com-
could easily be settled from the assignment of the chemical pound, (Z)-3-(4-methoxybenzylidene)thiochroman-4-one.
1
shift values of the vinyl protons in their H-NMR spectra. It
Experimental
is reported that b-vinylic proton cis and trans to the ester
General Procedure for the Synthesis of Allyl Phenyl Sulfides 3 and 4
To a solution of benzenethiol (110 mg, 1 mmol) dissolved in DMSO (5 ml)
were added TBAI (15 mg) and 15% aqueous NaOH solution (0.5 ml). The
mixture was stirred at room temperature for 30 min. The Baylis–Hillman
acetate 1 or 2 (1 mmol) was added and the solution stirred for another 30 or
60 min. After completion of the reaction (monitored by TLC), the mixture
was quenched with water (5 ml) and extracted with Et2O (3ꢁ10 ml). The
organic layer was dried (Na2SO4) and concentrated. The crude product was
group resonates at ca. d 7.5 and 6.5 respectively when R is
aryl.18,44) The same proton cis and trans to the ester group ap-
pears at ca. d 6.8 and 5.7 respectively when R is alkyl.45,46)
Similarly the b-vinylic proton cis and trans to the nitrile
group appears at ca. d 7.6 and 6.8 respectively when R is
aryl47,48) while the same proton cis and trans to the nitrile
group resonates at ca. d 6.3 and 6.1 when R is alkyl.49,50)
purified by column chromatography (silica gel, 2% EtOAc in hexane) to
afford the pure (Z)- or (E)-allyl phenyl sulfide 3 or 4.
These values are useful in determining the stereochemistry
The spectral (IR, H- and 13C-NMR and MS) and analytical data of some
1
representative products are given below.
Product 3a: Colorless oil; IR (KBr): nmax 1725, 1622, 1591, 1463 cmꢂ1
;
1H-NMR (CDCl3, 200 MHz): d 7.71 (1H, s), 7.39—7.28 (6H, m), 7.23—
7.14 (4H, m), 3.99 (2H, s), 3.78 (3H, s); 13C-NMR (CDCl3, 75 MHz): d
167.2, 141.0, 136.1, 135.4, 134.2, 132.0, 130.4, 128.8, 128.5, 128.2, 128.0,
127.7, 126.1, 51.6, 31.7; FAB-MS: m/z 307 [MꢃNa]ꢃ.
Product 3c: Colorless oil; IR (KBr): nmax 1722, 1633, 1585, 1478 cmꢂ1
;
1H-NMR (CDCl3, 200 MHz): d 7.70 (1H, s), 7.50—7.33 (4H, m), 7.32—
Fig. 1.
7.17 (3H, m), 6.92—6.81 (2H, m), 4.05 (2H, s), 3.85 (3H, s), 3.77 (3H, s);
Chart 2

1276
Vol. 55, No. 8
13C-NMR (CDCl3, 75 MHz): d 168.1, 160.4, 141.8, 136.5, 131.5, 130.4, 128.6,
127.5, 126.8, 125.9, 114.4, 55.2, 52.1, 32.6; FAB-MS: m/z 337 [MꢃNa]ꢃ.
16) Buchholz R., Hoffmann H. M. R., Helv. Chim. Acta, 74, 1213—1220
(1991).
17) Basavaiah D., Krishnamacharyulu M., Hyma R. S., Sarma P. K. S.,
Kumaragurabaran N., J. Org. Chem., 64, 1197—1200 (1999).
Product 3f: Colorless oil; IR (KBr): nmax 1718, 1642, 1437, 1288 cmꢂ1
;
1H-NMR (CDCl3, 200 MHz): d 7.40 (2H, dd, Jꢀ8.0, 2.0 Hz), 7.28—7.19
(3H, m), 6.79 (1H, t, Jꢀ7.0 Hz), 3.75 (5H, s), 1.99—1.87 (2H, m), 1.38— 18) Basavaiah D., Sarma P. K. S., Bhavani A. K. D., J. Chem. Soc., Chem.
1.12 (6H, m), 0.90 (3H, t, Jꢀ7.0 Hz); 13C-NMR (CDCl3, 75 MHz): d 167.2,
Commun., 1994, 1091—1092 (1994).
145.8, 135.9, 132.2, 128.5, 128.0, 127.2, 52.6, 31.2, 28.5, 28.2, 22.0, 13.7; 19) Park D. Y., Gowrisankar S., Kim J. N., Tetrahedron Lett., 47, 6641—
FAB-MS: m/z 301 [MꢃNa]ꢃ.
6645 (2006).
Product 4a: Colorless oil; IR (KBr): nmax 2218, 1588, 1486, 1405 cmꢂ1
;
20) Das B., Banerjee J., Chowdhury N., Majhi A., Mahender G., Helv.
Chim. Acta, 89, 876—883 (2006).
21) Basavaiah D., Bhavani A. K. D., Pandiraju S., Sarma P. K. S., Synlett,
1995, 243—244 (1995).
22) Basavaiah D., Sarma P. K. S., J. Chem. Soc., Chem. Commun., 1992,
955—957 (1992).
1H-NMR (CDCl3, 200 MHz): 7.61—7.20 (10H, m), 6.60 (1H, s), 3.72 (2H,
s); 13C-NMR (CDCl3, 75 MHz): d 144.7, 133.4, 132.5, 131.7, 130.3, 128.8,
128.6, 128.5, 127.9, 112.3, 107.4, 41.0; FAB-MS: m/z 274 [MꢃNa]ꢃ.
Product 4d: Colorless oil; IR (KBr): nmax 2219, 1633, 1582, 1439 cmꢂ1
;
1H-NMR (CDCl3, 200 MHz): d 7.38 (2H, dd, Jꢀ8.0, 2.0 Hz), 7.32—7.20
(3H, m), 5.92 (1H, t, Jꢀ7.0 Hz), 3.53 (2H, s), 2.31—2.20 (2H, m), 1.31— 23) Rabe J., Hoffmann H. M. R., Angew. Chem. Int. Ed. Engl., 22, 796—
1.09 (6H, m), 0.85 (3H, t, Jꢀ7.0 Hz); 13C-NMR (CDCl3, 75 MHz): d 149.7,
799 (1983).
132.1, 128.8, 127.2, 116.2, 111.0, 38.4, 30.9, 30.3, 27.1, 21.6, 13.1; FAB- 24) Kim J. N., Chung Y. M., Im Y. J., Tetrahedron Lett., 43, 6209—6211
MS: m/z 268 [MꢃNa]ꢃ.
(2002).
Synthesis of (Z)-3-(4-Methoxybenzylidene)thiochroman-4-one Con-
25) Chung Y. M., Lee H. J., Hwang S. S., Kim J. N., Bull. Korean Chem.
Soc., 22, 799—800 (2001).
version of 3c into 3c1: To a stirred solution of the allyl sulfide 3c (2 mM,
0.628 g) in acetone (1 ml) was added aqueous KOH (2 g in 5 ml water) at 26) Jadav J. S., Gupta M. K., Pandey S. K., Reddy B. V. S., Sarma A. V. S.,
room temperature. After 20 h, the reaction mixture was neutralized with cold Tetrahedron Lett., 46, 2761—2763 (2005).
conc. HCl and extracted with ether (3ꢁ10 ml). The combined organic layer 27) Fuocaud A., EI Guemmount F., Bull. Soc. Chim. Fr., 1989, 403—405
was dried over anhydrous Na2SO4. The solvent was evaporated and the crude
product was purified by crystallization (in MeOH) to afford pure 3c1 in 85%
yield (0.492 g), as a white solid, mp 210—212 °C; IR (KBr): nmax 3449,
(1989).
28) Basavaiah D., Satyanarayana T., Tetrahedron Lett., 43, 4301—4303
(2002).
29) Kundu M. K., Bhat S. V., Synth. Commun., 29, 93—101 (1999).
1
1671, 1600, 1511, 1267 cmꢂ1; H-NMR (CDCl3, 200 MHz): d 7.86 (1H, s),
7.51 (2H, d, Jꢀ8.0 Hz), 7.42 (2H, d, Jꢀ8.0 Hz), 7.31—7.24 (3H, m), 6.90 30) Basavaiah D., Dharma Rao P., Suguna H. R., Tetrahedron, 52, 8001—
(2H, d, Jꢀ8.0 Hz), 4.09 (2H, s), 3.82 (3H, s); FAB-MS: m/z 323 [MꢃNa]ꢃ.
Cyclization of 3c1: To a stirred solution of 3c1 (1 mM, 0.3 g) in anhydrous
dichloromethane was added trifluoroacetic anhydride (TFAA, 1 mM, 0.210 g)
8062 (1996).
31) Liu Y., Xu X., Zheng H., Xu D., Xu Z., Zhang Y., Synlett, 2006, 571—
574 (2006).
and heated under reflux for 1 h. The reaction mixture was diluted with water 32) Srihari P., Singh A. P., Jain R., Yadav J. S., Synthesis, 2006, 2772—
(4 ml) and extracted with ether (3ꢁ10 ml). The combined organic extract 2776 (2006).
was dried over anhydrous Na2SO4. The solvent was evaporated and the crude 33) For our contribution to the stereoselective synthesis of trisubstituted
solid obtained was crystallized (3% EtOAc in hexane) to provide 5 as a yel-
alkenes using Baylis–Hillman adducts and their derivatives, see ref.
Das B., Chowdhury N., Banerjee J., Majhi A., Tetrahedron Lett., 47,
6615—6618 (2006).
low crystalline solid in 92% yield (0.259 g), mp 133—136 °C; IR (KBr):
nmax 3448, 1663, 1609, 1588, 1438, 1294 cmꢂ1 1H-NMR (CDCl3, 200
;
MHz): d 8.19 (1H, d, Jꢀ8.0 Hz), 7.78 (1H, s), 7.39 (2H, d, Jꢀ8.0 Hz),
7.34—7.22 (3H, m), 6.98 (2H, d, Jꢀ8.0 Hz), 4.18 (2H, s) 3.85 (3H, s); 13C-
NMR (CDCl3, 75 MHz): d 185.2, 160.0, 141.1, 137.6, 132.5, 132.2, 131.0,
130.7, 130.1, 127.3, 127.1, 125.4, 113.8, 55.1, 29.2; FAB-MS: m/z 305
[MꢃNa]ꢃ.
34) Das B., Majhi A., Banerjee J., Chowdhury N., Tetrahedron Lett., 47,
7619—7623 (2006).
35) Das B., Banerjee J., Chowdhury N., Majhi A., Holla H., Synlett, 2006,
1879—1882 (2006).
36) Das B., Chowdhury N., Banerjee J., Majhi A., Mahender G., Chem.
Lett., 35, 358—359 (2006).
Acknowledgement The authors thank CSIR and UGC, New Delhi for
financial assistance.
37) Das B., Majhi A., Banerjee J., Chowdhury N., Venkateswarlu K.,
Tetrahedron Lett., 46, 7913—7915 (2005).
38) Das B., Majhi A., Banerjee J., Chowdhury N., Venkateswarlu K.,
Chem. Lett., 34, 1192—1193 (2005).
References and Notes
1) Part 108 in the series, “Studies on Novel Synthetic Methodologies and 39) Das B., Mahender G., Chowdhury N., Banerjee J., Synlett, 2005,
Their Applications.”
1000—1002 (2005).
2) Evans D. A., Andrews G. C., Acc. Chem. Res., 7, 147—155 (1974).
3) Werstiuk N. H., Tetrahedron, 39, 205—268 (1983).
4) Block E., “Reactions of Organosulfur Compounds,” Academic Press,
New York, 1978.
40) Das B., Banerjee J., Majhi A., Mahender G., Tetrahedron Lett., 45,
9225—9227 (2004).
41) Das B., Banerjee J., Mahender G., Majhi A., Org. Lett., 6, 3349—3352
(2004).
5) Streiff S., Ribeiro N., Desaubry L., J. Org. Chem., 69, 7592—7598
(2004).
42) Das B., Banerjee J., Ravindranath N., Tetrahedron, 60, 8357—8361
(2004).
6) Perales J. B., Makino N. F., van Vanken D. L., J. Org. Chem., 67,
6711—6717 (2002).
43) Das B., Banerjee J., Ravindranath N., Venkataiah B., Tetrahedron Lett.,
45, 2425—2426 (2004).
7) Conrad J. C., Parnas H. H., Snelgrove J. L., Fogg D. E., J. Am. Chem. 44) Larson G. L., dekaifer C. F., Seda R., Torres L. E., Ramirez J. R., J.
Soc., 127, 11882—11883 (2005).
Org. Chem., 49, 3385—3388 (1984).
8) Bach T., Körber C., J. Org. Chem., 65, 2358—2367 (2000).
9) Castro A. M. M., Chem. Rev., 104, 2939—3002 (2004).
10) Wood J. L., Org. React., 3, 240—245 (1946).
45) Baraldi P. G., Guarneri M., Pollini G. P., Simoni D., Barco A., Benetti
S., J. Chem. Soc., Perkin Trans. 1, 1984, 2501—2505 (1984).
46) Tanaka K., Yamagishi N., Tanikaga R., Kaji A., Bull. Chem. Soc. Jpn.,
52, 3619—3625 (1979).
11) Guy R. G., “The Chemistry of Thiocyanates and Their Thio Deriva-
tives,” Part 2, Chap. 18, ed. by Patai S., Wiley, New York, 1977, p. 47) Minami I., Yahara M., Shimizu I., Tsuji J., J. Chem. Soc., Chem. Com-
819.
mun., 1986, 118—119 (1986).
12) Morita K., Suzuki Z., Hirose H., Bull. Chem. Soc. Jpn., 41, 2815
(1968).
48) Oda M., Yamamura A., Watabe T., Chem. Lett., 1979, 1427—1428
(1979).
13) Baylis A. B., Hillman M. E. D., German Patent 2155113 (1972)
[Chem. Abstr., 77, 34174q (1972)].
49) Matsuda I., Okada H., Izumi Y., Bull. Chem. Soc., Jpn., 56, 528—532
(1983).
14) Basavaiah D., Rao A. J., Satyanarayana T., Chem. Rev., 103, 811—891
(2003) and references cited therein.
50) Boche G., Buckl K., Martens D., Schneider D. R., Tetrahedron Lett.,
1979, 4967—4970 (1979).
15) Hoffmann H. M. R., Rabe J., Angew. Chem. Int. Ed. Engl., 24, 94—
110 (1985).
51) Nakib T. Al., Bezjak V., Meegan M. J., Chandy R., Eur. J. Med. Chem.,
25, 455—462 (1990).