Zeolite mediated stereoselective synthesis of γ-alkylidenebutenolides

Article abstract of DOI:10.1081/SCC-120004083

Stereoselective synthesis of Z-γ-alkylidenebutenolides has been achieved through H-ZSM 5 mediated dehydration.

Full text of DOI:10.1081/SCC-120004083

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ZEOLITE MEDIATED STEREOSELECTIVE SYNTHESIS OF γ-
ALKYLIDENEBUTENOLIDES
N. Sundar a , Mrinal K. Kundu a , P. Veera Reddy a , G. Mahendra a & Sujata V. Bhat b
a Department of Chemistry , Indian Institute of Technology , Powai, Mumbai, 400 076, India
b Department of Chemistry , Indian Institute of Technology , Powai, Mumbai, 400 076, India
Published online: 17 Oct 2011.
To cite this article: N. Sundar , Mrinal K. Kundu , P. Veera Reddy , G. Mahendra & Sujata V. Bhat (2002) ZEOLITE MEDIATED
STEREOSELECTIVE SYNTHESIS OF γ-ALKYLIDENEBUTENOLIDES, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:12, 1881-1886, DOI: 10.1081/SCC-120004083
To link to this article: http://dx.doi.org/10.1081/SCC-120004083
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SYNTHETIC COMMUNICATIONS, 32(12), 1881–1886(2002)
ZEOLITE MEDIATED
STEREOSELECTIVE SYNTHESIS OF
c-ALKYLIDENEBUTENOLIDES
N. Sundar, Mrinal K. Kundu, P. Veera Reddy,
*
G. Mahendra, and Sujata V. Bhat
Department of Chemistry, Indian Institute of
Technology, Powai, Mumbai 400 076, India
ABSTRACT
Stereoselective synthesis of Z-ꢀ-alkylidenebutenolides has been
achieved through H-ZSM 5 mediated dehydration.
Key Words: H-ZSM 5 zeolite; Dehydration; Z-ꢀ-alkyli-
denebutenolides; Stereoselective synthesis
Butenolides[1] being the major component in several natural products
has become an interesting target in organic synthesis. Over the past few
decades, an increasing number of stereo defined ꢀ-alkylidenebutenolides[2]
have been isolated from natural sources and some of them have been
found to display a wide range of biological activities. A great variety of
substitution patterns of natural ꢀ-alkylidenebutenolides have been
observed. In view of biological activities such as inhibition of cholesterol
biosynthesis,[3] antitumor[4] and antibacterial,[5] ꢀ-alkylidenebutenolides
*Corresponding author. E-mail: svbhat@chem.iitb.ac.in
1881
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1882
SUNDAR ET AL.
have become the cynosure of synthetic organic chemistry in the recent
years.
There are several reports available in the literature for the synthesis
of ꢀ-alkylidenebutenolides via 1) 2-oxyfurans,[6] 2) ꢀ-lactones,[7] 3) maleic
anhydride.[8] However these alkylidene reactions are nonselective and yield
both E- and Z-isomers. Therefore stereoselective synthesis of either E- or
Z-stereoisomer of ꢀ-alkylidenebutenolides exclusively is always a challenge
to synthetic chemists. Recently stereoselective synthesis of ꢀ-alkylidenebute-
nolides have been reported using metal catalysed lactonization reactions
employing metals such as silver,[9] palladium,[10] rhodium[11] or use of
vinyl silanes.[12] Herein we report a simple and efficient method for the
stereoselective synthesis of ꢀ-alkylidenebutenolides under mild conditions.
The reaction of the aldehydes (1–4) with butenolide in the presence of
DABCO in dry THF gave the alcohols 1a–4a as well as the E-ꢀ-alkylidene-
butenolides 1b–4b in moderate yields (Scheme 1). The results are summar-
ized in Table 1. The dehydration of the alcohols 1a–4a using POCl3 and
pyridine in toluene at 60ꢀC was found to be non-stereoselective, which gave
Scheme 1.
Table 1. Reaction of Butenolide with Aldehydes (R-CHO) in the
Presence of DABCO
Product (% Yield)
Compound
No.
Time
(h)
Entry
R-
1a–4a
1b–4b
1
2
3
4
1
2
3
4
4-(OMe)-C6H4
2,5-(OMe)2-C6H3
C4H3S
2648
30
12
1652
8
44
56
5
14
5-(Me)-C4H3S
12

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SYNTHESIS OF c-ALKYLIDENEBUTENOLIDES
1883
Table 2. Dehydration of Compounds 1a–4a Using H-ZSM-5
Compound
No.
Time
(h)
Product
(% Yield)
Entry
1
2
3
4
1a
2a
3a
4a
12
14
11
12
1c (90.8)
2c (84.6)
3c (87.6)
4c (84.1)
both the E- and Z-ꢀ-alkylidenebutenolides. The alcohols (1a–4a) were then
dehydrated using H-ZSM 5 zeolite in dry benzene under reflux condition for
12 h, which yielded exclusively the Z-ꢀ-alkylidenebutenolides 1c–4c
(Table 2).
The microwave irradiation of a mixture of thiophene aldehyde,
butenolide and DABCO in THF yielded adduct 3a along with the corres-
ponding E-ꢀ-alkylidenebutenolide 3b.
The IR spectra of the compounds (1a–4a) showed peaks around 3500,
1774, 1740 cmꢁ1 corresponding to the hydroxyl group and five membered
lactone moiety. The absence of peak around 3500 cmꢁ1 in the IR spectra of
compounds (1c–4c) confirms the absence of hydroxyl group. The stereo-
chemistry of products 1b–4b and 1c–4c was based on the 1H NMR
(300 MHz) coupling constants of Ha and Hc protons. In compounds
1b–4b long range coupling between Ha and Hc is observed. Larger long
range couplings have been reported for the protons with trans relationship
over many bonds than those with cis relationship.[13] All compounds gave
satisfactory spectral data, and microanalysis.[14]
In conclusion, the present report constitutes a simple method for the
stereoselective synthesis of ꢀ-alkylidenebutenolides in moderate to good
yield. In view of large amount of bioacitivity associated with ꢀ-alkylidene-
butenolides the present study assumes greater importance. The methodology
is simple and has applications for industrial scale synthesis.
EXPERIMENTAL
General Procedure for Alkylation of Butenolide
Using DABCO (Compounds 1a–4a)
To a solution of appropriate aldehyde (10 mmol) in dry THF (5 ml)
was added butenolide (10 mmol, 0.84 g) followed by DABCO (1.12 g,
10 mmol) and stirred for the period mentioned in Table 1. THF was then
evaporated in vacuo and the residue was extracted with ethyl acetate,

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1884
SUNDAR ET AL.
washed with water, brine and dried over anhydrous Na2SO4. The solvent
was then evaporated in vacuo and the residue was subjected to the column
chromatography over silicagel. (100–200-mesh) using petroleum ether (b.p.
60–80ꢀC) and ethyl acetate (3 : 1) as eluant to yield compounds 1a–4a and
1b–4b. The yields are tabulated in Table 1.
General Procedure for Dehydration of Compounds 1a–4a
Using H-ZSM-5 Zeolite
To the solution of alcohol (1a–4a, 10 mmol) in dry benzene (10) was
added H-ZSM-5 zeolite (twice by weight of alcohol) and was refluxed for the
duration mentioned in Table 2. The solution was then filtered, the solid
residue was washed three times with ethyl acetate (3 ꢂ 5 ml) and the com-
bined filtrate was evaporated in vacuo. The residue was then subjected to
column chromatography over silica gel (100–200 mesh) with petroleum ether
and ethyl acetate as eluant to give the Z-ꢀ-alkylidenebutenolides 1c–4c
(Table 2).
TheCondensation of ThiopheneCarboxaldehydewith
But-2-enolidein thePresenceof Microwave
A mixture of thiophene carboxaldehyde (2 mmol, 0.244 g), but-2-eno-
lide (2 mmol, 0.168 g), DABCO (200 mg) and dry THF (5 ml) was taken in a
sealed glass tube and kept in side microwave oven for 15 min at power 5.
The sealed tube was kept outside in regular intervals of 5 min for cooling.
After 15 min the tube was opened and the residue was subjected for column
chromatography over silica gel (100–200 mesh) with petroleum ether and
ethyl acetate as eluant to yield the condensation products 3a (52%) and
3b (31%).
Compound 1b: IR (ꢁmaxCHCl3): 3090, 3020, 2918, 1775, 1742, 1640,
1540 cmꢁ1. U.V. (MeOH): ꢂmax 362.4 (ꢃmax ¼ 35960), 241.8 (ꢃmax ¼ 12425).
1H NMR (300 MHz, CDCl3): ꢄ 7.78 (1H, d, 5.5 Hz), 7.33 (2H, brd,
J ¼ 9 Hz), 6.96 (2H, d, J ¼ 9), 6.74 (1H, bd, J ¼ 1.5 Hz), 6.29 (1H, dd,
J ¼ 5.5, 1.5 Hz), 3.87 (3H, s). Mass: m/z 202 (Mþ). Anal. calcd for
C12H10O3: C, 71.28%; H, 4.98%. Found: C, 71.18%; H, 4.74%.
Compound 1c: IR (ꢁmaxCHCl3): 3108, 3022, 2927, 1778, 1748, 1643,
1551 cmꢁ1. U.V. (MeOH): ꢂmax 357.8 (ꢃmax ¼ 35804), 239.0 (ꢃmax ¼ 12392).
1H NMR (500 MHz, CDCl3): ꢄ 7.75 (2H, d, J ¼ 9 Hz), 7.45 (1H, d,
J ¼ 5.31 Hz), 6.91 (2H, d, J ¼ 9 Hz), 6.14 (1H, d, J ¼ 5.31 Hz), 5.98 (1H, s),
3.84 (3H, s). Mass: m/z 202 (Mþ). Anal. calcd for C12H10O3: C, 71.28%; H,
4.98%. Found: C, 71.12%; H, 4.84%.

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SYNTHESIS OF c-ALKYLIDENEBUTENOLIDES
1885
Compound 2b: IR (ꢁmax Neat): 3125, 2914, 1780, 1754, 1632,
1584 cmꢁ1
.
1H NMR (300 MHz, CDCl3): ꢄ 7.7 (1H, d, J ¼ 3.0 Hz), 7.5 (1H, d,
J ¼ 5.2 Hz), 7.04 (1H, s), 6.87 (1H, d, J ¼ 3.0 Hz), 6.55 (1H, s), 6.18 (1H,
dd, J ¼ 5.2 Hz, 0.6), 3.83 (3H, s), 3.81 (3H, s). Mass: m/z 232 (Mþ). Anal.
calcd for C13H12O4: C, 67.23%; H, 5.21%. Found: C, 67.05%; H, 5.09%.
Compound 2c: IR (ꢁmax CHCl3): 3120, 3090, 2920, 1788, 1755, 1650,
1591 cmꢁ1
.
1H NMR (300 MHz, CDCl3): ꢄ 7.77 (1H, d, J ¼ 2.93 Hz), 7.5 (1H, d,
J ¼ 5.31 Hz), 6.87 (1H, d, J ¼ 2.93 Hz), 6.84 (1H, s), 6.55 (1H, s), 6.18 (1H, d,
J ¼ 5.31 Hz), 3.84 (3H, s), 3.82 (3H, s). MS: m/z 232 (Mþ). Anal. calcd for
C13H12O4: C, 67.23%; H, 5.21%. Found: C, 67.17%; H, 5.16%.
Compound 3b: IR (ꢁmax CCl4): 1793, 1763, 1640 cmꢁ1
.
1H NMR (300 MHz, CDCl3): ꢄ 7.52 (1H, d, J ¼ 5.1 Hz), 7.43 (1H, d,
J ¼ 5.3 Hz), 7.17 (1H, d, J ¼ 3.6Hz), 7.0 (1H, dd, J ¼ 3.6, 5.1), 6.32 (1H, s),
6.2 (1H, dd, J ¼ 5.3, 0.7 Hz). Mass: m/z 178 (Mþ). Anal. calcd for C9H6O2S:
C, 60.66%; H, 3.39%; S, 17.99%. Found: C, 60.51%; H, 3.16%; S, 17.72%.
Compound 3c: IR (ꢁmax CCl4): 3110, 2927, 1774, 1740, 1632 cmꢁ1
.
1H NMR (300 MHz, CDCl3): ꢄ 7.52 (1H, d, J ¼ 4.9 Hz), 7.47 (1H, d,
J ¼ 5.31 Hz), 7.40 (1H, d, J ¼ 3.6Hz), 7.1 (1H, dd, J ¼ 3.6& 4.9 Hz), 6.3
(1H, s), 6.2 (1H, dd, J ¼ 5.31 Hz). Mass: m/z 178 (Mþ). Anal. calcd for
C9H6O2S: C, 60.66%; H, 3.39%; S, 17.99%. Found: C, 60.53%; H,
3.12%; S, 17.75%.
Compound 4b: IR (ꢁmax CHCl3): 1796, 1760, 1643 cmꢁ1
.
1H NMR (300 MHz, CDCl3): ꢄ 7.96(1H, d, J ¼ 5.5 Hz), 6.95 (1H, d,
J ¼ 3.5 Hz), 6.73 (1H, d, J ¼ 1.8 Hz), 6.68 (1H, m), 6.26 (1H, dd, J ¼ 5.5 &
1.8 Hz), 2.41 (3H, s). Mass: m/z 192 (Mþ). Anal. calcd for C10H8O2S: C,
62.48%; H, 4.19%; S, 16.68%. Found: C, 62.22%; H, 4.03%; S, 16.41%.
Compound 4c: IR (ꢁmax CHCl3): 1793, 1760, 1623 cmꢁ1
.
1H NMR (300 MHz, Cycle3): ꢄ 7.44 (1H, d, J ¼ 5.5 Hz), 7.17 (1H,
d, J ¼ 3.5), 6.73 (1H, DD, J ¼ 3.5 & 1.0 Hz), 6.23 (1H, s), 6.13 (1H,
d, J ¼ 5.5 Hz), 2.41 (3H, s). Mass: m/z 192 (Mþ). Anal. calcd for
C10H8O2S: C, 62.48%; H, 4.19%; S, 16.68%. Found: C, 62.24%; H,
4.03%; S, 16.45%.
ACKNOWLEDGMENT
We thank RSIC, Bombay and TIFR, Bombay for the spectral data,
and Lady Tata Trust, Bombay, CSIR and ICMR, Delhi for the financial
assistance.

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1886
SUNDAR ET AL.
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Received in the Netherlands March 9, 2001