Titanocene(III) chloride mediated radical-induced one-pot synthesis of α-methylene-γ-butyrolactones

Article abstract of DOI:10.1016/j.tetlet.2007.03.036

A simple and efficient methodology has been developed for the one-pot preparation of α-methylene-γ-butyrolactones by free-radical induced Barbier-type reaction of methyl 2-(bromomethyl)acrylate and aldehydes followed by in situ lactonization. The radical

Full text of DOI:10.1016/j.tetlet.2007.03.036

Tetrahedron Letters 48 (2007) 3205–3207
Titanocene(III) chloride mediated radical-induced one-pot
synthesis of a-methylene-c-butyrolactones
Moumita Paira, Biplab Banerjee, Samaresh Jana,
Samir Kumar Mandal and Subhas Chandra Roy*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 17 January 2007; revised 27 February 2007; accepted 7 March 2007
Available online 12 March 2007
Abstract—A simple and efficient methodology has been developed for the one-pot preparation of a-methylene-c-butyrolactones by
free-radical induced Barbier-type reaction of methyl 2-(bromomethyl)acrylate and aldehydes followed by in situ lactonization. The
radical initiator titanocene(III) chloride (Cp2TiCl) was easily generated in situ from commercially available Cp2TiCl2 and activated
zinc dust in THF. Ketones remained unaffected under the reaction conditions.
ꢀ 2007 Elsevier Ltd. All rights reserved.
a-Methylene-c-butyrolactones are versatile structural
i) Cp2TiCl / THF
CHO
units present in various important natural products
which exhibit interesting biological activities such as
antibacterial, anticancer, antimalarial, inhibition of
microbial and plant growth, and both convulsant and
anti-convulsant activity.1 Due to their widespread
occurrence in nature and broad range of biological
activities, much attention has been devoted to the syn-
thesis of a-methylene-c-butyrolactones. Several methods
are available for the introduction of an exo-methylene
unit into a c-lactone ring,2 and for organometal-medi-
ated nucleophilic 2-carboalkoxyallylation of carbonyl
compounds.3 In continuation of our studies4 towards
radical-promoted carbon–carbon bond formation reac-
tions, we have developed a mild and efficient method
for the one-pot synthesis of a-methylene-c-butyrolac-
tones using the Ti(III)-mediated 2-carbomethoxyallyl-
ation of aldehydes followed by treatment with aqueous
20% H2SO4 which promoted in situ lactonization
(Scheme 1). The radical initiator Cp2TiCl was easily gen-
erated in situ from commercially available Cp2TiCl2 and
activated Zn dust in THF.5 Although several efficient
methodologies are reported in the lit.,3 the present meth-
odology is comparable in terms of mildness, simplicity
and product yields.
COOMe
Br
rt, 5 h
O
+
O
ii) 20% H2SO4
5 h - 11 h
48-68%
R
R
1
2
Scheme 1.
Thus a series of aldehydes was treated with methyl 2-
(bromomethyl)acrylate in the presence of Cp2TiCl and
the results are summarized in Table 1. Aromatic alde-
hydes 1a–j, aliphatic aldehydes 1k, m and conjugated
aldehyde 1l reacted smoothly to give the corresponding
lactones 2a–m in moderate to good yields.6 All the prod-
ucts were characterized by IR, NMR and HRMS and
were compared with authentic samples.3e–j Sensitive
functionalities such as chloro, allylic and propargylic
groups remained unaffected under the reaction condi-
tions. In the case of a,b-unsaturated aldehyde 1l, the
reaction proceeded exclusively via a 1,2-addition pro-
ducing lactone 2l in good yield. Reaction of methyl
2-(bromomethyl)acrylate with allyl and propargyl pro-
tected salicylaldehydes 1h and 1i furnished the expected
lactones 2h and 2i, respectively, without any intramole-
cular cyclization as previously observed in our labora-
tory.7 This is probably due to the fact that the
formation of radicals from methyl 2-(bromomethyl)-
acrylate is much faster compared to the aldehydes.
It is noteworthy that under the reaction conditions,
ketones such as acetophenone and cyclohexanone did
Keywords: Titanocene(III) chloride; Radical reaction; a-Methylene-
c-butyrolactones.
*
Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473
2805; e-mail: ocscr@iacs.res.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.036

3206
M. Paira et al. / Tetrahedron Letters 48 (2007) 3205–3207
Table 1. Cp2TiCl Mediated synthesis of a-methylene-c-butyrolactones
Entry
1
Substrate
Product
Time (h)
12
Yielda (%)
64
CHO
O
O
1a
2a
CHO
O
O
O
O
O
2
16
62
O
1b
2b
MeO
MeO
CHO
MeO
MeO
O
O
3
4
14
10
61
68
1c
2c
CHO
OMe
O
O
O
Me
Me
Me
Me
OMe
1d
1e
2d
CHO
O
5
12
52
2e
2f
CHO
O
O
6
7
15
14
48
60
Cl
Cl
1f
CHO
O
O
MeO
MeO
1g
2g
CHO
O
O
O
8
12
62
O
O
1h
2h
CHO
O
O
O
O
9
10
11
13
12
16
66
59
51
1i
2i
CHO
CHO
CHO
O
1j
2j
O
O
O
O
1k
1l
2k
12
13
10
15
63
67
2l
n-C5H11CHO
1m
O
n-C H
O
5
11
2m
a Yield refers to pure isolated product.

M. Paira et al. / Tetrahedron Letters 48 (2007) 3205–3207
3207
14, 481–484; (e) Uneyama, K.; Ueda, K.; Torii, S. Chem.
Lett. 1986, 15, 1201–1202; (f) Zhou, J.-Y.; Jia, Y.; Yao,
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hury, P. K.; Foubelo, F.; Yus, M. Tetrahedron Lett. 1998,
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S.-H.; Chu, S.-F. Tetrahedron Lett. 2002, 43, 8489–8492; (k)
Mattes, H.; Benezra, C. Tetrahedron Lett. 1985, 26, 5697–
5698.
not undergo lactone formation, but instead self-coupling
products of methyl 2-(bromomethyl)acrylate were gen-
erated by radical-induced dimerization.
In conclusion, we have developed a mild and efficient
methodology for the preparation of synthetically impor-
tant substituted a-methylene-c-butyrolactones in satis-
factory yields via titanocene(III) chloride promoted
radical Barbier-type reaction of methyl 2-(bromo-
methyl)acrylate and aldehydes followed by in situ
lactonization.
4. (a) Mandal, P. K.; Maiti, G.; Roy, S. C. J. Org. Chem.
1998, 63, 2829–2834; (b) Roy, S. C.; Rana, K. K.; Guin, C.
J. Org. Chem. 2002, 67, 3242–3248; (c) Jana, S.; Guin, C.;
Roy, S. C. Tetrahedron Lett. 2004, 45, 6575–6577; (d) Jana,
S.; Guin, C.; Roy, S. C. Tetrahedron Lett. 2005, 46, 1155–
1157; (e) Mandal, S. K.; Jana, S.; Roy, S. C. Tetrahedron
Lett. 2005, 46, 6115–6117.
Acknowledgements
We thank the Department of Science and Technology,
New Delhi for financial assistance. M.P., S.J. and
S.K.M. thank the CSIR, New Delhi for awarding
fellowships.
5. RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994,
116, 986–997, and references cited therein.
6. Representative procedure: A solution of titanocene dichlo-
ride (249 mg, 1 mmol) in dry deoxygenated THF (10 mL)
was stirred with activated zinc dust (196 mg, 3 mmol)
(activated zinc dust was prepared by washing 20 g of
commercially available zinc dust with 60 mL of 4 N HCl
followed by thorough washing with water until the wash-
ings became neutral and finally washing with dry acetone
and then drying in vacuo) for 1 h under argon. The
resulting green solution was added dropwise to a stirred
solution of aldehyde 1i (80 mg, 0.5 mmol) and methyl
2-(bromomethyl)acrylate (90 mg, 0.5 mmol) in dry THF
(5 mL) over 1 h at room temperature under argon. The
reaction mixture was further stirred for an additional 4 h
and then decomposed by stirring with 20% aqueous H2SO4
(15 mL) for 11 h. Most of the THF was removed under
reduced pressure and the residue obtained was extracted
with diethyl ether (4 · 25 mL). The combined ether
layer was successively washed with aqueous NaHCO3
(2 · 15 mL), water (2 · 10 mL), brine (10 mL) and finally
dried (Na2SO4). After removal of the solvent under reduced
pressure, the crude residue obtained was purified by column
chromatography over silica gel (10% ethyl acetate in
petroleum ether) to afford lactone 2i (76 mg, 66%) as a
viscous oil. IR (neat): 1764, 1604, 1492, 1249, 1224, 1130,
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