Reaction of substituted alkynols with alkoxycarbene complexes of chromium: a facile synthesis of substituted α,β-unsaturated-γ-butyrolactones

Article abstract of DOI:10.1016/j.tetlet.2009.06.076

Substituted α,β-unsaturated-γ-butyrolactones, were synthesized from Fischer chromium carbenes and substituted alkynols in a two-step sequence. This method demonstrates a novel and mild route for the synthesis of this class of molecules.

Full text of DOI:10.1016/j.tetlet.2009.06.076

Tetrahedron Letters 50 (2009) 5001–5004
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Tetrahedron Letters
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Reaction of substituted alkynols with alkoxycarbene complexes of chromium:
a facile synthesis of substituted
a,b-unsaturated-
c-butyrolactones
b
b
b
Subhabrata Sen a, , Kailaskumar Borate , Parag Kulkarni , Nandini R. Pai
*
a BASF-India Limited, Research and Development, 12 TTC Area, Thane Belapur Road, Turbhe, Navi Mumbai 400 705, Maharashtra, India
b Department of Chemistry, D. G. Ruparel College, Matunga, Mumbai 400 016, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted
a,b-unsaturated-c-butyrolactones, were synthesized from Fischer chromium carbenes and
Received 20 March 2009
Revised 11 June 2009
Accepted 16 June 2009
Available online 18 June 2009
substituted alkynols in a two-step sequence. This method demonstrates a novel and mild route for the
synthesis of this class of molecules.
Ó 2009 Elsevier Ltd. All rights reserved.
a
,b-Unsaturated-
c
-butyrolactones are key structural subunits
ylenebutyrolactones (other than 3k) are unstable. We observed
that these molecules start converting to ,b-unsaturated-
belonging to a number of molecules with pronounced biological
activity. These range from (À)-Arctigenins, a bisbenzylobutyrolac-
tone that exhibits anti-HIV properties1 to Asimicin2 and Bullata-
cin3, two diastereomeric members of the Annonaceous
acetogenins which are not only known for their anti-tumor
activity but also known for being potent anti-malarial, immuno-
suppressive, pesticidal, and anti-feedant agents. Their profound
biological activity led to various strategies for the synthesis of
these compounds.4–13
In the late 1990s, Kerr and Mori had described reactions of alk-
oxy Fischer chromium carbenes with terminal alkynols toward the
synthesis of 4–7-membered lactones.14,15 Taking a cue from their
work we have developed a novel approach toward the synthesis
a
c-
butyrolactones (4) within 15–20 min of isolation. Hence we could
only obtain the weight of the isolated product and a quick 1H/13
NMR for these molecules.
C
It is also known from the literature that
lactones such as 3 undergo rearrangement in the presence of
TsOH to furnish ,b-unsaturated-
-butyrolactones.19 Hence to
facilitate the conversion of to 4, we further treated the
intermediate -methylenebutyrolactones (3a–k) with methane-
sulfonic acid (MSA) in aq.THF to generate the desired ,b-unsat-
urated- -butyrolactones. All but 3k were converted successfully
to the desired ,b-unsaturated- -methylenebutyrolactones 4a–j
c-methylenebutyro-
a
c
3
c
a
c
a
c
(Table 2). In the case of 3k, we could only isolate the unreacted
of substituted
a,b-unsaturated-c-butyrolactones by rearrange-
starting material.
ment of -methylenebutyrolactones derived from alkoxy Fischer
c
To improve the procedure we have performed a one-pot synthe-
chromium carbene complexes 1a,b and substituted alkynols 2a–j
sis of a,b-unsaturated-c-butyrolactone from the corresponding
(Table 1).
carbene and alkynol. As an example, carbene 2f was reacted with
1a. Once the carbene was consumed the crude reaction mixture
was further treated with MSA and water and stirred for 2–3 days.
The desired product 4f was obtained as colorless oil after column
purification (isolated yield 37%).
The structures of compounds 3a–j and 4a–j were clearly distin-
guished from the 1H NMR spectra. The 1H NMR of 3a showed a sin-
glet at d 4.40 corresponding to the benzylic proton, which was
missing in 4a, also the ethereal alkyl group present in 3a was
absent in 4a (Scheme 1).
The alkoxy Fischer chromium carbene complexes 1a–b and
alkynes 2a–j used in the reaction were prepared using standard
literature procedures.16–18
The key reaction between alkoxy Fischer chromium carbenes
and substituted alkynols was performed under thermal condi-
tions in the presence and absence of solvents. While the reactions
in solvents (viz THF, toluene, and o-xylene) gave poor yields
(17–58%), the solvent-free reaction conditions generated the
butyrolactones in decent yields. The reaction time was consider-
ably reduced (from 8 to 0.5 h) (Table 1). However these
c
-meth-
A plausible mechanism for the formation of the intermediate
c
-methylenebutyrolactones (3a–j) is depicted in Scheme 2. This
mechanism is based on the work by Solà and co-workers.20
In conclusion, we have described a facile synthesis of substi-
tuted racemic butyrolactones via Fischer chromium carbenes and
substituted alkynols. Work is in progress toward understanding
the mechanism for conversion of 3a–j to 4a–j and toward
* Corresponding author. Tel.: +91 120 436 3222; fax: +91 120 258 0310.
E-mail addresses: subhabrata_sen@jchemsys.com, organic6@hotmail.com
(S. Sen).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.076

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S. Sen et al. / Tetrahedron Letters 50 (2009) 5001–5004
Table 1
Reactions of alkoxy Fischer chromium carbenes with alkynols
R4
R1 R2
R3
R3
Compound
Solvent
or Solvent Free
60-80 ºC
2a / 3a
2b / 3b
2c / 3c
2d / 3d
2e / 3e
2f / 3f
n-Bu Me Me p-Me
n-Bu Me Me p-OMe
R2
R4
O
O
O
R1
n-Bu Me
n-Bu Me
n-Bu Me Et
n-Bu Me
n-Bu Me
n-Bu Me
n-Bu Me
Me
n-Bu Me
H
Et
o-Me
p-Me
p-OMe
p-OMe
p-Me
H
p-F
p-t-Bu
p-TBS
(CO)5Cr
+
R4
H
H
H
H
H
H
2g / 3g
2h / 3h
2i / 3i
O
R2
2a-k
R3
3a-k
R1
HO
1a: R1 = Me; R4= n-Bu
1b: R1 = n-Pr; R4 = Me
2j / 3j
n-Pr
2k / 3k
Entry
Alkynol
c
-Methylenebutyrolactone
Yields (%) (solvents)c
Yield (%) (solvent free)
O
O
OH
nBu
1
17 (THF/toluene)
45
MeO
2a
3aa
O
O
OH
nBu
MeO
2
20 (THF/toluene)
48
MeO
2b
MeO
O
3ba
O
OH
nBu
3b
15 (THF/toluene)
62
MeO
2c
3ca
O
O
OH
nBu
4
21 (THF/o-xylene)
63
MeO
2d
3da
O
O
OH
MeO
nBu
5
6
7
20 (THF, toluene and o-xylene)
68
45
49
MeO
2e
MeO
3ea
O
O
OH
nBu
MeO
25 (THF)
MeO
2f
MeO
O
3fa
O
OH
nBu
21 (THF/toluene)
MeO
2g
3ga

S. Sen et al. / Tetrahedron Letters 50 (2009) 5001–5004
5003
Table 1 (continued)
Entry
Alkynol
c
-Methylenebutyrolactone
Yields (%) (solvents)c
22 (THF/toluene)
Yield (%) (solvent free)
O
O
nBu
8
9
59
51
OH
MeO
2h
3ha
O
O
OH
nBu
F
23 (THF, toluene and o-xylene)
MeO
2i
F
3ia
O
O
OH
OPr
10
28 (THF/toluene)
49
2j
3jb
O
O
nBu
OH
Si
MeO
11
56 (THF)
72
t-Bu
Si
2k
3ka
a
1a Fischer chromium carbenes were used.
1b Fischer chromium carbenes were used.
Temperatures for reaction in solvents are as follows: 60 °C (THF), 80 °C (toluene) and 135 °C (o-xylene).
b
c
R2
O
O
Table 2
O
R2
O
Conversion of butyrolactones to butenolides
R4
R4
O
R2
O
O
R2
O
O
O
R3
R3
MSA, aq. THF, stirred in air 2-3d
R1
R4
R4
R3
O
O
R3 R1
R3
4
3
O
R1
R3
(CO)5Cr
+
+
R4
Substrate
Product
Yield (%)
R2
HO
HO
R2
Br
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
4h
4i
84
83
80
83
84
82
82
81
85
82
0
Scheme 1. Synthetic strategy.
OMe
R3
OMe
3j
3k
4j
4k
-CO
OH
(CO)5Cr
+
OH
(CO)4Cr
OMe
R3
OMe
O
O
HO
the synthesis of their optically active analogues. These
preliminary results establish foundation to expand this
methodology and demonstrate its utility in the synthesis of bio-
logically significant molecules and provide for diversity in the
preparation of compounds for structure–activity relationship
(SAR) studies.
R3
.
a
O
R3
Cr(CO)3
Scheme 2. Mechanism for the conversion of alkoxy Fischer chromium carbenes to
butyrolactones.

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S. Sen et al. / Tetrahedron Letters 50 (2009) 5001–5004
Wood, K. V.; McLaughlin, J. L.; Hanson, P. R.; Zhuang, S.; Hoye, T. R. J. Am. Chem.
Acknowledgment
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