Baylis-Hillman chemistry: synthesis of cis- and trans-α-methylene-γ-lactones

Article abstract of DOI:10.1016/j.tetlet.2006.04.063

syn-Homoallylic alcohols prepared from Baylis-Hillman adducts react with CBr₄/PPh₃ to give trans-α-methylene-γ-lactones. Notably, the same alcohols yield the cis-α-methylene-γ-lactones in the presence of traces of p-toluenesulfonic a

Full text of DOI:10.1016/j.tetlet.2006.04.063

Tetrahedron Letters 47 (2006) 4187–4189
Baylis–Hillman chemistry: synthesis
of cis- and trans-a-methylene-c-lactones
*
George W. Kabalka, Bollu Venkataiah and Chunlan Chen
The University of Tennessee, Departments of Chemistry and Radiology, Knoxville, TN 37997-1600, USA
Received 3 March 2006; revised 6 April 2006; accepted 11 April 2006
Abstract—syn-Homoallylic alcohols prepared from Baylis–Hillman adducts react with CBr /PPh to give trans-a-methylene-c-
4
3
lactones. Notably, the same alcohols yield the cis-a-methylene-c-lactones in the presence of traces of p-toluenesulfonic acid.
Ó 2006 Published by Elsevier Ltd.
a-Methylene-c-lactone derivatives have attracted atten-
reaction conditions, and functional group compatabil-
ity. As part of our general interest in Baylis–Hillman
chemistry, we recently developed a cross-coupling reac-
tion of Baylis–Hillman adducts with bis(pinacolato)-
diboron that produces 3-substituted-2-alkoxycarbonyl
allylboronates; these boronates readily react with alde-
6
tion over the years, since they are important functional
1
components in a wide range of natural products. The
a-methylene-c-lactone moiety, due to its propensity for
Michael-type addition reactions, may play an important
role in the biological activity on many naturally occurr-
2
ing products. A variety of methodologies have been
hydes in the presence of a silica supported BF catalyst
3
developed to synthesize a-methylene-c-lactones; the
to form highly functionalized homoallylic alcohols in
excellent yields (Scheme 1).
7
most common method involves the reaction of allylic
3
derivatives with carbonyl compounds. This chemistry
has been used successfully by employing allyl derivatives
The homoallylic alcohols 2 obtained in this reaction are
useful due to the presence of multiple functionalities in
close proximity. We felt that these alcohols would be
excellent precursors to certain biologically important
heterocycles. As part of our investigation, we attempted
to brominate the syn-homoallylic alcohol with carbon
tetrabromide and triphenylphospene. The reaction did
not produce the expected brominated intermediate, but
yielded the corresponding trans-a-methylene-c-lactone
(Scheme 2). The trans stereochemistry was somewhat
3
a
3b
3c
3d
of zinc, tin, chromium, and indium. Recently,
substituted allylborates were also used for the synthesis
4
of a-methylene-c-lactones. However, the reported
procedures generally result in the generation of cis-a-
methylene-c-lactones. Paquette and Andino used organ-
oindium chemistry to produce 3:2 ratio of cis and trans
3
d
substituted a-methylene-c-lactones.
Liu utilized a
tungsten-promoted, intramolecular alkoxycarbonylation
5
to prepare a trans-a-methylene-c-lactone. However,
3
,7
available syntheses of trans-a-methylene-c-lactones
remain limited. We wish to report new, straightforward
methods for preparing both trans- and cis-a-methylene-
c-lactones using Baylis–Hillman adducts as precursors.
surprising in light of the earlier studies. Several homo-
allylic alcohols were synthesized using the one pot cross-
coupling/allylboration reaction (Scheme 1), and then
8
treated with CBr4 and PPh3 at room temperature.
trans-a-Methylene-c-lactones were produced in moderate
The Baylis–Hillman reaction is one of the most versatile
carbon–carbon bond-forming reactions in modern
organic synthesis. It has drawn considerable attention
in the past few decades due to its atom economy, mild
O
O
O
O
B
B
OAc
O
OH
R1CHO
OMe
Ph
OMe
+
Pd2(dba)3, 50 o
R1
C
Lewis acid,
rt
Keywords: Lactone; Baylis–Hillman; Allylboronate; Homoallylic alco-
Ph
O
toluene
hol; Cross-coupling.
1
2
*
Corresponding author. Tel.: +1 865 974 3260; fax: +1 865 974
997; e-mail: kabalka@utk.edu
2
Scheme 1. Synthesis of homoallylic alcohols.
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.04.063

4188
G. W. Kabalka et al. / Tetrahedron Letters 47 (2006) 4187–4189
R'
Br
O
OCH3
OH
Ph
+
R
Ph3P O
Br
Br
OMe CBr /PPh3
OMe
4
R
Ph
P
+
2
3
R
+
R
O
R'
O
R'
O
Ph
R'
O
7
2
3
4
6
Scheme 2. Formation of trans-a-methylene-c-lactones.
Scheme 4. Formation of a phosphonium intermediate.
the same reaction conditions used for lactone formation.
None of the expected a-methylene-c-lactone formed.
Additional experiments were carried out in which the
same butanoate was allowed to react separately with
CBr and PPh . Again, none of the lactone formed. It
to good yields (Table 1). The reaction yields were quite
good when electron withdrawing groups were present on
the aromatic ring. The presence of electron donating
groups inhibited the formation of the lactone, and
bromination products were isolated (Table 1, entry 10).
Homoallylic alcohol derived from an aliphatic Baylis–
Hillman adduct also gave the corresponding trans-a-
methylene-c-lactones along with a small quantity of the
brominated byproduct (Table 1, entry 2).
4
3
is possible that triphenylphoshpine reacts with the bro-
minating agent to form dibromotriphenylphosphorane
6
, which would then be expected to react with the
4
-hydroxy substituent in 2 to form a benzylic phospho-
nium intermediate 7 (Scheme 4). An intramolecular
cyclization of 7 via a Mitsunobu-like substitution (or
9
The reaction does not appear to be limited to CBr /PPh
4
3
via a benzylic cation ) would result in the formation of
bromination reagent. Indeed, a good yield of the lactone
was obtained utilizing NBS (Table 1, entry 5). In con-
trast, lactonization of 2 using p-toluenesulfonic acid
produced the expected cis-a-methylene-c-lactones 5 in
isolated yields ranging from 94% to 99% in all cases
the thermodynamically more stable trans lactone 3.
Further mechanistic studies are currently underway.
In conclusion, we have utilized syn-homoallylic alcohols,
prepared via a one pot cross-coupling/allylboration
reaction, to synthesize cis- and trans-a-methylene-c-lac-
tones. The methods are quite straightforward; by simply
changing the ring closing reagent one can stereoselec-
tively obtain either the cis or trans, bio-active a-methyl-
ene-c-lactones.
9
,10
(
Scheme 3).
Although a detailed mechanistic study has not been
undertaken for the formation of trans-a-methylene-c-
lactones, we believe that the reaction does not proceed
via a brominated intermediate. We base this conclusion
on a series of experiments in which the brominated
product isolated from the reaction of methyl 4-hydr-
oxy-3-methyl-2-methylene-4-phenylbutanoate (see entry
Acknowledgements
2
, Table 1) was allowed to react with CBr /PPh under
4 3
We wish to thank the Department of Energy and the
Robert H. Cole Foundation for supporting this research.
a,b
Table 1. Synthesis of trans-a-methylene-c-lactones
0
References and notes
Entry
R
R
3
4
1
2
3
4
Phenyl
Phenyl
Phenyl
Methyl
Phenyl
p-Tolyl
p-Tolyl
p-Methoxyphenyl 70
1-Napthyl
p-Chlorophenyl
56
49 17
68
71
66
0
1
. Yoshioka, H.; Mabry, T. J.; Timmermann, B. N. Sesqui-
terpene Lactones; University of Tokyo Press: Tokyo, 1973.
. (a) Kupchan, S. M.; Fessler, D. C.; Eakin, M. A.;
Giacobbe, T. J. Science 1970, 168, 376; (b) Kupchan, S.
M.; Eakin, M. A.; Thomas, A. M. J. Med. Chem. 1971, 14,
p-Nitrophenyl
p-Nitrophenyl
p-Nitrophenyl
p-Nitrophenyl
p-Nitrophenyl
p-Nitrophenyl
0
0
0
0
0
0
0
59
2
c
c
5
6
7
8
9
1
147; (c) Cassady, J. M.; Suffness, M. In Anticancer Agents
52
63
67
0
Based on Natural Product Models; Cassady, J. M.,
Douros, J. D., Eds.; Academic: New York, 1980; Vol. 7,
pp 201–269.
p-Trifluoromethylphenyl Phenyl
p-Methoxyphenyl Tolyl
1
0
3
4
. (a) Lambert, F.; Kirschleger, B.; Villieras, J. J. Organomet.
Chem. 1991, 406, 71; (b) Nokami, J.; Otera, J.; Sudo, T.;
Okawara, R. Organometallics 1983, 2, 191; (c) Drews, S.
E.; Hoole, R. F. A. Synth. Commun. 1985, 15, 1067; (d)
Mendez-Andino, J.; Paquett, L. A. Adv. Synth. Catal.
2002, 344, 303.
a
Unless otherwise noted, reactions carried out at rt for 15 h in the
presence of 1.5 equiv of CBr
Isolated yields.
Reaction carried out in the presence of 1.5 equiv of NBS in CH
for 12 h.
4 3 2 2
and PPh in CH Cl .
b
c
2 2
Cl
. (a) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002,
1
24, 898; (b) Ramachandran, P. V.; Pratihar, D.; Biswas,
D.; Srivastava, A.; Reddy, M. V. R. Org. Lett. 2004, 6,
481; (c) Kennedy, J. W. J.; Hall, D. G. J. Org. Chem. 2004,
69, 4412.
R'
OH
R
OMe
p-toluenesulfonic acid
R
O
R'
O
5. Chen, C.-C.; Fan, J.-S.; Shieh, S.-J.; Lee, G.-H.; Peng,
O
S.-M.; Wang, S.-L.; Liu, R.-S. J. Am. Chem. Soc. 1996,
1
18, 9279.
2
5
6
. For reviews on Baylis–Hillman reactions see: (a) Drewes,
S. E.; Ross, G. H. P. Tetrahedron 1988, 44, 4653; (b)
Scheme 3. Synthesis of cis-a-methylene-c-lactones.

G. W. Kabalka et al. / Tetrahedron Letters 47 (2006) 4187–4189
4189
Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
003, 103, 811.
After completion of the reaction, the solvent was removed
and the product was isolated by column chromatography.
9. Yu, S. H.; Fergusaon, M. J.; McDonald, R.; Hall, D. G.
J. Am. Chem. Soc. 2005, 127, 12808.
10. General experimental procedure for cis-a-methylene-lact-
ones: The homoallylic alcohol (1 mmol) was dissolved in
dichloromethane (5 mL) and the solution cooled to 0 °C.
p-Toluenesulfonic acid (0.1 mmol) was added, and the
reaction mixture allowed to stir at room temperature
overnight under a nitrogen atmosphere (reaction moni-
tored by TLC). After completion of the reaction, the
solvent was removed and the product was isolated by
column chromatography.
2
7
. (a) Kabalka, G. W.; Venkatiah, B.; Dong, G. J. Org.
Chem. 2004, 69, 5807; (b) Kabalka, G. W.; Venkatiah, B.;
Dong, G. Tetrahedron Lett. 2005, 46, 4209; (c) Kabalka,
G. W.; Venkatiah, B. Tetrahedorn Lett. 2005, 46, 7325.
. General experimental procedure for trans-a-methylene-
lactones: The homoallylic alcohol (1 mmol) was dissolved
in dichloromethane (5 mL) and the solution cooled to 0 °C.
Carbon tetrabromide (1.5 mmol) and triphenylphosphene
8
(
1.5 mmol) were added sequentially, and the reaction
mixture allowed to stir at room temperature overnight
under a nitrogen atmosphere (reaction monitored by TLC).