The intramolecular Baylis-Hillman reaction: Easy preparation of versatile substrates, facile reactions, and synthetic applications

Article abstract of DOI:10.1039/b311951c

We have developed a general and highly efficient method for the preparation of diverse ω-formyl-aα,β-unsaturated carbonyl compounds and optimized the conditions for the intramolecular Baylis-Hillman reactions of these compounds to provide various biologic

Full text of DOI:10.1039/b311951c

The intramolecular Baylis–Hillman reaction: easy preparation of
versatile substrates, facile reactions, and synthetic applications†
Jung Eun Yeo, Xiuling Yang, Hee Jin Kim and Sangho Koo*
Department of Chemistry, Myong Ji University, Yongin, Kyunggi-Do, 449-728, Korea.
E-mail: sangkoo@mju.ac.kr; Fax: +82 31 335 7248; Tel: +82 31 330 6185
Received (in Cambridge, UK) 26th September 2003, Accepted 20th October 2003
First published as an Advance Article on the web 10th November 2003
We have developed a general and highly efficient method for
the preparation of diverse w-formyl-a,b-unsaturated carbonyl
compounds and optimized the conditions for the intramolecular
Baylis–Hillman reactions of these compounds to provide
various biologically important polycyclic compounds.
cially available 2-cyclohexene-1-one and 2-cycloheptene-1-one
were acetoxylated by Pb(OAc)4 at the reflux temperature of toluene
yielding cycloalkenones 1 in 85% and 97% yield, respectively.4
Various nucleophiles including NaBH4, PhLi, MeLi, EtMgBr, and
n-BuLi were utilized for the 1,2-addition to cycloalkenones 1.
Cycloalkene-1,2-diols 2 can be obtained directly when more than 2
eq. of nucleophiles are used, or by hydrolysis of the acetate of the
initial adduct. A mixture of diastereomers was obtained in these
addition reactions. Oxidative ring cleavage of 1,2-diols 2 by
Pb(OAc)4 proceeded efficiently in MeCN to give 3. This reaction
was so fast that it took only ~ 30 s for 50% conversion and less than
10 min for completion, with the initially formed Z-isomer
isomerizing to the more stable E-isomer. The Z-isomer was isolated
when the reaction was stopped within 5 min. The crude products
were pure enough to be used for the Baylis–Hillman reaction
without further purification.
Only a few intramolecular Baylis–Hillman reactions have been
reported, most of which suffered from low yields.3 In our initial
study this reaction seemed to be impractical for 3a presumably due
to its easy polymerization through the intermolecular Michael
reaction. However, we were able to optimize the intramolecular
Baylis–Hillman reaction of 3a after careful studies with several
nucleophiles and various solvents and conditions (entries 1–7,
More than 500 research papers during the last decade have reported
the ever-increasing importance of the Baylis–Hillman reaction in
organic synthesis, where efficient formation of the C–C bond
between Michael acceptors and carbonyl or imine compounds with
diverse functional group compatibility can be realized under mild
reaction conditions.1 Moreover, highly functionalized molecules
can be assembled by this reaction, which can be utilized for the
construction of complicated molecular frameworks.1,2 The study of
the intramolecular version3 of this reaction that would lead to
versatile cyclization products, however, is still in its infancy
partially due to the limited access to these rather unstable
substrates, e.g. w-formyl-a,b-unsaturated carbonyl compounds.
Instead of applying the mono Wittig reaction to symmetrical
dialdehydes, which not only lowered the reaction yield but also
limited the possible substituents within the molecule,3 we devised
a new approach to produce w-formyl-a,b-unsaturated carbonyl
compounds with various substituents in decent yields. We opti-
mized the intramolecular Baylis–Hillman reaction conditions of
these versatile substrates to give rise to a variety of conjugated
cycloalkenones containing an a-carbinol moiety. Further cycliza-
tions of these well-equipped Baylis–Hillman products led to useful
polycyclic compounds such as chromones and the 6,8-dioxabicy-
clo[3.3.1]octane ring.
As delineated in Table 1, our synthetic approach to w-formyl-
a,b-unsaturated carbonyl compounds 3 relied on the Pb(OAc)4-
promoted oxidative ring cleavage4 of cycloalkene-1,2-diols 2 that
can be readily obtained by the 1,2-addition of various nucleophiles
to aA-acetoxy-substituted conjugated cycloalkenones 1. Commer-
Table 2). A stoichiometric amount of nucleophile was required to
induce the intramolecular cyclization to give 4a, while a catalytic
amount of nucleophile produced no cyclization product at all. PPh3
Table 2 Intramolecular Baylis–Hillman reactions
Yield of
4 (%)
Entry
3
Nucleophilea Solventb
Conditions
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
a
a
a
a
a
a
a
b
b
b
c
c
c
d
d
d
e
e
f
PPh3
PPh3
PPh3
PPh3
PPh3
DABCO
PMe3
PPh3
PPh3
PPh3
PPh3
PPh3
PMe3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
THF
20 °C, 38 h
20 °C, 29 h
20 °C, 24 h
20 °C, 72 h
30 °C, 12 h
30 °C, 18 h
30 °C, 3 h
20 °C, 22 h
70 °C, 2 h
30 °C, 6 h
20 °C, 24 h
80 °C, 10 h
30 °C, 22 h
20 °C, 43 h
20 °C, 48 h
40 °C, 15 h
20 °C, 22 h
30 °C, 25 h
80 °C, 29 h
80 °C, 29 h
14
36
48
48
98
33
CH2Cl2
Acetone
MeCN
t-BuOH
t-BuOH
t-BuOH
MeCN
EtOAc
t-BuOH
MeCN
t-BuOH
t-BuOH
MeCN
CH2Cl2
t-BuOH
MeCN
t-BuOH
t-BuOH
MeCN
Table 1 An efficient method of preparation of versatile substrates for the
intramolecular Baylis–Hillman reaction
c
—
99
20
78
83
76
Yield
of 2a (%)
Yield of
3b (%)
Compound
n
R
a
b
c
d
e
f
1
1
1
1
1
2
H
81
71
89
76
81
96
68 (85)
70 (98)
89 (99)
62 (83)
93 (99)
97 (99)
Ph
Me
Et
Bu
H
c
—
48
36
78
60
83
73
53
a A mixture of diastereomers. b Crude yields are given in parentheses.
f
† Electronic Supplementary Information (ESI) available: experimental
procedures, characterization data, and 1H NMR spectra. See http://
www.rsc.org/suppdata/cc/b3/b311951c/
a 1.0 equiv of nucleophile was used. b 0.1 M solution. c decomposition of
the starting material was observed.
236
C h e m . C o m m u n . , 2 0 0 4 , 2 3 6 – 2 3 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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was found to be superior to DABCO, and only the decomposition
of the starting material was noticed when PMe3 was used. A
dramatic solvent effect was observed in these reactions; polar
solvents such as t-BuOH and MeCN provided high yields of the
desired cyclic products, while less polar solvents such as THF,
CH2Cl2, acetone and EtOAc gave only marginal yields, in accord
with the results of Roush5 and Krische6 for the vinylogous
intramolecular Morita–Baylis–Hillman reaction. Dilution may help
the intramolecular reactions, however, it was not critical in the
above cases and the reactions were conducted at 0.1 M concentra-
tion. Good to excellent yields of 4b–f were also obtained using this
optimized reaction condition. A higher temperature and longer
reaction time were required for cyclization to a 6-membered ring.
The general applicability of our present process was demon-
strated in the efficient preparation of the required substrates 3g–i
for the intramolecular Baylis–Hillman reaction leading to chro-
mones 5g–i (Table 3). MOM-protected o-bromophenol and o-
bromothiophenol were lithiated by t-BuLi, and the resulting
nucleophiles were added to 6-acetoxy-2-cyclohexene-1-one or
7-acetoxy-2-cycloheptene-1-one to give 1,2-diols 2g–i. The intra-
molecular Baylis–Hillman reaction of compounds 3g–i, prepared
by the oxidation of 2g–i by Pb(OAc)4, proceeded smoothly under
the above-optimized conditions (PPh3 in MeCN at reflux or t-
BuOH at 30 °C) to produce the cyclic products 4g–i. Deprotection
of the MOM group by 3 M HCl in THF followed by reflux in
benzene with catalytic p-TsOH induced a further cyclization to
provide chromones in decent yields. It is noteworthy that the
deprotection of the MOM group was accompanied by Pb(OAc)4-
promoted oxidation of 2g to 3g (P = H). No direct double
cyclization of 3g to 5g through the intramolecular conjugate
addition of the phenolic OH followed by the aldol reaction was
observed under the Baylis–Hillman reaction conditions. In the case
of 4i, deprotection of the MOM group in 3 M HCl triggered a
spontaneous cyclization to 5i at 30 °C.
Scheme 1 A ring expansion protocol.
The preparation of the above w-formyl-a,b-unsaturated carbonyl
compounds and the intramolecular Baylis–Hillman reaction overall
constitutes a ring-contraction protocol, e.g. from cyclohexenone to
cyclopentenol. We wanted to show the possibility of ring-
expansion by the application of our present sequence (Scheme 1).
Acetoxylation (91% yield) of cyclohexanone by Pb(OAc)4 and the
addition of vinylmagnesium bromide (85% yield) to 6 followed by
the oxidative ring cleavage (94% yield) of 7 produced the novel w-
formyl-a,b-unsaturated carbonyl compound 8 containing a termi-
nal methylene unit. The facile intramolecular Baylis–Hillman
reaction (PPh3 in t-BuOH at 20 °C for 4 h) of 8 produced the ring-
expanded cycloheptanone 9 in 84% yield. Compound 9 has been
reported to produce the polycyclic compound containing the
6,8-dioxabicyclo[3.2.1]octane ring,7 which constitutes the basic
structure of a number of pheromones.8
In conclusion, we have developed an efficient method of
preparation of diverse w-formyl-a,b-unsaturated carbonyl com-
pounds and optimized the conditions for the intramolecular Baylis–
Hillman reactions of these compounds. Our present sequence is
quite general and applicable to the syntheses of various biologically
important polycyclic compounds, as demonstrated by the syntheses
of chromones and the precursor of the compound containing the
6,8-dioxabicyclo[3.2.1]octane ring.
This work was supported by the Korea Research Foundation
Grant (KRF-2003-015-C00342).
Notes and references
1 S. E. Drewes and G. H. P. Roos, Tetrahedron, 1988, 44, 4653; D.
Basavaiah, P. D. Rao and R. S. Hyma, Tetrahedron, 1996, 52, 8001; E.
Ciganek, Org. React., 1997, 51, 201; P. Langer, Angew. Chem., Int. Ed.,
2000, 39, 3049; D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem.
Rev., 2003, 103, 811.
2 J. N. Kim and K. Y. Lee, Curr. Org. Chem., 2002, 6, 627.
3 F. Roth, P. Gygax and G. Fráter, Tetrahedron Lett., 1992, 33, 1045; S. E.
Drewes, O. L. Njamela, N. D. Emslie, N. Ramesar and J. S. Field, Synth.
Commun., 1993, 23, 2807; G. P. Black, F. Dinon, S. Fratucello, P. J.
Murphy, M. Nielsen, H. L. Williams and N. D. A. Walshe, Tetrahedron
Lett., 1997, 38, 8561; F. Dinon, E. Richards, P. J. Murphy, D. E. Hibbs,
M. B. Hursthouse and K. M. A. Malik, Tetrahedron Lett., 1999, 40, 3279;
G. E. Keck and D. S. Welch, Org. Lett., 2002, 4, 3687.
Table 3 Reaction yields of the intermediate compounds in chromone
synthesis
Yield (%)
ˆ
4 M. L. Mihailovic and Z. Cekovicˆ, Encyclopedia of Reagent for Organic
Comp.
n
X
2
3
4
5
Synthesis ed. L. A. Paquette, John Wiley & Sons, Chichester, 1995, vol.
5, p. 2949.
5 S. A. Frank, D. J. Mergott and W. R. Roush, J. Am. Chem. Soc., 2002,
124, 2404.
6 L.-C. Wang, A. L. Luis, K. Agapiou, H.-Y. Jang and M. J. Krische, J. Am.
Chem. Soc., 2002, 124, 2402.
7 H. M. R. Hoffmann and U. Vogt, Synlett, 1990, 10, 581.
8 N. Daude, U. Eggert and H. M. R. Hoffmann, J. Chem. Soc., Chem.
Commun., 1988, 206.
g
h
i
1
2
2
O
O
S
58
84
87
98a
84
75
91a,b
75d
65b
93c
85e/71c
81e
a A phenol product was obtained in which the MOM group was deprotected.
b t-BuOH at 30 °C. c p-TsOH in benzene at reflux. d MeCN at reflux. e 3 M
HCl in THF at 30 °C.
C h e m . C o m m u n . , 2 0 0 4 , 2 3 6 – 2 3 7
237