A remarkable rate acceleration of the Baylis-Hillman reaction

Article abstract of DOI:10.1039/b103644k

Treatment of α-naphthyl acrylate with both aliphatic and aromatic aldehydes in the presence of DABCO (30 mol%) afforded the desired (α-methylene-β-hydroxy)esters with reasonable chemical yields (51-88%) within 20 min.

Full text of DOI:10.1039/b103644k

A remarkable rate acceleration of the Baylis–Hillman reaction
Wei-Der Lee, Kung-Shuo Yang and Kwunmin Chen*
Department of Chemistry, National Taiwan Normal University, 88 Sec. 4 TingChow Road, Taipei,
Taiwan 116, ROC. E-mail: kchen@scc.ntnu.edu.tw; Fax: +886-2-29324249; Tel: +886-2-89315831
Received (in Cambridge, UK) 24th April 2001, Accepted 28th June 2001
First published as an Advance Article on the web 9th August 2001
Treatment of a-naphthyl acrylate with both aliphatic and
aromatic aldehydes in the presence of DABCO (30 mol%)
afforded the desired (a-methylene-b-hydroxy)esters with
reasonable chemical yields (51–88%) within 20 min.
yield at room temperature in 20 min (entry 1). Similar results
were observed with different chain aldehydes (entries 2–4). The
reaction was slightly less effective when a-branched aldehyde
was used (entry 5). trans-Cinnamaldehyde was employed to
give the desired product with 60% yield in 20 min (entry 6).
Next, substituted aromatic aldehydes were subjected to the
same reaction conditions. Reaction of p-nitrobenzaldehyde and
p-fluorobenzaldehyde with 1g under the same conditions
Increasing interest has been focused on the coupling of an
aldehyde with acrylate in the presence of DABCO (Baylis–
Hillman reaction).1 The resulting (a-methylene-b-hydroxy)-
esters are versatile intermediates that allow for further func-
tional group manipulation. One of the major drawbacks of this
transformation is the poor reaction rates which limits the range
Table 1 Reaction of benzaldehyde with various acrylates 1a–g in the
a
presence of DABCO
2
of substrates that are tolerated. Many aromatic aldehydes and
branched aliphatic aldehydes are reluctant to serve as substrates.
It is not surprisingly that numerous methods including physical
as well as chemical attempts have been made to increase the
3
reaction rate. Modest increases in rates have been obtained
under modified reaction conditions. No practical methods have
been developed so far. We wish to report here that an extremely
rapid rate can be achieved using a-naphthyl acrylate as the
Michael acceptor for the Baylis–Hillman reaction.
b
Entry
Acrylate
t/h
Product
Yield (%)
A plausible mechanism for the Baylis–Hillman reaction is
proposed and the addition of ammonium enolate with an
aldehyde is believed to be the rate-determining step. Stabiliza-
tion of the enolate species would shift the equilibrium forward
and therefore to accelerate the rates. The use of Lewis acid to
catalyze this transformation is a common strategy. The use of
1
2
3
4
5
6
7
a
1a
1b
1c
1d
1e
1f
48 (4)c
2a
2b
2c
2d
2e
2f
62 (68)
50 (90)
86 (78)
80
34
70
4
15 (28 days)
d
e
2 (3)
15
48
5
lanthanides and group III metal triflates to accelerate the
1g
1/3
2g
88
Baylis–Hillman reaction have been studied.3
e–g
However
All reactions were conducted using 1+1 ratio of acrylate and aldehyde in
CN at room temperature in the presence of DABCO (50 mol%).
Isolated yield. Numbers in parentheses are reported data. For experi-
structural variants of acrylates for this transformation have not
CH
3
5
been studied systematically. This promoted us to screen a
b
c
range of substituted acrylates 1a–g as Michael acceptor. The
substituted acrylates may provide stereo- and/or stereoelec-
tronic effects to stabilize the oxy anion intermediate and
subsequently accelerate the following aldol reaction. To test this
hypothesis various acrylates 1a–g with diverse steric, geometric
and electronic properties were prepared and benzaldehyde was
used as a probe electrophile (Table 1). Reaction of methyl
mental details see ref. 3j. d Ref. 2. e Ref. 5.
a
Table 2 Reaction of 1g with various aldehydes
3
acrylate (1.0 equiv.) with benzaldehyde (1.0 equiv.) in CH CN
in the presence of DABCO (50 mol%) at room temperature gave
the corresponding product 2a in 62% yield for 48 h (entry 1).
The use of tert-butyl acrylate affords a similar result (entry 2).
The use of phenyl acrylate 1c gave the desired product 2c with
Entry
RCHO (RN)
t/min
3 (% yield)b
86% yield in 2 h (entry 3). Treatment of benzyl acrylate with
benzaldehyde under the same reaction conditions provided 2d
with 80% yield in 15 h (entry 4). The desired product 2e was
1
2
3
4
5
6
7
8
9
CH
CH
(CH
PhCH
(CH
3
20
20
20
20
20
20
10
20
70
77
62
65
51
60
82
65
71
35
71
72
3
CH
2
isolated in 34% yield when the commercial available
3
)
2
2
2
CHCH
CH
CH
2
6
1
,1,1,3,3,3-hexafluoroisopropyl acrylate 1e was used (entry 5).
2
The use of b-naphthyl acrylate 1f gave 2f with 70% yield in 5
h (entry 6). A significant rate acceleration was observed when
a-naphthyl acrylate 1g was employed. Thus, treatment of 1g
with benzaldehyde in the presence of DABCO affords the
desired product with 88% yield in 20 min (entry 7). The
unexpected rate acceleration using a-naphthyl acrylate for the
Baylis–Hillman reaction is amazing and was studied in more
detail.
To further determine the feasibility of this system, various
aldehydes were then studied using a-naphthyl acrylate under
the optimum conditions and the results are tabulated in Table 2.
Thus, treatment of 1g with acetaldehyde affords 3a with 70%
3
)
trans-C H CHNCH
6
4
p-NO
p-FC
p-MeC
p-OMeC
p-OMeC
2
C
6
H
4
6
H
4
6
H
4
20
1
1
1
a
0
1
2
6
H
H
4
20 h
96 h
20
6
4
3-Pyridyl
All reactions were conducted using 1+1 molar ratio of acrylate and
CN at room temperature. The amounts of DABCO used
aldehyde in CH
3
was reduced to 30 mol% to minimize the formation of the cyclic acetates 4.
Isolated yield.
b
1612
Chem. Commun., 2001, 1612–1613
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b103644k

in the presence of DABCO (30 mol%) provided the correspond-
ing a-methylene b-hydroxy carbonyl derivatives with reason-
able material yields within 20 min. This represents, to the best
of our knowledge, one of the best rate acceleration systems for
wide ranges of aldehydes in Baylis–Hillman reactions under
atmospheric pressure. The pronounced acceleration of this
reaction further extends the Baylis–Hillman reaction into a
viable transformation. The asymmetric version of the Baylis–
Hillman reaction using this reaction system is underway in our
laboratory.
Scheme 1 The synthesis of 1,3-dioxan-4-ones 4a–c.
We thank the National Science Council (NSC) for financial
support of this work.
provide the desired products with 82 and 65% yield, re-
spectively (entries 7 and 8). Although the use of p-
methylbenzaldehyde gave a similar result, the use of p-
methoxybenzaldehyde requires 96 h to obtain comparable yield
Notes and references
1
For reviews of the Baylis–Hillman reaction, see: (a) P. Langer, Angew.
Chem., 2000, 39, 3049; (b) E. Ciganek, Org. React., 1997, 51, 201; (c) D.
Basavaiah, D. P. Rao and R. S. Hyma, Tetrahedron, 1996, 52, 8001; (d)
S. E. Drewes and G. H. P. Roos, Tetrahedron, 1988, 44, 4653.
(
entries 9 and 11). This may be due to the relatively strong
electron donating ability of the methoxy group that deacceler-
ates the reaction rate. The detailed mechanistic speculation is
premature at this stage and work is underway to study this
phenomenon in more detail.
2 Y. Fort, M. C. Berthe and P. Caubere, Tetrahedron, 1992, 48, 6371.
3
(a) M. K. Kundu, S. B. Mukherjee, N. Balu, R. Padmakumar and S. V.
Bhat, Synlett, 1994, 444; (b) R. J. W. Schuurman, A. Linden, R. P. F.
Grimbergen, R. J. M. Nolte and H. S. Scheeren, Tetrahedron, 1996, 52,
The reaction of various aldehydes with a-naphthyl acrylate
1
g was very fast as mentioned above. In addition to the
8
307; (c) M. Shi and Y.-S. Feng, J. Org. Chem., 2001, 66, 406; (d) M.
conventional Baylis–Hillman products isolated, small quan-
tities (3–10%) of cyclic acetates were identified dependent upon
the substrates used. The minor product may come from the
addition of the initial product with the unreacted aldehyde
Kawamura and S. Kobayashi, Tetrahedron Lett., 1999, 40, 1539; (e)
V. K. Aggarwal, G. J. Tarver and R. McCague, J. Chem. Soc., Chem.
Commun., 1996, 2713; (f) V. K. Aggarwal, A. Mereu, G. J. Tarver and R.
McCague, J. Org. Chem., 1998, 63, 7183; (g) V. K. Aggarwal and A.
Mereu, J. Chem. Soc., Chem. Commun., 1999, 2311; (h) J. Auge, N.
Lubin and A. Lubineau, Tetrahedron Lett., 1994, 35, 7947; (i) Y. M. A.
Yamada and S. Ikegami, Tetrahedron Lett., 2000, 41, 2165; (j) S. Rafel
and J. W. Leahy, J. Org. Chem., 1997, 62, 1521; (k) L. J. Brzezinski, S.
Rafel and J. W. Leahy, J. Am. Chem. Soc., 1997, 119, 4317.
5
followed by elimination of a-naphthol anion. The cyclic acetal
7
products are of great synthetic interest. The preparation of
various 1,3-dioxan-4-ones under several different reaction
systems have been reported.3
k,5,6
In this study, the use of excess
amounts of aldehydes (4.0 equiv.) under prolonged reaction
time gave 1,3-dioxan-4-ones 4a–c with good to high chemical
yields (Scheme 1).
In summary, we have developed an efficient method for the
synthesis of highly functionalized acrylates. Reaction of a-
naphthyl acrylate 1g with both aliphatic and aromatic aldehydes
4
5
J. S. Hill and N. S. Issacs, J. Phys. Org. Chem., 1990, 285.
P. Perlmutter, E. Puniani and G. Westman, Tetrahedron Lett., 1996, 37,
1
715.
6
Y. Iwabuchi, M. Nakatani, N. Yokoyama and S. J. Hatakeyama, J. Am.
Chem. Soc., 1999, 121, 10 219 and also footnote 8.
7 J. Zimmermann and D. Seebach, Helv. Chim. Acta, 1987, 70, 1104.
Chem. Commun., 2001, 1612–1613
1613