The use of DMAP as catalyst in the baylis-hillman reaction between methyl acrylate and aromatic aldehydes

Article abstract of DOI:10.1081/SCC-120018699

We found an efficient methodology for the Baylis-Hillman reaction of p-nitrobenzaldehyde (1), naphtaldehyde (4a), and pyperonal (4b) with methyl acrylate by using 4-dimethylaminopyridine (DMAP) as a catalyst, without solvent, additives, or any sophisticat

Full text of DOI:10.1081/SCC-120018699

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The Use of DMAP as Catalyst in the Baylis-Hillman
Reaction Between Methyl Acrylate and Aromatic
Aldehydes
Rodrigo Octavio a , M. A. de Souza a & Mário Luiz A. A. Vasconcellos a
a Núcleo de Pesquisas de Produtos Naturais–Universidade Federal do Rio de Janeiro, Centro
de Ciências da Saúde, Ilha do Fundão, RJ, Brazil
Published online: 15 Aug 2006.
To cite this article: Rodrigo Octavio , M. A. de Souza & Mrio Luiz A. A. Vasconcellos (2003) The Use of DMAP as Catalyst in
the Baylis-Hillman Reaction Between Methyl Acrylate and Aromatic Aldehydes, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 33:8, 1383-1389, DOI: 10.1081/SCC-120018699
To link to this article: http://dx.doi.org/10.1081/SCC-120018699
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 8, pp. 1383–1389, 2003
The Use of DMAP as Catalyst in the
Baylis-Hillman Reaction Between Methyl
Acrylate and Aromatic Aldehydes
Rodrigo Octavio, M.A.de Souza, and
*
Mario Luiz A.A.Vasconcellos
Nucleo de Pesquisas de Produtos
Naturais–Universidade Federal do Rio de Janeiro,
Centro de Ciencias da Saude, Ilha do Fundao, RJ Brazil
ABSTRACT
We found an efficient methodology for the Baylis-Hillman reaction
of p-nitrobenzaldehyde (1), naphtaldehyde (4a), and pyperonal (4b)
with methyl acrylate by using 4-dimethylaminopyridine (DMAP)
as a catalyst, without solvent, additives, or any sophisticated
equipment. A very important temperature effect was observed.
*Correspondence: Mario Luiz A. A. Vasconcellos, Nucleo de Pesquisas de
Produtos Naturais–Universidade Federal do Rio de Janeiro, Laboratorio
H1-029, bloco H, Centro de Ciencias da Saude, Ilha do Fundao, 21941-590 RJ
Brazil; Fax: þ00-55-21-2702683; E-mail: mlaav@nppn.ufrj.br.
1383
DOI: 10.1081/SCC-120018699
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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1384
Octavio, de Souza, and Vasconcellos
The Baylis-Hillman reaction (Fig. 1) is an emerging method for
carbon–carbon bond formation.[1–4] It involves the coupling of an
activated alkene with an aldehyde or ketone. Usually, a tertiary amine
or phosphine is required as a catalyst, and 1,4-diazabicyclo[2.2.2]octane
(Dabco, Fig. 1) is the most popular one.
A great inconvenience of the Baylis-Hillman reaction is its slow rates.
The literature reports reaction which could last up to 45 days.[1] Many
efforts were done to accelerate the reaction, and there have been some
examples of activation with Lewis acid,[5,6] lithium perchlorate,[7] the
use of ultrasound technique,[8,9] high pressure,[10,11] or microwave
irradiation.[12]
The 4-(N,N-dimethylamino)pyridine (DMAP), a very good nucleo-
philic catalyst,[13] is more basic than Dabco (pKa of the conjugated acids:
Dabco ¼ 8.5, DMAP ¼ 9.7). DMAPis accessible in most of the organic
synthesis laboratories, however Gaied and Rezgui describe the only
example of its use as catalyst in the Baylis-Hillman reaction (hydroxy-
methylation reaction of 2-cyclohexanone).[14]
The objective of this article is to describe an efficient methodology
for the Baylis-Hillman reaction between methyl acrylate and aromatic
aldehydes using DMAPas catalyst under simple reaction conditions.
We began our studies by treating the p-nitrobenzaldehyde (1)
with methyl acrylate (2) and 10% mol of DMAPas catalyst at room
temperature. Several solvents were tested (methanol, THF, pyridine, and
dioxane) but all were inefficient and no reaction or very poor yield was
obtained (<10%). On the other hand, the use of methyl acrylate (excess)
without solvent presented the most satisfactory result (72% yield) (Entry 2,
Table 1).
We investigated the rate acceleration temperature effect of this
reaction and found some very interesting effects. First, a great increase
in yield and rate was obtained conducting the reaction at 76ꢀC (Entries 1
and 2, Table 1). A yield of 93% was obtained (Entry 5, Table 1) when the
reaction was carried out for only 15 min using a domestic microwave
oven.[12] The use of ultrasound technique also seemed to cause an
Figure 1. R, R1 ¼ H, Alkyl, Aryl. EWG ¼ CO2R, CN, COR.

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DMAP in Baylis-Hillman Reaction
1385
Table 1.
Entry
T (ꢀC)
Time
Yield (%)a
1
2
3
4
5
6
76
25
5 h
4 days
5 h 40 min
6 h
>99
72 (97)a
65 (75)a
No reaction
93
ꢁ4
ꢁ36
Microwaveb
Ultrasoundc
15 min
3 h
85
aConsidering the recovery of the departure aldehyde; bA domestic microwave
(700 W) was used and all the reactions were carried out in sealed tube; cA
Bransonic 2210R-MT ultrasound was used.
Figure 2.
incremental increase in the reaction rate[8] (Entry 6, Table 1). Surprisingly,
we also found that the reaction is faster at ꢁ4ꢀC than at room tempera-
ture (Entry 3, Table 1). A few years ago, Rafel and Leahy also described
this rate acceleration under low temperature.[15] One way to rationalize
this is to consider the two purported ionic intermediates I and II (Fig. 2).
These intermediates should be in equilibrium with the starting materials
and react with p-nitrobenzaldehyde at different rates. Their relative
concentration can be different at 0ꢀC and at room temperature. The
observed changes in the rates of the Baylis-Hillman reaction likely reflect
this difference.[15] Unfortunately, no product was obtained conducting

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1386
Octavio, de Souza, and Vasconcellos
Table 2.
Entry
Ara
T (ꢀC)
Time
Yield (%)
1
2
3
4
5
6
7
8
A
A
A
A
B
B
B
B
76
25
5 days
12 days
6 days
3 h
60 (85)b
47 (98)b
ꢁ4
Microwave
76
65 (97)b
15 (98)b
6 days
15 days
4 days
1 h
47 (70)b
25
ꢁ4
44 (55)b
No reaction
No reaction
Microwave
b
aAr: A ¼ b-Naphtyl; B ¼ Pyperonyl; considering the recovery of the aldehyde.
the reaction at ꢁ36ꢀC possibly due to heterogeous reaction condition at
this temperature.
In order to investigate this process we used naphtaldehyde (4a) and
pyperonal[8] (4b) as starting materials (Table 2). Moderated results were
obtained regarding increase in rate and yield when reaction was carried
out at room temperature. (Entries 2 and 6). The reaction with 4a is com-
pleted in 12 days at r.t. in 47% yield, however in 5 days in 60% yield at 76ꢀC
(Entries 1 and 2). Only moderated yields were obtained for 4b at room
temperature (40%, 12 days, Entry 6) and 76ꢀC (47%, 6 days, Entry 5), so far
the best result described for 4b.[8] Similar to the observation with aldeyde 1,
we also found that the reaction for 4a procceded faster upon cooling to
ꢁ4ꢀC then at r.t. (65% yield). No product was obtained for 4b (Entries 3
and 7) under these condictions. Surprisingly, poor results were obtained
when the reaction was performed in the microwave (Entries 4 and 8).
CONCLUSION
In this work, we developed a simple, economical, and efficient
methodology for the Baylis-Hillman reaction with aromatic aldehydes,
and DMAPas the catalyst in place of Dabco. In these cases, the use
of DMAPwas more efficient than Dabco. We obtained product 3 in 5 h
at 76ꢀC (quantitative yield) and in 15 min (93%), using a domestic
microwave oven. We found the same rate acceleration temperature

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DMAP in Baylis-Hillman Reaction
1387
effect conducting the reaction at ꢁ4ꢀC as described by Leahy (using
Dabco as catalyst). The compounds 5a–b were prepared in satisfactory
yields and rates, comparable with the literature.[8,9] The use of higher
temperatures (76ꢀC) is the best condition.
EXPERIMENTAL SECTION
General Methods
The Baylis-Hillman adducts are known[3,8,9] and were characterized
by 1H NMR Varian Spectra (200 MHz) in CDCl3 with CHCl3 as internal
reference (ꢀ 7.26 ppm) and 13C NMR Varian Spectra (50 MHz) in CDCl3
solution with CHCl3 (77.0 ppm) as internal reference. Chromatographic
methods: A Lachrom HPLC system Merck equipped with a model
D7000 interface, an L-7100 pump, an L-7450A diode array detector
(DAD) and an L-7612 solvent degasser was used. Shim-Pack C-8
column (250 ꢂ 10 mm); 5 micron 100 ANG A. Separation were done in
gradient mode, using acetonitrile:water (t0 ¼ 20%water and t30 ¼ 100%
acetonitrile) at a flow rate of 2.0 mL/min with an injection volume of
20 mL and UV detection was at 280 nm. The analysis time was about
30 min. UV detection was performed using DAD in the range
210–300 nm.
General Procedure for the Aducts 3, 5a, and 5b
In a mixture of 1 mmol of the aromatic aldehyde, 10% mol of 4-N,N-
dimethylaminopyridine (DMAP), 0.5 mL of methyl acrylate was added.
The mixture was conducting at T ꢀC until the end of the reaction (TLC
analysis, 2:8 ethyl acetate/hexane). The mixture was evaporated and
filtered in silica gel. Purification of the products by silica-gel column
chromatography (1:9 ethyl acetate/hexane) gave 3,[3] 5a,[3] and 5b[8] in
X% yield (Tables 1 and 2).
1
Product 3: H NMR (CDCl3): ꢀ 1.57 (s, 1H), 3.74 (s, 3H), 5.63 (d,
J ¼ 6.32 Hz, 1H), 5.87 (s, 1H), 6.40 (s, 1H), 7.61 (m, 2H), 8.25 (m,2H).
13C NMR (CDCl3): ꢀ 52.066 (CH3), 72.528 (CH), 123.460 (CH), 127.063
(CH2), 127.209 (CH), 140.865 (C), 147.307 (C), 148.490 (C), 166.222 (C).
HPLC: tR ¼ 12.7 min, >99%.
1
Product 5a: H NMR (CDCl3): ꢀ 1.57 (s, 1H), 3.73 (s, 3H), 5.75 (d,
J ¼ 5.77 Hz, 1H), 5.88 (t, J1 ¼ 1.14 Hz, J2 ¼ 1.10 Hz, 1H), 6.39 (s, 1H),

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1388
Octavio, de Souza, and Vasconcellos
7.50 (m, 3H), 7.78 (m, 4H). 13C NMR (CDCl3): ꢀ 51.857 (CH3), 73.184
(CH), 124.453 (CH), 125.399 (CH), 125.909 (CH), 126.018 (CH2),
126.800 (CH), 127.510 (CH), 127.983 (CH), 128.056 (CH), 132.896 (C),
133.105 (C), 138.482 (C), 141.767 (C), 166.669 (C). HPLC: tR ¼
15.63 min,>99%.
1
Product 5b: H NMR (CDCl3): ꢀ 1.57 (s, 1H), 3.73 (s, 3H), 5.49
(d, J ¼ 5.49 Hz, 1H), 5.86 (t, J1 ¼ 1.26 Hz, J2 ¼ 1.21 Hz, 1H), 5.96
(d, J ¼ 0.86 Hz, 2H), 6.33 (t, J1 ¼ 1.09 Hz, J2 ¼ 0.8 Hz, 1H), 6.87 (m, 3H).
13C NMR (CDCl3): ꢀ 51.784 (CH3), 72.655 (CH), 100.887 (CH2), 107.038
(CH), 107.939 (CH), 120.030 (CH), 125.571 (CH2), 135.161 (C), 141.821
(C), 146.998 (C), 147.544 (C), 166.541 (C). HPLC: tR ¼ 11.6 min, >99%.
ACKNOWLEDGMENTS
National Research Council of Brazil (CNPq), Jose Bonifacio
University Foundation (FUJB-Brazil), and Research Foundation of the
Rio de Janeiro (FAPERJ) for a fellowship.
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Received in the USA June 15, 2002

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