Ultrasound in Baylis-Hillman reactions with aliphatic and aromatic aldehydes: Scope and limitations

Article abstract of DOI:10.1016/S0040-4020(02)00822-0

The utilization of ultrasound radiation in the Baylis-Hillman reaction with several aldehydes (aromatics and aliphatics) and different α,β-unsaturated reactants is described. For all aldehydes tested, the utilization of ultrasound sources augmented the reaction rate and the chemical yields. The use of ultrasound with two different catalysts (tri-n-butylphosphine and 1,4-diazabicyclo[2.2.2]octane [DABCO]) was also investigated. It was clearly demonstrated that DABCO is much more effective for catalyzing a Baylis-Hillman reaction under the influence of ultrasound than is tri-n-butylphosphine. No effect on reaction rate was observed when the concentration of DABCO was increased.

Full text of DOI:10.1016/S0040-4020(02)00822-0

Tetrahedron 58 (2002) 7437–7447
Ultrasound in Baylis–Hillman reactions with aliphatic and
aromatic aldehydes: scope and limitations
b
a
a
Fernando Coelho,a Wanda P. Almeida, Demetrius Veronese, Cristiano R. Mateus,
,
,
*
*
a
Elizandra C. Silva Lopes, Rodrigo C. Rossi, Gabriel P. C. Silveira and Cesar H. Pavam
a
a
a
´
a
´
ˆ
Depto. de Quımica Organica, IQ-UNICAMP, P.O. Box 6154, 13083-970 Campinas, SP, Brazil
ˆ ´
Instituto de Ciencias da Saude, Universidade Paulista, 13043-0045 Campinas, SP, Brazil
b
Received 31 January 2002; accepted 11 July 2002
Abstract—The utilization of ultrasound radiation in the Baylis–Hillman reaction with several aldehydes (aromatics and aliphatics) and
different a,b-unsaturated reactants is described. For all aldehydes tested, the utilization of ultrasound sources augmented the reaction rate and
the chemical yields. The use of ultrasound with two different catalysts (tri-n-butylphosphine and 1,4-diazabicyclo[2.2.2]octane [DABCO])
was also investigated. It was clearly demonstrated that DABCO is much more effective for catalyzing a Baylis–Hillman reaction under the
influence of ultrasound than is tri-n-butylphosphine. No effect on reaction rate was observed when the concentration of DABCO was
increased. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
aldehydes are used, under standard conditions (room
temperature or solvent reflux), the major drawbacks from
this reaction are its relative slowness (typically 1 to 4 weeks
to be completed) associated with very low chemical yields
(5–10%).
In the last few years the Baylis–Hillman reaction has
attracted the attention of many organic chemists,1 because it
is a simple and straightforward method to generate a new
C–C s bond. This reaction may be broadly defined as a
condensation between the a-position of activated double
bond (I) with carbon electrophiles containing an electron-
deficient sp2 carbon atom (II) under the influence of suitable
catalysts, such as phosphines or tertiary amines, producing
multifunctional molecules with high synthetic potential
(Scheme 1).1c,2,3
Due to the synthetic potentiality of Baylis–Hillman adducts
obtained from aromatic aldehydes,4 various modifications
of the experimental protocol have been proposed, e.g. the
use of microwaves,5 salts and metals,6 ionic liquids7 and an
aqueous medium.8
In a preliminary communication, we demonstrated that the
use of ultrasound dramatically accelerates the rate and
increases the chemical yield of the Baylis–Hillman
reaction, especially when aromatic aldehydes are used as
electrophile.9 Roos et al.10 have already reported the use of
ultrasound in the Baylis–Hillman reaction. However, their
attention was focused on the association of temperature with
ultrasound and little attention was paid to the substrate.
Besides the synthetic potential, the Baylis–Hillman reac-
tion is a totally atom-efficient process, since all the carbon
atoms from the reagents are incorporated in the end product,
thus being an inherently green transformation.3
Aldehydes are the most used carbon electrophiles in this
reaction. However, aromatic aldehydes are reluctant to
serve as substrates for the Baylis–Hillman reaction under
the usual relatively mild conditions. When aromatic
In a current research program directed towards the
Scheme 1. Formation of a-methylene-b-hydroxy compounds by the Baylis–Hillman reaction.
Keywords: Baylis–Hillman reaction; a,b-unsaturated compounds; 1,4-diazabicyclo[2.2.2]octane (DABCO).
*
Corresponding author. Tel.: þ55-19-3788-3085; fax: þ55-19-3788-3023; e-mail: coelho@iqm.unicamp.br; wpalmeida@ig.com.br
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00822-0

7438
F. Coelho et al. / Tetrahedron 58 (2002) 7437–7447
Table 1. Baylis–Hillman reaction using n-Bu3P or DABCO as bases, without and with ultrasound
Entry
Aldehydes
Without ultrasound
With ultrasounda
Product
c
%
Bases
Time (h)b
Product
(%)c
Time (h)b
1
2
3
4
5
R¼H (Benzaldehyde)
n-Bu3P
DABCO
n-Bu3P
DABCO
n-Bu3P
DABCO
n-Bu3P
DABCO
n-Bu3P
DABCO
96
144
96
240
504
480
96
192
96
72
1
1
2
2
3
3
4
4
5
5
–
25
–
25
–
30
–
74
–
96a
96b
96
1
1
2
2
3
3
4
4
5
5
,30d
74
R¼4-OCH3 (p-Anisaldehyde)
R¼3,4-OCH2O- (Piperonal)
R¼4-Cl, ( p-Chlorobenzaldehyde)
R¼4-NO2 ( p-Nitrobenzaldehyde)
32d
90e
–
96b
504
96
73e
22d
87
40d
88f
96
48
96c
16
45
a
Ultrasonic source: 1000 W, 25 kHz.
b
c
d
e
f
Time after which the composition of the reaction mixture no longer evolved.
Isolated yield.
Determined by GC (HP-5 column).
Yield based on recovered aromatic aldehyde.
With 4-nitrobenzaldehyde the solvent (methanol) was replaced by dichloromethane, because we observed the formation of a byproduct (<30–40%) coming
from the 1,4-addition of methanol to the double bond of the Baylis–Hillman adduct.
preparation of intermediates for the synthesis of natural
products,2 we needed to prepare several Baylis–Hillman
adducts from aromatic and aliphatic aldehydes, on a large
scale. To achieve this we studied the use of ultrasound
radiation while performing these reactions. Our intention
was on establishing when the utilization of this type of
radiation would be more indicated.
different types). Our choices were based on the influence of
the substituents on the electrophilicity of the carbon atom of
the carbonyl group. Thus, we investigated one aldehyde
without any substituents on the aromatic ring (1, benz-
aldehyde), two substituted with electron donating groups
(OCH3 and 3,4-methylenedioxy, 2 and 3, respectively) and
two substituted with electron-withdrawing groups (Cl and
NO2, 4 and 5). Initially, the reactions were performed
without the presence of ultrasound.
To our surprise, a careful search of the literature revealed
that there is no systematic study in situations where the use
of ultrasound radiation could be advantageous.
The literature reports the use of phosphines in the Baylis–
Hillman reaction (mainly triphenyl- and tri-cyclohexyl-
phoshines).11 For all aldehydes we tested in our study we
employed either tri-n-butylphoshine or 1,4-diazabicyclo-
[2.2.2]octane (DABCO), as the catalyst. As standard
experimental conditions, we established the following
concentration ratio: aldehyde (1.0)/DABCO or phoshine
(0.65)/methyl acrylate (1.3). All reactions were performed
at room temperature. The first set of reactions (with each
of the five aldehydes) was carried out with magnetic
stirring. The second set (same five aldehydes) was carried
out in the presence of an ultrasound source. The results are
summarized in Table 1.
Having these objectives in mind, we describe herein a
complementary study focused on the determination of the
scope and limitations of use of the ultrasound technique on
the Baylis–Hillman reaction with aliphatic and aromatic
aldehydes and different a,b-unsaturated reactants. In this
study, the main emphasis was given to aromatic aldehydes,
because they are harder to react in Baylis–Hillman than
aliphatic one.
Our interest was centered on evaluating the influence of the
association of different catalysts with ultrasound on the rate
of the Baylis–Hillman reaction. Moreover, the influence of
the substituents incorporated into the structure of the
aromatic aldehydes on the rate of this reaction was also
investigated. No special attention was paid in verifying the
influence of the temperature associated with the use of
ultrasound on the rate of the Baylis–Hillman reaction,
because a study of these effects has already been published
by Roos et al.10
2.1. The ultrasound effect
Without the presence of the ultrasound radiation, only poor
to moderate yields (25–74%) were obtained when DABCO
was used. Moreover, the reaction times are completely
unsuitable for synthetic purposes (Table 1). In addition, in
all cases where tri-n-butylphosphine was used as catalyst,
the formation of the Baylis–Hillman adducts could be only
detected in very low yields (by GC/HP5 column). On the
other hand, we were able to detect (by TLC and GC) a large
amount of degradation products. The reaction medium
immediately became dark when phosphine was added to the
2. Results and discussions
We initiated our study using only aromatic aldehydes (three

F. Coelho et al. / Tetrahedron 58 (2002) 7437–7447
7439
Figure 1. Chemical yield as a function of the DABCO concentration used in the Baylis–Hillman reaction in the presence of ultrasound.
aldehyde and acrylate mixture. We attempted to overcome
these unexpected results by performing these reactions at
low temperature (08C), for longer times (5–10 days) or
by changing the addition sequence of the reagents.
Unfortunately, in all situations, the reaction worked very
badly. The tendency of phosphines (especially tri-n-
butylphoshine) to catalyze the dimerization reaction of
acrylate derivatives has already been reported.12 This
dimerization tendency can probably explain the results we
had.
mining the influence of the DABCO concentration on the
rate of the reaction.
To evaluate this influence, we established four different
experimental conditions, in which the DABCO concen-
tration was varied relative to the concentration of acrylate,
which remained constant. In the first set of experiments, we
decreased the ratio DABCO/acrylate to 0.3:1.3. In the
second set, we increased the ratio to 1.3/1.3. In the third and
fourth sets, the amount of DABCO was progressively
increased to ratios of 2.0/1.3 and 2.6/1.3, respectively.
The effect caused by ultrasound radiation in organic
media is well documented.13,14 Due to the cavitation effect,
it is possible to transfer locally a huge amount of energy,
which can effectively contribute to produce a dramatic
acceleration of the reaction rate of several organic
processes.14 Thus, we decided to repeat these reactions
under the influence of an ultrasound source, using the same
experimental conditions as before. The results obtained
under these conditions are also shown in Table 1.
All reactions were carried out using ultrasound without
external heating. The ultrasonic bath temperature stayed at
35–408C. The results are plotted in Fig. 1.
In order to compare all the reactions under the same
experimental conditions, we stopped the Baylis–Hillman
reactions after 96 h, the only exception being the reaction
with 4-nitrobenzaldehyde which was complete after 16 h
(no starting material detected). This decision was based on
preliminary experimental observations that, after this time,
no significant increases of the chemical yields are perceived.
The results clearly show that when DABCO is used,
associated with ultrasound, a remarkable augmentation of
the rate and of the chemical yield of the reaction is observed
(Table 1). Under the influence of ultrasound radiation it was
possible to obtain moderate to good yields (70–90%) of the
Baylis–Hillman adducts associated with a dramatic
decrease in the reaction time (all reactions were at least
50% faster). However, these observations were not
duplicated with tri-n-butylphosphine and ultrasound radia-
tion. For these cases, TLC and GC (HP-5 column)
indicated that the reaction is very sluggish and still gives
several by-products, as commented above.
As can be seen in Fig. 1, augmentation of DABCO
concentration had little influence on either the rate or the
chemical yield of the reaction. In other words, with a ratio of
0.65:1 (DABCO/acrylate) it is possible to achieve a
reasonable chemical yield for all these reactions. No effect
was observed on the rate of the reaction when we increased
the DABCO concentration during the reaction (starting with
0.65 and increasing the concentration ratio to 2.6, after
96 h).
Based on these data, we decided to give up the use of tri-n-
butylphosphine, because it was not adequate for our
purposes. Thus, we concentrated our attention on deter-
From our point of view, at this stage of the work we had
optimized experimental conditions. Now our interest was
focused on determining for which cases the utilization of

7440
F. Coelho et al. / Tetrahedron 58 (2002) 7437–7447
Table 2. Use of aromatic and aliphatic aldehydes in the Baylis–Hillman reaction in the presence of an ultrasound source
Entry
Aldehydes
B–H adduct
Time without
ultrasound (h)a
Time with
ultrasound (h)
Yield without
ultrasound (%)b
Yield with
ultrasound (%)b
1
2
3
4
5
6
7
8
3-Bromobenzaldehyde
4-Hydroxybenzaldehyde
6
7
8
9
192
480
170
480
144
480
480
480
480
480
192
192
96
102
196
240
168
120
168
168
48
96
48
480
60
192
480
32
60
96
72
96
16
26
72
71
12
73
0
88
54
80
0
70
4-Trifluoromethoxybenzaldehyde
4-Dimethylaminobenzaldehyde
4-Methylsulphonylbenzaldehyde
3-Methoxy-4-hydroxybenzaldehyde
3-Methoxy-4-hydroxy-5-iodobenzaldehydec
6-Bromo-1,3-benzodioxole-5-carbaldehydee
7-Methoxy-1,3-benzodioxole-5-carbaldehydef
3-Hydroxy-4-methoxybenzaldehyde
3,4,5-Trimethoxybenzaldehyde
2-Hydroxy-3-methoxybenzaldehyde
2-Fluorobenzaldehyde
2-Bromobenzaldehyde
4-Methylbenzaldehyde
Formaldehyde
Acetaldehyde
Propionaldehyde
n-Butyraldehyde
n-Pentanaldehyde
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
40
0
54
0d
0
,5d
75
9
0
0
52g
51g
72
10
11
12
13
14
15
16
17
18
19
20
34
20
50
12
15
66i
88i
71i
85i
74i
67h
100g
73g
79
120
96
72
72
74
90
72
85
48
82
a
All reactions were carried out using standard conditions (see text).
Isolated yield.
Commercial product or prepared according the procedure described in Ref. 15.
Determined by GC.
Prepared according Ref. 16.
See Ref. 17 for the preparation of this aldehyde from 3-methoxy-4-hydroxy-5-iodobenzaldehyde.
Yield based on recovered aldehyde.
A chromene derivative was produced by a SN20 mechanism involving the participation of the phenolic hydroxyl group, see Ref. 18.
See Ref. 19a–d.
b
c
d
e
f
g
h
i
ultrasound could be considered a valuable tool to accelerate
the rate of the Baylis–Hillman reaction with aromatic and
aliphatic aldehydes.
some cases (see Table 2, entries 6–10), we have
dramatically altered the situation, since without ultrasound
the reaction did not go at all.
2.2. Generalization of the method
Even in the presence of ultrasound radiation, some aromatic
aldehydes are quite reluctant to react. The presence of an
amino group on the ring changes completely the chemical
profile of this reaction (entry 4). It is worth mentioning that
this reaction normally is very clean. However, with this
aldehyde (entry 4) the reaction is dirty and several
by-products were observed by TLC and GC. Several
experimental modifications were tried (use of acetonitrile
as solvent instead of methanol, use of methyl acrylate as
solvent, both increasing and decreasing the temperatures),
however no effect on the rate of the reaction was perceived.
Probably, the tertiary amine group is in competition with
DABCO for the acrylate.
2.2.1. Aliphatics and substituted aromatic aldehydes.
To answer these questions, various additional aldehydes
(aliphatics and aromatics) were tested. For aromatic ones
our preference was clearly directed to aldehydes substituted
with electron donating groups, because this type of aldehyde
is more resistant to undergoing the Baylis–Hillman
reaction.
As expected, the presence of electron withdrawing groups
on the aromatic ring accelerates the rate of the reaction,
while the presence of an electron donating group causes a
decrease in the rate. However, it is not clear to us which
substitution pattern on the aromatic ring could be success-
fully used under the influence of ultrasonic radiation. The
results obtained are summarized in Table 2.
A similar behavior was observed when an iodine atom was
conjugated with other electron donating groups (entry 7). In
this case we are able to detect by gas chromatography the
presence of the Baylis–Hillman adduct in the reaction
medium, in approximately 5–10% yield, after 480 h.
However, in general, even for aldehydes with several
electron donating substituents on ring, the reaction worked
quite well (entries 8–11). These results demonstrate that
ultrasound accelerates the Baylis–Hillman reaction with
most, but not all, aromatic aldehydes.
For majority of the cases, ultrasound radiation increased
enormously the efficiency of the reaction. For aldehydes
with electron-withdrawing groups, the utilization of ultra-
sound certainly increases the rate of the reaction, however
no substantial increase in the chemical yield was observed.
Otherwise, the effect of ultrasound is more remarkable when
aldehydes with electron-donating groups are used.
However, for all aliphatic aldehydes tested (entries 16–20),
we observed a dramatic decrease in reaction time associated
with an increase in the chemical yields of the reaction.
In most cases, we observed a considerable increase in
chemical yield as well as a decrease in reaction time. For

F. Coelho et al. / Tetrahedron 58 (2002) 7437–7447
7441
Table 3. Use of aromatic heterocyclic aldehydes in the Baylis–Hillman reaction in the presence of an ultrasound sources
Entry
Aldehydes
B–H adduct Time without ultrasound
(h)a
Yield
(%) without ultrasoundb
Time with ultrasound
(h)a
Yield
(%) with ultrasoundb
1
2
3
4
5
2-Furancarboxaldehyde
2-Pyridinecarboxaldehyde
3-Pyridinecarboxaldehyde
2-Thiophenecarboxaldehyde 29
2-Thiazolecarboxaldehyde 30
26
27
28
24c
16
4d
72d
1
76
97
,82
97
6
4
2
8
0.25
80
98
97
100
92
86
a
All reactions were carried out using standard conditions (see text and Section 4).
b
c
d
Isolated yield.
See Ref. 20.
See Ref. 21.
2.2.2. Aromatic heterocyclic aldehydes. To evaluate the
generality of this method we decided to test the use of
ultrasound radiation in a Baylis–Hillman reaction using as
electrophiles some aromatic heterocyclic aldehydes. Thus,
2- and 3-pyridinecarboxaldehyde, 2-thiophenebenzalde-
hyde, furfural and 2-thiazolecarboxaldehyde were sub-
mitted to the same experimental conditions described
previously. Unfortunately, when the reactions were per-
formed using methanol or dichloromethane as solvent, in
the presence of ultrasound, we observed no significant
enhancement in the chemical yield or/and in the rate of the
reaction.
literature. For some cases (entries 3 and 5), we also observed
an increase in the chemical yield of the reaction. For one
aldehyde, e.g. thiazolecarboxaldehyde (Table 3, entry 5) the
reaction is complete in only 15 min, with a quite good
chemical yield. Undoubtedly, the utilization of ultrasound
radiation to perform the Baylis–Hillman reaction with
aliphatic and aromatic aldehydes is really advantageous.
2.2.3. Other a,b-unsaturated reactants. In order to
demonstrate that the utilization of ultrasound radiation
was compatible with different situations, we performed
some additional experiments using other a,b-unsaturated
reactants commonly employed in the Baylis–Hillman
reaction. We selected acrylonitrile and methyl vinyl ketone,
based on two features of these compounds: they are prone
to polymerize; normally their reactions require special
attention; they provide synthetically interesting Baylis–
Hillman adducts. In Table 4 we summarize the results
obtained.
Aiming to circumvent these problems, we decided to
remove the solvent (methanol) and perform the reactions
without any additional solvent when in the presence of
ultrasound. This condition has already been tested with the
aromatic non-heterocyclic aldehydes, however no enhance-
ment of the reaction parameters was observed with these
substrates.
Once again, the utilization of ultrasound radiation demon-
strated its usefulness. For all combinations (aromatic
aldehydes and a,b-unsaturated reactants) the results
obtained are quite reasonable. It was possible to shorten
the reaction time and increase, or at least maintain the
chemical yield. For one case (entry 1, Table 4), we observed
a decrease in the reaction rate associated with a decrease in
the chemical yield. This reaction was specially not clear-cut
and the formation of several by-products was observed.
To our surprise, under this new experimental protocol, we
observed an augmentation in the chemical yields and a large
decrease in the reaction time in those cases where
ultrasound radiation was used. The results are summarized
in Table 3.
Some results are worth special comment. For all cases
where heterocyclic aromatic aldehydes were used in the
presence of ultrasound, we perceived a reasonable decrease
in the reaction time, compared with those described in the
However, in general, when we compare the results obtained
Table 4. Use of different a,b-unsaturated compounds in the Baylis–Hillman reaction in the presence of an ultrasound sources
Entry
Aldehydes/a,b-unsaturated compounds
B–H
adduct
Time without
ultrasound (h)a
Yield without
ultrasound (%)b
Time with
ultrasound (h)a
Yield with
ultrasound (%)b
1
2
3
4
5
6
7
Piperonal/acrylonitrile
31
32
33
34
35
36
37
48c
192d
50
95c
61d
54
15
48
24
3/4
3/4
8
78
60
73
98
90
80
82
4-Chlorobenzaldehyde/methyl vinylketone
4-Nitrobenzaldehyde/methyl vinyl ketone
2-Pyridinecarboxaldehyde/acrylonitrile
2-Pyridinecarboxaldehyde/methyl vinyl ketone
Propionaldehyde/acrylonitrile
24e
24e
40
92e
81e
81f
84g
Propionaldehyde/methyl vinyl ketone
24
5
a
All reactions were carried out using standard conditions (see text and Section 4).
b
c
d
e
f
Isolated yield.
See Ref. 22.
See Ref. 23.
See Ref. 24.
See Ref. 25.
See Ref. 26.
g

7442
F. Coelho et al. / Tetrahedron 58 (2002) 7437–7447
with the Baylis–Hillman reaction carried out in the
presence of ultrasound radiation, with those obtained
without it, it is obvious that ultrasound radiation should be
seriously taken into consideration while performing this
type of condensation reaction.
4.2. General procedure for the preparation of Baylis–
Hillman adducts 1–5, 6–20 (aromatic aldehydes) and
21–25 (aliphatic aldehydes)
A mixture of the aliphatic or aromatic aldehyde (18–
20 mmol), methyl acrylate (1.3 equiv.) and DABCO
(0.65 equiv.) in methanol, dichloromethane or acetonitrile
(2 cm3/mmol, indicated for each aldehyde), was sonicated
for 16–120 h. In some cases where no Baylis–Hillman
adduct was detected after this time, the mixture was
sonicated for 504 h (the reaction time for each aldehyde
has been indicated together with the spectral data).
Ultrasound bath temperature was constantly monitored
and kept at 30–408C during the reaction, through ice
addition or by using a refrigerated recirculator. After the
reaction time, the mixture was diluted with dichloromethane
(50 cm3). The organic solution was washed with 10%
aqueous HCl (2£20 cm3), concentrated under reduced
pressure and dried over MgSO4. After filtration and solvent
removal, the residue was filtered through a pad of silica gel
(eluent indicated for each adduct).
3. Conclusion
Our results demonstrate unambiguously the great influence
of ultrasound radiation on the Baylis–Hillman reaction with
several substituted aromatic and aliphatic aldehydes. For
most cases tested, a moderate to quite good chemical yield
was obtained. Without ultrasound radiation, many of these
Baylis–Hillman reactions did not work at all or required a
long reaction times before observing the formation of the
adduct, normally in very low yield. For most aldehydes
employed, we observed a remarkable increase of the rate of
the reaction accompanying the increase in the chemical
yield.
It was also pointed out that the utilization of ultrasound is
compatible with other a,b-unsaturated reactants normally
employed in the Baylis–Hillman process as nucleophiles.
Unfortunately, some aromatic aldehydes are reluctant to
react even under the influence of ultrasound radiation.
Finally, these results properly demonstrate that ultrasound
radiation should be seriously taken in consideration, as a
good alternative to perform a Baylis–Hillman reaction,
specially when aromatic aldehydes are employed as
electrophiles.
4.2.1. (6)-Methyl 2-[hydroxy(phenyl)methyl]acrylate
(1). Reaction time: 96 h, dichloromethane solvent; 74% of
a colorless viscous oil purified by silica gel column
chromatography (eluting with hexane/ethyl acetate 65:35);
1
IR nmax/cm21 3482, 3062, 1714, 1336 (film); H NMR
(500 MHz, CDCl3) d 7.4–7.2 (m, 5H, aromatic), 6.33 (s,
1H), 5.83 (s, 1H), 5.55 (s, 1H), 3.71 (s, 3H), 3.14 (br s, 1H,
exchangeable with D2O); 13C NMR (75.4 MHz, CDCl3) d
166.9, 142.1, 141.4, 128.5, 127.9, 126.7, 126.1, 73.2, 51.9;
MS (70 eV, m/e, %) 192 (Mþ, 34), 191 (30), 160 (30), 159
(12), 132 (56), 115 (32), 105 (100), 91 (10), 79 (40), 77 (50),
55 (28). Anal. calcd for C11H12O3: C, 68.74%; H, 6.29%.
Found C, 68.69%; H, 6.30%.
4. Experimental
4.1. General
4.2.2. (6)-Methyl 2-[hydroxy(4-methoxyphenyl)methyl]-
acrylate (2). Reaction time: 96 h, methanol solvent; 90% of
a white solid (yield based on recovered aldehyde) purified
by silica gel column chromatography (eluting with hexane/
ethyl acetate 80:20); mp 54–568C; IR nmax/cm21 3073,
2960, 2924, 2871, 2353, 1706, 1634, 1456, 1385, 1319,
1141, 1034, 909, 808 (film); 1H NMR (CDCl3, 300 MHz) d
5.80–5.66 (m, 1H), 5.07–5.00 (m, 2H), 2.52 (dd, J¼14.0,
8.4 Hz, 1H), 2.47–2.28 (m, 2H), 2.17 (dd, J¼14.0, 8.4 Hz),
2.0–1.87 (m, 2H), 1.85–1.75 (m, 1H), 1.74–1.65 (m, 1H),
1.64–1.50 (m, 1H), 1.0 (s, 3H), 0.91 (d, J¼7.0 Hz, 3H); 13C
NMR (75.4 MHz, CDCl3) d 216.2, 135.4, 117.6, 52.3, 40.8,
38.5, 38.4, 29.1, 24.3, 18.9, 15.2; MS (70 eV, m/e, %) 222
(Mþ, 25), 190 (16), 162 (18), 135 (100), 108 (46), 94 (20),
77 (33). Anal. calcd for C12H14O4: C, 64.85%; H, 6.35%.
Found C, 64.82%; H, 6.30%.
The 1H and 13C spectra were recorded on a Varian GEMINI
BB-300 at 300 and 75.4 MHz, respectively, or on an Inova
instrument at 500 and 125 MHz, respectively. The mass
spectra were recorded using a HP model 5988A GC/MS
with a High Resolution Autospec-Micromass/EBE. IR were
obtained with a Nicolet model Impact 410. Melting points
were measured in open capillary tubes using an Electro-
thermal apparatus model 9100, and are uncorrected. Yields
were determined from GC analyses on a HP6890 equipment
with a flame ionization detector, using a HP-5 capillary
(crosslinked 5% PH ME Siloxane, 28 m) column. Manipu-
lations and reactions were not performed under dry
atmospheres or employing dry solvents, unless otherwise
specified. Purification and separations by column chroma-
tography were performed on silica gel, using normal or flash
chromatography. TLC visualization was achieved by
spraying with 5% ethanolic phosphomolybdic acid and
heating. All Baylis–Hillman reactions were sonicated in an
ultrasonic cleaner UNIQUE model GA 1000 (1000 W,
25 kHz). Ice was added occasionally to avoid increasing the
temperature of the water bath of the ultrasonic cleaner,
which was maintained between 30 and 408C. Aromatic
aldehydes were purchased from Aldrich, Acros or Lancaster
and were used without previous purification.
4.2.3. (6)-Methyl 2-[1,3-benzodioxol-5-yl(hydroxy)-
methyl]acrylate (3). Reaction time: 96 h, methanol solvent;
73% yield of a white solid (yield based on recovered
aldehyde) purified by silica gel column chromatography
(eluting with hexane/ethyl acetate 75:25); mp 40–418C; IR
1
n
max/cm21 3492, 3119, 1706, 1620; H NMR (500 MHz,
CDCl3): d 6.87 (dd, J¼1.9, 0.46 Hz, 1H), 6.84 (ddd, J¼
7.96, 1.74, 0.55 Hz, 1H), 6.77 (d, J¼8.0 Hz, 1H), 6.3 (s, H),
5.9 (s, OCH2O), 5.85 (m, H), 5.45 (d, CH, J¼5 Hz), 3.7 (s,
CH3), 3.0 (d, OH, J¼5 Hz); 13C NMR (125 MHz, CDCl3) d

F. Coelho et al. / Tetrahedron 58 (2002) 7437–7447
7443
166.7, 147.7, 147.2, 141.9, 135.2, 125.9, 120.1, 108.1,
107.1, 101.0, 72.9, 51.9; MS (70 eV, m/e, %) 236 (Mþ, 84),
204 (30), 176 (27), 151 (40), 149 (100), 93 (55), 65 (44);
HRMS (Mþ) calcd for C12H12O5 236.06847. Found
236.06849. Anal. calcd for C12H12O5: C, 61.01%; H,
5.12%. Found C, 60.81%; H, 4.93%.
4.2.8. (6)-Methyl 2-{hydroxy[4-(trifluoromethoxy)phenyl]-
methyl}acrylate (8). Reaction time: 48 h, methanol solvent,
80% yield of a viscous colorless oil purified by silica gel
column chromatography (eluting with hexane/ethyl acetate
70:30); IR nmax/cm21 3467, 3039, 3005, 2958, 2908, 1712,
1
1631, 1508, 1442, 1273, 1227, 1181, 1045, 849; H NMR
(300 MHz, CDCl3): d 7.4 (d, J¼8.8 Hz, 2H), 7.2 (d, J¼
8.8 Hz, 2H); 6.3 (t, J¼0.73 Hz, 1H), 5.8 (t, J¼1.1 Hz, 1H),
5.5 (br s, 1H), 3.7 (s, 3H), 3.0 (br s, 1H, changeable with
D2O); 13C NMR (75.4 MHz, CDCl3) d 166.4, 148.5, 141.5,
139.8, 127.9, 126.2, 120.7, 72.5, 52.0; MS (70 eV, m/e, %)
276 (Mþ, 18), 259 (10), 244 (18), 216 (40), 189 (100), 115
(10), 95 (12), 77 (47), 55 (20); HRMS (Mþ) calcd for
C12H11F3O4 276.0609. Found 276.06104.
4.2.4. (6)-Methyl 2-[(4-chlorophenyl)(hydroxy)methyl]-
acrylate (4). Reaction time: 48 h, methanol solvent, 87%
yield of a white solid purified by silica gel column
chromatography (eluting with hexane/ethyl acetate 70:30);
mp 428C, lit.11 428C; IR nmax/cm21 3512, 2992, 1724, 1634;
1H NMR (300 MHz, CDCl3): d 7.30 (s, 4H, aromatics), 6.33
(s, 1H), 5.82 (s, 1H), 5.51 (d, 1H, J¼5.86 Hz, CHOH), 3.72
(s, 3H), 3.15 (d, J¼5.89 Hz, 1H, exchangeable with D2O);
13C NMR (75.4 MHz, CDCl3) d 116.4, 141.8, 139.9, 133.7,
128.7, 128.1, 126.4, 72.7, 52.0; MS (70 eV, m/e, %) 226
(Mþ, 28), 194 (21), 166 (50), 137 (52), 139 (100), 77 (80),
55 (35). Anal. calcd for C11H11ClO3: C, 58.29%; H, 4.89%.
Found C, 58.27%; H, 4.88%.
4.2.9. (6)-Methyl 2-{hydroxy[4-(methylsulfonyl)phenyl]-
methyl}acrylate (10). Reaction time: 60 h, methanol
solvent, 70% yield of a viscous oil-purified by silica gel
column chromatography (eluting with hexane/ethyl acetate
80:20); IR nmax/cm21 3494, 3020, 2954, 2927, 1712
(CvO), 1631, 1439, 1296, 1146, 1049, 980; 1H NMR
(300 MHz, CDCl3): d 7.8 (d, J¼7.68 Hz, 2H, aromatics),
7.5 (d, J¼8.42 Hz, 2H, aromatics), 6.3 (s, 1H), 5.9 (s, 1H),
5.6 (d, J¼5.4 Hz, 1H), 3.73 (s, 3H), 3.5 (d, J¼5.4 Hz, 1H,
exchangeable with D2O), 3.0 (s, 3H); 13C NMR (75.4 MHz,
CDCl3) d 166.1, 147.5, 140.9, 139.5, 127.36, 127.3, 126.8,
72.5, 52.1, 44.4; MS (70 eV, m/e, %) 270 (Mþ, 37), 253
(12), 238 (10), 210 (45), 183 (93), 158 (20), 157 (18), 131
(45), 130 (43), 103 (55), 77 (100), 55 (63), 52 (50); HRMS
(Mþ) calcd for C12H14O5S 270.05619. Found 270.05515.
4.2.5. (6)-Methyl 2-[hydroxy(4-nitrophenyl)methyl]-
acrylate (5). Reaction time: 16 h, dichloromethane solvent,
88% yield of a yellow tinged solid purified by silica gel
column chromatography (eluting with hexane/ethyl acetate
70:30); mp 73–748C, lit.11 748C; IR nmax/cm21 3512, 2992,
1
1724, 1634; H NMR (300 MHz, CDCl3): d 8.71 (d, J¼
8.79 Hz, 2H, aromatics), 7.56 (d, J¼8.79 Hz, 2H, aro-
matics), 6.40 (s, 1H), 5.89 (s, 1H), 5.64 (d, J¼5.86 Hz, 1H,
CHOH), 3.75 (s, 3H), 3.40 (d, J¼6.34 Hz, 1H, exchangeable
with D2O); 13C NMR (75.4 MHz, CDCl3) d 166.6, 148.7,
147.6, 141.1, 127.48, 127.4, 123.7, 72.8, 72.7, 61.3, 52.2;
MS (70 eV, m/e, %) 237 (Mþ, 20), 220 (58), 205 (40), 177
(90), 155 (100), 131 (22), 115 (30), 104 (25), 77 (73), 55
(80). Anal. calcd for C11H11NO5: C 55.70% H 4.67%.
Found C, 55.67%; H, 4.63%.
4.2.10. (6)-Methyl 2-[hydroxy(4-hydroxy-3-methoxy-
phenyl)methyl]acrylate (11). Reaction time: 96 h,
methanol solvent, 54% yield of a viscous yellow tinged
oil-purified by silica gel column chromatography (eluting
with hexane/ethyl acetate 70:30); IR nmax/cm21 3460, 1716,
1632; 1H NMR (300 MHz, CDCl3): d 6.9 (s, 1H, aromatics),
6.8 (dd, J¼13.9, 8.0 Hz, 2H, aromatics), 6.3 (bs, 2H, one
hydrogen exchangeable with D2O, OH phenolic), 5.85
(t, J¼1.09 Hz, 1H), 3.8 (s, 3H, OCH3), 3.7 (s, 3H, OCH3
ester), 3.2 (bs, 1H, exchangeable with D2O); 13C NMR
(75.4 MHz, CDCl3) d 166.8, 161.1, 146.5, 145.2, 142.0,
133.2, 125.8, 119.6, 114.1, 109.1, 73.0, 55.9, 51.9. Anal.
calcd for C12H14O5: C, 60.5%; H, 5.92%. Found C, 60.43%;
H, 5.89%.
4.2.6. (6)-Methyl 2-[(3-bromophenyl)(hydroxy)methyl]-
acrylate (6). Reaction time: 72 h, methanol solvent, 88%
yield of a viscous colorless oil purified by silica gel column
chromatography (eluting with hexane/ethyl acetate 80:20);
IR nmax/cm21 3467, 3082, 3001, 2951, 1716, 1631, 1570,
1439, 1292, 1192, 1153, 1045, 960, 787; 1H NMR
(300 MHz, CDCl3): d 7.5 (t, J¼1.8 Hz, 1H), 7.4 (dt, J¼
1.1, 8.0 Hz, 1H), 7.3 (m, 1H), 7.2 (t, J¼7.7 Hz), 6.3 (t, J¼
1.1 Hz, 1H), 5.8 (t, J¼1.1 Hz, 1H), 5.5 (br s, 1H), 3.7 (s,
3H), 3.2 (br s, 1H, exchangeable with D2O); 13C NMR
(75.4 MHz, CDCl3) d 166.3, 143,.5, 141.1, 130.7, 129.8,
129.5, 126.4, 125.1, 122.4, 72.5, 52.0; MS (70 eV, m/e, %)
271 (Mþ, 45), 238 (25), 211 (25), 184 (60), 156 (48), 115
(100), 77 (90); HRMS (Mþ) calcd for C11H11BrO3
269.98915. Found 269.98907.
4.2.11. (6)-Methyl 2-[(6-bromo-1,3-benzodioxol-5-yl)-
(hydroxy)methyl]acrylate (13). Reaction time: 32 h
methanol solvent, 75% yield of a viscous yellow tinged
oil purified by silica gel column chromatography, eluting
with hexane/ethyl acetate 80:20); IR nmax/cm21 3483, 2954,
2920, 2854, 1720, 1631, 1477, 1261, 1234, 1038; 1H NMR
(500 MHz, CDCl3): d 6.94 (s, 1H), 6.92 (s, 1H), 6.26 (s,
1H), 5.91 (s, 2H), 5.78 (s, 1H), 5.54 (s, 1H), 3.71 (s, 3H); 13C
NMR (125.4 MHz, CDCl3) d 166.9, 147.9, 147.6, 140.6,
133.1, 126.8, 113.6, 112.6, 108.2, 101.8, 71.4, 52.1; MS
(70 eV, m/e, %) 315 (Mþ2, 17), 313 (Mþ, 15), 235 (87), 203
(43), 175 (24), 149 (100), 122 (81), 113 (66), 63 (60);
HRMS (Mþ) calcd for C12H11BrO5 313.97898. Found
313.97930.
4.2.7. (6)-Methyl 2-[hydroxy(4-hydroxyphenyl)methyl]-
acrylate (7). Reaction time: 96 h, methanol solvent, 54%
yield of a colorless oil purified by silica gel column
chromatography (eluting with hexane/ethyl acetate 80:20);
IR nmax/cm21 3470, 3001, 1716, 1632; 1H NMR (300 MHz,
CDCl3): d 7.13 (d, J¼8.4 Hz, 2H), 6.7 (d, J¼8.4 Hz, 2H),
6.61 (br s, 1H), 5.86 (t, J¼1.1 Hz, 1H), 5.48 (br s, 1H), 3.68
(s, 3H); 13C NMR (75.4 MHz, CDCl3) d 166.8, 155.4, 141.6,
132.6, 128.0, 125.7, 115.3, 72.7, 52.1. Anal. calcd for
C11H12O4 C, 63.45%; H 5.81%. Found C, 63.39%; H, 5.79%.
4.2.12. (6)-Methyl 2-[hydroxy(7-methoxy-1,3-benzo-
dioxol-5-yl)methyl]acrylate (14). Reaction time: 60 h,

7444
F. Coelho et al. / Tetrahedron 58 (2002) 7437–7447
methanol solvent, 52% yield of a viscous colorless oil
(based on recovered aldehyde) purified by silica gel column
chromatography, eluting with hexane/ethyl acetate 70:30)
IR nmax/cm21 3467, 3001, 2920, 1712, 1631, 1504, 1431,
124.1, 124.0, 115.3, 115.0, 67.0, 52.0; HRMS (Mþ) calcd
for C11H11FO3 210.0692. Found 210.0690.
4.2.17. (6)-Methyl 2-[(2-bromophenyl)(hydroxy)methyl]-
acrylate (19). Reaction time: 26 h, methanol solvent, 73%
yield of a viscous colorless oil purified by silica gel column
chromatography (eluting with hexane/ethyl acetate 70:30);
IR nmax/cm21 3437, 3062, 3000, 2951, 1717, 1590, 1568,
1
1311, 1122, 1034; H NMR (500 MHz, CDCl3): d 6.59 (d,
J¼0.78 Hz, 1H), 6.53 (d, J¼1.22 Hz, 1H), 6.33 (s, 1H), 5.96
(s, 2H), 5.84 (t, J¼0.78 Hz, 1H), 5.46 (br s, 1H), 3.89 (s,
3H), 3.74 (s, 3H); 13C NMR (125 MHz, CDCl3) d 166.7,
148.8, 143.5, 141.7, 135.9, 134.7, 126.1, 106.1, 101.5,
100.8, 73.1, 56.5, 52.0. Anal. calcd for C13H14O6: C,
58.65%; H, 5.30%. Found C, 58.60%; H, 5.27%.
1
1468, 1438, 1400, 1269, 1195, 1147, 1052, 962, 758; H
NMR (300 MHz, CDCl3): d 7.55 (dd, J¼1.4, 8.0 Hz, 1H),
7.35 (m, 1H), 7.17 (m, 1H), 6.35 (d, J¼0.74 Hz, 1H), 5.94
(br s, 1H), 5.57 (t, J¼1.1 Hz, 1H), 3.78 (s, 3H), 2.95 (br s,
1H, exchangeable with D2O); 13C NMR (75.4 MHz, CDCl3)
d 166.7, 140.4, 139.6, 132.6, 129.1, 128.2, 127.5, 126.9,
122.9, 71.4, 52.1; HRMS (Mþ) calcd for C11H11BrO3
269.9891. Found 269.9889.
4.2.13. (6)-Methyl 2-[hydroxy(3-hydroxy-4-methoxy-
phenyl)methyl]acrylate (15). Reaction time: 96 h, metha-
nol solvent, 51% yield of a viscous colorless oil purified by
silica gel column chromatography, (eluting hexane/ethyl
acetate 70:30); IR nmax/cm21 3433, 3005, 2954, 1712, 1628,
1
1593, 1508, 1439, 1273; H NMR (300 MHz, CDCl3): d
4.2.18. (6)-Methyl 2-[hydroxy(4-methylphenyl)methyl]-
acrylate (20). Reaction time: 72 h, methanol solvent, 79%
yield of a viscous colorless oil purified by silica gel column
chromatography (eluting with hexane/ethyl acetate 70:30);
IR nmax/cm21 3447, 3024, 2951, 2922, 1722, 1629, 1512,
1438, 1397, 1275, 1195, 1149, 1040, 957; 1H NMR
(300 MHz, CDCl3) d 7.22 (d, J¼8.0 Hz, 2H), 7.13 (d, J¼
8.0 Hz, 2H), 6.35 (s, 1H), 6.31 (s, 1H), 5.10 (s, 1H), 3.73 (s,
3H), 2.33 (s, 3H); 13C NMR (75.4 MHz, CDCl3) d 166.9,
142.2, 138.5, 137.6, 129.2, 126.6, 125.9, 73.0, 51.8, 20.9;
HRMS (Mþ) calcd for C12H14O3 206.0942. Found 206.0938.
6.90–6.78 (m, 3H), 6.31 (t, J¼1.1 Hz, 1H), 5.86 (t, J¼
1.1 Hz, 1H), 5.46 (br s, 1H), 3.85 (s, 3H), 3.70 (s, 3H); 13C
NMR (75.4 MHz, CDCl3) d 166.5, 146.0, 145.3, 134.4,
125.6, 118.2, 112.8, 110.3, 72.7, 55.9, 51.9; MS (70 eV,
m/e, %) 238 (Mþ, 55), 207 (20), 178 (20), 151 (100), 124
(15), 93 (28), 65 (12); HRMS (Mþ) calcd for C12H14O5
238.0841. Found 238.0840.
4.2.14. (6)-Methyl 2-[hydroxy(3,4,5-trimethoxyphenyl)-
methyl]acrylate (16). Reaction time: 72 h, dichloro-
methane solvent, 72% yield of a viscous colorless oil
purified by silica gel column chromatography eluting with
hexane/ethyl acetate 70:30) IR nmax/cm21 3491, 2997,
2943, 1716, 1631, 1593, 1504, 1327, 1234; 1H NMR
(300 MHz, CDCl3): d 6.58 (br s, 2H), 6.32 (t, J¼1.1 Hz,
1H), 5.85 (t, J¼1.1 Hz, 1H), 5.49 (br s, 1H), 3.83 (s,
6H), 3.82 (s, 3H), 3.74 (s, 3H); 13C NMR (75.4 MHz,
CDCl3) d 166.5, 152.9, 141.6, 137.1, 136.7, 125.8, 103.4,
72.9, 60.7, 55.9, 51.9; MS (70 eV, m/e, %) 282 (Mþ, 100),
250 (47), 222 (22), 195 (60), 169 (30), 138 (12), 113 (6);
HRMS (Mþ) calcd for C14H18O6 282.11033. Found
282.10639.
4.2.19. (6)-Methyl 3-hydroxy-2-methylene-propanoate
(21). Reaction time 120 h, no additional solvent, 74% yield
of a pale yellow oil purified by distillation under reduced
pressure; bp 65–708C (1 mm Hg); IR (nmax/neat) 3446,
2999, 2902, 1720, 1635 cm21; 1H NMR (300 MHz, CDCl3)
d 6.26 (s, 1H), 5.87 (s, 1H), 4.32 (s, 2H), 3.78 (s, 3H), 3.4–
3.2 (br s, 1H, exchangeable with D2O); 13C NMR (CDCl3,
75.4 MHz) d 167, 139.5, 125.5, 62, 52; MS (70 eV, m/e, %)
116 (Mþ, 2), 115 (2), 87 (100), 85 (75), 84 (86), 55 (65).
4.2.20. (6)-Methyl 3-hydroxy-2-methylenebutanoate
(22). Reaction time: 96 h, no additional solvent, 90%
yield of a yellow tinged oil purified by distillation under
reduced pressure; bp 94–958C (15 mm Hg); IR (nmax/neat)
3470, 2937, 1712, 1635 cm21; 1H NMR (300 MHz, CDCl3)
d 6.16 (d, J¼1.4 Hz, 1H), 5.8 (d, J¼1.2 Hz, 1H), 4.75 (m,
1H), 3.73 (s, 3H), 3.0 (br d, J¼3.8 Hz, 1H), 1.22 (d, J¼
6.8 Hz, 3H); 13C NMR (CDCl3, 75.4 MHz) d. Other spectral
data were identical to those previously reported.19b
4.2.15. Methyl 8-methoxy-2H-chromene-3-carboxylate
(17). Reaction time: 96 h, methanol solvent, 67% yield of
a viscous yellow tinged oil purified by silica gel column
chromatography (eluting with hexane/ethyl acetate 85:15);
IR nmax/cm21 2997, 2951, 2839, 1705, 1639, 1577, 1481,
1
1265, 1211, 1111; H NMR (300 MHz, CDCl3): d 7.39 (t,
J¼1.47 Hz, 1H), 6.85 (m, 3H), 6.74 (m, 1H), 5.0 (br s, 2H),
3.84 (s, 3H), 3.78 (s, 3H); 13C NMR (75.4 MHz, CDCl3) d
164.4, 147.4, 143.5, 133.2, 121.0, 120.5, 114.1, 64.4, 55.7,
51.6; HRMS (Mþ) calcd for C12H12O4 220.0735. Found
220.0730.
4.2.21. (6)-Methyl 3-hydroxy-2-methylene-pentanoate
(23). Reaction time: 72 h, no additional solvent, 72%
yield of a pale yellow oil purified by silica gel column
chromatography (eluting with hexane/ethyl acetate 80:20);
IR (nmax/neat) 3473, 2966, 2937, 2879, 1716, 1633,
4.2.16. (6)-Methyl 2-[(2-fluorophenyl)(hydroxy)methyl]-
acrylate (18). Reaction time: 16 h, methanol solvent, 100%
yield of a viscous colorless oil purified by silica gel column
chromatography (eluting with hexane/ethyl acetate 70:30);
IR nmax/cm21 3437, 2954, 1721, 1588, 1491, 1456, 1439,
1399, 1226, 1152, 1042; 1H NMR (300 MHz, CDCl3): d 7.4
(m, 1H), 7.29 (m, 1H), 7.16 (m, 1H), 7.0 (m, 1H), 6.34 (br s,
1H), 5.88 (br s, 1H), 5.76 (m, 1H), 3.76 (s, 3H), 2.90 (br s,
1H, exchangeable with D2O);13C NMR (75.4 MHz, CDCl3)
d 166.6, 161.4, 158.1, 140.5, 129.4, 129.3, 127.9, 126.3,
1
1441 cm21; H NMR (300 MHz, CDCl3) d 6.2 (br s, 1H),
5.7 (br s, 1H), 4.3 (t, J¼7 Hz, 1H), 3.8 (s, 3H), 3.4 (br s, 1H),
1.8–1.3 (m, 2H), 0.9 (t, J¼7 Hz, 3H); 13C NMR (CDCl3,
75.4 MHz) d 166.6 (CvO), 142.1, 124.6, 72.3, 51.5, 29.0,
9.8. Calcd for C7H12O3 C 58.34; H 8.33%. Found C,
58.30%; H, 8.32%.
4.2.22. (6)-Methyl 3-hydroxy-2-methylene-hexanoate
(24). Reaction time: 72 h, no additional solvent, 85%

F. Coelho et al. / Tetrahedron 58 (2002) 7437–7447
7445
yield of a pale yellow oil purified by silica gel column
chromatography (eluting with hexane/ethyl acetate 80:20);
IR (nmax/neat) 3600, 3500, 2980, 2940, 2850, 2100, 1700,
d 3.68 (3H, s); 5.78 (1H, s); 6.05 (1H, s); 6.36 (1H, s); 7.43
(2H, d, J¼4.58 Hz); 8.45 (2H, d, J¼4.58 Hz); 13C NMR
(75.4 MHz, CDCl3) d 52.3, 71.7, 123.6, 126.5, 143.8, 149.9,
154.3, 167.3; MS (70 eV, m/e, %) 193 (Mþ, 55), 192 (35),
161 (100), 133 (94), 118 (25), 117 (23), 106 (82), 83 (45), 55
(42); HRMS (Mþ) calcd for C10H11NO3 193.07389. Found
193.07377.
1
1620, 1430 cm21; H NMR (300 MHz, CDCl3) d 6.22 (t,
J¼1 Hz, 1H), 5.80 (t, J¼1 Hz, 1H), 4.43 (q, J¼7 Hz, 1H),
3.78 (s, 3H), 2.72 (br d, J¼6.5 Hz, 1H, OH), 1.75–1.2 (m,
4H), 0.9 (t, J¼7 Hz, 3H); 13C NMR (CDCl3, 75.4 MHz) d
166.7 (CvO), 142.4, 124.6, 71.2, 60.3, 38.3, 19.0, 13.8.
Calcd for C8H14O3 C, 60.74%; H, 8.92%. Found C, 60.68%;
H, 8.90%.
4.3.3. (6)-Methyl 2-[hydroxy(pyridin-3-yl)methyl]acryl-
ate (28). Reaction time: 2 h; no additional solvent, 97%
yield of a yellow tinged amorphous solid purified by silica
gel column chromatography (eluting with hexane/ethyl
acetate/methanol 60:40:0.02); mp 99–1018C; lit.21b 1008C;
IR (KBr) nmax/cm21 3422, 3125, 2954, 2850, 1716, 1629,
1593, 1439, 1330, 1297, 1150, 1061, 977; 1H NMR
(300 MHz, CDCl3) d 8.51 (d, J¼1.6 Hz, 1H), 8.39 (dd,
J¼4.76, 1.47 Hz, 1H), 7.78 (dt, J¼8.0, 1.83 Hz, 1H), 7.35
(dd, J¼7.3, 5.1 Hz, 1H), 6.35 (bs, 1H), 6.11 (bs, 1H), 5.59
(s, 1H), 4.86 (bs, 1H, exchangeable with D2O), 3.63 (s, 3H);
13C NMR (75.4 MHz, CDCl3) d 167.1, 149.0, 148.9, 143.8,
140.1, 136.7, 125.5, 124.9, 70.7, 52.2; HRMS (Mþ) calcd
for C10H11NO3 193.07389. Found 193.07377.
4.2.23. Methyl 3-hydroxy-2-methylene-heptanoate (25).
Reaction time: 48 h, no additional solvent, 85% yield of a
pale yellow oil purified by silica gel column chroma-
tography (eluting with hexane/ethyl acetate 70:30); IR
(nmax/neat) 3600 (O–H), 3500, 2980, 2850, 2100, 1705
(CvO), 1620 (CvC), 1430 cm21 1H NMR (300 MHz,
;
CDCl3) d 6.22 (t, J¼1 Hz, 1H), 5.80 (t, J¼1 Hz, 1H), 4.43
(t, J¼6.5 Hz, 1H), 3.77 (s, 3H), 2.70 (br s, 1H, OH), 1.75–
1.2 (m, 4H), 0.9 (t, J¼6.9 Hz, 3H); 13C NMR (CDCl3,
75.4 MHz) d 166.7, 142.4, 124.7, 71.5, 51.8, 35.9, 27.9,
22.5, 14.0. Calcd for C9H16O3 C, 62.77%; H, 9.36%. Found
C, 62.72%; H, 9.35%.
4.3.4. (6)-Methyl 2-[hydroxy(thien-2-yl)methyl]acrylate
(29). Reaction time: 8 h; no additional solvent, 100% yield
of a yellow tinged viscous oil, no purification needed;
IR (Film) nmax/cm21 3485, 3106, 2951, 2877, 1714, 1631,
1620, 1439, 1277, 1151, 1040, 990, 794; 1H NMR
(300 MHz, CDCl3) d 7.22 (d, J¼1, 4 Hz, 1H), 6.95 (m,
1H), 6.92 (m, 1H), 6.34 (s, 1H), 5.97 (s, 1H), 5.76 (s, 1H),
3.48 (br s, 1H, exchangeable with D2O), 3.73 (s, 3H); 13C
NMR (75.4 MHz, CDCl3) d 166.2, 145.7, 141.3, 126.5,
125.7, 124.9, 124.5, 69.1, 51.9. Other spectral data were
identical with those previously reported.20
4.3. General procedure for preparation of Baylis–
Hillman adducts 26–30 (aromatic heterocyclic
aldehydes)
A mixture of the aromatic heterocyclic aldehyde (4.4–
4.8 mmol), methyl acrylate (1.3 equiv.) and DABCO
(0.65 equiv.) was sonicated (the reaction time for each
aldehyde has been indicated together with the spectral data).
Ultrasound bath temperature was constantly monitored and
kept at 30–408C during the reaction, through ice addition or
by using a refrigerated recirculator. After the reaction time
(monitored by TLC), the solvent was evaporated under
reduced pressure and the residue was dissolved in ethyl
acetate (40 mL). The organic layer was washed with
distilled water (40 mL). The aqueous phase was extracted
with ethyl acetate (4£40 mL). The combined organic phases
were washed with brine (40 mL), dried over Na2SO4 and
the solvent was removed under reduced pressure to furnish
the Baylis–Hillman adducts. For some cases, no chromato-
graphic purification is needed.
4.3.5. (6)-Methyl 2-[hydroxy(1,3-thiazol-2-yl)methyl]-
acrylate (30). Reaction time: 0.25 h; no additional solvent,
92% yield of a viscous oil purified by silica gel column
chromatography (eluting with hexane/ethyl acetate 60:40).
IR (Film) nmax/cm21 3228, 3122, 2952, 1728, 1633, 1504,
1
1445, 1333, 1259, 1155, 1045, 964, 930, 818; H NMR
(300 MHz, CDCl3) d 7.67 (d, J¼1.8 Hz, 1H), 7.3 (d, J¼
1.8 Hz, 1H), 6.41 (bs, 1H), 6.0 (br s, 1H), 5.78 (s, 1H), 4.53
(br s, 1H, exchangeable with D2O), 3.73 (s, 3H); 13C NMR
(75.4 MHz, CDCl3) d 172.5, 166, 141.8, 139.4, 127.7,
119.7, 71.1, 52.1; MS (70 eV, m/e, %); 199 (Mþ, 2), 182 (8),
167 (40), 139 (100), 123 (25), 111 (55), 86 (82), 57 (87);
HRMS (Mþ) calcd for C8H9NO3S 199.03032. Found
199.03034.
4.3.1. (6)-Methyl 2-[2-furyl(hydroxy)methyl]acrylate
(26). Reaction time: 6 h; no additional solvent, 80% yield
of a viscous oil purified by silica gel column chroma-
tography (eluting with hexane/ethyl acetate 90:10); IR
(Film) nmax/cm21 3467, 3120, 3001, 2954, 2850, 1716,
1
1635, 1504, 1450, 1284, 1146, 1041, 952, 820, 747; H
4.4. General procedure for preparation of Baylis–
Hillman adducts 31–35 (methyl vinyl ketone and
acrylonitrile as nucleophiles)
NMR (300 MHz, CDCl3) d 7.34 (m, 1H), 6.36 (m. 1H), 6.30
(dd, J¼3.3, 1.83 Hz, 1H), 6.23 (m, 1H), 3.70 (s, 3H); 13C
NMR (75.4 MHz, CDCl3) d 166.3, 154, 142.2, 139.3, 126.6,
110.2, 107, 110.2, 107, 66.9, 51.9. Other spectral data were
identical to those previously reported.20
A mixture of the aromatic aldehyde (4–10 mmol), DABCO
(0.65 equiv.) and acrylate derivative (1.3 equiv.) in metha-
nol, dichloromethane (2 cm3/mmol, indicated for each
aldehyde) or without any additional solvent, was sonicated
(the reaction time for each aldehyde has been indicated
together with the spectral data). Ultrasound bath tempera-
ture was constantly monitored and kept at 30–408C during
the reaction, through ice addition or by using a refrigerated
recirculator. After the reaction time (monitored by TLC),
4.3.2. (6)-Methyl 2-[hydroxy(pyridin-2-yl)methyl]acryl-
ate (27). Reaction time: 4 h; no additional solvent, 98%
yield of a yellowish viscous solid, no purification needed;
mp 102–1058C, lit.21b 1028C; IR (KBr) nmax/cm21 3418,
3125, 2959, 2850, 1712, 1605, 1564, 1441, 1417, 1341,
1290, 1225, 1191, 1141, 816; 1H NMR (300 MHz, CD3OD)

7446
F. Coelho et al. / Tetrahedron 58 (2002) 7437–7447
the mixture was diluted with dichloromethane (50 cm3).
The organic solution was washed with 10% aqueous HCl
(2£20 cm3), concentrated under reduced pressure and dried
over MgSO4. After filtration and solvent removal, the
residue was filtered through a pad of silica gel (eluent
indicated for each adduct).
(300 MHz, CDCl3) d 8.37 (d, J¼4.6 Hz, 1H), 7.52 (td,
J¼1.8, 7.7 Hz, 1H), 7.30 (d, J¼7.9 Hz, 1H), 7.05 (dd, J¼
5.0, 7.3 Hz, 1H), 6.1 (s, 1H), 6.0 (s, 1H), 5.6 (s, 1H), 4.99 (br
s, 1H, exchangeable with D2O), 2.19 (s, 3H); 13C NMR
(75.4 MHz, CDCl3) d 199.3, 159.9, 149.7, 136.5, 126.4,
122.2, 121.2, 70.9, 26.1. Other spectral data were identical
with those previously reported.23
4.4.1. 2-[1,3-Benzodioxol-5-yl(hydroxy)methyl]acrylo-
nitrile (31). Reaction time: 15 h, no additional solvent,
78% yield of a colorless viscous oil no purification needed;
IR (Film) nmax/cm21 3458, 2989, 2901, 2232, 1610, 1504,
4.4.6. (6)-2-(1-Hydroxypropyl)acrylonitrile (36). Reac-
tion time: 8 h, no additional solvent used, 80% yield of a
pale yellow oil purified by distillation under reduced
pressure: bp 64–658C (1 mm Hg); IR (film) nmax/cm21
1
1489, 1445, 1248, 1099, 1038, 932; H NMR (300 MHz,
1
CDCl3) d 6.81–6.76 (m, 3H), 6.1 (d, J¼1.46 Hz, 1H) 1H),
6.0 (d, J¼1.47 Hz, 1H), 5.99 (s, 2H), 5.17 (s, 1H) 2.6 (br s,
1H, exchangeable with D2O); 13C NMR (75.4 MHz, CDCl3)
d 147.9, 147.8, 132.9, 129.4, 126, 120.2, 108.2, 106.7,
101.2, 73.7; MS (70 eV, %) 203 (Mþ, 65), 172 (2), 151
(100), 121 (5), 93 (55), 65 (35); HRMS (Mþ) calcd for
C11H9NO3 203.05824. Found 203.05734.
3460, 220, 1620; H NMR (300 MHz, CDCl3) d 5.95 (s,
2H), 4.1 (t, 1H), 3.4 (br s, 1H), 1.67 (q, 2H), 0.91 (t, 3H); 13C
NMR (75.4 MHz, CDCl3) d 130.3, 126.9, 117, 73, 29.1, 9.0.
Other spectral data were identical with those previously
reported.25
4.4.7. (6)-3-(1-Hydroxypropyl)but-3-en-2-one (37).
Reaction time: 5 h, no additional solvent used, 82% yield
of a colorless oil purified by silica gel column chroma-
tography (eluting with hexane/ethyl acetate 90:10); IR
4.4.2. (6)-[(4-Chlorophenyl)(hydroxy)methyl]buten-3-
en-2-one (52). Reaction time: 48 h, dichloromethane used
as solvent, 60% yield of a colorless viscous oil purified by
silica gel column chromatography (eluting with hexane/
1
(film) nmax/cm21 3450, 1683, 1661; H NMR (300 MHz,
CDCl3) d 6.43 (s, 1H), 5.96 (s, 1H), 4.46 (m, 1H), 2.68 (br, s,
exchangeable with D2O), 2.17 (s, 3H), 1.67 (q, 2H), 0.97 (t,
3H); 13C NMR (75.4 MHz, CDCl3) d 199.5, 145.4, 126.1,
69.9, 28.2, 26.5, 7.7. Other spectral data were identical with
those previously reported.26
1
ethyl acetate 70:30); IR (film) nmax/cm21 3423, 1674; H
NMR (300 MHz, CDCl3) d 7.72 (s, 4H), 6.19 (s, 1H), 6.0 (s,
1H), 5.56 (s, 1H), 2.31 (s, 3H); 13C NMR (75.4 MHz,
CDCl3) d 200, 149.6, 140.1, 133.2, 128.4, 127.8, 126.7,
71.8, 26.3; MS (70 eV, m/e, %) 212 (30), 210 (100), 195
(20), 175 (80), 157 (10), 139 (18), 77 (4 5); HRMS (Mþ)
calcd for C11H11ClO2 210.04476. Found 210.04474.
Acknowledgments
4.4.3. (6)-3-[Hydroxy(4-nitrophenyl)methyl]but-3-en-2-
one (33). Reaction time: 24 h, dichloromethane used as
solvent, 73% yield of a colorless viscous oil purified by
silica gel column chromatography (eluting with hexane/
The authors thank FAPESP for financial support
(#98/14640-0) and for fellowships to RCR (#98/13779-4)
and CRM (#01/01558-8 and #98/13424-1). F. C. and D. V.
thank CNPq for fellowships. We also thank Professor C. H.
Collins for the revision of this text.
1
ethyl acetate 70:30); IR (film) nmax/cm21 3425, 1678; H
NMR (300 MHz, CDCl3) d 8.17 (d, J¼1.83 Hz, 1H), 7.55
(d. J¼1.83 Hz, 1H), 6.28 (s, 1H), 6.0 (s, 1H), 5.68 (s, 1H),
3.38 (br s, 1H, exchangeable with D2O), 2.35 (s, 3H); 13C
NMR (75.4 MHz, CDCl3) d 199.9, 149.0, 148.9, 147.1,
127.6, 127.2, 123.4, 71.8, 26.2; MS (70 eV, m/e, %) 221 (5),
220 (15), 204 (100), 174 (85), 131 (33), 115 (28), 77 (18);
HRMS (Mþ) calcd for C11H11NO4 221.06881. Found
221.06882.
References
1. For reviews see: (a) Drewes, S. E.; Roos, G. H. P. Tetrahedron
1988, 44, 4653–4670. (b) Basavaiah, D.; Rao, P. D.; Hyma,
R. S. Tetrahedron 1996, 52, 8001–8062. (c) Ciganek, E.
Organic Reactions, Wiley: New York, 1997; Vol. 51. Chapter
2, p 201. (d) Almeida, W. P.; Coelho, F. Quim. Nova 2000, 23,
98–101.
4.4.4. (6)-2-[Hydroxy(pyridin-2-yl)methyl]acrylonitrile
(34). Reaction time: 3/4 h, no additional solvent, 98% yield
of a yellow amorphous solid purified by silica gel column
chromatography (eluting with dichloromethane); mp 66–
678C, lit.23 66–678C; IR (Film) nmax/cm21 3200, 2225,
1600; 1H NMR (300 MHz, CDCl3) d 8.57 (m, 1H), 7.76 (m,
1H), 7.39 (m, 1H), 7.29 (m, 1H), 6.22 (s, 1H), 6.05 (s, 1H),
5.27 (s, 1H); 13C NMR (75.4 MHz, CDCl3) d 156, 148.5,
137.5, 130.9, 125.8, 123.7, 121.2, 116.7, 72.8. Other
spectral data were identical with those previously
reported.23
2. (a) Mateus, C. R.; Feltrin, M. P.; Costa, A. M.; Almeida, W. P.;
Coelho, F. Tetrahedron 2001, 57, 6901–6908. (b) Masunare,
A.; Ishida, E.; Trazzi, G.; Almeida, W. P.; Coelho, F. Synth.
Commun. 2001, 31, 2127–2136.
3. Langer, P. Angew. Chem. Int. Ed. 2000, 39, 3049–3052.
4. Basavaiah, D.; Bakthadoss, M.; Reddy, G. J. Synthesis 2001, 6,
919–923.
5. (a) Basavaiah, D.; Sreenivasulu, B.; Reddy, R. M.;
Muthukumaran, K. Synth. Commun. 2001, 31, 2987–2995.
(b) Yadav, J. S.; Reddy, B. V. S.; Madan, C. New J. Chem.
2001, 25, 1114–1117. (c) Shanmugam, P.; Singh, P. R. Synlett
2001, 8, 1314–1316. (d) Ravichandran, S. Synth. Commun.
2001, 31, 2055–2057. (e) Shi, M.; Feng, Y. S. J. Org. Chem.
2001, 66, 406–411. (f) Micuch, P.; Fisera, L.; Cyranski, M. K.;
Krygowski, T. M.; Krajcik, J. Tetrahedron 2000, 56,
4.4.5. (6) 3-[Hydroxy(pyridin-2-yl]but-3-en-2-one (35).
Reaction time: 3/4 h, no additional solvent used, 98% yield
of a viscous oil purified by silica gel column chroma-
tography (eluting with hexane/ethyl acetate/methanol
70:20:10); IR (film) nmax/cm21 3350, 1685; 1H NMR

F. Coelho et al. / Tetrahedron 58 (2002) 7437–7447
7447
5465–5472. (g) Kataoka, T.; Kinoshita, H.; Kinoshita, S.;
Iwamura, T.; Watanabe, S. Angew. Chem. Int. Ed. 2000, 39,
2358–2360. (h) Micuch, P.; Fisera, L.; Cyranski, M. K.;
Krygowski, T. M. Tetrahedron Lett. 1999, 40, 167–170.
(i) Iwama, T.; Tsujiyama, S.; Kinoshita, H.; Kanematsu, K.;
Tsurukami, Y.; Iwamura, T.; Watanabe, S.; Kataoka, T. Chem.
Pharm. Bull. 1999, 47, 956–961. (j) Basavaiah, D.;
Muthukumaran, K.; Sreenivasulu, B. Synlett 1999, 8,
1249–1250. (k) Iwama, T.; Kinoshita, H.; Kataoka, T.
Tetrahedron Lett. 1999, 40, 3741–3744. (l) Kundu, M. K.;
Mukherjee, S. B.; Balu, N.; Padmakumar, R.; Bhat, S. V.
Synlett 1994, 6, 444. (m) Cablewski, T.; Faux, A. F.; Strauss,
C. R. J. Org. Chem. 1994, 59, 3408–3412.
13. (a) Ley, S. V.; Low, C. M. R. Ultrasound in Synthesis. Series:
Reactivity and Structure. Springer: New York, 1989.
(b) Suslick, K. S. Ultrasound: Its Chemical, Physical, and
Biological Effects. VCH: New York, 1988.
14. (a) Mason, T. J. Chem. Soc. Rev. 1997, 26, 443–451.
(b) Davidson, R. S.; Safdar, A.; Spencer, J. D.; Robinson, B.
Ultrasonics 1987, 25, 35–39.
15. (a) Thorn, D. G.; Purves, C. B. Can. J. Chem. 1954, 32,
373–387. (b) Nishinaga, A.; Matsuura, T. J. Org. Chem. 1964,
29, 1812–1817.
16. Meyers, A. J.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc.
1987, 109, 5446–5452.
17. (a) Schneiders, G. E.; Stevenson, R. J. Org. Chem. 1981, 46,
2969–2971. (b) Banerjee, S. K.; Manolopoulo, M.; Pepper,
J. M. Can. J. Chem. 1962, 40, 2175–2177. (c) Crawford,
L. W.; Eaton, E. O.; Pepper, J. M. Can. J. Chem. 1956, 34,
1562–1566.
6. (a) Shi, M.; Jiang, J. K.; Cui, S. C. Tetrahedron 2001, 57,
7343–7347. (b) Akiyama, H.; Fujimoto, T.; Ohshima, K.;
Hoshino, K.; Saito, Y.; Okamoto, A.; Yamamoto, I.; Kakehi,
A.; Iriye, R. Eur. J. Org. Chem. 2001, 12, 2265–2272.
(c) Comins, D. L.; Hiebel, A. C.; Huang, S. L. Org. Lett. 2001,
3, 769–771. (d) Shi, M.; Feng, Y. S. J. Org. Chem. 2001, 66,
406–411. (e) Kataoka, T.; Kinoshita, H.; Kinoshita, S.;
Iwamura, T.; Watanabe, S. Angew. Chem. Int. Ed. Engl.
2000, 39, 2358–2360. (f) Akiyama, H.; Fujimoto, T.;
Ohshima, K.; Hoshino, K.; Yamamoto, I.; Iriye, R. Org.
Lett. 1999, 1, 427–430. (g) Aggarwal, V. K.; Mereu, A.;
Tarver, G. J.; McCague, R. J. Org. Chem. 1998, 63,
7183–7189.
18. Kaye, P. T.; Nocanda, X. W. J. Chem. Soc. Perkin Trans 1
2000, 1331–1332.
19. (a) Mathias, L. J.; Kosefoglu, S. H. US Patent 4,889,948, 1989;
CAS 1990, 112, 236009s. (b) Roush, W. R.; Brown, B. B.
J. Org. Chem. 1993, 58, 2151–2161. (c) Perlmutter, P.;
Tabone, M. J. Org. Chem. 1995, 60, 6515–6522. (d) Hill, J. S.;
Isaacs, N. S. J. Chem. Res. (S) 1988, 330–331. (e) Hoffmann,
H. M. R.; Rabe, J. J. Org. Chem. 1985, 50, 3849–3854.
20. (a) Foucaud, A.; El Guemmout, F. Bull. Soc. Chim. Fr. 1989,
403–408. (b) Fort, Y.; Berth, M. C.; Caubere, P. Tetrahedron
1992, 48, 6371–6384.
7. Rosa, J. N.; Afonso, C. A. M.; Santos, A. G. Tetrahedron
2001, 57, 4189–4193.
8. (a) Yu, C. Z.; Liu, B.; Hu, L. Q. J. Org. Chem. 2001, 66,
21. (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem. Int. Ed. Engl.
1983, 22, 795–796. (b) Ameer, F.; Drewes, S. E.; Freese, S.;
Kaye, P. T. Synth. Commun. 1988, 18, 495–500.
22. Becker, A. French Demande FR 2602507, 1988; Chem. Abstr.
1988, 110, 75549j; US Patent 4789743, 1988.
´
5413–5418. (b) Auge, J.; Lubin, N.; Lubineau, A.
Tetrahedron Lett. 1994, 35, 7947–7948.
9. Almeida, W. P.; Coelho, F. Tetrahedron Lett. 1998, 39,
8609–8612.
10. Roos, G. H. P.; Rampereadh, P. Synth. Commun. 1993, 23,
1261–1266.
23. Basavaiah, D.; Gowriswari, V. V. L.; Dharma Rao, P.;
Bharathi, T. K. J. Chem. Res. (M) 1995, 1656–1673.
24. Bode, M. L.; Kaye, P. T. J. Chem. Soc. Perkin Trans. 1 1993,
1809–1813.
11. (a) Morita, K.; Suzuki, K.; Hirose, H. Bull. Soc. Chem. Jpn
1968, 41, 2815. (b) Lu, X. Y.; Zhang, C. M.; Xu, Z. R. Acc.
Chem. Res. 2001, 34, 535–544. (c) Hayase, T.; Shibata, T.;
Soai, K.; Wakatsuki, Y. Chem. Commun. 1998, 12,
1271–1272.
25. Basavaiah, D.; Gowriswari, V. V. L. Synth. Commun. 1987,
17, 587–591.
26. Hoffmann, H. M. R.; Eggert, U.; Poly, W. Angew. Chem. Int.
Ed. Engl. 1987, 26, 1015–1017.
12. Jenner, G. Tetrahedron Lett. 2000, 41, 3091–3094.