Imidazole-catalysed Baylis-Hillman reactions: A new route to allylic alcohols from aldehydes and cyclic enones

Article abstract of DOI:10.1016/S0040-4039(02)01515-0

An efficient one-pot synthesis of cyclic Baylis-Hillman adducts is described. An imidazole-catalysed coupling reaction between cyclic enones and both aliphatic and aromatic aldehydes leads to allylic alcohols in moderate to good yields.

Full text of DOI:10.1016/S0040-4039(02)01515-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7835–7836
Imidazole-catalysed Baylis–Hillman reactions: a new route to
allylic alcohols from aldehydes and cyclic enones
Rafik Gatri and Mohamed Moncef El Ga¨ıed*
Laboratoire de Chimie Organique, Faculte´ des Sciences de Tunis, Campus Universitaire, 1060 Tunis, Tunisia
Received 21 May 2002; revised 8 July 2002; accepted 19 July 2002
Abstract—An efficient one-pot synthesis of cyclic Baylis–Hillman adducts is described. An imidazole-catalysed coupling reaction
between cyclic enones and both aliphatic and aromatic aldehydes leads to allylic alcohols in moderate to good yields. © 2002
Elsevier Science Ltd. All rights reserved.
The coupling reaction between activated non-cyclic
alkenes and aldehydes, through the Baylis–Hillman
reaction, is commonly catalysed by 1,4-diazabicy-
clo[2.2.2]octane (DABCO).1 However, this tertiary
amine was found to be inefficient in a-
hydroxyalkylation2 of cyclic enones. In addition, DBU3
and aqueous trimethylamine4 lead to self dimerisation
of the cyclic enones. Recently the first examples of
coupling reactions between cyclohexenones and
aqueous formaldehyde using 4-dimethylaminopyridine
(DMAP)2 as catalyst have been reported and various
equiv.) was carried out in the presence of 20 mol%
imidazole, at room temperature. The desired adduct 2a
was obtained after 17 days in 93% isolated yield
(Scheme 1, Table 1: entry 1). It is worth noting that the
yield decreased severely when using more than 20 mol%
of imidazole.
Encouraged by the mild reaction conditions and the
high yield (93%) of the allylic alcohol 1, we successfully
carried this coupling reaction between 2-cyclopentenone
3 and formaldehyde in the presence of 5 mol% imida-
zole in aqueous THF at room temperature. Thus, the
useful intermediate in organic synthesis 4a,6 leading to
applications in biology,7–10 was obtained after 17 days
in 86% yield11 (Scheme 1, Table 1: entry 2).
5
6
catalysts, such as chalcogenides-TiCl4 or TiCl4 with-
out a Lewis base, have been proposed to effect a-
hydroxyalkylation of cyclic enones.
In continuation of our study on a-functionalisation of
cyclic enones using new catalysts, we wish to report
herein our results on the imidazole mediated Baylis–
Hillman reaction between cyclic enones and both
aliphatic and aromatic aldehydes in aqueous media.
We first explored the hydroxymethylation of 2-cyclo-
hexenone 1 catalysed by imidazole in aqueous THF.
The best results were obtained when the reaction
between this enone and 30% aqueous formaldehyde (2
Scheme 1.
Table 1. Baylis–Hillman reaction of enones 1 and 3 with formaldehyde
Entry
n
Product
R
Catalyst (mol%)
Temp.
Time (days)
Yield (%)
1
2
2
1
2a
4a
H
H
Imidazole (20)
Imidazole (5)
rt
rt
17
17
93
86
* Corresponding author. Fax: +216 71 885008; e-mail: moncef.elgaied@mes.rnu.tn
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01515-0

7836
R. Gatri, M. M. El Ga¨ıed / Tetrahedron Letters 43 (2002) 7835–7836
Table 2. Baylis–Hillman reaction of enones 1 and 3 with aliphatic and aromatic aldehydes (10 mol% of imidazole as
catalyst)
Entry
n
Product
R
Temp. (°C)
Time (days)
Yield (%)
1
2
3
4
5
6
7
8
9
2
2
2
2
2
1
1
1
1
2b
2b
2c
2d
2e
4b
4c
4d
4e
Ph
Ph
rt
50
rt
50
50
50
rt
50
50
65
20
10
15
16
2
6
3
16
69
61
65
70
60
35
62
51
60
p-NO2Ph
Mea
s-Bu
Ph
p-NO2Ph
Mea
s-Bu
a Excess of acetaldehyde (10 equiv.) was used.
In order to investigate the scope and limitations of this
synthetic methodology, we examined, in the second
part of this study, the coupling reaction of enones 1 and
3 with a variety of aldehydes. Our preliminary attempts
were carried out using 2-cyclohexenone 1 and benzalde-
hyde, at room temperature, in the presence of 10 mol%
imidazole in aqueous THF. This coupling reaction took
a very long time (65 days) but led to the desired
compound 2b in 69% yield (Scheme 1, Table 2: entry 1).
Interestingly, by heating the reaction mixture, at 50 °C,
compound 2b was isolated after 20 days with only a
slight decrease in yield (61% yield) (Scheme 1, Table 2:
entry 2).
2. Rezgui, F.; El Ga¨ıed, M. M. Tetrahedron Lett. 1998, 39,
5965.
3. Hwu, J. R.; Hakimelahi, G. H.; Chou, C.-T. Tetrahedron
Lett. 1992, 33, 6469.
4. Basavaiah, D.; Krinshnamacharyulu, M.; Rao, A. J.
Synth. Commun. 2000, 30, 2061.
5. (a) Kataoka, T.; Iwama, T.; Tsujiyama, S.; Iwamura, T.;
Watanabe, S. Tetrahedron 1998, 54, 11813; (b) Iwama, T.;
Kinoshita, H.; Kataoka, T. Tetrahedron Lett. 1999, 40,
3741.
6. Li, G.; Wei, H.; Gao, J. J.; Caputo, T. D. Tetrahedron
Lett. 2000, 41, 1.
7. Smith, A. B., III; Wexler, B. A.; Slade, J. S. Tetrahedron
Lett. 1980, 21, 3237.
8. (a) Smith, A. B., III; Branca, S. J. J. Am. Chem. Soc.
1978, 24, 7767; (b) Smith, A. B., III; Branca, S. J.; Pilla,
N. N.; Guaciaro, M. A. J. Org. Chem. 1982, 47, 1855.
9. Takao, I.; Kunimito, K.; Masanobu, S.; Kiyohiro, N.;
Takemitsu, N. Chem. Abstr. 1987, 106, 49660m.
10. Kabat, M. M.; Kiegel, N.; Cohen, K. T.; Wovkulich, P.
M.; Malmas, Uskokovic, M. J. Org. Chem. 1996, 61, 118.
11. Preparation of 2-(hydroxymethyl)-2-cyclopentenone 4a:
A 100 mL round-bottomed flask was charged with 2-
cyclopentenone 3 (4.9 g, 60 mmol), 30% aqueous formal-
dehyde (12 mL, 120 mmol), 12 mL of THF and imidazole
(0.4 g, 3 mmol). The resulting mixture was stirred for 17
days at room temperature. When the reaction, followed
by TLC was finished, the mixture was acidified with
aqueous HCl (1.5 M) and extracted with methylene chlo-
ride. After the usual work up, chromatography of the
crude product on silica gel, using ether as eluent, gave
pure 2-(hydroxymethyl)-2-cyclopentenone 4a8 in 86%
Finally, the reaction of enones 1 and 3 with activated
aromatic and aliphatic aldehydes was examined in the
presence of catalytic amounts of imidazole (10 mol%).
Therefore, the allylic alcohols 2c–e (Table 2: entries
3–5) and 4b–e (Table 2: entries 6–9) were prepared
under the experimental conditions described in Table 2.
In conclusion, we have developed a short and simple
procedure for the preparation of cyclic Baylis–Hillman
derivatives in moderate to good yields. Moreover, this
large-scale method, using imidazole as a catalyst, allows
both hydroxymethylation and hydroxyalkylation of
cyclic enones.
References
1
yield; IR (cm-1, CHCl3): 3450, 1690; H NMR (300 MHz,
1. (a) Baylis, A. B.; Hillman, M. E. D. German Patent
2,155,113, 1972; Chem. Abstr. 1972, 77, 341174q; (b)
Drews, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653;
(c) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron
1996, 52, 8001; (d) Ciganec, E. Org. React. 1997, 51,
201.
CDCl3): 7.58 (m, 1H), 4.34 (s, 2H), 3.15 (br s, OH), 2.64
(m, 2H), 2.45 (m, 2H); 13C NMR (75 MHz, CDCl3):
209.7, 159.3, 145.0, 56.7, 34.8, 26.6; MS (EI) m/z: 70 (54),
83 (42), 84 (31), 97 (16), 112 (M+, 100); HRMS calcd for
C6H8O2: 112.0524. Found: 112.0527.