Octanol-accelerated Baylis-Hillman reaction

Article abstract of DOI:10.1055/s-2007-968032

The Baylis-Hillman reaction was greatly accelerated by use of octanol as an additive. Under the octanol-accelerated Baylis-Hillman conditions, unactivated aldehydes such as aliphatic aldehydes and aromatic aldehydes with electron-withdrawing substituents

Full text of DOI:10.1055/s-2007-968032

LETTER
395
Octanol-Accelerated Baylis–Hillman Reaction
O
ctanol-Accelerat
w
e
d
Baylis–Hillman
a
Reaction ng-Su Park,a Jinyoung Kim,a Hyunah Choo,*b Youhoon Chong*a
a
Department of Bioscience and Biotechnology, Institute of Biomedical Science and Technology, Konkuk University,
1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Korea
Fax +82(2)4548217; E-mail: chongy@konkuk.ac.kr
b
Life Sciences Division, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, Korea
E-mail: hchoo@kist.re.kr
Received 23 October 2006
O–
O
H
H
Abstract: The Baylis–Hillman reaction was greatly accelerated by
use of octanol as an additive. Under the octanol-accelerated Baylis–
Hillman conditions, unactivated aldehydes such as aliphatic alde-
hydes and aromatic aldehydes with electron-withdrawing substitu-
ents were readily converted into the desired products in good to high
yields.
O
O
Me
R3+N
Me
Me
Me
[Step 3]
3
4
[Step 2]
MeCHO
Key words: Baylis–Hillman reaction, octanol, additive, rate accel-
eration, aliphatic aldehydes
O–
O
H
R3N
H
Me
Me
The Baylis–Hillman reaction (BHR) is a synthetically
useful method for the preparation of b-hydroxy-a-methyl-
ene carbonyl compounds in one step from electrophilic
alkenes and carbonyl compounds by using a tertiary
amine or tertiary phosphine as an organic catalyst.1 The
commonly accepted mechanism for the Baylis–Hillman
reaction involves reversible conjugate addition of the
nucleophilic amine catalyst to the activated alkene to
generate an enolate (Step 1, Scheme 1), nucleophilic at-
tack of the enolate on the aldehyde to generate a second
zwitterionic intermediate (Step 2, Scheme 1), and then
elimination to generate the product (Step 3, Scheme 1)
and liberate the amine catalyst. In the case of reactive
activated alkenes (such as alkyl vinyl ketones), however,
Michael-type dimers are formed (Step 2¢, Scheme 1) as
side products because they themselves act as electro-
philes.
[Step 1]
R3+N
1
2
[Step 2']
1
O–
O
H
O
O
Me
Me
Me
Me
[Step 3']
R3+N
5
6
Scheme 1 Proposed mechanism of the BHR
after stirring the reaction mixture at room temperature for
10 days. Moreover, the Michael-type dimer (6, Scheme 1)
is always obtained as a by-product in almost the same
yield as that of the desired compound.
Several efforts have been directed to surmount the prob-
lem of a slow reaction rate of the Baylis–Hillman reaction.
Applications of Lewis acid,2 microwave irradiation,3 use
of excess catalyst,4 installation of a hydroxy group either
in the catalyst or in the substrate,5 aqueous medium,6
ultrasound,7 high pressure,8 and PPh3/nitrophenol co-
catalyst9 have been examined for rate acceleration and
considerable success has been achieved in this direction.
Particularly, protic solvents are known to accelerate the
Baylis–Hillman reaction, and it has been proposed that
this acceleration occurs through formal proton transfer
from the a-keto methine to the alkoxide in the zwitterion
to facilitate liberation of the product and regeneration of
the catalyst through elimination (Scheme 2).10
Usually, the Baylis–Hillman reaction is a slow reaction
requiring a few days to a few weeks for completion de-
pending upon the reactivity of both the activated alkene
and electrophile. Moreover, while the original protocol
used a tertiary amine, prolonged reaction time was needed
even when a stoichiometric amount of a rather strong ba-
sic amine such as 1,4-diazabicyclo[2,2,2]octane (DAB-
CO) was used. For this reason, the Baylis–Hillman
reaction of unactivated aldehydes such as aliphatic alde-
hydes or aromatic aldehydes with electron-donating sub-
stitutents has rarely been reported. During our own
investigation on the reaction of acetaldehyde with methyl
vinyl ketone (MVK) in DMF or DMSO catalyzed by
DABCO, we found that the reaction proceeds very slowly
to give the desired product in less than 10% yield even
Interestingly, however, even though the remarkable rate
acceleration under the protic solvent such as water or
methanol has widely been notified, acceleration of the
Baylis–Hillman reaction by other alcoholic solvents has
rarely been reported. Thus, we set out to investigate rate
SYNLETT 2007, No. 3, pp 0395–0398
1
5.
0
2.
2
0
0
7
Advanced online publication: 07.02.2007
DOI: 10.1055/s-2007-968032; Art ID: U12606ST
© Georg Thieme Verlag Stuttgart · New York

396
K.-S. Park et al.
LETTER
H
R
of the dimer (data not shown). In spite of the remarkable
rate acceleration, the use of solvents with high boiling
temperatures such as octanol and cyclohexanol limited the
application of this method to various Baylis–Hillman
reactions due to the difficulties in the purification process.
Particularly, removal of cyclohexanol from the reaction
mixture required repeated purification by column
chromatography. Thus, we tested if octanol could be used
as an additive to the normal Baylis–Hillman conditions
but not as a solvent (Table 2).
O
O–
H
R
H
O-
O
H
H
O
O
Me
Me
Me
R3+N
Me
Me
Me
R3+N
O
O
3
4
Scheme 2 Protic solvents accelerate proton transfer in BHR
Table 1 Baylis–Hillman Reaction of Acetaldehyde with MVK
under Various Protic Solvent Systemsa
Table 2 Baylis–Hillman Reaction of Acetaldehyde with MVK
under Various Solvents with Octanol Additivea
Solvent
Yield (%)
Solventb
Octanol (mL)
Yield (%)
4
6
4
6
8
0
9
6
H2O
0b
28
30
31
50
52
65
50
68
0b
0b
Octanol
THF
–
65
12
10
90
MeOH
12
10
11
10
22
8
0.7 mL (2 equiv)
1.0 mL (3 equiv)
0.7 mL (2 equiv)
EtOH
MeOH
Nonec
i-PrOH
BuOH
a The reaction was stopped after 12 h.
b Volume of the solvent was fixed to 3 mL.
c No solvent was used.
Pentanol
Octanol
CH3(CH2)11OH
Cyclohexanol
PhOH
9
The rate acceleration by octanol additive was completely
diminished under the normal aprotic (THF) or protic
(MeOH) solvent systems (Table 2). However, to our sur-
prise, even more remarkable rate acceleration was ob-
served by addition of 2 equivalents of octanol into the
mixture of acetaldehyde, MVK and DABCO in the ab-
sence of solvent. The desired product 411 was obtained in
90% yield along with the dimer 611 in a slightly decreased
yield (6%).
10
0b
a A mixture of acetaldehyde (100 mg, 2.27 mmol) and MVK (159 mg,
2.27 mmol) in 3 mL of the solvent was treated with DABCO (0.037
mL, 0.34 mmol), and the reaction mixture was stirred at r.t. for 12 h.
The reaction mixture was concentrated under reduced pressure, and
the resulting residue was purified by column chromatography on sili-
ca gel.
b Starting material decomposed.
The Baylis–Hillman reactions of various aliphatic and
aromatic aldehydes with MVK and other Michael accep-
tors were tested under our reaction conditions using
octanol as an additive (Method B, Table 3) in comparison
with the general Baylis–Hillman conditions using MeOH
as a solvent (Method A, Table 3).
acceleration of the Baylis–Hillman reaction of acetalde-
hyde and MVK under various protic solvent systems
(Table 1).
The yield of the Baylis–Hillman reaction in Table 1 is not
optimized but the reactions were stopped after 12 hours in
order to obtain an idea about the influence of protic sol-
vents on the reaction rates. It is worth noting that the yield
of the reaction gradually increases as the aliphatic chain
length of the protic solvents increases from methanol to 1-
octanol or cyclohexanol. However, as in the case of 1-
dodecanol, the yield of the Baylis–Hillman reaction de-
creases as the chain becomes longer than octanol
(Table 1). On the other hand, the reaction mixture decom-
posed in water as well as phenol solvent systems, indicat-
ing that the acceleration of the reaction rate depends
specifically on aliphatic alcohols. Also, it is of importance
to note that the yield of the Michael-type dimer 6 was kept
almost unchanged throughout the aliphatic solvent sys-
tems tested (Table 1). Dilution of the reaction mixture as
well as inverse addition of MVK to the premixed mixture
of acetaldehyde and DABCO did not influence the yield
It is quite interesting to note that the aliphatic aldehydes
(7a–c) which showed very slow transformation under the
general Baylis–Hillman conditions (0–7% yield, Method
A, Table 3) gave the desired products in moderate to high
yield in octanol-promoted reaction conditions (31–91%
yield, Method B, Table 3). However, almost the same
amount of the MVK dimer 8 was obtained in both reaction
conditions, which indicates that the production of the
dimer is the result of the low reactivity of the aldehyde but
not the reaction conditions. By the same token, it is no sur-
prise that electron-rich aldehydes such as 2-furaldehyde,
4-methoxybenzaldehyde, and 4-hydroxybenzaldehyde do
not undergo the Baylis–Hillman reaction easily, even
under the octanol-accelerated conditions (7d–f, Table 3)
because, in this case, attack of the aldehyde by the enolate
(Step 2, Scheme 1) would become the rate-limiting step.9
4-Hydroxybenzaldehyde provided neither the desired
Synlett 2007, No. 3, 395–398 © Thieme Stuttgart · New York

LETTER
Octanol-Accelerated Baylis–Hillman Reaction
397
Table 3 Baylis–Hillman Reaction under Reaction Conditions Using Methanol as a Solvent versus Octanol as an Additivea
H
O
H
R
R
R
+
R'CHO
+
R
R'
1
7
8
Yield (%)
Method Ab
Method Bc
R
R¢CHO
7
8
7
8
7a
7b
7c
COMe
7
7
91
31
70
9
CHO
CHO
CHO
COMe
COMe
0
0
10
12
15
20
7d
7e
COMe
COMe
27
0
15
8
26
18
10
43
O
CHO
CHO
MeO
HO
7f
COMe
COMe
COMe
COMe
0
47
20
16
0
9
0
0
0
100
100
100
0
0
0
0
CHO
7g
7h
7i
CHO
CHO
NC
F3C
CHO
NO2
7j
COMe
COMe
COOMe
CN
18
10
12
36
0
0
0
0
70
70
0
0
0
0
CHO
CHO
O2N
Cl
7k
7l
90
CHO
CHO
Cl
7m
100
Cl
a The reaction was stopped after 12 h.
b Method A: A mixture of acetaldehyde (100 mg, 2.27 mmol) and MVK (159 mg, 2.27 mmol) in 3 mL of MeOH was treated with DABCO
(0.037 mL, 0.34 mmol), and the reaction mixture was stirred at r.t. for 12 h. The reaction mixture was concentrated under reduced pressure, and
the resulting residue was purified by column chromatography on silica gel.
c Method B: A mixture of acetaldehyde (100 mg, 2.27 mmol), MVK (159 mg, 2.27 mmol), and DABCO (0.037 mL, 0.34 mmol) was treated
with octanol (4.54 mmol, mL) and the reaction mixture was stirred at r.t. for 12 h. The reaction mixture was directly purified by column
chromatography on silica gel.
product nor the dimer under both reaction conditions, but nucleophile. The octanol-accelerated Baylis–Hillman
the major product (18% yield) was a Michael adduct be- conditions provided the best result in the reactions of
tween the aldehyde and MVK in which the 4-hydroxy the activated aromatic aldehydes with MVK and other
group of the aldehyde attacked the g-carbon of MVK as a Michael acceptors (7g–m, Table 3). In these cases, under
Synlett 2007, No. 3, 395–398 © Thieme Stuttgart · New York

398
K.-S. Park et al.
LETTER
(2) (a) Kataoka, T.; Kinoshita, H.; Kinoshita, S.; Iwamura, T.;
Watanabe, S. Angew. Chem. Int. Ed. 2000, 39, 2358.
(b) Shi, M.; Jiang, J.-K.; Feng, Y. S. Org. Lett. 2000, 2,
2397. (c) Shi, M.; Jiang, J. K. Tetrahedron 2000, 56, 4793.
(d) Li, G.; Wei, H. X.; Gao, J. J.; Caputo, T. D. Tetrahedron
Lett. 2000, 41, 1. (e) Shi, M.; Feng, Y. S. J. Org. Chem.
2001, 66, 406. (f) Shi, M.; Jiang, J.-K.; Cui, S.-C.
Tetrahedron 2001, 57, 7343. (g) Patra, A.; Batra, S.; Joshi,
B. S.; Roy, R.; Kundu, B.; Bhaduri, A. P. J. Org. Chem.
2002, 67, 5783. (h) Basavaiah, D.; Sreenivasulu, B.; Rao, A.
J. J. Org. Chem. 2003, 68, 5983. (i) Pei, W.; Wei, H.; Li, G.
Chem. Commun. 2002, 1856. (j) Pei, W.; Wei, H.; Li, G.
Chem. Commun. 2002, 2412. (k) Kinoshita, H.; Kinoshita,
S.; Munechika, Y.; Iwamura, T.; Watanabe, S.; Kataoka, T.
Eur. J. Org. Chem. 2003, 4852. (l) Kinoshita, H.; Osamura,
T.; Kinoshita, S.; Iwamura, T.; Watanabe, S.; Kataoka, T.;
Tanabe, G.; Muraoka, O. J. Org. Chem. 2003, 68, 7532.
(3) Kundu, M. K.; Mukherjee, S. B.; Balu, N.; Padmakumar, R.;
Bhat, S. V. Synlett 1994, 444.
the octanol-accelerated conditions, reactions were com-
plete after 12 hours to give the desired compound in high
yields (70–100%, Method B, Table 3). The MVK dimer 8
was not isolated in the reactions of activated (electron-
poor) aldehydes.
Acceleration of the Baylis–Hillman reaction observed in
this study might be related with efficient proton transfer
by octanol (Scheme 2) but, at this point, it is not clear how
the long aliphatic chain of the protic solvents promotes
proton transfer and why octanol has the optimum chain
length. A plausible mechanism might include involve-
ment of alcohol dimer in the rate-limiting proton-transfer
step in which straight aliphatic alkyl chains of octanol
dimer12 stabilize the transition state through van der
Waals interaction (Scheme 3).
(4) (a) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44,
4653. (b) Basavaiah, D.; Dharma Rao, P.; Suguna Hyma, R.
Tetrahedron 1996, 52, 8001. (c) Ciganek, E. In Organic
Reactions, Vol. 51; Paquette, L. A., Ed.; Wiley: New York,
1997, 201.
(5) (a) Ameer, F.; Drewes, S. E.; Freese, S.; Kaye, P. T. Synth.
Commun. 1988, 18, 495. (b) Drewes, S. E.; Freese, S.;
Emslie, N. D.; Roos, G. H. P. Synth. Commun. 1988, 18,
1565. (c) Basavaiah, D.; Sarma, P. K. S. Synth. Commun.
1990, 20, 1611. (d) Bailey, M.; Marko, I. E.; Ollis, W. D.;
Rasmussen, P. R. Tetrahedron Lett. 1990, 31, 4509.
(6) Auge, J.; Lubin, N.; Lubineau, A. Tetrahedron Lett. 1994,
35, 7947.
(7) (a) Almeida, W. P.; Coelho, F. Tetrahedron Lett. 1998, 39,
8609. (b) Coelho, F.; Almeida, W. P.; Veronese, D.; Mateus,
C. R.; Silva Lopes, E. C.; Rossi, R. C.; Silveira, G. P. C.;
Pavam, C. H. Tetrahedron 2002, 58, 7437.
(8) (a) Hill, J. S.; Isaacs, N. S. Tetrahedron Lett. 1986, 27,
5007. (b) Hill, J. S.; Isaacs, N. S. J. Chem. Res., Synop. 1988,
330. (c) Schuurman, R. J. W.; v. d. Linden, A.; Grimbergen,
R. P. F.; Nolte, R. J. M.; Scheeren, H. W. Tetrahedron 1996,
52, 8307.
H
O
H
O–
O
H
Me
R3+N
Me
O
Scheme 3 Octanol dimer might be involved in the proton-transfer
step
In summary, a remarkable acceleration of the Baylis–Hill-
man reaction was observed by using octanol as an
additive. Under the octanol-accelerated Baylis–Hillman
conditions, compared with the normal reaction condi-
tions, aliphatic aldehydes and aromatic aldehydes with
electron-withdrawing substituents were converted into the
desired products more rapidly in moderate to high yield.
Acknowledgment
(9) Shi, M.; Liu, Y.-H. Org. Biomol. Chem. 2006, 4, 1468.
(10) Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones, G. C. Angew.
Chem. Int. Ed. 2005, 44, 1706.
This work was supported by grant KRF-2006-003-C00176 from the
Korea Research Foundation, Republic of Korea (MOEHRD, Basic
Research Promotion Fund) and by grants from Biogreen 21 (Korea
Ministry of Agriculture and Forestry), and the second Brain Korea
21 (Korea Ministry of Education). Jinyoung Kim is supported by
the second Brain Korea 21.
(11) Spectroscopic Data for Compound 4.
IR (neat): 3415, 1665, 1635, 1088 cm–1. 1H NMR (400 MHz,
CDCl3): d = 1.32 (d, J = 6.5 Hz, 3 H), 2.36 (s, 3 H), 3.31 (br
s, 1 H), 4.66 (br s, 1 H), 6.08 (s, 1 H), 6.11 (s, 1 H). 13C NMR
(100 MHz, CDCl3): d = 200.19, 151.09, 124.27, 65.89,
25.90, 21.76. HRMS (ESI): m/z calcd for C6H10O2 [M + H]:
114.0681; found: 114.0685.
References and Notes
Spectroscopic Data for Compound 6.
1H NMR (400 MHz, CDCl3): d = 6.04 (s, 1 H), 5.85 (s, 1 H),
2.61–2.57 (m, 1 H), 2.55–2.50 (m, 1 H), 2.34 (s, 3 H), 2.13
(s, 3 H). 13C NMR (100 MHz, CDCl3): d = 207.59, 199.24,
147.52, 126.01, 42.20, 29.47, 25.61, 25.05.
(1) (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron
1996, 52, 8001. (b) Ciganek, E. Org. React. 1997, 51, 201.
(c) Langer, P. Angew. Chem. Int. Ed. 2000, 39, 3049.
(d) Basavaiah, D.; Rao, A. J.; Satyanayana, T. Chem. Rev.
2003, 103, 811.
(12) MacCallum, J. L.; Tieleman, D. P. J. Am. Chem. Soc. 2002,
124, 15085.
Synlett 2007, No. 3, 395–398 © Thieme Stuttgart · New York