Self-assisted tandem Michael-aldol reactions of α,β-unsaturated ketones with aldehydes

Article abstract of DOI:10.1039/b106022h

The tandem Michael-aldol reaction of 1-[2-(methylsulfanyl)phenyl]prop-2-en-1-one (1) or the seleno congener 4 with p-nitrobenzaldehyde in the presence of BF₃,Et₂O gave the Baylis-Hillman adduct 2 or 5 and onium salt 3 or 6, respectiv

Full text of DOI:10.1039/b106022h

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Self-assisted tandem Michael-aldol reactions of a,b-unsaturated
ketones with aldehydes
Tadashi Kataoka,* Sayaka Kinoshita, Hironori Kinoshita, Masaru Fujita, Tatsunori Iwamura and
Shin-ichi Watanabe
Gifu Pharmaceutical University, 6-1 Mitahora-higashi 5-chome, Gifu 502-8585, Japan.
E-mail: kataoka@gifu-pu.ac.jp
Received (in Cambridge, UK) 11th July 2001, Accepted 24th August 2001
First published as an Advance Article on the web 10th September 2001
The tandem Michael-aldol reaction of 1-[2-(methylsulfanyl)-
phenyl]prop-2-en-1-one (1) or the seleno congener 4 with p-
nitrobenzaldehyde in the presence of BF3·Et2O gave the
Baylis–Hillman adduct 2 or 5 and onium salt 3 or 6,
respectively, and selenochromanone 7 from 4.
The Baylis–Hillman reaction is one of the most popular
reactions, and a great number of papers have been recently
published on it.1 This reaction is quite slow, and many changes
have been made to it to overcome this drawback.2 We
developed the chalcogenide–TiCl4-mediated reactions of elec-
tron-deficient alkenes with aldehydes.3 The reactions had been
deemed to be a chalcogenide version of the Baylis–Hillman
reaction because the Baylis–Hillman adducts were given after
purification of the products by preparative TLC on silica gel.
Scheme 1
However, a detailed examination of the reactions revealed that
the original products were a-chloromethyl aldols and that
dehydrochlorination occurred during purification by the pre-
parative TLC on silica gel.4 Similar reactions using TiCl4 have
been reported by other groups.5 Very recently, we obtained
methyl 3-methylsulfanyl-2-(a-hydroxy-p-nitrobenzyl)acrylate
from the reaction of methyl propiolate with p-nitrobenzalde-
hyde in the presence of TiBr4–SMe2 as a minor product.6 This
finding implied that SMe2 worked as a Lewis base and
suggested to us that the intramolecular Michael addition of a
sulfanyl group to an enone moiety would proceed more
efficiently than the intermolecular one. In other words, the
sulfanyl substituent assists the intramolecular Michael addition
to form a cyclic sulfonium betaine. Cyclisation of enone
sulfides with a Lewis acid has been reported from a different
viewpoint.7 These reports encouraged us to conduct the
reactions of 1-[2-(methylsulfanyl)phenyl]prop-2-en-1-one with
aldehydes in the presence of BF3·Et2O. In this paper, we would
like to describe a new type of tandem Michael-aldol reaction of
an enone sulfide with aldehydes using a Lewis acid.†
A chloride ion reacted with an a,b-unsaturated carbonyl
compound as a nucleophile in the reaction of the enone with an
aldehyde using chalcogenide–TiCl4.4 In order to avoid this
reaction and allow a chalcogenide to react with the enone
instead of a chloride ion, we selected a Lewis acid such as metal
fluoride or triflate, which releases non-nucleophilic anion,
although BF3·Et2O and triflates of the lanthanide metals had
been ineffective for the intermolecularly chalcogenide-pro-
moted tandem Michael-aldol reactions.3
(21%) and 3a (42%)§ (entry 7). When 2 equiv. of BF3·Et2O
were used, the highest yields of 2a (18%) and 3a (62%)§ were
given from the reaction at 0 °C for 1 h (entry 2). The use of
lithium perchlorate and aluminium sulfate gave no product, and
1 was recovered without loss.
Other aromatic aldehydes and 3-phenylpropionaldehyde
similarly reacted with 1 to give 2 and 3 in low to moderate yields
(Scheme 2 and Table 2). Since the reactions of various
aldehydes were slower than that of p-nitrobenzaldehyde, the
reactions were conducted for 2 h and then worked up with
aqueous NaHCO3. Seleno derivative 4‡ reacted with aromatic
aldehydes to give a-methylene aldol 5, aldol selenonium salt
6§, and 3-(a-hydroxybenzyl)selenochromanone 7. Demethyla-
tion of 6 occurred more easily during the reactions than that of
3 to give 7 as a mixture of diasteroisomers. The syn- and anti-
diastereoisomers were assigned in comparison of the coupling
constants of the methine protons [C-CH(OH)-C], syn- (0–2.4
Hz) and anti-isomer (7.8–8.3 Hz), with those of the cyclohex-
anone derivative.8
1H NMR spectra of the residues obtained by concentration of
the reaction mixtures were measured in order to examine
whether a-methylene aldol 2 or 5 was formed via the Baylis–
Hillman reaction or the b-elimination of 3 or 6 by a work-up
with a saturated aqueous NaHCO3 solution. Vinyl proton
Table 1 Lewis acids for reactions of 1-[2-(methylsulfanyl)phenyl]prop-
2-en-1-one 1 with p-nitrobenzaldehyde.
Various Lewis acids were examined for the reactions of
1-[2-(methylsulfanyl)phenyl]prop-2-en-1-one (1)‡ with p-
nitrobenzaldehyde (Scheme 1). The reaction mixture was
quenched with a saturated aqueous NaHCO3 solution. Results
of the reactions are summarised in Table 1. Reactions using
BF3·Et2O were monitored by TLC and stopped when p-
nitrobenzaldehyde disappeared (entries 1–3). The reaction was
accelerated with increase of the amount of BF3·Et2O and the
reaction time was shortened. Prolonged reaction time decreased
the yield of 3a and increased 2a (entries 1 and 4). Reactions
using BF3·Et2O–LiBF4 (1+1) or TiF4 afforded 2a only in low
yields (entries 5 and 6). Reaction catalyzed Yb(TfO)3 gave 2a
Entry Lewis acid (equiv.) Time
Products (Yield %)
1
2
3
4
5
BF3·Et2O (1)
BF3·Et2O (2)
BF3·Et2O (3)
BF3·Et2O (1)
BF3·Et2O–LiBF4
(1:1)
2 h
1 h
45 min
24 ha
2 h
2a (24), 3a (50)
2a (18), 3a (62)
2a (36), 3a (34)
2a (42), 3a (29)
2a (10)
6
7
TiF4 (2)
Yb(TfO)3 (2)
2 h
2 h
2a (33)
2a (21), 3a (42)
a Room temperature.
1958
Chem. Commun., 2001, 1958–1959
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106022h

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The reaction conditions presented here were not sufficiently
optimised, but this methodology will be the starting point for the
development of tandem Michael-aldol reactions as well as the
Baylis–Hillman reaction.
This research was partially supported by the Ministry of
Education, Science, Sports and Culture, Grant-in-Aid for
Scientific Research (C), 12672056.
Notes and references
† A typical example: BF3·OEt2 (126 ml, 1.00 mmol) was added to a stirred
solution of p-nitrobenzaldehyde (76 mg, 0.50 mmol) and 1-[2-(methylsulfa-
nyl)phenyl]prop-2-en-1-one (1) (178 mg, 1.00 mmol) in dry MeCN (1.5 ml)
at 0 °C. The mixture was stirred at the same temperature for 2 h, and the
reaction was quenched by addition of saturated aqueous NaHCO3 (3 ml).
The precipitate of the inorganic material was removed by filtration through
Celite and washed with MeCN. The filtrate and the washing were combined,
and the solvent was evaporated under reduced pressure. The residue was
washed with CH2Cl2, and crystals were filtered and recrystallised from
MeCN–CH2Cl2 to give 3-[(4-nitrophenyl)(hydroxy)methyl]-1-methyl-
4-oxo-3,4-dihydro-2H-thiochromenium tetrafluoroborate (3a), as a white
powder of a mixture of diastereoisomers: major isomer: dH 3.10 (3H, s,
SMe), 3.60 (1H, dd, J = 5 and 15), 3.61 (1H, ddd, J = 3, 5 and 10), 4.02
(1H, dd, J = 10 and 15), 4.36 (1H , d, J = 4, OH), 5.79 (1H, dd, J = 3 and
4, benzylic H), 7.71 (2H, d, J = 9, ArH), 7.89–7.94 (3H, m, ArH), 8.29 (2H,
d, J = 9, ArH), 8.38 (2H, dd, J = 2 and 7, ArH). The 1H NMR signals of the
minor isomer could not be clearly assigned because of the overlapping
absorptions. The washing was concentrated to dryness, and the residue was
purified by preparative TLC on silica gel (ethyl acetate–hexane = 1+2, v/v)
to give 2-[(4-nitrophenyl)(hydroxy)methyl]-1-[2-(methylsulfanyl)phenyl]-
prop-2-en-1-one (2a) as yellow oil: dH 2.40 (3H, s, SCH3), 3.50 (1H, br s,
OH), 5.80 and 6.09 (each 1H, s, olefinic H), 5.91 (1H, s, benzylic H), 7.17
and 7.43 (each 1H, t, J = 8, ArH), 7.27 and 7.34 (each 1H, d, J = 8, ArH),
7.66 and 8.21 (each 2H d, J = 9, ArH); dC 17.0 (q), 72.4 (d), 123.8 (d), 124.6
(d), 127.3 (d), 127.4 (d), 129.7 (d), 130.1 (t), 131.7 (d), 136.9 (s), 139.3 (s),
147.5 (s), 149.1 (s), 149.2 (s), 198.2 (s); EIMS m/z 329 (M+); Found: C,
61.9; H, 4.9; N, 4.0. C17H15NO4S requires C, 62.0; H, 4.6; N, 4.3%.
‡ Compounds 1 and 4 were prepared in a similar way as for 1-[2-(ethylsulfa-
nyl)-4,5-dimethoxyphenyl]prop-2-en-1-one in Ref. 7b.
Scheme 2
Table 2 Reactions of 1-[2-(methylchalcogenyl)phenyl]prop-2-en-1-ones 1
and 4 with aldehydes.
Entry Aldehyde, R
Conditions
Products (Yield %)
1
2
3
4
5
p-ClC6H4
p-CF3C6H4
Ph
PhC2H4
p-NO2C6H4
0 °C, 2 h
0 °C, 2 h
2b (24), 3b (37)
2c (49), 3c (17)
0 °C, 2 h then rt, 3 h 2d (24), 3d (37)
0 °C, 2 h then rt, 3 h 2e (54)
0 °C, 2 h
5a (30), 6a (45), 7a
(15) (3+2)a
6
p-ClC6H4
0 °C, 2 h
5b (25), 6b (25), 7b
(28) (3+2)a
a Diastereoisomer ratio (syn+anti-isomer).
signals of 2 and 5 were observed in the region of d 5.80, 6.09
and d 5.76, 6.06, respectively. This indicates that a-methylene
aldol 2 or 5 was formed during the reaction. However, the
intensities of the +X-Me signals of 3 and 6 were decreased, and
those of the X-Me signals of 2 and 5 were increased after
treatment with saturated aqueous NaHCO3 solution. Therefore,
some of the onium salts 3 or 6 suffered b-elimination by the
work-up with the saturated aqueous NaHCO3 solution to form 2
or 5, respectively.§
§ The onium salts 3 and 6 were obtained as mixtures of stereoisomers based
on two chiral carbons and a chalcogenide atom. However, their stereo-
structures and isomer ratios could not be determined. The stereostructures of
onium salts 3 and 6 and their reactivity against a base will be described in
the full paper.
Next, the residue obtained from the reaction of 1 or 4 (2
equiv.) with p-nitrobenzaldehyde (1 equiv.) using BF3·Et2O (2
equiv.) as a Lewis acid was treated with triethylamine (2 equiv.)
instead of saturated aqueous NaHCO3 solution in order to obtain
a-methylene aldol 2 or 5 (Scheme 3). The reaction of sulfide 1
afforded 2a in 75% yield, but the reaction of the selenium
congener 4 gave 5 (64%) and the demethylated product 7
(10%).
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Scheme 3
Chem. Commun., 2001, 1958–1959
1959