Traditional Morita-Baylis-Hillman reaction of aldehydes with methyl vinyl ketone co-catalyzed by triphenylphosphine and nitrophenol

Article abstract of DOI:10.1039/b600854b

The development of a chiral Broonsted acid-catalyzed asymmetric Morita-Baylis-Hilman reaction of cyclone with aldehyde in the presence of triethyphosphine (PE₃) was analyzed using nuclear magnetic resonance (NMR). Another catalytic system for t

Full text of DOI:10.1039/b600854b

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Traditional Morita–Baylis–Hillman reaction of aldehydes with methyl vinyl
ketone co-catalyzed by triphenylphosphine and nitrophenol†
Min Shi* and Ying-Hao Liu
Received 19th January 2006, Accepted 7th February 2006
First published as an Advance Article on the web 22nd February 2006
DOI: 10.1039/b600854b
In the Morita–Baylis–Hillman reaction of aldehydes with
methyl vinyl ketone (MVK), we found that in the presence
of a catalytic amount of phenol, the Lewis base triph-
enylphosphine can effectively promote the reaction to give
the corresponding normal Morita–Baylis–Hillman adducts
of benzaldehyde (0.8 mmol) or p-chlorobenzaldehyde (0.8 mmol)
with MVK (2.4 mmol) in tetrahydrofuran (THF, 2.0 mL) (Table 1,
entries 1 and 7). In addition, the corresponding adducts were
always formed along with some impurities (see ESI†). With
methyldiphenylphosphine (PPh
2
Me), dimethylphenylphosphine
31
(PPhMe ), trimethylphosphine (PMe ) and tributylphosphine
in good yields. The mechanism has been investigated by
P
2
3
(
PBu ) as catalysts, similar results were also obtained. It is difficult
3
NMR spectroscopy. The solvent and substituent effects were
also examined.
to get the corresponding Morita–Baylis–Hillman reaction product
in good yield and high purity with a phosphine Lewis base as a
promoter under mild conditions. However, with the addition of
various phenols including pentafluorophenol (Table 1, entries 3
and 9) (30 mol%), as a kind of weak Brønsted acid, into this
reaction system, we found that the reactions were accelerated
Great progress has been made in the execution of the Morita–
1
2
Baylis–Hillman reaction, since the seminal report in 1972
that described the reaction of acetaldehyde with ethyl acrylate
and acrylonitrile in the presence of catalytic amounts of 1,4-
diazabicyclo[2.2.2]octane (DABCO). Recent advances include
(
Fig. 1), and that the corresponding adducts could be obtained
3
in good yields and high purities under the same conditions in
THF (Table 1, entries 2–6 and 8–12) (see ESI†). The acidity of the
phenol also affected the reaction rate, particularly in the case of
p-chlorobenzaldehyde, which has an electron-withdrawing group
several catalytic asymmetric versions of the reaction. In the
generally accepted mechanism of the Morita–Baylis–Hillman
1,2
reaction, the aldol reaction of the ammonium or phosphonium
enolates derived from the nucleophilic promoter DABCO or
triphenylphosphine with Michael acceptors with electrophiles
has long been believed to be the rate-determining step. However,
in a detailed mechanistic investigation into this reaction, it
was recently reported that the rate-determining step in the
Morita–Baylis–Hillman reaction is the proton transfer rather
on the benzene ring. Among the phenol additives employed, p-
7
nitrophenol (pK
a
= 7.2), which has the highest acidity, gave the
best result in THF (Table 1, entries 7–12).
4
than the aldol reaction. In addition, Schaus has reported the
development of a chiral Brønsted acid-catalyzed asymmetric
Morita–Baylis–Hillman reaction of cyclohexenone with aldehyde
3b
in the presence of triethylphosphine (PEt ). On the basis of all
3
these new findings, we attempted to develop another catalytic
system for the traditional Baylis–Hillman reaction of aldehydes
with methyl vinyl ketone, which includes a Brønsted acid as
proton source and phosphine Lewis base as a promoter. During
our ongoing investigation on this very simple and useful reaction,
we have so far disclosed several new results on Lewis base and
Fig. 1 The effect of an additive (p-nitrophenol, 0.24 mmol) on the
Morita–Baylis–Hillman reaction of p-chlorobenzaldehyde (0.8 mmol) with
MVK (2.4 mmol) catalyzed by PPh (0.16 mmol) in THF (2.0 mL).
3
5
Lewis acid co-catalyzed systems. Moreover, Leitner has recently
reported a new bifunctional activation mechanism for the catalytic
5g,6
Using PPh as a Lewis base promoter and p-nitrophenol
3
asymmetric aza-Baylis–Hillman reaction.
Herein we wish to
as additive, the solvent effect was examined. The results are
summarized in Table 2. As can be seen from Table 2, THF and
dimethylsulfoxide (DMSO) are the best solvents for this reaction
report that triphenylphosphine (PPh ) can promote the traditional
3
Morita–Baylis–Hillman reaction of aldehydes 1 with methyl vinyl
ketone (MVK) 2, in the presence of a catalytic amount of
p-nitrophenol, to give the corresponding Morita–Baylis–Hillman
adducts 3 in good-to-high yields under mild conditions.
(Table 2, entries 1–7). Therefore, the best reaction conditions are
to carry out this reaction with PPh as a Lewis base promoter in
3
the presence of p-nitrophenol in THF or DMSO.
In an initial examination, we found that PPh (20 mol%)
3
Under these optimized conditions, we next examined a
variety of aldehydes. The results are shown in Table 3. For aryl
aldehydes having an electron-withdrawing group on the aromatic
ring, such as p-nitrobenzaldehyde, m-nitrobenzaldehyde, o-
nitrobenzaldehyde, p-bromo- or p-chlorobenzaldehyde, p-fluoro-
or m-fluorobenzaldehyde, and pyridylaldehyde, the corresponding
Morita–Baylis–Hillman adducts 3 were obtained in good-to-high
itself could not efficiently catalyze the Baylis–Hillman reaction
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai,
2
00032, China. E-mail: mshi@pub.sioc.ac.cn
†
Electronic supplementary information (ESI) available: Spectroscopic
data, Figs. 2–5 and detailed description of experimental procedures. See
DOI: 10.1039/b600854b
1
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Table 1 Morita–Baylis–Hillman reaction of aryl aldehydes (0.8 mmol)
Table 3 Morita–Baylis–Hillman reaction of aldehydes (0.8 mmol) with
with MVK (2.4 mmol) co-catalyzed by PPh
3
(0.16 mmol) and phenol
MVK (2.4 mmol) co-catalyzed by PPh
(0.24 mmol)
3
(0.16 mmol) and phenol
(
0.24 mmol)
1
a
1
a
Entry
R
Additive
—
pK
a
Yield of 3 (%)
Entry
R
Product
Yield of 3 (%)
1
2
H
H
—
9.8
25
48
1
2
3
4
5
6
7
8
9
H
p-Cl
p-NO
m-NO
o-NO
p-CH
p-CH
o,p-Cl
p-F
m-F
p-Br
3a
3b
3c
3d
3e
3f
3g
3h
3i
52
92
98
90
98
42
35
95
87
93
83
72
2
2
2
3
4
H
H
—
32
3
3
O
2
1
1
1
0
1
2
3j
3k
3l
7.2
52
5
6
H
H
10.0
9.9
51
65
1
3
3m
80
7
8
p-Cl
p-Cl
—
—
9.8
50
78
a
Isolated yields.
9
p-Cl
p-Cl
—
71
92
yields (Table 3, entries 2–5, 8–11 and 13). But for benzaldehyde, p-
methyl- and p-methoxybenzaldehyde, the corresponding adducts
3
were obtained in moderate yields under similar conditions
1
0
7.2
(
Table 3, entries 1, 6 and 7). For an aliphatic aldehyde, the
corresponding Morita–Baylis–Hillman adduct 3l was obtained in
good yield under the standard conditions (Table 3, entry 12). For
1
1
1
2
p-Cl
p-Cl
10.0
9.9
72
70
2
-pyridine carboxaldehyde, the reaction also proceeded smoothly
to give the corresponding Morita–Baylis–Hillman adduct 3m in
good yield under the standard conditions (Table 3, entry 13).
According to the generally accepted mechanism of the Morita–
1,2
a
Baylis–Hillman reaction, we believe that p-nitrophenol (a weak
Brønsted acid) in the co-catalyzed systems can stabilize the
enolate intermediate in the conjugate addition step through its
hydrogen-bonding with the enolate, driving the reaction forward
and accelerating the reaction rate (Scheme 1).
Isolated yields.
Table 2 Solvent effects on the Morita–Baylis–Hillman reaction of p-
chlorobenzaldehyde with MVK co-catalyzed by PPh
3
and p-nitrophenol
In order to get more mechanistic insight into these PPh -
3
3
1
and p-nitrophenol-co-catalyzed systems, we carried out P NMR
spectroscopic measurements (in CDCl , referenced to 85% H PO
3
3
4
)
of the Lewis base PPh
and p-nitrophenol. PPh
ESI†), and PPh
3
in the absence and presence of MVK
3
showed a signal at −4.46 ppm (Fig. 2,
3
with MVK (molar ratio = 1 : 5) showed an
a
Entry
Solvent
Et
THF
DMSO
Yield of 3b (%)
additional signal at +29.96 ppm, which is believed to correspond
3l,8
to the phosphonium enolate (Fig. 3, ESI), but PPh with MVK
3
1
2
3
4
5
6
7
2
O
60
92
92
80
35
21
66
and p-nitrophenol (molar ratio = 1 : 5 : 1) only showed a signal
31
at +29.96 ppm (Fig. 4, ESI). A significant feature in the
P
DMF
NMR of PPh with the addition of MVK is the formation of
3
Ethanol
Pentanol
Dichloromethane
the new signal at +29.96 ppm. The ratio of the new signal and
the signal at −4.46 ppm (PPh ) is 1 : 3 ratio, indicating that
3
a
the phosphonium enolate formed in situ is in equilibrium with
Isolated yields.
3l,8
free PPh
3
.
In the case of PPh
3
with the addition of MVK and
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Foundation of China for financial support (20472096, 203900502,
and 20272069).
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+
We thank the State Key Project of Basic Research (Project 973)
(
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3
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1
470 | Org. Biomol. Chem., 2006, 4, 1468–1470
This journal is © The Royal Society of Chemistry 2006