A cooperative catalysis approach to the Borita-Aylis-Hillman reaction of aryl vinyl ketones

Article abstract of DOI:10.1055/s-0030-1260468

The Morita-Baylis-Hillman (MBH) reaction of aryl vinyl ketones has been achieved for the first time through cooperative catalysis of proline and brucine N-oxide. A unique mode of activation of the aldehydes through proline iminium intermediates has been i

Full text of DOI:10.1055/s-0030-1260468

1960
PAPER
A Cooperative Catalysis Approach to the Morita–Baylis–Hillman Reaction of
Aryl Vinyl Ketones
M
orita–Baylis–Hil
y
lma
n
Reactio
u
n
of
A
ryl
V
i
nyl
Ketonesgsoo Oh,* Jian-Yuan Li
Department of Chemistry and Chemical Biology, Indiana University–Purdue University Indianapolis (IUPUI), Indianapolis, IN 46202,
USA
Fax +1(317)2744701; E-mail: ohk@iupui.edu
Received 15 March 2011
rate acceleration was observed in the presence of alcohol-
Abstract: The Morita–Baylis–Hillman (MBH) reaction of aryl vi-
ic additives.
nyl ketones has been achieved for the first time through cooperative
catalysis of proline and brucine N-oxide. A unique mode of activa-
tion of the aldehydes through proline iminium intermediates has
been identified as a key reaction parameter for the successful MBH
reaction of aryl vinyl ketones. The reaction pathways leading to 1:2
MBH products under typical nucleophilic catalysis conditions were
investigated. A systematic study revealed two different reaction
pathways leading to 1:2 MBH products: (1) the second reaction of
normal MBH products with aryl vinyl ketones as a dominating re-
action pathway at the initial stage of the reaction, and (2) the aldol
reaction pathway of Rauhut–Currier products with aldehydes (auto-
catalysis by alcohol products) as a major reaction pathway during
the later stage of reaction.
In addition, the interplay between a nucleophilic catalyst
and electron-deficient alkenes (or latent enolates) can lead
to the coupling of two Michael acceptors, known as the
Rauhut–Currier (RC) reaction.5 Although the extent to
which the RC reaction occurs during MBH reactions can
be controlled to some extent either by using an excess of
aldehydes or by employing weak Michael acceptors, such
self-coupling of Michael acceptors is inevitable under the
current paradigm of nucleophilic catalyst systems for
MBH reactions. In particular, the MBH reaction of phenyl
vinyl ketone 4 leads to the formation of a mixture of 1:2
adduct 6 and the RC product 7 (Scheme 2),6 while the cor-
responding alkyl vinyl ketones predominantly give rise to
normal MBH products. There are currently two indirect
approaches that can be used to access the normal MBH
products through functionalized aryl vinyl ketones.
Kataoka and co-workers developed a two-step chalcogeno
MBH reaction, where 2-(methylchalcogeno)phenyl vinyl
ketones are subjected to Lewis acid-promoted intramolec-
ular Michael reaction, followed by aldol and elimination
reactions to provide the normal MBH products 10.7 In
2009, Trofimov and Gevorgyan reported the sila-MBH re-
action using a-silylated aryl vinyl ketones, where a 1,3-
Brook rearrangement was exploited to prevent the forma-
tion of the 1:2 adduct and RC product, in the presence of
phosphine catalysts.8 To date, no direct approach to the
MBH product 11 using unfunctionalized aryl vinyl ke-
tones exists.
Key words: aldol reaction, alkaloids, catalysis, ketones, nucleo-
philes
The Morita–Baylis–Hillman (MBH) reaction enables fac-
ile access to highly functionalized alkenes in the presence
of nucleophilic catalysts.1 While considerable progress
has been made in the development of a variety of catalyst
systems for MBH reactions,2 there are still significant
challenges to broadening its substrate scope. As shown in
Scheme 1, interactions of the nucleophilic catalyst and
substrates at the molecular level during the MBH reac-
tions are known to be two-fold: (1) preferential a-H elim-
ination by hemiacetal anions (McQuade mechanism),3 for
which second order kinetics for aldehydes was observed
at the initial stage of the reaction, and (2) preferential a-H
elimination by MBH products at the later stage of the re-
action (Aggarwal/Lloyd-Jones mechanism),4 for which a
O
R
H
O
H
Ar
Ar
OR1
O
Et
Me
O
nucleophilic
catalyst
OH
O
O
O
O
N
O
H
1
R2
OR1
O
Ph
O
N
3
R2
H
N
N
2
McQuade TS-1
(R1 = Me, R2 = Ar)
Aggarwal/Lloyd-Jones TS-2
(R1 = Et, R2 = Ph)
Scheme 1 The two-fold mechanism for the Morita–Baylis–Hillman reactions
SYNTHESIS 2011, No. 12, pp 1960–1967
x
x.
x
x
.
2
0
1
1
Advanced online publication: 17.05.2011
DOI: 10.1055/s-0030-1260468; Art ID: C29711SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Morita–Baylis–Hillman Reaction of Aryl Vinyl Ketones
1961
OBF2
O
OBF2
Ar
O
OH
2. Et3N
Ar
S
S
S
BF4
BF4
1. BF3⋅OEt2
Me
Me
Me
8
9
10
OH
O
O
O
O
O
nucleophilic
R1
catalyst
Ar
Ar
Ar
Ar
Ar
H
Ar
Ar
(R1 = H)
4
5
6
7
O
O
R3P
O
O
Si
OH
sila-MBH reaction
(R1 = SiMe3)
Ar
R3P
Ar
Ar
Ar
11
Scheme 2 The chalocogeno- and sila-MBH reactions of functionalized aryl vinyl ketones
We have previously shown that the asymmetric MBH re- (entry 8).12 While a longer reaction time had a positive ef-
action of alkyl vinyl ketones 4 (R1 = Me, Et) can be cata- fect on the chemical conversion (entry 10), the diminished
lyzed by either brucine N-oxide (BNO) or a dual catalyst reaction rate led us to look into the use of alternative reac-
system of brucine N-oxide and proline (Scheme 3).9 The tion parameters.13 The use of excess o-nitrobenzaldehyde
cooperative catalyst activity between proline and N-oxide (5a) resulted in better chemical conversions within
is of particular interest to us because it provides a novel 18 hours (entry 11), however a significant deceleration in
way of controlling the rate-determining step of the MBH the reaction rate was observed beyond 18 hours (entry
reaction (a-H elimination) through the involvement of 12). To our delight, the use of excess phenyl vinyl ketone
proline iminium intermediate 12.10 To validate the poten- (4a) increased the reaction rate, providing 86% yield of
tial use of such cooperative catalyst systems, we explored 11a in 42 hours.
the MBH reaction of aryl vinyl ketones.
With the optimized conditions in hand, the scope of the
We first examined the MBH reaction of phenyl vinyl ke- MBH reaction of aryl vinyl ketones was investigated
tone (4a) and o-nitrobenzaldehyde (5a) in the presence of (Table 2). Electron-deficient aldehydes typically provid-
various amounts of catalyst (Table 1). In contrast to the ed excellent yields of MBH products within 42 hours (en-
successful MBH reactions of alkyl vinyl ketones, BNO tries 1–6), while other electron-neutral and electron-rich
did not catalyze the reaction of phenyl vinyl ketone either aldehydes were less reactive under our cooperative catal-
in the absence or presence of solvent (entry 1).11 The use ysis conditions (entries 7–10). Furthermore, studies with
of proline as a sole catalyst also failed to provide the de- other aryl vinyl ketones also revealed a similar reactivity
sired MBH product 11a (entry 2). Upon combining BNO pattern, providing excellent yields of MBH products (en-
and proline, the formation of ( )-11a was observed in 1,4- tries 11–13). The above results are consistent with our
dioxane, albeit in low yield (entry 3). A different ratio and proposed mechanism, whereby aldehydes are activated by
loading of both catalysts was then examined (entries 4 and proline to generate proline iminium intermediates that
5), and a pronounced improvement in yields was evident subsequently control the rate-determining step (a-H elim-
when the loadings of both catalysts were set to 100 mol% ination) of the MBH reaction.
O
COO
N
R1
H
H
OH
O
proline
N-oxide
Ar
Ar
O
Ar
Ar
H
NR3
4
12
N
O
Ar
R1
R1
O
O
O
O
OOC
11
R1
Ar
H
O
cooperative catalysis TS-3
5
(R1 = Me, Et)
NR3
13
Scheme 3 The cooperative catalysis approach to MBH reactions of alkyl vinyl ketones
Synthesis 2011, No. 12, 1960–1967 © Thieme Stuttgart · New York

1962
K. Oh, J.-Y. Li
PAPER
Table 1 Cooperative Catalysis of Brucine N-Oxide and L-Prolinea
O
N
O
O
OH
O
MeO
MeO
O
BNO
H
H
L-proline
COOH
H
Ph
N
Ph
H
N
H
1,4-dioxane
50 °C
NO2
NO2
L-proline
O
4a
5a
( )-11a
brucine N-oxide (BNO)
Entry
1
N-Oxide (equiv)
L-Proline (equiv)
Time (h)
Yield (%)b
0.15
–
–
18
18
18
18
18
18
18
18
18
42
18
42
18
42
0
0
2
0.15
0.15
0.15
0.3
0.3
0.6
1.0
1.5
1.0
1.0
1.0
1.0
1.0
3
0.15
0.3
0.15
0.3
0.6
1.0
1.5
1.0
1.0
1.0
1.0
1.0
2
4
12
9
5
6
15
34
49
27
69
55
53
51
86
7
8
9
10
11c
12c
13d
14d
a Reaction conditions: 4a (0.33 mmol), 5a (0.33 mmol), 1,4-dioxane (2.5 mL), 50 °C.
b Isolated yield of 11a after column chromatography. The remaining mass accounts for unreacted starting materials (4a and 5a).
c Reaction with 5a (3.0 equiv).
d Reaction with 4a (3.0 equiv).
To shed light on the mechanistic details of the MBH reac- The above control experiments suggested that a major
tion of phenyl vinyl ketone (4a), a series of experiments pathway to 1:2 MBH adduct 6 at the later stage of the re-
were conducted to examine the formation of 1:2 MBH ad- action may not involve 4a. To delineate the role of RC
duct 6 and RC product 7. While a proposed mechanism product 7 in the formation of 1:2 MBH adduct 6, o-ni-
for the formation of 1:2 MBH adduct 6 invokes a fast sec- trobenzaldehyde (5a) and RC product 7 were reacted un-
ond reaction of the transient normal MBH product 11a der the typical MBH reaction conditions (Scheme 5). In
with 4a,6 our control experiments suggested an alternative agreement with an earlier report by Shi et al.,6 the forma-
interpretation of the MBH reaction of phenyl vinyl ketone tion of 1:2 MBH adduct 6 was not observed after 24 hours
(Scheme 4). Our first control experiment addressed the at ambient temperature. However, we found that the reac-
stability of 4a under the typical MBH reaction conditions tion between 5a and 7 could be facilitated by the presence
in the absence of o-nitrobenzaldehyde (5a) [DABCO (10 of even a small amount of protic additive such as metha-
mol%), DMF, 23 °C].14 Under these reaction conditions, nol (0.1 equiv), to give 1:2 MBH adduct 6 (1:2, syn/anti;
4a was completely consumed within two hours to provide 10% yield in 48 h).16 This result clearly demonstrates that
RC product 7. It was also confirmed that depletion of 4a the direct aldol reaction of RC product 7 is responsible for
was complete in less than six hours of the MBH reaction the formation of 1:2 MBH adduct 6, presumably by auto-
with o-nitrobenzaldehyde (5a), while the formation of 1:2 catalysis of alcohol products 6, and possibly by 11a.
MBH adduct 6 continued to increase beyond six hours.15
Synthesis 2011, No. 12, 1960–1967 © Thieme Stuttgart · New York

PAPER
Morita–Baylis–Hillman Reaction of Aryl Vinyl Ketones
1963
O
O
O
DABCO (0.1 equiv)
Ph
Ph
Ph
DMF, 23 °C, 2 h
100% conv.
4a
7
O
OH
*
O
O
O
O
DABCO (0.1 equiv)
DMF, 23 °C
*
H
Ph
Ph
Ph
Ph
Ph
NO2
NO2
O
4a (2 equiv)
5a (1 equiv)
6
7
6 h
(no
left)
> 50%
4a
~ 50% conv.
(syn/anti = 1:2)
60 h
75 % (> 95% conv.)
(syn/anti = 1:2)
15%
Scheme 4 Formation of 1:2 MBH product 6 and RC product 7
To understand the reaction of normal MBH product 11a the second reaction of 11a with 4a does not proceed at all,
with phenyl vinyl ketone (4a), an equal molar ratio of two implying a unique activation pathway of aldehydes by
reactants (4a and 11a) was also subjected to the standard proline.
reaction conditions and it was found that the RC reaction
pathway dominates over the second reaction of 11a with
4a in a ratio of 2:1 (Scheme 6). In addition, we have con-
firmed that, under our cooperative catalysis conditions,
Although more detailed kinetic studies are needed to elu-
cidate the exact reaction mechanism of the MBH reaction
of aryl vinyl ketones, our preliminary kinetic study using
phenyl vinyl ketone (4a) and its deuterated counterpart
O
OH
*
O
O
O
DABCO (0.1 equiv)
DMF, 23 °C
*
H
Ph
Ph
Ph
Ph
NO2
NO2
O
7 (1 equiv)
5a (1 equiv)
6
24 h
0%
48 h
(10 mol% MeOH)
10% conv.
syn/anti = 1:2)
(
Scheme 5 Direct aldol reaction pathway of RC product 7
OH
O
OH
*
O
O
O
O
catalysis
*
Ph
Ph
Ph
Ph
Ph
Ph
NO2
NO2
O
7
4a (1 equiv)
11a (1 equiv)
6
> 60%
(no 4a left)
30% conv.
(syn/anti = 1:2)
DABCO (0.1 equiv)
DMF, 23 °C, 4 h
BNO/L-proline
1,4-dioxane
50 °C, 18 h
0%
< 5% conv.
(> 95% 4a left )
0%
Scheme 6 The reaction of normal MBH product 11a with phenyl vinyl ketone 4a
Synthesis 2011, No. 12, 1960–1967 © Thieme Stuttgart · New York

1964
K. Oh, J.-Y. Li
PAPER
O
D/H
Ph
OH
O
H
H
BNO
L-proline
Ar
Ar
O
O
4
Ph
H
NR3
N
1,4-dioxane
50 °C, 18 h
NO2
O
O
Ph
OOC
11a
H
NO2
5a
cooperative catalysis TS-3
4a
49%
7%
4a-[D]
Scheme 7 The kinetic isotope effect for the rate-determining step
Table 2 Scope of the Morita–Baylis–Hillman Reaction of Aryl
4a-[D] indicated a strong possibility that the rate-deter-
mining-step for the current cooperative catalysis approach
is the a-H elimination of aryl vinyl ketones (TS-3 in
Scheme 7).
Vinyl Ketonesa (continued)
Entry 11
Time Yield
(h)
(%)b
Table 2 Scope of the Morita–Baylis–Hillman Reaction of Aryl
F
OH
OH
O
O
O
Vinyl Ketonesa
9c
10c
11
11i
11j
11k
42
15
Ph
Ph
Entry 11
Time Yield
(h)
(%)b
OH
O
42
42
8
1
2
3
4
11a
42
86
Ph
NO2
NO2 OH
OH
OH
O
70
11b
11c
11d
42
42
18
86
82
98
Ph
Cl
O2N
O2N
NO2 OH
O
O
O
O
12
13
11l
18
18
98
98
Ph
Ph
O2N
O2N
Cl
NO2 OH
NO2 OH
11m
OMe
O2N
a Reaction conditions: 4 (1.95 mmol), 5 (0.65 mmol), BNO (0.65
mmol), L-proline (0.65 mmol), 1,4-dioxane (5 mL), 50 °C.
b Isolated yield after column chromatography.
c Incomplete reaction.
NO2 OH
O
MeO
5
6
11e
11f
42
42
80
90
Ph
Ph
NO2 OH
O
Taken together, the results of the above experiments sug-
gest that formation of the 1:2 MBH adduct 6 under tradi-
tional MBH reaction conditions takes place by two
different reaction pathways: (1) the second reaction of
MBH product 11a with phenyl vinyl ketone (4a) is the
dominating reaction pathway during the initial stage of
the reaction; (2) the aldol reaction pathway of RC product
7 with o-nitrobenzaldehyde (5a) is the major pathway dur-
ing the later stage of reaction. It should be noted that,
under our cooperative catalysis reaction conditions, for-
mation of the 1:2 MBH adduct 6 and RC product 7 are
completely eliminated; no reaction was observed between
MBH product 11a and 4a in the absence of aldehyde. This
result clearly illustrates the importance of proline iminium
OH
O
7c
8c
11g
11h
66
42
34
33
O
O
Ph
NO2
CF3 OH
O
Ph
Synthesis 2011, No. 12, 1960–1967 © Thieme Stuttgart · New York

PAPER
Morita–Baylis–Hillman Reaction of Aryl Vinyl Ketones
1965
drous 1,4-dioxane (5.0 mL) at ambient temperature, was added 4a
(0.259 mL, 1.95 mmol) in one portion. The resulting suspension
was stirred at 50 °C for 42 h, then loaded directly onto silica gel for
flash column chromatography (EtOAc–hexanes, 20:80) to give
MBH product 11a.
intermediates in the cooperative catalysis for the success-
ful MBH reaction of aryl vinyl ketones.
In summary, we have developed a Morita–Baylis–
Hillman reaction of aryl vinyl ketones using cooperative
catalysis of brucine N-oxide and proline. The current
study demonstrates the synthetic potential of iminium in-
termediates derived from aryl aldehydes and proline, and
illustrates the mild nucleophilic nature of BNO; these fea-
tures enable the efficient formation of normal MBH prod-
ucts of aryl vinyl ketones for the first time. We are
currently investigating the asymmetric MBH reaction of
aryl vinyl ketones using this cooperative catalysis ap-
proach, and our results will be reported in due course.
2-[Hydroxy(2-nitrophenyl)methyl]-1-phenylprop-2-en-1-one
(11a)
Yield: 158 mg (86%); yellowish liquid.
IR (neat): 3450, 3064, 2920, 2851, 1650, 1524, 1345 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.01–7.97 (m, 2 H), 7.73–7.67 (m,
3 H), 7.57–7.54 (m, 1 H), 7.49–7.42 (m, 3 H), 6.31 (s, 1 H), 5.82 (d,
J = 0.75 Hz, 1 H), 5.77 (s, 1 H), 4.14 (d, J = 1.75 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 198.5, 147.8, 147.6, 136.7, 136.2,
133.6, 133.0, 129.7, 129.0, 128.6, 128.4, 127.7, 124.7, 69.4.
HRMS (CI): m/z [M – H]– calcd for C16H12NO4: 282.0772; found:
283.0845.
All reactions were carried out under an argon atmosphere with
oven-dried glassware. The progress of the reactions were monitored
by thin-layer chromatography on Dynamic Adsorbent, Inc. precoat-
ed silica gel plates (250 mm) and visualized by ultra-violet light or
by staining with KMnO4 stain. HPLC grade anhydrous 1,4-dioxane
was used without further purification. All commercially available
aldehyde substrates were used as received. Aryl vinyl ketones were
prepared according to the previously reported procedure.17 The 1H
and 13C NMR spectra were obtained with Bruker 500 MHz Fourier
transform spectrometers at the Indiana University Purdue Universi-
ty Indianapolis NMR facility. Chemical shifts are reported in ppm
downfield from residual non-deuterated solvent or tetramethylsi-
lane and all coupling constants are reported in hertz. Infrared spec-
tra were obtained with a Thermo Nicolet IR 300 Spectrometer.
Silica gel (32–64 mm; Dynamic Adsorbent, Inc.) was used for flash
chromatography.
2-[Hydroxy(4-nitrophenyl)methyl]-1-phenylprop-2-en-1-one
(11b)
Yield: 159 mg (86%); yellowish liquid.
IR (neat): 3458, 3066, 2925, 1655, 1519, 1347 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.19 (d, J = 8.75 Hz, 2 H), 7.68–
7.66 (m, 2 H), 7.63 (d, J = 8.5 Hz, 2 H), 7.58–7.54 (m, 1 H), 7.44–
7.41 (m, 2 H), 6.12 (s, 1 H), 5.88 (s, 1 H), 5.84 (s, 1 H), 3.74 (s,
1 H).
13C NMR (125 MHz, CDCl3): d = 197.9, 148.7, 147.6, 147.4, 136.8,
133.1, 129.5, 128.5, 128.1, 127.2, 123.7, 73.5.
HRMS (CI): m/z [M – H]– calcd for C16H12NO4: 282.0772; found:
283.0845.
1-(4-Chlorophenyl)prop-2-en-1-one (4b)
Prepared according to a previously reported procedure.17 Yellowish
liquid.
2-[Hydroxy(3-nitrophenyl)methyl]-1-phenylprop-2-en-1-one
(11c)
Yield: 151 mg (82%); yellowish liquid.
IR (neat): 3451, 3088, 2922, 1654, 1529, 1351 cm–1.
IR (neat): 3091, 2912, 2850, 1671, 1609, 1590, 1406, 1236, 1093,
998, 777 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.87 (d, J = 8.5 Hz, 2 H), 7.43 (d,
J = 8.5 Hz, 2 H), 7.10 (dd, J = 17, 10.5 Hz, 1 H), 6.43 (dd, J = 17,
1.5 Hz, 1 H), 5.93 (dd, J = 10.5, 1.5 Hz, 1 H).
1H NMR (500 MHz, CDCl3): d = 8.34 (s, 1 H), 8.15–8.12 (m,
8.3 Hz, 1 H), 7.82 (d, J = 7.5 Hz, 1 H), 7.70–7.68 (m, 2 H), 7.58–
7.51 (m, 2 H), 7.45–7.42 (m, 2 H), 6.15 (d, J = 1.0 Hz, 1 H), 5.92 (s,
1 H), 5.84 (d, J = 5.5 Hz, 1 H), 3.67 (d, J = 5.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 189.6, 139.4, 135.5, 131.9, 130.6,
13C NMR (125 MHz, CDCl3): d = 198.0, 148.4, 147.5, 143.7, 136.9,
130.0, 128.9.
133.1, 132.6, 129.5, 129.4, 128.5, 128.4, 122.8, 121.4, 73.6.
HRMS (CI): m/z [M + H]– calcd for C9H8ClO: 167.0258; found:
166.0185.
HRMS (CI): m/z [M – H]– calcd for C16H12NO4: 282.0772; found:
283.0845.
1-(4-Methoxyphenyl)prop-2-en-1-one (4c)
Prepared according to a previously reported procedure.17 Yellowish
liquid.
2-[(2,4-Dinitrophenyl)(hydroxy)methyl]-1-phenylprop-2-en-1-
one (11d)
Yield: 209 mg (98%); yellowish liquid.
IR (neat): 3458, 3112, 2926, 1651, 1606, 1535, 1346 cm–1.
IR (neat): 3009, 2937, 2840, 1665, 1590, 1401, 1243, 1172, 994,
788 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.97 (d, J = 9.0 Hz, 2 H), 7.17 (dd,
J = 17, 10.5 Hz, 1 H), 6.96 (d, J = 9.0 Hz, 2 H), 6.43 (dd, J = 17,
2 Hz, 1 H), 5.87 (dd, J = 10.5, 2 Hz, 1 H), 3.87 (s, 3 H).
1H NMR (500 MHz, CDCl3): d = 8.85 (d, J = 2.0 Hz, 1 H), 8.52 (dd,
J = 8.5, 2.0 Hz, 1 H), 8.26 (d, J = 8.5 Hz, 1 H), 7.71–7.69 (m, 2 H),
7.61–7.58 (m, 1 H), 7.48–7.44 (m, 2 H), 6.38 (d, J = 4.4 Hz, 1 H),
5.85 (s, 1 H), 5.84 (s, 1 H), 4.21 (d, J = 4.7 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 189.1, 163.5, 132.0, 130.9, 130.1,
13C NMR (125 MHz, CDCl3): d = 198.1, 147.7, 147.3, 146.5, 142.9,
129.1, 113.8, 55.4.
136.2, 133.4, 130.8, 129.7, 128.6, 128.6, 127.5, 120.2, 69.5.
HRMS (CI): m/z [M + H]– calcd for C10H11O2: 163.0754; found:
162.0681.
HRMS (CI): m/z [M + H]+ calcd for C16H13N2O6: 329.0768; found:
328.0695.
Morita–Baylis–Hillman Reaction of Phenyl Vinyl Ketone (4a);
Typical Procedure
To a stirred solution of 5a (100 mg, 0.65 mmol), brucine N-oxide
(269 mg, 0.65 mmol) and L-proline (74 mg, 0.65 mmol) in anhy-
2-[Hydroxy(3-methoxy-2-nitrophenyl)methyl]-1-phenylprop-
2-en-1-one (11e)
Yield: 263 mg (80%); yellowish liquid.
IR (neat): 3440, 2941, 2851, 1653, 1532, 1282 cm–1.
Synthesis 2011, No. 12, 1960–1967 © Thieme Stuttgart · New York

1966
K. Oh, J.-Y. Li
PAPER
1H NMR (500 MHz, CDCl3): d = 7.73 (d, J = 8.0 Hz, 2 H), 7.57–
7.54 (m, 1 H), 7.47–7.42 (m, 3 H), 7.31 (d, J = 8.0 Hz, 1 H), 6.99
(d, J = 8.5 Hz, 1 H), 6.03 (d, J = 1.0 Hz, 1 H), 5.86 (s, 1 H), 5.81 (d,
J = 5.9 Hz, 1 H), 4.09 (d, J = 5.9 Hz, 1 H), 3.90 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 199.3, 151.0, 145.7, 136.7, 134.1,
133.0, 131.3, 129.7, 129.4, 128.4, 119.5, 112.12, 70.4, 56.5.
Hz), 127.4, 124.3 (d, J = 3.4 Hz), 115.3 (d, J = 21.3 Hz), 68.8 (d,
J = 3.8 Hz).
HRMS (CI): m/z [M + H]– calcd for C16H14FO2: 257.0972; found:
256.0900.
2-[Hydroxy(phenyl)methyl]-1-phenylprop-2-en-1-one (11j)
Yield: 12 mg (8%); colorless liquid.
IR (neat): 3467, 3061, 2923, 2852, 1683, 1654, 1449, 979, 700 cm–1.
HRMS (CI): m/z [M + H]+ calcd for C17H15NO5: 314.1023; found:
313.0950.
1H NMR (500 MHz, CDCl3): d = 7.71–7.69 (m, 2 H), 7.55–7.52 (m,
1 H), 7.47–7.40 (m, 5 H), 7.37–7.33 (m, 2 H), 6.07 (s, 1 H), 5.79 (s,
2 H), 3.31 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 198.3, 148.8, 141.3, 137.3, 132.7,
129.6, 128.5, 128.3, 127.8, 126.7, 126.5, 74.2.
HRMS (CI): m/z [M + H]– calcd for C16H15O2: 239.1067; found:
238.0994.
2-[Hydroxy(1-nitronaphthalen-2-yl)methyl]-1-phenylprop-2-
en-1-one (11f)
Yield: 195 mg (90%); yellowish liquid.
IR (neat): 3434, 3064, 2922, 1654, 1527 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.02 (d, J = 8.5 Hz, 1 H), 7.90 (d,
J = 7.5 Hz, 1 H), 7.83 (d, J = 8.5 Hz, 1 H), 7.79 (d, J = 8.5 Hz, 1 H),
7.74–7.72 (m, 2 H), 7.66–7.52 (m, 3 H), 7.44–7.42 (m, 2 H), 6.06–
6.04 (m, 2 H), 5.91 (s, 1 H), 4.05 (d, J = 4.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 198.1, 146.5, 146.2, 136.8, 133.4,
133.0, 131.2, 130.5, 129.7, 129.1, 128.8, 128.4, 128.0, 127.6, 124.4,
124.1, 121.8, 70.2.
1-(4-Chlorophenyl)-2-[hydroxy(2-nitrophenyl)methyl]prop-2-
en-1-one (11k)
Yield: 145 mg (70%); yellowish liquid.
IR (neat): 3469, 3068, 2924, 2853, 1680, 1658, 1589, 1525, 1346,
1092 cm–1.
HRMS (CI): m/z [M – H]– calcd for C20H15NO4: 332.0928; found:
333.1001.
1H NMR (500 MHz, CDCl3): d = 8.03 (dd, J = 8.2, 1.1 Hz, 1 H),
7.97 (d, J = 7.6 Hz, 1 H), 7.73–7.67 (m, 3 H), 7.51–7.48 (m, 1 H),
7.43–7.42 (m, 2 H), 6.29 (s, 1 H), 5.80 (s, 1 H), 5.74 (s, 1 H), 3.96
(s, 1 H).
13C NMR (125 MHz, CDCl3): d = 197.2, 147.6, 139.6, 136.0, 135.0,
133.8, 131.1, 129.0, 128.8, 128.7, 128.7, 127.4, 124.9, 69.4.
2-[Hydroxy(6-nitrobenzo[d][1,3]dioxol-5-yl)methyl]-1-phenyl-
prop-2-en-1-one (11g)
Yield: 72 mg (34%); yellowish liquid.
IR (neat): 3444, 3086, 2919, 1652, 1519, 1262, 1035 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.74 (d, J = 7.5 Hz, 2 H), 7.59–
7.56 (m, 2 H), 7.46–7.42 (m, 3 H), 6.28 (s, 1 H), 6.14 (d, J = 4.5 Hz,
2 H), 5.80 (s, 1 H), 5.73 (s, 1 H), 4.12 (s, 1 H).
HRMS (CI): m/z [M + H]– calcd for C16H13ClNO4: 318.0528; found:
317.0455.
13C NMR (125 MHz, CDCl3): d = 198.8, 152.5, 147.8, 147.3, 141.6,
136.8, 134.1, 133.0, 129.8, 128.4, 127.1, 108.0, 105.7, 103.1, 69.5.
1-(4-Chlorophenyl)-2-[(2,4-dinitrophenyl)(hydroxy)meth-
yl]prop-2-en-1-one (11l)
Yield: 231 mg (98%); yellowish liquid.
IR (neat): 3458, 3104, 2923, 1655, 1588, 1535, 1346 cm–1.
HRMS (CI): m/z [M – H]– calcd for C17H12NO6: 326.0670; found:
327.0743.
1H NMR (500 MHz, CDCl3): d = 8.86 (d, J = 2.25 Hz, 1 H), 8.53
(dd, J = 8.65, 2.25 Hz, 1 H), 8.26 (d, J = 8.65 Hz, 1 H), 7.66 (d, J =
8.5 Hz, 2 H), 7.44 (d, J = 8.5 Hz, 2 H), 6.36 (s, 1 H), 5.81 (s, 2 H),
4.09 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 196.8, 147.6, 147.4, 146.7, 142.8,
140.0, 134.5, 131.1, 130.8, 129.0, 128.3, 127.6, 120.3, 69.3.
2-{Hydroxy[2-(trifluoromethyl)phenyl]methyl}-1-phenylprop-
2-en-1-one (11h)
Yield: 66 mg (33%); yellowish liquid.
IR (neat): 3447, 3067, 2920, 1655, 1313, 1160, 1123 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.89 (d, J = 8.0 Hz, 1 H), 7.75 (d,
J = 8.0 Hz, 2 H), 7.69 (d, J = 7.5 Hz, 1 H), 7.63 (t, J = 7.5 Hz, 1 H),
7.59–7.56 (m, 1 H), 7.47–7.43 (m, 3 H), 6.18 (s, 1 H), 5.80 (s, 1 H),
5.66 (s, 1 H), 3.75 (s, 1 H).
HRMS (CI): m/z [M + H]– calcd for C16H12ClN2O6: 363.0378;
found: 326.0306.
13C NMR (125 MHz, CDCl3): d = 198.7, 148.5, 139.1, 137.0, 132.9,
132.1, 129.7, 129.7, 128.7, 128.3, 128.3, 128.3, 128.3, 125.9 (d,
J = 5.5 Hz), 69.2.
2-[(2,4-Dinitrophenyl)(hydroxy)methyl]-1-(4-methoxyphe-
nyl)prop-2-en-1-one (11m)
Yield: 228 mg (98%); yellowish liquid.
HRMS (CI): m/z [M + H]– calcd for C17H14F3O2: 307.0940; found:
IR (neat): 3404, 3109, 2923, 2851, 1649, 1599, 1535, 1346 cm–1.
306.0868.
1H NMR (500 MHz, CDCl3): d = 8.83 (d, J = 2.3 Hz, 1 H), 8.51 (dd,
J = 8.65, 2.3 Hz, 1 H), 8.27 (d, J = 8.65 Hz, 1 H), 7.74–7.72 (m,
2 H), 6.95–6.92 (m, 2 H), 6.31 (d, J = 4.15 Hz, 1 H), 5.77 (s, 1 H),
5.75 (s, 1 H), 4.52 (d, J = 4.75 Hz, 1 H), 3.87 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 196.9, 164.1, 147.7, 147.3, 146.1,
143.0, 132.3, 130.7, 128.7, 127.4, 127.0, 120.1, 113.9, 70.1, 55.6.
2-[(2-Fluorophenyl)(hydroxy)methyl]-1-phenylprop-2-en-1-
one (11i)
Yield: 25 mg (15%); yellowish liquid.
IR (neat): 3445, 3065, 2920, 1655, 1489, 1450, 1314, 980, 760 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.74–7.72 (m, 2 H), 7.60–7.51 (m,
2 H), 7.43 (m, 2 H), 7.29–7.25 (m, 1 H), 7.19–7.16 (m, 1 H), 7.06–
7.02 (m, 1 H), 6.00 (s, 2 H), 5.80 (s, 1 H), 3.76 (s, 1 H).
HRMS (CI): m/z [M + H]– calcd for C17H15N2O7: 359.0874; found:
358.0801.
13C NMR (125 MHz, CDCl3): d = 198.6, 159.9 (d, J = 245 Hz),
147.6, 137.1, 132.9, 129.6, 129.4, 129.4, 128.3, 128.2 (d, J = 3.6
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Synthesis 2011, No. 12, 1960–1967 © Thieme Stuttgart · New York

PAPER
Morita–Baylis–Hillman Reaction of Aryl Vinyl Ketones
1967
(7) Kinoshita, H.; Kinoshita, S.; Munechika, Y.; Iwamura, T.;
Watanabe, S.; Kataoka, T. Eur. J. Org. Chem. 2003, 4852.
(8) Trofimov, A.; Gevorgyan, V. Org. Lett. 2009, 11, 253.
(9) Oh, K.; Li, J.-Y.; Ryu, J. Org. Biomol. Chem. 2010, 8, 3015.
(10) The synthetic potential of proline iminium species derived
from proline and aldehydes was originally suggested by
Eschenmoser and Seebach, see: Seebach, D.; Beck, A. K.;
Badine, D. M.; Limbach, M.; Eschenmoser, A.;
Treasurywala, A. M.; Hobi, R.; Prikoszovich, W.; Linder, B.
Helv. Chim. Acta 2007, 90, 425.
(11) Reactions in various apolar and polar solvents, including
MeOH, DMF, DMSO, and 1,4-dioxane, were examined, but
no MBH reaction was observed.
(12) A catalytic amount of both brucine N-oxide and proline can,
in principle, be used, but the catalytic turnover number
(TON) remains 2–3 after five days; use of 30 mol% of both
catalysts provided up to 60–70% conversion after five days
at 50 °C.
(13) No significant conversion was observed after 42 h, although
the crude NMR spectrum of the reaction mixture clearly
indicated that the four reaction components were present
(4a, 5a, brucine N-oxide, and proline) together with the
MBH product 11a.
(14) The Rauhut–Currier reaction of phenyl vinyl ketone was
reported using 15 mol% DABCO (neat conditions) to give
the RC product in 62% isolated yield in 15 min, see:
Basavaiah, D.; Gowriswari, V. V. L.; Bharathi, T. K.
Tetrahedron Lett. 1987, 28, 4591.
(15) After 60 h at 23 °C, the 1:2 MBH adduct 6 was isolated in
70–80% yield from 2 equiv phenyl vinyl ketone, see also ref.
6.
(16) For the tertiary amine-catalyzed direct aldol reaction, see:
(a) Markert, M.; Mulzer, M.; Schetter, B.; Mahwald, R.
J. Am. Chem. Soc. 2007, 129, 7258. (b) Gutsche, C. D.;
Redmore, D.; Buriks, R. S.; Nowotny, K.; Grassner, H.;
Armbruster, C. W. J. Am. Chem. Soc. 1967, 89, 1235.
(17) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem.
Soc. 2002, 124, 15156.
Acknowledgment
This research was supported by IUPUI. The Bruker 500 MHz NMR
spectrometer was purchased through an NSF-MRI award (CHE-
0619254). We thank Dr. Karl Dria for his assistance with mass
spectra analysis (CHE-0821661).
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Synthesis 2011, No. 12, 1960–1967 © Thieme Stuttgart · New York