A Convenient Method for Preparing Aromatic α,β-Unsaturated Ketones from α,β-Unsaturated Acyl Chlorides and Arylboronic Acids via Suzuki-Miyaura Type Coupling Reaction

Article abstract of DOI:10.1055/s-2003-44347

Aromatic α,β-unsaturated ketones are synthesized efficiently by palladium-catalyzed cross-coupling reaction of arylboronic acids with α,β-unsaturated acyl chlorides in the presence of K ₃PO₄ hydrate in toluene.

Full text of DOI:10.1055/s-2003-44347

2882
SPECIAL TOPIC
A Convenient Method for Preparing Aromatic , -Unsaturated Ketones from
, -Unsaturated Acyl Chlorides and Arylboronic Acids via Suzuki-Miyaura
Type Coupling Reaction
A
Convenient
Met
o
hod for Pre
p
s
aring
A
ro
h
,
-U
n
i
saturat
o
ed
K
etones Urawa,*a Katsutoshi Nishiura,a Shigeru Souda,a Katsuyuki Ogura*b
a
Process Research Laboratories, Eisai Co., Ltd, 22-Sunayama, Hasaki-machi, Kashima-gun, Ibaraki 314-0255, Japan
Fax +81(479)464956; E-mail: y-urawa@hhc.eisai.co.jp
b
Graduate School of Science and Technology, Chiba University, 1-33 Yayoicho, Inageku, Chiba 263-8522, Japan
Received 22 September 2003
tion or in situ by an activator such as pivalic anhydride or
dimethyl dicarbonate.1b,c From a point of view that the re-
action is performed in a large (or industrial) scale, acyl
chlorides are preferred as a starting material because most
of them are commercially available or easily prepared.
Bumagin2 reported another example for the unsaturated
ketone synthesis via palladium-catalyzed cross-coupling
of sodium tetraaryl borates and , -unsaturated acyl chlo-
ride in acetone (Equation 2). The starting borate is not the
popular compound that we can get conveniently.
Abstract: Aromatic , -unsaturated ketones are synthesized effi-
ciently by palladium-catalyzed cross-coupling reaction of arylbo-
ronic acids with , -unsaturated acyl chlorides in the presence of
K3PO4 hydrate in toluene.
Key words: boron, catalysis, cross-coupling, ketones, palladium
As well known, aromatic , -unsaturated ketones are use-
ful intermediates for synthesizing biologically active
compounds including a large number of natural products
and active pharmaceutical ingredients (APIs). Hence,
many methods have been developed for their preparation.
One of the straightforward routes leading to the aromatic
, -unsaturated ketones is the Friedel–Crafts acylation of
aromatic hydrocarbons with unsaturated acyl halides.
This route has some disadvantageous points: the Friedel–
Crafts acylation requires a stoichiometric amount of alu-
minum chloride that brings about the environmental pol-
lution after work-up and is not applicable to the synthesis
of acid-sensitive aromatic , -unsaturated ketones. This
is mainly because most of aromatic , -unsaturated ke-
tones are easily polymerized by an acid. In order to over-
come these drawbacks, our attention was drawn to the use
of palladium-mediated cross-coupling reaction. Lately,
the palladium-mediated cross-coupling between a boronic
acid and the activated derivative of an acid has been inves-
tigated significantly because it can be performed in the
presence of a catalytic amount of palladium under basic
conditions. Several reports have appeared on the synthesis
of functionalized diaryl ketones as well as alkyl aryl ke-
tones (Equation 1).1
O
C
O
C
[Pd]
NaBAr4
+
Cl
Ar
R2
R2
Equation 2
In our precedent paper, the palladium-catalyzed cross-
coupling reaction of boronic acids with acyl chlorides was
revealed to proceed efficiently in the presence of K3PO4
hydrate in toluene.3 Note worthily, alphatic acyl chlorides
can be used as a starting material and, in this reaction sys-
tem, the hydrated water play a significant role as a source
of water to activate the catalytic system. Against these
backgrounds, we started our investigation to extend this
simple and practical procedure to a preparative method of
aromatic , -unsaturated ketones. Herein, we wish to de-
scribe that various aromatic , -unsaturated ketones 3 can
be prepared from arylboronic acids 1 and , -unsaturated
acyl chlorides 2 using (Ph3P)2PdCl2 as catalyst in the pres-
ence of K3PO4 hydrate (Equation 3).
R2
O
R2
O
When we surveyed the literature on the palladium-cata-
lyzed synthesis of the , -unsaturated ketones, only two
examples were noticed. One example uses the activated
derivatives that have to be formed either prior to the reac-
(Ph3P)2PdCl2
ArB(OH)2
+
R1
Cl
R1
Ar
hydrated K3PO4
in toluene
R3
R3
1
2
3
O
O
[Pd]
Equation 3
Ar-X
+
R
Y
R
Ar
The reaction of phenylboronic acid (1; Ar = Ph) with (E)-
2-methylbut-2-enoyl chloride (2; R1 = R3 = Me, R2 = H)
took place smoothly in toluene containing dichloro-
bis(triphenylphosphine)palladium and hydrated K3PO4
under nitrogen. The reaction was accomplished by heating
at 80 °C for 4 hours to give the expected 3 (Ar = Ph,
R1 = R3 = Me, R2 = H) in 99% yield. These reaction con-
Y=activating group
Equation 1
SYNTHESIS 2003, No. 18, pp 2882–2885
Advanced online publication: 19.11.2003
DOI: 10.1055/s-2003-44347; Art ID: C13903SS.pdf
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
3

SPECIAL TOPIC
A Convenient Method for Preparing Aromatic , -Unsaturated Ketones
2883
ditions could be applied to other arylboronic acids 1 and This protected material was chosen because the boronic
, -unsaturated acyl chlorides 2. The results are summa- acid 1 (Ar = o-cyanophenyl) undergoes intermolecular
rized in Table 1. It is noteworthy that 2-methyl substituent condensation under anhydrous conditions.4 To our de-
of 2 raised up the yield of the corresponding 3 (entries 1– light, the expected 5 was obtained in 89% yield under the
6). To our surprise, methacryloyl chloride (2; above mentioned reaction conditions (Equation 4). The
R1 = R2 = H, R3 = Me) that is known to be unstable at an yield of 5 decreased to 77% in the reaction at a higher tem-
elevated temperature formed 3 (Ar = Ph, R1 = R2 = H, perature (110 °C). When PPh3/Pd(OAc)2 was used instead
R3 = Me) in good yield. In the absence of a substituent at of (Ph3P)2PdCl2, the yield of 5 was slightly decreased to
the 2-position, the conversion of 1 and 2 into 3 was low, 82%.
probably because it competes against the easy polymer-
ization of 2 (R3 = H).
O
CN
CN
(Ph3P)2PdCl2
COCl
O
O
+
H3C
H3C
Now, we needed o-cyanobenzophenone derivatives that
are useful synthetic intermediates for some pharmaceuti-
cals. We also attempted to couple 2 (R1 = R3 = Me,
R2 = H) with 2-(1,3,2-dioxaborinan-2-yl)benzonitrile (4)
that was selected instead of (o-cyanophenyl)boronic acid.
B
CH3
CH3
hydrated K3PO4
in toluene
4
5
89%
Equation 4
Since the boronic acids are usually supplied as a mixture
with the corresponding boroxine that is intramolecular
condensed product of the boronic acid, we examined the
use of a boroxine derivative as the starting boronic com-
pounds. Interestingly, the expected product 7 was pro-
duced in a high yield (82%) by the reaction of
triphenylboroxine (6) with 2 (R1 = R3 = Me, R2 = H) un-
der the present conditions (Equation 5).
Table 1 Pd-Catalyzed Reaction of Acyl Chlorides 2 with Arylbo-
ronic Acids 1 in the Presence of K3PO4 Hydrate
En- Acyl Chloride ArB(OH)2
trya
Product
Yield
(%)b
1
2
3
4
99
98
96
90
COCl
O
B(OH)2
O
O
O
B(OH)2
COCl
B
+
H3C
O
B
O
B
CH3
O
B(OH)2
6
O
(Ph3P)2PdCl2
H3C
B(OH)2
B(OH)2
hydrated K3PO4
in toluene
CH3
82%
5
6
88
30
S
O
O
S
Equation 5
In summary, the palladium-catalyzed cross-coupling re-
action of arylboronic acids with , -unsaturated acyl
chlorides was achieved by using K3PO4 hydrate as a base
to afford aromatic , -unsaturated ketones in good to ex-
cellent yields. Instead of the boronic acids, a (1,3,2-dioxa-
borinan-2-yl) compound and a boroxine derivative can be
employed as the starting boronic compound under the
present conditions. Further studies on the scope of this re-
action are in progress.
B(OH)2
B(OH)2
B(OH)2
B(OH)2
COCl
7c
8c
9
64
7
COCl
O
O
COCl
35
COCl
All reactions were carried out under a positive pressure of N2. 2-
(1,3,2-Dioxaborinan-2-yl)benzonitrile (4) was prepared from 2-
bromobenzonitrile (according to a patent5). K3PO4·H2O was pur-
chased from Kishida Chemical Co., Ltd. Other reagents are com-
mercially available and were used without further purification. IR
spectra were recorded on a Perkin-Elmer Spectrum One spectrom-
O
a Reaction conditions: acyl chloride (1 mmol), boronic acid (1.2
mmol), hydrated K3PO4 (1.2 mmol), (Ph3P)2PdCl2 (2 mol%), toluene
(4 mL), 80 °C, 4 h.
eter. H NMR and 13C NMR spectra were recorded on a Jeol AL-
400 spectrometer (400 MHz). All NMR data were obtained in
CDCl3 solutions containing tetramethylsilane as an internal stan-
1
b Isolated yields.
c Reaction carried out at 60 °C.
Synthesis 2003, No. 18, 2882–2885 © Thieme Stuttgart · New York

2884
Y. Urawa et al.
SPECIAL TOPIC
dard. HRMS spectra were obtained on a Micromass Q-Tof Ultima
global.
13C NMR (CDCl3): = 12.92, 14.68, 127.30, 132.65, 132.88,
137.42, 137.49, 143.41, 189.8.
HRMS (ESI): m/z calcd for C9H11OS [MH]+: 167.0531; found:
167.0541.
(E)-2-Methyl-1-phenylbut-2-en-1-one (Entry 1, Table 1); Typi-
cal Procedure
To a mixture of phenylboronic acid (1; Ar = Ph, 146 mg, 1.20
mmol), (Ph3P)2PdCl2 (14.0 mg, 0.02 mmol) and hydrated K3PO4
(286 mg, 1.20 mmol) in toluene (4 mL) under N2 was added tigloyl
chloride (2; R1 = R3 = Me, R2 = H, 119 mg, 1.00 mmol) by syringe.
The reaction mixture was heated at 80 °C for 4 h. After removal of
the insolubles by filtration, purification of the filtrate by silica gel
column chromatography (hexane–EtOAc, 100:1) gave the corre-
sponding product (158 mg, 99%); colorless oil (Table 1).
3-Methyl-1-phenylbut-2-en-1-one (Entry 6, Table 1)
IR (neat): 2912, 1660, 1614, 1247, 1011, 700 cm–l.
1H NMR (CDCl3): = 2.01 (d, 3 H, J = 1.0 Hz), 2.20 (d, 3 H, J = 1.2
Hz), 6.74 (t, 3 H, J = 1.2 Hz), 7.42–7.45 (m, 2 H), 7.50–7.54 (m, 1
H), 7.91–7.94 (m, 2 H).
13C NMR (CDCl3): = 21.22, 28.01, 121.11, 128.07, 128.17,
128.32, 129.95, 132.16, 139.15, 156.52, 191.35.
IR (neat): 2924, 1647, 1276, 704 cm–l.
HRMS (ESI): m/z calcd for C11H12ONa [MNa]+: 188.0786; found:
1H NMR (CDCl3): = 1.88 (dq, 3 H, J = 1.5, 6.6 Hz), 1.97 (m, 3 H),
6.41 (qq, 1 H, J = 7.0, 1.5 Hz), 7.38–7.44 (m, 2 H), 7.46–7.52 (m,
1 H), 7.58–7.63 (m, 2 H).
13C NMR (CDCl3): = 12.29, 14.92, 127.84, 129.02, 131.06,
137.48, 138.64, 141.37, 198.61.
HRMS (ESI): m/z calcd for C11H13O [MH]+: 161.0966; found:
161.0972.
188.0788.
2-Methyl-1-phenylpropenone (Entry 7, Table 1)
IR (neat): 3063, 1656, 1332, 1199, 710 cm–l.
1H NMR (CDCl3): = 2.07 (dd, 3 H, J = 1.5, 6.6 Hz), 5.63 (m, 1 H),
5.91–5.92 (m, 1 H), 7.41–7.46 (m, 2 H), 7.51–7.56 (m, 1 H), 7.71–
7.78 (m, 2 H).
13C NMR (CDCl3): = 18.78, 126.96, 127.00, 128.0, 128.58,
129.25, 131.84, 137.53, 143.56, 198.05.
HRMS (ESI): m/z calcd for C10H11O [MH]+: 147.081; found:
147.0819.
(E)-2-Methyl-1-(4-methylphenyl)but-2-en-1-one (Entry 2, Ta-
ble 1)
IR (neat): 2923, 1646, 1607, 827, 739 cm–l.
1H NMR (CDCl3): = 1.87(d, 3 H, J = 6.8 Hz), 1.97 (s, 3 H), 2.40
(s, 3 H), 6.35–6.40 (m, 1 H), 7.21 (d, 2 H, J = 7.6 Hz), 7.53 (d, 2 H,
J = 7.6 Hz).
13C NMR (CDCl3): = 12.47, 14.80, 21.63, 128.52, 129.29, 135.76,
137.44, 140.25, 141.66, 198.42.
HRMS (ESI): m/z calcd for C12H15O [MH]+: 175.1123; found:
175.1151.
1-Phenylpropenone (Entry 8, Table 1)
IR (neat): 3060, 1684, 1598, 1449, 1104 cm–l.
1H NMR (CDCl3): = 5.94 (dd, 1 H, J = 1.7, 10.6 Hz), 6.44 (dd, 1
H, J = 1.7, 17.1 Hz), 7.16 (dd, 1 H, J = 10.5, 17.1 Hz), 7.49 (m, 2
H), 7.58 (tt, 1 H, J = 2.2, 7.3 Hz), 7.95 (m, 2 H).
13C NMR (CDCl3): = 128.54, 128.62, 130.12, 132.30, 132.91,
137.18, 190.93.
HRMS (ESI): m/z calcd for C9H8ONa [MNa]+: 155.0473; found:
155.0477.
(E)-2-Methyl-1-(3-methylphenyl)but-2-en-1-one (Entry 3, Ta-
ble 1)
IR (neat): 2923, 1647,1281, 796, 729 cm–l.
1H NMR (CDCl3): = 1.88 (dq, 3 H, J = 6.8, 1.0 Hz), 1.96 (m, 3 H),
2.39 (s, 3 H), 6.40 (qq, 1 H, J = 6.8, 1.5 Hz), 7.28–7.32 (m, 2 H),
7.36–7.40 (m, 1 H), 7.41–7.43 (m, 1 H).
(E)-1,3-Diphenylprop-2-en-1-one (Entry 9, Table 1)
IR (neat): 3060, 1664, 1606, 1450, 1216, 1017, 747 cm–l.
1H NMR (CDCl3): = 7.41–7.45 (m, 3 H), 7.49–7.64 (m, 4 H),
13C NMR (CDCl3): = 12.30, 14.90, 21.48, 126.24, 127.63, 129.46,
131.79, 137.55, 137.66, 138.70, 141.15, 198.84.
HRMS (ESI): m/z calcd for C12H15O [MH]+: 175.1123; found:
7.64–7.67 (m, 2 H), 7.82 (d, J = 15.9 Hz, 1 H), 8.02–8.04 (m, 2 H).
13C NMR (CDCl3): = 121.93, 128.30, 128.35, 128.48, 128.81,
130.40, 132.64, 134.70, 138.01, 144.68, 190.29.
HRMS (ESI): m/z calcd for C15H13O [MH]+: 209.0966; found:
175.1161.
209.0963.
(E)-2-Methyl-1-(2-methylphenyl)but-2-en-1-one (Entry 4, Ta-
ble 1)
2-[(E)-2-Methylbut-2-enoyl]benzonitrile (Equation 4)
IR (neat): 2926, 1654, 1639,1292, 127, 1977, 888, 734 cm–l.
IR (neat): 2927, 2229, 1654, 1637, 1295, 760 cm–l.
1H NMR (CDCl3): = 1.84 (dq, 3 H, J = 6.8, 1.0 Hz), 1.95 (m, 3 H),
2.24 (s, 3 H), 6.34 (qq, 1 H, J = 6.8, 1.2 Hz), 7.13–7.20 (m, 3 H),
7.27–7.31 (m, 1 H).
13C NMR (CDCl3): = 11.01, 15.18, 19.61, 124.83, 127.21, 128.96,
130.30, 135.34, 138.97, 139.72, 143.90, 200.55.
HRMS (ESI): m/z calcd for C12H15O [MH]+: 175.1123; found:
175.1105.
1H NMR (CDCl3): = 1.92 (dq, 3 H, J = 1.5, 6.6 Hz), 2.00 (m, 3
H,), 6.35 (qq, 1 H, J = 6.8, 1.2 Hz), 7.49 (dt, 1 H, J = 7.6, 0.7 Hz),
7.55 (dt, 1 H, J = 1.2, 7.6 Hz), 7.63 (dt, 1 H, J = 1.2, 7.6 Hz), 7.73
(dt, 1 H, J = 7.6, 1.2 Hz).
13C NMR (CDCl3): = 11.42, 15.40, 111.20, 116.96, 128.77,
129.99, 131.95, 133.17, 138.30, 143.27, 145.34, 195.60.
HRMS (ESI): m/z calcd for C12H12NO [MH]+: 186.0919; found:
186.0874.
(E)-2-Methyl-1-(2-thienyl)but-2-ene-1-one (Entry 5, Table 1)
IR (neat): 3100, 2923, 1626, 1416, 1283, 861, 829, 727 cm–l.
Acknowledgment
1H NMR (CDCl3): = 1.90 (dq, 3 H, J = 7.2, 1.2 Hz), 1.96 (m, 3 H),
6.60 (qq, 1 H, J = 7.2, 1.2 Hz), 7.09 (dd, 1 H, J = 4.8, 3.4 Hz), 7.55
(dd, 3 H, J = 3.4, 1.2 Hz), 7.65 (dd, 1 H, J = 4.9, 1.2 Hz).
We thank Ms. Mami Gomibuchi for HRMS analysis.
Synthesis 2003, No. 18, 2882–2885 © Thieme Stuttgart · New York

SPECIAL TOPIC
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Synthesis 2003, No. 18, 2882–2885 © Thieme Stuttgart · New York