A new efficient synthetic route for the synthesis of the antiallergic drug, olopatadine hydrochloride, via stereospecific palladium-catalyzed reaction

Article abstract of DOI:10.1021/op200312m

A new practical and efficient synthetic route for the synthesis of olopatadine hydrochloride via the intramolecular stereospecific seven-membered ring cyclization from an alkyne intermediate using palladium catalyst and hydride source was established. Furthermore, the optimization of that key stereospecific reaction was examined by design of experiment (DoE), and the desired Z-isomer could be obtained with high yield.

Full text of DOI:10.1021/op200312m

Article
pubs.acs.org/OPRD
A New Efficient Synthetic Route for the Synthesis of the Antiallergic
Drug, Olopatadine Hydrochloride, via Stereospecific Palladium-
Catalyzed Reaction
Koichiro Nishimura* and Masahiko Kinugawa
Chemical Process Research and Development Laboratories, Kyowa Hakko Kirin Co., Ltd., 1-1-53, Takasu-cho, Sakai, Osaka
590-8554, Japan
ABSTRACT: A new practical and efficient synthetic route for the synthesis of olopatadine hydrochloride via the intramolecular
stereospecific seven-membered ring cyclization from an alkyne intermediate using palladium catalyst and hydride source was
established. Furthermore, the optimization of that key stereospecific reaction was examined by design of experiment (DoE), and
the desired Z-isomer could be obtained with high yield.
Scheme 1. Strategy of the new synthesis route
INTRODUCTION
■
Olopatadine hydrochloride (1) is an antiallergic drug which was
developed by Kyowa Hakko Kirin Co. Ltd. It is produced for
commercial use by the synthesis route using Wittig reaction.1
Generally, the stereospecific synthesis of the Z-isomer is the
challenging issue when producing a trisubstituted alkene like
olopatadine hydrochloride. However, it was recently reported
that 1 could be obtained in high yield from the E/Z mixture of
the t-Bu ester derivative of olopatadine by the preferential
crystallization with isomerization under acidic condition.2 On
the other hand, an interesting synthetic route of 1 via
Mizoroki−Heck reaction using palladium catalyst was reported
in a patent.3 In this synthetic route, stereochemistry of the Z-
isomer was controlled by the intramolecular cyclization of the
E-alkene intermediate via Mizoroki−Heck reaction. Herein we
describe a new, more efficient, synthetic route of applying the
intramolecular cyclization using palladium catalyst and a
hydride source for the alkyne intermediate. The retrosynthesis
of the new synthetic route is outlined in Scheme 1.
The key reaction of this strategy is the intramolecular
stereoselective cyclization from alkyne 5 using palladium
catalyst and a hydride source. Such stereospecific ring
cyclization is already known.4 Especially, forming dibenz[b,e]-
oxepine possessing exo-olefin was reported by Finch.5
The ring cyclization precursor 5 could be introduced from
the inexpensive starting material 2 via bromination and
Sonogashira coupling with 3-butyn-1-ol. This process could
then be continued to the key ring cyclization, and the final
product 1 could be synthesized after dimethylamination of
terminal alcohol.
protected compound 8 was prepared in moderate yield via the
Sonogashira coupling reaction. The deprotection of metox-
ymethyl group in 8 was carried out using dilute HCl, but the
mixture of desired deprotected product 4 and undesired ketone
11 was obtained. It was anticipated that the alkyne group in 4
was easily hydrated to form 11 under acidic conditions.7
Next, we tested the deprotection of 10 protected by acetyl
group under basic conditions, but the mixture of 4 and
benzofuran 12 was obtained. With a very short reaction time, 4
was afforded in 76% yield. However the yield of 4 was greatly
decreased, and a lot of benzofuran 12 was afforded with an
increase of the reaction scale, since the reaction quenching in
very short time was difficult in large-scale production. In the
end, the intermediate 4 was very unstable under acidic and
basic conditions, and it was proved that this procedure via 4
RESULT AND DISCUSSION
■
Synthesis of the Seven-Membered Ring Cyclization
Precursor 5. The preparation of 3 was performed with
quantitative yield via bromination from 2 according to known
procedures.6 Then the protection of hydroxy group in 3 was
introduced before the Sonogashira coupling reaction to avoid
producing benzofuran as a byproduct.
First, the methoxymethyl group which could be deprotected
under a weak acidic condition was introduced to 3. The
Received: November 2, 2011
Published: December 22, 2011
© 2011 American Chemical Society
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Scheme 2. Synthesis of the seven-membered ring cyclization precursor (5)
Scheme 3. Seven-membered ring cyclization and the synthesis of olopatadine hydrochloride
was not appropriate for a constant production. Therefore, we
replanned the synthesis strategy of 5.
Once the intermediate 14 is obtained, it is expected that the
iodine group of 14 would react with 3-butyn-1-ol prior to the
bromine group in the Sonogashira coupling. The synthesis of
14 could be performed by O-alkylation of monoiodineted
compound 13 with 2-bromobenzylbromide. We tried iodina-
tion of 2 using inexpensive reagents, I2 or ICl, but the mixture
of monoiodinated compound 13 and diiodinated compound
was obtained. It was supposed that the selective monoiodina-
tion of 2 was difficult in this reaction condition. We next tried
to iodinate 15 after protection of the hydroxy group in 2 with
2-bromobenzyl group. As a result, the product 14 was obtained
from 15 in high yield when using Ag2SO4 and I2.8 Furthermore,
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Sonogashira coupling reaction for 14 with 3-butyn-1-ol
proceeded at the iodine position prior to bromine as expected.
We could produce the precursor 5 of the seven-membered ring
cyclization in the high yield from starting material 2. (Scheme
2)
The Seven-Membered Ring Cyclization Using Palla-
dium Catalyst. We then performed the seven-membered ring
cyclization of 5 using palladium catalyst based on the
aforementioned reference.4 The Z-isomer dibenz[b,e]oxepin 6
could be obtained as a sole product. However the yield of 6 in
the key ring cyclization was moderate since considerable
amounts of some byproducts ― 17, 18 and 19 ― were
produced. (Scheme 3)
Optimization of the Seven-Membered Ring Cycliza-
tion by DoE. We next tried to find the optimal conditions of
the key reaction to investigate the seven-membered ring
cyclization by DoE. Five factors (phosphine ligand, formic acid,
piperidine, DMF, temperature) were investigated as a candidate
of critical factors. Although Pd(OAc)2 may be a very important
factor, we did not investigate it here since it was estimated that
the reactivity would increase linearly as the amount of
Pd(OAc)2 increased.
Levels of the five factors are shown in Table 3. The 25−1
fractional factorial design with a center point was experimented
with using the automatic synthesis machine SK233.
The result of the DoE investigation was evaluated by the
product ratio calculated by HPLC area %. The product ratio of
each product for 17 runs is shown in Table 4. The HPLC area
% of 6 is a convenient response by which to evaluate the yield
of 6, but it cannot evaluate the behavior of byproducts properly.
Here the selectivity of 6 was focused on another important
response. This shows the ratio of 6 for all known products,
which is calculated by following the simple formula: 6/(6 + 17
+ 18 + 19). Upon seeing Table 4, we understood that the
conditions of run 6 are preferred in both the product ratio and
the selectivity of 6.
The results of Table 4 were analyzed using the statistical
analysis software “Design Expert”. The half normal plot of
HPLC area % and the selectivity of 6 are shown in Figure 1,
from which it is possible to estimate the effect of each factor.
Temperature was the most critical factor in both responses.
This result could be easily understood because of the reactivity
generally increasing at higher temperatures. The second critical
factor was a little different between the two responses. In the
product ratio, the second critical factor was the interaction of
formic acid and temperature, but it was greatly lower than that
of temperature alone. On the other hand, in the selectivity, the
second critical factor was formic acid, the effect of which was as
high as the effect of temperature. In the end, it was revealed
that formic acid influenced the selectivity. Figure 2 shows the
relevancy of temperature and formic acid. These figures
indicate that higher temperature and less formic acid were
appropriate for affording 6.
To increase the yield of 6, screening of phosphine ligands in
catalysts and solvents were investigated. As a result, P(o-tolyl)3,
P(cyclohexyl)3, and dppe were found to be effective (Table 1).
a
Table 1. Screening of phosphine ligands
b
product ratio
entry
phosphine ligand
5
6
17
18
19
1
2
3
4
5
6
7
8
9
PPh3
15
1
24
49
20
61
54
29
30
22
23
36
3
21
8
<1
3
c
P(o-tolyl)3
P(m-tolyl)3
P(p-tolyl)3
P(tBu)3
P(cyclohexyl)3
dppe
50 (47)
1
23
24
11
45
45
6
<1
<1
14
<1
<1
1
3
13
41
4
<1
16
<1
<1
<1
24
58
20
dppp
dppf
34
<1
a
All reactions were carried out on a 100 mg scale in 2 mL of
acetonitrile at 60 °C with Pd(OAc)2 (0.10 equiv), phosphine ligand
(0.20 equiv), formic acid (3.0 equiv), and piperidine (6.0 equiv).
b
c
Product ratios were calculated by HPLC peak area. Yield of 6 by
HPLC assay
It was clarified that the bulky phosphine ligands were suitable
for this type of cyclization, which was already mentioned by
Cacch9. Then screening for various solvents was carried out,
and aprotic solvents such as acetonitrile were effective (Table
The influence of formic acid for this reaction was explained
from the next supposed mechanism (Scheme 4). The
byproduct 17 was produced when the intermediate A reacted
with hydride source before the reaction passed from A to B. If a
lot of formic acid existed in the reaction mixture, the negative
pass from A to C would occur.
Actually, reducing formic acid tends to increase the yield of 6
(Table 5). The highest yield was achieved using 1.1 equiv of
formic acid. The yield of 6 could be greatly improved in
comparison to that from our initial study.
Next, four other factors in addition to formic acid were
optimized. The amount of piperidine was increased to 7.0 equiv
because a higher level was appropriate for the selectivity. On
the other hand, the amount of solvent could be fixed freely
within the examined design space because its effect was
marginal. The remaining two factors, phosphine ligand and
temperature, were especially important in the palladium-
catalyzed reaction. Generally, the ratio of phosphine ligand to
palladium often influenced the reactivity of catalytic reaction.
Temperature was the most critical factor in this reaction as
already mentioned. The best condition for phosphine ligand
and temperature was examined using the response surface
model (RSM). Figure 3 shows the contour graph of the
a
Table 2. Screening of solvents
b
product ratio (%)
entry
solvent
5
6
17
18
19
c
1
2
3
4
5
6
7
8
MeCN
toluene
EtOH
EtOAc
DMF
1
50 (47)
20
10
13
15
30
32
36
23
21
10
12
9
3
1
29
29
26
<1
<1
<1
<3
32
23
40
51
53
51
34
1
1
16
12
9
1
DMA
DMI
<1
<1
5
NMP
30
a
All reactions were carried out on a 100 mg scale in 2 mL of solvent at
60 °C with Pd(OAc)2 (0.10 equiv), P(o-tolyl)3 (0.20 equiv), formic
acid (3.0 equiv), and piperidine (6.0 equiv). Product ratios were
b
c
calculated by HPLC peak area. Yield of 6 by HPLC assay
2). Consequently, the combination of P(o-tolyl)3 and DMF
seemed to be suitable taking into account the cost of those
reagents. Though acetonitrile may also be appropriate for this
reaction, a lot of palladium black stuck to a vessel at the end of
the reaction.
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Table 3. Levels of the five factors in the 25‑1 fractional factorial design
factor
low level (−1)
center point (0)
high level (+1)
A: P(o-tolyl)3
B: formic acid
C: piperidine
D: DMF
0.1 equiv
2.0 equiv
5.0 equiv
10 v/w
0.2 equiv
3.0 equiv
6.0 equiv
20 v/w
0.3 equiv
4.0 equiv
7.0 equiv
30 v/w
E: temperature
50 °C
70 °C
90 °C
a
Table 4. Experiment of the 25‑1 fractional factorial design
b
factor
product ratio (%)
c
run
A
B
C
D
E
5
6
17
18
19
selectivity of 6
1
−1
+1
−1
+1
−1
+1
−1
+1
−1
+1
−1
+1
−1
+1
−1
+1
0
−1
−1
+1
+1
−1
−1
+1
+1
−1
−1
+1
+1
−1
−1
+1
+1
0
−1
−1
−1
−1
+1
+1
+1
+1
−1
−1
−1
−1
+1
+1
+1
+1
0
−1
−1
−1
−1
−1
−1
−1
−1
+1
+1
+1
+1
+1
+1
+1
+1
0
+1
−1
−1
+1
−1
+1
+1
−1
−1
+1
+1
−1
+1
−1
−1
+1
0
0
55
16
15
44
11
66
50
15
16
63
45
19
61
18
17
56
49
4
14
29
25
13
11
6
34
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
59
53
30
47
46
71
54
46
48
67
48
38
65
60
42
59
53
2
62
40
0
3
5
4
26
1
5
67
0
6
16
37
2
7
0
8
57
60
0
16
17
16
12
26
5
9
1
10
11
12
13
14
15
16
17
15
37
4
0
42
0
28
0
64
51
0
11
22
19
2
19
10
2
34
a
b
c
All reactions were carried out on a 100 mg scale. Product ratios were calculated by HPLC peak area. Selectivity was calculated by 6/(6 + 17 + 18
+ 19).
Figure 1. Half normal plot. Product ratio of 6 (left graph), selectivity of 6 (right graph).
estimated value about the yield of 6. The maximum value,
which is indicated by the vertex of the contour, was not more
than 80%. It was difficult to achieve a yield higher than 80%.
However, when this result was rethought from a different view,
we could confirm that conditions around the vertex were
robust. Finally we validated the best estimated condition on the
vertex point of the contour model. The resulting experimental
value approximately matched the estimated value, and the
reproducibility for high yield and high selectivity of 6 in this
stereospecific palladium-catalyzed reaction was confirmed
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Figure 2. Interaction graph. Product ratio of 6 (left graph), selectivity of 6 (right graph).
Scheme 4. Reaction mechanism of producing byproducts
The Synthesis of Olopatadine Hydrochloride. The
substitution reaction of the mesylate prepared from 6 by a
dimethylamine was performed to afford 16, and olopatadine
hydrochloride (1) was obtained by hydrolysis of 16 (Scheme
5).10
CONCLUSION
■
We established the new efficient synthetic route of olopatadine
hydrochloride (1). In the Sonogashira reaction, the alkyne
moiety was introduced on iodine of 14 with perfect selectivity.
Then, in the seven-membered cyclization of 5, the 80% yield
was achieved by optimization using DoE studies. From 6,
olopatadine hydrochloride could be prepared via mesylation,
dimethylamination, and hydrochloridation in high yield.
Though this established route was incomplete as a scalable
process this time, it is expected that further optimization will
make this procedure more practical.
EXPERIMENTAL SECTION
■
General Information. All reagents and solvents are
commercially available (Tokyo Kasei Kogyo Co., Ltd., Sigma-
Aldrich Co.) and used without further purification. H NMR
1
spectra were obtained on a JEOL JNM-LA300 spectrometer
(300 MHz). Chemical shifts (δ) are reported in ppm.
Multiplicities are given as: s (singlet), d (doublet), t (triplet),
q (quartet), dd (doublet of doublets), dt (triplet of doublets),
m (multiplet), brs (broad singlet). Proton-decoupled 13C NMR
spectra were obtained on a JEOL JNM-LA300 spectrometer
(75 MHz). Mass spectra was obtained on a Micromass LCT
spectrometer. HPLC analyses were performed on a Hitachi L-
7000 system.
HPLC Analyses. The HPLC data in Tables 1, 2, 4, 5, 6 were
obtained under the following conditions: detector, ultraviolet
absorption photometer (wavelength 254 nm); column, Imtact
CD-003; mobile phase, a mixture of 0.05 mol/L KH2PO4/
CH3CN (10/17); flow rate, 1.0 mL/min; column temperature,
30 °C; tR (min) 19 (1.7), 6 (12.4), 17 (13.4), 18 (19.8), 5
(31.2).
a
Table 5. Optimizing formic acid
b
entry
formic acid (equiv)
yield of 6 (%)
1
2
3
4
5
2.0
1.6
1.2
1.1
1.0
59
62
71
80
72
a
All reactions were carried out on a 100 mg scale in 1 mL of solvent at
90 °C with Pd(OAc)2. (0.10 equiv), P(o-tolyl)3 (0.20 equiv), and
b
piperidine (7.0 equiv). HPLC assay.
(Table 6). Though we did not try this reaction in a large-scale
production, the reaction conditions would be expected scalable
because of a homogeneous reaction. We found the good
reaction conditions of the cyclization using Pd catalyst by DoE
studies, and the yield of the key intermediate 6 was greatly
improved.
Methyl 4-(2-Bromobenzyloxy)phenylacetate (15). To
a solution of methyl 4-hydroxyphenylacetate (2) (5.00 g, 30.1
mmol) in DMF (50 mL) was added 2-bromobenzylbromide
(7.50 g, 1.0 equiv) and K2CO3 (6.28 g, 1.5 equiv) at room
temperature. The mixture was stirred at 25 °C for 4 h, and then
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Figure 3. Response surface model (RSM) of the seven-membered ring cyclization.
a
Table 6. Validation of the estimated value of RSM
b
product ratio (%)
c
d
phosphine ligand (equiv)
temp (°C)
5
6
17
18
19
yield of 6 (%)
selectivity of 6
estimated
0.25
0.25
92
92
2
4
70
69
15
15
4
0
0
79
79
80
79
experimental
3
a
b
A reaction was carried out on a 200 mg scale in 2 mL of solvent at the best conditions of RSM. Product ratios were calculated by HPLC peak area.
HPLC assay. Selectivity was calculated by 6/(6 + 17 + 18 + 19).
c
d
Scheme 5. New synthetic route of olopatadine hydrochloride
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water and EtOAc were added to the mixture. The organic layer
was extracted, washed by water, and concentrated at 50 °C to
give the title compound 15 (10.25 g, quant.) as a pale-yellow
(dd, J = 8.4, 2.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.74 (t, J =
7.5 Hz, 1H), 5.18 (brs, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.69 (s,
3H), 3.53 (s, 2H), 2.68 (dt, J = 7.5, 6.1 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): δ 172.4, 154.6, 145.3, 141.4, 133.6, 132.1,
130.0, 129.1, 127.5, 126.2, 125.7, 124.0, 119.7, 70.5, 62.6, 52.1,
40.1, 33.3; MS ESI (+) m/z 325 [M + H]+.
1
oil: H NMR (CDCl3, 300 MHz) δ 7.58 (dd, J = 7.7, 1.1 Hz,
1H), 7.53 (dd, J = 7.7, 1.3 Hz, 1H), 7.32 (td, J = 7.7, 1.3 Hz,
1H), 7.21 (d, J = 8.8 Hz, 2H), 7.17 (td, J = 7.7, 1.1 Hz, 1H),
6.93 (d, J = 8.8 Hz, 2H), 5.17 (s, 2H), 3.68 (s, 3H), 3.57 (s,
2H); 13C NMR (CDCl3, 75 MHz): δ 172.3, 157.6, 136.3, 132.6,
130.3, 129.2, 128.9, 127.6, 126.7, 122.2, 115.0, 69.5, 52.0, 40.3;
MS ESI (+) m/z 337, 335 [M + H]+.
(Z)-11-[(3-Dimethylamino)propylidene]-6,11-
dihydrobenz[b,e]oxepin-2-acetic Acid Hydrochloride
(1). To methyl (Z)-11-[(3-hydroxy)-propyridene]-6,11-
dihydrobenz[b,e]oxepin-2-acetate (6) (21.0 g, 64.7 mmol) in
pyridine (160 mL) was added methanesulfonyl chloride (28.0
g, 3.8 equiv) gradually at 5 °C. The reaction mixture was heated
to room temperature and stirred for 2 h. The mixture was
quenched with water and then extracted with ethyl acetate. The
organic layer was washed with saturated aqueous NaCl and
concentrated. To a solution of obtained oil in MeOH (400 mL)
was add 50% aqueous dimethylamine (120 mL,18.0 equiv). and
the mixture was stirred under reflux for 3 h. NaOH solution (2
mol/L, 100 mL) was added to the reaction mixture, then the
mixture was stirred under reflux for 2 h. Water and butyl acetate
were added to the reaction mixture, and the aqueous layer was
adjusted to pH 2 with 2 mol/L HCl. The organic layer was
concentrated to afford the title compound 1 (21.4 g, 88.4%).
Methyl 4-(2-Bromobenzyloxy)-3-iodophenylacetate
(14). Iodine (7.28 g, 1.0 equiv) and AgSO4 (8.71 g, 1.0
equiv) were added to methanol (15 mL), and the mixture was
stirred until iodine was dissolved. To the mixture was added a
solution of methyl 4-hydroxyphenylacetate (15) (9.44 g, 28.1
mmol) in methanol (15 mL) at room temperature. The mixture
was stirred at 18 °C for 2 h, then the mixture was filtrated and
washed with EtOAc. The filtrate was concentrated at 50 °C to
form a yellow solid. The solid was slurried in methanol and
corrected by filtration to give the title compound 14 (11.00 g,
86%) as a white colorless crystal; 1H NMR (CDCl3, 300 MHz)
δ 7.78 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.59 (dd, J
= 7.9, 1.1 Hz, 1H), 7.37 (td, J = 7.9, 1.0 Hz, 1H), 7.25−7.21
(m, 2H), 6.83 (d, J = 8.3 Hz, 1H), 5.18 (s, 2H), 3.70 (s, 3H,),
3.55 (s, 2H); 13C NMR (CDCl3, 75 MHz): δ 171.7, 156.1,
140.2, 135.8, 132.6, 132.4, 130.4, 129.1, 128.7, 127.7, 121.5,
112.4, 86.5, 70.3, 52.1, 39.6; MS ESI (−) m/z 461, 459 [M −
H]−.
Methyl 4-(2-Bromobenzyloxy)-3-(4-hydroxybutynyl)-
phenylacetate (5). Under N2 atmosphere, a solution of
methyl 4-(2-bromobenzyloxy)-3-iodophenylacetate (14) (5.0 g,
10.8 mmol), PdCl2(PPh3)2 (381 mg, 0.05 equiv), CuI (103 mg,
0.1 equiv), 3-butyn-1-ol (1.84 mL, 2.0 equiv). and Et3N (6.06
mL, 4.0 equiv) in DMF (50 mL) was stirred at 25 °C for 5 h.
The mixture was quenched with water and then extracted with
ethyl acetate. The organic layer was washed with saturated
aqueous NaCl and filtered to remove Pd residue. Then the
organic layer was concentrated and purified by silica gel column
chromatography (EtOAc/hexane = 1:1) to afford the title
compound 5 (4.34 g, 100%) as an amber oil; 1H NMR (CDCl3,
300 MHz) δ 7.64 (ddJ = 7.7, 1.7 Hz, 1H,), 7.57 (dd, J = 7.7, 1.1
Hz, 1H), 7.34 (td, J = 7.7, 1.1 Hz, 1H), 7.33 (d, J = 2.2 Hz,
1H), 7.18 (td, J = 7.7, 1.7 Hz, 1H), 7.14 (dd, J = 8.6, 2.2 Hz,
1H), 6.85 (d, J = 8.6 Hz, 1H), 5.18 (s, 2H), 3.80 (t, J = 6.1 Hz,
2H), 3.69 (s, 3H), 3.53 (s, 2H), 2.73 (t, J = 6.1 Hz, 2H); 13C
NMR (CDCl3, 75 MHz): δ 171.9, 158.1, 136.1, 134.1, 132.5,
130.1, 129.2, 128.6, 127.6, 126.6, 121.8, 113.4, 112.7, 91.0, 78.7,
70.0, 61.1, 52.1, 40.0, 24.2; MS ESI (+) m/z 405, 403 [M +
H]+.
AUTHOR INFORMATION
Corresponding Author
koichiro.nishimura@kyowa-kirin.co.jp
■
ACKNOWLEDGMENTS
■
We thank Dr. Toru Sugaya for giving us this attractive research
subject, and Dr. Hitoshi Arai for giving us helpful advice on this
manuscript.
REFERENCES
■
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Methyl (Z)-11-[(3-Hydroxy)propylidene]-6,11-
dihydrobenz[b,e]oxepin-2-acetate (6). Under N2 atmos-
phere, a solution of methyl 4-(2-bromobenzyloxy)-3-(4-
hydroxybutynyl)-phenylacetate (5) (200 mg, 0.496 mmol),
Pd(OAc)2 (11.1 mg, 0.1 equiv), tri-o-tolylphosphine (37.7 mg,
0.25 equiv), piperidine (344 μL, 7.0 equiv), and formic acid
(20.5 μL, 1.1 equiv) in DMF (2.0 mL) was stirred at 92 °C for
3 h. The mixture was quenched with water and then extracted
with ethyl acetate. The organic layer was washed with saturated
aqueous NaCl. The organic layer was concentrated, and the
obtained oil was purified by silica gel column chromatography
(ethyl acetate/hexane = 1:2) to afford the title compound 6
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1
(114 mg, 71%) as a white colorless crystal; H NMR (CDCl3,
300 MHz) δ 7.34−7.23 (m, 4H), 7.17 (d, J = 2.2 Hz, 1H), 7.04
231
dx.doi.org/10.1021/op200312m | Org. ProcessRes. Dev. 2012, 16, 225−231