Intramolecular palladium-catalyzed cyclization of alkenylboronate prepared from hydroboration of terminal acetylene and its application to the stereoselective synthesis of (E)-doxepin

Article abstract of DOI:10.1016/j.tet.2007.09.085

The hydroboration of 2-[(2-ethynylphenyl)methoxy]-1-iodobenzene with bis(pinacolato)diboron in the presence of palladium catalyst and followed by consecutive oxidative addition, cis-cyclocarbopalladation, and cis-β-elimination could give highly stereosele

Full text of DOI:10.1016/j.tet.2007.09.085

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Tetrahedron 64 (2008) 248e254
www.elsevier.com/locate/tet
Intramolecular palladium-catalyzed cyclization of alkenylboronate
prepared from hydroboration of terminal acetylene and its application
to the stereoselective synthesis of (E)-doxepin
*
Cuihua Xue, Shi-Hao Kung, Jian-Zhung Wu, Fen-Tair Luo
Institute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan, ROC
Received 26 July 2007; received in revised form 12 September 2007; accepted 14 September 2007
Available online 22 October 2007
Abstract
The hydroboration of 2-[(2-ethynylphenyl)methoxy]-1-iodobenzene with bis(pinacolato)diboron in the presence of palladium catalyst and
followed by consecutive oxidative addition, cis-cyclocarbopalladation, and cis-b-elimination could give highly stereoselective exocyclic alke-
nylboronate ester. The following cross-coupling of the exocyclic alkenylboronate ester with 2-bromo-N,N-dimethylacetamide in the presence
of palladium catalyst and followed by LAH reduction gives (E)-doxepin in fair yields.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the Pd(0) catalyst and give stereodefined exocyclic carbone
carbon double bond.4 With this in mind, we envisioned that
a substrate of 2-[(2-ethynylphenyl)methoxy]-1-iodobenzene
1 would undergo oxidative addition and intramolecular cyclo-
carbopalladation,4,5 then the incipient exocyclic alkenylpalla-
dium intermediate may undergo cross-coupling reaction with
2-bromo-N,N-dimethylacetamide, and if successful this metho-
dology might allow us stereoselective access to the domino-
type synthesis of (Z)-b,g-unsaturated amide. However, we
failed to get any detectable amount of the desired products un-
der various reaction conditions; instead, a mixture of uniden-
tified products was obtained as judged by their crude 1H
NMR spectral analysis. We then turned our attention to the
trapping of the expected alkenylpalladium intermediate with
bis(pinacolato)diboron as similarly reported by Miyaura.6 To
the best of our knowledge, the challenging seven-membered
ring formation through the palladium-catalyzed cyclocarbo-
palladation is still very rare.5a,b,d,7 Herein, we report the novel
domino-type reaction of hydroboration and the following
intramolecular cyclic carbopalladation by using aryl iodide
with terminal acetylene 1 and bis(pinacolato)diboron in the
presence of palladium catalyst and the identification of
the corresponding stereoselective alkenylboronates by their
Palladium-catalyzed reactions have steadily increased in
importance in the last decade. They are among the most ver-
satile processes for forming carbonecarbon bonds. A vast
range of such methods are known, which usually feature
a high tolerance of many functional groups as well as a high
regio- and stereoselectivities.1 In order to improve the effi-
ciency in increasing complexity and selectivity in product for-
mation of such reactions, many papers have reported the
design of multiple transformations in consecutive or cascade
or domino types of reactions in a one pot without isolating
any of the intermediates.1,2 Thus, the domino processes are be-
coming more popular nowadays. Recently, we have reported
a facile Suzuki-type cross-coupling reaction of alkenylborane
with 2-bromo-N,N-dimethylacetamide as a convenient way for
the synthesis of (E)-b,g-unsaturated amides.3 We also reported
previously that the alkenylpalladium(II) intermediate gener-
ated by intramolecular cyclic carbopalladation of alkynes
can be further cross-coupled with trapping reagents to recycle
* Corresponding author.
E-mail address: luoft@chem.sinica.edu.tw (F.-T. Luo).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.085

C. Xue et al. / Tetrahedron 64 (2008) 248e254
249
Table 1
Effects of Pd catalysts and ligands in the formation of 2 from 1a
HRMS, 2D-COSY, NOESY, HMQC, and HMBC spectral
analyses, as well as the application to the stereoselective syn-
thesis of (E)-doxepin8 as an antidepressant drug.9
Entry
Pd catalyst
Ligand
Isolated yield
of 2b (%)
1
PdCl2(dppf)
d
d
d
d
d
12c
0
2
2. Results and discussion
3
Palladacycled
Pd(OAc)2
10
<5
<5
<5
<5
51
42
16
29
23
32
24
37
41
4
The results of the consecutive Pd-catalyzed hydroboration
and intramolecular cyclic carbopalladation of 1 by using bis-
(pinacolato)diboron are summarized in Scheme 1 and Table 1.
Initially, in order to test the trapping ability of bis(pinacolato)di-
boron for the attempted cyclized exocyclic alkenylpalladium in-
termediate obtained from the oxidative addition and the
following intramolecular carbopalladation of 1, prepared from
2-iodobenzyl alcohol via Sonogashira reaction [trimethylsilyl-
acetylene, CuI, PdCl2(PPh3)2], bromination (PBr3), and Wil-
liamson ether synthesis (2-iodophenol, potassium carbonate)10
(Scheme 1), compound 1 was treated with bis(pinacolato)di-
boron (1.1 equiv) in the presence of PdCl2(dppf) (5 mol %)
and potassium acetate (3 equiv) in DMSO at 80 ꢀC for 4 h.6
The reaction temperature was finally optimized at 70 ꢀC. Ei-
ther lower or higher than 70 ꢀC will give lower yields of the
isolated products. Interestingly, in contrast to our original
prediction of obtaining the exocyclic (Z)-alkenylboronate
ester, we found that only exocyclic (E)-alkenylboronate ester
2 in 12% yield along with 25% yield of uncyclized hydrobora-
tion product 3 and unidentified polymerized products were
obtained (entry 1, Table 1). The yield of uncyclized hydrobora-
tion product 3 can reach up to 70% if the reaction is quenched
after half an hour. This result indicated that 3 was the reaction
intermediate for the formation of 2. Attempts to use K3PO4,
5
Pd(PPh3)4
PdCl2(PPh3)2
Pd(dba)2
d
d
d
6
7
8
PdCl2(dppf)
Palladacycle
Pd(OAc)2
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
PPh3
P(o-tol)3
PCy3
9
10
11
12
13
14
15
16
a
Pd(PPh3)4
PdCl2(PPh3)2
Pd(dba)2
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
The reaction was run with KOAc and bis(pinacolato)diboron in DMSO at
70 ꢀC.
b
The major byproducts were unidentified polymers.
Compound 3 was isolated in 25% yield.
c
OAc
Pd
d
Palladacycle¼
, R¼o-tolyl.
)
2
R
R
(Tables 2 and 3). The stereochemistry of the hydroboration of
the terminal acetylene to form the carbonecarbon double
bond in 3 was proved by its 1H NMR spectral analysis (the cou-
pling constant between the two vinylic protons H-14 and H-15 is
18 Hz). It is also interesting to observe that there are cross-peaks
between H-12 and H-15, and between H-7 and H-5, H-9, H-14,
H-15, H-17 in 2D NOESY spectrum of 3. Calculations from mo-
lecular modeling (Spartan’04) showed that the distances be-
tween H-7 and H-5, H-9, H-14, H-15, and H-17 in 3 are
i
K2CO3, Ba(OH)2, NEt3, PrNEt2, CsF,11 KF,11 or Cs2CO3 as
the base did not provide any improvement in the yields. Adding
either cuprous halides or Cu2O12 did not improve the yields.
No reaction was observed and the starting material 1 was
isolated almost completely when the reaction was run in the
absence of palladium catalyst (entry 2, Table 1). The structures
˚
˚
˚
˚
˚
2.246 A, 3.440 A, 2.789 A, 2.938 A, and 2.715 A, respectively
(Molecular Mechanics//MMFF). The molecular ion of 3 in the
EI-GCeMS spectrum can be observed at 25 eV. Electron volt-
ages at 70, 30, and 20 or lower than 20 do not show a detectable
amount of molecular ion in the EI-GCeMS spectrum. The ste-
reochemistry of the exocyclic double bond in 2 was proved by its
2D NOESY NMR spectral analysis (there is a cross-peak
1
of 2 and 3 were confirmed according to their H, 13C NMR,
as well as their 2D-COSY, NOESY, HMQC, HMBC,
NMR, HRMS, and EI-GCeMS (at 25 eV) spectral analysis
OH
7
5
9
8
6
O
I
Br
O
I
10
11
4
3
PdCl2(dppf) cat.
Pd(0) cat.
I
K2CO3, acetone
reflux, 12 h
65%
O
O
O
14
1
13
B
B
12
2
O
15
P(t-Bu)3
KOAc, DMSO
70 °C
SiMe3
O
B
H
O
1
16
17
3
5
9
7
Me
N
6
8
O
4
10
11
7
5
9
8
O
6
O
Br
Me
4
10
11
18
3
14
13
1
LAH
12
O
2
14
3
15
13
1
O
O
12
2
Pd(dba)2
PCy3
K3PO4
H
B
O 16
17
15
H
H
N
N
16
17
THF, 70 °C
2 (51%)
(E)-Doxepin (42%)
Scheme 1. Synthesis of (E )-alkenylboronates and (E )-doxepin and the corresponding number for the carbon atoms in 2, 3, and (E )-doxepin.

250
C. Xue et al. / Tetrahedron 64 (2008) 248e254
Table 2
1H and 13C NMR spectral data, HMBC, NOESY, and COSY correlations for 3
Position
H (ppm)
C (ppm)
HMBC correlation (H/C)
NOESY (H/H)
COSY (H/H)
1
d
86.86
139.51
122.87
129.35
113.13
134.01
68.77
2
7.79 (d)
6.73 (t)
7.28 (t)
6.90 (d)
d
C-4, C-13
C-5, C-1
C-2, C-13
C-3, C-1
H-3
3
H-4
H-3, H-5
H-7, H-4
H-2, H-4
H-3, H-5
H-4
4
5
6
7
5.28 (s)
d
C-9, C-6, C-8, C-13
C-10, C-6
H-5, H-9, H-14, H-15, H-17
8
136.04
127.89
128.08
128.76
126.28
157.34
145.64
120.00
83.41
9
7.61 (d)
7.3e7.4 (m)
7.3e7.4 (m)
7.61 (d)
d
H-7, H-10
H-9
H-12
H-10
10
11
12
13
14
15
16
17
H-9, H-11
H-10, H-12
H-11
C-11
H-11, H-15
7.65 (d)
6.13 (d)
d
C-12, C-8
C-14, C-8
H-7
H-12
H-15
H-14
1.31 (s)
24.80
C-16
between H-2 and H-15). It is also interesting to observe that
there are cross-peaks between H-7 and H-5, H-9, H-15, H-17
in the 2D NOESY spectrum of 2. Calculations from molecular
modeling (Spartan’04) showed that the distances between H-7
reported in the literature.11,13 Changing the palladium catalyst
from PdCl2(dppf), to palladacycle, Pd(OAc)2, Pd(PPh3)4,
PdCl2(PPh3)2, or Pd(dba)2, while used potassium acetate as
the base and DMSO as the solvent did not greatly improve
the yields (entries 3e7, Table 1). The major byproducts
were the unidentified polymers. However, we found that the
addition of the sterically hindered chelating phosphine ligand,
P(t-Bu)3, furnished good yield in the above reactions to afford
up to 51% yield of the desired product by using PdCl2(dppf) as
the catalyst (entries 8e13, Table 1). Thus, PdCl2(dppf) seems
to be superior to other palladium catalysts in the above reac-
tions. Furthermore, using other ligands such as PPh3, P(o-tol)3,
or PCy3 produced somewhat lower yields than when using
PdCl2(dppf) as the catalyst (entries 14e16, Table 1). It was
noted that attempts to run the hydroboration by the use of
pinacolboronate and Rh(PPh3)3Cl, Rh(CO)CPPh3)2Cl, or
NiCpPPh3Cl as the catalyst as described by Srebnik14 to run
the hydroboration of 1 were failed. The hydroboration for
˚
˚
and H-5, H-9, H-15, and H-17 in 2 are 4.270 A, 2.413 A,
˚
˚
3.800 A, and 3.263 A, respectively (Molecular Mechanics//
MMFF). This result showed that the highly stereoselective
formation of 2 plausibly took place through the oxidative addi-
tion, cis-cyclocarbopalladation, and cis-b-elimination of 3in the
presence of palladium catalyst (Scheme 2). These results
indicated that the coupling product initially went through the
hydroboration of terminal acetylene and followed by the
intramolecular cyclocarbopalladation. In other words, under
these reaction conditions, the oxidative addition of 1 is slower
than the hydroboration of 1 in the presence of palladium
catalyst.
We then tried to study the above reaction by using different
palladium catalysts or in the presence of ligands as commonly
Table 3
1H and 13C NMR spectral data, HMBC, NOESY, and COSY correlations for 2
Position
H (ppm)
C (ppm)
HMBC correlation (H/C)
NOESY (H/H)
COSY (H/H)
1
d
124.18
132.62
120.05
128.88
120.45
154.80
70.41
2
7.01 (d)
6.77 (t)
7.00 (t)
6.79 (d)
d
C-15, C-4
C-5, C-1
C-2
H-3, H-15
H-4, H-2
H-3
3
H-2, H-4
H-3, H-5
H-4
4
5
C-3
6
7
5.35 (s)
d
C-9, C-6, C-13
C-11, C-13
H-5, H-9, H-15, H-17
H-7
8
141.61
130.74
127.09
128.32
129.25
134.22
181.51
145.39
83.95
9
7.44 (d)
7.22 (t)
7.30 (t)
7.28 (d)
d
H-10
10
11
12
13
14
15
16
17
H-9, H-11
H-10, H-12
H-11
d
7.50 (s)
d
1.33 (s)
C-2, C-6, C-13
C-16
H-2, H-17
24.80
H-7, H-12, H-15

C. Xue et al. / Tetrahedron 64 (2008) 248e254
251
Pd(0) cat.
2
3
Pd(0) oxidative addition
O
cis-β-elimination
O
H
PdI
O
cis-carbopalladation
O
B
IPd
B
O
H
O
Scheme 2. The plausible reaction pathway for the formation of 2 from 3.
1
ortho-substituted phenylacetylene as 1 by using bis(pinacola-
to)diboron and copper reagent (CuCl/KOAc/PBu3 or CuCl/
KOAc/LiCl) reported by Miyaura was also failed to give any
detectable amount of the desired product.15 Thus, as to our
best knowledge, this is the first example to the success of
the hydroboration for ortho-substituted phenylacetylene by
using bis(pinacolato)diboron in the presence of palladium
catalyst.
temperature they became two doublets in the H NMR spec-
trum at 0 ꢀC and became well separated at 223 K or lower
temperature (Fig. 1). It is interesting to note that while (E)-
doxepin shows ring flexibility in its seven-membered ring at
room temperature, compound 2 with a seven-membered ring
in the structure and with two protons at C-7 appearing at
d 5.35 ppm as a singlet did not show ring flexibility at room
temperature. The detailed mechanism for the hydroboration
of the terminal acetylene in 1 by using bis(pinacolato)diboron
in the presence of palladium catalyst and tri(tert-butyl)phos-
phine in DMSO to give 3 is still under investigation in our
laboratory.
The synthesis of (E)-doxepin is shown in Scheme 1. Thus,
treatment of 2 with 2-bromo-N,N-dimethylacetamide16 in the
presence of a catalytic amount of tricyclohexylphosphine,
Pd(dba)2, and K3PO4 in THF at 70 ꢀC could give b,g-unsatu-
rated amide.3 The b,g-unsaturated amide seemed to be very
unstable at room temperature. The following LAH reduction
of the b,g-unsaturated amide in THF could give (E)-doxepin
in 42% total yield. The structure of (E)-doxepin was proved
3. Conclusion
In conclusion, we have succeeded in the synthesis of (E )-
doxepin via the hydroboration of 1 with bis(pinacolato)di-
boron in the presence of palladium catalyst. The following
consecutive oxidative addition, cis-cyclocarbopalladation,
and cis-b-elimination in the presence of palladium catalyst
could give highly stereoselective exocyclic alkenylboronate
1
by its GCeMS, H, and 13C NMR, as well as by its low tem-
1
perature H NMR (Fig. 1) and 2D NOESY spectral analysis
(Table 4). Since the signals for two protons at C-7 in (E)-dox-
epin were broad singlets at d 4.72 ppm and 5.50 ppm by the
ring flexibility17 of the tricyclic compound at room
Figure 1. The 1H NMR spectra of (E )-doxepin at various temperatures.

252
C. Xue et al. / Tetrahedron 64 (2008) 248e254
Table 4
1H and 13C NMR spectral data, HMBC, NOESY, and COSY correlations for (E )-doxepin
Position
H (ppm)
C (ppm)
HMBC correlation (H/C)
NOESY (H/H)
COSY (H/H)
1
d
127.20
130.27
121.23
129.39
119.39
155.29
70.24
2
7.20 (d)
6.85 (t)
7.10 (t)
6.73 (d)
d
C-4, C-6
C-1
C-2, C-6
H-3, H-15
H-3
3
H-2, H-4, H-5
H-2, H-3, H-5
H-3, H-4
H-2, H-4
H-3, H-5
H-4
4
5
6
7
4.72 (br s), 5.50 (br s)
d
8
141.26
128.85
128.18
128.46
127.90
134.43
141.04
128.30
26.96
9
7.33 (t)
7.28 (t)
7.31 (d)
7.24 (d)
d
C-8, C-11
C-11
H-10
10
11
12
13
14
15
16
17
18
H-9, H-11
H-10, H-12
H-11
H-16, H-17
d
5.97 (t)
2.40 (m)
2.50 (m)
C-1, C-14
H-2, H-16, H-17
H-12, H-15, H-17, H-18
H-12, H-15, H-18
H-16, H-17
H-16
H-15, H-17
H-16
58.82
44.75
ester 2. The following sequential cross-coupling of 2 with 2-
bromo-N,N-dimethylacetamide in the presence of palladium
catalyst and the LAH reduction of the b,g-unsaturated amide
intermediate could give (E)-doxepin in fair yields.
and benzene (15 mL) under nitrogen atmosphere was added
dropwise trimethylsilylacetylene (3.0 mL, 22 mmol) at room
temperature. The color of the solution would turn from pale
yellow to dark brown when trimethylsilylacetylene was added
in excess. The mixture was stirred for another half an hour at
room temperature. The volatile material was removed by rota-
vap and to the residue was added water (25 mL). The aqueous
layer was extracted with ethyl acetate (30 mLꢁ3) and the
combined organic layer was dried over MgSO4. After filtration
and removal of the solvent under reduced pressure, the residue
was purified by column chromatography (hexane/ethyl
acetate¼5:1) to afford 2-[(trimethylsilyl)ethynyl]benzyl alco-
hol (3.88 g, 19 mmol) as an brown oil in 95% yield: 1H
NMR (CDCl3, TMS) d 0.27 (s, 9H), 4.82 (s, 2H), 7.24 (t,
J¼7 Hz, 1H), 7.33 (t, J¼7 Hz, 1H), 7.41 (d, J¼7 Hz, 1H),
7.46 (d, J¼7 Hz, 1H) ppm.
4. Experimental section
4.1. General experimental
All reactions were carried out under an atmosphere of nitro-
gen. Tetrahydrofuran (THF) was treated with dried NaH first
and then distilled over sodium/benzophenone ketyl whenever
needed. All organic extracts were dried over anhydrous mag-
nesium sulfate. TLC was done on aluminum sheets with
precoated silica gel 60 F254 (40ꢁ80 mm) from Merck.
Purification by column chromatography was carried out with
neutral silica gel 60 (70e230 mesh ASTM). The purity of
4.1.2. 2-[(Trimethylsilyl)ethynyl]benzyl bromide18d
1
each compound was judged to be >95% by H NMR or 13C
To a solution of 2-[(trimethylsilyl)ethynyl]benzyl alcohol
(1.84 g, 9 mmol), pyridine (1.0 mL, 12.4 mmol), and chloro-
form (10 mL) under nitrogen atmosphere was added dropwise
PBr3 (1.0 mL, 10 mmol) at 0 ꢀC and the resulting mixture was
warmed to room temperature with stirring for 12 h. The vola-
tile material was removed by rotavap and to the residue was
added water (15 mL). The aqueous layer was extracted with
ethyl acetate (20 mLꢁ3) and the combined organic layer
was dried over MgSO4. After filtration and removal of the sol-
vent under reduced pressure, the residue was purified by col-
umn chromatography (hexane/ethyl acetate¼20:1) to afford
the title compound (1.68 g, 6.3 mmol) as an orange oil in
NMR spectral analyses. Melting points were taken on
a MEL-TEMP capillary tube apparatus and are uncorrected.
1H NMR and 13C NMR spectra were recorded in CDCl3 solu-
tion on 300 MHz, 400 MHz, or 500 MHz instrument using
TMS (0 ppm) and CDCl3 (77.0 ppm) as internal standards.
HRMS spectra were collected on an Autospec orthogonal ac-
celeration time-of-flight mass spectrometer with a resolution
of 6000 (5% valley definition), and fitted with a magnet bypass
flight tube. MALDI-MS spectra were collected on spectrome-
ter equipped with a nitrogen laser (337 nm) and operated in the
delayed extraction reflector mode. EIMS spectra were deter-
mined on a Shimadzu QP-1000 spectrometer or Fisons
MD800 GC/MS, Focus GC/DSQ, or VG 70-250S
spectrometer.
1
70% yield: H NMR (CDCl3, TMS) d 0.29 (s, 9H), 4.66 (s,
2H), 7.29 (dt, J¼7.5, 1.5 Hz, 1H), 7.34 (dt, J¼7.5, 1.5 Hz,
1H), 7.45 (dd, J¼7.5, 1.5 Hz, 1H), 7.51 (dd, J¼7.5, 1.5 Hz,
1H) ppm; 13C NMR (CDCl3, TMS) d ꢂ0.17, 31.75, 100.71,
101.90, 123.01, 128.30, 128.94, 129.58, 132.62, 139.66 ppm;
MS m/z 268, 266 (Mþ), 251, 187, 171, 129; HRMS calcd
for C12H15BrSi 266.0126, found 266.0131.
4.1.1. 2-[(Trimethylsilyl)ethynyl]benzyl alcohol18
To a solution of 2-iodobenzyl alcohol (4.68 g, 20 mmol),
PdCl2(PPh3)2 (0.42 g, 0.6 mmol), CuI (0.11 g, 0.6 mmol),

C. Xue et al. / Tetrahedron 64 (2008) 248e254
253
4.1.3. 2-{[2-(3,3-Dimethyl-3-silabut-1-ynyl)-
phenyl]methoxy}-1-iodobenzene
128.76, 129.35, 134.01, 136.04, 139.51, 145.64, 157.13 ppm;
EI-GCeMS (25 eV) m/z 462 (Mþ), 461, 447, 401, 327,
243, 207; HRMS calcd for C21H23O3BI 461.0785, found
461.0781.
1H NMR (CDCl3, TMS) d 0.25 (s, 9H), 5.29 (s, 2H), 6.67
(t, J¼7.5 Hz, 1H), 6.83 (d, J¼8 Hz, 1H), 7.22 (t, J¼8 Hz, 1H),
7.25 (t, J¼8 Hz, 1H), 7.34 (t, J¼7.5 Hz, 1H), 7.47 (d,
J¼7.5 Hz, 1H), 7.67 (d, J¼7.5 Hz, 1H), 7.77 (d, J¼7.5 Hz,
1H) ppm; 13C NMR (CDCl3, TMS) d 0.22, 69.08, 86.83,
100.37, 102.35, 112.61, 121.11, 122.95, 127.19, 127.60,
129.16, 129.65, 132.27, 138.85, 139.73, 157.28 ppm; MS
m/z 406 (Mþ), 264, 249, 219, 187, 159; HRMS calcd for
C18H19OISi 406.0250, found 406.0248.
4.1.6. 2-(6H-Dibenzo[c,f]oxepan-11-ylidenemethyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (2)
The procedure was similar to that for the preparation of 3
except stirring the reaction for another 3 h after dropwise add-
ing all the chemicals at 70 ꢀC. The above reaction mixture was
quenched by dropwise adding water at 0 ꢀC and followed by
adding ethyl acetate. The organic layer was separated, drying
over magnesium sulfate, filtrated, and concentrated at lower
pressure. The residue was purified by column chromatography
(hexane/ethyl acetate¼30:1) to afford the title compound
(0.34 g, 1.0 mmol) as a white solid in 51% yield: mp 43e
45 ꢀC. 1H NMR (CDCl3, TMS) d 1.33 (s, 12H), 5.35 (s,
2H), 6.77 (t, J¼7 Hz, 1H), 6.79 (d, J¼7 Hz, 1H), 7.00 (t,
J¼7 Hz, 1H), 7.01 (d, J¼7 Hz, 1H), 7.22 (t, J¼7 Hz, 1H),
7.28 (d, J¼7 Hz, 1H), 7.30 (t, J¼7 Hz, 1H), 7.44 (d,
J¼7 Hz, 1H), 7.50 (s, 1H) ppm; 13C NMR (CDCl3, TMS)
d 24.80, 70.41, 83.95, 120.05, 120.45, 124.18, 127.09,
128.32, 128.88, 129.25, 130.74, 132.62, 134.22, 141.61,
145.39, 154.80, 181.51 ppm; EI-GCeMS (25 eV) m/z 334
(Mþ), 234, 233, 215; HRMS calcd for C21H23O3B 334.1740,
found 334.1742.
4.1.4. 2-[(2-Ethynylphenyl)methoxy]-1-iodobenzene (1)
To a solution of 2-iodophenol (1.10 g, 5 mmol), K2CO3
(0.81 g, 5.9 mmol) in acetone (10 mL) under nitrogen atmo-
sphere was added dropwise a solution of 2-[(trimethylsilyl)-
ethynyl]benzyl bromide18 (1.20 g, 4.5 mmol) in 5 mL of
acetone at room temperature and the resulting mixture was re-
fluxed with stirring for another 12 h. The volatile material was
removed by rotavap and the residue was recrystallized via
methanol to afford the title compound (1.09 g, 3.3 mmol) as
1
a white solid in 65% yield: mp 58e60 ꢀC. H NMR (CDCl3,
TMS) d 3.39 (s, 1H), 5.36 (s, 2H), 6.74 (t, J¼7 Hz, 1H),
6.90 (d, J¼7 Hz, 1H), 7.30 (t, J¼7 Hz, 2H), 7.43 (t, J¼7 Hz,
1H), 7.54 (d, J¼7 Hz, 1H), 7.80 (d, J¼7 Hz, 1H), 7.83 (d,
J¼7 Hz, 1H) ppm; 13C NMR (CDCl3, TMS) d 68.75, 80.79,
82.66, 86.60, 112.64, 119.60, 122.83, 126.94, 127.39,
129.27, 129.44, 132.53, 138.90, 139.52, 156.98 ppm; MS
m/z 334 (Mþ), 207, 115; HRMS calcd for C15H11OI 333.9855,
found 333.9853. Anal. Calcd for C15H11OI: C, 53.92; H,
3.32. Found: C, 53.85; H, 3.37.
4.1.7. (E)-Doxepin
To a mixture of Pd(dba)2 (29 mg, 0.05 mmol), PCy3
(28 mg, 0.1 mmol), K3PO4 (1.28 g, 6 mmol) in 10 mL of dry
THF was added 2-bromo-N,N-dimethylacetamide16 (0.25 g,
1.5 mmol) at 70 ꢀC. After stirring for 20 min, the alkenylbor-
onate 2 (0.33 g, 1 mmol) in 5 mL of THF was added and the
mixture was stirred for another 16 h at 70 ꢀC. The mixture
was quenched with water, extracted with EtOAc, and purified
by flash column chromatography (hexane/EtOAc¼2:1). After
removing the volatile solvents and without further purification
of the residue, the crude amide (0.23 g, 0.78 mmol), LiAlH4
(0.11 g, 3 mmol), and THF (10 mL) were stirred for 48 h at
room temperature. The mixture was treated with AcOEt
(1 mL) and 10% NaOH (2 mL) and then extracted with ether
(10 mLꢁ3). The extraction layers were combined and dried
over MgSO4 and concentrated to give 0.12 g (42%) of (E)-
4.1.5. 2-({2-[(1E)-2-(4,4,5,5-Tetramethyl(1,3,2-dioxa-
borolan-2-yl))vinyl]phenyl}methoxy)-1-iodobenzene (3)
To a pre-heated solution of bis(pinacolato)diboron (1.02 g,
4 mmol) and potassium acetate (0.39 g, 5 mmol) in DMSO
(20 mL) under nitrogen atmosphere in 100 mL of two-necked
round-bottomed flask at 70 ꢀC was dropwise added a solution
of PdCl2(dppf) (dichloro[1,10-bis(diphenylphosphino)ferroce-
ne]palladium(II)) (22 mg, 0.03 mmol) and P(t-Bu)3 (12 mg,
0.06 mmol) in 10 mL of DMSO and followed by the addition
of a solution of 2-[(2-ethynylphenyl)methoxy]-1-iodobenzene
1 (0.67 g, 2 mmol) in 7 mL of DMSO and keep stirring for an-
other half an hour at 70 ꢀC. The above reaction mixture was
dropwise added into a stirring solution of ethyl acetate
(100 mL) and water (100 mL) at 0 ꢀC. After stirring for an-
other 10 min, the organic layer was separated, drying over
magnesium sulfate, filtrated, and concentrated at lower pres-
sure. The residue was purified by column chromatography
(hexane/ethyl acetate¼50:1) to afford the title compound
(0.65 g, 1.4 mmol) as a pale yellow solid in 70% yield: mp
1
doxepin as a colorless oil: H NMR (CDCl3, TMS) d 2.26
(s, 6H), 2.35e2.45 (m, 2H), 2.45e2.55 (m, 2H), 4.72 (br s,
1H), 5.50 (br s, 1H), 5.97 (t, J¼7 Hz, 1H), 6.73 (d, J¼7 Hz,
1H), 6.85 (t, J¼7 Hz, 1H), 7.10 (t, J¼7 Hz, 1H), 7.20 (d,
J¼7 Hz, 1H), 7.24 (d, J¼7 Hz, 1H), 7.28 (t, J¼7 Hz, 1H),
7.31 (t, J¼7 Hz, 1H), 7.33 (d, J¼7 Hz, 1H) ppm; 13C NMR
(CDCl3, TMS) d 26.96, 44.75 (2C0s), 58.82, 70.24, 119.39,
121.23, 127.20, 127.90, 128.18, 128.30, 128.46, 128.85,
129.39, 130.27, 134.43, 141.04, 141.26, 155.29 ppm; EI-
GCeMS m/z 279 (Mþ), 277, 219, 202, 189, 178, 165, 152,
139, 128, 115, 58; FAB m/z 280 (Mþþ1); HRMS calcd for
C19H22ON 280.1701, found 280.1697.
1
47e49 ꢀC. H NMR (CDCl3, TMS) d 1.31 (s, 12H), 5.28 (s,
2H), 6.13 (d, J¼18 Hz, 1H), 6.73 (t, J¼8 Hz, 1H), 6.90 (d,
J¼8 Hz, 1H), 7.28 (t, J¼8 Hz, 1H), 7.30e7.36 (m, 2H), 7.61
(d, J¼8 Hz, 2H), 7.65 (d, J¼18 Hz, 1H), 7.79 (d, J¼8 Hz,
1H) ppm; 13C NMR (CDCl3, TMS) d 24.80, 68.77, 83.41,
86.86, 113.13, 120.00, 122.87, 126.28, 127.89, 128.08,

254
C. Xue et al. / Tetrahedron 64 (2008) 248e254
Chem.dEur. J. 2002, 8, 401; (g) Salem, B.; Klotz, P.; Suffert, J. Org.
Lett. 2003, 5, 845.
Acknowledgements
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The authors thank the National Science Council of ROC and
Academia Sinica for their kind financial support. Thanks are
given to Dr. Suching Lin of the NMR instrument center and
Ms. Ping-Yu Lin of the MS instrument center in our institute
for assistance in obtaining 1D and 2D NMR and MS spectra.
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10. 2-{[2-(3,3-Dimethyl-3-silabut-1-ynyl)phenyl]methoxy}-1-iodobenzene
with trimethylsilyl group attached at the acetylene group was isolated in
24% yield.
Supplementary data
11. Littke, A. F.; Dai, C.; Fu, G. J. Am. Chem. Soc. 2000, 122, 4020.
12. Liu, X.; Deng, M. Chem. Commun. 2002, 622.
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2007.09.085.
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