Synthesis of 6,7-dihydro-5H-dibenzo[c,e]azepines and biaryls by palladium-catalyzed Ullmann reaction

Article abstract of DOI:10.1016/j.tet.2009.02.040

A novel palladium-catalyzed Ullmann protocol is described for the synthesis of 6,7-dihydro-5H-dibenzo[c,e]azepines and biaryls. In the presence of Pd(OAc)₂ and KOAc, intramolecular or intermolecular Ullmann coupling of aryl halides proceeds efficiently under ligand-free and aerobic conditions to afford the corresponding 6,7-dihydro-5H-dibenzo[c,e]azepines and biaryls in moderate to excellent yields.

Full text of DOI:10.1016/j.tet.2009.02.040

Tetrahedron 65 (2009) 3409–3416
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 6,7-dihydro-5H-dibenzo[c,e]azepines and biaryls by palladium-
catalyzed Ullmann reaction
,b,
Ming Yu a, Ri-Yuan Tang a, Jin-Heng Li a
*
a College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325035, China
b Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal University, Changsha 410081, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel palladium-catalyzed Ullmann protocol is described for the synthesis of 6,7-dihydro-5H-di-
benzo[c,e]azepines and biaryls. In the presence of Pd(OAc)2 and KOAc, intramolecular or intermolecular
Ullmann coupling of aryl halides proceeds efficiently under ligand-free and aerobic conditions to afford
the corresponding 6,7-dihydro-5H-dibenzo[c,e]azepines and biaryls in moderate to excellent yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 December 2008
Received in revised form 13 February 2009
Accepted 17 February 2009
Available online 25 February 2009
Keywords:
Palladium
The Ullmann reaction
6,7-Dihydro-5H-dibenzo[c,e]azepine
Biaryls
1. Introduction
reaction has not yet been extensively explored (only three exam-
´
ples). Domınguez and co-workers have also reported an efficient
The Ullmann-type coupling of aryl halides has emerged as one
of the most popular methods for the synthesis of biaryls.1–5 Tra-
ditionally, copper and its complexes were used as the catalysts for
the reaction.1,2 However, these copper-mediated transformations
are usually conducted under harsh conditions (neat, >200 ꢀC) be-
sides the requirement of a stoichiometric amount of Cu catalyst. A
room temperature Ullmann coupling has been developed by Lie-
beskind and co-workers, however, both 2.5–3.0 equiv of copper(I)
thiophene-2-carboxylate catalyst and substrates (aryl halides)
bearing ortho-activated substitutes are necessary.2e To overcome
these drawbacks, an array of transition metal catalysts were
evaluated and found as an available and efficient alternative to
copper.1,3–6 Impressive progress has been made for the palladium-
catalyzed Ullmann coupling reaction during the last several years.4–6
However, additives, such as reducing agents (H2, zinc, indium or
hydroquinone, etc.), ligand, LiCl or n-Bu4NBr, were required to
improve the Ullmann coupling reaction.4 Moreover, only few pa-
pers on the palladium-catalyzed intramolecular Ullmann coupling
to construct carbocycles and heterocycles have been reported.4f,4g,6
Rawal and co-workers have described an intramolecular reductive
Ullmann coupling method using Pd(OAc)2/As(o-tol)3/hydroquinone
system.4g However, the scope of this intramolecular Ullmann
palladium-catalyzed stannylation/biaryl coupling protocol for the
synthesis of phenanthro[9,10-d]pyrazoles, but both PPh3 and excess
stoichiometric amount of Me6Sn2 were added.6 An efficient Pd–C/
In/LiCl catalytic system was found for the intramolecular Ullmann
coupling recently, and only three examples were tested.4f There-
fore, the development of some novel and additive-free routes for
palladium-catalyzed Ullmann reactions, in particular for intra-
molecular Ullmann coupling, is still challenging in view of both
economy and environment. Here, we wish to report an additive-
free and aerobic palladium-catalyzed Ullmann coupling method for
constructing 6,7-dihydro-5H-dibenzo[c,e]azepines, nitrogen-con-
taining seven-member-ring compounds, and biaryls in moderate to
excellent yields (Scheme 1).
X
R1
R1
Pd(OAc)2, KOAc
R
N
R
N
ligand-free or dppf
DMF, 100 °C
R2
R2
X'
Pd(OAc)2, KOAc
acetone, 100 °C
I
R
R
* Corresponding author. Tel./fax: þ86 577 8836 8607.
E-mail address: jhli@hunnu.edu.cn (J.-H. Li).
Scheme 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.040

3410
M. Yu et al. / Tetrahedron 65 (2009) 3409–3416
2. Results and discussion
were less efficient than Pd(OAc)2 (entries 16–18), and these ligands
have no effect on the reaction (entries 19–22).
The intramolecular Ullmann coupling of N,N-bis(2-iodo-
benzyl)benzenamine was conducted to screen the optimal reaction
conditions, and the results are summarized in Table 1. Initially, the
temperature effect was tested, and heat was found to favor the
reaction (entries 1–4). While at room temperature trace amount of
the target product 2 was observed in the reaction of substrate 1a
with Pd(OAc)2 and KOAc (entry 1), the yield of 2 was enhanced
sharply to 93% at 100 ꢀC (entry 4). Subsequently, effect of solvents
was examined. We found that both DMA (N,N-dimethylacetamide)
and acetone were inferior to DMF (entries 4–6). The screening
results demonstrated that the amount of KOAc affected the reaction
to some extent (entries 7–11). Two equivalents of KOAc, for in-
stance, reduced the yield of 2 to 45%, and no reaction was observed
without bases. Other two bases, K2CO3 and Cs2CO3, were less effi-
cient for the reaction (entries 12 and 13). It is worth noting that
a moderate yield is still achieved even at 5 mol % loading of
Pd(OAc)2, but no reaction takes place in the absence of Pd (entries
14 and 15). Finally, a set of other Pd catalytic systems, such as PdCl2,
PdCl2(PPh3)2, Pd–C, Pd(OAc)2/dppf (1,10-bis(diphenylphosphino)
ferrocene), Pd(OAc)2/S-Phos (2-(dicyclohexylphosphino)-20,60-dime-
thoxy-1,10-biphenyl) or Pd(OAc)2/X-Phos (2-(dicyclohexylpho-
sphino)-20,40,60-tri-i-propyl-1,10-biphenyl), were evaluated (entries
16–22). The results turned out that PdCl2, PdCl2(PPh3)2, and Pd–C
Next, scope of the intramolecular Ullmann coupling was ex-
plored under the standard conditions (Table 2). Substitutes on the
N-aryl moiety were firstly examined, and we were pleased to find
that functional groups, including methyl, chloro, and methoxy
groups were perfectly tolerated (entries 1–7). Treatment of N,N-
bis(2-iodobenzyl)-4-methylbenzenamine (1b) with Pd(OAc)2 and
KOAc afforded the corresponding product 3 in 95% yield (entry 1),
and substrates 1d–1g bearing a chloro group also provided good
yields under the same conditions (entries 3–7). However, the
presence of dppf reduced the yield of 3 to 63% (entry 2). It was
found that analogous amide with the N-aryl group replaced by
a benzyl group still provided a good yield (entry 8), but by an n-
butyl group was not a suitable substrate (entry 9). Subsequently,
substrates 1j–1m bearing alkoxy groups on the N-benzyl moieties
were tested, and moderate yields were still achieved from the
reactions of these substrates in the presence of Pd(OAc)2 and
KOAc (entries 10–13). N-(2-Iodo-4-methoxybenzyl)-N-(2-iodoben-
zyl)benzenamine (1j), for instance, underwent the intramolecular
Ullmann coupling with Pd(OAc)2 and KOAc smoothly to give the
target product 11 in 61% yield (entry 10). The Ullmann couplings
between two different groups on the same substrates were also
investigated (entries 14–21). We found that the reaction between
iodide and bromide was conducted successfully to afford the cor-
responding seven-member-ring compound 2 in 63% yield without
ligands (entry 14), and 74% in the presence of dppf (entry 15).
Identical results to dppf were obtained using S-Phos and
X-phos (entries 16 and 17). However, the reaction of N-(2-chloro-
benzyl)-N-(2-iodobenzyl)benzenamine (1o) was unsuccessful even
in the presence of ligand, such as dppf, S-Phos and X-phos (entries
18–21). We found that no reaction occurred using N,N-bis(2-bro-
mobenzyl)-3-methoxybenzenamine substrate (1p) under ligand-
free conditions. Gratifyingly, dibromides 1p and 1q could undergo
the reaction smoothly in the presence of dppf (entries 22–24).
Treatment of N,N-bis(2-bromobenzyl)-3-methoxybenzenamine
(1p), for example, with Pd(OAc)2, KOAc, and dppf provided the
corresponding target product 15 in 60% yield (entry 23). Finally,
synthesis of nitrogen-containing six-member-ring compound was
attempted, and the effect of solvents was found to affect the re-
action to some extent (entries 25–28). No desired product was
observed in DMF (entry 25), whereas phenanthridine 16 was iso-
lated in 21% yield after 24 h using acetone as the solvent (entry 26).
We found that the ligands displayed low activities for the reaction,
and affected the reaction of substrate 1s slightly (entries 27 and 28).
As shown in Table 3, homocoupling of aryl halides was explored
under additive-free and aerobic conditions. Surprisingly, only a low
yield of the desired product 17 was isolated from the reaction of 1-
iodo-4-nitrobenzene (1t) with Pd(OAc)2 and KOAc in DMF (entry 1).
After a series of trials, we were happy to disclose that effect of
solvents play a crucial role in the homocoupling reaction. In ace-
tone, the yield of 17 was enhanced sharply to 92% (entry 2). Iden-
tical results were also obtained for another electron-deficient aryl
iodide (1s), 4-iodobenzonitrile (entry 3). It was found that the
prolonging reaction time was necessary to give good yields from
the electron-rich aryl iodides 1v and 1w (entries 4 and 5). 1-Iodo-4-
methylbenzene (1v), for instance, reacted with Pd(OAc)2 and KOAc
in acetone could afford 78% yield after 48 h (entry 4). Note that 2-
iodothiophene (1x) is also a suitable substrate providing 96% yield
(entry 6). However, the homocoupling reactions of aryl bromides,
either electron-deficient or electron-rich, were conducted with low
yields (entries 7 and 8).
Table 1
Palladium-catalyzed intramolecular Ullmann reaction of N,N0-bis(2-iodobenzyl)-
aniline (1a)a
I
Pd
Ph
N
Ph
N
2
I
1a
Entry
Pd (mol %)
Base (equiv)
T (ꢀC)
Isolated yield (%)
1b
2
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
d
KOAc (5)
KOAc (5)
KOAc (5)
KOAc (5)
KOAc (5)
KOAc (5)
KOAc (4)
KOAc (3)
KOAc (2)
KOAc (1)
d
rt
60
80
Trace
32
62
93
75
54
86
82
45
43
0
85
Trace
60
0
68
71
86
65
91
89
92
3
4
100
100
100
100
100
100
100
100
100
100
100
100
100
100
86
5c
6d
7
8
9e
10e
11
12
13
14
15
16
17
18
19f
20g
21h
22i
K2CO3 (5)
Cs2CO3 (5)
KOAc (5)
KOAc (5)
KOAc (5)
KOAc (5)
86
KOAc (5)
KOAc (5)
KOAc (5)
KOAc (5)
PdCl2 (10)
PdCl2(PPh3)2 (10)
Pd/C (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
100
100
100
100
a
Reaction conditions: 1 (0.2 mmol), Pd and base in DMF (1 mL) under argon at-
mosphere for 3 h.
b
>95% of 1a was recovered.
DMA (1 mL) instead of DMF for 24 h.
Acetone (1 mL) instead of DMF. 13% of 1a was recovered.
About 25% of 1a was recovered.
Dppf (5 mol %) was added.
Dppf (10 mol %) was added.
S-Phos (10 mol %) was added.
X-Phos (10 mol %) was added.
c
d
e
Compared with the earlier reported palladium-catalyzed Ull-
mann coupling methods, the present reaction did not require the
reported reducing agents such as H2, Zn, In, i-hydroquinone, PrOH,
or formate salts. Although Lemaire has reported ligand-free
f
g
h
i

M. Yu et al. / Tetrahedron 65 (2009) 3409–3416
3411
Table 2
Palladium-catalyzed intramolecular Ullmann reactions of 1a
X
R1
R1
Pd(OAc)2, KOAc
R
N
R
N
DMF, 100 °C, 3 h
n = 0, 1
n
n
R2
R2
X'
1
Entry
Substrate 1
Product
Yield (%)b
I
N
Me
Me
N
1
95
63
(3)
(1b)
I
2c
(1b)
(3)
I
N
MeO
3
81
85
91
89
70
MeO
N
(4)
(1c)
I
I
N
Cl
4
N
Cl
(1d)
(5)
I
I
N
5
N
Cl
Cl
(6)
I
I
(1e)
N
6
N
Cl
Cl
(7)
(1f)
I
I
MeO
MeO
N
7d
N
Cl
Cl
(8)
I
(1g)
I
N
Bn
N
Bn
8
88
(9)
(1h)
I
(continued on next page)

3412
M. Yu et al. / Tetrahedron 65 (2009) 3409–3416
Table 2 (continued)
Entry
Substrate 1
Product
Yield (%)b
I
N
9e
10
11
Trace
N
(10)
I
(1i)
I
OMe
OMe
N
61
N
(11)
I
(1j)
I
I
OMe
OMe
OMe
N
57
N
OMe
(12)
(1k)
I
OMe
OMe
OMe
OMe
N
Me
N
OMe
12
44
OMe
OMe
OMe
(13)
I
(1l)
I
O
O
O
O
O
O
O
Me
N
N
Me
13
56
O
(14)
I
(1m)
I
N
N
14
63
(2)
Br
(1n)
15c
16f
17g
(1n)
(1n)
(1n)
(2)
(2)
(2)
74
73
80
I
N
18
N
0
(2)
Cl
(1o)
19c
20f
21g
(1o)
(1o)
(1o)
(2)
(2)
(2)
0
0
0

M. Yu et al. / Tetrahedron 65 (2009) 3409–3416
3413
Table 2 (continued)
Entry
Substrate 1
Product
Yield (%)b
Br
MeO
N
22
N
Trace
MeO
(15)
Br
(1p)
23c
(1q)
(15)
60
Br
N
24c
65
N
N
(2)
Br
(1r)
H
N
I
25d
Trace
I
(16)
(1s)
26h
(1s)
(1s)
(1s)
(16)
(16)
(16)
21
3
24
27f,h
28g,h
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (10 mol %), and KOAc (5 equiv) in DMF (1 mL) at 100 ꢀC for 3 h under air atmosphere.
Isolated yield.
b
c
Dppf (10 mol %) was added for 24 h.
For 24 h.
>95% of substrate 1 was recovered.
S-Phos (10 mol %) was added.
X-Phos (10 mol %) was added.
In acetone (1 mL) for 24 h.
d
e
f
g
h
palladium-catalyzed Ullmann coupling for the synthesis of bithio-
phenes using Pd(OAc)2/(i-Pr)2NEt system, the mechanism was not
discussed because the reducing agent was not confirmed.5 This
identical problem is now presented in the present reaction. To
elucidate the mechanism, three controlled reactions were con-
ducted as listed in Scheme 2 to evaluate the role of oxygen. The
former reaction was carried out under nitrogen atmosphere, and
a high yield was still obtained (Eq. 1). The second reaction was
carried out under nitrogen atmosphere with a reduced yield (Eq. 2).
The oxidative Ullmann coupling reaction was not observed using N-
(2-iodobenzyl)-N-benzylbenzenamine as the substrates (Eq. 3). The
controlled results suggested that oxygen has no effect on the
Table 3
Palladium-catalyzed homocoupling of aryl halidesa
Pd(OAc)2, KOAc
I
2
R
R
R
Entry
1b
Substrate 1
Time (h)
12
Isolated yield (%)
O2N
I
I
15 (17)
92 (17)
94 (18)
78 (19)
47 (20)
96 (21)
38 (17)
(1t)
(1t)
O2N
2
3
4
5
6
7
12
12
48
48
12
48
I
NC
Me
I
(1u)
(1v)
Pd(OAc)2, KOAc
I
(1)
(2)
(3)
Ph
N
Ph
N
DMF, 100 °C, N2, 3 h
MeO
I
2 (92%)
MeO
(1w)
I
Pd(OAc)2, KOAc
OMe
MeO
I
I
2
S
(1x)
acetone, 100 °C, N2, 24 h
Pd(OAc)2, KOAc
20 (21%)
I
O2N
Br
(1y)
(1z)
N
8
MeO
Br
48
19 (20)
N
DMF, 100 °C
Air, 48 h
a
Reaction conditions: 1 (0.4 mmol), Pd(OAc)2 (10 mol %), and KOAc (5 equiv) in
22
acetone (1 mL) at 100 ꢀC under nitrogen atmosphere.
b
In DMF (1 mL).
Scheme 2. Three controlled reactions.

3414
M. Yu et al. / Tetrahedron 65 (2009) 3409–3416
intramolecular Ullmann coupling reaction, but affected the in-
termolecular Ullmann homocoupling reaction. On the other hand,
the results in Table 1 showed that the amount of both Pd and KOAc
was found to affect the reaction (entries 7 and 11 in Table 1). Par-
ticularly, 5 equiv of KOAc was required to provide the best results.
Thus, we deduced that KOAc might play the same role of the
precursor of reductant as formic salts.4i,4j
consumption of starting material as monitored by TLC and GC–MS
analysis. Then the mixture was washed with saturated NaCl and
extracted with diethyl ether. The organic layers were dried with
anhydrous Na2SO3 and evaporated under vacuum, the residue was
purified by flash column chromatography (hexane/ethyl acetate) to
afford the pure product.
Thus, a working Pd(II) mechanism for the present reaction is
proposed as outlined in Scheme 3 on the basis of the earlier reported
mechanism.4,6,7 Initially, aryl-Pd(II)-X complexes A are generated
from the reaction of Pd(0) with aryl halides, followed by the second
reaction with aryl halides to afford intermediate Ar–Pd–Ar (B) and
PdX2. Intermediate B undergoes reductive elimination to give the
product and regenerate the active Pd(0) species. PdX2 can be re-
duced readily by ligand or reducer (H2) to afford the active Pd(0)
species. H2 may be obtained in situ from the reaction of CHCOꢁ2 and
water.4i,4j,7 Further study of the true mechanism is in progress.
4.3. Typical experimental procedure for the palladium-
catalyzed homocoupling of aryl halides (Table 3)
A mixture of aryl halide 1 (0.4 mmol), Pd(OAc)2 (10 mol %), and
KOAc (5 equiv) was stirred in acetone (1 mL) at 100 ꢀC for the
indicated reaction time until complete consumption of starting
material as monitored by TLC and GC–MS analysis. Then the mix-
ture was filtered with a crude column chromatography and washed
with diethyl ether. The organic layers were evaporated under vac-
uum, the residue was purified by flash column chromatography
(hexane, or hexane/ethyl acetate) to afford the pure product.
Pd(OAc)2
L
4.3.1. 6-Phenyl-6,7-dihydro-5H-dibenzo[c,e]azepine (2)
Yellow liquid; 1H NMR (300 MHz)
d
: 7.58 (d, J¼7.6 Hz, 2H),
7.510–7.36 (m, 6H), 7.24 (t, J¼8.0 Hz, 2H), 7.06 (d, J¼8.2 Hz, 2H), 6.74
Pd(0)
(t, J¼8.0 Hz, 1H), 4.14 (s, 4H); 13C NMR (75 MHz)
d: 149.5, 140.9,
134.9, 129.6, 129.2, 128.9, 127.7, 127.5, 118.2, 115.0, 52.2; LRMS (EI,
70 eV) m/z (%): 271 (Mþ, 88), 270 (Mþꢁ1, 100); HRMS (EI) for
C20H17N (Mþ): calcd 271.1361, found 271.1361.
L or reducer
R
R
PdX
R
4.3.2. 6-p-Tolyl-6,7-dihydro-5H-dibenzo[c,e]azepine (3)
PdX2
A
Yellow liquid; 1H NMR (300 MHz)
d
: 7.89 (d, J¼8.0 Hz, 2H), 7.35–
7.21 (m, 4H), 7.00 (t, J¼7.9 Hz, 4H), 6.46 (d, J¼8.2 Hz, 2H), 4.54 (s,
4H), 2.24 (s, 3H); 13C NMR (75 MHz)
: 141.1, 136.3, 135.7, 134.5,
d
X
129.7, 129.1, 129.0, 127.8, 127.5, 59.1, 54.8, 21.0; LRMS (EI, 70 eV) m/z
(%): 285 (Mþ, 86), 284 (Mþꢁ1, 100); HRMS (EI) for C21H19N (Mþ):
calcd 285.1518, found 285.1517.
Pd
R
R
R
B
Scheme 3. A possible mechanism.
4.3.3. 6-(4-Methoxyphenyl)-6,7-dihydro-5H-dibenzo[c,e]-
azepine (4)
Yellow solid, mp 107–109 ꢀC (uncorrected); 1H NMR (300 MHz)
3. Conclusion
d
: 7.54 (d, J¼7.7 Hz, 2H), 7.47–7.43 (m, 2H), 7.34–7.32 (m, 4H), 6.98
(d, J¼7.7 Hz, 2H), 6.86 (d, J¼8.0 Hz, 2H), 4.04 (s, 4H), 3.75 (s, 3H); 13C
In summary, we have developed a simple and additive-free
palladium-catalyzed Ullmann coupling protocol. This method al-
lows not only for efficient cyclization of a variety of dihalides into
the corresponding 6,7-dihydro-5H-dibenzo[c,e]azepines, but also
for homocoupling of aryl halides into the desired biaryls. It is
noteworthy that these products are important compounds that
widely occur in nature pharmacological products and materials as
well as are often utilized as intermediates in organic synthesis.
NMR (75 MHz) d: 160.8, 153.1, 140.7, 134.8, 129.5, 128.2, 128.0, 127.6,
117.4, 114.5, 55.6, 53.4; LRMS (EI, 70 eV) m/z (%): 302 (21), 301 (Mþ,
100), 300 (78), 286 (54); HRMS (EI) for C21H19NO (Mþ): calcd
301.1467, found 301.1466.
4.3.4. 6-(4-Chlorophenyl)-6,7-dihydro-5H-dibenzo[c,e]azepine (5)
Yellow solid, mp 141–143 ꢀC (uncorrected); 1H NMR (300 MHz)
d
: 7.54 (d, J¼8.2 Hz, 2H), 7.48–7.46 (m, 2H), 7.35–7.33 (m, 4H), 7.22
(dd, J¼6.8 Hz, J¼2.2 Hz, 2H), 6.91 (d, J¼8.2 Hz, 2H), 4.09 (s, 4H); 13C
4. Experimental section
4.1. General
NMR (75 MHz) d: 148.0, 140.6, 134.5, 129.5, 128.9, 128.4, 128.1, 127.7,
123.6, 116.1, 52.3; LRMS (EI, 70 eV) m/z (%): 307 (Mþþ2, 32), 306
(47), 305 (Mþ, 88), 304 (Mþꢁ1, 100), 270 (–Cl, 2), 269 (4), 268 (5);
35
ClN (Mþ): calcd 305.0971, found 305.0971.
NMR spectroscopy was performed on both a Bruck-300 spectro-
meter operating at 300 MHz (1H NMR) and 75 MHz (13C NMR) and
a Bruck-400 spectrometer operating at 400 MHz (1H NMR) and
100 MHz (13C NMR). TMS (tetramethylsilane) was used an internal
standard and CDCl3 was used as the solvent. Mass spectrometric
analysis was performed on GC–MS analysis (SHIMADZU GCMS-QP
2010 plus).
HRMS (EI) for C20
H
16
4.3.5. 6-(3-Chlorophenyl)-6,7-dihydro-5H-dibenzo[c,e]azepine (6)
Yellow liquid; 1H NMR (300 MHz)
: 7.57 (d, J¼7.4 Hz, 2H), 7.50–
7.45 (m, 2H), 7.37–7.35 (m, 4H), 7.19 (t, J¼8.0 Hz, 1H), 6.96–6.80 (m,
3H), 4.13 (s, 4H); 13C NMR (75 MHz)
: 150.4, 140.6, 135.0, 134.4,
d
d
130.0, 129.5, 128.4, 128.2, 127.8, 117.8, 114.5, 112.8, 51.9; LRMS (EI,
70 eV) m/z (%): 307 (Mþþ2, 31), 306 (48), 305 (Mþ, 90), 304 (Mþꢁ1,
35
4.2. Typical experimental procedure for the palladium-
catalyzed intramolecular Ullmann reaction (Tables 1 and 2)
100), 268 (MþꢁCl, 5); HRMS (EI) for C20
H
ClN (Mþ): calcd
16
305.0971, found 305.0970.
A mixture of dihalides 1 (0.2 mmol), Pd(OAc)2 (10 mol %), dppf
(the indicated loading), and KOAc (5 equiv) was stirred in DMF
(1 mL) at 100 ꢀC for the indicated reaction time until complete
4.3.6. 6-(2-Chlorophenyl)-6,7-dihydro-5H-dibenzo[c,e]azepine (7)
Yellow solid, mp 62.0 ꢀC (uncorrected); 1H NMR (300 MHz)
d:
7.56 (d, J¼7.4 Hz, 2H), 7.47–7.33 (m, 7H), 7.16–7.12 (m, 2H), 6.98

M. Yu et al. / Tetrahedron 65 (2009) 3409–3416
3415
(m, 1H), 4.00 (s, 4H); 13C NMR (75 MHz)
d
: 148.7, 140.9, 139.7, 134.7,
(d, J¼8.0 Hz, 1H), 6.56 (t, J¼2.4 Hz, 1H), 6.42 (d, J¼8.0 Hz, 1H), 4.16
(s, 4H), 3.84 (s, 3H); 13C NMR (75 MHz)
: 160.7, 150.8, 140.7, 134.8,
129.8, 129.6, 128.3, 128.1, 127.7, 107.9, 102.8, 101.5, 55.2, 52.1; LRMS
(EI, 70 eV) m/z (%): 302 (27), 301 (Mþ, 100), 300 (98), 286 (54);
HRMS (EI) for C21H19NO (Mþ): calcd 301.1467, found 301.1467.
130.8, 129.7, 128.1, 128.0, 127.5, 127.1, 123.2, 121.4, 54.3; LRMS (EI,
d
70 eV) m/z (%): 307 (Mþþ2, 27), 306 (48), 305 (Mþ, 73), 304 (Mþꢁ1,
35
100), 268 (MþꢁCl, 5); HRMS (EI) for C20
H
ClN (Mþ): calcd
16
305.0971, found 305.0971.
4.3.7. 6-(2-Chloro-5-methoxyphenyl)-6,7-dihydro-5H-dibenzo-
4.3.14. Phenanthridine (16)4
: 9.26 (s, 1H), 8.57 (t, J¼9.3 Hz,
2H), 8.17 (d, J¼8.0 Hz, 1H), 8.02 (d, J¼8.0 Hz, 1H), 7.86–7.81 (m, 1H),
7.75–7.56 (m, 3H); 13C NMR (75 MHz)
: 153.5, 144.4, 132.6, 131.0,
[c,e]azepine (8)
Yellow solid; 1H NMR (300 MHz)
d
Pale yellow liquid; 1H NMR (300 MHz)
d
: 7.55 (d, J¼6.8 Hz, 2H),
7.49–7.46 (m, 2H), 7.37–7.30 (m, 5H), 6.66 (s, 1H), 6.53 (d, J¼8.7 Hz,
1H), 4.00 (s, 4H), 3.74 (s, 3H); 13C NMR (75 MHz)
: 158.8, 149.5,
d
d
130.1, 128.8, 128.7, 127.5, 127.1, 126.4, 122.2, 121.9; LRMS (EI, 70 eV)
140.9, 134.7, 131.0, 129.8, 128.2, 128.1, 127.6, 119.5, 108.1, 107.6, 55.4,
54.3; LRMS (EI, 70 eV) m/z (%): 335 (Mþ, 79), 334 (Mþꢁ1, 100), 300
(MþꢁCl, 6); HRMS (EI) for C18H14ClNO3 (Mþ): calcd 327.0662, found
327.0662.
m/z (%): 179 (Mþ, 100).
4.3.15. 4,40-Dinitrobiphenyl (17)4
Yellow solid; 1H NMR (300 MHz)
d
: 8.36 (d, J¼8.8 Hz, 4H), 7.78
: 148.0, 145.0, 128.3, 124.4;
(d, J¼8.8 Hz, 4H); 13C NMR (75 MHz)
d
4.3.8. 6-(4-Methylbenzyl)-6,7-dihydro-5H-dibenzo[c,e]azepine (9)
LRMS (EI, 70 eV) m/z (%): 244 (Mþ, 100).
Yellow liquid; 1H NMR (300 MHz)
d
: 7.52 (d, J¼7.7 Hz, 2H), 7.51–
7.35 (m, 8H), 7.20 (d, J¼7.7 Hz, 2H), 3.68 (s, 2H), 3.40 (s, 4H), 2.39 (s,
3H); 13C NMR (75 MHz)
: 141.1, 136.4, 135.7, 129.7, 129.1, 128.9,
4.3.16. Biphenyl-4,40-dicarbonitrile (18)4
d
Pale yellow solid; 1H NMR (300 MHz)
d
: 7.76 (dd, J¼6.6 Hz,
127.8, 127.5, 59.1, 54.8, 21.0; LRMS (EI, 70 eV) m/z (%): 300 (32), 299
(Mþ, 100), 298 (95); HRMS (EI) for C22H21N (Mþ): calcd 299.1674,
found 299.1674.
1.9 Hz, 4H), 7.67 (dd, J¼6.6 Hz, 1.9 Hz, 4H); 13C NMR (75 MHz)
d:
143.5, 132.9, 127.9, 118.4, 112.5; LRMS (EI, 70 eV) m/z (%): 204
(Mþ, 100).
4.3.9. 2-Methoxy-6-phenyl-6,7-dihydro-5H-dibenzo[c,e]-
4.3.17. 4,40-Dimethylbiphenyl (19)4
azepine (11)
White solid; 1H NMR (300 MHz)
d
: 7.47 (d, J¼8.0 Hz, 4H), 7.23
Yellow liquid; 1H NMR (300 MHz)
d
: 7.51–7.44 (m, 3H), 7.35–
7.28 (m, 4H), 7.03–7.00 (m, 3H), 6.92 (s, 1H), 6.83 (t, J¼8.0 Hz, 1H),
4.15 (s, 4H), 3.83 (s, 3H); 13C NMR (75 MHz)
: 159.4, 149.5, 140.5,
(d, J¼8.0 Hz, 4H), 2.38 (s, 6H); 13C NMR (75 MHz)
d: 138.3, 126.7,
129.4, 126.8, 21.0; LRMS (EI, 70 eV) m/z (%): 182 (Mþ, 100), 167
(MþꢁCH3, 55).
d
136.2, 134.6, 133.2, 129.6, 129.2, 128.8, 128.2, 127.4, 118.2, 115.0,
114.9, 113.6, 55.3, 52.4; LRMS (EI, 70 eV) m/z (%): 301 (Mþ, 99), 300
(Mþꢁ1, 100), 286 (MþꢁCH3, 5); HRMS (EI) for C21H19NO (Mþ): calcd
301.1467, found 301.1466.
4.3.18. 4,40-Dimethoxy-biphenyl (20)4
White solid; 1H NMR (400 MHz, CDCl3)
d
: 7.46 (d, J¼8.8 Hz,
4H), 6.94 (d, J¼8.8 Hz, 4H), 3.83 (s, 6H); 13C NMR (100 MHz,
CDCl3) d: 158.7, 133.5, 127.7, 114.1, 55.3; LRMS (EI, 70 eV) m/z (%):
4.3.10. 2,10-Dimethoxy-6-phenyl-6,7-dihydro-5H-dibenzo[c,e]-
azepine (12)
214 (Mþ, 100).
Yellow solid, mp 107–109 ꢀC (uncorrected); 1H NMR (300 MHz)
4.3.19. 2,20-Bithiophene (21)4
d
: 7.40 (d, J¼8.4 Hz, 2H), 7.30–7.27 (m, 2H), 7.00–6.94 (m, 4H), 6.88
Colorless liquid; 1H NMR (300 MHz)
d: 7.22–7.19 (m, 4H), 7.04–
(s, 2H), 6.81 (t, J¼8.0 Hz, 1H), 4.11 (s, 4H), 3.82 (s, 6H); 13C NMR
7.00 (m, 2H); 13C NMR (75 MHz)
d: 137.4, 127.8, 124.3, 123.8; LRMS
(75 MHz)
d
: 159.0, 135.8, 133.0, 129.1, 128.5, 118.1, 115.0, 114.9, 113.6,
(EI, 70 eV) m/z (%): 166 (Mþ, 100).
55.3, 52.5; LRMS (EI, 70 eV) m/z (%): 332 (24), 331 (Mþ, 100), 330
(78); HRMS (EI) for C22H21NO2 (Mþ): calcd 331.1572, found 331.1572.
Acknowledgements
4.3.11. 2,3,9,10-Tetramethoxy-6-phenyl-6,7-dihydro-5H-dibenzo-
We thank the National Natural Science Foundation of China (No.
20872112), New Century Excellent Talents in University (No. NCET-
06-0711), and Zhejiang Provincial Natural Science Foundation of
China (No. Y407116) for financial support.
[c,e]azepine (13)
Yellow solid, mp 72 ꢀC (uncorrected); 1H NMR (300 MHz)
d:
7.32–7.30 (m, 3H), 7.03–6.98 (m, 4H), 6.86 (s, 2H), 4.09 (s, 4H), 3.98
(s, 6H), 3.90 (s, 6H); 13C NMR (75 MHz)
d: 149.6, 148.8, 148.4, 133.1,
129.1, 127.5, 118.0, 114.8, 112.9, 110.6, 56.2, 56.0, 52.0; LRMS (EI,
70 eV) m/z (%): 392 (25), 391 (Mþ,100), 390 (73), 376 (MþꢁCH3, 30),
286 (49); HRMS (EI) for C24H25NO4 (Mþ): calcd 391.1784, found
391.1783.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.02.040.
4.3.12. Product (14)
Yellow solid, mp 176 ꢀC (uncorrected); 1H NMR (300 MHz)
d:
References and notes
7.07 (d, J¼8.4 Hz, 2H), 6.91 (s, 2H), 6.87 (d, J¼8.5 Hz, 2H), 6.78
(s, 2H), 5.97 (s, 4H), 3.94 (s, 4H), 2.27 (s, 3H); 13C NMR (75 MHz)
d:
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4.3.13. 6-(3-Methoxyphenyl)-6,7-dihydro-5H-dibenzo[c,e]-
azepine (15)
Yellow oil; 1H NMR (300 MHz)
7.45 (m, 2H), 7.38–7.36 (m, 4H), 7.23 (d, J¼8.4 Hz, 1H), 6.68
d
: 7.57 (d, J¼7.8 Hz, 2H), 7.50–

3416
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