Palladium-catalyzed double N-arylation to synthesize multisubstituted dibenzoazepine derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.09.042

Palladium-catalyzed double N-arylation of primary amines with (Z)-1,2-bis(2-bromophenyl)ethenes was investigated. A variety of dibenzoazepine derivatives were synthesized in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2012.09.042

Tetrahedron Letters 53 (2012) 6406–6408
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Tetrahedron Letters
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Palladium-catalyzed double N-arylation to synthesize multisubstituted
dibenzoazepine derivatives
⇑
Xiaoyun Zhang, Yuan Yang, Yun Liang
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education, Key Laboratory of Resource Fine-Processing and Advanced Materials of
Hunan Province, Hunan Normal University, Changsha, Hunan 410081, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2012
Revised 4 September 2012
Accepted 11 September 2012
Available online 18 September 2012
Palladium-catalyzed double N-arylation of primary amines with (Z)-1,2-bis(2-bromophenyl)ethenes was
investigated. A variety of dibenzoazepine derivatives were synthesized in good to excellent yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Dibenzoazepine
(Z)-1,2-Bis(2-bromophenyl)ethene
Palladium
Double N-arylation
Double heteroatom-arylation of conjugated di-halo compounds
is a strong tool to construct the heterocyclic compounds.1–5 Thus,
useful synthesis of N-heterocyclic compounds was developed by
applying double N-arylation of conjugated di-halo compounds with
primary amines. For example, Nozaki and co-workers reported the
synthesis of carbazoles via double N-arylation of the 2,20-dihalobi-
phenyl compounds.2 Willis and co-workers developed a series of
methods to synthesize indoles using 2-(2-haloalkenyl)-aryl halides
as substrates.3 Buchwald,4a Li4b and Xi,4c respectively, used conju-
gated 1,4-dihalo-1,3-dienes to synthesize pyrroles by Cu catalyzed
tandem C–N bond formation. Recently, we used o-halo-(2,2-dihalo-
vinyl)benzenes, alkynes, and amines as substrates to construct
functional group-intolerant conditions and low yields, the syn-
thetic application of these approaches is limited. Although transi-
tion-metal-catalyzed synthesis of dibenzoazepines would be
ideal for overcoming the limitation, only a few examples have been
reported. Guy and co-workers developed a novel palladium-
catalyzed Heck-amination reaction sequence giving access to
dibenzoazepines using o-iodoaniline and o-bromostylene as sub-
strate.9 Recently, Buchwald demonstrated a similar method to syn-
thesize dibenzoazepines from o-choloaniline with o-bromostylene
in high yields.10 Derat and Catellani reported a new palladium-
catalyzed reaction that leads to dibenzoazepine derivatives when
starting with aryl iodides, o-bromoanilines, and either norbornene
or norbornadiene.11 Although these reported methods are useful
and interesting, synthetic methods for the synthesis of dibenzoaze-
pine, especially for synthesis of N-substituted dibenzoazepine with
various functional groups, are still limited. In addition, diversified
starting materials and synthetic strategies are desired to make
dibenzoazepine derivatives more readily accessible. Nevertheless,
the development of new and efficient procedures for the selective
synthesis of N-substituted (functionalized) dibenzoazepine with
various functional groups continues to represent an important
and challenging goal.
a
-alkynyl indoles in one pot.5 Therefore, we envisioned that
conjugated di-halo compounds such as 1,2-bis(2-bromophenyl)eth-
ene might be useful building blocks for the construction of seven-
membered nitrogen-containing heterocyclic compounds via double
N-arylation. Herein, we would like to disclose a useful application of
(Z)-1,2-bis(2-bromophenyl)ethene and a novel synthetic method
for the production of dibenzoazepine derivatives.
Dibenzoazepines are important building blocks for the synthe-
sis of anticonvulsant, antidepressant, and antiepileptic drugs.6
Consequently, the research and development of synthetic methods
for dibenzoazepines continues to be one of the most active areas in
synthetic chemistry. Classical methods usually apply the dehydro-
genation of iminobibenzyls7 and the rearrangement of arylindoles8
to the synthesis of dibenzoazepines. Due to required harsh,
In our present work, 5-phenyl-5H-dibenzo[b,f]azepine was
formed in good yields from (Z)-1,2-bis(2-bromophenyl)ethene12
1a and aniline in one-pot, via a Pd-catalyzed double amination
reaction.13 Two Csp2-N bonds are constructed in the one-pot pro-
cess. Table 1 shows the results of reaction optimization conditions
screening. Double N-arylation of coupling reaction between 1a and
aniline 2a was investigated using Pd2(dba)3 as the catalyst. Firstly,
⇑
Corresponding author. Tel.: +86 10 8887 2576; fax: +86 10 8887 2531.
E-mail address: liangyun1972@126.com (Y. Liang).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.042

X. Zhang et al. / Tetrahedron Letters 53 (2012) 6406–6408
6407
Table 1
Reaction optimizationa
[Pd] (5 mol%)
Ligand (10 mol%)
+
Ph NH2
Base (2.5equiv)
N
Ph
3a
Solvent, 120 oC,12 h
Br Br
1a
2a
Entry
[Pd]
Ligand
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
DPEphos
Xantphos
dppf
dppp
dpppe
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaOt-Bu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
Toluene
Toluene
Toluene
96
52
74
75
66
67
12
53
72
75
95
0
PPh3
Pt-Bu3
DPEphos
DPEphos
DPEphos
Xantphos
DPEphos
9
10
11c
12d
a
Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), Pd2(dba)3 (2.5 mol %) or Pd(OAc)2 (5 mol %), ligand (10 mol %), base (2.5 equiv), solvent (2 ml), under nitrogen
atmosphere in sealed Schlenk tube, at 120 °C, 12 h.
b
PPh2
Isolated yields.
24 h.
c
Ph2P
PPh2
Fe
d
n
(Z)-1,2-bis(2-bromophenyl)ethene was replaced by (E)-1,2-bis(2-bromophenyl)ethene.
O
O
PPh2
PPh2
PPh2
PPh2
PPh2
n = 3, dppp
DPEphos
Xantphos
n = 5, dpppe
dppf
we screened the efficiency of ligands. Results indicated that DPE-
phos ligand is the best for this coupling reaction (entries 1–7).
Next, we changed the base to NaOt-Bu (from Cs2CO3) (entry 8),
or the solvent to dioxane (from toluene) (entry 9), all resulting in
decreased yields of the product. Finally, Pd(OAc)2 was found to
be an efficient catalyst in the double amination of (Z)-1,2-bis(2-
bromophenyl)ethene 1a with aniline (entry 11). The reaction be-
came slower, however, and longer reaction times were required
(24 h to obtain compound 3a in 95% yield). To our surprise, When
(Z)-1,2-bis(2-bromophenyl)ethene was replaced by (E)-1,2-bis(2-
bromophenyl)ethene, the target product 3a could not be detected
(entry 12). Thus, the optimized reaction condition was as follows:
1a (0.3 mmol), 2a (0.3 mmol), Pd2(dba)3 (2.5 mol %), DPEphos
(10 mol %), and Cs2CO3 (0.75 mmol), in toluene (2 mL) at 120 °C.
The double amination of (Z)-1,2-bis(2-bromophenyl)ethene
with various amines were next investigated using the optimized
reaction conditions. As shown in Table 2, a variety of N-substituted
dibenzoazepines were prepared. The substituent of N moiety (R)
could be Aryl (Type I), Benzyl (Type II), alkyl, or allyl (Type III). For
type I (R = Ar), the phenyl ring could be substituted with either
electron-withdrawing groups such as F, or NO2 (3b–d) or electron-
donating groups Me, OMe, or OCF3 (3e–h). Importantly, compounds
bearing the acetylene bond of aniline could be efficiently reacted
with 1,2-bis(2-bromophenyl)ethene to obtain corresponding
product in model yields (3j, 3k). These results showed that the
variety of groups could be tolerated in this palladium-catalyzed
system. Similarly, N-benzyl dibenzoazepines (3l–o) could be ob-
tained in good to perfect isolated yields. For example, 5-(furan-2-
ylmethyl)-5H-dibenzo[b,f]azepine was achieved in 98% yield under
the optimized reaction conditions. For type III, N-alkyl and N-allyl
dibenzoazepines (3p–s) could be obtained in moderate to good
isolated yields. This protocol was however found to be general since
a wide range of aliphatic and allylic amines reacted successfully.
Meanwhile, we focused our attention on the reactivity of (Z)-
1,2-bis(2-bromophenyl)ethene with different groups (Table 3). As
expected, the reaction was found to be efficiently performed under
optimized reaction conditions. The benzene ring of (Z)-1,2-bis(2-
bromophenyl)ethene bearing of either electron-withdrawing
Table 2
Double amination coupling of (Z)-1,2-bis(2-bromophenyl)ethene
Pd2dba3 (2.5 mol%)
DPEphos (10 mol%)
R
NH2
+
N
R
3
Cs2CO3 (2.5 equiv)
Toluene, 120 oC
Br Br
1a
2
3a: Ar = Ph, (96%, 12 h)
3b: Ar = 4-F-Ph, (81%, 10 h)
3c: Ar = 3, 4-2F-Ph, (66%, 9 h)
3d: Ar = 3-NO2-Ph, (67%, 20 h)
3e: Ar = 4-Me-Ph, (99%, 14 h)
3f: Ar = 2-Me-Ph, (69%, 13 h)
3g: Ar = 4-OMe-Ph, (92%, 14 h)
3h: Ar = 2-OCF3-Ph, (72%, 10 h)
3i: Ar = 1-naphthalenyl, (72%, 11 h)
3j: Ar = 4-trimethylsilylethynyl)-Ph
(63%, 10 h)
Type I
N
Ar
3k: Ar = 4-(4-phenylethynyl)-Ph (62%, 10 h)
3l: Ar = Ph, (99%, 9 h)
3m: Ar = 4-F-Ph, (88%, 11 h)
3n: Ar = 4-OMe-Ph, (81%, 12 h)
3o: Ar = 2-furanyl, (98%, 9 h)
Type II
N
Ar
3p: R = Propyl, (69%, 15 h)
3q: R = Amyl, (87%, 18 h)
3r: R = C8H17, (87%, 18 h)
3s: R = Allyl, (48%, 14 h)
Type III
N
R
groups such as F, Cl, or CN(1b–g) or electron-donating groups Me
or OMe (1h–i) gave the corresponding dibenzoazepines in moder-
ate to high isolated yields. Significantly, medicinally attractive
fluorine-substituted dibenzoazepines (4a–h) could be readily
introduced in good yields.
In conclusion, we have described a novel and efficient route for
the synthesis of N-substituted dibenzoazepine with various func-
tional groups via a palladium-catalyzed double amination coupling
of (Z)-1,2-bis(2-bromophenyl)ethene with amines. The transfor-
mation is distinguished by its mild conditions, allowing the

6408
X. Zhang et al. / Tetrahedron Letters 53 (2012) 6406–6408
Table 3
ment (12A095) and Aid Program for Science and Technology Inno-
vative Research Team in the Higher Educational Institutions of
Hunan Province for financial support.
Double amination coupling of substituted (Z)-1,2-bis(2-bromophenyl)ethene
Pd2dba3 (2.5 mol%)
DPEphos (10 mol%)
R2
R
NH2
+
R1
N
R
4
Supplementary data
Cs2CO3 (2.5 equiv)
Toluene, 120 o
R2
R1
Br Br
C
2
1
Supplementary data associated (experimental procedures and
characterization data for all new compounds and copies of NMR
spectra) with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.09.042.
4a: R = Ph, (73%, 12 h)
4b: R = Bn, (78%, 12 h)
N
R
F
References and notes
4c: R = Ph, (73%, 19 h)
4d: R = Bn, (90%, 19 h)
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We thank the Natural Science Foundation of China (21072054),
New Teachers’ Fund for Doctor Stations, Ministry of Education of
China (20094306120003), Training Program Foundation for the
Young Talents by Hunan Normal University of China (ET21003),
Hunan Provincial Natural Science Foundation of China (12JJ2009),
Scientific Research Fund of Hunan Provincial Education Depart-