I2-Promoted Intramolecular Oxidative Cyclization of Butenyl Anilines: A Facile Route to Benzo[b]azepines

Article abstract of DOI:10.1002/asia.202100710

A metal-free approach for the synthesis of seven-membered N-heterocycles has been developed by the I₂-promoted intramolecular cross-coupling/annulation of butenyl anilines. This cyclization reaction involves C?H activation and C?C bond formation and exhibits good functional group tolerance. A series of benzo[b]azepine derivatives are obtained in moderate to good yields.

Full text of DOI:10.1002/asia.202100710

doi.org/10.1002/asia.202100710
Communication
I2-Promoted Intramolecular Oxidative Cyclization of Butenyl
Anilines: A Facile Route to Benzo[b]azepines
Zhenyu An+,[a] Yi Ren+,[a] Yafeng Liu,[b] and Rulong Yan*[a]
necyclopropanes (Scheme 1c). Although some approaches have
been established to provide benzo[b]azepines, the majority of
them have significant limitations, such as transition metal
Abstract: A metal-free approach for the synthesis of seven-
membered N-heterocycles has been developed by the I2-
promoted intramolecular cross-coupling/annulation of
catalysts, multiple reaction steps, harsh conditions, and complex
butenyl anilines. This cyclization reaction involves CÀ H
substrates. Thus, a facile strategy to benzo[b]azepines under
activation and CÀ C bond formation and exhibits good
mild conditions is still desirable.
functional group tolerance. A series of benzo[b]azepine
Molecular iodine, an inexpensive and low-toxic oxidant,
derivatives are obtained in moderate to good yields.
shows a remarkable ability to promote the oxidative cross-
coupling reaction to form CÀ X (X=C, N, O, or S) bond.[14] In
particular, I2-mediated oxidative CÀ C bond formation has been
Azepines, as valuable seven-membered N-heterocycles, are
important structural motifs embedded in bioactive molecules,
pharmaceuticals, and natural products.[1] In particular, benzo[b]
azepine derivatives exhibit various bioactive and pharmaceut-
ical properties (Figure 1),[2] such as antiparasitic activity (I),[3]
antitumor activity (II),[4] nonpeptidic vasopressin V2 receptor
agonist (III),[5] and respiratory syncytial virus inhibitor (IV).[6] In
addition, 1-propyl-1-benzazepines (V) exhibits potent CCR5
antagonistic activity, which is selected as promising anti-HIV-1
agent.[7]
proved to be an efficient method for the synthesis of
heterocyclic compounds.[15] For example, Larock[16a] and
Liang[16b] achieved intramolecular oxidative cross-coupling/
annulation reactions through the formation of CÀ C bond in the
presence of molecular iodine, respectively. Inspired by these
Due to the wide applications, continuous efforts have been
focused on efficient strategies to afford benzo[b]azepine
skeletons.[8] Recent years, a series of [m+n] cycloadditions have
emerged as versatile methods to access various benzo[b]
azepines.[9] Besides these methods, benzo[b]azepine skeletons
could be assembled through intramolecular cross-coupling
reactions,[10a–d] photocatalytic radical reactions,[10e] ring expan-
sion reactions,[10f–g] and others.[10h–k] For instance, Wang[11]
developed a method for the construction of benzo[b]azepines
via copper-catalyzed oxidative C(sp3)À H/C(sp2)À H cross-coupling
(Scheme 1a). Kim[12] reported the Lewis acid catalyzed synthesis
of ring-fused 1-benzazepine derivatives from 2-(aryl)
cyclopropane 1,1-diesters via [1,5]-hydride shift/cyclization
sequences (Scheme 1b). In 2018, Shi[13] disclosed a Ni-catalyzed
method for the preparation of benzo[b]naphtho[1,2-d]azepines
via intramolecular cyclization of alkyl bromide-tethered alkylide-
Figure 1. Bioactive compounds containing benzo[b]azepine core.
[a] Z. An,+ Y. Ren,+ Prof. Dr. R. Yan
State Key Laboratory of Applied Organic Chemistry
Key laboratory of Nonferrous Metal Chemistry and Resources Utilization of
Gansu Province
College of Chemistry and Chemical Engineering
Lanzhou University
Lanzhou 730000 (P. R. China)
E-mail: yanrl@lzu.edu.cn
[b] Y. Liu
Chemical Science and Engineering College
North Minzu University
Yinchuan 750000 (P. R. China)
[+] These authors contribute equally to this work.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/asia.202100710
Scheme 1. Approaches for the synthesis of benzo[b]azepines.
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works, we report a facile approach for the synthesis of benzo[b]
azepine derivatives from butenyl anilines through I2-promoted
intramolecular cross-coupling of two C(sp2)À H bonds.
entry 19). So the optimized reaction conditions were estab-
lished as Table 1, entry 14.
Based on the optimal reaction conditions, we investigated
the substituent scope of this protocol by the synthesis of a
variety of benzo[b]azepines. As shown in Scheme 2, substrates
1 with electron-donating or electron-withdrawing groups on
aniline moiety performed smoothly and gave the desired
products in moderate yields. These results illustrate that the
electronic effect of substituents on the aniline moiety have a
slight influence on the reaction. For example, substrate 1h
bearing strong electron-withdrawing group CF3 gave the
product 2h in 46% yield. Furthermore, substrates 1i–1q derived
from meta- and ortho-substituted anilines produced the corre-
sponding products 2i–2q in 52–62% yields, indicating that the
steric effect was negligible. Notably, disubstituted substrates
1r–1s were also tolerated to afford 2r–2s in moderate yields.
Encouraged by the above results, we next investigated the
scope of R2 moieties of substrates 1, and the results are shown
in Scheme 3. Under the optimized reaction conditions, sub-
strates 1t–1z with different groups on the para-position of the
benzene ring of R2 moieties were compatible with this trans-
formation and generated the desired products 2t–2z in
moderate yields. Among them, the yields of R2 moieties with
electron-withdrawing groups were slightly higher than those
with electron-donating groups. Moreover, the substrates 1aa–
1af with groups on both aniline moieties and R2 moieties were
also suitable for this transformation, generating desired prod-
ucts in 49–75% yields. Unfortunately, this method was not
compatible with naphthyl substrate 1ag and only a trace
amount of 2ag was detected.
Initially, we attempted to optimize the reaction conditions
for this I2-promoted intramolecular cross-coupling/cyclization of
N-(3-phenylbut-3-en-1-yl)aniline 1a. As shown in Table 1, the
reaction was conducted in the presence of I2 (1.0 equiv) in DCE
°
at 100 C for 12 h under argon atmosphere. Pleasingly, the
reaction proceeded smoothly to afford the desired product 2a
in 35% yield (Table 1, entry 1). The structure of 2a was
determined by X-ray diffraction analysis (see the Supporting
Information for details). Next, the product 2a was obtained in
30–48% in THF, HFIP, and CH3CN, but no product was formed in
DMF (Table 1, entries 2–5). Furthermore, some mixture solvents
were screened, and the yield was increased to 60% using the
mixture of HFIP/tBuOH (2:1) as the solvent (Table 1, entries 6–
9). Either decreasing or increasing the temperature failed to
improve the yield of 2a (Table 1, entries 10–11). The reaction
was unable to occur in the absence of I2 (Table 1, entry 12),
indicating that molecular iodine was essential for this reaction.
Subsequently, we investigated the effect of the amount of
iodine and found that when the dosage of I2 was increased to
2.0 equiv, the yield of product 2a was increased to 71%
(Table 1, entries 13–14). However, further increase in the
amount of I2 did not lead to significant difference in the yield
(Table 1, entry 15). A series of acids were screened as additives,
but none of them gave a better result (Table 1, entries 16–18).
Finally, the reaction was also carried out with 2.0 equiv. of I2 in
HFIP, and the product 2a was isolated in 53% yield (Table 1,
Table 1. Optimization of the reaction conditions.[a]
°
Entry
I2 [eq.]
Additive
Solvent
Temp. [ C]
Yield[b] [%]
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
–
1.5
2.0
2.5
2.0
2.0
2.0
2.0
–
–
–
–
–
–
–
–
–
–
–
DCE
THF
DMF
HFIP
100
100
100
100
100
100
100
100
100
80
120
100
100
100
100
100
100
100
100
35
30
0
48
32
47
44
55
60
54
40
0
66
71
69
43
63
61
53
CH3CN
HFIP/DCE (1:1)
HFIP/THF (1:1)
HFIP/tBuOH (1:1)
HFIP/tBuOH (2:1)
HFIP/tBuOH (2:1)
HFIP/tBuOH (2:1)
HFIP/tBuOH (2:1)
HFIP/tBuOH (2:1)
HFIP/tBuOH (2:1)
HFIP/tBuOH (2:1)
HFIP/tBuOH (2:1)
HFIP/tBuOH (2:1)
HFIP/tBuOH (2:1)
HFIP
9
10
11
12
13
14
15
16
17
18
19
–
–
–
CF3COOH
BF3 ·OEt2
FeCl3
–
[a] Reaction conditions: 1a (0.2 mmol), I2, and solvent (3 mL) for 12 h under argon. [b] Isolated yield. Entry in bold highlights optimized reaction conditions,
and the reaction time was monitored by TLC.
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Scheme 4. Radical inhibition experiment and proposed mechanism.
not suppressed (Scheme 4a-1). It can be inferred that a radical
process is impossible in this transformation. When the reaction
was carried out using Br2, FeBr3, AlCl3, or BF3 ·OEt instead of I2 as
additive, it was found that no desired product was obtained
(Scheme 4a-2). This result indicated that iodine was crucial for
this process. On the basis of the above results and previous
reports,[16–17] a possible mechanism is outlined in Scheme 4b.
Initially, iodonium intermediate A is generated through the
coordination of C=C bond of substrate 1a with iodine cation.
Then, the aromatic ring of the aniline moiety attacks the
activated double bond to form intermediate B. Finally, the
elimination of HI produces the desired product 2a.
Scheme 2. Scope of substrates 1. Reaction conditions: 1 (0.2 mmol), I2
°
(0.4 mmol) in HFIP/tBuOH (2 mL/1 mL) at 100 C for 12 h under argon.
In conclusion, we have developed an I2-mediated intra-
molecular oxidative cyclization reaction, which includes func-
tionalization of C(sp2)À H bond and construction of CÀ C bond.
This atom-economical and metal-free approach provides facile
access to a variety of benzo[b]azepine derivatives from butenyl
anilines.
Acknowledgements
This work was supported by National Natural Science Foundation
of China (21672086).
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Butenyl anilines · Benzo[b]azepines · I2-promoted ·
Intramolecular annulation · Metal-free
Scheme 3. Scope of substrates 1. Reaction conditions: 1 (0.2 mmol), I2
°
(0.4 mmol) in HFIP/tBuOH (2 mL/1 mL) at 100 C for 12 h under argon.
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Manuscript received: June 28, 2021
Revised manuscript received: July 11, 2021
Version of record online: ■■■, ■■■■
Chem Asian J. 2021, 16, 1–5
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COMMUNICATION
Z. An, Y. Ren, Y. Liu, Prof. Dr. R. Yan*
1 – 5
I2-Promoted Intramolecular
Oxidative Cyclization of Butenyl
Anilines: A Facile Route to Benzo
[b]azepines
An efficient strategy for the synthesis
of benzo[b]azepine derivatives has
been developed by the I2-promoted
intramolecular cross-coupling/annula-
tion of butenyl anilines. This cycliza-
tion reaction involves CÀ H activation
and CÀ C bond formation. A series of
benzo[b]azepine derivatives are
obtained in moderate to good yields.