Novel and facile synthesis of 1-benzazepines via copper-catalyzed oxidative C(sp3)-H/C(sp2)-H cross-coupling

Article abstract of DOI:10.1039/c7cc07027f

A novel and facile synthetic strategy for the construction of 1-benzazepines has been developed via copper-catalyzed oxidative C(sp³)-H/C(sp²)-H cross-coupling directly from two inert C-H bonds. This transformation represents an atom- and step-economical way to synthesize biologically important seven-membered benzo-heterocycles compared with the known methods.

Full text of DOI:10.1039/c7cc07027f

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Novel and Facile Synthesis of 1-Benzazepines via Copper-
Catalyzed Oxidative C(sp3)-H/C(sp2)-H Cross-Coupling†
Received 00th January 20xx,
Accepted 00th January 20xx
Rui Wang, Ruo-Xing Jin, Zi-Yang Qin, Kang-Jie Bian and Xi-Sheng Wang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel and facile synthetic strategy for the construction of 1-
benzazepines has been developed via copper-catalyzed oxidative
C(sp3)-H/C(sp2)-H cross-coupling directly from two inert C-H
bonds. This transformation represents an atom- and step-
economic way to synthesize biologically important seven-
membered benzo-heterocycles compared with the known
methods.
Benzannulated heterocycles exist extensively as key structural
motifs in multitudinous biologically active molecules, including
different kinds of natural products, pharmaceuticals, and
agrochemicals.1 Among these pivotal heterocycles, benzo-
fused, seven-membered, aza-heterocycles, commonly known
as 1-benzazepines, have already been incorporated into many
commercial pharmaceuticals, such as Fedovapagon
(antidiuretic), Benazepril (ACE inhibitor), Imipramine
(antidepressant) and Eslicarbazepine (anticonvulsant), as core
skeletons due to their significant value in drug development
and medicinal chemistry (Fig. 1).2 Hence, the development of
efficient methods to construct 1-benzazepine skeletons in a
facile way is always of great academic and practical values.
Various synthetic methods have been reported by a number of
research groups, for instance, Beckmann or Schmidt
rearrangements,3 transition-metal catalyzed cross-coupling,4
cooperative NHC/Pd-catalyzed annulation5 etc.
benzazepines (Scheme 1a). However, all these methods are
Fig. 1 Pharmaceuticals and bioactive compounds containing 1-
benzazepine structures.
limited to the functionalization of a single relatively active C-H
bond, and the cross-coupling of inert aromatic and inert
aliphatic C-H bonds,9 obviously the most efficient and ideal
method to make 1-benzazepines, still remains an unresolved
problem. As one part of our continuous efforts to develop new
methods for selective cross-coupling of C(sp3)-H and C(sp2)-H
bonds,10 herein, we report a novel copper-catalyzed oxidative
C(sp3)-H/C(sp2)-H cross-coupling for facile construction of
various 1-benzazepines (Scheme 1b). The key to success is
that the selective cleavage of C(sp3)-H bonds in alkyl chains can
be realized via [1,5]-hydrogen atom transfer ([1,5]-HAT) with
aniline used as the directing group. It should be noted that the
starting material for this transformation can be easily obtained
from inexpensive and easily available anilines and ketones (see
From an ecological and economical point of view and in
consideration of green and sustainable chemistry, seeking
more efficient methods to construct C-C bonds remains a big
challenge and has drawn great interest for synthetic chemists.
Accordingly, several novel strategies based on direct C-H
functionalization, including Friedel-Crafts reaction,6 Mannich-
type reactions7 and [1,5]-hydride shift/7-endo cyclization,8
have been reported for the efficient synthesis of 1-
the ESI†).
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electron-donating groups, such as alkyl (2b
-d, 2i, 2n), phenyl
(
2e) and methoxy (2m), and electron-withdrawing groups,
such as halogen (2g-g, 2h) and trifluoromethyl (2k), were well
Table 1 Optimization of reaction conditionsa
entry
[Cu] (mol%)
[Ag] (equiv) base (equiv)
Ag2CO3 none
AgOTf (4.0) none
Ag2O (2.0) none
%yieldb
19 (20c)
0
1
2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
3
4
5
6
48
7
AgOAc (4.0) none
AgOAc (4.0) Na2CO3 (2.0)
AgOAc (4.0) Na2CO3 (2.0)
44
34
Cu2O (10)
Cu2(OH)2CO3
(10)
7
AgOAc (4.0) Na2CO3 (2.0)
61
8
9 d
CuO (20)
AgOAc (4.0) Na2CO3 (2.0)
AgOAc (4.0) Na2CO3 (2.0)
AgOAc (4.0) NaOAc (4.0)
AgOAc (4.0) K3PO4 (1.3)
70
77
61
50
CuO (20)
CuO (20)
CuO (20)
CuO (20)
CuO (20)
10 d
11 d
12 d
13 d,e
14 d,e,f CuO (20)
15 d,e,f none
Our initial study began with aniline 1a (0.3 mmol) as the
pilot substrate in the presence of a catalytic amount of
Cu(OAc)2 (20 mol%) in DCE (2.0 mL). As expected, the desired
AgOAc (4.0) NaHCO3 (4.0) 85
AgOAc (4.0) NaHCO3 (4.0) 88
AgOAc (4.0) NaHCO3 (4.0) 91 (93c)
AgOAc (4.0) NaHCO3 (4.0) n.d.
Scheme
1 Synthesis of 1-benzazepines via direct C-H
functionalization.
product 2a was successfully obtained with addition of Ag2CO3
(2.0 equiv) at 135 ˚C for 24 h, albeit with a relatively low yield 16d,e,f CuO (400)
none
NaHCO3 (4.0) trace
aUnless otherwise noted, the reaction conditions were as
(20%, Table 1, entry 1). To increase the yield further, a careful
screening of the oxidants (Table S2, ESI†) was then performed,
follows: 1a (0.1 mmol), [Cu] (a mol%), [Ag] (b equiv) and [base]
b
(c equiv) in 1,2-DCE (0.05 M) at 135 °C for 24 h. GC yields are
which showed that Ag2O gave the best result with 48% yield
(entry 3). However, further optimization of the reaction
conditions with Ag2O as the oxidant failed to provide higher
yields. While AgOAc had been demonstrated not as a good
oxidant (entry 5), addition of extra Na2CO3 as base into the
reaction system exhibited significant increment of yield.
Copper catalysts were next examined with AgOAc and Na2CO3
reported; n.d., not detected. cIsolated yield, 1a (0.3 mmol). d30
e
h. Na2SO4 (2.0 equiv) was added and the reaction was stirred
at rt for 5 min before heating. f125 °C.
compatible with this transformation in good to excellent
yields. 1-Naphthyl-derived benzazepine 2f could be obtained
as well, albeit in a low yield (21%). Meanwhile, a number of
used, which revealed that CuO was optimal (Table S5, ESI
Table 1, entries 8, 9). After re-screening of the bases (Table S6,
ESI ), NaHCO3 was eventually selected as the best choice (85%,
†;
anilines
groups on the aryl rings were smoothly cyclized to furnish the
corresponding 1-benzazepines with good to excellent yields.
Interestingly, methyl (2i), chloro (2j) and trifluoromethyl (2k
1 with para-, meta-, as well as ortho-substituted
†
Table 1, entry 12). After further careful investigation of
experimental details, it was interesting to find that
introduction of Na2SO4 into this system and stirring the
reaction system at room temperature for 5 min before heating
could slightly improve the yield (entry 13). Moreover, lowering
2
)
at the meta-position cyclized selectively at the less sterically
hindered position in good yields, showing a significant steric
effect in this transformation. Yet intriguingly, the meta-cyano-
substituted aniline 1l and the meta-methoxy-substituted
aniline 1m afforded both 8- and 6-substituted cyclic products
with 2.22:1 (2l) and 1.04:1 (2m) selectivity, respectively, which
indicated that the electronic effect might also play an
important role in the regioselectivity. Notably, ortho-methyl
substrate could be well tolerated with good yield (55%, 2n).
Not surprisingly, the corresponding yields decreased slightly
along with the increase of steric hindrance of alkyl groups at α-
the reaction temperature to 125 °C afforded 1-benzazepine 2a
,
with the best isolated yield (93%, entry 14). Finally, control
experiments showed that almost none of 2a was detected
without addition of either copper catalyst or silver oxidant
(entries 15, 16).
With the optimal conditions in hand, the scope of this
strategy was then elucidated by synthesis of a variety of 1-
benzazepines (Scheme 2). First, the investigation of
substituent effects of the aryl ring indicated that both
position of nitrogen atom (2o-r). In particular, the C-H/C-H
2 | J. Name., 2012, 00, 1-3
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testament to the synthetic utility of our strategy. Gratifyingly,
the corresponding coupling products bearing different
Scheme
3 Radical Inhibition Experiment and Proposed
Mechanism.
substituent groups, including Me, Cl, F, and CF3, could be
obtained smoothly with good yields (2v aa). It is worth noting
-
that the iminodibenzyl derivatives serve as a class of important
frameworks with various uses, including natural occurrence,11
synthetic applications12 and versatile biological activities.13 For
instance, it is the only precursor for present-day construction
of tricyclic antidepressant (TCA) drugs,14 such as Imipramine,
Clomipramine and Trimipramine. Meanwhile, the cross-
coupling occurred exclusively at the tertiary C(sp3)-H site, and
the relatively more active benzylic C(sp3)-H bond has not been
affected, which further revealed the excellent regioselectivity
of our method was controlled only by 1,5-HAT. To confirm the
seven-membered ring structure of the products, an interesting
aniline 1ab, which possesses a 9,9-diphenylfluorene motif that
is useful in pharmaceuticals and photoelectric devices, was
synthesized and tested in our reaction system. Fortunately,
benzazepine 2ab was obtained successfully with 85% yield,
and the exact structure was further confirmed by X-ray
analysis.15
cyclization of anilines bearing both tertiary C(sp3)-H and
primary (2p) or secondary (2q) C(sp3)-H bonds occurred at the
Scheme 2 Substrate scopea
aUnless otherwise noted, the reaction conditions were as
follows:
NaHCO3 (4.0 equiv) and Na2SO4 (2.0 equiv) in 1,2-DCE (6.0 mL)
at 125 °C for 30 h; for 2f, 2v aa, reactions were performed on
1 (0.3 mmol), CuO (20 mol%), AgOAc (4.0 equiv),
-
1
To verify the mechanism of this novel transformation,
several free radical inhibitors, including TEMPO, BHT and
galvinoxyl, were added to the standard conditions, and all of
them showed strong inhibition effects, even with only 30 mol%
loading (Table S8; Scheme 3a). Based on these results and our
previous report,10 a conceivable mechanism is outlined in
Scheme 3b. Initial interaction of Cu(II) with aniline 1a
(0.3 mmol), Cu(OAc)2 (20 mol%) and Ag2CO3 (1.5 equiv) in 1,2-
DCE (6.0 mL) at 125 °C for 8 h; isolated yields were reported.
c
e
f
g
b25 h. AgOAc (3.0 equiv). d20 h. 140 °C. 35 h. 45 h, CuO (30
mol%). h2-DCE/cyclohexane (1:1) as the solvent. i6 h.
tertiary
C-H
position
exclusively.
The
excellent
chemoselectivity could be explained by the relatively higher
stability of the tertiary carbon radical. A symmetric substrate
with two C(sp3)-H bonds suitable for [1,5]-hydrogen atom
abstraction in both alkyl side chains also worked pretty well
generates the nitrogen radical I. The carbon-centered radical II
is then formed via [1,5]-hydrogen atom transfer and
subsequently captured by the phenyl ring of the aniline. After
further oxidation and deprotonation, the final 7-membered
product 2a is obtained.
(
2s). Importantly, a spiro skeleton, normally difficult to make,
could also be obtained in good yield (2t). Moreover, the
secondary C(sp3)-H bond could be selectively cleaved and
coupled as well, albeit in a lower but still acceptable yield (2u).
As one more representative structure of 1-benzazepine
derivatives, iminodibenzyl has also been examined as a further
In conclusion, we have developed a novel method for the
facile construction of 1-benzazepines via copper-catalyzed
oxidative C(sp3)-H/C(sp2)-H cross-coupling. Compared with
known methods, this transformation represents an atom- and
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(973 Program 2015CB856600), and the National Science
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