Iodine(III)-mediated construction of the dibenzoxazepinone skeleton from 2-(aryloxy)benzamides through oxidative C-N formation

Article abstract of DOI:10.1039/c5ra20258b

Dibenzoxazepinone compounds were conveniently synthesized from 2-(aryloxy)benzamides through hypervalent iodine(iii)-mediated oxidative cyclization under mild reaction conditions.

Full text of DOI:10.1039/c5ra20258b

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ARTICLE TYPE
Iodine(III)-Mediated Construction of Dibenzoxazepinone Skeleton from
2-(Aryloxy)benzamides through Oxidative C-N Formation
Xuliang Guo,† Daisy Zhang-Negrerie,† and Yunfei Du*,†,‡
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Dibenzoxazepinone
compounds
were
conveniently
O
synthesized from 2-(aryloxy)benzamides through hypervalent
iodine(III)-mediated oxidative cyclization under mild reaction
conditions. Differing from the existing strategies, this metal-
10 free approach features an oxidative C-N bond-forming
process for the construction of the skeleton in the final step.
O
O
N
O2N
O
N
N
HCl
N
O
O
OMe
NHOH
O
HDAC inhibitor (B)
Sintamil I (C)
Dibenzepin (A)
N
The dibenzoxazepinone skeleton is an important heterocyclic
motif which have been found to show many biological activities,
such as antidepressant,1 antitumor,2 and antiꢀHIV3 activities.
15 Besides, they also show pharmacological and neurochemical
activities and can be used as potential central nervous system
agents4 and potential atypical antipsychotics.5 For examples, both
dibenzoxazepinone (A),3 a potent nonꢀnucleoside HIVꢀ1 reverse
transcriptase inhibitor and histone deacetylase (HDAC) inhibitor
20 (B)2 possess the dibenzoxazepinone skeleton in their chemical
structures. Furthermore, the dibenzoxazepinone compounds could
also be used as the building blocks for the synthesis of other
pharmaceutical agents with various biological activities. For
instances, Sintamil I (C) was reported to be used as an
25 antidepressant agent.1 Amoxapine (D),5 a derived skeleton of
N
N
N
N
Cl
Cl
O
O
Amoxapine (D)
Loxapine (E)
Figure 1 Representative active biologically dibenzoxazepinones and their
50
derivatives.
dibenzoxazepinone, was
a marketed antidepressant drug.
Loxapine (E), bearing a dibenzoxazepinone skeleton and a
methylpiperazine system,6 is a drug used in the treatment of
schizophrenia.
30
Owning to its wide occurrence in biological compounds, many
synthetic efforts have been devoted to the construction of this
privileged skeleton. In 1982, Nagai reported an intermolecular
Figure 2 The existing strategies for the construction of
dibenzoxazepinone skeleton.
acylation
of
1ꢀisoꢀcyanatoꢀ2ꢀphenoxybenzens,
affording
dibenzoxazepinone in good yield7 (Figure 2, path a). In 2006,
35 Bunce and Schammerhorn realized the synthesis of
dibenzoxazepinone through a reductionꢀlactamization reaction
under dissolving metal conditions using iron and acetic acid8
(Figure 2, path b). In 2011, Ma reported an effective
regioselective synthesis of fused oxazepinone skeleton via Smiles
40 rearrangement reaction using commercially available Nꢀ
substituted salicylamides and 1,2ꢀdifluorobenzenes9 (Figure 2,
path c ). An intramolecular carbonylation reaction has also been
applied by Lu and Alper, using 2ꢀiodophenol and substituted 1ꢀ
fluoroꢀ2ꢀnitrobenzene as starting materials10 (Figure 2, path d).
45 Besides, Klunder reported a method involving the condensation
of 2ꢀaminophenols with 2ꢀchloroꢀ5ꢀnitrobenzoyl chloride using
THF as solvent3 (Figure 2, path e). An alternative approach
55
Figure 3 A general retrosynthetic analysis for the construction of
dibenzoxazepinone skeleton.
involves the heating of xanthenꢀ9ꢀone oximes with phosphorus
pentachloride, providing the dibenzoxazepine system via
60 Beckmann rearrangement11 (Figure 2, path f).
Although existing methods have their own advantages in the
preparation of the corresponding dibenzoxazepine compounds,
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Table 1 CuIꢀmediated coupling reaction of methyl 2ꢀphenoxybenzoatea
40
Table 2 Conditions optimization of the cyclization reactiona
Yieldb(%)
of 7
64
Yieldb(%)
of 2a
37
Entry
R1
R2
Product 7
Entry
Oxidant
Solvent
Conc. (M)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H
mꢀMe
mꢀBr
mꢀF
mꢀCl
mꢀF
H
H
H
H
H
H
pꢀBr
pꢀBr
pꢀCl
pꢀBr
pꢀBr
pꢀBr
pꢀCl
pꢀCl
H
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
1
2
3
4
5
6
7
8
9
10
11
12
13
PIFA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PhIO
DMP
IBX
DCE
DCE
DMF
THF
toluene
TFA
HFIP
TFE
TFE
TFE
DCE
DCE
DCE
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.1
52
61
53
58
57
58
56
46
47
60
51
59
63
45
49
46
66
70
43
32
84
89
83
H
mꢀBr
pꢀCl
mꢀMe
pꢀCl
mꢀMe
mꢀOMe
H
0.2
80
0.05
0.05
0.05
trace
ND
ND
aReaction conditions: 1a (1.0 mmol) and oxidant (1.2 mmol), in solvent
pꢀMe
2,3ꢀdimethyl
(20 mL), 40 min, rt. bIsolated yield.
H
aGeneral conditions: 6 (1.0 equiv), 4 (1.2 equiv) in toluene (0.5 M), then
added Cs2CO3 (1.5 equiv) and CuI (1.0 equiv), stirred at reflux for 10 h.
45 hydrolysis15 and the subsequent Nꢀmethoxyamidation,13 crossꢀ
coupled esters were converted to amides 1 for cyclization purpose
(see Supporting Information for details).
5
some of them require the use of transition metals or harsh
conditions. In this paper, we report an alternative construction of
the dibenzoxazepinone skeleton from the readily available
substituted 2ꢀ(aryloxy)benzamides through an intramolecular
10 cyclization involving a direct oxidative C−N bond formation in
the final step.
Hypervalent iodine reagent have been widely used as a nonꢀ
metallic oxidant for the construction of CꢀN bonds,12 especially
the intramolecular cyclization of Nꢀmethoxyamide derivatives
15 through a nitrenium ion intermediates. For example, our group
has reported the assemblage of the 1,4ꢀbenzodiazepine
framework from the readily available substituted Nꢀmethoxyꢀ2ꢀ
(methylphenylamino)benzamide through an intramolecular
oxidative C−N bond formation.12j Inspired by this work, we
20 envisaged that dibenzoxazepinone, an analog of 1,4ꢀ
benzodiazepine by changing the N moiety with an O atom, may
also be accessed by using the same strategy.
NꢀMethoxyꢀ2ꢀphenoxybenzamide 1a was chosen as the model
substrate to probe the feasibility of the proposed cyclization
50 reaction. At first, phenyliodine bis(trifluoroacetate) (PIFA) was
used as oxidant and DCE as solvent, and the reaction at room
temperature for 40 minutes revealed that the product was exactly
the target compound, with the yield of 37% (Table 2, entry 1).
Replacing phenyliodine bis(trifluoroacetate) (PIFA) with the less
55 potent phenyliodine diacetate (PIDA) could increase the yield to
46% (Table 2, entry 2). Other hypervalent iodine oxidants such as
Iodosobenzene (PhIO), DessꢀMartin periodinane (DMP) and oꢀ
iodoxybenzoic acid (IBX) were also tested, but none of them was
effective for the reaction (Table 2, entries 11ꢀ13). Further solvent
60 screening studies showed that the reaction in THF afforded 2a in
a moderate yield of 70% (Table 2, entry 4). Further optimization
study found that using TFE as solvent, and adjusting the substrate
concentration to 0.05 M, the yield of the desired product 2a could
be enhanced to 89% (Table 2, entry 8).
Figure 3 describes the retrosynthesis for the construction of the
desired dibenzoxazepinone 2. We envisaged that tricycle 2 could
25 be formed through the intramolecular oxidative C−N bond
formation of 1, and substrate 1 could be accessible by the
amidation of carboxylic acid 3.13 Through the known rossꢀ
coupling reaction, we anticipated that acid 3 could be prepared
from the substituted phenol 4 and 2ꢀiodobenzoic acid 5.14
30 However, although we found that when oꢀiodobenzoic acid 5
bearing electronꢀwithdrawing group could be converted to the
desired coupled 3 in acceptable yields, the method was not
applicable to the substrates bearing electronꢀdonating groups
since the yield of the desired product to be trace. After many
35 trials we finally found that methyl oꢀiodobenzoate, upon
treatment with cuprous iodide and cesium carbonate, provided the
crossꢀcoupled product in moderated to good yield (see Table 1).
Under the optimal conditions, a variety of the crossꢀcoupled
products were prepared in moderate to good yields. Through
65
With the optimal conditions in hand, we next explored other 2ꢀ
(aryloxy)benzamides to examine the scope and limitation of the
method. As results in Table 3 indicated, the method was found to
tolerate a range of different substituents on the phenyl ring in the
substrates. When the phenyl ring B bears no substituents, the
70 corresponding
substrates
were
converted
into
the
dibenzoxazepinone products in excellent yields (Table 3, entries
1−5), respectively. The substrates with halogen substituted on
phenyl ring B also proceed successfully to afford the desired
products in moderate to good yields (Table 3, entries 6−13).
75 Unfortunately, when the substrates bearing electronꢀdonating
group on ring B (Table 3, entries 14−15) were applied, the
reaction was found to give a complex mixture. Reducing the
temperature or the concentration of reaction did not lead a better
result. Finally, when treated these electronꢀrich substrates with
80 iodosobenzene (PhIO) in TFE and reflux temperature, the desired
2
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ARTICLE TYPE
Table 3 Iodine(III)ꢀmediated synthesis of dibenzoxazepinone derivativesa
Yield(%)b
Substrate 1
Product 2
Yield(%)b
Entry
9
Entry
1
Substrate 1
Product 2
O
O
O
O
74
Br
89
Br
Br
Br
NH
N
NH
N
O
OMe
O
O
OMe
O
OMe
O
OMe
1a
2a
1i
2i
Cl
Cl
O
O
O
O
2
75
95
Br
93
95
10
11
Br
NH
OMe
N
OMe
NH
OMe
N
O
O
O
OMe
1b
2b
1j
2j
O
O
O
Br
Br
3
Br
Cl
Br
Cl
Cl
NH
OMe
N
NH
OMe
N
O
O
OMe
O
O
O
O
OMe
1c
2c
1k
2k
Cl
Cl
O
O
O
O
72
85
F
F
12
13
4
5
89
96
NH
OMe
N
NH
OMe
N
O
OMe
O
O
OMe
1l
2l
1d
2d
Cl
Cl
O
O
O
O
Cl
N
NH
OMe
NH
OMe
N
OMe
O
O
O
OMe
1m
2m
1e
2e
O
O
O
O
F
Br
Br
F
Br
Br
59
6
7
80
14
NH
OMe
N
OMe
NH
OMe
N
OMe
O
O
O
O
O
1f
2f
1n
2n
O
O
O
O
91
43
33
15
16
NH
OMe
N
OMe
NH
OMe
N
O
O
O
OMe
1g
2g
1o
2o
O
O
O
O
Cl
Cl
8
91
S
S
NH
OMe
N
NH
OMe
N
OMe
OMe
O
O
O
O
1h
2h
1p
2p
aGeneral conditions for 1a-m: 1 (1.0 equiv), PIDA (1.2 equiv) in TFE (0.05 M), rt, 40 min; General conditions for 1n-p: 1 (1.0 equiv), PhIO (2.2 equiv) in
5
TFE (0.05 M), stirred at reflux for 15 h. bIsolated yields.
cyclized products could be achieved in acceptable yields. It is
worthy to note that when the ring A was a thienyl ring, the
desired cyclized product could also be obtained in an acceptable
33% yield (Table 3, entry 16). Exceptionally, when the substrate
position in ring B, the cyclization did not occur and the reaction
afforded product 2q, not the desired cyclized product (Scheme 1,
eq 1). This result indicates that the presence of a strong electronꢀ
withdrawing group in the phenyl ring B prevents the cyclization
10 bears a strong electronꢀwithdrawing NO2 group at the para 15 which allows the generated nitrenium ion intermediate to be
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captured by a nucleophilic trifluoethanol. It is worthy to note that, 40 aSchool of Pharmaceutical Science and Technology, Tianjin University,
when the para position of ring B was a methoxy group, substrate
1r was converted to the spiro 2r in 62% yield under standard
conditions (Scheme 1, eq 2). It is evident that the presence of the
methoxy group facilities the ipso attack of the
Tianjin 300072, China. E-mail: duyunfeier@tju.edu.cn;
Fax: +86-22-27404031; Tel: +86-22-27404031
bCollaborative Innovation Center of Chemical Science and Engineering
(Tianjin), Tianjin 300072, China. E-mail: duyunfeier@tju.edu.cn;
45 Fax: +86-22-27404031; Tel: +86-22-27404031
5
Notes and references
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50
55
P. Upadhyaya, Eur. J. Med. Chem., 1986, 21, 21.
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Adams, J. Med. Chem., 1992, 35, 1887.
Scheme 1 Other models that failed to afford dibenzoxazepinone
(4) J.ꢀF. F. Liegeois, F. A. Rogistert, J. Bruhwyler, J. Damas, T. P.
Nguyen, M.ꢀO. Inarejos, E. M. G. Chleide, M. G. A. Mercier and J. E.
Delarget, J. Med. Chem., 1994, 37, 519.
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O
O
Pd/C, H2, AcOH
70 oC, 24 h
76%
N
NH
8a
OMe
O
O
2a
Scheme 2 The removal of methoxy group in 2a
65
Med. Chem., 1982, 25, 1065.
10
(8) R. A. Bunce and J. E. Schammerhorn, J. Heterocycl. Chem., 2006, 43,
nitrenium ion onto the ring B. The Nꢀunsubstitued products are
also potential building block for the synthesis of important
pharmaceutical agents with biological activities.1ꢀ6 As illustrated
in Scheme 2, the Nꢀmethoxy dibenzoxazepinone could be readily
15 converted to Nꢀunsubstitued dibenzoxazepinone, through
palladium catalyzed hydrogenation reaction,16 which allows for
the further derivatization of the free NH moiety for synthesizing
antidepressant dibenzoxazepinone and HDAC inhibitor B2.
1031.
(9) Y. Liu, C. Chu, A. Huang, C. Zhan, Y. Ma and C. Ma, Comb. Sci.,
2011, 13, 547.
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Jacobsen and J. W. Mickelson, Tetrahedron. Lett., 1996, 37, 2361. (c)
75
80
85
M. T. Herrero, I. Tellitu, E. Domínguez, S. Hernández, I. Moreno
and R. SanMartin, Tetrahedron, 2002, 58, 8581. (d) E. Miyazawa, T.
Sakamoto and Y. Kikugawa, Heterocycles, 2003, 59, 149. (e) S.
Serna, I. Tellitu, E. Domínguez, I. Moreno and R. SanMartin,
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I. Moreno and R. SanMartin, J. Org. Chem., 2005, 70, 2256. (g) K.
Inoue, Y. Ishikawa and S. Nishiyama, Org. Lett., 2010, 12, 436. (h)
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J. Org. Chem., 2014, 79, 955.
20 Conclusions
In summary, we have developed a novel method for the
construction
(aryloxy)benzamides
of
the
through
biologically
an
interesting
iodine(III)ꢀmediated
2ꢀ
25 intermolecular CꢀN bond formation. Advantages of the method
include the readily availability of the starting materials, the mild
reaction conditions, and the transitionꢀ metalꢀfree feature.
Moreover, the transformation tolerates a wide range of functional
groups, and the Nꢀmethoxy group in the final products can be
30 readily removed and allows for further derivatization.
(13) (a) T. Akbarzadeh, S. A. Tabatabai, M. J. Khoshnoud, B. Shafaghic
and A. Shafieea, Bioorg. Med. Chem., 2003, 11, 769. (b) M. J.
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353, 1591.
95 (15) M. O. Anderson, M. Jamie, S. John and R. K. Guy, Synlett 2004, 13,
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(16) A. M. Birch, P. W. Kenny, N. G. Oikonomakos, L. Otterbein, P.
Schofield, P. R. O. Whittaamore and D. P. Whalley, Bioorg. Med.
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Acknowledgements
We acknowledge the National Science Foundation of China
35 (#21472136) and the National Basic Research Project
(2015CB856500) for financial support.
Notes and references
100
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