Synthesis of substituted benzo[: B] [1,4]oxazepine derivatives by the reaction of 2-aminophenols with alkynones

Article abstract of DOI:10.1039/c9ob02450f

We have developed a novel synthetic method accessing benzo[b][1,4]oxazepines that are one of the rare classes of benzoxazepine derivatives by reaction of 2-aminophenols with alkynones in 1,4-dioxane at 100 °C. A series of benzo[b][1,4]oxazepine derivatives can be prepared by using this synthetic protocol. Mechanistic experiments indicated that the hydroxy proton of the aminophenol could play a crucial role in the formation of an alkynylketimine intermediate that undergoes 7-endo-dig cyclization.

Full text of DOI:10.1039/c9ob02450f

Organic &
Biomolecular Chemistry
View Article Online
View Journal
COMMUNICATION
Synthesis of substituted benzo[b][1,4]oxazepine
derivatives by the reaction of 2-aminophenols with
alkynones†
Cite this: DOI: 10.1039/c9ob02450f
Received 13th November 2019,
Accepted 17th December 2019
Kohei Oshimoto, Biao Zhou,
Hiroaki Tsuji * and Motoi Kawatsura
*
DOI: 10.1039/c9ob02450f
rsc.li/obc
We have developed a novel synthetic method accessing benzo pines in high yields (Scheme 1a).7 Later, Cui and co-workers
[b][1,4]oxazepines that are one of the rare classes of benzoxaze- reported the efficient synthesis of substituted benzo[b][1,4]oxa-
pine derivatives by reaction of 2-aminophenols with alkynones in zepines from enaminones in the presence of Cs2CO3 as the
1,4-dioxane at 100 °C. A series of benzo[b][1,4]oxazepine deriva- promoter (Scheme 1b).8 However, these methods require the
tives can be prepared by using this synthetic protocol. Mechanistic use of a precious metal catalyst and a stoichiometric amount
experiments indicated that the hydroxy proton of the aminophenol of base.
could play a crucial role in the formation of an alkynylketimine
On the other hand, we have recently reported the synthesis
of benzoxazoles via the copper-catalyzed hydroamination of
alkynones with 2-aminophenols.9 During the optimization of
the reaction conditions of the copper catalysis, we found that
the reaction of 2-aminophenols with 1.2 equivalents of alky-
nones in o-xylene at 100 °C gave benzo[b][1,4]oxazepines in
good yields. We now report a novel synthetic method that
allows easy and efficient access to benzo[b][1,4]oxazepines by
intermediate that undergoes 7-endo-dig cyclization.
Benzoxazepine derivatives are one of the important seven-
membered heterocycles that are known to exhibit potent
pharmacological activities.1,2 Due to their attractive features,
the synthetic study of the privileged heterocyclic compounds
has received a great deal of attention from the synthetic com-
munity and thus the syntheses of a wide variety of benzoxaze-
pine derivatives, such as dibenzoxazepinones,3 dibenzoxaze-
pines,4 and benzoxazepinones,5 have been achieved in the past
few decades.6 However, there are few examples for the
synthesis of the most simple benzoxazepines that consist of
benzene and oxazepine rings, because the conventional
synthetic methods usually rely on the aromatic nucleophilic
substitution, transition metal-catalyzed coupling reaction of
aromatic halides, and condensation of carboxylic acid deriva-
tives. Given the fact that benzoxazepine analogues would
exhibit potentially high biological activities, developing syn-
thetic tools to produce such a rare class of benzoxazepines
remains highly desirable. As an example for the preparation of
benzoxazepines, Jiang and co-workers reported the synthesis
of benzo[b][1,4]oxazepine derivatives, in which the three-com-
ponent coupling reaction of 2-aminophenols, bromoalkynes,
and isocyanides proceeded in the presence of a palladium
catalyst to give the corresponding 4-amine-benzo[b][1,4]oxaze-
Department of Chemistry, College of Humanities & Sciences, Nihon University,
Sakurajosui, Setagaya-ku, Tokyo 156-8550, Japan. E-mail: tsuji@chs.nihon-u.ac.jp,
kawatsur@chs.nihon-u.ac.jp
†Electronic supplementary information (ESI) available. CCDC 1958661. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9ob02450f
Scheme 1 Synthesis of substituted benzo[b][1,4]oxazepines. (a) Jiang’s
work. (b) Cui’s work. (c) This work.
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
the reaction of 2-aminophenols with alkynones (Scheme 1c). (entry 10). On the other hand, the use of 2.2 and 2.5
In this method, the reaction can proceed without the use of equivalents of 2a led to a decrease in the yield of 3aa
additional reagents, such as a transition metal catalyst and a (entries 11 and 12).
base, thus providing an efficient protocol for the synthesis of
benzo[b][1,4]oxazepines that are one of the rare classes of ben- ined the reaction of several 2-aminophenols 1 with alkynone
zoxazepine derivatives.
2a under the optimized reaction conditions (Scheme 2).11 The
With the optimized reaction conditions in hand, we exam-
At the outset of our study, we examined the optimization of reaction of 4-methyl-2-aminophenol (1a) with alkynone 2a can
the reaction conditions (Table 1). We carried out the reaction be scaled up to 3 mmol scale without any loss of the reaction
of 4-methyl-2-aminophenol (1a) with 1.2 equivalents of alky- efficiency, providing the desired product 3aa in 79% yield. The
none 2a in o-xylene at 100 °C (entry 1). We confirmed that reaction of 2-aminophenol (1b) and 5-methyl-2-aminophenol
benzo[b][1,4]oxazepine 3aa was formed in 23% yield as a side (1c) with alkynone 2a smoothly proceeded to give the desired
product along with the formation of benzoxazole 4 in 48% benzo[b][1,4]oxazepines 3ba and 3ca in 77% and 81% yield,
yield. We speculate that the benzoxazole 4 would be obtained respectively. 2-Aminophenols 1d and 1e bearing methoxy and
by the conjugate addition of 1a to 2a10 and subsequent intra- trifluoromethyl groups on their aromatic rings underwent the
molecular cyclization/elimination of an acetone sequence. reaction to afford the desired products 3da and 3ea in moder-
Motivated by this finding, we sought to develop a novel ate yields. A 5-fluoro substituent on the aromatic ring was tol-
method for the synthesis of benzo[b][1,4]oxazepines. We erated during this transformation, giving the benzo[b][1,4]oxa-
initially tested various solvents (entries 2–8). As a result, the zepine 3fa in 60% yield. On the other hand, the reaction of
ether type solvents, such as 1,4-dioxane, CPME, and diglyme, 2-aminophenols 1g and 1h bearing 5-chloro and 5-bromo sub-
were found to be effective for the reaction. In particular, the stituents led to low yields of 3ga and 3ha. Benzo[b][1,4]oxaze-
use of 1,4-dioxane as the solvent afforded the desired product pine 3ia having a phenyl group at the 4 position on the aro-
3aa in 63% yield as the main product (entry 3). With the suit- matic ring was obtained in 51% yield.
able solvent in hand, we next evaluated the effect of the
We next investigated the reaction of 2-aminophenol (1b)
loading amount of alkynone 2a (entries 9–12). To our delight, with a wide variety of alkynones 2 (Scheme 3).11 The reaction
the reaction of aminophenol 1a with 1.5 equivalents of alky- of 1b with alkynones bearing methyl (2b) and methoxy (2c)
none 2a was performed in 1,4-dioxane at 100 °C to give the substituents at the para position on their phenyl rings took
desired benzo[b][1,4]oxazepine 3aa in 70% yield (entry 9). place to give benzo[b][1,4]oxazepines 3bb and 3bc in 73% and
When 2.0 equivalents of 2a were employed in this reaction 69% yield, respectively. The structure of 3bc was determined
system, the yield of 3aa was further improved to 76% by X-ray crystallographic analysis as shown in Scheme 4.
Table 1 Optimization of the reaction conditionsa
Entry
X
Solvent
Yield of 3aab (%)
Yield of 4b (%)
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
2.0
2.2
2.5
o-Xylene
Toluene
1,4-Dioxane
CPME
Diglyme
DMSO
DMF
23
21
63
53
55
4
41
16
48
38
11
24
15
2
12
25
10
7
tAmOH
9
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
70
10
11
12
76 (77)c
74
7
5
69
a Reaction conditions: 1a (0.30 mmol) and 2a (1.2–2.5 equiv.) in
solvent (0.6 mL) at 100 °C for 19 h. b The yields were determined by 1H
NMR analyses of the crude reaction mixture using dibromomethane as
an internal standard. c Isolated yield.
Scheme 2 Scope of 2-aminophenols 1. Reaction conditions:
(0.30 mmol) and 2a (0.60 mmol) in 1,4-dioxane (0.6 mL) at 100 °C for
19 h. a 3 mmol scale.
1
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2019

View Article Online
Organic & Biomolecular Chemistry
Communication
butyl (3bi) substituents can be introduced to the oxazepine
skeleton instead of the methyl group in good yields. The reac-
tion of 1b with alkynone 2j bearing a sterically bulky ketone
consisting of a secondary butyl group also proceeded to give
the desired product 3bj in 44% yield, albeit with a mixture of a
trace amount of an inseparable impurity. Unfortunately, the
reaction with alkynones bearing an electron-poor aromatic
ring (R1 = 4-CF3C6H4, R2 = Me), aliphatic alkyne groups (R1 =
phenethyl or hexyl, R2 = Me), and an aromatic ketone group
(R1 = Ph, R2 = Ph) did not work well under the reaction
conditions.
We next demonstrated the mechanistic consideration of the
transformation (Scheme 5). We initially examined the mechan-
istic experiments as shown in Schemes 5a and b. We con-
firmed that the reaction of o-anisidine 5 or o-hydroxyacetani-
lide 6 with 2.0 equivalents of alkynone 2a under the reaction
conditions did not proceed at all (Scheme 5a). Furthermore,
while the reaction of aminophenol 1b with 2.0 equivalents of
acetophenone under the reaction conditions afforded the
corresponding ketimine in a 20% NMR yield, no ketimine
product was observed in the reaction with o-anisidine 5
(Scheme 5b). These results indicated that the presence of a
phenolic proton might be necessary for the formation of an
Scheme 3 Scope of alkynones 2. Reaction conditions: 1b (0.30 mmol)
a
and 2 (0.60 mmol) in 1,4-dioxane at 100 °C for 19 h. With a trace
amount of inseparable impurities.
Scheme 4 X-ray crystal structure of 3bc.
Alkynone 2d having a chloro atom underwent the reaction to
give the desired product 3bd in 64% yield.
meta-Tolyl- and ortho-tolyl-substituted benzo[b][1,4]oxaze-
pines 3be and 3bf were obtained in good yields. The use of
alkynone 2g bearing a thiophene ring led to a low yield of the
desired benzo[b][1,4]oxazepine 3bg. The propyl (3bh) and iso- Scheme 5 Mechanistic consideration.
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
2 For examples of pharmacologically active benzoxazepine
derivatives, see: (a) Y. Nagai, A. Irie, H. Nakamura, K. Hino,
H. Uno and H. Nishimura, J. Med. Chem., 1982, 25, 1065–
1070; (b) J. M. Klunder, K. D. Hargrave, M. West, E. Cullen,
K. Pal, M. L. Behnke, S. R. Kapadia, D. W. McNeil, J. C. Wu,
G. C. Chow and J. Adams, J. Med. Chem., 1992, 35, 1887–
1897; (c) Y. Liao, B. J. Venhuis, N. Rodenhuis,
W. Timmerman and H. Wikström, J. Med. Chem., 1999, 42,
2235–2244; (d) T. Miki, M. Kori, H. Mabuchi, R. Tozawa,
T. Nishimoto, Y. Sugiyama, K. Teshima and H. Yukimasa,
J. Med. Chem., 2002, 45, 4571–4580; (e) R. A. Smits,
H. D. Lim, B. Stegink, R. A. Bakker, I. J. P. de Esch and
R. Leurs, J. Med. Chem., 2006, 49, 4512–4516.
3 For examples see: (a) S.-M. Lu and H. Alper, J. Am. Chem.
Soc., 2005, 127, 14776–14784; (b) R. A. Bunce and
J. E. Schammerhorn, J. Heterocycl. Chem., 2006, 43, 1031–
1035; (c) Q. Yang, H. Cao, A. Robertson and H. Alper, J. Org.
Chem., 2010, 75, 6297–6299; (d) Y. Liu, C. Chu, A. Huang,
C. Zhan, Y. Ma and C. Ma, ACS Comb. Sci., 2011, 13, 547–
553; (e) M. O. Kitching, T. E. Hurst and V. Snieckus, Angew.
Chem., Int. Ed., 2012, 51, 2925–2929; (f) N. C. Ganguly,
P. Mondal, S. Roy and P. Mitra, RSC Adv., 2014, 4, 55640–
55648; (g) C. Shen, H. Neumann and X.-F. Wu, Green
Chem., 2015, 17, 2994–2999; (h) S. Liu, Y. Hu, P. Qian,
Y. Hu, G. Ao, S. Chen, S. Zhang and Y. Zhang, Tetrahedron
Lett., 2015, 56, 2211–2213; (i) T. E. Hurst, M. O. Kitching,
L. C. R. M. da Frota, K. G. Guimarães, M. E. Dalziel and
V. Snieckus, Synlett, 2015, 26, 1455–1460; ( j) C. Shen and
X.-F. Wu, Catal. Sci. Technol., 2015, 5, 4433–4443;
(k) X. Guo, D. Zhang-Negrerie and Y. Du, RSC Adv., 2015, 5,
94732–94736; (l) E. Zhang, X. Zhang, W. Wei, D. Wang,
Y. Cai, T. Xu, M. Yan and Y. Zou, RSC Adv., 2015, 5, 5288–
5294; (m) Y. Zhou, J. Zhu, B. Li, Y. Zhang, J. Feng, A. Hall,
J. Shi and W. Zhu, Org. Lett., 2016, 18, 380–383; (n) J. Shi,
J. Wu, C. Cui and W.-M. Dai, J. Org. Chem., 2016, 81,
10392–10403 and also see ref. 2a and b.
Scheme 6 Transformation of benzo[b][1,4]oxazepine 3aa.
alkynylketimine intermediate. Based on these results, we pro-
posed the possible reaction mechanism as shown in
Scheme 5c. Initially, the reaction of aminophenol 1b with alky-
none 2a would occur to produce an alkynylketimine intermedi-
ate. We surmised that this process would be accelerated by the
hydrogen bonding interaction between the carbonyl group of
alkynone 2a and the phenolic proton of aminophenol 1b.12 The
alkynylketimine intermediate would undergo intramolecular
7-endo-dig cyclization to give the desired benzoxazepine 3ba.13
Next, we attempted to examine the transformation of benzo
[b][1,4]oxazepine 3aa (Scheme 6). Benzo[b][1,4]oxazepine 3aa
was converted into 4,5-dihydrobenzo[b][1,4]oxazepine deriva-
tive 7 in 78% yield by reduction with NaBH4 in MeOH.
Conclusions
In conclusion, we have achieved the efficient synthesis of
benzo[b][1,4]oxazepines that belong to one of the rare classes
of benzoxazepine derivatives by the reaction of 2-aminophe-
nols with alkynones. A series of benzo[b][1,4]oxazepines were
obtained in good yields using the novel synthetic method.
Mechanistic experiments indicated that the phenolic proton
on the aminophenols might be involved in the formation of
the alkynylketimine intermediate that would undergo intra-
molecular 7-endo-dig cyclization to produce benzo[b][1,4]oxaze-
pines. The extension of the substrate scope and the detailed
mechanistic study are currently underway in our laboratory.
4 (a) A. V. Konstantinova, T. N. Gerasimova, M. M. Kozlova
and N. I. Petrenko, Chem. Heterocycl. Compd., 1989, 25,
451–454; (b) D. Tsvelikhovsky and S. L. Buchwald, J. Am.
Chem. Soc., 2011, 133, 14228–14231; (c) J.-B. Feng and
X.-F. Wu, Green Chem., 2015, 17, 4522–4526; (d) F. Hu,
H. Liu, J. Jia and C. Ma, Org. Biomol. Chem., 2016, 14,
11076–11079; (e) V. Jamsheena, C. K. Mahesha, M. N. Joy
and R. S. Lankalapalli, Org. Lett., 2017, 19, 6614–6617;
(f) X.-Y. Chen, Z.-H. Li, J.-Q. Liu and X.-S. Wang, Synthesis,
2019, 51, 1662–1668; (g) W. Hu, F. Teng, H. Hu, S. Luo and
Q. Zhu, J. Org. Chem., 2019, 84, 6524–6535, and also see ref.
2c and e.
5 (a) A. D. Cale, Jr., T. W. Gero, K. R. Walker, Y. S. Lo,
W. J. Welstead, Jr., L. W. Jaques, A. F. Johnson,
C. A. Leonard, J. C. Nolan and D. N. Johnson, J. Med.
Chem., 1989, 32, 2178–2199; (b) K. Kamei, N. Maeda,
R. Ogino, M. Koyama, M. Nakajima, T. Tatsuoka, T. Ohno
and T. Inoue, Bioorg. Med. Chem. Lett., 2001, 11, 595–598;
(c) K. Kamei, N. Maeda, K. Nomura, M. Shibata,
R. Katsuragi-Ogino, M. Koyama, M. Nakajima, T. Inoue,
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research (C) from the Japan Society for the Promotion of
Science (17K05794). We thank Mr Yoshiyuki Takahashi for his
experimental support.
References
1 For a review, see: J. N. Sangshetti, A. Altamash Shakeel
Ahmad, F. A. Kalam Khan and Z. Zaheer, Mini-Rev. Org.
Chem., 2015, 12, 345–354.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2019

View Article Online
Organic & Biomolecular Chemistry
Communication
T. Ohno and T. Tatsuoka, Bioorg. Med. Chem., 2006, 14,
1978–1992; (d) L. Banfi, A. B. G. Guanti, P. Lecinska and
R. Riva, Org. Biomol. Chem., 2006, 4, 4236–4240;
(e) G. Chouhan and H. Alper, Org. Lett., 2010, 12, 192–195;
(f) Y. Liu, Y. Ma, C. Zhan, A. Huang and C. Ma, Synlett,
2012, 23, 255–258; (g) S. Pandey, S. V. Kumar, R. Kant and
P. M. S. Chauhan, Org. Biomol. Chem., 2014, 12, 5346–5350;
(h) K. Singh, B. K. Malviya, T. K. Roy, V. S. Mithu,
V. K. Bhardwaj, V. P. Verma, S. S. Chimni and S. Sharma,
J. Org. Chem., 2018, 83, 57–68 and also see ref. 2d.
215–218; (c) S. M. Bromidge, D. A. Entwistle, J. Goldstein
and B. S. Orlek, Synth. Commun., 1993, 23, 487–494;
(d) W. Liu, C. Chen and Q. Zhang, Org. Biomol. Chem.,
2011, 9, 6484–6486; (e) S. Roy, M. P. Davydova, R. Pal,
K. Gilmore, G. A. Tolstikov, S. F. Vasilevsky and
I. V. Alabugin, J. Org. Chem., 2011, 76, 7482–7490;
(f) J. Shao, X. Huang, X. Hong, B. Liu and B. Xu, Synthesis,
2012, 44, 1798–1805; (g) G. Cheng, X. Zeng, J. Shen,
X. Wang and X. Cui, Angew. Chem., Int. Ed., 2013, 52,
13265–13268.
6 For other related examples, see: (a) F. Ji, M.-F. Lv, W.-B. Yi 11 We confirmed the formation of small amounts of the
and C. Cai, Adv. Synth. Catal., 2013, 355, 3401–3406;
(b) C. K. Shahi, A. Bhattacharyya, Y. Nanaji and
corresponding benzoxazoles in the reaction of 2-aminophe-
nols 1 and alkynones 2.
M. K. Ghorai, J. Org. Chem., 2017, 82, 37–47; 12 Examples of the reaction involving the intermolecular phe-
(c) V. Srinivasulu, I. Shehadeh, M. A. Khanfar, O. G. Malik,
H. Tarazi, I. A. Abu-Yousef, A. Sebastian, N. Baniowda,
M. J. O’Connor and T. H. Al-Tel, J. Org. Chem., 2019, 84,
934–948.
7 B. Liu, Y. Li, M. Yin, W. Wu and H. Jiang, Chem. Commun.,
2012, 48, 11446–11448.
8 J. Shen, L. Xue, X. Lin, G. Cheng and X. Cui, Chem.
Commun., 2016, 52, 3292–3295.
9 K. Oshimoto, H. Tsuji and M. Kawatsura, Org. Biomol.
Chem., 2019, 17, 4225–4229.
nolic hydrogen bonding interaction with the carbonyl
group, see: (a) Y. M. A. Yamada and S. Ikegami, Tetrahedron
Lett., 2000, 41, 2165–2169; (b) D. C. Braddock,
I. D. MacGilp and B. G. Perry, Synlett, 2003, 1121–1124;
(c) N. T. McDougal and S. E. Schaus, J. Am. Chem. Soc.,
2003, 125, 12094–12095; (d) Y. E. Türkmen and
V. H. Rawal, J. Org. Chem., 2013, 78, 8340–8353.
13 Related 7-endo-dig cyclization of alkynone derivatives, see:
(a) Y. Chen, X. Liu, M. Lee, C. Huang, I. Inoyatov, Z. Chen,
A. C. Perl and W. H. Hersh, Chem. – Eur. J., 2013, 19, 9795–
9799; (b) Y. Chen, C. Huang, X. Liu, E. Perl, Z. Chen,
J. Namgung, G. Subramaniam, G. Zhang and W. H. Hersh,
J. Org. Chem., 2014, 79, 3452–3464 and also see ref. 5h.
10 (a) V. K. Tripathi, P. S. Venkataramani and G. Mehta,
J. Chem. Soc., Perkin Trans. 1, 1979, 36–41; (b) T. Sakamoto,
T. Nagano, Y. Kondo and H. Yamanaka, Synthesis, 1990,
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem.