A one-pot three-component reaction providing tricyclic 1,4-benzoxazepine derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.03.131

A new one-pot, three-component reaction of aromatic aldehydes, 2-aminophenol, and dimedone for the synthesis of tricyclic 1,4-benzoxazepine derivatives in moderate to good yields is described.

Full text of DOI:10.1016/j.tetlet.2013.03.131

Tetrahedron Letters xxx (2013) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A one-pot three-component reaction providing tricyclic
1,4-benzoxazepine derivatives
Mehdi Ghandi a, , Tayebeh Momeni a, Mohammad Taghi Nazeri a, Nahid Zarezadeh a, Maciej Kubicki b
⇑
a School of Chemistry, College of Science, University of Tehran, PO Box 14155 6455, Tehran, Iran
b Faculty of Chemistry, Adam Mickiewicz University in Poznan, Umultowska 89b, 61-614 Poznan, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A new one-pot, three-component reaction of aromatic aldehydes, 2-aminophenol, and dimedone for the
synthesis of tricyclic 1,4-benzoxazepine derivatives in moderate to good yields is described.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 30 January 2013
Revised 14 March 2013
Accepted 28 March 2013
Available online xxxx
Keywords:
1,4-Benzoxazepine
Enamines
Dimedone
2-Aminophenol
Multicomponent reactions (MCRs) are processes in which at
least three different simple substrates react in one-pot to give
the target materials.1 These reactions, which have gained signifi-
cant attention during the past years, do not occur through a
single-step procedure, but rather via several sequential steps
involving cascades or domino reactions.2 Simplicity, greater
efficiency, and atom economy with generation of molecular com-
plexity and diversity in one-pot transformations are some advanta-
ges of these reactions.3
Benzo-fused seven-membered heterocycles containing two het-
eroatoms at positions 1 and 4 are used in medicinal chemistry due
to their wide spectrum of biological activities.4 Examples include
1,4-benzodioxepine, 1,4-benzodithiepine, 1,4-benzoxazepine,
1,4-benzoxathiepine, 1,4-benzothiazepine, and 1,4-benzodiaze-
pine.5 Benzodiazepines and benzoxazepines are known as
non-peptide vasopressin V2 receptor agonists.5 Benzoxazepine
derivatives form an important class of compounds with various
biological activities.6 Among compounds containing this fragment
are psychotropic and neurotropic agents,7 a non-nucleoside HIV-1
reverse transcriptase inhibitor,8 calcium antagonists,9 antidepres-
sants,10 and analgesics.11
proceeded smoothly to completion within 24 h in the presence of
trifluoroacetic acid (TFA) (20 mol %), affording the tricyclic 1,4-
benzoxazepine 2a in 68% yield (Scheme 1).12 The analytical and
spectroscopic data of 2a were in agreement with the proposed
structure.13 For example, the 1H NMR spectrum of 2a contained
characteristic singlets at d 1.06, 1.09, 2.65, 6.53, and 9.21 due to
the two methyl groups, CH2CO, CHPh, and NH protons, respec-
tively, together with an AB quartet at d 2.18 for the CH2C@C group.
The 13C NMR spectrum of 2a exhibited 21 distinct signals including
one at d 192.6 due to the C@O group.
We next examined the substrate scope by reacting 2-aminophe-
nol and dimedone with different aldehydes in DCE (Scheme 2). As
indicated in Table 1, reactions of various aldehydes 1a–l afforded
the corresponding 1,4-benzoxazepine derivatives 2a–l. Gratify-
ingly, aldehydes with electron-donating or electron-withdrawing
groups underwent this multicomponent sequence (Table 1).14
H
1: DCE
NH2
OH
O
N
O
reflux, 4h
+
Herein, we report a one-pot, three-component synthesis of
1,4-benzoxazepine derivatives via the multicomponent reaction
of commercially available 2-aminophenol, dimedone, and various
aromatic aldehydes. To our delight, the reaction of preheated
2-aminophenol and dimedone in DCE with benzaldehyde
O
2: TFA (20%)
reflux, 24h
O
O
2a
1a
⇑
Corresponding author. Tel.: +98 21 61112250; fax: +98 21 66495291.
E-mail address: ghandi@khayam.ut.ac.ir (M. Ghandi).
Scheme 1. Synthesis of 1,4-benzoxazepine 2a.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.131
Please cite this article in press as: Ghandi, M.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.03.131

2
M. Ghandi et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Table 1 (continued)
H
N
1: DCE
NH2
OH
O
Entry
Aldehyde
Product
Yield (%)
reflux, 4 h
+
O
O
2: TFA (20%)
reflux, 24 h
O
H
O
N
O
O
R
O
O
HO
8
58
2a-l
1h
R
1a-l
HO
2h
O
N
H
N
Scheme 2. Synthesis of 1,4-benzoxazepine derivatives 2a–l.
9
10
11
59
73
69
O
1i
Table 1
Isolated yields of 1,4-benzoxazepines 2a–l
N
2i
Entry
Aldehyde
Product
Yield (%)
O
H
N
O
Cl
Br
Cl
H
N
O
O
O
O
O
1j
1
68
O
O
Cl
2j
1a
O
2a
H
N
O
H
N
O
1k
O
2
77
Br
Cl
2k
1b
O
Cl
Br
H
N
2b
2c
O
H
N
12
O
75
Cl
Cl
1l
O
3
4
5
6
73
63
82
65
O
Cl
2l
Br
1c
O
H
N
O
O
O
1d
2d
O
H
N
O
NO2
1e
NO2
Ph
2e
2f
O
H
N
O
O
O
Ph
1f
O
H
N
O
O2N
7
78
1g
O2N
2g
Figure 1. X-ray crystal structure of compound 2a.
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M. Ghandi et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
Angew. Chem., Int. Ed. 2005, 44, 1602–1634; (d) Zhu, J. Eur. J. Org. Chem. 2003,
1133–1144.
4. Khaleghi, F.; Din, L. B.; Jantan, I.; Yaacob, W. A.; Khalilzadeh, M. A. Tetrahedron
Lett. 2011, 52, 7182–7184.
5. Yadav, D. B.; Morgans, G. L.; Aderibigbe, B. A.; Madeley, L. G.; Fernandes, M. A.;
Michael, J. P.; de Koning, C. B.; van Otterlo, W. A. L. Tetrahedron 2011, 67, 2991–
2997.
H
N
O
NH2
OH
+
OH
I
O
O
O
OH
O
6. (a) Liégeois, F.; Deville, M.; Dilly, S.; Lamy, C.; Mangin, F.; Résimont, M.; Tarazi,
F. I. J. Med. Chem. 2012, 55, 1572–1582; (b) Duncton, M. A. J.; Smith, L. M. I. I.;
Burdzovic-Wizeman, S.; Burns, A.; Liu, H.; Mao, Y.; Wong, W. C.; Kiselyov, A. S. J.
Org. Chem. 2005, 70, 9629–9963; (c) Bihel, F.; Kraus, J.-L. Org. Biomol. Chem.
2003, 1, 793–799; (d) Ellenbroek, B. A.; Liégeois, J.-F. Drug Rev. 2003, 9, 41–57;
(e) Miki, T.; Kori, M.; Mabuchi, H.; Tozawa, R.; Nishimotos, T.; Sugiyama, Y.;
Teshima, K.; Yukimasa, H. J. Med. Chem. 2002, 45, 4571–4580.
7. (a) Nagarajan, K.; David, J.; Bhat, G. A. Indian J. Chem. 1985, 24B, 840–844; (b)
Jilek, J. O.; Pomykacek, J.; Metysova, J.; Metys, J.; Protiva, M. Collect. Czech. Chem.
Commun. 1965, 30, 363–371.
8. (a) Xing, X. L.; Wu, J. L.; Luo, J. L.; Dai, W. Synlett 2006, 2099–2103; (b) Klunder,
J. M.; Hargrave, K. D.; West, M.; Cullen, E.; Pal, K.; Behnke, M. L.; Kapadia, S. R.;
McNeil, D. W.; Wu, J. C.; Chow, G. C.; Adams, J. J. Med. Chem. 1992, 35, 1887–
1897; (c) Merluzzi, V. J.; Hargrave, K. D.; Labadia, M.; Grozinger, K.; Skoog, M.;
Wu, J. C.; Shih, C.-K.; Eckner, K.; Hattox, S.; Adams, J.; Rosenthal, A. S.; Faanes,
R.; Eckner, R. J.; Koup, R. A.; Sullivan, J. L. Science 1990, 250, 1411–1413.
9. Li, R.; Farmer, P. S.; Wang, J.; Boyd, R. J.; Cameron, T. S.; Quilliam, M. A.; Walter,
J. A.; Howlett, S. E. Drug Des. Discov. 1995, 12, 337–358.
TFA
1a
H
N
N
or
2a
O
OH
O
OH
III
II
Scheme 3. Suggested mechanism for the formation of 2a.
10. Nagarajan, K.; David, J.; Kulkarni, Y. S.; Hendi, S. B.; Shenoy, S. J.; Upadhyaya, P.
Eur. J. Med. Chem. Chim. Ther. 1986, 21, 21–26.
11. (a) Wu, J.; Jiang, Y.; Dai, W. M. Synlett 2009, 1162–1166; (b) Hallinan, E. A.;
Hagen, T. J.; Tsymbalov, S.; Stapelfeld, A.; Savage, M. A. Bioorg. Med. Chem. 2001,
9, 1–6; (c) Hallinan, E. A.; Hagen, T. J.; Tsymbalov, S.; Husa, R. K.; Lee, A. C.;
Stapelfeld, A.; Savage, M. A. J. Med. Chem. 1996, 39, 609–613.
12. General procedure for the synthesis of 1,4-benzoxazepine 2a. A stirred solution of
2-aminophenol (0.109 g, 1 mmol) and dimedone (0.168 g, 1.2 mmol) in DCE
(5 mL) was heated at reflux for 4 h. After completion of this step as indicated by
TLC, benzaldehyde (0.106 g, 1 mmol) and TFA (0.023 g, 0.2 mmol) were added
and heating at reflux was continued for 24 h. After completion, aqueous
NaHCO3 (10 mL, 20%) was added and the organic phase was separated, washed
with H2O (10 mL), and dried over anhydrous Na2SO4. The solvent was
evaporated under reduced pressure and the residue was recrystallized from
30% EtOAc in hexane.
Unambiguous evidence for the structure of 2a was obtained by
single-crystal X-ray-diffraction analysis (Fig. 1).15
Mechanistically, the reaction presumably proceeds via the ini-
tial formation of the enamine I, produced from condensation of
2-aminophenol with dimedone. Subsequent trapping with alde-
hyde 1a via either the intermediate imine II16 or oxonium ion
III,17 and intramolecular cyclization finally afford 2a (Scheme 3).
Inspection of the results revealed that whereas an unsubstitut-
ed aldehyde afforded 2a in moderate yield (entry 1 Table 1), those
bearing electron-withdrawing groups produced the corresponding
products in higher yields (entries 2, 3, 5, 7, and 10, Table 1). On the
other hand, lower yields of 1,4-benzoxazepines were obtained by
introducing electron-donating groups on the aromatic aldehyde
(entries 4, 6, and 8, Table 1). This behavior supports the suggested
mechanism since the introduction of an electron-withdrawing
group on the phenyl ring accelerates the rate of formation or con-
sumption of either intermediates II or III.
13. 3,3-Dimethyl-11-phenyl-3,4,5,11-tetrahydrodibenzo[b,e][1,4]oxazepin-1(2H)-one
(2a). White solid: (398 mg, 68%); mp: 269–271 °C; IR (KBr)
m: 3344 (NH), 1739
(CO) cmꢀ1 1H NMR (300 MHz, DMSO-d6) d 1.06 (s, 3H, Me), 1.09 (s, 3H, Me),
;
2.18 (AB quartet, 2H, J = 16.0 Hz, C@CCH2), 2.65 (s, 2H, CH2CO), 6.53 (s, 1H,
CHPh), 6.61 (d, 1H, J = 7.3 Hz, Ar), 6.70 (t, 1H, J = 7.3 Hz, Ar), 6.82 (dd, 1H,
J = 7.5 Hz, Ar), 7.03 (d, 2H, J = 8.5 Hz, Ar), 7.42–7.47 (m, 3H, Ar), 7.57 (d, 1H,
J = 6.3 Hz, Ar), 9.21 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) d 27.6, 28.2, 31.8,
43,7, 49.3, 78.5, 104.4, 145.8, 116.3, 118.0, 119.0, 123.4, 123.9, 128.0, 130.1,
132.2, 134.0, 138.7, 149.0, 154.9, 192.6 (CO); MS (El) m/z: 319 (92, M+), 318
(100), 242 (30), 234 (14), 77 (23); Anal. Calcd for C21H21NO2: C, 78.97; H, 6.63;
N, 4.39. Found: C, 78.54; H, 6.98; N, 4.45.
In conclusion, a range of 1,4-benzoxazepines 2a–l has been syn-
thesized in moderate to high yields via the one-pot, three-compo-
nent reaction of 2-aminophenol, dimedone, and aldehydes 1a–l.
These new compounds broaden the scope of MCRs and may be of
potential interest in drug discovery.
14. 11-([1,10-Biphenyl]-4-yl)-3,3-dimethyl-3,4,5,11-
tetrahydrodibenzo[b,e][1,4]oxazepin-1(2H)-one (2f). White solid: (395 mg, 65%);
mp 277–279 °C; IR (KBr) m ;
: 3324 (NH), 1741 (CO) cmꢀ1 1H NMR (300 MHz,
DMSO-d6) d 1.10 (s, 3H, Me), 1.11 (s, 3H, Me), 2.21 (AB quartet, 2H, J = 15.9 Hz,
C@CCH2), 2.68 (s, 2H, CH2CO), 6.62 (s, 1H, CHPh), 6.67 (d, 1H, J = 7.8 Hz, Ar),
6.76–6.83 (m, 2H, Ar), 7.04 (d, 1H, J = 7.7 Hz, Ar), 7.18 (d, 2H, J = 8.1 Hz, Ar),
7.29 (t, 1H, J = 7.1 Hz, Ar), 7.38 (t, 2H, J = 7.1 Hz, Ar), 7.47 (d, 2H, J = 8.1 Hz, Ar),
7.55 (d, 2H, J = 7.29 Hz, Ar), 9.19 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) d
27.5, 28.4, 31.9, 43.6, 49.4, 78.8, 109.4, 120.2, 122.8, 123.2, 123.9, 126.2, 126.5,
126.7, 127.2, 127.4, 128.8, 128.9, 129.0, 129.2, 134.0, 138.9, 139.1, 139.3, 146.0,
154.8, 192.6 (CO); MS (El) m/z: 395 (81, M+), 394 (100), 318 (41), 242 (40), 234
(7); Anal. Calcd for C27H25NO2: C, 82.00; H, 6.37; N, 3.54. Found: C, 82.27; H,
6.44; N, 3.41.
Acknowledgment
The authors acknowledge the University of Tehran for the finan-
cial support of this research.
15. CCDC-921136. Copies of these data can be obtained free of charge via http://
References and notes
www.ccdc.cam.ac.uk/conts/retrieving.html
(or
from
the
Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk).
16. (a) Kashiwagi, T.; Kotani, S.; Sugiura, M.; Nakajima, M. Tetrahedron 2011, 67,
531–539; (b) Karthikeyan, S. V.; Perumal, S.; Balasubramanian, K. K.
Tetrahedron Lett. 2007, 48, 6133–6136.
17. (a) Saito, A.; Takayama, M.; Yamazaki, A.; Numaguchi, J.; Hanzawa, Y.
Tetrahedron 2007, 63, 4039–4047; (b) Larghi, E. L.; Kaufman, T. S. Synthesis
2006, 187–220.
1. (a) Liang, B.; Kalidindi, S.; Porco, J. A., Jr.; Stephenson, C. R. J. Org. Lett. 2010, 12,
572–575; (b) Ganem, B. Acc. Chem. Res. 2009, 42, 463–472; (c) Cui, S. L.; Lin, X.
F.; Wang, Y. G. Org. Lett. 2006, 8, 4517–4520.
2. Kriis, K.; Ausmees, K.; Pehk, T.; Lopp, M.; Kanger, T. Org. Lett. 2010, 12, 2230–
2233.
3. (a) Dömling, A. Chem. Rev. 2006, 106, 17–89; (b) Banfi, L.; Riva, R. Org. React.
2005, 65, 1–140; (c) Ramón, D. J.; Yus, M. Angew. Chem. 2005, 117, 1628–1661.
Please cite this article in press as: Ghandi, M.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.03.131