Dibenzoxepino[4,5-d]pyrazoles: A facile approach via the Ullmann-ether reaction

Article abstract of DOI:10.1016/S0040-4039(00)00621-3

The application of a synthetic sequence of amine-exchange/Ullmann-ether reaction to 1,2-diarylenaminoketones for the access to dibenzoxepino[4,5- d]pyrazoles is reported. The reaction proceeds efficiently, permitting to incorporate a variety of substituents. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00621-3

Tetrahedron Letters 41 (2000) 4353±4356
Dibenzoxepino[4,5-d]pyrazoles: a facile approach via the
Ullmann-ether reaction
Roberto Olivera, Raul SanMartin and Esther Domõnguez*
Kimika Organikoa Saila, Zientzi Fakultatea, Euskal Herriko Unibertsitatea, PO Box 644, 48080 Bilbao, Spain
Received 9 March 2000; accepted 7 April 2000
Abstract
The application of a synthetic sequence of amine-exchange/Ullmann-ether reaction to 1,2-diarylenamino-
ketones for the access to dibenzoxepino[4,5-d]pyrazoles is reported. The reaction proceeds eciently,
permitting to incorporate a variety of substituents. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: dibenzoxepines; Ullmann reaction; exchange reaction.
It is well known that the preparation of new tetracyclic compounds bearing the azepine or
oxepine ring led to a new era in the ®eld of pharmacopsychiatry.1 In this context, the anti-
psychotic properties exhibited by dibenzoxepino[b,f]fused heterocycles such as maroxepine,
savoxepine2a and the pyrrolidine ORG-5222,2b provide an alternative to the employment of
azepine derivatives in the treatment of anxiety disorders and psychosis of schizophrenic origin.
Compounds with the formerly mentioned framework have found applications to a lesser extent
against certain types of ovary cancer,3a as antiin¯ammatory3b or as antispasmodic agents.3c
Encouraged by these antecedents, we embarked on a project directed at the synthesis of the title
derivatives with the aim of exploring their biological properties.4 In this paper, we wish to report
an ecient and facile method for the synthesis of tetracycles 1. Our synthetic strategy was
designed as shown in Scheme 1. This challenging approach relies on the successful cyclization of
the halohydroxyaryl pyrazoles 2 into the fused system 1, contrasting with the literature procedures
for the syntheses of dibenzoxepines, generally based on preformed diaryl ether derivatives.5
Following our ongoing research on the chemistry of new phenanthro heterocyclic compounds,6 we
planned to prepare the required diarylpyrazoles 2 by amine-exchange reaction of the corresponding
1,2-diarylenaminoketones 3.
The synthetic pathway carried out is outlined in Scheme 1. Thus, enaminoketones 3,7 easily
obtained by aminomethylenation of the corresponding aryl benzyl ketones8 with dimethyl-
formamide dimethyl acetal, were transformed into the 1-phenyl-4,5-diarylpyrazoles 2 by amine-
exchange/heterocyclization with phenylhydrazine, leading regioselectively to the target heterocycle
* Corresponding author. Tel: +34 94 601 2577; fax: +34 94 464 8500; e-mail: qopdopee@lg.ehu.es
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00621-3

4354
ꢀ
.
Scheme 1. Reagents and conditions. (a) PhNH±NH2 HCl, MeOH±H2O, Na2CO3/AcOH (pH=4), 140 C, 9±15 h; (b)
KOtBu, DMF, 0ꢀC, 0.25 h, (c) NaOH, MeOH±H2O, NBnEt3Cl (8 mol%) (sealed tube), 9 h; (d) KOH, MeOH±H2O,
.
70 C, 2 h; (e) CuBr SMe2, NaH, Py, 120 C, 2±8 h
ꢀ
ꢀ
4. This approach overwhelms the lack of regioselectivity classically associated with the usual
reaction between 1,3-dicarbonyl compounds and hydrazines.9 The deprotection step, performed
by basic hydrolysis, furnished the halohydroxy pyrazoles 2 in excellent yields, except in the case
of the tosylate 2a, which required unexpectedly harsh hydrolysis conditions.
Finally, after screening a variety of copper derivatives such as Cu2O, CuI, CuCl, CuO, CuOTf
and Cu in DMSO, DMF, NMP or toluene, the crucial Ullmann-ether reaction was successfully
e€ected by treating the sodium phenoxides in situ generated from pyrazoles 4, with the complex
.
CuBr SMe2 in pyridine, leading to the formation of the target dibenzoxepines 1 in good yield
(Table 1).10,11 We found that in the presence of copper(I) 2-thiophenecarboxylate (CuTC), the
reaction took place with comparable eciency.12
Table 1
Synthesis of dibenzoxepinopirazoles 1 and pyrazoles 2 and 4

4355
It is noteworthy that the reaction yield is not dependent on the electronic nature of the sub-
stituents. However, in terms of the phenol component of the reaction, the substrates bearing
electron-withdrawing groups 2d±e were found to react considerably faster, compared to the elec-
tron-rich (2b±c and 2f±h) or -neutral phenols (2a).
In summary, our synthetic pathway provides an ecient access to dibenzoxepino[4,5-d]pyrazoles
by using a modern variant of the Ullmann reaction, that operates in relatively mild conditions
and allows the accommodation of a variety of substitution patterns. Besides, it provides a practical
alternative to other known methodologies for the synthesis of dibenzoxepine derivatives. Application
of our synthetic pathway to the construction of thiepine derivatives and other dibenzoxepino-
fused heterocycles is currently under way.
Acknowledgements
This research was supported by the University of the Basque Country (Project UPV
170.310G37/98), the Ministry of Education and Culture (PB97-0600) and the Basque Government
(GV170.310-G0053/96). R.O. thanks the Basque Government for a predoctoral scholarship.
References
1. For a review, see: (a) Claghorn, J.; Lesem, M. D. Prog. Drug Res. 1996, 46, 243±262; (b) Sperling, W.; Demling, J.
Drugs Today 1997, 33, 95±102.
2. (a) Bischho€, S. In Novel Antipsychotic Drugs; Meltzer: New York, 1992; pp. 117±134. (b) Andree, B.; Halldin, C.;
Vrijmoed, M.; Farde, L. Psycopharmacol. 1997, 113, 339±345.
3. (a) Kanamaru, T.; Hida, T.; Muroi, M. Eur. Pat. Appl. EP 342,665 (CA: 113: 5954). (b) Boris, A. Eur. Pat. Appl.
EP 39,059 (CA: 96: 57777). (c) Bramcaccio, G.; Lettieri, G.; Monforte, P.; Larizza, A. Farmaco 1982, 37, 711±718.
4. A biological evaluation of the synthesized dibenzoxepine derivatives is being carried out by Fabrica Espanola de
Productos Quõmicos y Antibioticos (F.A.E.S S.A.) PO Box 555 48080 Bilbao, Spain.
5. Roswsky, A. In The Chemistry of Heterocyclic Compounds: Seven-Member Heterocyclic Compounds Containing
Oxygen and Sulfur; Weissberger, W.; Taylor, E. C., Eds.; Wiley-Interscience, 1975; pp. 154±176.
6. Olivera, R.; Pascual, S.; Herrero, M.; SanMartin, R.; Domõnguez, E. Tetrahedron Lett. 1998, 39, 7155±7158.
7. The presence of a free ortho-hydroxy group in deoxybenzoins may interfere with the amine-exchange process
leading to the corresponding iso¯avone. See: SanMartin, R.; Martõnez de Marigorta, E.; Domõnguez, E.
Tetrahedron 1994, 50, 2255±2264. After several alternatives were eliminated, benzoic and sulfonic esteres proved
optimal.
8. The preparation of o,o0-disubstituted aryl benzyl ketones was carried out by alkylation of acyl anion equivalents of
a-aminonitrile type or by Friedel±Crafts acylation. The followed method for the synthesis of o,o0-disubstituted
deoxybenzoins will be published elsewhere.
9. Elguero, J. Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.; Rees, C. W.; Schriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996; Vol. 3, Chapter 2.1.
10. Typical procedure for the Ullmann-ether coupling of halohydroxypyrazoles 2: NaH was added in portions (95%,
.
24 mg, 0.9 mmol) to a stirred solution of the pyrazole 2c (441 mg, 0.88 mmol) and CuBr SMe2 (355.5 mg, 1.74
mmol) in dry pyridine (9.5 mL) under Ar. After stirring the resulting mixture at room temperature for 15 min, it
was heated at 120ꢀC for 4.5 h and then cooled to room temperature. The reaction was quenched with HCl (5%)
(80 ml), stirred at room temperature for 30 min and extracted with CH2Cl2. The organic layer was washed with a
solution of CuSO4, dried over anhydrous Na2SO4 and the solvent was eliminated in vacuo. The obtained viscous
residue was puri®ed by ¯ash column chromatography (SiO2, 80% CH2Cl2/hexane) and the resulting oil was
crystallized from Et2O a€ording the dibenzoxepine 1c as a white powder (225 mg, 69%).
11. All new compounds showed analytical and spectroscopic data consistent with the reported structure. Selected data
for representative compounds: (a) 10,11-Dimethoxy-1-phenyldibenzo[2,3:6,7]oxepino[4,5-d]pyrazole 1c (m.p.:

4356
166±167ꢀC (Et2O)): 250 MHz 1H NMR (CDCl3) ꢀ 3.30 (3H, s, OMe), 3.90 (3H, s, OMe), 6,20 (1H, s, Harom), 6,90
(1H, s, Harom), 7.20±7.27 (1H, m, Harom), 7.30 (1H, dd, J=8.1, 1.5 Hz, Harom), 7.38±7.58 (7H, m, Harom) and 8.03
(1H, s, H-3); 63 MHz 13C NMR (CDCl3) ꢀ 55.4, 56.0 (OMe), 105.5, 110.1 (Carom-H), 113.9, 119.6 (Carom-C, C-4),
121.3, 125.5 (Carom-H), 125.7 (Carom-C), 127.1, 128.0, 128.5, 129.2 (Carom-H), 136.4 (Carom-N), 137.8 (C-3), 140.0
(C-12b) and 145.6, 150.4, 155.9 (Carom-O); EIMS (m/z,%) 370 (M+, 100), 323 (15), 295 (24), 169 (13), 77 (17).
Anal. calcd for C23H18N2O3: C, 74.58; H, 4.90; N, 7.56. Found: C, 74.49; H, 4.96; N, 7.61. (b) 5-(4,5-Dimethoxy-
2-iodophenyl)-4-(2-hydroxyphenyl)-1-phenylpyrazole 2c (m.p.: 225±226ꢀC (EtOAc)): 250 MHz 1H NMR (CDCl3)
ꢀ 3.66 (3H, s, OMe), 3.83 (3H, s, OMe), 5.52 (1H, bs, OH), 6.68 (1H, s, Harom), 6.78 (1H, ddd, J=8.5, 7.6, 1.2 Hz,
Harom), 6.88 (1H, dd, J=8.3, 1.2 Hz, Harom), 6.97 (1H, dd, J=7.7, 1.9 Hz, Harom), 7.13 (1H, s, Harom), 7.17 (1H,
ddd, J=8.5, 8.3, 1.9 Hz, Harom), 7.28±7.32 (5H, m, Harom), and 7.93 (1H, s, H±3); 63 MHz 13C NMR (CDCl3) ꢀ
56.0 (OMe), 89.0 (Carom-I), 114.3, 115.5 (Carom-H), 117.6, 118.6 (Carom-C, C-4), 120.3, 121.2, 124.2 (Carom-H),
125.3 (Carom-C), 127.2, 128.2, 128.9, 130.7 (Carom-H), 139.8 (Carom-N), 140.3 (C-3), 142.4 (C-5), 149.1, 149.7
(Carom-O) and 153.4 (Carom-OH); EIMS (m/z,%) 498 (M+, 39), 371 (100), 355 (25), 327 (10), 77 (35). Anal. Calcd
for C23H19IN2O3: C, 55.44; H, 3.84; N, 5.62. Found: C, 55.39; H, 3.80; N, 5.69.
12. CuTC has been applied to carry out Ullmann biaryl coupling in extremely mild conditions, see: Zhang, S.; Zhang,
D.; Liebeskind, L. S. J. Org. Chem. 1997, 62, 2312±2313.