A novel palladium intramolecular diaryl ether formation

Article abstract of DOI:10.1016/S0040-4039(00)00622-5

This paper presents an efficient methodology for the preparation of dibenzoxepino[4,5-d]pyrazoles using a novel intramolecular palladium catalyzed diaryl ether formation. The effect of different chelating ligand systems, along with the unusual coupling reaction of phenoxides with aryl iodides and non-activated aryl moieties are also reported. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00622-5

Tetrahedron Letters 41 (2000) 4357±4360
A novel palladium intramolecular diaryl ether formation
Roberto Olivera, Raul SanMartin and Esther Domõnguez*
Kimika Organikoa Saila, Zientzi Fakultatea, Euskal Herriko Unibertsitatea, PO Box 644, 48080 Bilbao, Spain
Received 22 February 2000; accepted 7 April 2000
Abstract
This paper presents an ecient methodology for the preparation of dibenzoxepino[4,5-d]pyrazoles using
a novel intramolecular palladium catalyzed diaryl ether formation. The e€ect of di€erent chelating ligand
systems, along with the unusual coupling reaction of phenoxides with aryl iodides and non-activated aryl
moieties are also reported. # 2000 Elsevier Science Ltd. All rights reserved.
Due to the wide range of biological properties exhibited by dibenzoxepine drugs their use is
widespread. Some of these drugs have a heterocyclic moiety fused to the dibenz[b,f]oxepino
framework.1,2 Encouraged by the potential pharmacological applications of such molecules,2,3
and following our ongoing research on the chemistry of diaryl substituted heterocycles,4 and their
biaryl coupling reactions leading to new phenanthroheterocyclic systems,5 we planned a challenging
approach to dibenzoxepino fused heterocycles from adequately o,o0-hydroxyhalosubstituted diaryl
heterocycles via a ®nal biaryl ether coupling step. In this context, the recent advances in practical
palladium catalyzed carbon±heteroatom coupling methodologies6 have provided useful altern-
atives to copper mediated (Ullmann)7 and direct nucleophilic substitution,8 which usually
require a large excess of reagent, strongly polar solvents, harsh reaction conditions or highly
activated aryl halides.9 However, the scope of the palladium catalyzed diaryl ether synthesis is
still limited and the in¯uence of the catalytic system are dicult to be predicted, as the crucial
step, the C±O bond forming reductive elimination of ethers from the palladium complex remains
as a substrate dependant process.10 In fact, very few examples of this recent reaction have been
reported up to date, all of them performed in an intermolecular fashion.11
In this paper we wish to report the results obtained when Pd catalyzed C±O bond-forming coupling
procedures (Buchwald±Hartwig reaction) were applied to the preparation of dibenzoxepino[4,5-
d]pyrazoles.
Our initial assays were based on the procedure developed by Gingras et al. for the preparation
of molecular wires.12 Thus, phenolic diarylpyrazoles 1 and 213 were treated with KOtBu and
Pd(PPh3)4 as catalyst, but only the corresponding dehalogenated products 4 and 5 were obtained
(66±77% yield) (Scheme 1).
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00622-5

4358
Scheme 1.
We then focussed our attention on the use of bulky, chelating phosphine ligands such as
BINAP14 and DPPF15 which could signi®cantly accelerate the reductive elimination step, as it has
previously proposed.11a,16 Besides, in order to employ better oxygen nucleophiles, phenoxide
derivatives 6 and 7 were prepared by treatment of phenols 1 and 2 under standard procedures
and immediately submitted to the reaction conditions indicated below,17 a€ording the target
dibenzoxepino[4,5-d]pyrazole tetracycles 318 with the results summarized in Table 1.
Table 1
Synthesis of dibenzoxepinopyrazoles 3
Although the use of both BINAP and DPPF bidentate ligands, which have slightly di€erent
bite angle values,19 provided dibenzoxepines 3, better results were obtained when DPPF was used
as the catalyst chelating ligand. Otherwise, considering that the reported outcomes constitute the
®rst example of an intramolecular palladium catalyzed diaryl ether synthesis so far, it should
be also pointed out not only the moderate to good yields obtained from the reaction of iodide
derivatives 6a, 6b, 6d and 7a±c,20 but also the observed coupling of electron rich or neutral

4359
haloarenes 6±7. These signi®cant, unusual features are the consequence of the intramolecular
nature of the reported reaction, as the high constraint generated in the corresponding oxidative
addition intermediate would be released by the otherwise dicult reductive elimination process.
The latter theory would also explain the lack of reactivity of pyrazole 6c, since the steric
hindrance induced by the methoxy (R7=OMe) and N-phenyl substituents could even avoid the
displacement of the halide ligand to form the corresponding octacyclic Ar±Pd±OAr0 complex.21
On the other hand, the comparison of the obtained results from the coupling of substrates 6d and
6e suggests that the presence of an electron-donating substituent ortho to the hydroxy group
might dicult the formation of the latter intermediate, probably due to the unstability of the
initially formed aryl palladium(II) halide, which is more remarkable in the case of iodide derivative
6d. This behaviour of aryl iodides for this type of transformation has been previously reported.11b
To sum up, a series of new dibenzoxepino[4,5-d]pyrazoles has been obtained by a convenient
palladium catalyzed C±O coupling reaction of o,o0-halohydroxysubstituted diarylpyrazoles. This
novel palladium catalyzed intramolecular diaryl ether formation has been carried out with two
di€erent chelating ligands, a€ording moderate to good yields of the target tetracycles prepared by
coupling of phenoxides with non-activated arene and aryl iodide moieties.
We are currently investigating the expansion of the scope of the coupling conditions set up to
other diaryl heterocyclic systems, as well as trying to develop new palladium catalytic systems for
related transformations.
Acknowledgements
Financial support from the University of the Basque Country (Project UPV 170.310G37/98),
the Ministerio de Educacion y Cultura (PB97-0600), the Basque Government (GV170.310-
G0053/96) and a fellowship granted to R.O. are also gratefully acknowledged.
References
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13. Olivera, R. PhD Thesis, University of the Basque Country, 2000.
14. BINAP: 2,20-Bis(diphenylphosphino)-1,10-binaphthyl.
15. DPPF: 1,1'-bis(diphenylphosphino)ferrocene.
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17. Typical procedure: 1-Phenyldibenzo[2,3:6,7]oxepino[4,5-d]pyrazole 3a. Ground NaOH ( 0.023 g, 0.56 mmol) was
added to a stirred solution of pyrazole 1a (0.222 g, 0.51 mmol) in dry toluene (14 cm3) under argon at room
temperature. After re¯uxing for 30 min, the mixture was allowed to cool without stirring. The resulting
supernatant orange solution of phenoxide 6a was separated from the precipitate by transferring via cannula to
an empty ¯ask and degassed by bubbling argon through it for 20 min. A mixture of Pd2(dba)3 (16.5 mg, 0.018
mmol) and DPPF (mg, 0.072 mmol) in dry, degassed THF (1.6 ml) was stirred for 20 min and added dropwise to
the previously prepared solution of fenoxide 6a. This reaction mixture was heated to 100ꢀC for 17 h, and after
cooling, it was ®ltered through Celite# and the solid washed with THF. Evaporation of the solvents in vacuo
a€orded a yellow oil which was puri®ed by ¯ash chromatography using 20% hexane/CH2Cl2 as eluent, providing
dibenzoxepine 3a (0.109 g, 69%) as a white powder.
18. Selected data of representative dibenzoxepino[4,5-d]pyrazole 3a: 250 MHz 1H NMR (CDCl3) ꢀ 6.81 (1H, dd,
J=7.9, 1.6 Hz, Harom), 6.94 (1H, ddd, J=8.1, 7.9, 1.6 Hz, Harom), 7.20±7.52 (10H, m, Harom), 7.57 (1H, dd, J=6.9,
1.6 Hz, Harom) and (1H, s, H-3); 63 MHz 13C NMR (CDCl3) ꢀ 120.3 (Carom-C, C-4), 121.5, 122.3 (Carom-H), 122.9
(Carom-C, C-4), 124.7, 125.1, 125.5, 127.0, 127.9, 128.6, 128.7, 129.2, 130.2 (Carom-H), 136.2 (Carom-N), 137.9 (C-3),
140.2 (C-12b), 155.9, 156.5 (Carom-O); EIMS (m/z %) 310 (M+, 100), 281 (12), 206 (12), 151 (8), 127 (7), 77 (12).
Anal. calcd for C21H14N2O: C, 81.27; H, 4.55; N, 9.03. Found: C, 81.39; H, 4.64; N, 9.17.
19. Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 3694±3703 and references cited therein.
20. The observed GC/MS yields for dibenzoxepinopyrazole 3b were 64 and 51% when DPPF and BINAP were the
chelating ligands, respectively. The di€erence between the observed and isolated yields is adduced to the resinous
nature of the product and the substrate, which made the puri®cation of the target compound considerably
dicult.
21. Similar intermediates have been proposed in the arylation of alkoxides and phenoxides. See Ref. 11b±c