Revisiting the Ullmann-ether reaction: A concise and amenable synthesis of novel dibenzoxepino[4,5-d]pyrazoles by intramolecular etheration of 4,5-(o,o′-halohydroxy)arylpyrazoles

Article abstract of DOI:10.1021/jo025767j

A concise synthesis of a series of novel dibenzoxepino[4,5-d]pyrazoles was accomplished by implementation of an intramolecular Ullmann-ether reaction on o,o'-halohydroxy-4,5-diarylpyrazoles mediated by CuBr·DMS. An alternative useful approach based on the palladium-catalyzed biarylether linkage formation (Buchwald-Hartwig reaction) was also successfully applied, offering limitations with regard to the steric demand of the substituents. The synthesis of the key o,o′-halohydroxy-4,5-diarylpyrazole intermediates proceeds through the construction of the heterocyclic ring by a tandem amine-exchange/heterocyclization sequence of 3-N,N-(dimethylamino)-1,2-diarylpropenones with phenylhydrazine followed by basic hydrolysis for deprotection. The enamino ketone precursors were conveniently prepared from the corresponding O-sulfonyloxy and O-benzoyloxy ortho-substituted 1,2-diarylethanones, starting from inexpensive salicylaldehyde or phenylacetic derivatives. Preliminary binding affinity experiments against peripheral and central nervous system receptors have been done with negative results.

Full text of DOI:10.1021/jo025767j

Revisitin g th e Ullm a n n -Eth er Rea ction : A Con cise a n d Am en a ble
Syn th esis of Novel Diben zoxep in o[4,5-d ]p yr a zoles by
In tr a m olecu la r Eth er a tion of 4,5-(o,o′-Ha loh yd r oxy)a r ylp yr a zoles
Roberto Olivera,‡ Raul SanMartin, Fa´tima Churruca, and Esther Dom´ınguez*
Kimika Organikoa II Saila, Zientzi Fakultatea, Euskal Herriko Unibertsitatea, P.O. Box 644, 48080
Bilbao, Spain
qopdopee@lg.ehu.es
Received March 27, 2002
A concise synthesis of a series of novel dibenzoxepino[4,5-d]pyrazoles was accomplished by
implementation of an intramolecular Ullmann-ether reaction on o,o′-halohydroxy-4,5-diarylpyrazoles
mediated by CuBr‚DMS. An alternative useful approach based on the palladium-catalyzed biaryl-
ether linkage formation (Buchwald-Hartwig reaction) was also successfully applied, offering
limitations with regard to the steric demand of the substituents. The synthesis of the key o,o′-
halohydroxy-4,5-diarylpyrazole intermediates proceeds through the construction of the heterocyclic
ring by a tandem amine-exchange/heterocyclization sequence of 3-N,N-(dimethylamino)-1,2-
diarylpropenones with phenylhydrazine followed by basic hydrolysis for deprotection. The enamino
ketone precursors were conveniently prepared from the corresponding O-sulfonyloxy and O-
benzoyloxy ortho-substituted 1,2-diarylethanones, starting from inexpensive salicylaldehyde or
phenylacetic derivatives. Preliminary binding affinity experiments against peripheral and central
nervous system receptors have been done with negative results.
In tr od u ction
compared with other classical psychopharmaceuticals.5
Most of these molecules elicit significant effects upon
biological systems in such a way that the mechanism of
action on the central nervous systems remains elusive.
This might be related to the affinity of these compounds
for the 5-HT2 or D2-dopamine receptors in brain, as
A variety of medicinally important compounds contain-
ing a dibenzo[b,f]oxepine framework have attracted
considerable attention because of their unique biological
activity. Bermoprofen, an eminent example of this type
of compound, has found extensive clinical use as a
nonsteroid antiinflammatory agent.1 Over the last past
few years, dibenzoxepine derivatives containing a fused
heteroaromatic ring at 4,5-positions have served as leads
for the development of a new class of psychoactive drugs.2
In fact, the introduction of newer tetracyclic compounds,
such as savoxepine or maroxepine,3 has provided a
different outlook in the field of pharmacotherapy for the
treatment of depression, compulsive behavior, anxiety
disorders, and, in particular, schizophrenic psychoses.4
Concretely, the piperidine ORG 4428 (beloxepin) and
pyrrolidine ORG 5222 represent the members of a
growing class of new potential antidepressant drugs,
showing an improved tolerance and potent activity
(5) For lead references on the synthesis and biological evaluations
of ORG 4428 (Beloxepin) and ORG 5222 and patent claims, see: (a)
Prinsse, E. P. M.; Koek, W.; Kleven, M. S. Eur. J . Pharmacol. 2000,
388, 57-67. (b) Miguel-Hidalgo, J . J . Drugs 2000, 2, 85-92. (c) Van
Bemmel, A. L.; Vermeeren, M. T. G.; Ruigt, G.; Sennef, C. Neuropsy-
chobiology 1999, 40, 107-114. (d) Andrews, J . S. Patent WO 9932108
(Chem. Abstr. 131, 54031). (e) van Delft, A. M. L.; Ruigt, G. S. F.; van
Proosdij, J . N. Neuropsychopharmacology 1994, 10, (Suppl. Part 2),
24. (f) Delbressine, L. P. C.; Wieringa, J . H. Patent WO 9523600. (g)
Room, P.; Tielemans, A. J . P. C.; de Boer, T.; VanDelft; A. M. L.; J eroen,
J . A. D. M. Eur. J . Pharmacol. 1991, 205, 233-240. (h) Costall, B.;
Domeney, A. M.; Kelly, M. E.; Naylor, R. J .; Tomkins, D. M. Pharmacol.
Biochem. Behav. 1990, 35, 607-615. (i) Ruigt, G. S. F.; van Proosdij,
J . N. Eur. J . Pharmacol. 1990, 183, 1467-1468.
(6) Andree, B.; Halldin, C.; Vrijmoed-De Vries, M.; Farde, L.
Psychopharmacol. 1997, 131, 339-345. Several (diazabicycloalkyl)-
dibenzoxepines have exhibited activity as D2-dopamine receptor an-
tagonists: Power, P. L.; Rakhit, S. U.S. Patent 5703072 (Chem. Abstr.
128, 88936).
* To whom correspondence should be addressed. Phone: (+34) 94
6012577. Fax: (+34) 94 4648500. E-mail: qopdopee@lg.ehu.es.
‡ Present address: FAES FARMA S.A., R&D Department, P.O. Box
555, 48080 Bilbao, Spain.
(7) Few natural products containing an oxepine ring have been
isolated to date. For example, see: (a) Pacharin, a constituent of the
heartwood of Bauhinia racemosa lamk: Comber, M. F.; Sargent, M.
V. J . Chem. Soc., Perkin Trans 1 1990, 5, 1371-1373. (b) Isolation of
a bioactive dihydrobenzodioxepin from J uncus effusus: Della-Greca,
M.; Fiorentino, A.; Molinaro, A.; Monaco, P.; Previtera, L. Phytochem-
istry 1993, 34, 1182-1184. Isolation and characterization of new
natural dibenzo[b,f]oxepines (Artocarpols) from the root bark of
Artocarpus rigida have recently been achieved. Several of them have
exhibited potent antiinflammatory effects: (c) Artocarpol A: Chung,
M.-I.; Ko, H.-H.; Yen, M.-H.; Lin, C.-N.; Yang, S.-Z. Tsao, L.-T.; Wang,
J .-P. Helv. Chim. Acta 2000, 83, 1200-1204. (d) Artocarpols C and D:
Ko, H.-H.; Lin, C.-N.; Yang, S.-Z. Helv. Chim. Acta 2000, 83, 3000-
3005. (e) Artocarpol F: Ko, H.-H.; Yang, S.-Z.; Lin, C.-N. Tetrahedron
Lett. 2001, 42, 5269-5270.
(1) Nagai, Y.; Irie, A.; Nakamura, H.; Hino, K.; Uno, H.; Nishimura,
H. J . Med. Chem. 1982, 25, 1065-1070.
(2) For a review, see: Missir, A.; Limban, C.; Stecoza, C.; Morusciag,
L.; Chirita, I. Farmacia 1998, 46, 17-30.
(3) (a) Bischoff, S. In Novel Antipsychotic Drugs, Meltzer: New York,
1992, pp. 117-134. (b) Storni, A. Actual Chim. Ther. 1989, 16, 143-
150.
(4) For reviews, see: (a) Zimmermann, K.; Waldmeier, P. C.; Tatton,
W. G. Pure Appl. Chem. 1999, 71, 2039-2046. (b) Sperling, W.;
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10.1021/jo025767j CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/19/2002
J . Org. Chem. 2002, 67, 7215-7225
7215

Olivera et al.
CHART 1
envisioned the preparation of a new type of pyrazolo-
fused compounds, dibenzoxepino[4,5-d]pyrazoles 1, as
potential psychoactive substances. Perusal of the litera-
ture revealed that photocyclization of halosubstituted
acetophenone derivatives,12 intramolecular Friedel-
Crafts acylation,13 and cyclodehydration of phenoxyphe-
nylacetic acid derivatives13 are the most commonly used
methods for the preparation of dibenzo[b,f]oxepines,13 but
the methods are often limited by the need of a preformed
diaryl ether framework. Moreover, many of these meth-
ods suffer from some drawbacks, including the use of
toxic and/or hazardous materials, strongly acidic condi-
tions, unsatisfactory yields, longer reaction times, and
lack of selectivity (inter alia). In this context and in
connection with our previous contributions for the syn-
thesis of phenanthro-fused heterocycles,14 herein we
report a facile, practical protocol to construct these
oxygen-containing benzoannealed seven-membered het-
erocycles 1 as illustrated in the retrosynthetic scheme
below. Our proposed synthetic approach was based upon
the rationale that a flexible synthetic route could be
derived from the postponement of the heterocyclic ring
closure, which constitutes a scarcely applied strategy for
the preparation of dibenzoxepines.15 This notion of using
o,o′-halohydroxy-4,5-diarylpyrazoles 2 as the key inter-
mediates is particularly attractive taking into account
reported for ORG 5222,5a,6 or to the ability for selective
adrenalin reuptake, as in the case of beloxepin.5e,iLikewise,
and despite their scarce appearance in nature,7 there has
been an increased interest of late in dibenzoxepino-fused
heterocycles, because of their wide range of applications
in pharmaceutical industry, as reflected by a vast number
of reports and patent claims.8,9
Taking into account the important role played by the
pyrazole nucleus as a pharmacophore element in a recent
variety of synthetic bioactive compounds, such as the
recently marketed nonsteroidal antiinflammatory drug
celecoxib (Celebrex)10 and other therapeutic agents,11 we
(11) (a) A number of synthetic pharmacophores, with the activities
indicated as follows, are based upon a diaryl-substituted pyrazole
motif: (a) Neuropsychiatric disorders. Application of corticotropin
releasing factor (CRF) as receptor modulators: Gilligan, P. J .; Rob-
ertson, D. W.; Zaczek, R. J . Med. Chem. 2000, 43, 1641-1660. (b)
Application of ER-38930, a retinoic acid receptor (RARa) agonist for
dermatologic and immunological diseases: Hibi, S.; Tagami, K.;
Kikuchi, K.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.; Yamauchi,
T.; Nagai, M. Bioorg. Med. Chem. Lett. 2000, 10, 623-625. See also:
Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.;
Yamauchi, T.; Nagai, M. Med. Chem. Lett. 2000, 10, 619-622.
Likewise, particularly appealing is the potency exhibited by this kind
of heterocycle as (c) estrogen receptor a-selective agonists: Stauffer,
S. R.; Coletta, C. J .; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J .;
Katzenellenbogen, B. S.; Katzenellenbogen, J . A. J . Med. Chem. 2000,
43, 4934-4947. (d) Interleukine-2 (IL-2) inhibitors: Djuric, S. W.;
BaMaung, N. Y.; Basha, A.; Liu, H.; Luly, J . R.; Madar, D. J .; Sciotti,
R. J .; Tu, N. P.; Wagenaar, F. L.; Wiedeman, P. E.; Zhou, X.; Ballaron,
S.; Bauch, J .; Chen, Y.-W.; Chiou, X. G.; Fey, T.; Gauvin, D.; Gubbins,
E.; Hsieh, G. C.; Marsh, K. C.; Mollison, K. W.; Pong, M.; Shaughnessy,
T. K.; Sheets, M. P.; Smith, M.; Trevillyan, J . M.; Warrior, U.; Wegner,
C. D.; Carter, G. W. J . Med. Chem. 2000, 43, 2975-2981.
(8) Diverse applications of dibenzoxepino-fused heterocycles have
been claimed: (a) Analgesic agents: Martin, L. L.; Setescak, L. L. U.S.
Patent 4576960 (Chem. Abstr.:104, 224840). (b) Antiarthritic agent:
Cherkofsky, S. C.; Sharpe, T. R. U.S. Patent 4198421 (Chem. Abstr.
93, 71783). (c) Antihistamine agents: Kumazawa, T.; Ohsima, E.;
Obase, H. Patent J P 61152673 (Chem. Abstr. 106, 4904). (d) Anties-
pasmodic agents: Bracaccio, G.; Lettieri, G.; Monforte, P.; Larizza, A.
Farmaco 1982, 37, 711-718. (e) Anti-neurodegenerative agents: Zim-
mermann, K.; Roggo, S.; Betschart, C. Patent WO 9745422 (Chem.
Abstr. 128, 61439). (f) Antioxidants: J inno, S.; Okita, T. Heterocycles
1999, 51, 303-314. (g) Tracheal smooth muscle relaxants: Yamashita,
S.; Takeo, J .; J inno, S.; Kogure, Y.; Onuki, H.; Okita, T.; Hata, J .;
Fukuda, Y.; Ohtsuka, N. Patent WO 9725985 (Chem. Abstr. 127,
149089). (h) Antipsychotic, cardiovascular and gastroprotectors: Gil-
Lopetegui, P.; Ferna´ndez-Gadea, F. J .; Meert, T. F. Patent WO
97338991, and (i) Antiasthmatic and respiratory tract hypersensitivi-
ness inhibitors: J inno, S.; Okita, T.; Ohtsuka, N.; Yamashita, S.; Hata,
J .; Takeo, J . Patent WO 0075127 (Chem. Abstr. 134, 29329).
(9) These type of compounds have also exhibited efficiency for the
treatment of diseases such as: (a) Asthma: Lever, O. W.; King, A. N.;
Harfenist, M.; Chao, E. Y. H. Patent WO 9015599 (Chem. Abstr. 16,
20960). (b) Arteriosclerosis: Nakazawa, H.; Ando, K.; Kuge, Y.; Sugaya,
T.; Kasai, M.; Tomioka, S. Patent J P 06306070 (Chem. Abstr. 122,
160492). (c) Cancers related to estrogen regulation disorders: Kan-
amaru, T.; Hida, T.; Muroi, M. Patent EP 342665 (Chem. Abstr. 113,
5954).
(12) Nagaoka; H.; Kamino, S.; Onuki, H. Patent J P 10204079 (Chem.
Abstr. 129, 189246).
(13) Rosowsky, A. In The Chemistry of Heterocyclic Compounds:
7-membered Heterocyclic Compounds containing Oxygen and Sulfur;
Weissberger, A., Taylor, E. C., Eds., Wiley-Interscience: New York,
1972; pp 154-176 and references therein.
(14) (a) Olivera, R.; SanMartin, R.; Dom´ınguez, E. J . Org. Chem.
2000, 65, 6398-6411. (b) Olivera, R.; SanMartin, R.; Dom´ınguez, E.
J . Org. Chem. 2000, 65, 7010-7019. (c) Olivera, R.; SanMartin, R.;
Dom´ınguez, E. Synlett 2000, 7, 1028-1030.
(15) (a) de la Fuente, M. C.; Castedo, L.; Domı´nguez, D. Tetrahedron
1996, 52, 4917-4924. (b) Burden, P. M.; Capper, H. R.; Allan, R. D.;
J ohnston, G. A. R. J . Chem. Soc., Perkin Trans. 1 1991, 3291-3294.
(10) Drug Data Rep. 2000, 22, 376-378.
7216 J . Org. Chem., Vol. 67, No. 21, 2002

Revisiting the Ullmann-Ether Reaction
the recent advances in the chemistry of diaryl ethers.16,17
Likewise, we intend to expand the scope of our methodol-
ogy for the preparation of diarylpyrazoles,14b by amine-
exchange reaction/heterocyclization of hydrazines with
enamino ketones 3, readily available from deoxybenzoins
4. The latter tactic is becoming widespread as the method
of choice for the synthesis of pyrazoles;18 moreover, using
suitable 1,4-dinucleophilic components enables the de-
velopment of versatile routes to other classes of hetero-
cycles.19
SCHEME 1a
a
Reagents and conditions: (i) ArSO2Cl, py, 80 °C. (ii) ArSO2Cl,
Herein we report our full results on the synthesis of
dibenzoxepino[4,5-d]pyrazoles via final formation of the
biaryl ether linkage along with preliminary pharmaco-
logical evaluation.
K2CO3, rt (for 7f). (iii) KCN, Me2NH‚HCl, MeCN, H2O, rt.
As shown in Table 1, R-aminonitriles 823 were obtained
in moderate to high yields except for sulfonates 7b-d
bearing electron-withdrawing substituents, leading to an
unresolved multicomponent mixture. All the same, al-
Resu lts a n d Discu ssion
(20) Upon first encountering the facility with which 3-(dimethy-
lamino)-2-hydroxybenzylidene-aminobenzofuran 6 is produced when
starting from commercial salicylaldehyde, protection of hydroxyl
functionality became necessary. We speculate that the formation of
this benzofuran could arise from the attack of the forming R-amino-
nitrile to the remaining aldehyde, triggered by the intramolecular
addition of the hydroxyl nucleophile at the adjacent cyano group.
Equilibration of the initially formed imine, followed by dehydration,
would render the detected benzofuran, as illustrated below. Isolation
and complete structural elucidation of 6 was not possible due to
extensive decomposition over the purification process. 1H and 13C NMR
analysis of chromatographed fractions provided clear evidence for the
structure of 6. GC/MS spectrum showed a concordance of 99% when
compared with the authentic one contained in a Wiley MS database.
1. Syn th esis of 2,2′-(Ha loh yd r oxy)d eoxyben zoin s.
We have recently reported that the alkylation of 2-ha-
loaryl R-aminocarbonitriles with 2-haloarylmethyl ha-
lides constitutes an excellent method for the preparation
of 2,2′-dihalodeoxybenzoins,14a enabling the construction
of adequately functionalized phenanthro[9,10-d]hetero-
cycles.14b,c In this context, salicylaldehyde and ortho-
halogenated aldehyde derivatives 5 seemed to be a
suitable starting material to supply the aforementioned
deoxybenzoins. Nevertheless, in our initial approach,
attempts to synthesize R-aminonitriles derived from
salicylaldehyde on standard conditions (KCN/Me2NH‚
HCl) proved to be unsuccessful.20 In view of this observa-
tion, and considering the tendency of o-hydroxyaryl-3-
enamino ketones to give isoflavones under basic
conditions,21 it was decided to protect salicylaldehyde
derivatives as the corresponding arylsulfonates 7 at this
early stage under standard conditions (Scheme 1). The
choice of this sparingly utilized but extremely robust
hydroxyl-protecting group22 corresponds to the necessity
to endure the range of conditions required during the
aminomethylenation and heterocyclization steps.
(16) For recent reviews and monographs: (a) Sawyer, J . S. Tetra-
hedron 2000, 56, 5045-5065. (b) Theil, F. Angew. Chem., Int. Ed. 1999,
111, 2345-2347. (c) Hartwig, J . F. Angew. Chem., Int. Ed. 1998, 111,
2046-2067. (d) Chiu, C. K.-F. In Comprehensive Organic Functional
Groups Transformations, Katritzky, A. R., Meth-Cohn, O., Rees, C.
W., Eds.; Pergamon Press: Cambridge, 1995; Vol. 2, Chapter 2.13, pp
683-685.
(17) Other leading references on the topic: (a) Kuwabe, S.-I.;
Torraca, K. E.; Buchwald, S. L. J . Am. Chem. Soc. 2001, 123, 12202-
12206. (b) Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L.
J . Am. Chem. Soc. 2001, 123, 10776-10781. (c) Torraca, K. E.; Kuwabe,
S.-I.; Buchwald, S. L. J . Am. Chem. Soc. 2000, 122, 12907-12908. (d)
Cundy, D. J .; Forsyth, A. S. Tetrahedron Lett. 1999, 39, 7979-7982.
(e) Woiwode, T. F.; Rose, C.; Wandless, T. J . J . Org. Chem. 1998, 63,
9594-9596. (f) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters,
M. P. Tetrahedron Lett. 1998, 39, 2933-2936. (g) Palucki, M.; Wolfe,
J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119, 3395-3396. (h)
Lindley, J . Tetrahedron 1984, 40, 1433-1456.
(18) (a) Pleier, A.-K.; Glas, H.; Grosche, M.; Sirsch, P.; Thiel, W. R.
Synthesis 2001, 55-62. (b) Okada, E.; Tsukushi, N.; Shimomura, N.
Synthesis 2000, 1822-1824.
(19) (a) Braun, R. U.; Zeitler, K.; Mu¨ller, T. J . J . Org. Lett. 2000, 2,
4181-4184. (b) Mu¨ller, T. J . J .; Braun, R. U.; Ansorge, M. Org. Lett.
2000, 2, 1967-1970. (c) Tyvorskii, V. I.; Bobrov, D. N.; Kulinkovich,
O. G.; Aelterman, W.; De Kimpe, N. Tetrahedron 2000, 56, 7313-7318.
(d) Dawood, K. M.; Kandeel, Z. E.; Farag, A. M. Heteroatom Chem.
1999, 10, 417-422. (e) Bejan, E.; A¨ıt-Hadou, H.; Daran, J .-C.; Bala-
voine, G. G. A. Eur. J . Org. Chem. 1998, 2907-2912.
(21) Pelter, A.; Ward, R. S.; Ashdown, D. H. J . Synthesis 1978, 843-
846 and references therein.
(22) (a) Kuntz, H.; Waldman, H. In Comprehensive Organic Syn-
thesis; Trost; B. M., Fleming, I., Schreiber, S. L., Eds.; Pergamon
Press: Oxford, 1991; Vol. 4, Chapter 3.1, pp 643-663. (b) Kocienski,
P. J . In Protecting Groups, 2nd ed.; Enders, D., Noyori, R., Trost, B.
M., Eds.; Thieme: Stuttgart, 1994; pp 21-85.
(23) Syntheses of R-aminonitriles and corresponding starting ortho-
iodinated aldehydes were performed according to the method reported
in ref 14a.
(24) Under a variety of related conditions, 4-nitro-2-phenylsulfony-
loxybenzaldehyde 7d failed to give the corresponding alcohol, leading
to gummy, crude mixtures of difficult manipulation.
(25) Verheyden, J . P. H.; Moffatt, J . G. J . Org. Chem. 1972, 51,
2289-2299. Attempts to perform bromination of the so-obtained
alcohols with HBr in acetic acid yielded mainly the acetyl derivatives
as a result of the high reactivity of the desired bromomethyl com-
pounds. Concretely, when 5-chloro-2-(phenylsulfonyloxy)phenyl]metha-
nol 9b was submitted to such conditions, a mixture of the target
bromide 10b (23% yield) and 5-chloro-2-(phenylsulfonyloxy)phenyl]-
methyl acetate 10e (41% yield) was afforded.
J . Org. Chem, Vol. 67, No. 21, 2002 7217

Olivera et al.
SCHEME 3a
TABLE 1. Syn th esis of Ar ylsu lfon a tes 7 a n d
r-Am in on itr iles 8
a
b
Yield of pure crystallized compound. Multicomponent mix-
ture was obtained. c Isolated yield. ArSO2Cl/K2CO3 system was
required instead of typical protection conditions, which gave an
intractable mixture including the target sulfonate 7f in a valueless
yield (12%).
d
SCHEME 2a
a
Reagents and conditions: (i) NaH, DMF, -19 °C; (ii) 10, -19
°C to room temperature; (iii) concd HCl, MeOH, H2O, 90 °C.
the analysis of the NMR and MS spectra of the crude
reactions.27 This result contrasts with the diasteroselec-
tive obtention of E-ethenylamines when an analogous
reaction was applied to the preparation of o,o′-dihalo-
substituted deoxybenzoins,14a which discloses not only the
coexistence of different mechanisms for this apparently
simple nucleophilic substitution, but also the remarkable
effect of ortho-substituents on the aryl groups.
a
Reagents and conditions: (i) LAH, THF, rt; (ii) CBr4, PPh3,
On the other hand, it is noteworthy to say that
naphthyl-R-aminonitrile 8e underwent slow decomposi-
tion upon reacting with 2-iodo- and 2-bromobenzyl chlo-
ride, resulting in no deoxybenzoin formation, in contrast
to the fast reaction of R-aminonitrile 8g with naphthyl-
methyl bromide 10c. The observed different behavior
suggests that alkylation is specially sensitive to the steric
hindrance at the reaction site. Conceivably, the presence
of H-8 at the adjacent naphthyl ring obliges a constrained
conformation of the aminocarbonitrile moiety flanked by
the bulky sulfonate group, hindering the access of the
electrophile.
DCM, rt; (iii) PhSO2Cl, py, 80 °C; (iv) NBS, AIBN, CCl4, 95 °C.
TABLE 2. Ar ylm eth yl Der iva tives 9 a n d 10 P r ep a r ed
a
b
Yield of pure crystallized compound (Et2O). Yield of pure
crystallized compound (CHCl3). c Yield of pure chromatographed
compound.
To our surprise, acidic hydrolysis of intermediate
amines 11 was thwarted by concomitant formation of the
deprotected product, as evidenced by the isolation of 4j
(58% yield) in the case of deoxybenzoin 4a , when per-
formed at higher temperature than 90 °C (Scheme 4).
This result is in concordance with the remarkable lability
of ortho-formylated sulfonyl esters upon treatment with
mineral acids, as reported by Bhatt.28
dehydes 7b-e were used as counterparts for the substi-
tution reaction of R-aminonitriles after a reduction/
bromination sequence (Scheme 2). Initial reduction with
LAH proceeded quantitatively to provide arylmethanols
9, except for nitro derivative 7d .24 Thus, while application
25
of the system CBr4/PPh3 afforded the arylmethyl bro-
In parallel with this strategy, we also considered
embarking on the synthesis of polymethoxylated deoxy-
mides 10a -c, brominated derivative 10d was obtained
by action of NBS catalyzed by AIBN on o-cresol previ-
ously sulfonylated (Table 2).
Adequate combination of deprotonated R-aminonitriles
8 with arylmethyl bromides 10 or commercial 2-iodoben-
zyl chloride,26 followed by acidic hydrolysis, afforded the
desired deoxybenzoins 4a -f in moderate yields (Scheme
3, Table 3). Interestingly, this alkylation proceeds through
a mixture of Z,E- ethenylamines 11, as concluded from
(26) In our hands (see ref 14a), when using 2-iodobenzyl chloride
as alkylating agent, inverse addition of the electrophile was necessary
to optimize the yield of 4a .
(27) Pairs of olefinic signals in the range of 5.3-5.6 and 146.1-
150.4 ppm have respectively been recorded in the 1H NMR and 13C
NMR spectra of the crude reaction, assignable to H-2 and C-1.
(28) Shashidhar, M.; Bhatt, M. V. J . Chem. Soc., Chem. Commun.
1987, 654-656.
7218 J . Org. Chem., Vol. 67, No. 21, 2002

Revisiting the Ullmann-Ether Reaction
TABLE 3. Syn th esis of Deoxyben zoin s 4, En a m in o Keton es 3, P r otected 4,5-d ia r ylp yr a zoles 15 a n d
o,o′-h a loh yd r oxy-4,5-d ia r ylp yr a zoles 2
a
b
d
Yield of pure crystallized compound. Yield of pure chromatographed compound. c Target product was not detected. Reaction was
performed in THF. e Reaction was performed in 1,4-dioxane. f Combined yield of the O-protected pyrazole 15i and debenzoylated pyrazole
2i (85%).
SCHEME 4a
SCHEME 5a
a
Reagents and conditions: (i) SOCl2, PhMe, 140 °C; (ii) 1,2,3-
(MeO)Ph, AlCl3, DCM, 55 °C (for 13a ,b); (iii) 1,3,5-(MeO)Ph,
BF3‚OEt2, PhMe, 140 °C (for 13c); (iv) 1,3,5-(MeO)Ph, AlCl3, PhMe,
55 °C (for 13d ); (v) AcCl, NaOH, TEBA (cat.) 1,4-dioxane, rt.
or iodination (ICl), respectively, in HOAc of the parent
acid and assayed F-C acylation with some polymethoxy-
lated arenes (Scheme 5). Reactions of acid chlorides of
12a ,b with 1,2,3-trimethoxybenzene in the presence of
AlCl3 as catalyst in dichloromethane (DCM) proceeded
clearly to provide the o,o′-halohydroxy deoxybenzoins
13a ,b in fair to good yields (45-79%). Surprisingly,
performing the acylation reaction on the acid chloride of
12b with 1,3,5-trimethoxybenzene upon the same reac-
tion conditions yielded the fully methoxylated compound
13d . Forcing conditions gave rise to useless mixtures of
polyhydroxylated compounds. However, the application
of the less active Lewis catalyst BF3‚OEt2 allowed isola-
tion of the desired compound 13c in 65% yield. In
contrast with iodo congener 13c, the bromo analogue
remained inaccessible, despite changes in solvent (THF,
acetonitrile), catalysts (TiCl4, Sc(OTf)3)31 (both in sto-
ichiometric/substoichiometric quantities), or/and prolon-
a
Reagents and conditions: (i) NaH, DMF, -19 °C; (ii) 8a , -19
°C to room temperature; (iii) concd HCl, MeOH, H2O, 115 °C.
benzoins to have available a more complete set of
substrates, regarding the electronic nature of the sub-
stituents. In this context, we considered the Friedel-
Crafts (F-C) acylation of arenes with arylacetyl chlo-
rides, a classical route to this type of deoxybenzoin.29 In
addition, there are some literature precedents related to
the concomitant demethylation during this process of
o-methoxy substituents to the carbonyl group, upon the
action of a Lewis acid catalyst.30 With this advantageous
precedent in mind, we prepared 6-bromo- (12a ) and
6-iodohomoveratric acid (12b) by direct bromination (Br2)
(29) (a) Wa¨ha¨la, K.; Hase, T. A. J . Chem. Soc., Perkin Trans. 1 1991,
3005-3008. (b) Anstead, G. M.; Katzenellenboguen, J . A. J . Med. Chem.
1988, 31, 1754-1761.
(30) Dom´ınguez, E.; Lete, E.; Villa, M. J .; Iriondo, C. Heterocycles
1984, 22, 1217-1224.
(31) Scandium triflate has been reported as an excellent catalyst
for F-C acylation, see: Tsuchimoto, T.; Tobita, K.; Hiyama, T.;
Fukuzawa, S.-I. J . Org. Chem. 1997, 62, 6997-7005.
J . Org. Chem, Vol. 67, No. 21, 2002 7219

Olivera et al.
SCHEME 6a
afforded the isoflavone 14a in a rapid and clean reaction
at room temperature, as a consequence of the loss of
acetyl group by the action of the methoxide ion coming
from the imino derivative in equilibrium with DMFDMA
in solution or generated in the aminomethylenation step,
and subsequent displacement of NMe2 group, as depicted
in the proposed mechanistic pathway.33 As we put
forward previously and shown in Table 3, this unexpected
deprotection process was sorted out by performing the
reaction with benzoates 4g-i, obtaining in this way the
desired products 3 in moderate yield.33
Following our synthetic objectives, we next proceeded
to convert enamino ketones 3 to the corresponding 4,5-
diarylpyrazoles 15 by direct heterocyclization with phe-
nylhydrazine in aqueous methanol (Scheme 6). Aside
from the sterically impeded naphthoenamino ketone 3f,
which undergoes extensive decomposition, pyrazoles 15
were obtained regioselectively in excellent yields (Table
3), proving the efficiency of this approach to highly
functionalized 4,5-diarylpyrazoles, even when bulky ortho-
substituents were present. Thus, in striking contrast to
Tupper’s observations regarding a closely related het-
erocyclization,34 we may infer the apparent insensitivity
to the presence of bulky substituents at both ortho-
positions on the aryl groups, which is supported by the
production of the 3(5),4-naphthylarylpyrazole 16 (Scheme
6), wherein the substitution of phenylhydrazine by hy-
drazine itself and, consistently, the steric relief permitted
the easy cyclization of naphthoenamino ketone 3f. None-
theless, we also found that this method was not inde-
pendent of the nature of the enamino ketone used. Thus,
a
Reagents and conditions: (i) DMFDMA, PhMe, 90 °C. (ii)
PhNHNH2‚HCl, H2O, MeOH, NaOAc, HOAc, 140 °C. (iii) NHNH2‚-
2HCl, H2O, MeOH, NaOAc, HOAc, 100 °C (for 3f). (iv) NaOH,
MeOH, H2O, TEBA (cat.), 140 °C (sealed tube) (for 15a ). (v) KtBuO,
DMF, 0 °C (for 15b-e, 16). (vi) KOH, MeOH, H2O, 70 °C, (for
15g-i).
gation of reaction time/temperature. Importantly, this
observation on the noticeably different reactivity of both
substrates is consistent with the proposal of direct
interaction of bromo substituent with the Lewis catalyst,
which would impinge upon the subsequent demethyla-
tion.
(33) Proposed synthetic pathway for the formation of isoflavone 14a .
The formation of isoflavones was suppressed by starting from benzoy-
lated deoxybenzoins 13a -c. All the same, the partial lability of this
protecting group on deoxybenzoins 13b and 13a upon enaminomethy-
lation conditions was made clear, as shown by the isolation of the
corresponding isoflavones 14a ,b as minor products in 10 and 16% yield,
respectively.
It is obvious that this result cannot be rationalized by
invoking a mere steric effect of the halogens at the
reaction site, since it would be considerably greater for
the iodo derivative 12b.
The reasoning that led to protection of phenolic deoxy-
benzoins 13a -c as alkyl esters was based on the known
resistance of this moiety to alkoxide-type bases and acidic
media envisaged to apply in the remaining synthetic
steps. Acetylation of 13b upon the Schotten-Baumann
protocol failed, probably due to the insolubility of the
substrate in aqueous medium. Pefrorming a modified
protocol of Illi for the esterification of phenols32 (AcCl/
NaOH) using triethylbenzylammonium chloride (TEBA)
as catalyst furnished the acetate 4k (98% yield) (Scheme
5). As will be discussed later, it was necessary to prepare
benzoates 4g-i (Table 3) using the aforementioned
conditions (BzCl, NaOH), but the change of 1,4-dioxane
for THF proved to be crucial to achieve an acceptable
conversion degree for 4g and 4i.
2. Syn th esis of o,o′-Ha loh yd r oxy-4,5-d ia r ylp yr a -
zoles. With O-protected deoxybenzoins 4 in hand, their
enaminomethylated derivatives 3 were easily prepared
by treatment with dimethyl formamide dimethyl acetal
(DMFDMA) (Scheme 6. Table 3) in a Vilsmeier-Haack-
type reaction. To our surprise, O-acetylated product 4j
(32) Illi, V. O. Tetrahedron Lett. 1979, 26, 2431-2432.
7220 J . Org. Chem., Vol. 67, No. 21, 2002
(34) Tupper, D. E.; Ray, M. R. Synthesis 1997, 337-341.

Revisiting the Ullmann-Ether Reaction
SCHEME 7a
attempts conducted with substrates 3b,c bearing chloro
atoms in remote positions on the benzylic ring were not
successful enough (61 and 12% yield, respectively), rais-
ing the concern that the number of electron-withdrawing
substituents on the latter ring may be critical for the
amine exchange/heterocyclization sequence.
Finally, deprotection of sulfonates 15a -e and 16
proved to be a troublesome task, due to the extreme
robustness of the sulfonyl group to undergo basic hy-
drolysis under a wide range of conditions (NaOH/Me2-
CO, H2O;35a KOH/MeOH;35b KOH/THF;35c KOH/DMF,
MeOH;35d NaOMe/MeOH35e), which were too sluggish to
afford pyrazoles 2 either in acceptable yield or conversion
degree. However, a modification of the conditions of
Moberg et al.35f using directly KtBuO (Scheme 6) fur-
nished phenolic pyrazoles through an instantaneous
reaction in good yields (64-82% yield), as shown in Table
3. The difference in reactivity between sulfonates 15b-
e, 16 and tosylate 15a was somewhat perplexing, since
this latter compound required comparatively stringent
hydrolysis conditions (NaOH, MeOH, H2O, 140 °C under
pressure, TEBA (8 mol %)) to give the parent phenolic
pyrazole 2a (88% yield).
In clear contrast, benzoates 15g-i were smoothly
hydrolyzed upon standard basic conditions (KOH/ MeOH,
H2O), furnishing the corresponding phenolic pyrazoles in
excellent yield (Scheme 6. Table 3).
a
Reagents and conditions: (i) n-BuLi, THF, TMEDA, -78 °C;
(ii) (a) B(OMe)3 or B(OiPr)3, -78 °C to room temperature; (b) H3O+.
3. Bia r yl Eth er Cou p lin g Attem p ts via Bor on ic
Acid Der iva tives. Despite the considerable success to
date reached by the introduction of the thallium(III)-
mediated oxidative macrocyclization36a or the enzymatic
oxidative phenolic coupling methodologies,36b widely ap-
plied in the synthesis of glycopeptide antibiotics such as
vancomycin, by far, the difficult task of forming a C-O
diaryl ether bond relies on (i) the classical Ullmann-
ether synthesis,17h recently revitalized by modern and
useful variations,16a (ii) SNAr-based reactions on aryl
fluorides, (iii) SNAr-based reactions to arene-metal (Mn,
Ru, and Fe mainly) π-complexes, (iv) to a much lesser
extent, the recently introduced but not less promising
Buchwald-Hartwig reaction of haloarenes and phenols,16a,c
and (v) copper(II)-mediated coupling of boronic acids and
phenols.17d,f,37
Attracted by the latter method, featuring the extremely
mild conditions applied and the use of inexpensive
catalysts, the preparation of the required boronic acid
derivatives of selected O-protected and phenolic pyrazoles
15 and 2 was respectively undertaken (Scheme 7). All
attempts at reacting aryllithium derivatives of the se-
lected models with B(OMe)3 or B(OiPr)3 met with failure,
yielding the dehalogenated arenes 18 as the major
isolable materials (Table 4).
TABLE 4. Meta la tion /Bor on a tion Assa ys on
4,5-d ia r ylp yr a zoles
product
substrate
R1
R2
(% yield)a
2a
2g
15a
15g
H
OMe
H
H
H
Ts
H
18a (71)
18b (44)
18c (54)
19 (56)
OMe
a
Isolated yields.
This result is in consonance with our earlier findings
wherein an analogous behavior was exhibited by o,o′-
dihaloaryl heterocycles,14c presumably ascribable to an
unusually stable aggregation state of the organolithium
intermediates generated. As shown in Scheme 7, it was
noted that in the case of the benzoate 15g, the sole
isolated product was the pyrazole 19, which, formally,
had undergone debromination and intramolecular ben-
zoyl group transfer. It is reasonable to assume that the
product of the initial metal-bromine exchange might
attack intramolecularly to the ester group, generating an
oxepane-type intermediate (vide infra), which, after
cleavage, would render the isolated product 19 with the
benzoyl group located on the C-4 aryl ring. Spectrometric
analysis (H1 NMR and GC/MS) of the crude reaction
revealed the absence of byproducts due to the direct
attack of n-BuLi on the ester moiety, highlighting the
rapidity of this process and reinforcing the hypothesis of
its intramolecular nature.
(35) (a) Bordwell, F. G.; Boutan, P. J . J . Am. Chem. Soc. 1957, 79,
717-722. (b) Wolff, S.; Hoffmann, H. M. R. Synthesis 1988, 760-763.
(c) Civitello, E. R.; Rapoport, H. J . Org. Chem. 1994, 59, 3775-3782.
(d) Theuns, H. G.; Lenting, H. B. M.; Salemink, C. A.; Tanaka, H.;
Shibata, M. Heterocycles 1984, 22, 1995-2005. (e) Belanger, P. C.;
Scheigetz, J .; Young, R. N. Can. J . Chem. 1983, 61, 2177-2182. (f)
Levacher, V.; Adolfsson, H.; Moberg, C. Acta Chem. Scand. 1996, 50,
454-457.
(36) (a) Neuville, L.; Bois-Choussy, M.; Zhu, J . Tetrahedron Lett.
2000, 41, 1747-1751 and references therein. (b) Malnar, I.; Sih, C. J .
Tetrahedron Lett. 2000, 41, 1901-1911.
(37) (a) Simon, J .; Salzbrunn, S.; Prakash, G. K. S.; Petasis, N. A.;
Olah, G. A. J . Org. Chem. 2001, 66, 633-634. (b) Evans, D. E.; Katz,
J . L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937-2940.
4. P a lla d iu m -Ca ta lyzed In tr a m olecu la r O-Ar yla -
tion of o,o′-Ha loh yd r oxy-4,5-d ia r ylp yr a zoles. In light
of these results, we examined the feasibility of using the
Buchwald-Hartwig reaction16c,38 for access to the target
tetracyclic system, encouraged by the wide application
of this reaction, due in part, to the mild reaction condi-
J . Org. Chem, Vol. 67, No. 21, 2002 7221

Olivera et al.
SCHEME 8a
that DPPF, a ligand with a larger cone angle than
BINAP, did give the optimal results.42 The similar yields
obtained from all the assayed pyrazoles 2 are highly
relevant, which is in concert with Buchwald’s previous
observations of the apparent insensitivity of the Pd-
catalyzed intramolecular formation of cyclic ethers to the
electronic nature of the involved substituents.43
Thus, apart from the failed reactions of halophenol 2i
and halonaphthol 17 (probably due to the formidable
steric interactions in the course of the formation of the
alkoxo intermediate with the N-phenyl or H-3 on the
pyrazole nucleus respectively), it is rather complicated
from the inspection of Table 5 to unravel the various
factors that contribute to facilitate the desired O-aryla-
tion. To our knowledge, only another efficient Pd-
catalyzed etheration had been reported to date in a
similar constrained system,17c expanding in some way the
scope of this important transformation. On the other
hand, it is also illustrative to verify the ability of iodo
derivatives to promote this reaction, in contrast to the
vast majoriy of previous reports that strongly recommend
the use of bromoarenes as coupling partners. It is
therefore tempting to speculate that the most plausible
reasons why the Buchwald-Hartwig reaction worked on
our starting halophenolic pyrazoles 2 are the thermody-
namic stability of the ultimate heterocycle, along with
the strain release on the supposed eight-membered
palladacycle intermediate in the C-O bond formation.
5. Syn th esis of Diben zoxep in o[4,5-d ]p yr a zoles via
Ullm a n n -Eth er Rea ction . At this point of the re-
search, the aim of a more efficient approach prompted
us to seek an alternative method to achieve our goal by
implementation of an intramolecular Ullmann-ether
coupling to the oxepine ring. Toward this end, halophe-
nolic pyrazoles 2a , 2g, 2h , taken as models, were submit-
ted to a selected survey of Ullmann-ether reaction
conditions. Results of our screening studies involving the
use of different copper species are listed in Table 6,
wherein it can be discerned that many of the methods
employed suffer from some drawbacks, such as longer
reaction times and high temperatures, mainly due to the
insolubility of copper reagents in the medium. In that
respect, to overcome this apparent problem the use of
completely soluble copper(I) complexes (entries 1, 7, 8)
or CuO (entry 9) permitted increase of the reaction rate.
It should be highlighted that the excellent performance
of the novel protocol requires copper(I) triflate (entry 7)
employed catalytically in the presence of Cs2CO3 as base44
to furnish the target product at an unusual low temper-
ature for this process (110 °C). Likewise, the use of
copper(I) thiophenecarboxylate (CuTC) (entry 8), which
has been reported to promote Ullmann-biaryl coupling
at room temperature,45 also worked efficiently but at a
considerably higher temperature (145 °C), which had not
been applied to the formation of a biaryl-ether linkage
to date. Finally, copper(I) and -(II) oxides (entries 2,9),
which usually are employed mixed with metallic copper
a
Reagents and conditions: (i) NaOH, PhMe, 135 °C; (ii)
Pd2(dba)3/Ligand(4-9 mol %), PhMe, THF, 100 °C (sealed tube)
(iii) CuBr‚DMS, NaH, py, 120 °C.
tions and high functional group compatibility. Thus, by
submitting phenolic pyrazoles 2a , 2g and 2h as models
to the conditions reported by Gingras (NaH, Pd(PPh3)4,
t-BuOH, 100 °C) to prepare diaryl ether-based molecular
wires,39 only the dehalogenated products 18a ,b were
obtained (64-71%). It is known that Pd-catalyzed C-O
bond forming is a difficult task, due to the low nucleo-
philicity of the oxygen and, therefore, very slow reductive
elimination from the arylpalladium alkoxo complex in-
termediate. Likewise, this process is strongly dependent
on the steric features of the active catalytic system
employed and alkali nature/concentration,40d in such a
way that, until the introduction of bidentate (2,2′-bis-
(diarylphosphino)-1,1′-binaphthyl-17g or 1,1′-(dialkylphos-
phino)ferrocene-type,40b,c mainly) or specifically designed
monodentate dialkylphosphinobiphenyl ligands,17a,b,40a,c
only electron-rich or -neutral aryl bromides could be
applied. In this context, the obtained result with a first-
generation ligand such as PPh3 is fully consistent with
literature precedents, proving that the use of such simple
catalytic system may operate only in certain specific
cases. To our delight, despite the fact that phenoxides
are even less nucleophilic than alkoxides, when pre-
formed sodium phenolates 20 derived from pyrazoles 2
and 17 (Scheme 8) were treated with Pd2(dba)3 in the
presence of a bidentate ligand in a mixture of toluene
and THF, after prolonged reaction times (17-21 h), the
desired dibenzoxepines 1 were isolated in fair to moderate
yields (Table 5). Slightly better yields were obtained when
the catalytic system was based on the commercial ligands
1,1′-bis(diphenylphosphino)ferrocene (DPPF) rather than
2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP),41
requiring for the latter a greater ratio of catalyst (6.5-9
vs 4-7.5 mol %). In terms of the ability of the applied
phosphines to promote the reductive elimination of the
putative Pd-aryloxide intermediate, it is worth noting
(38) (a) Hartwig, J . F. Acc. Chem. Res. 1998, 31, 852-860. (b) Wolfe,
J . P.; Wagaw, S.; Marcoux, J .-F.; Buchwald, S. L. Acc. Chem. Res. 1998,
31, 805-818.
(39) Pinchart, A.; Dallaire, C.; Gingras, M. Tetrahedron Lett. 1998,
39, 543-546.
(40) (a) Parrish, C. A.; S.-I.; Buchwald, S. L. J . Org. Chem. 2001,
66, 2498-2500. (b) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig,
J . F. J . Am. Chem. Soc. 1999, 121, 3224-3225. (c) Aranyos, A.; Old,
D. W.; Kiyomori, A.; Wolfe, J . P.; Sadighi, J . P.; Buchwald, S. L. J .
Am. Chem. Soc. 1999, 121, 4369-4378. (d) Widenhoefer, R. A.; Zhong,
H. A.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119, 6787-6795.
(41) Control experiments were conducted in the same solvent
mixture in the absence of a palladium catalyst, but none of the desired
products were detected, and starting halide was completely recovered
(>90%).
(42) Mann, G.; Hartwig, J . F. Tetrahedron Lett. 1997, 38, 8005-
8008.
(43) Palucki, M.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc.
1996, 118, 10333-10334.
(44) Marcoux, J .-F.; Poye, S.; Buchwald, S. L. J . Am. Chem. Soc.
1997, 119, 10538-10540.
(45) Zhang, S.; Zhang, D.; Liebeskind, L. S. J . Org. Chem. 1997,
62, 2312-2313.
7222 J . Org. Chem., Vol. 67, No. 21, 2002

Revisiting the Ullmann-Ether Reaction
TABLE 5. Resu lts Obta in ed in th e Syn th esis of Diben zoxep in o[4,5-d ]p yr a zoles 1
a
b
R9dPh (for 2a -i). R9dH (for 17). Isolated yield of chromatographed compound estimated to be of >95% purity, as indicated by 1H
NMR and GC/MS analyze. Yield calculated from the starting halophenolic pyrazoles 2. c Yields obtained by method A (Buchwald-Hartwig
reaction) when DPPF was used as ligand. Reactions were conducted with 4-7.5 mol % Pd2(dba)3 at 100 °C for 17-19 h. Figures in
d
parentheses refer to yields obtained when (R)-BINAP was used as ligand in method A. Reactions were conducted with 6.5-9 mol %
Pd2(dba)3 at 100 °C for 17.5-48 h. e Yield of pure crystallized compound obtained by method B (Ullmann-ether synthesis). f Yield of
pure chromatographed product. Yield in parentheses was determined by GC/MS with reference to an internal standard. Manipulation of
g
product 1e proved to be troublesome and induced a dramatic decrease in the isolated yield. None of the tetracyclic product was detected.
h
Low yield of the expected product 1h (12%) was measured by GC/MS with reference to an internal standard.
to promote Ullmann-ether reaction,40,46 required unac-
ceptable, prolonged heating periods. Interestingly, com-
parison of the results for substrates 2g and 2h in Table
6 reveals a slightly more efficient reactivity for the iodo-
substituted pyrazole 2h than the brominated analogue
2g, both in terms of yield and reaction rate.
excess of the copper complex (8-12 mol % excess), the
reaction proceeded readily to completion in sluggish
substrates, in contrast with the deleterious effect of an
increase of temperature. Disgracefully, and despite the
fact of working with other systems under stringent
conditions, insurmountable difficulty was encountered in
attempting to utilize the naphthopyrazole 17. In the light
of the results obtained from more hindered substrates
such as 1c, 1g, and 1h , and taking into account the
known ability of pyrazole nucleus to complex a wide
range of transition metals,49 we surmise that, once N-1
on the pyrazole ring has been deprotonated, complexation
of the ring with the copper reagent might be responsible
for the failure of further reaction rather than a virtual
steric hindrance between the naphthyl substituent and
H-3 in the transition state.
Once we had established the excellence of the CuBr‚
DMS reagent to accomplish the ultimate ring closure,
halophenolic pyrazoles 2 were subjected to its action,
resulting in the formation of the target tetracycles 1 in
good yields. Table 5 illustrates the scope of this approach
and permits us to state its convenience compared with
the Pd-catalyzed C-O bond forming one, both in terms
of yield and substitution range. As a matter of fact,
compounds not obtainable by the Buchwald-Hartwig
reaction, such as the constrained polymethoxylated diben-
zoxepine 1h , were isolated in a surprising good yield
(72%). Additionally, it is of interest to note that the ortho-
substituted dibenzoxepines around the ether linkage (1c
and 1g) did not suffer from lack of reactivity, in striking
contrast to the literature precedents supporting the
pernicious effect of substituents at that position on the
Ullmann-ether reaction.48 Despite the diverse substitu-
tion pattern, the isolated yields of dibenzoxepines 1 did
not vary excessively, confirming the excellence of this
protocol to carry out the dibenzoxepine ring closure,
except in the case of diethylamino-substituted product
1e. We surmise that, as occurred in previous precursors
as well but to a larger extent, its low solubility in organic
solvents and tendency to give gummy solids of trouble-
some manipulation may cause a significant loss of yield
in the purification stage. We found that with a slight
6. P r elim in a r y P h a r m a cologica l Eva lu a tion . Sev-
eral selected dibenzoxepines 1 were evaluated for their
affinity on a complete panel of peripheral and central
nervous system receptors [serotonin (5-HT1A, 5-HT2A
,
5-HT3), serotonin uptake, dopamine (D1, D2), dopamine
uptake, noradrenaline (R1, R2), noradrenaline uptake,
and histamine H1 and muscarinic receptors] by radioli-
gand binding assays. As summarized in Table S1 (see
Supporting Information), no assay exhibited a significant
response (higher than 50% inhibition at 1 µM concentra-
tion) except for dibenzoxepine 1g, which showed a limited
binding affinity to D2 dopamine receptors.
To our knowledge, a general, easily extensible technol-
ogy for the construction of this novel structural family
via the dibenzoxepine ring closure starting from 1,2-
diarylethanones had not been described yet. Thus, and
according to the previously shown discouraging pharma-
cological results, at present, further studies are underway
to extend our novel ring closing tactic to enable develop-
ment of versatile routes to other important classes of
condensed N- and O-heteroaromatics that may exhibit
the desired bioactivity.
(46) Evans, D. A.; Ellmann, J . A. J . Am. Chem. Soc. 1989, 111,
1063-1072.
(47) It is commonly accepted that SNAr mainly occurs with activated
fluoro and chloroarenes; see: Paradisi, C. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Perga-
mon Press: New York, 1991; Vol. 4, p 423. Control experiments were
carried out in the absence of copper species (Table 6, entry 10), leading
to the full recovery of starting phenolates, ruling out the operativity
of this reaction pathway.
(48) Moroz, A. A.; Shvartsberg, M. S. Russ. Chem. Rev. 1974, 43,
679.
(49) Grimmett, M. R.; Iddon, B. Heterocycles 1994, 37, 2087-2149.
J . Org. Chem, Vol. 67, No. 21, 2002 7223

Olivera et al.
TABLE 6. Resu lts fr om th e Ullm a n n -Eth er Cou p lin g
Assa ys on Ha lop h en olic P yr a zoles 2a ,g-i
Further, we have proved the validity of the amine
exchange/heterocyclization sequence to prepare o,o′-ha-
loarylsulfonyloxy- and o,o′-halobenzoyloxy-4,5-diarylpyra-
zoles. The strategically substituted aryl groups intro-
duced on the 3-N,N-(dimethylamino)-o,o′-disubstituted-
1,2-diarylpropenone precursors have shown the limitations
imposed by electronically deactivated C-1 aryl groups or
sterically demanding substituents at C-2.
Finally, preliminary pharmacological in vitro evalua-
tion has shown the inability of the synthesized com-
pounds to interact with the most common peripheral and
central nervous system receptors.
reaction
conditions
1 (%
t (h) yield)a,b
entry substrate
1
2a
2g
2h
2a
2g
2h
2a
2g
2h
2a
2g
2h
2a
2g
2h
2a
2g
2h
2a
2g
2h
2a
2g
2h
2a
2g
2h
2a
2g
2h
CuBr‚DMS,e NaH, py, 120 °C
4
6
1a (87)c
1g (74)c
Exp er im en ta l Section
5,5 1g (78)c
In str u m en ta tion , Gen er a l P r oced u r es, a n d Ma ter ia ls.
For general experimental details, see ref 14a.
Syn th esis of Diben zoxep in o[4,5-d ]p yr a zoles (1).51
2
Cu2O, NaH, py, 130-165 °C 6,5
1a (69)
1g (61)
1g (66)
1a (81)
1g (66)
1g (74)
1a (42)
1g (46)
1g (41)
1a (55)
1g (59)
1g (51)
1a (9)
1g (11)
1g (16)
1a (71)
1g (64)
1g (73)
1a (74)
1g (62)
1g (68)
1a (69)
1g (57)
1g (69)
f,g
24
19
Meth od A (Ullm a n n -Eth er Rea ction ). 1-P h en yld iben -
zo[2,3:6,7]oxep in o[4,5-d ]p yr a zole (1a ). Typ ica l P r oce-
d u r e. NaH (95% in oil dispersion, 12.6 mg, 0.50 mmol) was
added to a stirred solution of halophenolic pyrazole 2a (0.2 g,
0.46 mmol) and CuBr‚Me2S (99%, 0.188 g, 0.91 mmol) in
anhydrous pyridine (5 mL) under an atmosphere of Ar at
ambient temperature. After stirring for 15 min, as the reaction
mixture turned black, it was heated at 120 °C for 5.5 h, until
consumption of starting material was confirmed by TLC (2%
EtOAc/DCM). The mixture was allowed to cool, poured into
1.37 M HCl (40 mL), and extracted with DCM (5 × 10 mL).
The organic layer was washed with 0.31 M CuSO4 (1 × 5 mL),
dried (anhyd Na2SO4), filtered off, and the solvent was removed
in vacuo. The crude oil was absorbed on silica gel (1 g) and
flash chromatographed eluting with the gradient 80f100%
DCM/hexanes as eluant. The pure eluate was crystallized from
MeOH affording dibenzoxepine 1a (0.125 g, 87%) as a white
powder: mp 171-173 °C (MeOH); Rf 0.82 (2% EtOAc/DCM);
1H NMR (CDCl3) δ 6.81 (1H, dd, J ) 7.9, 1.6 Hz), 6.94 (1H,
ddd, J ) 8.1, 7.9, 1.6 Hz), 7.20-7.52 (10H, m), 7.57 (1H, dd, J
) 6.9, 1.6 Hz), 8.01 (1H, s); 13C NMR (CDCl3) δ 120.3, 121.5,
122.3, 122.9, 124.7, 125.1, 125.5, 127.0, 127.9, 128.6, 128.7,
129.2, 130.2, 136.2, 137.9, 140.8, 155.9, 156.5; FTIR (neat film,
cm-1) 1597; EIMS (m/z, %) 310 (M+, 100), 281 (12), 206 (12),
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.
3
CuI,d K2CO3, py, 125-140 °C 6,5
18
14
4
5
5
4
4
Cu, KI, DMSO, 180-200 °C
5
CuCl, 18-crown-6, Na2CO3,
NMP, 150 °C
5
4,5
36
36
36
7
9
7,5
3
5
3
22
92
54
6
CuBr, NaH, py, 150 °C
7
(CuOTf)2‚PhH (5 mol %),
Cs2CO3, PhMe, 110 °C
8
CuTC,e NaH, py, 145 °C
CuO, K2CO3, py, 150 °C
9
10
(1) NaOH, PhMe, 135 °C; 24
(2) DMF, 150 °C
24
24
a
b
GC/MS with reference to an internal standard. Reactions
went to completion upon adding a slight excess (8-12 equiv mol
%) of copper species. c Isolated yield of chromatographed compound
estimated to be of >95% purity as indicated by 1H NMR and GC
By using the same procedure and starting from the ap-
propriate intermediate compound of preceding step, the fol-
lowing products were obtained.
d
analysis. Initially, experiments were carried out by applying
ultrasounds at 19-65 °C (see ref 50), but starting material was
completely recovered. e CuBr‚DMS, copper(I) bromide-dimethyl
sulfide complex; CuTC, copper(I) thiophene carboxylate. f Recovery
5-Ch lor o-1-p h en yld iben zo[2,3:6,7]oxep in o[4,5-d ]p yr a -
zole (1b), after crystallization from EtOH: 88%, as an off-white
powder; mp 199-201 °C (EtOH); Rf 0.47 (30% EtOAc/hexanes);
1H NMR (CDCl3) δ 6.79 (1H, dd, J ) 7.1, 1.6 Hz), 6.94 (1H,
ddd, J ) 8.0, 7.5, 2.0 Hz), 7.25-7.52 (10H, m), 8.02 (1H, s);
13C NMR (CDCl3) δ 119.2, 122.2, 122.6, 122.7, 124.9, 125.1,
126.7, 127.2, 128.1, 128.3, 128.6, 129.2, 130.4, 130.6, 136.4,
137.8, 139.8, 154.3, 156.2; FTIR (neat film, cm-1) 1597; EIMS
(m/z, %) 346 (M + 2, 36), 344 (M+, 100), 308 (10), 281 (77), 77
(16). Anal. Calcd for C21H13ClIN2O: C, 73.15; H, 3.80; N, 8.12.
Found: C, 73.21; H, 3.94; N, 8.06.
g
of the starting material (>90%). See ref 47.
Con clu sion s
In summary, we have developed an operationally
straightforward method for the preparation of the unre-
ported dibenzoxepino[4,5-d]pyrazoles. Our protocol is
amenable to construct multisubstituted electron-rich,
-neutral, and -poor dibenzoxepino[4,5-d]pyrazoles that
would not be easily obtained by other methods, from o,o′-
halohydroxy-4,5-diarylpyrazoles by an efficient biaryl-
ether coupling promoted by CuBr‚DMS complex. More-
over, an alternative approach to the target dibenzoxepine
derivatives relies on the Pd-catalyzed C-O bond forma-
tion of the biaryl-ether linkage, exhibiting limitations
in terms of yield and steric demand of the generated
compounds. In this approach, the use of a bidentate
ligand (BINAP or preferably, DPPF) is crucial to reach
the target compounds in reasonable yield.
(50) Bello´n, R. F.; Carrasco, R.; Milia´n, V.; Rode´s, L. Synth.
Commun. 1995, 25, 1077-1083.
(51) Alternative substitutive nomenclature of dibenzoxepino[4,5-d]-
pyrazoles 1 as azulene derivatives may also be accepted. According to
this, the systematic names of the synthesized tetracycles 1 are as
follows: 1a, 1-phenyl-1H-8-oxa-1,2-diazadibenzo[e,h]azulene; 1b, 7-chlo-
ro-1-phenyl-1H-8-oxa-1,2-diazadibenzo[e,h]azulene; 1c: 5,7-dichloro-1-
phenyl-1H-8-oxa-1,2-diazadibenzo[e,h]azulene; 1d , 10,11-dimethoxy-
1-phenyl-1H-8-oxa-1,2-diazadibenzo[e,h] azulene; 1e, 10-diethylamino-
1-phenyl-1H-8-oxa-1,2-diazadibenzo[e,h]azulene; 1g, 1-phenyl-5,6,9,10-
tetramethoxy-1H-8-oxa-1,2-diazadibenzo[e,h] azulene; 1h , 1-phenyl-
5,6,10,12-tetramethoxy-1H-8-oxa-1,2-diazadibenzo[e,h] azulene.
7224 J . Org. Chem., Vol. 67, No. 21, 2002

Revisiting the Ullmann-Ether Reaction
5,7-Dich lor o-1-p h en yld ib en zo[2,3:6,7]oxep in o[4,5-d ]-
p yr a zole (1c), after crystallization from Et2O: 76%, as an
amber glassy solid; mp 105-107 °C (Et2O); Rf 0.42 (30%
EtOAc/hexanes); 1H NMR (CDCl3) δ 6.81 (1H, dd, J ) 7.9, 1.6
Hz), 6.97 (1H, ddd, J ) 7.9, 7.9, 2.0 Hz), 7.34 (1H, dd, J ) 7.9,
1.6 Hz), 7.37-7.47 (6H, m), 7.58 (1H, d, J ) 1.2 Hz), 7.61 (1H,
d, J ) 1.2 Hz), 8.03 (1H, s); 13C NMR (CDCl3) δ 122.5, 123.1,
125.2, 125.3, 127.8, 128.3, 128.5, 128.7, 129.3, 130.5, 130.6,
137.9, 139.7, 149.6, 155.9; FTIR (neat film, cm-1) 1593; EIMS
(m/z, %) 382 (M + 4, 13), 380 (M + 2, 71), 378 (M+, 100), 342
(12), 279 (14), 77 (36). Anal. Calcd for C21H12Cl2IN2O: C, 66.51;
H, 3.19; N, 7.39. Found: C, 66.46; H, 3.45; N, 7.44.
109.1, 117.6, 120.0, 122.2, 126.6, 128.6, 134.0, 137.2, 142.7,
146.7, 149.0, 149.7, 156.4, 160.4, 162.3; FTIR (neat film, cm-1
1615; EIMS (m/z, %) 430 (M+, 100), 415 (17), 387 (9), 215 (10),
77 (15). Anal. Calcd for C25H22N2O5: C, 69.76; H, 5.15; N, 6.51.
Found: C, 69.99; H, 5.21; N, 6.61.
)
Meth od B (Bu ch w a ld -Ha r tw ig Rea ction ). 1-P h en yl-
d iben zo[2,3:6,7]oxep in o[4,5-d ]p yr a zole (1a ). Typ ica l P r o-
ced u r e. Ground NaOH (99%, 0.023 g, 0.56 mmol) was added
to a stirred suspension of halophenolic pyrazole 2a (0.22. g,
0.51 mmol) in anhydrous PhMe (14 mL) at ambient temper-
ature under an atmosphere of Ar. The resultant mixture was
heated to reflux for 30 min and allowed to cool without stirring.
The supernatant orange solution containing the phenolate 20a
was transferred via cannula to an empty flask and was
degassed by bubbling with Ar (20 min). A mixture of Pd2(dba)3
(99%, 16.5 mg, 17.9 µmol) and DPPF (97%, 40.9 mg, 71.6 µmol)
in anhydrous and degassed THF (1.6 mL) was stirred for 20
min at ambient temperature under an atmosphere of Ar and
added dropwise to the previously prepared solution of pheno-
late 20a . The reaction mixture was heated at 100 °C for 17 h,
until consumption of starting material was confirmed by TLC
(2% EtOAc/DCM). After cooling to ambient temperature, the
crude mixture was filtered through a pad of Celite and
thoroughly washed with THF and the filtrate was evaporated
under reduced pressure. The residue was flash chromato-
graphed on silica gel eluting with the gradient 80f100% DCM/
hexanes to give dibenzoxepine 1a (0.11 g, 69%) as an off-white
powder.
10,11-Dim eth oxy-1-p h en yld iben zo[2,3:6,7]oxep in o[4,5-
d ]p yr a zole (1d ), after crystallization from Et2O: 69%, as a
white powder; mp 166-167 °C (Et2O), Rf 0.44 (2% EtOAc/
DCM); 1H NMR (CDCl3) δ 3.30 (3H, s), 3.90 (3H, s), 6.20 (1H,
s), 6,90 (1H, s), 7.20-7.27 (1H, m), 7.30 (1H, dd, J ) 8.1, 1.5
Hz), 7.38-7.58 (7H, m), 8.03 (1H, s); 13C NMR (CDCl3) δ 55.4,
56.0, 105.5, 110.1, 113.9, 119.6, 121.3, 125.5, 125.7, 127.1,
128.0, 128.5, 129.2, 136.4, 137.8, 140.0, 145.6, 150.4, 155.9;
FTIR (neat film, cm-1) 1612; EIMS (m/z, %) 370 (M+, 100),
323 (15), 295 (24), 169 (13), 77 (17). Anal. Calcd for C23H18
-
N2O3: C, 74.58; H, 4.90; N, 7.56. Found: C, 74.49; H, 4.96; N,
7.61.
10-N,N-Dieth ylam in o-1-ph en yldiben zo[2,3:6,7]oxepin o-
[4,5-d ]p yr a zole (1e), after purification by flash chromatog-
raphy using 80% DCM/hexanes as eluant: 57%, as a yellow
oil; Rf 0.64 (40% EtOAc/hexanes); 1H NMR (CDCl3) δ 1.15 (6H,
t, J ) 6.7 Hz), 3.34 (4H, q, J ) 6.7 Hz), 6.22 (1H, dd, J ) 8.9,
2.6 Hz), 6.60 (1H, d, J ) 8.9 Hz), 6.61 (1H, d, J ) 2.6 Hz),
7.20-7.46 (7H, m), 7.55 (2H, dd, J ) 7.5, 1.6 Hz), 7.99 (1H, s);
13C NMR (CDCl3) δ 12.5, 44.4, 104.0, 107.8, 121.5, 125.1, 125.3,
127.0, 127.5, 128.2, 129.0, 129.2, 137.8, 140.7, 155.7, 158.2;
FTIR (neat film, cm-1) 1622; EIMS (m/z, %) 381 (M+, 81), 364
(100), 338 (20), 337 (38), 308 (8), 281 (8), 181 (20), 77 (24).
Anal. Calcd for C25H23N3O: C, 78.71; H, 6.08; N, 11.02. Found:
C, 78.56; H, 6.20; N, 11.19.
The application of this procedure on the appropriate halophe-
nolic pyrazole 2 afforded the corresponding dibenzoxepine
derivative 1 in the yield indicated in Table 5. The same
protocol was followed when (R)-BINAP was used as ligand
instead of DPPF. Catalyst ratio was increased in the case of
deactivated substrates. In all cases, the purity of the obtained
dibenzoxepines was >95% according to their spectroscopic (1H
NMR) and spectrometric (GC/MS) analyses.
1-P h en yl-5,6,9,10-tetr am eth oxydiben zo[2,3:6,7]oxepin o-
[4,5-d ]p yr a zole (1g), after crystallization from Et2O: 78%, as
a white powder; mp 187-189 °C (Et2O); Rf 0.54 (2% EtOAc/
DCM); 1H NMR (CDCl3) δ 3.82 (3H, s), 3.92 (6H, s), 4.08 (3H,
s), 6.46 (1H, d, J ) 9.1 Hz), 6.51 (1H, d, J ) 9.1 Hz), 6.98 (1H,
s), 7.05 (1H, s), 7.37-7.48 (3H, m), 7.52 (2H, dd, J ) 8.7, 1.5
Hz), 7.99 (1H, s); 13C NMR (CDCl3) δ 56.0, 56.1, 56.3, 61.8,
105.9, 108.2, 108.7, 117.0, 117.4, 119.5, 122.9, 125.1, 127.7,
129.1, 135.8, 137.3, 140.2, 141.7, 149.1, 149.2, 150.5, 154.3;
FTIR (neat film, cm-1) 1600; EIMS (m/z, %) 430 (M+, 100),
415 (16), 387 (10), 77 (10). Anal. Calcd for C25H22N2O5: C,
69.76; H, 5.15; N, 6.51. Found: C, 69.94; H, 5.10; N, 6.67.
1-P h en yl-5,6,10,12-t et r a m et h oxyd ib en zo[2,3:6,7]oxe-
p in o[4,5-d ]p yr a zole (1h ), after purification by flash chro-
matography on silica gel eluting with the gradient 50f70%
EtOAc/hexanes and subsequent crystallization of the pure
eluate from EtOH: 72%, as a white powder; mp 151-153 °C
(EtOH); Rf 0.43 (60% EtOAc/hexanes); 1H NMR (CDCl3) δ 3.01
(3H, s), 3.84 (3H, s), 3.92 (6H, s), 6.09 (1H, d, J ) 2.2 Hz),
6.56 (1H, d, J ) 2.2 Hz), 7.24 (1H, d, J ) 7.7 Hz), 7.36 (2H,
Ack n ow led gm en t. This research was financially
supported by the University of the Basque Country
(UPV 170.310G37/98), the Ministry of Education and
Culture of Spain (PB97-0600) and the Basque Govern-
ment (GV170.310-G0053/96). R.O. and F.C. thank the
Basque Government and the Ministry of Education and
Culture, respectively, for their predoctoral scholarships.
We are gratefully indebted to Dr. Aurelio Orjales and
Luis Labeaga (Director of Research and Head of Phar-
macology Department respectively at FAES FARMA,
Leioa-Lamiako (Bizkaia, Spain) for the preliminary
pharmacological evaluation and invaluable discussion
of the results.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of precursors and intermediates (2-
17); pharmacological results (Table S1) and the corresponding
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org
dd, J ) 7.7, 7.7 Hz), 7.45 (2H, d, J ) 7.7 Hz), 7.97 (1H, s); 13
NMR (CDCl3) δ 54.3, 55.5, 56.1, 56.3, 95.9, 98.8, 105.2, 105.6,
C
J O025767J
J . Org. Chem, Vol. 67, No. 21, 2002 7225