Palladium-catalyzed synthesis of 1-azaazulenes from cycloheptatrienylmethyl ketone O-pentafluorobenzoyl oximes

Article abstract of DOI:10.1246/cl.2002.606

Substituted 1-azaazulenes are synthesized from cycloheptatrienylmethyl ketone O-pentafluorobenzoyloximes by the intra-molecular Heck-type amination catalyzed by Pd(dba)₂-(t-Bu)₃P.

Full text of DOI:10.1246/cl.2002.606

606
Chemistry Letters 2002
Palladium-Catalyzed Synthesis of 1-Azaazulenes from Cycloheptatrienylmethyl Ketone
O-Pentafluorobenzoyl Oximes
Mitsuru Kitamura, Shunsuke Chiba, Osamu Saku, and Koichi Narasakaꢀ
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
(Received February 18, 2002;CL-020155)
Substituted 1-azaazulenes are synthesized from cyclohepta-
trienylmethyl ketone O-pentafluorobenzoyloximes by the intra-
molecular Heck-type amination catalyzed by Pd(dba)2–(t-Bu)3P.
Table 1. Synthesis of 1-azaazulene 4a from oxime 1a
Recently, we reported that N-O bond of oxime derivatives is
cleaved by the oxidative addition to Pd(0) complexes to generate
alkylidenaminopalladium(II) species.1 This procedure provides
an alternative method to generate alkylidenaminopalladium(II)
species which have been prepared previously by the ligand
exchange of carbopalladium species with imines.2 We have
demonstrated that Mizoroki-Heck-type cyclization (amino-Heck
reaction) of olefinic oxime derivatives proceeds via the amino-
palladium complexes, affording various azaarenes such as
pyrroles,1a pyridines,1b isoquinolines,1b and spiroimines.1c
Although azaazulene derivatives have received much interest
for several decades due to their physical properties as aza-
nonbenzenoid aromatics and pharmacological activities,3 few
preparative methods have been known.3;4 Therefore, we tried to
apply this amino-Heck reaction to the synthesis of 1-azaazulenes
from cycloheptatrienylmethyl ketone oximes.
By employing 2-(2,4,6-cycloheptatrienyl)-1-phenylethan-1-
one O-pentafluorobenzoyloxime (1a),5 intramolecular amino-
Heck reaction was examined under various reaction conditions as
shown in Table 1. After heating a mixture of 1a, triethylamine,
and a catalytic amount of Pd(PPh3)4 in DMF at 80 ꢁC for 5 h and
1
an usual work up, H NMR of the crude mixture exhibited the
formation of 3,4-dihydro-2-phenyl-1-azaazulene (3a), a small
amount of isomers of 3a, 2-phenyl-1-azaazulene (4a), and ketone
5a. Successive treatment of the crude mixture with MnO24d gave
1-azaazulene 4a and ketone 5a in 25% and 35% yield,
respectively (run 1). Addition of MS 4A was effective to increase
the yield of 1-azaazulene 4a and to suppress the ketone formation,
as is observed in the previous synthesis of spiroimines1c (run 2).
When the reaction was carried out by using bis(dibenzylidene-
acetone)palladium [Pd(dba)2] and (t-Bu)3P instead of Pd(PPh3)4,
the yield of 4a was improved to 78% (run 3). Concerning bases
examined, no remarkable influence was observed on the product
yields except DBU (runs 4–7).
converted to 2-styrylazaazulene 4f in 68% yield (run 6). Alkynyl
ketone oxime 1g gave nitrile 6 via the fragmentation of
alkylidenaminopalladium intermediate 2g6 (run 7). 2,3-Disub-
stituted azaazulenes 4h–j were prepared in moderate yields from
ꢀ-substituted cycloheptatrienylmethyl ketone oximes 1h–j (runs
8–10).
This method can be applied also to the synthesis of polycyclic
derivatives. ꢀ-Cycloheptatrienyltetralone oxime (1k) cyclized to
benzo[g]cyclohepta[b]indole (8) and 5,6-Dihydro-benzo[g]-
cyclohepta[b]indole (9) in 86% combined yield (eq 1).
Cyclization products of different type were obtained in the
reaction of oxime of ꢀ-keto ester. 2-(2,4,6-Cycloheptatrienyl)-1-
ethoxycarbonylethan-1-one O-pentafluorobenzoyloxime (1l) un-
derwent the cyclization, leading the desired azulenyl ester 4l in
only 19% yield, and quinoline 10 and isoquinoline 11 were
obtained in 33% combined yield7 (eq 2).
This method was then applied to the cyclization of various
cycloheptatrienyl O-pentafluorobenzoyloximes, and the results
are summarized in Table 2. In the reaction of 1b having bulky
tert-butyl group as R1 at 80 ꢁC, it required 4.5 h to consume the
starting material 1b and gave the desired 1-azaazulene 4b in 64%
yield, while 4b was obtained in 84% yield at 110 ꢁC within 0.5 h
(run 2). The oximes bearing secondary alkyl groups such as
isopropyl and cyclopropyl groups 1c, d cyclized at 80 ꢁC to give
the corresponding azaazulenes 4c, d in good yields (runs 3, 4). In
contrast, 2-methylazaazulene 4e was obtained in low yield (run
5). ꢀ; ꢁ-Unsaturated ketone oxime 1f having styryl group was
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
607
Table 2. Synthesis of azaazulene 4 from oxime 1 by amino-
Heck reaction
As described above, the amino-Heck cyclization of O-
pentafluorobenzoyloximes of cycloheptatrienylmethyl ketones
proceeds by the catalytic use of Pd(dba)2–(t-Bu)3P. As the
starting materials, oximes 1, are readily prepared by the addition
of ketone derivatives to cycloheptatrienyl tetrafluoroborate5 and
the successive oximation and O-pentafluorobenzoylation,1a the
present method provides a simple procedure to prepare various 2-
substituted and 2,3-disubstituted 1-azaazulenes.
This research was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘‘Exploitation of Multi-Element
Cyclic Molecules’’ from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
References and Notes
1
a) H. Tsutsui and K. Narasaka, Chem. Lett., 1999, 45. b) H.
Tsutsui and K. Narasaka, Chem. Lett., 2001, 526. c) M.
Kitamura, S. Zaman, and K. Narasaka, Synlett, 2001, 974.
Recently, palladium(0)-catalyzed synthesis of nitriles from
cyclobutanone oximes was reported via alkylidenaminopal-
ladium species;see d) T. Nishimura and S. Uemura, J. Am.
Chem. Soc., 122, 12049 (2000).
ꢀ
J. P. Wolfe, J. Ahman, J. P. Sadighi, R. A. Singer, and S. L.
Buchwald, Tetrahedron Lett., 38, 6367 (1997);G. Mann, J. F.
2
´
Hartwig, M. S. Driver, and C. Fernandez-Rivas, J. Am. Chem.
Soc., 120, 827 (1998).
3
4
N. Abe, in ‘‘Recent Research Developments in Organic and
Bioorganic Chemistry,’’ ed. by S. G. Pandalai, Transworld
Research Network, Trivandrum (2001), Vol. 4, p 14.
a) N. Abe, H. Fujii, K. Tahara, and M. Shiro, Heterocycles, 55,
1659 (2001). b) T. Takayasu and M. Nitta, J. Chem. Soc.,
Perkin Trans. 1, 1999, 687. c) T. Takayasu, K. Ito, and M.
Nitta, Heterocycles, 43, 2667 (1996). d) K. Ito and M. Nitta,
Heterocycles, 36, 2247 (1993). e) Y. Sugimura, N. Soma, and
Y. Kishida, Bull. Chem. Soc. Jpn., 45, 3174 (1972).
I. D. Reingold, H. A. Trujillo, and B. E. Kahr, J. Org. Chem.,
51, 1627 (1986).
5
6
Formation of diarylacetylene 12 in the reaction of 1g
(Table 2, run 7) suggested 6 was formed by ꢁ-alkynylelimi-
nation from 2g and successive decarboxylation.
7
When the reaction of 1l was carried out with Pd(dba)2–(t-
Bu)3P instead of Pd(PPh3Þ4, 4l, 10, and 11 were obtained in 5,
10, and 10% yields, respectively.