Naphthalenes, isoquinolines, and a benzazocine from zirconocene - Copper-mediated coupling of benzocyclobutadiene with nitriles and alkynes

Article abstract of DOI:10.1021/ol034040u

(Matrix presented) Commercially available 1-bromobenzocyclobutene is a potentially useful synthon particularly with the application of organometallic methodology. Here we show that it is readily converted into Cp ₂Zr(benzocyclobutadiene), which couples with alkynes or nitriles giving five-membered zirconacycles. Treatment of these alkyne- or nitrile-derived zirconacycles with CuCl yields substituted naphthalenes, isoquinolines, or in the presence of MeO₂C-CC-CO₂Me, a 2-benzazocine containing an eight-membered ring.

Full text of DOI:10.1021/ol034040u

ORGANIC
LETTERS
2003
Vol. 5, No. 6
877-879
Naphthalenes, Isoquinolines, and a
Benzazocine from
Zirconocene−Copper-Mediated Coupling
of Benzocyclobutadiene with Nitriles
and Alkynes
T. V. V. Ramakrishna and Paul R. Sharp*
Department of Chemistry, UniVersity of Missouri-Columbia,
Columbia, Missouri 65211
sharpp@missouri.edu
Received January 9, 2003
ABSTRACT
Commercially available 1-bromobenzocyclobutene is a potentially useful synthon particularly with the application of organometallic methodology.
Here we show that it is readily converted into Cp2Zr(benzocyclobutadiene), which couples with alkynes or nitriles giving five-membered
zirconacycles. Treatment of these alkyne- or nitrile-derived zirconacycles with CuCl yields substituted naphthalenes, isoquinolines, or in the
presence of MeO C−CC−CO Me, a 2-benzazocine containing an eight-membered ring.
2
2
Reactions mediated by transition metals have played an
important role in synthetic methodology during the last
quarter century.1 Zirconocene complexes have attracted much
interest in this regard.2 Recently, transmetalation of zircona-
cycles onto Cu and Ni have opened new avenues in carbon-
carbon and carbon-heteroatom bond coupling chemistry.3
Benzocyclobutenes are useful synthons in organic chem-
istry.4 Application of organometallic methodology could
greatly expand their usefulness. To this end, we recently
reported the zirconocene complex, Cp2ZrMe(1-benzocy-
clobutenyl) 2, readily prepared from commercially available
1-bromobenzocyclobutene 1, its thermolysis to yield the
novel complex Cp2Zr(η2-benzocyclobutadiene)(PMe3) 3, and
the reactions of 3 with alkynes, nitriles, and isocyanides to
give zirconacycles fused to the benzocyclobutene (Scheme
1).5
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New York, 2002.
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K.; Kotora, M. J. Am. Chem. Soc. 2002, 124, 576-582.
10.1021/ol034040u CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/14/2003

butadiene complex, formed by methane elimination from 2,
must be stabilized with trimethylphosphine prior to the
insertion reactions. We have therefore worked to shorten the
procedure and eliminate the use of trimethylphosphine. This
can be achieved by trapping the η2-benzocyclobutadiene
complex by immediate cycloaddition of the alkynes and
nitriles and by adding CuCl to the reaction mixture.
Scheme 1
A smooth reaction occurs when benzocyclobutenyl com-
plex 2 is heated with diphenylacetylene and the coupled
product 4 is formed directly. Addition of THF and 2 equiv
of CuCl to the reaction mixture gives 2,3-diphenylnaphtha-
lene 6 in 78% isolated yield (Scheme 3 and Table 1).
We now report that when these zirconacycles are treated
with 2 equiv of CuCl, naphthalenes6 6-8 and isoquinolines7
9 and 10 are obtained and, if dimethylacetylenedicarboxylate
(DMAD) is added to the reaction of 5 (R ) t-Bu),
benzazocine8,9 11 is formed in 57% isolated yield based on
5 (Scheme 2). Isolated yields of the naphthalene and
Scheme 3
Scheme 2
A similar procedure with the alkynes, RCCH (R ) SiMe3
and Ph), and Me3Si-CC-Me gives the corresponding
(6) Recent naphthalene syntheses: (a) Yasukawa, T.; Satoh, T.; Miura,
M.; Nomura, M. J. Am. Chem. Soc. 2002, 124, 12680-12681. (b) Edwards,
A. J.; Willis, A. C.; Wenger, E. Organometallics 2002, 21, 1654-1661.
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Chem. Soc. 2002, 124, 12650-12651. (d) Duan, Z.; Nakajima, K.;
Takahashi, T. Chem. Commun. 2001, 1672-1673. (e) Yoshikawa, E.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2000, 39, 173-175. (f) Iwasawa,
N.; Shido, M.; Maeyama, K.; Kusama, H. J. Am. Chem. Soc. 2000, 122,
10226-10227. (g) Pena, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Am. Chem.
Soc. 1999, 121, 5827-5828.
(7) Recent isoquinoline syntheses: (a) Huang, Q.; Larock, R. C.
Tetrahedron Lett. 2002, 43, 3557-3560. (b) Huang, Q.; Hunter, J. A.;
Larock, R. C. J. Org. Chem. 2002, 67, 3437-3444. (c) Abdou, W. M.;
Fahmy, A. F. M.; Kamel, A. A.-A. Eur. J. Org. Chem. 2002, 1696-1701.
(d) Tsutsui, H.; Narasaka, K. Chem. Lett. 2001, 526-527. (e) Prauda, I.;
Reiter, J. J. Heterocycl. Chem. 2001, 38, 199-204. (f) Prauda, I.; Kovesdi,
I.; Trinka, P.; Reiter, J. J. Heterocycl. Chem. 2001, 38, 403-414. (g)
Hussain, H.; Kianmehr, E.; Durst, T. Tetrahedron Lett. 2001, 42, 2245-
2248. (h) Huang, Q.; Hunter, J. A.; Larock, R. C. Org. Lett. 2001, 3, 2973-
2976. (i) Campos, P. J.; Caro, M.; Rodriguez, M. A. Tetrahedron Lett. 2001,
42, 3575-3577. (j) Ameur Meziane, M. A.; Royer, S.; Bazureau, J. P.
Tetrahedron Lett. 2001, 42, 1017-1020. (k) Ishii, H.; Imai, Y.; Hirano,
T.; Maki, S.; Niwa, H.; Ohashi, M. Tetrahedron Lett. 2000, 41, 6467-
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56, 2941-2951. (m) Brun, E. M.; Gil, S.; Mestres, R.; Parra, M. Synthesis
2000, 273-280.
isoquinolines, based on 4 or 5, are given in Table 1. Detailed
procedures for these reactions and following reactions and
compound characterization data can be found in Supporting
Information.
Table 1. Isolated Yields for Naphthalenes and Isoquinolines
compound
method of Scheme 2 94% 90% 89% 85% 89%
method of Scheme 3 78% 72% 75% 61% 70% 85%
6
7
8
9
10
12
13
(8) Azocine review: Evans, P. A.; Holmes, A. B. Tetrahedron 1991,
47, 9131-9166.
(9) Recent azocine syntheses: (a) Hamamoto, H.; Anilkumar, G.; Tohma,
H.; Kita, Y. Chem. Commun. 2002, 450-451. (b) Gil, L.; de Freitas Gil,
R. P.; dos Santos, D. C.; Marazano, C. Tetrahedron Lett. 2000, 41, 6067-
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441-446. (d) Nicolaou, K. C.; Namoto, K. Chem. Commun. 1998, 1757-
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Ponticelli, F. Tetrahedron Lett. 1996, 37, 5783-5786.
While the reactions in Scheme 2 give high yields of the
naphthalenes, isoquinolines, and benzazocine, the procedure
from commercially available 1-bromobenzocyclobutene in-
volves multiple workups and the critical η2-benzocyclo-
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878
Org. Lett., Vol. 5, No. 6, 2003

naphthalenes 7, 8, and 12, respectively (Scheme 3). Interest-
ingly, the bulky acetylene, Me3Si-CC-SiMe3, which does
not react with 3, does react with 2 and yields directly the
naphthalene, 2,3-bistrimethylsilylnaphthalene 13 without
addition of CuCl. The mechanism involved in this transfor-
mation remains to be clarified.
The shortened procedure gives the naphthalenes in 70-
85% isolated yield based on 2 (Table 1). Reaction of 2 with
t-BuCN and Ph-CN were carried out in a similar fashion
(Scheme 3). t-BuCN gives isoquinoline 10 in 61% yield, but
PhCN gives only traces of 3-phenylisoquinoline 9.
Attempts to further shorten the procedure by eliminating
the isolation of 2 have not yet been successful. Complex 2
only forms cleanly in THF, yet the thermolysis of 2 proceeds
cleanly only in toluene.
the naphthalene or isoquinoline. Alternatively, this sequence
could be reversed with Cu elimination from 14 giving Dewar
structure 16, which then opens. Since species such as 16 are
known to be reasonably stable at ambient temperatures,10
15 is favored. Azocine formation can then occur by coupling
of the second alkyne with 14 or 15. It should be noted that
naphthalenes and isoquinolines have previously been pre-
pared from benzocyclobutenes and alkynes or nitriles but
by a different nonmetal-mediated pathway involving ben-
zocyclobutene ring opening followed by cycloaddition of the
alkyne or nitrile to the reactive ring-opened product.11
In conclusion, we have demonstrated that Cp2ZrMe(1-
benzocyclobutenyl), 2, is a reactive and useful reagent in
benzocyclobutene chemistry. This usefulness is based on
metal-mediated processes, including insertion, coupling,
transmetalation, and reductive elimination, and has resulted
in new methods for the formation of substituted naphthalenes,
isoquinolines, and benzazocines. It is anticipated that 2 and
its derivatives will be useful in the synthesis of a number of
interesting new natural and unnatural products. Further results
will be reported in due course.
A proposed pathway for the CuCl reactions is shown in
Scheme 4 and is initiated by transmetalation from Zr to Cu
Scheme 4
Acknowledgment. We thank the National Science Foun-
dation for supporting this work (CHE-0101348) and for
providing a portion of the funds for the purchase of the NMR
(CHE 9221835) equipment. We also thank Professor Mike
Harmata for helpful discussions.
Supporting Information Available: Detailed descrip-
tions of experimental procedures and compound character-
ization data and references. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL034040U
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B. A. J. Org. Chem. 1996, 61, 2885-2887. (c) Craig, D.; Robson, M. J.;
Shaw, S. J. Synlett 1998, 1381-1383.
to give intermediate 14. Opening of the four-membered ring
may then occur to give 15 from which Cu elimination gives
Org. Lett., Vol. 5, No. 6, 2003
879