J. Am. Chem. Soc. 2001, 123, 3157-3158
3157
Scheme 1
Synthesis of Pyridine-Containing Macrocycles by
Cobalt-Mediated Trimerization of Triply-Bonded
Species
Alessandro F. Moretto, Han-Cheng Zhang, and
Bruce E. Maryanoff*
The R.W. Johnson Pharmaceutical Research Institute
Spring House, PennsylVania 19477
ReceiVed NoVember 22, 2000
Transition metal reagents have garnered an important role in
the synthesis of cyclic organic compounds.1 Recently, ring-closing
metathesis (RCM)2 has emerged as a powerful method for
generating diverse ring systems, including macrocycles,3 and
intramolecular cyclopropanation has also been remarkably suc-
cessful.4 These reactions are noteworthy among transition metal-
mediated cyclizations because of the efficient formation of
medium- and large-size rings, which probably derives from the
ability of the metal to coordinate both ends of the acyclic substrate
to pre-organize the system and reduce entropic costs. Beyond these
reaction classes, there is a paucity of useful transition metal-
mediated macrocyclization techniques.5
Scheme 2
We became interested in the potential of cobalt-catalyzed
alkyne cyclotrimerization1i as a macrocyclization method. The
proposed process is exemplified by the conversion of bis-alkyne
1 to arene-fused macrocycle 2, along with possible meta- and
paracyclophane isomers (Scheme 1). In this transformation, the
transition metal could well provide a templating effect by
coordination of the alkyne termini of 1 followed by intermolecular
cycloaddition of another alkyne. Of course, the key issue is
identifying reaction conditions that would favor the desired
reaction pathway.
Although there are some reported examples of intramolecular
cobalt-mediated alkyne trimerization, the formation of macro-
cycles has been limited to the synthesis of polycyclic cage
compounds, wherein all three alkyne groups are tethered to the
same backbone.6 A previous attempt to execute the more
challenging intermolecular reaction was unsuccessful in that the
cobalt-mediated addition of a long-chain bis-alkyne to a monoalkyne
yielded a stable bis-η4-cyclobutadienecobalt complex.7 We have
investigated this area of chemistry and now describe the successful
macrocyclization of long-chain bis-alkynes with nitriles to obtain
fused pyridine macrocycles, particularly pyridine-cyclophanes.
Also, we report the regiospecific macrocyclization of an alkyne-
nitrile with an alkyne.
Initially, we conducted studies on macrocyclization of a bis-
alkyne and a monoalkyne to produce arene-cyclophanes. However,
reaction of bis-alkyne 1 with excess bis(trimethylsilyl)acetylene
in the presence of CpCo(CO)2 (15 mol %) at 140 °C, with
irradiation by visible light, did not yield any desired macrocycle.
Rather, a bis-cyclobutadiene-cobalt complex, 3, was formed in
8% yield (∼100% yield relative to catalyst loading). On reducing
the relative concentration of the monoalkyne to 1 equiv (with
o-xylene as solvent), we obtained only intractable presumably
polymeric material. The negative results for this reaction can be
appreciated by analysis of the mechanism of cobalt-catalyzed
alkyne cyclotrimerization (Scheme 2).8
(1) (a) Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263-3283.
(b) Ali, B. E.; Alper, H. Synlett 2000, 161-171. (c) Padwa, A.; Straub, C. S.
AdV. Cycloaddition 1999, 6, 55-95. (d) Montgomery, J. Acc. Chem. Res.
2000, 33, 467-473. (e) Malacria, M. Chem. ReV. 1996, 96, 289-306. (f)
Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96,
635-662. (g) Dyker, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 2223-2224.
(h) Schore, N. E. Chem. ReV. 1988, 88, 1081-1119. (i) Vollhardt, K. P. C.
Angew. Chem., Int. Ed. Engl. 1984, 23, 539-556. (j) Yet, L. Chem. ReV.
2000, 100, 2963-3007.
(2) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 4413-4450. Grubbs, R.
H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446-452. Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3013-3043.
(3) Ojima, I.; Lin, S.; Inoue, T.; Miller, M. L.; Borella, C. P.; Geng, X.;
Walsh, J. J. J. Am. Chem. Soc. 2000, 122, 5343-5353 and references therein.
(4) Doyle, M. P.; Hu, W.; Chapman, B.; Marnett, A. B.; Peterson, C. S.;
Vitale, J. P.; Stanley, S. A. J. Am. Chem. Soc. 2000, 122, 5718-5728. Doyle,
M. P.; Peterson, C. S.; Protopopova, M. N.; Marnett, A. B.; Parker, D. L., Jr.;
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(5) For examples of other reaction types, see: (a) Saito, S.; Tsuboya, N.;
Yamamoto, Y. J. Org. Chem. 1997, 62, 5042-5047. Saito, S.; Salter, M. M.;
Gevorgyan, V.; Tsuboya, N.; Tando, K.; Yamamoto, Y. J. Am. Chem. Soc.
1996, 118, 3970-3971. (b) Wang, H.; Wulff, W. D. J. Am. Chem. Soc. 1998,
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1999, 578, 223-228.
(6) Granier, T.; Cardenas, D. J.; Echavarren, A. M. Tetrahedron Lett. 2000,
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The first step is formation of two possible cobaltacyclopenta-
diene intermediates, pathways A and B. If A is taken, then
intermediate 4 would be formed, and it could coordinate with
the alkyne monomer to give the desired ring closure or with the
bis-alkyne to give oligomers. It has been shown that this
intermediate will not form stable cyclobutadiene-cobalt com-
plexes.7 If path B is taken, then intermediate 5 would be formed,
and it could proceed to a stable bis-η4-cyclobutadiene-cobalt
complex (by formal [2 + 2] cycloaddition) or the desired ring-
closed product. From our isolation of 3, it appears that pathway
B predominates in this case and that the rate of ring closure to
the desired product (kclosure) is much slower than the rate of
cyclobutadiene complex formation (k[2+2]).
(7) Brisbois, R. G.; Fogel, L. E.; Nicaise, O. J.-C.; DeWeerd, P. J. J. Org.
Chem. 1997, 62, 6708-6709.
(8) Hardesty, J. H.; Koerner, J. B.; Albright, T. A.; Lee, G.-Y. J. Am. Chem.
Soc. 1999, 121, 6055-6067 and references therein.
10.1021/ja004049g CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/13/2001