systems may give different isomers due to a reversal of
HOMO-LUMO interactions, but still be regioselective.24
In the present study, we have found experimental evidence
supporting the concept that electronics can dictate the
regiochemical outcome of nickel-catalyzed alkyne insertions.
Comparison of annulations of 1-phenyl-1-propyne with 1 and
4a strongly suggests that steric control is at least partially
overcome in the reaction presented here. Since the isomeric
ratios of entries 3 and 11 (Table 2) are nearly identical while
the steric profile of the two parent systems vary dramatically,
we believe that electronics dominate the selectivity. Specif-
ically, the electron-rich parent ring is nucleophilic enough
that steric preferences are overcome, and thus reorientation
of the alkyne during the insertion event is not a significant
factor in determining regioselectivity. While this may be
deleterious for highly efficient annulations with electron-
rich parent rings, these findings can help provide an
understanding of the regioselective capacity of nickel
catalysis.
Scheme 2. Rationale for Observed Regioselectivity in the
Annulation of 1 with Phenylacetylene
Alternatively, competing mechanisms may exist that give
rise to the observed regiochemical outcome, though at this
time these mechanisms are not well understood. This
possibility is suggested by the highly regioselective insertion
of ynoates such as 11 and 12. Cheng previously argued that
a Michael-type attack on the activated alkyne by the proximal
imine could explain the observed regiochemistry,12 and this
pathway may be preferred in the pyrazolic context as well.
However, this mechanism is unlikely to occur with alkynes
other than ynoates.
In summary, we have developed a nickel (or palladium)-
catalyzed annulation of alkynes onto iodopyrazolecarbox-
imines that allows for rapid access to polyfunctionalized
pyrazolo[3,4-c]pyridines s a heterocycle that shows promise
in medicinal chemistry. We also found that the regiochem-
istry of the reaction is influenced by the electronic nature of
the carbon ligand arising from the iodide. Continued
investigation into the mechanism of the nickel-catalyzed
annulation, application to the pyrazolo[3,4-d]pyridine system,
and further efficiency enhancement of the annulation will
be presented in due course.
catalyzed pyrazolopyridine synthesis. Disappointingly, the
yield of 14 was rather low, and we observed several side
products, though no Sonogashira coupling product was
isolated.18
LCMS analysis of the crude reaction mixture revealed a
major peak corresponding to the tert-butyl pyrazolo[3,4-
c]pyridinium salt. NMR of the crude mass confirmed this
assignment.19 Scheme 2 shows the two possible isomers
formed from an annulation reaction. Both can form the tert-
butyl pyrazolo[3,4-c]pyridinium salt, but the strain induced
from the presence of a proximal phenyl group in 21 allows
it to collapse to the pyrazolo[3,4-c]pyridine 14, whereas 20
lacks this driving force and thus persists as a salt. A similar
result and mechanistic explanation has been reported in the
palladium catalyzed annulation-based preparation of carbo-
lines.20
Though previous reports on the nickel-catalyzed annulation
of terminal acetylenes with haloimines claim that the initial
insertion step is regioselective,12 the isolation of equal
amounts of regioisomer from annulation reactions with
1-phenyl-1-propyne (Table 2, entries 3 and 11) along with
the identification of 20, a major side product in the annulation
of phenylacetylene, implies that, in the context of hetero-
cycles explored in this paper, regioselectivity of insertion
breaks down.
To the best of our knowledge, the loss of regiochemical
control during nickel-catalyzed alkyne insertion with aryl-
alkyl alkynes has not been previously reported.21 The
regioselectivity of insertion into unsymmetrical alkynes is
thought to be, with the exception of ynoates,22 largely
sterically controlled.23 Later studies using DFT calculations
supported this finding, also speculating that electron-rich
Acknowledgment. We thank Mark Holmes for NMR
support.
Supporting Information Available: 1H and 13C NMR
data and purification procedures for 1-19, experimental
details for catalysis reactions as well as the preparation of
1, 4a, 4b, and 6. This material is available free of charge
OL701784W
(20) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 9318.
(21) For recent examples of highly regioselective nickel-catalyzed C-C
bond forming transformations, see: (a) Intermolecular coupling of enones
and alkynes: Herath, A.; Thompson, B. A.; Montgomery, J. J. Am. Chem.
Soc. 2007, 129, 8712. (b) Allylcyanation of alkynes: Nakao, Y.; Yukawa,
T.; Hirata, Y.; Oda, S.; Satoh, J.; Hiyama, T. J. Am. Chem. Soc. 2006, 128,
7116. (c) [3 + 2 + 2] Cocyclization of alkynes and cyclopropylidene
acetate: Komagawa, S.; Saito, S. 2006, Angew. Chem., Int. Ed. 2006, 45,
2446.
(18) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86.
(19) Assigned as 20 by comparison with the isolated tert-butylpyridinium
bromide that was isolated by Larock; Zhang, H.; Larock, R. C. J. Org.
Chem. 2003, 68, 5132.
(22) Bennett, M. A.; Wenger, E. Organometallics 1995, 14, 1267.
(23) Huggins, J. M.; Bergman, R. G. J. Am. Chem. Soc. 1981, 103, 3002.
(24) Bennett, M. A.; Macgregor, S. A.; Wenger, E. HelV. Chim. Acta
2001, 84, 3084.
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Org. Lett., Vol. 9, No. 24, 2007