A nickel-catalyzed route to pyridines

Article abstract of DOI:10.1021/ja0508931

A mild and general route for preparing pyridines from nitriles and diynes is described. Ni/imidazolyidene complexes were used to mediate cyclization alkynes and both aryl and alkyl nitriles at ambient temperature. In addition, the efficacy of this protoco

Full text of DOI:10.1021/ja0508931

Published on Web 03/19/2005
A Nickel-Catalyzed Route to Pyridines
Michael M. McCormick, Hung A. Duong, Gang Zuo, and Janis Louie*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850
Received February 11, 2005; E-mail: louie@chem.utah.edu
The ubiquity of pyridine rings in natural and synthetic pharma-
ceutical compounds has been a driving force for developing
generalized methods for their synthesis. A particularly straightfor-
ward protocol is the transition metal mediated cycloaddition of
alkynes and nitriles. Although a variety of stoichiometric methods
have been described,1,2 catalytic systems have been restricted to
Fe, Rh, Co, and Ru complexes.3 Unfortunately, both the Fe and
Rh systems use elevated temperatures and afford more arene
byproducts than the desired pyridine.4 The versatility of Co catalysts
makes an attractive approach to pyridines; however, elevated
temperatures, photolytic conditions, and relatively high catalyst
loadings are typically required.5,6 In general, milder conditions are
employed with Ru catalysts.7 Nevertheless, substrates are currently
limited to activated nitriles (e.g., dicyanides).
Ni complexes catalyze a variety of cycloaddition reactions,8 yet
a Ni-catalyzed route to pyridines remains elusive, which may be
due to an inability to generate a nickelapyrrole intermediate through
the oxidative coupling of alkynes and nitriles.9 Interestingly, the
requisite nickelacycle can be prepared via transmetalation between
an azazirconapyrrole and Ni(PPh3)2Cl2 (Scheme 1).2 Subsequent
addition of alkynes does ultimately afford asymmetrically substi-
tuted pyridines, albeit through the use of stoichiometric amounts
of both Ni and Zr.
(eq 1). Ultimately, a protocol similar to the one found effective for
our previous cycloadditions afforded pyridine 3.10-12 Excellent
yields (as determined using gas chromatography) were obtained
using 3% of Ni(COD)2, 6% of SIPr,16 and diyne and nitrile
concentrations of 0.1 M in toluene at ambient temperature (eq 1).
With the optimized cycloaddition conditions at hand, we
examined pyridine formation with a range of diyne and nitrile
substrates (Table 1). In general, both aryl- and alkylnitriles were
readily converted to the respective pyridine, although alkylnitriles
gave slightly diminished yields. Both arylnitriles bearing either an
electron-withdrawing group (p-CF3, 2c) or an electron-donating
group (p-OMe, 2b) readily cyclized (entries 2 and 3, respectively).17
Notably, sterically hindered nitriles [such as o-tolunitrile (2d), tert-
butyl nitrile (2g), and naphthalene-1-carbonitrile (2h)] delivered
the desired pyridines (entries 4, 7, and 8, respectively). Pyridine
yield was unaffected when degassed, but not dried, acetonitrile was
employed (entry 5). Diynes devoid of internal substitution, such
as 3,9-dodecadiyne (12) and diynes containing either an internal
amino group (15) or the analogous ether (17), also coupled with
nitriles to give pyridines (entries 10-14). Importantly, heteroarylni-
triles are readily converted to pyridines in high yields (entry 9).18
In addition, the reaction of 2,9-undecadiyne (20) afforded fused
seven-membered ring pyridine 21 after cycloaddition (entry 15).
We also investigated pyridine synthesis from the cycloaddition
of an untethered alkyne. Subjecting 3-hexyne (2 equiv) and
benzonitrile (2a) to the optimized conditions described above (3%
of catalyst, rt) afforded pyridine 22 in 82% yield (eq 2).19
Scheme 1. Stoichiometric Protocol for Pyridine Synthesis via
Nickelapyrrole Intermediate
We have recently developed a general Ni/NHC (NHC )
N-heterocyclic carbene) based catalyst system for the cycloaddition
of diynes and carbonyl substrates (CO2,10 isocyanates,11 and
aldehydes12). We surmised that this combination may be nucleo-
philic enough to promote oxidative coupling of an alkyne and nitrile
such that products possessing a pyridine ring could be obtained
catalytically. At the onset of this research, it was not clear whether
cycloaddition or carbocyanation13 of the alkyne would occur.
Furthermore, it was possible that the active Ni/NHC catalyst would
be incompatible with good donor ligands, such as nitriles14 and
pyridines.15 We now report that the combination of Ni/SIPr
effectively catalyzes the cycloaddition of diynes and nitriles at
ambient temperature to afford pyridines in excellent yields.
A variety of conditions were evaluated using diyne 1 and
benzonitrile (2a) as model substrates for the cycloaddition reaction
Previously, when asymmetrically substituted diynes were used
in our Ni/NHC-catalyzed cycloaddition reaction, complete regio-
selectivity was observed when the size difference between terminal
substituents was large.10b In accordance with these observations,
the coupling of diyne 23 and benzonitrile (2a) afforded pyridine
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10.1021/ja0508931 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Ni-Catalyzed Cycloaddition of Diynes and Nitrilesa
Both intramolecular and intermolecular reactions were catalyzed
by a combination of a Ni(0) precursor and an imidazolylidene
ligand. Furthermore, cycloaddition of an asymmetrical diyne
afforded a single pyridine regioisomer.
Acknowledgment. We gratefully acknowledge the University
of Utah, ACS (PRF Type G), and the NSF (Career Award) for
support of this research.
Supporting Information Available: Detailed experimental pro-
cedures and compound characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
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(15) Both SIPr and IPr ligands readily dissociate from Ni(0), even upon the
addition of COD (see ref 10a).
(16) Unsaturated analogue IPr gave slightly lower conversion under identical
reaction conditions (99% versus 66% for SIPr and IPr, respectively)
(IPr ) 1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene; SIPr ) 1,3-bis-
(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene).
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electron-deficient isocyanates required elevated temperatures for complete
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(19) Cycloaddition with acetonitrile (2e) afforded 2,3,4,5-tetraethyl-6-meth-
ylpyridine (25) in 25% yield. See Supporting Information.
a Reaction conditions: 0.1 M diyne, 0.1 M nitrile, 3% of Ni(COD)2,
6% of SlPr, rt. b Isolated yields (average of two runs). c Isolated yield of
reaction with MeCN that was degassed, but not dried.
24 as a single regioisomer in 58% yield (eq 3). Initial oxidative
coupling of the TMS-terminated alkyne and nitrile followed by
insertion of the methyl-terminated alkyne explains the observed
regioselectivity.
In conclusion, we have developed a mild and efficient method
for preparing a wide range of pyridines from alkynes and nitriles.
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