Cobalt-catalyzed alkyne-nitrile cyclotrimerization to form pyridines in aqueous solution.

Article abstract of DOI:10.1021/ol006327m

A new, water-soluble cobalt(I) catalyst has been used in the aqueous, chemospecific, cyclotrimerization of one nitrile with two alkynes for the synthesis of highly functionalized pyridines. Several different functional groups are well incorporated in this

Full text of DOI:10.1021/ol006327m

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3131-3133
Cobalt-Catalyzed Alkyne−Nitrile
Cyclotrimerization To Form Pyridines in
Aqueous Solution
Anson W. Fatland† and Bruce E. Eaton*
Department of Chemistry, Washington State UniVersity, P.O. Box 644630,
Pullman, Washington 99164-6430
anson.fatland@colorado.edu
Received July 12, 2000
ABSTRACT
A new, water-soluble cobalt(I) catalyst has been used in the aqueous, chemospecific, cyclotrimerization of one nitrile with two alkynes for the
synthesis of highly functionalized pyridines. Several different functional groups are well incorporated in this transformation, including unprotected
alcohols, ketones, and amines. Double isotopic crossover data, as well as nitrile dependence on the rate of product formation, suggest
associative rate-determining coordination of the nitrile.
An increasing number of useful chemical transformations
are being conducted in aqueous solution.1 Environmental
concerns around volatile organic solvents have created an
impetus to develop these new chemistries.2 Moreover, water
has also been shown to induce rate enhancements,3 chemo-
selectivity,4 and stereoselectivity5 in various synthetic trans-
formations. Numerous transition-metal-catalyzed transfor-
mations employing oxidatively stable metal species are
conducted in water.6 We recently reported on the first
examples of benzene formation by cyclotrimerization of
alkynes in aqueous solution employing a new cobalt catalyst.7
Typically, cyclopentadienylcobalt(dicarbonyl) (1) catalyzed
cyclotrimerizations are photochemical and conducted in
refluxing aprotic solvents. The organic substrates commonly
used in these cyclizations have protected functional groups
presumably because of the sensitivity of low oxidation state
cobalt complexes.8 Transition-metal-catalyzed cyclotrimer-
ization is a powerful synthetic methodology that Vollhardt9
has elegantly exploited in the synthesis of numerous complex
carbo- and heterocyclic aromatic molecules. Herein we report
the first example of cobalt-mediated pyridine formation in
aqueous solution with a new cobalt catalyst, 2 (eq 1), under
* To whom correspondence should be addressed at: NCSU, Department
of Chemistry, Colleges of Physical and Mathematical Sciences, Campus
Box 8204, Raleigh, NC 27695-8204.
† Current address: University of Colorado, Department of Chemistry
and Biochemistry, Campus Box 215, Boulder, CO 80309-0215.
(1) (a) Chan, T. H.; Ma, J. Tetrahedron Lett. 1998, 39, 2499. (b) Paquette,
L. A.; Rothhaar, R. R.; Isaac, M.; Rogers, L. M.; Rogers, R. D. J. Org.
Chem. 1998, 63, 5463. (c) Li, C. J.; Meng, Y.; Yi, X. H. J. Org. Chem.
1998, 63, 7498. (d) Chan, T. H.; Yang, Y. J. Am. Chem. Soc. 1999, 121,
3228. (e) Chan, T. H.; Yang, Y. Tetrahedron Lett. 1999, 40, 3863. (f) Chan,
T. H.; Yang, Y.; Li, C. J. J. Org. Chem. 1999, 64, 4452.
(6) Li, C. J.; Chan, T. H. Organic Reactions in Aqueous Media; John
Wiley and Sons: New York, 1997.
(7) Sigman, M. S.; Fatland, A. W.; Eaton, B. E. J. Am. Chem. Soc. 1998,
120, 5130.
(2) (a) Presidential Green Chemistry Challenge Awards Program: EPA744-
K-96-001, July, 1996. (b) Paquette, L. A. In Green Chemistry: Frontiers
in Benign Chemical Synthesis and Processing; Anastas, P., Williamson,
T., Eds.; Oxford University Press: New York, 1998.
(3) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7817.
(4) Grotjahn, D. B.; Zhang, X. J. Mol. Catal. A 1997, 116, 99.
(5) Breslow, R.; Maitra, U. Tetrahedron Lett. 1992, 25, 1239.
(8) There are a few examples of cyclotrimerizations conducted with
unprotected functional groups. See: Grotjahn, D. B. In ComprehensiVe
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Hegedus, L. S., Eds.; Pergamon: Tarrytown, NY, 1995.
(9) (a) Vollhardt, K. P. C.; Bergman, R. G. J. Am. Chem. Soc. 1974, 96,
4996. (b) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539.
(c) Grotjahn, D. B.; Vollhardt, K. P. C. Synthesis 1993, 579.
10.1021/ol006327m CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/14/2000

purely thermal conditions without photochemical activation
or the need to supply the nitrile reagent in excess.
Table 1. Pyridine Product Yields from Various Nitriles
Cyclotrimerized with 3 under the General Reaction Conditions15
Cobalt-catalyzed cyclotrimerization of alkynes and nitriles
to form pyridines was first reported by Wakatsuki and
Yamazaki.10 Recently, exciting work by Heller11 on cobalt-
catalyzed cyclotrimerization to form pyridines under pho-
tochemical conditions and with the inclusion of surfactants
in the aqueous reaction medium has sparked renewed interest
in cobalt-catalyzed formation of pyridines. To date, many
transition-metal-catalyzed cyclotrimerizations used in the
synthesis of pyridines yield a substantial amount of the
corresponding benzene as a side product.12 This significantly
diminishes the utility of this methodology for the synthesis
of heterocycles and can lead to the use of excess reagents,
which is a serious limitation when expensive nitriles are
required.13 Creative methods have been employed to suppress
the competing side reaction to form benzenes in these
cyclotrimerizations with varying success.14
We previously reported that a wide range of functional
groups were tolerated by 2 in alkyne cyclotrimerizations to
form benzenes.7 To investigate the tolerance of nitrile
functional groups in cyclotrimerization with alkynes cata-
lyzed by 2 to form pyridines, 2-butyne-1,4-diol (3) was
treated with acetonitrile (4, 20 equiv) and 2 (2.5 mol % based
on alkyne).15 After less than 2 h at 85 °C, there was an
appreciable amount of precipitate in the reaction vessel. After
a total reaction time of 20 h, workup of the reaction mixture
revealed the precipitate to be the desired pyridine 16. In a
series of experiments, the concentration of 4 was systemati-
cally reduced from 20 equiv to 0.5 equiv relative to 3 and
still afforded the desired pyridine 16. To determine if the
nitrile substituent would have an impact on the stoichiometry
required for successful cyclotrimerization with 3 to form
pyridines, the nitriles shown in Table 1 were tested under
the standard reaction conditions using a 2:1 alkyne:nitrile
ratio.15
a Isolated yields of cyclotrimerization products of listed nitriles and 3.
b An asterisk indicates the position of the nitrile carbon. 5 is a 50/50 mixture
of cis and trans isomers.
were the nitriles 8 and 9, which gave poor yields of the
expected pyridine.16 This negative effect on cyclotrimeriza-
tion may have its origin in the juxtaposition of the nitrile
and ether (or sulfide) functionalities in 8 (or 9), but future
investigation is required to better understand this result.
Substrate 10 gave a good yield of 22, showing that an ether
functionality can be included as a nitrile substituent in this
cyclotrimerization method.
For all the examples reported in Table 1, no benzene side
products from competing alkyne cyclotrimerization were
isolated or observed by NMR. To detect even trace amounts
of benzene side products, reactions were analyzed using LC-
MS. As representative examples, nitriles 4 and 11, which
are both sterically and electronically different, were chosen
to react with 3 for this LC-MS study (Figure 1). These
reactions were monitored by 1H NMR and LC-MS for greater
than 3 half-lives.15 All samples contained less than 1% of
the hexa(hydroxymethyl)benzene side product.
Table 1 illustrates that most functional groups tested were
incorporated with good to excellent yield. The exceptions
(10) Wakatsuki, Y. Tetrahedron Lett. 1973, 36, 3383.
(11) (a) Heller, B.; Oehme, G. J. Chem. Soc., Chem. Commun. 1995,
179. (b) Karabet, F.; Heller, B.; Kortus, K.; Oehme, G. AdV. Organomet.
Chem. 1995, 9, 651. (b) Heller, B.; Heller, D.; Oehme, G. J. Mol. Catal. A
1996, 110, 211.
(12) Schore, N. E. ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Paquette, L. A., Eds.; Pergamon: Elmsford, NY, 1991, and
references therein.
Cyclotrimerizations catalyzed by 1 to form pyridines in
organic solvents have not shown any nitrile concentration
dependence on the rate of product formation.17 To better
understand catalyst 2, kinetic studies were performed in
(13) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281.
(14) (a) Wakatsuki, Y.; Yamazaki, H. Synthesis 1975, 26. (b) Naiman,
A.; Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1977, 16, 708. (c)
Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539.
(15) See Supporting Information.
(16) Bo¨nnemann, H.; Brijoux, W. Aspects of Homogeneous Catalysis;
Ugo, R., Ed.; Reidel: Dordrecht, 1984.
(17) (a) Bo¨nnemann, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 505.
(b) Reference 12.
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Org. Lett., Vol. 2, No. 20, 2000

at 2:1 alkyne:nitrile stoichiometry. Pyridines are well know
to serve as good ligands in transition metal complexes.18 It
was of interest to determine what effect a pyridine product
could have on an alkyne cyclotrimerization catalyzed by 2.
We began by conducting a cyclotrimerization using 3 and
monitoring the conversion to hexa(hydroxymethyl)benzene
1
by H NMR. After 1 half-life, pyridine 16 (50 mol %) was
added and the rate of hexa(hydroxymethyl)benzene formation
dropped by more than an order of magnitude. After following
the cyclotrimerization of 3 for 5 h, a stoichiometric amount
of 4 was added and the rate of pyridine 16 formation was
followed by 1H NMR. The rate of cyclotrimerization of 3 to
give hexa(hydroxymethyl)benzene was found to be ap-
proximately 100 times slower under these conditions than
the reaction of 3 and 4 to give 16. Taken together, these
results imply the formation of a cobalt-pyridine complex
that is too tightly coordinated to be displaced by an alkyne
yet weak enough to be substituted by a nitrile in an
associative process.
In summary, we have extended the applicability of aqueous
cyclotrimerizations to include the formation of highly func-
tionalized pyridines under mild conditions without the need
for photochemical activation. The reaction requires only a
stoichiometric amount of nitrile and a low catalyst loading,
making the use of expensive nitriles more feasible. The
reaction conditions are amenable to a wide range of
unprotected functional groups with good to excellent yields
in most examples. Double isotopic crossover data show there
is no dissociation of ligands during the catalytic cycle. The
results of the nitrile dependence on the rate of pyridine
formation, as well as the product inhibition studies, suggest
associative rate-determining coordination of the nitrile. It
appears that 2 has some interesting and unforeseen attributes
as a cyclotrimerization catalyst. Given the ease in the
preparation of 2, and the mild thermal conditions under which
nitrile-alkyne cyclotrimerization occurs, it is anticipated that
this catalyst will find significant utility in the synthesis of
highly functionalized pyridines.
Figure 1. LC trace of the cyclotrimerization between 3 and 11.
triplicate under pseudo-first-order conditions by increasing
the concentration of 4 while keeping the concentration of 2
and 28 constant. Increasing the concentration of 4 resulted
in a corresponding increase in the rate of pyridine formation
(Figure 2). A plot of the pseudo-first-order rate constant (kobs)
Acknowledgment. We are grateful for financial support
from NeXstar Pharmaceuticals. A. Fatland would also like
to thank NeXstar Pharmaceuticals for a predoctoral fellow-
ship. We would also like to thank T. Tarasow and M. Sigman
for stimulating discussions. Some NMR data were obtained
from the WSU NMR Center supported in part by NIH
(RR0631401) and NSF (CHE-09115282).
Figure 2. Dependence of concentration of acetonitrile on the rate
of pyridine formation: (O) 250 mM acetonitrile, (0) 500 mM, ())
1 M, (4) 2.5 M.
Supporting Information Available: Experimental details
and chemical characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
vs the concentration of 4 gave good linearity (r ) 0.9989)
and a second-order rate constant of 4.1 × 10-5 M-1 s-1 (see
inset graph in Figure 2). The observed nitrile dependence is
unprecedented in alkyne-nitrile cyclotrimerization.
The results presented thus far do not explain the unprec-
edented chemoselectivity of 2 to form exclusively pyridines,
OL006327M
(18) Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G. Principles
and Applications of Organotransition Metal Chemistry; University Science
Books: California, 1987.
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