Selective formation of substituted pyridines from two different alkynes and a nitrile: Novel coupling reaction of azazirconacyclopentadienes with alkynes [8]

Full text of DOI:10.1021/ja000474y

4994
J. Am. Chem. Soc. 2000, 122, 4994-4995
Selective Formation of Substituted Pyridines from
Two Different Alkynes and a Nitrile: Novel Coupling
Reaction of Azazirconacyclopentadienes with Alkynes
Tamotsu Takahashi,* Fu-Yu Tsai, and Martin Kotora
Catalysis Research Center and Graduate School of
Pharmaceutical Sciences, Hokkaido UniVersity
CREST, Science and Technology Corporation (JST)
Sapporo 060-0811, Japan
mixture of two regioisomers due to the orientation of the nitrile
molecule. Consequently, therefore, there has been no general
preparative method which could control the selectivity of the
intermolecular coupling of two different alkynes and one nitrile,
although the orientation of the nitrile was controlled when alkynes
bearing a COOR group were used as Wakatsuki et al. reported.2d
We would like to report a novel coupling reaction of azazir-
conacyclopentadienes, which were in situ prepared from an alkyne
and a nitrile, with a different alkyne to afford only single isomers
of pyridines as shown in eq 2.
ReceiVed February 8, 2000
Cocycloaddition of two alkynes and a nitrile using transition
metals is a straightforward and attractive method for the prepara-
tion of pyridines.1-6 Cobalt complexes have been extensively used
for this process, and the mechanistic aspect of the reaction has
been intensively investigated.2,3 It is generally accepted that
metallacyclopentadienes formed by coupling of two alkynes are
intermediates for the formation of pyridines in catalytic and
stoichiometric reactions and even in the case of cocycloaddition
of R,ω-cyanoalkynes with alkynes.1 However, there is a critical
problem as regards the selectivity in the pyridine formation by
the intermolecular coupling of two different alkynes and one
nitrile as shown in eq 1. Reaction of metallacyclopentadienes
prepared from two different alkynes with a nitrile affords a
(1) For review see: (a) Schore, N. E. ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds; Pergamon Press Ltd: Oxford, 1991; Vol. 5;
pp 1129-1162. (b) Schore, N. E. Chem. ReV. 1988, 88, 1081. (c) Bo¨nnemann,
H. Angew. Chem., Int. Ed. Engl. 1978, 17, 505-515. (d) Vollhardt, K. P. C.
Angew. Chem., Int. Ed. Engl. 1984, 23, 539-556. (e) Bo¨nnemann, H. Angew.
Chem., Int. Ed. Engl. 1985, 24, 248-262.
Recently, we have developed highly selective coupling of an
alkyne and a nitrile using Cp2ZrEt2 which gave azazirconacyclo-
pentadienes 1.7 Initially, we investigated the coupling reaction
of the azazirconacyclopentadienes 1 with an alkyne in the presence
of 2 equiv of CuCl,8 since the direct reaction of 1 with alkynes
did not proceed. However, no formation of pyridine was observed
in the presence of CuCl. Very recently, we have developed
transmetalation reaction of zirconacyclopentadienes to Ni using
NiCl2(PPh3)2.9 In the presence of 1 equiv of NiCl2(PPh3)2, the
coupling reaction of triethylazazirconacyclopentadiene 1a (R1 )
R3 ) Et) with 3-hexyne proceeded and pentaethylpyridine 2a was
obtained in 71% yield.
The typical procedure is as follows. To a solution of triethyl-
azazirconacyclopentadiene 1a in situ prepared from 1 mmol of
3-hexyne, 1 mmol of Cp2ZrEt2, and 1 mmol of propionitrile in
10 mL of THF were added 3-hexyne (2.5 mmol) and NiCl2(PPh3)2
(1.0 mmol) at room temperature. The mixture was warmed to 50
°C, stirred for 9 h, quenched with 20% NaHCO3, and extracted
with diethyl ether. GC analysis showed that the pentaethylpyridine
was formed in 71% yield. After workup, column chromatography
on silica gel afforded pentaethylpyridine in 55% isolated yield.
This novel reaction could be used for the coupling of azazir-
conacyclopentadienes with a second different alkyne. It is note-
worthy that the reaction of 1b, which was prepared from 3-hexyne
and acetonitrile, with 4-octyne gave 2b in 86% yield as a single
product. On the other hand, azazirconacyclopentadiene 1c which
was prepared from 4-octyne and acetonitrile reacted with 3-hexyne
to give 2c as a single product. In both cases the pyridines were
(2) For Co: (a) Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc., Chem.
Commun. 1973, 280. (b) Wakatsuki, Y.; Yamazaki, H. Tetrahedron Lett. 1973,
3383-3384. (c) Wakatsuki, Y.; Yamazaki, H. Synthesis 1976, 26-28. (d)
Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc., Dalton 1978, 1278-1282. (e)
Wakatsuki, Y.; Nomura, O.; Kitaura, K.; Morokuma, K.; Yamazaki, H. J.
Am. Chem. Soc. 1983, 105, 1907-1912. (f) Wakatsuki, Y., Yamazaki, H.
Bull. Chem. Soc. Jpn. 1985, 58, 2715-2716. (g) Vollhart, K. P. C.; Bergman,
R. G. J. Am. Chem. Soc. 1974, 96, 4996-4998. (h) Naiman, A.; Vollhardt,
K. P. C. Angew. Chem., Int. Ed. Engl. 1977, 16, 708-709. (i) Brien, D. J.;
Naiman, A.; Vollhardt, K. P. C. J. Chem. Soc., Chem. Commun. 1982, 133.
(j) Bo¨nnemann, H.; Brinkmann, R.; Schenkluhn, H. Synthesis 1974, 575-
577. (k) Bo¨nnemann, H.; Brinkmann, R. Synthesis 1975, 600-602. (l) Bo¨nne-
mann, H.; Brijoux, W.; Brinkmann, R.; Meurers, W.; Mynott, R.; von Philips-
born, W.; Egolf, T. J. Organomet. Chem. 1984, 272, 231-249. (m) Vitulli,
G.; Bertozzi, S.; Lazzaroni, R.; Salvadori, P. J. Organomet. Chem. 1984, 307,
C35-C37. (n) Vitulli, G.; Bertozzi, S.; Vignali, M.; Lazzaroni, R.; Salvadori,
P. J. Organomet. Chem. 1987, 326, C33-C36. (o) Chiusoli, G. P.; Pallini,
L.; Terenghi, G. Transition Met. Chem. 1983, 8, 250. (p) Chiusoli, G. P.;
Pallini, L.; Terenghi, G. Transition Met. Chem. 1984, 9, 360. (q) Varela, J.
A.; Castedo, L.; Saa´, C. J. Am. Chem. Soc. 1998, 120, 12147-12148.
(3) For application of pyridine formation using Co, see: (a) Tatone, D.;
Dich, T. C.; Nacco, R.; Botteghi, C. J. Org. Chem. 1975, 40, 2987. (b)
Salvadori, P.; Rosini, C.; Bertucci, C.; Pini, D.; Marchetti, M. J. Chem. Soc.,
Perkin Trans. 1983, 2, 399-402. (c) Geiger, R. E.; Lalonde, M.; Stoller, H.;
Schleich, K. HelV. Chim. Acta 1984, 67, 1274-1282. (d) Parnell, C. A.;
Vollhardt, K. P. C. Tetrahedron 1985, 41, 5791-5796. (e) Hillard, R. L., III;
Parnell, C. A.; Vollhardt, K. P. C. Tetrahedron 1983, 39, 905-911.
(4) For Rh: (a) Cioni, P.; Diversi, P.; Ingrosso, G.; Lucherini, A.; Ronca,
P. J. Mol. Catal. 1987, 40, 337. (b) Diversi, P.; Ingrosso, G.; Lucherini, A.;
Minutillo, J. Mol. Catal. 1987, 40, 359. (c) Bianchini, C.; Meli, A.; Peruzzini,
M.; Cacca, A.; Vizza, F. Organometallics 1991, 10, 645-651.
(5) For Ti: Hill, J. E.; Balaichi, G.; Fanwick, P. E.; Rothwell, I. P.
Organometallics 1993, 12, 2911-2924.
(6) For Ta: (a) Strickler, J. R.; Bruck, M. A.; Wigley, D. E. J. Am. Chem.
Soc. 1990, 112, 2814-2816. (b) Smith, D. P.; Strickler, J. R.; Gray, S. D.;
Bruck, M. A.; Holmes, R. S.; Wigley, D. E. Organometallics 1992, 11, 1275-
1288. (c) Takai, K.; Yamada, M.; Uchimoto, K. Chem. Lett. 1995, 851-852.
(7) Takahashi, T.; Xi, C.; Xi, Z.; Kageyama, M.; Fischer, R.; Nakajima,
K.; Negishi, E. J. Org. Chem. 1998, 63, 6802-6806 and references therein.
(8) For transmetalation of zirconacyclopentadienes to CuCl for benzene
formation, see: (a) Takahashi, T.; Xi, Z.; Yamazaki, A.; Liu, Y.; Nakajima,
K.; Kotora, M. J. Am. Chem. Soc. 1998, 120, 1672-1680. (b) Takahashi, T.;
Kotora, M.; Xi, Z. J. Chem. Soc., Chem. Commun. 1995, 361-362.
(9) Takahashi, T.; Tsai, F.-Y.; Li, Y.; Nakajima, K.; Kotora, M. J. Am.
Chem. Soc. 1999, 121, 11093-11100.
(10) (a) Buchwald, S. L.; Watson, B. T.; Huffman, J. C. J. Am. Chem.
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10.1021/ja000474y CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/05/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 20, 2000 4995
Table 1. One-Pot Preparation of Substituted Pyridine Derivatives
from Two Different Alkynes and a Nitrile Using Zirconocene and
Nickel Complexes
prepared from the same combination of alkynes and a nitrile such
as 3-hexyne, 4-octyne and acetonitrile. However, the different
order afforded the different isomers as single products cleanly.
It is interesting to note that azazirconacyclopentadiene 1d10
prepared from diphenylzirconocene and a nitrile reacted with
diphenylacetylene to produce a substituted isoquinoline derivative
2d in 46% yield (eq 5).
When unsymmetrical alkynes such as 1-phenyl-1-propyne,
1-phenyl-1-butyne, and diphenylbutadiyne were used as the
second alkyne, the coupling reaction proceeded with high regio-
selectivity1 and only single products were obtained (eq 6).
The reaction mechanism is not clear yet. However, as we
reported in the selective benzene formation,9 reaction of NiCl2-
(PPh3)2 with azazirconacyclopentadienes 1 to give azanickelacy-
clopentadienes 3 is plausible, although the formation of azanick-
elacyclopentadienes 3 has not yet been observed during the
reactions. The formation of Cp2ZrCl2 was detected (>98% NMR
yield). One possible path from 3 to 2 is insertion of the second
alkyne into 3. There are two pathways for insertion of the second
alkyne into azanickelacyclopentadienes as shown in Scheme 1.
Scheme 1
a GC yields. Isolated yields are given in parentheses.
3
one-pot procedure to produce substituted pyridine derivatives with
high selectivities. The results of the one-pot reaction are shown
in Table 1.
4
Clarification of the reaction mechanism of the formation of
pyridines from azazirconacyclopentadienes await further inves-
tigations.
When the second alkyne inserts into the Ni-C bond of 3, the
azanickelacycloheptatrienes 4 is formed. On the other hand, when
the insertion occurs in the Ni-N bond of 3, the corresponding
complex 5 is produced. Intramolecular reductive coupling of 4
or 5 affords the substituted pyridine derivatives 2. Although there
is no strong evidence for the intermediate 4 or 5, the insertion of
the second alkyne into the Ni-C bond is more likely.
Acknowledgment. We thank the Ministry of Education, Science,
Sport and Culture, Japan, for support of a part of this study (09440212).
Dedicated to Professor Masanobu Hidai on the occasion of his 60th
birthday.
Supporting Information Available: Experimental details and spec-
troscopic characterization of compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Combination of azazirconacyclopentadiene formation using
Cp2ZrEt2 and its coupling with an alkyne provided an efficient
JA000474Y