Selective preparation of pyridines, pyridones, and iminopyridines from two different alkynes via azazirconacycles

Article abstract of DOI:10.1021/ja017507+

Selective preparation of pyridine derivatives from two different alkynes and a nitrile was achieved by a novel procedure in which an alkyne and a nitrile couple first to give an azazirconacyclopentadiene followed by reaction with the second alkyne in the

Full text of DOI:10.1021/ja017507+

Published on Web 04/05/2002
Selective Preparation of Pyridines, Pyridones, and
Iminopyridines from Two Different Alkynes via
Azazirconacycles
Tamotsu Takahashi,* Fu-Yu Tsai, Yanzhong Li, Hui Wang, Yoshihiko Kondo,
Masamichi Yamanaka, Kiyohiko Nakajima,† and Martin Kotora
Contribution from the Catalysis Research Center and Graduate School of Pharmaceutical
Sciences, Hokkaido UniVersity, and CREST, Science and Technology Corporation (JST),
Sapporo 060-0811, Japan, and Department of Chemistry, Aichi UniVersity of Education,
Igaya, Kariya, Aichi 448-8542, Japan
Received November 10, 2001
Abstract: Selective preparation of pyridine derivatives from two different alkynes and a nitrile was achieved
by a novel procedure in which an alkyne and a nitrile couple first to give an azazirconacyclopentadiene
followed by reaction with the second alkyne in the presence of 1 equiv of NiCl2(PPh3)2. This procedure
gives only single products of pyridine derivatives from two different symmetrical alkynes and a nitrile. Our
novel procedure can be used even with two similar alkyl-substituted alkynes such as 3-hexyne and 4-octyne.
Two possible pyridine isomers from 3-hexyne, 4-octyne, and acetonitrile could be completely and
independently prepared as single products by this method. The origin of the selectivity comes from the
addition order of two different alkynes. This method was applied for the formation of pyridones and
iminopyridines using isocyanate and carbodiimide derivatives instead of nitriles, respectively. Reaction of
an alkyne with Cp2ZrEt2 and an isocyanate or a carbodiimide gives an azazirconacycle. Treatment of the
azazirconacycle with the second alkyne in the presence of 1 equiv of NiCl2(PPh3)2 gave a pyridone or an
iminopyridine derivative. The use of two different unsymmetrical alkynes afforded the pyridine with five
different substituents when the first alkyne has a trialkylsilyl group and the second alkyne has a phenyl
group as functional groups. On the other hand, azazirconacyclopentadienes reacted with propargyl bromide
in the presence of CuCl with excellent regioselectivity to give tetrasubstituted pyridine derivatives as single
products. With the assistance of the trialkylsilyl groups, pyridines with all different substituents including H
were also prepared.
Scheme 1
Introduction
Transition metal catalyzed or mediated formation of hetero-
cycles has always received considerable synthetic attention.1-13
Among them the preparation of pyridines directly from alkynes
and nitriles is especially attractive methodology, because it
enables the construction of compounds with a high degree of
complexity from a rather simple starting material (Scheme 1).
A great deal of work has been done in this area with regard to
mechanistic and synthetic aspects of this reaction and the most
effective reagents for this type of cycloaddition are those based
on Co complexes.2,3 The pyridine formation from two alkynes
and a nitrile with Co complexes was originated by Wakatsuki
and Yamazaki.2a Although this method is very effective, there
is a critical problem for the selective intermolecular coupling
of two different alkynes with a nitrile. In a few cases, a single
product of the pyridines was obtained with the assistance of a
functional group such as an alkoxy carbonyl group.2d However,
in most cases a mixture of two regioisomers is obtained. The
major reason can be attributed to the reaction mechanism.14
Studies on pyridine formation have shown that the first step
is the intermolecular coupling of two alkynes forming a
cobaltacyclopentadiene (Scheme 2; M ) Co).3d Then a nitrile
reacts with the cobaltacyclopentadiene to give a pyridine
compound. In the case of a cobaltacyclopentadiene prepared
from two different alkynes, there are two possible orientations
for the nitrile as shown in Scheme 2 (M ) Co). Therefore,
pyridines are usually obtained as a mixture of two regioisomers.
In some cases the ratio of the regioisomers can be controlled
* Address correspondence to this author at Hokkaido University.
E-mail: tamotsu@cat.hokudai.ac.jp.
† Present address: Aichi University of Education.
(1) For reviews, see: (a) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996,
96, 49-92. (b) Grotjahn, D. B. ComprehensiVe Organometallic Chemistry
II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Elsevier Science
Ltd: Oxford, 1995; Vol. 12; pp 741-770. (c) Schore, N. E. ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds; Pergamon Press Ltd:
Oxford, 1991; Vol. 5, pp 1129-1162. (d) Harrington, P. J. Transition Metals
in Total Synthesis; John Wiley & Sons: New York, 1990; pp 200-240.
(e) Schore, N. E. Chem. ReV. 1988, 88, 1081-1119. (f) Vollhardt, K. P.
C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539-556. (g) Saito, S.;
Yamamoto, Y. Chem. ReV. 2000, 100, 2901-2915.
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A R T I C L E S
Takahashi et al.
Scheme 2. Pyridine Formation from Two Different Alkynes
due to the substituents or sometimes a single isomer can be
obtained. This selectivity is completely dependent on the
substituents of alkynes.
(Symmetrical) and a Nitrile via Metalacyclopentadiene
However, to develop a useful procedure for the formation of
a single isomer of pyridine derivatives from two different
alkynes and a nitrile, a novel procedure via azametalacyclo-
pentadienes as shown in Scheme 3 has an advantage. This
procedure always affords a single isomer of pyridine derivatives
from two symmetrical alkynes.
We have recently reported the formation of azazirconacy-
clopentadienes from one alkyne and a nitrile.13 This preparative
method of azazirconacyclopentadienes could be used for our
(2) Pyridine formation for Co: (a) Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc.,
Chem. Commun. 1973, 280-281. (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 Trans 1978, 1278-1282. (e) Wakatsuki, Y.; Yamazaki, H. Bull.
Chem. Soc. Jpn. 1985, 58, 2715-2716. (f) Vollhardt, K. P. C.; Bergman,
R. G. J. Am. Chem. Soc. 1974, 96, 4996-4998. (g) Naiman, A.; Vollhardt,
K. P. C. Angew. Chem., Int. Ed. Engl. 1977, 16, 708-709. (h) Brien, D.
J.; Naiman, A.; Vollhardt, K. P. C. J. Chem. Soc., Chem. Commun. 1982,
133-134. (i) Bonnemann, H.; Brinkmann, R.; Schenkluhn, H. Synthesis
1974, 575-577. (j) Bonnemann, H.; Brinkmann, R. Synthesis 1975, 600-
602. (k) Bonnemann, H.; Brijoux, W.; Brinkmann, R.; Meuers, W.; Mynott,
R.; von Phillipsborn, W.; Egolf, T. J. Organomet. Chem. 1984, 272, 231-
249. (l) Vitulli, G.; Bertozzi, S.; Lazzaroni, R.; Salvadori, P. J. Organomet.
Chem. 1986, 307, C35-C37. (m) Vitulli, G.; Bertozzi, S.; Vignali, M.;
Lazzaroni, R.; Salvadori, P. J. Organomet. Chem. 1987, 326, C33-C36.
(n) Chiusoli, G. P.; Pallini, L.; Terenghi, G. Transition Met. Chem. 1983,
8, 250-252. (o) Chiusoli, G. P.; Pallini, L.; Terenghi, G. Transition Met.
Chem. 1984, 9, 360. (p) Battaglia, L. P.; Delledonne, D.; Nardelli, M.;
Predieri, G.; Chiusoli, G. P.; Costa, M.; Pelizzi, C. J. Organomet. Chem.
1989, 363, 209-222. (q) Zhou, Z.; Battaglia, L. P.; Chiusoli, G. P.; Costa,
M.; Nardelli, M.; Pelizzi, C.; Predieri, G. J. Organomet. Chem. 1991, 417,
51-63. (r) Jerome, K. S.; Parsons, E. J. Organometallics 1993, 12, 2991-
2993. (s) Viljoen, J. S.; du Plessis, J. A. K. J. Mol. Catal. 1993, 79, 75-
84. (t) Heller, B.; Oehme, G. J. Chem. Soc., Chem. Commun. 1995, 179-
180. (u) Varela, A.; Castedo, L.; Saa´, C. J. Org. Chem. 1997, 62, 4189-
4192. (v) Varela, A.; Castedo, L.; Saa´, C. J. Am. Chem. Soc. 1998, 120,
12147-12148. (w) Varela, A.; Castedo, L.; Saa´, C. Org. Lett. 1999, 1,
2141-2143. (x) Eaton, B. E.; Fatland, A. W Org. Lett. 2000, 2, 3131-
3133.
Scheme 3. Pyridine Formation from Two Different Alkynes
(Symmetrical) and a Nitrile via Azametalacyclopentadiene
(3) For application of pyridine formation with Co: (a) Tatone, D.; Dich, T.
C.; Nacco, R.; Botteghi, C. J. Org. Chem. 1975, 40, 2987-2990. (b)
Salvadori, P.; Rosini, C.; Bertucci, C.; Pini, D.; Marchetti, M. J. Chem.
Soc., Perkin Trans. 2 1983, 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. (f) Saa´, C.; Crotts, D. D.; Hsu, G.; Vollhardt, K. P. C. Synlett 1994,
487-489. (g) Chelluci, G. Tetrahedron Asymmetry 1995, 6, 811-826.
(4) Pyridine formation for Rh: (a) Cioni, P.; Diversi, P.; Ingrosso, G.; Lucherini,
A.; Ronca, P. J. Mol. Catal. 1987, 40, 337-357. (b) Cioni, P.; Diversi, P.;
Ingrosso, G.; Lucherini, A.; Ronca, P. J. Mol. Catal. 1987, 40, 359-377.
(c) Bianchini, C.; Meli, A.; Peruzzini, M.; Cacca, A.; Vizza, F. Organo-
metallics 1991, 10, 645-651. (d) Diversi, P.; Ermini, L.; Ingrosso, G.;
Lucherini, A. J. Organomet. Chem. 1993, 447, 291-298. (e) Costa, M.;
Diaz, F. S.; Chiusoli, G. P.; Gazzola, G. L. J. Organomet. Chem. 1995,
488, 47-53.
novel procedure. Very recently we have preliminarily reported
the selective formation of pyridine derivatives from two different
alkynes and a nitrile.16 In this paper we report the details of the
strategy and extension of this method to selective formation of
pyridones and iminopyridines via azazirconacycles in the
presence of NiCl2(PPh3)2. We also report the formation of
pyridine derivatives with five different substituents from two
different unsymmetrical alkynes and a nitrile with assistance
from functional groups. Furthermore, we report here the
selective formation of pyridine derivatives by the reaction of
azazirconacyclopentadienes with propargyl halides with excel-
lent regioselectivity in the presence of CuCl.
(5) Pyridine formation for Ru: (a) Yamamoto, Y.; Ogawa, R.; Itoh, K. J. Am.
Chem. Soc. 2001, 123, 6189-6190. (b) Yamamoto, Y.; Okuda, S.; Itoh,
K. Chem. Commun. 2001, 1102-1103.
(6) Pyridine formation for Ti: (a) Hill, J. E.; Balaich, G.; Fanwick, P. E.;
Rothwell, I. P. Organometallics 1993, 12, 2911-2924.
(7) Pyridine formation 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.;
Utimoto, K. Chem. Lett. 1995, 851-852.
Results and Discussion
(8) Pyridone formation for Co: (a) Hong, P.; Yamazaki, H. Tetrahedron Lett.
1977, 1333-1336. (b) Hong, P.; Yamazaki, H. Synthesis 1977, 50-52.
(c) Earl, R. A.; Vollhardt, K. P. C. J. Org. Chem. 1984, 49, 4786-4800.
(d) Diversi, P.; Ingrosso, G.; Luchering, A.; Malquori, S. J. Mol. Catal.
1987, 40, 267.
Selective Pyridine Formation from Two Different Sym-
metrical Alkynes and a Nitrile. To develop the substituent-
independent procedure for the formation of pyridine derivatives
(9) Pyridone formation for Ni: (a) Hoberg, H.; Oster, B. W. J. Organomet.
Chem. 1982, 234, C35-C38. (b) Hoberg, H.; Oster, B. W. Synthesis 1982,
324-325. (c) Hoberg, H.; Oster, B. W. J. Organomet. Chem. 1983, 252,
359-364.
(14) (a) Wakatsuki, Y.; Kuramitsu, T.; Yamazaki, H. Tetrahedron Lett. 1974,
4549-4552. (b) Yamazaki, H.; Wakatsuki, Y. J. Organomet. Chem. 1977,
139, 157-167. (c) Wakatsuki, Y.; Nomura, O.; Kitaura, K.; Morokuma,
K.; Yamazaki, H. J. Am. Chem. Soc. 1983, 105, 1907-1912.
(15) (a) Takahashi, T.; Xi, C.; Xi, Z.; Kageyama, M.; Fischer, R.; Nakajima,
K.; Negishi, E. J. Org. Chem. 1998, 63, 6802-6806. (b) For a preliminary
report, see: Takahashi, T.; Kageyama, M.; Denisov, V.; Hara, R.; Negishi,
E. Tetrahedron Lett. 1993, 34, 687-690.
(10) Pyridone formation for Rh: Flynn, S. T.; Hasso-enderson, S. E.; Parkins,
A. W. J. Mol. Catal. 1985, 32, 101-105.
(11) Pyridone formation for Ru: Yamamoto, Y.; Takagishi, H.; Itoh, K. Org.
Lett. 2001, 3, 2117-2119.
(12) Iminopyridine formation for Co: see refs 8a,b.
(13) Iminopyridine formation for Ni: Hoberg, H.; Burkhart, G. Synthesis 1979,
525-526.
(16) Takahashi, T.; Tsai, F.-Y.; Kotora, M. J. Am. Chem. Soc. 2000, 122, 4994-
4995.
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Preparation of Pyridines, Pyridones, and Iminopyridines
A R T I C L E S
Scheme 4. Selective Preparation of Pyridines from 3-Hexyne,
Table 1. Formation of Pyridone Derivatives
4-Octyne, and Benzonitrile
from two different alkynes and a nitrile, the preparation of
pyridines via azametalacyclopentadienes has been investigated.
As shown in Scheme 3, by this method via azazirconacyclo-
pentadienes there is only one possible orientation for the second
symmetric alkynes. Therefore, this procedure always gives a
single isomer of the pyridines. It is independent from the
substituents of the alkynes. The orientation of two different
symmetrical alkynes is dependent on the order of addition of
those two alkynes. The first alkyne always couples with the
carbon of the nitrile and the second alkyne makes the bond with
the nitrogen of the nitrile. This selectivity can be completely
controlled by this method.
In the case of cobalt complexes, coupling of an alkyne and
a nitrile is not convenient. As Saa´ and co-workers showed in
the mechanism, it is believed that two alkynes couple first but
not the coupling of an alkyne and a nitrile.2u-w Recently, we
have reported the formation of azazirconacyclopentadienes from
one alkyne and a nitrile via C-C bond cleavage of zirconacy-
clopentenes. We found that the azazirconacyclopentadienes did
not directly react with the second alkyne, but in the presence
of Ni(II) complexes, they reacted to give pyridine derivatives.17
As shown in Scheme 3, when two different symmetrical alkynes
were used, always only one isomer among two possible isomers
was obtained. Usually, the recognition of the difference between
3-hexyne and 4-octyne is quite difficult. By this method two
isomers of pyridines from 3-hexyne and 4-octyne and a nitrile
could be completely controlled as shown in Scheme 4.
a NMR or GC yields are given in parentheses. b The reaction was carried
out with (4-methylphenyl)isocyanate.
zirconacyclopentenes and isocyanates.18 The structure of 4 is
not clear yet. It might be in equilibrium between 4a and
oxazirconacycle 4b. Fortunately, this problem is of no impor-
tance for further steps in the preparation of pyridones. The
reaction of 4 with the second alkyne in the presence of NiCl2-
(PPh3)2 gave the corresponding pyridone 6 as a single isomer.
Results are shown in Table 1. It is noteworthy that when
unsymmetrically substituted alkynes were used as the first
alkyne or as the second alkyne, only one regioisomer was
obtained for 6e, 6d, and 6h. This could be achieved either by
Formation of Pyridones and Iminopyridines via Azazir-
conacycles. Our novel addition-order-dependent selective cou-
pling reactions can be applied for other heterocycle formations
such as pyridones3-11 and iminopyridines.12,13 Recently we have
reported the formation of azazirconacyclopentenones 4 from
(17) For a detailed discussion concerning the reaction mechanism with trans-
metalation to Ni, see: (a) Reference 16. (b) Takahashi, T.; Tsai, F.-Y.; Li,
Y.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 1999, 121, 11093-11100.
(18) Takahashi, T.; Li, Y.; Tsai, F.-Y.; Nakajima, K. Organomatallics 2001,
20, 595-597.
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A R T I C L E S
Takahashi et al.
Scheme 5
Scheme 6
Scheme 7
alkynes such as DMAD to give 6f, although the yield of the
product was rather low.
A plausible reaction mechanism involves the formation of
azanickelacyclopetenone 5 by transmetalation of 4 to Ni and
the subsequent insertion of the second alkyne to give 6. In fact,
it has been reported that azanickelacyclopentenone 5 with a
TMEDA ligand instead of PPh3 (R1 ) R2 ) Ph) reacted with
DMAD to give 6f.9c
Table 2. Formation of Iminopyridines
The formation of iminopyridines is similar to that of pyridones
and it proceeds through the same reaction mechanism and under
the identical reaction conditions, except for the use of a
carbodiimide instead of an isocyanate (Scheme 6). The reaction
proceeds through intermediates 7 and 8. Some typical examples
are given in Table 2. The reaction proceeded as expected,
affording the corresponding iminopyridines in good yields. Once
again the selective formation of regioisomers is illustrated by
the synthesis of 9d and 9e. The structure of 9a was confirmed
by X-ray analysis.
Selective Pyridine Formation from Two Different Unsym-
metrical Alkynes and a Nitrile. As mentioned above, we have
developed a novel procedure for the selective preparation of
pyridine derivatives, pyridones, and iminopyridines from two
different symmetrical alkynes. This procedure was independent
from the substituents of the alkynes. To develop a selective
method using unsymmetrical alkynes, the procedure should be
dependent on the functional groups of the alkynes. Here we
would like to demonstrate a novel combination of our new
method described above (the addition-order-dependent selective
coupling reaction) and the functional-group-dependent selective
coupling of unsymmetrical alkynes.
As we reported, silyl-substituted unsymmetrical alkynes and
nitriles can provide azazirconacyclopentadienes with complete
regioselectivity.19 It is noteworthy that when phenyl- and alkyl-
the regioselective preparation of an unsymmetrically substituted
zirconacyclopentene or by regioselective insertion of the second
alkyne. Note that compounds 6d and 6e are regioisomers.
Preparation of these isomers can be controlled by this method.
The reaction also may be carried out with electron-deficient
(19) (a) Takahashi, T.; Xi, Z.; Nishihara, Y.; Huo, S.; Kasai, K.; Aoyagi, K.;
Denisov, V.; Negishi, E. Tetrahedron 1997, 53, 9123-9134. (b) Xi, Z.;
Hara, R.; Takahashi, T. J. Org. Chem. 1995, 60, 4444-4446. (c) See also
ref 15a. (d) Takahashi, T.; Xi, Z.; Rousset, C. J.; Suzuki, N. Chem. Lett.
1993, 1001-1002.
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Preparation of Pyridines, Pyridones, and Iminopyridines
A R T I C L E S
Scheme 8
Table 3. Regioselective Formation of Pentasubstituted Pyridines from Two Different Unsymmetrical Alkynes
a GC yields. Isolated yileds are given in parentheses.
substituted alkynes were used as the second alkynes, the
coupling reaction proceeded selectively and only a single
product was obtained as reported. Phenyl group-substituted
carbon in the C-C triple bond always makes a bond with the
nitrogen atom of the azametalacyclopentadienes. Those two
selective reactions could be combined as shown to give pyridine
derivatives from two different unsymmetrical alkynes as shown
in Scheme 8.
We have previously shown that such R,R′-trimethylsilyl-
substituted zirconacycles, prepared by the reaction of Cp2ZrBu2
(Negishi reagent) with 2 equiv of a trimethylsilylalkyne, undergo
substitution of one of the alkyne moieties via â,â′-carbon-
carbon cleavage with a number of unsaturated compounds
including a nitrile. Moreover, the remaining trimethylsilyl group
always occupies an R-position to the zirconium atom.20 There-
fore by using this method the reaction of Negishi reagent with
2 equiv of trimethylsilylalkyne afforded zirconacyclopentadiene,
which was followed by the subsequent substitution with the
nitrile resulting in the formation of an azazirconacyclopentadiene
10. As far as the reaction with the nitrile is concerned, the
nitrogen atom of azazirconacyclopentadiene is always bonded
to the zirconium atom. Results are shown in Table 3.
The regiochemistry of the trimethylsilyl group and an R1
group was determined in the hydrolysis products 12a-e. In all
cases, only single isomers were obtained with complete regi-
oselectivity. The regiochemistry of a phenyl group and an alkyl
group (R3) in 11a-e were determined by observation of the
NOEs between the trimethylsilyl group and the alkyl group (R3)
in their NMR spectra.
(20) Hara, R.; Xi, Z.; Kotora, M.; Xi, C.; Takahashi, T. Chem. Lett. 1996, 1003-
1004.
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A R T I C L E S
Takahashi et al.
Scheme 9
Table 4. Regioselective Formation of Tetrasubstituted Pyridines
from the Reaction of Azazirconacyclopentadienes with Propargyl
Bromide
In all cases, we obtained the pyridines with five different
groups as single products. No traces of regioisomers were found.
The trimethylsilyl group always occupied a γ-position and the
phenyl group from the second alkyne was at an R-position in
the pyridine ring.
Although the intermediate after transmetalation of azazir-
conacyclopentadienes to Ni(II) is still unclear, we believe that
azanickelacyclopentadienes are formed, since the nickelacyclo-
pentadiene has been isolated in the case of the reaction of bis-
(cyclopentadienyl)tetraphenylzirconacyclopentadiene with NiCl2-
(dppe). The regiochemistry of the second alkyne was controlled
by the difference between a phenyl group and an alkyl group.16
Reaction of Azazirconacyclopentadienes with Propargyl
Halides in the Presence of CuCl. Azazirconacyclopentadienes
have two different bonds such as the Zr-C and the Zr-N bonds.
This difference can be used for the regioselective coupling of
the second alkynes. We found that in the presence of CuCl,
propargyl bromides reacted with azazirconacyclopentadienes to
afford tetrasubstituted pyridine derivatives with excellent regi-
oselecitvity on the propargyl compounds as shown in Scheme
9.21 It is well-known that the sp2-C in the zirconacycles readily
transmetalates from Zr to Cu. Therefore, in this case the selective
transmetalation of the sp2-C from Zr to Cu is the first step.
Successive addition of the alkenyl copper moiety to the allene
moiety leads to the formation of pyridine derivatives.
In Table 4 are given some characteristic examples. It is
important to stress that as the result of the reaction mechanism
in all cases this approach furnishes selectively 2,3,4,6-substituted
pyridines 15. Once again no other isomers were detected in any
of the reaction mixtures. Alkyl- and aryl-tetrasubstituted py-
ridines prepared from symmetrical alkynes through the azazir-
conacyclopentadiene pathway were obtained in good yields. The
pyridines with five different substituents including H also could
be prepared by this method with assistance from the trimeth-
ylsilyl group or triethylsilylphenylethyne, where an almost
quantitative yield of the pyridine was obtained.
Conclusion
We have presented a general strategy for the regioselective
preparation of nitrogen-containing heterocycles such as py-
ridines, pyridones, and iminopyridines by the reaction of
azazirconacycles with alkyne derivatives. Selective formation
of pyridines, pyridones, and iminopyridines could be achieved
via azazirconacycles. The selectivity is not dependent on the
substituents of alkynes. The orientation of two different alkynes
and a nitrile is dependent on the order of addition of alkynes.
When two different unsymmetrical alkynes were used, the
assistance of the functional groups was required. Two regiose-
a GC yields. Isolated yields are given in parentheses.
lective reactions were combined for the selective formation of
five different substituted pyridines. For the first alkyne, the
complete selectivity was given by the role of trialkylsilyl groups.
The trialkylsilyl groups always occupy the R-position of the
azazirconacycles. The excellent regioselectivity of the second
alkynes can be attributed to the selective coupling of phenyla-
(21) The similar reaction mechanism accounts for the formation of benzenes
by the reaction of zirconacyclopentadienes with propargyl chloride. Kotora,
M.; Noguchi, Y.; Takahashi, T. Collect. Czech. Chem. Commun. 1999,
64, 1119-1124.
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Preparation of Pyridines, Pyridones, and Iminopyridines
A R T I C L E S
3-Methyl-1,4,5,6-tetraphenylpyrid-2-one (6e): isolated yield 65%;
white solid, mp 245-247 °C; 1H NMR (CDCl3, Me4Si) δ 2.07 (s, 3H),
6.70-7.40 (m, 20H); 13C NMR (CDCl3, Me4Si) δ 14.94, 120.97,
125.59, 126.44, 126.73, 126.78, 126.93, 127.09, 127.41, 127.56, 128.39,
128.70, 129.02, 130.73, 131.49, 134.53, 137.15, 138.42, 139.52, 143.53,
150.65, 162.88; IR (Nujol) 2970, 2847, 1649, 1608, 1527, 1487, 1443,
745, 698 cm-1; HRMS calcd for C30H23NO 413.1780, found 413.1794.
5,6-Dicarbomethoxy-1,3,4-triphenylpyrid-2-one (6f): isolated yield
lkylethynes in the presence of Ni(II) complexes. Selective
transmetalation of the Zr-C bond in the azazirconacycles to
Cu led to excellent regioselectivity for the reaction with
propargyl bromide.
Experimental Section
General Information. All reactions involving air or moisture
sensitive organometallic reactions were carried out under dry nitrogen.
THF was distilled over sodium and benzophenone. Zirconocene
dichloride was purchased from Nichia Chemical Co., Inc. Alkynes were
purchased from Aldrich Chemical Co., Inc. n-BuLi (1.6 M solution in
hexane) and EtMgBr (1.0 M solution in THF) were purchased from
Kanto Chemical Co., Ltd. 1H and 13C NMR spectra were recorded for
CDCl3 (containing 1% TMS) solution at 25 °C on a Bruker ARX-400
or a JEOL JNM-AL300 NMR spectrometer. GC analysis was performed
on a Shimadzu GC-14A equipped with the fused silica capillary column
Shimadzu CBP1-M25-O25 and Shimadzu C-R6A-Chromatopac inte-
grator.
A Typical Procedure for the Preparation of Pyridones (6). To a
solution of Cp2ZrCl2 (365 mg, 1.25 mmol) in THF (5 mL) was added
EtMgBr (2.5 mmol) at -78 °C. After the mixture was stirred for 1 h
at the same temperature an alkyne (1.0 mmol) was added and the
reaction mixture was allowed to warm to 0 °C. After this mixture was
stirred for 3 h, phenylisocyanate (1.5 mmol) was added to the reaction
mixture and stirring was continued at 50 °C for 3 h. After cooling to
room temperature an alkyne (2.0 mmol) and NiCl2(PPh3)2 (1.2 mmol)
were added to the reaction mixture and stirring was continued at 50
°C for 3 h. Then the reaction mixture was quenched with NH4OH and
extracted with ether. The extract was washed with water and dried over
MgSO4. The solvent was evaporated in vacuo and the residue was
purified by chromatography on silica gel.
1
20%; yellow solid, mp 238.5-239 °C; H NMR (CDCl3, Me4Si) δ
3.41 (s, 3H), 3.50 (s, 3H), 6.90-7.60 (m, 15H); 13C NMR (CDCl3,
Me4Si) δ 52.28, 52.95, 113.09, 127.29, 127.43, 127.69, 127.76, 128.02,
128.45, 129.10, 129.30, 130.69, 133.19, 134.01, 137.03, 137.66, 141.24,
148.21, 160.93, 162.03, 165.77; IR (Nujol) 2961, 2957, 2857, 1746,
1715, 1669, 1589, 1491, 1456, 1433, 1319, 1263, 1240, 1219, 723,
698 cm-1; HRMS calcd for C27H21NO5 439.1420, found 439.1413.
5,6-Diethyl-1-(4-methylphenyl)-3,4-diphenylpyrid-2-one (6g): iso-
lated yield 49%; yellow solid, mp 155-156 °C; 1H NMR (CDCl3, Me4-
Si) δ 0.89 (t, J ) 7.3 Hz, 3H), 1.04 (t, J ) 7.3 Hz, 3H), 2.33 (q, J )
7.3 Hz, 2H), 2.38 (s, 3H), 2.49 (q, J ) 7.3 Hz, 2H), 7.00-7.30 (m,
14H); 13C NMR (CDCl3, Me4Si) δ 13.66, 15.22, 21.02, 21.69, 23.42,
117.79, 125.91, 126.70, 126.80, 127.38, 128.09, 128.98, 129.29, 129.73,
130.77, 136.00, 136.63, 137.98, 138.18, 146.85, 152.39, 162.27; IR
(Nujol) 2957, 2951, 2945, 1649, 1574, 1508, 1460, 799, 696 cm-1
HRMS calcd for C28H27NO 393.2093, found 393.2086.
;
5-Butyl-1,3,4,6-tetraphenylpyrid-2-one (6h): isolated yield 58%;
1
yellow solid, mp 176-178 °C; H NMR (CDCl3, Me4Si) δ 0.38 (t, J
) 7.3 Hz, 3H), 0.65-0.80 (m, 2H), 0.95-1.10 (m, 2H), 2.00-2.10
(m, 2H), 7.10-7.30 (m, 20H); 13C NMR (CDCl3, Me4Si) δ 12.99, 22.23,
28.99, 32.51, 118.37, 126.31, 126.96, 127.07, 127.40, 127.51, 127.70,
127.95, 128.39, 129.13, 129.24, 130.08, 130.88, 131.18, 134.64, 135.89,
137.95, 139.58, 145.18, 152.33, 161.68; IR (Nujol) 2995, 2968, 1649,
1643, 1526, 1491, 746, 696 cm-1; HRMS calcd for C33H29NO 455.2249,
found 455.2257.
1,3,4,5,6-Pentaphenylpyrid-2-one (6a): isolated yield 67%; white
1
solid, mp 239-240 °C; H NMR (CDCl3, Me4Si) δ 6.80-7.40 (m,
25H); 13C NMR (CDCl3, Me4Si) δ 121.26, 125.71, 126.38, 126.46,
126.91, 126.97, 127.06, 127.11, 127.30, 127.52, 128.40, 129.04, 129.90,
130.32, 130.59, 131.05, 131.60, 134.48, 135.69, 136.98, 137.90, 139.27,
145.79, 151.29, 162.07; IR (Nujol) 2953, 2930, 2926, 1649, 1489, 1458,
1444, 742, 694 cm-1. Anal. Calcd for C35H25NO: C, 88.39; H, 5.30;
N, 2.95. Found: C, 88.41; H, 5.41; N 2.90.
Typical Experimental Procedure for the Preparation of Imi-
nopyridines (9). To a solution of zirconacyclopentene (1.0 mmol),
prepared from diethylzirconocene and an alkyne (1.0 mmol), was added
diphenylcarbodiimide (1.0 mmol). The mixture was allowed to warm
to 50 °C for 3 h, then alkyne (2.5 mmol) and NiCl2(PPh3)2 (1.0 mmol)
were added. After this mixture was stirred for an additional 3 h at 50
°C the solution was quenched with saturated aquous NaHCO3 and
extracted with EtOAc. Column chromatography on silica gel afforded
products.
3,4,5,6-Tetraethyl-1-phenyl-2-phenylimino-1,2-dihydropyridine
(9a): isolated yield 61%; yellow solid, mp 134-135 °C; 1H NMR
(CDCl3, Me4Si) δ 0.86 (t, J ) 7.4 Hz, 3H), 1.07-1.25 (m, 9H), 2.32
(q, J ) 7.3 Hz, 2H), 2.48-2.66 (m, 6H), 6.34-6.36 (m, 2H), 6.57-
6.60 (m, 1H), 6.87-6.91 (m, 2H), 7.06-7.20 (m, 5H); 13C NMR
(CDCl3, Me4Si) δ 13.48, 13.70, 14.73, 15.54, 21.19, 21.28, 22.62, 23.31,
118.54, 119.11, 121.79, 127.81, 128.20, 128.45, 129.12, 133.25, 140.88,
146.98, 150.30, 150.82, 151.38. IR (KBr) 2971, 2932, 2903, 2872, 1612,
1591, 1553, 1514, 1489, 766, 746, 694 cm-1; HRMS calcd for C25H30N2
358.2409, found 358.2405.
1,3,4-Triphenyl-5,6-dipropylpyrid-2-one (6b): isolated yield 61%;
1
1H NMR yield 72%; yellow liquid; H NMR (CDCl3, Me4Si) δ 0.65
(t, J ) 7.3 Hz, 3H), 0.68 (t, J ) 7.2 Hz, 3H), 1.20-1.35 (m, 2H),
1.40-1.55 (m, 2H), 2.20-2.30 (m, 2H), 2.30-2.45 (m, 2H), 6.90-
7.60 (m, 15H); 13C NMR (CDCl3, Me4Si) δ 14.24, 22.73, 24.22, 31.06,
32.60, 117.07, 126.03, 126.79, 126.93, 127.43, 128.23, 128.47, 129.06,
129.13, 129.39, 130.83, 136.03, 138.28, 139.46, 145.67, 152.56, 162.26;
IR (neat) 2961, 2872, 1632, 1578, 1532, 1491, 733, 702 cm-1; HRMS
calcd for C29H29NO 407.2249, found 407.2242.
1-Phenyl-3,4,5,6-tetrapropylpyrid-2-one (6c): isolated yield 40%;
GC yield 46%; yellow liquid; 1H NMR (CDCl3, Me4Si) δ 0.66 (t, J )
7.3 Hz, 3H), 0.96 (t, J ) 7.4 Hz, 3H), 1.03 (t, J ) 7.3 Hz, 3H), 1.07
(t, J ) 7.3 Hz, 3H), 1.30-1.40 (m, 2H), 1.45-1.60 (m, 6H), 2.20-
2.30 (m, 2H), 2.30-2.40 (m, 2H), 2.45-2.60 (m, 4H), 7.10-7.50 (m,
5H); 13C NMR (CDCl3, Me4Si) δ 14.18, 14.61, 14.64, 14.82, 22.32,
22.76, 23.95, 24.90, 29.84, 30.47, 32.05, 32.24, 116.81, 128.00, 128.50,
128.65, 129.12, 139.90, 142.98, 150.43, 162.96; IR (neat) 2932, 2872,
1682, 1640, 1599, 1527, 1466, 754, 696 cm-1; HRMS calcd for C23H33-
NO 339.2560, found 339.2575.
5,6-Diethyl-1-phenyl-2-phenylimino-3,4-dipropyl-1,2-dihydropy-
1
ridine (9b): isolated yield 56%; yellow solid, mp 100-101 °C; H
NMR (CDCl3, Me4Si) δ 0.75 (t, J ) 7.4 Hz, 3H), 0.82 (t, J ) 7.5 Hz,
3H), 1.05 (t, J ) 7.4 Hz, 3H), 1.14 (t, J ) 7.4 Hz, 3H), 1.43-1.57 (m,
4H), 2.16-2.22 (m, 2H), 2.35-2.45 (m, 6H), 6.30-6.31 (m, 2H), 6.55-
6.57 (m, 1H), 6.85-7.15 (m, 7H); 13C NMR (CDCl3, Me4Si) δ 13.12,
14.23, 14.77, 15.84, 21.05, 22.06, 22.97, 24.00, 30.22, 31.69, 116.38,
117.93, 120.05, 126.99, 128.00, 128.38, 129.12, 129.87, 142.23, 144.28,
146.46, 150.95, 152.74; IR (KBr) 2961, 2934, 2872, 1615, 1591, 1564,
1520, 1489, 756, 698 cm-1. Anal. Calcd for C27H34N2: C, 83.89; H,
8.87; N, 7.25. Found: C, 83.86; H, 8.96; N, 7.25.
5-Methyl-1,3,4,6-tetraphenylpyrid-2-one (6d): isolated yield 56%;
1
white solid: mp >300 °C; H NMR (CDCl3, Me4Si) δ 1.62 (s, 3H),
6.90-7.30 (m, 20H); 13C NMR (CDCl3, Me4Si) δ 17.35, 112.95,
126.38, 127.03, 127.13, 127.42, 127.84, 127.95, 127.98, 128.40, 128.98,
129.18, 129.95, 130.85, 130.93, 135.14, 135.88, 138.51, 139.64, 144.90,
152.47, 161.86; IR (Nujol) 2884, 2866, 2847, 1643, 1583, 1524, 1491,
748, 706 cm-1. Anal. Calcd for C30H23NO: C, 87.14; H, 5.61; N, 3.39.
Found: C, 87.05; H, 5.81; N 3.29.
3,4-Diethyl-1-phenyl-2-phenylimino-5,6-dipropyl-1,2-dihydropy-
ridine (9c): isolated yield 69%; yellow solid, mp 85-86 °C; 1H NMR
(CDCl3, Me4Si) δ 0.60 (t, J ) 7.3 Hz, 3H), 1.00 (t, J ) 7.4 Hz, 3H),
9
J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002 5065

A R T I C L E S
Takahashi et al.
1.18 (t, J ) 7.5 Hz, 3H), 1.30-1.36 (m, 5H), 1.54-1.60 (m, 2H), 2.14-
2.18 (m, 2H), 2.34-2.38 (m, 2H), 2.50 (q, J ) 7.5 Hz, 2H), 2.86 (q,
J ) 7.2 Hz, 2H), 6.66-6.67 (m, 2H), 6.74-6.78 (m, 1H), 6.90-7.07
(m, 7H); 13C NMR (CDCl3, Me4Si) δ 13.49, 14.20, 14.60, 14.88, 21.19,
22.47, 22.86, 24.93, 30.51, 32.17, 115.57, 118.00, 120.21, 127.05,
128.05, 128.32, 129.99, 130.75, 142.22, 143.48, 147.27, 150.79, 152.81;
IR (KBr) 2971, 2870, 1616, 1590, 1557, 1520, 1489, 692 cm-1. Anal.
Calcd for C27H34N2: C, 83.89; H, 8.87; N, 7.25. Found: C, 83.86; H,
8.80; N, 7.13.
1H); 13C NMR (CDCl3, Me4Si) δ -0.32, 14.01, 22.55, 25.94, 29.69,
30.15, 31.07, 31.64, 140.43, 157.03, 200.52; IR (neat) 2957, 2930, 2859,
1676, 1593, 1366, 1250, 1211, 1051, 853, 750, 693 cm-1; HRMS calcd
for C13H26OSi 226.1753, found 226.1757.
(2E)-2-Hexyl-1-(4-methylphenyl)-3-(trimethylsilyl)prop-2-en-1-
1
one (12e): isolated yield 76%; pale yellow liquid; H NMR (CDCl3,
Me4Si) δ 0.17 (s, 9H), 0.83 (t, J ) 7.0 Hz, 3H), 1.22-1.38 (m, 8H),
2.39 (s, 3H), 2.53 (t, J ) 7.3 Hz, 2H), 5.98 (s, 1H), 7.21 (d, J ) 8.0
Hz, 2H), 7.65 (d, J ) 8.0 Hz, 2H); 13C NMR (CDCl3, Me4Si) δ -0.11,
13.99, 21.59, 22.51, 29.23, 29.50, 31.61, 32.63, 128.83, 129.92, 134.99,
138.58, 142.90, 156.42, 198.99; IR (neat) 2957, 2928, 2859, 1657, 1607,
1408, 1337, 1248, 1177, 928, 860, 841, 760, 693 cm-1; HRMS calcd
for C19H31OSi 303.2144, found 303.2139.
General Procedure for Synthesis of Pyridines (11). To a solution
of zirconacyclopentadiene, prepared from Cp2ZrCl2 (292 mg, 1.0 mmol),
was added a nitrile (1.0 mmol) at room temperature, and the mixture
was stirred for 3 h at 50 °C. Then the reaction mixture was dried under
reduced pressure, and dissolved in THF (5 mL) again. To the solution
were added the second alkyne (2.5 mmol) and NiCl2(PPh3)2 (654 mg,
1.0 mmol) at room temperature, and the mixture was stirred for 12 h
at 50 °C. The reaction mixture was quenched by addition of saturated
aqueous NaHCO3 and extracted with EtOAc. Column chromatography
on silica gel afforded the title compounds.
1,5,6-Triphenyl-2-phenylimino-3,4-dipropyl-1,2-dihydropyri-
dine (9d): isolated yield 35%; yellow solid, mp 153-154 °C; 1H NMR
(CDCl3, Me4Si) δ 0.70 (t, J ) 6.9 Hz, 3H), 0.89 (t, J ) 6.9 Hz, 3H),
1.39 (m, 2H), 1.66 (m, 2H), 2.25 (t, J ) 7.5 Hz, 2H), 2.60 (t, J ) 7.3
Hz, 2H), 6.42-6.44 (m, 2H), 6.52-6.55 (m, 1H), 6.70-7.06 (m, 17H);
13C NMR (CDCl3, Me4Si) δ 14.45, 14.54, 22.15, 23.29, 30.48, 32.89,
118.70, 120.41, 120.82, 126.15, 126.24, 126.66, 127.30, 127.68, 127.99,
130.49, 130.66, 130.80, 131.38, 135.38, 138.12, 142.10, 144.10, 145.55,
149.83, 151.81; IR (KBr) 2961, 2870, 1618, 1603, 1591, 1520, 1485,
694 cm-1; HRMS calcd for C35H34N2 482.2722, found 482.2700.
1,3,4-Triphenyl-2-phenylimino-5,6-dipropyl-1,2-dihydropyri-
dine (9e): isolated yield 78%; orange solid, mp 199-200 °C; 1H NMR
(CDCl3, Me4Si) δ 0.68 (t, J ) 7.3 Hz, 3H), 0.73 (t, J ) 7.2 Hz, 3H),
1.30-1.36 (m, 2H), 1.48-1.54 (m, 2H), 2.18-2.22 (m, 2H), 2.35-
2.39 (m, 2H), 6.29-6.40 (m, 3H), 6.62-6.77 (m, 7H), 6.95-6.97 (m,
2H), 7.08-7.14 (m, 3H), 7.38-7.49 (m,5H); 13C NMR (CDCl3, Me4-
Si) δ 14.00, 22.36, 23.71, 31.13, 32.70, 119.01, 120.11, 120.50, 125.29,
126.25, 126.38, 126.90, 127.12, 128.01, 128.16, 128.37, 128.91, 128.99,
130.76, 135.41, 137.26, 140.30, 147.95, 150.53, 154.11; IR (KBr) 2963,
3-Butyl-2-ethyl-5-methyl-6-phenyl-4-(trimethylsilyl)pyridine
1
(11a): GC yield 77%; isolated yield 52%; yellow liquid; H NMR
(CDCl3, Me4Si) δ 0.45 (s, 9H), 0.98 (t, J ) 7.0 Hz, 3H), 1.29 (t, J )
7.5 Hz, 3H), 1.43-1.52 (m, 4H), 2.30 (s, 3H), 2.74-2.78 (m, 2H),
2.83 (q, J ) 7.5 Hz, 2H), 7.33 (tt, J ) 7.0, 1.6 Hz, 1H), 7.38-7.45
(m, 4H); 13C NMR (CDCl3, Me4Si) δ 3.74, 14.01, 14.55, 21.80, 23.11,
28.24, 31.68, 35.27, 127.25, 128.04, 129.24, 133.04, 139.46, 142.21,
147.76, 155.97, 157.74; IR (neat) 2961, 2932, 2872, 1719, 1535, 1460,
1385, 1254, 860, 843, 764, 700 cm-1; HRMS calcd for C21H31NSi
325.2226, found 325.2223.
2930, 2870, 1613, 1590, 1557, 1512, 1493, 1477, 1452, 752, 694 cm-1
HRMS calcd for C35H34N2 482.2722, found 482.2719.
;
General Procedure for Synthesis of r,â-Unsaturated Ketones
(12). To a solution of zirconacyclopentadiene, prepared from Cp2ZrCl2
(292 mg, 1.0 mmol), was added a nitrile (1.0 mmol) at room
temperature, and the mixture was stirred for 3 h at 50 °C. Then 3 N
HCl was added and the reaction mixture was stirred for 12 h at room
temperature. Column chromatography on silica gel afforded the
products.
(1E)-2-Butyl-1-(trimethylsilyl)pent-1-en-3-one (12a): isolated yield
91%; pale yellow liquid; 1H NMR (CDCl3, Me4Si) δ 0.16 (s, 9H), 0.87
(t, J ) 6.9 Hz, 3H), 1.06 (t, J ) 7.3 Hz, 3H), 1.24-1.33 (m, 4H), 2.32
(t, J ) 7.8 Hz, 2H), 2.68 (q, J ) 7.3 Hz, 2H), 6.49 (s, 1H,); 13C NMR
(CDCl3, Me4Si) δ -0.26, 8.65, 13.92, 23.10, 30.75, 31.14, 32.32,
138.41, 156.79, 203.41; IR (neat) 2959, 2938, 1678, 1460, 1379, 1250,
1175, 862, 839, 691 cm-1; HRMS calcd for C12H24OSi 212.1596, found
212.1596.
3-Butyl-5-ethyl-6-phenyl-2-propyl-4-(trimethylsilyl)pyridine (11b):
1
GC yield 75%; isolated yield 53%; yellow liquid; H NMR (CDCl3,
Me4Si) δ 0.44 (s, 9H), 0.81 (t, J ) 7.4 Hz, 3H), 0.98 (t, J ) 7.3 Hz,
3H), 0.99 (t, J ) 6.9 Hz, 3H), 1.42-1.49 (m, 4H), 1.72 (qt, J ) 7.4,
6.8 Hz, 2H), 2.71-2.79 (m, 6H), 7.32 (tt, J ) 7.4, 1.6 Hz, 1H), 7.37-
7.41 (m, 4H); 13C NMR (CDCl3, Me4Si) δ 4.13, 13.94, 14.38, 16.98,
23.14, 23.66, 25.18, 32.09, 35.03, 37.19, 127.08, 128.01, 129.00, 139.85,
140.08, 142.52, 146.71, 155.93, 156.50; IR (neat) 2961, 2932, 2872,
1534, 1466, 1383, 1254, 860, 843,762, 700 cm-1; HRMS calcd for
C23H35NSi 353.2539, found 353.2542.
2,2′-[3-Butyl-5-ethyl-6-phenyl-4-(trimethylsilyl)]bipyridine
(11c): GC yield 62%; isolated yield 49%; brown liquid; 1H NMR
(CDCl3, Me4Si) δ 0.49 (s, 9H), 0.66 (t, J ) 7.3 Hz, 3H), 0.86 (t, J )
7.4 Hz, 3H), 1.09-1.21 (m, 4H), 2.85 (q, J ) 7.4 Hz, 2H), 3.00 (t, J
) 8.2 Hz, 2H), 7.24 (ddd, J ) 7.7, 7.3, 1.8 Hz, 1H), 7.33 (d, J ) 7.2
Hz, 1H), 7.38 (dd, J ) 8.0, 7.7 Hz, 2H), 7.44 (d, J ) 7.7 Hz, 2H),
7.61 (d, J ) 8.0 Hz, 1H), 7.74 (ddd, J ) 7.7, 7.6, 1.8 Hz, 1H), 8.60 (d,
J ) 7.6 Hz, 1H); 13C NMR (CDCl3, Me4Si) δ 4.00, 13.58, 16.84, 22.61,
25.46, 31.32, 34.42, 122.20, 124.79, 127.24, 128.01, 129.08, 136.54,
141.18, 142.02, 142.60, 148.15, 148.39, 153.86, 155.90, 160.41; IR
(neat) 3058, 2961, 2930, 2872, 1588, 1568, 1470, 1379, 1254, 1071,
1049, 1026, 852, 762, 747, 702 cm-1; HRMS calcd for C25H32N2Si
388.2335, found 388.2346.
(1E)-2-Butyl-1-(trimethylsilyl)hex-1-en-3-one (12b): isolated yield
90%; pale yellow liquid; 1H NMR (CDCl3, Me4Si) δ 0.16 (s, 9H), 0.87
(t, J ) 7.1 Hz, 3H), 0.91 (t, J ) 7.4 Hz, 3H), 1.22-1.33 (m, 4H), 1.59
(tq, J ) 7.4, 7.3 Hz, 2H), 2.32 (t, J ) 7.3 Hz, 2H), 2.62 (t, J ) 7.4 Hz,
2H), 6.48 (s, 1H); 13C NMR (CDCl3, Me4Si) δ -0.25, 13.85, 13.93,
18.14, 23.10, 31.10, 32.29, 39.54, 138.52, 157.09, 203.00; IR (neat)
2959, 2936, 2874, 1676, 1593, 1461, 1379, 1250, 1172, 845, 754, 694
cm-1; HRMS calcd for C13H26OSi 226.1753, found 226.1746.
(2E)-2-Butyl-1-(2-pyridyl)-3-(trimethylsilyl)prop-2-en-1-one
1
(12c): isolated yield 85%; brown liquid; H NMR (CDCl3, Me4Si) δ
0.15 (s, 9H), 0.85 (t, J ) 7.1 Hz, 3H), 1.29-1.46 (m, 4H), 2.55 (t, J
) 7.0 Hz, 2H), 6.33 (s, 1H), 7.34 (ddd, J ) 7.3, 4.8, 1.5 Hz, 1H), 7.68
(ddd, J ) 7.9, 1.1, 1.1, Hz, 1H), 7.75 (ddd, J ) 7.8, 7.6, 1.6 Hz, 1H),
8.62 (ddd, J ) 4.9, 1.7, 1.1 Hz, 1H); 13C NMR (CDCl3, Me4Si) δ 0.28,
13.87, 18.34, 22.92, 31.73, 123.92, 125.31, 136.52, 144.25, 148.67,
155.29, 156.01, 196.55; IR (neat) 2959, 2932, 2874, 1665, 1584, 1468,
1433, 1250, 995, 860, 841, 752, 693 cm-1; HRMS calcd for C15H24-
OSi 262.1627, found 262.1633.
3-Ethyl-5-hexyl-6-methyl-2-phenyl-4-(trimethylsilyl)pyridine
1
(11d): GC yield 69%; isolated yield 59%; yellow liquid; H NMR
(CDCl3, Me4Si) δ 0.44 (s, 9H), 0.81 (t, J ) 7.4 Hz, 3H), 0.90 (t, J )
6.7 Hz, 3H), 1.31-1.34 (m, 4H), 1.42-1.46 (m, 4H), 2.54 (s, 3H),
2.73 (t, J ) 7.4 Hz, 2H), 2.76 (q, J ) 6.6 Hz, 2H), 7.32 (tt, J ) 8.3,
1.5 Hz, 1H), 7.37-7.40 (m, 4H); 13C NMR (CDCl3, Me4Si) δ 4.06,
14.05, 17.08, 22.65, 22.76, 25.14, 29.74, 31.47, 31.69, 33.01, 127.15,
128.07, 128.93, 140.17, 140.77, 142.33, 146.60, 152.79, 155.88; IR
(neat) 2957, 2928, 2827, 1468, 1445, 1383, 1254, 860, 843, 762, 700
cm-1; HRMS calcd for C25H35NSi 353.2539, found 353.2531.
(3E)-3-Hexyl-4-(trimethylsilyl)but-3-en-2-one (12d): isolated yield
87%; pale yellow liquid; 1H NMR (CDCl3, Me4Si) δ 0.16 (s, 9H), 0.84
(t, J ) 7.1 Hz, 3H), 1.23-1.38 (m, 8H), 2.28-2.31 (m, 5H), 6.53 (s,
9
5066 J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002

Preparation of Pyridines, Pyridones, and Iminopyridines
A R T I C L E S
3-Hexyl-5-methyl-2-(4-methylphenyl)-6-phenyl-4-(trimethylsilyl)-
pyridine (11e): GC yield 58%; isolated yield 45%; yellow liquid; H
14.20, 23.57, 24.36, 38.14, 121.66, 126.70, 127.05, 127.69, 127.81,
129.20, 130.59, 132.11, 138.32, 139.78, 149.35, 156.48, 159.93; IR
(KBr) 2957, 2901, 2870, 1586, 1541, 1499, 1462, 1439, 1381, 1358,
1201, 1074, 868, 771, 700 cm-1; HRMS calcd for C21H21N 287.1674,
found 287.1667.
1
NMR (CDCl3, Me4Si) δ 0.49 (s, 9H), 0.79 (t, J ) 7.1 Hz, 3H), 1.04-
1.16 (m, 6H), 1.23-1.33 (m, 2H), 2.36 (s, 3H,), 2.39 (s, 3H,), 2.78 (t,
J ) 8.0 Hz, 2H), 7.18 (d, J ) 7.9 Hz, 2H), 7.30-7.36 (m, 3H), 7.39
(d, J ) 7.8 Hz, 2H,), 7.47 (dd, J ) 7.9, 1.8 Hz, 2H); 13C NMR (CDCl3,
Me4Si) δ 3.62, 13.95, 21.21, 21.94, 22.28, 29.02, 31.22, 32.11, 32.67,
127.28, 127.94, 128.59, 128.98, 129.36, 134.51, 136.73, 139.24, 140.20,
141.88, 148.52, 155.74, 156.41; IR (neat) 3027, 2957, 2926, 2857, 1726,
A Typical Procedure for the Preparation of Trimethylsilyl-
Substituted Pyridines (15f,g). To a solution of Cp2ZrCl2 (365 mg,
1.25 mmol) in THF (5 mL) was added n-BuLi (2.5 mmol) at -78 °C.
After the mixture was stirred for 1 h at the same temperature
1-trimethylsilyl-1-hexyne (2.0 mmol) was added and the reaction
mixture was allowed to warm to room temperature for 1 h. Then a
nitrile (1.0 mmol) was added to the reaction mixture which was then
stirred at 50 °C for 1 h. After cooling to 0 °C propargyl bromide (1.5
mmol) and CuCl (1.0 mmol) were added to the reaction mixture which
was then stirred at 50 °C for 1 h. The reaction mixture was quenched
with saturated NaHCO3 and extracted with ether. The extract was
washed with water and brine and dried over MgSO4. The solvent was
evaporated in vacuo and the residue was purified by column chroma-
tography on silica gel.
1599, 1510, 1493, 1445, 1377, 1254, 1020, 856, 839, 766, 700 cm-1
HRMS calcd for C28H37NSi 415.2695, found 415. 2693.
;
A Typical Procedure for the Preparation of Alkyl-Aryl-
Substituted Pyridines (15a-e). To a solution of Cp2ZrCl2 (365 mg,
1.25 mmol) in THF (5 mL) was added EtMgBr (2.5 mmol) at -78 °C.
After the mixture was stirred for 1 h at the same temperature an alkyne
(1.0 mmol) was added and the reaction mixture was allowed to warm
to 0 °C for 3 h. Then a nitrile (1.0 mmol) was added to the reaction
mixture which was then stirred at 50 °C for 1 h. After cooling to 0 °C
propargyl bromide (1.5 mmol) and CuCl (1.0 mmol) were added to
the reaction mixture which was then stirred at 50 °C for 1 h. The
reaction mixture was quenched with saturated NaHCO3 and extracted
with ether. The extract was washed with water and brine and dried
over MgSO4. The solvent was evaporated in vacuo and the residue
was purified by column chromatography on silica gel.
3-Butyl-6-methyl-2-phenyl-4-(trimethylsilyl)pyridine (15f): GC
1
yield 54%; isolated yield 46%; orange liquid; H NMR (CDCl3, Me4-
Si) δ 0.36 (s, 9H), 0.63 (t, J ) 7.2 Hz, 3H), 1.06-1.20 (m, 4H), 2.54
(s, 3H), 2.65 (t, J ) 7.2 Hz, 2H), 7.18 (s, 3H), 7.33-7.41 (m, 5H); 13
C
NMR (CDCl3, Me4Si) δ 0.35, 13.48, 22.78, 24.17, 32.39, 33.51, 127.38,
127.77, 128.10, 128.82, 137.69, 141.85, 149.20, 153.72, 158.44; IR
(neat) 2957, 2930, 2874, 1570, 1524, 1495, 1460, 1447, 1416, 1368,
1298, 1252, 1092, 918, 855, 839, 754, 700 cm-1; HRMS calcd for
C19H27N 297.1913, found 297.1894.
2-(4-tert-Butylphenyl)-6-methyl-3,4-dipropylpyridine (15a): GC
1
yield 93%; isolated yield 81%; orange liquid; H NMR (CDCl3, Me4-
Si) δ 0.78 (t, J ) 7.5 Hz, 3H), 1.00 (t, J ) 7.5 Hz, 3H), 1.34-1.46 (m,
11H), 1.63 (q, J ) 7.5 Hz, 2H), 2.50-2.62 (m, 7H), 6.93 (s, 1H), 7.30
(d, J ) 8.1 Hz, 2H), 7.40 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3,
Me4Si) δ 14.31, 14.39, 23.81, 24.18, 24.31, 30.63, 31.38, 34.33, 34.53,
122.39, 124.95, 128.32, 130.87, 139.06, 150.03, 150.33, 154.45, 159.15;
IR (neat) 2961, 2934, 2872, 1591, 1553, 1466, 1433, 1399, 1379, 1364,
1267, 1109, 1020, 839 cm-1; HRMS calcd for C22H30N 308.2378, found
308.2354.
3,4-Diethyl-6-methyl-2-phenylpyridine (15b): GC yield 98%;
isolated yield 77%; orange liquid; 1H NMR (CDCl3, Me4Si) δ 0.96 (t,
J ) 7.5 Hz, 3H), 1.25 (t, J ) 7.5 Hz, 3H), 2.52-2.61 (m, 5H), 2.65
(q, J ) 7.5 Hz, 2H), 6.98 (s, 1H), 7.32-7.40 (m, 5H); 13C NMR (CDCl3,
Me4Si) δ 14.65, 15.20, 21.45, 24.21, 25.02, 121.98, 127.37, 128.08,
128.68, 132.01, 141.92, 151.69, 154.75, 158.90; IR (neat) 2969, 2934,
2876, 1591, 1555, 1497, 1464, 1449, 1429, 1387, 1339, 1055, 1028,
872, 764, 700 cm-1; HRMS calcd for C16H18N 224.1439, found
224.1443.
2-Ethyl-6-methyl-3,4-dipropylpyridine (15c): GC yield 57%;
isolated yield 43%; orange liquid; 1H NMR (CDCl3, Me4Si) δ 0.97 (t,
J ) 7.5 Hz, 3H), 1.00 (t, J ) 7.5 Hz, 3H), 1.24 (t, J ) 7.5 Hz, 3H),
1.43-1.67 (m, 4H), 2.45 (s, 3H), 2.49-2.59 (m, 4H), 2.75 (q, J ) 7.5
Hz, 2H), 6.77 (s, 1H); 13C NMR (CDCl3, Me4Si) δ 14.26, 14.64, 14.70,
23.78, 24.07, 24.34, 28.50, 30.00, 34.44, 121.42, 130.14, 149.79, 154.42,
160.89; IR (neat) 2961, 2934, 2874, 1593, 1559, 1456, 1379, 1256,
1233, 1090, 1051, 949, 845 cm-1; HRMS calcd for C14H23N 205.1830,
found 205.1820.
3-Butyl-6-methyl-2-propyl-4-(trimethylsilyl)pyridine (15g): GC
1
yield 34%; isolated yield 27%; orange liquid; H NMR (CDCl3, Me4-
Si) δ 0.32 (s, 9H), 0.95-1.04 (m, 6H), 1.43-1.49 (m, 4H), 1.68-1.76
(m, 2H), 2.47 (s, 3H), 2.63-2.75 (m, 4H), 7.01 (s, 1H); 13C NMR
(CDCl3, Me4Si) δ 0.31, 13.90, 14.46, 23.33, 23.87, 24.13, 32.60, 34.29,
37.01, 126.41, 137.29, 148.33, 153.75, 159.05; IR (neat) 2959, 2934,
2874, 1574, 1530, 1433, 1373, 1252, 1148, 1084, 860, 839, 756, 689
cm-1; HRMS calcd for C16H29NSi 263.2069, found 263.2076.
2-Ethyl-6-methyl-3-phenyl-4-(triethylsilyl)pyridine (15h). To a
solution of Cp2ZrCl2 (365 mg, 1.25 mmol) in THF (5 mL) was added
n-BuLi (2.5 mmol) at -78 °C. After the mixture was stirred for 1 h at
the same temperature triethylsilylphenylethyne (1.0 mmol) was added
and the reaction mixture was allowed to warm to room temperature
for 3 h. Then propionitrile (1.0 mmol) was added to the reaction mixture
which was then stirred at room temperature for 3 h. After cooling to 0
°C propargyl bromide (1.5 mmol) and CuCl (1.0 mmol) were added to
the reaction mixture which was then stirred at 50 °C for 3 h. The
reaction mixture was quenched with saturated NaHCO3 and extracted
with ether. The extract was washed with water and brine and dried
over MgSO4. The solvent was evaporated in vacuo and column
chromatography on silica gel afforded 253 mg (81%) of the product
as an orange solid (GC yield 94%): mp 60 °C; 1H NMR (CDCl3, Me4-
Si) δ 0.43 (q, J ) 7.8 Hz, 6H), 0.76 (t, J ) 7.8 Hz, 9H), 1.32 (t, J )
7.5 Hz, 3H), 2.51(s, 3H), 2.92 (q, J ) 7.5 Hz, 2H), 6.77 (s, 1H), 7.20-
7.23 (m, 2H), 7.32-7.36 (m, 3H); 13C NMR (CDCl3, Me4Si) δ 5.39,
8.04, 15.26, 24.13, 32.37, 122.09, 124.10, 127.64, 127.70, 128.90,
143.81, 156.76, 159.10, 168.96; IR (neat) 2957, 2874, 1574, 1520, 1493,
1466, 1441, 1375, 1350, 1073, 1001, 880, 768, 733, 700 cm-1; HRMS
calcd for C20H29NSi 311.2069, found 311.2059.
2-(4-tert-Butylphenyl)-6-methyl-3,4-diphenylpyridine (15d): GC
1
yield 73%; isolated yield 50%; orange solid, mp 159 °C; H NMR
(CDCl3, Me4Si) δ 1.24 (s, 9H), 2.67 (s, 3H), 6.85-6.88 (m, 2H), 7.01-
7.07 (m, 5H), 7.18-7.19 (m, 8H); 13C NMR (CDCl3, Me4Si) δ 24.45,
31.25, 34.42, 122.97, 124.56, 126.29, 127.13, 127.54, 127.78, 129.29,
129.48, 131.38, 131.52, 138.00, 138.05, 139.80, 149.92, 149.99, 156.81,
157.78; IR (KBr) 2963, 2867, 1584, 1537, 1474, 1429, 1364, 1271,
1113, 841, 770, 700 cm-1; HRMS calcd for C28H26N 376.2065, found
376.2057.
6-Methyl-3,4-diphenyl-2-propylpyridine (15e): GC yield 66%;
isolated yield 57%; orange solid, mp 67 °C; 1H NMR (CDCl3, Me4Si)
δ 0.79 (t, J ) 7.2 Hz, 3H), 1.55-1.68 (m, 2H), 2.60-2.65 (m, 5H),
7.01-7.04 (m, 5H), 7.12-7.25 (m, 6H); 13C NMR (CDCl3, Me4Si) δ
Supporting Information Available: Crystallographic data,
positional and thermal parameters, and lists of bond lengths and
angles for 9a (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JA017507+
9
J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002 5067