Preparation of Highly Substituted Pyridines
bridge.5 Oxazoles were considered, but when reactions
are carried out with these substrates, the fragmentation
of the oxa-bridge can prove problematic.5 Similarly,
pyrimidines are capable of serving as pyridine precursors,
but in this case the mode of cycloaddition (C-2/C-5 vs C-4/
N-1) and the observed regioselectivity are dependent
upon the dienophile employed, as well as the substitution
pattern of the parent pyrimidine.5
SCHEME 1
With 1,2,4-triazines 1, addition across C-3/C-6 is nearly
always favored.6-9 One of the most popular versions of
this reaction utilizes enamines 2 as dienophiles in an
inverse-electron-demand Diels-Alder reaction, followed
by in situ loss of nitrogen from 3 and subsequent
elimination/aromatization (Scheme 1).6,8,9 This classical
methodology, widely used, had two main limitations,
namely, the requirement for a preformed enamine and
the unusual stability of the intermediate 4, especially
when using enamines derived from cyclohexanones.6,8
Boger et al. circumvented these difficulties for 1,2,4-
triazine and 3-substituted-1,2,4-triazines by the addition
of 4A molecular sieves, which allowed in situ enamine
formation and catalyzed the elimination step, forming
pyridine 5 from dihydropyridine 4, although yields
remained low (19-66%).9
However, when we tried to apply the methodology
developed by Boger et al. to disubstituted 1,2,4-triazines
(e.g., 1a,10 Scheme 2), we found that although the DA/
retro-DA sequence proceeded smoothly, in situ aromati-
zation was not observed and the dihydropyridine inter-
mediate (e.g., 4a) was isolated in excellent yield. Aromati-
zation of 4a to 5a was accomplished in a separate step
via Cope elimination8i of the corresponding N-oxide
intermediate (Scheme 2).
(4) (a) Robinson, R. S.; Taylor, R. J. K. Synlett 2005, 1003-1005.
(b) Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K. Org. Biomol. Chem. 2004,
2, 788-796. (c) Raw, S. A.; Taylor, R. J. K. J. Am. Chem. Soc. 2004,
126, 12260-12261. (d) Raw, S. A.; Taylor, R. J. K. Tetrahedron Lett.
2004, 45, 8607-8610. (e) McManus, J. C.; Carey, J. S.; Taylor, R. J.
K. Synlett 2003, 365-368. (f) McManus, J. C.; Genski, T.; Carey, J.
S.; Taylor, R. J. K. Synlett 2003, 369-371. (g) Raw, S. A.; Wilfred, C.
D.; Taylor, R. J. K. Chem. Commun. 2003, 2286-2287.
SCHEME 2
(5) For reviews covering the cycloaddition reactions of heterocyclic
azadienes, see: (a) Boger, D. L.; Weinreb, S. N. Hetero Diels-Alder
Methodology in Organic Synthesis; Academic Press: London, 1987;
Chapter 10, pp 300-358. (b) Boger, D. L. Chem. Rev. 1986, 86, 781-
793. (c) Boger, D. L. Tetrahedron 1983, 39, 2869-2939. For recent
reviews covering the cycloaddition reactions of nonheterocyclic aza-
dienes, see: (d) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P.
Tetrahedron 2002, 58, 379-471. (e) Buonora, P.; Olsen, J.-C.; Oh, T.
Tetrahedron 2001, 57, 6099-6138. (f) Behforouz, M.; Ahmadian, M.
Tetrahedron 2000, 56, 5259-5288.
(6) For reviews covering the cycloaddition reactions of 1,2,4-triaz-
ines, see ref 5a-c. (a) Nicolaou, K. C.; Snyder, S. A. Classics in Total
Synthesis II; Wiley-VCH: Weinheim, 2003; Chapter 2, pp 15-30. (b)
Neunhoeffer, H. Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996;
Vol. 6, Chapter 6.11, pp 507-573. (c) Neunhoeffer, H. Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Perga-
mon: Oxford, 1984; Vol. 3, Chapter 2.19, pp 385-456.
(7) For recent reports on cycloaddition reactions of 1,2,4-triazines
not involving enamines, see: (a) Lahue, B. R.; Lo, S.-M.; Wan, Z.-K.;
Woo, G.-H.; Snyder, J. K. J. Org. Chem. 2004, 69, 7171-7182. (b)
Lahue, B. R.; Wan, Z.-K.; Snyder, J. K. J. Org. Chem. 2003, 68, 4345-
4354. (c) Ibrahim, Y. A.; Al-Saleh, B.; Mahmoud, A. A. A. Tetrahedron
2003, 59, 8489-8498. (d) Lindsley, C. W.; Wisnoski, D. D.; Wang, Y.;
Leister, W. H.; Zhao, Z.; Tetrahedron Lett. 2003, 44, 4495-4498. (e)
Stanforth, S. P.; Tarbit, B.; Watson, M. D. Tetrahedron Lett. 2002, 43,
6015-6017. (f) Sauer, J.; Heldmann, D. K.; Pabst, G. R. Eur. J. Org.
Chem. 1999, 313-321.
(8) (a) Kozhevnikov, V. N.; Kozhevnikov, D. N.; Shabunina, O. V.;
Rusinov, V. L.; Chupakhin, O. L.; Tetrahedron Lett. 2005, 46, 1791-
1793. (b) Kozhevnikov, V. N.; Kozhevnikov, D. N.; Shabunina, O. V.;
Rusinov, V. L.; Chupakhin, O. L.; Tetrahedron Lett. 2005, 46, 1521-
1523. (c) Branowska, D. Molecules 2005, 10, 265-273. (d) Branowska,
D. Tetrahedron 2004, 60, 6021-6027. (e) Branowska, D. Synthesis
2003, 2096-2100. (f) Kozhevnikov, V. N.; Kozhevnikov, D. N.; Nikitina,
T. V.; Rusinov, V. L.; Chupakhin, O. L.; Zabel, M.; Ko¨nig, B. J. Org.
Chem. 2003, 68, 2882-2888. (g) Rykowski, A.; Branowska, D.; Kielak,
J. Tetrahedron Lett. 2000, 41, 3657-3659. (h) Taylor, E. C.; Macor, J.
E. J. Org. Chem., 1989, 54, 1249-1256. (i) Chenard, B. L.; Ronau, R.
T.; Schulte, G. A. J. Org. Chem. 1988, 53, 5175-5177. (j) Taylor, E.
C.; Macor, J. E. Tetrahedron Lett. 1985, 26, 2415-2418.
Ideally, we required a procedure that could be utilized
to prepare these more substituted pyridines without the
need to employ a discrete aromatization step (particularly
one requiring the use of a peracid). This paper describes
two complementary procedures for the “one-pot” synthe-
sis of highly substituted pyridines, one employing mi-
crowave irradiation as the key technological advance, and
the second approach based on tethered imine-enamine
(TIE) methodology.11
Results and Discussion
Highly Substituted Pyridines via Solvent-Free
Microwave Synthesis. The present investigation com-
menced with the search for improved reaction conditions
for the direct synthesis of highly substituted pyridines
from 1,2,4-triazines 1. In certain published examples
higher temperatures (and the addition of carboxylic acids)
have been shown to facilitate elimination to give pyri-
dines,8e,9c and so we first investigated if this would solve
the problematic elimination step en route to highly
substituted pyridines. We therefore took 5,6-difuran-2-
(9) (a) Boger, D. L.; Panek, J. S. J. Am. Chem. Soc. 1985, 107, 5745-
5754. (b) Boger, D. L.; Panek, J. S.; Meier, M. M. J. Org. Chem. 1982,
47, 895-897. (c) Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46,
2179-2182.
(10) O’Rourke, M.; Lang, S. A.; Cohen, E. J. Med. Chem. 1977, 20,
723-726.
(11) Raw, S. A.; Taylor, R. J. K. Chem. Commun., 2004, 508-509.
J. Org. Chem, Vol. 70, No. 24, 2005 10087