A concise route to pyridines from hydrazides by metal carbene N-H insertion, 1,2,4-triazine formation, and Diels-Alder reaction

Article abstract of DOI:10.1021/ol901502u

Image Presented A simple, new three-step sequence for the conversion of hydrazides into pyridines is reported in which the key steps are N-H insertion by a copper carbene intermediate derived from r-diazo-β-ketoesters into the hydrazide, reaction with amm

Full text of DOI:10.1021/ol901502u

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3686-3688
A Concise Route to Pyridines from
Hydrazides by Metal Carbene N-H
Insertion, 1,2,4-Triazine Formation, and
Diels-Alder Reaction
Baolu Shi,† William Lewis,† Ian B. Campbell,‡ and Christopher J. Moody*,†
School of Chemistry, UniVersity of Nottingham, UniVersity Park, Nottingham NG7
2RD, U.K., and GlaxoSmithKline, Gunnels Wood Road, SteVenage SG1 2NY, U.K.
c.j.moody@nottingham.ac.uk
Received July 1, 2009
ABSTRACT
A simple, new three-step sequence for the conversion of hydrazides into pyridines is reported in which the key steps are N-H insertion by
a copper carbene intermediate derived from r-diazo-ꢀ-ketoesters into the hydrazide, reaction with ammonium acetate to give 1,2,4-triazines,
followed by Diels-Alder reaction with norbornadiene.
1,2,4-Triazines are a well-known class of nitrogen hetero-
cycles with a range of applications,1 particularly in the
pharmaceutical arena where they can be regarded as azapy-
rimidines, and hence have given rise to a large number of
aza- nucleotides and -nucleosides.2,3 From a chemical
perspective, one of the most useful properties of 1,2,4-
triazines is their ability to act as 2-azadienes in the hetero-
Diels-Alder reaction.4-6 This reaction, which is usually an
inverse electron demand Diels-Alder reaction, results in
addition of an electron-rich dienophile across C3-C6 of the
triazine to give, after extrusion of nitrogen from the initial
adduct, pyridines in synthetically useful yields.7-12 We now
report a new route to 1,2,4-triazines based on the N-H
insertion reactions of carbene intermediates into hydrazides.
One of the most useful synthetic methodologies to emerge
in the past two decades involves the transition-metal-
catalyzed reactions of diazocarbonyl compounds.13,14 Our
own contributions have focused on the synthesis of nitrogen
heterocycles using carbene N-H insertion reactions as key
steps. Thus we previously reported the rhodium carbene
(7) For recent examples, see refs 7-12; Stanforth, S. P.; Tarbit, B.;
Watson, M. D. Tetrahedron Lett. 2002, 43, 6015
.
(8) Stanforth, S. P.; Tarbit, B.; Watson, M. D. Tetrahedron 2004, 60,
8893
.
† University of Nottingham.
(9) Raw, S. A.; Taylor, R. J. K. J. Chem. Soc., Chem. Commun. 2004,
‡ GlaxoSmithKline.
508
.
(1) Neunhoeffer, H. In ComprehensiVe Heterocyclic Chemistry II;
Boulton, A. J., Ed.; Pergamon: Oxford. 1996; Vol. 6, p 507.
(10) Raw, S. A.; Taylor, R. J. K. J. Am. Chem. Soc. 2004, 126, 12260
(11) Sainz, Y. F.; Raw, S. A.; Taylor, R. J. K. J. Org. Chem. 2005, 70,
10086
.
(2) Seela, F.; He, Y. J. Org. Chem. 2003, 68, 367
.
.
(3) Seela, F.; Chittepu, P. J. Org. Chem. 2007, 72, 4358
(4) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in
Organic Synthesis; Academic Press: San Diego, 1987; Vol. 47
(5) Barluenga, J.; Tomas, M. AdV. Heterocycl. Chem. 1993, 57, 1
(6) Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1
.
(12) Catozzi, N.; Wasnaire, P.; Taylor, R. J. K. Tetrahedron Lett. 2008,
49, 2865
.
.
(13) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
.
for Organic Synthesis with Diazo Compounds; John Wiley: New York, 1998
.
.
(14) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577
.
10.1021/ol901502u CCC: $40.75
Published on Web 07/29/2009
 2009 American Chemical Society

now report the realization of this second strategy, which
when followed by a Diels-Alder reaction with norborna-
diene constitutes a new, simple three-step route from
hydrazides to pyridines.
Scheme 1
.
Possible Carbene N-H Insertion Routes to
1,2,4-Triazines
Scheme 2. Conversion of Hydrazides into 1,2,4-Triazines 5 and
Subsequent Diels-Alder Reaction with Norbornadiene To Give
Pyridines 6
insertion reaction into the N-H bond of N-alkylanilines as
a key step in a modified Bischler synthesis of indoles,15,16
while subsequently Janda and co-workers have developed a
solid-phase variant of this reaction.17 Similarly we have
shown that a range of carboxamides undergo dirhodium(II)-
catalyzed reaction with R-diazo-ꢀ-ketoesters to give 1,4-
dicarbonyl compounds, readily converted into oxazoles or
thiazoles by dehydration or thionation, respectively.18,19 The
reaction has subsequently been applied in the synthesis of
the oxazole building blocks of a range of natural prod-
ucts,20-29 and also has been adapted to solid phase.30,31
Therefore we were attracted to the idea of using carbene
N-H insertion as a simple route to 1,2,4-triazines. Two
routes were considered, both starting from a readily available
R-diazo-ꢀ-ketoester 1 (Scheme 1). The first involves the
familiar insertion into a carboxamide N-H followed by
reaction of the product 2 with hydrazine and aromatization
to give the 1,2,4-triazine-5-carboxylate 3, whereas the second
uses hydrazides as the N-H insertion partner, followed by
reaction of the intermediate 4 with ammonia and aromati-
zation leading to the isomeric triazine-6-carboxylate 5. We
Figure 1. X-ray crystal structure of methyl 5-methyl-3-phenyl-1,2,4-
triazine-6-carboxylate 5a.
Although a range of N-H compounds (amines, anilines,
amides, carbamates, ureas) have been reported to participate
in carbene N-H insertion reactions, as far as we are aware
there have been no accounts describing such reactions with
hydrazides. Using benzhydrazide as a model substrate with
methyl 2-diazo-3-oxobutanoate as the diazocarbonyl com-
ponent, we quickly established that copper(II) acetate was
the catalyst of choice and that the reaction was most
conveniently carried out in a microwave reactor. The product
was then treated with ammonium acetate in acetic acid to
give after chromatography the 1,2,4-triazine 5a in modest
yield. The nature of the intermediate in this process remains
unknown, although we speculate that the initial product of
N-H insertion (compound 4 in Scheme 1) is readily oxidized
in the presence of copper(II) and air, and it is the resulting
azo compound (or more likely its hydrazone tautomer) that
subsequently reacts with ammonia to give the aromatic
triazine 5a directly. Indeed treatment of related acylhydra-
zones with ammonium acetate is known to give 1,2,4-
triazines.32,33 Alternatively, the product of N-H insertion
(1,5-dicarbonyl compound 4) condenses with ammonia, and
(15) Moody, C. J.; Swann, E. Synlett 1998, 135
(16) Bashford, K. E.; Cooper, A. L.; Kane, P. D.; Moody, C. J.;
Muthusamy, S.; Swann, E. J. Chem. Soc., Perkin Trans. 1 2002, 1672
.
.
(17) Lee, S. H.; Clapham, B.; Koch, G.; Zimmermann, J.; Janda, K. D.
J. Comb. Chem. 2003, 5, 188.
(18) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J. J. Chem.
Soc., Perkin Trans. 1 1998, 591
.
(19) Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60,
3967
.
(20) Moody, C. J.; Bagley, M. C. J. Chem. Soc., Perkin Trans. 1 1998,
601
.
(21) Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J. Org.
Chem. 2005, 70, 5840
.
(22) Bagley, M. C.; Hind, S. L.; Moody, C. J. Tetrahedron Lett. 2000,
41, 6897
.
(23) Bagley, M. C.; Moody, C. J.; Pepper, A. G. Tetrahedron Lett. 2000,
41, 6901
.
(24) Davies, J. R.; Kane, P. D.; Moody, C. J. J. Org. Chem. 2005, 70,
7305
.
(25) Palmer, F. N.; Lach, F.; Poriel, C.; Pepper, A. G.; Bagley, M. C.;
Slawin, A. M. Z.; Moody, C. J. Org. Biomol. Chem. 2005, 3, 3805
(26) Lachia, M.; Moody, C. J. Nat. Prod. Rep 2008, 25, 227
(27) Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.; Moody, C. J. J. Am.
Chem. Soc. 2000, 122, 3301
(28) Hughes, R. A.; Thompson, S. P.; Alcaraz, L.; Moody, C. J. J. Am.
Chem. Soc. 2005, 127, 15644
.
.
.
.
(29) Linder, J.; Blake, A. J.; Moody, C. J. Org. Biomol. Chem. 2008, 6,
3908
.
(30) Clapham, B.; Spanka, C.; Janda, K. D. Org. Lett. 2001, 3, 2173
(31) Clapham, B.; Lee, S. H.; Koch, G.; Zimmermann, J.; Janda, K. D.
.
(32) Konno, S.; Sagi, M.; Takaharu, E.; Fujimura, S.; Hayashi, K.;
Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 1721
.
Tetrahedron Lett. 2002, 43, 5407
Org. Lett., Vol. 11, No. 16, 2009
.
(33) Ohsumi, T.; Neunhoeffer, H. Tetrahedron 1992, 48, 651.
3687

in boiling chlorobenzene for several hours and gave the
pyridines 6 in modest to excellent yield (Table 1).
Table 1. Conversion of Hydrazides into 1,2,4-Triazines 5 and
Subsequent Diels-Alder Reaction with Norbornadiene To Give
Pyridines 6
In conclusion, we have developed a new, simple route to
pyridines from readily available hydrazides by way of 1,2,4-
triazines. This three-step process illustrates the power and
versatility of transition-metal mediated carbene N-H inser-
tion reactions in organic synthesis, and in particular the
synthesis of important heterocyclic compounds.
R1
R2
5
yield (%)
6
yield (%)
Ph
Me
Me
Me
Me
Me
Me
Me
4-FC6H4
5a
5b
5c
5d
5e
5f
43
35
43
32
38
38
28
58
6a
6b
6c
6d
6e
6f
91
40
52
80
87
45
90
94
2-MeC6H4
4-MeOC6H4
4-NO2C6H4
4-BrC6H4
2-Furyl
Acknowledgment. We thank the EPSRC and Glaxo-
SmithKline for support of this work under the Array
Chemistry Programme.
4-Pyridyl
Ph
5g
5h
6g
6h
Supporting Information Available: Full experimental
details, copies of 1H and 13C NMR spectra of compounds 5
and 6, and cif file for X-ray crystal structure of compound
5a. This material is available free of charge via the Internet
at http://pubs.acs.org.
the resulting dihydrotriazine is readily oxidized/aromatized
in air.
The structure of triazine 5a was confirmed by X-ray
crystallography (Figure 1), and subsequently a range of
substituted benzhydrazides were converted into 1,2,4-triaz-
ines 5b-5h (Table 1). With a range of 1,2,4-triazines in
hand, their conversion into pyridines by a hetero-Diels-Alder
reaction was investigated using norbornadiene as an ethyne
equivalent as the dienophile.7,8,34-36 The reaction was carried
out by heating the triazine 5 with an excess of norbornadiene
OL901502U
(34) For other examples of use of norbornadiene, see refs 34-36;
Barlow, M. G.; Haszeldine, R. N.; Simpkin, D. J. J. Chem. Soc., Chem.
Commun. 1979, 658.
(35) Pabst, G. R.; Sauer, J. Tetrahedron Lett. 1998, 39, 6687.
(36) Altuna-Urquijo, M.; Gehre, A.; Stanforth, S. P.; Tarbit, B. Tetra-
hedron 2009, 65, 975.
3688
Org. Lett., Vol. 11, No. 16, 2009