The preparation of 1,2,4-triazines from α,β-diketo-ester equivalents and their application in pyridine synthesis

Article abstract of DOI:10.1016/j.tetlet.2005.06.163

The α-Chloro-α-acetoxy-β-keto-esters were prepared from β-keto-esters in good overall yields. These compounds reacted as α,β-diketo-ester equivalents with amidrazones yielding triazines, generally in good yields, or with an amidrazone and 2,5-norbornadien

Full text of DOI:10.1016/j.tetlet.2005.06.163

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6111–6113
The preparation of 1,2,4-triazines from a,b-diketo-ester
equivalents and their application in pyridine synthesis
Marta Altuna-Urquijo,a Stephen P. Stanfortha,* and Brian Tarbitb
aSchool of Applied Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, UK
bSeal Sands Chemicals Ltd., Seal Sands Road, Seal Sands, Middlesbrough TS2 1UB, UK
Received 12 May 2005; revised 23 June 2005; accepted 29 June 2005
Available online 20 July 2005
Abstract—The a-Chloro-a-acetoxy-b-keto-esters were prepared from b-keto-esters in good overall yields. These compounds reacted
as a,b-diketo-ester equivalents with amidrazones yielding triazines, generally in good yields, or with an amidrazone and 2,5-norbor-
nadiene in a one-pot aza Diels–Alder reaction to give the corresponding pyridines.
Ó 2005 Elsevier Ltd. All rights reserved.
Pyridine derivatives occupy a central position in modern
heterocyclic chemistry and consequently new and
efficient methods for the preparation of this important
heterocyclic ring system are of contemporary interest.1
The aza Diels–Alder reaction has become an important
and versatile method for the preparation of pyridine
derivatives and several recent reviews have discussed
the scope and application of this useful reaction.2
1,2,4-Triazines3 have been used as 2-azadiene equiva-
lents on many occasions and these heterocycles have
been reacted with suitable acetylene equivalents, includ-
ing 2,5-norbornadiene,4 yielding pyridine derivatives.
We have recently described the Ôone-potÕ reaction of
amidrazones 1 (R1 = CO2Et or 2-pyridyl) with the a,b-
diketo-ester derivatives 2 (R2 = Ph, n-Pr or i-Pr) in the
presence of 2,5-norbornadiene 5 in ethanol at reflux
yielding the appropriate pyridine derivatives 4 in good
overall yield without isolation of the 1,2,4-triazine inter-
mediates 3 (Scheme 1).5
The a,b-diketo-esters 2 were prepared from commer-
cially available b-keto-esters (R2COCH2CO2Et) by a
diazo-transfer reaction giving the corresponding diazo-
compounds [R2COC(N2)CO2Et] and subsequent
t
treatment of these with BuOCl.6 Although these a,b-
di-keto-esters 2 are hydrated at the a-carbonyl group,
they have been depicted in their keto form for simplicity.
From a manufacturing perspective the large scale use of
these diazo-compounds would not be attractive and
their replacement by other a,b-diketo-ester equivalents
would be highly desirable. a,b-Diketo-esters are also
commonly prepared by ozonolysis of phosphorane pre-
cursors [R2COC(@PPh3)CO2Et] and this subject has
recently been reviewed by Wassermann and Parr.7 This
NH2
NH2
O
O
CO2Et
R2
CO2Et
R2
N
CO2Et
R2
N
EtOH, reflux
EtOH, reflux
N
R1
R1
N
R1
N
4
1
2
3
5
Scheme 1.
Keywords: 1,2,4-Triazines; a,b-Diketo-esters; Aza Diels–Alder reaction.
*
Corresponding author. Tel.: +44 191 2274784; fax: +44 191 2273519; e-mail: steven.stanforth@unn.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.163

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M. Altuna-Urquijo et al. / Tetrahedron Letters 46 (2005) 6111–6113
AcO
Cl
CO2Et
R2
CO2Et
R2
CO2Et
R2
CO2Et
R2
Cl
AcO
O
(i)
(ii)
(iii)
O
O
O
9a R2 = Ph
6a R2 = Ph
7a R2 = Ph
8a R2 = Ph
8b R2 = n-Pr
9b R2 = n-Pr
6b R2 = n-Pr
7b R2 = n-Pr
Scheme 2. Reagents and conditions: (i) SO2Cl2, CH2Cl2, rt; (ii) Et3N, AcOH, DMF, rt; (iii) SO2Cl2, CH2Cl2, rt.
method of preparing a,b-diketo-esters would generate
large quantities of triphenylphosphine oxide as a
by-product which would not be desirable on a manufac-
turing scale.
the corresponding bipyridyls 4 were formed in moderate
yield (50% and 63%, respectively), being identical with
the compounds described previously.5c
In conclusion, we have prepared the a,b-diketo-ester
equivalents 9a and b and shown that these compounds
react with amidrazones giving 1,2,4-triazines 3 in good
yields.
As a continuation of our previous studies,5 we have been
interested in preparing triazines 3 as substrates for aza
Diels–Alder reactions. In view of the limitations
described above, we have prepared the a-chloro-a-acet-
oxy-b-keto-ester derivatives 9a and b as representative
examples of a,b-diketo-ester equivalents (Scheme 2).
Thus, the a-chloro-b-keto-esters 7a and b were prepared
by chlorination of the b-keto-esters 6a and b with sulfur-
yl chloride8 and then treatment of products 7a and b
with a mixture of acetic acid and triethylamine in
dimethylformamide at room temperature yielded the
acetates 8a (95%) and 8b (90%), reported previously9,10
by treatment of 6a and b, respectively, with lead tetra-
acetate. Chlorination of these acetates 8a and b using
sulfuryl chloride gave the novel compounds 9a (77%)
and 9b (98%) as oils that did not require further
purification.11
Acknowledgement
We thank Seal Sands Chemicals Ltd. for generous finan-
cial support and the EPSRC mass spectrometry service
for high resolution mass spectra.
References and notes
1. (a) Bagley, M. C.; Dale, J. W.; Hughes, D. D.; Ohnesorge,
M.; Phillips, N. G.; Bower, J. Synlett 2001, 1523–1526; (b)
Bagley, M. C.; Dale, J. W.; Bower, J. Chem. Commun.
2002, 1682–1683; (c) Bagley, M. C.; Lunn, R.; Xiong, X.
Tetrahedron Lett. 2002, 43, 8331–8334; (d) Bagley, M. C.;
Hughes, D. D.; Sabo, H. M.; Taylor, P. H.; Xiong, X.
Synlett 2003, 1443–1446; (e) Henry, G. D. Tetrahedron
2004, 60, 6043–6061 (review article); (f) Cave, G. W. V.;
Raston, C. L. Tetrahedron Lett. 2005, 46, 2361–2363; (g)
Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102, 3129–
3170.
2. (a) Behforouz, M.; Ahmadian, M. Tetrahedron 2000, 56,
5259–5288; (b) Buonora, P.; Olsen, J.-C.; Oh, T. Tetra-
hedron 2001, 57, 6099–6138; (c) Jayakumar, S.; Ishar, M.
P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379–471; (d)
Boger, D. L. Tetrahedron 1983, 39, 2869–2939.
Compounds 9a and b were reacted in boiling ethanol
solution with a range of amidrazones 1 giving the corre-
sponding 1,2,4-triazine derivatives 3 (Table 1).12 The
best yields were obtained with 2equiv of the amidraz-
one. The work-up for this reaction was straightforward;
the solvent was evaporated and the residue was taken
up into dichloromethane, washed with water and, after
drying and evaporating the organic layer, almost pure
tri- azines were produced as indicated by 1H NMR
spectroscopy.
Additionally, when compounds 9a and b were reacted
with 2equiv of the amidrazone 1 (R1 = 2-pyridyl) and
an excess of 2,5-norbornadiene 5 in ethanol at reflux
3. Neunhoeffer, H. In Comprehensive Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon, 1996; Vol. 6, Chapter 6.11, pp 507–573 and
references therein.
4. (a) Pabst, G. R.; Sauer, J. Tetrahedron Lett. 1998, 39,
6687–6690; (b) Pabst, G. R.; Schmid, K.; Sauer, J.
Tetrahedron Lett. 1998, 39, 6691–6694; (c) Pabst, G. R.;
Sauer, J. Tetrahedron Lett. 1998, 39, 8817–8820; (d)
Table 1. Preparation of triazines 3
Triazine 3
Yield (%)
R1
R2
Pfuller, O. C.; Sauer, J. Tetrahedron Lett. 1998, 39,
¨
8821–8824; (e) Pabst, G. R.; Pfuller, O. C.; Sauer, J.
¨
Tetrahedron Lett. 1998, 39, 8825–8828; (f) Pabst, G. R.;
2-Pyridyl
2-Pyridyl
Ph
Ph
n-Pr
Ph
n-Pr
Ph
n-Pr
Ph
98
97
82
65
77
83
54
53
Pfuller, O. C.; Sauer, J. Tetrahedron 1999, 55, 8045–8064;
¨
(g) Kozhevnikov, V. N.; Kozevnikov, D. N.; Nikitina, T.
V.; Rusinov, V. L.; Chupakhin, O. N.; Zabel, M.; Ko¨nig,
B. J. Org. Chem. 2003, 68, 2882–2888; (h) Kozhevnikov,
V. N.; Kozevnikov, D. N.; Shabunina, O. V.; Rusinov, V.
L.; Chupakhin, O. N. Tetrahedron Lett. 2005, 46, 1791–
1793.
Ph
SMe
SMe
Me
Me
n-Pr

M. Altuna-Urquijo et al. / Tetrahedron Letters 46 (2005) 6111–6113
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5. (a) Stanforth, S. P.; Tarbit, B.; Watson, M. D. Tetra-
hedron Lett. 2002, 43, 6015–6017; (b) Stanforth, S. P.;
Tarbit, B.; Watson, M. D. Tetrahedron Lett. 2003, 44,
693–694; (c) Stanforth, S. P.; Tarbit, B.; Watson, M. D.
Tetrahedron 2004, 60, 8893–8897.
6. Detering, J.; Martin, H.-D. Angew. Chem., Int. Ed. Engl.
1988, 27, 695–698.
7. Wasserman, H. H.; Parr, J. Acc. Chem. Res. 2004, 37, 687–
701.
8. Cabon, O.; Buisson, D.; Larcheveque, M.; Azerad, R.
Tetrahedron: Asymmetry 1995, 6, 2199–2210.
9. Jucker, E.; Lindenmann, A. Helv. Chim. Acta 1961, 44,
1249–1257.
10. Russell, G. A.; Weiner, S. A. J. Am. Chem. Soc. 1967, 89,
6623–6628.
11. Compound 9a: 1H NMR (270 MHz, CDCl3): d 8.13 (d,
2H, J = 7 Hz, PhH), 7.64 (t, 1H, J = 7 Hz, PhH), 7.50
(m, 2H, PhH), 4.31 (q, 2H, J = 7 Hz, –CO2CH2CH3), 2.23 (s,
3H, OCOCH3) and 1.29 (t, 3H, J = 7 Hz, –CO2CH2CH3).
HRMS (EI+) for C13H13ClO5: calculated mass of mole-
cular ion: 285.0524 (M+H); measured mass: 285.0526.
Compound 9b: 1H NMR (270 MHz, CDCl3): d 4.32
(q, 2H, J = 7 Hz, –COCH2CH3), 2.85 (q, 2H, J = 7 Hz,
–COCH2–), 2.24 (s, 3H, –OCOCH3), 1.69 (sextet, 2H,
J = 7 Hz, –CH2–), 1.32(t, 3H, J = 7 Hz, –CO2CH2CH3)
and 0.96 (t, 3H, J = 7 Hz, –CH3). HRMS (EI+) for
C10H15ClO5: calculated mass of molecular ion: 268.0946
(M+NH4); measured mass: 268.0948.
1
12. All triazine derivatives gave satisfactory H NMR spectra
and high resolution mass spectra.