Niementowski-type synthesis of pyrido[3,2-e][1,2,4]triazines: potent aza-analogs of pyrido[2,3-b]pyrazine fungicides

Article abstract of DOI:10.1016/j.tetlet.2010.03.032

Novel trisubstituted pyrido[3,2-e][1,2,4]triazines have been found to possess similar biological activity to the corresponding pyridopyrazine fungicides against important phytopathogens such as Mycosphaerella graminicola (wheat leaf blotch), Magnaporthe g

Full text of DOI:10.1016/j.tetlet.2010.03.032

Tetrahedron Letters 51 (2010) 2652–2654
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Niementowski-type synthesis of pyrido[3,2-e][1,2,4]triazines: potent
aza-analogs of pyrido[2,3-b]pyrazine fungicides
b
b
a
Patrick J. Crowley a, Clemens Lamberth b, , Urs Müller , Sebastian Wendeborn , Olivia-A. Sageot ,
John Williams , Alexander Bartovic
*
a
ˇ c
a Syngenta, Chemistry Department, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom
b Syngenta Crop Protection AG, Crop Protection Research, Research Chemistry, Schaffhauserstr. 101, CH-4332 Stein, Switzerland
c Synkola Ltd, Mlynska dolina, areal PvF UK, 84215 Bratislava, Slovakia
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel trisubstituted pyrido[3,2-e][1,2,4]triazines have been found to possess similar biological activity to
the corresponding pyridopyrazine fungicides against important phytopathogens such as Mycosphaerella
graminicola (wheat leaf blotch), Magnaporthe grisea (rice blast), and Rhizoctonia solani (rice sheath blight).
They have been prepared for the first time from a monocyclic triazine by Niementowski-type ring
condensation.
Received 19 January 2010
Revised 5 March 2010
Accepted 9 March 2010
Available online 15 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycle
Triazine
Pyridotriazine
Niementowski reaction
Fungicide
1. Introduction
2. Results and discussion
The pyrido[2,3-b]pyrazines are a novel class of experimental
fungicides, which are highly active against several different phyto-
pathogens such as Mycosphaerella graminicola (wheat leaf blotch),
Puccinia recondita (wheat brown rust), and Magnaporthe grisea (rice
blast).1 Their fungicidal efficacy is due to their ability to promote
fungal tubulin polymerization, which leads to a disruption of
microtubule dynamics. The same mode of action is also used in
the treatment of several cancer diseases with natural products
such as taxol and vinca alkaloids, like vinblastine and vincristine.2
During the course of our further exploration of this area, we stud-
ied the influence of different modifications of the pyridopyrazine
scaffold on the fungicidal activity. It turned out that the replace-
ment of one carbon atom in the pyrazine moiety of 1 by nitrogen
led to the pyrido[3,2-e][1,2,4]triazine 2a with interesting fungi-
cidal properties (Fig. 1). A literature survey revealed that such spe-
cial pyridotriazines, which are unsubstituted in the triazine ring
and persubstituted in the pyridine moiety, have not been reported
so far. Herewith, we describe an efficient procedure for the prepa-
ration of pyrido[3,2-e][1,2,4]triazines with three substituents in
the pyridine ring.
So far, only a few syntheses of pyrido[3,2-e][1,2,4]triazines have
been published.3 Surprisingly, all these six different publications
start from a monocyclic nitro- and hydrazino-substituted pyridine,
which is transformed by heteroannelation into a pyridotriazine.
This synthesis method did not serve our needs, because our envis-
aged target molecules with three different substituents in the
pyridine moiety of the pyridotriazine would then require penta-
substituted pyridine starting materials, which are not readily
accessible. Therefore we tried to achieve the pyridotriazine synthe-
sis for the first time from a triazine ring, to which a pyridine ring is
F
F
F
F
F
F
F
F
F
F
NH
NH
N
N
F
N
F
N
N
F
N
N
F
2a
1
a pyridopyrazine fungicide
a pyridotriazine analog
* Corresponding author. Tel.: +41 61 3232373; fax: +41 61 3238726.
E-mail address: clemens.lamberth@syngenta.com (C. Lamberth).
Figure 1. Pyrido[2,3-b]pyrazine fungicide
analog 2a.
1
and its pyrido[3,2-e][1,2,4]triazine
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.032

P. J. Crowley et al. / Tetrahedron Letters 51 (2010) 2652–2654
2653
added through a Niementowski-type ring condensation. In the
Niementowski reaction4,5 a sub-type of the Friedlaender quinoline
synthesis,6 a 2-amino aroyl or heteroaroyl acid derivative reacts
with an active methylene compound directly to give oxygenated
aza-naphthalenes.
Several other primary and secondary amines could also be
introduced into position 5 of the pyrido[3,2-e][1,2,4]triazine scaf-
fold (Table 1). With the exception of 2b, all aminations proceeded
either regioselectively or at least predominantly in position 5. In
some cases, however, especially with nucleophilic amines, consid-
erable amounts of the diamination products 11a–h could be iso-
lated, which are devoid of any fungicidal activity.
5,7-Dichloro-6-(2,4,6-trifluorophenyl)-pyrido[3,2-e][1,2,4] tri-
azine 9 could be transformed into some novel trisubstituted hete-
robicyclics, in a similar manner to the monoamination of the
difluoro building block 10. Thus reaction of 9 with a thiolate, such
as sodium cyclopentylthiolate, or an alkoxide, such as sodium
methylate, leads similar to the monoamination of the correspond-
ing difluoro building block 10, regioselectively to the introduction
of the new substituent into position 5, delivering the sulfide 12 and
the ether 13. The chlorine atom of 13 was exchanged with a cyano
group by reaction with sodium cyanide, delivering 15, and by
isopropyl amine, leading to 16. Both reactions were performed un-
der microwave irradiation.10 Finally, the reaction of 9 with cyclo-
hexylmagnesium bromide led to the 5-cyclohexyl derivative 14
(Scheme 2).
The required 6-amino-[1,2,4]triazine-5-carboxylic acid ethyl
ester (6) was obtained in three steps from commercially available
5-amino-4,6-dichloropyrimidine (3) following a literature proce-
dure (Scheme 1).7 This 1,2,4-triazine was then converted
under Niementowski-type conditions by acylation with 2,4,6-
trifluorophenylacetyl chloride and subsequent base-mediated ring
closure of the intermediate amide 7 to the dihydroxypyrido[3,2-e]-
as-triazine 8. According to NMR analysis, the oxygen substituent in
position 7 forms a lactam function together with the adjacent
ring nitrogen atom. 5-Hydroxy-6-(2,4,6,-trifluorophenyl)-8H-pyr-
ido[3,2-e][1,2,4]triazin-7-one (8) was then further transformed
with phosphorus oxychloride to the dichloro-derivative 9, which
in turn underwent a halogen exchange reaction with spray-dried
potassium fluoride to its difluorinated analog 10. Finally, the regio-
selective replacement of the fluoro substituent in position 5 with
(S)-2,2,2-trifluoroisopropylamine delivered the desired pyr-
ido[3,2-e][1,2,4]triazine 2a with three different substituents in
the pyridine moiety (Scheme 1).8,9 In our screening, the pyridopyr-
azine 11 and its pyridotriazine analog 2a showed similar potency
against the fungal plant pathogens M. graminicola (wheat leaf
blotch), M. grisea (rice blast), and Rhizoctonia solani (rice sheath
blight).
In conclusion, we have achieved the synthesis of the first pyr-
ido[3,2-e][1,2,4]triazines with three substituents in the pyridine
moiety. In contrast to some earlier published protocols, which all
used pyridine starting materials, for the first time this biheterocy-
clic scaffold was prepared from a monocyclic triazine building
block. The halogen atom in position 5 of 5,7-dihalogenated pyrido-
Br2,
EtOH,
H2O
F3H2C6CH2CO2H,
(COCl)2, NEt3
Cl
Cl
Cl
O
O
CH(OEt)3,
HCl
NH2
Cl
NH2
N
N
N
H2NNH2
89 %
N
N
N
OEt
O
F
NH2
NH
N
N
F
F
70 %
71 %
78 %
N
N
N
H
N
N
H
N
NH2
N
NH
5
4
6
7
3
O
F
F
F
K2CO3
90 %
F
F
F
F
F
F
F
F
F
F
Cl
NH
OH
(S)-F3CCH(Me)NH2,
NEt3
N
N
N
N
N
POCl3
KF
N
F
F
N
N
N
F
46 %
67 %
88 %
N
N
F
N
N
Cl
N
F
N
N
H
O
9
2a
10
8
Scheme 1. Synthesis of the trisubstituted pyrido[3,2-e][1,2,4]triazine 2a.
Table 1
Synthesis of pyrido[3,2-e][1,2,4]triazines 2a–h with different amine moieties (all yields and ratios isolated material)
F
F
F
F
F
F
R1
R2
R1
R2
F
N
N
N
N
R1R2NH, NEt3
N
N
N
F
+
F
F
N
N
N
R2
N
N
F
N
F
N
N
R1
2a-h
11a-h
10
Compound
R1
R2
Yield of 2 (%)
Mp of 2 (°C)
Ratio 2:11
2a
2b
2c
2d
2e
2f
(S)-F3C(Me)CH–
Me2CH–
Me2CHCH2–
Et(Me)CH–
Me3C–
H
H
H
H
H
H
46
18
34
43
43
62
40
30
93–94
92–93
1:0
1:3
1:1
3:2
1:0
1:0
3:1
3:1
128–129
102–104
116–118
121–123
153–154
136–138
.-
2g
2h
–CH2CH2CH2–
–CH2CH2CH2CH2–

2654
P. J. Crowley et al. / Tetrahedron Letters 51 (2010) 2652–2654
3911–3913; (c) Son, J. K.; Kim, S. I.; Jahng, Y. Heterocycles 2001, 55, 1981–1986;
(d) Domon, L.; Le Coeur, C.; Grelard, A.; Thiery, V.; Besson, T. Tetrahedron Lett.
2001, 42, 6671–6674; (e) Zhou, Z.-L.; Navratil, J. M.; Cai, S. X.; Whittemore, E.
R.; Espitia, S. A.; Hawkinson, J. E.; Tran, M.; Woodward, R. M.; Weber, E.; Keana,
J. F. W. Bioorg. Med. Chem. 2001, 9, 2061–2071.
F
F
F
F
F
F
Cl
N
S
c-Pent-SH,
NaH
N
N
6. (a) Thummel, R. P. Synlett 1992, 1–12; (b) Cheng, C.-C.; Yan, S.-J. Org. React.
1982, 28, 37–201.
7. Temple, C.; Kussner, C. L.; Montgomery, J. A. J. Org. Chem. 1971, 36, 2974–2978.
8. Crowley, P. J.; Dobler, M.; Müller, U.; Williams, J. WO 2004/056829 (Syngenta);
Chem. Abstr. 2004, 141, 89107.
N
F
F
F
F
N
25 %
N
Cl
N
N
Cl
9
12
c-Hex-MgCl, ZnBr2,
LiCl, CuCN
9. Typical synthesis procedure for compound 2:
A
solution of 2,4,6-
NaOMe
57 %
trifluorophenylacetyl chloride (10.5 g, 50 mmol) in 30 ml of dichloromethane
is added at 0 °C to a solution of 6-amino-[1,2,4]triazine-5-carboxylic acid ethyl
ester7 (6, 8.5 g, 50 mmol), pyridine (4.0 g, 50 mmol), and catalytic amounts of
4-N,N-dimethylaminopyridine in 170 ml of dichloromethane. The resulting
suspension is stirred for 16 h at room temperature and then extracted with 2 N
hydrochloric acid and water. The organic layer is washed with brine, dried over
sodium sulfate, and evaporated. The remainder is purified by chromatography
on silica gel, using cyclohexane/ethyl acetate 3:1 as eluent, to give 6-[2-(2,4,6-
trifluorophenyl)-acetylamino]-[1,2,4]triazine-5-carboxylic acid ethyl ester (7,
12 g, 35 mmol, 70%) as a viscous oil, which solidified. Mp 106–107 °C. 1H NMR
(CDCl3): d (ppm) 1.46 (t, 3H, J = 7.2 Hz), 4.10 (s, 2H), 4.48 (q, 2H, J = 7.2 Hz), 6.73
(t, 2H, J = 8.5 Hz), 9.62 (s, 1H), 10.03 (s, 1H). MS m/z: 341 (C14H11F3N4O3+H)+. A
mixture of 7 (6.0 g, 18 mmol) and anhydrous potassium carbonate (3.75 g,
27 mmol) in 50 ml of N,N-dimethylformamide is stirred for 2 h at 80 °C.
Subsequently the reaction mixture is cooled, poured into water, and acidified
to pH 5 with 5 N hydrochloric acid. After extraction with ethyl acetate, the
organic layer is dried over sodium sulfate and evaporated to give an orange
solid, which was triturated with tert-butyl methyl ether to deliver 5-hydroxy-
4 %
F
F
F
O
N
N
N
N
F
N
N
Cl
N
N
Cl
13
14
i-PrNH2,
MW (50 W, 10 min)
NaCN,
MW (50 W,
10 min)
62 %
79 %
F
F
F
O
O
6-(2,4,6,-trifluorophenyl)-8H-pyrido[3,2-e][1,2,4]triazin-7-one
(8,
4.7 g,
16 mmol, 90%) as a yellow powder. Mp 170–171 °C. 1H NMR ((CD3)2SO): d
(ppm) 7.29 (t, 2H, J = 8.4 Hz), 9.73 (s, 1H), 12.89 (s, 1H). MS m/z: 293
(C12H5F3N4O2ÀH)+. A solution of 8 (4.0 g, 14 mmol) in 20 ml of phosphorus
oxychloride was heated to 85 °C for 2 h. The reaction mixture is cooled to 55 °C
and the solvent is removed at this temperature in vacuo. The remaining oil is
diluted with ethyl acetate and washed with brine and aqueous sodium
bicarbonate solution. The organic layer is dried over sodium sulfate and
evaporated, the residue is purified by chromatography using cyclohexane/ethyl
acetate 3:1 as eluents to deliver 5,7-dichloro-6-(2,4,6-trifluorophenyl)-
pyrido[3,2-e][1,2,4]triazine (9, 3.9 g, 12 mmol, 88%) as reddish solid. Mp 143–
144 °C. 1H NMR (CDCl3): d (ppm) 6.96 (t, 2H, J = 8.5 Hz), 10.24 (s, 1H). MS m/z:
332 (C12H3Cl2F3N4+H)+. A suspension of 9 (2.9 g, 8.7 mmol) and spray-dried
potassium fluoride (1.5 g, 26 mmol) in 10 ml of sulfolane is heated to 130 °C for
2 h. The reaction mixture is cooled, poured into water, and extracted with ethyl
acetate. The combined organic layer is washed with brine, dried over sodium
sulfate, and evaporated. The residue is purified by chromatography using
cyclohexane/ethyl acetate 3:1 as eluents to give 5,7-difluoro-6-(2,4,6-
trifluorophenyl)-pyrido[3,2-e][1,2,4]triazine (10, 1.7 g, 5.8 mmol, 67%) as
N
N
F
N
N
N
N
N
N
N
NH
15
16
Scheme 2. Synthesis of the trisubstituted pyrido[3,2-e][1,2,4]triazine 2a.
pyrazines could be regioselectively replaced by amino, alkyl, alk-
oxy, and alkylthio groups.
References and notes
1. Crowley, P. J.; Lamberth, C.; Müller, U.; Wendeborn, S.; Nebel, K.; Williams, J.;
Sageot, O.-A.; Carter, N.; Mathie, T.; Kempf, H.-J.; Godwin, J.; Schneiter, P.;
Dobler, M. R.. Pest Manag. Sci. 2010, 66, 178–185.
2. (a) Zhou, J.; Giannakakou, P. Curr. Med. Chem. Anticancer Agents 2005, 5, 65–71;
(b) Honore, S.; Pasquier, E.; Braguer, D. Cell Mol. Life Sci. 2005, 62, 3039–3056;
(c) Jordan, M. A.; Wilson, L. Nat. Rev. Cancer 2004, 4, 253–265; (d) Li, Q.; Sham,
H. L. Expert Opin. Ther. Patents 2002, 12, 1663–1702; (e) Jordan, M. A. Curr. Med.
Chem. Anticancer Agents 2002, 2, 1–17.
3. (a) Reich, M. F.; Fabio, P. F.; Lee, V. J.; Kuck, N. A.; Testa, R. T. J. Med. Chem. 1989,
32, 2474–2485; (b) Ple, N.; Queguiner, G.; Pastour, P. CR Hebd. Seances Acad. Sci.,
Ser. C 1976, 283, 487–489; (c) Messmer, A.; Gelleri, A.; Benko, P.; Pallos, L. Magy.
Kem. Foly. 1976, 82, 173–179; (d) Benko, P.; Messmer, A.; Gelleri, A.; Pallos, L.
Acta Chim. Acad. Sci. Hung. 1976, 90, 285–299; (e) Gelleri, A.; Messmer, A.;
Benko, P.; Pallos, L. Acta Chim. Acad. Sci. Hung. 1976, 90, 301–311; (f) Lewis, A.;
Shepherd, R. G. J. Heterocycl. Chem. 1971, 8, 41–46.
yellow powder. Mp 160–161 °C. 1H NMR (CDCl3):
d (ppm) 6.95 (t, 2H,
J = 8.6 Hz), 10.21 (s, 1H). MS m/z: 299 (C12H3F5N4+H)+. 10 (0.25 g, 0.83 mmol)
is added to a mixture of (S)-2,2,2,-trifluoroisopropylamine (0.21 g, 1.84 mmol)
and catalytic amounts of 4-N,N-dimethylaminopyridine in 3 ml of N,N-
dimethylformamide. The reaction mixture is stirred for 16 h at room
temperature, then poured into ethyl acetate, and washed with brine. The
organic layer is dried over sodium sulfate and evaporated, the residue is
purified by chromatography on silica gel, using cyclohexane/ethyl acetate 3:1
as
eluents
to
deliver
[7-fluoro-6-(2,4,6-trifluorophenyl)-pyrido[3,2-
e][1,2,4]triazin-5-yl]-((S)-2,2,2-trifluoro-1-methyl-ethyl)-amine (2a, 0.15 g,
0.38 mmol, 46%) as a yellow solid. Mp 93–94 °C. 1H NMR (CDCl3): d (ppm)
1.45 (d, 3H, J = 7.0 Hz), 4.21 (dt, 1H, J = 9.2 Hz), 6.83–6.98 (m, 2H), 9.96 (s, 1H).
MS m/z: 392 (C15H8F7N5+H)+.
10. (a)Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim,
2006; (b) Kappe, C. O.; Stadler, A. Microwaves in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, 2005; (c)Microwave Assisted Organic
Synthesis; Lidström, P., Tierney, J. P., Eds.; Blackwell Scientific: Oxford, 2005.
4. Hisano, T. Org. Prep. Proced. Int. 1973, 5, 145–193.
5. For some recent applications of the Niementowski reaction see: (a) Alexandre,
F.-R.; Berecibar, A.; Wrigglesworth, R.; Besson, T. Tetrahedron 2003, 59, 1413–
1419; (b) Alexandre, F.-R.; Berecibar, A.; Besson, T. Tetrahedron Lett. 2002, 43,