Tandem oxidation processes for the regioselective preparation of 5-substituted and 6-substituted 1,2,4-triazines

Article abstract of DOI:10.1016/j.tetlet.2006.03.178

α-Hydroxyketones undergo MnO₂-mediated oxidation, followed by in situ trapping with 2-pyridylamidrazone, to give 3-pyridyl-5-substituted 1,2,4-triazines in a one-pot procedure, which avoids the need to isolate the reactive α-ketoaldehyde interm

Full text of DOI:10.1016/j.tetlet.2006.03.178

Tetrahedron Letters 47 (2006) 3865–3870
Tandem oxidation processes for the regioselective preparation
of 5-substituted and 6-substituted 1,2,4-triazines
Surat Laphookhieo, Stuart Jones, Steven A. Raw, Yolanda Fern a´ ndez Sainz
and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 16 February 2006; revised 19 March 2006; accepted 29 March 2006
Available online 27 April 2006
2
Abstract—a-Hydroxyketones undergo MnO -mediated oxidation, followed by in situ trapping with 2-pyridylamidrazone, to give
3
-pyridyl-5-substituted 1,2,4-triazines in a one-pot procedure, which avoids the need to isolate the reactive a-ketoaldehyde inter-
mediates. By modifying this procedure to allow condensation prior to oxidation, the corresponding 6-substituted 1,2,4-triazines
0
were obtained. The preparation of a novel unsymmetrical 2,2 -bipyridine using one of the pyridyl 1,2,4-triazines prepared herein
is also described.
Ó 2006 Elsevier Ltd. All rights reserved.
1
,2,4-Triazines are an important class of nitrogen-
straightforward. In this procedure, regio-isomeric
mixtures are often formed from unsymmetrical
diketones, although a-ketoaldehydes 4 normally give 5-
containing heterocycles with diverse applications in
medicine and agrochemistry and as ligands for a range
1
,2
1
of metal ions. In addition, 1,2,4-triazines are versatile
synthetic building blocks from which a wide-range of
heterocyclic systems can be accessed via an inverse-
electron-demand Diels–Alder sequence.3–6 The use of
this methodology to prepare pyridines is particularly
substituted 1,2,4-triazines. However, the high reactivity
7
of a-ketoaldehydes, especially alkyl-substituted examples,
can present difficulties. We have recently shown that
manganese dioxide-based tandem oxidation processes
(TOPs) can be employed with a-ketoalcohols; for
example, in the presence of diamines, the intermediate
a-ketoaldehydes can be trapped to give heterocyclic
3
–5
5
valuable,
and we have recently reported a micro-
4
a
wave (MW) variant of the Boger enamine procedure,
which allows the direct conversion of substituted 1,2,4-
triazines into highly functionalised pyridines and 2,2 -
bipyridines via an inverse-electron-demand enamine
8
systems. The first objective of the present study, there-
0
fore, was to investigate the direct conversion of
a-hydroxyketones 3 into 3-pyridyl-5-substituted tri-
azines 1 by in situ trapping of the intermediate a-keto-
5
Diels–Alder/retro-Diels–Alder/elimination
sequence
9
(
Scheme 1). We have also shown that substituted
aldehydes 4 with the pyridyl-substituted amidrazone 5
triazines can undergo a one-pot cascade process invol-
ving inverse-electron-demand Diels–Alder/retro-Diels–
Alder/intramolecular-Diels–Alder reactions producing
(Scheme 2).
Preliminary studies were carried out using the commer-
cially available a-hydroxyacetophenone 3a (R = Ph)
with 2-pyridylamidrazone 5 in the presence of activated
manganese dioxide (Table 1). Initially, thermal condi-
6
diaza-polycycles (Scheme 1).
We next wished to apply the former procedure to pre-
0
˚
pare a range of novel, unsymmetrical 2,2 -bipyridines,
tions were employed with added 4 A molecular sieves
but in order to do this we required efficient access to
but the results were disappointing (entries i and ii). With
excess manganese dioxide, as is normally employed, the
reaction was slow (72 h) and triazine 1a was obtained in
only 9% isolated yield (contaminated by 2a, R = Ph;
1a:2a ca. 19:1). It appeared that amidrazone 5 was
undergoing oxidative decomposition under these condi-
pyridyl-substituted triazines 1 and 2. Of the many
1
methods available to prepare triazines, the double
condensation of 1,2-dicarbonyl compounds with amidr-
azones developed by Neunhoeffer is one of the most
tions and so the amount of MnO was decreased to one
equivalent: this change increased the yield of 1a to 27%,
2
*
0
Corresponding author. E-mail: rjkt1@york.ac.uk
040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.178

3866
S. Laphookhieo et al. / Tetrahedron Letters 47 (2006) 3865–3870
Fur
Fur
N
N
O
Pyrrolidine, MW
120 °C, 20 min
91%
Fur
Fur
N
N
N
CHCl , mol. sieves
3
Δ, 5 h
N
Py
HN(CH CH=CH )
Nallyl
2
2 2
N
R2
O
N
N
N
5
6
Fur
Fur
N
1, R1
R1
= H
, R2 = H
88%
2
Scheme 1.
N
H N
2
N
N
5
R
O
R
O
O
H N
2
R
N
MnO2
N
OH
N
3
4
1
R
N
N
N
N
2
Scheme 2.
Table 1. Optimisation of the oxidation-trapping reaction of 3a to give triazine 1a
N
Ph
O
Ph
N
N
Ph
N
MnO , 5
N
2
+
N
OH
N
N
3
a
1a
2a
a
Entry
Equiv MnO
2
Conditions
Time
Isolated yield (%)
9
Ratio 1a:2a
˚
˚
i
9
1
2
1
1
1
CH
CH
CH
CH
CH
2
2
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
, reflux, 4 A mol. sieves
, reflux, 4 A mol. sieves
72 h
72 h
30 min
30 min
15 min
30 min
19:1
19:1
19:1
19:1
19:1
19:1
b
ii
iii
iv
v
27
c
, 55 °C, MWc
55
70
60
70
, 55 °C, MWc
, 55 °C, MW
c
vi
PhMe, 55 °C, MW
a
b
c
1
Determined by H NMR spectroscopy.
a (26%) recovered; 65% recovered after 24 h.
CEM Discover microwave reactor.
3

S. Laphookhieo et al. / Tetrahedron Letters 47 (2006) 3865–3870
3867
although unreacted starting material and non-cyclised
hydrazone intermediates were also obtained. In order
to speed up the oxidation-trapping process (and mini-
mise amidrazone degradation), we moved on to study
the microwave-induced process (Table 1, entries iii–vi).
We were delighted to find that on repeating the reaction
using dichloromethane and 2 equiv of MnO2 in a
focused monomode microwave reactor at a fixed
temperature (55 °C) in a sealed vessel, the reaction was
complete in 30 min and adduct 1a was isolated in 55%
yield (entry iii). Using the same conditions but with
1 equiv of MnO the yield improved to 70% (entry iv);
2
changing the reaction time to 15 min resulted in a lower
yield (entry v) but replacing dichloromethane with tolu-
ene also gave a 70% yield in 30 min (entry vi).
With this success in hand, we went on to look at a range
1
0
of a-hydroxyketones 3a–h (Table 2). As can be seen,
this one-pot process proved successful with a number
of aromatic and heteroaromatic systems, the products
a
Table 2. One-pot preparation of 3-pyridyl-5-substituted-1,2,4-triazines 1a–h
b
Entry
a-Hydroxy ketone 3
Triazine 1
Yield (%)
N
c
i
Ph
3a
1a
70
O
Ph
N
N
OH
N
N
4
-MeO-C H4
O
6
4
4
4
-MeO-C H4
6
N
N
ii
3b
3c
3d
1b
1c
1d
51
OH
N
N
4
4
-NO -C H
6 4
O
2
-NO -C H
N
2
6
4
11,12
iii
iv
76
OH
N
N
N
-Br-C H4
6
O
6
-Br-C H4
N
N
d
59
OH
N
N
O
N
N
v
O
S
3e
3f
O
S
1e
1f
65
69
N
OH
N
O
N
N
vi
N
OH
N
Me
O
Me
N
N
e
vii
3g
3h
1g
1h
19
OH
N
N
O
N
f
viii
18
N
OH
N
a
b
c
d
e
f
For a representative procedure see Ref. 11.
Isolated yield based on the starting a-hydroxyketone 3.
a:2a approx. 19:1.
d:2d approx. 19:1.
Hydrazone 6 (35%) was also isolated (see Scheme 3).
h:2h approx. 4:1.
1
1
1

3868
S. Laphookhieo et al. / Tetrahedron Letters 47 (2006) 3865–3870
1
a–f being obtained in fair to good yields (51–76%), pre-
dominantly or exclusively as the required regioisomers
entries i–vi).
in refluxing toluene,14 gave 3-pyridyl-6-phenyl 1,2,4-tri-
azine 2a in 73% yield, although it was contaminated
by a small amount of the 5-phenyl isomer 1a (ca. 5%).
Somewhat surprisingly, it appears that this 5-phenyl
by-product arises from the aerial oxidation of a-
hydroxyacetophenone 3a, followed by condensation
with the resulting aldehyde 4a. However, by rigorously
degassing the reaction mixture and carrying out the pro-
cess under an inert atmosphere, the sequence proceeded
(
Two aliphatic examples were also explored (entries vii–
viii): in these examples low yields of triazines 1g and
1
h were obtained. In the case of the methyl substituted
example (entry vii), 35% of the hydrazone by-product
(R = Me) was also isolated, indicating the competitive
6
1
nature of the condensation process in this system.
with total regioselectivity according to H NMR spec-
troscopy (entry ii). This sequence was then applied to
the cyclohexane-substituted a-hydroxyketone 3h, and
triazine 2h was obtained as a single regioisomer in
51% yield (73% using MW). Further studies are needed
to examine the scope of this procedure, but these pre-
liminary results, which involve both an aromatic and
an aliphatic a-hydroxyketone, indicate its potential.
This observation prompted us to investigate the one-pot
preparation of 3-pyridyl-6-substituted triazines 2 by an
initial condensation between hydroxyketone 3 and
amidrazone 5, giving intermediate adduct 6, followed
in situ by MnO -mediated oxidation and subsequent
2
condensation to produce the required product 2
(
Scheme 3).
Finally, to illustrate the value of the 1,2,4-triazines
Preliminary studies revealed that this approach shows
great potential (Table 3). Thus (entry i), condensation
of a-hydroxyacetophenone 3a with 2-pyridylamidrazone
prepared herein, 3-pyridyl-6-phenyl 1,2,4-triazine 2a
0
was converted into the novel, unsymmetrical 2,2 -bipyri-
1
5
dine 7 using the one-pot methodology we developed
5
5
followed by manganese dioxide oxidation–cyclisation
earlier (Scheme 4).
H N
2
N
H N
2
N
R
O
5
R
N
R
N
N
MnO2
N
N
Step I
Step II
OH
HO
H N
2
N
N
3
6
2
Scheme 3.
a
Table 3. One-pot preparation of 3-pyridyl-6-substituted 1,2,4-triazines 2a and 2h
b
Entry
Step I (condensation)
Step II (oxidation, etc.)
Product 2
Overall yield (%)
Ph
N
Ph
O
i
5 (2.0 equiv), PhMe,
MnO
2
, PhMe,
N
73 (2a:1a = 19:1)
5
5 °C, 1 h
reflux, 17 h
OH
N
N
3
3
a
2
a
Ph
N
Ph
O
N
ii
5 (2.0 equiv), PhMe,
5 °C, 1 h, degassed
MnO
reflux, 17 h
2
, PhMe,
71 (2a only)
OH
N
5
N
a
2a
N
O
N
13
c
iii
5 (1.0 equiv), PhMe,
5 °C, 2 h, degassed
MnO
PhMe, reflux, 17 h
2
, AcOH,
51 (73)
5
N
OH
3h
N
2h
a
b
c
For a representative procedure see Ref. 13.
Isolated yield over complete sequence based on the starting a-hydroxyketone 3.
Using microwave conditions (2 h).

S. Laphookhieo et al. / Tetrahedron Letters 47 (2006) 3865–3870
3869
O
N
N
N
N
N
N
Pyrrolidine, MW, 120 °C, 30 min
Ph
Ph
64%
2a
7
Scheme 4.
In summary, we have developed improved procedures
for the regioselective conversion of a-hydroxyketones
V. N.; Kozhevnikov, D. N.; Shabunina, O. V.; Rusinov,
V. L.; Chupakhin, O. N. Tetrahedron Lett. 2005, 46, 1791;
(
d) Altuna-Urquijo, M.; Stanforth, S. P.; Tarbit, B.
3
into both 5-substituted- and 6-substituted-3-pyridyl
Tetrahedron Lett. 2005, 46, 6111–6113.
. Raw, S. A.; Taylor, R. J. K. Chem. Commun. 2004, 508–
1
,2,4-triazines via one-pot oxidative sequences with
5
in situ trapping using 2-pyridylamidrazone (and presum-
ably other substituted amidrazones would be equally
5
09; Fernandez Sainz, Y.; Raw, S. A.; Taylor, R. J. K.
J. Org. Chem. 2005, 70, 10086–10095.
. Raw, S. A.; Taylor, R. J. K. J. Am. Chem. Soc. 2004, 126,
0
viable). A novel, unsymmetrical 2,2 -bipyridine has also
6
been prepared. We are currently optimising this chemis-
try and exploring applications in natural product
synthesis.
1
2260–12261.
7. Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50,
2198–2200.
8
. Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K. Chem.
Commun. 2003, 2286–2287; Raw, S. A.; Wilfred, C. D.;
Taylor, R. J. K. Org. Biomol. Chem. 2004, 2, 788–796; For
a review, see: Taylor, R. J. K.; Reid, M.; Foot, J.; Raw, S.
A. Acc. Chem. Res. 2005, 38, 851–869.
Acknowledgements
We are grateful to the EPSRC (S.A.R.) and the Univer-
sity of York (S.J. and Y.F.S.) for financial support. We
also acknowledge the Royal Golden Jubilee Program
9
. Case, F. H. J. Org. Chem. 1965, 30, 931–933.
10. Non-commercial a-hydroxyketones were prepared from
the corresponding methyl ketones using a published
procedure: Moriarty, R. M.; Berglund, B. A.; Penmasta,
R. Tetrahedron Lett. 1992, 33, 6065–6068.
(
Thailand) for a Visiting Scholarship (S.L., Prince of
Songkla University).
1
1. Representative procedure: 5-(4-nitrophenyl)-3-(pyridin-2-
Ò
yl) 1,2,4-triazine 1c: In a sealed 10 mL CEM Discover
reaction vial containing a magnetic follower was placed 2-
hydroxy-1-(4-nitrophenyl)ethanone 3c (54 mg, 0.3 mmol),
References and notes
. For reviews see: (a) Neunhoeffer, H. In Comprehensive
2
-pyridylamidrazone 5 (41 mg, 0.3 mmol), activated man-
1
ganese dioxide (Aldrich 21,764-6, 31 mg, 0.3 mmol) and
CH Cl (0.5 mL). The reaction mixture was irradiated at
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996;
Vol. 6, pp 507–573; (b) Lindsley, C. W.; Layton, M. E. In
Science of Synthesis; Weinreb, S. M., Ed.; Thieme:
Stuttgart, 2003; Vol. 17, pp 357–447; For recent examples
see: (c) Alphonse, F.-A.; Suzenet, F.; Keromnes, A.;
Lebret, B.; Guillaumet, G. Synthesis 2004, 2893–2899; (d)
Zhao, Z.; Leister, W. H.; Strauus, K. A.; Wisnowski, D.
D.; Lindsley, C. W. Tetrahedron Lett. 2003, 44, 1123–
2
2
55 °C for 30 min (maximum power, 50 W; maximum
pressure, 300 psi; run time, 10 min; stirring on; cooling
off). The reaction mixture was cooled to rt, diluted with
Ò
CH Cl (5 mL), filtered through Celite and concentrated
2
2
in vacuo to furnish a yellow solid (65 mg). This was
purified by flash column chromatography on silica gel
(EtOAc) to give the title compound 1c (64 mg, 76%) as a
1
2
bright yellow solid, R 0.28 (EtOAc), mp 256–258 °C (lit.
f
1
1
127; (e) see also Refs. 2–5.
246–248 °C), which displayed consistent H NMR data.
12. Culbertson, B. M.; Parr, G. R. J. Heterocycl. Chem. 1967,
4, 422–424.
2
. For the utility of triazines see: (a) Vzorov, A. N.;
Bhattacharyya, D.; Marzilli, L. G.; Compans, R. W.
Anitviral Res. 2005, 65, 57–67; (b) Wang, X.-L.; Chao, H.;
Li, H.; Hong, X.-L.; Liu, Y.-J.; Tan, L.-F.; Ji, L.-N. Inorg.
Biochem. 2004, 98, 1143–1150; (c) Hudson, M. J.; Drew,
M. G. B.; Foreman, M. R. StJ.; Hill, C.; Huet, N.; Madie,
C.; Youngs, T. G. A. Dalton Trans. 2003, 1675–1685; (d)
Abdel-Rahman, R. M. Pharmazie 2001, 56, 195–204; (e)
Croot, P. L.; Hunter, K. A. Anal. Chim. Acta 2000, 406,
13. Representative procedure: 6-(cyclohexyl)-3-(pyridin-2-yl)
1,2,4-triazine 2h: 1-Cyclohexyl-2-hydroxyethanone 3h
(93 mg, 0.65 mmol), 2-pyridylamidrazone
5
(89 mg,
0.65 mmol) and dry, degassed PhMe (1.0 mL) were stirred
at rt for 3 h under an atmosphere of argon. Analysis by
TLC indicated complete consumption of hydroxyketone
3h. After adding activated manganese dioxide (Aldrich
21,764-6, 0.665 g, 6.50 mmol), glacial acetic acid
(0.037 mL, 0.59 mmol) and PhMe (7.0 mL), the reaction
mixture was heated to reflux for 17 h. The reaction
mixture was cooled to rt, diluted with CH Cl (5.0 mL)
2
89–302.
3
. 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;
2
2
Ò
and filtered through a pad of Celite , covered by sodium
hydrogencarbonate (1.0 g) and magnesium sulfate. The
filtrate was concentrated in vacuo to furnish a brown oil
(185 mg), which was purified by flash column chromato-
graphy on silica gel (EtOAc) to give the title compound 2h
(
b) Boger, D. L. Chem. Rev. 1986, 86, 781–793; (c) Boger,
D. L. Tetrahedron 1983, 39, 2869–2939.
. (a) Boger, D. L.; Panek, J. S. J. Am. Chem. Soc. 1985, 107,
4
5
745–5754, and references cited therein; For recent exam-
ples see: (b) Kozhevnikov, V. N.; Kozhevnikov, D. N.;
Shabunina, O. V.; Rusinov, V. L.; Chupakhin, O. N.
Tetrahedron Lett. 2005, 46, 1521–1523; (c) Kozhevnikov,
(80 mg, 51%) as a pale yellow solid: R 0.16 (EtOAc); mp
f
ꢀ
1
110–111 °C; m
max
(film)/cm 2926, 1586; dH (400 MHz,
CDCl ) 8.81 (1H, ddd, J 4.5, 1.5, 1.0), 8.63 (1H, s), 8.61
3

3
870
S. Laphookhieo et al. / Tetrahedron Letters 47 (2006) 3865–3870
1H, ddd (appt dt), J 7.5, 1.0), 7.85 (1H, ddd (appt td), J
(
at 120 °C for 30 min (maximum power, 300 W; maximum
7
1
1
d
1
.5, 1.5), 7.40 (1H, ddd, J 7.5, 4.5, 1.0), 3.01–2.93 (1H, m),
.98–2.02 (2H, m), 1.84–1.89 (2H, m), 1.73–1.76 (1H, m),
.59–1.69 (2H, m), 1.35–1.47 (2H, m) 1.21–1.33 (1H, m);
pressure, 300 psi; run time, 15 min; stirring on; cooling off).
The reaction mixture was cooled to rt and diluted with
CH
by flash chromatography on silica gel (petroleum ether–
ethyl acetate, 1:1) gave 7 (0.017 g, 64%) as a yellow solid: R
2 2
Cl (1 mL). Concentration in vacuo and purification
C
(100 MHz, CDCl
3
) 164.7, 162.0, 152.9, 150.5, 149.0,
37.3, 125.5, 123.7, 42.1, 31.7, 25.7, 25.2; m/z (CI) 241
f
+
(
MH , 100) [HRMS (CI): calcd for C H N , 241.1453.
0.25 (petrol–EtOAc, 4:1); mp 121–122 °C (hexane–CHCl );
1
4
17
4
3
+
ꢀ1
Found: MH , 241.1446 (3.5 ppm error)].
4. Microwaves could also be employed for the second step
m
max (film)/cm 2956, 1583; d
H
(400 MHz, CDCl
3
) 8.72
1
1
(1H, ddd, J 4.8, 2.0, 0.8), 8.56 (1H, s), 8.20 (1H, ddd (appt
dt), J 7.6, 1.2), 7.83 (1H, ddd (appt dt), J 7.6, 2.0), 7.54–
7.38 (5H, m), 7.29 (1H, ddd, J 7.6, 4.8, 1.2), 3.45 (2H, t,
(
PhMe, 120 °C, 1 h), although the initial condensation
proceeded more efficiently under thermal conditions.
5. Representative procedure: 4-phenyl-1-(pyridin-2-yl)-6,7-
J 7.6), 3.05 (2H, t, J 7.6), 2.10 (2H, quint, J 7.6); d
(100 MHz, CDCl ) 157.98, 153.38, 150.65, 148.71, 146.52,
C
Ò
dihydro-5H[2]pyrindine 7: To a 10 mL CEM Discover
3
reaction vial, containing a magnetic follower, was placed
139.34, 137.70, 136.41, 133.67, 128.59, 128.54, 127.70,
123.01, 122.72, 33.35, 32.63, 25.50; m/z (CI): 273 (MH ,
+
6
-phenyl-3-pyridin-2-yl-1,2,4-triazine 2a (0.023 g, 0.1 mmol),
pyrrolidine (0.009 mL, 0.1 mmol) and cyclopentanone
0.009 mL, 0.1 mmol). The reaction mixture was irradiated
17 2
100%) [HRMS (CI): calcd for C19H N , 273.1392. Found:
+
(
MH , 273.1393 (ꢀ0.6 ppm error)].