Palladium-catalyzed 3-thiomethyltriazine-boronic acid cross coupling: Easy access to 3-substituted-1,2,4-triazines

Article abstract of DOI:10.1055/s-2002-20462

The palladium-catalyzed coupling reaction of 3-thiomethyl-1, 2,4-triazine 1 with different organoboron compounds in the presence of copper(I) 3-methylsalicylate proceeds to afford the corresponding 3-substituted-1,2,4-triazines in good yield. This approach leads very easily to a large range of C-5 and C-6 unsubstituted as-triazines.

Full text of DOI:10.1055/s-2002-20462

LETTER
447
Palladium-catalyzed 3-Thiomethyltriazine-boronic Acid Cross Coupling:
Easy Access to 3-Substituted-1,2,4-triazines
P
alladium-Cat
r
alyze
d
3
a
-Thiomethy
n
ltriazine-Bo
c
A
cid
e
Cross Coup
-
ling Aimée Alphonse,a,b Franck Suzenet,a Anne Keromnes,b Bruno Lebret,b Gérald Guillaumet*a
a
Institut de Chimie Organique et Analytique, UMR-CNRS 6005, Université d'Orléans, rue de Chartres, BP 6759, 45067 Orléans cedex 2,
France
b
Commissariat à l’Energie Atomique, CEA/Le Ripault, B.P.16, 37260 Monts, France
Fax +33(2)38417078; E-mail: gerald.guillaumet@univ-orleans.fr
Received 18 December 2001
prepared by condensation of glyoxal with S-methylthi-
osemicarbazide, followed by 3-chloroperoxybenzoic acid
oxidation requires strict anhydrous conditions during col-
umn chromatography.
Abstract: The palladium-catalyzed coupling reaction of 3-thiome-
thyl-1,2,4-triazine 1 with different organoboron compounds in the
presence of copper(I) 3-methylsalicylate proceeds to afford the cor-
responding 3-substituted-1,2,4-triazines in good yield. This ap-
proach leads very easily to a large range of C-5 and C-6
unsubstituted as-triazines.
At this stage, we thought it would be advantageous to de-
velop a cross-coupling strategy to enable us to directly
functionalize at C-3 under mild conditions with a large
range of aryl and alkenyl groups. Herein, we wish to re-
port an unusual palladium catalyzed cross-coupling reac-
tion between boronic acids and the readily available 3-
methylthiotriazine 19 in the presence of copper(I) 3-meth-
ylsalicylate (CuMeSal).
Recently, Liebeskind and Srogl indicated10,11 that het-
eroaromatic thioether-boronic acid cross-coupling medi-
ated by copper(I) carboxylates would be feasible. So, we
decided to study whether a palladium-catalyzed displace-
ment of the 3-methylthio group on as-triazines with bo-
ronic acids is possible.12 When 3-thiomethyl-1,2,4-
triazine 1 was first treated with 1.1 equiv of p-methoxy-
phenylboronic acid in the presence of (PPh3)4Pd (5%
mole) and 1.1 equiv of the readily accessible CuMeSal in
THF at 50 °C, 50% of the starting material was recovered
(Table 1, Entry 1). Finally, using 2.2 equiv of boronic acid
with 2.2 equiv of CuMeSal, cross coupling was completed
within 5 h and 3-(p-methoxyphenyl)-1,2,4-triazine 2 was
isolated in 85% yield (Table 1, Entry 3). Standard Suzuki
cross-coupling conditions (Table 1, Entry 4) are not effi-
cient and the presence of copper (I) (Table 1, Entry 5) is
essential. It is noteworthy that the cross-coupled product
has also been isolated in low yield in the presence of CuI
(Table 1, Entry 6).
Key words: as-triazine, copper, boron, thioethers, palladium cross-
coupling
1,2,4-Triazines are well-known class of heterocyclic com-
pounds.1 Many have been tested for use in agrochemistry,
medicine or as ligands for metal ion complexation.2 Fur-
thermore, 1,2,4-triazines have received considerable at-
tention as heterocyclic azadienes in inverse electron
demand Diels-Alder reactions with electron rich dieno-
philes.3
In the course of our studies on selective metal complex-
ation ligands,4 we were interested on carbon-carbon bond
formation at the 3 position of C-5, C-6 unsubstituted
1,2,4-triazines. The most frequently described synthesis
to C-3 monosubstituted triazines is the heteroatomic ring
formation by condensation of glyoxal with amidrazones
(Scheme).5 Unfortunately, easy access to the cyano pre-
cursor and chemical compatibility with the very nucleo-
philic hydrazine is required. Other methods to
functionalize 1,2,4-triazines at C-3 (metallation,6 halogen
substitution7) have been essentially described for triazines
substituted at C-5, the most reactive position towards nu-
cleophiles.
According to literature, nucleophilic replacement of me-
thylsulfinate group should be a good alternative.8 Unfor-
tunately, the isolation of 3-methylsulfone-1,2,4-triazine
As summarized in Table 2, we examined the cross-cou-
pling reaction of 3-thiomethyl-1,2,4-triazine with various
Scheme
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1437-2096,E;2002,0,03,0447,0450,ftx,en;G34501ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

448
F.-A. Alphonse et al.
LETTER
Table 1 Thiomethyltriazine-Boronic Acid Cross Coupling Conditions
Entry
Boronic acid
equivalent
Reaction Time (h)
Cofactor
Yield
(%)
Conversion (%)
1
2
3
4
5
6
1.1
1.5
2.2
2.2
2.2
2.2
24
24
5
CuMeSal
CuMeSal
CuMeSal
Na2CO3
28
50
85
0
45
60
100
0
24
24
24
Na2CO3, CuI
CuI
27
20
40
25
arylboronic acids.13 The reaction proceeded smoothly to The alkenylboronic acids examined afforded the corre-
afford the corresponding C-3 functionalized triazine prod- sponding 3-alkenyl-1,2,4-triazines in good yields
ucts in good to excellent yields. Both electron-withdraw- (Table 2, Entries 10,11).
ing (Table 2, Entries 3, 5, 8, 9) and electron-donating
Potassium alkenyltrifluoroborates have been described to
substituents (Table 1, Entry 3; Table 2, Entry 4) on the ar-
be: 1) suitable as nucleophiles in the palladium-catalyzed
omatic ring were found to be equally effective irrespective
cross-coupling reaction with arenediazonium salt and 2)
of the electronic effects. It is noteworthy that no homo-
much more efficient than the corresponding organoboron-
coupling adduct was observed using 3-bromophenylbo-
ic acids.15 In our case, with potassium -styryltrifluorob-
ronic
acid
(Table 2,
Entry
6)
and
3-
orate (Table 2, Entry 13), cross-coupled product was
obtained in low yield. This loss of reactivity could be ex-
plained by the fact that boron is already coordinated and
retards reaction by blocking coordination of the Cu (I)
carboxylate to the trivalent boron as suggested by Liebe-
skind and Srogl.10
methylthiophenylboronic acid (Table 2, Entry 7). We be-
lieve that the electron deficient nature of the triazine ring
probably makes this system far more reactive in cross-
coupling compared to the analogous phenyl ring.14 An at-
tempt with furan-2-boronic acid pinacol cyclic ester
(Table 2, Entry 12) was less efficient.
Table 2 Palladium and Copper Mediated Cross Coupling of Organoboron Reagents with 3-Thiomethyl-1,2,4-triazine 1
Entry
1
Substrates
Reaction Time (h) Products
0.5
Yield (%)a
70
3
2
3
24
4
4
5
80b
60
Synlett 2002, No. 3, 447–450 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Palladium-catalyzed 3-Thiomethyltriazine-boronic Acid Cross Coupling
449
Table 2 Palladium and Copper Mediated Cross Coupling of Organoboron Reagents with 3-Thiomethyl-1,2,4-triazine 1 (continued)
Entry
4
Substrates
Reaction Time (h) Products
2
Yield (%)a
60
6
5
6
2
7
8
60
80
17
7
8
17
5
9
80
60
10
9
24c
11
12
60(10)d
10
6
83
11
12
3
13
3
65
48
52 (10)d
13
48
12
42 (22)d
a Isolated yields after column chromatography.
b 10 mol % of Pd(PPh3)4 is necessary for 100% conversion rate.
c Reaction was carried out at reflux.
d In brackets, starting material recovered (%).
In conclusion, we have developed an efficient and useful boronic acids. The presence of copper (I) carboxylate is
synthesis of 3-aryl and 3-alkenyl-1,2,4-triazines starting essential to the success of the reaction.
from readily available 3-thiomethyl-1,2,4-triazine 1 and
Synlett 2002, No. 3, 447–450 ISSN 0936-5214 © Thieme Stuttgart · New York

450
F.-A. Alphonse et al.
LETTER
(9) Paudler, W. W.; Chem, I. K. J. Heterocyclic Chem. 1970, 7,
767.
Acknowledgement
We thank the Commissariat à l’Energie Atomique and the Conseil
Régional de la Région Centre for financial support.
(10) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122,
11260. (b) During the very late stages of the production of
this letter, Liebeskind and Srogl have disclosed to the
authors a prior art manuscript describing a general
heteroaromatic thioether-boronic acid cross-coupling.
(11) (a) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001,
3, 91. (b) Savarin, C.; Liebeskind, L. S. Org. Lett. 2001, 3,
2149.
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(13) Experimental Procedure: The following procedure for the
synthesis of 3-(p-methoxyphenyl)-1,2,4-triazine is
representative. To a mixture of 3-methylthio-1,2,4-triazine 1
(50 mg, 0.393 mmol, 1.0 equiv), CuMeSal (186 mg, 0.867
mmol, 2.2 equiv), p-methoxyphenylboronic acid (132 mg,
0.867 mmol, 2.2 equiv) in dry THF (3 mL) under argon, was
added Pd(PPh3)4 (23 mg, 0.02 mmol, 5% mol). The reaction
was stirred for 5 h at 50 °C. The mixture was quenched with
a Na2CO3 solution (2 N) and extracted with
dichloromethane. The combined organic phases were
washed with a Na2CO3 solution (2 N) and water, dried over
MgSO4 and concentrated in vacuo. After purification by
column chromatography on silica gel (petroleum ether–ethyl
acetate, 70:30), the desired 3-(p-methoxyphenyl)-1.2.4-
triazine 2 was obtained as yellow powder (63 mg, 85%); mp
90–91 °C; (M + H)+ (IS) 188; 1H NMR (250 MHz, CDCl3)
9.08 (d, 1 Htriazine, J = 2.1 Hz); 8.61 (d, 1 Htriazine, J = 2.1 Hz);
8.51 (d, 2 HAr, J = 7 Hz); 7.03 (d, 2 HAr, J = 7Hz); 3.90 (s, 3
HOMe); 13C NMR (62.5 MHz, CDCl3) 164.3, 163.1, 149.0,
147.4, 130.0, 127.6, 114.7, 55.8. Spectroscopic data for 3:
tan solid; mp 75 °C; (M + H)+ (IS) 148; 1H NMR (250 MHz,
CDCl3) 9.09 (d, 1 Htriazine, J = 2.5 Hz), 8.62 (d, 1 Htriazine, J
= 2.5 Hz), 7.72 (dd, 1 Hfuryl, J = 0.9, 1.6 Hz), 7.54 (dd, 1
Hfuryl, J = 0.9, 3.5 Hz), 6.65 (dd, 1 Hfuryl, J = 1.6, 3.5 Hz); 13
NMR (62.5 MHz, CDCl3) 158.1, 149.5, 148.8, 147.2,
146.6, 115.7, 112.3.
C
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Synlett 2002, No. 3, 447–450 ISSN 0936-5214 © Thieme Stuttgart · New York