A general approach to selective functionalization of 1,2,4-triazines using organometallics in palladium-catalyzed cross-coupling and addition reactions

Article abstract of DOI:10.1055/s-2004-834868

A selective way to obtain disubstituted 1,2,4-triazines in good yields by combining addition reactions and palladium-catalyzed cross-coupling reactions of organometallics with 3-methylsulfanyl-1,2,4-triazine is described.

Full text of DOI:10.1055/s-2004-834868

PAPER
2893
A General Approach to Selective Functionalization of 1,2,4-Triazines
Using Organometallics in Palladium-Catalyzed Cross-Coupling and Addition
Reactions
G
eneral
A
ppr
o
r
ac
h
to
S
a
e
lective
F
u
n
nctionalizati
c
e
Triazines -Aimée Alphonse,a,b Franck Suzenet,a Anne Keromnes,b Bruno Lebret,b Gérald Guillaumet*a
a
Institut de Chimie Organique et Analytique (ICOA), LRC M09, CNRS FR 2708, UMR-CNRS 6005, Université d’Orléans,
rue de Chartres, B.P. 6759, 45067 Orléans Cedex 2, France
Fax +33(2)38417281; E-mail: gerald.guillaumet@univ-orleans.fr
Commissariat à l’Energie Atomique, CEA/Le Ripault, B.P. 16, 37260 Monts, France
b
Received 8 February 2004; revised 2 August 2004
At this stage, we thought it would be interesting to be able
to supervise the functionalization order on the 1,2,4-triaz-
ine ring. Therefore, the reactivity of readily available 3-
methylsulfanyl-1,2,4-triazine (1)8 was investigated with
different organometallics: organolithium reagents, Grig-
nard reagents, boronic acids, organostannanes and orga-
nozinc reagents. This paper describes a suitable choice of
organometallics for the selective introduction of a wide
range of substituents at C-3, C-5 and C-6 positions. The
best combination between addition and palladium-cata-
lyzed cross-coupling to obtain 3,5-diaryl-1,2,4-triazines is
also reported. We first tried the addition reactions of orga-
nolithium reagents on 3-methylsulfanyl-1,2,4-triazine (1).
The results are summarized in Table 1.
Abstract: A selective way to obtain disubstituted 1,2,4-triazines in
good yields by combining addition reactions and palladium-cata-
lyzed cross-coupling reactions of organometallics with 3-methyl-
sulfanyl-1,2,4-triazine is described.
Key words: 1,2,4-triazines, palladium, cross-coupling, selective
addition, organometallics, catalysis
1,2,4-Triazine derivatives, especially aryl 1,2,4-triazines,
are well known in therapeutic chemistry as antifungal,1 or
antitumoral,1 in agronomy as insecticides2 and in selective
complexation as metallic cations ligands.3 Many of them
were prepared by cyclization of the triazine ring. 4+2
Atom combination of 1,2-dicarbonyl compounds with
amidrazones is the most frequently described synthesis of
aryl or hetaryl substituted 1,2,4-triazines.4 Unfortunately,
both cyano and diketone precursors are sometimes diffi-
cult to synthesize. Furthermore, diketones have to be sym-
metrical to avoid mixture of isomeric triazines and to
obtain better yields.5
As expected, the addition of 1.25 equivalents of aryllithi-
um to 1 led to 5-substituted compounds and a further oxi-
dation step gave 5-aryl-1,2,4-triazines 2–4 in good yields
(Table 1). Although the oxidation into furyl derivative 3
and pyridinyl derivative 4 with 2,3-dichloro-5,6-dicy-
anobenzoquinone (DDQ) gave byproducts, the use of
milder oxidant MnO2 was successful.
Another way to prepare those substituted triazines is the
direct functionalization of a triazine ring by carbon-car-
bon bond formation.6 Indeed, Yamanaka et al.7 have de-
scribed the addition of phenylmagnesium bromide on
1,2,4-triazines to form 5-phenyl-, 5,6-diphenyl- and 3,5,6-
triphenyl-1,2,4-triazines, subsequently. This study also
showed that the relative reactivity of positions 3, 5 and 6
of the 1,2,4-triazine ring with Grignard reagents is con-
trolled. Indeed, the most active position is position 5 and
the least active is position 3 (Scheme 1).
According to the literature, Grignard reagents react with
heteroaromatic thioethers in palladium or nickel-cata-
lyzed cross-coupling reactions.9,10 We attempted palladi-
um catalyzed cross-coupling reaction conditions on 3-
methylsulfanyl-1,2,4-triazine (1) (Table 2, entry 1). No
coupled product 6 was observed and only the addition
compound, 2,5-dihydro-5-(p-methoxyphenyl)-3-methyl-
sulfanyl-1,2,4-triazine (5) was isolated. A further oxida-
tion step with 1.25 equivalents of DDQ gave
quantitatively the 5-(p-methoxyphenyl)-3-methylsulfa-
nyl-1,2,4-triazine (7). A control experiment showed that
the palladium catalyst is useless and triazine 5 was isolat-
ed in 85% yield without any transition metal (Table 2, en-
try 2).
2nd
N
6
5
N
3
N
1st
3rd
To summarize, regarding Grignard reagents, the C-5 posi-
tion of the 1,2,4-triazine ring is more reactive towards ad-
dition reaction than the C-3 position towards transition
metal catalyzed cross-coupling reaction.
Scheme 1 Reactivity of 1,2,4-triazine towards Grignard reagents
We were then curious to evaluate the behavior of 3-meth-
ylsulfanyl-5-substituted-1,2,4-triazine towards palladi-
um- or nickel-catalyzed cross-coupling reactions. When
5-(2-furyl)-3-methylsulfanyl-1,2,4-triazine (3) was treat-
SYNTHESIS 2004, No. 17, pp 2893–2899
Advanced online publication: 15.10.2004
DOI: 10.1055/s-2004-834868; Art ID: T01604SS
x
x.
x
x
.
2
0
0
4
© Georg Thieme Verlag Stuttgart · New York

2894
F.-A. Alphonse et al.
PAPER
Table 1 Addition Reactions of Aryllithium Reagents with 3-Methylsulfanyl-1,2,4-triazine (1)
H
H
N
H
N
N
H
N
N
Ar-Li
NH
oxidation
N
THF, –78 °C
SMe
(DDQ or MnO2)
N
Ar
SMe
Ar
N
SMe
1
2–4
Entry
1
Time (h)
3
Oxidation conditions
Products
Yield (%)a
1.25 equiv
DDQ, toluene,
r.t., 24 h
60
H
N
N
N
SMe
2
3
2
3
2b
10 equiv
MnO2,
CH2Cl2,
r.t., 24 h
66
70
H
N
N
N
SMe
SMe
O
2
10 equiv
MnO2,
CH2Cl2,
r.t., 24 h
H
N
N
N
N
4
a Yields after column chromatography.
b Reaction was performed in Et2O instead of THF.
However, when 5-(2-furyl)-3-methylsulfanyl-1,2,4-triaz-
ine (3) was treated without catalyst with 2.4 equivalents of
p-methoxyphenylmagnesium bromide in THF for 24
hours, only the addition product 8 was isolated in 45%
yields (Table 3, entry 3). Treatment of non aromatic com-
pound 8 with 1.25 equivalents of DDQ led quantitatively
to 5-(2-furanyl)-6-(p-methoxyphenyl)-3-methylsulfanyl-
1,2,4-triazine (10).
Table 2 Attempt to Palladium and Nickel-Catalyzed Cross-Cou-
pling of p-Methoxyphenylmagnesium Bromide with 1
H
N
N
5
H
N
H
N
NH
N
N
p-MeOPhMgBr
"cat", THF,
+
MeO-Ph
SMe
H
N
Ph-OMe
H
N
SMe
r.t., 24 h
6
1
Considering the lack of selectivity of the transition metal
catalyzed reaction, we thought it would be interesting to
use non-nucleophilic organometallics.
H
N
N
1.25 equiv DDQ,
MeO-Ph
N
SMe
toluene, r.t., 1 h
quant.
Recently, Liebeskind and Srogl indicated11,12 that het-
eroaromatic thioether-boronic acid cross-coupling medi-
ated by copper (I) carboxylates would be feasible. Indeed,
this method has been successfully reported for 3-methyl-
sulfanyl-1,2,4-triazine (1).13 Various 3-aryl-1,2,4-triaz-
ines were obtained in good yields using palladium-
catalyzed cross-coupling reactions between boronic acids
and 3-methylsulfanyl-1,2,4-triazine (1) in the presence of
copper (I) methylsalicylate (CuMeSal) as cofactor
(Scheme 2). The reactions were typically carried out at
55–60 °C in THF using 5–10 mol% of Pd(PPh3)4, 2.2
equivalents of boronic acid and 2.2 equivalents of CuMe-
Sal. No addition product was observed.
7
Entry
Catalyst
5 (%)a
6 (%)
1
2
PdCl2(dppf)
–
73
85
–
–
a Isolated after column chromatography.
ed with 1.2 equivalents of p-methoxyphenylmagnesium
bromide in THF with 10 mol% PdCl2(dppf) for 24 hours,
we isolated a mixture of C-6 addition product 8 (7%) and
C-3 coupled product 9 (20%) (Table 3, entry 1). With
NiCl2(dppe), a few traces of 8 were observed (Table 3, en-
try 2). Although, few palladium catalysts were tested
[Pd(PPh3)4, PdCl2(PPh3)2, Pd2dba3/AsPh3], none was se-
lective towards cross-coupling reaction.
Considering the advantages of using trialkylorganotin
species [they are readily available (especially alkenyl and
heteroaromatic stannanes)],14 we investigated this strate-
gy on heteroaromatic stannanes.15 Many vinyl and aryl-
stannanes were coupled in excellent yields using 2.2
Synthesis 2004, No. 17, 2893–2899 © Thieme Stuttgart · New York

PAPER
General Approach to Selective Functionalization of 1,2,4-Triazines
2895
Table 3 Attempt to Palladium and Nickel-Catalyzed Cross-Coupling of p-Methoxyphenylmagnesium Bromide with 3
H
H
O
N
p-MeO-Ph
N
H
N
N
N
p-MeOPhMgBr
"cat", THF,
N
+
N
Ph-p-OMe
N
SMe
N
SMe
r.t., 24 h
O
O
8
3
9
p-MeO-Ph
O
N
N
1.25 equiv DDQ, toluene,
N
r.t., 1 h
quant.
SMe
10
Entry
Catalyst
PdCl2(dppf)
NiCl2(dppe)
–
8 (%)a
7
9 (%)a
1
2
3
20
–
Traces
45b
–
a Isolated after column chromatography.
b 2.4 Equiv of Grignard reagent were used instead of 1.2 equiv.
N
groups.16 Furthermore, with the growing interest for the
Negishi reaction (among others for the synthesis of bi-
hetaryl compounds),17 many organozinc derivatives are
commercially available or their synthesis is described in
the literature.18
N
2.2 equiv R-B(OH)2, 2.2 equiv CuMeSal,
N
N
Pd(PPh3)4 (5%mol), THF, 50 °C, 5–24 h
N
SMe
N
R
1
X
EWG
EDG
R =
R1
On the basis of recent results of Casalnuovo and
Angiolelli19 on palladium-catalyzed cross-coupling reac-
tions of benzylzinc reagents with methylthio azaheterocy-
cles, 3-methylsulfanyl-1,2,4-triazine (1) was treated with
two equivalents of benzylzinc bromide in THF using 10
mol% of Pd(PPh3)4 (Table 4, entry 1). Surprisingly, we
exclusively isolated the addition product 11 in 73%
yields. The presence of the catalyst is not necessary since
compound 11 was isolated in 60% yield when the reaction
was conducted without palladium (Table 4, entry 2). The
oxidation of the unstable dihydro compound 11 with ten
equivalents of MnO2 led to 13 in 28% yields (Scheme 4).
R1 = Bu, Ph
(65–88%)
X = O, S
(70–80%)
EWG = CN, COMe, EDG = OMe, SMe,
NHCOMe,
(60–85%)
Br, NO2, CF3
(60–85%)
Scheme 2 Palladium and copper mediated cross-coupling of or-
ganoboron reagents with 3-methylsulfanyl-1,2,4-triazine (1)
equivalents of organostannanes, 2.2 equivalents of Cu-
Br·Me2S with 5–10 mol% of Pd(PPh3)4, in refluxing THF
or DME (Scheme 3). No addition product was observed.
We were then interested in organozinc compounds. They
are versatile reagents for metal catalyzed cross-coupling
reactions and are compatible with many functional
We also tested palladium-catalyzed cross-coupling reac-
tions between phenylzinc bromide and 3-methylsulfanyl-
1,2,4-triazine (1) under similar conditions. In this case 3-
phenyl-1,2,4-triazine (12) was isolated in 30% yield
(Table 4, entry 3) probably due to the lower nucleophilic
phenylzinc reagent.
N
N
N
2.2 equiv R-SnBu3, 2.2 equiv CuBr·Me2S,
N
N
Pd(PPh3)4 (5–10 mol%), THF or DME,
reflux, 5–48 h
N
SMe
At this stage, we investigated whether the original func-
tionalization order (C-5, C-6 and C-3) of the 1,2,4-triazine
ring towards nucleophiles could be deliberately modified
using different organometallics species.
R
1
X
R =
R2
Ph
N
We examined two pathways to obtain regioselectively
3,5-disubstituted-1,2,4-triazines starting from 3-methyl-
sulfanyl-1,2,4-triazine (1):
R2 = OMe (80%)
NO2 (80%)
X = O (90%)
S (90%)
(60%)
(70%)
Scheme 3 Palladium and copper mediated cross-coupling of orga-
nostannane reagents with 3-methylsulfanyl-1,2,4-triazine (1)
Pathway 1: addition reaction + cross-coupling reaction
Pathway 2: cross-coupling reaction + addition reaction
Synthesis 2004, No. 17, 2893–2899 © Thieme Stuttgart · New York

2896
F.-A. Alphonse et al.
PAPER
Table 4 Addition Reactions and Palladium-Catalyzed Cross-Coupling of 3-Methylsulfanyl-1,2,4-triazine (1) with Organozinc Reagents in
THF for 48 h
Entry
1
Ar-ZnBr
Time(h)
48
Catalyst
Products
Yield (%)a
73
ZnBr
Pd(PPh3)4
H
N
N
NH
SMe
11
11
2
3
48
2
/
60
Pd(PPh3)4
30b
ZnBr
N
N
N
12
a Isolated yields after column chromatography.
b Reaction was performed with 20 mol% of Pd(PPh3)4.
H
N
N
H
N
NH
N
10 equiv MnO2, CH2Cl2, r.t., 24 h
28%
SMe
N
SMe
13
11
Scheme 4 Oxidation of 2,5-dihydro-5-benzyl-3-methylsulfanyl-1,2,4-triazine (11) with MnO2
As summarized in Table 5, addition products 3, 4 and 7 In conclusion, we have extended addition reactions on
were coupled with p-methoxyphenyl boronic acid in the 1,2,4-triazines to organolithiums and benzylzinc reagents.
presence of palladium and CuMeSal,13 to afford 3,5-di- Furthermore, 3-methylsulfanyl-1,2,4-triazine (1) was suc-
substituted-1,2,4-triazines 9, 14 and 15, respectively, in cessfully coupled with boronic acids and organostannanes
good yields (pathway 1). In the case of 3-(p-methoxyphe- in the presence of copper (I) and a catalytic amount of
nyl)-5-(pyridin-2-yl)-1,2,4-triazine (14), 3.2 equivalents Pd(PPh3)4.
of CuMeSal were necessary to observe complete cross-
With all those new functionalization tools combined with
coupling reaction probably because of complexation of
Yamanaka’s results,7 one can regioselectively functional-
copper in the coordination site N-C-C-N of the starting
ize the 1,2,4-triazine ring to obtain 5-aryl-, 3-aryl-, 3,5-di-
material 4.
aryl-, 5,6-diaryl- and 3,5,6-triaryl-1,2,4-triazines
The same 3,5-disubstituted-1,2,4-triazines 9, 14 and 15 (Scheme 6).
were also isolated when the coupled product 613,15 was
treated with selected aryllithiums and Grignard reagents
RMgX
N
(pathway 2).
N
6
5
3
To sum up, the functionalization order of the 1,2,4-triaz-
ine ring can be easily modified (Scheme 5): position 3 can
be first substituted followed by position 5 or position 5
can be first substituted followed by position 3, both of
them leading to similar yields.
N
RMgX,
RLi,
BnZnX
RB(OH)2,
RSnBu3,
ArZnX
Scheme 6 New tools to functionalize the 1,2,4-triazine ring
N
6
1H NMR and 13C NMR spectra were recorded on a Bruker Avance
250 MHz spectrometer. H NMR spectra are reported as follows:
N
1
5
3
N
1st or 2nd
chemical shifts in ppm (d) downfield from TMS as an internal stan-
dard, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet and br = broadened), integration and coupling con-
stants spectra (Hz). 13C NMR spectra reported in ppm (d) relative to
the central line of triplet for CDCl3 at 77 ppm. IR spectra were re-
corded on a Perkin-Elmer FT PARAGON 1000PC spectrometer
2nd or 1st
Scheme 5 Alternative functionalization orders of 1,2,4-triazine
Synthesis 2004, No. 17, 2893–2899 © Thieme Stuttgart · New York

PAPER
General Approach to Selective Functionalization of 1,2,4-Triazines
2897
Table 5 Different Combinations Between Addition Reaction and Cross-Coupling Reaction Starting with 1
N
Pathway 1
N
Ar1
N
SMe
Ar2-M2
Ar1-M1
3, 4, 7
N
N
N
N
N
Ar1
Ar2
N
SMe
1
9, 14, 15
Ar2-M2
Pathway 2
N
Ar1-M1
N
N
Ar2
6
Entry
1
Ar1-M1
Ar2-M2
Products, Yields (pathway 1/pathway 2) (%)a
O
9, 44:17
B(OH)2
B(OH)2
B(OH)2
Li
MeO
MeO
MeO
2
3
14, 55:55
15, 55:47
N
Li
MgBr
MeO
a Isolated after column chromatography.
and absorption are reported in cm–1. HRMS (CI) were acquired on
a Thermofinnigan-MAT instrument 95 XL Analytical spectrome-
ter. Melting points, uncorrected values, were measured on a Büchi
510 instrument. Microanalyses were taken on a ThermoFinnigan
Flash EA1112 CHNS/O + MAS apparatus. Analytical TLC was
performed on 0.2 mm precoated Kieselgel 60 F254 (Merck) plates.
5-(2-Furanyl)-3-methylsulfanyl-1,2,4-triazine (3)
Purified by flash chromatography (silica gel, petroleum ether–
EtOAc, 70:30). Yield: 66%; yellow solid; mp 83–85 °C (lit.20 mp
88–90 °C).
IR (KBr): 1490, 1253, 1107, 767 cm–1.
1H NMR (CDCl3): d = 9.22 (s, 1 H), 7.71 (m, 1 H), 7.46 (d, J = 3.4
Hz, 1 H), 6.65 (dd, J = 2.3, 3.7 Hz, 1 H), 2.69 (s, 3 H).
THF and 1,2-dimethoxyethane (DME) were distilled over sodium
and benzophenone before use. 3-Methylsulfanyl-1,2,4-triazine (1)
was prepared according to the litterature.8 Compounds 6 and 12
were described in previous papers.13,15 All other compounds used
were commercially available.
13C NMR (CDCl3): d = 173.7, 149.1, 147.6, 146.1, 140.5, 116.9,
113.7, 14.2.
3-Methylsulfanyl-5-(pyridin-2-yl)-1,2,4-triazine (4)
Purified by flash chromatography (silica gel, petroleum ether–
EtOAc–Et3N, 90:10:01). Yield: 70%; yellow solid; mp 128–130 °C.
IR (KBr): 1533, 1507, 1469, 1311, 1301, 1234 cm–1.
1H NMR (CDCl3): d = 9.95 (s, 1 H), 8.79–8.76 (m, 1 H), 8.51 (d,
J = 7.9 Hz, 1 H), 7.89 (td, J = 1.8, 7.9 Hz, 1 H), 7.48 (ddd, J = 1.2,
4.9, 7.9 Hz, 1 H), 2.77 (s, 3 H).
13C NMR (CDCl3): d = 173.5, 153.2, 151.7, 150.1, 142.7, 137.4,
126.6, 123.0, 14.1.
Addition of Organolithium Derivatives; Typical Procedure
To a solution of 3-methylsulfanyl-1,2,4-triazine (1) (100 mg, 0.79
mmol) in anhyd THF (3 mL) cooled to –78 °C under Ar was added
dropwise phenyllithium (2 M, 500 mL, 1.25 equiv). The reaction
mixture was kept at this temperature for 3 h and then was allowed
to warm to r.t. over a period of 2 h. The reaction was quenched with
a sat. solution of NH4Cl and extracted twice with Et2O. The crude
product was dissolved in toluene (7 mL) under Ar and 2,3-dichloro-
5,6-dicyanoquinone (188 mg, 1.25 equiv) was added by portion. Af-
ter stirring for 1 h at r.t., the reaction mixture was filtrated on celite
and the filtrate was diluted with a sat. solution of K2CO3 and ex-
tracted with CH2Cl2. Purification by flash chromatography (silica
gel, petroleum ether–EtAOc, 90:10) afforded aromatic product 2
(96 mg, 60% yield) as a pale yellow solid.
HRMS (CI): m/z [M + H]+ calcd for C9H9N4S: 205.0548; found:
205.05420.
Addition of Organomagnesium Derivatives; Typical Procedure
To a solution of 3-methylsulfanyl-1,2,4-triazine (1) (200 mg, 1.57
mmol) in anhyd THF (5 mL) under Ar was added dropwise p-meth-
oxyphenylmagnesium bromide (0.5 M, 3.8 mL, 1.2 equiv.) at r.t.
The reaction mixture was stirred for 20 h, was then diluted with a
sat. solution of NH4Cl and extracted twice with CH2Cl2. Purifica-
tion by flash chromatography (silica gel, petroleum ether–EtOAc,
70:30) afforded non-aromatic product 5 (314 mg, 85% yield) as a
pale yellow oil. Oxidative step with 2,3-dichloro-5,6-dicyanoquino-
ne was carried like in the case of organolithium. Purification by
flash chromatography (silica gel, petroleum ether–EtAOc, 50:50)
3-Methylsulfanyl-5-phenyl-1,2,4-triazine (2)6e,8
Yields 60%; pale yellow solid; mp 97–99 °C (lit.8 mp 99–100 °C).
IR (NaCl): 1597, 1538, 1501, 1237, 761, 663 cm–1.
1H NMR (CDCl3): d = 9.37 (s, 1 H), 8,15 (dd, J = 1.6, 7.9 Hz, 2 H),
7.61-7.55 (m, 3 H), 2.73 (s, 3 H).
13C NMR (CDCl3): d = 173.9, 154.6, 142.0, 133.2, 132.8, 129.5
(2 × C), 127.8 (2 × C), 13.9.
Synthesis 2004, No. 17, 2893–2899 © Thieme Stuttgart · New York

2898
F.-A. Alphonse et al.
PAPER
5-Benzyl-2,5-dihydro-3-methylsulfanyl-1,2,4-triazine (11)
afforded quantitatively aromatic product 7 (311 mg) as a yellow
powder.
Yield: 60%; orange oil.
IR (NaCl): 3019, 1215, 771 cm–1.
2,5-Dihydro-5-p-methoxyphenyl-3-methylsulfanyl-1,2,4-triaz-
ine (5)
Yield: 85%; yellow pale oil.
1H NMR (CDCl3): d = 8.39 (br s, 1 H, NH), 7.29 (d, J = 8.4 Hz, 2
H), 6.90 (d, J = 8.4 Hz, 2 H), 6.75 (d, J = 2.2 Hz, 1 H), 6.68 (d, J =
2.2 Hz, 1 H), 3.79 (s, 3 H), 2.44 (s, 3 H).
13C NMR (CDCl3): d = 159.5, 154.7, 141.5, 133.1, 129.9 (2 × C),
114.5 (2 × C), 57.9, 55.7, 14.0.
1H NMR (CDCl3): d = 7.09 (br s, 1 H, NH), 7.34–7.21 (m, 5 H), 6.64
(d, J = 3.4 Hz, 1 H), 3.98 (ddd, J = 2.0, 6.5, 8.2 Hz, 1 H), 3.09–3.03
(dd, J = 6.4, 13.5 Hz, 1 H), 2.95–2.86 (dd, J = 6.4, 13.5 Hz, 1 H),
2.44 (s, 3 H).
13C NMR (CDCl3): d = 154.8, 141.3, 137.6, 129.6 (2 × C), 128.5
(2 × C), 126.6, 55.9, 38.9, 13.7.
5-Benzyl-3-methylsulfanyl-1,2,4-triazine (13)
Yield: 28%; brown oil.
IR (NaCl): 3241, 3160, 3056, 3003, 1725, 1677, 1530, 1142 cm–1.
1H NMR (CDCl3): d = 8.21 (s, 1 H), 7.40–7.25 (m, 5 H), 4.29 (s, 2
H), 2.67 (s, 3 H).
5-p-Methoxyphenyl-3-methylsulfanyl-1,2,4-triazine (7)20,21
Quantitative yield; yellow powder; mp 108–110 °C (lit.20 mp 106–
107 °C).
IR (KBr): 3074, 3002, 2927, 2839, 1603, 1506, 1243, 1175 cm–1.
13C NMR (CDCl3): d = 156.5, 149.0, 143.6, 134.7, 129.6 (2 × C),
129.2 (2 × C), 128.8, 39.6, 14.1.
1H NMR (CDCl3): d = 9.25 (s, 1 H), 8.07 (d, J = 9.1 Hz, 2 H), 6.98
(d, J = 9.1 Hz, 2 H), 3.86 (s, 3 H), 2.68 (s, 3 H).
13C NMR (CDCl3): d = 173.1, 163.3, 153.7, 141.2, 129.3 (2 × C),
124.9, 114.6 (2 × C), 55.4, 13.6.
Anal. Calcd for C11H11N3S: C, 60.80; H, 5.10; N, 19.34; S, 14.76.
Found: C, 60.52; H, 5.15; N, 19.26; S, 14.71.
Palladium-Catalyzed Cross-Coupling Reaction with Boronic
Acids; Typical Procedure
1,6-Dihydro-5-(2-furanyl)-6-p-methoxyphenyl-3-methylsulfa-
nyl-1,2,4-triazine (8)
Purified by flash chromatography (silica gel, petroleum ether–
To
a mixture of 5-substituted-3-methylsulfanyl-1,2,4-triazine
(0.393 mmol, 1.0 equiv), CuMeSal (0.867 mmol, 2.2 equiv), boron-
ic acid (0.867 mmol, 2.2 equiv) in anhyd THF (3 mL) under Ar, 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, 5 mL) and extracted with CH2Cl2 (3 × 5 mL). The
combined organic phases were washed with a Na2CO3 solution (2
N, 15 mL) and water, dried over MgSO4 and concentrated in vacuo.
The products were purified by column chromatography on silica
gel.
EtOAc: 70:30). Yield: 45%; red oil.
IR (NaCl): 3452, 2940, 2846, 1608, 1510, 1252, 1177, 1029, 756
cm–1.
1H NMR (CDCl3): d = 7.58 (d, J = 1.6 Hz, 1 H), 7.20 (d, J = 8.8 Hz,
2 H), 7.02 (d, J = 3.1 Hz, 1 H), 6.83 (d, J = 8.8 Hz, 2 H), 6.50 (dd,
J = 1.6, 3.1 Hz, 1 H), 6.3 (br s, 1 H, NH), 5.13 (s, 1 H), 3.76 (s, 3
H), 2.34 (s, 3 H).
13C NMR (CDCl3): d = 159.9, 152.6, 150.2, 150.0, 146.7, 129.3,
128.4 (2 × C), 117.1, 114.3 (2 × C), 112.8, 55.3, 50.9, 13.6.
5-(2-Furanyl)-3-(p-methoxyphenyl)-1,2,4-triazine (9)
Purified by flash chromatography (silica gel, petroleum ether–
EtOAc, 95:5). Yield: 70%; yellow solid; mp 144–146 °C.
IR (KBr): 2956, 2924, 2854, 1610, 1599, 1535, 1259 cm–1.
1H NMR (CDCl3): d = 9.39 (s, 1 H), 8.54 (d, J = 9.1 Hz, 2 H), 7.73
(m, 1 H), 7.57 (d, J = 3.7 Hz, 1 H), 7.04 (d, J = 9.1 Hz, 2 H), 6.68
(dd, J = 1.8, 3.7 Hz, 1 H), 3.91 (s, 3 H).
5-(2-Furanyl)-6-p-methoxyphenyl-3-methylsulfanyl-1,2,4-tri-
azine (10)
Purified by flash chromatography (silica gel, petroleum ether–
EtOAc, 50:50). Quantitative yield; red oil.
IR (NaCl): 3137, 3118, 2928, 2835, 1609, 1573, 1523, 1480, 1358,
1250, 1185, 1054, 832 cm–1.
1H NMR (CDCl3): d = 7.57 (dd, J = 0.6, 1.9 Hz, 1 H), 7.50 (d, J =
8.8 Hz, 2 H), 7.0 (d, J = 8.8 Hz, 2 H), 6.70 (dd, J = 0.6, 3.6 Hz, 1
H,), 6.43 (dd, J = 1.9, 3.6 Hz, 1 H,), 3.88 (s, 3 H), 2.74 (s, 3 H).
13C NMR (CDCl3): d = 170.7, 160.9, 151.4, 148.7, 146.8, 144.7,
130.5 (2 × C), 127.8, 118.7, 114.2 (2 × C), 112.6, 55.5, 14.0.
HRMS (CI): m/z [M + H]+ calcd for C15H14N3O2S: 300.0807; found:
13C NMR (CDCl3): d = 163.4, 163.0, 149.9, 147.2, 142.2, 130.5
(2 × C), 127.8, 126.3, 116.1, 114.5 (2 × C), 113.5, 55.8.
HRMS (CI): m/z [M + H]+ calcd for C4H12N3O: 254.0930; found:
254.09325.
3-(p-Methoxyphenyl)-5-(pyridin-2-yl)-1,2,4-triazine (14)
Purified by flash chromatography (silica gel, petroleum ether–
EtOAc: 80:20). Yield: 79%; yellow solid; mp 147–149 °C.
300.08001.
Addition of Organozinc Derivatives; Typical Procedure
3-Methylsulfanyl-1,2,4-triazine (1) (200 mg, 1.57 mmol) was
placed in a 25 mL Schlenk tube under Ar and a solution of benzyl-
zinc bromide (0.5 M in THF, 6.3 mL, 2 equiv) was added dropwise
at r.t. After stirring for 24 h, the reaction mixture was quenched with
a sat. solution of NaHCO3, filtrated on celite and extracted twice
with EtOAc. Purification by flash chromatography (silica gel, pe-
troleum ether–EtOAc, 95:5) afforded non-aromatic product 11 (206
mg, 60% yield) as an orange oil. To a solution of 2,5-dihydro-5-ben-
zyl-3-methylsulfanyl-1,2,4-triazine (11) (136 mg, 0.66 mmol) in
CH2Cl2 (10 mL) under Ar was added MnO2 (1.1 g, 10 equiv) por-
tiowise. After stirring for 24 h at r.t., the reaction mixture was fil-
trated on celite. Purification by flash chromatography (silica gel,
petroleum ether–EtAOc: 95:5) afforded aromatic product 13 (80
mg, 28% yield) as a brown oil.
IR (KBr): 1609, 1537, 1257, 1027, 782 cm–1.
1H NMR (CDCl3): d = 10.11 (s, 1 H), 8.71–8.69 (m, 1 H), 8.69 (d,
J = 7.8 Hz, 1 H), 8.68–8.59 (m, 2 H), 7.98–7.91 (td, J = 2.0, 7.8 Hz,
1 H), 7.25–7.47 (ddd, J = 1.2, 4.6, 7.8 Hz, 1 H), 7.09–7.05 (m, 2 H),
3.92 (s, 3 H).
13C NMR (CDCl3): d = 163.0, 162.8, 153.6, 152.5, 149.9, 144.2,
137.4, 130.2 (2 × C), 127.6, 126.4, 122.8, 114.3 (2 × C), 55.5.
HRMS (CI): m/z [M + H]+ calcd for C15H13N4O: 265.1089; found:
265.10885.
3,5-bis-(p-Methoxyphenyl)-1,2,4-triazine (15)
Purified by flash chromatography (silica gel, petroleum ether–
EtOAc: 90:10). Yield: 80%; yellow solid; mp 139–141 °C.
Synthesis 2004, No. 17, 2893–2899 © Thieme Stuttgart · New York

PAPER
General Approach to Selective Functionalization of 1,2,4-Triazines
2899
IR (KBr): 1606, 1510, 1498, 1252, 1167 cm–1.
van der Plas, H. C. Org. Prep. Proced. Int. 2001, 33, 501–
514. (d) Szczepkowska-Sztolcman, J.; Katrusiak, A.;
Wojtowicz-Rajchel, H.; Golankiewicz, K. J. Chem. Soc.,
Perkin Trans. 1 2002, 2549; and references cited therein.
(e) Branowska, D.; Ostrowski, S.; Rykowski, A. Chem.
Pharm. Bull. 2002, 50, 463.
1H NMR (CDCl3): d = 9.42 (s, 1 H), 8.57 (d, J = 9.0 Hz, 2 H), 8.20
(d, J = 9.0 Hz, 2 H), 7.04 (d, J = 9.0 Hz, 4 H), 3.88 (s, 3 H), 3.87 (s,
3 H).
13C NMR (CDCl3): d = 163.2, 162.9, 162.6, 154.4, 143.1, 130.1
(2 × C), 129.3 (2 × C), 127.8, 126.1, 114.8 (2 × C), 114.2 (2 × C),
55.6, 55.5.
(7) Konno, S.; Sagi, M.; Yoshiba, N.; Yamanaka, H.
Heterocycles 1987, 26, 3111.
(8) Paudler, W. W.; Chem, I. K. J. Heterocycl. Chem. 1970, 7,
HRMS (CI): m/z [M + H]+ calcd for C17H16N3O2: 294.1243; found:
294.12386.
767.
(9) Pridgen, L. N.; Killmer, L. B.; Lee Webb, R. J. Org. Chem.
1982, 47, 1985.
Acknowledgment
(10) (a) Pridgen, L. N.; Jones, S. S. J. Org. Chem. 1982, 47,
1590. (b) Alvarez-Ibarra, C.; Asperilla, R.; de Dios-
Corredor, C.; Martinez-Santos, E.; Luz Quiroga, M.
Heterocycles 1991, 32, 2127.
We thank the Commissariat à l’Energie Atomique and the Conseil
Régional du Centre for financial support.
(11) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122,
11260.
(12) (a) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001,
3, 91. (b) Savarin, C.; Liebeskind, L. S. Org. Lett. 2001, 3,
2149.
References
(1) Lacefield, W. B. US Patent, US 3948894, 1974; Chem.
Abstr. 1974, 85, 33089.
(13) Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.;
Guillaumet, G. Synlett 2002, 447.
(14) (a) Pereyre, M.; Quintard, J.-P.; Rahm, A. Tin in Organic
Synthesis; Butterworth: London, 1987. (b) Lee, A. S.-Y.;
Dai, W.-C. Tetrahedron 1997, 53, 859; and references
therein. (c) Smith, N. D.; Mancuso, J.; Lautens, M. Chem.
Rev. 2000, 100, 3257.
(2) (a) Neunhoeffer, H. In Chemistry of Heterocyclic
Compounds, Vol. 33; Weissberger, A.; Taylor, E. C., Eds.;
J. Wiley Interscience: New York, 1978, 189. (b) Konno, S.;
Osawa, N.; Yamanaka, H. J. Agric. Food Chem. 1995, 43,
838.
(3) Gschneidner, K. A.; Eyring, L.; Choppin, G. R.; Lander, G.
H. Handbook on the Physics and Chemistry of Rare Earths,
Vol. 18; Gschneidner, K. A.; Eyring, L., Eds.; Elsevier: New
York, 1994, 197–238.
(15) Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.;
Guillaumet, G. Org. Lett. 2003, 5, 803.
(16) Metal-catalysed Cross-coupling Reactions; Diederich, F.;
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
(17) (a) Gros, P.; Fort, Y. Synthesis 1999, 754. (b) Fang, Y.-Q.;
Hanan, G. S. Synlett 2003, 852. (c) Sakamoto, T.; Kondo,
Y.; Murata, N.; Yamanaka, H. Tetrahedron Lett. 1992, 33,
5373.
(18) Knochel, P.; Almena Perea, J. J.; Jones, P. Tetrahedron
1998, 54, 8275.
(19) Angiolelli, M. E.; Casalnuovo, A. L.; Selby, T. P. Synlett
2000, 905.
(4) (a) Neunhoeffer, H. In Comprehensive Heterocyclic
Chemistry II, Vol. 6; Katrizky, A. R.; Rees, C. W.; Scriven,
E. F. V., Eds.; Pergamon Press: Oxford, 1996, 507.
(b) Zhao, Z.; Leister, W. H.; Strauss, K. A.; Wisnoski, D. D.;
Lindsley, C. W. Tetrahedron Lett. 2003, 44, 1123.
(5) (a) Limanto, J.; Desmond, R. A.; Gauthier, D. R.; Devine, P.
N.; Reamer, R. A.; Volante, R. P. Org. Lett. 2003, 5, 2271.
(b) Ohsumi, T.; Neunhoffer, H. Tetrahedron 1992, 48, 651.
(c) Taylor, E. C.; French, L. G. J. Org. Chem. 1989, 54,
1245.
(20) Heilman, W. P.; Heilman, R. D.; Scozzie, J. A.; Wayner, R.
J.; Gullo, J. M.; Ariyan, Z. S. J. Pharm. Sci. 1980, 69, 282.
(21) Taylor, E. C.; Pont, J. L.; Warner, J. C. Tetrahedron 1987,
43, 5159.
(6) (a) Charushin, V. N.; Alexeev, S. G.; Chupakhin, O. N. Adv.
Heterocycl. Chem. 1989, 46, 73; and references cited
therein. (b) Rykowski, A.; Makoska, M. Liebigs Ann. Chem.
1988, 627. (c) Rykowski, A.; Olender, E.; Branowska, D.;
Synthesis 2004, No. 17, 2893–2899 © Thieme Stuttgart · New York