New heteroaromatic aminations on 5-aryl-1,2,4-triazines and 1,2,4,5-tetrazines by palladium catalysis

Article abstract of DOI:10.1016/j.tet.2010.03.099

The efficient and original palladium-catalyzed amination of 5-Aryl-1,2,4-triazines and 1,2,4,5-tetrazines is reported. This Buchwald-Hartwig type reaction leads to the formation of aminated heterocycles via methylsulfur release. The reaction is optimized and a wide range of amines is used to determine the scope and limitations of this methodology.

Full text of DOI:10.1016/j.tet.2010.03.099

Tetrahedron 66 (2010) 4383e4389
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Tetrahedron
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New heteroaromatic aminations on 5-aryl-1,2,4-triazines and 1,2,4,5-tetrazines
by palladium catalysis
,
Laurent Pellegatti a, Emeline Vedrenne a, Jean-Michel Leger b, Christian Jarry b, Sylvain Routier a
*
a Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 6005, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France
b EA 4138, Pharmacochimie, Université Victor Segalen Bordeaux II, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficient and original palladium-catalyzed amination of 5-Aryl-1,2,4-triazines and 1,2,4,5-tetrazines
is reported. This BuchwaldeHartwig type reaction leads to the formation of aminated heterocycles via
methylsulfur release. The reaction is optimized and a wide range of amines is used to determine the
scope and limitations of this methodology.
Received 16 February 2010
Received in revised form 22 March 2010
Accepted 26 March 2010
Available online 14 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
envisioned the development of methodologies giving access to
such aminated heterocycles.
Pyrimidines are important scaffolds, which have attracted in-
terest in the scientific community. Indeed this skeleton is present in
many natural products and a variety of biologically active com-
pounds. Among them, 2-aminopyrimidines cores are particularly
interesting as they were found in molecules exhibiting promising
antifungal, insecticide (Scheme 1, I),1 antihistaminic, anti-
anaphylactic,2 antitumoral (II-IV),3 and antidepressant activities.4
We recently described the C-3 palladium-catalyzed amination
of 3-methylsulfanyl-1,2,4-triazines.6,7 This desulfurative cross-
coupling reaction8 proved to be highly efficient in the presence of
Cs2CO3, Pd(OAc)2, Xantphos, and CuMeSal,9 under microwave ir-
radiations. Herein, we would like to complete our proposal and
broaden this methodology to the use of accessible 5-aryl-3-meth-
ylsulfanyl-1,2,4-triazines and 3,6-dimethylsulfanyl-1,2,4,5-tetra-
zine as starting materials (Scheme 2).
CN
H
N
N
R1
R2
N
N
N
O
N
CO2Me
(1.2 equiv.)
N
H
N
N
SO2
R2
R
S
N
R= Ar
S
N
N
N
H
N
H
N
CuMeSal, Cs2CO3,
Pd(OAc)2, Xantphos
R
S
N
R = Ar
R1
R1 = Ar,
N
N
OH
I
H
(Het)Ar
II
N
NH2
N
N
toluene, 170°C
N
R2 = H
F
microwave irradiations
N
N
R2
S
N
S
N
MeO
F
R1
SO2Me
N
O
N
Scheme 2. Desulfurative cross-coupling reaction in triazine and tetrazine series.
N
N
H
NO2
N
N
H
III
IV
2. Results and discussion
Scheme 1. Biologically active 2-aminopyrimidines.
2.1. Preparation of 5-aryl-3-SMe-1,2,4-triazines
Based on the interests of our group in the synthesis of bi-
ologically active compounds, we thought that a functionalized
3-amino-1,2,4-triazines and 3-amino-1,2,4,5-tetrazines,5 could be
considered as aza-bioisosters of 2-aminopyrimidines. We thus
3-SMe-1,2,4-triazines were thus chosen as new targets for our
palladium-catalyzedamination. Theyweresynthesizedbythepartial
oxidation of the corresponding acetophenones by SeO2, followed by
the quench of the glyoxal intermediates (not isolated) with methyl-
thiosemicarbazide, as limiting reactant, in basic media (Table 1).10
The desired triazines were obtained in good to excellent yields,
except for compound 3, which was only isolated in 55% yield. Steric
hindrance of the OMe group could explain this lack of reactivity.
* Corresponding author. Tel.: þ33 238 494 853; fax: þ33 238 417 281; e-mail
address: sylvain.routier@univ-orleans.fr (S. Routier).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.099

4384
L. Pellegatti et al. / Tetrahedron 66 (2010) 4383e4389
Table 1
Synthesis of derivatives 1e5
already been observed with electron-enriched anilines in our last
report.
In order to propose an alternative pathway giving access to 7, we
N
O
N
1) SeO2 (1.1 equiv.), dioxane / H2O, rflx, 4 h
R
R
also envisioned its preparation by nucleophilic substitution. Under
numerous reaction conditions, the direct reaction of 1 with p-OMe
aniline failed, indicating that palladium catalysis is required for the
sulfanylmethyl displacement. We then oxidized the sulfur atom of 1
at room temperature in the presence of m-CPBA. Nevertheless,
a mixture of the corresponding sulfoxide and sulfone was obtained
(Scheme 3). These compounds were too unstable to be purified and
the crude mixture was engaged in the next step.
N
S
2) methyl thiosemicarbazide (0.66 equiv.)
Na2CO3 (0.73 equiv.), H2O / EtOH, 0°C, 6 h
1-5
Entry
1
R
Product
Yielda (%)
Quant.
p-OMe
m-OMe
1
2
N
N
OMe
2
73
N
SO
CH3
N
N
N
MeO
NH2
m-CPBA
+
1
NH
3
4
o-OMe
p-F
3
4
55
87
N
N
EtOH
r.t., 1h
CH2Cl2
r.t., 2h
N
MeO
SO2
CH3
7, 45%
MeO
OMe
Scheme 3. Nucleophilic substitution leading to compound 7.
The nucleophilic substitution with 4-methoxyaniline occurred
but led to 7 in only 45% yield. Our convenient palladium-catalyzed
methodology under microwave irradiation gave 7 with a better
yield and with fewer steps.
5
p-NO2
5
72
a
Yields are given for isolated products.
2.2. Optimization of the conditions for the preparation of
derivative 7
2.3. Scope and limitations of aminations
In order to explore scope and limitations of this methodology,
we next envisioned to modify the nature of the amine (Table 3)
using our previously optimized conditions. The use of 3-methoxy-
aniline with 1 afforded the 3-aminotriazine 8 in 75% yield. The
displacement of the electron-donating from the C-4 to the C-3
position of the aniline diminished the nitrogen nucleophilic effect
and also the efficiency of the cross-coupling reaction (entries 1).
The same behavior was observed with 4-methylaniline and aniline
(entries 2 and 3).
With those five compounds in hand, we then tried to achieve the
methylsulfur displacement of triazine 1 using the conditions we re-
cently described for the synthesis of triazine 6 (Table 2, entry 1).6,11
Table 2
Optimization of the conditions for the preparation of derivative 7
Table 3
Synthesis of derivatives 8e27
Entry
R
Time
Product
Yield (%)
1
2
3
4
H
2 h
25 min
2 h
6
7
7
7
91
13a
66a
81
p-OMe phenyl
p-OMe phenyl
p-OMe phenyl
3 h
a
Some starting material was recovered.
Entry
1
R
R1R2NH
Product
Yield (%)
75
Several assays were performed to optimize the reaction time for
these new triazine series. Compound 1 and 4-methoxyaniline were
irradiated in toluene at 170 ꢀC for 25 min in the presence of Cs2CO3,
copper(I) 3-methylsalicylate (CuMeSal), and Pd(OAc)2/Xantphos
(respectively 10 mol % and 20 mol %) as catalytic system. Only 13%
of the desired aminotriazine 7 were isolated (entry 2) after purifi-
cation. Fortunately, an increase of the reaction time to 2 h led to the
isolation of 66% of 7 (entry 3). In each reaction some starting ma-
terial was characterized, indicating an incomplete reaction.
p-OMe
m-OMe aniline
2
3
p-OMe
p-OMe
p-Me aniline
72
67
aniline
Finally, 3-methylsulfanyltriazine 1 was fully consumed after 3 h
of microwave irradiations, yielding to 7 in 81% yield (entry 4). No
starting material was detected. The presence of the C-5 aryl group,
bearing an electron-donating group, on the triazine seems to
slightly decrease the reactivity of the C-3 sulfanylmethyl leaving
group, as only 2 h were needed to obtain complete conversion with
C-3 unsubstituted triazines (entry 1).6 A similar behavior has
4
5
p-OMe
p-OMe
p-Cl aniline
m-Cl aniline
64
55

L. Pellegatti et al. / Tetrahedron 66 (2010) 4383e4389
4385
Table 3 (continued)
aminopyridine, n-butylamine and piperidine, only led to starting
material 1 (entries 14e16).
The BuchwaldeHartwig amination by S-alkyl displacement
appeared as very efficient when steric effects and nucleophilic
depletion are minored for the amine. The presence of acidic hy-
drogens deactivates the catalytic system.
Entry
R
R1R2NH
Product
Yield (%)
62
6
p-OMe
3,5-difluoroaniline
To close our investigations on the 1,2,4-triazine series, we were
then interested in the variation of the substitution on the C-5 aryl
ring and thus used derivatives 2e5 with 4-OMe aniline (entries
17e20). Whatever the position and the electronic effect of the C-5
phenyl substituents were, the reactions were performed without
any difficulties. Slight variations in yields were mainly due to the
purification step.
7
8
p-OMe
p-OMe
p-NO2 aniline
p-CF3 aniline
60
59
All the NMR, IR, and HMRS spectral data are in concordance with
the structure of the synthesized 3-aminotriazines 7e15, 20, 24e27.
In addition, X-ray crystallography of 10 confirmed that the ami-
nation was achieved (Fig. 1). The N(7) is in the sp3 hybridation state
with N(7)dC(8) and N(7)dC(6) single bonds at 1.361(2) and 1.405
(3) Å, respectively. A hydrogen bond occurs between N(7)(x,y,z) and
N(12)(xꢁ1,y,z) with N(7)/H(7)/N(12)¼2.953(3) Å. The triazine
ring is almost planar. The angle between plane I [C(1),C(2),C(3),C(4),
C(5),C(6)] and plane II [C(8),N(9),C(10),C(11),N(12),N(13)] is 30,5
(1)ꢀ, and between plane II and plane III [C(14),C(15),C(16),C(17),C
(18),C(19)] is 18.6(1)ꢀ.12
9
p-OMe
p-OMe
o-Cl aniline
NDa
NDa
10
o-OMe aniline
11
12
13
p-OMe
p-OMe
p-OMe
p-OH aniline
m-OH aniline
p-OBn aniline
NDa
NDa
49a
14
p-OMe
4-aminopyridine
NDa
15
16
p-OMe
p-OMe
n-butylamine
NDa
NDa
Figure 1. X-ray structure of compound 10.
2.4. Reactivity of the 1,2,4,5-tetrazine series
piperidine
We then turned our attention to 3,6-dimethylsulfanyl-1,2,4,5-
tetrazine 28. We already used this tetrazine in our previous com-
munication and showed, through a unique assay, that it is a good
cross-coupling partner, as aminotetrazine 29 was obtained in 88%
yield.5 No additive reaction with the residual C-5 sulfanylmethyl
group (Table 4, entry 1) was observed.
17
18
19
m-OMe
o-OMe
p-F
p-OMe aniline
p-OMe aniline
p-OMe aniline
p-OMe aniline
85
82
68
72
Table 4
Synthesis of derivatives 29e32
20
p-NO2
Entry RR’NH
Product
Yield (%)
a
ND Not Detected, starting material was recovered.
1
2
3
4-OMe aniline
29 88%
Yields decreased again when we introduced an electron-with-
drawing group on the aromatic aniline ring, nevertheless the de-
sired triazines 11e15 were still obtained in a range of 55e62% using
3- or 4-chloro, 3,5-difluoro, 4-nitro, and 4-trifluoromethyl anilines
(entries 4e8).
With sterically hindered anilines such as 2-chloro and 2-
methoxy anilines (entries 9 and 10), the reactions were inefficient.
Using 3- or 4-hydroxy anilines, the reactions did not work as well.
Fortunately, the reactivity was restored starting from the O-benzyl
protected 4-hydroxyaniline (entry 13). Less nucleophilic 4-
3-OMe aniline
30 83%
31 NDa
32 79%
2-OMe aniline
4
5-amino- 2-methoxypyridine
a
ND Not Detected.

4386
L. Pellegatti et al. / Tetrahedron 66 (2010) 4383e4389
In order to confirm this first result, we envisioned to explore the
performed using silica gel TLC plates (silica Merck 60 F254). Spots
were visualized by UV light at 254 nm and 356 nm. Column chro-
matography were performed using silica gel 60 (0.063e0.200 mm,
Merck).
reactivity of 28 with representative amines and present herein our
findings. All reactions were achieved in only 3 h. Reaction with 3-
methoxyaniline gave the desired compound 30 in good yield (entry
2).13 As described with 1,2,4-triazines, the amination failed with
sterically hindered 2-methoxyaniline (entry 3) and 4-
hydroxyaniline.
The same behavior was observed with 4-aminopyridine, but an
assay run with the electron rich 5-amino-2-methoxy-pyridine
furnished the attempted compound 32 in very good yield (entry 4).
In summary, the amination of 3,6-dimethylsulfanyl-1,2,4,5-tet-
razine 28 thus depends on steric and electronic effects. Using our
conditions, the coupling reaction only occurred on one methyl-
sulfur moiety and the residual SMe group on 29e32 never gave
additional reactions. It seems that the newly introduced amino
group fully deactivated this function.
Having already established with 1,2,4-triazines that electron-
poor methylsulfanyl-heteroaromatic derivatives gave better results,
we thought that the reactivity of 29 could be restored by protecting
the nitrogen of the newly installed amine with a benzenesulfonyl
group (Scheme 4). Aminotetrazine 33 was thus obtained in 78%
yield, when a solution of 29 in DMF was stirred at room tempera-
ture for 1 h in the presence of sodium hydride and phenylsulfonyl
chloride. Unfortunately, the cross-coupling reaction proved to be
inefficient, as only the starting material 33 was fully recovered.
4.1.1. N-(4-Methoxyphenyl)-N-(6-(methylthio)-1,2,4,5-tetra zin-3-yl)
benzenesulfonamide (33). Under Argon atmosphere, NaH (22 mg,
0.56 mmol) was added to a solution of compound (29) (70 mg,
0.28 mmol) in dry DMF (10 mL) at 0 ꢀC. Benzenesulfonyl chloride
(71.0 mL, 0.56 mmol) was then added and the solution was stirred at
room temperature until completion of the reaction (1 h). Water
(20 mL) was added and the resulting mixture was extracted with
ethyl acetate (3ꢂ50 mL). The combined organic layers were washed
several times with water (10 mL) and brine (10 mL), dried on
MgSO4, and evaporated under reduced pressure. Compound 33 was
isolated without further purification as a reddish solid (85 mg,
78%). Rf (CH2Cl2/MeOH 95/5) 0.51; mp 156e158 ꢀC; IR (ATR Di-
amond, cmꢁ1
(250 MHz, CDCl3)
)
n
3055, 2942, 1587, 1438, 1269, 1225, 1141; 1H NMR
2.67 (s, 3H), 3.85 (s, 3H), 6.97 (d, J¼8.7 Hz, 2H),
d
7.21e7.26 (m, 2H), 7.53e7.59 (m, 2H), 7.63e7.70 (m, 1H), 8.11 (d,
J¼8.7 Hz, 2H); 13C NMR (62.5 MHz, CDCl3)
d 13.5 (CH3), 55.5 (CH3),
115.0 (CH), 128.9 (2ꢂCH), 129.1 (Cq), 129.3 (2ꢂCH), 131.3 (2ꢂCH),
133.8 (2ꢂCH), 138.7 (Cq), 160.4 (Cq), 161.5 (Cq), 172.6 (Cq); HRMS
(EIMS): m/z calcd for C16H16N5O3S2: 390.0672 [MþHþ], found:
390.0668.
4.2. General procedure A for the preparation of compounds
1e5
NaH (2.0 equiv.)
S
N
N
O
S
N
N
O
N
PhSO2Cl (1.5 equiv.)
N
N
N
N
H
N
DMF, 25°C, 1 h
78%
In a 250 mL round bottom flask, selenium dioxide was dissolved
in a mixture of dioxane/water (30/1) at 60 ꢀC. The appropriate
acetophenone was then added. The resulting mixture was refluxed
for 4 h, cooled to room temperature and filtered through a CeliteÒ
pad, which was washed with acetone till CeliteÒ became white. The
combined organic layers were concentrated under reduced pres-
sure. The crude reddish brown oil was then dissolved in water and
then methylthiosemicarbazide and Na2CO3 were added. The
resulting mixture was cooled to 0 ꢀC and stirred for 6 h. Ethanol
was added to avoid solidification of the solution. The mixture was
filtered at room temperature to give a yellow solid, which was dried
and isolated without further purification.
SO2Ph
29
33
NH2
O
CuMeSal, Cs2CO3,
Pd(OAc)2, Xantphos
H
N
N
N
O
33
+
N
O
N
N
toluene, 170°C, 3 h
microwave irradiation
SO2Ph
34
1.2 equiv.
Scheme 4. Amination starting from compound 33.
3. Conclusion
In this paper, we have shown that our palladium-catalyzed
amination with SMe release methodology could be applied to dif-
ferent C-5-aryl-1,2,4-triazines and 3,6-dimethylsulfanyl-1,2,4,5-
tetrazine. Good to excellent yields were obtained with a wide range
of amines. In general electron-rich aromatic amines gave the best
results for both series. Several assays are in progress in fused tri-
azinic and tetrazinic series and results will be published in due
course.
4.2.1. 5-(4-Methoxyphenyl)-3-(methylthio)-1,2,4-triazine (1). Com-
pound 1 was obtained as a yellow solid (6.2 g, 100%) following
general procedure
A
with 4-methoxyacetophenone (4 g,
26.6 mmol), selenium dioxide (3.3 g, 29.3 mmol), dioxane (30 mL),
water (1 mL), methylthiosemicarbazide (3.52 g,17.7 mmol), sodium
bicarbonate (1.75 g, 19.5 mmol), water (150 mL), ethanol (5 mL). Rf
(CH2Cl2/MeOH 95/5) 0.35; mp 124e125 ꢀC; IR (ATR Diamond,
cmꢁ1 3079, 3004, 2929, 2840, 1601, 1504, 1394, 1241, 1173; 1H
) n
NMR (250 MHz, CDCl3)
d 2.71 (s, 3H, SMe), 3.90 (s, 3H, OMe), 7.04
4. Experimental section
4.1. General methods
(d, J¼9.0 Hz, 2H), 8.14 (d, J¼9.0 Hz, 2H), 9.30 (s, 1H); 13C NMR
(62.5 MHz, CDCl3)
d
13.8 (CH3), 55.5 (CH3), 114.8 (2ꢂCH), 125.2 (Cq),
129.4 (2ꢂCH), 141.4 (CH), 153.9 (Cq), 163.4 (Cq), 173.3 (Cq); HRMS
(EIMS): m/z calcd for C11H11N3OSNa: 256.0521 [MþNaþ], found:
256.0529.
1H NMR and 13C NMR spectra were recorded on a Bruker DPX
250 or 400 MHz instrument using CDCl3 or DMSO-d6. The chemical
shifts are reported in parts per million (
d
scale) and all coupling
4.2.2. 5-(3-Methoxyphenyl)-3-(methylthio)-1,2,4-triazine (2). Com-
pound 2 was obtained as a yellow solid (4.5 g, 73%) following
constants (J) values are in hertz (Hz). The splitting patterns are
designated as follows: s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet), and dd (doublet doublet). Melting points are un-
corrected. IR absorption spectra were obtained on a Perkin Elmer
PARAGON 1000 PC and values were reported in cmꢁ1. MS spectra
(Ion Spray) were performed on a Perkin Elmer Sciex PI 300. HRMS
were performed by the Centre Commun de Spectrométrie de Masse
(Clermont Ferrand, France). Monitoring of the reactions was
general procedure
A
with 3-methoxyacetophenone (4.0 g,
26.6 mmol), selenium dioxide (3.3 g, 29.3 mmol), dioxane (30 mL),
water (1 mL), methylthiosemicarbazide (3.52 g,17.7 mmol), sodium
bicarbonate (1.75 g, 19.5 mmol), water (150 mL), ethanol (5 mL). Rf
(CH2Cl2/MeOH 95/5) 0.35; mp 112e113 ꢀC; IR (ATR Diamond, cmꢁ1
n
)
3079, 3004, 2929, 2840, 1601, 1504, 1394, 1241, 1173; 1H NMR
(250 MHz, CDCl3)
d
2.73 (s, 3H), 3.90 (s, 3H), 7.13 (dd, J¼5.3, 5.0 Hz,

L. Pellegatti et al. / Tetrahedron 66 (2010) 4383e4389
4387
1H), 7.46 (t, J¼5.0 Hz, 1H), 7.68e7.71 (m, 2H), 9.35 (s, 1H); 13C NMR
0.43 mmol), 4-methoxyaniline (64 mg, 0.52 mmol), CuMeSal
(216 mg, 0.860 mmol), Cs2CO3 (279 mg, 0.94 mmol), Pd(OAc)2
(10 mg, 0.043 mmol), Xantphos (50 mg, 0.086 mmol), toluene
(5 mL). Rf (CH2Cl2/MeOH 95/5) 0.40; mp>250 ꢀC; IR (ATR Diamond,
(62.5 MHz, CDCl3)
d 13.9 (CH3), 55.5 (CH3), 112.6 (CH), 118.5 (CH),
119.9 (CH), 130.3 (CH), 134.5 (Cq), 142.0 (CH), 154.3 (Cq), 160.3 (Cq),
173.7 (Cq); HRMS (EIMS): m/z calcd for C11H11N3OSNa: 256.0521
[MþNaþ], found: 256.0519.
cmꢁ1
) n
3016, 2921, 2841, 1603, 1505, 1439, 1248, 1172, 1024; 1H
NMR (250 MHz, DMSO-d6)
d
3.75 (s, 3H), 3.86 (s, 3H), 6.95 (d,
4.2.3. 5-(2-Methoxyphenyl)-3-(methylthio)-1,2,4-triazine (3). Com-
pound 3 was obtained as a yellow solid (3.4 g, 55%) following
J¼9.0 Hz, 2H), 7.15 (d, J¼9 Hz, 2H), 7.69 (d, J¼9.0 Hz, 2H), 8.24 (d,
J¼9.0 Hz, 2H), 9.37 (s, 1H), 9.87 (s, 1H); 13C NMR (62.5 MHz, DMSO-
general procedure
A
with 2-methoxyacetophenone (4.0 g,
d6)
d
55.0 (CH3), 55.2 (CH3), 113.7 (2ꢂCH), 114.4 (2ꢂCH), 121.2
26.6 mmol), selenium dioxide (3.3 g, 29.3 mmol), dioxane (30 mL),
water (1 mL), methylthiosemicarbazide (3.52 g, 17.7 mmol), sodium
bicarbonate (1.75 g, 19.5 mmol), water (150 mL), ethanol (5 mL). Rf
(2ꢂCH), 125.7 (Cq), 128.8 (2ꢂCH), 132.4 (Cq), 137.6 (CH), 152.3 (Cq),
154.7 (Cq), 154.8 (Cq), 162.3 (Cq); HRMS (EIMS): m/z calcd for
C17H17N4O2: 309.1352 [MþHþ], found: 309.1347.
(CH2Cl2/MeOH 95/5) 0.78; mp 84e85 ꢀC; IR (ATR Diamond, cmꢁ1
) n
1525, 1488, 1300, 1239, 1019; 1H NMR (400 MHz, DMSO-d6)
d
2.71
4.3.2. 5-(4-Methoxyphenyl)-N-(3-methoxyphenyl)-1,2,4-triazin-3-
amine (8). Compound 8 was obtained as a yellow solid (99 mg,
75%) following general procedure B with compound 1 (100.0 mg,
0.43 mmol), 3-methoxyaniline (64.0 mg, 0.52 mmol), CuMeSal
(216 mg, 0.860 mmol), Cs2CO3 (279 mg, 0.94 mmol), Pd(OAc)2
(10 mg, 0.04 mmol), Xantphos (50 mg, 0.08 mmol), toluene (5 ꢁm1L).
(s, 3H, SMe), 3.96 (s, 3H, OMe), 7.04(d, J¼8.4 Hz, 1H), 7.11 (td, J¼8.4,
J¼1.6 Hz, 1H), 7.53 (td, J¼8.4, J¼1.6 Hz, 1H), 8.12 (dd, J¼8.0 J¼1.6 Hz,
1H), 9.63 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 13.8 (CH3), 55.7
(CH3), 111.6 (CH), 121.5 (CH), 122.3 (Cq), 131.5 (CH), 133.7 (CH), 145.9
(CH), 154.4 (Cq), 158.6 (Cq), 173.2 (Cq); HRMS (EIMS): m/z calcd for
C11H11N3OSNa: 256.0521 [MþNaþ], found: 256.0518.
Rf (CH2Cl2/MeOH 95/5) 0.41; mp 213 ꢀC; IR (ATR Diamond, cm
) n
3049, 2965, 1509, 1459, 1296, 1252, 1174; 1H NMR (400 MHz,
4.2.4. 5-(4-Fluorophenyl)-3-(methylthio)-1,2,4-triazine
pound 4 was obtained as a yellow solid (5.57 g, 87%) following
general procedure with 4-fluoroacetophenone (3.5 mL,
(4). Com-
DMSO-d6)
d
3.78 (s, 3H), 3.87 (s, 3H), 6.61 (d, J¼8.0 Hz, 1H), 7.16 (d,
J¼9.6 Hz, 2H), 7.25 (t, J¼8.0 Hz, 1H), 7.38 (d, J¼8.0 Hz, 1H), 7.55 (s,
A
1H), 8.27 (d, J¼9.6 Hz, 2H), 9.44 (s, 1H), 10.07 (s, 1H); 13C NMR
26.6 mmol), selenium dioxide (3.3 g, 29.3 mmol), dioxane (30 mL),
water (1 mL), and methylthio- semicarbazide (4.5 g, 19.3 mmol),
sodium bicarbonate (1.75 g, 19.5 mmol), water (150 mL), ethanol
(5 mL). Rf (CH2Cl2/MeOH 95/5) 0.34; mp 140e141 ꢀC; IR (ATR Di-
(62.5 MHz, DMSO-d6) d 54.9 (CH3), 55.5 (CH3), 105.0 (CH), 107.4
(CH), 111.6 (CH), 114.7 (2ꢂCH), 125.6 (CH), 129.3 (2ꢂCH), 129.4 (Cq),
138.4 (Cq), 140.8 (Cq), 154.1 (CH), 159.5 (Cq), 159.8 (Cq), 162.6 (Cq);
HRMS (EIMS): m/z calcd for C17H17N4O2: 309.1352 [MþHþ], found:
309.1361.
amond, cmꢁ1
(250 MHz, DMSO-d6)
8.34e8.42 (m, 2H), 9.79 (s, 1H); 13C NMR (62.5 MHz, DMSO-d6)
) n
1598, 1504, 1490, 1234, 1160, 1140; 1H NMR
d
2.66 (s, 3H, SMe), 7.39e7.49 (m, 2H),
4.3.3. 5-(4-Methoxyphenyl)-N-(4-tolyl)-1,2,4-triazin-3-amine
(9).
d
13.3 (CH3), 116.7 (d, J¼21.9 Hz, 2ꢂCH), 129.3 (d, J¼2.8 Hz, Cq),
Compound 9 was obtained as a yellow solid (91 mg, 72%) following
general procedure B with 5-(4-methoxyphenyl)-3-(methylthio)-
1,2,4-triazine 1 (100 mg, 0.43 mmol), 4-methylaniline (55 mg,
0.52 mmol), CuMeSal (216 mg, 0.860 mmol), Cs2CO3 (279 mg,
0.946 mmol), Pd(OAc)2 (10 mg, 0.043 mmol), Xantphos (50 mg,
0.086 mmol), toluene (5 mL). Rf (CH2Cl2/MeOH 95/5) 0.43; mp
130.8 (d, J¼9.3 Hz, 2ꢂCH), 142.7 (CH), 153.2 (Cq), 165.1 (d,
J¼250.1 Hz, Cq), 172.5 (Cq); HRMS (EIMS): m/z calcd for C10H8N3SF:
244.0321 [MþNaþ], found: 244.0333.
4.2.5. 5-(4-Nitrophenyl)-3-(methylthio)-1,2,4-triazine
(5). Com-
pound 5 was obtained as a yellow solid (4.32 g, 72%) following
general procedure A with 4-nitroacetophenone (4.0 g, 24.2 mmol),
selenium dioxide (2.69 g, 24.2 mmol), dioxane (30 mL), water
(1 mL), methylthiosemicarbazide (3.76 g, 16.1 mmol), sodium bi-
carbonate (1.88 g, 17.8 mmol), water (150 mL), ethanol (5 mL). Rf
(CH2Cl2/MeOH 95/5) 0.78; mp 222e223 ꢀC; IR (ATR Diamond,
263 ꢀC; IR (ATR Diamond, cmꢁ1
1028; 1H NMR (250 MHz, DMSO-d6)
)
n
3015, 2919, 1506, 1433, 1249,
2.28 (s, 3H), 3.87 (s, 3H), 7.15
d
(d, J¼8.7 Hz, 2H), 7.16 (d, J¼8.7 Hz, 2H), 7.68 (d, J¼8.7 Hz, 2H), 8.25
(d, J¼8.7 Hz, 2H), 9.40 (s, 1H), 9.95 (s, 1H); 13C NMR (62.5 MHz,
DMSO-d6)
d
20.4 (CH3), 55.5 (CH3), 114.7 (2ꢂCH), 119.5 (2ꢂCH),
125.8 (Cq), 129.1 (2ꢂCH), 129.4 (2ꢂCH), 131.0 (Cq), 137.1 (Cq), 138.2
(CH), 154.2 (Cq), 159.9 (Cq), 162.6 (Cq); HRMS (EIMS): m/z calcd for
C17H17N4O: 293.1402 [MþHþ], found: 293.1412.
cmꢁ1
DMSO-d6)
) n
1519, 1494, 1344, 1328, 1301, 1241, 1136; 1H NMR (250 MHz,
d
2.71 (s, 3H, SMe), 8.42 (d, J¼9.0 Hz, 2H), 8.56 (d,
J¼9.0 Hz, 2H), 9.93 (s, 1H); 13C NMR (62.5 MHz, DMSO-d6)
d 13.2
(CH3), 124.1 (2ꢂCH), 129.3 (2ꢂCH), 138.8 (Cq), 143.1 (CH), 149.7
(Cq), 152.2 (Cq), 172.7 (Cq); HRMS (EIMS): m/z calcd for
C10H8N4O2SNa: 271.0266 [MþNaþ], found: 271.0280.
4.3.4. 5-(4-Methoxyphenyl)-N-(phenyl)-1,2,4-triazin-3-amine (10).
Compound 10 was obtained as a yellow solid (89 mg, 67%) fol-
lowing general procedure
B
with compound
1
(100 mg,
0.43 mmol), aniline (48 mg, 0.52 mmol), CuMeSal (216 mg,
0.86 mmol), Cs2CO3 (279 mg, 0.94 mmol), Pd(OAc)2 (10.0 mg,
0.04 mmol), Xantphos (50.0 mg, 0.08 mmol), toluene (5 mL). Rf
4.3. General procedure B for the preparation of compounds
7e15, 20, 24e27, 29, 30e32
(CH2Cl2/MeOH 95/5) 0.41; mp 266 ꢀC; IR (ATR Diamond, cmꢁ1
) n
In a 2e5 mL sealed microwave vial were successively added the
SMe derivative, the amine (1.2 equiv), copper(I) methylsalicylate
(2.0 equiv), Cs2CO3 (2.2 equiv), Pd(OAc)2 (10 mol %), and Xantphos
(20 mol %). Dry toluene was added and the suspension was sub-
jected to microwave irradiations at 170 ꢀC for 3 h. The reaction
mixture was cooled to room temperature and the solvent was re-
moved under reduced pressure. The crude material was immedi-
ately purified by chromatography on silica gel to afford the
attempted compound.
3242, 3015, 2921, 1505, 1430, 1250, 1027; 1H NMR (250 MHz,
DMSO-d6)
3.87 (s, 3H), 7.03 (t, J¼7.3 Hz, 1H), 7.16 (d, J¼8.8 Hz, 2H),
7.36 (t, J¼7.3 Hz, 2H), 7.83 (d, J¼7.3 Hz, 2H), 8.27 (d, J¼8.8 Hz, 2H),
9.43 (s, 1H), 10.06 (s, 1H); 13C NMR (62.5 MHz, DMSO-d6)
55.2
d
d
(CH3), 114.4 (2ꢂCH), 119.3 (2ꢂCH), 121.8 (CH), 125.6 (Cq), 128.1
(2ꢂCH), 128.9 (2ꢂCH), 138.0 (Cq), 139.3 (CH), 154.0 (Cq), 159.7 (Cq),
162.4 (Cq); HRMS (EIMS): m/z calcd for C16H15N4O: 279.1246
[MþHþ], found: 279.1257.
4.3.5. 5-(4-Methoxyphenyl)-N-(4-chlorophenyl)-1,2,4-triazin-3-
amine (11). Compound 11 was obtained as a yellow solid (85 mg,
64%) following general procedure B with compound 1 (100 mg,
0.43 mmol), 4-chloroaniline (66 mg, 0.52 mmol), CuMeSal (216 mg,
4.3.1. 5-(4-Methoxyphenyl)-N-(4-methoxyphenyl)-1,2,4-triazin-3-
amine (7). Compound 7 was obtained as a yellow solid (107 mg,
81%) following general procedure B with compound 1 (100 mg,

4388
L. Pellegatti et al. / Tetrahedron 66 (2010) 4383e4389
0.86 mmol), Cs2CO3 (279 mg, 0.94 mmol), Pd(OAc)2 (10 mg,
(OAc)2 (10 mg, 0.04 mmol), Xantphos (50 mg, 0.08 mmol), toluene
0.04 mmol), Xantphos (50 mg, 0.08 mmol), toluene (5 mL). Rf
(5 mL). Rf (CH2Cl2/MeOH 95/5) 0.43; mp>270 ꢀC; IR (ATR Diamond,
(CH2Cl2/MeOH 95/5) 0.43; mp>250 ꢀC; IR (ATR Diamond, cmꢁ1
)
n
cmꢁ1 3017, 2922, 1604, 1507, 1434, 1321, 1250, 1114; 1H NMR
) n
3238, 3017, 2949, 1603, 1553, 1510, 1490, 1254, 1027; 1H NMR
(250 MHz, DMSO-d6)
3.87 (s, 3H), 7.15 (d, J¼9.0 Hz, 2H), 7.41 (d,
J¼9.0 Hz, 2H), 7.86 (d, J¼9.0 Hz, 2H), 8.27 (d, J¼9.0 Hz, 2H), 9.47 (s,
1H), 10.20 (s, 1H); 13C NMR (62.5 MHz, DMSO-d6)
55.1 (CH3), 114.4
(250 MHz, DMSO-d6)
J¼8.8 Hz, 2H), 8.06 (d, J¼8.7 Hz, 2H), 8.31 (d, J¼8.7 Hz, 2H), 9.54 (s,
1H), 10.49 (s, 1H); 13C NMR (62.5 MHz, DMSO-d6)
55.2 (CH3), 114.5
d
3.88 (s, 3H), 7.18 (d, J¼8.8 Hz, 2H), 7.72 (d,
d
d
d
(2ꢂCH), 118.7 (2ꢂCH), 125.4 (q, J¼7.8 Hz, 2ꢂCH), 129.1 (CH), 138.9
(Cq), 154.2 (Cq), 159.4 (q, J¼4.6 Hz, 2ꢂCH), 162.6 (Cq); HRMS
(EIMS): m/z calcd for C17H14F3N4O: 347.1120 [MþHþ], found:
347.1106.
(2ꢂCH), 120.6(2ꢂCH), 125.4 (Cq), 127.9 (2ꢂCH), 128.9 (2ꢂCH), 138.2
(CH), 138.3 (Cq), 148.6 (Cq), 151.2 (Cq), 153.9 (Cq), 162.4 (Cq); HRMS
(EIMS): m/z calcd for C16H14N4OCl: 313.0856 [MþHþ], found:
313.0845.
4.3.10. 5-(4-Methoxyphenyl)-N-(4-benzyloxyphenyl)-1,2,4-triazin-3-
amine (20). Compound 20 was obtained as a yellow solid (81 mg,
49%) following general procedure B with compound 1 (100 mg,
0.43 mmol), 4-benzyloxyaniline (102 mg, 0.52 mmol), CuMeSal
(216 mg, 0.860 mmol), Cs2CO3 (279 mg, 0.94 mmol), Pd(OAc)2
(10 mg, 0.04 mmol), Xantphos (50 mg, 0.08 mmol), toluene (5 mL).
Rf (dichloromethane/MeOH 95/5) 0.55; mp>250 ꢀC; IR (ATR Di-
4.3.6. 5-(4-Methoxyphenyl)-N-(3-chlorophenyl)-1,2,4-triazin-3-
amine (12). Compound 12 was obtained as a yellow solid (74 mg,
55%) following general procedure B with compound 1 (100 mg,
0.43 mmol), 3-chloroaniline (66 mg, 0.52 mmol), CuMeSal (216 mg,
0.86 mmol), Cs2CO3 (279 mg, 0.94 mmol), Pd(OAc)2 (10 mg,
0.04 mmol), Xantphos (50 mg, 0.08 mmol), toluene (5 mL). Rf
(CH2Cl2/MeOH 95/5) 0.43; mp 226e227 ꢀC; IR (ATR Diamond,
amond, cmꢁ1
)
n
3247, 3017, 1603,1505, 1435,1250, 1232, 1172,1023;
3.87 (s, 3H), 5.10 (s, 2H), 7.03 (d,
cmꢁ1
)
n
3235, 3019, 2951, 1603, 1506, 1322, 1253, 1026; 1H NMR
1H NMR (250 MHz, DMSO-d6)
d
(250 MHz, DMSO-d6)
d
3.87 (s, 3H), 7.07 (dd, J¼8.0, 2.0 Hz, 1H), 7.17
J¼8.3 Hz, 2H), 7.15 (d, J¼8.5 Hz, 2H), 7.37e7.48 (m, 5H), 7.69 (d,
(d, J¼9.0 Hz, 2H), 7.37 (t, J¼8.0 Hz, 1H), 7.75 (dd, J¼8.0, 2.0 Hz, 1H),
J¼8.5 Hz, 2H), 8.24 (d, J¼8.3 Hz, 2H), 9.37 (s, 1H), 9.88 (s, 1H); 13C
8.04 (s, 1H), 8.28 (d, J¼9.0 Hz, 2H), 9.50 (s, 1H), 10.27 (s, 1H); 13C
NMR (62.5 MHz, DMSO-d6)
d
55.1 (CH3), 69.5 (CH2), 114.4 (2ꢂCH),
NMR (62.5 MHz, DMSO-d6)
d
55.6 (CH3), 114.8 (2ꢂCH), 117.6 (CH),
114.8 (2ꢂCH), 121.1 (2ꢂCH), 125.7 (Cq), 127.0 (2ꢂCH), 127.2 (CH),
127.9 (2ꢂCH), 128.8 (2ꢂCH), 132.7 (Cq), 137.0 (Cq), 137.6 (CH), 153.7
(Cq), 153.9 (Cq), 159.7 (Cq), 162.3 (Cq); HRMS (EIMS): m/z calcd for
C23H21N4O2: 385.1665 [MþHþ], found: 385.1680.
121.5 (CH), 125.5 (CH), 129.5 (2ꢂCH),130.3 (Cq), 133.0 (CH), 139.1
(Cq), 141.3 (Cq), 154.5 (CH), 159.7 (Cq), 162.8 (Cq), 167.1 (Cq); HRMS
(EIMS): m/z calcd for C16H14N4OCl: 313.0856 [MþHþ], found:
313.0869.
4.3.11. 5-(3-Methoxyphenyl)-N-(4-methoxyphenyl)-1,2,4-triazin-3-
amine (24). Compound 24 was obtained as a yellow solid (112 mg,
85%) following general procedure B with compound 2 (100 mg,
0.43 mmol), 4-methoxyaniline (64 mg, 0.52 mmol), CuMeSal
(216 mg, 0.860 mmol), Cs2CO3 (279 mg, 0.94 mmol), Pd(OAc)2
(10 mg, 0.04 mmol), Xantphos (50 mg, 0.08 mmol), toluene (5 mL).
Rf (dichloromethane/MeOH 95/5) 0.43; mp 215e216 ꢀC; IR (ATR
4.3.7. 5-(4-Methoxyphenyl)-N-(3,5-difluorophenyl)-1,2,4-triazin-3-
amine (13). Compound 13 was obtained as a yellow solid (84 mg,
62%) following general procedure B with compound 1 (100 mg,
0.43 mmol), 3,5-difluoroaniline (66 mg, 0.52 mmol), CuMeSal
(216 mg, 0.86 mmol), Cs2CO3 (279 mg, 0.94 mmol), Pd(OAc)2
(10 mg, 0.04 mmol), Xantphos (50 mg, 0.08 mmol), toluene (5 ꢁm1L).
Rf (CH2Cl2/MeOH 95/5) 0.43; mp 256 ꢀC; IR (ATR Diamond, cm
)
n
Diamond, cmꢁ1
)
n
3263, 3204, 3056, 2961, 1504, 1464, 1230, 1084,
3.75 (s, 3H), 3.86 (s, 3H), 6.95
3263, 3213, 3054, 2968, 1572, 1432, 1256, 1113; 1H NMR (250 MHz,
DMSO-d6)
3.88 (s, 3H), 6.84 (t, J¼8.5 Hz, 1H), 7.18 (d, J¼9.1 Hz, 2H),
7.61 (d, J¼8.5 Hz, 2H), 8.27 (d, J¼9.1 Hz, 2H), 9.55 (s, 1H), 10.49 (s,
1H); 13C NMR (62.5 MHz, DMSO-d6)
55.6 (CH3), 96.8 (CH), 101.7
1034; 1H NMR (250 MHz, DMSO-d6)
d
d
(d, J¼9.0 Hz, 2H), 7.19 (dd, J¼8.0, 2.9 Hz, 1H), 7.51 (t, J¼8.0 Hz, 1H),
7.70 (d, J¼9.0 Hz, 2H), 7.78 (s, 1H), 7.81 (t, J¼8.0 Hz, 1H), 9.43 (s, 1H),
d
9.98 (s, 1H); 13C NMR (62.5 MHz, DMSO-d6)
d 55.2 (CH3), 55.3 (CH3),
(2ꢂCH), 114.9 (2ꢂCH), 125.4 (Cq), 129.5 (2ꢂCH), 139.6 (Cq), 142.5
(Cq), 154.6 (CH), 159.6 (Cq), 161.4 (Cq, J¼60 Hz), 162.9 (Cq), 163.9
(Cq); HRMS (EIMS): m/z calcd for C16H13F2N4O: 315.1057 [MþHþ],
found: 315.1061.
112.3 (CH), 113.8 (2ꢂCH), 118.1 (CH), 119.8 (CH), 121.3 (2ꢂCH), 130.3
(CH), 132.5 (Cq), 135.2 (Cq), 138.5 (CH), 154.4 (Cq), 154.8 (Cq), 159.8
(Cq), 160.1 (Cq); HRMS (EIMS): m/z calcd for C17H17N4O2: 309.1352
[MþHþ], found: 309.1339.
4.3.8. 5-(4-Methoxyphenyl)-N-(4-nitrophenyl)-1,2,4-triazin-3-
amine (14). Compound 14 was obtained as a yellow solid (83 mg,
60%) following general procedure B with compound 1 (100 mg,
0.43 mmol), 4-nitroaniline (71 mg, 0.52 mmol), CuMeSal (216 mg,
0.86 mmol), Cs2CO3 (279 mg, 0.94 mmol), Pd(OAc)2 (10 mg,
0.04 mmol), Xantphos (50 mg, 0.08 mmol), toluene (5 mL). Rf
4.3.12. 5-(2-Methoxyphenyl)-N-(4-methoxyphenyl)-1,2,4-triazin-3-
amine (25). Compound 25 was obtained as a yellow solid (108 mg,
82%) following general procedure B with compound 3 (100 mg,
0.43 mmol), 4-methoxyaniline (64 mg, 0.52 mmol), CuMeSal
(216 mg, 0.86 mmol), Cs2CO3 (279 mg, 0.94 mmol), Pd(OAc)2
(10 mg, 0.04 mmol), Xantphos (50 mg, 0.08 mmol), toluene (5 mL).
Rf (dichloromethane/MeOH 95/5) 0.43; mp 195e196 ꢀC; IR (ATR
(CH2Cl2/MeOH 95/5) 0.43; mp>250 ꢀC; IR (ATR Diamond, cmꢁ1
3262, 3044, 2976, 1499, 1467, 1319, 1256, 1194, 1074, 1027; 1H NMR
(250 MHz, DMSO-d6)
3.90 (s, 3H), 7.17 (d, J¼8.6 Hz, 2H), 8.11 (d,
J¼8.6 Hz, 2H), 8.25 (d, J¼9.3 Hz, 2H), 8.29 (d, J¼9.3 Hz, 2H), 9.53 (s,
1H), 10.59 (s, 1H); 13C NMR (62.5 MHz, DMSO-d6)
55.2 (CH3), 114.5
) n
Diamond, cmꢁ1
1017; 1H NMR (250 MHz, CDCl3)
)
n
3262, 3204, 3056, 2962, 1614, 1509, 1232, 1108,
3.82 (s, 3H), 3.95 (s, 3H), 6.93 (d,
d
d
J¼8.5 Hz, 2H), 7.03 (d, J¼8.0 Hz, 1H), 7.12 (td, J¼8.0, 1.2 Hz, 1H), 7.51
(td, J¼8.0 Hz, J¼1.2 Hz, 1H), 7.63 (d, J¼8.5 Hz, 2H), 7.76 (s, 1H), 8.04
(dd, J¼8.0 Hz, J¼2.0 Hz, 1H), 9.35 (s, 1H); 13C NMR: (62.5 MHz,
d
(2ꢂCH), 118.1 (2ꢂCH), 124.4 (2ꢂCH), 125.1 (Cq), 129.3 (2ꢂCH), 139.6
(CH), 140.9 (Cq), 145.9 (Cq), 154.4 (Cq), 159.2 (Cq), 162.7 (Cq); HRMS
(EIMS): m/z calcd for C16H14N5O3: 324.1097 [MþHþ], found:
324.1092.
CDCl3)
d
55.8 (CH3), 55.9 (CH3), 111.8 (CH), 114.4 (2ꢂCH), 121.6 (CH),
121.9 (2ꢂCH), 123.5 (Cq), 131.5 (CH), 132.1 (Cq), 133.3 (CH), 142.9
(CH), 155.8 (Cq), 156.0 (Cq), 158.7 (Cq), 160.7 (Cq); HRMS (EIMS):
m/z calcd for C17H17N4O2: 309.1352 [MþHþ], found: 309.1348.
4.3.9. 5-(4-Methoxyphenyl)-N-(4-trifluoromethylphenyl)-1,2,4-tri-
azin-3-amine (15). Compound 15 was obtained as a yellow solid
(74 mg, 59%) following general procedure B with compound 1
(100 mg, 0.43 mmol), 4-trifluoromethylaniline (83 mg, 0.52 mmol),
CuMeSal (216 mg, 0.86 mmol), Cs2CO3 (279 mg, 0.94 mmol), Pd
4.3.13. 5-(4-Fluorophenyl)-N-(4-methoxyphenyl)-1,2,4-triazin-3-
amine (26). Compound 26 was obtained as a yellow solid (91 mg,
68%) following general procedure B with compound 4 (100 mg,
0.45 mmol), 4-methoxyaniline (67 mg, 0.54 mmol), CuMeSal

L. Pellegatti et al. / Tetrahedron 66 (2010) 4383e4389
4389
(208 mg, 0.90 mmol), Cs2CO3 (324 mg, 0.99 mmol), Pd(OAc)2
(10 mg, 0.04 mmol), Xantphos (52 mg, 0.09 mmol), toluene (5 mL).
Rf (dichloromethane/MeOH 95/5) 0.43; mp>250 ꢀC; IR (ATR Di-
6.80 (d, J¼8.5 Hz, 1H), 7.41e7.42 (m, 1H), 7.96 (dd, J¼9.0, 3.0 Hz,1H),
8.32 (d, J¼1.0 Hz, 1H); 13C NMR (62.5 MHz, CDCl3)
d 13.6 (CH3), 55.7
(CH3), 110.9 (CH), 132.5 (CH), 133.7 (Cq), 139.3 (CH), 160.0 (Cq), 161.2
(Cq), 168.9 (Cq); HRMS (EIMS): m/z calcd for C9H11N6OS: 250.0621
[MþHþ], found: 250.0618.
amond, cmꢁ1
)
n
3243, 3010, 2929, 2838, 1599, 1503, 1436, 1317,
1264; 1H NMR (250 MHz, DMSO-d6)
d
3.77 (s, 3H), 6.95 (d, J¼9.0 Hz,
2H), 7.40 (t, J¼9.0 Hz, 2H), 7.68 (d, J¼9.0 Hz, 2H), 8.28 (td, J¼9.0 Hz,
J¼2.0 Hz, 2H), 9.34 (s, 1H), 9.67 (s, 1H); 13C NMR (62.5 MHz, DMSO-
Acknowledgements
d6)
d
55.0 (CH3), 113.7 (2ꢂCH), 115.7 (d, J¼22.0 Hz, 2ꢂCH), 121.3
(2ꢂCH), 129.6 (d, J¼9.0 Hz, 2ꢂCH), 130.7 (d, J¼3.0 Hz, Cq), 132.2
(Cq), 137.7 (CH), 153.3 (Cq), 154.8 (Cq), 159.8 (Cq), 164.2 (d,
J¼249.0 Hz, Cq); HRMS (EIMS): m/z calcd for C16H14FN4O: 297.1152
[MþHþ], found: 297.1147.
The authors thanks the Ligue Contre le Cancer Région Grand
Ouest, le Cancéropôle Grand Ouest and the MESR for financial
support.
Supplementary data
4.3.14. 5-(4-Nitrophenyl)-N-(4-methoxyphenyl)-1,2,4-triazin-3-
amine (27). Compound 27 was obtained as a yellow solid (94 mg,
72%) following general procedure B with compound 5 (100 mg,
0.40 mmol), 4-methoxyaniline (60 mg, 0.48 mmol), CuMeSal
(185 mg, 0.80 mmol), Cs2CO3 (289 mg, 0.88 mmol), Pd(OAc)2
(9.0 mg, 0.04 mmol), Xantphos (47.0 mg, 0.08 mmol), toluene
(5 mL). Rf (dichloromethane/MeOH 95/5) 0.43; mp>250 ꢀC; IR (ATR
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.03.099.
References and notes
1. Lamberth, C. Heterocycles 2006, 68, 561.
2. Bernstein, T. B.; Feinberg, S. M. J. Allergy 1948, 19, 393.
Diamond, cmꢁ1
1026; 1H NMR (250 MHz, DMSO-d6)
2H), 7.69 (d, J¼8.5 Hz, 2H), 8.42 (d, J¼8.5 Hz, 2H), 8.48 (d, J¼8.5 Hz,
2H), 9.52 (s, 1H), 10.16 (s, 1H); 13C NMR (62.5 MHz, DMSO-d6)
55.2
)
n
3246, 3027, 2957, 1607, 1509, 1437, 1349, 1234,
3.76 (s, 3H), 6.96 (d, J¼8.5 Hz,
3. (a) Sayle, K. L.; Bentley, J.; Boyle, F. T.; Calvert, A. H.; Cheng, Y.; Curtin, N. J.;
Endicott, J. A.; Golding, B. T.; Hardcastle, I. R.; Jewsbury, P.; Mesguiche, V.;
Newell, D. R.; Noble, M. E. M.; Parsons, R. J.; Pratt, D. J.; Wang, L. Z.; Griffin, R. J.
Bioorg. Med. Chem. Lett. 2003, 13, 3079; (b) Wang, S.; Wood, G.; Meades, C.;
Griffiths, G.; Midgley, C.; McNae, I.; McInnes, C.; Anderson, S.; Jackson, W.;
Mezna, M.; Yuill, R.; Walkinshaw, M.; Fisher, P. M. Bioorg. Med. Chem. Lett. 2004,
14, 4237; (c) Wang, S.; Meades, C.; Wood, G.; Osnowski, A.; Anderson, S.; Yuill,
R.; Thomas, M.; Mezna, M.; Jackson, M.; Midley, C.; Griffiths, M.; Fleming, I.;
Green, S.; McNae, I.; Wu, S.-Y.; McInnes, C.; Zheleva, D.; Walkinshaw, M. D.;
Fisher, P. M. J. Med. Chem. 2004, 47, 1662; (d) Chu, X.-J.; De Pinto, W.; Bartkovitz,
D.; So, S.-S.; Vu, B. T.; Packman, K.; Lukacs, C.; Ding, Q.; Jiang, N.; Wang, K.;
Goelzer, P.; Yin, X.; Smit, M. A.; Higgins, B. X.; Chen, Y.; Xiang, Q.; Moliterni, J.;
Kaplan, G.; Graves, B.; Lovey, A.; Fotouhi, N. J. Med. Chem. 2006, 49, 6549.
4. Dounay, A. B.; Barta, N. S.; Bikker, J. A.; Borosky, S. A.; Campbell, B. M.; Crawford,
C.; Denny, L.; Evans, L. M.; Gray, D. L.; Lee, P.; Lenoir, E. A.; Xu, W. Bioorg. Med.
Chem. Lett. 2009, 19, 1159.
5. For examples of activities of functionalized 3-amino-1,2,4-triazines, see: (a)
Bondinell, W.E.; Holt, D.A.; Lago, M.A.; Neeb, M.J. Semones, M.A. Compounds
useful as kinase inhibitors for the treatment of hyperproliferative diseases. WO
076984, 2002; (b) Cao, J.; Green, J.; Moon, Y.C.; Wang, J.; Ledeboer, M.; Gao, H.
Harrington, E. Inhibitors of C-JUN N-Terminal kinases (JNK) and others protein
kinases. WO 083667, 2002; (c) Lewi, P.J.; De Jonge, M.R.; Koymans, L.M.H.;
Vinkers, H.M.; Dayeaert, F.F.D.; Heeres, J.; Leenders, R.G.G.; Hoornaert, G.J.C.;
Kilonda, A.; Ludovici, D.W. HIV inhibiting 1,2,4-triazines. WO 074266, 2004; (d)
Hoornaert, G.J.C.; Kilonda, A.; Heeres, J.; Lewi, P.J.; De Jonge, M.R.; Dayeaert, F.F.
D.; Vinkers, H.M.; Koymans, L.M.H. HIV inhibiting 1,2,4-triazin-6-one de-
rivatives. WO 015985, 2006; (e) Boyle, R.G.; Travers, S. Pharmaceuticals Com-
pounds. WO 059259, 2008.
d
d
(CH3), 113.9 (2ꢂCH), 121.5 (2ꢂCH), 124.2 (2ꢂCH), 128.9 (2ꢂCH),
132.2 (Cq), 138.5 (CH), 140.0 (Cq), 149.4 (Cq), 152.7 (Cq), 155.0 (Cq),
160.1 (Cq); HRMS (EIMS): m/z calcd for C16H14N5O3: 324.1097
[MþHþ], found: 324.1106.
4.3.15. N-(4-Methoxyphenyl)-6-(methylthio)-1,2,4,5-tetrazin-3-
amine (29). Compound 29 was obtained as a yellow solid (126 mg,
88%) following general procedure B with compound 28 (100 mg,
0.57 mmol), 4-methoxyaniline (85 mg, 0.68 mmol), CuMeSal
(264 mg, 1.14 mmol), Cs2CO3 (411 mg, 1.25 mmol), Pd(OAc)2 (13 mg,
0.05 mmol), Xantphos (66 mg, 0.11 mmol), toluene (5 mL). Rf
(CH2Cl2/MeOH 95/5) 0.44; mp 177e178 ꢀC; IR (ATR Diamond,
cmꢁ1 3263, 3090, 1616, 1571, 1510, 1249, 1233, 1029; 1H NMR
) n
(400 MHz, DMSO-d6)
d
2.65 (s, 3H), 3.75 (s, 3H), 7.57 (d, J¼9.1 Hz,
2H), 6.95 (d, J¼9.1 Hz, 2H), 10.49 (s, 1H); 13C NMR (100 MHz, DMSO-
d6)
d
13.1 (CH3), 55.2 (CH3), 114.0 (2ꢂCH), 121.5 (2ꢂCH), 131.2 (Cq),
155.3 (Cq), 160.0 (Cq), 166.1 (Cq). HRMS (EIMS): m/z calcd for
C10H12N5OS: 250.0734 [MþHþ], found: 250.0733.
6. Pellegatti, L.; Vedrenne, E.; Leger, J.-M.; Jarry, C.; Routier, S. Synlett 2009, 2137.
7. For other Pd-catalyzed C-3 functionalizations, see: (a) Alphonse, F.-A.; Suzenet,
F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Org. Lett. 2003, 5, 803; (b) Alphonse,
F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Synthesis 2004, 17,
2893; (c) Garnier, E.; Audoux, J.; Pasquinet, E.; Suzenet, F.; Poullain, D.; Lebret,
B.; Guillaumet, G. J. Org. Chem. 2004, 69, 7809.
8. For others desulfuratives cross-coupling reactions reported by our group, see:
(a) Silva, S.; Tardy, S.; Routier, S.; Suzenet, F.; Tatibouët, A.; Rauter, A. P.; Rollin, P.
Tetrahedron Lett. 2008, 49, 5583; (b) Silva, S.; Sylla, B.; Suzenet, F.; Tatibouët, A.;
Rauter, A. P.; Rollin, P. Org. Lett. 2008, 10, 853.
9. (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260; (b) Savarin, C.;
Liebeskind, L. S. Org. Lett. 2001, 3, 91; (c) Savarin, C.; Srogl, J.; Liebeskind, L. S.
Org. Lett. 2001, 3, 2149; (d) Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 801; (e)
Prokopcová, H.; Kappe, O. Angew. Chem., Int. Ed. 2008, 47, 2.
10. (a) Heilman, W. P.; Heilman, R. D.; Scozzie, J. A.; Wayner, R. J.; Gullo, J. M.;
Ariyan, Z. S. J. Med. Chem. 1979, 22, 671; (b) Joshi, K. C.; Dubey, K.; Dandia, A.
Heterocycles 1981, 16, 671.
4.3.16. N-(3-Methoxyphenyl)-6-(methylthio)-1,2,4,5-tetrazin-3-
amine (30). Compound 30 was obtained as a yellow solid (119 mg,
83%) following general procedure B with compound 28 (100 mg,
0.57 mmol), 3-methoxyaniline (85 mg, 0.68 mmol), CuMeSal
(264 mg, 1.14 mmol), Cs2CO3 (411 mg, 1.25 mmol), Pd(OAc)2 (13 mg,
0.05 mmol), Xantphos (66 mg, 0.10 mmol), toluene (5 mL). Rf
(CH2Cl2/MeOH 95/5) 0.43; mp 175e177 ꢀC; IR (ATR Diamond, cmꢁ1
3263, 3056, 1504, 1464, 1230, 1084, 1034; 1H NMR (250 MHz, CDCl3)
2.71 (s, 3H), 3.85 (s, 3H), 6.71 (dd, J¼5.3, 1.5 Hz, 1H), 7.19 (dd, J¼5.2,
2.0 Hz, 1H), 7.28e7.33 (m, 2H), 7.50 (s, 1H); 13C NMR (62.5 MHz,
CDCl3) 13.7 (CH3), 55.4 (CH3),105.5 (CH),109.6 (CH),111.8(CH),120.0
) n
d
d
(Cq), 130.1 (CH), 138.4 (Cq), 159.8 (Cq), 160.4 (Cq); HRMS (EIMS): m/z
calcd for C10H12N5OS: 250.0734 [MþHþ], found: 250.0741.
11. More than 20 h were needed to get full completion when the reaction was run
under reflux conditions. See Ref. 5.
12. CCDC 755055 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.uk/cont/retrieving.
html (or from Cambridge Crystallographic Data Centre, University Chemical Lab,
12, Union Road, Cambridge, CB2 1EZ, U.K.; E-mail: deposit@ccdc.cam.ac.uk).
13. Fields and Boger described that N-substituted 6-(methylthio)-1,2,4,5-tetrazin-
3-amines could be obtained through the direct displacement of the SMe moiety
by amines, without the use of palladium catalysis. However the reported yields
were poor. See: (a) Fields, S. C.; Parker, M.; Erickson, W. R. J. Org. Chem. 1994, 59,
8284; (b) Boger, D. L.; Schaum, R. P.; Garbaccio, R. M. J. Org. Chem. 1998, 63, 6329
and references quoted therein. Besides control experiments run without Pd
(OAc)2/CuMeSal, in the 1,2,4-triazine and 1,2,4,5-tetrazine series failed in our
hands.
4.3.17. N-(6-Methoxypyridin-3-yl)-6-(methylthio)-1,2,4,5-tetrazin-
3-amine (32). Compound 32 was obtained as a yellow solid
(113 mg, 79%) following general procedure B with compound 28
(100 mg,
0.40 mmol),
6-methoxypyridin-3-amine
(64 mg,
0.48 mmol), CuMeSal (185 mg, 0.80 mmol), Cs2CO3 (289 mg,
0.88 mmol), Pd(OAc)2 (9.0 mg, 0.04 mmol), Xantphos (47.0 mg,
0.08 mmol), toluene (5 mL). Rf (CH2Cl2/MeOH 95/5) 0.43; mp
182e184 ꢀC; IR (ATR Diamond, cmꢁ1
)
n
3221, 3022,1545,1474,1238,
1087, 1030; 1H NMR (250 MHz, CDCl3)
d
2.68 (s, 3H), 3.95 (s, 3H),