General synthesis of 4-aryloxy-6-methylpyrimidin-2-amines and their fragmentation under positive electrospray ionization

Article abstract of DOI:10.1134/S1070428015100127

A number of 4-aryloxy-6-methylpyrimidin-2-amines were synthesized by reaction of 2-amino-6-methylpyrimidin-4-yl 4-methylbenzenesulfonate with phenols. The main fragmentation pathway of these compounds under positive electrospray ionization is decomposition of the heterocycle.

Full text of DOI:10.1134/S1070428015100127

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 10, pp. 1430–1433. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © A.V. Erkin, O.S. Yuzikhin, V.I. Krutikov, Sh.S. Papinyan, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 10,
pp. 1461–1464.
General Synthesis of 4-Aryloxy-6-methylpyrimidin-2-amines
and Their Fragmentation under Positive Electrospray Ionization
A. V. Erkina, O. S. Yuzikhinb, V. I. Krutikova, and Sh. S. Papinyanb
a St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: anerkin@yandex.ru
b Kirov St. Petersburg State Forest Technical University,
Institutskii per. 5, St. Petersburg, 194021 Russia
Received July 1, 2015
Abstract—A number of 4-aryloxy-6-methylpyrimidin-2-amines were synthesized by reaction of 2-amino-6-
methylpyrimidin-4-yl 4-methylbenzenesulfonate with phenols. The main fragmentation pathway of these
compounds under positive electrospray ionization is decomposition of the heterocycle.
DOI: 10.1134/S1070428015100127
Up to now, no general method has been proposed
for the synthesis of 4-aryloxy-6-methylpyrimidin-2-
amines 1 that are structural analogs of biologically
active 4-aryloxypyrimidin-2-amines [1] and 4-aryl-
amino-6-methylpyrimidin-2-amines [2]. Some repre-
sentatives were obtained by reaction of 6-chloro-4-
methylpyrimidin-2-amine (2) with phenol [3] and
4-chlorophenol [4] in the presence of potassium hy-
droxide at ~100°C, as well as by treatment of 2 with
phenol and naphthalen-1-ol at 165°C under microwave
activation [5]. 6-(2-Methoxyphenoxy)-4-methylpyrim-
idin-2-amine was synthesized in less than 10% yield
by reaction of 2 with 2-methoxyphenol in boiling
toluene in the presence of metallic sodium [6].
by methanesulfonyloxy group greatly activated the
substrate to nucleophilic substitution in reactions with
salicylic acid esters, and the corresponding products
were obtained in up to 77% yield [10].
The electrophilicity of C4 in molecule 4 is higher
than in 2; the charge on C4 in 4 and 2 was estimated at
+0.414 and +0.329, respectively. Compound 4 was
synthesized by reaction of 3 with p-toluenesulfonyl
chloride in 5% aqueous sodium hydroxide at a tem-
1
perature not exceeding 15–20°C. The H NMR spec-
trum of 4 contained a two-proton singlet at δ 6.9 ppm
due to NH2 group, and in the IR spectrum of 4 we
observed absorption bands at 1379 and 1190 cm–1
typical of O–SO2 group [11]. These data confirmed
sulfonylation of the oxygen atom in 4.
The above procedures for the synthesis of com-
pounds 1 require fivefold excess of phenols; further-
more, they involve the necessity of preparing inter-
mediate chloro derivative 2 by reaction of 2-amino-6-
methylpyrimidin-4(3H)-one (3) with highly toxic
phosphoryl chloride [7] or its mixture with phosphorus
pentachloride [8]. In the latter case, the chlorination of
3 gives mainly N-(6-methyl-4-chloropyrimidin-2-yl)-
phosphoramidic dichloride [9].
Scheme 1.
O
OTs
TsCl
HN
N
H2N
N
Me
H2N
OAr
N
Me
3
4
In order to avoid the aforesaid difficulties in the
synthesis of aminopyrimidines 1, we tried an alter-
native approach based on the reaction of phenols with
2-amino-6-methylpyrimidin-4-yl 4-methylbenzenesul-
fonate (4). As a result, we isolated a series of aryloxy-
pyrimidinamines 1a–1h (Scheme 1). Replacement of
the halogen atom in 2-chloro-4,6-dimethoxypyrimidine
ArOH
N
H2N
N
Me
1a–1h
Ar = Ph (a), 4-EtC6H4 (b), 2-FC6H4 (c), 4-ClC6H4 (d), 4-BrC6H4 (e),
4-IC6H4 (f), 3,4-Me2C6H3 (g), 2,4-Cl2C6H3 (h).
1430

GENERAL SYNTHESIS OF 4-ARYLOXY-6-METHYLPYRIMIDIN-2-AMINES
1431
Scheme 2.
Me
N
[C4HN + H]+
[M + H]+
+ H
Me
NH+
–HN=C=NH
–ArH, –H2O
–ArOCN
–H2N–C CH
≡
H2N
m/z 64
m/z 83
m/z 42
Published data on the O-mesylation of 3 are contra-
dictory [12, 13]. According to [13], the reaction of 3
with 4-bromobenzenesulfonyl chloride under analo-
gous conditions afforded 2-amino-6-methylpyrimidin-
4-yl 4-bromobenzenesulfonate (5). Recrystallization of
5 from propan-2-ol gave 2-amino-6-methyl-4-oxo-3,4-
dihydropyrimidinium 4-bromobenzenesulfonate, pre-
sumably due to partial hydrolysis of 5 with water
present in the solvent.
1a–1h implies elimination of several neutral species,
including the corresponding arene, from [M + H]+ with
formation of [C4HN + H]+ (m/z 64).
Thus, the reaction of 2-amino-6-methylpyrimidin-
4-yl 4-methylbenzenesulfonate with phenols may be
regarded as a general method for the synthesis of
4-aryloxy-6-methylpyrimidin-2-amines.
EXPERIMENTAL
To prevent hydrolysis, compound 4 was recrys-
tallized from a mixture of anhydrous benzene and
cyclohexane, but the yield of pure 4 did not exceed
30%. We succeeded in improving the yield by 15–20%
by Soxhlet extraction of 4 with a minimum amount of
the same solvent system instead of recrystallization.
1
The H NMR spectra were recorded on a Bruker
Avance III-400 spectrometer at 400 MHz using
DMSO-d6 as solvent; the chemical shifts were meas-
ured relative to the residual proton signal of the
solvent. The IR spectrum of 4 was taken in KBr on
a Shimadzu FTIR-8400S spectrometer. The mass
spectra were obtained on a Waters XEVO TQD tandem
quadrupole mass spectrometer (positive electrospray
ionization, capillary voltage 2 kV, ion source tempera-
ture 150°C) coupled with a Waters Acquity UPLC
liquid chromatograph (Acquity UPLC BEH C18 col-
umn, 2.1×100 mm; temperature 35±1°C; eluent aceto-
nitrile–2% formic acid). The elemental compositions
were determined on a Leco CHNS-932 analyzer. The
purity of the isolated compounds was checked by TLC
on Sorbfil PTSKh-AF-V-UF plates using acetone–
hexane (1:1, A) or butan-1-ol–acetic acid–water
(1:1:1, B) as eluent; spots were visualized under UV
light (λ 254 nm). The charges on atoms in molecules 2
and 4 were calculated according to the extended
Hückel approximation (ChemDraw Ultra 11.0).
The reactions of 4 with phenols, including ortho-
substituted ones, were carried out by heating equimolar
amounts of the reactants at 140°C without a solvent or
catalyst. These conditions ensured homogeneity of the
melt. After cooling, the solid product was treated with
10% aqueous sodium hydroxide. Chromatographically
pure aryloxypyrimidines 1a–1h were thus isolated in
45–83% yield.
1
The structure of 1a–1h was confirmed by H NMR
and mass spectra. Compounds 1a–1h displayed in the
1H NMR spectra signals from the methyl group at
δ 2.2 ppm, amino group at δ 6.3–6.5 ppm, and aro-
matic protons in the region δ 6.8–7.7 ppm. The mass
spectra of 1a–1h (positive electrospray ionization)
contained [M + H]+ ion peaks. Compounds 1a–1c and
1g also displayed peaks of doubly protonated molec-
ular ions [M + 2H]2+. A characteristic feature of all
aryloxypyrimidines 1a–1h is the presence in their mass
spectra of three fragment ion peaks with m/z 83, 64,
and 42, originating from decomposition of the hetero-
cycle. An exception was compound 1c which showed
a low-intense ion peak with m/z 202 (Irel <5%)
resulting from elimination of hydrogen fluoride from
the [M + 2H]2+ ion. A probable scheme of pyrimidine
ring fragmentation includes the formation of [MeCN +
H]+ ion (m/z 42) via decomposition of intermediate
4-methylazet-2-aminium ion (m/z 83) (Scheme 2).
Less probable fragmentation of the pyrimidine ring in
4-Aryloxy-6-methylpyrimidin-2-amines 1a–1h
(general procedure). A mixture of 0.6 g (2.1 mmol) of
p-toluenesulfonate 4 and 2.1 mmol of the correspond-
ing phenol was heated for 1 h at 140°C. The melt was
cooled and thoroughly ground with 10% aqueous
sodium hydroxide. The undissolved material was
filtered off, washed with water, and dried at 70°C until
constant weight. Analytical samples were obtained by
recrystallization from appropriate solvent, followed by
drying at 70°C until constant weight.
4-Methyl-6-phenoxypyrimidin-2-amine (1a).
Yield 0.29 g (67%), mp 201°C (from cyclohexane–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 10 2015

ERKIN et al.
1432
benzene, 1 :2); published data [3]: mp 194–195°C;
Rf 0.49 (A). H NMR spectrum, δ, ppm: 2.19 s (3H,
H 2.78; N 12.39. C11H10IN3O. Calculated, %: C 40.39;
H 3.08; N 12.85.
1
Me), 5.94 s (1H, CH), 6.46 s (2H, NH2), 7.11–7.44 m
(5H, Ph). Mass spectrum, m/z (Irel, %): 202.06 (77)
[M + H]+, 203.12 (13) [M + 2H]2+, 83.01 (49), 63.91
(3), 42.05 (100). Found, %: C 65.27; H 5.65; N 20.57.
C11H11N3O. Calculated, %: C 65.66; H 5.51; N 20.88.
4-(3,4-Dimethylphenoxy)-6-methylpyrimidin-2-
amine (1g). Yield 0.37 g (75%), mp 239°C (from
1
propan-2-ol), Rf 0.60 (A). H NMR spectrum, δ, ppm:
2.17 s (3H, Me), 2.23 s (6H, Me), 5.88 s (1H, CH),
6.43 s (2H, NH2), 6.81 d (1H, Harom), 6.88 s (1H,
4-(4-Ethylphenoxy)-6-methylpyrimidin-2-amine
Harom), 7.14 d (1H, Harom). Mass spectrum, m/z (Irel, %):
(1b). Yield 0.22 g (45%), mp 196°C (from EtOH),
230.17 (99) [M + H]+, 231.11 (31) [M + 2H]2+, 83.01
(49), 63.84 (5), 41.98 (96). Found, %: C 68.12; H 6.43;
N 18.27. C13H15N3O. Calculated, %: C 68.10; H 6.59;
N 18.33.
1
Rf 0.56 (A). H NMR spectrum, δ, ppm: 1.23 t (3H,
MeCH2), 2.19 s (3H, Me), 2.64 q (MeCH2), 5.89 s
(1H, CH), 6.39 s (2H, NH2), 7.00 d (2H, Harom), 7.23 d
(2H, Harom). Mass spectrum, m/z (Irel, %): 230.11 (100)
[M + H]+, 231.17 (33) [M + 2H]2+, 83.07 (51), 63.97
(6), 42.05 (97). Found, %: C 67.67; H 6.46; N 18.19.
C13H15N3O. Calculated, %: C 68.10; H 6.59; N 18.33.
4-(2,4-Dichlorophenoxy)-6-methylpyrimidin-2-
amine (1h). Yield 0.47 g (81%), mp 202°C (from
1
MeCN), Rf 0.71 (A). H NMR spectrum, δ, ppm:
2.22 s (3H, Me), 6.09 s (1H, CH), 6.50 s (2H, NH2),
7.33 d (1H, Harom), 7.46 d (1H, Harom), 7.69 s (1H,
4-(2-Fluorophenoxy)-6-methylpyrimidin-2-
amine (1c). Yield 0.31 g (66%), mp 186°C (from
MeCN), Rf 0.87 (A). H NMR spectrum, δ, ppm:
Harom). Mass spectrum, m/z (Irel, %): 269.99 (92)
1
[M + H]+, 83.01 (52), 63.91 (7), 42.11 (100). Found,
%: C 48.57; H 3.12; N 15.43. C11H9Cl2N3O. Calculat-
ed, %: C 48.91; H 3.36; N 15.56.
2.22 s (3H, Me), 6.06 s (1H, CH), 6.45 s (2H, NH2),
7.20–7.31 m (4H, Harom). Mass spectrum, m/z (Irel, %):
220.09 (85) [M + H]+, 221.09 (15) [M + 2H]2+, 202.06
(3), 83.01 (51), 64.03 (3), 42.05 (100). Found, %:
C 59.89; H 4.63; N 18.79. C11H10FN3O. Calculated, %:
C 60.27; H 4.60; N 19.17.
2-Amino-6-methylpyrimidin-4-yl 4-methylben-
zenesulfonate (4). 2-Amino-6-methylpyrimidin-
4(3H)-one (3) [14], 2 g (16 mmol), was dissolved in
a 5% aqueous solution of sodium hydroxide (1 g), and
3.05 g (16 mmol) of p-toluenesulfonyl chloride was
added in portions under vigorous stirring, maintaining
the temperature at 15–20°C. The mixture was stirred
for 3 h at that temperature, and the precipitate was
filtered off, thoroughly washed with water, and dried in
air until constant weight. The product was Soxhlet
extracted with benzene–cyclohexane (2:1), the extract
was cooled, and the precipitate was filtered off,
washed with cyclohexane, and dried at 70°C until con-
stant weight. Yield 2.08 g (46%), mp 142°C, Rf 0.56
(B). IR spectrum, ν, cm–1: 1657 s (δ NH2), 1596 s,
4-(4-Chlorophenoxy)-6-methylpyrimidin-2-
amine (1d). Yield 0.39 g (78%), mp 227°C (from
H2O–EtOH, 1:3); published data [4]: mp 220–221°C;
1
Rf 0.53 (A). H NMR spectrum, δ, ppm: 2.20 s (3H,
Me), 6.00 s (1H, CH), 6.49 s (2H, NH2), 7.16 d
(2H, Harom), 7.45 d (2H, Harom). Mass spectrum, m/z
(Irel, %): 236.06 (78) [M + H]+, 83.01 (50), 63.84 (4),
42.05 (100). Found, %: C 58.71; H 4.10; N 17.54.
C11H10ClN3O. Calculated, %: C 56.06; H 4.28; N 17.83.
4-(4-Bromophenoxy)-6-methylpyrimidin-2-
amine (1e). Yield 0.47 g (78%), mp 242°C (from
1
1
1552 s (C=N, C=C), 1379 s, 1190 s (OSO2). H NMR
EtOH–DMF, 8:1), Rf 0.77 (A). H NMR spectrum, δ,
spectrum, δ, ppm: 2.22 s (3H, Me), 2.44 s (3H, Me),
6.15 s (1H, CH), 6.90 s (2H, NH2), 7.47 d (2H, Harom),
7.95 d (2H, Harom). Found, %: C 51.72; H 4.24;
N 14.71. C12H13N3O3S. Calculated, %: C 51.60;
H 4.69; N 15.04.
ppm: 2.21 s (3H, Me), 5.98 s (1H, CH), 6.44 s (2H,
NH2), 7.09 d (2H, Harom), 7.56 d (2H, Harom). Mass
spectrum, m/z (Irel, %): 280.00 (73) [M + H]+, 83.07
(50), 63.97 (5), 42.05 (100). Found, %: C 46.67;
H 3.75; N 14.81. C11H10BrN3O. Calculated, %:
C 47.17; H 3.60; N 15.00.
REFERENCES
4-(4-Iodophenoxy)-6-methylpyrimidin-2-amine
(1f). Yield 0.68 g (83%), mp 260°C (decomp., from
(EtOH–DMF, 1:1), Rf 0.55 (A). H NMR spectrum, δ,
ppm: 2.20 s (3H, Me), 6.00 s (1H, CH), 6.48 s (2H,
NH2), 6.97 d (2H, Harom), 7.73 d (2H, Harom). Mass
spectrum, m/z (Irel, %): 327.99 (68) [M + H]+, 83.07
(50), 63.97 (8), 42.05 (100). Found, %: C 40.02;
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