Synthesis and reactions of [1,2,4]triazolo[1,5-a]pyrimidinium-2-aminides

Article abstract of DOI:10.1039/a900942f

[1,2,4]Triazolo[1,5-a]pyrimidinium-2-amides were synthesised by treating an appropriate triazolo[1,5-a]pyrimidinium salt with sodium hydroxide or from the reaction of 4-alkyl-3,5-diamino-1,2,4-triazoles with pentane-2,4-dione or 1,1,3,3-tetramethoxypropan

Full text of DOI:10.1039/a900942f

View Online / Journal Homepage / Table of Contents for this issue
Synthesis and reactions of [1,2,4]triazolo[1,5-a]pyrimidinium-2-
aminides
Brian C. Bishop,*a Hugh Marley,a† Peter N. Preston*b and Stanley H. B. Wrighta
a Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire,
UK EN11 9BU
b Department of Chemistry, Heriot-Watt University, Riccarton, Edinburgh, UK EH14 4AS
Received (in Cambridge) 3rd February 1999, Accepted 19th April 1999
[1,2,4]Triazolo[1,5-a]pyrimidinium-2-amides were synthesised by treating an appropriate triazolo[1,5-a]pyrimidinium
salt with sodium hydroxide or from the reaction of 4-alkyl-3,5-diamino-1,2,4-triazoles with pentane-2,4-dione or
1,1,3,3-tetramethoxypropane.
ative (1c) were readily obtained through two routes. The
Introduction
latter (1c) was prepared through a Dimroth rearrangement8
The unusual rearrangement and dimerisation of certain
of 5,7-dimethyl-2-phenylamino[1,2,4]triazolo[1,5-a]pyrimidine
putative [1,2,4]triazolo[4,3-a]pyrimidinium-3-aminides1 and
and this product proved to be identical to that obtained by
[1,2,4]triazolo[4,3-a][1,3,5]triazinium-3-aminides2 have been
treating 3-amino-5-phenylamino-1,2,4-triazole9 with pentane-
described. We have also reported3 the preparation of [1,2,4]-
2,4-dione (see Scheme 1); the triazole route was also used for
triazolo[1,5-a]pyrimidinium-2-olates and disclosed the interest-
ing 1,3-dipolar cycloaddition reactions of these compounds
Me
N
N
Me
N
NHNHCSNHPh
with acetylenes and other derivatives. It was, therefore, of inter-
est to investigate the synthesis and reactions of the related
[1,2,4]triazolo[1,5-a]pyrimidinium-2-aminides.
i
ii
N
1c
N
N
NHPh
Me
Me
Results and discussion
Synthesis
H
N
H2N
NHR
iii
1a,b
Alkylation reactions of heterocycles have been used for the syn-
thesis of a number of mesoionic compounds, particularly 1,2,4-
triazoliumolates,4–6 although mixtures of products were often
obtained. Also in the synthesis of the tricyclic system (3) the
preparation of the salts (2) by alkylation of 2-amino[1,2,4]-
triazolo[1,5-a]pyrimidines (1) was described.7 Thus, in this work
N
N
4
R
H
a
b
Ph
Scheme 1 Reagents: (i) DCC, toluene, (ii) 2 M aq. NaOH, (iii) pentane-
2,4-dione.
Ph
R1
N
N
N
synthesis of 1a. Alkylation of the triazolopyrimidines was ini-
tially carried out in boiling acetic acid, in which the phenyl
derivative (1c) reacted with benzyl bromide to give the salt (5a)
in 51% yield. Treatment of the salt 5a with Amberlite resin (OH
O
NHR2
R1
N
_
N
N
N
(Br)
NHR2
+
N
R1
R1
R1
R3
1
R2
2
R1
N
a, Me
b, Ph
c, Me
H
N
_
NHR2
H
(X)
+
N
Ph
N
R1
Ph
R1
_
N
N
N
R1
R2
R3
PhCH2
Me
X –
Br
MeSO4
EtSO4
Br
Cl
Cl
Cl
Cl
5
a
(Br)
N
Me
Me
Me
Me
Me
Me
Me
H
Ph
Ph
Ph
H
H
H
+
R2
N
b
c
d
e
f
Et
R1
PhCH2
PhCH2
Me
(CH2)2Me
CH2Ph
3
H
H
the alkylation of [1,2,4]triazolo[1,5-a]pyrimidines to yield the
target betaines was attempted at the outset.
g
h
The desired precursor heterocycles, 2-amino-5,7-dimethyl-
[1,2,4]triazolo[1,5-a]pyrimidine (1a) and the phenyl deriv-
form) gave N-phenyl-3-benzyl-5,7-dimethyl-3H-8λ5-[1,2,4]tri-
azolo[1,5-a]pyrimidin-8-ylium-2-aminide (6a) in 85% yield. The
use of dialkyl sulfates as alkylating agents with the phenylamine
1c gave better results in dimethylformamide as solvent, giving
† Present address: Glaxo Wellcome, Temple Hill, Dartford, Kent, UK
DA1 5AH.
J. Chem. Soc., Perkin Trans. 1, 1999, 1527–1532
1527

View Online
R3
N3
3-position in the previous synthesis. A characteristic feature in
the H NMR spectra of compounds 5 and 6 is the appearance
1
R1
N
_
5
NR2
of the 7-Me resonance as a doublet (J ~ 0.8 Hz) although H-6
exists as a broadened resonance (see our earlier characterisation
of [1,2,4]-triazolo[1,5-a]pyrimidinium-2-olates and -thiolates).3
Reaction of the diamino-1,2,4-triazole (8c) with 1,1,3,3-tetra-
methoxypropane in ethanol and hydrochloric acid gave the
pyrimidinium chloride 5h in 86% yield, but attempted isolation
of betaine 6g by basification was unsuccessful.
+
N
N
7
1
R1
R2
6
a
b
c
d
e
f
R1
R3
Me
Me
Me
Me
Me
Me
H
Ph
Ph
Ph
H
PhCH2
Me
Et
PhCH2
Me
Reactions
H
H
(CH2)2Me
PhCH2
PhCH2
The betaines 6d–f, unsubstituted on the exocyclic nitrogen
atom, were not completely stable, but the mixtures of
decomposition products did not include dimeric compounds
analogous to the [1,2,4]triazolo[4,3-a]pyrimidinium-3-aminide
rearrangement products previously reported.1,2
g
h
H
Me
CO2Et
Y
Y
Me
Me
PhCH2
i
Y
Y
Acylation of the betaine 6d with ethyl chloroformate in alka-
line solution gave the stable ethoxycarbonyl derivative 6h.
Attempted 1,3-dipolar cycloaddition reactions of the betaines
6d and 6e with dimethyl acetylenedicarboxylate (DMAD) or
methyl propiolate were unsuccessful; an alternative process of
conjugate addition occurred to give the adducts 6i–l. Previous
studies11 of such additions to acetylenic esters have shown that
the stereochemical outcome depends on a number of factors
including the structure of the starting components, the solvent
and reaction conditions. In this work the stereochemistry of
adducts 6i,j from DMAD was not determined but the analo-
gous products 6k,l derived from methyl propiolate were
assigned as (E)-configuration from observation of relatively
j
Me
k
Me
Me
PhCH2
Me
Y
l
Y
Y = CO2Me
the salts 5b and 5c in 63 and 42% yield, respectively; treatment
of the latter (5b,c) with aqueous sodium hydroxide gave the
betaines 6b and 6c in 69 and 91% yield, respectively. Attempted
alkylation of the primary amine 1a with dialkyl sulfates under
these conditions gave complex mixtures, but with benzyl
bromide, the salt 5d was obtained in 41% yield. Treatment of
the salt 5d with aqueous sodium hydroxide gave the betaine
1
large coupling constants in the H NMR spectra (J ~ 13 Hz)
characteristic of trans-olefinic protons.
It is notable that the [1,2,4]triazolo[1,5-a]pyrimidinium
betaines prepared in this work are stable and isolable,
independent of whether the group on the exocyclic nitrogen is
H (6d–g), Ph (6a–c) or an electron withdrawing moiety [e.g.
CO Et (6h), C(CO Et)᎐CHCO Et (6i)]. Since the molecular
᎐
2
2
2
1
6d, which was isolated as a dihydrate. Spectral data (IR, H
dimerisative rearrangement of analogous [1,2,4]triazolo[4,3-a]-
pyrimidinium-3-aminides can be induced by an external base, it
was decided to qualitatively evaluate the acidity of the methyl
NMR) fully supported the structures 5d and 6d whereby alkyl-
ation had occurred at the 3-position. However, due to the
limited success of this method for the preparation of the unsub-
stituted betaines (5, R2 = H), an alternative, unambiguous route
to these compounds was sought.
The new procedure for the preparation of 2-unsubstituted
aminides 6d–f involved the development of a synthetic route to
4-alkyl-3,5-diamino-1,2,4-triazoles (8a–c, Scheme 2). Alkyl
1
groups (R1) in the pyrimidine ring of the aminides 6. The H
NMR spectrum of phenyl derivative 6b in deuterated methanol
shows a single peak (δ 2.4) for the 7-methyl substituent with
almost complete exchange of the 5-methyl protons (δ 2.5). The
1H NMR spectrum of the betaine 6d in deuterated methanol
indicates almost total exchange of the protons of both the 5
and 7 methyl groups. Evaporation of the solution, dissolution
in methanol and after 15 minutes re-evaporation gave a sample,
the 1H NMR of which recorded in CD2Cl2, showed the 5-
methyl signal (δ 2.50) had reappeared, whereas the 7-methyl
signal (δ 2.42) was still largely absent. These experiments indi-
cate the ease with which these compounds may be deproton-
ated, particularly at the 5-methyl position.
R
H2N
N
CN
CN
NH2
i
ii
R
N
5e–g
N
N
8
7
R
a
b
c
Me
(CH2)2Me
PhCH2
Conclusions
[1,2,4]Triazolo[1,5-a]pyrimidinium-2-aminides (6), unsubsti-
tuted or substituted at the exocyclic nitrogen may be obtained
as crystalline solids by two different synthetic methods. The
aminides 6d,e do not react with activated acetylenes through
1,3-dipolar cycloaddition but rather by conjugate addition of
the exocyclic aminide nitrogen. Although the 5-methyl group of
these compounds is readily deprotonated, unlike the isomeric
[1,2,4]triazolo[4,3-a]pyrimidinium-3-aminides, no evidence of
rearrangement and dimerisation of the compounds was found.
Scheme 2 Reagents: (i) N2H4ؒH2O, (ii) CH3COCH2COCH3, HCl.
dicyanamides 7a–c, prepared by the method of Benders and
Hackmann10 reacted with hydrazine hydrate to give the tri-
azoles 8a–c in 29–64% yield. Reaction of the diamino-1,2,4-
triazoles with pentane-2,4-dione in ethanol in the presence
of hydrochloric acid gave the 2-amino[1,2,4]triazolo[1,5-a]-
pyrimidinium chlorides 5e–g as colourless crystalline solids
in 74–93% yield. Treatment of salts 5e–g with aqueous
sodium hydroxide gave the betaines 6d–f as yellow crystalline
dihydrates, which rapidly darkened on attempted drying at
temperatures >20 ЊC, in 42–78% yield. The benzyl derivative
(6d) was identical (IR, 1H NMR) to that obtained by the alkyl-
ation method, confirming that alkylation had occurred at the
Experimental
Mps were determined on a Buchi 510 mp apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer 781
1528
J. Chem. Soc., Perkin Trans. 1, 1999, 1527–1532

View Online
spectrophotometer. 1H NMR and 13C NMR spectra were
obtained on Bruker AM-250 or Bruker DPX 250 spectrometers
with tetramethylsilane as internal standard. Chemical shifts
were measured in ppm and coupling constants (J) in Hz. Mass
spectra were obtained using a VG-Micromass- 16F spec-
trometer using a direct insertion probe. Pre-coated Merck
Kieselgel 60 F 254 plates were used for analytical TLC.
mmol) in acetic acid (15 ml) was heated under reflux for 24 h.
The resulting orange solution was cooled and the precipitate
collected by filtration. The solid obtained was recrystallised
from methanol to give 3-benzyl-5,7-dimethyl-2-phenylamino-
3H-8λ5-[1,2,4]triazolo[1,5-a]pyrimidin-8-ylium bromide (5a) as
yellow needles (209 mg, 51%), mp 270 ЊC (decomp.) (Found: C,
58.55; H, 4.9; N, 16.9. C20H20BrN5 requires C, 58.55; H, 4.9; N,
17.1%); νmax (Nujol) 1620, 1565 and 758 cmϪ1; δH [(CD3)2SO]
2.69 (s, 3H, 5-CH3), 2.81 (s, 3H, 7-CH3). 5.79 (s, 2H, CH2Ph),
7.13–7.51 (m, 8H, Ar-H), 7.22 (s, 1H, H-6), 7.78 (m, 2H, Ar-H),
10.42 (s, 1H, NH); δC [(CD3)2SO] 16.18 (C-7a), 24.41 (C-5a),
45.36 (N-CH2), 115.49 (C-6), 119.90 (Ar-C), 124.20 (Ar-C),
127.26 (Ar-C), 128.15 (Ar-C), 128.71 (Ar-C), 129.16 (Ar-C),
133.68 (Ar-C), 137.47 (C-7), 145.50 (C-3a), 149.96 (Ar-C),
151.54 (C-2), 168.11 (C-5).
5,7-Dimethyl-3-phenylamino[1,2,4]triazolo[4,3-a]pyrimidine
A mixture of 1-(4,6-dimethylpyrimidin-2-yl)-4-(phenyl)thio-
semicarbazide12 (0.50 g, 1.8 mmol) and dicyclohexylcarbodiim-
ide (0.57 g, 2.7 mmol) in toluene (20 ml) was heated
under reflux for 1 h. The mixture was allowed to cool to
room temperature and the precipitated product was collected
by filtration. Recrystallisation of the crude product from
propan-2-ol gave 5,7-dimethyl-3-phenylamino[1,2,4]triazolo-
[4,3-a]pyrimidine as yellow plates (0.28 g, 64%), mp 190–
192 ЊC; νmax (Nujol) 3160, 1630 and 750 cmϪ1; δH [(CD3)2CO]
2.49 (s, 3H, 7-CH3), 2.68 (d, 3H, J = 1 Hz, 5-CH3), 6.75–6.85
(m, 4H, 3 × Ar-H and H-6), 7.16–7.25 (m, 2H, Ar-H);
δC [(CD3)2CO] 17.86, 25.17, 111.93, 115.39, 120.36, 130.00,
143.13, 144.75, 146.20, 153.88, 165.06; m/z (EI) 239 (100%)
(Mϩ). This compound was not purified to analytical standard,
but was used for the conversion to 1c.
N-Phenyl-3-benzyl-5,7-dimethyl-3H-8ë5-[1,2,4]triazolo[1,5-a]-
pyrimidin-8-ylium-2-aminide (6a)
3-Benzyl-5,7-dimethyl-2-phenylamino-3H-8λ5-[1,2,4]triazolo-
[1,5-a]pyrimidin-8-ylium bromide (5a) (200 mg, 0.5 mmol) was
dissolved in hot methanol. To the resultant solution was added
Amberlite resin [IRA 400 (OH form)] (200 mg) and the mixture
stirred for 5 min then filtered. The filtrate was concentrated
to give N-phenyl-3-benzyl-5,7-dimethyl-3H-8λ5-[1,2,4]triazolo-
[1,5-a]pyrimidin-8-ylium-2-aminide (6a) as golden needles (136
mg, 85%), mp 191–192 ЊC (Found: C, 72.7; H, 5.9; N, 21.1.
C20H19N5 requires C, 72.95; H, 5.8; N, 21.25%); νmax (CHCl3)
1625, 1612, 1578, 1555, 1140 and 690 cmϪ1; δH (CDCl3) 2.63 (s,
3H, 5-CH3), 2.71 (d, 3H, J = 0.7 Hz, 7-CH3), 5.79 (br s, 2H,
CH2Ph), 6.91 (s, 1H, H-6), 6.95–7.85 (m, 10H, Ar-H); m/z 329
(89%) (Mϩ), 328 (57), 252 (20), 180 (25), 167 (100), 108 (28), 91
(99), 67 (18), 65(30), 28 (66).
5,7-Dimethyl-2-phenylamino[1,2,4]triazolo[1,5-a]pyrimidine
(1c)
Method A. A stirred mixture of 5,7-dimethyl-3-phenylamino-
[1,2,4]triazolo[4,3-a]pyrimidine (5.0 g, 21 mmol) and 2 M
aqueous sodium hydroxide (100 ml) was heated at 70 ЊC for 2 h.
The resulting mixture was cooled to room temperature and the
product collected by filtration, washed with water (20 ml) and
recrystallised from acetic acid to give 5,7-dimethyl-2-phenyl-
amino[1,2,4]triazolo[1,5-a]pyrimidine (1c) as colourless
needles (4.05 g, 81%), mp 285–286 ЊC (Found: C, 65.2; H, 5.6;
N, 29.15. C13H13N5 requires (C, 65.25; H, 5.5; N, 29.25%); νmax
(Nujol) 3270, 1605, 1560 and 745 cmϪ1; δH [(CD3)2SO] 2.57 (s,
3H, 5-CH3), 2.72 (br s, 3H, 7-CH3), 6.81 (s, 1H, H-6), 6.88–7.66
(m, 5H, Ar-H); m/z (EI) 239 (100%) (Mϩ).
3,5,7-Trimethyl-2-phenylamino-3H-8ë5-[1,2,4]triazolo[1,5-a]-
pyrimidin-8-ylium methyl sulfate (5b)
5,7-Dimethyl-2-phenylamino[1,2,4]triazolo[1,5-a]pyrimidine
(5.0 g, 21.0 mmol) was suspended in dimethylformamide (40
ml). The suspension was treated with dimethyl sulfate (3.16 g,
25.1 mmol) and the mixture heated at 100–110 ЊC for 1 h. The
resulting dark green solution was cooled to room temperature
for 30 min and the precipitated solid collected by filtration and
rinsed through with dimethylformamide (10 ml). The filtrate
was diluted with tert-butyl methyl ether (50 ml) over 15 min and
the resulting slurry stirred for 10 min. The solid was collected
by filtration, washed with 3:1 tert-butyl methyl ether–dimethyl-
formamide (15 ml) and dried in vacuo at 50 ЊC to afford the title
compound as a dark green solid (4.84 g, 63%); δH (d6-DMSO)
2.72 (s, 3H, 5-CH3), 2.80 (s, 3H, 7-CH3), 3.36 (s, 3H, CH3SO4),
3.85 (s, 3H, N-CH3), 7.18 (m, 1H, Ar-H), 7.47 (m, 2H, Ar-H),
7.68 (s, 1H, H-6), 7.78 (m, 2H, Ar-H); δC (d6-DMSO) 16.0, 24.3,
29.4, 52.7, 114.9, 119.4, 123.9, 129.1, 137.5, 145.5, 149.3, 152.0,
167.7. This compound was not purified to analytical standard
and was used immediately for the synthesis of 6b.
Method B. 3-Amino-5-phenylamino[1,2,4]triazole9 (20.0 g,
114 mmol) and pentane-2,4-dione (13.71 g, 137 mmol) were
dissolved in propan-2-ol (400 ml) and the solution heated to
reflux temperature for 48 h. The resulting slurry was cooled to
room temperature and the solid collected by filtration. The
solid was washed with propan-2-ol (200 ml) and dried in vacuo
at 50 ЊC to afford a pale apricot solid (15.54 g, 57%). A second
crop of product was collected from the filtrate, washed with
propan-2-ol and dried in vacuo at 50 ЊC (7.80 g, 29%). Overall
crude yield = 23.34 g, 86%. The crude product was recrystal-
lised from dimethylformamide to afford the title compound as a
white crystalline solid (21.74 g, 80%) mp 287–289 ЊC. This
product was spectroscopically identical (IR, NMR) to the com-
pound described above.
N-Phenyl-3,5,7-trimethyl-3H-8ë5-[1,2,4]triazolo[1,5-a]-
pyrimidin-8-ylium-2-aminide (6b)
5,7-Dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-amine (1a)
3,5-Diamino[1,2,4]triazole (10.0 g, 100 mmol) and pentane-
2,4-dione (10.1 g, 100 mmol) were dissolved in glacial acetic
acid and the solution heated to reflux overnight. The resulting
slurry was cooled to room temperature, the solid collected by
filtration, washed with ethyl acetate and dried in vacuo at 50 ЊC
to afford the title compound as pale yellow crystals (12.22 g,
75%), mp 355–357 ЊC (lit.,13 357 ЊC).
3,5,7-Trimethyl-2-phenylamino-3H-8λ5-[1,2,4]triazolo[1,5-a]-
pyrimidin-8-ylium methyl sulfate (3.40 g, 9.3 mmol) was dis-
solved in water (100 ml). The resulting deep green solution was
treated with 2 M aqueous sodium hydroxide (7.0 ml, 14.0
mmol) whereupon a solid immediately precipitated. The solid
was collected by filtration, washed with water (50 ml) and dried
in vacuo at 50 ЊC over P2O5 to afford a dark green solid (2.20 g,
94%). The crude product was recrystallised from propan-2-ol to
afford the pure title compound as dark green needles (1.61 g,
69%) mp 216–218 ЊC (decomp.) (Found: C, 66.38; H, 6.02; N,
27.65. C14H15N5 requires C, 66.38; H, 5.97; N, 27.65%);
δH (CD2Cl2) 2.51 (s, 3H, 5-CH3), 2.62 (s, 3H, 7-CH3), 3.53 (s,
3-Benzyl-5,7-dimethyl-2-phenylamino-3H-8ë5-[1,2,4]triazolo-
[l,5-a]pyrimidin-8-ylium bromide (5a)
A mixture of 5,7-dimethyl-2-phenylamino[1,2,4]triazolo[1,5-a]-
pyrimidine (239 mg, 1 mmol) and benzyl bromide (855 mg, 5
J. Chem. Soc., Perkin Trans. 1, 1999, 1527–1532
1529

View Online
3H, N-CH3), 6.68 (s, 1H, H-6), 6.81 (m, 1H, Ar-H), 7.22 (m,
2H, Ar-H), 7.46 (m, 2H, Ar-H). δC (CD2Cl2) 16.9, 24.0, 27.2,
111.8, 119.5, 123.2, 128.4, 144.5, 150.1, 160.9.
Propyl dicyanamide (7b). Colourless liquid (12.0 g, 38%) bp
60–72 ЊC/2–3 mbar (lit.,10 bp 94–94.5 ЊC/12 Torr).
Benzyl dicyanamide (7c). Colourless liquid (10.0 g, 63%) bp
120–125 ЊC/0.1 mbar (lit.,10 bp 93–95 ЊC/0.2–0.3 Torr).
5,7-Dimethyl-3-ethyl-2-phenylamino-3H-8ë5-[1,2,4]triazolo[1,5-
a]pyrimidin-8-ylium ethyl sulfate (5c)
General method for the preparation of 4-alkyl-3,5-diamino-
1,2,4-triazoles (8a–c)
5,7-Dimethyl-2-phenylamino[1,2,4]triazolo[1,5-a]pyrimidine
(5.0 g, 21.0 mmol) was suspended in dimethylformamide (40
ml) and the suspension was treated with diethyl sulfate (3.87 g,
25.0 mmol). The mixture was heated at 100–110 ЊC for 24 h.
The resulting deep green solution was cooled to room temper-
ature and then to 0 ЊC whereupon a solid crystallised. The solid
was collected by filtration, washed with cold DMF (10 ml) and
dried in vacuo at 50 ЊC to afford the title compound as a pale
pink solid (3.44 g, 42%) mp 208–210 ЊC (Found: C, 51.98; H,
5.89; N, 17.85; S, 8.20. C17H23N5O4S requires C, 51.90; H, 5.89;
N, 17.80; S, 8.15%); δH (d6-DMSO) 1.10 (t, 3H, J = 6.5 Hz,
CH2CH3), 1.43 (t, 3H, J = 6.5 Hz, CH2CH3), 2.72 (s, 3H,
5-CH3), 2.79 (s, 3H, 7-CH3), 3.76 (q, 2H, J = 6.5 Hz, CH2CH3),
4.44 (q, 2H, J = 6.5 Hz, CH2CH3), 7.19 (m, 1H, Ar-H), 7.48
(m, 2H, Ar-H), 7.69 (s, 1H, H-6), 7.80 (m, 2H, Ar-H); δC
(d6-DMSO) 19.7, 21.7, 22.7, 31.0, 44.7, 67.8, 121.7, 126.4,
135.8, 144.2, 151.9, 156.0, 157.9, 174.4.
A solution of the appropriate alkyl dicyanamide (1.0 equiv.) in
industrial methylated spirits (IMS) was added over 30 min to a
solution of hydrazine monohydrate (1.1 equiv.) in methylated
spirits at 0 ЊC. The mixture was stirred at room temperature
for 4–18 h. The reaction mixture was partially concentrated
in vacuo and the crude products isolated by filtration. The
crude products were recrystallised from ethanol. The following
compounds were prepared.
3,5-Diamino-4-methyl-1,2,4-triazole (8a). Colourless needles
(2.04 g, 29%), mp 265–273 ЊC (Found: C, 31.83; H, 6.18; N,
61.69%. C3H7N5 requires C, 31.85; H, 6.24; N, 61.91%); νmax
-
;
(Nujol) 3320, 3125 (N–H), 1650, 1630 and 1555 cmϪ1
δH (d6-DMSO) 3.11 (s, 3H, CH3), 5.30 (br s, 4H, 2 × NH2); δC
(d6-DMSO) 27.0, 150.8.
3,5-Diamino-4-propyl-1,2,4-triazole (8b). Colourless needles
(7.60 g, 65%), mp 251–252 ЊC (Found: C, 42.43; H, 7.81; N,
49.51%. C5H11N5 requires C, 42.53; H, 7.86; N, 49.61%);
νmax(Nujol) 3330, 3120 (NH), 1635 and 1540 cmϪ1; δH (CD3OD)
0.93 (t, 3H, J = 7.5 Hz, CH2CH2CH3), 1.70 (apparent sextet,
2H, J = 7.5, 8.0 Hz, CH2CH2CH3), 3.63 (t, 2H, J = 7.5 Hz,
CH2CH2CH3); δC (CD3OD) 11.0, 22.5, 43.8, 153.2.
N-Phenyl-5,7-dimethyl-3-ethyl-3H-8ë5-[1,2,4]triazolo[1,5-a]-
pyrimidin-8-ylium-2-aminide
(6c).
5,7-Dimethyl-3-ethyl-
2-phenylamino-3H-8λ5-[1,2,4]triazolo[1,5-a]pyrimidin-8-ylium
ethyl sulfate (3.0 g, 7.62 mmol) was dissolved in water (100 ml)
with warming on a steam bath. The dark green solution was
cooled to room temperature and treated, dropwise, with 2 M
aqueous sodium hydroxide (4.0 ml, 8.0 mmol). The resulting
green-yellow slurry was stirred at room temperature for one
hour, the solid was collected by filtration, washed with water
and dried in vacuo at 45 ЊC over P2O5 to afford the title com-
pound as a yellow solid (1.85 g, 91%) mp 192–195 ЊC (decomp.)
(Found: C, 67.34; H, 6.45; N, 26.16. C15H17N5 requires C, 67.39;
H, 6.41; N, 26.20%); δH (CD2Cl2) 1.40 (t, 3H, J = 6.5 Hz,
CH2CH3), 2.50 (s, 3H, 5-CH3), 2.60 (s, 3H, 7-CH3), 4.14 (q, 2H,
J = 6.5 Hz, CH2CH3), 6.66 (s, 1H, H-6), 6.80 (m, 1H, Ar-H),
7.20 (m, 2H, Ar-H), 7.46 (m, 2H, Ar-H); δC (CD2Cl2) 13.3, 17.2,
24.3, 36.3, 111.9, 119.7, 123.4, 128.7, 144.6, 146.2, 150.4, 154.2,
161.1.
3,5-Diamino-4-benzyl-1,2,4-triazole (8c). Colourless prisms
(3.85 g, 64%), mp 285–298 ЊC (Found: C, 56.99; H, 5.89; N,
37.02%. C9H11N5 requires C, 57.13; H, 5.86; N, 37.01%); νmax
(Nujol) 3440, 3330, 3120 (NH), 1640, 1595 and 1550 cmϪ1; δH
(CD3OD/DCl) 5.18 (br s, 2H ϩ H2O, CH2Ph), 7.26–7.44 (m,
5H, ArH); δC (CD3OD/DCl) 45.9, 127.8, 129.5, 130.1, 134.6,
151.5.
General method for the preparation of 3-alkyl-2-amino-5,7-
dimethyl-3H-8ë5-[1,2,4]triazolo[1,5-a]pyrimidin-8-ylium
chlorides (5e–h)
The appropriate 4-alkyl-3,5-diamino-1,2,4-triazole (1.0 equiv.),
pentane-2,4-dione (1.1 equiv.) and concentrated hydrochloric
acid (1.5 equiv.) were heated together at reflux in IMS for 1 h.
The mixture was cooled to room temperature and partially
concentrated in vacuo. The precipitated solid was collected by
filtration, washed with cold IMS and dried in vacuo at 40 ЊC.
The following compounds were prepared.
2-Amino-5,7-dimethyl-3-benzyl-3H-8ë5-[1,2,4]triazolo[1,5-a]-
pyrimidin-8-ylium bromide (5d)
5,7-Dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-amine (3.0 g,
18.4 mmol) and benzyl bromide (3.72 g, 22.0 mmol) were
heated together at 120 ЊC in DMF (60 ml) for 1.5 h. The dark
greenish solution was allowed to cool to room temperature and
then cooled to 0 ЊC for 30 min, whereupon a solid crystallised.
The solid was collected by filtration, washed with cold DMF
then dichloromethane and dried in vacuo at 40 ЊC to afford the
title compound as a pale pink solid (2.5 g, 41%), mp 255–257 ЊC
(Found: C, 50.21; H, 4.86; N, 20.92. C14H16N5Br requires: C,
50.31; H, 4.83; N, 20.95%); δH (d6-DMSO) 2.66 (s, 3H, 7-Me),
2.72 (s, 3H, 5-Me), 5.50 (s, 2H, CH2Ph), 7.34–7.46 (m, 5H, Ph),
7.66 (s, 1H, H-6), 8.28 (s, 2H, NH2); δC (d6-DMSO) 15.7, 23.7,
44.4, 114.6, 133.3, 145.1, 148.6, 154.8, 165.9.
2-Amino-3-benzyl-5,7-dimethyl-3H-8ë5-[1,2,4]triazolo[1,5-a]-
pyrimidin-8-ylium chloride monohydrate (5e). Colourless needles
(12.7 g, 88%), mp 270–280 ЊC (Found: C, 54.54; H, 5.94; N,
22.69; Cl, 11.65%. C14H16N5ClؒH2O requires C, 54.63; H, 5.89;
N, 22.75; Cl, 11.52%); νmax(Nujol) 3510, 3450, 3320 (NH), 3040
and 1650 cmϪ1; δH (CD3OD) 2.72 (s, 3H, 5-CH3), 2.78 (d, 3H,
J = 0.8 Hz, 7-CH3), 5.51 (s, 2H, CH2Ph), 7.29–7.49 (m, 6H,
5 × ArH ϩ 6-H).
2-Amino-3,5,7-trimethyl-3H-8ë5-[1,2,4]triazolo[1,5-a]-
pyrimidin-8-ylium chloride (5f). Colourless needles (3.05 g, 81%),
mp >300 ЊC (Found: C, 44.90; H, 5.67; N, 32.68; Cl, 16.72%.
C8H12N5Cl requires C, 44.97; H, 5.66; N, 32.78; Cl, 16.59%);
νmax (Nujol) 3350, 3260 (NH), 1815 and 1665 cmϪ1; δH
(CD3OD) 2.72 (s, 3H, 5-CH3), 2.75 (d, 3H, J = 0.8 Hz, 7-CH3),
3.76 (s, 3H, N-CH3), 7.45 (s, 1H, 6-H).
Alkyl dicyanamides (7a–c)
These compounds were prepared according to the method of
Benders and Hackmann10 by reaction of cyanogen bromide
with the appropriate amine in the presence of triethylamine.
The following compounds were prepared.
Methyl dicyanamide (7a). This compound was prepared in
quantitative crude yield and used for subsequent transform-
ations without further purification.
2-Amino-5,7-dimethyl-3-propyl-3H-8ë5-[1,2,4]triazolo[1,5-a]-
pyrimidin-8-ylium chloride (5g). Colourless needles (2.53 g,
1530
J. Chem. Soc., Perkin Trans. 1, 1999, 1527–1532

View Online
74%) mp 275–276 ЊC (decomp.) (Found: C, 49.55; H, 6.69; N,
28.75; Cl, 14.64%. C10H16N5Cl requires C, 49.68; H, 6.67; N,
28.98; Cl, 14.67%); νmax(Nujol) 3330, 3210 (NH), 1655, 1600
and 1560 cmϪ1; δH (CD3OD) 1.15 (t, 3H, J = 7.5 Hz,
CH2CH2CH3), 1.92 (sextet, 2H, J = 7.5 Hz, CH2CH2CH3), 2.73
(s, 3H, 5-CH3), 2.78 (d, 3H, J = 0.8 Hz, 7-CH3), 4.23 (t, 2H,
J = 7.5 Hz, CH2CH2CH3), 7.48 (s, 1H, 6-H).
(0.31 g, 48%) mp 193–195 ЊC (Found: C, 62.78; H, 5.94; N,
21.48%. C17H19N5O2 requires C, 62.75; H, 5.89; N, 21.53%);
νmax(Nujol) 3050, 1630, 1580 and 1530 cmϪ1; δH (CD2Cl2) 1.27
(t, 3H, J = 7.5 Hz, CH2CH3), 2.61 (s, 3H, 5-CH3), 2.77 (d, 3H,
J = 0.8 Hz, 7-CH3), 4.09 (q, 2H, J = 7.5 Hz, CH2CH3), 5.31 (s,
2H, CH2Ph), 6.97 (s, 1H, 6-H), 7.26–7.48 (m, 5H, ArH).
Reaction of 3,5,7-trimethyl-3H-8ë5-[1,2,4]triazolo[1,5-a]pyrim-
idin-8-ylium-2-aminide with dimethyl acetylenedicarboxylate—
formation of adduct 6j
2-Amino-3-benzyl-3H-8ë5-[1,2,4]triazolo[1,5-a]pyrimidin-8-
ylium chloride (5h). 3,5-Diamino-4-benzyl-1,2,4-triazole (1.0 g,
5.3 mmol) and 1,1,3,3-tetramethoxypropane (0.88 ml, 5.3
mmol) were heated together at reflux in methylated spirits (15
ml) and concentrated hydrochloric acid (2 ml) for 1 h. The mix-
ture was cooled to room temperature and the white solid col-
lected by filtration, washed with cold water and dried in vacuo at
40 ЊC to afford the title compound as colourless needles (1.19 g,
86%), mp 275–277 ЊC (Found: C, 55.08; H, 4.69; N, 26.76;
Cl, 13.52%. C12H12N5Cl requires C, 55.07; H, 4.62; N, 26.76;
To a solution of 3,5,7-trimethyl-3H-8λ5-[1,2,4]triazolo[1,5-a]-
pyrimidin-8-ylium-2-aminide (0.1 g, 0.47 mmol) in dichloro-
methane (20 ml) at room temperature was added dimethyl
acetylenedicarboxylate (0.1 g, 0.09 ml, 0.70 mmol). The yellow
solution immediately became orange. The solution was stirred
at room temperature for 2 h when TLC (SiO2, 95% CH2Cl2–5%
MeOH) showed no starting material remaining and one major,
less polar product. The mixture was concentrated in vacuo to a
residue which was recrystallised from IMS to afford the adduct
6j as orange needles (0.09 g, 70%) mp 214–216 ЊC (decomp.)
(Found: C, 52.74; H, 5.40; N, 21.93. C14H17N5O4 requires C,
52.66; H, 5.37; N, 21.93%); δH (CD2Cl2) 2.63 (s, 3H, 5-CH3),
2.75 (d, 3H, J = 0.8 Hz, 7-CH3) 3.6 (s, 3H, N-CH3), 3.62 (s, 3H,
CO2CH3), 3.82 (s, 3H, CO2CH3), 6.04 (s, 1H, olefinic H), 6.97 (s,
1H, 6-H).
Cl, 13.55%); νmax(Nujol) 3330, 3200 (N–H) and 1655 cmϪ1
;
δH (CD3OD) 5.64 (s, 2H, CH2Ph), 7.44–7.58 (m, 5H, benzyl
ArH), 7.78 (m, 1H, 6-H), 9.05 (m, 1H, 5-H), 9.32 (m, 1H, 7-H).
General method for the preparation of 5,7-dimethyl-3-alkyl-3H-
8ë5-[1,2,4]triazolo[1,5-a]pyrimidin-8-ylium-2-aminides (6d–f)
The appropriate 5,7-dimethyl-3-alkyl-2-amino[1,2,4]triazolo-
[1,5-a]pyrimidinium chloride was dissolved in water and the pH
adjusted to 14 with 2.0 M aqueous sodium hydroxide. The
mixture was chilled to 0 ЊC and the crystalline solid collected
by filtration, washed with chilled water and dried in vacuo at
room temperature over P2O5. The following compounds were
prepared.
Reaction of 3-benzyl-5,7-dimethyl-3H-8ë5-[1,2,4]triazolo[1,5-a]-
pyrimidin-8-ylium-2-aminide with dimethyl acetylene-
dicarboxylate–formation of adduct 6i
To a solution of 3-benzyl-5,7-dimethyl-3H-8λ5-[1,2,4]triazolo-
[1,5-a]pyrimidin-8-ylium-2-aminide (0.1 g, 0.35 mmol) in
dichloromethane (20 ml) at room temperature was added
dimethyl acetylenedicarboxylate (0.09 ml, 0.73 mmol). The
resulting orange solution was stirred at room temperature for
24 h. TLC analysis then showed a trace of starting material
remaining and one major, less polar product. Solvent was
removed in vacuo and the residue recrystallised from IMS to
afford the adduct (6i) as yellow needles (0.1 g, 81%) mp 204–
206 ЊC (Found: C, 60.77; H, 5.39; N, 17.79. C20H21N5O4
requires C, 60.75; H, 5.35; N, 17.71%); νmax(thin solid film)
1730, 1690, 1595 and 1530 cmϪ1; δH (CD2Cl2) 2.62 (s, 3H, 5-
CH3), 2.69 (d, 3H, J = 0.8 Hz, 7-CH3), 3.62 (s, 3H, CO2CH3),
3.83 (s, 3H, CO2CH3), 5.28 (s, 2H, CH2Ph), 6.01 (s, 1H, olefinic
H), 6.94 (s, 1H, 6-H), 7.25–7.56 (m, 5H, ArH).
3-Benzyl-5,7-dimethyl-3H-8ë5-[1,2,4]triazolo[1,5-a]pyrimidin-
8-ylium-2-aminide dihydrate (6d). Yellow plates (1.55 g, 78%),
mp 156–158 ЊC (decomp.) (Found: C, 57.86; H, 6.57; N,
24.09%. C14H15N5ؒ2H2O requires C, 58.12; H, 6.62; N, 24.20%);
νmax(Nujol) 3450, 3310, 3270 (NH) and 1640 cmϪ1; δH (CD2Cl2)
2.47 (s, 3H, 5-CH3), 2.52 (d, 3H, J = 0.8 Hz, 7-CH3), 3.47 (br s,
1H, NH), 5.13 (s, 2H, CH2Ph), 6.68 (s, 1H, 6-H), 7.25–7.51 (m,
5H, ArH).
3,5,7-Trimethyl-3H-8ë5-[1,2,4]triazolo[1,5-a]pyrimidin-8-
ylium-2-aminide dihydrate (6e). Yellow needles (0.88 g, 56%),
mp 176–179 ЊC (decomp.) (Found: C, 44.70; H, 7.11; N,
33.12%. C8H11N5ؒ2H2O requires C, 45.06; H, 7.09; N, 32.84%);
δH (CD2Cl2) 2.47 (s, 3H, 5-CH3), 2.53 (d, 3H, J = 0.8 Hz,
7-CH3), 3.42 (s, 3H, N-CH3), 3.91 (br s, 1H, NH), 6.66 (s, 1H,
6-H).
Reaction of 3-benzyl-5,7-dimethyl-3H-8ë5-[1,2,4]triazolo[1,5-a]-
pyrimidin-8-ylium-2-aminide dihydrate with methyl
propiolate—formation of adduct 6k
5,7-Dimethyl-3-propyl-3H-8ë5-[1,2,4]triazolo[1,5-a]pyrim-
idin-8-ylium-2-aminide (6f). Yellow needles (0.18 g, 42%), mp
122–126 ЊC, νmax(thin solid film) 3370, 3260 (NH), 1653 and
1560 cmϪ1; δH (CD2Cl2) 0.98 (t, 3H, J = 7.5 Hz, CH2CH2CH3)
1.82 (sextet, 2H, J = 7.5 Hz, CH2CH2CH3) 2.47 (s, 3H, 5-CH3)
2.53 (d, 3H, J = 0.8 Hz, 7-CH3) 3.72 (br s, 3H, NH ϩ H2O) 3.90
(t, 2H, J = 7.5 Hz, CH2CH2CH3) 6.68 (s, 1H, 6-H).
3-Benzyl-5,7-dimethyl-3H-8λ5-[1,2,4]-triazolo[1,5-a]pyrimidin-
8-ylium-2-aminide dihydrate (0.5 g, 1.73 mmol) and methyl pro-
piolate (0.23 ml, 2.58 mmol) were stirred together in methylene
chloride at room temperature for 18 h. The mixture was concen-
trated in vacuo to residue. The brown solid residue was tritur-
ated with ethanol and the yellow solid collected by filtration.
The solid was recrystallised from ethanol to afford the adduct
6k as yellow needles (0.26 g, 45%), mp 193–195 ЊC (Found: C,
64.10; H, 5.76; N, 20.70%. C18H19N5O2 requires: C, 64.08; H,
N-Ethoxycarbonyl-3-benzyl-5,7-dimethyl-3H-8ë5-[1,2,4]tri-
azolo[1,5-a]pyrimidin-8-ylium-2-aminide (6h)
5.68; N, 20.76%.); νmax (Nujol) 1680, 1630 and 1570 cmϪ1
;
To a solution of 3-benzyl-5,7-dimethyl-3H-8λ5-[1,2,4]triazolo-
[1,5-a]pyrimidin-8-ylium-2-aminide (0.5 g, 1.97 mmol) in
dichloromethane (50 ml) was added 2 M aqueous sodium
hydroxide (25 ml). To the vigorously stirred solution at 0 ЊC was
then added ethyl chloroformate (0.21 ml, 2.17 mmol, 1.1
equiv.). The mixture was allowed to warm to room temperature
during 0.5 h. when TLC (SiO2, 90% CH2Cl2–10% MeOH)
showed complete reaction. The CH2Cl2 layer was separated,
washed with water (25 ml), dried (Na2SO4) and concentrated in
vacuo to residue. The crude product was recrystallised from
acetone to afford the title compound as off-white fluffy needles
δH (CD2Cl2) 2.58 (s, 3H, 5-CH3), 2.69 (s, 3H, 7-CH3), 3.64 (s,
3H, CO2CH3), 5.26 (s, 2H, CH2Ph), 5.35 (d, 1H, J = 13.0 Hz,
NCH᎐CHCO CH ), 6.89 (s, 1H, H-6), 7.27–7.51 (m, 5H, Ph),
᎐
2
3
8.55 (d, 1H, J = 13.0 Hz, NCH᎐CHCO CH ).
᎐
2
3
Reaction of 3,5,7-trimethyl-3H-8ë5-[1,2,4]triazolo[1,5-a]-
pyrimidin-8-ylium-2-aminide dihydrate with methyl propiolate—
formation of adduct 6l
3,5,7-Trimethyl-3H-8λ5-[1,2,4]triazolo[1,5-a]pyrimidin-8-
ylium-2 aminide dihydrate (1.70 g, 7.97 mmol) and methyl
J. Chem. Soc., Perkin Trans. 1, 1999, 1527–1532
1531

View Online
3 H. Marley, S. H. B. Wright and P. N. Preston, J. Chem. Soc., Perkin
Trans. 1, 1989, 1727.
propiolate (0.84 ml, 9.44 mmol) were stirred together in methyl-
ene chloride (120 ml) at room temperature for 18 h. The pre-
cipitated solid was collected by filtration and recrystallised from
ethanol to afford the adduct 6l as golden needles (0.97 g, 47%),
mp 200–202 ЊC (Found: C, 55.20; H, 5.79; N, 26.93; O, 12.39%.
C12H15N5O2 requires C, 55.16; H, 5.79; N, 26.80; O, 12.25%);
νmax (Nujol) 3072, 1680 and 1630 cmϪ1; δH (CD2Cl2) 2.64 (s, 3H,
5-CH3), 2.75 (s, 3H, 7-CH3), 3.61 (s, 3H, N-CH3), 3.67 (s, 3H,
4 G. Palazzo and L. Baiocchi, Ann. Chim. (Rome), 1965, 55, 935.
5 S. Kubota and M. Uda, Chem. Pharm. Bull., 1976, 24, 1336.
6 A. Saito and B. Shimizu, Bull. Chem. Soc. Jpn., 1977, 50, 1596.
7 A. G. Maidannick, V. A. Chuiguk and A. I. Tolmachev, Ukr. Khim.
Zh. (Russ. Ed.), 1986, 52, 200 (Chem. Abstr., 1987, 106, 119819w).
8 cf. G. W. Miller and F. L. Rose, J. Chem. Soc., 1963, 5642.
9 (a) J. S. Davidson, J. Chem. Soc. (C), 1967, 2471; (b) ibid., 1969, 194.
10 P. H. Benders and J. Th. Hackmann, Recl. Trav. Chim. Pays-Bas,
1972, 91, 343.
CO CH ), 5.35 (d, 1H, J = 13.0 Hz, NCH᎐CHCO CH ), 7.08
᎐
2
3
2
3
(s, 1H, H-6), 8.56 (d, 1H, J = 13.0 Hz, NCH᎐CHCO CH ).
᎐
2
3
11 R. M. Acheson and N. F. Elmore, Adv. Heterocycl. Chem., 1978, 23,
263.
12 K. Sirakawa, Yakugaku Zasshi, 1960, 80, 1542, (Chem. Abstr., 1961,
References
55, 10450e).
13 J. A. Bee and F. L. Rose, J. Chem. Soc. (C), 1966, 2031; T. Okabe,
B. Bhooshan, T. Novinson, I. W. Hillyard, G. E. Garner and
R. K. Robins, J. Heterocycl. Chem., 1983, 20, 735.
1 B. C. Bishop, H. Marley, K. J. McCullough, P. N. Preston and
S. H. B. Wright, J. Chem. Soc., Perkin Trans. 1, 1993, 705.
2 D. L. Crabb, K. J. McCullough, P. N. Preston, G. M. Rosair,
B. C. Bishop, S. H. B. Wright, W. Clegg and S. Coles, J. Chem. Soc.,
Perkin Trans. 1, preceding paper.
Paper 9/00942F
1532
J. Chem. Soc., Perkin Trans. 1, 1999, 1527–1532