On triazoles XLIV [1]. Synthesis of new ring systems containing imidazo[2′, 1′:3,4][1,2,4]triazolo[1,5-a]pyrimidine and imidazo[1′,2′:2,3][1,2,4]triazolo[1,5-a]pyrimidine skeleton

Article abstract of DOI:10.1002/jhet.5570390213

Ring transformation of 2-cyanoimido-3-methyl-1,3-oxazolidine (10) yielded 5-amino-3-[N-(2-hydroxyethyl)-N-methyl] amino-1H-1,2,4-triazole (6) that was ring closed with different β-keto esters to 2-[N-(2-hydroxyethyl)-N-methyl]amino-1,2,4-triazolo[1,5-a]py

Full text of DOI:10.1002/jhet.5570390213

Mar-Apr 2002
On Triazoles XLIV [1]. Synthesis of New Ring Systems Containing
Imidazo[2',1':3,4][1,2,4]triazolo[1,5-a]pyrimidine and
Imidazo[1',2':2,3][1,2,4]triazolo[1,5-a]pyrimidine Skeleton
Gábor Berecz and József Reiter*
319
EGIS Pharmaceuticals Ltd., P. O. Box 100, H-1475 Budapest, Hungary
Gyula Argay and Alajos Kálmán
Institute of Chemistry, Chemical Research Center of the Hungarian Academy of Sciences,
P. O. Box 17, H-1525 Budapest, Hungary
Received May 18, 2001
th
Dedicated to Dr. János Császár on the occasion of his 70 birthday
Ring transformation of 2-cyanoimido-3-methyl-1,3-oxazolidine (10) yielded 5-amino-3-[N-(2-hydrox-
yethyl)-N-methyl]amino-1H-1,2,4-triazole (6) that was ring closed with different β-keto esters to 2-[N-(2-
hydroxyethyl)-N-methyl]amino-1,2,4-triazolo[1,5-a]pyrimidinones (4). Cyclisation of derivatives 4 led to
imidazo[2',1':3,4][1,2,4]triazolo[1,5-a]pyrimidines (2) and imidazo[1',2':2,3][1,2,4]triazolo[1,5-a]pyrim-
idines (3) representing 10 novel ring systems. Besides spectroscopical evidence of structure of derivatives 2
and 3 X-ray diffraction analysis of derivative 2b was also performed.
J. Heterocyclic Chem., 39, 319 (2002).
The antidepressant, sedative, spasmolytic and local
anaesthetic activity of type 1 cycloalka- and heterocy-
cloalka[d]-1,2,4-triazolo[1,5-a]pyrimidin-5-ones [2-3]
(Scheme 1) prompted us to add a further heterocyclic ring
to the bi- or tricyclic heteroring systems of derivatives 1
originally present.
was obtained with excellent yield (Scheme 3). The same
result was achieved when the reaction of 7 and 8 was car-
ried out analogously to Ref. [5] in ether at room tempera-
ture for 36 hours.
Biological considerations led us to choose the imidazoli-
dine ring as the further one condensed to 1. Such com-
pounds are derivatives 2 and 3 that were expected to form
from intermediates 4 easily obtainable by the condensation
of β-oxo-esters (5) with 5-amino-3-[N-(2-hydroxyethyl)-
N-methyl]amino -1H-1,2,4-triazole (6) (Scheme 2).
Triazole 6 was prepared earlier [4] by treating the reac-
tion mixture of dimethyl N-cyanoimidodithiocarbonate (7)
and 2-(methylamino)ethanol (8) with hydrazine hydrate
through the not isolated isothiourea derivative 9 (Scheme
3). However, the yield of this reaction was rather poor, 14
% only, and we needed a large quantity of 6 as starting
material for the planned synthetical routes. In the hope of
increasing the yield of the above reaction we tried to iso-
late the intermediate 9, but during its isolation
methanethiol was liberated and only the oxazolidine 10

320
G. Berecz and J. Reiter, G. Argay and A. Kálmán
Vol. 39
14 (R = methyl and cyclopentanon-2-yl, respectively)
were isolated and their structure proved spectroscopically.
Luckily a simple work up of the mixtures of 4 and 14 with
diluted sodium hydroxide solution or their reesterification
with n-butanol led to pure derivatives 4 in good yield
(Table I, for their nmr data see Table II).
The ring closure of derivatives 4 to the mixture of iso-
meric compounds 2 and 3 (Scheme 2) was performed analo-
gously to the ring closure of some azasteroids [11] by heat-
ing them in polyphosphoric acid (PPA) at 120-130°. Work
up of the reaction mixture led to 60-79 % of derivatives 2
and 4-6 % of derivatives 3 (Tables III and V, for their nmr
data see Tables IV and VI, respectively). The assignment of
the nmr signals being in full accordance with the structure of
derivatives 2 and 3 was confirmed by 2D-nmr.
The structure of derivatives 2 and 3 was also corrobo-
rated by the analogy of their cmr and uv spectra with those
of isomeric compounds 15 and 16 (Scheme 6) prepared ear-
lier [12]. Thus the chemical shifts of carbon atoms 4a and
ωa of derivatives 2 were analogous with the chemical shifts
of the corresponding carbon atoms 10a and 2, respectively,
of derivative 15 (Scheme 6). On the other hand the chemi-
cal shifts of carbon atoms 3a and 4a of derivatives 3 were
analogous with those of the corresponding carbon atoms 2
and 10a, respectively, of derivative 16 (Scheme 6).
It was known from the literature [6] that heating of
2-cyanoimino-3-R-thiazolidine derivatives (11) with
hydrazine hydrate in ethanol led to ring transformation to
yield in case of R = electron donating group (EDG) the
corresponding 3,5-diamino-1,2,4-triazole derivatives (12)
(Scheme 4) isolated as disulfide dimers, while in case of
R = electron withdrawing group (EWG) to the correspond-
ing 5-amino-3-alkylthio-1,2,4-triazoles (13).
Based on the above analogy ring transformation of 10
with hydrazine hydrate was attempted (Scheme 5).
Interestingly, when performing the reaction at conditions
described in Ref. [6], i.e. in hot ethanol only red tars were
obtained. On the other hand, the heterogeneous reaction in
ether at room temperature afforded 62 % of the desired 6.
2
10a
Having in hand a good synthetical route for the prepara-
tion of 6 its ring closure with different β-oxo-esters (5) was
attempted (Scheme 2). As the required 1,2,4-triazolo[1,5-
a]pyrimidine-5-one isomers were previously formed pref-
erentially in acidic media [7-10], the reactions were per-
formed in hot acetic acid as solvent (Method A), but the
use of the corresponding β-oxo-ester (5) as solvent was
also attempted (Method B). However, at both reaction con-
ditions the hydroxyl group of derivatives 4 was partly
acylated to yield a mixture of 4 and 14 (R = methyl and
cyclopentanon-2-yl, respectively) (Scheme 5). Derivatives
Interestingly, the N-methylene carbon atoms 3 of deriva-
tives 2 were strongly shifted upfield compared with those
of the corresponding carbon atoms 1 of derivatives 3. This
observation is analogous to those of the N-benzyl methyl-
enes of derivatives 15 as compared with the N-benzyl
methylenes of derivatives 16 (Scheme 6). This fact further
corroborates the structure of derivatives 2 and 3.
In the uv spectra the two maxima of derivatives 2 were
analogous to those of derivative 15, while the three max-
ima of derivatives 3 were analogous to those of derivative
16, respectively (Scheme 6).

Mar-Apr 2002
On Triazoles XLIV
321
Table I
1
2
Compound
R
R
Method Reaction Yield
Mp (°C)
(Cryst from)
Molecular
Formula
(MW)
ms
(M )
Analysis
Calcd / Found
H
ir.
uv (EtOH)
+
-1
-3
Time
(%)
ν (cm )
λ
(ε .10 )
max
(hours)
C
N
S
4a
4b
Me
H
B
2.5
74
235-241
C H N O
13 5 2
223.23
EI
48.42 5.87 31.37
1694
1674
1587
230 (23.4)
276 (9.1)
9
(CH CN/EtOH)
223 48.36 5.99 31.18
3
-(CH ) -
A
B
1.5
2.5
77
250-259 (dec)
C H N O
11 15 5 2
EI
51.15 6.25 27.12
1653
1577
232.5 (28.1)
279 (13.0)
2 3
•1/2 H O
42 (CH CN/EtOH)
•1/2H O
249 51.16 6.24 26.86
2
3
2
258.28
4c
4d
4e
-(CH ) -
A
B
1
1
70
250-258 (dec)
C
H N O
263.30
EI
54.74 6.51 26.60
1654
1577
232.5 (28.4)
279.5 (12.3)
2 4
12 17 5 2
74 (CH CN/EtOH)
263 54.96 6.38 26.63
3
-(CH ) -S-
A
A
0.5
12
88
69
281-293 (dec)
C
H N O S EI
46.96 5.37 24.89 11.40 1656
281 47.02 5.51 24.76 11.37 1641
1585
257.5 (28.8)
304.5 (8.1)
2 3
11 15 5 2
(EtOH/H O)
281.34
C H N O
18 22 6 2
2
-CH -NBn-(CH ) -
213-230 (dec)
EI
61.00 6.26 23.71
1674
1609
1590
233.5 (30.5)
281.5 (10.1)
2
2 2
(CH CN/EtOH)
354.42
354 60.92 6.44 23.69
3
Table II
nmr (DMSO-d )
6
1
2
Compound OH OCH NCH
NMe
2
5
5a
(ω-1)a ωa
150.7 148.8
152.0 150.9
145.0 149.7
140.3 149.1
143.2 149.9
NH
bs
R + R
2
2
bs
(CO)
4a
4.7 3.58 t 3.44 t
58.8 52.3
3.02 s
36.5
5.64 s
98.7
(CH-6)
12.8
12.9
12.5
12.8
12.55
2.22 s
18.5
(7-Me)
164.6 155.5
164.4 154.2
164.4 155.8
164.4 153.2
164.4 155.6
4b
•1/2 H O
4.7 3.60 t 3.45 t
58.8 52.3
3.03 s
36.5
2.85 t
31.3
2.05 qi 2.63 t
21.7 27.1
(CH -8) (CH -7) (CH -6)
110.1
106.0
103.7
104.2
2
2
2
2
4c
4d
4e
4.7 3.60 t 3.45 t
58.8 52.3
3.03 s
36.5
2.54 t
26.3
1.70 m (4H)
21.4
(CH -9) (CH -8) (CH -7) (CH -6)
2.34 t
21.5
21.2
2
2
2
2
4.65 3.59 t 3.45 t
58.7 52.3
3.03 s
36.4
2.67 t
26.1*
2.04 m
21.9
2.90 m
25.3*
(CH -9) (CH -8) (CH -7)
2
2
2
4.6 3.58 t 3.44 t
58.7 52.3
3.02 s
36.4
3.38 s
51.5
2.69 t
49.1
2.44 t
21.7
(CH -9) (CH -7) (CH -6)
2
2
2
3.67 s
7.25-7.40 m (5H)
60.9
138.0 (s); 127.5 (p)
(PhCH ) 129.1 (m); 128.6 (o)
2
2
The only exceptions from the above uv rules were
R = -(CH ) -] was also performed (Figure 1) being in full
2 3
1
2
shown by the sulfur containing derivatives 2 [R + R =
accordance with that of expected [14].
1
2
-(CH ) -S-] and 3 [R + R = -(CH ) -S-] having a sul-
2 3
2 3
fur atom attached to the imidazo-triazolo-pyrimidinone
chromophore causing a batochromic shift of the spectra.
Such a batochromic shift was observed previously in the
analogous sulfur-containing derivatives [7,13].
However, the cmr spectra characterised also these deriv-
atives unequivocally.
EXPERIMENTAL
Melting points were determined on a Kofler-Boëtius micro
apparatus and are uncorrected. The infrared spectra were obtained
as potassium bromide pellets using Perkin-Elmer 882 spectropho-
tometer. The ultraviolet spectra were obtained by using a Varian
Cary 1E UV-VIS instrument. The pmr and the cmr measurements
were performed on Bruker WM-250 and Varian Unity Inova 400
To corroborate the decisions made on the basis of the
1
cmr and uv spectra X-ray diffraction analysis of 2b [R +

322
G. Berecz and J. Reiter, G. Argay and A. Kálmán
Vol. 39
Table III
1
2
Compound
R
R
Reaction Yield
mp (°C)
Molecular
Formula
(MW)
ms
(M )
Analysis
Calcd/Found
H
ir
uv (EtOH)
+
-1
-3
Time
(%) (Cryst. from)
ν (cm )
λ
(ε.10 )
max
(hours)
C
N
S
2a
2b
2c
2d
2e
Me
H
2
6
4
7
65
71
69
79
60
305-307
C H N O
EI
205
(100%)
EI
231
(100%)
EI
245
(75%)
EI
263
(100%)
EI
52.68 5.40 34.13
52.75 5.56 34.04
1690
1656
1596
1690
1647
1595
1690
1639
1595
224.5 (32.8)
282.5 (9.2)
9
11 5
(EtOH/H O)
205.22
H N O
11 13 5
2
-(CH ) -
307-309
C
57.13 5.67 30.28
57.05 5.80 30.18
227.5 (35.6)
283.5 (9.8)
2 3
(EtOH/H O)
231.26
H N O
12 15 5
2
-(CH ) -
297-300 (dec)
C
58.76 6.16 28.55
58.82 6.34 28.48
226.5 (33.3)
283.5 (9.8)
2 4
(EtOH/H O)
245.29
H N OS
11 13 5
2
-(CH ) -S-
328-333 (dec)
C
50.18 4.98 26.60
50.23 5.12 26.51
12.18 1671
12.07 1650
1612
246.5 (19.0)
263.5 (sh)
317 (8.1)
227 (36.9)
284 (9.8)
2 3
(EtOH/H O)
263.32
C H N O
18 20 6
2
-CH -NBn-(CH ) - 12
220-240 (dec)
64.27 5.99 24.98
64.18 6.11 25.03
1672
1650
2
2 2
(EtOH/H O)
336.40
336
2
(25%)
1610
5-Amino-3-[N-(2-hydroxyethyl)-N-methyl]amino-1H-1,2,4-tria-
zole (6).
To a suspension of 25.02 g (0.2 mole) of 2-cyanoimido-3-
methyl-1,3-oxazolidine (10) in 150 ml of diethyl ether 10.51 g
(10.2 ml, 0.21 mole) of 100 % hydrazine hydrate was added
with stirring at room temperature. The exothermicity kept the
ether refluxing for 1 hour. The mixture was stirred for further
24 hours at room temperature. The red reaction mixture
obtained was decanted, the solid residue washed with 50 ml of
ether and stirred at 5° for 30 minutes with 30 ml of 2-propanol.
The crystalline product was isolated by filtration and washed
with cold 2-propanol and diethyl ether to yield 19.5 g (62 %) of
tlc pure material, mp 148-151°. An analytical sample was
recrystallised from a 1:1 mixture of ethanol and acetonitrile,
1
2
Figure 1. Perspective view of 2b [R + R = -CH ) -]. Atomic thermal
2 3
mp 150-152° (Lit. [4] mp 147-149°); pmr (DMSO-d ): δ, ppm,
6
ellipsoids are on 50% probability level.
2.84 (s, 3H, CH ), 3.26 (t, 2H, NCH ), 3.52 (q, 2H, OCH ),
3
2
2
4.68 (t, 1H, OH), 5.6 (bs, 2H, NH ), 10.8 (bs, 1H, NH); cmr
2
(400 MHz) instruments. To confirm the assignments in some
cases standard Varian HSQC and HMBC 2D-nmr programs were
used. The ms spectra were recorded on a Kratos MS25RFA instru-
ment using direct inlet probe in EI or CI mode, as well as on a VG
Quattro instrument (APCI or ES). The dry column flash chro-
matographies were performed according to [15].
(DMSO-d ): δ, ppm, 36.8 (CH ), 53.0 (NCH ), 59.2 (OCH ),
6
3
2
2
157 and 162.5 (broad peaks, triazole C-3 and C-5). ms (ES):
+
(M + 1) = 158.
General Method for the Synthesis of 2-[N-(2-hydroxyethyl)-N-
methyl]amino-1,2,4-triazolo[1,5-a]pyrimidin-5-ones (4) –
Method A.
2-Cyanoimido-3-methyl-1,3-oxazolidine (10).
To a solution of 5.50 g (0.035 mole) of 5-amino-3-[N-(2-
hydroxyethyl)-N-methyl]amino-1H-1,2,4-triazole (6) in 10 ml
of acetic acid 0.04 mole of the corresponding β-oxo-ester 5
was added and the mixture heated with stirring at 130° (oil
bath) for 0.5-12 hours (Table I). After cooling the crystals that
precipitated while hot were isolated by filtration and washed
with acetic acid and ethanol to yield the corresponding deriva-
tives 4 contaminated with a small amount of the correspond-
ing O-acetyl derivatives 14 (R = methyl). This was placed into
a 5 % aqueous solution of sodium hydroxide and stirred at
room temperature for 30 minutes. The pH of the solution was
adjusted with concentrated hydrochloric acid to 6, the crystals
that precipitated were isolated by filtration and washed with
water and acetonitrile to yield the title products 4 (Tables I
and II).
To a solution of 29.25 g (0.2 mole) of dimethyl N-cyanoimi-
dodithiocarbonate (7) [16] in 400 ml of diethyl ether a solution of
15.2 g (0.2 mole) of 2-(methylamino)ethanol (8) (Aldrich) in 80
ml of diethyl ether was added dropwise with stirring at room tem-
perature over a period of 2 hours (the methanethiol liberated dur-
ing the reaction was trapped with a sodium hydroxide solution).
The reaction mixture was stirred at room temperature for 36
hours. During strirring the white oily product separated and crys-
tallised. This was filtered off and washed with diethyl ether to
yield 24.5 g (98 %) of 2-cyanoimido-3-methyl-1,3-oxazolidine
(10) as a slightly hygroscopic powder, mp 60-62°. ir: ν (CN) =
-1
2193 cm ; pmr (deuteriochloroform): δ, ppm, 2.99 (s, 3H, CH ),
3
3.81 (m, 2H, NCH ), 4.62 (m, 2H, OCH ); cmr (deuteriochloro-
2
2
form): δ, ppm, 31.4 (CH ), 48.3 (NCH ), 66.1 (OCH ), 115.4
3
2
2
+
(CN), 163.2 (C=N). ms (APCI): (M + 1) = 126.

Mar-Apr 2002
On Triazoles XLIV
323
Table IV
nmr (deuteriochloroform)
1
2
Compound N-Me
2
3
4a
5a
(ω-3)a
ω-2
ωa
R + R
(s)
(m)
(m)
(CO)
2a [a]
2b
3.05
32.6
4.06
55.2
4.23
40.6 146.0
6.01s
103.7
(C-6) (CH-7)
2.28 s
23.8
(6-Me)
2.88 t
34.8
161.7
156.8
155.2
157.3
154.1
156.6
158.0
158.2
158.3
158.3
158.0
3.06
32.7
4.04
55.2
4.21
40.6 146.5
2.10 m
22.1
2.84 t
27.3
166.3
157.8
151.3
155.3
115.5
(C-8a)
(CH -6)
(CH -7) (CH -8)
2
2
2
2c [a]
2d
3.04
32.8
4.03
55.4
4.19
40.6 144.2
2.60 t
32.1
1.75 m (4H)
2.60 t
22.65
112.8
(C-9a)
22.6
22.2
(CH -6) (CH -7) (CH -8) (CH -9)
2
2
2
2
3.04
32.1
4.08
55.0
4.23
40.7 142.5
2.74 t
31.0
2.19 m
22.9
2.96 m
26.0
(CH -8)
110.3
(C-9a)
(CH -6)
(CH -7)
2
2
2
2e [a]
3.03
32.6
4.01
55.2
4.15
40.4 144.5
3.43 s
57.0
2.74 s (4H)
49.8 22.8
(CH -8) (CH -9)
110.4
(C-9a)
(CH -6)
2
2
2
N-CH Ph:
2
3.70 s 7.25-7.40 m (5H)
62.3 137.6 (s); 127.2 (p)
(PhCH ) 129.1 (m); 128.3 (o)
2
[a] Assignment corroborated by 2D method.
Table V
1
2
Compound
R
R
Reaction Yield
mp (°C)
Molecular
Formula
(MW)
ms
(M )
Analysis
Calcd /Found
H
ir
uv (EtOH)
+
-1
-3
Time
(%) (Cryst from)
ν (cm )
λ
(ε.10 )
max
(hours)
C
N
S
3a
3b
3c
3d
3e
Me
H
2
6
4
7
5
5
6
6
4
158-162
(ether)
C H N O
EI
205
(100%)
EI
231
(100%)
EI
52.68 5.40 34.13
52.55 5.55 34.11
1665
1563
1522
1668
1564
1530
1650
1563
1533
1651
1564
230 (24.0)
250 (10.5)
290 (7.7)
232.5 (25.4)
257 (12.8)
293 (8.4)
231 (26.0)
257 (14.3)
291.5 (8.8)
229 (16.7)
279.5 (11.3)
326.5 (8.6)
232 (27.0)
252 (14.6)
292.5 (8.5)
9
11 5
205.22
H N O
11 13 5
231.26
H N O
12 15 5
-(CH ) -
188-189.5
(ether)
C
C
57.13 5.67 30.28
57.25 5.72 30.24
2 3
-(CH ) -
208-210
(ether)
58.76 6.16 28.55
58.65 6.24 28.61
2 4
245.29
245
(100%)
-(CH ) -S-
223-228 (dec) C
(EtOAc)
H N OS EI
50.18 4.98 26.60
50.31 5.09 26.48
12.18
12.11
2 3
11 13 5
263.32
C H N O
18 20 6
263
(100%)
EI
336
(27 %)
-CH -NBn-(CH ) - 12
190-200 (dec)
(ether)
64.27 5.99 24.98
64.33 6.09 25.06
1656
1582
1544
2
2 2
336.40
Isolation of 2-[N-(2-Acetoxyethyl)-N-methyl]amino-8-benzyl-
6,7,8,9-tetrahydropyrido[3,4-d]-1,2,4-triazolo[1,5-a]pyrimidin-
5(10H)-one.
3.68 (s, 2H, PhCH ), 4.21 (t, 2H, OCH ), 7.25-7.40 (m, 5H, PhH),
2 2
12.6 (bs, 1H, NH); cmr (DMSO-d ): δ, ppm, 20.8 (CH ), 21.7
6
3
(CH -6), 36.1 (NCH ), 48.6 (NCH ), 49.1 (CH -7), 51.5 (CH -
2
3
2
2
2
9), 60.8 (PhCH ), 61.5 (OCH ), 104.2 (C-5a), 127.3 (PhC-4'),
128.4 (PhC-2',6'), 128.9 (PhC-3',5'), 137.9 (PhC-1'), 143.1 (C-9a),
149.8 (C-10a), 155.5 (C-5), 170.4 (C=O, ester).
2
2
14e (R = methyl) from the Mixture of 4e and 14e (R = methyl).
A small amount of the mixture of 4e and 14e (R = methyl) was
chromatographed on a Kieselgel 60 H column (eluent a 50:1 mix-
ture of dichloromethane and methanol) to yield 2-[N-(2-ace-
toxyethyl)-N-methyl]amino-8-benzyl-6,7,8,9-tetrahydropy-
rido[3,4-d]-1,2,4-triazolo[1,5-a]pyrimidin-5(10H)-one 14e (R =
methyl), mp 190-205° (dec) (ethyl acetate). ir: ν (C=O) = 1743
Anal. Calcd. for C
H N O (MW = 396.44): C, 60.59; H,
20 24 6 3
6.10; N, 21.20. Found: C, 60.38; H, 6.12; N, 21.01.
Synthesis of 2-[N-(2-Hydroxyethyl)-N-methyl]amino-cyclo-
penta[d]-6,7-dihydro-8H-1,2,4-triazolo[1,5-a]pyrimidin-5(9H)-
one (4b) – Method B.
-1
-1
-3
cm (ester) and 1672 cm (amide); uv (EtOH): λ , nm (ε.10 ):
max
+
280.5 (12.1) and 233 (32.6); ms (EI): M = 396; pmr (DMSO-d ):
A mixture of 0.943 g (0.006 mole) of 5-amino-3-[N-(2-
hydroxyethyl)-N-methyl]amino-1H-1,2,4-triazole (6) and 3.75 g
(0.024 mole) of ethyl 2-oxocyclopentanecarboxylate (4.0 g, 95 %
6
δ, ppm, 1.96 (s, 3H, CH ), 2.44 (t, 2H, CH -6), 2.69 (t, 2H, CH -
3
2
2
7), 3.02 (s, 3H, NCH ), 3.38 (t, 2H, CH -9), 3.63 (t, 2H, NCH ),
3
2
2

324
G. Berecz and J. Reiter, G. Argay and A. Kálmán
Vol. 39
Table VI
nmr (deuteriochloroform)
1
2
Compound
N-Me
(s)
1
(m)
2
(m)
4a
5a
(ω-3)a
ω-2
3a
(CO)
R + R
3a [a]
3b
3.18
32.0
4.25
51.1
4.00
52.7
5.90 s
102.5
(CH-7)
2.31 s
24.4
(6-Me)
2.86 t
35.2
161.7
162.4
159.4
158.0
159.2
165.7
(C-6)
157.0
155.2
157.4
154.3
156.9
168.3
168.3
168.4
168.0
168.2
3.17
32.0
4.26
51.1
3.97
52.6
2.08 m
21.9
2.81 t
26.8
170.7
161.7
155.9
160.0
114.4
(C-8a)
(CH -6)
(CH -7)
(CH -8)
2
2
2
3c [a]
3d
3.16
32.2
4.21
51.2
3.97
52.8
2.66 t
32.5
1.75 m (4H)
22.1 22.15
2.54 t
22.6
111.9
(C-9a)
(CH -6) (CH -7) (CH -8) (CH -9)
2
2
2
2
3.17
32.0*
4.25
51.1
4.00
52.7
2.78 t
31.9*
2.17 m
23.2
2.95 m
26.2
109.2
(C-9a)
(CH -6)
(CH -7)
(CH -8)
2
2
2
3e [a]
3.15
32.0
4.20
51.1
3.96
52.7
3.51 s
57.6
2.7 m (4H)
49.4 22.3
(CH -8) (CH -9)
109.7
(C-9a)
(CH -6)
2
2
2
N-CH Ph:
2
3.71 s
62.1
(PhCH )
7.25-7.40 m (5H)
137.7 (s); 127.1 (p)
129.1 (m); 128.3 (o)
2
[a] Assignment corroborated by 2D method.
Fluka) was heated at 120-125° (oil bath) with stirring for 2.5
hours. The hot suspension obtained was diluted with 6 ml of ace-
tonitrile, the crystals that precipitated while hot were isolated by
filtration and washed with acetonitrile and ether to yield 0.88 g of
a mixture of derivatives 4b and 14b (R = cyclopentanon-2-yl). To
this mixture 10 ml of n-butanol was added and stirred at 100°
overnight. The reaction mixture obtained was evaporated in
vacuo to dryness, the residue was triturated with acetonitrile and
the crystals obtained isolated by filtration and washed with ace-
tonitrile and ether to yield 0.63 g (42 %) of 2-[N-(2-hydrox-
yethyl)-N-methyl]amino-cyclopenta[d]-6,7-dihydro-8H-1,2,4-
triazolo[1,5-a]pyrimidin-5(9H)-one (4b) that after recrystallisa-
tion from a mixture of 30 ml of acetonitrile and 12 ml of ethanol
decomposed at 250-259°. For its analytical and spectral data see
Tables I and II.
2H, CH -8), 3.01 (s, 3H, NCH ), 3.27 (t, 1H, cyclopentane-CH),
2 3
3.65 (t, 2H, NCH ), 4.26 (t, 2H, OCH ), 13.0 (bs, 1H, NH); cmr
2
2
(DMSO-d ): δ, ppm 20.5 (cylopentane-CH -4'), 21.7 (CH -7),
6
2
2
27.0 (cylopentane-CH -3'), 27.1 (CH -6), 31.3 (CH -8), 36.1
2
2
2
(NCH ), 37.7 (cylopentane-CH -5'), 48.6 (NCH ), 54.4
3
2
2
(cylopentane-CH), 62.4 (OCH ), 110.1 (C-5a), 151.0 (C-9a),
2
152.2 (C-8a), 154.2 (C-5), 169.4 (C=O, ester), 212.4 (CO,
ketone).
Anal. Calcd. for C
H N O (MW = 359.38): C, 56.81; H,
17 21 5 4
5.89; N, 19.49. Found: C, 56.74; H, 5.87; N, 19.34.
Continuing the chromatography with a 19:1 mixture of
dichloromethane and methanol 0.40 g of 4b was obtained, mp
250-258° (dec). For its analytical and spectral data see Tables I
and II.
General Method for the Synthesis of Imidazo[2',1':3,4][1,2,4]tri-
azolo[1,5-a]pyrimidine (2) and Imidazo[1',2':2,3][1,2,4]tria-
zolo[1,5-a]pyrimidine (3) Derivatives.
Isolation of 2-[N-(Cyclopentanon-2-yl-carbonyloxyethyl)-N-
methyl]amino-cyclopenta[d]-6,7-dihydro-8H-1,2,4-triazolo[1,5-a]-
pyrimidin-5(9H)-one (14b, R = cyclopentanon-2-yl) from the
Mixture of 4b and 14b (R = cyclopentanon-2-yl).
A mixture of 0.029 mole of the corresponding derivative 4
with 54 g of polyphosphoric acid (Fluka) was strirred at 130° (oil
bath) for 2-12 hours (Table III). The honey-like brown solution
obtained was dissolved in 3 x 100 ml of water keeping the tem-
perature of the mixture continuously below 50°. The pH of the
intensively stirred solution was adjusted by addition of 60 g of
sodium hydrogen carbonate to 5 (in small portions; the intensive
foaming could be ceased by addition of a few drops of ether). To
the cold suspension obtained 30 ml of concentrated ammonium
hydroxide was added dropwise over a period of a few minutes to
yield a suspension of pH = 11. The product that pecipitated was
filtered off and washed with diluted aqueous ammonium hydrox-
ide solution to yield the raw derivative 2. This was dry column
flash chromatographed on a short Kieselgel 60 H column [eluent:
chloroform and different mixtures of chloroform and methanol
(up to 5 %)] and after evaporation of the appropriate fractions in
The mixture of derivatives 4b and 14b (R = cyclopentanon-2-
yl) (1.05 g) obtained according to the previous experiment was
chromatographed on a Kieselgel 60 H column (eluent dichloro-
methane and different mixtures of dichloromethane and acetoni-
trile up to 4:1) to yield 0.49 g of 2-[N-(cyclopentanon-2-yl-car-
bonyloxyethyl)-N-methyl]amino-cyclopenta[d]-6,7-dihydro-8H-
1,2,4-triazolo[1,5-a]pyrimidin-5(9H)-one (14b, R = cyclopen-
tanon-2-yl) that after recrystallisation from acetonitrile decom-
-1
posed at 240-244°. ir: ν (C=O) = 1758, 1722, 1649 cm ; uv
-3
(EtOH): λ , nm (ε.10 ): 279 (14.2) and 232.5 (29.7); ms
max
+
(EI): M = 359; pmr (DMSO-d ): δ, ppm 1.75 (m, 1H, cylopen-
6
tane-4'-α), 1.90 (m, 1H, cylopentane-4'-β), 2.0 (m, 1H, cylopen-
tane-3'-α), 2.05 (m, 2H, CH -7), 2.15 (m, 1Η, cylopentane-
2
3'-β), 2.2 (m, 2H, cyclopentane-5'), 2.64 (t, 2H, CH -6), 2.86 (t,
2

Mar-Apr 2002
On Triazoles XLIV
325
vacuo the residue was recrystallised from aqueous ethanol
(Tables III and IV).
tra, and to Dr. Éva Szabó, Mr. Kálmán Ujszászy, Mr. Tamás
Karancsi and Dr. Péter Slégel for recording the ms spectra.
The original aqueous mother liquor (pH = 11) was extracted
with 3 x 40 ml portions of chloroform, the combined organic lay-
ers were dried over sodium sulfate, evaporated to dryness and dry
column flash chromatographed on a short Kieselgel 60 H column
(eluents different mixtures of ethyl acetate and acetonitrile). The
tlc pure 3 obtained was triturated with an appropriate solvent
(Tables V and VI) and filtered.
REFERENCES AND NOTES
[1] For Part XLIII see I. Prauda, I. Kövesdi, P. Trinka and J.
Reiter, J. Heterocyclic Chem., 38, 403 (2001).
[2] J. Reiter, E. Rivó, K. Esses-Reiter, M. Fekete, F. Görgényi,
L. Peto´´cz, I. Gacsályi and I. Gyertyán, Hung. Pat. No. 198484, Chem.
Abstr., 109, P 66903x (1988).
[3] K. Esses-Reiter, J. Reiter, Z. Budai, E. Rivó, P. Trinka, L.
Peto´´cz, G. Gigler, I. Gyertyán and I. Gacsályi, Hung. Pat. No. 205117,
Chem. Abstr., 114, P 81872h (1991).
Crystal structure analysis of 2b {1-Methyl-2,3,6,7-tetrahydro-
8H-cyclopenta[d]-imidazo[2',1':3,4][1,2,4]triazolo[1,5-a]pyrim-
idin-9(1H)-one} [14].
[4] J. Reiter, L. Pongó, T. Somorai and P. Dvortsák, J.
Heterocyclic Chem., 23, 401 (1986).
The X-ray diffraction was performed according to the follow-
ing parameters: C H N O, Fwt.: 231.26, orthorhombic, space
11 13
5
[5] R. Sauter and W. Reuter, Ger. Offen. 2,205,745, Chem.
Abstr., 79, 146548n (1973).
[6] Ch. Iwata, M. Fujimoto, Sh. Okamoto, Ch. Nishihara, M.
Sakae, M. Katsurada, M. Watanabe, T. Kawakami, T. Tanaka and T.
Imanishi, Heterocycles, 31, 1601 (1990).
[7] K. Esses-Reiter and J. Reiter, J. Heterocyclic Chem., 24,
1503 (1987).
[8] J. Reiter and L. Pongó, Org. Prep. Proced. Int., 21, 163
(1989).
[9] J. Reiter, G. Berecz and I. Pallagi, J. Heterocyclic Chem.,
28, 721 (1991).
[10] J. Reiter, L. Pongó, T. Somorai and I. Pallagi, Monatsh.
Chem., 121, 173 (1990).
[11] I. Lalezari and S. Sadeghi-Milani, J. Heterocyclic Chem.,
16, 707 (1979).
[12] G. Berecz and J. Reiter, J. Heterocyclic Chem., 38, 237
(2001).
[13] J. Reiter and K. Esses-Reiter, J. Heterocyclic Chem., 28,
561 (1991).
[14] Crystallographic data for structure 2b reported in this paper
have been deposited at the Cambridge Crystallographic Data Center
(deposition number CCDC 158157).
[15] L. M. Harwood, Aldrichimica Acta, 18, 25 (1985).
[16] B. T. Heitke and C. G. McCarty, J. Org. Chem., 39, 1522
(1974).
group P n a 2 , a = 7.743(1) Å, b = 9.074(1) Å, c = 15.023(2) Å, V
1
3
= 1055.5(2) Å , T = 293(2)K, Z = 4, F(000) = 488, Dx
3
-1
=1.455Mg/m , µ = 0.100mm , crystal size: 0.20 x 0.20 x 0.10
mm. Intensities of 2728 reflections (2547 unique [R(int) =
0.0037]; 1511 observed with I >2σ(I)) were collected on an Enraf-
Nonius CAD4 diffractometer with graphite monochromated Mo-
Kα radiation (λ = 0.71070Å) at 293(2)K in the range 2.62° ≤ θ ≤
27.99° using ω-2θ scans. A psi-scan absorption correction was
applied to the data. The structure was solved by direct methods
2
and refined in anisotropic mode by full-matrix least-squares on F
for all non-hydrogen atoms to R1 = 0.0406 and wR2 = 0.1075 for
observed and R1 =0.0906 and wR2 = 0.1256 for all intensity data
(goodness-of-fit = 0.743; the maximum shift/esd 0.000; extinction
coefficient = 0.0046(18)). Number of parameters = 156. The max-
imum and minimum residual electron density in the final differ-
3
ence map was 0.178 and -0.168e/Å . Hydrogen atomic positions
were located from assumed geometries but were not refined.
Acknowledgement.
The authors wish to express their thanks to Mrs. Hirkóné
Magdolna Csík for performing the elemental analyses, to Mrs.
Sándorné Sólyom for recording the ir spectra, to Miss Zsófia
Kárpáti for recording the uv spectra, to Mrs. Magdolna Nagy, Mr.
Attila Fürjes and Dr. István Kövesdi for recording the nmr spec-