DABCO-based ionic liquids: Introduction of two metal-free catalysts for one-pot synthesis of 1,2,4-triazolo[4,3-a] pyrimidines and pyrido[2,3-d] pyrimidines

Article abstract of DOI:10.1039/c8nj01455h

Straightforward methods for the synthesis of 1,2,4-triazolo[4,3-a]pyrimidine and pyrido[2,3-d]pyrimidine derivatives are described through three-component condensation of aromatic aldehydes, malononitrile, and 3-amino-1,2,4-triazole or 6-amino-1,3-dimethyluracil. In both procedures two affordable and metal-free DABCO-based ionic liquids are employed as catalysts and the obtained outcomes are compared with each other. All reactions are performed under mild conditions during acceptable reaction times in good to high yields. After ensuring the efficiency of the catalysts in both reactions, four new derivatives are synthesized and their structures are characterized by FT-IR, ¹H NMR and ¹³C NMR. Simplicity, easy work-up procedures and recoverability of the catalysts are other advantages of these methods.

Full text of DOI:10.1039/c8nj01455h

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DABCO-based ionic liquids: introduction
of two metal-free catalysts for one-pot
synthesis of 1,2,4-triazolo[4,3-a]pyrimidines
and pyrido[2,3-d]pyrimidines†
Cite this:DOI: 10.1039/c8nj01455h
N. Jamasbi, M. Irankhah-Khanghah, F. Shirini, * H. Tajik and M. S. N. Langarudi
Straightforward methods for the synthesis of 1,2,4-triazolo[4,3-a]pyrimidine and pyrido[2,3-d]pyrimidine
derivatives are described through three-component condensation of aromatic aldehydes, malononitrile,
and 3-amino-1,2,4-triazole or 6-amino-1,3-dimethyluracil. In both procedures two affordable and
metal-free DABCO-based ionic liquids are employed as catalysts and the obtained outcomes are
compared with each other. All reactions are performed under mild conditions during acceptable
reaction times in good to high yields. After ensuring the efficiency of the catalysts in both reactions, four
new derivatives are synthesized and their structures are characterized by FT-IR, 1H NMR and 13C NMR.
Simplicity, easy work-up procedures and recoverability of the catalysts are other advantages of these
methods.
Received 25th March 2018,
Accepted 14th April 2018
DOI: 10.1039/c8nj01455h
rsc.li/njc
Due to them having three nitrogens in their structure, com-
pounds which have a 1,2,4-triazole moiety possess a wide array
Introduction
Since the first synthesized ionic liquid (IL) introduced in of pharmaceutical and therapeutic activities such as anti-
1914,1 ILs have caused a drastic change in synthetic chemistry. inflammatory,29 antiviral,30 antimicrobial,31–34 antitumor35
Nowadays, ILs are known as environmentally benign and conveni- anticonvulsant,30 analgesic,36 antihypotensive,37 antiparasitic,
ent catalysts or dual solvent-catalysts to improve and facilitate fungicidal, insecticidal, herbicidal and plant growth regulatory
organic reactions by omitting traditional solvents.2–4 Functionalized activities.38–41 Many drugs with the triazole moiety are manufac-
ILs, so-called ‘‘task-specific ionic liquids’’, have been designed for tured, including ribavarin (or tribavirin, an antiviral medication for
use in particular reactions. Hence, versatile ILs with acidic and basic treating RSV infection, hepatitis C, and viral hemorrhagic fever),
functional groups have been synthesized through metathesis of alprazolam (or Xanax, an anxiolytic medication used to treat
halide salts or quaternization of appropriate amines and utilized to anxiety disorders) and letrozole (an anticancer medication for
accelerate different organic transformations.5
treatment of local or metastatic breast cancer) (Fig. 1(a)). Moreover,
1,4-Diazabicyclo[2.2.2]octane (DABCO) as a cage-like tertiary triazolopyrimidines are an attractive purine analogue because of
amine with weak alkalescence is an adequate alternative to their structure which is constructed from two five- and six-fused
former linear tertiary amines, imidazole and pyrimidine deri- rings containing nitrogens like purine (Fig. 1(b)).
vatives which have been employed to prepare various ILs. The
cage-like structure of DABCO leads to an increase in the energy
barrier of nitrogen inversion, which is about 7 kcal molꢀ1 for a
trialkylamine. As a result, the lone pair of nitrogen in DABCO is
precisely localized and makes DABCO more attuned for quater-
nization. In recent decades, this feature of DABCO has been
applied for the synthesis of different DABCO-based ILs6–28 as
far as they are classified in a distinct category.
Department of Chemistry, College of Science, University of Guilan, Rasht,
41335-19141, Iran. E-mail: shirini@guilan.ac.ir, fshirini@gmail.com;
Fax: +981313233262; Tel: +981313233262
† Electronic supplementary information (ESI) available: Full experimental details
Fig. 1 The structures of (a) some triazole-containing drugs, (b) purine,
and NMR spectra for all new compounds. See DOI: 10.1039/c8nj01455h
and (c) uramustine.
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Many nitrogen-containing, biologically important compounds, the absence of solvent for both catalysts (Table 1, entries 5 and 6).
containing uracil as a structural block, have been recently An increase of the catalyst amounts led to an increase in reaction
reported such as pyrazolopyridines,42 pyramidopyrimidines,43 times and decrease in yields, so the best conditions could be
pyridopurines,44 pyrazolopyrimidines45 and xanthine deriva- achieved when 0.016 mmol of the catalysts was used under
tives.46 This considerable interest is correlated with a vast range solvent-free conditions at 100 1C (Table 1, entry 5). On the other
of biological activities such as antitumor,47 antihypertensive,48 hand, using ethanol as a solvent in the synthesis of 7-amino-5-(4-
hepatoprotective,48 cardiotonic49 and antifolate activities.50 chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido-
Besides, uracil derivatives like uramustine (Fig. 1(c)) have been [2,3-d]pyrimidine-6-carbonitrile (6b) led to reaction completion
utilized as chemotherapy drugs by damaging DNA, because (Table 1, entries 14–17); however, the amounts of the catalysts
cancer cells take up uracil to make nucleic acids during their were not the same and [H2-DABCO][ClO4]2 could complete the
cycles of cell division.
reaction in smaller amounts (Table 1, entries 14 and 15). The
best conditions for both reactions, extracted from Table 1, are
portrayed in Scheme 1.
Furthermore, to investigate the efficiency of these methods,
different aliphatic and aromatic aldehydes with electron-
Results and discussion
In recent years, our research group has pursued the goal of withdrawing and -donating functional groups were employed
developing more efficient organic processes. For this reason, new to synthesize other structurally functionalized derivatives of
DABCO-based ILs were synthesized and used as catalysts and dual 1,2,4-triazolo[4,3-a]pyrimidine and pyrido[2,3-d]pyrimidine. Despite
catalyst-solvents in various organic transformations.19–21,25–28 In the successful reaction of aromatic aldehydes, these methods could
continuation of these studies, we were interested in investigating not realize the preparation of corresponding derivatives of aliphatic
the catalytic activity of [H2-DABCO][H2PO4]2 and [H2-DABCO][ClO4]2, aldehydes. The obtained results are compiled in Table 2. According
as two DABCO-based ILs, in the synthesis of diverse structurally to this table, all reactions gave products in good to high yields in
functionalized 1,2,4-triazolo[4,3-a]pyrimidines and pyrido[2,3-d]- decent reaction times.
pyrimidines and in comparing the effect of anion exchange in
the activity of these ILs.
In this step, it is necessary to provide a comparative table to
show the utility of these methods vs. former procedures used
At first, to select the best conditions for the reactions, the for the synthesis of 1,2,4-triazolo[4,3-a]pyrimidine and pyrido-
syntheses of 1,2,4-triazolo[4,3-a]pyrimidine and pyrido[2,3-d]- [2,3-d]pyrimidine derivatives. For this reason, the syntheses of
pyrimidine derivatives of 4-chlorobenzaldehyde were chosen as 4a and 6b are selected as models and the comparisons are
models and the effects of various amounts of the catalysts, carried out in terms of catalyst amounts, reaction times and
different solvents and temperatures on reaction times and yields, and turnover frequencies (TOFs) (Table 3).
yields were investigated.
Although it seems that the described methods are time-
Despite using aprotic and protic solvents in the synthesis consuming, they are cost-saving and efficient due to the
of 5-amino-7-(4-chlorophenyl)-7,8-dihydro[1,2,4]triazolo[4,3-a]- smaller amounts of the catalysts; the calculated TOFs support
pyrimidine-6-carbonitrile (4a), the reaction was completed in this claim.
Table 1 Optimization of the amounts of the catalysts, temperature and solvent in the synthesis of 5-amino-7-(4-chlorophenyl)-7,8-dihydro-
[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonitrile (4a, entries 1–6) and 7-amino-5-(4-chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]-
pyrimidine-6-carbonitrile (6b, entries 7–17)
Catalyst amount (mmol)
Solvent
Aa
Temp. (1C)
Time (min)
Aa
Conversion (isolated yield %)
Entry
Aa
Bb
Bb
Aa
Bb
Bb
Aa
Bb
1
2
3
4
5
6
7
8
0.016
0.016
0.016
0.016
0.016
0.026
0.032
0.026
0.016
0.032
0.032
0.032
0.032
0.032
0.026
0.016
0.026
EtOH
H2O
H2O : EtOH (1 : 1)
MeCN
—
—
H2O
H2O
H2O
70
70
70
70
100
100
70
70
70
70
r.t.
70
100
70
70
75
60
65
70
40
80
60
70
70
80
100
95
100
40
55
65
110
90
80
70
70
50
80
80
80
90
70
100
90
100
50
50
60
100
Not completed
Not completed
Not completed
Not completed
100 (95)
100 (90)
Trace
Trace
Trace
Trace
Not completed
Not completed
Not completed
100 (95)
100 (90)
100 (93)
100 (96)
100 (93)
0.032
0.032
80
90
9
10
11
12
13
14
15
16
17
H2O : EtOH (2 : 1)
H2O : EtOH (1 : 1)
MeCN
—
EtOH
EtOH
EtOH
EtOH
100 (90)
100 (95)
70
r.t.
Not completed
a
b
A: [H2-DABCO][H2PO4]2. B: [H2-DABCO][ClO4]2.
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Scheme 1 Synthesis of 1,2,4-triazolo[4,3-a]pyrimidine and pyrido[2,3-d]pyrimidine derivatives using [H2-DABCO][H2PO4]2 and [H2-DABCO][ClO4]2 as
the catalysts.
Once again, the syntheses of 1,2,4-triazolo[4,3-a]pyrimidine When intermediate c is attacked by 3-amino-1,2,4-triazole 3 or
and pyrido[2,3-d]pyrimidine derivatives of 4-chlorobenzaldehyde intermediate j takes part in a reaction with intermediate b,
were chosen as the models to investigate the reusability of the intermediate h can be produced. ILs exchange hydrogen in
catalysts. After completion of the reactions, water was poured intermediate h to lead to an intra-cyclization (intermediate i).
into the reaction mixtures (for the synthesis of pyrido[2,3- Finally, a hydrogen shift in intermediate i leads to the
d]pyrimidine derivative, it was added after filtering off the product (4a–j).
solvent) in order to separate the catalysts. Afterwards the reaction
It is notable that if intermediate c were attacked with N2, the
mixtures were filtered off and the filtrates were evaporated under corresponding product would be 7. However, according to the
vacuum at 70 1C. The obtained white precipitates were washed with spectral data for new compound 4j, the observed doublet peaks
diethyl ether and reused three times for both catalysts. The at 8.79 and 5.31 related to NH and CH, respectively, show a
achieved results, presented in Fig. 2 and 3, show the least variation coupling (J = 2 Hz) between them in pyrimidine ring. This
in reaction times and yields after three runs.
proves that aliphatic CH and NH are neighbors in the ring. The
The postulated mechanisms for the synthesis of 1,2,4- same result was observed in the spectral data for compound 4i.
triazolo[4,3-a]pyrimidine and pyrido[2,3-d]pyrimidine derivatives The spectra of new compounds are presented in ESI† and
are depicted in Scheme 2, based on previous literature.26,28 To correlated with previous literature.51
begin with, carbonyl group of aldehyde is activated through
hydrogen bonding with ILs to obtain intermediate a. The struc-
tures delimited in dashed lines show how carbonyl group is
activated by hydrogen bonding. After that, the mechanism
pathway divides into three routes. In route 1, intermediate b,
Experimental
Materials
produced from malononitrile 2, attacks the activated carbonyl All aldehydes, malononitrile, 6-amino-1,3-dimethyluracil, and
group to change into intermediate c. Activated by ILs, inter- 3-amino-1,2,4-triazole were purchased from Merck chemical
mediate c is attacked by 6-amino-1,3-dimethyluracil 5, which company (Munich) and were used without further purification.
leads to intermediate d. A hydrogen shift takes place in inter- The purity of them was monitored by thin layer chromato-
mediate d to convert to intermediate e. In this step, intermediate e graphy (TLC). DABCO (CAS: 280-57-9, MW: 112.17 g molꢀ1
,
is able to undergo an intra-cyclization to produce intermediate f. assay Z99% w/w), phosphoric acid (CAS: 7664-38-2, MW:
Two steps of hydrogen shift (in intermediate f) and aromatization 98.00 g molꢀ1, concentration Z85% v/v) and perchloric acid
(in intermediate g) lead to the product (6a–p). In general, product (CAS: 7601-90-3, MW: 100.46 g molꢀ1, assay Z70% v/v) were
(4a–j) is produced from routes 2 and 3, but at the beginning, they purchased from Sigma-Aldrich (Mumbai). Both assays were
differ in the formation of intermediates c and j. In route 2, reported by the manufacturer and were not examined more.
intermediate b makes for activated carbonyl group to convert into All solvents were obtained from Merck (Munich) and were
intermediate c, whereas in route 3 the reaction starts with kept sealed in airtight bottles to minimize the absorption of
preparation of an imine (intermediate j) through the attack atmospheric moisture. Moreover, they were distilled before
of amino group of 3-amino-1,2,4-triazole 3 to intermediate a. being used.
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Table 2 Preparation of 1,2,4-triazolo[4,3-a]pyrimidine and pyrido[2,3-d]pyrimidine derivatives using [H2-DABCO][H2PO4]2 (A) and [H2-DABCO][ClO4]2
(B) as the catalysts
Time (min)
Yielda (%)
MP (1C)
Entry
1
Aldehyde
Product
A
B
A
B
Found
Rep.
Ref.
51
4-ClC6H4CHO
40
50
95
96
90
95
96
93
93
90
258–259
265–268
260–262
251–253
244–246
215–220
243–246
257–258
2
3
4
5
6
7
2-ClC6H4CHO
4-BrC6H4CHO
4-FC6H4CHO
35
45
30
50
75
55
25
50
40
45
60
60
90
96
95
92
90
90
263–266
264–266
252–254
245–246
218–219
245–247
51
51
51
51
51
51
4-MeC6H4CHO
4-OMeC6H4CHO
4-NO2C6H4CHO
8
9
4-Me2NC6H4CHO
50
70
60
60
90
93
90
95
244–248
280–284
242–245
51
2-Naphthaldehyde
—
New
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Table 2 (continued)
Time (min)
Yielda (%)
MP (1C)
Entry
10
Aldehyde
Product
A
B
A
B
Found
Rep.
Ref.
New
3-MeOC6H4CHO
55
50
95
90
90
218–221
307–308
—
11
C6H4CHO
45
55
93
4300
52
12
4-ClC6H4CHO
40
50
95
95
311–315
4300
53
13
14
3-ClC6H4CHO
40
40
50
45
93
91
90
93
301–304
300–304
4300
4300
53
53
2-ClC6H4CHO
15
4-OHC6H4CHO
70
75
89
90
297–302
4300
54
16
4-FC6H4CHO
50
65
95
96
300–302
4300
53
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Table 2 (continued)
Time (min)
Yielda (%)
MP (1C)
Entry
17
Aldehyde
Product
A
B
A
B
Found
Rep.
Ref.
55
4-BrC6H4CHO
65
80
95
96
92
95
303–307
304–310
302–307
4300
4300
4300
18
3-BrC6H4CHO
50
75
90
53
19
4-MeC6H4CHO
35
45
92
52
20
4-OMeC6H4CHO
70
75
85
93
300–303
4300
52
21
4-NO2C6H4CHO
60
70
87
92
307 (Dec.)b
4300
55
22
23
3-NO2C6H4CHO
95
75
100
92
90
93
93
298–300
4300
4300
53
54
2-NO2C6H4CHO
80
303 (Dec.)
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Table 2 (continued)
Time (min)
Yielda (%)
MP (1C)
Entry
Aldehyde
Product
A
B
A
B
Found
Rep.
Ref.
56
24
2-Naphthaldehyde
80
90
89
90
310–315
4300
25
3-CHOC6H4CHO
30
30
93
92
4300
—
New
26
4-NMe2C6H4CHO
90
90
90
90
4300
—
New
a
b
Isolated yields. Decomposition.
Table 3 Comparison of the activity of [H2-DABCO][H2PO4]2 and [H2-DABCO][ClO4]2 with those of other reported catalysts in the synthesis of 5-amino-
7-(4-chlorophenyl)-7,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonitrile (4a, entries 1–6) and 7-amino-5-(4-chlorophenyl)-1,3-dimethyl-2,4-
dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (6b, entries 7–17)
Entry Catalyst
Amount (mol) Conditions
Time (min) Yield (%) TOF (minꢀ1
)
Ref.
1
2
3
4
5
6
7
8
NaOH
NaOH
Boric acid
2 ꢁ 10ꢀ4
2 ꢁ 10ꢀ4
0.2
Reflux/EtOH
US/H2O
CTAB and H2O/60 1C 20
30
60
82
88
95
90
95
96
96
90
80
92
92
71
90
92
94
95
95
13666.67
7333.35
23.75
6
148437.5
120 000
202.02
24 000
—
16.73
3.83
—
—
—
51
51
57
58
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)
[H2-DABCO][H2PO4]2
[H2-DABCO][ClO4]2
1
Reflux/EtOH
15
40
50
720
15
20
16 ꢁ 10ꢀ6
Solvent-free/100 1C
Solvent-free/100 1C
H2O/90 1C
H2O/80 1C
Solvent-free/60 1C
This work
This work
55
53
59
54
60
61
16 ꢁ 10ꢀ6
Triethylbenzylammonium chloride (TEBAC) 66 ꢁ 10ꢀ5
Nano-MgO
25 ꢁ 10ꢀ5
0.02 g
0.1
0.2
—
9
SBA-15-Pr-SO3H
Urea
Triethanolamine (TEOA)
Electrolysis
Electrolysis
Al-HMS-20
[C4(DABCO)2]ꢂ2OH
[H2-DABCO][H2PO4]2
[H2-DABCO][ClO4]2
10
11
12
13
14
15
16
17
H2O : EtOH (1 : 1)/r.t. 55
H2O/80 1C
EtOH/KBr
EtOH/NaBr
EtOH/r.t.
Grinding/r.t.
EtOH/70 1C
EtOH/70 1C
120
20
20
720
7
40
50
—
62
63
56
0.03 g
0.1
134.29
74218.75
73076.92
32 ꢁ 10ꢀ6
This work
This work
26 ꢁ 10ꢀ6
The purity determination of the substrate and reaction monitor-
ing were accomplished by TLC on silica-gel Polygram SILG/UV
Characterization techniques
Products were characterized by their physical constants, com- 254 plates. Melting points were measured by an Electrothermal
parison with authentic samples and IR and NMR spectroscopy. IA9100 melting point apparatus in capillary tubes. The starting
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Fig. 2 The reusability of [H2-DABCO][H2PO4]2 (runs 1–3, the columns in purple) and [H2-DABCO][ClO4]2 (runs 4–6, the columns in blue) in the synthesis
of 5-amino-7-(4-chlorophenyl)-7,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonitrile (4a).
Fig. 3 The reusability of [H2-DABCO][H2PO4]2 (runs 1–3, the columns in purple) and [H2-DABCO][ClO4]2 (runs 4–6, the columns in blue) in the synthesis
of 7-amino-5-(4-chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (6b).
temperature of the approximate melting range was input via the repeatedly (3 ꢁ 15) to remove non-ionic residues and then dried
keyboard and the melting point range was observed visually. under vacuum to give [H2-DABCO][H2PO4]2 as a white solid in
FT-IR spectra were recorded with a PerkinElmer Spectrum BX 97% yield (2.417 g) (Fig. 4(a)). The purity of the product was
series and KBr pellets were used for solid samples. Mass spectra determined by melting point, and mass, FT-IR, 1H NMR and
were obtained with an Agilent Technologies 5975C spectrometer 13C NMR spectra.26
via a mass selective detector (MSD) operating at an ionization
Spectral data for [H2-DABCO][H2PO4]2: white solid; m.p.
potential of 70 eV. 1H NMR and 13C NMR spectra were obtained 98 1C; MS: m/z = 308 (M+); FT-IR (KBr, cmꢀ1) nmax: 3421, 2823,
with a Bruker AV-400 using TMS (0.00 ppm) as internal standard 2380, 1638, 1115, 1053, 961; 1H NMR (400 MHz, DMSO-d6):
and DMSO-d6 as solvent.
d (ppm) 3.54 (s, 6H), 6.70 (s, 1H, NH), 10.90 (s, 1H, H2PO4);
13C NMR (100 MHz, DMSO-d6): d (ppm) 43.4.
Preparation of 1,4-diazabicyclo[2.2.2]octane-1,4-diium
dihydrogen phosphate {[H2-DABCO][H2PO4]2}
Preparation of 1,4-diazabicyclo[2.2.2]octane-1,4-diium
perchlorate {[H2-DABCO][ClO4]2}
A mixture of DABCO (0.909 g, 8.1 mmol) in dry dichloro-
methane (50 mL) was charged into a 100 mL round-bottomed After dissolving DABCO (0.673 g, 6 mmol) in 50 mL dry dichloro-
flask and was stirred in an ice-bath for 1 min. Then, a stoichio- methane in a 100 mL round-bottomed flask, the mixture was stirred
metric amount of phosphoric acid (85% v/v, 1 mL, 1.84 g) was in an ice-bath for 1 min. Then a stoichiometric amount of perchloric
added dropwise to this mixture during a period of 25 min. After acid (70%, 1 mL, 12 mmol) was added dropwise to the mixture in
the addition, the flask, fitted with a reflux condenser, was 5 parts (5 ꢁ 0.2 mL) within 25 min. After completion of the addition,
immersed in a recirculating heated water-bath for 24 h. After the mixture was stirred at room temperature for 20 h. At this point,
that, the obtained ionic liquid was washed with diethyl ether the solvent was decanted and the obtained white solid was
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Scheme 2 The presumed mechanism for the synthesis of 1,2,4-triazolo[4,3-a]pyrimidine and pyrido[2,3-d]pyrimidine derivatives using [H2-DABCO][H2PO4]2
and [H2-DABCO][ClO4]2 as the catalysts.
repeatedly washed with diethyl ether (3 ꢁ 15 mL) to remove non-
Spectral data for [H2-DABCO][ClO4]2: white solid; m.p.
ionic residues. At last, the obtained IL was dried under vacuum to 55 1C; MS: m/z = 313 (M+); FT-IR (KBr, cmꢀ1) nmax: 3470, 1150,
afford [H2-DABCO][ClO4]2 in 95% yield (1.78 g) (Fig. 4(b)). For 1082, 798, 623; 1H NMR (400 MHz, DMSO-d6): d (ppm) 3.35
being certain about the purity of the product, it was checked by (s, 6H), 5.42 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
melting point, and mass, FT-IR, 1H NMR and 13C NMR spectra.64 d (ppm) 43.4.
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(0.010 g, 0.032 mmol, Method A) or [H2-DABCO][ClO4]2 (0.008 g,
0.026 mmol, Method B). The mixture was stirred magnetically
at 70 1C to dissolve all components. However, the precipitate
of product appeared in the reaction medium after a short
time. Besides, the reaction progress was traced to completion
by TLC (n-hexane : ethyl acetate; 2 : 8). After completion of
the reaction, the mixture was filtered off and the obtained
residue was washed with water to remove the catalyst. Finally,
the crude product was recrystallized from ethanol if necessary
(6a–p).
5,50-(1,3-Phenylene)bis(7-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-
tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile) (6o)
Fig. 4 The preparation of [H2-DABCO][H2PO4]2 (a) and [H2-DABCO][ClO4]2 (b).
White powder; m.p. 4300 1C; IR (KBr, n, cmꢀ1): 3445, 3346,
3240, 3035, 2959, 2222, 1704, 1663, 1624, 1566; 1H NMR
(400 MHz, DMSO-d6): 8.59 (s, 1H, CH–Ph), 8.08 (dt, J1 = 8 Hz,
J2 = 1.6 Hz, J3 = 1.2 Hz, 1H, CH–Ph), 7.77 (s, 2H, NH2), 7.72 (t, J =
8 Hz, 1H, CH–Ph), 7.59 (dt, J1 = 7.6 Hz, J2 = 1.6 Hz, J3 = 1.2 Hz,
1H, CH–Ph), 3.50 (s, 6H, Me), 3.07 (s, 6H, Me); 13C NMR (100 MHz,
DMSO-d6): 160.7, 160.2, 160.1, 158.5, 157.3, 153.6, 150.7, 138.4,
133.3, 130.8, 129.8, 129.2, 115.5, 114.1, 113.1, 98.5, 88.0, 82.1,
29.6, 27.7.
General procedure for preparation of 1,2,4-triazolo[4,3-
a]pyrimidines
To a mixture of aromatic aldehyde 1 (1 mmol), malononitrile 2
(1 mmol) and 3-amino-1,2,4-triazole 3 (1 mmol) in a 25 mL
round-bottom flask, [H2-DABCO][H2PO4]2 (0.005 g, 0.016 mmol,
Method A) or [H2-DABCO][ClO4]2 (0.005 g, 0.016 mmol, Method B)
was added. Then the mixture was stirred magnetically under
solvent-free conditions at 100 1C for the appropriate time.
Meanwhile, the reaction process was carefully monitored by
TLC (n-hexane : ethyl acetate; 8 : 2). After completion of the
reaction, 5 mL water was poured into the reaction medium
and then filtered off so as to separate the catalyst. Finally, the
obtained precipitate was recrystallized from ethanol to afford
the required product (4a–j).
7-Amino-5-(4-(dimethylamino)phenyl)-1,3-dimethyl-2,4-dioxo-
1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (6p)
Orange powder; m.p. 4300 1C; IR (KBr, n, cmꢀ1): 3395, 3352,
3233, 2918, 2202, 1660, 1613, 1564; 1H NMR (400 MHz, DMSO-
d6): 7.82 (dd, J1 = 9.2 Hz, J2 = 2 Hz, 2H, CH–Ph), 6.84 (dd, J1 = 9.2
Hz, J2 = 2 Hz, 2H, CH–Ph), 6.78 (s, 2H, NH2), 3.23 (s, 3H, C–Me),
3.10 (s, 6H, NMe2), 3.07 (s, 3H, C–Me); 13C NMR (100 MHz,
DMSO-d6): 161.3, 158.8, 154.2, 151.5, 133.5, 118.7, 116.2, 115.5,
111.7, 74.8, 68.5, 29.2, 27.0.
5-Amino-7-(naphthalen-2-yl)-7,8-dihydro[1,2,4]triazolo[4,3-
a]pyrimidine-6-carbonitrile (4i)
White powder; m.p. 280–284 1C; IR (KBr, n, cmꢀ1): 3360, 3256,
3183, 2189, 1657, 1629, 1526; 1H NMR (400 MHz, DMSO-d6):
8.88 (d, J = 2.4 Hz, 1H, NH), 7.90–7.97 (m, 3H, NQCH–N and
CH–Ph), 7.77 (d, J = 10.8 Hz, 2H, CH–Ph), 7.50–7.55 (m, 3H,
CH–Ph), 7.31 (d, J = 2.8 Hz, 2H, NH2), 5.56 (d, J = 2 Hz, 1H, CH);
13C NMR (100 MHz, DMSO-d6): 153.9, 151.9, 147.0, 140.3, 132.6,
132.5, 128.7, 127.9, 127.6, 127.5, 126.5, 126.2, 124.6, 124.4,
119.0, 54.3.
Conclusions
In this paper, the syntheses of 1,2,4-triazolo[4,3-a]pyrimidine
and pyrido[2,3-d]pyrimidine derivatives are investigated in the
presence of [H2-DABCO][H2PO4]2 and [H2-DABCO][ClO4]2 as
efficient catalysts. All products are prepared in good reaction
times and excellent yields without any by-products. The work-up
procedures are simple and obtained products are purified without
need of column chromatography. Above all, small amounts of
catalysts are used in both procedures, which indicate them as
affordable and cost-saving procedures. Finally, the reusability
of both catalysts is investigated and the catalysts show utility in
recycling during 3 runs.
5-Amino-7-(3-methoxyphenyl)-7,8-dihydro[1,2,4]triazolo[4,3-a]-
pyrimidine-6-carbonitrile (4j)
White powder; m.p. 218–221 1C; IR (KBr, n, cmꢀ1): 3427, 3245,
3098, 2192, 1678, 1623, 1515; 1H NMR (400 MHz, DMSO-d6):
d (ppm) 8.79 (d, J = 2.4 Hz, 1H, NH), 7.72 (s, 1H, NQCH–N), 7.31
(t, J = 8 Hz, 1H, CH–Ph), 7.23 (d, J = 2.4 Hz, 2H, NH2), 6.82–6.91
(m, 3H, CH–Ph), 5.31 (d, J = 2 Hz, 1H, CH), 3.74 (s, 3H, OMe);
13C NMR (100 MHz, DMSO-d6): d (ppm) 159.3, 151.8, 144.7,
130.6, 129.9, 120.2, 118.0, 112.0, 55.0, 53.7.
Conflicts of interest
There are no conflicts to declare.
General procedure for preparation of pyrido[2,3-d]pyrimidines
Acknowledgements
5 mL ethanol was poured into a 25 mL round-bottom flask
containing aldehyde 1 (1 mmol), malononitrile 2 (1 mmol), We are grateful to the Research Council of University of Guilan
6-amino-1,3-dimethyluracil 5 (1 mmol) and [H2-DABCO][H2PO4]2 for the partial support of this research.
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