Synthesis and antimycobacterial activity of alkyl 1-heteroaryl-1H-1,2,3- triazole-4-carboxylates

Article abstract of DOI:10.1002/jhet.5570420620

A series of alkyl 1-heteroaryl-1H-1,2,3-triazole-4-carboxylates 6a-u were synthesised in four steps from methyl (Z)-2-benzyloxycarbonylamino-3- (dimethylamino)prop-2-enoate (1) and heterocyclic amines 2a-s. Triazoles 6a-o were tested against antimycobacte

Full text of DOI:10.1002/jhet.5570420620

Synthesis and Antimycobacterial Activity of Alkyl 1-Heteroaryl-
1H-1,2,3-triazole-4-carboxylates.
Sep-Oct 2005
1167
Boštjan Japelj, Simon Rečnik, Petra Čebašek, Branko Stanovnik*, and Jurij Svete*
Faculty of Chemistry and Chemical Technology, University of Ljubljana,
Aškerčeva 5, 1000 Ljubljana, Slovenia
Received April 1, 2005
A series of alkyl 1-heteroaryl-1H-1,2,3-triazole-4-carboxylates 6a–u were synthesised in four steps from
methyl (Z)-2-benzyloxycarbonylamino-3-(dimethylamino)prop-2-enoate (1) and heterocyclic amines 2a–s.
Triazoles 6a–o were tested against antimycobacterial activity. For the most active compound, n-pentyl 1-(6-
phenylpyridazin-3-yl)-1H-1,2,3-triazole-4-carboxylate (6n), minimum inhibitory concentration 3.13 µg/ml
was determined.
J. Heterocyclic Chem., 42, 1167 (2005).
Scheme 1
Tuberculosis (TB), a chronic and fatal bacterial infec-
tion, can be caused by Mycobacterium tuberculosis and, to
a lesser degree, by Mycobacterium bovis and
Mycobacterium africanum. Cases of TB dropped rapidly
in the 1940s and 1950s when the first effective antibiotic
therapies for TB were introduced. For this reason, many
people think TB is a disease of the past. However, in 1985
the decline of TB ended and the number of active TB cases
began to rise again. Each year, 8 million people worldwide
develop active TB and 3 million die. A growing problem
also is HIV-infected patients, which are particularly vul-
nerable to turn infection with M. tuberculosis into active
TB [1].
In the last two decades, a series of 2-substituted alkyl 3-
(dimethylamino)prop-2-enoates and related enaminones
were prepared and used as versatile reagents for the prepa-
ration of various heterocyclic systems, functionalised hete-
rocyclic compounds, and natural product analogues [2–7].
Just recently, the enaminone methodology has been
employed in combinatorial synthesis [8–10]. The use of 2-
acylamino and 2-vinylamino substituted alkyl 3-
(dimethylamino)propenoates also offers an easy access to
various 3-amino-4H-quinolizin-4-ones and 3-amino sub-
stituted fused pyrimidones, which can be transformed into
the corresponding diazonium tetrafluoroborates as versa-
tile intermediates for further transformations [11–15]. In
this connection, we have previously reported a three-step
synthesis of stable diazonium tetrafluoroborates 5a–n
starting from methyl (Z)-2-benzyloxycarbonylamino-3-
(dimethylamino)prop-2-enoate (1) and heterocyclic
amines 2a–o. Upon heating with primary alcohols at 60°,
diazonium salts 5a–n underwent ‘ring switching’ transfor-
mation to furnish alkyl 1-azinyl-1H-1,2,3-triazole-4-car-
boxylates 6a–n [11,13] (Scheme 1).
Reaction conditions: (i) Methyl (Z)-2-benzyloxycarbonylamino-3-
(dimethyl-amino)prop-2-enoate (1), AcOH, AcONa, reflux; (ii)
HBr–AcOH, 50°; (iii) NaNO (aq.), HCl, H O, 0°, then 50% HBF (aq.);
2
2
4
3
(iv) R OH, 60°.
ment with the propenoate 1 in refluxing acetic acid fol-
lowed by deprotection of the amino group in azolopy-
rimidones 3o–s with 33% HBr in acetic acid at 50°.
Nitrosation of 6-amino-5H-thiazolo[3,2–a]pyrimidin-5-
one (4o) and 6-aminoimidazo[1,2–a]pyrimidin-5(1H)-
one (4p) with aqueous sodium nitrite in the presence of
fluoroboric acid afforded stable diazonium tetrafluorob-
orates 5o and 5p in 80% and 75% yield, respectively. On
the other hand, nitrosation of 6-aminopyrazolo[1,5–a]-
pyrimidin-7(1H)-one (4q) and 6-amino-2-methyl-
pyrazolo[1,5–a]pyrimidin-7(1H)-one (4r) with aqueous
sodium nitrite furnished the 3-brominated diazo com-
pounds 5t and 5u. Bromination at position 3 could be
explained by oxidation of HBr with nitrous acid to give
in situ formed bromine, which then undergoes elec-
trophilic substitution at position 3. In order to avoid
bromination, amines 4q and 4r were diazotised with
In this paper, we report the synthesis of novel methyl 1-
azolyl-1H-1,2,3-triazole-4-carboxylates 6o–u and the
results of antimicrobial evaluation of the previously pre-
pared alkyl 1-azinyl-1H-1,2,3-triazole-4-carboxylates
6a–o against Mycobacterium tuberculosis.
Heterocyclic amines 4o–s were prepared, according to
the general literature procedures [13,16], in 81–90%
yields over two steps from aminoazoles 2o–s via treat-

1168
B. Japelj, S. Rečnik, P. Čebašek, B. Stanovnik, and J. Svete
Vol. 42
Scheme 2
Table 1
Compounds 2–7
Compound
R
X
Yield (%)
3
4
5
6
7
2o–6o
2p–6p
2q–7q
2r–6r
2s–7s
5t, 6t
-
-
S
96
95
99
90
85
89[a]
95
90
90
97
80
75
87
57
93
80
75
40
48
33
15
26
16
9
NH
CH
CH
N
C–Br
C–Br
H
Me
H
H
Me
51
48
5u, 6u
[a] Isolated as free amine.
pyrazolo[1,5–a]pyrimidin-7(1H)-one (7q) and [1,2,4]-
triazolo[1,5–a]pyrimidin-7(1H)-one (7s), respectively.
When heating of diazo compounds 5q–u in methanol was
carried out in the presence of 3 equivalents of 37%
hydrochloric acid, the desired ‘ring switching’ transforma-
tion took place to give methyl 1-azolyl-1H-1,2,3-triazole-
4-carboxylates 6q–u in 9–48% yields (Scheme 3, Table 1).
Structures of all novel compounds were determined by
spectroscopic (nmr, ir, ms, hrms) methods and by analyses
for C, H, and N. Compounds 5q,r,t and 6q–u were not pre-
pared in analytically pure form. Their identities were con-
firmed by ms and hrms. Identities of known compounds 7q
[17], and 7s [18] were confirmed by melting points and
spectral data.
Reaction conditions: (i) AcOH, AcONa, reflux; (ii) HBr–AcOH, 50°; (iii)
NaNO , HCl, H O, 0°, then 50% HBF (aq.) (Procedure A); (iv) NaNO ,
2
2
4
2
50% HBF (aq.), AcOH or AcOEt, 0° (Procedure B); (v) tert-butyl
4
nitrite, BF xEt O, i-PrOH, –15→0° (Procedure C).
3
2
tert-butyl nitrite and BF –Et O in 2-propanol to give the
3
2
1-Pyridinyl (6a–g), 1-pyridazinyl (6h–n), and thiazolyl
(6o) substituted alkyl 1H-1,2,3-triazole-4-carboxylates
were tested for antimicrobial activity. Primary screening
was conducted at 6.25 µg/ml against Mycobacterium
3-unsubstituted diazo heterocycles 5q and 5r. In the
same manner, 6-diazo[1,2,4]triazolo[1,5–a]pyrimidin-
7(6H)-one (5s) was prepared (Scheme 2, Table 1).
Heating of diazonium tetrafluoroborates 5o,p in
methanol resulted in ‘ring switching’ transformation into
1-thiazol-2-yl (6o) and 1-imidazol-2-yl (6p) substituted
methyl 1H-1,2,3-triazole-4-carboxylates, which were iso-
lated in moderate yields. However, heating of 6-diazo-
pyrazolo[1,5–a]pyrimidin-7(6H)-one (5q) and 6-diazo-
[1,2,4]triazolo[1,5–a]pyrimidin-7(6H)-one (5s) in
methanol resulted in reduction (dediazonation) to give
tuberculosis H Rv (ATCC 27294) in BACTEC 12B
37
medium using a broth micro dilution assay, the Microplate
Alamar Blue Assay [19]. Compounds exhibiting fluores-
cence were tested in the BACTEC 460 radiometric system
[19]. Compounds 6c,e,k,n, which exhibited more than
90% inhibition in the primary screening, were re-tested at
lower concentrations against M. tuberculosis H Rv to
37

Sep-Oct 2005
Synthesis and Antimycobacterial Activity
1169
Scheme 3
Table 2
In vitro antimicrobial activity of compounds 6a–o against
Mycobacterium tuberculosis H Rv.
37
Compound
[b]
R
% Inhibition[a]
MIC (µg/ml)
6a
6b
6c
6d
6e
6f
6g
6h
6i
methyl
ethyl
n-pentyl
methyl
ethyl
n-propyl
n-butyl
methyl
n-propyl
n-butyl
methyl
ethyl
25
74
99
0
98
70
89
2
13
20
99
4
[c]
[c]
>6.25
[c]
>6.25
[c]
[c]
[c]
[c]
[c]
6j
6k
6l
>6.25
[c]
6m
6n
6o
n-propyl
n-pentyl
-
41
99
1
[c]
3.13
[c]
[a] % Inhibition values are relative to the primary test at 6.25 µg/ml
against Mycobacterium tuberculosis H Rv (ATCC 27294) in BACTEC
37
12B medium using a broth micro dilution assay, the Microplate Alamar
Blue Assay [19]; [b] The minimum inhibitory activity (MIC) is defined
as the lowest concentration effecting a reduction in fluorescence of 90%
relative to controls. The MIC values are relative to the secondary test at
Reaction conditions: (i) MeOH, reflux (Procedure A); (ii) MeOH, 37%
aq. HCl (3 equiv.), reflux (Procedure B).
concentrations < 6.25 µg/ml against Mycobacterium tuberculosis H Rv
37
(ATCC 27294);[c] Not determined.
determine the actual minimum inhibitory concentration
(MIC) in the MABA. Upon re-testing, the MIC value 3.13
µg/ml was established for n-pentyl 1-(6-phenylpyridazin-
3-yl)-1H-1,2,3-triazole-4-carboxylate (6n), while the MIC
values for compounds 6c,e,k were found to be >6.25
µg/ml (Table 2).
eroaryl-1H-1,2,3-triazole-4-carboxylic acid esters and
other derivatives, which would enable preparation of
libraries of 1-heteroaryl-1H-1,2,3-triazole-4-carboxylic
acid derivatives for further biological evaluations.
In conclusion, various 1-heteroaryl substituted alkyl 1H-
1,2,3-triazole-4-carboxylates 6 are available in four steps
starting from heterocyclic amines 2 and methyl (Z)-2-ben-
zyloxycarbonylamino-3-(dimethylamino)prop-2-en-oate
(1). The yields in the last step are only moderate, however,
the methodology is general and the key-intermediates 5 are
available in good yields over the first three steps. The
results of the primary antimicrobial evaluation of com-
pounds 6a–o indicate, that 1-heteroaryl-1H-1,2,3-triazole-
4-carboxylic acid scaffold might be used in development
of antimicrobial compounds. Consequently, we are now
developing combinatorial approaches towards 1-het-
Experimental
Melting points were determined on a Kofler micro hot stage.
The nmr spectra were obtained on a Bruker Avance DPX 300 at
1
13
300 MHz for H and 75.5 MHz for C nucleus, using dimethyl
sulfoxide-d and deuteriochloroform with tetramethylsilane as
6
the internal standard, as solvents. Mass spectra were recorded on
an AutoSpecQ spectrometer, ir spectra on a Perkin-Elmer
Spectrum BX FTIR spectrophotometer. Microanalyses were per-
formed on a Perkin-Elmer CHN Analyser 2400. Column chro-
matography was performed on silica gel (Fluka, silica gel 60,
0.04–0.06 mm).

1170
B. Japelj, S. Rečnik, P. Čebašek, B. Stanovnik, and J. Svete
Vol. 42
Heterocyclic amines 2o–s are commercially available (Fluka
General Procedure for the Synthesis of Heterocyclic Amines
AG). Methyl (Z)-2-benzyloxycarbonylamino-3-(dimethy-
lamino)prop-2-enoate (1) was prepared according to the literature
procedure [20].
4o–s.
A mixture of the protected amine 3o–s (2 mmol) and a solution
of HBr in acetic acid (33%, 5 ml) was stirred at 50–60° for 2 h.
The reaction mixture was cooled to room temperature, the precip-
itate was collected by filtration, and washed with ethyl acetate to
give aminopyrimidones 4o–s.
General Procedure for the Synthesis of Azolo Fused Pyrimidones
3o–s.
A mixture of enaminone 1 (1.390 g, 5 mmol), heterocyclic amine
2o–s (5 mmol), and acetic acid (100%, 15 ml) was heated under
reflux for 1–4 h. Volatile components were evaporated in vacuo, the
residue was triturated with ethanol–water (1:3), and the precipitate
was collected by filtration to give fused pyrimidones 3o–s.
The following compounds were prepared in this manner:
6-Amino-5H-thiazolo[3,2–a]pyrimidin-5-one (4o).
Prepared from 3o. Yield: 0.442 g (89%) of a pale yellow solid,
mp 167–170°, lit [16] mp 165–168°. Spectral data for compound
4o were in agreement with those, reported in the literature [16].
The following compounds were prepared in this manner:
6-Benzyloxycarbonylamino-5H-thiazolo[3,2–a]pyrimidin-5-one
(3o).
6-Aminoimidazo[1,2–a]pyrimidin-5(1H)-one Dihydrobromide
(4p).
Prepared from 1 and 2-aminothiazole (2o); reflux for 4 h.
Yield: 1.45 g (96%) of a pale yellow solid, mp 182–184°, lit [16]
mp 183–184°. Spectral data for compound 3o were in agreement
with those, reported in the literature [16].
Prepared from 3p. Yield: 0.57 g (95%) of a light brown solid,
mp 281–283°; ir (potassium bromide): 3150, 2681, 2488, 1718
–1 1
(C=O), 1634, 1494, 1292, 750 cm . H nmr (dimethyl sulfoxide-
d ): δ 7.72 (1H, d, J = 2.3 Hz, 2–H), 7.79 (1H, s, J = 2.6 Hz,
6
6-Benzyloxycarbonylaminoimidazo[1,2–a]pyrimidin-5(1H)-one
(3p).
3–H), 8.19 (1H, s, 7–H), 9.75 (2H, br s, NH ); NH proton
2
exchanged.
Anal. Calcd. for C H Br N O: C, 23.10; H, 2.58; N, 17.96.
Found: C, 23.45; H, 2.57; N, 17.69.
6
8
2 4
Prepared from 1 and 2-aminoimidazole sulfate (2p); reflux for
4 h. Yield: 1.35 g (95%) of a pale yellow solid, mp 199–202°; ir
(potassium bromide): 3498, 3033, 2819, 1657 (C=O), 1541,
6-Aminopyrazolo[1,5–a]pyrimidin-7(1H)-one Dihydrobromide
(4q).
–1
1
1255, 1085, 747 cm . H nmr (dimethyl sulfoxide-d ): δ 5.10
6
(2H, s, CH ), 7.31–7.46 (5H, m, Ph), 7.55 (1H, d, J = 2.6 Hz,
2
Prepared from 3q. Yield: 0.56 g (90%) of a pale yellow solid, mp
3–H), 7.64 (1H, d, J = 2.6, 2–H), 8.03 (1H, s, 7–H), 8.53 (1H, br
s, NH), 12.80 (1H, br s, NH).
>300° (decomp.); ir (potassium bromide): 3432, 3115, 2559, 1709
–1 1
(C=O), 1596, 1445, 1154, 826, 738 cm . H nmr (dimethyl sulfox-
Anal. Calcd. for C
H N O : C, 59.15; H, 4.25; N, 19.71.
14 12 4 3
ide-d ): δ 6.35 (1H, d, J = 1.9 Hz, 3–H), 8.02 (1H, d, J = 1.9 Hz,
6
Found: C, 59.39; H, 4.20; N, 19.46.
2–H), 8.24 (1H, s, 5–H), 9.82 (2H, br s, NH ), 12.84 (1H, br s, NH).
2
6-Benzyloxycarbonylaminopyrazolo[1,5–a]pyrimidin-7(1H)-
one (3q).
Anal. Calcd. for C H Br N O: C, 23.10; H, 2.58; N, 17.96.
Found: C, 23.43; H, 2.61; N, 17.62.
6
8
2 4
Prepared from 1 and 3-aminopyrazole (2q); reflux for 2 h.
Yield: 1.42 g (99%) of a pale yellow solid, mp >250° (decomp.);
ir (potassium bromide): 3412, 3138, 1726 (C=O), 1661 (C=O),
6-Amino-2-methylpyrazolo[1,5–a]pyrimidin-7(1H)-one
Dihydrobromide (4r).
Prepared from 3r. Yield: 0.59 g (90%) of a yellow solid, mp
–1
1
1530, 1204, 756 cm . H nmr (dimethyl sulfoxide-d ): δ 5.12
6
>300° (decomp.); ir (potassium bromide): 3130, 2707, 2512,
(2H, s, CH ), 6.18 (1H, d, J = 2.3 Hz, 3–H), 7.30–7.45 (5H, m,
2
–1
1
1668 (C=O), 1482, 1326, 814, 746 cm . H nmr (dimethyl sul-
Ph), 7.90 (1H, d, J = 2.3 Hz, 2–H), 8.12 (1H, s, 5–H), 8.68 (1H, br
s, NH), 12.80 (1H, br s, NH).
foxide-d ): δ 2.33 (3H, s, Me), 6.17 (1H, s, 3–H), 8.11 (1H, s,
6
5–H), 9.73 (2H, br s, NH ), 12.62 (1H, br s, NH).
2
Anal. Calcd. for C
H N O : C, 59.15; H, 4.25; N, 19.71.
14 12 4 3
Anal. Calcd. for C H Br N O: C, 25.79; H, 3.09; N, 17.19.
7
10
2 4
Found: C, 59.29; H, 4.17; N, 19.44.
Found: C, 25.81; H, 2.94; N, 17.05.
6-Benzyloxycarbonylamino-2-methylpyrazolo[1,5–a]pyrimidin-
7(1H)-one (3r).
6-Amino[1,2,4]triazolo[1,5–a]pyrimidin-7(1H)-one Dihydro-
bromide (4s).
Prepared from 1 and 3-amino-5-methylpyrazole (2r); reflux
for 1 h. Yield: 1.34 g (90%) of a yellow solid, mp 293–295°; ir
(potassium bromide): 3328, 3118, 1662 (C=O), 1545, 1232, 749
Prepared 3s. Yield: 0.61 g (97%) of a white solid, mp 240°
(decomp.); ir (potassium bromide): 3544, 3126, 2850, 1738
–1 1
(C=O), 1682 (C=O), 1643 (C=O), 1311, 1250, 751 cm . H nmr
–1
1
cm . H nmr (dimethyl sulfoxide-d ): δ 2.29 (3H, s, Me), 5.11
6
(dimethyl sulfoxide-d ): δ 8.25 (1H, s, 2–H), 8.52 (1H, s, 5–H),
6
(2H, s, CH ), 5.99 (1H, s, 3–H), 7.28–7.45 (5H, m, Ph), 8.03 (1H,
2
NH protons exchanged.
s, 5–H), 8.62 (1H, br s, NH), 12.21 (1H, br s, NH).
Anal. Calcd. for C H Br N O: C, 19.19; H, 2.25; N, 22.38.
5
7
2 5
Anal. Calcd. for C
H N O : C, 60.40; H, 4.73; N, 18.78.
15 14 4 3
Found: C, 19.51; H, 2.41; N, 22.45.
Found: C, 60.64; H, 4.84; N, 18.88.
General Procedures for the Preparation of Diazonium Salts 5o,p
and Diazo Compounds 5q–u.
6-Benzyloxycarbonylamino[1,2,4]triazolo[1,5–a]pyrimidin-
7(1H)-one (3s).
Procedure A. Synthesis of Compound 5o.
Prepared from 1 and 3-amino-1H-1,2,4-triazole (2s); reflux for
4 h. Yield: 1.22 g (85%) of a white solid, mp 222–224°, lit [16]
mp 215–217°. Spectral data for compound 3s were in agreement
with those, reported in the literature [16].
A solution of sodium nitrite (0.760 g, 11 mmol) in water (4 ml)
was added slowly to a stirred solution of the amine 4o (1.672 g,
10 mmol) in 6 N hydrochloric acid (24 ml) at 0° and the reaction

Sep-Oct 2005
Synthesis and Antimycobacterial Activity
1171
mixture was stirred at 0° was for 15 min. Then aqueous fluoro-
boric acid (50%, 6 ml) was added and the precipitate was col-
lected by filtration and washed thoroughly with cold (0°) water,
methanol, and diethyl ether to give 5o.
6-Diazo[1,2,4]triazolo[1,5–a]pyrimidin-7(6H)-one (5s).
Prepared from 4s (0.310 g, 1 mmol), Procedure C. Yield: 0.15
g (93%) of a white solid, mp 237–239°; ir (potassium bromide):
–1
1
3404, 3133, 3019, 2204, 2184, 1709, 1546, 765 cm . H nmr
Procedure B. Synthesis of Compounds 5p,t,u.
(dimethyl sulfoxide-d ): δ 8.43 (1H, s, 7–H), 9.10 (1H, s, 2–H).
6
+
+
MS (m/z) 162 (M ), 163 (MH ).
A mixture of amine dihydrobromide 4p,q,r (2 mmol), aqueous
fluoroboric acid (50%, 0.51 g), and acetic acid (10 ml) or ethyl
acetate (10 ml) was stirred at room temperature for 30 min. Then
aqueous sodium nitrite (20%, 0.7 g) was added slowly and the
reaction mixture was stirred at room temperature for 1 h. The pre-
cipitate was collected by filtration and washed thoroughly with
ethyl acetate and diethyl ether to give compounds 5p,t,u.
Anal. Calcd. for C H N O: C, 37. 05; H, 1.24; N, 51.84.
5
2 6
Found: C, 36.70; H, 1.28; N, 52.17.
3-Bromo-6-diazopyrazolo[1,5–a]pyrimidin-7(6H)-one (5t).
Prepared from 4q (0.620 g, 2 mmol) in ethyl acetate,
Procedure B. Yield: 0.38 g (80%) of a yellow solid, mp
224–227°; ir (potassium bromide): 3413, 3064, 3015, 2226,
Procedure C. Synthesis of Diazo Compounds 5q–s.
–1
1
2155, 1697, 1576, 1529, 949, 734 cm . H nmr (dimethyl sul-
13
foxide-d ): δ 8.24 (1H, s, 2–H), 8.80 (1H, s, 5–H). C nmr
A suspension of amine 4q–s (1 mmol) in 2-propanol (7 ml)
was added, while stirring, to cooled (–15°) boron trifluoride ethyl
etherate (0.28g, 1 mmol) and the mixture was stirred at –15° for
15 min. Then a solution of tert-butyl nitrite (0.1 g) in 2-propanol
(3 ml) was slowly added and the mixture was stirred at –15° for
30 min and at 0–5° for 1 h. The precipitate was collected by fil-
tration and washed thoroughly with cold (0°) methanol, chloro-
form, and ether to give diazo compounds 5q–s.
6
(dimethyl sulfoxide-d ): δ 78.4, 91.1, 146.5, 147.7, 150.9, 154.6.
6
+
+
Ms (m/z) 239, 241 (M ), 240, 242 (MH ).
3-Bromo-6-diazo-2-methylpyrazolo[1,5–a]pyrimidin-7(6H)-one
(5u).
Prepared from 4r (0.330 g, 1 mmol) in ethyl acetate, Procedure
B. Yield: 0.19 g (75%) of a yellow solid, mp 199–201°; ir (potas-
sium bromide): 3474, 3026, 2211, 2141, 1689, 1578, 1317, 1040,
The following compounds were prepared in this manner:
–1
1
734 cm . H nmr (dimethyl sulfoxide-d ): δ 2.32 (3H, s, Me),
6
5-Oxo-5H-thiazolo[3,2–a]pyrimidine-6-diazonium Tetrafluoro-
borate (5o).
+
+
8.66 (1H, s, 5–H). Ms (m/z) 253, 255 (M ), 254, 256 (MH ).
Anal. Calcd. for C H BrN O: C, 33.09; H, 1.59; N, 27.57.
7
4
5
Prepared from 4o, Procedure A. Yield: 2.155 g (80%) of a light
Found: C, 32.85; H, 1.53; N, 27.24.
brown solid, mp 195–197°; ir (potassium bromide): 3128, 2194,
General Procedures for the Preparation of Alkyl 1-Heteroaryl-
1H-1,2,3-triazole-4-carboxylates 6o–u and Azolo[1,5–a]pyrim-
idin-7(1H)-ones 7q,s.
–1
1
1726, 1510, 1035, 724 cm . H nmr (dimethyl sulfoxide-d ): δ
6
8.18 (1H, d, J = 4.9 Hz, 2–H), 8.67 (1H, d, J = 4.9 Hz, 3–H), 9.41
13
(1H, s, 7–H). C nmr (DMSO-d ): δ 90.8. 122.4, 125.5, 153.0,
6
+
–
160.9, 172.3. Ms (m/z) 179 (M –BF ).
4
Procedure A. Synthesis of Compounds 6o,p and 7q,s.
Anal. Calcd. for C H BF N OS: C, 27.09; H, 1.14; N, 21.06.
6
3
4 4
A mixture of compound 5 (0.100 g) and methanol (15 ml) or
ethanol (15 ml) was stirred at 60–70° for 20–40 h. Volatile com-
ponents were evaporated in vacuo and the residue was purified
by column chromatography. Fractions containing the product
were combined and evaporated in vacuo to give compounds 6o,p
and 7q,s.
Found: C, 27.09; H, 1.10; N, 20.84.
5-Oxo-1,5-dihydroimidazo[1,2–a]pyrimidine-6-diazonium
Tetrafluoroborate Hydrobromide (5p).
Prepared from 4p (0.620 g, 2 mmol) in acetic acid, Procedure
B. Yield: 0.48 g (75%) of a light brown solid, mp 238–240°; ir
(potassium bromide): 3416, 3154, 2675, 2205, 2181, 1725, 1542,
Procedure B. Synthesis of Compounds 6q–u.
–1 1
1064, 749 cm . H nmr (dimethyl sulfoxide-d ): δ 7.66 (1H, d, J
6
A mixture of compound 5 (0.100 g), methanol (15 ml), and
hydrochloric acid (37%, 0.2 ml) was stirred at 60–70° for 35–45
h. Volatile components were evaporated in vacuo and the residue
was purified by column chromatography. Fractions containing
the product were combined and evaporated in vacuo to give com-
pounds 6q–u.
= 1.9 Hz, 2–H), 7.98 (1H, d, J = 1.9 Hz, 3–H), 9.01 (1H, s, 7–H),
+
–
NH proton exchanged. Ms (m/z) 162 (M –BF –HBr).
4
Anal. Calcd. for C H BBrF N O: C, 21.85; H, 1.53; N, 21.23.
6
5
4 5
Found: C, 22.14; H, 1.29; N, 21.15.
6-Diazopyrazolo[1,5–a]pyrimidin-7(6H)-one (5q).
The following compounds were prepared in this manner:
Prepared from 4q (0.310 g, 1 mmol), Procedure C. Yield: 0.14
g (87%) of a yellow solid, mp 208° (decomp.); ir (potassium bro-
mide): 3418, 3102, 3040, 2216, 2139, 1703, 1570, 1113, 909, 738
Methyl 1-(Thiazol-2-yl)-1H-1,2,3-triazole-4-carboxylate (6o).
–1
1
Prepared from 5o (0.100 g, 0.376 mmol), Procedure A, reflux
for 40 h, column chromatograpy (EtOAc–hexanes, 2:1). Yield:
0.31 g (40%) of a white solid, mp 161–163°; ir (potassium bro-
cm . H nmr (dimethyl sulfoxide-d ): δ 6.66 (1H, d, J = 1.5 Hz,
6
3–H), 8.06 (1H, d, J = 1.8 Hz, 2–H), 8.71 (1H, s, 5–H). Ms (m/z)
+
+
161 (M ), 162 (MH ).
–1
1
mide): 3114, 1730 (C=O), 1543, 1273, 1260, 1031 cm . H nmr
6-Diazo-2-methylpyrazolo[1,5–a]pyrimidin-7(6H)-one (5r).
Prepared from 4r (0.310 g, 1 mmol), Procedure C. Yield: 0.10
(deuteriochloroform): δ 4.01 (3H, s, OMe), 7.35 (1H, d, J = 3.4
Hz, 5’–H), 7.73 (1H, d, J = 3.4 Hz, 4’–H), 8.92 (1H, s, 5–H).
13
C
nmr (deuteriochloroform): δ 52.9, 119.3, 125.2, 140.9, 141.2,
g (57%) of a yellow solid, mp >300° (decomp.); ir (potassium
+
+
–1
156.7, 160.8. Ei-ms (m/z) 210 (M ), fab-ms (m/z) 211 (MH ).
Anal. Calcd. for C H N O S: C, 39.99; H, 2.88; N, 26.65.
bromide): 3448, 2208, 2168, 1687, 1678, 1580, 1240, 814 cm
.
1
H nmr (dimethyl sulfoxide-d ): δ 2.31 (3H, s, Me), 6.49 (1H, s,
7
6 4 2
6
+
+
3–H), 8.66 (1H, s, 5–H). Ms (m/z) 175 (M ), 176 (MH ).
Found: C, 40.37; H, 2.92; N, 26.35.

1172
B. Japelj, S. Rečnik, P. Čebašek, B. Stanovnik, and J. Svete
Vol. 42
Methyl 1-(Imidazol-2-yl)-1H-1,2,3-triazole-4-carboxylate (6p).
(9%) of a pale yellow solid, mp 195–198°; ir (potassium bro-
mide): 3347, 3222, 3123, 1695 (C=O), 1337, 1239, 1036, 955,
Prepared from 5p (0.100 g, 0.3 mmol), Procedure A, reflux for
40 h, column chromatography (ethyl acetate). Yield: 0.028 g (48%)
of a pale yellow solid, mp 180–183°; ir (potassium bromide):
–1
1
781 cm
. H nmr (dimethyl sulfoxide-d ): δ 2.32 (3H, s,
6
5’–Me), 3.89 (3H, s, OMe), 9.18 (1H, s, 5–H), 13.70 (1H, br s,
NH). Ms (m/z): 285, 287 (M ), 286, 288 (MH ). Hrms Calcd.
+
+
–1
3415, 3146, 2959, 1742 (C=O), 1586, 1268, 1035, 776, 768 cm .
+
for C H BrN O : m/z = 284.986136 (M ). Found: m/z =
1
8
8
5
2
H nmr (deuteriochloroform): δ 4.00 (3H, s, OMe), 7.12 (2H, br s,
+
284.987200 (M ).
4’–H, 5’–H), 8.86 (1H, s, 5–H), 10.21 (1H, br s, NH). Ms (m/z):
193 (M ), 194 (MH ). Hrms Calcd. for C H N O : m/z =
193.059979 (M ). Found: m/z = 193.060550 (M ).
+
+
Pyrazolo[1,5–a]pyrimidin-7(1H)-one (7q).
7
7 5 2
+
+
Prepared from 5q (0.100 g, 0.62 mmol) and methanol,
Procedure A, reflux for 30 h, column chromatography (chloro-
form–hexanes, 15:1). Yield: 0.043 g (51%) of a pale yellow solid,
mp 335–339°, lit [17] mp 338–340°; ir (potassium bromide):
Methyl 1-(1H-Pyrazol-3-yl)-1H-1,2,3-triazole-4-carboxylate
(6q).
Prepared from 5q (0.100 g, 0.62 mmol), Procedure B, reflux
for 45 h, column chromatography (ethyl acetate). Yield: 0.040 g
(33%) of a pale yellow solid, mp 229–232°; ir (potassium bro-
mide): 3437, 3161, 2989, 2927, 1728 (C=O), 1262, 1209, 1045,
–1
1
3414, 3140, 2923, 1678 (C=O), 1624, 1582, 1360, 796 cm . H
nmr (dimethyl sulfoxide-d ): δ 5.68 (1H, d, J = 7.4 Hz, 6–H),
6
6.18 (1H, d, J = 2.0 Hz, 3–H), 7.86 (1H, d, J = 7.4 Hz, 5–H), 7.87
(1H, d, J = 2.0 Hz, 2–H), 12.38 (1H, br s, NH).
–1
1
775 cm . H nmr (dimethyl sulfoxide-d ): δ 3.88 (3H, s, OMe),
6
6.78 (1H, deg t, J = 2.3 Hz, 4’–H), 7.99 (1H, deg t, J = 2.3 Hz,
5’–H), 9.17 (1H, s, 5–H), 13.36 (1H, br s, NH). Ms (m/z): 193
(M ), 194 (MH ). Hrms Calcd. for C H N O : m/z =
[1,2,4]Triazolo[1,5–a]pyrimidin-7(1H)-one (7s).
Prepared from 5s (0.100 g, 0.61 mmol) and methanol,
Procedure A, reflux for 20 h, column chromatography (chloro-
form–hexanes, 15:1). Yield: 0.040 g (48%) of a pale yellow solid,
mp 300°, lit [18] mp 295–299°; ir (potassium bromide): 3446,
+
+
7
7
5
2
+
+
193.059979 (M ). Found: m/z = 193.060650 (M ).
Methyl 1-(5-Methyl-1H-pyrazol-3-yl)-1H-1,2,3-triazole-4-car-
boxylate (6r).
–1
1
3097, 1704 (C=O), 1595, 1475, 1314, 1169, 814, 749 cm . H
nmr (dimethyl sulfoxide-d ): δ 5.94 (1H, d, J = 7.5 Hz, 6–H),
6
Prepared from 5r (0.100 g, 0.57 mmol), Procedure B, reflux for
45 h, column chromatography (ethyl acetate). Yield: 0.016 g
(15%) of a pale yellow solid, mp 257–260°; ir (potassium bro-
7.99 (1H, d, J = 7.5 Hz, 5–H), 8.23 (1H, s, 2–H), 13.29 (1H, br s,
+
NH). Ms (m/z): 136 (M ).
–1 1
mide): 3214, 3150, 2948, 1724 (C=O), 1337, 1233, 1041 cm . H
Acknowledgements.
nmr (dimethyl sulfoxide-d ): δ 2.32 (3H, s, 5’–Me), 3.88 (3H, s,
6
Antimycobacterial data were provided by the Tuberculosis
Antimicrobial Acquisition and Coordinating Facility (TAACF)
through a research and development contract with the US
National Institute of Allergy and Infectious Diseases.
The financial support from the Ministry of Science and
Technology, Slovenia through grants P0-0502-0103, P1-0179,
and J1-6689-0103-04 is gratefully acknowledged.
OMe), 6.53 (1H, s, 4’–H), 9.10 (1H, s, 5–H), 13.03 (1H, br s, NH).
+
+
Ms (m/z): 207 (M ), 208 (MH ). Hrms Calcd. for C H N O : m/z
8
9 5 2
+
+
= 207.075625 (M ). Found: m/z = 207.076250 (M ).
Methyl 1-(1H-1,2,4-triazol-3-yl)-1H-1,2,3-triazole-4-carboxy-
late (6s).
Prepared from 5s (0.100 g, 0.61 mmol), Procedure B, reflux
for 35 h, column chromatography (ethyl acetate). Yield: 0.030 g
(26%) of a pale yellow solid, mp 234–236°; ir (potassium bro-
REFERENCES AND NOTES
–1 1
mide): 3273, 3125, 1718 (C=O), 1564, 1330, 1036 cm . H nmr
(dimethyl sulfoxide-d ): δ 3.89 (3H, s, OMe), 8.84 (1H, s, 5’–H),
[1] For an illustration and review see National Institute of
Allergy and Infectious Diseases (NIAID) web site:
http://www.niaid.nih.gov/factsheets/tb.htm.
[2] B. Stanovnik, J. Svete, Chem. Rev., 104, 2433 (2004).
[3] J. Svete, Monatsh. Chem., 135, 629 (2004).
[4] J. Svete, J. Heterocyclic Chem., 39, 437 (2002).
[5] B. Stanovnik, J. Svete, Targets in Heterocyclic Systems, 4, 105
(2000).
[6] B. Stanovnik, J. Svete, Synlett, 1077 (2000).
[7] B. Stanovnik, J. Heterocyclic Chem., 36, 1581 (1999).
[8] S. Pirc, D. Bevk, S. Golič Grdadolnik, J. Svete, ARKIVOC,
(xiv) 37 (2003).
[9] P. Čebašek, J. Wagger, D. Bevk, R. Jakše, J. Svete, B.
Stanovnik, J. Comb. Chem., 6, 356 (2004).
[10] J. Westman, R. Lundin, Synthesis, 1025 (2003).
[11] S. Rečnik, J. Svete, A. Meden, B. Stanovnik, Heterocycles,
53, 1793 (2000).
6
13
9.25 (1H, s, 5–H), 14.75 (1H, br s, NH). C nmr (deuteriochlo-
roform): δ 53.0, 129.0, 139.9, 146.5, 155.2, 161.1. Ms (m/z): 194
+
+
(M ), 195 (MH ). Hrms Calcd. for C H N O : m/z =
6
6
6
2
+
+
194.055224 (M ). Found: m/z = 194.056010 (M ).
Methyl 1-(4-Bromo-1H-pyrazol-3-yl)-1H-1,2,3-triazole-4-car-
boxylate (6t).
Prepared from 5t (0.100 g, 0.41 mmol), Procedure B, reflux
for 45 h, column chromatography (ethyl acetate). Yield: 0.018 g
(16%) of a pale yellow solid, mp 175–178°; ir (potassium bro-
mide): 3455, 3230, 3144, 2990, 2934, 1734 (C=O), 1634, 1210,
–1
1
776 cm . H nmr (deuteriochloroform): δ 4.03 (3H, s, OMe),
7.98 (1H, s, 5’–H), 8.86 (1H, s, 5–H), 12.10 (1H, br s, NH). Ms
+
+
(m/z): 271, 273 (M ), 272, 274 (MH ). Hrms Calcd. for
+
C H BrN O : m/z = 270.970486 (M ). Found: m/z = 270.971240
7
6
5 2
[12] S. Rečnik, J. Svete, B. Stanovnik, Eur. J. Org. Chem., 3705
(2001).
+
(M ).
[13] T. Kočar, S. Rečnik, J. Svete, B. Stanovnik, ARKIVOC, (viii),
143 (2002).
[14] S. Rečnik, J. Svete, B. Stanovnik, Heterocycles, 57, 2091
(2002).
Methyl 1-(4-Bromo-5-methyl-1H-pyrazol-3-yl)-1H-1,2,3-tria-
zole-4-carboxylate (6u).
Prepared from 5u (0.100 g, 0.39 mmol), Procedure B, reflux
[15] S. Rečnik, J. Svete, A. Meden, B. Stanovnik, Z. Naturforsch,
for 45 h, column chromatography (ethyl acetate). Yield: 0.011 g

Sep-Oct 2005
Synthesis and Antimycobacterial Activity
1173
53b, 380 (2004).
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41, 1004 (1997).
[16] R. Toplak, J. Svete, S. Golič Grdadolnik, B. Stanovnik, Coll.
Czech. Chem. Commun., 64, 177 (1999).
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3252 (1970).
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Heterocyclic Chem., 36, 225 (1999).