Synthesis, structure and properties of N-acetylated derivatives of methyl 5-amino-1H-[1,2,4]triazole-3-carboxylate

Article abstract of DOI:10.1248/cpb.52.192

Methyl 5-amino-1H-[1,2,4]triazole-3-carboxylate hydrochloride (1) and free ester (2) were obtained and 2 was reacted with Ac₂O to give the acetylated products 3-6. Compounds 1-6 were studied using HPLC, GCMS, FTIR and multinuclear NMR spectroscopy, including the cross-polarisation magic angle spinning (CPMAS) technique. The results of the acetylation of 2 were compared to those of the acetylation of 5-amino-1H-[1,2,4]triazole, and for 2 a significant decrease in the susceptibility to acetylation was found. The reaction of 2 with Ac₂O at 20°C, regardless of the amount and the concentration of the latter, including neat Ac₂O, proceeds fully regioselectively and leads to one product: methyl 1-acetyl-5-amino-1H-[1,2,4]triazole-3-carboxylate (3). In sharp contrast to 5-amino-1H-[1,2,4]triazole, neither an additional monoacetylated isomer, whether annular or exocyclic, nor any diacetylated derivative could be detected. The diacetylation of 2 requires the process to be carried out in neat boiling Ac₂O and, as in the case of 5-amino-1H-[1,2,4]triazole, gives two diacetylated isomers. These are methyl 1-acetyl-3-(acetylamino)-1H-[1,2,4]triazole-5-carboxylate (4) and 1-acetyl-5-(acetylamino)-1H-[1,2,4]triazole-3-carboxylate (5). Hypothetical pathways of their formation have been suggested. A mixture of 4 and 5 upon hydrolysis of the ring acetyl group gives the monoacetylated derivative methyl 5-(acetylamino)-1H-[1,2,4]triazole-3-carboxylate (6). The spectroscopic, structural and conformational characteristics of compounds 1-6 have been given and methods for their preparation have been provided.

Full text of DOI:10.1248/cpb.52.192

1
92
Chem. Pharm. Bull. 52(2) 192—198 (2004)
Vol. 52, No. 2
Synthesis, Structure and Properties of N-Acetylated Derivatives of Methyl
-Amino-1H-[1,2,4]triazole-3-carboxylate
5
·
a
,a
·
a
b
Anetta DZYGIEL, Barbara RZESZOTARSKA,* Elzbieta MASIUKIEWICZ, Piotr CMOCH, and
Bohdan KAMIE N´ SKIb
a
b
Institute of Chemistry, University of Opole; Oleska 48, 45–052 Opole, Poland: and Institute of Organic Chemistry,
Polish Academy of Sciences; Kasprzaka 44/52, 01-224 Warsaw, Poland.
Received August 4, 2003; accepted November 1, 2003
Methyl 5-amino-1H-[1,2,4]triazole-3-carboxylate hydrochloride (1) and free ester (2) were obtained and 2
was reacted with Ac O to give the acetylated products 3—6. Compounds 1—6 were studied using HPLC, GC-
2
MS, FTIR and multinuclear NMR spectroscopy, including the cross-polarisation magic angle spinning (CPMAS)
technique. The results of the acetylation of 2 were compared to those of the acetylation of 5-amino-1H-[1,2,4]tri-
azole, and for 2 a significant decrease in the susceptibility to acetylation was found. The reaction of 2 with Ac O
2
at 20 °C, regardless of the amount and the concentration of the latter, including neat Ac O, proceeds fully regio-
2
selectively and leads to one product: methyl 1-acetyl-5-amino-1H-[1,2,4]triazole-3-carboxylate (3). In sharp con-
trast to 5-amino-1H-[1,2,4]triazole, neither an additional monoacetylated isomer, whether annular or exocyclic,
nor any diacetylated derivative could be detected. The diacetylation of 2 requires the process to be carried out in
neat boiling Ac O and, as in the case of 5-amino-1H-[1,2,4]triazole, gives two diacetylated isomers. These are
2
methyl 1-acetyl-3-(acetylamino)-1H-[1,2,4]triazole-5-carboxylate (4) and 1-acetyl-5-(acetylamino)-1H-[1,2,4]tria-
zole-3-carboxylate (5). Hypothetical pathways of their formation have been suggested. A mixture of 4 and 5 upon
hydrolysis of the ring acetyl group gives the monoacetylated derivative methyl 5-(acetylamino)-1H-[1,2,4]tria-
zole-3-carboxylate (6). The spectroscopic, structural and conformational characteristics of compounds 1—6 have
been given and methods for their preparation have been provided.
1
13
15
Key words acylation; hetareneamino acid; intramolecular hydrogen bonding; FTIR spectrum; H, C, N spectrum; cross-po-
larisation magic angle spinning (CPMAS) spectrum
Azoleamino acids have the potential to form hetarene
oligoamides, which belong to the most promising small mol-
1
—3)
ecules controlling gene expression
and, moreover, to be
4
)
5)
6,7)
the constituents of natural, modified and artificial pep-
tides useful for biological and non-biological purposes. Fur-
thermore, they can serve as external, molecular scaffolds for
8
—11)
the stabilisation of secondary peptide structures.
Their
usefulness results from the flat, rigid ring system capable of
acting as both a hydrogen bond acceptor and/or donor. It
seems that the readily accessible C-amino-[1,2,4]triazole-car-
1
2)
boxylic acid could also be applied to the above ends. How-
ever, its chemistry, including the structural and spectral prop-
1
2)
erties of its derivatives, of which only the methyl ester 2
1
3)
and its 1-acetyl congener 3 are mentioned in the literature,
is little recognised.
The exocyclic amino group of azoleamino acids offers a
significant resistance to acylation and makes the synthesis
1
4)
of the carboxamides difficult. The ability of C-amino-
1,2,4]triazole-carboxylic acid to undergo acylation is unex-
[
plored. In this paper, we present the studies on the acetyla-
tion of methyl 5-amino-1H-[1,2,4]triazole-3-carboxylate (2)
with neat Ac O. The ester 2 is the simplest protected form of
2
C-amino-[1,2,4]triazole-carboxylic acid allows one to avoid
undesired side reactions at its free carboxyl group. As tools
for structure determination we used various analytical meth-
ods: HPLC, GC-MS, FTIR, and multinuclear NMR spec-
troscopy, including the cross-polarisation magic angle spin-
ning (CPMAS) technique. The results were compared to
those from the acetylation of the parent substance of the in-
1
5)
vestigated acid, i.e. 5-amino-1H-[1,2,4]triazole (AT). The
structures of compounds 1—6 obtained in this work are Preparative and NMR Connectivity
given in Chart 1.
Chart 1. Structure of the Obtained Compounds 1—6 together with Their
···: Intramolecular hydrogen bonds.
∗
To whom correspondence should be addressed. e-mail: rzeszot@uni.opole.pl
© 2004 Pharmaceutical Society of Japan

February 2004
193
1
15
Results and Discussion
The multinuclear NMR, the H– N gradient heteronuclear
single quantum coherence (g-HSQC), the gradient heteronu-
Methyl 5-Amino-1H-[1,2,4]triazole-3-carboxylate Hy-
drochloride (1) and Free Ester (2) Ester 2 was obtained
in 42% yield by direct esterification of the corresponding
acid in the presence of gaseous HCl, and subsequent neutrali-
clear multiple bond connectivity (g-HMBC) in DMF-d and
7
the CPMAS experiment (Tables 2, 3; Chart 1) reveal that in
both solutions and the solid state, 2 has the structure of
methyl 5-amino-1H-[1,2,4]triazole-3-carboxylate and its hy-
drochloride 1 has an 1H,4H -triazolium cation. The cations
of this tautomeric type are commonly found in the crystals
of 5-amino-1H-[1,2,4]triazolium salts.
spectrum of 2 contains the broad multiplet band in the region
of the bonded NH and the broad CϭO band centred at
1
2)
sation. We applied the SOCl –MeOH method, highly rec-
2
1
6)
ϩ
ommended for efficient esterification in peptide chemistry
and used the advised threefold excess of SOCl , which pro-
duced the hydrochloride 1 in an 87% isolated yield. The
crude 1 was neutralised to furnish 77% of free ester 2 based
on the initial acid (Table 1).
2
1
7—21)
The CCl FTIR
4
Table 1. Methyl 5-Amino-1H-[1,2,4]triazole-3-carboxylates 1 and 2 and Acetylated Derivatives 3—6
Elemental analysis
Calcd. (Found) (%)
Molecular
a)
b)
mp
(
TLC Rf
HPLC
Yield
(%)
formula
mass)
Compd.
°C)
(
A
B
C
D
tR (min) Purity (%)
C
H
N
1
2
180
233
214
0.78
0.78
0.72
0.82
0.82
0.72
0.44
0.44
0.62
0.18
0.18
0.57
0.59
0.59
0.63
2.47
2.47
8.22
9.27
7.83
4.13
99.6
100.0
99.7
95.5
99.3
99.5
C H N O ·HCl
26.90
(26.91)
33.80
(34.10)
39.14
(39.10)
42.48
(42.67)
41.65
3.95
(3.83)
4.26
(4.11)
4.38
(4.43)
4.46
(4.58)
4.59
31.35
(31.29)
39.42
(39.28)
30.41
(30.28)
24.77
(24.77)
24.28
87.2
4
6
4
2
2
3
(
178.58)
c)
d,e)
C H N O
76.8
100.0
58.4
4
6
4
(
142.13)
f)
3
4
5
6
a
C H N O
6
8
4
g)
2
26
(184.15)
C H N O
4
247
159
229
0.42
0.42
0.17
8
10
4
(
226.19)
a
a
0.54
0.80
C H N O ·0.25H O
60.0
8
10
4
4
2
(
230.69)
C H N O
3
(41.84)
39.14
(4.38)
4.38
(24.19)
30.41
98.0
6
8
4
(
184.15)
(39.11)
(4.56)
(30.18)
Ϫ1
a) Recorded on a DSC-2010 calorimeter (Thermal Analysis Instruments) under nitrogen in a closed copper vessel with a heating rate of 10 °C·min
.
b) TLC aluminum
sheets covered with silica gel 60 (Merck 105553); A, n-BuOH–AcOH–AcOEt–H O (1 : 1 : 1 : 1 v/v/v/v); B, CHCl –MeOH–dioxane–NH OH concd. (12 : 7 : 5 : 1 v/v/v/v);
2
3
4
12)
12)
C, CHCl –MeOH–AcOH (95 : 5 : 3 v/v/v); D, AcOEt. Visualised with ninhydrin and Cl -tolidine reagent. c) mp 220 °C.
d) Based on the initial acid. e) Yield 41.5%.
3
2
1
3)
f ) mp 216 °C.
g) Mp upon crystallization from methanol–diethyl ether.
1
13
1
Table 2. Chemical Shifts (ppm) of H, C and the Half-Height Width of H-NMR Signals (Hz) for Methyl 5-Amino-1H-[1,2,4]triazole-3-carboxylates 1
and 2 and Acetylated Derivatives 3—6
NH
amide
NH
ring
H C–O–CO
H C–CO–N
H C–CO–N
3
3
3
Compd.
NH2
C-3
C-5
ester
amide
ring
a)
1
10.70
7.15
10.70
4.11
3.80
3.80
3.96
3.90
53.2
55.0
52.0
157.8
158.5
161.6
143.7
141.1
152.4
154.6
151.5
158.7
CPMAS
b)
2
13.40
[5.50]
12.90
[
8.20]
6.45
7.62
8.63
a)
2
51.9
53.3
52.8
161.7
161.5
160.9
152.9
150.5
152.6
158.7
156.9
158.2
CPMAS
b)
3
a
2.56
2.62
23.1
23.1
172.5
172.6
[
[
16.8]
7.70
12.7]
a)
3
a
52.6
161.0
153.2
158.5
CPMAS
4
53.4
53.0
160.7
162.0
21.2
23.6
172.9
172.0
152.8
152.5
157.9
151.3
a)
c)
d)
d)
10.40
3.96
2.37
24.2
21.9
169.2
169.2
2.73
[
12.3]
e)
c)
CPMAS
55.2
158.8
25.5
172.8
173.5
172.7
150.9
152.5
5
6.6
160.1
23.9
172.1
26.9
b)
f)
f)
f)
f)
f)
f)
5
a
16.70
50.7]
15.90
3.98
4.16
53.5
2.46
2.44
2.46
2.44
[
a)
f)
5
a
53.2
158.4
25.7
25.7
172.4
171.4
149.4
156.6
[
268.0]
g)
g)
g)
g)
CPMAS
54.2
52.5
158.2
161.2
26.3
172.8
170.3
22.9
149.5
151.8
156.4
150.6
b)
6
a
12.15
14.58
[7.2]
14.12
3.90
3.90
2.24
2.24
23.0
22.9
24.0
[
5.4]
a)
6
a
11.70
52.2
53.0
161.2
160.9
170.2
171.0
152.1
150.2
150.8
150.2
[
68.0] [91.6]
CPMAS
a) Measured at 30 °C. b) Measured at Ϫ50 °C. c) The C atom connected with the COOMe group. d) The C atom connected with the NH group. e) Doubled signals
13
probably owing to two solid state forms. f ) Not recorded in a C-NMR spectrum. g) The signals could be reversed in the corresponding pairs.

1
94
Vol. 52, No. 2
1
5
Table 3. Chemical Shifts (ppm) of N-NMR for Methyl 5-Amino-1H-
1,2,4]triazole-3-carboxylates 1 and 2 and Acetylated Derivatives 3—6
[
Compound
NH2
NHamide
N-1
N-2
N-4
a)
1
Ϫ321.5
Ϫ311.0
Ϫ333.0
Ϫ333.0
Ϫ334.3
Ϫ313.5
Ϫ314.3
Ϫ309.8
Ϫ198.4
Ϫ208.2
Ϫ200.0
Ϫ198.1
Ϫ94.1
Ϫ98.3
Ϫ93.6
Ϫ91.0
Ϫ222.6
Ϫ230.1
Ϫ169.0
Ϫ164.3
CPMAS
b)
c)
d)
c)
d)
c)
d)
c)
d)
2
a)
2
CPMAS
Ϫ189.8
Ϫ99.3
Ϫ173.9
b)
e)
e)
e)
3
3
a
a
a)
Ϫ164.3
Ϫ165.4
Ϫ88.0
Ϫ93.4
Ϫ97.3
Ϫ105.2
Ϫ155.0
Ϫ158.7
Ϫ167.8
Ϫ174.5
Ϫ145.8
Ϫ153.6
Ϫ156.2
Ϫ123.6
CPMAS
a)
d)
d,g)
f)
d,g)
g)
4
Ϫ254.0
Ϫ253.9
Ϫ252.8
Ϫ204.6
Ϫ205.5
Ϫ253.9
Ϫ253.3
Ϫ250.7
h)
CPMAS
f)
g)
Ϫ92.1
Ϫ161.3
a)
i)
i)
5
a
CPMAS
Ϫ166.3
Ϫ89.4
Ϫ134.8
b)
e)
6a
a
Ϫ186.9
Ϫ86.9
a)
e)
e)
6
Ϫ152.9
Ϫ163.0
CPMAS
Ϫ189.3
Ϫ93.7
Fig. 1. Reactivity of AT with Neat Ac O and Products Obtained (in
Bold)
2
15)
1
15
a) Measured at 30 °C. b) Measured at Ϫ50 °C. c) Measured using H– N NMR
15
g-HMBC or g-HSQC correlation experiments. d) Measured using N-NMR invgate
sequence. e) Lack of correlation signals in the N-NMR g-HMBC experiment.
15
Ϫ1
1
734 cm , thus proving some degree of association. The lat- f ) The –Nϭatom. g) The N atom substituted with the MeCO group. h) Doubled
15
signals probably owing to two solid state forms. i) Not recorded in the N-NMR
ter band has a high-frequency inflexion and was decomposed
into two curve-fitted components to obtain the stretching fre-
spectrum obtained using invgate sequence.
Ϫ1
quency for the carbonyl free CϭOester-f, 1744 cm , and
Ϫ1
bonded CϭOester-b, 1730 cm (Table 4).
FTIR spectrum in KBr (Tables 2, 4) correspond to those of
Methyl 1-Acetyl-5-amino-1H-[1,2,4]triazole-3-carboxy- the methyl 1-acetyl-5-amino-1H-[1,2,4]triazole-3-carboxy-
1
5)
late (3) We have previously found the acetylation of AT late that was obtained via univocal linear substrate cyclisa-
1
3)
15
in DMF or DMSO solutions with 1 eq Ac O at 20 °C to be tion. The analysis of N-NMR data in DMF-d , based on 2
2
7
almost instantaneous. Firstly the kinetic product 1-acetyl-3- and the effect of the N-acetylation in the pyrrole mole-
2
2,23)
amino-1H-[1,2,4]triazole was formed (Fig. 1A), which we cule,
could not isolate. This quickly was transformed into the ther- acetyl group (Table 3, Chart 1). The X-ray crystal analysis
indicates that it is the N-1 atom which bears the
2
4)
modynamic compound 1-acetyl-5-amino-1H-[1,2,4]triazole. confirms 3 to be the 1-acetyl-5-amino isomer and reveals that
The latter is also unstable at room temperature and easily iso- its NH group is hydrogen-bonded intermolecularly with the
2
merises into the 5-acetylamino derivative, both in solutions CϭOester and intramolecularly with the CϭON-ring. So, in the
and in the solid state.
solid state the compound has the conformation 3a. This en-
Ϫ1
The monoacetylation of ester 2 is slower than that of AT. ables us to consider the band at 1736 cm in its FTIR spec-
Under the same conditions, AT reacts with 1 eq Ac O in trum in KBr as the coincidental singlet originating from two
2
7
4%, whereas 2 reacts merely in 15% (dilute DMSO solu- indistinguishable frequencies, viz., of the CϭOester-b and the
tion, 20 °C, 2 min). In sharp contrast to AT, the reaction of 2 CϭON-ring-b (Table 4).
with acetic anhydride at 20 °C, whatever amount and concen-
The solution FTIR spectra point to compound 3 as being
tration of the latter, including neat Ac O, proceeds fully re- in form 3a, i.e. monomer with the intramolecular hydrogen
2
gioselectively and only results in compound 3. Neither an ad- bond. The stretching frequencies of its amino group, 3516
Ϫ1
Ϫ1
ditional monoacetylated isomer, whether annular or exo- and 3394 cm in CCl and 3504 and 3388 cm in CH Cl ,
4
2
2
cyclic, nor any diacetylated derivative could be detected. correspond to those of the methyl anthranilate amino group,
Ϫ1
25)
Hence, preparing the compound 3 in quantitative yield is fea- 3509 and 3380 cm , measured in the latter solvent. The
sible when neat anhydride is used as a medium. Compound anthranilate is a well-known molecule with the bonded
3
, unlike monoacetylated amino-1H-[1,2,4]triazoles, is stable H N···CϭO
intramolecularly. The broad carbonyl band
2
ring
Ϫ1
with a long shelf-life. After one year of storage at room tem- centred at 1737 cm , found in the CCl solution of 3a,
4
perature, we observed neither the formation of the 5-acetyl- shows a high-frequency inflexion. The curve fitting proce-
amino isomer 6 nor any other change. In a saturated DMF or dure results in two components, one of the CϭO
Py solution up to 70 °C, the acetyl transfer is rather slow but 1751 cm and the other of the CϭON-ring-b at 1736 cm . In
at
ester-f
Ϫ1
Ϫ1
it is much quicker at higher temperatures. For example, after the CH Cl solution, these bands are clearly separated and
2
2
Ϫ1
heating 3 at 120 °C for 15 min, it reaches several percentages. the stretching frequency of the CϭOester-f is several cm red-
Deacetylation accompanies this isomerisation unless a spe- shifted. However, the CϭON-ring-b frequency remains the
cial moisture proofing is applied. In general, the higher the same in each of these solvents as well as in DMSO, indicat-
2
6,27)
temperature the larger amount of 2 produced. Upon quick ing the inaccessibility of this carbonyl to solvents.
The
heating of 3 to the melting point (214 °C), 61% of 6 is resonance of the NH protons of 3a at Ϫ50 °C appears as two
2
formed, but longer heating causes some significant decompo- clearly separated singlets down field shifted as compared to
sition. So, the thermal rearrangement of 3 would not be the the corresponding signals of 2 (Table 2). At 30 °C, both pro-
best way to prepare the compound 6.
tons give only one signal, however also down field shifted.
The H- and C-NMR spectra of 3 in DMSO-d and the The NH nitrogen signal is at about Ϫ314 ppm, i.e. down
1
13
6
2

February 2004
195
Ϫ1
Table 4. Selected Frequencies (cm ) of 5-Amino-1H-[1,2,4]triazole (AT), 5-Amino-3-carbomethoxy-1H-[1,2,4]triazole (2) and Acetylated Derivatives
3
—6
NH
ring
free
NH
ring
bonded
NH
amide
free
NH
amide
bonded
CϭO
ester
free
CϭO
ester
bonded
CϭO
N-ring
free
CϭO
N-ring
bonded
CϭO
amide
free
CϭO
amide
bonded
Compd. Medium nasNH2 nsNH2
dsNH2
a)
b)
AT
2
CH Cl
KBr
CCl4
3486
3396
3453
3163
1625
2
2
d)
c)
3425
3346
3225
1653
1722
1730
e)
e)
f)
e)
a)
a)
1744
1730
g)
g)
g)
DMSO
3201
h)
i)
i)
3
4
5
6
a
KBr
(3434, 3275, 3219, 3143)
3394
1635
1628
1630
1641
1736
1736
a)
CCl4
3516
1751
1744
1735
1736
1736
1735
1746
1746
1743
CH Cl2
3504
3388
2
g)
g)
DMSO
KBr
CCl4
3319, 3265 1738
1714
1724
1716
1710
1716
1735
3330
1754
1743
1743
CH Cl2
3337
2
g)
DMSO
KBr
CCl4
1771
1767
a
a
(3449, 3416, 3126) 1737
1737
1735
1735
1729
a)
3419
1743
1735
1729
1705
a)
a)
a)
CH Cl2
3422
3396
1723
1714
2
g)
a)
a)
DMSO
KBr
CCl4
1751
3208
3397
3208
1733
1737
1703
1707
1707
1700
a)
3434 3305—3221 1751
a)
a)
CH Cl2
3392
3409
1742
1735
2
g)
g)
DMSO
Ϫ1
a) The position of the band obtained by a curve-fitting procedure. b) The NHring-f vibration of [1,2,4]triazole in CCl is at 3464 cm
.
c) For AT in KBr nϭ3416, 3351,
4
Ϫ1 17)
3
216, 1660 cm
.
d) Insoluble in CH Cl . e) Not detectable owing to poor solubility. f ) A broad multiplet band. g) Not given owing to the presence of the bands of
2
2
Ϫ1 13)
24)
DMSO and water. h) 3425, 3280, 3220, 3145, 1730, 1635 cm
.
i) The assignment of the CϭO frequencies for the free and bonded group, based on the X-ray structure.
Fig. 2. Incipient Time Courses of the Reaction of 2, 3 and 6 as Starting Substrates with Neat Boiling Ac O
2
᭹: Compound 3, ᭿: compound 4, ᭡: compound 5, ᭜: compound 6.
field shifted by ca. 20 ppm in relation to 3 (Table 3), is invari- does not react, 6 under the same conditions relatively quickly
able with temperature change and in the CPMAS spectrum yields a significant amount of the diacetylated derivative 4
also appears at Ϫ309.8 ppm.
and a small amount of its isomer 5 (data not included). The
Methyl 1-Acetyl-3-(acetylamino)-1H-[1,2,4]triazole-5- diacetylation of 2 and the second acetylation of the mono-
carboxylate (4) and Methyl 1-Acetyl-5-(acetylamino)-1H- acetylated 3 require the process to be carried out at boiling
[
1,2,4]triazole-3-carboxylate (5) AT with neat Ac O at point and Fig. 2 presents the incipient time courses of such
2
room temperature after a few days yields quantitatively the reactions with 2, 3 and also with 6. Expectedly, the first prod-
diacetylated derivative 1-acetyl-3-(acetylamino)-1H-[1,2,4]- uct of acetylation of 2 is the compound 3. This is converted
triazole. In parallel to monoacetylation, firstly the kinetic primarily into the diacetylated derivative 4. Moreover, 5 and
product 1-acetyl-5-(acetylamino)-1H-[1,2,4]triazole appears, 6 appear in a small amount. Later, the amount of 4 decreases,
which was unable to be isolated, as during the reaction it con- that of 5 increases while that of 6 remains constant. As we
verts completely into the final isomer (Fig. 2B). AT in boil- started with 3, this disappears quickly and the remaining pic-
ing anhydride also forms in addition to the diacetylated com- ture is similar to the above described, but the summary
pound a triacetylated species, 1-acetyl-3(5)-(diacetylamino)- amount of two products 4 and 5 upon 5 min reaction is larger.
1
5)
1
H-[1,2,4]triazole (Fig. 2C).
Compound 6 as a substrate rapidly vanishes to a constant
The exoamino group of 2 does not react with neat Ac O at level. The summary amount of the two products upon 5 min
2
2
0 °C at all. It took 10 d for the diacetylated compound 4 to reaction is the largest and the further picture is similar to the
appear and then it was only a minute quantity. The long-last- two previous. The equilibrium between 4 (27%), 5 (65%) and
ing acetylation of the separate monoacetylated derivative 3 6 (7%) is reached upon the reflux of 2 in neat Ac O within
2
and 6 at room temperature shows that whereas 3 practically 6 h, and no triacetylation was observed. The isomerisation

1
96
Vol. 52, No. 2
form an intramolecular hydrogen bond and the chemical shift
of its NHCOCH3 proton amounts to 10.40 ppm against
1
5.90 ppm in molecule 5 with such a hydrogen bond. All sig-
nals in the CPMAS spectra of 4 are very similar to those in
the solution spectra. However, they occur as doublets show-
ing two independent molecules with different spatial arrange-
ments. The cause may be overcrowding with two sterically
demanding vicinal substituents, the carbomethoxy and
acetyl, as was observed in the crystal of a related [1,2,4]tria-
2
4)
zole derivative. In sum, this proves that we are dealing
Chart 2. Hypothetical Pathways of the Acetylation of 2 with Neat Boiling with methyl 1-acetyl-3-(acetylamino)-1H-[1,2,4]triazole-5-
Ac O
carboxylate. In the stable compound 5, the CPMAS spectrum
2
indicates the N-2 atom has the pyridine character and that it
4
6
→5 should be therefore considered a process mediated by is the N-1 atom, which bears the acetyl group. So, we are
, but not an intramolecular rearrangement. All together sug- dealing with methyl 1-acetyl-5-(acetylamino)-1H-[1,2,4]tria-
gests the pathways of the acetylation of 2 with boiling Ac O, zole-3-carboxylate. The difference, ca. 80 ppm, in nitrogen
2
shown in Chart 2. The firstly-formed monoacetylated 3 un- shift between the NH group in compound 2 (Ϫ333.0 ppm)
2
dergoes transacetylation to the isomeric 6 that in turn is and the NHCOCH group in 4 or 6 (ca. Ϫ254.0 ppm) gives a
3
acetylated to the kinetic diacetylated product 4 and this is deshielding effect of the acetyl group. For compound 5, this
converted into the thermodynamic product 5. However, the deshielding effect amounts to as much as ca. 130 ppm. The
hypothetical methyl 1-acetyl-3-amino-1H-[1,2,4]triazole-5- mentioned NHCOCH proton at 15.90 ppm, is also strongly
3
carboxylate cannot be completely ruled out as an intermedi- deshielded, and moreover the signal is broad even at low tem-
ate between 3 and 4.
perature. Collectively this documents the structure of 5a with
The isomer 5 is stable with a long shelf life. After half a the intramolecular hydrogen bond. The CPMAS spectra are
year of storage at 20 °C, we observed no change in its chro- very similar to those in solution, so the bond occurs in the
matographic purity. The isomer 4, after half a year of storage solid state, too.
in a refrigerator, was converted into 6 in about 30%, but
compound 5 was not detected. However, after storage at tion of the NH group lies at 3330/3337 cm and that of the
room temperature for the same time, 4 disappears completely CϭON-ring group at 1746/1743 cm depending on the solvent
In the spectra of 4 in both chlorinated solvents, the vibra-
Ϫ1
Ϫ1
and the residue contains 6 and 5 (ca. 80 : 20). Considering (Table 4). The spectra do not change with the dilution of so-
the stability of 5, the hydrolysis and transacetylation of 4 has lutions even to the limit of detection, which means that com-
to proceed simultaneously. In neutral water at ambient tem- pound 4 probably forms the cyclic dimer linked by these
perature, 4 totally hydrolyses into 6 after 10 min. In contrast, groups. In DMSO solution, the CϭO
becomes free and
N-ring
Ϫ1
compound 5 is more resistant and its hydrolysis into 6 re- appears at 1771 cm . Compound 5 populates chlorinated
quires 24 h before it is completed. It is interesting to note, solvents most largely as a monomer with the intramolecular
that no difference in the susceptibility to hydrolysis of both hydrogen bond, i.e. 5a, as was seen from the NMR data. The
Ϫ1
isomeric diacetylated amino-[1,2,4]triazoles has been NHamide-b frequency is found at 3419/3396 cm depending
1
5)
found.
on the solvent. The corresponding CϭO
vibration oc-
N-ring-b
Ϫ1
The study brings the following suggestions for preparing 4 curs at 1735 cm and is invariable by the solvent change.
and 5. Because isomer 4 is the kinetic product of the acetyla- This band is massive and overwhelming in intensity in both
tion of 6 (Chart 2), its highest yield can be reached through solvents. In CCl , it coincides with the CϭOamide-f band and
4
the reaction of 6 with Ac O under mild conditions. The short in CH Cl with the CϭO
band. There are also other
2
2
2
ester-f
warming to 45—50 °C of the suspension of this substrate in chemical entities. In CCl , some association is documented
4
Ϫ1
Ac O only for dissolving proved to be enough to obtain a by the CϭOamide-b vibration at 1705 cm and in CH Cl we
2
2
2
mixture with 82% of isomer 4. This still contains 16% of have found some population of the molecules 5 with no in-
compound 6, but only 2% of isomer 5. One crystallisation tramolecular hydrogen bond. This population shows the
Ϫ1
from ethyl acetate removes the latter completely and the for- curve-fitted NHamide-f absorption at 3422 cm and the re-
Ϫ1
mer partially, leaving 58% of 4 of 96% purity. Because iso- spective CϭON-ring-f absorption at 1767 cm . The DMSO
Ϫ1
mer 5 is the thermodynamic product of the acetylation of 6, spectrum contains the very broad, strong band at 1729 cm ,
its formation demands heating, and 2 can be used as the which originates primarily from the coincidental CϭOester-f
starting material to give the mentioned above equilibrium and CϭON-ring-b vibrations. The band has a high-frequency
mixture of 5, 4 and 6 (65 : 27 : 7). Physicochemical properties inflexion from the component CϭO
of the closely related isomers 4 and 5 are similar in the ma- 1751 cm and is derived from the fraction of molecules 5
band positioned at
N-ring-f
Ϫ1
jority. However, due to their different susceptibilities to hy- with no intramolecular hydrogen bond. At the low-frequency
Ϫ1
drolysis, compound 4 can be hydrolysed into 6, without the edge of this combined band (1729 cm ), there is the com-
Ϫ1
loss of 5 and then the separation of 5 from 6 succeeds simply ponent at 1714 cm
ascribable to the vibration of the
2
8)
by silica gel column chromatography.
CϭOamide-f
.
The NMR data (Tables 2, 3) gives the unequivocal struc-
Methyl 5-(Acetylamino)-1H-[1,2,4]triazole-3-carboxy-
tures of compound 4 and 5. The N-2 nucleus of 4 is the most late (6) The most convenient way for preparing 5-(acetyl-
shielded out of the ring nitrogen nuclei in this compound. amino)-1H-[1,2,4]triazole relies on the exhaustive diacetyla-
This proves its pyrrole character. The molecule of 4 cannot tion of AT followed by hydrolysis of the labile acetyl

February 2004
197
1
5)
groups (Figs. 1C, D). The same concerns the preparation hydrolysis of a ring acetyl group. Compounds 3, 5 and 6 are
of 6 that can simply be obtained via diacetylation of 2. The intramolecularly hydrogen-bonded (3a, 5a, 6a) both in solu-
process of acetylation and hydrolysis is quantitative and its tions and in the solid state, which was documented by FTIR,
final product needs no purification.
multinuclear NMR and CPMAS spectroscopy. The hydrogen
Deshielding the exocyclic nitrogen nucleus of 6, ca. bond is a stabilising factor and these compounds have a long
0 ppm, compared to the respective nucleus of 2, points to shelf life, whereas the AT counterpart of 3 is very unstable
8
the NH group as bearing the acetyl group. The chemical and that of 5 has so far been unable to be isolated.
2
shift of the N-1 nucleus proves its pyrrole type. The ring NH
proton, at 14.12 ppm and the N-1 nucleus, at Ϫ186.9 ppm are Experimental
C-Amino-[1,2,4]triazole-carboxylic acid hemihydrate of 98% purity
deshielded in relation to the respective 12.90 and Ϫ200.0
ppm in the spectra of 2 and argue for structure 6a with the
intramolecular hydrogen bond. The CPMAS data indicate the
(
Aldrich # 28,207,3) was used without further purification. A good many
1
3
broad, unsymmetrical signals in CPMAS spectra ( C-CPMAS d: 146.6,
15
1
51.4, 158.7, 160.0 ppm and N-CPMAS d: Ϫ113.5, Ϫ122.2, Ϫ206.5,
same molecular structure 6a in the solid state (Tables 2, 3). Ϫ211.6, Ϫ216.9, Ϫ220.7, Ϫ238.9, Ϫ313.7, Ϫ318.3 ppm) does not allow an
No FTIR spectra of 6 (Table 4) reveal a frequency near 3464 univocal structure to be ascribed to this compound. Volatiles from reaction
Ϫ1
mixtures and fractions after column chromatography separation were re-
moved in vacuum on a rotary evaporator, and unless otherwise indicated, at a
bath temperature not exceeding 40 °C. Details about mps’ determination and
TLC are given in Table 1.
or 3453 cm (the NHring-f group of triazole or AT, respec-
tively). The NHring and CϭOamide are observed only as hydro-
gen-bonded. In CCl , a population of the molecules exist
4
Ϫ1
with the NHamide-f vibration at 3434 cm and the CϭOester-f
Analytical Chromatography The purity of final products (Table 1) was
checked and the results of acetylation experiments (Fig. 3) were followed
using a Beckman chromatographic system. The separations were performed
on an Alltech Alltima, C-18 RP, 5 mm, 150ϫ4.6 mm column. The mobile
phase was 0.1% aqueous trifluoroacetic acid–acetonitrile (90 : 10 v/v) at a
Ϫ1
vibration at 1751 cm . The latter band is localised upon de-
composition of the strong, asymmetric CϭO
the maximum at 1737 cm and with a high-frequency in-
band with
ester-b
Ϫ1
flexion, into two curve-fitted components, at 1737 and
Ϫ1
flow rate of 1 ml min . Detection was made at 210 nm.
Ϫ1
1
751 cm . The intramolecular hydrogen bond in the above
The GC-MS analyses were performed on an HP 6890 gas chromatograph
with an HP-5 column and an MS 5973 (EI) mass spectrometer as detector.
chemical species may be identified by the frequency of the
1
13
Ϫ1
Ϫ1
Multinuclear NMR Spectra The H- and C-NMR spectra in DMSO-
d were recorded on a Bruker Avance DRX 300 with TMS as internal stan-
NHring-b at 3397 cm and the CϭOamide-b at 1707 cm . In
Ϫ1
6
addition, the multiplet NH-band at 3305—3221 cm proves
1
13
15
dard. The H-, C- and N-NMR spectra in DMF-d7 solution were per-
numerous associates. The main entity represented by band formed on a Bruker Avance DRX 500 spectrometer. A Bruker TBI 500SB
Ϫ1
3
305 cm may be a cyclic dimer similar to the cyclic dimer H-C/BB-D-05ZG probehead, which is 5 mm, inverse, variable temperature,
13 15
and PFG were used for the liquid-phase experiments. The C- and N-
NMR spectra were recorded using power-gated decoupling and inverse-
gated decoupling sequence, respectively.
of 4. Fortunately, no visible association of 6 happens in
CH Cl solution. The spectra in the sample regions exhibit
2
2
only three well-shaped bands, at 3400 (broad, combined),
1
13
The H– C g-HMBC spectra were obtained with an acquisition time of
Ϫ1
1
742 (the CϭOester-f) and 1707 (the CϭOamide-b) cm . This 0.2 s, spectral windows of 9000 Hz (F2) and 22000 Hz (F1), 2048 data
Ϫ1
first consists of two curve-fitted components, at 3409 cm
points, 512 time increments (zero filled to 1024), a 1.5 s relaxation delay and
Ϫ1
8 transients per increment. The proton and carbon p/2 pulse lengths were ca.
for the NHamide-f and at 3392 cm for the NHring-b. The
DMSO spectrum shows the absorption originating from the
CϭOester-f at 1735 cm and the CϭOamide-b at 1700 cm . So,
1
15
8
.0 and 12 ms, respectively. The H– N g-HSQC and g-HMBC spectra were
optimised for coupling constants of 100 Hz or 2 Hz, respectively. The experi-
Ϫ1
Ϫ1
mental conditions were as follows: an acquisition time ca. 0.3 s, spectral
compound 6 presents itself in CH Cl and DMSO as the windows of 9000 Hz (F2) and 16000 Hz (F1), 2048 data points, 512 time in-
2
2
crements (zero filled to 1024), a 1.4 s relaxation delay and 16 transients per
monomer with the intramolecular hydrogen bond, i.e. as 6a.
1
13
increment. For the H- and C-NMR spectra, TMS was used as internal
1
5
standard, whereas for N-NMR spectra CH NO was applied as external
3
2
Conclusion
standard. The spectra measured at Ϫ50 °C were calibrated using spectral ref-
The acetylation by means of neat Ac O of C-amino-1H-
2
erence taken from measurements at 30 °C.
1
3
15
13
15
[
1,2,4]triazole-carboxylic acid protected with the methyl
C- and N-CPMAS Spectra The natural abundance C- and N-
CPMAS spectra of 1—6 were measured on a Bruker Avance DRX 500 spec-
ester (2) has been investigated and compared to the acetyla-
tion of 5-amino-1H-[1,2,4]triazole (AT). For 2, a significant
decrease in the susceptibility to acetylation was found. How-
trometer with a Bruker MASVTN500SB BL4 probehead using 4 mm zirco-
2
9)
nia rotors. The 10 kHz spinning speed was applied. The ramp was imple-
1
mented on proton channel of cross-polarisation pulse sequence. The H de-
ever, two monoacetylated derivatives 3 and 6 and two di- coupling rf field strength of 73.5 kHz (3.4 ms p/2 pulse length) was used and
3
0)
acetylated derivatives 4 and 5 (Chart 1) can be obtained. two pulse phase-modulation decoupling sequence was applied. The fol-
1
3
lowing parameters were used for C-spectra: a frequency 125.77 MHz, a
spectral width 31 kHz; a contact time 4 ms; an acquisition time 30 ms; a re-
laxation delay was ca. 10—60 s. The spectra were referenced to solid
Compound 3 has been synthesised regioselectively and quan-
titatively by mild acetylation of 2 in a suspension in Ac O at
2
2
0 °C. Whereas 6 undergoes the second acetylation at room
glycine and recalculated to TMS scale [d(CH in glycine)ϭ43.3 ppm]. The
2
1
5
temperature, diacetylation of 2 and the second acetylation of
N-CPMAS spectra were recorded at a frequency 50.68 MHz; a spectral
3
requires boiling Ac O. All these processes furnish a mix- width 20—31 kHz; a contact time 6 ms; an acquisition time 30—35 ms; a re-
2
laxation delay was ca. 20—60 s. The spectra were referenced to solid
ture of primarily two products, one kinetic 4 and one thermo-
dynamic 5 (Chart 2). Both have been obtained in a moderate
yield, the former by mild, very short solution acetylation of 6
glycine and recalculated to CH NO scale [d(NH2 in glycine)ϭϪ347.6
3
2
ppm].
FTIR Spectra These were recorded on a Philips Analytical PU9800
Ϫ1
with Ac O warmed to 45—50 °C, the latter from an equilib- FTIR spectrometer at 2 cm nominal resolution in a KBr pellet, moreover
2
in CCl , CH Cl , and DMSO solutions using liquid cells (KBr) of 2.86 mm
rium mixture of 4 and 5 upon a prior hydrolysis of 4. Com-
pound 4 in contrast with its stable AT counterpart, left stand-
ing undergoes, simultaneously, hydrolysis to give 6, and iso-
merisation to give 5. The other monoacetylated derivative 6
4
2
2
optical pathlength for the former two solvents and 0.1 mm for the latter one.
Because of poor solubility, saturated solutions in chlorinated solvents were
measured. Only the solutions of 4 were further diluted and measured to the
limit of detection to verify solute-solute interactions. DMSO solutions were
Ϫ2
can be gained quantitatively via the diacetylation of 2 and the 10 M and for this concentration no association was observed. Attention

1
98
Vol. 52, No. 2
Ϫ1
was focused on the frequency domain 3500—3100 cm characteristic of the 3H, Ac), 3.82 (s, 3H, CH O), 11.66 (br, 1H, NHamide), 13.95 (br, 1H, NHring).
3
Ϫ1
13
NH stretching vibrations and 1800—1600 cm characteristic of the CϭO
stretching and NH2 scissoring vibrations. If necessary, the spectra were 160.2 (CϭO ), 169.2 (CϭO
analysed with the GRAMS/386 program and the curve fitting procedure with the multinuclear NMR data in DMF-d and N-CPMAS chemical shifts are
the mixed Gaussian–Lorentzian sum functions was applied.
Methyl 5-Amino-1H-[1,2,4]triazole 3-carboxylate Hydrochloride (1) (%): 184 (M , 11), 156 (33), 142 (72), 111 (18), 98 (11), 84 (18), 43 (100).
Methanol (25 ml) was cooled to Ϫ15 °C, SOCl2 (6.4 ml, 89.5 mmol) was
C-NMR (DMSO-d ) d: 22.7 (Ac), 52.0 (CH O), 149.3 (C-3), 150.9 (C-5),
6
3
). The analytical data is given in Table 1,
ester
amide
1
5
7
3
1)
collected in Tables 2 and 3. FTIR data is presented in Table 4. EI-MS m/z
ϩ
added dropwise under stirring and followed by C-amino-[1,2,4]triazole-car-
boxylic acid hemihydrate (3.427 g, 25 mmol). Stirring was continued at Opole for the financial support. We would like also to thank Prof. Pawel
Acknowledgements We express our gratitude to The University of
⁄
Ka-
room temperature for 24 h and volatiles were evaporated. The crude hy- farski for providing the access to a Bruker Avance DRX 300 MHz spectrom-
1
drochloride was crystallised from methanol–diethyl ether. White powder. eter and to Dr. Tomasz Cierpicki for recording and interpreting some H-
Yield 3.89 g (87%). The analytical data is given in Table 1 and NMR data in NMR spectra in DMSO-d6.
Tables 2 and 3.
Methyl 5-Amino-1H-[1,2,4]triazole-3-carboxylate (2) The crude hy- References
drochloride (1) was dissolved in MeOH (30 ml) and 5% aqueous NaHCO3
75 ml) was added in portions. The resulting precipitate was filtered and
washed with water and acetone. White powder. Yield 2.73 g (77%). H-
1) Dervan P. B., Bioorg. Med. Chem., 9, 2215—2235 (2001).
2) Kopka M. L., Goodsell D. S., Han G. W., Chiu T. K., Lown J. W.,
Dickerson R. E., Structure, 5, 1033—1046 (1997).
(
1
NMR (DMSO-d ) (d: 3.78 (s, 3H, CH O), 6.22 (s, 2H, NH ), 12.64 (s, 1H,
3) Johnson D. S., Boger D. L., “Comprehensive Supramolecular Chem-
istry,” Vol. 4, ed. by Lehn J.-M., Atwood J. L., Davies J. E. D., Macni-
col D. D., Vogtle F., Pergamon Press, Oxford, 1996, pp. 73—176.
4) Voyer N., “Topics in Current Chemistry,” Vol. 184, ed. by
Schmidtchen F. P., Springer Verlag, Berlin, 1997, pp. 1—37.
5) Janecka A., Janecki T., Shan S., Bowers C., Folkers K., J. Med. Chem.,
37, 2238—2241 (1994).
6
3
2
13
NH ). C-NMR (DMSO-d ) d: 51.5 (CH O), 151.8 (C-3), 157.5 (C-5),
ring
6
3
1
60.7 (CϭO). The analytical data is given in Table 1, the multinuclear NMR
data in DMF-d and CPMAS chemical shifts are collated in Tables 2 and 3.
7
ϩ
FTIR data is presented in Table 4. EI-MS m/z (%): 142 (M , 75), 125 (25),
1
10 (27), 98 (48), 84 (100), 69 (14), 57 (66), 42 (85).
Methyl 1-Acetyl-5-amino-1H-[1,2,4]triazole-3-carboxylate (3) (A)
Ac O (2.83 ml, 30 mmol) was added to a stirred suspension of 2 (2.84 g,
6) Ishida H., Inoue Y., Biopolymers (Peptide Science), 55, 469—478
(2000).
2
2
0 mmol) in DMF (40 ml). Stirring was continued for 18 h and MeOH
(
35 ml) was added. After 1 h, the precipitate was filtered and washed with
7) Kubik S., Goddard R., Eur. J. Org. Chem., 2001, 311—322 (2001).
8) Kirsten C. N., Schrader T. H., J. Am. Chem. Soc., 119, 12061—12068
(1997).
cold methanol. White powder. Yield 3.208 g (87%). Mp 214 °C. (B) A sus-
pension of 2 (2.84 g, 20 mmol) in Ac O (20.68 ml, 220 mmol) was stirred for
2
4
.5 h and volatiles were evaporated to leave the title compound. Yield 3.68 g
9) Saweczko P., Kraatz H.-B., Coord. Chem. Rev., 190—192, 185—198
(1999).
1
(
(
100%). H-NMR (DMSO-d ) d: 2.60 (s, 3H, Ac), 3.87 (s, 3H, CH O), 7.69
6 3
13
s, 2H, NH ). C-NMR (DMSO-d ) d: 22.7 (Ac), 52.0 (CH O), 151.8 (C-3), 10) Saweczko P., Enright G. D., Kraatz H.-B., Inorg. Chem., 40, 4409—
2
6
3
1
13
1
57.1 (C-5), 159.7 (CϭOester), 171.4 (CϭO
) ( H- and C-data agreeable
4419 (2001).
N-ring
to the data from ref. 13). The analytical data is given in Table 1, the multinu- 11) Unterberg C., Gerlach A., Schrader T., Gerhards M., Eur. Phys. J. D.,
clear NMR data in DMF-d and CPMAS chemical shifts are collected in Ta-
20, 543—550 (2002).
bles 2 and 3. FTIR data are presented in Table 4. EI-MS m/z (%): 184 (M , 12) Cipen G. E., Grinstein V., Latvijas PSR Zinatnu Akad. Vestis Kim. Ser.,
0), 142 (100), 111 (16), 84 (11), 43 (17).
1965, 204—208 [Chem. Abst., 63, 13243f (1965)].
Methyl 1-Acetyl-3-(acetylamino)-1H-[1,2,4]triazole-5-carboxylate (4) 13) Saalfrank R. W., Wirth U., Chem. Ber., 122, 519—522 (1989).
7
ϩ
1
Compound 6 (1.84 g, 10 mmol), suspended in Ac O (34 ml, 360 mmol) and 14) Baird E. E., Dervan P. B., J. Am. Chem. Soc., 118, 6141—6146 (1996).
2
·
stirred was warmed to 45—50 °C until a clear solution formed. This was im- 15) Dzygiel A., Masiukiewicz E., Rzeszotarska B., J. Agric. Food Chem.,
mediately evaporated at 20 °C to dryness and the residue was crystallised
50, 1383—1388 (2002).
from EtOAc (50 ml). White powder. Yield 1.32 g (58%). H-NMR (DMSO- 16) Kohlbau H.-J., Thürmer R., Voelter W., “Synthesis of Peptides
1
d ) d: 2.22 (s, Acamide), 2.66 (s, 3H, Acring), 3.90 (s, 3H, CH O), 10.60 (s, 1H,
(Houben-Weyl Methods of Organic Chemistry),” Vol. E22a, ed. by
Goodman M., Felix A., Moroder L., Toniolo C., George Thieme,
Stuttgart, 2002, pp. 193—237.
6
3
13
NH). C-NMR (DMSO-d ) d: 23.5 (CϭON-ring), 23.6 (CH3amide), 52.6
6
(
CH O), 149.7 (C-5), 151.3 (C-3), 159.2 (CϭOester), 168.5 (CϭOamide),
3
1
70.1 (CϭON-ring). The analytical data is given in Table 1, the multinuclear 17) Gabryszewski M., Wieczorek B., Polish J. Chem., 73, 2061—2066
(1999).
and. 3. FTIR data are presented in Table 4. EI-MS m/z (%): 226 (M , 8), 18) Byriel K. A., Kennard C. H. L., Lynch D. E., Smith G., Thompson J.
84 (40), 169 (50), 142 (83), 110 (12), 43 (100).
G., Aust. J. Chem., 45, 969—981 (1992).
Methyl 1-Acetyl-5-(acetylamino)-1H-[1,2,4]triazole-3-carboxylate (5) 19) Lynch D. E., Smith G., Byriel K. A., Kennard C. H. L., Acta Crystal-
Compound 2 (1.42 g, 10 mmol) in Ac O (34 ml, 360 mmol) was refluxed
logr., C48, 1265—1267 (1992).
under dry nitrogen for 6 h. Volatiles were evaporated, water (60 ml) was 20) Lynch D. E., Smith G., Byriel K. A., Kennard C. H. L., Acta Crystal-
added and the resulting suspension was stirred for 10 min. Again, volatiles
logr., C50, 1291—1294 (1994).
were evaporated, EtOAc (50 ml) was added and evaporated. EtOAc was 21) Smith G., Lynch D. E., Byriel K. A., Kennard C. H. L., Acta Crystal-
added once more (25 ml) and the insoluble precipitate of 6 filtered off. The
logr., C52, 231—235 (1996).
filtrate was concentrated in vacuo and chromatographied on a short col- 22) McNab H., J. Chem. Soc. Perkin Trans. 1, 1987, 657—660 (1987).
NMR data in DMF-d , and CPMAS chemical shifts are collected in Tables 2
7
ϩ
1
2
28)
umn (Silica gel 60H, Merck 107736; f 30 mm, l 70 mm) equilibrated and 23) Claramunt R. M., López C., Sanz D., Alkorta I., Elguero J., Heterocy-
eluted with EtOAc. The appropriate fractions (TLC) were collected and
cles, 55, 2109—2121 (2001).
evaporated. White powder. Yield 1.356 g (60%). H-NMR (DMSO-d ) d: 24) Wawrzycka-Gorczyca I., Rzeszotarska B., Dzygiel A., Masiukiewicz
1
·
6
1
3
⁄
2
.21 (s, 6H, Acamide, Acring), 3.92 (s, 3H, CH O), 15.61 (s, 1H, NH). C-
E., Koziol A. E., Z. Kristallogr., 218, 480—487 (2003).
3
NMR (DMSO-d ) d: 25.3 (Acamide, Acring), 52.8 (CH O), 149.3 (C-3), 156.6 25) Denisov G. S., Kuzina L. A., J. Mol. Struct., 271, 9—18 (1992).
6
3
(
C-5), 158.4 (CϭOester), 171.5 (CϭOamide, CϭON-ring). The analytical data is 26) Parmentier J., De Wael K., Zeegers-Huyskens Th., J. Mol. Struct., 270,
given in Table 1, the multinuclear NMR data in DMF-d and CPMAS chem-
217—227 (1992).
ical shifts are collected in Tables 2 and 3. FTIR data are presented in Table 27) Pless M., Griehl C., Kolbe A., J. Mol. Struct., 570, 203—214 (2001).
7
ϩ
4
(
. EI-MS m/z (%): 226 (M , 9), 184 (48), 169 (59), 142 (100), 110 (14), 43
97).
Methyl 5-(Acetylamino)-1H-[1,2,4]triazole-3-carboxylate (6) A sus-
28) Hunt B. J., Rigby W., Chem. & Ind., 1967, 1868—1869 (1967).
29) Metz G., Wu X., Smith S. O., J. Magn. Reson., A110, 219—227
(1994).
pension of 2 (1.42 g, 10 mmol) in Ac O (30 ml, 320 mmol) was refluxed for 30) Bennett A. E., Rienstra C. M., Auger M., Lakshimi K. V., Griffin R.
2
3
0 min until a clear solution formed. The solution was evaporated to dry-
G., J. Chem. Phys., 103, 6951—6958 (1995).
ness, water (40 ml) added, a suspension stirred for 24 h and water evapo- 31) GRAMS/386 Version 3.01B, Galactic Industries Corp., Salem NH
1
rated. White powder. Yield 1.80 g (98%). H-NMR (DMSO-d ) d: 2.11 (s,
(1994).
6