Preparation of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles via chemoselective сyclocondensation of electrophilically activated nitroalkanes to (thio)semicarbazides or thiohydrazides

Article abstract of DOI:10.1007/s10593-020-02775-5

[Figure not available: see fulltext.] Unusual reaction proceeding via the electrophilic activation of nitroalkanes in the presence of polyphosphoric acid has been discovered. Subsequent nucleophilic attack with semicarbazides or thiosemicarbazides allows

Full text of DOI:10.1007/s10593-020-02775-5

DOI 10.1007/s10593-020-02775-5
Chemistry of Heterocyclic Compounds 2020, 56(8), 1067–1072
Preparation of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles
via chemoselective сyclocondensation of electrophilically activated
nitroalkanes to (thio)semicarbazides or thiohydrazides
Nicolai A. Aksenov1*, Nikolai A. Arutiunov1, Nikita K. Kirillov1,
Dmitrii A. Aksenov1, Alexander V. Aksenov1, Michael Rubin1,2*
1 Department of Chemistry, North Caucasus Federal University,
1a Pushkin St., Stavropol 355017, Russia; e-mail: naksenov@ncfu.ru
2 Department of Chemistry, University of Kansas,
1567 Irving Hill Rd., Lawrence, KS 66045-7582, USA; e-mail: mrubin@ku.edu
Submitted August 3, 2020
Accepted August 9, 2020
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(8), 1067–1072
Unusual reaction proceeding via the electrophilic activation of nitroalkanes in the presence of polyphosphoric acid has been discovered.
Subsequent nucleophilic attack with semicarbazides or thiosemicarbazides allows to access 2-amino-1,3,4-oxadiazoles and 2-amino-1,3,4-
thiadiazoles, respectively.
Keywords: nitroalkanes, 1,3,4-oxadiazoles, semicarbazides, 1,3,4-thiadiazoles, thiosemicarbazides, Brønsted acid catalysis, cascade
reaction, nucleophilic cycloadition.
Importance of 1,3,4-thiadiazoles and closely related
1,3,4-oxadiazoles is hard to overemphasize.1 These versatile
structures are considered to be privileged scaffolds for drug
discovery and for decades were widely used in the design
of new synthetic medicinal agents. Among marketed drugs
featuring 1,3,4-thiadiazole core are antibiotics cefazolin2–5
and sulfamethizole6–9 and anticonvulsant acetazolamide
(Diamox, Diacarb)10–15 (Fig. 1). In addition, there are
multiple examples of 1,3,4-thiadiazole derivatives show-
casing promising antibiotic,16,17 anti-inflammatory and
analgesic,18 anticancer,19–22 antiparasitic,23–25 antiviral,26,27
anticonvulsant,28,29 antidepressant,30 and antioxidant31,32
activities. These types of molecules are also applied in
agromedicinal chemistry as insecticides,33 fungicides,34,35
virucides,35 and plant growth regulators.36 It is not
surprising that these molecules are in high demand, with
more than a million of individual structures have been
already synthesized.
their synthetic equivalents (esters, acyl chlorides, nitriles,
COCl2, CS2, etc.).1 These methods are very popular and
easily amenable to design a diversity-oriented or combina-
torial automated preparation of large libraries for drug
discovery.37,38 At the same time, new synthetic approaches
toward these important targets are still in high demand, and
they are continuing to emerge. Most recent reports
showcase cyclizations of hydrazides with isothiocyanates,39
tosylhydrazones with elemental sulfur,40 and oxidative
cyclization of thiosemicarbazides with aldehydes.41 Herein
we wish to report a novel approach to 1,3,4-oxadiazoles
Synthetic approaches to these heterocyclic compounds
typically involve cyclocondensations of acylhydrazines
with carboxylic acid equivalents (in the presence of P2S5 or
Lawesson's reagent to access thiadiazoles). Alternatively,
thiosemicarbazides, thiocarbazides, or thiocarbazates can be
employed, again in combination with carboxylic acids or
Figure 1. Biologically active 1,3,4-thiadiazoles.
0009-3122/20/56(8)-1067©2020 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2020, 56(8), 1067–1072
Scheme 1. Activation of nitroalkanes toward
nucleophilic attack by amines
and 1,3,4-thiadiazoles via unusual cyclization of semi-
carbazides or thiosemicarbazides with nitroalkanes
activated in polyphosphoric acid (PPA).42
For several years our group was instrumental in the
development and implementation of novel synthetic
methodologies, involving acid-mediated transformations of
nitroalkenes and nitroalkanes and targeting materials
science and medicinal chemistry applications. It was found
that nitroalkanes 1 in PPA convert into phosphorylated
nitronates 2 showing strong electrophilic properties. This
allowed the design of several cascade transformations,
employing electron-rich arenes as carbon-based nucleo-
philes.43–45 It was also found that nucleophilic amines 3 can
also be employed in this type of reactions, providing an
unconventional approach toward benzoxazoles 5,45
benzimidazoles 6,45,46 diazines 7,47,48 or imidazolines 849
(Scheme 1). We have also shown that nucleophilic attack at
phosphorylated nitronate species 2 could be carried out
with participation of N-acylhydrazides, which offered an
access to 1,3,4-oxadiazoles 9 (Schemes 1, 2).50 Indeed,
such nucleophilic attack would initially afford (2-acyl-
hydrazinyl)alkaniminium species 14, very well suited for a
5-exo-trig cyclization involving the carbonyl group of the
hydrazide function and providing 4,5-dihydro-1,3,4-oxa-
diazol-3-ium ion 15. The latter after deprotonation formed
2,3-dihydro-1,3,4-oxadiazole 16, which after the
elimination of O-phosphorylated hydroxylamine afforded
1,3,4-oxadiazole 9 (Scheme 2).50 We pondered, if the same
transformation could be performed with thiohydrazides 11.
If successful, this should open an avenue toward
preparation of valuable 1,3,4-thiadiazoles 17 (Scheme 2).
To assess this idea, 86% PPA was heated at reflux with
nitromethane (1a) for 30 min, and benzothiohydrazide
(11a) was added in small portions, and the refluxing was
continued for 1 h. Gratifyingly, the desired 1,3,4-thia-
diazole 17aa was formed as sole isolable product in 52%
yield (Scheme 3). Reactions of compound 11a with 1-nitro-
propane (1b) and ethyl nitroacetate (1c) were also per-
formed under the same conditions to afford the cor-
responding thiadiazoles 17ab and 17ac in 58 and 54%
yields, respectively (Scheme 3).
Scheme 2. Mechanistic rationale for the formation
of compounds 9, 17–19
OPO(OH)2
OPO(OH)2
R2 NH
R2
N
OPO(OH)2
X
X
2
NH2
NH
R1
N
H
R1
N
H
– H3PO4
14
10–13
R2
H
N
2 H
R
OPO(OH)2
– H3PO4
OPO(OH)2
N
X
X
NH
R1
NH
N
R1
N
16
H
H2PO4
15
R2
X
R1
– NH2OPO(OH)2
N
N
9, 17–19
9, 10 R1 = Ar, X = O (Ref. 49)
11, 17 R1 = Ar, X = S (this work)
Inspired by successful initial results we decided to
examine the possibility to employ semicarbazides 12a,b
and thiosemicarbazides 13a,c–e as nucleophilic component
in this cyclization to access 1,3,4-oxadiazoles with amine
substituent at C-2. To this end, first we performed reaction
between N-phenylhydrazinecarboxamide (12a) and 1-nitro-
propane (1b). We were pleased to find that oxadiazole
product 18ab was obtained in this reaction in 65% yield
(Scheme 4). We also tested N-(pyridin-2-yl)hydrazinecarb-
oxamide (12b) in reaction with nitromethane (1a),
nitropropane (1b), and nitroethane (1d) to obtain the
corresponding products 18ba, 18bb, and 18bd in 62, 75,
and 70% yield, respectively (Scheme 4).
12, 18 R1 = NHAr; X = O (this work)
13, 19 R1 = NH2, NHAlk, NAlk2; X = S (this work)
Scheme 3. Preparation of 1,3,4-thiadiazoles 17aa–ac
in the reaction of benzothiohydrazide 11a
with nitroalkanes 1a–c
Finally, we investigated the cyclization involving
thiosemicarbazides as nucleophilic component to get access
to pharmaceutically attractive 2-amino-1,3,4-thiadiazole
structures 19. To this end, we first employed N-phenyl-
hydrazine carbothioamide (13a) in combination with
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Chemistry of Heterocyclic Compounds 2020, 56(8), 1067–1072
Scheme 4. Preparation of 2-amino-1,3,4-oxadiazoles
18ab,ba,bb,bd in the reaction of semicarbazides 12a,b
with nitroalkanes 1a,b,d
Figure 2. Molecular structure of compound 19ab with atoms
represented as thermal vibration ellipsoids of 50% probability.
quite lipophilic products 19db and 19eb were formed.
Extraction of these compounds from the aqueous phase was
not complicated, and these materials were obtained in very
good yields (Scheme 5).
In conclusion, an unusual process was developed involving
electrophilic activation of nitroalkanes in the presence of
polyphosphoric acid and subsequent nucleophilic attack
with semicarbazides or thiosemicarbazides. This reaction
allowed for convenient and expeditious access to 2-amino-
1,3,4-oxadiazoles and 2-amino-1,3,4-thiadiazoles.
1-nitropropane (1b), carrying the reaction under the same
general conditions. Product 19ab was formed uneventfully,
although due to high solubility in H2O, unavoidable losses
during aqueous workup and extraction rendered the yield
quite moderate (58%, Scheme 5). Formation of this
compound was unambiguously confirmed by single crystal
X-ray diffraction (Fig. 2). High solubility in H2O was also
a major issue in the preparation of compounds 19ca and
19cb, originated from nonsubstituted semicarbazide (13c).
Although these compounds were the only products detect-
able in the reaction mixtures and the conversions were
quite high, isolated yields were quite marginal, 55 and
45%, respectively (Scheme 5). In addition to this, con-
current nucleophilic attack with primary amine moiety
occured in reactions of compound 13c with nitroethane
(1d) and 1-nitropropane (1b) affording the corresponding
acylated products 20cb and 20cd, respectively (Scheme 5).
This side process could be partially suppressed, if only
slight excess of nitroalkane (1.4–1.5 equiv) is employed.
In this case, predominant formation of compounds 19cb
and 19cd was observed (Scheme 5). In reactions of
thiosemicarbazides 13d,e bearing tertiary amine moiety,
Experimental
IR spectra were registered on a Shimadzu IRTracer-100
FTIR spectrometer with the attenuated total reflectance
1
(ATR) attachment PIKE MIRacle in NaCl. H and 13C
NMR spectra were acquired on a Bruker Avance III
spectrometer (400 and 100 MHz, respectively) in DMSO-d6 or
CDCl3, with TMS as internal standard. In several instances,
the signal of the NH protons was not observed; due to rapid
proton exchange it overlapped with the water signal. High-
resolution mass spectra were recorded on a Bruker Maxis
Impact mass spectrometer in MeCN–H2O solutions,
calibration against HCO2Na–HCO2H, electrospray ioniza-
tion (Q/TOF). Melting points were determined on a Stuart
SMP30 apparatus. Monitoring of the reaction progress and
assessment of the purity of synthesized compounds were
performed by TLC on Silufol UV-254 plates.
Scheme 5. Preparation of 2-amino-1,3,4-thiadiazoles 19aa,ab,ca–cd,db,eb and 20cb,cd in the reaction
of thiosemicarbazides 13a,c–e with nitroalkanes 1a–d
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Chemistry of Heterocyclic Compounds 2020, 56(8), 1067–1072
Starting nitroalkanes 1a–d and compounds 11a, 12a,
m, H Ph); 2.86 (2H, q, J = 7.6, CH2); 1.40 (3H, t, J = 7.6,
CH3). 13C NMR spectrum (CDCl3), δ, ppm: 165.8; 154.3;
141.5; 129.6 (2C); 123.5 (2C); 118.1; 15.8; 9.2. Found, m/z:
190.0977 [M+H]+. C10H12N3O. Calculated, m/z: 190.0975.
N-(1,3,4-Oxadiazol-2-yl)pyridin-2-amine (18ba). Yield
100 mg (62%), white solid, mp 120–121°C (Me2CO),
Rf 0.36 (EtOAc–hexane, 1:1). IR spectrum, ν, cm–1: 3253,
1682, 1581, 1532, 1435, 1367, 1305, 1245, 1159, 1006.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 12.11 (1H,
br. s, NH); 8.56 (1H, d, J = 1.2, H Ar); 8.49 (1H, d, J = 3.8,
H Ar); 8.19 (1H, d, J = 8.3, H Ar); 8.00 (1H, dd, J = 8.3,
J = 4.6, H Ar); 7.38 (1H, dd, J = 6.7, J = 4.6, H Ar).
13C NMR spectrum (DMSO-d6), δ, ppm: 152.5; 148.5;
147.1; 139.3; 134.4; 122.2; 113.0. Found, m/z: 185.0431.
[M+Na]+. C7H6N4NaO. Calculated, m/z: 185.0434.
13a,c were purchased from commercial sources. Com-
pounds 12b,51 13d,52 and 13e53 were synthesized according
to the published procedures and their physical and spectral
properties were identical to those reported in literature.
Synthesis of 2-amino-1,3,4-oxadiazoles 17aa–ac,
18ab,ba,bb,bd and 2-amino-1,3,4-thiadiazoles 19aa,ab,db,ca–
cd,eb, 20cb,cd (General method). A 10-ml Erlenmeyer
flask equipped with reflux condenser and magnetic stirrer
was charged with 86% polyphosphoric acid (2.00 g) and
nitroalkane 1 (5.00 equiv; for preparation of compounds
19cb, 19cc, and 19cd, 1.5 equiv were used). The mixture
was placed in the oil bath preheated to 120°C and stirred
for 30 min. Nucleophilic component (thiohydrazide 11,
semicarbazide 12, or thiosemicarbazide 13, 1.00 mmol)
was added by small portions over 1 h period, and the
stirring at reflux was continued for additional 1 h. Then, the
mixture was poured into cold H2O (5 ml), neutralized with
aqueous ammonia to pH 6–7, and extracted with EtOAc
(4×5 ml). The combined extracts were concentrated under
vacuum, and the residue was purified by preparative
column chromatography on silica gel, eluting with a
mixture of acetone and hexane.
N-(5-Ethyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine (18bb).
Yield 142 mg (75%), yellow oil, Rf 0.58 (Me2CO–hexane,
1:1). IR spectrum, ν, cm–1: 3370, 2926, 1773, 1747, 1672,
1599, 1582, 1496, 1434, 1386, 1311, 1288, 1249, 1158,
1
1072. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 8.80
(1H, br. s, NH); 8.34–8.10 (2H, m, H Py); 7.75–7.65 (1H,
m, H Py); 7.08–6.96 (1H, m, H Py); 2.42 (2H, q, J = 7.5,
CH2); 1.23 (3H, t, J = 7.5, CH3). 13C NMR spectrum
(CDCl3), δ, ppm: 172.7; 151.8; 149.9; 147.5; 138.7; 119.7;
114.4; 30.8; 9.5. Found, m/z: 213.0751 [M+Na]+.
C9H10N4NaO. Calculated, m/z: 213.0747.
2-Phenyl-1,3,4-thiadiazole (17aa). Yield 84 mg (52%),
pale-yellow solid, mp 40–42°C (Me2CO) (mp 46°C54),
Rf 0.40 (Me2CO–hexane, 1:2). IR spectrum, ν, cm–1: 3051,
2780, 1957, 1892, 1745, 1681, 1599, 1456, 1425, 1401,
N-(5-Methyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine (18bd).
Yield 122 mg (70%), yellow solid, mp 50–52°C (Me2CO),
Rf 0.71 (Me2CO–hexane, 1:1). IR spectrum, ν, cm–1: 3252,
1681, 1580, 1531, 1434, 1368, 1304, 1242, 1158, 1008.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 9.27 (1H, br. s,
NH); 8.40–8.10 (2H, m, H Py); 7.71 (1H, ddd, J = 8.5,
J = 7.4, J = 1.9, H Py); 7.03 (1H, ddd, J = 7.4, J = 5.0,
J = 1.0, H Py); 2.19 (3H, s, CH3). 13C NMR spectrum
(CDCl3), δ, ppm: 169.2; 151.9 (2C); 147.3; 138.8; 119.8;
114.6; 24.7. Found, m/z: 199.0587. [M+Na]+. C8H8N4NaO.
Calculated, m/z: 199.0590.
N-Phenyl-1,3,4-thiadiazol-2-amine (19aa). Yield 69 mg
(39%), white solid, mp 172–173°C (EtOH) (mp 173°C55),
Rf 0.64 (Me2CO–hexane, 1:1). IR spectrum, ν, cm–1: 3745,
3276, 2933, 2055, 1752, 1632, 1530, 1341, 1137, 1032.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 10.41 (1H,
br. s, NH); 8.89 (1H, s, H thiadiazole); 7.64 (2H, d, J = 8.1,
H Ph); 7.34 (2H, dd, J = 8.1, J = 7.7, H Ph); 6.99 (1H,
t, J = 7.7, H Ph). 13C NMR spectrum (DMSO-d6),
δ, ppm: 164.3; 143.7; 140.4; 129.0 (2C); 121.8; 117.5 (2C).
Found, m/z: 178.0434 [M+H]+. C8H8N3S. Calculated, m/z:
178.0433.
1
1315, 1242. H NMR spectrum (DMSO-d6), δ, ppm: 9.64
(1H, s, CH); 8.05–7.98 (2H, m, H Ph); 7.60–7.54 (3H, m,
H Ph). 13C NMR spectrum (DMSO-d6), δ, ppm: 168.1;
154.3; 131.8; 130.0 (2C); 129.9; 128.3 (2C). Found, m/z:
185.0143 [M+Na]+. C8H6N2NaS. Calculated, m/z: 185.0144.
2-Ethyl-5-phenyl-1,3,4-thiadiazole (17ab). Yield 110 mg
(58%), colorless oil, Rf 0.29 (Me2CO–hexane, 1:1).
IR spectrum, ν, cm–1: 3051, 2978, 2868, 1956, 1892, 1769,
1
1698, 1538, 1456, 1427, 1317, 1244. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 7.93–7.83 (2H, m, H Ph); 7.44–
7.35 (3H, m, H Ph); 3.11 (2H, q, J = 7.6, CH2); 1.41 (3H, t,
J = 7.6, CH3). 13C NMR spectrum (CDCl3), δ, ppm: 171.6;
168.3; 130.8; 130.3; 129.1 (2C); 127.8 (2C); 23.9; 14.3.
Found, m/z: 213.0455 [M+Na]+. C10H10N2NaS. Calculated, m/z:
213.0457.
Ethyl 5-phenyl-1,3,4-thiadiazole-2-carboxylate (17ac).
Yield 126 mg (54%), white solid, mp 105–106°C
(Me2CO), Rf 0.52 (Me2CO–hexane, 1:2). IR spectrum,
ν, cm–1: 2992, 1751, 1630, 1460, 1388, 1372, 1333, 1295,
1247, 1203, 1068, 1022. 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 8.00 (2H, dd, J = 4.1, J = 1.9, H Ph); 7.47–
7.45 (3H, m, H Ph); 4.51 (2H, q, J = 7.2, CH2); 1.40 (3H, t,
J = 7.2, CH3). 13C NMR spectrum (CDCl3), δ, ppm: 172.7;
159.6; 158.7; 132.2; 129.5 (3C); 128.4 (2C), 63.4; 14.2.
Found, m/z: 257.0341 [M+Na]+. C11H10N2NaO2S. Calcu-
lated, m/z: 257.0355.
5-Ethyl-N-phenyl-1,3,4-thiadiazol-2-amine (19ab). Yield
118 mg (58%), pale-yellow solid, mp 119–120°C
(Me2CO), Rf 0.28 (Me2CO–hexane, 1:2). IR spectrum,
ν, cm–1: 3736, 3582, 3568, 3249, 2926, 2849, 1941, 1870,
1
1714, 1562, 1520, 1494, 1441, 1379, 1187, 1026. H NMR
5-Ethyl-N-phenyl-1,3,4-oxadiazol-2-amine (18ab). Yield
122 mg (65%), yellow oil, Rf 0.36 (Me2CO–hexane, 1:2).
IR spectrum, ν, cm–1: 3732, 3579, 291, 1749, 1644, 1569,
1500, 1374, 1274, 1242, 1042. 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 7.43 (3H, td, J = 9.2, J = 3.2, H Ph); 7.33
(1H, ddd, J = 11.2, J = 8.0, J = 4.7, H Ph); 7.24–7.19 (1H,
spectrum (CDCl3), δ, ppm (J, Hz): 7.42–7.33 (4H m,
H Ph); 7.13 (1H, dt, J = 8.4, J = 2.3, H Ph); 3.03 (2H, q,
J = 7.6, CH2); 1.40 (3H, t, J = 7.6, CH3). 13C NMR
spectrum (CDCl3), δ, ppm: 166.6; 160.9; 140.4; 129.6
(2C); 123.7; 118.4 (2C); 24.0; 14.0. Found, m/z: 206.0746
[M+H]+. C10H12N3S. Calculated, m/z: 206.0746.
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Chemistry of Heterocyclic Compounds 2020, 56(8), 1067–1072
N-Benzyl-5-ethyl-N-methyl-1,3,4-thiadiazol-2-amine
3.07 (2H, q, J = 7.6, CH2); 2.77 (2H, q, J = 7.5, CH2); 1.41
(3H, t, J = 7.6, CH3); 1.30 (3H, t, J = 7.5, CH3). 13C NMR
spectrum (CDCl3), δ, ppm: 172.9; 166.6; 160.6; 29.6; 23.6;
14.1; 9.3. Found, m/z: 186.0693 [M+H]+. C7H12N3OS.
Calculated, m/z: 186.0696.
N-(5-Methyl-1,3,4-thiadiazol-2-yl)acetamide (20cd).
Yield 71 mg (45%), white solid, mp 294–295°C (EtOH)
(mp 292°C60), Rf 0.57 (EtOAc–hexane, 2:1). IR spectrum,
ν, cm–1: 2989, 2875, 2062, 1773, 1756, 1696, 1652, 1573,
1502, 1375, 1319, 1247. 1H NMR spectrum, δ, ppm
(DMSO-d6): 12.35 (1H, br. s, NH); 2.59 (3H, s, CH3); 2.16
(3H, s, CH3). 13C NMR spectrum (DMSO-d6), δ, ppm:
168.5; 159.1; 158.5; 22.4; 14.8. Found, m/z: 158.0385
[M+H]+. C5H8N3OS. Calculated, m/z: 158.0383.
(19db). Yield 170 mg (73%), yellow oil, Rf 0.60 (Me2CO).
IR spectrum, ν, cm–1: 2996, 2882, 1752, 1633, 1372, 1238,
1196, 1017. 1H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 7.53–749 (5H, m, H Ph); 5.45 (2H, s, CH2Ph); 2.70
(2H, q, J = 6.7, CH2CH3); 1.57 (3H, s, NCH3); 1.21 (3H, t,
J = 6.7, CH2CH3). 13C NMR spectrum (DMSO-d6), δ, ppm:
178.6; 171.2; 140.3; 128.7 (3C); 127.6 (2C); 65.1; 20.6;
19.1; 11.2. Found, m/z: 234.1061 [M+H]+. C12H16N3S.
Calculated, m/z: 234.1059.
1,3,4-Thiadiazol-2-amine (19ca). Yield 55 mg (55%),
white solid, mp 198–200°C (Me2CO) (mp 198–199°C56),
Rf 0.34 (EtOAc–Me2CO, 2:1). IR spectrum, ν, cm–1: 2978,
2926, 2849, 1773, 1756, 1716, 1536, 1505, 1458, 1375,
1
1245. H NMR spectrum (DMSO-d6), δ, ppm: 8.6 (1H, s,
X-ray structural analysis of compound 19ab. Single
crystals of compound 19ab were prepared by slow
evaporation of saturated solution in EtOAc. A suitable
crystal was selected and glued by acrylic glue on glass stick
and placed on a SuperNova, Dual, Cu at home/near,
AtlasS2 diffractometer. The crystal was kept at 111(16) K
during data collection. Using Olex2,61 the structure was
solved with the ShelXT62 structure solution program using
Intrinsic Phasing and refined with the ShelXL63 refinement
package using Least Squares minimization. Crystal data for
C10H11N3S (M 205.28 g/mol): monoclinic, space group
P21/c (no. 14), a 13.1084(3), b 7.50110(10), c 11.0984(2) Å;
β 109.514(2)°; V 1028.59(4) Å3; Z 4; T 111(16) K;
μ(CuKα) 2.487 mm–1, dcalc 1.326 g/cm3; 6193 reflections
measured (7.154° ≤ 2Θ ≤ 152.824°), 2155 unique (Rint 0.0291,
CH); 7.2 (2H, br. s, NH). 13C NMR spectrum (DMSO-d6),
δ, ppm: 168.3; 142.7. Found, m/z: 102.0121. [M+H]+.
C2H4N3S. Calculated, m/z: 102.0120.
5-Ethyl-1,3,4-thiadiazol-2-amine (19cb). Yield 56 mg
(44%), white solid with red impurity, mp 200–203°C
(EtOH) (mp 200–203°C57), Rf 0.15 (EtOAc). IR spectrum,
ν, cm–1: 3743, 3267, 2923, 2051, 1751, 1718, 1632, 1525,
1
1333, 1139, 1022. H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 6.98 (2H, br. s, NH); 2.79 (2H, q, J = 7.5, CH2);
1.20 (3H, t, J = 7.5, CH3). 13C NMR spectrum (DMSO-d6),
δ, ppm: 168.2; 159.8; 23.2; 13.9. Found, m/z: 130.0434
[M+H]+. C4H8N3S. Calculated, m/z: 130.0433.
Ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (19cc).
Yield 77 mg (45%), pale-yellow solid, mp 195–196°C
(EtOH), Rf 0,60 (Me2CO–hexane, 1:1). IR spectrum, ν, cm–1:
3362, 3121, 2996, 1712, 1621, 1496, 1478, 1452, 1366,
Rsigma 0.0302) which were used in all calculations. The final
R1 was 0.0308 (I > 2σ(I)) and wR2 was 0.0814 (all data).
The complete crystallographic dataset was deposited at the
Cambridge Crystallographic Data Center (deposit CCDC
2020654).
1
1299, 1277, 1247. H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 12.55 (2H, br. s, NH); 4.31 (2H, q, J = 7.1, CH2);
1.28 (3H, t, J = 7.1, CH3). 13C NMR spectrum (DMSO-d6),
δ, ppm: 172.2; 158.7; 147.4; 61.6; 13.8. Found, m/z: 196.0152.
[M+Na]+. C5H7N3NaO2S. Calculated, m/z: 196.0151.
5-Methyl-1,3,4-thiadiazol-2-amine (19cd). Yield 44 mg
(38%), white solid, mp 236–239°C (EtOH) (mp 236–
237.5°C58), Rf 0.45 (Me2CO–hexane, 1:1). IR spectrum,
ν, cm–1: 3291, 3104, 2928, 1612. 1H NMR spectrum
(DMSO-d6), δ, ppm: 12.98 (2H, br. s, NH); 2.19 (3H, s,
CH3). 13C NMR spectrum (DMSO-d6), δ, ppm: 165.7;
148.9; 11.2. Found, m/z: 116.0274 [M+H]+. C3H6N3S.
Calculated, m/z: 116.0277.
This work was supported by the Russian Foundation for
Basic Research (grant 18-33-20021 mol_a_ved, 20-33-90026).
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