Studies on pyrazine derivatives. 38*. Synthesis, reactions, and tuberculostatic activity of pyrazinyl-substituted derivatives of hydrazinocarbodithioic acid

Article abstract of DOI:10.1023/B:COHC.0000048293.68655.d5

The synthesis of N'-[amino(6-chloro- and 6-cycloaminopyrazin-2-yl) methylene]carbodithioic acid mono- and diesters and their reactions are described. Cyclization of monoesters with secondary amines in acidic media gave the 1,3,4-thiadiazole derivatives, w

Full text of DOI:10.1023/B:COHC.0000048293.68655.d5

Chemistry of Heterocyclic Compounds, Vol. 40, No. 9, 2004
STUDIES ON PYRAZINE DERIVATIVES.
38. SYNTHESIS, REACTIONS, AND
TUBERCULOSTATIC ACTIVITY OF
PYRAZINYL-SUBSTITUTED DERIVATIVES
OF HYDRAZINOCARBODITHIOIC ACID
H. Foks1, I. Trapkowska1, M. Janowiec2, Z. Zwolska2, and E. Augustynowicz-Kopec2
The synthesis of N'-[amino(6-chloro- and 6-cycloaminopyrazin-2-yl)methylene]carbodithioic acid
mono- and diesters and their reactions are described. Cyclization of monoesters with secondary amines
in acidic media gave the 1,3,4-thiadiazole derivatives, while the cyclization of diesters with amines
yielded 1,2,4-triazoles with the amine substituent in position 3. The in vitro tuberculostatic activity of the
prepared compounds was tested.
Keywords: 6-chloro-2-cyanopyrazine, amidrazones, mono- and diesters of hydrazinocarbodithioic
acids, imino esters, 1,3,4-thiadiazole-2-thiol, 1,2,4-triazoles, carbon disulfide, tuberculostatics.
Amidrazones can react easily with carbon disulfide. It is known that the reactions of phenyl- and
pyridylamidrazones with carbon disulfide in neutral medium give exclusively 5-substituted 1,3,4-triazolo-2-
thiones [1]. We have reported [2, 3] that reactions of carbon disulfide with pyrazine derivatives of amidrazone
give various products, depending on the reaction condition. It was found that carbon disulfide and amidrazone
addition product can be alkylated to give mono- and diesters of pyrazinecarbiminodithiocarbazoic acid. The
latter reacts with amines, yielding heterocyclic compounds difficultly obtainable by other methods. Some of
these products showed high tuberculostatic activity.
This paper presents reactions of 6-chloropyrazine-2-carbamidrazone with carbon disulfide, as well as
application of the products formed to the syntheses of other organic compounds.
The presence of chlorine in position 6 of the pyrazine ring opens new possibilities for the synthesis of
pyrazine derivatives compared to those reported for unsubstituted pyrazinecarbamidrazone.
CHEMISTRY
In a first step of this study the possibility of formation of thiadiazoles bearing the thiol or S-alkyl group
in position
2
of the ring was tested. As expected, carbon disulfide reacted easily with
6-chloropyrazinecarbamidrazone in ethanolic medium to give 5-(6-chloropyrazin-2-yl)-1,3,4-thiadiazole-2-thiol
(1). Thus, the reaction proceeded analogously as reported earlier [1]. It was also found that addition of alkyl
halide (MeI, ClCH2Ph) to the reaction mixture led to the corresponding S-alkylthiadiazole derivatives 2a-b.
__________________________________________________________________________________________
1
Department of Organic Chemistry, Medical University of Gdansk, 80-416 Gdansk, Poland; e-mail:
2
hfoks@farmacja.amg.gda.pl. Department of Microbiology, Institute of Tuberculosis and Pulmonary Diseases
01-138 Warszawa, Poland. Published in Khimiya Geterotsiclicheskikh Soedinenii, No. 9, 1368-1376,
September, 2004. Original article submitted March 25, 2002.
0009-3122/04/4009-1185©2004 Springer Science+Business Media, Inc.
1185

N
N
N
N
N
N
N
N
Cl
C
N–NH–C(=S)R
N
N
b
N
N
2, 3a R = Me,
b R = CH2Ph,
N
N
Cl
SH
Cl
SR
R
R
S
S
NH2
N
11a,b
6a, 7d, 8a,c,
11a, 12a,
1
6a,b
2a,b
O
d
14a R = N
d
e
a
N
N
N
N
N
N
H
N
N
N
N
c
i
Cl
R
6b, 7e, 8b,d, 11b, 12b
Cl
C
N
N
Cl
Cl
C
N
NH2
Cl
C
=N–N=C(SR)2
S
S
f
N
Ph
N
e
N
14b R =
NH2
C
SMe
NH2
NH2
14a,b
e
4
3a,b
S
h
g
l
N
j
N
N
N
7a R =
N
R
R1
CN
Cl
OBn
C
N
N
R
C
N
N=C(SMe)2
NH
N
R =
b
c
N
N
N
5
8a–d
k
NH2
N
N
N
O
N
C
–NH–C–SMe
S
N
O
N
CN
R =
7a–e
N
d
e
NH2
N
d
8a,d R1 =
b, c R1 =
O
10
N
j
h
N
N
N
N
H
N
N
N
i
O
N
C
N
N
C
S
O
N
C
N
SMe
O
O
Bn
N
Ph
S
N
NH2
R
NH
N
13
9
12a,b
a) CS2, EtOH; b) KOH, RX, EtOH; c) CS2, KOH, MeI, EtOH; d) EtOH, H+; e) amines, boiling; f) CS2, KOH, EtOH, 2RX; g) H2NNH2, EtOH; h)
H2NNHCSSMe, MeOH; i) H2NNH–C(=S)–NR; j) BnOH, benzene; k) morpholine, benzene; l) amines, DMF, boiling 0.25 h

TABLE 1. Characteristics of the Newly Synthesized Pyrazinyl Compounds
Found, %
Calculated, %
H
mp, °C
(solvent for
crystalization)
——————
Com-
pound
Empirical
formula
Yield, %
(method)
C
N
1
C6H3ClN4S2
C7H5ClH4S2
31.41
31.24
1.53
1.31
24.43
24.28
205-206
(EtOH)
64
2a
34.43
34.36
2.12
2.06
23.02
22.89
102-103
(EtOH–H2O)
40 (A)
65 (B)
95 (C)
2b
3a
3b
4
C13H9ClN4S2
C8H10ClN5S2
C20H18ClN5S2
C7H8ClN5S2
C14H19N7O2
C26H29N9
48.90
48.67
3.11
2.83
17.52
17.46
100-102
(MeOH)
30
82
63
34.73
34.84
3.82
3.65
25.56
25.39
152-153
(EtOH)
56.02
56.13
4.33
4.24
16.42
16.36
133-134
(EtOH)
32.27
32.12
3.19
3.08
26.70
26.75
174→360
(MeOH)
45 (A)
60 (B)
6a
6b
7a
7b
7c
7d
7e
8a
52.85
52.99
6.14
6.03
31.13
30.90
273-275
(dioxane–MeOH)
40
40
80
95
95
90
95
66.81
66.79
6.50
6.25
27.13
26.96
267-269
(dioxane–MeOH)
C12H18N6S2
C13H20N6S2
C14H22N6S2
C12H18N6OS2
C18H23N7S2
C14H18N6O2S
46.26
46.43
5.97
5.84
27.18
27.07
171-173
(EtOH)
48.34
48.12
6.36
6.21
25.86
25.90
153-154
(MeOH)
49.74
49.68
6.83
6.55
24.96
24.83
128-130
(MeOH)
44.26
44.15
5.71
5.56
25.62
25.74
158-159
(MeOH)
126-127
(MeOH)
53.76
53.84
5.93
5.77
24.56
24.42
45.94
45.88
5.16
4.95
23.20
22.93
273-275
(dioxane–EtOH)
35 (A)
75 (B)
55 (C)
45 (D)
8b
C26H28N8S
64.61
64.43
5.96
5.82
23.37
23.12
244-247
(dioxane)
30
8c
C20H23N7O3
C20H23N7O3
C16H18N4O2
C11H16N6OS2
C10H13ClN6OS
C16H18ClN7S
C14H21N7O2S
C20H26N8OS
C11H13N5OS2
C10H10ClN5OS
C16H15ClN6S
58.77
58.67
5.82
5.66
24.18
23.94
216-217
(dioxane)
85 (A)
75 (B)
8d
58.81
58.67
5.62
5.66
23.98
23.94
249-250
(dioxane)
85
50
80
65
55
70
50
90
90
70
9
64.58
64.41
6.17
6.08
18.92
18.78
152-154
(benzene)
10
42.51
42.29
5.32
5.16
27.03
26.90
155→280
(EtOH)
11a
11b
12a
12b
13
40.14
39.93
4.51
4.36
28.12
27.94
152-154
(EtOH–dioxane)
51.24
51.13
4.97
4.83
26.18
26.08
124-126
(EtOH)
47.96
47.85
6.18
6.02
28.12
27.90
170-280
(EtOH)
56.47
56.32
6.26
6.14
26.38
26.27
180-182
(EtOH)
14.91
14.73
4.62
4.44
23.93
23.71
189-190
(dioxane)
14a
14b
42.42
42.33
3.78
3.55
24.84
24.68
181-182
(MeOH)
53.50
53.55
4.26
4.21
23.57
23.42
198-200
(EtOH)
1187

TABLE 2. IR and 1H NMR data for compounds 1-14
Com-
pound
IR, cm-1
2
1H NMR, δ, ppm, solvent
1
3
1
3109, 2965, 2864, 1433, 1398,
1231, 1166, 1143, 1070,1005,
743, 455
DMSO-d6: 8.95 and 9.20 (2s, 2H pyrazine)
2a
2b
3a
3051, 2930, 1511, 1346, 1311,
1164, 1150, 1008, 812, 453
3040, 1511, 1338, 1165, 1144,
1025, 1006, 715, 454
CDCl3: 2.90 (3H, s, CH3); 8.68
and 9.45 (2s, 2H pyrazine)
CDCl3: 4.65 (2H, s, CH2); 7.35-7.50 (m, 5H phenyl);
8.65 and 9.45 (2s, 2H pyrazine)
3469, 3355, 1615, 1486, 1435,
1401, 1174, 1039, 1010, 945,
876, 449
CDCl3: 2.55 and 2.60 (6H, 2s, 2CH3);
6.00 (2H, br. s, NH2); 8.63 and 9.45 (2s, 2H pyrazine)
3b
3494, 3387, 1614, 1494, 1434,
1170, 1017, 703
CDCl3: 4.35 and 4.45 (4H, 2s, 2CH2);
5.80 (2H, br. s, NH2); 7.30-7.50 (10H, m, 2 phenyl);
8.60 and 9.40 (2s, 2H pyrazine)
4
3433, 3283, 3061, 2916, 1625,
1502, 1368, 1318, 1170, 1006
(CD5)2CO: 2.57 (3H, s, CH3); 6.98 (2H, br. s, NH2);
8.78 and 9.32 (2s, 2H pyrazine); 11.10 (1H, br. s, NH)
6a
3164, 3080, 2958, 2863, 1535,
1520, 1442, 1261, 1114, 923,
761
DMSO-d6: 3.30-3.70 (2m, 16H morpholine);
8.33 and 8.36 (2s, 2H pyrazine)
6b
7a
7b
3175, 3061, 2829, 1599, 1538,
1518, 150, 1446, 1232, 1158,
940, 757, 692
DMSO-d6: 3.37; 3.60 and 3.88 (16H, 3m, 2 pyrazine);
6.80-7.32 (3m, 10H phenyl);
8.42 and 8.45 (2s, 2H pyrazine)
3440, 3283, 2963, 2920, 2848,
1619, 1578, 1526, 1499, 1429,
1217, 1172, 1026, 848, 469
CDCl3: 1.95 and 3.40 (2m, 8H pyrolidine);
2.45 and 2.50 (6H, 2s, 2CH3); 5.90 (2H, br. s, NH2);
7.70 and 8.65 (2s, 2H pyrazine)
3459, 3288, 2921, 2851, 1621,
1571, 1524, 1498, 1427, 1258,
1215, 1181, 1125, 1024, 998,
934, 469
CDCl3: 1.60:3.50 (2m, 10H piperidine);
2.42 and 2.50 (6H, 2s, 2CH3); 5.85 (2H, br. s, NH2);
8.05 and 8.65 (2s, 2H pyrazine)
7c
7d
7e
3446, 3300, 2923, 2848, 1614,
1569, 1524, 1438, 1154, 1024,
997
CDCl3: 1.40 and 1.90 (8H, 2m, 4CH2);
2.45 and 2.50 (6H, 2s, 2CH3); 3.60 (4H, t, 2CH2N);
5.90 (2H, br. s, NH2); 8.95 and 9.60 (2s, 2H pyrazine)
3449, 3307, 2952, 2851, 1613,
1571, 1525, 1440, 1260, 1205,
1117, 1022, 1003, 935
CDCl3: 2.45 and 2.50 (6H, 2s, 2CH3);
3.40 and 3.90 (2m, 8H morpholine);
5.85 (2H, br. s, NH2); 8.10:8.75 (2s, 2H pyrazine)
3482, 3368, 1615, 1573, 1523,
1494, 1446, 1232, 1002, 938,
756, 692
CDCl3: 2.52 and 2.58 (6H, 2s, 2CH3);
3.34 and 3.79 (2m, 8H piperazine); 6.97 (2H, br. s, NH2);
6.89:7.36 (2m, 5H phenyl);
8.23 and 8.86 (2s, 2H pyrazine)
8a
8b
2960, 2902, 1510, 1446, 1253,
1198, 1115, 910
CDCl3: 3.60-3.90 (2m, 16H morpholine);
8.13 and 8.77 (2s, 2H pyrazine)
2822, 1599, 1493, 1452, 1264,
1229, 761, 695
CDCl3: 3.40 and 3.85 (2m, 16H piperazine);
7.20-7.35 (10H, 2m, 2 phenyl);
8.20 and 8.77 (2s, 2H pyrazine)
8c
8d
9
2959, 2854, 1503, 1447, 1259,
1229, 1119, 936, 764
DMSO-d6: 3.40-3.90 (16H, 4m, 8CH2);
7.00-7.40 (2m, 5H phenyl);
8.37 and 8.50 (2s, 2H pyrazine)
3058, 2959, 2851, 2827, 1599,
1567, 1497, 1446, 1267, 1234,
1116, 904, 758, 690
CDCl3: 3.35-3.90 (16H, 3m, 8CH2);
6.95-7.40 (2m, 5H phenyl);
8.20 and 8.76 (2s, 2H pyrazine)
3275, 3062, 2965, 2843, 1648,
1574, 1530, 1476, 1448, 1348,
1267, 1238, 1118, 1002, 865,
733, 445
DMSO-d6: 3.60-3.75 (m, 8H morpholine);
5.37 (2H, s, CH2); 7.32-7.50 (m, 5H phenyl);
8.27 and 8.49 (2s, 2H pyrazine); 9.28 (s, 1H, NH)
10
3394, 3279, 3123, 2858, 1668,
1601, 1533, 1414, 1297, 1262,
1117, 991, 877
(CD3)2CO: 2.44 (3H, s, SCH3); 2.55 (3H, s, SCH3);
3.65-3.85 (16H, 2m, 2 × morpholine);
6.60 (2H, br. s, NH2); 8.33 (s, 1H pyrazine);
8.62 (d, 2H pyrazine); 8.69 (s, 1H pyrazine).
Two isomers 1:1 [9]
1188

TABLE 2 (continued)
1
2
3
11a
3401, 3306, 3262, 2919, 2855,
1637, 1528, 1434, 1360, 1279,
1173, 1112, 1008, 848
DMSO-d6: 3.50-3.90 (2m, 8H morpholine);
8.90 and 9.20 (2s, 2H pyrazine)
11b
3288, 3147, 1664, 1634, 1599,
1495, 1429, 1367, 1340, 1303,
1266, 1228, 1169, 1016, 927,
757, 692, 453
CDCl3: 3.35 and 4.20 (2m, 8H piperazine);
6.95 and 7.30 (2m, 5H phenyl);
8.66 and 9.20 (2s, 2H pyrazine)
12a
12b
3476, 3359, 3276, 2972, 2857,
1677, 1560, 1527, 1429, 1303,
1260, 1116, 1024, 891
DMSO-d6: 3.35-3.90 (16H, m, 2 morpholine);
8.57 and 8.60 (2s, 2H pyrazine); 12.67 (1H, s, NH)
3383, 3033, 2853, 1664, 1598,
1532, 1427, 1347, 1301, 1260,
1233, 1118
CDCl3: 3.28; 3.73; 3.87 and 4.20 (4m, 16H morpholine
and piperazine); 6.30 (2H, br. s, NH2);
6.90-7.35 (2m, 5H phenyl);
8.31 and 8.40 (2s, 2H pyrazine); 13.36 (1H, s, NH)
13
3067, 2963, 2859, 1577, 1525,
1469, 1360, 1260, 1209, 1118,
1082, 993, 948, 859
CDCl3: 2.84 (3H, s, CH3);
3.64 and 3.86 (2m, 8H morpholine);
8.18 and 8.79 (2s, 2H pyrazine)
14a
14b
2921, 2864, 1512, 1264, 1164,
1118, 1006, 906
1600, 1513, 1450, 1399, 1310,
1298, 1273, 1230, 1162, 1026,
1008, 933, 764, 696, 456
CDCl3: 3.51 and 3.90 (2m, 8H morpholine);
8.58 and 9.36 (2s, 2H pyrazine)
CDCl3: 3.37 and 3.84 (2m, 8H morpholine);
7.00 and 7.32 (2m, 5H phenyl);
8.56 and 9.35 (2s, 2H pyrazine)
The alkylation reaction proceeded differently in alkaline medium, and the reaction products depended on
the molar ratios of the reagents. The use of at least double molar excess of the base and the alkyl halide produced
pure dithiocarbazoic acid diesters 3a,b in very good yields, while the use of stoichiometric amounts of the
reagents gave dithiocarbazoic acid monoester 4 as the main product, and only small amounts of the diester. The
mixtures of mono and diesters were difficult to separate, and for this reason another way of monoester 4
synthesis was designed. Namely, benzyl-6-chloropyrazine-2-carbimide (5), synthesized according to the known
method [4], was reacted with dithiocarbazoic acid methyl ester to give the desired compound.
In the next step of the study, the reactivity of the synthesized dithiocarbazoic acid mono- and diesters
towards secondary amines was tested. Because of the two potential reaction centers in the substrate molecules,
namely, the halide and methylthio groups, the reaction products depended strongly on the solvent, molar ratios
of the reagents, and the way the reactions were carried out. Prolonged heating of the diester 3a with morpholine
and 4-phenylpiperazine led to the formation of 1,2,4-triazole derivatives 6a,b, with amine substituents in
position 6 of the pyrazine ring and in position 3 of the triazole ring. Low-boiling amines, pyrrolidine, piperidine,
and homopiperidine, in spite of long reflux, gave only the products of chlorine atom substitution. In addition,
yields of the products 7a-e were poor, and the compounds were strongly contaminated. Good yields of pure
compounds 7a-e were obtained in the reactions with all the amines upon heating for 15-30 min in
dimethylformamide.
The reactions of dithiocarbazoic acid monoester 4 with morpholine and 4-phenylpiperazine gave
different products. In this case, attempts at selective substitution of the chlorine atom in the piperazine ring or the
methylthio group failed. Short heating in the neat amines and in various solvents led to difficultly separable
mixtures, while prolonged heating in neat amines produced compounds 8a and 8b formed by replacement of
both chlorine atom and the methylthio group by the amine residue, and simultaneous cyclization to the
1,3,4-thiadiazole system.
The structures of compounds 8a and 8b were confirmed by independent synthesis. Thus, imino esters 5
and 9 were reacted with hydrazinocarbodithioic acid methyl ester, as well as with hydrazino-, morpholino- and
1-phenylpiperazine-4-carbothioic acid hydrazide, to give compounds 11a,b and 10, 12a,b, respectively.
1189

Compounds 10 and 11a,b in acidic media underwent cyclization to the corresponding 1,3,4-triazole derivatives
13 and 14a,b, similarly as compound 2a obtained from methyl N'-[amino(6-chloropyrazin-2-
yl)methylene]hydrazinocarbodithioate (4). Heated in an excess of morpholine or 1-phenylpiperazine, compounds
2a, 13, and 14a,b yielded the pyrazinylthiadiazole derivatives 8a,b. The same compounds were formed by
cyclization of compounds 12a,b in acidic media.
Variation of the secondary amine in the above reactions would, presumably, make possible synthesis of
analogues of compounds 8a,b with any desired amine substituent. The reactions of compounds 13 and 14a with
1-phenylpiperazine seem to confirm this presumption, as the phenylpiperazine substituent was found in position
2 of the 1,2,4-thiadiazole system of compound 8c and in the pyrazine ring of compound 8d.
MICROBIOLOGY
The tuberculostatic activity of the new compounds was tested towards Myc. tbc H37Rv strain and two
"wild" strains isolated from tuberculosis patients: one resistant to p-aminosalicylic acid (PAS), isonicotinic acid
hydrazide (INH), ethambutol (EMB), and ryfampycine (RFP), and the other fully sensitive to the drugs
administered.
In vitro investigations were carried on by a classical test tube method [5] of successive dilutions with
Youman's fluid medium containing 10% of bovine serum.
The determined minimum concentrations inhibiting the growth of tuberculous strains (MIC) showed the
tested group of compounds to be of low activity. MIC values for most of the compounds were within the limits
125-500 µg/ml.
The highest activity was shown by compound 8, with MIC value for H37Rv strain 32 µg/ml, and
63 µg/ml for both "wild" strains, and by compound 4, with MIC value 32 µg/ml for all the strains used.
EXPERIMENTAL
Melting points were determined with a Boetius apparatus and are uncorrected. The IR spectra were taken
with a Satellite spectrophotometer. The 1H NMR spectra were taken with a Varian Gemini 200 spectrometer BS-
487c. Reaction yields and the physical constants of the compounds obtained are given in Table 1.
5-(6-Chloropyrazin-2-yl)[1,3,4]thiadiazole-2-thiol (1). To
a
solution of 6-chloropyrazine-
carbamidrazone [5] (0.85 g, 5 mmol) in ethanol (25 ml), carbon disulfide (0.6 ml, 10 mmol) was added and the
mixture was refluxed for 1 h. After cooling, the resulting precipitate was filtered off and recrystallized.
5-(6-Chloropyrazin-2-yl)-2-methylthio[1,3,4]thiadiazole (2a). A. To a solution of 6-chloro-
pyrazinecarbamidrazone (0.85 g, 5 mmol) in ethanol (25 ml), carbon disulfide (0.5 ml, 8 mmol) was added and
after 5 min MeI (0.35 ml, 5 mmol) was introduced to the reaction mixture, which was refluxed for 1 h. After
cooling, the resulting precipitate was filtered off and recrystallized.
B. Compound 1 (0.22 g, 10 mmol) was added to a solution of KOH (0.56 g, 10 mmol) in ethanol (5 ml),
then MeI (0.6 g, 10 mmol) was introduced and the mixture was refluxed for 0.5 h. The product precipitated after
cooling.
C. To a solution of compound 4 (0.26 g, 1 mmol) in ethanol (5 ml) concentrated HCl (0.5 ml) was added
and the mixture was heated to boiling. On cooling, 20 g of ice was added and the precipitated compound 2a
filtered off.
3-Benzylthio-5-(6-chloropyrazin-2-yl)[1,3,4]thiadiazole (2b). This compound was obtained as
described for 2a (see Method A) taking benzyl chloride (0.8 ml, 5 mmol) instead of MeI.
1190

N'-[Amino-(6-chloropyrazin-2-yl)methylene]hydrazinocarbodithioic Acid Dimethyl Ester (3a). A
mixture of 6-chloropyrazinecarbamidrazone (10.3 g, 0.06 mmol), methanol (200 ml), triethylamine (20 ml,
0.15 mmol), CS2 (8 ml, 0.13 mmol), and MeI (10 ml, 0.16 mmol) was refluxed until homogenization and
allowed to cool. After additional ice-cooling the precipitated compound 3a was filtered off and recrystallized.
N'-[Amino-(6-chloropyrazin-2-yl)methylene]hydrazinocarbodithioic Acid Dibenzyl Ester (3b).
Obtained as described for 3a, starting from chloroamidrazone (3.4 g, 20 mmol), methanol (20 ml), triethylamine
(6 ml, 40 mmol), CS2 (2 ml, 33 mmol), and benzyl chloride (5.5 ml, 50 mmol).
N'-[Amino-(6-chloropyrazin-2-yl)methylene]hydrazinocarbodithioic acid methyl ester (4). A. To 6-
chloropyrazinecarbamidrazone (8.5 g, 50 mmol) dissolved in ethanol (100 ml) a solution of KOH (2.8 g,
50 mmol) in ethanol (50 ml) was added, and then, through a reflux condenser, CS2 (3 ml, 5 mmol) was
introduced. Water was added to the suspension until the solution clarified (ca 50 ml) and then MeI (3.2 ml,
50 mmol) was added dropwise. The mixture was allowed to stand for 0.5 h, then evaporated to half of its initial
volume and cooled. The precipitate was collected and recrystallized. TLC analysis showed a small admixture of
compound 3a.
B. A warm solution of compound 5 [4] (2.5 g, 10 mmol) in methanol (10 ml) was treated with
hydrazinocarbodithioic acid methyl ester [6] (1.2 g, 10 mmol) dissolved in methanol (20 ml) and stirred for
0.5 h. A few seconds after combining both solutions, a yellow crystalline precipitate appeared. After another
hour of standing and cooling the mixture, the compound was filtered off.
3-Morpholino-5-(6-morpholinopyrazin-2-yl)[1,2,4]triazole (6a). Compound 3a (0.45 g, 2 mmol) and
morpholine (2 ml, 25 mmol) were refluxed for 10 h. After cooling, methanol was added (5 ml) and the
precipitated product was collected and recrystallized.
3-(4-Phenylpiperazin-1-yl)-5-[6-(4-phenylpiperazin-1-yl)pyrazin-2-yl][1,2,4]triazole (6b). Compound
3a (1.38 g, 5 mmol), 1-phenylpiperazine (3.5 ml, 20 mmol), and DMF (2 ml) were refluxed for 3 h.
Methanethiol was evolved vigorously throughout the procedure. After cooling to ambient temperature, the
mixture was treated with methanol (5 ml), ice-cooled, and a precipitate of compound 6b was collected.
N'-[Amino(6-cycloaminopyrazin-2-yl)methylene]hydrazinocarbodithioic Acid Dimethyl Esters (7a-
e). Compound 3a (1.38 g, 5 mmol), the corresponding amine (3 ml), and DMF (3 ml) were refluxed for 15 min.
The mixture was then poured on ice (30 g) and the precipitate was collected and recrystallized.
3-Morpholino-5-(6-morpholinopyrazin-2-yl)[1,3,4]thiadiazole (8a). A. Compound 4 (1.3 g, 5 mmol)
and morpholine (5 ml, 50 mmol) were refluxed for 3 h. On cooling, a precipitate was formed. The solid was
filtered off, washed with methanol, and crystallized.
B. Compound 12a (0.9 g, 2.5 mmol) dissolved in warm methanol (10 ml) was treated with concentrated
HCl (0.5 ml) and allowed to stand until cooled. The precipitate was collected and recrystallized.
C. Compound 2a or 13 (2 mmol), morpholine (3 ml, 50 mmol), and DMF (2 ml) were refluxed till the
methanethiol evolution ceased (about 20 h). On cooling, water (10 ml) was added, the mixture was allowed to
cool, and the precipitate was filtered off.
D. The compound was obtained as described above (see Method C) from 14c by heating in neat
morpholine for 3 h.
2-(4-Phenylpiperazin-1-yl)-5-[6-(4-phenylpiperazin-1-yl)pyrazin-2-yl][1,3,4]thiadiazole
(8b).
Compound 4 (0.65 g, 2.5 mmol) and 1-phenylpiperazine (1.5 ml, 10 mmol) in anhydrous dioxane (5 ml) were
refluxed for 20 h. Then water (20 ml) was added and the mixture was cooled in ice. The crystalline residue was,
after decantation of the liquid, purified by recrystallization.
2-(4-Phenylpiperazin-1-yl)-5-(6-morpholinopyrazin-2-yl)[1,3,4]thiadiazole (8c). A. Compound 13
(0.26 g, 1 mmol), 1-phenylpiperazine (2 ml, 13 mmol), and DMF (1 ml) were refluxed for 4 h and allowed to
stand for crystallization. Then MeOH (5 ml) was added and the product collected and recrystallized.
B. A solution of compound 10 (0.3 g, 1 mmol) in chloroform (2 ml) was added to a solution of
4-phenylpiperazinecarbodithioic acid hydrazide (0.24 g, 1 mmol) in DMSO (2 ml) and the mixture was stirred
for 48 h. Then methanol (10 ml) and concentrated HCl (1 ml) were added. The oily deposit crystallized while
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stirred. The whole was neutralized with saturated NaHCO3 solution. On cooling, the precipitate was filtered off,
washed with water, and crystallized from MeOH–water mixture.
2-Morpholino-5-[6-(4-phenylpiperazin-1-yl)pyrazin-2-yl][1,3,4]thiadiazole (8d). Compound 14a
(0.46 g, 2.5 mmol), 1-phenylpiperazine (1.5 ml, 10 mmol), and dioxane (3 ml) were refluxed for 2 h. On boiling,
the amine hydrochloride deposited. After cooling to ambient temperature the mixture was additionally ice-
cooled. The precipitate was collected and recrystallized from dioxane.
6-Morpholinopyrazine-2-carboimidic Acid Benzyl Ester (9). Obtained as described for compound 5;
2-cyano-6-morpholinopyrazine [8] (3.8 g, 20 mmol) and benzyl alcohol (3 ml, 30 mmol) were taken for the
reaction.
N'-[Amino(6-morpholinopyrazin-2-yl)-methylene]hydrazinocarbodithioic Acid Methyl Ester (10).
Compound 9 (1.5 g, 5 mmol) was dissolved in hot MeOH (25 ml), and a solution of hydrazinecarbodithioic acid
methyl ester [7] (1.22 g, 10 mmol) in MeOH (10 ml) was added. The mixture was stirred for 2 h. After strong
cooling, the product was filtered off and recrystallized from ethanol.
Morpholine-4-carbothioic Acid N'-[Amino(6-chloropyrazin-2-yl)methylene]hydrazide (11a). To
compound 5 (1.28 g, 5 mmol) dissolved in hot MeOH (10 ml) a hot solution of morpholine-4-carbothioic acid
hydrazide [7] (0.8 g, 5 mmol) in MeOH (15 ml) and water (5 ml) was added. The mixture was stirred for 2 h,
then ice-cooled and the product filtered off. From the filtrate an additional portion of product was precipitated by
water.
4-Phenylpiperazine-1-carbothioic Acid N'-[Amino(6-chloropyrazin-2-yl)methylene]hydrazide
(11b). To a solution of 4-phenylpiperazinecarbothioic acid hydrazide (0.24 g, 1 mmol) in DMSO (2 ml),
compound 4 (0.25 g, 1 mmol) was added and the mixture was stirred for 48 h. Then the reaction mixture was
diluted with water (10 ml) and extracted twice with CHCl3 (3 × 30 ml). The combined extracts were dried with
anhydrous MgSO4, chloroform was evaporated, and the residue was crystallized from ethanol.
Morpholine-4-carbothioic Acid N'-[Amino(6-morpholinopyrazin-2-yl)methylene]hydrazide (12a).
Obtained by analogy to compound 10; morpholine-4-carbothioic acid hydrazide (5 mmol) was taken for the
reaction instead of H2NNHCSSMe.
4-Phenylpiperazine-1-carbothioic Acid N'-[Amino(6-morpholinopyrazin-2-yl)methylene]hydrazide
(12b). Obtained as described for compound 11b; compound 9 was taken for the reaction instead of 4.
2-(5-Methylthio)-5-(6-morpholinopyrazin-2-yl)[1,3,4]thiadiazole (13). Compound 10 (1.1 g,
3.3 mmol) dissolved in hot MeOH (40 ml) was treated with concentrated HCl (1 ml) and allowed to cool down.
After additional ice-cooling the product was filtered off.
5-(6-Chloropyrazin-2-yl)-2-morpholino[1,3,4]thiadiazole (14a). Obtained by analogy to compound 13
from compound 11a (1.5 g, 5 mmol).
5-(6-Chloropyrazin-2-yl)-2-(4-phenylpiperazino)[1,3,4]thiadiazole (14b). To a solution of 4-phenyl-
piperazine-1-carbodithioic acid hydrazide (0.24 g, 1 mmol) in DMSO (2 ml), compound 4 (0.25 g, 1 mmol) was
added and the mixture was stirred for 48 h. Then the reaction mixture was diluted with water (10 ml) and treated
with concentrated HCl (1 ml). On cooling, the deposited product was filtered off and crystallized from ethanol.
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