The reactions of hydroiodide of 2-amino-1-substituted guanidine derivatives with aromatic isothiocyanates

Article abstract of DOI:10.3987/COM-02-9461

In the reaction of hydroiodide of methyl ester of S-methylthio-semicarbazide with primary amines hydroiodides of 2-amino-1-substitutedguanidine were obtained (1). These compounds were then converted to respective 3-arylamino-4-substituted Δ²-1,2,4-triazoline-5-thione and 3- benzylamino-4-substituted Δ²-1,2,4 -triazoline-5-thione (2) in the reactions with isothiocyanates.

Full text of DOI:10.3987/COM-02-9461

HETEROCYCLES, Vol. 57, No. 6, 2002, pp. 1135-1141, Received, 25th February, 2002
THE REACTIONS OF HYDROIODIDE OF 2-AMINO-1-SUBSTITUTED
GUANIDINE DERIVATIVES WITH AROMATIC ISOTHIOCYANATES
Maria Dobosz* and Monika Wujec
Department of Organic Chemistry, Medical University, Staszica 6, 20-081 Lublin,
Poland, wujec@panaceum.am.lublin.pl
Abstract - In the reaction of hydroiodide of methyl ester of S-methylthio-
semicarbazide with primary amines hydroiodides of 2-amino-1-
substitutedguanidine were obtained (1). These compounds were then converted
to respective 3-arylamino-4-substituted ∆2-1,2,4-triazoline-5-thione and 3-
benzylamino-4-substituted ∆2-1,2,4-triazoline-5-thione (2) in the reactions with
isothiocyanates.
INTRODUCTION
The salts of aminoguanidine are used as starting materials for preparation of 3-amino-1,2,4-triazole and
its derivatives which have numerous practical applications as the compounds of antiseptic action.1-18
The 3-amino-1,2,4-triazole known under the name of Amitrole or Amisole has also the herbicidal
properties.19-22 Their presence in soils causes the increase of carbohydrates content in plants,23 inhibits the
growth of Ochromonas denica, Euglena gracilis and Spirodella digoriza bacteria,23-28 as well as slows
down their reproduction processes owing to photosynthesis inhibition.
The reactions of aminoguanidine salts with isothiocyanates lead to formation of hydrochlorides of 4-
substituted derivatives of 1-amidinethiosemicarbazide29 or p-toluenesulfonates.30
Thiosemicarbazide derivatives cyclized in basic medium have converted to 4-substituted derivatives of 3-
amino-1,2,4-triazoline-5-thione23,30 whereas in acidic media the derivatives of 1,3,4-thiadiazole were
formed.30
Aminoguanidine salts have a composition similar to amidrazones salts, so they can give the similar
reactions as amidrazones salts. The reaction of amidrazones salts with isothiocyanates leads to 3,4-
disubstituted ∆2-1,2,4-triazoline-5-thione according to Scheme 1.31,32
The similar course of the reaction cyclization with aromatic isothiocyanates is should in the case of use of
the salts of aminoguanidine derivatives.

Scheme 1
R'
N
NH R'
N
N
C
S
N H R"
R"
R
C
R C
NCS
NH2
NH2
HCl
HCl
N
N
C
R"
R
C
NH4Cl
S
N
R'
R, R’, R” = alkyl, aryl
RESULTS AND DISCUSSION
In this paper we report a formation of aminoguanidine salts in the reaction of hydroiodide of S-
methylthiosemicarbazide with aniline, 3-toluidine and benzylamine. The products of above were cyclized
by reaction with aromatic isothiocynates.
The reaction were performed according to the Scheme 2.
Scheme 2
N
NH2
N
NH2
R1
H
R1
C
1
CH3
S
C
CH3SH
NH2
HI
NH2
HI
R2
NCS
N
N
NH
NH
C
1
R
C
H2N C
C
S
S
N
R2
N
R2
2
3
The reactions of hydroiodide of S-methylthiosemicarbazide with aniline, 3-toluidine and benzylamine in
dry methanol at room temperature were realized. The cyclization of new obtaining hydroiodides (1) with
aromatic isothiocyanates was carried out in dry ethanol in boiling point for 3 h or in N,N-
dimethylacetamide at temperature 90oC for 5 h. The conditions of the reactions were established
experimentally.
Based on the preliminary tests33 it was found that depending on temperature the reaction had a two-
pathway character (product (2) or product (3)). Product (2) was the result of the reaction carried out at 78-

90oC. Product (3) was obtained by using aromatic isothiocyanates in the reaction at temperature 110-
120oC. There were the same compounds as the ones obtained in the reaction of salts of aminoguanidine
1
with aromatic isothiocyanates.33 Mixed melting points have not shown any depression. The IR and H
NMR spectra of compounds (3) were also identical with compounds described previously.33
Table 1
Product
R1
Yield
[%]
84
C6H5NH-
1a
1b
1c
3-CH3C6H4NH- 90
C6H5CH2NH-
79
Table 2
Product
R1
Yield
[%]
72
R2
C6H5NH-
C6H5
2a
2b
2c
2d
2e
2f
C6H5NH-
C6H5NH-
4-CH3C6H4 70
4-CH3OC6H4 65
3-CH3C6H4NH- C6H5
72
3-CH3C6H4NH- 4-CH3C6H4 75
3-CH3C6H4NH- 4-CH3OC6H4 78
C6H5CH2NH-
C6H5CH2NH-
C6H5CH2NH-
C6H5
70
2g
2h
2i
4-CH3C6H4 64
4-CH3OC6H4 52
The structure of the new products obtained was confirmed by elemental analyses as well as by IR and 1H
NMR spectra.
EXPERIMENTAL
Melting points were determined in Fisher-Johns blocs and presented without any corrections. IR spectra
1
were recorded in KBr using Specord IR-75 spectrophotometer. The H NMR spectra were recorded on
Tesla BS-567 A spectrometer (100 MHz) in DMSO-d6 with TMS as internal standard. Chemicals were
purchased from Merck Co. or Fluka Ltd. and used without further purification. Purity was checked by

TLC on Merck Co. plates Aluminium oxide 60 F254 in a CHCl3/C2H5OH (10:1) solvent system with UV
visualization.
2-Amino-1-phenylguanidine hydroiodide (1a), 2-amino-1-(3-tolyl)guanidine hydroiodide (1b) and 2-
amino-1-benzylguanidine hydroiodide (1c)
2.3 g (0.01 mol) of hydroiodide of S-methylthiosemicarbazide and 0.01 mol of amine dissolved in 30 mL
of dry methanol were placed in reaction flask and kept for 48 h at rt. Then the reaction mixture was
distilled under reduced pressure (water-solution pump) in order to removal methanol, and then the residue
(1/3 of starting volume) was treated with dry ether. The product was filtered off, dried and finally
crystallized from ethanol (79-90%). The results are collected in the Table 1.
o
1
2-Amino-1-phenylguanidine hydroiodide (1a): mp 124-125 C. H NMR (DMSO-d6) δ: 5.72(s, 2H,
+
NH2); 7.20-7.60(m, 5H, arom); 7.83(s, 3H, NH2 H); 10.35(s, 1H, NH). Anal. Calcd for C7H11N4I: C
30.23, H 3.99, N 20.15. Found: C 30.15, H 4.31, N 21.01.
o
1
2-Amino-1-(3-tolyl)guanidine hydroiodide (1b): mp 116-118 C. H NMR (DMSO-d6) δ: 2.50(s, 3H,
+
CH3); 5.98(s, 2H, NH2); 7.30-7.64(m, 4H, arom); 7.92(s, 3H, NH2 H); 10.35(s, 1H, NH). Anal. Calcd for
C8H13N4I: C 32.89, H 4.49, N 19.18. Found: C 33.70, H 4.80, N 19.91.
o
1
2-Amino-1-benzylguanidine hydroiodide (1c): mp 123-125 C. H NMR (DMSO-d6) δ: 4.43(d, 2H,
+
CH2); 5.61(s, 2H, NH2); 7.11-7.46(m, 5H, arom); 7.91(s, 3H, NH2 H); 8.66(s, 1H, NH). Anal. Calcd for
C8H13N4I: C 32.89, H 4.49, N 19.18. Found: C 33.12, H 4.52, N 19.31.
3-Arylamino-4-substituted ∆2-1,2,4-triazoline-5-thione (2a-2f) and 3-benzylamino-4-substituted ∆2-1,2,4-
triazoline-5-thione and (2g-2i)
a) Procedure for 2c, 2e,2f, 2g, 2h, 2i.
0.01 Mol of hydroiodides (1a-1c) and 0.01 mol of aromatic isothiocyanates dissolved in 30 mL of dry
ethanol were refluxed for 3 h. Then the reaction mixture was distilled under reduced pressure. The
product of the reaction was washed carefully with water and ether, dried and crystallized from ethanol
(52-78%). The results are collected in the Table 2.
o
3-Phenylamino-4-(4-methoxyphenyl)-∆2-1,2,4-triazoline-5-thione (2c): mp 205-207 C. IR (cm-1): 3340
1
NH; 3007 CH arom; 2967, 1456 CH aliph; 1588 C=N; 1513 C-N; 1316 C=S; 1250 C-O-C. H NMR
(DMSO-d6) δ: 3.83(s, 3H, CH3); 7.14-7.37(m, 9H, arom); 10.93(s, 1H, NH); 13.97(2s, 1H, NH-C=S).
Anal. Calcd for C15H14N4OS: C 60.38, H 4.73, N 18.78. Found: C 61.11, H 4.55, N 18.54.
o
3-(3-Tolyl)amino-4-(4-methylphenyl)-∆2-1,2,4-triazoline-5-thione (2e): mp 133-136 C. IR (cm-1): 3248
1
NH; 3042 CH arom; 2923, 1458 CH aliph; 1572 C=N; 1515 C-N; 1373 C=S. H NMR (DMSO-d6) δ:
2.08(s, 3H, CH3); 2.39(s, 3H, CH3); 7.09-7.50(m, 8H, arom); 10.23(s, 1H, NH); 13.97(s, 1H, NH-C=S).
Anal. Calcd for C16H16N4S: C 64.84, H 5.44, N 18.90. Found: C 64.54, H 5.51, N 18.84.

3-(3-Tolyl)amino-4-(4-methoxyphenyl)-∆2-1,2,4-triazoline-5-thione (2f): mp 142-144 oC. IR (cm-1): 3232
1
NH; 3038 CH arom; 2970, 1462 CH aliph; 1595 C=N; 1511 C-N; 1378 C=S; 1257 C-O-C. H NMR
(DMSO-d6) δ: 2.65(s, 3H, CH3); 3.73(s, 3H, CH3); 7.04-7.53(m, 8H, arom); 10.14(s, 1H,NH); 13.94(s,
1H, NH-C=S). Anal. Calcd for C16H16N4OS: C 61.58, H 5.16, N 17.94. Found: C 61.50, H 5.12, N 17.84.
o
3-Benzylamino-4-phenyl-∆2-1,2,4-triazoline-5-thione (2g): mp 180-182 C. IR (cm-1): 3169 NH; 3047
CH arom; 2959, 1459 CH aliph; 1596 C=N; 1548 C-N; 1364 C=S. 1H NMR (DMSO-d6) δ: 4.48(d, J=5.6
Hz, 2H, CH2); 7.19-7.57(m, 10H, arom); 9.96(s, 1H, NH); 10.25(s, 1H, NH-C=S). Anal. Calcd for
C15H14N4S: C 63.80, H 4.50, N 19.84. Found: C 63.54, H 4.44, N 19.73.
o
3-Benzylamino-4-(4-tolyl)-∆2-1,2,4-triazoline-5-thione (2h): mp 163-165 C. IR (cm-1): 3149 NH; 3045
1
CH arom; 2949, 1457 CH aliph; 1589 C=N; 1510 C-N; 1347 C=S. H NMR (DMSO-d6) δ: 2.27(s, 3H,
CH3); 4.72(d, J=5.6 Hz, 2H, CH2); 7.08-7.85(m, 9H, arom); 9.59(s, 1H, NH); 10.17(s, 1H, NH-C=S).
Anal. Calcd for C16H16N4S: C 64.84, H 5.44, N 18.90. Found: C 64.53, H 5.28, N 18.98.
3-Benzylamino-4-(4-methoxyphenyl)-∆2-1,2,4-triazoline-5-thione (2i): mp 65-66 oC. IR (cm-1): 3152 NH;
3063 CH arom; 2950, 1446 CH aliph; 1591 C=N; 1514 C-N; 1360 C=S; 1262 C-O-C. 1H NMR (DMSO-
d6) δ: 3.74(s, 3H, CH3); 4.49(d, J=5.7 Hz, 2H, CH2); 6.85-7.52(m, 9H, arom); 9.42(s, 1H, NH); 10.91(s,
1H, NH-C=S). Anal. Calcd for C16H16N4OS: C 61.50, H 5.16, N 17.94. Found: C 61.28, H 5.07, N 17.80.
b) Procedure for 2a, 2b, 2d
0.01 Mol of hydroiodide (1a-1b) and 0.01 mol of aromatic isothiocyanates dissolved in 20 mL of N,N-
dimethylacetamide were placed in a round-bottomed flask and heated for 5 h on an oil bath at temperature
90oC. Then the reaction mixture was distilled under reduced pressure. The product of the reaction was
washed carefully with water and ethyl ether, dried and crystallized from dry ethanol (70-72%). The
results are collected in the Table 2.
o
3-Phenylamino-4-phenyl-∆2-1,2,4-triazoline-5-thione (2a): mp 165-167 C. IR (cm-1): 3427 NH; 2959
1
CH arom; 1597 C=N; 1548 C-N; 1368 C=S. H NMR (DMSO-d6) δ: 7.06-7.61(m, 10H, arom); 10.35(s,
1H, NH); 14.02(s, 1H, NH-C=S). Anal. Calcd for C14H12N4S: C 62.66, H 4.51, N 20.88. Found: C 62.24,
H 4.34, N 20.63.
o
3-Phenylamino-4-(4-methylphenyl)-∆2-1,2,4-triazoline-5-thione (2b): mp 80-82 C. IR (cm-1): 3501 NH;
3097 CH arom; 2968, 1457 CH aliph; 1572 C=N; 1514 C-N; 1365 C=S. 1H NMR (DMSO-d6) δ: 2.50(s,
3H, CH3); 7.09-7.51(m, 9H, arom); 10.24(s, 1H, NH); 13.97(s, 1H, NH-C=S). Anal. Calcd for
C15H14N4S: C 63.80, H 5.00, N 19.84. Found: C 63.64, H 5.01, N 19.64.
o
3-(3-Tolyl)amino-4-phenyl-∆2-1,2,4-triazoline-5-thione (2d): mp 135-137 C. IR (cm-1): 3504 NH; 3095
CH arom; 2958, 1452 CH aliph; 1594 C=N; 1546 C-N; 1367 C=S. 1H NMR (DMSO-d6) δ: 2.51(s, 3H,
CH3); 7.35-7.64(m, 9H, arom); 10.35(s, 1H, NH); 14.00(s, 1H, NH-C=S). Anal. Calcd for C15H14N4S:

C 63.80, H 4.50, N 19.84. Found: C 63.54, H 4.52, N 19.83.
3-Amino-4-substituted ∆2 -1,2,4-triazoline-5-thione (3). General procedure:
0.01 Mol of hydroiodide (1a-1c) and 0.01 mol of aromatic isothiocyanates dissolved in 20 mL of N,N-
dimethylacetamide were placed in a round-bottomed flask and heated for 5 h on an oil bath at temperature
110-120oC. Then the reaction mixture was distilled under reduced pressure. The product of the reaction
was washed carefully with water and ether, dried and crystallized fromdry ethanol (82-90%).
3-Amino-4-phenyl-∆2 -1,2,4-triazoline-5-thion (3a): mp 268-269 oC, lit., 34 mp 267-268 oC. Yield 84%.
o
34
o
3-Amino-4-(4-methylphenyl)-∆2 -1,2,4-triazoline-5-thion (3b): mp 286-287 C, lit.,
mp 286-287 C.
Yield 90%.
o
34
o
3-Amino-4-(4-methoxyphenyl)-∆2 -1,2,4-triazoline-5-thion (3c): mp 255-257 C, lit., mp 255-256 C.
Yield 86%.
o
34
o
3-Amino-4-(4-bromophenyl)-∆2 -1,2,4-triazoline-5-thion (3d): mp 290-292 C, lit.,
mp 289-290 C.
Yield 82%.
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