Use of tetramethylthiuram disulfide in synthesis of nitrogen-containing heterocyclic compounds

Article abstract of DOI:10.1007/s10593-005-0200-x

We have developed a method for synthesis of aryl isothiocyanates by means of thiocarbamoylation of aromatic amines by tetramethylthiuram disulfide followed by degradation of the intermediate N₍₁₎-aryl-N,N- dimethylthiourea by concentrated HCl. We have shown that thiocarbamoylation of 4-amino-5-ethyl-4H-1,2,4-triazole-3-thiol occurs at the 2 position of the triazole ring, while thiocarbamoylation of 4-amino-3-methyl-6-phenyl-4,5- dihydro-1,2,4-triazin-5-one leads to the dihetaryl-substituted thiourea. We consider the possibility of using N₍₁₎-aryl-N,N-dimethylthioureas as analogs of isothiocyanates in reactions with N-nucleophiles. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0200-x

Chemistry of Heterocyclic Compounds, Vol. 41, No. 5, 2005
USE OF TETRAMETHYLTHIURAM DISULFIDE
IN SYNTHESIS OF NITROGEN-CONTAINING
HETEROCYCLIC COMPOUNDS
A. M. Demchenko1, V. A. Yanchenko1, V. V. Kisly1, and M. S. Lozinskii2
We have developed a method for synthesis of aryl isothiocyanates by means of thiocarbamoylation of
aromatic amines by tetramethylthiuram disulfide followed by degradation of the intermediate N(1)-aryl-
N,N-dimethylthiourea by concentrated HCl. We have shown that thiocarbamoylation of 4-amino-5-ethyl-
4H-1,2,4-triazole-3-thiol occurs at the 2 position of the triazole ring, while thiocarbamoylation of 4-
amino-3-methyl-6-phenyl-4,5-dihydro-1,2,4-triazin-5-one leads to the dihetaryl-substituted thiourea. We
consider the possibility of using N(1)-aryl-N,N-dimethylthioureas as analogs of isothiocyanates in
reactions with N-nucleophiles.
Keywords: N(2)-(3-chloro-2-methylphenyl)-2-amino-5,6-dihydro-4H-1,3-thiazine, 4-amino-3-methyl-6-
phenyl-4,5-dihydro-1,2,4-triazin-5-one, N(1)-aryl-N,N-dimethylthioureas, aryl isothiocyanates, N-aryl-
N(1)-(5-mercapto-3-methyl-4H-1,2,4-triazol-4-yl)thioureas, 6-(4-bromophenylamino)-3-methyl[1,2,4]-
triazolo[3,4-b][1,3,4]thiadiazole, tetramethylthiuram disulfide.
Aryl isothiocyanates are widely used in preparative organic synthesis, but their accessibility is limited
primarily by the cost and risk of the thiophosgene method [1]. So it is important to look for alternative methods
for synthesis of aryl isothiocyanates using a process that is accessible, low cost, and safe.
In reactions with aliphatic and aromatic amines, tetramethylthiuram disulfide (TMTD) forms
N(1)-alkyl(aryl)-N,N-dimethylthioureas [2-5]. The latter, when treated with excess acetic anhydride, acetyl
chloride, sulfuric or hydrochloric acid, undergo degradation to form the corresponding isothiocyanates [5].
We have developed a one-pot method for obtaining the aryl isothiocyanates 3a-e from the corresponding
aromatic amines 1a-e and 80% wettable TMTD powder. Preliminary isolation and purification of the active
substance from off-grade TMTD fungicide does not result in a significant increase in the yield of the final
reaction product, so thiocarbamoylation of the aromatic amines was carried out by boiling equimolar amounts of
the reagents in ethanol together with the filler. The thioureas 2a-g obtained in this case, when boiled with a
three-fold excess of concentrated hydrochloric acid, form the corresponding aryl isothiocyanates 3 (Scheme 1).
We know [6] that when substituted o-aminophenols are boiled with TMTD, the reaction does not stop in
the step of formation of the corresponding thiourea but rather further cleavage of the N,N-dimethylamino group
occurs, followed by cyclization to form substituted 2-mercaptobenzoxazoles. When TMTD is reacted with
5-(2-aminophenyl)-1,3,4-oxadiazole-2-thiol, after initial formation of thiourea, the adduct undergoes a series of
sequential rearrangements with formation of 2-mercapto-1,3,4-thiadiazole[2,3-b]quinazolin-5-one [7]. Based on
__________________________________________________________________________________________
1
T. G. Shevchenko Chernigov State Pedagogical University, Chernigov 14038, Ukraine; e-mail:
2
demch@cn.relc.com. Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 775-780, May, 2005. Original article
submitted February 26, 2003.
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0009-3122/05/4105-0668©2005 Springer Science+Business Media, Inc.

Scheme 1
S
Me
N
S
Me
S
Me
NCS
HN
N
NH2
Me
S
N
Me
S
Me
HCl
TMTD
R
R
R
1a–g
2a–g
3a–e
1-3 a R = H, b R = 2-Me, c R = 3-Me, d R = 4-Me, e R = 4-ОMe, f R = 3-Cl-2-Me, g R = 4-Br
these data, we hypothesized that as a result of reaction of 4-amino-5-ethyl-3-mercapto-4H-1,2,4-triazole (4) with
TMTD, either 3-ethyl-6-mercapto[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (5) or N,N-dimethyl-N'-(3-ethyl-5-
mercapto-4H-1,2,4-triazol-1-yl)thiourea (6) can form. Elemental analysis data for the product of reaction of
compound 4 with TMTD indicate formation of compound 6. However, according to the 1H NMR spectra, instead
of the expected addition of the dimethylaminomethylthione group at the exocyclic amino group of the
heterocycle, addition occurs at the 2 position of the triazole ring with formation of 1-[(N,N-dimethyl)-
thiocarbamoyl]-4-amino-3-ethyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole (7).
N
N
N
S
SH
N
N
TMTD
+
N
Et
N
SH
Et
NH2
5
4
S
NMe2
S
N
SH
N
S
N
N
N
Et
N
N
NMe2
H
Et
NH2
6
7
1
Thus in the H NMR spectrum of compound 7, we observe a two-proton singlet for the N-amino group
at 5.52 ppm and two singlets for the dimethylamino group at 3.50 ppm and 3.59 ppm, while the protons of the
methyl and methylene groups of the ethyl substituent resonate at 1.86 ppm and 2.65 ppm, depending on their
multiplicity.
The aryl isothiocyanates 3 obtained were reacted with 4-amino-3-mercapto-5-methyl-4H-1,2,4-triazole
(8).
N
Me
N
N
Me
N
ArNCS
N
N
HN
S
SH
H2N
SH
H
N
8
Ar
9a–d
9 a Ar = Ph, b Ar = 2-MeС6Н4, c Ar = 3-MeС6Н4, d Ar = 4-MeOС6Н4
669

After brief heating of equimolar amounts of the corresponding starting materials in benzene, we isolated
1
N-aryl-N(1)-(5-mercapto-3-methyl-4H-1,2,4-triazol-4-yl)thioureas 9a-d, in the H NMR spectra of which signals
from both NH groups were recorded in the 9.9-10.2 ppm region along with a one-proton singlet from the SH
group in the 13.3-13.4 ppm region.
When thiourea 2f is boiled with 3-amino-1-propanol in alcohol for 1 h, we obtain N-(3-hydroxypropyl)-
N(1)-(3-chloro-2-methylphenyl)thiourea (10), which when boiled in hydrochloric acid forms N(2)-(3-chloro-2-
methylphenyl)-2-amino-5,6-dihydro-4H-1,3-thiazine (11).
S
S
HN
NH(CH2)3OH
HCl
HN
N
Me
Cl
Me
Cl
HO(CH2)3NH2
2f
10
11
A distinguishing feature of the 1H NMR spectrum of compound 11 compared with disubstituted thiourea
10 is disappearance of the one-proton singlet from the OH group at 4.15 ppm and the one-proton singlet from the
NH group at 9.94 ppm. We also observe a shift of the multiplet for the three aromatic protons from the 7.13-7.22
ppm region upfield to the 6.64-6.94 ppm region.
After heating (30 h) N(1)-(4-bromophenyl)-N,N-dimethylthiourea (2g) with 4-amino-3-mercapto-5-
methyl-4H-1,2,4-triazole in DMF at 110°C, we isolated 6-(4-bromophenylamino)-3-methyl[1,2,4]triazolo-
[3,4-b][1,3,4]thiadiazole (12), completely identical to the product of reaction between 4-amino-3-mercapto-5-
1
methyl-4H-1,2,4-triazole and 4-bromophenyl isothiocyanate under the same conditions. In the H NMR
spectrum of amidine 12, the three-proton singlet of the methyl group appears in the 2.05 ppm region, while the
amidine proton is detected in the 10.1 ppm region as a one-proton singlet.
N
SH
N
Br
N
N
S
N
Me
NH2
N
N
2g
N
Me
H
12
Ph
Ph
O
N
N
NMe2
O
N
N
NH2
N
N
HN
N
HN
N
S
H2N
O
Me
TMTD
Me
O
Me
Me
HN
N
S
N
O
Me
N
Ph
N
Ph
N
13
N
14
Ph
N
15
670

When equimolar amounts of 4-amino-3-methyl-6-phenyl-4,5-dihydro-1,2,4-triazin-5-one (13) and
TMTD are boiled in ethanol, instead of the expected thiourea 14 we obtained the urea 15 in satisfactory yield. A
1
characteristic feature of the H NMR spectrum of the latter is the disappearance of the signals from the protons
of the N–NH2 group characteristic of the starting compound 13, and the appearance of a two-proton singlet from
the two NH groups at 13.8 ppm.
EXPERIMENTAL
The 1H NMR spectra were recorded on a Bruker-300 (300 MHz) in DMSO-d6, internal standard TMS.
N,N-Dimethyl-N(1)-(3-chloro-2-methylphenyl)thiourea (2f). A mixture of 3-chloro-2-methylaniline
(1f) (2.82 g, 0.02 mol) and 80% wettable powder of the fungicide TMTD (6 g, 0.02 mol) in ethanol (20 ml) was
boiled for 5 h. The hot reaction mixture was filtered to remove the filler and insoluble impurities and then cooled
down. The precipitate was filtered out and purified by crystallization from ethanol. Yield 3.71 g (81%); mp 149-
151°C. 1H NMR spectrum, δ, ppm: 2.24 (3H, s, CH3), 3.32 (6H, s, N(CH3)2); 7.03-7.24 (3H, m, C6H3); 8.74 (1H,
s, NH). Found, %: N 12.5; S 14.2. C10H13ClN2S. Calculated, %: N 12.3; S 14.0.
N(1)-(4-Bromophenyl)-N,N-dimethylthiourea (2g) was obtained similarly as compound 2f from
equimolar amounts of 4-bromoaniline 1g and 80% wettable powder of the fungicide TMTD. Yield 76%;
1
mp 165-167°C. H NMR spectrum, δ, ppm: 2.03 (6H, s, N(CH3)2); 7.32 and 7.50 (4H, dd, C6H4); 9.57 (1H, s,
NH). Found, %: Br 30.5; N 11.0. C9H11BrN2S. Calculated, %: Br 30.8; N 11.0.
Phenyl Isothiocyanate (3a) (General Procedure). A mixture of aniline (1a) (93 ml, 1 mol) and 80%
wettable powder of the fungicide TMTD (300 g, 1 mol) in ethanol (400 ml) was boiled for 5 h (~100°C). Then it
was distilled down to 2/3 of the solvent volume and, after cooling, conc. HCl (300 ml) was added. The reaction
mixture was boiled for another 5 h and, without cooling, the filler was filtered out. The filler was washed on the
filter with CCl4 (100 ml). The organic layer was separated and dried with calcined potassium carbonate. The
carbon tetrachloride was driven off and the phenyl isothiocyanate was distilled under vacuum. Yield 125 g
(93%); bp 109-111°C (20 mm Hg), nD20 1.6521.
The aryl isocyanates 3b-e were obtained similarly.
2-Methylphenyl Isothiocyanate (3b). Yield 81%; bp 122-123°C (20 mm Hg), nD 1.6365. According
20
to the data in [8], bp 108°C (5 mm Hg).
20
3-Methylphenyl Isothiocyanate (3c). Yield 84%; bp 126-128°C (20 mm Hg), nD 1.6331. According
to the data in [8], bp 110°C (5 mm Hg).
20
4-Methylphenyl Isothiocyanate (3d). Yield 86%; bp 120-121°C (20 mm Hg), nD 1.6349. According
to the data in [8], bp 116°C (5 mm Hg).
4-Methoxyphenyl Isothiocyanate (3e). Yield 79%; bp 156-157°C (20 mm Hg), nD20 1.6485. According
to the data in [8], bp 142°C (5 mm Hg).
1-[(N,N-Dimethyl)thiocarbamoyl]-4-amino-3-ethyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole (7) was
obtained as for compound 2f from equimolar amounts (0.02 mol each) of compound 4 and 80% wettable powder
of the fungicide TMTD. Yield 2.73 g (59%); mp 183-184°C. 1H NMR spectrum, δ, ppm: 1.86 (3H, t, CH3); 2.65
(2H, q, CH2); 3.50 (3H, s, NCH3); 3.59 (3H, s, NCH3); 5.52 (2H, s, NH2). Found, %: N 30.0; S 27.9. C7H13N5S2.
Calculated, %: N 30.3; S 27.7.
N(1)-(5-Mercapto-3-methyl-4H-1,2,4-triazol-4-yl)-N-phenylthiourea (9a) (General Procedure). A
mixture of 4-amino-5-methyl-4H-1,2,4-triazole-3-thiol (8) (1.30 g, 0.01 mol) and phenyl isothiocyanate 3a
(1.35 g, 0.01 mol) was boiled in benzene (20 ml) for 1 h and cooled. The precipitate was filtered out and
1
crystallized from an ethanol–DMF mixture. Yield 2.20 g (83%); mp 212-213°C. H NMR spectrum, δ, ppm:
2.28 (3H, s, CH3); 7.17-7.63 (5H, m, C6H5); 10.1 (1H, s, NH); 10.2 (1H, s, NH); 13.3 (1H, s, SH). Found, %:
N 26.5; S 23.9. C10H11N5S2. Calculated, %: N 26.4; S 24.2.
Thioureas 9b-d were obtained similarly.
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N-(2-Methylphenyl)-N(1)-(5-mercapto-3-methyl-4H-1,2,4-triazol-4-yl)thiourea (9b). Yield 81%;
mp 214-215°C. 1H NMR spectrum, δ, ppm: 2.26 (3H, s, CH3); 2.28 (3H, s, CH3); 7.15-7.24 (4H, m, C6H4); 9.88
(1H, s, NH); 10.2 (1H, s, NH); 13.3 (1H, s, SH). Found, %: N 25.0; S 22.9. C11H13N5S2. Calculated, %: N 25.1;
S 23.0.
N-(3-Methylphenyl)-N(1)-(5-mercapto-3-methyl-4H-1,2,4-triazol-4-yl)thiourea (9c). Yield 86%;
mp 229-230°C. 1H NMR spectrum, δ, ppm: 2.22 (3H, s, CH3); 2.32 (3H, s, CH3); 7.01-7.38 (4H, m, C6H4); 10.2
(2H, s, NH); 13.4 (1H, s, SH). Found, %: N 25.3; S 23.1. C11H13N5S2. Calculated, %: N 25.1; S 23.0.
N-(4-Methoxyphenyl)-N(1)-(5-mercapto-3-methyl-4H-1,2,4-triazol-4-yl)thiourea (9d). Yield 79%;
1
mp 222-223°C. H NMR spectrum, δ, ppm: 2.27 (3H, s, CH3); 3.88 (3H, s, OCH3); 6.83 and 7.44 (4H, dd,
C6H4); 9.98 (1H, s, NH); 10.0 (1H, s, NH); 13.3 (1H, s, SH). Found, %: N 24.0; S 21.5. C11H13N5OS2.
Calculated, %: N 23.7; S 21.7.
N-(3-Hydroxypropyl)-N(1)-(3-chloro-2-methylphenyl)thiourea (10). A mixture of compound 2f
(2.29 g) and 3-amino-1-propanol (0.75 g) in ethanol (40 ml) was boiled for 3 h on a water bath and then cooled.
The precipitate was filtered out and crystallized from 2-propanol. Yield 2.18 g (84%); mp 118-119°C. 1H NMR
spectrum, δ, ppm: 1.69 (2H, q, CH2); 2.26 (3H, s, CH3); 3.49 (2H, q, CH2); 3.57 (2H, q, CH2); 4.15 (1H, s, OH);
7.13-7.22 (3H, m, C6H3); 7.64 (1H, s, NH); 9.94 (1H, s, NH). Found, %: N 10.5; S 12.5. C11H15ClN2OS.
Calculated, %: N 10.8; S 12.4.
N(2)-(3-Chloro-2-methylphenyl)-2-amino-5,6-dihydro-4H-1,3-thiazine (11). A solution of compound
10 (1.5 g) in conc. HCl (20 ml) was boiled for 5 h and then cooled down. The reaction mixture was neutralized
with conc. NH4OH to ~pH 8. The precipitate was filtered out and crystallized from 2-propanol. Yield 1.39 g
(82%); mp 128-129°C. 1H NMR spectrum, δ, ppm: 2.03 (2H, q, CH2); 2.14 (3H, s, CH3); 2.94 (2H, t, CH2); 3.32
(2H, t, CH2); 6.64-6.94 (3H, m, C6H3); 7.13 (1H, s, NH). Found, %: N 11.5; S 13.5. C11H13ClN2S. Calculated, %:
N 11.6; S 13.3.
6-(4-Bromophenylamino)-3-methyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (12). A mixture of thiourea
2g (2.6 g), thiol 4 (1.30 g), and DMF (20 ml) was heated for 30 h at 110°C and cooled down. The reaction
mixture was poured into water, the crystallized precipitate was filtered out and crystallized from an ethanol–
DMF mixture. Yield 1.36 g (44%); mp 220-222°C. 1H NMR spectrum, δ, ppm: 2.05 (3H, s, CH3); 7.49 and 7.59
(4H, dd, C6H4); 10.1 (1H, s, NH). Found, %: N 22.5; S 10.5. C10H8BrN5S. Calculated, %: N 22.6; S 10.3.
N(1),N(2)-Di(3-methyl-5-oxo-6-phenyl-4,5-dihydro-1,2,4-triazin-4-yl)thiourea (15). A mixture of
compound 13 (2 g, 0.01 mol) and pure TMTD (2.4 g, 0.01 mol) in ethanol (20 ml) was boiled for 5 h and cooled
down. The precipitate was filtered out and recrystallized from DMF. Yield 0.83 g (37%); mp 251-252°C.
1H NMR spectrum, δ, ppm: 2.32 (6H, s, CH3); 7.43 (6H, m, C6H5); 8.07 (4H, d, C6H5); 13.8 (2H, s, NH).
Found, %: N 25.3; S 7.29. C21H18N8O2S. Calculated, %: N 25.1; S 7.18.
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