Synthesis of 2-(3-Substitutedamino-2,4-Dithiobiuretoformamidino-4-isobutoxyphenyl)-4-Methyl-5-Carboxy-1,3-Thiazoles

 

A. S. Shendge, D. T. Tayade^*, P. R. Kale

Department of Chemistry, Government Vidarbha Institute of Science and Humanities, Amravati 444604.

 

ABSTRACT:

A novel method has been developed for the synthesis of 2-(3-substitutedamino-2,4-dithiobiuretoformamidino-4-isobutoxyphenyl)-4-methyl-5-carboxy-1,3-thiazoles by the reaction of 2-(3-substitutedthioamidoformamidino-4-isobutoxyphenyl)-4-methyl-5-carboxy-1,3-thiazoles with substituted isothiocyanate in 60% ethanol-acetone. The method provides rapid and easy access to compounds in good yields by using 60% ethanol-acetone medium.

 

 

 

INTRODUCTION:

Heterocyclic compounds offer a high degree of structural diversity and have proven to be broadly and economically useful as therapeutic agents1. Dithiobiurato nucleus containing heterocyclic compounds show anti-tubercular, antibacterial, antifungal, antiviral, and anti-inflammatory activities2-6. The heteroacycles viz. thiocarbamides, dithiazoles, thiadiazoles, thiadiazines, dithiazines, triazines, dithiobiuretes compound have their own identity, importance and applications in medicinal, biological, agricultural, industrial and biochemical sciences7-11. Dithiobiuretes and their derivatives were used to synthesise various important 1,2,4-triazoles, 1,3,5-thiadiazolidines, 1,3,5-dithiazines, 1,3,5-thiadiazines and s-triazines heterocycles.

 

RESULTS AND DISCUSSION:

By considering all these things, we have developed new research schemes. During designing this scheme it was also planned to developed a new green route for the synthesis of  2-(3-substitutedamino-2,4-dithiobiureto formamidino-4-isobutoxyphenyl)-4-methyl-5-carboxy-1,3-thiazoles by the interactions of 2-(thioamidoformamidino-4-isobutoxyphenyl)-4-methyl-5-carboxy-1,3-thiazole and various substitute disothiocyanate in acetone, ethanol, ethanol-acetone medium at various percentage compositions and ratio. The main objective of this work is to synthesize a novel series of 2-(3-substitutedamino-2,4-dithiobiureto formamidino-4-isobutoxyphenyl)-4-methyl-5-carboxy-1,3-thiazoles  and also to investigate a new reaction medium for such types of  reactions and also to set up new reaction condition to reduce the time span of such type of reactions and at the same time it was also thought to increase the yield of product by maintaining the purity and green chemistry parameters. During the study, it was observed that the 60% ethanol-acetone medium was the best solvent which curtails the time span. This work is useful to incoming researcher in organic chemistry. In the synthesized compound the dithiobiurato substituent may enhance the potency of the compounds (Scheme 1).

 

 

Scheme-1

 

We developed new reaction condition in which the yield of products increase by decreasing time duration of the reaction mentioned in the literature. The literature survey reveals that previously such reactions were carried out in acetone medium. So different type of solvents with their percentage compositions were used to improve the yield and to reduce the time span of reaction. During the work it was observed the 60% ethanol-acetone mixture is the best solvent which increases the yield of product as well as curtail time span of reaction up to 4 hours by maintaining the purity of products. The results obtained during work are depicted (Table 1).

 

Sr. No.	Solvents	Time (h).	Yield (%)
1.	Acetone*	08	67
2.	Ethanol*	10	58
3.	Benzene	18	47
4.	Carbon tetrachloride	18	48
5.	Ethanol-Acetone (40%)	10	65
6.	Ethanol-Acetone (50%)	10	80
7.	Ethanol-Acetone (60%)	02	92
8.	Ethanol-Acetone (70%)	10	74
9.	Ethanol-Acetone (80%)	10	68
10.	Ethanol-Acetone (90%)	10	63

 

EXPERIMENTAL:

General remarks:

All reagents were purchased from commercial suppliers and used without further purification. Dry methanol and diethyl ether were purchased from Aldrich and were used as such. All reactions were run in oven-dried round bottom flask or vial containing a teflon-coated stir bar and sealed with septum. Analytical thin layer chromatography was carried out on silica pre-coated glass plates (Silica gel 60 F254, 0.25 mm thickness) and visualized with UV light at 254 nm. 1H NMR spectra were recorded on Bruker 400-MHz Ultrashield Advance II 400 model (400 and 100 MHz, respectively) at ambient temperature with CDCl3 or DMSO-d6 as solvents. Data for 1H are recorded as follows: δ chemical shift (ppm), multiplicity (s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m, multiplet), coupling constant (Hz), integration. Spectra were referenced internally to the residual proton resonance in CDCl3 (δ 7.26 ppm), DMSO-d6 (δ 2.50 ppm) or with tetramethylsilane (TMS, δ 0.00 ppm) as the internal standard. Chemical shifts (δ) were reported as part per million (ppm) in δ scale downfield from TMS. Liquid chromatography/mass spectrometry (LC/MS) data was obtained to verify molecular mass and analyze purity of products. The specifications of the LC/MS instrument are the following: Electrospray (+) ionization, mass range of 100-1000 Da, 20V cone voltage, Acquity BEH C-18 column (2.1 x 100mm, 1.7 μm), and gradient mobile phase consisting of 5 mm ammonium acetate in water and acetonitrile, and a flow rate of 0.5 mL/min.

 

General procedure for the synthesis of 2-(3-substitutedamino-2,4-dithio biuretoformamidino-4-isobutoxyphenyl)-4-methyl-5-carboxy-1,3-thiazole (5a-h)

 

A reaction mixture of 2-(3-thioamidoformamidino-4-isobutoxyphenyl)-4-methyl-5-carboxy-1,3-thiazole (1.0 mmol) (3a) and   substituted isothiocynate   (1.0 mmol) (4a-h) was refluxed in 60% ethanol-acetone medium (60 ml) on water bath for 2 h. The reaction mixture was concentrated under reduced pressure to remove medium and the residue was triturated in diethyl ether at 0oC to afford solids which was collected by filtration and washed with ice cooled diethyl ether to afford the pure product. Recrystallized from ethanol.

 

2-(3-Phenylamino-2,4-dithiobiuretoformamidino-4-isobutoxy–phenyl)-4-methyl-5-carboxy-1,3-thiazole(5a):(444 mg, 87%) white solid; melting point 1580C; 1H NMR (400 MHz,DMSO-d6): 11.7823   (1 H S), 8.2165 (1 H, S J=16 Hz), 8.1568 (1 H, S J=16 Hz), 7.4757 (1 H, S), 7.1152 (5H, S), 5.0043 (1 H S), 3.5022 (2 H d J=12 Hz), 1.7684 (1 H J=12Hz m), 1.8264, (6 H d), 1.2185 (3 H S), 1.0233 (1 H S) 1.0066 (1 H S); 13C: 198, 192.2, 175.3, 162.3, 164.5, 154.3, 152.5, 148.5, 146.3, 143.1, 142, 138.5, 134.2, 130.2, 128.0, 42.1, 36.2, 29.2, 25.8;  IR: 3212.06 S, 1645.9 S, 1599.11 S, 1338.10 S, 1426.11 S, 1035.06 S; LCMS calcd for C24H25N5O2S3 (M+) 511.43, found 511.89.

 

2-(3-Tert-butylamino-2,4-dithiobiuretoformamidino-4-isobutoxy-phenyl)-4-methyl-5-carboxy-1,3-thiazole(5b):(411 mg, 84%) brown solid; melting point 1660C; 1H NMR (400 MHz,DMSO-d6): 11.1760 (1 H S), 8.2350 (1 H, S J=16 Hz), 8.1582 (1 H, S J=16 Hz), 8.5264 (1 H, S), 5.0681 (1 H S), 3.0421 (2 H d J=12 Hz), 1.6671 (1 H J=12Hz m), 1.1292, (6 H d), 1.4704 (3 H S), 1.1432, (1 H S), 1.1114 (1 H S), 1.0014 (9 H S) 13C: 198, 190.2, 177.3, 163.3, 165.5, 155.3, 153.5, 144.5, 142.3, 141.1, 140, 138.5, 133.2, 130.2, 74, 42.1, 36.2, 29.2, 25.8 21.4; IR: 3353.70 S, 1623.12 S, 1511.17 S, 1426.14 S, 1298.15 S, 1060.10 S.  LCMS calcd for C22H28N5O2S3 (M+) 490.43, found 490.56.

 

2-(3-Methylamino-2,4-dithiobiuretoformamidino-4-isobutoxy-phenyl)-4-methyl-5-carboxy-1,3-thiazole(5c):(414.9 mg, 90%) white solid; melting point 1790C; 1H NMR (400 MHz,DMSO-d6): 11.9091   (1 H S), 8.1453 (1 H, S J=16 Hz), 8.0342 (1 H, S J=16 Hz), 709841 (1 H, S), 4.5120 (1 H S), 3.2112 (2 H d J=14 Hz), 1.9541 (1 H J=14Hz m), 1.213, (6 H d), 1.2147 (3 H S), 1.1012, (1 H S), 1.01542 (1 H S), 1.0014 (3 H S); 13C: 194, 186.2, 175.3, 165.4, 162.5, 151.6, 149.5, 146.5, 144.3, 142.1, 139.8, 140.4, 136.2, 128.2, 42.1, 37.2, 28.2, 24.8 22.4; IR: 3251.2 S, 1635.5 S, 1560.3 S, 1426.1 S, 1286.3 S, 1086.2 S. LCMS calcd for C20H23N5O2S3 (M+) 461.30, found 461.50.

 

2-(3-Ethylamino-2,4-dithiobiuretoformamidino-4-isobutoxy-phenyl)-4-methyl-5-carboxy-1,3-thiazole(5d):(408 mg, 86%) dark brown solid; melting point 1800C; 1H NMR (400 MHz,DMSO-d6): 11.9610   (1 H S), 8.6750 (1 H, S J=16 Hz), 8.5213 (1 H, S J=16 Hz), 7.9841 (1 H, S), 4.4650 (1 H S), 3.3242 (2 H d J=14 Hz), 1.9541 (1 H J=14Hz m), 1.3990, (6 H d), 1.2564 (3 H S), 1.1458, (1 H S), 1.1124 (1 H S), 1.1150 (2 H S), 1.1024 (3 H S); 13C: 196, 189.2, 174.3, 166.4, 164.5, 152.6, 148.5, 145.5, 145.3, 140.1, 142.8, 140.4, 135.2, 129.2, 65.4,42.1, 37.2, 28.2, 24.8 22.4; IR: 3350.2 S, 1680.3 S, 1533.3 S, 1430.4 S, 1201.5 S, 1102.6 S; LCMS calcd for C21H25N5O2S3 (M+) 475.20, found 475.70.

 

2-(3-p-Chlorophenylamino-2,4-dithiobiuretoformamidino-4-isobutoxyphenyl)-4 methyl-5-carboxy-1,3-thiazole(5e):

(431.32 mg, 82%) brown solid; melting point 2170C; 1H NMR (400 MHz,DMSO-d6): 12.5470   (1 H S), 8.1240 (1 H, S J=13 Hz), 8.0321 (1 H, S J=13 Hz), 7.452 (1 H, S), 7.3582 (4 H, S),  3.987 (1 H S), 2.5142 (2 H d J=14 Hz), 1.2512 (1 H J=14Hz m), 1.42135, (6 H d), 1.3241 (3 H S), 1.2521, (1 H S), 1.1425 (1 H S); 13C: 198, 185.2, 177.3, 164.4, 165.5, 154, 150.6,148, 146.5, 144.5, 145.5, 145.3, 141.1, 140.8, 139.4, 137.2, 128.2,41.1, 37.8, 29.2, 25.8 ; LCMS calcd for C24H24N5O2S3Cl (M+) 545.36, found 545.42. IR: 3375.01 S, 1618.1 S, 1540.51 S, 1440.35 S, 1297.11 S, 1168.21 S.

 

2-(3-o-Tolylamino-2,4-dithiobiuretoformamidino-4-isobutoxy-phenyl)-4-methyl-5-carboxy-1,3-thiazole(5f):

(411 mg, 84%) dark brown solid; melting point 1760C; 1H NMR (400 MHz,DMSO-d6): 11.5472 (1 H S), 8.3221 (1 H, S J=11 Hz), 8.1241 (1 H, S J=11 Hz), 7.1210 (1 H, S), 7.4512 (4 H, S),  4.2513 (1 H S), 3.2142 (2 H d J=16 Hz), 1.5421 (1 H J=16Hz m), 1.4521, (6 H d), 1.5412 (3 H S), 1.2012, (1 H S), 1.1012 (1 H S), 1.0412 (3 H S); 13C: 192, 190.2, 178.3, 165.4, 164.5, 155, 153.6,150.4, 147.5, 146.5, 144.5, 142.3, 141.1, 140.8, 139.4,  138.6, 137, 135.4, 128.2, 41.1, 37.8, 29.2, 25.8 18.4; LCMS calcd for C25H27N5O2S3 (M+) 526.23, found 526.68. IR: 3212.5 S, 1640.5 S, 1540.3 S, 1428.1 S, 1289.7 S, 1112.36 S.

 

2-(3-m-Tolylamino-2,4-dithiobiuretoformamidino-4-isobutoxy- phenyl)-4-methyl-5-carboxy-1,3-thiazole(5g):

(448 mg, 87%) dark brown solid; melting point 1780C; 1H NMR (400 MHz,DMSO-d6): 12.5472 (1 H S), 8.5422 (1 H, S J=18Hz), 8.4241 (1 H, S J=18 Hz), 7.3210 (1 H, S), 7.6321 (4 H, S),  3.984 (1 H S), 3.0212 (2 H d J=16 Hz), 1.4521 (1 H J=15Hz m), 1.2521, (6 H d), 1.4214 (3 H S), 1.2142, (1 H S), 1.2412 (1 H S), 1.4112 (3 H S); 13C: 190, 189.2, 176.3, 164.7, 165.6, 155.4, 154.6,149.4, 148.5, 147.5, 146.5, 141.3, 140.9, 140.1, 139.4,  138.1, 137.5, 136.4, 128.2, 42.1, 37.8, 30.2, 24.8 17.9; IR: 3315.0 S, 1690.13 S, 1590.16 S, 140017 S, 1200.19 S, 1113.5 S; LCMS calcd for C25H27N5O2S3 (M+) 526.03, found 526.42.

2-(3-p-Tolylamino-2,4-dithiobiuretoformamidino-4-isobutoxy-phenyl)-4-methyl-5-carboxy-1,3-thiazole(5h):

(447.1 mg, 85%) dark brown solid; melting point 2050C; 1H NMR (400 MHz,DMSO-d6): 12.1240 (1 H S), 8.5421 (1 H, S J=11 Hz), 8.4652 (1 H, S J=11 Hz), 7.38540 (1 H, S), 7.0140 (4 H, S),  5.0513 (1 H S), 3.2141 (2 H d J=12 Hz), 1.5421 (1 H J=12Hz m), 1.4521, (6 H d), 1.5241 (3 H S), 1.2012, (1 H S), 1.1210 (1 H S), 1.0412 (3 H S), 13C: 193, 190.2, 179.3, 165.7, 164.6, 154.4, 148.4, 147.5, 146.5, 142.3, 140.9, 138.1, 137.4,  135.1, 134.5, 131.4, 129.2, 41.1, 38.8, 31.2, 25.8 19.3; IR: 3405.5 S, 1617.17 S, 1585.85 S, 1420.20 S, 1200.30 S, 1019.32 S;LCMS calcd for C25H27N5O2S3 (M+) 526.20, found 526.70.

 

CONCLUSION:

This is one step process and increases yields, higher selectivity. This preparation has consequently easier work-up and products obtained are in comparatively pure form. In this preparation green parameters are also maintained.

 

ACKNOWLEDGEMENTS:

Authors are thankful to the UGC New Delhi for giving fellowship to author.

 

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Received on 29.07.2017                Accepted on 18.08.2017               

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