Preparations of diversely substituted thiosemicarbazides and N -hydroxythioureas

Thiosemicarbazides 5 (yields 50-97%) and N -hydroxythioureas 6 (yields 71-99%) of variable substitution patterns are prepared efficiently by reactions of 1-(thiocarbamoyl)benzotriazoles 4a–i with hydrazines or hydroxylamines, respectively.


Scheme 1
Seventeen classes of N-substituted thiosemicarbazides can exist as shown in Table 1: three of mono (A, B, C), five of di (D through H), five of tri (I through M), three of tetra (N, O, P), and one of penta (Q) substitution).Of these seventeen, nine have previously been reported in the literature (Table 1 classes A, B, C, D, E, F, G, H, M).While most of the other classes could potentially be made by one or more of the existing methods; a literature sub-structural search showed no known examples of compounds of classes I, J, K, L, N, O, P, Q. Method i is convenient for the preparation of classes A, E, F. Methods ii and iii are mainly used for the preparation of class F with a single example of class D using iii.Classes B, C, G, H, M are easily prepared using methods iv and v (Table 1).The work now presented provides an efficient route to the hither to unexplored classes J and L together with alternative access or potential access to classes A, B, C, E, F, G, H, M, P.

N N' O NN NO N'O NN' NN'O NNN' NNO NNN'O Class
This work R: Reported; P: Possible but no example reported; -: not possible by this method Recently, we reported efficient synthesis of di-and trisubstituted thioureas 7 utilizing 1-(alkylor-arylthiocarbamoyl)benzotriazoles 4 (Scheme 3). 22We have now expanded this methodology to include the synthesis of thiosemicarbazides 5 and N-hydroxythioureas 6.
Structures 5 and 6 are fully defined in Tables 3 and 4  Substituted thiosemicarbazides 5 were prepared via a single step reaction of 1-(alkyl-orarylthiocarbamoyl)benzotriazoles 4a-i with the appropriate hydrazine (Scheme 4, Table 3).Stirring 1 equiv. of 4 in methylene chloride at room temperature with 1.1 equiv. of the hydrazine and 2 equiv. of triethylamine followed by a 5% Na 2 CO 3 wash afforded 5 in excellent yields (Table 3).The reaction reached completion after 2 h.as monitored by TLC.Substituted thiosemicarbazides 5 were purified using column chromatography (EtOAc/Hex) and characterized using NMR ( 1 H, 13 C).Melting points for known 5 agreed with reported values (see the Experimental Section).Novel 5 were characterized by 1 H, 13 C NMR spectra and elemental analyses (see the Experimental Section).
N-Hydroxythioureas 6 were prepared from the reaction of 1-(alkyl-orarylthiocarbamoyl)benzotriazoles 4a-i in methylene chloride at room temperature with 1.5 equiv. of the corresponding hydroxylamine and 3 equiv.of triethylamine (Scheme 4, Table 4).Starting materials disappeared completely after 5-12 h. as monitored by TLC.Formation of a white precipitate (benzotriazole triethylamine salt) marked the completion of the reaction.The precipitate was filtered and the filtrate washed with 5% Na 2 CO 3 .The organic layer was extracted with methylene chloride (3 times), evaporated under vacuum, and chromatographed (EtOAc/Hex) to give N-hydroxythioureas 6 in excellent yields (Table 4).N-Hydroxythioureas 6 were fully characterized using NMR ( 1 H, 13 C) and elemental analysis.Melting points for known 6 agreed with reported values (see the Experimental Section).Novel 6 were characterized by 1 H, 13 C NMR spectra and elemental analyses (see the Experimental Section).

Conclusion
A new route providing easy access to thiosemicarbazides and N-hydroxythioureas of diverse substitution patterns in excellent yields has been established.Tables 1 and 2 compare our method to already reported routes of preparation of thiosemicarbazides and N-hydroxythioureas.Our method is particularly advantageous for the preparation of trisubstituted thiosemicarbazides (Table 1) and mono and disubstituted N-hydroxythioureas (Table 2).It is efficient with relatively short reaction time, and avoids the use of unstable isothiocyanates which are the classical starting materials for preparation of thiosemicarbazides and N-hydroxythioureas.

Experimental Section
General Procedures.Melting points were determined on a hot-stage apparatus and are uncorrected.NMR spectra were recorded in CDCl 3 , or DMSO-d 6 with TMS as the internal standard for 1 H (300 MHz) or a solvent as the internal standard for 13 C NMR (75 MHz).Column chromatography was conducted on silica gel (200−425 mesh).Bis-benzotriazol-1-ylmethanethione 3 was prepared according to a previously reported procedure; Mp 171-172°C, yield 98%, (Lit.Mp 170-171 °C, yield 90%). 23 General procedure for the preparation of 4a-i.1-Thiocarbamoyl benzotriazoles 4a-i were synthesized by the reaction of compound 3 (2 mmol) and the appropriate primary amine (2 mmol) in methylene chloride at room temperature for 2 h according to reported procedure. 22elting points and spectral data were used to characterize known 4a-f, h-i and were found to be identical to reported values: General procedure for the preparation of compounds 6.To a stirred solution of (2.0 mmol) 4a-i in 15ml of dichloromethane, was added (3.0 mmol) of the corresponding hydroxylamine hydrochloride followed by (9.0 mmol) of triethylamine.The mixture was stirred for 5 hours at room temperature.Completion of the reaction is marked by the formation of a white precipitate (benzotriazole triethylamine salt).The reaction mixture was evaporated under reduced pressure then redissolved in diethyl ether.The precipitate formed was filtered, followed by addition of 10 ml of 5% Na 2 CO 3 to remove excess benzotriazole.The solution was extracted with dichloromethane (3x50ml) and the organic layer was dried over magnesium sulfate.Evaporating the solvent under reduced pressure followed by column chromatography (EtOAc/Hex gradient) afforded pure 6 in 71-99% yield.N-Benzyl-N-hydroxythiourea (6a-a). 16 Scheme 4

Table 1 .
The possible classes of substituted thiosemicarbazides 1 and reported methods of preparation