Journal of Sulfur Chemistry Oxidation of thiourea and

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Journal of Sulfur Chemistry

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Oxidation of thiourea and substituted thioureas: a review

Sandhyamayee Sahua; Prangya Rani Sahooa; Sabita Patelb; B. K. Mishraa a Department of Chemistry, Center of Studies in Surface Science and Technology, Sambalpur University, Jyoti Vihar, India b Department of Chemistry, National Institute of Technology, Rourkela, India First published on: 27 January 2011

To cite this Article Sahu, Sandhyamayee , Rani Sahoo, Prangya , Patel, Sabita and Mishra, B. K.(2011) 'Oxidation of

thiourea and substituted thioureas: a review', Journal of Sulfur Chemistry,, First published on: 27 January 2011 (iFirst) To link to this Article: DOI: 10.1080/17415993.2010.550294 URL: http://dx.doi.org/10.1080/17415993.2010.550294

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Journal of Sulfur Chemistry iFirst, 2011, 1–27

REVIEW ARTICLE

Oxidation of thiourea and substituted thioureas: a review Sandhyamayee Sahua , Prangya Rani Sahooa , Sabita Patelb and B.K. Mishraa * a Department

of Chemistry, Center of Studies in Surface Science and Technology, Sambalpur University, Jyoti Vihar 768019, India; b Department of Chemistry, National Institute of Technology, Rourkela 769008, India (Received 21 July 2010; final version received 19 December 2010 )

Downloaded At: 17:33 28 January 2011

Thioureas, containing sulfur and nitrogen atoms, are susceptible to oxidation by a large number of oxidants giving rise to various products including ureas, sulfides, oxides of sulfur, and nitrogen. Some novel cyclized products were also obtained during oxidation. The reaction conditions and types of oxidants steer the formation of different products. This review comprises basically the synthetic aspects, and the mechanism/schemes of the reactions discussed in the manuscript are based on stoichiometry and products of the reactions.

O R NH C NH2 or S R NH C NH2

NH2 [Oxidation]

R N

C

S

R N

C

S

NH2 or [Other products] Keywords: thiourea; oxidation; thiazole; disulfide; urea

1.

Introduction

Thiourea (NH2 CSNH2 ), a sulfur-containing compound, is of high industrial potential. Reaction of thiourea with hydrogen peroxide under certain conditions produces a powerful reductive bleaching agent, which is routinely used in the textile industry (1, 2). Thiourea and its derivatives are used as corrosion inhibitors (3) in industrial equipment such as boilers, which develop scales due to corrosion (4). The corrosion products generally consist of metals and their oxides in small amounts. The slow buildup of the corrosion products over a period adversely affects the performance of the boilers (5). Solution of thiourea in dilute hydrochloric acid is used as a complexing agent for removing scales from boilers (6). Besides this, several thiourea derivatives *Corresponding author. Email: [email protected]

ISSN 1741-5993 print/ISSN 1741-6000 online © 2011 Taylor & Francis DOI: 10.1080/17415993.2010.550294 http://www.informaworld.com


2 S. Sahu et al.

have various agricultural and analytical applications which include applications in rubber industries as accelerators, in photography as fixing agents and to remove stains from negatives, and in agriculture as fungicides, herbicides, and rodenticides. The use of an aqueous solution of thiourea as a leaching agent for gold has been widely reported in the literature. Thiourea is also used as a spectrophotometric reagent for the determination of several metals (7). The presence of thiourea in urine was reported to be a non-specific indicator of cancer (8). Thiourea is found to be toxic owing to its influence on the metabolism of carbohydrates (9). Moreover, it has been tagged as carcinogenic (10) and so all work with this compound should be performed with the greatest care to prevent direct exposure to human. Thiourea and 1,3-dimethyl-2-thiourea (DMTU) are effective scavengers of reactive oxygen intermediates (ROIs) (11–15). DMTU is reported to be capable of preventing ROI-induced lung injury in vitro and in vivo (16, 17). Dong et al. (18) have investigated the antioxidant activities of a series of novel phenethyl-5-bromo-pyridyl thioureas (PEPT) (1) with potent anti-HIV activity (19, 20). The pyridylthiourea group in PEPT and S-alkylated derivatives forms an intramolecular hydrogen-bonded heterocyclic ring observed by X-ray crystallography, which would facilitate the formation of the sulfhydryl form (2) of the compounds. Both compounds effectively inhibit oxidation-induced green fluorescence emission from the free radical-sensitive indicator dye 2 , 7 dichlorodihydrofluorescein diacetate, in CEM human T-cells and Nalm-6 human B-cells exposed to hydrogen peroxide. Since alkylated PEPT derivatives are inactive, the activity center in these compounds has been assigned to the sulfhydryl group. The free thiourea group is proposed to be responsible for the anti-HIV activity of the PEPT compounds. Thiourea also inhibits the growth of Nitrosomonas and prevents active nitrification at certain concentration (21). S HN

SH

R N

N

N

H

N

Br

Br

(1)

(2)

R N H

R = H, 2-OMe, 3-OMe, 4-OMe, 2,5-di-OMe, 2-F, 3-F, 4-F, 2-Cl, etc.

N-substituted thioureas are found to be good model compounds to investigate the fundamentals of bonding in the molecule such as internal rotation around the C−N bond, changes in conformation, and inter- and intramolecular hydrogen bonding. In N-substituted thioureas, the substituents can adopt four different conformations with respect to the central C9S bond. The preferred conformations have been investigated using 1 H, 13 C, and 15 N NMR spectroscopy in solution (22–24) as well as in the solid state (25). The stability of different conformers has been predicted by using molecular mechanics (22). It has been observed that among the four possible conformations (3–6), only the anti–anti conformation is destabilized due to steric reasons. S H

N

C

Ph

(3) Anti-Syn

S

S N H

R

Ph

N

C

H

N H

(4) Syn-Syn

R

Ph

N

C

H

S N R

(5) Syn-Anti

H

H

N Ph

C

N

H

R

(6) Anti-Anti

Journal of Sulfur Chemistry 3

In order to determine the favored conformation in the solid state as well as to rationalize the results of solid-state NMR measurements, Woinisk et al. (26) have obtained the crystal structure of N -phenyl-N -propylthiourea and studied the structural similarities and differences between N phenylurea derivatives together with their average geometry and relationships between changes of the structural parameters of these fragments. Hydrogen bonding and mesomerism involving ionic structures seem to be the dominant factors in changing the geometrical parameters of ureas and thioureas. The conformation of the thiourea fragment is found to be anti–syn, which enables an N· · · H· · · S hydrogen bonding between the parent molecules leading to the formation of a dimer (7). No significant difference between CN bond lengths [N(alkyl)C(=S) = 1.336 Å and N(aryl)C(=S) = 1.328 Å] has been observed. Both of them seem to be equal almost to the optimal value (27). As a result of equalization of the CN bonds and the conjugation of lone electron pairs of N atoms with a double C−S bond, the thiourea fragment can exist in three resonating structures (6, 8, and 9). CH3

( CH2 )

HN

2

C


N

S

H

H

S

N C ( CH2 )

NH

2

CH3

(7) -

-

S H

C

+

N Ph

S N

H

R

(8)

2.

H

N

C

Ph

+

N

H

R (9)

Oxidation of thiourea

Thiourea, which is the simplest and one of the most reactive sulfur compounds, can be oxidized by a wide variety of oxidizing agents (28–39). The reaction pathways and the final products of the oxidation reaction depend on the reagents used and condition of the reaction mixtures. The oxidation products may be urea, disulfide, and, in some cases, it may undergo either oxidative cyclization or degradation. Oxidation of thiourea by iodate (40), chlorite (41), and bromate (42) has been found to give complex kinetic behavior. With iodate, the reaction displays oligo-oscillation, in which the concentration of iodide goes through several maxima in a single reaction (40). Simoyi et al. (28) have used chlorine dioxide at low pH in excess of thiourea to afford sulfur and cyanamide. With excess of chlorine dioxide, formamidine sulfanic acid was obtained. When pH > 3, sulfate was detected as a byproduct. In a closed system, the reaction between chlorite and thiourea showed a long induction period followed by a rapid production of ClO2 (41). The long induction period was explained by invoking a two-step process in which the thiourea reduced the chlorite to HOC1, followed by the reaction between HOC1 and chlorite to give C1O2 (Scheme 1). The reaction between thiourea and excess bromate in acidic medium also proceeded by a long induction period involving a slow evolution of bromine (42). The too long induction period might be resulted from 8 BrO3- + 5 SC ( NH2 ) + 8 H++ 6 H2O 2

Scheme 1.

4 Br2 + 5 (NH4 ) SO4 + 5 CO2 2

4 S. Sahu et al.

a two-step process, in which thiourea reduced bromate to bromide followed by the reaction of bromide with bromate to give bromine (Scheme 2). 2-

ClO2 + 2 CS (NH2 )2 + 4 H2O

4 NH4++ 2 CO 3 + Cl- + 2S

+ ClO2 + CS (NH2 )2 + 2 H2O + H

2 NH4+ + CO 3 + HOCl + S

2-

-

3 HOCl + S + H2O

3 Cl-+ SO 42 + 5 H+

+ HOCl + 2 ClO2 + H

2 ClO2 + Cl- + H2O

Scheme 2. Vaidya et al. (29) reported the dye-sensitized photo-oxidation of thiourea to corresponding urea (Scheme 3). However, under acidic conditions, with excess of sodium peroxydisulfate or 2− hydrogen peroxide, the oxidation of thiourea led to the formation of NH+ 4 , sulfur, SO4 , and CO2 (31). But in excess thiourea, the formamidine disulfide was formed at low pH, and thiourea dioxide was produced under neutral conditions (1, 31, 32). hv


1D 0

1

1

3O

1

D1 + 3 D1

*

1D + 1O 0 2

O O

1

H2N C

D1

3D 1

H2N O O C S H2N

O* 2

S

H2N H2N C O + SO H2N 3 SO

S2O + SO 2 3 S + SO2

2S2O SO 2 + H2O + 12O2

H2SO 4

Scheme 3. Some aroylthioureas exhibited abnormal oxidative behavior during their reactions with 2,3diphenylcyclopropenone resulting in (E/Z)-3-(aroylthioureido)-2-phenylcinnamic acids (43). The unusual reaction was due to the nucleophilic addition of N followed by hydrolysis, ring opening, and oxidation processes (Scheme 4). Ph

O Ar

O

S N H

N

H

Scheme 4.

Ar

Ar

R O

H2O

O

O

Ph

Ph

S N

N

H

R

H

-

Ph

S

O +

N

N

H

R H

Ph

OH OH O2 Ph

O

Ph

Ar

O Ar

S N

N

H

R

H

Ph

S N

N

H

R

Ph

O COOH +

Ph

Ar

Ph

S

Ph

N

N

H

R

COOH


Sahu et al. (44) reported the formation of aryl isocyanide from the oxidation of arylthiourea by cetyltrimethylammonium dichromate (CTADC) in organic solvent leading to arylurea and isonitrile in different reaction conditions. The formation of arylnitrile, a non-conventional product, is the contribution of the novel oxidant, CTADC, a phase transfer oxidant, which is also responsible for some bizarre products obtained from oxidation of various organic substrates (45). The reagent, being insoluble in water, reduces contamination of Cr(VI) in aqueous medium, and thus can be considered as a green reagent. The oxidation of arylthioureas by CTADC both in neutral and under microwave irradiation produced a mixture of corresponding arylureas and isonitriles (44). In acidic condition, the products were found to be corresponding ureas only. A probable mechanism for the formation of isocyanide was proposed, wherein the first step involves coupling of −NH2 and −SH of one molecule to the −NH2 and −SH of another molecule, respectively, which is followed by removal of nitrogen and sulfur (Scheme 5). H N

C

NH2

N


S

NH2 CTADC Acetonitrile SH

C

S

S

N C

C N N N

+

N C

-

Phenylisocyanide

Scheme 5.

2.1. Oxidation of thiourea to urea The conversion of thioureas into ureas has attracted the interest of chemists since long (46). The conversion of toxic thiourea to biologically benign urea can be achieved by both biological as well as chemical oxidants including dioxygen (47). 1,3-Dimethyl thiourea exhibits protective effect to inactivate reactive oxygen species through desulfurization (48–50). The kinetics and mechanism of oxidation of thiourea to corresponding urea have been studied by various workers using different reagents such as bromine water (Br2 /H2 O) (28), bromate (BrO− 3 ) (51–53), peroxide in alkali (H2 O2 /HO− ) (54), peroxide-hypo chloride-bicarbonate (H2 O2 /NaOCl/HCO− 3 ) (55), KHSO5 in phosphate buffer (56), ferrate(V) (57), ferrate(VI) (58), etc. In a recent report, Sahoo et al. proposed the mechanism (Scheme 6) for the desulfurization reaction of thiourea by CTADC. From the investigation on the effect of surfactants such as cetyltrimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS), it was proposed that the oxidation occurs at the interface of the CTADC aggregates (59). Simoyi et al. (28) reported the kinetics of oxidation of thiourea in aqueous bromine in the pH range 1.5–4. The reaction occurs in two steps: a initial fast step, in which 1 mol of bromine is consumed for each mole of thiourea, followed by a slower second step, in which the rest of the bromine is consumed. Within the pH range 2–4, thiourea is oxidized by bromine water to urea (Scheme 7). However, at a lower pH, thiourea is converted to ammonium sulfate (Scheme 8). Earlier studies on thiourea showed that the C=S double bond is extremely polar (28), which is due to the mismatch in size between the carbon and sulfur atoms resulting in an incomplete π -bond overlap. Thus, a permanent negative dipole resides on the sulfur atom, making it extremely vulnerable to electrophilic attack (60). Based on this fact, a mechanism was proposed for the oxidation (Scheme 9), wherein the initial step involves the rapid electrophilic attack of bromine on the sulfur resulting in the formation

6 S. Sahu et al.

O +

O

-

CTA O Cr O

+

O +

S+ H

C

+

O CTA

C H2N

+

O

H2N PhNH

-

S O C

S O

PhNH

-

S Cr OCrO2O CTA HO OH

PhNH

+

S Cr OCrO2O CTA OH OH

H2N

+

C H2N

-

C


+

O

PhNH

-

O

SH

PhNH -

O

O

+

C +

O

SH + HO Cr O Cr

H2N

-

O CTA

H2N

H2N O

O

+

C +

+ CTA + HO Cr O Cr

PhNH

PhNH

PhNH

O

O -

+ O CTA + H

O Cr

+

Cr OCrO2O CTA OH O

Cr OCrO2O CTA OH O

O C O + S + HO Cr

-

+

OCrO2O CTA

H2N

Scheme 6. 4Br2 + SC(NH2)2 + 5H2O

8Br- + OC(NH2)2 + SO42- + 10H+

Scheme 7. 4Br2 + SC(NH2)2 + 6H2O

8Br- + (NH4)2SO4 + CO2 + 8H+

Scheme 8. NH2 Br2 + S

NH2

+

Br S

-

+ Br

NH2

NH2

10

NH2 + H2O NH2

+

Br S

HO S C

+ NH + 2 H + Br

NH2 11

O HO S C

NH + Br2 + H2O

HO S C

NH2

-

+

NH + 2 Br + 2 H

NH2 12

Scheme 9. of sulfenyl bromide as the intermediate (10). In the second step, 11 undergoes hydrolysis to yield the sulfenyl acid. Further, electrophilic attack by bromine occurs on the sulfur atom in 11. The rate-limiting step involves the oxidation of sulfur from the zero oxidation state (sulfenic acid) to the +2 oxidation state (sulfinic acid, 12). Sulfur in the +2 oxidation state is quite labile and hence, 12 immediately oxidizes to sulfate (Scheme 10). Bromide ion, thus formed, catalyzes the reaction by stabilizing the intermediate (12) formed after electrophilic attack on 11 (Scheme 11).

Journal of Sulfur Chemistry 7 O HO

S

-

4 Br + CO(NH2)2 + 6 H+ + SO42

C NH + 2 Br2 + 3 H2O NH2

Scheme 10.

HO S C NH + Br2 + BrNH2

Br -H O HO S C NH + Br 2

12 + 3 Br- + 2 H+

Br NH2

Scheme 11. Oxidation of thiourea by bromate in acidic medium was found to proceed via oxygen additions on sulfur, subsequently forming HOSC(NH)NH2 , HO2 SC(NH)NH2 , HO3 SC(NH)NH2 , and SO2− 4 (51). The mechanism for the bromate–thiourea reaction is complicated and takes place via several steps involving oxybromine and oxysulfur interactions (Scheme 12). Downloaded At: 17:33 28 January 2011

BrO3- + SC(NH2)2 + H+ HOBr2 + SC(NH2)2 HOBr + SC(NH2)2 HOSC(NH)NH2 + SC(NH2)2 NH2(NH)CS-CS(NH)NH2 + HOBr + H2O HOBr + Br- + H+ Br2 + SC(NH2)2 + H2O HOBr2 + Br- + H+ HOBr + HOSC(NH)NH2 HOBr + HO2SC(NH)NH2 HO3SC(NH)NH2 + HOBr + H2O HO3SC(NH)NH2 + HOSC(NH)NH2 HO3SC(NH)NH2 + SC(NH2)2

HOSC(NH)NH2 + HBrO2 HOSC(NH)NH2 + HOBr HOSC(NH)NH2 + Br- + H+ NH2(NH)CS-CS(NH)NH2 + H2O 2HO2SC(NH)NH2 + Br- + H+ Br2 + H2O HOSC(NH)NH2 + 2Br- + 2H+ 2HOBr HO2SC(NH)NH2 + Br- + 2H + HO3SC(NH)NH2 + Br- + H+ SO42- + OC(NH2)2 + 3H+ + Br2HO2SC(NH)NH2 HO2SC(NH)NH2 + HOSC(NH)NH2

Scheme 12. Reduction of chromium(VI) to chromium(III) by thiourea in chromium(VI)–thiourea– polyacrylamide gel polymer system, used in oil recovery processes, was reported by Thomas et al. (61). Oxidation of the sulfur atom in a molecule of thiourea by chromium(VI) proceeds via a two-step reaction. In the first step, the sulfur atom in thiourea is oxidized from its oxidation state of −2 to −1, converting thiourea to a disulfide and chromium(VI) to chromium(III). In the second step, the sulfur atoms in the disulfide are oxidized from −1 to +6 oxidation state, converting the disulfide to sulfate and chromium(VI) to chromium(III) (Scheme 13). 6(H2N)2CS +2HCrO4-+ 8H++ 4H2O

3(H2N)(HN)CSSC(NH)(NH2)+10Cr(H2O)63+

Scheme 13. 1-Butyltriphenylphosphonium dichromate [(Bun PPh3 )2 Cr2 O7 ] has been used as Cr(VI) oxidant for the transformation of thio- to their corresponding oxo-derivatives (62). The oxidation has been carried out both in solution and under solid-state microwave irradiation. The reagent is found to

8 S. Sahu et al.

be stable, inexpensive, and efficient for deprotection of thioamides, thioureas, thiono esters, and thioketones (Scheme 14).

R1 C R2

S

(Bun PPh3)2Cr2O 7 CH3CN (reflux) or MW R1 C O 1-300 min, 70-98% R2

Scheme 14. Guanyl thiourea (14), an important biological and industrial molecule, is oxidized by acidic bromate leading to complete desulfurization to yield guanylurea (Scheme 15) (53). NH H2N

N H

S NH2

(14) Downloaded At: 17:33 28 January 2011

NH -

4 BrO3 + 3 H2N

N H

NH

S NH2 + H2O

-

4 Br + 3 H2N

N H

O -

2 + NH2 + 3 H + 6 SO4

Scheme 15. Ethylene thiourea (ETU), 2-imidazolidinethion, is of special interest and concern because of potential human exposure and adverse health effects and also a liver and thyroid carcinogen in mice and/or rats (63–65). Therefore, its degradation is essential for an eco-friendly environment. ETU is generally oxidized to ethylene urea and sulfate (66). The mechanism of hydrogen peroxide and hypochlorite-mediated oxidation of ETU has been suggested by Marshall (55). In water, a radical dissociation of the intermediate 2-imidazolin-2-yl sulfinate and subsequent trapping by solvent result in the formation of 2-imidazoline hydrosulfite which is, in turn, rapidly oxidized to 2-imidazoline hydrosulfate. 2-Imidazolin-2-yl sulfinate is oxidized to 2-imidazolin-2-yl sulfonate in low yield. In 1% bicarbonate solution, ethylene urea is the major product of ETU oxidation by either hypochlorite or hydrogen peroxide oxidants (Scheme 16). James et al. (54) have used peroxide in aqueous medium at different pH for the oxidative degradation of ETU (Im-SH) to yield corresponding sulfenic (Im-SOH), sulfinic (Im-SO2 H), sulfonic (Im-SO3 H) acids, and some other products (Scheme 17). The proposed mechanism of the oxidation process is given in Scheme 18. The mechanism of formation of ethylene urea and degradation by acyclic compounds is presented in Scheme 18. The oxidative degradation of thioureas with potassium monopersulfate in a neutral medium was found to be very fast leading to quantitative desulfurization to corresponding ureas, whereas in acidic medium the products were due to the undesired thiourea disulfide (Scheme 19) (56). A potential process was developed for an on-site treatment of boiler chemical cleaning wastes (BCCWs), which involves an alkali treatment to precipitate metals such as hydroxides followed by oxidation of thiourea with hydrogen peroxide to urea and sulfate (67). The oxidative destruction of simulated BCCWs by air (O2 ) at an activated charcoal surface was examined in an alkaline medium (68) where major products were 1-cyanoguanidine and thiosulfate; urea and sulfur were the minor products. Sharma et al. (58) used hypervalent iron, ferrate (Fe(VI), for the destruction of thiourea from BCCWs and measured the rates as a function of pH (8.8–11.5) and temperature (10– 35◦ C). The reaction of Fe(VI) with thiourea radical was performed on a premix pulse radiolysis

Journal of Sulfur Chemistry 9 O S H

-

O H

N

N

H

O S H

N

N

H

H

H

+

N

N

H

O

ETU

O

O O

ETU-O

H

S +

N

N

H

+

SO4

-

EU

ETU O3

S

H

N

N

S N

O OH N

O OH . S O. H H N N

H

OH

ETU-O2

O Downloaded At: 17:33 28 January 2011

H

O

N

N

N

N

. 2 H SO 2

H 4

H

O

-

N

H HO H

H HSO 4 + H N N H

H HSO3 + H N N H -

-

OH

OH O

H

O

NH2 N H

N

..

S

H2N

NH2

N H

N C H

-

OH NH2

H2N O

O

+ 2 O

-

O

EDA

+

H

O C O

-

FORM ATE

-

Scheme 16.

setup. The mechanism for the stepwise oxidation of sulfur from the oxidation state of −2 to +6 by Fe(VI) is given in Scheme 20. Oxidation of thiourea has also been carried out by Fe(V) in aqueous solution (57). The rate of oxidation is first order with respect to the reactant and the hydrogen ion concentration. The reaction of Fe(V) with thiourea proceeds via a concerted two-electron oxidation mechanism, which converts Fe(V) to Fe(III). The reactivity of Fe(V) with thiourea is three orders of magnitude faster than with Fe(VI); in addition, Fe(V) reacts preferentially at the sulfur center of thiourea affording urea as the oxidized product (Scheme 21). From the spectral studies of the reaction of Fe(V) with thiourea, no characteristic spectrum of Fe(IV) was detected during the reaction (69). From the crossover experiments, it was found that the intermediates, Fe(IV) and thiourea radical, are not involved in the reaction of Fe(V) with thiourea. The reaction between Fe(V) and thiourea is, therefore, stoichiometric and may be occurring via a concerted two-electron oxidation, which converts Fe(V) to Fe(III). Oxidation of trimethylthiourea (TMTU) by chlorite in slightly acidic media also afforded corresponding urea (Scheme 22) (70). The reaction was found to be much faster than the oxidation of the unsubstituted thiourea. The reaction occurs in two steps. Initially it starts with S-oxygenation

10 S. Sahu et al. S H

H N

N

N

H

S

H

EU


S

H

O N

N H

b

c

d

N

S

N Im-S-S-Im

ETU

H

N

a

N

N

H

H

N N

N

N H

Jaffe's Base

Im

(a)

H2O2/methanol/HCl,

(b)

N-Chlorosuccinimide/ethanol, NaOCl or alcoholic hydrobromous or hydrochlorous acid

(c)

H2O2

(d)

H2O2/OH- or NaOCl/OH S H

SH N

N ETU

H

N

SO n H N

Im-SH

H

N

N

H

Im-SOnH

(Oxidation of ETU to corresponding sulfenic (n =1), sulfinic (n =2), sulfonic (n =3) acid)

Scheme 17. at the sulfur center of TMTU to yield the sulfinic acid, which then hydrolyses in the second step to produce trimethylurea and the sulfoxylate anion. The oxidation of phenylthiourea (PTU) by chlorite in acidic medium is extremely complex with reaction dynamics strongly influenced by the pH of the reaction medium (71). In excess chlorite concentrations, the reaction stoichiometry involves the complete desulfurization of PTU to yield phenylurea and sulfate, whereas in excess of PTU, mixtures of corresponding sulfinic and sulfonic acids are formed. The reaction proceeds through the formation of two stable intermediates: the sulfinic acid and the sulfonic acid on the pathway toward total desulfurization to form phenylurea. Fairlie et al. (72) demonstrated that thiourea bound to the [Ru(NH3 )5 ]3+ moiety undergoes hydrolysis in basic aqueous solution. This reaction results in an S–C bond cleavage of thiourea, forming [(NH3 )5 RuSSRu(NH3 )5 ]4+ and urea. Kinetics and mechanism of the oxidation of N ,N -dimethylthiourea by dioxygen in the presence of Co(II)octasulfophenyltetrapyrazinoporphyrazine, [Co(II){PyzPz(PhSO3 )8 }(H2 O)2 ]− 8 are found to be significantly different compared to those in other catalytic oxidation of thioureas (73). The reaction includes the formation of an anionic five-coordinate complex as the intermediate, followed by an unusual two-electron oxidation to produce the corresponding urea and elemental sulfur (S8 ) (Scheme 23). Drastic differences have been observed in catalytic activity of cobalt and iron octasulfophenyltetrapyrazinoporphyrazines. Singh et al. (74) used diacetoxyiodobenzene (DIB) as an N-acylating agent for the conversion of some asymmetric 1,3-disubstituted thioureas to regioselective N -acetylurea. Regioselectivity is found to be dependent on the pKa values of the amine attached to the thiourea moiety with acylation taking place toward the amine having a lower pKa (Scheme 24). Mild reaction conditions, shorter reaction times, high efficiencies, environmentally benign methods, and facile isolation of the desired product make the technique a most suitable alternative to other conventional methods.


S H

SH H

N

N

N

N

H

NH2CH2CH2NH2

HCO2H -

H2O2 O S H

H

N

N

H

O

H2O2

H

N EU

-

+

N

H2O2 N

OH

H

Im +

+

H

H H2O2

SO2H

N

N

N

Im-SO H H2O2

-S


-

OH H

SOH

ETU S- Oxide

H

NH2CH2CH2NHCHO

H2O2

N

N

OH

Im-SH

ETU

SO3H H

N

H2O2 + H

Im-SO2 H

N

H

Im-S O3 H

H

Scheme 18. S

SOnH 5 equiv. KHSO5 C C RHN NHR Phosphate buffer RN NHR ° 15a-c (pH-7), 20 C , 1min (n = 1-3) 5 equiv. KHSO5

RN

H2O , 20°C , 1min RHN (15-17) a b

Et S HN

+

C RHN NHR 16 a-c

NHR C

S

S

17a-c

C NR

R H

c

O

N

Scheme 19. Lead acetate and lead nitrate are found to perform similar regioselective N-acylation of both symmetrical and unsymmetrical thioureas (75). A linear correlation has been observed between the pKa values of the amines and the regioselective N-acylation. The mechanism of the reaction is illustrated in Scheme 25. 2.2. Oxidation of thiourea to formamidinium disulfide Among other oxidized products, formamidine disulfide is also obtained from the oxidation of thiourea by various oxidants. Copper(II) perchlorate in acetonitrile has been shown to be an effective oxidant for a variety of compounds, including thiourea (76, 77). Zatko and Kratochvil (78)

12 S. Sahu et al.

HFeO4- + H2NCSNH2

k1

H2FeO4-+ NH2NHCS

HFeO4- + NH2NHCS + H2O

k2

H2FeO4-+ NH2NHCSOH

H2FeO4-+ NH2NHCSOH + H2O

k3

Fe(OH)3 + NH2NHCSO2H + OH-

H2FeO4-+ NH2NHCSO2H + H2O 2H2FeO4-+ NH2NHCSO3H + 4OH-

k4

Fe(OH)3 + NH2NHCSO3H + OH-

k5

2Fe(OH)3 + NH2CONH2

Scheme 20. -

-

2 8 Fe(OH ) 3+ 3 NH2CONH2 + 3SO4 + 2OH

8 HFeO4 + 3 H2NCSNH2 + 9 H2O

Scheme 21. 2ClO2 + Me2N ( NHMe ) C

-

2Cl + Me2N NHMe C

S + H2O

2-

+

O + SO4 + 2H


Scheme 22. CH3HN

NHCH3

CH3HN

S

L DM TU

Co

L

Co

CH3HN

NCH3

C S

ET -L , -H+

S

Co-

O2

Co -

O2 O2

L CH3HN L

SH O2 , L -S

Co

Co

NCH3

C

L

L O2

C

ET - DM TU, -L

-

O2

L , H+

-

OH NHCH3 CH3HN

+

C

C

S

S

Co

H2O - H+

NHCH3

Co L

L

Scheme 23.

H N

H N S

I

O

OCOCH3 OCOCH3

Et3N , CH3CN

H N

N O

Scheme 24. have reported the oxidation of a series of thiourea to corresponding disulfides (18) by copper(II) in acetonitrile (Scheme 26). Mruthyunjaya and Murthy (79) have reported the oxidation of coordinated thiourea in copper(I)–thiourea complex under similar reaction conditions (Scheme 27). When a suspension of such a complex in acetonitrile is titrated with copper(II)-perchlorate in the same solvent, thiourea


OAc Pb Pb

OAc S N

C

H

N

N

N H

H

Et3N O N

C

OAc

S

OAc O H N

N

O

C

O N C N

HN

OAc

+ PbS

Scheme 25. +


S

R2N 2Cu(I ) + C R2N

2 Cu(II) + 2 R2N C NR2

NR2 S

S

C

+

NR2

Scheme 26. NH2 2 Cu S

+ 6 Cu(ClO4)2

C NH2

3

H2N

NH2

3

C

S

S

+ 8 CuClO4+ 4 HClO4+ 2 HCl

C

HN

NH

NH2 Cu S

SO 4 2 H2O + 6 Cu(ClO4)2

C NH2

3

2

H2N

NH2

3

C

S

S

C

HN

+ 8 CuClO 4 + H2SO4 + 4 HClO4

NH

NH2 2 (Cu)2 S

(NO 3)2 3 H2O + 10 Cu(ClO4)2

C NH2

5

H2N 5

NH2 C

HN

S

S

+ 14CuClO4 + 6 HClO 4 + 4 HNO3

C NH

Scheme 27. is oxidized to formamidine disulfide, and copper(II) is reduced to copper(I), which remains in solution as a complex with acetonitrile. The reaction was studied potentiometrically, and stiochiometry was found to vary depending on the type of salt taken. An outer-sphere oxidant, IrCl2− 6 , was used to oxidize thiourea, to formamidine disulfide (19) (Scheme 28) (80). The other thiourea derivatives such as N ,N -dimethylthiourea and 2-imidazolinethione also afforded corresponding disulfide derivatives as the oxidized products.

14 S. Sahu et al.

S 2-

3-

2 IrCl6 + 2 NH2 C NH2

+

2 IrCl6 + 2H

HN + C H2N

NH S

S

C NH2

Scheme 28. Lilani et al. (81) used hexacyanoferrate(III) to oxidized thiourea and N-substituted thiourea under acidic condition. The reaction proceeds by an outer-sphere mechanism (Scheme 29) to yield formamidine disulfide. H+ + [Fe(CN)6]3H[Fe(CN)6]2-+ TU H[Fe(CN)6.TU]22-

H[Fe(CN)6.TU] + TU

K K1 K2 K3

H[Fe(CN)6]2H[Fe(CN)6.TU]2[Fe(CN)6]3- + TU [Fe(CN)6]3- + TU2


Scheme 29. Earlier it was reported that sulfur-containing compounds show a complex free-radical chemistry, which is very different from that exhibited by carbon-centered free radicals (82–86). For example, sulfur-centered radicals are able to form three-electron-bonded intermediates such as RSSR•− , • R2 SSR•+ 2 , or R2 SOH (87). The radiation-induced chemistry of thiourea in aqueous solution has been studied (88–97), emphasizing its potential application as a radio-protectant. During the process, formamidine disulfide is found to be the major product. In addition to this several sulfurfree nitrogen-containing compounds, sulfate ion and elemental sulfur have also been observed. These products are probably, in most cases, the hydrolysis products of the disulfide (98). The reaction of hydroxy radical, generated radiolytically, on thiourea resulted in the formation of different products both in the presence and absence of oxygen (99). The rates of reactions were fast and determined through a competitive reaction protocol, where radicals generated during the reaction process were quenched by 2-propanol and sodium azide. In the absence of oxygen, the formation of disulfide was due to coupling of thioformamidine radical with thiourea, without involving proton abstraction from a thiol. This mechanism was supported by similar results, considering N ,N ,N ,N -tetramethylthiourea as the substrate, where there is no scope of thioenolization (Scheme 30). In aerobic condition, dioxygen cleaved the disulfide radical cation through the formation of sulfoperoxy radical (Scheme 31). The other products generated during the reaction were sulfur, cyanamide, and thiourea monoxide. Recently, oxidation of thiourea by permanganate in a dilute perchloric acid solution was studied by using the conventional spectrophotometric technique (100). The reaction proceeds through the formation of colloidal MnO2 as an intermediate, the stability of which depends on [H+ ] (Scheme 32). The stoichiometry has been found to be 1:2 (MnO2 :thiourea). Investigation of the reaction mechanism in organized assemblies has become an area of rapidly increasing interest because many of the biological processes proceed in micro-heterogeneous systems, which contain aqueous and lipophilic domains (101). Among the biochemical functions, the redox processes are of primary importance (102). Recently, Ahmad et al. (103) studied the effect of CTAB micelles on rates of oxidation of thiourea by permanganate (Scheme 33). The effects of + [MnO− 4 ], [thiourea], and [H ] on the reaction rate were determined in the presence of CTAB. It was observed that the rate constant decreases with an increase in initial [MnO− 4 ]. This abnormal behavior was attributed to the flocculation of colloidal particles. A decrease in the rate constant was also observed with an increase in [CTAB] due to the association/incorporation of MnO− 4 to the

Journal of Sulfur Chemistry 15 +

NR2

NR2

C S

C S OH

NR2

NR2

-OH

NR2

-

C S NR2

NR2 C S NR2 +

NR2

+

NR2

C S

NR2

NR2

NR2

NR2

NR2

.

NH2

NR2 C S-S C

C S -S C

S C NR2

NR2

+

NR2

NR2

Scheme 30. +

NH2 C

S

S

C

O O

NH2 S

O O + C

C

S

S

.

NH2

O+ C

NH2

S

NH2

S

O

S

S

O

NH2 NH2

S

OH + C

.

S

NH2

NH2

C

S

OH

NH2

NH2 NH C

C +

NH C

NH2

NH

NH2 C

.

O +

S

NH2

NH2

NH2 NH2

NH2 C

S

NH2

+

NH2

.

+

NH2

.

O O+C

S

NH2

+

C

C

NH2

NH2


+

NH2

OH

N C

NH2 + HSOH

NH2 2 HSOH

S2 + 2 H2O

Scheme 31. positive head group of CTAB aggregates through electrostatic interactions. The reaction proceeds more slowly in the micellar phase than in the bulk phase. The positively charged thiourea partitions to the water phase due to electrostatic repulsion from the cationic micellar surface, while MnO− 4 resides at the surface. The observed inhibitory effect of CTAB may be explained in terms of the Menger–Portnoy model (104) which takes into consideration of incorporation/solubilization of only one reactant into a single micelle (Scheme 34). Sodium N -chloro-p-toluenesulfonamide or chloramine-T (CAT) has been found to be effective in bringing the oxidation of thiourea and some N-substituted thioureas to the corresponding formamidine disulfides in the presence of HClO4 (105). The oxidation reaction is first order with respect to [CAT], [thiourea], and [H+ ]. Ionic strength of the medium and addition of p-toluenesulfonamide or halide ions have negligible influence on the rate of oxidation. Under comparable experimental conditions, the rate of oxidation of thioureas increases in the order: N-allylthiourea > N -phenylthiourea > N -methylthiourea > thiourea > N -tolylthiourea.

16 S. Sahu et al.

S

SH

Ka

+ NH2 C NH2 + H

+

NH2 C NH2

SH

SH +

Kad

+

(MnO2)n + NH2 C NH2

(MnO2)n NH2 +

K'ad

H Mn(III) +

SH

. S

NH2 C

C NH2

+

+

(MnO2)n NH2

H

C NH2

NH 2 NH2 C

. S

Dimerization

H2N

NH2 C

NH

S

S

C

HN

NH

Scheme 32.


S NH2 C NH2 + MnO4 S

fast

+

Kad

(MnO2)n + NH2 C NH2

complex

M n(IV) + other products

-

k

(MnO2)n thiourea complex . S

(MnO2)n -1+ Mn(III) + NH2 C

+

NH2 radical . S

2 NH2 C

Dimerization

H2N

NH2 C

+

NH2

S

S

C

HN

M n(II) + Thiourea

NH

Mn(III) +

radical

Scheme 33. SH H2N C

+

NH2 + HMnO4

Products

+ H+

S H2N C NH2

MnO4+ +

H2O

+

H2 O

H 2O +

MnO4-

Br-

H2O

+

+

H2 O

+

= CH(CH2)15CH2N(CH3)3

Scheme 34.

Br-


The reaction mechanism involves the interaction of conjugate acid (CH3 C6 H4 SO2 NHCl) and substrate giving an intermediate complex, in a slow step (Scheme 35). ( fast ) TsNCl + H+ k 1 TsNHCl k -1 ( fast ) HN

H2N C

C

S

HN C

H + TsNHCl

S

S

H

RHN

RHN

RHN

H HN k2 C S + + TsNH Slow and rate limiting RHN Cl

H H

HN C RHN

S+

N H S

Cl

C NHR

k 3 ( fast ) - HCl

H

HN C RHN

NH

S

S

+

C NHR

+

-H HN

NH


C

S

S

RHN R= H,

CH3 ,

CH2CH CH2 ,

C6H5 ,

C NHR

C6H5CH3

Scheme 35.

2.3. Oxidative degradation Thiourea, an antioxidant, after oral administration to human and animals, is almost completely absorbed and is excreted largely unchanged via the kidneys. However, some metabolic oxidation can take place by biological oxidants. It is oxidized by thyroid gland peroxidase in the presence of iodine or iodide and hydrogen peroxide to form formamidine disulfide. Formamidine disulfide, being unstable, decomposes at pH > 3.0, forming cyanamide, elemental sulfur, and thiourea. It was shown in vitro and in vivo that both cyanamide and thiourea are inhibitors of thyroid peroxidase (106). In liver microsomes, it has been shown that flavin-containing monooxygenase catalyses the S-oxygenation of thiourea to the reactive electrophilic formamidine sulfenic acid and formamidinesulfinic acid (Scheme 36) (107). Oxidation of thiourea also occurs in the intact rat liver (105). In the presence of glutathione, formamidinesulfenic acid is rapidly reduced to thiourea with concomitant formation of glutathione disulfide both in vitro and in vivo (107, 108). As thiourea is toxic and a cancer-supporting agent, the environmental concerns have promoted studies on the destruction of thiourea. Oxidative degradation of ETU, the most noxious and carcinogenic metabolite of the widely used ethylene bisdithiocarbamate fungicides, has been intensively studied (109, 110). This is usually degraded by using oxidants such as potassium permanganate (111), sodium hypochlorite (55), or hydrogen peroxide (49). However, the oxidants either contain heavy metals or halogen atoms leading to unwanted byproducts. Meunier (112) reported a very fast degradation of thioureas with potassium monopersulfate as oxidant in neutral medium at room temperature, yielding non-carcinogenic ureas as final products. Potassium peroxodisulfate is known to degrade diphenylthiourea under strongly basic conditions to a mixture of the corresponding urea, sulfur, and phenyl isothiocyanate (46, 113). Silver, mercury, and lead oxides in water at room temperature eliminate hydrogen sulfide from the thiourea molecule giving cyanamide (114). 1-Alkylthioureas are oxidized with mercury oxide and water

18 S. Sahu et al.

SH

O OH S OH NADPH C C O 2 HN NH2 HN NH2 Formamidine Formamidine sulfenic acid sulfenic acid S

NADPH C HN NH2 O2 Thiourea

GSH

GSSG

Cyanamide, Formamidine sulfenic acid urea NADPH GSSG = oxidized glutathione, GSH = reduced glutathione, NADPH = reduced nicotinamide adenine dinucleotide phosphate


Scheme 36. on heating to form alkyl cyanamides and hydrogen sulfide, while 1,3-disubstituted thioureas under similar conditions are oxidized to the appropriate 1,3-disubstituted ureas (115). Thiourea and its lower homologs are uniquely useful in an acidic process for dissolving utility power plant boiler scales containing iron oxides and copper. During the oxidative destruction of thiourea in BCCWs, solutions can easily be accomplished by neutralizing the acid to an excess of the base, adding powdered charcoal and purging with air or O2 (67). The reaction leads to the formation of dicyandiamide and sodium thiosulfate as major products, with urea and sulfur as the minor products (Scheme 37). S 2 H2N C NH2 + 2NaOH + O2 S 2H2N C NH2 + O 2

NH Na2S2O3. 5 H2O + H2N

C NHC N

O 2 H2N C NH2 + 2S

Scheme 37. A quantitative characterization of different fragments of the oxidation products of thiourea by hydrogen peroxide was reported by Gao et al. (116). A reversed-phase ion-pair high-performance liquid chromatography (HPLC) technique was employed to monitor the concentrations of a variety of sulfur-containing species with different oxidation states and to elucidate the relative phase relations among them. Experimental results were in good agreement with simulations from an eight-step reaction mechanism (Scheme 38). HPLC could directly identify various species such as thiourea, formamidine disulfide, thiourea dioxide, and thiourea trioxide, and also provided real-time tracking of multiple sulfur species during the oxidation of thiourea. 2.4.

Oxidative cyclization

Oxidation of binary mixture of thioureas has provided good methods for the synthesis of various substituted 1,2,4-thiadiazoline derivatives (117–121). Joshua and Sujatha (122) used hydrogen peroxide to oxidize a mixture of 1-alkyl-3-aryl thiourea and thiourea in acidic solution to obtain two isomeric 3-amino-1,2,4-thiadiazolines (20 and 21). The reaction proceeds via a rearrangement of bis(formamidine)sulfide to aminothiourea derivatives (Scheme 39).


H2O + SC(NH2)2

HOSC(NH)NH2 + H2O

HOSC(NH)NH2 + SC(NH2)2

NH2(NH)CSS(NH)NH2 + H2O

NH2(NH)CSSC(NH)NH2 + H2O2

2 HOSC(NH)NH2

HOSC(NH)NH2 + H2O2

HO2SC(NH)NH2 + H2O

HO2SC(NH)NH2 + H2O2

HO3SC(NH)NH2 + H2O

HO3SC(NH)NH2 + H2O2

HSO3- + OC(NH2)2 + H+

HSO3- + H2O2

SO42- + H2O + H+ SC(NH2)2 + S + other species

NH2(NH2)CSSC(NH)NH2

Scheme 38. NHR + H2N

ArNH C

S

S ArNH C

S

S C


NR ArNH C

C NH2

H2O2 ArNH C S + H / C2H5OH NR

NH2.HCl

ArNH C

NH S

NR

NH

RHN C

NH2.HCl

NH

R

N C NH2.HCl + RHN C

S

NH Ar

N C

S NH2

N RN

NH2.HCl

NH C

NR

Ar

NH2.HCl

C

S

S C

Ar

NH2.HCl

NH NH2

N N S

20

+ ArN

N S

21

Scheme 39. Earlier it has been reported that oxidation of 1-monoacyl derivatives of thiourea afforded the appropriate 3,5-bis-(acylamino)-1,2,4-thiadiazoles derivatives (35, 123, 124). A complicated mechanism was proposed with 1-arylthiourea (125–129), where dimeric compounds were isolated as intermediates, followed by cyclized oxidation leading to the formation of 5-imino-4-phenyl-3phenylamino-4H -1,2,4-thiadiazoline-type bases (126, 130, 131). The compounds were subjected to isomerization to form 3,5-diarylamino-1,2,4-thiadiazoles (22) (Scheme 40) (125, 127).

2 PhHN

NH2 S

1) 2 PhI( OCOCF3 ) 2 /M eCN 2) i-PrOH /Na2CO3 aq. ( pH 8 )

Ph

AcHN

N N S

NH

22

Scheme 40. Mamaeva and Bakibaev (130) oxidized 1-acetylthiourea (ATU) in the presence of equimolar quantities of DIB in chloroform or in the presence of equimolar quantities of bis(trifluoroacetoxy)iodobenzene (BTI) in acetonitrile, for oxidative cyclization to form 3,5diacetylamino-1,2,4-thiadiazole (23; Scheme 41). Similarly in the presence of DIB, 1-phenylthiourea (PTU) was subjected to azacyclization to yield 3,5-dianilino-1,2,4-thiadiazole (24; Scheme 42) (130).

20 S. Sahu et al. AcHN 2 AcHN

NH2 2 PhI( OCOCF ) / CHCl 3 2 3

N N

S

S

NHAc

23

Scheme 41.

2 PhHN

NH2 S

PhI( OAc ) 2 / M eCN -20°C , 30 min. 55%

PhHN

N N S

NHPh


Scheme 42. The reaction mechanism of the formation of 1,2,4-thiadiazoles 26a and 26b is presented in Scheme 43. With BIA, 1-substituted thioureas 25a and 25b dimerize to form 1-R-3-Ramidinothioureas via the polyvalent iodine compound with elimination of the sulfur atom followed by easy oxidative azacyclization to form the appropriate bases 26a and 26b. In contrast to PTU conversion in the reaction with DIB, the same reaction initiated by BTI (Scheme 40) results in the formation of corresponding trifluoroacetate in situ, which without preliminary isolation, on neutralization with Na2 CO3 affords 5-imino-4-phenyl-3-phenylamino-4H -1,2,4-thiadiazoline. In comparison to the ATU conversion in reaction with BIA, the reaction of PTU with BTI leads to a different type of mechanism. In the later case, strong trifluoroacetic acid (TFA) generated during the reaction is the crucial factor on the formation of the final product, 22. Thus, the TFA leads to the protonation of intermediate bases, resulting in the formation of adduct instead of its isomer. The crux in Scheme 44 is 1-phenyl-1-phenylamidinothiourea formation in the presence of TFA instead of 1-phenyl-3-phenylamidinothiourea, which steers the oxidation reaction. Benzothiazoles are found to be potentially active compounds of interest in both synthetic organic chemistry and biological fields. Among several methods for the synthesis of various substituted benzothiazoles, the most versatile and economical method involves the treatment of arylthioureas with oxidative cyclizing agents in different reaction conditions (131). For the cyclization of 2-bromophenylthioureas derivatives, copper ion in the presence of N -(4,5-dihydrooxazol2-yl)benzamide was used to afford 2-aminobenzothiazoles (132). Oxidative cyclization of N -methyl-N -(benzelene-1-yl) thioureas to 2-N -(methyl amino) benzothiazoles can be achieved successfully by using bromine and acetic acid (Scheme 45) (133). 1,2-Bis-(3-methyl-2-thioureido) derivatives formed from the reaction of methylthio isocyanate and aryldiamine undergo intramolecular cyclization to give 2-marcapto benzimidazoles and N ,N dimethyl thiourea as a byproduct (134). Formation of these two products has been explained by the initial nucleophilic attack of the internal nitrogen of one thioureido derivative on the thio-carbon of the other leading to the formation of a cyclic intermediate, which is further oxidized to afford the desired products (Scheme 46). An efficient method for cyclization of substituted thiourea to benzimidazole derivative has been reported by Murru et al. (135). They have proposed that cyclization takes place via S-alkylation of thioureas followed by Cu-catalyzed intramolecular arylamination to the benzimidazole derivatives (Scheme 47). Furthermore, 2-mercapto benzimidazoles substituted with a p-methoxybenzyl group can easily be converted to corresponding benzimidazolethione, a substituted cyclic thiourea. In an attempt to reinvestigate the reaction of bromoacetone with benzoyl thiourea, Singh et al. (136) reported the formation of 1-benzoyl-3-phenyl-4-methylthiazolidene-2-imine (28) (Scheme 48). They used 1,1 -(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT) as the brominating agent in situ, while treating 1-benzoyl-3-phenylthiourea with acetone. During the reaction,

Journal of Sulfur Chemistry 21 2 PhHN

NH2

PhHN

PhI(OCOCF3 ) 2 2 CF3CO 2H

S

S

S

I

NH

NHPh PhI

NH

Ph

Ph PhHN

S

. 2 CF3CO2H

NH 2

H N

PhHN

S

NH CF3OCO

S

NH

I

. CF3CO2H

NH

S

. CF3CO2H PhI(OCOCF3 ) 2 2 CF3CO 2H

Ph

PhHN

N N

PhI

NH2

Ph

PhHN

NH

N

PhHN S CF3CO 2H

N N

Na2CO 3 aq.

NH

S

Ph

2 RHN

NH2 + PhI(OCOR ) 2

S

RHN 2 R′CO 2H

S NH

I

H N

NHR PhI

S

Ph

H N

RHN

NHR S

NH


25a, b H H N

HRN

NH

S

NHR + PhI (OCOR′ ) 2

HRN R′CO2H

N

NR

NH

S

R′OCO

I

RHN

N

R′CO 2H N PhI

NHR

S

Ph

26a, b R=Ac (25a, 26a), R′=Me, CF3: R=Ph (25b, 26b), R′=Me

Scheme 43.

2 PhHN

NH2

PhHN

PhI(OCOCF3 ) 2 2 CF3CO2H

S

S NH

I

S

NHPh PhI

NH

Ph

Ph PhHN

S

. 2 CF3CO2H

NH 2

H N

PhHN

NH S

NH CF3OCO

I

PhI

N

PhHN S CF3CO2H

NH

NH2 S

Ph

PhHN

S

NH

Ph

PhHN

N N

. CF3CO2H PhI(OCOCF3 ) 2 2 CF3CO2H

. CF3CO2H

Na2CO3 aq.

N N S

NH

Ph

Scheme 44.

EDPBT brominates acetone to bromoacetone in the first step which is fooled by the attack of sulfur of thiourea on the carbon of the bromomethyl group. In the presence of a base such as triethylamine, the abstraction of the NH proton flanked by a carbonyl and a thiocarbonyl moiety is facilitated activating the attack of sulfur. Intramolecular attack of the second NH

22 S. Sahu et al.

R1

R1

R2 R3

NH2

S

+

C

H

MeOH

S N

HH

R3

N

H

H N

R2

CH3

H

CH3

Br2 -ACOH

R1 R2

N

R3

S

NHCH3

H

Scheme 45. H Downloaded At: 17:33 28 January 2011

NH2 + R

S

N 2 CH3

N C

S EtOH

NH CH3 NH

R

NH2

S

NH CH3 1,4 dioxane H

N

N

SH

N

NH CH3

SH N

R H S

R

NH CH3

S

NH CH3

NH CH3

S N SH + H3C

N H

N H

R

N H

CH3

Scheme 46. H N

1

R

N

S

Et3N, R3X HN R2 CuI, ligand, base X

SR 3 1

N

R

X = Br, I H N

R2 R3 = PMB debenzylation in THF S

1

R

N R2

Scheme 47.


group of the isothiourea intermediate on the carbonyl group produces 1-benzoyl(4-hydroxy-3,4diphenylthiazolidine)-2-imine (27) which was followed by dehydration of the tertiary alcohol leading to the formation of 28. O

O EDPHT

Br + HBr

R

R

Ph N

Ph

Et3N

H

Ph

H

N O

R Ph O

S

HN

N S

O

Ph

Ph O

O

N

H O

S R

Isothiourea R

H 27 Et3NHBr

Br Ph

Ph


N Ph

N

N

O S

-H2O Ph N

S

+

R

H O

28

O

R

H

H

Scheme 48. Jordan et al. (137) have described a method for the facile conversion of aryl thioureas to 2-aminobenzothiazoles with an equimolar amount of benzyltrimethylammonium tribromide (PhCH2 NMe3 Br3 ) as the oxidative coupling agent (Scheme 49). R4NBr3

R4NBr + Br2 +

N H

C

-

S Br Br

S NHMe

N H

NHMe -HBr H

S

S -

NHMe HBr N

NHMe Br +

N

Scheme 49. Zaware et al. (138) have reported the kinetics of reaction between 3-chloroacetylacetone and various substituted thioureas, which resulted in the formation of 2-(substituted amino)-4-methyl5-acetyl thiazoles (Scheme 50). Recently, oxidative cyclization of some substituted thioureas has been achieved by using bromoketones in the presence of molecular iodine as the catalyst. Iodine induces an increase in electron deficiency at the carbonyl carbon facilitating the condensation of thiourea with bromoketones (Scheme 51) (139).

24 S. Sahu et al.

O O

C C

Cl

R1

CH3

NH2 C

S

H

slow

-

+

N H

N NHR2

NHR2 H S

1

R

R2

fast

H3C

+

H

NH

OH

H

H3C

R1

S –H2O

H3C 1=

R

H3C

2=

R

N

1

NHR2

R

S O H, phenyl, p-methylphenyl, p-ethoxypheny l, p-chloropheny l

Scheme 50. I2

OH

O 1


R

S Br CH2

I2 R

2

+

1

R H2N

NH

C

CH2 Br

HN

NH

R2

S R1

R1 C

C

CH

CH2

1

R

C

H2O CH2 Br

N

S

Tautomerization N

S NHR2

N

S N R2

N H

Scheme 51. 3.

Conclusions

Albeit thiourea and substituted thioureas are not naturally occurring substances, these are of versatile applications in industrial domain. These compounds are hazardous, while the corresponding oxidized products, ureas, are non-toxic and useful to natural habitats. Further, these compounds can be oxidized to various nitrogenous heterocyclic compounds having pharmaceutical activities and are also synthon components in cyanine dyes. A large number of oxidants with varied oxidation potentials have been used for oxidizing thioureas to obtain corresponding oxo derivatives, disulfides, or heterocyclic products. The oxidation, sometimes, occurs via free radical mechanism. However, in most cases, thioureas form complexes with the oxidants in the first step, which is followed by decomposition to the oxidized products of thioureas. Acknowledgements BKM thanks University Grants Commission for financial assistance through a research project. SS thanks Council of Scientific and Industrial Research, New Delhi for Senior Research Fellowship.

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