The oxidative cleavage of an anti-Hugerschoff product: a mild environmentally benign one pot synthesis of ureas from isothiocyanates

Abstract

In a simple, one-pot procedure, H₂O₂ has been utilised for the synthesis of unsymmetrical ureas from thioureas obtained by the reaction of aryl isothiocyanates with aliphatic secondary amines. The reaction proceeds via the formation of a thioamido guanidino moiety (the anti-Hugerschoff product) which then undergoes further oxidative desulfurization in the presence of excess H₂O₂ to afford the desired product. The scope of this phosgene free urea synthesis has been extended to various substrates.

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Introduction

Ureas are frequently encountered subunits of synthetic targets with applications in agrochemical, petrochemicals and pharmaceuticals. They have been widely used in the manufacture of hair dyes, detergents, polymers, corrosion inhibitors and as antioxidants in gasoline. Their biological activities as plant growth regulators, agroprotectives as well as tranquillising and anticonvulsant agents are also noteworthy.¹ In addition, ureas have gained enormous attention as potent HIV-1 protease inhibitors² (1 and 2, Fig. 1), pharmacophores and ligands for catalysis (3 and 4, Fig. 1) and as insecticides^1b (5 and 6, Fig. 1). Anti-viral drugs such as zidovudine (AZT) and ripavirine (7 and 8, Fig. 1) and anti-cancer drugs such as azacytidine and temozolomide (9 and 10, Fig. 1), all contain the urea functionality.³ The ureido sub unit is present in several biologically relevant molecules such as uric acid, flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), riboflavin (Vitamin B₂), biotin, etc. and nucleic acid bases such as cytosine, uracil, thymine.³

Fig. 1 Examples of some biologically important molecules having ureido moiety.

Due to its various applications, much effort has been devoted in the past towards the synthesis of ureas. The classical method follows the coupling of amines with phosgene or the condensation of amines with isocyanates.⁴ However; both of these reagents are associated with serious toxicological and environmental problems and demand cautious handling and storage. Over the years, more sophisticated phosgene equivalents/substitutes have been developed such as bis(4-nitrophenyl)carbonate,⁵N,N-carbonylbisimidazole,⁶N,N-carbonylbisbenzotriazole,⁷ tri-phosgene [bis(trichloromethyl) carbonate)],⁸di-tert-butyldicarbonate [(BOC)₂O],⁹S,S-dimethyldithiocarbonate,¹⁰ trihaloacetylchlorides,¹¹etc. These reagents, however, are developed from phosgene itself and therefore have failed to do away with the environmental issues associated with its use.

On the other hand, oxidative carbonylation of amines using CO₂ and CO in catalytic processes¹² have brought about the convenient large scale production of urea derivatives. However, besides the toxicity of CO, these methods are associated with high risks owing to the potentially explosive mixture of CO and O₂. In addition, even though carbamates have been widely used for the synthesis of urea as a phosgene-free alternative,¹³ their preparation from toxic CO or CO₂ and the use of metal catalysts such as Zr(Ot-Bu)₄, AlMe₃, etc. as well as the requirement for high pressure, dry reaction conditions and low yields makes the methods disadvantageous. Other methods include the sequential trans-amination of urea with anilines and dialkylamines,¹⁴N-alkylation of urea,¹⁵ reductive amination of aldehydes with monoalkylureas¹⁶ and zeolite based reaction of amines with ethyl acetoacetate.¹⁷

In recent years, due to environmental legislation on the use of toxic chemicals, more benign reagents and reaction methodologies are being sought for organic synthesis and in this context, there is much room for improvement for the synthesis of ureas.

Results and discussion

Hydrogen peroxide is a safe, effective, selective though powerful and versatile oxidant which is next best to molecular oxygen in terms of environmental benignity. It has therefore, been widely used in various organic transformations such as catalytic asymmetric epoxidation,¹⁸ conversion of dithioesters into carboxylic acids or esters under an alkaline conditions¹⁹ and desulfurization of thioamides into amides over a ZrCl₄ catalyst.²⁰

In an independent work, our group has studied the desulfurization ability of H₂O₂ in the conversion of thioamides to cyanamides²¹ and we have also been exploring its versatility in various oxidative synthetic transformations.²² Recently, we have reinvestigated the classical Hugerschoff reaction where it was observed that addition of piperidine to phenyl isothiocyanate followed by treatment with the bromine equivalent 1,1′(ethane-1,2-diyl)dipyridinium bis-tribromide (EDPBT) in CH₂Cl₂ gave a thioamido guanidino moiety (the anti-Hugerschoff product) as the major product instead of the expected 2-aminobenzothiazole.²³ The disulfide intermediate formed in the medium undergoes an imine disulfide rearrangement with the expulsion of sulfur to give the anti-Hugerschoff product. Since the anti-Hugerschoff product formation goes via an oxidative path, we were interested in achieving the same conversion using cheap and innocuous H₂O₂ instead of the expensive ditribromide reagent.²⁴

Consequently, when the in situ generated thiourea, obtained by the reaction of phenyl isothiocyanate (14) and morpholine (a) in ethylacetate was treated with H₂O₂ (2 equiv.), the formation of the expected anti-Hugerschoff product was observed in about 60% conversion along with the unreacted thiourea. To attain total conversion, the reaction was treated further with 2 equiv. of H₂O₂, thereby, it was observed that the unreacted thiourea and the anti-Hugerschoff product both got consumed giving a new product exclusively having lower R_f as judged from TLC. Isolation and characterization showed the product to be morpholine-4-carboxylic acid phenylamide (14a, Table 1).

Table 1 Preparation of unsymmetrical ureas using H₂O₂^a

Substrate	sec-Amine	Product^b	Yield (%)^c
a Reactions were monitored by TLC. b Confirmed by IR, ^1H NMR and ^13C NMR. c Isolated yield.

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This result prompted us to develop a one pot method for the synthesis of unsymmetrical urea from aryl/alkyl isocyanates and secondary amines using innocuous oxidant hydrogen peroxide. James et al. have reported the oxidative degradation of ethylene thiourea (ETU) using H₂O₂ at different pH.²⁵Urea was reported to form under basic conditions whereas under neutral conditions, formation of 4,5-dihydro-1H-imidazole-2-thiol was observed.

Thus, there is no synthetically useful preparation of ureas from thioureas using either H₂O₂ or any other cheap and environmentally acceptable oxidants.²⁶

The mechanism essentially involves the formation of alkyl/aryl thiourea from isothiocyanates and sec-amine to give the anti-Hugherschoff product (11) via an oxidative path (Scheme 1).²³ The intermediacy of the product (11) has been confirmed by its isolation and characterization. The intermediate isolated from the reaction of 4-trifluoro phenyl isothiocyanate and morpholine in H₂O₂ could be crystallized. X-Ray crystallographic analysis of the intermediate (11) clearly shows the formation of a thioamidoguanido moiety (Fig. 2). The soft thiolate sulfur (=S) of the product (11) attacks the H₂O₂ to give species (12) which undergoes an intramolecular rearrangement involving the cleavage of the C–N bond giving species (13). The attack of water on the immenium carbon of (13) is associated with the sequential cleavage of the C–S and S–O bonds with the concurrent expulsion of sulfur. This oxidative desulfurization path has been confirmed by treating the isolated anti-Hugherschoff product (11) with H₂O₂ wherein sulfur precipitation was observed.

Fig. 2 ORTEP views of N-((E)-(4-(trifluoromethyl)phenylimino) (morpholino)methyl)-N-(4-(trifluoromethyl)phenyl)morpholine-4-carbothioamide (11).

Scheme 1 Formation of urea from in situ generated thiourea.

Among the various solvents tested such as DMSO, CH₃CN, 1-propanol, MeOH, EtOH, EtOAc, and acetone, the later three solvents were found to be equally effective giving good yields of products. The use of EtOH and acetone requires evaporation followed by extraction with EtOAc which is not the case with EtOAc, thus it was used for all the reactions. The starting material alkyl and aryl isothiocyanates were prepared following our environmentally benign, cost effective protocol for the synthesis of isothiocyanates from dithiocarbamic acid salts using molecular iodine²⁷ or methyl acrylate²⁸

Using phenyl isothiocyanate (14) as the test substrate, we investigated the versatility of this methodology employing various aliphatic secondary amines such as morpholine (a), piperidine (b), 4-hydroxy piperidine (c), diethylamine (d) and diisopropylamine (e). All the in situ generated thioureas from their respective amines reacted smoothly to afford the corresponding ureas 14a–14e on treatment with 3 equiv. H₂O₂ (Table 1). The structure of the product 14a has been further confirmed by X-ray crystallographic analysis as shown in Fig. 3. The aryl isothiocyanate bearing the deactivating substituent (15) underwent the reaction smoothly to give the ureas 15a–15d in good yields.

Fig. 3 ORTEP view of morpholine-4-carboxylic acid phenylamide (14a)

Aryl isothiocyanate having electron donating substituent (16) also underwent the reaction to give the corresponding ureas 16a–16e in moderate yield. Benzyl isothiocyanates react with various secondary amines (a, b and e) under the present reaction condition to give the products 17a, 17b and 17e in high yields. Thus, this method is equally successful irrespective of the nature of the sec-amines.

After establishing the versatility of the present method, we further explored the methodology to various other aryl and alkyl isothiocyanates. Thus, various isothiocyanates were reacted with morpholine (a) and piperidine (b) and the results are summarized in Table 2. Isothiocyanates bearing electron withdrawing substituents (18, 19, 20 and 25, Table 2) reacted with secondary amines smoothly giving the corresponding ureas (18a, 18b, 19a, 20a and 25b) in good yields. Similar results were also obtained in case of aryl isothiocyanates having electron donating substituents (such as 21 and 26), alkyl isothiocyanates (22 and 23) as well as naphthyl isothiocyanate (24).

Table 2 Preparation of unsymmetrical ureas using H₂O₂^a

Sec-amine	Substrate	Product^b	Yield (%)^c
a Reactions were monitored by TLC. b Confirmed by IR, ^1H NMR and ^13C NMR. c Isolated yield

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From our recent work,²³ we have observed that deactivated aryl thioureas gave exclusively anti-Hugerschoff products, whereas in the case of activated aryl thioureas, the Hugerschoff product 2-aminobenzothiazole was the major product. Formation of 2-aminobenzothiazole essentially involves an intramolecular aromatic electrophilic substitution reaction of the activated aryl ring to give the thiocarbonyl group of a thiourea and the process is facilitated by thiophilic bromine. On the other hand, as hydrogen peroxide is less thiophilic and the hydroxyl group is a poor leaving group, no cyclization occurs to yield 2-aminobenzothiazole, rather the substrates prefers an oxidative dimerization (S–S bond formation) followed by an imine disulfide rearrangegement²³ resulting in the formation of the anti-Hugerschoff product exclusively.

Conclusion

In a one-pot procedure, unsymmetrical ureas can be prepared from isothiocyanates and secondary amines in an ethylacetate medium using innocuous oxidant H₂O₂. It is noteworthy that no additives, strong bases or toxic solvents were used in the reactions and the majority of the products can be easily isolated by recrystallization from the crude reaction mixture without column chromatography. Although literature enumerates a number of procedures for the preparation of ureas, the simplicity, environmental acceptability and cost effectiveness of the present strategy makes it a practical alternative.

General procedure

To a solution of phenyl isothiocyanate 14 (270 mg, 2 mmol) in ethylacetate (5 mL), morpholine (a) (174 mg, 2 mmol) was added. The complete formation of unsymmetrical thiourea was observed within 15 min as adjudged from the precipitation of thiourea as well as from TLC. To this, 50% H₂O₂ (348 μL, 6 mmol) was added drop-wise with constant stirring over a period of 10–15 min whilst the solid thiourea slowly redissolved and subsequent precipitation of elemental sulphur was observed. The formation of urea was observed within 5–10 min of the complete addition of H₂O₂. Completion of the reaction was confirmed by TLC. The water present in hydrogen peroxide was removed by drying over anhydrous Na₂SO₄ and the organic layer was decanted and filtered to get rid of precipitated sulphur. The organic layer was concentrated and left to crystallize. The product 14a was isolated in 93% yield (381 mg).

In general, all oily and gummy products were purified over a short column of silica by eluting it with petroleum ether and ethylacetate.

Acknowledgements

B. K. P acknowledges the support of this research by the Department of Science and Technology (DST) (SR/S1/OC-79/2009), New Delhi, and the Council of Scientific and Industrial Research (CSIR) (01(2270)/08/EMR-II). LJ and NK thank CSIR for fellowships. Thanks are due to Central Instruments Facility (CIF) IIT Guwahati for NMR spectra and DST-FIST for XRD facility.

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra. CCDC reference numbers 815734, 815735. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1ra00278c

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