Thiourea-Mediated Regioselective Synthesis of Symmetrical andUnsymmetrical Diversified ThioethersPitchai Manivel,† Kamalakannan Prabakaran,† Varadhan Krishnakumar,† Fazlur-Rahman Nawaz Khan,*,†

and Thandavarayan Maiyalagan‡

†Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of Advanced Sciences, VIT-University,Vellore 632 014, Tamil Nadu India‡Materials Science and Engineering Program The University of Texas at Austin, Austin, Texas 78712, United States

*S Supporting Information

ABSTRACT: An efficient and simple thiourea-mediated regioselective synthesis of symmetrical and unsymmetrical diversifiedthioethers is reported. The regioselective reaction avoids byproduct formation and offers simplified methodology, widerapplicability, and easy workability and an environmentally friendly approach toward symmetrical and unsymmetrical thioethers.The mechanism of formation of thiols and symmetrical and unsymmetrical thioethers involving a sulfur surrogate is described.

1. INTRODUCTION

Organo sulfur compounds, especially thiols, play a significantrole because of the presence of a sulfur atom, a reactive centerof variable valency, and form an important part in manychemical transformations and biochemical processes asmetabolic products.1 Organosulfur compounds such as thiolsand thioethers are versatile intermediates for synthetictransformations.2 The photochemical reactions of aryl halideswith thiourea afford aryl methyl sulfides, diaryl sulfides, diaryldisulfides, and arylthiols.3 Several methodologies in theregioselective synthesis of thioethers are known;4 however,they suffer from regiocontrol, side product formation ofdisulfides by self-oxidation, etc. For example, there are reportson thioether preparations utilizing thiourea, such as the reactionof pyrrole with iodine or potassium triiodide and thiourea withthe formation of isothiouranium iodides, which react withhalides to offer thioethers; however, this required a two-stepreaction and also the involvement of additives such as hydrazinehydrates to avoid side products.5 Similarly, photoinducedreactions of aryl halides and a thiourea anion afford arenethiolate ions in dimethyl sulfoxide (DMSO), which uponsubsequent aliphatic nucleophilic substitution yield aryl methylsulfides, also with the formation of disulfides; this reaction againrequired the initiator t-BuOK, irradiation for 3 h to form athiolate anion, and subsequent reaction with aryl halides3a toafford a mixture of products including dehalogenated arenes,disulfides, etc. There is a report on thioethers from thechlorodipicolinates utilizing thiourea; these reactions exclu-sively provide symmetrical thioethers.3b In order to overcomethese drawbacks, an effort was made to develop an efficientmethodology for the regioselective synthesis of symmetricaland unsymmetrical thioether, which is reported. It is evidentthat the amount of thiourea plays an important role in theregioselective control of thiol formation of symmetrical andunsymmetrical thioethers (Scheme 1).

2. EXPERIMENTAL SECTION

2.1. Methods and Materials. Melting points weremeasured on a open-capillary melting point apparatus and areuncorrected. The purity of the compounds was checked usingprecoated thin-layer chromatography (TLC) plates (Merck,60F-254). IR spectra (KBr, ν in cm−1) were recorded on aPerkinElmer BX series Fourier transform infrared (FTIR)spectrophotometer. 1H NMR (400 MHz) and 13C NMR (100MHz) spectra were recorded on a Bruker 400 MHzspectrometer in CDCl3 or DMSO (with tetramethylsilane for1H NMR and DMSO for 13C NMR as internal references).Liquid chromatography−mass spectrometry (LC−MS) anal-yses were performed with a LCMS Agilent 1100 series ion trap.

2.2. General Preparation of 1-Chloroisoquinolines1a−1l. 3-Arylisoquinolinone (15 g, 0.068 mol) and phosphorylchloride (90 mL) were mixed. The mixture was refluxedovernight under a nitrogen atmosphere in an oil bath until TLCshowed completion of the reaction. Then the reaction mixturewas added to ice-cold water, and it was extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate.Removal of the solvent under vacuum gave a crude product,which was further purified by column chromatography on silicagel (230−400 mesh) with ethyl acetate−hexane (2%) as theeluent to afford the pure products 1-chloro-3-phenylisoquino-line (1a) in 92% yield, which are characterized by their 1H and13C NMR spectra and compared with reports in theliterature.6,7

2.3. General Procedure for the Synthesis of 3-Substituted Isoquinoline-1-thiols 3a−3l. 1-Chloro-3-aryli-soquinoline (1; 2.04 mmol, 1.0 equiv) and thiourea (2; 1.938mmol, 0.95 equiv) were mixed in an absolute ethanol solvent(10 mL, 20 vol) at ambient temperature under a nitrogen

Received: January 11, 2014Revised: March 29, 2014Accepted: April 14, 2014Published: April 14, 2014

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© 2014 American Chemical Society 7866 dx.doi.org/10.1021/ie500119p | Ind. Eng. Chem. Res. 2014, 53, 7866−7870

atmosphere. The resulting mixture was refluxed for 6 h. Thereaction progress was monitored by TLC. Usually all reactioncompleted in a 6−12 h period; upon completion, the reactionmixture was cooled to ambient temperature, and the productslowly crystallized and was filtered off, washed with 5 mL ofpetroleum ether, and dried under reduced pressure over aperiod of 1 h. In some cases, the solid was not formed at thisstage; under such circumstances, ethanol was completelystripped off and 10 mL of petroleum ether was added. Solidprecipitates were filtered and dried under reduced pressure overa period of 1 h. A yellow crystalline solid was obtained in allcases with high purity and good yield (79−91%).2.4. General Procedure for the Synthesis of Sym-

metrical Thioethers 4a−4k. Chloro compounds 1 (2.04mmol, 1.0 equiv) and thiourea 2 (1.02 mmol, 0.5 equiv) weremixed in an absolute ethanol solvent (10 mL, 20 vol) atambient temperature under a nitrogen atmosphere. Theresulting mixture was refluxed for 6 h. The reaction progresswas monitored by TLC. Usually all reaction completed in a 6−8 h period; upon completion, the reaction mixture was cooledto ambient temperature, and the product slowly crystallized andwas filtered off, washed with 5 mL of petroleum ether, anddried under reduced pressure over a period of 1 h. A yellowcrystalline solid was obtained in all cases with high purity andgood yield (79−95%).2.5. General Procedure for the Synthesis of Unsym-

metrical Thioethers 6a−6e. Chloro compounds 1a (2.04mmol, 1.0 equiv) and thiourea 2 (1.938 mmol, 0.95 equiv)were mixed in an absolute ethanol solvent (10 mL, 20 vol) atambient temperature under a nitrogen atmosphere. Theresulting mixture was refluxed for 6 h. The reaction progresswas monitored by TLC. After 6 h, the reaction mixture wascooled to ambient temperature. At ambient temperature, R1Cl(5; 2.04 mmol) was added, and reflux was continued for aperiod of 6−8 h. Upon completion, the reaction mixture wascooled to ambient temperature, and the product slowlycrystallized and was filtered off, washed with 5 mL of petroleumether, and dried under reduced pressure over a period of 1 h. Ayellow crystalline solid was obtained in all cases with highpurity and good yield (84−91%).

3. RESULTS AND DISCUSSIONIn a continuation of our research in isoquinolines,6 initially 3-substituted chloroisoquinolines7 were similarly derived from

homophthalic acid, which were when thionated with equimolarthiourea in ethanol and afforded thiols (Scheme 2) successfullyin 6 h with good yield.Optimization of the reaction conditions was carried out with

thionation of 1-chloro-3-(4-chlorophenyl)isoquinoline 1b and

Scheme 1. Synthesis of Symmetrical and Unsymmetrical Thioethers and 3-Arylisoquinoline-1-thiols

Scheme 2. Synthesis of 3-Arylisoquinoline-1-thiol 3b

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thiourea 2 as the model reaction (Scheme 2 and Table 1). Asshown in Table 1, the reaction proceeds with equimolarthiourea, with an excellent product yield. However, higherconcentration reduced the yields (Table 1, entries 5−7)because of the formation of a disulfide byproduct (5−15%).With the optimized conditions in hand, varoius isoquinoline

thiols were prepared from their corresponding chlorocompounds (Scheme 2 and Table1; see Table 1s in theSupporting Information, SI) in good yield without theformation of a thiol dimer.

Interestingly, lesser loading of thiourea produced lesser yieldsof thiols (Table 1, entries 1−4) because of the formation ofsymmetrical thioether as a byproduct in the reaction. It isenvisioned that symmetrical thioether could be obtained inexcellent yield by reduced loading (50%) of thiourea.In the further screening of thiourea 2, loading gave exciting

results, as shown in Table 2. The results illustrated that theformation of symmetrical thioether can be achieved by varyingthe concentration of thiourea. The increase in the concen-tration of thiourea proportionally increased symmetricalthioether 4b (Table 2, entries 1−3), and the optimized amountof 0.5 equiv produced higher yield. It should be noted that inthis concentration range no thiol formation is observed (entries1−3) and that thiol product is seen to form at above 0.5 equivof thiourea. Thus, an optimized amount of 0.5 equiv of thethiourea concentration is necessary for the regioselectivesynthesis of symmetrical thioethers in good yield and purity.In our continued interest in symmetrical thioether, wegeneralized this approach to some commercially available N-heteroaryl chlorides 1m−1w, and the yields are shown inScheme 3 and Table 2s in the SI.The interesting results prompted us to extend the method-

ology to unsymmetrical thioethers by adopting a one-potsynthesis. Initially, the thiols were obtained with an optimumamount of thiourea in an ethanol solvent refluxed for 6 h andby avoiding their isolation; the desired unsymmetricalthioethers 6 were obtained in good yield by refluxing furtherwith the other chloro derivatives 5. Under optimizedconditions, diversified unsymmetrical thioethers were obtained,as summarized in Scheme 4 and Table 3s in the SI.

Table 1. Optimization of the Thiourea Concentration in theReaction of 1ba

entry thiourea (mol equiv) yieldb (%)

1 0.70 502 0.85 743 0.90 804 0.95 905 1.00 84c

6 1.05 79d

7 1.10 72e

8 1.15 68f

aReaction conditions: 1b (2.04 mmol), ethanol (10 mL), reflux 12 h.bIsolated yields. cDisulfide byproduct yield: 5%. dDisulfide byproductyield: 10%. eDisulfide byproduct yield: 12%. fDisulfide byproductyield: 15%.

Table 2. Optimization of the Thiourea Concentration in theReaction of 1ba

yieldb (%)

entry thiourea (mol equiv), 2 product 3b product 4b

1 0.204 nil 202 0.408 nil 363 0.5 nil 883 0.612 10 404 0.816 60 325 1.020 84 156 1.2 79 12

aReaction conditions: 1b (2.04 mmol), ethanol (10 mL), reflux 6 h.bLC−MS yields.

Scheme 3. Synthesis of Symmetrical Thioethers 4

Scheme 4. Synthesis of Unsymmetrical Thioethers 6

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The products of all three regioselective reactions wereisolated and purified by recrystallization in an ethanol/petroleum ether solvent mixture. All of the pure compoundswere identified by various spectral techniques such as FTIR, 1Hand 13C NMR, LC−MS, and CHN analysis.The proposed mechanism of the reaction is depicted in

Scheme 5. The chloro compounds undergo an aromaticnucleophilic substitution (SNAr) reaction using thiourea asthe sulfur source to form an isothiouronium salt. This saltfurther gets converted to thiol in the presence of water (derivedfrom 99.9% absolute ethanol). The mechanism explains clearlythat the reaction takes place to produce initially thiol, whichfurther gets converted to symmetric thioethers and unsym-metrical thioethers in the presence of different concentrationsof thiourea and halo derivative similarly.

4. CONCLUSION

In conclusion, an efficient and facile regioselective synthesis of3-substituted isoquinoline-1-thiols and symmetrical and unsym-metrical thioethers is reported. The regioselective reactionsavoid byproduct formation and offer simplified methodology,wider applicability, and easy workability and an environmentallyfriendly approach (avoid the intermediate foul-smelling thiolisolation) toward symmetrical and unsymmetrical thioethers.

■ ASSOCIATED CONTENT

*S Supporting InformationSpectral values and 1H and 13C NMR spectra. This material isavailable free of charge via the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATIONCorresponding Author*E-mail: nawaz_f@yahoo.co.in.NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThe authors express their gratitude to the Indian Institute ofScience, SAIF, Bangalore, and IIT Madras for their support ofNMR, LCMS, and IR facilities.

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