Article pubs.acs.org/IECR
Thiourea-Mediated Regioselective Synthesis of Symmetrical and Unsymmetrical Diversified Thioethers Pitchai 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 diversified thioethers is reported. The regioselective reaction avoids byproduct formation and offers simplified methodology, wider applicability, 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
2. EXPERIMENTAL SECTION 2.1. Methods and Materials. Melting points were measured on a open-capillary melting point apparatus and are uncorrected. The purity of the compounds was checked using precoated thin-layer chromatography (TLC) plates (Merck, 60F-254). IR spectra (KBr, ν in cm−1) were recorded on a PerkinElmer BX series Fourier transform infrared (FTIR) spectrophotometer. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a Bruker 400 MHz spectrometer in CDCl3 or DMSO (with tetramethylsilane for 1 H NMR and DMSO for 13C NMR as internal references). Liquid chromatography−mass spectrometry (LC−MS) analyses were performed with a LCMS Agilent 1100 series ion trap. 2.2. General Preparation of 1-Chloroisoquinolines 1a−1l. 3-Arylisoquinolinone (15 g, 0.068 mol) and phosphoryl chloride (90 mL) were mixed. The mixture was refluxed overnight under a nitrogen atmosphere in an oil bath until TLC showed completion of the reaction. Then the reaction mixture was added to ice-cold water, and it was extracted with ethyl acetate. 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 silica gel (230−400 mesh) with ethyl acetate−hexane (2%) as the eluent to afford the pure products 1-chloro-3-phenylisoquinoline (1a) in 92% yield, which are characterized by their 1H and 13 C NMR spectra and compared with reports in the literature.6,7 2.3. General Procedure for the Synthesis of 3Substituted Isoquinoline-1-thiols 3a−3l. 1-Chloro-3-arylisoquinoline (1; 2.04 mmol, 1.0 equiv) and thiourea (2; 1.938 mmol, 0.95 equiv) were mixed in an absolute ethanol solvent (10 mL, 20 vol) at ambient temperature under a nitrogen
Organo sulfur compounds, especially thiols, play a significant role because of the presence of a sulfur atom, a reactive center of variable valency, and form an important part in many chemical transformations and biochemical processes as metabolic products.1 Organosulfur compounds such as thiols and thioethers are versatile intermediates for synthetic transformations.2 The photochemical reactions of aryl halides with thiourea afford aryl methyl sulfides, diaryl sulfides, diaryl disulfides, and arylthiols.3 Several methodologies in the regioselective synthesis of thioethers are known;4 however, they suffer from regiocontrol, side product formation of disulfides by self-oxidation, etc. For example, there are reports on thioether preparations utilizing thiourea, such as the reaction of pyrrole with iodine or potassium triiodide and thiourea with the formation of isothiouranium iodides, which react with halides to offer thioethers; however, this required a two-step reaction and also the involvement of additives such as hydrazine hydrates to avoid side products.5 Similarly, photoinduced reactions of aryl halides and a thiourea anion afford arene thiolate ions in dimethyl sulfoxide (DMSO), which upon subsequent aliphatic nucleophilic substitution yield aryl methyl sulfides, also with the formation of disulfides; this reaction again required the initiator t-BuOK, irradiation for 3 h to form a thiolate anion, and subsequent reaction with aryl halides3a to afford a mixture of products including dehalogenated arenes, disulfides, etc. There is a report on thioethers from the chlorodipicolinates utilizing thiourea; these reactions exclusively provide symmetrical thioethers.3b In order to overcome these drawbacks, an effort was made to develop an efficient methodology for the regioselective synthesis of symmetrical and unsymmetrical thioether, which is reported. It is evident that the amount of thiourea plays an important role in the regioselective control of thiol formation of symmetrical and unsymmetrical thioethers (Scheme 1). © 2014 American Chemical Society
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January 11, 2014 March 29, 2014 April 14, 2014 April 14, 2014 dx.doi.org/10.1021/ie500119p | Ind. Eng. Chem. Res. 2014, 53, 7866−7870
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Scheme 1. Synthesis of Symmetrical and Unsymmetrical Thioethers and 3-Arylisoquinoline-1-thiols
3. RESULTS AND DISCUSSION In a continuation of our research in isoquinolines,6 initially 3substituted chloroisoquinolines7 were similarly derived from
atmosphere. The resulting mixture was refluxed for 6 h. The reaction progress was monitored by TLC. Usually all reaction completed in a 6−12 h period; upon completion, the reaction mixture was cooled to ambient temperature, and the product slowly crystallized and was filtered off, washed with 5 mL of petroleum ether, and dried under reduced pressure over a period of 1 h. In some cases, the solid was not formed at this stage; under such circumstances, ethanol was completely stripped off and 10 mL of petroleum ether was added. Solid precipitates were filtered and dried under reduced pressure over a period of 1 h. A yellow crystalline solid was obtained in all cases with high purity and good yield (79−91%). 2.4. General Procedure for the Synthesis of Symmetrical Thioethers 4a−4k. Chloro compounds 1 (2.04 mmol, 1.0 equiv) and thiourea 2 (1.02 mmol, 0.5 equiv) were mixed in an absolute ethanol solvent (10 mL, 20 vol) at ambient temperature under a nitrogen atmosphere. The resulting mixture was refluxed for 6 h. The reaction progress was monitored by TLC. Usually all reaction completed in a 6− 8 h period; upon completion, the reaction mixture was cooled to ambient temperature, and the product slowly crystallized and was filtered off, washed with 5 mL of petroleum ether, and dried under reduced pressure over a period of 1 h. A yellow crystalline solid was obtained in all cases with high purity and good yield (79−95%). 2.5. General Procedure for the Synthesis of Unsymmetrical Thioethers 6a−6e. Chloro compounds 1a (2.04 mmol, 1.0 equiv) and thiourea 2 (1.938 mmol, 0.95 equiv) were mixed in an absolute ethanol solvent (10 mL, 20 vol) at ambient temperature under a nitrogen atmosphere. The resulting mixture was refluxed for 6 h. The reaction progress was monitored by TLC. After 6 h, the reaction mixture was cooled to ambient temperature. At ambient temperature, R1Cl (5; 2.04 mmol) was added, and reflux was continued for a period of 6−8 h. Upon completion, the reaction mixture was cooled to ambient temperature, and the product slowly crystallized and was filtered off, washed with 5 mL of petroleum ether, and dried under reduced pressure over a period of 1 h. A yellow crystalline solid was obtained in all cases with high purity and good yield (84−91%).
Scheme 2. Synthesis of 3-Arylisoquinoline-1-thiol 3b
homophthalic acid, which were when thionated with equimolar thiourea in ethanol and afforded thiols (Scheme 2) successfully in 6 h with good yield. Optimization of the reaction conditions was carried out with thionation of 1-chloro-3-(4-chlorophenyl)isoquinoline 1b and 7867
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Table 1. Optimization of the Thiourea Concentration in the Reaction of 1ba entry
thiourea (mol equiv)
yieldb (%)
1 2 3 4 5 6 7 8
0.70 0.85 0.90 0.95 1.00 1.05 1.10 1.15
50 74 80 90 84c 79d 72e 68f
Scheme 4. Synthesis of Unsymmetrical Thioethers 6
a
Reaction conditions: 1b (2.04 mmol), ethanol (10 mL), reflux 12 h. Isolated yields. cDisulfide byproduct yield: 5%. dDisulfide byproduct yield: 10%. eDisulfide byproduct yield: 12%. fDisulfide byproduct yield: 15%. b
Interestingly, lesser loading of thiourea produced lesser yields of thiols (Table 1, entries 1−4) because of the formation of symmetrical thioether as a byproduct in the reaction. It is envisioned that symmetrical thioether could be obtained in excellent 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 the formation of symmetrical thioether can be achieved by varying the concentration of thiourea. The increase in the concentration of thiourea proportionally increased symmetrical thioether 4b (Table 2, entries 1−3), and the optimized amount of 0.5 equiv produced higher yield. It should be noted that in this concentration range no thiol formation is observed (entries 1−3) and that thiol product is seen to form at above 0.5 equiv of thiourea. Thus, an optimized amount of 0.5 equiv of the thiourea concentration is necessary for the regioselective synthesis of symmetrical thioethers in good yield and purity. In our continued interest in symmetrical thioether, we generalized this approach to some commercially available Nheteroaryl chlorides 1m−1w, and the yields are shown in Scheme 3 and Table 2s in the SI. The interesting results prompted us to extend the methodology to unsymmetrical thioethers by adopting a one-pot synthesis. Initially, the thiols were obtained with an optimum amount of thiourea in an ethanol solvent refluxed for 6 h and by avoiding their isolation; the desired unsymmetrical thioethers 6 were obtained in good yield by refluxing further with the other chloro derivatives 5. Under optimized conditions, diversified unsymmetrical thioethers were obtained, as summarized in Scheme 4 and Table 3s in the SI.
Table 2. Optimization of the Thiourea Concentration in the Reaction of 1ba yieldb (%)
a b
entry
thiourea (mol equiv), 2
product 3b
product 4b
1 2 3 3 4 5 6
0.204 0.408 0.5 0.612 0.816 1.020 1.2
nil nil nil 10 60 84 79
20 36 88 40 32 15 12
Reaction conditions: 1b (2.04 mmol), ethanol (10 mL), reflux 6 h. LC−MS yields.
thiourea 2 as the model reaction (Scheme 2 and Table 1). As shown in Table 1, the reaction proceeds with equimolar thiourea, with an excellent product yield. However, higher concentration 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 chloro compounds (Scheme 2 and Table1; see Table 1s in the Supporting Information, SI) in good yield without the formation of a thiol dimer. Scheme 3. Synthesis of Symmetrical Thioethers 4
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Scheme 5. Proposed Mechanism of Regioselectivity of the Reactions
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The products of all three regioselective reactions were isolated and purified by recrystallization in an ethanol/ petroleum ether solvent mixture. All of the pure compounds were identified by various spectral techniques such as FTIR, 1H and 13C NMR, LC−MS, and CHN analysis. The proposed mechanism of the reaction is depicted in Scheme 5. The chloro compounds undergo an aromatic nucleophilic substitution (SNAr) reaction using thiourea as the sulfur source to form an isothiouronium salt. This salt further gets converted to thiol in the presence of water (derived from 99.9% absolute ethanol). The mechanism explains clearly that the reaction takes place to produce initially thiol, which further gets converted to symmetric thioethers and unsymmetrical thioethers in the presence of different concentrations of thiourea and halo derivative similarly.
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors express their gratitude to the Indian Institute of Science, SAIF, Bangalore, and IIT Madras for their support of NMR, LCMS, and IR facilities.
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REFERENCES
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4. CONCLUSION In conclusion, an efficient and facile regioselective synthesis of 3-substituted isoquinoline-1-thiols and symmetrical and unsymmetrical thioethers is reported. The regioselective reactions avoid byproduct formation and offer simplified methodology, wider applicability, and easy workability and an environmentally friendly approach (avoid the intermediate foul-smelling thiol isolation) toward symmetrical and unsymmetrical thioethers.
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AUTHOR INFORMATION
Corresponding Author
ASSOCIATED CONTENT
* Supporting Information S
Spectral values and 1H and 13C NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org. 7869
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