- Email: [email protected]
heteroaroyl thiophenes
Accepted Manuscript Base catalyzed reaction of 1,4-dithiane-2,5-diol with α-oxoketene dithioacetals: A new general method for the synthesis of 2-methylthio-3-aroyl/heteroaroyl thiophenes C.S. Pradeepa Kumara, G. Byre Gowda, K.S. Vinay Kumar, N. Ramesh, M.P. Sadashiva, H. Junjappa PII: DOI: Reference:
S0040-4039(16)31032-2 http://dx.doi.org/10.1016/j.tetlet.2016.08.033 TETL 48004
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
25 June 2016 6 August 2016 10 August 2016
Please cite this article as: Pradeepa Kumara, C.S., Byre Gowda, G., Vinay Kumar, K.S., Ramesh, N., Sadashiva, M.P., Junjappa, H., Base catalyzed reaction of 1,4-dithiane-2,5-diol with α-oxoketene dithioacetals: A new general method for the synthesis of 2-methylthio-3-aroyl/heteroaroyl thiophenes, Tetrahedron Letters (2016), doi: http:// dx.doi.org/10.1016/j.tetlet.2016.08.033
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Graphical Abstract
Base catalyzed reaction of 1,4-dithiane-2,5- Leave this area blank for abstract info. diol with α-oxoketene dithioacetals: A new general method for the synthesis of 2-methylthio-3-aroyl/heteroaroyl thiophenes C. S. Pradeepa Kumara a,b, G. Byre Gowda a,b, K. S. Vinay Kumar a, N. Rameshb, M. P. Sadashiva a,, H. Junjappa b, a
Department of Studies in Chemistry, University of Mysore, Mysuru 570 006, India Department of Chemistry, REVA Institute of Science and Management, Yelahanka,, Bengaluru 560 064, India
b
Tetrahedron
Letters
Base catalyzed reaction of 1,4-dithiane-2,5-diol with α-oxoketene dithioacetals: A new general method for the synthesis of 2-methylthio-3-aroyl/heteroaroyl thiophenes C. S. Pradeepa Kumara a, b, G. Byre Gowda a, b, K. S. Vinay Kumar a, N. Ramesh b, M. P. Sadashiva a, H. Junjappa b a
Department of Studies in Chemistry, University of Mysore, Mysuru 570 006, India Department of Chemistry, REVA Institute of Science and Management, Yelahanka,, Bengaluru 560 064, India
b
Dedicated to Prof. Sukh Dev, on his 93rd birth anniversary.
A RT I C L E I N F O
A BS T RA C T
Article history: Received Received in revised form Accepted Available online
The α-oxoketene dithioacetals and 1,4-dithiane-2,5-diol a dimer of mercapto acetaldehyde, react in the presence of anhydrous potassium carbonate in boiling ethanol to yield the corresponding 2-(methylthio)-3-aroyl/heteroaroyl thiophenes in 55-70% overall yields.
Keywords:
α-oxoketenedithio acetals 1,4-dithiane-2,5-diol mercapto acetaldehyde
2009 Elsevier Ltd. All rights reserved .
———
Scheme 1 * Corresponding author. Tel.: +91 98453 72078 Email address: [email protected]; [email protected]
3 The area of thiophene chemistry has been drawing extensive attention in recent years due to their wide spread applications in many areas of human activities.1 Majority of them fall in the area of pharmaceuticals such as anti-bacterials2, anti-protozoals3, antivirals4, anti-oxidants5 and a variety of many biologically important areas. Hence there is a rigorous activity to develop structurally diverse and functionally rich thiophenes in the recent past. Many of these methods involve functionally rich open chain fragments as a novel class of building blocks to construct structurally divers thiophene ring system. Also among others the α-oxoketene dithioacetals and the corresponding β-oxodithioates have been known to be the powerful class of open chain building blocks for the synthesis of thiophenes besides their applications in the synthesis of five and six membered heterocycles.6
diol to afford the corresponding tetrahydrothiophenes which on aromatization yielded the corresponding 2-aroyl-thiophene-3carboxylates in 61-81% yields.
Mike southern and co-workers7 reacted 1,4-dithiane-2,5-diol with nitroalkenes in the presence of triethylamine to afford the corresponding tetrahydrothiophenes which were oxidized by chloranil to yield the aromatized thiophenes in moderated yields. Stuk and co-workers8a selected a protocol from an outdated patent8b in which 1,4-dithiane-2,5-diol was treated with acrolein to yield the corresponding dihydrothiophene-3-aldehyde which was then dehydrated to yield thiophene-3-aldehyde in 90% yield.
Scheme 2
Baxendale and co-workers9 reported a new thiophene synthesis starting from aryl substituted nitriles through modified Gewald reaction in presence of triethylamine in trifluoroethanol to yield the corresponding 2-amino-3-aroylthiophenes in excellent yields. Sun, guo and Wang10 have reported the reaction 1,4-dithiane-2,5diol with ynal and succinimides to afford the in presence of triethylamine to yield the corresponding 2-phenyl thiophene-3carboxaldehyde in 86% yield. They also reacted nitroketene S,Nacetals with dithiane diol in presence of potassium carbonate in boiling ethanol to yield the corresponding 2-amino-3nitrothiophenes in 89-98% overall yields. Similartly, they have also reported11 the reaction with succinimides in the presence of DCM-triethylamine followed by in situ oxidation (DDQ and MnO2) to afford the corresponding 3-thieno imides in high yields. Zhang and coworkers12 developed a fiber catalyst called PPANF which catalyzed activated nitriles to react with 1,4-dithiane-2,5diol to afford the corresponding 2-amine-3-substituted thiophenes in 65-91% overall yields. They also reacted13 1,4-dithiane-2,5diol with ethyl cyano acetate under similar reaction conditions to afford the corresponding 2-amino-3-carboxy thiophene in 91% yield. Punniyamurthy and co-workers14 reacted 1,3-enynes with 1,4dithiane-2,5-diol in the presence of DABCO to afford tetrasubstituted thiophenes in good yields. Perumal and co-workers15 have investigated the reaction of 1,4dithiane-2,5-diol with various α-nitroketene S,N-aryl/alkylamino acetals in the presence of potassium carbonate in refluxing ethanol to afford the corresponding N-substituted-3nitrothiophene-2-amines, their studies also included the reaction of 1,4-dithiane-2,5-diol with phenyl nitrostyrine which yielded in two steps to afford 2-aryl-3-nitro thiophenes in good yields. Srinivasan and co-workers16 have reported that trans-2-aryl-3nitrocyclopropane-1,1-dicarboxylate reacts with 1,4-dithiane-2,5-
Recently, we have reported two methods for the synthesis of thiophenes: In the first communication,17 we have reacted ethylthioglycolate with β-aryl-β-methylthio acroleins in the presence of potassium carbonate in boiling ethanol to afford the corresponding 2-carbethoxy-5-substituted/4,5-annulated thiophenes in high yields. In our communication18 the potassium salt of β-oxodithioates were reacted with bromoacetaldehyde diethylacetal 4 (Scheme 2) to yield the corresponding mixed acetals 6 in excellent yields. These acetals on refluxing with ethanolic orthophosphoric acid underwent intramolecular cyclization to afford the corresponding thiophenes 3 (Scheme 2) in moderate to good yields. We have similarly envisioned that the α-oxoketene dithioacetals and 1,4-dithiane-2,5-diol could be reacted to afford the 2,3functionalized thiophenes in good yields. We here in describe our results involving reaction of α-oxoketene Table 1: Synthesis of 2-methylthio-3-aroyl/heteroaroyl thiophenes
interesting to note that these thiophenes are the same as those we have recently reported. The present method is superior in terms of overall yields and number of steps. The 2-methylthio-3aroyl/heteroaroyl functional groups are of great synthetic importance, which can be easily transformed in to thiophenothiophenes, isothiazolothiophenes, pyrazolothiophenes, isoxazolothiophenes etc. Thus they can be considered as potential 1,3-dielectrophilic building blocks, and our current abjective is to explore these possibilities.
Scheme 3 The mechanism governing this one pot reaction is depicted in Scheme 3. The 1,4-dithiane-2,5-diol a dimer of mercapto acetaldehyde breaks down to 2-molecules of potassium salt of mercapto acetaldehyde and adds to α-oxoketene dithioacetal in the 1,4-fashion to yield the corresponding potassium enolate 7 which follows intra molecular addition on aldehyde carbonyl group to yield the corresponding tetrahydrothiophene salt 8. The tetrahydrothiophene enolate on exchanging the proton from solvent gets eliminated as water. Similarly methylmercaptan is eliminated yielding the aromatic 2-methylthio-3-aroyl thiophenes 3 in good yields. Elimination of methylmercaptan as methyl thiolate appears to be protonated from solvent and escapes from the reaction mixture to facilitate the progress of the reaction.
*marked compounds 3a-b, 3f-m are reported earlier while the remaining 3d and 3e were not reported by our earlier method18 Reaction condition20: α-oxoketene dithioacetal (0.1 mol), 1,4-dithiane-2,5-diol (0.05 mol), K2CO3 (0.12 mol), EtOH (10 mL), 80 oC.
dithioacetals with 1,4-dithiane-2,5-diol in the presence of potassium carbonate in boiling ethanol to yield the corresponding 2-methylthio-3-aroyl thiophenes 3 (Scheme 1) in moderate to good yields. The α-oxoketene dithioacetals 1a-m (Table 1) derived from respective acetyl derivatives, reacted with half equivalent of 1,4dithiane-2,5-diol (2) in boiling ethanol in the presence of anhydrous potassium carbonate for a period ranging from 20-35 minutes (Table 1). The reaction mixtures after work up followed by purification over silica gel eluting with ethyl acetate petroleum ether (5:95) yielded the corresponding 2-methylthio-3aroyl/heteroaroyl thiophenes 3a-m in 55-70% overall yields. Interestingly, when the doubly activated α-oxoketene dithioacetals were reacted with thioglycolate19, the intermediate mixed acetal undergoes deprotonation to afford the carbanian which attacks carbonyl carbon followed by elimination of water to yield the corresponding 2-carbethoxy-3-substituted-5methylthio thiophenes in good yields. The structural assignment for the thiophenes was confirmed by crystal analysis of compound 3g (Figure 1). It is therefore
3g Figure 1. X-ray structure: ORTEP diagram of chlorophenyl)(2-(methylthio)thiophen-3-yl)methanone (3g).
(4-
In conclusion, we have successfully demonstrated that, the αoxoketene dithioacetals react with an inexpensive reagent mercapto acetaldehyde to yield the corresponding 2-methylthio3-aroyl/heteroaroyl thiophenes. The method described in this paper yields the same thiophenes as described in our two step methodology, which is much simpler involving single step and moreover to our knowledge it is one of the best base catalyzed methods known till date for this class of thiophenes.
Acknowledgments H.J. is grateful to Indian National Science Academy (INSA) for the award of Sr. Scientist. We gratefully acknowledge the CSIR, New Delhi (02(0106)/12 EMR-II Dated 01/11/12) for the financial support through the project. We thank Dr. M. Chandrasekharam, IICT Hyderabad and IOE, University of Mysore, Mysuru for spectral analysis. CSP thank to Chancellor,
5 Dr. P. Shyama Raju, REVA University, Yelahanka, Bengaluru560 064, for research fellowship.
Supplementary Material Supplementary data associated with this article can be found, in the online version, at: References and notes 1.
2. 3. 4.
5. 6.
7. 8. 9. 10.
11.
12. 13. 14. 15. 16. 17. 18. 19. 20.
(a) Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.; Obach, R. S.; O’Donnell, J. P. Chem. Res. Toxicol. 2002, 15, 269299. (b) Junker, A.; Yamaguchi, J.; Itami, K.; Wunsch, B. J. Org. Chem. 2013, 78, 5579. (c) Romagnoli, R.; Baraldi, P. G.; LopezCara, C.; Preti, D. J. Med. Chem. 2013, 56, 9296. (d) Lepage, P. H.; Peytavi, R.; Bergeron, M. G.; Leclerc, M. Anal. Chem. 2011, 83, 8086. Salahuddin, M.; Kakad, S.; Shantakumar, S. Eur. J. Chem. 2009, 6, 801. Mavrora, A. T.; Vuchdev, D.; Anichina, K.; Vassilev, N. Med. Chem. 2010, 45, 5856. Rashad, A. E.; Shamroukh, A. H.; Abdel-Megeid, R. E.; Mostafa, A.; El-Shesheny, R.; Kandeil, A; Ali, M. A; Banert. K. Eur. J. Med. Chem. 2010, 45 (11), 5251. Kotaiah, Y.; Harikrishna, N.; Nagaraju, K.; Venkata, R. C. Eur. J. Med. Chem. 2012, 58, 340. (a) Dieter, R. K.; Jeffrey, R. F. Tetrahedron Lett. 1986, 27 (33), 3823. (b) H. Junjappa, H. Ila and C. V. Asokan. Tetrahedron, 1990, 46 (16), 5428. (c) Yokoyama, M.; Imamoto, T. Synthesis. 1984, 797. (d) Zhang, L.; Dong, J.; Xu, X.; Liu, Q. Chem. Rev. 2016, 116 (2), 287. O’connor, C. J.; Roydhhouse, M. D.; Przybyl, A. M.; wall, M. D.; Southern, J. M. J. Org. Chem. 2010, 75 (8), 2534. (a) Huckabee, B. K.; Stuk, T. L. Synt. Comm. 2001, 31 (10), 1527. (b) Ramag R; Johnstone A, European patent App: 0234688, 1987 Malia, C. J.; Englert, L.; Walter, G. C.; Baxendale, I. R. Beilstein J. Org. Chem. 2015, 11, 875. Wenjuan, S.; Li, W.; Yimin, H.; Shaofa, S.; Wenjuan, L.; Yanhong, P.; Minghu, W.; Haibing, G.; Jian, W. Tetrahedron Lett. 2015, 56 (16), 2083. Wenjuan, S.; Shaofa, S.; Yimin, H.; Tao, G.; Yanhong, P.; Minghu, W.; Haibing, G.; Jian, W. Tetrahedron Lett. 2015, 56 (25), 3861. Li, P.; Jianguo,D.; Yujia, X.; Tao, M.; Zhang, W. ACS Sustainable Chem. Eng. 2016, 4 (3), 1139. Lichao, M.; Liewei, Y.; Changzhu, X.; Guowei, L.; Minli, T.; Wenqin, Z. Synthesis. 2012, 45, 0045. Bharathiraja, G.; Sathishkannan, G.; Punniyamurthy, T. J. Org. Chem. 2016, 81 (6), 2670. Kumar, S. V.; Muthusubramanan, S.; Menendez, J. C.; Perumal, S. Beilstein J. Org. Chem. 2015, 11, 1707. Selvi, T.; Vanmathi, G.; Srinivasan, K. RSC. Adv. 2015, 5, 49326. Byre Gowda, G.; Pradeepa Kumara, C. S.; Ramesh, N.; Sadashiva, M. P.; Junjappa, H. Tetrahedron lett. 2016, 57 (8), 928. Pradeepa Kumara, C. S.; Byre Gowda, G.; Ramesh, N.; Sadashiva, M. P.; Junjappa, H. Tetrahedron lett. 2016, 57 (23), 2520. Sommen, G.; Comel, A.; Kirsch, G. Synthesis. 2003, 5, 0735. General procedure for the preparation of 5-methylthio-3substituted-2-carboxaldehyde (3a-m): The α-oxoketene dithioacetal (0.1 mol) and 1,4-dithiane-2,5-diol (0.05 mol) were taken in dry ethanol (10 mL) and anhydrous potassium carbonate (0.12 mol) was then added. The reaction mixture was refluxed on water bath for 25-35 minutes (condenser is protected by calcium chloride guard tube). The progress of the reaction was monitored by TLC and the catalyst was filtered off and washed with fresh ethanol and the combined ethanol solution was removed on rotary evaporator to get the viscous liquid. The crude product purified by passing through silica gel and eluted with 5% ethyl acetate and petroleum ether to yield the pure product. (3a-m, Table 1).
Highlights of the communication
New general method for the synthesis of 2-methylthio-3-aroyl/heteroaroyl thiophenes
Simple method involving single step with a clear atom economy and high yields.
Method of choice for the synthesis of substituted thiophenes for further applications.
S0040-4039(16)31032-2 http://dx.doi.org/10.1016/j.tetlet.2016.08.033 TETL 48004
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
25 June 2016 6 August 2016 10 August 2016
Please cite this article as: Pradeepa Kumara, C.S., Byre Gowda, G., Vinay Kumar, K.S., Ramesh, N., Sadashiva, M.P., Junjappa, H., Base catalyzed reaction of 1,4-dithiane-2,5-diol with α-oxoketene dithioacetals: A new general method for the synthesis of 2-methylthio-3-aroyl/heteroaroyl thiophenes, Tetrahedron Letters (2016), doi: http:// dx.doi.org/10.1016/j.tetlet.2016.08.033
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Graphical Abstract
Base catalyzed reaction of 1,4-dithiane-2,5- Leave this area blank for abstract info. diol with α-oxoketene dithioacetals: A new general method for the synthesis of 2-methylthio-3-aroyl/heteroaroyl thiophenes C. S. Pradeepa Kumara a,b, G. Byre Gowda a,b, K. S. Vinay Kumar a, N. Rameshb, M. P. Sadashiva a,, H. Junjappa b, a
Department of Studies in Chemistry, University of Mysore, Mysuru 570 006, India Department of Chemistry, REVA Institute of Science and Management, Yelahanka,, Bengaluru 560 064, India
b
Tetrahedron
Letters
Base catalyzed reaction of 1,4-dithiane-2,5-diol with α-oxoketene dithioacetals: A new general method for the synthesis of 2-methylthio-3-aroyl/heteroaroyl thiophenes C. S. Pradeepa Kumara a, b, G. Byre Gowda a, b, K. S. Vinay Kumar a, N. Ramesh b, M. P. Sadashiva a, H. Junjappa b a
Department of Studies in Chemistry, University of Mysore, Mysuru 570 006, India Department of Chemistry, REVA Institute of Science and Management, Yelahanka,, Bengaluru 560 064, India
b
Dedicated to Prof. Sukh Dev, on his 93rd birth anniversary.
A RT I C L E I N F O
A BS T RA C T
Article history: Received Received in revised form Accepted Available online
The α-oxoketene dithioacetals and 1,4-dithiane-2,5-diol a dimer of mercapto acetaldehyde, react in the presence of anhydrous potassium carbonate in boiling ethanol to yield the corresponding 2-(methylthio)-3-aroyl/heteroaroyl thiophenes in 55-70% overall yields.
Keywords:
α-oxoketenedithio acetals 1,4-dithiane-2,5-diol mercapto acetaldehyde
2009 Elsevier Ltd. All rights reserved .
———
Scheme 1 * Corresponding author. Tel.: +91 98453 72078 Email address: [email protected]; [email protected]
3 The area of thiophene chemistry has been drawing extensive attention in recent years due to their wide spread applications in many areas of human activities.1 Majority of them fall in the area of pharmaceuticals such as anti-bacterials2, anti-protozoals3, antivirals4, anti-oxidants5 and a variety of many biologically important areas. Hence there is a rigorous activity to develop structurally diverse and functionally rich thiophenes in the recent past. Many of these methods involve functionally rich open chain fragments as a novel class of building blocks to construct structurally divers thiophene ring system. Also among others the α-oxoketene dithioacetals and the corresponding β-oxodithioates have been known to be the powerful class of open chain building blocks for the synthesis of thiophenes besides their applications in the synthesis of five and six membered heterocycles.6
diol to afford the corresponding tetrahydrothiophenes which on aromatization yielded the corresponding 2-aroyl-thiophene-3carboxylates in 61-81% yields.
Mike southern and co-workers7 reacted 1,4-dithiane-2,5-diol with nitroalkenes in the presence of triethylamine to afford the corresponding tetrahydrothiophenes which were oxidized by chloranil to yield the aromatized thiophenes in moderated yields. Stuk and co-workers8a selected a protocol from an outdated patent8b in which 1,4-dithiane-2,5-diol was treated with acrolein to yield the corresponding dihydrothiophene-3-aldehyde which was then dehydrated to yield thiophene-3-aldehyde in 90% yield.
Scheme 2
Baxendale and co-workers9 reported a new thiophene synthesis starting from aryl substituted nitriles through modified Gewald reaction in presence of triethylamine in trifluoroethanol to yield the corresponding 2-amino-3-aroylthiophenes in excellent yields. Sun, guo and Wang10 have reported the reaction 1,4-dithiane-2,5diol with ynal and succinimides to afford the in presence of triethylamine to yield the corresponding 2-phenyl thiophene-3carboxaldehyde in 86% yield. They also reacted nitroketene S,Nacetals with dithiane diol in presence of potassium carbonate in boiling ethanol to yield the corresponding 2-amino-3nitrothiophenes in 89-98% overall yields. Similartly, they have also reported11 the reaction with succinimides in the presence of DCM-triethylamine followed by in situ oxidation (DDQ and MnO2) to afford the corresponding 3-thieno imides in high yields. Zhang and coworkers12 developed a fiber catalyst called PPANF which catalyzed activated nitriles to react with 1,4-dithiane-2,5diol to afford the corresponding 2-amine-3-substituted thiophenes in 65-91% overall yields. They also reacted13 1,4-dithiane-2,5diol with ethyl cyano acetate under similar reaction conditions to afford the corresponding 2-amino-3-carboxy thiophene in 91% yield. Punniyamurthy and co-workers14 reacted 1,3-enynes with 1,4dithiane-2,5-diol in the presence of DABCO to afford tetrasubstituted thiophenes in good yields. Perumal and co-workers15 have investigated the reaction of 1,4dithiane-2,5-diol with various α-nitroketene S,N-aryl/alkylamino acetals in the presence of potassium carbonate in refluxing ethanol to afford the corresponding N-substituted-3nitrothiophene-2-amines, their studies also included the reaction of 1,4-dithiane-2,5-diol with phenyl nitrostyrine which yielded in two steps to afford 2-aryl-3-nitro thiophenes in good yields. Srinivasan and co-workers16 have reported that trans-2-aryl-3nitrocyclopropane-1,1-dicarboxylate reacts with 1,4-dithiane-2,5-
Recently, we have reported two methods for the synthesis of thiophenes: In the first communication,17 we have reacted ethylthioglycolate with β-aryl-β-methylthio acroleins in the presence of potassium carbonate in boiling ethanol to afford the corresponding 2-carbethoxy-5-substituted/4,5-annulated thiophenes in high yields. In our communication18 the potassium salt of β-oxodithioates were reacted with bromoacetaldehyde diethylacetal 4 (Scheme 2) to yield the corresponding mixed acetals 6 in excellent yields. These acetals on refluxing with ethanolic orthophosphoric acid underwent intramolecular cyclization to afford the corresponding thiophenes 3 (Scheme 2) in moderate to good yields. We have similarly envisioned that the α-oxoketene dithioacetals and 1,4-dithiane-2,5-diol could be reacted to afford the 2,3functionalized thiophenes in good yields. We here in describe our results involving reaction of α-oxoketene Table 1: Synthesis of 2-methylthio-3-aroyl/heteroaroyl thiophenes
interesting to note that these thiophenes are the same as those we have recently reported. The present method is superior in terms of overall yields and number of steps. The 2-methylthio-3aroyl/heteroaroyl functional groups are of great synthetic importance, which can be easily transformed in to thiophenothiophenes, isothiazolothiophenes, pyrazolothiophenes, isoxazolothiophenes etc. Thus they can be considered as potential 1,3-dielectrophilic building blocks, and our current abjective is to explore these possibilities.
Scheme 3 The mechanism governing this one pot reaction is depicted in Scheme 3. The 1,4-dithiane-2,5-diol a dimer of mercapto acetaldehyde breaks down to 2-molecules of potassium salt of mercapto acetaldehyde and adds to α-oxoketene dithioacetal in the 1,4-fashion to yield the corresponding potassium enolate 7 which follows intra molecular addition on aldehyde carbonyl group to yield the corresponding tetrahydrothiophene salt 8. The tetrahydrothiophene enolate on exchanging the proton from solvent gets eliminated as water. Similarly methylmercaptan is eliminated yielding the aromatic 2-methylthio-3-aroyl thiophenes 3 in good yields. Elimination of methylmercaptan as methyl thiolate appears to be protonated from solvent and escapes from the reaction mixture to facilitate the progress of the reaction.
*marked compounds 3a-b, 3f-m are reported earlier while the remaining 3d and 3e were not reported by our earlier method18 Reaction condition20: α-oxoketene dithioacetal (0.1 mol), 1,4-dithiane-2,5-diol (0.05 mol), K2CO3 (0.12 mol), EtOH (10 mL), 80 oC.
dithioacetals with 1,4-dithiane-2,5-diol in the presence of potassium carbonate in boiling ethanol to yield the corresponding 2-methylthio-3-aroyl thiophenes 3 (Scheme 1) in moderate to good yields. The α-oxoketene dithioacetals 1a-m (Table 1) derived from respective acetyl derivatives, reacted with half equivalent of 1,4dithiane-2,5-diol (2) in boiling ethanol in the presence of anhydrous potassium carbonate for a period ranging from 20-35 minutes (Table 1). The reaction mixtures after work up followed by purification over silica gel eluting with ethyl acetate petroleum ether (5:95) yielded the corresponding 2-methylthio-3aroyl/heteroaroyl thiophenes 3a-m in 55-70% overall yields. Interestingly, when the doubly activated α-oxoketene dithioacetals were reacted with thioglycolate19, the intermediate mixed acetal undergoes deprotonation to afford the carbanian which attacks carbonyl carbon followed by elimination of water to yield the corresponding 2-carbethoxy-3-substituted-5methylthio thiophenes in good yields. The structural assignment for the thiophenes was confirmed by crystal analysis of compound 3g (Figure 1). It is therefore
3g Figure 1. X-ray structure: ORTEP diagram of chlorophenyl)(2-(methylthio)thiophen-3-yl)methanone (3g).
(4-
In conclusion, we have successfully demonstrated that, the αoxoketene dithioacetals react with an inexpensive reagent mercapto acetaldehyde to yield the corresponding 2-methylthio3-aroyl/heteroaroyl thiophenes. The method described in this paper yields the same thiophenes as described in our two step methodology, which is much simpler involving single step and moreover to our knowledge it is one of the best base catalyzed methods known till date for this class of thiophenes.
Acknowledgments H.J. is grateful to Indian National Science Academy (INSA) for the award of Sr. Scientist. We gratefully acknowledge the CSIR, New Delhi (02(0106)/12 EMR-II Dated 01/11/12) for the financial support through the project. We thank Dr. M. Chandrasekharam, IICT Hyderabad and IOE, University of Mysore, Mysuru for spectral analysis. CSP thank to Chancellor,
5 Dr. P. Shyama Raju, REVA University, Yelahanka, Bengaluru560 064, for research fellowship.
Supplementary Material Supplementary data associated with this article can be found, in the online version, at: References and notes 1.
2. 3. 4.
5. 6.
7. 8. 9. 10.
11.
12. 13. 14. 15. 16. 17. 18. 19. 20.
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Highlights of the communication
New general method for the synthesis of 2-methylthio-3-aroyl/heteroaroyl thiophenes
Simple method involving single step with a clear atom economy and high yields.
Method of choice for the synthesis of substituted thiophenes for further applications.