A new microwave-assisted thionation-heterocyclization process leading to benzo[c]thiophene-1(3H)-thione and 1H-isothiochromene-1-thione derivatives

Abstract

The first example of a tandem thionation/S-cyclization process leading to benzo[c]thiophene-1(3H)-thione and 1H-isothiochromene-1-thione derivatives, starting from 2-alkynylbenzoic acids, is reported. The reaction is carried out in CH₂Cl₂ using 1 equiv. of Lawesson's reagent under MW irradiation at 100 °C and 300 W for 1 h. Depending on the nature of the substituent at the distal β carbon of the triple bond, either benzothiophenethiones or isothiochromenethiones were obtained selectively, in high to excellent yields. The structure of the representative compounds has been confirmed by X-ray diffraction analysis.

---

Heterocyclization of acetylenic substrates bearing a suitably placed nucleophilic group is widely recognized as a methodology of primary importance for the direct preparation of a variety of heterocyclic systems in a regioselective fashion, starting from readily available acyclic precursors.¹ This reaction can be promoted by strongly basic conditions, which favor the deprotonation of the nucleophilic group, followed by intramolecular nucleophilic attack on the triple bond (Scheme 1, pathway a; only the exo-dig mode is shown for simplicity). To avoid possible substrate and/or product degradation, the heterocyclization is more conveniently carried out by electrophilic activation of the triple bond, usually ensuing from triple bond coordination to a suitable metal center (as in metal-catalyzed heterocyclizations, Scheme 1, pathway b) or from the interaction with an electrophilic species (such as iodine, as in the case of iodocyclization reactions that lead to iodinated heterocycles, Scheme 1, pathway c).

Scheme 1 Possible heterocyclization pathways of acetylenic substrates bearing a heteronucleophilic group (YH) leading to heterocycles (only the exo-dig mode is shown for simplicity).

Compared to the considerable number of examples reported in the literature for the synthesis of O- or N-heterocycles (Scheme 1, Y = O or NR), there are still relatively few examples of heterocyclizations of S-containing alkyne substrates leading to sulfur heterocycles (Scheme 1, Y = S). This is probably connected with the relatively low stability of the thiol group as compared to the hydroxyl or the amino group and, in the case of metal-catalyzed heterocyclization, to the “poisoning” effect exerted by the sulfur atom on the metal catalyst, owing to its strong coordinating and adsorptive properties.²

Nevertheless, during the last years, several important S-cyclization reactions, starting from substrates bearing a free as well as a masked thiol group, have been developed,^1a,3 including several contributions from our research group.^3b,i,j,4

In this work, we report a new thionation-heterocyclization process leading to benzo[c]thiophene-1(3H)-thione and 1H-isothiochromene-1-thione derivatives (2 and 3, respectively)^5–7 in one step starting from readily available 2-alkynylbenzoic acids 1^8,9 (Scheme 2). The tandem process is carried out under microwave (MW) irradiation,¹⁰ in the presence of 1 equiv. of the Lawesson's reagent.^11,12 2-Alkynylbenzodithioic acids I,¹³ obtained in situ by thionation of 1, undergo S-cyclization to give 2 or 3 without the need for activation from an external electrophilic promoter (Scheme 2).

Scheme 2 MW-assisted tandem thionation-heterocyclization of 2-alkynylbenzoic acids 1, carried out in the presence of 1 equiv. of the Lawesson's reagent, that leads to (Z)-3-alkylidenebenzo[c]thiophene-1(3H)-thiones 2 and 1H-isothiochromene-1-thiones 3 through the formation of 2-alkynylbenzodithioic acids I as intermediates.

The initial substrate we tested was 2-(2-phenylethynyl)benzoic acid 1a (R¹ = R² = H, R = Ph), which was allowed to react with 1 equiv. of the Lawesson's reagent in CH₂Cl₂ at 100 °C under MW irradiation. After 1 h, (Z)-3-benzylidenebenzo[c]thiophene-1(3H)-thione 2a was obtained in 90% isolated yield, with complete regio- and stereoselectively (Scheme 3).

Scheme 3 Synthesis of (Z)-alkylidenebenzo[c]thiophene-1(3H)-thiones 2 and 1H-isothiochromene-1-thiones 3.

It is worth noting that the same reaction, carried out under conventional heating (refluxing CH₂Cl₂, 1,2-dichloroethane, toluene or MeCN for 6–24 h) led to the formation of 2a in only small amounts (0–5%), with partial decomposition of the substrate. A peculiar aspect of our MW-assisted synthetic approach is that the S-cyclization of the intermediate 2-alkynylbenzodithioic acids I occurs without the need for the presence of an external electrophilic promoter.

The structure of products 2 was elucidated by ¹H NMR and ¹³C NMR spectroscopies and MS spectrometry. In particular, the Z stereochemistry around the exocyclic double bond was assigned on the basis of selective 1D NOESY experiments, carried out on compound 2a (Fig. 1A). When H₄ was irradiated (7.53 ppm), the selective 1D NOESY spectrum clearly showed cross-peaks between H₄ and H₈ (7.94 ppm), H₄ and H_orto (7.62 ppm) in the phenyl substituent, as the result of the spatial proximity of these protons, which is only possible if they are in the Z-configuration. The Z stereochemistry was further confirmed by X-ray crystallographic analysis (Fig. 2, see the ESI† for additional details).¹⁴

Fig. 1 Molecular structure of compounds 2a (A) and 3d (B) optimized by Gaussian at 6-31g**b3lyp level.

Fig. 2 X-ray crystal structures of products 2a and 3d, showing 50% probability ellipsoids for non-H atoms and spheres of arbitrary size for H atoms.

Our protocol could be also be successfully applied to substrates substituted in ortho or in para with respect to the carboxyl group, as in the case of 1b (R² = Me) and 1c (R¹ = Cl), which led to the corresponding benzo[c]thiophene-1(3H)-thiones 2b and 2c in 91% and 85% yields, respectively (Scheme 3). Moreover, a substrate bearing a p-fluorophenyl substituent on the triple bond, such as 1f, led to the corresponding benzo[c]thiophene-1(3H)-thione derivative 2f in high yield (88%, Scheme 3).¹⁵

Interestingly, 2-alkynylbenzoic acids carrying on the triple bond an alkyl substituent (such as propyl, as in 1g) or a phenyl group substituted in the para position with a strong π-donating group (such as methoxyl, as in 1d) selectively underwent, after in situ thionation, a 6-endo-dig rather than a 5-exo-dig cyclization, to give the corresponding 1H-isothiochromene-1-thiones 3g and 3d, respectively, in excellent yields (Scheme 3).¹⁶ The structure of products 3 was confirmed by MS spectrometry, ¹H NMR and ¹³C NMR spectroscopies (in particular, no NOESY effect was observed by irradiation of proton H₄ in compound 3d, see Fig. 1B), and confirmed by X-ray crystallographic analysis (Fig. 2; see the ESI† for additional details).¹⁴

Quite consistently, a substrate bearing on the triple bond a phenyl group substituted in para position with a weakly electron-donating substituent (such as the n-pentyl, as in 1e) afforded (Z)-3-(4-pentylbenzylidene)benzo[c]thiophene-1(3H)-thione 2e as the major product (70% yield) together with 3-(4-pentylphenyl)-1H-isothiochromene-1-thione 3e in 20% yield (Scheme 3). The observed change in regioselectivity moving from an electron-withdrawing substituent to an electron-donating substituent on the triple bond is in agreement with the results previously obtained in other heterocyclizations of functionalized alkynes.¹⁷

Mechanistically, the cyclization process may start with MW-induced dissociation of the dithiocarboxyl group¹⁸ of I with simultaneous proton coordination by the triple bond, with formation of intermediate II, as shown in Scheme 4. This intermediate, according to the electronic nature of the triple bond, can lead to compound 2 or 3. In particular, the presence of an electron withdrawing group at the β carbon of the triple bond promotes the protonation on this carbon followed by the anti 5-exo-dig intramolecular nucleophilic attack of the dithiocarboxylate group, leading to the formation of compound 2. An anti intramolecular attack is in perfect agreement with the observed Z stereochemistry of the final product 2. Alternatively, the presence of an electron releasing group on the β carbon of the triple bond promotes the 6-endo-dig cyclization, with protonation on the more negative carbon of the triple bond (β carbon), thus leading to the formation of 1H-isothiochromene-1-thione derivatives 3.

Scheme 4 Proposed mechanism for the heterocyclization of 2-alkynylbenzodithioic acids I: the initial MW-induced dissociation of the dithiocarboxyl group, with simultaneous proton coordination by the triple bond, is followed by anti 5-exo-dig or by 6-endo-dig intramolecular nucleophilic attack of the dithiocarboxylate group to the electrophilically-activated triple bond.

Conclusions

In summary, we have reported the first example of tandem thionation/heterocyclization of 2-alkynylbenzoic acids 1. The process occurs using 1 equiv. of the Lawesson's reagent as the thionation agent under MW irradiation (100 °C at 300 W) in CH₂Cl₂ for 1 h, and leads to (Z)-benzothiophenethiones 2 or isothiochromenethiones 3, depending on the nature of the substituent at the distal β position of the carbon–carbon triple bond. In particular, compounds 2 were regio- and stereoselectively obtained starting from substrates bearing an aryl group (Ph, 4-F-C₆H₄, or 4-pentyl-C₆H₄) as substituent on the carbon–carbon triple bond, through thionation followed by a 5-exo-dig cyclization, while substrates carrying an alkyl group (such as Pr) or an electron-rich aryl substituent (such as p-MeOC₆H₄) at the same position selectively underwent a 6-endo-dig cyclization to yield 3. The study of the bioactivity of the newly synthesized S-heterocycles is currently underway and will be reported in due course.

Notes and references

1. For recent reviews, see: (a) R. Mancuso and B. Gabriele, Molecules, 2014, 19, 15687; (b) B. Gabriele, R. Mancuso and R. C. Larock, Curr. Org. Chem., 2014, 18, 341; (c) X.-F. Wu, H. Neumann and M. Beller, Chem. Rev., 2013, 113, 1; (d) B. Alcaide and P. Almendros, Acc. Chem. Res., 2014, 47, 939; (e) B. Gabriele, R. Mancuso and G. Salerno, Eur. J. Org. Chem., 2012, 6825; (f) J. J. Wen, Y. Zhe and Z.-P. Zhan, Asian J. Org. Chem., 2012, 1, 108; (g) I. Nakamura, J. Synth. Org. Chem., Jpn., 2012, 70, 581; (h) K. C. Majumdar, S. Samanta and B. Sinha, Synthesis, 2012, 817; (i) B. Godoi, R. F. Schumacher and G. Zeni, Chem. Rev., 2011, 111, 2937; (j) K. C. Majumdar, RSC Adv., 2011, 1, 1152; (k) B. Alcaide, P. Almendros and J. M. Alonso, Molecules, 2011, 16, 7815; (l) L.-N. Guo, X.-H. Duan and Y.-M. Liang, Acc. Chem. Res., 2011, 44, 111.
2. (a) G. V. Smith, F. Notheisz, Á. G. Zsigmond and M. Bartók, Stud. Surf. Sci. Catal., 1993, 75, 2463; (b) L. L. Hegedus and R. W. McCabe, Catalyst Poisoning, Marcel Dekker, New York, NY, USA, 1984.
3. For some recent representative examples, see: (a) M. Borah, P. Gogoi, K. Indukuri and A. K. Saikia, J. Org. Chem., 2015, 80, 2641; (b) R. Mancuso, C. S. Pomelli, C. Chiappe, R. C. Larock and B. Gabriele, Org. Biomol. Chem., 2014, 12, 651; (c) Z. Fang, P. Liao, Z. Yang, Y. Wang, B. Zhou, Y. Yang and X. Bi, Eur. J. Org. Chem., 2014, 924; (d) C.-C. Chen, C.-M. Chen and M.-J. Wu, J. Org. Chem., 2014, 79, 4704; (e) S. S. Santana, D. B. Carvalho, N. S. Cassemiro, L. H. Viana, G. R. Hurtado, M. S. Amaral, N. M. Kassab, P. G. Guerrero Jr, S. L. Barbosa, M. J. Dabdoub and A. C. M. Baroni, Tetrahedron Lett., 2014, 55, 52; (f) C. R. Reddy, R. R. Valleti and M. D. Reddy, J. Org. Chem., 2013, 78, 6495; (g) S. Adhikari, K. N. Baryal, D. Zhu, X. Li and J. Zhu, ACS Catal., 2013, 3, 57; (h) R. F. Schumacher, A. R. Rosário, M. R. Leite and G. Zeni, Chem.–Eur. J., 2013, 19, 13059; (i) B. Gabriele, R. Mancuso, L. Veltri, V. Maltese and G. Salerno, J. Org. Chem., 2012, 77, 9905; (j) B. Gabriele, R. Mancuso, G. Salerno and R. C. Larock, J. Org. Chem., 2012, 77, 7640; (k) G. Ferrara, T. Jin, M. Akhtaruzzaman, A. Islam, L. Han, H. Jiang and Y. Yamamoto, Tetrahedron Lett., 2012, 53, 1946; (l) Y. Cui and P. E. Floreancing, Org. Lett., 2012, 14, 1720; (m) S. S. Santana, D. B. Carvalho, N. S. Casemiro, G. R. Hurtado, L. H. Viana, N. M. Kassab, S. L. Barbosa, F. A. Marques, P. G. Guerrero Jr and A. C. M. Baroni, Tetrahedron Lett., 2012, 53, 5733; (n) Z. Fang, H. Yuan, Y. Liu, Z. Tong, H. Li, J. Yang, B.-D. Barry, J. Liu, P. Liao, J. Zhang, Q. Liu and X. Bi, Chem. Commun., 2012, 48, 8802.
4. (a) B. Gabriele, R. Mancuso, E. Lupinacci, L. Veltri, G. Salerno and C. Carfagna, J. Org. Chem., 2011, 76, 8277; (b) B. Gabriele, G. Salerno and A. Fazio, Org. Lett., 2000, 2, 351.
5. 3-Alkylidenebenzo[c]thiophene-1(3H)-thiones (3-alkylidene-2-dithiophthalides) have been previously obtained from 3-alkylidene-2-thiophthalides using phosphorus pentasulphide (P₂S₅) as thionating agent: H. Paulussen, P. Adriaensens, D. Vanderzande and J. Gelan, Tetrahedron, 1996, 52, 11867.
6. 1H-Isothiochromene-1-thione derivatives (isothiocumarin-thiones) have been previously obtained by iodine-mediated cyclization of lithium 2-(vinyl)dithiobenzoate derivatives: (a) S. Fukumachi, H. Konishi and K. Kobayashi, Heterocycles, 2009, 78, 169, or by treatment of 2-chloro-N-cyanomethyl-N-methyl-5-nitrobenzamide with sodium hydride in DMSO or DMF and carbon disulfide: (b) W. Dolling, M. Biedermann and H. Hartung, Eur. J. Org. Chem., 1998, 1237.
7. 3-Alkylidenebenzo[c]thiophene-1(3H)-thione and 1H-isothiochromene-1-thione derivatives constitute promising classes of heterocycles, with potential pharmacological applications, in view of the known biological activities (including anti-ischemic and anti-cancer activity) shown by their O,S-analogues; see, for example: (a) J. Wu, L. Ling, X. Wang, T. Li, J. Liu, Y. Lai, H. Ji, S. Peng, J. Tian and Y. Zhang, J. Med. Chem., 2012, 55, 7173; (b) D. Kaminskyy, A. Kryshchyshyn, I. Nektegayev, O. Vasylenko, P. Grellier and R. Lesyk, Eur. J. Med. Chem., 2014, 75, 57.
8. 2-Alkynylbenzoic acids were easily prepared by Sonogashira coupling between methyl 2-iodobenzoates (prepared by esterification of commercially available 2-iodobenzoic acids) and 1-alkynes followed by hydrolysis: see the experimental section for details. For representative recent examples of Sonogashira coupling conditions, see: (a) R. Romeo, S. V. Giofrè, A. Garozzo, B. Bisignano, A. Corsaro and M. A. Chiacchio, Bioorg. Med. Chem., 2013, 21, 5688; (b) R. Romeo, M. Navarra, S. V. Giofrè, C. Carnovale, S. Cirmi, G. Lanza and M. A. Chiacchio, Bioorg. Med. Chem., 2014, 22, 3379; (c) R. Romeo, S. V. Giofrè, C. Carnovale, M. A. Chiacchio, A. Campisi, R. Mancuso, S. Cirmi and M. Navarra, Eur. J. Org. Chem., 2014, 5442.
9. The heterocyclization of 2-alkynylbenzoic acids and their derivatives has been of great significance for the formation of heterocyclic compounds such as isocoumarins, 3-alkylidenephthalides, 2H-isoquinolin-1-ones, 3-aryl(alkyl)idene-isoindolones, 3-benzazepinones, isoindolinones and isobenzofuranimines; for representative recent examples, see: (a) R. Mancuso, I. Ziccarelli, D. Armentano, N. Marino, S. V. Giofrè and B. Gabriele, J. Org. Chem., 2014, 79, 3506; (b) B. Y.-W. Man, A. Knuhtsen, M. J. Page and B. A. Messerle, Polyhedron, 2013, 61, 248; (c) E. Marchal, P. Uriac, B. Legouin, L. Toupet and P. van de Weghe, Tetrahedron, 2007, 63, 9979; (d) C. Kanazawa and M. Terada, Tetrahedron Lett., 2007, 48, 933; (e) Y. Yu, G. A. Stephenson and D. Mitchell, Tetrahedron Lett., 2006, 47, 3811.
10. For some recent reviews on MW-assisted organic syntheses, see: (a) A. K. Rathi, M. B. Gawande, R. Zboril and R. S. Varma, Coord. Chem. Rev., 2015, 291, 68; (b) N. Kaur, Synth. Commun., 2014, 44, 3483; (c) S. D. Joshi, U. A. More, V. H. Kulkarni and T. M. Aminabhavi, Curr. Org. Chem., 2013, 17, 2279; (d) D. Garella, E. Borretto, A. Si Stilo, K. Martina, G. Cravotto and P. Cintas, MedChemComm, 2013, 4, 1323; (e) H. M. A. Hassan, S. Harakeh, K. A. Sakkaf and I. Denetiu, Aust. J. Chem., 2012, 65, 1647; (f) S. L. Pedersen, A. P. Tofteng, L. Malik and K. J. Jensen, Chem. Soc. Rev., 2012, 41, 1826; (g) R. B. N. Baig and R. S. Varma, Chem. Soc. Rev., 2012, 41, 1559; (h) R. T. McBurney, F. Portela-Cubillo and J. C. Walton, RSC Adv., 2012, 2, 1264; (i) A. Dastan, A. Kulkarni and B. Torok, Green Chem., 2012, 14, 17.
11. For recent reviews on the use of Lawesson’s reagent in organic synthesis, see: (a) L. A. Kayokova, K. D. Praliyev, V. G. Gut'yar and G. P. Baitursynova, Russ. J. Org. Chem., 2015, 51, 148; (b) T. Ozturk, E. Ertas and O. Mert, Chem. Rev., 2007, 107, 5210; (c) M. Jesberger, T. P. Davis and L. Barner, Synthesis, 2003, 1929.
12. To the best of our knowledge, the Lawesson’s reagent has never been reported for similar S-heterocyclization reactions.
13. Thioacids are a well-established and versatile class of organic compounds which, due to their nucleophilicity, have found broad applications. For representative examples, see: (a) D. Crich, K. Sana and S. Guo, Org. Lett., 2007, 9, 4423; (b) K. N. Barlett, R. V. Kolakowski, S. Katukojvala and L. J. Williams, Org. Lett., 2006, 8, 823; (c) A. K. Mapp and P. B. Dervan, Tetrahedron Lett., 2000, 41, 9451.
14. CCDC 1442210 (2a) and 1442211 (3d) contain the supplementary crystallographic data for this paper.
15. The selectivity toward the 5-exo-dig products 2a–c and 2f was virtually complete; in fact, no detectable amounts of the isomeric products deriving from a 6-endo-dig cyclization mode were observed in the reaction crudes by GLC and GLC/MS analyses.
16. The selectivity toward the 6-endo-dig product 3g was practically complete, while small amounts of the 5-exo-dig cyclization product 2d (5%) were observed in the reaction mixture deriving from 1d.
17. See, for example: B. Gabriele, G. Salerno, A. Fazio and R. Pittelli, Tetrahedron, 2003, 59, 6251.
18. The ionization of a benzodithioic acid is a well-known process [for a recent paper, see, for example: J. Vandanapu and S. Rachuru, Adv. Phys. Chem., 2012, 598243,  DOI:10.1155/2012/598243.

---

Footnote

† Electronic supplementary information (ESI) available: Synthetic procedures, characterisation of compounds, NMR spectra. CCDC 1442210 and 1442211. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra01329e

---