Temperature Controlled Selective C–S or C–C Bond Formation

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. 2018, 20, 648−651

Temperature Controlled Selective C−S or C−C Bond Formation: Photocatalytic Sulfonylation versus Arylation of Unactivated Heterocycles Utilizing Aryl Sulfonyl Chlorides Santosh K. Pagire, Asik Hossain, and Oliver Reiser* Institut für Organische Chemie, Universität Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany S Supporting Information *

ABSTRACT: A visible-light-induced photocatalytic method for the arylsulfonylation of heterocycles has been developed. The synthetic utility of this reaction is reflected by the direct use of commercially available sulfonyl chlorides and heterocycles under room temperature conditions. Complementarily, the photocatalytic arylation of heterocycles by sulfonyl chlorides via extrusion of SO2 is feasible at elevated temperature conditions, allowing switching between arylation or arylsulfonylation with excellent chemoselectivity.

S

ulfur-containing organic compounds have been recognized as important building blocks for synthetic as well as for medicinal chemistry.1 The introduction of a sulfur group on the aryl or heteroaryl moiety in the form of a sulfanyl, a sulfinyl, or a sulfonyl often enhances the synthetic utility and biological activity of the resulting organic compounds.2 In particular, sulfonylcontaining heterocyclic derivatives have widespread applications in agrochemicals and pharmaceuticals.3 For example, L-737,126 (A) and B (Figure 1) are highly selective and potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors,4 whereas SR 33805 (C) is a potent Ca2+ channel antagonist, which binds allosterically to the a1-subunit of L-type Ca2+ channels (Kd = 20 pM) and also inhibits PDGF-stimulated smooth muscle cell proliferation.5 The bis-sulfone derivative D has been found to be a cannabinoid CB2 receptor ligands,6 while Serotonin E is a 5-HT6 receptor antagonist.7 Consequently, a great number of elegant synthetic approaches have been developed for C−S bond formation by thermal8 as well as by photochemical methods.9,10 There are several indirect routes available for the synthesis of sulfonylated heteroarenes, which either includes preactivation/prefunctionalization of heterocyclic compounds11 or utilizes modified sulfonyl sources.12 Moreover, controlling desulfonylation13 or over-reduction of sulfonyl groups is a challenging task.10,14 In such cases, the reoxidation of the corresponding sulfides becomes necessary to reinstate the desired sulfonyl moiety.15 Consequently, additional reaction steps are required,16 usually involving strong oxidants and harsh reaction conditions, which are incompatible with a variety of functional groups.17 The direct aryl sulfonylation of nonactivated heteroaromatics, arguably the most straightforward way to sulfonyl-containing © 2018 American Chemical Society

Figure 1. Representative biologically active molecules containing aryl sulfonyl moiety.

heterocycles, has to date not been accomplished. The aryl sulfonyl chlorides are attractive as reagents, generally being bench-stable, biocompatible, and commercially available at low cost.18 Being known for sulfonylation reactions,19 they have also been Received: December 5, 2017 Published: January 12, 2018 648

DOI: 10.1021/acs.orglett.7b03790 Org. Lett. 2018, 20, 648−651

Letter

Organic Letters Table 1. Optimization of the Reaction Parametersa

Scheme 1. Reaction Scope for Sulfonylation at Room Temperaturea

yield (%)b entry

photocatalyst (mol %)

additive

temp (°C)

3a

4a

1 2 3 4 5 6 7 8 9 10 11 12 13

[Ru(bpy)3Cl2] (3) [Ru(bpy)3Cl2] (3) [Ru(bpy)3Cl2] (3) [Ru(bpy)3Cl2] (3) [Ru(bpy)3Cl2] (3) fac[Ir(ppy)3] (1) fac[Ir(ppy)3] (1) fac[Ir(ppy)3] (1) fac[Ir(ppy)3] (1) fac[Ir(ppy)3] (1) fac[Ir(ppy)3] (1) no catalyst fac[Ir(ppy)3] (1), no light

Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 − K2CO3 K2HPO4 Na2HPO4 Na2CO3 Na2CO3

rtc 30 35 45 60 rt 45 rt rt rt rt rt rt

67 49 27 − − 80 − 28 74 71 69 − −

− 07 31 66 65 − 75 − − − − − −

a

Reaction conditions: Benzenesulfonyl chloride 1a (1.0 mmol, 1 equiv), N-methylpyrrole 2a (1.5 equiv), Photocatalyst (1−3 mol %), additive (1.5 equiv), dry MeCN (3 mL), LED455, 48 h. bIsolated yields. c Room temperature (20−23 °C).

a

Reaction conditions: Aryl sulfonyl chloride 1 (1.0 mmol, 1 equiv), heteroarene 2 (1.5 equiv), fac[Ir(ppy)3] (1 mol %), Na2CO3 (1.5 equiv), MeCN (3 mL), LED455, 48 h, 20−23 °C. bReaction performed at 45 °C. cReaction performed at 60 °C.

employed for C−C bond formation reactions through the cleavage of their C−S bonds under elevated temperature conditions.20 Thus, developing conditions for selective C−S or C−C bond formation using such reagents could lead to a complementary approach for arylsulfonylation or arlyation. Following our interest in visible-light photoredox catalyzed sulfonylation of alkenes, 21,22 we herein explored C−H sulfonylation of heteroaromatics utilizing aryl or alkyl sulfonyl chlorides.23 We began our investigations with benzenesulfonyl chloride 1a (E1/2 = −0.95 V vs SCE), N-methyl pyrrole 2a, and Na2CO3 utilizing the oxidative quenching cycle of the [Ru(bpy)3Cl2]24 (E1/2 (III/*II) = −0.81 V vs SCE, bpy = 2,2′-bipyridine) catalyst with blue light irradiation (LED455, Table 1, entry 1). At room temperature conditions (20−23 °C), we exclusively found the C2-sulfonylation product 3a in 67% yield, but no C2-arylation product 4a, contrasting with a recent study, which reports exclusively arylation under very similar conditions.13 When the reaction temperature was gradually raised, the arylation product 4a started to appear, which was exclusively formed above 45 °C (entries 2−5). The yield of 3a or 4a could be increased to 80% and 75% (Table 1, entries 6, 7) by switching to fac[Ir(ppy)3]25 (E1/2(IV/*III) − 1.73 V vs SCE, ppy = 2phenylpyridine), which was efficient already at a catalyst loading of 1 mol %. Again, the chemoselectivity was perfectly controlled via the reaction temperature. Further optimization revealed that the reaction proceeded sluggishly without the addition of Na2CO3 (Table 1, entry 8), while the addition of other inorganic bases such as K2CO3, K2HPO4, and Na2HPO4 were found to be less efficient (Table 1, entries 9−11). Further control experiments proved that the combination of blue light and the photocatalyst is required to accomplish the desired sulfonylation (Table 1, entries 12−13). Given the number of existing methods already known for the arylation of heterocycles, which mainly includes palladium

catalyzed cross-coupling reactions,26 photoredox catalysis,27 or dual Cu and photocatalysis,28 we subsequently focused on the synthesis of sulfonylated heterocycles. Using the established reaction conditions (Table 1, entry 6), we were able to utilize a diverse range of electronically differentiated aryl sulfonyl chlorides 1 (E1/2 = −0.44 to −1.39 V vs SCE; see the Supporting Information (SI) for details) in the coupling of pyrroles, thiazole, 2-acetyl thipophene, or indoles as a trapping reagent (Scheme 1). In all those cases, high yields of 3 were obtained without the formation of the corresponding arylated products 4. Selected reactions were run at elevated temperatures (45−60 °C), which now exclusively gave rise to the arylated products (Scheme 2). Noteworthy, the utilization of an oxidative quenching cycle29 (see also the mechanistic proposal) efficiently forms the desired product 3 or 4 even if low amounts of the trapping reagents (here 1.5 equiv of 2) are employed. This might be due to the absence of a sacrificial electron donor, which typically facilitates the direct reduction over the C−C bond formation under the reductive quenching cycle, thus making larger amounts (5−25 equiv) of the trapping reagent necessary.30 Methanesulfonyl chloride is also an amenable substrate for sulfonylation (3j), which in this case does not undergo desulfonylation even at higher temperatures (45−60 °C) to provide the expected methylated pyrrole derivative (4j). This is surprising in light of the significant lower bond dissociation energy (BDE) of CH3SO2CH3 (C−S = 66.8 kcal/mol) compared to PhSO2CH3 (Ph−S = 82.3 kcal/mol) and the very low BDE of CH3SO2· (21.4 kcal/mol) for SO2 extrusion.31 Notably, the chemoselective sulfonylation of indoles giving rise to 3n or 3o was achieved in high yields, contrasting the recently reported coupling between N-methylindole and tosyl chloride under similar photochemical conditions ([Ru(bpy)3Cl2], 40 °C, 23 W fluorescent light).10 In this case, exclusive sulfenylation caused by initial reduction of the sulfonyl chloride to the 649

DOI: 10.1021/acs.orglett.7b03790 Org. Lett. 2018, 20, 648−651

Letter

Organic Letters Scheme 2. Reaction Scope for Arylation at Elevated Temperaturea

Scheme 4. Formal Synthesis of SR 33805 (C)

a

Reaction conditions: Aryl sulfonyl chloride 1 (1.0 mmol, 1 equiv), heteroarene 2 (1.5 equiv), fac[Ir(ppy)3] (1 mol %), Na2CO3 (1.5 equiv), MeCN (3 mL), LED455, 48 h, 45 °C. bCf. ref 13. cReaction performed at 60 °C.

corresponding sulfenyl chloride was observed, and given the results obtained here we attribute the different outcome of the reaction to the light source that was used. In all cases, the presence or absence of the SO2 group in the product 3 or 4 was readily confirmed by the HRMS and NMR analysis (see SI); in addition, 3b and 3k were unambiguously characterized by single X-ray crystal analysis (Scheme 1). The arylsulfonylation works well with electron-rich heterocyles, in which also electron-withdrawing substituents are tolerated (3m, 3p). However, furan, 2-methylfuran, benzofuran, pyridine, pyridine N-oxide, imidazole, and N-methylindazole did not provide the desired sulfonylation products. Given the operational simplicity and generality of the sulfonylation protocol, we aimed to demonstrate the utility of this methodology for the construction of representative highprofile biologically active sulfonyl containing drug candidates (cf. Figure 1). By employing our standard conditions, the direct C3sulfonylation of indole derivative 2g was successfully achieved utilizing benzenesulfonyl chloride 1a in 72% yield (Scheme 3).

Figure 2. Proposed reaction mechanism.

heteroarenes, while at elevated temperature SO2 extrusion occurs, which results in net arylation of the heterocyclic coupling partner. The observed temperature dependence is remarkable in that, generally above 45 °C, a complete switch from arylsulfonylation to arylation is observed. In summary, we have developed a visible-light photocatalyzed method for the direct sulfonylation or arylation of heteroaromatic systems at different temperature conditions without the need for preactivating a heterocyclic ring and a sulfonyl source. Moreover, the value of this transformation has been highlighted via the formal synthesis of relevant biologically active molecules using commercially available starting materials under environmentally benign reaction conditions.

Scheme 3. Formal Synthesis of Anti-HIV-1 RT (A)

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03790. Experimental details; compound characterization; electrochemical measurements; X-ray data; NMR spectra (PDF)

The resulting 3-sulfonylated indole 3p was shown to be a key intermediate in the synthesis of biologically active HIV-1 RT (L737, 126) A.32 Likewise, starting from indole derivative 2e the sulfonylated adduct 3q is obtained in 74% yield in a single step (Scheme 4). From this intermediate 3q, the synthesis of a Ca2+ channel blocker C (SR 33805) was previously achieved.33 As a plausible reaction mechanism, we propose the formation of arylsulfonyl radicals of type I by the oxidative quenching cycle of the Ir(III)-catalyst (Figure 2). This radical is sufficiently stable at room temperature to effectively undergo coupling with

Accession Codes

CCDC 1589740 and 1589742 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 650

DOI: 10.1021/acs.orglett.7b03790 Org. Lett. 2018, 20, 648−651

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Organic Letters

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(13) For photochemical arylation of heterocycles utilizing aryl sulfonyl chlorides, see: Natarajan, P.; Bala, A.; Mehta, S. K.; Bhasin, K. K. Tetrahedron 2016, 72, 2521. (14) Yang, F.-L.; Tian, S.-K. Angew. Chem., Int. Ed. 2013, 52, 4929. (15) (a) Chen, Y.; Cho, C.-H.; Shi, F.; Larock, R. C. J. Org. Chem. 2009, 74, 6802. (b) Vedejs, E.; Little, J. D. J. Org. Chem. 2004, 69, 1794. (16) Kobayashi, K.; Kobayashi, A.; Ezaki, K. Tetrahedron 2013, 69, 7936. (17) Graybill, B. M. J. Org. Chem. 1967, 32, 2931. (18) Nara, S. J.; Harjani, J. R.; Salunkhe, M. M. J. Org. Chem. 2001, 66, 8616. (19) For a leading review on sulfonyl chloride activation by visible-light photocatalysis, see: Chaudhary, R.; Natarajan, P. ChemistrySelect 2017, 2, 6458. (20) (a) Deng, G.-B.; Wang, Z.-Q.; Xia, J.-D.; Qian, P.-C.; Song, R.-J.; Hu, M.; Gong, L.-B.; Li, J.-H. Angew. Chem., Int. Ed. 2013, 52, 1535. (b) Xia, J.-D.; Deng, G.-B.; Zhou, M.-B.; Liu, W.; Xie, P.; Li, J.-H. Synlett 2012, 23, 2707. (21) For [Cu]- and [Ir]-catalyzed sequential C−S bond formations, see: Pagire, S. K.; Paria, S.; Reiser, O. Org. Lett. 2016, 18, 2106. (22) For Cu-catalyzed C−S bond formations, see: (a) Bagal, D. B.; Kachkovskyi, G.; Knorn, M.; Rawner, T.; Bhanage, B. M.; Reiser, O. Angew. Chem., Int. Ed. 2015, 54, 6999. (b) Rawner, T.; Knorn, M.; Lutsker, E.; Hossain, A.; Reiser, O. J. Org. Chem. 2016, 81, 7139. (23) For selected leading reviews on visible-light photocatalysis, see: (a) Tellis, J. C.; Kelly, C. B.; Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander, G. A. Acc. Chem. Res. 2016, 49, 1429. (b) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116, 10035. (c) Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. J. Org. Chem. 2016, 81, 6898. (d) Hopkinson, M. N.; Tlahuext-Aca, A.; Glorius, F. Acc. Chem. Res. 2016, 49, 2261. (e) Reiser, O. Acc. Chem. Res. 2016, 49, 1990. (f) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322. (g) Ravelli, D.; Protti, S.; Fagnoni, M. Chem. Rev. 2016, 116, 9850. (24) Teplý, F. Collect. Czech. Chem. Commun. 2011, 76, 859. (25) Sun, J.; Wu, W.; Zhao, J. Chem. - Eur. J. 2012, 18, 8100. (26) For [Pd]-catalyzed arylation reactions, see: (a) Gemoets, H. P. L.; Kalvet, I.; Nyuchev, A. V.; Erdmann, N.; Hessel, V.; Schoenebeck, F.; Noël, T. Chem. Sci. 2017, 8, 1046. (b) Jafarpour, F.; Olia, M. B. A.; Hazrati, H. Adv. Synth. Catal. 2013, 355, 3407. (c) Jin, R.; Yuan, K.; Chatelain, E.; Soulé, J.-F.; Doucet, H. Adv. Synth. Catal. 2014, 356, 3831. (d) Zhang, M.; Zhang, S.; Liu, M.; Cheng, J. Chem. Commun. 2011, 47, 11522. (e) Hfaiedh, A.; Yuan, K.; Ben Ammar, H.; Ben Hassine, B.; Soule, J.-F.; Doucet, H. ChemSusChem 2015, 8, 1794. (27) For visible-light photocatalyzed arylation reactions, see: Ghosh, I.; Marzo, L.; Das, A.; Shaikh, R.; König, B. Acc. Chem. Res. 2016, 49, 1566. (28) Michelet, B.; Deldaele, C.; Kajouj, S.; Moucheron, C.; Evano, G. Org. Lett. 2017, 19, 3576. (29) For representative examples of the oxidative quenching cycle, see: (a) Staveness, D.; Bosque, I.; Stephenson, C. R. J. Acc. Chem. Res. 2016, 49, 2295. (b) Koike, T.; Akita, M. Inorg. Chem. Front. 2014, 1, 562. (30) For representative examples of arylations utilizing the reductive quenching cycle, see: (a) Marzo, L.; Ghosh, I.; Esteban, F.; König, B. ACS Catal. 2016, 6, 6780. (b) Ghosh, I.; König, B. Angew. Chem., Int. Ed. 2016, 55, 7676. (c) Ghosh, I.; Ghosh, T.; Bardagi, J. I.; König, B. Science 2014, 346, 725. (d) Das, A.; Ghosh, I.; König, B. Chem. Commun. 2016, 52, 8695. (31) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic Compounds; CRC Press: New York, 2003; pp 288−289. (32) Gao, D.; Back, T. G. Synlett 2013, 24, 389. (33) Gubin, J.; de Vogelaer, H.; Inion, H.; Houben, C.; Lucchetti, J.; Mahaux, J.; Rosseels, G.; Peiren, M.; Clinet, M.; Polster, P.; Chatelain, P. J. Med. Chem. 1993, 36, 1425.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Oliver Reiser: 0000-0003-1430-573X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by DAAD (fellowship for S.K.P.) and DFG (Graduiertenkolleg 1626). We are also thankful to the following colleages (all University of Regensburg): Ms. Birgit Hischa and Dr. U. Chakraborty for carrying out the X-ray crystal structure analyses of 3b and 3m and Mrs. R. Hoheisel for cyclic voltammetry measurements.

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REFERENCES

(1) (a) Granchi, D.; Scarso, A.; Bianchini, G.; Chiminazzo, A.; Minto, A.; Sgarbossa, P.; Michelin, R. A.; Di Pompo, G.; Avnet, S.; Strukul, G. Eur. J. Med. Chem. 2013, 65, 448. (b) Pinnen, F.; Cacciatore, I.; Cornacchia, C.; Sozio, P.; Cerasa, L. S.; Iannitelli, A.; Nasuti, C.; Cantalamessa, F.; Sekar, D.; Gabbianelli, R.; Falcioni, M. L.; Di Stefano, A. J. Med. Chem. 2009, 52, 559. (2) (a) Gijsen, H. J. M.; Cleyn, M. A. J.; de Surkyn, M.; van Lommen, G. R. E.; Verbist, B. M. P.; Nijsen, M. J. M. A.; Meert, T.; van Wauwe, J.; Aerssens, J. Bioorg. Med. Chem. Lett. 2012, 22, 547. (b) Caddick, S.; Aboutayab, K.; West, R. Synlett 1993, 1993, 231. (c) Asai, T.; Takeuchi, T.; Diffenderfer, J.; Sibley, D. L. Antimicrob. Agents Chemother. 2002, 46, 2393. (d) Lavey, B. J.; Kozlowski, J. A.; Hipkin, R. W.; Gonsiorek, W.; Lundell, D. J.; Piwinski, J. J.; Narula, S.; Lunn, C. A. Bioorg. Med. Chem. Lett. 2005, 15, 783. (3) Benhamu, B.; Martin-Fontecha, M.; Vazquez-Villa, H.; Pardo, L.; Lopez-Rodriguez, M. L. J. Med. Chem. 2014, 57, 7160. (4) (a) Tocco, G.; Begala, M.; Esposito, F.; Caboni, P.; Cannas, V.; Tramontano, E. Tetrahedron Lett. 2013, 54, 6237. (b) La Regina, G.; Coluccia, A.; Brancale, A.; Piscitelli, F.; Gatti, V.; Maga, G.; Samuele, A.; Pannecouque, C.; Schols, D.; Balzarini, J.; Novellino, E.; Silvestri, R. J. Med. Chem. 2011, 54, 1587. (5) Cazorla, O.; Lacampagne, A.; Fauconnier, J.; Vassort, G. Br. J. Pharmacol. 2003, 139, 99. (6) Tong, L.; Shankar, B. B.; Chen, L.; Rizvi, R.; Kelly, J.; Gilbert, E.; Huang, C.; Yang, D.-Y.; Kozlowski, J. A.; Shih, N.-Y.; Gonsiorek, W.; Hipkin, R. W.; Malikzay, A.; Lunn, C. A.; Lundell, D. J. Bioorg. Med. Chem. Lett. 2010, 20, 6785. (7) Liu, K. G.; Robichaud, A. J.; Bernotas, R. C.; Yan, Y.; Lo, J. R.; Zhang, M.-Y.; Hughes, Z. A.; Huselton, C.; Zhang, G. M.; Zhang, J. Y.; Kowal, D. M.; Smith, D. L.; Schechter, L. E.; Comery, T. A. J. Med. Chem. 2010, 53, 7639. (8) (a) Chen, F.; Meng, Q.; Han, S.-Q.; Han, B. Org. Lett. 2016, 18, 3330. (b) Qiu, J.-K.; Hao, W.-J.; Wang, D.-C.; Wei, P.; Sun, J.; Jiang, B.; Tu, S.-J. Chem. Commun. 2014, 50, 14782. (9) For photochemical C−S bond formations, see: (a) Wang, X.; Cuny, G. D.; Noël, T. Angew. Chem., Int. Ed. 2013, 52, 7860. (b) Majek, M.; von Wangelin, A. J. Chem. Commun. 2013, 49, 5507. (c) Meyer, A. U.; Wimmer, A.; Konig, B. Angew. Chem., Int. Ed. 2017, 56, 409. (d) Bottecchia, C.; Rubens, M.; Gunnoo, S. B.; Hessel, V.; Madder, A.; Noël, T. Angew. Chem., Int. Ed. 2017, 56, 12702. (10) Chen, M.; Huang, Z.-T.; Zheng, Q.-Y. Chem. Commun. 2012, 48, 11686. (11) (a) Liang, S.; Zhang, R.-Y.; Xi, L.-Y.; Chen, S.-Y.; Yu, X.-Q. J. Org. Chem. 2013, 78, 11874. (b) Hu, F.; Lei, X. ChemCatChem 2015, 7, 1539. (12) (a) Katrun, P.; Mueangkaew, C.; Pohmakotr, M.; Reutrakul, V.; Jaipetch, T.; Soorukram, D.; Kuhakarn, C. J. Org. Chem. 2014, 79, 1778. (b) Yang, Y.; Li, W.; Xia, C.; Ying, B.; Shen, C.; Zhang, P. ChemCatChem 2016, 8, 304. 651

DOI: 10.1021/acs.orglett.7b03790 Org. Lett. 2018, 20, 648−651