As described in the former section, sulfonyl chlorides are highly flexible reagents that can participate in a great variety of transformations that take place through ionic mechanisms. Alternatively, these sulfinate derivatives can also react through radical processes. Under appropriate reaction conditions, the sulfur-chlorine bond can undergo homolytic scission, generating a sulfonyl radical.164 The use of these short-lived intermediates in organic synthesis was particularly expanded during the 1980s at the same time as the renaissance of radical chemistry.165
Sulfonyl radicals can be generated from sulfonyl chloride derivatives following several methods:
- Thermolysis. A covalent bond is generally cleaved to its radical fragments at temperatures higher than 800 °C. Covalent bonds that can be cleaved at a
164 Selected reviews: a) F. Freeman, M. C. Keindl, Sulfur Reports 1985, 4, 231. b) C. Chatgilialoglu C, The Chemistry of Sulfones and Sulfoxides, (Eds.: S. Patai, Z. Rappoport C. J. M. Stirling) Wiley, Chichester, 1988, 1089. c) M. Bertrand, Org. Prep. Proc. Int. 1994, 26, 257. d) M. P. Bertrand, C. Ferreri, Radicals in Organic Synthesis (Eds.: P. Renaud, M. Sibi), Wiley-VCH, Weinheim, Germany, 2001, vol. 2, 485. e) X-Q.
Pan, J-P. Zou, W-B. Yi, W. Zhang, Tetrahedron 2015, 71, 7481.
165 For a timeline of selected milestones in radical chemistry see: M. Yan, J. C. Lo, J. T. Edwards, P. S.
Baran, J. Am. Chem. Soc. 2016, 138, 12692.
2. Sulfonyl Chloride Derivatives
127 temperature below 150 °C are limited to weak bonds whose dissociation energies are under 30-40 kcal/mol. Depending on the substitution, the sulfur-chlorine bond in sulfonyl chlorides may undergo scission under thermal conditions166 (SO2Cl2 Bond Dissociation Energy BDE = 46±4 kcal/mol167).
- Reaction with radical initiatiors, such as peroxides, azo compounds or silanes and boranes combined with oxygen.168 These molecules usually undergo homolytic cleavage of a weak bond under mild conditions, generating a radical species that is able to react with the sulfonyl chloride, delivering the desired sulfonyl radical.
- Redox reaction. Different transition metal complexes have proved to be very efficient at mediating homolysis of sulfonyl chlorides. Metal centers such as copper(I or II),169 iron(II)170 or cobalt(II)171 can be used to generate sulfonyl radicals from their chloride precursor. Ruthenium(II) and iridium(III) are also employed, especially under photoredox catalytic conditions.172 In this regard, organophotocatalysts can also promote the generation of this kind of intermediates.173
The nature of these short-lived sulfonyl radicals is electrophilic.174 There are several synthetically interesting processes involving these radical species:
- Sulfonylation by C-H functionalization. The main synthetic applications of sulfonyl radicals rely on their ability to add different π-systems. These reactions are properly considered among the best methods for preparing sulfone derivatives. Both unactivated and activated alkenes are suitable substrate for the reaction with sulfonyl radicals.173,175 Moreover, these system
166 For a recent example of thermally-promoted carbon-sulfur bond scission, see: D. Wang, J. Zhao, W.
Xu, C. Shao, Z. Shi, L. Li, X. Zhang, Org. Biomol. Chem., 2017,15, 545.
167 K. Wray, E. V. Feldman, J. Chem. Phys. 1971, 54, 3445.
168 C. Chatgilialoglu, L. Lunazzi, K. U. Ingold, J. Org. Chem. 1983, 48,3588.
169 A. A. Pudikova, N. P. Gerasimova, Yu. A. Moskvichev, E. M. Alov, A. S. Danilova, O. S. Kozlova, Russ.
J. Org. Chem. 2010, 46, 352.
170 X. Zeng, L. Ilies, E. Nakamura Org. Lett. 2012,14, 954.
171 M. R. Ashcroft, P. Bougeard, A, Bury, C. J. Cooksey, M. D. J. Johnson, J. Org. Chem.1984, 49, 1751.
172 H. Jiang, X. Chen, Y. Zhang, S. Yu, Adv. Synth. Catal. 2013, 355, 809.
173 X. Li, D. Liang, W. Huang, H. Zhou, Z. Li, B. Wang, Y. Ma, H. Wang, Tetrahedron 2016, 72, 8442.
174 a) C. C. M. Da Silva Correa, W. A. Waters, J. Chem. Soc. Perkin Trans. 2 1972, 1575. b) C. M. M. Da Silva Correa, M. D. Fleming, M. A. Oliveira, M. P. Gonçalves, Rev. Port. Quim. 1973, 15, 100. c) Y.
Takahara, M. Ino, M. Matsuda, Bull. Chem. Soc. Japan 1976, 49, 2268. d) C. M. M. Da Silva Correa, M.
D. Fleming, J. Chem. Soc. Perkin Trans. 2 1987, 103.. e) A. C. Serra, C. M. M. Da Silva Correa, M. L. C. Do Vale, Tetrahedron 1991, 47, 9463. f) A. S. Gozdz, P. Maslak, J. Org. Chem. 1991, 56,2179.
175 a) H. Jiang, Y. Cheng, Y. Zhang, S. Yu, Eur. J. Org. Chem. 2013, 24, 5485.b) X. Liu, X. Chen, J. T. Mohr, Org. Lett. 2015, 17, 3572. c) S. K. Pagire, S. Paria, O. Reiser, Org. Lett. 2016,18, 2106.
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can be involved in atom transfer radical additions (ATRA), which are among the most synthetically useful radical transformations regarding the functionalization of carbon-carbon multiple bonds.176 It is a very effective way to difunctionalize alkenes177 and alkynes,170 both in beta and remote positions depending on the substrate substitution. For instance, reaction of p-toluenesulfonyl chloride 50 with norbornene 49 under photoredox catalytic conditions provided the corresponding ATRA product in high yield and diastereomeric ratio (Scheme 15, A).177c The oxidative quenching cycle is initiated by activation of the photocatalyst by visible light absorption to produce the exited state of the catalyst *PCn. This species undergoes oxidation via single electron transfer (SET) to the sulfonyl chloride 50, generating the radical anion 52 that evolves to the sulfonyl radical 53. The radical then undergoes addition to the alkene. The ATRA product can subsequently be formed via two different routes: either by propagation or by oxidation to the cation followed by nucleophilic trapping.
Also, Nakamura and coworkers developed the regio- and stereoselective synthesis of chlorovinylsulfones 57 from terminal alkynes 56 and aromatic sulfonyl chlorides 41 in the presence of an iron(II) catalyst and a phosphine ligand following a conceptually similar process (Scheme 15, B):170
176 a) M. S. Kharasch, E. V. Jensen, W. H. Urry, Science 1945, 102, 128. b) M. S. Kharasch, P. S. Skell, P.
Fischer, P. J. Am. Chem. Soc. 1948, 70, 1055. c) D. P. Curran, Synthesis 1988, 489. d) J. Byers, Radicals in Organic Synthesis, (Eds.: P. Renaud, M. P. Sibi), Wiley-VCH, Weinheim, 2001, Vol. 1, 72. e) K. Severin, Curr. Org. Chem. 2006, 10, 217. f) T. Pintauer, K. Matyjaszewski, Chem. Soc. Rev. 2008, 37, 1087. g) W.
T. Eckenhoff, T. Pintauer, Catal. Rev. 2010, 52, 1. h) T. Pintauer, K. Matyjaszewski, Encyclopedia of Radicals, Wiley, Hoboken, 2012, Vol. 4, , 1851.
177 a) L. Quebatte, K. Thommes, K. Severin, J. Am. Chem. Soc. 2006, 128, 7440. b) R. P. Nair, T. Ho Kim, B. J. Frost, Organometallics 2009, 28, 4681. c) C-J. Wallentin, J. D. Nguyen, P. Finkbeiner, C. R. J.
Stephenson, J. Am. Chem. Soc. 2012, 134, 8875.
2. Sulfonyl Chloride Derivatives
129 Scheme 15 ATRA of sulfonyl chlorides to alkenes and alkynes
Tandem processes can be triggered by reaction of a sulfonyl radical with properly substituted alkenes to produce complex compounds from simple starting materials. In this regard, Liang and coworkers reported an efficient strategy for the synthesis of sulfone-containing isoquinolinonediones via radical cascade addition/cyclization of acrylamide with arylsulfonyl chlorides under visible light-induced conditions (Scheme 16).178
178 d) X-F. Xia, S-L. Zhu, D. Wang, Y-M. Liang, Adv. Synth. Catal. 2017, 359, 859.
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Scheme 16 Tandem reactions
Additional transformations such as C-H functionalization of arenes can also be achieved. In this context, a copper-catalyzed regioselective remote functionalization of naphthylamide derivatives with both arenesulfonyl and alkanesulfonyl chlorides was developed by Lu and coworkers this year (Scheme 17).179 Picolineamide derivatives were used as directing group.
Scheme 17 C-H functionalization of arenes.
Challenging sulfonylation of unactivated C-H bonds can also be carried out using this methodology. Zheng and coworkers reported a visible light-mediated dehydrogenative arylsulfonylation of tertiary aliphatic amines with arylsulfonyl chlorides in moderate yields (Scheme 18): 180
Scheme 18 -functionalization of alkylamines
179 X) J-M. Li, Y-H. Wang, Y. Yu, R-B. Wu, J. Weng, G. Lu, ACS Catal. 2017, 7, 2661.
180 a) S. Kamijo, M. Hirota, K. Tao, M. Watanabe, T. Murafuji, Tetrahedron Lett. 2014, 55, 5551. b) M.
Chen, Z-T. Huang, Q-Y. Zheng, Org. Biomol. Chem. 2014, 12, 9337.
2. Sulfonyl Chloride Derivatives
131 - -scission to generate centered radicals. The formation of
carbon-centered radicals by -scission of sulfonyl radicals is a well-established process that has been used to generate alkyl and aryl radicals involved in chain reactions.150,154, 181 Depending on the substitution of the sulfonyl chloride derivative, the loss of sulfur dioxide requires different temperatures. One of the most important applications of this methodology is the generation of trifluoromethyl radical species from trifluoromethanesulfonyl chloride.182 The trifluoromethyl group enjoys a privileged role in the realm of medicinal chemistry.183 For this reason, the scientific community has been increasingly studying new trifluoromethyl sources, either nucleophilic, electrophilic or radical, for the formation of C-CF3 bonds.184 In this regard, MacMillan and coworkers reported a mild, operationally simple strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes usfing trifluoromethanesulfonyl chloride as the CF3 source (Scheme 19).184a The photoredox catalytic cycle is initiated via excitation of photocatalyst Ru(phen)32+ to its excited state with a household light bulb. This species undergoes single electron transfer (SET) to the sulfonyl chloride 68, delivering the radical anion 72. This high energy species spontaneously collapses to form CF3 radical 73, which selectively combines with aromatic systems 67 enabling direct CF3 substitution. The new radical species 74 is oxidized to form the cyclohexadienyl cation 75, whose facile deprotonation provides the desired trifluoromethylated arene 71.
181 a) F. Bertrand, F. L. Guyader, L. Liguori, G. Ouvry, B. Quiclet-Sire, S. Seguin, S. Z. Zard, C. R. Acad. Sci.
Paris, Chimie/Chemistry 2001, 4, 547; b) S. Kim, S. Kim, Bull. Chem. Soc. Jpn. 2007, 80, 809.
182 a) D. A. Nagib, D. W. C. MacMillan, Nature 2011, 480, 224. b) H. Jiang, C. Huang, J. Guo, C. Zeng, Y.
Zhang, S. Yu, Chem. Eur. J. 2012, 18, 15158.
183 a) K. Muller, C. Faeh, F. Diederich, Science 2007, 317, 1881. b) S. Purser, P. R. Moore, S. Swallow,V.
Gouverneur, Chem. Soc. Rev. 2008, 37, 320. c) W. K. Hagmann, J. Med. Chem. 2008, 51, 4359. d) J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem. Rev. 2011, 111, 455.
184 For selected reviews on the trifluoromethylation of organic compounds, see: a) A. Studer, Angew.
Chem. Int. Ed. 2012, 51, 8950. b) T. Besset, C. Schneider, D. Cahard, Angew. Chem. Int. Ed. 2012, 51, 5048. c) P. Chen, G. Liu, Synthesis 2013, 45, 2919. d) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem.
Int. Ed. 2013, 52, 8214. e) L. Chu, F.-L. Qing, Acc. Chem. Res. 2014, 47, 1513. f) J. Xu, X. Liu, Y. Fu, Tetrahedron Lett. 2014, 55, 585. g) D. L. Browne, Angew. Chem. Int. Ed. 2014, 53, 1482.
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Scheme 19 Arene trifluoromethylation using triflyl chloride
Apart from trifluoromethyl radicals, this strategy also enables the formation of alkyl and aryl radical species by changing the substitution of the starting sulfonyl chloride. These radicals usually add to diverse π-systems. As previously found for sulfonyl radicals, chlorine ATRA reactions to olefins are also feasible processes.185 In addition, these organic radical can undergo C-H functionalization of arenes.186 For instance, 5-membered ring heretoarenes can be functionalized in different positions using this methodology.188b Alkynes can also be functionalized with organic radicals generated from sulfonyl chloride derivatives. This radical addition usually triggers inter- or intramolecular cascade reactions.187 In this regard, Li and coworkers reported a 1,6-enyne cyclization that involves arylsulfonyl chlorides promoted by visible-light photoredox catalysis (Scheme 20).186c A series of 10a,11-dihydro-10H-benzo[b]fluorenes 77 were synthetized, which are present in many
185 L. Cao, K. Weidner, P. Renaud, Adv. Synth. Catal. 2011, 353, 3467.
186 a) L. Gu, C. Jin, J. Liu, H. Dinga, B. Fan, Chem. Commun. 2014, 50, 4643. b) P. Natarajan, A. Bala, S.K.
Mehta, K.K. Bhasin, Tetrahedron 2016, 72, 2521. c) X. Li, D. Liang, W. Huang, H. Zhou, Z. Li, B. Wang, Y.
Ma, H. Wang, Tetrahedron 2016, 72, 8442.
187 a) X. Zeng, L. Ilies, E. Nakamura, J. Am. Chem. Soc. 2011, 133, 17638. b) J-D. Xia, G-B. Deng, M-B.
Zhou, W. Liu, P. Xie, J-H. Li, Synlett 2012, 23, 2707. c) G-B. Deng, Z-Q. Wang, J-D. Xia, P-C. Qian, R-J.
Song, M. Hu, L. Gong, J-H. Li, Angew. Chem. Int. Ed. 2013, 52, 1535. d) L. Gu, C. Jin, W. Wang, Y. He, G.
Yangc, G. Li, Chem. Commun. 2017, 53, 4203.
2. Sulfonyl Chloride Derivatives
133 natural products, biomolecules, optoelectronic materials, and devices. An aryl radical 78 is firstly formed by a single electron transfer (SET) from the excited catalytic species *Ru(bpy)32+ to the arylsulfonyl chloride 41. Subsequent addition of the aryl radical 78 to the carbon–carbon triple bond in substrate 76 results in radical intermediate 79, which undergoes cyclization with the alkene to yield radical intermediate 80. Intramolecular cyclization of 80 with an arene ring gives rise to radical intermediate 81, whose oxidation and subsequent deprotonation furnish the final product 77 regenerating the active catalytic species.
Scheme 20 1,6-enyne cascade cyclization
Part B, General Aspects
134