Accounting for Different Reactivities of Sulfinate and Thiosulfate Salts in Regioselective Azetidine Coupling via C–H Sulfenylation of Indoles

Abstract

The regioselective incorporation of azetidines into heteroaromatic compounds is reported via a formal C–H sulfenylation reaction. While sodium sulfinate salts undergo C3 sulfenylation of electron-rich indoles only, the corresponding thiosulfate salts have proved to be more generally useful. A mechanistic hypothesis for the different reactivities of sulfinate and thiosulfate salts is provided.

The direct C–H functionalization of aromatic compounds has seen a recent surge in research activity and a range of C–C and C–heteroatom bond-forming processes have now become well established.[1] One particularly effective application of this methodology is in its employment in the direct coupling of fragments that are of value to the fine chemicals industry, especially those that are rich in sp³-based centers. In this context, small-ring heterocycles have been targeted as valuable molecules because of their attractive chemical and physical properties,[2] and this has inspired several approaches for the direct coupling of these fragments.[3] Our own interest in this field has led to the discovery of a C–S bond-forming coupling of azetidine and oxetanesulfinate salts to indoles as a direct means of generating indole 2-sulfones.[4] More specifically, as shown in Scheme [1], the iodine-promoted sulfonylation reaction developed by Deng and Kuhakarn[5] offered a convenient means for incorporating azetidines and oxetanes at C2. Preliminary studies suggested that a regiocomplementary process could be developed that delivered C3-substituted sulfides from the same starting materials, using the same authors’ reductive coupling variant.[6] We report herein the scope and limitations of this process, and a mechanism-driven hypothesis that has led to the discovery of thiosulfate (Bunte) salts as generally useful reagents for regioselective sulfenylation of indoles and pyrroles.

We began our studies by exploring the generality of C3 sulfenylation of indoles using sodium sulfinate 1 in the presence of PPh₃ and iodine, and the scope is summarized in Scheme [2].

Coupling of the parent indole proceeded smoothly to generate 2 in high yield. Moreover, incorporation of a Me group on the benzene moiety, indole nitrogen, and C2-positions were well tolerated, providing 3–5 in excellent yield. We were also able to include a MeO group at all positions on the arene ring, as well as a free phenol, giving azetidine sulfides 6–10. Incorporation of a substituent at the indole C3-position resulted in a turnover of regioselectivity, providing 11 in modest yield. We next opted to explore indoles bearing electron-withdrawing groups and were surprised to find that we were unable to observe any of the expected sulfides, and starting indole was recovered in each case (representative examples shown in Scheme [2]).

The proposed mechanism of the indole C3 sulfenylation involves the stepwise reduction of the sodium sulfinate salt to sulfenyl iodide B via the sulfoxinium iodide A (Scheme [3]).[6] The reaction of sulfenium iodides and indoles is well established, and has been found to proceed efficiently with indole substrates bearing a range of electron-rich/deficient groups.[7] The narrow scope depicted in our results shown in Scheme [2] did not therefore appear to be consistent with this mechanism.

We speculated that the intermediate sulfinyl iodide A, if generated, would be an extremely reactive electrophile and wondered whether these intermediates were in fact involved in the C–S bond-forming step. In order to investigate the veracity of this hypothesis, we prepared the corresponding sulfoxide of azetidine sulfide 8 and subjected it to iodine/PPh₃. As shown in Scheme [4] (eq. 1), the sulfoxide underwent reduction under these conditions to return 8 in modest yield. Moreover, subjecting an equal mixture of the same sulfoxide and indole to the reaction conditions generated both 2 and 8 (Scheme [4], eq. 2). Moreover, during the preparation of this manuscript, Lu et al. showed that the PPh₃/NaI-promoted trifluoromethylthiolation of indoles (via a putative sulfenium chloride) generated a sulfoxide byproduct.[8] We believe therefore that a mechanism involving indole sulfoxide formation followed by reduction should be considered alongside the currently accepted sulfenyl iodide S _E Ar pathway.

As the mechanistic studies suggested that the methodology depicted in Scheme [2] may not proceed through a sulfenium iodide intermediate, we decided to explore alternative means by which this electrophilic intermediate could be accessed. In this regard, Bunte salts represent a convenient source of sulfenium cations as they are readily prepared stable crystalline solids.[9] Moreover, Luo and Wang reported the elegant and pioneering use of these salts for the formation of indole 3-sulfides.[10] In order to investigate the potential of these salts as a vehicle for incorporating small-ring heterocycles, we explored the preparation of the required azetidine thiosulfate salt (azetidine Bunte salt), our results are shown in Scheme [5]. In the event, the addition of sodium thiosulfate to commercially available iodide 12 delivered the corresponding salt 13 in quantitative yield.

With the azetidine thiosulfate salt 13 in hand, we set about exploring the scope of the sulfenylation reaction using this compound, and our results are summarized in Scheme [6]. We initially targeted the synthesis of a selection of indole azetidine sulfides prepared by the earlier sulfinate salt method (Scheme [2]) and were pleased to find that this chemistry worked well providing compounds 2, 3, 7–10 and 2-Ph-substituted indole 14 in high yield. Given the simple synthesis of precursor 13 in comparison to the corresponding sulfinate salt 1, this represents a very convenient method to access these compounds. We next turned our attention to substrate bearing a halide on the aryl ring that had proved to be unsuccessful in our earlier studies. The use of Bunte’s salt 13 in this case delivered a series of halide-substituted products 15–19 in excellent yield. In addition, the chemistry could be extended to previously unreactive electron-deficient indoles, generating carbonyl derivatives 20 and 21. Moreover, nitrogen-containing substrates at the nitro- and amine-oxidation levels could be prepared with similar efficiencies (22, 23). Finally, arylboronic esters were found to be compatible as were azaindoles, delivering functionalized scaffolds 24 in high yield. Overall therefore, we have found azetidine thiosulfate salt 13 to offer several advantages over the corresponding sulfinate salt 1, including ease of synthesis and improved scope of reactivity.

Finally, we have been able to extend this method for the introduction of azetidines to other aromatic systems. As shown in Scheme [7], azaindole provided 25 in high yield, and pyrroles could undergo mono- and disulfenylation depending on reaction time and stoichiometry to give 26–28 with excellent regiocontrol. Moreover, we were able to couple azetidines to imidazo[1,2-a]pyridine to furnish 29 in excellent yield and regiocontrol. Reaction regiochemistry was confirmed in this case by X-ray crystallography.[11] Finally, we were also able to couple azetidines to less nucleophilic aromatic systems via the corresponding organometallic intermediates[12] as illustrated by the synthesis of benzene and thiophene bases azetidine thioethers 30 and 31. This reaction was facilitated by the use of Et₄NI which we believe improves the solubility of the thiosulfate salt.

In conclusion, we report a simple method for the coupling of azetidines to indoles via sulfinate and thiosulfate salts,[13] [14] the latter appearing to show significantly broader scope. Although both salts have been proposed to function as reactive electrophiles through the intermediacy of a sulfenyl iodide, the significant differences in reactivities observed in their reaction with indoles has led us to propose that the sulfinate salts react via an S _E Ar reaction of an in situ generated sulfoxonium iodide.

• References and Notes


For representative reviews on C–H activation, see:
• 1a Shin K. Kim H. Chang S. Acc. Chem. Res. 2015; 48: 1040
  CrossrefSearch in Google Scholar
• 1b Daugulis O. Roane J. Tran LD. Acc. Chem. Res. 2015; 48: 1053
  CrossrefSearch in Google Scholar
• 1c Song G. Li X. Acc. Chem. Res. 2015; 48: 1007
  CrossrefSearch in Google Scholar
• 1d Girard SA. Knauber T. Li C.-J. Angew. Chem. Int. Ed. 2014; 53: 74
  CrossrefSearch in Google Scholar
• 1e Sarkar SD. Liu W. Kozhushkov I. Ackermann L. Adv. Synth. Catal. 2014; 356: 1461
  CrossrefSearch in Google Scholar
• 1f Song G. Wang F. Li X. Chem. Soc. Rev. 2012; 41: 3651
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• 1g Lyons TW. Sanford M. Chem. Rev. 2010; 110: 1147
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• 2a Carreira EM. Fessard TC. Chem. Rev. 2014; 114: 8257
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• 2b Burkhard JA. Wuitschik G. Rogers-Evans M. Müller K. Carreira EM. Angew. Chem. Int. Ed. 2010; 49: 9052
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• 3a Duncton MA. J. Estiarte MA. Tan D. Kaub C. O’Mahony DJ. R. Johnson RJ. Cox M. Edwards WT. Wan M. Kincaid J. Kelly MG. Org. Lett. 2008; 10: 3259
  CrossrefPubMedSearch in Google Scholar
• 3b Duncton MA. J. Estiarte MA. Johnson RJ. Cox M. O’Mahony DJ. R. Edwards WT. Kelly MG. J. Org. Chem. 2009; 74: 6354
  CrossrefSearch in Google Scholar
• 3c Presset M. Fleury-Brégeot N. Oehlrich D. Rombouts F. Molander GA. J. Org. Chem. 2013; 78: 4615
  CrossrefSearch in Google Scholar
• 3d Molander GA. Traister KM. O’Neill BT. J. Org. Chem. 2014; 79: 5771
  CrossrefPubMedSearch in Google Scholar
• 3e Gianatassio R. Kawamura S. Eprile CL. Foo K. Ge J. Burns AC. Collins MR. Baran PS. Angew. Chem. Int. Ed. 2014; 53: 9851
  CrossrefSearch in Google Scholar
• 3f Barré B. Gonnard L. Campagne R. Reymond S. Marin J. Ciapetti P. Brellier M. Guérinot A. Cossy J. Org. Lett. 2014; 16: 6160
  CrossrefPubMedSearch in Google Scholar
• 3g Parmar D. Henkel L. Dib J. Rueping M. Chem. Commun. 2015; 51: 2111
  CrossrefPubMedSearch in Google Scholar
• 4 Nassoy A.-CM. A. Raubo P. Harrity JP. A. Chem. Commun. 2015; 51: 5914
  CrossrefSearch in Google Scholar
• 5a Xiao F. Chen H. Xie H. Chen S. Yang L. Deng G.-J. Org. Lett. 2014; 16: 50
  CrossrefSearch in Google Scholar
• 5b Katrun P. Mueangkaew C. Pohmakotr M. Reutrakul V. Jaipetch T. Soorukram D. Kuhakarn C. J. Org. Chem. 2014; 79: 1778
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• 6a Xiao F. Xie H. Liu S. Deng G.-J. Adv. Synth. Cat. 2014; 356: 364
  CrossrefSearch in Google Scholar
• 6b Katrun P. Hongthong S. Hlekhlai S. Pohmakotr M. Reutrakul V. Soorukram D. Jaipetch T. Kuhakarn C. RSC Adv. 2014; 4: 18933
  CrossrefSearch in Google Scholar
• 7a Raban M. Chern L.-J. J. Org. Chem. 1980; 45: 1688
  CrossrefSearch in Google Scholar
• 7b Yi S. Li M. Mo W. Hu X. Hu B. Sun N. Jin L. Shen Z. Tetrahedron Lett. 2016; 57: 1912
  CrossrefSearch in Google Scholar
• 8 Lu K. Deng Z. Li M. Li T. Zhao X. Org. Biomol. Chem. 2017; 15: 1254
  CrossrefPubMedSearch in Google Scholar
• 9 Distler H. Angew. Chem., Int. Ed. Engl. 1967; 6: 544
  CrossrefSearch in Google Scholar
• 10a Qi H. Zhang T. Wan K. Luo M. J. Org. Chem. 2016; 81: 4262
  CrossrefSearch in Google Scholar
• 10b Li J. Cai Z.-J. Wang S.-Y. Ji S.-J. Org. Biomol. Chem. 2016; 14: 9384
  CrossrefSearch in Google Scholar
• 11 The supplementary crystallographic data for compounds 14, 22, and 29 have been deposited with the Cambridge Crystallographic data Center as supplementary publication numbers CCDC 1534462, 1534463, and 1534461, respectively. This data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 12 Reeves JT. Camara K. Han ZS. Xu Y. Lee H. Busacca CA. Senanayake CH. Org. Lett. 2014; 16: 1196
  CrossrefSearch in Google Scholar
• 13 General Procedure A: Coupling of Azetidine Sulfinate Salt 1 to Indoles Iodine (1.0 equiv) was added to indole (1.0 equiv), PPh₃ (2.0 equiv), and sodium 1-(tert-butoxycarbonyl) azetidine-3-sulfinate (1, 2.0 equiv) in EtOH (0.5 mL) at r.t. The resulting solution was stirred at 70 °C for 1 d. All volatiles were removed in vacuo. Purification by recrystallization or by flash chromatography over silica gel, eluting with PE/EtOAc (0–30%) afforded the desired thioindoles. Synthesis of tert-butyl 3-[(1H-Indol-3-yl)thio]azetidine-1-carboxylate (2) Following general procedure A, 1H-indole (12 mg, 0.103 mmol), azetidine sulfinate salt (50 mg, 0.206 mmol), PPh₃ (54 mg, 0.206 mmol), and iodine (26 mg, 0.103 mmol) afforded the desired product as a brown gum (26 mg, 84%). ¹H NMR (400 MHz, CDCl₃): δ = 8.64 (br, 1 H), 7.79–7.75 (m, 1 H), 7.45–7.38 (m, 2 H), 7.31–7.21 (m, 2 H), 4.19–4.12 (m, 2 H), 3.92–3.84 (m, 2 H), 3.77 (tt, J = 8.0, 5.5 Hz, 1 H), 1.38 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 156.2, 136.3, 130.5, 129.7, 122.9, 120.8, 119.1, 111.6, 102.5, 79.6, 56.0 (br), 35.6, 28.3. FTIR (neat): ν_max = 3278 , (s), 305, (w), 2975, (m), 2882 , (m), 1675 (s) cm^–1. HRMS: m/z [M + H]⁺ calcd for C₁₆H₂₁N₂O₂S: 305.1324; found: 305.1319. Synthesis of tert-Butyl 3-[(5-Methyl-1H-indol-3-yl)thio]azetidine-1-carboxylate (3) Following the general procedure A, using 5-methyl-1H-indole (14 mg, 0.103 mmol), azetidine sulfinate salt 1 (50 mg, 0.206 mmol), PPh₃ (54 mg, 0.206 mmol), and iodine (26 mg, 0.103 mmol) afforded the desired product as a pale brown solid (32 mg, 97%); mp 119–120 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.57 (br, 1 H), 7.52 (s, 1 H), 7.33 (d, J = 1.5 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 7.08 (dd, J = 8.5, 1.5 Hz, 1 H), 4.16–4.10 (m, 2 H), 3.91–3.82 (m, 2 H), 3.74 (tt, J = 8.0, 5.5 Hz, 1 H), 2.48 (s, 3 H), 1.37 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 156.4, 134.7, 130.8, 130.0, 129.9, 124.4, 118.5, 111.4, 101.4, 79.7, 56.0, 35.4, 28.3, 21.5. FTIR (neat): ν_max = 3282 (br), 3060 (w), 2974 (m), 2930 (m), 2877 (m), 1675 (s) cm^–1. HRMS: m/z [M + Na]⁺ calcd for C₁₇H₂₂N₂O₂S: 319.1480; found: 319.1473. General Procedure B: Coupling of Azetidine Bunte Salt 13 to Indoles To a flame-dried Schlenk tube with a magnetic stirring bar was added indole (1.0 equiv), azetidine thiosulfate 13 (1.5 equiv), and iodine (20 mol%). The tube was closed with a rubber septum, and placed under an atmosphere of argon, followed by the addition of DMSO via syringe (2 mL). The septum was replaced by a Teflon^TM screw cap under argon flow. The reaction mixture was stirred at 80 °C for 12 h. After cooling to r.t., a saturated solution of Na₂S₂O₃ was added and the product extracted with EtOAc. The combined organic layers was washed with H₂O and brine, dried over MgSO₄, filtered, and then concentrated in vacuo. Purification by recrystallization or by flash chromatography over silica gel, eluting with PE/EtOAc (0–30%) afforded the desired thioindoles.
• 14 General Procedure B: Coupling of Azetidine Bunte Salt 13 to Indoles To a flame-dried Schlenk tube with a magnetic stirring bar was added indole (1.0 equiv), azetidine thiosulfate 13 (1.5 equiv), and iodine (20 mol%). The tube was closed with a rubber septum, and placed under an atmosphere of argon, followed by the addition of DMSO via syringe (2 mL). The septum was replaced by a Teflon^TM screw cap under argon flow. The reaction mixture was stirred at 80 °C for 12 h. After cooling to r.t., a saturated solution of Na₂S₂O₃ was added and the product extracted with EtOAc. The combined organic layers was washed with H₂O and brine, dried over MgSO₄, filtered, and then concentrated in vacuo. Purification by recrystallization or by flash chromatography over silica gel, eluting with PE/EtOAc (0–30%) afforded the desired thioindoles. Synthesis of tert-Butyl 3-[(2-Phenyl-1H-indol-3-yl) thio]azetidine-1-carboxylate (14) To a flame-dried Schlenk tube with a magnetic stirring bar was added indole (1.0 equiv), azetidine thiosulfate 13 (1.5 equiv), and iodine (20 mol%). The tube was closed with a rubber septum, and placed under an atmosphere of argon, followed by the addition of DMSO via syringe (2 mL). The septum was replaced by a Teflon^TM screw cap under argon flow. The reaction mixture was stirred at 80 °C for 12 h. After cooling to r.t., a saturated solution of Na₂S₂O₃ was added and the product extracted with EtOAc. The combined organic layers was washed with H₂O and brine, dried over MgSO₄, filtered, and then concentrated in vacuo. Purification by recrystallization or by flash chromatography over silica gel, eluting with PE/EtOAc (0–30%) afforded the desired thioindoles. Synthesis of tert-Butyl 3-[(5-Fluoro-1H-indol-3-yl)thio]azetidine-1-carboxylate (15) Following the general procedure B, using 5-fluoro-1H-indole (47 mg, 0.344 mmol), azetidine Bunte salt 13 (151 mg, 0.517 mmol), and iodine (17 mg, 0.069 mmol) the desired product was afforded as a white solid (81 mg, 73%); mp 161–162 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.21 (br, 1 H), 7.40–7.35 (m, 2 H), 7.30 (dd, J = 9.0, 4.5 Hz, 1 H), 6.98 (td, J = 9.0, 2.5 Hz, 1 H), 4.19–4.09 (m, 2 H), 3.86–3.79 (m, 2 H), 3.71 (tt, J = 8.0, 5.5 Hz, 1 H), 1.37 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 158.6 (d, J = 236.5 Hz), 156.3, 132.8, 132.4, 130.5 (d, J = 10.0 Hz), 112.5 (d, J = 9.5 Hz), 111.3 (d, J = 26.5 Hz), 104.0 (d, J = 24.0 Hz), 102.1 (d, J = 3.5 Hz), 79.9, 55.9, 35.4, 28.3. ¹⁹F NMR (377 MHz, CDCl₃): δ = 110.3. FTIR (neat): ν_max = 3267 (br), 3040 (w), 2979 (m). 2881 (m), 1675 (s) cm^–1. HRMS: m/z [M + Na]⁺ calcd for C₁₆H₁₉FN₂O₂S: 345.1043; found: 345.1042.

• References and Notes


For representative reviews on C–H activation, see:
• 1a Shin K. Kim H. Chang S. Acc. Chem. Res. 2015; 48: 1040
  CrossrefSearch in Google Scholar
• 1b Daugulis O. Roane J. Tran LD. Acc. Chem. Res. 2015; 48: 1053
  CrossrefSearch in Google Scholar
• 1c Song G. Li X. Acc. Chem. Res. 2015; 48: 1007
  CrossrefSearch in Google Scholar
• 1d Girard SA. Knauber T. Li C.-J. Angew. Chem. Int. Ed. 2014; 53: 74
  CrossrefSearch in Google Scholar
• 1e Sarkar SD. Liu W. Kozhushkov I. Ackermann L. Adv. Synth. Catal. 2014; 356: 1461
  CrossrefSearch in Google Scholar
• 1f Song G. Wang F. Li X. Chem. Soc. Rev. 2012; 41: 3651
  CrossrefSearch in Google Scholar
• 1g Lyons TW. Sanford M. Chem. Rev. 2010; 110: 1147
  CrossrefSearch in Google Scholar
• 2a Carreira EM. Fessard TC. Chem. Rev. 2014; 114: 8257
  CrossrefSearch in Google Scholar
• 2b Burkhard JA. Wuitschik G. Rogers-Evans M. Müller K. Carreira EM. Angew. Chem. Int. Ed. 2010; 49: 9052
  CrossrefPubMedSearch in Google Scholar
• 3a Duncton MA. J. Estiarte MA. Tan D. Kaub C. O’Mahony DJ. R. Johnson RJ. Cox M. Edwards WT. Wan M. Kincaid J. Kelly MG. Org. Lett. 2008; 10: 3259
  CrossrefPubMedSearch in Google Scholar
• 3b Duncton MA. J. Estiarte MA. Johnson RJ. Cox M. O’Mahony DJ. R. Edwards WT. Kelly MG. J. Org. Chem. 2009; 74: 6354
  CrossrefSearch in Google Scholar
• 3c Presset M. Fleury-Brégeot N. Oehlrich D. Rombouts F. Molander GA. J. Org. Chem. 2013; 78: 4615
  CrossrefSearch in Google Scholar
• 3d Molander GA. Traister KM. O’Neill BT. J. Org. Chem. 2014; 79: 5771
  CrossrefPubMedSearch in Google Scholar
• 3e Gianatassio R. Kawamura S. Eprile CL. Foo K. Ge J. Burns AC. Collins MR. Baran PS. Angew. Chem. Int. Ed. 2014; 53: 9851
  CrossrefSearch in Google Scholar
• 3f Barré B. Gonnard L. Campagne R. Reymond S. Marin J. Ciapetti P. Brellier M. Guérinot A. Cossy J. Org. Lett. 2014; 16: 6160
  CrossrefPubMedSearch in Google Scholar
• 3g Parmar D. Henkel L. Dib J. Rueping M. Chem. Commun. 2015; 51: 2111
  CrossrefPubMedSearch in Google Scholar
• 4 Nassoy A.-CM. A. Raubo P. Harrity JP. A. Chem. Commun. 2015; 51: 5914
  CrossrefSearch in Google Scholar
• 5a Xiao F. Chen H. Xie H. Chen S. Yang L. Deng G.-J. Org. Lett. 2014; 16: 50
  CrossrefSearch in Google Scholar
• 5b Katrun P. Mueangkaew C. Pohmakotr M. Reutrakul V. Jaipetch T. Soorukram D. Kuhakarn C. J. Org. Chem. 2014; 79: 1778
  CrossrefPubMedSearch in Google Scholar
• 6a Xiao F. Xie H. Liu S. Deng G.-J. Adv. Synth. Cat. 2014; 356: 364
  CrossrefSearch in Google Scholar
• 6b Katrun P. Hongthong S. Hlekhlai S. Pohmakotr M. Reutrakul V. Soorukram D. Jaipetch T. Kuhakarn C. RSC Adv. 2014; 4: 18933
  CrossrefSearch in Google Scholar
• 7a Raban M. Chern L.-J. J. Org. Chem. 1980; 45: 1688
  CrossrefSearch in Google Scholar
• 7b Yi S. Li M. Mo W. Hu X. Hu B. Sun N. Jin L. Shen Z. Tetrahedron Lett. 2016; 57: 1912
  CrossrefSearch in Google Scholar
• 8 Lu K. Deng Z. Li M. Li T. Zhao X. Org. Biomol. Chem. 2017; 15: 1254
  CrossrefPubMedSearch in Google Scholar
• 9 Distler H. Angew. Chem., Int. Ed. Engl. 1967; 6: 544
  CrossrefSearch in Google Scholar
• 10a Qi H. Zhang T. Wan K. Luo M. J. Org. Chem. 2016; 81: 4262
  CrossrefSearch in Google Scholar
• 10b Li J. Cai Z.-J. Wang S.-Y. Ji S.-J. Org. Biomol. Chem. 2016; 14: 9384
  CrossrefSearch in Google Scholar
• 11 The supplementary crystallographic data for compounds 14, 22, and 29 have been deposited with the Cambridge Crystallographic data Center as supplementary publication numbers CCDC 1534462, 1534463, and 1534461, respectively. This data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 12 Reeves JT. Camara K. Han ZS. Xu Y. Lee H. Busacca CA. Senanayake CH. Org. Lett. 2014; 16: 1196
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• 13 General Procedure A: Coupling of Azetidine Sulfinate Salt 1 to Indoles Iodine (1.0 equiv) was added to indole (1.0 equiv), PPh₃ (2.0 equiv), and sodium 1-(tert-butoxycarbonyl) azetidine-3-sulfinate (1, 2.0 equiv) in EtOH (0.5 mL) at r.t. The resulting solution was stirred at 70 °C for 1 d. All volatiles were removed in vacuo. Purification by recrystallization or by flash chromatography over silica gel, eluting with PE/EtOAc (0–30%) afforded the desired thioindoles. Synthesis of tert-butyl 3-[(1H-Indol-3-yl)thio]azetidine-1-carboxylate (2) Following general procedure A, 1H-indole (12 mg, 0.103 mmol), azetidine sulfinate salt (50 mg, 0.206 mmol), PPh₃ (54 mg, 0.206 mmol), and iodine (26 mg, 0.103 mmol) afforded the desired product as a brown gum (26 mg, 84%). ¹H NMR (400 MHz, CDCl₃): δ = 8.64 (br, 1 H), 7.79–7.75 (m, 1 H), 7.45–7.38 (m, 2 H), 7.31–7.21 (m, 2 H), 4.19–4.12 (m, 2 H), 3.92–3.84 (m, 2 H), 3.77 (tt, J = 8.0, 5.5 Hz, 1 H), 1.38 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 156.2, 136.3, 130.5, 129.7, 122.9, 120.8, 119.1, 111.6, 102.5, 79.6, 56.0 (br), 35.6, 28.3. FTIR (neat): ν_max = 3278 , (s), 305, (w), 2975, (m), 2882 , (m), 1675 (s) cm^–1. HRMS: m/z [M + H]⁺ calcd for C₁₆H₂₁N₂O₂S: 305.1324; found: 305.1319. Synthesis of tert-Butyl 3-[(5-Methyl-1H-indol-3-yl)thio]azetidine-1-carboxylate (3) Following the general procedure A, using 5-methyl-1H-indole (14 mg, 0.103 mmol), azetidine sulfinate salt 1 (50 mg, 0.206 mmol), PPh₃ (54 mg, 0.206 mmol), and iodine (26 mg, 0.103 mmol) afforded the desired product as a pale brown solid (32 mg, 97%); mp 119–120 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.57 (br, 1 H), 7.52 (s, 1 H), 7.33 (d, J = 1.5 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 7.08 (dd, J = 8.5, 1.5 Hz, 1 H), 4.16–4.10 (m, 2 H), 3.91–3.82 (m, 2 H), 3.74 (tt, J = 8.0, 5.5 Hz, 1 H), 2.48 (s, 3 H), 1.37 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 156.4, 134.7, 130.8, 130.0, 129.9, 124.4, 118.5, 111.4, 101.4, 79.7, 56.0, 35.4, 28.3, 21.5. FTIR (neat): ν_max = 3282 (br), 3060 (w), 2974 (m), 2930 (m), 2877 (m), 1675 (s) cm^–1. HRMS: m/z [M + Na]⁺ calcd for C₁₇H₂₂N₂O₂S: 319.1480; found: 319.1473. General Procedure B: Coupling of Azetidine Bunte Salt 13 to Indoles To a flame-dried Schlenk tube with a magnetic stirring bar was added indole (1.0 equiv), azetidine thiosulfate 13 (1.5 equiv), and iodine (20 mol%). The tube was closed with a rubber septum, and placed under an atmosphere of argon, followed by the addition of DMSO via syringe (2 mL). The septum was replaced by a Teflon^TM screw cap under argon flow. The reaction mixture was stirred at 80 °C for 12 h. After cooling to r.t., a saturated solution of Na₂S₂O₃ was added and the product extracted with EtOAc. The combined organic layers was washed with H₂O and brine, dried over MgSO₄, filtered, and then concentrated in vacuo. Purification by recrystallization or by flash chromatography over silica gel, eluting with PE/EtOAc (0–30%) afforded the desired thioindoles.
• 14 General Procedure B: Coupling of Azetidine Bunte Salt 13 to Indoles To a flame-dried Schlenk tube with a magnetic stirring bar was added indole (1.0 equiv), azetidine thiosulfate 13 (1.5 equiv), and iodine (20 mol%). The tube was closed with a rubber septum, and placed under an atmosphere of argon, followed by the addition of DMSO via syringe (2 mL). The septum was replaced by a Teflon^TM screw cap under argon flow. The reaction mixture was stirred at 80 °C for 12 h. After cooling to r.t., a saturated solution of Na₂S₂O₃ was added and the product extracted with EtOAc. The combined organic layers was washed with H₂O and brine, dried over MgSO₄, filtered, and then concentrated in vacuo. Purification by recrystallization or by flash chromatography over silica gel, eluting with PE/EtOAc (0–30%) afforded the desired thioindoles. Synthesis of tert-Butyl 3-[(2-Phenyl-1H-indol-3-yl) thio]azetidine-1-carboxylate (14) To a flame-dried Schlenk tube with a magnetic stirring bar was added indole (1.0 equiv), azetidine thiosulfate 13 (1.5 equiv), and iodine (20 mol%). The tube was closed with a rubber septum, and placed under an atmosphere of argon, followed by the addition of DMSO via syringe (2 mL). The septum was replaced by a Teflon^TM screw cap under argon flow. The reaction mixture was stirred at 80 °C for 12 h. After cooling to r.t., a saturated solution of Na₂S₂O₃ was added and the product extracted with EtOAc. The combined organic layers was washed with H₂O and brine, dried over MgSO₄, filtered, and then concentrated in vacuo. Purification by recrystallization or by flash chromatography over silica gel, eluting with PE/EtOAc (0–30%) afforded the desired thioindoles. Synthesis of tert-Butyl 3-[(5-Fluoro-1H-indol-3-yl)thio]azetidine-1-carboxylate (15) Following the general procedure B, using 5-fluoro-1H-indole (47 mg, 0.344 mmol), azetidine Bunte salt 13 (151 mg, 0.517 mmol), and iodine (17 mg, 0.069 mmol) the desired product was afforded as a white solid (81 mg, 73%); mp 161–162 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.21 (br, 1 H), 7.40–7.35 (m, 2 H), 7.30 (dd, J = 9.0, 4.5 Hz, 1 H), 6.98 (td, J = 9.0, 2.5 Hz, 1 H), 4.19–4.09 (m, 2 H), 3.86–3.79 (m, 2 H), 3.71 (tt, J = 8.0, 5.5 Hz, 1 H), 1.37 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 158.6 (d, J = 236.5 Hz), 156.3, 132.8, 132.4, 130.5 (d, J = 10.0 Hz), 112.5 (d, J = 9.5 Hz), 111.3 (d, J = 26.5 Hz), 104.0 (d, J = 24.0 Hz), 102.1 (d, J = 3.5 Hz), 79.9, 55.9, 35.4, 28.3. ¹⁹F NMR (377 MHz, CDCl₃): δ = 110.3. FTIR (neat): ν_max = 3267 (br), 3040 (w), 2979 (m). 2881 (m), 1675 (s) cm^–1. HRMS: m/z [M + Na]⁺ calcd for C₁₆H₁₉FN₂O₂S: 345.1043; found: 345.1042.

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