Download PDF
Synlett 2023; 34(16): 1920-1924
DOI: 10.1055/a-2102-6927
letter

A New Method for the Introduction of an Acylsulfonamide Moiety Applied to a 3-Substituted Functionalized Indole Framework ­Related to the Welwitindolinone Alkaloids

Miriam Ruiz-Serrano
a   Unidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense. Plaza de Ramón y Cajal s.n., 28040 Madrid, Spain
,
Pilar López-Alvarado
a   Unidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense. Plaza de Ramón y Cajal s.n., 28040 Madrid, Spain
,
J. Carlos Menéndez  ∗
› Author AffiliationsFinancial support was obtained from Ministerio de Ciencia e Innovación (grant TED2021-129408B-I00).
› Further Information
    Permissions and Reprints All articles of this category


Abstract

The one-pot reaction between an α-formylcyclohexanone derivative and tosyl azide in the presence of rhodium trifluoroacetate dimer afforded an acylsulfonamide derivative. This transformation is proposed to arise from a domino mechanism involving the in situ generation, through the Regitz method, of an α-diazoketone, followed by its transformation into a rhodium carbenoid and its combination with N-tosylformamide, generated as a side product of the first step of the mechanism. Overall, this transformation leads to the generation of a C–N bond between the formyl carbon and the azide nitrogen adjacent to the sulfonyl group.

Key words

indoles - Michael addition - diazo compounds - rhodium catalysis - carbenoids - domino reaction

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2102-6927.
  • Supporting Information


Publication History

Received: 24 April 2023

Accepted after revision: 30 May 2023

Accepted Manuscript online:
30 May 2023

Article published online:
07 July 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References and Notes

  • 1 Ammazzalorso A, De Filippis B, Giampietro L, Amoroso R. Chem. Biol. Drug Des. 2017; 90: 1094
    CrossrefPubMed
  • 2 Francisco KR, Varricchio C, Paniak TJ, Kozlowski MC, Brancale A, Ballatore C. Eur. J. Med. Chem. 2021; 218: 113399
    CrossrefPubMed

      • For reviews, see:
    • 3a Avendaño C, Menéndez JC. Curr. Org. Synth. 2004; 1: 65
      Crossref
    • 3b Menéndez JC. Top. Heterocycl. Chem. 2007; 11: 63
      Crossref
    • 3c Brown LE, Konopelski JP. Org. Prep. Proced. Int. 2008; 40: 411
      Crossref
    • 3d Wood JL. Nat. Chem. 2012; 4: 341
      CrossrefPubMed
    • 3e Huters AD, Styduhar ED, Garg NK. Angew. Chem. Int. Ed. 2012; 51: 3758
      CrossrefPubMed
    • 3f Bhat V, Dave A, MacKay JA, Rawal VH. In The Alkaloids: Chemistry and Biology, Vol. 73. Knölker H.-J. Academic Press, London, 2014; 65;
      Google Scholar
    • 4a Bhat V, Allan KM, Rawal VH. J. Am. Chem. Soc. 2011; 133: 5798
      CrossrefPubMed
    • 4b Bhat V, Rawal VH. Chem. Commun. 2011; 47: 9705
      CrossrefPubMed
    • 4c Allan KM, Kobayashi K, Rawal VH. J. Am. Chem. Soc. 2012; 134: 1392
      CrossrefPubMed
    • 5a Huters AD, Quasdorf KW, Styduhar ED, Garg NK. J. Am. Chem. Soc. 2011; 133: 15797
      CrossrefPubMed
    • 5b Quasdorf KW, Huters AD, Lodewyk MW, Tantillo DJ, Garg NK. J. Am. Chem. Soc. 2012; 134: 1396
      CrossrefPubMed
    • 5c Weires NA, Styduhar ED, Baker EL, Garg NK. J. Am. Chem. Soc. 2014; 136: 14710
      CrossrefPubMed
  • 6 Komine K, Nomura Y, Ishihara J, Hatakeyama S. Org. Lett. 2015; 17: 3918
    CrossrefPubMed
    • 7a Fu T.-h, McElroy WT, Shamszad M, Martin SF. Org. Lett. 2012; 14: 3834
      CrossrefPubMed
    • 7b Fu T.-h, McElroy WT, Shamszad M, Heidebrecht RW. Jr, Gulledge B, Martin SF. Tetrahedron 2013; 69: 5588
      CrossrefPubMed
    • 8a Konopelski JP, Deng H, Schiemann K, Keane JM, Olmstead MM. Synlett 1998; 1105
      Article in Thieme Connect
    • 8b Elliott GI, Konopelski JP, Olmstead MM. Org. Lett. 1999; 1: 1867
      Crossref
    • 8c Elliott GI, Konopelski JP. Tetrahedron 2001; 57: 5683
      Crossref
    • 8d Konopelski JP, Lin J, Wenzel PJ, Deng H, Elliott GI, Gerstenberger BS. Org. Lett. 2002; 4: 4121
      CrossrefPubMed
    • 8e Deng H, Konopelski JP. Org. Lett. 2001; 3: 3001
      CrossrefPubMed
    • 8f Xia J, Brown LE, Konopelski JP. J. Org. Chem. 2007; 72: 6885
      CrossrefPubMed
    • 8g López-Alvarado P, García-Granda S, Alvarez-Rúa C, Avendaño C. Eur. J. Org. Chem. 2002; 1702
      Crossref
    • 8h Jung ME, Slowinski F. Tetrahedron Lett. 2001; 42: 6835
      Crossref
    • 9a Wood JL, Moniz GA, Pflum DA, Stoltz BM, Holubec AA, Dietrich HJ. J. Am. Chem. Soc. 1999; 121: 1748
      Crossref
    • 9b Wood JL, Holubec AA, Stoltz BM, Weiss MM, Dixon JA, Doan BD, Shamji MF, Chen JM, Heffron TP. J. Am. Chem. Soc. 1999; 121: 6326
      Crossref
    • 9c Freeman DB, Holubec AA, Weiss MW, Dixon JA, Kakefuda A, Ohtsuka M, Inoue M, Vaswani RG, Ohki H, Doan BD, Reisman SE, Stoltz BM, Day JJ, Tao RN, Dieterich NA, Wood JL. Tetrahedron 2010; 66: 6647
      CrossrefPubMed
    • 9d MacKay JA, Bishop RL, Rawal VH. Org. Lett. 2005; 7: 3421
      CrossrefPubMed
    • 9e Baudoux J, Blake AJ, Simpkins NS. Org. Lett. 2005; 7: 4087
      CrossrefPubMed
    • 9f Greshock TJ, Funk RL. Org. Lett. 2006; 8: 2643
      CrossrefPubMed
    • 9g Lauchli R, Shea KJ. Org. Lett. 2006; 8: 5287
      CrossrefPubMed
    • 9h Boissel V, Simpkins NS, Bhalay G, Blake AJ, Lewis W. Chem. Commun. 2009; 1398
      CrossrefPubMed
    • 9i Boissel V, Simpkins NS, Bhalay G. Tetrahedron Lett. 2009; 50: 3283
      Crossref
    • 9j Tian X, Huters AD, Douglas CJ, Garg NK. Org. Lett. 2009; 11: 2349
      CrossrefPubMed
    • 9k Trost BM, McDougall PJ. Org. Lett. 2009; 11: 3782
      CrossrefPubMed
    • 9l Brailsford JA, Lauchli R, Shea KJ. Org. Lett. 2009; 11: 5330
      CrossrefPubMed
    • 9m Heidebrecht RW. Jr, Gulledge B, Martin SF. Org. Lett. 2010; 12: 2492
      CrossrefPubMed
    • 9n Ruiz M, López-Alvarado P, Menéndez JC. Org. Biomol. Chem. 2010; 8: 4521
      CrossrefPubMed
    • 9o Bhat V, MacKay JA, Rawal VH. Org. Lett. 2011; 13: 3214
      CrossrefPubMed
    • 9p Bhat V, MacKay JA, Rawal VH. Tetrahedron 2011; 67: 10097
      CrossrefPubMed
    • 9q Zhang M, Tang W. Org. Lett. 2012; 14: 3756
      CrossrefPubMed
    • 9r Ruiz M, López-Alvarado P, Menéndez JC. Eur. J. Org. Chem. 2013; 2802
      Crossref
    • 9s Lam SM, Wong WT, Chiu P. Org. Lett. 2017; 19: 4468
      CrossrefPubMed
  • 10 Bartoli G, Bosco M, Dalpozzo R, Giuliani A, Marcantoni E, Mecozzi T, Sambri L, Torregiani E. J. Org. Chem. 2002; 67: 9111
    CrossrefPubMed
  • 11 Yadav JS, Abraham S, Reddy BV. S, Sabitha G. Synthesis 2001; 2165
    Article in Thieme ConnectPubMed
  • 12 Kumar V, Kaur S, Kumar S. Tetrahedron Lett. 2006; 47: 7001
    CrossrefPubMed
  • 13 Ma S, Yu S, Peng Z. Org. Biomol. Chem. 2005; 3: 1933
    CrossrefPubMed
  • 14 Wang S.-Y, Ji S.-J, Loh T.-P. Synlett 2003; 2377
    CrossrefPubMed
  • 15 Ji S.-J, Wang S.-Y. Ultrason. Sonochem. 2005; 12: 339
    CrossrefPubMed
  • 16 2-[1-Methyl-1-(1-methyl-1H-indol-3-yl)ethyl]cyclohexanone (4b) A solution of 1-methylindole (2, R = Me; 1.0 g, 7.6 mmol), 2-isopropylidenecyclohexanone (3; 1.05 g, 7.6 mmol, 1 equiv), and PTSA (0.14 g, 0.76 mmol, 0.1 equiv) in absolute EtOH (20 mL) was irradiated in an ultrasound bath in an open flask for 3 h. CH2Cl2 (20 mL) was added, and the mixture was washed with H2O (3 × 20 mL). The organic layer was dried (Na2SO4) and concentrated, and the residue was purified by chromatography [silica gel, PE–EtOAc (7:1)] to give a white solid; yield: 1.74 g (85%); mp 91–92 °C. IR (NaCl): 2934, 1707 (CO) cm–1. 1H NMR (250 MHz, CDCl3): δ = 7.80 (d, J = 8.0 Hz, 1 H, H-4′), 7.35 (d, J = 7.8 Hz, 1 H, H-7′), 7.27 (dt, J = 6.8 and 1 Hz, 1 H, H-6′), 7.14 (dt, J = 8.0 and 1.0 Hz, 1 H and H-5′), 6.88 (s, 1 H, H-2′), 3.78 (s, 3 H, NCH3), 3.21 (dd, J = 12.0 and 4.2 Hz, 1 H, H-2), 2.61–2.3 (m, 2 H, H-6), 2.11–1.47 (m, 6 H, H-3, H-4 and H-5), 1.69 (s, 3 H, CH3), 1.59 (s, 3 H, CH3). 13C NMR (63 MHz, CDCl3): δ = 213.4 (CO), 138.2 (C-7a′), 126.6 (C-2′), 126.2 (C-3a′), 124.0 (C-3′), 121.5 (C-4′), 121.4 (C-6′), 118.7 (C-5′), 109.9 (C-7′), 58.5 (C-2), 44.8 (C-6), 37.2 [C(CH3)2], 33.0 (NCH3), 31.3, 29.0, and 26.55 (C-3, C-4, & C-5), 27.6 and 23.7 (CH3). Anal. Calcd for C18H23NO (M = 269.38): C, 80.26; H, 8.61; N, 5.20. Found: C, 79.90; H, 8.43; N, 5.27.
    • 18a Regitz M, Rüter J. Chem. Ber. 1968; 101: 1263
      Crossref
    • 18b Mander L, McLachlan M. J. Am. Chem. Soc. 2003; 125: 2400
      CrossrefPubMed
  • 19 (2Z)-2-(Hydroxymethylene)-6-[1-methyl-1-(1-methyl-1H-indol-3-yl)ethyl]cyclohexanone (5a)A solution of compound 4a (1.18 g, 4.4 mmol) in anhyd THF (50 mL) was added to a suspension of NaH (1.76 g, 40 mmol, 10 equiv) in anhyd THF (50 mL), and the resulting suspension was stirred at rt for 5 min, then cooled to 0 °C. HCO2Et (3 mL, 37.8 mmol, 8.6 equiv) was added, and the suspension was stirred at 0 °C for 1 h and at rt for 3 h. MeOH (15 mL) was added, and the mixture was acidified with 2 M aq HCl to pH 1 and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated to give an orange oil; yield: 1.3 g (99%). This was sufficiently pure to be used in the crude state for the next step. An analytical sample was obtained by chromatography [silica gel, PE–EtOAc (5:1)].IR (NaCl): 2932, 1620 (CO) cm–1. 1H NMR (250 MHz, CDCl3): δ = 8.63 (d, J = 3.5 Hz, 1 H, =CHOH), 7.84 (d, J = 8.0 Hz, 1 H, H-4′), 7.37 (d, J = 8.0 Hz, 1 H, H-7′), 7.29 (td, J = 7.9 and 1 Hz, 1 H, H-6′), 7.16 (td, J = 8.0 and 1.0 Hz, 1 H, H-5′), 6.85 (s, 1 H, H-2′), 3.80 (s, 1 H, N-CH3), 3.28 (t, J = 8.4 Hz, 1 H, H-6), 2.41–2.11 (m, 2 H, H-3), 1.85 (s, 3 H, CH3), 1.72 (dd, J = 7.6 and 2.6 Hz, 1 H, H-5), 1.48 (s, 3 H, CH3), 1.48–1.20 (m, 3 H, H-5 and 2 H-4). 13C NMR (63 MHz, CDCl3): δ = 190.1 (C-1), 186.3 (=CHOH), 138.2 (C-7′a), 126.6 (C-3′a), 126.0 (C-2′), 124.0 (C-3′), 121.8 (C-6′), 121.3 (C-4′), 118.9 (C-5′), 111.9 (C-2), 109.9 (C-7′), 48.9 (C-6), 39.6 [C(CH3)2], 33.1 (N–CH3), 30.2 [C(CH3)2], 26.6 (C-3), 24.8 (C-5*), 23.9 [C(CH3)2], 23.3 (C-4*). Anal. Calcd for C19H23NO2 (M = 297.39): C, 76.73; H, 7.80; N, 4.71. Found: C 76.87; H, 7.62; N, 4.87
  • 20 cis-3-[1-Methyl-1-(1-methyl-1H-indol-3-yl)ethyl]-N-tosyl-2-oxocyclohexanecarboxamide (7)Et3N (270 μL, 2 equiv) was added to a solution of compound 5a (1.1 g, 3.74 mmol) in anhyd MeCN (25 mL). The solution was cooled to 0 °C in an ice bath and TsN3 (958 mg, 1.3 equiv) was added. The mixture was stirred at rt for 24 h, then poured onto 1 M aq NaOH (30 mL). The solvent was removed under reduced pressure at rt, and H2O (30 mL) was added to the residue. The aqueous phase was extracted with EtOAc (3 × 25 mL), and the combined organic layers were washed sequentially with 1 M aq NaOH (30 mL), H2O (30 mL), and brine (30 mL) then dried (Na2SO4) and evaporated to dryness.In parallel, a 250 mL round-bottomed flask containing montmorillonite K-10 (10 g) was oven dried for 15 min, then cooled under an argon stream. Anhyd CH2Cl2 (100 mL) was then added under argon. Rh2(TFA)4 (10 mg, 0.4% mol) was added to the resulting suspension, and then a solution of the crude α-diazoketone 6 in anhyd CH2Cl2 (40 mL) was slowly added over 20 min. Immediately after the completion of the addition, the mixture was filtered through Celite covered with a thin layer of silica gel. The silica gel–Celite layer was washed with EtOAc (3 × 20 mL) and MeOH (2 × 20 mL), and the combined washings were evaporated under reduced pressure. The residue was purified by column chromatography [silica gel, PE–EtOAc (gradient from10:1 to 1:1)] to give a pale yellow oil; yield: 1.13 g (65%).IR (NaCl): 3248 (NH), 1710 (CO), 1631 and 1157 (SO2) cm–1. 1H NMR (250 MHz, CDCl3): δ = 10.52 (s, NH), 7.90 (d, J = 6.7 Hz, 2 H, H-3′′ and H-5′′), 7.55 (d, J = 8.0 Hz, 1 H, H-7′), 7.27 (d, J = 6.7 Hz, 2 H, H-2′′ and H-6′′), 7.15 (d, J = 8.0 Hz, 1 H, H-4′), 7.14 (td, J = 7.2 and 1.2 Hz, 1 H, H-6′), 6.95 (td, J = 6.9 and 1.2 Hz, 1 H, H-5′), 6.72 (s, 1 H, H-2′), 3.65 (s, 3 H, NCH3), 3.19 (dd, J = 12.8 and 5.4 Hz, 1 H, H-6), 3.05 (dd, J = 12.0 and 4.4 Hz, 1 H, H-2), 2.29 (s, 3 H, TosCH3), 2.29–2.15, 2.83–1.26 (m, 6 H, H-3, H-4 and H-5), 1.48 (s, 3 H, CH3), 1.40 (s, 3 H, CH3). 13C NMR (63 MHz, CDCl3): δ = 211.4 (C1=O), 168.4 (NHCO), 145.3 (C-4′′), 138.1 (C-7a′), 136.1 (C-1′′), 130.0 (C-5′′ and C-3′′), 128.9 (C-2′′ and C-6′′), 126.7 (C-2′), 125.8 (C-3a′), 123.0 (C-3′), 121.5 (C-6′), 121.1 (C-7′), 118.9 (C-5′), 110.0 (C-4′), 59.3 (C-2), 58.0 (C-6), 36.9 [C(CH3)2], 34.9, 32.1 and 25.7 (C-3, C-4 and C-5), 33.1 (N-CH3), 27.0 (CH3), 24.0 (CH3) and 22.1 (TosCH3). Analysis: Calculated for C26H30N2O4S (M = 466.59): C, 66.93; H, 6.48; N, 6.00. Found: C, 66.76. H, 6.45. N 5.99.
  • 21 2-Diazo-6-[1-Methyl-1-(1-methyl-1H-indol-3-yl)ethyl]cyclohexanone (11)Et3N (61 μL, 2 equiv) was added to a solution of compound 5a (250 mg, 0.85 mmol) in anhyd MeCN (8 mL). The solution was cooled to 0 °C in an ice bath and TsN3 (215 mg, 1.3 equiv) was added. The mixture was stirred at rt for 24 h, then poured onto 1 M aq NaOH (8 mL). The solvent was removed under reduced pressure at rt, and H2O (8 mL) was added to the residue. The aqueous phase was extracted with EtOAc (3 × 15 mL), and the combined organic layers were washed sequentially with 1 M aq NaOH (8 mL), H2O (8 mL), and brine (8 mL), then dried (Na2SO4) and evaporated to dryness. The crude residue was purified by chromatography [silica gel, PE–EtOAc (5:1)] acetate to give a yellow oil; yield: 180 mg (73%).IR (NaCl): 2929, 2078 (N2), 1613 (CO) cm–1. 1H NMR (250 MHz, CDCl3): δ = 7.65 (d, J = 8.0 Hz, 1 H, H-4′), 7.21 (dd, J = 7.8 and 1.1 Hz, 1 H, H-7′), 7.13 (td, J = 8.1 and 1.05 Hz, 1 H, H-6′), 6.99 (td, J = 6.87 and 1.2 Hz, 1 H, H-5′), 6.69 (s, 1 H, H-2′), 3.66 (s, 3 H, N-CH3), 2.88 (dd, J = 10.6 and 6.1 Hz, 1 H, H-6), 2.62–2.43, 1.70–1.13 (2m, 6 H, H-3, H-4 and H-5), 1.72 (s, 3 H, CH3), 1.33 (s, 3 H, CH3). 13C NMR (63 MHz, CDCl3): δ = 197.3 (CO), 138.1 (C-7a′), 126.4 (C-3a′), 126.0 (C-2′), 123.9 (C-3′), 122.6 (C-6′), 121.3 (C-4′), 118.9 (C-5′), 109.8 (C-7′), 65.7 (C-N2), 53.5 (C-6), 39.5 [C(CH3)2], 33.0 (N-CH3), 30.0 (CH3), 26.7 (C-3), 23.7 (CH3), 23.2 and 22.5 (C-4 and C-5). Anal. Calcd for C18H21N3O (M = 295.38): C, 73.19, H, 7.17, N, 14.23. Found: C, 73.25, H, 7.19, N, 14.22. .