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
    CrossrefPubMedSearch in Google Scholar
  • 2 Francisco KR, Varricchio C, Paniak TJ, Kozlowski MC, Brancale A, Ballatore C. Eur. J. Med. Chem. 2021; 218: 113399
    CrossrefPubMedSearch in Google Scholar
  • 6 Komine K, Nomura Y, Ishihara J, Hatakeyama S. Org. Lett. 2015; 17: 3918
    CrossrefPubMedSearch in Google Scholar
  • 10 Bartoli G, Bosco M, Dalpozzo R, Giuliani A, Marcantoni E, Mecozzi T, Sambri L, Torregiani E. J. Org. Chem. 2002; 67: 9111
    CrossrefPubMedSearch in Google Scholar
  • 11 Yadav JS, Abraham S, Reddy BV. S, Sabitha G. Synthesis 2001; 2165
    Thieme ConnectPubMed
  • 12 Kumar V, Kaur S, Kumar S. Tetrahedron Lett. 2006; 47: 7001
    CrossrefPubMedSearch in Google Scholar
  • 13 Ma S, Yu S, Peng Z. Org. Biomol. Chem. 2005; 3: 1933
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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.
  • 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. .