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Synlett 2005(3): 449-452  
DOI: 10.1055/s-2005-862363
LETTER
© Georg Thieme Verlag Stuttgart · New York

Nucleophilic Aromatic Substitution on 4-Fluorophenylsulfonamides: Nitrogen, Oxygen, and Sulfur Nucleophiles

Elena Badetti, Marcial Moreno-Mañas*, Roser Pleixats, Rosa M. Sebastián, Anna Serra, Roger Soler, Adelina Vallribera
Department of Chemistry, Universitat Autònoma de Barcelona, Cerdanyola, 08193 Barcelona, Spain
Fax: +34(9)35811254; e-Mail: marcial.moreno@uab.es;
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Publication History

Received 10 November 2004
Publication Date:
04 February 2005 (online)

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Abstract

Improved conditions are reported for the stoichiometric reaction of nitrogen, oxygen, and sulfur nucleophiles with weakly activated 4-fluorophenylsulfonamides.

Key words

nucleophilic aromatic substitution - phase transfer ­catalysis - cesium - macrocycles - diaryl oxides - diarylamines

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3

Compound 2a (72%): mp 230 °C. Compound 2b (40%): oil. Compound 2c (65%): mp 84-85 °C.

10

Compound 3, mp 39-40 °C, was prepared by reaction of 4-fluorobenzenesulfonyl chloride with diethylamine in CH2Cl2.

11

Method A of Table 1. Typical Experiment:
A 1.6 M solution of n-BuLi in hexane (3.4 mL, 5.34 mmol) was added dropwise into a solution of di-n-octyl amine (1.1 mL, 3.56 mmol) in anhyd THF (3 mL) cooled at -40 °C (MeCN-liquid nitrogen bath). The mixture was stirred at -40 °C for 15 min. Then, a solution of sulphonamide 3 (0.82 g, 3.56 mmol) in anhyd THF (5 mL) was added. The mixture was stirred at r.t. for one day and evaporated. The residue was partitioned between CHCl3 and diluted HCl, the organic layer was dried (Na2SO4) and evaporated to afford 1.6 g (ca. 100%) of 4b as an ochre oil. IR (Attenuated Total Reflectance, ATR): 2924, 2853, 1594, 1333, 1147 cm-1. 1H NMR (250 MHz, CDCl3): δ = 0.88 (t, J = 6.6 Hz, 6 H), 1.12 (t, J = 7.2 Hz, 6 H), 1.29 (m, 20 H), 1.57 (m, 4 H), 3.18 (q, J = 7.2 Hz, 4 H), 3.26 (t, J = 7.1, 4 H), 6.56 (d, J = 9.1 Hz, 2 H), 7.57 (d, J = 9.1 Hz, 2 H). 13C NMR (62.5 MHz, CDCl3): δ = 14.2, 14.4, 22.7, 27.2, 29.4, 29.5, 31.9, 42.1, 51.1, 110.5, 124.7, 129.1, 150.8. Anal. Calcd for C26H48N2O2S: C, 68.98; H, 10.69; N, 6.19; S, 7.08. Found: C, 68.79; H, 10.69; N 6.05; S, 6.74.
Good elemental analyses (at least three elements) were secured for 4b,c,e-g (with 0.5 mol of H2O), and 4d (as picrate, mp 109-110 °C). Product 4a: HRMS: m/z calcd for C16H28N2O2S: 312.1871; found: 312.1867.

13

Method C of Table 2; Typical Experiment
A solution of 3 (1.05 g, 4.55 mmol) and tetrabutyl-ammonium chloride (1.52 g, 5.2 mmol) in anhyd THF
(5.5 mL) was added under argon via cannula to a stirred suspension of sodium phenolate in anhyd THF (4 mL), made from NaH (60% suspension in mineral oil, 0.30 g, 7.55 mmol) and phenol (0.52 g, 5.52 mmol). The mixture was stirred overnight and MeOH (2 mL) was added. The solvents were evaporated and the residue was taken in EtOAc. The organic solution was washed with 5% aq NaOH, dried (Na2SO4), and evaporated to afford a dark yellow oil that crystallized upon standing (83%). It was recrystallized from t-butyl methyl ether to afford pure 5d (52%); mp 80-82 °C. IR (ATR): 3090, 2972, 2932, 2879, 1579, 1491, 1332, 1238, 1200, 1169, 1089, 1014, 934 cm-1. 1H NMR (250 MHz, CDCl3): δ = 1.14 (t, J = 7.0 Hz, 3 H), 3.23 (q, J = 7.0 Hz, 4 H), 7.02 (d, J = 9.0 Hz, 2 H), 6.94-7.08 (m, 2 H), 7.21 (tt, J = 6.9 and 1.2 Hz, 1 H), 7.40 (m, 2 H), 7.75 (d, J = 9.0 Hz, 2 H). 13C NMR (62.5 MHz, CDCl3): δ = 14.2, 42.0, 117.6, 120.2, 124.8, 129.1, 130.1, 134.2, 155.3, 161.1. HRMS calcd for C16H19NO3S: 305.1086; found: 305.1100.
Good elemental analyses (at least three elements) were secured for 5a-c, 6a-d, and 7.