Synthesis of Benzothiadiazines, Benzothiadiazepines, and Benzothiadiazocines from Intramolecular Azide Reactions and Iodocyclisations

Abstract

N-Homoallyl-substituted (2-aminoaryl)sulfonamides undergo intramolecular iodocyclisation to furnish aziridine-fused 1,2,6-benzothiadiazocines. The identical aziridine-fused 1,2,6-benzothiadiazocines were also available from an intramolecular azide to alkene 1,3-diploar cycloaddition involving the corresponding N-homoallylic (2-azidoaryl)sulfonamides in boiling carbon tetrachloride. The use of boiling DMF as solvent for the same reaction gave pyrrolo-fused benzothiadiazines. Intramolecular azide-alkene cycloadditions also allowed access to aziridine-fused pyrrolobenzothiadiazepines and pyrrolobenzodiazepines.

Key words

aziridine - azide - benzodiazocine - benzodiazepine

References and Notes

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17

Typical Procedure for the Synthesis of Compounds 8a-c
To a stirred solution of the homoallylic 2-aminobenzene-sulfonamide 6a-c (0.15-0.30 g, 1.0 equiv) and NaHCO₃ (3.0 equiv) i n dry MeCN (10 mL) was added portionwise finely powdered iodine (3.0 equiv). The reaction mixture was stirred at r.t. until TLC showed no starting material (ca. 4 h) at which point the reaction mixture was treated with sat. aq Na₂S₂O₃ until decolourisation occurred. The resulting solution was extracted with CH₂Cl₂ (3 × 20 mL), and the combined organic extracts dried (MgSO₄), filtered, and concentrated by rotary evaporation. The crude product was purified by gravity column chromatography (SiO₂) using PE-EtOAc (3:2) as the eluent. Compound 8a was obtained single spot pure [R _f  = 0.3 (PE-EtOAc, 2:3)] as a yellow oil (0.161 g, 49% yield) from the N-(butenyl)-2-aminobenzenesulfonamide (6a, 0.320 g).
Analytical Data
^¹H NMR (400 MHz, CDCl₃): δ = 1.35 (3 H, s, Me), 1.51 (1 H, dd, J = 11.2, 8.4 Hz, CMeCH ₂CH₂NH), 2.02 (1 H, ddd,
J = 8.4, 5.9, 2.5 Hz, CMeCH ₂CH₂NH), 2.11 (1 H, s, aziridino CH), 2.33 (1 H, s, aziridino CH), 3.36 (1 H, m, CH₂CH ₂NH), 3.79 (1 H, ddd, J = 15.0, 7.5, 6.1 Hz, CH₂CH ₂NH), 5.32 (1 H, t, J = 6.1 Hz, SO₂NH), 6.85 (1 H, d, J = 7.9 Hz, ArH), 6.98 (1 H, dt, J = 8.4, 0.8 Hz, ArH), 7.35 (1 H, dt, J = 8.4, 1.4 Hz, ArH), 7.83 (1 H, dd, J = 7.9, 1.3 Hz, ArH). ^¹³C NMR (100 MHz, CDCl₃): δ = 20.2 (CH₃), 35.8 (CH₂), 39.2 (CH₂), 40.2 (CH₂), 43.9 (q), 121.7 (CH), 122.0 (CH), 128.6 (CH), 129.6 (q), 133.0 (CH), 147.8 (q). IR: ν_max = 3101 (br m), 2953 (m), 2896 (m), 1591 (m), 1472 (s), 1439 (m), 1333 (s), 1216 (s), 1158 (s), 866 (m) cm^-¹. HRMS (ES⁺): m/z calcd for C₁₁H₁₄N₂O₂S: 239.0849; found: 239.0845 (100%) [M + H]⁺.

18

Typical Procedure for the Synthesis of Compounds 11a-c
A solution of the N-(butenyl)-2-azidobenzenesulfonamide 9a-c (ca. 100 mg) in DMF (5 mL) was heated at reflux temperature until TLC showed no starting material (2-3 h). The mixture was cooled, the solvent removed by reduced pressure rotary evaporation, and the residue purified by flash silica column chromatography (PE-EtOAc = 3:2). As an example, pyrrolo-1,2,4-benzothiadiazine 11b (76 mg, 45%) was obtained from azidobenzenesulfonamide 9b (130 mg).
Analytical Data
^¹H NMR (400 MHz, CDCl₃): δ = 1.73 (3 H, s, CH₃), 1.78 (3 H, d, J = 7.2 Hz, CH₃), 1.88 (1 H, dd, J = 13.0, 10.2 Hz, CMeCHHCHMe), 2.21 (1 H, dd, J = 13.0, 7.1 Hz, CMeCHHCHMe), 2.41-2.48 (1 H, m, [(CH₂)₂CHMe], 3.23 (1 H, dd, J = 10.3, 7.0 Hz, NCHH), 3.58 (1 H, dd, J = 10.0, 7.0 Hz, NCHH), 4.56 (1 H, s, NH), 6.61 (1 H, d, J = 8.4 Hz, ArH), 6.76 (1 H, t, J = 8.0 Hz, ArH), 7.24 (1 H, td, J = 8.4, 1.3 Hz, ArH), 7.68 (1 H, dd, J = 8.0, 1.3 Hz, ArH). ^¹³C NMR (100 MHz, CDCl₃): δ = 18.6 (CH₃), 27.2 (CH₃), 28.3 (CH), 51.0 (CH₂), 57.9 (CH₂), 79.8 (q), 115.3 (CH), 117.5 (CH), 129.3 (CH), 133.2 (CH), 142.3 (q), 145.0 (q). IR (thin film): ν_max = 3366 (s), 2965 (s), 2932 (s), 1677 (m), 1605 (s), 1484 (s), 1453 (s), 1322 (s), 1157 (s), 751 (s) cm^-¹. HRMS (ES⁺): m/z calcd for C₁₂H₁₆N₂O₂S + H⁺: 253.1005; found: 253.1008 [M + H]⁺.

30

Analytical Data for Compound 16 (X = CO, R ^¹  = R ^²  = H)
^¹H NMR (400 MHz, CDCl₃): δ = 2.00 (1 H, d, J = 3.6 Hz, aziridine CH₂), 2.04-2.16 (3H, m, CH₂ + CHH), 2.18-2.26 (1 H, m, CHH), 2.53 (1 H, d, J = 4.3 Hz, aziridine CH₂), 2.78 (1 H, ddd, J = 9.5, 4.3, 3.6 Hz, aziridine CH), 3.34 (1 H, ddd, J = 9.5, 2.9, 1.6 Hz, pyrrolidine CH), 3.62-3.69 (1 H, m, NCH₂), 3.81-3.95 (1 H, m, NCH₂), 7.01 (1 H, dt, J = 7.9, 0.7 Hz, ArH), 7.11 (1 H, d, J = 8.1 Hz, ArH), 7.44-7.52 (1 H, m, ArH), 7.74 (1 H, d, J = 7.9 Hz, ArH). ^¹³C NMR (100 MHz, CDCl₃): δ = 23.1 (CH₂), 29.4 (CH₂), 32.7 (CH₂), 44.8 (CH), 46.1 (CH₂), 58.1 (CH), 122.0 (CH), 122.9 (CH), 126.8 (q), 129.7 (CH), 131.2 (CH), 145.6 (q), 150.3 (q). IR (thin film): ν_max = 3063 (m), 2979 (m), 1625 (s), 1456 (s), 1405 (s), 1039 (m), 922 (m), 766 (s), 730 (s), 704 (s) cm^-¹. HRMS (ESI⁺): m/z calcd for C₁₃H₁₄N₂O + H⁺: 215.1179; found: 215.1178 [M + H]⁺.