A Straightforward Route to Piloty’s Acid Derivatives: A Class of Potential Nitroxyl-Generating Prodrugs

Abstract

A series of Piloty’s acid derivatives were easily prepared under mild and neutral conditions. The ease of isolation of the final product offers a marked advantage over well-known procedures. This methodology is particularly attractive as it cleanly provided low molecular weight aliphatic sulfohydroxamic acids, which are very interesting for their tendency to generate HNO under physiological conditions.

Key words

Piloty’s acid - NO - HNO - MgO - sulfohydroxamic acids

References and Notes

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15

During the recrystallization of benzenesulfohydroxamic acid previously prepared via a classical sulfonylation procedure Engel et al. (ref. 14b) have isolated and characterized several side products such as, for example: PhSO₃ ^- + H₃NNHSO₂Ph and PhSH (accounted for the reduction of PhSO₂Cl by NH₂OH).

18

Low molecular weight aliphatic sulfohydroxamic acids are the most important compounds for their tendency to generate HNO under physiological condition (at about pH 7, see Scheme  [¹] ).

24

The structure of 2a was verified by ^¹H NMR and ^¹³C NMR and mass spectroscopy.

25

General Procedure for the Sulfonylation of Hydroxylamine in the Presence of MgO; N -Hydroxy-2-methylbenzenesulfonamide (2b): Hydroxylamine hydrochloride (0.72 g, 10 mmol) in MeOH-H₂O (3:2, 5 mL) was treated with MgO (0.34 g, 8.6 mmol), then a solution of o-toluenesulfonyl chloride (1a; 0.8 g, 4.3 mmol) in THF (30 mL), and MgO (0.17 g, 4.3 mmol) were added. The reaction was vigorously stirred at r.t. until the sulfonyl chloride had completely disappeared (TLC: EtOAc-hexane, 1:1; 2 h). Then, the mixture was filtered first through a pad of Celite, and then on a short plug of silica gel. The clear filtrate was dried over MgSO₄ and evaporated to dryness to give the resulting N-hydroxysulfonamide 2b (0.59 g, 74%) as a crystalline white solid (96% purity); mp 178-180 ˚C. ^¹H NMR (CDCl₃): δ = 7.93 (d, J = 8.0 Hz, 1 H), 7.75 (br s, 1 H), 7.42 (t, J = 7.3 Hz, 1 H), 7.27 (t, J = 7.5 Hz, 2 H), 2.62 (s, 3 H). ^¹³C NMR (CDCl₃): δ = 138.3, 134.8, 133.1, 132.3, 130.7, 125.9, 20.5. HRMS (ESI): m/z [M + H⁺] calcd for C₇H₁₀NO₃S: 188.0381; found: 188.0377. Anal. Calcd for C₇H₉NO₃S: C, 44.91; H, 4.85; N, 7.48. Found: C, 44.83; H, 4.71; N, 7.57.
4- tert -Butyl- N -hydroxybenzenesulfonamide (2c): According to the procedure previously described for 2b, the sulfohydroxamic acid 2c was isolated as a white waxy solid in 77% yield (98% purity). ^¹H NMR (DMSO): δ = 9.53 (s, 1 H), 7.52 (d, J = 8.5 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 2 H), 1.24 (s, 9 H). ^¹³C NMR (DMSO): δ = 156.4, 134.7, 125.9, 125.5, 35.1, 31.3. HRMS (ESI): m/z [M + H⁺] calcd for C₁₀H₁₆NO₃S: 230.0851; found: 230.0857. Anal. Calcd for C₁₀H₁₅NO₃S: C, 52.38; H, 6.59; N, 6.11. Found: C, 52.44; H, 6.39; N, 6.01.
N -Hydroxy-2,4,6-triisopropylbenzenesulfonamide (2d): According to the procedure previously described for 2b, the sulfohydroxamic acid 2d was isolated as a crystalline white solid in 90% yield (96% purity); mp 212-213 ˚C (dec.). ^¹H NMR (DMSO): δ = 7.51 (br s, 2 H), 6.92 (s, 2 H), 4.53 (m, 2 H), 2.75 (m, 1 H), 1.13 (d, J = 6.9 Hz, 6 H), 1.07 (d, J = 6.8 Hz, 12 H). ^¹³C NMR (DMSO): δ = 147.4, 146.9, 141.8, 121.5, 33.4, 28.2, 24.9, 23.9. HRMS (ESI): m/z [M + H⁺] calcd for C₁₅H₂₆NO₃S: 300.1633; found: 300.1626. Anal. Calcd for C₁₅H₂₅NO₃S: C, 60.17; H, 8.42; N, 4.68. Found: C, 60.23; H, 8.49; N, 4.45.
N -Hydroxy-2,6-dimethoxybenzenesulfonamide (2e): According to the procedure previously described for 2b, the sulfohydroxamic acid 2e was isolated as a crystalline white solid in 95% yield (97% purity); mp 158-160 ˚C. ^¹H NMR (DMSO): δ = 8.59 (d, J = 3.5 Hz, 1 H), 7.96 (d, J = 3.5 Hz, 1 H), 6.82 (d, J = 8.7 Hz, 1 H), 5.83 (m, 2 H), 3.02 (d, J = 6.6 Hz, 6 H). ^¹³C NMR (DMSO): δ = 164.8, 158.3, 132.9, 116.4, 105.2, 56.2, 55.8. HRMS (ESI): m/z [M + H⁺] calcd for C₈H₁₂NO₅S: 234.0436; found: 234.0430. Anal. Calcd for C₈H₁₁NO₅S: C, 41.20; H, 4.75; N, 6.01. Found: C, 41.31; H, 4.70; N, 6.12.
N -Hydroxythiophene-2-sulfonamide (2f): According to the procedure previously described for 2b, the sulfo-hydroxamic acid 2f was isolated as a waxy solid in 96% yield (97% purity). ^¹H NMR (CDCl₃): δ = 7.75 (m, 1 H), 7.71 (m, 1 H), 7.35 (br s, 2 H), 7.16 (m, 1 H). ^¹³C NMR (CDCl₃): δ = 134.5, 133.9, 127.5, 116.5. HRMS (ESI): m/z [M + H⁺] calcd for C₄H₆NO₃S₂: 179.9789; found: 179.9793. Anal. Calcd for C₄H₅NO₃S₂: C, 26.81; H, 2.81; N, 7.82. Found: C, 26.74; H, 2.90; N, 7.74.
N -Hydroxy-2-nitrobenzenesulfonamide (2g): According to the procedure previously described for 2a, the sulfo-hydroxamic acid 2g was isolated as a crystalline yellow solid in 97% yield (99% purity); mp 154-157 ˚C. ^¹H NMR (DMSO): δ = 7.83 (d, J = 7.8 Hz, 1 H), 7.55 (m, 3 H). ^¹³C NMR (DMSO): δ = 130.7, 130.0, 129.1, 122.4. HRMS (ESI): m/z [M + H⁺] calcd for C₆H₇N₂O₅S: 219.0076; found: 219.0065. Anal. Calcd for C₆H₆N₂O₅S: C, 33.03; H, 2.77; N, 12.84. Found: C, 32.91; H, 2.81; N, 12.92.
4- tert -Butyl- N -methoxy- N -methylbenezenesulfonamide (2j): According to the procedure previously described for 2b, the sulfohydroxamic acid 2j was isolated as a crystalline white solid in 97% yield (99% purity); mp 112-114 ˚C. ^¹H NMR (CDCl₃): δ = 7.80 (d, J = 8.3 Hz, 2 H), 7.57 (d, J = 8.3 Hz, 2 H), 3.82 (s, 3 H), 2.79 (s, 3 H), 1.36 (s, 9 H). ^¹³C NMR (CDCl₃): δ = 157.6, 129.5, 129.2, 125.8, 63.7, 39.2, 35.2, 31.0. HRMS (ESI): m/z calcd for C₁₂H₁₉NO₃S: 257.1086; found: 257.1081. Anal. Calcd for C₁₂H₁₉NO₃S: C, 56.01; H, 7.44; N, 5.44. Found: C, 55.89; H, 7.48; N, 5.37.
(7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)- N -hydroxymethanesulfonamide (2o): According to the procedure previously described for 2b, the sulfohydroxamic acid 2o was isolated as a crystalline white solid in 98% yield (98% purity); mp 122-124 ˚C; [α]^²0 _D +27.89 (c = 0.384, MeOH). ^¹H NMR (DMSO): δ = 9.65 (s, 1 H), 9.05 (s, 1 H), 2.96 (d, J = 14.8 Hz, 1 H), 2.49 (m, 1 H), 2.32 (m, 2 H), 2.05 (t, J = 4.7 Hz, 1 H), 1.92 (m, 2 H), 1.43 (m, 2 H), 1.02 (s, 3 H), 0.80 (s, 3 H). ^¹³C NMR (DMSO): δ = 185.76, 176.39, 59.40, 49.44, 45.45, 43.07, 42.75, 26.99, 26.88, 19.88, 19.3. HRMS (ESI): m/z calcd for C₁₀H₁₇NO₄: 247.0878; found: 247.0871. Anal. Calcd for C₁₀H₁₇NO₄S: C, 48.57; H, 6.93; N, 5.66. Found: C, 48.52; H, 6.87; N, 5.71.