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Synlett 2009(13): 2149-2153  
DOI: 10.1055/s-0029-1217565
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Andrea Porcheddu*, Lidia De Luca, Giampaolo Giacomelli
Dipartimento di Chimica, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari, Italy
Fax: +39(079)212069; e-Mail: anpo@uniss.it;
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Publication History

Received 22 April 2009
Publication Date:
15 July 2009 (online)

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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

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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.