Synthesis of S-Pixyl Derivatives for Mass Spectrometric Applications

Safraz Khan; Pablo L. Bernad; Vladimir A. Korshun; Edwin M. Southern; Mikhail S. Shchepinov

doi:10.1055/s-2005-872703

LETTER

Synthesis of S-Pixyl Derivatives for Mass Spectrometric Applications

Safraz Khan^a, Pablo L. Bernad^a, Vladimir A. Korshun^b, Edwin M. Southern^a, Mikhail S. Shchepinov*^a
^a Tridend Technologies (a Division of OGT) Hirsch Building, Begbroke Business & Science Park, Sandy Lane, Yarnton, Oxford, OX5 1PF, UK
Fax: +44(1865)841916; e-Mail: misha@tridend.com;
^b Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, Moscow, 117 997, Russia

Abstract

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Abstract

Synthesis of novel S-pixyls based on the thioxanthyl skeleton is described. Thioxanthone derivatives were prepared by a regioselective intramolecular Friedel-Crafts acylation reaction and converted into S-pixyl derivatives by Grignard synthesis. S-Pixyl carbocations stabilised by electron donating groups on the thioxanthyl backbone produced exceptional mass spectra under (MA)LDI conditions (laser desorption ionisation, both with and without matrix), and can be detected down to femtomol levels.

Key words

S-pixyls - regioselective Friedel-Crafts acylation - (MA)LDI analysis - functionalised thioxanthen-9-ones - 2-aroylpyrene

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References

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12

General Procedure for the Copper-Mediated Ullmann Reaction, Selected Compounds 9a and 20. To a solution of thiosalicylic acid (0.2 mol) in 300 mL of DMF was added aryl halide (0.2 mol), K₂CO₃ (0.2 mol) and Cu powder (0.2 equiv), the mixture was warmed to reflux. After 16-24 h the mixture was cooled to r.t., filtered and poured into 1 N HCl and then extracted with EtOAc (4 ×). The combined organic phases were then washed with H₂O (4 ×), and dried over Na₂SO₄, filtered and concentrated in vacuo. The product was dried under high vacuum and used with out further purification (78-95%).
Analytic data of 9b: ¹H NMR (200 MHz, DMSO-d ₆): δ = 8.30-7.50 (d, J = 9.2 Hz, 1 H), 7.50-7.35 (dd, J = 9.6 Hz, 1 H), 7.30-7.18 (t, J = 7.5 Hz, 1 H), 7.15-7.00 (m, 3 H), 6.85-6.74 (d, J = 9.0 Hz, 1 H), 3.8 (s, 3 H). ¹³C NMR (400 MHz, DMSO-d ₆): δ = 168.00, 160.99, 142.35, 134.16, 133.26, 131.79, 131.68, 128.51, 127.88, 125.59, 120.77, 115.98, 56.15. HRMS (ESI): m/z calcd for C₁₄H₁₂NaO₃S [M + Na⁺]: 283.0405; found: 283.0416.
Analytic data of 20: ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.50-8.30 (m, 8 H), 8.25-8.12 (t, J = 7.65 Hz, 1 H), 8.10-8.00 (d, J = 8.7 Hz, 1 H), 6.80-6.70 (d, J = 8.8 Hz, 1 H), 5.70-5.60 (d, J = 2.4 Hz, 1 H), 3.50-3.40 (br OH, 1 H), 3.35 (s, 3 H). ¹³C NMR (400 MHz, DMSO-d ₆): δ = 167.95, 162.98, 145.59, 135.73, 134.73, 134.04, 133.23, 131.49, 131.15, 130.22, 129.75, 128.12, 127.74, 127.12, 126.76, 126.44, 125.48, 125.18, 124.34, 119.95, 113.49, 109.61. HRMS (ESI): m/z calcd for C₂₄H₁₆NaO₃S [M + Na⁺]: 407.0718; found: 407.0717.

13

General Procedure for the Intramolecular Friedel-Crafts Acylation Reaction, Selected Compounds 10, 12, 13 and 21.Preparation of Acid Chlorides.
o-(Phenylthio)benzoic acid derivatives (0.1 mol), placed in a dry 250 mL round-bottom flask under a positive pressure of argon. Then, 100 mL of dry CH₂Cl₂ were added and the reaction cooled to 0 °C. A few drops of DMF were added followed by the dropwise addition of oxalyl chloride (1.5 equiv) with stirring. The reaction was stirred for 1 h or longer until the suspension had completely dissolved. The product was concentrated in vacuo and dried under high vacuum to give the acid chloride, which was used without further purification (90-100%).
Intramolecular Friedel-Crafts Acylation.
The acid chloride (0.1 mol) was placed in a dry 250 mL round-bottom flask under a positive pressure of argon. Then, 100 mL of dry CH₂Cl₂ were added and the reaction was stirred at r.t., AlCl₃ (1.5 equiv) was added slowly and the reaction was stirred for 1-2 h. The reaction was quenched with H₂O and extracted with CH₂Cl₂ (2 ×). The combined organic phases were washed with dilute NaHCO₃ and dried over Na₂SO₄, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel, hexane-EtOAc gradient elution to give the desired product (80-95%).
Analytic data of 10: ¹H NMR (400 MHz, CDCl₃): δ = 8.65-8.58 (d, J = 8.1 Hz, 1 H), 8.55-8.50 (d, J = 9.0 Hz, 1 H), 7.60-7.40 (m, 3 H), 7.05-6.97 (d, J = 11.6 Hz, 1 H), 6.90 (d, J = 2.4 Hz, 1 H), 3.90 (s, 3 H). ¹³C NMR (400 MHz, CDCl₃): δ = 179.02, 162.48, 139.54, 136.89, 132.88, 131.92, 129.69, 129.27, 126.28, 125.71, 123.02, 115.08, 107.79, 55.66. HRMS (ESI): m/z calcd for C₁₄H₁₁NaO₂S [M + H]: 243.0480; found: 243.0473.
Analytic data of 12: ¹H NMR (400 MHz, CDCl₃): δ = 8.65-8.60 (d, J = 8.3 Hz, 1 H), 8.02 (d, J = 2.8 Hz, 1 H), 7.60-7.45 (m, 4 H), 7.30-7.20 (d, J = 8.9 Hz, 1 H), 3.95 (s, 3 H). ¹³C NMR (400 MHz, CDCl₃): δ = 179.65, 158.35, 137.49, 131.99, 130.19, 129.84, 129.14, 128.55, 127.27, 126.06, 125.97, 122.72, 110.29, 55.67. HRMS (ESI): m/z calcd for C₁₄H₁₁NaO₂S [M + H]: 243.0480; found: 243.0469.
Analytic data of 13: ¹H NMR (400 MHz, CDCl₃): δ = 8.60-8.50 (d, J = 4.5 Hz, 1 H), 7.05-6.98 (d, J = 5.1 Hz, 1 H), 6.90 (s, 1 H), 3.90 (s, 3 H). ¹³C NMR (400 MHz, CDCl₃): δ = 178.30, 162.21, 139.12, 131.75, 123.03, 114.81, 107.98, 55.64. HRMS (ESI): m/z calcd for C₁₅H₁₃NaO₃S [M + H]: 273.0585; found: 273.0576.
Analytic data of 21: ¹H NMR (200 MHz, CDCl₃): δ = 8.90 (s, 1 H), 8.70-8.60 (d, J = 8.9 Hz, 1 H), 8.59-8.48 (d, J = 9.3 Hz, 1 H), 8.35-7.90 (m, 6 H), 7.24-7.00 (m, 2 H), 4 (s, 3 H). ¹³C NMR (500 MHz, CDCl₃): δ = 180.14, 162.71, 138.72, 132.18, 131.98, 131.73, 131.01, 129.15, 128.44, 128.37, 127.79, 127.56, 126.79, 126.50, 126.21, 125.87, 125.78, 125.49, 124.20, 122.58, 122, 115.33, 108.53, 55.84. HRMS (ESI): m/z calcd for C₂₄H₁₅O₂S [M + H]: 267.0793; found: 267.0797.