Asymmetric Synthesis of Sulindac by Iron-Catalyzed Sulfoxidation

Abstract

An iron-catalyzed asymmetric sulfide oxidation is the key step in the synthesis of the non-steroidal anti-inflammatory drug Sulindac. Both enantiomers of the chiral product can be prepared with 92% ee in good yield.

asymmetric catalysis - chiral sulfoxides - iron catalyst - oxidation - Sulindac

References

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2

Review on biologically active sulfoxides: Legros, J.; Dehli, J. R.; Bolm, C. submitted for publication.

Reviews on asymmetric sulfoxidation:

3a Kagan HB. Luukas T. In Transition Metals for Organic Synthesis, Beller M., Bolm C.   2nd ed.:  Wiley-VCH; Weinheim: 2004.  p.in press 

3b Bolm C. Muñiz K. Hildebrand JP. In Comprehensive Asymmetric Catalysis   Jacobsen EN. Pfaltz A. Yamamoto H. Springer-Verlag; Berlin: 1999.  p.697 

3c Kagan HB. In Catalytic Asymmetric Synthesis   2nd ed.:  Ojima I. Wiley-VCH; New York: 2000.  p.327 

3d For a recent review on chiral sulfoxides, see: Fernández I. Khiar N. Chem. Rev.  2003,  103:  3651 

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4b Legros J. Bolm C. Angew. Chem. Int. Ed.  2004,  43:  4225 

5 Buschmann H. Christoph T. In Analgesics   Buschmann H. Christoph T. Friderichs E. Maul C. Sundermann B. Wiley-VCH; Weinheim: 2002.  p.106 ; and references cited therein

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8 Maguire AR. Papot S. Ford A. Touhey S. O’Connor R. Clynes M. Synlett  2001,  41 

9

In their paper (ref. [8] ) Maguire et al. also describe an unsuccessful attempt to use the vanadium-catalyzed sulfide oxidation reported by Bolm et al. (ref. 10a-c) in the preparation of Sulindac. It should be noted, however, that this result was achieved with an inappropriately substituted Schiff base ligand.

Schiff bases of this type have also been used in vanadium-catalyzed asymmetric sulfoxidations, see:

10a Bolm C. Bienewald F. Angew. Chem., Int. Ed. Engl.  1995,  34:  2640 

10b Bolm C. Schlingloff G. Bienewald F. J. Mol. Catal. A: Chem.  1997,  117:  347 

10c Bolm C. Bienewald F. Synlett  1998,  1327 

10d Pelotier B. Anson MS. Campbell IB. Macdonald SJF. Priem G. Jackson RFW. Synlett  2002,  1055 

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11

Recently (July 7, 2004 at ISOCS-XXI), Naso reported on an enantioselective synthesis of Sulindac using catalytic amounts of a chiral titanium complex. In this protocol the product is obtained with 77-90% ee.

12 Brunel JM. Diter P. Duetsch M. Kagan HB. J. Org. Chem.  1995,  60:  8086 

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15

Experimental Procedure for the Synthesis of ( S )-(-)-6-Fluoro-3-(4-methanesulfinyl-benzyl)-2-methyl-1 H -indene ( 3): Fe(acac)₃ (7.1 mg, 0.02 mmol) and (S)-4 (18.9 mg, 0.04 mmol) were dissolved in CH₂Cl₂ (0.7 mL), and the clear red solution was stirred until it turned clear brown (15 min). This solution was then transferred into a 10 mL flask containing a suspension of 4-methoxybenzoic acid (5a, 1.5 mg, 0.01 mmol) in CH₂Cl₂ (0.5 mL). The resulting mixture was stirred for 10 min. A solution of sulfide 2 (284 mg, 1.00 mmol) in CH₂Cl₂ (0.8 mL) was then added to the previous solution, followed by dropwise addition of aq H₂O₂ (35%; 1.20 mmol). The flask was then capped and the reaction mixture slowly stirred at r.t. (approximately 150 rpm). After 16 h, the aqueous layer was separated, the organic layer was dried (MgSO₄), filtered, and the solvent was removed in vacuo. Purification by flash chromatography on silica gel (pentane-Et₂O 1:2, then EtOAc) led to (S)-3 as a white solid (213 mg, 71% yield, 92% ee). [α]_D ²⁵ -70.4 (c 1.0, CHCl₃); mp 101-102 °C. IR (KBr): ν = 1038 (S-O) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.13 (s, 3 H, CH₃), 2.69 (s, 3 H, SOCH₃), 3.37 (s, 2 H, CH₂), 3.91 (s, 2 H, CH₂), 6.82-6.95 (m, 2 H), 7.09 (dd, J = 8.6, 2.3 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.2 (CH₃), 31.1 (CH₂), 42.6 (d, ⁴ J _CF = 2.3 Hz, CH₂), 43.9 (CH₃), 110.9 (d, ² J _CF = 23.7 Hz, CH), 112.5 (d, ² J _CF = 22.1 Hz, CH), 118.7 (d, ³ J _CF = 8.4 Hz, CH), 123.6 (CH), 129.1 (CH), 133.6 (C), 139.9 (d, ⁴ J _CF = 3.8 Hz, C), 141.7 (C), 143.0 (C), 143.1 (C), 144.1 (d, ³ J _CF = 8.4 Hz, C), 160.7 (d, ¹ J _CF = 241.0 Hz, C) ppm. MS (EI/DIP): m/z (%) = 301 (16) [M⁺ + H], 300(70) [M⁺], 285 (11), 283 (30), 236 (12), 153 (26), 148 (11), 147 (100), 146 (20), 138 (13), 137 (34), 107 (18). HPLC conditions (Chiralpak AS column; λ = 254 nm; Temp = 20 °C; flow rate = 0.5 mL/min; heptane-i-PrOH, 7:3): t _R R = 59.8 min, t _R S = 75.0 min.

16 For a recent mechanistic study on iron-catalyzed epoxidations with combinations of acetic acid and hydrogen peroxide, see: Fujita M. Que L. Adv. Synth. Catal.  2004,  346:  190 

17

Attempts to perform the oxidation of Sulindac sulfide gave unsatisfying results, presumable due to the presence of the carboxylic moiety in the molecule. For the effect of an excess of acid, see ref. 4b.