Selective Functionalization of Silyl-N-Cbz-1,3-Thiazolidines with Aldehydes to Homologated α-Hydroxy Thiazolidines and Fused Oxazolidinones

Abstract

N-Cbz-2-trimethylsilyl-1,3-thiazolidine can be easily functionalized under fluoride ion conditions with aldehydes as electrophiles. The reaction selectively affords new cyclo-fused oxazolidinones or homologated α-hydroxy thiazolidines depending on the temperature of the reaction and the nature of the aldehyde.

Key words

silyl thiazolidines - fluoride-ion catalysis - cyclization - bicyclic compounds - fused oxazolidinones

References and Notes

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15

Typical Procedure: A solution of thiazolidine (1, 50 mg, 0.17 mmol), benzaldehyde (2a, 36 mg, 0.34 mmol) and activated MS (4 Å, 300 mg) was stirred at r.t. in freshly distilled THF (3 mL) under an inert atmosphere. TBAF (68 mL of a 1 M THF solution, 0.07 mmol) was added dropwise (0.2 equiv every hour). The mixture was stirred at r.t. and progression of the reaction was monitored by TLC. The reaction was quenched with H₂O and the product was extracted into Et₂O (2 mL). The resulting organic layer was washed with brine, dried over Na₂SO₄ and the solvent evaporated under vacuum. Purification using column chromatography (hexane-EtOAc, 4:1) afforded 13 mg (34%) of anti-3a and 13 mg (34%) of syn-3a. anti-3a: ¹H NMR (200 MHz, CDCl₃): δ = 3.04-3.15 (m, 2 H), 4.42-4.53 (m, 2 H), 4.99 (d, J = 1.8 Hz, 1 H), 5.52 (d, J = 1.8 Hz, 1 H), 7.36-7.42 (m, 5 H); ¹³C NMR (50 MHz, CDCl₃): δ = 30.5, 40.5, 72.0, 79.9, 127.2, 127.4, 128.1, 138.3, 157.4; MS: m/z (%) = 221 (49) [M⁺], 130 (32), 115 (55), 91 (100), 87 (90), 77 (34). syn-3a: ¹H NMR (200 MHz, CDCl₃): δ = 2.90-3.01 (m, 2 H), 3.10-3.25 (m, 1 H), 4.36-4.44 (m, 1 H), 5.41 (d, J = 5.8 Hz, 1 H), 5.92 (d, J = 5.8 Hz, 1 H), 7.20-7.45 (m, 5 H). ¹³C NMR (50 MHz, CDCl₃): δ = 30.3, 41.5, 69.9, 81.2, 127.2, 127.6, 128.3, 138.6, 157.4. MS: m/z (%) = 221 (31) [M⁺], 130 (36), 115 (39), 91 (100), 87 (78), 77 (38).

16

Variable amounts of benzyloxytrimethylsilane were detected in the reactions affording cyclic compounds 3. However, we were unable to detect silylated derivatives of 5 even before work-up, either under TLC or GC/MS conditions.

17

Characterization of Compounds 3g and 5g: diastereomers were separated by preparative TLC (silica gel, hexane-EtOAc, 4:1). 7-(Thiophen-2-yl)tetrahydroxooxazolo[4,3- b ]thiazol-5-one ( 3g): (anti-3g): ¹H NMR (200 MHz, CDCl₃): δ = 2.95-3.10 (m, 2 H), 4.40-4.50 (m, 2 H), 5.14 (d, J = 1.6 Hz,1 H), 5.74 (d, J = 1.6 Hz, 1 H), 7.00-7.10 (m, 1 H), 7.14-7.20 (m, 1 H), 7.28-7.40 (m, 1 H); ¹³C NMR (50 MHz, CDCl₃): δ = 31.8, 49.4, 71.3, 78.1, 126.8, 127.0, 127.1, 146.1, 157.6; MS: m/z (%) = 227 (74) [M⁺], 183 (19), 136 (33), 128 (29), 127 (47) 115 (50), 97 (26), 91 (40), 87 (100), 60 (59). (syn-3g): ¹H NMR (200 MHz, CDCl₃): δ = 2.95-3.10 (m, 2 H), 4.40-4.50 (m, 2 H), 5.36 (d, J = 5.6 Hz, 1 H), 6.10 (d, J = 5.6 Hz, 1 H), 7.00-7.10 (m, 1 H), 7.14-7.20 (m, 1 H), 7.28-7.40 (m, 1 H); ¹³C NMR (50 MHz, CDCl₃): δ = 31.3, 49.7, 71.5, 77.8, 126.6, 126.8, 127.0, 145.6, 157.6; MS: m/z (%) = 227 (8) [M⁺], 149 (26), 111 (54), 97 (38), 91 (100), 71 (55). 1-[2-(Hydroxy(thiophen-2-yl)methyl]thiazolidin-3-yl)-2-phenylethanone ( 5g): (anti-5g): ¹H NMR (200 MHz, CDCl₃): δ = 2.50-2.70 (m, 1 H), 2.70-2.90 (m, 1 H), 3.20-3.50 (m, 1 H), 3.95-4.20 (m, 1 H), 5.15 (d, J = 6.6 Hz, 1 H), 5.19 (m, 2 H), 5.44 (d, J = 6.6 Hz, 1 H), 7.00-7.10 (m, 1 H), 7.14-7.30 (m, 2 H), 7.32-7.45 (m, 5 H); ¹³C NMR (50 MHz, CDCl₃): δ = 31.3, 49.4, 68.0, 71.5, 74.5, 125.7, 126.6, 127.0, 128.1, 128.3, 128.6, 135.0, 151.1. (syn-5g): ¹H NMR (200 MHz, CDCl₃): δ = 2.50-2.70 (m, 1 H), 2.70-2.90 (m, 1 H), 3.79-3.91 (m, 1 H), 4.20-4.35 (m, 1 H), 5.19 (m, 2 H), 5.29 (br s, 1 H), 5.52 (br s, 1 H), 7.00-7.10 (m, 1 H), 7.14-7.32 (m, 2 H), 7.33-7.46 (m, 5 H).

18

anti -Benzyl 2-[hydroxy(phenyl)methyl]thiazolidine-3-carboxylate (anti-5a): ¹H NMR (200 MHz,CDCl₃): δ = 2.38-2.60 (m, 1 H), 2.61-2.80 (m, 1 H), 3.10-3.40 (m, 1 H), 3.92-4.19 (m, 1 H), 4.87 (d, J = 6.6 Hz, 1 H), 5.16 (m, 2 H), 5.45 (d, J = 6.6 Hz, 1 H), 7.18-7.45 (m, 10 H); ¹³C NMR (50 MHz, CDCl₃): δ = 30. 5, 49.4, 68.0, 71.6, 79.0, 125.5, 127.3, 128.2, 128.4, 134.9, 136.0, 150.9.

19

A referee suggested that one equivalent of fluoride is necessary for total reaction with benzaldehydes substituted with an electron-withdrawing group because there may be an ineffective TMS transfer in these cases. In this event a classical nucleophilic reaction involving the complete desilylation by fluoride would operate.