Organocatalytic Asymmetric Hetero-Diels-Alder Reaction of Oxindoles under High Pressure [¹]

Abstract

A general and efficient protocol for the high-pressure-promoted asymmetric hetero-Diels-Alder reactions of oxindoles has been developed. These reactions can be realized by using chiral thiourea-derived organocatalysts, and the desired adducts are obtained in good to high yields with good to moderate enantioselectivity.

asymmetric hetero-Diels-Alder reaction - oxindoles - chiral thiourea catalyst - high pressure

References and Notes

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5a

see Ref. 3b.

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Recently, a new strategy using homologous cycloaddition was disclosed:

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7 Mori K. Maddaluno J. Nakano K. Ichikawa Y. Kotsuki H. Synlett  2009,  2346 

8

Most of these catalysts are known. The new catalysts, 1a, 1b, 1d, 1f, and 1g, were simply prepared by condensation of 3,5-bis(trifluoromethyl)phenylisothiocyanate with chiral amine precursors. 1a: mp 130.5-133 ˚C (hexane-CH₂Cl₂), [α]_D ^²6
-16.4 (c = 1.0, CHCl₃); 1b: mp 48-50 ˚C (hexane-CH₂Cl₂), [α]_D ^²0 -93.7 (c = 1.0, CHCl₃); 1d: mp 129.0-132.0 ˚C (hexane-CH₂Cl₂), [α]_D ^²¹ +48.8 (c = 0.90, CHCl₃); 1f: mp 151-153 ˚C (hexane-CH₂Cl₂), [α]_D ^²6 +3.96 (c = 0.15, CHCl₃); 1g: mp 149.5-151 ˚C (hexane-CH₂Cl₂), [α]_D ^²6 +10.3 (c = 0.16, CHCl₃).

9

General Procedure: A mixture of diene 2 (1.0 mmol) and ketone 3 (0.25 mmol) in the presence of 1a (0.1 mmol) in toluene or CH₂Cl₂ (ca. 2.5 mL) was placed in a Teflon reaction vessel, and the mixture was allowed to react at 1.0 GPa and r.t. for 12 h. After the pressure was released, the mixture was concentrated and purified by silica gel column chromatography (elution with hexane-Et₂O) to afford the pure adduct 4.

10

At lower pressures, the yield and enantioselectivity were both decreased for the reaction of 2a with 3a using 30 mol% of 1e in CH₂Cl₂: at 0.6 GPa, r.t., 4.5 d, 31% yield, exo-4a (49% ee, R), endo-4a (62% ee, R).

11

Not optimized.

12 Lattanzi A. Synlett  2007,  2106 

13 The observed low diastereoselectivities can be ascribed to the weak secondary π-orbital interactions; however, it is likewise difficult to rule out stepwise cyclization pathways. See: Danishefsky SJ. Larson E. Askin D. Kato N.
J. Am. Chem. Soc.  1985,  107:  1246 

14

In general, the exo-adducts were less polar than the endo-adducts. TLC data (hexane-EtOAc, 4:1); exo-4a: R _f 0.42 and endo-4a: R _f 0.34.
Compound exo-4a: colorless oil. FTIR (neat): 1777, 1733, 1606, 1478, 1467 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.65 (s, 9 H), 2.26 (dd, J = 17.6, 6.0 Hz, 1 H), 2.71 (ddd, J = 17.6, 6.0, 2.0 Hz, 1 H), 3.25 (s, 3 H), 5.34 (d, J = 2.0 Hz, 1 H), 6.00-6.04 (m, 1 H), 6.15-6.20 (m, 1 H), 7.12 (t, J = 8.0 Hz, 1 H), 7.34 (m, 1 H), 7.70 (d, J = 7.6 Hz, 1 H), 7.86 (d,
J = 8.0 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 28.1 (3 ×), 31.2, 55.2, 73.8, 84.7, 95.7, 114.8, 124.3, 125.2, 125.9, 126.1, 129.4, 129.7, 139.0, 149.1, 173.9.
Compound endo-4a: colorless oil. FTIR (neat): 1780, 1731, 1606, 1478, 1467 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.63 (s, 9 H), 2.32-2.37 (m, 1 H), 2.68-2.73 (m, 1 H), 3.43 (s, 3 H), 5.25 (s, 1 H), 5.98-6.02 (m, 1 H), 6.19-6.23 (m, 1 H), 7.17 (t, J = 8.0 Hz, 1 H), 7.39 (t, J = 8.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 28.1 (3 ×), 30.0, 55.2, 74.1, 84.5, 96.0, 115.3, 123.9, 124.6, 126.2, 126.4, 128.9, 130.2, 139.4, 149.4, 172.5.

15

Chiral HPLC analysis results: Chiralpak AD-H column, 0.46 × 25 cm, hexane-2-propanol (80:20), flow rate: 1.0 cm^³/min, λ = 254 nm; t _R (S-isomer) = 7.8 min; t _R (R-isomer) = 9.5 min. See also ref. 4i.