Polymer-Supported α-Aminonitriles: Alkylation Reactions and Carbonyl Compound Cleavage

Abstract

A polystyrene-supported α-aminonitrile has been prepared and its successive mono- and dialkylations achieved. Complementary procedures allow cleavage of the alkylated moities in either carbonyl or acetal form.

aminonitriles - alkylations - solid-phase synthesis - cleavage - carbanions

References and Notes

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19 Resin 1 was prepared according to the procedure described in the supporting information of the following paper: Schunk S. Enders D. J. Org. Chem.  2002,  67:  8034 

20

Preparation of Resin 2
Under argon, chloroacetonitrile (0.052 mL, 0.82 mmol) and Et₃N (0.115 mL, 0.82 mmol) were added to amine resin 1 (0.097 g, 0.062 mmol) pre-swollen in anhyd DMF (1 mL). The mixture was heated at 90 ˚C for 4 d. The resin was recovered by filtration then washed successively with DMF (20 mL), a mixture of DMF-H₂O (1:1, 20 mL), CH₂Cl₂ (20 mL), MeOH (20 mL), CH₂Cl₂ (20 mL), and MeOH (20 mL). The resin was finally dried over P₂O₅ under reduced pressure. HR-MAS ^¹H NMR (300 MHz, CDCl₃): δ = 3.4-3.6 (H2), 3.9-4.1 (H4 and H3). HR-MAS ^¹³C NMR (75 MHz, CDCl₃): δ = 41 (C2), 58 (C3 and C4), 115 (C1). Combustion analysis N: 1.58% (1.13 mmol g^-¹).

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23

General Alkylation
Under an atmosphere of argon, a solution of LDA [prepared from 1.6 M BuLi in hexane (5 equiv) and DIPA (5 equiv)] and optionally HMPA (20 equiv) in THF (4 mL) at -70 ˚C was added dropwise by cannula to a carefully stirred suspension of supported aminonitrile 2 or 5a (0.3 mmol) pre-swollen in anhyd THF (4 mL) and cooled to -70 ˚C. After
2 h, electrophile 4 (15 equiv) was added dropwise, and the mixture was stirred at -70 ˚C for a further 6 h. Saturated NH₄Cl solution (10 mL) was then added, and the mixture was allowed to warm to r.t. The resin was recovered by filtration and washed successively with H₂O (50 mL), a mixture of THF-H₂O (1:1, 50 mL), CH₂Cl₂ (50 mL), and MeOH (50 mL). The resin was finally dried under reduced pressure over P₂O₅ overnight.

24

Oxalic Acid Hydrolysis
Aminonitrile resin 5 or 10 (0.3 mmol) was swollen in THF (15 mL) at r.t., then a solution of 30% aq oxalic acid (15 mL) was added. The mixture was heated at reflux overnight, then cooled to r.t., then a mixture of ice-H₂O was added. The resin was removed by filtration and washed with H₂O
and CHCl₃. Liquid phases (filtrate and washings) were separated, and the aqueous phase was extracted once with CHCl₃. Combined organic extracts were dried over MgSO₄ and evaporated under reduced pressure to give the carbonyl compound 6 or 7. Product purity and identity (comparison with reference samples) was assessed by GC-MS.

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27

Copper Sulfate Methanolysis Procedure
Aminonitrile resin 5 (0.2 mmol) was swollen in a few drops of DMF at r.t., then a solution of CuSO₄˙5H₂O (2 equiv) in anhyd MeOH (4 mL) was added. The mixture was heated at reflux overnight, then cooled to r.t. The resin was removed by filtration and washed with pentane and CH₂Cl₂. Combined filtrate and washings were dried over MgSO₄, and evaporated under reduced pressure to give the dimethyl acetal 8. The reaction product was analyzed by GC-MS. Product purity and identity (comparison with reference samples) was assessed by GC-MS.