Synlett 2010(19): 2913-2917  
DOI: 10.1055/s-0030-1259032
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Virginie Beaufort-Droala,b, Elisabeth Pereiraa,b, Fabrice Vergnec, David J. Aitken*a,d
a Clermont Université, Université Blaise Pascal, Laboratoire SEESIB, BP 10448, 63000 Clermont-Ferrand, France
b CNRS, UMR 6504, SEESIB, 24 Avenue des Landais, 63177 Aubière Cedex, France
c Sanofi-Aventis, 13 Quai Jules Guesde, BP 14, 94403 Vitry-sur-Seine Cedex, France
d Université Paris-Sud, ICMMO, CNRS-UMR 8182, Bât. 420, 15 Rue Georges Clemenceau, 91405 Orsay Cedex, France
Fax: +33(1)69156278; e-Mail: [email protected];
Further Information

Publication History

Received 23 September 2010
Publication Date:
10 November 2010 (online)

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.

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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).

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.

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.