[1,2]-Wittig Rearrangement of (Benzyloxy)acetamides

 

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Abstract

[1,2]-Wittig rearrangement of (benzyloxy)acetamides can lead to substituted α-hydroxyamides in good yields and good ­diastereoselectivity.

References and Notes

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Representative Procedure for the Preparation of (Benzyloxy)acetamides 3
To a solution of alcohol 1 (1.1 mmol) and bromoacetyl-pyrrolidine (2, 1 mmol) in toluene (15 mL), at r.t., was added n-Bu₄NHSO₄ (0.2 mmol) and a 35% aq NaOH solution (15 mL). The mixture was then stirred vigorously at r.t., and the reaction was monitored by TLC. After 3-4 h, H₂O (20 mL) and Et₂O (20 mL) were added at 0 ˚C. The aqueous layer was extracted with Et₂O (5 × 30 mL), and the combined organic layers were washed with sat. aq NH₄Cl soln (50 mL), dried over MgSO₄, and concentrated in vacuo. The crude residue was purified on SiO₂ (PE-EtOAc) to afford(benzyloxy)acetamide 3. Amide 3k with R^¹ = (CH₂)₂OTBS (Table  [²] , entry 11) was obtained from amide 3f (Table  [¹] , entry 6) by using the following sequence: 1) O₃, MeOH, -78 ˚C then Ph₃P, CH₂Cl₂, -78 ˚C to r.t.; 2) NaBH₄, EtOH, 0 ˚C; 3) TBSCl, Et₃N, DMAP, CH₂Cl₂, 0 ˚C (60% over 3 steps).

Representative Procedure for the [1,2]-Wittig Rearrangement of (Benzyloxy)acetamides 3
To a solution of(benzyloxy)acetamide 3 (0.2 mmol) in THF (3 mL), at -30 ˚C, was added dropwise a 1 M solution of LiHMDS in THF (2.5 equiv). The reaction mixture was then warmed to 0 ˚C over 2-3 h, before being hydrolyzed with sat. aq NH₄Cl soln (10 mL). The aqueous layer was then extracted with Et₂O (3 × 20 mL). The combined organic layers were dried over MgSO₄, and concentrated in vacuo. The crude residue was purified on SiO₂ (PE-EtOAc) to afford α-hydroxyamide 4.

Similarities in term of chemical shift between the different hydroxyamides 4 were particularly relevant for the proton at the α-position of the amide, for which δ_major < δ_minor in all cases.

In all cases ^³ J _major > ^³ J _minor except for hydroxyamide 4i (Table  [²] , entry 9). For compound 4i, ^³ J _major = 4.3 Hz and ^³ J _minor = 5.0 Hz. Therefore, the syn stereochemistry remained ambiguous in this latter case.