Control of Transient Aluminum–Aminals for Masking and Unmasking Reactive Carbonyl Groups

Abstract

A new reagent, the dimethylaluminum N,O-dimethylhydroxylamine complex, is effective at masking reactive carbonyl groups in situ from nucleophilic addition. This reagent allows chemoselective addition of reducing reagents, Grignard reagents, organolithiums, Wittig reagents, and enolates into substrates with multiple carbonyl groups. Moreover, the trapped carbonyl group, a stable aminal, can be unmasked in situ for additional synthetic manipulations.

<i>In Situ</i> Protection Methodology in Carbonyl Chemistry

“…Equation 1 of Chart 13 shows their strategy, and as optimization of conditions addition of i-PrMgCl before adding nucleophile gave the best result 18,19) (Chart 13, Eq. 2).…”

Chemoselective Reduction and Alkylation of Carbonyl Functions Using Phosphonium Salts as an <i>in Situ</i> Protecting Groups

“…There are several reports of such transformations using in situ protection methods, in which the more reactive carbonyl group is protected during the transformation of the less reactive carbonyl group, and then reformed during workup. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Additionally, there are several reports for reversing the reactivities of carbonyl functions in chemoselective catalytic reduction by using transition metals. 21,22) However, most of the reported methods have drawbacks, such as narrow substrate scopes, the need for strict stoichiometric control, and the use of expensive reagents; therefore, although they simplify the preparative sequences, these methods have rarely been used in synthetic organic chemistry.…”

Effect of Substituents and Stability of Transient Aluminum–Aminals­ in the Presence of Nucleophiles

“…Specifically, we aimed to create a discrete aluminum reagent that would form the aminal in one step. 13 In order to achieve this objective, adding n -BuLi or i -PrMgCl to HN(OMe)Me•HCl succeeded in consuming the acidic proton of the hydrochloride and then subsequent treatment with Me 3 Al formed the requisite aluminum–amide complex. Substrates 1–3 , each with two distinct carbonyl groups, participated in this more efficient method and provided access to products 4–11 upon addition of organolithiums, Grignard reagents, reducing reagents, Wittig reagents, and enolate anions (Table 2).…”

“…Compounds 4–6 8 and 7–11 13 have been previously described. Syntheses of amines 15a , 17 15b , 18 15c , 19 15d , 20 and 17 16 were conducted according to the literature methods.…”