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DOI: 10.1055/sos-SD-025-00326

Eckhardt, M.Science of Synthesis, (200725493.

Electrophilic α-amination of aldehydes with azodicarboxylates, mediated by D- or L-proline as a chiral catalyst, is an expedient approach to enantiomerically highly enriched 2-aminoaldehydes (Scheme 25).[‌113‌‌115‌] The reaction is operationally simple, uses readily available and inexpensive starting materials, can be efficiently performed on a multigram scale, and employs a nontoxic catalyst that is widely available in both enantiomeric forms. The α-amination is performed by mixing all the components in one pot, circumventing formation of an enol or an enolate, or an explicit derivatization of the aldehyde, e.g. by converting it into an imine, etc., because of the formation of an enamine in situ from the aldehyde and proline. Typically, 1.5 equivalents of the aldehyde is used with respect to the azodicarboxylate, in acetonitrile or dichloromethane at 0°C to room temperature. Other solvents, or solventless conditions, can be employed without affecting either the stereoselectivity or the yield, the solventless approach being both environmentally friendly and economical. Typically 10mol% of proline is used, but the transformation proceeds nearly as well with catalyst loadings as low as 2mol%, although extended reaction times are then necessary. In either event, the product should be isolated or further elaborated in situ as soon as the solution loses its yellow hue (this indicates complete consumption of the azodicarboxylate) to prevent racemization (or epimerization, as the case may be). Various azodicarboxylates, containing di-tert-butyl, dibenzyl, or diethyl groups, exhibit similar efficiency with respect to yield and enantioselectivity, but acidic conditions cleave tert-butoxycarbonyl residues and hydrogenolytic conditions remove benzyl groups. The NN bond of the initial adducts can be cleaved concurrently or in a separate step to furnish the free α-amino group. The mild reaction conditions allow to α-aminate a broad range of α-monosubstituted aldehydes and a number of α,α-disubstituted aldehydes as well.[‌117‌] The reaction of the aldehyde with the azodicarboxylate shows unusual kinetic behavior, similar to that observed during the 2-aminoxylation of aldehydes (i.e., an increasing reaction rate and an amplification of product enantioselectivity as the reaction proceeds).[‌57‌,‌116‌] The 2-aminoaldehydes 63 are usually not isolated due to the lability of the α-stereogenic carbon atom. Instead, the aminated product is further derivatized in situ, for example by reduction (or oxidation) to deliver the configurationally and chemically more stable α-aminated alcohols (or α-aminated carboxylic acids). Indeed, most of the yields and enantioselectivities compiled in Scheme 25 refer to the corresponding alcohols 64 or oxazolidinones 65 that are obtained after reduction with sodium borohydride, or reduction and subsequent base-induced cyclization.

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Meeeeeeeeee 88

M8 M8 M8 Meeeeeeee Meeeeeeeee ee (%) Meeee (%) Mee
Me M Mee MeMM, 8°M ee ee >88 88e [‌888‌]
Me M MM8Me MM8Me8, ee 88 88e [‌888‌]
Me M Mee MeMM, 8°M ee ee 88 88e [‌888‌]
eMe M Mee MeMM, 8°M ee ee 88 88e [‌888‌]
eMe M MM8Me MM8Me8, ee 88 88e [‌888‌]
e-Me M MM8Me MM8Me8, ee 88 88e [‌888‌]
MM8MM=MM8 M MM8Me MM8Me8, ee 88 88e [‌888‌]
Me M Mee MeMM, 8°M ee ee >88 88e [‌888‌]
Me M MM8Me MM8Me8, ee 88 88e [‌888‌]
Me Me MM8Me MM8Me8, ee 88 88e [‌888‌]
Me Me MM8Me MM8Me8, ee 88 88e [‌888‌]
8-eeeeeeee Me MM8Me MM8Me8, ee 88 88e [‌888‌]
8-MeMM8M8 Me MM8Me MM8Me8, ee 88 88e [‌888‌]

e Meeeeeee ee eee eeeeeee 88, eeeee eeeeeeeee.

e Meeeeeee ee eee eeeeeeeeeeeee 88, eeeee eeeeeeeee eee eeeeeeeeeee.

e Meeeeeee ee eee eeeeeeee 88.

Meeeeeeeeeee Meeeeeeee

Meeeeeee 8-[(M)-8-(Meeeeeeeeeeee)-8-eeeeeeeeeeee]eeeeeeeee-8,8-eeeeeeeeeeeee (88, M8=eMe; M8=M; M8=Mee); Meeeeee Meeeeeeee:[‌888‌]

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