Direct a-amination

A mechanistic rationalization of the unusual product-acceleration behavior observed for the proline-catalyzed a-amination of linear aldehydes (19a, = H) 

Recently, DFT calculations showed that in this proline-catalyzed process an enamine carboxylic acid mediated transition model rules under base-free conditions, giving the expected product stereochemistry, while an enamine carboxylate pathway operates in the presence of base, leading to the opposite enantiomer [23]. 

Complex molecules have also been synthesized by sequential use of the orga-nocatalytic a-amination of aldehydes by azodicarboxylates catalyzed by some of the systems shown above and by other reaction processes, such as the Passerini reaction [40], Homer-Wadsworth-Emmons olefination [41], Wittig olefination [42], and allylation reaction followed by a ring-closing metathesis [43]. In addition, the combination of catalysts in cycle-specific organocascade processes [44] has allowed the synthesis of chiral complex molecules with good results. 

The organocatalyzed a-amination reaction using azodicarboxylates can be also performed using ketones as substrates. Thus, silyloxyproline 39 promoted the 

Another way to carry out the electrophilic amination of a carbonyl compound is by the reaction of an enamine or enolate with a nitroso derivative, the so-called hydroxyamination, oxyamination, or N-nitroso aldol reaction. The regio- and enan-tioselectivity of the transformation have been studied by DFT calculations for the reaction between achiral enamines and nitrosobenzene (70a) promoted by a chiral Br0nsted acid catalyst, such TADDOL [64]. The results suggested a transition state that involves the enamine, nitrosobenzene, and two or more organic acid molecules, forming a cluster-like structure, where hydrogen-bonds play an important role. 

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The direct a-amination of aldehydes by azodicarboxylates as the electrophilic nitrogen source can be catalyzed by, for example i-proline 3a, to give the a-hydrazino aldehydes 4 having (R -configuration in moderate to good yields and with excellent enantioselectivities (89-97% ee) (Scheme 2.27) [4]. The optically active a-hydrazino aldehydes 4 are prone to racemization, and it was found beneficial to reduce them directly with NaBFU to stereochemical stable compounds which, by treatment with NaOH, can cyclize to form the N-amino oxazolidinones 5 in a one-pot process. The N-amino group in 5 could be cleaved with Zn/acetone to give the oxazolidinone 6 (Scheme 2.27). 

The same authors have shown that the direct a-amination reaction could also be used to construct the quaternary stereocenter in the enantioselective total synthesis of the cell-adhesion inhibitor BIRT-377 [7b]. The i-proline-derived tetrazole 3c catalyzed the direct a-amination of 3-(4-bromophenyl)-2-methylpropanal 8 with dibenzyl azodicarboxylate 2b to give the amino aldehyde 9 in 95% yield and with... 

Antagonists of metabotropic glutamate receptors and G-protein-coupled receptors associated with various neurodegenerate diseases have been prepared by proline-catalyzed direct a-amination reactions (Scheme 2.30) [7c]. Both, indane carbaldehyde 10 and analogous compounds having an ester functionality [leading to l-aminoindan-l,5-dicarboxylic acid (AIDA)] and or a phosphonate substituent [(RS)-l-amino-5-phosphonoindan-l-carboxylic acid APICA], all reacted with di-... 

The a-cyanoacetates 12 are optimal substrates for the approach outlined in Scheme 2.26 due to the low pKa of the a-proton. It has been reported that the quinidine-derived alkaloid /fisocupridine (/ -ICD) can catalyze the direct a-amination of a-cyanoacetates 12 (Eq. 4) and /fdicarbonyl compounds [10], probably by an enolate having a chiral /MCD-H+ counterion as the intermediate. The a-amination of a-cyanoacetates 12 with di-tert-butyl azodicarboxylate 2c is an efficient process that proceeds with only 0.5 mol% of /MCD. The expected products 13, having a stereogenic quaternary carbon center, were isolated in excellent yields and with excellent levels of enantioselectivity independently by the nature of the aryl-substituent in the a-cyanoacetates, while the / -dicarbonyl compounds give slightly lower enantioselectivty (83-90% ee). 

Direct Asymmetric a-Amination Reaction of 2-Keto Esters. The cir-DiPh-Box copper complex catalyzes highly enantioselective direct a-amination reaction of 2-keto esters with dialkyl azodicarboxylates and thus provides convenient access to optically active jyn-3-amino-a-hydroxy esters (eq 2). This enantioselective, direct a-amination is applicable to a range of 2-keto esters when dibenzyl azodicarboxylate is used as the nitrogen source. The immediate product of the amination reaction is prone to racemization. Stereoselective reduction of the keto functionality by L-selectride enables further synthetic operations to be carried out without loss of enantiopurity. 

The direct a-amination of aldehydes and ketones provides a useful method for the synthesis of amino acids and, consequently, the asymmetric variant of this process using either metal-based complexes or organocatalysts has received much attention. 

FIGURE 11.4. Brpnsted base catalysts for the direct a-amination of 1,3-dicarbonyl compounds. 

TABLE 11.4. Direct a-Amination of a-Snbstitnted a-Cyanoacetates with Different Br0nsted Base Catalysts... 

SCHEME 11.9. Direct a-amination of 3-substituted 2-oxindoles catalyzed by 26. 

Importantly, compound 90 is capable of inducing direct a-amination of ketone... 

Cecere G, Konig CM, Alieva JL, MacMillan DWC (2013) Enantioselective direct a-amination of aldehydes via a photoredox mechanism a strategy fOT asymmetric amine fragment coupling. J Am Chem Soc 135 11521-11524... 

As another test reaction, we investigated the direct a-amination ofa-substituted P-ketoesters with azodicarboxylates for which an efficient copper(ll)-BOX-catalyzed version had previously been reported by Jorgensen and coworkers [26]. Here again, the trisox systems proved to be superior to the corresponding BOX-Cu catalysts. 

Aldehydes, ketones and esters, XCOCH2R (X = H, alkyl, aryl, MeO, etc.), have been directly a-aminated via copper(II) bromide catalysis. An a-bromo carbonyl species is proposed as intermediate (138), followed by nucleophilic displacement of the bromide by the amine. Done in air at ambient temperature and various solvents (DMSO is best), the intermediate (138) is proposed to generate transient XCOCH(Br)R. Amine attack, as well as giving product, releases HBr, and this - together with oxygen - converts CuBr by-product back to catalyst. 

In addition, chiral nitrogen-substituted quaternary stereocenters can be accomplished by using 1,3-dicarbonyliccompounds as substrates in the direct a-amination process. Thus, several cyclic (i-ketoesters 46 (Scheme 27.9) were submitted to electrophilic amination under phase-transfer conditions catalyzed by the chiral binaphthyl phosphonium salt 47 [50a], Different substituents on the aromatic ring were tolerated, but lower yields were obtained using a six-membered ring cyclic... 

Auxiliary Synthesis Both the (S)- and (R)- enantiomers of the camphor-derived ACC 54 are available in seven steps from commercially available and inexpensive (S)- and (R)-camphor sulfonic acid, respectively (Scheme 7.9). The seven-step process provides an overall yield of approximately 40%. A key step in the synthesis of 54 and 55 is the direct A -amination of the corresponding oxazolidinones, 61 and 62. This transformation is effectively achieved in a straightforward manner using a modification of a procedure recently reported by Hynes et al. ° Application of this amination procedure to commercially available (R)- or (5)-4-benzyloxazolidinone ((R)-62 or (S)-62, respectively) provides phenyl alanine-derived auxiliaries (R)-55 or (S)-55 in excellent yield. 

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