Aldehydes, alkylation transfer hydrogenation

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

A possible mechanism for the P-alkylation of secondary alcohols with primary alcohols catalyzed by a 1/base system is illustrated in Scheme 5.28. The first step of the reaction involves oxidation of the primary and secondary alcohols to aldehydes and ketones, accompanied by the transitory generation of a hydrido iridium species. A base-mediated cross-aldol condensation then occurs to give an a,P-unsaturated ketone. Finally, successive transfer hydrogenation of the C=C and C=0 double bonds of the a,P-unsaturated ketone by the hydrido iridium species occurs to give the product. 

As an alternative strategy, lysine residues can be modified through reductive alkylation. Fig. 2e. This method is most frequently carried out by exposing the protein to aldehydes in the presence of hydride-containing agents that reduce the transiently formed imines. NaB(CN)H3 and NaB(OAc)3H are commonly used for this purpose. As an alternative, transfer hydrogenation can be carried out in the presence of an Ir(III)[Cp ]2(bipyridyl) catalyst, which allows imine reduction to occur under mild conditions using buffered formate as the hydride source (14). 

The strategies presented in Table 8.1 can be generalized in the following manner (1) carbanion addition to aldimine or ketimine derivatives (2) sequential amination-alkylation of aldehydes (carbanion addition to in situ formed aldimine derivatives) (3) transfer hydrogenation or hydrogenation of imines (4) reductive amination of ketones and (5) N-acetylenamide reduction. Because of the difficulty of their synthesis, a-alkyl,-alkyl substituted amines are highlighted whenever possible. 

A transition metal catalyst has also been used to effect the reductive alkylation of amino groups on proteins [41], This reaction uses [Cp Ir(4-4 -dimethoxybipy)(H20)]S04 31 as a mild transfer hydrogenation catalyst and formate ion as the stoichiometric hydride source, in Fig. 10.3-11 (a). Presumably, this reaction occurs via the reversible formation of imine 33 with free amino groups on the protein surface, followed by reduction of iridium hydride 32. For most proteins, multiple modifications are observed (Fig. 10.3-ll(b)), although the overall level of conversion can be altered through variation of either the reaction temperature or the concentrations of the aldehyde and catalyst. In general, the reaction has shown excellent reliability for protein alkylation between pH 5 and 7.4. 

Since no reaction occurred at all in the absence of either the aldehyde catalyst or the base or both of them, as well as other proofs such as control reactions using high purity bases (>99.99 % purity), the authors concluded that the reaction is a true TM-free transformation. In addition to the aldehydes catalytic effect, the authors proved that imine intermediates and other TM-free oxidants could also be employed to initiate the reaction, which is consistent with, and further supports, the TM-free N-aUcylation mechanism (Scheme 39). Along with other results of mechanistic studies, the authors proposed a mechanism for the aldehyde-catalyzed A -alkylation reaction (Scheme 41). Firstly, the external aldehydes condense with amines/amides to give imine intermediates, which were then reduced by alcohols via a TM-free MPV-0 transfer hydrogenation process to give product amines and regenerate byproduct aldehydes as the new alkyl source in next reaction cycle. In the key TM-ffee transfer... 

Transfer hydrogenation followed by alkylation of oc,P-unsaturated aldehydes mediated by a combination of cycle-specific catalysts of 115 and ent-196 was also developed [135]. 

In subsequent studies, Esteruelas et at disclosed the synthesis of another cationic complex, [(IPr)Os(OH)(p-cymene)][OTf] 52, which was an efficient pre-catalyst for transfer hydrogenation of aldehydes with isopropanol, for hydration of nitriles into amides, and for a-alkylation of arylacetonitriles and methyl ketones with alcohols (Scheme 7.10). All these transformations were assumed to involve cationic hydrido intermediates formed by hydrogen transfer from one of the substrates to the osmium active species. 

The quantum yields for oxetane formation have not been determined in every case, and only a few relative rate constants are known. The reactivities of singlet and triplet states of alkyl ketones are very nearly equal in attack on electron rich olefins. 72> However, acetone singlets are about an order of magnitude more reactive in nucleophilic attack on electron-deficient olefins. 61 > Oxetane formation is competitive with a-cleavage, hydrogen abstraction and energy-transfer reactions 60 64> so the absolute rates must be reasonably high. Aryl aldehydes and ketones add to olefins with lower quantum yields, 66> and 3n-n states are particularly unreactive. 76>... 

Similar reductions were effected by heating of triethylaluminum (triethyl-alane) in ether with aldehydes and ketones. The alcohols are formed by hydrogen transfer from the alkyl groups which are transformed to alkenes. 

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