Alkyl imines

The acetate (1) and its mosylate analog (79) have been shown to undergo cydoad-dition with the CN double bond of alkyl imines to generate substituted pyrrolidines in the presence of nickel or palladium catalyst [35]. For example, both the phenyl imine (80) and the diazene (81) gave reasonable yields of adducts (82) and (83) respectively (Scheme 2.23). 

There are similar reactions involving nitrogen analogs called imine anions. The alkylated imines can be hydrolyzed to the corresponding ketone, and this reaction is discussed in Section 1.3. 

Rapid monoalkylations are achieved in good yield compared with classical methods. Of particular interest is the synthesis of ot-amino acids by alkylation of aldimines with microwave activation. Subsequent acidic hydrolysis of the alkylated imine provides leucine, serine, or phenylalanine in preparatively useful yields within 1-5 min [50], Alkylation of phenylacetonitrile was performed by solid-liquid PTC in 1-3 min under microwave irradiation (Eq. 36 and Tab. 5.14). The nitriles obtained can subsequently be quickly hydrolyzed in a microwave oven to yield the corresponding amides or acids [56]. 

Oxidation of A-alkyl imines with dimethyldioxirane (DMD) in a solution of dichloromethane-acetone gives nitrones without the apparent formation of oxaziridines (13). Under the conditions of phase transfer, imines can be oxidized into nitrones upon treatment with permanganate ion MnC>4 (19). 

The nature of the substituent directly attached to the N-atom influences the properties (basicity, reduction potential, etc.) of the C = N function more than the substituents at the carbon atom. For example, it was found that Ir-dipho-sphine catalysts that are very active for N-aryl imines are deactivated rapidly when applied for aliphatic imines [7], or that titanocene-based catalysts are active only for N-alkyl imines but not for N-aryl imines [8, 20, 21]. Oximes and other C = N-X compounds show even more pronounced differences in reactivity. 

Until now, few acyclic N-alkyl imines or the corresponding amines have been found to be of practical industrial importance. Most studies reported herein were carried out with model substrates, especially with the N-benzyl imine of acetophenone 5a and some analogues thereof (Fig. 34.7). One reason for this choice could be the easy preparation of a pure crystalline starting material, and another reason might be that the chiral primary amines can be obtained by hy-drogenolysis of the benzyl group. As can be seen in Table 34.4, there are several catalyst systems with fair to good ee-values and activities. 

Table 34.4 Selected results for the enantioselective hydrogenation of N-alkyl imines and enamines (for structures, see Fig. 34.7) Catalytic system, reaction conditions, enantioselectivity, productivity and activity.

The electron-deficient alkene (5.2 mmol) in MeCN (5 ml) is added to an intimate mixture of powdered K2C03 (1 g) and NaOH (0.2 g), the (S)-menthone-protected ethyl glycine (1.27 g, 5 mmol), and TBA-Br (0.16 g, 0.5 mmol) in MeCN (20 ml). The mixture is stirred for 1 h at 0°C and then filtered. The solid is washed with MeCN (10 ml) and the combined organic solutions are evaporated and the residue is taken up in Et20. The ethereal solution is washed well with H20, dried (MgS04), and evaporated to produce the alkylated imine, which can be converted into the amino acid upon hydrolysis with aqueous acid. 

Keywords Alcohols Alkenes Asymmetric transfer hydrogenation C-alkylation Imines Ketones W-aUcylation Oxidation Reduction Transfer hydrogenation... 

Both aryl and alkyl imines react well to furnish the product. The scope of this reaction is depicted in Table 5. The reaction proceeds smoothly not only in ionic... 

The deprotonation of Af-alkyl imines 1 with LDA to give 2-azaallyl anions 2 is a well-known reaction34 At least one stabilizing substituent R2 such as phenyl35 or alkoxycarbonyl36 at the carbon atom is necessary to achieve the deprotonation. The deprotonation of iV-benzylimines, which contain no acidic a-protons in the R1 group proceeds under relatively mild conditions37-38. 

Asymmetric alkylation of benzylamine via the imine 6A, with ( + )-D-camphor (5 A) as chiral auxiliary is possible. Deprotonation with butyllithium and subsequent alkylation with haloalkanes, (R X) afforded the alkylated imines 7 A with reasonable yield but variable diastereo-selectivity. The diastereoselectivity depends strongly on the haloalkane with methoxy-substi-tuted halomethylbenzenes moderate to good diastereoselectivity (d.r. 80 20-90 10) is obtained, however, with haloalkanes or 3-halopropenes only low optical purities (< 50%) were observed. 

Despite the highly selective alkylations of azaenolates, the optical purity of the final products is rather low in several cases, due to partial racemization during hydrolysis of the alkylated imines. In general, racemization occurs very fast in basic media, whereas in acidic solutions, especially in two-phase systems, the degree of racemization is rather low and depends on the nature of the carbonyl compounds. 

A highly enantioselective direct Mannich reaction of simple /V-Boc-aryl and alkyl- imines with malonates and /1-kclo esters has been reported.27 Catalysed by cinchona alkaloids with a pendant urea moiety, bifunctional catalysis is achieved, with the urea providing cooperative hydrogen bonding, and the alkaloid giving chiral induction. With yields and ees up to 99% in dichloromethane (DCM) solvent, the mild air- and moisture-tolerant method opens up a convenient route to jV-Boc-amino acids. 

S )-r-Butylsulfinylferrocene has been added to a range of aryl- and alkyl-imines, via o-lithiation some imines gave complete stereocontrol of the three stereocentres in the product, as shown by single-crystal X-ray analysis.38... 

Nucleophilic carbon radicals can C-alkylate imines, a process which is found to be substantially facilitated by an o-phenolic substituent as in e.g. (32).85 The hydroxyl is presumed to stabilize an intermediate aminyl radical. An enantioselective version of the reaction is also reported. 

Some bifunctional 6 -OH Cinchona alkaloid derivatives catalyse the enantioselective hydroxyalkylation of indoles by aldehydes and a-keto esters.44 Indole, for example, can react with ethyl glyoxylate to give mainly (39) in 93% ee. The enan- tioselective reaction of indoles with iV-sulfonyl aldimines [e.g. (40)] is catalysed by the Cu(OTf)2 complex of (S)-benzylbisoxazoline (37b) to form 3-indolylmethanamine derivatives, in up to 96% ee [e.g. (41a)] 45 Some 9-thiourea Cinchona alkaloids have been found to catalyse the formation of 3-indolylmethanamines [e.g. (41b)] from indoles and /V-PhS02-phenyli mines in 90% ee.46 Aryl- and alkyl-imines also give enantioselective reactions. 

The resulting aza-enolate reacts like a ketone enolate with Sn2-reactive alkylating agents—here, benzyl chloride—to form the new carbon-carbon bond and to re-form the imine. The alkylated imine is usually hydrolysed by the mild acidic work-up to give the alkylated aldehyde. 

Whereas isolated imines are relatively unstable and readily undergo hydrolysis to form carbonyl compounds, alkylated imines and imino derivatives are found as stable compounds in a variety of situations. Thus a number of nitrogen derivatives of aldehydes and ketones, such as the oxime, semicarbazone and hydrazone, contain an imino fragment. 

Hydrazones and other compounds with C=N bonds can be similarly alkylated.The use of chiral amines or hydrazines (followed by hydrolysis 16-2 of the alkylated imine) can lead to chiral alkylated ketones in high optical yields (for an example, see p. 170). 

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