Benzylic amines, also

The strategy for the asymmetric reductive acylation of ketones was extended to ketoximes (Scheme 9). The asymmetric reactions of ketoximes were performed with CALB and Pd/C in the presence of hydrogen, diisopropylethylamine, and ethyl acetate in toluene at 60° C for 5 days (Table 20) In comparison to the direct DKR of amines, the yields of chiral amides increased significantly. Diisopropylethylamine was responsible for the increase in yields. However, the major factor would be the slow generation of amines, which maintains the amine concentration low enough to suppress side reactions including the reductive aminafion. Disappointingly, this process is limited to benzylic amines. Additionally, low turnover frequencies also need to be overcome. 

Reaction selectivity of the parent ortho-QM has also been explored with a variety of amino acid and related species.30 In these examples, the rates of alkylation and adduct yields were quantified over a range of temperatures and pH values. The initial QM3 was generated by exposing a quaternary benzyl amine (QMP3) to heat or ultraviolet radiation (Scheme 9.10). Reversible generation of QM3 was implied by subsequent exchange of nucleophiles at the benzylic position under alternative photochemical or thermal activation.30 Report of this work also included the first suggestion that the reversible nature of QM alkylation could be used for controlled delivery of a potent electrophile. 

Several recent articles describe the ring-opening of chiral epoxides under microwave irradiation conditions (see also Scheme 6.103). In the context of the preparation of novel /32-adrenoceptor agonists related to formoterol and salmeterol, Fairhurst and a team from Novartis have described the synthesis of chiral ethanolamines by solvent-free microwave-assisted ring-opening of a suitable chiral epoxide precursor with secondary benzylated amines (Scheme 6.129) [262]. At 110 °C, the reaction occurred... 

Recently, Borner and coworkers described an efficient Rh-deguphos catalyst for the reductive amination of a-keto acids with benzyl amine. E.e.-values up to 98% were obtained for the reaction of phenyl pyruvic acid and PhCH2COCOOH (entry 4.9), albeit with often incomplete conversion and low TOFs. Similar results were also obtained for several other a-keto acids, and also with ligands such as norphos and chiraphos. An interesting variant for the preparation of a-amino acid derivatives is the one-pot preparation of aromatic a-(N-cyclohexyla-mino) amides from the corresponding aryl iodide, cyclohexylamine under a H2/ CO atmosphere catalyzed by Pd-duphos or Pd-Trost ligands [50]. Yields and ee-values were in the order of 30-50% and 90 >99%, respectively, and a catalyst loading of around 4% was necessary. 

The oxidative behaviour of the acridinium carbocations 61 was also explored by the group of Lacour in the photoinduced electron transfer reaction [160]. In the amount of 2 mol%, the achiral hindered acridinium salt 61 catalyzed the aerobic photooxidation of the primary benzylic amine to benzylimine in the yield of 74% (Scheme 63). 

Similarly, CALB has been used in combination with a palladium/alkaline earth metal-based racemization catalyst to effect a DKR on the benzylic amine 56e (Scheme 2.27). The (R)-amide 57e was obtained in very good yield and excellent optical purity. Several other substrates also underwent the reaction [29],... 

The addition of nitromethane (56% yield/168h 87% ee) or methyl a-cyanoacetate (94% yield/52h 82% ee) as alternative CH-acidic methylene compounds required increased reaction temperatures (60 to 80 °C) to furnish the adducts 7 and 8. As exemplarily depicted in Scheme 6.69 for benzylic alcohol thiourea 12 catalyzes the transformation of the obtained malononitrile Michael products to the respective carboxyhc acid derivatives (89% yield/88h). This method of derivatization also described for methanol (87% yield/24h rt), benzyl amine (77% yield/3h rt), and N,0-dimethylhydroxyamine (75% yield/20h 60°C) as nucleophiles was reported to be feasible as a one-pot strategy without isolation of the initially formed Michael adduct [222]. 

Thenyl chloride is more reactive than benzyl chloride. The rates of formolyses (ki x 104s-1) in 20% dioxane at 20 °C are as follows (75H(3)l) benzyl chloride, 0.85 2-thenyl chloride, 1.51 and furfuryl chloride, 695.0. The rates of reaction with various amines also increase in the same order. Normal replacement of the chlorine in 2-thenyl chloride by CN takes place in 30% aqueous MeCN with NaCN or KCN (conditions under which an abnormal product is exclusively formed with furfuryl chloride). 

Diisothiocyanates react with aryl amines to form the 1,3,5-triazine via the thiadiazinone intermediate (88 Scheme 53) (81CB2075). The reaction also works for benzylic amines. 

As illustrated by the examples in Table 3.9, resin-bound 4-alkoxybenzylamides often require higher concentrations of TFA and longer reaction times than carboxylic acids esterified to Wang resin. For this reason, the more acid-sensitive di- or (trialkoxy-benzyl)amines [208] are generally preferred as backbone amide linkers. The required resin-bound, secondary benzylamines can readily be prepared by reductive amination of resin-bound benzaldehydes (Section 10.1.4 and Figure 3.17 [209]) or by A-alkyla-tion of primary amines with resin-bound benzyl halides or sulfonates (Section 10.1.1.1). Sufficiently acidic amides can also be A-alkylated by resin-bound benzyl alcohols under Mitsunobu conditions (see, e.g., [210] attachment to Sasrin of Fmoc cycloserine, an O-alkyl hydroxamic acid). 

In a similar way indole isomerizes to benzyl cyanide, pyridine to cyano-butadiene and quinoline to cinnamic acid nitrile. Aniline and o-phenylenedi-amine also form large amounts of unsaturated nitriles in glow discharges. 

If the arenes are very electron-deficient direct attack of the nucleophile at the arene might also compete with displacement of the benzylic leaving group, to yield complex structures such as that shown in Scheme 4.28. 2-Nitrobenzyl halides can also react with amines to yield, instead of simple products of nucleophilic substitution, 2fi-indazoles [122] (Scheme4.28). 4-Nitrobenzyl halides, however, yield the expected benzyl amines on treatment with amines [123]. 

This reaction also proceeds well with a variety of other substituted stilbene derivatives. Thus, the boranes obtained by hydroboration of E and Z stilbenes 80 undergo the thermal boron migration with excellent diastereoselectivity leading to the anti and syn organoboranes 81. After amination of 81 the corresponding benzylic amines (anti and syn 82) were obtained in 66 and 40 % yield and with diastereoselectivity better than 90 10 between C(l) and C(2) (Scheme 16) [7, 8,13],... 

Cr3+ can also be integrated into the structures of layered double hydroxides. A mixed oxide, prepared by calcination of ZnCr-LDH-CCh, was used in combination with t-BuOOH for the ketonization of alkyl and of benzyl pyridines and for the oxidation of benzyl amines to give Schiff bases (67,68). In contrast to MgAl-LDHs, for example, these materials display hardly any basicity so that base-catalyzed side reactions such as aldol condensations are avoided. 

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