Substrate amines

In cases of some derivatives bearing an amino substituent, conversions to acylamines, alkylamines, and amidines have been reported. These substrate amines include the above-mentioned two amino compounds 157 and 159 as well as other compounds shown in Scheme 25. 

In the literature, there are numerous reports regarding the interactions between amines and both electron and proton acceptors132, but less attention has been devoted to interactions between amines and aromatic electron acceptors, in particular when the substrate/amine system is a reacting system, as in the case of nucleophilic aromatic substitution (SjvAr) reactions between amines and substrates activated by nitro or by other electron-withdrawing groups. 

Diazonium salts can be prepared directly by replacement of an aromatic hydrogen without the necessity of going through the amino group.136 The reaction is essentially limited to active substrates (amines and phenols), since otherwise poor yields are obtained. Since the reagents and the substrate are the same as in reaction 1-3, the first species formed is the nitroso compound. In the presence of excess nitrous acid, this is converted to the diazonium... 

Catalytic kinetic resolution of amines has been a typical domain of enzymatic transformations. Attempts to use low-molecular-weight catalysts have notoriously been frustrated by the rapid uncatalyzed background reaction of the amine substrate with the acyl donor [40]. The first solution to this problem was recently developed by Fu, who used the planar chiral catalyst 21d and O-acyl azlactone 40 as the acyl donor (Scheme 12.19) [41]. In this process, the acyl transfer from the azlactone 40 to the nucleophilic catalyst 21d is rapid relative to both direct transfer to the substrate and to the transfer from the acylated catalyst to the substrate amine. Under these conditions, which implies use of low reaction temperatures, selectivity factors as high as 27 were achieved (Scheme 12.19) [41]. 

Although the usual practice still involves mixing the reactants of Mannich synthesis (substrate, amine, and aldehyde) with or without following a particular order of addition, the use of preformed aminomethylating reagents is becoming more and more frequent. Some of them, particularly those deriving from common amines, are available commercially. 

Chiral derivatives or compounds having a prochiral group in the reactive center are frequently present among substrates, amines, and aldehydes used as reagents in Mannich synthc.sis. When at least two out of the three reagents are chiral or prochiral, the resulting Mannich base will be made up of a diastcrcomeric mixture of products. The main possible combinations of chiral or prochiral couples of reactants leading to diastereo-meric derivatives are reported in Fig. 36. 

Substrates containing all the three reactive moieties of Mannich synthesis, that is, substrate, amine, and aldehyde, such as 161 (Fig. 56) also have been subjected to cy-clization. - Two carbonyl functions are present in these molecules, which may produce intramolecular aminoalkylation. 

Hbhne et al. reported a substrate protection strategy that enhanced both the rate and the enantioselectivity of transaminase catalyzed kinetic resolution reactions [32]. The co transaminase catalyzed resolution of the pharmaceutically important syn thons 3 amino pyrrolidine 53 and 3 aminopiperidine 54 was imp roved by the addition of protecting groups to the substrate amines. Reaction rates were improved by up to 50 fold, and product ee was improved from 86 to 99% (Figure 14.23). 

The area of double carbonylation has been recently reviewed by des Abbayes and Salaiin. Both stoichiometric and catalytic systems are surveyed, covering monometallic complexes of Co, Pd, Fe and Ni, although the main emphasis is on catalytic monometallic systems of Co and Pd with a variety of substrates (amines, alcohols, organic halides). A general scheme for the double carbonylation of organic halides with a palladium is shown below (Scheme 29). 

The crystal structures of substrate-reduced amine oxidases have been solved, along with site-directed mutantsmetal-substituted forms, enzyme complexes with inhibitors, the O2 mimic nitric oxide (NO) and peroxide. These have been correlated with a wealth of biochemical and spectroscopic data that form the basis for the catalytic mechanism proposed in Scheme 8. A Schiff base complex species (b) is formed between substrate amine and TPQ C-5. Base-catalyzed proton abstraction from substrate a-methylene group, via the conserved active-site aspartate residue, yields the reduced cofactor in a product Schiff-base complex, species (c). Hydrolysis releases product aldehyde, leaving the cofactor in the reduced aminoquinol form, species (d). 

As noted above, the reaction of amines, carbon dioxide and electrophiles has been reported in the literature, but the products generally are derived from attack on the nitrogen center, liberating CO2 and producing the substituted amine or amide. Both the ACDC-I and -II chemistries rely on the production of the carbamate anion from the reaction of carbon dioxide with the substrate amine. Very few reports have appeared which have addressed the issue of utilizing the carbamate anion as an oxygen- nucleophile in direct substitution reactions (9-14). 

In order to probe the effect of the substrate amine structure on this chemistry forming carbamates, a series of reactions were run under identical conditions to those described for Table I using benzyl chloride as the electrophile and tetramethylcyclohexyl guanidine as the co-base. The reaction rates are tabulated as relative rates with the rate for n-octyl amine set as 1. The results are summarized in Table II. 

The intramolecular addition of nudeophiles to palladium-activated triple bonds generates the palladated intermediate 9 (Scheme 6.13). While the latter can be protonated to liberate product, the reactivity of palladium can also be employed to intercept this intermediate with other bond forming reactions. These have provided methods to derivatize the heterocycle at the same time as it is generated. A range of substrates have been coupled with cydization via this approach, including aryl or vinyl halides, allylic and related R-X substrates, amines, halides, as well as carbon monoxide and olefins. 

A series of patents issued to Asahi Chemical Industry Co., deal with the modification of hexamethylenediamine by reaction with (meth)acrylic-, glycidyl ether-, hydroxyl-, amino-, amido-, or carboxy-substituted vinyl compounds, isocyanate, and amino acid compounds (Table IV). These modified amine curing agents are active at low temperatures and, in some cases, on wet substrates. Amine-substituted resole phenolics have also been described as useful epoxy curing agents." " Preparation of these curing agents is via condensation of the phenol, formaldehyde, and polyamine (Eq. 8). 

Amines are valuable synthetic targets because of their abundance in medicine, agrochemicals, and materials science [47]. Transition metal-catalyzed direct conversions of aromatic C—H bonds to C—N bonds are attractive synthetic routes toward accessing aryl amines [48]. These reactions are more advantageous over the conventional amination methods that either requires harsh conditions (e.g., nitration followed by reduction) [49] or prefunctionalized substrates (amination of aryl halides) [50, 51]. The Hartwig group recently reported the first example of Pd-catalyzed intermo-lecular amination of arenes (Scheme 24.55) [52a],... 

In 2009, Williams and co-workers described the [Cp Irl2l2-catalyzed N-alkylation of anilines, benzylic and aliphatic primary amines with diisopropylamine (Eq. 77) [220]. Although both substrate amines could be oxidized to give different imines and possibly different product amines, excellent selectivity could still be obtained. For example, the reaction of diisopropylamine and benzylamine gave exclusively A-isopropyl-A-benzylamine without any tertiary amine and dibenzy-lamine byproducts. 

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