Aldehydes primary amine addition

The initial product 508 of AFC reactions of aromatic aldehydes, primary amines, and indoles is highly reactive and further addition of indoles gives undesired adduct 509 (Scheme 104) <2006OL4939>. In addition, aromatic aldehydes are themselves known to react with indoles directly to afford the undesired bisindolyl product 509. After screening catalysts (AcOH, TFA, Sc(DS)3, dodecylbenzenesulfonic acid, carboxylic acids from -C7Hi5 to -Ci3H27), it was revealed that decanoic acid ( -C9Hi9C02H) efficiently promoted the reaction without formation of product 509. 

A number of compounds of the general type H2NZ react with aldehydes and ketones m a manner analogous to that of primary amines The carbonyl group (C=0) IS converted to C=NZ and a molecule of water is formed Table 17 4 presents exam pies of some of these reactions The mechanism by which each proceeds is similar to the nucleophilic addition-elimination mechanism described for the reaction of primary amines with aldehydes and ketones... 

Primary amines undergo nucleo philic addition to the carbonyl group of aldehydes and ketones to form carbinol amines These carbinolamines dehydrate under the conditions of their formation to give N substituted imines Secondary amines yield enamines... 

Analogously, aldehydes react with ammonia [7664-41-7] or primary amines to form Schiff bases. Subsequent reduction produces a new amine. The addition of hydrogen cyanide [74-90-8] sodium bisulfite [7631-90-5] amines, alcohols, or thiols to the carbonyl group usually requires the presence of a catalyst to assist in reaching the desired equilibrium product. 

Reaction of primary amines with aldehydes and ketones (Section 17.10) Imines are formed by nucleophilic addition of a primary amine to the carbonyl group of an aldehyde or a ketone. The key step is formation of a carbinolamine intermediate, which then dehydrates to the imine. 

Formation of C—Nu The second mode of nucleophilic addition, which often occurs with amine nucleophiles, involves elimination of oxygen and formation of a C=Nu bond. For example, aldehydes and ketones react with primary amines, RNH2, to form imines, R2C=NR. These reactions proceed through exactly the same kind of tetrahedral intermediate as that formed during hydride reduction and Grignard reaction, but the initially formed alkoxide ion is not isolated. Instead, it is protonated and then loses water to form an imine, as shown in Figure 3. 

The addition of (E)- and (Z)-crotylboronates 7 to aldoximes 6 has been realized in good yield by performing the reaction under 3-6 x 10° Torr pressure10. The resulting hydroxylamines 8 can easily be reduced to yield the primary amines. The addition of E-l leads preferentially to the anh-diastereomcr 8, while (Z)-crotylboronate 7 shows a modest selectivity towards formation of the vyy -diastereomer 8 (same sense as in the reaction with aldehydes). Some effort has been made to elucidate the mechanism, but this is not yet well understood. 

The synthesis of imidazoles is another reaction where the assistance of microwaves has been intensely investigated. Apart from the first synthesis described since 1995 [40-42], recently a combinatorial synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles has been described on inorganic solid support imder solvent-free conditions [43]. Different aldehydes and 1,2 dicarbonyl compounds 42 (mainly benzil and analogues) were reacted in the presence of ammonium acetate to give the trisubstituted ring 43. When a primary amine was added to the mixture, the tetrasubstituted imidazoles were obtained (Scheme 13). The reaction was done by adsorption of the reagent on a solid support, such as silica gel, alumina, montmorillonite KIO, bentonite or alumina followed by microwave irradiation for 20 min in an open vial (multimode reactor). The authors observed that when a non-acid support was used, addition of acetic acid was necessary to obtain good yields of the products. 

For the addition of an organometailic compound to an imine to give a primary amine, R in RCH=NR would have to be H, and such compounds are seldom stable. However, the conversion has been done, for R = aryl, by the use of the masked reagents (ArCH=N)2S02 [prepared from an aldehyde RCHO and sulfamide (NH2)2S02]. Addition of R"MgX or R"Li to these compounds gives ArCHR"NH2 after hydrolysis. ... 

Derivatization of the optically active aldehydes to imines has been used for determination of their enantiomeric excess. Chi et al.3 have examined a series of chiral primary amines as a derivatizing agent in determination of the enantiomeric purity of the a-substituted 8-keto-aldehydes obtained from catalysed Michael additions. The imine proton signals were well resolved even if the reaction was not completed. The best results were obtained when chiral amines with —OMe or —COOMe groups were used [2], The differences in chemical shifts of diastereo-meric imine proton were ca. 0.02-0.08 ppm depending on amine. This method has been also used for identification of isomers of self-aldol condensation of hydrocinnamaldehyde. 

To date, the most frequently used ligand for combinatorial approaches to catalyst development have been imine-type ligands. From a synthetic point of view this is logical, since imines are readily accessible from the reaction of aldehydes with primary or secondary amines. Since there are large numbers of aldehydes and amines that are commercially available the synthesis of a variety of imine ligands with different electronic and steric properties is easily achieved. Additionally, catalysts based on imine ligands are useful in a number of different catalytic processes. Libraries of imine ligands have been used in catalysts of the Strecker reaction, the aza-Diels-Alder reaction, diethylzinc addition, epoxidation, carbene insertions, and alkene polymerizations. 

Several trivial but highly useful reactions are known to convert one acceptor-substituted allene into another. For example, the transformation of allenic carboxylic acids is possible both via the corresponding 2,3-allenoyl chlorides or directly to 2,3-allen-amides [182,185], Allenylimines were prepared by condensation of allenyl aldehydes with primary amines [199]. However, the analogous reaction of allenyl ketones fails because in this case the nucleophilic addition to the central carbon atom of the allenic unit predominates (cf. Section 7.3.1). Allenyl sulfoxides can be oxidized by m-CPBA to give nearly quantitatively the corresponding allenyl sulfones [200]. The reaction of the ketone 144 with bromine yields first a 2 1 mixture of the addition product 145 and the allene 146, respectively (Scheme 7.24). By use of triethylamine, the unitary product 146 is obtained [59]. The allenylphosphane oxides and allene-... 

When the secondary amine 33 was used instead of a primary amine, a different type of three-component coupling reaction took place with aldehyde 34 and 1-alkynes 35 to afford the corresponding allylamines (36 and 37) [22]. In this reaction, Ir-hydride generated by amine (33) with Ir, would be a key intermediate. The reaction may proceed by addition of the Ir-hydride to the enamine derived from amine 33 and alkyne 34, followed by insertion of aldehyde and dehydration to give the coupling product (36 and 37). 

The addition of primary amines to the carbonyl group of aldehydes and ketones is generally followed by elimination of water (dehydration), and the product is called an imine or Schiff base. 

The Jacobsen group independently focussed on the development of primary amine-functionalized thiourea derivatives and published, in 2006, the thioureas 100-103 incorporating the established tert-leucine (amide) motif (Figure 6.14) and the diaminocyclohexane or diphenylethylenediamine chiral backbone, respectively (Figure 6.31) [262]. The catalyst screening was carried out in the asymmetric Michael addition [149-152] of 2-phenylpropionaldehyde, an a,a-disubstituted aldehyde, to 1-nitrohex-l-ene (at 20mol% loading, DCM, rt, variable equiv. of H2O)... 

Thus, the characteristic potentiometric selectivity of calix[6]arene hexaester 29 for primary amine guests can be reasonably interpreted on the basis of the structural factors relevant to the nonpolar moieties of guests. Such a mode of discrimination can also be achieved by a calix[6]arene hexaester with short alkyl chains [28 (R = H)]. In addition, the selectivity was found to be essentially the same in the presence or absence of lipophilic anionic site HFPB added in the membrane (Table 3). Potentiometric discrimination of protonated amines by host 28 (R = H, Bu ) as well as of aldehydes (as the protonated hydrazones generated in situ) by hosts 26 (R = Bu ) and 28 (R = H) was also reported. Recently, quantitative estimation of optical selectivities for alkali metal ions or protonated amines were made with liquid membranes containing chromogenic derivatives of calixarenes. ... 

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