Carbonyl-amine reactions availability

In creating synthetic routes for the development of drug molecules, the synthetic chemist wants to create a molecular entity in which functional groups (carbonyls, amines, etc.) are correctly positioned in three-dimensional space this will enable the creation of functional biophoric fragments such as the pharmacophore. The synthetic chemist has ten general classes of reactions available for such synthetic tasks ... 

Regarding acylation reactions, acylation of alcohols produces esters and acylation of amines produces amides Both of these transformations are illustrated in Figure 8.2. These, in addition to the introduction of acyl groups adjacent to carbonyls (Scheme 8.11), only hint at the breadth of related acylation reactions available and useful in organic synthesis. One additional reaction is the Friedel-Crafts acylation illustrated in Scheme 8.12. Through this transformation, extended functionalization of aryl groups becomes accessible. 

Dialkyl cyanomethylphosphonates are routine reagents readily accessible on laboratory scale and also available from a number of chemical suppliers. Since the review by Pudovik and Yastrebova published in 1970, ° the use of dialkyl cyanomethylphosphonates in Homer-Wadsworth-Enunons reactions has been covered in several comprehensive and excellent reviews. AU the factors governing the reaction (nature of the carbanions and carbonyl group, reaction conditions, mechanism, and stereochemistry) have been studied in depth. We invite the reader to refer to these papers. In contrast, we discuss here the synthetic applications resulting directly from the use of dialkyl cyanomethylphosphonate, which is the pathway of choice for the preparation, via a,p-unsaturatcd nitriles, of a,P-unsaturated aldehydes, cyanoethyl compounds, allylamines, and saturated amines. 

The close agreement of the three methods supports the contention that protonation at low temperatures first occurs at nitrogen and is followed by a proton shift to give the iminium salt (M). The rate of this rearrangement is dependent on temperature, the nature of the amine, and the nature of the carbonyl compound from which the enamine was made. Even with this complication the availability of iminium salts is not impaired since the protonation reaction is usually carried out at higher temperatures than —70°. Structurally complicated enamines such as trichlorovinyl amine can be readily protonated (17,18). 

The most widely employed methods for the synthesis of nitrones are the condensation of carbonyl compounds with A-hydroxylamines5 and the oxidation of A+V-di substituted hydroxylamines.5 9 Practical and reliable methods for the oxidation of more easily available secondary amines have become available only recently.10 11 12 13. These include reactions with stoichiometric oxidants not readily available, such as dimethyldioxirane10 or A-phenylsulfonyl-C-phenyloxaziridine,11 and oxidations with hydrogen peroxide catalyzed by Na2W044 12 or Se02.13 All these methods suffer from limitations in scope and substrate tolerance. For example, oxidations with dimethyldioxirane seem to be limited to arylmethanamines and the above mentioned catalytic oxidations have been reported (and we have experienced as well) to give... 

Antibody molecules can be labeled with any one of more than a dozen different fluorescent probes currently available from commercial sources. Each probe option has its own characteristic spectral signals of excitation (or absorption) and emission (or fluorescence). Many derivatives of these fluorescent probes possess reactive functionalities convenient for covalently linking to antibodies and other molecules. Each of the main fluorophore families contains at least a few different choices in coupling chemistry to direct the modification reaction to selected functional groups on the molecule to be labeled. These choices include amine-reactive, sulfhydryl-reactive, and carbonyl-reactive. Examples of some of the more popular varieties of fluorescent probes can be found in Chapter 9. 

Trifluoroalanine has also been prepared by reducing trifluoropyruvate imines (ethyl trifluoropyruvate is available commercially it is prepared either from per-fluoropropene oxide or by trifluoromethylation of ethyl or f-butyl oxalate). These imines are obtained by dehydration of the corresponding aminals or by Staudinger reaction. They can also be obtained by palladium-catalyzed carbonylation of trifluoroacetamidoyl iodide, an easily accessible compound (cf. Chapter 3) (Figure 5.4). Reduction of the imines affords protected trifluoroalanines. When the imine is derived from a-phenyl ethyl amine, an intramolecular hydride transfer affords the regioisomer imine, which can further be hydrolyzed into trifluoroalanine. ... 

Numerous chiral amines are reported to be useful in the asymmetric alkylation reaction of carbonyl compounds via their imine derivatives (see Section 1.1.1.4.1.)2,4. The asymmetric alkylation of chiral imines was first reported using simple, commercially available amines such as a-methylbenzeneethanamine (amphetamine)1, benzeneethanamine1 5 and exo-l, 7,7-trimethyl-bicyclo[2.2.1]heptan-2-amine (isobomylamine). In the case of cyclohexanone alkylation using these chiral auxiliaries, enantiomeric excesses of up to 72% were obtained1. 

Many such activated acyl derivatives have been developed, and the field has been reviewed [7-9]. The most commonly used irreversible acyl donors are various types of vinyl esters. During the acylation of the enzyme, vinyl alcohols are liberated, which rapidly tautomerize to non-nucleophilic carbonyl compounds (Scheme 4.5). The acyl-enzyme then reacts with the racemic nucleophile (e.g., an alcohol or amine). Many vinyl esters and isopropenyl acetate are commercially available, and others can be made from vinyl and isopropenyl acetate by Lewis acid- or palladium-catalyzed reactions with acids [10-12] or from transition metal-catalyzed additions to acetylenes [13-15]. If ethoxyacetylene is used in such reactions, R1 in the resulting acyl donor will be OEt (Scheme 4.5), and hence the end product from the acyl donor leaving group will be the innocuous ethyl acetate [16]. Other frequently used acylation agents that act as more or less irreversible acyl donors are the easily prepared 2,2,2-trifluoro- and 2,2,2-trichloro-ethyl esters [17-23]. Less frequently used are oxime esters and cyanomethyl ester [7]. S-ethyl thioesters such as the thiooctanoate has also been used, and here the ethanethiol formed is allowed to evaporate to displace the equilibrium [24, 25]. Some anhydrides can also serve as irreversible acyl donors. 

According to the available experimental data, it is impossible to distinguish between these mechanisms, but the second mechanism seems to be preferred [Scheme (7)] for, according to this Scheme, the reaction of amine addition proceeding through a cyclic transition state is completed in one step, whereas for the reaction to occur according to Scheme (2) or (6) it is additionally necessary to transfer the proton. Then, it is probable that the different mechanisms [Schemes (3) and (5)] may precede formation of one and the same transition state [Scheme (7)]. Note finally that the mechanism of bifunctional catalysis [Scheme (7)] is extremely popular in different reactions of nucleophilic substitution at the saturated carbon atom and reactions with participation of a carbonyl group32>. 

Since ketimine formation is not possible in the reductive alkylation of secondary amines, this reaction must involve the hydrogenolysis of an alcoholamine. However, if either carbon a to the starting carbonyl has a hydrogen available, the enamine formation is possible. 

---