Primary amines 1,3-dicarbonyl derivatives

The formation of vinylogous amides from primary amines and -dicarbonyl compounds gives rise to hydrolyzable amine derivatives with greatly decreased nucleophilicity of the nitrogen function. Thus these derivatives have found some use as protecting groups in peptide syntheses 617-619). 

Most of the reactions of the 1,4-dicarbonyl compounds are the conventional reactions expected for isolated carbonyl groups. An important exception is formation of azacyclopentadiene (pyrrole) derivatives from 1,4-dicarbonyl compounds and ammonia or primary amines ... 

From a retrosynfhetic viewpoint, N-aryl-l,2-diimine Ni precatalysts are synthesized by (i) reaction of 1,2 diimines with nickel halides from (ii) 1,2-diimine ligands which in turn are obtained by (iii) condensing 1,2-dicarbonyl substrates with two equivalents of primary aromatic amines, usually under acidic conditions [11]. In analogy, the synthesis of N-hetaryl 1,2 diimine catalysts starts from the corresponding substituted N-heterocyclic primary amines as the amine building blocks. The synthesis of three types of such heterocycles, N-amino-pyrroles, -indoles and -carbazoles, and their corresponding diimine derivatives is presented in the following sections. 

In general, Radziszewski reaction is the synthesis of an imidazole derivative 4 by the condensation of an a-dicarbonyl compound 1 (e.g., glyoxal, pyruvaldehyde, porphyrin-2,3-diones, and benzil), an aldehyde 2, and two equivalents of dry ammonia in alcohol. Interestingly, the replacement of one equivalent of ammonia with a primary amine 3 results in the formation of 1-substituted imidazoles 4 (Scheme 12.1). 

A plausible mechanistic hypothesis for this reaction is that the two molecules of ammonia (or primary amine) react with the a-dicarbonyl compound 1 to form an a-diimine 5, which condenses with the aldehyde 2 giving an intermediate (6) that cyclizes to give imidazole derivative 4, as a main product, but it can render also oxazole 7 as a by-product (Scheme 12.2) [1]. 

Dicarbonyl compounds of various types can be used for pyridine formation. For instance, glutaconic dialdehyde (155) undergoes cyclization with NH3, primary amines, or hydroxylamine to give pyridine or pyridine derivatives, for example, ... 

Satyanarayana and Sivakumar [51] developed a simple, rapid, and efficient synthesis of 2,5-dimethyl-N-substituted pyrrole derivatives (15) by tiie Paal-Knorr reaction [45,46] by means of the one-pot condensation of 1,4-dicarbonyl compoxmds (13) and substituted primary amines (14) using uranyl nitrate hexahydrate as catalyst under ultrasonic irradiation (Scheme 5). The authors studied tiie reaction of methanol, ethanol, acetonitrile, dichlorometh-ane, or chloroform in solvents, as well as in the absence of solvent. The best yields were obtained with methanol under sonication for 5 min. 

Chen et al. s synthesis In 2007, Chen et al. reported on an organocatlytic asymmetric Michael addition of 1,3-dicarbonyl compounds to enone for the synthesis of warfarin using the cinchona-derived primary amine 9-amino-9-deoxyepiquinine as the organocatalyst (Table 9.14)." In the presence of 9-amino-9-deoxye-piquinine in trifluoroacetic acid, 89-99% of enantio-selectivities and 55-93% of yields were achieved for... 

Cinchona-based primary amine catalysis in the asymmetric functionalization of carbonyl compounds has been reviewed and their modularly designed thioamide 0 derivatives have been applied successfully to direct cross-aldol reactions between aldehydes and ketones, reactions of activated carbonyl compounds (isatins) with acetylphosphonate as the enol precursor, and C( 1) functionalization of 1,3-dicarbonyl compounds by aldehydes and ketones. Cross-aldol addition to C(3) of isatins by the methyl group of 4-aryl-tra 5 -cf, -unsaturated methyl ketones has also been promoted... 

Dihydro-1,3-benzoxazines (196) are formed by the reaction of phenols with a mixture of formaldehyde and primary aromatic amines in the molar ratio 2 1. Presumably the phenol first reacts with the appropriate iminium species to form an intermediate amine (195), which is then cyclized in a Pictet-Spengler type reaction (Scheme 81) (44JA1875). If 2-hydroxybenzylamines are employed then methylene derivatives are obtained, and if the formaldehyde is replaced by a-dicarbonyl compounds dehydro dimers (197) are produced (Scheme 82) <70BCJ226>. 

The Michael-type addition, a nucleophilic addition of an anion to the carbon-carbon double bond of an a,(3-unsaturated ketone, aldehyde, nitrile, nitro, sulphonyl, or carboxylic acid derivative, provides a powerful tool for carbon-carbon bond formation. The reaction is most successful with relatively nonbasic ( soft ) nucleophiles such as thiols, cyanide, primary and secondary amines, and P-dicarbonyl compounds. There is often a competition between direct attack on the carbonyl carbon (1,2-addition) and conjugate addition (1,4-addition) when the substrate is an a,(3-unsaturated carbonyl compound. 

The dicarbonyl compoimd 51 was oxidized to the anhydride 52, which subsequently reacted with primary or secondary amines to form a-amino acids, a-amino amides and dipeptides 53 (Scheme 14) [48]. 3-Hydroxy j8-lactams obtained from imines derived from carbohydrates [49,50] or prepared via the Sharpless AD reaction [51-53] were directly oxidized to anhydrides by treatment with NaOCl and TEMPO. Anhydrides 54-56 were used for the synthesis of compounds related to the family of polyoxins represented by 57 (Scheme 15) [49-53]. 

After these initial results by Tsuji, this elementary step was incorporated into a catalytic process by Hata and co-workers at Toray Industries and by Atkins and co-workers at Union Carbide. These groups reported reactions of allylic phenyl ethers, allylic alcohols, and allylic acetates with carboxylates, alcohols, primary and secondary amines, and methyl acetoacetate catalyzed by Pd(0) complexes and precursors to Pd(0) complexes (Equation 20.3). - After these initial reports, early developments focused on reactions of "soft" carbanions derived from 3-dicarbonyl compounds, cyanoesters, and related compounds containing two electron-withdrawing groups attached to the nucleophilic carbon. Although these reactions occur with allylic halides in the absence of a catalyst, these reactions are greatly accelerated by palladium catalysts. Thus, the palladium catalyst allows these reactions to occur under mild conditions with allylic acfetates, which are more accessible than allylic halides, and with selectivities that are altered by the metal catalyst. 

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