Nucleophilic Additions to Unsaturated Nitrogen

The direct introduction of either a nitrogen or an oxygen atom adjacent to a carbonyl group in a catalytic enantioselective maimer using a chiral organo-catalyst has been described only recently. The chiral products of these reactions represent fundamental building blocks for the construction of complex natural products and other important bioactive molecules.  

Recent Developments in Asymmetric Organocatalysis By Helene Pellissier Helene Pellissier 2010 

The a-oxycarbonyl group is a common feature of many natural and biologically active compounds. Furthermore, this functionality is an obvious precursor in the synthesis of other important building blocks such as diols. Among the already existing methods for the asymmetric synthesis of chiral a-hydroxy 

In 2009, Wang et al. developed an asymmetric synthesis of 3-hydroxyl-2-alkanones via a tandem organocatalytic aminoxylation of aldehydes and a chemoselective diazomethane homologation. An accelerating effect of water was observed for the aminoxylation catalysed by L-proline, while MgCl2 served 

The reactions between nitrosobenzene and enamines as activated carbonyl compounds are known to provide aminoxylation or hydroxyamination products, depending on the catalyst used. In the absence of relatively strong acids such as carboxylic acids, the organocatalytic reaction of aldehydes with nitrosobenzene led to hydroxyamination products exclusively. This phenomenon was checked by Maruoka and Kano by performing the precedent reaction in the presence of a closely related catalyst which did not bear a carboxylic 

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The second pattern in Scheme 13 is based upon nucleophilic addition to an a,/3-unsaturated carbonyl compound and has been developed where the nitrogen substituent X is arenesulfonyl. Base-catalyzed condensation of N- (p-toluenesulfonyl)glycine with a,(3 -unsaturated ketones gives intermediate 1-p-toluenesulfonyldihydropyrroles which can be aromatized by base-catalyzed elimination of the p -toluenesulfinate anion (equation 116) (65JCS4389). 

An extension of the idea for generating other anionic nucleophiles by F" addition to unsaturated precursors has been realised for nitrogen, sulphur and more recently for oxygen (Scheme 52). High reaction ability of tetrafluoropyridazine and tetra-fluoropyrimidine towards nucleophiles made it useful in trapping experiments for anions 327, 329 and 331 [196-199]. 

Figure 5.16 Photoactivation of a phenyl azide group with UV light results in the formation of a short-lived nitrene. Nitrenes may undergo a number of reactions, including insertion into active carbon-hydrogen or nitrogen-hydrogen bonds and addition to points of unsaturation in carbon chains. The most likely route of reaction, however, is to ring-expand to a dehydroazepine intermediate. This group is highly reactive toward nucleophiles, especially amines.

The conjugate addition of activated nitrogen nucleophiles, such as hydroxylamine and hydrazine derivatives, to a,/3-unsaturated bicyclic lactam 284 gave the corresponding /3-amino product 285 in good yield and excellent diastereoselectivity. These products can be manipulated to afford enantiopure /3-aminopyrrolidinones of potential application as conformationally constrained, substituted glutamate templates (Equation 45) <2001J(P1)2997>. 

The disulfide dimers of 2-aminothiophenols have also been used in the syntheses of benzothiazines. In this case, nitrogen acts as a nucleophile and sulfur as an electrophile. Reagents that have nucleophilic carbons adjacent to an electrophilic carbon can be reacted with these disulfides. Examples include a,(3-unsaturated esters that undergo conjugate addition followed by enolate addition to sulfur (Equation 86) <1983J(P1)567>, and 1,3-dicarbonyl compounds such as ethyl acetoacetate <2005AXEo2716> and dimethyl malonate <2006ARK(xv)68> (Scheme 63). 

Ethoxymethylene)-2-phenyl-5(47/)-oxazolone 404, readily available from hippuric acid and triethyl orthoformate, has also been used as a starting material for other unsaturated oxazolones via addition-elimination reactions. Nitrogen nucleophiles are most commonly used and amines give rise to 4-(aminomethyl-ene)-2-phenyl-5(4//)-oxazolones 405 (Scheme 7.130 Table 7.37, Fig. 7.48) which, in many cases have been evaluated as antihypertensives. 

Boron—nitrogen coordination polymers, with ferrocene, 6, 208 Boron nucleophiles, in conjugate additions asymmetric 1,4-additions, 10, 388 mechanisms, 10, 384 to nitroolehns, 10, 388 to a,/3-unsaturated amides, 10, 386 to a,/3-unsaturated esters, 10, 386 to a,/3-unsaturated ketones, 10, 384 Boron-silicon bonds, addition to alkenes, 10, 760 to alkynes, 10, 758 to allenes, 10, 760 to carbenoids, 10, 766 to 1,3-dienes, 10, 762 to isocyanides, 10, 765... 

The Michael addition of a nitrogen nucleophile to an a,P-unsaturated system has been advocated as a method to prepare P-amino acid derivatives (Scheme 2.24).88 91 However, the method is not... 

An interesting methodology to highly oxygenated p)razolidines and indolizidines from 2,3-unsaturated sugar lactones was presented by Chmielewski [84]. The synthesis was initiated by a 1,4-addition of nitrogen nucleophiles to unsaturated lactones 93, which resulted in formation of appropriate heterocyclic derivative 94 (O Scheme 38). 

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