Aldehyde condensation nitrones

The nitroaldol condensation reaction involving aldehydes and nitronates, derived from deprotonation of nitroalkanes by bases. 

Amide enolates undergo silylation at both carbon and oxygen, depending upon the chloride used. Silyl acetals, which can be prepared from aldehydes, give /5-amino esters, or /5-lactams with Schiff bases. Silyl substituents also play a stereoselective role in the synthesis of aldol type systems, and protect nitrone-aldehyde condensates in dipolar additions that produce isoxazolidines and isoxazolines. ... 

O-Trimethylsilyl nitronates 1036 have been used in fluoride-catalyzed aldol-type condensations with aldehydes and ketones to give a-trimethylsilyloxy-nitro com-... 

Z- Configuration is typical of the majority of a-aryl(hetaryl)-/V-alkylaldo-nitrones. The isolation of -isomers in the condensation of aromatic aldehydes with iV-j3-]ihenyletli Tliydroxylamine has been described (155). The synthesis of a, N -diary lnitrones gives best results if acidic catalysis is employed (156), or when clay is used as a catalyst (157). Significant reduction of reaction time and increase in the yields of nitrones can be achieved if microwave irradiation is used (158, 159). On the basis of polymeric arylaldehydes, the synthesis of polymeric a,-diarylnitrones has been described (160). 

Condensation of N -substituted hydroxylamines with aldehydes and ketones is widely used in the synthesis of various spin traps and biologically active nitrones (Fig. 2.5) (161-186). 

Nitrones resulting from the condensation of aldehydes and ketones with N-monosubstituted hydroxylamines were used in a four component Ugi reaction in a one-pot synthesis of a-acyloxyamino-amides (260). 

Yet another approach to the synthesis of five-membered cyclic nitronates (5) is based on the Henry condensation of a-halo-substituted aldehydes (9) with primary AN followed by cyclization of nitroaldols (Scheme 3.14, Eq. 4) to give five-membered nitronates containing the hydroxy group at the C-4 atom. 

The mechanism of the condensation described is plain, and corresponds entirely to the production of nitrones from phenylhydroxylamine and aldehydes (p. 178) ... 

Since then, optically active a-aminophosphonates have been obtained by a variety of methods including resolution, asymmetric phosphite additions to imine double bonds and sugar-based nitrones, condensation of optically active ureas with phosphites and aldehydes, catalytic asymmetric hydrogenation, and 1,3-dipolar cycloadditions. These approaches have been discussed in a comprehensive review by Dhawan and Redmore.9 More recent protocols involve electrophilic amination of homochiral dioxane acetals,10 alkylation of homochiral imines derived from pinanone11 and ketopinic acid,12 and alkylation of homochiral, bicyclic phosphonamides.13... 

Starting material which, upon oxidation with PSP, gave aldehydes. These were in turn condensed with primary hydroxylamines, promoted by polymer-bound acetate, to produce nitrones. The nitrones assembled using either method then underwent 1,3-dipolar cyclo-addition reactions with various alkenes to give the corresponding isoxazolidines (Scheme 2.46 and 2.47). 

Intramolecular 1,3-dipolar cycloadditions have proven to be especially use fid in synthesis. The addition of nitrones to alkenes serves both to form a carbon-carbon bond and to introduce oxygen and nitrogen functionality.86 Entry 7 in Scheme 6.5 is an example. The nitrone B is generated by condensation of the aldehyde group with 7V-methylhydrox-ylamine and then goes on to product by intramolecular cycloaddition. 

The acyclic precursor is an oc, 3-unsaturated amido aldehyde that was condensed with iV-methylhydroxylamine to generate the nitrone ( )-48, which then underwent a spontaneous cycloaddition with the alkene to afford the 5,5-ring system of the isoxazolidinyl lactam 47. The observed product arises via the ( )-nitrone transition state A [or the (Z)-nitrone equivalent] in which the position of the benzyl group ot to the nitrone effectively controls the two adjacent stereocenters while a third stereocenter is predicted from the alkene geometry. Both transition states maintain the benzyl auxiliary in an equatorial position and thus avoid the unfavorable 1,3-diaxial interaction with the nitrone methyl or oxygen found in transition state B. Semiempirical PM3 calculations confirm the extra stability, predicting exclusive formation of the observed product 47. Related cycloadducts from the intramolecular reaction of nitrones containing ester- rather than amide-tethered alkene functionality are also known (83-85). 

Aldehydes will condense with pyridinium ylides in a manner similar to the Knoevenagel condensation (Scheme 66) (53AG617). However, the corresponding condensation of aromatic nitroso compounds results in the elimination of the parent heterocycle, the product being a nitrone. The reaction is illustrated with phenacylisoquinolinium bromide (71 Scheme 66). 

Mukund Sibi of North Dakota State University has developed (J. Am. Chem. Soc. 2004,126,718) a powerful three-component coupling, combining an a,(5-unsaturated amide 9, a hydroxylamine 10, and an aldehyde 11. The hydroxylamine condenses with the aldehyde to give the nitrone, which then adds in a dipolar sense to the unsaturated ester. The reaction proceeds with high diastereocontrol, and the absolute configuration is set by the chiral Cu catalyst. As the amide 9 can be prepared by condensation of a phosphonacetate with another aldehyde, the product 12 can be seen as the product of a four-component coupling, chirally-controlled aldol addition and Mannich condensation on a starting acetamide. 

Imidazole synthesis. A new synthesis of 4,5-diarylimidazoles (2) involves reaction of catalytic amounts of aqueous elhanolic K.CN with N-methyl-C-aryl nitrones (1), prepared by condensation of aryl aldehydes with N-methyl-hydroxylamine. The reaction involves an intermediate cyanoimine (n). 

The earliest and to date most extensively studied class of intramolecular cycloadditions involves unsaturated nitrones.4 These are most readily available from condensation of an unsaturated aldehyde with a hydroxylamine or an unsaturated hydroxylamine with an aldehyde. Another approach is simply to oxidize an unsaturated hydroxylamine. Nitronic esters are nitrones containing an alkoxy substituent attached to the N-atom they can be prepared from nitro compounds. Frequently an unsaturated nitrone can be isolated and purified, although much work has been done with the nitrone generated in situ eventual cyclization can provide three new contiguous chiral centers, often with only one diastereomer actually formed. 

In addition to the pathways described above, nitrones can derive from condensation of a primary hydroxylamine with an aldehyde or ketone140. Under simulated biological conditions, Beckett and coworkers were able to demonstrate that primary hydroxylamines metabolically formed from amphetamine, mexiletine or norfenfluramine readily combined with ketones produced by metabolic deamination of the primary amines141. Reactions can be formulated according to equation 13, where R1 = aryl, alkyl or aralkyl, and R2 = alkyl or H. 

This topological rule readily explained the reaction product 211 (>90% stereoselectivity) of open-chain nitroolefins 209 with open-chain enamines 210. Seebach and Golinski have further pointed out that several condensation reactions can also be rationalized by using this approach (a) cyclopropane formation from olefin and carbene, (b) Wittig reaction with aldehydes yielding cis olefins, (c) trans-dialkyl oxirane from alkylidene triphenylarsane and aldehydes, (d) ketenes and cyclopentadiene 2+2-addition, le) (E)-silyl-nitronate and aldehydes, (f) syn and anti-Li and B-enolates of ketones, esters, amides and aldehydes, (g) Z-allylboranes and aldehydes, (h) E-alkyl-borane or E-allylchromium derivatives and aldehydes, (i) enamine from cyclohexanone and cinnamic aldehyde, (j) E-enamines and E-nitroolefins and finally, (k) enamines from cycloalkanones and styryl sulfone. 

It should be added that improved formation of products of type 126 was achieved by choosing a different reaction strategy [133], A typical proline-catalyzed aldol reaction (starting from aldehydes as donors and compounds 125 as acceptors), followed by conversion of the C=0 functionality of the aldol adduct into a nitrone group by condensation with a hydroxylamine component led to products of type 126 in good yield and with high enantioselectivity (up to 96% ee) [133],... 

The enolate A or the nitronate A, respectively, initially adds to the C=0 double bond of the aldehyde or the ketone. The primary product in both cases is an atkoxide, D, which contains a fairly strong C,H acid, namely, of an active-methylene compound or of a nitroalkane, respectively. Hence, intermediate D is protonated at the atkoxide oxygen and the C-fi atom is deprotonated to about the same extent as in the case of the respective starting materials. An OH-substituted enolate C is formed (Figures 13.52 and 13.53), which then undergoes an Elcb elimination, leading to the condensation product B. The Knoevenagel condensation and the aldol condensation have in common that both reactions consist of a sequence of an enolate hydroxy alkylation and an Elcb elimination. 

The formation of bicyclic nitrones of the 2-azetidinone A-oxide type, 32 and (33), has been achieved in a two-step route, through condensation of the corresponding 2-azetidinone tethered-alkenyl(alkynyl)aldehyde with hydroxylamine followed by phenylselenyl bromide treatment <02JOC7004>. 

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