Nitroalkenes aldehydes

Pianetary baii miii, two steei baiis, 20Hz, 1 h, aldehyde nitroalkene NaHCOs catalyst 1.2 1 0.2 0.2moi. 

The sequential organocatalyzed Stetter and Michael-aldol condensation of aromatic aldehydes, nitroalkenes, and a,p-unsaturated aldehydes via the [1-I-2-I-2]... 

Scheme 43.30 Dual hydrogen-bond/enamine catalyzed enantioselective aldehyde-nitroalkene-aldehyde domino reaction.

The Barton-Zard (BZ) pyrrole synthesis is similar both to the van Leusen pyrrole synthesis that uses Michael acceptors and TosMlC (Section 6.7) and the Montforts pyrrole synthesis using a,P-unsaturated sulfones and alkyl a-isocyanoacetates." An alternative to the use of the reactive nitroalkenes 1 is their in situ generation from P-acetoxy nitroalkanes, which are readily prepared via the Henry reaction between an aldehyde and a nitroalkane followed by acetylation. Examples are shown later. 

The direct conversion of nitroalkenes into ketones is especially useful for the preparation of arylacetones. They are readily prepared by the condensation of aromatic aldehydes with nitroethane and by the subsequent Nef reaction. "Typical examples are presented in Eq. 6.22 and Eq. 6.23 the product of Eq. 6.23 is used for total synthesis of perylenequinone, calphosdn D, which is a potent inhibitor of protein kmase C. "... 

Nitroalkenes are shown to be effective Michael acceptor B units In three sequential re fA + B + C couplingi in one reaction vessel. The sequence is initialed by enolate nucleophiles fA and is terminated by aldehydes or acrylate electrophiles fC. The utility of this protocol is for rapid assembly of complex stnictures from simple and readily available components. A short total synthesis of a pyrroLmdine alkaloid is presented in Scheme 10.16. ... 

The stereochemical outcome of the addition of lithium enolates of aldehydes and ketones to nitroalkenes is dependent upon the geometry of the nitroalkene and the enolate anion. The synjanti selectivity in the reaction of the lithium enolates of propanal, eyelopentanone and cyclohexanone with ( )- and (Z)-l-nitropropene has been reported1. 

Rovis and co-workers have also extended the intermolecular Stetter reaction to inclnde nitroaUcenes as the electrophilic component. Fluorinated triazolinm precatalyst 155 was effective in catalysing the reaction of a variety of heteroaromatic aldehydes 153 with nitroalkenes 154 to generate P-nitroketones in excellent yields and enantioselectivities. The authors propose that stereoelectronically induced conformational effects on the catalyst skeleton are key to the high selectivities observed with flnorinated catalyst 155 (Scheme 12.33) [69],... 

The 3-nitro alcohols are generally obtained in good yield by the reaction of aldehydes with nitroalkanes in the presence of a catalytic amount of base. When aryl aldehydes are used, the (3-nitro alcohols formed may undergo elimination of water to give aryl nitroalkenes. Such side reactions are not always disadvantageous, for nitroalkenes are sometimes the ultimate target for the Henry reaction. The choice of reaction conditions is important to stop the reaction at the stage of 3-nitro alcohols in aromatic cases. 

Conjugated nitroalkenes are isomerized to allylic nitro compounds under basic conditions. Reactions of a,P-unsaturated nitro compounds with aldehydes under basic conditions lead directly to y,8-unsaturated P-nitro alcohols (Eq. 3.24). 3 This reaction is very useful for preparing allylic nitro compounds. 

A1203 can be used both as a base for the Henry reaction and as a dehydrating agent. Thus, nitroalkenes are simply prepared by mixing of aldehydes and nitroalkanes with A1203 and subsequent warming at 40 °C (Eq. 3.30).53... 

In general, base-catalyzed reactions of aromatic aldehydes with nitroalkanes give nitroalkenes directly (Knoevenagel reaction).54 The reaction is very simple heating a mixture of aromatic aldehydes, nitroalkanes, and amines in benzene or toluene for several hours using a Dean-Stark water separator gives the desired nitroalkenes in good yield, as shown in Eqs. 3.31-3.34.54-58... 

Nitroalkenes prepared from aromatic aldehydes are especially useful for natural product synthesis. For example, the products are directly converted into ketones via the Nef reaction (Section 6.1) or indoles (Section 10.2) via the reduction to phenylethylamines (Section 6.3.2). The application of these transformations are discussed later here, some examples are presented to emphasize their utility. Schemes 3.3 and 3.4 present a synthesis of 5,6-dihydroxyindole66 and asperidophytine indole alkaloid,67 respectively. 

The base-catalyzed joint reaction of nitroalkenes with thiophenol in the presence of aldehydes gives y-phenylthio-P-nitro alcohols in one pot (Eq. 4.5).8 The joint reaction of nitroalkenes with thiols and a,p-unsaturated nitriles (or esters) has also been achieved. (Eq. 4.6).9 P-Nitro sulfides thus prepared show unique reactivity toward nucleophiles or tin radicals. The nitro... 

The addition of alkoxides to 2-nitro-l-phenylthio-l-alkenes affords P-nitro-aldehyde acetals.276 The reaction of the same nitroalkenes with amines gives nitroenamines.270 They are important intermediates for organic synthesis and are generally prepared by the reaction of nitroalkanes with triethylorthoformate in the presence of alcohols or secondary amines.2"1 0 The methods of Eqs. 4.20 and 4.21 have some merits over the conventional methods, for variously substituted (3-nitro-aldehydes acetals or nitroenamines are readily prepared by these methods. 

Barrett and coworkers have explored hetero-substituted nitroalkenes in organic synthesis. The Michael addition of nucleophiles to 1-alkoxynitroalkenes or 1-phenylthionitroalkenes followed by oxidative Nef reaction (Section 6.1) using ozone gives a-substituted esters or thiol esters, respectively.41 As an alternative to nucleophilic addition to l-(phenylthio)-nitroalkenes, Jackson and coworkers have used the reaction of nucleophiles with the corresponding epoxides (Scheme 4.4).42 Because the requisite nitroalkenes are readily prepared by the Henry reaction (Chapter 3) of aldehydes with phenylthionitromethane, this process provides a convenient tool for the conversion of aldehydes into ot-substituted esters or thiol esters. 

The review by Barrett (Ref. 127) documents synthetic application of hetero-substituted nitroalkenes (see also Chapter 4). 1-Chloro-l-nitroalkenes are readily obtained either by the Henry reaction of chloronitromethane with aldehydes or chlorination of l-nitroalkenes. Dauzonne and coworkers have used 1-chloro-l-nitroalkenes for construction of dihydrobenzo-furan or dihydrobenzopyran frameworks. (Eq. 5.83).133... 

The conversion of primary or secondary nitro compounds into aldehydes or ketones is normally accomplished by use of the Nef reaction, which is one of the most important transformations of nitro compounds. Various methods have been introduced forthis transformation (1) treatment of nitronates with acid, (2) oxidation of nitronates, and (3) reduction of nitroalkenes. Although a comprehensive review is available,3 important procedures and improved methods published after this review are presented in this chapter. The Nef reaction after the nitro-aldol (Henry reaction), Michael addition, or Diels-Alder reaction using nitroalkanes or nitroalkenes has been used extensively in organic synthesis of various substrates, including complicated natural products. Some of them are presented in this chapter other examples are presented in the chapters discussing the Henry reaction (Chapter 3), Michael addition (Chapter 4), and Diels-Alder reaction (Chapter 8). 

The preparation of resin-bound nitroalkenes via a microwave-assisted Knoevenagel reaction of resin-bound nitroacetic acid with aryl and alkyl substituted aldehydes is reported. The potential of these resin-bound nitroalkenes for application in combinatorial chemistry is demonstrated by a Diels-Alder reaction with 2,3-dimethylbutadiene (Scheme 8.9). It is also used for one-pot three-component tandem [4+2]/[3+2] reactions with ethyl vinyl ether and styrene 46... 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

Denmark and coworkers have found that methylaluminum bis (2,6-di-tert-butyl-4-methyl-phenoxide) (MAD) or methylaluminum bis(2,6-diphenylphenoxide) (MAPh) is effective as the Lewis acid promoter for cycloaddition of 2,2-disubstituted 1-nitroalkenes (Eq. 8.100).158 Other Lewis acids such as SnCl4, TiCl4, and TiCl2(Oi-Pr)2 fail to promote the cycloaddition of 2,2-disubstituted 1-nitroalkenes. The products are converted into 3,3-disubstituted pyrrolidines via hydrogenolysis.158 Reductive cleavage of N-0 bonds produces oxime hemiacetals, which are further reduced to amido aldehydes and finally to pyrrolidines. This reaction provides a useful synthetic method for pyrrolidines, which is discussed later. 

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the direct nucleophilic addition of acyl anions to nitroalkenes using silyl-protected thiazolium carbinols <06JA4932>. In the presence of a fluoride anion, carbinol 186 is not cleaved to an aldehyde... 

Microwave-assisted Knoevenagel reactions have also been utilized in the preparation of resin-bound nitroalkenes [56], The generation of various resin-bound nitroalkenes employing resin-bound nitroacetic acid has been described the latter was condensed with a variety of aldehydes under microwave conditions (Scheme 7.40). 

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