Nitroalkenes, Henry 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. 

Chiu et al. developed the first example of a reductive intramolecular Henry reaction induced by Stryker s reagent (Scheme 30) [53]. The conjugate reduction of keto-nitroalkenes with [Ph3PCuH]6 (150 mol%) triggers spontaneous nitro-aldol reaction at - 40 °C to produce (f-hydroxy nitro compounds in moderate yield. 

The synthesis of cyclic nitroalkenes via nitration of cycloalkenes is summarized in Table 2.2. Acyclic nitroalkenes are more readily prepared via the Henry reaction than by nitration of alkenes (see Section 3.2.1). 

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. 

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... 

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). 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

The condensation reaction of neat carbonyl compounds with nitroalkanes to afford nitroalkenes, Henry reaction, also proceeds rapidly via this MW approach in the presence of only catalytic amounts of ammonium acetate, thus avoiding the use of a large excess of polluting nitrohydrocarbons normally employed (Scheme 6.22) [72],... 

The nucleophilic addition of nitroalkane to carbonyl groups is known as the Henry reaction. The products of the Henry reaction are 2-nitroalkanols,115 which are useful intermediates for nitroalkenes, 2-amino alcohols, and 2-nitro-ketones. However, this does not always give high yields because of the possible O-alkylation in preference to C-alkylation during the Henry reaction. 

Reaction of nitromethane and monosaccharide-derived dialdehydes is a useful tool that has been broadly used for the preparation of nitro and amino sugars, and carbocycles.30 Dialdehydes can easily be obtained by oxidative cleavage of conveniently protected monosaccharides with sodium periodate. Their subsequent Henry reaction with a nitroalkene, commonly nitromethane, usually gives isomeric mixtures that require the isolation of the major isomer.31 Thus, treatment of the D-ribose derivative 27 with sodium periodate gave dialdehyde 28, which was subjected to a Henry reaction with nitromethane, to afford nitrosugar 29 as an epimeric mixture (Scheme 11).32... 

For a review of this reaction with respect to nitroalkancs (often called the Henry reaction), see Baer Urbas. in Feuer, Ref. 180, pp. 76-117. See also Rosini Ballini Sorrenti Synthesis 1983, 1014 Matsumoto Angew. Chem. Int. Ed. Engl. 1984,23, 617 Angew. Chem. 96, 599) Eyer Seebach J. Am. Chemr Soc. 1985, 107. 3601. For reviews of the nitroalkenes that are the products of this reaction, see Barrett Graboski Chem. Rev. 1986,66.751-762 Kabalka Varma Org. Prep. Proced. Int. 1987, 19. 283-328. 

Keywords nitroalkane, aromatic aldehyde, Henry reaction, microwave irradiation, nitroalkene... 

The oxidation of the alcohol was performed with supported perruthenate (8.48, Fig. 8.46) to produce clean aldehydes 8.91 after filtration. The Henry reaction was performed in the presence of a commercially available, supported strong base 8.92 and an excess of volatile nitroalkenes, giving clean nitroalcohols 8.93 after filtration and evaporation. The reaction mixtures from the trifluoroacetylation/elimina-tion steps were purified with commercially available amino PS resin 8.58 to scavenge the trifluoroacetates and with acidic ion-exchange resin 8.76 to remove the TEA-derived salts. Again, the nitrostyrenes 8.94 were obtained cleanly after filtration and evaporation. Cycloaddition with isocyanoacetate was promoted by the commercially available, supported guanidine base 8.95, while the subsequent N-alkylation of the pyrroles 8.96 was performed with an excess of halide in the presence of the commercially available, supported phosphazene 8.97. In this case, the excess halide was removed by treatment with supported 8.58, and filtra-... 

The synthesis of the bisbenzannelated spiroketal core of the y-rubromycins was achieved by the research team of C.B. de Koning." The key step was the Nef reaction of a nitroolefin, which was prepared by the Henry reaction between an aromatic aldehyde and a nitroalkane. The nitroolefin was a mixture of two stereoisomers, and it was subjected to catalytic hydrogenation in the presence of hydrochloric acid. The hydrogenation accomplished two different tasks it first converted the nitroalkene to the corresponding oxime and removed the benzyl protecting groups. The oxime intermediate was hydrolyzed to a ketone that underwent spontaneous spirocyclization to afford the desired spiroketal product. 

By employing the primary amine catalyst 160, Zhong and coworkers developed the tandem Michael-Henry reaction of ketones with nitroalkenes to provide highly functionalized chiral hexanes and pentanes with high diastereo- and enantioselec-tivity [49]. The selected examples depicted in Scheme 9.56 show that, in the presence of 160 (10-15 mol%), various Michael donors and nitroalkenes smoothly underwent the tandem reaction with almost quantitative yield and extremely high enantios-electivity with the complete diastereoselectivity of the products. Further details of this reaction can be seen in Section 10.4. 

Concerning the reaction mechanism, the transformation of an aldehyde into a nitroalkene can occur via two different pathways the first involves nitroalcohol formation through a traditional Henry reaction, which is then followed by water elimination to form the double bond the second proceeds through an imine intermediate rather than the nitroalcohol. The authors predicted that nitroalkene formation goes through an imine intermediate (Scheme 3.9) rather than the nitroalcohol as they did not observe nitroalcohol formation at any point in the reaction. In addition, when the nitroalcohol is placed in the presence of swollen capsules, no nitroalkene formation is observed this inability to... 

The Henry reaction is performed, in the presence of catalysts (organic or inorganic bases, quaternary ammonium salts, etc.), protic and aprotic organic solvents [161], water [162], supercritical fluids [163] or ionic liquids [164], Nitroalkenes can be obtained as by-products, via dehydration of p-nitroalcohols. Considerable efforts have been made to increase the yield and selectivity and to control the basicity of the medium and the reaction time. 

The base-catalysed condensation of nitromethane with aldehydes to give nitroalkenes -13 (the Henry reaction). One example -14 was used in a Corey prostaglandin synthesis.2... 

For a review of the Henry reaction, i.e. the reaction of nitroalkenes with carbonyl compounds, see H. H. Baer and L. Urbas, in The Chemistry of the Nitro and Nitroso Groups , ed. H. Feuer, Interscience, New York,... 

Aza-Henry reaction is rendered asymmetric by quaternary salts of Cinchona alkaloids. Addition reactions. Changing the 9-hydroxy group of Cinchona alkaloids to a 9-epiamino group not only is synthetically expedient, such products often show excellent catalytic activities in many asymmetric reactions. Those derived from dihydrocinchona alkaloids mediate Michael reactions to good results, including addition of indole to enones, and carbonyl compounds to nitroalkenes. Salt 4 has also been successfully employed in the alkenylation of t-butyl a-aryl-a-cyanoacetate. ... 

Catalyzed Reactions. Many aldehydes react with nitroalka-nes in the presence of a catalytic amount of LiAIH4 at 0 °C to give 2-nitroalkanols in excellent yields (eq 48). Li AIH4 is an effective catalyst and a practical alternative to classical bases in Henry reactions. This method avoids the dehydration of 2-nitroalkanols into nitroalkenes even in the case of aromatic aldehydes. In the case of a, 8-unsaturated aldehydes, no Michael addition is observed. 

The most recent entry to bicyclic P-lactam compounds through this approach, has been introduced by Barrett and his coworkers [120] by using an intramolecular Michael type reaction of a Af-silyl p-lactam to a nitroalkene induced by fluoride ion (Scheme 45). Namely, the known P-lactam 299 [32a] readily prepared from CSI addition to 1,5-hexadiene, was protected by using TBDMSCI and DIPEA to produce the p-lactam 300. Subsequent ozonolysis, gave the aldehyde 301. Henry reaction of the aldehyde 301 with (phenylthio)-nitromethane furnished, after dehydration of the resulting nitroaldol, the nitroalkene 302 which smoothly cyclized to the carbapenam 303 in the presence of... 

---