Henry reaction., nitroalkene synthesis

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 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). 

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 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). 

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. 

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. 

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... 

Most recently, Xu et al. have demonstrated the first example of a diastereo-and enantioselective aza-MBH-type reaction by the asymmetric synthesis of p-nitro-y-enamines via a (li ,2i )-diaminocyclohexane thiourea derivative (182) mediated tandem Michael addition and aza-Henry reaction in good yields (up to 95%) with high enantioselectivities (up to 91% ee) and diastereoselectivities (up to 1 99 dr) (Scheme 2.90) easily prepared A -tosylimines and nitroalkene are employed as the starting materials. ... 

Nitroalkene Synthesis. Henry reaction of (phenylthio)nitro-methane with aldehydes fohowed by dehydration has been used to prepare (. -l-nitro-l-phenylthioalkenes. potassium 7eri-butoxide-catalyzed addition and dehydration via mesylation (eq 1), or direct condensation catalyzed by piperidinium acetate (eq 2), are the methods of choice. Henry reaction can be also carried out by reaction of the nitroalkene dianion with aldehydes. ... 

The Henry reaction, or nitroaldo reaction, is one of the classic carbon-chain formation methods utilized in organic synthesis. It involves the condensation of nitroalkanes with aldehydes or ketones in the presence of bases (often catalytic amount) to afford the mixtures of diastereomeric 2-nitroalcohols, which in turn can be converted into other useful synthetic intermediates, such as 2-aminoalcohols, a-hydroxyketones, homologous ketones, and perhaps most importantly, nitroalkenes through various functional transformations. 

The Henry reaction is a base-catalyzed C-C bond-forming reaction between nitroalkanes and aldehydes or ketones. It is similar to the aldol addition, and is also referred to as the nitroaldol reaction. Since its discovery in 1895 [1] the Henry reaction has become one of the most useful reactions for the formation of C-C bonds, and most particularly for the synthesis of P-nitroalcohol derivatives [2]. The general features of this reaction are (i) the potential offered by the nitro and hydroxyl groups on the products for transformation into other compound families such as P-amino alcohols, P-amino acids, or nitroalkenes (ii) only a catalytic amount of base is required (iii) up to two contiguous stereogenic centers may be created in a single step concomitantly to the C-C bond formation. Several recent reviews with a focus on the asymmetric Henry reaction and its applications have appeared [3j. 

In our group, we have described the synthesis of nitroalkenes starting from iodo-glycosides via a novel tandem metallation-elimination-Henry reaction [60]. The reaction can be promoted either by the metal system zinc-indium or by n-BuLi, leading to different results in both cases. Thus, reaction of 5-iodo-ribofuranoside 3 with bromonitromethane in the presence of zinc (10 equivalents) and indium (1 equivalent) in THF/H2O 4 1 under sonication at 40°C, afforded a 5 4 mixture of nitrohexene 76 and bromonitrohexene 77, from which nitrohexene 76 was isolated in a 39% yield... 

The 1,6,7-asymmetric induction reaction has also been used to obtain anti aldol adducts. In total synthesis of epi-cochlioquinone A 322, an inhibitor of acyl-CoA cholesterol acyltransferase (Scheme 8.53), adduct 315 was submitted to a one-pot protection-ozonolysis procedure to give aldehyde 316. One-pot Henry reaction-dehydration afforded nitroalkene 317, which was converted into... 

Michael/Henry/dehydration/aromatisation reaction of 2-(2-oxoethyl) benzal-dehydes and nitroalkenes mediated by pyrrolidine to obtain polysubstituted naphthalene derivatives. DBU catalysed the conjugate additions of alcohols to ot,p-unsaturated nitriles, esters and ketones. Perhaps more important are the aza-Michael addition reactions of amines to a,p-unsaturated ketones, nitriles and esters. Recently, Costa, Vilarrasa and coworkers described the addition of lactams, imides, 2-pyridone, pyrimidine-2,4-diones and inosines to methyl propiolate and other similar compounds, DABCO and DMAP being the best catalysts. As mentioned before, tertiary amines give zwitterionic species with activated allynes. It was as early as 1932 when Diels and Alder used the reaction of pyridine with dimethyl acetylenedicarbojylate (DMAD) for the synthesis of heterocycles. The interception of the corresponding intermediate with Al-tosylimines and activated olefins provided access to l-azadienes ° and highly substituted butadienes (Scheme 2.6). When the quenching species of the zwitterionic intermediate is a 1,2-diketone, dibenzoyl maleates or cyclopentenedione derivatives could be obtained (Scheme 2.6). The interception of the zwitterionic species of N-methyl imidazole (NMI) and DMAD with ketenes to obtain unsaturated esters has also been shown. ... 

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