Nitroalkenes acylation

The addition-elimination reaction of hetero-atom-substituted nitroalkenes provides functionalized derivatives of unsaturated nitro compounds.26 Nitroenamines are generally prepared from a-nitro ketones and amines (see Chapter 5 regarding acylation of nitro compounds).26... 

Seebach and Brenner have found that titanium enolates of acyl-oxazolidinones are added to aliphatic and aromatic nitroalkenes in high diastereoselectivity and in good yield. The effect of bases on diastereoselectivity is shown in Eq. 4.59. Hydrogenation of the nitro products yields y-lactams, which can be transformed into y-amino acids. The configuration of the products is assigned by comparison with literature data or X-ray crystal-structure analysis. 

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 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... 

The reactions of nitroalkenes (42) with various enols (43b) (vinyl ethers, silyl, and acyl enolates, ketene acetals) have been studied in most detail (110, 111, 125—154). As a mle, these reactions proceed smoothly to give the corresponding nitronates (35f) in yields from high to moderate. As in the reactions with enamines, the formation of compounds (44b) is attributed to the ambident character of the anionic centers in zwitterionic intermediates analogous to those shown in Scheme 3.43. 

The chemistry of acyl nitronates derived from secondary AN has received much more attention. Yoshikoshi and coworkers (226-228) developed a reliable procedure for the synthesis of these derivatives from readily available precursors (ketones and a-nitroalkenes), they demonstrated that the resulting acyl nitronates (123) are convenient reagents for the preparation of various heterocyclic and acyclic derivatives (226) (Scheme 3.104). 

Chiral 4-phenyloxazolidin-2-one has been iV-alkylated with nitroalkenes, and the products subsequently converted into chiral amino acids and diamines <99EJ02583>. AT-acylation of... 

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

Typically, oc,0-unsaturated esters, a,0-unsaturated aldehydes and a,0-unsaturated nitriles are poor acceptors for the Lewis acid catalyzed silylallylation procedure, but they are excellent acceptors for the complementary fluoride ion mediated allylation procedure (cf. Volume 4, Chapter 1.2, Section 1.2.2.1.7). Other suitable acceptors include 1,4-quinones,70 a,0-unsaturated acyl cyanides (162),718 silyl ot,0-enoates (163)71b and nitroalkenes (Scheme 26) 72 reduction (titanium(III) trichloride) of the intermediate nitronates arising from nitroalkene allylation affords y,8-enones (166). 

Thiamine-catalyzed transformations are reversible, thus TV,/V-dialkyl hydrazones were selected as alternative acyl anion equivalents that were reported to react with electrophiles without acidic activation.41 One especially reactive example, formaldehyde hydrazone resin 13, was constructed from polymer-supported hydrazines and was employed in the first polymer-supported, uncatalyzed acyl anion additions (Fig. 8).38 As test substrates, nitroalkenes (as Michael acceptors) and activated aldehydes were selected. Reactivity of these acyl anion equivalents depended critically not only on the nature of the starting hydrazine, but also on the protocol for hydrazine formation. 

Direct nucleophilic acylation of nitroalkenes (164), promoted by a combination of (g) fluoride anion and thiourea catalyst (165), has been developed, using the thiazolium derivative (163) as the umpolung reagent (<20 1 dr, 74% ee).214 ... 

Sn-chelated glycine ester enolates have been proved efficient nucleophiles for highly stereoselective 1,4-additions toward nitroalkenes.37 In the presence of acyl halides the tin also acts as a reducing agent of the nitronate intermediates, giving direct access to nitriles in a one-pot protocol. 

Mattson AE, Zuhl AM, Reynolds TE, Scheldt KA (2006b) Direct nucleophilic acylation of nitroalkenes promoted by a fluoride anion/thiourea combination. J Am Chem Soc 128 4932-4933... 

The polarographic behavior of S-hydroxynitroalkanes is sometimes complicated in acid solution by the dehydration to the more easily reducible nitroalkene [61,62], Nitroalkenes are also obtained from a,j6-dibromonitroalkanes on reduction [35]. Reduction in DMF of acylated 0-hydroxynitroalkanes produces alkenes [63] vicinal dinitroalkanes are reduced similarly [64]. 

In 2006, Scheidt and coworkers [44] reported the first enantioselective direct nucleophilic addition ofthe silylated thiazolium salt 148, a precursor of the equivalent acyl anion, to nitroalkene 149 in the presence of tetramethylammonium fluoride (TMAF) and stoichiometric amounts of quinine-based thiourea 81b, producing the chiral [3-nitroketone 150 in 67% yield and with 74% ee (Scheme 9.51). The acyl anion equivalent 152 can be generated by the desilylation of 148 with TMAF, followed by the 1,2-H shift of the resulting alkoxide 151. The observed asymmetric induction indicates that there is a strong interaction between the thiourea and the nitroalkene during the carbonyl anion addition step. 

Synthesis of left-hand segment began with 7-benzyloxyindole 197. A Vilsmeier-Haack formylation followed by condensation afforded nitroalkene 198. Reduction, acylation with succinic anhydride, and subsequent Bischler-Napieralski cyclization provided dihydro-p-carboline 199. Noyori asymmetric reduction of 199, further treatment with A-iodosuccinimide, followed by activation with silver triflate in the presence of dimethoxy-N,N-diallylaniline furnished the desired coupling product 200. Subsequent saponification and cyclization via a ketene intermediate gave the rearrangement precursor 201. Oxidative skeletal rearrangement initiated by m-CPBA followed by removal of the Fmoc group and conversion of the aniline to the hydrazine furnished Fischer indole precursor 202 (Scheme 35). 

Previously unreported yn-diastereoselectivity in the synthesis of 6-niuoesters (94) from enals (95) and nitroalkenes (96) has been achieved, using an NHC (97, reminiscent of dialkylprolinol TMS ether) designed to avoid the established acyl anion/Stetter pathway and favour the homoenolate route.The method has been further exploited in a mild and elegant one-pot synthesis of 6-lactams (98) from similar starters. 

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