Nitroalkenes reaction

The Barton-Zard reaction refers to the base-induced reaction of nitroalkenes 1 with alkyl a-isocyanoacetates 2 to afford pyrroles 3. Solvents used are THF or alcohols (or mixtures) and the reaction often proceeds at room temperature. 

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. 

In 1985, in the course of their interest in nitroalkane chemistry, Barton and Zard reported the base-catalyzed reaction of nitroalkenes with a-isocyanoacetates leading to pyrrole esters having an ideal substitution pattern for the synthesis of porphyrins and bile... 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

The final class of reactions to be considered will be the [4 + 2]-cycloaddition reaction of nitroalkenes with alkenes which in principle can be considered as an inverse electron-demand hetero-Diels-Alder reaction. Domingo et al. have studied the influence of reactant polarity on the reaction course of this type of reactions using DFT calculation in order to understand the regio- and stereoselectivity for the reaction, and the role of Lewis acid catalysis [29]. The reaction of e.g. ni-troethene 15 with an electron-rich alkene 16 can take place in four different ways and the four different transition-state structures are depicted in Fig. 8.16. 

A short synthesis of ptostaglandm derivatives via a three component coupling reaction reported, in which the enolates are trapped v/ith nitroalkenes. The nitro group is removed v... 

Reactions of zinc-copper reagents bearing acidic hydrogen and sulfur ftincdonliiities v/ith various electrophiles, including nitroalkenes, have been reported, as shovm in Eq. 4.86 ° and Eq. 4.87, °" respectively. 

The reaction of conjugated nitroalkenes v/ith a,fi-unsaturated esters, ketones, nitnles, and sulfones is catalyzed by TMG to give the Michael adduct of allyiic nitro compounds fEq. 4.108. -... 

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. "... 

Nitro compounds have been converted into various cyclic compounds via cycloaddidon reactions. In particular, nitroalkenes have proved to be nsefid in Diels-Alder reactions. Under thermal conditions, they behave as electron-deficient alkenes ind react v/ith dienes to yield 3-nitrocy-clohexenes. Nitroalkenes c in also act as heterodienes ind react v/ith olefins in the presence of Lewis acids to yield cyclic alkyl nkronates, which undergo [3- 2 cycloaddidon. Nitro compounds are precursors for nitnie oxides, alkyl nitronates, and trialkylsilyl nitronates, which undergo [3- 2 cycloaddldon reacdons. Thus, nitro compounds play important roles in the chemistry of cycloaddidon reacdons. In this chapter, recent developments of cycloaddinon chemistry of nitro compotmds and their derivadves are summarized. 

Functionalized nitroalkenes are important chenophiles in the Diels-Alder ri example, fE -methyl fi-nitroactylate is an impottant reagent in organic synthesis The nitre group can be readily eliminated the Diels-Alder reaction of fi-nitroactylate is equivalent to that of ethyl propiolate with an inverse regiochemistry fEq. 8.4. ... 

Node and co-workers have found that the Diels-Alder reaction of nitroalkenes v/ith 1-methoxy-3-trimethylsilyloxy-l,3-butadiene (Danishefsky s dienesi exhibit abnormal exo-se-lecdvity Electrostadc repulsion between the nitro and the silyloxy group of the diene induces this abnormal exc-selecdvity (Tq 8 10 This selecdve reacdon has been used for the asymmetric synthesis of various naniral products as shovm in Scheme 8 6... 

The Diels-Alder reaction of nitroalkenes with Danishefsky s dienes is applied to synthesis of truncated carbocyclic analogues of a potent neuraminidase inhibitor 4-guanidino-NemAc en fsee Scheme 8.5. Carbocyclic analogs are found to retain interesting levels of antiviral activity comparable to those shovm by their oxygen-containing compounds in Scheme 8.5. 

Diels-Alder reactions in which nitroalkenes act as dienophiles are acceleratedin thepresence of 4 M l.iClOi) in nitromethane This acceleration is higher than that observed when l.iClO is used in diethyl ether The diastereoselecdve Diels-Aider reaction using homochiial nitroalkenes shown in Eq 8 31 has been demonstrated... 

One-pot tandem reactions, starting v/ith nitroalkenes and allyl alcohols leading to fitnaion-alized tetrahydrofitrans, have been repotted fEq. 8.87. ... 

Intra [4+2]/inter [3+2] This type of tandem reaction nsmg nitroalkenes has n been extensively explored, and one example has been reported fEq 8 111 ... 

Inter [4+2]/intra [3+2] This typeof tandem reaction nsmg nitroalkenes hasbeen expbred most extensively Four subfamilies of tandem cycloaddiQon exist, which anse from the font different pomts of attachment of the dipolarophihc tether They are defined as fused, spiro, and bridged modes, as depicted m Scheme 8 37... 

DBU IS most widely employed as the base m the Barton-Zard reaction Stronger nonionic bases such as PrMeNCH-,CH-j,N and the phosphazene base Csiipplied by Flukai are more effective to induce pyrrole formadon in the reaction of nitroalkenes v/ith isocyano esters than DBU Sterically hindered nitroalkenes are converted into the corresponding pyrroles using these bases, as shovm in Eq 10 35, but DBU is not effective in this transformation... 

The direct aziridinadon of nitroalkanes has been repotted for the first dme. Treatment of nitroalkene with an excess of CaO and NsONHCO-.Et fNs =4-nitroben2enesulfonyl gives the ct-nitroaziridine in good yields fEq. 10.70. ° The reaction proceeds via aza-Michael reaction followed by a ring closure. 

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. ... 

A high degree of syn selectivity can be obtained from the addition of enamines to nitroalkenes. In this case, the syn selectivity is largely independent of the geometry of the acceptor, as well as the donor, double bond. Next in terms of selectivity, are the addition of enolates. However, whether one obtains syn or anti selectivity is dependent on both the geometry of the acceptor and the enolate double bond, whereas anti selectivity of a modest and unreliable level is obtained by reaction of enol silyl ethers with nitroalkenes under Lewis acid catalysis. 

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. 

High syn selectivity can be obtained from the addition of enamines to nitroalkenes. The reaction of 4-(1-cyclohexenyl)morpholine with ( )-l-bromo-4-(2-nitroethenyl)benzene gives, after acid hydrolysis, exclusively the. ryw-adduct, the relative configuration of which was unequivocally... 

The initial addition step is reversible allowing isomerization of the ( )- and (Z)-nitroalkenes and equilibration between the initially formed syn- and ann -imminium ion adducts. The spn-ad-duct is identical to that obtained from the lithium enolate of cyclohexanone and ( >(2-nitro-cthenyl)benzenc. The preference for the. yyu-adduct can be rationalized by inferring the transition state 1 which is similar to that proposed for the reaction of (-E)-nitroalkcnes with ( )-eno-lates11, l2. 

The Lewis acid catalyzed reactions of silyl enol ethers with nitroalkenes have been reviewed, however the diastereoselectivity of these reactions has not been addressed17. 

The Lewis acid mediated addition of allylic tin reagents to nitroalkenes has been reported. The condensation reaction of tributyl[(Z)-2-butenyl]tin(IV) with (E)-(2-nitroethenyl)benzene or (L)-l-nitropropene catalyzed by titanium(IV) chloride proceeded with modest anti diastereoselectivity. Poorer diastereoselection resulted when diethyl ether aluminum trichloride complex was employed as the Lewis acid 18. 

The enantiomeric (2/ ,l S)-nitro ketone was obtained starting from the corresponding enantiomeric (f )-enamine. The stereochemical outcome of these reactions was rationalized by assuming a transition state in which steric interactions between the enamine and the nitroalkene are minimized. 

The addition of (Z)-3-(alkylamino)-2-butenoic acid esters to nitroalkenes derived from open-chain sugars gave a 50 50 mixture of diastereomeric products 32. The reaction of chiral 2-sub-stituted l-(2-nitroethenyl)pyrrolidines with zinc enolates of 3-substituted tetrahydro-2//-pyran-2-oncs in 1,2-dimethoxyethane at — 78 °C afforded the corresponding 3,3-disubstituted products in 82-96% ee via an addition-elimination process33. The stereochemical course of the reaction was determined by chemical correlation of (S)-( )-3-ethyltetrahydro-3-(2-ni-troethenyl)-2//-pyran-2-one with ( + )-quebrachamine. 

A great acceleration was also observed in the cycloadditions of alkylidene derivatives of 5-iminopyrazoles with nitroalkenes, as electron-poor dienophiles, under MW-irradiation in solvent-free conditions [40c]. Some results are illustrated in Scheme 4.10. All the reactions took place with loss of HNO2 and/or NHMei after the cycloaddition, inducing aromatization of the final product. 

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