Reactive nitroalkenes

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. 

A DFT study of the polar Diels-Alder reaction of 4-aza-6-nitrobenzofuroxan with cyclopentadiene found only one highly asynchronous transition state structure associated with the formation of the 4 + 2-adduct.178 4-Nitrobenzodifuroxan has been shown to be a highly reactive nitroalkene in Diels-Alder reactions with common dienes (cyclopentadiene) to produce stable NED adducts and with ethyl vinyl ether to produce IED adducts.179 Unlike a-acylfuran, 2-nitrofurans have been shown to be active dienophiles in thermal NED Diels-Alder reactions with a variety of buta-1,3-dienes, including Danishefsky s diene.180... 

NBS was used for the allylic bromination and protection was needed for the thiol nucleophile to avoid over-reaction (chapter 5). The reactive nitroalkene 24 was introduced by elimination from 2-nitroethyl acetate. 

The atmospheric lifetimes of nitroalkenes with respect to reaction with OH radicals are calculated to be around 10 days for CH2=CHN02 and about 3 h for cycto-CeH9N02 (the most reactive nitroalkene studied to date). It is expected that the reaction of OH with nitroalkenes proceeds by an addition to the C C double bond, as for simple alkenes. The reactions of the nitroalkenes with ozone and NO3 radicals have not been reported, but they are expected to be significant,... 

Nitroalkenes can be replaced by ct,fi-iinsatiirated siilfones in the Barron-Zard pyrrole synthesis Each method has its own merit Nitroalkenes are more reactive than a,fi-iinsatiirated siilfones therefore, nitroalkenes should be used in less reactive cases. On the other hand, cychc a,fi-nnsanirated siilfones are more easily prepared than cychc nitroalkenes pyrrole synthesis using siilfones is the method of choice in such cases, as shovm in Eq. 10.41. 

Nitroalkenes are also reactive Michael acceptors under Lewis acid-catalyzed conditions. Titanium tetrachloride or stannic tetrachloride can induce addition of silyl enol ethers. The initial adduct is trapped in a cyclic form by trimethylsilylation.316 Hydrolysis of this intermediate regenerates the carbonyl group and also converts the ad-nitro group to a carbonyl.317... 

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 rationalization of stereoselectivity is based on two assumptions. (1) The 1-arylthio-1-nitroalkenes adopt a reactive conformation in which the ally lie hydrogen occupies the inside position, minimizing 1,3-allylic strain. (2) The epoxidation reagent can then either coordinate to the ally lie oxygen (in the case of Li), which results in preferential syn epoxidation or in the absence of appropriate cation capable of strong coordination (in the case of K) steric and electronic effects play a large part, which results in preferential anti epoxidation (Scheme 4.7).52... 

Although Lewis acid-catalyzed-Diels-Alder reactions of enones are common, there are few reports on the catalysis of Diels-Alder reaction of nitroalkenes. The reaction of nitroalkenes with alkenes in the presence of Lewis acids undergoes a different course of reaction to give cyclic nitronates (see Section 8.3). Knochel reported an enhanced reactivity and selectivity of the intramolecular Diels-Alder reaction using silica gel as Lewis acid in hexane (Eq. 8.19).31... 

Asymmetric Diels-Alder reactions using chiral sulfinylalkenes have been extensively studied by Koizumi and coworkers.55 Fuji and coworkers have extended this strategy to chiral l-(alkyl-sulfinyl)-2-nitroalkenes. Such nitroalkenes react with reactive dienes such as Danishefsky s dienes to produce an adduct with a high enantiomeric excess (ee) (see Eqs. 8.34 and 8.35).57... 

Simple dienes are not reactive enough toward chiral l-(alkylsulfinyl)-2-nitroalkenes. To resolve this problem, the reaction of optically active l-(alkylsulfinyl)-2-nitroalkenes with simple... 

The reactions of 4-nitrobenzodifuroxan 242 with a series of common dienes, such as cyclopentadiene, cyclohexa-diene, isoprene, 2,3-dimethylbutadiene, and 1-acetoxybutadiene, with ethoxymethyleneacetylacetone were found to proceed very readily to afford stable cycloadducts, which are the result of highly stereoselective normal electron-demand (NED) Diels-Alder reactions. Due to the additional activation provided by the two adjacent furoxan rings, the nitroalkene double bond of compound 242 is also prone to undergo NED reactions with less reactive dienic structures, such as the enol form of ethoxymethyleneacetylacetone and the in situ generated 2-ethoxy-4-(2-furfur-yl)buta-l,3-diene <2004TL1037, 2005T8167>. 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

Initially, a complex of nitroalkene (42) with LA (A) is reversibly formed. The efficient concentration of the latter is determined by the reaction conditions and the nature of heterodiene (42) and LA. This complex acts as a Michael substrate and adds alkene (43) to give bipolar adduct B, which undergoes cycliza-tion to give cationic intermediate C. The latter eliminates LA to yield target nitronate (35). In the case of nonconcerted cycloaddition, ionic intermediate B can undergo different isomerization reactions, some of which are considered below. The stereoselectivity of the process depends on the reactive conformation... 

The formation of nitrocyclobutanes (44) is attributed to the contribution of the structure B" to the reactivity of stabilized zwitterionic intermediate B. The contribution of C-alkylation decreases due to steric hindrance caused by the presence of substituents at the a-position of the initial nitroalkene (42). 

Several nitroalkenes show high reactivity and/or low stability, individually indexed... 

As we have seen in Chapter 2 (Scheme 2.3, equation 3), the doubly deprotonated nitroalkanes are nitroalkenes with reactivity inversion which violate the Lapworth model of alternating polarities and react with electrophiles at the ipso- and a-positions ... 

On the other hand, doubly deprotonated nitroalkenes are reagents with a double reactivity inversion (Scheme 5.30) provided they are used to prepare normal 0-, A-derivatives [1]. For instance, the 1-nitrobutadiene dianion 43 reacts with electrophiles to give a mixture of a- and y-isomers, 44a and 44b. Addition of the dianion 43 to 2-cyclohexenone gives only the y-adduct 45 which was transfomed into the 1,7-ketoaldehyde 46 by a Nef-type reaction with TiCl3 [38]. As shown in Scheme 5.30, although the resulting product is a "consonant system" (1,7-C), the... 

When nitroalkenes were used as Michael acceptors, high yields and enantioselectivities of the desired Michael addition products were also obtained (Scheme 5.22). In these reactions, a well-defined chiral Ru amido complex (Figure 5.9) was an efficient catalyst. The mild reaction conditions and high reactivities and stereoselectivities allowed a large-scale reaction in the presence 1 mol% Ru catalyst. By using a chiral Pd(II) catalyst, an asymmetric allylic arylation was reported by Mikami and coworkers to give the cross-couphng product via the activation of both allylic C H and aryl C H bonds in moderate enantioselectivity (Scheme 5.23). ... 

Avalos et al. (223,224) also found that simpler 2-aminothioisomiinchnones react with nitroalkenes to give dihydrothiophenes and other products, work that includes detailed MO calculations that rationalize both the reactivity of the thioisomilnch-nones and the observed regioselectivity (224). These same thioisomtinchnones (324) react with aryl aldehydes to provide p-lactams 325 following fragmentation and subsequent cyclization of the primary cycloadducts (225). Novel 1,2,4-triazines are produced when 324 is exposed to diethyl azodicarboxylate (226), and detailed synthetic and mechanistic studies have been reported for the reactions of 324 with alkynes (227) and chiral 1,2-diaza-l,3-butadienes (228). 

Noltes et al. [31] have already described the reaction of diethylzinc with diphe-nylphosphane leading to organozinc-phosphorus adducts which have been shown to be very reactive but very insoluble. In our synthesis of the phosphite 45 with the nitroalkenes 46 in the presence of Et2Zn the precipitation of a solid could be observed as well, which was unreactive at -78 °C but underwent addition to the nitroalkenes at 0 °C. In the presence of TMEDA even at these low temperatures the desired Michael adducts 47 were formed with very good yields and high diastereomeric excesses (de - 84-96%) (Scheme 1.1.12). After removal of the... 

The most reactive Michael acceptors, such as alkylidene malonates, gem-dicyanoalkenes and nitroalkenes, react with a-halozinc esters in a conjugate fashion. Beautiful examples were offered by two stereocontrolled conjugate additions to piperidinone 102 and pyrro-lidinone 104 leading to optically active bicyclic lactams 103147 (equation 60) and 105 (equation 61)148. With these electron-poor alkenes a Grignard two-step protocol is to be adopted in order to avoid the single electron transfer reactions from the metal to the Michael acceptor, which should afford olefin dimers. The best solvent is found to be a... 

In contrast to the ester enolates, the a.O-carboxylic dianions are intrinsically more reactive and their use in conjugate reactions is thus limited. Typically, a-substituted-a.O-carboxylic dianions add exclusively to a,(3-unsaturated esters155a and nitroalkenes,155b while additions to ot,(3-enones are sensitive to the substitution pattern of the enones.155c>d Notable is the conjugate addition of dihydrobenzoic acid dianions (207), from Birch reduction of benzoic acids, to oi,3-unsaturated esters (Scheme 77).155e... 

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