Nonactivated alkenes

Secondary amines can be added to certain nonactivated alkenes if palladium(II) complexes are used as catalysts The complexation lowers the electron density of the double bond, facilitating nucleophilic attack. Markovnikov orientation is observed and the addition is anti An intramolecular addition to an alkyne unit in the presence of a palladium compound, generated a tetrahydropyridine, and a related addition to an allene is known.Amines add to allenes in the presence of a catalytic amount of CuBr " or palladium compounds.Molybdenum complexes have also been used in the addition of aniline to alkenes. Reduction of nitro compounds in the presence of rhodium catalysts, in the presence of alkenes, CO and H2, leads to an amine unit adding to the alkene moiety. An intramolecular addition of an amine unit to an alkene to form a pyrrolidine was reported using a lanthanide reagent. 

The synthesis of alcohols, ethers, and ketones by metal-catalyzed addition of water or alcohols to alkenes and alkynes is a well-established reaction in organic chemistry. Many regio- and stereoselective modifications of these reactions are known. In contrast, the analogous addition of ammonia or primary and secondary amines to nonactivated alkenes and alkynes has not had a comparable development, in spite of extensive efforts. In this section, we summarize the recent results of amination to unsaturated compounds. 

In the addition to nonactivated alkenes, where the direct anodic oxidation is less, satisfactorily good yields can be achieved when Mn(OAc)2 is used as mediator (Table 8, entries 6, 7). Sorbic acid precursors have been obtained in larger scale and high current efficiency by a Mn(III)-mediated oxidation of acetic acid/acetic anhydride in the presence of butadiene [112]. 

Good yields can be obtained with nonactivated alkenes, when the reaction... 

The breakthrough came already in 1996, one year after Curd s prediction, when Yang and coworkers reported the C2-symmetric binaphthalene-derived ketone catalyst 6, with which ee values of up to 87% were achieved. A few months later, Shi and coworkers reported the fructose-derived ketone 7, which is to date still one of the best and most widely employed chiral ketone catalysts for the asymmetric epoxidation of nonactivated alkenes. Routinely, epoxide products with ee values of over 90% may be obtained for trans- and trisubstituted alkenes. Later on, a catalytic version of this oxygen-transfer reaction was developed by increasing the pH value of the buffer. The shortcoming of such fructose-based dioxirane precursors is that they are prone to undergo oxidative decomposition, which curtails their catalytic activity. 

Nonactivated alkenes do not undergo reactions with thiocarbonyl ylides. However, the strained ( )-cyclooctene reacts easily with 16, 52, and 69 to yield the corresponding trans-fused tetrahydrothiophenes (94). 

Certain allyl cations react quite efficiently with nonactivated alkenes to give cyclobutanes. Such cations can be generated by Lewis acid catalyzed dehalogenation of allyl halides, protonation of conjugated dienes and Lewis acid eomplexation of conjugated carbonyl derivatives. For example, 2-chloro-2,4-dimethylpent-3-ene ( ) reacts with alkenes in the presence of zinc(II) chloride to give the corresponding cyclobulanes.1 Alkyl substitution of the allyl cation at the 2-position results in [3 + 2]-cycloaddition products. 

As in the case of catalyzed cycloadditions of alkenes, reactions of allenes catalyzed by Lewis acids or via vinyl cations proceed more efficiently than their thermal counterparts. Even nonactivated allenes can be induced to react with nonactivated alkenes to give good yields of cyclobutanes. Such reactions could not be carried out under noncatalyzed conditions.1... 

Electrophilic ailenes such as alkyl buta-2,3-dienoates react with nonactivated alkenes, e.g. (Z)-and (jE)-but-2-ene,3 hex-l-ene,3 2-ethylbut-l-ene,3 cycloalkenes,4 and cycloocta-1,5-diene,4 in the presence of Lewis acids giving methylenecyclobutanes both regio- and stereospecifically.3 5... 

Ketene itself and simple alkylketenes are inert towards nonactivated alkenes. F or the preparation of cyclobutanones formally derived from ketene or an alkylketene and nonactivated alkenes, the more reactive dichloroketene or alkylchloroketenes can be used. The corresponding a,a-dichloro- or oc-chlorocyclobutanones can readily be dechlorinated by treatment with zinc in acetic acid, or tributyltin hydride in near quantitative yields. F or example cycloaddition of substituted cyclohexene to dichloroketene gave dichlorocyclobutanone 1 which was dechlorinated to 2 with zinc.13,18 Likewise cycloaddition of cycloalkcnes to chloro(methyl)ketene gave 3 which was dechlorinated to 4.14... 

Reactions of ketenes with electron-rich alkenes proceed more readily than with nonactivated alkenes and in the case of enol ethers, enol sulfides and ketene acetals, the cycloaddition is regiospecific (see Table 6). With tetraalkoxyethene, cycloaddition with the relatively inert ketene can be carried out 124 however, with less activated alkenes the use of metal catalysts such as zinc(ll) chloride is required for cycloaddition of the parent ketene.115... 

Metal catalysed cyclopropanation using other types of intermediate is also possible. Lithiated tert-butyl alkyl sulphones bring about the cyclopropanation of various nonactivated alkenes under nickel(II) acetylacetonate catalysis (equation 88)131,132. Sulphonium ylides of type 90 react with simple alkenes under copper catalysis to give the corresponding cyclopropane adduct (equation 89)113,134. In this example the ylide (90) is the sulphonium equivalent of ethyl diazoacetate134. 

Azomethine ylides are not typically isolable but must be used in situ. They undergo cycloaddition reactions that produce highly functionalized pyrrolidines, dihydropyiroles and pyrroles. The success of these reactions often depends on a judicious choice of dipole and dipolarophile. Azomethine ylides are reluctant to cycloadd to nonactivated alkenes, in large part owing to electronic considerations. The LUMO of most azomethine ylides is high in energy and there is a large gap with the HOMO of a nonactivated alkene. 

Diels-Alder reactions are a very versatile means of synthesizing several ring systems in a single-step process. This protocol has been used to form octahydroacridine derivatives by taking A-arylimines which contain a nonactivated alkene functionality appropriately... 

Illustrative examples for the latter precaution are the contradictory results on PET cyclizations of nonactivated alkene-silylamine systems as independently reported by the groups of Pandey [35a,b] and Mariano [62] (Sch. 37). In his study, Mariano obtained the pyrrolidinone 78 when he repeated the DCN-sensitized irradiation of 19 under condition which closely matched those of Pandey. Aware of this obvious discrepancy, Pandey launched a detailed study on the experimental conditions of this application. After he proofed the correctness of his earlier results and even extended the photoreaction to other nonactivated systems, he concluded that the only significant difference in the experimental conditions used by Mariano was a gap of ca. 40 nm in the applied wavelength. 

The intramolecular oxime-alkene cyclizations, also known as tandem 1,2-prototropic-cycloadditions, with nonactivated alkenes was first reported by Oppolzer and Keller in 1970 <70TLiii7> but their use for the heterocycles of this chapter was first reported in the 1990s <91T4007>. The methodology is shown in Schemes 46 and 47 in an expedient synthesis of chiral, unfunctionalized... 

There are many examples of transition catalyzed addition of nitrogen compounds to alkenes, alkynes,and so on. Secondary amines can be added to certain nonactivated alkenes if paUadium(II) complexes are used as catalysts. ... 

Satisfactory to good yields of adducts have been found for styrenes [Eq. (21a), Y = phenyl], conjugated dienes (Y = vinyl), enamines (Y = NR2), and enol ethers (Y = alkoxy), particularly if they are unsubstituted at the 6-carbon atom to Y. Nonactivated alkenes react less satisfactorily. In the oxidation of anionized 1,3-dicarbonyl compounds (Table 11, numbers 1-8) at potentials between 0.6 and 1.4 V (SCE) and in the presence of butadiene, only the additive dimer LXII is obtained in the presence of ethyl vinyl ether only the disubstituted monomers LXVI or LXVII arise, but with styrene both types of products LXII and LXVI are formed. This result indicates that the primary adduct LXIII is oxidized rapidly between 0.6 to 1.4 V to the carbenium ion in the case of an ethoxymethyl radical (Y = OEt), and slowly in the case of an allyl radical (Y = vinyl). 

Under the assistance of external nucleophiles, simple, nonactivated alkenes can undergo intramolecular attack to give nitrogen-containing heterocyclic compounds, via the iminium salt. 

As mentioned previously, acyliminium ions are electrophilic enough to react intramolecularly even with nonactivated alkenic ir-systems. These cyclization reactions have been recognized and elaborated as valuable tools in the stereoselective total synthesis of quinolizidine, indolizidine and pyrrolizidine alkaloids. A typical example from Speckamp s laboratory is the highly stereospecific acid-catalyzed cyclization of (81) to (83 Scheme 40), presumably via the corresponding acyliminium ion (82). Analogously, other more complex natural products, such as the antiulcerogenically active alkaloid ma-trine (85), can be built up with high stereocontrol (Scheme 41), with an enol ether function as a more electron-rich nucleophile for the intermediate iminium ion (84). ... 

Considerably more important are reactions involving an endocyclic attack of C-nucleophiles. Besides rarer reactions with aromatic nucleophiles (the oxa analog of the Pictet-Spengler reaction) the use of vinylic nucleophiles especially provides an efficient route to critical , medium-sized oxygen-containing heterocycles. Thus, even nonactivated alkenes like (104) readily undergo acid-catalyzed cyclization in remarkable yields (Scheme 51). ... 

Vinylsilanes as nucleophilic terminators offer several additional advantages over ordinary nonactivated alkenes (c/. Section 4.2.2.1). The silyl group is readily substituted stereo- and regio-selectively by the electrophilic carbon atom of the oxocarbenium ion, as demonstrated in Overman s synthesis of alkyl-idenetetrahydropyran (109 Scheme 53). This strategy was also applied to the preparation of five- and seven-membered cyclic ethers. ... 

In exceptional cases, addition of nucleophiles across nonactivated alkenes bearing a leaving group gives electrophilic cyclopropanes. An example is the reaction of an allylic geminal diacetate with tetramethyl ethane-1,1,2,2-tetracarboxylate in the presence of a palladium catalyst which gives the cyclopropane tetracarboxylate derivative 11. ... 

Bis(camphorquinone-a-dioximato)cobalt(II) (10) has been developed as a catalyst for enan-tioselective cyclopropanation reactions. It allows selective carbene transfer from diazoacetic esters to terminal C-C double bonds which are in conjugation with vinyl, aryl, alkoxycarbonyl or cyano groups, but not to alkyl-substituted alkenes, cycloalkenes, 1,3-dienes and al-lenes. The unusual chemoselectivity and some other experimental observations make the two mechanistic pathways proposed vide supra) questionable for these special carbene-transfer reactions. In contrast, the cobalt(II) complex 11 allows not only the cyclopropanation of styrene but also of oct-l-ene, a nonactivated alkene (ethyl diazoacetate, 35 °C, 3mol% of catalyst yield 50-60%). ... 

The cisjtrans ratio of the cyclopropanes formed in this transformation depends to some extent on the nature of the salts and the solvent. A particularly high cisitram ratio was obtained when copper(II) acetate, calcium chloride, and ethanol were employed (no values given). Cyclopropane synthesis from active methylene compounds and nonactivated alkenes was also possible with the help of iodine and a base under phase-transfer conditions. Intra-and intermolecular reactions to give 6 and 5, respectively, have been carried out. The intramolecular reaction is nonstereospecific with respect to the C-C double bond. Although an iodo-substituted intermediate has been isolated in one case, all the details of the reaction mechanism are not yet clear. 

The use of zero-valent transition metal (mainly nickel and cobalt) complexes as promoters of the homo-Diels-Alder reaction has been an important development. These catalysts allow 1,4-dienes to react with nonactivated alkenes and alkynes, broadening the scope of the homo-... 

The electronic state of the metal center basically determines reactivity and selectivity. When, for example, the 27t-component is strongly electron deficient, as in maleic anhydride, acrylal-dehyde or acrylonitrile, it tends to be firmly coordinated to the metal thus forming a stable, unreactive complex. When, however, the alkene is only weakly bound, e.g. in the case of some nonactivated alkenes, cyclodimerization of methylenecyclopropane may occur predominantly or exclusively instead of cocyclodimerization. The same is true for phosphorus-free catalyst systems even in the presence of electron-deficient alkenes. A precoordination of the alkene to the metal center is thus necessary in order to accomplish both co- and the homocyclodimerization reaction. 

The basic selectivity principles introduced for the reactions of nonactivated alkenes vide supra) are also valid for polar, activated alkenes such as alkyl acrylates. Whereas monosubstituted methylenecyclopropanes usually lead to the formation of product mixtures regardless of whether nickel(0) or palladium(0) is employed as catalyst, methylenecyclopropanes with (identical) geminal substituents usually give rise to only one major product and are thus especially useful for preparative syntheses. In this section general features of these reactions of substituted methylenecyclopropanes are exemplified for selected substituents and substitution patterns. 

More interestingly, this type of cycloisomerization can be performed even in the case of a nonactivated alkene moiety. In a palladium(0)-catalyzed reaction, 2-methylenetricyclo-[3.3.3.0 ]undecane (25) is obtained from hydrocarbon 24 in 74 /o yield. 

The addition of diethyl 1-fluoro- or 1,1-difluoro-l-iodomethylphosphonates to nonactivated alkenes at room temperature in the presence of catalytic amounts of PdtPPh Jj affords good to excellent yields (63-91%) of mono- or difluorinated diethyl 3-iodo-l,l-difluoroalkylphospho-nates.285-287 yjjg CuCl-medialed addition of diethyl trichloromethylphosphonate to activated and non-activated alkenes has also been described. 2 8... 

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