Acceptor-substituted alkenes

Enamines 1 are useful intermediates in organic synthesis. Their use for the synthesis of a-substituted aldehydes or ketones 3 by reaction with an electrophilic reactant—e.g. an alkyl halide 2, an acyl halide or an acceptor-substituted alkene—is named after Gilbert Stork. 

Enamines react with acceptor-substituted alkenes (Michael acceptors) in a conjugate addition reaction for example with o ,/3-unsaturated carbonyl compounds or nitriles such as acrylonitrile 8. With respect to the acceptor-substituted alkene the reaction is similar to a Michael addition ... 

Scheme 36 Synthesis of donor-acceptor-substituted cyclopropanes 165 and cyclopentenes 166 from complexes 163 and acceptor-substituted alkenes 164 [115,116]...

Heteroatom-substituted carbene complexes are less electrophilic than the corresponding methylene, dialkylcarbene, or diarylcarbene complexes. For this reason cyclopropanation of electron-rich alkenes with the former does not proceed as readily as with the latter. Usually high reaction temperatures are necessary, with radical scavengers being used to supress side-reactions (Table 2.16). Also acceptor-substituted alkenes can be cyclopropanated by Fischer-type carbene complexes, but with this type of substrate also heating is generally required. 

The transition metal-catalyzed reaction of diazoalkanes with acceptor-substituted alkenes is far more intricate than reaction with simple alkenes. With acceptor-substituted alkenes the diazoalkane can undergo (transition metal-catalyzed) 1,3-dipolar cycloaddition to the olefin [651-654]. The resulting 3//-pyrazolines can either be stable or can isomerize to l//-pyrazolines. 3//-Pyrazolines can also eliminate nitrogen and collapse to cyclopropanes, even at low temperatures. Despite these potential side-reactions, several examples of catalyzed cyclopropanations of acceptor-substituted alkenes with diazoalkanes have been reported [648,655]. Substituted 2-cyclohexenones or cinnamates [642,656] have been cyclopropanated in excellent yields by treatment with diazomethane/palladium(II) acetate. Maleates, fumarates, or acrylates [642,657], on the other hand, cannot, however, be cyclopropanated under these conditions. 

The order of reactivity of these three catalysts towards alkenes (but also towards oxygen) is 1 > 3 > 2. As illustrated by the examples in Table 3.18, these catalysts tolerate a broad spectrum of functional groups. Highly substituted and donor- or acceptor-substituted olefins can also be suitable substrates for RCM. It is indeed surprising that acceptor-substituted alkenes can be metathesized. As discussed in Section 3.2.2.3 such electron-poor alkenes can also be cyclopropanated by nucleophilic carbene complexes [34,678] or even quench metathesis reactions [34]. This seems, however, not to be true for catalysts 1 or 2. 

Interestingly, sulfonium ylides generated from electrophilic carbene complexes and sulfides can react with carbonyl compounds, imines, or acceptor-substituted alkenes to yield oxiranes [1320-1325], aziridines [1321,1326,1327] or cyclopropanes [1328,1329], respectively. In all these transformations the thioether used to form the sulfonium ylide is regenerated and so, catalytic amounts of thioether can be sufficient for complete conversion of a given carbene precursor into the... 

Besides direct nucleophilic attack onto the acceptor group, an activated diene may also undergo 1,4- or 1,6-addition in the latter case, capture of the ambident enolate with a soft electrophile can take place at two different positions. Hence, the nucleophilic addition can result in the formation of three regioisomeric alkenes, which may in addition be formed as E/Z isomers. Moreover, depending on the nature of nucleophile and electrophile, the addition products may contain one or two stereogenic centers, and, as a further complication, basic conditions may give rise to the isomerization of the initially formed 8,y-unsaturated carbonyl compounds (and other acceptor-substituted alkenes of this type) to the thermodynamically more stable conjugated isomer (Eq. 4.1). 

One of the problems associated with thermal cyclodimerization of alkenes is the elevated temperatures required which often cause the strained cyclobutane derivatives formed to undergo ring opening, resulting in the formation of secondary thermolysis products. This deficiency can be overcome by the use of catalysts (metals Lewis or Bronsted acids) which convert less reactive alkenes to reactive intermediates (metalated alkenes, cations, radical cations) which undergo cycloaddilion more efficiently. Nevertheless, a number of these catalysts can also cause the decomposition of the cyclobutanes formed in the initial reaction. Such catalyzed alkene cycloadditions are limited specifically to allyl cations, strained alkenes such as methylenccyclo-propane and donor-acceptor-substituted alkenes. The milder reaction conditions of the catalyzed process permit the extension of the scope of [2 + 2] cycloadditions to include alkene combinations which would not otherwise react. 

Catalyzed cycloadditions of donor-acceptor-substituted alkenes have been reported in instances in which alkenes are not sufficiently activated for thermal cycloadditions to proceed. The cycloaddition of vinylpyridines to enamincs constitutes a preparative method for the synthesis of aminocyclobutanes.7 This reaction is catalyzed by /Moluenesulfonic acid. The pyridine substituent can be hydrogenated to the piperidine group. 

Alkanes can be prepared by the addition of carbon radicals to C=C double bonds (Figure 5.4). The highest yields are usually obtained when electron-rich radicals (e.g. alkyl radicals or heteroatom-substituted radicals) add to acceptor-substituted alkenes, or when electron-poor radicals add to electron-rich double bonds. These reactions have also been performed on solid phase, and polystyrene-based supports seem to be particularly well suited for radical-mediated processes [39,40]. 

Support-bound alkylating agents have been used to N-alkylate pyridines and dihydropyridines (Entries 7 and 8, Table 15.21). Similarly, resin-bound pyridines can be N-alkylated by treatment with a-halo ketones (DMF, 45 °C, 1 h [267]) or other alkylating agents [246]. Polystyrene-bound l-[(alkoxycarbonyl)methyl]pyridinium salts can be prepared by N-alkylating pyridine with immobilized haloacetates (Entry 8, Table 15.21). These pyridinium salts react with acceptor-substituted alkenes to yield cyclopropanes (Section 5.1.3.6). Pyridinium salts have also been prepared by reaction of resin-bound primary amines with /V-(2,4-dinitrophenyl)pyridinium salts [268,269]. 

Another approach for the ring expansion of epoxides uses low-valent iron complexes which open epoxides under reductive conditions, as reported by Hilt et al. [106]. The iron complexes are reduced and after coordination of the epoxide to the iron center an electron transfer initiates the radical-type ring opening of the epoxide. Under formal insertion of an alkene, regioselective formation of tetrahy-drofurans was observed (Scheme 9.46). The reaction is applicable to a broad range of acceptor-substituted alkenes bearing another double or triple bond system in conjugation with the inserted carbon-carbon double bond. 

A highly reactive natural product which contains such a geminally donor-acceptor substituted alkene is protoanemonin (Scheme 3.12), a toxic, skin-irritating lactone produced by various plants (ranunculaceae). The natural precursor to this compound is the glucoside ranunculin [44, 45], which yields protoanemonin enzymatically on maceration of plant tissue. Protoanemonin is unstable and quickly polymerizes or dimerizes to the less toxic anemonin. 

A major advantage is the potential to lock (and protect) written information in the photobistable material. A number of chemical gated systems involving mutual regulation of the photochromic event and, for instance, fluorescence, ion binding, or electrochemical properties have been reported.1501 Scheme 19 illustrates a chiral gated response system based on donor-acceptor substituted alkene 17.[511 The photochemical isomerization process of both the M-ds and the P-trans form was effectively blocked by the addition of trifluoroacetic acid. Protonation of the dimethyl-amine donor unit of M-rfs-17a and P-trons-17b resulted in an ineffective acceptor-acceptor (nitro and ammonium) substituted thioxanthene lower half. Since the stereoselective photoisomerization of 17 relies on the presence of both a donor and acceptor unit, photochemical switching could be restored by deprotonation by the addition of triethylamine. 

Fig. 1.15. NaBH4-mediated addition of (/3-hydroxy-atkyl)mercury(II) acetates to an acceptor-substituted alkene.

Nucleophiles can be added to acceptor-substituted alkenes. In that case, enolates and other stabilized carbanions occur as intermediates. Reactions of this type are discussed in this book only in connection with 1,4-additions of organometallic compounds (Section 10.6), or enolates (Section 13.6) to a,/J-unsaturated carbonyl and carboxyl compounds. 

Fig. 10.47. Nucleophilic substitution I on an acceptor-substituted alkene with a leaving group in the /3-position.

Fig. 10.49. Nucleophilic substitution IE on acceptor-substituted alkenes with a leaving group in the / -position.

A Michael addition consists of the addition of the enolate of an active-methylene compound, the anion of a nitroalkane, or a ketone enolate to an acceptor-substituted alkene. Such Michael additions can occur in the presence of catalytic amounts of hydroxide or alkoxide. The mechanism of the Michael addition is shown in Figure 13.67. The addition step of the reaction initially leads to the conjugate base of the reaction product. Protonation subsequently gives the product in its neutral and more stable form. The Michael addition is named after the American chemist Arthur Michael. 

Acceptor-substituted alkenes that are employed as substrates in Michael additions include... 

We saw in Section 15.3.3 that 1,3-butadienes with a donor in the 1-position react with acceptor-substituted alkenes to form cycloadducts with high ort/ o -selectivity. The amount of... 

Diazomethane is an electron-rich 1,3-dipole, and it therefore engages in Sustmann type I 1,3-dipolar cycloadditions. In other words, diazomethane reacts with acceptor-substituted alkenes or alkynes (e. g., acrylic acid esters and their derivatives) much faster than with ethene or acetylene (Figure 15.36). Diazomethane often reacts with unsymmetrical electron-deficient... 

Sulfide groups can also be introduced by this methodology (entry 24) [405]. Simpkins and coworkers found that the reaction of acceptor-substituted alkenes 363 with diphenyl disulfide in the presence of 10 mol% of Co(eobe)2 344 and PhSiH3 as the stoichiometric hydrogen source furnished 31-71% of a-(phenylthio) carbonyl compounds 364. The intermediacy of radicals was proven by a 5-exo cyclization occurring in competition to the SH2 reaction at sulfur. 

Not unexpectedly, no asymmetric induction was observed in the reduction step of the adduct radical. This reaction works only for acceptor-substituted alkenes even styrene did not react with the highly nucleophilic glycosyl radical. Gagne and colleagues later disclosed a similar nickel-catalyzed approach (see Sect. 2.3). 

Acceptor-substituted alkenes that are employed as substrates in Michael additions include a./l-unsaturated ketones (for example, see Figure 10.59), a,/3-unsaturated esters (Figure 10.60), and a,/3-unsaturatcd nitriles (Figure 10.61). The corresponding reaction products are bifunctional compounds with C=0 and/or C=N bonds in positions 1 and 5. Analogous reaction conditions allow Michael additions to vinyl sulfones or nitroalkenes. These reactions lead to sulfones and nitro compounds that carry a C=0 and/or a O N bond at the C4 carbon. 

Cycloadditions are called Diels-Alder reactions in honor of Otto Diels and Kurt Alder, the chemists who carried out the first such reaction. The substrate that reacts with the diene in these cycloadditions is called the dienophile. As you saw in Figure 12.1, the simplest Diels-Alder reactions, i.e., the ones between ethene and butadiene and between acetylene and butadiene, respectively, occur only under drastic conditions. Well-designed Diels-Alder reactions, on the other hand, occur much more readily. In the vast majority of those cases acceptor-substituted alkenes serve as dienophiles. In the present section we will be concerned only with such Diels-Alder reactions (see Figures 12.16,12.17, and 12.22 for exceptions). 

Diels-Alder reactions of the type shown in Table 12.1, that is, Diels-Alder reactions between electron-poor dienophiles and electron-rich dienes, are referred to as Diels-Alder reactions with normal electron demand. The overwhelming majority of known Diels-Alder reactions exhibit such a normal electron demand. Typical dienophiles include acrolein, methyl vinyl ketone, acrylic acid esters, acrylonitrile, fumaric acid esters (fnms-butenedioic acid esters), maleic anhydride, and tetra-cyanoethene—all of which are acceptor-substituted alkenes. Typical dienes are cy-clopentadiene and acyclic 1,3-butadienes with alkyl-, aryl-, alkoxy-, and/or trimethyl-silyloxy substituents—all of which are dienes with a donor substituent. 

A haloalkene that already contains a stereogenic C=C double bond usually can be coupled with alkenes via the Heck reaction without isomerization. The reaction pah-in Figure 13.27 provides two sets of examples. As can be seen, both the cis- and the fnms-configured iodoalkenes react with acceptor-substituted alkenes with complete retention of the C=C double bond configuration. These coupling reactions thus arc stereoselective and—when considered as a pair—stereospecific. 

The prototype of copper-mediated conjugate addition reactions is the transformation of acceptor-substituted alkenes and alkynes into the corresponding adducts (Scheme 1). Whereas full control of the regio- and chemoselectivity in these Michael additions has been possible for a long time,3 the emphasis of the last decade has been put on the use of new copper reagents, the broadening of the substrate scope, and the control of the stereoselectivity of the conjugate addition. 

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