Alkenes, activated, intermolecular

The inclusion of a separate chapter on catalysed cyclopropanation in this latest volume of the series is indicative of the very high level of activity in the area of metal catalysed reactions of diazo compounds. Excellent, reproducible catalytic systems, based mainly on rhodium, copper or palladium, are now readily available for cyclopropanation of a wide variety of alkenes. Both intermolecular and intramolecular reactions have been explored extensively in the synthesis of novel cyclopropanes including natural products. Major advances have been made in both regiocontrol and stereocontrol, the latter leading to the growing use of chiral catalysts for producing enantiopure cyclopropane derivatives. 

In contrast to the well documented conjugate addition of carbon nucleophiles to activated alkenes, similar intermolecular attempts with activated alkynes with non-cuprate reactants are typically non-productive due to competing multiple addition processes.87 6 However, protic intramolecular conjugate additions of ketones as shown for the syntheses of griseofulvin and hirsutic acid,222 are successful. Recently, several aprotic intramolecular conjugate additions to activated alkynes have been reported, as... 

III. MIXED HYDROCOUPLING OF ACTIVATED ALKENES A. Intermolecular Mixed Hydrocouplings... 

Due to its marked atom economy, the intramolecular hydroamination of alkenes represents an attractive process for the catalytic synthesis of nitrogen-containing organic compounds. Moreover, the nitrogen heterocycles obtained by hydroamination/cyclisation processes are frequently found in numerous pharmacologically active products. The pioneering work in this area was reported by Marks et al. who have used lanthanocenes to perform hydroamination/cyclisation reactions in 1992. These reactions can be performed in an intermolecular fashion and transition metals are by far the more efficient catalysts for promotion of these transformations via activation of the... 

Intermolecular bis-silylation of unactivated alkenes has been achieved initially with a zerovalent platinum catalyst such as Pt(PPh3)4 (Equations (30) and (31)).101 1,2-Difluorotetramethyldisilane undergoes addition to ethylene and norbornene in the presence of Pt(PPh3)4 catalyst at 150 °G to give the corresponding adducts in 95% and 26% yields, respectively. For the addition of 1,2-diphenyltetramethyldisilane to ethylene, Pt(PMe3)4 (33% yield) was found to be more active than Pt(PPh3)4 (4% yield). 

A development of the last two decades is the use of Wacker activation for intramolecular attack of nucleophiles to alkenes in the synthesis of organic molecules [9], In most examples, the nucleophilic attack is intramolecular, as the rates of intermolecular reactions are very low. The reaction has been applied in a large variety of organic syntheses and is usually referred to as Wacker (type) activation of alkene (or alkynes). If oxygen is the nucleophile, it is called oxypalladation [10], Figure 15.4 shows an example. During these reactions the palladium catalyst is often also a good isomerisation catalyst, which leads to the formation of several isomers. 

Intermolecular addition of radicals, generated by photo-electrochemical catalysis, to activated alkenes can also be brought about. The reaction of 66 is used as a key step in one synthesis of the insect pheromone, brevicomin [219]. The reaction of a secondary radical from 67 occurs at low cathode potentials and without photochemical assistance [219]. This illustrates the equiibrium between a secondary al-kylcobalt(m) species and the radical - cobalt(ii) pair. The carbon radical is eventually captured by reaction with the alkene. Further steps in the synthesis lead to four isomers of the pheromone, multistriatin, each of which is a pure enantiomer since... 

C-Glycoside synthesis via the intermolecular addition of anomeric radicals to activated alkenes has been pioneered by Giese and co-workers [120]. A wide variety of acceptors have been used in this area and both simple [131,132] and more complex (a C-disaccharide 290) [133] examples are shown (Scheme 77). 

The thermolytic preparation by De Shong et al. (74) of azomethine ylides from aziridines and their intermolecular reactions are the first examples of singly stabilized ylides of this type. However, the protocol has been further extended to include intramolecular processes. Aziridines tethered to both activated and unactivated alkenes were subjected to flash vacuum thermolysis generating cycloadducts in moderate-to-excellent yields. While previously singly activated alkenes had furnished low material yields via an intermolecular process, the intramolecular analogue represents a major improvement. Typically, treatment of 222 under standard conditions led to the formation of 223 in 80% yield as a single cis isomer. Similarly, the cis precursor furnished adduct 224 in 52% yield, although as a 1 1 diastereomeric mixture (Scheme 3.77). 

The same research group has demonstrated a similar intramolecular process in the construction of bicychc adducts 326 (92). The CsF desilyation of precursors 327, after subsequent reaction of the internal dipolarophile, dehvered the expected cycloadducts with complete stereocontrol when either thioether and ether tethers or activated and unactivated dipolarophiles were used. In contrast with intermolecular protocols, the reaction was successful with both activated and unactivated alkenes. In addition, unlike the previous example, formation of both six (n = 2)- and five (n= l)-membered rings occurs (Scheme 3.109). 

The use of mediators to improve reactivity or selectivity in nitrone cycloaddition chemistry begins with the nitrone generation step. As is well known, the N-alkyla-tion of oximes provides one of the most direct and convenient synthetic routes to N-alkylated nitrones from readily available aldehydes and ketones. Electrophilic mediators have been employed to activate alkenes for N-alkylation, both in intramolecular and intermolecular reactions. They include activation of the internal alkene function by the action of (a) strong nonmetallic electrophiles such as phenyl-selenenyl sulfate (159), and (b) metallic catalysts such as Ag(I) (160) and Pd(II) ions... 

Although thermal [2 + 2] cycloadditions are forbidden as concerted reactions by the orbital symmetry conservation rules the same structural features which promote intermolecular cy-cioadditions will also promote intramolecular reactions. In addition, the proximity between two alkene moieties dictated by the tether length and rigidity would make these processes entropically favorable. A few reports have documented thermal intramolecular cycloadditions to cyclopropenes and activated alkenes. The thermal Cope rearrangement of allylcyclopropenes apparently proceeds by a two-step mechanism in which intramolecular [2 + 2] adducts have been observed.72-73... 

Addition of Active Methylenes In the previous decade Cinellu et al. studied certain 1,3-dicarbonyl gold complexes and some applications in organic synthesis were subsequently proposed [78]. Intermolecular addition of activated methylene compounds to alkenes was developed by using AuCl3/AgOTf [79]. 

Mechanistic studies of the rearrangement activity of the ring-opening metathesis polymerization catalyst [Ru(H20)6]2+ were reported for unfunctionalized alkenes (112). The mechanism was found to be intermolecular, the alkene isomerization proceeding through an addition-elimination mechanism with a metal hydride catalytic species. This interpretation was... 

The major problem of the application of zeolites in alkane-alkene alkylation is their rapid deactivation by carbonaceous deposits. These either strongly adsorb on acidic sites or block the pores preventing the access of the reactants to the active sites. A further problem is that in addition to activity loss, the selectivity of the zeolite-catalyzed alkylation also decreases severely. Specifically, alkene formation through oligomerization becomes the dominant reaction. This is explained by decreasing ability of the aging catalyst to promote intermolecular hydride transfer. These are the main reasons why the developments of several commercial processes reached only the pilot plant stage.356 New observations with Y zeolites reconfirm the problems found in earlier studies.358,359... 

This C—C bond-forming process has been used very often in the intermolecular case97 to produce a-hydroxyalkyl-a,(3-unsaturated esters, ketones, nitriles, sulfones, etc. by treatment of the activated alkene... 

Palladium(II) salts, in the form of organic solvent soluble complexes such as PdCl2(RCN)2, Pd(OAc>2 or Li2PdCU, are by far the most extensively utilized transition metal complexes to activate simple (unactivated) alkenes towards nucleophilic attack (Scheme 1). Alkenes rapidly and reversibly complex to pal-ladium(II) species in solution, readily generating alkenepalladium(II) species (1) in situ. Terminal monoalkenes are most strongly complexed, followed by internal cis and trans (respectively) alkenes. Geminally disubstituted, trisubstituted and tetrasubstituted alkenes are only weakly bound, if at all, and intermolecular nucleophilic additions to these alkenes are rare. 

Alcohols and carboxylic acids also readily add to metal-activated alkenes2 and industrial processes for the conversion of ethylene to vinyl acetate, vinyl ethers and acetals are well established. However, very little use of intermolecular versions of this chemistry with more complex alkenes has been developed. In... 

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