Alkenes heteroatom-directed addition

HETEROATOM-DIRECTED ADDITION Ol GRIGNARD REAGENTS TO ALKENES... 

The /Tamino alcohol structural unit is a key motif in many biologically important molecules. It is difficult to imagine a more efficient means of creating this functionality than by the direct addition of the two heteroatom substituents to an olefin, especially if this transformation could also be in regioselective and/ or enantioselective fashion. Although the osmium-mediated75 or palladium-mediated76 aminohydroxylation of alkenes has been studied for 20 years, several problems still remain to be overcome in order to develop this reaction into a catalytic asymmetric process. 

Several reviews have been published within the year which are of general relevance to the photoreactions of aromatic compounds. The subjects of these reviews include photochemistry in ionic liquids and in isotropic and anisotropic media, organic synthesis utilizing photoinduced electron-transfer reactions," heteroatom-directed photoarylation processes, photochromism, and photochemical molecular devices. Reviews more directly pertinent to the sections in the present chapter include those of the photoisomerization of five-membered heteroaromatic azoles, the photocycloaddition of benzene derivatives to alkenes, Diels-Alder additions of anthracenes, advances in the synthesis of polycyclic aromatic compounds, diarylethene-based photochromic switches, the photo-Fries rearrangement, and the application of Diels-Alder trapping of photogenerated o-xylenols to the synthesis of novel compounds. " A number of chapters in the two recently published handbooks of photochemistry and photobiology and in the revised edition of the text on photochromism are also pertinent to the current subject matter. 

The major focus in this chapter will be on synthesis, with emphasis placed on more recent applications, particularly those where regiochemistry and stereochemistry are precisely controlled. The reader is referred to the earlier reviews for full mechanistic information and details of historic interest. Electrophilic addition of X—Y to an alkene, where X is the electrophile, gives products with functionality Y (3 to the heteroatom X. Further transformations of X and/or Y provide the basis for diverse synthetic applications. These transformations include replacement of Y by hydrogen, elimination to form a ir-bond (either including the carbon bonded to X or (3 to that carbon so that X is now in an allylic position), and nucleophilic or radical substitution. Representative examples of these synthetic methods will be given below. This chapter will include examples of heterocycles formed in one-pot reactions where the the initial alkene-electrophile adduct contains an electrophilic group that can react further. Examples of heterocycles formed in several steps from alkene-electrophile adducts will also be considered. Cases in which activation by an external electrophile directly results in addition of an internal heteroatom nucleophile are treated in Chapter 1.9 of this volume. 

A useful aspect of the mercury(II) hydride method is that it can be directly coupled with the many standard techniques for heteromercuration of alkenes and cyclopropanes. The resulting overall transformation adds a heteroatom and a carbon atom across the carbon-carbon double bond of an alkene or the carbon-carbon single bond of a cyclopropane. This is a difficult transformation to conduct by standard ionic techniques. An alkene thus becomes an equivalent of synthon (12) and a cyclopropane of synthon (13 Scheme 34). Many equivalent transformations (like haloetherification and phenylselenolactoniza-tion) are available to make precursors for tin hydride mediated additions. 

Intramolecular cyclopropanations of pendant alkenes are more favorable. Heteroatom-substituted 2-aza- and 2-oxabicyclo[3.1.0]hexanes, together with 2-oxabicyclo[4.1.0] heptanes, can be prepared from chromium and tungsten Fischer carbenes having a tethered alkene chain. An interesting carbene formation via a cationic alkylidene intermediate, nucleophilic addition (see Nucleophilic Addition Rules for Predicting Direction), and intramolecular cyclopropanation is shown in Scheme 59. An intramolecular cyclopropanation via reaction of alkenyl Fischer carbene complex (28) andpropyne was used in a formal synthesis of carabrone (Scheme 60). 

The force field covers all alkenes, with the exception of those containing directing groups where additional double bonds or three-membered rings are at least three bonds (two saturated carbon atoms) and every other type of unsaturation or heteroatoms at least four bonds (three saturated carbon atoms) apart from the double bond to be epoxidized, and those where the double bond is not part of a cyclopropane or cyclobutane system. 

The vast majority of work on asymmetric Diels-Alder reactions deals with additions of 1,3-dienes to a, -alkenic carbonyl derivatives XXI) where the chirophore R is attached to the carbonyl group eiAer directly or via a heteroatom X, permitting subsequent removal of the auxiliary (e.g. by attack of a nucleophile Nu Scheme 75). 

Carbon-Nitrogen Bond Formation. Apart from the CAN-mediated reactions in which solvent (e.g., acetonitrile) incorporation results in carbon-heteroatom bond formation, the oxidative generation and subsequent addition of heteroatom-centered radicals to alkenes or alkynes provide means of direct construction of carbon-hetereoatom bonds. ... 

A starting material that is suitable for the direct construction of a heterocycle by an intramolecular Heck-type reaction has to fulfil some simple but fundamental requiranents there has to be the halide function or a triflate for the oxidative addition onto the Pd catalyst, a side chain with an unsaturated functionality such as an alkene or an alkyne in an appropriate distance, and of course the heteroatom in this side chain. Figure 1 presents a substrnctnre typical for very many starting materials, which were transformed to heterocycles by intramolecnlar Heck-type reactions (X = halide, Het = heteroatom). This type of substrnctnre with an allylic side chain is easily accessible by derivatization of 2-bromo- and 2-iodo anilines, phenols, and thiophenols and leads to interesting heterocycles such as indoles and benzofurans, which are related to many natural products and other biological active componnds. 

Hydrocyanation is the addition of HCN across carbon-carbon or carbon-heteroatom multiple bonds to form products containing a new C-C bond. The majority of examples from organometallic chemistry involve the addition of HCN across carbon-carbon multiple bonds, as shown in Equations 16.2 and 16.3. Lewis acids and peptides have been used to catalyze the enantioselective addition of HCN to aldehydes and imines to form cyanohydrins and precursors to amino acids.The addition of HCN to unactivated olefins requires a catalyst because HCN is not sufficiently acidic to add directly to an olefin, and the C-H bond is strong enough to make additions by radical pathways challenging. However, a large number of soluble transition metal compounds catalyze the addition of HCN to alkenes and alkynes. 

The direct, Pd(II)-catalyzed addition of heteroatom and stabilized carbon nucleophiles to alkenes is generally not a successful reaction. An exception is the addition of water, which gives carbonyl compounds and has been developed into an important indnstrial process, the Wacker process. This has been reviewed extensively.By contrast, the stoichiometric addition of nucleophiles such as amines is facile. - However, if alkenes could be converted catalytically into Tr-allylpalladium complexes, the problems with nucleophilic addition to alkenes could be circumvented and amines and other heteroatom nucleophiles could be employed. A range of alkenes have been converted into rr-allyl complexes in a stoichiometric fashion,t "t but catalytic reactions have proved more difficult. However, aUyl acetates and similar compounds readily exchange the acetate group for heteroatom nucleophiles in a Pd(0)-catalyzed reaction, which proceeds via 7T-allylpalladinm(ll) intermediates (Scheme 1). Since this reaction has been developed into a very important synthetic reaction, an efficient procedure for catalytic conversion of alkenes into aUyl acetates would have great synthetic potential. 

It should be noted that formation of trans-product can be achieved in an anti-addition reaction through the outer-sphere mechanism. Theoretical studies have demonstrated that syn-addition and anti-addition reactions may start from the same 7i-complex, and direction of the multiple bond activation depends on the polarity of solvent [17, 18]. Relative reactivity in the inner-sphere and outer-sphere mechanisms contributes to the overall -/Z- selectivity of the addition reaction to alkynes (stereoselectivity issue). In some cases it is possible to switch the direction of C-Het bond formation by finding a suitable ligand [19]. In case of alkenes syn-addition and a f -addition processes do not necessarily result in different stereochemistry (unrestricted rotation around the single C-C bond in the product). Occurrence of these mechanisms for the N [20, 21], P [22, 23], O [24-26], S, Se [27, 28] heteroatom groups and application of different metal catalysts are discussed in detail in the other chapters of this book. Stereochemical pathways of nucleometallation and development of enantioselective catalytic procedures were reviewed [29]. In this chapter we focus our attention on the mechanism of irmer-sphere insertion reaction involving double and triple carbon-carbon bonds. 

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