Alkylation early examples

In 1974, Hegedus and coworkers reported the pa]ladium(II)-promoted addition of secondary amines to a-olefins by analogy to the Wacker oxidation of terminal olefins and the platinum(II) promoted variant described earlier. This transformation provided an early example of (formally) alkene hydroamination and a remarkably direct route to tertiary amines without the usual problems associated with the use of alkyl halide electrophiles. 

Early examples of enantioselective extractions are the resolution of a-aminoalco-hol salts, such as norephedrine, with lipophilic anions (hexafluorophosphate ion) [184-186] by partition between aqueous and lipophilic phases containing esters of tartaric acid [184-188]. Alkyl derivatives of proline and hydroxyproline with cupric ions showed chiral discrimination abilities for the resolution of neutral amino acid enantiomers in n-butanol/water systems [121, 178, 189-192]. On the other hand, chiral crown ethers are classical selectors utilized for enantioseparations, due to their interesting recognition abilities [171, 178]. However, the large number of steps often required for their synthesis [182] and, consequently, their cost as well as their limited loadability makes them not very suitable for preparative purposes. Examples of ligand-exchange [193] or anion-exchange selectors [183] able to discriminate amino acid derivatives have also been described. 

As mentioned above nonconjugated dienes give stable complexes where the two double bonds can form a chelate complex. A common pathway in palladium-catalyzed oxidation of nonconjugated dienes is that, after a first nucleophilic addition to one of the double bonds, the second double bond inserts into the palladium-carbon bond. The new (cr-alkyl)palladium complex produced can then undergo a /(-elimination or an oxidative cleavage reaction (Scheme 2). An early example of this type of reaction, although not catalytic, was reported by Tsuji and Takahashi (equation 2)12. 

An obvious approach to biguanides is the ammonolysis or aminolysis of the sulphm--function in amidinothioureas (IX), and their S-alkyl-deriv-atives (XIV). An early example of this reaction is due to Bamberger 30). 

Early examples of successful, highly diastereoselective alkylations of bicyclic /1-lactams include reactions of the enolates from penicillin and cephalosporin derivatives (e.g., 1 and 4). These enolates have also been used in aldol-type additions, acylations and in the preparation of hetero-substituted penicillins and cephalosporins1. 

Among the six-membered ring heterocycles, diketopiperazines are most commonly prepared by cyclative cleavage. Indeed, diketopiperazine formation is often observed as an undesirable by-product during peptide synthesis20 and the facile nature of this cyclization makes it an obvious choice for library generation. In an early example from Pfizer,21 a set of 10 immobilized a-amino acids was reductively alkylated with 10 aldehydes, followed by acylation with 10 a-amino acids and cyclization (Fig. 6). By... 

Early examples of intramolecular aryl radical addition reactions to heteroatom containing multiple bonds included cyclizations on N=N and C=S moieties [52, 53]. Recently, cyclizations to imines have been used as part of a new enantio-selective approach to indolines (Scheme 8). In the first step of the sequence, the required ketimines 19 were obtained by phase-transfer catalyzed alkylation of 2-bromobenzyl bromides 20 with glycinyl imines 21 in the presence of a cincho-nidinium salt [54], Due to the favorable substitution pattern on the imine moiety of 19, the tributyltin hydride mediated radical cyclization to 22 occurred exclusively in the 5-exo mode. The indoline synthesis can therefore also be classified as a radical amination. 

These compounds are formed by addition of lithium alkyls to alkylpyrazines, followed by hydrolysis (see Section V,A). They readily oxidize to pyrazines on exposure to air. Some early examples of 1,4-dihydropyrazines have recently been shown to have 1,2-dihydro structures.384 ... 

Cyclisation of iodonitrile 10559 to 107 was an early example of an anionic cyclisation. Slow transmetallation of the choronitrile 108 allowed the BuLi to attack the nitrile instead, leading to a quite different cyclisation product 109. The successful iodine-lithium exchange of primary alkyl iodide 105 to give 106 even with n-BuLi must be driven by the cyclisation itself. 

The facile reaction of CAA and BAA with nucleosides and nucleotides is one example of many of the applications of the bifunctional reactivity of halogenated aldehydes and ketones in modification of biomolecules. In an early example of the extensive use of halogenated ketones as protease substrate analogues, l-V-tosylamido-2-phenylethyl chloro-methyl ketone (TPCK) 30 was synthesized as a chymotrypsin substrate analogue. Stoichiometric inhibition was accompanied by loss of one histidine residue as a result of alkylation by the chloromethyl moiety68. A host of similar analogues were subsequently prepared and used as selective enzyme inhibitors, in particular for the identification of amino acid residues located at enzyme active sites69. 

The first example of a Friedel-Crafts type reaction in an ionic liquid medium dates back to 1976 when the electrochemical oxidation of hexamethylbenzene in [C2py]Br-AlCl3 afforded a mixture of alkylated polyphenyl compounds.[69] Other early examples include the alkylation of benzene in C2Ciim C1-A1C137 and the acylation of ferrocene in [C2Ciim]I-AlClJ71 There are now numerous examples of Lewis- or Bronsted acid-catalysed Friedel-Crafts type reactions in ionic liquids. These include alkylation,[72 76] acylation,[71,77"83] arylation,[77 841 sulfonylation,[851 sulfoamylation[86] and O-acetylation of alcohols.[87,881... 

The fact that hyperenergetic molecules such as the 1,2-dioxetanes should be prone by catalytic decomposition is not surprising. Early examples include the protecting effect of molecular oxygen on the thermal decomposition of 3,4-diethoxydioxetane, the efficient catalytic decomposition of this dioxetane by amines, and of alkyl-substituted dioxetanes by transition-metal ion impurities. However, all of these catalytic decompositions are competing dark reactions that greatly diminish the chemiluminescence efficiency of the dioxetanes. 

The second is in situ, where generation of the EGB by reduction of the PB takes place in the presence of reactant(s). The advantage of this mode of operation is that the EGB can be short-lived, and the applied current can control the amount of base present at any time. The major disadvantage is that the PB must be more easily reduced than the reactant(s). This method is the one most commonly used. An early example of a radical anion EGB is shown in Scheme 3. The method has also frequently been used to generate carbanion EGBs from alkyl or aryl halides as illustrated schematically in Scheme 2. 

Magat first reported the use of r-alkyl halides as Ritter reaction substrates but, in general, these were less satisfactory than the use of the corresponding alcohol or alkene analogs. This process has since come into its own for polycyclic systems, where simple methods of generating bridgehead halides are often available. An early example is Stetter s conversion of 1-bromoadamantane to the acetamide (30), there-... 

Introduction of an alkyl group at the C-13 position of the protoberber-ine ring system is readily accomplished by direct alkylation of either the 8-acetonyl base 77) or the dihydro derivative (78) of the appropriate alkaloid. Reduction of the resulting salt, usually without isolation, affords the corresponding epimeric 13-methyltetrahydro bases. The conversion (79) of palmatine (V) to corydaline (VI) and mesocorydaline (VII) via the salt VIII exemplifies the use of this reaction which constitutes an early example of the now well-known C-alkylation of an enamine. 

Villieras and coworkers have contributed a considerable number of synthetic methods employing lithium halocarbenoids. An early example was the alkylation of dibromomethyllithium and higher homologs (Scheme 15). The anion (15) is easily generated from 1,1-dibromoalkanes by deprotonation with LDA in THF at low temperature. Alkenes can then be generated simply by treating the products with Bu"Li in EtjO, Alkylation of dichloromethyllithium with primary alkyl halides followed by reaction of the dichloroalkanes with Bu"Li represents a method for the preparation of 1 -alkynes. ... 

This section covers the union of two aryl moieties, one of which is a fully alkylated phenol, and the other is either a free phenol or a phenol ether. Clearly, radical dimerization is not operative in such reactions. An early example is to be found in the work of Pitcher and Dietrich (1924) ° who showed that 3,3, 4,4 -tetramethoxybiphenyl was among the products of electrolytic oxidation of veratrole in sulfuric acid using a lead dioxide anode the biaryl was formed in about 20% yield based on reacted veratrole. 

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