Reactions with activated alkyl halides

It is possible to replace one isocyanide by triphenylphosphine, or to replace two isocyanides with diphos, giving phosphine analogues of these complexes. These species are not available from analogous reactions of phosphine-palladium(O) and (II) complexes. Reactions with active alkyl halides proceeds with oxidation nitric oxide also oxidizes these complexes. [Eqs. (31, 32)]. 

Alkylation of hydroxylamine with primary halides and sulfonates is rarely used nowadays for preparation of A-alkylhydroxylamines due to the competing formation of N,N-dialkylhydroxylamines. A number of older procedures have been reported with low to moderate yields of Al-alkylhydroxylamines. Yet, in many cases the reported low yields can be attributed to workup losses during distillation and crystallization steps rather than to the polyalkylation. Use of excess of hydroxylamine in reactions with primary alkyl halides (e.g. 3) improves the yields of monoalkylation (equation 2). Most of the examples of alkylation of hydroxylamine in good yield involve a substitution of an activated halogen atom at benzylic positions as well as in haloacetamides 4 leading to alkylhydroxylamines such as 5 where dialkylation rates are lower (equation 3). 

The Co reagent 192, prepared by the reaction of Co2(CO)8 with sodium, is reactive, and the acylcobalt complex 193 is formed by the reaction of acyl halides. Insertion of butadiene at the Co-acyl bond generates the 7r-allylcobalt complex 194, from which the acylbutadiene 195 is formed by deprotonation with a base [82]. Based on this reaction, various acyldienes are prepared by Co2(CO)8-catalysed reaction of active alkyl halides, conjugated dienes and CO. The Co-catalysed reaction can be carried out smoothly under phase-transfer conditions. For example, 6-phenyl-3,5-hexadien-2-one (197) was prepared in 86% yield by the reaction of Mel, 1-phenylbutadiene (196) and CO in the presence of cetyltrimethylammonium bromide [83]. 

A number of metal nitrosyl complexes react with activated alkyl halides to yield, ultimately, organic nitrogen-containing products. The most widely studied reagent is [Ru(NO)2(PPh3)2] (229), though other compounds such as [CoCl(NO)(CO)2] (230) and [Fe(NO)(CO)3] (231) have been used. These reactions have been discussed in depth elsewhere (6). Another reaction of some industrial importance is the catalytic reaction of NO gas with alkenes. Over Ag20 or PbO the product from propene is acrylonitrile. In a study of this type of reaction (232),... 

A further extension of these concepts is the alkylation of enolate / secondary amine complexes. Following several early observations [141-143]/ systematic investigations were undertaken by the Koga group [24,25,147-149]. These efforts have resulted in a very selective asymmetric alkylation of cyclohexanone and a-tetralone with activated alkyl halides (Scheme 3.25). As listed in Table 3.10, alkylation of these ketones affords up to 96% enantioselectivity. During the optimization studies, Koga observed an increase in enantioselectivity and chemical yield as the reaction time increased, and ascribed the phenomenon to the formation of a mixed aggregate that includes the lithium bromide formed as the reaction proceeds. Further experiments revealed that addition of one equivalent of lithium... 

In the past decade, several other structural motifs were used for the development of effective chiral PTC. In 2002, Shibasaki and co-workers [61] demonstrated the high potential of tartaric acid-derived bidentate PTC. They reported the preparation and evaluation of tartrate-derived diammonium PTCs of type XXXV for alkylation of 1 with activated alkyl halides (Scheme 8.6), and the salt XXXVa was foimd to be optimal PTC for asymmetric alkylation reactions from more that 70 constructed tartrate-based ammonium salts [62]. 

Reaction of (lS,2S,5S)-2-hydroxypinan-3-one (539) with glycine t-butyl ester in the presence of Bp3,OEt2 gives the Schiff base (540) in good yield. Treatment of (540) with two equivalents of lithium di-isopropylamide, presumably to give a dilithio-salt, followed by reaction with an alkyl halide [RX = Mel, Bu I, PhCH2Br, or 3,4-(MeO)2CgH3CH2Br] afforded the alkylated Schiff bases (541) which, upon mild hydrolysis with aqueous citric acid, were converted into the D-a-amino t-butyl esters (optical yield 65—85%) and (539 75 % recovered). Since a-pinene is available from natural sources in both optically active forms, this synthesis allows the production of both D- and L-isomers of various a-amino-acids by alkylation of the... 

Scheme Z48 Suzuki-Miyaura cross-coupling reactions of activated alkyl halides with aryl boranes.

Zinc, Cadmium, and Mercury.—Slurries of finely divided Cd or Zn, formed by codeposition of the appropriate metal vapour with a solvent, are active enough to form organometallic reagents (presumed to be metal dialkyls) by reaction with simple alkyl halides. Not only a-bromoesters, but also a-bromoketones, can be reacted with Zn to give Reformatsky-like reagents. Subsequent reaction with an... 

While these four schemes by no means exhaust the possibilities, they represent a broad spectrum of mechanisms in terms of molecularity and polarity of the transition state. Some organolithium reactions, e.g., thermal decomposition, very probably proceed via radical formation. Furthermore, there is evidence that the coupling reaction with an alkyl halide may involve radicals (72), although these systems must be more extensively investigated. Reaction scheme iv) can probably be ruled out immediately it would require an inordinately high activation energy, would probably lead to a negligible lithium kinetic isotope effect, and would not account for stereospecificity in olefin polymerization 68, 73). It possibly becomes an important pathway, however, in the presence of more polar molecules such as ethers. 

Which of these two opposite stereochemical possibilities operates was determined in experiments with optically active alkyl halides In one such experiment Hughes and Ingold determined that the reaction of 2 bromooctane with hydroxide ion gave 2 octanol having a configuration opposite that of the starting alkyl halide... 

Triflates of aluminum, gallium and boron, which are readily available by the reaction of the corresponding chlorides with triflic acid, are effective Fnedel-Crafis catalysis for alkylation and acylation of aromatic compounds [119, 120] Thus alkylation of toluene with various alkyl halides m the presence of these catalysts proceeds rapidly at room temperature 111 methylene chloride or ni-tromethane Favorable properties of the triflates in comparison with the correspond mg fluorides or chlorides are considerably decreased volatility and higher catalytic activity [120]... 

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

The method is quite useful for particularly active alkyl halides such as allylic, benzylic, and propargylic halides, and for a-halo ethers and esters, but is not very serviceable for ordinary primary and secondary halides. Tertiary halides do not give the reaction at all since, with respect to the halide, this is nucleophilic substitution and elimination predominates. The reaction can also be applied to activated aryl halides (such as 2,4-dinitrochlorobenzene see Chapter 13), to epoxides, " and to activated alkenes such as acrylonitrile. The latter is a Michael type reaction (p. 976) with respect to the alkene. 

The first palladium-catalyzed formation of aryl alkyl ethers in an intermolecular fashion occurred between activated aryl halides and alkoxides (Equation (28)), and the first formation of vinyl ethers occurred between activated vinyl halides and tin alkoxides (Equation (29)). Reactions of activated chloro- and bromoarenes with NaO-Z-Bu to form /-butyl aryl ethers occurred in the presence of palladium and DPPF as catalyst,107 while reactions of activated aryl halides with alcohols that could undergo /3-hydrogen elimination occurred in the presence of palladium and BINAP as catalyst.110 Reactions of NaO-/-Bu with unactivated aryl halides gave only modest yields of ether when catalyzed by aromatic bisphosphines.110 Similar chemistry occurred in the presence of nickel catalysts. In fact, nickel catalysts produced higher yields of silyl aryl ethers than palladium catalysts.108 The formation of diaryl ethers from activated aryl halides in the presence of palladium catalysts bearing DPPF or a CF3-subsituted DPPF was also reported 109... 

Further experimental studies involved the determination of the rate constant of the reaction of several alkyl halides with a series of electrochemically generated anion radicals so as to construct activation driving force plots.39,40,179 Such plots were later used to test the theory of dissociative electron transfer (Section 2),22,49 assuming, in view of the stereochemical data,178 that the Sn2 pathway may be neglected before the ET pathway in their competition for controlling the kinetics of the reaction. 

The same electrochemical process was also used for the coupling between aldehydes or ketones and activated alkyl halides such as a-chloroesters, -nitriles, and -ketones as well as aya-dichloroesters.334 Electroanalytical studies have shown initial electroreduction of Fe(n) to Fe(i) and subsequent formation of an iron organometallic intermediate (e.g., a 7t-allyliron complex in Equation (27)) before reaction with the corresponding carbonyl compounds.335... 

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