Halides, alkyl, from mesylates

The synthesis of organozinc compounds by electrochemical processes from either low reactive halogenated substrates (alkyl chlorides) or pseudo-halogenated substrates (phenol derivatives, mesylates, triflates etc.) remains an important challenge. Indeed, as mentioned above, the use of electrolytic zinc prepared from the reduction of a metal halide or from zinc(II) ions does not appear to be a convenient method. However, recent work reported by Tokuda and coworkers would suggest that the electroreduction of a zinc(II) species in the presence of naphthalene leads to the formation of a very active zinc capable of reacting even with low reactive substrates (equation 23)11. 

The table summarizes the general pattern of reactivity expected from various structural classes of alkyl halides (or tosylates, mesylates) in reactions with a representative range of nucleophiles (which may behave as bases). 

C-X disconnection in aliphatic compounds (ii) gives a nucleophile XH and an electrophilic carbon species usually represented by an alkyl halide, tosylate, or mesylate. These compounds can all be made from alcohols (ii) and as alcohols can be made by C-C bond formation (Chapter 10) we shall treat the alcohol as the central functional group (Table 4.2). 

Woodward el al. have reported a series of stereo- and enantioselective alkylations of non-symmetrical allylic electrophiles derived from MBH products. The allyl halides or allyl mesylate 225 derived from a MBH adduct are chemo- and regiospecifically transformed into 3, (3-disubstituted a-methylene-propionates 226 on treatment with either diorganozincs or organozinc halides in the presence of catalytic amounts of copper(i) salts (3-20mol.%) in high... 

Alkyl azides are conveniently prepared from the reaction of alkali metal azides with an alkyl halide, tosylate, mesylate, nitrate ester or any other alkyl derivative containing a good leaving group. Reactions usually work well for primary and secondary alkyl substrates and are best conducted in polar aprotic solvents like DMF and DMSO. The synthesis and chemistry of azido compounds is the subject of a functional group series. ... 

Intermolecular reactions of hydroxylamines with secondary alkyl halides and mesylates proceed slower than with alkyl triflates and may not provide sufficiently good yield and/or stereoselectivity. A nseful alternative for these reactions is application of more reactive anions of 0-alkylhydroxamic acids or 0-alkoxysulfonamides ° like 12 (equation 8) as nucleophiles. The resulting Af,0-disubstituted hydroxamic acids or their sulfamide analogs of type 13 can be readily hydrolyzed to the corresponding hydroxylamines. The same strategy is also helpful for synthesis of hydroxylamines from sterically hindered triflates and from chiral alcohols (e.g. 14) through a Mitsunobu reaction (equation 9). 

S )-3-Hydroxy-4-butanolide (1), which is readily available from (—)-(S)-malic acid, can be converted into the dianion and the latter alkylated with alkyl halides or mesylates with moderate yields but with high diastereoselectivity (d.r. >98 2)39. 

Wittig reactions can also be performed with support-bound phosphorus ylides. Polystyrene-bound alkylphosphonium salts have been prepared from the corresponding alkyl mesylates or halides and trialkyl- or triarylphosphines (Figure 5.8 [60,80]). Because polystyrene is a hydrophobic support, salt formation does not proceed smoothly and quaternization of phosphines generally requires forcing conditions. The... 

Ni(0) complexes react with halides and pseudohalides. Their reactions are somewhat different from those of Pd(0). Chlorides add to Ni(0) much more easily than to Pd(0). Even C—O bonds such as aryl alkyl ether bonds are cleaved with Ni(0) under certain conditions. Not only triflates, but also mesylates react with Ni(0). Oxidative addition to Ni(0) and subsequent transformations are summarized in Scheme 3.6. 

Sulfonates such as mesylates or tosylates are readily prepared from alcohols under mild conditions, and are therefore attractive alternatives to halides as electrophiles. Although sulfonates often undergo clean displacement by nucleophiles, alternative reaction pathways are accessible to these intermediates, which can lead to unexpected results. If the nucleophile used is strongly basic, metalation instead of displacement of the sulfonate can occur. Some potential reactions of such metalated sulfonates include fragmentation into sulfenes and alcoholates, or into sulfmates and carbonyl compounds, or self-alkylation (Scheme4.15). 

We have focussed on alkyl halides but tosylates from TsCl and mesylates from MsCl can be used too. The conversion of alcohols to chlorides and bromides is discussed earlier in this chapter and the combination of reagents used to make thiols is discussed in the next chapter. 

Longer-chain alkyl halides may not be commercially available, but they are readily made in one step from the corresponding alcohols (Larock, 1999), as are tosylates and mesylates. Similarly, longer-chain terminal alkynes are not commercially available, but can be readily made by reaction of alkyl halides with lithium acetylide-ethylene diamine complex in dry... 

A novel ionic liquid methodology for pyrrole C-alkylation is described (Equation 136) <20050L1231>. The pyrrole alkylation is achieved with various simple alkyl halides (1-bromopentadecane, l-(bromomethyl)-, l-(3-chloropropyl)- and l-(3-iodopropyl)benzenes, 2-(2-bromoethyl)- and 2-(3-bromopropyl)naphthalenes) and mesylates (3-phenylpropyl-, l-methyl-3-phenylpropyl-, 2-(2-naphthyl)ethyl- and 3-(2-naphthyl)propyl methanesulfonates) selectively at C(2)- and C(5)-positions in good yields with minimal by-products under relatively mild conditions in various ionic liquids. 2-(3-Phenylpropyl)pyrrole 569 was synthesized from pyrrole and l-bromo-3-phenylpropane in a mixed solvent system, [Bmim][SbF6] and MeCN, in 81% yield at 115°C for 44h with 5% yield of dialkylated compound. 

From alcohols. Alcohols can be transformed into phenylselenides in a stepwise manner via mesylation and reaction with lithium phenylselenolate. This procedure offers obvious advantages over the formation of the corresponding bromides or iodides when subsequent reaction with strong nucleophiles, such as organolithium compounds, are necessary to prepare the radical precursors. The diol 8 is converted to the bis(phenylselenide) 9 via the corresponding bis(mesylate) as shown in Scheme 2 [6]. Compound 9 is converted to the radical precursor 11 via reaction with lithium phenylacetylide followed by alkylation with allylbromide and a Pauson-Khand reaction. Such a reaction sequence would not be feasible with an alkyl halide. The cyclization afforded the expected tricyclic compound 12 in 95% yield. 

The synthesis of stereodefined acyclic alkenes via 3-elimination reactions—such as (1) dehydration of alcohols, (2) base-induced eliminations of alkyl halides or sulfonates (tosyl or mesyl esters), and (3) Hofmann eliminations of quaternary ammonium salts—often suffers from a lack of regio- and stereoselectivity, producing mixtures of isomeric alkenes. 

As noted above, alkyne anions are very useful in Sn2 reactions with alkyl halides, and in acyl addition reactions to a carbonyl.46 Alkyl halides and sulfonate esters (tosylates and mesylates primarily) serve as electrophilic substrates for acetylides. A simple example is taken from Kaiser s synthesis of niphatoxin B, in which propargyl alcohol (36) is treated with butyllithium and then the OTHP derivative of 8-bromo-1-octanol to give a 47% yield of 37.48... 

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