Alkyl halides simple

Among compounds other than simple alkyl halides a halo ketones and a halo esters have been employed as substrates m the Gabriel synthesis Alkyl p toluenesul fonate esters have also been used Because phthalimide can undergo only a single alkyl ation the formation of secondary and tertiary amines does not occur and the Gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines... 

Unlike simple alkyl halides, ethyl chloroformate appears to react with primary and secondary amino groups in any position to give directly the corresponding urethane, e.g. (258) (64JMC364). Such alkylations proceed in pyridine, aqueous alkali or even warm benzene (62JOC982). 

Furthermore they claimed that the dichloromethyhndolenine 17 could be converted into the quinohne 18 by hot ethanolic sodium ethoxide. They also reported other similar cases of ring expansion of the dichloromethyl bases, with loss of hydrogen chloride, on further treatment with sodium ethoxide (cf. ref. 67). They considered that chloroform acted like a simple alkyl halide giving jS-alkylation of the... 

In general the Stork reaction gives moderate yields with simple alkyl halides better yields of alkylated product are obtained with more electrophilic reactants such like allylic, benzylic or propargylic halides or an a-halo ether, a-halo ester or a-halo ketone. An example is the reaction of 1-pyrrolidino-l-cyclohexene 6 with allyl bromide, followed by aqueous acidic workup, to yield 2-allylcyclohexanone ... 

Generally the desired substituted carbonyl compound 3 is obtained after hydrolytic workup under acidic conditions. With simple alkyl halides an irreversible A-alkylation may take place as a side-reaction to give a quaternary ammonium salt 7 ... 

In addition to their systematic names, many simple alkyl halides are also named by identifying first the alkyl group and then the halogen, for example, CH3T can be called either iodomethane or methyl iodide. Such names are well entrenched in the chemical literature and in daily usage, but they won t be used in this book. 

Simple alkyl halides can be prepared by radical halogenation of alkanes, but mixtures of products usually result. The reactivity order of alkanes toward halogenation is identical to the stability order of radicals R3C- > R2CH- > RCH2-. Alkyl halides can also be prepared from alkenes by reaction with /V-bromo-succinimide (NBS) to give the product of allylic bromination. The NBS bromi-nation of alkenes takes place through an intermediate allylic radical, which is stabilized by resonance. 

Dihalides are reduced by Cr(II) to the corresponding olefin ". Allylic and benzylic halides and polyhalides are reduced more readily than simple alkyl halides, but even the latter are readily reduced by an ethylenediamine complex ofCr(ri) . ... 

Reduction of simple alkyl halides to alkanes by ethylenediamine complexes of Cr(II), denoted Cr"(en) occurs readily , e.g. for isopropyl chloride in aqueous dimethylformamide at 25 °C simple second-order behaviour is found with ki dependent on [en]/[Cr(II)] but reaching a limiting value of 1.6x 10 l.mole . sec . Competition studies between a mixture of two alkyl chlorides for Cr(II) was achieved by estimating alkane products by gas-liquid chromatography and... 

A s-sulfide accelerates the solvolysis nearly 3000-fold compared to the simple alkyl halide and approximately 15,000-fold compared to the B-chloroether. On the other hand, the y-sulfide offers no assistance apparently closure to the four-membered cyclic sulfon-ium ion cannot compete with direct displacement by the external nucleophile. 

The direct addition of simple alkyl groups onto aldehydes is the most challenging in water. Mitzel reported the indium-mediated alkylation of carbonyl compounds with a-sulfur stabilized systems.224 Recently, Li and co-workers reported an efficient addition of simple alkyl halides to aldehydes mediated by Zn/Cul with a catalytic amount of InCl in water (Eq. 8.89).225... 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

This is clearly an elimination/addition mechanism [in contrast to the addition/elimination of SN2 (aromatic)] and formally parallels, in its genesis, the elimination reactions of simple alkyl halides that we shall consider subsequently (p. 246). Direct evidence in support of the aryne pathway is provided by the fact that the halides (98), (99) and (100),... 

Simple alkyl halides show the following general order of reactivity in SN2 reactions ... 

Earlier, in Sect. 8.3.1, a generalized mechanistic scheme for the reduction of simple alkyl halides was presented. What distinguishes aryl halides (ArX) from alkyl halides (RX) is the finite lifetime of the initially electrogenerated anion radical (ArX ). Thus, although ArX exhibits the same kinds of reactions as RX, a key difference is that the transient anion radical (ArX ) can undergo a homogeneous electron-transfer reaction with the aryl radical (Ar) (Eq. 4) ... 

If the potential leaving group is attached to unsaturated carbon, as in vinyl chloride or phenyl chloride, attack by nucleophiles is also extremely difficult, and these compounds are very unreactive in Sn2 reactions compared with simple alkyl halides. In these cases, the reason is not so much steric but electrostatic, in that the nucleophile is repelled by the electrons of the unsaturated system. In addition, since the halide is attached to carbon through an 5p -hybridized bond, the electrons in the bond are considerably closer to carbon than in an 5/ -hybridized bond of an alkyl halide (see Section 2.6.2). Lastly, resonance stabilization in the halide gives some double bond character to the C-Hal bond. This effectively strengthens the bond and makes it harder to break. This lack of reactivity is also tme for SnI reactions (see Section 6.2). 

Diastereoselective alkylation of tartaric acid. The enolate (2) of the acetonide of dimethyl (R, R)-tartrate (1) can be generated with LDA in THF-HMPT at — 70° and is sufficiently stable for alkylation with allyl and benzyl halides, but not with other simple alkyl halides, and for addition to acetone (60% yield). The main products (3) of allylation and benzylation have the /ranr-configuration, and thus the substitution occurs with retention of configuration.7... 

The facile asymmetric synthesis of a-amino acids usually inaccessible by enzymatic processes becomes feasible by employing appropriate electrophiles such as ortho-disubstituted benzyl bromides. In the reaction with simple alkyl halides such as ethyl iodide, the use of aqueous cesium hydroxide (CsOH) as a basic phase at a lower reaction temperature is generally recommended [7e]. 

By using CsOHH20 in place of 50% KOH, the asymmetric alkylation of 2 with a simple alkyl halide such as ethyl iodide proceeded smoothly at — 20 °C to furnish the corresponding a-alkyl-a-amino acids in good yield, with high enantioselectivity Table 5.2, entries 20 and 21). 

As shown in Scheme 4.1, during an Sn2 reaction at sp3-hybridized carbon the nucleophile approaches the electrophile from the side opposite to the leaving group. Hence, if the remaining three substituents at the electrophilic carbon are large, the nucleophile will have to overcome repulsive forces, especially so if the nucleophile also is large. This steric repulsion is believed to be the main reason for the strong dependence of bimolecular substitution rates on the structure of simple alkyl halides (Table 4.1). 

Alkylpalladium complexes generated by oxidative addition of Pd(0) to alkyl halides with a /3 hydrogen can undergo /3-elimination to yield an alkene and a Pd-hydrido complex (as in the Heck reaction Scheme8.7). Nevertheless, this process is relatively slow compared with transmetalations and reductive eliminations, and simple alkyl halides or tosylates with /3 hydrogen can be cross-coupled with carbon nucleophiles under optimized conditions if the nucleophile is sufficiently reactive [9, 73-75] (Scheme8.6). 

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