The Reaction with Alkyl Halides

The SH2y mechanism is most clearly shown by the exchange of RaSn-(155,156), and by the reaction with alkyl halides (157, 158). 

Under the conditions of the Birch reduction, IV-Boc amides such as 60 can be reductively alkylated in high yields, presumably via a dianion intermediate which is protonated by ammonia at C-5 leaving an enolate anion at C-2 <96JOC7664>. Quenching the reaction with alkyl halides or ammonium chloride then affords the 3-pyrrolines 61. 

Experiments have been carried out to mimic the reactions of model systems for coenzyme F430 that is involved in the terminal step in the biosynthesis of methane, and that is able to dechlorinate CCI4 successively to CHCI3 and CH2CI2 (Krone et al. 1989). Nickel(I) isobacteriochlorin anion was generated electrolytically and used to examine the reactions with alkyl halides in dimethylformamide (Helvenston and Castro 1992). The three classes of reaction were the same as those observed with Fe(II) deuteroporphyrin IX that have already been noted. 

Compound 162 undergoes alkylation at the N-3 position by the reaction with alkyl halides in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) forming derivatives 163 (Equation 10) <2002JME3337>. 

The first pathway is realized in the reaction with alkyl halides and gives betaines [Eq. (99)]. 

These reactions may be considered to be a method of obtaining 1,3,2,5-dioxaborataphosphoniarinanes with different substituents at carbon and phosphorus atoms of the ring. Comparing the properties of cyclic oxyalkyl-phosphines and boryloxyalkylphosphines, it should be noted that in both cases the reaction with alkyl halides results in the formation of a tertiary phosphonium salt. The reaction with electrophilic reagents such as diphe-nylchlorophosphine and diphenylchloroborane proceeded quite differently [Eq. (100)]. 

Numerous other reactions of Co(CN)s3 have been observed with a wide variety of substances. For example, the reaction with alkyl halides can be shown as follows ... 

The oxidative addition of acids is another instructive example. It resembles the reactions with alkyl halides and may result in an "amphoteric" hydride ... 

It is these reactions that are thought to provide some justification for equation (vii) [in Section VI B3] according to which p-phenethylbi-guanide in methanol exists to some extent as biguanidium methoxide. This being so, the reaction with alkyl halides is the nucleophihc displacement of the halogen ion by methoxide with formation of the methyl ether and the salt of the biguanide. 

The hfs-lactim ether (190) was metallated with BuLi regiospecifically in the alanine part of the molecule to produce, after the reaction with alkyl halides, the (3R)-adducts... 

They react with alkyl halides to give internal alkynes (see Section 5.5.2) via nucleophilic substitution reactions. This type of reaction also is known as alkylation. Any terminal alkyne can be converted to acetylide and alkynide, and then alkylated by the reaction with alkyl halide to produce an internal alkyne. In these reactions, the triple bonds are available for electrophilic additions to a number of other functional groups. 

The equilibrium constant appears to be of the order of 10 7. Consequently, it appears that the bis complex, NiL2, is present in sufficient amounts to be the principal reactant in the reactions with alkyl halides. 

Alkylation is a very broad reaction type and it can, depending on the nature of the alkylating agent, proceed either as a substitution or as an addition reaction. The alkylation by substitution of, for example, aromatic hydrocarbons, phenols or amines is based on the reaction with alkyl halides or alcohols. Some evidence indicates that, at least partly, the alkylation proceeds through the intermediate formation of alkenes from the alkylating agent when the reaction is conducted at atmospheric pressure and at high temperature. 

The products were isolated as esters by reaction of the acylcobalt carbonyls with an alcohol and iodine. In the case of the alkyl halides, carbon monoxide was normally absorbed, but under nitrogen, acylcobalt tricarbonyls must be formed. The reaction with alkyl halides was slow and some isomerization was noted using M-propyl iodide (formation of n-butyrates and isobutyrates). Absence of carbon monoxide promoted the isomerization. Isopropyl iodide gave no reaction. When ethyl a-bromopropionate was used, no isomerization was found at — 25 °C under carbon monoxide, but the isomerized product, diethyl succinate, was the major product at 25° C under carbon monoxide or nitrogen. Under the conditions of the experiments no isomerization of the alkyl halide itself was found. 

The 2-cyano-cycloalkanones are easy to prepare but only in moderate yields [18]. The introductions of nitro- [6] and sulfone- [5] [116] [117] groups are simpler than the cyano group, and the yields are better. Sulfone and cyano compounds are most suitable for the introduction of the side chain. Beside the Michael reaction [16] [97], and the Pd(O) catalyzed addition [15], and the reactions with alkyl halides [16] [17] proceed in good yields. In contrast to other compounds, 2-nitroketones generally do not undergo nucleophilic substitution with non-activated alkyl halides. However, Michael addition products [2], as well as products synthesized by Pd(O) catalyzed alkylation [118], are well known derivatives of 2-nitrocycloalkanones. 

Cross coii ing of Grignard reagents with 1-alkenyl halides, in marked contrast to alkyl halides, occurs readily with the reduced iron catalyst, as described above. The iron-catalyzed reaction of Grignard reagents with 1-alkenyl halides can, however, be differentiated from the reaction with alkyl halides. Thus, a mixture of propenyl bromide and ethyl bromide on reaction with methylmagnesium bromide afforded butene-2 but no cross-over products such as pentene-2 or propylene. The latter certainly would have resulted if a propenyliron species per se were involved in the catalytic process. Cross coupling under tEese circumstances clearly merits further study. 

This method has also been quite useful for the synthesis of triorganoarsenic compounds. Arsenide anions, which can be prepared by several methods (vide infra), react with alkyl and aryl halides. Several examples are shown in equations 18 , 19 , 20 °, 21 , 22 23 , 24 and 25 . In the reaction with alkyl halides inversion of configuration at the sp carbon atom takes place and in the reaction of vinyl halides retention of configuration has been observed (equations 18 and 21). Photostimulated reaction with aryl halides has been reported to proceed via the Sjj l mechanism thus, the ketone group is compatible with the reaction conditions as shown in equation 23 . 

In the reaction with alkyl halides inversion of configuration at the... 

Reduction of Co2(CO)g with sodium-amalgam in THF solution gives Na[Co(CO)4]. Na[Co(CO)4] has high nucleophilicity, and the reaction with alkyl halides gives alkyl-cobalt complexes. It is generally difficult to isolate the alkylcobalt complexes, but in the presence of alkenes and alkynes, acylated compounds are obtained in good yields (eq (10)) [13]. 

With /V-acylthioamides the reaction proceeds very slowly and the products are difficult to purify. Therefore, the Af-acylthioamides 32 are first converted into the S -alkyl derivatives 33 by the reaction with alkyl halides under strongly basic conditions. The resulting A -acylthioimi-dates 33 react with amidines and guanidines in alcoholic solution in the presence of sodium alkoxide to form 2,4,6-trisubstituted 1,3,5-triazines 34 in moderate to good yields.438,439 This procedure is an extension of the synthesis of trisubstituted 1,3,5-triazines from A -acylimidates 17 and amidines (vide supra).325... 

The nucleophilic character of the complexes is apparent from the reactions with alkyl halides or acyl halides. With the iron complex, unsymmetrical ketones are formed 91). 

Because of the solubility of copper cyanide in l-methyl-2-pyrrolidone the latter has been recommended447 as solvent for the reaction with alkyl halides. 

When lithium bromide is added prior to the reactions with alkyl halides and oxirane, the deprotonation equilibrium shifts completely to the left side and functionalization of isoprene does not take place. 

If, instead of the imine CH3CH=N—f-Bu, LDA is used in excess, a corresponding amount of dialkylation product is formed in the reactions with alkyl halides the metallations of the other imines are carried out with a 5% molar excess of LDA. 

The molecule of ammonia has an electron lone pair on the nitrogen atom and is a strong nucleophile. In the reaction with alkyl halides it yields amines. The reaction mechanism includes removing hydrogen halide as the leaving group. 

Friedel-Crafts alkylation has the problem of cation rearrangement, but there is another problem with this reaction. When benzene reacts with 2-bromopro-pane and AICI3, it gives a mixture of 53 (1-methylethylbenzene or isopropylbenzene, also known as cumene), which is the expected product however, it also gives the disubstituted product 54. The latter may be the major product if an excess of 2-bromopropane is used. Therefore, the reaction with alkyl halides may lead to polyalkylation of the benzene ring, which is the second of the two problems noted for Friedel-Crafts alkylation. The only way to explain formation of 54 is via a Friedel-Crafts alkylation of the initially formed product 53 with 2-bromopropane. This result suggests that 53 must react more quickly with the carbocation derived from 2-bromopropane than does benzene. This point will be discussed in more detail later. 

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