Racemization alkyl halides

Simple alkylation of the chiral chelate complex leads to formation of chiral dialkylacetic acids (Scheme 109).3S5 388 Simpler chiral enamines can also be used. The formation of chiral propanoic acids results from a resolution of racemic alkyl halides by the interaction of a chiral lithiooxazoline, which recognizes and reacts with one enantiomer at the expense of the other (Scheme 110).389 The above aspects of the asymmetric carbon—carbon bond formation from chiral oxazolines have been reviewed by Meyers.390... 

The addition of HX (X = C1, Br, I) to an alkene, to form alkyl halides, occurs in two steps. The first step involves the addition of a proton (i.e. the electrophile) to the double bond to make the most stable intermediate carbocation. The second step involves nucleophilic attack by the halide anion. This gives a racemic alkyl halide product because the carbocation is planar and hence can be attacked equally from either face. (These addition reactions are the reverse of alkyl halide elimination reactions.)... 

The enantioselective ester syntheses from acid salts, chlorides and anhydrides with racemic alkyl halides, catalysed by optically active polyaminesalmost certainly proceed via in situ formation of chiral ammonium salts, and therefore fall within the scope of phase transfer catalysts. Though the optical yields obtained are low, the work is important because it explores the use of polyamine species with a potential chirality derived from the polymerization of optically active oxazolines, and as such is again a novel approach. 

Partial but not complete loss of optical activity m S l reactions probably results from the carbocation not being completely free when it is attacked by the nucleophile Ionization of the alkyl halide gives a carbocation-hahde ion pair as depicted m Figure 8 8 The halide ion shields one side of the carbocation and the nucleophile captures the carbocation faster from the opposite side More product of inverted configuration is formed than product of retained configuration In spite of the observation that the products of S l reactions are only partially racemic the fact that these reactions are not stereospecific is more consistent with a carbocation intermediate than a concerted bimolecular mechanism... 

The mechanisms by which sulfonate esters undergo nucleophilic substitution are the same as those of alkyl halides Inversion of configuration is observed m 8 2 reac tions of alkyl sulfonates and predominant inversion accompanied by racemization m 8 1 processes... 

The few studies that have been carried out with optically active tertiary alcohols indicate that almost complete racemization accompanies the preparation of tertiary alkyl halides by this method... 

A possible mechanism proposed by Kuivila was based on the fact that retardation by hydroquinone has been observed 72) (see however 73)) and that optically active alkyl halides RX have been transformed into racemic RD 72). 

Although the tin hydride reductions of alkyl halides seem simple, one must be careful because these reactions occur by a free radical mechanism. This is important, because the carbon radical produced in the reaction can isomerize68,78 and one often obtains two different stereoisomers from the synthesis. Another problem is that chiral centres can be lost in tin hydride reductions when an optically active halide is reduced. One example of this is the reduction of benzyl-6-isocyanopenicillanate with tributyltin deuteride78 (Scheme 14). The amount of isomerization depends on the temperature, the concentration of the tin hydride and the presence of and /-substituents78-82. However, some authors have reported tin hydride reductions where no racemization was observed78. 

Racemic fra .s-A--benzyl-2.5-bis-(ethoxycarbonyl)pyrrolidine has been resolved via its dicarboxylic acid, followed by subsequent transformation to offer (2R,5R)-21 or (25,5S -21. The absolute configuration of the alkylated carboxylic acids indicates that the approach of alkyl halides is directed to one of the diastereotopic faces of the enolate thus formed. In the following case, the approached face is the 57-face of the (Z)-enolate. By employing the chiral auxiliary (2R,5R)-21 or its enantiomer (25.55)-21. the (/ )- or (S)-form of carboxylic acids can be obtained with considerably high enantioselectivity (Table 2-4). 

Figure 8.17 Reaction of an alkyl halide with hydroxide ion. (a) A primary halide reacts by an SN2 mechanism, causing Walden inversion about the central, chiral carbon, (b) A tertiary halide reacts by an SN1 mechanism (the rate-determining step of which is unimolecular dissociation, minimizing the extent of Walden inversion and maximizing the extent of racemization). Secondary alcohols often react with both Sn 1 and SN2 mechanistic pathways proceeding concurrently...

Addition of hydroxide occurs as a rapid follow-up reaction. Even if the alkyl halide was chiral before the carbocation formed, racemization occurs about the central carbon atom because the hydroxide can bond to the planar central carbon from either side (see Figure 8.17(b)). Statistically, equal numbers of each racemate are formed, so the angle through which the plane polarized light rotated during reaction will, therefore, decrease toward 0°, when reaction is complete. 

We have seen that substitution in secondary and tertiary alkyl halides proceeds by an SN1 mechanism in which there is first slow ionisation resulting in the formation of a flat carbocation and hence the attack by the nucleophilic reagent can take place equally well from either side, i.e., equal amounts of (+) and (-)- forms are likely to be produced giving a racemic product ... 

It has been shown that a complete shift in stereochemistry of the nucleophilic reactions of (29), with alkyl halides such as 2-bromobutane or cis-2-bromomethoxycyclohexane, from racemization to complete inversion, is induced by increase in the inner-sphere stabilization of the transition state from 0 to 3 kcal mol" This has been ascribed to competition between inner-sphere 5)vr2 and outer-sphere electron-transfer processes the former being extremely sensitive towards inner-sphere stabilization. 

Cross coupling between an aryl halide and an activated alkyl halide, catalysed by the nickel system, is achieved by controlling the rate of addition of the alkyl halide to the reaction mixture. When the aryl halide is present in excess, it reacts preferentially with the Ni(o) intermediate whereas the Ni(l) intermediate reacts more rapidly with an activated alkyl halide. Thus continuous slow addition of the alkyl halide to the electrochemical cell already charged with the aryl halide ensures that the alkyl-aryl coupled compound becomes the major product. Activated alkyl halides include benzyl chloride, a-chloroketones, a-chloroesters and amides, a-chloro-nitriles and vinyl chlorides [202, 203, 204], Asymmetric induction during the coupling step occurs with over 90 % distereomeric excess from reactions with amides such as 62, derived from enantiomerically pure (-)-ephedrine, even when 62 is a mixture of diastereoisomcrs prepared from a racemic a-chloroacid. Metiha-nolysis of the amide product affords the chiral ester 63 and chiral ephedrine is recoverable [205]. 

Comparison of the configuration of the stannane with the prodncts of reaction reveals that primary alkyl halides that are not benzyhc or a to a carbonyl react with inversion at the lithium-bearing carbon atom. In the piperidine series, the best data are for the 3-phenylpropyl compound, which was shown to be >99 1 er. In the pyrrolidine series, the er of the analogous compound indicates 21-22% retention and 78-79% inversion of configuration. Activated alkyl halides such as benzyl bromide and teri-butyl bromoacetate afford racemic adducts. In both the pyrrolidine and piperidine series, most carbonyl electrophiles (i.e. carbon dioxide, dimethyl carbonate, methyl chloroformate, pivaloyl chloride, cyclohexanone, acetone and benzaldehyde) react with virtually complete retention of configuration at the lithium-bearing carbon atom. The only exceptions are benzophenone, which affords racemic adduct, and pivaloyl chloride, which shows some inversion. The inversion observed with pivaloyl chloride may be due to partial racemization of the ketone product during work-up. 

Electrophiles, which lead to high yields, are methyl iodide, trialkyltin- and trialkylsUyl chlorides, diphenylphosphinyl chloride, acid chlorides, aldehydes and carbon dioxide. Remarkably, though highly acidic ketones are formed on acylation, no deprotonation or racemization by excess of carbanionic species occurs. Other alkyl halides than methyl iodide react very sluggishly with low yields. Benzylic and aUylic halides lead to partial racemization, presumably due to single-electron transfer (SET) in the alkylation step. As very recently found by Papillon and Taylor, racemization of 42 can be suppressed by copper-zinc-lithium exchange before alkylation to 43 via the Knochel cuprates (equation 7) °. 

An efficient resolntion of the racemic lithinm tert-bntylphosphine-borane complex 203 dnring deprotonation by n-BnLi/(—)-sparteine (11) and alkylation was reported by Liv-inghonse and Wolfe (eqnation 47) . One of the epimers 204/cp/-204 on warming to 0 °C crystallizes during a dynamic thermodynamic resolntion, and reaction with alkyl halides fnmishes the alkylation prodncts 205 with high ee values. Applying dihalides, essentially enantiomerically pure diphosphines snch as 206, besides few of the mcio-diastereomer, were obtained. Borane is removed by treatment with diethylamine to yield the free tertiary phosphines 207. 

Tab. 10.8 summarizes the application of rhodium-catalyzed allylic etherification to a variety of racemic secondary allylic carbonates, using the copper(I) alkoxide derived from 2,4-dimethyl-3-pentanol vide intro). Although the allyhc etherification is tolerant of linear alkyl substituents (entries 1-4), branched derivatives proved more challenging in terms of selectivity and turnover, the y-position being the first point at which branching does not appear to interfere with the substitution (entry 5). The allylic etherification also proved feasible for hydroxymethyl, alkene, and aryl substituents, albeit with lower selectivity (entries 6-9). This transformation is remarkably tolerant, given that the classical alkylation of a hindered metal alkoxide with a secondary alkyl halide would undoubtedly lead to elimination. Hence, regioselective rhodium-catalyzed allylic etherification with a secondary copper(l) alkoxide provides an important method for the synthesis of allylic ethers. 

Alkylations of lithiated chiral 4,5-dihydrooxa7oles with 2.0 equivalents of a racemic secondary alkyl halide proceed under kinetic resolution10-16. The (S)-alkyl halide is assumed to react preferentially, and, after quenching with water, the excess (7 )-alkyl halide is isolated in 92-99% purity (determined by GC) and in 5 49% optical purity10. Hydrolysis of the alkylated 4,5-di-hydrooxazoles provides the chiral 3-alkylalkanoic acids in 99-99.8% purity (determined by GC) and 13-47% optical purity10. 

Seebach and Naef1961 generated chiral enolates with asymmetric induction from a-heterosubstituted carboxylic acids. Reactions of these enolates with alkyl halides were found to be highly diastereoselective. Thus, the overall enantioselective a-alkyla-tion of chiral, non-racemic a-heterosubstituted carboxylic acids was realized. No external chiral auxiliary was necessary in order to produce the a-alkylated target molecules. Thus, (S)-proline was refluxed in a pentane solution of pivalaldehyde in the presence of an acid catalyst, with azeotropic removal of water. (197) was isolated as a single diastereomer by distillation. The enolate generated from (197) was allylated and produced (198) with ad.s. value >98 %. The substitution (197) ->(198) probably takes place with retention of configuration 196>. 

Problem 7.20 Optically pure (S)-(-i-)-CH3CHBr-n-CjH,3 has [a] = -1-36.0°. A partially racemized sample having a specific rotation of -i-30° is reacted with dilute NaOH to form (R)-(-)-CH,CH(OH)-n-CsH,3 ([ ] =-5. 97°), whose specific rotation is -10.3° when optically pure, (a) Write an equation for the reaction using projection formulas, (b) Calculate the percent optical purity of reactant and product, (c) Calculate percentages of racemization and inversion, (d) Calculate percentages of frontside and backside attack, (e) Draw a conclusion concerning the reactions of 2° alkyl halides. (/) What change in conditions would increase inversion ... 

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