Chiral alkyl halides

Alkylation of aldol type educts, e.g., /3-hydroxy esters, using LDA and alkyl halides leads stereoselectively to erythro substitution. The erythro threo ratio of the products is of the order of 95 5. Allylic and benzylic bromides can also be used. The allyl groups can later be ozonolysed to gjve aldehydes, and many interesting oligofunctional products with two adjacent chiral centres become available from chiral aldol type educts (G. Prater, 1984 D. Seebach, 1984 see also M. Nakatsuka, 1990, p. 5586). 

The same cannot be said about reactions with alkyl halides as substrates The conver Sion of optically active 2 octanol to the corresponding halide does involve a bond to the chirality center and so the optical purity and absolute configuration of the alkyl halide need to be independently established... 

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 mechanism of the asymmetric alkylation of chiral oxazolines is believed to occur through initial metalation of the oxazoline to afford a rapidly interconverting mixture of 12 and 13 with the methoxy group forming a chelate with the lithium cation." Alkylation of the lithiooxazoline occurs on the less hindered face of the oxazoline 13 (opposite the bulky phenyl substituent) to provide 14 the alkylation may proceed via complexation of the halide to the lithium cation. The fact that decreased enantioselectivity is observed with chiral oxazoline derivatives bearing substituents smaller than the phenyl group of 3 is consistent with this hypothesis. Intermediate 13 is believed to react faster than 12 because the approach of the electrophile is impeded by the alkyl group in 12. 

Variations and Improvements on Alkylations of Chiral OxazoUnes Metalated chiral oxazolines can be trapped with a variety of different electrophiles including alkyl halides, aldehydes,and epoxides to afford useful products. For example, treatment of oxazoline 20 with -BuLi followed by addition of ethylene oxide and chlorotrimethylsilane yields silyl ether 21. A second metalation/alkylation followed by acidic hydrolysis provides chiral lactone 22 in 54% yield and 86% ee. A similar... 

The chiral bicyclic imidazolidine 74 is deprotonated at the 2 position by s-BuLi and the resulting anion adds to alkyl halides, acid chlorides, chlorofor-mates, phenyl isocyanate, and aldehydes. The use of this compound as a chiral formyl anion equivalent seems to be limited, however, since the diastereoselectiv-ity in the addition to aldehydes is poor and hydrolysis of the products 75 to give aldehydes also produces cyclohexane-1,2-diamine, necessitating isolation of the aldehyde as its 2,4-dinitrophenylhydrazone (96SL1109 98T14255). 

The triazole 76, which is more accurately portrayed as the nucleophilic carbene structure 76a, acts as a formyl anion equivalent by reaction with alkyl halides and subsequent reductive cleavage to give aldehydes as shown (75TL1889). The benzoin reaction may be considered as resulting in the net addition of a benzoyl anion to a benzaldehyde, and the chiral triazolium salt 77 has been reported to be an efficient asymmetric catalyst for this, giving the products (/ )-ArCH(OH)COAr, in up to 86% e.e. (96HCA1217). In the closely related intramolecular Stetter reaction e.e.s of up to 74% were obtained (96HCA1899). 

Oxathiane 101 is readily deprotonated using s-BuLi, and the resulting anion reacts with alkyl halides, ketones, and benzonitrile (85JOC657). The majority of work in this area, however, is due to Eliel and coworkers and has involved chiral 1,3-oxathianes as asymmetric acyl anion equivalents. In the earliest work it was demonstrated that the oxathianes 102 and 103, obtained in enantiomeri-cally pure form by a sequence involving resolution, could be deprotonated with butyllithium and added to benzaldehyde. The products were formed with poor selectivity at the new stereocenter, however, and oxidation followed by addition... 

Alcohols react with p-toluenesulfonyl chloride (tosyJ chloride, p-TosCl) in pyridine solution to yield alkyl tosylates, ROTos (Section 11.1). Only the 0-H bond of the alcohol is broken in this reaction the C—O bond remains intact, so no change of configuration occurs if the oxygen is attached to a chirality center. The resultant alkyl tosylates behave much like alkyl halides, undergoing both SN1 and Sjsj2 substitution reactions. 

One consequence of tetrahedral geometry is that an amine with three different substituents on nitrogen is chiral, as we saw in Section 9.12. Unlike chiral carbon compounds, however, chiral amines can t usually be resolved because the two enantiomeric forms rapidly interconvert by a pyramidal inversion, much as an alkyl halide inverts in an Sfg2 reaction. Pyramidal inversion occurs by a momentary rehybridization of the nitrogen atom to planar, sp2 geometry, followed by rehybridization of the planar intermediate to tetrahedral, 5p3 geometry... 

Alkyl halides or alkyl sulfates, treated with the salts of sulfinic acids, give sulfones. A palladium catalyzed reaction with a chiral complexing agent led to sulfones with modest asymmetric induction. Alkyl sulfinates (R SO—OR) may be side products. Sulfonic acids themselves can be used, if DBU (p. 1337) is... 

The mechanism of these reactions is usually Sn2 with inversion taking place at a chiral RX, though there is strong evidence that an SET mechanism is involved in certain cases, ° especially where the nucleophile is an a-nitro carbanion and/or the substrate contains a nitro or cyano group. Tertiary alkyl groups can be introduced by an SnI mechanism if the ZCH2Z compound (not the enolate ion) is treated with a tertiary carbocation generated in situ from an alcohol or alkyl halide and BF3 or AlCla, or with a tertiary alkyl perchlorate. ... 

Optically active, a-branched lactams 30 have been built by means of Meyers chiral auxiliaries [ 10]. The key step included the diastereoselective a-alkylations of the initially formed co-i -sulfonamido oxazolines 26. The R or S configuration in the product 27 was obtained reacting the appropriately configured intermediate aza enolates with alkyl halides, high diastereoselectivities have been reported. Several attempts to achieve a complete ring closure to the lactams 30 (via 29) by an acidic cleavage of the oxazolines 27 failed. Varying mixtures of... 

Chapter 1 deals with alkylation of carbon nucleophiles by alkyl halides and tosylates. We discuss the major factors affecting stereoselectivity in both cyclic and acyclic compounds and consider intramolecular alkylation and the use of chiral auxiliaries. 

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... 

An enantioselective synthesis of both (R)- and (5)-a-alkylcysteines 144 and 147 is based on the phase-transfer catalytic alkylation of fert-butyl esters of 2-phenyl-2-thiazoline-4-carboxylic acid and 2-ort/ro-biphenyl-2-thiazoline-4-carboxylic acid, 142 and 145 <06JOC8276>. Treatment of 142 and 145 with alkyl halides and potassium hydroxide in the presence of chiral catalysts 140 and 141 gives the alkylated products, which are hydrolyzed to (R)- and (S)-a-alkylcysteines 144 and 147, respectively, in high enantioselectivity. This method may have potential for the practical synthesis of chiral a-alkylcysteines. 

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). 

Successive treatments of chiral acylsultam 50 with -BuLi or NaHMDS and primary alkyl halides, followed by crystallization, give the pure a,a-alkylation product 52 (Scheme 2-28). Under these conditions, the formation of C-10-alkylated by-product is inevitable. It is worth mentioning, however, that product 52 can readily be separated from the C(a)-epimers by crystallization. In fact,... 

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. 

This means that if a reaction is carried out on a compound that has no stereoisomers, it cannot be stereospecific but at most stereoselective. The concerted reactions, including SN2 displacements, E2 elimination of alkyl halides, anti and Syn addition to alkenes are all stereoselective. In the case of chiral or geometric substrates the nature of the product depends on the unique stereoelectronic requirement of the reaction. These are examples of stereospecific reactions. 

The polarity of carbon-halogen bond of alkyl halides is responsible for their nucleophilic substitution, elimination and their reaction with metal atoms to form organometallic compounds. Nucleophilic substitution reactions are categorised into and on the basis of their kinetic properties. Chirality has a profound role in understanding the reaction mechanisms of Sj l and Sj 2 reactions. Sj 2 reactions of chiral all l halides are characterised by the inversion of configuration while Sj l reactions are characterised by racemisation. 

Reaction between acetonitrile and the radical-cations of secondary alkyl halides is almost entirely S l in character. Both direct substitution and 1,2-hydride shift reactions occur and the products from a chiral alkyl halide such as 2-iodooctane, are almost totally racemised [25]. 

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]. 

Alkylation of hydroxylamines with secondary alkyl halides and alkyl sulfonates like 10 (equation 7) is one of the most frequently used synthetic approaches, especially to enantiomerically pure hydroxylamines such as 11 (equation 7). The reaction proceeds with inversion of configuration and does not produce appreciable amounts of diaUcyla-tion products. Both hydroxylamine as well as N- and O-alkylhydroxylamines have been successfully used. Alkyl trillates are probably the most useful substrates for these transformations since they can be prepared from a large pool of commercially available enantiomerically pure chiral secondary alcohols. 

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). 

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