Butyllithium alkylation reactions

Meyers has demonstrated that chiral oxazolines derived from valine or rert-leucine are also effective auxiliaries for asymmetric additions to naphthalene. These chiral oxazolines (39 and 40) are more readily available than the methoxymethyl substituted compounds (3) described above but provide comparable yields and stereoselectivities in the tandem alkylation reactions. For example, addition of -butyllithium to naphthyl oxazoline 39 followed by treatment of the resulting anion with iodomethane afforded 41 in 99% yield as a 99 1 mixture of diastereomers. The identical transformation of valine derived substrate 40 led to a 97% yield of 42 with 94% de. As described above, sequential treatment of the oxazoline products 41 and 42 with MeOTf, NaBKi and aqueous oxalic acid afforded aldehydes 43 in > 98% ee and 90% ee, respectively. These experiments demonstrate that a chelating (methoxymethyl) group is not necessary for reactions to proceed with high asymmetric induction. 

Some further examples of stereoselective deprotonation/alkylation reactions of tricarbonyl-chromium complexed (V-methyl tetrahydroisoquinolines have been reported27. Starting with the enantiomerically pure (35)-methyl tetrahydroisoquinoline reaction with hexacarbonyl-chromium led to a mixture of endo- (40%) and exo- (60%) complexes, which were deprotonated with butyllithium and subsequently methylated with iodomethane. In this way methylation occurred firstly at the 4- and secondly at the 1-position. In all cases, the methyl group entered anti to the chromium complexed face. After separation of the alkylated complexes by chromatography and oxidative decomplexation, the enantiomerically pure diastereomers (—)-(l 5,35,47 )-and ( + )-(17 ,35,45)-1,2,3,4-tetrahydro-l,2,3,4-tetramethylisoquinolme were obtained, benzylic amines such as tetrahydroisoquinoline to 2-amino-4,5-dihydrooxazoles. Deprotona... 

The alkylation of anhydrous pseudoephedrine sarcosinamide is similar to the alkylation of anhydrous pseudoephedrine glycinamide, with one important experimental modification, wherein the reaction is conducted in the presence of 1 equiv of N-methylethanolamine. The optimum conditions for alkylation of anhydrous pseudoephedrine sarcosinamide involve the addition of n-butyllithium or LDA (2.95 equiv) to a suspension of anhydrous pseudoephedrine sarcosinamide (1 equiv), anhydrous lithium chloride (6.00 equiv), and A-methylethanolamine (1.00 equiv) in THF at —78°C, followed by warming the resulting slurry to 0°C and the addition of an alkylating agent (1.1-1.5 equiv) (eq 17). The presence of A-methylethanolamine in the alkylation reaction is necessary to achieve reproducible diastere-oselectivity and may function by facilitating anionic equilibration. 

General Considerations. The title reagent can he sequentially alkylated a to the carbonyl group in a stereocontrolled fashion (eq 2). Lithiation of the parent hicyclic lactam with s-Butyllithium and reaction with an alkyl halide affords the monoalkylated product. The epimeric mixture is treated again with s-BuLi and a second alkyl halide to give the dialkylated hicyclic lactam. The initial epimeric mixture is used directly in the second alkylation since this step proceeds via a planar enolate. It is the second alkylation that dictates the final diastereomeric ratio. The opposite stereochemistry at C-6 can be obtained by inverting the order of electrophile addition. 

A further interesting example is the use of l,l-di(phenylthio)med)yllithium to open an epoxide followed by a Grob fragmentation process as shown in Scheme 56 (entry b). The reaction of 1,1-di-(thio)methyllithium with epoxides has also been used - in the one-pot synthesis of l,l-di(thio)cyclopropanes involving an intramolecular cyclization of the 7-tosyloxydi(phenylthio)alkylli-thium. This intramolecular alkylation reaction proceeds even more efficiently than its intermolecular version, and allows the synthesis of a large variety of l,l-di(thio)cyclopTDpanes from 3-chloro- and 3-phenylthio-l,l-di(thio)alkanes and n-butyllithium in THF (Scheme 57 and Scheme 58). 

Treatment of bromoarenes with butyllithium generally proceeds smoothly and quantitatively [4, 168]. The halogenated arenes are accessible by electrophilic substitution or diazotation. The exchange reaction can be carried out in Et20 as well as in THF but in the latter solvent the reaction is considerably faster. However, Et20 may be preferred in some syntheses, since in this solvent the undesired alkylation reaction between ArLi and butyl bromide is relatively slow. 

The (S)-lactone acid 1, obtained from L-glutamic acid by nitrous acid deamination, was converted to the acid chloride, then treated with excess diazomethane followed by hydrogen iodide to yield the keto-lactone 2. Amidation occurred quantitatively to give the partially racemized amide 3, which was purified by repeated recrystallizations. The vicinal diol resulting from reaction with excess methylmagnesium iodide was protected as the acetonide 4. An isomeric mixture of olefins (Z , 26 74) was obtained from the subsequent Wittig reaction. Reduction followed by separation on silver nitrate coated silica gel gave the (Z)-and ( )-alcohols in 20% (6) and 61% (5) yield, respectively. Conversion of the (S)-( )-alcohol (5) to the chloride then afforded the thioether (7) on reaction with sodium phenylsulfide. The thio ether anion was formed by treatment with n-butyllithium. Alkylation with the allylic chloride" (8), followed by removal of sulfur, then yielded the diene 9, which was converted in several steps to (/ ) (-t-)-10,11 -epoxy famesol. 

Alkylation Reactions. Alkylation of chloromethyl /i-tolyl sulfone with alkyl halides can be effected either by using a pbase-transfer catalyst or butyllithium as a base (eqs 4 and 5). /t-Tolylsulfonylcbloromethylmagnesium, prepared by the reaction with ethylmagnesium bromide, is stable and undergoes normal Grignard reactions, e.g., carbonylation and carbonyl addition reactions. ... 

As an alternative to the use of auxiliaries for the asymmetric alkylation of carboxylic acid derivatives, in 2011, Zakarian and Stivala reported on the direct stereoselective alkylation of arylacetic acids with chiral lithium amide bases.This method offers an alternative to traditional auxiliary-based methods and operates through the formation of enediolates also, it builds on earlier work by Shioiri and Ando and by Koga and Matsuo . Zakarian and Stivala examined several C2-symmetric tetramines for their enan-tiodirecting power. After significant experimentation, conditions were established that used 4 equivalents of -BuLi and a slight excess of the tetramine that provided clean formation of the desired product. The enantioselectivity was found to be dependent on the quality of the -butyllithium. The reaction scope was examined with a variety of... 

The dilithiation can also be carried out with butyllithium in a 1 1 mixture of hexane and THF at -20°C (reaction time about 45 min). Subsequent alkylation is much faster than in diethyl ether. 

The a-selectivity is illustrated by the fact that 2-alkyl-, > 2-methoxy-, > and 2-alkyIthio-thiophenes and alkyl thenyl sul-fides ° are metalated exclusively in the 5-position. In electrophilic aromatic substitution, as previously mentioned, an appreciable amount of 3-substitution is obtained with some of these groups. After acetalization ketones can also be metalated. Thus from the diethyl ketal of 2-acetylthiophene, 2-acetyl-5-thiophenealdehyde was obtained after metalation with n-butyllithium followed by the reaction of the metalorganic compound with A,A -dimethylformamide. ... 

Metalated epoxides can react with organometallics to give olefins after elimination of dimetal oxide, a process often referred to as reductive alkylation (Path B, Scheme 5.2). Crandall and Lin first described this reaction in their seminal paper in 1967 treatment of tert-butyloxirane 106 with 3 equiv. of tert-butyllithium, for example, gave trans-di-tert-butylethylene 110 in 64% yield (Scheme 5.23), Stating that this reaction should have some synthetic potential , [36] they proposed a reaction pathway in which tert-butyllithium reacted with a-lithiooxycarbene 108 to generate dianion 109 and thence olefin 110 upon elimination of dilithium oxide. The epoxide has, in effect, acted as a vinyl cation equivalent. 

Reaction of alkyl phenylmethanesulphinates 100 with n-butyllithium in tetrahydro-furan at — 80 °C afforded the corresponding benzyl n-butyl sulphoxide160 (equation 53). Preparation of optically active sulphoxides by this reaction will be discussed later in this chapter. 

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