Butyllithium, alkylation

An enantioselective synthesis of CR)-amino acids has been developed which utilizes L-valine as the chiral auxiliary (81AG(E)798). The diketopiperazine cycZo-(L-Val-Gly) (780) was converted to its bis-lactim ether (781) by methylation with Meerwein s salt, and the ether metallated in the glycine portion by n-butyllithium. Alkylation of the delocalized... 

Primary amines have been transformed into imines which when metallated react with carbonyl compounds. Treatment with butyllithium, alkylation with allyl bromide and hydrolysis gives highly substituted aldehydes (Scheme 6). Thus, in this example, the carbon adjacent to the original amino nitrogen atom becomes the carbonyl carbon. The technique has been used several times in the course of total synthesis, as with a recent approach to crinine and as the key step in a recent highly regioselective preparation of a,3 unsaturated aldehydes (equation 33). ... 

O-Alkylation of dioxopiperazines with oxonium salts yields bislactim ethers, e.g. 4, which are used as reagents for the asymmetric synthesis of amino acids (bislactimether method, Schollkopf 1979). The chiral bislactim ether 4 is converted into the 6 r-anion 5 (under kinetic control) by n-butyllithium. Alkylation proceeds with high stereoselectivity (greater than 95%). Acid hydrolysis of the alkylation product 6 leads to (unnatural) (R)-mnno acids 7 and recovery of the chiral auxiliary (5)-valine, from which the starting material dioxopiperazine 3 was derived [160]. 

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. 

Compound 7 can be converted to a metalloenamine by addition (not deprotonation) of rerr-butyllithium. Alkylation and hydrolysis gives the alkylated ketone. The product of this sequence is the same one which would be expected... 

The alkylations proceeded much more slowly, when ethyl- or butyllithium in diethyl ether, prepared from the alkyl bromides, had been used for the metallation of allene, in spite of the presence of THF and HMPT as co-solvents. 

Note 1. If the lithiation of the allenic ether is performed with butyllithium in hexane and THF as a co-solvent, subsequent alkylation (in the presence of a small amount of HMPT) is much faster. The separation of the volatile product from the hexane and THF is difficult, however. 

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. 

In readily available (see p. 22f.) cyclic imidoesters (e.g. 2-oxazolines) the ot-carbon atom, is metallated by LDA or butyllithium. The heterocycle may be regarded as a masked formyl or carboxyl group (see p. 22f.), and the alkyl substituent represents the carbon chain. The lithium ion is mainly localized on the nitrogen. Suitable chiral oxazolines form chiral chelates with the lithium ion, which are stable at —78°C (A.I. Meyers, 1976 see p. 22f.). 

Kyba and eoworkers prepared the similar, but not identical compound, 26, using quite a different approach. In this synthesis, pentaphenylcyclopentaphosphine (22) is converted into benzotriphosphole (23) by reduction with potassium metal in THF, followed by treatment with o "t/20-dichlorobenzene. Lithium aluminum hydride reduction of 23 affords l,2-i>/s(phenylphosphino)benzene, 24. The secondary phosphine may be deprotonated with n-butyllithium and alkylated with 3-chlorobromopropane. The twoarmed bis-phosphine (25) which results may be treated with the dianion of 24 at high dilution to yield macrocycle 26. The overall yield of 26 is about 4%. The synthetic approach is illustrated in Eq. (6.16), below. 

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. 

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. ... 

Tlie interest in the preparation and use of dithiolium salts in connection with the synthesis of TTF derivatives led to the development of a new uses of heteroaromatic cations in organic synthesis. Based on that, a new carbonyl olefination for the synthesis of numerous heterofulvalenes was developed (77S861). For example, 2-dimethoxyphosphinyl-l,3-benzodithiole was deprotonated with butyllithium in THF at -78°C and the resulting phosphonate carbanion reacted with 9-alkyl-acridones to give the dithia-azafulvalenes of type 45 (78BCJ2674) (Scheme 15). 

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... 

Many initiators, such as alkyl and aryllithium and sodium and lithium suspensions in liquid ammonia, effect the polymerization. For example, acrylonitrile combined with n-butyllithium forms a carbanion intermediate ... 

The synthesis of phosphonium iodide 24, the precursor of phos-Br phorus ylide 12, begins with the alkylation of 5-lithio-2-methyl- furan,10 derived from the action of n-butyllithium on 2-methylfuran 17 (16), with 1,4-dibromobutane (17) to give 15 in 75% yield (see... 

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