Alkylations hexamethyldisilazide

To a solution of the silylated glycinate (50 mmol) in ether (50 ml), cooled to —10 to 0°C, was added a solution of sodium hexamethyldisilazide (55 mmol) in ether (100ml) with stirring. Stirring was continued at ambient temperature for a short time, and then the alkyl halide (50 mmol) was added dropwise. The mixture was heated under reflux for 10-15 h, cooled, filtered, and the product was distilled directly (52-70%). 

C-Alkylations of l,4-dihydro-27/-pyrazino[2,l-A]quinazoline-3,6-diones at positions C-l and CM were studied in detail. Compounds of type 57 could be alkylated diastereoselectively at C-l, owing to the geometry of the piperazine ring, which is locked in a flat boat conformation with the R4 or R1 substituent in a pseudoaxial position to avoid steric interaction with the nearly coplanar C(6)-carbonyl group. Alkylation of 57 (R2 = Me, Bn, R4 = Me) in the presence of lithium hexamethyldisilazide (LHMDS) with benzyl and allyl halides resulted, under kinetic control, in the 1,4-trans-diastereomer 59 as the major product, with retention of the stereocenter at CM (Scheme 5). 

Meyers lactams are widely used in synthesis of substituted synthons of interest and their functionalization is carried out under strong base conditions giving C-alkyl derivatives. Alkylation of bicyclic lactam 182 with electrophiles (alkyl, allyl, benzyl halides, chlorophosphonate), and a strong base (j-BuLi, LiHMDS, or KHMDS HMDS = hexamethyldisilazide) in THF at — 78 °C gave an endo-exo mixture of products where the major one is the rro/o-compound 183 in good yields. The ratios were determined by H NMR spectroscopy and are usually up to... 

Almost complete retention of chirality was achieved in the alkylations of l-propionyl-l,4-dihydro-2//-3,1-benz-oxazines 242 bearing a stereogenic center in the substituent at position 2 (TBDPS = /< rt-butyldiphenylsilyl, KHMDS = potassium hexamethyldisilazide). The alkylations took place with high de s (70-92%) in favor of isomers 243, isolated after chromatographic separation. The allyl-substituted compound 243 (R = allyl) was reduced with LAH to yield the enantiopure (R)-3-methylpent-4-en-l-ol 244 and the N-unsubstituted 3,1-benzoxazine 245 as a 5 1 diastereomeric mixture (Scheme 45) <2000JOC6540>. 

Iminomethyldithiolane 7 can be deprotonated with potassium hexamethyldisilazide in THF at — 78 °C and alkylated to give 8 in good yield and with high diastereoselectivity. From 8, a-aminoalkylphosphonic acids 5 are easily obtained by mild acidic hydrolysis. 

The racemic C2-symmetric l,3-diacyl-1,3-imidazolidinones 1 and 2 can be obtained from either rra/t.v-l,2-diaminocyclohexane or nwM-l,2-diphenyl-l,2-ethanediamineu 13. On deprotona-tion with potassium hexamethyldisilazide in THF at —78 C these furnish dianions which are alkylated by activated halides or iodomethane (R2X) to give mixtures of diastereomeric dialky-lated products 3-5 and 6-812,13. 

The cyclic cobalt-acyl complex 1 undergoes a-proton abstraction from the least-hindered face opposite the phosphane ligand upon treatment with lithium hexamethyldisilazide at 0 °C to generate the chiral enolate species 283. Treatment of 2 with primary iodoalkanes diastereoselec-tively produces the alkylated cobaltocycles 3 also via attack of the reagent on the face opposite the bulky phosphane. 

Page et al. (see [298] and references therein) have shown that generally excellent stereocontrol in organic reactions can be obtained by using DITOX (1,3-dithiane-l-oxide) derivatives as chiral auxiliaries. The one-pot stereo-controlled cycloalkanone synthesis given here outlines some aspects of the chemistry worked out for efficient acylation-alkylations steps. Of note are the use of N-acyl imidazoles under mixed base (sodium hexamethyldisilazide/n-butyllithium) conditions to yield the lithium enolates of 2-acyl-l,3-dithiane-l-oxides) and the sequential alkylation-cyclization of the latter (steps (iv) and (v)). 

The acid is converted with thionyl chloride into the corresponding acid chloride, which reacts in a second step with the anion of the Lvans oxazolidinone 3714 to give an /V-acyloxazolidinone. This is then deprotonated with sodium hexamethyldisilazide and subsequently alkylated selectively with methyl iodide to produce compound 8. 

Lactams may be alkylated at the a-position by reaction with a strong base, such as LDA or hexamethyldisilazide, followed by treatment with an alkyl halide. Baldwin and coworkers have used this methodology in their synthesis of unnatural amino acids from protected pyroglutamates (equation 81)563. The same reaction has been used for alkylating 5- to 9-membered lactams564. It is noteworthy that a-alkylated 7- to 9-membered lactams are... 

Danopoulos and co-workers reported on the preparation of NHC ligands with pendant indenyl and fluorenyl groups.19 Deprotonation of the alkyl -indene or -fluorene imidazolium salts with one equivalent of potassium hexamethyldisilazide leads to NHCs functionalised with neutral indene or fluorene moieties (IndH-NHC and F1H-NHC). Further deprotonation with... 

Methyl ethers are usually prepared by some variant of the Williamson ether synthesis in which an alcohol reacts with either iodomethane, dimethyl sulfate, or methyl triflate (HAZARD) in the presence of a suitable base. A word of caution dimethyl sulfate and methyl triflate, tike all powerful alkylating agents, are potentially carcinogenic and therefore should only be handled in a well-ventilated fume hood. For the 0-methylation of phenols (pKa 10) a comparatively weak base such as potassium carbonate in conjunction with dimethyl sulfate is sufficient,193 whereas simple aliphatic alcohols require stronger bases such as sodium hydride [Scheme 4.111]22 or lithium hexamethyldisilazide [Scheme 4.112].203 The latter transformation is notable for the fact that 0-methyiation was accomplished without competing elimination. 

Macrocyclic ketones. A recent method for synthesis of macrocyclic ketones involves intramolecular alkylation of protected cyanohydrins. Sodium hexamethyldisilazide... 

The term amidolithium is the unambiguous name for the compounds RR NLi (R, R = alkyl, aryl, silyl, etc.) more often termed lithium amides. They derive their importance from the near-ubiquity of their bulkier members lithium diisopropy-lamide (LDA), lithium tetramethylpiperidide (LTMP), and lithium hexamethyldisilazide (LHMDS) in organic synthesis. Using such powerful but nonnucleophilic bases, many useful reactions may be performed, notably the enolization of ketones and esters, which can proceed both regio- and stereoselectively under kinetic control at low temperatures. ... 

Reactions of the Enolate of (1) with Electrophiles. Addition of the dioxolanones (1) to solutions of Lithium Diiso-propylamide or Lithium Hexamethyldisilazide in THF at dry-ice temperature generates the corresponding enolates which react with alkyl halides, - carbonyl compounds, and nitroalkenes almost exclusively from the face remote from the t-Bu group to give products of type (2). These can be hydrolyzed to simple ot-hydroxy-ot-methyl carboxylic acids or further elaborated. Four examples are shown in (3)-(6) in which the part of the molecule originating from lactic acid is indicated in bold. 

Two equivalents of LiHMDS (HMDS = hexamethyldisilazide) have been used to deprotonate a 1,3-dioxoIan-lone derived from malic acid having an acetic acid group at C-5 alkylation and acid work-up then gave the substituted dioxolanone (Equation 23) <2005TL3815>. 

Deprotonation of alkylnitriles with LDA or lithium hexamethyldisilazide (LHMDS" ) and treatment of the resultant ambident a-nitrile anions with 1° and 2°-alkyl halides affords C-alkylated products in good yield. However, the a-anions of highly substituted nitriles may undergo N-alkylation to give amides on aqueous workup. 

E)-Styrenes. The phosphoranium salts are prepared by alkylation of the phosphine immediately after its generation from the corresponding phosphine oxide. The stereoselectivity of the Wittig reaction with ArCHO is very sensitive to the base used. Potassium hexamethyldisilazide is the preferred base for obtaining ( )-styrenes. 

What is needed for the alkylation is rapid conversion of the ester into a reasonably stable enolate, so rapid in fact that there is no unenolised ester left. In other words the rate of proton removal must be faster than the rate of combination of enolate and ester. These conditions are met when lithium enolates are made from esters with lithium amide bases at low temperature, often 78 °C. Hindered bases must be used as otherwise nucleophilic displacement will occur at the ester carbonyl group to give an amide. Popular bases are LDA (Lithium Di-isopropyl Amide, 66), lithium hexamethyldisilazide 67, and lithium tetramethylpiperidide 68, the most hindered of all. These bases are conveniently prepared from the amine, e.g. 65 for LDA, and BuLi in dry THF solution. 

This reaction can sometimes be useful in synthesis. In the Honda et al. formal synthesis of securinine,2h N-benzylamino-ketone (97) was treated with lithium hexamethyldisilazide and then sorbic anhydride. This gave dienyl ester 98 by O-alkylation of the initially formed enolate anion. When the nitrogen protecting group was... 

Exposure of 877 to lithium hexamethyldisilazide ( — 78° 0 °C) results in intramolecular alkylation of the ester enolate to afford 878. Reduction of the ester to an alcohol and oxidation of sulfur followed by elimination of the resulting sulfoxide introduces the unsaturation leading to 869. This is then converted to ( H- )-heliotridine (850) by reduction of the carbonyl group. 

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