Carbonyls hexamethyldisilazide

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). 

When one of the reacting partners in the Wittig-Horner reaction, either the phosphine oxide or the carbonyl compound, has a double bond, the product is a diene. The Wittig-Horner reaction was utilized by Smith and coworkers in the total synthesis of milbemycin (equation 98)170. They found that when sodium hexamethyldisilazide was employed as a base, the desired E-diene selectivity is high (85%). Some examples from the literature where the Wittig-Horner reaction has been utilized for the construction of E-double bonds present in dienes and polyenes are given in Table 19171. 

Enolate hydroxylation (cf. 11, 108).2 Enolates of ketones or esters are oxidized by this oxaziridine to a-hydroxy carbonyl compounds. Yields are highly dependent on the base they are highest with potassium hexamethyldisilazide. Yields are generally higher than those obtained with the Vedejs reagent (MoOPH, 8, 207). 

Potassium hydride and potassium hexamethyldisilazide are the most commonly used metal sources to generate the alkoxide . But recently, the indium(I)-mediated tandem carbonyl addition-oxy-Cope rearrangement of y-pentadienyl anions to cyclohexenones and conjugated aromatic ketones has been reported. For example, indium alkoxide 8.32, obtained after the addition of 5-bromopenta-1,3-diene (8.31) to the aromatic conjugated ketones 8.30, undergoes a spontaneous oxy-Cope rearrangement to give 8.33 in 55% yield (Scheme 8.9). 

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. 

A similar carbonyl addition with benzaldehyde derivatives having an ortho-allylic ether led to a benzopyranone when treated with potassium hexamethyldisilazide. ° These reactions are not successful when the alkene contains electron-withdrawing groups, such as halo or carbonyl groups. A free-radical initiator is required, usually peroxides or UV light. The mechanism is illustrated for aldehydes but is similar for the other compounds ... 

Carboxylic acid derivatives. Homologation of aryl and heteroaryl halides by the catalyzed carbonylation in the presence of amines leads to amides. For the preparation of primary amides, hexamethyldisilazide provides the amino group. ... 

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. 

Cbz Cp DABCO DBU DDQ (DHQD)2CLB (DHQD)2PYR DMF DME DMPU DMSO Et Fmoc HMPA ia KHMDS LDA LiHMDS Me MEM Ms NaHMDS Ph Piv PMB Pr Py (saltmen)Mn(N) benzyloxy carbonyl p 5 -cyclopentadienyl l,4-diazabicyclo[2.2.2]octane l,8-diazabicyclo[5.4.0]undec-7-ene 2,3 -dichloro-5,6-dicyanobenzoquinone dihydroquinidinyl p-chlorobenzoale (see Chart 1) dihydroquinidinyl pyrimidine (see Chart 1) dimethylformamide dimethoxyethane l,3-dimethyl-3,4,5,6-tetrahydro-2(l//)-pyrimidinone dimethylsulfoxide ethyl 9-fluorenylmethoxy carbonyl hexamethylphosphoric triamide inverse addition potassium hexamethyldisilazide lithium diisopropylamide lithium hexamethyldisilazide methyl (2-methoxy ethoxy )methyl methanesulfonyl sodium hexamethyldisilazide phenyl pivaloyl p -methoxy benzyl propyl pyridine nitrido[A,A/-(l,l,2,2-tetramethyl) bis(salicylideneaminato)]manganese (see Chart 1)... 

Amines. In situ transformation of the Grignard reaction products of carbonyl compounds into amines is accomplished by the addition of lithium hexamethyldisilazide and LiC104. 

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. 

The sites of deprotonation of a series of A -benzyl lactams have been determined. For five- and six-membered lactams, kinetic deprotonation occurred exclusively a to the carbonyl, while seven-and eight-membered lactams gave exclusively the products arising from deprotonation at the benzylic position. The alkylation of the anion derived from (121), however, gave an approximately 3 1 ratio of (122) to (123) (R = Bu", allyl and Bn) (Equation (5)) <87JA4405>. By contrast, the deprotonation of A -(BOC)caprylolactam with lithium hexamethyldisilazide in THF at — 78°C gave the expected enolate, which could be alkylated with iodomethane (81% yield) or phenylselenyl chloride (65% yield) <90SL63>. 

The (Z)/( ) stereoselectivity of enolate formation is dictated by the structure of the starting carbonyl compound and the base used for deprotonation. Compared to LDA, Lithium 2,2,6,6-Tetra-methylpiperidide usually favors ( )-enolates whereas Lithium Hexamethyldisilazide preferentially leads to (Z)-enolates (eq 10). With a caveat for any generalization, enolate configuration usually determines the stereochemical result in the product for example, using a hindered ester and a bulky aldehyde combination, excellent stereoselectivities in aldol reactions are observed (eq 11). ... 

Reaction with Carbonyl Compounds. Although seldom used in comparison with bromomagnesium diisopropylamide, bromomagnesium hexamethyldisilazide has the unique feature of high solubility in organic solvents. 

Base for a-Deprotonation of Carbonyl Compounds. Potassium hexamethyldisilazide, KN(TMS)2 (KHMDS) has been... 

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