Lithium diisopropylamide, reaction with amides

Having retraced the remarkably efficient sequences of reactions which led to syntheses of key intermediates 14 and 15, we are now in a position to address their union and the completion of the synthesis of the spiroketal subunit (Scheme 6b). Regiocontrolled deprotonation of hydrazone 14 with lithium diisopropylamide (LDA), prepared from diisopropylamine and halide-free methyl-lithium in ether, furnishes a metalloenamine which undergoes smooth acylation when treated with A-methoxy-A-methylcarboxa-mide 15 to give the desired vinylogous amide 13 in 90% yield. It is instructive to take note of the spatial relationship between the... 

Different functional groups can be introduced at the 5-position of thieno[2,3- / -l,2,3-thiadiazole-6-carbo-xylates 43a and 43b by lithiation and subsequent reaction with the desired electrophile <1999JPR341>. For example, reaction of carboxylic acid 43a with lithium diisopropylamide (LDA) followed by CI3CCCI3 produced the 5-chloro product 44a while amide 43b treated with -BuLi then dimethylformamide (DMF) gave aldehyde 44b (Equations 4 and 5). 

This section deals with the alkylation reactions of such enolates. In the presence of strong bases, amides carrying at least one a-hydrogen 1 can be deprotonated to form enolate ions which, on subsequent alkylation, give alkylated amides. Further reaction, e g., hydrolysis or reduction, furnishes the corresponding acids or primary alcohols, respectively. The pKa values for deprotonation are typically around 35 (extrapolated value DMSO3 7) unless electron-withdrawing substituents are present in the a-position. Thus, deprotonation usually requires non-nucleophilic bases such as lithium diisopropylamide (extrapolated 8 pKa for the amine in DMSO is around 44) or sodium hexamethyldisilazanide. 

Eliminations of epoxides lead to allyl alcohols. For this reaction to take place, the strongly basic bulky lithium dialkylamides LDA (lithium diisopropylamide), LTMP (lithium tetramethylpiperidide) or LiHMDS (lithium hexamethyldisilazide) shown in Figure 4.18 are used. As for the amidine bases shown in Figure 4.17, the hulkiness of these amides guarantees that they are nonnucleophilic. They react, for example, with epoxides in chemoselective E2 reactions even when the epoxide contains a primary C atom that easily reacts with nucleophiles (see, e.g., Figure 4.18). 

The same type of ring opening was observed when salt 91 was treated with lithium amides or mesityllithium in THE at -78 °C. Addition of lithium diisopropylamide to 91 cleanly regenerated phosphaalkene 90 in 90% yield. When lithium dicyclohexylamide was used, a 50 50 mixture of / -(dicyclohexylamino)phosphaalkene 156 and its isomer 157 was isolated. Monitoring this reaction by P NMR at -78 °C proved the initial formation of 156 with phosphaalkene 157 only appeared on warming to room temperature. Lastly, yellow, oily 7 -(mesityl)phosphaalkene 158 resulted from the combination of 91 and mesityllithium (70%) <1994JA6149> (Scheme 51). 

Amide Enolates. The lithium (Z)-enolate can be generated from (5)-4-benzyl-3-propanoyl-2,2,5,5-tetra-methyloxazolidine and Lithium Diisopropylamide in THF at —78 °C. Its alkylations take place smoothly in the presence of Hexamethylphosphoric Triamide with high diastereoselec-tivity (eq 3), and its Michael additions to a,(3-unsaturated carbonyl compounds are also exclusively diastereoselective (eq 4). Synthetic applications have been made in the aldol reactions of the titanium (Z)-enolates of a-(alkylideneamino) esters. ... 

Wrackmeyer etal. described how (Z)-2-chloro-(dimethyl)stannyl-3-diethylborylpent-2-ene 44, obtained by reacting chlorodimethyl(prop-l-ynyl)stannane with triethylborane, isomerizes into (Z)-3-chloro-(dimethyl)stannyl-2-diethyl-borylpent-2-ene 45 when treated in THE with powdered sodium amide at 65 °C (Scheme 3) <2002ZN1251>. Pure 3,5-diethyl-l,l,2,4-tetramethyl-2,3-dihydro-l//-l,3-stannaborole 29a was obtained by the reaction of 45 in hexane with a suspension of lithium diisopropylamide (LDA) in toluene at —78°C. The reaction goes to completion by allowing the reaction mixture to reach room temperature and then by briefly heating to reflux. The yields of compounds 45 and 29a were 78% and 93%, respectively. 

A related intramolecular trapping of cyclopropylideneamine intermediate 51 by alkoxide was proposed to explain the formation of the rearranged amides 53 from the Favorskii-type reaction of a, -epoxyketimines 50 with lithium diisopropylamide. ... 

Alkyl and arylmagnesium halides react with 2-methylquinoxaline by addition of one mole of reactant to the 3,4-bond. After hydrolysis the 2-alkyl- or 2-aryl-l,2-dihydro-3-methylquinoxalines (52) are obtained. When ethylmagnesium bromide is used a dimeric by-product (53) is also isolatedReaction of 2,3-dimethylquinoxaline with benzonitrile and lithium amide gives l-amino-l-phenyl-2-(3-methyl-2-quinoxalinyl)-ethylene (54). The mono- and dilithium salts of 2,3-dimethylquinoxaline have been generated from the quinoxaline by reaction with one or two equivalents of lithium diisopropylamide (LiNPr, respectively. These salts have been reacted with a variety of electrophilic reagents such as alkyl halides, aryl ketones, esters, and nitriles. " ... 

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