Lithium A-isopropylcyclohexylamide

A number of other methods exist for the a halogenation of carboxylic acids or their derivatives. Acyl halides can be a brominated or chlorinated by use of NBS or NCS and HBr or HCl. The latter is an ionic, not a free-radical halogenation (see 14-2). Direct iodination of carboxylic acids has been achieved with I2—Cu acetate in HOAc. " ° Acyl chlorides can be a iodinated with I2 and a trace of HI. Carboxylic esters can be a halogenated by conversion to their enolate ions with lithium A-isopropylcyclohexylamide in THF and treatment of this solution at -78°C with... 

A one-step synthesis of acridones takes advantage of somewhat similar chemistry . Treatment of methyl A-methylanthranilate 570 with lithium A-isopropylcyclohexylamide (LilCA) in THE generated A-lithio salt 571 addition of a halobenzene as the aryne source then produced the acridone 572 as shown, in good yield (40-60%). Substituted haloarenes gave substituted acridones. Utility of the method was demonstrated with a short synthesis of the alkaloid acronyeine 573. 

In a 1971 paper, Rathke and Lindert reported that lithium N-isopropylcyclohexylamide (LICA) is a superior reagent for the generation of ester enolates. Subsequent workers, however, have found that LDA works just as well. This base has the added virtue of being derived from a relatively volatile amine (the b.p. of diisopropylamine is 84 C). 

Claisen rearrangement of ally silyl ethers (4,307-308). Katzenellenbogen and Christy have extended the rearrangement of silyl enol ether derivatives of allylic acetates to y,S-unsaturated acids to systems in which a trisubstituted double bond is generated. Thus 3-acetoxy-2-methyl-l-nonene (1) was treated with lithium N-isopropylcyclohexylamide (LilCA) in THF at -78° and then with f-butyldimethylchlorosilane to give the f-butyldimethylsiloxyvinyl ether... 

Other activated sulfoxides. This alkylative elimination reaction has been extended by Trost and Bridges to a one-pot synthesis of alkenes, vinyl sulfides, a, l-unsaturated sulfoxides, and a,j3-unsaturated nitriles. The sulfoxides (1-4) are converted into the anions by lithium N-isopropylcyclohexylamide or sodium hydride and are then alkylated at 20° in THE or DME elimination is then effected by raising the temperature to reflux. In some cases trimethyl phosphite is added as a scavenger for phenylsulfenic acid. Typical results are formulated in the equations. The elimination reaction is facilitated by an aryl, thioaryl, or... 

Dienic carboxylic acids. Prater has described a method for addition of an isoprene unit to an allylic alcohol. The method is iUustrated for the conversion of the ester (1) of geraniol into farnesenic acid (3). The ester is treated with lithium N-isopropylcyclohexylamide (LilCA, 4, 306-309) and then with trimethylchlorosilane. The resulting trimethylsilylketene acetal (a) undergoes... 

Bromination of a polyunsaturated carboxylic acid. Bromination of an acid of this type by the method of Rathke and Lindert (4, 306) proved unsatisfactory owing to low yields, but was accomplished by conversion of 1 into the a-anion with lithium N-isopropylcyclohexylamide, bromination with diethyl dibromomalonate at — 78°, and removal of the ester group. The pure acid 3 is fairly stable. ... 

Lithium N-isopropylcyclohexylamide a-Halogenocarboxylic from carboxylic acid esters... 

The chemistry of preformed enolates emerged in temporal and causal coherence vith the EDA area . Although lithium and magnesium salts of diisopropylamine vere first developed in the nineteen-fifties [40], lithium diisopropylamide (EDA) has been a videly used reagent since 1970, because of its behavior as a soluble, strong, and non-nucleophilic base [14]. EDA and related bases, for example lithium hexamethyldisilazane (LIHMDS) [41], lithium N-isopropylcyclohexylamide (LICA) [42], and lithium 2,2,6,6-... 

Another successful tactic is to make the group R as large as possible to discourage attack at the carbonyl group. Tertiary butyl esters are particularly useful in this regard, because they are readily made, f-butyl is extremely bulky, and yet they can can still be hydrolysed in aqueous acid under mild conditions by the method discussed on pp. 652-3. In this example, deprotonation of f-butyl acetate with LICA (lithium isopropylcyclohexylamide) gives a lithium enolate that reacts with butyl iodide as the reaction mixture is warmed to room temperature. 

KHMDS = potassium hexamethyldisilazane s-BuOK = potassium 1-methylpropoxide LICA = lithium isopropylcyclohexylamide. b Refers to the RjS ratio at the newly generated a-hydroxy chiral carbon atom. 

A recent synthesis of acridinones uses lithiated ethyl anthranilate and benzyne (from a bromobenzene) at temperatures well below 0°C. In this reaction, lithium -isopropylcyclohexylamide (LilCA, prepared from butyl-lithium and iV-isopropylcyclohexylamine) was more effective than LDA or lithium 2,2,6,6-tetramethylcyclohexylamide. 

A side-chain acyl chloride cyclizes on to a neighbouring thiol group (formed in situ by demethylation of a methylthio ether) under mild conditions. The corresponding thiopyran-4-one is obtained by the reaction of a 2-mercaptobenzoate ester and bromobenzene with lithium -isopropylcyclohexylamide (LICA) at low temperature. 

One-pot malonic ester synthesis. A separate hydrolysis step can be avoided by use of the dilithium salt of ethyl malonate, prepared by reaction of the ester with 2 eq. of lithium isopropylcyclohexylamide (4, 306-309) in THE at -78° HMPT and the alkyl hahde are then added and the reaction mixture is allowed to come to room temperature for 2 hr. Decarboxylation is then effected by overnight reflux. 

The lithium enolates of a series of l-(2-thienyl)alkyl alkanoates, generated by treatment with 2.2 equivalents of Uthium TV-isopropylcyclohexylamide undergo the Claisen rearrangement in refluxing THF to yield 2-(3-thienyl)alkyl alkanoic acids in 30-80% yield (Equation (1)) <83Bai665>. 

---