Organolithiums carboxylation with carbon

Carboxylic acid groups can also be installed in molecules using the reaction of an organometallic compound with carbon dioxide. This is a reductive method since the carbon dioxide is reduced to a carboxylic acid by formation of a new carbon-carbon bond. Both Grignard reagents and organolithium compounds work well in this reaction. 

Acyl anions (RC(=0)M) are unstable, and quickly dimerize at temperatures >-100 °C (Section 5.4.7). These intermediates are best generated by reaction of organolithium compounds or cuprates with carbon monoxide at -110 °C and should be trapped immediately by an electrophile [344—347]. Metalated formic acid esters (R0C(=0)M) have been generated as intermediates by treatment of alcoholates with carbon monoxide, and can either be protonated to yield formic acid esters, or left to rearrange to carboxylates (R0C(=0)M —> RC02M) (Scheme 5.38) [348]. Related intermediates are presumably also formed by treatment of alcohols with formamide acetals (Scheme 5.38) [349]. More stable than acyl lithium compounds are acyl silanes or transition metal acyl complexes, which can also be used to perform nucleophilic acylations [350],... 

Fig. 6.45. Chemoselective acylation of organolithium compounds with lithium-carboxylates (A). In order to generate the substrates the choice is between the deprotonation of the corresponding carboxylic acid and the addition of an organolithium compound to carbon dioxide, i.e. via C,C bond formation.

The Weinreb amide syntheses in Figure 6.50 proceeding via the stable tetrahedral intermediates B and F are chemoselective SN reactions at the carboxyl carbon atom of carbon acid derivatives that are based on strategy 1 of the chemistry of carboxylic acid derivatives outlined in Figure 6.41. Strategy 2 of the chemistry of carboxylic acid derivatives in Figure 6.41 also has a counterpart in carbon acid derivatives, as is demonstrated by a chemoselective acylation of an organolithium compound with chloroformic acid methyl ester in this chapter s final example ... 

Dithioesters can be made by a method that would seem odd if you thought only of ordinary esters. Organolithium or Grignard reagents combine well with carbon disulfide (CS2—the sulfur analogue of CO2) to give the anion of a dithioacid. This is a much more nucleophilic species than an ordinary carboxylate anion and combines with alkyl halides to give dithioesters. 

As discussed elsewhere in this review, Lewis bases such as tetrahydrofuran are known to promote disaggregation of polymeric organolithium speciesThus, in the presence of excess tetrahydrofuran, both poly(styryl)lithium and poly(isopre-nyl)lithium would be expected to be unassociated (or at least much less associated). Therefore, in the presence of sufficient tetrahydrofuran, the carbonation reaction would take place with unassociated organolithium chain ends and ketone formation (Eq. (73)) would only be an intermolecular reaction (rather than an essentially intramolecular reaction as in the case with the aggregated species) competing with carbonation. In complete accord with these predictions, it was found that the carbonation of poly(styryl)lithium, poly(isoprenyl)lithium, and poly(styrene-h-isoprenyl)lithium in a 75/25 mixture (by volume) of benzene and tetrahydrofuran occurs quantitatively to produce the corresponding carboxylic add chain ends. The observation by Mansson that THF has no apparent influence was complicated by the use of methyl-cyclohexane, which is a Theta solvent for poly(styrene) (60-70 °C) furthermore. 

Both organolithiums and Grignard reagents react with carbon dioxide to yield carboxylic acids, as illustrated below for n-butyllithium ... 

Recent Trends in Functionalization of Telechelics. As described before, the direct carboxylation of polymeric organolithium with carbon dioxide in hydrocarbon solution often results in inefficient functionalization (170). Alternatively, an ortho-ester functionalized alkyl chloride, namely 4-chloro-l,l,l-trimethoxy butane, was used to prepare ortho-ester functionalized polymers (194). 

Wyman, Allen and Altares (20) reported that the carbonation of poly-(styryl)lithium in benzene with gaseous carbon dioxide produced only a 60% yield of carboxylic acid the acid was contaminated with significant amounts of the corresponding ketone (dimer) and tertiary alcohol (trimer) as shown in eq. 6. A recent, careful, detailed investigation of the carbonation of polymeric organolithium compounds has... 

As further illustrated in Scheme 2, the 1-methyl- and 1,3,3-trimethylcyclopropene are rapidly metallated with organolithium reagents in ether to afford stable solutions of the 1-lithiocyclopropenes (18) In comparison, solutions of the metallocyclopropenes (16) are significantly less stable and even at — 40°C are observed to degrade slowly to a mixture of dimeric and trimeric products apparently formed by nucleophilic addition of 16 to the highly reactive cyclopropene n system L Alkylation of 18 (R=H or Me) with methyl iodide produced 1,2-dimethyl- and 1,2,3,3-tetramethylcyclopropene . The trimethyl derivative 18 (R = Me) has also been carbonated and acylated to afford the corresponding 2,3,3-trimethylcyclopropene carboxylic acid, methyl ketone and carboxaldehyde. 

While most of the chemistry discussed in this chapter has been developed in the past decade, several important methods have withstood the test of time and have made important contributions in areas such as natural product synthesis. Methods such as cuprate acylation and the addition of organolithiums to carboxylic acids have continued to enjoy widespread use in organic synthesis, whereas older methods including the reaction of organocadmium reagents with acid halides, once virtually the only method available for acylation, has not seen extensive utilization recently. In the following discussion, we shall be interested in cases where selective monoacylation of nonstabilized carbanion equivalents has been achieved. Especially of concern here are carbanion equivalents or more properly organometallics which possess no source of resonance stabilization other than the covalent carbon-metal bond. Other sources of carbanions that are intrinsically stabilized, such as enolates, will be covered in Chapter 3.6, Volume 2. 

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