Carboxylation 3-lithiated

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

In a related procedure A -melhyl-o-loluidine can be A-lithiated, carboxylated and C-lithiated by sequential addition of n-butyllithium, CO2, and n-butyl-lithium[5]. The resulting dilithiated intermediate reacts with esters to give 1.2-disubstituted indoles. 

Lithiation and Subsequent Transformations. Lithiation is the most geneial means of intioducing a 2-substituent on the indole hng. Three intermediates have been used most frequendy in this context. These ate 1-phenylsulfonylindole (19), l-/-butoxycarbonylindole (20), and hthium indole-l-carboxylate (21). 

Lithiated pyrazoles prepared from CtH or preferably from C-Br pyrazoles (B-76MI40402) can be transformed into carboxylic acids. In this way pyrazole-4-carboxylic acids (504 ... 

Isoxazolyl Grignard reagents react normally in that a 4-carboxylic acid or 4-methanol can be obtained by reaction with CO2 or ketones (63AHC(2)365). Lithiation of 3,5-disub-... 

Lithiation of 2-(2-alkylphenyl)-l,2,3,4-tetrahydropyrimidines 427 with 1.3 M BuLi in the presence of A/, A/, A, A -tetramethylethylenediamine, then with 1.3 M -BuLi, followed by the addition of a carboxylic acid methyl ester, and treatment of the reaction mixture with pTSA afforded 3,4-dihydro-2/f-pyrimido[2,l-u]isoquinolines 428 after chromatographic work-up (98JMC1050). 

Seebach and coworkers examined the deprotonation/electrophile trapping of phe-nylthioaziridine carboxylates 236 (Scheme 5.58). These thioesters were found to be more stable than their oxy-ester congeners when lithiated treatment of 236 with LDA at -78 °C, followed by trapping with Mel at -100 °C, stereoselectively afforded aziridine 237 [83]. 

In another approach, a glucose-derived titanium enolate is used in order to accomplish stereoselective aldol additions. Again the chiral information lies in the metallic portion of the enolate. Thus, the lithiated /m-butyl acetate is transmetalated with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene- -D-glucofuranos-3-0-yl)titanium (see Section I.3.4.2.2.I. and 1.3.4.2.2.2.). The titanium enolate 5 is reacted in situ with aldehydes to provide, after hydrolysis, /i-hydroxy-carboxylic acids with 90 95% ee and the chiral auxiliary reagent can be recovered76. 

The aryl bromides undergo facile metalation with butyl lithium to produce aryllithium derivatives with the expected organometallic activity.9 For example, reaction of lithiated PPO with carbon dioxide produces a carboxylated PPO which exhibits unique blending characteristics18. 

P-Ketodicarboxylic esters can be synthesized in a similar way using CDI and an a-lithiated carboxylic ester [58]... 

Aminoisoxazoles 22 have been synthesized by nucleophilic addition of lithiated alkyl nitriles to a-chloroximes <06OL3679>. The cyclization of oxime dianions with diethyl oxalate afforded isoxazole-5-carboxylates 23 by acid-mediated dehydration of intermediate hydroxyisoxazolines <06S2515>. 

Upon treatment with n-butyllithium at — 78 °C, 1-methylbenzotriazole 380 is lithiated on the methyl group to give l-(lithiomethyl)benzotriazole 381. Rapid addition of a carboxylic ester to the solution provides a-(benzotriazol-l-yl)alkyl ketone 382 in high yield (Scheme 61) <1997JOC4142>. This easy access to ketones 382 and their reactivity makes them valuable intermediates in several syntheses. Their chemistry is discussed separately in Section 5.01.8.4. 

Addition of a silyl substituent into a-position of the a-(benzotriazol-l-yl)alkyl ether brings additional possibilities. Thus, lithiation of silyl ether 770 followed by treatment with an aldehyde or ketone gives unstable P-hydroxy-a-silyl-a-(benzotriazol-l-yl)alkyl ether 771 that spontaneously eliminates silanol to give vinyl ether 772 (Scheme 121). Treatment with ZnBr2 followed by hydrolysis with a diluted acid removes both the benzotriazolyl and the methyl groups to furnish carboxylic acid 773. In this way, in a simple manner, aldehydes and ketones are converted to one-carbon homologated carboxylic acid <1996S1425>. 

The benzotriazolyl derivative of acrolein acetal, compound 882, is lithiated, treated with chlorodiphenylphosphine, and the obtained intermediate is oxidized with hydrogen peroxide to phosphine oxide 883 (Scheme 145). The relatively acidic proton in derivative 883 is easily removed by a base, and the obtained anion adds to a carbonyl group of aldehyde or ketone. Subsequent rearrangement and elimination of the phosphorane group generates diene 884. For the derivatives of aldehydes (884, R2 = H), (E)-(E) stereoselectivity of the elimination is observed. Acidic alcoholysis of dienes 884 affords esters of P,y-unsaturated carboxylic acids 885 < 1997JOC4131>. 

Lithiation of the germyl hydride S -3 with BuLi in ether and subsequent protonolysis led to recovered hydride of [a]o — 18.5 (86% retention)2. It is assumed that both steps proceed with predominant retention of configuration. Carboxylation of the lithio derivative afforded the carboxylic acid R-12, also with retention of configuration (Scheme 4). The corresponding methyl ester underwent decarbonylation upon heating to afford the methoxy derivative R-15, which was subsequently reduced with LiAlH4 to the (—)-hydride S-... 

Thermal decarboxylation of pyrimidylcarboxylic organotin esters is another means to prepare the corresponding stannylpyrimidines [33]. This method obviates the intermediacy of lithiated pyrimidine species that would undergo undesired reactions at higher temperatures. The decarboxylation occurs at the activated positions. Therefore, thermal decarboxylation of tributyltin carboxylate 62, derived from refluxing carboxylic acid 61 with bis(tributyltin) oxide, provided 4-stannylpyrimidine 63. Addition of certain Pd(II) complexes such as bis(acetonitrile)palladium(II) dichloride improved the yields, whereas AIBN and illumination failed to significantly affect the yield. 

One of the first hyperbranched polymers described in the literature was polyphenylenes, which were presented by Kim et al. [30-32] who also coined the term hyperbranched . The polyphenylenes were prepared via Pd(0) or Ni(II) catalyzed coupling reactions of various dihalophenyl derivatives such as di-bromophenylboronic acid. The polymers were highly branched polyphenylenes with terminal bromine groups which could be further transformed into a variety of structures such as methylol, lithiate, or carboxylate (Fig. 5). 

Eaton and co-workers also reported the synthesis of 1,3,5-trinitrocubane and 1,3,5,7-tetranitrocubane (39) ° The required tri- and tetra-substituted cubane precursors were initially prepared via stepwise substitution of the cubane core using amide functionality to permit ort/jo-lithiation of adjacent positions. The synthesis of precursors like cubane-1,3,5,7-tetracarboxylic acid was long and inefficient by this method and required the synthesis of toxic organomercury intermediates. Bashir-Hashemi reported an ingenious route to cubane-1,3,5,7-tetracarboxylic acid chloride (35) involving photochemical chlorocarbonylation of cubane carboxylic acid chloride (34) with a mercury lamp and excess oxalyl chloride. Under optimum conditions this reaction is reported to give a 70 8 22 isomeric mixture of 35 36 37... 

Whereas the repeated lithiation-trimethylsilylation sequence of trimethyl-silylbicyclopropylidene 43 a yielded predominantly the cyclopropene derivative 51 [54], bicyclopropylidenecarboxylates 42-Me, 42-fBu after repeated deprotonation and carboxylation retain the bicyclopropylidene moiety and give 2,2-disubstituted products 52-R only (Scheme 9) [55]. So far, alkylbicyclopropyl-idenes 43 e, f, g have not been induced to undergo deprotonation and a second substitution [56a]. The urethane 53 with a nitrogen directly attached to the skeleton, more easily than any other bicyclopropylidene derivative, rearranges to... 

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