Hydroxy-, derivatives lithiation

Crossed aldol condensation of an anion generated a- to a ketone equivalent with o, /3-unsaturated aldehyde, dehydration and release of the ketone is an effective way of generation of dienones. Corey and Enders found that a-lithiated /V,/V-dirnethylhydrazones undergo 1,2-addition to the aldehydes and ketones to form /1-hydroxy derivatives. Sequential treatment of the intermediate with sodium periodate and methanesulphonyl chloride-triethylamine furnishes , -2,4-dienone derivative (equation 57)94. 

Lithiated DBU (40), prepared from DBU and -butyllithium, was reacted with benzophenone, acetophenone, benzaldehyde, phenylacetyl chloride, benzyl chloride, 1-bromopentadecane and phenyl isocyanate to give the respective 6-substituted pyrimido-[l,2-a]azepines (562-564) (86JHC885). When heated at 150 or 180°C, the hydroxy derivatives 562 decomposed and the starting ketones and DBU were recovered. 

Reactions.—All the mono- and poly-bromo-derivatives, as well as iodo-derivatives, of thieno[2,3-h]thiophen have been prepared by direct bromination or iodination, or from the lithium compounds, and characterized by their n.m.r. spectra. Boronic acids were obtained from several alkyl- and aryl-thienothiophens via lithiation and were converted by hydrogen peroxide oxidation into the tautomeric hydroxy-derivatives. It was shown by n.m.r. that all thieno[2,3-h]-thiophen systems exist as thieno[2,3-h]thiophen-2(3 )-ones, while in the case of... 

The 1,3-oxathiane 8, derived from (5)-l,2,4-butanetriol, is lithiated to form the equatorial anion 9, which adds benzaldehyde with high induced but moderate simple diastereoselectivity (4 1) to form the alcohols 10 and 1117. The selectivity is enhanced to 7 1 by metal exchange by means of magnesium bromide. Deprotection affords (5)-2-hydroxy-l,2-diphenylethanone with 75% ee. It is expected that the method could be extended to aliphatic aldehydes. 

The reagents prepared by lithiation (see Section 1.3.3.3.1.2.) and titanium exchange of (S)-(Z)-l-methyl-2-butenyl diisopropylcarbamate106 show a diminished reactivity when compared with those derived from the ( -isomer, indicating that in both metalation steps the doublebond geometry is retained16. After treatment of the lithium -TMEDA complex with chlorotris-(diethylamino)titanium and 2-methylpropanal, the homoaldol adduct (3S,47f)-(Z)-4-hydroxy-1,3,5-trimethyl-l-hexenyl diisopropylcarbamate [( + )-4], is formed with 88% ee16. 

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. 

Treatment of a-dichloromethyl phenyl sulfoxide with lithium diisopropylamide in THF gave monolithiated derivative 122, which upon further treatment with aldehyde afforded the )S-hydroxy-a-dichlorosulfoxide 123. Thermolysis of 123 gave dichloroketone 124, by extruding benzenesulfenic acid as shown below . Similarly, in the reaction of lithio-a-fluoromethyl phenyl sulfoxide and aldehyde, fluoromethyl ketone 126 was obtained, after thermolysis of the hydroxy intermediate 125. Diethylphosphorylmethyl methyl sulfoxide was shown by Miko/ajczyk and coworkers to be lithiated with n-BuLi to intermediate 127, which upon treatment with carbonyl compounds afforded the corresponding a, -unsaturated sulfoxides 128 in good yields. 

The mechanism of the stereoselective syntheses of (K)-3-aryl-5-(hydroxy-methyl)oxazolidinones via the Mannenin reaction of aryl carbamic acid esters with (Jt)-glycidyl butyrate has been explored in detail by Brickner et al. [60]. Namely, N-lithiated carbamate derivatives of anilines are allowed to react with the commercially available (K)-glycidyl butyrate (96-98% enantiomeric excess ee) under appropriate conditions to obtain enantiomerically pure (Jt)-3-aryl-5-(hydroxymethyl)oxazolidinones in 85-99% yields, according the pathways depicted in Scheme 19. 

Pyrrolo[l,2- ][l,2]oxazines are a class of compounds with very few references regarding synthesis and reactivity. An interesting preparation has been described by intramolecular cyclization of IV-hydroxy pyrrolidines carrying a methoxyallene substituent at C-2 (242, Scheme 32). These compounds were obtained by addition of a lithiated allene to chiral cyclic nitrones 241. Cyclization occurred spontaneously after some days at relatively high dilution (0.05 M). Compounds 243 (obtained with excellent diastereoselectivity) can be submitted to further elaboration of the double bond or to hydrogenolysis of the N-O bond to form chiral pyrrolidine derivatives (Section 11.11.6.1) <2003EJ01153>. 

In contrast to the rich chemistry of alkoxy- and aryloxyallenes, synthetic applications of nitrogen-substituted allenes are much less developed. Lithiation at the C-l position followed by addition of electrophiles can also be applied to nitrogen-containing allenes [10]. Some representative examples with dimethyl sulfide and carbonyl compounds are depicted in Scheme 8.73 [147, 157]. a-Hydroxy-substituted (benzotriazo-le) allenes 272 are accessible in a one-pot procedure described by Katritzky and Verin, who generated allenyl anion 271 and trapped it with carbonyl compounds to furnish products 272 [147]. The subsequent cyclization of 272 leading to dihydro-furan derivative 273 was achieved under similar conditions to those already mentioned for oxygen-substituted allenes. 

Lithium homoenolates derived from carboxylic acids were generated from the corresponding /3-chloro acids by means of an arene-catalyzed lithiation. Chloro acids 186 were deprotonated with n-butyllithium and lithiated in situ with lithium and a catalytic amount of DTBB (5%) in the presence of different carbonyl compounds to yield, after hydrolysis, the expected hydroxy acids (187). Since the purification of these products is difficult, they were cyclized without isolation upon treatment with p-toluenesulfonic acid (PTSA) under benzene reflux, into substituted y-lactones 188 (Scheme 64) . 

An early effort to generate a 3-lithiated propionic acid derivative and react it with (external) electrophiles was reported in 1978 [42]. Since simple 3-lithioesters failed to undergo the required reaction, the alkyl carboxylate portion was protected by preceding conversion to the carboxylate anion. Treatment of lithium 3-bromo-propionate with lithium naphthalide generated the desired dilithiated propionic acid, which gave moderate yields of y-hydroxy acid addition products with carbonyl compounds, Eq. (45). 

Lithiation of 3-methoxyselenophene occurs in the 2-position (76BSF265). Selenienyl f-butyl ethers are convenient precursors of the corresponding hydroxy compounds they are available from the corresponding lithio derivative (Scheme 10) (76ACS(B)10l). 

The antihypertensive agent 278 has been 14C-labelled by carbonation of the 2-lithiated indole, 279 (R = Li), with 14CC>2 and subsequent combination with a preformed peptide side chain. In 279 (R = H) the indole nitrogen has been converted into its benzenesulphonyl derivative to direct properly the lithiation while the 2-hydroxy-3-isopropylaminopropoxy side chain has been protected as oxazolidin-2-one290. 

Carbamate 282, derived from (V-benzylpiperidine-2-methanol 281, undergoes stereoselective deprotonation when treated with. r-butyllithium and tetramethylethylenediamine to give lithiate 283, which can be trapped with numerous electrophiles to give, after hydrolysis of the carbamate, a single diastereoisomer of /(-hydroxy piperidines 284 (Scheme 67) <1999S1915>. 

The chiral binaphthyl-derived dithiepin 294 has been lithiated and allowed to react with aldehydes for the synthesis of enantiomerically enriched a-hydroxy ketones (up to 80% ee), after deprotection with mercury(II) perchlorate465. 

Phenylsulfonyl)tetrahydropyran 369 has been lithiated with w-BuLi at — 78 °C to give the anion 370, which has been allowed to react with alkyl halides and carbonyl compounds (Scheme 97)548. The corresponding 2-substituted derivatives suffered after aqueous work-up spontaneous /3-elimination of benzenesulfmic acid to give products 371. When the alkyl halide has an additional protected hydroxy group at the y- or 5-position (such as in compound 372), spiroketals (e.g. compound 373, Scheme 97) were obtained, this methodology having been applied to the synthesis of ionophore antibiotic CP 61,405 (routiennocin)550. 

Af-(Phenylsulfanylmethyl)oxazolidinones derived from camphor 494 can be lithiated with n-BuLi at —78°C to give the chiral formyllithium equivalent 478683 (Scheme 128). This intermediate added to aldehydes in good yields, but lower stereoselectivity than compound 477, to afford crystalline adducts, which allowed the isolation of the major diastereomer 495. Hydrolysis of these adducts gave a-hydroxy aldehydes, which can be oxidized with PCC to the corresponding a-hydroxy acids. 

Hydrolysis of alkylated products and carbonyl compound adducts derived from a-lithiated DHF and DHP with 2 M HC1 in THF at room temperature gave y- and 5-hydroxy ketones, respectively824,865 (Scheme 162). Jones oxidation generated keto acids866,887 and when the R substituent bears an hydroxy group, cyclization occurred in the presence of pyridinium tosylate (PPTS) in CH2C12 or HC1 in ether to provide spiroketals875,883,894,901. 

Chiral secondary a-hydroxy aldehydes, Rf HOHCHO. The chiral acyl derivatives 3, obtained from 1 by lithiation and reaction with an aldehyde followed by Swem oxidation, can be reduced stereoselectively before cleavage to the secondary a-hydroxy aldehydes. 

Reactions subsequent to lithiation at C-2 of the 1,3-oxathianes derived from 5-hydroxy-1-tetralone 45 <03EJO337> and from myrtenal 46 <03JOC6619> result in the equatorial product. 

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