Acetals, lithiation

The Boekelheide reaction has found utility in other synthetic methodology. An approach to 2,3-pyridynes made use of this chemistry in the preparation of the key intermediate 30. Treatment of 28 with acetic anhydride produced the desired pyridone 29. Lithiation was followed by trapping with trimethylsilyl chloride and exposure to triflic anhydride gave the pyridyne precursor 30. Fluoride initiated the cascade of reactions that resulted in the formation of 2,3-pyridyne 31 that could be trapped with appropriate dienes in Diels-Alder reactions. 

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 addition of lithium enolates to 2-alkoxyaldehydes occurs either in a completely non-stereoselective manner, or with moderate selectivity in favor of the product predicted by the Cram-Felkin-Anh model28 ( nonchelation control 3, see reference 28 for a survey of this type of addition to racemic aldehydes). Thus, a 1 1 mixture of the diastereomeric adducts results from the reaction of lithiated tert-butyl acetate and 2-benzyloxypropanal4,28. 

In Entry 5, the carbanion-stabilizing ability of the sulfonyl group enables lithiation and is then reductively removed after alkylation. The reagent in Entry 6 is prepared by dilithiation of allyl hydrosulfide using n-bulyl lithium. After nucleophilic addition and S-alkylation, a masked aldehyde is present in the form of a vinyl thioether. Entry 7 uses the epoxidation of a vinyl silane to form a 7-hydroxy aldehyde masked as a cyclic acetal. Entries 8 and 9 use nucleophilic cuprate reagents to introduce alkyl groups containing aldehydes masked as acetals. 

These efforts began with directed lithiation [53] of commercially available 4-methoxybenzaldehyde dimethyl acetal (117, Scheme 1.12), followed by quenching with amide 118 to produce chloro acetophenone 119 (52 %). Conversion... 

Acyl hydrazides are useful precursors for the synthesis of 1,2,4-triazoles. Reaction of acyl hydrazides 149 with imidoylbenzotriazoles 148 in the presence of catalytic amounts of acetic acid under microwave irradiation afforded 3,4,5-trisubstituted triazoles 150 <06JOC9051>. Treatment of A-substituted acetamides with oxalyl chloride generated imidoyl chlorides, which reacted readily with aryl hydrazides to give 3-aryl-5-methyl-4-substituted[ 1,2,4]triazoles <06SC2217>. 5-Methyl triazoles could be further functionalized through a-lithiation and subsequent reaction with electrophiles. ( )-A -(Ethoxymethylene)hydrazinecarboxylic acid methyl ester 152 was applied to the one-pot synthesis of 4-substituted-2,4-dihydro-3//-1,2,4-triazolin-3-ones 153 from readily available primary alkyl and aryl amines 151 <06TL6743>. An efficient synthesis of substituted 1,2,4-triazoles involved condensation of benzoylhydrazides with thioamides under microwave irradiation <06JCR293>. 

Two sequential lithiations and treatments with different bifunctional electrophiles make possible one-pot syntheses of relatively complex molecules. Thus, in the [1+2+2] annulation depicted in Scheme 69, alkylation of 1-benzylbenzotriazole 399 with 2-bromoacetaldehyde diethyl acetal to give intermediate 426 is followed by alkylation with W-benzylideneaniline to produce derivative 427. Following treatment with formic acid causes cyclization to ethoxypyrrolidine 428 that subsequently eliminates ethanol and benzotriazole to give pyrrole 429 <1997JHC1379>. 

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>. 

Novel bicyclic imidazo-oxazaphosphinines have been synthesized in high diastereoselectivity by Marsault and Just <1996TL977>. In the first step, iV-tritylimidazole 209 was lithiated and, subsequently, treated with (.S )-propylcnc oxide as a chiral auxiliary and acetic acid to give the intermediate 210, which was reacted with alkyl dichlorophos-phite to yield the ring-closed product 211 as a single diastereomer (Scheme 33). Extension of these approaches for further derivatives 212 has also been published <1998NN939>. 

Addition of lithiated heterocycles to aldonolactones yields carbon-linked nucleosides (56). Thus, the reaction of 2,3 5,6-di-O-isopropylidene-L-gu-lono-1,4-lactone (9b) or 2,3-O-isopropylidene-D-ribono-l,4-lactone (16a) with various lithiated heterocycles gave gulofuranosyl derivatives 53a-g or ribofuranosyl derivatives 54b,c. Gulonolactols 53a-g and ribonolactols 54b,c were acetylated with acetic anhydride in pyridine to yield their acetyl derivatives. The stereochemistry of compounds 53a-g and 54b,c was discussed in terms of the Cotton effect of circular-dichroism curves of the ring-opened alcohols formed upon reduction by sodium borohydride. The configuration at C-l of 53g was proved by means of X-ray analysis (57,58). 

A variety of optically active 4,4-disubstituted allenecarboxylates 245 were provided by HWE reaction of intermediate disubstituted ketene acetates 244 with homochiral HWE reagents 246 developed by Tanaka and co-workers (Scheme 4.63) [99]. a,a-Di-substituted phenyl or 2,6-di-tert-butyl-4-methylphenyl (BHT) acetates 243 were used for the formation of 245 [100]. Addition of ZnCl2 to a solution of the lithiated phos-phonate may cause binding of the rigidly chelated phosphonate anion by Zn2+, where the axially chiral binaphthyl group dictates the orientation of the approach to the electrophile from the less hindered si phase of the reagent. Similarly, the aryl phosphorus methylphosphonium salt 248 was converted to a titanium ylide, which was condensed with aromatic aldehydes to provide allenes 249 with poor ee (Scheme 4.64) [101]. 

Additions of lithiated alkoxyallenes to alkyl-substituted isocyanates and isothiocyanates as electrophiles were recently disclosed by Nedolya and co-workers [87-91]. A short route to N-[2(5H)-furanylidene]amines 133 consists in the addition of lithiated methoxyallene 42 to alkyl isocyanates 132 and silver acetate-mediated cydi-zation of the intermediate (Scheme 8.33) [87]. 

Allenylboranes can also be prepared from lithiated propargyl chloride [20]. As noted above, these intermediates react with acetic acid to afford allenes (Table 9.11). 

Prior to the actual metathesis event, coupling of 13 and 28 via an ester linkage was required (Scheme 2.3). Two methods were employed in this connection. The first involved the aforementioned two-carbon expansion of aldehyde 28. Thus, condensation of 28 with Rathke anion (lithiated tert-butyl acetate) generated a mixture of dia-stereomeric alcohols the major product was shown to have the requisite 3S configuration. TBS protection of ester 29 and subsequent ester hydrolysis generated the desired add, 31, which could be further esterified with alcohol 13 in 78 % yield. 

The lithiation of phenols protected as acetals—methoxymethyl acetals like 140 in particular—is especially valuable the second oxygen supplies a powerful coordination component to their directing effect (Scheme 69) The regioselective lithiation of 141 was used in the synthesis of the pterocarpans 4 -deoxycabenegrins A-I. 

Attempts to make C2-symmetric ferrocenes by double lithiation of a bis-acetal met with only limited success . A second lithiation of the ferrocenylacetal 298 leads to functionalization of the lower ring of the ferrocene, in contrast with the second adjacent lithiation of the oxazolines described below. This can be used to advantage if, for example, the first-formed aldehyde 301 is protected in situ by addition of the lithiopiperazine 53 °, directing f-BuLi to the lower ring (Scheme 139) °. The same strategy can be used to introduce further functionalization to products related to 302. For example, silane 303, produced in enantiomerically pure form by the method of Scheme 138, may be converted to the ferrocenophane 304 by lithiopiperazine protection, lithiation and functionalization (Scheme 140) . 

The malic acid-derived auxiliary which gives good results in the ferrocene series also looks promising among the chromium complexes, and the six-membered acetal of 400 is much more easily hydrolysed than the tartrate-derived acetals of Scheme 164 . Lithiation and bromination of 400 gives, after hydrolysis of the acetal, the complex 401 in 90% ee, increasing to >99% after recrystallization (Scheme 165). 401 is an intermediate in a formal synthesis of (—)-steganone (Scheme 182, Section III.B.2.b). 

Among derivatives of acetophenone, the acetal 399 (R = Me) perfonns the best . Lithiation with f-BuLi in THF and electrophilic quench gives 402a in 60-85% yield and with about 95 5 diastereoselectivity (Scheme 166). Switching to Et20 as the solvent leads to a precipitate which reacts with completely reversed diastereoselectivity, giving 402b. 

The problem of auxiliary removal is overcome when acetals are replaced with the much more labile aminals, formed by reaction of benzaldehydechromium tricarbonyl 403 with diamines, and readily cleaved with mild acid. The best choice of diamine is 404, because the aminal 405 lithiates with good to excellent regioselectivity in the ortho position (Scheme 167) the same could not be said for diamines lacking further lithium-coordinating side-chains . Treatment of 405 with three equivalents of n-BuLi in... 

The deactivating effect of a phenoxide oxyanion is removed in the ether series, but in cases such as 531 where ortholithiation can compete with lateral lithiation, mixtures of products are frequently obtained . The MOM acetal 532 is fully ortto-selective in its reaction with t-BuLi (Scheme 209/ . ... 

The lithiation of y-chloro acetal 175 with lithium and a catalytic amount of naphthalene (4%) allowed the preparation of the intermediate 176, which can be considered as a masked lithium homoenolate, and was used for the preparation of the hydroxy ketone 179 through the hydroxy acetal 177 and dithiane 178 using known chemistry (Scheme 62)" . 

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