Double lithiation

In spite of the evident simplicity, the concept of the development of reaction sequences for activation of the carbon skeleton of AN has been ignored in the literature until recent years. Nevertheless, the data on double lithiation of AN (446, 447) (Scheme 3.186) clearly demonstrated that these ideas hold promise. 

Reactions of 23 with LiCMe3 in a molar ratio 1 4 in pentane at 20°C (reaction time 24 hours) indicate that metallation of the second PH group in 26 to yield LiP[Si(CMe3)2]2PLi (27) is possible. A white solid is formed in this reaction, and the consumption of LiCMe3 corresponds to a double lithiation of compound 23. There are signs that the dilithiated compound 27 is characterized in the P-NMR spectrum by 5 = —280 ppm, but it has been impossible to obtain compound 27 in a pure form despite repeated metallation reactions. 

Sulphides are weak orthodirectors (Scheme 42), and the lithiation of thioanisole 89 with BuLi leads to a mixture of a- and ortholithiated compounds 90 and 91 ". The ortholithiated compound forms about one third of the kinetic product mixture, but slow isomerization to the a-lithiated sulphide follows. The isomerization is much faster (and therefore the yield of a-lithiated sulphide much higher) if BuLi is used in the presence of DABCO". With two equivalents of BuLi, clean ortho - -a double lithiation occurs, giving 92 the SCH2Li group is itself an ortAo-director" , though a weaker one than... 

Double lithiation of the xanthene derivative 146 is the key step in an important synthesis of the ligand xantphos 147 Benzofuran 148 is also doubly lithiated by excess BuLi/TMEDA (Scheme 72) . 

In aromatic compounds bearing two rotationally restricted amide groups, diastereoiso-meric atropisomers can arise because of the relative orientation of the amides. Ortholithi-ation can therefore lead to diastereoselectivity if the ortholithiation forms one of the two diastereoisomers selectively. A simple case is 169, whose double lithiation-ethylation leads only to the C2-symmetric diamide 170, indicating the probable preferred conformation of the starting material (Scheme 85) . 

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) . 

Double lithiation of bisoxazoline 314 is possible with either s-BuLi or f-BuLi, and each base gives different planar diastereoselectivity. Double lithiation with i-BuLi, quenching the dianion with ClPPh2, leads to the C2-symmetric bisphosphine 315 as the... 

Lithiation of the dicarboxamide 365 is similarly diastereoselective, and after two successive n-BuLi-(—)-sparteine lithiations C2-symmetric products such as 367 can be made with high ee (Scheme 156) Attempted double lithiation of 365 in one pot fails with n-BuLi with s-BuLi-(—)-sparteine the major product is the meso isomer of 367 ". The amidophosphine 366 has been used as a chiral ligand for Pd chemistry the amides can be reduced to amino groups with BHsiTHF . 

Some headway has been made using sulphoxides to direct the lithiation of arenechromium tricarbonyls in the manner of Kagan s work with ferrocenes . Diastereoselectiv-ities in the lithiation-quench of 392 are excellent, though yields are poor with most electrophiles. Diastereoselectivity reverses on double lithiation, because the last-formed anionic site in 394 is the most reactive (Scheme 163). 

A completely different reaction to give 1,2-dilithio synthons was performed by double lithiation of thianthrene 426 (Y = S) under catalytic conditions. Thus, after the first lithiation with lithium and DTBB (4%) in THF at —90 °C, the corresponding intermediate (of... 

The double lithiation and subsequent substitution of 2-alkyl-4(3//7-quinazolinethiones has also been performed <2004S363>, and a number of 3-amino- and 3-acylamino-2-alkyM(3//)-quinazolinones 570 have also been deriva-tized via their dianions <1995J(P1)1029, 1996JOC647, 1996JOC656, 2000H(53)1839, 2004S2121>. 

It is interesting to contrast these double lithiations of secondary N-allyl amides with the double lithiation of a secondary N-silyl amine 59, which leads to vinylic y-lithiation, rather than allylic a-lithiation.41 42 The product 60 cyclises onto carbonyl electrophiles to yield pyrroles such as 61. 

BuLi, clean ortho+a double lithiation occurs, giving 229 the SCH2Li group is itself an ortho-director,207 though a weaker one than OMe, since doubly lithiated 230 has the regiochemistry 231.208 A methylthio substituent in conjunction with a methoxy substituent directs to their mutual ortho position (232 - 233). 

The schematically shown double lithiated centers are generated not at once under reaction conditions, i.e. the reaction proceeds via two monolithiated intermediates. 

The toluidine 262 has been shown to undergo double lithiation to provide the intermediate 263, which may be subsequently reacted with ethyl trifluoroacetate to provide the target heterocycle 264 (Scheme 31) <1996H(43)1471>. 

In the reaction of tetraisopropylthiuram disulfide (TITD) with the dianioii obtained by double lithiation of 3-amino-2-ethylquinazolin-4(3//)-one with lithium diisopropylamide, deamination takes place to afford 2-substituted quinazolin-4(377)-one 22. °... 

Tandem Double Lithiation The asymmetric synthesis of camptothecin Tandem Lithiation of Pyridine A-Oxides and Nucleophilic Substitution... 

Tandem Double Lithiation The asymmetric synthesis of camptothecin... 

Alkylation of 4-Boc-2-oxopiperazines at C-3 is initiated by treatment with r-BuLi. >1 dimethylamino)methane undergoes double lithiation. ... 

It should be noted that there are a few specific examples where (-)-sparteine can be used to generate either product-type enantiomer for example via trans-metallation [17, 53], the use of electrophiles with different leaving groups [68], double lithiation in the generation of planar chirahty [69], or a solvent switch [70]. 

Miscellaneous. Double lithiations of the parent compounds give the dianions (25) and (26), both of which react with electrophiles preferentially at the benzyl positions. Addition of RLi to the carbonyl group of compound (27), followed by reduction of the initial product, gives access to 4-alkyl-2,6-di-t-butylanilines. Low-temperature reactions between aldehydes and RLi in the presence of asymmetric auxiliaries such as (28) give secondary alcohols with up to 40% enantiomeric... 

Finally, Seebach has used the cyclic urea (69), DMPU, as a co-solvent in double lithiations, oxirane ring-opening, Wittig reactions, Michael additions of lithiated dithianes to cycloalkenones, and the selective generation of enolates." The interesting point here is that DMPU exhibits the same solvent effect as the carcinogen HMPA and might therefore be a safe substitute. 

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