Metalation with Buli

In general, imines are too reactive to be used to protect carbonyl groups. In a synthesis of juncusol, however, a bromo- and an iodocyclobexylbnine of two identical aromatic aldehydes were coupled by an Ullmann coupling reaction modified by Ziegler. The imines were cleaved by acidic hydrolysis (aq. oxalic acid, THE, 20°, 1 h, 95% yield). Imines of aromatic aldehydes have also been prepared to protect the aldehyde during ring metalation with. -BuLi. ... 

The hfs-lactim ether (190) was metallated with BuLi regiospecifically in the alanine part of the molecule to produce, after the reaction with alkyl halides, the (3R)-adducts... 

Methoxy-substituted aromatic compound 4 is lithiated metalation with Buli in THF, a step in which it proves useful to include lithium chloride. Because of the greater basicity of /t-butyllithium relative to 4. direct metallation is in fact possible thermodynamically, but /i-butyllithium is generally present in solution as a tetra-mer, and this reduces its reactivity. Addition of lithium chloride destroys these aggregates, and that eliminates the kinetic inhibition. Lithiated aromatic species 18 is further stabilized through chelate formation between lithium and the orr/icr-methoxy groups (ortho effect).8... 

Chlorophosphepines 86 were synthesized in low yield (20-25%) from binaphthyls 84 in two steps, via initial metallation with BuLi and a subsequent reaction of 85 with phosphorus trichloride <2002TL4849>. 

The synthon of the a-acrylate anion is available from a secondary a-keto carboxamide by the Shapiro reaction. The secondary a-ketoamide trisylhydrazones ate ptepar in a one-pot synthesis by reaction of the isocyanides with acid chloride, water and trisylhydrazine in sequence. In DME solvent, the hydra-zone (103) is smoothly metallated with BuLi to give Ae trianion (KH). Allylation of the trianion (104) gives the hydrazone (105). Alternatively, warming (104) up to room temperature yields the dianion (106) which can be intercepted with several electrophiles (Scheme 23). The adduct (107) is readily transformed into the rran -iodo lactone (108) stereospecifically (equation 56). This chemistry also has been applied to a new synthesis of -lactams (Scheme 24). ... 

It has been shown that treatment of dialkyl 2-oxopropylphosphonates with NaH in THF produces a monoanion, and subsequent metallation with -BuLi generates the P-ketophosphonate 1,3-dian-ion. When p-ketophosphonate 1,3-dianions are treated with a variety of alkylating agents. 

Stable but as with the imidazolide it may be protected as the TBS ether to improve its stability. The pyrrole carbinol is sufficiently stable as the lithium salt that aryl halides may be metalated with BuLi. These derivatives may also be converted directly to a,P-unsat-urated esters using the Wadsworth-Horner-Emmons olefination using the Masamune-Roush protocol. Deprotection is accomplished with catalytic DBU or NaOMe. ... 

Slocum and co-workers (18) recently examined the effect of TMEDA on directed metalation reactions. N,N-Dimethylbenzylamine, /3-phenyl-ethyldimethylamine, N,N-dimethylaniline, and anisole, all known to undergo ortho metalation with BuLi but at a relatively slow rate, were each lithiated under conditions similar to those previously reported, except that one equivalent of TMEDA was added to each metalation reaction. In three cases, the metalation rate was increased significantly with only a slight loss in overall yield. These workers also found that the site of ring metalation with p-methoxy-N,N-dimethylbenzylamine can be reversed by using TMEDA. 

Metallated allenic tertiary amines have been obtained in three ways. In a few cases, direct metallation with BuLi in THF at about — 30 °C is the most attractive way dimethylaminoallene and morpholinoallene can be obtained with a purity of about 95% by base-catalyzed isomerization of the easily accessible propargylic amines [7,103] ... 

N-Methylpyrrole can be lithiated very quickly using BuLi TMEDA in an apolar solvent (compare Exp. 14). This method is more suitable than the metallation with BuLi f-BuOK described in Exp. 39 if condensations with enolisable carbonyl... 

This ternary mixture gives more satisfactory results than the binary mixture of /-BuOK and BuLi, which is insoluble in alkanes and therefore requires the use of a very large excess of benzene [235]. Naphthalene and the cocktail of the three bases produce a 85 15 mixture of 2-naphthylpotassium and the 1-isomer in a reasonable yield, together with some 1,8-dipotassionaphthalene [9]. As 2-naphthyl derivatives in general are not easily accessible by the other methods, the metallation with BuLi /-BuOK TMEDA has some practical importance. 

A new method was found to prepare 2,3,4,4a-tetrahydro-l,2,3-benzotriazines following the rare C-C-N-N-N-C mode (a). The azo link in l-(2,6-dimethylphenyl)-3,3-di(primary alkyl)triazenes activates the a-methylene groups at N-3 sufficiently to undergo lithiation and, at the same time, most likely complexes the Li-atom brought in by metalation with BuLi. The carbanionic carbon in turn attacks a phenyl carbon atom ortAo to N-1, which is novel, since otherwise functionalized carbon atoms such as CN or a carbonyl group at C-2 are attacked (Equation (102) Section 9.01.9). No predictions regarding a wider applicability, though, are possible at present. 

In contrast, if X = N, Y = CR, R = H, and R = Me is metalated with BuLi and the resulting dianion is added to the nitroolefin, the product of a benzylic lithiation-Michael addition is isolated. 

Phosphinophenyl)-oxazolines [51] such as 19 can be easily prepared in two steps from 2-bromobenzonitrile (Scheme 23). An alternative route involves oxazoline formation from benzonitrile and an amino alcohol, followed by or-tho-metallation with BuLi [52] and subsequent reaction with Ph2PCl (Scheme 24). Starting from commercially available optically active amino alcohols, a variety of differently substituted enantiomerically pure ligands is readily accessible. 

Homologation of aldehydes can be achieved by reaction of the anion (26) with the aldehyde, metallating with BuLi, and hydrolysing the intermediate thus obtained. " The alkenyl-lithiums (27) and (28) provide routes to functionalized carbonyl compounds, both cyclic and acyclic, on reaction with a variety of conventional electrophiles. By employing bulky substituents at the carbonyl group of the enones (29a and b), a -activity is enforced. Lithium amides may be carbonylated to give the corresponding carbamoyl-lithiums (30), which are useful acyl anion equivalents. ... 

In a somewhat different approach, TIPS was used to protect the C-2 carbon of benzothiophene by treatment with LDA followed by TIPSCl (eq 17). Subsequent metalation with BuLi in hexane/TMEDA produced the desired 7-lithio-2-triisopropylsilyl-benzothiophene which reacted with a Boc-protected piperidone to afford the 7-substituted benzothiophene. The TIPS group was removed by treatment with TEA in CH2CI2. 

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