Lithiation positional selectivity

Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

In their synthesis of (+)-cerulenin, Mani and Townsend employed lithiated epoxysilane 157, which they trapped with (4E,7 )-nonadienal to give a 77% yield of 158, which was further manipulated to give the natural product (Scheme 5.37) [58], as-ot, 3-Epoxy-Y,S-vinylsilanes 159 are regioselectively lithiated at the a-silyl position, and can subsequently be stereo selectively trapped with a range of electrophiles to give a-substituted epoxyvinylsilanes 160, which can in turn be isomerized to a-silyl-P-vinylketones 161 (Scheme 5.38) [59]. 

When a heteroatom, such as N, O, or a halogen, is present in a molecule containing an aromatic ring or a double bond, lithiation is usually quite regio-selective. The lithium usually bonds with the sp carbon closest to the hetero atom, probably because the attacking species coordinates with the hetero atom. Such reactions with compounds such as anisole are often called directed metala-tions. In the case of aromatic rings, this means attack at the ortho position.Two examples are... 

Later work examined substituent effects on kinetically controlled alkylations [68, 69] (Scheme 32). Substitution at the 5-position is well tolerated in these reactions. Reductive lithiation of a series of 4-phenylthio-l,3-dioxanes and quenching of the axial alkyllithium intermediate with dimethyl sulfate provided the flzzfz -l,3-diols in good yield, with essentially complete selectivity. 

The ortfe-directed lithiation protocol allows selective functionalization of 3-arylsydnones in the aryl ring, the C4 position of the sydnone ring, or both simultaneously. The method allows access to fused ring structures (Sections 5.03.5.2.4 and 5.03.7.1.1). Reliable routes to otherwise unknown oxadiazolidines have been established (Section 5.03.9.4). Regiospecificity can now be achieved by judicious choice of substituents when propargylic esters react with sydnones to form pyrazoles (Section 5.03.5.2.6). 

Terminal trimethylsilylacetylenes are deprotonated at the propargylic position by using sBuLi to yield a lithiated species which undergoes transmetallation with ZnBr2 to afford the allenylzinc reagent (Eq. 9.125) [99]. Additions to a-alkoxyalde-hydes are relatively unselective (Table 9.48), whereas additions to a-alkoxy imines are highly anti selective (Eq. 9.126). 

Blocking either the 2- or 4-position allows lithiation at the other EDA or BuLi can be used to 4-lithiate the 2-blocked 3-fluoropyridines 186 °, 187 ° and 188 (Scheme 95) ° and BuLi 2-lithiates the 4-blocked 3-fluoropyridine I89204.208,209 jjjg selectivity for... 

In many ways, the electron-rich five-membered aromatic heterocycles behave very much like carbocyclic aromatic compounds when it comes to lithiation. Lithiation a to O or S of furan and thiophene is straightforward (Scheme 130) . The usual selection of orf/io-directing groups allows lithiation at other positions and some examples... 

Better for the lateral lithiation of phenols are the A(,A(-dialkylcarbamate derivatives 533. These may be lithiated with LDA, allowing complete selectivity for the lateral position, presumably because this is the thermodynamic product . With i-BuLi, ortholithiation is... 

In addition to the parent heterocycle, both AT,N-diethyl-l-methylpyr-role-3-carboxamide and l-methylpyrrole-3-carboxaldehyde have been selectively a-lithiated in the 2-position (85TL6213 87JOC104), the latter compound via the intermediacy of an a-(Af-methylpiperazino) alkoxide (Scheme 6). The a-amino alkoxide is formed in situ, via the addition of... 

The tricarbonylchromium (0) complex of pyridine 94 has also recently been shown to undergo selective lithiation at the C-2 position with LDA, to give 95 [JCS(P1)501]. However, this result is not synthetically significant since the starting material 94 was actually prepared by desilylation of the... 

Snieckus and co-workers reported the directed lithiation of 3-furanecarboxylic acid diethylamide (6.21.), which proceeded selectively in the 2-position, and the subsequent zinc-lithium exchange. The so formed fiiranylzinc reagent underwent Negishi-coupling with 2-bromotoluene in the presence of a palladium-triphenylphosphine catalyst to give 2-(o-tolyl)furane in good yield.26... 

It has been shown that lithiation with lithium amides can also be regioselective (see 2-21).277 In the case of the cubane derivative 30, a saturated unactivated position was regio-selectively lithiated.278... 

Lithiation of thiazolo[5,4-b]pyridine-N-oxides (503) by n-butyllithium at -65°C is selectively directed by the pyridine N-oxide moiety, whereas lithiation of the parent heterocycle by LDA at -78°C exclusively occurs at the C-4 position (89TL183). Interestingly, no metalation of the furan ring occurred (Scheme 152). 

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