Lithiation selectivity

Lithiation can be diverted away from C-2 of indole by the use of a bulky N-substituent. Although 1-methylgramine is cleanly lithiated at C-2, l-(triisopropylsilyl)gramine is lithiated selectively at C-4 and can lead to useful 4-substituted indoles electrophiles include 1,2-dibromoethane, DMF, and diphenyl sulfide (Scheme 60) (93H(36)29). 

Anilide 4 is lithiated selectively in ortho-position to the pivaloyl amide group.4 5 The organolithium species is generated by reaction of 4 with two equivalents of n-butyllithium below 5 °C in MTBE, since the amide proton is also acidic and is deprotonated to yield resonance-stabilized anion IS before the ort/zo-lithiation of the aromatic system with the second equivalent of n-butyllithium takes place. The resulting organolithium species 16 then undergoes nucleophilic attack of ester 176 to give dianion 18. 

The relative product ratios of the regioisomers 6 and rac-5 varied according to the reaction conditions. The highest (relative) amount of compound 6(11 1 product ratio) was found using the polar solvent THF, and the product ratio most in favor of rac-5 (2.4 1) was found in the non-polar solvent n-pentane. We made a similar observation during the lithiation of benzyldimethyl-(piperidinomethyl)silane [Ig]. When benzyldimethyl(piperidinomethyl)silane was treated with 1 equiv of fert-butyllithium in n-pentane or toluene at -90 °C, one of the methyl groups was lithiated selectively. Selective metalation of the benzyl position under formation of 1 occurs only when the same reaction is carried out in a polar donor solvent, such as THF. 

Furans and thiophenes normally undergo a-lithiation, but when substituted at the 2-position by an activating group, a competition arises between metalation at the 3-position (ortho lithiation) and the S-posi-tion (a-lithiation). 2-Oxazolinylthiophenes may be lithiated selectively at either the 3- or 5-position by adjusting the reaction conditions tertiary amides give little or no ortho selectivity, but secondary amides direct ortho lithiation reasonably well, as seen in Scheme 23. Both thiophenes and furans that are substituted with an oxazoline or tertiary amide at the 2-position may be dilithiated at the 3- and S-po-sitions. 76 Although secondary amides are less successful at directing ortho lithiation of furans than thiophenes, A, Af,M,lV -tetramethyldiamido phosphates work quite well. Subsequent hydrolysis affords access to butenolides. A typical example is shown in Scheme 24. 

Triple bromination of A -TIPS-pyri ole (6) with NBS affords tribromopyrrole 12 (97%) [22], which can either be deprotected to afford the marine acorn worm metabolite 2,3,4-tribromoindole 13 [22,23] or lithiated selectively at C-2 to give, after quenching with carbon dioxide, pyrrole carboxylic acid 14 [24],... 

Fig. 5 Examples of complexes that can be lithiated selectively at the ortho position...

One of the most effective A-substituents for C-2 lithiation of indoles and pyrroles is the t-butylcarbamoyl group, the lithiated derivatives of which react with a wide range of electrophiles such as trimethylsilyl chloride, A,7V-dimethylbenzamide, and carbon dioxide, to give the substituted products in 45-95% yield <9isi079>. Removal of the Af-group can be effected by treatment with lithium hydroxide in methanolic THF (Scheme 39). 1-Methoxyindole also can be lithiated selectively at C-2 and converted to substituted products hydrogenolysis removes the methoxy group <91H(32)22i>. Even 7V-phenylpyrrole can be selectively monolithiated at the pyrrole C-2 position. 

As noted earlier (Scheme 4), 3-iodo-A -(phenylsulfonyl)indole 6 was lithiated selectively at C2 (thus avoiding halogen-metal exchange) by treatment with LDA [14, 183-185]. This selectivity has also been observed with 3-bromoindole 43 [159, 183, 184, 186], functionalized 3-bromoindoles (not shown) [159, 187], and 3-cyanoindole 44 [103, 188]. Examples of the C2-lithiation of these substrates in the synthesis of 2,3-disubstituted indoles 39 are shown below (Table 6). 

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]. 

It should be noted that the sense of asymmetric induction in the lithiation/ rearrangement of aziridines 274, 276, and 279 by treatment with s-butyllithium/ (-)-sparteine is opposite to that observed for the corresponding epoxides (i.e. removal of the proton occurs at the (S)-stereocenter) [102], If one accepts the proposed model to explain the selective abstraction of the proton at the (R) -stereo-center of an epoxide (Figure 5.1), then, from the large difference in steric bulk (and Lewis basicity) between an oxygen atom and a tosyl-protected nitrogen atom, it is obvious that this model cannot be applied to the analogous aziridines. 

Another class of configurationally stable a-mctallo amines is derived from the N-tert-butoxy-carbonyl-protected piperidines 32 and 3516, l7. Addition of the lithiated piperidines to aldehydes leads to mixtures of the anti- and. yin-diastereoiners. Although the diastereoselectivity is low, the diastereomers can be readily separated by chromatography since the. vyn-isomer is often in a cyclized form 34. The stereochemistry of the products obtained from piperidines 32 are consistent with an equatorial a-lithiation followed by addition to the aldehyde with retention of configuration. However, with piperidine 35 selective axial lithiation is observed. 

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. 

With titanated 2-alkenyl carbamates, the opposite regioselectivity can also be observed. Lithiated l-(4-methylphenylsulfonyl)-2-alkenyl diisopropylcarbamates, after metal exchange with chlorotriisopropoxytitanium, add to aldehydes y-selectivelylls. The less reactive titanat-ing reagent tetraisopropoxytitanium does not apparently react with these stabilized lithium carbanions, because in its presence a-selectivity is retained (Section 1.3.3.3.1.3.2.). 

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 contrast to the amt-selective reaction of lithiated imines with aldehydes, titanated imines, prepared by transmetalation of the corresponding lithium azaenolates, give predominantly. sFH-adducts2. 

Enhanced anti selectivity is observed in reactions of lithiated 4.5-dihydrooxazoles bearing an additional substituent which facilitates the formation of rigid azaenolates by internal chelation of lithium13. Thus, reaction of 2-ethyl-4,5-dihydro-4,4-dimethyloxazole (10) with 2-methylpropanal gives a 56 44 mixture of adducts while (R)-2-ethyl-4,5-dihydro-4-(methoxymethyl)-oxazolc (12) reacts with the same aldehyde to yield a 90 10 mixture of adducts 1313. 

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... 

While the steric explanation is consistent with the observed selectivity, it nonetheless presents an incomplete explanation, as alkylation of 2-methyl-4-cyano-l,3-dioxane 17 also proceeded with very high syn-selectivity [11] (Eq. 5). The selective equatorial alkylation can be rationalized as an anfz-anomeric effect that disfavors axial alkylation of the ketene iminate through filled-shell repulsion. Simple lithiated nitriles are known to exist as ketene iminates, but it would be easy to rationalize the preference for equatorial alkylation by considering the relative stability of hypothetical equatorial and axial alkyllithium reagents, vide infra. Preferential equatorial alkylation was also observed by Beau... 

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. 

OS 70] [R 25] [P 51] The temperature of a lithiation step was raised from -78 °C (batch) to -15 °C (micro reactor) without losing selectivity [83]. The temperatare of the subsequent alkylation of a ketone to a chiral alcohol could also be increased from -60 °C (batch) to 0 °C (micro reactor). 

---