Ethers, diethyl deprotonation

O A strong base must be used to ensure complete deprotonation in this step. The solvent must not have any acidic hydrogens. An ether (diethyl ether, DME, THF, dioxane) or DMF is commonly used. 

For the deprotonation of less acidic precursors, which do not lead to mesomerically stabilized anions, butyllithium/TMEDA in THF or diethyl ether, or the more reactive, but more expensive,. seobutyllithium under these conditions usually are the most promising bases. Het-eroatomic substitution on the allylic substrate, which docs not contribute to the mesomeric or inductive stabilization often facilitates lithiation dramatically 58. In lithiations, in contrast to most other metalations, the kinetic acidity, caused by complexing heteroatom substituents, may override the thermodynamic acidity, which is estimated from the stabilization of the competing anions. These directed lithiations59 should be performed in the least polar solvent possible, e.g.. diethyl ether, toluene, or even hexane. 

The lithium-(-)-sparteine complex, generated by deprotonation of 1-methylindene, does not lose its configuration in diethyl ether solution even at room temperature80 presumably, the observed major diastcreonier is the thermodynamically determined product. Substitution with carbonyl compounds leads to 1-substituted (fl)-l-methyl-l//-indenes with >95% ee in high yields81. 

While ephedrine derivatives showed some selectivity, the most promising results were obtained with cinchona alkaloids. Lithium alkoxides and lithium acetylides (n-BuLi or LiHMDS used to deprotonate both the acetylene and the alcohol) gave better results than the corresponding sodium or magnesium salts. Higher enan-tioselectivity was obtained in THF (homogeneous) than in toluene or diethyl ether (heterogeneous). 

Conversion of tight ion pairs into crown ether-separated ion pairs leads in many cases to increased basicity. For example, Dietrich and Lehn (1973) have shown that a homogeneous solution of sodium t-amyloxide in benzene is unable to deprotonate triphenylmethane, whereas the reaction occurs rapidly in the presence of [2.2.2]-cryptand [37]. In THF or diethyl ether, alkali metal enolates do not react with triphenyl- or diphenylmethane (Pierre et al.,... 

In general the deprotonation of a polyborane B H +m (to = 4,6) leads to the anions [BnHn+m-i] or [B H +m 2]2 by removal of one or two protons from a BHB 3c2e bridge with formation of a B-B single bond. Cluster expansion with a BH3 unit, usually offered as diborane in diethyl ether or tetrahydrofuran, produces borane anions [B +1H +m+2] or [B +1H +m+1]2 and these in turn on protonation give the polyboranes Bn+iHn+m+-. These may be stable species. However, in most cases they loose H2 which results in a cluster expansion by one BH unit. Several examples of this method are described in the following sections. 

OLi by deprotonation of OH prior to the halogen/metal permutation. Solvent (Sv) DEE = diethyl ether, THF = tetrahydrofuran. 

Lithio-l-methoxyallene 183 ° , readily accessible by deprotonation of methoxyal-lene with n-butyllithium in diethyl ether, turned out to be a versatile C-3 building blocL It adds to aldehydes and ketones giving hydroxyaUcylated allenes 184, which undergo a ring-closure reaction under basic conditions. Thus, 3-methoxy-2,5-dihydrofurans 185 are obtained. Subsequent acid hydrolysis leads to the formation of dihydro-3(2//)-... 

Since the (—)-sparteine reagent does not support the deprotonation of the neopentyl carbamate 29a (1.5 equivalents of s-BuLi, diethyl ether, 5 h at —78 °C) it becomes evident that fraw5-l,2-bis(dimethylamino)cyclohexane, which is available in both enantiomers , is the chiral additive of choice for bulky alkyl carbamates. (—)-a-Isosparteine (14), which holds two fraw5-fused piperidine rings, does not support the deprotonation of alkyl carbamates at alP . 

An efficient kinetic resolution was also observed during the (—)-sparteine-mediated deprotonation of the piperidin-2-yhnethyl carbamate rac-112 (equation 25). By treatment of rac-112 with s-BuLi/(—)-sparteine (11), the pro-S proton in (/ )-112 is removed preferentially to form the lithium compound 113, which undergoes intramolecular cyclo-carbolithiation, and the indolizidinyl-benzyllithium intermediate 114 was trapped with several electrophiles. The mismatched combination in the deprotonation of (5 )-112, leading to cp/-113, does not significantly contribute to product formation. Under optimized conditions [0.75 equivalents of s-BuLi, 0.8 equivalents of (—)-sparteine, 22 h at —78°C in diethyl ether] the indolizidine 115 was isolated with 34% yield (based on rac-112), d.r. = 98 2, e.r. = 97 3 optically active (5 )-112 was recovered (46%, 63% ee). 

The enantioselective deprotonation of the borane complex 248 of A-methylisoindoline was investigated by Simpkins and coworkers (eqnation 59) . Deprotonation with i-BuLi/(—)-sparteine (11) in diethyl ether at —78°C for 1 h, followed by quenching with chlorotrimethylsilane, yielded the silanes 251, ent-252, 252, ent-25 in a ratio of 86.3 0.4 6.3 7.0 after destroying the chiral centre at nitrogen by treatment of the whole mixture with triethylamine, an e.r. 253/ewf-253 of 86.7 13.3 is expected. 

Racemic, cyclic and open-chain 1,2-diarylalkanes have been deprotonated under the regime of the sparteine protocoP . )V-Methyl-4-phenyl-l,2,3,4-tetrahydroisoquinoline (276) was deprotonated by i-BuLi/(—)-sparteine (11) and the intermediates 277 were quenched by MeOD. When performing the reaction in diethyl ether, (R)-278 was isolated with high ee values, up to 88% (equation 68). ... 

In comparison to other vinylic compounds , the vinyl proton in 1-alkenyl carbamates, deprotonation has a very high kinetic acidity . After protection of the 4-hydroxy group in the homoaldol products by silylation, deprotonation (w-BuLi, TMEDA, diethyl ether or THF) of enol carbamate 384 is complete at —78 °C (equation 103), and the resulting vinyUithium 385 can be kept at this temperature without decomposition for several hours. Stannylation , silylation , methoxycarbonylation (with methyl chloroformate) ... 

The Sparteine Method 42 was applied successfully to generate chiral a-lithiated pyrrolidine when using the Boc-protected (tcrt-butoxycarbonyl)pyrrolidine and sec-butyllithium/sparteine as an asymmetric deprotonating agent in diethyl ether at — 78 °C. Alkylation, silylation, stanny-lation and methylation occurred with good yield (70-75%) and high selectivity (95% ee)53. 

S,)-4,5-Dihydro-4-isopropyl-2-piperidinooxazole (1), easily available from chiral (5)-2-ethoxy-4,5-dihydro-4-isopropyloxazole and piperidine, can be deprotonated quantitatively by sec-butyllithium/TMEDA in diethyl ether/THF to 2 as is evident from subsequent silylation in high yield to give 3 (R = TMS). Only one single diastereomer could be detected by capillary gas chromatography. The same result was found on alkylation of 2 with iodomethane as electrophile, but the yield of 3 (R = CH3) drops to 30% in this case59. 

The enantiomerically pure l-[(benzyl(dimethyl)silyl)methyl]pyrrolidine, obtained from ben-zyl(chloro)(dimethyl)silane and (5,)-2-(methoxymethyl)pyrrolidine , afforded after deprotonation and subsequent alkylation the diastereomerically pure (by NMR spectroscopy) (a-alkylben-zyl)silanes2. To obtain this high degree of diastereoselectivity, the alkylation had to be performed in the weakly complexing solvent diethyl ether. In THF a diastereomeric ratio of only 3 1 was found with iodomethane as alkylating agent. 

All prepared magnesium enolates 17 are stable in refluxing diethyl ether. Deuteriation, and reactions with various electrophiles confirm their structure (see section HI). It is noteworthy that the lithiated carbanion-enolate analogue, directly obtained by deprotonation of an a-ketoester 18 with lithiated bases (LDA, for example), is not stable and immediately degrades in the medium, whatever the temperature. Comparatively, the magnesium chelate 17 shows a higher stability, which allows its preparation and synthetic applications. 

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