Methyl ethers, deprotonation

Geminal substituted dibromoalkenes can be prepared by the alkylation of dibromomethyllithium with a-chloroalkyl methyl ethers. Deprotonation of the alkylation products results in the elimination of methanol and the formation of the corresponding 1,1-dibromoalkenes. Despite the lower acidity of 1 -bromo-1 -chloroalkyllithiums relative to the dibromo analogs they exhibit similar nucleophilic proper-ties. Alkyl dichloroacetates can also be deprotonated with lithium diethylamide and alkylated with a range of alkyl halides. ... 

Another useful reagent for introduction of the carbonyl carbon is dichloromethyl methyl ether. In the presence of a hindered alkoxide base, it is deprotonated and acts as a nucleophile toward boron. Rearrangement then ensues with migration of two boron substituents. Oxidation gives a ketone. 

By careful optimization, Widdowson and coworkers were able to show that methoxy-methyl ethers of phenols are better substrates for alkyllithium-diamine controlled enan-tioselective deprotonation, and (—)-sparteine 362 is then also the best ligand among those surveyed the BuLi-(—)-sparteine complex deprotonates 447 to give, after electrophilic quench, compounds such as 449 in 58% yield and 92% ee (Scheme 180) . Deprotonation of the anisole complex 410 (see Scheme 169) under these conditions gave products of opposite absolute stereochemistry with poor ee. 

In general, however, particularly strong bases are required in order to bring about the deprotonation of alkyl ethers. Thus, the metalation of f-butyl methyl ether has been reported to be feasible by means of the Lochmann-Schlosser base (equation 29) a-lithiated tetrahydrofuran, however, undergoes a fragmentation to give ethene and lithium ethenoate . 

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

Tricarbonylchromium-complexed benzyl methyl ether was deprotonated using (eri-butvllithi-um and alkylated at the benzylic position without any Wittig rearrangement1. 

Recently, enantiomerically enriched 3-phenylalkanoic acid derivatives were prepared directly from a racemic dilithiated species obtained by double deprotonation of the A -m ethyl carboxamide with 2-3 equivalents of sec-butyllithium in THF/tm-butyl methyl ether (1 1) at — 78 °C after complexation with sparteine. Silylation or alkylation proceeded with good yields (77-86%) and enantioselectivity (80-94% ee)38. 

Deprotonation of the alkyloxonium ion leads to formation of tert-butyl methyl ether. 

Based on these reactivities various derivatives of carbenes, such as the aminocarbene 238, are prepared by displacement of the OR group in 237 with amine via addition elimination, analogous to transesterification [74,75], As an example the carbanion 240, generated by deprotonation of 239, attacks ethylene oxide to give the lactone equivalent 241, which is further alkylated by chloromethyl methyl ether, again at the -position. Finally the oc-methylene-y-lactone 242 is obtained by oxidative demetallation with a Ce(TV) salt [76],... 

The aldimine of Figure 13.34 is a chiral and enantiomerically pure aldehydrazone C. This hydrazone is obtained by condensation of the aldehyde to be alkylated, and an enantiomerically pure hydrazine A, the S-proline derivative iS-aminoprolinol methyl ether (SAMP). The hydrazone C derived from aldehyde A is called the SAMP hydrazone, and the entire reaction sequence of Figure 13.34 is the Enders SAMP alkylation. The reaction of the aldehydrazone C with LDA results in the chemoselective formation of an azaenolate D, as in the case of the analogous aldimine A of Figure 13.33. The C=C double bond of the azaenolate D is fraws-configured. This selectivity is reminiscent of the -preference in the deprotonation of sterically unhindered aliphatic ketones to ketone enolates and, in fact, the origin is the same both deprotonations occur via six-membered ring transition states with chair conformations. The transition state structure with the least steric interactions is preferred in both cases. It is the one that features the C atom in the /3-position of the C,H acid in the pseudo-equatorial orientation. 

Dimethylated cumulenyllithium 783 has been prepared by deprotonation of the corresponding cumulenyl methyl ether with n-BuLi in ether or THF at — 30 °C. These anions reacted with aldehydes and ketones to produce the corresponding adducts (55-90% yield)1097. However, due to the instability of these types of compounds, they have not been used in organic synthesis as acyllithium equivalents. 

Benzylic deprotonation is often an inefficient process. It may be more important than it would appear from the end products, however, since radical cation deprotonation followed by reduction of the radical and reprotonation may regenerate the starting material. This mechanism has been proposed to explain the inefficiency of some PET alkylations [68]. In suitable models such a process has been revealed, e.g. deuterium incorporation at the bis-benzylic position in 2-(4-methoxyphenyl)-2-phenylethyl methyl ether and cis-trans isomerization in 2-methoxy-l-(4-methoxyphenyl)indane (but not in the corresponding 3-methoxyphenyl derivatives) [204], as well as deconjugation of 1-phenylalkenes to 3-phenylalkenes in the presence of 1,4-dieyanobenzene, biphenyl (as a secondary donor) and a hindered pyridine as the base [205]. Deprotonation of N,N-dimethylaniline has likewise been observed (Scheme 38) [206-207],... 

Examples of benzylic alkylation, aromatic ring deprotonation, and nucleophilic addition to a -position were used in a synthesis of (+)-20-methoxy-serrulat-14-en-7,8-diol. Deprotonation of the optically active complex (54) followed by reaction with chloromethyl methyl ether affords (55)... 

In a preliminary study (284) on the photolysis of the t-butyl methyl ether-02 CT-complex some products have been identified and their quantum yields determined. They are peroxidic compounds (4i = 0.15), t-butyl formate (cj) = 0.21), t-butanol ((j> = 0.035), 2-methoxy-2-methylpropionaldehyde ( = 0.03), formaldehyde ((j> = 0.04), water (iji = 0.3), and carbon dioxide (cj) = 0.007). It was noted (284) that deprotonation of the t-butyl methyl ether radical cation, although it largely occurs at the methyl group next to the oxygen (product, t-butyl formate), is also possible at the 8-posltlon (product, 2-methoxy-2-methylpropionaldehyde). 

The total synthesis of the cembranoid diterpene (+)-crassin acetate methyl ether was accomplished by W.G. Dauben et al. In the final stages of the total synthesis, the sensitive a-methylene group was introduced onto the six-membered lactone by using the Eschenmoser methenylation procedure. The lactone was deprotonated with LDA and then treated with Eschenmoser s salt. In the second step, the dimethylamino group was exhaustively methylated and the quaternary ammonium salt underwent a smooth Hofmann elimination upon deprotonation with DBU. 

Unsymmetrical ketoximes or ketoxime methyl ethers undergo rapid deprotonation to give syn dianions or monoanions, which react regioselectively with electrophilic reagents. ° ° Axial alkylation is observed in conformationally rigid systems. Aldoximes can also be converted to their dianions and alkylated in high yields. ... 

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