Amides directed lithiation

These efforts began with directed lithiation [53] of commercially available 4-methoxybenzaldehyde dimethyl acetal (117, Scheme 1.12), followed by quenching with amide 118 to produce chloro acetophenone 119 (52 %). Conversion... 

Amides of aminopyridines have also been widely used to direct lithiation, and are most effective when lithiated with BuLi in the absence of TMEDA (Scheme 38) . The lithiation of 80 can be used as a key step in the synthesis of naphthyridines and other condensed polycyclic heterocycles" . 

No heterocycle containing a C=N bond is as powerful a director as the oxazolines or tetrazoles described above, but their imidazoline analogues 132 direct well if deprotonated to the amidine equivalent 133 of a secondary amide anion (Scheme 61). Pyrazoles 134 also direct lithiation, but need protecting with a bulky Af-substituent to prevent nucleophilic attack by the base (Scheme 62). ... 

The most popular method for generation of a-thio-carbanion (migration terminus) is direct lithiation (deprotonation) with alkyllithium or lithium amide. These deprotonation methods are widely applicable to various substrates, not only benzyl or allyl sulfides , but also dithioacetals 142 which form 143 (equation 83), and a phosphonate substituted system 144 which gives 145 (equation 84). ... 

The mechanism of directed lithiation appears to involve an association between the amide substituent and the lithiating agent.50... 

Thiophene is sufficiently acidic to be directly metallated upon treatment with n-BuLi (see Figure 4.1). This direct lithiation can also be realized with polystyrene-bound 3-(alkoxymethyl)thiophene [96]. The resulting organolithium compounds react as expected with several electrophiles, such as amides (to yield ketones), alkyl halides, aldehydes, and Me3SiCl [96]. 

Phenanthrols via directed lithiation.1 Biphenyl diethyl amides substituted by a 2 -methyl group (1), prepared by cross coupling of arylboronic acids and aryl bromides,2 undergo directed lithiation to provide 9-phenanthrols. 

Rather more details about the mechanism of a-lithiation are known than about many other lithiations, and the sequence of events in the lithiation of 1 have been used as a model for directed lithiations in general. Stopped flow infra-red studies show that a complex between the amide and the organolithium forms much faster than the amide is lithiated.2 3 This complex, presumably approximating to 2, is believed to represent the first step in the lithiation sequence. The kinetics of the reaction are consistent with a deprotonation within the complex to give the organolithium 3.2>3... 

Snieckus and coworkers used the combination of a tertiary amide with a methylenedioxy groiq) to direct lithiation to the ortho position, and then converted the lithiated inteimediate to the 2-hydroxybenz-amide (25), which was used as a starting material for the synthesis of acridones (Scheme 10). 

The directed metalation of aromatic systems that was discussed in Section 2.1.3.3 has one ramification that was not mentioned there the directed lithiation of an o-methyl group. Although the resultant species is formally a resonance-stabilized anion, and therefore covered in Volume 2 of this series, we mention it here for consistency with the other topics covered. In particular, the examples that have appeared in recent years involve substrates having a methyl ortho to a tertiary amide. Intentional use of such a directed lithiation has been used in the synthesis of the isocoumarin natural products hydrangenol and pyllodul-cin.137,138 Interestingly, the directed metalation of 5-methyl-oxazoles and -thiazoles occurs in preference to deprotonation at a 2-methyl group (azaenolate) (Scheme 33). ... 

Directed lithiations of a,3- and -y.b-unsaturated amides " have been extensively studied. Illustrative examples are shown in Scheme 44. Prior complexation of the alkyllithium base with the amide carbonyl oxygen directs the base to the thermodynamically less acidic -position in a,3-unsaturated amide (31), which adds to benzophenone and subsequently lactonizes. Analysis of the NMR spectrum reveals that the organolithium added the benzophenone in the equatorial position. A Afferent kinetic deprotonation is seen in y,8-unsaturated amide (32), where -lithiation to form an allylic anion predominates over a-lithiadon to form an enolate. > Addition of the lithium anion to acetone affords poor regioselectivity, but transmetalation to magnesium before carbonyl addition yields a species which adds exclusively at the 8-position. ... 

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. 

Beak, P., Snieckus, V. Directed lithiation of aromatic tertiary amides an evolving synthetic methodology for polysubstituted aromatics. Acc. Chem. Res. 1982,15, 306-312. 

A full report has appeared on the direct lithiation of NN-di-isopropylformamide by t-butyl-lithium and the use of the acyl carbanion thus obtained in the synthesis of a-keto-amides. The lithium enolate of NN-dimethylacetamide has been isolated for the first time, as a white solid, and has been shown to react well with a usual range of electrophiles. A Canadian group have also discussed the synthesis and reactions of such enolates, in particular their behaviour with ketones from which 70% yields of jS-hydroxyamides can routinely be obtained. " These enolates when generated as in the above methods, using lithium di-isopropylamide, also afford good yields of a-(methylthio)-amides when treated with dimethyl disulphide, in contrast to when sodium in liquid ammonia is used as base, which results in polysulphenylation of the amide. ... 

Ortiz [47] recently described the ortho-directed lithiation of R,R-diphenylami-nophosphazenes 64 followed by electrophilic quenching as an efficient process for the preparation of / -chiral ort/io-functionahzed P-chirogenic amidophosphinates 65 in good yields and diastereoselectivities. The usefulness of the method was shown with the preparation under mild reaction conditions of a variety of functionalized P-chiral compounds 66 in high yield and excellent stereoselectivity, including phosphinic esters, amides, thioamides, phosphine oxides, and (2-aminophenyl)phosphine boranes (Scheme 21). 

Direct lithiation of a-methoxyacrylic acid (or derived secondary amides) using Bu Li produces the vinyl-lithium species (355) which condenses with aliphatic aldehydes to give... 

P. Beak and V. Snieckus, Directed Lithiation of Aromatic Tertiary Amides An Evolving Synthetic Methodology for Polysubstituted Aromatics , Acc. Chem. Res., 1982, 15, 306. 

Use of LTMP as base [52] in situ with Me3SiCl allows straightforward access to a variety of synthetically useful a, 3-epoxysilanes 232 at near ambient temperature directly from (enantiopure) terminal epoxides 231 (Scheme 5.55) [81]. This reaction relies on the fact that the hindered lithium amide LTMP is compatible with Me3SiCl under the reaction conditions and that the electrophile trapping of the nonstabilized lithiated epoxide intermediate must be very rapid, since the latter are usually thermally very labile. 

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