Ortho lithiation conversion

For conversion of functionalized diorganozincs into tertiary amines, aromatic compounds which contain a directed metallation group, such as Af,Af-dialkylbenzamides, methoxymethyl phenyl ether, phenyl oxazolines and phenyl Af,Af-dialkylcarbamates, were ortho-lithiated, transmetallated and then aminated with 2a in good yields, but with a slower reaction rate (Scheme 19). 

A route in which a synthon for such a dialdehyde is central depends on ortho lithiation of an aryl bromide for conversion to ortho bromoaryl aldehyde, then palladium-catalysed replacement of the halide with an alkyne, subsequent reaction with ammonia producing the isoquinoline. The sequence below shows how this type of approach can be used to produce naphthyridine mono-A-oxides by reaction of the alkynyl-aldehyde with hydroxylamine instead of ammonia. 

The starting point for the metallation sequence was /7-chlorophenol, whose directing power was first maximised by conversion to the carbamate 3. Ortholithiation and reaction with N,N-diethylcarbamoyl chloride gave the amide 4. The second ortho carbonyl substituent was then introduced simply by allowing the lithiated carbamate 5 to undergo an anionic ortho-Fries rearrangement to the bis-amide 6. The phenol was protected as its methyl ether 7. 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

Lithiation at a thiophene P-position, in the presence of a free a-position, can be achieved with the assistance of an ort/to-directing substituent at C-2. Thiophene-2-carboxylic acid lithiates at C-3, via ortho assistance, using n-butylhthium, but at C-5 using lithium diispropylamide. 3-(Hydroxyalkyl)thiophenes, again with orthx) assistance, are lithiated at C-2. The lithiation of 2-chloro-5-methoxythiophene at C-4 and C-3, in a ratio of 2 1, is instructive, as is the deprotonation of 2- and 3-bromothiophenes at 5- and 2-positions, respectively, with lithium diisopropylamide. The conversion of 3-isopropylthiophene into the 2-aldehyde by Vilsmeier formylation, but into the 5-aldehyde via lithiation, presents a nice contrast. Lithiation of 3-hexyloxythiophene can be carried out with thermodynamic control at C-2 using n-butyllithium and with kinetic control using lithium diisopropylamide at C-5. ... 

In another variant of the Niementowski reaction, it was found that this transformation can be carried out under relatively mild, base-catalyzed conditions. Since a variety of substituted anthranilamides (29) can be prepared by a regiospecific ortho metalation-amination sequence, this method appears to be a very versatile modification of the Niementowski quinoline synthesis. Lithiation of 28 with 5-butyllithium was followed by treatment with tosyl azide. Reduction of the azide with sodium borohydride under phase transfer conditions furnished 29. After conversion of 29 into the corresponding imine 30, treatment of 30 with LDA afforded 31 in good yield. 

---