Carboxylates directed lithiation

The metalation of phenoxazine has also been investigated, but in contrast to phenothiazine, direct lithiation at C-l can only be achieved in very low yield (58JA2195 68JMC807). Fortunately, however, the carboxylate protection method is just as efficient as that with phenothiazine, and the... 

Particularly powerful synthetically is the ability of two m ta-disposed methoxy groups jointly to direct lithiation to the position between them.234 235 Lithiation and carboxylation of 1,3-dimethoxybenzene, for example, is a key step in the synthesis of methicillin.91... 

Directed lithiations. Arylboronic acids containing an o-carboxyl group are prepared from the corresponding neopentyl esters via directed lithiation and boration. Chiral o-hydroxyaryl phosphine oxides which are potential chiral ligands are obtained from a... 

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. ... 

Whereas the repeated lithiation-trimethylsilylation sequence of trimethyl-silylbicyclopropylidene 43 a yielded predominantly the cyclopropene derivative 51 [54], bicyclopropylidenecarboxylates 42-Me, 42-fBu after repeated deprotonation and carboxylation retain the bicyclopropylidene moiety and give 2,2-disubstituted products 52-R only (Scheme 9) [55]. So far, alkylbicyclopropyl-idenes 43 e, f, g have not been induced to undergo deprotonation and a second substitution [56a]. The urethane 53 with a nitrogen directly attached to the skeleton, more easily than any other bicyclopropylidene derivative, rearranges to... 

More powerful directing groups such as those based on amides and sulphonamides are successful with pyridines as with carboxylic rings, and will not be discussed separately. The enhanced acidity of pyridine ring protons makes the simple carboxylate substituent an ideal director of lithiation in pyridine systems . The pyridinecarboxylic acids 232-234 are deprotonated with BuLi and then lithiated with an excess of LiTMP all the substitution patterns are lithiated nicotinic acid 233 is lithiated in the 4-position (Scheme 113). The method provides a valuable way of introducing substituents into the picolinic, nicotinic and isonicotinic acid series. 

Methoxymethyl protection of the indole NH group has also been investigated in conjunction with lithio directing 2-substituents, and compounds successfully lithiated at the 3-position have included the 2-carboxylic acid [89H(29)1661], and the related diethylcarboxamide (Scheme 23) (90PAC2047). 

The addition of carbonylated electrophiles to the 2-lithio derivative of 4-oxazolinyloxazole 132 allowed the efficient preparation of 5-phenyloxazoles 134 bearing a variety of hydroxyalkyl groups at C-2 position and a carboxyl (or formyl) function at C-4. This protocol suppresses the troublesome electrocyclic ring-opening reaction and allows access to the target compounds by simple chemical transformation of the oxazoline moiety of 133 <02JOC3601>. A direct chemoselective C-2 silylation of oxazoles was performed by treatment of the lithiated parent compounds with silyl triflates <02TL935>. 

Direct introduction of a carboxyl group can be achieved via the Grignard reagent or lithiated imidazole (see Section 7.2.2). This approach is especially valid for making 2-carboxylic acids, but 4- and/or 5-carboxylation is possible when C-2 is blocked (see Scheme 7.2.2), and if the differential reactivities of anions at these positions are utilized by careful control of reaction conditions. An example has been included in Section 7.2.2, and many others are listed in Iddon and Ngochindo s recent review [2]. 

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