Furan directed lithiation

Snieckus and co-workers reported the directed lithiation of 3-furanecarboxylic acid diethylamide (6.21.), which proceeded selectively in the 2-position, and the subsequent zinc-lithium exchange. The so formed fiiranylzinc reagent underwent Negishi-coupling with 2-bromotoluene in the presence of a palladium-triphenylphosphine catalyst to give 2-(o-tolyl)furane in good yield.26... 

Although a limited range of Grignard reagents is available, the most widely used group is undoubtedly the lithio group introduced by direct lithiation (see Section 3.3.1.6.2). The ready formation of the lithio derivatives of pyrroles, furans and thiophenes and their benzo-fused derivatives has had a most important impact on the chemistry of these heterocyclic systems. Reaction of the... 

Directed lithiations of alkoxy furans have potential in the synthesis of butenolides, and the tetramethyldiamidophosphate moiety has been successfully used to prepare 3-substituted furans (22). Acidic cleavage of the phosphorus residue then allows access to the corresponding 2-substituted butenolide (23), and the overall process becomes equivalent to using the anion (24) (Scheme 8). 

Proton abstraction and electrophilic quench provides a method for the function-alizahon of heteroaromahc compounds. The hve-membered heterocycles fiaran and thiophen are deprotonated easily with n-butyhithium at the 2-position. The resulhng 2-hthiofuran or 2-lithiothiophen react with electrophiles such as carbonyl compounds or primary alkyl halides. For example, furan and thiophen have been converted to the 2-substituted derivatives 131 and 132 using such directed lithiation chemistry (1.122). 

Directive effects on lithiation have also been studied. The regiospecific /3-metallation of A-methylpyrrole derivatives and 2-substituted furans has been effected by employing the directive effect of the oxazolino group (82JCs(Pl)1343). 2-Substituted furans and thiophenes are metallated in the 5-position. The formation of 2-lithio-3-bromofuran on treatment of... 

Direct metallation of 2-substituted furan can be realized when 2-furancarboxamide is allowed to react with f-BuLi in the presence of TMEDA. Treatment of the lithiated 2-furancarboxyamide with acetaldehyde provides the corresponding 2,3-disubstituted furan in 52% yield <00SL1788>. 3-TrialkyIsilyl-2-furancarboxamide can also be afforded in high yield if 2-... 

In many ways, the electron-rich five-membered aromatic heterocycles behave very much like carbocyclic aromatic compounds when it comes to lithiation. Lithiation a to O or S of furan and thiophene is straightforward (Scheme 130) . The usual selection of orf/io-directing groups allows lithiation at other positions and some examples... 

Electron-rich heterocycles, snch as pyrrole and furan, bear more resemblance to car-bocyclic rings their side chains are mnch less acidic, and undergo lateral lithiation mnch less readily. Without a second directing group, methyl groups only at the 2-position of fnran, pyrrole or thiophene may be deprotonated. 

Lithiation of thiazolo[5,4-b]pyridine-N-oxides (503) by n-butyllithium at -65°C is selectively directed by the pyridine N-oxide moiety, whereas lithiation of the parent heterocycle by LDA at -78°C exclusively occurs at the C-4 position (89TL183). Interestingly, no metalation of the furan ring occurred (Scheme 152). 

Directive effects on lithiation have also been studied. The regiospecific (3-metallation of N-methylpyrrole derivatives and 2-substituted furans has been effected by employing the directive effect... 

A flexible means of access to functionalized supports for solid-phase synthesis is based on metallated, cross-linked polystyrene, which reacts smoothly with a wide range of electrophiles. Cross-linked polystyrene can be lithiated directly by treatment with n-butyllithium and TMEDA in cyclohexane at 60-70 °C [1-3] to yield a product containing mainly meta- and para-Iithiated phenyl groups [4], Metallation of noncross-linked polystyrene with potassium ferf-amylate/3-(lithiomethyl)heptane has also been reported [5], The latter type of base can, unlike butyllithium/TMEDA [6], also lead to benzylic metallation [7]. The C-Iithiation of more acidic arenes or heteroar-enes, such as imidazoles [8], thiophenes [9], and furans [9], has also been performed on insoluble supports (Figure 4.1). These reactions proceed, like those in solution, with high regioselectivity. 

The lithiation of 3-(A -/i t7-butoxycarbonylamino)furan occurred regioselectively at the 2-position as a result of the apparent ort o-directing effect of the NHBOC group, providing 2-substituted-3-aminofurans after subsequent reactions with electrophiles, as represented in Scheme 25 <2006SL789>. In contrast, the lithiation of Z-(N-tert-butoxycarbonylamino)furan took place exclusively at the 5-position instead of the 3-position <2003T5831>. 

The C-2 proton of benzo[/ ]furan 82 underwent regioselective metallation by treatment with -butyllithium to form 2-lithiated benzo[/ ]furan, which directly reacted with electrophiles, such as 1,4-cyclohexadienone to form 4-(ben-zo[/ ]furan-2-yl) -hydroxy-2,5-cyclohexadien-l-one in high yield, as shown in Equation (71) <2005TL7511>. 

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. 

One last word of warning with regard to a-lithiations. The benzofuran 158 has a methoxy group on the benzene ring and we might expect this to direct an ortfto-lithiation. It would be easy to overlook the a-lithiation of the furan ring this, in fact, happens instead. 

Lithiation of furans with non-directing groups at C-2 provides a route to 2,5-disubstituted furans, but appropriate choice of Uthiating conditions can outweigh ortho-directing effects, as illustrated. ... 

Lithiofuran, best obtained fj-om 3-bromofuran, reacts with bis(trimethylsilyl)-peroxide to provide the trimethylsilyl ether of 3-hydroxyfuran directly. Oxidation of a 2-boronate ester is a means for the synthesis of butenolides (section 15.13.1). Furan-2- and 3-boronic acids have been made by reaction of the lithiated species with tributylborate in the usual way. ... 

The temporary protection of furancarboxaldehydes as a device to direct metallation has been used in a number of different ways. Lithiation of the diethylacetal of furan-2-carboxaldehyde occurs... 

---