Lithiation, also

Planar chiral compounds should also be accessible from the chiral pool. An example (with limited stereoselectivity) of such an approach is the formation of a ferrocene derivative from a -pinene-derived cyclopentadiene (see Sect. 4.3.1.3 [81]). A Cj-symmetric binuclear compound (although not strictly from the chiral pool, but obtained by resolution) has also been mentioned [86]. Another possibility should be to use the central chiral tertiary amines derived from menthone or pinene (see Sect. 4.3.1.3 [75, 76]) as starting materials for the lithiation reaction. In these compounds, the methyl group at the chiral carbon of iV,iV-dimethyl-l-ferrocenyl-ethylamine is replaced by bulky terpene moieties, e.g., the menthane system (Fig. 4-2 le). It was expected that the increase in steric bulk would also increase the enantioselectivity over the 96 4 ratio, as indicated by the results with the isopropyl substituent [118]. However, the opposite was observed almost all selectivity was lost, and lithiation also occurred in the position 3 and in the other ring [134]. Obviously, there exists a limit in bulkiness, where blocking of the 2-position prevents the chelate stabilization of the lithium by the lone pair of the nitrogen. 

The predominant y-metallation of f-butoxyallene with lithium dicyclohexyl-amide (LCHA) must be the consequence of a steric repulsion between the two bulky groups with ra-butyllithium a-deprotonation is the only reaction, while methoxyallem is lithiated also at the a-carbon atom by LCHA [98] ... 

Merour [137, 190, 191], Dormoy [86], Mahboobi [85], and Bisagni [76] have reported the selective C2-lithiation of various A -(phenylsulfonyl)azaindoles using LDA and -butyllithium. The following example with 5-azaindole 45 is illustrative (Scheme 7) [137]. With a 7-azaindole substrate, lithiation also occurred in the arylsulfonyl ring [190]. 

The lithiation of allene can also be carried out with ethyllithium or butyl-lithium in diethyl ether (prepared from the alkyl bromides), using THF as a cosolvent. The salt suspension which is initially present when the solution of alkyllithium is cooled to -50°C or lower has disappeared almost completely when the reaction between allene and alkyllithium is finished. 

A solution of 0.20 mol of butyl lithium in about 140 ml of hexane was cooled to -6Q°C and 140 ml of dry THF were added. The mixture was cooled to about -80 C (liquid nitrogen bath) and 0.23 mol of the allenic hydrocarbon (see Chapter VI, Exp. 1, 2, 44) was added in 5 min (methylal1ene was added as a 1 1 solution in THF). The solutions were kept for 1 h at -55°C. Into another 1-1 flask (see also Fig. 1, but without a dropping funnel), cooled at -90°C by immersion in liquid nitrogen, was poured a solution of dry carbon dioxide (from a cylinder) in 130 ml of dry THF. This solution was obtained by introducing about 40 g of carbon dioxide (note 1) into the THF at -90°C. The gas inlet was removed from the second flask and the solution of the lithiated allene (still cooled below -60 C) was poured... 

Propargylic alcohol, after lithiation, reacts with CO2 to generate the lithium carbonate 243, which undergoes oxypalladation. The reaction of allyl chloride yields the cyclic carbonate 244 and PdC. By this reaction hydroxy and allyl groups are introduced into the triple bond to give the o-allyl ketone 245[129]. Also the formation of 248 from the keto alkyne 246 with CO2 via in situ formation of the carbonate 247 is catalyzed by Pd(0)[130]. 

Lithiation at C2 can also be the starting point for 2-arylatioii or vinylation. The lithiated indoles can be converted to stannanes or zinc reagents which can undergo Pd-catalysed coupling with aryl, vinyl, benzyl and allyl halides or sulfonates. The mechanism of the coupling reaction involves formation of a disubstituted palladium intermediate by a combination of ligand exchange and oxidative addition. Phosphine catalysts and salts are often important reaction components. 

Carbocyclic substitution can also be achieved by first introdueing a reactive organomelallic substituent. Preparation of organolithium reagents can be done by one of the conventional melhods. especially halogen-metal exchange or directed lithiation. Table 14.2 gives examples. 

Each of these intermediates can be hthiated in the 2-position in good yield. The reactivity toward hthiation is due to the inductive effect of the nitrogen atom and coordination by oxygen from the N-substituent. A wide variety of electrophiles can then carry out substitution at the 2-position. Lithiation at other positions on the ring can be achieved by halogen—metal exchange 3-hthio and 5-hthioindoles have also been used as reactive intermediates. 

The second step is also heterogeneous and involves the breakdown of the intermediate compound with further lithiation into lithium sulfide [12136-58-2] and finely divided iron [7439-89-6] particles. 

Other large monocarbaboranes include /<7( -6-(NR3)-6-CB2H [f/oj o-l-CB H J [38192-43-7] and closo-C ]H. ][ [39102-46-0]. The closo monocarbaboranes can be functionalized at carbon via lithiation using reagents such as -butyl lithium in a manner similar to the dicarbaboranes. The small monocarbaboranes /oj o-l-CB H [25301-90-0], nido-2-C [12385-35-2], and a variety of their alkylated derivatives are also known (127,128). 

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... 

Benzisothiazole is lithiated at the 3-position, which corresponds to the 5-position in the mononuclear series (75JHC877). 4-Methylisothiazole forms the 5-lithio derivative, but the presence of by-products produced in subsequent reactions suggests the possibility of lithi-ation at the 3-position also (72AHC(14)l). 3-Substituted 1,2-benzisothiazoles suffer attack at sulfur and cleavage of the N—S bond (72AHC(14)43, 73SST(2)556). 

Commonly employed anion-stabilizing groups are those containing silicon (Table 5.4, Entries 1-5). Magnus et al. reported that epoxysilane 147 could be deproto-nated with t-BuLi, and that the lithiated epoxide 148 thus generated could be trapped with allyl bromide to give epoxysilane 149 in a synthetically useful yield (Scheme 5.34) [55], Iodomethane (88%) and chlorotrimethylsilane (60%) could also be trapped. 

Molander and Mautner demonstrated that deprotonation of cis-a, 3-epoxysilane 150 with s-BuLi/TMEDA was complete in 10 minutes, whereas the corresponding trows-isomer 150 required 4 hours [56]. Similarly, treatment with butyraldehyde was more efficient with cis-151 (Scheme 5.35), which could also be trapped with a wide variety of other carbonyl-containing electrophiles. The results demonstrated that lithiated epoxides cis- and trons-151 were configurationally stable at -116 °C for periods of up to 4 hours. Only in the case of cis-151 (t-butyl = n-octyl) was the lithiated epoxysilane found to be configurationally unstable. 

Florio and coworkers have also reported the use of oxazolinyl groups as anion-stabilizing substituents. Lithiation/electrophile trapping of oxazolinylepoxide 202 provided access to acyloxiranes 205 [72], while deprotonation/electrophile trapping of oxazolinylepoxide 206 with nitrones gave access to enantiopure a-epoxy- 3-amino acids 208 (Scheme 5.48) [73],... 

As well as for metalated epoxides, the trifluoromethyl moiety also proved an effective organyl-stabilizing group for metalated aziridines. Lithiated aziridine 241 reacted stereoselectively with carbonyl-containing electrophiles, and phenyl disulfide and chlorotrimethylsilane were also trapped in good yield (Scheme 5.60) [70b, 85],... 

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