Carbolithiation reactions

Scheme 18 Synthesis of (-)-l through carbolithiation reaction. Reagents and conditions (a) Ti(OEt)4, XcOH, 0.1 torr, 75 °C, 1 h, 65% (b) n-BusR PhSeSePh, H2O, CH3CN, 0 °C, 1 h, 83% (c) MeLi, cumene/THF (d) C13H27CHO, HMPA, CH2CI2, -78 °C, 62% (two steps) (e) NiCb, NaBH4, THF/MeOH, 91% (117a/117b=3.5 l) (f) K2CO3, MeOH, rt, 82%...

When butyllithium was added to thioethyl-substituted enyne, a carbolithiation reaction occurs to give the allenyllithium species, which may further react with allylzinc (equation 42). This reaction affords thioalkyl-substituted gem-dimetal66. 

Due to its high ionic character, the carbon-lithium bond is very reactive and adds under mild conditions to ethylene or dienes and under more severe conditions to other alkenes. Some functionalized alkenes can be used, and high regio- and stereo-selectivity is usually observed in these carbolithiation reactions, especially if a precoordination of the lithium organometallic with the alkene is possible. Intramolecular carbolithiations of alkenes proceed under mild conditions and allow the preparation of several stereochemically well defined mono- and bi-cyclic compounds. Alkynes are too reactive, and can lead, with organolithium derivatives, to several side reactions, and seldom afford the desired carbolithiated product in good yield. 

An effective and general method for the synthesis of 2,3-dihydrobenzofuran derivatives has been developed via an intramolecular carbolithiation reaction of o-lithioaryl ethers (Scheme 16).89 This process was the first example in which the carbolithiation reaction has been stopped at the 2,3-dihydrobenzofuran stage by appropriate selection of the ether moiety. 

Scheme 3 Synthesis of dimethylamino-functionalised titanocenes from the carbolithiation reaction of 6-/V,/V-dimcthylamino fulvene and aryl lithium species...

Unfortunately, the carbolithiation reaction of lithium species with 6-/V, /V-dimethylamino fulvene and subsequent transmetallation reaction leads to titano-cenes with stereoisomers, as an equimolar mixture of the R and S form of the substituted lithium cyclopentadienide is formed. Subsequently, this equimolar mixture of R and S configured substituted lithium cyclopentadienide is used for the transmetallation reaction and therefore, a mixture of the 25% of RJt, 25% of the S,S and 50% of the R.S form of the chiral titanocene dichloride is obtained. 

In order to avoid the presence of stereoisomers, a further pathway including a carbolithiation reaction delivering achiral titanocene dichlorides was explored. Different aryl or heteroaryl lithium species were reacted with 6-bis-/V,/V-di methyl -amino fulvene and therefore, the intermediate lithium cyclopentadienide and the resulting 6-bis-/V./V-dimethylamino-functionalised titanocene dichlorides become achiral. 

Within this review we describe a second reaction pathway, which includes a carbolithiation reaction and leads to achiral-substituted titanocene dichlorides also. Therefore, aryl lithium species are added to the identical substituted 6-aryl fulvenes. This leads to the formation of highly substituted, but achiral diarylmethyl-functionalised lithium cyclopentadienides as seen in Scheme 5, which can still be used in the transmetallation reaction with titanium tetrachloride. 

The carbolithiation reaction followed by additions of various reagents usually renders a mixture of open-chain and cyclic products, as observed in the conventional Barbier reaction122. Nevertheless, Yus and coworkers40 found that when the alkene is substituted by aromatic moieties, only the cyclization reaction takes place (Schemes 59 and 60). They have previously found that the use of an excess of lithium powder and a catalytic amount of an arene (4,4 -di-tert-butylbiphenyl, DTBB, is most commonly used) is an adequate procedure to carry out chlorine-lithium exchange under very mild reaction conditions123. 

On the other hand, alkenyl aryllithiums can undergo diastereoselective cyclizations in very good yields. Pedrosa and coworkers163 reported that chiral 2-(o-bromophenyl)-substitutedperhydro-l,3-benzooxazines 281, initially transformed to the aryllithium derivative, gave the intramolecular 6-exo carbolithiation reaction with unactivated double bonds attached to the nitrogen substituent of the heterocycle (Scheme 87). By adding 2 equivalents of TMEDA to the aryllithium derivative 1,3-benzooxazines 281 prepared at —90 °C,... 

The carbolithiation of unactivated alkenes has also proven very successful for the synthesis of complex polycyclic systems. This has typically been achieved by reaction sequences utilizing an intramolecular carbolithiation process to generate a variety of carbocycles185 and heterocycles186. To achieve the intermolecular carbolithiation reaction required to initiate a controlled cascade reaction sequence for the generation of indole ring scaffold, Kessler and coworkers44 have expanded the synthetic utility of the styrene... 

The first vinyllithium carbolithiation reaction was reported by Chamberlin and Bloom15, who showed that Shapiro-derived organolithium 10 cyclized onto a terminal alkene giving stereoselectively (>50 1) bicyclic compounds 11, after treatment with electrophiles (Scheme 4). The intermediate alkyllithiums 12 are generated via a 5-exo-trig cyclization reaction from 10, which undergo the carbolithiation reaction at approximately the same rate as reported by Bailey for the simple parent compound 5-hexenylIithium, i.e. with a half-life of a few minutes at 0 °C. 

Although all these carbolithiation reactions are thermodynamically favourable processes since they produce a carbon-carbon a-bond (bond energy ca 88 kcal mol 1 ... 

The kinetics of the cyclization reaction of 5-hexynyllithiums 19 was also studied showing that (6-phenyl-5-hexynyl)lithium (19, R = Ph) has a half-life of ca 6 min at —50.6 °C, whereas cyclization reaction of 5-decynyllithium (19, R = Bu) is some 106 times slower. The rather dramatic increase in the rate of cyclization on going from an alkyl-substituted 5-hexyn-l-yllithium to a phenyl-substituted substrate is most likely a consequence of a reduction in A// due to stabilization of the incipient vinyllithium product by the phenyl group19. It is also interesting to note that the 5-exo-dig cyclization reaction of 19 (R = Bu) is slower than the corresponding 5-exo-trig carbolithiation reaction of 5-hexenyllithium. 

One general aspect to consider about intramolecular carbolithiation reactions is the fact that the isomerizations of unsaturated organolithiums could, in principle, proceed via... 

Chamberlin and coworkers proposed a similar chair-like transition state 29 to account for the stereoselectivity of the carbolithiation reaction of vinyllithium 10 to 1224. The observed diastereoselectivity is consistent with a four-centre transition state where a preferred coplanar approach of the carbon-lithium bond to the double bond would give the obtained major product (Scheme 8). 

Control of absolute stereoselectivity in the intramolecular carbolithiation reactions is not a completely solved subject and several approaches have been used ... 

Without careful design of the starting material it is not usually possible to form three-and four-membered rings by intramolecular carbolithiation reaction onto carbon-carbon... 

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