Intramolecular carbolithiation

A novel approach to 3-substituted indolines and indoles via the anionic cyclization of 2-bromo-lV,lV-diallyanilines has been developed simultaneously by Bailey <96JOC2596> and Liebeskind <96JOC2594>. Thus, treatment of 2-bromo-lV,lV-diallylanilines 78 with 2 equivalents of BuLi at -78 °C leads to the formation of the intermediate 79 which may be trapped with an electrophile to afford 3-substituted indolines 80. Aside from ease of preparation, an additional benefit of the intramolecular carbolithiation of <7-lithio-W,Al-diallyl-anilines is the production of Al-allyl-protected indolines, which are easily deprotected using... 

Scheme 2.121. General principle of inter-/intramolecular domino carbolithiations.

Methods for the enantioselective synthesis of 3-substituted indolines by means of the asymmetric intramolecular carbolithiation of 2-bromo-A,-allylanilines in the presence of (-)-sparteine were reported simultaneously by Bailey <00JA6787> and Groth <00JA6789>. Thus, addition of 89 to 2.2 equiv of /BuLi in the presence of the chiral ligand generates the lithium intermediate 90 which upon quenching with methanol affords the chiral indoline 91 in a process that is highly solvent dependent. 

The intramolecular carbolithiation of 6-lithio-l-hexene (9) was studied after lithiation of 6-chloro-l-hexene (8) in the presence of a catalytic amount of DTBB (5%). At —78 °C the corresponding organolithium compound 9 is stable, giving the expected products 10 by reaction with different electrophiles. However, when the lithiation step was carried out at — 30 °C a cyclization reaction took place, so that a new organolithium intermediate 11 was formed, which reacted with the same electrophiles to give cyclic products 12 (Scheme 5). ... 

An interesting chain elongation of 4-oxo-l-tributylstannylbutyl carbamate 83 by ethynyl A,A-diisopropyl carbamate (82) to the dicarbamate 84 and the subsequent intramolecular carbolithiation to form the alkenyllithium 86 has been reported very recently (equation 18). 86 was trapped by electrophiles to yield—as expected—both epimers 87 and 88 in essentially equal amounts. From an X-ray analysis of a derivative, the shown absolute configuration and the ( )-stereochemistiy at the double bond was concluded. Thus, the attack at the triple bond here took place in the anti fashion, which is quite unusual. We suggest that a lithium cation in 85, captured by the second carbamoyl group, catalyses the anti addition. ... 

An efficient kinetic resolution was also observed during the (—)-sparteine-mediated deprotonation of the piperidin-2-yhnethyl carbamate rac-112 (equation 25). By treatment of rac-112 with s-BuLi/(—)-sparteine (11), the pro-S proton in (/ )-112 is removed preferentially to form the lithium compound 113, which undergoes intramolecular cyclo-carbolithiation, and the indolizidinyl-benzyllithium intermediate 114 was trapped with several electrophiles. The mismatched combination in the deprotonation of (5 )-112, leading to cp/-113, does not significantly contribute to product formation. Under optimized conditions [0.75 equivalents of s-BuLi, 0.8 equivalents of (—)-sparteine, 22 h at —78°C in diethyl ether] the indolizidine 115 was isolated with 34% yield (based on rac-112), d.r. = 98 2, e.r. = 97 3 optically active (5 )-112 was recovered (46%, 63% ee). 

In order to avoid polymerization and to achieve better stereocontrol by quasi-intramolecular addition, a carbanion-stabilizing group and a complexing substituent for capturing alkyllithium/(—)-sparteine in the substrate are useful. This carbolithiation protocol was realized with great success by Marek, Normant and coworkers (equation 125) Addition of n-BuLi/(—)-sparteine (11) onto the lithium alcoholate derived from ( )-cinnamyl alcohol (457) in cumene at 0°C afforded the addition product with 82% yield and 80% ee. 

Other examples of intramolecularly coordinated (by 0 as well as by N groups) organolithium compounds can be found in Setzer and Schleyer (2) and Seebach (4). Two recent reviews are also pertinent. Klumpp (34) deals with 0- and N-assisted lithiation and carbolithiation of nonaromatic compounds, and Snieckus (34a) deals with directed (by amide and carbamate groups) ortho metalation in polysubstituted aromatics. 

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. 

Scheme 16). This regioisomer is also obtained in appreciable amounts if bulky lithium organometallies are used. Intramolecular carbolithiations have been reported, such as the cyclization of 5-alkynyl-lithium compounds to furnish the cyclized products in low yields.3... 

Carbocyclization of m-alkcnyl-z-methoxybcnzy I lithiums to form five- or six-membered rings has been studied 101 the five-membered ring is formed with a cis-stereochemical relationship between the methoxy substituent and the adjacent methyl group. Intramolecular carbolithiation of vinyl sulfides at — 105°C in THF has been found to occur non-stereospecifically with regard to the newly formed C—Li centre.102. The stereochemistry of selective tandem Michael addition alkylation reactions of vinylphosphonates has been explored.103... 

Hoppe, D. Woltering, M. J. Oestreich, M. Frohlich, R. (-)-Sparteine-mediated asymmetric intramolecular carbolithiation of alkenes synthesis of enantiopure cyclopentanes with three consecutive stereogenic centers. Helv. Chim. Acta 1999, 82, 1860-1877. 

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. 

The addition of organolithiums to polarised C=X bonds is one of the most widely used ways of making C-C bonds, and (excepting some unusual intramolecular cases) will not be discussed in this book other than to say it is a reliable and successful reaction. With a few exceptions,1 3 stereoselectivity is not a general feature of organolithium addition reactions to C=0 n bonds. Much of this chapter will concern controlled addition of organolithiums to C=C 7i bonds after an overview of carbolithiation, we shall review the development of intramolecular carbolithiation, or anionic cyclisation. 

The fulvene 145 offered the opportunity for a sequential inter-intramolecular carbolithiation the intermediate cyclopentadienyllithium 146 undergoes 3-exo cyclisation to give 147, a precursor to longifolene.71... 

The carbolithiation of alkenes and alkynes is a useful transformation for the generation of a new carbon—carbon bond, specially when the alkenes and alkynes are activated by conjugation to carbonyl and related electron-withdrawing groups. Similarly to the intramolecular carbolithiation, it is possible to carry out this reaction with high diastere-o selectivity. 

It is presumed that the initial step for the intermolecular as well as intramolecular carbolithiation is an energetically favorable coordination of the lithium atom with the n-system, which serves to establish the geometry of the system prior to addition. The chiral benzylic organolithium compound 45, obtained after the carbolithiation step, reacted diastereoselectively with a number of electrophiles, yielding a formal inversion of the configuration. 

Major advances have been made in the intermolecular carbolithiation of unactivated alkenes (such as 128) and alkynes in recent years. Wei and Taylor designed a tandem intermolecular-intramolecular carbolithiation sequence, giving rise to cyclic products, 129 (Scheme 42), using organolithium reagents as difunctional reagents106. 

The first stereoselective intramolecular carbolithiation of alkynes was recently achieved by Hoppe and coworkers109. Several 4-functionalized 5-hexynyl carbamates, e.g. (5-145), were efficiently cyclized in the presence of the chiral base (—)sparteine, to 146Z, providing... 

The enantioselective metalation at the a-position of a carbamate in the presence of (—)-sparteine followed by a diastereoselective intramolecular carbolithiation onto a double120 or triple bond121 was recently studied. The precursor 185 was deprotonated with s-BuLi/(—(-sparteine in Et20 at — 78 °C, the reaction mixture was stirred for 20 to 30 h at this temperature and the electrophilic reagent was subsequently added (Scheme 57)60. 

For 6-chloro-2-phenylhex-l-ene, 197, the DTBB-catalyzed lithiation, even at — 78 °C, gives the cyclic intermediate 198 (probably formed by an intramolecular carbolithiation), which by reaction with some electrophiles afforded, after hydrolysis, the corresponding products 199 (Scheme 59). The conversion is total after about 1 h the rest of the starting material is transformed into a mixture of compounds, among them the reduced product... 

The intramolecular carbolithiation of carbon—carbon double bonds is an interesting route to functionalized carbocyclic and heterocyclic systems that has been developed in the past years and widely used in organic synthesis. In this context, aryllithiums have been described to carbometalate double bonds allowing the preparation of indanes,... 

Carbon—carbon bond formation by an intramolecular carbolithiation (anionic cycliza-tion) reaction to give heterocyclic systems has been gaining increasing use in organic... 

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,... 

Bis(2-lithioallyl)amines 297, a class of non-conjugated dilithio reagents which were formed from 296, were reported by Barluenga and coworkers to react with carboxylic esters affording cyclic alcohols 299 after hydrolysis (Scheme 91)169. A dilithiated dihydropyrrol 298 was generated from 297 via intramolecular carbolithiation of a lithiated double bond and served as the key intermediate. 

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... 

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