Lithium 4,4-Di-t-butylbiphenylide1

[61217-61-6]  · C20H26Li  · Lithium 4,4-Di-t-butylbiphenylide  · (MW 273.40)

(reductive lithiations of thiophenyl ethers,11 carbonyl groups,23 phosphinates;25 generation of alkyllithiums,2 a-lithio ethers,3 allyllithiums,17,18 b-,g-,d-lithio alkoxides;19 propellane bond cleavage22)

Alternate Name: LDBB.

Solubility: sol THF

Preparative Methods: anhydrous THF and 4,4-di-t-butylbiphenyl (DBB) are cooled to 0 °C under a blanket of argon and stirred with a glass-coated stirring bar; Lithium foil (or ribbon) is added in portions and the mixture is stirred for 5 h at 0 °C; the appearance of the deep blue-green radical anion appears within 5 min.

Handling, Storage, and Precautions: LDBB will slowly decompose at room temperature.

Reductive Lithiation.

There are several advantages for using LDBB over the traditional Lithium Naphthalenide or Sodium Naphthalenide (LN, NaN). LDBB is a more powerful reducing agent than the alkali naphthalenides and the resulting carbanion will be trapped as an organolithium. The high steric environment of the t-butyl groups lead preferentially to electron transfer and to little or no radical combination. This is in contrast to LN, where alkylation of naphthalene is frequently observed. Another advantage is the ease in separation of nonvolatile DBB from the reaction mixture.2

LDBB has been used in place of Lithium 1-(Dimethylamino)naphthalenide (LDMAN), leading to slightly higher yields of the desired products or when reaction conditions dictate.3

Alkyllithiums.

The conversion of alkyl halides to alkyllithiums is highly effective with LDBB. The corresponding hydrocarbons can be formed in high yields upon the addition of H2O (eq 1).2

The alkyllithiums can be trapped by a variety of electrophiles including aldehydes (eq 2),4 carbon dioxide (eq 3)5 and aryl groups (eq 4).6 The use of LDBB to generate the organolithium in the latter example proved critical since other methods (n-Butyllithium, t-Butyllithium, s-Butyllithium, and Methyllithium) led to lower yields and longer reaction times. One possible reason for the enhancement in organolithium activity may be a result of lowered aggregation.6

The geminal dilithio species can also be generated and trapped with electrophiles in good yields (eqs 5 and 6).7

The generation of alkyllithium (1) proved pivotal in the enantioselective synthesis of spiculisporic acid.8 Derived from the corresponding alkyl bromide, this homoenolate equivalent could not be made from lithium metal and the corresponding Grignard reagent led to the wrong isomer.

Reductive Lithiation of Thiophenyl Ethers.

A variety of thiophenyl ethers are reduced with LDBB and can be trapped with electrophiles, leading to 1-substituted bicyclo[1.1.1]pentanes9 and vinyl substituted compounds (eqs 7 and 8).10 The latter procedure to generate the alkenyllithium is a better and more cost efficient route than the Bond modification of the Shapiro reaction. The cuprate reagent from both the bicyclo[1.1.1]pentane and alkenyl compounds can be generated and reacted with electrophiles.

Homoenolate (2) is produced from the reductive lithiation of the corresponding phenylthio derivative and can be reacted with many electrophiles in high yields (72-83%).11

The use of LDBB was advantageous in the total synthesis of (+)-(9S)-dihydroerythronolide A, converting the thiophenyl group in (3) to an alkyllithium and then to a Grignard reagent.12

An unusual 1,4 O -> C silicon shift was observed when a tris(trimethylsilyl) ether was treated with LDBB to yield the scyllo-tris(trimethylsilylmethyl)cyclohexanetriol.13

a-Lithio Ethers.

The generation of a-lithio ethers can be performed using LDBB followed by trapping with electrophiles. The a-lithio ethers of 1-methoxy-1-phenylthiocyclopropanes are reacted with conjugated aldehydes or ketones to yield 1-cyclopropylallyl alcohols. The addition of Trifluoromethanesulfonic Anhydride led, after rearrangement, to 2-vinylcyclobutanones (eq 9).3a Previous investigations of these cyclopropanes used LDMAN for reductive lithiation, which led to lower yields of the alcohol and, for acid sensitive compounds, significant drops in yield.

The reductive lithiation of 2-(phenylthio)tetrahydropyrans led selectively to the axial 2-lithio species which, upon equilibration, could be converted to the more thermodynamic equatorial a-lithio ether. Treatment with electrophiles such as acetone led to good yields of products (eq 10).3b The use of LDBB led to higher yields and cleaner reductions compared with LDMAN or LN.

The placement of a vinyl group at the 6-position on the tetrahydropyran moiety and addition of LDBB leads to competing [1,2] and [2,3] Wittig rearrangements, with inversion of configuration at the lithium bearing carbon (eq 11).14 A t-butyl group at position 4 significantly changes the reaction course, leading to a small amount of [2,3] Wittig rearranged product. The major product is derived from a 1,4-transannular H-transfer to the lithium-bearing carbon, with inversion of configuration.15

(Dialkoxymethyl)lithium compounds can be generated from the corresponding phenylthio derivative and reacted with aldehydes and ketones (eq 12).16 The cyclic lithium reagent could be generated from LN, while the acyclic required LDBB.

Allyllithiums.

The treatment of allyl phenylthio ethers with Lithium 1-(Dimethylamino)naphthalenide leading to allyllithiums has been performed. Allyllithiums derived from treatment with LDBB can be converted to the allylcerium reagent and trapped with unsaturated aldehydes. Homoallylic alcohols were obtained by 1,2-addition with attack by the least substituted terminus of the allyl anion (eq 13).17 Regiocontrol of the double bond is attained by a slight temperature modification.

The ability to control the regiochemistry of allyllithium terminus and double bond geometry led to a one-pot synthesis of the Comstock mealy bug sex pheromone in a 45% yield, and a four-step synthesis of the California red scale pheromone in 23% yield.18

b-,g-,d-Lithio Alkoxides.

The treatment of epoxides with LDBB leads to b-lithio alkoxides which can be reacted with an aldehyde or ketone to yield varying amounts of a diol and an alcohol.19 The diol is obtained from cleavage of the least substituted carbon oxygen bond, while the other alcohol arrives via a hydride transfer (eq 14). Reductive lithiation of vinyloxiranes led to ring opening in the opposite direction. The allylic anions could be treated with TiIV or CeIII and added to aldehydes at the most or least substituted terminus, respectively.

The generation of g-lithio alkoxides from the corresponding oxetanes require higher temperatures (0 °C) than epoxide ring opening with LDBB.20 g-Lithio alkoxides can be trapped by electrophiles in modest yields. The addition of trialkylaluminums yields the lithium trialkylaluminates, which react with electrophiles in modest yields (eq 15).

The next higher analog, d-lithio alkoxides, can be obtained by LDBB reductive lithiation in the presence of Boron Trifluoride Etherate.21 The Lewis acid helps stabilize the resulting open-chain oxyanion. Treatment with various electrophiles led to products in high yields and is a good protocol for the preparation of the synthetically useful [5.n] spiroacetal units (eq 16). The most branched alcohol is obtained upon cleavage of substituted epoxides and oxetanes, while the opposite regioselectivity is observed for THF.

Propellanes.

The central bond in [1.1.1]propellanes can be reductively cleaved to the corresponding dilithio species, which can be trapped by electrophiles to make bicyclo[1.1.1]pentane derivatives (eq 17).22

Carbonyl groups.

Aromatic ketones, benzylic alcohols, and ethers can be converted to the dilithio species with lithium and a catalytic amount of DBB followed by trapping with electrophiles (eq 18).23 The generation of aliphatic ketones in good yield from the corresponding esters proceeds with LDBB (eq 19), whereas sodium leads to high yields of the acyloin product.24

Phosphinates.

Reduction of diastereomerically pure menthyl phosphinate with LDBB followed by treatment with alkyl halides yields the phosphine oxides in good yield with high optical purity (eq 20).25


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Mark D. Ferguson

Wayne State University, Detroit, MI, USA



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