Use of Aromatic Radical-Anions in the Absence of THF. Tandem Formation and Cyclization of Benzyllithiums Derived from the Attack of Homo- and Bishomoallyllithiums on α-Methylstyrenes:  Two-Pot Synthesis of Cuparene¹

Abstract

When a homo- or bishomoallyllithium, generated by reductive lithiation of the corresponding phenyl thioether by the radical anion lithium 1-(dimethylamino)naphthalenide (LDMAN), is added to alpha-methylstyrene, a tandem addition/cyclization to a phenyl-substituted five- or six-membered-ring occurs. The yields are compromised by polymerization of the alpha-methylstyrene, a process favored by tetrahydrofuran (THF), the solvent used to generate lithium aromatic radical anions. Thus, a new method of generating LDMAN (unsuccessful for other common radical anions) in the absence of THF has been developed. The radical anion can be generated and the reductive lithiation performed in dimethyl ether at -70 degrees C. After the addition of diethyl ether or other solvent, and evaporation of the dimethyl ether in vacuo, the alpha-methylstyrene is added and the solution is warmed to -30 degrees C. When the unsaturated alkyllithium is primary, no adduct forms in THF due to polymerization of the alpha-methylstyrene, but moderate yields are attained in a solvent containing mainly hexanes. It was also found that the cyclized organolithiums, which would have become protonated in the presence of THF, can be captured by an electrophile, even at ambient temperature. A two-pot synthesis, the most efficient reported, of the sesquiterpene (+/-)-cuparene in 46% yield, using this technology is reported.

Reductive Lithiation and Multilithiated Compounds in Synthesis

“…However, the necessity to employ THF as a solvent could be considered as a weakness of the procedure [2]. Indeed, it is well known that organolithiums are able to remove a proton from the 2-position of THF [11], a reaction severely limiting the stability of the more basic reagents, thus requiring the employment of low to very low reaction temperatures.…”

“…According to these findings, different groups investigated the possibility of substituting THF with less problematic solvents. After useless attempts to generate lithium radical anions of several PAHs in solvents such as Et 2 O or 1,2-dimethoxyethane (DME), Cohen et al [2] successfully employed dimethyl ether (Me 2 O) in the generation of lithium dimethylaminonaphthalenide (LiDMAN). This finding was successfully applied to overcome the poor results obtained by these authors in different reductive-lithiation-promoted cyclization reactions performed in THF (Scheme 12.1).…”

“…Thanks to the impressive work developed in this field by the groups of Cohen, Screttas, and Yus, the reductive lithiation procedure established itself in the last decades as an alternative and a complement to the widely employed deprotonation procedures showing, in several instances, distinct advantages in terms of chemo-, regio-, and stereoselectivities as well as mildness of reaction conditions, and strongly expanding the number of precursors that can be transformed into the desired organometals. Indeed, besides halides, the reductive lithiation procedure was extended to a variety of sulfur (mainly phenyl thioethers and thioacetals, but also sulfones, sulfates, and sulfides), nitrogen (amines, amides, and benzotriazoles), oxygen (allylic and benzylic ethers, acetals, and α-aminoethers, esters), carbon (nitriles), and selenium (selenides)-based leaving groups [2].…”

Stereochemical course of the reductive spiroannulations of N-Boc and N-benzyl 2-cyanopiperidines

“…10 Trapping of these cyclic imines with a nucleophilic cyanide source would produce the unprotected 2-cyanopiperidines. 11,12 Starting with 2-methylpiperidine (19), N-chlorination using N-chlorosuccinimide (NCS) produced N-chloro-2-methylpiperidine (20), which was reacted in unpurified form in a regioselective elimination mediated by lithium 2,2,6,6-tetramethylpiperidide (LTMP) (Scheme 4). Direct addition of an aqueous solution of KCN and gradual warming to room temperature produces diastereomeric 2-cyanopiperidines trans-and cis-21 in 52% overall yield from 19.…”

The superiority of properly prepared lithium 1-N,N-dimethylaminonaphthalenide (LDMAN) over other aromatic radical-anions for the generation of organolithiums by reductive lithiation

“…The former, 1, has the advantage over lithium naphthalenide that the byproduct of electron transfer, 1-dimethylaminonaphthalene, can be readily separated from the desired product in most cases by a dilute acid wash and of course it can be recycled; a subsidiary advantage is that LDMAN can be used in solvents other than THF, the solvent universally used in synthetic procedures involving aromatic lithium radical-anions. 5 The latter, 2, has the advantage that it is a more powerful reducing agent than LN and presumably less subject to attack by the intermediate radical generated in the process of reductive lithiation.…”