Birch Reductive Alkylation of Biaryls: Scope and Limitations

Abstract

Birch reductive alkylation of biaryls has been carried out by varying the nature of the substituents on the aromatic rings. Our investigations have focused on electron-rich substituents such as OMe, OH, and NR(2) groups as they are present on the skeleton of targeted alkaloids. The regioselectivity is strongly affected by the electronic nature of these substituents on both rings. The 3,5-dimethoxyphenyl moiety is selectively reduced and then alkylated, while phenols and anilines do not react under these conditions. A biaryl possessing both a 3,5-dimethoxyphenyl moiety and a phenol ring may, however, be reduced and alkylated provided the acidic phenolic proton is removed prior to the treatment with Li in NH(3). Similarly, biaryls possessing a o-sulfonamide group are reduced regioselectively and alkylated with alpha-chloroacetonitrile or N-tosylaziridine to provide the corresponding dienes in reasonable to good yields. A survey of the alkylating agents was also performed showing that various functional groups may be introduced at the benzylic position, including esters, primary and tertiary amides, nitriles, epoxides, and acetals and also unfunctionalized sterically hindered t-Bu groups and cyclopropyl substituents. The introduction of the latter indicates that both a S(N)2 and a SET mechanism may take place during the alkylating step.

Unexpected ring contraction of 1-aryl-cyclohexa-2,5-dienes under palladium catalysis

“…[20][21] Our preliminary studies began by reacting cyclohexadiene 3a with phenyl iodide 4a in the presence of Pd(OAc) 2 under cationic Heck reaction conditions. 22 We observed no trace of heterocyclization product such as II in the mixture, which instead contained mainly starting material in 44% yield, an unexpected cyclopropane containing product 5a (31%) and a third product (25%), which structure could not be determined (Scheme 2).…”

“…To a solution of 2-(1-Phenyl-cyclohexa-2,5-dienyl)-ethylamine 20,21 (536 mg, 2.69 mmol) in DCM (26 mL) was added triethylamine (760 µL, 5.42 mmol) and methanesulfonyl chloride (210 µL, 2.71 mmol) at 0°C. After stirring overnight at room temperature, the organic layer was washed with water then brine, dried over sodium sulfate and filtered.…”

“…After stirring overnight at room temperature, the organic layer was washed with water then brine, dried over sodium sulfate and filtered. Evaporation of the solvents gave a white solid which was purified through silica gel chromatography (Petroleum ether/EtOAc 80: 20) …”

3‐tert‐Butyl‐Substituted Cyclohexa‐1,4‐dienes as Isobutane Equivalents in the B(C6F5)3‐Catalyzed Transfer Hydro‐tert‐Butylation of Alkenes

“…Transfer reagent 2 was readily obtained in one step by Birch reductive alkylation of biphenyl (not shown) . We also pursued the synthesis of surrogate 3 (Scheme ) to replace difficult‐to‐remove biphenyl with toluene as the stoichiometric byproduct of the transfer hydro‐ tert ‐butylation.…”

Palladium‐Catalyzed Enantioselective Desymmetrizing Aza‐Wacker Reaction: Development and Application to the Total Synthesis of (−)‐Mesembrane and (+)‐Crinane

“…[14] Heating atoluene solution of 1a in the presence of Pd(OAc) 2 ,p yridine,a nd Na 2 CO 3 under an O 2 atmosphere afforded 2a in 65 %y ield ( Table 1, entry 1). [14] Heating atoluene solution of 1a in the presence of Pd(OAc) 2 ,p yridine,a nd Na 2 CO 3 under an O 2 atmosphere afforded 2a in 65 %y ield ( Table 1, entry 1).…”