 Benzyne (1 ) is an important cornerstone in modern preparative organic chemistry. It functions as a highly derivatisable and reactive aromatic building block enabling rapid access to ortho-substituted products that in most cases cannot be directly made via classical routes. The ortho-benzyne intermediate (2 ) is normally synthesised via an elimination process from the aryl anion orthoto the nucleofuge.The classical substrates, 2-trimethylsilylaryl trifluoromethylsulfonates (2  ), were originally reported by Kobayashi et. al. in 1983. These substrates are accessed via a one-pot synthesis pioneered by Guitian where a (2-bromoaryloxy)trimethylsilane (3 ) reacts with n-butyllithium at �100 �C in a lithium halide exchange and undergoes a retro-Brook rearrangement. The obtained ortho-TMS-phenolate lithium salt (4 ) is than trapped by triflic anhydrdide to give the desired product. This protocol suffers from severe penalties, especially on scale due to cryogenic temperatures and slow mass transfer, manifesting in long reaction times, poor purity profiles and the necessity for extensive purification by column chromatography or distillation.In this work we present a continuous flow approach enabling a multistep sequence similar to Guitian's giving the target 2-trimethylsilylaryl perfluorosulfonates (1 ) in excellent yields (88 � 97%, 7 examples). The process is conducted at room temperature and is scalable from 2 to 20 mmol per hour. Furthermore, expensive and hazardous triflic anhydride can been replaced with 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (nonaflyl fluoride, NfF) to afford the respective 2-trimethylsilylaryl perfluorobutylsulfonates in excellent yield and purity (82 � 90% yield, 7 examples). Initial scalability experiments have demonstrated that this protocol works on scales from 2 to 20 mmol per hour.This method produces novel compounds, which have to date not been used in benzyne type chemistry. The lower atom efficiency is compensated by the cost of nonaflyl fluoride ($224/100g) over triflic anhydride ($575/100g) and its significant ease in handling and storage.

Continuous flow synthesis of trimethylsilylphenyl perfluorosulfonates: Highly efficient benzyne precursor synthesis at room temperature

248th National Meeting (2014)

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