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Published on: November 30, 2022
Three Component Thio- and Carboboration of Alkynes: A Modular Route to Functionalised Bicyclic Boronates
Laura Winfrey1, Gary S Nichol1, Stephen P Thomas1
1EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK.
Abstract:
The three-component elemento-boration of alkynes using a borane and a nucleophile is a highly efficient method to generate complex alkenyl-boranes. Benzoxaborinines are a class of alkenyl boranes of considerable importance, including in the fight against antibiotic resistance. However, a three-component elemento-boration process to form functionalised benzoxaborinines was an unmet challenge before this work. Herein, we report operationally simple three-component thio- and carbo-boration reactions to form functionalised benzoxaborinines using commercially available reagents. The processes also were applicable to form functionalised benzazaborinines, which are of interest as naphthalene bioisosteres. The nucleophile scope included thioethers, thiols, and (hetero)arenes. In contrast, when using amine nucleophiles, alkyne hydroamination occurred to form boranils. Mechanistic studies revealed a disparity between thioboration using thioethers and using thiols. While thioethers are effective nucleophiles in their own right, when using thiols the in situ formation of tri-thioboranes ((RS)3B) proceeded prior to thioboration, with thioborate anions ([(RS)4B)]-) calculated to be the key nucleophile. Note, combining Et2O∙BF3/RSH and a hindered base is attractive as a simple route to form tri-thioboranes in situ. Overall, this work is a notable addition to the toolbox for making functionalised bicyclic boronates, while demonstrating that the ubiquitous borane Et2O·BF3 can still be used to discover new borylation processes.
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02:47Alkynes to Aldehydes and Ketones: Hydroboration-Oxidation
One of the convenient methods for the preparation of aldehydes and ketones is via hydration of alkynes. Hydroboration-oxidation of alkynes is an indirect hydration reaction in which an alkyne is treated with borane followed by oxidation with alkaline peroxide to form an enol that rapidly converts into an aldehyde or a ketone. Terminal alkynes form aldehydes, whereas internal alkynes give ketones as the final product.
03:08Hydroboration-Oxidation of Alkenes
02:38Electrophilic Addition to Alkynes: Halogenation
Halogenation is another class of electrophilic addition reactions where a halogen molecule gets added across a π bond. In alkynes, the presence of two π bonds allows for the addition of two equivalents of halogens (bromine or chlorine). The addition of the first halogen molecule forms a trans-dihaloalkene as the major product and the cis isomer as the minor product. Subsequent addition of the second equivalent yields the tetrahalide.
02:36Regioselectivity and Stereochemistry of Hydroboration
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.
02:27Preparation of Alkynes: Alkylation Reaction
Alkylation of terminal alkynes with primary alkyl halides in the presence of a strong base like sodium amide is one of the common methods for the synthesis of longer carbon-chain alkynes. For example, treatment of 1-propyne with sodium amide followed by reaction with ethyl bromide yields 2-pentyne.
02:34Preparation of Alkynes: Dehydrohalogenation
Alkynes can be prepared by dehydrohalogenation of vicinal or geminal dihalides in the presence of a strong base like sodium amide in liquid ammonia. The reaction proceeds with the loss of two equivalents of hydrogen halide (HX) via two successive E2 elimination reactions.