Iterative reactions of transient boronic acids enable sequential C–C bond formation

Abstract

(2016). Iterative reactions of transient boronic acids enable sequential C-C bond formation. Nature Chemistry, 8 (4), 360-363. Copyright and re-use policySee http://shura.shu.ac.uk/information.html Sheffield Hallam University Research Archivehttp://shura.shu.ac.uk The ability to form multiple carbon-carbon bonds in a controlled sequence and thus rapidly build molecular complexity in an iterative fashion is an important goal in modern chemical synthesis. In recent times, transition metal-catalysed coupling reactions have dominated in the development of C-C bond forming processes. A desire to reduce the reliance on precious metals and a need to obtain products with very low levels of metal impurities has brought a renewed focus on metal-free coupling processes. Here, we report the in situ preparation of reactive allylic and benzylic boronic acids, obtained by reacting flow-generated diazo compounds with boronic acids, and their application in controlled iterative C-C bond forming reactions is described. Thus far we have shown the formation of up to three C-C bonds in a sequence including the final trapping of a reactive boronic acid species with an aldehyde to generate a range of new chemical structures. Iterative reactions of transient boronic acids enable sequential C-C bond formation IntroductionThe generation of C-C bonds is at the heart of synthetic organic chemistry. 1 The ability to form multiple C-C bonds using iterative or one-pot methods allows a rapid increase in molecular complexity.2-5 While many such sequences are known, there is still room to exploit new reactivity patterns and different chemical combinations derived from reactive intermediates. 6 In recent times, transition metal chemistry has dominated C-C bond cross-coupling strategies. [7][8][9][10][11][12][13] This powerful approach has been central to the planning and execution of modern synthesis programs both in academia and industry. Nevertheless, the desire of industry to reduce its reliance on the use of precious metals in coupling reactions and the need for very low metal levels in active pharmaceutical ingredients has increased interest in metal-free coupling processes considerably. 14 Boronic esters 15 and acids 16 are considered to be important coupling partners as they are versatile intermediates for the preparation of a wide variety of molecules. For example, Barluenga 17 and others [18][19][20] recently demonstrated the powerful application of a reductive metal-free cross-coupling between tosylhydrazones and boronic acids. The reaction likely proceeds via a carbene-like species which on combination with a boronic acid initiates a sequence of reactions that terminates in the formation of a coupling product. However, high temperatures are necessary to affect these coupling processes so that any further exploitation of potentially useful intermediates in the reaction has not been possible so far.From our own mechanistic studies based on the use of flow-generated diazo compounds, 21 in the metal-free cross-coupling with aryl boronic a...

A Versatile Route to Unstable Diazo Compounds via Oxadiazolines and their Use in Aryl–Alkyl Cross‐Coupling Reactions

“…In particular, this allowed us to intercept the putative unstable boronic species and thereby enable access to alcohols6 and powerful iterative bond‐forming processes 7. Nevertheless, these studies were limited to the generation of “semi‐stabilized diazo compounds”, bearing either an aryl or vinyl group adjacent to the diazo moiety.…”

A multicomponent approach for the preparation of homoallylic alcohols

“…23–38 In a continuation of our work in the area (Fig. 1), 39–44 we report here a new multi-component coupling to prepare homoallylic alcohols which was first discovered using flow chemistry 45 methods and later transferred to a batch protocol, involving reactions of vinyl boronic acids with trimethylsilyl diazomethane (TMSCHN 2 ) 46–49 to generate the allylic boronic species in situ which are then intercepted with aldehydes to form new C–C bonds.…”

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

“…Under flow conditions, diazo compounds were reacted with boronic acids in order to generate reactive allylic and benzylic boronic acids further employed for iterative C–C bond forming reactions [86]. The generation of unstable diazo species was possible using a cheap, recyclable and less toxic oxidant, MnO 2 .…”