A modular synthesis of functionalised phenols enabled by controlled boron speciationOrg. Biomol. Chem.


John J. Molloy, Robert P. Law, James W. B. Fyfe, Ciaran P. Seath, David J. Hirst, Allan J. B. Watson
Organic Chemistry / Physical and Theoretical Chemistry / Biochemistry


Congress at York

A. of York

Total Synthesis of Verruculogen and Fumitremorgin A Enabled by Ligand-Controlled C–H Borylation

Yu Feng, Dane Holte, Jochen Zoller, Shigenobu Umemiya, Leah R. Simke, Phil S. Baran


Organic &

Biomolecular Chemistry


Cite this: DOI: 10.1039/c5ob00078e

Received 14th January 2015,

Accepted 21st January 2015

DOI: 10.1039/c5ob00078e www.rsc.org/obc

A modular synthesis of functionalised phenols enabled by controlled boron speciation†

John J. Molloy,a Robert P. Law,a,b James W. B. Fyfe,a Ciaran P. Seath,a David J. Hirstb and Allan J. B. Watson*a

A modular synthesis of functionalised biaryl phenols from two boronic acid derivatives has been developed via one-pot Suzuki–Miyaura cross-coupling, chemoselective control of boron solution speciation to generate a reactive boronic ester in situ, and oxidation. The utility of this method has been further demonstrated by application in the synthesis of drug molecules and components of organic electronics, as well as within iterative cross-coupling.


The biaryl phenol moiety is a privileged structure that has found wide-ranging applications within the pharmaceutical, agrochemical, and material industries (Fig. 1a).1 For example, the basic biaryl phenol skeleton represents the principle architecture of (i) the breast cancer treatment raloxifene2 and the non-steroidal anti-inflammatory drug (NSAID) diflunisal,3 (ii) the fungicide bitertanol,4 and (iii) components of the E7 liquid crystal blend.5 Biaryl phenols are also of continued interest within academic research, particularly in total synthesis where many structurally unique natural products, such as (+)-Cavicularin6 and Biphenomycin A,7 feature this motif.

Of the methods available for the synthesis of biaryl phenols,

Suzuki–Miyaura cross-coupling8 of, for example, halophenols with boronic acid derivatives is perhaps the most direct method. However, many of these processes can be problematic, with diminished yields due to issues with boronate formation from the free phenol.9 Use of a protected phenol or suitable latent hydroxyl may therefore be preferable in these cases.

We considered a novel approach towards the synthesis of biaryl phenols using two boron species in which a reactive boronic ester takes part in a Suzuki–Miyaura cross-coupling to establish the required C–C bond and a protected boronic ester acts as a latent hydroxyl unit (Fig. 1b).10 We have previously demonstrated the formal homologation of aryl boronic acid pinacol esters (BPin) using boronic acid N-methyliminodiacetic acid (BMIDA) esters11 via chemoselective control of boron solution speciation.12 This method provides a one step synthesis of a new reactive BPin ester primed for further reaction, such as further Suzuki–Miyaura cross-coupling, while avoiding ancillary deprotection and isolation steps. Herein we show how this controlled speciation process can be smoothly coupled to an oxidative event providing a one-pot, stepefficient, modular synthesis of functionalised biaryl phenols.

Results and discussion

To probe the appropriateness of controlled speciation in this context, we established the reactivity of aryl BPin and BMIDA

Fig. 1 (a) Importance of biaryl phenols. (b) A modular biaryl phenol synthesis enabled by chemoselective boron speciation. †Electronic supplementary information (ESI) available: Experimental procedures and characterisation data for all products. See DOI: 10.1039/c5ob00078e aWestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK. E-mail: allan.watson.100@strath.ac.uk bGlaxoSmithKine, Medicines Research Centre, Gunnels Wood Road, Stevenage,

Hertfordshire SG1 2NY, UK

This journal is © The Royal Society of Chemistry 2015 Org. Biomol. Chem.

Pu bl ish ed o n 21

Ja nu ar y 20 15 . D ow nl oa de d by

N or th er n

Ill in oi s U ni ve rs ity o n 28 /0 1/ 20 15 1 2: 59 :4 3.

View Article Online

View Journal esters towards oxidation using oxidants known to be effective for similar transformations (Table 1). BPin esters are very labile towards oxidation10 while BMIDA esters have previously been shown to withstand common neutral or acidic oxidative conditions such as Swern, TPAP/NMO, and DMP oxidations as well as the comparatively harsh Jones oxidation.13 However, tolerance of oxidation in basic media was anticipated to be low as BMIDA esters are readily hydrolysed to liberate the readily oxidisable parent boronic acid.14 As expected, biphenyl BPin 1, with available p orbital, was efficiently oxidized with peroxide (entries 1 and 3), however, little oxidation was observed with

Oxone®, NaOCl, or NaBO3 (entries 5, 7, and 9). BMIDA 2 was surprisingly inert, even under basic reaction conditions and with the more nucleophilic peroxide oxidants, due to the occupied p orbital (entries 2, 4, 6, 8, and 10). A small quantity of oxidation is observed if there is sufficient hydrolysis of the

BMIDA to the parent oxidatively labile boronic acid (e.g., entry 2). These results further demonstrate the remarkable resilience of BMIDA esters towards oxidation as well as confirm the requirement for use of a more reactive boronic ester in the designed process.

With chemoselective boronic ester oxidation demonstrated, we sought to generate a one-pot protocol for the synthesis of biaryl phenols (Scheme 1). PhBPin (4) was reacted with haloaryl BMIDA 5 under conditions that promote chemoselective generation of a reactive BPin intermediate (6). Subsequent one-pot treatment with H2O2 generated the desired phenolic product 3a in 80% isolated yield.

Having identified effective conditions for the modular phenol synthesis, we sought to ascertain the generality of our protocol through application to a diverse range of BPin and

BMIDA components (Fig. 2). A library of functionalised phenolic products was rapidly prepared from commercial building blocks and with typically high levels of synthetic efficiency, especially for BMIDA units with electron-withdrawing functionality. For those reactions in which the cross-coupling was found to be slow, use of a more active catalyst system

Table 1 Selection and optimisation of oxidant


Boronic ester Oxidant 3aa (%) 1 1 30% aq. H2O2 98 2 2 30% aq. H2O2 10 3 1 UHPb 87 4 2 UHPb 2 5 1 Sat. aq. Oxone® 9 6 2 Sat. aq. Oxone® — 7 1 NaOCl — 8 2 NaOCl — 9 1 NaBO3·4H2O 18 10 2 NaBO3·4H2O 1 aDetermined by HPLC analysis using an internal standard.15 bUHP = urea-hydrogen peroxide.