Angewandte
Chemie
DOI: 10.1002/anie.201410751
Multicomponent Reactions
Double Heteroatom Functionalization of Arenes Using Benzyne
Three-Component Coupling**
Josꢀ-Antonio Garcꢁa-Lꢂpez, Meliha C¸ etin, and Michael F. Greaney*
Abstract: Arynes participate in three-component coupling
reactions with N, S, P, and Se functionalities to yield 1,2-
heteroatom-difunctionalized arenes. Using 2-iodophenyl aryl-
sulfonates as benzyne precursors, we could effectively add
magnesiated S-, Se-, and N-nucleophilic components to the
strained triple bond. In the same pot, addition of electrophilic
N, S, or P reagents and a copper(I) catalyst trapped the
intermediate aryl Grignard to produce a variety of 1,2-
difunctionalized arenes.
1,2-Heteroatom-functionalized arenes represent privi-
leged structures in pharmaceuticals and catalysis
(Scheme 1).[1] Covering a vast area of chemical structure
and function, their synthesis usually entails multistep sequen-
ces with attendant multiple purification steps. In the 2-
functionalized aniline series, for example, an ortho-halo-
À
nitrobenzene is commonly used for initial SNAr C X bond
À
formation, followed by nitro reduction and a second C N
bond forming reaction at the amine functional group.[2] More
À
À
recently, sequential metal-catalyzed C N and C S bond
formations have been developed on suitably differentiated
haloarene precursors.[3] Our interest in benzyne chemistry[4]
led us to speculate whether this compound class could be
made in a single operation through a three component
coupling of two heteroatom moieties and an aryne.[5]
Nucleophilic addition to benzyne to form a reactive aryl
anion intermediate 2, followed by trapping with an electro-
philic component, is a fundamental reaction mode in benzyne
chemistry that has seen extensive application in synthesis.[6,7]
Perhaps surprisingly, the three-component coupling of ben-
zyne and two heteroatom moieties has yet to be described as
a general method.[8,9] The development of this reaction would
yield valuable heteroatom-functionalized arenes in a single
step, with broad application in synthesis.
Scheme 1. 1,2-Heteroatom-functionalized arenes and proposed ben-
zyne three-component coupling approach.
efficient addition to benzynes generated from 2-iodophenyl
i
arylsulfonates 4 with PrMgCl, with the resulting adducts
being trapped with simple carbon electrophiles in good
yield.[10] Using this chemistry for the initial nucleophilic
addition, we then planned to try O-benzoyl N,N-dialkyl-
hydroxylamines as the nitrogen source. These electrophilic
aminating agents are simple to prepare as stable, crystalline
We chose to study tandem S- and N-addition to benzyne in
the first instance. Important precedent from Knochel and co-
workers had shown that magnesium thiolates undergo
solids, and have recently been shown to have excellent
[11]
[*] Dr. J.-A. Garcꢀa-Lꢁpez, Dr. M. C¸etin,[+] Prof. M. F. Greaney
School of Chemistry, University of Manchester
Oxford Rd, Manchester, M13 9PL (UK)
versatility in C N bond formation.
À
Treatment of 2-iodophenyl-sulfonate 4 with two equiv-
i
alents of PrMgCl in the presence of 4-tert-butyl-benzene-
E-mail: michael.greaney@manchester.ac.uk
thiolate 5 at À788C in THF, followed by warming of the
mixture to 08C, afforded the expected 2-magnesiated benzo-
thioether 6 (Scheme 2). Pleasingly, dropwise addition of this
intermediate Grignard to a mixture containing one equivalent
of O-benzoyl N-hydroxylpiperidine and catalytic CuCl2
(5 mol%) in dry THF, yielded the desired 2-(2-piperidine
phenyl)benzenethioether 7a in 35% yield.
[+] Visiting researcher from Uludag¯ University
Faculty of Arts and Science, Department of Chemistry
16059 Bursa (Turkey)
˙
˙
[**] We thank TꢂBITAK-BIDEB (scholarship to M.C¸.), Fundaciꢁn Sꢃneca
(CARM, Spain) (Fellowship to J.-A.G.-L.) and the EPSRC (Leader-
ship Fellowship to M.F.G.) for funding. Dr. James Raftery is thanked
for X-ray crystallography.
An optimization study (see the Supporting Information,
SI) focusing on reaction stoichiometry and catalyst choice
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!