Organic Letters
Letter
boronic acids that can be used as a platform for diversity-
oriented synthesis within drug discovery.
Scheme 3. Formal Homologation of Boronic Acids: A
Platform for Diversity-Oriented Synthesis
a
ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
Experimental procedures, characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was supported by the Engineering and Physical
Sciences Research Council (EPSRC). We thank the EPSRC
UK National Mass Spectrometry Facility at Swansea University
for analyses and GlaxoSmithKline for financial and material
support.
REFERENCES
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reactive within the following processes: (a) Frost, C. G.; Penrose, S.
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a
Reaction conditions: (a) 3v (1.1 equiv), 4-bromobenzonitrile (1
equiv), PdCl2dppf (5 mol %), K3PO4 (3 equiv), H2O (5 equiv), THF,
70 °C, 1 h; (b) 3v (1.5 equiv), morpholine (1 equiv), Cu(OAc)2 (10
mol %), MS 4 Å, O2, CH2Cl2, 40 °C, 24 h; (c) 3v (1 equiv), methyl
vinyl ketone (2 equiv), [Rh(COD)Cl]2 (2 mol %), Na2CO3 (2 equiv),
H2O, 80 °C, 16 h; (d) 3v (1 equiv), H2O2 (10 equiv), THF, rt, 2 h;
(e) 3v (1 equiv), methyl acrylate (1.5 equiv), 1,4-benzoquinone (1
equiv), Pd(OAc)2 (2 mol %), phenanthroline (2.5 mol %), MeCN, 60
°C, 16 h; (f) 3v (1 equiv), N-bromosuccinimide (1.5 equiv), THF, rt,
16 h; (g) 3v (1 equiv), benzyl bromide (1.5 equiv), PdCl2dppf (5 mol
%), K3PO4 (4 equiv), H2O (20 equiv), THF, 90 °C, 5 h.
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The versatility of the boronic acid motif can then be
exploited using established chemistries. For example, further
Suzuki−Miyaura reactions using sp2- and sp3-hybridized
electrophiles provided 9a and 9g, respectively in excellent
yield. 9g can be readily converted to the parent compound 6
using existing methods.13 Chan−Evans−Lam coupling pro-
vided the morpholine derivative 9b in 78% yield while Hayashi-
type 1,4-addition efficiently delivered 9c in 74% yield.
Straightforward Brown-type oxidation to the phenol 9d
proceeded quantitatively. An oxidative Heck reaction with
methyl acrylate efficiently produced 9e and, last, the reactivity
of the boron-bearing carbon could be inverted by bromination
to give 9f. It is important to note that several of these products
(e.g., 9b, 9c, 9f) cannot be so readily achieved with either the
corresponding BMIDA or BPin derivative of 3v;2a,d these
derivatives would require either further processing or
alternative, less straightforward chemistries.
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In summary, we have developed a boronic acid formal
homologation reaction using boronic acids and conjunctive
bromoaryl/vinyl BMIDA components. The process relies upon
careful control of the basic biphase to enable cross-coupling of
haloaryl BMIDA components while avoiding premature
hydrolysis. This process gives direct access to functionalized
C
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