@WILEY-VCH
`Edited by
`Dennis C. Hall T
`
`Boronic Acids
`
`Preparatiun. Applications in
`Organic Synthesis and Medicine
`
`X. 2118 - 1/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 1/16
`
`

`
`Boronic Acids
`
`Preparation and Applications in Organic Synthesis
`and Medicine
`
`Edited by Dennis C. Hall
`
`WILEY-
`VCH
`
`WILEY-VCH Verlag GmbH 8:, Co. KGaA
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 2/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 2/16
`
`

`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 3/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 3/16
`
`

`
`Boronic Acids
`
`Edited by
`D. C. Hall
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 4/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 4/16
`
`

`
`Further Titles ofInterest
`
`S.-I. Murahashi (Ed.)
`
`Ruthenium in Organic Synthesis
`2004
`ISBN 3-527-30692-7
`
`A. de Meijere, F. Diederich (Eds.)
`
`Metal-Catalyzed Cross-Coupling
`Reactions
`2004
`ISBN 3-527-30518-1
`
`P. A. Evans (Ed.)
`
`Modern Rhodium-Catalyzed
`Organic Reactions
`2004
`ISBN 3-527-30683-8
`
`M. Beller, C. Bolm (Eds.)
`
`Transition Metals
`
`for Organic Synthesis
`Building Blocks and Fine Chemicals
`2004
`ISBN 3-527-30613-7
`
`A. Berkessel, H. Gréger.
`
`Asymmetric Organocatalysis
`From Biomimetic Concepts to
`Applications in Asymmetric Synthesis
`2004
`ISBN 3-527-30517-3
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 5/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 5/16
`
`

`
`Boronic Acids
`
`Preparation and Applications in Organic Synthesis
`and Medicine
`
`Edited by Dennis C. Hall
`
`WILEY-
`VCH
`
`WILEY-VCH Verlag GmbH 8:, Co. KGaA
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 6/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 6/16
`
`

`
`Editor
`
`Prof Dennis C. Hall
`University of Alberta
`Department of Chemistry
`W5—07 Chemistry Building
`T6G 2G2 Edmonton (Alberta)
`Canada
`
`All books published by Wiley-VCH are carefully pro-
`duced. Nevertheless, authors, editor, and publisher do
`not warrant the information contained in these books,
`including this book, to be free of errors. Readers are
`advised to keep in mind that statements, data, illustra-
`tions, procedural details or other items may inadver-
`tently be inaccurate.
`
`Library of Congress Card No.: Applied for
`
`British Library Cataloguing-in-Publication Data:
`A catalogue record for this book is available from the
`British Library.
`
`Bibliographic information published by
`Die Deutsche Bibliothek
`Die Deutsche Bibliothek lists this publication in the
`Deutsche Nationalbibliografie; detailed bibliographic
`data is available in the Internet at <htt'p://dnb.ddb.de>.
`
`© 2005 WILEY-VCH Verlag GmbH 8: Co. KGaA,
`Weinheim
`
`All rights reserved (including those of translation into
`other languages). No part of this book may be repro-
`duced in any form — nor transmitted or translated into
`machine language without written permission from
`the publishers. Registered names, trademarks, etc.
`used in this book, even when not specifically marked
`as such, are not to be considered unprotected by law.
`
`Printed in the Federal Republic of Germany
`
`Printed on acid-free paper
`
`Typesetting TypoDesign Hecker GmbH, Leimen
`Printing Strauss GmbH, Morlenbach
`Bookbinding Litges 8: Dopf Buchbinderei Gmbl-I,
`Heppenheim
`
`ISBN-13:
`ISBN-10:
`
`978-3-527-30991-7
`3-527-30991-8
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX .2118 -7/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 7/16
`
`

`
`3 C
`
`oupling Reactions of Areneboronic Acids or Esters with
`
`Aromatic Electrophiles
`
`Akiru Suzuki
`
`3.1
`Introduction
`
`Recently, there have been many reports of applications of organoboronic acid deriva-
`tives in various fields. Especially, such compounds provide unique and useful syn-
`thetic methodologies. Carbon—carbon bond formation reactions are important
`processes in chemistry, as they constitute key steps in the building of more complex
`molecules from simple precursors. During the initial stage of our exploration of or-
`ganic syntheses employing organoboron compounds and organic halides, we found
`that the cross-coupling reaction of vinyl boron derivatives with vinyl halides proceeds
`smoothly in the presence of a base and a catalytic amount of a palladium complex to
`give the expected conjugated alkadienes and alkenynes stereo- and regioselectively in
`excellent yields. Not only vinyl borane derivatives, but other types of organoboron
`compounds react with organic electrophiles under these reaction conditions. Thus,
`(sp3)C—B compounds (alkylboron compounds) and (sp2)C—B compounds (aryl- and
`alkenylboron derivatives) readily cross-couple with several organic electrophiles to
`produce coupled products selectively in high yields. Additionally, American and Ger-
`man chemists independently established the reactivity of (sp)C—B compounds (1-
`alkynylborane derivatives) with electrophiles under specific conditions to yield the
`corresponding coupled products. The present author has most recently published a
`book on the reaction [la], which covers publications until 2000.
`Recently,
`several synthetic applications using such cross-coupling reactions
`have become powerful tools for the construction of new organic compounds. Among
`these reactions, aromatic—aromatic (or heteroaromatic) couplings are used most
`frequently, because of their importance in pharmaceutical processes and polymer
`sciences.
`
`In this chapter, only new advances reported between 2001 and 2003 on aromat-
`ic—aromatic, aromatic—heteroaromatic, and heteroaromatic—heteroaromatic coupling
`reactions will be discussed due to space limitations. Readers are also encouraged to
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 8/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 8/16
`
`

`
`124
`
`3 Coupling Reactions ofAreneboronic Acids or Esters with Aromatic Electrophiles
`
`refer to other reviews that also cover other types of substrates such as alkenylboronic
`acids [1b—d].
`
`3.2
`
`Coupling Reactions of Areneboronic Acid Derivatives
`
`3.2.l
`
`With Aryl Halides. Synthesis of Biaryls
`
`The importance of biaryl units as components of many kinds of compounds, such as
`pharmaceuticals, herbicides, and natural products, as well as engineering materials
`such as conducting polymers, molecular wires, and liquid crystals, has attracted enor-
`mous interest from the chemical community. Palladium-catalyzed Suzuki coupling is
`the most important and efficient strategy for the construction of symmetrical and un-
`symmetrical biaryl compounds.
`
`3.2.1.1 Aromatic—Aromatic Coupling
`To study the charge distribution in bis-dioxolene radical metal complexes,
`biphenyl 1 was synthesized by Suzuki coupling (Equation 1) [2].
`
`the
`
`OMe
`
`OMe
`
`t-Bu
`
`OMe
`
`t-Bu
`
`OMe
`
`+
`
`B(OH)2
`
`Br
`
`Pd(PP|-.3)‘,
` >
`
`aq. Na2CO3
`EtOH-toluene
`
`t-Bu
`
`MeO
`
`OMe
`
`t-Bu
`
`OMe
`
`8
`
`O
`
`OMe
`
`99 "/0
`
`BBr3, -78 °C
`
`T»
`
`H20
`
`OH
`
`I-Bu 0 OH
`
`HO
`
`Q
`
`OH
`
`FBU
`
`1
`
`99 %
`
`(1)
`
`An important synthesis of hydroxylated polychlorinated biphenyls (PCBs), which
`are structurally related to the major hydroxy PCB congeners identified in human
`plasma, was reported. Coupling of chlorinated aryl boronic acids with chloro anisoles
`using the standard conditions of the Suzuki coupling gave hydroxylated PCB metabo-
`lites in good to excellent yields. The approach offers the advantages of high selectivi-
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 9/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 9/16
`
`

`
`3.2 Coupling Reactions ofAreneboronic Acid Derivatives
`
`‘I25
`
`ty and good yields compared to conventional methods such as the Cadogan reaction,
`and allows the use of less toxic starting materials (Equation 2) [3].
`
`CI
`
`CI
`
`HO
`
`Cl
`
`Pd(PPh3)4
`
`Br + (Ho)2B T» HO O O (2)
`aq.Na2CO3
`CI
`toluene
`Cl
`CI
`83%
`
`An efficient method for the preparation of 3-arylsalicylaldehydes by palladium-cat-
`alyzed cross-coupling reaction of arylboronic acids and 3-bromo-5-tert-butylsalicy-
`laldehyde has been reported. Although Stille coupling also gave the similar coupled
`product, such a reaction required prolonged heating at high temperature and gave a
`relatively low product yield (Equation 3) [4].
`
`0H
`
`M
`
`OHC
`
`3'
`
`t-Bu
`
`OHC
`
`Pd(PPhs)4
`+ T,
`M = B(OH)2 :
`KZCO3
`DME, H20
`90 °C, 16 h
`
`OH
`
`H3”
`
`(3)
`
`M = snBu3;
`toluene
`100 °C, 3 d
`
`M = B(OH)2 100%
`
`M = SnBu3 67%
`
`Ortho lithiation — in-situ boration using lithium 2,2,6,6-tetramethylpiperidide
`(LTMP) in combination with triisopropylborate is a highly efficient and experimen-
`tally straightforward process for the preparation of ortho substituted arylboronic es-
`ters. The mild reaction conditions allow the presence of functionalities such as ester,
`cyano groups, and halogen substituents that are usually not compatible with the con-
`ditions used in directed ortho-metalation of arene. Arylboronic esters prepared by or-
`tho-metalation underwent Suzuki coupling reaction with a range of aryl halides, fur-
`nishing biaryls in good to excellent yields (Equation 4) [5].
`
`C003
`
`LTMP
`B(Oi-Pr)3
`T»
`
`11.”:
`_78 cc
`
`HO
`
`:><
`
`HO
`T»
`
`toluene
`rt
`
`CODE‘
`
`-_
`B(O/ Pr)2
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 10/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 10/16
`
`

`
`‘I26 | 3 Coupling Reactions ofAreneboronic Acids or Esters with Aromatic Electrophiles
`COOEt
`Br CHO O CODE‘
`:1:8/0 T»
`
`(4)
`
`.
`O
`
`92 %
`
`Pd(PPh3)4
`K3P04
`dioxane
`
`CHO
`
`80 0/
`°
`
`The tris-bidentate ligand 1,3,5-tris(5-tert-butyl-3,4-dihydroxyphenyl)benzene was
`synthesized by Suzuki coupling in an excellent yield, which affords high-spin metal
`complexes containing a ferromagnetically coupled tris(semiquinone) ligand (Equa-
`tion 5) [6].
`
`OMe
`
`M60
`
`t'BU
`
`+
`
`Br
`
`Br
`
`T)
`
`aq. Na2CO3
`
`B(OH)2
`
`Br
`
`E*0H
`
`OMe
`
`MeO
`I
`t—Bu
`I 0 I
`
`OMe
`
`93 %
`
`t—Bu
`
`t—Bu
`MeO
`
`BBF3
`
`T,
`
`OMe
`OMe
`
`t—Bu
`Ho
`
`OH
`
`HO
`,«_Bu
`0
`I 0 OH
`8 OH
`
`(5)
`
`OH
`
`t_Bu
`
`With “C-labeled samples, internuclear distances of up to 7 A can be measured by
`solid-state NMR, thus providing a powerful tool for probing ligand—receptor interac-
`tions. However, limitations in measurable distances, and appreciable background sig-
`nal due to naturally occurring “C, present problems in solid-state “C NMR. To over-
`come these disadvantages, a set of reference compounds with known F—F distances,
`namely, quinolinol, p-biphenyl, and p-terphenyl-bearing trifluoromethyl and trifluo-
`romethylthio groups, have been synthesized by Suzuki coupling (Equation 6) [7].
`1,8-Diaryl cofacial naphthalenes as well as cyclophanes continue to be useful mod-
`el compounds to study the interactions between aromatic rings held near or below
`van der Waals interatomic distance. In such naphthalenes, the two aromatic rings are
`held cofacial but are splayed from each other and can rotate about the bonds attach-
`ing them to the rigid naphthalene frame, thereby giving rise to atropisomers. Such
`1,8-diaryl naphthalenes were prepared by Suzuki coupling (Equation 7) [8].
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 11/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 11/16
`
`

`
`3.2 Coupling Reactions ofAreneboronic Acid Derivatives
`
`127
`
`SCF3
`
`0
`
`8 C
`
`F3
`82 %
`
`B(OH)2
`SCF3 O Pd(PPh3)4
`
`+
`
`Br
`
`T»
`aq. Na2CO3
`I
`
`G to uene
`CF3
`
`0‘
`
`Br
`
`+
`
`OMe
`
`B(OH)2
`
`Pd(PPh3)4
`aq. Na2CO3
`DME
`
`OMe
`
`GOO
`
`(7)
`
`83 "/o
`
`Suzuki coupling of optically active (S)-binaphthyl bromide 2 with (S) -binaphthyl-
`boronic acid 3 produced a diastereomeric mixture (1:1 mixture) of tetrabutoxyquater-
`naphthyl 4. The C-1 and C-1’ axis of the compound has an unusually high rotational
`barrier (Equation 8) [9].
`
`BUO OBU
`
`BuO OBu
`
`HeXBr + HeXB(OH)2
`
`2
`
`3
`
`BuO OBu
`
`BuO OBu
`
`Pd(PPh3)4
`
`aq Na2CO3
`
`O 0
`L» O
`EtOH/toluene Q 6 Q G
`
`4 90% (1:1 mixture)
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 12/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 12/16
`
`

`
`‘I28
`
`3 Coupling Reactions ofAreneboronic Acids or Esters with Aromatic Electrophiles
`
`A series of novel hydrophobic, bulky X2-constrained phenylalanine and naphthy-
`lalanine derivatives were designed and synthesized by Suzuki coupling of oc-amino
`acid derivatives with boronic acids to afford these aromatic substituted amino acids
`
`in high yields and with high enantioselectivity (Equation 9) [10].
`
`NHCbz
`
`OMe
`
`B’
`
`Pd(OAc)2, P(o-to|y|)3
`O
`+ T»
`
`at NHCbz
`
`W6
`
`(9)
`
`8‘
`
`B(OH)2
`
`K2003, DME
`
`O
`
`1oo %
`
`Azulene oligomers and polymers are intriguing molecules in terms of the con-
`struction of functional substances. Some synthetic studies on azulene dimers have
`been reported. The synthetic methods, however, were considered to restrict the de-
`velopment of further studies. Thus, Ullman coupling reactions at high temperature
`or some sophisticated reactions based on Hafner’s azulene synthesis, starting from
`bipyridyls, were used. To obtain azulene oligomers, the Suzuki coupling has been ap-
`plied recently (Equations 10 and 11) [11].
`
`EtOgC
`
`H2N Br
`3020
`
`/
`
`/%\¢
`+
`
`O
`
`0/
`
`EtO2C
`
` ’ 2
`
`PdC|2(PPh3)2
`
`Ba(OH)2
`
`H N
`
`/\ / \
`
`// /
`
`_
`
`EtO2C
`
`T 2
`
`PdC|2(PPh3)2
`
`Ba(OH)2
`DME-H20
`
`(10)
`
`'
`
`/V/W)
`
`/A ,//4
`
`/ / §
`
`/ /
`
`28 %
`
`HN / / \\
`
`/ /
`
`Etozc
`
`Various substituted phenyl pyrenes, synthesized by Suzuki coupling, have been in-
`vestigated by fluorescence spectroscopy (Equation 12) [12].
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 13/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 13/16
`
`

`
`3.2 Coupling Reactions ofAreneboronic Acid Derivatives
`
`‘I29
`
`
`
`/0
`, /
`
`Pd(PPh3)4
`‘ T’
`aq Na2CO3
`
`toluene
`
`/
`
`.§/
`
`/
`
`87%
`
`(12)
`
`CN
`
`Br
`
` \
`
`CN
`
`A new example of magnetic non-equivalence of chemically equivalent atoms was
`identified from the proton and carbon resonance spectra of 9,10-di(9,9-dioctylfluo-
`renyl)anthracene with the aid of its conformation in the crystalline state. The desired
`compound was synthesized by a Suzuki reaction (Equation 13) [13].
`
`. B(OH)2
`Oct Oct
`
`+
`
`Pd(PPh3)4
`N\ \
`i
`l T.
`\@\/ /
`aq.Na2CO3
`ll3r
`toluene
`
`/ i\
`
`Oct 00‘
`
`\l<\>/\;
`
`(13)
`
`at \—/>~c
`l
`
`
`Cd om
`
`\ g/
`
`92 %
`
`Water-soluble conjugated polymers are of particular interest in biosensor schemes.
`To compensate for the hydrophobic nature of the backbone, these polymers contain
`charged groups for solubility in aqueous media. As one of many syntheses of such
`oligomers, Suzuki coupling has been applied (Equation 14) [14].
`
`Me2N(CH2)s
`
`(CH2)sNMe2
`
`O O Br
`
`+
`
`(H0)2B B(0H)2
`
`Me2N(CH2)e
`
`(CH2)sNMe2
`
`Me2N(CH2)e(CH2)sNMe2
`
`l.F"‘°'2“"""’
`
`aq.K2CO3
`THF
`
`</ \
`
`< \
`
`/ \
`
`77%
`
`/ \
`
`</
`
`\>
`
`(14)
`
`The novel class of tetrakis(phenothiazinylphenyl)methane 6, showing remarkably
`large Stokes shift and a reversible low oxidation potential, can be prepared in good
`yield by Suzuki coupling of tetrakis(p-bromophenyl)methane 5, (Equation 15) [15].
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 14/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 14/16
`
`

`
`‘I30 | 3 Coupling Reactions ofAreneboronic Acids or Esters with Aromatic Electrophiles
`Br
`
`
`
`y
`
`\
`
`\
`
` » B(OH)2
`
`N
`
`Pd(PPh)34 CV \
`aq.Na2CO3
`4\
`DME
`
`B’
`
`N/
`/ \
`i Q
`S
`/ >
`
`US»
`
`Palladium-catalyzed Suzuki coupling of the iodide (S)-7 with areneboronic acids
`using the phosphine-free procedure gave aryl aldehydes, such as 8, in excellent yields
`when barium hydroxide was used as the base (Equation 16) [16].
`
`CH0
`
`+
`
`(HO)2B
`
`Cfik.
`Te
`<0)
`7
`
`Pd(OAc)2 ?
`OMe T. Te
`Ba(0H) $
`THF
`2 <3
`8
`
`CH0
`
`100%
`
`(16)
`
`OMe
`
`Asymmetric synthesis of a fully protected ent-actinoidinic acid derivative (9) was
`reported using a diastereoselective Suzuki coupling as the key step (Equation 17) [17].
`
`M90
`
`M80
`
`/
`
`\
`
`Cl
`3
`
`Cr(CO)
`
`o
`< 1 +
`O
`
`c_Ho
`
`OMe
`
`Pd(PPh3)4
` >
`aq Na2CO3
`toluene/EtOH
`
`l3(OH)2
`
`M60
`
`/‘i\
`
`OMe
`M60
`
`88 °/o
`
`MeO
`
`__:_ MeO«/,,,_
`
`(-)-(FM/L3)-9
`
`The ligandless palladium-catalyzed Suzuki coupling reaction of potassium aryl-
`and heteroaryltrifluoroborates with aryl- or heteroaryl halides or triflates proceeds
`readily with very good yields. Cross coupling can be effected in methanol or Water, us-
`ing Pd(OAc)2 as a catalyst in the presence of KZCO3. Various functional groups are
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 15/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 15/16
`
`

`
`3.2 Coupling Reactions ofAreneboronic Acid Derivatives
`
`‘I31
`
`tolerated. Moreover, under these conditions, the reactions could be performed in air
`without any effect on the high yield of biaryls (Equation 18) [18].
`
`BF3K
`
`+
`
`Pd(OAc)2
`T’
`KZCO3
`MeOH
`
`;
`‘
`/
`
`88%
`
`(13)
`
`The variant of the reaction using trifluoroborate salts, gives very good results when
`performed in refluxing methanol. Previous reports have indicated that water was
`required as a co-solvent for the trifluoroborate coupling reactions [19, 20], and that
`one or more hydroxy groups displace fluorides on the tetracoordinate boron species
`involved in the transmetallation step of the catalytic cycle [20—22]. Molander and Ito
`have conducted experiments by heating PhBF3K in methanol at reflux, with the
`addition of 0, 1, 2, and 3 equiv of base. After 2 h, all reaction mixtures were filtered,
`and equal amounts of deuterated acetone were added to each one; the resulting
`solutions were then analyzed using “B and 19F NMR spectroscopy. The 19F NMR
`spectra showed the absence of fluorine bonded to the boron atom after adding
`3 equiv. ofbase. “B NMR shifts revealed a quadruplet at 4.35 ppm when no base was
`added and a singlet at 5.47 ppm when 3 equiv of base was added. Molander and Ito
`thus concluded that the trifluoroborates do not remain intact under the reaction con-
`ditions and that an intermediate that does not retain all of the fluorides on the boron
`
`species is involved in the key transmetallation step [19]. Using a different analysis,
`Batey and Quach previously came to the same conclusion [20]. These results strong-
`ly support the mechanism of palladium-catalyzed coupling of organoboranes pro-
`posed by Suzuki and co-workers [22]. From mechanistic studies of Suzuki reactions
`[22], it is likely that the boron reagent first reacts with the base to give the correspon-
`ding boronate, which serves as the actual nucleophile. It then transfers the organic
`ligand to the hydroxypalladium(II) complex formed by insertion of the Pd(0) into the
`C—X bond followed by the displacement of X with the hydroxide ion. In this system
`the aqueous layer contains the base, and the organic phase contains the aryl halide.
`The palladium catalyst and the boronate salt are partitioned between aqueous and
`organic phases.
`
`3.2.1.2 Aromatic—Heteroaromatic and Heteroaromatic—Heteroaromatic Couplings
`Pd-mediated Suzuki coupling reactions provide a flexible entry to substituted
`pyridines (Equation 19) [23].
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2118 - 16/16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2118 - 16/16