Nobel Lectures
`
`Angewandte
`Chemie
`
`6722
`
`www.angewandte.org
`
` 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
`
`Angew. Chem. Int. Ed. 2011, 50, 6722 – 6737
`
`PETITIONER NPC EX. 1024
` Page 1 of 16
`
`

`

`Suzuki Coupling
`
`Nobel Review
`Cross-Coupling Reactions Of Organoboranes: An Easy
`Way To Construct CC Bonds (Nobel Lecture)**
`
`DOI: 10.1002/anie.201101379
`
`Akira Suzuki*
`
`Biography
`
`I was born on September 12, 1930 in Mukawa, a small town in
`Hokkaido, Japan. I attended the primary school there and
`entered secondary school at Tomakomai, where we had one
`of the biggest paper companies in Japan. During my high
`school, I was interested in mathematics. Consequently, when I
`entered Hokkaido University in Sapporo, I was thinking of
`studying it. In the junior course, I became interested in
`organic chemistry by reading the book “Textbook of Organic
`Chemistry,” written by L. F. Fieser and M. Fieser. Finally, I
`decided to major in organic chemistry.
`The title of my doctoral thesis was “Synthesis of the
`Model Compounds of Diterpene Alkaloids”. In the study, I
`used organometallic compounds, Grignard reagents, and
`organozinc compounds as synthetic intermediates, and I
`perceived that such organometallic compounds are interest-
`ing and versatile intermediates for organic synthesis. After I
`completed the PhD program at the Graduate School of
`Science, Hokkaido University, in 1959, I was employed as a
`research assistant in the Chemistry Department. In October
`1961, after two years and six months, I was invited to become
`an assistant professor of the Synthetic Organic Chemistry
`Laboratory at the newly founded Synthetic Chemical Engi-
`neering Department in the Faculty of Engineering. In April
`1973, I succeeded Professor H. Otsuka at the Third Labo-
`ratory in the Applied Chemistry Department. In total, I have
`spent 35 years at Hokkaido University as a staff member—
`two and a half years in the Faculty of Science, and another
`thirty-two and a half years in the Faculty of Engineering.
`Other than about two years of study in America, and a few
`months at other places overseas, most of my life has been
`spent at the Faculty of Engineering. Including my nine years
`as a student, the majority of my life has been at Hokkaido
`University. After my retirement from Hokkaido University in
`1994, I joined two private universities in Okayama prefec-
`ture—Okayama Science University and Kurashiki University
`of Science and Arts—and I retired from the universities in
`2002. In the following I would like to describe a few memories
`of my life in chemistry.
`
`cross-coupling · organoboranes · palladium ·
`Suzuki coupling
`
`trying experiences tend to fade with time. I think now mainly
`about the fun things, and I will describe a few memories that I
`have from my work.
`It was on a Saturday afternoon in 1962. I visited the
`Maruzen bookstore in Sapporo. As I browsed the chemistry
`books, I discovered a very unacademic looking volume, bound
`in red and black. This book was Hydroboration by H. C.
`Brown, the 1979 Nobel Laureate in Chemistry. I took the
`book in my hands, and began looking through its pages to find
`words written in Professor Browns unique style. I purchased
`the book and returned home. I can still remember clearly how
`I picked it up after dinner that evening, and could not put it
`down. It is not very long, but it remains as one of the few
`scholarly books which I have stayed up all night to read. At
`the time, I had just transferred to the Faculty of Engineering
`from Science, and I wanted to begin research in a new area at
`my new workplace. This is perhaps one reason why this book
`had such an impact on me.
`Inspired by this experience, I went to Purdue University in
`Indiana in the August of 1963 (Figure 1) and spent almost two
`years at Professor Browns laboratory researching the newly
`discovered hydroboration reaction as a postdoctoral research
`associate (Figure 2). It was my first time in a foreign country,
`and one of the things that left an impression on me was the
`strength that America had at that time. For instance, one
`American dollar was worth 360 yen. My monthly salary as a
`doctoral researcher was four times what I received even as an
`assistant professor in Japan. There was little difference in the
`food between the rich and the poor. There were many such
`things that I found that were unimaginable in Japan. Purdue
`University has a strong relationship with Hokkaido Univer-
`sity. In the past, the former president of the university,
`Professor S. Ito, had studied at Purdue. Professor S. Nomachi
`and Professor T. Sakuma were at Purdue at the same time as I
`was.
`From Professor Brown I learned many things, including
`his philosophy towards research, but there is one thing he said
`that I can recall with clarity: “Do research that will be in the
`textbooks”. It is not easy to do this kind of work, but this has
`remained my motto. Professor Brown was 51 years old, and he
`
`Professor Herbert C. Brown and Purdue University
`
`As I reflect on these long years, I see that there were many
`difficult periods as well as joyful ones. Memories of the tough,
`
`[*] Prof. A. Suzuki
`Hokkaido University
`Sapporo, Hokkaido (Japan)
`[**] Copyright The Nobel Foundation 2010. We thank the Nobel
`Foundation, Stockholm, for permission to print this lecture.
`
`Angew. Chem. Int. Ed. 2011, 50, 6723 – 6737
`
` 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
`
`6723
`
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`

`

`Nobel Lectures
`
`A. Suzuki
`
`Figure 3. With Professor and Mrs. Brown at their home in IN (USA),
`June 1995.
`
`an advantage in some cases. For example, we could use these
`compounds in the presence of water without any special care.
`I decided that there might be some way to use these
`compounds in organic reactions, and I created a new research
`plan upon my return to Japan in April 1965 (Figure 4).
`
`Figure 1. Leaving Tokyo/Haneda Airport for the US, August 1963.
`
`Figure 4. My family, October 1969.
`
`Discovery of Alkyl Radical Formation from R3B
`
`At the time, I focused on three characteristics of organoboron
`compounds. First, compared to other organometallic com-
`pounds, the difference in the electronegativity of the CB
`bond is small, meaning that it is an almost perfect covalent
`bond. Second, the boron atom has an open p-electron
`structure, meaning that it might be susceptible to nucleophilic
`reagents. This suggested that the compounds might undergo
`reactions as shown in Equation (a). Third, studies of the CB
`
`Figure 2. Working at Professor H. C. Brown’s Lab., Purdue Univ.,
`August 1964.
`
`was an extremely active researcher. He visited Hokkaido
`University three times. I had the opportunity to meet him and
`Mrs. Brown more than ten times (Figure 3), but we missed
`them in 2004 and 2005, unfortunately.
`Hydroboration is the reaction of alkenes with borane to
`produce organic boron compounds. These boron compounds
`differ from other organometallic compounds: they are chemi-
`cally inactive, particularly in ionic reactions. For example,
`organic boron compounds are stable in the presence of water
`and alcohol, and do not undergo Grignard-type reactions.
`Therefore, it was thought that such compounds would be
`unsuitable as synthetic intermediates. Between 1963 and 1965,
`when I was at Purdue, there were more than 30 doctoral
`researchers and graduate students from all over the world in
`the Brown Lab. Many of these friends shared the opinion that
`the boron compounds were inactive. In contrast, I thought
`that the stable character of organoboron compounds could be
`
`6724
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`www.angewandte.org
`
` 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
`
`Angew. Chem. Int. Ed. 2011, 50, 6722 – 6737
`
`PETITIONER NPC EX. 1024
` Page 3 of 16
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`

`

`Suzuki Coupling
`
`bonding distance showed that it was almost equal to the CC
`bonding distance.
`In consideration of these three points, I decided to study
`the reaction of organic boron compounds with a,b-unsatu-
`rated ketones. In other words, I hypothesized that intermedi-
`ate (I) in Equation (b) would be obtained through a
`
`purchased from Hokkai Sanso (now called Air Water Inc.),
`which we further purified. Nevertheless, trace amounts of
`oxygen were still present in our nitrogen gas. The oxygen
`acted as a catalyst and promoted the reaction. In the USA,
`extremely pure nitrogen could easily be purchased in those
`days, and the nitrogen gas did not contain sufficient amounts
`of oxygen to cause the reaction.
`From such unexpected results, we found that with small
`amounts of oxygen catalyst, organoboron compounds would
`produce alkyl radicals. Furthermore, the reaction followed
`the radical chain mechanism as shown in Equation (c), rather
`than the coordination mechanism that we had inferred
`previously [Eq. (b)].
`
`quasihexagonal transition state, which would be hydrolyzed
`to give a saturated ketone. When we examined methyl vinyl
`ketone in the reaction, we found that the predicted corre-
`sponding saturated ketone was produced in a quantitative
`yield [Eq. (b)]. We obtained these results in 1966, and I
`notified Professor Brown of our findings in a letter, and he
`was extremely interested. He told us that he wanted to
`explore the results at Purdue as well. I supported his proposal,
`and we continued to study a,b-unsaturated ketones at
`Hokkaido, while a,b-unsaturated aldehydes would be inves-
`tigated at Purdue. We analyzed the scope of the reaction, and
`tried several types of a,b-unsaturated ketone reactions and
`found that each produced favorable amounts of the corre-
`sponding saturated ketones at room temperature. Although
`we discovered that compounds with a substituent in the
`b position, such as compounds II, would not react at room
`temperature, we found that the expected proportions of
`products could be formed in THF (tetrahydrofuran) solution
`at reflux temperature. I received a letter from G. Kabalka
`(now professor at the University of Tennessee), who was then
`a graduate student doing related research at Purdue. Accord-
`ing to the letter, something similar was found for a,b-
`unsaturated aldehydes. None of the corresponding saturated
`aldehydes were produced by the reaction of compounds such
`as III, which had a substitution group in the b position, even
`though many similar compounds such as acrolein reacted
`easily at room temperature. I proposed that each laboratory
`confirm the results of the other, and we began experiments on
`III and found that the reaction proceeded in THF at reflux
`temperature. However, subsequent experiments at the Brown
`lab did not find that our reaction occurred. I remember a
`sentence in the letter I received from Professor Brown
`reporting their results. “Chemistry should be international.
`Why do we have such a big difference between two places,
`Sapporo, Japan, and West Lafayette, USA?”
`When we looked more closely at these contradictory
`results, we discovered something quite unexpected. A trace
`amount of oxygen contaminating in the nitrogen gas we used
`in our reaction system was catalyzing the reaction. At the
`time, we knew that organoboron compounds reacted with
`oxygen, so both we and the Brown Lab conducted the
`reactions in nitrogen gas. In our laboratory, we used nitrogen
`
`Serendipity
`
`One often hears lately of the idea of “serendipity” in research.
`Serendipity refers to the capability to discover the crucial and
`essential components from unexpected phenomena. I believe
`that any researcher has the chance to exhibit serendipity.
`However, in order to make the most of such opportunities, a
`researcher must have the humility to see nature directly, an
`attentiveness that does not let even the dimmest spark escape,
`and an insatiable appetite for research. Some amount of luck
`also matters, but what can be said with certainty is that little
`will come of a half-hearted effort.
`
`Quick Publication
`
`In 1970, we were performing experiments to directly produce
`carboxylic acid from organoboron compounds. One possibil-
`ity we explored was to use complexes derived from organo-
`boron compounds and a cyanide ion which react with protonic
`acids. We were not able to obtain our intended result, but we
`discovered that these cyano complexes could produce sym-
`metrical ketones in good yield when reacted with electrophilic
`reagents like benzoyl chloride. Nonetheless, I was busy
`preparing for a presentation at an international conference
`to be held in Moscow in 1971, and we left for the conference
`without finishing our paper on it. After I had successfully
`given my invited lecture, I left the lecture hall to quench my
`thirst with a glass of water. At that time, a tall foreign man
`introduced himself to me. That man was Professor A. Pelter
`of Manchester University in the UK. He later transferred to
`the University of Wales, Swansea, and served as the chair of
`the Department of Chemistry as well as the Vice-Chancellor
`of the university. At our first encounter in Moscow, I had no
`
`Angew. Chem. Int. Ed. 2011, 50, 6723 – 6737
`
` 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
`
`www.angewandte.org
`
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`Nobel Lectures
`
`idea that he was studying organoborane chemistry. We spoke
`about many things that day and, to my surprise, I learned that
`he had also performed the very research that we had just
`done, and had already published his results the previous
`month in Chemical Communications. As a result, our work
`remains unpublished. Today, that reaction is sometimes called
`the Pelter reaction. Knowing about our situation, Professor
`Pelter sympathized with us and consoled us, but no one else
`knew anything about it. We learned from it. When doing
`research, we must keep three things in mind. First, we must
`study the existing literature carefully and comprehensively.
`Second, we need to be aware that other researchers, near and
`far, are thinking about the same things that we are. Third, we
`must quickly publish papers on our results (not just oral
`presentations).
`
`Tragic Accident
`
`Thinking back on that conference—the International Confer-
`ence on Organo-Metallic Chemistry in Moscow 1971—I
`cannot help but think of the tragic accident, in which an
`ANA passenger jet collided with a Japan Self-Defense Force
`aircraft in the skies above Shizuku-ishi in Iwate prefecture.
`On that day, I had flown from Sapporo/Chitose to Tokyo/
`Haneda to stay for one night before boarding an Aeroflot
`plane to Moscow the next day. I flew on a Japan Airlines flight
`in the afternoon, with no idea that the plane that departed
`only thirty minutes earlier would be involved in such a terrible
`accident. Knowing nothing of the tragedy, I landed in Haneda,
`and headed to the Haneda Tokyu Hotel near the Airport, and
`then learned of the accident. All passengers and crew, 162
`persons, were killed.
`
`Haloboration Reaction
`
`Thereafter, our group carried out research on the synthesis of
`organic compounds through haloboration. I had one memory
`from this that I will reflect upon. This research was based on
`the discovery that a certain type of haloborane derivative
`adds to terminal carbon–carbon triple bonds. This reaction
`was discovered in 1981, but we first disclosed part of this
`research in the United States in 1982. That fall, the American
`Chemical Society hosted a symposium in Midland, Michigan,
`on organic synthesis involving organoboron compounds. I was
`one of the special invited speakers, and was preparing to
`travel to the US when I received a letter from Professor
`Brown. It was an invitation to visit Purdue to give a lecture
`before the symposium. The topic of
`that
`lecture was
`haloboration. Professor Brown listened to my presentation
`intently, and raised his hand to comment the moment I
`finished speaking. He said that his group had studied the
`possibility and usefulness of the same reaction at almost the
`same time as we had. They had looked at haloboration
`reactions for acetylene compounds, but they had only looked
`at reactions of the internal acetylenes as substrates. Their
`work was unsuccessful, and they ended the research. The
`goddess of fortune is capricious, indeed.
`
`A. Suzuki
`
`Over many long years, I have had many different
`experiences. I have encountered many friends at the Faculty
`of Engineering, Hokkaido University, especially among many
`of the people who continue to work at the Third Laboratory
`of the Applied Chemistry Department, and the Organic
`Synthetic Chemistry Laboratory in the Synthetic Chemical
`Engineering Department. They have allowed me to enjoy a
`long career in research. I conclude by expressing my sincere
`gratitude to these students and colleagues in research.
`I have won several awards for my work, listed below:
`* The Chemical Society of Japan Award, 1989.
`* The Society of Synthetic Organic Chemistry Japan,
`Special Award, 2004.
`* Japan Academy Award, 2004.
`* The Order of the Sacred Treasure, Gold Rays with
`Neck Ribbon, 2005.
`* P. Karrer Gold Medal, 2009.
`* Nobel Prize in Chemistry, 2010.
`* The Order of Culture of Japan, 2010.
`* H. C. Brown Award of the American Chemical Society,
`2011.
`
`Nobel Lecture
`
`Introduction
`
`Carbon–carbon bond-formation reactions are important
`processes in chemistry, because they provide key steps in the
`building of complex, bioactive molecules developed as
`medicines and agrochemicals. They are also vital in develop-
`ing the new generation of ingeniously designed organic
`materials with novel electronic, optical, or mechanical
`properties, likely to play a significant role in the burgeoning
`area of nanotechnology.
`During the past 40 years, most important carbon–carbon
`bong-forming methodologies have involved using transition
`metals to mediate the reactions in a controlled and selective
`manner. The palladium-catalyzed cross-coupling reaction
`between different types of organoboron compounds and
`various organic electrophiles including halides or triflates in
`the presence of base provides a powerful and general
`methodology for the formation of carbon–carbon bonds.
`The (sp2)CB compounds (such as aryl- and 1-alkenylboron
`derivatives) and (sp3)CB compounds (alkylboron com-
`pounds) readily cross-couple with organic electrophiles to
`give coupled products selectively in high yields. Recently, the
`(sp)CB compounds (1-alkynylboron derivatives) have also
`been observed to react with organic electrophiles to produce
`the expected cross-coupled products.
`Some of representative reactions between various orga-
`noboranes and a number of organic electrophiles are shown in
`Scheme 1. The numbers in parentheses indicate the year they
`were first reported by our group.
`Such coupling reactions offer several advantages:
`ready availability of reactants;
`(1)
`(2) mild reaction conditions and high product yields;
`(3) water stability;
`
`6726
`
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`
` 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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`Angew. Chem. Int. Ed. 2011, 50, 6722 – 6737
`
`PETITIONER NPC EX. 1024
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`

`Suzuki Coupling
`
`tetracoordinate organoboron compounds,
`instead of tricoordinate organoboron deriv-
`atives. According to the study by Gropen
`and Haaland,[2] the methyl group in tetra-
`methylborate was observed to be 5.5 times
`more electronegative than the methyl group
`in trimethylborane. Such behavior was also
`expected for the reaction of triorganobor-
`anes in the presence of base. Thus, we found
`that the reaction of vinylic boron com-
`pounds with vinylic halides proceeds
`smoothly in the presence of a base and a
`catalytic amount of a palladium complex to
`provide the expected conjugated alkadienes
`and alkenynes stereo- and regioselectively
`in excellent yields (Table 1).
`
`Scheme 1.
`
`(4)
`
`easy use of the reaction both under aqueous and
`heterogeneous conditions;
`toleration of a broad range of functional groups;
`(5)
`(6) high regio- and stereoselectivity;
`(7)
`insignificant affect of steric hindrance
`(8) use of a small amount of catalyst;
`(9)
`application in one-pot synthesis;
`(10) nontoxic reaction;
`(11) easy separation of inorganic boron compound;
`(12) environmentally friendly process.
`
`As one of the defects of the reaction, one would point out
`the use of bases. However, the difficulty can be overcome by
`using suitable solvent systems and adequate bases. Conse-
`quently, these coupling reactions have been actively utilized
`not only in academic laboratories but also in industrial
`processes.
`
`Coupling Reactions of (sp2)CB Compounds
`
`Reactions of Vinylic Boron Compounds with Vinylic Halides
`Synthesis of Conjugated Alkadienes
`
`Cross-coupling reactions between vinylic boranes and
`vinylic halides were not reported to proceed smoothly in the
`presence of only palladium catalysts. During the initial stage
`of our exploration, we postulated that a drawback of the
`coupling is caused by the following aspects of the mechanism.
`The common mechanism of transition-metal-catalyzed cou-
`pling reactions of organometallic compounds with organic
`halides involves sequential a) oxidative addition, b) trans-
`metalation, and c) reductive elimination.[1] It appeared that
`one of the major reasons that 1-alkenylboranes cannot react
`with 1-alkenyl halides is step (b). The transmetalation process
`between RMX (M = transition metal, X = halogen) and
`organoboranes does not occur readily because of the weak
`carbanion character of the organic groups in the organo-
`boranes. To overcome this difficulty we anticipated the use of
`
`Table 1: Cross-coupling reaction of 1 with 2.
`
`1[a] Cat.[b] (mol %) Base (equiv/2)
`
`Solvent
`
`t [h] Yield [%] of 3
`
`1 b PdL4 (3)
`1 b PdL4 (3)
`1 a PdL4 (3)
`1 b PdL4 (1)
`
`6
`THF
`none
`benzene 6
`none
`2 m NaoEt(2)-EtOH THF
`2
`2 m NaOEt(2)-EtOH benzene 2
`
`0
`0
`73
`86
`
`[a] 1 a, X2 = (Sia)2 (Sia = 1,2-dimethylpropyl); 1 b, X2 = catecholate. [b] L =
`PPh3.
`
`Although the coupling reaction of (E)-1-alkenylboranes,
`readily obtained by the hydroboration of appropriate alkynes
`with disiamylborane or dicyclohexylborane, proceeds readily
`with (E)- and (Z)-1-alkenyl bromides and iodides to give the
`corresponding dienes (Table 2), (Z)-1-alkenylboranes, pre-
`pared by hydroboration of 1-haloalkynes followed by reaction
`with tert-butyllithium, gave low product yields, near 50 %
`(Table 3).
`it was found that high yields and high
`Fortunately,
`stereoselectivity could be achieved by coupling (Z)-1-alkenyl
`halides with (Z)-1-alkenyldialkoxyboranes,
`instead of dis-
`iamyl- and dicyclohexylborane derivatives (Table 3).[3] Con-
`sequently, the cross-coupling reaction of 1-alkenylboranes
`with 1-alkenyl halides can be achieved readily for the
`
`Table 2: Cross-coupling reaction of (E)-1-vinyldisiamylboranes.[a]
`
`1-Alkenylbor-
`ane
`
`1-Alkenylbro-
`mide
`
`Product
`
`Yield [%]
`(purity [%])
`
`86 (98)
`
`88 (99)
`
`89 (98)
`
`[a] Reaction conditions: [Pd(PPh3)4], NaOEt, benzene, reflux, 2 h.
`
`Angew. Chem. Int. Ed. 2011, 50, 6723 – 6737
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` 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
`
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`

`Nobel Lectures
`
`A. Suzuki
`
`Table 3: Cross-coupling of (Z)-1-hexenyldisiamyl- or (Z)-1-hexenyldiiso-
`propoxyborane.
`
`Mechanism of the Vinylic-Vinylic Cross-Coupling
`
`BY2 in 4
`
`B(Sia)2
`B(OiPr)2
`
`Yield [%] of 5
`
`Purity [%] of 5
`
`49
`87
`
`> 98
`> 99
`
`synthesis of all kinds of conjugated alkadienes. The reaction
`has been applied to the synthesis of many natural and
`unnatural compounds which have conjugated alkadiene
`structures.[4–7] Among the many synthetic applications of the
`Suzuki coupling reaction for conjugated alkadienes, the total
`synthesis of palytoxin (Scheme 2), a complex and toxic
`is an epoch-making contribution.[8] As
`natural product,
`another example, the total synthesis of lucilactaene is shown
`in Scheme 3.[9]
`
`The principal features of the cross-coupling reaction are
`as follows: a) Small catalytic amounts of the palladium
`complexes (1–3 mol %) are required to obtain the coupled
`products. b) The coupling reactions are highly regio- and
`stereoselective and take place while retaining the original
`configurations of both the starting alkenylboranes and the
`haloalkenes. The isomeric purity of the products generally
`exceeds 98 %. c) A base is required to carry out a successful
`coupling. In the initial stage of the study, as mentioned
`previously, we considered that tetracoordinate organoboron
`compounds facilitate the transfer of organic groups from the
`boron to the palladium complex in the transmetalation step.
`In order to check this possibility, the reaction of lithium (1-
`hexenyl)methyldisiamylborate was examined, as shown in
`Equation (1). The coupled product, however, was obtained
`only in 9 % yield. On the other hand, it was found that
`(trichlorovinyl)palladium(II) complexes 6 and 9, both pre-
`pared as pure solids, reacted with vinylborane 7 to give diene
`8 [Eqs. (2) and (3)]. In the case of 6, no reaction occurs
`without a base, whereas the coupling reaction proceeds
`
`Scheme 2. Synthesis of palytoxin.
`
`Scheme 3. Synthesis of lucilactaene.
`
`smoothly in the presence of a base to give the coupled product
`in 89 % yield. The intermediate 9 readily reacts with 7 without
`a base to provide the same product 8 in almost quantitative
`yield after 1 h. Consequently, such evidence suggests that
`vinylic alkoxypalladium(II) compounds such as 9 were
`necessary intermediates in these cross-coupling reactions.
`Accordingly,
`it is considered that the reaction proceeds
`through the catalytic cycle shown in Scheme 4.[10]
`
`Reactions with Aryl Halides
`
`As described in the previous section, it was discovered
`that vinylic boron compounds readily react with vinylic
`halides to give coupled products—conjugated alkadienes.
`
`6728
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`

`Table 5: Coupling of 1-alkenylboranes with various organic halides.
`
`1-Alkenylborane
`
`Halide
`
`Product[a]
`
`Yield [%]
`
`100
`
`98
`
`3 1
`
`00
`
`87
`
`83
`
`89
`
`97
`
`93
`
`95
`
`Phl
`
`PhBr
`
`PhCl
`
`PhCH2Br
`BrCCPh
`BrCCHex
`
`[a] Isomeric purity > 98 %.
`
`Aromatic Boron Compounds
`Reactions with Aromatic Halides
`Synthesis of Biaryls
`
`The coupling of aryl halides with copper at very high
`temperature is called the Ullmann reaction, which is of broad
`scope and has been used to prepare many symmetrical biaryls.
`However, when a mixture of two different aryl halides is used,
`there are three possible biaryl products. Consequently, the
`development of a selective and general synthesis of all kinds
`of biaryls has been desired.
`The first method to prepare biaryls by the cross-coupling
`of aryl boranes with haloarenes was reported in 1981
`[Eq. (5)].[12] The reaction proceeds even under heterogeneous
`
`conditions to give the corresponding coupled products
`selectively in high yields. Since this discovery, various
`modifications have been made to the reaction conditions.
`As the bases, Na2CO3, NaHCO3, Tl2CO3, K3PO4, etc. are
`employed. In some cases, CsF or Bu4NF can be used instead of
`the usual bases [Eq. (6)].[13] Phosphine-based palladium
`
`Suzuki Coupling
`
`Scheme 4. Catalytic cycle for the coupling reaction of alkenylboranes
`with haloalkenes.
`
`We next attempted to examine the reaction of 1-alkenylbor-
`anes with haloarenes which also have sp2-hybridized carbon–
`halogen bonds, and found that the reaction takes place
`smoothly. Representative results are shown in Table 4.
`
`Table 4: Cross-coupling reaction of 10 with iodobenzene.
`
`Base
`
`none
`NaOEt
`NaOMe
`NaOH
`
`t [h]
`
`Yield [%]
`
`Ratio of 11/12
`
`6
`2
`2
`2
`
`0
`100
`100
`100
`
`100:0
`100:0
`100:0
`
`This reaction has one more advantage that only one
`product 11 (head-to-head coupled product) is formed. Addi-
`tional coupling reactions of vinylic boranes are shown in
`Table 5. Aromatic bromides and iodides easily react with
`vinylic boron compounds, but aromatic chlorides do not
`participate in the coupling, except reactive chlorides, such as
`allylic and benzylic derivatives. Heteroaromatic halides can
`also be used as coupling partners. Ortho substituents on the
`benzene ring do not give difficulty. Thus, the cross-coupling
`reaction can be used for the synthesis of benzo-fused
`heteroaromatic compounds [Eq. (4)].[11]
`
`Angew. Chem. Int. Ed. 2011, 50, 6723 – 6737
`
` 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
`
`www.angewandte.org
`
`6729
`
`PETITIONER NPC EX. 1024
` Page 8 of 16
`
`

`

`Nobel Lectures
`
`catalysts are generally employed since they are stable to
`prolonged heating; however, extremely high coupling reac-
`tion rates can sometimes be achieved by using palladium
`catalysts without a phosphine ligand, such as Pd(OAc)2, [{(h3-
`C3H5)PdCl}2], and [Pd2(dba)3].
`Carbon–carbon bond-forming reactions employing orga-
`noboron compounds and organic electrophiles have been
`recently recognized as powerful tools for the construction of
`new organic compounds. Among such reactions, aromatic–
`aromatic (or heteroaromatic) couplings between aromatic
`boronic acids or esters and aromatic electrophiles to provide
`symmetrical and unsymmetrical biaryls selectively in high
`yields have been used most frequently. The importance of
`biaryl units as components in many kinds of compounds,
`pharmaceuticals, herbicides, and natural products, as well as
`engineering materials, such as conducting polymers, molec-
`ular wires, and liquid crystals, has attracted enormous interest
`from the chemical community. Such aromatic–aromatic,
`aromatic–heteroaromatic, and heteroaromatic–heteroaro-
`matic coupling reaction have been recently reviewed in
`detail.[14]
`
`Coupling of Aryl Boronic Acid Derivatives Having Highly Sterically
`Hindered or Electron-Withdrawing Functionalities
`
`Although steric hindrance of aryl halides is not a major
`factor in the formation of substituted biaryls, low yields result
`when ortho-disubstituted aryl boronic acids are used. For
`example, the reaction with mesitylboronic acid proceeds only
`slowly because of steric hindrance during the transmetalation
`to the palladium(II) complex. The reaction of mesitylboronic
`acids with iodobenzene at 80 8C in the present of [Pd(PPh3)4]
`and various bases has been reported.[15] The results are
`summarized in Table 6.
`
`Table 6: Reaction of mesitylboronic acid with iodobenzene under
`different conditions.
`
`A. Suzuki
`
`DME. On the other hand, the addition of stronger bases, e.g.,
`aqueous NaOH or Ba(OH)2, both in benzene and DME,
`exerts a remarkable effect on the acceleration rate of the
`coupling. By using aqueous Ba(OH)2 in DME at 80 8C,
`mesitylboronic acid couples with iodobenzene within 4 h to
`give the corresponding biaryl in a quantitative yield. Some
`such coupling reactions are depicted in Equations (7) and (8).
`
`An alternative procedure, using the esters of boronic acids
`and anhydrous base, has been developed for sterically
`hindered aryl boronic acids and provide high yields. The
`coupling can be readily achieved by using the trimethylene
`glycol ester of mesitylboronic acid and Cs2CO3 or K3PO4 in
`DMF at 100 8C to give a quantitative yield of the coupled
`products [Eq. (9)].[15]
`
`Base
`
`Solvent
`
`T [8C]
`
`Na2CO3
`Na2CO3
`K3PO4
`NaOH
`Ba(OH)2
`
`benzene/H2O
`DME/H2O
`DME/H2O
`DME/H2O
`DME/H2O
`
`80
`80
`80
`80
`80
`
`8 h
`
`25 (6)
`50 (1)
`70 (0)
`95 (2)
`99 (2)
`
`Yield [%][a]
`24 h
`
`77 (12)
`66 (2)
`
`48 h
`
`84 (25)
`83 (7)
`
`[a] GLC yields of the coupling product based on iodobenzene; the yields
`of mesitylene are shown in parentheses.
`
`Aqueous Na2CO3 in benzene or DME (dimethoxyethane)
`is not effective as a base for the coupling of mesitylboronic
`acid and the reaction is not completed even after two days.
`Although the side reactions such as homocoupling are
`negligibly small, the formation of mesitylene by hydrolytic
`deboronation was observed, increasing with the reaction time.
`It is noteworthy that such hydrolytic deboronation is faster in
`benzene/H2O than in the modified conditions of aqueous
`
`Even without sterically hindered substrates, the reaction
`under aqueous conditions is often undesirable because of
`competitive hydrolytic deboronation. A kinetic study[16] into
`the reaction of substituted aryl boronic acids showed that
`electron-withdrawing substituents accelerate the deborona-
`tion. Although there is no large difference between meta- and
`para-substituted phenylboronic acids, substituents at
`the
`ortho position may greatly increase the rate of deboronation.
`For example, a 2-formyl group on aryl boronic acids is known
`to accelerate the rate of hydrolytic deboronation.[16] Indeed,
`the coupling of 2-formylphenylboronic acid with 2-iodoto-
`luene at 80 8C using Na2CO3 in DME/H2O gives only a 54 %
`yield of the corresponding biaryl, with accompanying benzal-
`dehyde (39 %). Aprotic conditions are desirable for such
`boronic acids that are sensitive to aqueous base. Thus, the
`trimethylene glycol ester of 2-formylphenylboronic acid
`
`6730
`
`www.angewandte.org
`
` 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
`
`Angew. Chem. Int. Ed. 2011, 50, 6722 – 6737
`
`PETITIONER NPC EX. 1024
` Page 9 of 16
`
`

`

`Suzuki Coupling
`
`readily couples with iodobenzene at 100 8C in DMF to give
`the coupled product in a yield of 89 %, with less than 10 %
`benzaldehyde formed [Eq. (10)].[15]
`
`Table 8: Suzuki