Livret 15062012 final

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Livret 15062012 final
GRIGNARD : 100 ans de
modernité d’un Prix Nobel
21-22 Juin 2012
CPE Lyon - École Supérieure de Chimie Physique Électronique de Lyon
Université Claude Bernard Lyon 1
Journées organisées
sous l’égide de l’Académie des Sciences
1
et avec le soutien de la Société
Chimique de France
GRIGNARD : 100 ans de
modernité d’un Prix Nobel
21-22 Juin 2012
CPE Lyon - École Supérieure de Chimie Physique Électronique de Lyon
Université Claude Bernard Lyon 1
Journées organisées
sous l’égide de l’Académie des Sciences
2
et avec le soutien de la Société
Chimique de France
GRIGNARD : 100 ans de modernité d’un Prix Nobel
Victor Grignard a reçu le prix Nobel de chimie en 1912 pour ses travaux réalisés alors qu’il
était professeur assistant à la Faculté des Sciences de Lyon. Victor Grignard a aussi dirigé
l’ESCIL (École Supérieure de Chimie Industrielle de Lyon), devenue CPE Lyon, de 1921 à
1935. C’est à ce titre que CPE Lyon, en collaboration avec l’Université Claude Bernard
Lyon 1 et l’Institut de Chimie de Lyon, ont décidé de célébrer le centenaire du prix Nobel
de Victor Grignard en organisant les journées « Grignard : 100 ans de modernité d’un Prix
Nobel » les 21 et 22 juin 2012. Cet évènement est également soutenu par la famille
Grignard.
La découverte par Victor Grignard de la réactivité des organomagnésiens vis-à-vis
d'électrophiles carbonés a révolutionné la façon dont sont construites les liaisons carbonecarbone dans les molécules organiques. Au cours du siècle précédent, un grand nombre de
méthodes de synthèse initiées par les travaux de Grignard ont vu le jour et ont permis de
construire des molécules carbonées toujours plus complexes, trouvant des applications
dans de nombreuses disciplines, de la chimie de spécialité jusqu'à la médecine. Cent ans
après le prix Nobel attribué à Victor Grignard, cette chimie s'est largement diversifiée et
modernisée, s'étendant à des métaux plus sélectifs comme le zinc et le bore, et bénéficiant
de l'apport de la catalyse par les métaux de transition. Ainsi, le prix Nobel de chimie 2010
attribué à Richard F. Heck, Ei-Ichi Negishi et Akira Suzuki témoigne de cet héritage et de
l'impact toujours puissant de ces travaux. Dans un début de vingt-et-unième siècle marqué
par la recherche de voies de synthèse plus efficaces, sélectives et éco-compatibles, les
réactifs de Grignard sont plus que jamais d'actualité en raison de l'innocuité et l'abondance
du magnésium et des métaux apparentés. Les applications industrielles et la maîtrise de
ces composés particulièrement réactifs au moyen de réacteurs intensifiés seront aussi
décrites. Ce symposium rendra hommage à ce grand chimiste lyonnais et, à travers des
conférences de spécialistes du domaine, démontrera la modernité toujours vibrante de ses
travaux.
La Division Histoire de la Chimie de l'American Chemical Society (ACS) a choisi
d’honorer l'Université de Lyon en lui décernant son "Chemical Breakthrough Award" en
2010, pour la publication originale sur les organomagnésiens de Victor Grignard. C’est
dans le bâtiment du même nom que l'Université Claude Bernard Lyon 1 a choisi de lui
rendre hommage en affichant cette prestigieuse distinction et en découvrant la plaque aux
côtés de tous les congressistes comme de la famille Grignard.
2
GRIGNARD : the Nobel Prize, 100 years of innovation
Victor Grignard was awarded the Nobel Prize in Chemistry in 1912 for his work on
organomagnesium reagents. These landmark discoveries were made while he served as
assistant professor at the Faculté des Sciences de Lyon. Victor Grignard directed the ESCIL
(École Supérieure de Chimie Industrielle de Lyon), now CPE Lyon, from 1921 to 1935.
Thus, it is appropriate that CPE Lyon, the Université Claude Bernard Lyon 1, and the
Institut de Chimie de Lyon should join together to celebrate the 100th anniversary of
Victor Grignard’s Nobel Prize with a symposium entitled “GRIGNARD : the Nobel Prize,
100 years of innovation.” The event will take on June 21-22, 2012, and will be attended by
members of the Grignard family.
The breakthrough discovery of the reactivity of organomagnesium reagents with carbon
electrophiles revolutionized the manner in which carbon-carbon bonds are formed in the
synthesis of organic molecules. Over the course of the last century, a tremendous number
of new synthetic methods have been developed based on Grignard’s original discovery.
These methods have enabled the synthesis of ever-more complex organic structures and
have found applications in fields ranging from specialty chemicals to medicine. In the 100
years since the Nobel Prize was awarded to Victor Grignard, the chemistry of
organometallic nucleophiles has been continuously diversified and improved. It has been
extended to more selective metals including zinc and boron and has benefited from the
power of transition metal catalysis. The 2010 Nobel Prize awarded to Richard F. Heck, Eiichi Negishi and Akira Suzuki attests to the powerful impact Grignard’s discovery
continues to have today. As we continue to search for ever-more efficient, selective, and
eco-friendly synthetic methods in the 21st century, Grignard reagents are more relevant
than ever, considering the low toxicity of magnesium and related metals. Industrial
applications of these highly reactive compounds are facilitated by the development of
intensified reactors. The conference, led by world-renown scientists, will honour the great
chemist from Lyon and present the full range of innovation, discovery, and excitement
that this landmark discovery continues to stimulate today.
The Division of the History of Chemistry of the American Chemical Society (ACS) has
chosen to honor Victor Grignard’s work by granting the Université de Lyon its prestigious
2010 Citation for Chemical Breakthrough award for his landmark publication in Comptes
Rendus 1900. The Université Claude Bernard Lyon 1 will unveil the plaque in the building
that carries Grignard’s name, during an award ceremony in the presence of conference
attendees, university and government officials, and members of the Grignard family.
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4
Sommaire / Outline
Victor Grignard, Université de Lyon, France
Nobel Prize 1912
Sur quelques nouvelles combinaisons organométalliques du magnésium et leur application à des
synthèses d’alcools et d’hydrocarbures.
6
Jean-Marie Lehn, ISIS-Université de Strasbourg, France
Nobel Prize 1987
Perspectives in Chemistry: From Supramolecular Chemistry Towards Adaptive Chemistry
10
Yves Chauvin, Lyon, France
Nobel Prize 2005
12
Alexandre Alexakis, Université de Genève, Switzerland
Some aspects of using Grignard reagents in asymmetric synthesis.
14
Marika Blondel-Mégrelis, Club « Histoire de la Chimie », SCF
Victor Grignard, chimiste français.
16
Yves Fort, Nancy-Université, France
Lithiated Polar Organometallics: towards toolboxes for regioselective functionalization of
azaheterocycles.
18
Paul Knochel, Ludwig-Maximilians-University, Munich, Germany
Polyfunctional magnesium and zinc reagents in organic synthesis.
22
Bruce H. Lipshutz, University of California, Santa Barbara, USA
Organometallic Chemistry in Just Water at Room Temperature. What Would Victor Grignard Think?
24
Jacques Maddaluno, Université de Rouen, France
Nucleophilic addition of alkyllithiums: enantioselective and catalytic?
26
Ilan Marek, Technion, Israël
Selectivity in Carbon-Carbon Bond Activation.
28
William R. Roush, The Scripps Research Institute, Floride, USA
Synthesis of Bifunctional Allylboron Reagents via Allene Hydroboration Reactions.
30
Victor Snieckus, Queen’s University, Canada
Following the star of Grignard and those of Wittig and Gilman.
32
Jun-Ichi Yoshida, Kyoto University, Japan
Hot reagents in High-tech Reactors.
36
Remerciements / Acknowledgements
40
Comités / Committees
41
Programme / Programme
42
5
VICTOR GRIGNARD†
Professeur, Université de Lyon, France
François Auguste Victor Grignard was born in Cherbourg
on May 6, 1871. In 1889 He won a scholarship to the École
Normale Spécial at Cluny. After two years, the school was
closed because of a dispute between supporters of the
"classic" and "modern" methods of secondary education.
Grignard himself had the good fortune to join the University
of Lyon where He gains the degree “Licencié ès Sciences
Mathématiques” in 1894. The same year, He joins as a junior
faculty member and then began his long association with
Philippe Barbier. He obtained the degree “Licencié-èsSciences Physiques” and in 1898 he became “chef des
travaux pratiques” and also wrote his first paper, jointly with
Barbier. His discovery of the classic preparation of
magnesium alkyl halides was first communicated by Henri
Moissan to the Académie des Sciences on May 11, 1900. In
1901 he submitted his brilliant thesis on organic magnesium
compounds Sur les Combinaisons organomagnésiennes mixtes, and was awarded the degree
Docteur ès Sciences de Lyon. In 1905, He was appointed Maître de Conférences at the
University of Besançon but he returned to Lyon in 1906 with a similar position until his
election as Professeur-adjoint de Chimie Générale in 1908. In 1909 he took charge of the
Department of Organic Chemistry at Nancy, and in the following year he became Professor of
Organic Chemistry. At the beginning of the First World War, Grignard was mobilized in his
former rank of corporal, but he was soon to be commissioned to study, at Nancy, the cracking
of benzols and, later, to work on problems of chemical warfare in Paris. He visited the United
States during 1917-18 as the chemical representative on the Tardieu Committee and he
delivered a lecture at the Mellon Institute. After the war he returned to Nancy and in 1919 he
succeeded Barbier as Professor of General Chemistry at Lyon. In 1921 he took an additional
position as Director of École de Chimie Industrielle de Lyon (NFR: now CPE Lyon), becoming
a member of the University Council, and in 1929 he became Dean of the Faculty of Sciences.
Grignard's investigations concerned branched unsaturated hydrocarbons, organomagnesium
compounds (on Barbier's recommendation!), constitution of unsaturated compounds by
quantitative ozonization, condensation of aldehydes and ketones, ketone splitting of tertiary
alcohols, the cracking of hydrocarbons in presence of aluminium chloride and catalytic
hydrogenation and dehydrogenation processes under reduced pressures. Grignard quickly
developed the immediate applications of the elegant and simple organomagnesium reagents,
which were destined to play such an important part in organic synthesis that, at the time of his
death in 1935, there were over 6,000 references in the literature.
Grignard was the author of some 170 publications and, at his death on December 13, 1935, he
was working to fulfil his ambition to see a great chemical reference work in the French
language. Two volumes of his Traité de Chimie Organique (Treatise on organic chemistry) had
already been published, two more were ready for the press and the editorial work for another
two was well advanced. In 1937, two of his students, Jean Cologne and Roger Grignard - V.
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Grignard’s son - published Précis de Chimie Organique (Survey of organic chemistry) which is
based on Grignard's lecture course in organic chemistry.
Victor Grignard received several Awards including the Cahours Prize (Institut de France 1901 and 1902), the Berthelot Medal (1902), the Prix Jecker (1905), the Lavoisier Medal (1912),
the Nobel Prize for Chemistry (1912), the Légion d'Honneur (He was appointed Chevalier in
1912, Officier in 1920 and Commandeur in 1933).
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Jean-Marie LEHN
Professeur Honoraire au Collège de France, Paris
Professeur émérite à l’Université de Strasbourg
Jean-Marie LEHN was born in Rosheim, France in 1939.
In 1970 he became Professor of Chemistry at the
Université Louis Pasteur in Strasbourg and from 1979 to
2010 he was Professor at the Collège de France in Paris.
He is presently Professor Emeritus at the University of
Strasbourg. He shared the Nobel Prize in Chemistry in
1987 for his studies on the chemical basis of “molecular
recognition” (i.e. the way in which a receptor molecule
recognizes and selectively binds a substrate), which also
plays a fundamental role in biological processes.
Over the years his work led him to the definition of a
new field of chemistry, which he has proposed calling
“supramolecular chemistry” as it deals with the
complex entities formed by the association of two or
more chemical species held together by non-covalent
intermolecular forces, whereas molecular chemistry
concerns the entities constructed from atoms linked by
covalent bonds. Subsequently, the area developed into the chemistry of "self-organization"
processes and more recently towards "adaptive chemistry".
Author of more than 900 scientific publications, Lehn is a member of many academies and
institutions. He has received numerous international honours and awards including the
CNRS Bronze Medal (1963), the Prix Adrian of the Société Chimique de France (1968), the
CNRS Silver Medal (1972), the Prix Raymond Berr of the Société Chimique de France
(1978), the CNRS Gold Medal (1981), the Pierre Bruylants Medal, Louvain (1981), the Prix
Paracelse of the Société Chimique Suisse (1982), the Alexander von Humboldt
Forschungspreis (1982), the Rolf-Sammet Price of the Frankfurt Univeristy (1985), the
George Kenner Price from the University of Liverpool (1987), the Nobel Price for
Chemistry (1987).
10
Perspectives in Chemistry: From Supramolecular Chemistry Towards
Adaptive Chemistry
Jean-Marie LEHN
ISIS, Université de Strasbourg, France
Supramolecular chemistry explores the design of systems undergoing self-organization, i.e.
systems capable of generating well-defined functional supramolecular architectures by
self-assembly from their components, thus behaving as programmed chemical systems.
Chemistry may therefore be considered as an information science, the science of informed
matter.
The design of molecular information-controlled functional self-organizing systems also
provides an original approach to nanoscience and nanotechnology.
Supramolecular chemistry is intrinsically a dynamic chemistry in view of the lability of the
interactions connecting the molecular components of a supramolecular entity and the
resulting ability of supramolecular species to exchange their constituents. The same holds
for molecular chemistry when the molecular entity contains covalent bonds that may form
and break reversibility, so as to allow a continuous change in constitution by
reorganization and exchange of building blocks. These features define a Constitutional
Dynamic Chemistry (CDC) on both the molecular and supramolecular levels. CDC takes
advantage of dynamic constitutional diversity to allow variation and selection in response
to either internal or external factors to achieve adaptation.
Implementations of this approach for chemical reactivity and dynamic materials will be
discussed.
The merging of the features: - information and programmability, - dynamics and
reversibility, -constitution and structural diversity, points towards the emergence of
adaptive and evolutive chemistry.
References
Lehn, J.-M., Supramolecular Chemistry: Concepts and Perspectives, VCH Weinheim, 1995.
Lehn, J.-M., Dynamic combinatorial chemistry and virtual combinatorial libraries, Chem. Eur. J.,
1999, 5, 2455.
Lehn, J.-M., Programmed chemical systems : Multiple subprograms and multiple
processing/expression of molecular information, Chem. Eur. J., 2000, 6, 2097.
Lehn, J.-M., Toward complex matter: Supramolecular chemistry and self-organization, Proc. Natl.
Acad. Sci. USA, 2002, 99, 4763.
Lehn, J.-M., Toward self-organization and complex matter, Science, 2002, 295, 2400.
Lehn, J.-M., Dynamers : Dynamic molecular and supramolecular polymers,
Prog. Polym. Sci., 2005, 30, 814.
Lehn, J.-M., From supramolecular chemistry towards constitutional dynamic chemistry
and adaptive chemistry, Chem. Soc. Rev., 2007, 36, 151.
11
YVES CHAUVIN
CPE Lyon, France
“I was born on 10 October 1930 in Menin (Menen in
Flemish) in western Flanders, on the border
between Belgium and France. To be perfectly
truthful, I was not a very brilliant student, even at
chemistry school. I chose chemistry rather by
chance, because I firmly believed (and still do) that
you can become passionately involved in your work
whatever it is. Various circumstances, mainly to do
with my military service, prevented me from doing
a PhD and I have often regretted it, though you do
need to choose the "right" supervisor in the "right"
discipline – no easy task when you are totally
inexperienced. So I took a job in industry, but the
fact that process development consisted primarily
of copying what already existed, with no possibility
of exploring other fields, prompted me to resign.
Furthermore, I discovered that this was a very
common attitude among managers. They are afraid
of anything new: "Do what everyone else does and
change as little as possible: at least we know it will work." It is the opposite of my way of
thinking, which, I must admit, is a bit of an obsession! I have often got into arguments
about it. My motto is more, "If you want to find something new, look for something new!"
There is a certain amount of risk in this attitude, as even the slightest failure tends to be
resounding, but you are so happy when you succeed that it is worth taking the risk. The
whole contradiction of research (whether applied or fundamental) generally lies in the fact
that we have to start out with the knowledge handed down by our predecessors, but be
able to depart from it "at the right time. I joined Institut Français du Pétrole in 1960 and
managed to focus my work on what I thought would be most interesting. I got married the
same year and over the course of time we had two sons and five grandsons.
The oil industry essentially uses heterogeneous catalysis: cracking, reforming,
hydrodesulphurization, hydrogenation, etc., but that was not what interested me. I have
always tried to avoid areas that have been perfected with time. At the time, nothing much
was being done in France on coordination chemistry, organometallics or homogeneous
catalysis by transition metals and I was fascinated by the achievements in Italy (G. Natta),
Great Britain (J. Chatt), Germany (at the Max-Planck-Institute in Mülheim) and the United
States. As a result, I unwittingly became the French specialist in these disciplines, which
brought me into contact with both the positive and the unwieldy aspects of the various
commissions at the CNRS. I spent the best part of my time on applied chemistry, which
was what I had been employed for and which I was quite happy about. This was how I
came to develop two homogeneous catalysis processes.
The first one, which uses a nickel-based catalyst, was called "Dimersol" and exists in 2
basic versions. The "gasoline" version consists of dimerising propene to high-octane
12
isohexenes. There is, quite often, an excess of propene, especially in oil refineries that do
not have petrochemicals, as in the United States. There are currently (NDR as in 2005) 35
plants in operation (including 18 in the USA ), with a combined annual output of 3.5
million tonnes. It was the first and only time that coordination catalysis had been used in
refining. The "chemical" version of the process consists of dimerising n-butenes to
isooctenes, basic inputs for plasticizers, using the "oxo" reaction. Current production levels
stand at 400,000 tonnes a year.
The second process I developed, and which uses a titanium-based catalyst, was called
"Alphabutol." It consists of dimerising ethylene to 1-butene, the co-monomer of lowdensity linear polyethylene. The benefits of such a process were not evident to begin with
and stem from a number of causes. There are currently 20 plants operating worldwide,
with a combined output of 400,000 tonnes a year. However, others are under construction,
which will take total output to over 0.5 million tonnes a year.
While there are obvious drawbacks to not having done a PhD (especially when you
supervise them!), the advantage is that at least your mind is free to focus on whatever
presents itself. At the time, I was working on batteries and, in particular, the non-aqueous
electrolytes used to extend their electrochemical window. I thought it would be a good
idea to try to use these electrolytes, which belong to the class of ionic liquids, as catalyst
solvents. These liquids feature very low vapour pressure and virtual non-solubility in
hydrocarbons, paving the way for a biphasic catalysis. The mixture of alkylimidazolium
chloride and aluminium chloride forms a liquid with a very low melting point (below
ambient temperature) (Figure 4). It proved to be a first-rate solvent for nickel-based
dimerisation catalysts ("Dimersol" catalysts). The diagram for this process, called "Difasol,"
is shown in Figure 5. The reaction volume required for a biphasic system is 10 times
smaller than for a homogeneous system (important for safety: refineries do not like to have
large volumes in reaction because they are potential "bombs," especially at start-up);
likewise for nickel consumption. This new process, dealt with in a PhD project in 1990,
will see the light of day thanks to the inventiveness and determination of Hélène OlivierBourbigou, who took over from me in the laboratory.
What applied chemistry has taught me is the need for absolute solidarity between the
research laboratory and the "downstream" side (pilot testing, marketing, setting up industrial
plant): same enthusiasm, same determination, especially when everything goes wrong!
There is no difference between fundamental research and applied research. Although this
is my view, based on personal taste and the areas I have worked in, it is not necessarily
true for others. The PhD either led to, or were derived from processes. I have spoken so
much about "processes" because they took up about three-quarters of my working time.
However, I also took an interest in other aspects of coordination chemistry, such as
palladium catalysis, rhodium catalysis, asymmetric amino-acid synthesis, and so on. After
retiring in 1995, I was invited to work in J.-M. Basset's laboratory in Lyon (at the CPE Lyon
facilities), which allows me to pursue a reasonable level of activity.”
From “Les Prix Nobel”. The Nobel Prizes 2005, Editor Karl Grandin, [Nobel Foundation], Stockholm, 2006.
This autobiography/biography was written at the time of the award and first published in the book series Les
Prix Nobel. It was later edited and republished in Nobel Lectures.
Yves Chauvin is still active in research, working in particular with Dr. Catherine Santini in the Laboratory
of Chemistry, Catalysis, Polymers and Processes headed by Professor Bernadette Charleux, at CPE Lyon.
13
Alexandre ALEXAKIS
Professor of Organic Chemistry, University of Geneva, Switzerland
Professor Alexandre Alexakis was born in
Alexandria in 1949. He graduated from Paris VI
University in 1971 and received his PhD in 1975.
After a postdoctoral stay at Johns Hopkins
University, he joined the CNRS at Pierre et Marie
Curie University in 1977, as Attaché de Recherche,
then Directeur de Recherche in 1985. In 1994 he
was awarded the silver Medal of the CNRS. After
being appointed full Professor at Pierre et Marie
Curie University, in 1996, he moved to the
University of Geneva in 1998. He was awarded the
Novartis Lectureship in 2002.
Professor Alexakis current research interests are in
several fields: asymmetric synthesis and
methodologies by using both metal (particularly
copper reagents) and nonmetallic catalysts
(organocatalysis); Chiral bases and chiral
protonation reagents; on the development of new
reactions and new methodologies for organic synthesis ; The design of new chiral ligands,
particularly the ones derived from C2 symmetrical diamines and diols and last the
application to the synthesis of natural products.
14
Some aspects of using Grignard reagents in asymmetric synthesis
Alexandre ALEXAKIS
Dpt of Organic Chemistry, University of Geneva
30 quai Ernest Ansermet, Geneva 4, Switzerland 1211
[email protected]
The conjugate addition of usual organometallic reagents (RMgX, R2Zn, R3Al …) is
generally performed under Cu catalysis. The asymmetric version of this reaction needs
chiral appropriate ligands for this metal. The Michael acceptor is usually a cyclic or acyclic
enone, ester, lactone, lactame or nitro-alkene. Despite this variety, several challenges still
remains. One of these is the conjugate addition to substrates bearing a trisubstituted
double bond, leading to all-carbon chiral quaternary centers. We shall focus on the use of
Grignard reagents in these reactions, which appear to be the most efficient in this case.
O
2% CuTC, 4% L*
+
R-M
O
*
R
On the other hand, the allylic substitution is a powerful synthetic tool if the regio-,
stereo- and enantioselectivities can be controlled. Copper catalysis allows the introduction
of non-stabilized nucleophiles, whereas other transition metals are more suitable for
stabilized nucleophiles. We have found that phosphoramidite ligands are efficient in Cu
catalysis with Grignard reagents, providing high regio- and enantioselectivities.
GP
+
R'
R
Mét
R-Mét.
GP
+
R-Mét.
R'
R
References:
1. For reviews see : a) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221. d) Hayashi,
T., Acc. Chem. Res. 2000, 33, 354. b) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rössle, M.
Synthesis 2007, 1279 c) Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M.
Chem. Rev. 2008, 108, 2796; d) Harutyunyan, S.R.; den Hartog, T.; Geurts, K.; Minnard,
A.J.; Feringa, B.L. Chem. Rev. 2008, 108, 2824. e) C. Hawner, A. Alexakis, Chem. Commun.
2010, 46, 7295-7306.
2. For reviews see : a) A. Alexakis, C. Malan, L. Lea, K. Tissot-Croset, D. Polet, C. Falciola,
Chimia 2006, 60, 124-130; b) C. A. Falciola, A. Alexakis, Eur. J. Org.Chem. 2008, 3765-3780;
c) A. Alexakis, J. E. Bäckvall, N. Krause, O. Pamies, M. Diéguez, Chem. Rev. 2008, 108, 27962823.
15
Marika BLONDEL-MEGRELIS
Club « Histoire de la Chimie », SCF, France
Marika Blondel-Mégrelis, Ingénieur ESCIL ((École Supérieure de Chimie Industrielle de
Lyon, actuellement CPE Lyon), Docteur-Ingénieur, Docteur en Philosophie, a exercé son
activité dans le cadre de l'IHPST (CNRS/Paris I). En étudiant certaines séquences de
l'histoire de la chimie (chimie organique du 19è siècle, chimie agricole, chimie théorique en
France...), et en relation avec les sciences voisines, elle s'est efforcé d'identifier et de situer
la nature et les mécanismes du progrès scientifique.
Elle a organisé la journée scientifique Victor Grignard et le Traité de Chimie organique, qui
s'est tenue en 2003 à CPE Lyon.
16
Victor Grignard, chimiste français
Marika BLONDEL-MEGRELIS
Club « Histoire de la Chimie », SCF, France
Victor Grignard (1871-1935) est un chimiste de nos provinces que rien ne prédestinait à la
chimie. Chercheur puis professeur conscient de ses devoirs et de ses responsabilités, il a
sans doute été l'un des derniers chimistes à pouvoir embrasser l'ensemble de la chimie
organique. Sa personnalité, à la fois traditionnelle et novatrice, est résumée dans ses prises
de position dans le travail d'élaboration d'une nomenclature internationale dans lequel il a
pris une part importante. Ce chimiste apparemment si tranquille, s'est battu avec énergie
pour que la France se dote et de laboratoires de recherche et d'une industrie chimique, et
accède ainsi à une autonomie économique, seule voie pour la pacification des relations
internationales, au lendemain du premier conflit mondial.
17
Yves FORT
Full Professor of Organic Chemistry, Université de Lorraine, France
Since 1998, professor Yves Fort is full Professor in
organic and organometallic chemistry at Nancy
University, presently Université de Lorraine, after
being CNRS researcher from 1985. Before that, He
studied organic chemistry and photochemistry under
the supervision of Pr J-P. Pete in Reims University
(PhD (Thèse de 3ème cycle), 1983, summa cum laude)
and organometallic chemistry under the supervision of
P. Caubère (Doctorat d'Etat, 1987, summa cum laude).
From 1983 to 1985, Yves Fort was appointed by AAUL
(Association des Amis des Universités de Lorraine) as
associated researcher and worked for SNPE (Société
Nationale des Poudres et Explosifs, Vert le Petit).
In 1988, in a post-doctoral context, He was seconded
from CNRS to Atochem (presently Arkema) and worked in the field of acrylic chemistry.
Deputy director in 2005-08, Yves Fort is head since 2009 of the Molecular Chemistry
Department of Université de Lorraine (SRSMC, University/CNRS research unit 7565, ca.
130 people).
At the University, He is responsible of the Bachelor of chemistry and member of scientific
committee. He is also involved in national scientific committees such as ANR (Agence
Nationale de la Recherche), AERES (Agence d'Evalaution de la Recherche et de
l'Enseignement Supérieur) and C-Nano (Network in Nanotechnologies).
Since 1983, Yves Fort is the author or co-author of more than 150 articles, 8 reviews, 8
world patents, 7 applications and 1 French patent, as well as 30 conferences and seminars
and more than 150 communications. He has directed 27 PhD and 3 Habilitation theses,
and participated to 50 PhD committees.
Professor Fort research efforts are presently devoted to Li superbases, Ni catalysts usable
for C-C or C-N bond formation, heterocyclic chemistry with potential applications in
biology and in molecular materials and nanomaterials for hearth.
18
Lithiated Polar Organometallics: towards toolboxes for regioselective
functionalization of azaheterocycles.
Yves FORT
Equipe SOR-HéCRIN (HeteroCycles: Reactivity and Interactions)
UMR 7565 SRSMC, Université de Lorraine CNRS
F-54506 Vandoeuvre-lès-Nancy, France
Over the past few decades, many efforts have been made to develop metalation reactions
for the functionalisation of heterocycles. Such reactions are proving to be powerful tools
because of the large range of functionalities that can be introduced.
In this context, for several years, our group has had a great interest in the development of
new polar organometallic reagents (i.e. superbases) as powerful lithium reagents.1 In
pioneering works, it was discovered that the combination of n-BuLi and an aminoalkoxide
forms aggregates which exhibit specific interactions on the pyridine nitrogen atom of
azaheterocycles. New polar organometallic reagents resulting from a bi-site (anionicneutral activation) were born. The archetype of these reagents is the monometallic nonnucleophile [n-BuLi/LiDMAE] superbase, a simple association of n-BuLi with lithium
dimethyl-aminoethoxide (LiDMAE) in an apolar solvent (i.e. hexane).
This lithiated superbase [n-BuLi/LiDMAE] produced the regioselective and
unprecedented lithiation on the -position of pyridine nitrogen of azaheterocycles, even if
an ortho-directing group (Cl, SMe,…) is present. As the α-position is the primary site of
metalation in hexane, this reaction can be considered as a pyridino-direction.
The pyridino-direction principle
Many substituted pyridines, pyrazines, as well as fused azaheterocycles containing several
complexing heteroatoms (i.e. azaindoles and furopyridines) are then lithiated before
various functionalizations. 2
Extension of the bi-site activation of n-BuLi next conducted to other original reagents with
a particular interest in [TMSCH2Li-LiDMAE] which allows the deprotonation or halogenmetal exchange under non-cryogenic conditions.3
Recent works showed that the combination of superbases ([n-BuLi/LiDMAE],
[TMSCH2Li-LiDMAE]) with classical lithiating agents (n-BuLi, n-BuLi-TMEDA, LDA,
19
LiTMP) under appropriated conditions, constitutes a toolbox which allows the design of
original procedures of poly-functionalization of simple or fused heterocyclic derivatives.4
These procedures benefit from (i) classical ortho-directing metalations or halogen-metal
exchanges efficiently completed by (ii) pyridino-lithiations, unusual Cl/Li and SMe/Li
permutations as well as (iii) new one-pot Nu-E double functionalizations.5
H
Li
i) Regioselective metallation
Y,Z
X
E
ii) E-Nu
Y,Z
X
Y,Z
Nu
Azaheterocycles
with Y, Z = CH,N,O
X = F, Cl
One-pot double functionalization
Nowadays, it appeared that the present and future of polar organometallics have to be
discussed in terms of aggregates and their stabilization, aggregation degree and structure,
stabilizing or activating agents, dynamic reactivity as well as nucleophilicity/basicity
ratio, all the principles that Victor Grignard imagined a century ago.
References:
1. Gros, P. and Fort, Y Eur. J. Org. Chem. 2002, 3375-3383; Gros, P. and Fort, Y Eur. J.
Org. Chem. 2009, 4199-4209.
2. Khartabil H. K.; Gros P. C.; Fort Y.; Ruiz-Lopez M. J. Amer. Chem. Soc. 2010, 24102416.
3. Comoy, C.; Banaszak, E. and Fort, Y. Tetrahedron 2006, 62, 6036-6041; Chartoire, A.
Comoy, C. and Fort Y. Tetrahedron 2008, 64, 10867-10873; Chartoire, A. Comoy, C.
and Fort Y. J. Org. Chem. 2010, 75, 2227-2235;
4. Gros, P. and Fort, Y Curr. Org. Chem. 2011, 2329-2339.
5. Chartoire, A. Comoy, C. and Fort Y. Org. Biomol. Chem. 2011, 9, 1839-1845.
20
21
Paul KNOCHEL
Professor, Ludwig-Maximilians-University, Munich, Germany
Paul Knochel was born 1955 in Strasbourg
(France). He did his undergraduate studies at the
University of Strasbourg (France) and his Ph.D at
the ETH-Zürich with Prof. D. Seebach. He spent 4
years at the CNRS at the University Pierre and
Marie Curie in Paris with Prof. J.-F. Normant and
one year of post-doctoral studies at Princeton
University in the laboratory of Prof. M. F.
Semmelhack. In 1987, he accepted a position as
Assistant Professor at the University of Michigan
at Ann Arbor, Michigan. In 1991, he became Full
Professor at this University and in 1992, he
moved to Philipps-University at Marburg
(Germany) as C4-Professor in Organic Chemistry.
In 1999, he moved to the Chemistry Department
of Ludwig-Maximilians-University in Munich
(Germany). His research interests include the
development of novel organometallic reagents
and methods for use in organic synthesis,
asymmetric catalysis and natural product
synthesis.
Author of about 600 scientific publications and 50 books or book chapters, inventor in
more than 30 patents, Paul Knochel is a member of many academies and institutions. He
received several Awards including the Berthelot Medal of the Academie des Sciences
(Paris) 1992, the IUPAC Thieme Prize (1994), the ECS - European Chemical Society Chiroscience Award for Creative European Chemistry (1995), the Otto-Bayer-Prize (1995),
the Leibniz-Prize (1996), the Merck Sharp & Dohme Research Award (2000/2001), the V.
Grignard-Prize (2000), the Dr. Paul Janssen Prize for Creativity in Organic Synthesis
(2004), the Cope Scholar Award of the American Chemical Society (2005), the Lilly
European Distinguished Lectureship Award (2007), the Karl-Ziegler-Preis (2009), the Gold
Nagoya Medal of Organic Chemistry (2012).
22
Polyfunctional Mg and Zn Reagents in Organic Synthesis.
Paul KNOCHEL
Ludwig-Maximilians-University of Munich, Germany
New general methods for the preparation of functionalized organometallics will be
described. The first preparations involve a direct metal insertion, whereas the second
method involves a directed metalation. A range of new TMP-bases of Mg, Zn, Mn, Fe, La
and Al have been prepared for the regioselective metalation of various aromatic and
heterocyclic compounds providing polyfunctional organometallics. These highly
functionalized organometallics react with a range of electrophiles and undergo especially
mild cross-couplings. New BF3-promoted metalations allow a new access to
polyfunctional pyridines. Applications to the synthesis of bioactive molecules and
material precursors via new cross-coupling reactions will also be shown.
For leading articles, see :
a)
b)
c)
d)
e)
f)
g)
B. Haag, M. Mosrin, H. Ila, V. Malakhov, P. Knochel, Angew. Chem. Int. Ed. 2011, 50, 9794-7824.
Tomke Bresser, P. Knochel, Angew. Chem. Int. Ed. 2011, 50, 1914.
M. Jaric, K. Karaghiosoff, P. Knochel Angew. Chem. Int. Ed. 2010, 49, 5451-5455.
S. Bernhardt, G. Manolikakes, T. Kunz, P. Knochel, Angew.Chem. Int. Ed. 2011, 50, 9205-9209.
S. Duez, A. Steib, S. Manolikakes, P. Knochel Angew. Chem. Int. Ed. 2011, 50, 7686-7690.
T. Thaler, P. Knochel, Nature Chemistry 2010, 2, 125.
S. Seel, T. Thaler, K. Takatsu, P. Knochel J. Am. Chem. Soc. 2011, 133, 4774.
23
BRUCE H. LIPSHUTZ
Professor, University of California, Santa Barbara, USA
Bruce H. Lipshutz graduated from Yale University
in 1974, where he also received his doctor’s degree
under the supervision of Prof. Harry Wasserman in
1977. As a postdoctoral Research Fellowship from
the American Cancer Society (1977-1979) He worked
with E.J. Corey at Harvard University. He then
joined the faculty at the University of California,
Santa Barbara in 1979 as an assistant professor, then
Associate and professor in 1987.
Professor Lipshutz received several Honors,
Awards, and Professional Recognition including:
the American Cancer Society Junior Faculty
Research Award, 1981-1983 ; the Alfred P. Sloan
Foundation Fellow, 1984-1988 ; the Harold J. Plous
Memorial Teaching Award, UCSB, 1984 ; the
Camille and Henry Dreyfus Teacher-Scholar, 19841989 ; the American Chemical Society Arthur C.
Cope Scholar Award, 1997 ; UCSB Foundation Distinguished Faculty Teaching Award,
2002 ; the Solvias Ligand Prize, Basel, 2003.
24
Organometallic Chemistry in Just Water at Room Temperature.
What Would Victor Grignard Think?
Bruce H. LIPSHUTZ
Department of Chemistry & Biochemistry
University of California
Santa Barbara, CA 93106
New technology for effecting a variety of transition metal-catalyzed cross-coupling
reactions under green chemistry conditions; i.e., in water at room temperature, will be
described. These are enabled by virtue of the “designer” surfactant TPGS-750-M, which
quickly forms nanomicelles upon dissolution in water, in which the reactions take place.
Reactions to be discussed include unpublished results on Pd-catalyzed Stille couplings,
Cu-catalyzed conjugate additions, and Zn-mediated halide reductions
25
Jacques MADDALUNO
Université de Rouen, France
Jacques Maddaluno, born 1958, graduated from the
Ecole Nationale Supérieure de Chimie de Paris in 1982
and a PhD. in Organic Chemistry from the University of
Paris VI in 1986 under the supervision of Dr Jean
d’Angelo. Further, He received the Research Direction
Capacity (Habilitation) from the Université de Rouen in
1989.
After two postdoctoral positions in 1986 first at the
Laboratoire de Chimie Organique Théorique Université
Paris VI, France then at the Nancy Pritzker Laboratory ,
Stanford University, he joined the CNRS as Attaché de
Recherche, then Directeur de Recherche at the
Université de Rouen. Dr. Maddaluno is the Author of
more than 125 scientific papers, 6 book chapters and has
given more than 100 conferences. He has directed more
than 20 PhD work, served as Head of the board of the National Committee for Organic
Chemistry of CNRS (2008-2011) and He is currently Deputy Director of the Institute of
Chemistry (INC) at the CNRS headquarter in Paris.
Dr. Maddaluno main research area concern high pressure chemistry, functionalized dienes
and cycloadditions, asymmetric synthesis using chiral lithium amide: chemistry,
spectroscopy, theory and carbometallation of alkynes.
26
Nucleophilic addition of alkyllithiums: enantioselective and catalytic ?
Jacques MADDALUNO
Université de Rouen, France - [email protected]
Mixing chiral lithium amides and alkyllithium in THF at low temperature leads to
aggregates of well-defined stoichiometry and structure. These robust entities associate an
asymmetric partner to a highly reactive nucleophile, and can be employed for instance as
chiral equivalents of butyl- or methyllithium in asymmetric synthesis.
On the basis of previous spectroscopic and theoretical studies on the solution structure of
the aggregates of chiral 3-aminopyrrolidine lithium amides and alkyl, aryl and
vinyllithium derivatives, we will present recent extensions that have led to a catalytic
substoichiometric version of this reaction. Our results suggest that significant ee’s can be
obtained provided the spectroscopic and theoretical data are fully taken into consideration
to design the catalytic cycle.
27
Ilan MAREK
Professor, Technion, Israël
Ilan Marek, FRSC, born in Haifa in 1963 but educated in
France moved to the Technion-Israel Institute of
Technology in 1997. He is Professor of chemistry and
since 2005, he holds the Sir Michael and Lady Sobell
Academic Chair. The research group of Prof. Ilan Marek
is primarily concerned with the design and
development of new and efficient stereo- and
enantioselective strategies that do not have precedent in
classical organic chemistry for the synthesis of
important complex molecular structures. His vision is
that challenging synthetic problems should be answered
with efficiency and elegance.
Prof. Marek heads the Mallat Family Laboratory of
Organic Chemistry and is Fellow of the Royal Society of
Chemistry since 2011. He has received several major
international awards over the years including the 2012
Janssen Award for creativity in organic synthesis, the
2011 Royal Society Chemistry Organometallic Award, the 2011 Taiwan National Science
Council Visiting Scholar, the 2010 German-Technion Award for Academic Excellence and
Scientific Collaborations, the 2009 Henry Taub Prize for Academic Excellence, the 2005
Bessel Award of the Humboldt Foundation, the 2004 Merck Sharpe and Dohm Lecturer,
the 2003 Prize for Excellent Young Chemist from The Israel Chemical Society and the 2002
Michael Bruno Memorial Award 2002, administrated by the Rothschild Foundation. He
has received several awards for excellence in teaching.
Prof. Marek also serves on the Advisory board of international leading journals such as
Chemical Communications and Organic and Biomolecular Chemistry, both from the Royal
Society of Chemistry (RSC). He also serves as Associate Editor of Beilstein Journal of
Organic Chemistry and Associate Editor of Israel Journal of Chemistry, Wiley-VCH. He is
Member (and past chairman) of the International Scientific Committee of European
Symposium on Organic Chemistry (ESOC), and Vice-Chair of the organic division of the
European Association of Chemical and Molecular Sciences (EUCHEM) organic Division.
28
Selectivity in Carbon-Carbon Bond Activation.
Ilan MAREK
The Mallat Family Laboratory of Organic Chemistry
Schulich Faculty of Chemistry & the Lise Meitner-Minerva Center for Computational Quantum Chemistry
Technion-Israel Institute of Technology. Haifa, 32000 Israel
The presentation of Prof. Marek focuses on metal-promoted selective cleavage of carboncarbon bonds. This field is of major interest since it can lead to the design of new, selective
and efficient processes for the functionalization of non-reactive hydrocarbons. Following
the original activation of C-C single bonds of cyclopropylcarbinyl Grignard reagents, the
carbon-carbon activation of strained molecules through transition metal catalysts have
emerged. However, the attractive but often troublesome feature of such systems is their
multiform reactivities that may lead to the formation of a variety of products. A
predictable control of their reactivities would be synthetically important for the formation
of a unique product and therefore the design of new substrates in which only a restricted
numbers of possible reactions may occur is highly desirable. In this lecture, we are
proposing few solutions and the first approach concerns the zirconocene-mediated
transformations of substituted alkylidenecyclopropanes (ACPs). Through a mechanism
that will be discussed in details, the zirconocene-mediated reaction of ACPs followed by
the selective carbon-carbon bond activation and further selective reactions with two
different electrophiles led to linear adducts possessing several stereocenters including the
challenging all-carbon quaternary stereogenic centers in acyclic systems. Importantly,
distant stereoinduction is accessible via this strategy. To further demonstrate the utility of
this method, the complete synthesis of two interesting molecules will be performed such
as the challenging molecules: (R)-4-ethyl-4-methyloctane, the smallest possible fully
saturated chiral organic molecule with a quaternary stereogenic center, and the (S)-[2H1,
2H2, 2H3]-neopentane, with its Td symmetric electron distribution. The latter case is the
archetype of molecule that owes its chirality exclusively to an asymmetric distribution of
the masses of their nuclei. Then, taking advantages of allylic C,H-bond activation followed
by a carbon-carbon bond activation reaction, both promoted by the same zirconocene
complex, any cyclopropane derivatives possessing a remote double could be transformed
into the previously described linear products.
29
William R. ROUSH
Professor of Chemistry, The Scripps Research Institute, Floride, USA
Dr. William R. Roush, a native of Chula Vista, California,
received the Bachelors Degree in Chemistry, Summa Cum
Laude, from the University of California at Los Angeles in
1974, where he performed undergraduate research with
Professor Julius Rebek, and the Ph. D. Degree in Chemistry
from Harvard University in 1977 under the direction of
Professor R. B. Woodward. After an additional year as a
postdoctoral associate in Professor Woodward's laboratory, he
joined the faculty of the Massachusetts Institute of Technology
as Assistant Professor. He moved to Indiana University in 1987,
and was promoted to the rank of Professor in 1989 and
Distinguished Professor in 1995. In 1997 he moved to the
University of Michigan as the Warner Lambert/Parke Davis
Professor of Chemistry. He served as Chair of the Department
of Chemistry, University of Michigan, from 2002-2004. He
moved to the new Scripps Research Institute in Jupiter, Florida,
as Professor of chemistry, Executive Director of Medicinal
Chemistry, and Associate Dean of Scripps’ Kellogg Graduate School in 2005. Dr. Roush has been a
Fellow of the Alfred P. Sloan Foundation, an Eli Lilly Grantee, and the holder of the Roger and
Georges Firmenich Career Development Chair in Natural Products Chemistry at MIT. He received
a Merck Faculty Development Award in 1981, the 1992 Alan R. Day Award of the Philadelphia
Organic Chemist's Club, the 1994 Arthur C. Cope Scholar Award of the American Chemical
Society, and the 1996 American Chemical Society Akron Section Award. In 1998 he received a
Merit Award from the National Institute of General Medical Sciences, and in 1999 he received a
Distinguished Faculty Achievement Award from the University of Michigan. In 2002 Dr. Roush
received the Paul G. Gassman Distinguished Service Award of the American Chemical Society
Division of Organic Chemistry, and in 2004 he received the American Chemical Society Ernest
Guenther Award in the Chemistry of Natural Products. In 2006, Dr. Roush was elected Fellow of
the American Association for the Advancement of Science. Most recently, in 2009 Dr. Roush was
elected to the inaugural class of Fellows of the American Chemical Society.
Dr. Roush has served terms as Secretary-Treasurer and Chairman of the ACS Division of Organic
Chemistry, and as Chairman of the NIH Medicinal Chemistry Study Section. He currently is
Associate Editor of the Journal of the American Chemical Society, and serves on the Editorial
Advisory Boards of Organic Letters, Accounts of Chemical Research, Beilstein Journal of Organic
Chemistry, and Chemical Biology & Drug Design. He is a Director of Organic Reactions, Inc., and of
Organic Syntheses, Inc., and is a consultant for several companies.
Dr. Roush's research interests focus on the stereocontrolled synthesis of stereochemically complex
natural products, and on the design and development of new reactions and synthetic methods. He
is known for his stereochemical studies and synthetic applications of the intramolecular DielsAlder reaction and his work in the area of asymmetric and acyclic diastereoselective synthesis,
specifically the use of tartrate ester modified allylboronates and other allylmetal compounds for
the aldol-like construction of propionate-derived systems. He has also made important
contributions the synthesis of deoxyglycosides and polyhydroxylated natural products (his total
synthesis of olivomycin A is particularly noteworthy), and to the design and synthesis of inhibitors
of cysteine proteases targeting important human pathogens (e.g., Trypanosoma, Plasmodium and
Entamoeba species). Since moving to Scripps Florida, his program in chemical biology and
medicinal chemistry has expanded to include research on the development of inhibitors of kinases,
inhibitors of certain epigenetic targets, inhibitors and activators of nuclear receptors, and small
molecule inhibitors of carboxylic acid transporters as potential therapeutic agents.
30
Synthesis of Bifunctional Allylboron Reagents via Allene Hydroboration
Reactions, and Applications to the Synthesis of Natural Products.
William R. ROUSH
Department of Chemistry, Scripps Research Institute, Jupiter FL 33458, USA - [email protected]
During recent studies on the extension of the double allymetallation reaction developed in
our laboratory, we had occasion to examine the hydroboration reaction of racemic allene 1
with (dIpc)2BH.1 Remarkably, both enantiomers of racemic 1 undergo hydroboration by
(dIpc)2BH to give the same chiral allylborane reagent (S)-(E)-2 by chemically distinct
enantioselective pathways. This reaction constitutes an example of the enantioconvergent
reaction of the two enantiomers of a racemate to give a single, enantiomerically enriched
product. The details of this reaction will be analyzed, along with synthetic applications of
the new, enantioselective reagent (S)-(E)-2 which has proven to be exceptionally useful in
mismatched double asymmetric reactions with chiral aldehydes.
(1)
M. Chen and W. R. Roush, “Enantioconvergent Hydroboration of a Racemic Allene:
Enantioselective Synthesis of (E)-δ-Stannyl-anti-Homoallylic Alcohols via Aldehyde
Crotylboration,” J. Am. Chem. Soc. 2011, 133, 5744.
(2)
M. Chen and W. R. Roush, “Highly Stereoselective Synthesis of Anti, AntiSteriotriads: A Solution to the Long-Standing Problem of Challenging Mismatched
Double Asymmetric Crotylboration Reactions,” J. Am. Chem. Soc., 2012, 134, 3925
31
Victor SNIECKUS
Professor, Queen’s University, Canada
Victor Snieckus was born
in Kaunas, Lithuania in
1937
and
spent
his
childhood in Germany
during World War II. He
received the B.Sc. degree at
the University of Alberta
(1959) where he was
strongly influenced by an
iconoclastic teacher, Rube
Sandin, the discover of the
diphenyliodonium salt. At
the
University
of
California, Berkeley, he
received thorough training
in
physical
organic
chemistry (M.Sc. with D.S. Noyce) but decided that there should be more to organic
chemistry than Hammett sigma-row plots and migrated to Oregon where he learned that
he truly had a passion for synthesis by studying with teacher and research mentor par
excellence (Ph.D. with V. Boekelheide). He returned to Canada for a postdoctoral year
with O.E. Edwards, insufficiently recognized for steroid and alkaloid manipulations and
nitrene reactions (NSERC, Ottawa) and then joined the faculty at the University of
Waterloo in 1966. He held the Monsanto/NRC Industrial Research Chair, 1992-1998 and
the Bader Chair in Organic Chemistry, Queen's University, 1998-2009. He is now
continuing fundamental research as Bader Chair Emeritus as well as Director of Snieckus
Innovations, an institute for synthesis of small molecules for the pharmaceutical and
agrochemical industries.
32
Following the star of Grignard and those of Wittig and Gilman
Victor SNIECKUS
Queen’s University, Department of Chemistry, Kingston, Ontario, K7L 3N6, Canada
[email protected]
“Before the advent of DoM, the preparation of contiguously substituted (e.g. 1,2-, 1,2,3- or
1,2,3,4-) aromatic compounds, using the directing effect of the various substituents in SEAr
reactions was a major challenge and required many steps to accomplish”.
Kürti, László, Czakó, Barbara
Strategic Application of Named Reactions in
Organic Synthesis, Elsevier, Amsterdam, 2005, p 420
… but Kürti and Czakó failed to recognize the significance of VNS which should also be sine
qua non in the armamentarium of synthetic chemists, a reaction also o Name Reaction status.
The Directed ortho Metalation (DoM) reaction, discovered by Wittig and Gilman over 70
years ago and propelled into prominence by Hauser, Beak, Christensen, Gschwend,
Meyers, Muchowski, and others, is now beginning to infiltrate undergraduate organic
texts and is increasingly practiced on mg to metric ton scales, e.g. Sustiva™ (DupontMerck
BMS, anti-AIDS), Silthiofam™ (Monsanto, fungicide). The link of transition
metal catalyzed reactions (e.g. Heck, Suzuki, Sonogashira, Grubbs) to DoM is providing
the synthetic chemist with a variety of effective combined protocols and is also finding
application on large scale, e.g. Losartan™ (BMS, anti-inflammatory).
The common theme in our laboratories is the invention and development of new DoM
aromatic chemistry, separate and linked to transition metal catalyzed processes, and their
demonstration in bioactive molecule, natural product, and materials construction. A
selection of these themes (below) including new departures into Ir, Rh, and Ru catalyzed
DoM-enhancing connections will be described.
33
Hartung, C.G., Snieckus, V. In Astruc, D. Ed. Modern Arene Chemistry, Wiley-VCH; New York,
2002, pp 330-367
Whistler, M.C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem. Int. Ed. 2004, 43, 2206-2225
Anctil, E. Snieckus, V. In Diederich, F., de Meijere, A. Eds. Metal-Catalyzed Cross-Coupling
Reactions, 2nd Ed., 2004, pp 761-813
Macklin, T.; Snieckus, V. In Dyker., G. Ed. Handbook of C-H Transformations, 2005, Wiley-VCH, New
York, pp 106-119.
34
35
JUN-ICHI YOSHIDA
Professor, Kyoto University, Japan
Jun-Ichi Yoshida was born in Osaka, Japan in
1952. He graduated from Kyoto University in
1975, where he received his doctor’s degree
under the supervision of Prof. Makoto Kumada
in 1981. In 1979 Yoshida joined the faculty at
Kyoto Institute of Technology as an assistant
professor. In the meantime, he visited
University of Wisconsin during 1982-1983,
where he joined the research group of Prof. B.
M. Trost. In 1985 he moved to Osaka City
University, where he was promoted to an
associate professor in 1992. In 1994 he was
appointed as a full professor of Kyoto Univ. His
research interests include integrated organic
synthesis on the basis of reactive intermediates,
organic
electron
transfer
reactions,
organometallic reactions, and microreactors.
Professor Yoshida received several Awards including: the Progress Award of Synthetic
Organic Chemistry, Japan (1987), the Chemical Society of Japan Award for Creative Work
(2001). the Nagoya Medal Prize (Silver Medal) (2006), Humboldt Research Award (2007),
and Green and Sustainable Chemistry Award (2010).
36
Hot reagents in High-tech Reactors.
Jun-Ichi YOSHIDA
Department of Synthetic Chemistry and Biological Chemistry,
Kyoto University
Nishikyo-ku, Kyoto 615-8510, Japan
[email protected]
Grignard and organolithium reagents are most powerful carbanion equivalents and are
widely utilized in organic synthesis. Although high reactivity is the most advantageous
feature of these hot reagents, it also causes a serious problem, especially from a view point
of selectivity. Recently, flow microreactor synthesis has emerged as high-tech reactors for
synthesizing chemical substances and has enjoyed various applications in organic
chemistry and polymer chemistry.1 Flow microreactors are especially useful for
conducting extremely fast reactions in a highly controlled way and enable chemical
reactions that cannot be done in bat (flash chemistry).2Use of flow microreactors solves the
problems of Grignard and organolithium reagents without decreasing their reactivity, and
enhance the capability of the hot reagents not only in laboratory organic synthesis but also
in in chemical and pharmaceutical industries. This presentation provides a new aspect of
chemistry of these hot reagents using high-tech flow microreactors. We focus on the
following points:
1. Control of highly exothermic reactions by fast heat exchange3
2. Control of competitive consecutive reactions by fast micromixing4
37
3. Protecting-group-free synthesis based on high-resolution reaction time control5
Some industrial applications will also be presented.
References
1. (a) Hessel, V.; Hardt, S.; Löwe, H. Chemical Micro Process Engineering; Wiely-VCH
Verlag: Weinheim, 2004. (b) Wirth, T. Microreactors in Organic Synthesis and Catalysis;
Wiley-VCH Verlag: Weinheim, 2008. (c) Hessel, V.; Renken, A.; Schouten, J. C.; Yoshida,
J. Micro Process Engineering; Wiley-VCH Verlag: Weinheim, 2009.
2. (a) Yoshida, J. Flash Chemistry. Fast Organic Synthesis in Microsystems: Wiley-Blackwell,
2008. (b)Yoshida, J.; Nagaki, A.; Yamada, T. Chem. Eur. J. 2008, 14, 7450. (c) Yoshida, J.;
Kim, H.; Nagaki, A. Chem. Sus. Chem.2011, 4, 331, and references cited therein.
3. (a) Wakami, H.; Yoshida,J.Org. Process Res. Dev. 2005, 9, 787. See also (b)
H.Krummdradt, U.Koop and J.Stold, GIT Labor-Fachz., 1999, 43, 590. (c) Schwalbe,T.;
Autze, V.; Hohmann, M.; Stirner, W. Org. Process Res. Dev. 2004, 8, 440.(d) Riva, E.;
Gagliardi, S.; Martinelli, M.; Passarella, D.; Vigo, D.; Rencurosi, A. Tetrahedron 2010, 66,
3242
4. (a) Hessel, V.; Hofmann, C.; Löwe, H.; Meudt, A.; Scherer, S.; FSchönfeld, F.; Werner, B.
Org. Process Res. Dev., 2004. 8, 511.See also (b) Nagaki, A.; Togai, M.;Suga, S.; Aoki, N.;
Mae, K.; Yoshida, J. J. Am. Chem. Soc.2005, 127, 11666.
5. Kim, H.; Nagaki, A.; Yoshida, J. Nat. Commun.2011, 2: 264.See also(b) Nagaki, A.; Kim,
H.; Yoshida, J.Angew. Chem., Int. Ed. 2008, 47, 7833.(c) Nagaki, A.; Kim, H.; Yoshida, J.
Angew. Chem., Int. Ed. 2009, 48, 8063.
6. Tomida, Y.; Nagaki, A.; Yoshida, J. J. Am. Chem. Soc.2011, 133, 3744. See also (b) Nagaki,
A.; Takizawa, E.; Yoshida, J.J. Am. Chem. Soc.2009,131, 1654. (c) Nagaki, A.; Takizawa,
E.; Yoshida, J. Chem. Lett. 2009, 38, 486.
38
39
Remerciements / Acknowledgments
Le Comité d’Organisation tient à remercier l’Académie des Sciences, la Société Chimique
de France et l’Institut de Chimie du CNRS sans qui l’organisation de cet évènement aurait
été impossible.
La famille Grignard a apporté un soutien sans faille et continu en autorisant la
reproduction de l’ouvrage de Roger Grignard dédié à son père, en prêtant des objets de
valeur historique et en participant concrètement à l’exposition et à ces journées. Qu’ils en
soient remerciés avec l’espoir que le patrimoine scientifique et historique ainsi mis en
valeur puisse constituer la base d’un fond de documentation unifié.
Enfin, de nombreuses entreprises et organisations ont aidé concrètement à la réalisation de
cette fête de la chimie. Qu’elles en soient remerciées.
Académie des Sciences
Bayer Crop Science
Département de Chimie et Biochimie de la Faculté des Sciences et Technologies de Lyon
École Doctorale de Chimie de Lyon
École Supérieure de Chimie Physique Électronique de Lyon
Fondation de la Maison de la Chimie
Institut de Chimie de Lyon
Institut de Chimie du Centre National pour la Recherche Scientifique
Rockwood Lithium
Sigma-Aldrich
Société Chimique de France
Strem Chemicals
Université Claude Bernard Lyon 1
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Comités / Committees
Comité Scientifique et de Parrainage
Bernard Bigot, Président de la Fondation de la Maison de la Chimie
Gérard Ferey, Académie des Sciences, Vice-président de la Société Chimique de France
Sophie Jullian, Directrice scientifique, IFP Énergies Nouvelles
Philippe Sautet, Académie des Sciences, Directeur de l’Institut de Chimie de Lyon
Régis Réau, Directeur de l’Institut de Chimie du CNRS
Comité de Pilotage
François-Noël Gilly, Président de l’Université Claude Bernard de Lyon 1
Gérard Pignault, Directeur de l’Ecole Supérieure de Chimie Physique Électronique de Lyon
Jean-Marc Lancelin, Directeur de l’Ecole Doctorale de Chimie de Lyon
Loïc Blum, Directeur ICBMS, Lyon
Bernadette Charleux, Directrice C2P2, Lyon
Patrick Monassier, Président de l’association des ingénieurs CPE Lyon, ICPI & ESCIL
Jean-Marc Le Lann, Président de la Fédération Gay-Lussac
Comité d’organisation
Claude de Bellefon, Directeur Scientifique CGP, CPE Lyon - CNRS (Président /Chairman)
Olivier Baudoin, Université Claude Bernard Lyon 1
François Bayard, CPE Lyon - CNRS
Jacques Bousquet, Délégué général de la Fédération Gay-Lussac
Jacques Breysse, Club « Histoire de la Chimie » Société Chimique de France
Béatrice Dias, Université Claude Bernard Lyon 1
Peter Goekjian, Université Claude Bernard Lyon 1
Arnaud et Pierre Grignard
Christine Legrand, CPE Lyon
Hélène Parrot, Université Claude Bernard Lyon 1
41
Programme / Programme
Jeudi 21 juin / Thursday June 21st
8h00-9h30
Enregistrement / Registration
9h30-10h00
Accueil / Welcome address
Avec la participation de / With a contribution from Yves Chauvin, CPE Lyon
10h00-10h45 Following the star of Grignard and those of Wittig and Gilman.
Victor Snieckus, Queen’s University, Canada
10h45-11h30 Lithiated Polar Organometallics: towards toolboxes for regioselective
functionalization of azaheterocycles.
Yves Fort, Nancy-Université, France
11h30-12h15 Selectivity in Carbon-Carbon Bond Activation.
Ilan Marek, Technion, Israël
12h30-13h30 Pose de la plaque commémorative décernée par l’American Chemical Society
ACS Citation for chemical breakthrough award celebration
François-Noël Gilly, Président de l’Université Claude Bernard Lyon 1
Gérard Pignault, Directeur de CPE Lyon
Jeff Seeman, Division History of Chemistry ACS, Richmond, USA
Grignard Familly
13h30-14h30 Cocktail dans le hall de l’amphithéâtre Grignard, bâtiment UCBL
Light lunch at the Grignard amphitheatre hall, University building
14h30-15h15 Synthesis of Bifunctional Allylboron Reagents via Allene Hydroboration Reactions.
William R. Roush, The Scripps Research Institute, Floride, USA
15h15-16h15 Perspectives in Chemistry: From Supramolecular Chemistry Towards Adaptive Chemistry
Jean-Marie Lehn, ISIS-Université de Strasbourg, France
16h15-17h00 Victor Grignard, chimiste français.
Marika Blondel-Mégrelis, Club « Histoire de la Chimie », SCF
17h00-19h00 Exposition « Grignard, un Homme dans la science et l’éducation »
Exhibition “Grignard, a Man in science and education.”
18h00 -
Cocktail / Cocktail party
42
Programme / Programme
Vendredi 22 juin / Friday June 22nd
8h30-9h15
Polyfunctional magnesium and zinc reagents in organic synthesis.
Paul Knochel, Ludwig-Maximilians-University, Munich, Germany
9h15-10h00
Some aspects of using Grignard reagents in asymmetric synthesis.
Alexandre Alexakis, Université de Genève, Switzerland
10h00-10h45 Nucleophilic addition of alkyllithiums: enantioselective and catalytic?
Jacques Maddaluno, Université de Rouen, France
10h45-11h15 Pause / Cofee break
11h15-12h00 Hot reagents in High-tech Reactors.
Jun-Ichi Yoshida, Kyoto University, Japan
12h00-12h45 Organometallic Chemistry in Just Water at Room Temperature. What Would
Victor Grignard Think?
Bruce H. Lipshutz, University of California, Santa Barbara, USA
12h45-13h00 Clôture des journées / Closing
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FONDATION DE LA MAISON DE LA CHIMIE

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