P1254325833KdyPn

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DIAZINESFUNCTIONALIZATION via Metalation and
Cross-coupling Reactions
Biologically active molecules Organic materials
Pr. Nelly Plé UMR 6014 CNRS - IRCOF Rouen

10th ISCPP Strasbourg Juin 2006
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Diazines and Benzodiazines
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Research Interests in Diazines Series

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RESEARCH INTEREST
Nonlinear Optical chromophores
Biologically active compounds
DIAZINES
Liquid Crystals
Building Blocks
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Metalation of Diazines
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Functionalization via Metalation Reaction
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The nucleophilic Addition a competitive reaction

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Metalating Agents Lithium Alkylamides
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Results
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Metalation of pyridin-2-yl diazines
Could the 2-pyridyl group be an ortho-directing
group ?
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Regioselectivity

• Regioselectivity is depending on
• The Directing Group DG
• The metalating agent
• The kinetic or thermodynamic control
• The electrophile ( Iode, R3SnCl.. )

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Influence of the Directing Group DG
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Influence of the Directing Group DG
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Influence of the Directing Group DG
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Influence of the electrophile
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Mechanism
Successive metalation and transmetalation
reactions
Toudic, F. Heynderickx, A. Plé, N. Turck, A.
Quéguiner, G. Tetrahedron, 2003, 59, 6375 Buron,
F. Ple, N. Turck, A. Quéguiner, G. J. Org.
Chem. 2005, 70, 2616
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Regioselective Iodination
? Isomerization of 6 into 5 involves an
halogen-dance mechanism
Toudic, F. Plé, N. Turck, A. Quéguiner, G.
Tetrahedron, 2002 , 58, 283
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Metalation of benzodiazines
Cinnolines
Quinoxalines
Ortho-metalation of the diazine moiety
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Diastereoselectivity with a sulfinyl group
R de CH3 14 Ph
54 tBu gt 99
Le Fur, N. Mojovic, L. Plé, N. Turck, A.
Marsais, F. Tetrahedron, 2005, 61, 8924
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Diastereoselectivity with a sulfinyl group
R de P-Tol 26 tBu
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Metalation of 4-Methoxyquinazoline
Benzene ring
Diazine moiety
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4-Methoxyquinazoline
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And if the 5 position is occupied ?
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Synthesis of Bioactive compounds
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Synthesis of Pyrazine Alcaloids Botryllazines
A and B
Mahboobi,S. and all . Monatsch. Chem., 2004, 135,
333.
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Botryllazine B
Buron, F. Plé, N. Turck, A. Quéguiner, G. J.
Org. Chem. 2005
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Botryllazine A
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Botryllazine A
6 steps
Buron, F. Plé, N. Turck, A. Quéguiner, G. J.
Org. Chem. 2005
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Organic Materials
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Oligoarylenes with ?-conjugated
backbone Materials for
opto-electronic Liquid Crystals
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What are liquid crystals ?
An intermediate phase between the cristalline
(solid) and isotropic (liquid) states
Mesomorphic phase
Isotropic phase

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Liquid Crystals
Rod-shaped molecules

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With a Fluoropyrazine Core
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Some exemples of liquid crystals
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With a Trifluoromethylpyridazine Core

• The CF3 group is used to increase the electron
  deficiency of the ?-conjugated system
• Expected Properties Mesophases and
  fluorescence.

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First Synthesis of Trifluoromethylpyridazines
5 steps
Brulé, C. Bouillon, J.P. Nicolaï, E. Portella,
C. Synthesis, 2003, 3, 446
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Two steps Synthesis via Metalation
Overall yield 36
Plé, N. Turck, A. Heynderickx, A. Quéguiner,
G. J. Heterocyclic Chem., 1997, 34, 551
Achelle, S.  Plé, N. Turck, A. Bouillon
,J.P. Portella, C. J. Heterocyclic Chem, 2006,
under press
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Cross-Coupling Reaction
Achelle, S.  Plé, N. Turck, A. Bouillon ,J.P.
Portella, C. J. Heterocyclic Chem., 2006, under
press
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How to determine the presence of mesophases ?
Analysis by DSC (Differential Scanning
Calorimetry)
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Optical Polarizing Microscopy
Sc Smectic C
N Nematic
Measurements have been performed at the IPCMS
(Strasbourg)
n
n
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Trifluoromethylpyridazines Analysis of
mesophases by DSC and OPM
X OCH3, C4H9, C8H13, C12H25 ? no mesophases

86.9 117.3
X OC8H17 Cr N I
Measurements have been performed at the
Université Pierre et Marie Curie, UMR 7610-CNRS
Schlieren texture
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Backbones rigidified by an ethyne group
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Oligoarylenes with ethyne group

• Organic conductors
• Electroluminescent materials
• NLO substrates
• Construction of nanosized molecules

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Introduction of ethyne group
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Bis-alkynylpyridazines
Building Block
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ALKYNYLPYRIDAZINES
These compounds are fluorescent
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Alkynylpyridazines
Y H Building Block
These compounds are Liquid crystals
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Alain Turck Arnault Heynderickx Frédéric
Toudic Jérôme Audoux Nicolas Le Fur Alexandrine
Busch Frédéric Buron Sylvain Achelle Guy
Quéguiner
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• mécanisme

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• Les différentes mésophases

La phase nématique (N)
directeur n
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La phase smectique
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Synthèse de composés aux propriétés optiques non
linéaires
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Guidelines for molecular design of 2nd order NLO
materials
? - ?0 ? El
? El El ? El El El
Microscopic scale
Linear area
Non linear area
2nd order
3rd order
We must have b ? 0, i.e. non centrosymmetric
molecule
µ
Push-pull dipolar molecule
p- bridge
D
A

• Strength of the donor and acceptor moieties

Play with

• Length of the p-conjugated bridge and aromaticity

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Non linear Optics
Applications
Génération dune seconde harmonique ?
Frequency Doublers
Lecteurs CD et CD-ROM
capacités de stockage multipliées par 4
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Optical switching devices
Effet électro-optique ou effet Pockels
E1
n1
Transmission de données par fibres optiques
facilitée et optimisée
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Guidelines for molecular design of 3rd order NLO
materials
Two-Photon Absorption Spectroscopy
S2
hnA
S1
Electron Transfer, Energy Transfer, Photochemistry
,
hnF
Fluorescence
hnA
S0
A
DD
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Quadrupolar molecules
Strategies
19.4 (10-48 cm4s/photon)
Push-pull dipolar molecules

• Albota M., Marder S. R., Perry J. W. And Coll.,
• Science 1999, 281, 1653

• Reinhard B. A., Prasad P. N. and Coll,
• Chem. Mater. 1998, 10, 1863

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Système p-conjugué Benzo- ou Pyridodiazine
système p-conjugué
Le système p-conjugué peut être aromatique
benzène, naphtalène
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Structure des matériaux ONL organiques

• 4 facteurs indispensables
• matériau polarisable
• distribution de charge asymétrique
• système ?-électronique conjugué
• cristallisation non centrosymétrique

D N(CH3)2 OCH3 thiophène
furane pyrrole...
A CF3 NO2 COOH CN
pyridine
Noyau aromatique Enchaînement polyénique
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Stratégie de Synthèse
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Quinazolines
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Quinazolines disubstituées en positions
4,5 Chromophores avec interactions à travers
l espace
Système p A
Aromatique
Système p D
Stratégie différente selon le groupement en C4
fonctionnalisation en position 5
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1ère Stratégie de Synthèse
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Stratégie de Synthèse
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Chromophores ONL avec des interactions à travers
lespace
Système p A
Aromatique
Système p D
D OMe, NMe2, SMe A H, p-CN, p-CF3, m-NO2
Busch, A. Gautheron-Chapoulaud, V. Audoux, J.
Plé, N. Turck, A. Tetrahedron, 2004, 60, 5373 -
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Alain Turck Mircea Darabantu Camelia
Berghian Arnault Heynderickx Valérie
Chapoulaud-Gautheron Frédéric Toudic Jérôme
Audoux Ludovic Boully Nicolas Le Fur Alexandrine
Busch Frédéric Buron Sylvain Achelle Inès
Nouira
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Introduction liquid crystals
Authentical state of the mater
Thermodynamicly stable ( Intermediary
between crystalline state and isotropic liquid
state )
Mesomorphic phase
Isotropic phase
Obtained by - Solvent addition
lyotropic liquid crystals - Temperature
elevation thermotropic liquid crystals