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Reporter:
Zhang Lei
Supervisor: Prof. Mo
Date:
2016-11-11
1
Outline
1. Introduction
2. Synthetic Pathways to NHC Precursors
2.1 Cyclization by Introduction of the Precarbenic Atom
2.2 Ring Closing by the Final Introduction of the Backbone
2.3 Final Introduction of the Amino Moiety
3. Conclusion
2
Outline
1. Introduction
2. Synthetic Pathways to NHC Precursors
2.1 Cyclization by Introduction of the Precarbenic Atom
2.2 Ring Closing by the Final Introduction of the Backbone
2.3 Final Introduction of the Amino Moiety
3. Conclusion
3
Introduction
Vincent César
Born in 1977 in Nancy, France.
Now，CNRS researcher at the “Laboratoire
de Chimie de Coordination du CNRS” in
Toulouse.
His research is mainly focused on the design
and development of new N-heterocyclic
carbenes for organometallic chemistry and
homogeneous catalysis.
4
Introduction
Definition
History
1962
Finding
Wanzlick [1]
1970s and 1980s
Extensive work
Lappert [4]
1968
Using as ligands
Wanzlick [2] and Öfele [3]
1991
Isolation and full characterization
Arduengo [6]
1988
First stable NHC carbine
Bertrand [5]
[1]Wanzlick, H.-W. Angew. Chem., Int. Ed. Engl. 1962, 1, 75.
[2] Wanzlick, H.-W.; Schönherr, H. J. Angew. Chem., Int. Ed. Engl. 1968, 7, 141.
[3] Öfele, K. J. Organomet. Chem. 1968, 12, 42.
[4] For reviews, see: (a) Cardin, D. J.; Cetinkaya, B.; Lappert, M. F.Chem.Rev. 1972,72, 545.(b) Lappert, M. F. J.
Organomet. Chem. 1988, 358, 185.
[5] Igau, A.; Grützmacher, H.; Baceiredo, A.; Bertrand, G. J. Am. Chem. Soc. 1988, 110, 6463.
[6] Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361.
5
Introduction
Electronic character
nitrogen centers
σ-electron-withdrawing and π-electron-donating character
electron-rich nucleophilic species
form stronger bonds with metal centers
Structure character
better steric protection
6
Introduction
Applications
as ubiquitous ligands in organometallic chemistry
as excellent nucleophilic organocatalysts
Methods of synthesis
7
Introduction
Other methods
(i) Reduction of thiourea with molten potassium in boiling THF [1]
(ii) Vacuum pyrolysis of an NHC-volatile compound adduct (like MeOH,
CHCl3, CHF3, C6F5H) [2]
[1] Denk, M. K.; Hezarkhani, A.; Zheng, F. L. Eur. J. Inorg. Chem. 2007, 3527.
[2] Nyce, G. W.; Csihony, S.; Waymouth, R. M.; Hedrick, J. L. Chem.;Eur. J. 2004, 10, 4073.
8
Introduction
Other methods
(iii) In situ release of NHC from NHC-CO2 or NHC-metal (SnII, MgII, ZnII)
adducts [1]
(iv) Reduction of a chloroformamidinium salt with Hg(TMS)2 or with
Pd(0) and Ni(0) complexes [2]
[1] Voutchkova, A. M.; Appelhans, L. N.; Chianese, A. R.; Crabtree, R. H. J. Am. Chem. Soc. 2005, 127, 17624.
[2] Otto, M.; Conejero, S.; Canac, Y.; Romanenko, V. D.; Rudzevitch, V.; Bertrand, G. J. Am. Chem. Soc. 2004, 126,
1016.
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Introduction
General synthetic pathways to NHC precursors
• Ring closure by introduction of the precarbenic unit
• Ring closure by linkage of the backbone to the preassembled
precarbenic and amino units
• Ring closure by introduction of the amino moiety
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Outline
1. Introduction
2. Synthetic Pathways to NHC Precursors
2.1 Cyclization by Introduction of the Precarbenic Atom
2.2 Ring Closing by the Final Introduction of the Backbone
2.3 Final Introduction of the Amino Moiety
3. Conclusion
11
Outline
1. Introduction
2. Synthetic Pathways to NHC Precursors
2.1 Cyclization by Introduction of the Precarbenic Atom
2.2 Ring Closing by the Final Introduction of the Backbone
2.3 Final Introduction of the Amino Moiety
3. Conclusion
12
Synthetic Pathways to NHC Precursors
2.1 Cyclization by Introduction of the Precarbenic Atom
 Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit
 1,1-Bis(electrophile) Compounds as C1 Providers
 Using Paraformaldehyde as the Precarbenic Unit
 Cyclization via a Preinstalled Formamide
13
Synthetic Pathways to NHC Precursors
2.1 Cyclization by Introduction of the Precarbenic Atom
 Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit
 1,1-Bis(electrophile) Compounds as C1 Providers
 Using Paraformaldehyde as the Precarbenic Unit
 Cyclization via a Preinstalled Formamide
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Synthetic Pathways to NHC Precursors
Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit
The first report
Saba, S.; Brescia, A.-M.; Kaloustian, M. K. Tetrahedron Lett. 1991, 32, 5031.
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Synthetic Pathways to NHC Precursors
Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit
•
•
•
•
•
•
•
Condensation-Reduction Route
Bisacylation/Reduction Route
Acylation-Alkylation/Reduction Route
Starting from a Preformed Diamine Core
Reaction on a Bis-electrophilic Core
R-Amino Acids as Building Blocks
Triazolium Salts and Benzoxazolium
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Synthetic Pathways to NHC Precursors
• Condensation-Reduction Route
Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R.; Craig, H. A.; Goerlich, J. R.; Marshall, W. J.; Unverzagt, M.
Tetrahedron 1999, 55, 14523.
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Synthetic Pathways to NHC Precursors
• Condensation-Reduction Route
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Synthetic Pathways to NHC Precursors
• Condensation-Reduction Route
Van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 4954.
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Synthetic Pathways to NHC Precursors
• Condensation-Reduction Route
[1]
[3]
[2]
[1] Alcarazo, M.; Roseblade, S. J.; Alonso, E.; Fernandez,
R.; Alvarez, E.; Lahoz, F. J.; Lassaletta, J. M. J. Am.
Chem. Soc. 2004, 126, 13242.
[2] Enders, D.; Meiers, M. Synthesis 2002, 2542.
[3] Chung, C. K.; Grubbs, R. H. Org. Lett. 2008, 10, 2693.
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Synthetic Pathways to NHC Precursors
• Bisacylation/Reduction Route
[1]
[2]
[1] Dinger, M. B.; Nieczypor, P.; Mol, J. C. Organometallics 2003, 22, 5291.
[2] Yun, J.; Marinez, E. R.; Grubbs, R. H. Organometallics 2004, 23, 4172.
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Synthetic Pathways to NHC Precursors
• Bisacylation/Reduction Route
22
Synthetic Pathways to NHC Precursors
• Acylation-Alkylation/Reduction Route
[1]
[2]
[1] Paczal, A.; Bényei, A. C.; Kotschy, A. J. Org. Chem. 2006, 71, 5969.
[2] Chung, C. K.; Grubbs, R. H. Org. Lett. 2008, 10, 2693.
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Synthetic Pathways to NHC Precursors
• Starting from a Preformed Diamine Core
[1]
[2]
[1] Huynh, H. V.; Han, Y.; Jothibasu, R.; Yang, J. A. Organometallics 2009, 28, 5395.
[2] Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225.
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Synthetic Pathways to NHC Precursors
• Starting from a Preformed Diamine Core
[1]
[2]
[1] Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 6877.
[2] Min, K. S.; Weyermuller, T.; Bothe, E.; Wieghardt, K. Inorg. Chem. 2004, 43, 2922.
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Synthetic Pathways to NHC Precursors
• Starting from a Preformed Diamine Core
26
Synthetic Pathways to NHC Precursors
• Reaction on a Bis-electrophilic Core
[1]
[3]
[2]
[1] Jurcík, V.; Gilani, M.; Wilhelm, R. Eur. J. Org. Chem. 2006, 5103.
[2] Steinke, T.; Shaw, B. K.; Jong, H.; Patrick, B. O.; Fryzuk, M. D. Organometallics 2009, 28, 2830.
[3] Leuthäusser, S.; Schmidts, V.; Thiele, C. M.; Plenio, H. Chem.;Eur. J. 2008, 14, 5465.
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Synthetic Pathways to NHC Precursors
• Reaction on a Bis-electrophilic Core
[1]
[3]
[2]
Rivas, F. M.; Riaz, U.; Giessert, A.; Smulik, J. A.; Diver, S. T. Org. Lett. 2001, 3, 2673.
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Synthetic Pathways to NHC Precursors
• Reaction on a Bis-electrophilic Core
[2]
[1]
[1] Tennyson, A. G.; Rosen, E. L.; Collins, M. S.; Lynch, V. M.; Bielawski, C. W. Inorg. Chem. 2009, 48, 6924.
[2] Saravanakumar, S.; Kindermann, M. K.; Heinicke, J.; Köckerling, M. Chem. Commun. 2006, 640.
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Synthetic Pathways to NHC Precursors
• R-Amino Acids as Building Blocks
Tiede, S.; Berger, A.; Schlesiger, D.; Rost, D.; Lühl, A.; Blechert, S. Angew. Chem., Int. Ed. 2010, 49, 3972.
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Synthetic Pathways to NHC Precursors
• Triazolium Salts and Benzoxazolium
[1]
[2]
[1] Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkin Trans. 1 1998, 1891.
[2] Ma, Y.; Wei, S.; Lan, J.; Wang, J.; Xie, R.; You, J. J. Org. Chem. 2008, 73, 8256.
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Synthetic Pathways to NHC Precursors
Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit
• Using trialkyl orthoformate
• Acidic conditions
• A well-developed procedure
• Applicable to imidazolinium, benzimidazolium, tetrahydropyrimidinium
• Each methods having its own advantages and limitations
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Synthetic Pathways to NHC Precursors
2.1 Cyclization by Introduction of the Precarbenic Atom
 Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit
 1,1-Bis(electrophile) Compounds as C1 Providers
 Using Paraformaldehyde as the Precarbenic Unit
 Cyclization via a Preinstalled Formamide
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Synthetic Pathways to NHC Precursors
1,1-Bis(electrophile) Compounds as C1 Providers
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Synthetic Pathways to NHC Precursors
• gem-Dihalides as C1 Building Blocks
[1]
[2]
[1] Calder, I. C.; Spotswood, T. M.; Sasse, W. H. F. Tetrahedron Lett. 1963, 2, 95.
[2] Nonnenmacher, M.; Kunz, D.; Rominger, F.; Oeser, T. Chem. Commun. 2006, 1378.
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Synthetic Pathways to NHC Precursors
• Using Weiss' Reagent
Weiss, R.; Reichel, S.; Handke, M.; Hampel, F. Angew. Chem., Int. Ed. 1998, 37, 344.
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Synthetic Pathways to NHC Precursors
• Using Chloromethyl Ethers
Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R.; Craig, H. A.; Goerlich, J. R.; Marshall, W. J.; Unverzagt, M. Tetrahedron
1999, 55, 14523.
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Synthetic Pathways to NHC Precursors
• Using Chloromethyl Pivalate
Würtz, S.; Glorius, F. Acc. Chem. Res. 2008, 41, 1523.
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Synthetic Pathways to NHC Precursors
• Using Chloromethyl Pivalate
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Synthetic Pathways to NHC Precursors
2.1 Cyclization by Introduction of the Precarbenic Atom
 Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit
 1,1-Bis(electrophile) Compounds as C1 Providers
 Using Paraformaldehyde as the Precarbenic Unit
 Cyclization via a Preinstalled Formamide
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Synthetic Pathways to NHC Precursors
Using Paraformaldehyde as the Precarbenic Unit
41
Synthetic Pathways to NHC Precursors
• Imidazolium Salts
[1]Bildstein, B.; Malaun, M.; Kopacka, H.; Wurst, K.; Mitterbück, M.; Ongania, K.-H.; Opromolla, G.; Zanello, P.
Organometallics 1999, 18, 4325.
[2] Nolan, S. P. U. S. Patent 7,109,348, 2006; (b) Jafarpour, L.; Stevens, E. D.; Nolan, S. P. J. Organomet. Chem. 2000,
606, 49.
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Synthetic Pathways to NHC Precursors
• Imidazolium Salts
[1] Hintermann, L. Beilstein J. Org. Chem. 2007, 3, 22.
[2] Ogle, J. W.; Zhang, J.; Reibenspies, J. H.; Abboud, K.; Miller, S. A. Org. Lett. 2008, 10, 3677.
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Synthetic Pathways to NHC Precursors
• Via Oxidation of a Cyclic Aminal
[1] Mayr, M.; Wurst, K.; Ongania, K.-H.; Buchmeiser, M. R. Chem.; Eur. J. 2004, 10, 1256.
[2] Mayr, M.; Buchmeiser, M. R. Macromol. Rapid Commun. 2004, 25, 231.
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Synthetic Pathways to NHC Precursors
• Via Oxidation of a Cyclic Aminal
[1] Bildstein, B.; Malaun, M.; Kopacka, H.; Ongania, K.-H.; Wurst, K. J. Organomet. Chem. 1999, 572, 177.
[2] Schwarz, D. E.; Cameron, T. M.; Hay, P. J.; Scott, B. L.; Tumas, W.; Thorn, D. L. Chem. Commun. 2005, 5919.
45
Synthetic Pathways to NHC Precursors
2.1 Cyclization by Introduction of the Precarbenic Atom
 Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit
 1,1-Bis(electrophile) Compounds as C1 Providers
 Using Paraformaldehyde as the Precarbenic Unit
 Cyclization via a Preinstalled Formamide
46
Synthetic Pathways to NHC Precursors
 Cyclization via a Preinstalled Formamide
[1] Alcarazo, M.; Roseblade, S. J.; Cowley, A. R.; Fernandez, R.; Brown, J. M.; Lassaletta, J. M. J. Am. Chem. Soc.
2005, 127, 3290.
[2] Dorn, H.; Zubek, A.; Hilgetag, G. Chem. Ber. 1965, 98, 3377.
47
Outline
1. Introduction
2. Synthetic Pathways to NHC Precursors
2.1 Cyclization by Introduction of the Precarbenic Atom
2.2 Ring Closing by the Final Introduction of the Backbone
2.3 Final Introduction of the Amino Moiety
3. Conclusion
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Synthetic Pathways to NHC Precursors
2.2 Ring Closing by the Final Introduction of the Backbone
 Condensation onto an Aminal Moiety
 Cyclization Starting from a N,N’ -Disubstituted Formamidine
 Cyclization by Quaternization of an Imine
 Cyclization Starting from a N,P-Disubstituted Phosphaformamidinate
 Cyclization Starting from a Thioformamide
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Synthetic Pathways to NHC Precursors
 Condensation onto an Aminal Moiety
Arduengo, A. J., III U.S. Patent 5,077,414, 1991.
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Synthetic Pathways to NHC Precursors
 Cyclization Starting from a N,N’ -Disubstituted Formamidine
• Preparation of N,N’-DisubstitutedFormamidines
• Cyclization via a Bisalkylation Route
• Cyclization by AlkylationHydroiminiumation Sequence
• Cyclization by Alkylation-Condensation Reactions
• Cyclization via an Amination Reaction
• Cyclization via an Alkylation-Acylation Sequence
• Cyclization by Bisacylation of the Formamidine
• Introduction of an Inorganic
51
Synthetic Pathways to NHC Precursors
• Preparation of N,N’-DisubstitutedFormamidines
[1]
[3]
[2]
[1] Roberts, R. M. J. Org. Chem. 1949, 14, 277.
[2] Binobaid, A.; Iglesias, M.; Beetstra, D. J.; Kariuki, B.; Dervisi, A.; Fallis, I. A.; Cavell, K. J. Dalton Trans. 2009, 7099.
52
[3] Taylor, E. C.; Ehrhart, W. A. J. Org. Chem. 1963, 28, 1108.
Synthetic Pathways to NHC Precursors
• Cyclization via a Bisalkylation Route
[1] Jazzar, R.; Liang, H.; Donnadieu, B.; Bertrand, G. J. Organomet. Chem. 2006, 691, 3201.
[2] Kuhn, K. M.; Grubbs, R. H. Org. Lett. 2008, 10, 2075.
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Synthetic Pathways to NHC Precursors
• Cyclization by Alkylation-Hydroiminiumation Sequence
Jazzar, R.; Bourg, J.-B.; Dewhurst, R. D.; Donnadieu, B.; Bertrand, G. J. Org. Chem. 2007, 72, 3492.
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Synthetic Pathways to NHC Precursors
• Cyclization by Alkylation-Condensation Reactions
Togni, A., Hayashi, T., Eds. Ferrocenes; Wiley-VCH: Weinheim, Germany, 1995.
55
Synthetic Pathways to NHC Precursors
• Cyclization by Alkylation-Condensation Reactions
Hirano, K.; Urban, S.; Wang, C.; Glorius, F. Org. Lett. 2009, 11, 1019.
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Synthetic Pathways to NHC Precursors
• Cyclization via an Amination Reaction
[1] Sanderson, M. D.; Kamplain, J. W.; Bielawski, C. W. J. Am. Chem. Soc. 2006, 128, 16514.
[2] Tennyson, A. G.; Lynch, V. M.; Bielawski, C. W. J. Am. Chem. Soc. 2010, 132, 9420.
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Synthetic Pathways to NHC Precursors
• Cyclization via an Alkylation-Acylation Sequence
[1] Benhamou, L.; César, V.; Gornitzka, H.; Lugan, N.; Lavigne, G. Chem. Commun. 2009, 4720.
[2] Biju, A.; Hirano, K.; Fr€ohlich, R.; Glorius, F. Chem.-Asian J. 2009, 4, 1786.
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Synthetic Pathways to NHC Precursors
• Cyclization by Bisacylation of the Formamidine
59
Synthetic Pathways to NHC Precursors
• Introduction of an Inorganic
60
Synthetic Pathways to NHC Precursors
 Cyclization by Quaternization of an Imine
[1] Lavallo, V.; Canac, Y.; Präsang, C.; Donnadieu, B.; Bertrand, G. Angew. Chem., Int. Ed. 2005, 44, 5705.
[2] Zeng, X.; Frey, G. D.; Kinjo, R.; Donnadieu, B.; Bertrand, G. J. Am. Chem. Soc. 2009, 131, 8690.
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Synthetic Pathways to NHC Precursors
 Cyclization Starting from a N,P-Disubstituted Phosphaformamidinate
Frey, G. D.; Song, M.; Bourg, J.-B.; Donnadieu, B.; Soleilhavoup, M.; Bertrand, G. Chem. Commun. 2008, 4711.
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Synthetic Pathways to NHC Precursors
 Cyclization Starting from a Thioformamide
[1] Sheehan, J. C.; Hara, T. J. Org. Chem. 1974, 39, 1196.
[2] Vougioukalakis, G. C.; Grubbs, R. H. J. Am. Chem. Soc.
2008, 130, 2234.
[3] Jazzar, R.; Liang, H.; Donnadieu, B.; Bertrand, G. J.
Organomet. Chem. 2006, 691, 3201.
63
Outline
1. Introduction
2. Synthetic Pathways to NHC Precursors
2.1 Cyclization by Introduction of the Precarbenic Atom
2.2 Ring Closing by the Final Introduction of the Backbone
2.3 Final Introduction of the Amino Moiety
3. Conclusion
64
Synthetic Pathways to NHC Precursors
 Via a Heterocyclic Interconversion
[1] Barbier, D.; Marazano, C.; Das, B. C.; Potier, P. J. Org.
Chem. 1996, 61, 9596.
[2] Enders, D.; Gielen, H. J. Organomet. Chem. 2001, 617618, 70.
65
Synthetic Pathways to NHC Precursors
 Via a Heterocyclic Interconversion
Fürstner, A.; Alcarazo, M.; Cesar, V.; Lehmann, C. W. Chem. Commun. 2006, 2176.
66
Synthetic Pathways to NHC Precursors
 Through Condensation with a Hydrazine Derivative
[1]Fürstner, A.; Alcarazo, M.; Radkowski, K.; Lehmann,
C. W. Angew. Chem., Int. Ed. 2008, 47, 8302.
[2] Iglesias-Sigüenza, J.; Ros, A.; Díez, E.; Alcarazo, M.;
Alvarez, E.; Fernandez, R.; Lassaletta, J. M. Dalton Trans.
2009, 7113.
67
Outline
1. Introduction
2. Synthetic Pathways to NHC Precursors
2.1 Cyclization by Introduction of the Precarbenic Atom
2.2 Ring Closing by the Final Introduction of the Backbone
2.3 Final Introduction of the Amino Moiety
3. Conclusion
68
Conclusion
Beneficial features as ligands
(i) The stability of their complexes
(ii) The importance of steric effects
(iii) The modulable electronic character
(iv) The rich diversity and efficiency of synthetic methods
Three different strategies
(According to the unit introduced during the last cyclization step)
Each having its own advantages and limitations
69
Outlook
Beneficial features as ligands
(i) The stability of their complexes
(ii) The importance of steric effects
(iii) The modulable electronic character
(iv) The rich diversity and efficiency of synthetic methods
Three different strategies
(According to the unit introduced during the last cyclization step)
Each having its own advantages and limitations
70
The end
Thank you!
71