Costa Metallinos

Professor, Chemistry

Costa Metallinos

Office: Cairns 518
Lab:Cairns 542
905 688 5550 x3848

Research Interests

Synthetic organic and organometallic chemistry

Going clockwise: Costa Metallinos, Ngan Tran (PhD), Maria Laura Sechi (PhD), Jagandeep Saraya (BSc), Dusty Cadwallader (MSc), Lyzcel Talisic (BSc), Claire Snelgrove (BSc).

1. Annulated Chiral NHCs:

(a) Benzimidazolylidenes Derived from Phenanthrolines: Our group has developed innovative routes to several chiral imidazoline-type N-hetereocyclic carbenes (NHCs). We have prepared benzimidazolium-based NHCs via reduction of substituted phenanthrolines. In comparison to previous chiral benzimidazolylidenes, the compounds represented by the general structure 4 have several unique features that make them interesting for applications in asymmetric synthesis, both as NHCs and as non-carbenoid reagents: (a) they are amenable to structural diversification because many different substituents (alkyl, aryl) can be regioselectively introduced into the 2- or the 2,9-positions of 1,10-phenanthroline via nucleophilic aromatic substitution (NAS); (b) after reduction, the resulting octahydrophenanthrolines (2) have stereogenic centers within rings, the rigidity of which results in well-defined chiral environments for any reagents derived from them (3); (c) they may be electronically modified by electrophilic aromatic substitution (EAS) at the two open positions on the benzene ring, which are activated by the presence of nitrogen atoms para to those sites.

Metallinos Figure 1

(b) Stereoselective Synthesis of Pyrroloimidazol(in)ylidenes: Our NHC research has expanded to include a new series of C1-symmetric systems with pyrroloimidazol(in)ylidene (5) frameworks, which retain the annulated chiral structural motif that is a design feature of our reagents.  Mono-annulated chiral imidazolium NHC precatalysts 5 resemble much more common triazolium (6) and thiazolium (7) precatalysts, but they have seen limited use despite promising results demonstrating their divergent reactivity (2009 Org. Lett. 677) when they are employed as nucleophilic catalysts. We have developed a simple stereoselective synthesis of C5-substituted annulated chiral pyrroloimidazol(in)ylidene precatalysts (8 10 and 11 13) using an approach that borrows from our earlier work with phenanthroline-derived NHCs.

Metallinos Figure 2

2. Aminoferrocenes:

Differentially 1,2-disubstituted ferrocenes (e.g., 14) possess planar chirality, and as such, may complement the behavior of ligands such as phosphines 15 or binaphthyls 16 that have central or axial chirality. A resurgence of interest for induction of planar chirality into ferrocenes in the 1990s, based on stereoselective lithiation, has provided the synthetic community with many methods for preparing precursors to new ligands. Despite available methods, many axial and central chiral ligands of importance in catalysis still lack planar chiral ferrocenyl analogues, especially for aminoferrocenes where nitrogen is directly attached to the cyclopentadienyl ring. The limited examples may be attributed to impracticalities imposed by the previous synthetic routes. We have developed a direct enantioselective synthesis of planar chiral aminoferrocenes using BF3-activated lithiation (17 1819). Many products derived from this method have unusual substitution patterns, are uncommon, or completely unknown. Iridium complexes 21 of P,N-ligands such as 20 have shown encouraging catalytic activity in reactions with prochiral substrates. Work towards developing enantioselective reactions mediated by congeners of these ligands is ongoing in our group.

Metallinos Figure 3

3. L-Proline Hydantoin-Derived Chiral Auxiliaries:

We have developed a new chiral auxiliary derived from L-proline hydantoin and applied it to the highly diastereoselective synthesis of underexploited N-substituted planar chiral ferrocenes (22 23). This imidazolone auxiliary (1S-triethylsilyloxy-7aS-hexahydropyrrolo[1,2-c]imidazol-3-one, or SPI for short) is unique in that it simultaneously satisfies five design requirements: (a) it is available in large quantities from inexpensive starting materials; (b) it is stable to strong bases used in lithiation chemistry; (c) it provides products in high diastereomeric ratio (>95:5 dr) from lithiation−substitution of prochiral positions; (d) it may be converted to other functional groups, including ureas (24), amines (25) and imidazolones (26 and 27); (e) its anti epimer (anti22) affords enantiomers (ent26) without the need to prepare the enantiomeric starting material from expensive D-proline. Points (d) and (e) in particular distinguish our auxiliaries from classic oxazolidinones.

A result of this methodology is that we are able to synthesize chiral ligands with atypical architectures and properties. Iridium complex 28, for example, bears a monodentate N-heterocyclic carbene (NHC) ligand that was prepared from tetracyclic urea anti27. Complex 28 catalyzes asymmetric hydrogenation of prochiral quinolines in up to 90:10 er under very mild conditions (25 °C, 1-5 atm H2), suggesting that it operates by an outer-sphere reaction mechanism akin to Crabtree’s achiral complex 29.


Proline hydantoin-derived auxiliaries work equally well to induce planar chirality in π-arene Cr(CO)3 complexes (e.g., anti– and syn30). Additional applications of SPI-type auxullaries are under investigation in our laboratories to induce central and axial chirality on non-organometallic substrates.



Chapters in Books and Patents:

Metallinos, C.; Stromski, K., “Metalation Reactions of Pyridines, Quinolines, and Isoquinolines with Ate Bases and Their Alkali Metal Salt-Modified Congeners” in Metalation of Azines and Diazines (Topics in Heterocyclic Chemistry); Schnürch, M.; Mihovilovic, M. D. (Eds.), Springer, 2013, pp. 65-92.

Metallinos, C., “Method for Preparing Ortho-Substituted Aminoferrocenes”, United States Patent 7,982,064, July 19, 2011.

Deng, W.-P.; Snieckus, V.; Metallinos, C., “Stereoselective Synthesis of Planar Chiral Ferrocenes” in Chiral Ferrocenes in Asymmetric Catalysis: Synthesis and Applications; Dai, L.-X.; Hou, X.-L. (Eds.), Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany 2010, pp. 15-53.

Metallinos, C., “Product Class 8.1.24: Carbamoyllithium and Trihalomethyllithium Compounds” in Science of Synthesis, Vol. 8a; Majewski, M.; Snieckus, V. (Eds.), Georg Thieme-Verlag KG: Stuttgart, Germany 2006, pp. 795-804.


 Journal Papers:

Emberson, K.; Tran, N.; Metallinos, C., “Diastereoselective Lithiation of N-Benzyl Pyrroloimidazolones Derived from N-Proline Hydantoin”, Synlett 2017, in press (DOI: 10.1055/s-0036-1591206).

Wilson-Konderka, C.; Doxtator, K.; Metallinos, C., “Selective Synthesis of Enantiomeric η6-Arene Chromium Tricarbonyl Complexes with Epimeric Pyrroloimidazolones”, Adv. Synth. Catal. 2016, 358, 2599-2603.

Wilson-Konderka, C.; Lough, A. J.; Metallinos, C., “(+)-trans-Chlorido{2-[(Rp)-2-(methylsulfanyl)ferrocenyl]-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-3-ylidene}bis(triphenylphosphane-κP)palladium(II) hexafluoridophosphate dichloroform disolvate”, Acta Cryst. E 2016, 72, 1330-1334.

John, J.; Wilson-Konderka, C.; Metallinos, C., “Low Pressure Asymmetric Hydrogenation of Quinolines using an Annulated Planar Chiral N-Ferrocenyl NHC-Iridium Complex”, Adv. Synth. Catal. 2015, 357, 2071-2081.

Giannopoulos, D. P..; Wilson-Konderka, C.; Gagnon, K. J., Teat, S. J.; Escuer, A. Metallinos, C., Stamatatos, T. C., “Synthesis and First Use of Pyridine-2,6-diylbis-(pyrazine-2-ylmethanone) in Metal Cluster Chemistry: A {MnIII3Na2} Complex with an Ideal Trigonal Bipyramidal Geometry”, Dalton Trans. 2015, 44, 4318-4327.

Metallinos, C.; Sadraei, S. E.; Zhukovskaya, N., “Diastereoselective Synthesis of 5-Substituted Tetrahydro-1H-pyrrolo[1,2-c]imidazol-3(2H)-ones using an N-Silyl Protecting Group”, Heterocycles 2014, 88, 347-362 (by invitation).

Metallinos, C.; John, J.; Nelson, J.; Dudding, T.; Belding, L. “Reversal of Stereoselectivity in Lithiation of Ferrocenyl-imidazolones: Epimeric Substrates lead to Planar Chiral Enantiomers”, Adv. Synth. Catal. 2013, 355, 1211-1219.

Metallinos, C.; John, J.; Zaifman, J.; Emberson, K., “Diastereoselective Synthesis of N-Substituted Planar Chiral Ferrocenes Using a Proline Hydantoin-Derived Auxiliary” Adv. Synth. Catal. 2012, 354, 602-606.

Metallinos, C.; Van Belle, L., “Asymmetric Hydrogenation of Alkenes with Cationic Iridium(I) Complexes of Planar Chiral 2-Phosphino-1-Aminoferrocene Ligands ” J. Organomet. Chem. 2011, 696, 141-149 (by invitation).

Metallinos, C.; Zaifman, J.; Dudding, T.; Van Belle, L.; Taban, K., “Asymmetric Lithiation of BF3-Activated Aminoferrocenes: An Experimental and Computational Investigation”, Adv. Synth. Catal. 2010, 352, 1967-1982.

Metallinos, C.; Xu, S., “Stereoselective Synthesis of 5-Substituted Pyrrolo[1,2-c]imidazole-3-ones. Access to Annulated Chiral Imidazol(in)ium Salts”, Org. Lett. 2010, 12, 76-79.

Metallinos, C.; Zaifman, J.; Van Belle, L.; Dodge, L.; Pilkington, M., “Palladium(II), Platinum(II) and Iridium(I) Complexes of 2-Phosphino-1-dimethylaminoferrocenes: A Survey of Structure and Catalysis”, Organometallics 2009, 28, 4534-4543.

Metallinos, C.; Du, X. “Neutral and Cationic Iridium(I) Complexes Bearing Chiral Phenanthroline-Derived Benzimidazolylidenes: Synthetic, Structural and Catalytic Studies”, Organometallics 2009, 28, 1233-1242.

Metallinos, C.; Zaifman, J.; Dodge, L., “Aminoferrocene Lithiation by Boron Trifluoride Activation”, Org. Lett. 2008, 10, 3527-3530.

Metallinos, C.; Barrett, F. B.; Xu, S., “Brønsted Acid Catalyzed Asymmetric Reduction of 2- and 2,9-Substituted 1,10-Phenanthrolines”, Synlett 2008, 720-724.

Blanchet, J.; Macklin, T.; Ang, P.;Metallinos, C.; Snieckus, V., “Directed ortho Metalation-Cross Coupling Strategies. N-Cumyl Arylsulfonamides. Facile Deprotection and Expedient Route to 4- and 4,7-Substituted Saccharins”, J. Org. Chem. 2007, 72, 3199-3206.

Metallinos, C.; Dudding, T; Zaifman, J.; Chaytor, J. L.; Taylor, N. J., “An Experimental and Theoretical Study of the Asymmetric Lithiation of 1,2,3,5,6,7-Hexahydro-3a,4a-diazacyclopenta[def]phenanthren-4-one”, J. Org. Chem. 2007, 72, 957-963.

Metallinos, C.; Barrett, F. B.; Wang, Y.; Xu, S.; Taylor, N. J., “Reduction of Substituted 1,10-Phenanthrolines as a Route to Rigid Chiral Benzimidazolylidenes”, Tetrahedron 2006, 62, 11145-11157.

Metallinos, C.; Tremblay, D. T.; Barrett, F. B.; Taylor, N. J., “1,1′-Bis(phosphoranylidenamino)ferrocene Palladium(II) Complexes: An Unusual Case of Dative Fe→Pd Bonding”, J. Organomet. Chem. 2006, 691, 2044-2047.

Metallinos, C.; Barrett, F. B.; Chaytor, J. L.; Heska, M. E. A.,”A Benzimidazole-Based N-Heterocyclic Carbene Derived from 1,10-Phenanthroline”, Org. Lett. 2004, 6, 3641-3644.

Beierle, J. M.; Osimboni, E. B.; Metallinos, C.; Zhao, Y.; Kelly, T. R., “Synthesis of Louisianin C”, J. Org. Chem. 2003, 68, 4970-4972.

Metallinos, C.; Szillat, H.; Taylor, N. J.; Snieckus, V., “(–)-Sparteine-Mediated Directed ortho Metalation of N-Cumyl-N-Ethyl Ferrocenecarboxamide.  Versatile Routes to Planar Chiral Ferrocenecarboxamides, Amines, Esters and Phosphines”, Adv. Synth. Catal. 2003, 345, 370-382.

Metallinos, C., “The N-Cumyl Group for Facile Manipulation of Carboxamides, Sulfonamides and Aryl O-Carbamates Post-Directed ortho Metalation”, Synlett 2002, 1556-1557.

Metallinos C.; Snieckus, V., “(–)-Sparteine-Mediated Metalation of Ferrocenesulfonates.  The First Case of Double Asymmetric Induction of Ferrocene Planar Chirality”, Org. Lett. 2002, 4, 1935-1938.

Metallinos, C.; Nerdinger, S.; Snieckus, V., “N-Cumyl Benzamide, Sulfonamide and Aryl O-Carbamate Directed Metalation Groups.  Mild Hydrolytic Lability for Facile Manipulation of Directed ortho Metalation-Derived Aromatics”, Org. Lett. 1999, 1, 1183-1186.