Current Research & Publications

General Information and Publications in Refereed Journals

W&M undergraduate names in bold

General Overview:

We are interested in creating new reactions and studying reactive intermediates. In particular, we creating novel molecules using oxocarbenium ion and iodonium ion intermediates in cascade, or domino reaction sequences. These complex processes involve a number of discreet organic transformations in which the individual reactions must take place in a specific order for the overall reaction to afford products in reasonable yields. In essence, one reaction (domino) must fall (react) before the next reaction can proceed, and so-on.

Prins chemistry:

The Prins reaction was first described 100 years ago and is the result of attack of an activated ketone or aldehyde by an alkene followed by trapping by a nucleophile. In the last two decades, it has become increasingly important in the synthesis of tetrahydropyran and dihydropyran ring systems, which are prevalent in many anticancer, antifungal and antibiotic compounds. We began this area of research using catalytic quantities of BiX₃ (X = Br, Cl, OTf) using an intramolecular cyclization/nucleophilic addition strategy in collaboration with P. Andrew Evans, now at Queen’s University in Ontario. This cyclization creates an incipient oxocarbenium ion to which an alkene or silane nucleophile can add. At about this time, a paper appeared in which an alkyne was used to trap the intermediate oxocarbenium ion and we have been investigating this ever since. Please see below for publications and reaction abstracts.

Polyyne Syntheses and Bioactivity:

In collaboration with Doug Young, also in Chemistry at W&M, we recently published a study of simple diynes and their effects on bacterial cell cultures. Rather than examine derivatives of naturally-occurring diynes, we synthesized simpler analogues to determine the structural features that might be necessary for biological activity. We are currently pursuing funding to continue this work.

Emma A. Hale†, Hannah M. Ryan†, Alexandra M. McOsker†, Cody M. Funk, Lauren C. Green, Lauren E. Mazur, Diya M. Uthappa, Brian M. Flood, Douglas D. Young*, Robert J. Hinkle,* “Effects of Structural Variations on Antibacterial Properties for Conjugated Diynes Generated through Glaser Hay Couplings,” Chem. Med. Chem. e202200455. Online, 04 October 2022. (https://doi.org/10.1002/cmdc.202200455). Final paper published online, 29 October 2022.

Robert J. Hinkle, Daniel J. Speer, Brendon B. Carnell, Bethany L. Kanter, and Robert D. Pike, "Mild, Modular and Convergent Synthesis of Helical Naphtho[2.1-c]chromenes via a Multistep Cyclization/Aromatization Cascade Sequence," J. Org. Chem. 2019, 84, 15633-15640: https://doi.org/10.1021/acs.joc.9b02058

Robert J. Hinkle, Sarah E. Bredenkamp, Robert D. Pike, Seong Ik Cheon, “Electrophilic Cyclization of Phenylalkynediols to Naphthyl(aryl)iodonium Triflates with Chelating Hydroxyls: Preparation and X-ray Analyses ,” J. Org. Chem. 2017, ASAP article published online 17 August 2017. DOI: 10.1021/acs.joc.7b01619 (https://pubs.acs.org/doi/pdf/10.1021/acs.joc.7b01619).

Robert J. Hinkle, Yuzhou Chen, Colleen Nofi, and Shane E. Lewis, “Electronic effects on a one-pot aromatization cascade involving alkynyl-Prins cyclization,Friedel–Crafts alkylation and dehydration totricyclic benzo[f]isochromenes,” Org. Biomol. Chem. 2017. Published online 11 August 2017; DOI: http://pubs.rsc.org/en/Content/ArticleLanding/2017/OB/C7OB01412K

Robert J. Hinkle and Shane E. Lewis, “Atom Economical, One-Pot, Three-Reaction Cascade to Novel Tricyclic 2,4-Dihydro-1H-benzo[f]isochromene Derivatives,” Org. Lett. 2013, 15, 4070-4073. ASAP published online 01 August 2013; DOI http://dx.doi.org/10.1021/ol401600j

Frederick Lambert, Robert J. Hinkle,* Stephen E. Ammann, Yajing Lian, Jia Liu, Shane E. Lewis, and Robert D. Pike, “Bi(OTf)3-, TfOH-, and TMSOTf-Mediated, One-Pot Epoxide Rearrangement, Addition, and Intramolecular Silyl-Modified Sakurai (ISMS) Cascade toward Dihydropyrans: Comparison of Catalysts and Role of Bi(OTf)3,” J. Org. Chem. 2011, 76, 9269-9277; DOI https://pubs.acs.org/doi/abs/10.1021/jo201478d

Robert J. Hinkle,* Yajing Lian, Lee C. Speight, Heather E. Stevenson, Melissa M. Sprachman, Lauren A. Katkish, M. Christa Mattern, “Synthesis of 2,6-Disubstituted Dihydropyrans via an Efficient BiBr3-initiated Three Component, One-pot Cascade,” Tetrahedron 2009, 65, 6834–6839.

Yajing Lian, Robert J. Hinkle, ”BiBr3-Initiated Tandem Addition/Silyl-Prins Reactions to 2,6-Disubstituted Dihydropyrans,” J. Org. Chem. 2006, 71, 7071-7074.

Robert J. Hinkle, Yajing Lian, Nichole D. Litvinas, Alex T. Jenkins, Daniel C. Burnette, "BiBr3 Initiated Cyclization-Addition Reactions: Effect of Nucleophile and Total Synthesis of (+)-(S,S)-(cis-6-methyltetrahydropyran-2-yl)acetic Acid and its trans-Diastereomer," Tetrahedron 2005, 61, 11679-11685.

Evans, P. A.; Cui, J.; Gharpure, S. J; Hinkle, R. J. “Stereoselective Construction of Cyclic Ethers using a Tandem Two-Component Etherification: Elucidation of the Role of Bismuth Tribromide,” J. Am. Chem. Soc. 2003, 125, 11456-11457.

Hinkle, R. J. "Mikowski, A. M. "Kinetics of Stereoisomeric 2-Methyl-1-butenyl-(aryl)iodonium Triflates," Included in a special issue of ARKIVOC 2003, vi, 201-212, published 25 July 2003: http://www.arkat-usa.org/ark/journal/2003/Varvoglis/AV-745A/745A.pdf.

Tykwinski, R. R.†; Kamada, K.‡; Bykowski, D.†; Hegmann, F. A.†; Hinkle, R. J. "Nonlinear Optical Properties of Thienyl and Bithienyl Iodonium Salts as Measured by the Z-scan Technique," J. Opt. A: Pure Appl. Opt. 2002, 4, S202-206.

Bykowski, D.†; McDonald, R.†; Hinkle, R. J.; Tykwinski, R. R.† "Structural and Electronic Characteristics of Thienyl(aryl)iodonium Triflates," J. Org. Chem., 2002, 67, 2798-2804.

Hinkle, R. J.; McDonald, R.†, "(Z)-2-Methyl-1-buten-1-yl(aryl)iodonium Triflates Containing Electron-Withdrawing Groups on the Aryl Moiety." Acta Cryst. C. 2002, C58, o117-o121.

McNeil, A. J.; Hinkle, R. J.; Rouse, E. A.; Thomas, Q. A.; Thomas, D. B. "Vinyl Carbocations: Solution Studies of Alkenyl(aryl)iodonium Triflate Fragmentations," J. Org. Chem. 2001, 66, 5556-5565.

Hinkle, R. J.; Leri, A. C.; David, G. A.; Erwin, W. M. "Addition of Benzylzinc Halides to Alkenyl(phenyl)iodonium Triflates: Stereoselective Synthesis of Trisubstituted Alkenes," Org. Lett. 2000, 2, 1521-1523.

Hinkle, R. J.; McNeil, A. J.; Thomas, Q. A.; Andrews, M. N. “Vinyl Cations in Solution: Kinetics and Products of Alkenyl(aryl)iodonium Salt Fragmentations,” J. Am. Chem. Soc., 1999, 121, 7437-7438.

Hinkle, R. J.; Thomas, D. B. “Facile Fragmentations of Alkenyl(aryl)iodonium Triflates,” J. Org. Chem. 1997, 62, 7534-7535.

Hinkle, R. J.; Stang, P. J. "Stereospecific Synthesis of Trisubstituted Alkenyl(phenyl)-iodonium Salts from Vinylstannanes" Synthesis 1994, 313.

Hinkle, R. J.; Poulter, G. T.; Stang, P. J. "Palladium(II) and Copper(I) Co-Catalyzed Coupling of Stereodefined Alkenyl(phenyl)iodonium Salts and Unsaturated Tri-n-butyl-stannanes" J. Am. Chem. Soc. 1993, 115, 11626.

Hinkle, R. J.; Stang, P. J.; Arif, A. M. "Vinylplatinum Carbenes and Nitriles, Platinoxacyclic Complexes and Heck-Type Coupling Products Formed Via Reaction of (s-2-propenyl)bis(triphenylphosphine)platinum(II) Triflate with Alkynols, Nitriles, and Acrylate Esters. Molecular Structure of [(PPh3)2PtCH2C(O)OCH3] [OTf]" Organometallics 1993, 12, 3510.

Zhong, Z.; Hinkle, R. J.; Arif, A. M.; Stang, P. J. "Novel Synthesis of (η³-Allyl)platinum(II) Complexes from Enol Triflates and Simple Olefins and Their Regiospecific Deprotonation" J. Am. Chem. Soc. 1991, 113, 6196.

Hinkle, R. J.; Stang, P. J.; Kowalski, M. H. "Vinylphosphonium Salts: Stereoselective Palladium-Catalyzed Vinylation of Triphenylphosphine with Vinyl Triflates" J. Org. Chem. 1990, 55, 5033.

Kowalski, M. H.; Hinkle, R. J.; Stang, P. J. "A Simple Highly Stereospecific Preparation of Vinylphosphonium Salts: Palladium-Catalyzed Vinylation of Triphenyl-phosphine via Vinyl Triflates" J. Org. Chem. 1989, 54, 2783.

Pike, R. M.; Mayo, D. W.; Butcher, S. S.; Butcher, D. J.; Hinkle, R. J., "Microscale Organic Laboratory IV: A Simple and Rapid Procedure for Carrying Out Wittig Reactions" J. Chem. Ed. 1986, 63, 917.

†University of Alberta, Edmonton, Alberta, Canada