59th Annual Report on Research 2014

Progress toward the major goals outlined in this proposal for the term of the grant are given below.

Progress toward Goal A:  Establish a robust synthetic protocol to reliably synthesize single E or Z isomers of oxime ethers using a variety of imidoyl iodides and trifluoroborate salts

The PI and the undergraduate students working under her direction optimized palladium catalyzed Suzuki coupling and the palladium-catalyzed Sonogashira coupling of N-alkoxyimidoyl iodides and bromides, achieving excellent yields for a variety of coupling partners and demonstrated that this reaction proceeds with complete retention of geometry about the C=N bond (equations 1 and 2).

In addition, the palladium-catalyzed Negishi reaction was investigated.  It persisted in giving an aromatic nitrile byproduct, thought to result from zinc-assisted ionization of the halide on the imidoyl halide, and the yield of the coupling product from this reaction was only moderate.  All the above work resulted in a publication in the Journal of Organic Chemistry¹ with nine undergraduate coauthors.  Eight of these nine coauthors have proceeded to graduate school in chemistry.

As the Suzuki coupling outlined in equation 1 resulted in single geometric isomers of diaryl oxime ethers, this provided the opportunity to explore the palladium-catalyzed C-H activation/functionalization at the ortho position (equation 3).   The exploration of ortho-bromination and iodination of these compounds has been completed.   This work revealed that these compounds only undergo ortho halogenation on the ring trans to the N-OCH₃ group and the geometry of the C=N bond is maintained during the reaction.  This reaction tolerated a variety of substituents and gave good to excellent yields of the mono-ortho-halogenation product with small amounts of the di-ortho-halogenated product.  Independent synthesis of a diaryl oxime ether palladacycle was also successfully performed.  This palladacyle was found to produce the same mono-ortho-halogenation product when placed in the same conditions used for the catalytic reaction discussed above.  This finding helps elucidate a potential intermediate for this reaction pathway.  This work has just been published in Tetrahedron Letters² with three undergraduate coauthors (all of which are now currently in graduate school in chemistry). 

Additional work on the ortho alkoxylation of these diaryl oxime ethers is currently underway. 

Progress toward Goal B:  Investigate the above coupling technique with N-alkoxyimidoyl pseudohalides

The Suzuki coupling reactions were attempted with the N-alkoxyimidoyl tosylates [ArC(OTs)=NOR].  This reaction yielded no coupling products.  Attempts at making the N-alkoxyimidoyl triflates have demonstrated that these compounds are not stable to moisture and revert back to the starting material during the work up.  Because of the unreactivity of the tosylates in these reactions and the instability of the imidoyl triflates, further work in this area has been put on hold to pursue other successful lines of research.

Progress toward Goal C:  Investigate the coupling technique with other N-substituted imines

Work has been initiated using hydrazonyl bromides [R¹C(Br)=N-NR²R³] in palladium-catalyzed coupling reactions.  To date this work has been complicated by competing cyclization reactions depending on R² and R³.  If these reactions yield some of the palladium-catalyzed coupling products, optimization of the reaction conditions will be carried out.

Progress toward Goal D:  Utilize the established coupling reaction to make biologically-active compounds Exploration of nucleophilic addition to the diaryl oxime ethers was undertaken with a racemic mix of a model compound with a chiral center on the N-alkoxyl group (O-1-phenethyl oxime of benzophenone).  Reactions with organometallic reagents (alkyllithiums and Grignard reagents) demonstrated that the diaryl oxime ethers were reluctant to undergo nucleophilic addition.  To facilitate nucleophilic attack on these species, the O-1-(4-nitrophenethyl) oxime ether of benzophenone was synthesized.  While this did more readily react with organometallic reagents, it was found that upon addition, the compound rapidly underwent loss of the -OR group attached to nitrogen with simultaneous migration of an aryl group from the carbon of the C=N bond to the nitrogen.  This new imine species then underwent attack by another equivalent of the organometallic reagent.   Attempts at using organometallic reagents with a more azaphilic metal only resulted in unreacted starting material. The PI group has begun exploring other reaction types to convert the diaryl oxime ethers into asymmetric amines.  At present, work is being undertaken to asymmetrically reduce the diaryl oxime ethers to form asymmetric diaryl amines.  This work using an asymmetric oxazaborolidine-type catalyst is showing promising results as initial studies give enantiomeric excesses of 84%.  While these preliminary results are exciting, this project is only in the beginning stages and requires a significant amount of work in the future.

Progress toward the general goal of providing solid research training to undergraduates: 

The funds from the PRF grant have allowed the PI to productively engage undergraduate students in publishable research.  Three of the students financially supported by the PRF grant were co-authors on peer-reviewed publications.^1,2  All three of these students are now in graduate school in chemistry (University of Michigan, Purdue University and Louisiana State University).

The PRF support has allowed the PI to build a successful collaboration with two organic chemists at the University of Alabama (U.A).  It has allowed students to work with both the PI and the investigators at U.A. giving them an outstanding undergraduate research experience.  Additionally, this collaboration has allowed the PI to do more in-depth studies which have resulted in publications in top-tier chemistry journals.

References:  Dolliver, D. D.; Bhattarai, B. T.; Pandey, A.; Lanier, M. L.; Bordelon, A. S.; Adhikari, S.;  Dinser, J. A.; Flowers, P. F.; Wills, V. S.; Schneider, C. S.; Shaughnessy, K. H.; Moore, J. N.; Raders, S. M.; Snowden, T. S.; McKim, A. S.; Fronczek, F. R.; J. Org. Chem., 2013, 78 (8), 3676-3687.

2.    Bhattarai, B. T.; Adhikari S.; Kimball, E. A.; Moore, J. N.; Shaughnessy, K .H.; Snowden, T. S.; Fronczek, F. R.; Dolliver, D. D.  Tetrahedron Lett. 2014, 55, 4801-4806.

3.    Gallagher, P. T.; Hunt, J. C. A.; Lightfoot, A.P.; Moody, C.J. J. Chem. Soc., Perkin Trans.  1, 1997, 2633-2637.

4.    Wada, M.; Ohki, H.; Akiba, K.; Tetrahedron Lett. 1986, 27 (39), 4771-4774.