Reports: DNI150307-DNI1: Fluorophobic Effects in Homogeneous Catalysis

Mark R. Biscoe, PhD, City University of New York (City College)

As described in the PRF progress report submitted last year, the general direction of research in our laboratory has evolved since the submission date for the original PRF grant application.  Initially, we proposed to explore the effects of fluorophobicity on transition metal-catalyzed reactions.  The over-reaching goal of this proposed research was the development of a novel strategy to generate value added materials from resources derived from petroleum feedstocks.  The goal of developing new, useful methods to rapidly generate value added materials remains the general goal of our research program.  The major goal of our current direction is the development of general methods by which to employ configurationally-stable, optically-active nucleophiles in transition metal-catalyzed carbon-carbon bond-forming reactions.  By establishing the stereogenic center prior to the formation of the final desired bond, the rapid preparation of diverse libraries of single-enantiomer molecules would be achievable.

We previously reported general Ni-catalyzed processes for the cross-coupling of secondary alkylzinc and tertiary alkylmagnesium nucleophiles with aryl electrophiles.1a-1c These methods largely circumvented the b-hydride elimination/reinsertion sequences that had limited previous Pd-catalyzed systems.  In order to expand the versatility of cross-coupling reactions employing secondary alkyl nucleophiles, we sought to extend the processes to the use of isolable, configurationally stable, optically-active organometallic nucleophiles. The development of such transformations is impeded by the inverse relationship that exists between the nucleophilicity and configurational stability of carbon-metal bonds in main group organometallic nucleophiles.2 While increased covalency tends to coincide with enhanced configurational stability of the carbon-metal bond, it also tends to coincide with reduced nucleophilicity.  This trend, in addition to the inherent bulk of a secondary nucleophile, results in the prohibitively slow transmetallation of a secondary nucleophile as the covalency of the carbon-metal bond increases.  Because secondary alkylboron and secondary alkyltin reagents are most configurationally-stable, alkylbo ron and alkyltin are most conducive to development of a general method for the use of optically-active nucleophiles in cross-coupling reactions.

  We are excited to report that we have successfully developed a general Pd-catalyzed process for the cross-coupling of secondary alkyl azastannatrane nucleophiles and aryl electrophiles.3 This reaction displays no dependence on the electronic characteristics of either coupling partner and occurs with minimal concurrent isomerization of the secondary alkyltin nucleophile.  Aryl chlorides, bromides, iodides, and triflates are all viable electrophiles in this process.  Additionally, optically-active secondary alkyl azastannatranes undergo cross-coupling reactions with retention of absolute configuration using this method.  This process constitutes the first general method to employ secondary alkyltin reagents in cross-coupling reactions.  Overall, the combined generality of the transformation and stability of optically-active stannatranes result in a process that should accommodate the broad use of optically-active nucleophiles.

  Having established a viable method to employ optically-active secondary alkyltin reagents in cross-coupling reactions, we are beginning to explore the possibility of extending this process to the use of secondary alkylboron reagents.  During these investigations, we have developed a new, mild Pd-catalyzed method by which to generate primary alkylboron compounds from primary alkyl chlorides using bis(pinacolato)diboron as a boron source.4
This process accommodates the use of a wide range of functional groups on the alkyl bromide substrate.  Primary bromides react with complete selectivity in the presence of a secondary bromide.  The generality of this approach is additionally demonstrated by its extension to the use of alkyl iodides and alkyl tosylates, as well as borylation reactions employing bis(neopentyl glycolato)diboron as the boron source.

  The secured funding from the ACS Petroleum Research Fund has facilitated the development of the groundwork for the direct transition metal-catalyzed cross-coupling reaction of optically-active main group nucleophiles and aryl electrophiles.  We have demonstrated that optically-active secondary alkyl azastannatrane reagents can undergo a Pd-catalyzed cross-coupling reaction with retention of absolute configuration.  We are continuing to investigate the scope of this process, while also attempting to extend the method to alkylboron nucleophiles.  We expect that methods that enable the rapid creation of optically active molecules will have immediate applications in medicinal and material sciences.  This work will support future solicitations of funding from federal and private agencies, including a NSF CAREER proposal in the summer of 2013.  Students participating in this research have gained valuable experience in the field of organometallic catalysis.  Such transition metal-catalyzed methods are routinely employed in the fields of medicinal chemistry and drug discovery.


1)  (a) Joshi-Pangu, A.; Ganesh, M.; Biscoe, M. R. Org. Lett. 2011, 13, 1218.  (b) Joshi-Pangu, A.; Wang, C.-Y.; Biscoe, M. R. J. Am Chem. Soc. 2011, 133, 8478.  (c) Joshi-Pangu, A.; Biscoe, M. R. Synlett 2012, 23, 1103.

2)  Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem. Int. Ed. 2000, 39, 4414.

3)  Li, L.; Wang, C.-Y.; Huang, R.; Biscoe, M. R. Submitted

4)  Joshi-Pangu, A.; Ma, X.; Diane, M.; Iqbal, S.; Kribs, R. J.; Huang, R.; Wang, C.-Y.; Biscoe, M. R. J. Org. Chem. 2012, 77, 6629.