59th Annual Report on Research 2014

Our group has been developing catalytic homologous conjugate addition (HCA) reactions, additions to electron-deficient cyclopropanes, utilizing calcium(II) complexes to facilitate the reactions. While many methods exist for catalytic 1,4-additions of nucleophiles to electron deficient conjugated ¹-systems, the homologous reaction has yet to be fully realized. HCA reactions are usually performed under forcing conditions using stoichiometric or super-stoichiometric amounts of a Br¿nsted base and/or Lewis acid. Unlike Lewis acid metals commonly used in synthetic methodologies, calcium complexes are relatively inexpensive and many are environmentally benign. The large radii and electropositive nature of calcium leads to a similarity in coordination behavior and observed reactivity to lanthanide metals.

Current Results

Development of methodology for the addition of unactivated thiols to donor-acceptor (DA) cyclopropanes has been completed. After a catalyst screen, we found that commerically available calcium acetylacetonate (Ca(acac)₂) facilitated the addition of 4-chlorothiophenol, without prior activation or exogenous base, to cyclopropane 1 with conversion of 67% Reaction conditions were optimized and the reaction was probed for generality with regards to substitution on the thiols and the cyclopropane. Electron-rich and electron-deficient thiophenol derivatives as well as alkyl thiols added to provide the corresponding ?-sulfanyl malonates in good to excellent yield (eq 1). The electronic structure of the DA cyclopropane had minimal impact on the productivity of the reaction. This work has been published.[1]

We have expanded upon our calcium-catalyzed addition reactions by developing catalytic C–C bond forming reactions. Two classes of carbon nucleophiles are of particular interest and are being tested as substrates in the HCA reaction: (1) electron-rich aromatic and (2) heteroaromatic compounds. We began our investigation into these catalytic Friedel-Crafts reactions by examining the addition of 1-methylindole to cyclopropane 1 (R=Ph) at room temperature in dichloromethane. A screen of commerically available calcium(II) complexes revealed that 10% calcium triflimide (Ca(NTf₂)₂) facilitated production of a modest amount of the corresponding Friedel-Crafts product 3 (R=Ph). By increasing the temperature to 70° C and switching to 1,2-dichloroethane, the reaction proceeded with >99% conversion as determined by ¹H NMR (eq 2). Chlorinated solvents can be avoided by using cyclopentyl methyl ether, CPME, in which the reaction proceeds with 86% conversion. Cyclopropanes bearing electron-rich and electron-deficient aryl substitutions underwent addition of 1-methylindole to provide the corresponding products in good to excellent yield (up to 99%). Heteroaromatic substituted indole products were also obtained in very good yield (87-93%). This work was recently published.[2]

While reaction development has begun with malonate cyclopropanes, DA cyclopropanes with two different geminal electron-withdrawing groups would be extremely useful. Such cyclopropanes have additional opportunities for derivatization. For example, the products from addition to hemi-malonate cyclopropanes can undergo decarboxylation to leave one carbonyl. Nitrocyclopropane carboxylates can be selectively reduced and hydrolyzed to produce the corresponding amino acid, which can then undergo decarboxylation to give the amine or further reduction to give the amino alcohol. These two classes of DA cyclopropanes will be examined in due course.

We are beginning to expand our methodology beyond cyclopropanes bearing two electron-withdrawing groups. These new classes of substrates include cyclopropyl ketones, imines, and esters. It is anticipated that these substrates will be less reactive than their malonate counterparts, especially in the HCA reaction where the competing 1,2-additions may prevail. For the initial investigations, (2-phenyl)cycalopropyl phenyl ketone is being used as the model substrate and has been synthesized according to literature procedures; a synthetic protocol allows for flexibility in the aryl substitution. Preliminary results for the addition of 1-methylindole show modest conversion.

Impact

ACS-PRF support has enabled four research students to have a summer research experience and a dozen more to have supplies for research during the school year. Some of these students have graduated and are continuing their studies toward PhD, MD, and DDS degress. These students have made tremendous progress on their projects and were able to gain experience in reaction optimization, synthesis, purification methods, instrumentation usage, and data analysis. Their results were communicated in publications and numerous presentations including an award-winning poster presentation at 2012 SERM-ACS meeting.

[1] Braun, C. M.; Shema, A. M.; Dulin, C. C.; Nolin, K. A., "Homologous Conjugate Addition of Thiols to Electron Deficient Cyclopropanes Catalyzed By a Calcium(II) Complex" Tetrahedron Lett. 2013, 54, 5889–5891. j.tet http://dx.doi.org/10.1016/let.2013.08.102

[2] Dulin, C. C.; Murphy, K. L.; Nolin, K. A., "Calcium-Catalyzed Friedel-Crafts Addition of 1-Methylindole to Activated Cyclopropanes" <i.Tetrahedron Lett.2014, 55, 5280–5282. http://dx.doi.org/10.1016/j.tetlet.2014.07.108