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Research in our laboratory is directed at developing synthetic routes to medium-ring heterocycles, a class of compounds that displays a broad range of biological activity.  In particular, we are interested in exploiting the mild and selective rhodium-catalyzed hydroacylation as a strategy for the rapid construction of these ring systems.

Previously, we demonstrated that sulfur-containing 7- and 8-alkenals undergo intramolecular hydroacylation in the presence of Wilkinson's catalyst to yield cyclic sulfides (eq 1).  The analogous 7- and 8-alkynals yield enone-containing heterocycles.  While the reaction was rapid and high yielding for sulfides, the analogous ether and alkyl compounds (O or CH₂ substituted for S) failed to cyclize, suggesting that coordination of the sulfur atom to rhodium was required for successful hydroacylation.

We have since applied this chemistry to the synthesis of aminomethylbenzothiepinones, 1, which are intermediates in the synthesis of pharmaceutically interesting compounds.  Cyclization and installation of the amino functionality are accomplished in one reaction vessel, via a tandem hydroacylation-Michael addition sequence (eq 2). 

Most recently, we have applied our chelation-assisted hydroacylation strategy to the synthesis of nitrogen-containing heterocycles.  We have examined the reaction of several 2-(3-butenylamino)benzaldehyde substrates with Wilkinson's catalyst, Rh(PPh₃)₃Cl (eq 3).  Hydroacylation products are obtained in each case; however yields of product depend on the identity of the non-reacting amine substituent, R.  Significantly higher yields of hydroacylation product are obtained for the allyl amine, 2a, suggesting that the allyl substituent plays a key role in promoting hydroacylation, presumably as a ligand on rhodium. 

A similar trend is observed for for the analogous alkynes, 4,although the rate of reaction is significantly faster (eq 4).  Hydroacylation of 4a was judged by GC to be complete within 3 hours.  In all cases, the only significant product obtained was that due to hydroacylation.  Products due to decarbonylation or rhodium-mediated cleavage of the allyl group from the amine were not observed.

Recent and on-going work examines the scope and limitations of the reaction with respect to the range of ring sizes accessible by this chemistry and the tolerance of the reaction for substitution on the alkene, alkyne and carbon backbone (eq 5).  We have found that benzazocines (n = 2) can also be prepared via intramolecular hydroacylation.  Mono- and di-substituted alkenes as well as internal and terminal alkynes smoothly undergo hydroacylation.  However, tri-substituted alkenes fail to react.  Initial experiments with cationic rhodium catalysts, such as [Rh(dppe)]BF₄, have been successful and have produced results equal or superior to Wilkinson's catalyst.

We have also investigated the intermolecular hydroacylation of 2-aminobenzaldehydes, 6-8.  Initial experiments examined the reaction of alkenes (methyl acrylate, styrene, 1,4-pentadiene) and alkynes (1-octyne) with compounds 6-8, in the presence of Wilkinson's catalyst or [Rh(dppe)]BF₄.  Only trace amounts of hydroacylation products were observed in most cases.

Work on this project has been completed by undergraduate students at Lycoming College.  Funds from this grant supported two undergraduate research students during the summer of 2009 (Tess Duffin and Kyle Ruhl) and during the summer of 2010 (Robert Beamon and Lauren Bottorf).  The students prepared a variety of allyl amine substrates and subjected these compounds to the hydroacylation conditions. Tess also ran a number of intermolecular hydroacylation experiments.  Kyle Ruhl and Carrie Harsomchuck were indirectly supported by this grant for their work during the 2009-2010 academic year.  Carrie investigated the use of allyl amines as intermolecular hydroacylation substrates.  Kyle Ruhl ('11), Robert Beamon ('11) and Lauren Bottorf ('12) are chemistry majors at Lycoming College.  Carrie Harsomchuck graduated with a B.A. in chemistry in May 2010 and is now enrolled in the Physician Assistant program at Salus University.  Tess Duffin graduated in May 2010 with a B.S in chemistry.  Tess attends Villanova University and is pursuing graduate studies in chemistry.