60th Annual Report on Research 2015

1) Cu-Catalyzed Interrupted Cross-Coupling: Over the last year we have made significant advances toward development of Cu-catalyzed diarylation of alkenes by interrupted cross-coupling (i.e., vicinal dicarbofunctionalization of alkenes).  We have identified that treatment of readily prepared substrate 1.1 with Cu-catalyst 1.2, PhI and NaOt-Bu led to the formation of benzofuran in good yield (Scheme 2A).  This process has been extended to various aryl iodides (e.g., 1.4) and to the formation of nitrogen heterocycles (e.g., 1.6-1.7).  The catalytic cycle of this reaction has been determined by isolation of key intermediates and proceed by the following elementary steps: 1) transmetallation to generate Cu-complex 1.10, 2) migratory insertion of the pendant alkene into the Cu-Ar bond to furnish 1.11, and 3) capture of the Csp³-Cu-complex 1.11 with PhI (Scheme 2B). 

This method has been extended in two key directions:  1) diastereoselective variants and 2) enantioselective transformations.

With respect to the former, two key observation have been made (Scheme 2C).  1) 1,2-disubstituted alkenes undergo reaction with high levels of diastereoselectivity (1.12 to 1.14).  These results suggest that the process proceeds by syn-migratory insertion to generation Csp³-Cu-complex 1.13 followed by stereoretentive cross-coupling.  2) Reaction with substrate 1.15 underwent highly diastereoselective diarylation to generate 1.17, likely proceeding through pretransition state 1.16 (Scheme 2C).

We have recently obtained preliminary results for catalytic enantioselective alkene interrupted cross-coupling (Scheme 3).  Through the evaluation of a set of chiral ligands related to dppBz, use of 3 mol % BenzP* 1.22 was effective for converting 1.18 to 1.20 in 55% yield and 97:3 er (Scheme 3). Furthermore, highly enantioselective synthesis of quaternary carbons is also possible (e.g., 1.21).  A preliminary substrate scope has been established and found to include a variety of aryl iodides and tolerate the formation of indoline products (1.24 – 1.26).  The future direction of this project aims to extend the scope of our enantioselective reaction as well as develop fully intermolecular variants.

2) Enantioselective [2+2] Cyclcoaddition: The studies outlined above describe the vicinal diacarbofunctionalization of alkenes by interrupted cross-coupling.  Along these lines our group has also recently taken an interest in [2+2] cycloadditions as these reaction accomplish a similar goal, yet also generate a ring.  In order to engage unactivated alkenes in [2+2] cycloadditions, the unique reactivity of allenes or ketenes needs to be accessed.  This is due to the orthogonal ¹-bonds that allow for a concerted yet asynchronous [_¹2_S+(_¹2_S+_¹2_S)] cycloaddition.  This initiative has led to the development of a unique chiral transfer [2+2] cycloaddition of highly enantiomerically enriched allenic ketones (Scheme 4).

The overall process is outlined in Scheme 4.  An alkynyl ketone is readily prepared in two steps from a simple epoxide and alkyne.  Ketone 1.3 is then treated with thiourea catalyst 1.4 for 1h to promote an enantioselective isomerization to provide chiral allene 1.3.  This intermediate can be isolated if desired, or Bi(OTf)₃ can be added to promote a [2+2] cycloaddition reaction.  Overall this method provides access to substituted cyclobutanes (e.g., 1.6 and 1.7) with high levels of enantioselectivity.  This method also represents rare example of a chiral transfer [2+2] cycloaddition.  Future efforts aim to extend this strategy to the formation of other ring systems and intermolecular variants.

            Conclusions:  Through development of the two processes outlined above, solutions to the long-standing challenge of vicinal dicarbofunctionalization of unactivated alkenes have been provided.  A graduate student will continue to work on the Cu-catalyzed interrupted cross-coupling with support from the ACS-PRF.