60th Annual Report on Research 2015

The cationic aza-Cope rearrangement—Mannich cyclization is a tandem [3,3]-sigmatropic rearrangement of iminium cation 3 followed by cyclization of the resulting enol 4 onto the transposed iminium cation to produce acylpyrrolidine 5 (Scheme 1) [1,2].  The reaction is initiated by the formation of iminium cation 3, most frequently achieved via acid-mediated amine-aldehyde condensation (1 → 3) or oxazolidine ionization (2 → 3).

In the past year, we have continued our investigation of enantioselectivity in the aza-Cope—Mannich reaction.  We found previously that oxazolidine 6 could undergo aza-Cope—Mannich reaction to form a 13:1 mixture of diastereomers [3].  However, subjecting oxazolidine 9 to similar conditions resulted in very poor diastereoselectivity (Scheme 2).  Furthermore, we were able to determine that chirality transfer in the first reaction occurred primarily via the carbinol carbon rather from the amine protecting group (not shown).  We hypothesize that incomplete chirality transfer (in either case) is a result of C-C bond rotations prior to the rate-determining aza-Cope rearrangement.  Thus, increasing the rotational barrier should diastereoselectivity. 

Scheme 2

To that end, we recently prepared oxazolidine 13 in moderate yield and subjected it to slightly more rigorous aza-Cope—Mannich conditions, as was required for reaction of the more substituted oxazolidine (Scheme 3).  Very preliminary results indicate that appending the two methyl groups does lead to greater chirality transfer, as indicated by the >20:1 selectivity in room temperature reactions.  We anticipate increasing the amount of Lewis acid and/or increasing the temperature to optimize conversion. 

Scheme 3

  Additionally, we have developed a protecting group-free aza-Cope—Mannich reaction initiated from an imine.  This approach allows us to form cis-2,4-disubstituted pyrrolidines, a complementary method to the procedure we have developed for accessing the analogous trans compounds (see previous year’s report).  Furthermore, to our knowledge, these are the first examples of imine-initiated aza-Cope—Mannich reactions.  We formed the requisite imines by epoxide aminolysis of isoprene monoxide (15) followed by condensation with benzaldehyde (Scheme 4).  Subjecting imine 16 to the usual aza-Cope—Mannich conditions resulted in no reaction (entries 1 and 2).  However, reaction with FeCl₃ gave significant conversion to the cis-acylpyrrolidine 18 (entry 3). 

Scheme 4

Following a Lewis acid screen, we found that ZnCl₂ provided cis-acylpyrrolidine 22 in the highest yield and with the greatest diastereoselectivity (Scheme 5).  Again, this provides a complementary approach to our previous work, in which we accessed trans-acylpyrrolidines 20 in high stereoselectivity and yield (Scheme 5).

Scheme 5

Finally, we have shown that these reactions are robust to both electron withdrawing and donating groups on the aromatic ring (Scheme 3), although electron withdrawing substituents result provide much better diastereoselectivity.  In addition, reactions of imines bearing electron withdrawing aryl substituents proceed much faster than those with electron donating substituents; prolonged stirring leads to product epimerization.  

Scheme 6

Students that have participated in this project during this reporting cycle are an equal mixture of undergraduate and graduate students at Eastern Michigan University.  In addition, on ACS Project SEED student worked on a related project.  Over half of these students plan to either enroll in PhD programs or continue on to work in chemistry either as community college faculty or in industry.  This year four students presented posters at the fall national American Chemical Society meeting in Boston. 

References

[1] Overman, L. E.; Kakimoto, M.-A.  J. Am. Chem. Soc.  1979, 101, 1310-1312.

[2] For reviews of the aza-Cope rearrangement—Mannich cyclization and related reactions, see (a) The Intramolecular Mannich and Related Reactions Overman, L.; Ricca, D. in Comprehensive Organic Synthesis, Trost, B. M., Ed.; Pergamon: New York, 1991; Vol. 8, pp s1007-1046; (b) Overman, L.  Acc. Chem. Res. 1992, 25, 352-359; (c) Overman, L. E. Aldrichimica Acta 1995, 28, 107-120; (d) Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311-2352; (e) Overman, L. E. Tetrahedron 2009, 65, 6432–6446.

[3] For BF₃OEt₂ mediated iminium cation formations in the aza-Cope-Mannich reaction, see (a) Overman, L. E.; Shim, J.  J. Org. Chem. 1991, 56, 5005; (b) Overman, L. E.; Shim, J. J. Org. Chem. 1993, 58, 4662.