Tetrasubstituted Pyrrolidines via a Tandem Aza-Payne/Hydroamination Reaction

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/asap/abs/ja068077w.html

From Prof. Babak Borhan's group at Michigan State University in East Lansing, MI

The work involves a new and mild methodology in intramolecular hydroamination of alkynes. The process is activated by the formation of an epoxide in the molecule following an openning of the N-protected aziridine ring through an aza-Payne rearrangement process. The reaction then resulted in the exocyclic methylene epoxy pyrrolidine, i.e. 5.

The reaction sequence is catalytic in the formation of the pyrrolidine ring. However, the aza-Payne rearrangement requires stoichimetric amount (2-4 equiv) of base. The aziridinol starting materials 2 are preapred by Grignard reaction of aziridinyl aldehydes and ketones. The diastereoselectivity of the Grignard addition is crucial in the success of the latter cyclization process as only the syn-isomer of the aziridinol will produce the epoxide intermediate with nitrogen nucleophile in the right orientation to cyclize (Scheme 2).Different starting materials were prepared as shown in the table below.Notes for the results in Table 1:

- The presence of an R group syn to the carbonyl eroded the diastereoselectivity (1a and 1o)while the use of a trans disubstituted aziridine aldehyde gave only moderate dr (1b and 1c).

- However, the use of 2,2,3-trisubstituted aziridine aldehydes gave the syn-aziridinols as the sole detectable product (1d-1m).

- Also of note was the excellent diastereoselectivity obtained in the generation of quaternary hydroxyl centers from aziridine ketones (1j and 1k).

The process could proceed in one pot providing that excess base, dimethylsulfoxonium methylide, (2-4 equiv) is employed at rt. The following table summarizes the results of this process.

Notes for the results in Table 2:

- For 2a and 2c, the desired syn-aziridinol substrate could not be cleanly separated from the anti-isomer. Therefore 2a and 2c were treated with NaH in THF to give mixtures of the epoxy amines, which were separated by column chromatography before the desired diastereomer was subjected to hydroamination conditions.

- Alternatively, the hydroamination could be run on the mixture of syn/anti compounds, and the epoxy amine (resulting from reaction of the anti diastereomer) was separated from the desired pyrrolidine (2o).

- The remaining substrates (2b, 2d-2n) contained only the syn-aziridinol, and the majority underwent hydroamination smoothly. The exceptions were alkynes substituted with alkyl or silyl groups (2h, 2l, and 2m) as it may be necessary for terminally substituted alkynes to contain a group capable of stabilizing a developing negative charge on the carbon adjacent to the newly forming C-N bond.

- The TMS-substituted alkyne 2l did deliver the desilylated product 5d, presumably as a result of initial deprotection of the TMS group.

- The Z-stereochemistry of the enamides obtained from aryl-substituted alkynes (2i and 2k) may result from prior coordination of the sulfoxonium to the opposite face of the alkyne, thus leading to rapid proton transfer and the observed stereochemistry.

- A 64% yield of 5d was obtained from the epoxy amine 4d using 0.2 equiv of ylide, confirming that the hydroamination reaction is catalytic in base.

As mentioned before, the facile hydroamination was suspected to be aided by the preorientation of the nitrogen and the alkyne on the same side of the epoxide by the aza-Payne rearrangement (Scheme 2). This hypothesis was tested by subjecting an unfunctionalized amino alkyne (8) to several different hydroamination conditions (Scheme 3), but no pyrrolidine product was obtained, implying a decrease in activation entropy of the cyclization is the underlying reason for the favorable hydroamination reaction.