Guthrie, David B.
(2009)
Mechanism and Chirality Transfer in Cyclizations of Amides and Related Compounds.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The role of halogens in the 5-endo-trig cyclizations of radicals derived from N-cyclohexenyl-α-haloacetamides on the product distribution has been thoroughly investigated. Under reductive radical conditions, α-chloroamides produce octahydroindolones, while α-iodoamides primarily give a mixture of hexahydroindolones and N-cyclohexenylacetamides. Kinetic studies showed the rate constants of cyclization are not critically halogen-dependent, but the ratio of cyclized to oxidized products is dependent on the halogen used in the radical precursor. When the starting halide is easily reducible, a single electron transfer from cyclized intermediates to starting material overrides the normal reductive chain process. This process spurs an ionic, acid-driven reductive halogenation process, which disrupts the anticipated radical chain mechanism. Addition of excess base suppresses the reductive dehalogenation pathway.<br><br>Enantioenriched derivatives of N-allyl-o-iodoarylcarbamates undergo radical cyclizations to give enantioenriched dihydroindoles in 87-100% yields and 83-92% chirality transfers. Anionic cyclizations of these substrates proceed in 58-74% yields and 84-99% chirality transfers. N-Aryl barriers to rotation were measured and found to be comparable to similar o-iodoacetanilides. The radical and anionic cyclizations proceed with the same sense of chirality.<br><br>Radical cyclizations of N-cyclohexenyl-o-iodoanilides may only occur through the syn atropisomer when an additional ortho substituent is present on the aromatic ring. When a second ortho substituent is not present, N-aryl rotation of the intermediate radical is faster than all competing processes. Heck cyclizations on these substrates proceed through the anti atropisomer, requiring simultaneous N-aryl and N-cyclohexenyl rotations to achieve the necessary transition state. The β-elimination step of these Heck reactions occurs with complete syn selectivity.<br><br>Radical cyclizations of axially chiral α-haloacetanilides which contain an ortho-radical acceptor produce dihydroquinolin-2-ones in high yields and with high levels of chirality transfer (80-100%). A model of chirality transfer has been determined by absolute configuration determination of a substrate / product pair by X-ray crystallography. Secondary α-haloamides faithfully cyclize with exclusive trans selectivity. This methodology has been applied to a tandem 6-exo-trig/5-exo-trig radical cyclization, which proceeds with good diastereo- and enantioselectivity.
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| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
28 January 2009 |
| Date Type: |
Completion |
| Defense Date: |
25 November 2008 |
| Approval Date: |
28 January 2009 |
| Submission Date: |
21 November 2008 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
5-endo-trig; anilides; atropisomers; axial chirality; barrier to rotation; carbamates; chirality transfer; lithium-halogen exchange; radical cyclization; SET |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-11212008-143719/, etd-11212008-143719 |
| Date Deposited: |
10 Nov 2011 20:05 |
| Last Modified: |
15 Nov 2016 13:51 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9753 |
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