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Mechanism and Chirality Transfer in Cyclizations of Amides and Related Compounds

Guthrie, David B. (2009) Mechanism and Chirality Transfer in Cyclizations of Amides and Related Compounds. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Guthrie, David
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairCurran, Dennis Pcurran@pitt.eduCURRAN
Committee MemberDoemling, Alexander Sasd30@pitt.eduASD30
Committee MemberWilcox, Craig Sdaylite@pitt.eduDAYLITE
Committee MemberFloreancig, Paul Eflorean@pitt.eduFLOREAN
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:, etd-11212008-143719
Date Deposited: 10 Nov 2011 20:05
Last Modified: 15 Nov 2016 13:51


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