Subscriber access provided by READING UNIV
Communication
Dynamic Ligand Exchange as a Mechanistic Probe in Pd-Catalyzed Enantioselective C-H Functionalization Reactions Using Monoprotected Amino Acid Ligands David E. Hill, Katherine Lynn Bay, Yun-Fang Yang, R Erik Plata, Ryosuke Takise, Kendall N. Houk, Jin-Quan Yu, and Donna G Blackmond J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b11962 • Publication Date (Web): 07 Dec 2017 Downloaded from http://pubs.acs.org on December 7, 2017
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of the American Chemical Society
Dynamic Ligand Exchange as a Mechanistic Probe in PdCatalyzed Enantioselective C-H Functionalization Reactions Using Monoprotected Amino Acid Ligands David E. Hill,1 Katherine L. Bay,2 Yun-Fang Yang,2 R. Erik Plata,1 Ryosuke Takise,3 K.N. Houk,2 JinQuan Yu,1 and Donna G. Blackmond1*. 1
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037 USA; 2Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095 USA; 3Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya 464-8602 Japan
ABSTRACT: A new tool for probing enantioselective
reaction mechanisms is introduced. Monitoring the temporal change in product enantiomeric excess after addition of the opposite enantiomer of the ligand during reaction provides a means of probing dynamic ligand exchange in enantioselective C-H iodination catalyzed by Pd with monoprotected amino acid ligands (MPAA). This work has general potential for providing insights about the dynamics of catalyst and ligand molecularity and exchange.
Pd-catalyzed C-H functionalizations employing monoprotected amino acid (MPAA) ligands have emerged as a powerful class of reactions that provide striking ligand-accelerated catalysis, and, in cases of prochiral substrates, highly enantioselective transformations.1 Both experimental2 and computational3 mechanistic studies have contributed to our understanding of these reaction systems, invoking weak coordination of substrates and ligands to Pd. It has been shown that MPAA-ligated Pd catalysts exhibit significant rate accelerations over nonligated Pd.1 Most recently, a novel role for Pd(IV) in enantioselective iodination was uncovered in the highly selective desymmetrization of diarylmethylamines via iodination catalyzed by Pd(MPAA) ( MPAA ) 2c,4 (Scheme 1).
In the present study, we show how temporal monitoring of product enantioselectivity may be employed as a probe of dynamic ligand exchange in reactions where the opposite hand of the MPAA ligand is introduced as the reaction proceeds. Understanding the capability of the chiral ligand to undergo exchange with different Pd species along the catalytic cycle provides a new tool that uses the reaction itself to probe and report on enantioselective reaction mechanisms. Our initial studies followed the optimized system developed by Yu and coworkers,4a employing benzoylprotected leucine Bz-Leu-OH as the MPAA ligand. We found that this ligand reacts to produce palladacycle 4 upon mixing with Pd(OAc)2.2c Species 4 is an inert precatalyst that is rapidly iodinated to produce 5 upon exposure to the reaction conditions of Scheme 1. Complex 6 was synthesized as an analogous catalyst so that the reaction could be followed by 19F NMR spectroscopy. All three Pd species produce competent catalysts and give similar kinetic profiles in the reaction of Scheme 1. Interestingly, however, we found that none of the species 4-6 interacts with substrate 1 in the absence of I2.2c This observation led to 19F-NMR spectroscopic studies as well as electrochemical investigations that implicate a Pd(IV) species 7, formed from oxidative addition of I2 to 6, in the catalytic cycle prior to addition of the diarylmethylamine substrate. HO
Scheme 1. Iodination of Diarylmethylamines 10 mol% Pd(OAc) 2 20 mol% MPAA ligand
NHTf + I2 H 1
2
CsOAc (3 equiv) Na 2CO3 (3 equiv) DMSO, t-AmylOH 50 °C
HO N
O Pd
3
O
N
O
F
Pd O
5
Pd I
O
O
N
O
4
I
HO
HO O
O
I
HO
NHTf
O
O O
6
F
N O R H O Pd I O F O
7
Figure 1 shows that nearly identical rates are observed for Pd:ligand ratios from 1:1.25 to 1:4 in the reaction of Scheme 1. In addition, the reaction exhibits first order kinetics in [Pd] 2c and no nonlinear effect in ligand enan-
ACS Paragon Plus Environment
F
Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Paragon Plus Environment
Page 2 of 5
Page 3 of 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of the American Chemical Society
ACS Paragon Plus Environment
Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Paragon Plus Environment
Page 4 of 5
Page 5 of 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of the American Chemical Society
ACS Paragon Plus Environment
