CH Amination Catalysis from High-Spin Ferrous Complexes The Harvard community has made this ...

221 Pages·2013·21.63 MB·English

by  Elisabeth Hennessy

C-H Amination Catalysis from High-Spin Ferrous
Complexes
Citation
Hennessy, Elisabeth Therese. 2013. C-H Amination Catalysis from High-Spin Ferrous
Complexes. Doctoral dissertation, Harvard University.
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http://nrs.harvard.edu/urn-3:HUL.InstRepos:11169787
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C–H Amination Catalysis from High-Spin Ferrous
Complexes
A dissertation presented
by
Elisabeth Therese Hennessy
to
The Department of Chemistry and Chemical Biology
in partial fulfillment of the requirements
for the degree of
Doctor of Philosophy
in the subject of
Chemistry

Harvard University
Cambridge, Massachusetts

August 2013
©2013 – Elisabeth Therese Hennessy
All rights reserved.
Adviser: Professor Theodore A. Betley Elisabeth Therese Hennessy
C–H Amination Catalysis from High-Spin Ferrous Complexes

Abstract
The C–H amination and olefin aziridination chemistry of iron supported by
dipyrromethene ligands (RL , L=1,9-R -5-aryldipyrromethene, R = Mes, 2,4,6-Ph C H , tBu, Ad,
Ar 2 3 6 2
10-camphoryl, Ar = Mes, 2,4,6-Cl C H ) was explored. The weak-field, pyrrole-based
3 6 2
dipyrrinato ligand was designed to generate an electrophilic, high-spin metal center capable of
accessing high valent reactive intermediates in the presence of organic azides. Isolation of the
reactive intermediate in combination with a series of mechanistic experiments suggest the N-
group transfer chemistry proceeds through a rapid, single-electron pathway and maintains an
overall S=2 electronic configuration throughout the catalytic cycle. We have established the
catalysts’ strong preference for allylic amination over aziridination with olefin containing
substrates. Aziridination is limited to styrenyl substrates without allylic C–H bonds, while allylic
amination has been demonstrated with both cyclic and linear aliphatic alkenes. Notably, the
functionalization of α-olefins to linear allylic amines occurs with outstanding regioselectivity.
We have applied the complex AdL FeCl towards the generation of complex pyrrolidines
Ar
using simple linear aliphatic azides via an intramolecular C–H amination reaction. A series of
substrates were synthesized in order to probe the mechanism of cyclization. An intramolecular
kinetic isotope effect of 5.3 suggested a stepwise mechanism for benzylic substrates, which is
consistent with the intermolecular amination reaction. The stereospecificity of cyclization of an
enantiopure substrate and the preservation of the cyclopropyl unit in a radical clock experiment
suggest that if a stepwise mechanism is operative, the radical intermediate following H–atom
abstraction is extremely short-lived. Efforts to synthesize diastereoselective and enantioselective
catalysts have been taken. Exposure of AdL FeCl to potassium phenoxide generates AdL FeOPh,
Ar Ar
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which is extremely selective for the formation of cis-2,5-disubstituted pyrrolidines. Incorporation
of camphor substituents to the ligand platform has led to the design of a chiral, C -symmetric Fe-
2
dipyrrinato complex. Application of this complex to the cyclization of 1-azido-4-phenylbutane
results in the formation of 2-phenylpyrrolidine with modest levels of enantiomeric excess.

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Table of Contents
Chapter 1: Transition Metal Catalyzed C–H Amination and Olefin Aziridination 1!
1.1! Introduction 1!
1.2! Rhodium-Catalyzed C–H Amination Chemistry 3!
1.3! C–H Functionalization Chemistry of Cytochrome P450 9!
1.4! Amination and Aziridination Chemistry of Synthetic Porphyrin Complexes 12!
1.5! Interrogation of Reactive Intermediates in C–H Functionalization 16!
1.6! C–H Amination Chemistry of High-Spin Ferrous Dipyrrinato Complexes 24!
Chapter 2: Catalytic C–H Bond Amination from High-Spin Iron-Imido Complexes 29!
2.1! Introduction 29!
2.2! Metal Complex Synthesis 31!
2.3! Intermolecular, Catalytic N-Group Transfer with Organic Azides 34!
2.4! Proposed Mechanism 35!
2.5! Conclusions 41!
2.6! Experimental Methods 43!
Chapter 3: Intermolecular N-Group Transfer Chemistry with Olefinic Substrates 74!
3.1! Introduction 74!
3.2! Benzylic Amination and Aziridination of Substituted Substrates with Organoazides 77!
3.3! Mechanism of Benzylic Aziridination and Amination Reactions 80!
3.4! Allylic Amination 84!
3.5! Conclusion 89!
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3.6! Experimental Methods 89!
Chapter 4: Complex N-Heterocycle Synthesis via Iron-Catalyzed, Direct C–H Bond
Amination 98!
4.1! Introduction 98!
4.2! Stoichiometric Intramolecular C–H Bond Amination and Cyclization 101!
4.3! Catalytic Pyrrolidine Formation 103!
4.4! Accessing Alternate Ring Sizes 108!
4.5! Proposed Mechanism 110!
4.6! Conclusions 112!
4.7! Experimental Methods. 113!
Chapter 5: Advances in the Diastereoselectivity and Enantioselectivity of N-Heterocycle
Formation 157!
5.1! Introduction 157!
5.2! Diastereoselective N-Heterocycle Formation 160!
5.3! Progress towards an Enantioselective Catalyst 166!
5.4! Conclusions 174!
5.5! Experimental Methods 175!

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to my Mom and Dad
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Acknowledgements
Thank you to the members of the Betley Group, past and present. To the residents of the
most festive box of all: Evan, thank you for making this project what it is and for teaching me the
ropes. Your ability to problem solve with such cool confidence has always inspired me. Diana,
thank you for the amazing contributions you’ve already made to this project, just one year in. I
am absolutely motivated by your dedication and precision and I can’t wait to see where you take
things next. Matt, thanks for being the guy who knows how to fix anything, including a GC, a
calculation, this Word document, or a bad day. I really couldn’t have asked for anyone better to
paint the box red (or yellow or purple) with. To my classmates: Tamara, thanks for being such an
amazing brainstorming partner, whether it be about chemistry, fashion, or our futures. I don’t
think I’ll ever find a desk buddy as wonderful as you. Graham, I am always fired up after having
conversations with you about science, setting you up in volleyball, or playing you in a game of
21. Thanks for being such an amazing teammate on and off the court. Austin, you have an
amazing knack for keeping things in perspective and always making me laugh. Also, thank you
for the Merck Index. Sarah, thank you for always being a calming voice of reason and for
introducing my family to the art of homemade bread. To the next generation: Raul, thanks for
being the sauvest chemist on the East Coast. Your readiness to learn, to teach, and to toast is
unmatched and the group is all the better for it. Benji, thanks for always asking the toughest
questions and giving the most honest answers. And to Brian, thanks for keeping us all in line. To
the undergrads: Thank you Polina, Ryan, Richard, and Lucy for all of your help in lab and
keeping me up-to-date on what’s cool. I am consistently impressed by your ability to balance so
many things at once and to take pride in all of them. To the postdocs: Thank you all for being
such great role-models. Alison, you’ve shown me that it’s possible to do it all. And Dave, your
enthusiasm for science and camaraderie is utterly contagious.
Thanks to Justin for getting me hooked on chemistry and being an incredible sounding
board long after leaving the farm. Thanks to Nichole for teaching me everything I know about
working in lab and looking cool while doing it. Thanks to Tobias for challenging me to give my
project more focus and to always consider the big picture. Thanks to Eric for all of your support
and encouragement and launching me into the next phase of my education. Thanks to Ted for
exposing me to the world of inorganic chemistry and giving me a gift of a project. You have
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taught me so much about how to be a better scientist, how to think critically and creatively, how
to be more confident, and how to heckle opponents in softball. You have been such a wonderful
mentor and I will really miss working for you.
Thanks to Ben. Going to work with my best friend everyday for the past five years has
been pretty incredible. I’ve loved every lunch, dinner, and coffee break we’ve ever taken
together and I feel stronger and happier knowing you are at my side. Thanks to my brother. I’m
so lucky that we’ve managed to follow one another around the globe for the past twenty-seven
years. I’m really going to miss being your next-door neighbor; you make every new city we
conquer together feel like home. Thanks to Grandmere and Grandpere for always believing in
me and celebrating in my successes. And, most of all, thanks to my mom and dad. You are the
two greatest parents in the world. You have always been in my corner and knowing that I have
your full love and support has given me the confidence to tackle anything that comes my way. I
wish Boston were in Houston so we could meet up for some Good Company every now and
again.

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