Carbonyl-catalyzed Hydration of α-Amino Nitriles by Bashir Hussain Thesis submitted to

110 Pages·2014·3.84 MB·English

Catalysis via Induced Intramolecularity:
Carbonyl-catalyzed Hydration of α-Amino Nitriles

by

Bashir Hussain

Thesis submitted to the
Faculty of Graduate and Postdoctoral Studies
University of Ottawa
In partial fulfillment of the requirements for the
M.Sc. degree in the

Ottawa-Carleton Chemistry Institute
University of Ottawa

Candidate Supervisor

Bashir Hussain Dr. André M. Beauchemin
© Bashir Hussain, Ottawa, Canada, 2014
Abstract
In the last decade, there has been a surge of interest from the chemistry community in
developing synthetic catalysts that emulate the remarkable rate accelerations observed for
enzymatic reactions. One approach utilized by enzymes involves preorganization of substrate(s)
using a favourable binding event to orient the substrate(s) in a reactive arrangement. Although
the “induced intramolecularity” is entropically unfavourable, it is facilitated by the enzymes and
utilized to accelerate the subsequent chemical transformation. Chemists have often used a
conceptually related stepwise approach in which temporary tethers are assembled to induce a
temporary intramolecularity. This preorganization often enables difficult intermolecular
reactions, and typically leads to increased regio-, chemo-, and stereoselectivity in chemical
reactions. Seeking to develop a catalytic approach, we focused our efforts in developing a mild,
carbonyl-catalyzed hydration protocol for - and -amino nitriles to give the corresponding -
and -amino amide and acid. This work highlights the value of employing induced
intramolecularity in accessing structurally important chemical motifs that otherwise require
harsh reaction conditions. Additionally, this thesis presents the background material, design
process, optimization and scope of this reactivity.

ii
Acknowledgements
It has been an exciting and life-changing experience as a graduate student at the
University of Ottawa. Not only did I have the opportunity to learn a great deal about chemistry,
but I had the pleasure to engage with extremely intelligent and highly motivated students, lab
mates, and members of the faculty and administration. First and foremost, I would like to
extend my gratitude to Professor Andre Beauchemin who accepted me as a graduate student.
Undoubtedly, Andre is one of the most brilliant chemists that I know of, whose sincere passion
and enthusiasm for chemistry inspired me every day to work hard and pursue my best. Even in
times of difficulty, Andre was always positive and supportive, making my stay even more
enjoyable. Of course the graduate experience would not be the same without the support of
my lab mates. It was a pleasure to have a work desk next to Amanda, who always had a positive
attitude and a work ethic I looked up to. It was always fun to have chats with Colin, whether it
was about chemistry or just random topics. Nick was my mentor when I first started – a brilliant
chemist whom I hope to cross paths with again in the future. J.F.’s intensity in both chemistry
and squash matches will be missed – although I will still be in Ottawa so we can have a
rematch! I’ve also really enjoyed the chats with Chris about chemistry and life after graduate
school. A special thanks goes out to Kashif and Sampada, whom I’ve worked closely with on my
thesis project. Both are extremely hard working and clever chemists and I wish them the best in
their future endeavors. I’d also like to thank my remaining lab mates who have been very
supportive: Nic, Pouyan, Melissa, Keira, Lyanne, Charlotte, Kaitlyn, and Brittany. Additionally,
the enjoyable times with my next-door lab mates Aboud and Meshal will also be missed.
iii
I’ve also like to thank my family for their continued love and support in both my
personal and career endeavors. A special thanks goes to my wife Saja, whose companionship,
support and love has made it possible for me to reach this point.

iv
Catalysis via Induced Intramolecularity:
Carbonyl-catalyzed Hydration of α-Amino Nitriles
Table of Contents
Abstract ............................................................................................................................................ii
Acknowledgements ......................................................................................................................... iii
List of Abbreviations ..................................................................................................................... viii
List of Figures ................................................................................................................................. xii
List of Schemes.............................................................................................................................. xiii
List of Tables .................................................................................................................................. xv
Chapter 1. Introduction and Tethering Strategies in Synthesis ...................................................... 1
1.1 Introduction ........................................................................................................................... 2
1.2 Tethering Approach ............................................................................................................... 5
1.2.1 Diels-Alder reaction ........................................................................................................ 7
1.2.2 Olefin Metathesis ........................................................................................................... 9
1.2.3 Glycosylations ............................................................................................................... 12
1.2.4 Conclusion ..................................................................................................................... 14
1.3 Metal Catalysis Approach .................................................................................................... 15
1.3.1 Rhodium-Catalyzed Intermolecular ortho-Arylation of Phenols .................................. 16
1.3.2 Rhodium-Catalyzed Branched-Selective Hydroformylation ......................................... 18
v
1.3.3 Rhodium-catalyzed Intermolecular Hydroacylation ..................................................... 21
1.3.4 Conclusion ..................................................................................................................... 24
1.4 Organocatalysis Approach ................................................................................................... 25
1.4.1 Carbonyl-catalyzed systems ......................................................................................... 26
1.4.2 Hydrolysis of Esters ....................................................................................................... 27
1.4.3 Alcoholysis of Esters ..................................................................................................... 30
1.4.4 Hydrolysis of Amides .................................................................................................... 31
1.4.5 Hydroaminations .......................................................................................................... 32
1.4.6 Hydration of Nitriles ..................................................................................................... 35
1.4.7 Desymmetrization and Site-Selective Catalysis ............................................................ 39
1.4.8 Conclusion ..................................................................................................................... 41
Chapter 2. Re-investigation of the Commeyras Carbonyl-catalyzed Hydration of α-Amino Nitriles
....................................................................................................................................................... 42
2.1 Results and Discussion ........................................................................................................ 43
2.1.1 Carbonyl Catalyst Scan.................................................................................................. 44
2.1.2 Optimization: Solvent Scan and Catalyst Loading ........................................................ 47
2.1.3 Influence of N-substitution ........................................................................................... 49
2.1.4 Full substrate Scope ...................................................................................................... 54
2.1.5 Additional Carbonyl Catalyst Scans – Implications in the Emergence of Life .............. 56
vi
2.1.6 Towards Accessing α-Amino Acids and β-Amino Amides and Acids ............................ 59
2.2 Conclusion and Outlook ...................................................................................................... 60
Chapter 3. Supporting Information ............................................................................................... 62
3.1 General Methods................................................................................................................. 63
3.2 Carbonyl Catalyst Screening ................................................................................................ 63
3.3 Synthesis of α-aminonitriles ................................................................................................ 64
3.4 Synthesis of N-allyl-α-aminonitriles .................................................................................... 67
3.5 Synthesis of α-aminoamides via formaldehyde-catalyzed hydration of α-aminonitriles ... 70
Appendix I. Proton and Carbon NMR Spectra .............................................................................. 78

vii
List of Abbreviations
Ac acetyl
acac acetylacetonyl
anti against, opposite
aq aqueous
Ar aryl
Bn benzyl
Boc tert-butoxycarbonyl
bp boiling point
Bu butyl
°C degree Celsius
cat. catalytic
CDG catalytic directing group
cis on the same side
COD 1,5-cyclooctadiene
conc. concentrated
Cy cyclohexyl
δ chemical shift in parts per million
d deuterium (in NMR solvents)
DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
DIPEA N,N-diisopropylethylamine
viii
D O deuterium oxide
2
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
E Ger., entgegen
ee enantiomeric excess
EI electron impact
equiv equivalent
Et ethyl
FT Fourier transform
g gram
h hour
hν light; electromagnetic radiation
HMDS 1,1,1,3,3,3-hexamethyldisilazane
HRMS high-resolution mass spectrometry
Hz Hertz
i iso
IAD intramolecular aglycon delivery
IR infrared
J coupling constant
L litre; ligand
μL microlitre
m meta
ix
M molar; metal
Me methyl
mg milligram
min minute
mL millilitre
mmol millimole
MS molecular sieves
n normal
Nu nucleophile
NMO N-methylmorpholine-N-oxide
NMR nuclear magnetic resonance
p para
PMB 2-O-para-methoxybenzyl
PMP pentalmethylpiperidine
Ph phenyl
ppm parts per million
Pr propyl
py pyridine
PPY 4-pyrrolidinopyridine
R carbon-based substituent
rt room temperature
s secondary
x