1. PUBLISHABLE SUMMARY

Summary Description of Project Objectives
As detailed in the Midterm Report, approaches to the proposed SOMO catalysis project were
unsuccessful despite significant investigation. It was felt that continuation along this direction
would not prove fruitful and would severely hamper the future prospects of the fellow as a result.
After a period of approximately 8 months into the fellowship an alternative strategy was taken
into the C-H arylation of amines using photoredox catalysis. Despite the change in direction of
the research the fellow has achieved all of the objectives detailed in the original proposal. The
specific objectives for the research undertaken became: 1) Demonstrate applicability to a range
of amine structures; 2) Apply the protocol to a diverse range of aromatic and heteroaromatic
structures and 3) Demonstrate the use of a convenient protecting group.

Description of Work and Main Results
Formation of Benzyl Amines via PhotoredoxMediated C–H Bond Funtionalisation. One of the
most prominent structural motifs in medicinal agents
is the benzylic amine. A sense of its importance can
be garnered from the observation that 12 of the top
100 selling pharmaceuticals are embedded with this
motif (and several others are related by simple
derivatisation).
A number of well-established
methods are typically employed to construct this
motif but can suffer from long, impractical synthetic
sequences. Given our discovery of an aniline-cyano
arene coupling reaction, we envisioned that a
milder, direct method would involve conversion of an
-amino C-H bond to a C-Ar bond mediated by
photoredox catalysis (Scheme 8). With only visible
light required, a room-temperature reaction with
operationally trivial experimental protocols would be
highly desirable for synthetic purposes.
Et2NPh,E1/2ox = 0.78 V vs. SCE in CH3CN). The
photocatalyst in its now reduced form can promote
single electron transfer to the cyanoarene 2 (e.g.
Ir(ppy)32+ E1/2ox = –2.2 V vs. SCE in CH3CN and 1,4dicaynobenzene, E1/2red = –1.61 V vs. SCE in
CH3CN) and thus return the catalyst to its original
ground state.
Scheme 8. New and Valuable Bond Formations Via Photoredox Catalysis
NC
N
PG
N
N
NC
Me
N
Me
PG
 commercial reagents
 mild conditions
 operationally trivial
N
PG
Photoredox
Direct coupling
N
N
Me
Me
N
PG
Acyclic and Cyclic
Benzylic Amines
important motif
Our proposed mechanism for the transformation is
shown in Scheme 9. Visible light excitation of
photocatalysts of the type Ir(ppy)3 allows facile
oxidation of the aniline substrate 1 (e.g.
The result of this electron shuttling is amine radical
cation 3 and arene radical anion 4.
The protons adjacent to the nitrogen in 3 are
weakened by approximately 60 kcal/mol and the
arene radical anion 4 accordingly behaves as a
base leading to a pair of neutral radicals 5 and 6.
Radical combination and elimination of HCN affords
the rearomatised arylated product. Support for this
mechanism is found from a study of related systems
by Ohashi.
The new arylation process has proven to be
extremely general. We first began exploring the
scope of the reaction by examining a range of
different amine structures. Various cyclic and acyclic
derivatives were easily accommodated within the
new arylation reaction. Substitution of the phenyl
moiety was also possible with alkyl and halide
groups. In all cases, exceptionally high yields were
obtained of the arylated products.
Scheme 10. Photoredox C-H Arylation - Amine Scope
CN
R
N
Ph
Ir(ppy)3 (1 mol %)
26 W light source
R
Ar = Ph-4-CN
N
Ph
95%
98%
Ar
N
Ph
Ar
Me
R
Benzonitriles
as reagents for
photoredox
arylation
O
O
N
Ph
N
Et
N
Ph
92%
N
p-F = 91%
CN
OEt
O P OEt
Ar
94%
CN
CO2Et
44%
 regiocontrol
 broad scope
 high utility
Ar
45%
CN
EWG
Ar
72%
Me
71%
CN
Me
CN
CN
10
CN
p-Br = 91%
11
85%
R
As well as the amine structures in Scheme 10, a
selection of important amine containing motifs such
as
indolines,
tetrahydroquinolines
and
tetrahydroisoquinolines were examined. The issue
of regioselectivity also became apparent with these
particular substrates. In the case of indoline, the
arylated product 7 was obtained in 81% yield and
with a 10:1 preference for arylation at the ring site.
Similarly, tetrahydroquinoline product 8 was
obtained as a single isomer with arylation again
occurring at the ring site in 88% yield. Interestingly,
the benzylic position was preferred of the
tertrahydro isoquinoline system forming 9 in 77%
yield.
CN
n
CN
Electron–deficient heterocycles are amongst the
most widespread moieties found in medicinally
relevant compounds and therapeutics. Furthermore,
considering the scale and frequency that this class
of compounds are synthesized and manipulated,
methods for their coupling to other frameworks are a
foundation in the manufacture of pharmaceutical
compounds. Our preliminary efforts towards
heterobenzylic amines have yielded some highly
promising results (Scheme 13). In particular, cyanosubstituted pyridines have proven effective
substrates. Also, aza-indoles also appear to be
highly applicable to this methodology. This area is to
be heavily investigated in future studies due to the
importance of the structures formed.
Scheme 13. Heterobenzylic Amines
Scheme 11. Photoredox C-H Arylation - Important Amine Motifs
N
R
N N
N
N
O
OEt
65%
Ar
95%
N
p-Me = 98%
N
Ph
N
Ph
81%
N
Ph
96%
Ar
Me
R
Boc
N
O
Ar
Scheme 12. Susbtituted Benzonitrile Scope
NaOAc, 23 ºC
DMA
CN
N
Ph
CN
range of different benzonitriles can be coupled in
this process.
Esters, amides, tetrazoles and
phosphonate esters all participated readily in the
reaction. Even extreme hinderence can be tolerated
as in the case of 10.
Importantly it was
demonstrated that regiocontrol could be achieved in
the case of 1,2-dicyano benzene 11. Efforts in this
area are ongoing in order to improve the efficiency
of these processes.
Me
Ir(ppy)3 (1 mol %)
26 W light source
n
NaOAc, 23 ºC
DMA
N
R
CN
N
Ph
N
71%
N
Ph
NH
N
Ph
N
87%
N
Ph
N
N
26%
61%
Ar = Ph-4-CN
N
N
Ar
7
Ph
81%, 10:1 ring/Bn
N
Ar
8 Ph
88%, >20:1 ring/Bn
9
Ph
Ar
77%, >20:1 ring/Bn
Our attention then turned to the arene coupling
partner. In analogies to other coupling reactions
that use specific handles to mediate the bondforming event (e.g. halides etc.), we aimed to
demonstrate that the cyano group could fulfil this
task. Scheme 12 demonstrates that providing an
electron withdrawing substituent is present then a
Finally, a convenient protecting group for the
benzylic amine products is required in order for
further manipulation. Through the development of
new photocatalysts, PMP protected amines can now
function effectively within this manifold (Scheme 14).
Scheme 14. Extention to PMP-Protected Amines
t-Bu
CN
N
PMP
CN
t-Bu
Ir(4t-BuPh-4t-Bu-Py)3
(1 mol %)
26W light source
NaOAc, 23 ºC
DMA
N
N
PMP
N
CN
Ir3+
t-Bu
N
t-Bu
t-Bu
t-Bu
Potential Impact and Use Of Final Results
The discoveries made by the fellow are anticipated to produce and impact in both academia and
industrial settings. From an academic perspective, the research is highly novel and will attract
interest from a mechanistic and utility standpoint. In terms of practical importance, the benzylic
amine structures produced are amongst the most widespread motif found in compounds
designed as medicinal agents. Commonplace methods for the synthesis of benzylic amines can
involve long, drawn out synthetic routes and the use of highly reactive metal bases and
dangerous oxidants. The results presented by the fellow indicate that the same structures can
be achieved in a simple room temperature protocol using photoredox catalysts and with only
visible light as a source of energy. As such this makes the new process highly attractive from
practical and environmental point of view.
The outgoing advisor has developed a number of links with major pharmaceutical companies in
the US through consulting and other actives. Already, a number of scientists from these
organisations have requested our expertise in order to apply this methodology to their current
projects. Even at this premature stage, this interest is highly encouraging for the use of this
methodology in a real-life setting. It is therefore felt that the discoveries made by the fellow
present a genuine tool for the pharmaceutical industry. The benefits of which would include
streamlined synthesis and more efficient and green techniques for the production of medicines.
Currently, a manuscript has been prepared for submission of the described results for Science.
The article is anticipated to be published within a relatively short time frame.