A chemoselective and scalable transfer hydrogenation of aryl imines by rapid continuous flow photoredox catalysis

Article abstract of DOI:10.2533/chimia.2019.823

The chemoselective reduction of diaryl imines in the presence of competitively reducible groups is uniquely accessed through precise control of reaction and irradiation time by continuous flow visible light photoredox catalysis. The method enables the mild and efficient transfer hydrogenation of diaryl imines in the presence of sensitive functionality including halides, ester, ketone, and cyano groups. The flow protocol is efficient, rapid (>98% conversion within 9 min) and readily scaled to deliver multigram quantities of amine products in high purity.

Full text of DOI:10.2533/chimia.2019.823

Continuous Flow Chemistry – industry and aCademia PersPeCtives
CHIMIA 2019, 73, No. 10 823
doi:10.2533/chimia.2019.823
Chimia 73 (2019) 823–827 © Swiss Chemical Society
A Chemoselective and Scalable Transfer
Hydrogenation of Aryl Imines by Rapid
Continuous Flow Photoredox Catalysis
Rowan L. Pilkingtona, Nikolai P. Rossouwa, Dean J. van Asa, and Anastasios Polyzos*ab
Abstract: The chemoselective reduction of diaryl imines in the presence of competitively reducible groups
is uniquely accessed through precise control of reaction and irradiation time by continuous flow visible light
photoredox catalysis. The method enables the mild and efficient transfer hydrogenation of diaryl imines in
the presence of sensitive functionality including halides, ester, ketone, and cyano groups. The flow protocol
is efficient, rapid (>98% conversion within 9 min) and readily scaled to deliver multigram quantities of amine
products in high purity.
Keywords: Flow chemistry · Imines · Photoredox · Radicals · Transfer hydrogenation
Rowan L. Pilkington was born in England
before moving to Australia in later life.
He studied Science (Chemistry) at the
the University of Melbourne, working in
his final year under the supervision of Dr.
A. Polyzos on photoredox carbonylation
in flow. He has completed an MSc in the
same group, with research interests in the
development of novel photoredox processes
and their application in flow processing.
Anastasios Polyzos was awarded his
PhD in 2005 from La Trobe University
and appointed to Research Fellow at the
Australian national science agency, CSIRO
in the same year. In 2008 he pursued post-
doctoralresearchatUniversityofCambridge
under guidance of Professor Steven V. Ley
FRS. In 2011 he returned to Australia to
lead the flow chemistry and catalysis group
at CSIRO in Australia. He established an
independent research career with appointment to Senior Lecturer
Nikolai P. Rossouw was born in Richards within the School of Chemistry, University of Melbourne in 2015.
Bay, South Africa, before immigrating Hisresearchinterestsincludethedevelopmentofnewmethodsand
to Australia. He graduated with a BSc enabling technologies for organic synthesis, photocatalysis, C–H
(Chemistry) from the University of reaction discovery, and the development of sustainable industrial
Melbourne, working on photoredox process chemistry. Anastasios currently serves as Director of the
thiolation in flow and synthesis of organic Australian Research Council Industrial Transformation Training
photoredox catalysts with Dr. A. Polyzos. Centre for Chemical Industries.
He is continuing a MSc with the Polyzos
laboratory developing natural product total
synthesis in flow.
The ubiquity of aryl amines in pharmaceutical, agrochemical
and industrial products has fostered the development of methods
enabling their straightforward and scalable production.[1]
Dean J. van As grew up in Melbourne, Innumerous protocols for the synthesis of aryl amines exist,
Australia. He obtained an MSc from the encompassing SNAr of aryl fluorides,[2] Ulmann, Buchwald-
chemistry department at the University of Hartwig and Chan-Evans-Lam coupling,[3] and hydrogen
Melbourne in 2015 under the supervision of borrowing.[4] One of the most robust and well-established
Dr. W. Wong. He is currently completing his methods is reductive amination by heterogeneous catalytic
PhD studies at the University of Melbourne hydrogenation of imines on platinum and palladium metal.
under the supervision of Dr. A. Polyzos in Whilst catalytic hydrogenation is scalable and generally
photoredox catalysis. His areas of interest economically viable, chemoselectivity is challenged by the
involve the development of new visible light presence of multiple unsaturated bonds or other reducible
photocatalytic methods for the synthesis groups on the intermediates and products.[5] The development
and functionalization of amines in batch and flow.
of methods for reductive amination under mild conditions
with requisite chemoselectivity and functional group tolerance
remains a focus in industrial, and academic laboratories.[6] These
requirements become progressively important when reductive
amination is required in the late-stage functionalisation of
targets with increasing complexity, including bioactive lead
molecules and natural products. Mild hydride transfer agents
*Correspondence: Dr. A. Polyzosab, E-mail: anastasios.polyzos@unimelb.edu.au
aSchool of Chemistry, The University of Melbourne, Parkville, VIC 3010, Australia; bCSIRO Manufacturing, Clayton, VIC 3068, Australia

824 CHIMIA 2019, 73, No. 10
Continuous Flow Chemistry – industry and aCademia PersPeCtives
Scheme 1. Continuous flow
processing enabling the scalable,
chemoselective photoredox
transfer hydrogenation of imines.
FG = functional group.
Our Previous Work:
Ir(ppy)2dtbbpy(PF6) (1.5 mol%)
NEt3 (5 eq.)
N
HN
MeCN, N2
Ar
Ar
Ar
Ar
14 W blue LEDs
H
FG over-reduction at extended reaction times: challenge for scale up
+ e
+ e
+ H
+ H
PC
I
I
H
PC
+ H
N
HN
Ar
HN
Ar
Ar
Ar
Ar
Ar
This Work:
Ir(ppy)2dtbbpy(PF6) (0.5 mol%)
NEt3 (5 eq.)
FG
FG
N
HN
H
Ar
Ar
Ar
Ar
7 - 9 mins
MeCN, N2
14 W blue LED photo/flow reactor
Chemoselectivity and scalability with continuous flow photoredox
including NaCNBH4 and NaBH(OAc)3 offer opportunities for
chemoselective reduction of imines, however a dependence on
acidic conditions, solvent polarity and imine electrophilicity
impedes application to a broader selection of substrates.[7]
Furthermore, therequirementforstoichiometrichydridetransfer
reagent and the formation of cyanide by-products (in the case of
NaCNBH4) may limit the translation of these methods beyond
laboratory preparation.[6]
We recently disclosed a visible light photoredox method for
the catalytic transfer hydrogenation of diaryl-ketimines (Scheme
1).[8] The process utilises triethylamine as a highly economical
single source of electron, proton and hydrogen atom. The
reaction was characterised by high product yields, fast reaction
times and visible light as the solitary energy source. Based on
literature reports,[9] our mechanistic hypothesis (Scheme 2) was
centralised on the direct single electron reduction of the diaryl-
ketimine moiety (I) to the corresponding α-aminyl radical anion
species (II) by the photoredox catalyst, followed by subsequent
protonation and hydrogen atom transfer (HAT) from triethylamine
radical cation (IV) and triethylamine (III) respectively to afford
the hydrogenated diaryl amine (VI).
Through the course of these investigations, we observed that
imines bearing an aryl-iodo substituent underwent competitive
protodehalogenation with extended reaction times. To address this
limitation, we reasoned that the different rates of single electron
transfer (SET) to the imine moiety relative to the aryl halide,
could be exploited to furnish chemoselectivity that was dependent
on reaction time. Continuous flow photochemistry methods[10]
offer the temporal and spacial resolution necessary to enable the
kinetically favoured reduction of the imine whilst minimising
unwantedprotodehalogenation.Thisselectivitymodecanbereadily
achieved by establishing a finely-tuned set of reaction conditions
that impede the time-dependent over-reduction of the aryl halide
and can be extended to other reducible substituents. Furthermore,
improved photocatalytic activity can be expected since greater
light permittivity is effected over the smaller pathlength in tubular
NEt2
H
NA
NEt2
r
R
VI
H
H
V
Ar
NEt3
III
IV
NEt2
Ir(II)
Ir(III)*
r
NA
R
NEt2
Blue
Ar
II
H
LEDs
Ir(III)
Ar
N
R
Ar
I
Scheme 2. Proposed mechanism of photoredox-catalysed transfer
hydrogenation.
flow reactors compared to standard reaction glassware,[11] and
the continuous nature of flow chemistry could be leveraged to
efficiently scale the photocatalytic chemoselective reduction.[12]
We initiated the study by assembling a flow platform
consisting of a commercially available syringe pumping system
(Syrris Asia) fitted with an injection port and sample loop (any
commercially available system is suitable for this application).
A bespoke tubular photoreactor was fitted, consisting of two 7
W 447 nm LED arrays and a coiled perfluoralkoxy alkane (PFA)
tube (3 mL, 0.75 mm i.d.). The system was pressurised by a back
pressure regulator, rated to 40 PSI (Fig.1) and the solvent reservoir
was continually sparged with nitrogen.
The photoredox transfer hydrogenation of the aryl iodide
bearing imine 1a was investigated and studies to establish
conditions for the quantitative production of iodoamine 1b over
the protodehalogenated product 1c were undertaken. Following

Continuous Flow Chemistry – industry and aCademia PersPeCtives
CHIMIA 2019, 73, No. 10 825
Fig. 1. Reaction time screening for substrate 1a. Conversions determined by 1H NMR analysis of the crude reaction mixture. Performed on a 0.10
mmol scale.
optimisation of residence time (Fig. 1) excellent conversions flow reactor configuration was modified to accommodate the
(>97%) of the substituted imine 1a were achieved with rapid processing of larger volumes of reagent and solvent . The sample
T as low as 7 min. Incomplete conversion of 1a was observed loops were removed and the reagents were delivered from a
atRT below 6.5 min, indicating that the transfer hydrogenation single flask under an N atmosphere. FlowIR™ infra-red (FTIR)
wasRincomplete at faster flow rates. Slower flow rates resulting spectroscopic monitori2ng was utilised to monitor the reaction
in TR more than 7 min increased protodeiodination of 1b to 1c. mixture in-line to provide real-time information on the progress
Background dehalogenation by photodissociation under blue light of the continuous run (9 h).[13] The establishment of steady-state
irradiation was not detected when the photocatalyst was omitted conditions was readily identified by in-line FTIR and the reaction
from the reaction. With the optimised reaction time (TR = 7 min) product stream was collected when a steady-state was observed.
in hand, the preparation of iodoamine 1c was successfully scaled The reaction front and tail (non-steady-state reaction plug) was
to 0.4 mmol and isolated in 87% yield.
diverted away from the collection flask to ensure unreacted
To demonstrate practicality and scalability of the method, material and by-products generated by dispersion effects were
we embarked on a multi-gram preparation of 1b (Fig. 2). The not collected. The desired amine 1b was isolated in 77% (7.68
.ꢀ.
9
3 ml
d
N
14 W, 447 nm LEDs
fan cooled
TR= 7 or 9 mins
PhꢀPh
1a (X= 1) 9.16 g, 23.89 mmol
or 2a (X= Br) 9.29 g, 27.63 mmol
1b (X= 1) 77 % (1.81 mmol/h)
or 2
b
(X= Br) 79 % (1. 9 mmol/h)
5
9 houꢀ run-time
r(
)
d
+
(P
) (0.
)
5 mol
ꢀ
l
ppy i tbbpy
F
6
Degassed MeCN (0.1 M]
0.2
ꢀ
ꢁ
-
Peak at 707 an-1
Peak at 1069 cm-1
Steady state paꢂ,t,oꢃ
ꢀ 0.1
ꢀ o.oꢁ
�
ꢀ
ꢁ
--
--
-�
�
-
�
-�-
--ꢂ-�--ꢃ
-
-
�
o
Time(h)
Fig. 2. Large-scale continuous flow photoredox transfer hydrogenation of iodo- and bromo- substituted aryl imines. In-line FTIR trace and peak
absorption of diagnostic IR bands used to partition the reaction mixture at steady state (for 1b).

826 CHIMIA 2019, 73, No. 10
Continuous Flow Chemistry – industry and aCademia PersPeCtives
g) with a space-time yield (STY) of 1.81 mmol/h. Parasitic
In summary, a versatile flow system for the photoredox transfer
protodehalogenation of 1b was minimised comparably to the hydrogenation of sensitive imines was developed, uniquely
smaller scale reaction, with < 4% conversion to 1c detected in facilitating the scalable synthesis of substituted diaryl amines
the crude residue by 1H-NMR.
with time-dependent retention of functionality. Further studies
We next addressed the 4-bromo substituted diphenyl are underway to implement and scale this photoredox transfer
aryl imine 2a which, according to cyclic voltammetry and hydrogenation protocol in new multistage flow systems.
unpublished experimental data, is also reducible under our
photoredox system.[14] The T was extended to 9 min to effect
Supplementary Information
complete transfer hydrogenatRion, affording 2b in 84% isolated
Supplementary information is available on https://www.ingentacon-
yield at 0.40 mmol scale. The bromo-substituted imine 2a was
nect.com/content/scs/chimia
Scheme 3. Selected scope of
imines with sensitive functional
groups. Isolated yields are shown
FG
FG
and reactions were performed on
0.40 mmol scale. FG = functional
group.
N
HN
Ar
40 PSI
4 mL
Ar
Ar
Ar
[0.10 M]
MeCN
3 mL
N2 flow
14 W, 440nm LEDs
fan cooled
+ NEt3 (5 eq.)
TR = 7 or 9 mins
+ Ir(ppy)2dtbbpy(PF6) (0.5 mol%)
O
I
Br
1b
HN
Ph
HN
Ph
HN
Ph
87 %
2b
2c
TR = 7 mins
84 %
94 %
Ph
Ph
Ph
Ph
O
CN
Ph
OEt
HN
Ph
HN
Ph
HN
2e
2f
2d
71 %
0 %
98 %
Ph
Ph
NO2
submitted to the scaled procedure with in-line FTIR monitoring,
providing 6.44 g of the corresponding amine in 79% yield, with
a space-time yield of 1.59 mmol/h. Notably, the scaled reaction
products could be isolated in high purity by simple filtration
through silica and trituration with hexanes from the crude
reaction mixture.
Substrates with cyano, aryl ketone and ester substituents on
the diphenylimine scaffold were investigated as other potentially
reducible groups under the reaction conditions (Scheme 3).[14] The
functional groups were well tolerated with preferential reduction
of the imine and with complete conversions to the corresponding
amine at 0.4 mmol scale. A nitro-substituted imine did not afford
the product 2f under the optimised reaction conditions, most
likely due to preferential electron transfer to the electron deficient
aryl ring.
Ir(ppy)2dtbbpy(PF6)
(0.5 mol%)
A
I
I
NEt3 (5 eq.)
1b
1c
N
MeCN (0.10 M),
#
99 % conversion
N2, r.t., 3 h
Ph
Ph
1a
64 % 1c#
BATCH, 1 mmol
B
NaBH4 (1.5 eq.)
1b
N
MeOH,
30 % conversion#
N2, 0 °C to r.t., 24 h
Ph
Ph
1a
BATCH, 1 mmol
To validate the effectiveness of the flow procedure, the rate
of conversion and protodehalogenation of 1a was examined
under batch photoredox conditions (Scheme 4A). The reduction
of 1a on 1 mmol scale proceeded as expected with 99%
conversion of the starting imine effected after 3 h of irradiation
with TLC monitoring, however 64% protodehalogenation was
C
Pd(PPh)4 (5 mol%)
CuI (10 mol%)
Ph
I
Ph
(1.1 eq.)
HN
Ph
HN
Ph
NEt3/THF,
1
Ph
1b
N2, 60 °C, 20 h
Ph
1d
observed by H NMR analysis. A traditional reduction with
82 %
NaBH4 (Scheme 4B) did not effect complete conversion to 1b
even after 24 h. Finally, the halogenated product 1b prepared
via the chemoselective photocatalytic reduction protocol was
submitted to a representative Sonogashira coupling reaction[15]
with phenylacetylene to afford a further functionalised alkynyl
product in 82% yield (Scheme 4C).
Scheme 4. A) Protodehalogenation behaviour under standardised batch
photoredox conditions. Progress was monitored by TLC. B) Transfer
hydrogenation of diaryl ketimine with NaBH4. C) Further transformation
of the chemoselectively reduced iodo-amine.[16] # = Determined by 1H
NMR analysis of the crude reaction mixture.

Continuous Flow Chemistry – industry and aCademia PersPeCtives
CHIMIA 2019, 73, No. 10 827
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Acknowledgements
The authors acknowledge Mr Vir H. Ghandi who assisted RLP
with the experimental procedures and Professor Paul Francis (Deakin
University) for the kind loan of the Syrris Asia syringe pump system.
DvA acknowledges the University of Melbourne, Melbourne Research
Scholarship (MRS). AP acknowledges the University of Melbourne and
CSIRO for the joint Establishment Grant.
Received: May 8, 2019
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