One Amine–3 Tasks: Reductive Coupling of Imines with Olefins in Batch and Flow

Article abstract of DOI:10.1002/chem.201904483

Owing to their wide range of biological properties, γ-aminobutyric acid derivatives (GABA) have been extensively studied and found noteworthy industrial applications. However, atom-economical and efficient processes for their production are scarce and would greatly benefit from further investigations. Herein, we demonstrate that an iridium-based photocatalyst promotes the direct reductive cross-coupling of imines with olefins upon irradiation with visible light to give GABA derivatives in good yields and selectivities. We also stress the enabling triple role of tributylamine additive in this process, discuss the advantages of strategies based on proton-coupled electron transfer (PCET) and demonstrate the scale-up of this reaction in continuous flow.

Full text of DOI:10.1002/chem.201904483

A Journal of
Accepted Article
Title: One Amine - 3 Tasks: Reductive Coupling of Imines with Olefins
in Batch and Flow
Authors: Quentin Lefebvre, Riccardo Porta, Anthony Millet, Jiaqi Jia,
and Magnus Rueping
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201904483
Link to VoR: http://dx.doi.org/10.1002/chem.201904483
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10.1002/chem.201904483
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One Amine - 3 Tasks: Photoredox Reductive Coupling of Imines
with Olefins in Batch and Flow
Quentin Lefebvre, Riccardo Porta, Anthony Millet, Jiaqi Jia, and Magnus Rueping*
Abstract Owing to their wide range of biological properties, γ-
aminobutyric acid derivatives (GABA) have been extensively studied
and found noteworthy industrial applications. However, atom-
economical and efficient processes for their production are scarce
and would greatly benefit from further investigations. Herein, we
demonstrate that an iridium-based photocatalyst promotes the direct
reductive cross-coupling of imines with olefins upon irradiation with
visible light to give GABA derivatives in good yields and selectivities.
We also stress the enabling triple role of tributylamine additive in this
process, discuss the advantages of strategies based on proton-
coupled electron transfer (PCET) and demonstrate the scale-up of
this reaction in continuous flow.
opens new retrosynthetic opportunities for the synthesis of
complex molecules.[4] Although Umpolung of aldehydes and
ketones has been extensively investigated,[4] the number of
efficient methods for Umpolung of imines are limited.[5] A now
common strategy is the deprotonation of imines to form 2-
azaallyl anions.[5] These intermediates can be used in
organocatalyzed or metal-catalyzed cross-coupling processes,
yielding alkylated or arylated Umpolung products.[6] A major
shortcoming of this strategy is the need for strong bases and
biased substrates to ensure regioselectivity in the
functionalization of the 2-azaallyl anion. Another strategy is the
one-electron reduction of an imine to give a free amino radical
anion or a 3-membered metalacycle depending on the reductant
used.[7] However, direct electron-transfer is difficult due to the
red
high reduction potentials of imines (E1/2 = – 1.98 V vs SCE for
Introduction
N-benzylideneaniline),[8] and either specially designed
substrates with lower reduction potentials or overstoichiometric
amounts of highly reducing metals salts based on zirconium,[7a]
samarium[7b,c] or titanium[7d,e] are required.
Over the last decade, the synthetic potential of visible light
photoredox catalysis became more and more evident. Low
loadings of catalysts, inexpensive light sources as well as mild
reaction conditions contrast with most of the requirements for
classical thermal or UV-mediated radical reactions.[1] Ruthenium-
and iridium-based photocatalysts[1c,e] with bipyridine and
phenylpyridine ligands offer highly tunable and predictable
reduction and oxidation potentials and therefore were applied by
our group and others to a vast number of transformations.
Interestingly, although a multitude of catalysts were designed for
reductive quenching catalytic cycles, mostly aiming at a high
excited-state oxidation potential (E1/2ox(M*/M–) = 1.21 V vs SCE
for Ir[dF(CF3)ppy]2(dtbbpy)+, 1.45 V vs SCE for Ru(bpz)32+),[2]
catalysts with high excited-state reduction potential, used in
oxidative quenching cycles, are virtually limited to Ir(ppy)3
(E1/2red(M*/M+) = - 1.73 V vs SCE).[3] Therefore, understanding
the oxidation of ground-state catalysts in reductive quenching
cycles is of importance to widen the scope of accessible
substrates.
We previously showed that visible light induced reduction
of imines to α-amino radicals using photocatalysts with low
ground state reduction potentials is possible by a strategic
choice of reductive quencher.[9,10] Tributylamine acted as both
electron-donor for the catalyst and hydrogen-bond donor for the
substrate,[9] permitting a proton-coupled electron transfer[11,12] as
key step. The resulting radical then underwent dimerization to
give symmetrical diamines. Very recently, various groups
reported photoredox-catalyzed radical-radical cross-couplings
between the persistent radical formed by reduction of an imine
one amine - 3 tasks
Bu
Me
N
Bu
ν
h
*
IrIII
Reductive
quenching
[1,2]-H
shift
Bu
N
•+
Bu
Bu
Me
N
The development of methods for the Umpolung of carbonyl
compounds has been of great interest over the past years, as it
Me
BH+
H
Bu
A
IrIII
IrII
R'
N
1
R
Proton-coupled
electron transfer
[*]
Dr. Q. Lefebvre,[†] Dr. R. Porta,[†] Dr. A. Millet, Dr. J. Jia, Prof. Dr. M.
Rueping
Bu
Bu
R'
Bu
Me
N
H
HN
Institut of Organic Chemistry, RWTH Aachen
Landoltweg 1, 52074 Aachen (Germany)
E-mail: magnus.rueping@rwth-aachen.de
Me
N
R'
Bu
R
N
D
B
R
Dr. R. Porta
Bu
EWG
N
Dipartimento di Chimica, Università degli Studi di Milano
Via Golgi 19, 20133, Milano (Italy)
C
2
Bu
F
R'
R'
Prof. Dr. M. Rueping
HN
HN
King Abdullah University of Science and Technology (KAUST),
KAUST Catalysis Center (KCC), Thuwal, 23955-6900 (Saudi
Arabia)
Hydrogen
Atom
R
EWG
R
EWG
E
3
Transfer
[†]
These authors contributed equally to the work.
Scheme 1. Proposed mechanism for the visible light photoredox-catalyzed
Supporting information for this article is given via a link at the end of
the document.
reductive coupling of imines with olefins ([1,2]-H shift: 1,2-hydrogen shift).
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10.1002/chem.201904483
Chemistry - A European Journal
FULL PAPER
and a transient radical formed by oxidation, however the
photoredox-catalyzed reductive cross-coupling of imines with
olefins has been less investigated.[13,14] We therefore questioned
the possibility of a general cross-coupling reaction exploiting the
α-amino radical intermediate.
irradiated at 450 nm with blue LEDs for 24 hours to give the
expected product 3a in 84% yield (Table S2, entry 7). Slightly
higher yields could be obtained by running the reaction for 24
additional hours (Table S2, entry 8). No conversion was
observed in the absence of tributylamine or photocatalyst, in the
dark, or under air atmosphere. Addition of catalytic amounts of
bases completely inhibited the reaction, confirming a proton-
coupled electron transfer as the key step.[19]
Although these reaction conditions were satisfying from a batch
photochemistry point of view, we wondered whether we could
decrease the reaction time and the catalyst loading. We
therefore investigated the outcome of the reaction under
continuous flow conditions.[20] Pleasingly, when a 5 mL flow
microreactor (PTFE tubing, id = 0.8 mm, l = 10 m) was irradiated
with blue LEDs, a six-fold decrease in reaction time could be
observed. Additionally, the catalyst loading could even be
reduced from 2 mol% to 1 mol%, without substantial loss in yield
and selectivity.[19] Performing a flow experiment on a 0.5 mmol
scale using 1 mol% of 4a and a residence time of 4 hours gave
3a in 80% yield, emphasising once more the advantages of flow
over batch, for scaling-up photocatalyzed reactions (Scheme
We hypothesized that such
a cross-coupling might be
mechanistically similar to our previously reported coupling of α-
chloroamides with olefins (Scheme 1)[15]: upon excitation by
visible light, the photocatalyst becomes highly oxidizing and is
reduced by tributylamine to give the corresponding radical cation
A, which rapidly undergoes a 1,2-hydrogen shift to form the α-
ammonium radical BH+. This intermediate activates the imine 1
as C for a subsequent proton-coupled electron transfer which
regenerates the catalyst and gives the α-amino radical D along
with B. Cross-coupling between these two nucleophilic radicals
is disfavored in the presence of electron-deficient olefins 2, onto
which D readily adds in accordance with the polar effect.[16] The
resulting electrophilic radical E undergoes hydrogen atom
transfer from B to give F and the expected saturated product
3.[17] Thus, the additive plays here a triple role: reduction of the
excited-state catalyst, hydrogen-bonding to render the reduction
of the imine less endergonic, and finally hydrogen-atom donation. 2).[21]
Noticeably, such a reaction manifold avoids side-reactions
typically observed when using trialkylamines as reductive
quenchers,[18] such as reduction of D by HAT from tributylamine
or B and radical addition of D onto F.
BLUE LEDs
Ph
N
CO2Me
Ph
Ph
(3 equiv.)
NH
Ph
2a
1a
4a
(1 mol%)
CO2Me
, 80%
(0.5 mmol scale)
Results and Discussion
(1.5 equiv)
NBu3
3a
EtOH [0.1 M]
= 5mL)
Flow Microreactor (Vi
Based on our previous studies, we started our investigation on
the photoredox-catalyzed reductive cross-coupling of imines with
olefins by irradiating a mixture of imine, tributylamine and methyl
acrylate in DMF, using Ir[F(CF3)ppy]2(bpy)PF6 4a or
Ir(ppy)2(dtbbpy)PF6 4b as photoredox catalyst (see Figure 1 for
the structure of the catalysts). In contrast with many other N-
protected substrates, N-benzylideneaniline gave little to no
imino-pinacol coupling and selectively coupled with the olefin in
43% and 59% yield respectively (Table S2, entries 1 and 3).
Flow rate = 1.25 mL/h
Residence time = 4 h
Scheme 2. Photoredox-catalyzed reductive coupling in continuous flow.
The integration of inline analytical devices into the flow stream of
a synthetic methodology improves process automation and also
reduces risks associated to handling and isolation of
intermediates. In particular, IR flow cells have recently proved to
be effective tools for reaction monitoring, mechanistic
investigations as well as quantitative measurements in multistep
processes and self-optimization studies.[22] In order to have a
better understanding of the reaction kinetics we next decided to
monitor the reaction profile using a FlowIR instrument equipped
CF3
t-Bu
N
N
N
N
N
N
-
F
F
-
IrIII
IrIII
PF6
PF6
N
N
with
a DiComp ATR (diamond-composite attenuated total
t-Bu
reflection) probe. For inline analysis we identified signals at ν =
1633 cm-1 and ν = 1607 cm-1 corresponding to starting imine 1a
and product 3a, respectively. Monitoring the flow photoredox
coupling of 1a and 2a under optimal conditions at different
reaction times, substrate consumption and product formation
could be observed in real-time (Figure 2 and Figure S2). As
depicted in Figure 3, the comparison between batch and
continuous flow conditions clearly demonstrates that both
processes have a similar reaction profile, but light irradiation in
CF3
4a
4b
Figure 1. Iridium-photocatalysts discussed in this work.
Further optimisation showed that no additives other than
tributylamine were needed, and that the use of ethanol as a
sustainable alternative to DMF greatly enhanced the yield.
Under the optimal conditions, N-benzylideneaniline 1a was
dissolved in ethanol in the presence of 3 equivalents of methyl
acrylate, 1.5 equivalents of tributylamine and 2 mol% of 4a and
flow microreactor ensures
a faster transformation, which
undergoes completion after 4 hours only.
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10.1002/chem.201904483
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4a
NBu3
Ar2
Ar2
Ar1
(1.5 equiv.)
R1
N
NH R1
+
R2
EtOH [0.1M], Ar
blue LEDs, 30 °C, 24 h
Ar1
R2
1
2
3
NH
NH
NH
O
N
CN
O
O
[a]
3b
, 81%
3a
, 84%
3c
, 57%
80% in flow
73% in flow
62% in flow
Figure 2. 3D time-resolved spectral data obtained from Flow-IR inline analysis
showing substrate consumption (peak at 1633 cm-1) and product formation
(peak at 1607 cm-1).
NH
NH
NH
Ph
O
O
O
S
O
O
[a]
O
[a]
3d
3e
, 80%
3f
, 74%
, 43%
NH
NH
NH
O
C2F5
O
OH
2
O
N
2
O
O
[a]
O
[a]
[a]
3g
3h
3i
, 69%
, 80%
, 57%
NH
NH
NH
O
Ph
O
Br
O
2
O
, 72%[a], dr 3:1
O
[a]
O
[a]
3j
3k
, 62%
3l
, 67%
dr 4:1
dr 3:1
69%, dr 3:1 in flow
Figure 3. Comparison of batch and flow trend-curves of 3a formation obtained
with FlowIR inline monitoring.
CO2Me
NH NHAc
O
NH
NH
O
O
O
O
O
[a]
, 86%[a], dr 2:1
3m
, 89%[a], dr 3:2
3n
3o
, 61%
Once the best reaction conditions were identified for both batch
and flow regimes, we evaluated the scope of the reaction
(Scheme 3). First, we established that not only acrylates, but
also various radical acceptors such as acrylonitrile, acrylamides
as well as vinyl sulfones can be coupled with 1a in good yields.
Next, we showed that acrylates with side-chains of various size
and lipophilicity gave the corresponding products in very good
yields. A free hydroxy group (3h) as well as a trialkyl amine (3i)
were tolerated, without signs of oxidation under the reaction
54% in flow
84%, dr 3:2 in flow
84%, dr 2:1 in flow
NH
NH
NH
CO2Me
CO2
Me
CO2Me
MeO
OMe
,
3p
3q
3r
, 51%
50%
, 64%
60% in flow
51% in flow
conditions.[23,24]
A
bromide-containing acrylate derivative
NH
NH
NH
smoothly reacted to give the Br-containing product 3l, even
though reduction of alkyl bromides by photoredox catalysis has
been reported.[25] As alkyl bromides and imines have similar
reduction potentials,[26] this example further demonstrates how
our strategy involving reductive quenching followed by proton-
coupled electron transfer provides exquisite selectivity compared
to alternative oxidative quenching strategies. Methacrylate and
itaconate derivatives gave the expected products (3j, 3n
respectively) in good yields and selectivities, while using methyl
2-acetamidoacrylate as acceptor gave the highly valuable γ-
aminobutyric amino acid derivative 3m in high yield and
moderate selectivity. Conjugated dienes were also competent
substrates and, use of methyl 4-methylpentadien-2,4-oate as
acceptor resulted in 3o as the only product in good yield. Next,
we decided to investigate the substrate scope regarding imines
(Scheme 3).
CO2
Me
CO2
Me
CO2Me
F
F
Cl
Cl
Br
,
3s
3t
, 56%
57% in flow
3u
, 57%
61%
58% in flow
MeO
NH
NH
NH
CO2Me
CO2Me
CO2Me
3v
, 56%
3w
, 56%
52% in flow
3x
, 35%
38% in flow
Scheme 3. Reaction scope. Reaction conditions: imine 1 (0.2 mmol, 1 equiv.),
olefin (0.6 mmol, equiv.), NBu3 (0.3 mmol, 1.5 equiv.),
Ir[F(CF3)ppy]2(bpy)PF6 4a (2 mol%) in degassed EtOH (2 mL) under argon
and blue LEDs (11 W rubber strip) for 24 hours, yields after purification.
Reactions in flow performed as indicated in Scheme 2. [a] The reaction was
performed with 5 equivalents of olefin.
2
3
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10.1002/chem.201904483
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FULL PAPER
While trying to broaden the scope of the nitrogen protecting
group, we found that several imines underwent decomposition,
pinacol coupling, reduction, or simply did not react at all under
the standard reactions conditions. N-arylimines however were
robust and cleanly afforded the desired products in most cases.
Electron-rich as well as electron deficient groups were tolerated
and, once again, no dehalogenation was observed (3s-w). The
synthetically valuable product 3x was obtained in moderate yield.
Noticeable, for all examples tested in flow, the products were
obtained in yields and selectivities comparable to the ones
obtained in batch. The conversion of γ-aminobutyric ester
derivatives 3a, 3j, 3m and 3n to the corresponding γ-lactams 5
proceeded almost quantitatively by heating the starting materials
in toluene in the presence of catalytic amounts of para-
toluenesulfonic acid (Scheme 4a).[13b] Additionally, our reaction
was not only limited to reductive alkylation but could also be
extended to reductive allylation of imines by using appropriate
allyl sulfone derivatives as coupling partners (Scheme 4b).[27]
Intramolecular conjugate addition of the products 6a and 6b
would generate 2,4-disubstituted pyrrolidines in one step.[28]
Experimental Section
Procedure for the Visible Light Photoredox-Catalyzed Reductive
Cross-Coupling of Imines with Olefins. In an oven-dried test tube
equipped with a magnetic stir bar were placed Ir[F(CF3)ppy]2(bpy)PF6 4a
(3.9 mg, 0.004 mmol, 0.02 equiv.), imine 1 (0.2 mmol, 1.0 equiv.) and
olefin 2 (1.0 mmol, 5.0 equiv., if solid). The tube was closed with a
septum and purged three times with a sequence vacuum/argon before
addition of degassed ethanol (2.0 mL), NBu3 (71 µL, 0.3 mmol, 1.5
equiv.), and the corresponding olefin 2 (1.0 mmol, 5.0 equiv., if liquid).
The tube was placed in a beaker wrapped with 11W blue LEDs stripes
and irradiated for 24 hours. After complete conversion, the reaction
mixture was concentrated in vacuo, and the residue was purified by
column chromatography on silica gel (see below for eluent used). In
some cases, residual amounts of tributylamine were observed after
column chromatograpy; they were removed by co-evaporation in vacuo
with isopropanol or water followed by toluene.
Acknowledgements
RP thanks DAAD for a scholarship. The research leading to these
results has received funding from the European Research Council
under the European Union's Seventh Framework Programme
(FP/2007-2013)/ERC Grant Agreement no. 617044 (SunCatChem).
γ
-lactams
a) Synthesis of
R
O
H
N
CO2Me
PTSA (10 mol%)
Ph
N
Ph
toluene, 120 °C, 5 h
Ph
R
Ph
Keywords: Visible light photoredox catalysis • imine Umpolung •
proton-coupled electron transfer • heterocycles synthesis •
continuous flow photocatalysis
3a:
R = H
5a: R = H; 86%
R = CH3
R = CH
3j:
5j:
3; 92%
R = NHAc; 82%
R = CH
5m:
5n:
3m:
3n:
R = NHAc
R = CH2CO2Me
2CO2Me; 75%
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NBu3
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N
R
Ts
EtOH [0.1M], Ar,
blue LEDs, 30 °C, 24 h
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R
[2]
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R = 4-tBuPh; 38%
[3]
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Scheme 4. Application of our methodology to the synthesis of nitrogen-
containing heterocycles.
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10.1002/chem.201904483
Chemistry - A European Journal
FULL PAPER
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10.1002/chem.201904483
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
Quentin Lefebvre, Riccardo Porta,
BLUE LEDs
Anthony Millet, Jiaqi Jia, Magnus
Rueping*
Ph
N
Ph
Ph
Me
CO2
NH
Ph
Page No. – Page No.
Me
CO2
80% yield
(0.5 mmol scale)
Photocatalyst
NBu
3, EtOH
One Amine - 3 Tasks: Reductive
Coupling of Imines with Olefins in
Batch and Flow
Residence time = 4 h
Text for Table of Contents
+ 24 examples in batch and flow
+ Ethanol as sustainable solvent
+ Synthesis of GABA derivatives
γ
+ Synthesis of
-lactams
Gamma-aminobutyric acid derivatives could easily be synthesized by the visible-light photoredox-catalyzed coupling of imines with
olefins. The reaction works well for a range of substrates and tolerates many functional groups. A continuous-flow strategy
considerably improved the efficiency of this methodology.
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