Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow

Article abstract of DOI:10.1039/c8cc02169d

We report an acridium-based organic photocatalyst as an efficient replacement for iridium-based photocatalysts to oxidise boronic acid derivatives by a single electron process. Furthermore, we applied the developed catalytic system to the synthesis of four active pharmaceutical ingredients (APIs). A straightforward scale up approach using continuous flow photoreactors is also reported affording gram an hour throughput.

Full text of DOI:10.1039/c8cc02169d

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Organic photocatalysis for the radical couplings
of boronic acid derivatives in batch and flow†
Cite this:DOI: 10.1039/c8cc02169d
a
a
Fabio Lima,
Lars Grunenberg, ‡a Husaini B. A. Rahman,‡a Ricardo Labes,
Joerg Sedelmeierb and Steven V. Ley
*
a
Received 19th March 2018,
Accepted 12th April 2018
DOI: 10.1039/c8cc02169d
rsc.li/chemcomm
We report an acridium-based organic photocatalyst as an efficient photocatalysts,5a,6 we sought to identify a suitable organic
replacement for iridium-based photocatalysts to oxidise boronic replacement to the previously used iridium photosensitisers.7
acid derivatives by a single electron process. Furthermore, we Ideally this protocol could be scaled up using a continuous flow
applied the developed catalytic system to the synthesis of four reactor and its utility demonstrated by synthesising pharma-
active pharmaceutical ingredients (APIs). A straightforward scale up ceutically relevant compounds in an efficient manner.
approach using continuous flow photoreactors is also reported
affording gram an hour throughput.
To start this investigation, we chose a model radical conju-
gate addition reaction of boronic ester 1 or boronic acid 2 with
methyl vinyl ketone (MVK, 3) as radical acceptor.3b We sub-
Visible-light photoredox catalysis has become an important tool jected these species to a series of photoredox catalysts in the
for radical species generation without the need for stoichio- presence of catalytic amount of Lewis base (LB = quinuclidin-3-ol
metric reagents.1 Using these methods, a large number of or DMAP) and under blue LEDs (14 W at l = 450 nm) irradiation to
applications have emerged for the catalytic generation of carbon produce the coupled products 4 or 5 (Scheme 1). A wide range of
radical species via single electron oxidation of charged anionic visible-light absorbing organic photocatalysts were screened using
species, such as carboxylates, silicates, and trifluoroborate salts.2 these two model reactions (full table in ESI†).
We recently developed a photoredox method to generate radicals
from neutral boronic acids or esters, making use of an additional
Lewis base catalyst (LB) to activate the trivalent boronic species
towards single-electron oxidation.3 The substantial number of
compatible substrates, combined with their commercial avail-
ability makes it a method of choice to generate carbon radicals
catalytically and engage them in versatile radical-based coupling
reactions. However, effective oxidation of these redox-active
complexes has until now only been realised using costly iridium
based photoredox catalysts (Ir-1 or Ir-2). Despite the promises
offered by the photoredox disconnections for pharmaceutical
products synthesis,4 industry has to comply with residual transi-
tion metal limits in final products (oral permitted daily exposure
for iridium r100 mg per day).5 To comply with these low residual
metal levels, costly purification protocols have to be carried
out after transformations using transition metal catalysts. With
the recent development of efficient new generation organic
a Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge CB2 1EW, UK. E-mail: svl1000@cam.ac.uk;
Web: http://www.leygroup.ch.cam.ac.uk
b Novartis Pharma AG, Novartis Campus, 4002 Basel, Switzerland
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc02169d
‡ These authors contributed equally to the project.
Scheme 1 Selected examples of catalyst performance. See ESI† for full
optimisation.
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Along with rose bengal (RB), two recently developed organic
dyes (4CzlPN8 and Mes-Acr-46) emerged from this screening as
potential organic replacement to Ir-1 and Ir-2. While organic
dyes degradation upon prolonged irradiation can be a potential
pitfall, no discolouration (or photobleaching) occurred during
the course of the irradiation with these three photocatalysts. It
was therefore postulated that these dyes were stable enough to
be used without decline of reactivity. Finally, as Mes-Acr-4 con-
sistently led to the highest yields (similar to Ir-1 and Ir-2)
with both the boronic ester (1, entry 4) and acid (2, entry 9),
it was chosen as a promising replacement to the iridium-based
photocatalysts.
We then further compared the generality of Mes-Acr-4 against
Ir-2 with a wider range boronic acid derivatives (Table 1). As far
as the cross-coupled product yields are concerned, the perfor-
mance of the Mes-Acr-4 dye was often equivalent to the Ir-2
photocatalyst.
While products 4, 5 and 14 were obtained in the same
isolated yields with both photocatalysts, the organic dye was
superior to the iridium one for reactions leading to 11, 13 and
Fig. 1 Reaction following of Mes-Acr-4 against Ir-2 in NMR tube. Reaction
monitoring using 1H-NMR, comparison between Mes-Ar-4 (dots) and Ir-2
(squares). Reactions carried out at 0.05 mmol of 2, 0.2 mmol of 3, 2 mol% of
the indicated PC and 20 mol% DMAP in deuterated solvents.
15. However, in some cases, inferior yields were observed with To do this, reagents were dissolved in a deuterated solvent
the organic dye (see compounds 9, 10 and 12). Although no mixture and irradiated inside a borosilicate NMR tube. At
apparent correlation between the structure of the boronic acid different time points, the light was turned off, thereby putting
derivative and their reactivity could be drawn, no reactivity the reaction on hold to conduct a 1H-NMR measurement. Using
shutdown was observed by replacing the iridium-photocatalyst 1,3,5-trimethoxy benzene as an internal standard, it was possible
by Mes-Acr-4.
to determine the yield in the deuterated product (5d) over time.
To more finely compare the two catalysts, a reaction profile Using this method, we were able to conveniently monitor the
of the conjugate addition of the cyclohexyl boronic acid (2) was reaction progress with minimal material usage (0.05 mmol of 2).
recorded by following the reaction using NMR spectroscopy (Fig. 1).
While the two catalysts performed equally after the 24 h of
irradiation (5 in Table 1), we could observe that they do not
share the same reaction profile (Fig. 1). Although the two curves
seem to follow similar initial kinetics, the slope of the Ir-2 curve
suddenly drops after 30 min while the Mes-Acr-4 one continues to
follow a more regular path. We postulated that this behaviour is a
sign of a catalyst deactivation pathway.9 Indeed, radical alkylation
of the pyridyl ligands has already been observed on similar
iridium-based photoredox catalysts.9 Also, 2,20-bipyridyl (bpy)
ligand substitution (of Ir-2) in acetonitrile solvent was identified
as another deactivation pathway for these photocatalysts.10 We
therefore postulated that the strongly nucleophilic DMAP catalyst
can result in bpy displacement on the iridium centre of Ir-2 and
lead to catalyst deactivation. DiRocco demonstrated that the
Mes-Acr-4 catalyst was reasonably stable under similar conditions.6
From this analysis we discovered that the Mes-Acr-4 catalyst brings
faster kinetics than Ir-2 at the same catalyst loading and is
therefore more effective for this reaction.
Table 1 Performance of Mes-Acr-4 against Ir-2 for several radical alkylations
of boronic acid derivatives
Pleasingly, this reaction monitoring also informed us that
the reaction can be completed in 70 min, with this new catalyst.
This relatively short reaction time, combined with the benefits
of microscale on photoreactions,11 motivated us to study the
transferability of this process in a continuous flow reactor.
To facilitate this transfer, we initially compared the reaction
profile observed in the NMR tube (14 W at l = 450 nm) to the
yields obtained in a Vapourtec UV-150 reactor equipped with blue
LEDs (17 W at l = 420 nm). These reactions were performed
individually with different residence times, and the kinetic profile
Isolated yields. Reactions carried out with 0.2 mmol of 6 or 7, 0.8 mmol
of 3, 2 mol% of Mes-Acr-4 and 20 mol% of the indicated Lewis base
(LB). a DMAP was used as a Lewis base. Isolated yield obtained with Ir-2
for the same product in parentheses.
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Scheme 2 Larger scale reaction in photosyn (420 W at l = 450 nm).
Reaction carried out at 0.1 M concentration of 2 in acetone : methanol
(1 : 1) using 2 mol% of Mes-Acr-4 and 20 mol% of DMAP.
photoreactor, we decided to explore its application for effec-
tive active pharmaceutical ingredients synthesis.4a As powerful
approaches using photogenerated a-amino radicals were reported
for the concise synthesis of baclofen13 and pregabalin,14 we were
therefore naturally inclined to test the applicability of the recently
developed methodology for the synthesis of active pharmaceutical
ingredients (API) from the g-amino butyric acid (GABA) family.
This approach uses the Boc-protected amino boronic ester
(16) as the a-amino radical source. This substrate would undergo
our recently developed Lewis base and photoredox dual catalysed
addition to diethyl malonate-derived olefins (17).3b The resulting
coupled product (18) could then be deprotected, hydrolysed and
decarboxylated using aqueous HCl (6 M) and heating to reveal
the amino acid hydrochlorides (19).13 We initially studied the
feasibility of this transformation in batch (Table 2). After a brief
optimisation of the reaction conditions, we could couple the
methyl-amino building block (16) to malonate derived trisubsti-
tuted olefins in high yields (20 to 22). A further excess of 16 and
longer irradiation time (48 h instead of 18 h) was required to
couple the tetra-substituted olefin in acceptable yield (23).
The isolated drug precursors were then subjected to one pot
deprotection, hydrolysis, and decarboxylation using aqueous
HCl. While phenibut was obtained without residual lactam
formation after only 1 h of reflux, the other precursors required
prolonged heating (24 h) to fully hydrolyse their corresponding
Fig. 2 Yield comparison between NMR tube and flow irradiation. Com-
parison between batch (black) and flow (grey) modes. UV-150 (10 mL FEP
coil) and Photosyn (5 mL PFA coil).
proved to be similar (Fig. 2). While observed kinetics for photo-
reactions limited by photon-flux are often significantly different
in a large batch vessel than in the small channels of a photo flow
reactor,11a we observed similar yields after the same time of
irradiation between the two systems.
We hypothesised that the inner diameter (i.d.) of the NMR
tube (i.d. = 5.0 mm) was not large enough compared to the FEP
tubing of the UV-150 coil (i.d. = 1.3 mm) to observe a significant
difference in terms of light absorption efficiency. With these
reaction conditions and using reported data on similar photo-
catalysts,11c approximately 90% of the light is absorbed within
the first 0.3 mm of the solution. Reaction rate could also be
dependent on the mass transfer.11b Nevertheless, as the reaction
following curve obtained via NMR matched with the kinetics
observed in the UV-150 photoreactor (10 mL), we decided to use
the NMR reaction monitoring to predict the residence time
required to reach the full conversion in the flow photoreactor.
As every substrate will require a different irradiation time, we will
be able to circumvent the material- and time-consuming residence
time optimisation on the flow equipment by simulating the
required irradiation time with a single batch experiment.12
To complete this flow photoreactor investigation, we examined
this model reaction in a photoreactor (Photosyn) recently developed
by Uniqsis Ltd and that was made available in our lab for a brief
testing period. The powerful LEDs (420 W at l = 450 nm) equipped
on this reactor allowed faster rates to be observed in a 5 mL
investigation coil (PFA, i.d. = 1.0 mm). This massive power increase
brought the irradiation time necessary to reach 80% yield of 5 from
70 min in the UV-150 reactor to 30 min in the Photosyn. This
significant rate enhancement encouraged us to run a larger scale
experiment on a 50 mL coil (PFA, i.d. = 2.4 mm) using the same
irradiation system (Scheme 2). Pleasingly the results obtained in
the 5 mL coil translated well in the 50 mL coil in which we could
obtain 3.7 g (24.1 mmol, 81% yield) of 5 in 3 h, corresponding to a
Table 2 Application to g-amino butyric acids analogues synthesis in
batch
throughput of 8.0 mmol hꢀ1
With a robust organocatalytic system in hand to activate
.
Isolated yields. Step 1 carried out at 0.1 M concentration of 17 in
a
acetone : methanol (1 : 1). Step 1 deviating from standard conditions,
b
0.60 mmol of 16 and 48 h of irradiation. Step 2 deviating from
boronic acid derivatives and transfer the chemistry in a flow standard conditions, only 1 h of refluxing is necessary.
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Table 3 Application to g-amino butyric acids precursors synthesis in flow
central nervous system drugs from the GABA family in batch
and flow modes.
We are grateful to Novartis Pharma AG (F. L.), Erasmus
Scholarship Scheme (L. G.) and the EPSRC (S. V. L., Grant
No. EP/K009494/1, EP/K039520/1 and EP/M004120/1) for financial
support. We thank Dr Berthold Schenkel and Dr Gottfried
Sedelmeier form Novartis for insightful discussions. We thank
Dr Mark Ladlow (UNIQSIS Ltd, UK) for the loan of the large
scale Photosyn reactor.
Isolated yields. 0.5 mmol scale reaction in UV-150 (17 W at l = 420 nm).
Reaction carried out at 0.1 M concentration of 17 in acetone : methanol
(1 : 1) using 2 mol% of Mes-Acr-4 and 20 mol% of DMAP.
Conflicts of interest
There are no conflicts to declare.
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