Visible-Light-Induced Nickel-Catalyzed Negishi Cross-Couplings by Exogenous-Photosensitizer-Free Photocatalysis

Article abstract of DOI:10.1002/anie.201802656

The merging of photoredox and transition-metal catalysis has become one of the most attractive approaches for carbon–carbon bond formation. Such reactions require the use of two organo-transition-metal species, one of which acts as a photosensitizer and t

Full text of DOI:10.1002/anie.201802656

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Accepted Article
Title: Visible Light-Induced Nickel-Catalyzed Negishi Cross-
Coupling. A New Approach to Exogenous Photosensitizer-free
Photocatalysis.
Authors: Jesus Alcazar, Angel Diaz-Ortiz, Antonio de la Hoz, M.
Victoria Gomez, Alberto Fontana, and Irini Abdiaj
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802656
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10.1002/anie.201802656
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Visible Light-Induced Nickel-Catalyzed Negishi Cross-Coupling. A
New Approach to Exogenous Photosensitizer-free
Photocatalysis.
Irini Abdiaj,[a] Alberto Fontana,[a] M. Victoria Gomez,[b] Antonio de la Hoz[b] and Jesús Alcázar*[a]
Dedication ((optional))
Abstract: The merging of photoredox and transition-metal catalysis
has become one of the most attractive approaches for carbon-carbon
bond formation. The procedure requires the use of two transition
organometallic species, one of which acts as a photosensitizer and
the other as a cross-coupling catalyst. We report here a new
exogenous photosensitizer-free photocatalytic protocol that allows the
formation of carbon-carbon bonds by direct acceleration of the well-
known nickel-catalyzed Negishi cross-coupling using two naturally
abundant metals. This finding will open new avenues in cross-
coupling chemistry involving the direct visible light absorption of
organometallic catalytic complexes.
Initially, we selected methyl 4-bromobenzoate 2 and benzylzinc
bromide 1 as coupling partners and ran the reaction in the
presence of 1 mol % of iridium photocatalyst and 2 mol % of nickel
coupling catalyst in batch. There was clear evidence for the
formation of the expected product in the crude mixture (see
supporting information). Photochemical reactions are often
enhanced on using flow[15,16] and it was therefore decided to apply
this technology (Table 1). As anticipated, a higher conversion
was achieved in flow than that detected in batch (entry 1). Control
reactions were carried out in an effort to determine whether this
process was driven by temperature or light. To our surprise, while
irradiation was essential for the reaction (entry 3), the use of a
photocatalyst was not (entry 2). A temperature of 60 ºC was
required to achieve full conversion (entry 4). The use of our flow
protocol for the formation of the organozinc derivative,[12] instead
of the commercially available reagent, also led to full conversion,
but in the absence of light a conversion of 78% was obtained
(entry 5), so the thermally driven process was much higher for our
zincate than for the commercial one.
The development of carbon-carbon bond formation through
transition-metal mediated cross-coupling chemistry has changed
the way that organic synthesis is carried out.[1,2] More recently, the
advent of dual catalysis, where organometallic catalysis is
combined with a photosensitizer, has opened new avenues in
C(sp3)–C(sp2) bond formation.[3-5] However, the photocatalyst
used is based on rare metals, such as ruthenium or iridium
complexes, and this makes the protocols less suitable and
sustainable for scalability purposes. Different alkyl boron,[6,7]
ammonium alkylsilicates,[8] O-benzyl xanthates[9] and -
heteroatom-containing carboxylic acids[10] have been used to
promote the formation of nucleophilic alkyl radicals.
Baran’s group recently reported the use of organozinc derivatives
in combination with light for C(sp3)–C(sp2) coupling but, as
reported by the authors, the reaction is a pure thermal process
and light did not add value to the reaction.[11] Beyond this article,
other reports on the use of organozinc reagents in
a
photochemical reaction have not been published to date.
Considering the lack of knowledge about the behavior of these
intermediates in photochemical processes and given our
experience in organozinc chemistry,[12-14] we decided to explore
the use of these reagents in dual catalysis as a replacement for
other organometallic reagents reported previously (Figure 1).[6-8]
Figure 1. Comparison of dual catalysis with light induced Negishi coupling.
To reduce the effect of the thermal component of the reaction, we
selected 4-bromoanisole as a coupling partner, a substrate that
has not been described in Negishi couplings using nickel as
catalyst. Using the commercially available reagent no reaction
was observed (see supporting information). Nevertheless, on
using the flow zincate, a conversion of 53% was achieved with
2% catalyst loading (entry 7) and full conversion was achieved
when the catalyst loading was increased to 5% (entry 8). The
same conditions in the absence of light provided the compound
with 55% conversion (entry 9).
[a]
[b]
Irini Abdiaj, Alberto Fontana and Jesús Alcázar
Oncology & Discovery Chemistry
Janssen Research and Development, Janssen-Cilag, S.A.,
Jarama 75A, 45007 Toledo (Spain)
E-mail: jalcazar@its.jnj.com
Mº Victoria Gomez and Antonio de la Hoz
Facultad de Ciencias Químicas
Universidad de Castilla-La Mancha
Av. Camilo José Cela 14, 13005 Ciudad Real, Spain
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Even though the difference in conversion between the pure
thermal Negishi and the new light-driven reaction was only 45%,
we considered it sufficient to follow the conversion in flow at
different time points either in the presence or absence of light (see
Figure S1 in supporting information). This experiment proved the
reaction is accelerated in the presence of light and that this
It is important to highlight the ability of chloroarenes to participate
in this reaction, since these coupling partners have only rarely
been described in the literature in this context.[17] The case of
compound 19 clearly illustrates the value of the new protocol,
where irradiation with light became key to achieve a good yield of
the expected product when the chloroarene was used. It is also
acceleration is particularly marked at the beginning of the reaction. important to highlight that compound 23 can only be obtained in
Based on the findings outlined above, the scope of the reaction
was further explored by varying both reagents (Figure 2). This
study was focused on bromo- and chloroarenes as they are rarely
used in nickel-catalyzed Negishi cross-couplings.[17] To obtain
comparable results, the reactions were performed under the
same conditions either in presence or absence of light.
the presence of light. In order to demonstrate the value of this
methodology in a medicinal chemistry setting, compounds 25 and
26 were prepared using the corresponding chlorotriazolopyridine
core previously described in a series of compounds with activity
as positive allosteric modulators of the metabotropic glutamate
receptor 2, but never reported in a Negishi cross-coupling.[18-22]
Both examples clearly benefited from the light protocol and the
products were obtained in good to excellent yields, whereas little
or no conversion was observed in the absence of light. This
finding will be key to introduce C(sp3)-enriched motifs that could
improve physicochemical parameters such as solubility.[23,24]
Table 1. Optimization of the flow reaction.
Entry
T (ºC)
R
Irradiation
Photocatalyst
Conv.
(%)
1
2
3
4
5
6
7
8
40
40
40
60
60
60
60
60
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
MeO
450 nm
450 nm
----
fac-Ir(ppy)3
64
----
----
----
----
----
----
----
70
4
450 nm
----
100
78[a]
0
450 nm
450 nm
450 nm
MeO
53[a]
MeO
100[a,
b]
9
60
MeO
----
----
55[a,b]
Figure 2. Scope of organozinc and haloarene coupling partners in the light-
induced nickel-catalyzed Negishi coupling. Conversions by liquid
chromatography. Isolated yields in brackets. *Reactions run with 2 mol %
catalyst. See supplementary information for more details..
[a] Organozinc prepared in flow. [b] 5 mol % of nickel catalyst used.
Compounds with electron-withdrawing groups only required 2
mol % of nickel. The effect of the light on the reaction is specially
highlighted when strong electron-donating groups were present in
the molecule, compounds 8 and 10, where conversion rocketed
in the presence of light. Iodo-derivatives were also suitable but a
strong donating group, such as a free amino group, is required to
observe remarkable difference between the light irradiated and
thermal reactions (e.g., compound 18). The protocol is also
applicable to different alkylzinc reagents, either freshly prepared
or commercially available, beyond benzyl analogues, for instance
compounds 6, 7 and 12.
Preparation of compound 16 was selected to demonstrate the
scalability of the protocol. Organozinc preparation was carried out
in flow and the exiting stream was connected to a second solution
stream containing the haloarene and the catalytic complex before
entering in the photoreactor (see Figure S9 in supporting
information). This process was run continuously for 8 h and
compared with the same reaction in batch, by sampling at
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different timepoints (see Figure S10 in supporting information).
The flow protocol provided 6.7 g of isolated product (93% isolated
yield), with a productivity of 800 mg·h–1. In contrast, only a 39% of
isolated yield was achieved in batch. Considering the time and
reaction volumes, the space/time yield[25,26] was calculated and
this clearly favors the new flow process (see table of Figure S10
in supporting information).
Considering the spectra of Figure 3, preparation of compound 1a
was performed at different wavelengths to determine the effect on
the reaction outcome. The best conversion was obtained when
the reaction mixture was irradiated at 450 nm (blue light). Lower
conversions were achieved when the reaction was irradiated
either at 360 nm (black light) or 520 nm (green light) (see table S8
in supporting information). These results are consistent with the
absorption spectra.
Regarding the mechanism of the reaction, it is important to note
that
visible
light-induced
transition
metal-catalyzed
Key aspects for dual catalysis and light-induced reactions are the
single electron transfer processes (SET) and the formation of
radicals. In this respect, different reactions were carried out to
identify the presence of such radicals. However, conclusive
results were not obtained in these experiments (see Table S7 in
supporting information). Either traps reacted with the organozinc
derivative in the absence of catalyst or light, so the reaction was
quenched because of the reactivity of the zincate, or no trapping
was observed. Rearrangements of radical probes, also known as
radical clocks, cannot be used in the reaction discussed here as
radicals had been detected during the organozinc formation in
batch.[28] The use of flow did not make any difference in this
respect (see supporting information). None of the assays
provided suitable data to support the presence of radicals during
the coupling process, although the absence of radicals cannot be
ruled out.
transformations are known in literature and have been recently
reviewed.[27] Metals used for this reaction include cobalt, iron,
copper, palladium, gold and platinum. However, nickel has not
been described for this chemistry. The initial approach to clarify
the light induction of the reaction was the study of UV-visible
spectra for each component of the reaction and different mixtures.
It was found that only when the catalytic complex was mixed with
the organozinc reagent was a broad band observed in the visible
region (Figure 3). When NiCl2, i.e., Ni(II), was replaced by
Ni(COD), Ni(0), absorption in the visible region was not observed
and this demonstrates the need for nickel(II) species for light
absorption.
With the aim of shedding additional light on the mechanism of the
reaction, NMR spectroscopy was employed as an analytical tool
given its potential to elucidate molecular structures. The aim was
to study the reaction for the synthesis of compound 9 following
the signal of the trifluoromethyl group close to the reactive site by
19F NMR spectroscopy. The laser-diode based illumination device
previously reported by us[29] was used to activate the reaction
mixture in a 5 mm-NMR tube for in situ NMR monitoring.[30]
Reaction mixtures were freshly prepared and transferred quickly
to a 5 mm-NMR tube to record the 19F NMR spectrum.
Consecutive NMR experiments were recorded as a function of
monitoring time and light was switched on or off at different
monitoring times (see supporting information for more details of
the NMR experiments).
To try to detect the intermediate that is absorbing in the blue
region (Figure 3), a very rapid addition of equimolar amounts of
zincate derivative and nickel complex in an NMR tube allowed us
to see a new signal in the spectrum at -61.0 ppm. It should be
noted that the new signal is deshielded and appears around 2
ppm downfield from the signal of the original zincate, indicating a
reduction in the electron density on this reagent. The analysis of
consecutive NMR experiments turning the light on and off showed
that this signal is decreasing only in the presence of light (Figure
4, left). As this signal is decreasing in intensity, the signal
corresponding to dimer 28 clearly increased and followed the
same pattern observed for previous intermediate (Figure 4, right).
It has been widely reported that dimerization of organozinc
reagents is linked to the reduction of Ni(II) precatalyst to Ni(0) as
the first step to form the real catalytic complex.[17,31] The results
from this experiment demonstrated that this step is clearly
accelerated in the presence of light. Similar acceleration for the
Figure 3. Absorption spectra of mixtures of nickel complexes with the
organozinc reagent. Evolution of the absorption recorded over 20 minutes.
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conversion of Pd(II) to Pd(0) has been observed in light-induced
Heck reactions.[32,33]
approach in other bimetallic reactions is currently ongoing in our
laboratories.
Acknowledgements
The project leading to this application has received funding from
the European Union’s Horizon 2020 research and innovation
program under the Marie Sklodowska-Curie grant agreement No
641861. We also acknowledge financial support from the Spanish
MINECO (CTQ2017-84825-R). M.V.G. thanks MINECO for
participation in the Ramón y Cajal program (RYC2007-14768).
Keywords: Photocatalysis • Visible light • Negishi coupling •
C(sp3)–C(sp2) coupling • Flow Chemistry
Figure 4. Effect of light in the degradation of an intermediate signal and in the
acceleration of the formation of dimer 28. Green arrows mark when the light was
turned on and orange arrows when the light was turned off.
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I. Abdiaj, A. Fontana, M. V. Gomez, A.
de la Hoz and J. Alcázar*
Page No. – Page No.
Visible Light-Induced Nickel-
Catalyzed Negishi Cross-Coupling. A
New Approach to Exogenous
Photosensitizer-free Photocatalysis.
Visible acceleration: This new photocatalytic process involving two naturally
abundant metals expands the current scope of both Negishi and dual catalysis
cross-couplings. The methodology is applicable to drug discovery and scalable to
multigram amounts.
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