Photocatalyzed Transition-Metal-Free Oxidative Cross-Coupling Reactions of Tetraorganoborates**

Article abstract of DOI:10.1002/chem.202005282

Readily accessible tetraorganoborate salts undergo selective coupling reactions under blue light irradiation in the presence of catalytic amounts of transition-metal-free acridinium photocatalysts to furnish unsymmetrical biaryls, heterobiaryls and arylated olefins. This represents an interesting conceptual approach to forge C?C bonds between aryl, heteroaryl and alkenyl groups under smooth photochemical conditions. Computational studies were conducted to investigate the mechanism of the transformation.

Full text of DOI:10.1002/chem.202005282

Accepted Article
Accepted Article
Title: Photocatalyzed Transition-Metal-Free Oxidative Cross-Coupling
Reactions of Tetraorganoborates
Authors: Arif Music, Andreas N. Baumann, Florian Boser, Nicolas
Müller, Florian Matz, Thomas C. Jagau, and Dorian Didier
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To be cited as: Chem. Eur. J. 10.1002/chem.202005282
Link to VoR: https://doi.org/10.1002/chem.202005282
01/2020

10.1002/chem.202005282
Chemistry - A European Journal
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Photocatalyzed Transition-Metal-Free Oxidative Cross-Coupling
Reactions of Tetraorganoborates
Arif Music,[a] Andreas N. Baumann,[a] Florian Boser,[a] Nicolas Müller,[a] Florian Matz,[b] Thomas C.
Jagau[b] and Dorian Didier*[a]
[a]
Dr. A. Music, Dr. A. N. Baumann, B.Sc. F. Boser, Dr. D. Didier
Ludwig-Maximilians-Universität, Department Chemie
Butenandtstraße 5-13
81377 Munich, Germany
E-mail: dorian.didier@cup.uni-muenchen.de
B.Sc. F. Matz, Prof. T. C. Jagau
[b]
KU Leuven, Quantum Chemistry and Physical Chemistry Section
Celestijnenlaan 200f - box 2404
3001 Leuven, Belgium
Supporting information for this article is given via a link at the end of the document.
Abstract: Readily accessible tetraorganoborate salts undergo
selective coupling reactions under blue light irradiation in the
presence of catalytic amounts of transition-metal-free acridinium
photocatalysts to furnish unsymmetrical biaryls, heterobiaryls and
arylated olefins. This represents an interesting conceptual approach
to forge C-C bonds between aryl, heteroaryl and alkenyl groups under
smooth photochemical conditions. Computational studies were
conducted to investigate the mechanism of the transformation.
tunable control over oxidation and/or reduction steps for the
generation of desired reactive intermediates.[17]
Biaryl derivatives constitute an essential class of compounds for
the development of pharmaceuticals and organic materials.[1] The
use of transition metal catalysis to forge C-C bonds between two
aryls has become inevitable, following the pivotal groundwork laid
by Corriu-Kumada-Tamao,[2] Negishi,[3] Suzuki-Miyaura[4] and
Stille[5] in the 1970’s. Although these traditional methods dominate
the world of cross-coupling reactions, modern synthetic planning
also includes direct C-H functionalization[6] and decarboxylative
strategies.[7] Besides, efforts have been made towards
transition-metal-free alternatives using borates as templates for
intramolecular biaryl formation. Few methods depict
homocoupling reactions using chemical oxidants such as
VO(OEt)Cl2,[8] iridium[9] and zinc complexes[10] (Scheme 1A).
Pioneered by Geske in 1959,[11] the formation of symmetrical
biaryls under electrochemical oxidation was extended to
fluorinated substrates by Waldvogel in 2018.[12] However, the
intramolecular coupling of borate salts was restrained to
homocoupling products until very recently (Scheme 1B). Building
on methodologies developed in our group to access
functionalized
organoboron
derivatives,
we
recently
demonstrated an efficient and chemoselective electrochemical
synthesis of unsymmetrical biaryls[13] and heteroarylated
olefins[14] from readily accessible tetraorganoborate salts (TOBs).
The group of Studer similarly reported an elegant chemical
oxidation of mixed tetraorganoborates towards hetero-biaryls
using Bobbitt’s salt.[15]
The renaissance of photochemistry in past decades stems mainly
from the advantageous features it presents and the reactivity it
promotes in comparison with classical chemical processes.[16]
Photoredox catalysis is a rapidly expanding field as it offers a
Scheme 1. Previous and present contributions to coupling reactions of TOBs.
However, only few examples have been reported on the formation
of C-C bonds between two aryl moieties through photoredox
catalysis. The groups of Sanford, Duan and König employed
either transition-metal photocatalysts ([Ru][18] or [Zn]-PDI[19]
1
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complexes), or organophotocatalysts (Eosin Y or PDI)[20] to
reduce diazo-compounds and electron-poor aryl bromides under
photo-irradiation towards intermolecular aryl-aryl bond formation.
The only example of photochemical borate rearrangement was
described by Doty in 1971. Rose Bengal was employed under UV-
light irradiation for the formation of biphenyl (Scheme 1C) from
NaBPh4 through oxygen-relayed electron transfer.[21] The authors
proposed that singlet oxygen is generated in situ, serving as the
oxidizing species in the transformation.
induces a temperature increase to 50 °C (self-heating), allowing to decrease the
reaction time to 16h, see SI.
Conditions were first optimized using mixed tetraarylborate salt
1a. Rhodamine 6G and acridinium-based photocatalysts (Acr)[22]
were tested in the presence of Cl3CBr or oxygen as oxidant,
respectively (Table 1). While rhodamine 6G only gave the desired
product 2a in 45% conversion within 48h under green light
irradiation ( = 530 nm), Acr-1 allowed for its formation in 57%
without oxidant (50% isolated yield). In the presence of oxygen,
the conversion went up to 85% and modifying the substitution
pattern of the photocatalyst (Acr-2 to Acr-4) gave similar results
(82 to 85% conversion). Switching the solvent to ethanol proved
The creation of C-C bonds under photochemical conditions is
therefore largely restricted to specific substrates. Herein, we
challenge the general transition-metal free photocatalyzed
formation of biaryls and arylated olefins, providing innovative
perspectives in the domain of photocatalysis.
less efficient (69% conversion within
8 days). However,
decreasing the catalyst loading to 5 mol% did not alter the rate of
coupling reaction, furnishing 2a in 78% yield after 48h under blue
light irradiation ( = 470 nm). Using a more powerful setup (13
W/cell)[23] allowed to decrease reaction times to 16h, which also
caused an increase in temperature to 50 °C. Importantly, no
traces of intermolecular coupling products were detected in all
cases.
Table 1. Optimization of the photo-coupling reaction.
We previously demonstrated that the first oxidation of a TOB salt
preferentially occurs on the most electron rich unsaturated
moiety.[13,14] As a logical consequence, structures 1 were
designed to possess one electron-richer aryl group (Ar1),
surrounded by electron-poorer groups (Ar2). With optimized
conditions and setup in hands, we started evaluating the scope of
the aryl-aryl photocoupling (Scheme 2). Worthy of note,
tetraarylborate salts were accessed ex-situ by reaction of an
aryltrifluoroborate species with the appropriate Grignard (or zinc)
reagent and were engaged further without purification. The yields
in Scheme 2 are therefore given for the two-step sequence. In the
presence of Acr-1 under blue light irradiation, we were able to
push the conversion to its maximum for the formation of biphenyl
2b (91%), showing great improvement in comparison with the
conditions previously described by the group of Doty (75% under
UV irradiation). Varying the substitution pattern of Ar1 by
introducing methyl, trimethylsilyl and ether moieties led to
structures 2c-j in good to excellent yields (up to 92%). Scaling up
the reaction to 3 mmol also gave 2h in a reasonable yield (77%).
Interestingly, these conditions allowed for an efficient coupling of
unprotected phenol derivatives 2k-l in up to 83% isolated yield,
verifying the functional group tolerance of the method. Amides
and nitriles also proved tolerable (2m-n), although lower yields
were obtained (47 to 53%). This can be attributed to the lower
reactivity of organozinc reagents (necessary for the tolerance of
amides and nitriles) towards starting trifluoroborates in the initial
formation of TOB salts. Electron-rich heteroaryls such as
benzoxadiazole and benzofurans were successfully coupled,
yielding compounds 2o-r (up to 70%). The transformation of
electron-poor pyridyl and quinolyl TOB derivatives proved more
difficult to achieve and compounds 2s-t were only isolated in up
to 56% yields. However, the presence of dibenzofurans as Ar2
groups led to 78% of coupling product (2u). Functionalization of
the pharmacologically relevant celecoxib structure gave 2v in
38% yield. The photocoupling reaction of sensitive halogenated
and pseudo-halogenated scaffolds was examined next, as they
open the possibility for further functionalization. While classical
cross-coupling methods usually give complex mixtures of
products through uncontrolled oxidative additions,[24] we have
previously demonstrated that an electrochemical process can be
Photocatalyst
Deviation from conditions
Conversion[b]
(Isolated yield)
Rhodamine 6G
Acr-1
Cl3CBr instead of O2,  = 530 nm
45%
without O2
57% (50%)
85% (77%)
69%
Acr-1
none
Acr-1
EtOH instead of MeCN, 8 days
Acr-2
none
82%
Acr-3
none
83%
Acr-4
none
85% (78%)
85% (78%)
91% (83%)
Acr-1
5 mol% catalyst loading
5 mol% cat., 50 °C, 16h[c]
Acr-1
[a] Control experiments show no conversion of starting material in the absence
[b]
of photocatalyst or light (see SI).
undecane as internal standard.
Conversions determined by GC using n-
Switching to a more powerful LED setup
[c]
2
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employed to gain control over the formation of desired
functionalized compounds.[13]
Scheme 2. Scope of the photo-coupling of TOBs. [a] Borate salts were generated in-situ from the corresponding organotrifluoroborates and organomagesium species.
[b] Yields are given over two steps, see SI. [c] Photocoupling was conducted on pure, isolated salts. [d] Prepared from organozinc reagents.
Remarkably, iodinated and brominated substrates were tolerated
under our photocatalyzed conditions, furnishing halogenated
biaryls 2w-2z in up to 69% yield. Nitrile-substituted trifluoroborate
substrates were also used in this two-step sequence, leading to
structures 2aa-ab in moderate yields (47 to 63%).
yield and similar conditions to the ones used for biaryl formation
only pushed the conversion to 65% (Table 2).
Table 2. Optimization of the photo-olefination reaction.
Having supported the proof of concept for photocoupling
reactions with a broad scope of biaryl products, we set out to
examine olefinations under similar conditions, as those would
provide an interesting alternative for the formation of styryl
derivatives. Model substrate 3a was employed for optimizations,
assuming that the oxidation of the alkenyl substituent would be
preferred over the remaining aryl groups.[14] Performing the
reaction with 5 mol% of Acr-1 without oxidant afforded 4a in 35%
Conversion[a]
(Isolated yield)
Conversion[a]
(Isolated yield)
oxidant
oxidant
3
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More than adding synthetic interest to the method, these findings
indicate that the oxidant plays an essential role in the
transformation and its associated catalytic cycle. In contrast to the
work from Doty, our different set of conditions leads us to believe
that oxygen plays a role in the re-oxidation of the catalyst, rather
than in the oxidation of the substrate itself. We therefore propose
a reaction mechanism in which the oxygen is implicated as the
oxidant that enables the catalyst regeneration (Scheme 4). Blue
light irradiation (470 nm) allows for the acridinium to reach its
active, excited state to abstract an electron from substrate 1a. The
O2
65% (<10%)[b]
PhSSPh
K2HPO4
57% (40%)
73% (57%)
none
45% (35%)
[a] Conversions determined by GC.[b] The epoxide 5a (from 4a) was isolated, see
Scheme 3.
However, the main product was found to be the overoxidized
epoxide 5a (see Scheme 3). Diphenyldisulfide did not improve the
conversion of 3a, and dipotassium phosphate furnished 4a in 57%
isolated yield (73% conversion of 3a). These last conditions (cond.
A, Scheme 3A) were therefore used in the exploration of the
reaction scope. -styryl moieties were evaluated first, providing
(E)-bisarylated olefins 4a-e with up to 57% yield. Interestingly,
engaging (E)- alkenyl substrates led to the stereospecific
formation of products (E)-4 under thermodynamic control. Cyclic
olefins 4f-j were synthesized next, although conversions were
generally lower than for acyclic ones, with the exception of 4i
(69% isolated yield). When oxygen was used instead of K2HPO4,
trans-epoxides 5a and 5b were formed in up to 54% yield.
.
resulting oxidized species [1a ] undergoes a pseudo 1,2-metallate
rearrangement,[13,14] giving the cyclic intermediate 6, which further
opens towards 7 through [TS]#. Oxygen further intervenes to
regenerate the photocatalyst from its reduced form, producing
.
[O2] -.[25] As witnessed in the reaction of alkenyl derivatives, we
know that oxygen interacts with the intermediates to produce the
corresponding epoxides. In consequence, we advance that an
active oxygen species reacts with 7 to promote an elimination
reaction towards the formation of 2a.
Scheme 4. Theoretical studies and proposed mechanism.
To assess a plausible reaction path, we performed a series of
density functional theory calculations on 1a using the software Q-
Chem[26] with the B3LYP functional[27] and the 6-31G* basis set.
Here we determined equilibrium structures and computed the
.
Gibbs free energies for the initial anion 1a and radical [1a ] as well
as for the radicals 6 and 7. We found a transition state between 6
and 7 at a barrier height of 50 kJ·mol-1 as depicted in Scheme 4.
This completes the picture of the reaction mechanism: the
oxidation of the anion is followed by a relaxation during which the
reacting six-membered rings rotate to face each other, therefore
Scheme 3. Photo-olefination of alkenylborates. [a] Borate salts were generated
[b]
in-situ from the corresponding organotrifluoroborates. Yields are given over
two steps, see SI. [c] Photocoupling was conducted on pure, isolated salts.
4
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rotationally averaging over the atomic positions of the methoxy
group. During the reaction, the B-C bond is cleaved while the C-
C bond is formed. The CS symmetry is maintained while the bond
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transition state is 60° and shrinks further while the tetrahedral
coordination at the carbon atom in the oxidized ring is restored.
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chemoselective coupling of tetraorganoborates using organo-
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under blue light irradiation, in a simple and practical setup. A
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Acknowledgements
D.D., A.M and A.N.B. are grateful to the Fonds der Chemischen
Industrie, the Deutsche Forschungsgemeinschaft (DFG grant: DI
2227/2-1), the SFB749 and the Ludwig-Maximilians University for
PhD funding and financial support. F.M. is grateful to the
European Union for co-funding by the Erasmus+ program. T.C.J.
gratefully acknowledges funding from the European Research
Council (ERC) under the European Union’s Horizon 2020
research and innovation program (Grant Agreement No. 851766).
Prof. Christof Sparr and his group are kindly acknowledged for
supplying some of the acridinium photocatalysts used in this
project. We thank Dr. Marcel Leroux for helping designing the
photochemical reactor.
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Keywords: cross-coupling • organoborates • photocatalysis •
oxidation • hetero-coupling
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[6]
5
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Entry for the Table of Contents
Shining light on organoborates: A photocatalyzed oxidative cross-coupling reaction of functionalized organoborates is described,
providing a diverse range of biaryl and olefin products. The mechanism of this C-C bond formation was investigated through quantum
chemical calculations, revealing an unusual boracyclic intermediate.
Institute and/or researcher Twitter usernames: @didier_group
6
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