Continuous Flow Synthesis of [Au(NHC)(Aryl)] (NHC=N-Heterocyclic Carbene) Complexes

Article abstract of DOI:10.1002/chem.202102379

The use of weak and inexpensive bases has recently opened promising perspectives towards the simpler and more sustainable synthesis of Au(I)-aryl complexes with valuable applications in catalysis, medicinal chemistry, and materials science. In recent years, continuous manufacturing has shown to be a reliable partner in establishing sustainable and controlled process scalability. Herein, the first continuous flow synthesis of a range of Au(I)-aryl starting from widely available boronic acids and various [Au(NHC)Cl] (NHC=N-heterocyclic carbene) complexes in unprecedentedly short reaction times and high yields is reported. Successful synthesis of previously non- or poorly accessible complexes exposed fascinating reactivity patterns. Via a gram-scale synthesis, convenient process scalability of the developed protocol was showcased.

Full text of DOI:10.1002/chem.202102379

Communication
doi.org/10.1002/chem.202102379
Chemistry—A European Journal
Continuous Flow Synthesis of [Au(NHC)(Aryl)] (NHC=N-
Heterocyclic Carbene) Complexes
Thibault Cauwenbergh,[a] Nikolaos V. Tzouras,[a] Thomas Scattolin,[a] Subhrajyoti Bhandary,[a]
Andreas Simoens,[b] Kristof Van Hecke,[a] Christian V. Stevens,*[b] and Steven P. Nolan*[a]
handling of the associated metal complexes have rendered
Abstract: The use of weak and inexpensive bases has
recently opened promising perspectives towards the sim-
them indispensable in modern organic synthesis.[6]
Simple synthetic access to gold-aryl complexes has long
pler and more sustainable synthesis of Au(I)-aryl complexes
been hampered by the requirement for inert conditions, high
with valuable applications in catalysis, medicinal chemistry,
temperatures, toxic solvents or multistep procedures alongside
and materials science. In recent years, continuous manufac-
limited functional group tolerance.[4a,7] In a recent report, we
turing has shown to be a reliable partner in establishing
have disclosed an operationally simple and mild procedure for
sustainable and controlled process scalability. Herein, the
the synthesis of various NHC- and phosphine-bearing Au(I)-aryl
first continuous flow synthesis of a range of Au(I)-aryl
complexes.[8] This protocol revolves around the use of a weak
starting from widely available boronic acids and various
[Au(NHC)Cl] (NHC=N-heterocyclic carbene) complexes in
unprecedentedly short reaction times and high yields is
reported. Successful synthesis of previously non- or poorly
base such as K2CO3 allowing for room temperature synthesis in
air using green solvents (e.g. acetone, ethanol, ethyl acetate or
water). The efficacy of this so-called weak base route has been
demonstrated in the synthesis of various other valuable
accessible complexes exposed fascinating reactivity pat-
transition metal complexes as well.[5a,9]
terns. Via
a gram-scale synthesis, convenient process
Notwithstanding the many assets brought about by the
weak base approach, reactivity issues remain the largest
concern. Reaction times may easily amount up to 20 h while
only substantial excesses of base allow for reaching full
conversion to the product. As evidenced by recent reports on
the synthesis of [Cu(NHC)Cl] and [Cu(IPr)(Cbz)] (Cbz=carbazol-
yl), mechano-chemistry might assist in lowering reaction times
yet multiple equivalents of base are still required to reach full
conversion.[9f,10]
Continuous flow synthesis is considered an attractive
alternative to traditional batch synthesis, not in the least as it
represents an ideal tool in the pursuit for more sustainable
chemical processes.[11] Mainly as a direct consequence of small
reactor dimensions, continuous manufacturing has much to
offer. Efficient heat and mass transfer allow for reduced reaction
times, enhanced product selectivity and a lowered energy
demand.[12] Precise control over reaction parameters is enabled
through simple reaction automation and in situ monitoring, all
increasing product quality, ensuring greater operational safety,
and a reduction in waste generation.[13]
scalability of the developed protocol was showcased.
Gold-aryl complexes occupy a prominent place in the panorama
of organometallic compounds owing to their involvement in
many gold-catalyzed reactions, both as efficient pre-catalysts as
well as reactive intermediates.[1,2] In addition, various gold-aryl
derivatives have found application in the fields of medicinal
chemistry and materials science by virtue of their fascinating
bioactive and photophysical properties.[3,4] In recent years, N-
heterocyclic carbenes (NHCs) have emerged as powerful
ancillary ligands in the stabilization of organometallic com-
plexes and have thereby successfully secured their place among
their illustrious phosphine counterparts. Their large structural
diversity and rich coordination behavior to various transition
and main group elements have made them important tools in
organometallic chemistry.[5] Increased stability and ease of
We have recently developed an operationally simple and
readily scalable continuous flow procedure for the preparation
of NHC-supported copper, gold and palladium complexes from
the imidazolium salt and appropriate metal source.[14] A solution
of the corresponding -ate complex in technical grade acetone
was hereto injected into a packed bed reactor charged with
triturated K2CO3, yielding the desired product in no time.
Fostered by these fascinating results, we were incited to extend
this protocol to the synthesis of various other organometallic
species. In the present work, we report the continuous flow
synthesis of a range of gold(I)-aryl complexes, to further
evaluate the efficacy of the developed setup (Scheme 1).
[a] T. Cauwenbergh, N. V. Tzouras, Dr. T. Scattolin, Dr. S. Bhandary,
Prof. Dr. K. Van Hecke, Prof. Dr. S. P. Nolan
Department of Chemistry and Centre for Sustainable Chemistry
Ghent University
Krijgslaan 281, S3, 9000 Ghent (Belgium)
E-mail: steven.nolan@ugent.be
[b] A. Simoens, Prof. Dr. C. V. Stevens
Department of Green Chemistry and Technology Synthesis
Biosources and Bioorganic Chemistry (SynBioC) Research Group
Ghent University
Coupure Links 653, 9000 Ghent (Belgium)
E-mail: chris.stevens@ugent.be
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202102379
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Chemistry—A European Journal
negatively affects reaction yields. One simple way to circumvent
the latter is to increase the solubility by using a co-solvent. THF
was chosen as the most suitable solvent for this purpose given
the enhanced solubility of the studied complexes, as generally
observed in batch. As exemplified by the synthesis of complex
3a, results have however indicated that 2-MeTHF and acetone,
generally considered as greener alternatives to THF, perform
equally well (Entries 7 and 8, Table 2).[15] Parameter optimization
for the synthesis of [Au(IPr)Ph] (2) showed that low temper-
°
atures (30 C) or short residence times (2 minutes) can be
established with preservation of high reaction yields (Entries 4–
6, Table 1).
Batch conditions have revealed the propensity of some
boronic acid reagents to undergo protodeboronation, referring
to undesired protonolysis of organoborane compounds in the
presence of a proton source.[16] Especially reactions performed
at high temperatures in an acidic or alkaline medium prove
problematic. In this context, boronate esters have shown to be
less prone to protonolysis reactions and are therefore fre-
quently applied in batch synthesis where long reaction times
are typically required.[8a,17] For the synthesis in continuous flow,
no notable signs of side-reactivity were observed, indicating
that – even though the reagents are exposed to an extremely
large base excess – the short residence times prove beneficial
in suppressing protodeboronation. Nonetheless, the synthesis
of [Au(IPr)Ph] was tested starting from the boronic acid pinacol
ester (BPin) as a comparison to the reaction performed with the
analogous boronic acid (Entries 2–3, Table 1). Reaction condi-
Scheme 1. Batch and reported continuous flow protocol for the synthesis of
[Au(NHC)Ar] (Ar=aryl).
As a general proof-of-concept, the continuous transmetala-
tion of [Au(IPr)Cl] (1) and phenylboronic acid was attempted.
°
Reaction in acetone with a residence time of 5 minutes at 60 C
resulted in a low conversion to the product (Entry 1, Table 1).
Changing the solvent to ethanol gave access to the desired
product in a 100% conversion (Entry 2, Table 1). Even though
ethanol is a greener alternative to acetone, there are several
issues related to its use in the continuous flow synthesis
protocol reported here. First, changing the solvent to ethanol
entails
a considerable increase in viscosity (1.095 cP as
°
compared to 0.316 cP for acetone, measured at 300 K). For
microreactors of any type, this implies a significant pressure
buildup with all associated process-related consequences. These
issues can partly be addressed by using more durable, yet also
more expensive, equipment. Most importantly, the reported
starting materials and products are only sparely soluble in
ethanol. While being of no major concern to the batch process,
suspensions are inherently incompatible with continuous flow
technology, mainly due to the risk of reactor clogging. Besides
these inconveniences – which are of mere practical nature –
product might be retained on the packed bed column, which
tions of 5 minutes residence time at a temperature of 60 C only
resulted in a conversion of 43%. The lower reactivity of the
associated pinacol boronate ester requires longer reaction times
and higher temperatures. Faster reactions, milder conditions
and a lower reagent cost all favor the boronic acid approach, a
clear asset provided by continuous flow synthesis.
Encouraged by the results obtained for complex 2, the focus
was directed to the synthesis of the gold(I) complex 3a bearing
an electron-donating methoxy group in the para position, a
valuable precursor in the synthesis of various active gold
Table 2. Optimization of the continuous flow protocol.
Table 1. Optimization of the continuous flow protocol.
Entry[a] Co-sol-
vent[b]
T
Residence Time Conversion Isolated
Entry[a] Solvent
T
Residence Time
Conversion Isolated Yield
°
[ C] [min]
[%]
yield [%]
°
[ C] [min]
[%]
[%]
1
THF
THF
THF
THF
THF
THF
60
60
60
45
30
30
5
2
2
2
5
2
2
2
100
100
100
100
100
65
77
79
82
89
77
–
88
[b]
1
Acetone 60
5
18
–
2
3[c]
4
2
EtOH
EtOH
EtOH
EtOH
EtOH
60
60
30
50
40
5
5
5
2
2
100
43
95
-
3[c]
4
[b]
100
100
45
86
5
6
[d]
5
6
96
[b]
–
7
8
2-MeTHF 60
Acetone 60
100
100
90
[a] Conditions unless otherwise stated: [Au(IPr)Cl] (31 mg, 0.05 mmol),
Phenylboronic acid (1.1 equiv.), 5 mL of solvent (1:1 EtOH/THF). [b]
Incomplete conversion. [c] From the corresponding pinacol acid boronic
ester.
[a] Conditions unless otherwise stated: [Au(IPr)Cl] (31 mg, 0.05 mmol), 4-
methoxyphenylboronic acid (1.1 equiv.), 5 mL of solvent. [b] EtOH (eluent).
[c] 4-methoxyphenylboronic acid (1.0 equiv.). [d] Incomplete conversion.
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complexes.[8a,18] The established conditions allowed access to
the product in full conversion, except for the mildest reaction
acids gave clean access to the desired complex under the
established conditions (4). Electron-deficient boronic acids have
shown to be compatible as well (5). Complex 5 could both be
accessed through reaction with the boronic acid as the boronic
acid neopentyl glycol ester in comparable yields, under the
same set of reaction conditions. Additionally, a series of
polyaromatic hydrocarbon (PAH) ligated complexes has been
synthesized (6 to 8). Due to the presence of extended π-
conjugation, these complexes are photochemically active – or
are expected to be – and are therefore valuable in the field of
OLED technology.[5b–d,19]
The compatibility of a series of supporting NHC ligands was
assessed in a next stage (Scheme 3). Complex 3b bearing a
carbene ligand with a saturated backbone was obtained in a
70% yield. Other complexes bearing aromatic NHCs with
distinctly different steric surroundings were cleanly obtained
under the established reaction conditions (3c and 3d). As a last
example, complex 3e stabilized by the electron rich N-
adamantyl-substituted NHC was obtained in appreciable yields.
Complex 3d bearing the highly sterically encumbered IPr*
(N,N’-bis-[2,6-bis(diphenylmethyl)-4-methylphenyl]imidazol-2-yl-
idene) was synthesized for the first time and its X-ray molecular
structure is depicted in Figure 1. Its synthesis has already been
attempted using the weak base route under traditional batch
conditions, yet we could only obtain maximal conversions of
90%. When compared to related complexes reported in the
literature, complex 3d has a CNHC-Au bond length which is on
average smaller while the Au-CAr bond length is elongated.[8a]
The bond angle about the gold center is comparable to the one
reported for [Au(IAd)(C6H5)] which is slightly larger than is the
case for complexes such as [Au(IPrCl)(C7H7O)] or [Au-
(ItBu)(C7H7O)].
°
conditions of 2 minutes residence time at 30 C (Entry 6,
Table 2). In contrast with the established batch conditions,
adding an equimolar amount of 4-methoxyphenyl boronic acid
still resulted in full conversion to the desired product (Entry 3,
Table 2). Next, a gram synthesis of complex 3a was performed
to assess the scalability of the reported continuous flow setup.
Over the course of 2 h, 1.075 g of product was obtained in a
near quantitative yield (96%), indicating that continuous flow
synthesis can easily rival the batch process. Even though the
latter allows for the synthesis of larger amounts of product at
once, reaction times are significantly longer as compared to the
reported continuous flow process.[8a]
To explore the versatility of the continuous flow setup in
synthesizing gold(I)-aryl complexes, the boronic acid scope was
further expanded (Scheme 2). Sterically demanding boronic
Scheme 2. Scope of boronic acid reagents used in this study.
Figure 1. X-ray molecular structure of [Au(IPr*)(C7H7O)] (3d) showing thermal
displacement ellipsoids at the 50% probability level, hydrogen atoms
omitted for clarity (CNHC-Au=2.026(3) Å, Au-CAr =2.052(3) Å, CNHC-Au-
[20]
°
Scheme 3. Scope of N-heterocyclic carbene ligands used in this study.
C
Ar =178.73(1) ) CCDC: 2093663.
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Chemistry—A European Journal
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In conclusion, we have developed an operationally simple
procedure for synthesizing Au(I)-aryl complexes in continuous
flow. Parameter optimization for the synthesis of complexes 2
and 3a indicated that very short residence times and low
reaction temperatures suffice to reach full conversion to the
product. Therefore, the targeted Au(I)-aryl complexes can be
accessed in unprecedentedly mild conditions, which was
showcased in the large-scale preparation of complex 3a.
Through variation in the nature of the supporting NHC ligand
and the boronic acid substrate, we demonstrated the versatility
of the outlined procedure. Studies regarding the implementa-
tion of the developed continuous flow setup in the synthesis of
other valuable complexes are ongoing in our laboratories.
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Acknowledgements
We are grateful to the SBO (D2M to SPN) and the BOF (starting
and senior grants to SPN) as well as the iBOF C3 project for
financial support. The Research Foundation – Flanders (FWO) is
also gratefully acknowledged for a Fundamental Research PhD
fellowship to NVT (11I6921N) and project 1275221N to SB and
KVH. Umicore AG is gratefully acknowledged for generous gift
of materials.
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Keywords: continuous-flow synthesis
heterocyclic carbenes · sustainability · weak-base routes
·
gold(I)-aryl
·
N-
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Manuscript received: July 1, 2021
Accepted manuscript online: July 29, 2021
Version of record online: ■■■, ■■■■
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COMMUNICATION
T. Cauwenbergh, N. V. Tzouras, Dr. T.
Scattolin, Dr. S. Bhandary, A. Simoens,
Prof. Dr. K. Van Hecke, Prof. Dr. C. V.
Stevens*, Prof. Dr. S. P. Nolan*
1 – 5
Continuous Flow Synthesis of [Au-
(NHC)(Aryl)] (NHC=N-Heterocyclic
Carbene) Complexes
The continuous synthesis of a range
of gold(I)-aryl complexes is reported
for the first time. The recently
showcased weak base route is suc-
cessfully implemented into an opera-
tionally simple and readily scalable
continuous flow procedure. The
reported protocol allows for high
reaction rates and mild reaction con-
ditions, all in favor of more efficient
and sustainable access to products
which are valuable in catalysis,
materials science and medicinal
chemistry.