Cross dehydrogenative C-O coupling catalysed by a catenane-coordinated copper(i)

Article abstract of DOI:10.1039/d0sc05133k

Catalytic activity of copper(i) complexes supported by phenanthroline-containing catenane ligands towards a new C(sp3)-O dehydrogenative cross-coupling of phenols and bromodicarbonyls is reported. As the phenanthrolines are interlocked by the strong and flexible mechanical bond in the catenane, the active catalyst with an open copper coordination site can be revealed only transiently and the stable, coordinatively saturated Cu(i) pre-catalyst is quickly regenerated after substrate transformation. Compared with a control Cu(i) complex supported by non-interlocked phenanthrolines, the catenane-supported Cu(i) is highly efficient with a broad substrate scope, and can be applied in gram-scale transformations without a significant loss of the catalytic activity. This work demonstrates the advantages of the catenane ligands that provide a dynamic and responsive copper coordination sphere, highlighting the potential of the mechanical bond as a design element in transition metal catalyst development.

Full text of DOI:10.1039/d0sc05133k

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Cross dehydrogenative C–O coupling catalysed by
a catenane-coordinated copper(I)†
Cite this: DOI: 10.1039/d0sc05133k
a
ab
Lihui Zhu,a Jiasheng Li,a Jun Yang
and Ho Yu Au-Yeung
*
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Catalytic activity of copper(I) complexes supported by phenanthroline-containing catenane ligands towards
a new C(sp3)–O dehydrogenative cross-coupling of phenols and bromodicarbonyls is reported. As the
phenanthrolines are interlocked by the strong and flexible mechanical bond in the catenane, the active
catalyst with an open copper coordination site can be revealed only transiently and the stable,
coordinatively saturated Cu(I) pre-catalyst is quickly regenerated after substrate transformation.
Compared with a control Cu(I) complex supported by non-interlocked phenanthrolines, the catenane-
supported Cu(I) is highly efficient with a broad substrate scope, and can be applied in gram-scale
transformations without a significant loss of the catalytic activity. This work demonstrates the advantages
of the catenane ligands that provide a dynamic and responsive copper coordination sphere, highlighting
the potential of the mechanical bond as a design element in transition metal catalyst development.
Received 17th September 2020
Accepted 31st October 2020
DOI: 10.1039/d0sc05133k
rsc.li/chemical-science
demanding ligands, bulkiness of the ligands will have to be
carefully balanced to maintain catalytic activity.6 Another
Introduction
approach would be the use of a chelating, hemilabile ligand
consists of both strongly and weakly coordinating donors, in
which the former acts as an anchor to the copper centre and the
latter can dissociate and re-coordinate easily for substrate
transformation and pre-catalyst regeneration.7
Copper is an attractive alternative to precious metals in transition
metal-catalysed cross couplings because of its Earth abundance
and relatively low price.1 Mechanistically, copper-catalysed
couplings are very diverse and can involve Cu(I)/Cu(II)/Cu(III)
intermediates and different pathways such as double-electron
oxidative addition–reductive elimination, electrophilic substitu-
tion, radical substitution and bimetallic reduction.2 The optimal
coordination environment for the copper at various stages of the
coupling could be very different, and a ligand that can accom-
modate the changing copper coordination characteristics in the
catalytic cycle will be key to the development of an efficient
copper catalyst. Generally, an open coordination site is required
for substrate coordination and transformation, but a coor-
dinatively saturated copper at the resting state can prolong the
catalyst lifetime and minimise off-target reactivity.3 For a coor-
dinatively saturated copper precatalyst, dissociation of the parent
ligand will precede substrate coordination to produce an active
catalyst.4 However, the presence of an open coordination site can
also subject the active catalyst to unproductive side reactions,
and regenerating the stable precatalyst by intermolecular coor-
dination of the dissociated parent ligand may not be kinetically
favourable.5 While stable copper complexes with an open coor-
dination site can be obtained by using low dentate, sterically
In contrast to these strategies that focus only on designing
an optimal ligand covalent framework, we propose that
a responsive copper coordination sphere can be attained by the
use of mechanically interlocked ligands for transiently revealing
an open coordination site for catalysis, while maintaining
a saturated coordination at the resting state for a good stability.8
For example, a 4-coordinate, tetrahedral copper(I) supported by
a catenane derived from two interlocked, phenanthroline-
containing macrocycles is highly stable because of the kinetic
stabilisation from the strong mechanical bond.9 Flexibility of
the mechanical bond could also result in a change of the cate-
nane conformation in response to an external stimulus,10 and
an open copper coordination site could be temporarily revealed
for catalysis. Because the ligands are mechanically bonded,
intramolecular re-coordination of any dissociated donor to
regenerate the stable, tetrahedral precatalyst will also be
kinetically favourable. The mechanical bond can thus prevent
the active catalyst from participating non-productive side reac-
tions, prolong the catalyst lifetime, and possibly stabilise reac-
tive intermediates and facilitate product dissociation to effect
a faster turnover (Fig. 1).11 In spite of these potential advantages
and that copper(I) has been one most studied metal template in
the synthesis of various types of mechanically interlocked
molecules (MIMs),12 the use of copper-coordinated MIMs for
catalysis is yet to be reported.
aDepartment of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong,
P. R. China. E-mail: hoyuay@hku.hk
bState Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam
Road, Hong Kong, P. R. China
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, computational details, HRMS spectrum and 1H, 13C NMR
spectra. See DOI: 10.1039/d0sc05133k
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Here we report that Cu(I) complexes supported by a catenane catalysed by 5 mol% of [Cu(L1)]PF6 in the presence of 2 eq. of
consists of two interlocked, phenanthroline-derived macro- K2CO3 to give 3a in 80% yield (Table 1, entry 1). Scavenging
cycles can catalyse a new cross dehydrogenative C(sp3)–O other possible copper species by virtue of the very strong Cu(I)
coupling (CDC) between phenols and bromodicarbonyls. The affinity of an additional 1 mol% or 5 mol% of L1 resulted in
catenane-supported Cu(I) is highly efficient with a broad a similar yield of 3a in 77% and 78% respectively (Table 1,
substrate scope, and can be applied in a gram-scale synthesis entries 2 and 3).9b Furthermore, when [Cu(L1)]PF6 was replaced
without compromising the catalytic activity. Of note, C(sp3)–O by [Cu(MeCN)4]PF6, yield of 3a decreased to 44% (Table 1, entry
cross dehydrogenative coupling, in particular with phenolic 4), showing that the observed catalytic effect was due to [Cu(L1)]
substrates, is the most challenging among various CDC due to PF6. Other copper complexes also gave 3a in only ca. 30–50%
the strong, non-selective oxidation tendency and propensity of yields, reinforcing the effect of the interlocked ligand on the
other side reactions of phenols such as hydroxylation and C- coupling reaction (Table S2†). LC-ESI-MS analysis of the mixture
oxidation.13,14 Currently, there are only few reports of C(sp2)–O aer the CDC showed [Cu(L1)]+ (m/z ¼ 1184.1) remained as the
dehydrogenative coupling of phenols with anilines,15 formam- only detectable copper-containing species in the system
ides,16 acrylates17 and catechols.18 C(sp3)–O cross coupling is (Fig. S1†), supporting that the catenane-coordinated copper(I) is
even more challenging, and the use of a hypervalent iodine stable yet catalytically active. On the other hand, with a slightly
oxidant19 or a metal-free condition are among the few reported tighter mechanical bond, [Cu(L2)]PF6 gave 3a in only 52% yield
examples of C(sp3)–O cross coupling in the literatures.20 under the same condition. In contrast, a 77% yield of 3a was
Preliminary mechanistic studies on the catenane-supported observed when the less tight [Cu(L3)]PF6 was used as the cata-
Cu(I) suggest the CDC involves a mononuclear, radical- lyst (Table 1, entries 5 and 6). These results agree with our
involving pathway. Removing the mechanical bond in the proposal that a responsive copper coordination sphere for
Cu(I) catalyst not only resulted in a much lower catalytic activity, switching between the catalytically active and the stable pre-
but also the CDC was found likely to proceed via binuclear catalytic states can be obtained by the use of a strong and
species. The good stability and catalytic activity of the inter- exible mechanical bond. In fact, stabilisation of a metal centre
locked copper catalysts thus demonstrate the huge potential by mechanically bonded ligands is kinetic in nature and origi-
and opportunities in exploring the ligand topological space for nates from the increased barrier of the reorganization and
developing new generations of copper catalysts.
complete dissociation of the interlocked ligands. Steric
hindrance at the metal center is not necessarily enhanced by the
presence of mechanical bond.9a,b It is therefore possible to tune
the ligand dissociation and reorganisation kinetics, and hence
the metal reactivity, by a careful tuning of the tightness of the
mechanical bond in the interlocked ligands,22 highlighting an
unique feature of mechanical bond in ligand design for
Results and discussion
As part of our program on exploring the chemistry of mechan-
ical bond,21 we discovered that the dehydrogenative coupling of
phenol 1a and diethyl bromomalonate 2a can be effectively
Fig. 1 Comparison of a Cu(I) catalysts supported by a catenane ligand (top) and non-interlocked ligands (bottom). For complexes supported by
catenane ligands, the stable resting state can change its coordination environment for substrate transformation and be regenerated by facile
intramolecular coordination of the dissociated ligand. On the other hand, re-coordination of dissociated ligand that is non-interlocked will be
kinetically less favourable. Empty coordination sites created after ligand dissociation may be filled by solvents and bi/multinuclear complexes
could be formed. The active complex may be more susceptible to side reactions with a shorter lifetime.
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Table 1 Screening of the CDC reactiona
Entry
Cu complex
K2CO3
Temp
Yield of 3ab
1
2
3
4
5
6
7
8
5 mol% [Cu(L1)]PF6
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
0 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
25 ꢀ
25 ꢀ
25 ꢀ
25 ꢀ
25 ꢀ
25 ꢀ
25 ꢀ
25 ꢀ
25 ꢀ
25 ꢀ
50 ꢀ
50 ꢀ
50 ꢀ
50 ꢀ
50 ꢀ
50 ꢀ
50 ꢀ
50 ꢀ
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
80%
77%
78%
44%
52%
77%
78%
77%
77%
28%
92%c
83%
26%
71%
42%
55%
35%
70%
5 mol% [Cu(L1)]PF6 + 1 mol% L1
5 mol% [Cu(L1)]PF6 + 5 mol% L1
5 mol% [Cu(MeCN)4]PF6
5 mol% [Cu(L2)]PF6
5 mol% [Cu(L3)]PF6
2 mol% [Cu(L1)]PF6
1 mol% [Cu(L1)]PF6
1 mol% [Cu(L1)]PF6 (under argon)
1 mol% [Cu(L1)]PF6
9
10
11
12d
13
14
15
16
17d
18
1 mol% [Cu(L1)]PF6
0.005 mol% [Cu(L1)]PF6
1 mol% [Cu(L1)]PF6 + 1 eq. TEMPO
1 mol% [Cu(L4)2]PF6
1 mol% [Cu(L5)2]PF6
1 mol% [Cu(L4)2]PF6 + 1 eq. TEMPO
0.005 mol% [Cu(L4)2]PF6
1 mol% [Cu(L5)2]PF6 + 1 eq. TEMPO
a
b
Reaction was conducted with 1a (0.1 mmol) and 2a (0.22 mmol) in 0.5 mL MeCN for 24 hours. Determined by 1H NMR using 1,3,5-
trimethoxybenzene as internal standard. Isolated yield ¼ 90%. d With 0.47 g (5 mmol) 1a and 1.76 g (11 mmol) 2a for 72 hours.
c
transition metal catalyst development. Other unique properties (Table 1, entry 11). Moreover, loading of [Cu(L1)]PF6 can be
of MIMs that have also been exploited for catalytic applications further lowered down to 0.005 mol% in a gram-scale trans-
include co-conformation switching of rotaxanes for switchable formation without compromising the catalytic efficiency (Table
catalysis,23,24 topological chirality as the chiral element in 1, entry 12). It is worth noting that L1 and related catenane
asymmetric catalysis,25 and the strong binding affinity of an ligands can also be obtained in gram-scale in spite of its non-
interlocked host for catalyst activation.26 Together with this trivial topology (see ESI for details†),27 demonstrating the
work that demonstrates the use of the strong and exible practical applicability of these interlocked ligands in transition
mechanical bond for a dynamic control of the copper coordi- metal catalysis.
nation site, it is clear that mechanical bond can offer many new
Possible intermediates involved in the CDC were also
opportunities in catalyst design.
studied. First, a reaction of 1a and 2a catalysed by [Cu(L1)]PF6 at
Optimisation of the CDC showed that reducing the catalyst a reaction time of 30 min was analysed by 1H NMR, which
loading to as low as 1 mol% did not signicantly affect the showed the presence of 3a and diethyl phenoxymalonate 3a0 in
catalytic efficiency (Table 1, entries 7 and 8). This is in great ca. 10% and 70% yield respectively (Fig. S4†). As the reaction
contrast to most other copper-catalysed reactions, in which proceeded, amount of 3a continued to increase while that of 3a0
a low catalyst loading would oen lead to a decrease in the decreased, and the reaction was completed aer ꢁ20 hours.
product yield (see below), suggesting that the mechanical bond These results led us to propose that formation of 3a is preceded
in L1 could stabilise the pre-catalytic state and prohibit non- by a nucleophilic substitution of 2a by 1a that gives 3a0, which is
productive side reactions. Consistent with this, the CDC can also consistent with the essential role of K2CO3 in the CDC.
be performed under air, and protecting the reaction under Indeed, an independent reaction between 2a and 3a0 with
argon had no signicant effect on the product yield (Table 1, 5 mol% [Cu(L1)]PF6 at room temperature gave 3a in 70% yield,
entry 9). This also suggests that 2a is the internal oxidant, which conrming that 3a can be formed from 3a0 under the CDC
was conrmed by the presence of diethyl malonate in the condition (Scheme 1a). The reaction between 1a and gem-
product mixture (Fig. S6†). It was found that K2CO3 is essential dibromodicarbonyl 2a0 was also tested, but 3a was formed in
and eliminating the base from the reaction resulted in only 28% a low yield of 20%, showing that the CDC may not involve
of 3a (Table 1, entry 10 and see ESI for more screening details†). bromodicarbonyl disproportionation (Scheme 1b).28 Further-
Further optimising the reaction condition by increasing the more, the presence of 1 eq. of the radical scavenger 2,2,6,6-
temperature to 50 ꢀC and using 1 mol% of [Cu(L1)]PF6 with 2 eq. tetramethylpiperidine-1-oxyl (TEMPO) led to a sharp decrease in
of K2CO3 in a 24-hour reaction gave 3a in a good yield of 92% the yield of 3a to 26% (along with 3a0 in 65%), suggesting that
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Scheme
1 Control reactions for studying possible intermediates
involved in the CDC: (a) phenol (1a) was replaced by diethyl phenox-
ymalonate (3a0) that showed the formation of CDC product is
preceded by a SN reaction; (b) diethyl bromomalonate (2a) was
replaced by diethyl dibromomalonate (2a0) that showed the CDC did
not involve disproportionation of 2a; (c) 1 eq. of TEMPO was added that
showed the CDC catalysed by the catenane-supported Cu(I) could
involve a radical species.
radicals may be involved in the reaction (Table 1, entry 13 and
Scheme 1c). Although the formation of a copper–TEMPO
complex that leads to the formation of non-CDC products could
be another plausible reason for the reduced yield of 3a,29 no
product other than 3a0 from the SN reaction of 1a and 2a was
identied. The highly preorganised phenanthrolines in L1 also
suggest that regenerating the stable [Cu(L1)]+ from any tran-
sient, L1-supported copper–TEMPO complex will be kinetically
favourable. Further 1H NMR and ESI-MS studies on [Cu(L1)]PF6
in the presence of 50 eq. of TEMPO also showed no formation of
any copper–TEMPO complex (Fig. S2 and S7†). On the other
hand, generation of an alkyl radical from the corresponding
halide with a CuI supported by chelating N-based ligands is
well-accepted in copper-catalysed atom transfer radical addition
and polymerization reactions.3 Our initial DFT studies indeed
showed that the formation of [CuII(L1)Br]+ along with
[CH(COOEt)2]c radical is viable with an energy difference of
6.53 kcal molꢂ1, suggesting that the coupling product could be
formed from a radical substitution involving [C(OPh)(COOEt)2]c
radical (Fig. 2). Although the large molecular size of the copper
catenanes would impose a huge demand on a high-level
computational study and our mechanistic study remains
preliminary, it would be kinetically improbable for the inter-
locked phenanthrolines in L1 to completely dissociate and
formation of bi/multinuclear species are likely to be irrelevant.
Roles of the mechanical bond in [Cu(L1)]PF6 was further
studied by comparing with the CDC that employed the non-
interlocked [Cu(L4)2]PF6 and [Cu(L5)2]PF6. A lower yield of 3a
in 71% and 42%, as compared with that of 92% for [Cu(L1)]PF6,
was observed when 1 mol% of [Cu(L4)2]PF6 and [Cu(L5)2]PF6
was used respectively under the optimised condition (Table 1,
entries 14 and 15). While the addition of 1 eq. of TEMPO had
signicantly lowered the yield of 3a by 66% in the case of
[Cu(L1)]PF6, there was only a 16% decrease in the yield of 3a
when [Cu(L4)2]PF6 was used as the catalyst (Table 1, entry 16).
Fig. 2 Proposed mechanisms of CDC catalysed by [Cu(L1)]PF6 (above)
and [Cu(L5)2]PF6 (below).
Further comparison of the effect of the catalyst loading also
showed a great contrast between [Cu(L4)2]PF6 and [Cu(L1)]PF6.
The CDC product 3a was obtained in only 35% yield when
0.005 mol% of [Cu(L4)2]PF6 was used, suggesting that the non-
interlocked complex could be more susceptible to non-
productive side reactions and/or degradation (Table 1, entry
17). Interestingly, the presence of 1 eq. of TEMPO increased the
yield of 3a to 70% when [Cu(L5)2]PF6 was used as the catalyst
(Table 1, entry 18). The opposite effect of the radical scavenger
hence suggests the copper-catalysed CDC proceed via different
pathways for the mechanically interlocked and non-interlocked
systems. ESI-MS analysis of a reaction mixture of 1a and 2a with
[Cu(L5)2]PF6 as the catalyst showed the presence of
binuclear copper species such as [Cu2II,II(L5)2(HCOO)2(OH)]+ at
m/z ¼ 649.2 and [Cu2I,I(L5)2 (MeCN)2Br]+ at m/z ¼ 703.4
(Fig. S3†). A bimetallic mechanism that involves an enolate is
proposed, which is also supported by a preliminary DFT study
(Fig. 2b). A similar binuclear mechanism has also been
proposed for a related enolate chlorination.30 Furthermore,
a time-dependent study on 3a formation catalysed by [Cu(L5)2]
PF6 showed that the reaction was completed by a much shorter
time (ca. 6 hours) than that by [Cu(L1)]PF6 (ca. 20 hours), further
reinforcing that the non-interlocked ligands may render the
(binuclear) active copper species more susceptible to side
reactions or catalyst degradation (Fig. S5†). Altogether, these
results not only highlight again the efficiency and applicability
of the catenane-coordinated copper in the new C(sp3)–O cross
coupling of phenols and bromodicarbonyls, but also demon-
strate the advantages of a dynamic copper coordination site that
is enabled by the strong and exible mechanical bond in the
catenane ligands.
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Table 2 Substrate scope of the CDCa
pyridazines, which have been demonstrated as a potent phar-
macophore for inhibiting the pro-inammatory cytokine tumor
necrosis factor a (TNF-a) for treating a diverse range of
inammatory, infectious and malignant conditions.31 For
example, compound 3e, obtained in 81% yield from the corre-
sponding CDC catalysed by [Cu(L1)]PF6, can be converted in two
simple steps to chloroimidazo[1,2-b]pyridazine 5 that can be
further functionalised to give various drug candidates for tar-
getting TNF-a (Fig. 3).32
Conclusions
In conclusion, the use of a catenane ligand to support a copper
catalyst for the cross dehydrogenative C(sp3)–O coupling of
phenols and bromodicarbonyls is reported. The exible and
strong mechanical bond in the catenane creates a dynamic and
responsive copper coordination environment, such that the
catalytically active state is available only transiently when
substrate transformation is to be mediated by the metal, or
otherwise a stable, coordinatively saturated resting state is
maintained. The CDC catalysed by [Cu(L1)]PF6 is highly efficient
with a low catalyst loading and a wide substrate scope, and the
catalyst can be employed in a gram-scale transformation
without a signicant loss in its catalytic efficiency.
The phenanthroline-derived copper catenanes used in this
work are one of the most classical types of MIMs obtained from
a templated synthesis. MIMs synthesis based on other transi-
tion metal templates with different coordination properties are
also well developed, and incorporating a mechanical bond in
metal complexes is therefore no longer considered as
a forbidden task. With the newly discovered C(sp3)–O cross
coupling activity in our copper catenanes, it can be envisioned
that mechanical interlocking of coordination ligand will be
a promising direction for exploiting the unique properties of
mechanical bond in the development of next generation tran-
sition metal catalysts. More studies on catenane ligands and
related MIMs for catalytic applications are currently underway
in our laboratory.
a
Reactions are performed with 1a (0.1 mmol) and 2a (0.22 mmol) in
b
0.5 mL MeCN for 24 h. Presented are isolated yields. The phenol
substrates are easily air-oxidized and the reactions were performed
under argon.
To put the C(sp3)–O dehydrogenative coupling in a synthetic
and application perspective, the scope of the CDC catalysed by
[Cu(L1)]PF6 with various phenol and bromodicarbonyl
substrates was investigated. As shown in Table 2, different
bromomalonates, b-ketoester and 1,3-diketone, as well as
phenols with either electron-rich or electron-decient substit-
uents, were found to give good yields of the coupling products
(Table 2, entries 1–15). Moreover, multiple substituted phenols,
including those with bulky ortho-substituents (e.g. –NO2 and
–tBu), performed equally well in the CDC (Table 2, entries 16–
19), demonstrating a wide substrate scope of the CDC. When
Conflicts of interest
There are no conicts to declare.
catechol was used as the phenolic substrate,
a double
substituted ve-membered ring product was obtained (Table 2,
entry 20). Due to the importance of phenol/catechol analogues
in naturally occurring small molecules and smart materials,
this wide substrate scope will have strong implications in the
synthesis of natural products, agrochemicals and pharmaceu-
ticals with good step and atom economy. In fact, the CDC
products can serve as an efficient precursor to imidazo[1,2-b]
Acknowledgements
This work is supported by the Croucher Foundation. We
acknowledge UGC funding administered by The University of
Hong Kong for support of the Electrospray Ionization Quadru-
pole Time-of-Flight Mass Spectrometry Facilities under the
support for Interdisciplinary Research in Chemical Science. We
thank Dr Vanessa K.-Y. Lo and Prof. C. M. Che for helpful
discussion.
Notes and references
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Fig. 3 Conversion of the CDC product 3e to imidazo[1,2-b]pyridazine 5.
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