Angewandte
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Chemie
with increasing amounts of pyridine showed a single set of up-
field shifted protons belonging to pyridine (Scheme 2) in
a similar way as it was observed with the titration studies
between L and pyridine (Supporting Information, Figur-
es S11, S12).[18]
Having established that L enables the binding of pyridine
inside the zinc(II)-porphyrin pocket simultaneously to the
coordination of the N,N-chelating unit towards the poten-
tially, catalytically active iridium center, we embarked in the
catalytic assessment of L as a supramolecular ligand in
In our case, we only detected trace amounts of borylated
toluene and up to 15% (based on B2pin2) in the case of the
reaction performed at higher 808C, that again exhibited
À
excellent meta-selectivity for the C H bond borylation of
pyridine (Table 1, entry 6). For instance, with 58 times more
toluene than pyridine in the reaction mixture, our supra-
molecular catalyst exhibits a high preference for the pyridine
substrate than for the aromatic toluene one with an overall
selectivity S estimated at 380 for the most unfavorable
scenario.[25] Decreasing the temperature to 608C completely
inhibited the catalysis (Table 1, entry 7). This suggests that the
substrate-catalyst or product-catalyst binding via Zn···N
coordination is strong and it only becomes reversible to
enable turnovers in catalysis at higher temperatures.[26]
Switching the toluene solvent for a more bulky p-xylene led
to no borylation at the solvent and high reactivity towards
meta-selectivity in only 12 hours (Table 1, entry 8). Doubling
the amounts of both B2pin2 and the iridium catalyst led to the
bis-borylated, meta-selective product 2 in an isolated yield of
70% (Table 1, entry 9), which represents the best result so far
obtained for bis-functionalization to date.[27] The fact that
aromatic apolar solvents such as toluene or p-xylene are
crucial for the activity and selectivity of the catalysis,
indirectly indicates that the polar ones (ethers) significantly
À
iridium-catalyzed C H bond borylations between unfunc-
tionalized pyridine and bis(pinacolato)diboron (B2pin2) as
a model reaction (Table 1). This reaction is well-known to
give a mixture of meta- and para-borylated products with
classical bipyridine ligands[15a] and it represents a benchmark
test for evaluating the activity and the regio-selectivity
outcome.[13] Initially, we screened solvents that were known
À
to be used in iridium catalyzed C H bond borylation of
(hetero)arenes such as heptane and ethers at temperatures
near to their boiling point.[10–15,22] Although poor conversions
were observed, an exquisite meta selectivity was evidenced as
only the products resulting from mono- and bis-borylation
1 and 2 formed without any detectable para or ortho
regioisomers 3 or 4 (Table 1, entries 1–4). The reaction in
toluene as solvent at 708C revealed as the optimal one for
obtaining the mono-functionalized product with meta selec-
tivity in an isolated yield of 54% (Table 1, entry 5, GC-yield
90%).[23] This is rather unexpected because non-functional-
ized arenes (such as toluene) are typically more reactive than
disturb the binding of the substrate to the ligand L.[28]
A
similar reasoning may explain the higher reactivity encoun-
tered when using [Ir(COD)(Cl)]2 instead of the typically more
[9–13,15,17,22–24]
reactive [Ir(COD)(OMe)]2
as the released meth-
oxide anion from the former could bind to the zinc(II) center
in L (Table 1, entry 2). The reactions performed in the
absence of iridium or in the absence of ligand L, respectively,
led to no conversion of pyridine substrate (Supporting
Information, Table S1).[18]
pyridine using bipyridine- or phenantroline-derived ligands
[13,22,24]
À
for iridium-catalyzed C H bond borylation reactions.
À
Table 1: Reaction optimization for the iridium-catalyzed C H bond
To further rationalize the origin of this high meta-
borylation of pyridine.[a]
À
selectivity for the iridium-catalyzed C H bond borylation
reaction, a number of control experiments were performed
(Scheme 3). First, the catalysis was attempted replacing the
supramolecular ligand L for the individual components
forming it, that is, zinc(II)-tetraphenylporphyrin (ZnTPP)
and the N,N-chelating ligand L* (Scheme 3A). Under the
standard reaction conditions, the starting material pyridine
was fully recovered unreacted, highlighting the relevance of
covalently linking the substrate recognition site to the
catalytically active site as it is the case in the supramolecular
ligand L. For comparison purposes, the reaction performed
using 4,4’-di-tert-butyl-2,2’-dipyridyl (dtbpy) as ligand with or
without the presence of ZnTPP led to an almost statistical
mixture of meta- and para-borylated products (Scheme 3
B).[15a] The relevance of the substrate binding to the zinc(II)-
porphyrin pocket was further evidenced by the lack of
reactivity observed for pyridines having no lone pair available
for binding (pyridinium derivatives, Scheme 3C) as well as for
pyridines unable to bind to the zinc atom owing to steric
shields (2-methylpyridine, Scheme 3C).[28,29] A last experi-
ment was performed adding to the standard reaction con-
ditions zinc(II)-salphen (ZS) as a substrate competitive
inhibitor (Scheme 3D) since it is known that zinc(II)-salphen
derivatives bind to pyridine derivatives typically two orders of
magnitude higher than zinc(II)-porphyrins.[28a,30] In this sce-
Entry Solvent
T [8C] t [h] Conv. [%][b] (1+2):3:4[c]
1:2[d]
1
heptane
heptane
THF
80
80
50
80
80
70
80
60
80
80
48
48
48
48
24
24
24
24
12
48
30
21
0
33
17
100:0:0
100:0:0
–
100:0:0
100:0:0
100:0:0
100:0:0
–
90:10
100:0
–
89:11
100:0
90:10
25:75
–
2[e]
2
3
MTBE
4
5
6
7
2-MeTHF
toluene
toluene
toluene
p-xylene
p-xylene
>99 (54)[f]
>99
<5
8
>99
100:0:0
100:0:0
40:60
13:87
9[g]
>99 (70)[f]
[a] Reaction conditions: pyridine (0.162 mmol), B2pin2 (0.162 mmol),
[Ir(COD)(Cl)]2 (1.5 mol%), L (3 mol%), solvent (1 mL). [b] Conversion
determined as pyridine consumption. [c] Ratio meta/para/ortho func-
tionalization of pyridine determined by 1H NMR and GC using n-
dodecane as internal standard. [d] Ratio mono/bis-functionalization of
the meta-borylated product determined by 1H NMR and GC-MS using n-
dodecane as internal standard. [e] Reaction performed with [Ir(COD)-
(OMe)]2 instead of [Ir(COD)(Cl)]2. [f] Isolated yield of the main product
displayed in brackets. [g] Reaction performed with 3 equivalents of
B2pin2, 3 mol% of [Ir(COD)(Cl)]2 and 6 mol% of L.
&&&&
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Angew. Chem. Int. Ed. 2021, 60, 2 – 10
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