CuII/H-USY as a regenerable bifunctional catalyst for the additive-free C-H amination of azoles

Article abstract of DOI:10.1039/c9cy02153a

A copper-exchanged H-USY zeolite catalyst was developed for the direct C-H amination of azoles with secondary amines in HFIP. The reaction was performed under air without any external additive. The Cu/H-USY catalyst could be regenerated for further re-use without significant decrease in activity.

Full text of DOI:10.1039/c9cy02153a

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DOI: 10.1039/C9CY02153A
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CuII/H-USY as a regenerable bifunctional catalyst for the additive-
free C‒H amination of azoles
Mickaël Henrion,a Simon Smoldersa and Dirk E. De Vos*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A copper-exchanged H-USY zeolite catalyst was developed for the acid or base additive. Indeed, the low cost associated with the
direct C‒H amination of azoles with secondary amines in HFIP. The high stability, ion-exchange capacity and modularity of zeolite
reaction was performed under air without any external additive. materials are very interesting features that can be
The Cu/H-USY catalyst could be regenerated for further re-use advantageous for catalytic organic transformations.9
without significant decrease in activity.
After testing a wide array of copper-exchanged zeolites
and studying the influence of the reaction parameters, we
optimized the model reaction between benzoxazole 1a and
morpholine 2a (Tables S1 and S2, ESI†). Thus, the resulting
aminoazole 3a was obtained in 91% yield in the presence of
Cu/H-USY catalyst (3 mol% Cu) after 24 h at 50 °C in HFIP.
Ultrastable Y zeolite (USY), derived from zeolite Y, not only
provides strong acidity, but also a sufficiently large pore size
which grants the reactants access to the pores. To our delight,
the reaction could be performed under air without the use of
any external additive. Several other amines were tested under
the optimal reaction conditions (Table 1).
The formation of sp2 C‒N bond by transition-metal catalyzed
reactions is of great interest for the preparation of
(hetero)arylamines which are prevalent in biological,
pharmaceutical and material sciences.1 The transition metal-
catalyzed amination of aryl (pseudo)halides, such as the
Buchwald-Hartwig coupling,2 is probably one of the most
reliable ways to construct these C‒N bonds. Nevertheless, the
direct amination of aromatic C‒H bonds is regarded as a more
powerful alternative by virtue of its high atom economy, and
the wide variety of available reactants with C‒H bonds.3
In particular, direct C‒H amination has been recently
studied as a straightforward pathway to biologically relevant 2-
aminoazoles.4 Significant progress has been realized by
Benzoxazole reacted efficiently with simple cyclic amines with
5-, 6- or 7-membered rings (89-96 % for 3b-d). Besides 2a,
other heteroatom-containing cyclic amines were also shown to
be suitable substrates, achieving good yields of the desired
coupling products 3e-g. An exception concerns the use of
thiomorpholine 2h, a S-containing amine which led to catalyst
inhibition, as only 34% yield of 3h was obtained. Secondary
aliphatic and benzylic amine derivatives were also shown react
smoothly, giving the corresponding aminoazoles 3i-l with good
to excellent yields. In contrast, and as observed in most of the
transition-metal catalyzed azole aminations, primary aliphatic
(cyclohexylamine) or aromatic (aniline) amines did not lead to
any coupling product formation. The reason for such
observation is not known, but we assume that they are too
reactive substrates as intractable complex mixtures were
obtained in both cases.
employing either
a
homogeneous5 or heterogeneous6
transition metal-based catalyst in combination with a simple
amine under oxidative conditions. Metal-free approaches have
also been described and mainly rely on the use of an iodine
catalyst with stoichiometric organic oxidant, or on
electrochemical synthesis.7 However, despite these significant
efforts, these methods require in most cases the use of high
temperatures and large amounts of catalyst and/or additives.
Thus, in line with our desire to develop sustainable methods in
catalytic C‒H activation,8 we aimed at designing a simple and
efficient catalyst for the direct amination of azoles. Given the
success of copper catalysts in the presence of either a base or
an acid additive, we reasoned that using an acid zeolite
support, partially exchanged with copper ions, may provide a
bifunctional catalyst that can circumvent the need for an extra
a. Centre for Membrane Separations, Adsorption, Catalysis and Spectroscopy for
Sustainable Solutions (cMACS), KU Leuven, Celestijnenlaan 200F, 3001 Leuven,
Belgium. E-mail: dirk.devos@kuleuven.be
†Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
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Table 1 Scope of the amination of 1a with aminesa,b
reaction between 1a and 2a. Powder X-ray diffraction (PXRD)
analysis demonstrated the structural stability of the zeolite
View Article Online
DOI: 10.1039/C9CY02153A
R
R
N
N
Cu/H-USY
H
H
N
N
+
HFIP, 50 °C
24 h, air
during reaction (Fig. 1a), but a hot filtration test and recycling
experiment hinted towards partial Cu leaching (Fig. S1, ESI†).
Therefore, we regenerated the catalyst by ion-exchange to
reincorporate the leached Cu centres. Interestingly, the
resulting regenerated solid gave almost identical catalytic
activity, and this could be performed seven times with only a
slight decrease of activity (Fig. 1b).
O
O
R'
R'
2a-n
3a-n
1a
N
O
N
O
N
O
n = 1, 3b, 92%
n = 2, 3c, 96%
n = 3, 3d, 89%
3a, 91% / > 97%c
N
without Cu: n.d.c,d
n
without H-USY: n.d.c,e
Cu + H-USY: 24%c,f
N
N
O
N
O
N
N
N
N
O
3e, 78%
3f, 82%
N
N
O
N
N
O
N
N
O
n
n
OH
S
3g, 68%
3h, 34%
n = 3, 3i, 95%
n = 7, 3j, 91%
N
N
O
N
N
O
H
N
N
Ph
O
R
3k, 89%
3l, 84%
R = Cy, 3m, n.d.
R = Ph, 3n, n.d.
a
Reaction conditions: heteroarene (0.5 mmol), 2a (1 mmol), HFIP
(2 mL), catalyst (3 mol% Cu, 200 mg), 50 °C, 24 h. b Isolated yields. c
GC conversions. Reaction performed with H-USY only (200 mg).
Reaction performed with Cu(OAc)2.H2O only (3 mol%). Reaction
performed with Cu(OAc)2.H2O (3 mol%) + H-USY (200 mg).
d
e
f
Subsequently, we briefly examined the scope of heteroarenes
in the Cu-catalyzed amination with 2a (Table 2).
Table 2 Scope of the amination of heteroarenes with 2aa,b
Cu/H-USY
heteroAr
H
+
H
N
O
heteroAr
N
O
HFIP, 50 °C
24 h, air
1b-g
3o-t
Fig. 1 (a) PXRD patterns of H-USY, fresh Cu/H-USY and Cu/H-
USY after 4 runs; (b) catalytic activity of the regenerated Cu/H-
USY after 8 runs.
2a
O2N
MeO
Cl
N
N
N
N
O
N
O
N
O
O
O
O
3o, 83%
3p, 94%
3q, 25%
In an attempt to gain insights into this Cu/zeolite-catalyzed
azole amination, we first performed X-Ray absorption
spectroscopy (XAS) on the freshly prepared Cu/H-USY to
probe the Cu centres. Fig. 2a reports a comparison between
the normalized XANES spectra collected for Cu/H-USY and
Cu(OAc)2 which was used for its preparation, along with other
representative Cu samples. While Cu(0) and Cu(I) references
display a close but distinct pre-edge at 8982 and 8983 eV,
respectively, Cu(II) reference materials (CuO and Cu(OAc)2)
display a pre-edge at 8967 eV. Interestingly, the spectrum of
Cu/H-USY presents a shoulder around 8967 eV which suggests
that the Cu ions are mostly in the +2 oxidation state.10 Also,
the EXAFS spectra of Cu/H-USY and Cu(OAc)2 show similar
peaks at around 1.5 Å (no phase shift correction applied)
which are typical of Cu‒O bonds (Fig. 2b). Nevertheless, the
characteristic Cu‒Cu peak of Cu(OAc)2 is no longer present in
the Cu/H-USY sample. Instead, a new peak at around 2.6 Å
appeared, which might indicate a true exchange of copper ions
N
N
N
N
N
O
N
N
O
O
N
O
S
Ph
3r, 61%
3s, n.d.
3t, n.d.
a
Reaction conditions: heteroarene (0.5 mmol), 2a (1 mmol), HFIP (2
mL), catalyst (3 mol% Cu, 200 mg), 50 °C, 24 h. b Isolated yields.
Unfortunately, no coupling product was obtained when using
benzothiazole
or
1-methylbenzimidazole.
However,
benzoxazoles bearing electron-donating or -withdrawing
substituents at the C5 position, such as methoxy (1b) and
chloro (1c) groups, reacted smoothly to give very high yields.
In contrast, the reaction with 5-nitrobenzoxazole gave a low
yield of the desired product. Interestingly, 5-phenyl-1,3,4-
oxadiazole proved to be reactive as the coupling product was
obtained with 61 % yield.
Under optimized reaction conditions, the stability and
recyclability of the Cu/H-USY were evaluated in the model
2 | J. Name., 2012, 00, 1-3
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into the zeolite, rather than a simple impregnation of Cu(OAc)2 are thus less hydrophobic (Table S1, ESI†). AnVoietwheArrticalesOpnelincet
DOI: 10.1039/C9CY02153A
concerns the use of HFIP as a solvent; it is reasonable to
species.
Secondly, we performed a series of control experiments to try assume that it participates in the stabilization of metal
to understand the reaction mechanism of this C‒H amination. intermediates via hydrogen bonding.11 Finally, we decided to
Either running a Cu-, zeolite- or air-free reaction resulted in no investigate the potential involvement of the ring-opened
reaction at all, while the in situ combination of Cu(OAc)2.H2O amidine derivative 4 which is very commonly observed and
and H-USY under air gave catalytic activity (Tables 1 and S2, was proven to be a true intermediate in similar azole
ESI†). This underlines the crucial role of both the copper amination processes. However, under the optimized
1
catalyst and the zeolite, the association of which is crucial in conditions, this product was never observed by GC or H NMR
order to reach high catalytic activity. This strongly contrasts analysis of the crude mixture. In a parallel experiment, we
with other metal-supported catalysts employed for similar synthesized this compound and reacted it alone with Cu/H-
direct azole amination where the solid support only serves as USY. No product formed, and full recovery of 4 was observed
an anchor point for the metal sites.6
instead, ruling out a ring-opening step of 1a in the present
reactions. All the obtained results, along with recent findings
showing that Cu/O2 systems likely participate in catalytic C‒H
functionalizations via single electron transfer processes,12
allow us to propose a plausible mechanism for this Cu/H-USY
catalyzed azole amination (Fig. 2c). First, deprotonation of the
amine substrate (assisted by an X ligand, which can be either a
residual acetate from the preparation of Cu/H-USY or the
negatively charged zeolite framework) results in the formation
of a copper-amido complex. Subsequent protonation of the
azole by the acid zeolite protons facilitates the addition of the
amine species on the C2-position, with concomitant reduction
of Cu(II) to Cu(I). Finally, oxidative rearomatization of the
obtained radical intermediate occurs in order to form the
product along with a water molecule, and regenerate the
Cu(II) catalyst.
In conclusion, we have shown that the copper(II)-
exchanged zeolite, Cu/H-USY, can efficiently catalyze the direct
amination of azole derivatives with secondary amines. The use
of a small amount of copper, air as the oxidant and the fact
that no extra additives are needed, are significant practical
advantages. Furthermore, the catalyst could be recovered,
regenerated and re-used three times with very little loss of
activity. More work is under way in order to better understand
the beneficial role of the zeolite during this process.
R
R
R
N
CuII
(c)
N
H
R
HX
CuI
N
O
CuIIX
H
N
R
R
N
R
R
N
N
O
O
H2O
1/2 O2
instead of:
R
N
M cat.
N
O2
R
R
N
R2NH
N
R
N
O
- H2O
O
OH
4 (not reactive)
The authors gratefully acknowledge the NMBP-01-2016
Program of the European Union’s Horizon 2020 Framework
Program under grant agreement no. [720996] and the FWO
(Aspirant grant and grant for project no. [G0D0518N]) for
financial support. The XAS experiments were performed on
beamline BM26A at the European Synchrotron Radiation
Facility (ESRF), Grenoble, France. We are grateful to D.
Banerjee at the ESRF for providing assistance in using beamline
BM26a.
Fig 2 (a) Normalized Cu-XANES spectra showing Cu(0), Cu(I)
and Cu(II) model compounds with Cu/H-USY; (b) EXAFS spectra
of Cu(OAc)2 (blue), fresh Cu/H-USY (red) and spent Cu/H-USY
(green). (c) possible mechanism for the copper-catalyzed
amination of azoles
The zeolite plays three important roles here: (i) the acidic
protons of Cu/H-USY activate the benzoxazole ring, which
favours attack of the amine reactant on the C2-position
(significantly lower activities were obtained when using either
Cu/Na-USY or Cu/NH4-USY; see Table S1, ESI†); (ii) it may
stabilize Cu intermediates by weak interaction, as a rather low
amount of Cu can be employed compared to the literature
(the large majority of homogeneous Cu-catalyzed direct
aminations require at least 10 mol% Cu);5 (iii) the high
hydrophobicity of the strongly dealuminated Y zeolite can
assist in removing water molecules that are formed in this
C‒H/H‒N oxidative coupling; indeed, we observed lower
activities with zeolites possessing lower Si/Al ratios, and which
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
(a) Amino Group Chemistry From Synthesis to the Life
Sciences, ed. A. Ricci, Wiley-VCH, Weinheim, 2008; (b)
Modern Amination Methods, ed. A. Ricci, Wiley-VCH,
Weinheim, 2000.
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CuII/H-USY as a regenerable bifunctional catalyst for the additive-freDeOIC: 1‒0.1H039/C9CY02153A
amination of azoles
Mickaël Henrion, Simon Smolders, Dirk E. De Vos*
Cu/H-USY
HFIP
R
R
N
O
N
O
Y
Y
H
H
N
N
+
50 °C, 24 h
R'
R'
no additive
air
(Y = C, N)
The use of bifunctional CuII/H-USY catalyst for the direct amination of azoles under air and
without additive has been disclosed.