Silica-Supported Silver Nitrate as a Highly Active Dearomatizing Spirocyclization Catalyst: Synergistic Alkyne Activation by Silver Nanoparticles and Silica

Article abstract of DOI:10.1002/anie.201608263

Silica-supported AgNO₃(AgNO₃–SiO₂) catalyzes the dearomatizing spirocyclization of alkyne-tethered aromatics far more effectively than the analogous unsupported reagent; in many cases, reactions which fail using unsupporte

Full text of DOI:10.1002/anie.201608263

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201608263
German Edition: DOI: 10.1002/ange.201608263
Supported Catalysts
Silica-Supported Silver Nitrate as a Highly Active Dearomatizing
Spirocyclization Catalyst: Synergistic Alkyne Activation by Silver
Nanoparticles and Silica
Aimee K. Clarke, Michael J. James, Peter OꢀBrien, Richard J. K. Taylor,* and
William P. Unsworth*
Abstract: Silica-supported AgNO (AgNO –SiO ) catalyzes
3
3
2
the dearomatizing spirocyclization of alkyne-tethered aromat-
ics far more effectively than the analogous unsupported
reagent; in many cases, reactions which fail using unsupported
AgNO3 proceed effectively with AgNO –SiO . Mechanistic
3
2
studies indicate that this is a consequence of silver nanoparticle
formation on the silica surface combined with a synergistic
effect caused by the silica support itself. The remarkable ease
with which the reagent can be prepared and used is likely to be
of much synthetic importance, in particular, by making nano-
particle catalysis more accessible to non-specialists.
Figure 1. AgNO –SiO mediated dearomatizing spirocyclization.
3
2
[7–9]
as catalysts previously,
but to the best of our knowledge,
P
ioneered in the 1960s, silica-supported AgNO (AgNO –
the catalytic role of Ag-NPs formed while supporting silver
salts on silica has not been documented. In this paper, we
highlight AgNO –SiO as an easily prepared and highly active
3
3
SiO ) is well-known for its use as a support in the separation
2
[1]
of E- and Z-alkenes by column chromatography. However,
3
2
the synthetic potential of AgNO –SiO as a catalyst has been
catalyst for dearomatizing spirocyclizations (Figure 1), show-
casing the methodology with the AgNO –SiO -mediated
3
2
mostly over-looked, with just a handful of reports on its use as
3
2
[
2]
a reagent in organic synthesis. To the best of our knowledge,
examples are limited to syntheses of 5-membered hetero-
synthesis of 23.6 g of a spirocycle in a simple continuous
flow set-up. Furthermore, our mechanistic finding of the
synergistic alkyne activation by Ag-NPs and silica provides
a new alkyne activation pathway that could have much
synthetic scope for alkyne functionalization.
[
2a]
cycles from alkynes and allenes, reported by Marshall and
[
2b,c]
Knight.
spirocyclization reactions,
catalytic potential of AgNO –SiO due to its limited previous
As part of a wider program on dearomatizing
[
3,4]
we decided to investigate the
To start, we examined the conversion of ynone 1a into
3
2
[
10]
use in synthesis and with the intention of exploiting the
spirocyclic indolenine 2a.
Commercial AgNO –SiO (10
3 2
[5]
practical benefits of using a solid-supported reagent. To our
surprise, we found that AgNO –SiO offers vastly superior
wt% AgNO on silica) was found to effect this transformation
3
[11]
with reasonable efficiency, and following additional opti-
mization (see Supporting Information) it was discovered that
3
2
reactivity compared with unsupported AgNO in dearomatiz-
3
[
3]
[12]
ing spirocyclization reactions of alkyne-tethered hetero-
“home-made” AgNO –SiO with a reduced AgNO loading
3
2
3
[
4]
aromatics of the type shown in Figure 1.
of 1 wt% was an even more effective catalyst; stirring ynone
Of much significance, several dearomatization reactions
1a at RT in CH Cl with catalytic (1 mol%) 1 wt% AgNO –
2
2
3
that previously failed with unsupported AgNO can now be
SiO led to the formation of spirocycle 2a in 98% isolated
3
2
carried out in high yield with the AgNO –SiO catalyst. These
yield in 30 minutes (Scheme 1, conditions A). Interestingly,
this is significantly faster than the same reaction with
3
2
unexpected findings prompted a mechanistic investigation
which ultimately, via the combined use of in situ infrared
spectroscopy (via ReactIR) and TEM, implicated a key role
[
4a]
unsupported AgNO3 (6 h, conditions B).
Even more
dramatic differences were seen in the reactions of ynones
tethered to other aromatics; phenol 3a, pyrrole 5a and
benzofuran 7 were reacted with both catalyst systems, and
while spirocyclic products 4a, 6a, and 8 were isolated in high
yields when 1 wt% AgNO –SiO was used, AgNO alone led
[
6]
for silver nanoparticles (Ag-NPs) formed during the prep-
aration of AgNO –SiO together with a synergistic effect from
3
2
the silica support itself. Pre-prepared Ag-NPs have been used
3
2
3
[
13,14]
to no reaction in all three cases (Scheme 1).
[*] A. K. Clarke, M. J. James, Prof. P. O’Brien, Prof. R. J. K. Taylor,
In view of these marked differences, a mechanistic study
was initiated. We first monitored the conversion of ynone 1a
into spirocycle 2a with in situ infrared spectroscopy (via
ReactIR), using the decrease in intensity of the CꢀC stretch
Dr. W. P. Unsworth
University of York
York, YO10 5DD (UK)
E-mail: richard.taylor@york.ac.uk
william.unsworth@york.ac.uk
À1
of ynone 1a (2208 cm ) to monitor reaction progress. Using
1
mol% of the 1 wt% AgNO –SiO catalyst, ynone 1a was
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201608263.
3 2
converted into spirocycle 2a in 30 min (blue line, A, Figure 2),
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the silver for further catalysis and increasing the turnover
rate.
Our results also indicate a clear difference between the
supported AgNO –SiO catalyst and unsupported AgNO in
3
2
3
the presence of silica (which should have the same elemental
composition). This led us to propose that AgNO is a pre-
3
catalyst in the unsupported reaction and that the induction
period is connected to the time taken for Ag-NPs to form
in situ. To test this, unsupported AgNO3 was “aged” by
stirring the standard reaction dose in CH Cl for 24 h before
2
2
adding ynone 1a; the expectation was that by ageing the
catalyst, Ag-NPs would form in advance and alter the reaction
[
16]
profile.
during the ageing process, which is indicative of Ag-NP
The initially colorless solution became yellow
[
17]
formation,
and the aged catalyst did indeed perform
differently (gray line, D). The reaction proceeded at a similar
rate to the standard AgNO reaction (purple line, B), but
3
I
crucially there was no induction period. A mercury drop test
was also performed which led to the complete cessation of the
Scheme 1. Supported and unsupported Ag -catalyzed spirocyclization.
[
18]
reaction, adding additional support to the idea that Ag-NPs
are the true catalyst. Further supporting evidence was
obtained using transmission electron microscopy (TEM);
AgNO was stirred for 24 h at RT in CH Cl and an aliquot of
3
2
2
the solution ( ꢁ 5 mL) was removed and dropped onto
a copper TEM grid. The deposit that remained after the
CH Cl had evaporated was then analyzed using TEM, and
2
2
Ag-NPs were found to be present (Figure 3).
Figure 2. 2D ReactIR plots of the conversion of 1a into 2a using
catalysts A–D (1 mol%) in CH Cl at RT.
2
2
Figure 3. TEM images for AgNO “aged” in CH Cl .
3
2
2
fully consistent with the synthetic reaction. In contrast, as
expected from the synthetic work, the unsupported AgNO3
reaction was much slower, requiring > 6 h to reach comple-
tion (purple line, B); interestingly, there was a clear induction
period of around 2 h, and even after this time the reaction was
slower.
In view of the above results, we considered it likely that
Ag-NPs were also present in our standard supported AgNO3–
SiO (1 wt%) catalyst system, as they could potentially form
2
during the preparation of the supported reagent. This was
confirmed by TEM imaging of the supported catalyst;
crystalline Ag-NPs were observed (Figure 4) and the electron
diffraction pattern enabled the identification of a cubic silver
crystal phase (space group Fm3m) and showed that the
particles had a spacing of around 0.205 nm, which is
To explore the role of silica, AgNO and silica were both
3
added to a solution of 1a in CH Cl (i.e. the AgNO was not
2
2
3
supported on the silica in advance). In this experiment (pink
line, C), an induction period was still observed (around
[
19]
9
0 min), but once this period had passed, the reaction
representative of cubic silver.
proceeded at a similar rate to the standard AgNO –SiO2
Thus, it appears that in both the supported and unsup-
3
reaction (blue line, A). Silica is not able to promote
spirocyclization on its own (stirring ynone 1a in silica in
CH Cl led to no reaction after several days) but clearly its
ported systems, Ag-NPs rather than AgNO are predom-
3
inantly responsible for the conversion of 1a into 2a. Silica was
also shown to be important, leading to an increased reaction
rate, even when added separately to the silver. This may be
due to faster protodemetallation, and hence more effective
catalyst turnover and/or its role may also be to adsorb the Ag-
NPs and control their growth/aggregation.
2
2
presence significantly increases the rate of the Ag-mediated
spirocyclization reaction. We suggest that this may be due to
[
15]
accelerated protodemetallation; silanol groups on the silica
surface might be expected to facilitate this step, thus releasing
2
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ples. The quantitative formation of spirocycles 6e–g is
especially noteworthy, given the rarity of dearomatized
[
20]
products derived from 3-pyrroles. Thus a wide range of
substituted aromatics are compatible with this simple, mild
method, and furthermore, even broader functional group
tolerance was demonstrated by an extensive robustness
[21]
screen, detailed in the Supporting Information.
Finally, the use of our AgNO –SiO catalyst in a contin-
3
2
[
22]
uous flow reaction has been demonstrated. A 0.1m solution
of ynone 1a in toluene was simply passed through a 1 cm
diameter column packed with 1.93 g of our standard 1 wt%
Figure 4. TEM images for AgNO –SiO .
3
2
À1
catalyst (19.3 mg of AgNO ) at a flow rate of 0.3 mLmin ,
3
1
concentrated in vacuo, and analyzed using H NMR spectros-
Next, to more fully evaluate the synthetic utility of our
AgNO –SiO catalyst, the optimized spirocyclization condi-
tions were applied to other alkyne-tethered aromatics, and
copy. This reaction proceeded very efficiently, converting
a total of 23.6 g of ynone 1a into spirocycle 2a in quantitative
yield over a 51 h period (Scheme 3). This corresponds to
a total catalyst loading of 0.12 mol% and an NMR aliquot
measured after 51 h showed that the product was still being
formed cleanly, indicating that the catalyst remained active.
3
2
compared to unsupported AgNO in each case (Scheme 2).
3
Indolyl spirocyclic products 2a–e were all obtained in
excellent yields (94–100%), with AgNO –SiO2 promoting
3
a faster transformation than with unsupported AgNO in all
In summary, 1 wt% AgNO –SiO2 is a very effective
3
3
cases. More pronounced differences in reactivity were
observed for 2- and 4-phenol derivatives 3a–f; these sub-
catalyst for the dearomatizing spirocyclization of alkyne-
tethered heteroaromatics, with its efficacy believed to stem
from a synergistic relationship between the silica support and
Ag-NPs formed during its preparation. It is much more
strates did not react at all using unsupported AgNO , but
3
using AgNO –SiO spirocyclic dienones 4a–f were all formed
3
2
in high yield, notably including compound 4 f, an advanced
intermediate in a published route to spirobacillene A.
Pyrrole derivatives 5a–g are also well tolerated, with
reactive than unsupported AgNO , and in our hands, it is also
3
[14a]
more reactive than silica-supported Ag-NPs made by liter-
ature methods in which the Ag-NPs were prepared sepa-
[
23]
AgNO –SiO superior to unsupported AgNO in all exam-
rately. In contrast to existing methods to prepare supported
3
2
3
I
Scheme 2. Supported and unsupported Ag -catalyzed spirocyclization. Isolated yields (following catalyst removal) are quoted, or for incomplete
1
reactions, conversion (conv.) was calculated based on analysis of the H NMR spectrum on the unpurified product mixture.
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[
6a,8b]
Ag-NPs,
our catalyst is easy to prepare with full silver
incorporation into the supported catalyst and it can be stored
in the dark at RT for several months with no loss of activity.
The reactions are easy to perform and are purified simply by
removing the supported catalyst by filtration, which can then
be reused five times with no apparent loss of activity. ICP-
MS analysis confirmed that spirocycle 2a formed under the
standard conditions contains ca. 60 ppm silver (which is
pleasing given that no aqueous work-up or chromatography
was performed on the analyzed samples), and by performing
the same reaction in toluene rather than CH Cl , silver
contamination in the product could be reduced to just 5 ppm,
which is significantly below the 17 ppm limit set by the FDA
for the permissible amount in a drug. All of these findings
have potential implications in both previous and future work;
it may now be considered that the processes previously
described by Marshall and Knight using AgNO –SiO also
benefitted from the presence of Ag-NPs, while moving
forwards, AgNO –SiO may also represent a more convenient
[12]
[
[
24]
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2
2
[
25]
[
3
2
3
2
[10] For a review on spirocyclic indolenines, see; M. J. James, P.
OꢀBrien, R. J. K. Taylor, W. P. Unsworth, Chem. Eur. J. 2016, 22,
2856.
source of Ag-NPs than those prepared by conventional
methods.
[
11] Ynone 1a (0.1 mmol) was stirred with 10 mol% of AgNO -SiO2
3
(
10 wt%, Sigma Aldrich, 248762) in CH Cl for 10 min, resulting
2 2
in full conversion into spirocycle 2a.
Acknowledgements
[
12] 1 wt% AgNO –SiO was prepared by adding AgNO (100 mg)
3
2
3
to a slurry of Fluka silica gel (9.90 g, pore size 60 ꢃ, 220–440
mesh particle size) in deionized water (27 mL). The mixture was
stirred for 15 min, concentrated in vacuo at 608C to form a free-
flowing powder and dried by heating to 1408C under high
vacuum for 4–5 h.
We thank the University of York (A.K.C., M.J.J., W.P.U.) and
the Leverhulme Trust (for an Early Career Fellowship, ECF-
2
015-013, W.P.U.) for financial support. We are also grateful
for help from Dr. Charlotte Elkington (ReactIR), Robert
Mitchell and Alan Reay (TEM) and Dr. Victor Chechik for
helpful advice.
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Keywords: dearomatization · flow chemistry ·
heterogeneous catalysis · silver nanoparticles · spirocycles
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[
4
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[
[
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18] The reaction of ynone 1a with unsupported AgNO was allowed
3
to proceed to ca. 50% conversion, before mercury was added
(
200 equivalents with respect to AgNO ), which stopped any
[23] Silica-supported Ag-NPs synthesized by literature methods
(references [6a] and [8b]) were tested in the transformation of
ynone 1a into spirocycle 2a, resulting in 45% and 28%
conversion into 2a, respectively, with unreacted starting material
accounting for the remainder of the mass balance.
3
further reaction.
[
[
19] Qualitatively, the supported Ag-NPs appear to be much more
uniform in size than those obtained from aged AgNO3 in
CH Cl ; more detailed studies will be required in future to probe
2
2
this observation and its implications more rigorously.
20] For exceptions, see: a) D. A. Shabalina, M. Y. Dvorkoa, E. Y.
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[24] See Supporting Information for details. Very consistent (high)
yields were achieved in these recycling studies, highlighting the
reliability and reproducibility of these reactions.
[25] ICH, Guideline for Elemental Impurities, Q3D, 2014.
Received: August 24, 2016
[
21] K. D. Collins, F. Glorius, Nat. Chem. 2013, 5, 597.
Published online: && &&, &&&&
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Communications
Supported Catalysts
Nanoparticle catalysis: Silica-supported
AgNO catalyzes the dearomatizing
3
A. K. Clarke, M. J. James, P. O’Brien,
R. J. K. Taylor,*
spirocyclization of alkyne-tethered aro-
matics far more effectively than the
analogous unsupported reagent. Mecha-
nistic studies indicate that this is a con-
sequence of silver nanoparticle formation
on the silica surface combined with
a synergistic effect caused by the silica
support itself.
W. P. Unsworth*
&&&& — &&&&
Silica-Supported Silver Nitrate as a Highly
Active Dearomatizing Spirocyclization
Catalyst: Synergistic Alkyne Activation by
Silver Nanoparticles and Silica
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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