An in Situ Generated Palladium on Aluminum Oxide: Applications in Gram-Scale Matsuda-Heck Reactions

Article abstract of DOI:10.1021/acs.orglett.6b03268

In situ generated palladium on aluminum oxide provides an active catalytic system for Matsuda-Heck reactions in gram-scale. The novel catalyst proceeded through a significantly higher catalytic activity compared to the classical Pd/C system. Based on the high catalytic activity the first α,β,β-triarylation of methyl acrylate in good yields could be provided in one-step.

Full text of DOI:10.1021/acs.orglett.6b03268

Letter
pubs.acs.org/OrgLett
An in Situ Generated Palladium on Aluminum Oxide: Applications in
Gram-Scale Matsuda−Heck Reactions
Simon Pape,† Lauryna Dauksaite,† Sandra Lucks,† Xiaoting Gu,‡ and Heiko Brunner*,†
̌
̇
†Atotech Deutschland GmbH, Erasmusstrasse 20, D-10553 Berlin, Germany
‡Atotech USA Inc., c/o Case Western Reserve University, 2111 Martin Luther King Jr. Drive, Cleveland, Ohio 44106, United States
S
* Supporting Information
ABSTRACT: In situ generated palladium on aluminum oxide
provides an active catalytic system for Matsuda-Heck reactions
in gram-scale. The novel catalyst proceeded through a
significantly higher catalytic activity compared to the classical
Pd/C system. Based on the high catalytic activity the first
α,β,β-triarylation of methyl acrylate in good yields could be
provided in one-step.
he Matsuda−Heck reaction1,2 using aryldiazonium salts as
presence of tertraethylenglycole and aluminum-tri-sec-butoxide
in butanol.18
T
electrophiles represents a powerful tool in the synthesis of
suitable building blocks and natural products.3−9
Stimulated by the excellent results published by Felpin et al.
concerning the high efficiency of homemade palladium/carbon
catalysts13 and the fact that alumina is a quite common
supporting material in catalysis19 we decided to embark on a
simple catalytic system based on palladium immobilized on
alumina.
Hence, this investigation represents our first preliminary
results toward the utilization of in situ generated Pd/Al2O3
catalysts in the Matsuda−Heck reaction.
The high reactivity of these starting materials enables benign
reaction conditions combined with an ample tolerance against a
plethora of functional groups including carbonyl groups as well
as halides. The application of ligand-free conditions in alcoholic
and/or aqueous media completes the positive features and
nurtures a growing interest in the development of catalysts for
applications toward more sustainable processes.
Hence, the design of more reactive and efficient catalytic
systems has attracted a major interest.10
The starting point of our study was the examination and
comparison of aluminum oxide versus charcoal as supporting
materials for immobilized Pd-catalysts. Aluminum oxide 90,
which is frequently used in chromatography, was chosen as
palladium carrier. Before starting the Matsuda−Heck reaction, a
reactive Pd/Al2O3 catalyst was prepared by 30 min
prereduction of Pd(OAc)2 by methanol in the presence of
methyl acrylate and aluminum oxide 90 (1.9 wt % Pd(OAc)2).
Aside from the obtained yields and product ratios, both
catalytic systems were compared by kinetic data like conversion
rates and turnover frequencies (TOF)14,4f (Table 1):
Regarding the results presented in Table 1, it is obvious that
the Pd/Al2O3 catalyst distinguishes itself on the one hand by a
higher yield and on the other hand by a higher turnover
frequency and conversion rates compared to the palladium on
charcoal system.
Specifically, the development of new supported palladium
catalysts has attracted a significant interest because of an easier
metal recovery and recycling in combination with a lower
contamination of the product by toxic palladium residues.
Therefore, a multitude of heterogeneous catalysts has been
described in the literature.11−13
Beside the aforementioned aspects, the application of
supported Pd-catalysts as a remarkable instrument for
enhancing the reactivity and reduction of side products
frequently presents an underappreciated tool in the scientific
community for the Matsuda−Heck reaction. Thus, we could
show that the utilization of an instantly generated palladium on
charcoal had a tremendously positive aspect on the reaction
rate and yield of functionalized benzalacetones obtained by the
Matsuda-Heck reaction.14
Although a broad range of supporting materials like charcoal,
carbon,12,13 agarose15 and calcium carbonate16 was used the
reports on aluminum oxide as supporting material are scarce.
Thus, Beller et al.17 reported the utilization of commercial
available Pd/Al2O3.18 Wei and co-workers recently described
the coupling of diazonium salts with acrylates and styrene
catalyzed by aluminum hydroxide supported palladium colloids.
However, it has to be pointed out that this catalytic system
was prepared via a laborious sequence from Pd(PPh3)4 in the
Surprised and pleased by these interesting results we tried to
rationalize the outcome by a more detailed investigation using
scanning transmission electron microscopy (STEM) in SEM. In
both cases the formation of Pd(0) clusters could be verified.
However, it was revealed that the formation of smaller Pd-
Received: October 31, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03268
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Letter
Table 1. Comparison of the Catalytic Systems
Table 2. Scope of the Catalytic System
entry
R
product
yield (%)
a
1
4-OMe
3-OMe
2-OMe
4-Cl
2a
2b
2c
2d
2e
2f
95
75
93
98
94
86
82
91
78
97
75
96
63
yield
(%)
ratio
2a:3a
conv rate
TOF
(h−1
entry
cat.
(mmol*mL−1*h−1
)
)
2
1
2
Pd/Al2O3
Pd/C
95
80
97.0:3.0
96.6:3.4
1.467
0.796
440
241
3
4
5
4-Br
b
6
4-I
clusters is clearly favored on aluminum oxide in contrast to
charcoal. This is distinctively reflected by the particle size
distribution (Figure 1):
7
4-NO2
2-NO2
4-COOMe
4-CN
2g
2h
2i
8
9
c
c
10
11
12
13
2j
4-SO3H
H
2k
2l
3,4,5-OMe
2m
a
b
3.0% diarylated product determined by HPLC. 10% of dimethyl-
c
3,3′-(1,4-phenylene)(2E,2′E)-diacrylate was formed. Reaction was
conducted at 40 °C.
For all experiments discussed in this study a prereduction of
30 min was performed. We noticed over the time that the color
of supporting material turned from yellow to gray within
approximately 15 min. Our curiosity and former findings of
Felpin et al.13 animated us to run additional investigations
concerning the impact of the preconditioning time on the one
hand and the supporting material on the other hand (Table 3).
Figure 1. Particle size distribution of palladium on aluminum oxide
and charcoal.
Table 3. Impact of Pre-reduction Time
The two catalysts significantly distinguish themselves by their
particle sizes of deposited Pd-clusters. In the case of charcoal
the mean particle sizes of 149.3 nm is approximately three
times larger than in the case of aluminum oxide (52.3 nm).
Despite these large particle sizes, good results concerning yield
and conversion rate were obtained in the case of charcoal.
Charcoal also exhibits a very broad particle size distribution,
whereas the range of particle sizes is comparatively narrow on
aluminum oxide. These aspects might serve as an explanation
for the differences in the catalytic activity of both systems. In
spite of the higher reactivity and the superior yield realized with
Pd/Al2O3 the same product ratio was obtained for each catalyst.
In this regard, the high reactivity of the Pd/Al2O3-catalyst goes
hand in hand with a good selectivity.
Based on this outcome, we explored the scope of our
catalytic system with a variety of diazonium salts (Table 2):
It is noteworthy to mention that all reactions were conducted
in gram-scale (10 mmol). As depicted in Table 2, all products
were obtained in good to excellent yields. Surprisingly it had to
be stated that in the case of 4-iodo-benzenediazonium
tetrafluoroborate 10% of the diacrylate were formed (entry
6). Unfortunately, a reduction of the methyl acrylate quantity to
1 equiv did not diminish this side reaction (8% of the diacrylate
were formed in the case of 1 equiv of methyl acrylate).
Removal of Pd-traces from crude product has attracted
considerable attention in the pharmaceutical industry. To our
pleasure only traces of palladium (<10 ppm), determined via
ICP-MS could be detected after filtration of the catalyst in the
crude product 2a.
entry
prereduction
yield (%)
ratio 2a:3a
Al2O3
TOF (h−1
)
1
2
3
4
30 min
15 min
−
95
98
98
97
97.0:3.0
95.9:4.1
94.9:5.1
95.2:4.8
yes
yes
yes
no
440
478
595
341
30 min
For the comparison of the four experiments, it revealed that
longer prereduction times correspond to reduced conversion
rates, which might be related to a pronounced Pd-
agglomeration (entries 1−3). Nevertheless, a prereduction
time up to 30 min did not have a significant impact on the
yield, but seemed to be beneficial for the selectivity. However,
the renouncement of a prereduction goes along with an
increase of the catalyst activity (entry 3). This result is in
accordance with the findings of Felpin et al. for the palladium
on carbon catalysts.13 Especially, the abandonment of any
supporting material (entry 4) reveals the benefit of the
utilization of aluminum oxide as supporting material in our
catalytic system. Without using the supporting material, a
significant decrease of catalytic activity had to be stated (entry
4).
B
DOI: 10.1021/acs.orglett.6b03268
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Organic Letters
Letter
Having these results in our hand the palladium loading could
be lowered up to 10 times by abandonment of the
prereduction. Hence, electron-rich as well as electron-poor
diazonium salts could easily be converted in excellent yields
using classical glassware (Scheme 1):
Scheme 2. One-Pot Synthesis of a Nonsteroidal Estrogen
Antagonist 4 via Matsuda−Heck Reaction Using Pd(OAc)2
on Al2O3
Scheme 1. Matsuda−Heck Reaction Using 0.1 mol %
Pd(OAc)2 on Al2O3
yield of this synthetic protocol compared to the multistep
synthesis of Cattaneo and Gelmi indicates a new synthetic
access to this biological important class of substances.
Stimulated by our findings and the high activity of our
catalytic systems we prospected to rewarding synthetic targets.
Correia et al. have described in a series of excellent
publications the diarylation of acrylates20 and maleic acid
anhydride.21,3f These publications represent a landmark
concerning the utilization of the Matsuda-Heck reaction for
multiple arylations of olefins. However, a α,β,β-triarylation was
not yet described to our best knowledge.
In summary, we report a novel catalytic system that can be
easily prepared by mixing palladium acetate and commercially
available and low-cost aluminum oxide. This protocol features
benign reaction conditions combined with high catalytic activity
and excellent yields. The high catalytic activity could be
validated by kinetic investigations in combination with scanning
transmission electron microscopy (STEM). As such, the new
catalyst helps to increase the realm of catalysts for the Matsuda-
Heck reaction. Due to the high catalytic activity, the first α,β,β-
triarylation of methyl acrylate could be realized in good yields.
Further developments will be reported in due course.
Triarylated α,β,β-unsaturated carbonylic compounds are
frequently described as nonsteroidal estrogen antagonists.22
A
well-known representative of these compounds is the methyl-
tri-(4-methoxyphenyl)acrylate 4 (Figure 2).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03268.
Experimental procedures and analytical data for all
isolated products (PDF)
AUTHOR INFORMATION
■
Figure 2. Example for a nonsteroidal estrogen antagonist.
Corresponding Author
*E-mail: heiko.brunner@atotech.com.
ORCID
The preparation of these derivatives is normally accom-
plished by a multistep synthesis. Thus, Cattaneo and Gelmi23
could synthesize methyl-tri-(4-methoxyphenyl) acrylate 4
starting from anisophenone in a synthetic four-step sequence
in a total yield of 51%. Despite the good results, this presented
synthetic procedure is laborious on the one hand and on the
other hand, the utilization of moisture sensitive and/or
hazardous reagents like butyllithium and diazomethane
hampers the usefulness of this synthetic approach. Therefore,
an improved synthetic access to this valuable class of substances
is still tempting.
The synthetic usefulness of our new catalytic procedure
could be extended to the facile preparation of the nonsteroidal
estrogen antagonist 4. Therefore, 3.3 equiv of 4-methoxy-
benzenediazonium tetrafluoroborate were converted at 60 °C
using 4 mol % of Pd(OAc)2 in the presence of aluminum oxide
in methanol with methyl acrylate to the nonsteroidal estrogen
antagonist in a one-pot procedure in an overall yield of 71%.
(Scheme 2).
Heiko Brunner: 0000-0001-8980-0343
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.P. thanks the Atotech Deutschland GmbH for a PhD
scholarship. L.D. thanks the Atotech Deutschland GmbH for a
scholarship for her Master thesis.
REFERENCES
■
(1) Roglans, A.; Pla-Quintana, A.; Moreno-Manas, M. Chem. Rev.
2006, 106, 4622−4643.
̃
(2) (a) Taylor, J. G.; Moro, A. V.; Correia, C. R. D. Eur. J. Org. Chem.
2011, 2011, 1403−1428. (b) Felpin, F.-X.; Nassar-Hardy, L.; Le
Callonnec, F.; Fouquet, E. Tetrahedron 2011, 67, 2815−2831.
(3) (a) de Oliveira Silva, J. S.; Angnes, R. A.; da Silva, V. H. M.;
Servilha, B. M.; Adeel, M.; Braga, A. A. C.; Aponick, A.; Correia, C. R.
D. J. Org. Chem. 2016, 81, 2010−2018. (b) Oliveira, C. C.; Pfaltz, A.;
Correia, C. R. D. Angew. Chem., Int. Ed. 2015, 54, 14036−14039.
(c) Finelli, F. G.; Godoi, M. N.; Correia, C. R. D. J. Braz. Chem. Soc.
To our best knowledge, this is the first α,β,β-triarylation of an
olefin via Matsuda-Heck conditions. The surprisingly good
C
DOI: 10.1021/acs.orglett.6b03268
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2015, 26, 910−915. (d) Angnes, R. A.; Oliveira, J. M. O.; Oliveira, C.
C.; Martins, N. C.; Correia, C. R. D. Chem. - Eur. J. 2014, 20, 13117−
13121. (e) Prediger, P.; da Silva, A. R.; Correia, C. R. D. Tetrahedron
2014, 70, 3333−3341. (f) Canto, K.; Ribeiro, R. S.; Biajoli, A. F. P.;
Correia, C. R. D. Eur. J. Org. Chem. 2013, 2013, 8004−8013.
(g) Oliveira, C. C.; Angnes, R. A.; Correia, C. R. D. J. Org. Chem. 2013,
78, 4373−4385. (h) Soldi, C.; Moro, A. V.; Pizzolatti, M. G.; Correia,
C. R. D. Eur. J. Org. Chem. 2012, 2012, 3607−3616. (i) Schwalm, C.
S.; Correia, C. R. D. Tetrahedron Lett. 2012, 53, 4836−4840. (j) Biajoli,
A. F. P.; da Penha, E. T.; Correia, C. R. D. RSC Adv. 2012, 2, 11930−
11935. (k) Barancelli, D. A.; Salles, A. G.; Taylor, J. G.; Correia, C. R.
D. Org. Lett. 2012, 14, 6036−6039. (l) Oliveira, C. C.; dos Santos, E.
A. F.; Nunes, J. H. B.; Correia, C. R. D. J. Org. Chem. 2012, 77, 8182−
J.; Moreno-Manas, M.; Pla-Quintana, A.; Roglans, A. Org. Lett. 2003, 5,
̃
1559−1561. (d) de Oliveira Silva, J.; Menezes da Silva, V. H.; Servilha,
B. M.; Adeel, M.; Braga, A. A. C.; Aponick, A.; Correia, C. R. D. J. Org.
Chem. 2016, 81, 2010−2018. (e) Dai, M.; Liang, B.; Wang, C.; Chen,
J.; Yang, Z. Org. Lett. 2004, 6, 221−224. (f) Andrus, M. B.; Song, C.;
Zhang, J. Org. Lett. 2002, 4, 2079−2082. (g) Penafiel, J.; Pastor, J. M.;
̃
Yus, M. Eur. J. Org. Chem. 2012, 2012, 3151−3156. (h) Mohammadi,
E.; Movassagh, B. J. Mol. Catal. A: Chem. 2016, 418−419, 158−167.
́
́ ́
(11) (a) Molnar, A. Chem. Rev. 2011, 111, 2251−2320. (b) Molnar,
́
A, Ed. Palladium-Catalyzed Coupling Reaction; Wiley-VCH: Weinheim,
Germany, 2013. (c) Felpin, X.-F. Synlett 2014, 25, 1055−1067.
(12) Oger, N.; Le Grognec, E.; Felpin, F.-X. Curr. Org. Chem. 2015,
19, 695−707.
(13) Rossy, C.; Fouquet, E.; Felpin, F.-X. Synthesis 2012, 44, 37−41.
́
8190. (m) Prediger, P.; Barbosa, L. F.; Genisson, Y.; Correia, C. R. D.
(14) Stern, T.; Ruckbrod, S.; Czekelius, C.; Donner, C.; Brunner, H.
̈
J. Org. Chem. 2011, 76, 7737−7749. (n) Moro, A. V.; dos Santos, M.
R.; Correia, C. R. D. Eur. J. Org. Chem. 2011, 2011, 7259−7270.
(o) Siqueira, F. A.; Taylor, J. G.; Correia, C. R. D. Tetrahedron Lett.
2010, 51, 2102−2105. (p) Taylor, J. G.; Correia, C. R. D. Quim. Nova
2010, 33, 2070−2074. (q) Machado, A. H. L.; De Sousa, M.; Patto, D.;
Azevedo, L.; Bombonato, F. I.; Correia, C. R. D. Tetrahedron Lett.
2009, 50, 1222−1225. (r) Pastre, J. C.; Correia, C. R. D. Adv. Synth.
Catal. 2009, 351, 1217−1223. (s) Moro, A. V.; Cardoso, F. S. P.;
Correia, C. R. D. Org. Lett. 2009, 11, 3642−3645. (t) Moro, A. V.;
Cardoso, F. S. P.; Correia, C. R. D. Tetrahedron Lett. 2008, 49, 5668−
5671. (u) da Silva, K. P.; Godoi, M. N.; Correia, C. R. D. Org. Lett.
2007, 9, 2815−2818. (v) Meira, P.; Moro, A. V.; Correia, C. R. D.
Synthesis 2007, 2007, 2279−2286. (w) Pastre, J. C.; Correia, C. R. D.
Org. Lett. 2006, 8, 1657−1660. (x) Severino, E. A.; Costenaro, E. R.;
Garcia, A. L. L.; Correia, C. R. D. Org. Lett. 2003, 5, 305−308.
(y) Severino, E. A.; Correia, C. R. D. Org. Lett. 2000, 2, 3039−3042.
(z) Oliveira, D. F.; Severino, E. A.; Correia, C. R. D. Tetrahedron Lett.
1999, 40, 2083−2086.
Adv. Synth. Catal. 2010, 352, 1983−1992.
(15) Gholinejad, M. Appl. Organomet. Chem. 2013, 27, 19−22.
̂
(16) (a) Brunner, H.; de Courcy, N.; Genet, J.-P. Tetrahedron Lett.
1999, 40, 4815−4818. (b) Brunner, H.; Le Cousturier de Courcy, N.;
Genet
̂
, J.-P. Synlett 2000, 2000, 201−204.
(17) Beller, M.; Kuhlein, K. Synlett 1995, 1995, 441−442.
̈
(18) Li, X.; Wang, L. C.; Chang, H. H.; Zhang, C. X.; Wei, W. L.
Appl. Catal., A 2013, 462−463, 15−22.
(19) (a) Oberlander, R. K. Aluminas for Catalysts - Their Preparation
and Properties. In Applied Industrial Catalysis Vol. 3; Academic Press
Inc.; Leach, B. E., Ed.; Academic Press, Inc.: London, U.K., 1984; pp
́
63−112. (b) Gniewek, A.; Ziołkowski, J. J.; Trzeciak, A. M.; Zawadzki,
M.; Grabowska, H.; Wrzyszcz, J. J. Catal. 2008, 254, 121−130.
(20) (a) Taylor, J. G.; Ribeiro, R. S.; Correia, C. R. D. Tetrahedron
Lett. 2011, 52, 3861−3864. (b) Taylor, J. G.; Correia, C. R. D. J. Org.
Chem. 2011, 76, 857−869.
(21) Burtoloso, A. C. B.; Garcia, A. L. L.; Miranda, K. C.; Correia, C.
R. D. Synlett 2006, 2006, 3145−3149.
(22) Lednicer, D. Strategies for Organic Drug Synthesis and Design;
John Wiley & Sons, Inc.: Hoboken, USA, 2009.
(4) (a) Schmidt, B. Chem. Commun. 2003, 1656−1657. (b) Schmidt,
B.; Holter, F.; Berger, R.; Jessel, S. Adv. Synth. Catal. 2010, 352, 2463−
̈
2473. (c) Schmidt, B.; Holter, F.; Kelling, A.; Schilde, U. J. Org. Chem.
̈
(23) Cattaneo, A.; Gelmi, G. Il Farmaco 1960, 632−641.
2011, 76, 3357−3365. (d) Schmidt, B.; Elizarov, N.; Berger, R.;
Holter, F. Org. Biomol. Chem. 2013, 11, 3674−3691. (e) Schmidt, B.;
Elizarov, N.; Schilde, U.; Kelling, A. J. Org. Chem. 2015, 80, 4223−
4234. (f) Schmidt, B.; Elizarov, N.; Riemer, N.; Holter, F. Eur. J. Org.
̈
Chem. 2015, 2015, 5826−5841. (g) Schmidt, B.; Wolf, F.; Brunner, H.
Eur. J. Org. Chem. 2016, 2016, 2972−2982.
(5) (a) El Bakouri, O.; Fernan
́
dez, M.; Brun, S.; Pla-Quintana, A.;
, M.;
Padrosa, J.; Pla-Quintana, A.; Parella, T.; Roglans, A. Adv. Synth. Catal.
2011, 353, 2003−2012. (c) Salabert, J.; Sebastian, R. M.; Vallribera, A.;
Roglans, A.; Najera, C. Tetrahedron 2011, 67, 8659−8664.
Roglans, A. Tetrahedron 2013, 69, 9761−9765. (b) Raduan
́
́
́
(6) Gaikwad, D. S.; Pore, D. M. Synlett 2012, 23, 2631−2634.
(7) Sugiyama, Y.; Ishihara, K.; Masuda, Y.; Kobayashi, Y.; Hamamoto,
H.; Matsugi, M. Tetrahedron Lett. 2013, 54, 2060−2062.
(8) Li, Z.; Ip, C. F.; Ip, N. Y.; Tong, R. Chem. - Eur. J. 2015, 21,
11152−11157.
(9) (a) Felpin, F.-X.; Fouquet, E.; Zakri, C. Adv. Synth. Catal. 2008,
350, 2559−2565. (b) Felpin, F.-X.; Ibarguren, O.; Nassar-Hardy, L.;
Fouquet, E. J. Org. Chem. 2009, 74, 1349−1352. (c) Felpin, F.-X.;
Coste, J.; Zakri, C.; Fouquet, E. Chem. - Eur. J. 2009, 15, 7238−7245.
(d) Ibarguren, O.; Zakri, C.; Fouquet, E.; Felpin, F.-X. Tetrahedron
Lett. 2009, 50, 5071−5074. (e) Felpin, F.-X.; Miqueu, K.;
Sotiropoulos, J.-M.; Fouquet, E.; Ibarguren, O.; Laudien, J. Chem. -
Eur. J. 2010, 16, 5191−5204. (f) Laudien, J.; Fouquet, E.; Zakri, C.;
Felpin, F.-X. Synlett 2010, 2010, 1539−1543. (g) Nassar-Hardy, L.;
Fabre, S.; Amer, A. M.; Fouquet, E.; Felpin, F.-X. Tetrahedron Lett.
2012, 53, 338−341. (h) Susperregui, N.; Miqueu, K.; Sotiropoulos, J.-
M.; Le Callonnec, F.; Fouquet, E.; Felpin, F.-X. Chem. - Eur. J. 2012,
18, 7210−7218. (i) Oger, N.; Le Callonnec, F.; Jacquemin, D.;
Fouquet, E.; Le Grognec, E.; Felpin, F.-X. Adv. Synth. Catal. 2014, 356,
1065−1071.
(10) (a) Selvakumar, K.; Zapf, A.; Spannenberg, A.; Beller, M. Chem.
- Eur. J. 2002, 8, 3901−3906. (b) Oliveira, C. C.; Angnes, R. C.;
Correia, C. R. D. J. Org. Chem. 2013, 78, 4373−4385. (c) Masllorens,
D
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