Transition-Metal-Free Lactonization of sp2 C-H Bonds with CO2

Article abstract of DOI:10.1021/acs.orglett.6b03601

The transition-metal-free lactonization of heteroaryl and alkenyl C-H bonds with carbon dioxide is reported to synthesize important coumarin derivatives in moderate to excellent yields. These redox-neutral reactions feature a broad substrate scope, good functional group tolerance, facile scalability, and easy product derivatization.

Full text of DOI:10.1021/acs.orglett.6b03601

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free Lactonization of sp2 C−H Bonds with CO2
Zhen Zhang,†,‡,§,∥ Tao Ju,‡,∥ Meng Miao,‡ Jie-Lian Han,‡ Yi-Han Zhang,‡ Xing-Yong Zhu,‡
Jian-Heng Ye,‡ Da-Gang Yu,*,‡ and Yong-Gang Zhi*,†
†Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
‡Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, China
§University of the Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: The transition-metal-free lactonization of heteroaryl and
alkenyl C−H bonds with carbon dioxide is reported to synthesize
important coumarin derivatives in moderate to excellent yields. These
redox-neutral reactions feature a broad substrate scope, good functional
group tolerance, facile scalability, and easy product derivatization.
Scheme 1. Lactonization/Lactamization of C−H Bond with
CO2
ransformations of carbon dioxide (CO2) to high-value-
Tadded chemicals have received much attention because
CO2 is a nontoxic, abundant, and recyclable C1 building block.1
CO2 may represent a more user-friendly carbonyl source than
the hazardous and toxic carbon monoxide (CO)2 and
phosgene,3 which have been widely used in the laboratory
and industry. However, the oxidative carbonylation reaction
involving CO and oxidants is still one of the most developed
and widely used methods to approach the important carbonyl-
containing heterocycles.4 Considering its higher oxidation state
than CO, CO2 could act as the combination of CO and
oxidants in redox-neutral carbonylation reactions to generate
carbonyl-containing heterocycles.
Due to high atom- and step-economy, direct C−H
functionalization with CO2 shows great power and efficiency
in carboxylation5 and heterocycle formation.6−9 In 2013, the
Iwasawa and Takaya group developed an unprecedented
palladium-catalyzed carboxylation of alkenyl C−H bonds of
2-alkenylphenols with CO2 to afford the corresponding
coumarins via a lactonization process (Scheme 1A).6 Our
group7a and Xi’s group8 independently realized the transition-
metal-free lactamization of sp2 C−H bonds in 2-alkenylanilines
and 2-(hetero)arylanilines with CO2 (Scheme 1B). Very
recently, Zhang and Lu’s group also developed a novel
transformation of 1-propenyl ketones to α-pyrones via CO2
utilization (Scheme 1C).9 However, hydroxyl group directed
lactonization of aryl C−H bonds, especially heteroaryl C−H
bonds, with CO2 has not been reported yet.10 As a continuation
of our interest in construction of heterocycles with CO2,7a,b
herein, we report a challenging transition-metal-free and redox-
neutral lactonization of heteroaryl and alkenyl C−H bonds with
CO2 (Scheme 1D).11
coumarin derivatives through lactonization with CO2.13 As
shown in Table 1, we tested the reaction of 2-(imidazo[1,2-
a]pyridin-2-yl)phenol (1a) with CO2 as a model reaction.
Inspired by our previous work on lactamization reactions
(Scheme 1B),7a we first screened different solvents (entries 1−
4) with KOtBu as the base and found diglyme to perform much
better than others. The reason might be that diglyme has a
similar structure to the crown ether, which can enhance the
basicity and make the in situ generated potassium salts,
including phenoxide and carbonate, more stable and soluble in
the reaction conditions.14 Furthermore, many kinds of bases
(entries 4−11) were tested, and KOtBu was found to be the
The compounds containing an imidazo[1,2-a]pyridine (IP)
scaffold, such as necopidem, saripidem, and zolpidem, have
attracted much attention due to their biological activities.12 We
wonder if we can directly functionalize the C−H bonds in
imidazo[1,2-a]pyridines to obtain a class of hybrid structures of
Received: December 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03601
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Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Lactonization of 2-(Imidazo[1,2-a]pyridin-2-
a
yl)phenols with CO2
a
Reaction conditions: 1a (0.2 mmol), base (4.5 equiv), 1 atm of CO2,
b
2 mL of solvent, 24 h, 140 °C. GC yields are given with dodecane as
c
an internal standard and the isolated yields are given in parentheses. 6
d
e
f
g
h. 1 h. KOtBu (3.0 equiv). KOtBu (1.0 equiv). Cs2CO3 (3.0 equiv),
Pd(OAc)2 (10 mol %).
best choice. Moderate to good yields were obtained even if the
reaction time was shortened to 6 or 1 h (entries 12 and 13).
When a lower amount of KOtBu was used, the yield of 2a was
decreased dramatically (entries 14 and 15), which indicated the
high importance of base in this transformation. Although
palladium catalyst could promote the reaction in the presence
of Cs2CO3 as the base, the efficiency was still not good enough
at this stage (entry 16).6
a
Reaction conditions: 1 (0.2 mmol), KOtBu (4.5 equiv), 1 atm of
b
CO2, 2 mL of diglyme, 24 h, 140 °C. Isolated yields. 48 h.
With the optimized reaction conditions in hand, we
investigated the substrate scope of this transformation (Scheme
2). First, we set out to investigate the scope of the substrates
bearing substituents on the phenol ring (1b−g). As shown in
Scheme 2, different substituents at the meta (1b−d) and para
position (1e−g) of the phenol ring did not affect the reaction.
Several kinds of carbon−halo bonds (1c−f) were well-tolerated
under the current reaction conditions, thus providing great
opportunity for further functionalization.15 Furthermore, we
investigated the effect of substitutions on the imidazo[1,2-
a]pyridine scaffold (1h−q). We found that a variety of
substrates with different substitutions on the IP scaffold also
gave the desired products in good to excellent yields. Notably,
many kinds of functional groups, such as methoxyl (1i, 1k, 1p),
trifluoromethyl (1l), and carbon−halo bonds (1m, 1n), did not
inhibit the reaction. The substrates (1i, 1o−q) with electron-
donating groups gave the corresponding products in higher
yields than those (1l, 1m) with electron-withdrawing groups,
which might arise from higher electron density at the
nucleophilic site of the substrate. Besides the imidazo[1,2-
a]pyridine motif, 2-(benzo[d]imidazo[2,1-b]thiazol-2-yl)-
phenol (1r) could also be applied in this reaction to give 2r
in 53% yield.
Scheme 3. Lactonization of 2-(1-Arylvinyl)phenols with
CO2
a
a
Reaction conditions: 1 (0.2 mmol), KOtBu (3.5 equiv), 1 atm of
CO2, 2 mL of DMF, 24 h, 150 °C. Isolated yields are shown.
After developing the methodology, we further demonstrated
its utility. First, the reaction of 1a could be scaled up to gram
quantity with 87% yield (Scheme 4A). Moreover, the product
2a could be easily transformed to 2-(3-(2-hydroxypropan-2-
yl)imidazo[1,2-a]pyridin-2-yl)phenol (3), 2-(2-
hydroxyphenyl)imidazo[1,2-a]pyridine-3-carboxylic acid (4),
and 2-(3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)phenol
(5) in the presence of nucleophiles or a reductant (Scheme
4B; see the SI for details), all of which demonstrate that this
transformation can be useful in organic synthesis.
Concerning the mechanism, there are two possible pathways
for 1a to react with CO2 to generate 2a (Scheme 5) because
both the phenoxide and imidazole motif are electron-rich and
nucleophilic. To gain insight into the reaction mechanism, a
series of experiments were conducted.
Furthermore, we were pleased to find that 2-alkenylphenols
could also be suitable for this transformation (Scheme 3).16
With slightly modified reaction conditions, 2s was obtained in
38% yield, along with byproducts from carboxylation at the
ortho and para position of phenol ring.17 To our delight, the
substrates (1u, 1v) with substituents on the para position of the
phenol ring could generate the corresponding products 2u and
2v in moderate to good yields.
B
DOI: 10.1021/acs.orglett.6b03601
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Letter
indicated that 1w underwent decomposition at high temper-
ature to generate 1a, which further reacted with CO2 to give
other intermediates and the final product 2a.
Scheme 4. Large-Scale Reaction and Synthetic Applications
At this stage, we speculated the phenoxide played an
important role in CO2 fixation and activating the γ-position,
which is highly electron-rich and nucleophilic. Based on the
above results and previous reports,7,18 we proposed a
preliminary reaction mechanism for this reaction (Scheme 7).
Scheme 7. Proposed Mechanism
Scheme 5. Possible Pathways for the Reaction
Compound 1a undergoes deprotonation in the presence of
strong base KOtBu to form 1a-1, which can generate 1a-2
through reaction with CO2 or the in situ generated adduct of
CO2 with KOtBu (e.g., KOCOOtBu). Next, 1a-2 further reacts
with CO2 or the adduct of CO2 to give the intermediate 1a-3.18
Intramolecular nucleophilic attack and deprotonation with
assistance from the base might produce the desired product 2a
along with HOtBu/K2CO3 or KHCO3 as byproducts. Further
mechanistic studies are in progress in our laboratory.
In conclusion, we have developed a novel lactonization of
heteroaryl and alkenyl C−H bonds with CO2 to synthesize
important coumarin derivatives under transition-metal-free and
redox-neutral conditions. A variety of coumarin derivatives are
generated in moderate to excellent yields. These reactions
feature a broad substrate scope, good functional group
tolerance, facile scalability, and easy product derivatization.
Given the importance of coumarin derivatives, this user- and
eco-friendly synthetic strategy is expected to find wide
application in the pharmaceutical industry.
At first, we wondered whether compound 4 is one key
intermediate that can transfer to the product 2a through the
lactonization reaction (Scheme 5, path A). However, only a
trace of the target product 2a was detected under the standard
conditions (eq 1), which indicated that path A might be
unfavored.
On the basis of the the above results, nucleophilic attack
from oxygen in phenols may be a possible path for the reaction
(Scheme 5, path B). On the basis of our previous work,7a the
Boc-protected substrate 1w was considered as possible
intermediate and tested in this transformation (Scheme 6).
Although 1w could give the product 2a under the standard
conditions in 89% yield, we could not detect the 1w formation
in the reaction of 1a anytime. Moreover, when 1w was applied
as the starting material in the reaction conditions without CO2,
2a was not detected, and only the free phenol 1a was obtained.
These results excluded the possibility of 1w as intermediate and
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.6b03601.
Experimental procedures and characterization of all
products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Scheme 6. Mechanistic Studies with 1w
*E-mail: dgyu@scu.edu.cn.
*E-mail: 2411714859@qq.com.
ORCID
Da-Gang Yu: 0000-0001-5888-1494
Author Contributions
∥Z.Z. and T.J. contributed equally.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b03601
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
14360. (n) Ueno, A.; Takimoto, M.; O, W. N.; Nishiura, M.; Ikariya,
T.; Hou, Z. Chem. - Asian J. 2015, 10, 1010.
(6) Sasano, K.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2013, 135,
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21502124), the “1000-Youth Talents Program”, a Start-up
Grant from Sichuan University, and the “973” Project from the
MOST of China (2015CB856600) for financial support. We
also thank the comprehensive training platform of the
Specialized Laboratory in the College of Chemistry at Sichuan
University for compound testing.
10954.
(7) (a) Zhang, Z.; Liao, L.-L.; Yan, S.-S.; Wang, L.; He, Y.-Q.; Ye, J.-
H.; Li, J.; Zhi, Y.-G.; Yu, D.-G. Angew. Chem., Int. Ed. 2016, 55, 7068.
(b) Ye, J.-H.; Song, L.; Zhou, W.-J.; Ju, T.; Yin, Z.-B.; Yan, S.-S.;
Zhang, Z.; Li, J.; Yu, D.-G. Angew. Chem., Int. Ed. 2016, 55, 10022. For
a very recent multicomponent reaction, see: (c) Sun, S.; Hu, W.-M.;
Gu, N.; Cheng, J. Chem. - Eur. J. 2016, 22, 18729.
(8) Wang, S.; Shao, P.; Du, G.; Xi, C. J. Org. Chem. 2016, 81, 6672.
(9) Zhang, W.-Z.; Yang, M.-W.; Lu, X.-B. Green Chem. 2016, 18,
4181.
REFERENCES
■
(1) For reviews on transformation of CO2: (a) Braunstein, P.; Matt,
D.; Nobel, D. Chem. Rev. 1988, 88, 747. (b) Sakakura, T.; Choi, J.-C.;
Yasuda, H. Chem. Rev. 2007, 107, 2365. (c) Correa, A.; Martín, R.
Angew. Chem., Int. Ed. 2009, 48, 6201. (d) Sakakura, T.; Kohno, K.
Chem. Commun. 2009, 1312. (e) Dong, D.; Yang, P.; Hu, W. Prog.
Chem. 2009, 21, 1217. (f) Aresta, M. Carbon Dioxide as Chemical
(10) For a recent review on ester formation via C−H
functionalization, see: (a) Liu, B.; Hu, F.; Shi, B.-F. ACS Catal.
2015, 5, 1863. For oxidative carbonylation of 2-(hetero)arylphenols
with CO, see: (b) Luo, S.; Luo, F.-X.; Zhang, X.-S.; Shi, Z.-J. Angew.
Chem., Int. Ed. 2013, 52, 10598. (c) Lee, T.-H.; Jayakumar, J.; Cheng,
C.-H.; Chuang, S.-C. Chem. Commun. 2013, 49, 11797. (d) Inamoto,
K.; Kadokawa, J.; Kondo, Y. Org. Lett. 2013, 15, 3962. (e) Shin, Y.;
Yoo, C.; Moon, Y.; Lee, Y.; Hong, S. Chem. - Asian J. 2015, 10, 878.
(f) Zhang, J.; Zhang, X.; Fan, X. J. Org. Chem. 2016, 81, 3206. For
oxidative alcohol-directed carbonylation of aryl C−H bonds with CO,
see: (g) Lu, Y.; Leow, D.; Wang, X.; Engle, K. M.; Yu, J.-Q. Chem. Sci.
2011, 2, 967. (h) Wang, Y.; Gevorgyan, V. Angew. Chem., Int. Ed. 2015,
54, 2255.
(11) Lactonization of phenols with CO2 is difficult, with the
following challenges: (a) competitive background reactions of direct
ortho and/or para carboxylation, well-known as the “Kolbe−Schmitt
reaction”; (b) competitive hydrolysis of the lactones under basic
reaction conditions; (c) challenging O-carboxylation than N-
carboxylaiton; (d) compatibility of carboxylation and condensation
under the same system.
Feedstock; Wiley-VCH: Weinheim, 2010. (g) Glueck, S. M.; Gumus, S.;
̈
̈
Fabian, W. M. F.; Faber, K. Chem. Soc. Rev. 2010, 39, 313.
(h) Mikkelsen, M.; Jørgensen, M.; Krebs, F. C. Energy Environ. Sci.
2010, 3, 43. (i) Riduan, S. N.; Zhang, Y. Dalton Trans. 2010, 39, 3347.
(j) Cokoja, M.; Bruckmeier, C.; Rieger, B.; Herrmann, W. A.; Kuhn, F.
̈
E. Angew. Chem., Int. Ed. 2011, 50, 8510. (k) Huang, K.; Sun, C. L.;
Shi, Z.-J. Chem. Soc. Rev. 2011, 40, 2435. (l) Martin, R.; Kleij, A. W.
ChemSusChem 2011, 4, 1259. (m) Wang, J.-L.; Miao, C.-X.; Dou, X.-
Y.; Gao, J.; He, L.-N. Curr. Org. Chem. 2011, 15, 621. (n) Wang, W.;
Wang, S.; Ma, X.; Gong, J. Chem. Soc. Rev. 2011, 40, 3703. (o) Yang,
Z.-Z.; Zhao, Y.-N.; He, L.-N. RSC Adv. 2011, 1, 545. (p) Tsuji, Y.;
Fujihara, T. Chem. Commun. 2012, 48, 9956. (q) Yang, Z.-Z.; He, L.-
N.; Gao, J.; Liu, A.-H.; Yu, B. Energy Environ. Sci. 2012, 5, 6602.
(r) Zhang, W.; Lu, X. Chin. J. Catal. 2012, 33, 745. (s) He, M.; Sun, Y.;
Han, B. Angew. Chem., Int. Ed. 2013, 52, 9620. (t) Cai, X.; Xie, B.
Synthesis 2013, 45, 3305. (u) Zhang, L.; Hou, Z. Chem. Sci. 2013, 4,
3395. (v) Kielland, N.; Whiteoak, C. J.; Kleij, A. W. Adv. Synth. Catal.
2013, 355, 2115. (w) Centi, G., Perathoner, S., Eds. Green Carbon
Dioxide: Advances in CO2 Utilization; Wiley-VCH: Weinheim, 2014.
(x) Aresta, M.; Dibenedetto, A.; Angelini, A. Chem. Rev. 2014, 114,
1709. (y) Maeda, C.; Miyazaki, Y.; Ema, T. Catal. Sci. Technol. 2014, 4,
1482. (z) Yeung, C. S.; Dong, V. M. Top. Catal. 2014, 57, 1342.
(aa) Liu, Q.; Wu, L.; Jackstell, R.; Beller, M. Nat. Commun. 2015, 6,
5933. (ab) Pinaka, A.; Vougioukalakis, G. C. Coord. Chem. Rev. 2015,
288, 69. (ac) Yu, B.; He, L. N. ChemSusChem 2015, 8, 52.
(12) For recent examples of biologically active imidazo[1,2-a]pyridyl
derivatives, see: (a) Okubo, T.; Yoshikawa, R.; Chaki, S.; Okuyama, S.;
Nakazato, A. Bioorg. Med. Chem. 2004, 12, 423. (b) Hanson, S. M.;
Morlock, E. V.; Satyshur, K. A.; Czajkowski, C. J. Med. Chem. 2008, 51,
́
7243. (c) Veron, J.-B.; Allouchi, H.; Enguehard-Gueiffier, C.; Snoeck,
R.; Andrei, G.; De Clercq, E.; Gueiffier, A. Bioorg. Med. Chem. 2008,
16, 9536. (d) Wiegand, M. H. Drugs 2008, 68, 2411. (e) Gallud, A.;
Vaillant, O.; Maillard, L. T.; Arama, D. P.; Dubois, J.; Maynadier, M.;
Lisowski, V.; Garcia, M.; Martinez, J.; Masurier, N. Eur. J. Med. Chem.
2014, 75, 382. (f) Meng, T.; Wang, W.; Zhang, Z.; Ma, L.; Zhang, Y.;
Miao, Z.; Shen, J. Bioorg. Med. Chem. 2014, 22, 848.
(ad) Borjesson, M.; Moragas, T.; Gallego, D.; Martin, R. ACS Catal.
̈
2016, 6, 6739. (ae) Wang, S.; Du, G.; Xi, C. Org. Biomol. Chem. 2016,
14, 3666.
(13) For one example of oxidative lactonization reaction of 1a with
CO in 85%, see ref 10f.
(14) Hodgson, K. O.; Raymond, K. N. Inorg. Chem. 1972, 11, 3030.
(15) (a) Larock, R. C. Comprehensive Organic Transformations: A
Guide to Functional Group Preparations; VCH: New York, 1989. (b) de
(2) (a) Tafesh, A. M.; Weiguny, J. Chem. Rev. 1996, 96, 2035.
(b) Otera, J. Modern Carbonyl Chemistry; Wiley-VCH, 2000.
(c) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.
̈
2009, 48, 4114. (d) Wu, L.; Fang, X.; Liu, Q.; Jackstell, R.; Beller, M.;
Wu, X.-F. ACS Catal. 2014, 4, 2977.
Meijere, A.; Brase, S.; Oestreich, M. Metal-Catalyzed Cross-Coupling
̈
Reactions and More; Wiley-VCH: Weinheim, 2014.
(3) Oertel, G. Polyurethane Handbook; Hanser Publishers: Munich,
1985.
(16) (a) Similar results were also observed in the Supporting
Information of ref 6. For oxidative carbonylation of 2-alkenylphenols
with CO, see:. (b) Ferguson, J.; Zeng, F.; Alper, H. Org. Lett. 2012, 14,
(4) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1.
(5) For reviews and highlights, see: (a) Dalton, D. M.; Rovis, T. Nat.
Chem. 2010, 2, 710. (b) Ackermann, L. Angew. Chem., Int. Ed. 2011,
50, 3842. (c) Boogaerts, I. I. F.; Nolan, S. P. Chem. Commun. 2011, 47,
3021. For recent elegant progress, see: (d) Olah, G. A.; Torok, B. l.;
Joschek, J. P.; Bucsi, I.; Esteves, P. M.; Rasul, G.; Surya Prakash, G. K.
J. Am. Chem. Soc. 2002, 124, 11379. (e) Boogaerts, I. I. F.; Fortman, G.
C.; Furst, M. R. L.; Cazin, C. S. J.; Nolan, S. P. Angew. Chem., Int. Ed.
2010, 49, 8674. (f) Boogaerts, I. I. F.; Nolan, S. P. J. Am. Chem. Soc.
2010, 132, 8858. (g) Nemoto, K.; Yoshida, H.; Egusa, N.; Morohashi,
N.; Hattori, T. J. Org. Chem. 2010, 75, 7855. (h) Vechorkin, O.; Hirt,
N.; Hu, X. Org. Lett. 2010, 12, 3567. (i) Zhang, L.; Cheng, J.; Ohishi,
T.; Hou, Z. Angew. Chem., Int. Ed. 2010, 49, 8670. (j) Mizuno, H.;
Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2011, 133, 1251. (k) Inomata,
H.; Ogata, K.; Fukuzawa, S.-i.; Hou, Z. Org. Lett. 2012, 14, 3986.
(l) Gu, M.; Cheng, Z. Ind. Eng. Chem. Res. 2014, 53, 9992. (m) Suga,
T.; Mizuno, H.; Takaya, J.; Iwasawa, N. Chem. Commun. 2014, 50,
5602. (c) Seoane, A.; Casanova, N.; Quinones, N.; Mascarenas, J. L.;
̃
̃
Gulías, M. J. Am. Chem. Soc. 2014, 136, 834. (d) Liu, X.-G.; Zhang, S.-
S.; Jiang, C.-Y.; Wu, J.-Q.; Li, Q.; Wang, H. Org. Lett. 2015, 17, 5404.
(17) (a) Lindsey, A. S.; Jeskey, H. Chem. Rev. 1957, 57, 583.
(b) Aresta, M.; Quaranta, E.; Tommasi, I.; Giannoccaro, P.; Ciccarese,
A. Gazz. Chim. Ital. 1995, 125, 509.
(18) (a) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368.
(b) Chen, F.-F.; Huang, K.; Zhou, Y.; Tian, Z.-Q.; Zhu, X.; Tao, D.-J.;
Jiang, D.; Dai, S. Angew. Chem., Int. Ed. 2016, 55, 7166. (c) Zhou, H.;
Wang, G.-X.; Zhang, W.-Z.; Lu, X.-B. ACS Catal. 2015, 5, 6773.
D
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