Palladium-Catalyzed Oxidative Arylation of 1H-Indazoles with Arenes

Article abstract of DOI:10.1002/ejoc.202001313

A simple method for the direct Pd(OAc)₂-catalyzed oxidative arylation of inactivated 1H-indazole derivatives with simple arenes is reported. This method exhibits good reaction efficiency and good functional-group tolerance. Using the developed method, 28 arylated products were prepared in yields up to 80 %.

Full text of DOI:10.1002/ejoc.202001313

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Palladium-Catalyzed Oxidative Arylation of 1H-Indazoles with
Arenes
Authors: Saïd El Kazzouli, Khadija Gambouz, Abdelmoula El Abbouchi,
Sarah Nassiri, Franck Suzenet, Mustapha Bousmina,
Mohamed Akssira, and Gérald Guillaumet
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001313
Link to VoR: https://doi.org/10.1002/ejoc.202001313
01/2020

10.1002/ejoc.202001313
European Journal of Organic Chemistry
Palladium-Catalyzed Oxidative Arylation of 1H-Indazoles with
Arenes
Khadija Gambouz,†,‡,§,£ Dr. Abdelmoula El Abbouchi,‡,§,£ Sarah Nassiri,‡,§,£ Prof. Franck
Suzenet,‡ Prof. Mustapha Bousmina§, Prof. Mohamed Akssira,† Prof. Gérald Guillaumet,‡,§ Prof.
Saïd El Kazzouli§,*
†Laboratoire de Chimie Physique et Chimie Bioorganique URAC 22 FSTM Université Hassan II – Casablanca, BP
146, 28800 Mohammedia, Morocco.
‡Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 7311, BP 6759, Orléans cedex 2
54067, France.
§Euromed Research Center, Engineering School of Biomedical and Biotechnology, Euromed University of Fes
(UEMF)–Route de Meknès, 30000 Fes, Morocco.
£ These authors contributed equally to this manuscript
* s.elkazzouli@ueuromed.org
Key words: 1H-indazole, oxidative arylation, palladium, C-H/C-H activation, arenes.
ABSTRACT
A simple method for the direct Pd(OAc)2-catalyzed oxidative arylation of inactivated 1H-indazole
derivatives with simple arenes is reported. This method exhibits good reaction efficiency and good
functional-group tolerance. Using the method developed, twenty-eight arylated products were
prepared in yields up to 80%.
INTRODUCTION:
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001313
European Journal of Organic Chemistry
In many natural products, pharmaceuticals, functional materials, and biologically active
compounds, arylated 1H-indazoles are paramount motifs1. The construction of C−C bonds, which
links indazole with arenes and heteroarenes, was ordinarily achieved by transition-metal-catalyzed
reactions such as Suzuki-Miyaura2, Heck3, Sonogashira4, Stille5 and Negishi6. Since these methods
use arylboronic acids, aryl halides, or other aryl organometallic compounds, they are less atom
economical and less green than more recently developed C-H activation methods (eq 1, scheme 1).
The subsequent development of C−H activation led to the direct arylation of 1H-indazole without
the need for the prefunctionalization of the starting material7. This method increasingly gained
interest because of its ability to further the development of efficiency in synthesis (eq 2, scheme
1). Another major advance in the development of C−H arylation is oxidative arylation8, which
provides a highly step- and atom-economical process in which neither of the partners requires
prefunctionalization.
Scheme 1: C-H activation of indazole
To date, the transition metal-catalyzed direct oxidative C−H/C−H arylation of benzo[h]quinolines9,
benzoxazoles10, xanthine11, and imidazo[1,2-a]pyridine12 have been reported with good yields. In
addition, Goa and You13 reported a palladium-catalyzed oxidative cross-coupling of electron-
deficient 2H-indazole with electro-rich heteroarenes to construct a large library of biheteroaryl
fluorophores, using Pd(PPh3)4 (5 mol %), Cu(OAc)2·H2O (1.5 equiv.), and pyridine (1.0 equiv.) in
1,4-dioxane at 120 °C for 24 hours. Notably, while our manuscript was in preparation, an elegant
2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001313
European Journal of Organic Chemistry
mechanochemical oxidative arylation of 1H-indazole in position 3 with 5-membered heteroarenes
using 20 mol % of Pd2(dba)3 in the presence of Cu(OAc)2·H2O and Na2SO4 has been
described14.This new protocol afforded C3-heteroarylated indazoles in moderate yields up to 45%.
Based on the previous antitumor drug candidates’ structures (Figure 1, E707015-17 and
ER3574518,19), indazole derivatives having sulfonamide moieties at C7 position (A) have been
developed in our laboratory,2d. This compound has significant cytotoxicities in vitro (Figure 1, A)
against human (colon and prostate) and murine (leukemia) cancer cell lines. Also, 7-NO2-1H-
indazoles, known as 7-NI, are believed to play a key role in the inhibition of all nitric oxide synthase
isoforms20. They have shown substantial neuroprotective effects against hypoxic damage (such as
stroke) and animal models of Parkinson disease21-25. Accordingly, we selected 1-methyl-7-nitro-
1H-indazole 1 as the benchmark reaction partner.
Figure 1: Examples of bioactive compounds containing indole or indazole.
To the best of our knowledge, so far, no examples of oxidative C3 arylation of 1H-indazole with
simple arenes have been reported. Herein, we wish to report the first example of a palladium-
catalyzed oxidative arylation of 1H-indazole using arenes as coupling partners in the presence of
10 mol % of Pd(OAc)2, 10 mol % of phenanthroline (Phen), Ag2CO3 and NaOH at 130 °C for 48
hours. Another coupling cycle was found necessary to achieve total reaction conversions by adding
5 mol % of Pd(OAc)2 and 5 mol % of Phen and heating the reaction mixture again for an additional
24 hours at the same temperature.
RESULTS AND DISCUCSSION:
3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001313
European Journal of Organic Chemistry
With indazole 1 and benzene as a substrate, we initiated our screening of different oxidants, bases,
palladium sources and ligands. The coupling partners also played the role of solvent.
Table 1: Optimization of direct oxidative arylation of 1-methyl-7-nitro-1H-indazole.
Entry
Catalyst
Ligand
Oxidant (2 equiv.)
Cu(OAc)2.H2O
Cu(OAc)2
Ag2CO3
Base
T °C
130
130
130
130
130
130
130
Time (h)
Yield (%)
Tracesa (95)b
0 (98)
Pd(OAc)2 20%
Pd(OAc)2 20%
Pd(OAc)2 20%
Pd(OAc)2 20%
Pd(OAc)2 20%
Pd(OAc)2 20%
Pd(OAc)2 20%
Phen 20%
Phen 20%
Phen 20%
Phen 20%
Phen 20%
Phen 20%
PPh3 20%
-
48
48
48
48
48
48
48
1
2
3
4
5
6
7
-
-
15 (77)
Ag2CO3
K2CO3 (1 eq)
K2CO3 (2 eq)
K2CO3 (2.5 eq)
K2CO3 (2 eq)
33 (50)
Ag2CO3
48 (41)
Ag2CO3
16 (72)
Ag2CO3
0 (92)
Pd(PPh3)2Cl2 20%
Pd(OAc)2 20%
Phen20%
Phen 20%
Ag2CO3
Ag2CO3
K2CO3 (2 eq)
Cs2CO3 (2 eq)
130
130
48
48
27 (65)
0 (94)
8
9
Pd(OAc)2 20%
Pd(OAc)2 10 + 5%
Pd(OAc)2 10%
Pd(OAc)2 15%
Pd(OAc)2 20%
Phen 20%
Phen 10 +5%
Phen 10%
Phen 15%
Phen 20%
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
NaOH (2 eq)
NaOH (2 eq)
NaOH (2 eq)
NaOH (2 eq)
NaOH (2 eq)
130
130
140
140
140
48
48 + 24
72
57 (36)
68 (traces)c
49 (40)d
10
11
12
13
14
72
55 (32)d
72
67 (traces)d
a yield of isolated product 2a; b yield of recovered starting material 1 in parentheses. c in this case the reaction was carried out using
two cycles 1 and 2. For cycle 1 the reaction was heated at 130 °C for 48 h, the 5 mol of Pd(OAc)2 10 % and 5 mol % of Phen were
added and the reaction was heated again for 24h. d in this case, the reaction mixture was heated at 140 °C for 72 h.
In initial screens, the use of 20 mol % of Pd(OAc)2, 20 mol % of Phen in the presence of 2 equiv.
of Cu(OAc)2.H2O or Cu(OAc)2 as oxidant gave only traces or no arylated product 2a (Table 1,
entries 1 and 2). In contrast, the use of 2 equiv. Ag2CO3 as oxidant provided more promising results
(Table 1, entry 3). This oxidant was then selected for further optimization studies. Remarkably, the
yield of product 2a was nearly trebled to 33 % by adding 1 equiv. of K2CO3 as base (Table 1, entry
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001313
European Journal of Organic Chemistry
4). When using 2 equiv. of K2CO3, the desired product was isolated with a promising 48 % yield
(Table 1, entry 5). With 2.5 equiv. of K2CO3, the yield dropped to 16 % (Table 1, entry 6). We
decided then to test Pd(PPh3)2Cl2 and PPh3 as the catalyst and ligand system. This proved
unsuccessful as only a slight amount of product 2a and unreacted starting material were recovered
(Table 1, entries 7 and 8). When employing 20 mol% of Pd(OAc)2 and 20 mol% of Phen in the
presence of both Ag2Co3 and Cs2CO3 at 130°C for 48 hours, no reaction was observed and only
starting material was recovered in 94%. Other bases were investigated and NaOH appeared to give
2a in the highest yield of 57 % (Table 1, entry 10).
Nevertheless, we noticed that after 48 hours, the reaction reached a stagnation point, with the
reaction mixture still containing the arylated product 2a, starting product 1 and benzene. Based on
this observation, we decided to add 10 mol% of Pd(OAc)2 and 5 mol% of the ligand and extend
the reaction to 24 hours. With this strategy, we were pleased to observe the completion of the
reaction and the arylated product 2a was isolated in 68% yield (entry 11, table 1). In order to avoid
the use of two reaction cycles, we decided to further optimize the reaction conditions. When the
mixture was heated at 140 °C instead of 130 °C for 72 hours using under the same reaction
conditions used for reaction cycle 1, the desired product 2a was isolated in 49% yield and the
starting material 1 was recovered in 40% yield (Table 1, entry 12). The increase of both the catalyst
and the ligand charges from 10 to 15 mol% led to the expected product 2a in 55% yield. But again,
32% of starting material was recovered (Table 1, entry 13). Finally, when using 20 mol % of
Pd(OAc)2 and 20 mol % of Phen, the reaction led to compound 2a in 67 % yield and only traces
of starting material 2 were observed (Table 1, entry 14). Interestingly, this yield was almost the
same as that obtained when using two reaction cycles (Table 1, entries 11 and 14).
With the optimized reaction conditions in hand, multiple simple arenes as coupling partners were
investigated to study the scope and limitation of this reaction. The arylated 1H-indazole 2a-f were
isolated with yields ranging from 60 to 80 % (from 58 to 80 % with two cycles, Table 2). In some
cases, the use of monosubstituted arenes generated a mixture of isomers regardless of electron-
donating or electron-withdrawing substituents, and the reaction took place mainly at less hindered
meta- and para-positions.
First, the starting material 1-methyl-7-nitro-1H-indazole was used with differently substituted
arenes (Table 2). The arylation partners toluene and chlorobenzene generated a mixture of isomers
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001313
European Journal of Organic Chemistry
(compounds 2b and 2c), while nitrobenzene provided only the para-arylated isomer 2d with a good
yield of 78 % (77 % with two cycles). When using disubstituted arenes, the reaction was sensitive
to steric hindrance and only occurred at the less hindered position. The use of o-xylene and o-
dichlorobenzene afforded the single coupling products 2e and 2f with good yields, 70 % and 80 %
respectively (71 % and 80 % respectively, with two cycles). The use of 2,3-dimethoxybenzene as
coupling partner led to the expected product 2g as one isomer in 57 % yield (Table 2).
Table 2: Oxidative arylation of 1-methyl-7-nitro-1H-indazole with arenes
a the yields calculated for reactions carried out using two cycles are in parentheses. b mixture of isomers (p/m/o): ratio calculated
by NMR integration.
Likewise, substrates bearing a nitro group at either the 6- or the 5-position gave the desired 3-
arylated products group (Table 3) in good yields (52-61 %). Regardless of the arenes involved
bearing either electron donating or electron withdrawing groups, the reaction yield was only
slightly impacted (compounds 3(a-c), 4(a-c) and 5(a-e)). In the case of the arylation of 5-
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001313
European Journal of Organic Chemistry
nitroindazole with toluene, a mixture of isomers was obtained 4b. Subsequently,1-methyl-1H-
indazole 4 was also investigated as starting material. Indazole 5 underwent the oxidative arylation
reaction to give the expected C3-arylated indazoles in moderate yields (Table 3). One isomer 5a
was obtained when using benzene as a coupling partner in a yield of 41 % (40 % yield with two
reaction cycles). Using monosubstituted arenes led to a mixture of isomers, with electron-
withdrawing groups giving slightly better yields than the electron-donor groups (compounds 5b
and 5c), while only the para-arylated indazole 5d was isolated with a moderate yield of 60 % (57
% yield with two reaction cycles) when using nitrobenzene as coupling partner. When employing
2,3-dimethoxybenzene as coupling partner, the expected product 5e was isolated as one isomer in
38 % yield (Table 3).
Table 3: Oxidative arylation of 1-methyl-1H-indazole derivatives with arenes
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001313
European Journal of Organic Chemistry
a the yields calculated for reactions carried out using two cycles are in parentheses. b mixture of isomers (p/m/o): ratio calculated
by NMR integration
Then, we decided to investigate the oxidative arylation reaction using benzene and various
indazoles containing electron withdrawing or electron donating functional groups at either
positions 5 or 6 as coupling partners. Regardless of the nature of the functional group (either
electron donating or electron withdrawing groups) on the indazoles employed as coupling partners,
the reaction yields were only slightly impacted (Table 4). The desired products 6(a-e) were isolated
in moderate yields ranging between 40 and 51 %. Nevertheless, when 1-methyl-1H-indazole-5-
carbonitrile was used as starting material, the arylated product 6f was isolated in a low yield (21
%). An improved yield was obtained with 1-methyl-1H-indazole-6-carbonitrile: in this case, the
expected product 6g was achieved in 34 % yield (Table 4).
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001313
European Journal of Organic Chemistry
Table 4: Oxidative arylation of 1-methyl-1H-indazole derivatives with benzene
Notably, the optimized conditions turned out to be effective also for 1-benzyl-5-nitro-1H-indazole
7. This starting material reacted with benzene to give 7a in 54 % yield (55 % with two reaction
cycles), while the reaction with toluene 7b and chlorobenzene 7c generated a mixture of isomers
with yields of 51% and 54% yield, respectively (53 to 57 % yield, respectively with two reaction
cycles, Table 5).
Table 5: Oxidative arylation of 1-benzyl-5-nitro-1H-indazole with arenes.
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001313
European Journal of Organic Chemistry
a the yields calculated for reactions carried out using two cycles are in parentheses. b mixture of isomers (p/m/o): ratio calculated
by NMR integration.
Based on previous mechanistic studies1,12,25, a plausible mechanism is proposed for this reaction in
Scheme 2. First, the starting material 1-methyl-7-nitro-1H-indazole 1 coordinates with the catalyst,
formed in situ from Pd(OAc)2 and 1,10- phenanthroline, to assemble the intermediate 1. Afterward,
the intermediate 1 reacts with benzene, leading to the intermediate 2 via a C-H activation of the C3
position of indazole. Then, the intermediate 2 undergoes reductive elimination to give the desired
product 2a. Finally, the Pd is oxidized by Ag+ to regenerate Pd(OAc)2.
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001313
European Journal of Organic Chemistry
Scheme 2. Plausible mechanism of oxidative arylation of indazole 1.
CONCLUSION
In conclusion, we have developed the first C3-oxidative arylation of 1H-indazole using arenes as
coupling partners. The optimized reaction conditions showed good compatibility with different 1H-
indazole derivatives and tolerance to arenes bearing various functional groups. In some cases, good
regioselectivities were observed while in other cases, mixtures of two or three isomers were
obtained.
REFERENCES :
11
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001313
European Journal of Organic Chemistry
1- S. El Kazzouli, G. Guillaumet, Tetrahedron, 2016, 72, 6711.
2- (a) V. Collot, P. Dallemagne, P. R.Bovy, S. Rault, Tetrahedron, 1999, 55, 6917 (b) L. Bouissane,
S. El Kazzouli, J. M. Leger, C. Jarry, E. M. Rakib, M. Khouili, G. Guillaumet, Tetrahedron, 2005,
61, 8218 (c) S. El Kazzouli, L. Bouissane, M. Khouili, G. Guillaumet, Tetrahedron Lett. 2005, 46,
6163 (d) L. Bouissane, S. El Kazzouli, S. Leonce, B. Pfeiffer, E. M. Rakib, M. Khouili, G.
Guillaumet, Bioorg. Med. Chem. 2006, 14, 1078 (e) F. Crestey, E. Lohou, S. Stiebing, V. Collot, S.
Rault, Synlett, 2009, 615 (f) J. M. Salovich, C. W. Lindsley, C. R. Hopkins, Tetrahedron Lett. 2010,
51, 3796 (g) A. Migliorini, C. Oliviero, T. Gasperi, M. A. Loreto, Molecules, 2012, 17, 4508 (h) A.
Ben-Yahia, M. Naas, N. El Brahmi, S. El Kazzouli, J. P. Majoral, E. M. Essassi, G. Guillaumet,
Curr. Org. Chem. 2013, 17, 304 (i) M. A. Duefert, K. L. Billingsley, S. L. Buchwald, J. Am. Chem.
Soc. 2013, 135, 12877 (j) L. Ye, X. Ou, Y. Tian, B. Yu, Y. Luo, B. Feng, H. Lin, J. Zhang, S. Wu,
Eur. J. Med. Chem. 2013, 65, 112 (k) R. Li, B. Cui, Y. Li, C. Zhao, N. Jia, C. Wang, Y. Wu, A.
Wen, Eur. J. Pharmacol. 2014, 724, 77 (l) P. Padmaja, M. Yedukondalu, R. Sridhar, S. Busi, M. V.
B. Rao, Lett. Drug Des. Discov. 2013, 10, 625 (m) M. Brzozowski, N. J. O’Brien, D. J. D. Wilson,
B. M. Abbott, Tetrahedron, 2014, 70, 318 (n) S. Gogireddy, A. M.Kalle, P. K.Dubey, A. V.Reddy,
J. Chem. Sci. 2014, 126, 1055 (o) S. Babu, R. Jr. Dagnino, M. A. Ouellette, B. Shi, Q. Tian, S. E.
Zook, WO/2006/048745, PCT/IB2005/003300 (p) S. Babu, R. Jr. Dagnino, A. Haddach, M. B.
Mitchell, M. A.Ouellette, J. E. Saenz, J. K. Srirangam, S. E. Zook, WO/2006/048761,
PCT/IB2005/003348 (q) B. A. Egan, P. M. Burton, RSC Adv. 2014, 4, 27726 (r) N. J. Kallman, C.
Liu, M. H. Yates, R. J. Linder, J. C. Ruble, E. F. Kogut, L. E. Patterson, D. L. T. Laird, M. M.
Hansen, Org. Biomol. Chem. 2014, 18, 501 (s) S. A. Sadler, A. C. Hones, B. Roberts, D. Blakemore,
T. B. Marder, P. G. Steel J. Org. Chem. 2015, 80, 5308.
3- (a) V. Collot, D. Varlet, S. Rault, Tetrahedron Lett. 2000, 41, 4363 (b) M. Singh, O. Odusanya, G.
M. Wilmes, H. B. Eitouni, E. D. Gomez, A. J. Patel, V. L. Chen, M. J. Park, P. Fragouli, H. Iatrou,
N. Hadjichristidis, D. Cookson, N. P. Balsara, Macromolecules, 2007, 40, 4578 (c) R. J. Elly, O.
Rixe, Target. Oncol. 2009, 4, 297 (d) R. J. Kelly, O. Rixe, Recent Results Canc. Res. 2010, 184, 33
(e) L. H. Zhai, L. H. Guo, Y. H. Luo, Y. Ling, B. W. Sun, Org. Process Res. Dev. 2015, 19, 849.
4- (a) A. Arnautu, V. Collot, J. C. Ros, C. Alayrac, B. Witulski, S. Rault, Tetrahedron Lett. 2002, 43,
2695 (b) B. Witulski, J. R. Azcon, C. Alayrac, A. Arnautu, V. Collot, S. Rault, Synthesis, 2005, 771
(c) E. Merkul, F. Klukas, D. Dorsch, U. Graedler, H. E. Greiner, T. J. J. Mueller, Org. Biomol.
Chem. 2011, 9, 5129.
5- (a) A. Fraile, M. Rosario Martin, J. L. Garcia Ruano, D. J. Antonio, E. Arranz, Tetrahedron, 2011,
67, 100 (b) M. De Angelis, F. Stossi, K. A. Carlson, B. S. Katzenellenbogen, J. A.
Katzenellenbogen, J. Med. Chem. 2005, 48, 1132 (c) G. D. Zhu, V. B. Gandhi, J. Gong, S. Thomas,
12
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001313
European Journal of Organic Chemistry
K. W. Woods, X. Song, T. Li, R. B. Diebold, Y. Luo, X. Liu, R. Guan, V. Klinghofer, E. F. Johnson,
J. Bouska, A. Olson, K. C. Marsh, V. S. Stoll, M. Mamo, J. Polakowski, T. J. Campbell, R. L.
Martin, G. A. Gintant, T. D. Penning, Q. Li, S. H. Rosenberg, V. L. Giranda, J. Med. Chem. 2007,
50, 2990.
6- A. Unsinn, P. Knochel, Chem. Commun. 2012, 48, 2680.
7- (a) K. Hattori, K. Yamaguchi, J. Yamaguchi, K. Itami, Tetrahedron, 2012, 68, 7605 (b) M. Ye, A.
J. F. Edmunds, J. A. Morris, D. Sale, Y. Zhang, J. Q. Yu, Chem. Sci. 2013, 4, 2374 (c) M. Naas, S.
El Kazzouli, E. M. Essassi, M. Bousmina, G. Guillaumet, J. Org. Chem. 2014, 79, 7286.
8- (a) Y. Yang, J. Lan, J. You, Chem. Rev. 2017, 117, 8787. (b) R. Narobe, S. J. S. Düsel, J. Iskra. B.
König, Adv. Synth. Catal. 2019, 361, 3893. (c) H. Kim, R. S. Thombal, H. D. Khanal Y. R. Lee,
Chem. Commun. 2019, 55, 13402.
9- K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2007, 129, 11904.
10- G. Wu, J. Zhou, M. Zhang, P. Hu, W. Su, Chem. Commun. 2012, 48, 8964.
11- C. C. Malakar, D. Schmidt, J. Conrad, U. Beifuss, Org. Lett. 2011, 13, 1378.
12- T. Guo, J. J. Liang, S. Yang, H. Chen, Y. N. Fu, S. L. Han, Y. H. Zhao, Org. Biomol. Chem. 2018,16,
6039.
13- Y. Cheng, G. Li, Y. Liu, Y. Shi, G. Gao, D. Wu, J. Lan, J. You, J. Am. Chem. Soc. 2016, 138, 14,
4730.
14- J. Yu, X. Yang, C. Wu, W. Su, J. Org, Chem. 2020, 85, 1009.
15- (a) T. Owa, H. Yoshino, T. Okauchi, N. Sugi, Y. Ozawa, T. Nagasu, Y. Fujikawa, Y. Sawa, K.
Kitoh, K. Yoshimatsu, Ann. Oncol. Suppl. 1996, 7, 399 (b) Y. Ozawa, N. Sugi, T. Watanabe, T.
Nagasu, T. Owa, N. Koyanagi, K. Kitoh, K. Yoshimatsu, Ann. Oncol. Suppl. 1996, 7, 140 (c) T.
Watanabe, N. Sugi, Y. Ozawa, T. Owa, T. Nagasu, N. Koyanagi, K. Kitoh, K. Yoshimatsu, Proc.
Am. Assoc. Cancer Res. 1996, 37, A2667, 391.
16- (a) T. Owa, H. Yoshino, T. Okauchi, K. Yoshimatsu, Y. Ozawa, N. H. Sugi, T. Nagasu, N.
Koyanagi, K. Ktoh, J. Med. Chem. 1999, 42, 3789 (b) Y. Oda, T. Owa, T. Sato, B. Boucher, S.
Daniels, H. Yamanaka, Y. Yamanaka, Y. Shinohara, A. Yokoi, J. Kuromitsu, T. Nagasu, Anal.
Chem. 2003, 75, 2159 (c) F. Abbate, A. Casini, T. Owa, A. Scozzafava, C. T. Supuran, Bioorg.
Med. Chem. Lett. 2004, 14, 217.
17- Y. Ozawa, N. H. Sugi, T. Nagasu, T. Owa, T. Watanabe, N. Koyanagi, H. Yoshino, K. Kitoh, K.
Yoshimatsu, Eur. J. Cancer, 2001, 37, 2275.
18- T. Owa, T. Okauchi, K. Yoshimatsu, N. H. Sugi, Y. Ozawa, T. Nagasu, N. Koyanagi, T. Okabe, K.
Kitoh, H. Yoshino, Bioorg. Med. Chem. Lett. 2000, 10, 1223 (b) T. Owa, A. Yokoi, K. Yamazaki,
K. Yoshimatsu, T. Yamori, T. Nagasu, J. Med. Chem. 2002, 45, 4913 (c) A. Yokoi, J. Kuromitsu,
13
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001313
European Journal of Organic Chemistry
T. Kawai, T. Nagasu, N. H. Sugi, K. Yoshimatsu, H. Yoshino, T. Owa, Mol. Cancer Ther. 2002, 1,
275.
19- T. Owa, H. Yoshino, T. Okauchi, T. Okabe, Y. Ozawa, N. H. Sugi, K. Yoshimatsu, T. Nagasu, N.
Koyanagi, K. Kitoh, Bioorg. Med. Chem. Lett. 2002, 12, 2097.
20- P. A. Bland-Ward, P. K. Moore, Life Sci. 1995, 57, 131.
21- G. J. Southan, C. Szabó. Biochem. Pharmacol. 1996, 51, 383.
22- P. K. Moore, P. Wallace, Z. Gaffen, S. L. Hart, R. C. Babbedge, Br. J. Pharmacol. 1993, 110, 219.
23- R. C. Babbedge, P. A. Bland-Ward, S. L. Hart, P. K. Moore, Br. J. Pharmacol. 1993, 110, 225.
24- P. K. Moore, R. C. Babbedge, P. Wallace, Z. A. Gaffen, S. L. Hart, Br. J. Pharmacol. 1993, 108,
296.
25- J. B. Schulz, R. T. Matthews, T. Klockgether, J. Dichgans, M. F. Beal, Mol. Cell. Biochem. 1997,
174, 193.
14
This article is protected by copyright. All rights reserved.