Cu-Catalyzed π-Core Evolution of Benzoxadiazoles with Diaryliodonium Salts for Regioselective Synthesis of Phenazine Scaffolds

Article abstract of DOI:10.1021/acs.orglett.8b01748

The Cu-catalyzed regioselective synthesis of phenazine N-oxides was realized from benzoxadiazoles and diaryliodonium salts. The process was initiated by the electrophilic arylation of benzoxadiazoles with diaryliodonium salts and followed by benzocyclization reactions. The further reduction of N-oxides in situ to phenazine scaffolds and deviation to organic fluorescent materials were readily accomplished.

Full text of DOI:10.1021/acs.orglett.8b01748

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cu-Catalyzed π‑Core Evolution of Benzoxadiazoles with
Diaryliodonium Salts for Regioselective Synthesis of Phenazine
Scaffolds
Jinyu Sheng,† Ru He,† Jie Xue, Chao Wu, Juan Qiao, and Chao Chen*
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education) & Key Lab of Organic
Optoelectronics and Molecular Engineering of Ministry of Education, Department of Chemistry, Tsinghua University, Beijing
100084, China
S
* Supporting Information
ABSTRACT: The Cu-catalyzed regioselective synthesis of phenazine N-oxides was realized from benzoxadiazoles and
diaryliodonium salts. The process was initiated by the electrophilic arylation of benzoxadiazoles with diaryliodonium salts and
followed by benzocyclization reactions. The further reduction of N-oxides in situ to phenazine scaffolds and deviation to organic
fluorescent materials were readily accomplished.
henazine derivatives, as well as their N-oxides and N,N′-
and lack of a sufficient force.9 We considered iodonium salts to
be efficient electrophiles, which could be used to realize our
design. To the best of our knowledge, direct heterocyclic ring
opening transformations by iodonium salts are unprecedented.
To this end, we report a novel modular method leading to
phenazine N-oxides with excellent regioselectivity (Scheme 2).
The new synthesis started with benzoxadiazoles and diary-
liodonium salts, via the regioselective arylation of N atom with
diaryliodonium salts, and rapidly yielded phenazines with
excellent selectivity.
In preliminary experiments, benzoxadiazole 4a was reacted
with di-4-tolyliodonium salt 5a under benign conditions with 10
mol % of CuBr at 55 °C, as shown in Table 1. To our delight,
phenazine N-oxide 2a was obtained in 76% yield (Table 1, entry
1). Moreover, only one syn-isomer (i.e., methyl group located at
the closer position to the O atom) was observed. The yields were
affected by reaction temperature: 89% yield was obtained at 70
°C. Solvent had greater influence on the reaction: DCM, CCl4,
EtOAc, and toluene were inferior to DCE. In terms of catalysts,
the reaction showed low efficiency in the absence of copper salts
and performed best with CuBr among the common copper salts.
The above results have shown the facile construction of
phenazine N-oxides with benzoxadiazoles and diaryliodonium
salts. Inspired by this, we further investigated the scope of
diaryliodonium salts by introducing various substituents.
Substituted diaryliodonium triflates are readily prepared by
known methods and are widely used in organic synthesis.10
P
dioxides, have been known for more than 150 years with
significant biological effects including antibacterial, antifungal,
antiviral, and antitumor activities.1 Aided by the rapid progress
of pharmacological study, various drug molecules bearing the
scaffold have been designed and evaluated.2 As a large electron-
deficient conjugated system, phenazines possess two dentate N
atoms and three fused aromatic rings. Due to these character-
istics, phenazines easily form hydrogen bonds, ionic bonds, and
π−π interactions, and very recently, they have been extensively
applied in supramolecular chemistry for molecular recognition
(MR), supramolecular self-assembly (MS-A), and organic optic-
electronics materials.3,4 The limited commercial availability of
substituted phenazines does not meet the increasing demand of
their applications and has ultimately challenged synthetic
chemists. To date, few efficient and generally applicable
syntheses of substituted phenazines exist.5,6 Some classical
reactions are known to produce phenazine derivatives (Scheme
1).1,7 However, these methods showed severe disadvantages
such as harsh reaction conditions, limited substrate scope, low
yield, as well as selectivity. Hence, the development of practical
approaches to phenazines from common building blocks bearing
more diversified substituents is still highly attractive and
challenging, especially for the synthesis of asymmetric
phenazines. We envision that benzoxadiazole derivatives may
serve this purpose using diaryliodonium salts via π-conjugation
expansion of benzoxadiazoles for the nucleophilicity of the
nitrogen atom and the polarized, cleavable N−O bond.8
However, a few transformations were realized from benzox-
adiazoles to other skeletons possibly because of low reactivity
Received: June 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01748
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
worked well with benzoxadiazole 4a to give desired products
2ab−al (isolated yields shown in Scheme 3). The reaction was
Scheme 1. Approaches to Asymmetric Phenazine Synthesis
Scheme 3. Facile Construction of Phenazine N-Oxides with
4a and Various Diaryliodonium Salts
readily scalable as demonstrated by the gram-scale synthesis of
2ac in 2.42 g yield. Gratifyingly, the substituents were exclusively
located at the syn-position to the N-oxide atom. When bis(2-
chlorophenyl)iodonium salt 5m was employed, a moderate yield
of product 2am was obtained at 100 °C, probably due to the
steric hindrance. Interestingly, bis(m-fluorophenyl)iodonium
salt 5n was reacted with 4a to give major product 2an, indicating
the benzocyclization mainly happened at the para-position,
rather than the ortho-position of fluorine. Finally, disubsituted
diaryliodonium triflates also worked in the reaction and gave
products 2ao and 2ap in synthetically useful yields.
Scheme 2. Construction of Phenazine N-Oxides 2
Encouraged by the successful benzocyclization of benzox-
adiazoles 4a with diaryliodoniums 5, we next attempted to
examine the reactions of substituted benzoxadiazoles 4 to
synthesize more phenazine N-oxides (isolated yields shown in
Scheme 4). Typically, when 5-methoxybenzoxadiazole 4b was
Table 1. Optimization of the Reaction Conditions
Scheme 4. Scope of Benzoxadiazoles 4 with 5
entry
temp (°C)
solvent
cat. 10 %
CuBr
CuI
Cu(OTf)2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
isolated yield (%)
1
2
3
4
5
6
7
8
55
55
55
70
80
70
70
70
70
70
70
70
70
70
70
70
DCE
DCE
DCE
DCE
DCE
DCM
CCl4
EtOAc
toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
76
66
45
89
82
83
39
21
46
18
67
70
57
82
72
84
9
10
11
12
13
14
15
16
CuCl
CuTc
Cu(OAc)2
Cu2O
CuF2
CuBr ·SMe2
Diaryliodoniums with a range of substituents at the para-
position involving halogen atoms (Br-, Cl-, and F-), as well as
other electron-donating and electron-withdrawing groups all
B
DOI: 10.1021/acs.orglett.8b01748
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reacted with 5a, product 2ba was formed exclusively in 77%
yield. The location of the methoxy group was attributed to the
electron-donating conjugation effect. The regioselectivity was
further demonstrated by other groups including fluoro,
morpholinyl, ethylthio, anisyl, and heptynyl groups. The
structure of anisylphenazine 5-oxide 2fa was unequivocally
demonstrated by X-ray crystal structure analysis.
Interestingly, when 5-(trifluoromethyl)benzoxadiazole 4j was
used, the major product was 3-methyl-7-(trifluoromethyl)-
phenazine 5-oxide 2ja (53% yield with 23% of regioisomer). As a
comparison, when 5-(ethylsulfonyl)benzoxadiazole 4m was
reacted, the sole product was 3-methyl-7-(ethylsulfonyl)-
phenazine 5-oxide 2ma, which showed a different selectivity to
5-(ethylthio)benzoxadiazole 4e. Benzoxadiazoles with 5,6-
dichloro and 5,6-dimethyl groups also worked well to supply
compounds 2ha and 2ia in good yields. Besides 5a, the reactions
of other iodonium salts 5c and 5e also proceeded regioselec-
tively to afford products 2dc and 2ce. The X-ray crystal structure
analysis has further confirmed the regioselective formation of
2dc.
electrophilic annulation to give intermediate IV, which would
lose the proton eventually to form the product 2ba. The series of
cationic intermediates in this cascade annulation ensured the
smooth process and high regioselectivity for asymmetric
benzoxadizoles 4.
The phenazine derivatives were often synthesized from the N-
oxides by reduction.14,15 Actually, the reduction reaction of 2ac
could be performed in one pot to give 1ac in 78% yield. When
the newly prepared N-oxides were isolated and further reduced
to by Zn/NH4Cl or P(OEt)3, the products were obtained in
good yields (Scheme 6).
Scheme 6. Reduction of Phenazine N-Oxides to the Parent
Forms
The above findings showed that the regioselectivity highly
depended on the electron effect of the subsitutents. In the
competition reaction of 4a with asymmetric diaryliodonium salt
(4-CH3Ph)(4-MeO2CPh)I+OTf− 5q, product 2aa was observed
exclusively without the formation of 2ah (Scheme 5, eq 1). This
Phenazines are an important kind of electron-deficient
chromophore in chemical luminescence.16 Our new method
provided the syn and anti arrangement of O atom of phenazine
N-oxides, which could be used and compared with the reduced
form (Scheme 7) in terms of the optical effect. Along this line, a
Scheme 5. Variations and Mechanistic Implications
Scheme 7. Synthesis of Compounds 8, 8a, 8b and 9, 9a, 9b
strongly donating group, di(4-biphenyl)amino, was designed to
conjugate the phenazine core with or without a phenyl bridge
(compound 8 and 9, respectively). These parent phenazines
could be readily obtained by reduction from their syn or anti N-
oxide, which could be prepared from the corresponding
benzoxadiazole. Actually, the bromo compound of 2ac was
replaced by diarylamino group (Buchwald−Hartwig amination)
to give 9b or a diarylamino phenyl group (Suzuki coupling) to
give 8b. On the other hand, the diarylamino group could also be
conjugated to the benzoxadiazole core first via the same
reactions to give precursors, which were reacted with 5b to give
products 8a and 9a, respectively (see the Supported Information
for details).
In summary, the Cu-catalyzed regioselective synthesis of
phenazine N-oxides was realized from benzoxadiazoles and
diaryliodonium salts under benign conditions. The process was
initiated by the electrophilic arylation of benzoxadiazoles with
diaryliodonium salts and followed by benzocyclization reactions.
The further reduction of N-oxides in situ to phenazine scaffolds
and deviation to organic fluorescent materials were readily
accomplished. A broad scope of substrates has been established
and scale synthesis can be realized, which further strengthens the
impact of this method.
was attributed to the dominant formation of 4-Tol+ (leading to
compound 2aa) rather than 4-MeO2CPh+ from 2q.11 Addition-
ally, when anthranil 6a was reacted with 2a under the standard
conditions, a similar benzocyclization reaction occurred to give
product 7aa in 65% yield (Scheme 5, eq 2). These results
strongly support an electrophilic process. It has been reported
that the diaryl iodonium salts could undergo a carbocation-like
reaction to nucleophiles catalyzed by copper salts via Ar-Cu(III)
species.10f,12 On the basis of the above results, we propose a
mechanism with Ar-Cu(III) species involved for the reaction
depicted in Scheme 5 (exemplified by 4b and 5a as the substrates
to show the substitution effect). Presumably, oxidative addition
to the CuBr with 5a gives a 4-tol-Cu(III) species I, which could
regioselectively arylate 3-N atom in 4b, based on the electronic
effect. The newly formed N-tolylbenzoxadiazole II is a highly
reactive species and quickly isomerizes to nitrogen cation III via
cleavage of the N−O bond.8,13 The cation III undergoes an
C
DOI: 10.1021/acs.orglett.8b01748
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(4) (a) Horiuchi, S.; Ishii, F.; Kumai, R.; Okimoto, Y.; Tachibana, H.;
Nagaosa, N.; Tokura, Y. Nat. Mater. 2005, 4, 163. (b) Horiuchi, S.;
Kumai, R.; Tokura, Y. J. Am. Chem. Soc. 2005, 127, 5010. (c) Lu, X.;
Lan, T.; Qin, Z.; Wang, Z.-S.; Zhou, G. ACS Appl. Mater. Interfaces
2014, 6, 19308. (d) Bunz, U. H. F.; Engelhart, J. U.; Lindner, B. D.;
Schaffroth, M. Angew. Chem., Int. Ed. 2013, 52, 3810. (e) Miao, Q. Adv.
Mater. 2014, 26, 5541.
(5) (a) Merz, R. Ber. Dtsch. Chem. Ges. 1886, 19, 725. (b) Emoto, T.;
Kubosaki, N.; Yamagiwa, Y.; Kamikawa, T. Tetrahedron Lett. 2000, 41,
355. (c) Spicer, J. A.; Gamage, S. A.; Rewcastle, G. W.; Finlay, G. J.;
Bridewell, D. J. A.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 2000, 43,
1350. (d) China Raju, B. C.; Veera Prasad, K. V.; Saidachary, G.;
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01748.
■
S
Details of the experiments and H and 13C NMR of all
new compounds (PDF)
1
Accession Codes
CCDC 1833659−1833660 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
́
Sridhar, B. Org. Lett. 2014, 16, 420. (e) Wrobel, Z.; Stachowska, K.;
Kwast, A. Eur. J. Org. Chem. 2014, 2014, 7721. (f) Koepf, M.; Lee, S. H.;
́
́
Brennan, B. J.; Mendez-Hernandez, D. D.; Batista, V. S.; Brudvig, G.
W.; Crabtree, R. H. J. Org. Chem. 2015, 80, 9881. (g) Seth, K.; Raha
Roy, S.; Chakraborti, A. K. Chem. Commun. 2016, 52, 922.
(6) An efficient method for phenazine synthesis while not being
applicable for a large-scale synthesis: Lian, Y.; Hummel, J. R.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2013, 135, 12548.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chenchao01@mails.tsinghua.edu.cn.
ORCID
(7) (a) Wohl, A.; Aue, W. Ber. Dtsch. Chem. Ges. 1901, 34, 2442.
(b) Bamberger, E.; Ham, W. Ann. Chem. 1911, 382, 82. (c) Haddadin,
M. J.; Issidorides, C. H. Tetrahedron Lett. 1965, 6, 3253.
(8) (a) Jin, H.; Huang, L.; Xie, J.; Rudolph, M.; Rominger, F.; Hashmi,
A. S. K. Angew. Chem., Int. Ed. 2016, 55, 794. (b) Yu, S.; Tang, G.; Li, Y.;
Zhou, X.; Lan, Y.; Li, X. Angew. Chem., Int. Ed. 2016, 55, 8696. (c) Zou,
M.; Liu, J.; Tang, C.; Jiao, N. Org. Lett. 2016, 18, 3030. (d) Zhou, A.-H.;
He, Q.; Shu, C.; Yu, Y.-F.; Liu, S.; Zhao, T.; Zhang, W.; Lu, X.; Ye, L.-W.
Chem. Sci. 2015, 6, 1265.
Juan Qiao: 0000-0002-9919-3927
Chao Chen: 0000-0002-7644-0884
Author Contributions
†J.S. and R.H. contributed equally.
Notes
(9) (a) Samsonov, V. A. Russ. Chem. Bull. 2007, 56, 2510. (b) Idris, I.;
́
Derridj, F.; Soule, J.-F.; Doucet, H. Adv. Synth. Catal. 2017, 359, 2448.
The authors declare no competing financial interest.
(c) Issidorides, C. H.; Haddadin, M. J. Heterocycles 1976, 4, 767.
(d) Haddadin, M. J.; Issidorides, C. H. Heterocycles 1993, 35, 1503.
(10) For synthesis: (a) Bielawski, M.; Zhu, M.; Olofsson, B. Adv.
Synth. Catal. 2007, 349, 2610. (b) Zhdankin, V. V.; Stang, P. J. Chem.
Rev. 2008, 108, 5299. (c) Merritt, E. A.; Olofsson, B. Angew. Chem., Int.
Ed. 2009, 48, 9052. (d) Skucas, E.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2012, 134, 9090. For the reactions: (e) Phipps, R. J.; Grimster, N.
P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. (f) Phipps, R. J.;
Gaunt, M. J. Science 2009, 323, 1593. (g) Wang, Y.; Chen, C.; Peng, J.;
Li, M. Angew. Chem., Int. Ed. 2013, 52, 5323. (h) Peng, J.; Chen, C.;
Wang, Y.; Lou, Z.; Li, M.; Xi, C.; Chen, H. Angew. Chem., Int. Ed. 2013,
52, 7574. (i) Gao, P.; Guo, W.; Xue; Zhao, J. Y.; Yuan, Y.; Xia, Y.; Shi, Z.
J. Am. Chem. Soc. 2015, 137, 12231. (j) Yang, Y.; Li, R.; Zhao, Y.; Zhao,
D.; Shi, Z. J. Am. Chem. Soc. 2016, 138, 8734.
(11) (a) Guo, W.; Li, S.; Tang, L.; Li, M.; Wen, L.; Chen, C. Org. Lett.
2015, 17, 1232. (b) Sheng, J.; Su, X.; Cao, C.; Chen, C. Org. Chem.
Front. 2016, 3, 501.
(12) (a) Chen, B.; Hou, X.-L.; Li, Y.-X.; Wu, Y.-D. J. Am. Chem. Soc.
2011, 133, 7668. (b) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc.
2011, 133, 4260. (c) Phipps, R. J.; McMurray, L.; Ritter, S.; Duong, H.
A.; Gaunt, M. J. J. Am. Chem. Soc. 2012, 134, 10773.
(13) Zhou, J.; Liu, L. L.; Cao, L. L.; Stephan, D. W. Angew. Chem., Int.
Ed. 2018, 57, 3322.
(14) Balicki, R.; Cybulski, M.; Maciejewski, G. Synth. Commun. 2003,
33, 4137.
(15) Bouffard, J.; Swager, T. M. Macromolecules 2008, 41, 5559.
(16) (a) Okazaki, M.; Takeda, Y.; Data, P.; Pander, P.; Higginbotham,
H.; Monkman, A. P.; Minakata, S. Chem. Sci. 2017, 8, 2677. For a
comparison with the anthracene-9,10-dione derivative, see: (b) Zhang,
Q.; Kuwabara, H.; Potscavage, W. J., Jr.; Huang, S.; Hatae, Y.; Shibata,
T.; Adachi, C. J. Am. Chem. Soc. 2014, 136, 18070.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21672120), the Fok Ying Tong
Education Foundation China (No. 151014), and The National
Key Research and Development Program of China
(2016YFB0401400). We thank Mr. Zi-Ang Nan(iChEM) for
his help with the single-crystal XRD analysis.
REFERENCES
■
(1) (a) Neves-Pinto, C.; Malta, V.; Pinto, M.; Santos, R.; de Castro, S.;
Pinto, A. J. Med. Chem. 2002, 45, 2112. (b) Cartwright, D.; Chilton, W.;
Benson, D. Appl. Microbiol. Biotechnol. 1995, 43, 211. (c) Ligon, J.; Hill,
D. S.; Hammer, P.; Torkewitz, N.; Hofmann, D.; Kempf, H.; Pee, K.
Pest Manage. Sci. 2000, 56, 688. (d) Makgatho, M.; Anderson, R.;
O’Sullivan, J.; Egan, T.; Freese, J.; Cornelius, N.; Van Rensburg, C. Drug
Dev. Res. 2000, 50, 195. (e) de Andrade-Neto, V.; Goulart, M.; da Silva
Filho, J.; da Silva, M. J.; Pinto, M.; Pinto, A.; Zalis, M.; Carvalho, L.;
Krettli, A. Bioorg. Med. Chem. Lett. 2004, 14, 1145. (f) Rewcastle, G. W.;
Denny, W. A.; Baguley, B. C. J. Med. Chem. 1987, 30, 843.
(g) McDonald, M.; Mavrodi, D. V.; Thomashow, L. S.; Floss, H. G.
J. Am. Chem. Soc. 2001, 123, 9459. (h) Price-Whelan, A.; Dietrich, L. E.
P.; Newman, D. K. Nat. Chem. Biol. 2006, 2, 71. (i) Guttenberger, N.;
Blankenfeldt, W.; Breinbauer, R. Bioorg. Med. Chem. 2017, 25, 6149.
(2) (a) Laursen, J. B.; Nielsen, J. Chem. Rev. 2004, 104, 1663.
(b) Pierson, L. S.; Pierson, E. A. Appl. Microbiol. Biotechnol. 2010, 86,
1659. (c) Kondratyuk, T. P.; Park, E.-J.; Yu, R.; van Breemen, R. B.;
Asolkar, R. N.; Murphy, B. T.; Fenical, W.; Pezzuto, J. M. Mar. Drugs
2012, 10, 451. (d) Cimmino, A.; Evidente, A.; Mathieu, V.; Andolfi, A.;
Lefranc, F.; Kornienko, A.; Kiss, R. Nat. Prod. Rep. 2012, 29, 487.
(3) (a) Xue, H.; Tang, X.-J.; Wu, L.-Z.; Zhang, L.-P.; Tung, C.-H. J.
Org. Chem. 2005, 70, 9727. (b) Brombosz, S. M.; Zucchero, A. J.;
Phillips, R. L.; Vazquez, D.; Wilson, A.; Bunz, U. H. F. Org. Lett. 2007, 9,
4519. (c) Gill, M. R.; Cecchin, D.; Walker, M. G.; Mulla, R. S.; Battaglia,
G.; Smythe, C.; Thomas, J. A. Chem. Sci. 2013, 4, 4512. (d) Li, W.; Qu,
W.; Zhang, H.; Li, X.; Lin, Q.; Yao, H.; Zhang, Y.; Wei, T. Youji Huaxue
2017, 37, 2639.
D
DOI: 10.1021/acs.orglett.8b01748
Org. Lett. XXXX, XXX, XXX−XXX