N-Bromosuccinimide-Induced C-H Bond Functionalization: An Intramolecular Cycloaromatization of Electron Withdrawing Group Substituted 1-Biphenyl-2-ylethanone for the Synthesis of 10-Phenanthrenol

Article abstract of DOI:10.1021/acs.orglett.8b01160

An NBS-induced intramolecular cycloaromatization for the synthesis of 10-phenanthrenols from electron-withdrawing group substituted 1-biphenyl-2-ylethanones is described. The in situ generated bromide was designed to act as an initiator for the radical C-H bond activation. An oxidative cross-dehydrogenative coupling reaction of a highly active C-H bond with an inert C-H bond readily occurs under mild conditions without the need for transition metals or strong oxidants.

Full text of DOI:10.1021/acs.orglett.8b01160

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
N‑Bromosuccinimide-Induced C−H Bond Functionalization:
An Intramolecular Cycloaromatization of Electron Withdrawing
Group Substituted 1‑Biphenyl-2-ylethanone for the Synthesis of
10‑Phenanthrenol
Ya-Ting Jiang, Zhen-Zhen Yu, Ya-Kai Zhang, and Bin Wang*
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research,
Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, People’s Republic of China
S
* Supporting Information
ABSTRACT: An NBS-induced intramolecular cycloaromatization for the
synthesis of 10-phenanthrenols from electron-withdrawing group substituted
1-biphenyl-2-ylethanones is described. The in situ generated bromide was
designed to act as an initiator for the radical C−H bond activation. An
oxidative cross-dehydrogenative coupling reaction of a highly active C−H
bond with an inert C−H bond readily occurs under mild conditions without
the need for transition metals or strong oxidants.
Scheme 1. Reported Methods and Our Design for the
Phenanthrene Synthesis
atural products containing a phenanthrene skeleton
1
2
Nshow various biological activities such as antitumor,
antimicrobial,3 antiallergic,4 and antimalarial activities.5 Fur-
ther, many synthetic phenanthrene frameworks are frequently
found in organic photoelectronic materials,6 carbon nano-
tubes,7 superconducting materials,8 and chelating ligands.9 The
traditional approaches toward the synthesis of phenanthrene
include photocyclization10 and McMurry coupling reaction.11
These early procedures are not always satisfying, and they
suffer from side reactions, low selectivity, and harsh conditions.
To address these drawbacks, much attention has been paid to
the development of new methods for the synthesis of
phenanthrene.12 Most research efforts have focused on the
transition-metal-catalyzed annulation reaction of functionalized
biphenyls with alkenes or alkynes (Scheme 1, a). A number of
elegant cycloaromatization reactions such as Ru-,13 Mo-,14 or
Fe15-catalyzed olefin metathesis, Fe-,16 Pd-,17 Cu-,18 or Ir19-
catalyzed [4 + 2] benzannulation, and Pt-,20 Au-,21 Ag-,22 or
Cr23-catalyzed intramolecular annulation have been reported.
Recently, we have reported an efficient bromide-induced
cycloaromatization of arylethanone derivatives with alkynes,
which is applicable to the synthesis of naphthols and
carbazoles.24 During our studies on the reaction mechanism,
a key intermediate A was obtained from arylethanone and
“Br+” through bromination (Scheme 1, b). α-Arylethanone
radical was then formed from bromide A and initiated the
whole radical cycle. This observation led us to design a new
synthetic strategy for the construction of a phenanthrene
skeleton. The similar α-bromination of 2-acetyl biphenyls may
occur to give a bromide intermediate A′, which could provide
the corresponding radical intermediate. An intramolecular
homolytic aromatic substitution (HAS) reaction enables it to
close the ring (Scheme 1, c).25 On the basis of this design
principle, we report a bromide-induced cross-dehydrogenative
coupling(CDC) reaction for the synthesis of 10-phenanthre-
nols. This metal-free CDC reaction affords the annulation
products in good to excellent yields by utilizing the readily
available EWG-substituted 1-biphenyl-2-ylethanones as start-
ing materials and NBS as a catalyst under mild conditions. A
cross-coupling reaction between a highly active C−H bond
and an inert C−H bond was achieved.
Received: April 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To validate our hypothesis in Scheme 1, c, an initial
experiment was performed using ethyl 2-bromo-3-([1,1′-
biphenyl]-2-yl)-3-oxopropanoate A′ and TBHP in refluxing
THF. As expected, the desired phenanthrene 2a was obtained
in 44% isolated yield (eq 1). The catalytic cycloaromatization
mides, partial cycloaromatization and low yield of 2a were
observed (Table 1 entry 6). Other readily available bromine
sources led to the formation of 2a in only low to moderate
yields (Table 1, entries 7−11). It has been reported that the
mildly acidic or buffered reaction conditions are necessary for
efficient oxidative halogenation.26 We found that the addition
of an acid did promote the present reaction (Table 1, entries
12−14). An excellent yield of 2a was obtained in the presence
of 1.0 equiv of NaH2PO4·2H2O (Table 1 entry 14). When Br2
was used under the acidic conditions, a lower yield of 2a was
observed. (entry 15). With the optimal conditions in hand, the
reaction was further conducted on multigram scale, which
allowed the formation of 2.2 g of 2a in 76% yield (Scheme 2,
2a). In addition, the structure of 2a was unambiguously
established by single-crystal X-ray analyses.
reaction was then conducted under bromide-induced con-
ditions using ethyl 3-([1,1′-biphenyl]-2-yl)-3-oxopropanoate
1a instead of A′ as the starting material (Table 1). As shown in
a
Scheme 2. Scope of the Substrates
a
Table 1. Screening of the Reaction Conditions
entry
cat. Br
Br2
NBS
NBP
NBA
NBC
DBI
TBAB
HBr
KBr
additive
yield (%)
1
2
3
4
5
6
7
8
49
72
69
10
64
20
10
39
10
25
47
78
82
96
78
9
10
11
12
13
14
15
BEA
Ph3P·HBr
NBS
NBS
NBS
Br2
AcOH
citric acid
NaH2PO4·2H2O
NaH2PO4·2H2O
a
a
Reaction conditions: 1a (0.25 mmol), bromine catalyst (40 mol %),
Reaction conditions: 1 (0.25 mmol), NBS (40 mol %), NaH2PO4·
additive (1.0 equiv), TBHP (3.5 equiv, 70% aqueous solution), under
air; isolated yields.
H2O (1.0 equiv), TBHP (3.5 equiv, 70% aqueous solution), under air;
isolated yields.
Table 1, several well-known brominating reagents such as Br2,
N-bromosuccinimide (NBS), N-bromophthalimide (NBP), N-
bromoacetamide (NBA), and N-bromo-ε-caprolactam (NBC)
were investigated first (Table 1, entries 1−5). Among all of
these bromine reagents, NBS gave the best result, and the
desired product 2a was obtained in 72% yield (Table 1, entry
2). Dibromoisocyanuric acid (DBI) was also examined in the
transformation. Although DBI belongs to the N,N-dibromoa-
We next examined the scope of this transformation, and
biaryl substrates with various acetyl subunits were subjected to
the optimized conditions. As illustrated in Scheme 2, both
electron-donating and electron-withdrawing groups on the
above aromatic ring were tolerated (2a−p). All substrates
resulted in good to excellent conversion except for compound
1p bearing an ethenyl group since it underwent complicated
side reactions (2p). Interestingly, when o-isopropyl-substituted
B
DOI: 10.1021/acs.orglett.8b01160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substrate 1h was employed in the reaction, in addition to
yielding the expected product 2h in 25% yield, the cleavage of
the isopropyl substituent occurred to provide 2a in 45% yield.
The studies on this unexpected C−C bond-forming reaction
are ongoing in our laboratory. The cycloaromatization may
take place at two possible positions of m-methyl-substituted
substrate 1i. The results indicated that two isomers 2ia and 2ib
were formed, respectively, and the yield of 2ib was slightly
lower than that of 2ia. We think that the attack at the ortho-
position is hindered, which accounts for the observed
regioselectivity. Similarly, substrates 1j and 1k afforded the
corresponding products 2j and 2k in only moderate yields due
to the steric hindrance of methyl or methoxyl. The annulation
of 1w took place at the β position of nathphalene to afford a
single product 2w in 78% yield. We performed a computational
study to explain the complete regioselectivity. The detailed
results are provided in the Supporting Information. Biphenyls
with F, Cl, and MeO on the lower aromatic ring proved to be
efficient substrates, resulting in high yields of products (2q−v).
It is noteworthy that p-fluorobiphenyl 1r give the highest yield
among the three isomers (2q−s). 3,6,7-Trimethoxylphenan-
threne 2v, which is a common structural motif in
phenanthroindolizidine and phenanthroquinolizine alkaloids
such as cryptopleurine and tylocrebrine,1b was prepared in
almost quantitative yield using the present method. Two
polycyclic aromatic compounds 2w and 2x were also
synthesized successfully in high yields. In addition to the
COOEt-substituted biphenyl-2-ylethanone, substrates bearing
N-phenylamide and a cyano group formed the phenanthrenes
2y and 2z in 85% and 99% yield, respectively. Furthermore,
substrate 1aa incorporating a pyrrole ring underwent the
desired transformation in satisfactory yield (2aa).
reaction (eqs 6 and 7). On the basis of our results and previous
reports,27 a plausible reaction mechanism is proposed in
Scheme 4. The reaction begins with the formation of
Scheme 4. Proposed Mechanism
intermediate A′, which yields radical B to initiate the radical
cycle through the homolytic cleavage of C−Br bond.27 Then
an intramolecular HAS reaction25 of B takes place to provide
radical C. Further, radical anion D is generated from C through
deprotonation. Oxidation of D by A′ gives product 2 and
radical anion [A′]•−. Finally, radical B and Br− are regenerated
through fragmentation of [A′]•− (route I). Alternatively,
radical C undergoes an oxidation to form intermidate E,
which produces the final product 2 through deprotonation
(route II).
In summary, we have developed an efficient method for the
synthesis of 10-phenanthrenol from readily available starting
materials under mild conditions. A metal-free intramolecular
CDC reaction of a highly active C−H bond with an inert C−H
bond has been achieved. The catalytic utilization of bromine
reagents in C−H bond functionalization has been realized
through an in situ bromination and followed homolytic
cleavage. The present example disclosed a new strategy for
radical C−H bond activation, which would be valuable for the
development of green and sustainable chemistry.28
The mechanism of the cycloaromatization was investigated
after we established the substrate scope (Scheme 3).
Scheme 3. Control Experiments
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01160.
The formation of bromide A′ was observed during the
reaction, and its structure was determined by NMR (eq 1).
This observation and the result of eq 1 suggested that the
cyclization involved an in situ bromination. The annulation of
1a did not take place in the absence of NBS and TBHP
(Scheme 3 eq 2). Moreover, both NBS and TBHP were
necessary for the reaction to occur (eqs 3 and 4). Radical
scavenger experiments were conducted with TEMPO and
BHT under standard conditions. The yields of 2a were
significantly decreased (eq 5). Moreover, when intermediate
A′ was subjected to the standard conditions, the addition of
TEMPO retarded the annulation (eqs 6 and 7). The results
indicate that a radical pathway may be involved in the present
Detailed experimental procedures and spectral data
(PDF)
Accession Codes
CCDC 1535154 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB21EZ, UK; fax: + 44 1223 336033.
C
DOI: 10.1021/acs.orglett.8b01160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
12577. (j) Matsushima, T.; Kobayashi, S.; Watanabe, S. J. Org. Chem.
2016, 81, 7799. (k) Gupta, V.; Rao, V. U. B.; Das, T.; Vanka, K.;
Singh, R. P. J. Org. Chem. 2016, 81, 5663. (l) Connors, D. M.; Goroff,
N. S. Org. Lett. 2016, 18, 4262. (m) Bao, H.; Xu, Z.; Wu, D.; Zhang,
H.; Jin, H.; Liu, Y. J. Org. Chem. 2017, 82, 109. (n) Takahashi, I.;
Hayashi, M.; Fujita, T.; Ichikawa, J. Chem. Lett. 2017, 46, 392.
(o) Iwasaki, M.; Araki, Y.; Nishihara, Y. J. Org. Chem. 2017, 82, 6242.
(p) Kumar, T.; Mane, V.; Namboothiri, I. N. N. Org. Lett. 2017, 19,
4283. (q) Fujita, T.; Takahashi, I.; Hayashi, M.; Wang, J.; Fuchibe, K.;
Ichikawa, J. Eur. J. Org. Chem. 2017, 2017, 262.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wangbin@nankai.edu.cn.
ORCID
Bin Wang: 0000-0002-3674-8980
Notes
The authors declare no competing financial interest.
(13) Iuliano, A.; Piccioli, P.; Fabbri, D. Org. Lett. 2004, 6, 3711.
(14) Bonifacio, M. C.; Robertson, C. R.; Jung, J.-Y.; King, B. T. J.
Org. Chem. 2005, 70, 8522.
(15) (a) McAtee, C. C.; Riehl, P. S.; Schindler, C. S. J. Am. Chem.
Soc. 2017, 139, 2960. (b) Bera, K.; Sarkar, S.; Jalal, S.; Jana, U. J. Org.
Chem. 2012, 77, 8780.
(16) Matsumoto, A.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2011,
133, 6557.
(17) (a) Yao, T.; Zhang, H.; Zhao, Y. Org. Lett. 2016, 18, 2532.
(b) Larock, R. C.; Doty, M. J.; Tian, Q.; Zenner, J. M. J. Org. Chem.
1997, 62, 7536. (c) Ma, J.; Li, G. Q.; Qiao, Y.; Tu, J. X.; Liu, S.; Xu, F.
Synlett 2015, 26, 1991.
(18) (a) Hossain, M. L.; Ye, F.; Liu, Z.; Xia, Y.; Shi, Y.; Zhou, L.;
Zhang, Y.; Wang, J. J. Org. Chem. 2014, 79, 8689. (b) Ye, F.; Shi, Y.;
Zhou, L.; Xiao, Q.; Zhang, Y.; Wang, J. Org. Lett. 2011, 13, 5020.
(19) Chatterjee, T.; Lee, D. S.; Cho, E. J. J. Org. Chem. 2017, 82,
4369.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (Nos. 21172120 and 21472093) and
Tianjin Municipal Science and Technology Commission (No.
14JCYBJC20600) for the funding support.
REFERENCES
■
́
(1) (a) Kovacs, A.; Vasas, A.; Hohmann, J. Phytochemistry 2008, 69,
1084. (b) Li, Z. G.; Jin, Z.; Huang, R. Q. Synthesis 2001, 2001, 2365.
(2) (a) Pettit, G. R.; Singh, S. B.; Niven, M. L.; Schmidt, J. M. Can. J.
Chem. 1988, 66, 406. (b) De Alvarenga, M. A.; Gottlieb, O. R.;
Magalhaes, M. T. Phytochemistry 1976, 15, 844. (c) Wei, L.; Shi, Q.;
̃
Bastow, K. F.; Brossi, A.; Morris-Natschke, S. L.; Nakagawa-Goto, K.;
Wu, T.-S.; Pan, S.-L.; Teng, C.-M.; Lee, K.-H. J. Med. Chem. 2007, 50,
3674. (d) Wei, L.; Brossi, A.; Kendall, R.; Bastow, K. F.; Morris-
Natschke, S. L.; Shi, Q.; Lee, K.-H. Bioorg. Med. Chem. 2006, 14,
6560. (e) Yang, X.; Shi, Q.; Bastow, K. F.; Lee, K.-H. Org. Lett. 2010,
12, 1416. (f) Sherry, R. C. Curr. Bioact. Comp. 2009, 5, 2.
(3) (a) Fisch, M. H.; Flick, B. H.; Arditti, J. Phytochemistry 1973, 12,
437. (b) Yamaki, M.; Bai, L.; Inoue, K.; Takagi, S. Phytochemistry
1989, 28, 3503.
(20) (a) Thomson, P. F.; Parrish, D.; Pradhan, P.; Lakshman, M. K.
J. Org. Chem. 2015, 80, 7435. (b) Mamane, V.; Hannen, P.; Fu
A. Chem. - Eur. J. 2004, 10, 4556. (c) Furstner, A.; Mamane, V. J. Org.
Chem. 2002, 67, 6264.
̈
rstner,
̈
(21) Ling, H.-B.; Chen, Z.-S.; Yang, F.; Xu, B.; Gao, J.-M.; Ji, K. J.
Org. Chem. 2017, 82, 7070.
(22) Saunthwal, R. K.; Danodia, A. K.; Saini, K. M.; Verma, A. K.
Org. Biomol. Chem. 2017, 15, 6934.
(4) Matsuda, H.; Morikawa, T.; Xie, H. H.; Yoshikawa, M. Planta
Med. 2004, 70, 847.
(5) Colwell, W. T.; Brown, V.; Christie, P.; Lange, J.; Reece, C.;
Yamamoto, K.; Henry, D. W. J. Med. Chem. 1972, 15, 771.
(23) Yan, J.; Yoshikai, N. Org. Lett. 2017, 19, 6630.
(24) (a) Wang, H.; Wang, Z.; Wang, Y.-L.; Zhou, R.-R.; Wu, G.-C.;
Yin, S.-Y.; Yan, X.; Wang, B. Org. Lett. 2017, 19, 6140. (b) Lu, T.;
Jiang, Y.-T.; Ma, F.-P.; Tang, Z.-J.; Kuang, L.; Wang, Y.-X.; Wang, B.
Org. Lett. 2017, 19, 6344.
(25) For reviews of the HAS reaction, see: (a) Sun, C.-L.; Shi, Z.-J.
Chem. Rev. 2014, 114, 9219. (b) Yi, H.; Zhang, G. T.; Wang, H. M.;
Huang, Z. Y.; Wang, J.; Singh, A. K.; Lei, A. W. Chem. Rev. 2017, 117,
9016.
(26) For acid-promoted bromination reactions, see: (a) Goldberg,
Y.; Alper, H. J. Org. Chem. 1993, 58, 3072. (b) Goldberg, Y.; Alper, H.
J. Mol. Catal. 1994, 88, 377. (c) Duan, J. X.; Zhang, L. H.; Dolbier, W.
R., Jr. Synlett 1999, 1999, 1245. (d) Jagatheesan, R.; Joseph Santhana
Raj, K.; Lawrence, S.; Christopher, C. RSC Adv. 2016, 6, 35602.
(e) Das, B.; Venkateswarlu, K.; Mahender, G.; Mahender, I.
Tetrahedron Lett. 2005, 46, 3041. (f) Garbisch, E. W. J. Org. Chem.
1965, 30, 2109. (g) Yang, D.; Yan, Y.-L.; Lui, B. J. Org. Chem. 2002,
67, 7429. For reviews, see: (h) Vekariya, R. H.; Patel, H. D.
́
(6) (a) Machado, A. M.; Munaro, M.; Martins, T. D.; Davila, L. Y.
A.; Giro, R.; Caldas, M. J.; Atvars, T. D. Z.; Akcelrud, L. C.
Macromolecules 2006, 39, 3398. (b) Li, J.; Hu, G.; Wang, N.; Hu, T.;
Wen, Q.; Lu, P.; Wang, Y. J. Org. Chem. 2013, 78, 3001. (c) Wang, S.;
Yan, X.; Cheng, Z.; Zhang, H.; Liu, Y.; Wang, Y. Angew. Chem., Int.
Ed. 2015, 54, 13068.
(7) Matsuo, Y.; Sato, Y.; Hashiguchi, M.; Matsuo, K.; Nakamura, E.
Adv. Funct. Mater. 2009, 19, 2224.
(8) Mitsuhashi, R.; Suzuki, Y.; Yamanari, Y.; Mitamura, H.; Kambe,
T.; Ikeda, N.; Okamoto, H.; Fujiwara, A.; Yamaji, M.; Kawasaki, N.;
Maniwa, Y.; Kubozono, Y. Nature 2010, 464, 76.
(9) (a) Xu, Y.; Zhang, Y. X.; Sugiyama, H.; Umano, T.; Osuga, H.;
Tanaka, K. J. Am. Chem. Soc. 2004, 126, 6566. (b) Gao, B.; Luo, X.;
Gao, W.; Huang, L.; Gao, S.-m.; Liu, X.; Wu, Q.; Mu, Y. Dalton Trans.
2012, 41, 2755.
(10) (a) Martin, R. H. Angew. Chem., Int. Ed. Engl. 1974, 13, 649.
(b) Liu, L.; Yang, B.; Katz, T. J.; Poindexter, M. K. J. Org. Chem. 1991,
56, 3769. (c) Flammang-Barbieux, M.; Nasielski, J.; Martin, R. H.
Tetrahedron Lett. 1967, 8, 743.
̌
Tetrahedron 2014, 70, 3949. (i) Podgorsek, A.; Zupan, M.; Iskra, J.
Angew. Chem., Int. Ed. 2009, 48, 8424. (j) Saikia, I.; Borah, A. J.;
Phukan, P. Chem. Rev. 2016, 116, 6837.
(11) (a) McMurry, J. E.; Lectka, T.; Rico, J. G. J. Org. Chem. 1989,
54, 3748. (b) Dubois, F.; Gingras, M. Tetrahedron Lett. 1998, 39,
5039. (c) Gies, A.-E.; Pfeffer, M. J. Org. Chem. 1999, 64, 3650.
(12) (a) Harrowven, D. C.; Guy, I. L.; Nanson, L. Angew. Chem., Int.
Ed. 2006, 45, 2242. (b) Kim, Y. H.; Lee, H.; Kim, Y. J.; Kim, B. T.;
Heo, J.-N. J. Org. Chem. 2008, 73, 495. (c) Kwon, Y.; Cho, H.; Kim, S.
Org. Lett. 2013, 15, 920. (d) Murai, M.; Hosokawa, N.; Roy, D.;
Takai, K. Org. Lett. 2014, 16, 4134. (e) Iwasaki, M.; Araki, Y.; Iino, S.;
Nishihara, Y. J. Org. Chem. 2015, 80, 9247. (f) Murai, M.; Maekawa,
H.; Hamao, S.; Kubozono, Y.; Roy, D.; Takai, K. Org. Lett. 2015, 17,
708. (g) Roy, D.; Maekawa, H.; Murai, M.; Takai, K. Chem. - Asian J.
2015, 10, 2518. (h) Pati, K.; Michas, C.; Allenger, D.; Piskun, I.;
Coutros, P. S.; Gomes, G. d. P.; Alabugin, I. V. J. Org. Chem. 2015, 80,
11706. (i) Kondoh, A.; Aoki, T.; Terada, M. Chem. - Eur. J. 2015, 21,
(27) For reviews, see: (a) Studer, A.; Curran, D. P. Nat. Chem. 2014,
6, 765. (b) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55,
58. (c) Arceo, E.; Montroni, E.; Melchiorre, P. Angew. Chem., Int. Ed.
2014, 53, 12064.
(28) Wang, B.; Wong, H. N. C. Bull. Chem. Soc. Jpn. 2018, 91, 710.
D
DOI: 10.1021/acs.orglett.8b01160
Org. Lett. XXXX, XXX, XXX−XXX