Heterocyclic Iodoniums for the Assembly of Oxygen-Bridged Polycyclic Heteroarenes with Water as the Oxygen Source

Article abstract of DOI:10.1021/acs.orglett.8b01969

A diverse set of novel heterocyclic iodoniums was synthesized for the first time. The reactions of these unique iodoniums with environmentally benign water as the oxygen source provided structurally complex oxygen-incorporated heteropolycycles that are essential motifs in natural products and biologically active compounds. The transformation only required low-cost copper acetate. Further derivatization of the obtained polycycles expanded the structural diversity, which is important in the building of chemical libraries for drug discovery.

Full text of DOI:10.1021/acs.orglett.8b01969

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Heterocyclic Iodoniums for the Assembly of Oxygen-Bridged
Polycyclic Heteroarenes with Water as the Oxygen Source
Daqian Zhu,†,‡ Zhouming Wu,† Bingling Luo,† Yongliang Du,† Panpan Liu,† Yunyun Chen,‡
Yumin Hu,† Peng Huang,*,† and Shijun Wen*,†,‡
†State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University
Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China
‡School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou 510006, China
S
* Supporting Information
ABSTRACT: A diverse set of novel heterocyclic iodoniums
was synthesized for the first time. The reactions of these
unique iodoniums with environmentally benign water as the
oxygen source provided structurally complex oxygen-incorpo-
rated heteropolycycles that are essential motifs in natural
products and biologically active compounds. The trans-
formation only required low-cost copper acetate. Further
derivatization of the obtained polycycles expanded the
structural diversity, which is important in the building of
chemical libraries for drug discovery.
he past five years have witnessed significant advance-
ments in the synthetic chemistry field of cyclic diphenyl
iodoniums (CDPIs). Due to the unique triple-ring system of
CDPIs, it is naturally used to build complex polycyclic arenes.
CDPIs can react with various nucleophiles including reactive
carbon,1 nitrogen,2 and sulfur,3 leading to the formation of
polycyclic frameworks (Scheme 1). These obtained polycycles
heteroarenes (Scheme 1). However, such heterocyclic
iodoniums (HCIs) are rarely reported.6 Therefore, the
synthesis of ortho-iodo heteroaryl-aryls 1 that might be
precursors of HCIs has to be developed. Moreover, the
reactivity of HCIs also remains to be fully explored.
T
In our previous work using CDPIs, two phenyls siding by a
central hypervalent iodine ion likely have equal electronic
richness, and the iodine positions in the precursor 2-
iodobiphenyls are not essential (Scheme 1). However,
heteroaryls have varied electron properties in the precursors
1 and 1′ for the synthesis of HCIs (Figure 1). We envisioned
that positioning iodide in the heteroaryl ring could be more
viable to make HCIs due to the electronic richness of the
opposite phenyl. Therefore, a series of heteroaryl phenyl
compounds 1 were designed. To our delight, using the
standard conditions to synthesize CDPIs in our previous
work,2a a structurally diverse set of novel HCIs could be easily
obtained by oxidizing 1 with mCPBA under strong acidic
conditions (Figure 1). Thus, three major types of novel HCIs
containing heterocyclic motifs including flavone (2a−2g),
isoquinoline (2h−2k), and quinoline (2l−2r) were con-
structed for the first time. Meanwhile, other iodoniums fusing
dibenzo-oxepine (2s, 2t), coumarin (2u), and thioflavone (2v)
were also prepared. Furthermore, the structures of cyclic
iodomiums 2a and 2u were unambiguously clarified by X-ray
crystallographic analysis (Figures S1, S2).7 Our work
demonstrated the availability of such novel cyclic heteroaryl
iodoniums. These unique iodoniums might be ready for
potential transformations to build complex poylcyclic frame-
a
Scheme 1. Concept of HCIs for Synthesis of Polycycles
a
Bold bonds indicate the structural feature of iodoniums.
are often heavily hydrocarbon-oriented and lipophilic.4 In the
drug discovery field, heterocyclic frameworks with a consid-
erable number of heteroatoms are in demand to gain the
druggability of pharmacologically active compounds.5 Such
heterocyclic compounds may favor interactions with protein
targets by forming essential hydrogen bonds and π−π stacking
patterns, increasing their binding affinity to the targets.
Meanwhile, the heterocycles exhibit better performance in
terms of water solubility, a key drug property that is
indispensable for their bioavailability. Thus, the evolution of
CDPIs into cyclic iodoniums that are sided by heterocyclic
aryls would be promising for the construction of polycyclic
Received: June 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01969
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
from some disadvantages, for example, requirement of harsh
conditions such as high temperature and strong bases or acids,
or use of costly transition-metal catalysts. Thus, the develop-
ment of other efficient synthetic methods for structurally
diverse oxygen-containing heteropolycycles is in high demand.
Our research group and others have realized the insertion of
heteroatoms nitrogen and sulfur into the common CDPIs,
leading to the formation of carbazoles and dibenzothiophene-
s.2a,c,3,13 However, the oxygen insertion remained to be
investigated, likely due to the low reactivity of oxygen
functional groups. Indeed, 2-propanol was even used as
solvent in the reactions involving CDPIs in our previous
work. When using strong basic sodium alkoxide and sodium
phenoxide as nucleophiles, both cyclic and acyclic diphenylio-
doniums could react with these hydroxyl species.14 Recently, 2-
aminobenzoic was reported to be O-arylated by CDPIs.15
Water is undoubtedly the most environmentally benign oxygen
source.16 The reaction of our new prepared HCIs with a water
molecule to form oxygen-bridged polycycles would be valuable
and challenging (Figure 2c). Meanwhile, the reactivity of HCIs
also remained to be investigated.
Our investigation commenced on the reaction of HCI 2a
with water. With low cost Cu(OAc)2 (20%) as the catalyst and
Na2CO3 as the base, the desirable oxygen-bridged polycycle 3a
was obtained at a refluxing temperature in 2-propanol, albeit at
39% (Table S1, entry 1). A preliminary screening of copper
catalysts was then conducted, indicating that all the screened
copper species, regardless of their valence, mediated the
transformation at a similar efficacy (Table S1, entries 1−3).
The screening of additional ligands did not make a substantial
improvement (Table S1, entries 4−7). However, further study
found the reaction performed in DMF with 3 equiv of glycol as
a ligand at 100 °C could improve the yields significantly (Table
S1, entries 8−10). Compared to other bases, such as Cs2CO3,
K2CO3, and NaOH, Na2CO3 proved the best in terms of yields
(Table S1, entries 11−13). The copper catalyst could be
further decreased to 10% without an obvious sacrifice in yields
(Table S1, entry 14). However, no reaction was detected in the
absence of copper catalysts (Table S1, entry 15), indicating
that copper played an essential role in the transformations.
Notably, the success of the transformation required the
addition of an appropriate amount of water (Table S1, entry
16).
Figure 1. Synthesis of HCIs 2. Note: The counteranions in the
ORTEP drawings of 2a and 2u are omitted for clarity.
works that are core structural features in natural products and
biologically active compounds.8
In recent decades, oxygen-bridged heteropolycycles have
received considerable attention from the research community
due to their natural occurrence and potential pharmacological
activities (Figure 2a). For example, terpyridine as well as
Since polycyclic heteroarenes demonstrate various biological
properties, it is highly valuable to derivatize them to provide
more structural resources. While our currently designed HCIs
have a broad structural diversity (Figure 1), the translation of
our initial effort to other HCIs could enrich the structure
features of polycyclic heteroarenes (Figure 3). Like 2a, the
other flavone-containing HCIs 2b−2g reacted smoothly with
water under the standard conditions, leading to the formation
of a diverse set of polycycles 3b−3g that resemble the natural
product lupinalbin A. Notably, halogens (F, Cl, and Br) were
well-tolerated in the current conditions. The incorporation of
fluorine (3b) might show increased metabolic stabilities and
better pharmacokinetic properties compared to the non-
fluorinated analogues.17 Synthetically, both chlorinated and
brominated species (3c, 3d) could undergo further mod-
ifications to broaden the structural complexity. The motifs of
isoquinoline as well as quinoline are frequently found in
polycyclic heteroarenes. These nitrogen-incorporating HCIs
2h−2r reacting with water enabled the construction of
isoquinoline- or quinoline-fused benzofurans 3h−3r that
Figure 2. Oxygen-bridged polycyclic heteroarenes and their synthetic
strategies.
naturally occurring lupinalbin A, psoralidin, and artocarpol D2
have exhibited excellent biological activities.9 A variety of
synthetic methods have been developed to construct these
special oxygen-containing polycycles over the past few years.10
Intramolecular carbon−carbon bond formation in diaryl
ethers11 and carbon−oxygen bond formation in 2-biary
alcohols12 are common strategies (Figure 2b). Although
these synthetic methods enabled the efficient assembly of the
wanted oxygen-bridged polycyclic frameworks, they suffered
B
DOI: 10.1021/acs.orglett.8b01969
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scale-up Synthesis and Late Stage Diversification
of 3h
could be installed in 4a, resulting in the formation of 4b in a
good yield.19 The treatment of 4a with MsCl enabled the
generation of the lactam 4c.20 Meanwhile, subjection of 3h to a
reductive reaction condition provided 4d.21 The isoquinoli-
nium 4e could be generated while 3h was treated with methyl
iodide. The consequent anticancer evaluation found that 4e at
single-digit micromolar concentrations substantially inhibited
the growth of various cancer cells including pancreatic (PANC-
1), breast (BT549), lung (A549), and colon (HCT-116)
cancers as well as leukemia (HL-60) (Table S2). Further
biological study of its action mechanism is underway.
In order to gain more insight into the mechanism of this
transformation, some control experiments were conducted
(Scheme 3). While HCI 2a was subjected to the standard
Scheme 3. Control Experiments for the Mechanistic Study
conditions but in a short reaction time, the desired product 3a
as well as the hydroxyl intermediate 3ab was detected by
HRMS (Figure S3). Surprisingly, a trace of 3aa, the acetate
form of 3ab, was also identified. The appearance of 3aa
implied that acetate group from the copper catalyst might be
involved in the transformation, further verified by our
observation that the reaction mediated by CuI with additional
NaOAc dramatically increased the yield (Figure S4). While the
reaction was carried out in the presence of 18O-labeled water,
18O-3a was detected as a major product (Figure S5), indicating
that the origin of incorporated oxygen atom came from the
water.
In summary, we have successfully developed a series of novel
heterocyclic iodoniums with structural diversity and complex-
ity. Further transformation of these unique iodoniums with
water as the oxygen source into oxygen-incorporated polycyclic
heteroarenes is accomplished using low-cost Cu(OAc)2. A
variety of complex polycycles containing a heterocyclic motif
such as flavone, quinoline, isoquinoline, coumarin, and oxepine
are finally obtained in moderate to good yields. The present
method is general and straightforward for the diversity-
Figure 3. Conversion of HCIs to oxygen-bridged polycyclic
heteroarenes. Reaction conditions: HCI 2 (0.35 mmol), 5% H2O/
DMF (1.8 mL, 0.2 M), Ar, 100 °C, 12 h.
might have pharmacological activities.18 Moreover, the
reaction scope was broadened to more complex dibenzoox-
epine-fused HCIs (2s, 2t) to provide artocarpol D2-like
compounds 3s−3t. Meanwhile, the insertion of oxygen from
water into the coumarin-fused HCI 2u facilitated the formation
of 3u in a good yield. Thioflavone-containing HCI 2v proved
to be a suitable substrate to afford 3v. Another sulfur-
containing HCI 2w also reacted with water smoothly for the
synthesis of thienobenzofuran 3w. Finally, the pyridine-fused
HCI 2x gave the desired product (3x) in moderate yield.
To our delight, the reaction of HCI 2h with water was even
performed in a 2 g scale, providing 3h smoothly, suggesting the
potential for large-scale production of oxygen-incorporated
polycycles. Further diversification of 3h was performed to
obtain more complex heterocyclic compounds 4 (Scheme 2).
Via the oxidation by mCPBA, 3h was readily converted to the
quinoline N-oxide 4a. Subsequently, a tosyl functional group
C
DOI: 10.1021/acs.orglett.8b01969
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) Name Reactions in Heterocyclic Chemistry; Li, J., Corey, E. J., Eds.;
Wiley-Interscience: Hoboken, NJ, 2005.
oriented synthesis of polycyclic arenes, providing a comple-
mentary strategy to the reported synthetic routes. Further
studies on the applications of this method for developing
cytotoxic anticancer drugs are ongoing in our group.
(9) (a) Kwon, H.; Park, C.; Jeon, K.; Lee, E.; Park, S.; Jun, K.;
Kadayat, T.; Thapa, P.; Karki, R.; Na, Y.; Park, M.; Rho, S.; Lee, E.;
Kwon, Y. J. Med. Chem. 2015, 58, 1100−1122. (b) Miller, C.; Collini,
M.; Harris, H. Bioorg. Med. Chem. Lett. 2003, 13, 2399−2403.
(c) Costa, M.; Dias, T.; Brito, A.; Proenca, F. Eur. J. Med. Chem. 2016,
123, 487−507. (d) Paduraru, M.; Wilson, P. Org. Lett. 2003, 5, 4911−
4913.
(10) (a) Goel, A.; Kumar, A.; Raghuvanshi, A. Chem. Rev. 2013, 113,
1614−1640. (b) Jin, T.; Zhao, J.; Asao, N.; Yamamoto, Y. Chem. -
Eur. J. 2014, 20, 3554−3576. (c) Kumar, S.; Cruz-Hernandez, C.; Pal,
S.; Saunthwal, R.; Patel, M.; Tiwari, R.; Juaristi, E.; Verma, A. J. Org.
Chem. 2015, 80, 10548−10560. (d) Gai, R.; Back, D.; Zeni, G. J. Org.
Chem. 2015, 80, 10278−10287. (e) Pal, S.; Choudhary, D.; Jainth,
M.; Kumar, S.; Tiwari, R.; Verma, A. J. Org. Chem. 2016, 81, 9356−
9371.
(11) Truong, M.; Nakano, K. J. Org. Chem. 2015, 80, 11566−11572.
(12) Kaida, H.; Goya, T.; Nishii, Y.; Hirano, K.; Satoh, T.; Miura, M.
Org. Lett. 2017, 19, 1236−1239.
(13) Tan, Q.; Zhou, D.; Zhang, T.; Liu, B.; Xu, B. Chem. Commun.
2017, 53, 10279−10282.
(14) (a) Fuson, R. C.; Albright, R. L. J. Am. Chem. Soc. 1959, 81,
487−490. (b) Tolnai, G.; Nilsson, U.; Olofsson, B. Angew. Chem., Int.
Ed. 2016, 55, 11226−11230. (c) Lindstedt, E.; Stridfeldt, E.;
Olofsson, B. Org. Lett. 2016, 18, 4234−4237.
(15) Xie, H.; Ding, M.; Liu, M.; Hu, T.; Zhang, F. Org. Lett. 2017,
19, 2600−2603.
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.8b01969.
Full experimental procedures and copies of 1H, 13C
NMR spectra (PDF)
Accession Codes
CCDC 1581869−1581870 contain the supplementary crys-
tallographic 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wenshj@sysucc.org.cn.
*E-mail: huangpeng@sysucc.org.cn.
ORCID
(16) (a) Shen, D.; Saracini, C.; Lee, Y.; Sun, W.; Fukuzumi, S.; Nam,
W. J. Am. Chem. Soc. 2016, 138, 15857−15860. (b) Zhang, M.; de
Respinis, M.; Frei, H. Nat. Chem. 2014, 6, 362−367.
(17) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320−330.
Shijun Wen: 0000-0002-9347-8243
Notes
(18) (a) Anzini, M.; Cappelli, A.; Vomero, S.; Giorgi, G.; Langer, T.;
Hamon, M.; Merahi, N.; Emerit, B.; Cagnotto, A.; Skorupska, M.;
Mennini, T.; Pinto, J. J. Med. Chem. 1995, 38, 2692−2704. (b) Liu,
H.; Chen, A.; Yin, Q.; Li, Z.; Huang, S.; Du, G.; He, J.; Zan, L.; Wang,
S.; Xu, Y.; Tan, J.; Ou, T.; Li, D.; Gu, L.; Huang, Z. J. Med. Chem.
2017, 60, 5438−5454.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the grant support from the National
Natural Science Foundation of China (81672952, 81430060),
Guangdong Science and Technology Program
(2017A020215198), and Guangzhou Science and Technology
Program (201807010041).
(19) Su, Y.; Zhou, X.; He, C.; Zhang, W.; Ling, X.; Xiao, X. J. Org.
Chem. 2016, 81, 4981−4987.
(20) Xie, L.; Duan, Y.; Lu, L.; Li, Y.; Peng, S.; Wu, C.; Liu, K.; Wang,
Z.; He, W. ACS Sustainable Chem. Eng. 2017, 5, 10407−10412.
(21) McCallum, T.; Pitre, S.; Morin, M.; Scaiano, J.; Barriault, L.
Chem. Sci. 2017, 8, 7412−7418.
REFERENCES
■
(1) (a) Zhu, D.; Wu, Y.; Wu, B.; Luo, B.; Ganesan, A.; Wu, F.; Pi, R.;
Huang, P.; Wen, S. Org. Lett. 2014, 16, 2350−2353. (b) Peng, X.;
Luo, H.; Wu, F.; Zhu, D.; Ganesan, A.; Huang, P.; Wen, S. Adv. Synth.
Catal. 2017, 359, 1152−1156.
(2) (a) Riedmuller, S.; Nachtsheim, B. J. Beilstein J. Org. Chem. 2013,
̈
9, 1202−1209. (b) Zhao, K.; Duan, L.; Xu, S.; Jiang, J.; Fu, Y.; Gu, Z.
Chem. 2018, 4, 599−612. (c) Zhu, D.; Liu, Q.; Luo, B.; Chen, M.; Pi,
R.; Huang, P.; Wen, S. Adv. Synth. Catal. 2013, 355, 2172−2178.
(3) (a) Luo, B.; Cui, Q.; Luo, H.; Hu, Y.; Huang, P.; Wen, S. Adv.
Synth. Catal. 2016, 358, 2733−2738. (b) Wang, M.; Fan, Q.; Jiang, X.
Org. Lett. 2016, 18, 5756−5759. (c) Wang, M.; Wei, J.; Fan, Q.; Jiang,
X. Chem. Commun. 2017, 53, 2918−2921.
(4) (a) Mathew, B.; Yang, H.; Kim, J.; Lee, J.; Kim, Y.; Lee, S.; Lee,
C.; Choe, W.; Myung, K.; Park, J.; Hong, S. Angew. Chem., Int. Ed.
2017, 56, 5007−5011. (b) Yang, S.; Wang, F.; Wu, Y.; Hua, W.;
Zhang, F. Org. Lett. 2018, 20, 1491−1495. (c) Wu, Y.; Wu, F.; Zhu,
D.; Luo, B.; Wang, H.; Hu, Y.; Wen, S.; Huang, P. Org. Biomol. Chem.
2015, 13, 10386−10391. (d) Liu, Z.; Luo, B.; Liu, X.; Hu, Y.; Wu, B.;
Huang, P.; Wen, S. Eur. J. Org. Chem. 2016, 2016, 1110−1118.
(5) Erlanson, D.; Fesik, S.; Hubbard, R.; Jahnke, W.; Jhoti, H. Nat.
Rev. Drug Discovery 2016, 15, 605−619.
(6) Letessier, J.; Detert, H. Synthesis 2012, 2012, 290−296.
(7) Recrystallization from MeOH/CH2Cl2 afforded single crystals of
2a (CCDC No. 1581869) and 2u (CCDC No. 1581870), suitable for
X-ray diffraction analysis.
D
DOI: 10.1021/acs.orglett.8b01969
Org. Lett. XXXX, XXX, XXX−XXX