Copper-Catalyzed Annulation: A Method for the Systematic Synthesis of Phenanthridinium Bromide

Article abstract of DOI:10.1021/acs.orglett.6b00269

A novel procedure for the Cu-catalyzed systematic synthesis of phenanthridinium bromide is reported. This transformation was achieved with direct construction of central pyridinium core by using an in situ formed biaryl imine as a substrate. Tolerance of a very wide variety of N-substituents is indicated; this has never previously been disclosed by other reports. Application of this method to synthesis of the natural alkaloid bicolorine, and its derivatives, was also carried out in only three synthetic steps from commercially available compounds.

Full text of DOI:10.1021/acs.orglett.6b00269

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Annulation: A Method for the Systematic
Synthesis of Phenanthridinium Bromide
Yuan-Ye Jhang, Tai-Ting Fan-Chiang, Jun-Min Huang, and Jen-Chieh Hsieh*
Department of Chemistry, Tamkang University, New Taipei City 25137, Taiwan
S
* Supporting Information
ABSTRACT: A novel procedure for the Cu-catalyzed system-
atic synthesis of phenanthridinium bromide is reported. This
transformation was achieved with direct construction of central
pyridinium core by using an in situ formed biaryl imine as a
substrate. Tolerance of a very wide variety of N-substituents is
indicated; this has never previously been disclosed by other
reports. Application of this method to synthesis of the natural alkaloid bicolorine, and its derivatives, was also carried out in only
three synthetic steps from commercially available compounds.
henanthridinium is an important structural motif with many
P
natural alkaloids containing this building block1 (Figure 1).
As such, molecules of this genre are widely explored in antitumor
research and are of potential value to anticancer chemotherapy.
They exhibit cytotoxicity toward tumor cells by inhibiting diverse
targets such as DNA topoisomerase I/II,2 protein kinase C,3 and
others.4 Some derivatives have antibacterial5 and antimalaria6
functions as well. Recent research has demonstrated that
phenanthridiniums could be a new class of human DOPA
decarboxylase inhibitors, whichmight provide a newroute tocure
Parkinson’s disease.7 Apart from their medicinal properties, 5-
arylphenanthridiniums that have a high ability to engage in DNA
intercalation are commonly applied as DNA probes.8 Moreover,
due to their UV behavior, their applications as DNA fluorescent
dyes9 and switchable materials10 are feasible.
Figure 1. Selected phenanthridinium alkaloids.
catalyzed cyclizations involving C−N bond formation17
encouraged us to explore the possibility of constructing
phenanthridiniums with versatile substituents by Cu-mediated
catalysis. Herein, we report the first systematic synthesis of
phenanthridiniums through a Cu-catalytic cycle.
At the outset of our studies, the reaction conditions were
surveyedbyusing2′-bromo-[1,1′-biphenyl]-2-carbaldehyde(1a)
as a model substrate (Table 1). Initially, 1a (0.1 mmol) was
treated with 1.2 equiv of 2-methylpropan-1-amine (2a) and 5 mol
%ofCuIin1mLofTHFat100°Cfor24h;thedesiredproduct5-
isobutylphenanthridin-5-ium bromide(3aa)wasobtainedinonly
6%NMRyield(entry1). Product3aawasconfirmedby1HNMR,
13C NMR, HRMS, and X-ray analysis. After the reactions were
worked up, only substrates, product, and corresponding imine
were observed in the crude NMR spectra.
To optimize the reaction conditions, the effect of solvents,
ligands, copper salts, and reaction temperatures was investigated,
and the results are summarized in Table 1 (see the Supporting
Information for the effect of solvents and ligands in detail). We
first evaluated the effect of solvent on this reaction (entries 1−6)
and found that only t-BuOH effectively improved the yield of 3aa.
Other solvents such as aromatic solvents, polar solvents, ethers,
Despite these fascinating applications having received
significant attention, their preparation is still limited to specific
structures. Past reported methods have approached these
compounds mainly through a substitution from phenanthridines,
thus restricting their formation to N-primary and less hindered N-
secondary alkylphenanthridiniums.11 Transformations from
phenanthridinones12 and dihydrophenanthridines13 have also
been reported; however, a multistep synthetic route was required
for annulation of the central heterocycle. No tertiary alkyl and aryl
groups could be attached to the quaternary nitrogen atom of
phenanthridinium by these protocols. Construction of such
heterocyclic compounds via an intramolecular coupling reaction
of an imine might be able to address this issue. This concept has
caused methods to emerge for direct construction of
pyridinium,14 quinolinium, and isoquinolinium15 structures
with versatile N-substituents by late transition-metal catalysis. A
similar idea was also utilized to furnish a phenanthridinium
through a microwave-assisted intramolecular SNAr coupling
reaction of a biaryl imine.16 However, limitations on the synthesis
of N-primary alkylphenanthridiniums still exist. An effective
method for the synthesis of phenanthridinium derivatives with
various substituents on nitrogen is desired to support
pharmaceutical and materials research. Our experience in Cu-
Received: January 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00269
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
entry
[Cu]
CuI
ligand
solvent
THF
temp (°C)
yield (%)
1
2
3
4
5
6
100
100
100
100
100
100
100
100
100
100
100
100
100
100
120
90
6
c
CuI
aromatic solvents
3−14
18−23
0−12
4−27
31
d
CuI
polar solvents
e
CuI
ethers
f
CuI
ROH
CuI
t-BuOH
g
7
CuI
ethylene glycol
2,3-butanediol
catechol
t-BuOH
53
g
8
g
CuI
t-BuOH
51
9
CuI
t-BuOH
49
10
11
12
13
14
15
16
CuI
ethylene glycol
ethylene glycol
ethylene glycol
ethylene glycol
ethylene glycol
ethylene glycol
ethylene glycol
ethylene glycol
ethylene glycol
ethylene glycol
ethylene glycol
79
CuBr
CuCl
Cu(OAc)2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
89
88
71
h
96 (91)
97
83
93
68
99
7
i
17
100
100
100
100
j
18
k
19
20
a
b
Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), [Cu] (5 mol %), solvent (1.0 mL), indicated temperature, under air, 24 h. 1H NMR yield
c
d
based on internal standard mesitylene. Benzene, toluene, o-xylene, mesitylene, chlorobenzene, and o-dichlorobenzene were used. DMSO, DMF
and NMP were used. Et2O, 1,4-dioxane, and DME were used. EtOH, cyclohexanol, and i-PrOH were used. 20 mol % of ligand. Isolated yield in
0.5 mmol scale. 40 h. 16 h. Under N2.
e
f
g
h
i
j
k
a b
,
and alcohols are not effective for this reaction. We then employed
ligands to facilitate this Cu-catalyzed process. This demonstrated
that only diol ligands are efficient, improving the reaction yields
up to 53% (entries 7−9). This result suggests that a five-
membered cyclic copper complex might be the active catalyst.
The t-BuOH was then replaced with ethylene glycol, and the yield
of 3aa was significantly improved to 79% (entry 10). The copper
source was also influential in this reaction (entries 10−14).
Among the copper salts that we examined, CuCl2 showed the best
catalytic efficacy and improved the yield of 3aa to 96%. The
reaction proceeded smoothly at 90−120 °C (entries 15 and 16).
Higher reaction temperature or longer reaction time did not
further improve the reaction yield (entries 15 and 17), and the
reactionneededatleast24htocompletewhenitwasconductedat
less than or at 100 °C (entry 16, 18). Furthermore, the reaction
proceeded smoothly under a nitrogen atmosphere (entry 19) but
gave onlyatrace amount of 3aawithout thecopper catalyst (entry
20).
Scheme 1. Scope of Amines and Anilines
After the reaction conditions were optimized, the capacity of
this Cu-catalyzed cyclization to work with different amines and
anilines was then investigated (Scheme 1). The reaction tolerates
awiderangeofaminesandanilines, whiletheyieldsdependonthe
structures of the amine and aniline. Primary alkylamines were
smoothly converted to the desired products, with the yields of
products depending on the chain length (3ab−ad). Functional
alkyl groups provided slightly lower yields of the desired products
(3ae,af) accompanied by unidentified compounds. Reactions
with the cycloalkylamines proceeded smoothly, providing the
desired products 3ag−ai in moderate to good yields. Apart from
3aa,thestructureofcompound3ag(Figure2)wasalsoverifiedby
a
Reactions were carried out using 0.5 mmol (1.0 equiv) of 1a with 1.2
equiv of RNH2 (2) and 5 mol % of CuCl2 in 5.0 mL of ethylene glycol
b
c
at 100 °C for 24 h. Isolated yield. 130 °C.
single-crystal X-ray diffraction. N-Aryl compounds containing
both electron-donating (3ak−am) and electron-withdrawing
B
DOI: 10.1021/acs.orglett.6b00269
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Scheme 2. Scope of Phenanthridinium Salts
Figure 2. X-ray structure of compound 3ag.
groups (3an,ao) were obtainable by this method in good yield.
However, products 3an and 3ao could be generated only at 130
°C because of the low electron density on nitrogen. Their
corresponding imines (1an and 1ao) were not detected under
100 °C. It is worth remarking that the N-arylphenanthridinium
compounds are not able to be synthesized by other process. Our
methodology can give versatile N-arylphenanthridiniums, includ-
ing bromide (3am), and derivatives with strong electron-
donating (3al) and strong electron-withdrawing groups (3an
and 3ao) attached to the aryl ring.
Further investigation of the scope of our phenanthridinium
synthesis was also undertaken, and the results are shown in
Scheme 2. As indicated, substrates with electron-donating and
electron-deficient groups on the moieties of the benzaldehyde
and the aryl bromide engaged in this transformation (3bl−il);
higher electron density on the aromatic rings generally led to a
higher yield of the desired product (3bl, 3cl vs 3dl and 3fl, 3gl vs
3hl). Synthesis of heterocyclic compounds was also possible, with
the products 3el, 3jj, and 3jl being afforded in 74%, 72%, and 69%
yields, respectively.
a
Reactions were carried out using 0.5 mmol (1.0 equiv) of 1 with 1.2
equiv of RNH2 (2) and 5 mol % of CuCl2 in 5.0 mL of ethylene glycol
b
at 100 °C for 24 h. Isolated yield.
This method will contribute to pharmaceutical research toward
development of structure−activity relationships in the antitumor
field. Previous research2 has shown that the basic requirement for
inhibitors of topoisomerase is at least two oxygenated groups on
the left ring. Additional groups, which can offer more hydrogen
bonding, also have a favorable effect on the antitumor activities.
Therefore, a series of structures can be constructed by reacting
substrate 1i with various amines and anilines (3ia−is). Notably,
some interesting compounds with N-heterocyclic (3iq and 3ir)
and N-phenol groups (3is) were provided as well. No other
methods could be utilized for the synthesis of similar structures.
Moreover, the combination of different subunits established
diverse structures (3ka−ob) in moderate to good yields.
The present methodology was applied in the synthesis of the
Amaryllideceae alkaloid bicolorine (B1)20 and its derivatives
(B2−B7). To the best of our knowledge, this is the shortest
synthetic route to bicolorine from a commercial source (three
steps, 58% overall yield). Bicolorine and its analogues have
attracted considerable attention for a long time because of their
multibioactivities, particularly their anticancer effects.1−4,7 This
strategy represents an efficient pathway to these bioactive
compounds and will bring high convenience to this area of
medicinal research.
Scheme 3. Control Experiments
These experiments delivered two pieces of information. First, this
reaction does not involve a radical pathway (reactions were not
prevented by introducing two radical scavengers TEMPO and
DPE). Second, the reaction passes through an in situ formed
biaryl imine (reactions proceeded smoothly and provided slightly
higher yields via the supposed intermediate biaryl imines).
On the basis of previous reports17−19 and the above results, a
tentative reaction pathway can be proposed as shown below
(Scheme 4). The reaction is likely to be initiated by the
To study the reaction mechanism, some control experiments
were conducted to clarify the reaction pathway (Scheme 3).
C
DOI: 10.1021/acs.orglett.6b00269
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Phytochem. Rev. 2014, 13, 51. (c) Bernardo, P. H.; Wan, K.-F.; Sivaraman,
T.; Xu, J.; Moore, F. K.; Hung, A. W.; Mok, H. Y. K.; Yu, V. C.; Chai, C. L.
L. J. Med. Chem. 2008, 51, 6699. (d) Nakanishi, T.; Suzuki, M.; Saimoto,
A.;Kabasawa, T. J. Nat. Prod. 1999, 62, 864. (e)Zee-Cheng, R. K.-Y.;Yan,
S.-J.; Cheng, C. C. J. Med. Chem. 1978, 21, 199.
Scheme 4. Proposed Reaction Pathway
(5) Parhi, A.; Kelley, C.; Kaul, M.; Pilch, D. S.; LaVoie, E. J. Bioorg. Med.
Chem. Lett. 2012, 22, 7080.
(6) Rivaud, M.; Mendoza, A.; Sauvain, M.; Valentin, A.; Jullian, V.
Bioorg. Med. Chem. 2012, 20, 4856.
(7) Cheng, P.; Zhou, J.; Qing, Z.; Kang, W.; Liu, S.; Liu, W.; Xie, H.;
Zeng, J. Bioorg. Med. Chem. Lett. 2014, 24, 2712.
(8) (a) Stevens, N.; O’Connor, N.; Vishwasrao, H.; Samaroo, D.;
Kandel, E. R.; Akins, D. L.; Drain, C. M.; Turro, N. J. J. Am. Chem. Soc.
2008, 130, 7182. (b) van der Wiel, I. M.; Cheng, J.; Koukiekolo, R.; Lyn,
R. K.; Stevens, N.; O’Connor, N.; Turro, N. J.; Pezacki, J. P. J. Am. Chem.
Soc. 2009, 131, 9872. (c) O’Connor, N. A.; Stevens, N.; Samaroo, D.;
Solomon, M. R.; Martí, A. A.; Dyer, J.; Vishwasrao, H.; Akins, D. L.;
condensation of compound 1 with amine 2 to form the
corresponding biaryl imine. The biaryl imine then chelates to
the Cu(II) complex (A)with an electron transfer reducing Cu(II)
to Cu(I) (A′). A subsequent oxidative addition of the Cu(I)
affords a Cu(III) complex (B). Reductive elimination of the
Cu(III) complex provides desired product 3 and regenerates
Cu(II) via the intermediate 3′.
Kandel, E. R.; Turro, N. J. Chem. Commun. 2009, 2640. (d) Juranovic,
́
I.;
̌
Meic,
́
Z.; Piantanida, I.; Tumir, L.-M.; Zinic,
́
M. Chem. Commun. 2002,
1432. (e)Mullins, S.T.;Sammes,P. G.;West, R.M.;Yahioglu, G. J. Chem.
Soc., Perkin Trans. 1 1996, 75.
(9) Ihmels, H.; Otto, D. Top. Curr. Chem. 2005, 258, 161.
(10) (a) Chen, J.-J.; Li, K.-T.; Yang, D.-Y. Org. Lett. 2011, 13, 1658.
(b) Richmond, C. J.; Parenty, A. D. C.; Song, Y.-F.; Cooke, G.; Cronin, L.
J. Am. Chem. Soc. 2008, 130, 13059.
(11)Forselectedpapers, see:(a)Chen, W.-L.;Chen, C.-Y.;Chen, Y.-F.;
Hsieh, J.-C. Org. Lett. 2015, 17, 1613. (b) Cookson, J. C.; Heald, R. A.;
Stevens, M. F. G. J. Med. Chem. 2005, 48, 7198. (c)Watanabe, T.;Ohashi,
Y.;Yoshino, R.;Komano, N.;Eguchi, M.;Maruyama, S.;Ishikawa, T. Org.
Biomol. Chem. 2003, 1, 3024. (d) Nakanishi, T.; Suzuki, M. J. Nat. Prod.
1998, 61, 1263.
In conclusion, we have developed a novel method for the Cu-
catalyzed annulative synthesis of a wide range of phenanthridi-
nium bromides in moderate to excellent yields. In addition, this
methodology was applied in the synthesis of the natural alkaloid
bicolorine and its derivatives in a short synthetic route. Further
studies to explore other applications are currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
(12) (a) Lv, P.; Huang, K.; Xie, L.; Xu, X. Org. Biomol. Chem. 2011, 9,
3133. (b) Boger, D. L.; Wolkenberg, S. E. J. Org. Chem. 2000, 65, 9120.
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b00269.
(c) Treus, M.; Estev
2002, 43, 5323.
́ ́
ez, J. C.; Castedo, L.; Estevez, R. J. Tetrahedron Lett.
X-ray data for 3aa (CIF)
X-ray data for 3ag (CIF)
Experimental procedures, characterization, spectral data,
X-ray structure, and NMR spectra (PDF)
(13)(a)Ito, S.;Tokimaru, Y.;Nozaki, K. Chem. Commun. 2015, 51, 221.
(b) Ramani, P.; Fontana, G. Tetrahedron Lett. 2008, 49, 5262.
(c) Ishikawa, T.; Shimooka, K.; Narioka, T.; Noguchi, S.; Saito, T.;
Ishikawa, A.; Yamazaki, E.; Harayama, T.; Seki, H.; Yamaguchi, K. J. Org.
Chem. 2000, 65, 9143.
(14) (a) Luo, C.-Z.; Gandeepan, P.; Jayakumar, J.; Parthasarathy, K.;
Chang, Y.-W.; Cheng, C.-H. Chem. - Eur. J. 2013, 19, 14181. (b) Luo, C.-
Z.; Jayakumar, J.; Gandeepan, P.; Wu, Y.-C.; Cheng, C.-H. Org. Lett.
2015, 17, 924.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jchsieh@mail.tku.edu.tw.
(15) For selected papers, see: (a) Zhang, G.; Yang, L.; Wang, Y.; Xie, Y.;
Huang, H. J. Am. Chem. Soc. 2013, 135, 8850. (b) Senthilkumar, N.;
Gandeepan, P.; Jayakumar, J.; Cheng, C.-H. Chem. Commun. 2014, 50,
3106. (c)Liu, F.;Ding, X.;Zhang, L.;Zhou, Y.;Zhao, L.;Jiang, H.;Liu, H.
J. Org. Chem. 2010, 75, 5810. (d) Liu, Q.; Wu, Y.; Chen, P.; Liu, G. Org.
Lett. 2013, 15, 6210. (e) Jayakumar, J.; Parthasarathy, K.; Cheng, C.-H.
Angew. Chem., Int. Ed. 2012, 51, 197.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology of Republic of
China (MOST 103-2113-M-032-009-MY2) for financial support
of this research.
(16) Cairns, A. G.; Senn, H. M.; Murphy, M. P.; Hartley, R. C. Chem. -
Eur. J. 2014, 20, 3742.
(17) (a) Hsieh, J.-C.; Cheng, A.-Y.; Fu, J.-H.; Kang, T.-W. Org. Biomol.
Chem. 2012, 10,6404. (b)Chen, Y.-F.;Wu, Y.-S.;Jhan, Y.-H.;Hsieh, J.-C.
Org. Chem. Front. 2014, 1, 253. (c) Chen, Y.-F.; Hsieh, J.-C. Org. Lett.
2014, 16, 4642.
REFERENCES
■
(1) (a) Jin, Z. Nat. Prod. Rep. 2005, 22, 111. (b) Jin, Z. Nat. Prod. Rep.
2003, 20, 606. (c) Lewis, J. R. Nat. Prod. Rep. 1993, 10, 291.
(d) Tanahashi, T.; Zenk, M. H. J. Nat. Prod. 1990, 53, 579.
(18) (a) Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.;
(2) (a) Baechler, S. A.; Fehr, M.; Habermeyer, M.; Hofmann, A.; Merz,
K.-H.;Fiebig, H.-H.; Marko, D.; Eisenbrand, G. Bioorg. Med. Chem. 2013,
21, 814. (b)Casu, L.;Cottiglia, F.;Leonti, M.;De Logu, A.;Agus, E.; Tse-
Dinh, Y.-C.; Lombardo, V.; Sissi, C. Bioorg. Med. Chem. Lett. 2011, 21,
7041. (c) Morohashi, K.; Yoshino, A.; Yoshimori, A.; Saito, S.; Tanuma,
S.; Sakaguchi, K.; Sugawara, F. Biochem. Pharmacol. 2005, 70, 37.
(3) Chmura, S. J.; Dolan, M. E.; Cha, A.; Mauceri, H. J.; Kufe, D. W.;
Weichselbaum, R. R. Clin. Cancer Res. 2000, 6, 737.
Ribas, X. Chem. Sci. 2010, 1, 326. (b) Casitas, A.; Canta, M.; Sola,
Costas, M.; Ribas, X. J. Am. Chem. Soc. 2011, 133, 19386.
(19) (a) Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177.
(b) Casitas, A.; Ribas, X. Chem. Sci. 2013, 4, 2301. (c) Fier, P. S.; Hartwig,
J. F. J. Am. Chem. Soc. 2012, 134, 10795. (d) Wang, Z.-L.; Zhao, L.; Wang,
M.-X. Org. Lett. 2012, 14, 1472.
̀
M.;
(20) Viladomat, F.; Bastida, J.; Tribo, G.; Codina, C.; Rubiralta, M.
Phytochemistry 1990, 29, 1307.
(4) For selected papers, see: (a) Hatae, N.; Fujita, E.; Shigenobu, S.;
Shimoyama, S.; Ishihara, Y.; Kurata, Y.; Choshi, T.; Nishiyama, T.;
Okada, C.; Hibino, S. Bioorg. Med. Chem. Lett. 2015, 25, 2749.
́ ̆ ̌ ́ ́ ́ ́
(b) Slaninova, I.; Pencíkova, K.; Urbanova, J.; Slanina, J.; Taborska, E.
D
DOI: 10.1021/acs.orglett.6b00269
Org. Lett. XXXX, XXX, XXX−XXX