A concise construction of polycyclic quinolines via annulation of ω-cyano-1-alkynes with diaryliodonium salts

Article abstract of DOI:10.1021/ol402164s

A concise construction of polycyclic quinolines via intramolecular [2 + 2 + 2] annulation of ω-cyano-1-alkynes with diaryliodonium salts was realized. The process produced polycyclic quinolines in high yields with readily available staring materials and was tolerated with halogen substituents.

Full text of DOI:10.1021/ol402164s

ORGANIC
LETTERS
2013
Vol. 15, No. 18
4794–4797
A Concise Construction of Polycyclic
Quinolines via Annulation of ω‑Cyano-
1-alkynes with Diaryliodonium Salts
Yong Wang,†,‡ Chao Chen,*,† Shu Zhang,†,§ Zhenbang Lou,†,‡ Xiang Su,† Lirong Wen,‡
and Ming Li‡
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of
Education), Department of Chemistry, Tsinghua University, Beijing 100084, China,
College of Chemistry and Molecular Engineering, Qingdao University of Science and
Technology, Qingdao, Shandong 266042, China, and Department of Applied Chemistry,
China Agricultural University, Beijing 100193, China
chenchao01@mails.tsinghua.edu.cn
Received July 30, 2013
ABSTRACT
A concise construction of polycyclic quinolines via intramolecular [2 þ 2 þ 2] annulation of ω-cyano-1-alkynes with diaryliodonium salts was
realized. The process produced polycyclic quinolines in high yields with readily available staring materials and was tolerated with halogen
substituents.
Polycyclic quinolines are privileged scaffolds in various
bioactive natural products (especially in alkaloids) and
manysynthetictherapeutic agents.1 For instance, tacrine, a
tricyclic quinoline (under the trade name of Cognex,
Figure 1), was the first approved drug for the treat-
ment of Alzheimer’s disease as a centrally acting
anticholinesterase and indirect cholinergic agonist.2 To
date, there are already over 180 research papers related
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† Tsinghua University
‡ Qingdao University of Science and Technology
§ China Agricultural University
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10.1021/ol402164s
Published on Web 09/09/2013
2013 American Chemical Society

to tacrine published in J. Med. Chem.; most of them are
based on the development of new tacrine derivatives and
hybrids. Besides, luotonin A and camptothecin were found
as natural topoisomerases with structures typical of pen-
tacyclic quinoline (Figure 1).3 Therefore, a long-term
and strong demand exists for the chemistry community
to develop approaches toward polycyclic quinolines.4
Among the traditional name reactions for the construc-
quinolines, which are applied to a two-step synthesis of
tacrine derivatives.
tion of quinolines, probably only Niementowski5 and
We first examined the reaction of diphenyliodonium
hexafluorophosphate 1a with ω-cyano-1-phenyl-1-pentyne
2a, which was easily prepared by a Sonogashira coupling re-
action of ω-cyano-1-pentyne (see Supporting Information).
The reaction proceeded smoothly, catalyzed by Cu(OTf)2
(10 mol %) in DCE to give five-member ring-fused quino-
line 3aa in 95% isolated yield, where these conditions
were used in our previous study. Diphenyliodoniums 1
with a range of substituents involving 4-methyl, 4-trifluor-
omethyl, 2-fluoro, and 2,5-dimethyl groupsall workedwell
to give expected fused quinolines 3baꢀ3ea (Scheme 1).
There certainly existed lots of choices for R group in
cyano-pentyne 2 to be alternated to other substituents,
but we attempted to use ω-cyano-1-bromo-pentyne 2b
to prepare bromoquinoline, since it is important and use-
ful quinoline building block. To our delight, ω-cyano-1-
bromo-pentyne 2b reacted with diaryliodonium salts9
1aꢀ1c to give bromoquinoline 3abꢀ3cb in good yields.10
The structure 3cb of was further confirmed by XRD
(Figure 2).
6
Friedlander reactions are generally suitable for the synth-
€
esis of polycyclic quinolines. However, these methods
require toxic, unstable, and often inaccessible 2-aminoaryl
aldehydes, ketones, or carboxylate derivatives as starting
materials. Furthermore, these name reactions mostly pro-
ceedvia condensation, substitution, and addition reactions
under harsh conditions with a low tolerance of functional
groups. Consequently, the development of new methods to
conviniently construct polycyclic quinolines with readily
available starting materials is of great importance.
Figure 1. Some representative polycyclic quinolines.
As part of our study on heterocycle synthesis, we
have reported an efficient method to synthesize multi-
substituted quinolines from three readily available compo-
nents, including alkynes, nitriles, and diaryliodoniums.7
We envisaged that if ω-cyano-1-alkynes (i.e., alkynes
linearly tethered with nitriles) are used to react with diary-
liodoniums,8 polycyclic quinolines would be produced.
Herein, wewould like to reportthisnew strategytoprepare
5-, 6-, 7-, and 8-member ring-fused quinolines from readily
available starting materials and catalyst in one step (eq 1).
The process features electrophilic annulation in the mode
of formal intramolecular [2 þ 2 þ 2] cycloaddition and
is capable of directly synthesizing chloro- and bromo-
Figure 2. ORTEP drawing of 3cb (C13H9BrF3N) with 35%
probability ellipsoids.
Inspired by the successful preparation of five-member
ring-fused quinolines, we next prepared six-member ring-
fused quinolines using diaryliodonium salts and ω-cyano-
1-hexyne 2. Diphenyliodonium 1a reacted with ω-cyano-
1-phenyl-1-hexyne 2c to give fused quinoline 3ac in 90%
isolated yield. A range of substituents involving 4-methyl,
4-trifluoromethyl, 2-fluoro, 4-fluoro, 4-chloro, and 2,4-
dimethyl groups on the phenyl ring were well tolerated to
produce desired six-member ring-fused quinoline in excel-
lent yields (Scheme 2).
(5) (a) Martins, M. A. P.; Frizzo, C. P.; Moreira, N. D.; Buriol, L.;
Machado, P. Chem. Rev. 2009, 109, 4140. (b) Niementowski, S. J. Prakt.
Chem. 1895, 51, 564.
~ꢀ
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(6) (a) Banon-Caballero, A.; Guillena, G.; Najera, C. J. Org.
Chem. 2013, 78, 5349. (b) Shiri, M.; Zolgigol, M. A.; Kruger, H. G.;
Tanbakouchian, Z. Adv. Heterocycl. Chem. 2011, 102, 139. (c) Contelles,
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J. M.; Perez-Mayoral, E.; Samadi, A.; Carreiras, M. C.; Soriano, E.
Chem. Rev. 2009, 109, 2652.
(7) (a) Wang, Y.; Chen, C.; Peng, J.; Li, M. Angew. Chem., Int. Ed.
2013, 52, 5323. (b) Su, X.; Chen, C.; Wang, Y.; Peng, J.; Lou, Z.; Li, M.
Chem. Commun. 2013, 49, 6752. (c) Peng, J.; Chen, C.; Wang, Y.; Lou,
Z.; Li, M.; Xi, C.; Chen, H. Angew. Chem., Int. Ed. 2013, 52, 7574. (d)
Wang, F.; Chen, C.; Deng, G.; Xi, C. J. Org. Chem. 2012, 77, 4148.
(8) For reviews on diaryliodonium salts, see: (a) Yusubov, M. S.;
Maskaev, A. V.; Zhdankin, V. V. ARKIVOC 2011, 370. (b) Merritt,
E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052. (c) Zhdankin,
V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299. (d) Zhdankin, V. V.;
Stang, P. J. Chem. Rev. 2002, 102, 2523. (e) Grushin, V. V. Chem. Soc.
Rev. 2000, 29, 315. (f) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96,
1123.
(9) The anion of diaryliodonium salts 1 is triflate except 1a (PF6ꢀ).
Diaryliodonium salts 1 were easily synthesized according to literature
except commercially available 1a: (a) Skucas, E.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2012, 134, 9090. (b) Bielawski, M.; Zhu, M.; Olofsson,
B. Adv. Synth. Catal. 2007, 349, 2610. (c) Bielawski, M.; Olofsson, B.
Chem. Commun. 2007, 2521. (d) Olofsson, Bielawski, B. Org. Synth.
2009, 86, 308.
(10) Sargent, L. J.; Small, L. J. Org. Chem. 1946, 11, 359.
Org. Lett., Vol. 15, No. 18, 2013
4795

dibromoalkane and lithium phenylacetylide followed by
treatment with cyanomethyl lithium (eq 2). The reaction
of diphenyliodonium 1aꢀ1c with 2g produced 7-member
ring-fused quinolines 3agꢀ3cgin synthetically useful yields.
Eight-member ring-fused quinolines 3ah, 3ch, and 3hh
were made analogously from ω-cyano-1-octyne 2h, albeit
in lower yields.12
Scheme 1. Preparation of Dihydro-cyclopenta[b]quinoline
Scheme 3. Preparation of Tetrahydrocyclohepta[b]quinoline
and Hexahydrocycloocta[b]quinoline
Interestingly, di(1-naphthyl)iodonium 1i also reacted
with 2c to give tetracyclic quinoline 3ic in 71% yield.
The use of ω-cyano-1-naphthyl-1-hexyne 2d instead of
2c reacted with diaryliodoniums 1a and 1i to form 3ad
(76% yield) and 3id (65% yield), respectively. Analo-
gously, ω-cyano-1-bromo-hexyne 2e reacted with diarylio-
donium salts 1aꢀ1c to give bromoquinoline 3aeꢀ3ce in
good yields. Furthermore, ω-cyano-1-chloro-hexyne 2f
reacted with 1a to give chloroquinoline 3af in 75% yield.11
Scheme 2. Preparation of 1,2,3,4-Tetrahydroacridine
As shown above, we demonstrated that regular tricyclic
quinolines were facilely synthesized from diaryliodonium
salts and ω-cyano-1-alkynes. This strategy was extended to
prepare tetracyclic quinolines. For this goal, diphenylio-
donium 1a was chosen to react with cyclic ω-cyano-
1-alkyne 2i, and excitingly, tetracyclic quinoline 3ai was
obtained in 83% yield (eq 3). Sulfur-containing tacrines
have also received much attention and attracted us to
prepare using our method. For this target, Sulfur-contain-
ing ω-cyano-1-alkyne 2j was prepared from dibromopro-
pane and lithium phenylacetylide followed by treatment
with KSCN. The reaction of diphenyliodonium 1a with 2j
worked very well to supply product 3aj in 91% yield (eq 4).
Inspired by the results above, we attempted to prepare
7- and 8-member ring-fused quinolines using ω-cyano-
1-heptyne 2g and ω-cyano-1-octyne 2h. These two starting
materials were easily prepared via a linear process from
We recognized that many of the products were impor-
tant building blocks toward other quinolines. For example,
bromoquinoline 3ae was transferred into tacrine in 69%
(12) In the reaction mixture of 1a and 2h, no starting materials
remained after the completion of the reaction. Analyzing the reaction
mixture by ESI-MS, a few byproducts were observed, and most of them
could be assigned to the dimers of 3ah (for details see Supporting
Information, page S63).
(11) (a) Wang, Y.; Guan, X. L.; Wu, P. F.; Wang, C. M.; Cao, H.; Li,
L.; Guo, X. J.; Wang, F.; Xie, N.; Jiang, F. C.; Chen, J. G. J. Med. Chem.
ꢀ
2012, 55, 3588. (b) Szymanski, P.; Karpinski, A.; Mikiciuk-Olasik, E.
Eur. J. Med. Chem. 2011, 46, 3250.
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Org. Lett., Vol. 15, No. 18, 2013

Scheme 4. Derivation of Polycyclic Bromoquinolines
Scheme 5. Mechanism Proposed
transfers the phenyl group to the cyano of the ω-cyano-
1-alkyne (as exemplified by ω-cyano-1-hexyne) to give
intermediate I. Intermediate I is a highly reactive species
and is quickly attacked by intramolecular acetylene moiety
of the same ω-cyano-1-alkyne to give intermediate II.
Intermediate II undergoes an electrophilic annulation on
the phenyl ring to give the polycyclic quinoline product
(Scheme 5).
In summary, we have described a concise construction
of polycyclic quinolines via intramolecular [2 þ 2 þ 2]
annulation of ω-cyano-1-alkynes with diaryliodonium
salts. The process produced polycyclic quinolines in high
yield with readily available staring materials and catalyst
and was well tolerated with halogen substituents. Our
work proved that this method was suitable for the pre-
paration of a variety of tacrine analogues. Further design
and synthesis ofa bioactivecomplex and natural molecules
are in progress.
yield via amination with ammonium catalyzed by Cu2O.13
Other transformation involving amination with toluidine,14
ethynylation with tolyl acetylene (Sonogashira coupling
reaction),15 and arylation with m-tolyl boronic acid
(Suzuki coupling reaction) worked also well under classic
conditions and provided quinoline derivatives 4aꢀ4c.16
Analogously, bromoquinoline 3ab was aminated into 4d in
54% yield and arylated into 4e in 95% yield. (Scheme 4)
On the basis of the previous reports7 and our findings,
we proposed a mechanism for this reaction with ArꢀCu-
(III) species involved. Initially, oxidative addition to the
Cu(I) species (generated in situ from Cu(OTf)2 via reduc-
tion or disproportion) by the diaryliodonium salt (as
exemplified by Ph2Iþ) gives a PhꢀCu(III) species that
Acknowledgment. This work was supported by Na-
tional Natural Science Foundation of China (21102080)
and Tsinghua University Initiative Scientific Research
Program (2011Z02150).
Supporting Information Available. Full experimental
1
details, analytical and spectroscopic data (copies of H
and 13CNMR for new compounds). X-ray structures and
crystallographic information files (CIF) for compound
3cb. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Xu, H. H.; Wolf, C. Chem. Commun. 2009, 3035.
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(16) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b)
Miyaura, N.; Suzuki, A. Chem. Commun. 1979, 866.
The authors declare no competing financial interest.
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