Copper-Mediated Cascade C-H/N-H Annulation of Indolocarboxamides with Arynes: Construction of Tetracyclic Indoloquinoline Alkaloids

Article abstract of DOI:10.1021/acs.orglett.7b03580

An efficient and environmentally benign Cu-mediated method was developed for direct cascade C-H/N-H annulation to construct polyheterocyclic indoloquinoline scaffolds. This method highlights an emerging strategy for transforming inert C-H bonds into versatile functional groups in organic synthesis and provides a new versatile approach for the efficient synthesis of indolo[3,2-c] and [2,3-c]quinoline alkaloids.

Full text of DOI:10.1021/acs.orglett.7b03580

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Mediated Cascade C−H/N−H Annulation of
Indolocarboxamides with Arynes: Construction of Tetracyclic
Indoloquinoline Alkaloids
Ting-Yu Zhang,† Chang Liu,† Chao Chen,† Jian-Xin Liu,§ Heng-Ye Xiang,§ Wei Jiang,∥ Tong-Mei Ding,†
and Shu-Yu Zhang*,†,‡,∥
†School of Chemistry and Chemical Engineering, ‡Sixth People’s Hospital South Campus, and §Zhiyuan College, Shanghai Jiao Tong
University, Shanghai 200240, China
∥School of Chemistry & Environmental Engineering, International Healthcare Innovation Institute, Wuyi University, Jiangmen
529020, China
S
* Supporting Information
ABSTRACT: An efficient and environmentally benign Cu-mediated
method was developed for direct cascade C−H/N−H annulation to
construct polyheterocyclic indoloquinoline scaffolds. This method
highlights an emerging strategy for transforming inert C−H bonds into
versatile functional groups in organic synthesis and provides a new
versatile approach for the efficient synthesis of indolo[3,2-c] and [2,3-
c]quinoline alkaloids.
alaria is a tropical parasitic disease that is caused by
activity and unique structure of the tetracyclic indoloquinoline-
fused rings inspired us to devise a highly efficient synthetic
protocol. Some classical transformations have been established to
form isocryptolepine (e.g., Heck-type reaction,5a,d,e photo-
reaction,5b Pd-catalyzed oxidative C−N bond or tandem C−C/
C−N formation,5f,g CDC reaction,5h,i Beckmann rearrange-
ment,5j and electrochemical synthesis5k) or isoneocryptolepine
skeletons (e.g., Suzuki reaction,6a Heck reaction,6b photo-
cyclization,6c,d oxidative C−N bond6e). Synthetic access to
certain important polycyclic indoloquinoline skeletons remains
limited. An ideal and notable synthetic method should include a
versatile synthetic strategy to form indolo[2,3-c] and [3,2-
c]quinolones, with a synthesis protocol that avoids the use of
noble metal catalysts and oxidants due to potential pharmaceut-
ical chemical studies, and is highly efficient, economical, and
environmentally benign. Development of more efficient and
novel indoloquinoline formation methods continues to be
extensively investigated in synthetic chemistry.
M
protozoa of the genus Plasmodium, and significant efforts
tocontrol andtreat malaria resulted insomesuccess,1 includingin
plant-derived drugs, e.g., quinine,2a qinghaosu2b (Prof. Tu, 2015
Nobel Prize in Physiology or Medicine), and in new potent
antimalarial compound NITD6092c (IC50: 1 nM, P. falciparum)
(Figure 1). However, this devastating disease still affects more
Figure 1. Antimalarial agents.
Transition-metal-catalyzed direct selective conversion of
unactivated C−H bonds has emerged as an attractive and
arguably ideal strategy to synthesize heterocyclic molecules.7
Previously, we focused on the development of efficient and
selective unactivated C−H functionalizations and application to
the synthesis of natural biological products.8 We are focused on
developing cheap and environmentally friendly Cu-catalyzed9
cascade annulation to rapidly access structurally diverse
polyheterocyclic alkaloids.10 Benzynes,11 which are classical
than 500 million people around the world every year. In 2015,
429000 deaths were caused by malaria.1b To date, the search for
effective and safer antimalarial remedies remains at the forefront
of scientific research.
Indoloquinoline alkaloids,3 such as isocryptolepine4a,b (indolo-
[3,2-c]quinoline), isolated from the west African climbing shrub
Cryptolepis sanguinolenta (Lindl), are used in Central and West
Africa as traditional medicine for the treatment of malaria. Its
synthetic analogue isoneocryptolepine4c (indolo[2,3-c]-
quinoline) exhibits excellent antiplasmodial activity in the
nanomolar range on L6 cells as well as antitumor activity. The
Received: November 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03580
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Letter
highly electrophilic reactive intermediates, have attracted much
interest. Herein, we report our latest developments on Cu-
mediated selective cascade C−H/N−H annulation directed by
the N,N-bidentate directing group12 to synthesize tetracyclic
indolo[3,2-c] and [2,3-c]quinoline cores with benzynes under
mild conditions (Scheme 1). This method offers a practical and
arguably ideal strategy for rapid synthesis of polyheterocyclic
indoloquinolines from simple starting materials.
fluoride sources and additives (entries 2−9). Addition of more
TBAI, which is typically believed to further increase the benzyne
generation rates from the Kobayashi benzyne precursor,15
improved the yield of the reaction to 31% (entry 6). We obtained
an 83% isolated yield for 3 under optimized reaction conditions
(50mol%Cu(OAc)2,1.2equivCsF, and1.0equivTBAI, 80°Cin
1:1 DMF/MeCN under O2 for 12 h) (entry 9). O2, which is an
ideal oxidant because it is clean, green, and inexpensive, appeared
to significantly improve the Cu catalysis cycle (entry 10).16
The N-protecting groups (R1) of indole were very important in
these cascade C−H/N−H activation and annulation reactions.
Replacing N-methyl (1a) with N-H (1b) or other electron-
withdrawing N-protected groups, i.e., N-Cbz (1c) and N-Boc
(1d), were not afforded under standard conditions. Installation of
electron-donating protective groups (i.e., N-Bn (1e) and N-
MOM (1f)) did give the desired annulation products in 33 and
57% isolated yield. Next, we examined the effect of directing
groups (R2). The desired reaction was inhibited when OMe (1g),
Me (1h), or Ph (1i) was used in place of 1a. The 2-oxazolinyl (1j)
directinggrouponlyyieldedtraceamountsofannulationproduct.
TheseresultsindicatethattheN,N-bidentatedirectinggroup(i.e.,
8-aminoquinoline) plays a critical role in this Cu-mediated
cascade C−H/N−H activation and annulation reaction.
With an optimized set of conditions in hand, we probed the
substrate scope of 1a to survey the general reactions. Indole-3-
carboxamides that were substituted with a variety of functional
groups, such as alkyl, halogens, OMe, NO2, and CN, were well
tolerated in this Cu-catalyzed system and afforded tetracyclic
indolo[3,2-c]quinoline derivative C−H/N−H annulation prod-
ucts4−23 ingoodtoexcellentyields(Scheme 2). The4-, 5-, 6-, or
7-methyl-substituted indole-3-carboxamides 4a−7a were em-
ployed to examine remote steric effects. The lower steric
hindrance of 5- or 6-methyl-substituted N-quinolyl 1-methyl-
1H-indole-3-carboxamides (5a and 6a) resulted in the best yield.
X-ray crystallographic analysis of annulation product 4 effectively
Scheme 1. Strategies for Construction of Indoloquinolines via
Cu-Mediated Cascade C−H/N−H Annulation
Our initial attempt was focused on intermolecular annulation
of a model substrate (i.e., N-quinolyl 1-methylindole-3-
carboxamide (1a) with a Kobayashi benzyne precursor 2a13
(Table 1). After initial screening of various Cu catalysts and
solvents, theresults demonstrated thefeasibility ofthis reaction.14
Despite low yield, the desired tetracyclic indoloquinolinone 3 was
obtained using catalytic amounts of Cu(OAc)2 (0.35 equiv), CsF
(1.2 equiv), and TBAI (0.5 equiv) at 80 °C in a 1:1 DMF/MeCN
mixture under O2 as an oxidant for 12 h (Table 1, entry 1). To
promote the conversion of 1a, further studies surveyed a series of
a
Table 1. Optimization of the Reaction Conditions
a b
,
Scheme 2. Scope of Functionalized Indolo[3,2-c]quinolone
a
Reaction conditions: benzamide (0.2 mmol), 2a (0.4 mmol),
Cu(OAc)2 (0.5 equiv), CsF (0.24 mmol), and TBAI (0.2 mmol) in
a
b
All screening reactions were carried out in a 10 mL glass vial with a
1:1 DMF/MeCN (2 mL) at 80 °C under O2 for 12 h. Isolated yield
b
c
PTFE-lined cap at 0.2 mmol scale. Yields based on 1H NMR analysis.
after purification. Benzamide (0.2 mmol), 2a (0.4 mmol), Cu(OAc)2
c
Isolated yield in parentheses. See Supporting Information for more
(0.75 equiv), CsF (0.24 mmol), and TBAI (0.3 mmol) in 1:1 DMF/
conditions.
MeCN (2 mL) at 100 °C under O2 for 2 h.
B
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Letter
explainstheremotestericeffectsofsubstituted indoles. Thescope
of the functionalized aryne precursors as general annulation
partners for this reaction was investigated. Various substituted
indole-3-carboxamide substrates were reacted with various aryne
precursors 2b−2e to afford good to excellent annulation yields
(18−23).
Scheme 4. Proposed Reaction Pathway
Next, we examined the scope of the different N-protected
groups of indole-2-carboxamides 24−27. Substrates with
electron-donating groups, such as N-methyl (24a), N-Bn (25a),
andMOM(27a), affordedthedesiredtetracyclic24, 25, and27in
63, 64, and 65% isolated yield, respectively (Scheme 3). Electron-
a
Scheme 3. Scope of Functionalized indolo[2,3-c]quinolone
reductive elimination of III yielded the desired annulation
production(3), andtheCucatalystwasregeneratedbyoxygenfor
the next cycle.
To demonstrate the application of our non-noble metal Cu-
mediated cascade C−H/N−H annulation method as an efficient
and versatile synthetic strategy to form indolo[3,2-c] and [2,3-
c]quinolones, tetracyclic indoloquinolines 40 and 43 were
synthesized under these mild conditions (Scheme 5). A previous
Scheme 5. Synthetic Applicability and Removal of Auxiliary
a
Reaction conditions were the same as those of Scheme 2. See
Supporting Information for more reaction conditions. X-ray
determined the structure of 28.
withdrawing N-protected group (N-Cbz(26a))did notresultina
reaction under standard conditions. Based on these results, the N-
quinolyl 1-MOM-indole-2-carboxamides substituted with a
variety of functional groups were reacted with various aryne
precursors. These precursors were well-tolerated under the
Cu(OAc)2/O2 system and smoothly afforded the desired
indolo[2,3-c]quinoline derivative C−H/N−H annulation prod-
ucts 28−39 ingood toexcellent yields. These results demonstrate
that our approach has potential for use in the synthesis of
functionalized tetracyclic indolo[3,2-c] and indolo[2,3-c]-
quinoline cores.
To gain insight into the mechanism, we conducted a primary
intermolecularkineticisotopeeffectexperiment, andavalueof1.3
was observed (see the Supporting Information). Next, a radical
trapping experiment was performed. The reaction was not
inhibited by addition of 2 equiv of a radical scavenger (TEMPO),
and 1a still afforded 3 in a 76% isolated yield. These experiments
suggested that a SET mechanism was most likely not involved in
this reaction.17 Based on these experiments and previous
studies,8,16,17 a plausible organometallic C−H activation
mechanism via a Cu(III) intermediate18 was proposed for this
cascade C−H/N-H annulation. As shown in Scheme 4,
coordination of 1a was followed by reaction with Cu(OAc)2-
generated anionic complex I ligated by a N,N-bidentate directing
group. Complex I underwent an acetate-assisted intramolecular
C−H concerted metalation/deprotonation to yield five-mem-
bered complex II, which underwent carbocupration with the
aryne generated from 2 to afford intermediate III. Finally,
study reported that 8-amino-5-methoxyquinoline (MQ) can be
used rather than 8-aminoquinoline for easy extraction.19 The MQ
auxiliary of indolo[3,2-c]quinoline 23 can be readily removed by a
two-step sequence to afford 40, and the alkaloid isocryptolepine, a
natural antimalarial, can be synthesized from 40 under the simple
conditions reported.5d Removal of the MQ auxiliary of 41 affords
42, which can be used to obtain various isoneocryptolepine-type
indolo[2,3-c]quinolones. For example, 5H-indolo[2,3-c]-
quinolin-6(7H)-one 43 (Scheme 5, eq 2), which is a potent
tubulin polymerization inhibitor that inhibits the growth of
human breast cancer cells,20 was successfully synthesized from 42
in 92% yield under simple conditions.
In summary, we developed a highly efficient Cu-mediated
intermolecular cascade C−H/N−H annulation of indole
carboxamides with arynes. These reactions are operationally
simpleandrobust, andtheCu(OAc)2/O2 systemavoidstheuseof
sensitive and expensive noble metals and oxidants. The reaction
produced broad and structurally diverse polyheterocyclic indolo-
[3,2-c] and [2,3,-c]quinoline products. The directing group can
be easily removed under simple conditions, which results in an
efficient and straightforward strategy for the synthesis of
indoloquinoline alkaloids and activated motifs. Furthermore,
the application of this cascade C−H/N−H annulation method to
the synthesis of broader natural alkaloids is currently under
investigation.
C
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Tetrahedron 2006, 62, 4676. (c) Vaillard, V. A.; Buden
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ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b03580.
■
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Experimental procedures, NMR spectra, X-ray and
analytical data for all new compounds (PDF)
Accession Codes
CCDC 1586298−1586299 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 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 Author
*E-mail: zhangsy16@sjtu.edu.cn.
ORCID
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Shu-Yu Zhang: 0000-0002-1811-4159
Notes
The authors declare no competing financial interest.
(10) Ru-catalyzed C−H/Het−Hannulation: Ackermann, L. Acc. Chem.
Res. 2014, 47, 281.
ACKNOWLEDGMENTS
■
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This work was supported by the “Thousand Youth Talents Plan”,
NSFC (21672145, 51733007), the Shuguang program (16SG10)
from SEDF & SMEC, STCSM (17JC1403700), and the
Innovation Fund (IFPM016A002) from Shanghai Jiao Tong
University.
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