Rapid Access to Indeno[1,2-c]quinolines via Br?nsted Acid- Catalyzed Cascade Reaction

Article abstract of DOI:10.1002/adsc.201700190

A Br?nsted acid-catalyzed annulation strategy has been developed to construct indeno[1,2-c]quinolines. This tandem synthetic method proceeds through a sequential electrophilic addition followed by a Friedel–Crafts-type reaction. A variety of tetracyclic c

Full text of DOI:10.1002/adsc.201700190

Title: Rapid access to indeno[1,2-c]quinolines via Brønsted-Acid
Catalyzed Cascade Reaction
Authors: Sivasenthilkumar Boominathan
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10.1002/adsc.201700190
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Rapid access to indeno[1,2-c]quinolines via Brønsted-Acid
Catalyzed Cascade Reaction
Siva Senthil Kumar Boominathan,a and Jeh-Jeng Wanga,b*
a
Department of Medicinal & Applied Chemistry, Kaohsiung Medical University, No. 100, Shiquan 1st Rd, Kaohsiung
807, Taiwan.
Fax: (+886)-7-312-5339; phone: (+886)-7-312-1101; E-mail: jjwang@kmu.edu.tw
Department of Medical Research, Kaohsiung Medical University Hospital, No.100, Tzyou 1st Rd, Kaohsiung 807,
b
Taiwan.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
frameworks from carboamination of unactivated
alkynes promoted by
Abstract. A Brønsted acid catalyzed annulation strategy
has been developed to construct indeno[1,2-c]quinolines.
This tandem synthetic method proceeds through a
sequential electrophilic addition followed by a Friedel-
Crafts type reaction. A variety of tetracyclic compounds
were obtained in moderate to high yields under mild
reaction conditions in a short time.
bis(trifluoromethanesulfonyl)imide ((Tf)2NH) and p-
toluenesulfonic acid (p-TsOH) (eq. d).2d Encouraged
by these pioneering studies and driven by our
continuing efforts to develop new synthetic methods
from -keto sulfonamides,3 here we have
conceptualized a synthetic strategy using -hydroxy
sulfonamides as potential precursors, with the aid of a
Brønsted acid, to synthesize indeno[1,2-c]quinolines
(Scheme 1; eq. e).
Keywords: Indeno[1,2-c]quinolines, Brønsted acid
catalysis, cascade reaction, Polycyclic heterocycles,
Alkynes
In recent years, Brønsted acid catalysis has emerged as
a simple and powerful synthetic strategy that is
complimentary to Lewis acid catalysis to access C-C,
C-N, and C-O bond forming reactions.1 Although
Brønsted acids have long been employed in organic
synthesis, they have rather limited applications, such
as hydrolysis, ester formation, and C-O cleavage
reactions. The economic attractiveness and mild nature
of these catalysts have made their use significant in
recent decades. In general, Brønsted acid catalyzed
reactions proceed via the activation of carbonyl, imine,
alkyne, alkene, and hydroxy groups to beget reactive
electrophiles, which then trigger nucleophilic addition
reactions. The use of Brønsted acid promoted alcohol
pro-electrophiles trapped by alkynes could be a
judicious choice to construct polycyclic skeletons, but
to our knowledge, few studies have made use of this
strategy. In 2009, Yamamoto et. al. reported an elegant
approach to preparing spirocycles from alkynyl
tertiary alcohols using a catalytic amount of
trifluoromethanesulfonic acid (TfOH) (Scheme 1; eq.
a).2a Shortly after that, Jiao and co-workers reported a
direct C(sp)−C(sp3) coupling reaction in the presence
of Fe(OTf)3 and TfOH (eq. b).2b A trifluoroacetic acid
(TFA) promoted cascade cyclization yielding fused-
polycyclic cyclopenta[b]indoles was developed by
Hamada in 2013 (eq. c).2c Very recently, Niggemann
Scheme 1. Functionalization of alcohols with
alkynes/alkenes under Brønsted acid catalysis.
Cascade chemical reactions in organic synthesis
have intensely inspired the scientific community in-
disclosed
a
convenient method to quinoline
1
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10.1002/adsc.201700190
Advanced Synthesis & Catalysis
which has encouraged us to develop a practical route
to indene-fused quinoline analogues. In 2011, Wu et.
al. reported a palladium catalyzed domino type
reaction of alkynyl aryl halides with amines to prepare
5H-indeno[1,2-c]quinolines (Scheme 2, eq. a).9a
A
nazarov type electrocyclization approach towards
these tetracyclic compounds via Sc(OTf)3 or TfOH
reported by panda in 2011 (eq. b).9b An iron salts
mediated tandem carboarylation/cyclization of
propargylanilines with diethyl benzaldehyde acetals to
indeno[2,1-c]quinolines was developed by Yu et. al. in
2014 (eq. c).9c Yamamoto and coworkers were
developed a TBABr promoted photocyclization of
acrylanilides to these tetracyclic compounds (eq. d).9d
Recently, Wang et. al. developed a copper-catalyzed
1,7-enyne trifluoromethylation/bicyclization reaction
Figure
indenoquinolines.
1.
Bioactive
compounds
containing
with
Togni’s
reagent
to
indene
and
dihydroquinolinone fused heterocycles (eq. e).9e
Despite their great efforts, the available methods to
prepare these compounds are very limited and
suffering from certain limitations like harsh reaction
conditions, need of pre-constructed quinoline/indene
starting materials, limited substitution pattern,
transition-metal catalysts, and poor reaction yields.
These limitations and significance of these scaffolds
have encouraged us to develop a practical route to
indene-fused quinoline analogues. The present method
exemplifies the efficient construction of these
scaffolds using catalytic amount of TfOH under mild
reaction conditions in short time (Scheme 1; eq. e).
Scheme 3. Synthetic Scheme for Starting material
Initially, the desired precursors were synthesized
from commercially available starting materials as
shown in Scheme 3. The substituted 2-iodo anilines
undergo Sonogashira coupling with respective aryl
alkynes, followed by sulfonylation and subsequent
alkylation by corresponding -bromoaryl ketones to
give -keto sulfonamide derivatives (1) in a stepwise
manner in quantitative yields.3c Next, the keto group
of compound 1 is reduced in the presence of sodium
borohydride to afford -hydroxy sulfonamides (2),
which were used in the final step without further
purification (See SI for details).
We commenced our study by investigating the
reaction of compound 2a with various acid catalysts,
and the results are assembled in Table 1. The reaction
was first carried out with 10 mol % of TfOH in 1,2-
DCE at RT (Table 1; entry 1). Gratifyingly, the
expected tetracyclic compound 3a was obtained in
72% yield, and X-ray crystallographic analysis
confirmed the structure (Figure 2).10 We then screened
this tandem reaction with different acid catalysts such
as Tf2NH, TFA, p-TsOH, and BF3∙OEt2 (entries 2-5),
Scheme 2: Previous approaches to indene fused quinolines.
-recent years, as demonstrated by the vast number of
research articles and reviews published on the topic.4
These
reactions
provide
convenient
and
straightforward routes to achieving structural
complexity from simple precursors. Among the
ubiquitous
nitrogen-containing
heterocycles,
quinoline fused frameworks hold a special place due
to their prevalence in naturally occurring compounds,
pharmaceuticals, and materials. Evidently, indene-
fused quinolines derivatives have appear in several
bioactive molecules and have proven applications such
as topoisomerase I/II inhibitors,5 anti-osteoclastogenic
activators,6 anti-cancer
properties,7
and
anti-
mycobacterials (Figure 1).8 The available methods to
prepare these compounds (Scheme 2) are very limited,
2
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10.1002/adsc.201700190
Advanced Synthesis & Catalysis
and among them, only Tf2NH responded well to this
reaction. However, we settled on TfOH as the choice
of a catalyst, because it was significantly less costly
than Tf2NH. A short screening of solvents, such as
dichloromethane, chloroform, nitromethane, and
toluene (entries 6-9), resulted in significantly lower
product yield. Thus, we chose 1,2-DCE as the optimal
solvent. No reaction took place in the absence of acid
catalyst (entry 10). Increasing the amount of catalyst
from 10 to 20 mol % led to a further improvement in
the reaction yield from 72 to 84%, and we fixed this
entry as the optimal set of reaction conditions (Table
1, entry 11).
yields. Furthermore, the molecules with the phenyl
group at the R3 position changed to a p-tolyl group (3n-
Scheme 4. Substrate Scope
Table 1. Optimization Studiesa
entry catalyst
solvent
temp(oC)/
time (h)
RT/2
yielde
(%)
72
1
2
TfOH
Tf2NH
TFA
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
RT/2
RT/16
74
15
3
4b
5b
6
7c
8b
9
p-TsOH
RT-80/16
RT-80/16
RT/4
Trace
Trace
70
BF3∙OEt2 1,2-DCE
TfOH
TfOH
TfOH
TfOH
-
DCM
CHCl3
RT-60/4
RT-80/8
RT-80/12
RT-80/16
RT/2
55
CH3NO2
toluene
1,2-DCE
1,2-DCE
35
Trace
0
10
11d
TfOH
84
aGeneral reaction conditions: Compound 2a (0.25 mmol),
catalyst (10 mol %), solvent (0.05 M). bNo reaction occurred
c
at RT; thus, the reaction was heated to 80 °C. No reaction
d
occurred at RT; thus, the reaction was heated to 60 °C. 20
mol % catalyst was used. eIsolated yields.
The scope and limitations of this methodology were
investigated under the optimized reaction conditions
and summarized in Scheme 4. First, R1 on the phenyl
ring was replaced with methoxy, naphthyl, and chloro
(3a-d) groups, which led to the desired
annulatedproducts in good yields. Notably, the phenyl
ring appended with electron donating group reacted
very well in short time with excellent yields (3b).
Conversely, the substrates bearing electron
withdrawing groups such as a nitro group (3e) failed
to cyclize even at elevated temperature, possibly due
to lessened stability of the in situ generated benzylic
cation (vide infra). Similarly, the R1 at the C-2 position
(3f) also turned into a complex reaction mixture that
could not be identified by NMR analysis. Next, the
fluoro, and chloro substituents (3g-m) were smoothly
transformed into the respective products with high
General reaction conditions: Compound 2 (0.25 mmol), and
catalyst (20 mol %) in a solvent (0.05 M) were stirred at RT
a
for the mentioned time given in parenthesis. Reaction was
b
performed at 1.5 gram scale. No reaction occurred at RT;
c
thus, the reaction was heated to 60 °C. Reactions were
conducted at 0-5 °C for 60 min; longer reaction times
decreased the reaction yield.
3
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10.1002/adsc.201700190
Advanced Synthesis & Catalysis
o) underwent the tandem reaction with greater yields;
nevertheless, an alkyl group at the R3 position was
unsuccessful (3p). In addition, replacing the tosyl
group with phenyl sulfonyl (3q) and brosyl (Bs)
groups (3r) gave the expected tetracyclic compounds.
It is noteworthy that the thiophene appended
tetracyclic product was obtained in a short time with
high yield (3s), but the double bond present in the
cyclopentane ring was isomerized. Crystal studies
unambiguously confirmed the structure of 3s (Figure
2).9 The use of sulfonamides was essential to set off
the domino process, and its replacement with oxygen
to prepare indeno[1,2-c]chromenes was ineffective
(3t).
In summary, we have reported a simple and
straightforward route to indeno[1,2-c]quinolines via
Brønsted acid catalysis. Advantageously, water is the
only
by-product,
making
this
protocol
environmentally benign and atom-efficient. The
experimental simplicity, scalability, short reaction
time, simple precursors, and cascade reaction
sequence make this route highly intriguing from a
synthetic perspective, and it may find useful
applications in medicinal chemistry.
Experimental Section
General procedure for synthesis of compound 3a-s:
To a stirred solution of compound 2a (0.25 mmol) in 1,2-
DCE (0.05 M) was added with catalytic amount of TfOH
(20 mol%) and stirred at RT for mentioned time and
temperature. After reaction completed (monitored by TLC),
reaction mass partitioned between water and DCM. The
combined organic layer was washed with sat. NH4Cl
solution, dried on sodium sulphate and evaporated under
vacuum gives crude. Then, the crude was purified by flash
column chromatography on silica gel with suitable ratio of
Hexane/EtOAc to afford the corresponding product (3a).
Acknowledgements
Figure 2. ORTEP diagram of Compound 3a and 3s
The authors gratefully acknowledge funding from the Ministry of
Science and Technology (MOST), Taiwan, and the Centre for
Research Resources and Development of Kaohsiung Medical
University for 400 MHz NMR analyses.
Based on the observed results and the literature,2,11
a tentative reaction mechanism for this transformation
has been proposed in Scheme 5. First, the alcohol is
ionized by the aid of TfOH to give the putative
benzylic cation (A), which, after being further attacked
by a nucleophilic alkyne, gives a vinyl carbocation (B).
A subsequent Friedel-Crafts type reaction between the
aryl group and vinyl cation provides the indeno[1,2-
c]quinolines, and the expelled catalyst participates in
the next cycle.
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Advanced Synthesis & Catalysis
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10.1002/adsc.201700190
Advanced Synthesis & Catalysis
COMMUNICATION
Rapid access to indeno[1,2-c]quinolines via
Brønsted-Acid Catalyzed Cascade Reaction
Adv. Synth. Catal. Year, Volume, Page – Page
Siva Senthil Kumar Boominathan and Jeh-Jeng
Wang*
6
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