Synthesis of polysubstituted quinolines via transition-metal-free oxidative cycloisomerization of o -cinnamylanilines

Article abstract of DOI:10.1021/acs.orglett.5b00419

An efficient synthesis of 2-aryl 4-substituted quinolines from stable and readily available o-cinnamylanilines, prepared from anilines and cinnamylalcohols, has been developed. The reaction occurred via a regioselective 6-endo-trig intramolecular oxidative cyclization using KO^tBu as a mediator and DMSO as an oxidant at rt. The reaction showed a broad substrate scope with good to excellent yields.

Full text of DOI:10.1021/acs.orglett.5b00419

Letter
pubs.acs.org/OrgLett
Synthesis of Polysubstituted Quinolines via Transition-Metal-Free
Oxidative Cycloisomerization of o‑Cinnamylanilines
Mohammad Rehan, Gurupada Hazra, and Prasanta Ghorai*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Indore By-pass Road, Bhouri, Bhopal-462066,
India
S
* Supporting Information
ABSTRACT: An efficient synthesis of 2-aryl 4-substituted quinolines
from stable and readily available o-cinnamylanilines, prepared from anilines
and cinnamylalcohols, has been developed. The reaction occurred via a
regioselective 6-endo-trig intramolecular oxidative cyclization using KOtBu
as a mediator and DMSO as an oxidant at rt. The reaction showed a broad
substrate scope with good to excellent yields.
he quinoline skeleton is a key structural unit in a large
number of natural products, pharmaceuticals, and agro-
Driven by the fact that a wide variety of highly substituted o-
cinnamylanilines8 and their analogues are readily available from
cinnamyl alcohols and commercially available anilines, we
recently reported a methodology for the synthesis of 2-benzyl
indoles from such o-cinnamyl anilines (Scheme 2a).9 In an effort
T
chemicals.1 Functionalized quinolines are also widely used as
materials2 and catalysts for asymmetry synthesis.3 For this
reason, the development of synthetic protocols for functionalized
quinolines has always been an active area of research.4,5 The most
prevalent strategies for constructing quinoline rings are the
classic annulation reactions, including the Combes synthesis,6a−c
Skraup synthesis,6d−f Gould−Jacobs reaction,6g Conard−
Limpach synthesis,6h,i Doebner−von Miller reaction,6j,k and
Povarov reaction,6l−n where commercially available anilines are
still a common substrate.4 Strategically, in the above cases, N-
alkylation of anilines followed by cyclization occurs to provide
the corresponding quinolines (Scheme 1a). Recently, consid-
Scheme 2. Oxidative Cyclization of o-Cinnamylanilines
Scheme 1. Strategies for the Synthesis of Substituted
Quinolines from Anilines
to pursue the diversified application of such o-cinnamyl anilines,
we have turned our attention toward the possibility of achieving
the synthesis of functionalized quinolines from the same
(Scheme 2b). Herein, we report a transition-metal-free oxidative
cycloisomerization methodology using simple and economical
KOtBu in DMSO at room temperature. Functionalized quino-
lines were synthesized in high yields and with excellent
chemoselectivities. Nevertheless, from the standpoint of
sustainability and green chemistry, the development of
transition-metal-free reaction conditions has always been an
attractive strategy.10
The 2-arylquinoline moiety is commonly found in a wide
range of bioactive molecules such as antimalarials, antitumor
agents, and P-selectin antagonists (Figure 1).11 On the other
hand, 2-styrylquinolines are also important scaffolds having
considerable biological significance (Figure 1).12 However, there
are limited methods available for the synthesis of such scaffolds.13
erable attention has been focused toward the development of
strategies concerning the ortho-functionalization of anilines
followed by a cyclization reaction (Scheme 1b).7 Despite these
significant advances, the synthesis of such starting materials
remains a challenging task in many cases. In this context, the
development of a new synthetic protocol for the rapid
construction of highly functionalized quinolines with high
efficiency from easily available ortho-functionalized anilines
would be a significant contribution.
Received: February 9, 2015
Published: March 13, 2015
© 2015 American Chemical Society
1668
DOI: 10.1021/acs.orglett.5b00419
Org. Lett. 2015, 17, 1668−1671

Organic Letters
Letter
a b
,
Scheme 3. Variation of Aryl Amine
Figure 1. Biologically active quinoline skeleton containing a 2-aryl and
2-styryl substitutions.
Our studies began with (E)-2-(1,3-diphenylallyl)-4-methyl-
aniline 1a (Table 1). When a solution of 1a in dimethyl sulfoxide
a
Table 1. Optimization of the Reaction Conditions
b
entry
base (0.5 equiv)
solvent
DMSO
3a (%)
c
1
carbonates
−
2
LiOH
NaOH
KOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
−
3
22
25
58
83
53
−
16
12
−
4
a
Reaction conditions: o-allyl aniline 1 (0.20 mmol), KOtBu (0.5−1.5
b
5
NaH
equiv), DMSO (1 mL). Isolated yields after column chromatography.
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
c
d
1.0 equiv of KOtBu was used. 1.5 equiv of KOtBu was used.
6
7
8
1,4-dioxane
Et2O
on the aryl moiety were effectively converted to the
corresponding 2,4-diphenyl quinoline in good to excellent yields
(77−89%). Electron-withdrawing substituents such as 6-nitro
(3j), 6-fluoro (3k, 3o), 6-trifluoromethyl (3l), and 6-
trifluoromethoxy (3m) groups are also compatible with the
present reaction conditions and proceeded smoothly to afford
the desired quinolines. Even sensitive halogens such as bromo-
and chloro-substitutions on the aryl ring, which are sensitive to
KOtBu, were also nicely tolerated to afford the desired
halogenated quinolines (3n−p). Substitution ortho to the
NH2-group of 2-allyl aniline did not affect the reactivity (for
example, in case of 3q). Another type of aryl group, such as 9H-
fluorene-2-allyl-1-amine, was equally applicable to provide a
fused tetracyclic 3r quinoline in good yield (70%). In the case of
quinolines 3e−g and 3o−p, further addition of KOtBu was
required to achieve the complete consumption of the starting
material.
In Scheme 4, the oxidative cyclization of o-allylanilines
containing substitutions on the allyl counterpart is summarized.
Various symmetrically substituted 1′,3′-diaryl allyls such as p-
methyl, p-chloro-, and p-bromo-phenyls attached to anilines at
ortho-position reacted smoothly to provide the desired quino-
lines (5a−c, respectively) in moderate yields (80%, 76%, and
77%, respectively). Similar reactivity was found with o-allylaniline
having the 2-thiophenyl as well as 1-naphthyl group as an aryl
counterpart on the allyl moiety (5d and 5e, respectively).
Additionally, 2-aryl 4-alkyl quinolines (5f and 5g) were also
successfully synthesized using the present protocol. Besides, 4-
unsubstituted 2-aryl quinoline 5h was synthesized in 70% yield
using the current strategy. Simple 2-allyl aniline is also reacted to
9
10
11
12
13
THF
MeOH
EtOAc
CH2Cl2
12
−
a
The reaction was carried out with 1a (0.2 mmol), base (0.5 equiv), 4
b
h, 1 mL solvent, under an argon atmosphere. The isolated yields.
c
Carbonates such as Na2CO3, K2CO3, Cs2CO3 are used.
(DMSO) was stirred at rt in the presence of a catalytic amount of
various bases (such as Na2CO3, K2CO3, CsCO3, LiOH, NaOH,
KOH, NaH, and KOtBu, entries 1−6, respectively), it was
observed that KOtBu provided the desired 2,4-diphenylquinoline
3a (entry 6) in 83% isolated yield, which is found to be the best
among all the considered bases.
When the same reaction was carried out in other solvents such
as DMF,1,4-dioxane, Et2O, THF, MeOH, EtOAc, and CH2Cl2,
the reactivity of KOtBu remained less efficient than in DMSO
(entries 7−13, respectively). Further, various diamine ligands
were added in addition to KOtBu, aimed at increasing the yields
of the reaction; however, the desired improvement was not
observed (see Supporting Information for details). In any case,
we could not observe the formation of the indole 2.
The results summarized in Scheme 3 demonstrate that the
oxidative cyclization protocol is a robust one. We examined the
scope of the present reaction of o-allylanilines with substitution
on the aniline moiety. Electron-donating groups including 6-
methyl (3a), 6,7-dialkyl (3b, 3e), 6,7-dialkoxy (3c, 3f−g), 6,8-
dimethoxy (3d), 5,6,7-trimethoxy (3h), and 6-methylthio (3i)
1669
DOI: 10.1021/acs.orglett.5b00419
Org. Lett. 2015, 17, 1668−1671

Organic Letters
Letter
a b
,
a
Scheme 4. Variation of Allyl Counterpart
Table 2. One-Pot Protocol: Sequential Process
b
X
R1
C6H5
R2
C6H5
t1 (h) t2 (h) yield
1
2
3
4
−CH3
−SCH3
−CH3
−CH3
10
8
4
4
5
4
53
56
51
54
C6H5
C6H5
p-CH3C6H4
p-ClC6H4
p-CH3C6H4
p-ClC6H4
12
10
a
Reaction conditions: (i) alcohol (0.20 mmol), aniline (0.24 mmol),
Re2O7 (5 mol %) in CH3CN; (ii) KOtBu (1.2 equiv), DMSO (1 mL).
b
Isolated yields after column chromatography.
Scheme 6. Proposed Mechanism for Current Oxidative
Cyclization
a
Reaction conditions: o-allyl aniline 1 (0.20 mmol), KOtBu (1.5
b
c
equiv), DMSO (1 mL). Isolated yields. Reaction at 80 °C.
provide the desired unsubstituted quinoline (5i), except that a
slight increase in reaction temperature (80 °C) was needed. Not
only substitutions at the 2- and 4- position of quinolines but also
a simultaneous substitution at the 2,3- and 4-position could also
be achieved using this approach as shown in the case of 5j and 5k.
Notably, 2-styrylquinoline 5l and 5m that are difficult to prepare
using other strategies are also synthesized using our method-
ology.
is observed. We reasoned that the pKa values of the allylic C−H
bond (as shown in intermediate I) are responsible for such a
display of reactivity.
In summary, we have developed a novel and environmentally
benign method for the preparation of 2-arylquinoline and 2-
styrylquinolines from readily available o-cinnamylanilines using
tBuOK/DMSO as an economical and commercially available
reagent. A sequential synthesis of o-cinnamylaniline, starting
from corresponding anilines and substituted cinnamyl alcohols,
followed by oxidative cycloannulation has also been demon-
strated. The reaction displays a broad substrate scope and good
tolerance to a variety of substituents including aryl, alkyl, and
heterocyclic groups. 2-Arylquinoline and 2-styrylquinolines are
important compounds with potential applications in medicinal
chemistry11,12 that are now accessible via this inexpensive and
transition-metal-free approach. Extension of the present reaction
demonstrated toward the synthesis of related heterocyclic
moieties, and detailed mechanistic investigations are currently
in progress in our laboratory.
Further, the reaction of 1a was scaled 17-fold (1 g, 3.35 mmol)
under similar reaction conditions, resulting in a good yield (78%)
of the desired product as shown in Scheme 5.
Scheme 5. Gram Scale Synthesis
Finally, a one-pot, sequential FC-allylation of anilines with
t
allylalcohols using Re2O7 as the catalyst followed by BuOK/
DMSO mediated cyclization to provide 2,4-disubstituted
quinolines have been demonstrated (see Table 2). Although,
moderate yields are obtained, nevertheless, the one-pot method-
ology is expected to be of high synthetic utility.
ASSOCIATED CONTENT
* Supporting Information
■
S
A tentative mechanism for the current oxidative cyclization
reaction is proposed in Scheme 6. The initial step involves
KOtBu/DMSO mediated oxidation14 of 2-cinnamylaniline 1 to
generate intermediate II which undergoes 6π-electrocycliza-
tion15 to provide the quinolane III.
Experimental procedures, characterization data, and copies of
NMR spectra for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
Subsequent oxidation of intermediate III using KOtBu/
DMSO afforded product 3 or 5. In general, catalytic KOtBu
(0.5 equiv) is sufficient when R is an aryl group (as exemplified in
Scheme 3). However, the requirement of excess KOtBu is
realized when R is an alkyl or electron-rich aryl group (as
exemplified in Scheme 4); otherwise, a prolonged reaction time
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: pghorai@iiserb.ac.in.
Notes
The authors declare no competing financial interest.
1670
DOI: 10.1021/acs.orglett.5b00419
Org. Lett. 2015, 17, 1668−1671

Organic Letters
Letter
(k) Banon
́
-Caballero, A.; Guillena, G.; Naj
́
era, C. J. Org. Chem. 2013, 78,
̃
ACKNOWLEDGMENTS
■
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This work has been supported by the Department of Science &
Technology (DST), India, CSIR India and IISER Bhopal. We are
grateful to Drs. Deepak Chopra and Sreenivas Katukojvala,
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