Povarov-reductive amination cascade to access 6-aminoquinolines and anthrazolines

Article abstract of DOI:10.1021/ol4016354

A new strategy is reported for the synthesis of 6-aminoquinoline derivatives via a tandem Povarov reaction, dihydroquinoline oxidation, and imine reduction. These products allow access to symmetrical as well as unsymmetrical tetraarylpyrido[2,3-g]quinolines, potentially useful organic electronics.

Full text of DOI:10.1021/ol4016354

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Povarov-Reductive Amination Cascade
to Access 6‑Aminoquinolines
and Anthrazolines
Kasiviswanadharaju Pericherla,†,‡ Anil Kumar,‡ and Amitabh Jha*,†
Department of Chemistry, Acadia University, Wolfville, NS, B4P 2R6, Canada, and
Department of Chemistry, Birla Institute of Technology and Science, Pilani,
333031, India
ajha@acadiau.ca
Received June 10, 2013
ABSTRACT
A new strategy is reported for the synthesis of 6-aminoquinoline derivatives via a tandem Povarov reaction, dihydroquinoline oxidation, and imine
reduction. These products allow access to symmetrical as well as unsymmetrical tetraarylpyrido[2,3-g]quinolines, potentially useful organic
electronics.
Nitrogen containing heterocycles are ubiquitous scaffolds
in many natural products and biologically potent molecules.
The quinoline nucleus, a privileged substructure, is present in
an array of natural compounds1 and functional materials2
and is found to have extensive biological properties such as
antimalarial,3 anti-HIV,4 anticancer,5 and antituberculosis.6
Particularly, aminoquinolines act as fluorophores7 and have
been studied as potential organic semiconductors.8 Owing
to their importance in multidisciplinary fields, syntheses of
these heterocycles have attracted the interest of synthetic
chemists.
Since the first report by Skraup in 1880,9 several meth-
ods have been developed for the synthesis of the quinoline
nucleus. The Povarovreaction, aninverse electrondemand
hetero-DielsꢀAlder reaction, has proven to be one of the
convenient methods for the synthesis of 2,4-disubstituted
tetrahydroquinolines.10 This reaction is an excellent exam-
ple of multicomponent reactions with high atom economy
in organic synthesis. Multicomponent and tandem or cas-
cade reactions are found to be efficient when compared to
traditional stepwise linear synthesis because they often offer
excellent atom economy leading to reduction of waste.11
Several groups have reported the synthesis of 2,4-disubsti-
tuted quinolines with alkynes as dienophiles in a Povarov
protocol followed by either an aerobic oxidation or using
an additional oxidant. Imines, the substrate for the Povarov
reaction, are known to act as an oxidant to produce
quinolines from di- and tetrahydroquinolines, and the
† Acadia University.
‡ Birla Institute of Technology and Science.
(1) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166.
ꢀ
(2) (a) Francio, G.; Faraone, F.; Leitner, W. Angew. Chem., Int. Ed.
2000, 39, 1428. (b) Blaser, H. U.; Jalett, H. P.; Lottenbach, W.; Studer,
M. J. Am. Chem. Soc. 2000, 122, 12675. (c) Tonzola, C. J.; Kulkarni,
A. P.; Gifford, A. P.; Kaminsky, W.; Jenekhe, S. A. Adv. Funct. Mater.
2007, 17, 863. (d) Kulkarni, A. P.; Christopher J. Tonzola, C. J.; Amit
Babel, A.; Jenekhe, S. A. Chem. Mater. 2004, 16, 4556.
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(4) McCormick, J. L.; McKee, T. C.; Cardellina, J. H.; Boyd, M. R.
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(9) Skraup, Z. H. Berichte 1880, 13, 2086.
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L. Ferreira, M.; Lourenc-o, M. C. S. Bioorg. Med. Chem. 2009, 17, 1474.
(7) Bridhkoti, J. P.; Gahlaut, R.; Joshi, H. C.; Pant, S. J. Lumin. 2011,
131, 1869.
(10) For reviews on the Povarov reaction, see: (a) Povarov, L. S.
Russ. Chem. Rev. 1967, 36, 656. (b) V A Glushkov, V. A.; Tolstikov,
A. G. Russ. Chem. Rev. 2008, 77, 137. (c) Kouznetsov, V. V. Tetrahedron
2009, 65, 2721 and references cited therein.
(8) Nedeltchev, A. K.; Han, H.; Bhowmik, P. K. Tetrahedron 2010,
66, 9319.
(11) Foster, R. A. A.; Willis, M. C. Chem. Soc. Rev. 2013, 42, 63 and
references cited therein.
r
10.1021/ol4016354
XXXX American Chemical Society

corresponding amine would be a byproduct.12 Takasu and
co-workers reported the synthesis of quinolines via a Povarov
reaction and hydrogen transfer reaction using triflic imide
as an autotandem catalyst.13
(5a) of 1,4-phenylenediamine (1) should be isolated as the
major product. However, if the aromatization of the quino-
line ring is the dominating process (thermodynamic control),
then 6-benzylamino-2,4-diphenylquinoline (4a) should be
isolated as the major product (Scheme 1). Upon conducting
this reaction with the substrate stoichiometry required for
Recently, Gaddam et al. reported the synthesis of iso-
meric ellipticine derivatives via a Povarov reaction with
an imine as an oxidant.14 When the imine acts as an oxidant,
an equimolar amount of amine and aldehyde substrates
are exhausted which directly affects the atom economy
of the reaction. To the best of our knowledge, synthesis of
privileged 6-aminoquinoline derivatives is not reported in
the literature via a tandem multicomponent approach. With
our continued interest in multicomponent reactions for
the synthesis of heterocyclic compounds,15 we envisioned
that the synthesis of 6-aminoquinolines can be achieved via
a Povarov reaction and intramolecular hydrogen transfer.
In the present study, we wish to report the unprecedented
tandem multicomponent synthesis of 6-aminoquinoline
derivatives via a Povarov reaction, dehydrogenation, and
imine reduction sequence (Scheme 1) and their subsequent
use in the synthesis of symmetrical and unsymmetrical
anthrazolines or pyrido[2,3-g]quinolines.
the bis-Povarov product (5a) in the presence of BF3 Et2O
3
(5 mol %) in refluxing acetonitrile for 14 h, compound 4a
was isolated in 32% yield (Scheme 2). In addition to 4a, the
bis-Povarov product (5a, traces) and the mono-Povarov
product 2,4-diphenylquinolin-6-amine (6a, 18% yield) were
also identified in the product mixture. Surprisingly, N,N0-
dibenzyl-1,4-phenylene diamine, the transfer hydrogenation
product from the diimine, was not detected in the reaction
mass. Thus, it became clear that the Povarov cycloaddition
followed by the dehydrogenation and hydrogenation reac-
tion is the major process occurring under the employed
conditions. Also, the isolation of compound 6a was a surprise
based on the amount of benzaldehyde used; the correspond-
ing benzylideneimine (Schiff base) would have been a more
reasonable product from which 6a is likely a decomposition
product. It was realized that the formation of 4a required
substrates 1, 2, and 3 in the ratio 1:2:1 as opposed to the
1:2:2 requirement for the bis-Povarov reaction. At this point
we decided to optimize the conditions for the formation of
N-benzyl-6-amino-2,4-diphenylquinoline (4a) by varying the
substrate stoichiometry, solvent, catalyst, temperature, and
time. The results are summarized in Table 1.
Scheme 1. Retroanalysis for N-Benzyl-6-amino-2,4-diphenyl-
quinoline
Scheme 2. Reaction of Diamine with Benzaldehyde and Acetylene
Using BF3 Et2O
3
With the use of 1,4-phenylenediamine (1), benzaldehyde
(2), and phenylacetylene (3) as our model Povarov reaction
substrates, we were interested in understanding the kinetics
of the reaction ; whether the Povarov cycloaddition is a
kinetically controlled process and if it outcompetes the
dehydrogenation/hydrogenation reaction or if these pro-
cesses happen in tandem. It should be noted that dehydro-
genation and concomitant hydrogenation reactions, which
lead to aromatization of the quinolone ring, are secondary
processes which occur after the initial Povarov reaction. If
the Povarov cycloaddition is the faster process then the bis-
Povarov product 2,4,7,9-tetraphenylpyrido[2,3-g]quinoline
When substrates 1, 2, and 3 in a ratio of 1:2:1.5 were
reacted in the presence of BF3 Et2O (5 mol %) in acetoni-
3
trile at reflux for 14 h, compound 4a was isolated in 36%
yield (Table 1, entry 1). Prolonging the reaction times did
not help to improve the yields. By increasing the catalyst
loading to 20%, the yield of 4a increased to 44% (Table 1,
entry 2). Along with 4a, 5a (7%) and 6a (21%) were also
isolated from this reaction. However, a further increase in
the catalyst loading resulted in an inseparable mixture of
compounds. Several other Lewis and Bronsted acids,
namely aluminum chloride (AlCl3), p-toluenesulfonic acid
(p-TSA), trifluoroacetic acid (TFA), and acetic acid were
also screened as catalysts. AlCl3 and p-TSA resulted in
poor yields of 4a (Table 1, entries 3ꢀ4). Use of TFA as a
catalyst resulted in a mixture of components with trace
amounts of the desired compound 4a (Table 1, entry 5),
and no desired product was observed in the case of acetic
acid (Table 1, entry 6). Transition metal triflates have
proved to be efficient Lewis acid catalysts for the synthesis
of several important biologically active heterocyclic
(12) (a) Leardini, R.; Nanni, D.; Tundo, A.; Zanardi, G.; Ruggieri, F.
ꢁ
ꢁ
J. Org. Chem. 1992, 57, 1842. (b) Kouznetsov, V. V.; Melendez Gomez,
ꢁ
C. M.; Urbina Gonzalez, J. M.; Stashenko, E. E.; Bahsas, A.; Amaro
Luis, J. J. Het. Chem. 2007, 44, 551. (c) Tanaka, S. Y.; Yasuda, M.; Baba,
A. J. Org. Chem. 2005, 71, 800. (d) Kobayashi, S.; Ishitani, H.;
Nagayama, S. Chem. Lett. 1995, 423 and references cited therein.
(13) (a) Shindoh, N.; Tokuyama, H.; Takasu, K. Tetrahedron Lett.
2007, 48, 4749. (b) Shindoh, N.; Tokuyama, H.; Takemoto, Y.; Takasu,
K. J. Org. Chem. 2008, 73, 7451.
(14) Gaddam, V.; Ramesh, S.; Nagarajan, R. Tetrahedron 2010, 66,
4218.
(15) (a) Pericherla, K.; Khungar, B.; Kumar, A. Tetrahedron Lett.
2012, 53, 1253. (b) Kumar, A.; Rao, V. K. Synlett 2011, 2157. (c)
Vaughan, D.; Jha, A. Tetrahedron Lett. 2009, 50, 5709–5712. (d) Huang,
P. -J. J.; Stanley Cameron, T.; Jha, A. Tetrahedron Lett. 2009, 50, 51. (e)
Jha, A.; Beal, J. Tetrahedron Lett. 2004, 45, 8999. (f) Jha, A.; Huang,
P. -J. J.; Mukherjee, C.; Paul, N. K. Synlett 2007, 3127.
B
Org. Lett., Vol. XX, No. XX, XXXX

molecules because of their distinct properties such as
moisture insensitivities, stability, reusability, and high cat-
alytic activity.16 They have also been used efficiently for the
synthesis of quinoline derivatives;15b therefore we decided
to screen the effectiveness of Sc(OTf)3, Cu(OTf)2, Y(OTf)3,
andYb(OTf)3 (Table1,entries7ꢀ10).Yb(OTf)3 was found
to be the most effective (Table 1, entry 10) as compared to
all the catalysts studied.
synthesis of N-arylmethyl-6-amino-2,4-diarylquinolines,
and the results are summarized in Table 2. Initially, the
reaction of different aromatic aldehydes with 1,4-phenyl-
enediamine and phenylacetylene was studied.
Table 2. Substrate Scope for Tandem Synthesis of
N-Arylmethyl-6-amino-2,4-diphenylquinolinesa
Table 1. Optimization of Reaction Conditions for the Synthesis
of 4aa
entry
R1
R2
product
yield (%)b
1
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4a
4b
4c
4d
4e
4f
48
38
26
57
28
27
41
38
57c
39
32c
32c
42c
34c
37c
48
61
38
52
2
4-CH3
4-OCH3
3,4,5-OCH3
4-Cl
3
entry
catalyst
BF3-Et2O
solvent
yield (%)b
4
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1,4-dioxane
toluene
DCEf
36
5
2
BF3-Et2O
AlCl3
44c
22
6
4-F
3
7
3-NO2
4-NO2
H
4g
4h
4i
4
p-TSA
18
8
5
CF3CO2H
CH3CO2H
Sc(OTf)3
Cu(OTf)2
Y(OTf)3
trace
NDd
39
9
4-nC4H9C6H4
4-nC4H9C6H4
4-nC5H11C6H4
4-nC5H11 C6H4
4-nC5H11C6H4
4-nC5H11C6H4
4-nC5H11 C6H4
4-nC5H11C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
6
10
11
12
13
14
15
16
17
18
19
3-NO2
H
4j
7
4k
4l
8
22
4-CH3
4-OCH3
4-Cl
9
29
4m
4n
4o
4p
4q
4r
4s
10
11
12
13
14
15
16
17
Yb(OTf)3
CANe
48
16
4-F
cyanuric chloride
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
12
3-NO2
H
15
NDd
18
4-CH3
3-NO2
DMFg
DMEh
NDd
trace
a Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), 3 (1.5 mmol),
Yb(OTf)3 (0.05 mmol), acetonitrile (3.0 mL), 80 °C, 14 h. b Isolated
yields. c BF3ꢀEt2O (20 mol %) used instead Yb(OTf)3.
a Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), 3 (1.5 mmol),
catalyst (0.05 mmol), solvent (3.0 mL), 80 °C, 14 h. b Isolated yields.
c Catalyst (20 mol %). d Not detected. e Ceric ammonium nitrate. f 1,2-
Dichloroethane. g N,N-Dimethylformamide. h 1,2-Dimethoxyethane.
The results demonstrated that a wide range of aldehydes
with electron-donating and -withdrawing groups parti-
cipated in this tandem process to give the corresponding
N-arylmethyl-6-amino-2,4-diarylquinolines (4aꢀh) in mod-
erate to good yields (Table 2, entries 1ꢀ8). Unexpectedly,
3,4,5-trimethoxybenzaldehyde resulted in a higher yield
(Table 2, entry 4) compared to tolualdehyde and anisalde-
hyde (Table 2 entries 2ꢀ3). 4-Fluoro- and 4-chlorobenzal-
dehyde produced moderate yields (Table 2, entries 5ꢀ6).
Compared to 4-nitrobenzaldehyde, 3-nitrobenzaldehyde
gave better yields of corresponding N-arylmethyl-6-
aminoquinolines (Table 2, entries 8ꢀ7). Similarly, 4-butyl-
and 4-pentylphenyacetylenes reacted smoothly with different
aldehydes and 1,4-phenyldiamine to give reasonable yields
of N-arylmethyl-6-amino quinolines (4iꢀp) (Table 2, entries
9ꢀ16). 4-Methoxyphenylacetylene also reacted efficiently to
produce corresponding N-arylmethyl-4-(4-methoxyphenyl)-
2-phenylquinolin-6-amines (4qꢀs) in reasonable yields
(Table 2, entries 17ꢀ19). Further improvement in the yield
of compounds of series 4 may be achieved by the use of
molecular sieves as a moisture sponge along with further
optimization of reaction conditions. Phenylacetylene and
The high reactivity of Yb(OTf)3 isgenerally attributed to
the smaller radius of the Yb3þ cation and higher oxophilic
nature.15a,16 Ceric ammonium nitrate and cyanuric chloride
were found to be less effective (Table 1, entries 11, 12).
We investigated the effect of different solvents such as 1,4-
dioxane, toluene, 1,2-dichloroethane (DCE), N,N-dimethyl-
formamide (DMF), and dimethoxyethane (DME) (Table 1,
entries 13ꢀ17) on the yield of 4a using Yb(OTf)3 as the
catalyst. The yield of 4a was found to be best in CH3CN
compared to all solvents tested (Table 1, entry 10). Although
our optimization efforts led to improvement in the amount
of the isolated yield of desired compound 4a, we were unable
to find the conditions that exclusively formed 4a while
eliminating the formation of other products from competing
reactions.
Subsequently, we proceeded to explore the scope of
the developed tandem multicomponent reaction for the
(16) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W. L.
Chem. Rev. 2002, 102, 2227.
Org. Lett., Vol. XX, No. XX, XXXX
C

three of its electron-donating analogs were employed in this
study as alkyne substrates. We believe that arylacetylenes
bearing electron-withdrawing groups will also result in the
smooth formation of corresponding N-arylmethyl-6-amino-
2,4-diarylquinolines because Povarov and Povarov-type
reactions with arylacetylenes and arylacetylene equivalents
bearing electron-withdrawing groups are reported to work
well.17
It should also be noted that the synthesis of unsymmetrical
anthrazoline derivatives has been an unmet challenge so far.
Scheme 3. Synthesis of Anthrazoline Derivatives
As expected for 6-aminoquinoline derivatives,7 most
compounds in series 4 were found to be highly flourescent.
Visually, the fluorescence appeared to be dependent on
the aromatic substituents, but no further experiments
were conducted to ascertain their emission maxima and
quantum yields at this time. The 4-nitro derivative (4h) was
found to be nonflourescent.18
Having synthesized a variety of N-arylmethyl-6-amino-
2,4-diarylquinolines (4aꢀs), we wondered if these com-
pounds can be appropriately modified to produce sym-
metrical and unsymmetrical bis-Povarov products, i.e.
anthrazolines. Removal of the N-benzyl group from 4a
using palladium on charcoal and ammonium formate gave
easy access to 2,4-diphenyl-6-aminoquinoline (6a) in ex-
cellent yield (92%). Furthermore, compound 6a was sub-
jected to the Povarov reaction using Yb(OTf)3 as a catalyst
(Scheme 3) to produce anthrazoline derivatives. We were
able to synthesize symmetrical and unsymmetrical anthra-
zolines with reasonable yields (62% and 48% for 5a
and 5b, respectively). It should be noted that the anthrazo-
line derivatives have potential applications as organic
semiconductors.19 These heterocycles are generally syn-
thesized from complex starting materials.19b,20 Thus, our
method for direct access to 6-aminoquinoline derivatives
provides an easy access for these important heterocycles
from simple and commercially available starting materials.
In summary, we have developed a novel approach for
the synthesis of N-arylmethyl-6-amino-2,4-diarylquino-
lines via a tandem reaction of 1,4-phenylenediamines, aryl
aldehydes, and aryl acetylenes. Removal of the N-benzyl
group on a representative molecule by catalytic hydroge-
nation resulted in 6-amino-2,4-diphenylquinoline, which
was utilized in making symmetrical and unsymmetrical
anthrazoline derivatives. Further mechanistic studies and
the application of the developed procedure are currently in
progress.
Acknowledgment. The authors sincerely thank the
Natural Sciences and Engineering Research Council
(NSERC) of Canada and University Grant Commission
(UGC) of India for research funding. K.P. thanks
the Canadian Bureau for International Education for
awarding the Canadian Commonwealth Scholarship
and UGC for providing research fellowships.
(17) (a) Kulkarni, A.; Torok, B. Green Chem. 2010, 12, 875.
(b) Wang, X.-S.; Li, Q.; Wu, J.-R.; Li, Y.-L. Synth. Commun. 2009,
39, 702. (c) Wang, X.-S.; Li, Q.; Zhou, J.; Tu, S.-J. J. Heterocycl. Chem.
2009, 46, 1222.
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X.; Burn, P. L.; Meredith, P.; Shaw, P. E. Chem. Mater. 2011, 23, 789.
(19) (a) Tonzola, C. J.; Alam, M. M.; Kaminsky, W.; Jenekhe, S. A.
J. Am. Chem. Soc. 2003, 125, 13548. (b) Ahmed, E.; Briseno, A. L.; Xia,
Y.; Jenekhe, S. A. J. Am. Chem. Soc. 2008, 130, 1118. (c) Liu, S.; Wang,
Q.; Jiang, P.; Liu, R.; Song, G.; Zhu, H.; Yang, S.-W. Dyes Pigments
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Kruger, H. G.; Naicker, T.; Mohammadpoor Baltork, I. Tetrahedron
2012, 68, 6059.
Supporting Information Available. Experimental pro-
1
cedure, characterization data and copies of the H and
13C NMR of the synthesized compounds 4aꢀs, 5aꢀb,
and 6a. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX