One-pot sequential reactions featuring a copper-catalyzed amination leading to pyrido[2′,1′:2,3]imidazo[4,5-c]quinolines and dihydropyrido[2′,1′:2,3]imidazo[4,5-c]quinolines

Article abstract of DOI:10.1002/asia.201500266

Tetracyclic skeletons combining an imidazo[1,2-a]pyridine moiety with a quinoline framework such as pyrido[2′,1′:2,3]imidazo[4,5-b]quinoline are stimulating increasing interests since they are close isosteres of a series of powerful antiproliferative comp

Full text of DOI:10.1002/asia.201500266

CHEMISTRY
AN ASIAN JOURNAL
Accepted Article
Title: One-pot Sequential Reactions Leading to Pyrido[2’,1’:2,3]imidazo[4,5-
c]quinolines and Dihydropyrido[2’,1’:2,3]imidazo[4,5-c]quinolines Featured with
a Copper-catalyzed Amination
Authors: Xuesen Fan; Ju Zhang; Bin Li; Xinying Zhang
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Chemistry - An Asian Journal
10.1002/asia.201500266
COMMUNICATIONS
DOI: 10.1002/asia.200
One-pot Sequential Reactions Leading to Pyrido[2',1':2,3]imidazo[4,5-c]quinolines
and Dihydropyrido[2',1':2,3]imidazo[4,5-c]quinolines Featured with a Copper-
catalyzed Amination
Xue-Sen Fan,*[a] Ju Zhang,[a] Bin Li,[a] and Xin-Ying Zhang*[a]
Nitrogen-containing heterocyclic compounds are the subject of
continuous interest in organic synthesis owing to the fact that they
occur ubiquitously in biologically active natural products, multi-
purpose oriented functional materials, as well as highly potent
agrochemicals.1 Among the large family of N-heterocycles, the
imidazo[1,2-a]pyridine scaffold is particularly attractive as it has
been integrated in a number of commercial drugs such as
zolpidem, alpidem, saripidem, and necopidem,2-4 and embedded
in a plethora of compounds on the drug development pipeline
targeting different diseases.5-6
Recently, tetracyclic skeletons combining an imidazo[1,2-a]
pyridine moiety with a quinoline framework, such as pyrido
[2',1':2,3]imidazo[4,5-b]quinoline and pyrido[2',1':2,3]imidazo
[4,5-c]quinoline (PIQ), are stimulating increasing interests since
they are close isosteres of a series of powerful antiproliferative
compounds such as ellipticinem, datelliptium, as well as
pazellipticine.7-8 In this aspect, Kundu et al. reported that PIQ
could be obtained through Pictet-Spengler cyclization by treating
2-imidazo[1,2-a]pyridine-2-yl-phenylamine (IPPA) with aldehyde
in refluxing toluene in the presence of an acidic catalyst.7b While
this elegant process itself is quite efficient and reliable, a
retroactive look revealed that IPPA used therein was prepared
beforehand through the following steps: 1) condensation of 2-
aminopyridine with 2-nitrophenacyl bromide to furnish 2-(2-
nitrophenyl)imidazo[1,2-a]pyridine, and 2) reduction of the nitro
group in 2-(2-nitrophenyl)imidazo[1,2-a]pyridine by SnCl2 to
give IPPA (Scheme 1, (a)). The necessity of multi-step procedure
and the use of excess amounts of reducing reagent (SnCl2) might
compromise the sustainability and atom-economy of this strategy.
Hence, a more practical and sustainable method to construct the
tetracyclic PIQs is highly desirable.
starting materials undergo sequential transformations in the same
vessel to form multiple bonds are rapidly prevailing.9 Compared
with step by step operations, one-pot reactions are advantageous
owing to obviated isolation and purification of intermediates,
minimized generation of waste chemicals, and reduced reaction
time and cost.10 Meanwhile, one-pot sequential reactions featured
with copper-catalyzed C-N bonds formation turned out to be a
powerful tool for the construction of N-fused heterocycles.11-13 In
this regard, we developed some efficient synthetic processes14
leading to quinolizines,14a pyrazolo[1,5-c]quinazolines,14b and
pyrimido[4,5-b]quinolin-4-ones14c via copper-catalyzed amination
(by using aqueous ammonia as a cheap nitrogen source) and the
following cascade reactions it initiated. With the expertise in this
field, we envisioned that the above mentioned IPPA might be
obtained through a copper-catalyzed amination of 2-(2-bromo
phenyl)imidazo[1,2-a]pyridine, generated through condensation
of 2-aminopyridine with 2-bromophenacyl bromide. Furthermore,
the in situ formed IPPA may undergo a following condensation
and cyclization cascade when treated with an aldehyde to give the
desired PIQ in a one-pot manner (Scheme 1, (b)).
One-pot cascade reactions in which three or more different
[a]
Prof. X.-S. Fan, J. Zhang, B. Li, Prof. X.-Y. Zhang
School of Chemistry and Chemical Engineering, Collaborative
Innovation Center of Henan Province for Green Manufacturing of Fine
Chemicals, Key Laboratory of Green Chemical Media and Reactions,
Ministry of Education, Henan Key Laboratory for Environmental
Pollution Control, Henan Normal University, 46 Jianshe Road,
Xinxiang, Henan 453007, P. R. China
Scheme 1. Synthetic pathways leading to pyrido[2',1':2,3]imidazo[4,5-c]quinoline
To check the feasibility of our envisioned one-pot preparation
of PIQ as shown in Scheme 1 (b), 2-aminopyridine (1a) was
treated with 2-bromophenacyl bromide (2a) in the presence of
E-mail: xuesen.fan@htu.cn; xinyingzhang@htu.cn
o
Na2CO3 in DMF at 80 C. TLC analysis showed that 1a and 2a
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.200xxxxxx.
were consumed in 4 h to afford 2-(2-bromophenyl)imidazo[1,2-a]
pyridine. Then, CuI, 1,10-phen, and aqueous ammonia (3) were
1

Chemistry - An Asian Journal
10.1002/asia.201500266
Table1. Optimization of reaction conditions for the one-pot synthesis of 5a [a]
Table 2. Synthesis of pyrido[2',1':2,3]imidazo[4,5-c]quinolines 5a-5t [a,b]
Entry
1
Base
Catalyst
CuI
Ligand[b]
1.10-Phen
1.10-Phen
1.10-Phen
1.10-Phen
1.10-Phen
1.10-Phen
1.10-Phen
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
T/oC Yield (%)[c]
Na2CO3
Cs2CO3
K2CO3
t-BuOK
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
42
51
2
CuI
5a, 62%
5c, 53%
3
CuI
42
5b, 58%
4
CuI
46
.
5
K3PO4 3H2O
CuI
62
.
6
K3PO4 3H2O
CuCl
33
.
7
K3PO4 3H2O
CuBr
36
5d, 50%
5g, 54%
5e, 52%
5f, 45%
.
.
8
K3PO4 3H2O
CuCl2 H2O 1.10-Phen
Cu(OAc)2 1.10-Phen
20
.
9
K3PO4 3H2O
58
.
10
11
12
13
14
15
16
17
18
19
20
K3PO4 3H2O
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
DMEDA
TMEDA
L-Proline
DABCO
-
56
.
K3PO4 3H2O
57
5i, 52%
5h, 63%
.
K3PO4 3H2O
50
.
K3PO4 3H2O
41
.
K3PO4 3H2O
35
.
K3PO4 3H2O
1.10-Phen
1.10-Phen
10
.
5l, 53%
5k, 45%
K3PO4 3H2O
trace
trace
22
5j, 52%
.
K3PO4 3H2O
1.10-Phen 1.4-dioxane 80
.
K3PO4 3H2O
1.10-Phen
1.10-Phen
1.10-Phen
CH3CN
DMF
80
60
.
K3PO4 3H2O
42
.
K3PO4 3H2O
DMF
100
55
5n, 45%
5m, 54%
5o, 48%
[a] The reactions were run with: 1) 1a (0.5 mmol), 2a (0.5 mmol), base (0.6 mmol),
solvent (2 mL); 2) 3 (26%, 0.5 mL), catalyst (0.1 mmol), ligand (0.1 mmol); 3)
HCl (36%), 4a (0.5 mmol), air. [b] Ligand: 1,10-phenanthroline (1,10-phen), N,N'-
dimethylethylenediamine (DMEDA), N,N,N',N'-tetramethylethylene diamine
(TMEDA), and 1,4-diazabicyclo[2.2.2]octane (DABCO). [c] Isolated yield.
added and the mixture were stirred at 80 oC for another 8 h.
HPLC-MS and NMR studies confirmed the formation of IPPA.
However, subsequent treatment of the resulting mixture with
benzaldehyde (4a) failed to give the expected 6-phenylpyrido-
[2',1':2,3]imidazo[4,5-c]quinoline (5a). Considering that in
Kundu’s work the formation of PIQ from IPPA and aldehyde was
realized under acidic conditions, we then added concentrated
hydrochloric acid to the reaction vessel to adjust the pH value of
the mixture to a range of 4~5. To our delight, the envisioned
condensation occurred smoothly to give 5a in a total yield of 42%
(Table 1, entry 1). Encouraged by this preliminary result,
thorough optimization of the reaction conditions was then carried
out. Firstly, the effect of different bases on the first stage of this
5r, 42%
5q, 48%
5p, 44%
5t, 38%
5s, 35%
[a]
.
The reactions were run with: 1) 1a (0.5 mmol), 2a (0.5 mmol), K3PO4 3H2O
(0.6 mmol), DMF (2 mL), 80 oC, 4 h; 2) 3 (26%, 0.5 mL), CuI (0.1 mmol), 1,10-
Phen (0.1 mmol), 80 oC, 8 h; 3) HCl (36%), 4 (0.5 mmol), 80 oC, air, 4 h.
[b]
Isolated yield.
With the optimized reaction conditions in hand (Table 1, entry
5), the scope and generality of this copper-catalyzed one-pot
sequential reaction leading to PIQ was studied. Firstly, various
aldehydes (4) were tried. The results listed in Table 2 showed that
phenyl substituted aldehydes with either electron-donating
substituents including alkyl and alkoxyl groups, or electron-
withdrawing substituents including nitro, cyano and
trifluoromethyl groups on the phenyl ring underwent this cascade
process smoothly to give 5a-5n in reasonably good yields.
Notably, various functional groups were well tolerated with the
reaction conditions without showing obvious electronic and steric
effects. Halogenated aromatic moiety, which might participate in
copper-catalyzed coupling reactions, survived the reaction
conditions, allowing possible subsequent elaboration of the
products. In addition, with 1-naphthaldehyde and thiophene-2-
.
cascade process was studied. Among them, K3PO4 3H2O was the
most efficient (entries 1-5). Screening of different copper salts
.
revealed that CuCl, CuBr, CuCl2 H2O, and Cu(OAc)2 were less
effective than CuI (entries 5-9). It was noted that using ligands
other than 1,10-phen or in the absence of any ligand, the yield of
5a decreased considerably (entries 5, 10-14). Next, DMSO, NMP,
1,4-dioxane, and CH3CN were tried as possible media, but none
of them led to an increase in the yield of 5a (entries 5, 15-18). As
for the reaction temperature, 80 oC turned out to be the most
optimal (entries 5, 19-20). In summary of the opitimization study:
1) treatment of 2-aminopyridine with 2-bromophenacyl bromide
o
in the presence of K3PO4·3H2O in DMF at 80 C for 4 h; 2) the
mixture was added with CuI, 1,10-phen and aqueous ammonia
o
and then stirred at 80 C for 8 h; 3) the resulting mixture was
added with HCl and aldehyde and then stirred at 80 °C under air
for another 4 h to give 5a in a yield of 62% (entry 5).
2

Chemistry - An Asian Journal
10.1002/asia.201500266
carbaldehyde, the desired products 5o and 5p were obtained in
48% and 44% yield, respectively. Interestingly, the sequential
reactions of two α,-unsaturated aldehydes, cinnamaldehyde and
2-methylpent-2-enal, proceeded smoothly to give 5q and 5r in
moderate yields. Moreover, alkyl aldehydes were found to be also
suitable for this reaction to provide the corresponding products 5s
and 5t, albeit the yields were lower.
In the next stage, different 2-bromophenacyl bromides (2) and
2-aminopyridines (1) were tried for this one-pot sequential
process. The results listed in Table 3 showed that both 2-
bromobenzyl bromides (2) bearing methyl, methoxy, or chloro
group, and 2-aminopyridines (1) bearing methyl, chloro, or
trifluromethyl group reacted with aqueous ammonia (3) and
various aldehydes (4) to give 5u-5ai in reasonably good yields,
thus resulting in a highly versatile protocol toward structurally
diverse PIQs.
imidazo[4,5-c]quinoline (7a, Table 4) in 35% yield. Encouraged
by this result, we then explored the substrate scope of this reaction.
It turned out that either electron-rich or electron-deficient
acetophenone derivatives took part in this reaction smoothly to
afford the corresponding products 7a-7g in moderate yields
(Table 4). Aliphilic ketone such as butan-2-one was also suitable
for this reaction to give 7h. Interestingly, when cyclohexanone
and cycloheptanone were used, the reaction provided two spiro
products 7i and 7j successfully. Moreover, the reaction was found
to proceed smoothly for substrates with R1 or R2 as a CH3 group
to give the corresponding products 7k and 7l.
Table 4. Synthesis of 5,6-dihydropyrido[2',1':2,3]imidazo[4,5-c]quinolines 7a-7k [a,b]
Table 3. Synthesis of pyrido[2’,1’:2,3]imidazo[4,5-c]quinolines 5u-5ai [a,b]
7a, 35%
7d, 29%
7c, 30%
7f, 32%
7b, 31%
7e, 33%
5u, 54%
5w, 47%
5z, 51%
5ac, 54%
5v, 58%
5y, 43%
5ab, 51%
7g, 36%
7j, 30%
7h, 30%
7k, 28%
7i, 28%
7l, 26%
5x, 45%
5aa, 54%
[a]
.
The reactions were run with: 1) 1a (0.5 mmol), 2a (0.5 mmol), K3PO4 3H2O
(0.6 mmol), DMF (2 mL), 80 oC, 4 h; 2) 3 (26%, 0.5 mL), CuI (0.1 mmol), 1,10-
Phen (0.1 mmol), 80 oC, 8 h; 3) HCl (36%), 6 (0.5 mmol), 80 oC, N2, 4 h.
[b]
Isolated yield.
Based on the above observations, a plausible mechanism to
account for the formation of 6-phenylpyrido[2',1':2,3]imidazo
[4,5-c]quinoline (5a) is proposed in Scheme 2. Firstly, base-
promoted cascade condensation of 2-aminopyridine (1a) with 2-
bromophenacyl bromide (2a) affords 2-(2-bromophenyl)imidazo-
[1,2-a]pyridine (I). The following copper-catalyzed amination of
I with ammonia (3) as the nitrogen source via intermediates II
and III affords 2-imidazo[1,2-a]pyridine-2-yl-phenylamine (IV).
Condensation of IV with benzaldehyde (4a) gives an imine
intermediate V. The subsequent intramolecular nucleophilic
cyclization of V gives VI, which then undergoes an oxidative
dehydrogenation under air to afford 5a as the final product.
5af, 48%
5ad, 42%
5ag, 48%
5ae, 45%
5ah, 55%
5ai, 56%
[a]
.
The reactions were run with: 1) 1 (0.5 mmol), 2 (0.5 mmol), K3PO4 3H2O (0.6
mmol), DMF (2 mL), 80 oC, 4 h; 2) 3 (26%, 0.5 mL), CuI (0.1 mmol), 1,10-Phen
[b]
(0.1 mmol), 80 oC, 8 h; 3) HCl (36%), 4 (0.5 mmol), 80 oC, air, 4 h. Isolated
yield.
Having established an efficient protocol for the preparation of
PIQs via the one-pot sequential reactions of 2-aminopyridines
with 2-bromophenacyl bromides, aqueous ammonia, and
aldehydes, we were then interested in whether ketones were
suitable substrates for this reaction. If it would be possible,
dihydro-PIQs should also be synthesized in a one-pot manner. To
confirm this proposal, 1a, 2a, 3 and acetophenone (6a) were
subjected to the optimized operation procedure for the preparation
of 5 as described above except for a nitrogen atmosphere for the
final stage of the sequential process. We were pleased to find that
the envisioned one-pot cascade process proceeded smoothly to
give the expected 6-methyl-6-phenyl-5,6-dihydropyrido[2',1':2,3]
Scheme 2. Plausible mechanism for the formation of 5a
3

Chemistry - An Asian Journal
10.1002/asia.201500266
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In summary, we have developed a novel methodology for the
synthesis of pyrido[2',1':2,3]imidazo[4,5-c]quinolines through
one-pot sequential reactions of commercially available or readily
obtainable 2-aminopyridines, 2-bromophenacyl bromides,
aqueous ammonia and aldehydes. Substrate generality studies
showed that this novel process provided a facile route to access a
class of tetracyclic heterocylces with good structural diversity.
Moreover, dihydropyrido[2',1':2,3]imidazo[4,5-c]quinolines could
also be obtained in a similar manner by using various ketones as
the substrates in place of aldehydes. Notably, the whole procedure
combines condensation/amination/cyclization reactions in one-pot
to give complex compounds in a simple and practical manner.
Compared with literature methods, the synthetic strategy reported
herein has the advantages of readily available starting materials,
structural diversity of products, good functional group tolerance,
and obviation of step by step operations.
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Experimental Section
General procedure for the preparation of pyrido[2',1':2,3]imidazo[4,5-c]
quinolines (5).
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To a tube containing a solution of 2-aminopyridine (0.5 mmol) and 2-bromophenacyl
bromide (0.5 mmol) in DMF (2 mL) was added K3PO4·3H2O (0.6 mmol). It was then
stirred at 80 oC for 4 h. Next, CuI (0.1 mmol), 1,10-phen (0.1 mmol) and aqueous
ammonia (26%, 0.5 mL) were added. The tube was sealed and the mixture was
stirred at 80 oC for 8 h. After the pH value of the resulting mixture was adjusted to a
range of 4~5 by dropwise addition of HCl (36%), aldehyde (0.5 mmol) was added. It
was then stirred at 80 °C under air for another 4 h. Upon completion, the reaction
was quenched with water and extracted with ethyl acetate (10 mL × 3). The
combined organic layer was washed with H2O and brine, and then dried over
anhydrous Na2SO4. The solvent was evaporated under vacuum and the crude product
was purified by chromatography on silica-gel (petroleum ether/ethyl acetate = 3:1) to
afford pyrido[2',1':2,3]imidazo[4,5-c]quinolines (5).
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General procedure for the preparation of 5,6-dihydropyrido[2',1':2,3]imidazo
[4,5-c]quinolines (7).
To a tube containing a solution of 2-aminopyridine (0.5 mmol) and 2-bromophenacyl
bromide (0.5 mmol) in DMF (2 mL) was added K3PO4·3H2O (0.6 mmol). It was then
stirred at 80 oC for 4 h. Next, CuI (0.1 mmol), 1,10-phen (0.1 mmol) and aqueous
ammonia (26%, 0.5 mL) were added. The tube was sealed and the mixture was
stirred at 80 oC for 8 h. After the pH value of the resulting mixture was adjusted to a
range of 4~5 by dropwise addition of HCl (36%), ketone (0.5 mmol) was added. It
was then stirred at 80 °C under a nitrogen atmosphere for another 4 h. Upon
completion, the reaction was quenched with water and extracted with ethyl acetate
(10 mL×3). The combined organic layer was washed with H2O and brine, and then
dried over anhydrous Na2SO4. The solvent was evaporated under vacuum and the
crude product was purified by chromatography on silica-gel (dichloromethane/
methanol = 100:1) to afford 5,6-dihydropyrido[2',1':2,3]imidazo[4,5-c]quinolines (7).
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Acknowledgements
We are grateful to the National Natural Science Foundation of China (NSFC) (grant
numbers 21272058, 21172057), Program for Innovative Research Team in Science
and Technology in University of Henan Province (15IRTSTHN003), Program for
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Keywords: Pyrido[2',1':2,3]imidazo[4,5-c]quinolines • 5,6-
dihydropyrido[2',1':2,3]imidazo[4,5-c]quinolines • copper
catalysis • one-pot sequential reaction • amination
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4

Chemistry - An Asian Journal
10.1002/asia.201500266
Entry for the Table of Contents
Simplicity & Sustainability
Xue-Sen Fan,* Ju Zhang, Bin Li,
and Xin-Ying Zhang* Page – Page
One-pot Sequential Reactions
Leading
imidazo[4,5-c]quinolines
to
Pyrido[2',1':2,3]
and
A novel method for the synthesis of and aldehydes has been developed.
pyrido[2',1':2,3]imidazo[4,5-c]quin- By replacing aldehyde with ketone
olines via copper-catalyzed one-pot as the substrate, 5,6-dihydropyrido-
four-component sequential reactions [2',1':2,3]imidazo[4,5-c]quinolines
of 2-aminopyridines, 2-bromophen- could also be obtained through a
acyl bromides, aqueous ammonia similar process.
Dihydropyrido[2',1':2,3]imidazo
[4,5-c]quinolines Featured with a
Copper-catalyzed Amination
5