Base-Promoted Synthesis of Polysubstituted 4-Aminoquinolines from Ynones and 2-Aminobenzonitriles under Transition-Metal-Free Conditions

Article abstract of DOI:10.1002/adsc.202100023

A transition-metal-free and base-promoted one-pot reaction of ynones with 2-aminobenzonitriles is described. The reaction was initiated through sequential aza-Michael addition/intramolecular annulation to afford various multisubstituted 4-aminoquinolines

Full text of DOI:10.1002/adsc.202100023

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DOI: 10.1002/adsc.202100023
Base-Promoted Synthesis of Polysubstituted 4-Aminoquinolines
from Ynones and 2-Aminobenzonitriles under Transition-Metal-
Free Conditions
Ankit Kumar,a Pawan K. Mishra,a Kapil Mohan Saini,a and Akhilesh K. Vermaa,*
a
Department of Chemistry, University of Delhi, Delhi 110007, India;
E-mail: averma@acbr.du.ac.in
Manuscript received: January 7, 2021; Revised manuscript received: February 25, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100023
SARS-CoV-2 disease.[6] Additionally, some analog of
Abstract: A transition-metal-free and base-pro-
moted one-pot reaction of ynones with 2-amino-
benzonitriles is described. The reaction was initiated
4-aminoquinolines used analgesics or acetylcholines-
terase inhibitors.[7] However, chloroquine has been
restricted due to resistant strains of P. falciparum and
through sequential aza-Michael addition/intramolec-
toxicity problems.[8] Therefore; syntheses of new
ular annulation to afford various multisubstituted 4-
analog of 4-aminoquinolines are of continuous interest
aminoquinolines and 4-amino-1,8-naphthyridines in
to discover the antimalarial activity.[9]
good to excellent yields. Operational simplicity,
high atom-economy with broad substrate scope
Several synthetic approaches have been reported
for 4-aminoquinoline, which include the Friedlander
makes this protocol more attractive. Also, the gram-
reaction,[10] reduction of 4-azidoquinoline,[11] Buch-
scale synthesis and further transformation of the
wald-Hartwig amination.[12] Other alternative routes for
product were studied. Additionally, 2-haloarylyones
access of 4-aminoquinolines were multi-component
as substrate provide N-arylquinolones as the sole
reaction,[13] metal-catalyzed cascade reaction,[14] and
product via the SNAr mechanism.
cyclization with ynamides.[15] In a similar context, Liu
et al., developed Cu(II)-catalyzed desulfitative 6π
electro-cyclization reaction for the synthesis of 4-
Keywords: Aminoquinolines; SNAr; 2-Aminobenzo-
aminoquinolines (Scheme 1a).[16] In 2017, Popowycz
nitrile; Ynones; Aza-Michael addition
and co-workers have demonstrated a multi-step syn-
thesis of 4-aminoquinoline under super acidic con-
ditions (Scheme 1b).[17] Recently, Sahoo et al., devel-
Malaria is a serious infectious disease caused by oped the synthesis of 4-aminoquinoline from ynamides
Plasmodium species, still, become a major global with 2-aminobenzonitriles via Au(I)-catalyzed nitrile
health problem in the world.[1] Quinoline nucleus- activation (Scheme 1c).[18]
containing drugs have been attracted due to their
However, use of expensive catalyst, additive,
extensive application in medicinal chemistry.[2] Among limitation to the sensitive substrate and harsh reaction
them, 4-aminoquinolines are potential drugs candidate condition makes these methods less fruitful. These
for the treatment of malaria (Figure 1, A–C).[3–5] For limitations encourage us to develop a novel practical
instance, chloroquine and hydroxychloroquine (HCQ) approach to prepare highly substituted 4-aminoquino-
used as antimalarial drugs long ago. Recently, it lines in one-step with a high atom-economy. In our
emerged as a promising drug for the treatment of continuing interest on base-mediated heterocyclic
synthesis[19] herein, we report base-promoted subse-
quently aza-Michael addition/cascade annulation of 2-
amino benzonitriles with ynones for the synthesis of
highly substituted 4-aminoquinoline under transition-
metal-free conditions (Scheme 1d).
We began our investigation employing 1,3-diphe-
nylprop-2-yn-1-one 1a and 2-aminobenzonitrile 2a as
model substrates. When the reaction of 1a
(0.50 mmol) and 2a (0.60 mmol) was carried out in
Figure 1. Representative 4-aminoquinolines drugs.
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Table 1. Optimization of Reaction Conditions.[a]
Entry
Base (equiv.)
Solvent
Temp.
Yield of 3a
( C)
(%)[b]
°
1
2
3
4
5
6
7
8
KtOBu (2.0)
KtOBu (2.0)
KtOBu (2.0)
KtOBu (2.0)
KtOBu (2.0)
KtOBu (3.0)
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
25
20
45
70
85
65
84
0
71
58
50
45
0
60
80
100
120
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
KtOBu (2.0)
KtOBu (2.0)
KtOBu (2.0)
KtOBu (2.0)
KtOBu (2.0)
KtOBu (2.0)
LitOBu (2.0)
Cs2CO3(2.0)
KOH (2.0)
NaOH (2.0)
K3PO4 (2.0)
DBU (2.0)
DABCO (2.0)
9
DMA
NMP
10
11
12
13
14
15
16
17
18
19
20
dioxane
toluene
EtOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0
68
73
60
25
45
40
0
Scheme 1. Synthesis of Polysubstituted 4-Aminoquinolines.
presence of KtOBu (2.0 equiv.) in dimethylsulfoxide
°
solvent at 25 C, the desired product substituted 4-
aminoquinoline 3a was obtained in 20% yield (Ta-
ble 1, entry 1). To our delight, the desired product 3a
was obtained in high yield when the temperature of the
[a] Reactions were performed using 1a (0.5 mmol, 1.0 equiv.),
2a (0.6 mmol) and base (2.0 equiv.) in 2.0 mL of solvent.
[b] Isolated yield. DMF=dimethylformamide, DMA=Dimeth-
ylacetamide; CCDC No. (2027873).
°
°
reaction was increased from 25 C to 100 C (Table 1,
entries 2–4). At 120 C, the yield of 3a was signifi-
cantly dropped which possibly due to hydrolysis of 2a
(Table 1, entry 5).[20] Increase of KtOBu to 3.0 equiv.
did not significantly affect the yield of 3a (Table 1,
°
Interestingly, the presence of bulky substituents on
entry 6). Additionally, no desired product was formed the aryl group did not influence this transformation
in absence of a base (Table 1, entry 7). After screening and afforded the desired product 3h–i in 82% and 84%
other solvents, DMSO was proved to be the best yields respectively. However, electron-withdrawing
choice (Table 1, entries 8–13).
group (FÀ , CF3À ) substituted ynones (1j–1k) were
The effect of other bases was also investigated. For provided corresponding products 3j–k in moderate
example, Inorganic bases such as LitOBu, Cs2CO3, yields. When R2 as fused aryl and heteroaryl group in
KOH, NaOH, K3PO4 make possible the desired ynones were used as starting substrates, the corre-
product 3a in relatively lower yields (Table 1, entries sponding products 3l–3m were furnished in excellent
14–18). Furthermore, when organic base such as DBU yields. Notably, ynones with the R2 as aliphatic groups
and DABCO was employed in the reaction, only DBU such as cyclohexenyl (1n), cyclohexyl (1o), and
was found effective to deliver the desired product in cyclopropyl (1p) were viable substrates and afforded
acceptable yield (Table 1 entries 19–20). The product desired products 3n–3p in good yields. No desired
3a was further characterized by single X-Ray product was observed when R2 was a 2-pyridyl group.
crystallography.[21]
Next, the influence of R1 groups in ynones was also
With these optimized conditions in hand, we then screened. The substrates having electron-releasing
examine the scope and generality of this reaction by substituents such as À OMe and À Me at 4-position
employing various ynones and 2-aminobenzonitrile afforded desired products 3q–r in 86% and 90% yields
substrates (Table 2). Firstly, R2 substituents on the respectively. Ynones containing a heterocyclic struc-
terminal alkynes of ynones were investigated. A tural skeleton, thienyl, and furyl, for example, were
variety of ynones substrates (1b–1g) with electron- reacted well under the standard reaction condition to
donating substituents on aryl groups could react with deliver the corresponding 4-aminoquinolines 3s–3t in
2-aminobenzonitrile 2a, providing the corresponding good yields respectively. The ynones with the electron-
product 3b–3g in excellent yields.
donating group as R2 and the heteroaryl group as R1
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Table 2. Substrate Scope of Ynones.[a,b]
Table 3. Scope of Substituted 2-Aminobenzonitriles.[a,b]
[a] Reactions condition: 1 (0.5 mmol, 1.0 equiv.), 2 b–i
(0.6 mmol) and KtOBu (2.0 equiv.) in DMSO (2.0 mL) for
°
1 h at 100 C.
[b] Isolated yield.
substituted 2-aminobenzonitriles (2d–f) were also
compatible with the reaction and provided the corre-
sponding product 4d–f in good yields. The reaction of
2-amino-4-bromobenzonitrile (2g) and 2-amino-3,5-
dibromobenzonitrile (2h) with 1a, afforded the corre-
sponding product 4g and 4h in 78% and 74% yields
respectively. Highly substituted 4-aminoquinoline 4i
was obtained in 80% yield when substrate 1f reacted
with 2h under standard conditions. Unfortunately, the
reaction of 2-amino-5-nitro-benzonitrile containing a
strong electron-withdrawing nitro group, failed to
produce the desired product, probably due to the lower
nucleophilicity of the amine moiety.
[a] Reactions condition: 1a–w (0.5 mmol, 1.0 equiv.), 2a
(0.6 mmol) and KtOBu (2.0 equiv.) in DMSO (2.0 mL) for
°
1 h at 100 C.
[b] Isolated yield.
[c] Gram scale.
Gratifyingly, the scope of this protocol was further
extended towards the synthesis of biologically impor-
tant amino-1,8-naphthyridine derivatives 5a–d which
provided the desired product 3u and 3v in 85 and 88% are still not much explored.[22] To our delight, the
yield, respectively. The substrate having sulfonyl group reaction of 2-aminonicotinonitrile 2j with various
is also provides a successfully desired product 3w in ynones 1 proceeded smoothly to afford the correspond-
45% yield. The corresponding product 3x was not ing products 5a–d in good yields (Table 4).
formed when R1 group is methyl in ynone substrate 1x
Surprisingly, the desired 4-aminoquinoline as a
probably due to the self-condensation reaction in product was not obtained when reaction performed
presence of acidic methyl group. It is noteworthy that a between ortho-haloarylynones with various substituted
gram-scale reaction was performed under the standard 2-aminobenzonitriles under optimized protocols. After
condition that provides product 3a in 80% yield.
switching base to Cs2CO3 and increase the temperature
°
To understand the generality and practicability of up to 140 C, the N-arylquinolones 6a–c was formed
this reaction, we tested a range of 2-aminobenzonitriles as a solo product when 2-bromophenylynone 1y react
2 with various ynones (Table 3). 2-Aminobenzonitriles with substituted 2-aminobenzonitriles via tandem aza-
(2b–c) having electron-donating substituents such as Michael addition followed by aromatic nucleophilic
4-methyl and 4,5-dimethoxy group on reacting with substitution reaction in good yields. Additionally, 1,8-
ynones 1a, 1m, furnished the desired products 4a–c in naphtharidone 6d and 6e were also obtained in 55%
excellent yield. Notably, halogen (5-Br„ 5-Cl, 5-F) and 58% yields respectively when 2-chloropyridyl
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Table 4. Synthesis
of
4-Amino-1,8-naphthyridine
Derivatives.[a,b]
[a] Reactions condition: 1 (0.5 mmol, 1.0 equiv.), 2j (0.6 mmol)
t
°
and K OBu (2.0 equiv.) in DMSO (2.0 mL) for 1 h at 100 C.
[b] Isolated yield.
ynone 1z was used as starting substrate. The formation
of the N-arylquinolones suggests that after aza-Michael
addition, nucleophilic substitution on halogen is more
favorable than a nucleophilic attack on cyano group of
2-aminobenzonitiles (Table 5).[23]
Scheme 2. Synthetic Transformation of 4-Aminoquinoline.
The synthetic utility of the product was further radical pathway (Scheme 3a). No desired product was
demonstrated. The product 4g underwent various formed when diphenylacetylene 1aa react with 2-
palladium-catalyzed synthetic transformations such as aminobenzonitrile under standard reaction conditions.
Suzuki, Heck, and Sonogashira coupling to furnished This observation ruled out the possibility of [4+2]
the dervisfied products 7a–c in good yields cycloaddition reaction (Scheme 3b). When reaction
(Scheme 2).
performed between 4-aminobenzonitrile 2k with 1a,
To gain mechanistic insights into the current resulted in the product 8 that confirmed the aza-
protocol, several control experiments were performed Michael addition first then cyclization will happen
(Scheme 3) To find the reaction pathway whether ionic (Scheme 3c). No product was formed when 2a was
or radical in a basic medium, we have used 2.0 equiv. replaced by 2-hydroxy benzonitrile 2l under optimized
of TEMPO as a radical scavenger in the reaction of 1a conditions. The reason might be the low nucleophilic-
and 2a. The formation of product 3a in 75% yield ity of hydroxyl group in the basic medium due to
confirmed that the reaction did not proceed via the generation of phenoxide ion or instability of intermedi-
ate B which underwent retro-cyclization (ring-opening)
and retro-aza-Michael addition (Scheme 3d).
Table 5. Substrate Scope of o-Haloarylynones.[a,b]
Based on the above observation and previous
report,24] we proposed a mechanistic pathway for the
synthesis of polysubstituted 4-aminoquinolines as
described in Scheme 4. The mechanism initially leads
through the deprotonation of amine moiety of 2 which
facilitates nucleophilic attack on ynone via aza-
Micheal pathway to generate reactive species enolic-
allene A. The species A underwent C-cyclization to
produce unstable intermediate quinoline-4(1H)-imines
[a] Reactions condition: 1 (0.5 mmol, 1.0 equiv.), 2 (0.6 mmol)
°
and Cs2CO3 (2.0 equiv.) in DMSO (2.0 mL) for 2 h at 140 C.
[b] Isolated yield.
Scheme 3. Control Experiments.
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Acknowledgements
The research work was supported by SERB (EMR/2017/003218/
OC), IoE/FRP/PCMS/2020/27 and also USIC for instrumenta-
tion facilities. A.K, P.K.M, and K.M.S. are thankful to CSIR for
the fellowship respectively.
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Experimental Section
General Procedure for the Synthesis of products 3, 4, 5. In
an oven-dried 15 mL reaction vial, a solution of ynone 1
(0.5 mmol), 2-aminobenzonitrile 2 (0.6 mmol) and 2.0 equiv. of
anhydrous KOtBu in 2.0 mL of DMSO were added. The
°
resulting reaction mixture was stirred at 100 C for 1 h. Progress
of the reaction was monitored by TLC analysis, after
completion of starting materials; the reaction mixture was
poured in water and extracted by ethyl acetate (3×10 mL). The
organic layer was washed with saturated brine solution and
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(0.5 mmol), 2-aminobenzonitrile 2 (0.6 mmol) and 2.0 equiv. of
Cs2CO3 in 2.0 mL of DMSO were added. The resulting reaction
°
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was monitored by TLC analysis, after completion of starting
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Base-Promoted Synthesis of Polysubstituted 4-Aminoquino-
lines from Ynones and 2-Aminobenzonitriles under Transi-
tion-Metal-Free Conditions
Adv. Synth. Catal. 2021, 363, 1–7
A. Kumar, P. K. Mishra, K. M. Saini, A. K. Verma*