Synthesis of 2-arylamino-3-cyanoquinolines: Via a cascade reaction through a nitrilium intermediate

Article abstract of DOI:10.1039/c9ob02427a

A new method for the preparation of 2-amino-3-cyanoquinolines from readily available aryldiazonium salts, 2-aminoarylketones, and malononitrile via a cascade reaction is reported. This one-pot approach involves the in situ generation of an N-arylnitrilium intermediate from the direct reaction of aryldiazonium salts and malononitrile, which undergoes intermolecular amination, Knoevenagel condensation, and then aromatization to yield the desired compound in moderate to good yields. This methodology features a quick assembly of C2 and C3 functionalized quinolines.

Full text of DOI:10.1039/c9ob02427a

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DOI: 10.1039/C9OB02427A
Journal Name
ARTICLE
Synthesis of 2-Arylamino-3-cyanoquinolines via A Cascade
†
Reaction Through Nitrilium Intermediate
Mani Ramanathan, Jing Wan,≠a Yi-Hung Liu, Shie-Ming Peng and Shiuh-Tzung Liu
≠
a
a
a
a*
Received 00th January 20xx,
Accepted 00th January 20xx
A new method for the preparation of 2-amino-3-cyanoquinolines from readily available aryldiazonium salts, 2-
aminoarylketones, and malononitrile via a cascade reaction is reported. This one-pot approach involves in situ generation
of N-arylnitrilium intermediate from the direct reaction of aryldiazonium salts and malononitrile, which undergoes
intermolecular amination, Knoevenagel condensation, and then aromatization to yield the desired compound in moderate
to good yields. This methodology features a quick assembly of C2, C3 functionalized quinolines..
DOI: 10.1039/x0xx00000x
www.rsc.org/
report on the direct preparation of 2-arylamino-3-
cyanoquinolines. We envisioned that the incorporation of
arylamino and cyano groups in the quinolines could serve as
potential building blocks for further synthetic conversions or
exhibit biological activity analogous to 4-amino-3-
Introduction
Quinolines and its derivatives are privileged structural scaffolds
frequently found in various pharmacologically important
molecules with diverse activities such as antimalarial,
cyanoquinolines.
1
antifungal, and anti-inflammatory drugs. In addition,
N
quinolines are exploited as a potential intermediate in
2
numerous organic transformations. Synthesis of quinolines are
MeN
N
(CH2)3O
CN
3
a-b
often accomplished by classical methods such as Skraup,
HN
OMe
Combes,3 Doebner/Von Miller, Pfitzinger, Friedlander,3i
c-d
3e-f
3g-h
3
j
and Conard/Limpach synthesis. Despite formidable advances
in these methods, there are continuous efforts to develop new
procedures that allow the construction of multi-functionality in
Cl
Cl
Bosutinib (SK606)
O
N
4
the quinoline framework.
HN
CN
Among numerous quinolines, substituted-3-carbonitriles have
roused the interest of synthetic and medicinal chemists due to
their noteworthy biological and pharmacological properties. In
N
HN
Cl
R
O
Pelitinib R = F-
Neratinib R = 2-PyCH O-
5
2
particular, a series of 4-alkylamino-7-aryl-3-cyanoquinolines
have attracted drug development due to the LRRK2 kinase
Fig. 1. Structure of 3-cyanoquinoline based drugs
5
a-e
inhibitory activity of these compounds. Compound Bosutinib
In recent years, applications of in situ generated N-
arylnitrilium intermediate from aryldiazonium salts and nitriles
have received significant attention as they possess excellent
5
f
[
Bosulif (SK606)] (Fig. 1), known as a src-tyrosine-kinase
inhibitor, has been approved by US Food and Drug
5
i-5j
Administration. In addition, Neratinib and Pelitinib, are also
-cyanoquinoline-based drugs known for their potential anti-
7
reactivity and synthetic flexibility. In our recent work, N-
3
arylquinazolinium salts were prepared from aryldiazonium
salts, nitriles, and 2-aminoarylketones in a one-pot operation.
This method relies on the in situ generation of N-arylnitrilium
intermediate from the reaction of aryldiazonium salt with
cancer activity and inhibitor of epidermal growth factor (EGFR),
respectively. However, the preparation of this type of
compounds depends on the multi-step synthesis or the metal-
8
a
6
catalyzed cyanation of the halo-precursor, which limits the
nitrile,
which
undergoes
amination/cascade
variety of substituents in the molecules. Preparation of 2-
amino-4-methylquinoline-3-carbonitrile from 2-aminoaceto-
phenone and malononitrile in refluxing pyridine was reported
by Sarhan’ group.6g Other than this compound, there is no
cyclization/aromatization leading to the final product (Scheme
8
1
a). Based on the similar strategy, we speculate that the
nitrilium ion I generated from the reaction of diazonium salt
with malononitrile could further react with o-
aminoarylophenone, which then proceeds to the cyclization via
a Knoevenagel condensation to give the desired ring structure.
a. Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
E-mail: stliu@ntu.edu.tw Tel: +8862 3366-1661
†
Further
aromatization
affords
2-arylamino-3-cyano-4-
Electronic Supplementary Information (ESI) available: H, 13C NMR spectra for all
1
arylquinolines (II) as the desired product, (Scheme 1b), which
offers a preparation of C2 and C3 functionalized quinoline
synthesized compounds and crystal data. See DOI: 10.1039/x0xx00000x
≠
Equal contribution to this work
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
derivatives in a one-pot/tandem fashion. Herein, we disclose a
convenient method for this synthesis.
With the optimal conditions, we examined the scope of this
strategy by using various aryldiazonium salts with substituents
View Article Online
DOI: 10.1039/C9OB02427A
(a) Our previous work
Ph
in both steric and electronic nature in anhydrous malononitrile.
The results are shown in Figure 2. Regardless of the position, a
number of mono-substituted aryldiazonium salts participated
readily in the reaction and furnished the corresponding ortho,
para, and meta-substituted 2-arylamino-3-cyano-4-phenyl
quinolines in moderate to good yields (Fig. 2, 3a-3f). Moreover,
the disubstituted aryldiazonium salts also gave the expected
annulated products (Fig. 2, entries 3g-3i). Multiple substituted,
fused aryldiazonium salt with sterically demanding o-phenyl
groups were also viable and furnished the desired products in
moderate yields (Fig. 2, 3j-3k). To demonstrate the practical
utility, a gram-scale synthesis of 3a was performed under the
optimized conditions. Typically, the reaction of 1a (1.0 g) with
2-aminobenzophenone (1.08 g) in malononitrile delivered 3a
O
O
R
Ph Ar
N
RCN
ArN2+
N
H2N
-
N2 Ar
BF4-
N
R
Ph
N
H
Ar
N
BF4
R
(
b) This work.
NC
- N2
NH2
COR
Ar
CN
Ar N2+
BF4-
Ar
N
CN
I
H
N
Ar
N
N
R
NH
- H2O
(0.98 g, 59%). [Caution: The aryldiazonium tetrafluoroborates
CN
O
CN
are potentially explosive upon heating and reactions should be
performed using appropriate precautions.]. All compounds
were obtained in pure forms by simple purification and
characterized by NMR spectroscopy. X-ray crystallography of 3i
was determined to support the structure of the compound (Fig.
II
R
Scheme 1 Synthetic approaches
3
).
Results and discussion
R1
To explore the feasibility, we studied the reaction of 2-
aminobenzophenone (2a) with benzenediazonium tetra-
fluoroborate (1a) in anhydrous malononitrile under various
N
NH
CN
N
NH
CN
conditions (Table 1). When the reaction was carried out with 1
o
:
1.5 ratio of 1a to 2a at 110 C for 5 h, the desired product 3a
Ph
Ph
3j (44%)
was found in 62% yield. To our delight, a slight improvement in
product yield was observed when the reaction temperature was
3
a R1 = H (71%)
3
3
3
b R1 = 4-Me (67%)
c R1 = 3-Me (73%)
o
lowered to 80 C (Table 1, entry 2). Treatment of 2a with 1
N
NH
CN
o
equivalent of 1a at 110 C for 5 h gave no further improvement,
1
d R = 2-Me (64%)
3e R1 = 3-OMe (61%)
o
but the desired product was isolated in 71% at 80 C for 5h
1
3
3
3
3
f R = 4-OMe (54%)
(entry 4). However, carrying out the reactions in various
1
g R = 3,5-Me2 (67%)
Ph
3k (69%)
solvents gave disappointed results (entries 5-8).
1
h R = 3,4-Me2 (72%)
i R1 = 2,4,6-Me3 (65%)
Table 1 Reaction optimizationa
N2+BF4-
H
N
a
Reaction conditions: ArN
+
BF4 (0.52 mmol) and 2a (0.52 mmol) in malononitrile
-
NH2
2
N
o
NC
CN
(2mL) at 80 C for 5 h. Yields given refer to isolated yields.
O
CN
Fig. 2 Reactions of various aryldiazonium salts with 2a in malononitrilea
Ph
Ph
1a
2a
3a
1a : 2a
solvent
Temp
Yield (%)b
entry
C4
C3
o
1
2
3
4
5
1.5 : 1
1.5 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
CH
CH
CH
CH
CH
2
2
2
2
2
(CN)
(CN)
(CN)
(CN)
(CN)
2
2
2
2
110 C
62%
65%
65%
71%
54%
22%
21%
trace
29%
48%
o
C2
80 C
C5
C8
o
C12
C11
110 C
C6
C10
C1
N1
o
80 C
C13
C7
o
C14
C15
2
60 C
c
o
C23
6
7
8
9
CH
CH
CH (CN)
CH (CN)
CH (CN)
2
(CN)
(CN)
/toluene
/DMF
2
/THF
/DCE
80 C
C9
N2
C16
c
o
2
2
80 C
C18
C22
C21
C19
C20
c
o
2
2
110 C
C17
N3
c
o
2
2
110 C
C24
1
0d
2
2
80 oC
C25
a
Reaction conditions: a mixture of 1a (0.52 mmol), 2a (0.52 mmol) and anhydrous
b
c
malononitrile (2 mL) were heated in a sealed tube for 5 h. isolated yields. in
malononitrile /solvent (1 mL/ 3 mL). with molecular sieves.
Fig. 3. ORTEP Plot of 3i (30% probability ellipsoids)
d
2
| J. Name., 2012, 00, 1-3
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It is noted that aryldiazonium salt 1l, bearing an electron- result in poor yields (Table 2). In these reactions, aVilelwsAurbticsletrOantlienes
withdrawing ethoxycarbonyl group, underwent rapid azo were consumed, giving the desired prodDuOctI: a10c.c1o03m9/pCa9nOieB0d2b42y7Aa
coupling with malononitrile to give ethyl 4-(2- mixture of various products, indicating other competing
(dicyanomethylene)hydrazinyl)benzoate (3l’) in 57% yield pathways.
together with the desired product 3l (27%) (Scheme 2).
Similarly, the reaction of 4-fluorobenzenediazonium
tetrafluoroborate with 2a in malononitrile gave the azo
coupling product 3m’ in 72 % isolated yield. These observations
clearly indicate that the formation of N-arylnitrilium
intermediate is highly influenced by the electronic nature of the
aryldiazonium salts. We believe that electron-withdrawing
groups destabilize the nitrilium intermediate. Thus, the diazo
coupling becomes the competitive pathway over the formation
Table 2 Reaction scope with o-aminoacetophenonesa
R1
+
-
O
N2 BF4
R3
N
NH
CN
R2
R1
R2
NH2
R3
1
5
6
a - 6f
of nitrilium ion. 8
a, 9
entry
substituents
yield
Y
1
2
3
1
2
3
4
5
6
R = H, R = H, R = Me
6a (30%)
6b (28%)
6c (45%)
6d (39%)
6e (25%)
6f (28%)
+
N2 BF4-
Y
1
2
3
R = 4-Me, R = H, R = Me
2a
1
2
3
R = 2,4,6-(Me)
= 2-Me, R
3
, R = H, R = Me
= H, R = Me
NC
CN
HN
N
R
1
2
3
N
NH
CN
8
0 oC, 5 h
1
2
3
NC
R = H, R = 4-Br, R = Me
R = H, R = H, R = i-Pr
+
1
2
3
Y
CN
3l' (57%)
1
1
l Y = -COOEt
m Y = F
a
Ph
Reaction conditions: a mixture of diazonium salt (0.52 mmol) and 5 (0.52 mmol)
3
3
l (27%)
m (0%)
o
3
m' (72%)
in malononitrile (2mL) at 80 C for 5 h ; isolated yields.
Scheme 2 Reactions of 2a with aryldiazonium salts with electron-withdrawing
Finally, we prepared the Knoevenagel adduct 8 from 2a with
malononitrile, which was then treated with benzenediazonium
tetrafluoroborate under the optimal conditions. In this
sequential reactions, a mixture of various compounds appeared
with trace of 3a, as evidenced by the TLC analysis (Eqn. 1). This
observation suggests that the formation of nitrilium ion might
take place initially instead of the Knoevenagel condensation
substituents.
Next, we investigated the scope of this transformation with
differently substituted 2-aminoarylketones. We observed that,
2
-aminoarylketones with chloro and fluoro substituents at
various positions of the aryl ring led to the corresponding
halogenated products in good yields (Scheme 3, 4a-4d).
However, the fluoro substituted amino-benzophenone did not
give 4e in a good yield, presumably the electron-withdrawing
group slows down the condensation. Interestingly, multi-
halogenated 2-arylamino-3-cyano-4-phenyl quinolines (4f)
were also isolated in moderate yields, providing a potential
handle for further synthetic transformation.
(Scheme 1). However, the attempt to isolate the intermediate I
(
Scheme 1) failed due to the high reactivity leading to other
7
c, 8
products,
suggesting that the in situ generation followed by
the nucleophilic attack of o-aminoacetophenone is necessary to
warrant the success of this methodology. Instead of
malononitrile, when this reaction was carried out in methyl 2-
cyanoacetate under similar conditions, no desired product was
obtained.
N2+BF4-
R2
7
O
8
H
N
N
NC
CN
R3
NC
CN
R1
+
R2
0 oC, 5h
6
CN
PhN2BF4
8
H2N
5
Ph
(Eqn. 1)
trace of 3a
R1
R3
o
8
0 C, 5 h
4
4
4
4
4
4
a, R1 = H, R2 = 6-Cl, R3 = Ph, 76%
NH2
b, R1 = H, R2 = 6-Br, R3 = Ph, 71%
c, R1 = H, R2 = H, R3 = 4-MeC6H4, 62%
8
d, R1 = 3-OMe, R2 = H, R3 = 4-MeC6H4, 64%
e, R1 = H, R2 = H, R3 = 4-FC6H4, 28%
f, R1 = H, R2 = 6-Cl, R3 = 6'-ClC6H4, 46%
We also investigated the competitive reaction of diazonium
salt 1a toward acetonitrile and malononitrile. When running a
reaction of 1a with 2a in a mixture of acetonitrile and
aReaction conditions:
aminoarylketone (0.52 mmol) in malononitrile (2mL) at 80 C for 5 h; isolated yields
a mixture of diazonium salt (0.52 mmol) and
o
o
malononitrile at 110 C for 5h, both 3a and arylquinazolinium
8
a
salt 9 were obtained, favouring the formation of 3-
Scheme 3 Reaction scope of substituted 2-aminoarylketones.
cyanoquinoline product (Scheme 4).
H
N
CH3
N
N
With these encouraging results in hand, we then turned our
attention to 2-aminoaryl alkyl ketones. Reaction of 5a with 1a
in malononitrile under the optimal conditions gave the desired
compound 6a in 30% yield. Other substituents in o-
aminoacetophenones are also applicable to this method but
NC
CN
Ph
PhN +BF4- + 2a
N
2
+
Ph
CH3CN
CN
1a
Ph BF4
9 (10%)
Ph
3
a (42%)
This journal is © The Royal Society of Chemistry 20xx
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Scheme 4. Competitive reaction of 1a with two nitriles.
mL). Organic layer was dried over anhydrous MgSO
View Article Online
4
and
DOI: 10.1039/C9OB02427A
concentrated. Crude reaction mixture was purified by silica gel
column chromatography using Hexane-EA eluent (2% to 5%) to
obtained 4-phenyl-2-(phenylamino)quinoline-3-carbonitrile (0.98 g,
Conclusions
5
9%).
In summary, we have disclosed an efficient method to prepare
diversely substituted 2-arylamino-3-cyanoquinolines from easily 4-Phenyl-2-(p-tolylamino)quinoline-3-carbonitrile (3b).
accessible aryldiazonium salts, malononitrile and 2-amino
o
1
1
08 mg, 67%, pale yellow solid: mp 191-192 C; H NMR (400 MHz,
arylketones in a one-pot manner. A broad range of substituents and
functionalities are tolerated and the corresponding products were
isolated in good yields. Gram scale synthesis and experimental
simplicity are also notable features of this method. The biological
activity of these new compounds is under further investigation.
CDCl ) δ 7.83 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 10.8 Hz, 2H), 7.65 (ddd, J
3
=
7
1
15.2, 7.4, 1.2 Hz, 1H), 7.59-7.55 (m, 3H), 7.47-7.45 (m, 3H), 7.25-
.19 (m, 4H), 2.36 (s, 3H); C{1H} NMR (100 MHz) δ 156.7, 151.2,
48.6, 136.3, 134.5, 133.2, 132.6, 129.6, 129.4, 129.2, 128.7, 127.5,
13
126.9, 124.1, 121.6, 125.0, 116.1, 96.4, 20.8; HRMS (ESI-TOF) calcd
+
18
for C23H N
3
[M + H] m/z 336.1501, found 336.1495.
4
-Phenyl-2-(m-tolylamino)quinoline-3-carbonitrile (3c). 22
Experimental
General information.
o
1
1
16 mg, 73%, pale yellow solid: mp 167-168 C; H NMR (400 MHz,
) δ 7.85 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.66 (ddd, J =
spectrometer in 15.4, 7.8, 1.2 Hz, 1H), 7.60-7.55 (m, 4H), 7.49-7.45 (m, 3H), 7.29 (t, J
CN referenced to TMS. Malononitrile was dried = 7.6 Hz, 1H), 7.26-7.22 (m, 2H), 6.95 (d, J = 7.6 Hz, 1H), 2.40 (s, 3H);
CDCl
3
1H and 13C NMR were recorded in a 400 MH
CDCl and CD
over activated 4Å molecular sieves and all anilines were
Z
3
3
1
3
C{1H} NMR (100 MHz) δ 156.7, 151.1, 148.5, 138.9, 138.7, 134.5,
commercially purchased and used for diazotization without 132.7, 129.7, 129.2, 128.8 (2C), 127.6, 126.9, 124.4, 124.2, 121.6,
further purification. Other chemicals were used as purchased. 120.8, 117.3, 116.0, 96.5, 21.6; HRMS (ESI-TOF) calcd for C H N [M
2
3 18 3
+
Flash chromatography was performed using silica gel 230-400 + H] m/z 336.1501, found 336.1495.
mesh. In cases of known compounds, their spectral data were
4
-Phenyl-2-(o-tolylamino)quinoline-3-carbonitrile (3d).
compared with the literature values. Melting points were
determined on a Fargo MP-1D instrument. Unless otherwise
noted, all the reactions were performed without any special
precautions. All the substituted aryldiazonium salts were
synthesized by following the procedure reported in the previous
work.8
o
1
1
03 mg, 64%, pale yellow solid: mp 175-176 C; H NMR (400 MHz,
) δ 8.35 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 7.2
Hz, 1H), 7.60-7.57 (m, 3H), 7.50-7.47 (m, 3H), 7.31 (t, J = 7.6 Hz, 1H),
CDCl
3
7
.27-7.21 (m, 2H), 7.16 (brs, 1H), 7.10 (t, J = 7.6 Hz, 1H), 2.39 (s, 3H);
C{1H} NMR (100 MHz, CDCl ) δ 156.6, 151.4, 148.6, 137.2, 134.5,
3
32.6, 130.6, 129.7, 129.2, 129.0 (2C), 128.8, 127.7, 126.9, 126.6,
1
3
1
1
C
General procedure for the synthesis of 2-arylamino-3-cyano-4-
arylquinolines.
24.2, 122.0, 121.6, 116.1, 96.6, 18.0; HRMS (ESI-TOF) calcd for
+
23 18
H N
3
[M + H] m/z 336.1501, found 336.1506.
In a dry 10 mL glass sealed tube, aryldiazonium salt (100 mg,
2
-(3-Methoxyphenylamino)-4-phenylquinoline-3-carbonitrile (3e).
0
.52 mmol) and 2-aminobenzophenone (103 mg, 0.52 mmol) were
o
1
suspended in 2 mL of malononitrile. The tube was sealed with a Teflon 96 mg, 61%, pale yellow solid: mp 182-183 C; H NMR (400 MHz,
o
screw cap and heated in an oil bath (80 C) for 5 h. After cooling to CDCl ) δ 7.87-7.84 (d, J = 8.8 Hz, 1H), 7.74-7.73 (m, 1H), 7.67 (ddd, J
3
room temperature, reaction mixture was diluted with DCM (20 = 15.2, 7.4, 1.2 Hz, 1H), 7.59-7.55 (m, 3H), 7.49-7.45 (m, 3H), 7.30-
1
3
mL) and washed with saturated aq. NaHCO
The organic layer was dried over anhydrous Na
3
solution (5 mL). 7.23 (m, 4H), 6.69-6.66 (m, 1H), 3.87 (s, 3H); C{1H} NMR (100 MHz)
SO
δ 160.1, 156.7, 150.9, 148.5, 140.2, 134.5, 132.7, 129.7, 129.6, 129.2,
2
4
.
Solvents were removed, and the product was purified by 128.8, 127.7, 126.9, 124.4, 121.6, 116.0, 112.3, 109.1, 105.8, 96.6,
+
column chromatography (eluent: 2% to 5% EtOAc:Hexane) 55.2; HRMS (ESI-TOF) calcd for C H N O [M + H] m/z 352.1450,
2
3 18 3
to obtain the title compound.
found 352.1438.
2-(4-Methoxyphenylamino)-4-phenylquinoline-3-carbonitrile (3f).
4
-Phenyl-2-(phenylamino)quinoline-3-carbonitrile (3a).
o
1
o
1
1
CDCl
18 mg, 71%, pale yellow solid: mp 132-133 C; H NMR (400 MHz, 87 mg, 54%, pale yellow solid: mp 197-198 C; H NMR (400 MHz,
) δ 7.87-7.85 (d, J = 8.4 H, 3H), 7.67 (ddd, J = 15.4, 7.6, 1.6 Hz, CDCl ) δ 7.79 (d, J = 8.0 Hz, 1H), 7.73-7.69 (m, 2H), 7.63 (ddd, J = 15.2,
3
3
1
7
1
1
H), 7.61-7.55 (m, 3H), 7.49-7.46 (m, 3H), 7.43-7.38 (m, 2H), 7.27- 7.4, 1.2 Hz, 1H), 7.59-7.55 (m, 3H), 7.48-7.44 (m, 3H), 7.23-7.19 (m,
1
3
13
.20 (m, 2H), 7.15-7.11 (m, 1H); C{1H} NMR (100 MHz) δ 156.8, 1H), 7.12 (brs, 1H), 6.96-6.92 (m, 2H), 3.83 (s, 3H); C{1H} NMR (100
51.0, 148.4, 138.9, 134.5, 132.7, 129.7, 129.2, 128.9, 128.8, 127.6, MHz) δ 156.6, 156.1, 151.4, 148.8, 134.6, 132.6, 132.0, 129.6, 129.2,
26.9, 124.3, 123.5, 121.7, 120.2, 116.0, 96.5; HRMS (ESI-TOF) calcd 128.8, 127.6, 126.9, 124.0, 122.4, 121.6, 116.1, 114.2, 96.3, 55.5;
+
+
for C22
16
H N
3
[M + H] m/z 322.1344, found 322.1328.
23 18 3
HRMS (ESI-TOF) calcd for C H N O [M + H] m/z 352.1450, found
3
52.1444.
Gram scale procedure : A mixture of 2-aminobenzophenone (1.03 g,
5
.2 mmol) and aryldiazonium salt (1.0 g, 5.2 mmol) in dry 2-(3,5-Dimethylphenylamino)-4-phenylquinoline-3-carbonitrile
malononitrile (20 mL) was heated to 80 °C for 5 h. Reaction mixture (3g).
was cooled to room temperature and diluted with DCM (200 mL) and
washed with saturated NaHCO solution (100 mL x 2) and brine (20
3
o
1
1
CDCl
06 mg, 67%, pale yellow solid: mp 165-166 C; H NMR (400 MHz,
3
) δ 7.86 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.59-7.57 (m,
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 5 of 7
O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Journal Name
ARTICLE
3
2
1
1
+
H), 7.49-7.46 (m, 5H), 7.26-7.22 (m, 1H), 7.18 (brs, 1H), 6.78 (s, 1H), Ethyl 4-(2-(dicyanomethylene)hydrazinyl)benzoate (3l’).10
View Article Online
DOI: 10.1039/C9OB02427A
1
3
.37 (s, 6H); C{1H} NMR (100 MHz) δ 156.6, 151.1, 148.6, 138.7,
38.5, 134.5, 132.6, 129.6, 129.2, 128.7, 127.6, 126.9, 125.3, 124.1,
o
1
5
3
2 mg, 57%, orange solid: mp 181-182 C; H NMR (400 MHz, CDCl )
δ 9.90 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 4.36 (q,
J = 7 Hz, 2H), 1.38 (t, J = 7 Hz, 3H); C{1H} NMR (100 MHz) δ 165.4,
42.8, 131.5, 128.5, 115.5, 111.6, 107.8, 88.6, 61.3, 14.2; IR (CaF ,
2
cm ) υC=O 1706, υC=N 1608; HRMS (ESI-TOF) calcd for C12
21.5, 118.0, 116.0, 96.5, 21.5; HRMS (ESI-TOF) calcd for C24
H] m/z 350.1657, found 350.1651.
20
H N
3
[M
13
+
1
-1
2
-(3,4-Dimethylphenylamino)-4-phenylquinoline-3-carbonitrile
H
9
N
4
O
2
[M -
+
(
3h).
H] m/z 241.0726, found 241,0716.
o
1
1
CDCl
7
13 mg, 72%, pale yellow solid: mp 164-165 C; H NMR (400 MHz, N-(4-fluorophenyl)carbonohydrazonoyl dicyanide (3m’).11
) δ 7.83 (d, J = 8.8 Hz, 1H), 7.67-7.63 (m, 2H), 7.59-7.55 (m, 3H),
.52 (d, J = 2.0 Hz, 1H), 7.48-7.45 (m, 3H), 7.22 (ddd, J = 15.2, 7.8, 1.2
3
1 mg, 72%, yellow solid: mp 175-176 C, Ref: 172-174 C; 1H NMR
o
o
7
(
400 MHz, CDCl ) δ 9.89 (br, 1H, N-H), 7.31-7.28 (m, 2H, Ar-H), 7.14-
3
1
3
Hz, 2H), 7.16 (d, J = 8.0 Hz, 1H), 2.13 (s, 3H), 2.27 (s, 3H); C{1H} NMR
100 MHz) δ 156.6, 151.2, 148.6, 137.0, 136.5, 134.5, 132.6, 131.9,
29.9, 129.6, 129.2, 128.7, 127.5, 126.9, 124.0, 121.8, 121.5, 118.0,
13
1
7
1
8
-
.10 (m, 2H, Ar-H); C{1H} NMR (100 MHz) δ 160.0 (d, J C-F = 247 Hz),
(
1
1
3
2
36.1, 117.7 (d, J C-F = 7.8 Hz), 116.9 (d, J C-F = 24 Hz), 112.1, 108.3,
-1
6.6; IR (CaF
2
, cm ) υC=N 1604; HRMS (ESI-TOF) calcd for C
9
H
4
FN
4
[M
+
16.1, 96.4, 20.0, 19.1; HRMS (ESI-TOF) calcd for C24
20
H N
3
[M + H]
+
H] m/z 187.0434, found 187.0434.
m/z 350.1657, found 350.1644.
6
-Chloro-4-phenyl-2-(phenylamino)quinoline-3-carbonitrile (4a).
2
-(Mesitylamino)-4-phenylquinoline-3-carbonitrile (3i).
o
1
1
CDCl
16 mg, 76%, pale yellow solid: mp 231-232 C; H NMR (400 MHz,
) δ 7.82 (d, J = 7.6 Hz, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.60-7.58 (m,
o
1
1
CDCl
3
7
01 mg, 65%, pale yellow solid: mp 194-195 C; H NMR (400 MHz,
) δ 7.65 (dd, J = 8.8, 0.8 Hz, 1H), 7.61-7.58 (m, 3H), 7.57-7.51 (m,
3
3
4
H), 7.46-7.42 (m, 2H), 7.39 (d, J = 8.0 Hz. 3H), 7.29 (brs, 1H), 7.14 (t,
H), 7.46 (dd, J = 8.0, 1.2 Hz, 1H), 7.17 (ddd, J = 15.2, 7.4, 1.2 Hz, 1H),
.00 (s, 2H), 6.66 (s, 1H), 2.35 (s, 3H), 2.27 (s, 6H); 1 C{1H} NMR (100
MHz) δ 156.5, 152.6, 149.3, 136.5, 135.7, 134.7, 132.6, 132.3, 129.5,
29.2, 128.9, 128.7, 127.6, 126.8, 123.5, 121.3, 116.3, 95.3, 20.9,
13
J = 7.2 Hz, 1H); C{1H} NMR (100 MHz) δ 155.8, 151.1, 147.0, 138.7,
1
1
3
33.9, 133.2, 130.0, 129.9, 129.2, 129.1, 129.0, 128.9, 125.5, 123.7,
35
22.3, 120.3, 115.6, 97.4; HRMS (ESI-TOF) calcd for C22
H
15 ClN
3
[M +
1
1
+
H] m/z 356.0955, found 356.0950; HRMS (ESI-TOF) calcd for
+
8.6; HRMS (ESI-TOF) calcd for C25
22
H N
3
[M + H] m/z 364.1814,
37
+
C
6
1
CDCl
4
22
H
15 ClN
3
[M+H] m/z 358.0925, found 358.0927.
found 364.1807.
-Bromo-4-phenyl-2-(phenylamino)quinoline-3-carbonitrile (4b).
2
-(Naphthalen-1-ylamino)-4-phenylquinoline-3-carbonitrile (3j).
o
1
02 mg, 71%, pale yellow solid: mp 234-235 C; H NMR (400 MHz,
) δ 7.83 (d, J = 7.6 Hz, 2H), 7.71 (d, J = 7.6 Hz, 2H), 7.61-7.57 (m,
o
1
6
CDCl
7 mg, 44%, pale yellow solid: mp 212-213 C; H NMR (400 MHz,
) δ 8.45 (d, J = 7.2 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.90 (dd, J =
3
3
H), 7.47-7.42 (m, 2H), 7.40 (t, J = 6.4 Hz, 2H), 7.29 (brs, 1H), 7.14 (t,
7
3
1
1
1
3
.2, 2.8 Hz, 1H), 7.78-7.72 (m, 3H), 7.66-7.62 (m, 2H), 7.61-7.57 (m,
H), 7.56-7.49 (m, 5H), 7.27-7.22 (m, 1H); 1 C{1H} NMR (100 MHz) δ
51.9, 134.5, 134.3, 133.7, 132.7, 129.7, 129.2 (2C), 128.8 (2C),
27.7, 127.4, 126.9, 126.3, 126.0, 125.7, 125.0, 124.3, 121.8, 120.8,
19.6, 119.6, 96.6; HRMS (ESI-TOF) calcd for C26
13
J = 7.6 Hz, 1H); C{1H} NMR (100 MHz) δ 155.8, 151.2, 147.3, 138.6,
3
1
1
C
35.9, 133.9, 130.0, 129.3, 129.06 (2C), 129.01 (2C), 128.8, 123.9,
22.9, 120.4, 117.7, 115.6, 97.4; HRMS (ESI-TOF) calcd for
79
+
22 3
H15 BrN [M + H] m/z 400.0447, found 400.0445; HRMS (ESI-
+
H
18
N
3
[M + H] m/z
81
+
TOF) calcd for C22
H
15 BrN
3
[M + H] m/z 402.0429, found 402.0429.
72.1501, found 372.1497.
2
-(Phenylamino)-4-(p-tolyl)quinoline-3-carbonitrile (4c).
2
-([1,1'-Biphenyl]-2-ylamino)-4-phenylquinoline-3-carbonitrile
o
1
9
CDCl
(
7 mg, 62%, pale yellow solid: mp 185-186 C; H NMR (400 MHz,
) δ 7.86-7.80 (m, 3H), 7.66 (ddd, J = 15.2, 7.4, 1.2 Hz, 1H), 7.52
dd, J = 8.4, 1.2 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.37-7.34 (m, 4H),
(
3k).
3
o
1
1
CDCl
38 mg, 69%, pale yellow solid: mp 201-202 C; H NMR (400 MHz,
3
) δ 8.82 (d, J = 6.8 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 7.2
Hz, 1H), 7.52-7.48 (m, 4H), 7.46-7.44 (m, 4H), 7.41-7.31 (m, 4H), 7.32
d, J = 7.6 Hz, 2H), 7.21-7.17 (m, 1H); 1 C{1H} NMR (100 MHz) δ 156.6,
51.1, 148.4, 138.8, 136.2, 134.4, 132.6, 130.1, 129.7 (2C), 129.6,
29.2, 128.8, 128.6, 128.1, 127.9, 127.6, 126.9, 124.2, 123.2, 121.7,
20.7, 115.3, 97.0; HRMS (ESI-TOF) calcd for C28
13
7
.26 (d, J = 7.2 Hz, 2H), 7.13 (t, J = 7.2 Hz, 1H), 2.47 (s, 3H); C{1H}
NMR (100 MHz) δ 156.9, 151.0, 148.5, 139.8, 139.1, 132.6, 131.6,
3
(
1
9
29.5, 129.1, 128.9, 127.7, 127.0, 124.2, 123.4, 121.8, 120.1, 116.2,
1
1
1
3
+
6.5, 21.4; HRMS (ESI-TOF) calcd for C23
18
H N
3
[M + H] m/z 336.1503,
found 336.1501.
-(3-Methoxyphenylamino)-4-(p-tolyl)quinoline-3-carbonitrile
4d).
+
H
20
N
3
[M + H] m/z
2
(
98.1657, found 398.1659.
Ethyl 4-((3-cyano-4-phenylquinolin-2-yl)amino)benzoate (3l).
o
1
1
10 mg, 64%, pale yellow solid: mp 238-239 C; H NMR (400 MHz,
o
1
3
9 mg, 27%, pale yellow solid: mp 200-201 C; H NMR (400 MHz,
CDCl ) δ 8.10-8.07 (m, 2H), 8.00-7.96 (m, 2H), 7.91 (dd, J = 8.4, 0.4
Hz, 1H), 7.72 (ddd, J = 15.2, 7.6, 1.6 Hz, 1H), 7.60-7.56 (m, 3H), 7.52
dd, J = 8.4, 0.8 Hz, 1H), 7.48-7.44 (m, 3H), 7.31 (ddd, J = 15.2, 7.8, 1.2
3
CDCl ) δ 7.86-7.84 (m, 1H), 7.73 (brs, 1H), 7.66 (ddd, J = 15.4, 7.4, 1.2
3
Hz, 1H), 7.53-7.51 (m, 1H), 7.37-7.35 (m, 4H), 7.28-7.27 (m, 2H), 7.26-
.23 (m, 1H), 6.70-6.65 (m, 1H), 3.86 (s, 3H), 2.47 (s, 3H), 2.47 (s, 3H);
7
(
13
C{1H} NMR (100 MHz) δ 160.1, 157.0, 150.9, 148.2, 140.2, 139.8,
1
3
Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H); C{1H} NMR
100 MHz) δ 166.2, 157.1, 150.4, 148.1, 143.2, 134.3, 133.0, 130.8,
29.9, 129.2 (2C), 128.8, 127.7, 127.0, 125.0, 121.9, 118.8, 115.8,
1
1
C
32.7, 131.5, 129.6, 129.5, 129.1, 127.6, 127.0, 124.3, 121.8, 116.1,
(
12.3, 109.2, 105.9, 96.5, 55.2, 21.4; HRMS (ESI-TOF) calcd for
1
9
C
+
24 20
H N
3
O [M + H] m/z 366.1606, found 366.1611.
-1
6.8, 60.7, 14.3; IR (CaF
2
, cm ) υC=O 1710; HRMS (ESI-TOF) calcd for
[M + H] m/z 394.1556, found 394.1545.
+
4-(4-Fluorophenyl)-2-(phenylamino)quinoline-3-carbonitrile (4e).
25
H
20
N
3
O
2
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Page 6 of 7
ARTICLE
Journal Name
o
1
79
4
4 mg, 28%, pale yellow solid: mp 182-183 C; H NMR (400 MHz, 120.4, 117.6, 115.5, 97.9, 18.0; HRMS (ESI-TOF) calcd for C17H13 BrN
3
View Article Online
+
DOI: 10.1039/C9OB02427A
3
CDCl ) δ 7.80 (d, J = 8.0 Hz, 3H), 7.62 (ddd, J = 15.4, 7.8, 1.2 Hz, 1H), [M + H] m/z 338.0293, found 338.0310; HRMS (ESI-TOF) calcd for
.43-7.39 (m, 3H), 7.38-7.32 (m, 2H), 7.25-7.19 (m, 4H), 7.07 (t, J =
.6 Hz, 1H); C{1H} NMR (100 MHz) δ 163.5 (d, JC-F =247 Hz), 155.6,
51.0, 148.6, 138.9, 132.8, 131.2 (d, JC-F = 8.4 Hz), 130.5, 129.0 (2C),
8
1
+
7
7
1
1
C
17
H
13 BrN
3
[M + H] m/z 340.0272, found 340.0291.
1
3
1
4
-Isopropyl-2-(phenylamino)quinoline-3-carbonitrile (6f).
3
o
1
2
41 mg, 28%, pale yellow solid: mp 87-88 C; H NMR (400 MHz, CDCl
δ 8.07-8.05 (m, 1H), 7.84-7.82 (m, 3H), 7.67-7.63 (m, 1H), 7.40-7.31
m, 4H), 7.13-7.10 (m, 1H), 3.96 (sept, J = 7.2 Hz, 1H), 1.63 (d, J = 7.2
) δ 162.9, 151.4, 148.5, 139.0,
32.2, 128.8 (2C), 128.5, 123.8, 123.3, 120.7, 120.1, 116.6, 94.8, 29.6,
3
)
27.8, 126.6, 124.5, 123.6, 121.7, 120.2, 116.1 (d, JC-F = 22 Hz), 96.7;
+
HRMS (ESI-TOF) calcd for C22
3
H15FN
3
[M + H] m/z 340.1250, found
(
40.1228.
1
3
Hz, 6H); C{1H} NMR (100 MHz, CDCl
3
6
-Chloro-4-(2-chlorophenyl)-2-(phenylamino)quinoline-3-
1
2
carbonitrile (4f).
+
18 3
1.4; HRMS (ESI-TOF) calcd for C19H N [M + H] m/z 288.1495,
o
1
6
7 mg, 46%, pale yellow solid: mp 222-223 C; H NMR (400 MHz, found 288.1500.
CDCl ) δ 7.84-7.79 (m, 3H), 7.64-7.59 (m, 2H), 7.55 (m, 1H), 7.42-7.32
3
2
-((2-Aminophenyl)(phenyl)methylene)malononitrile (8).
1
3
(m, 3H), 7.26 (brs, 1H), 7.17-7.13 (m, 2H); C{1H} NMR (100 MHz,
A mixture of 2-aminobenzophenone (103 mg, 1 eq) in dry
malononitrile (2 mL) was heated to 80 °C for 5 h in a sealed tube.
Reaction mixture was cooled to room temperature and diluted with
DCM (20 mL) and washed with saturated NaHCO
Organic layer was dried over anhydrous MgSO
3
CDCl ) δ 153.2, 151.0, 146.9, 138.6, 133.6, 133.0, 132.9, 131.4, 130.5,
1
9
30.4, 130.2, 129.3, 129.0, 127.4, 125.0, 123.9, 122.0, 120.3, 114.9,
3
5
+
2 3
8.3; HRMS (ESI-TOF) calcd for C22H14 Cl N [M + H] m/z 390.0565,
3
7
+
3
solution (10 mL).
and concentrated.
2 3
found 390.0558; HRMS (ESI-TOF) calcd for C22H14 Cl N [M + H] m/z
4
3
4
4
92.0535, found 392.0528.
Crude reaction mixture was purified by silica gel column
chromatography using Hexane-EA eluent (2% to 5%) to obtain a pale
-Methyl-2-(phenylamino)quinoline-3-carbonitrile (6a).12
o
1
o
1
1 mg, 30%, pale yellow solid: mp 152-153 C; H NMR (400 MHz, yellow solid (20 mg, 16%): pale yellow solid: mp 188-189 C; H NMR
CDCl
3
) δ 7.84-7.78 (m, 4H), 7.68-7.64 (m, 1H), 7.40-7.33 (m, 3H), (400 MHz, CDCl
3
) δ 7.73-7.67 (m, 2H), 7.58-7.55 (m, 3H), 7.49-7.43
.13-7.09 (m, 2H), 2.83 (s, 3H); 13C{1H} NMR (100 MHz) δ 153.3, (m, 3H), 7.26-7.22 (m, 1H), 5.67 (brs 2H); C{1H} NMR (100 MHz,
13
7
1
1
3
50.8, 147.6, 139.0, 132.5, 128.9, 127.9, 124.8, 124.2, 123.3, 122.0, CDCl ) δ 157.4, 154.7, 147.9, 134.2, 133.1, 129.8, 129.1, 128.8, 127.2,
20.0, 116.0, 97.0, 17.9; HRMS (ESI-TOF) calcd for C22
H
17
N
2
O
2
[M 125.9, 124.1, 121.4, 115.7, 95.4; HRMS (ESI-TOF) calcd for C16
12
H N
3
+
+
+
H] m/z 260.1182, found 260.1188.
[M + H] m/z 246.1026, found 246.1029..
4
-Methyl-2-(p-tolylamino)quinoline-3-carbonitrile (6b).
Crystallography.
o
1
3
CDCl
3
(
5 mg, 24%, pale yellow solid: mp 164-165 C; H NMR (400 MHz, Crystals suitable for X-ray determination were obtained for 3i by
) δ 7.86 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.73-7.66 (m, recrystallization. Crystal data, complete bond distances and bond
H), 7.38 (dd, J = 8.2 Hz, 1H), 7.23-7.21 (m, 2H), 7.10 (brs, 1H), 2.87 angles of 3i are deposited as supporting information. CCDC 1954817.
3
1
3
s, 3H), 2.39 (s, 3H); C{1H} NMR (100 MHz) δ 153.1, 151.1, 147.9, These data can be also obtained free of charge via
1
9
2
36.4, 133.1, 132.5, 129.4, 128.0, 124.2, 124.0, 122.0, 120.4, 116.1, www.ccdc.cam.ac.uk/data_request/cif,
or
by
emailing
+
7.0, 20.8, 17.9; HRMS (ESI-TOF) calcd for C18
16
H N
3
[M + H] m/z data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: +44 1223 336033.
74.1339, found 274.1349.
2
-(Mesitylamino)-4-methylquinoline-3-carbonitrile (6c).
o
1
6
CDCl
(
9 mg, 45%, off-white solid: mp 179-180 C; H NMR (400 MHz,
) δ 7.82-7.80 (m, 1H), 7.60-7.54 (m, 2H), 7.30-7.26 (m, 1H), 6.97
s, 2H), 6.57 (brs, 1H), 2.87 (s, 3H), 2.34 (s, 3H), 2.23 (s, 3H); 13C{1H}
NMR (100 MHz) δ 153.1, 152.6, 148.5, 136.4, 135.8, 132.7, 132.2,
3
Acknowledgements
We thank the Ministry of Science and Technology, Taiwan
(
Grant No. MOST107-2113-M-002-005) for the financial support.
1
28.9, 127.9, 124.2, 123.4, 121.8, 116.2, 96.0, 20.9, 18.5, 17.7; HRMS
We also thank “National Taiwan University Mass Spectrometry-
based Proteomics Core Facility” for the measurement of ESI
mass data.
+
(ESI-TOF) calcd for C20
20
H N
3
[M + H] m/z 302.1652, found 302.1646.
4
-Methyl-2-(o-tolylamino)quinoline-3-carbonitrile (6d).28
o
1
5
CDCl
7
6 mg, 39%, pale yellow solid: mp 159-160 C; H NMR (400 MHz,
) δ 8.39-8.37 (m, 1H), 7.87-7.78 (m, 2H), 7.70-7.66 (m, 1H), 7.40-
.27 (m, 3H), 7.14-7.10 (m, 2H), 2.87 (s, 3H), 2.40 (s, 3H); 13C{1H}
NMR (100 MHz) δ 153.2, 151.2, 147.7, 137.2, 132.4, 130.5, 128.7,
3
Notes and references
1
Recent reviews: (a) O. Afzal, S. Kumar, M. R. Haider, M. R. Ali,
R. Kumar, M. Jaggi and S. Bawa, Eur. J. Med. Chem., 2015, 97,
1
27.9, 126.6, 124.2, 124.0 (2C), 122.0, 121.7, 116.0, 97.1, 17.9, 17.8;
8
2
71; (b) J. Zhang, S. Wang, Y. Ba and Z. Xu, Eur. J. Med. Chem.,
019, 174, 1; (c) Y.-Q. Hu, C. Gao, S. Zhang, L. Xu, Z. Xu, L.-S.
+
HRMS (ESI-TOF) calcd for C18
16
H N
3
[M + H] m/z 274.1339, found
2
6
4
74.1340.
Feng, X. Wu and F. Zhao, Eur. J. Med. Chem., 2017, 139, 22.
(a) L. M. Nainwal, S. Tasneem, W. Akhtar, G. Verma and M. F.
Khan, Eur. J. Med. Chem., 2019, 164, 121; (b) K. Li, J. Ou and S.
Gao, Angew. Chem. Int. Ed. 2016, 55, 14778; (c) J. Galambos,
G. Domany, K. Nogradi, G. Wagner, G. M. Keseru, A. Bobok, S.
Kolok, M. L. Miko-Bakk, M. Vastag, K. Saghy, J. Koti, Z. Szakacs,
Z. Beni, K. Gal, Z. Szombathelyi and I. Greiner, Bioorg. Med.
2
-Bromo-4-methyl-2-(phenylamino)quinoline-3-carbonitrile (6e).
o
1
0 mg, 25%, pale yellow solid: mp 221-222 C; H NMR (400 MHz,
) δ 7.97-7.96 (m, 1H), 7.80-7.78 (m, 2H), 7.72-7.66 (m, 2H), 7.40-
CDCl
.36 (m, 2H), 7.14-7.10 (m, 2H), 2.81 (s, 3H); C{1H} NMR (100 MHz)
δ 151.1, 138.6, 135.7, 129.5, 129.0 (2C), 126.6 (2C), 123.9, 123.3,
3
1
3
7
6
| J. Name., 2012, 00, 1-3
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