Iodine-promoted domino reaction leading to N -substituted 2-aminoquinoline-3-carbonitriles under microwave irradiation

Article abstract of DOI:10.1021/cc1000192

A new iodine-promoted domino reaction of 2-aminochromene-3-carbonitriles with various isocyanates is described, and a set of polyfunctionalized N-substituted 2-aminoquinoline-3-carbonitriles with high regioselectivity were successfully synthesized under microwave heating. In this reaction, the ring-opening/recyclization process occurs unexpectedly at the ring of 4H-pyran with different isocyanates.

Full text of DOI:10.1021/cc1000192

482
J. Comb. Chem. 2010, 12, 482–487
Iodine-Promoted Domino Reaction Leading to N-Substituted
2-Aminoquinoline-3-carbonitriles under Microwave Irradiation
Bo Jiang,†,‡ Chao Li,† Shu-Jiang Tu,*,†,‡ and Feng Shi†
School of Chemistry and Chemical Engineering, Xuzhou Normal UniVersity, Xuzhou, Jiangsu, 221116,
P.R. China, and College of Chemistry, Chemical Engineering, and Materials Science; Suzhou
UniVersity, Suzhou, 215123, P.R. China
ReceiVed February 7, 2010
A new iodine-promoted domino reaction of 2-aminochromene-3-carbonitriles with various isocyanates is
described, and a set of polyfunctionalized N-substituted 2-aminoquinoline-3-carbonitriles with high
regioselectivity were successfully synthesized under microwave heating. In this reaction, the ring-opening/
recyclization process occurs unexpectedly at the ring of 4H-pyran with different isocyanates.
Introduction
exhibit important biological properties. Quinoline derivatives
are important heterocyclic compounds that constitute core
structures of many naturally occurring substances that have
interesting biological and pharmaceutical properties.5 In this
family, aminoquinoline derivatives are especially important
because of these pharmaceutical activities including antima-
larial,6 anti-HIV,7 anti-Alzheimer disease,8 melanin-concen-
trating hormone 1 receptor (MCHR) antagonist,9 and Src
kinase inhibitor.10 Consequently, the development of new
and efficient methods for the synthesis of these molecules
has continued to be an important goal. Srinivasan et al.
reported the synthesis of 2-aminoquinoline-3-carbonitrile
from the reaction of arylidenemalononitriles with enaminone,
and also their antifungal properties were evaluated.11 How-
ever, the N-substituted 2-aminoquinoline-3-carbonitriles can
not be obtained through this method. Therefore, the design
of new and simple routes for the preparation of new
2-aminoquinolines, particularly those that are highly func-
tionalized, remains a significant challenge.
As a part of our continued interest in the development of
domino reactions for the construction of important hetero-
cyclic skeletons,12 we now report a new domino reaction
between 2-aminochromene-3-carbonitriles with isocyanates.
This reaction is very unique because the ring-opening/
recyclization process occurs unexpectedly at the 4H-pyran
ring, and new N-substituted 2-aminoquinoline-3-carbonitrile
derivatives, which are normally difficult to prepare, are
obtained in a very convenient manner. In addition, the
starting materials can be easily changed to obtain diverse
polyfunctional N-substituted 2-aminoquinoline-3-carbonitrile,
which can be used as versatile building blocks in organic
synthesis.
Creation of molecular complexity and diversity from
simple substrates, with simultaneous consideration of the
economic and environmental aspects, constitutes a great
challenge in modern organic chemistry, both from academic
and industrial points of view. In this context domino reactions
have proven to be very effective and attractive.1 The notable
feature of a domino process is that bonds and new func-
tionalities are constructed during the cascade, which, in turn,
react further in subsequent steps under identical conditions
to form new bonds and functionalities until termination leads
to a stable final product. Clearly, the quality of a domino
reaction is dependent on the number of bonds formed and
the complexity of the product. These reactions can avoid
time-consuming and costly processes, including the protec-
tion and deprotection of functional groups and the separation
and purification of intermediates. They are also environ-
mentally friendly and often proceed with excellent selectivity.
As a result, they are very useful in the drug discovery process
and serve as powerful tools in the total synthesis of complex
natural products.2
In recent years, molecular iodine has received considerable
attention as an inexpensive, non-toxic, and a readily available
catalyst for various organic transformations affording the
corresponding products with high selectivity in excellent
yields.3 Iodine has a high tolerance to air as well as moisture
and can be easily removed from reaction systems. Moreover,
the mild Lewis acidity associated with iodine enhanced its
usage in organic synthesis to perform several organic
transformations using stoichiometric levels to catalytic
amounts. Owing to the advantages associated with this eco-
friendly catalyst, molecular iodine has been explored as a
powerful reagent in organic synthesis.4
Results and Discussion
It is well-known that six-membered nitrogen-containing
heterocycles are abundant in numerous natural products that
We previously reported that,13 during the reactions of
arylidenemalononitrile and dimedone with aromatic amines
under microwave heating in N,N-dimethylformamide (DMF),
the desired N-aryl 2-aminoquinoline-3-carbonitrile can not
be obtained. Instead, the chromene-3-carbonitrile was gener-
* To whom correspondence should be addressed. E-mail: laotu@
xznu.edu.cn. Phone: 0086-516-83500065. Fax: 0086-516-83500065.
† Xuzhou Normal University.
‡ Suzhou University.
10.1021/cc1000192  2010 American Chemical Society
Published on Web 05/21/2010

N-Substituted 2-Aminoquinoline-3-carbonitriles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 483
Table 1. Optimization of Reaction Solvents and Temperature
Scheme 1. Synthesis of Chromene-3-carbonitriles
entry
solvent
T/°C
I2/equiv
time/min
yield/%
1
2
3
4
5
6
7
8
9
EtOH
water
toluene
CH2Cl2
DMF
DMF
DMF
DMF
DMF
100
100
100
100
100
100
100
120
150
1.0
1.0
1.0
1.0
1.0
0.5
1.5
1.0
1.0
25
25
25
25
25
25
25
25
20
0
0
41
34
78
42
79
80
85
Scheme 2. Synthesis of N-substituted
2-Aminoquinoline-3-carbonitrile
optimization of the reaction conditions, including reaction
temperature and the influence of iodine concentration, was
investigated. Impressively, after a series of experiments, the
yield of product 3a reached 85% without byproduct forma-
tion when the reaction was carried out in DMF at 150 °C
for 20 min using 1.0 equiv of iodine as an additive (Table
1, entry 9). Without iodine, the reaction did not proceed to
the desired product 3a. Similarly, when the reaction was
carried out in acidic media without iodine such as HOAc or
formic acid, 1,3-diphenylurea was obtained as a byproduct
instead of the desired compound 3a.
We therefore use 1.0 equiv of iodine as an additive for
further investigation. At the beginning to explore the
substrates 1 scope, phenyl isocyanate 2a was used as a model
substrate (Table 2, entries 1-6), and the results indicated
that the substrate 1 bearing either electron donating or
electron withdrawing functional group such as halogen, or
methoxy were able to synthesize compounds 3. To expand
the scope of isocyanates, different 2-aminochromene-3-
carbonitriles were employed as substrate and various isocy-
anates were examined including 4-chlorophenyl isocyanate
(2b), 4-bromophenyl (2c), cyclohexyl (2d), and 4-methox-
yphenyl (2e). In some cases (2b-2d), the reactions pro-
ceeded smoothly to give the corresponding N-aryl 2-ami-
noquinoline-3-carbonitriles in good yields (62-84%).
Unfortunately, instead of the desired product 3, isocyanate
2e only gave 1,3-di(4-methoxyphenyl)urea with high yield.
This result may be attributed to the electronic effect of
substitution on aryl isocyanate. It is worth noting that to the
best of our knowledge, there is no literature precedent for
the synthesis of N-aryl 2-aminoquinoline-3-carbonitriles.
Furthermore, the reaction is not only suitable for aryl
isocyanates (Table 2, entries 1-16) but also can be used
with alicyclic isocyanates such as cyclohexyl isocyanate
(Table 2, entries 17-19). When acyclic and heteroaryl
substituted 2-aminochromenes 1 were used as substrates, we
have not achieved good results yet since very complex
mixtures were generated.
ated in high yields (Scheme 1). The reason is that dimedone
has high reactivity, in which the enolization of carbonyl
group is converted to hydroxyl group, becoming a nucleo-
philic center. Therefore, there is a demand to develop a new
method for the preparation of N-aryl 2-aminoquinoline-3-
carbonitriles. In a further study, we are pleased to find that
treatment of 2-aminochromene-3-carbonitriles 1 with isocy-
anates 2 can lead to N-substituted 2-aminoquinoline-3-
carbonitrile 3 with good to excellent yield (Scheme 2). This
interesting result is of value to us not only because the new
domino reactions are developed to prepare new N-substituted
2-aminoquinoline-3-carbonitrile derivatives but also because
we were unable to find such convenient synthesis in the
literature.
2-Aminochromene-3-carbonitrile 1 possessing both elec-
trophilic and nucleophilic centers are versatile synthetic
intermediates in organic chemistry that combine the ambient
nucleophilicity of the amine group and the electrophilicity
of the cyano-group.14 They are frequently applied in the
preparation of heterocycles.15 Our strategy of synthesizing
the N-substituted 2-aminoquinoline-3-carbonitrile derivatives
was through the reaction of a preformed 2-aminochromene-
3-carbonitrile 1 with isocyanates 2 in the presence of iodine
under microwave heating using DMF as a solvent. Initially,
the reaction of 2-aminochromene-3-carbonitrile 1a with
phenyl isocyanate 2a in the presence of iodine was carried
out under microwave heating. All of the analytical data
showed that the synthesized product was a new N-aryl
2-aminoquinoline-3-carbonitrile derivative 3a with high
regioselectivity (Scheme 2).
Encouraged by the above interesting results, we devoted
our efforts to the study of the reaction of 1a with 2a as a
model reaction in the presence of iodine to optimize the
reaction conditions. Experiments were carried out in various
solvents such as toluene, CH2Cl2, EtOH, and water. Unfor-
tunately, the reaction does not proceed in water or EtOH as
isocyanate 2a was converted to 1,3-diphenylurea (Table 1,
entries 1-2); an incomplete reaction was observed in toluene,
or CH2Cl2 (Table 1, entries 3-4). In another case, when DMF
was used as the solvent, the reaction proceeded better, and
product 3a was obtained in 78% isolated yield by flash
chromatography (Table 1, entry 5). Subsequently, further
In general, the reaction is very fast and can be finished
within 20-36 min with CO2 as the major byproduct, which
makes workup convenient. Complete regioselectivity and
good to excellent yields were obtained for all cases that were
examined. The structures of all the synthesized compounds
were established on the basis of their spectroscopic data.
Although the exact mechanism of this transformation is
not clear right now, a possible reaction mechanism is
proposed (Scheme 3) based on the above results and the
known literature. It was reported that the reaction of
isocyanate with alkenes underwent [2 + 2] cyclization to

484 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Table 2. Domino Autocatalytic Synthesis of Products 3a
Jiang et al.
a Reagents and conditions: I2 (1.0 equiv), 150 °C, DMF, microwave heating. b Isolated yield.
Scheme 3. Proposed Reaction Mechanism of Formation Product 3
generate ꢀ-lactam derivatives.16 Similarly, a [2 + 2] cy-
clization reaction between 2-aminochromene-3-carbonitrile
1 and phenyl isocyanate 2 occurs, resulting in ꢀ-lactam A
as the key intermediate, which was hydrolyzed to ring-
opening B.17 Subsequently, the intermediate B releases
carbon dioxide to give intermediate C, which undergoes
intramolecular cyclization to afford the 1,4-dihydropyridine
D, followed dehydrogenation to the aromatized compound
3. We have not been able to separate the ꢀ-lactam A to
subject them to the reaction conditions with the goal of
probing this hypothesis.
crowave irradiation, providing N-substituted 2-aminoquino-
line-3-carbonitrile with high regioselectivity, has been de-
veloped. The reactions showed broad scopes of substrates
which can employ a wide range of common commercial
2-aminochromene-3-carbonitrile and isocyanate. The syn-
theses were finished within short periods (20-36 min) with
good to excellent chemical yields and regioselectivity that
avoided tedious workup isolations. New mechanism involv-
ing ring-opening/recyclization process has been proposed for
this reaction.
Experimental Section
Conclusion
General Procedures. Microwave irradiation was carried
out with microwave oven Emrys Creator from Personal
Chemistry, Uppsala, Sweden. Melting points were deter-
In conclusion, a new iodine-promoted domino reaction of
2-aminochromene-3-carbonitrile with isocyanate under mi-

N-Substituted 2-Aminoquinoline-3-carbonitriles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 485
mined in open capillaries and were uncorrected. IR spectra
were taken on a FT-IR-Tensor 27 spectrometer in KBr pellets
and reported in cm-1. 1H NMR spectra were measured on a
Bruker DPX 400 MHz spectrometer in DMSO-d6 or CDCl3
(100 MHz, 13C NMR) with chemical shift (δ) given in parts
per million (ppm) relative to tetramethysilane (TMS) as
internal standard. ESI-MS was determined by using the LCQ
Advantage HPLC/MS instrument (Thermo Finnigan). HRMS
(ESI) was determined by using microTOF-Q II HRMS/MS
instrument (Bruker).
General procedure for the synthesis of 4-(4-Chlorophenyl)-
5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-2-(phenylamino)quin-
oline-3-carbonitrile (3a) with microwave irradiation (Table
2, Entry 1). 2-Amino-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-
7,7-dimethyl-5-oxo-4H-chromene-3-carbonitrile (1a, 1 mmol,
0.33 g, 1 equiv.) was introduced into a 10-mL Emrys reaction
vial, phenyl isocyanate (2a, 1.1 mmol, 0.13 g, 1.1 equiv)
was then successively added, followed by I2 (1 mmol, 0.25 g,
1 equiv.) and DMF (1.5 mL). Subsequently, the reaction vial
was capped and then pre-stirred for 20 s. The mixture was
irradiated (initial power 100 W and maximum power 200
W) at 150 °C until TLC (petroleum ether/acetone 4:1)
revealed that conversion of the starting material 1a was
completed (20 min). The reaction mixture was then cooled
to room temperature and then diluted with cold water (40
mL). The solid product was collected by Bu¨chner filtration
and was purified by recrystallization from 95% EtOH to
afford the desired pure products 3a as a pale yellow solid,
Mp: 249-250 °C.
121.3, 118.1, 115.7, 115.5, 115.3, 95.0, 53.4, 48.1, 32.2, 28.2;
IR (KBr, ν, cm-1): 3316, 2957, 2226, 1676, 1609, 1572,
1548, 1497, 1256, 1311, 987, 837. HRMS (ESI): m/z calcd
for: 386.1664 [M+H]+; found: 386.1671.
5,6,7,8-Tetrahydro-7,7-dimethyl-5-oxo-4-phenyl-2-(phe-
nylamino)quinoline-3-carbonitrile (3d). A pale yellow
solid; Mp: 225-227 °C.
1H NMR (400 MHz, CDCl3) δ: 7.72 (d, J ) 7.6 Hz, 2H,
ArH), 7.50-7.49 (m, 3H, ArH), 7.45 (s, 1H, NH), 7.42 (d,
J ) 8.4 Hz, 2H, ArH), 7.26-7.19 (m, 3H, ArH), 3.04 (s,
2H, CH2), 2.46 (s, 2H, CH2), 1.14 (s, 6H, CH3). 13C NMR
(100 MHz, CDCl3) δ: 194.9, 167.8, 157.4, 156.0, 137.8,
137.1, 129.1, 128.8, 128.4, 127.1, 124.8, 121.2, 118.1, 115.4,
94.9, 53.3, 48.1, 32.2, 28.2. IR (KBr, ν, cm-1): 3313, 2929,
2228, 1675, 1611, 1547, 1497, 1446, 1297, 1257, 752.
HRMS (ESI): m/z calcd for: 368.1758 [M+H]+; found:
368.1757.
5,6,7,8-Tetrahydro-7,7-dimethyl-5-oxo-2-(phenylamino)-
4-p-tolylquinoline-3-carbonitrile (3e). A pale yellow solid.
Mp: 244-245 °C.
1H NMR (400 MHz, CDCl3) δ: 7.72 (d, J ) 8.8 Hz, 2H,
ArH), 7.45 (s, 1H, NH), 7.44-7.41 (m, 2H, ArH), 7.30 (d,
J ) 8.8 Hz, 2H, ArH), 7.21 (t, J ) 7.4 Hz, 1H, ArH), 7.15
(d, J ) 8.0 Hz, 2H, ArH), 3.03 (s, 2H, CH2), 2.46 (s, 2H,
CH2), 2.45 (s, 3H, CH3), 1.13 (s, 6H, CH3). 13C NMR (100
MHz, CDCl3) δ: 195.0, 167.7, 156.0, 138.7, 137.8, 134.1,
129.1, 128.8, 128.4, 127.1, 124.7, 121.2, 118.3, 115.4, 94.9,
53.3, 48.1, 32.2, 28.2, 21.5. IR (KBr, ν, cm-1): 3317, 2933,
2224, 1675, 1611, 1570, 1546, 1497, 1373, 1256, 746.
HRMS (ESI): m/z calcd for: 382.1913 [M+H]+; found:
382.1917.
1H NMR (400 MHz, CDCl3) δ: 7.71 (d, J ) 8.0 Hz, 2H,
ArH), 7.48-7.43 (m, 5H, NH, 1H and ArH 4H), 7.24-7.18
(m, 3H, ArH), 3.04 (s, 2H, CH2), 2.46 (s, 2H, CH2), 1.14 (s,
6H, CH3). 13C NMR (100 MHz, CDCl3) δ: 194.9, 168.0,
156.1, 156.0, 137.7, 135.5, 134.9, 129.1, 128.7, 128.7, 124.9,
121.3, 117.9, 115.2, 94.7, 53.3, 48.1, 32.2, 28.2. IR (KBr,
ν, cm-1): 3317, 2956, 2226, 1683, 1610, 1544, 1447, 1256,
889. HRMS (ESI): m/z calcd for: C24H20ClN3ONa, 424.1188;
found: 424.1202.
4-(4-Methoxyphenyl)-5,6,7,8-tetrahydro-7,7-dimethyl-
5-oxo-2-(phenylamino)quinoline-3-carbonitrile (3f). A pale
yellow solid; Mp: 249-252 °C.
1H NMR (400 MHz, CDCl3) δ: 7.72 (d, J ) 7.6 Hz, 2H,
ArH), 7.45 (s, 1H, NH), 7.42 (d, J ) 7.6 Hz, 2H, ArH),
7.22-7.20 (m, 3H, ArH), 7.21 (d, J ) 8.4 Hz, 2H, ArH),
3.89 (s, 3H, OCH3), 3.03 (s, 2H, CH2), 2.46 (s, 2H, CH2),
1.13 (s, 6H, CH3). IR (KBr, ν, cm-1): 3332, 2957, 2215,
1671, 1608, 1570, 1542, 1498, 1447, 1282, 1246, 1174, 1033,
748. HRMS (ESI): m/z calcd for: 398.1864 [M+H]+; found:
398.1869.
4-(4-Bromophenyl)-5,6,7,8-tetrahydro-7,7-dimethyl-5-
oxo-2-(phenylamino)quinoline-3-carbonitrile (3b). A pale
yellow solid; Mp: 263-265 °C.
1H NMR (400 MHz, CDCl3) δ: 7.71 (d, J ) 8.4 Hz, 2H,
ArH), 7.61 (d, J ) 8.4 Hz, 2H, ArH), 7.45 (s, 1H, NH),
7.46-7.41 (m, 2H, ArH), 7.22 (t, J ) 7.4 Hz, 1H, ArH),
7.13 (d, J ) 8.4 Hz, 2H, ArH), 3.03 (s, 2H, CH2), 2.45 (s,
2H, CH2), 1.13 (s, 6H, CH3). 13C NMR (100 MHz, CDCl3)
δ: 194.9, 168.0, 156.1, 156.0, 137.6, 136.0, 131.73, 129.1,
128.9, 124.9, 123.2, 121.3, 117.9, 115.2, 94.6, 53.3, 48.1,
32.2, 28.2. IR (KBr, ν, cm-1): 3317, 2933, 2225, 1678, 1611,
1568, 1546, 1496, 1446, 1255, 1011, 749. HRMS (ESI): m/z
calcd for: 446.0683 [M+H]+; found: 446.0687.
2-(4-Chlorophenylamino)-4-(4-chlorophenyl)-5,6,7,8-
tetrahydro-7,7-dimethyl-5-oxoquinoline-3-carbonitrile (3g).
A pale yellow solid; Mp: 247-249 °C.
1H NMR (400 MHz, DMSO) δ: 9.72 (s, 1H, NH), 7.69
(d, J ) 8.8 Hz, 2H, ArH), 7.51 (d, J ) 8.4 Hz, 2H, ArH),
7.41 (d, J ) 8.8 Hz, 2H, ArH), 7.27 (d, J ) 8.4 Hz, 2H,
ArH), 2.90 (s, 2H, CH2), 2.38 (s, 2H, CH2), 1.02 (s, 6H,
CH3). 13C NMR (100 MHz, DMSO) δ: 194.0, 167.1, 156.2,
155.8, 138.1, 136.7, 132.8, 129.3, 128.2, 124.3, 117.3, 115.0,
94.3, 52.5, 47.1, 31.7, 27.6. IR (KBr, ν, cm-1): 3301, 2954,
2235, 1681, 1612, 1546, 1488, 1371, 1256, 1090, 822.
HRMS (ESI): m/z calcd for: 436.0978 [M+H]+; found:
436.0976.
4-(4-Fluorophenyl)-5,6,7,8-tetrahydro-7,7-dimethyl-5-
oxo-2-(phenylamino)quinoline-3-carbonitrile (3c). A pale
yellow solid; Mp: 238-240 °C.
1H NMR (400 MHz, CDCl3) δ: 7.72 (d, J ) 8.0 Hz, 2H,
ArH), 7.45 (s, 1H, NH), 7.43-7.41 (m, 2H, ArH),
7.26-7.17(m, 5H, ArH), 3.04 (s, 2H, CH2), 2.46 (s, 2H,
CH2), 1.14 (s, 6H, CH3); 13C NMR (100 MHz, CDCl3) δ:
194.9, 167.9, 156.3, 156.0, 137.7, 129.3, 129.2, 129.1, 124.9,
2-(4-Chlorophenylamino)-4-(4-bromophenyl)-5,6,7,8-
tetrahydro-7,7-dimethyl-5-oxoquinoline-3-carbonitrile (3h).
A pale yellow solid; Mp: 253-255 °C.

486 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Jiang et al.
1H NMR (400 MHz, CDCl3) δ: 7.67 (d, J ) 8.8 Hz, 2H,
ArH), 7.62 (d, J ) 8.4 Hz, 2H, ArH), 7.43 (s, 1H, NH),
7.39 (d, J ) 8.8 Hz, 2H, ArH), 7.12 (d, J ) 8.4 Hz, 2H,
ArH), 3.03 (s, 2H, CH2), 2.46 (s, 2H, CH2), 1.13 (s, 6H,
CH3). 13C NMR (100 MHz, CDCl3) δ: 194.9, 167.9, 155.8,
155.2, 136.2, 135.8, 131.7, 129.1, 128.9, 123.3, 122.6, 115.1,
113.2, 94.8, 53.3, 48.0, 32.2, 28.2. IR (KBr, ν, cm-1): 3301,
2955, 2233, 1681, 1633, 1546, 1514, 1491, 1370, 1281, 1012,
824. HRMS (ESI): m/z calcd for: 480.0473 [M+Na]+; found:
480.0466.
A pale yellow solid; Mp: 264-265 °C.
1H NMR (400 MHz, DMSO-d6) δ: 9.72 (s, 1H, NH), 7.64
(d, J ) 8.4 Hz, 2H, ArH), 7.54 (d, J ) 8.8 Hz, 2H, ArH),
7.51 (d, J ) 8.4 Hz, 2H, ArH), 7.27 (d, J ) 8.0 Hz, 2H,
ArH), 2.91 (s, 2H, CH2), 2.39 (s, 2H, CH2), 1.02 (s, 6H,
CH3). IR (KBr, ν, cm-1): 3300, 2954, 2869, 2234, 1681,
1611, 1544, 1488, 1371, 1256, 1090, 822. HRMS (ESI): m/z
calcd for: 480.0473 [M+Na]+; found: 480.0471.
2-(4-Bromophenylamino)-4-(4-bromophenyl)-5,6,7,8-
tetrahydro-7,7-dimethyl-5-oxoquinoline-3-carbonitrile (3n).
A pale yellow solid; Mp: 268-270 °C.
2-(4-Chlorophenylamino)-4-(4-fluorophenyl)-5,6,7,8-tet-
rahydro-7,7-dimethyl-5-oxoquinoline-3-carbonitrile (3i).
A pale yellow solid; Mp: 241-243 °C.
1H NMR (400 MHz, DMSO-d6) δ: 9.72 (s, 1H, NH), 7.64
(d, J ) 8.4 Hz, 4H, ArH), 7.54 (d, J ) 8.8 Hz, 2H, ArH),
7.21 (d, J ) 8.4 Hz, 2H, ArH), 2.91 (s, 2H, CH2), 2.39 (s,
2H, CH2), 1.01 (s, 6H, CH3). IR (KBr, ν, cm-1): 3303, 2954,
2229, 1681, 1610, 1545, 1515, 1488, 1372, 1255, 1011, 822.
HRMS (ESI): m/z calcd for: 523.9968 [M+Na]+; found:
523.9984.
1H NMR (400 MHz, CDCl3) δ: 7.67 (d, J ) 8.8 Hz, 2H,
ArH), 7.43 (s, 1H, NH), 7.38 (d, J ) 8.4 Hz, 2H, ArH),
7.23-7.16 (m, 5H, ArH), 3.03 (s, 2H, CH2), 2.46 (s, 2H,
CH2), 1.14 (s, 6H, CH3). 13C NMR (100 MHz, CDCl3) δ:
195.0, 167.9, 161.8, 156.4, 155.8, 136.3, 129.9, 129.3, 129.2,
129.1, 122.6, 118.4, 115.7, 115.5, 115.2, 95.1, 53.3, 48.1,
32.2, 28.2. IR (KBr, ν, cm-1): 3301, 2956, 2233. 1681, 1613,
1548, 1491, 1409, 1280, 1255, 1220, 1094, 824. HRMS
(ESI): m/z calcd for: 420.1274 [M+H]+; found: 420.1279.
2-(4-Chlorophenylamino)-5,6,7,8-tetrahydro-7,7-dimeth-
yl-5-oxo-4-p-tolylquinoline-3-carbonitrile (3j). A pale yel-
low solid; Mp: 259-261 °C.
2-(4-Bromophenylamino)-4-(4-fluorophenyl)-5,6,7,8-tet-
rahydro-7,7-dimethyl-5-oxoquinoline-3-carbonitrile (3o).
A pale yellow solid; Mp: 237-238 °C.
1H NMR (400 MHz, DMSO-d6) δ: 9.70 (s, 1H, NH), 7.64
(d, J ) 8.8 Hz, 2H, ArH), 7.54 (d, J ) 8.8 Hz, 2H, ArH),
7.29-7.27 (m, 4H, ArH), 2.91 (s, 2H, CH2), 2.40 (s, 2H,
CH2), 1.02 (s, 6H, CH3). IR (KBr, ν, cm-1): 3301, 2955,
2870, 2233, 1680, 1611, 1546, 1488, 1371, 1255, 1077, 822.
HRMS (ESI): m/z calcd for: 464.0769 [M+H]+; found:
464.0784.
1H NMR (400 MHz, CDCl3) δ: 7.68 (d, J ) 8.8 Hz, 2H,
ArH), 7.40 (s, 1H, NH), 7.38 (d, J ) 8.8 Hz, 2H, ArH),
7.30 (d, J ) 8.0 Hz, 2H, ArH), 7.14 (d, J ) 8.0 Hz, 2H,
ArH), 3.03 (s, 2H, CH2), 2.46 (s, 2H, CH2), 2.45 (s, 3H,
CH3), 1.14 (s, 6H, CH3). 13C NMR (100 MHz, CDCl3) δ:
194.9, 167.6, 157.7, 155.8, 138.8, 136.5, 134.0, 129.7, 129.1,
129.1, 127.1, 122.4, 118.5, 115.5, 95.1, 53.4, 48.1, 32.2, 28.2,
21.5. IR (KBr, ν, cm-1): 3321, 2955, 2229, 1689, 1612, 1545,
1491, 1406, 1300, 1092, 824. HRMS (ESI): m/z calcd for:
416.1525 [M+H]+; found:.416.1539.
2-(4-Bromophenylamino)-5,6,7,8-tetrahydro-7,7-dimeth-
yl-5-oxo-4-p-tolylquinoline-3-carbonitrile (3p). A pale yel-
low solid; Mp: 292-293 °C.
1H NMR (400 MHz, CDCl3) δ: 9.64 (s, 1H, NH), 7.64
(d, J ) 8.8 Hz, 2H, ArH), 7.54 (d, J ) 8.8 Hz, 2H, ArH),
7.24 (d, J ) 8.0 Hz, 2H, ArH), 7.11 (d, J ) 8.0 Hz, 2H,
ArH), 2.90 (s, 2H, CH2), 2.38 (s, 5H, CH2 and CH3), 1.01
(s, 6H, CH3). IR (KBr, ν, cm-1): 3320, 2954, 2867, 2230,
1689, 1612, 1543, 1488, 1368, 1256, 1114, 821, 752. HRMS
(ESI): m/z calcd for: 460.1019 [M+H]+; found: 460.1026.
4-(4-Chlorophenyl)-2-(cyclohexylamino)-5,6,7,8-tetrahy-
dro-7,7-dimethyl-5-oxoquinoline-3-carbonitrile (3q). A
pale yellow solid; Mp: 247-248 °C.
2-(4-Chlorophenylamino)-5,6,7,8-tetrahydro-4-(4-meth-
oxyphenyl)-7,7-dimethyl-5-oxoquinoline-3-carbonitrile (3k).
A pale yellow solid; Mp: 241-242 °C.
1H NMR (400 MHz, CDCl3) δ: 7.68 (d, J ) 8.8 Hz, 2H,
ArH), 7.41 (s, 1H, NH), 7.38 (d, J ) 8.8 Hz, 2H, ArH),
7.20 (d, J ) 8.8 Hz, 2H, ArH), 7.01 (d, J ) 8.4 Hz, 2H,
ArH), 3.89 (s, 3H, OCH3), 3.02 (s, 2H, CH2), 2.47 (s, 2H,
CH2), 1.35 (s, 6H, CH3). IR (KBr, ν, cm-1): 3321, 2955,
2228, 1685, 1617, 1545, 1493, 1411, 1262, 1226, 1026, 824.
HRMS (ESI): m/z calcd for: 432.1474 [M+H]+; found:
.432.1474
1H NMR (400 MHz, CDCl3) δ: 7.43 (d, J ) 8.4 Hz, 2H,
ArH), 7.14 (d, J ) 8.4 Hz, 2H, ArH), 5.52 (d, J ) 7.2 Hz,
1H, NH), 4.20-4.17 (m, 1H, CH), 2.94 (s, 2H,CH2), 2.40
(s, 2H,CH2), 2.09-2.06 (m, 1H, CH2), 1.97-1.53 (m, 9H,
CH2), 1.11 (s, 6H, CH3). IR (KBr, ν, cm-1): 3330, 2931,
2852, 2216, 1673, 1627, 1558, 1457, 1284, 1089, 1016.
HRMS (ESI): m/z calcd for: 408.1838 [M+H]+; found:
408.1847.
2-(4-Chlorophenylamino)-5,6,7,8-tetrahydro-4-(3,4-
dimethoxyphenyl)-7,7-dimethyl-5-oxoquinoline-3-carbo-
nitrile (3l). A pale yellow solid; Mp: 235-237 °C.
1H NMR (400 MHz, DMSO-d6) δ: 9.62 (s, 1H, NH), 7.69
(d, J ) 8.8 Hz, 2H, ArH), 7.41 (d, J ) 8.8 Hz, 2H, ArH),
7.00 (d, J ) 8.4 Hz, 1H, ArH), 6.85 (s, 1H, ArH), 6.78-6.76
(m, 1H, ArH), 3.82 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 2.90
(s, 2H, CH2), 2.41 (s, 2H, CH2), 1.02 (s, 6H, CH3). IR (KBr,
ν, cm-1): 3319, 2991, 2267, 1685, 1608, 1543, 1523, 1445,
1225, 1141, 1026. HRMS (ESI): m/z calcd for: 462.1579
[M+H]+; found: 462.1580.
4-(4-Bromophenyl)-2-(cyclohexylamino)-5,6,7,8-tetrahy-
dro-7,7-dimethyl-5-oxoquinoline-3-carbonitrile (3r). A
pale yellow solid; Mp: 260-262 °C.
1H NMR (400 MHz, CDCl3) δ: 7.59 (d, J ) 8.4 Hz, 2H,
ArH), 7.08 (d, J ) 8.4 Hz, 2H, ArH), 5.52 (d, J ) 7.6 Hz,
1H, NH), 4.21-4.16 (m, 1H, CH), 2.94 (s, 2H, CH2), 2.40
(s, 2H, CH2), 2.10-2.06 (m, 2H, CH2), 1.84-1.80 (m, 2H,
CH2), 1.80-1.31 (m, 6H, CH2), 1.28 (s, 6H, CH3). 13C NMR
(100 MHz, CDCl3) δ: 195.0, 168.5, 157.6, 155.8, 136.5,
131.5, 128.8, 122.8, 116.0, 115.6, 92.9, 53.2, 50.2, 48.3, 32.9,
2-(4-Bromophenylamino)-4-(4-chlorophenyl)-5,6,7,8-
tetrahydro-7,7-dimethyl-5-oxoquinoline-3-carbonitrile (3m).

N-Substituted 2-Aminoquinoline-3-carbonitriles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 487
32.1, 28.2, 25.5, 24.9. IR (KBr, ν, cm-1): 3328, 2934, 2222,
1672, 1636, 1577, 1557, 1508, 1457, 1285. HRMS (ESI):
m/z calcd for: 452.1333 [M+H]+; found: 452.1334.
2-(Cyclohexylamino)-5,6,7,8-tetrahydro-4-(4-methox-
yphenyl)-7,7-dimethyl-5-oxoquinoline-3-carbonitrile (3s).
A pale yellow solid; Mp: 191-192 °C.
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1H NMR (400 MHz, CDCl3) δ: 7.14 (d, J ) 8.4 Hz, 2H,
ArH), 7.96 (d, J ) 8.4 Hz, 2H, ArH), 5.47 (d, J ) 7.6 Hz,
2H, NH), 4.19-4.13 (m, 1H, CH), 3.85 (s, 3H, OCH3), 2.91
(s, 2H, CH2), 2.38 (s, 2H, CH2), 2.08-2.04 (m, 2H, CH2),
1.81-1.23 (m, 8H, CH2), 1.09 (s, 6H, CH3). IR (KBr, ν,
cm-1): 3362, 2956, 2213, 1679, 1574, 1520, 1498, 1280,
1249, 1028, 813.
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Turner, C.; Lin, P.; Tong, X.; Wang, J.; Tan, C.; Feighner,
S.; Palyha, O.; Hreniuk, D. L.; Pan, J.; Sailer, A. W.; MacNeil,
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HRMS (ESI): m/z calcd for: 404.2333 [M+H]+; found:
404.2348.
Acknowledgment. We are grateful to financial support
from the National Science Foundation of China (No.
20672090), and the Qing Lan Project of Jiangsu Province
(No.08QLT001).
Supporting Information Available. Representative ex-
perimental procedures, spectral data of compounds 3a-3s.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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