L-Proline-promoted three-component reaction of anilines, aldehydes and barbituric acids/malononitrile: Regioselective synthesis of 5-arylpyrimido[4,5- b]quinoline-diones and 2-amino-4-arylquinoline-3-carbonitriles in water

Article abstract of DOI:10.1039/c2gc35765h

A green and efficient one-pot process to achieve 5-aryl-pyrimido[4,5-b] quinoline-dione derivatives, using a three-component reaction involving anilines, aldehydes and barbituric acids was developed. This protocol was accomplished efficiently using l-proline as catalyst in an aqueous medium to give the corresponding products in high yield. Also, 2-amino-4-arylquinoline-3- carbonitrile derivatives were obtained by replacing the barbituric acid with malononitrile in the designed protocol. The catalytic activity of l-proline in these reactions was tested over a set of aldehydes and amines, demonstrating that it is reactive towards a variety of functionalities. The multicomponent reactions showed good regioselectivity, and computational studies were used to investigate the selectivity.

Full text of DOI:10.1039/c2gc35765h

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ARTICLE TYPE
Lꢀprolineꢀpromoted threeꢀcomponent reaction of anilines, aldehydes
and barbituric acids/malononitrile: Regioselective synthesis of 5ꢀ
arylpyrimido[4,5ꢀb]quinolineꢀdiones and 2ꢀaminoꢀ4ꢀarylquinolineꢀ3ꢀ
carbonitriles in water
5
Ali KhalafiꢀNezhad,a* Samira Sarikhani,a Elham Shaikhi Shahidzadeh,a Farhad Panahia*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A green and efficient oneꢀpot process to achieve 5ꢀarylꢀpyrimido[4,5ꢀb]quinolineꢀdione derivatives, using
a threeꢀcomponent reaction involving anilines, aldehydes and barbituric acids was developed. This
10 protocol was accomplished efficiently using Lꢀproline as catalyst in an aqueous medium to give the
corresponding products in high yield. Also, 2ꢀaminoꢀ4ꢀarylquinolineꢀ3ꢀcarbonitrile derivatives were
obtained, by replacing barbituric acid with malononitrile in the desigend protocol. The catalytic activity
of Lꢀproline in these reactions was tested over a set of aldehydes and amines, demonstrating that it is
reactive toward a variety of functionalities. The multicomponent reactions showed a good regioselectivity
15 and computational studies used to investigate this selectivity.
Quinoline derivatives are common in nature, and many of the
derivatives exhibit various biological activities, such as
antimalarial, antitumor, anthelmintic, antibacterial, antiasthmatic,
and antiplatelet.12 Due to these useful pharmacophoric properties,
50 they were extensively studied.13 In view point of synthetic, MCRs
are known as an important strategy to extend the structural
diversity of quinolines.14 In this regard, the development of new
multicomponent protocols for the synthesis of new quinolineꢀ
incorporating heterocycles have attracted considerable interest in
55 the recent years.15
Moreover, pyrimido[4,5ꢀb]quinoline derivatives are of great
interest because of their biological activities including
antimalarial effects, antibacterial property, analgesic and
antitumor activities.16 They are also attractive for the synthesis of
Introduction
Recent advances in application of organocatalysts in organic
reactions have provided a green approach for efficient synthesis
of
a
wide range of molecules.1 Also, application of
20 organocatalysts in organic transformations due to their unique
characteristics, has been enormously considered.2 Utilizing
organic catalysts instead of inorganic Lewis and protic acids have
some advantages including, the possibility of application of acidꢀ
sensitive substrates in reactions and the fact that substrates
25 bearing basic functional groups or electronꢀdonating substituents
that are prone to capture the acidic catalysts do not affect the
reaction results.3 One of the most important classes of smallꢀ
molecule organocatalysts are amino acids, which are widely used
as catalyst in organic reactions in recent years.4 Among them, Lꢀ
30 proline and its derivatives have shown considerable catalytic
efficiency in different reactions.5 Lꢀproline, also has been used as
catalyst in different multicomponent reactions (MCRs), and the
studies have shown that this catalyst, efficiently promoted these
protocols.6ꢀ8
60 electroluminescent materials, because they exhibit
a high
fluorescence activity.17 It is noteworthy that, pyrimido[4,5ꢀ
b]quinolines can be synthesized using MCRs from a pyrimidine
starting
azapodophyllotoxins as
material.18
Researches
have
shown
that,
a
dihydropyrimidine analogue of
65 pyrimido[4,5ꢀb]quinolines has a antitumor activity by inhibition
of DNA topoisomerase II enzyme. This category of compounds
for the first time have been synthesized by Takeya et al. in a three
step process.19 In the subsequent studies, this class of compound
have been synthesized using a MCR between aldehydes, anilines,
70 and tetronic acid.7,8,20 Aknin et al. have used from barbituric acid
instead of tetronic acid to synthesis 5ꢀarylpyrimido[4,5ꢀ
b]quinolineꢀ2,4(1H,3H)ꢀdione derivatives.21 However, this
method is much less efficient for the synthesis of 5ꢀ
arylpyrimido[4,5ꢀb]quinolineꢀ2,4(1H,3H,5H,10H)ꢀdione
35 In multicomponent approaches, complex products and
biologically active molecules are synthesized from readily
available starting materials in a single step process. From this
point of view, MCRs have emerged as green and powerful tools
in organic synthesis and drug discovery.9,10 Also, in MCRs, by
40 selecting the different starting materials
a new class of
compounds can be synthesized which may show interesting
properties.11 Organocatalystꢀcatalyzed MCRs and the use of
environmentally benign solvent and reagents are particularly
attractive, because they incorporate many of the green chemistry
45 principles.
75 derivatives. In the current study, we would like to report a green
and efficient combinatorial approach for oneꢀpot and
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regioselective synthesis of 5ꢀarylpyrimido[4,5ꢀb]quinolineꢀ
2,4(1H,3H,5H,10H)ꢀdiones using reaction of anilines, aldehydes
and barbituric acids. This MCR was accomplished in refluxing
(Table 1, entry 12). It observed that further increase of the
catalyst loading to 25 mol% has no obvious influence on the
reaction yield (Table 1, entry 13). Thus, 20 mol % of Lꢀproline in
water and in the presence of a catalytic amount of Lꢀproline. In 40 water is sufficient to catalyze this reaction. Under the optimized
5
the other part of this study, malononitrile was used instead of
barbituric acid, resulting the production of 2ꢀaminoꢀ4ꢀ
arylquinolineꢀ3ꢀcarbonitrile derivatives.
reaction conditions (refluxing water and 20 mol% catalyst
loading of Lꢀproline), a series of 5ꢀarylpyrimido[4,5ꢀb]quinolineꢀ
2,4(1H,3H,5H,10H)ꢀdione derivatives (4bꢀ4k) were synthesized
and the results are summarized in Table 2.
Results and discussion
45 Table 2. The Products of Threeꢀcomponent Reaction of Anilines,
Aldehydes and Barbituric Acids in the Presence of Lꢀproline as Catalyst
in Watera
Synthesis of 5ꢀarylꢀpyrimido[4,5ꢀb]quinolineꢀdiones
10 To obtain proper conditions for the designed protocol based on
the reaction of 4ꢀOMeꢀaniline (1a), 3ꢀNO2ꢀbenzaldehyde (2a),
and barbituric acid (3a) as a model substrate, we checked
different catalysts, solvents and temperatures and the results of
this study are depicted in Table 1.
15 Table 1. Optimization of ThreeꢀComponent Coupling Reaction between
Benzaldehyde, Anilines, and Barbituric Acidsa
Entry Catalyst (mol%)
Solvent Temp (°C) Time (h) Yield of 4a
(%)b
1
2
3
4
5
ꢀ
EtOH
EtOH
EtOH
EtOH
EtOH
reflux
reflux
reflux
reflux
reflux
24
24
24
24
5
12
12
12
5
6
5
12
5
2
0
0
0
H3PW12O40 (2)
PTSA (50)
CF3CO2H (50)
Lꢀproline (20)
0
85
86
55
89c
81
51
59
48
81
87
6
7
8
Lꢀproline (20)
Lꢀproline (20)
Lꢀproline (20)
Lꢀproline (20)
Lꢀproline (20)
Lꢀproline (20)
Lꢀproline (15)
Lꢀproline (25)
EtOH
H2O
MeOH
CH2Cl2
CH3CN
ꢀ
r.t.
reflux
reflux
reflux
reflux
80
9
10
11
12
13
EtOH
EtOH
reflux
reflux
a Reaction conditions: Aniline (1 mmol), aldehyde (1 mmol), barbituric
50 acid (1 mmol), Lꢀproline (20 mol%) and H2O (2 mL).
a Reaction conditions: 4ꢀOMeꢀaniline (1 mmol), 3ꢀNO2ꢀbenzaldehyde (1
mmol), barbituric acid (1 mmol) and solvent (5 mL). b The yield of
20 isolated products. c 2 mL of H2O was used.
As clearly shown in Table 2, this multicomponent approach can
be used for both aromatic aldehydes with electronꢀwithdrawing
and electronꢀdonating groups. Similarly, heterocyclic aldehydes
can be applied under optimized conditions. Furthermore, a wide
55 range of aromatic amines were used successfully in this reaction
with excellent results.
Accordingly, we have been able to prepare a library of 5ꢀ
arylpyrimido[4,5ꢀb]quinolineꢀ2,4(1H,3H,5H,10H)ꢀdiones using
barbituric acid, aromatic aldehydes, and anilines under green
60 conditions. In this protocol, the products are separated from the
reaction mixture by simple filtration, because they are not soluble
in water and ethanol, while Lꢀproline and starting materials are
soluble. Consequently, after completion of reactions, by a simple
filtration and washing with water and ethanol, the pure products
65 can be obtained.
It was found that, when the reaction was carried out without any
catalysts no product was observed even after 24 h (Table 1, entry
1). To obtain desired product (4a), we tested the reaction using
some different Brønsted and Lewis acids (Table 1, entries 2ꢀ4).
25 As shown that, the use of these catalysts, led to the production of
any product after 24 h. Thus, Lꢀproline as the best catalyst was
tested for this reaction. In the presence of 20 mol% of Lꢀproline
compound 4a was isolated in 85% yield after only 5 h.
Performing the reaction in the presence of Lꢀproline at r.t.
30 resulted the production of 4a in lower yield (Table 1, entry 6).
Subsequently, the effect of solvent was examined and MeOH,
CH2Cl2 and CH3CN showed no superiority to EtOH as solvents
but in H2O a good yield of product was observed after 12 h
(Table 1, entry 7ꢀ10). We also investigated the amount of Lꢀ
35 proline required for this reaction and it was observed that with
decreasing the amount of catalyst, the yields also decreased
To extend our strategy further, we used from cyclohexanone
instead of aldehyde in this protocol. As
a result, spiroꢀ
pyrimido[4,5ꢀb]quinolineꢀdione derivatives were synthesized in
2
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good yield (Scheme 1). We could not obtain any product from
other ketones under optimized conditions.
The interest in orthoꢀaminocarbonitriles is related to the wide
scope of their biological activities and applications as precursor
30 for the synthesis of novel heterocyclic compounds.22 So, in this
part of study, we decided to investigate the reactions of
malononitrile with aldehydes and anilines using Lꢀproline as
catalyst in aqueous media. This reaction is resulted in the
production of 2ꢀaminoꢀ4ꢀarylquinolineꢀ3ꢀcarbonitrile derivatives.
35 As a control experiment, aniline (2a) and 4ꢀnitroꢀbenzaldehyde
(2b) were reacted with malononitrile (5) under optimized
conditions (Lꢀproline 20 mol% and refluxing H2O) and 2ꢀaminoꢀ
4ꢀ(4ꢀnitrophenyl)quinolineꢀ3ꢀcarbonitrile (6a) was produced with
89% isolated yield after 12 h (Scheme 3). As a result of this
40 experiment it was revealed that under aforementioned conditions
an oxidation process was also happened and so 2ꢀaminoꢀ4ꢀarylꢀ
quinolineꢀ3ꢀcarbonitrile product is obtained while the 2ꢀaminoꢀ
1,4ꢀdihydroꢀ4ꢀarylꢀquinolineꢀ3ꢀcarbonitrile is expected as
product.
Scheme 1 Synthesis of spiroꢀpyrimido[4,5ꢀb]quinolineꢀdiones using
threeꢀcomponent reaction of amines, barbituric acid and cyclohexanone
using Lꢀproline in aqueous media.
5
According to the literature,7 we proposed the following
mechanism for the reaction (Scheme 2). Activation of the
aldehyde is achieved by Lꢀproline. Simultaneously, Lꢀproline as
10 Brønsted acid/base assists the enolization of the barbituric acid.
Barbituric in enol form is reacted with adduct I to form
intermediate II. Intermediate II can lose a Lꢀproline molecule and
so barbiturate III as an unsaturated carbonyl compound is
generated (this adduct was isolated from the reaction mixture
15 before completion of the reaction). On the other hand, Lꢀproline
can activate the adduct III to undergo in reaction with aniline,
45
resulting in the production of IV and
V intermediates.
Scheme 3 The threeꢀcomponent reaction of aniline, 4ꢀNO2ꢀbenzaldehyde
and malononitrile using Lꢀproline catalyst in refluxing water. Reaction
conditions: each of starting materials 1 mmol and solvent 2 mL.
Intermediate V, subsequently undergoes in a intramolecular
reaction to give the desired product. It is noteworthy that, the
20 compounds were obtained as recemic. Although, Lꢀproline plays
a key role in this reaction but it does not affect in the generation
of chiral center and so the stereoselectivity does not occur.
The model reaction was also investigated under other conditions.
50 It observed that, increasing the amount of catalyst (25 mol%), did
not have any effect on the reaction progress and also type of
product. Moreover, decreasing the amount of catalyst to 15 and
10 mol% decreased the yield of product to 85 and 73%,
respectively. Although, the yield of 6a in EtOH was comparable
55 with water (12 h, 91%), but water was selected as a green solvent
for this reaction. To determine the scope of the designed protocol,
a number of commercially available aldehydes and amines were
condensed with malononitrile under optimized reaction
conditions, and the results are summarized in Table 3.
60 As shown in Table 3, both electronꢀdeficient and electronꢀrich
aromatic aldehydes were applicable to the reaction, affording the
products in excellent yields. In addition, the existence of electronꢀ
donating groups on aromatic amines decreased the reaction times
and also increased the yield of products.
Scheme 2 The proposed mechanism for oneꢀpot threeꢀcomponent
25 synthesis of 5ꢀarylꢀpyrimido[4,5ꢀb]quinolineꢀdiones using Lꢀproline as
catalyst
Synthesis of 2ꢀaminoꢀ4ꢀarylquinolineꢀ3ꢀcarbonitrile
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Table 3. Lꢀproline Catalyzed ThreeꢀComponent Coupling Reaction of
Amines and Aldehydes with Malononitrile in Watera
Fig. 1 Two predictable products from threeꢀcomponent reaction of
aldehydes, barbituric acids and mꢀsubstituted anilines
30 In these MCRs only one product is produced.7 The results of
NMR studies demonstrated that, the generation of compound A
or B not dependent to electron deficiency and electron donating
nature of G group. When G is an electron deficient group (such
as –NO2), the obtained product is only B and when G is an
35 electron donating group (–OH and –OMe) major product is B,
while a little amount of A (less than 10% using GC yield for –OH
group) was also produced. These observations can be explained
using NPA calculations23, thermodynamics and steric hindrance
effects. To investigate the nucleophilic nature of these positions
40 (1 and 2), considering G as an electronꢀwithdrawing or electronꢀ
donating group, NPA calculations were accomplished on 3ꢀ
nitroaniline and 3ꢀhydroxyaniline (Figure 2). The charges
indicated that in both 3ꢀnitroaniline and 3ꢀhydroxyaniline, 2 is
more reactive position than 1. Activation of both positions by
45 electron donating groups can justify the production of some
amount of product B.
Reaction condition: amine (1 mmol), aldehyde (1 mmol), malononitrile (1
mmol) and refluxing H2O (2 mL).
5
As shown in Table 3, in most cases, the MCR afforded 2ꢀaminoꢀ
4ꢀarylquinolineꢀ3ꢀcarbonitrile products with high yield (> 83%).
The reaction between o, m and pꢀnitrobenzaldehyde and 4ꢀ
methoxyaniline with malononitrile afforded up to 86% yield of
Fig. 2 The NPA charges at the MP2/6ꢀ31*G(d,p) level
On the other hand, thermodynamics and steric hindrance effects
50 suggest that the product B is more stable than A. The normalized
structures
of
8ꢀmethoxyꢀ5ꢀ(4ꢀnitrophenyl)pyrimido[4,5ꢀ
10 corresponding products (compound 6b, 6c and 6d). In this
protocol we also observed a good regioselectivity for mꢀ
substituted anilines. For example a high regioselectivity was
obtained for 3ꢀNitroꢀ and 3ꢀmethoxyꢀaniline (compound 6f and
6j). Using pꢀbromoꢀ and pꢀchloroꢀaniline, the 2ꢀaminoꢀ4ꢀ
15 arylquinolineꢀ3ꢀcarbonitrile products were obtained with the
excellent isolated yields (compounds 6g and 6h). The reaction of
1Hꢀindoleꢀ3ꢀcarbaldehyde and pꢀmethoxyaniline afforded 2ꢀ
aminoꢀ4ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ6ꢀmethoxyquinolineꢀ3ꢀcarbonitrile with
91% yield (compound 6i). No product was observed in case of
20 using ketones. The reaction pathway for this MCR is proposed
based on reaction mechanism in Scheme 2, while here barbituric
acid is replaced by malononitrile.
b]quinolineꢀ2,4(1H,3H,5H,10H)ꢀdione (4m) and 6ꢀmethoxyꢀ5ꢀ(4ꢀ
nitrophenyl)pyrimido[4,5ꢀb]quinolineꢀ2,4(1H,3H,5H,10H)ꢀdione
(4m′) are shown in Fig. 3. It seems that in compound 4m′ there is
55 a steric hindrance between –OMe group and aryl ring and this
instability may be one of the key factors in the regioselectivity of
these reactions.
Regioselectivity and product selectivity of reactions
When an aniline compound containing a functional group in the
25 meta position to –NH2 is used in the reaction, the production of
two products are expected (Figure 1).
Fig. 3 The optimized structure of compounds 4m and 4m′.
60 A partial of 1H NMR spectra of compounds 4j and 4k are shown
in Fig 4. A singlet at 6.83 and two doublets at 7.05 and 7.28 ppm
4
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mark the H1, H3 and H2 hydrogens of compound 4j, respectively.
7.87 ppm show the Ha, Hc and Hb hydrogens of compound 4k,
respectively, which is only expected for this molecule. Ha in
aniline ring of compound 4k appears at higher chemical shift of
8.21 ppm due to neighboring electronegative –NO2 group.
In aniline ring of compound 4j, H1 appears at lower chemical
shift due to the presence of –OH group. This pattern of peaks is
only possible to compound 4j and not the other regioisomer. Also
for compound 4k, a singlet at 8.21 and the doublets at 8.03 and
5
10
Fig. 4 Chemical shifts (250 MHz) of the aniline ring protons in compounds 4j (left) and 4k (right).
rather than the amino group.24 Also, the following equilibrium
Also, there are open questions with respect to the production of
two different products under identical conditions when only 25 has been predicted for 3ꢀaminocarbonitrile moiety in acidic
15 malononitrile is replaced with barbituric acid. As shown in Figure
5, in the presence of Lꢀproline catalyst and under refluxing water
condition, compound 6′ is converted to 6, while this process did
not work for compound 4 and so compound 4′ is not produced. It
seems that, these observations are related to special properties of
20 3ꢀaminocarbonitrile unit in the structure of compound 6.
media.25 In fact in acidic environment there is equilibrium
between nitrilum ion and iminium ion (Scheme 4).
Scheme 4 The nitrilumꢀiminium equilibrium in 3ꢀaminocarbonitrile
30 Considering the aerobic oxidative aromatization of Hantzsch 1,4ꢀ
dihydropyridines,26 it seems that the nitrilumꢀiminium
equabilirum has an important role in oxidation process of
compound 6′. In the presence of Lꢀproline 2ꢀaminoꢀ1,4ꢀdihydroꢀ
4ꢀarylꢀquinolineꢀ3ꢀcarbonitrile can be protonated to produce
35 corresponding nitrilum ion. The nitrilum ion is in equilibrium
with corresponding iminium ion. We believe that, this
equilibrium will create an intermediate, so that oxidation would
happen easily under reaction conditions.
Fig. 5
Conclusions
In 3ꢀaminocarbonitrile unit, the basic site is the cyano group
40 In summary, we have developed a convenient, green and efficient
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procedure for the regioselective synthesis of 5ꢀarylꢀpyrimido[4,5ꢀ
b]quinolineꢀdione and 2ꢀaminoꢀ4ꢀarylquinolineꢀ3ꢀcarbonitrile
derivatives using the threeꢀcomponent coupling reaction of
aromatic amines, aldehydes, and barbituric acids/malononitrile. A
variety of these compounds were produced in single step by use
of different starting materials with good to excellent yields.
Therefore, a new category of biologically active compounds for
applications in medicinal chemistry were synthesized. While, Lꢀ
proline as an environmentally friendly organocatalyst can
150.6. Anal. Cal. C18H14N4O5 (366.33): C, 59.02; H, 3.85; N,
15.29. Found: C, 59.25; H, 3.94; N, 15.43.
7ꢀmethoxyꢀ5ꢀ(2ꢀnitrophenyl)pyrimido[4,5ꢀb]quinolineꢀ
2,4(1H,3H,5H,10H)ꢀdione (4b)
60 Yield: 89%, white solid, mp: 183ꢀ190°C. IR (KBr): 3742, 3433,
5
2932, 2631, 1690, 1510, 1366, 1258, 1173, 1034, 826, 779, 548,
1
440 cmꢀ1. H NMR (250 MHz, DMSOꢀd6/TMS): δ = 3.73 (s, 3
H), 6.07 (s, 1 H), 6.95ꢀ7.01 (m, 2 H), 7.21ꢀ7.28 (m, 3 H), 7.42 (t,
J = 7.9 Hz, 2 H), 10.03 (s, 3 NH). 13C NMR (62.9 MHz, DMSOꢀ
65 d6/TMS): δ = 55.4, 56.0, 90.0, 114.8, 123.1, 123.6, 125.5, 125.9,
129.5, 130.5, 137.6, 149.9, 150.3, 164.3. Anal. Cal. C18H14N4O5
10 catalyze these MCRs in aqueous media, efficiently.
(366.33): C, 59.02; H, 3.85; N, 15.29. Found: C, 59.17; H, 3.93;
N, 15.38.
Experimental section
Chemicals were purchased from Merck and Aldrich chemical
companies. All the chemicals and solvents were used as received
without purification. For recording 1HNMR and 13C NMR spectra
15 we used Brucker (250 MHZ) Avance DRX was used and samples
were dissolved in pure deuterated DMSOꢀd6 solvent with
tetramethylsilane (TMS) as internal standard. Mass spectra were
5ꢀ(anthracenꢀ10ꢀyl)ꢀ7ꢀmethoxyꢀ2ꢀthioxoꢀ2,3ꢀ
70 dihydropyrimido[4,5ꢀb]quinolinꢀ4(1H,5H,10H)ꢀone (4c)
Yield: 91%, red solid, mp: >370°C. IR (KBr): 3742, 3117, 2924,
1744, 1674, 1535, 1520, 1458, 1427, 1381, 1304, 1150, 787, 718,
517, 455 cmꢀ1. 1H NMR (250 MHz, DMSOꢀd6/TMS): δ = 3.56 (s,
3 H), 6.82 (s, 1 H), 7.45ꢀ7.55 (m, 5 H), 7.94 (d, J = 8.9 Hz, 3 H),
75 8.11 (d, J = 7.6 Hz, 3 H), 8.64 (s, 1 NH), 9.00 (s, 2 NH). 13C
NMR (62.9 MHz, DMSOꢀd6/TMS): δ = 114.9, 123.9, 125.0,
125.5, 125.6, 126.4, 127.7, 128.3, 128.7, 129.0, 129.3, 130.4,
152.3, 158.3, 160.6. Anal. Cal. C26H19N3O2S (437.51): C, 71.38;
H, 4.38; N, 9.60; S, 7.33. Found: C, 71.46; H, 4.49; N, 9.73; S,
80 7.21.
7ꢀbromoꢀ5ꢀ(4ꢀhydroxyphenyl)ꢀ2ꢀthioxoꢀ2,3ꢀ
dihydropyrimido[4,5ꢀb]quinolinꢀ4(1H,5H,10H)ꢀone (4d)
Yield: 88%, orange solid, mp: 335ꢀ339°C. IR (KBr): 3742, 3194,
recorded on
a FINNIGANꢀMAT 8430 mass spectrometer
operating at 70 eV. FTꢀIR spectroscopy (Shimadzu FTꢀIR 8300
20 spectrophotometer), was employed for characterization of the
compounds. Melting points were determined in open capillary
tubes in a Barnstead Electrothermal 9100 BZ circulating oil
melting point apparatus. The reaction monitoring was
accomplished by TLC on silica gel PolyGram SILG/UV254
25 plates.
General procedure for the synthesis of 5ꢀarylꢀpyrimido[4,5ꢀ
b]quinolineꢀdione derivatives
1690, 1658, 1643, 1612, 1604, 1443, 1404, 1281, 1211, 1165,
85 980, 810, 633, 517, 490 cmꢀ1. 1H NMR (250 MHz, DMSOꢀ
d6/TMS): δ = 5.66 (s, 1 H), 6.55 (d, J = 8.6 Hz, 1 H), 6.81 (m, 2
H), 7.64 (q, J = 6.7, 2.0 Hz, 1 H), 7.91 (d, J = 0.6 Hz, 1 H), 8.30
(q, J = 7.1, 1.8 Hz, 2 H), 9.70 (s, 1 OH), 11.98 (s, 1 NH), 12.09
(s, 1 NH), 12.18 (s, 1 NH). Anal. Cal. C17H12BrN3O2S (402.27):
90 C, 50.76; H, 3.01; N, 10.45; S, 7.97. Found: C, 50.88; H, 3.12; N,
In a conical flask (10 mL), a mixture of aromatic amine
compound (1 mmol), barbituric acid (0.13 g, 1 mmol), aldehyde
30 (1 mmol), and Lꢀproline (0.05 g, 20 mol%) in refluxing H2O (2
mL) was stirred for the time indicated in Table 2. After
completion of the reaction as confirmed by TLC, the reaction
mixture was cooled to r.t. The precipitate was collected by
filtration and washed with H2O (10 mL) and EtOH (5 mL) to
35 afford the pure product (Table 2).
10.57; S, 8.03.
9ꢀmethoxyꢀ5ꢀ(thiophenꢀ2ꢀyl)ꢀ2ꢀthioxoꢀ2,3ꢀ
dihydropyrimido[4,5ꢀb]quinolinꢀ4(1H,5H,10H)ꢀone (4e)
Yield: 92%, yellow solid, mp: 310ꢀ312°C. IR (KBr): 3857, 3742,
General procedure for the synthesis of 2ꢀaminoꢀ4ꢀ
arylquinolineꢀ3ꢀcarbonitrile derivatives
95 3117, 2291, 1744, 1674, 1512, 1458, 1396, 1304, 1219, 1142,
741, 509 cmꢀ1. 1H NMR (250 MHz, DMSOꢀd6/TMS): δ = 2.49 (s,
1 H), 3.30 (s, 3 H), 7.35ꢀ7.39 (m, 2 H), 8.22 (d, J = 3.9 Hz, 2 H),
8.33 (q, J = 5.1, 1.1 Hz, 2 H), 8.58 (s, 1N H), 12.36 (s, 1 NH),
12.38 (s, 1 H). 13C NMR (62.9 MHz, DMSOꢀd6/TMS): δ = 111.7,
100 128.7, 136.6, 143.2, 146.4, 146.7, 160.8, 161.7, 178.3. Anal. Cal.
C16H13N3O2S2 (343.423): C, 55.96; H, 3.82; N, 12.24; S, 18.67
To a mixture of aromatic amine (1 mmol), aldehyde (1 mmol),
and malononitrile (1 mmol) in water (2 mL), Lꢀproline catalyst
40 (0.05 g, 20 mol%) was added and stirred at refluxing temperature
of H2O for the time specified in Table 3. The reaction was
followed by TLC. Upon completion of the reaction, the mixture
was cooled down to room temperature and filtered. Then the
precipitate was washed with H2O (10 mL) and EtOH (5 mL) in
45 order to obtain pure product.
found: C, 55.99; H, 3.89; N, 12.33; S, 18.60.
5ꢀphenylpyrimido[4,5ꢀb]quinolineꢀ2,4(1H,3H,5H,10H)ꢀdione
(4f)
105 Yield: 89%, white solid, mp: 225ꢀ230°C. IR (KBr): 3873, 3742,
Spectral data of synthesized compounds
3341, 3017, 1692, 1620, 1489, 1404, 1288, 1227, 1150, 779, 741,
687, 556 cmꢀ1. 1H NMR (250 MHz, DMSOꢀd6/TMS): δ = 5.90 (s,
1 H ), 6.94 (d, J = 2.5 Hz, 1 H), 7.01 (s, 1 H), 7.15 (d, J = 3.5 Hz,
2 H), 7.22 (d, J = 5.5 Hz, 2 H), 7.47 (d, J = 7.6 Hz, 2 H), 8.05 (d,
110 J = 3.5 Hz, 2 H), 10.06 (s, 2 NH), 11.22 (s, 1N H). 13C NMR
(62.9 MHz, DMSOꢀd6/TMS): δ = 45.4, 58.8, 119.7, 123.6, 124.4,
126.6, 127.4, 129.4, 144.3, 150.6, 167.7. Anal. Cal. C17H13N3O2
(291.304): C, 70.09; H, 4.50; N, 14.42. Found: C, 70.17; H, 4.56;
N, 14.51.
7ꢀmethoxyꢀ5ꢀ(3ꢀnitrophenyl)pyrimido[4,5ꢀb]quinolineꢀ
2,4(1H,3H,5H,10H)ꢀdione (4a)
Yield: 89%, white solid, mp: 238ꢀ240°C. IR (KBr): 3433, 1690,
50 1612, 1512, 1404, 1342, 1096, 818, 563, 463 cmꢀ1. 1H NMR (250
MHz, DMSOꢀd6/TMS): δ = 3.73 (s, 3 H), 6.04 (s, 1 H), 6.99 (q, J
= 6.9, 2.8 Hz, 2 H), 7.23 (q, J = 6.9, 1.9 Hz, 2 H), 7.46 (d, J = 5.2
Hz, 2 H), 7.80 (s, 1 H), 7.92 (t, J = 2.9 Hz, 1 H), 10.16 (s, 2 NH).
13C NMR (62.9 MHz, DMSOꢀd6/TMS): δ = 30.7, 55.4, 90.2,
55 114.8, 119.8, 121.0, 123.9, 124.6, 129.0, 133.8, 147.5, 147.7,
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

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6,9ꢀdimethoxyꢀ5ꢀ(3ꢀnitrophenyl)pyrimido[4,5ꢀb]quinolineꢀ
2,4(1H,3H,5H,10H)ꢀdione (4g)
149.9, 150.1, 150.6, 153.0, 161.5, 163.1, 192.0. Anal. Cal.
C17H11ClN4O4 (370.747): C, 55.07; H, 2.99; N, 15.11. Found: C,
55.14; H, 3.03; N, 15.19.
8'ꢀhydroxyꢀ1'Hꢀspiro[cyclohexaneꢀ1,5'ꢀpyrimido[4,5ꢀ
65 b]quinoline]ꢀ2',4'(3'H,10'H)ꢀdione (4l)
Yield: 90%, green solid, mp: 185ꢀ190°C. IR (KBr): 3842, 3742,
2932, 2816, 2353, 1697, 1566, 1520, 1458, 1404, 1342, 1227,
1
5
1042, 787, 679, 532 cmꢀ1. H NMR (250 MHz, DMSOꢀd6/TMS):
δ = 2.48 (s, 3 H), 4.31 (s, 3 H), 5.22 (s, 1 H), 6.34 (s, 1 H), 6.45
(s, 1 H), 7.51 (d, J = 29.1 Hz, 1 H), 7.73 (s, 1 H), 8.10 (d, J =
20.3 Hz, 2 H), 10.12 (s, 1 NH), 11.17 (s, 2 NH). 13C NMR (62.9
MHz, DMSOꢀd6/TMS): δ = 44.6, 52.2, 55.2, 55.7, 55.9, 98.3,
Yield: 85%, white solid, mp: 206ꢀ210°C. IR (KBr): 3476, 3020,
1705, 1562, 1470, 1393, 1323, 1250, 1080, 991, 856, 795, 764,
1
656, 629, 544, 525. H NMR (250 MHz, DMSOꢀd6/TMS): δ =
1.03 (t, J = 7.0 Hz, 1 H), 1.84ꢀ1.95 (m, 4 H), 2.23 (t, J = 6 Hz, 1
10 113.1, 113.6, 121.1, 123.1, 129.2, 135.3, 137.5, 140.0, 144.6, 70 H), 3.18 (q, J = 15.1, 7.8 Hz, 2 H), 3.43 (t, J = 7.3 Hz, 1 H), 4.24
147.5, 150.5, 151.3, 169.3, 206.4. Anal. Cal. C19H16N4O6
(396.354): C, 57.58; H, 4.07; N, 14.14. Found: C, 57.66; H, 4.12;
N, 14.27.
2ꢀ(7ꢀmethoxyꢀ2,4ꢀdioxoꢀ1,2,3,4,5,10ꢀhexahydropyrimido[4,5ꢀ
15 b]quinolinꢀ5ꢀyl)benzaldehyde (4h)
Yield: 82%, yellow solid, 260ꢀ265°C. IR (KBr): 3842, 3742,
(d, J = 7.3 Hz, 1 H), 6.17 (q, J = 4.3, 2.3 Hz, 1 H), 6.66 (d, J =
1.5 Hz, 1 H), 6.86 (d, J = 8.25 Hz, 1 H), 9.93 (s, 2 NH), 10.25 (s,
1 OH), 12.80 (s, 1 NH). 13C NMR (62.9 MHz, DMSOꢀd6/TMS):
δ = 23.1, 27.8, 45.4, 59.0, 80.1, 88.9, 101.9, 151.1, 151.6, 152.8,
75 165.2, 165.4, 167.7, 167.8, 170.6. Anal. Cal. C16H17N3O3
(299.324): C, 64.20; H, 5.72; N, 14.04. Found: C, 64.29; H, 5.78;
3618, 3418, 2361, 2314, 1749, 1651, 1620, 1535, 1512, 1450,
1265, 1011, 517 cmꢀ1. 1H NMR (250 MHz, DMSOꢀd6/TMS): δ =
3.76 (s, 3 H), 6.02 (s, 1 H), 7.01 (q, J = 8.0, 2.4 Hz, 2 H), 7.26ꢀ
N, 14.11.
7'ꢀmethoxyꢀ1'Hꢀspiro[cyclohexaneꢀ1,5'ꢀpyrimido[4,5ꢀ
b]quinoline]ꢀ2',4'(3'H,10'H)ꢀdione (4m)
20 7.34 (m, 2 H), 7.41 (t, J = 7.6 Hz, 1 H), 7.50 (s, 1 H), 7.62 (d, J = 80 Yield: 75%, brightꢀgreen solid, mp: >350°C. IR (KBr): 3749,
7.4 Hz, 1 H), 8.79 (d, J=11.4 Hz, 1 H), 9.99 (s, 1 H), 11.64 (s, 3
NH). 13C NMR (62.9 MHz, DMSOꢀd6/TMS): δ = 30.4, 55.4,
95.4, 95.6, 114.4, 114.9, 122.6, 123.7, 124.4, 126.8, 127.1, 128.6,
133.0, 135.9, 144.4, 158.8, 163.0, 172.9, 193.5. Anal. Cal.
3125, 2924, 2824, 2569, 1690, 1589, 1512, 1373, 1288, 1265,
1211, 1156, 1026, 872, 826, 532 cmꢀ1. 1H NMR (250 MHz,
DMSOꢀd6/TMS): δ = 2.46 (s, 6 H), 3.64 (s, 4 H), 3.66 (s, 3 H),
6.49 (s, 2 H), 6.60 (s, 1 H), 11.08 (s, 3 NH). 13C NMR (62.9
25 C19H15N3O4 (349.34): C, 65.32; H, 4.33; N, 12.03. Found: C, 85 MHz, DMSOꢀd6/TMS): δ = 55.2, 114.4, 115.7, 140.7, 141.1,
65.44; H, 4.38; N, 12.15.
5ꢀ(2,6ꢀdichlorophenyl)ꢀ7ꢀmethoxypyrimido[4,5ꢀb]quinolineꢀ
2,4(1H,3H,5H,10H)ꢀdione (4i)
151.3, 151.6, 167.5. Anal. Cal. C17H19N3O3 (313.35: C, 65.16; H,
6.11; N, 13.41. found: C, 65.23; H, 6.18; N, 13.49.
2ꢀaminoꢀ4ꢀ(4ꢀnitrophenyl) quinolineꢀ3ꢀcarbonitrile (6a)
Yield: 89%, orange solid, mp: 98ꢀ100 °C. IR (KBr): 3842, 3742,
90 2206, 1744, 1651, 1520, 1458, 342, 1103, 934, 849, 687, 509 cmꢀ
Yield: 85%, cream solid, mp: 188ꢀ195°C. IR (KBr): 3742, 2978,
30 2824, 2615, 1705, 1628, 1512, 1474, 1430, 1381, 1250, 1211,
1080, 1011, 887, 779, 710, 656, 540, 432 cmꢀ1. H NMR (250
1
1
1. H NMR (250 MHZ, CDCl3/TMS): δ = 1.26 (s, 2 NH), 7.15ꢀ
MHz, DMSOꢀd6/TMS): δ = 3.64 (s, 3 H), 5.78 (s, 1 H), 6.81 (t, J
= 6.0 Hz, 2 H), 7.17 (d, J= 7.6 Hz, 1 H), 7.41 (q, J = 6.6, 0.6 Hz,
7.45 (m, 3 H), 7.81 (s, 1 H), 7.81ꢀ8.03 (m, 2 H), 8.29ꢀ8.34 (m, 2
H). 13C NMR (62.9 MHz, CDCl3/TMS): δ = 115.0, 119.5, 124.6,
127.7, 131.3, 135.7, 139.1, 140.7, 148.6, 152.6, 156.8, 160.5,
95 168.2. Anal. Cal. C16H10N4O2 (290.28): C, 66.20; H, 3.47; N,
19.30. Found: C, 66.28; H, 3.51; N, 19.38.
1 H), 7.46 (s, 1 H), 7.49 (d, J = 2.0 Hz, 1 H) , 8.11 (s, 3 NH). 13
C
35 NMR (62.9 MHz, DMSOꢀd6/TMS): δ = 55.3, 56.0, 114.6, 118.7,
124.5, 126.5, 127.8, 129.2, 130.7, 131.8, 133.0, 134.8, 135.7,
139.6, 147.3, 150.0, 150.8, 151.6, 153.9, 160.4, 161.7, 164.0.
Anal. Cal. C18H13Cl2N3O3 (390.22): C, 55.40; H, 3.36; N, 10.77.
2ꢀaminoꢀ6ꢀmethoxyꢀ4ꢀ(3ꢀnitrophenyl)
carbonitrile (6b)
quinolineꢀ3ꢀ
Yield: 89%, yellow solid, mp: 83ꢀ88 °C. IR (KBr): 3842, 3742,
100 3449, 3055, 1921, 1620, 1520, 1350, 1242, 1026, 826, 756, 548
cmꢀ1. 1H NMR (250 MHZ, CDCl3/TMS): δ = 3.74 (s, 2 NH), 3.85
(s, 3 H), 6.97 (t, J = 4.5 Hz, 1 H), 7.26ꢀ7.32 (m, 1 H), 7.65 (t, J =
7.8 Hz, 1 H), 8.21ꢀ8.27 (m, 2 H), 8.6 (s, 1 H), 8.7 (s, 1 H). 13C
NMR (62.9 MHz, CDCl3/TMS): δ = 55.5, 105.3, 114.5, 122.5,
105 123.2, 125.1, 129.7, 133.8, 138.2, 143.5, 148.7, 153.7, 154.7,
159.0, 167.2. Anal. Cal. C17H12N4O3 (320.3): C, 63.75; H, 3.78;
N, 17.49. Found: C, 63.82; H, 3.84; N, 17.55.
Found: C, 55.56; H, 3.39; N, 10.85.
40 8ꢀhydroxyꢀ5ꢀ(pyridinꢀ4ꢀyl)pyrimido[4,5ꢀb]quinolineꢀ
2,4(1H,3H,5H,10H)ꢀdione (4j)
Yield: 87%, yellow solid, mp: 285ꢀ289°C. IR (KBr): 3742, 3433,
2361, 1690, 1612, 1512, 1443, 1204, 787, 532 cmꢀ1. H NMR
1
(250 MHz, DMSOꢀd6/TMS): δ = 5.41 (s, 1 H), 6.83 (s, 1 H), 7.05
45 (d, J = 13.5 Hz, 1 H), 7.29 (d, J = 11.7 Hz, 1 H), 8.44 (d, J = 5.0
Hz, 2 H), 8.59 (d, J = 8.3 Hz, 2H), 9.62 (s, 2 H), 10.26 (s, 1 H),
11.12 (s, 1 H). 13C NMR (62.9 MHz, DMSOꢀd6/TMS): δ = 59.2,
89.6, 123.5, 124.2, 145.0, 150.6, 151.4, 160.3, 164.6, 164.7,
164.8, 164.9, 171.1. Anal. Cal. C16H12N4O3 (308.291): C, 62.33;
2ꢀaminoꢀ6ꢀmethoxyꢀ4ꢀ(4ꢀnitrophenyl)
carbonitrile (6c)
quinolineꢀ3ꢀ
110 Yield: 91%, yellow solid, mp: 133ꢀ137 °C. IR (KBr): 3449, 2901,
1512, 1335, 1242, 1096, 1034, 833, 748, 679, 548 cmꢀ1. 1H NMR
(250 MHZ, CDCl3/TMS): δ = 2.17 (s, 2 NH), 3.80 (s, 3 H), 6.96
(q, J = 6.8, 2.1 Hz, 1 H), 7.26ꢀ7.33 (m, 2 H) 8.04ꢀ8.08 (m, 1 H)
8.29ꢀ8.33 (m, 2 H) 8.6 (s, 1 H). 13C NMR (62.9 MHz,
115 CDCl3/TMS): δ = 55.5, 95.6, 101.4, 105.3, 114.5, 122.6, 124.0,
129.1, 138.1, 139.4, 143.6, 147.3, 154.8, 163.6. Anal. Cal.
C17H12N4O3 (320.3): C, 63.75; H, 3.78; N, 17.49. Found: C,
63.79; H, 3.81; N, 17.53.
50 H, 3.92; N, 18.17. Found: C, 62.45; H, 3.98; N, 18.26.
5ꢀ(4ꢀchlorophenyl)ꢀ8ꢀnitropyrimido[4,5ꢀb]quinolineꢀ
2,4(1H,3H,5H,10H)ꢀdione (4k)
Yield: 84%, white solid, mp: 300ꢀ305°C. IR (KBr): 3749, 3202,
3078, 2847, 2361, 1751, 1705, 1674, 1574, 1489, 1443, 1342,
55 1288, 1204, 1096, 1018, 802, 517, 424 cmꢀ1. 1H NMR (250 MHz,
DMSOꢀd6/TMS): δ = 4.23 (s, 1 H), 7.50 (dd, J = 7.9, 1.7 Hz, 2
H), 7.65 (d, J = 8.5 Hz, 2 H), 7.87 (dd, J = 6.6, 1.7 Hz, 1 H), 8.03
(d, J = 8.4 Hz, 1 H), 8.21 (s, 1 H), 10.72 (s, 1 H), 11.26 (s, 1 H),
11.41 (s, 1 H). 13C NMR (62.9 MHz, DMSOꢀd6/TMS): δ = 119.5,
60 127.6, 128.0, 128.8, 129.3, 129.8, 131.1, 131.4, 134.6, 136.7,
2ꢀaminoꢀ6ꢀmethoxyꢀ4ꢀ(2ꢀnitrophenyl)
quinolineꢀ3ꢀ
120 carbonitrile (6d)
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7

Green Chemistry
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2ꢀaminoꢀ4ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ7ꢀmethoxyquinolineꢀ3ꢀcarbonitrile
(6j)
Yield: 86%, brown solid, mp: 115ꢀ119 °C. IR (KBr): 3726, 3310,
2339, 2206, 1605, 1512, 1443, 1250, 1173, 1026, 833, 748, 525
cmꢀ1. 1H NMR (250 MHZ, CDCl3/TMS): δ = 1.97 (s, 1 NH), 2.10
(s, 1 NH), 3.79 (s, 3 H), 6.96 (s, 1 H), 7.06 (d, J = 9.1 Hz, 1 H),
7.18 (q, J = 1.5, 0.4 Hz, 1 H), 7.33ꢀ7.41 (m, 1 H), 7.50 (d, J = 9.1
Hz, 2 H), 7.80 (s, 1 H). Anal. Cal. C17H12N4O3 (320.3): C, 63.75;
H, 3.78; N, 17.49. Found: C, 63.75; H, 3.78; N, 17.49.
Yield: 83%, yellow solid, mp: 227ꢀ230 °C. IR (KBr): 3279, 2222,
1566, 1497, 1435, 1342, 1234, 1150, 802, 741, 610, 448 cmꢀ1. 1H
65 NMR (250 MHZ, DMSOꢀd6/TMS): δ = 2.48 (s, 1 NH), 3.38 (s, 3
H), 7.22ꢀ7.33 (m, 3 H), 7.54ꢀ7.57 (m, 1 H), 8.02 (q, J = 6.0, 3.0
Hz, 2 H), 8.50 (s, 1 H), 8.67 (s, 1 H). 13C NMR (62.9 MHz,
DMSOꢀd6/TMS): δ = 69.2, 106.2, 111.0, 113.0, 115.8, 116.0,
119.0, 122.5, 124.0, 126.6, 129.5, 133.2, 136.1, 149.2, 152.5,
5
2ꢀaminoꢀ6ꢀmethoxyꢀ4ꢀ(2ꢀmethoxyphenyl)
carbonitrile (6e)
quinolineꢀ3ꢀ
10 Yield: 84%, cream solid, mp: 72ꢀ76 °C. IR (KBr): 3842, 3726, 70 166.6, 168.4. Anal. Cal. C19H14N4O (314.34): C, 72.60; H, 4.49;
3040, 2222, 1651, 1582, 1366, 1250, 1165, 1011, 748, 610 cmꢀ1.
1H NMR (250 MHZ, CDCl3/TMS): δ = 1.2 (t, J = 3.5 Hz, 1 NH),
1.57ꢀ1.66 (m, 1 NH), 3.90 (s, 3 H), 3.93 (s, 3 H), 6.95ꢀ7.11 (m, 3
H), 7.27 (s, 1 H), 7.54ꢀ7.62 (m, 1 H) 8.18 (q, J = 7.4, 5.0 Hz, 1
15 H), 8.30 (d, J = 6.3 Hz, 1 H). 13C NMR (62.9 MHz, CDCl3/TMS):
δ = 55.9, 93.5, 100.7, 104.4, 111.5, 115.0, 117.2, 121.2, 124.3,
128.9, 136.5, 145.7, 154.5, 163.4, 166.7. Anal. Cal. C18H15N3O2
(305.33): C, 70.81; H, 4.95; N, 13.76. Found: C, 70.87; H, 4.99;
N, 13.82.
N, 17.82. Found: C, 72.69; H, 4.55; N, 17.89.
Acknowledgements
We acknowledge Shiraz University for partial support of this
work.
75 Notes and references
a Department of Chemistry, College of Sciences, Shiraz University, Shiraz,
71454, Iran. E-mail: khalafi@chem.susc.ac.ir, panahi@shirazu.ac.ir;
Fax: +98-711-2280926; Tel: +98-711-2282380
20 2ꢀaminoꢀ7ꢀnitroꢀ4ꢀ(4ꢀnitrophenyl)
(6f)
quinolineꢀ3ꢀcarbonitrile
† Electronic Supplementary Information (ESI) available: Copy of 1H
80 NMR and 13C NMR spectra of compounds. See DOI: 10.1039/b000000x/
Yield: 89%, yellow solid, mp: 159ꢀ163 °C. IR (KBr): 3842, 3742,
3449, 2353, 1690, 1574, 1520, 1350, 1203, 934, 671, 509 cmꢀ1.
1H NMR (250 MHZ, CDCl3/TMS): δ = 1.55 (s, 2 NH), 7.20 (t, J =
25 0.3 Hz 1 H), 7.83 (s, 1 H), 7.98ꢀ8.04 (m, 3 H), 8.30ꢀ8.35 (m, 2
H). 13C NMR (62.9 MHz, CDCl3/TMS): δ = 124.6, 131.3, 135.8,
140.1, 142.2, 151.7, 156.9, 159.2, 169.2. Anal. Cal. C16H9N5O4
(335.27): C, 57.32; H, 2.71; N, 20.89. Found: C, 57.32; H, 2.71;
1
E. M. McGarrigle, E. L. Myers, O. Illa, M. A. Shaw, S. L.
Riches and V. K. Aggarwal, Chem. Rev., 2007, 107, 5841; M.
Bartók, Chem. Rev., 2010, 110, 1663; Huang, K. Zhu, W. Wu,
Z. Jin and J. Ye, Chem. Commun., 2012, 48, 461; H. S. Rho, S.
H. Oh, J. W. Lee, J. Y. Lee, J. Chin and C. E. Song, Chem.
Commun., 2008, 1208; N. Tada, K. Hattori, T. Nobuta, T.
Miura and A. Itoh, Green Chem., 2011, 13, 1669.
85
90
N, 20.89.
2
S. L. Jain, A. Modak and A. Bhaumik, Green Chem., 2011, 13,
586; X. Liu, L. Lin and X. Feng, Acc. Chem. Res., 2011, 44,
574; Y. Wei and M. Shi, Acc. Chem. Res., 2010, 43, 1005.;
Takano and Y. Kohari, Chem. Commun., 2010, 46, 4827; F. –
M. Gautier, S. Jones and S. J. Martin, Org. Biomol. Chem.,
2009, 7, 229; Y. Wei, G. N. Sastry and H. Zipse, J. Am. Chem.
Soc., 2008, 130, 3473.
30 2ꢀaminoꢀ6ꢀbromoꢀ4ꢀ(4ꢀnitrophenyl) quinolineꢀ3ꢀcarbonitrile
(6g)
Yield: 92%, yellow solid, mp: 176ꢀ180 °C. IR (KBr): 3842, 3742,
2314, 1744, 1697, 1651, 1512, 1420, 1342, 1103, 841, 509 cmꢀ1.
1H NMR (250 MHZ, CDCl3/TMS): δ = 1.18 (s, 1 NH), 1.49ꢀ1.55
35 (m, 1 NH), 7.07 (q, J = 6.8, 2.0 Hz, 2 H), 7.19 (s, 1 H), 7.48 (q, J
= 6.5, 2.3 Hz, 1 H), 8.01 (t, J = 2.0 Hz, 2 H), 8.26 (dd, J = 6.9,
2.0 Hz, 2 H), 8.47 (s, 1 H). 13C NMR (62.9 MHz, CDCl3/TMS): δ
= 112.2, 120.2, 122.6, 124.1, 129.5, 132.4, 134.9, 140.0, 149.8,
157.7, 166.2. Anal. Cal. C16H9BrN4O2 (369.17): C, 52.05; H,
95
3
4
A. KhalafiꢀNezhad, A. Parhami, A. Zare, A. R. Moosavi Zare,
A. Hasaninejad and F. Panahi, Synthesis 2008, 617; A. J.
Pearson and S. Panda, Org. Lett., 2011, 13, 5548; T. K. Sen, S.
C. Sau, A. Mukherjee, A. Modak, S. K. Mandal and D. Koley,
Chem. Commun., 2011, 47, 1172; D. Kühbeck, G. Saidulu, K.
R. Reddy and D. D. Díaz, Green Chem., 2012, 14, 378.
D. Ma and Q. Cai, Acc. Chem. Res., 2008, 41, 1450; J. E.
Imbriglio, M. M. Vasbinder and S. J. Miller, Org. Lett., 2003,
5, 3741; D. B. Ramachary and C. F. Barbas III, Org. Lett.,
2005, 7, 1577; H. Yang and M. W. Wong, J. Org. Chem.,
2011, 76, 7399; A. Córdova, H. Sundén, M. Engqvist, I.
Ibrahem and J. Casas, J. Am. Chem. Soc., 2004, 126, 8914; A.
Córdova, W. Zou, I. Ibrahem, E. Reyes, M. Engqvist and W. –
W. Liao, Chem. Commun., 2005, 3586; D. B. Ramachary and
M. Kishor, Org. Biomol. Chem., 2008, 6, 4176; P. Li and H.
Yamamoto, Chem. Commun., 2009, 5412.
100
105
110
115
120
40 2.46; N, 15.18. Found: C, 52.10; H, 2.49; N, 15.24.
2ꢀaminoꢀ6ꢀchloroꢀ4ꢀ(4ꢀnitrophenyl) quinolineꢀ3ꢀcarbonitrile
(6h)
Yield: 89%, white solid, mp: 240ꢀ245 °C. IR (KBr): 3441, 3086,
2824, 2438, 2245, 1929, 1605, 1520, 1350, 1204, 1111, 1018,
1
45 856, 718, 610 cmꢀ1. H NMR (250 MHZ, CDCl3/TMS): δ = 1.24
(d, J = 3.5 Hz, 1 NH), 1.59 (t, J = 1.8 Hz, 1 NH), 7.26ꢀ7.52 (m, 4
H), 8.04ꢀ8.10 (m, 3 H). Anal. Cal. C16H9ClN4O2 (324.72): C,
59.18; H, 2.79; N, 17.25. Found: C, 59.23; H, 2.83; N, 17.31.
2ꢀaminoꢀ4ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ6ꢀmethoxyquinolineꢀ3ꢀcarbonitrile
50 (6i)
5
N. Kumaragurubaran, K. Juhl, W. Zhuang, A. Bøgevig and K.
A. Jørgensen, J. Am. Chem. Soc., 2002, 124, 6254; S.
Chandrasekhar, C. Narsihmulu, N. R. Reddy and S. S. Sultana,
Chem. Commun., 2004, 2450; H. Liu, L. Peng, T. Zhang and
Y. Li, New J. Chem., 2003, 27, 1159; N. N. Karade, S. V.
Gampawar, V. S. Shinde and W. N. Jadhav, Chin. J. Chem.,
2007, 25, 1686; A. S. Lee, K. ꢀW. Tsao, Y. ꢀT. Chang and S. ꢀ
F. Chu, Tetrahedron Lett. 2007, 48, 6790; G. Chen, Y. Wang,
H. He, S. Gao, X. Yang and X. Hao, Heterocycles 2006, 68,
2327; D. Kundu, A. Majee and A. Hajra, Chin. J. Chem.,
2008, 26, 1545; N. S. Chowdari, D. B. Ramachary, C. F.
Barbas III, Synlett 2003, 1906; M. S. Rasalkar, M. K. Potdar,
S. S. Mohile and M. M. Salunkhe, J. Mol. Catal. A: Chem.
2005, 235, 267; H. Ikishima, Y. Sekiguchi, Y. Ichikawa and
Yield: 91%, yellow solid, mp: 225ꢀ228 °C. IR (KBr): 3286, 2222,
1566, 1497, 1435, 1350, 1234, 1150, 795, 741, 610, 448 cmꢀ1. 1H
NMR (250 MHZ, DMSOꢀd6/TMS): δ = 2.48 (d, J = 1.8 Hz, 1
NH), 3.54 (s, 3 H), 7.25ꢀ7.30 (m, 3 H), 7.55 (q, J = 5.0, 1.0 Hz, 2
55 H), 8.02 (t, J = 1.0 Hz, 1 H), 8.50 (s, 1 H), 8.67 (d, J = 1.8 Hz, 2
H), 12.63 (s, 1 NH). 13C NMR (62.9 MHz, DMSOꢀd6/TMS): δ =
55.7, 102.4, 107.6, 111.0, 113.0, 119.0, 120.7, 122.6, 124.0,
133.3, 139.8, 150.7, 152.6, 163.8, 172.4. Anal. Cal. C19H14N4O
(314.34): C, 72.60; H, 4.49; N, 17.82. Found: C, 72.68; H, 4.54;
60 N, 17.88.
8
| Journal Name, [year], [vol], 00–00
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H. Kotsuki, Tetrahedron Lett. 2006, 62, 311; A. Paraskar and
A. Sudali, Tetrahedron 2006, 62, 5756.
16 A. B. A. ElꢀGazzar, H. N. Hafez, G. A. M. Nawwar, Eur. J.
Med. Chem. 2009, 44, 1427; H. I. Ali, N. Ashidab, T.
Nagamatsu, Bioorg. Med. Chem. 2008, 16, 922; H.I. Ali, K.
Tomita, E. Akaho, M. Kunishima, Y. Kawashima, T.
Yamagishi and H. Ikeya, Eur. J. Med. Chem. 2008, 43, 1376;
H. I. Ali, K. Tomita, E. Akaho, H. Kambara, S. Miura, H.
Hayakawa, N. Ashida, Y. Kawashima, T. Yamagishi, H.
Ikeya, F. Yoneda and T. Nagamatsu, Bioorg. Med. Chem.
2007, 15, 242; A. A. Joshi, C. L. Viswanathan, Bioorg. Med.
Chem. Lett. 2006, 16, 2613; Y. L. Chen, K. C. Fang, J. Y.
Sheu, S. L. Hsu and C. C. Tzeng, J. Med. Chem. 2001, 44,
2374.
17 Z. He, G. Milburn, A. Danel, A. Puchala, P. Tomasik, D.
Rasala, J. Mater. Chem. 1997, 7, 2323; Y. T. Tao, C. H.
Chuen, C. W. Ko and J. W. Peng, Chem. Mater. 2002, 14,
4256; C. H. Chuen and Y. T. Tao, Appl. Phys. Lett. 2002, 81,
4499; C. W. Ko and Y. T. Tao, Appl. Phys. Lett. 2001, 79,
4234.
18 Y. Chena, S. Wub, S. Tub, F. Shib, C. Lib, J. Heterocycl.
Chem. 2008, 45, 1243; D. –Q. Shi, L. –H. Niu, H. Yao and H.
Jiang, J. Heterocycl. Chem. 2009, 46, 237; J. Quiroga, A.
Hormaza, B. Insuasty, A. J. Ortíz, A. Sánchez, M. Nogueras,
J. Heterocycl. Chem. 1998, 35, 231; J. Quiroga, J. Trilleras, B.
Insuasty, R. Abonía, M. Nogueras and J. Cobo, Tetrahedron
Lett. 2008, 49, 2689; J. Quiroga, J. Trilleras, B. Insuasty, R.
Abonía, M. Nogueras, A. Marchal and J. Cobo, Tetrahedron
Lett. 2010, 51, 1107; X. –S. Wang, Q. Li, J. –R. Wu and M. –
M. Zhang, Synth. Commun., 2009, 39, 3069; N. G. Kozlov and
L. I. Basalaeva, Russ. J. Org. Chem., 2007, 43, 432.
6
A. Kumar, M. K. Gupta and M. Kumar, Green Chem., 2012,
14, 290; H. Jiang, R. Mai, H. Cao, Q. Zhu and X. Liu, Org.
Biomol. Chem., 2009, 7, 4943; S. M. Rajesh, B. D. Bala, S.
Perumal and J. C. Menéndez, Green Chem., 2011, 13, 3248; S.
Guo and Y. Yuan, Chin. J. Chem., 2010, 28, 818; J. Pandey,
N. Anand and R. P. Tripathi, Tetrahedron 2009, 65, 9350; C.
Mukhopadhyay, P. K. Tapaswi and R. J. Butcher, Tetrahedron
Lett. 2010, 51, 1797; S. ꢀB. Guo, S. ꢀX. Wang and J. ꢀT. Li,
Synth. Commun., 2007, 37, 2111.
C. Shi, J. Wang, H. Chen and D. Shi, J. Comb. Chem., 2010,
12, 430.
Y. Li, H. Chen, C. Shi, D. Shi and S. Ji, J. Comb. Chem.,
2010, 12, 231.
M. GonzalezꢀLopez and J. T. Shaw, Chem. Rev., 2009, 109,
164; A. Dömling, Chem. Rev., 2006, 106, 17; V. Nair, C.
Rajesh, A. U. Vinod, S. Bindu, A. R. Sreekanth, J. S. Mathen,
and L. Balagopal, Acc. Chem. Res., 2003, 36, 899; V. Nair, R.
S. Menon, A. T. Biju and K. G. Abhilash, Chem. Soc. Rev.,
2012, 41, 1050; V. Cerulli, L. Banfi, A. Basso, V. Rocca and
R. Riva, Org. Biomol. Chem., 2012, 10, 1255; A. Kalafiꢀ
Nezhad anf F. Panahi, Synthesis 2011, 984.
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
7
8
9
85
90
10 J. Yu, F. Shi, and L. –Z. Gong, Acc. Chem. Res., 2011, 44,
1156; A. Shaabani, A. Sarvary, S. Ghasemi, A. Hossein
Rezayan, R. Ghadari and S. W. Ng, Green Chem., 2011, 13,
582; A. Kumar and S. Sharma, Green Chem., 2011, 13, 2017;
J. –N. Tan, M. Li and Y. Gu, Green Chem., 2010, 12, 908; V.
Estévez, M. Villacampa and J. C. Menéndez, Chem. Soc. Rev.,
2010, 39, 4402.
11 I. Monfardini, J. –W. Huang, B. Beck, J. F. Cellitti, M.
Pellecchia and A. Do mling, J. Med. Chem., 2011, 54, 890;
O. N. Burchak, L. Mugherli, M. Ostuni, J. J. Lacapère and M.
Y. Balakirev, J. Am. Chem. Soc., 2011, 133, 10058.
12 R. Daoud, J. Desneves, L. W. Deady, L. Tilley, R. J. Scheper, 105
P. Gros and Elias Georges, Biochemistry, 2000, 39, 6094; T.
Suzuki, N. Fukazawa and K. Sanꢀnohe, W. Sato and O. Yano,
T. Tsuruo, J. Med. Chem., 1997, 40, 2047; R. Klingenstein, P.
Melnyk, S. R. Leliveld, A. Ryckebusch and C. Korth, J. Med.
Chem., 2006, 49, 5300; C. –C. Peng, J. L. Cape, T. Rushmore, 110
G. J. Crouch and J. P. Jones, J. Med. Chem., 2008, 51, 8000;
A. Lilienkampf, J. Mao, B. Wan, Y. Wang, S. G. Franzblau
and A. P. Kozikowski, J. Med. Chem., 2009, 52, 2109; V. K.
Zishiri, M. C. Joshi, R. Hunter, K. Chibale, P. J. Smith, R. L.
Summers, R. E. Martin and T. J. Egan, J. Med. Chem., 2011, 115
54, 6956.
13 H. V. Mierde, N. Ledoux, B. Allaert, P. V. D. Voort, R.
Drozdzak, D. D. Vos and F. Verpoort, New J. Chem., 2007,
31, 1572; T. G. Back and J. E. Wulff, Chem. Commun., 2002,
1710; S. Rousseaux, B. Liégault and K. Fagnou, Chem. Sci., 120
2012, 3, 244; H. Huang, H. Jiang, K. Chen and H. Liu, J. Org.
Chem., 2009, 74, 5476; D. S. Bose and R. K. Kumar,
Heterocycles 2006, 68, 549; X.ꢀS. Wang, M.ꢀM. Zhang, Z.ꢀS.
Zeng, D.ꢀQ. Shi, S.ꢀJ. Tu, X.ꢀY. Wei and Z.ꢀM. Zong, Chem.
Lett. 2005, 34, 1316; M. Hatano and K. Mikami, J. Am. Chem. 125
Soc., 2003, 125, 4704; Chae S. Yi, Sang Young Yun and Ilia
A. Guzei, J. Am. Chem. Soc., 2005, 127, 5782.
95
100
19 Y. Hitosuyanagi, M. Kobayashi, H. Morita, H. Itokawa and K.
Takeya, Tetrahedron Lett. 1999, 40, 9107.
20 C. Tratrat, S. GiorgiꢀRenault and H. –P. Husson, Org. Lett.
2002, 4, 3187; R. Labruère, P. Helissey, S. DesbèneꢀFinck,
and S. GiorgiꢀRenault, J. Org. Chem. 2008, 73, 3642.
21 Refꢀ1 K. Aknin, S. DesbèneꢀFinck, P. Helissey, S. Giorgiꢀ
Renault, Mol. Divers. 2010, 14, 123.
22 H. Wu, W. Lin, Y. Wan, H. –Q. Xin, D. –Q. Shi, Y. –H. Shi,
R. Yuan, R. –C. Bo and W. Yin, J. Comb. Chem. 2010, 12, 31;
Y. M. Litvinov, A. A. Shestopalov, L. A. Rodinovskaya and
A. M. Shestopalov, J. Comb. Chem., 2009, 11, 914; V.
Peesapati, K. Anuradha and B. S. Suresh J. Chem. Res., Synop.
2000, 10, 496; E. S. Kurbatov, V. V. Krasnikov and V. V.
Mezheritskii, Russ. J. Org. Chem. 2006, 3, 460.
23 M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A.
Robb, J.R. Cheeseman, V.G. Zakrzewski, J.A. Montgomery
Jr., R.E. Stratmann, J.C. Burant, S. Dapprich, J.M. Millam,
A.D. Daniels, K.N. Kudin, M.C. Strain, O. Farkas, J. Tomasi,
V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C.
Adamo, S. Clifford, J. Ochterski, G.A. Petersson, P.Y. Ayala,
Q. Cui, K. Morokuma, D.K. Malick, A.D. Rabuck, K.
Raghavachari, J.B. Foresman, J. Cioslowski, J.V. Ortiz, A.G.
Baboul, B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I.
Komaromi, R. Gomperts, R.L. Martin, D.J. Fox, T. Keith,
M.A. AlꢀLaham, C.Y. Peng, A. Nanayakkara, M.
Challacombe, P.M.W. Gill, B. Johnson, W. Chen, M.W.
Wong, J.L. Andres, C. Gonzalez, M. HeadꢀGordon, E.S.
Replogle, J.A. Pople, Gaussian98, A. 9 Revision, Gaussian,
Inc., Pittsburgh, PA, 2003.
14 S. –J. Tu, B. Jiang, R. –H. Jia, J. –Y. Zhang, Y. Zhang, C. –S.
Yao and F. Shi, Org. Biomol. Chem., 2006, 4, 3664; R. A.
Batey and D. A. Powell, Chem. Commun., 2001, 2362; X. –S. 130
Wang, J. Zhou, M. –Y. Yin, K. Yang and S. –J. Tu, J. Comb.
Chem., 2010, 12, 266; J. Akbari, A. Heydari, H. R. Kalhor and
S. A. Kohan, J. Comb. Chem., 2010, 12, 137.
15 S. Tu, C. Li, G. Li, L. Cao, Q. Shao, D. Zhou, B. Jiang, J.
Zhou and M. Xia, J. Comb. Chem., 2007, 9, 1144; C. Che, J.
Xiang, G. –X. Wang, R. Fathi, J. –M. Quan and Z. Yang, J.
Comb. Chem., 2007, 9, 982; K. Kobayashi, S. Fujita, S.
Fukamachi and H. Konishi, Synthesis 2009, 3378; S.
Kobayashi and S. Nagayama, J. Am. Chem. Soc., 1996, 118,
8977.
24 A. Luna, O. Mo, M. Yanez, J. F. Gal, P. C. Maria, J. C.
Guillemin, Chem. ꢀEur. J. 2006, 12, 9254.
25 Hong Wu and Rainer Glaser, Chem. Res. Toxicol. 2005, 18,
111.
26 B. Han, Z. Liu, Q. Liu, L. Yang, Z. ꢀL. Liu and W. Yu,
Tetrahedron 2006, 62, 2492.
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L-proline was found as an efficient organocatalyst for the three-component reaction of
anilines, aldehydes and barbituric acids/malononitrile in boiling water.