Low transition temperature mixtures prompted one-pot synthesis of 5, 10 dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-dione derivatives

Article abstract of DOI:10.1007/s11164-017-3033-1

Abstract: An efficient green protocol has been investigated for the synthesis of pyrimido[4,5-b]quinolines derivatives via one-pot three-component condensation of 4-chloro aniline, aromatic aldehyde and barbituric acid using low transition temperature mixtures as new generation and sustainable solvents. The process was accomplished with the use of greener and recyclable reaction media, simple methodology, easy workup procedures and no chromatographic purification with high yield. This new approach is expected to discover some significance in combinatorial synthesis of biologically active scaffolds.

Full text of DOI:10.1007/s11164-017-3033-1

Res Chem Intermed
DOI 10.1007/s11164-017-3033-1
Low transition temperature mixtures prompted one-pot
synthesis of 5, 10 dihydropyrimido[4,5-b]quinoline-
2,4(1H,3H)-dione derivatives
Priyanka P. Mohire1 Reshma B. Patil1 Dattatraya R. Chandam2
•
•
•
Sunetra J. Jadhav1 Ajinkya A. Patravale
Jai S. Ghosh1 Madhukar B. Deshmukh1,2
Digambar R. Kumbhar
2,3
1
•
•
•
•
Received: 15 May 2017 / Accepted: 3 July 2017
Ó Springer Science+Business Media B.V. 2017
Abstract An efficient green protocol has been investigated for the synthesis of
pyrimido[4,5-b]quinolines derivatives via one-pot three-component condensation of
4-chloro aniline, aromatic aldehyde and barbituric acid using low transition temperature
mixtures as new generation and sustainable solvents. The process was accomplished
with the use of greener and recyclable reaction media, simple methodology, easy workup
procedures and no chromatographic purification with high yield. This new approach is
expected to discover some significance in combinatorial synthesis of biologically active
scaffolds.
Electronic supplementary material The online version of this article (doi:10.1007/s11164-017-3033-1)
contains supplementary material, which is available to authorized users.
&
Madhukar B. Deshmukh
shubhlaxmi111@gmail.com
1
2
3
Chemistry Research Laboratory, Department of Agrochemicals and Pest Management, Shivaji
University, Kolhapur, Maharashtra 416004, India
Heterocyclic Chemistry Laboratory, Department of Chemistry, Shivaji University, Kolhapur,
Maharashtra 416004, India
Department of Chemistry, Vivekanand College, Kolhapur, Maharashtra 416004, India
123

P. P. Mohire et al.
Graphical Abstract
Keywords Low transition temperature mixture Á Pyrimido[4,5-b]quinoline Á Multi-
component reaction Á Atom economy Á Green chemistry
Introduction
Multicomponent reactions (MCRs) have been established as well-known and
accessible pathways for the rapid creation of molecular diversity. MCRs are also
termed as cascade, domino and one-pot processes. By selecting simple starting
materials, a new class of compounds exhibiting interesting biological applications
can be synthesized via MCRs. THus, MCRs have become a popular tool for the
generation of complex molecular structures. MCRs show different applications in
the synthesis of natural products. MCRs has advantages, such as efficient bond
formation in single-step, high atom economy, easy workup, simple extraction and
purification procedures and reduction of waste products and the costs of starting
materials. Moreover, the reaction period can be considerably shortened. In recent
times, MCRs synthesis has increased popularity for the synthesis of the sustainable
and diversity-oriented types of heterocycles. Therefore, the development of new
multicomponent reactions towards pharmaceutical and agrochemicals scaffolds is
expected in the current instance [1–10].
In the advance of green chemistry, there is a challenge to develop an
environmentally safe methodology that reduces or replaces the use of hazardous
solvents in different organic transformations [11]. Low transition temperature
mixtures (LTTMs) or deep eutectic solvents (DESs) are new types of solvents which
are referred to as designer solvents as presented by Abbott and co-workers [12].
After the discovery of LTTMs Kroon et al. continued the work on LTTMs. This new
class of solvents is a mixture of hydrogen bond donors (HBD) and acceptors(HBA)
[13]. Natural LTTMs have been reported and characterized as green solvents for the
123

Low transition temperature mixtures prompted one-pot…
biomass delignification process [14]. LTTMs have been investigated as innovative
and sustainable solvents to dissolve CO2 [15, 16]. In recent times, DES have been
evaluated as potential lubricants and as extraction media for proteins [17, 18]. In
addition to this, LTTMs have a strong capacity to dissolve proteins and in the
formulation of drugs [19]. Also, DES or LTTM have been reported as catalysts for
different organic transformations, such as acid-catalyzed reactions, base-catalyzed
reactions, metal-catalyzed organic reactions, Suzuki coupling and Heck coupling
[20–26]. Various MCRs have been reported with DES or LTTM as a solvent. The
eco-friendly nature, easy preparation and handling, compatibility with water, low
vapor pressure and simply recycling are significant features of LTTMs [27, 28].
Considering all reports of LTTMs, we have decided to use a LTTM as a designer
solvent in the one-pot multicomponent synthesis of pyrimido[4,5-b]quinoline
derivatives.
Pyrimidines have been comprehensively studied due to their diverse agricultural
and pharmaceutical application. Most of the pyrimidine derivatives show biological
activities such as antimicrobial, antiviral, anti-inflammatory, adenosine receptor
antagonists, antimycobacterial, antituberculosis and anticancer [29]. On the other
hand, quinoline and its derivatives have been proved to be substantially anticancer,
anti-inflammatory, anti-allergic, antimicrobial and antifungal agents [30]. Based on
the nature and position of the substituent, pyrimido[4,5-b]quinolines scaffolds
continue to be given much importance in organic synthesis and medicinal and
material sciences because of their biological applications [31, 32]. Pyrimido[4,5-
b]quinolines (also recognized as 5-deazaflavins, dF) [33, 34] (Fig. 1) core has also
been utilized in miscellaneous pharmacological and biological consequences [35]
such as anticancer, anti-inflammatory, anti-allergic and antimicrobial activities [36].
A few methodologies have been reported during recent years for the synthesis of
the pyrimido[4,5-b]quinoline ring system [37–44]. However, these methodologies
have various drawbacks, such as the use of hazardous solvents, longer reaction
times, expensive catalysts, availability of reagents, and the generation of waste
products. Hence, in view of this goal and the prominent interest in the development
of greener protocols for the proficient preparation of various heterocyclic molecules
[45–47], and to minimize all drawbacks of the reaction as well as to set up an
ecosafe policy, we would like to report the synthesis of 7-Chloro-5-(aryl)-5,10-
dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)- dione using oxalic acid dihy-
drate:proline (LTTM) as a new designer solvent through a one-pot multicomponent
reaction.
F
R
O
O
N
R
N
O
O
N
1
1
1
1
N
N
R
R
R
R
3
3
N
N
3
N
3
N
R
R
R
R
N
N
R
O
O
N
R
O
N
O
2
2
2
2
R
R
[IV]
[III]
[II]
[I]
R= H, Me, Ar
Fig. 1 Naturally occurring products having pyrimido [4,5 b] quinoline moiety, namely 5-deazaflavins I,
flavins II and 5-deazaalloxazines III and IV
123

P. P. Mohire et al.
Experimental
Chemistry
All the chemicals used were purchased from Alfa Aesar and Spectrochem (Mumbai,
India) and used without purification. The reaction was monitored by TLC pet
ether:ethyl acetate (8:2). The desired structures of all the compounds were
confirmed by their relevant spectral data. The melting points were determined in an
open glass capillary tube and were found to be uncorrected. The compounds were
1
confirmed by IR, H NMR and 13C NMR. The IR spectra were recorded on a
JASCO FT-IR 4600 spectrum spectrophotometer and the values are expressed as m
max (cm-1). The 1H NMR and 13C, DEPT NMR spectra were recorded on a Bruker
Spectrospin Avance II-300 MHz and 75 MHz spectrophotometer relative to TMS as
an internal standard using DMSO-d6 as a solvent.
Preparation of oxalic acid dihydrate: proline LTTM
The LTTM was synthesized according to the reported method in the literature [48]. The
preparationoftheLTTMinvolvestheheatingofamixtureofproline(11.5 g,100 mmol)
andoxalicaciddihydrate(12.6 g,100 mmol)inthe ratioof1:1at80 °Cfor1 h.toobtain
viscous yellowish-colored liquid (LTTM) with 100% atom economy (Scheme 1).
General procedure for the synthesis of pyrimido[4,5-b]quinoline-diones (4C)
A mixture of 4-chloro aniline (1 mmol), barbituric acid (1 mmol) and aromatic
aldehyde (1 mmol) was taken in 25-ml round-bottomed containing oxalic acid:proline
LTTM(5 mL)asasolvent.Theresultantmixturewasheatedat80 °C forthe appropriate
time. The completion of the reaction was checked by TLC pet ether:ethyl acetate (8:2),
then 5 mL distilled water was added. The insoluble crude product was filtered, washed
with distilled water and recrystallized from ethanol to obtain the pure product.
Reusability of oxalic acid dehydrate: Proline (LTTM)
The reusability of the solvent is the main and essential aspect in a view of green
chemistry. The recyclability of the LTTM was studied using the reaction of
Cl
O
CHO
Cl
O
NH
LTTM
Reflux, 800C
+
+
Cl
NH
NH2
O
N
H
O
Cl
N
H
N
H
O
Scheme 1 Oxalic acid dihydrate:proline (LTTM)-mediated synthesis of pyrimido [4,5-b] quinoline-
diones (4C)
123

Low transition temperature mixtures prompted one-pot…
4-chloroaAniline (1 mmol), 4-chloro benzaldehyde (1 mmol) and barbituric acid
(1 mmol) in an oxalic acid:proline LTTM under optimized conditions. After the
completion of the reaction, 5 mL water was added to the reaction mixture and the
crude product was separated by filtration. Finally,the LTTM was recovered by
evaporating the water at 80 °C under vacuum and reused for the next reaction and
reused again (Scheme 2).
Spectroscopic data of the synthesized compounds
7-Chloro-5-(2-chlorophenyl)-5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-
dione (4A) White powder; yield 88%; mp 280–282 °C; IR (m max): 3281.29,
2985.27, 2816.53, 1724.05, 1650.77, 1613.16, 1545.67, 1487.81, 1461.78, 1416.46,
1
1337.39, 1313.29 cm-1; H NMR (300 MHz, DMSO-d6): d, 5.567 (s, 1H, –CH),
6.985–7.336 (m, 7H, Ar–H), 9.023 (s, 1H, NH), 10.392 (s, 1H, –NH), 10.540 (s, 1H,
–NH) ppm; 13C NMR (75 MHz, DMSO-d6): d, 37.06, 85.28, 117.49, 125.42,
125.98, 127.01, 127.34, 127.54, 127.90, 128.68, 129.32, 129.54, 129.95, 130.44,
133.60, 134.12, 146.25, 150.70, 150.80 ppm; mass (m/z): 360.1937(M?). Anal.
H
N
N
O
OH
OH
H
H
HO
O
O
+
O
O
O
OH
O
Ar
O
O
O
H
H
O
(2)
(1)
HN
H
OH
O
Ar
O
H
O
N
H
O
OH
N
(3)
H
H2N
O
O
O
N
H
Cl
Cl
H
NH
Ar
O
O
HO
OH
O
Cl
O
O
Ar
NH
NH
2
N
H
O
(4)
O
O
(9)
N
H
(10)
N
H
O
O
Ar
O
H
H
O
H
O
N
HN
NH
N
H
O
(8)
(5)
N
-H2O
H
HO
O
O
O
OH
O
H
O
Ar
OH
H
O
H
N
O
NH
O
N
H
O
H
-
O
Ar
N
H
(6)
O
(7)
Scheme 2 A plausible mechanism for the one-pot three-component synthesis of 5-aryl pyrimido[4,5-
b]quinoline-diones using oxalic acid dihydrate:proline (LTTM)
123

P. P. Mohire et al.
calcd. For C17H11Cl2N3O2: C, 56.59; H, 3.08; N, 11.67% Found: C, 56.60; H, 3.20;
N, 11.62%.
7-Chloro-5-(3-chlorophenyl)-5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-
dione (4B) White powder; yield 85%; mp 278–280 °C; IR (m max): 3371.92,
2942.84, 1721.16, 1684.52, 1594.84, 1546.63, 1491.67, 1407.78, 1337.39,
1301.72 cm-1
;
1H NMR (300 MHz, DMSO-d6): d, 5.839 (s, 1H, –CH),
6.912–6.938 (d, J = 7.8 Hz, 3H, Ar–H), 7.038–7.552 (m, 3H, Ar–H),
8.227–8.250 (d, J = 6.9 Hz, 1H, Ar–H), 10.417 (s, 2H, –NH), 11.247 (s, 1H, –
NH) ppm; 13C NMR (75 MHz, DMSO-d6): d, 38.06, 84.26, 117.49, 125.42, 125.98,
126.01, 127.34, 127.54, 127.80, 128.45, 128.82, 129.45, 133.10, 134.12, 134.43,
146.28, 150.75, 150.80 ppm; mass (m/z): 360.1937(M?). Anal. calcd. For
C17H11Cl2N3O2: C, 56.59; H, 3.08; N, 11.67% Found: C, 56.58; H, 3.18; N, 11.60%.
7-Chloro-5-(4-chlorophenyl)-5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-
dione (4C) White powder; yield 92%; mp 280–282 °C; IR (m max): 3283.21,
3062.41, 2992.98, 2877.27, 2818.45, 1701.87, 1607.38, 1551.45, 1479.13, 1455.03,
1
1421.28, 1331.61 cm-1; H NMR (300 MHz, DMSO-d6): d, 5.053 (s, 1H, –CH),
6.991–7.098 (m, 7H, Ar–H), 9.072 (s, 1H, –NH), 10.460 (s, 1H, –NH), 10.596 (s,
1H, –NH) ppm; 13C NMR (75 MHz, DMSO-d6): d, 30.93, 82.58, 125.44, 125.86,
127.21, 127.34, 127.54, 128.68, 129.02, 129.34, 129.44, 130.44, 131.60, 133.68,
134.12, 146.20, 150.25, 150.80, 161.19 ppm; mass (m/z): 360.1937(M?). Anal.
calcd. For C17H11Cl2N3O2: C, 56.59; H, 3.08; N, 11.67% Found: C, 56.60; H, 3.20;
N, 11.62%.
7-Chloro-5-phenyl-5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-dione (4D)
White powder; yield 88%; mp 274–276 °C; IR (m max): 3370.96, 2966.95, 1684.52,
1
1599.66, 1491.67, 1405.85, 1158.04 cm-1; H NMR (300 MHz, DMSO-d6): d,
5.808 (s, 1H, –CH), 6.790 (s, 1H, Ar–H), 7.087–7.126 (d, J = 11.7 Hz, 5H, Ar–H),
8.066 (s, 1H, Ar–H), 10.395 (s, 2H, –NH), 11.157–11.415 (t, 1H, –NH) ppm; 13C
NMR (75MHz, DMSO-d6): d, 34.79, 88.20, 115.22, 116.65, 119.96, 125.21,
126.96, 127.88, 128.32, 129.30, 129.77, 133.60, 134.79, 141.06, 150.54, 151.07,
163.86, 163.98 ppm; mass (m/z): 325.32579 (M?). Anal. calcd. For C17H12ClN3O2:
C, 62.68; H, 3.71; N, 12.90% Found: C, 62.70; H, 3.74; N, 12.94%.
5-(3-bromophenyl)-7-chloro-5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-
dione (4E) White powder; yield 86%; mp ›300 °C; IR (m max): 3351.68, 2944.77,
1
1682.59, 1593.88, 1553.38, 1490.7, 1407.78, 1337.39, 1301.72 cm-1; H NMR
(300 MHz, DMSO-d6): d, 5.750 (s, 1H, –CH), 6.816–6.837 (d, J = 6.3 Hz, 3H, Ar–
H), 7.196 (br, s, 2H, Ar–H), 8.067 (s, 1H, Ar–H), 8.239–8.284 (d, J = 13.5 Hz, 1H,
Ar–H), 10.542 (s, 2H, –NH), 11.157 (s, 1H, –NH) ppm; 13C NMR (75 MHz,
DMSO-d6): d, 31.07, 91.26, 115.22, 116.65, 121.26, 121.75, 126.11, 128.10,
129.55, 129.97, 137.70, 141.06, 146.83, 151.16, 152.26, 168.16 ppm; mass (m/z):
404.31698 (M?). Anal. calcd. For C17H11BrClN3O2: C, 50.46; H, 2.74; N, 10.38%
Found: C, 50.48; H, 2.78; N, 10.40%.
123

Low transition temperature mixtures prompted one-pot…
7-Chloro-5-(3-nitrophenyl)-5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-
dione (4F) Yellow powder; yield 82%; mp 282–284 °C; IR (m max): 3320.82,
2992.98, 1723.09, 1685.48, 1597.73, 1525.42, 1490.7, 1411.64, 1386.57, 1340.28,
1310.39 cm-1
;
1H NMR (300 MHz, DMSO-d6): d, 5.953 (s, 1H, –CH),
6.989–7.013 (d, J = 7.2 Hz, 2H, Ar–H), 7.235–7.253 (d, J = 5.4 Hz, 2H, Ar–H),
7.416–7.548 (m, 2H, Ar–H), 7.882–7.941 (t, 1H, Ar–H), 10.384 (br, s, 3H, –NH)
ppm; 13C NMR (75 MHz, DMSO-d6): d, 36.58, 91.26, 115.65, 119.59, 126.11,
128.10, 129.55, 129.97, 137.70, 141.06, 158.63, 158.74, 159.60, 168.16 ppm; mass
(m/z): 370.10225 (M?). Anal. calcd. For C17H11ClN4O4: C, 55.07; H, 2.99; N,
10.38% Found: C, 55.10; H, 2.96; N, 15.12%.
7-chloro-5-(3-methoxyphenyl)-5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-
dione (4G) White powder; yield 84%; mp 274–276 °C; IR (m max): 3605.08,
2940.91, 1692.23, 1596.77, 1490.7, 1403.92, 1248.68, 1230.36, 1143.58, 1094.4,
1038.48, 882.274, 856.239, 815.742, 798.385, 764.637, 689.427, 633.501, 553.47,
540.935 cm-1; 1H NMR (300 MHz, DMSO-d6): d, 3.426 (s, 3H, –OCH3), 5.742 (s,
1H, –CH), 6.550–6.872 (m, 2H, Ar–H), 7.002–7.030 (d, J = 8.4 Hz, 1H, Ar–H),
7.056–7.128 (m, 3H, Ar–H), 7.274–7.508 (m, 1H, Ar–H), 9.890 (s, 1H, –NH),
11.194(s, 1H, –NH), 11.371(s, 1H, –NH) ppm; 13C NMR (75MHz, DMSO-d6): d,
19.80, 36.58, 55.32, 58.35, 98.51, 101.10, 114.09, 119.69, 119.92, 129.92, 145.34,
158.03, 158.74, 159.60, 162.02, 163.11 ppm; mass (m/z): 355.7750 (M?). Anal.
calcd. For C18H14ClN3O3: C, 61.64; H, 3.16; N, 15.97% Found: C, 58.90; H, 2.98;
N, 14.68%.
4-(7-chloro-2,4-dioxo-1,2,3,4,5,10-hexahydropyrimido[4,5-b]quinolinyl)benzoni-
trile (4H) White powder; yield 90%; mp 290–292 °C; IR (m max): 3029.62,
2828.10, 1706.69, 1686.44, 1579.41, 1536.99, 1485.88, 1443.46, 1361.5, 1316.5,
1269.9, 1230.36, 1201.43, 1174.449, 1097.3, 1045.23, 859.132, 763.679, 688.463,
668.214, 589.147, 566.005, 552.306, 537.078, 506.223 cm-1; 1H NMR (300 MHz,
DMSO-d6): d, 5.834 (s, 1H, –CH), 6.802–6.830 (d, 2H, Ar–H), 7.062–7.091 (d,
J = 8.7 Hz, 2H, Ar–H), 7.247–7.479 (q, J = 8.1 Hz, 1H, Ar–H), 7.700 (s, 1H, Ar–
H), 7.958–7.982 (d, J = 7.2 Hz, 1H, Ar–H), 11.183 (s, 1H, –NH), 11.336(s, 1H, –
NH), 11.487(s, 1H, –NH) ppm; 13C NMR (75 MHz, DMSO-d6): d, 33.47, 88.74,
104.50, 104.74, 106.66, 114.67, 115.97, 124.26, 138.74, 150.67, 155.96, 162.74,
163.47, 164.56, 173.46, 182.71, 182.96 ppm; mass (m/z): 350.7585 (M?). Anal.
calcd. For C18H11ClN4O2: C, 61.64; H, 3.16; N, 15.97% Found: C, 58.90; H, 2.98;
N, 14.68%.
7-chloro-5-(4-hydroxyphenyl)-5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-
dione (4I) White powder; yield 88%; mp 286–288 °C; IR (m max): 3661..56,
3269.72, 3188.72, 3087.48, 2813.63, 1717.30, 1694.16, 1667.16, 1614.13, 1532.17,
1508.06, 1454.06, 1428.03, 1407.78, 1348.00, 1310.39, 1288.22, 1240.97, 1216.86,
1165.04, 1112.73, 1042.34, 886.131, 834.062, 784.886, 753.066, 697.141, 668.214,
;
654.15, 568.898, 540.935, 576.829 cm-1 1H NMR (300 MHz, DMSO-d6): d,
5.724 (s, 1H, –CH), 6.788–6.864 (q, 2H, Ar–H), 7.150–7.227 (t, 2H, Ar–H),
7.596–7.702 (t, 2H, Ar–H), 8.117–8.166 (d, J = 14.7 Hz, 2H, Ar–H), 9.615 (s, 1H,
–NH), 10.882–11.188 (t, 2H, –NH) ppm; 13C NMR (75 MHz, DMSO-d6): d, 59.48,
123

P. P. Mohire et al.
100.42, 100.89, 115.31, 116.16, 121.43, 122.17, 128.83, 130.01, 145.73, 158.10,
160.46, 173.08, 173.43, 175.37, 180.03, 192.71 ppm; mass (m/z): 341.7484 (M?).
Anal. calcd. For C17H12ClN3O3: C, 59.75; H, 3.54; N, 12.30% Found: C, 58.96; H,
3.24; N, 11.80%.
7-chloro-5-(2-chloro-6-methoxyquinolin-3-yl)-5,10-dihydropyrimido[4,5-b]quino-
line-2,4(1H,3H)-dione (4J) Red brown powder; yield 90%; mp ›300 °C; IR (m
max): 3588.05, 3072.05, 2840.63, 2266.91, 1751.05, 1693.19, 1661.37, 1625.70,
1606.41, 1545.67, 1504.2, 1472.38, 1415.49, 1381.75, 1302.68, 1263.15, 1234.22,
1176.36, 1154.19, 1124.3, 1096.8, 943.02, 922.771, 836.956, 824.42, 787.779,
1
750.174, 669.178, 599.753, 553.47, 509.115 cm-1; H NMR (300 MHz, DMSO-
d6): d, 3.640 (s, 3H, –OCH3), 6.110 (s, 1H, Ar–H), 6.585 (s, 1H, Ar–H),
6.604–6.670 (m, 1H, Ar–H), 7.062–7.088 (t, 2H, Ar–H), 7.205–7.259 (t, 2H, Ar–H),
7.476–7.526 (t, 1H, Ar–H), 7.778–7.803 (d, J = 7.5 Hz, 1H, Ar–H), 11.247 (br, s,
3H, –NH) ppm; 13C NMR (75MHz, DMSO-d6): d, 34.86, 101.22, 102.97, 107.61,
108.19, 108.66, 111.98, 112.96, 116.41, 121.63, 123.68, 127.36, 131.37, 134.86,
139.60, 147.87, 152.91, 156.44, 160.42, 162.57, 163.07, 173.75, 178.70 ppm; mass
(m/z): 441.2668 (M?). Anal. calcd. For C21H14Cl2N4O3: C, 57.16; H, 3.20; N,
12.70% Found: C, 54.18; H, 3.12; N, 11.94%.
7-chloro-5-(2,4-dichlorophenyl)-5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-
dione (4K) White powder; yield 90%; mp 284–286 °C; IR (m max): 3298.64,
2966.95, 2881.13, 2818.45, 1698.02, 1609.31, 1554.34, 1480.1, 1455.99, 1418.39,
1336.43, 1297.79, 1286.29, 1240, 1217.83, 1184.08, 1109.83, 1044.26, 920.843,
878.417, 853.347, 818.634, 794.528, 760.78, 739.567, 720.282, 669.178, 647.965,
1
623.859, 586.254, 552.506, 535.15, 511.044 cm-1; H NMR (300 MHz, DMSO-
d6): d, 5.522 (s, 1H, –CH), 6.883–7.275 (m, 4H, Ar–H), 7.884 (s, 2H, Ar–H), 9.044
(s, 2H, –NH), 10.363 (s, 1H, –NH) ppm; 13C NMR (75 MHz, DMSO-d6): d, 37.06,
84.49, 109.58, 118.23, 125.09, 125.44, 126.95, 127.79, 128.08, 128.49, 129.11,
129.33, 130.77, 132.34, 132.80, 133.91, 134.11, 144.14, 146.36, 147.91, 150.54,
161.34 ppm; mass (m/z): 394.6392 (M?). Anal. calcd. For C17H10Cl3N3O2: C,
51.74; H, 2.55; N, 10.65% Found: C, 50.68; H, 2.02; N, 10.14%.
Results and discussion
In a pilot reaction, 4-chloro benzaldehyde (1 mmol) and barbituric acid (1 mmol)
were taken in a 50-ml round-bottomed flask containing 5 ml of LTTM. The
resultant reaction mixture was stirred at room temperature and monitored by thin-
layer chromatography (TLC). After the formation of the Knoevenagel product,
4-cholro aniline (1 mmol) was introduced into the reaction mixture, and the reaction
mixture was refluxed at 80 °C in an oil bath until the completion of the reaction
which was monitored by TLC.
After the completion of the reaction, water was added to the reaction mixture and
simply filtered to isolate the product then recrystallized from ethanol to afford the
pure product (Scheme 1). The product was analyzed by IR, 1H NMR and 13C NMR
123

Low transition temperature mixtures prompted one-pot…
data. The structures of the products were confirmed on the basis of spectroscopic
data. The infrared (IR) spectra of the compound (4C) showed the characteristic band
at 1701 and 1607 cm-1 due to the presence of a carbonyl group, whereas 3283 and
1
3062 cm-1 showed the presence of a –NH group. The H showed a singlet at d
5.053 due to a benzylic (CH) proton, which confirmed the formation of the desired
product from 4-chloro aniline (1 mmol), 4-chloro benzaldehyde (1 mmol) and
barbituric acid (1 mmol). The signals that appeared between d 7.0 to 7.1 represented
the aromatic protons. The (NH) protons give signals at d 9.072, 10.460, and 10.596.
In the 13C NMR spectrum, the signal appeared at d30.93, which confirmed cyclized
carbon, whereas other signals appeared at 82.58, 125.44, 125.86, 127.21, 127.34,
127.54, 128.68, 129.02, 129.34, 129.44, 130.44, 131.60, 133.68, 134.12, 146.20, and
150.25 ppm to indicate aromatic carbons. Characteristic carbonyl carbons appeared
at 150.80 and 161.19 ppm. Mass spectra of the compound show a molecular ion
peak at (m/z) 360.1937(M?) which confirmed the proposed structure.
These preliminary results motivated us to study this reaction in detail. After this
initial success, to study the effect of the solvents, we have tried to develop a
convenient eco-friendly pathway based on the principles of green chemistry. This
model reaction was carried out in a catalyst-free and solvent-free condition, but the
reaction proceeds up to Knoevnagel condensation (Tables 1, Entry 1, 2, Entry 1). To
achieve the desired product, we have been screened the reaction using different
solvents such as water, ethanol, acetonitrile, mixture of water:ethanol and number of
LTTMs (Table 1) then screened up to 30–360 min. It has been observed that in
polar and non-polar solvents the yield of the product is poor.
After the study of effect of solvent, our attention is towards the study of the
efficiency of acid and base catalysts under same reaction conditions. It was observed
that, the reactions did not give satisfactory yields. After the study of effect of solvent
Table 1 Influence of solvent on yields of (4C)a
Sample no. Solvent
Temp. condition Reaction time (min) Yieldb (%)
1a
1b
2
Without solvent
30 °C
360
120
240
120
120
180
30
Knoevenagel
Without solvent
Water
Reflux (80 °C)
Reflux (80 °C)
Reflux (80 °C)
Reflux (80 °C)
Reflux (80 °C)
Knoevenagel
Knoevenagel
3
Acetonitrile
Water:Ethanol (8:2)
Ethanol
Knoevenagel
4
52
42
92
56
42
48
5
6
Oxalic acid dihydrate:proline Reflux (80 °C)
Choline chloride:urea
7
Reflux (80 °C)
Reflux (80 °C)
Reflux (80 °C)
80
8
Choline chloride:oxalic acid
Guanidine hydrochloride:urea
60
9
75
Highest yield in shortest reaction time shown in bold
a
Reaction condition: 4 Chloro Aniline (1 mmol), barbituric acid (1 mmol) and 4 chloro benzaldehyde
(1 mmol) heated at 80 °C in 5 mL of respective solvent
b
Yields refer to pure isolated products
123

P. P. Mohire et al.
Table 2 Comparative study of oxalic acid dihydrate:proline (LTTM) over different catalyst on yields of
(4C)a
Sr.
no.
Catalyst
Catalyst Load
(mol%)
Conditions
Time
(min)
Yieldb
(%)
1.
2.
Catalyst-free
–
–
–
30 °C
Reflux
360
120
44
48
(80 °C)
3.
4.
5.
6.
7.
Acetic acid
PTSA
20
20
20
20
–
Reflux
90
90
44
38
40
32
92
(80 °C)
Reflux
(80 °C)
Reflux
TEA
120
80
(80 °C)
Reflux
NaOH
(80 °C)
Reflux
(80 °C)
Oxalic acid
dihydrate:proline
30
Highest yield in shortest reaction time shown in bold
a
Reaction condition: 4-chloro Aniline (1 mmol), barbituric acid (1 mmol) and 4-chloro benzaldehyde
(1 mmol) heated at 80 °C in 5 mL of respective solvent
b
Yields refer to pure isolated products
and catalyst, it is clear from table, the desired product of 7-chloro-5-(4-chlorophenyl)-
5,10-dihydropyrimido-[4,5-b]quinoline-2,4(1H,3H)-dione was obtained an excellent
yield in Oxalic acid dihydrate:Proline (LTTM) (Table 2, Entry 7). The results shown
in Tables 1 and 2 indicate that oxalic acid dihydrate:proline (1:1) LTTM can act as
suitable, ecofriendly promoting medium.
With the promising results in our hand and using these optimized reaction
conditions, a series of 7-chloro-5-(aryl)-5,10-dihydropyrimido-[4,5-b]quinoline-
2,4(1H,3H)-dione derivatives (Table 3) were prepared in an excellent yields from
starting with aromatic aldehydes having electron-donating as well as electron-
withdrawing groups. The knoevenagel condensation takes place between aromatic
aldehyde with barbituric acid in ethanol. The nature of aldehyde leads to the yield of
the condensation product. Electron donating substituents will give the desired
product with almost quantitative yields, while electron withdrawing substituents
will give good yield of the product.
The functionoflow transitiontemperature mixture asa catalystor reactionendorsing
intermediate is not yet clear. A plausible mechanism for the synthesis of 7-Chloro-5-(4-
chlorophenyl)-5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-dione involves the
electrophilic activation ofcarbonylgroup of aromaticaldehyde because ofthe hydrogen
bonding nature of LTTM. Further Knoevenagel condensation of substituted aldehyde
and barbituric acid takes place to form 5-[(4-chlorophenyl)methylidene]pyrimidine-
2,4,6(1H,3H,5H)-trione. Further, the aza-Michael addition forms the ring nitrogen of
the 4-chloro aniline leading to the formation of an intermediary aza-Michael adduct
which was further cyclized to the product by intramolecular nucleophilic attack, again
123

Low transition temperature mixtures prompted one-pot…
123

P. P. Mohire et al.
123

Low transition temperature mixtures prompted one-pot…
123

P. P. Mohire et al.
H
O
OH
O
O
O
O
O
N
OH
Heated slowly to 800C
HO
+
OH
N
H
HO
O
H
2H2O
Oxallic acid dihydrate
LTTM
Proline
Scheme 3 Preparation of oxalic acid dihydrate: proline (LTTM)
from the endo-nitrogen on the amino heterocycle species. Finally, air oxidation leads to
the desired pyrimido[4,5-b]quinoline product. The plausible mechanism for the
formation of the product is shown in Scheme 3.
Finally, all the pure products can be simply obtained by washing the solid crude
products with water which avoids chromatographic purification. The recyclability of
the low transition temperature mixture is one of the important significance of this
Table 4 Reusability of LTTM
Run
Yield of 4C
Fresh
First
92
85
80
76
72
Second
Third
Fourth
Fig. 2 Reusability of LTTM
Fig. 3 Atom economy of the
products
123

Low transition temperature mixtures prompted one-pot…
protocol which is proved as economical and environmentally benign. After the
completion of the reaction, water was added to the reaction mixture, the aqueous
layer was evaporated to recover LTTM, which was reused as such for substrates
under identical conditions without further purification. Even after four successive
runs, the reaction-promoting activity of oxalic acid dihydrate:proline (1:1) LTTM
remains unharmed (Table 4, Fig. 2).
The environment friendliness of the protocol can very easily be demonstrated
from the percent atom economy of each scaffold (Fig. 3) which indicates maximum
conversion of the starting materials into the product and minimum waste exclusion.
Conclusion
We have successfully developed a new, highly efficient cost-effective and atom-
economic approach for the synthesis of 7-chloro-5,10-dihydropyrimido[4,5-
b]quinoline-2,4(1H,3H)-dione scaffolds using oxalic acid dihydrate:proline (LTTM)
as the designer solvent by replacing hazardous organic solvents. Operational
simplicity, greener approach, easy work-up procedure, good yields and high atom
economy are the main features of this protocol. The present methodology provides a
direct and convenient route to construct a more diverse and powerful pyrimido[4,5-
b]quinoline analog in biological consequences.
Acknowledgements The authors thank the Department of Science and Technology New Delhi, Govt. of
India, for the award of an INSPIRE fellowship (JRF) for financial support. We gratefully acknowledge the
Department of Chemistry, Shivaji University, Kolhapur, for providing NMR spectral analysis.
References
1. R.P. Gore, A.P. Rajput, Drug Discov. Today Technol. 5, 148–152 (2013)
2. E. Ruijter, V.A.O. Romano, Drug Discov. Today Technol. 10, 15–20 (2013)
3. J.E. Biggs-Houck, A. Younai, J.T. Shaw, Curr. Opin. Chem. Biol. 14, 371–382 (2010)
4. B. Jiang, T. Rajale, W. Wever, S.J. Tu, G. Li, Chem. Asian J. 5, 2318–2335 (2010)
5. S. Damavandi, R. Sandaroos, Chem. Sci. Trans. 1(1), 117–120 (2012)
6. M. Haji, Beilstein J. Org. Chem. 12, 1269–1301 (2016)
7. J.D. Sunderhaus, S.F. Martin, Chemistry 15(6), 1300–1308 (2009)
8. Y. Gu, Green Chem. 14, 2091–2128 (2012)
9. A.A. Otaibi, A. McCluskey, Ionic liquids: new aspects for the future http://dx.doi.org/10.5772/51937
¨
10. A. Domling, W. Wang, K. Wang, Chem. Rev. 112, 3083–3135 (2012)
11. P.T. Anastas, J.C. Warner, Green chemistry: theory and practice (Oxford University Press, New
York, 1998), p. 30
12. A.P. Abbott, G. Capper, D.L. Davies, R.K. Rasheed, V. Tambyrajah, Chem. Commun. 1, 70–71
(2003)
13. M. Francisco, A. Bruinhorst, M.C. Kroon, Angew. Chem. Int. Ed. 52, 3074–3085 (2013)
14. C.L. Yiin, A.T. Quitain, S. Yusup, M. Sasaki, Y. Uemura, T. Kida, Bioresour. Technol. 199, 258–264
(2016)
15. L.F. Zubeir, M.H.M. Lacroix, M.C. Kroon, J. Phys. Chem. B 118, 14429-14441 (2014)
16. X. Li, M. Hou, B. Han, X. Wang, L. Zou, J. Chem. Eng. Data 53, 548–550 (2008)
17. A.P. Abbott, E.I. Ahmed, R.C. Harris, K.S. Ryder, Green Chem. 16, 4156–4161 (2014)
18. Q. Zeng, Y. Wang, Y. Huang, X. Ding, J. Chen, K. Xu, Analyst 139, 2565–2573 (2014)
19. E. Su, A.M. Klibanov, Appl. Biochem. Biotechnol. 177, 753–758 (2015)
123

P. P. Mohire et al.
20. G. Imperato, S. Hoger, D. Lenoir, B. Konig, Green Chem. 8, 1051–1055 (2006)
21. S.B. Phadtare, G.S. Shankarling, Green Chem. 12, 458–462 (2010)
´
22. J.G. Alvarez, C. Vidal, Eur. J. Inorg. Chem. 31, 5147–5157 (2015)
23. F. Ilgen, B. Konig, Green Chem. 11, 848–854 (2009)
24. P. Liu, J.W. Hao, L.P. Mo, Z.H. Zhang, RSC Adv. 5, 48675–48704 (2015)
25. S. Khandelwal, Y.K. Tailor, M. Kumar, J. Mol. Liq. 215, 345–386 (2016)
26. U.N. Yadav, G.S. Shankarling, J. Mol. Liq. 191, 137–141 (2014)
27. D.R. Chandam, A.G. Mulik, D.R. Patil, A.P. Patravale, D.R. Kumbhar, M.B. Deshmukh, J. Mol. Liq.
219, 573–578 (2016)
28. N. Azizi, S. Dezfooli, M. Khajeh, M.M. Hashemi, J. Mol. Liq. 186, 76–80 (2013)
29. M.B. Hole, N.S. Dighe, S.R. Pattan, D.S. Musmade, V.M. Gawarel, S.S. Dengale, S.R. Butle,
Pharmacologyonline 1, 200–207 (2010)
30. M.M. Ghorab, F.A. Ragab, H.I. Heiba, W.M. Ghorabc, J. Heterocycl. Chem. 48, 1269–1279 (2011)
31. A.B.A. El-Gazzar, M.M. Youssef, A.M.S. Youssef, A.A. Abu-Hashem, F.A. Badria, Eur. J. Med.
Chem. 44, 609–624 (2009)
32. J. Azizian, A.S. Delbari, K. Yadollahzadeh, Synth. Commun. 44, 3277–3286 (2014)
33. S. Dudkin, V.O. Iaroshenko, V.Y. Sosnovskikh, A.A. Tolmachev, A. Villingera, P. Langer, Org.
Biomol. Chem. 11, 5351–5361 (2013)
´
34. J. Trilleras, L.G. Lopez, D.J. Pacheco, J. Quiroga, M. Nogueras, J.M. de la Torre, J. Cobo, Molecules
15, 7227–7234 (2010)
´
35. J. Quiroga, J. Trilleras, B. Insuasty, R. Abonıa, M. Nogueras, A. Marchal, J. Cobo, Tetrahedron Lett.
51, 1107–1109 (2010)
36. E.M.E. Fatma, I.A. Shatha, A.E. Ola, M.A. Hassan, J. King Saud. Univ. Sci. 18(1), 1–17 (2005)
37. S. Damavandi, R. Sandaroos, Chem. Sci. Trans. 1(1), 117–120 (2012)
38. B.S. Rane, S.V. Deshmukh, M.G. Ghagare, R.V. Rote, M.N. Jachak, J. Chem. Pharm. Res. 4(7),
3562–3567 (2012)
39. K. Tabatabaeian, A.F. Shojaei, F. Shirini, S.Z. Hejazi, M. Rassa, Chin. Chem. Lett. 25, 308–312
(2014)
40. D.Q. Shi, S.N. Ni, F. Yang, J.W. Shi, G.L. Dou, X.Y. Li, X.S. Wang, S.J. Ji, J. Heterocycl. Chem. 45,
693–702 (2008)
41. D.Q. Shi, L.H. Niu, H. Yao, H. Jiangc, J. Heterocycl. Chem. 46, 237–242 (2009)
42. A.K. Nezhad, S. Sarikhani, E.S. Shahidzadeh, F. Panahi, Green Chem. 14, 2876–2884 (2012)
43. M. Sankaran, C. Kumarasamy, U. Chokkalingam, P.S. Mohan, Bioorg. Med. Chem. Lett. 20,
7147–7151 (2010)
`
44. K. Aknin, S. Desbene-Finck, P. Helissey, S. Giorgi-Renault, Mol. Divers. 14, 123–130 (2010)
45. S.J. Jadhav, R.B. Patil, D.R. Kumbhar, A.A. Patravale, D.R. Chandam, M.B. Deshmukh, Res. Chem.
Intermed. 43, 2529–2543 (2017)
46. A.A. Patravale, A.H. Gore, D.R. Patil, G.B. Kolekar, M.B. Deshmukh, P.B. Choudhari, M.S. Bhatia,
P.V. Anbhule, Res. Chem. Intermed. 42, 2919 (2016)
47. P.P. Warekar, P.T. Patil, K.T. Patil, D.K. Jamale, G.B. Kolekar, Prashant V. Anbhule, Res. Chem.
Intermed. (2017). doi:10.1007/s11164-017-2865-z
48. D.R. Chandam, A.G. Mulik, P.P. Patil, S.D. Jagdale, D.R. Patil, S.A. Sankpal, M.B. Deshmukh, J.
Mol. Liq. 207, 14–20 (2015)
123