Synthesis of pyrimidine fused quinolines by ligand-free copper-catalyzed domino reactions

Article abstract of DOI:10.1021/acs.joc.7b03272

Herein, we report two novel methods for the synthesis of pyrimidine fused quinolines using a one-pot C-C and C-N bond forming strategy from the reaction of 6-aminouracils with 2-bromobenzaldehydes or 2-bromobenzyl bromide derivatives in the presence of 10 mol % CuCl₂ without using any ligand. The reaction of 2-bromobenzaldehyde or its derivatives with 6-aminouracils in the presence of K₂CO₃ as base and a catalytic amount of CuCl₂ in DMF medium under microwave heating conditions provides corresponding pyrimidine fused quinoline derivatives in good yields within 30 min. Alternatively, pyrimidine fused quinoline derivatives have been synthesized from the reaction of 2-bromobenzyl bromides with 6-aminouracil derivatives in the presence of molecular oxygen, CuCl₂ (10 mol %), and K₂CO₃ as base in DMF under reflux conditions. Structures of all the products were unambiguously confirmed by spectroscopic techniques and by recording single crystal XRD of 3a.

Full text of DOI:10.1021/acs.joc.7b03272

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Synthesis of Pyrimidine Fused Quinolines by Ligand-Free Copper-
Catalyzed Domino Reactions
Anoop Kumar Panday,† Richa Mishra,† Asim Jana,† Tasneem Parvin,*,‡ and Lokman H. Choudhury*,†
†Department of Chemistry, Indian Institute of Technology Patna, Patna-801103, Bihar, India
‡Department of Chemistry, National Institute of Technology Patna, Ashok Rajpath, Patna-800005, Bihar, India
S
* Supporting Information
ABSTRACT: Herein, we report two novel methods for the synthesis of pyrimidine fused quinolines using a one-pot C−C and
C−N bond forming strategy from the reaction of 6-aminouracils with 2-bromobenzaldehydes or 2-bromobenzyl bromide
derivatives in the presence of 10 mol % CuCl2 without using any ligand. The reaction of 2-bromobenzaldehyde or its derivatives
with 6-aminouracils in the presence of K2CO3 as base and a catalytic amount of CuCl2 in DMF medium under microwave
heating conditions provides corresponding pyrimidine fused quinoline derivatives in good yields within 30 min. Alternatively,
pyrimidine fused quinoline derivatives have been synthesized from the reaction of 2-bromobenzyl bromides with 6-aminouracil
derivatives in the presence of molecular oxygen, CuCl2 (10 mol %), and K2CO3 as base in DMF under reflux conditions.
Structures of all the products were unambiguously confirmed by spectroscopic techniques and by recording single crystal XRD of
3a.
or modern methods,12 still very limited one-pot single step
methods are available in the literature for the synthesis of
INTRODUCTION
■
Synthesis of fused heterocycles has remained a promising area
pyrimidine fused quinolines. Most of the known methods
in organic synthesis due to their abundance in natural as well as
employ either multistep reaction, harsh reaction conditions or
synthetic molecules with diverse applications in pharmaceut-
expensive catalyst, long reaction time, limited substrate scope,
icals, chemosensors, polymers and as ligands.1 Specially fused
or poor yields, etc. Considering the limitations of the existing
N-heterocycles, having privileged motifs like pyrimidine and
methods, as well as the wide applications of pyrimidine fused
quinolines, are found in many drugs and bioactive natural
quinolines, and in continuation of our work on the synthesis of
products.2
pyrimidine fused heterocycles,13 we shifted our attention to
Hybrid molecules having a pyrimidine ring fused with
develop an efficient and cost-effective one-pot domino method
quinoline as shown in Figure 1 are also known as deazaflavins
for the synthesis of a series of novel pyrimidine fused quinolines
or 5-deazaisoalloxazines. The N-5 analogues of these molecules
are known as flavins and available in biomolecules riboflavin
and flavin adenine dinucleotide (FAD). Considering their
structural resemblance with flavins, they are very useful
from the readily available substrates and catalyst.
Copper catalysis is a very popular, cost-effective, and efficient
strategy for the synthesis of diverse heterocycles.14 Very
recently, Xie and Su et al. have reported a copper(II) catalyzed
molecules in medicinal chemistry. A wide range of medicinal
properties such as antibacterial,3 antifungal,3 anticancer,4
synthesis of chromene fused quinolines using DMF as a one-
carbon source.15 Guo and Fossey et al. have demonstrated a
analgesic,5 antimalarial,6 antitumor,7 anti-inflammatory,5 anti-
Cu(OTf)2 catalyzed synthesis of purin fused polycycles.16
viral,8 and antioxidant5 are known for pyrimidine fused
Considering the virtue of copper catalysis, recently copper-
quinoline derivatives. Apart from their biological activities,
Reetz et al. have explored deazaflavins as mediators in
catalyzed cross-coupling reactions have been explored for the
construction of diverse fused N-heterocycles including quino-
cytochrome P450-BM3 catalyzed light driven C-H activating
line derivatives.17 However, to the best of our knowledge,
copper-catalyzed pyrimidine fused quinolines have not yet been
reported. 2-Halobenzaldehydes or their derivatives are very
popular starting materials for the synthesis of diverse fused N-
heterocycles by copper-catalyzed cross-coupling reactions.
hydroxylation.9
Considering their wide applications, design and development
of novel and efficient routes for the synthesis of pyrimidine
fused quinoline derivatives has remained an important topic.
Langer et al. reported a three step synthesis of 5-polyfluoroalkyl
pyrimidine fused quinolines starting from 6-chloro-1,3-
dimethyluracil.10 Although a plethora of methods are known
for the construction of a quinoline moiety by either classical11
Received: December 27, 2017
© XXXX American Chemical Society
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Figure 1. Structures and names of representative fused pyrimidines and their naturally available analogues.
Scheme 1. Comparison of Present Method with Other Known Methods for the Synthesis of Fused N-Heterocycles via Copper-
Catalyzed Coupling Reactions of 2-Bromobenzaldehydes
Zhang et al. reported a Cu(OAc)2 catalyzed and K2CO3
promoted one-pot multicomponent reactions of 2-bromoben-
zaldehydes with cyanoacetamides and aqueous ammonia,
followed by addition of aldehydes for the synthesis of 2-
aminoquinoline-3-carboamides and pyrimido[4,5-b]quinolin-4-
ones (Scheme 1a).18 Wu and co-workers have developed a
copper(I) iodide catalyzed three-component domino reaction
of 2-bromoarylaldehyde, benzylamines, and sodium azide for
the synthesis of quinazoline derivatives in the presence of
proline as ligand (Scheme 1b).19 Peng’s group reported a
copper(I) oxide catalyzed one-pot synthesis of indole-2-
carboxylic esters in the presence of cesium carbonate as base
and N-methylpyrolidone as solvent (Scheme 1c).20 Lee et al.
reported copper(I) iodide catalyzed, one-pot, three-component
reactions of 2-bromobenzaldehydes, primary amines, and
sodium azide in the presence of TMEDA as ligand and
DMSO as solvent for the synthesis of 2H-indazoles (Scheme
1d).21 Very recently, Kaeobamrung et al. have reported
copper(I) iodide catalyzed domino reactions of enaminones
and 2-bromo- or 2-iodobenzaldehydes for the synthesis of fused
quinoline derivatives in the presence of DMEDA as ligand and
toluene as solvent (Scheme 1e).22 In this paper, we are
reporting two novel methods for the synthesis of pyrimidine
fused quinolines from the reaction of 6-aminouracils with 2-
bromobenzaldehydes or 2-bromobenzyl bromide derivatives
using copper(II) catalyzed Ullman type domino reactions
generating two new bonds in one pot without using any ligand
as shown in Scheme 1f.
RESULTS AND DISCUSSION
■
Recently, we have explored 6-aminouracil derivatives for the
one-pot synthesis of diverse pyrimidine fused heterocycles.13 In
continuation of our works on development of one-pot, time
and cost-effective methodologies for the synthesis of fused
heterocycles, initially we started our investigation for the
synthesis of pyrimidine fused quinolines from the reaction of 2-
bromobenzaldehyde (1a) with 6-amino-1,3-dimethyluracil (2a)
as model reaction. When a 1:1 mixture of these starting
materials was refluxed in the presence of K2CO3 (2 equiv) in
DMF as solvent for 12 h, only a trace amount of fused
B
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pyrimidines 3a was observed (Table 1, entry 1). Next, the same
combination was tried under microwave heating at 150 °C in
various solvents like CH3CN, DMSO, and H2O (Table 1,
entries 13−15); however, in all of these screened solvents,
yields obtained were found lower as compared to DMF. We
also tried to find the best base for this transformation and
various bases like Cs2CO3, NaOH, KHCO3, NaHCO3, Et3N,
and Na2CO3 were screened in the presence of CuCl2 as catalyst
(Table 1, entries 16−21), and the observed results were not
encouraging. Interestingly, reaction without using any base in
the presence of CuCl2 provided only 10% yield of the product
3a (Table 1, entry 22). We also performed the model reaction
in the presence of 20 mol % PPh3 as well as in the presence of
1,10-phenanthroline as ligands and did not observe any
advantage of using ligands (Table 1, entries 23 and 24). After
having the best result using microwave heating under sealed
conditions at 150 °C (74−75 W), for 30 min in the presence of
CuCl2 (10 mol %) and 2 equiv of K2CO3 in DMF as solvent
(Table 1, entry 7), we also wanted to check if the same reaction
can be performed using a sealed tube and conventional heating.
Therefore, next we tried the model reaction in a sealed tube
keeping the temperature at 120 °C for 15 h without changing
any other parameters, and the corresponding fused quinoline
3a was obtained in 63%. Interestingly, when the same reaction
was performed at 150 °C in a sealed tube, within 12 h a better
yield (75%) was obtained (Table 1, entry 26). From these
observations, it is evident that pyrimidine fused quinolines can
be synthesized by either conventional or microwave heating
under sealed conditions. However, the best yield in this
reaction was obtained in microwave heating. Thus, the reaction
in the presence of 10 mol % CuCl2 along with 2 equiv of
K2CO3 in DMF under sealed and microwave heating at 150 °C
(74−75 W) for 30 min was considered as the optimum reaction
conditions.
After having the optimized reaction conditions in hand, then
we explored the scope and generality of this method by varying
2-bromobenzaldehydes and 6-aminouracils. The results are
summarized in Table 2. A wide variety of 2-bromobenzalde-
hyde derivatives having both electron donating and with-
drawing substituents at different positions of the aryl ring such
as −CH3, −OCH3, −CN, −NO2, −F, −Br, −CF3 were tested
with 6-amino-1,3-dimethyluracil, and the corresponding pyr-
imidine fused quinoline derivatives were obtained in moderate
to good yields (Table 2, 3a−3o). It was observed that 2-
bromobenzaldehydes having electron donating substituents
provided better yields than that of having electron withdrawing
substituents. Heterocyclic aldehyde such as 2-bromo-3-
pyridinecarboxaldehyde was also found suitable for this
strategy, and the corresponding product 3p was obtained in
62% yield.
a
Table 1. Screening of the Reaction Conditions
b
entry
catalyst
base
solvent
yield (%)
c
1.
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
NaOH
NaHCO3
KHCO3
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
DMSO
H2O
trace
5
3
CuI
55
43
58
48
81
34
64
59
45
61
50
48
30
64
63
18
20
12
67
10
76
77
4
CuBr
CuBr2
CuCl
CuCl2
CuO
Cu2O
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
CuSO4·5H2O
Cu(OTf)2
Cu(OAc)2
CuCl2
CuCl2
CuCl2
CuCl2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
Na2CO3
CuCl2
CuCl2 + PPh3 (20 mol %)
K2CO3
K2CO3
CuCl2 + 1,10-phenanthroline
(20 mol %)
d
25
26
CuCl2
CuCl2
K2CO3
K2CO3
DMF
DMF
63
e
75
a
Reaction conditions: 2-Bromobenzaldehyde (0.5 mmol), 6-amino-
1,3-dimethyluracil (0.5 mmol), K2CO3 (2.0 equiv), catalyst (10 mol
b
c
%). Isolated yield. Refluxed for 12 h. Except entries 1, 25, and 26, all
reactions were performed under microwave (74−75 W, monitored by
IR temperature sensor) heating for 30 min. Heating was performed
d
e
using silicon oil bath for 15 h in sealed tube at 120 °C. Heating was
performed using silicon oil bath for 12 h in sealed tube at 150 °C.
the presence of K2CO3. In this case, also only 5% of the desired
product 3a was observed (Table 1, entry 2). Interestingly, when
this model reaction was tried in the presence of 10 mol % of
CuI as catalyst along with 2 equiv of K2CO3 as base in DMF
medium under microwave heating at 150 °C under sealed
conditions for 30 min, the corresponding fused quinoline 3a
was obtained in 55% yield (Table 1, entry 3). The product was
Similar to 6-amino-1,3-dimethyluracil, 6-amino-1,3-dipropy-
luracil was also found suitable for this one-pot C−C and C−N
bond forming reactions under the similar reaction conditions,
and the corresponding fused molecules 3q−3t were found in
good yields. It is noteworthy to mention that, in these
reactions, solvent plays a very important role. A majority of
copper-catalyzed C−N coupling reactions are reported in the
presence of ligands. However, in this method, we have not used
any additive or ligand. We have observed that, when the
reaction is carried out in DMF as solvent even without adding
any additive or ligand, Cu(II) catalysts give good results. This
may be due to the good coordinating as well as reducing
property of DMF.
1
fully characterized by IR, H, and 13C NMR as well as by
HRMS. After having this encouraging result, next we wanted to
optimize the yield by screening various copper catalysts such as
CuBr, CuBr2, CuCl, CuCl2, CuO, Cu2O, CuSO4.5H2O,
Cu(OTf)2, and Cu(OAc)2, keeping base and solvent constants
under similar microwave conditions, and the results are
summarized in Table 1 (entries 4−12). Among all the screened
catalysts, CuCl2 was found as the best catalyst in terms of yield
obtained (81%) of the product (Table 1, entry 7). To screen
the effect of solvent, the model reaction was performed in
After having these encouraging results for the synthesis of
pyrimidie fused quinolines using 2-bromobenzaldehydes, next
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a b c
, ,
Table 2. Substrate Scope for the Synthesis of Pyrimidine Fused Quinolines
a
b
c
Conditions: 1 (0.5 mmol), 2 (0.5 mmol), K2CO3 (1.0 mmol), and CuCl2 (10-mol %) in DMF (2.0 mL). Isolated yield. Microwave heating was
performed at (74−75 W), 150 °C, for 30 min.
Table 3. Copper-Catalyzed Synthesis of Pyrimidine Fused Quinolines from the Reaction of 2-Bromobenzyl Bromides and 6-
a
Aminouracils
a
Conditions: 1 (1.0 mmol), 2 (1.0 mmol), K2CO3 (2.0 mmol), and CuCl2 (10-mol %) in DMF (5.0 mL) under O2 balloon at reflux (150 °C) for 4−
b
5 h. Isolated yield.
we wanted to develop an alternative method where we can
access the same products using 2-bromobenzyl bromides as the
starting materials. When we tried to do the reaction of 2-
bromobenzyl bromide with 6-amino-1,3-dimethyluracil using
the similar procedure used in Table 2, we obtained only 30%
yield of corresponding tricyclic product 3a. Then we tried to
optimize the reaction conditions for this method by changing
reaction conditions from microwave heating to reflux
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conditions. When the reaction was performed in the presence
of 10 mol % CuCl2 and 2 equiv of K2CO3 in DMF (5.0 mL)
under reflux conditions, within 5 h the corresponding desired
product 3a was obtained in 62% yield. Interestingly, when we
performed the reaction in the presence of an oxygen balloon,
within 4 h considerably good yield (72%) of the corresponding
product was observed. By increasing the reaction time, we did
not observe any significant change in yield obtained. Thus, the
reaction of benzyl bromides with aminouracil derivatives in the
presence of CuCl2 (10 mol %) and K2CO3 (2 equiv) and an
oxygen balloon in DMF under reflux conditions was considered
as optimum reaction conditions. Next, using these optimized
reaction conditions and by varying benzyl bromide derivatives,
we have prepared some pyrimidine fused quinolines (3o, 3d,
and 3h), and the results are summarized in Table 3. Likewise,
6-amino-1,3-dipropyluracils were reacted with different 2-
bromobenzyl bromide derivatives, and the corresponding
fused quinolines (Table 3, 3u−3x) were obtained in satisfactory
to good yields.
when B1 was subjected to microwave heating in DMF in the
presence of 2.0 equiv of K2CO3, and 10 mol % CuCl2, within 20
min the corresponding cyclic product 3a was obtained in 80%
yield. We also tried to isolate intermediate A1 by performing
reaction of 1a and 2a in DMF in the presence of CuCl2 (10 mol
%), K2CO3 (2.0 equiv) under the MW heating and stopping the
reaction after 5 min. However, in this case, also we could not
isolate our expected intermediate A1. Interestingly, the mass
analysis of crude reaction mixture, we found a very low
abundant peak corresponding to A1. Thus, we believe that both
the paths are feasible for the formation of 3a.
Similarly, to know the intermediate involved from the
reaction of 4a and 2a, we did a control experiment between
these two substrates in the presence of K2CO3 (2.0 equiv) in
DMF without adding any copper catalyst, and the mixture was
refluxed at 150 °C for 2 h (Scheme 3b). From this control
experiment, the obtained product was found to be C1 as
characterized by NMR and HRMS. Next, C1 was again refluxed
in DMF in the presence of CuCl2 and K2CO3 (2.0 equiv) and
an oxygen balloon for 3 h, and the desired product 3a was
obtained in 66%. From this study, we believe the reaction
follows path I (Scheme 3b) for the formation of 3a from 4a and
2a using our methodology.
To demonstrate the synthetic utility of this developed
protocol, next we tried to scale up the synthesis of pyridine
fused quinoline (3a) by performing the reaction of 2-
bromobenzaldehyde 1a (5.0 mmol) and 1,3-dimethyl-6-amino-
uracil 2a (5.0 mmol) under the standard reaction conditions in
10.0 mL of DMF in a 25 mL microwave vial (Scheme 2). This
CONCLUSION
■
In conclusion, we have developed two efficient methodologies
for the synthesis of pyrimidine fused quinoline derivatives by
Cu-catalyzed coupling reaction of 2-bromobenzaldehyde/2-
bromobenzyl bromide and 6-aminouracils. The present
methods are efficient and versatile methods for the synthesis
of diverse pyrimidine fused quinolines. Considering the
presence of bioactive quinoline and pyrimidine moiety in all
the products, it is expected that these molecules will find
applications in organic and medicinal chemistry.
Scheme 2. Gram Scale Synthesis of Pyrimidine Fused
Quinolines by Both the Methods
EXPERIMENTAL SECTION
■
General Information. All reagents and solvents were purchased
from commercial suppliers and were used without further purification.
Microwave irradiation was carried out with Initiator 2.5 Microwave
Synthesizers from Biotage, Uppsala, Sweden. All reactions were
monitored by TLC, followed by exposure of the mixtures to UV light
and/or an iodine chamber to visualize the reaction spots. Column
chromatography was performed using silica gel [ethyl acetate/hexane
(in different ratios) solvent system]. FTIR spectra were recorded by
ATR mode with the absorption in cm−1. NMR spectra were recorded
1
on a Bruker 400 MHz machine. H NMR (400 MHz) and 13C NMR
transformation proceeded smoothly to afford 0.92 g (76%)
yield of the desired product 3a. Similarly, using conventional
heating, the reaction of 2-bromobenzyl bromide 4a (10.0
mmol) with 1,3-dimethyl-6-aminouracil 2a (10.0 mmol)
provided 1.56 g (65%) of product 3a.
(100 MHz) spectra were recorded in CDCl3 or DMSO-d6 solvent at
25 °C. Chemical shifts (in ppm) were reported using tetramethylsilane
(δ = 0) as an internal standard in CDCl3 (δ = 7.26) or DMSO-d6 (δ =
2.50) solvent. The following abbreviations were used to define the
multiplicities: s = singlet; d = doublet; t = triplet; m = multiplet; dd
(doublet of doublets); td (triplet of doublets); brs (broad singlet),
coupling constants (J, in Hz). 13C NMR data were recorded in terms
of the chemical shift (ppm, scale), using the central peak of CDCl3
(77.0 ppm) or DMSO-d6 (δ = 39.5 ppm) as the internal standard.
HRMS analysis was carried out using a BRUKER Impact HD mass
spectrometer (Impact HD UHR-TOF, ESI with positive mode) and
Agilent 6520 Q-TOF mass spectrometer. Melting points were
recorded using a SRS EZ-Melt automated melting point apparatus
by capillary methods without correction.
Experimental Procedures. Typical Experimental Procedure for
the Synthesis of 3a Using Microwave Heating. A mixture of 6-
amino-1,3-dimethyluracil (0.5 mmol), 2-bromobenzaldehyde (0.5
mmol), and K2CO3 (1.0 mmol) in DMF (2.0 mL) was stirred at
room temperature for 5−10 min. To this mixture, 10 mol % of CuCl2
catalyst was added. Then the reaction mixture was kept under
1
All the products were fully characterized by IR, H and 13C
NMR as well as by HRMS. The structure of the products have
also been confirmed by X-ray crystallographic analysis of
compound 3a (see the Supporting Information). Next, to
understand the mechanism, we wanted to know the initial step
for this domino reaction, from the reaction of 2-bromobenzal-
dehyde and 6-amino-1,3-dimethyluracil. For this study, we did
the control reaction between 1a and 2a in the presence of
K2CO3 (2.0 equiv) and DMF medium without adding any
copper catalyst, and the mixture was heated under microwave
for 15 min. The reaction can follow either path I (Scheme 3a)
to give intermediate A1 or path II to provide intermediate B1.
After characterization of the product obtained from this control
experiment, we found that the obtained product is B1. Again,
E
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Scheme 3. (a) Proposed Mechanism for the Formation of 3a from 1a and 2a under MW Heating. (b) Proposed Mechanism for
the Formation of 3a from 4a and 2a under Reflux Conditions
microwave heating (74−75 W, monitored by IR temperature sensor)
under sealed and stirring conditions for 30 min, keeping the
temperature at 150 °C. After completion of the reaction, the reaction
mixture was cooled to room temperature and poured in ice. Solid
product was separated by just filtration and washed with cold water
twice. Finally, the pure product was obtained by recrystallization from
methanol. Using a similar procedure, all other products were prepared.
In some cases, compounds were purified by column chromatography
using silica gel and ethyl acetate mixture.
1,3,8-Trimethylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione (3b).
Eluent: hexane/ethyl acetate (4:1). Yield 108 mg (84%); white
1
solid; mp 224−225 °C. IR (ATR) 1701, 1659 cm−1. H NMR (400
MHz, CDCl3) δ 8.93 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H),
7.34 (d, J = 8.0 Hz, 1H), 3.80 (s, 3H), 3.51 (s, 3H), 2.58 (s, 3H) ppm.
13C NMR (100 MHz, CDCl3) δ 161.7, 151.8, 150.3, 148.7, 144.5,
139.7, 129.0, 128.3, 127.3, 122.9, 110.2, 29.7, 28.6, 22.4 ppm. HRMS
(ESI-TOF): m/z [M + H]+ calcd for C14H14N3O2 256.1081; found
256.1104.
8-Methoxy-1,3-dimethylpyrimido[4,5-b]quinoline-2,4(1H,3H)-
Typical Experimental Procedure for the Synthesis of 3a from 2-
Bromobenzyl Bromide and 6-Amino-1,3-dimethyluracil Using
Conventional Reflux Conditions. A mixture of 2-bromobenzyl
bromide (1.0 mmol), K2CO3 (2.0 mmol), 5.0 mL of DMF, and 6-
amino 1,3-dimethyluracil (1.0 mmol) was stirred at room temperature
for 10 min in a 25 mL round-bottom flask. Then 10 mol % of CuCl2
was added to the above mixture and stirred under reflux conditions for
4−5 h at 150 °C in the presence of an O2 balloon. After completion of
the reaction (monitored by TLC), the mixture was poured in ice. Solid
product was separated by just filtration and washed with cold water
twice. Finally, the pure product was obtained by recrystallization from
methanol or by column chromatography. Using a similar procedure, all
other products were prepared in Table 3.
dione (3c). Eluent: hexane/ethyl acetate (4:1). Yield 117 mg (86%);
1
white solid; mp 258−259 °C. IR (ATR) 1702, 1660 cm−1. H NMR
(400 MHz, CDCl3) δ 8.87 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.28 (s,
1H), 7.15 (d, J = 12.0 Hz, 1H), 4.00 (s, 3H), 3.81 (s, 3H), 3.52 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3) δ 164.1, 161.7, 152.4, 151.9,
149.2, 139.4, 130.5, 120.1, 119.5, 108.7, 106.4, 55.9, 29.7, 28.6 ppm.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H14N3O3 272.1030;
found 272.1057.
7-Methoxy-1,3-dimethylpyrimido[4,5-b]quinoline-2,4(1H,3H)-
dione (3d). Eluent: hexane/ethyl acetate (5:1). Yield 116 mg (85%);
1
white solid; mp 260−261 °C. IR (ATR) 1701, 1653 cm−1. H NMR
(400 MHz, CDCl3) δ 8.91 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.49 (dd,
J = 8.0 Hz & 4.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 3.95 (s, 3H), 3.82
(s, 3H), 3.53 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 161.7,
157.3, 151.8, 147.1, 146.2, 138.4, 129.6, 126.6, 125.7, 111.1, 106.0,
55.8, 29.7, 28.7 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for
C14H14N3O3 272.1030; found 272.1054.
1,3-Dimethylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione (3a).23
Purified by recrystallization from MeOH. Yield 98 mg (81%); white
1
solid; mp 210−211 °C. IR (ATR) 1708, 1654 cm−1. H NMR (400
MHz, CDCl3) δ 9.01 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0
Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 3.83 (s,
3H), 3.53 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 161.6, 151.8,
150.1, 148.6, 140.2, 133.3, 129.4, 128.3, 125.9, 124.9, 111.1, 29.8, 28.7
ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H12N3O2
242.0924; found 242.0923.
7,8-Dimethoxy-1,3-dimethylpyrimido[4,5-b]quinoline-2,4-
(1H,3H)-dione (3e).23 Purified by recrystallization from MeOH. Yield
128 mg (85%); white solid; mp 280−281 °C. IR (ATR) 1702, 1652
cm−1. 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 7.29 (s, 1H), 7.11
(s, 1H), 4.08 (s, 3H), 4.02 (s, 3H), 3.79 (s, 3H), 3.50 (s, 3H) ppm.
F
DOI: 10.1021/acs.joc.7b03272
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
13C NMR (100 MHz, CDCl3) δ 160.8, 154.8, 150.8, 148.5, 146.9,
146.7, 136.3, 119.3, 107.8, 105.8, 105.0, 55.5, 55.3, 28.6, 27.5 ppm.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H16N3O4 302.1135;
found 302.1132.
6-Hydroxy-7-methoxy-1,3-dimethylpyrimido[4,5-b]quinoline-2,4-
(1H,3H)-dione (3f). Eluent: hexane/ethyl acetate (4:1). Yield 118 mg
(82%); white solid; mp 271−272 °C. IR (ATR) 3061, 1710, 1667
cm−1. 1H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 7.67 (d, J = 8.0 Hz,
1H), 7.02 (d, J = 8.0 Hz, 1H), 4.06 (s, 3H), 3.86 (s, 3H), 3.53 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3) δ 161.1, 154.4, 151.6, 148.3,
142.5, 140.1, 129.2, 125.1, 113.3, 111.9, 111.8, 56.6, 30.0, 28.8 ppm.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H14N3O4 288.0979;
found 288.0955.
NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.26 (s, 1H), 8.11 (d, J = 8.0
Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 3.85 (s, 3H), 3.55 (s, 3H) ppm. 13C
NMR (100 MHz, CDCl3) δ 160.9, 158.8, 153.8, 151.5, 151.0, 150.1,
141.0, 129.4, 128.7 (q, J(C‑F) = 3.0 Hz), 127.23 (q, J(C‑F) = 4.0 Hz),
123.8 (q, J(C‑F) = 271.0 Hz), 112.1, 29.9, 28.8 ppm. HRMS (ESI-
TOF): m/z [M + H]+ calcd for C14H11F3N3O2 310.0798; found
310.0796.
1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimido[4,5-b]-
quinoline-8-carbonitrile (3n). Eluent: hexane/ethyl acetate (3:1).
Yield 93 mg (70%); white solid; mp 258−259 °C. IR (ATR) 2230,
1
1716, 1680 cm−1. H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H),
8.51 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 3.90 (s, 3H), 3.66
(s, 3H) ppm. 13C NMR (100 MHz, DMSO-d6) δ 159.8, 150.6, 149.4,
147.3, 139.1, 132.2, 130.8, 126.0, 125.5, 117.5, 114.7, 113.0, 28.8, 27.6
ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H11N4O2
267.0877; found 267.0876.
8-Fluoro-1,3-dimethylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione
(3g). Purified by recrystallization from MeOH. Yield 94 mg (72%);
1
white solid; mp 215−216 °C. IR (ATR) 1707, 1660 cm−1. H NMR
(400 MHz, CDCl3) δ 8.98 (s, 1H), 7.96−7.92 (m, 1H), 7.62 (d, J =
8.0, 1H), 7.33−7.29 (m, 1H), 3.81 (s, 3H), 3.52 (s, 3H) ppm. 13C
NMR (100 MHz, CDCl3) δ 167.0 and 164.5 (d, J(C‑F) = 254 Hz),
161.4, 151.7, 151.6, and 151.5 (d, J(C‑F) = 13.9 Hz), 149.5, 140.0, 131.8,
and 131.7 (d, J(C‑F) = 10.7 Hz), 121.9,116.9 and 116.6 (d, J(C‑F) = 25.6
Hz), 112.4 and 112.2 (d, J(C‑F) = 20.9 Hz), 110.5, 29.8, 28.7 ppm.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H11FN3O2 260.0830;
found 260.0828.
9,11-Dimethylbenzo[h]pyrimido[4,5-b]quinoline-8,10(9H,11H)-
dione (3o). Eluent: hexane/ethyl acetate (4:1). Yield 95 mg (65%);
1
white solid; mp 295−296 °C. IR (ATR) 1701, 1653 cm−1. H NMR
(400 MHz, CDCl3) δ 9.15 (d, J = 8.0 Hz, 1H), 8.91(s, 1H), 7.90 (d, J
= 8.0 Hz, 1H), 7.77−7.69 (m, 4H), 3.92 (s, 3H), 3.54 (s, 3H) ppm.
13C NMR (100 MHz, CDCl3) δ 161.6, 151.8, 149.3, 148.4, 138.7,
135.3, 130.4, 130.0, 128.2, 127.3, 127.1, 125.6, 125.4, 122.7, 110.4,
29.8, 28.7 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for
C17H14N3O2 292.1081; found 292.1078.
7-Fluoro-1,3-dimethylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione
(3h). Purified by recrystallization from MeOH. Yield 92 mg (71%);
1,3-Dimethylpyrimido[4,5-b][1,8]naphthyridine-2,4(1H,3H)-dione
1
white solid; mp 232−233 °C. IR (ATR) 1716, 1657 cm−1. H NMR
(3p).23 Eluent: hexane/ethyl acetate (3:1). Yield 75 mg (62%); white
1
solid; mp 265−266 °C. IR (ATR) 1715, 1670 cm−1. H NMR (400
(400 MHz, CDCl3) δ 8.96 (s, 1H), 8.02−7.99 (m, 1H), 7.63−7.55 (m,
2H), 3.82 (s, 3H), 3.53 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ
161.3, 161.1, and 158.6 (d, J(C‑F)= 247 Hz), 151.7, 148.2, 147.1, 139.5,
and 139.4 (d, J(C‑F)= 5.6 Hz), 130.7 and 130.6 (d, J(C‑F)= 8.8 Hz),
125.2 and 125.1 (d, J(C‑F)= 10 Hz), 123.7 and 123.5 (d, J(C‑F)= 25 Hz),
112.2 and 112.0 (d, J(C‑F)= 21.8 Hz), 111.7, 29.8, 28.7 ppm. HRMS
(ESI-TOF): m/z [M + H]+ calcd for C13H11FN3O2 260.0830; found
260.0827.
MHz, CDCl3) δ 9.18 (s, 1H), 9.06 (s, 1H), 8.33 (d, J = 8.0, 1H),
7.52−7.49 (m, 1H), 3.89 (s, 3H), 3.54 (s, 3H) ppm. 13C NMR (100
MHz, CDCl3) δ 160.8, 157.3, 157.1, 151.5, 151.4, 141.7, 138.6, 121.8,
119.4, 112.2, 30.3, 28.8 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd
for C12H11N4O2 243.0877; found 243.0876.
8-Methyl-1,3-dipropylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione
(3q). Eluent: hexane/ethyl acetate (6:1). Yield 123 mg (79%); white
1
solid; mp 125−126 °C. IR (ATR) 1707, 1652 cm−1. H NMR (400
7-Bromo-1,3-dimethylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione
(3i). Eluent: hexane/ethyl acetate (3:1). Yield 110 mg (69%); white
MHz, CDCl3) δ 8.95 (s, 1H), 7.83−7.78 (m, 2H), 7.34 (d, J = 8.0 Hz,
1H), 4.43 (t, J = 8.0 Hz, 2H), 4.08 (t, J = 8.0 Hz, 2H), 2.58 (s, 3H),
1.86−1.82 (m, 2H), 1.78−1.72 (m, 2H), 1.05−0.98 (m, 6H) ppm. 13C
NMR (100 MHz, CDCl3) δ 161.5, 151.3, 150.3, 148.4, 144.2, 139.7,
128.9, 128.1, 127.4, 122.9, 110.4, 44.2, 43.5, 22.4, 21.4, 21.2, 11.5, 11.4
ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H22N3O2
312.1707; found 312.1733.
1
solid; mp 232−233 °C. IR (ATR) 1712, 1656 cm−1. H NMR (400
MHz, DMSO-d6) δ 9.00 (s, 1H), 8.50 (s, 1H), 8.20 (d, J = 8.0 Hz,
1H), 7.99 (d, J = 8.0 Hz, 1H), 3.65 (s, 3H), 3.36 (s, 3H) ppm. 13C
NMR (100 MHz, DMSO-d6) δ 160.6, 147.5, 138.8, 138.4, 136.5,
135.9, 131.4, 129.7, 129.5, 125.6, 117.9, 29.8, 28.7 ppm. HRMS (ESI-
TOF): m/z [M + H]+ calcd for C13H11BrN3O2 320.0029; found
320.0027.
7,8-Dimethoxy-1,3-dipropylpyrimido[4,5-b]quinoline-2,4(1H,3H)-
6-Bromo-1,3-dimethylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione
dione (3r). Eluent: hexane/ethyl acetate (6:1). Yield 143 mg (80%);
(3j). Eluent: hexane/ethyl acetate (2:1). Yield 114 mg (71%); white
1
white solid; mp 180−181 °C. IR (ATR) 1696, 1649 cm−1. H NMR
1
solid; mp 240−241 °C. IR (ATR) 1710, 1657 cm−1. H NMR (400
(400 MHz, CDCl3) δ 8.93 (s, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 4.54 (t,
J = 8.0 Hz, 2H), 4.22 (s, 3H), 4.20 (t, J = 8.0 Hz, 2H), 4.16 (s, 3H),
1.99−1.94 (m, 2H), 1.90−1.85 (m, 2H), 1.17 (t, J = 8.0 Hz, 3H), 1.12
(t, J = 8.0 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 161.7, 155.7,
151.3, 149.5, 148.0, 147.5, 137.3, 120.4, 109.1, 107.0, 106.0, 56.5, 56.3,
44.1, 43.5, 21.4, 21.3, 11.5 ppm. HRMS (ESI-TOF): m/z [M + H]+
calcd for C19H24N3O4 358.1761; found 358.1758.
MHz, DMSO-d6) δ 9.00 (s, 1H), 7.97−7.92 (m, 2H), 7.80 (t, J = 8.0
Hz, 1H), 3.66 (s, 3H), 3.30 (s, 3H) ppm. 13C NMR (100 MHz,
DMSO-d6) δ 160.9, 151.5, 150.1, 149.7, 138.1, 134.2, 129.9, 128.1,
123.8, 122.8, 112.8, 29.9, 28.7 ppm. HRMS (ESI-TOF): m/z [M +
H]+ calcd for C13H11BrN3O2 320.0029; found 320.0027.
7-Chloro-1,3-dimethylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione
(3k). Eluent: hexane/ethyl acetate (5:1). Yield 99 mg (72%); white
1
solid; mp 271−272 °C. IR (ATR) 1716, 1657 cm−1. H NMR (400
8-Fluoro-1,3-dipropylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione
(3s). Eluent: hexane/ethyl acetate (5:1). Yield 112 mg (71%); white
MHz, CDCl3) δ 8.93 (s, 1H), 7.96−7.91 (m, 2H), 7.75 (dd, J = 8.0 Hz
& 4.0 Hz, 1H), 3.82 (s, 3H), 3.53 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3) δ 161.3, 151.6, 148.8, 148.5, 139.2, 134.1, 131.6, 129.9, 127.7,
125.4, 111.8, 29.8, 28.7 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd
for C13H11ClN3O2 276.0534; found 276.0533.
1
solid; mp 140−141 °C. IR (ATR) 1704, 1655 cm−1. H NMR (400
MHz, CDCl3) δ 8.98 (s, 1H), 7.93 (t, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0
Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.41 (t, J = 8.0 Hz, 2H), 4.07 (t, J =
8.0 Hz, 2H), 1.83−1.73 (m, 4H, CH2), 1.05−0.97 (m, 6H, CH3) ppm.
13C NMR (100 MHz, CDCl3) δ 166.9 and 164.4 (d, J(C‑F) = 253.0
1,3-Dimethyl-7-nitropyrimido[4,5-b]quinoline-2,4(1H,3H)-dione
Hz), 161.3, 151.64, and 151.50 (d, J(C‑F) = 14.0 Hz), 151.2, 149.2,
140.0, 131.69, and 131.58 (d, J(C‑F) = 11.0 Hz), 121.9, 116.74, and
116.48 (d, J(C‑F) = 26.0 Hz), 112.39 and 112.18 (d, J(C‑F) = 21.0 Hz),
110.66 and 110.64 (d, J(C‑F) = 20.0 Hz), 44.3, 43.6, 21.4, 21.2, 11.49,
11.47 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H19FN3O2
316.1456; found 316.1455.
(3l). Eluent: hexane/ethyl acetate (3:1). Yield 86 mg (60%); white
1
solid; mp 300−301 °C. IR (ATR) 1716, 1666, 1577, 1347 cm−1. H
NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.50 (s, 1H), 8.41 (s,
1H), 7.89 (s, 1H), 3.95 (s, 3H), 3.62 (s, 3H) ppm. 13C NMR (100
MHz, DMSO-d6) δ 159.9, 150.6, 147.4, 139.1, 132.2, 130.8, 126.0,
125.5, 117.5, 114.7, 113.0, 28.8, 27.6 ppm. HRMS (ESI-TOF): m/z
[M + H]+ calcd for C13H11N4O4 287.0775; found 287.0796.
7-Chloro-1,3-dipropylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione
(3t). Eluent: hexane/ethyl acetate (5:1). Yield 113 mg (68%); white
1,3-Dimethyl-7-(trifluoromethyl)pyrimido[4,5-b]quinoline-2,4-
(1H,3H)-dione (3m). Eluent: hexane/ethyl acetate (5:1). Yield 107 mg
(69%); white solid; mp 228−229 °C. IR (ATR) 1716, 1682 cm−1. 1H
1
solid; mp 186−187 °C. IR (ATR) 1702, 1655 cm−1. H NMR (400
MHz, CDCl3) δ 8.92 (s, 1H), 7.94−7.91 (m, 2H), 7.73 (d, J = 8.0 Hz,
G
DOI: 10.1021/acs.joc.7b03272
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The Journal of Organic Chemistry
Article
1H), 4.41 (t, J = 8.0 Hz, 2H), 4.07 (t, J = 8.0 Hz, 2H), 1.85−1.80 (m,
2H), 1.77−1.72 (m, 2H), 1.05−0.98 (m, 6H) ppm. 13CNMR (100
MHz, CDCl3) δ 161.1, 151.1, 148.5, 148.4, 139.2, 133.8, 131.4, 129.9,
127.6, 125.3, 111.9, 44.3, 43.7, 21.3, 21.2, 11.5, 11.4 ppm. HRMS (ESI-
TOF): m/z [M + H]+ calcd for C17H19ClN3O2 332.1160; found
332.1191.
1,3-Dipropylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione (3u). Elu-
ent: hexane/ethyl acetate (6:1). Yield 224 mg (75%); white solid; mp
148−149 °C. IR (ATR) 1704, 1655 cm−1. 1H NMR (400 MHz,
CDCl3) δ 8.99 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz,
1H), 7.80 (t, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 4.43 (t, J = 8.0
Hz, 2H), 4.08 (t, J = 8.0 Hz, 2H), 1.87−1.81 (m, 2H), 1.78−1.72 (m,
2H), 1.05−0.98 (m, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 161.4,
151.3, 150.1, 148.3, 140.1, 133.0, 129.3, 128.4, 125.8, 124.8, 111.2,
44.2, 43.6, 21.4, 21.2, 11.5 ppm. HRMS (ESI-TOF): m/z [M + H]+
calcd for C17H20N3O2 298.1550; found 298.1547.
was stirred under reflux conditions for 2 h. After completion of the
reaction, the mixture was poured to ice water and the crude product
was separated by just filtration. Finally, compound C1 was purified by
column chromatography.
6-Amino-5-(2-bromobenzyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-
dione (C1). Eluent: hexane/ethyl acetate (2:1). Yield 294 mg (85%);
1
white solid; mp 255−256 °C. IR (ATR) 3341, 1635, 1574 cm−1. H
NMR (400 MHz, CDCl3 + DMSO-d6) δ 7.47 (d, J = 8.0 Hz, 1H), 7.14
(t, J = 8.0 Hz, 1H), 7.02−6.95 (m, 2H), 6.21 (s, 2H), 3.66 (s, 2H),
3.36 (s, 3H), 3.17 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3
+
DMSO-d6) δ 161.9, 152.4, 151.0, 138.7, 131.8, 128.0, 127.2, 127.1,
124.5, 82.8, 29.8, 29.6, 27.5 ppm. HRMS (ESI-TOF): m/z [M + H]+
+
calcd for C13H14BrN3O2Na [M + Na] 346.0162; found 346.0159.
ASSOCIATED CONTENT
* Supporting Information
■
S
7-Methoxy-1,3-dipropylpyrimido[4,5-b]quinoline-2,4(1H,3H)-
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b03272.
dione (3v). Eluent: hexane/ethyl acetate (4:1). Yield 249 mg (76%);
1
white solid; mp 114−115 °C. IR (ATR) 1696, 1652 cm−1. H NMR
(400 MHz, CDCl3) δ 8.88 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.48−
7.45 (m, 1H), 7.16 (s, 1H), 4.41 (t, J = 8.0 Hz, 2H), 4.07 (t, J = 8.0
Hz, 2H), 3.94 (s, 3H), 1.86−1.72 (m, 4H), 1.05−0.98 (m, 6H) ppm.
13C NMR (100 MHz, CDCl3) δ 161.4, 157.1, 151.1, 146.7, 146.2,
NMR spectra (PDF)
Crystallographic data for 3a (CIF)
138.2, 129.6, 126.2, 125.5, 111.1, 105.8, 55.7, 44.0, 43.4, 21.3, 21.1,
11.38, 11.36 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for
C18H22N3O3 328.1656; found 328.1688.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: lokman@iitp.ac.in, lokman.iitp@gmail.com (L.H.C.).
*E-mail: tasneem@nitp.ac.in (T.P.).
ORCID
■
7-Fluoro-1,3-dipropylpyrimido[4,5-b]quinoline-2,4(1H,3H)-dione
(3w). Eluent: hexane/ethyl acetate (6:1). Yield 218 mg (69%); white
1
solid; mp 179−180 °C. IR (ATR) 1702, 1657 cm−1. H NMR (400
MHz, CDCl3) δ 8.95 (s, 1H), 7.99 (q, J = 4.0 Hz, 1H), 7.60−7.53 (m,
2H), 4.41 (t, J = 8.0 Hz, 2H), 4.08 (t, J = 8.0 Hz, 2H), 1.88−1.80 (m,
2H), 1.78−1.70 (m, 2H), 1.05−0.98 (m, 6H) ppm. 13C NMR (100
MHz, CDCl3) δ 161.2, 161.0, and 158.6 (d, J(C‑F)= 247 Hz), 151.1,
147.96, and 147.94 (d, J(C‑F)= 2.0 Hz), 147.2, 139.44, and 139.39 (d,
J(C‑F)= 5.6 Hz), 130.80 and 130.71 (d, J(C‑F)= 9.0 Hz), 125.19 and
125.09 (d, J(C‑F)= 10 Hz), 123.53 and 123.27 (d, J(C‑F)= 26.0 Hz),
112.08 and 111.86 (d, J(C‑F)= 22.0 Hz), 111.9, 44.3, 43.7, 21.4, 21.2,
11.49, 11.47 ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for
C17H19FN3O2 316.1456; found 316.1454.
Lokman H. Choudhury: 0000-0003-1735-1985
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful IIT Patna for providing basic research facilities
and fellowships to A.K.P., R.M., and A.J. T.P. is grateful to NIT
Patna. The authors are also grateful to DST, Govt. India, SAIF-
IIT Patna, and SAIF-CDRI Lucknow, for providing single
crystal XRD and HRMS data.
9,11-Dipropylbenzo[h]pyrimido[4,5-b]quinoline-8,10(9H,11H)-
dione (3x). Eluent: hexane/ethyl acetate (6:1). Yield 226 mg (65%);
1
white solid; mp 183−184 °C. IR (ATR) 1704, 1657 cm−1. H NMR
(400 MHz, CDCl3) δ 9.12 (d, J = 8.0 Hz, 1H), 8.91 (s, 1H), 7.91−
7.89 (m, 1H), 7.77−7.70 (m, 4H), 4.55 (t, J = 8.0 Hz, 2H), 4.10 (t, J =
8.0 Hz, 2H), 1.99−1.90 (m, 2H), 1.83−1.73 (m, 2H), 1.11 (t, J = 8.0
Hz, 3H), 1.02 (t, J = 8.0 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3)
δ 161.4, 151.3, 149.3, 148.1, 138.7, 135.3, 130.5, 129.9, 128.2, 127.3,
127.0, 125.5, 125.4, 122.7, 110.6, 44.6, 43.6, 21.4, 21.3, 11.7, 11.5 ppm.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H22N3O2 348.1707;
found 348.1737.
REFERENCES
■
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General Procedure for the Preparation of B1. A mixture of 2-
bromobenzaldehyde (1.0 mmol) and 6-amino-1,3-dimethyluracil (1.0
mmol) in 4.0 mL of DMF in the presence of K2CO3 (2.0 mmol) was
heated under microwave conditions at 150 °C for 15 min. After
completion of the reaction, the mixture was poured to ice water (20.0
mL) and the crude product was separated by just filtration. Finally,
compound B1 was purified by recrystallization from hot methanol.
5,5′-((2-Bromophenyl)methylene)bis(6-amino-1,3-dimethylpyri-
midine-2,4(1H,3H)-dione) (B1). Purified by recrystallization from
MeOH. Yield 429 mg (90%); white solid; mp 223−224 °C. IR
́
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1
(ATR) 3374, 1668, 1594 cm−1. H NMR (400 MHz, DMSO-d6) δ
7.47−7.40 (m, 3H), 7.31 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H),
7.01 (t, J = 8.0 Hz, 1H), 6.90 (br s, 2H), 5.66 (s, 1H), 3.35 (s, 6H),
3.19 (s, 3H), 3.04 (s, 3H). 13C NMR (100 MHz, CDCl3 + DMSO-d6)
δ 163.0, 162.0, 154.1, 154.0, 150.5, 139.9, 132.8, 129.1, 127.2, 126.7,
122.9, 86.7, 85.5, 36.8, 29.9, 28.2, 27.7 ppm. HRMS (ESI-TOF): m/z
[M + H]+ calcd for C19H22BrN6O4 477.0880; found 477.0886.
General Procedure for the Preparation of C1. A mixture of 2-
bromobenzyl bromide (1.0 mmol) and 6-amino-1,3-dimethyluracil
(1.0 mmol) in 4 mL of DMF in the presence of K2CO3 (2.0 mmol)
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DOI: 10.1021/acs.joc.7b03272
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