Design and synthesis of new naphtho[2,1-b]pyrano [2,3-d]pyrimidinones under classical and microwave conditions

Article abstract of DOI:10.3906/kim-1803-84

A fast and efficient method for the synthesis of naphthopyranopyrimidinones derivatives in excellent yields was developed through cyclocondensation reaction between previously prepared pyrimidinic hydrazides and some electrophilic species such as 2,4-pentanedione, 2,5-hexanedione, cyclic anhydrides, and phenylthioisocyanate under microwave irradiation. Compared to the conventional methods applied, it was found that better yields and shorter reaction times were achieved using microwave-assisted synthesis. Structures of all synthesized compounds were established on the basis of spectroscopic methods including ¹ H NMR,¹³ C NMR, and HRMS-ES.

Full text of DOI:10.3906/kim-1803-84

Turk J Chem
Turkish Journal of Chemistry
(2018) 42: 1623 – 1639
© TÜBİTAK
http://journals.tubitak.gov.tr/chem/
doi:10.3906/kim-1803-84
Research Article
Design and synthesis of new naphtho[2,1-b]pyrano [2,3-d]pyrimidinones under
classical and microwave conditions
Maher CHERIF,, Mariem DEBBABI,, Sarra CHORTANI,, Anis ROMDHANE∗,,
Hichem BEN JANNET,
Laboratory of Heterocyclic Chemistry, Natural Products, and Reactivity, Team of Medical Chemistry
and Natural Products, Department of Chemistry, Faculty of Sciences of Monastir, University of Monastir,
Monastir, Tunisia
Received: 31.03.2018
•
Accepted/Published Online: 24.07.2018
•
Final Version: 06.12.2018
Abstract: A fast and efficient method for the synthesis of naphthopyranopyrimidinones derivatives in excellent yields
was developed through cyclocondensation reaction between previously prepared pyrimidinic hydrazides and some elec-
trophilic species such as 2,4-pentanedione, 2,5-hexanedione, cyclic anhydrides, and phenylthioisocyanate under microwave
irradiation. Compared to the conventional methods applied, it was found that better yields and shorter reaction times
were achieved using microwave-assisted synthesis. Structures of all synthesized compounds were established on the basis
1
13
of spectroscopic methods including H NMR, C NMR, and HRMS-ES.
Key words: Pyrimidinic hydrazides, cyclocondensation, naphthopyranopyrimidinones derivatives, conventional synthe-
sis, microwave-assisted synthesis
1. Introduction
1−4
Pyrimidinone and its derivatives have been studied due to their chemical and biological significance.
A
literature survey revealed that fused pyrimidinones, and especially pyranopyrimidinone derivatives, are known
5
6
7
to exhibit potential antitubercular, anticancer, and antioxidant activities. Therefore, they gained much
attention as important pharmacophores and privileged structures in medicinal chemistry. On the other
hand, five-membered ring systems, such as pyrrole, pyrrolidinedione, pyrazole, or oxadiazolidinethione sub-
structures, proved to be promising drug candidates. Pyrroles and their derivatives exhibit different impor-
8
9
10
tant biological activities like antimicrobial, cytotoxic , and antiinflammatory activities. Furthermore, 2,5-
pyrrolidinediones are core structural units found in natural products and also in some approved drugs and clin-
11,12
ical drug candidates.
Moreover, pyrazolic compounds exhibit a broad spectrum of biological activities such
13
14
15
16
as antiinflammatory, antitumor, antifungal, and antiviral activities, whereas oxadiazolidinethione and
17
their derivatives are extensively used in medicine due to their pharmacological properties such as anticandidal,
antiviral, and antitumor activity.
18
19
Microwave-assisted organic synthesis is one of the high-speed techniques and efficient synthetic tools
that have attracted a substantial amount of attention in recent years, since the first reports by Gedye et al.
20,21
and Giguere et al. in 1986.
It is well known to induce a reduction in the time of various reactions, yield
enhancement, and cleaner chemistry. Many reactions have proven to result in higher yield and/or selectivity
∗Correspondence: anis_romdhane@yahoo.fr
1623
This work is licensed under a Creative Commons Attribution 4.0 International License.

CHERIF et al./Turk J Chem
22,23
under microwave irradiation compared with conventional heating.
Keeping in view the above and in con-
tinuation of our efforts directed toward the synthesis of new heterocyclic compounds with anticipated biological
24−26
activities,
we wish to report herein a comparative study of microwave-assisted synthesis and conventional
heating for the preparation of some new hybrid compounds combining naphthopyrano[3,2-d]pyrimidinone and
pyrrole, pyrrolidinedione, pyrazole, or oxadiazolidinethione rings.
2. Results and discussion
2.1. Synthesis
The 2-aminonaphthopyrano-3-carbonitriles 1a–1d served as key starting material. They were prepared in high
to excellent yields via a one-pot, three-component reaction of equimolar amounts of arylaldehyde, malononitrile,
and β -naphthol in aqueous ethanol using CuI, which is emerging as an effective Lewis acid catalyst for
27−30
various organic transformations.
The structures of these precursors were established on the basis of their
31
spectroscopic data according to our previous work (Scheme 1).
Scheme 1. Synthetic pathway to 2-aminonaphthopyrano-3-carbonitriles 1a–1d.
Mechanistically, the reaction starts with Knoevenagel condensation between the enol form of malononitrile
(I) and arylaldehyde in the presence of CuI as a catalyst to give the intermediate (II), which is immediately
transformed into another intermediate (III) as a result of the Michael addition of β -naphthol at the conjugated
C=C bond of (II), which leads to precursors 1a–1d in good yields by intramolecular concerted cyclization
(Scheme 2).
Our approach to the target hybrid molecules 4–9 first started by the synthesis of precursor 3 via
condensation reaction of 2-aminonaphthopyrano-3-carbonitrile 1 with acetic anhydride in the presence of a
catalytic amount of polyphosphoric acid (PPA) under reflux for 1 h. The obtained pyranopyrimidinones 2 were
N -alkylated by reaction with ethylchloroacetate to give the corresponding esters, which were subsequently
hydrazinolyzed by hydrazine hydrate (Scheme 3).
In the abovementioned precursors 3, the hydrazide moiety made them valuable key precursors for the
32−34
formation of several heterocyclic compounds
and aroused our interest to explore them in order to obtain the
desired hybrid compounds 4–9. Thus, we performed the cyclocondensation of pyrimidinic precursors 3 with some
electrophilic species, namely 2,4-pentanedione, 2,5-hexanedione, cyclic anhydrides, and phenylthioisocyanate,
under both microwave irradiation and classical heating conditions.
This part of our work was initiated with the reaction between pyrimidinic hydrazides 3 and 2,5-
hexanedione (Scheme 4). First, this reaction was carried out in a domestic microwave oven (Samsung MW71C,
800 W output power) under solvent-free conditions and was monitored by TLC. In order to determine the best
conditions for the preparation of new pyranopyrimidinones 4, we examined the reaction under various conditions
by changing the irradiation power and reaction time. We found that the best yields (87%–96%, Table 1) were
1624

CHERIF et al./Turk J Chem
Scheme 2. Proposed mechanism for the formation of compounds 1a–1d.
Scheme 3. Synthetic pathway to pyrimidinic hydrazides 3a–3d.
obtained after 3 min of irradiation at 300 W of an equimolar mixture of precursors 3 and 2,5-hexanedione. To
compare the microwave-assisted synthesis method with classical heating methods, the synthesis of pyranopy-
1625

CHERIF et al./Turk J Chem
rimidinones 4 was also performed under reflux in dioxane without catalyst (method A). Related experimental
results are shown in Table 1. It is clear that in all cases much shorter reaction times and higher yields were
achieved under microwave irradiation compared with classical heating. For example, with conventional heating,
pyrrolic derivative 4b was obtained in 57% yield in 12 h (method A), whereas under microwave conditions
(method B), after 3 min the yield of the reaction was 96%.
Scheme 4. Synthetic pathway to pyrrolic derivatives 4a–4c.
Table 1. Comparison between the conventional procedure (method A) and microwave irradiation (method B) for the
synthesis of compounds 4, 5, 7, and 8.
Method A
Time (h) Yield (%)
12
Method B
Time (min) Yield (%)
Entry
R
H
a
a
4a
4b
4c
5a
5b
5c
7a
7b
7c
8a
8b
45
57
52
52
58
64
43
47
60
45
55
58
3
3
3
3
3
3
5
5
5
5
5
5
87
96
92
88
92
96
86
92
88
94
96
95
MeO 12
Cl
H
Me
12
12
12
MeO 12
H
Me
12
12
MeO 12
H
Me
12
12
8c
MeO 12
a
Isolated yields.
1
The thus-formed new compounds 4 were characterized essentially by H NMR spectra showing, in
addition to the signals corresponding to the protons introduced by the naphthopyranopyrimidinone moiety, the
1626

CHERIF et al./Turk J Chem
presence of a singlet at δH 10.88–11.12 due to the NH group and one signal relative to methyl groups at δH
1.93–1.99 and ethylene protons at δH 4.74–4.82 and 4.90–4.96, for which chemical shifts and multiplicities were
in good agreement with the proposed structure.
Encouraged by this success, we became interested in applying this protocol for 2,4-pentanedione, two
cyclic anhydrides, and phenylthioisocyanate. Thus, cyclocondensation of pyrimidinic hydrazides 3 and 2,4-
pentanedione, in the same solvent-free reaction conditions (method B: 3 min of irradiation at 300 W), afforded
the new hydroxylated pyrazolic derivatives 5 (88%–96% yield, Table 1). Alternatively, compounds 5 were
obtained in yields ranging from 52% to 64% (Table 1) when an equimolar mixture of hydrazides 3 and pentane-
2,4-dione was heated under reflux with dioxane for 12 h (method A) (Table 1).
A plausible mechanism explaining the formation of these compounds is shown in Scheme 5. This
mechanism results in the nonisolable hydrazone intermediate 3', obtained by the nucleophilic attack of hydrazide
3 followed by dehydration, which develops an intramolecular cyclization to afford compounds 5.
Scheme 5. Synthetic pathway to pyrazolic derivatives 5a–5c and 6a–6b.
We note that the possibility of formation of a pseudo-six-membered ring, inducing a strong hydrogen
bond, may explain why the reaction has not evolved to compounds 6 under the same experimental conditions
that allowed access to compounds 4 (Figure).
Figure. Possibility of formation of hydrogen bonding in compounds 5.
Conventional heating of compounds 5 in dioxane in the presence of a catalytic amount of acetic acid
1627

CHERIF et al./Turk J Chem
afforded pyrazolic derivatives 6 in 48%–54% yield in 12 h (method A) due to a second dehydration. The same
reaction conducted for 10 min in DMF with microwave assistance at 300 W in the presence of a catalytic amount
of acetic acid (method B) afforded the same products, 6a and 6b, in yields ranging from 90% to 97% (Scheme
5; Table 2).
Table 2. Comparison between the conventional procedure (method A) and microwave irradiation (method B) for the
synthesis of compounds 6.
Method A
Time (h) Yield (%)
12
Method B
Time (min) Yield (%)
10
10
Entry
R
H
a
a
6a
48
54
90
97
6b
Me 12
Isolated yields.
a
The structures of new compounds 5 have been assigned from their analytical data and mass spectroscopy
1
(HR-ES-MS). Furthermore, the H NMR spectra of compounds 5 showed the duplication of some signals
confirming the obtaining of two nonseparable diastereoisomers due to the presence of two stereocenters C-5
at δC (35.2–36.1) and C-5''' at δC (90.6–90.7); therefore, the second dehydration, which in principle leads to
1
compounds 6, had not occurred. The H NMR spectra of these compounds indicate essentially the presence
of characteristic signals based on their chemical shifts, readily assigning the protons of the methylene group
(H-1''), which was found as a pair of two doublets at δH 4.91–5.18 (J = 17.4 and 17.7 Hz), and also the
presence of two singlets at δH 5.68–5.77 due to the H-5 proton and two broad D2 O-exchangeable singlets at δH
6.49–6.54 due to the OH group in the two diastereoisomers. Unambiguous proof for obtained products 5a–5c
13
arose from their C NMR data (see Section 3).
Similarly, the structures of isolated products 6 were confirmed on the basis of their spectral data. In
the H NMR spectrum, we note essentially the disappearance of the two doublets assigning the protons of the
1
methylene group (H-4''') and the two broad singlets due to the OH group and the appearance of a new singlet
at δH 6.02 relative to the proton H-4''' due to the formation of the double bond after the second dehydration.
13
The C NMR spectrum of this compound showed essentially the appearance of new signals at 111.6–111.7 and
144.6 ppm attributable to the ethylenic carbons C-4''' and C-5''', respectively.
On the other hand, heating pyrimidinic precursors 3 under reflux for 12 h with phthalic or tricyclic
anhydrides in glacial acetic acid (method A) furnished the corresponding new pyrrolidinediones 7a–7c and
8a–8c in 43%–60% yield. The same reaction conducted for 5 min under microwave assistance at 300 W in
DMF (method B) afforded the same products 7a–7c and 8a–8c in yields ranging from 86% to 96% (Scheme 6,
Table 1).
The structures of all new synthesized compounds 7 and 8 have been assigned from their analytical data
1
13
and IR, H NMR, C NMR, and mass spectroscopy (HRMS-ES).
Finally, our attention was focused on the reaction of hydrazide 3a with phenylisothiocyanate. However,
after 3 min of solvent-free irradiation at 300 W of an equimolar mixture of precursor 3a and phenylthioisocyanate
we obtained the new oxadiazolidinethione derivative 9 in 97% yield (method B). When the reaction was carried
out under refluxing dioxane for 6 h (method A), product 9 was yielded in 54% (Scheme 7). Mechanistically,
phenylisothiocyanate reacted with hydrazide 3a to give the nonisolable intermediate 3a'', which yields to
1628

CHERIF et al./Turk J Chem
Scheme 6. Synthetic pathway to derivatives 7a–7c and 8a–8c.
the formation of oxazolidinethione 9 via intramolecular cyclization followed by elimination of a molecule of
phenylamine.
Scheme 7. Synthetic pathway to oxathiazolidinethione 9.
1
13
The structure of newly synthesized compound 9 was characterized by H NMR and C NMR, which
show the absence of signals of the phenyl group, proving the elimination of a molecule of phenylamine and the
access to compound 9. Furthermore, the HRMS-ES mass spectra showed essentially the pseudomolecular ion
+
peaks [M+H] , which were in good agreement with the assigned structures.
2.2. Conclusions
In summary, a straightforward, efficient, and cost-effective method was achieved for the preparation of some
new hybrid molecules combining pyranopyrimidinones with pyrrole, pyrrolidine, pyrazole, or oxazolidinethione
(4–9) with the assistance of microwave irradiation from hydrazides 3 and some electrophilic species via cyclocon-
densation reactions. The method offers several advantages including good to high yields, cleaner products, and
1629

CHERIF et al./Turk J Chem
particularly a reduction in reaction time. In this study, the use of microwave irradiation reduced the reaction
time from 3–12 h to 3–5 min with better yields than those obtained by conventional methods, which makes this
method particularly attractive.
3. Experimental
3.1. General experimental procedures
All reactions were monitored by TLC using aluminum sheets of SDS silica gel 60 F254 , 0.2 mm. Melting
temperatures were determined on an Electrothermal 9002 apparatus and were reported uncorrected. NMR
1
13
spectra were recorded on a Bruker AC-300 spectrometer at 300 MHz ( H) and 75 MHz ( C). All chemical
shifts were reported as δ values (ppm) relative to residual nondeuterated solvent. Mass spectra were acquired
with an LCT Premier XE mass spectrometer (Waters, ESI technique, positive mode). Starting materials 2 and
35,36
3 were prepared according to the literature.
Microwave irradiation was performed in a domestic microwave
oven (Samsung MW71C, 800 W output power).
3.2. Synthesis
3.2.1. General procedure for the synthesis of 2-amino-3-cyanonaphthopyranes 1a–1d
A solution of aromatic aldehyde (10 mmol), malononitrile (10 mmol), β -naphthol (10 mmol), and CuI (0.37 g, 20
mol%) in 50 mL of ethanol and water (30:70 v/v) was stirred at room temperature for 1 h. The precipitated solid
was separated and purified by recrystallization in ethanol to give compounds 1a–1d in good yields (93%–97%).
31
Their spectral data were detailed in our previous work.
3.2.2. General procedure for the synthesis of hydrazides 3a–3d
Acetic anhydride (20 mL) was added to 2-amino-3-cyanonaphthopyranes 1 (10 mmol), and then orthophosphoric
acid (5 mL) was added carefully and the resulting hot mixture was refluxed for 3 h. After cooling, the mixture
was diluted with cold water, and the formed solid was collected by filtration, washed several times with cold
water, and subjected to crystallization from ethanol to afford compounds 2. In the second step, a mixture of 2
(10 mmol), ethyl chloroacetate (11 mmol), and anhydrous potassium carbonate (10.5 g) in dry DMF (100 mL)
was refluxed for 8 h. The reaction mixture was allowed to cool and then it was poured in water. The thus-formed
resultant solid was filtered off, dried, and crystallized from ethanol; then it was treated with hydrazine hydrate
(15 mmol) under reflux with 1,4-dioxane (50 mL) for 6 h. The excess of solvent was removed and the product
was crystallized from ethanol, giving the desired hydrazides 3.
3.2.2.1. 2-(2-Methyl-12-oxo-11-phenyl-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-3-yl)acetohydra-
zide (3a)
1
White solid, yield 72%, mp 262–264 °C (ethanol), H NMR (300 MHz, DMSO-d6): δ = 2.45 (s, 3H, CH3),
4.20 (s, 2H. NH2), 4.57 (d, 1H, H2 , J = 16.2 Hz), 4.72 (d, 1H, H2 , J = 16.2 Hz), 5.77 (s, 1H, H11'), 7.06
13
(t, 1H, J = 7.2 Hz, ArH), 7.15–7.52 (m, 7H, ArH), 7.90–7.99 (m, 3H, ArH), 9.22 (s, 1H, -NH); C NMR
(75 MHz, DMSO-d6): δ = 22.3 (-CH3), 36.2 (C11'), 44.9 (C2), 100.1 (C11'a), 116.5 (C10'b), 117.3 (C5'),
123.3 (C10'), 124.9 (C8'), 126.4 (C9'), 127.1 (C2'',6''), 128.1 (C7'), 128.2 (C6'), 128.5 (C3'',5''), 129.4 (C6'a),
1630

CHERIF et al./Turk J Chem
130.6 (C13'a), 131.1 (C4''), 144.1 (C1''), 147.9 (C4'a), 159.2 (C2'), 159.7 (C3'a), 161.5 (C12'), 165.6 (C1);
+
HRMS-ES calculated for [M+H] C24 H21 N4 O3 : 413.1502; found: 413.1510.
3.2.2.2. 2-(2-Methyl-11-(p-methylphenyl)-12-oxo-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-3-yl)
acetohydrazide (3b)
1
White solid, yield 68%, mp 258–260 °C (ethanol); H NMR (300 MHz, DMSO-d6): δ = 2.45 (s, 3H, CH3), 2.51
(s, 3H, CH3), 4.30 (s, 2H, NH2), 4.55 (d, 1H, H2 , J = 16,2 Hz), 4.69 (d, 1H, H2 , J = 16.2 Hz), 5.67 (s, 1H,
H11'), 6.73 (d, 2H, J = 8.7 Hz, ArH), 7.21 (d, 2H, J = 8.7 Hz, ArH), 7.40–7.52 (m, 3H, ArH), 7.91–7.97 (m,
13
3H, ArH), 9.41 (s, 1H, -NH); C NMR (75 MHz, DMSO-d6): δ = 22.3 (CH3 -Ar), 22.5 (-CH3), 35.2 (C11'),
44.8 (C2), 100.2 (C11'a), 116.6 (C10'b), 117.3 (C5'), 123.4 (C10'), 124.9 (C8'), 127.1 (C9'), 128.5 (C2'',6''),
129.1 (C7'), 129.4 (C6'), 130.4 (C3'',5''), 131.1 (C6'a), 136.2 (C13'a), 147.6 (C1''), 157.7 (C4'a), 158.8 (C2'),
+
159.7 (C3'a), 161.5 (C12'), 165.6 (C1); HRMS-ES calculated for [M+H] C25 H23 N4 O3 : 427.1623; found:
427.1617.
3.2.2.3. (2-Methyl-11-(p-methoxyphenyl)-12-oxo-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-3-yl)
acetohydrazide (3c)
1
White solid, yield 64%, mp 274–276 °C (ethanol); H NMR (300 MHz, DMSO-d6): δ = 2.45 (s, 3H, CH3),
3.62 (s, 3H, OCH3), 4.30 (s, 2H, NH2), 4.56 (d, 1H, H2 , J = 16.5 Hz), 4.69 (d, 1H, H2 , J = 16.5 Hz),
5.67 (s, 1H, H11'), 6.74 (d, 2H, J = 8.4 Hz, ArH), 7.21 (d, 2H, J = 8.4 Hz, ArH), 7.40–7.52 (m, 3H, ArH),
13
7.91–7.97 (m, 3H, ArH), 9.42 (s, 1H, -NH); C NMR (75 MHz, DMSO-d6): δ = 22.5 (-CH3), 35.2 (C11'), 44.8
(C2), 54.9 (-OCH3), 100.2 (C11'a), 113.6 (C3'',5''), 116.5 (C10'b), 117.3 (C5'), 123.4 (C10'), 124.9 (C8'), 127.2
(C9'), 128.5 (C7'), 129.2 (C2'',6''), 129.3 (C1''), 130.4 (C6'), 131.1 (C6'a), 136.2 (C1''), 147.6 (C4''), 157.7
+
(C4'a), 158.8 (C2'), 159.7 (C3'a), 161.4 (C12'), 165.8 (C1); HRMS-ES calculated for [M+H] C25 H23 N4 O4 :
443,1521; found: 443,1513.
3.2.2.4. (2-Methyl-11-(p-chlorophenyl)-12-oxo-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-3-yl)ace-
tohydrazide (3d)
1
White solid, yield 63%, mp 282–284 °C (ethanol); H NMR (300 MHz, DMSO-d6): δ = 2.46 (s, 3H, CH3),
4.21 (s, 2H, NH2), 4.58 (d, 1H, H2 , J = 15.9 Hz), 4.64 (d, 1H, H2 , J = 15.9 Hz), 5.79 (s, 1H, H11'),
13
7.22–7.53 (m, 7H, ArH), 7.61–7.99 (m, 3H, ArH), 9.30 (s, 1H, -NH); C NMR (75 MHz, DMSO-d6): δ =
22.3 (-CH3), 35.7 (C11'), 45.0 (C2), 99.6 (C11'a), 115.9 (C10'b), 117,3 (C5'), 123.3 (C10'), 125.0 (C8'), 127.2
(C9'), 128.1 (C3'',5''), 128.5 (C7'), 129.7 (C6'), 129.9 (C2'',6''), 130.5 (C6'a), 131.1 (C13'a), 131.2 (C4''), 142.9
+
(C1''), 147.9 (C4'a), 159.1 (C2'), 159.9 (C3'a), 161.3 (C12'), 165.5 (C1); HRMS-ES calculated for [M+H]
C24 H20 ClN4 O3 : 447,1146; found: 447,1152.
3.2.3. General procedure for synthesis of 2-(2-methyl-12-oxo-11-aryl-4H-naphtho[2,1-b]pyrano[2,3-
d]pyrimidin-1-yl)-N-(2,5-dimethylpyrrol-1-yl) acetamides 4
Method A (conventional method): A mixture of appropriate hydrazide 3 (1 mmol) and 2,5-hexanedione (1
mmol) was stirred under reflux with dry dioxane. After 12 h, the reaction mixture was cooled to room
1631

CHERIF et al./Turk J Chem
temperature, the dioxane was removed in vacuo, and the residue was purified by silica gel chromatography
(chloroform and ethyl acetate, 70:30) to give compounds 4.
Method B (microwave-assisted): An open 25-mL flask containing hydrazide 3 (1 mmol) and 2,5-
hexanedione (1 mmol) was introduced in a domestic microwave oven (Samsung MW71C, 800 W output power)
and irradiated for 3 min (300 W). The reaction was monitored by TLC, and after completion the flask was
cooled and the obtained residue was recrystallized from ethanol to give compounds 4.
3.2.4. 2-(2-Methyl-12-oxo-11-phenyl-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-1-yl)-N-(2,5-dimet-
hylpyrrol-1-yl) acetamide (4a)
White solid, mp 246–248 °C (ethanol), H NMR (300 MHz, DMSO-d6)δ = 1.93 (s, 6H, 2CH(a)), 2.46 (s,
1
3
3H, CH(3b)), 4.74 (d, 1H, H2 , J = 16.5 Hz), 4.90 (d, 1H, H2 , J = 16.5 Hz), 5.57 (s, 2H, H
), 5.73 (s,
3'',4''
1H, H11'), 7.02 (t, 1H, J = 7.2 Hz, ArH), 7.11–7.50 (m, 7H, ArH), 7.87–7.95 (m, 3H, ArH), 11.05 (s, 1H,
13
-NH); C NMR (75 MHz, DMSO-d6): δ = 10.7 (Ca), 22.6 (Cb), 35.9 (C11'), 45.3 (C2), 100.0 (C11'a),
103.1 (C3'',C4''), 116.2, 117.3, 123.4, 125.0, 126.5, 126.7 (C2''), 127.2, 128.1 (C3''',5'''), 128.2 (C2''',6'''),
128.5, 129.5, 130.4, 131.1, 143.9, 147.7 (C4'a), 158.9, 159.5, 161.3 (C12'), 166.1 (C1); HRMS-ES calculated for
+
[M+H] C30 H27 N4 O3 : 491,2005; found: 491,2012.
3.2.5. 2-(2-Methyl-12-oxo-11-(p-methoxyphenyl)-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-1-yl)-
N-(2,5-dimethylpyrrol-1-yl) acetamide (4b)
White solid, mp 252–254 °C (ethanol); H NMR (300 MHz, DMSO-d6): δ = 1.99 (s, 6H, 2CH(a)), 2.51 (s,
1
3
3H, CH(3b)), 3.63 (s, 3H, OCH3), 4.81 (d, 1H, H2 , J = 16.5 Hz), 4.96 (d, 1H, H2 , J = 16.5 Hz), 5.63 (s, 2H,
H3'',4''), 5.75 (s, 1H, H11'), 6.73 (d, 2H, J = 8.4 Hz, ArH), 7.22 (d, 2H, J = 8.4 Hz, ArH), 7.49–7.52 (m, 3H,
13
ArH), 7.91–7.98 (m, 3H, ArH), 11.12 (s, 1H, -NH); C NMR (75 MHz, DMSO-d6): δ = 10.9 (Ca , Cb), 22.5
(Cc), 35.1 (C11'), 45.8 (C2), 54.9 (Cd), 100.3 (C11'a), 103.1 (C3'' ,C4''), 113.6 (C3''',5'''), 116.4, 117.3, 124.9,
126.8 (C2''), 127.1, 128.2, 128.5, 129.1 (C2''',6'''), 129.5, 130.4, 131.1, 136.1, 147.6 (C4'a), 157.7, 158.8, 159.4,
+
161.3 (C12'), 166.1 (C1); HRMS-ES calculated for [M+H] C31 H29 N4 O4 : 521,2189; found: 521,2197.
3.2.6. 2-(2-Methyl-12-oxo-11-(p-chlorophenyl)-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-1-yl)-N-
(2,5-dimethylpyrrol-1-yl) acetamide (4c)
White solid, mp 264–266 °C (ethanol), H NMR (300 MHz, DMSO-d6): δ = 1.98 (s, 6H, 2 CH(a)), 2.15 (s,
1
3
3H, CH(3c)), 2.53 (s, 3H, CH(3b)), 4.82 (d, 1H, H2 , J = 16.5 Hz), 4.96 (d, 1H, H2 , J = 16.5 Hz), 5.62 (s,
2H, H3'',4''), 5.81 (s, 1H, H11'), 7.21 (d, 2H, J = 8.4 Hz, ArH), 7.34 (d, 2H, J = 8.4 Hz, ArH), 7.46–7.51
13
(m, 3H, ArH), 7.91–7.98 (m, 3H, ArH), 10.88 (s, 1H, -NH); C NMR (75 MHz, DMSO-d6): δ = 10.7 (Ca ,
Cb), 20.5 (Cd), 22.4 (Cc), 35.6 (C11'), 45.4 (C2), 99.7 (C11'a), 103.2 (C3'',C4''), 115.7, 117.3, 123.3, 124.9,
126.9 (C2''), 127.2, 128.1 (C3''',5'''), 128.5, 129.7, 129.9 (C2''',6'''), 130.4, 131.1, 131.2, 142.8, 147.9 (C4'a),
+
159.2, 159.7, 161.4 (C12'), 165.9 (C1). HRMS-ES calculated for [M+H] C30 H26 ClN4 O3 : 525,2139; found:
525,2148.
1632

CHERIF et al./Turk J Chem
3.3. General procedure for the synthesis of 3-(2-(4,5-dihydro-5-hydroxy-3,5-dimethylpyrazol-1-
yl)-2-oxoethyl)-2-methyl-5-aryl-4H-naphtho[2,1-b]pyrano[2,3-d] pyrimidin-4(5H)-ones 5
Method A (conventional method): A mixture of appropriate hydrazide 3 (1 mmol) and 2,4-pentanedione
(1 mmol) was stirred under reflux with dry dioxane. After 12 h, the reaction mixture was cooled to room
temperature, and the dioxane was removed in vacuo and the residue was purified by silica gel chromatography
(chloroform and ethyl acetate, 60:40) to yield compounds 5.
Method B (microwave-assisted): An open 25-mL flask containing hydrazide 3 (1 mmol) and 2,4-
pentanedione (1 mmol) was introduced in a domestic microwave oven (Samsung MW71C, 800 W output power)
and irradiated for 3 min (300 W). The reaction was monitored by TLC, and after completion the flask was
cooled and the obtained residue was recrystallized from ethanol to give compounds 5.
3.3.1. 3-(2-(4,5-Dihydro-5-hydroxy-3,5-dimethylpyrazol-1-yl)-2-oxoethyl)-2-methyl-5-phenyl-4H-
ꢀnaphtho[2,1-b]pyrano[2,3-d]pyrimidin-4(5H)-one (5a,a')
(a)
White solid, mp: 251–253 °C (ethanol), H NMR (300 MHz, DMSO-d6): δ = 1.73 (s, 6H, CH3(5a) and
1
CH(a) ), 2.01 (s, 6H, CH(b) and CH(b) ), 2.40 (s, 6H, CH(c) and CH(c) ), 2.82 (d, 2H, H4'''a(5a,a')
,
3(5a)
3(5a)
3(5a')
3(5a')
3(5a')
J = 18.4 Hz), 2.97 (d, 2H, H4'''b(5a,a') , J = 18.4 Hz), 4.91–5.16 (4d, 4H, J = 17.4 Hz, J = 17.7 Hz, H1''(5a)
and H1''(5a')), 5.75 and 5.77 (2s, 2H, H5(5a) and H5(5a')), 6.49 and 6.54 (2s, 2H, OH(5a) and OH(5a')), 7.07 (t,
2H, J = 6.9 Hz, ArH), 7.19 (t, 4H, J = 7.2 Hz, ArH), 7.32 (d, 4H, J = 7.2 Hz, ArH), 7.42–7.55 (m, 6H, ArH),
13
7.93–7.99 (m, 6H, ArH); C NMR (75 MHz, DMSO-d6): δ = 15.8 (Cb(5a) and Cb(5a')), 22.3 (Cc(5a) and
Cc(5a')), 25.6 and 25.7 (Ca(5a) and Ca(5a')), 36.1 (C5(5a) and C5(5a')), 46.2 and 46.3 (C1''(5a) and C1''(5a')),
52.0 (C4'''(5a) and C4'''(5a')), 90.6 and 90.7 (C5'''(5a) and C5'''(5a')), 99.9 and 100.0 (C4a(5a) and C4a(5a')),
116.4, 117.3, 123.4, 125.0, 126.5, 127.2, 128.1, 128.2, 128.5, 129.5, 130.4, 131.1, 144.1 (Carom.), 147.7 (C11a(5a)
and C11a(5a')), 156.2 and 156.3 (C3'''(5a) and C3'''(5a')), 159.0, 159.8 (Carom.), 161.3 (C4(5a) and C4(5a')),
+
163.1 and 163.3 (C2''(5a) and C2''(5a')); HRMS-ES calculated for [M+H] C29 H27 N4 O3 : 495,1954; found:
495,1947.
3.3.2. 3-(2-(4,5-Dihydro-5-hydroxy-3,5-dimethylpyrazol-1-yl)-2-oxoethyl)-2-methyl-5-(p-methyl
phenyl)-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-4(5H)-one (5b,b')
(a)
White solid, mp 248–250 °C (ethanol); H NMR (300 MHz, DMSO-d6): δ = 1.73 (s, 6H, CH3(5b) and CH(a) ),
1
3(5b')
(b)
3(5b)
2.01 (s, 6H, CH
and CH(b) ), 2.14 (s, 6H, CH(d) and CH(d) ), 2.39 (s, 6H, CH(c) and CH(c) ), 2.81
3(5b)
3(5b)
3(5b')
3(5b')
3(5b')
(d, 2H, H4'''a (5a,a') , J = 18.6 Hz), 2.96 (d, 2H, H4'''b (5a,a') , J = 18.6 Hz), 4.91–5.13 (4d, 4H, J = 17.4 Hz,
J = 17.7 Hz, H1''(5b) and H1''(5b')), 5.68 and 5.70 (2s, 2H, H5(5b) and H5(5b')), 6.50 and 6.53 (2s, 2H, OH(5b)
and OH(5b')), 6.98 (d, 4H, J = 7.8 Hz, ArH), 7.19 (d, 4H, J = 7.8 Hz, ArH), 7.40–7.53 (m, 6H, ArH), 7.91–7.98
13
(m, 6H, ArH); C NMR (75 MHz, DMSO-d6): δ = 15.8 (Cb(5b) and Cb(5b')), 20.4 (Cd(5b) and Cd(5b')), 22.3
(Cc(5b) and Cc(5b')), 25.6 and 25.7 (Ca(5b) and Ca(5b')), 35.6 (C5(5b) and C5(5b')), 46.2 and 46.3 (C1''(5b) and
C
1''(5b')), 51.9 (C4'''(5b) and C4'''(5b')), 90.6 and 90.7 (C5'''(5b) and C5'''(5b')), 100.2 and 100.3 (C4a(5b) and
1633

CHERIF et al./Turk J Chem
C4(5b')), 116.5, 117.3, 123.4, 124.9, 127.1, 128.0, 128.5, 128.8, 129.4, 130.4, 131.0, 135.6, 141.2 (Carom.), 147.6
(C11a(5b) and C11a(5b')), 156.2 and 156.3 (C3'''(5b) and C3'''(5b')), 158.9, 159.7 (Carom.), 161.3 (C4(5b) and
+
C
4(5b')), 163.2 and 163.3 (C2''(5b) and C2''(5b')), HRMS-ES calculated for [M+H] C30 H29 N4 O4 : 509.2111,
found: 509.2102.
3.3.3. 3-(2-(4,5-Dihydro-5-hydroxy-3,5-dimethylpyrazol-1-yl)-2-oxoethyl)-2-methyl-5-(p-methoxy
phenyl)-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-4(5H)-one (5c,c')
(a)
White solid, mp 244–246 °C (ethanol); H NMR (300 MHz, DMSO-d6)δ = 1.74 (s, 6H, CH3(5c) , and CH(a) ),
1
3(5c')
(b)
3(5c)
2.01 (s, 6H, CH
and CH(b) ), 2.44 (s, 6H, CH(c) and CH(c) ), 2.78 (d, 2H, H4'''a (5a,a') , J = 18.6
3(5c)
3(5c')
3(5c')
Hz), 2.97 (d, 2H, H4'''b (5a,a') , J = 18.6 Hz), 3.63 (s, 6H, OCH3(5c) and OCH3(5')), 4.98–5.18 (4d, 4H, J =
17.4 Hz, J = 17.7 Hz, H1''(5c) and H1''(5c')), 5.68 and 5.69 (2s, 2H, H5(5c) and H5(5c')), 6.50 and 6.54 (2s,
2H, OH(5c) and OH(5c')), 6.74 (d, 4H, J = 8.7 Hz, ArH), 7.22 (d, 4H, J = 8.7 Hz, ArH), 7.40–7.53 (m,
13
6H, ArH), 7.91–7.99 (m, 6H, ArH); C NMR (75 MHz, DMSO-d6): δ = 15.8 (Cb(5c) and Cb(5c')), 22.3
(Cc(5c) and Cc(5c')), 25.7 and 25.8 (Ca(5c) and Ca(5c')), 35.2 (C5(5b) and C5(5b')), 46.2 and 46.3 (C1''(5a)
and C1''(5a')), 51.9 (C4'''(5c) and C4'''(5c')), 54.9 (OCH3(5c) and OCH3(5'c)), 90.6 and 90.7 (C5'''(5c) and
C5'''(5c')), 100.1 and 100.2 (C4a(5c) and C4(5c')), 113.6, 116.5, 117.3, 123.4, 124.9, 127.1, 128.5, 129.1, 129.4,
130.4, 131.0, 136.2 (Carom.), 147.6 (C11a(5c) and C11a(5'c)), 156.2 and 156.3 (C3'''(5c) and C3'''(5c')), 157.7,
158.9, 159.6 (Carom.), 161.3 (C4(5c) and C4(5'c)), 163.2 and 163.3 (C2''(5c) and C2''(5c')). HRMS-ES calculated
+
for [M+H] C30 H29 N4 O5 : 525.2138; found: 525.2148.
3.4. General procedure for the synthesis of pyrrolidinedione derivatives 6
Method A (conventional method): Compound 5 (1 mmol) was stirred under reflux with dioxane in the presence
of a catalytic amount of glacial acetic acid. After 12 h, the reaction mixture was cooled to room temperature,
and the dioxane was removed in vacuo and the residue was purified by silica gel chromatography (chloroform
and ethyl acetate, 80:20) to yield compounds 6.
Method B (microwave-assisted): An open 25-mL flask containing compounds 5 (1 mmol) dissolved in
a minimum amount of DMF (2 mL) in the presence of a catalytic amount of acetic acid was irradiated in a
domestic microwave oven (Samsung MW71C, 800 W output power) for 10 min at 300 W. The reaction was
monitored by TLC, and after completion the flask was cooled and the obtained residue was purified by silica
gel chromatography (chloroform and ethyl acetate, 80:20) to yield compounds 6.
3.4.1. 3-(2-(4,5-Dihydro-3,5-dimethylpyrazol-1-yl)-2-oxoethyl)-2-methyl-5-(phenyl)-4H-naphtho[2,1-
b]pyrano[2,3-d]pyrimidin-4(5H)-one (6a)
White solid, mp 234–236 °C; H NMR (300 MHz, DMSO-d6)δ = 2.25 (s, 3H, CH(c)), 2.51 (s, 6H, 2CH3(a,b)),
1
3
5.32 (d, 1H, H1'', J = 18.3 Hz), 5.77 (d, 1H, H1'', J = 18.3 Hz), 5.87 (s, 1H, H5), 6.02 (s, 1H, H4'''), 7.15
(d, 2H, J = 8.4 Hz, ArH), 7.35 (d, 2H, J = 8.4 Hz, ArH), 7.39–7.48 (m, 4H, ArH), 7.80–7.84 (m, 3H, ArH).
13
C NMR (75 MHz, DMSO-d6): δ = 13.6 and 13.7 (Ca,b), 22.7 (Cc), 36.3 (C5), 47.5 (C1''), 100.0 (C4a),
1634

CHERIF et al./Turk J Chem
111.7 (C4'''), 116.0, 117.5, 123.5, 125.0, 127.1, 128.4, 128.5, 129.6, 129.8, 131.0, 131.6, 132.4, 142.2, 144.6,
+
148.2, 153.5, 158.5, 159.7, 162.1 (C4), 166.1 (C2); HRMS-ES calculated for [M+H] C29 H25 N4 O3 : 477,1848;
found: 477,1853.
3.4.2. 3-(2-(4,5-Dihydro-3,5-dimethylpyrazol-1-yl)-2-oxoethyl)-2-methyl-5-(p-methylphenyl)-4H-
naphtho[2,1-b]pyrano[2,3-d]pyrimidin-4(5H)-one (6b)
White solid, mp 237–239 °C; H NMR (300 MHz, DMSO-d6)δ = 2.22 (s, 3H, CH(d)), 2.31 (s, 3H, CH3(c)),
1
3
2.52 (s, 6H, 2CH(3a,b)), 5.30 (d, 1H, H1'' , J = 18 Hz), 5.83 (d, 1H, H1'' , J = 18.3 Hz), 5.88 (s, 1H, H5), 6.02
(s, 1H, H4'''), 7.01 (d, 2H, J = 7.8 Hz, ArH), 7.29–7.49 (m, 5H, ArH), 7.81 (d, 2H, J = 7.8 Hz, ArH), 7.95
13
(d, 1H, J = 8.1 Hz, ArH). C NMR (75 MHz, DMSO-d6): δ = 13.6 and 13.7 (Ca,b), 20.8 (Cd), 22.6 (Cc),
36.4 (C5), 47.4 (C1''), 101.6 (C4a), 111.6 (C4'''), 116.8, 117.4, 123.7, 124.8, 126.9, 128.3, 128.4, 129.0, 129.2,
131.2, 131.6, 136.1, 140.9, 144.6, 148.2, 153.5, 158.1, 159.7, 162.2 (C4), 166.2 (C2); HRMS-ES calculated for
+
[M+H] C30 H27 N4 O3 : 491,2038; found: 491,2024.
3.5. General procedure for the synthesis of pyrrolidinedione derivatives 7 and 8(a–c)
Method A (conventional method): A mixture of appropriate hydrazide 3 (1 mmol) and cyclic anhydride (1
mmol) was stirred under reflux with glacial acetic acid. After 12 h, the reaction mixture was allowed to cool
to room temperature and then was poured in water; the precipitate formed was filtered off, washed with water,
dried, and crystallized from ethanol to give the pyrrolidinediones 7 and 8.
Method B (microwave-assisted): An equimolar mixture of the appropriate hydrazide 3 (1 mmol) and
cyclic anhydride (1 mmol) was dissolved in a minimum amount of DMF (2 mL) and irradiated in a domestic
microwave oven (Samsung MW71C, 800 W output power) for 5 min at 300 W. The reaction was monitored
by TLC, and after completion the flask was cooled and the obtained residue was recrystallized from ethanol to
afford compounds 7 and 8.
3.5.1. 2-(2-Methyl-4-oxo-5-phenyl-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-3(5H)-yl)-N-(1,3-dioxo
isoindolin-2-yl) acetamide (7a)
White solid, mp 278–280 °C (ethanol), H NMR (300 MHz, DMSO-d6): δ = 2.60 (s, 3H, CH(a)), 5.01 (d,
1
3
1H, H1'' , J = 17.7 Hz), 5.21 (d, 1H, H1'' , J = 17.7 Hz), 5.88 (s, 1H, H5), 7.18 (t, 1H, J = 6.9 Hz, ArH),
7.29 (t, 2H, J = 7.2 Hz, ArH), 7.43 (d, 2H, J = 7.2 Hz, ArH), 7.47–7.64 (m, 3H, ArH), 8.02–8.13 (m, 7H,
13
ArH), 11.12 (s, 1H, -NH); C NMR (75 MHz, DMSO-d6): δ = 22.2 (Ca), 35.1 (C5), 44.5 (C1''), 100.1 (C4a),
116.3, 117.2, 123.4, 123.7 (C4''',7'''), 124.9, 126.5, 127.2, 128.1 (C3',5'), 128.2 (C2',6'), 128.5, 129.5 (C3'''a,7'''a),
130.4, 131.0, 135.3 (C5''',6'''), 135.7, 141.0, 147.5 (C11a), 158.9 (C3'''), 159.5, 161.3 (C4), 164.7 (C2''), 166.3
+
(C1''',3'''); HRMS-ES calculated for [M+H] C32 H23 N4 O5 : 543.1590; found: 543.1601.
3.5.2. 2-(2-Methyl-4-oxo-5(p-methylphenyl)-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-3(5H)-yl)-N-
(1,3-dioxoisoindolin-2-yl) acetamide (7b)
White solid, mp 278–280 °C (ethanol); H NMR (300 MHz, DMSO-d6): δ = 2.14 (s, 3H, CH(b)), 2.49 (s,
1
3
3H, CH(3a)), 4.89 (d, 1H, H1'' , J = 17.4 Hz), 5.12 (d, 1H, H1'' , J = 17.4 Hz), 5.71 (s, 1H, H5), 6.98 (d, 2H,
1635

CHERIF et al./Turk J Chem
J = 7.8 Hz, ArH), 7.20 (d, 2H, J = 7.8 Hz, ArH), 7.40–7.51 (m, 3H, ArH), 7.90–7.99 (m, 7H, ArH), 11.26 (s,
13
1H, -NH); C NMR (75 MHz, DMSO-d6): δ = 20.45 (Cb), 22.2 (Ca), 35.6 (C5), 44.3 (C1''), 100.2 (C4a),
116.4, 117.3, 123.4, 123.7 (C4''',7'''), 124.9, 127.1, 128.0 (C3',5'), 128.5, 128.8 (C2',6'), 129.4, 129.5 (C3'''a,7'''a),
130.4, 131.0, 135.2 (C5''',6'''), 135.6, 141.0, 147.5 (C11a), 158.9 (C3'''), 159.5, 161.1 (C4), 164.8 (C2''), 166.3
+
(C1''',3'''); HRMS-ES calculated for [M+H] C33 H25 N4 O5 : 557.1747, found: 557.1738.
3.5.3. 2-(2-Methyl-4-oxo-5(p-methoxyphenyl)-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-3(5H)-yl)-
N-(1,3-dioxoisoindolin-2-yl) acetamide (7c)
White solid, mp 274–276 °C (ethanol), H NMR (300 MHz, DMSO-d6): δ = 2.49 (s, 3H, CH(a)), 3.56 (s, 3H,
1
3
CH(3b)), 4.89 (d, 1H, H1'', J = 17.4 Hz), 5.12 (d, 1H, H1'', J = 17.4 Hz), 5.71 (s, 1H, H5), 6.74 (d, 2H, J =
7.8 Hz, ArH), 7.22 (d, 2H, J = 7.8 Hz), 7.42–7.51 (m, 3H, ArH), 7.90–7.99 (m, 7H, ArH), 11.30 (s, 1H, -NH);
13
C NMR (75 MHz, DMSO-d6): δ = 22.2 (Ca), 35.2 (C5), 44.3 (C1''), 54.9 (Cb), 100.2 (C4a), 113.6 (C3',5'),
116.5, 117.3, 123.4, 123.7 (C4''',7'''), 124.9, 127.1, 128.5, 129.1 (C2',6'), 129.4, 129.5 (C3'''a,7'''a), 130.4, 131.1,
135.2 (C5''',6'''), 136.1, 147.5 (C11a), 157.8 (C3'''), 159.4, 159.6, 161.2 (C4), 164.8 (C2''), 166.3 (C1''',3''');
+
HRMS-ES calculated for [M+H] C33 H25 N4 O6 : 573.1783, found: 573.1791.
3.5.4. 2-(2-Methyl-4-oxo-5-phenyl-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-3(5H)-yl)-N-(1,3-dioxo
pyrrolidino[3,4-d]hept[2.2.1]-5-en-2-yl) acetamide (8a)
1
White solid, mp 260–262 °C (ethanol); H NMR (300 MHz, DMSO-d6): δ = 1.54 (d, 1H, H6''', J = 9 Hz),
1.74 (d, 1H, H6''', J = 9 Hz), 2.43 (s, 3H, CH(a)), 3.28 (m, 2H, H2'''a ,4'''b), 3.44 (m, 2H, H2'''b,4'''a), 4.71 (d,
1H, H1'', J = 17.1 Hz), 4.96 (d, 1H, H1'' , J = 17.1 Hz), 5.71 (s, 1H, H5), 6.05 (m, 2H, H3''', H4'''), 7.08 (t,
1H, J = 7.2 Hz, ArH), 7.19 (t, 2H, J = 7.2 Hz, ArH), 7.42 (d, 2H, J = 7.2 Hz, ArH), 7.46–7.54 (m, 3H, ArH),
13
7.92–8.00 (m, 3H, ArH), 10.94 (s, 1H, -NH); C NMR (75 MHz, DMSO-d6): δ = 22.1 (CH3(a)), 36.1 (C5),
43.6 (C2'''b, 4'''a), 44.2 (C2'''a, 4'''b), 44.4 (C6'''), 51.2 (C1''), 100.0 (C4a), 116.3, 117.3, 123.4, 124.9, 126.5,
127.2, 128.1, 128.2 (C3', 5'), 128.5 (C2', 6'), 129.5, 130.4, 131.1, 134.5 (C3''',4'''), 143.9, 147.7 (C11a), 159.1
+
(C12a), 159.6, 161.4 (C4), 164.9 (C2''), 173.6 (C2''',5'''); HRMS-ES calculated for [M+H] C33 H27 N4 O5 :
559.1903, found: 559.1911.
3.5.5. 2-(2-Methyl-4-oxo-5(p-methylphenyl)-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-3(5H)-yl)-N-
(1,3-dioxopyrrolidino[3,4-d]hept[2.2.1]-5-en-2-yl)acetamide (8b)
1
White solid, mp 265–267 °C (ethanol); H NMR (300 MHz, DMSO-d6): δ = 1.53 (d, 1H, H6''', J = 9
Hz), 1.74 (d, 1H, H6''', J = 9 Hz), 2.19 (s, 3H, CH(b)), 2.58 (s, 3H, CH(a)), 3.31 (m, 2H, H2'''a ,4'''b), 3.42
(m, 2H, H2'''b,4'''a), 4.29 (d, 1H, H1'', J = 17.1 Hz), 4.98 (d, 1H, H1'', J = 17.1 Hz), 5.69 (s, 1H, H5),
6.16 (m, 2H, H3''', H4'''), 6.98 (d, 2H, J = 7.8 Hz, ArH), 7.25 (d, 2H, J = 7.8 Hz, ArH), 7.38–7.42 (m,
13
3H, ArH), 7.76–7.94 (m, 3H, ArH), 10.48 (s, 1H, -NH); C NMR (75 MHz, DMSO-d6): δ = 20.5 (CH3(b)),
22.4 (CH3(a)), 35.9 (C5), 43.8 (C2'''b, 4'''a), 44.5 (C2'''a, 4'''b), 45.6 (C6'''), 51.1 (C1''), 101.0 (C4a), 115.9,
1636

CHERIF et al./Turk J Chem
116.9, 123.2, 124.5, 126.6, 127.2, 128.0 (C3', 5'), 128.6 (C2', 6'), 128.9, 130.4, 131.1, 134.2 (C3''',4'''), 135.7,
140.4, 147.2 (C11a), 158.2 (C12a), 159.3, 161.1 (C4), 164.2 (C2''), 173.0 (C2''',5'''); HRMS-ES calculated for
+
[M+H] C34 H29 N4 O5 : 573.2138, found: 573.2155.
3.5.6. 2-(2-Methyl-4-oxo-5(p-methoxyphenyl)-4H-naphtho[2,1-b]pyrano[2,3-d]pyrimidin-3(5H)-yl)-
N-(1,3-dioxopyrrolidino[3,4-d]hept[2.2.1]-5-en-2-yl)acetamide (8c)
1
White solid, mp 266–268 °C (ethanol), H NMR (300 MHz, DMSO-d6): δ = 1.54 (d, 1H, H6''', J = 9 Hz),
1.73 (d, 1H, H6''', J = 9 Hz), 2.42 (s, 3H, CH(a)), 3.28 (m, 2H, H2'''a ,4'''b), 3.44 (m, 2H, H2'''b,4'''a), 3.57
(s, 3H, OCH3(b)), 4.72 (d, 1H, H1'', J = 17.1 Hz), 4.97 (d, 1H, H1'' , J = 17.1 Hz), 5.69 (s, 1H, H5), 6.05
(m, 2H, H3''', H4'''), 6.74 (d, 2H, J = 8.4 Hz, ArH), 7.21 (d, 2H, J = 8.4 Hz, ArH), 7.41–7.52 (m, 3H,
13
ArH), 7.91–7.99 (m, 3H, ArH), 10.94 (s, 1H, -NH); C NMR (75 MHz, DMSO-d6): δ = 22.2 (CH3(a)), 35.1
(C5), 43.7 (C2'''b, 4'''a), 44.6 (C2'''a, 4'''b), 45.4 (C6'''), 51.8 (C1''), 55.4 (CH3(b)), 101.0 (C4a), 113.6 (C3',5'),
116.5, 117.3, 123.4, 124.9, 127.2, 128.2, 128.5, 129.1 (C2', 6'), 129.4, 130.4, 131.1, 134.5 (C3''',4'''), 136.1, 147.5
+
(C11a), 157.7 (C12a), 158.8, 161.1 (C4), 164.3 (C2''), 173.7 (C2''',5'''); HRMS-ES calculated for [M+H]
C34 H29 N4 O6 : 589.2009, found: 589.2015.
3.6. Synthesis of 3-((4,5-dihydro-5-thioxo-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-5-phenyl-4H-nap-
htho[2,1-b]pyrano [2,3-d] pyrimidin-4(5H)-one 9
Method A (conventional method): A mixture of hydrazide 3a (1 mmol) and phenylthioisocyanate (1 mmol)
was stirred under reflux with dry dioxane. After 6 h, the reaction mixture was cooled to room temperature,
and the dioxane was removed in vacuo and the residue was purified by silica gel chromatography (chloroform
and ethyl acetate, 60:40) to give compound 9.
Method B (microwave-assisted): An open 25-mL flask containing hydrazide 3a (1 mmol) and phenylth-
ioisocyanate (1 mmol) was introduced in a domestic microwave oven (Samsung MW71C, 800 W output power)
and irradiated for 3 min (300 W). The reaction was monitored by TLC, and after completion the flask was
cooled and the obtained residue was recrystallized from ethanol to give compound 9.
3.6.1. 3-((4,5-Dihydro-5-thioxo-1,3,4-oxadiazol-2-yl)methyl)-2-methyl-5-phenyl-4H-naphtho[2,1-b]
pyrano[2,3-d] pyrimidin-4(5H)-one (9)
1
Yellow solid, mp 248–250 °C (ethanol), H NMR (300 MHz, DMSO-d6)δ = 2.58 (s, 3H, CH3), 5.22 (d, 1H,
H6'' , J =17.1 Hz), 5.36 (d, 1H, H6'' , J =17.1 Hz), 5.77 (s, 1H, H5), 7.06 (t, 1H, J = 7.2 Hz, ArH), 7.14 (t,
2H, J = 7.2 Hz, ArH), 7.32 (d, 2H, J = 7.2 Hz, ArH), 7.46–7.54 (m, 4H, ArH+NH) 7.91–7.98 (m, 3H, ArH);
13
C NMR (75 MHz, DMSO-d6): δ = 22.5 (CH3), 35.9 (C5), 39.0 (C6''), 100.2 (C4a), 116.2, 117.3, 123.4,
125.0, 126.6, 127.2, 128.1 (C3',5'), 128.2 (C2',6'), 128.5, 129.6, 130.3, 131.1, 143.8, 147.5 (C11a), 158.7 (C2''),
159.1 (C12a), 159.5, 160.9 (C4), 177.8 (C5''); HRMS-ES calculated for [M+H] C25 H19 N4 O3 S: 455.1100,
found: 455.1108.
+
1637

CHERIF et al./Turk J Chem
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