A New, Simple, Catalyst-free Method for the Synthesis of

Letters in Organic Chemistry

510

Send Orders for Reprints to [email protected] Letters in Organic Chemistry, 2017, 14, 510-516

RESEARCH ARTICLE ISSN: 1570-1786 eISSN: 1875-6255

A New, Simple, Catalyst-free Method for the Synthesis of Pyrazolopyranopyrimidines in Magnetized Water

Impact Factor: 0.664

BENTHAM SCIENCE

Mohammad Bakherad1,*, Rahele Doosti1, Ali Keivanloo1, Mostafa Gholizadeh2 and Amir H. Amin1 1

School of Chemistry, Shahrood University of Technology, Shahrood 3619995161, Iran; 2Department of Chemistry, Ferdowsi University of Mashhad, Mashhad 91779, Iran Abstract: Background: The design of biologically-active compounds is a challenging viewpoint in medicinal chemistry, and pyranopyrazoles and pyranopyrimidine play a crucial role as biologicallyactive molecules.

ARTICLE HISTORY Received: January 02, 2017 Revised: April 20, 2017 Accepted: April 26, 2017 DOI: 10.2174/1570178614666170511170329

Methods: At the moment, a few examples have been reported for the synthesis of pyrazolopyranopyrimidine derivatives. In this work, magnetized water was applied as a green promoting medium for one-pot, practical, efficient, and environmentally benign four-component reaction of an aldehyde, ethyl acetoacetate, hydrazine hydrate, and thiobarbituric acid under catalyst-free conditions. Results: The reactions proceeded rapidly for aromatic aldehydes with the electron-withdrawing or electron-donating groups at different positions of the ring, and heteroaryl aldehydes, and the desired products were isolated in high yields without any side product formation in very short reaction times. Conclusion: An efficient, catalyst-free, green, and convenient method was proposed for the synthesis of pyrazolopyranopyrimidines in magnetized water in good-to-high yields.. This method offers the advantages of short reaction times, low costs, quantitative yields, simple work-up, green, and no need of any organic solvent.

Keywords: Biologically-active compounds, catalyst-free, four-component reaction, magnetized water, pyrazolopyranopyrimidine, promoting medium. 1. INTRODUCTION The synthesis of pyranopyrazole derivatives has attracted significant attention due to their pharmacological properties [1, 2]. These compounds possess a number of significant biological roles; for instance, they exhibit bactericidal [3], insecticidal [4], analgestic [5], anti-inflammatory [6], and anti-cancer activities [7]. Furthermore, pyranopyrimidine derivatives have been found to be the structural units of a number of natural products [8]. On the other hand, a more pronounced effect is generally observed when two or more different heterocyclic moieties exist in a single molecule because it might possess the properties of all moieties and its pharmacological activities are thus enhanced. In this regard, we sought to explore a single structural framework by combining the pyranopyrazole and pyranopyrimidine motifs that could show promising medical properties. Our extensive literature survey showed that there are only a few reports related to the preparation of pyrazolopyranopyrimidines [914].

*Address correspondence to this author at the School of Chemistry, Shahrood University of Technology, Shahrood 3619995161, Iran; Tel: +982332395441; E-mail: [email protected] 1875-6255/17 $58.00+.00

A leading standpoint of green chemistry is the complete removal of solvents from the chemical processes or finding environmentally benign substitutes for unsafe solvents. Water, which is the cheapest, cleanest, and most environmentally friendly solvent, and is non-flammable and naturallyoccurring, with a high specific heat capacity, is the leading option. Furthermore, a meaningful rate enhancement has been noted in a lot of reactions carried out in water due to the hydrophobic interactions that lead to a desirable aggregation of polar components in water [15, 16]. On the other hand, water is an unusual substance exhibiting a unique reactivity and selectivity, considering the hydrogen bonds formed between its molecules and the amount of oxygen dissolved in its solutions [17]. These characteristics have enabled water to act as a solvent, a catalyst or a reactant, which is different from those observed in the conventional organic solvents. From the 1950s, we have known that water can be magnetized when exposed to an applied magnetic field, although the magnetization effect is very small [18-20]. Alim et al. [21] have reported the effect of magnetized water on the TiO2-based varistors; studying their electrical behavior has revealed that water magnetized at 0.3 T yields a higher varistor voltage compared to the non-magnetized deionized water. Wang and co-workers [22] have described the effect of an © 2017 Bentham Science Publishers

A New, Simple, Catalyst-free Method for the Synthesis of Pyrazolopyranopyrimidines

external magnetic field on the calcite growth under various operating conditions. They observed that the applied magnetic field indeed inhibited or stopped the growth of calcite seed for some instances. Recently, Gholizadeh et al. [23] have described the complexation reaction of La3+ cations with a macrocyclic ligand (kryptofix 22DD) in ordinary methanol and in magnetized methanol. They found that the stability constant for the (kryptofix 2DD.La)3+ complex in magnetized methanol decreased compared to ordinary methanol. Very recently, we have reported a straightforward synthesis of some pyrazole derivatives in magnetized water, as a green solvent [24]. Herein we wish to report, for the first time, a catalyst-free one-pot synthesis of some pyrazolopyranopyrimidine derivatives via the four-component reaction of ethyl acetoacetate, hydrazine hydrate, aldehydes, and thiobarbituric acid in magnetized water at 50ºC (Scheme 1).

Letters in Organic Chemistry, 2017, Vol. 14, No. 7

Table 1.

a

2. RESULTS AND DISCUSSION

511

Synthesis of pyrazolopyranopyrimidine 5a in different solventsa.

Entry

Solvent

Yield (%)b

1

Benzene

---

2

Toluene

---

3

CH3CN

5

4

CHCl3

5

5

MeOH

10

6

EtOH

10

7

Doubly distilled water

20

8c

Doubly distilled water

30

Reaction conditions: hydrazine hydrate 1 (1 mmol), ethyl acetoacetate 2 (1 mmol),

benzaldehyde 3a (1 mmol), thiobarbituric acid 4 (1.0 mmol), solvent (3 mL), reaction

In this work, the four-component reaction of hydrazine hydrate 1 (1 mmol), ethyl acetoacetate 2 (1 mmol), benzaldehyde 3a (1 mmol), and thiobarbituric acid 4 (1 mmol) at room temperature was studied in different solvents (Table 1). The target product was not formed in non-polar solvents (Table 1, entries 1 and 2), and even methanol and ethanol, as polar protic solvents, were unable to produce the desired pyrazolopyranopyrimidine 5a in an acceptable yield (Table 1, entries 5 and 6). It was found that water was a suitable solvent with respect to the reaction yield (Table 1, entry 7). This effect can be ascribed to the existence of powerful hydrogen bond interactions at the organic phase-water interface, which stabilizes the reaction intermediate [25]. Also when the reaction was carried out in doubly distilled water at 50ºC, the product 5a was obtained in a low yield even after the reaction time was prolonged to 3 h (Table 1, entry 8).

time of 3 h. b

Isolated yield.

c

50ºC.

Fig. (1). The pilot of magnetic apparatus.

Based on the results obtained (Table 1, entry 8), we tried to optimize the reaction conditions using magnetized water, which could help to reduce the reaction time and improve the yield of the target product.

Then the above model reaction was carried out in magnetized water. It seems that the water magnetization time plays an important role in achieving a high-yield product 5a. As indicated in Table 2 (entries 1-4), increase in the water magnetization time up to 10 min led to an excellent yield (95%) (Table 2, entry 3). In the optimization process, the reaction temperature was varied between 25 and 80ºC (Table 2,

Magnetized water was prepared using a static magnetic system of 0.6 T [24] field strength with a flow rate of 500 mL s-1 at different magnetic field time exposures (Fig. 1). Also doubly distilled water, deionized by a Millipore Q-Plus 185 system, was used throughout the experiments.

R 4' 3'

5' 6'

O NH2NH2 + (1)

O

CHO O +

+

O

magnetized water HN

NH

(2) R (3)

2' 1'

O 50 oC

S (4)

3a R= H

3d R= 2-OMe

3g R= 4-Br

3j R=2,3,4-(OMe)3

3b R= 2-OH

3e R= 2-Cl

3h R= 3-NO2

3k= furane-2-carbaldehyde

3c R= 4-OMe

3f R= 2,6-Cl2

3i R= 4-NO2

3l= thiophene-2-carbaldehyde

Scheme (1). Synthesis of some pyrazolopyranopyrimidine derivatives in magnetized water.

2

3 11

N

O

4

13

5

NH 6

N 10 O 12 N S H 7 9 H1 (5) 8 3m= pyridine-2-carbaldehyde

512 Letters in Organic Chemistry, 2017, Vol. 14, No. 7

Table 2.

a

Bakherad et al.

Synthesis of pyrazolopyranopyrimidine 5a under various reaction conditionsa.

Entry

Solvent (mL)

Magnetization Time (min)

Temp. (ºC)

Time (min)

Yieldb (%)

1

Magnetized water (5)

2

50

90

60

2


5

50

30

80

3


10

50

15

95

4


15

50

15

95

5


10

25

60

60

6


10

80

20

94

7


10

50

20

88

8


10

50

20

90

9c

Magnetized water

10

50

20

95

Reaction conditions: hydrazine hydrate (1 mmol), ethyl acetoacetate (1 mmol), benzaldehyde (1 mmol), thiobarbituric acid (1 mmol).

b

Isolated yield.

c

50 mmol scale.

entries 5 and 6), with 50 ºC giving the optimal reaction yield. Zhang et al. reported that this transformation could be completed in the presence of 10 mol% of meglumine in water [11]. Moreover, the volume of magnetized water had a low effect on the reaction yield (Table 2, entries 7 and 8). Further, to demonstrate the efficiency and practicability of this method in the synthesis of these types of compounds, the model reaction was carried out in a 50 mmol scale. As expected, the desired product could be obtained with 95% yield in 20 min (Table 2, entry 9). Some researchers have reported that when the applied magnetic field is removed from the magnetized water, its magnetization effect does not disappear immediately, and can be maintained for a relatively long period of time. This phenomenon is referred to as the “memory effect” of magnetized water, i.e. how long water magnetization effect remains after completion of the magnetic exposure [26, 27]. Therefore, we examined the memory effect of magnetized water. The model reaction was carried out in magnetized water at different times after completion of the magnetic exposure. After a magnetic exposure of 10 minutes, magnetized water was left standing for different time periods. We found that magnetized water maintained its magnetization property for up to 4 hours, and a reaction carried out in water magnetized for some time was as satisfactory as that done in a freshly-magnetized water, with a high reaction yield. As a result of these studies, we were encouraged to examine the reaction with a broad range of aldehydes to determine the specificity and scope of the aldehydes. Thus various aromatic, and hetero-aromatic aldehydes were reacted with thiobarbituric acid, ethyl acetoacetate, and hydrazine hydrate, and the results obtained are tabulated in Table 3. From the results obtained, it is evident that most of the reactions performed provided good-to-high yields. Aromatic aldehydes having electron-withdrawing groups (Table 3, entries 8 and 9) reacted at faster rates compared with those with electron-releasing groups (Table 3, entries 2-4, and 10). Also the heteroaryl aldehydes such as furane-2-carbaldehyde,

thiophene-2-carbaldehyde, and pyridine-2-carbaldehyde were well-tolerated to afford their corresponding products in good isolated yields (Table 3, entries 11-13). A plausible mechanism for the synthesis of pyrazolopyranopyrimidine 5a from hydrazine hydrate 1, ethyl acetoacetate 2, benzaldehyde 3a, and thiobarbituric acid 4 is shown in Scheme 2. As mentioned earlier, applying a magnetic field to water causes several changes in it, one of which is a change in the hydrogen bond distribution in magnetized water compared with that for normal water. Many researchers have shown that field-induced changes in the structure of water and the magnetic moment interactions strongly affect the hydrogen bond distribution and internal energy of water. An external magnetic field can weaken or even partly break the inter-molecular hydrogen bonds in water, and thus increase the number of monomer water molecules, which may result in some biological effects [28-31]. Toledo et al. [32] have proved the effect of an external magnetic field on the physical and chemical properties of water through an experimental procedure and a theoretical one. They have found that an external magnetic field influences the hydrogen bond networks. They have pointed out the existence of a competition between the intra- and inter-molecular hydrogen bond networks in water, which weakens the stronger intra-cluster hydrogen bonds, breaks the larger clusters, and forms the smaller ones with the stronger intercluster hydrogen bonds. Therefore, the number of hydrogen bonds between the magnetized water molecules and the reacting molecules increases. Thus we think that the hydrogen bonds between the molecules of magnetized water and the molecules of the substrates and intermediates involved in a reaction are responsible for the reaction activation. Pyrazolone I was formed by the condensation of hydrazine hydrate and ethyl acetoacetate, and was then converted to its corresponding enolate form II in the presence of magnetized water. Magnetized water plays a major role in its promoting activity for the formation of intermediate III, which is readily prepared in situ by the Knoevenagel condensation of


Table 3.

a


513

Synthesis of some pyranopyrazolopyrimidine derivatives.

Entry

Ar

Product

Reaction Time (min) a

Yield (%)b

Mp (ºC) (Lit.) [Ref.]

1

Ph

5a

15

95

222-221 (220-221) [11]

2

2-OH-C6H4

5b

25

85

204-205

3

4-MeO-C6H4

5c

25

85

224-225

4

2-MeO-C6H4

5d

30

84

219-220

5

2-Cl-C6H4

5e

20

88

286-287

6

2,6-Cl2-C6H 3

5f

25

83

226-227

7

4-Br-C6H4

5g

30

85

216-217

8

3-NO2-C6H 4

5h

15

95

211-212 (212-213) [11]

9

4-NO2-C6H 4

5i

10

96

234-235

10

2, 3, 4 (OMe) 3-C 6H2

5j

20

94

235-236

11

2'-furanyl

5k

25

87

205-206

12

2'-thiophenyl

5l

20

86

189-190

13

2'-Pyridinyl

5m

25

87

239-240

Reaction conditions: hydrazin hydrate (1 mmol), ethyl acetoacetate (1 mmol), aldehyde (1 mmol), thiobarbituric acid (1mmol), magnetized water (5 mL), magnetization time (10

min), at 50ºC. b

Isolated yield.

H O

H

O

H

O

OEt

H N

O

+ H2N NH2

H

H N

O

H

H

H O

O

HN

NH

O H Ph O

O +

Ph

H

Ph NH

N N H

O (5a)

O H

H

H O H O H H

OH H

O

O NH

Ph

-H2O

N H

S -H2O

H

HN

NH S (III)

O

N H H

O O

H

N O H H

Ph O

H NH

N

O H

O

S

O

N

(II)

HN

S (4)

Ph

H N

O

(I)

H H

H

O

S

NH

N HN O H

O

O

N H

S

H

Scheme (2). A plausible mechanism for the synthesis of pyrazolopyranopyrimidine 5a from hydrazine hydrate, ethyl acetoacetate, benzaldehyde, and thiobarbituric acid.

514 Letters in Organic Chemistry, 2017, Vol. 14, No. 7

benzaldehyde 3a with the highly active CH acidic thiobarbituric acid 4. Finally, the Michael-type addition of 3-methyl1H-pyrazol-5(4H)-one II to intermediate III followed by cyclization and tautomerization yielded pyrazolopyranopyrimidine 5a. 3. EXPERIMENTAL Reagents and solvents were supplied from Merck, Fluka or Aldrich. Melting points were determined using an electrothermal C14500 apparatus. All the known compounds were identified by comparing their melting points and 1H NMR data with those in the authentic samples. 1H NMR (300 MHz) and 13 C NMR (75 MHz) spectra were run on a Bruker Avance DPX-250 FT-NMR spectrometer. The chemical shift values were given as δ values against tetramethylsilane, as the internal standard, and the J values were given in Hz. Microanalysis was performed on a Perkin-Elmer 240-B microanalyzer. Copies of 1H NMR and 13C NMR spectra of all the new compounds are available in supplementary information. 3.1. Preparation of Magnetized Water Doubly distilled water, deionized by a Millipore Q-Plus 185 system, was used in the experiments. Therefore, there were no metallic and magnetic elements present in the purified water used. As shown in Fig. (1), a centrifugal pump was used to circulate water in the system. Water was treated in the system for 10 min, and 100 mL of magnetized water was used in the current work. 3.2. General Procedure for the Synthesis of Pyrazolopyranopyrimidine Derivatives (5a-m) To a mixture of ethyl acetoacetate (1 mmol, 0.13 g) and hydrazine hydrate (1 mmol, 0.05 g) in magnetized water was added an aldehyde (1 mmol) and thiobarbituric acid (1 mmol, 0.144 g). The reaction mixture was stirred at 50 ºC, and the reaction progress was monitored by TLC using chloroform as the eluent. After completion of the reaction, the precipitate formed was filtered and purified by recrystallization from ethanol to afford the desired product (Table 3). 3.3. 3-Methyl-4-(2-hydroxyphenyl)-7-thioxo-4,6,7,8-tetrahydropyrazolo-[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)one (5b) 279 mg (85% yield); 1H NMR (DMSO-d6, 300 MHz) δ: 2.29 (s, 3H,CH3), 5.65 (s, 1H,C4H), 6.97 (t, J = 7.2 Hz, 2H, C4'H,C5'H), 7.41 (t, J = 7.5 Hz, 1H, C3'H), 7.70 (d, J = 7.2 Hz, 1H, C6'H), 11.65 (s, 2H, NH) ppm; 13C NMR (DMSOd6, 75 MHz) δ = 10.4 (CH3), 31.7 (C4), 89.1 (C13), 113.1 (C1'), 114.0 (C11), 118.1 (C3'), 121.1 (C5'), 126.6 (C4'), 128.6 (C6'), 134.9 (C10), 143.5(C3),144.59 (C=O), 152.1 (C2'), 161.6 (C12), 171.9 (C=S) ppm; Anal. Calcd. for C15H12N4O3S: C, 54.87; H, 3.68; N, 17.06. Found: C, 54.66; H, 3.59; N, 17.25. 3.4. 3-Methyl-4-(4-methoxyphenyl)-7-thioxo-4,6,7,8-tetrahydropyrazolo-[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)one (5c) 290 mg (85% yield); 1H NMR (DMSO-d6, 300 MHz) δ = 2.21 (s, 3H, CH3), 3.68 (s, 3H, OCH3), 5.36 (s, 1H, C4H),

Bakherad et al.

6.76 (d, J = 8.4 Hz, 2H, C3’H, C5'H), 6.94 (d, J = 8.4 Hz, 2H,C2’H, C6'H), 10.16 (s, 2H, NH) ppm; 13C NMR (DMSOd6, 75 MHz) δ = 10.0 (CH3), 30.3 (C4), 55.9 (OCH3), 91.4 (C13), 104.9 (C3'), 125.1 (C11), 132.6 (C1'), 132.7 (C6'), 138.8 (C10), 143.3 (C3), 148.0 (C4'), 150.5 (C=O), 160.6 (C12), 171.3(C=S) ppm; Anal. Calcd. for C16H14N4O3S: C, 56.13; H, 4.12; N, 16.36. Found: C, 56.30; H, 4.20; N, 16.55. 3.5. 3-Methyl-4-(2-methoxyphenyl)-7-thioxo-4,6,7,8-tetrahydropyrazolo-[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)one (5d) 287 mg (84% yield); 1H NMR (DMSO-d6, 300 MHz) δ = 2.26 (s, 3H,CH3), 3.63 (s, 3H, OCH3)), 5.58 (s, 1H, C4H), 6.80 (d, J = 6.9 Hz, 1H,C3’H), 7.07 (t, J = 6.9 Hz, 2H, C4’H, C5'H ), 7.34 (d, J = 6.9 Hz, 1H, C6’H), 11.14 (s, 2H, NH) ppm; 13C NMR (DMSO-d6, 75 MHz) δ = 9.9 (CH3), 29.9 (C4), 56.1 (OCH3), 96.1 (C13), 105.3 (C1'), 111.4 (C3'), 111.7 (C11), 120.3 (C5'), 127.6 (C4'), 127.8 (C6'), 130.1 (C10), 139.7 (C2'), 143.5 (C=O), 160.4 (C12), 172.8 (C=S) ppm; Anal. Calcd. for C16H14N4O3S: C, 56.13; H, 4.12; N, 16.36. Found: C, 56.34; H, 4.22; N, 16.17. 3.6. 3-Methyl-4-(2-chlorophenyl)-7-thioxo-4,6,7,8-tetrahydropyrazolo-[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)one (5e) 304 mg (88% yield); 1H NMR (DMSO-d6, 300 MHz) δ = 2.27 (s, 3H,CH3), 5.39 (s, 1H, C4H), 6.99 (d, J = 8.4 Hz, 2H, C3’H, C6'H), 7.03 (d, J = 8.4 Hz, 1H, C6’H), 7.19-7.33 (m, 1H, C5’H), 11.52 (s, 2H, NH) ppm; 13C NMR (DMSO-d6, 75 MHz) δ = 11.1 (CH3), 30.3 (C4), 88.2 (C13), 127.8 (C11), 128.9 (C5'), 129.2 (C3'), 130.9 (C4'), 131.2 (C6'), 134.2 (C2'), 151.8 (C1'), 152.6 (C10), 156.6 (C=O), 161.0 (C12), 172.2 (C=S) ppm; Anal. Calcd. for C15H11ClN4O2S: C, 51.95; H, 3.20; N, 16.16. Found: C, 51.76; H, 3.29; N, 16.34. 3.7. 3-Methyl-4-(2,6-dichlorophenyl)-7-thioxo-4,6,7,8tetrahydropyrazolo-[4',3':5,6]pyrano[2,3-d]pyrimidin5(1H)-one (5f) 316 mg (83% yield); 1H NMR (DMSO-d6, 300 MHz) δ = 2.13 (s, 3H, CH3), 5.63 (s, 1H, C4H), 7.16 (d, J = 7.8 Hz, 1H, C3'H), 7.30 (d, J = 8.1 Hz, 1H, C5'H), 7.39-7.45 (m, 1H, C4'H), 11.38 (s, 2H, NH) ppm; 13C NMR (DMSO-d6, 75 MHz) δ = 11.2 (CH3), 30.4 (C4), 88.8 (C13), 127.7 (C11), 128.9 (C3'), 129.0 (C4'), 129.6 (C1'), 131.3 (C5'), 132.0 (C10), 132.2 (C3), 152.2 (C=O), 167.7 (C12), 172.3 (C=S) ppm; Anal. Calcd. for C15H10Cl2N4O2S: C, 47.26; H, 2.64; N, 14.70. Found: C, 47.47; H, 2.73; N, 14.90. 3.8. 3-Methyl-4-(4-bromophenyl)-7-thioxo-4,6,7,8-tetrahydropyrazolo-[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)one (5g) 332 mg (85% yield); 1H NMR (DMSO-d6, 300 MHz) δ = 2.24 (s, 3H, CH3), 5.67 (s, 1H, C4H), 6.98 (d, J = 8.4 Hz, 2H, C2'H, C6'H), 7.34 (d, J = 8.4 Hz, 2H, C3'H, C5'H), 11.53 (s, 1H, NH), 11.61 (s, 1H) ppm; 13C NMR (DMSO-d6 , 75 MHz) δ = 10.0 (CH3), 33.1 (C4), 88.7 (C13), 125.1 (C11), 126.3 (C4'), 127.2 (C3'), 130.9 (C6'), 131.1 (C2'), 138.6 (C1'), 139.3 (C10), 149.7 (C3), 155.3 (C=O), 163.0 (C13), 173.1(C=S) ppm; Anal. Calcd. for C15H11BrN4O2S: C, 46.05; H, 2.83; N, 14.32. Found: C, 46.24; H, 2.91; N, 14.50.


3.9. 3-Methyl-4-(4-nitrophenyl)-7-thioxo-4,6,7,8tetrahydropyrazolo-[4',3':5,6]pyrano[2,3-d]pyrimidin5(1H)-one (5i) 342 mg (96% yield); 1H NMR (DMSO-d6, 300 MHz) δ = 2.24 (s, 3H, CH3), 5.48 (s, 1H, C4H), 7.30 (d, J = 8.4 Hz, 2H, C2'H, C6'H), 8.10 (d, J = 8.4 Hz, 2H, C3'H, C5'H), 11.50 (s, 2H, NH) ppm; 13C NMR (DMSO-d6, 75 MHz) δ = 9.9 (CH3), 30.8 (C4), 96.0 (C13), 105.4 (C11), 126.1 (C3'), 127.1 (C6'), 128.1 (C10), 131.3 (C3), 139.0 (C1'), 143.7 (C4'), 154.6 (C=O), 163.2 (C12), 172.9 (C=S) ppm; Anal. Calcd. for C15H11N5O4S: C, 50.42; H, 3.10; N, 19.6. Found: C, 50.60; H, 3.01; N, 19.25. 3.10. 3-Methyl-4-(2,3,4-trimethoxyphenyl)-7-thioxo-4,6, 7,8-tetrahydropyrazolo-[4',3':5,6]pyrano[2,3-d] pyrimidin-5(1H)-one (5j) 382 mg (94% yield); 1H NMR (DMSO-d6, 300 MHz) δ = 2.03 (s, 3H, CH3, 3.88 (s, 3H, OCH3), 3.94 (s, 6H, OCH3), 4.94 (s, 1H, C4H), 6.66 (d, J = 8.7 Hz, 1H, C5'H), 6.96 (d, J = 8.7 Hz, 1H, C6'H), 11.42 (br, 2H, NH) ppm; 13C NMR (DMSO-d6, 75 MHz) δ = 10.4 (CH3), 27.2 (C4), 55.5 (OCH3), 59.7 (OCH3), 60.1 (OCH3), 91.6 (C13), 104.3 (C1'), 106.6 (C5'), 123.3 (C11), 129.2 (C6'), 131.1 (C10), 139.7 (C3'), 141.6 (C3), 143.5 (C2'), 151.7 (C4'), 161.5 (C12), 161.7 (C=O), 172.1(C=S) ppm; Anal. Calcd. for C18H18N4O5S: C, 53.72; H, 4.51; N, 13.92. Found: C, 53.91; H, 4.60; N, 14.10.


515

C4'H), 8.44 (d, J = 4.8 Hz, 1H, C6'H), 11.35 (s, 2H, NH) ppm; 13C NMR (DMSO-d6, 75 MHz) δ = 10.4 (CH3), 36.4 (C4), 91.2 (C13), 103.2 (C11), 121.2 (C5'), 122.4 (C3'), 128.2 (C10), 137.0 (C4'), 138.7 (C3), 141.8 (C6'), 143.6 (C2'), 162.4 (C=O), 172.2 (C=S) ppm; Anal. Calcd. for C14H11N5O2S: C, 53.66; H, 3.54; N, 22.35. Found: C, 53.45; H, 3.63; N, 22.52. CONCLUSION In conclusion, an efficient, catalyst-free, green, and convenient method was proposed for the one-pot four-component synthesis of some pyrazolopyranopyrimidine derivatives in magnetized water. This novel method not only offers substantial improvements in the reaction rates and yields but also avoids the use of catalysts or organic solvents. In addition, the promising points for the presented methodology are efficiency, generality, high yield, short reaction time, cleaner reaction profile, simple workup procedure, and finally, agreement with the green chemistry protocols, making it a useful and attractive process for the synthesis of the pyrazolopyranopyrimidine derivatives. Moreover, the presented method can be used in large scale synthesis. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST

3.11. 3-Methyl-4-(2'-furanyl)-7-thioxo-4,6,7,8tetrahydropyrazolo-[4',3':5,6]pyrano[2,3-d]pyrimidin5(1H)-one (5k)

The authors declare no conflict of interest, financial or otherwise.

262 mg (87% yield); 1H NMR (DMSO-d6, 300 MHz) δ = 2.08 (s, 3H, CH3), 5.41 (s, 1H, C4H), 6.46 (s, 1H, C5'H), 6.85 (t, J = 4.2 Hz, 1H, C4'H), 7.33 (d, J = 5.1 Hz, 1H, C3'H), 10.01 (s, 2H, NH) ppm; 13C NMR (DMSO-d6, 75 MHz) δ = 10.0 (CH3), 27.7 (C4), 80.1 (C13), 102.2 (C5'), 105.9 (C4'), 110.2 (C11), 138.8 (C10), 141.1 (C3'), 155.5 (C=O), 163.6(C12), 174.1 (C=S) ppm; Anal. Calcd. for C13H10N4O3S: C, 51.65; H, 3.33; N, 18.53. Found: C, 51.84; H, 3.42; N, 18.34.

ACKNOWLEDGEMENTS

3.12. 3-Methyl-4-(2'-thiophenyl)-7-thioxo-4,6,7,8-tetrahydropyrazolo-[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)one (5l)

SUPPLEMENTARY MATERIAL

273 mg (86% yield); 1H NMR (DMSO-d6, 300 MHz) δ = 2.21 (s, 3H, CH3), 5.51 (s, 1H, C4H), 6.59 (d, J = 3.0 Hz, 1H, C5'H), 6.80-6.88 (m, 1H, C4'H), 7.25 (d, J = 5.1 Hz, 1H, C3'H), 11.34 (s, 2H, NH) ppm; 13C NMR (DMSO-d6, 75 MHz) δ = 10.3 (CH3), 30.9 (C4), 79.6 (C13), 95.4 (C11), 104.1 (C5'), 112.6 (C4'), 112.9 (C3'), 127.5 (C10), 128.2 (C1'), 136.2 (C3), 163.4 (C=O), 173.0 (C=S) ppm; Anal. Calcd. for C13H10N4O2S2: C, 49.04; H, 3.17; N, 17.60. Found: C, 49.23; H, 3.09; N, 17.79.

We gratefully acknowledge the financial support of the Research Council of the Shahrood University of Technology. DISCLOSURE Part of this article has been reproduced from the previous publication in “Research on Chemical Intermediates 2017, 43, 1013-1029”.

Supplementary material (Copies of 1H NMR and 13C NMR spectra of all the new compounds) are available on the publisher’s website along with the published article. REFERENCES [1]

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3.13. 3-Methyl-4-(2'-pyridinyl)-7-thioxo-4,6,7,8-tetrahydropyrazolo-[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)one (5m)

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282 mg (87% yield); 1H NMR (DMSO-d6, 300 MHz) δ = 2.01 (s, 3H, CH3), 4.99 (s, 1H, C4H), 7.21 (t, J = 7.2 Hz, 1H, C5'H), 7.36 (d, J = 8.1 Hz, 1H, C3'H), 7.69-7.75 (m, 1H,

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