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Supporting Information

Uncatalyzed Four Component Synthesis of Pyrazolopyranopyrimidine Derivatives and Their

Antituberculosis Activities

Kirti T. Patila, Dattatrya K. Jamaleb, Navnath J. Valekarb, Priyanka T. Patila, Poojali P. Warekara, Govind B. Kolekarb and Prashant V. Anbhuleb*.

pvanbhule@gmail.com

Tel.: +91 231 260 9169; fax: +91 231 26923aDepartment of Agrochemicals and Pest Management, Shivaji University, Kolhapurb*Medicinal Chemistry Research Lab, Department of Chemistry, Shivaji University,

Kolhapur

Table of content: Page No.

A General Information 01B Typical Procedure 02C Spectral data of of Pyrazolopyranopyrimidine

Derivatives03-27

A. General Information

Melting points were taken in an open glass capillary and are found to be uncorrected.

The desired Structures of all of the compounds were confirmed by their relevant spectral data

IR spectra (KBr) were recorded on a Perkin- Elmer FT-IR Spectrum 100. The 1H NMR and

13C NMR spectra obtained (DMSO-d6) on a Bruker (300 MHz) using TMS as an internal

standard. The progress of reaction was checked by thin layer chromatography (TLC) using

silica gel G (LR). All commercially available chemicals were purchase from sigma Aldrich

and used without purification.

1

B. Typical Procedure

To a solution of hydrazine hydrate (0.063 g, 1 mmol) in ethanol (2 mL.) was added ethyl

aceto acetate (0.132 mL., 1 mmol) over 15 min. Next, an 3-nitrobenzaldehyde (0.150, 1

mmol), thiobarbituric acid (0.144g, 1 mmol), were added and the mixture was heated at reflux

temperature for the time indicated in Table 3. After completion of the reaction (as monitored

by TLC), the mixture was cooled and filtered. The precipitate was recrystalised from ethanol

to give pure target compounds. The physical and spectral data of the products as well as their

elemental analysis are given.

2

C. Spectral data of Synthesized Compound

(Table 3, Entry 1): 3-methyl-4-(3-nitrophenyl)-7-thioxo- 4, 6, 7, 8 tetrahydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (5a)

White solid; M. P. 240-2420C. IR (vmax): 3316, 3053, 1617, 1580 cm-1; 1HNMR(300MHz,

DMSO-d6) :δ (ppm): 2.27 (s, 3H, CH3), 5.51 (s, 1H,-CH), 7.52-7.54 (d, 2H, J = 6 Hz, Ar-H),

7.82 (s, 1H, Ar-H), 8.02-8.04 (d, 1H, J = 6 Hz ,Ar-H), 11.57(s, 1H, -NH); 13C NMR

(75MHz, DMSO- d6) :δ (ppm) : 10.37, 31.20, 95.99, 104.71, 121.43, 130.07, 134.22, 144.29,

144.90, 148.14, 159.08,163.89, 173.71 ; HRMS : mass calculated for [C15H11N5O4S] =357.344

[m/z] ; Obs. Mass= m/z= 357.098, (Anal.Calcd for C15H11N5O4S: C (50.42 %), H

(3.10%) ,N( 19.60%); Found: C (50.38%), H (3.08%), N(19.48%) (Fig. S1, S2, S3, S4)

(Table 3, Entry 2): 4-(3,4-dihydroxyphenyl)-3-methyl-7-thioxo-4,6,7,8-tetrahydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (5b)

White solid; M. P. 244-2460C IR (vmax) :3189, 2879, 1579 cm-1; 1H NMR (300MHz, DMSO-

d6) :δ(ppm): 2.21 (s, 1H, CH3), 5.28 (s, 1H, CH), 6.25-6.27 (d, 1H, J = 6 Hz ,Ar-H), 6.48-6.54

(t, 2H, Ar-H), 8.56 (brs, 1H, OH), 11.24 (s, 1H, -NH) 13C NMR= (75MHz, DMSO- d6): δ

(ppm) 10.28, 30.28, 96.89, 105.89, 114.66, 115.39, 117.90, 133.12, 143.10, 143.79, 144.80,

159.02, 164.15, 172.91; HRMS: mass calculated for [C15H12N4O4S] =344.345 [m/z] ; Obs.

Mass = m/z = 345.077 [M+H]+ , Anal.Calcd for C15H12N4O4S: C (52.32%), H (3.51%) , N

(16.27%); Found: C (52.35%) , H (3.54%), N(16.23%).(Fig. S5, S6, S7, S8)

(Table 3, Entry 3): 4-(3-methyl-5-oxo-7-thioxo-1,4,5,6,7,8-

hexahydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-4-yl)benzonitrile (5c)

White solid; M. P. 250-2520C. IR (vmax): 3361, 2576, 2223, 1658 cm-1; 1H NMR (300MHz,

DMSO-d6): δ(ppm) : 2.21 (s, 3H, CH3),5.44 (s, 1H, CH), 7.20-7.23 (d, 2H, J = 9 Hz, Ar-H),

7.48-7.66 (m, 2H, Ar-H), 13C NMR= (75MHz, DMSO-d6): δ (ppm): 10.31, 31.85, 95.76,96.08,

104.31, 108.71, 119.35, 125.99, 128.02, 128.16, 131.85, 142.99, 148.81, 158.89, 164.09, 173.32 ;

HRMS: mass calculated for [C16H11N5O2S] =337.355 [m/z] ; Obs. Mass = m/z= 338.343

3

[M+H]+, Anal.Calcd for C16H11N5O2S: C(56.96%), H (3.29%) , N (20.76%), Found: C

(56.91%), H (3.25%), N (20.71%) (Fig. S9, S10, S11, S12)

(Table 3, Entry 4): 4-(4-hydroxyphenyl)-3-methyl-7-thioxo-4,6,7,8-

tetrahydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (5d)

White solid; M. P. 250-2520C. IR (vmax: 1567, 2875, 3172, 3247 cm-1; 1H NMR(300MHz,

DMSO-d6) : δ (ppm): 2.18 (s, 1H, CH3), 3.43-3.48 (s, 1H, OH), 5.31 (s, 1H, CH), 6.54-6.57

(d, 2H, J = 9 Hz, Ar-H), 6.82-6.85 (d, 2H, J = 9 Hz, Ar-H), 9.02 (s, 1H, NH), 11.25 (s, 2H,

NH) 13C NMR= (75MHz, DMSO- d6 ): δ (ppm): 0.31, 10.38, 30.45, 96.78, 105.79, 114.95,

127.95, 132.63, 142.79, 155.16, 159.31, 164.04, 172.94, HRMS: mass calculated for

[C15H12N4O3S] =328.345 [m/z] ;Obs. Mass = m/z= 329.324 [M+H]+, Anal.Calcd for

C15H12N4O3S: C (54.87%), H (3.68%), N (17.66%), Found: C (54.83%), H (3.62%),

N(17.61%).(Fig. S13, S14, S15, S16)

(Table 3, Entry 5): 4-(1H-imidazol-2-yl)-3-methyl-7-thioxo-4,6,7,8-

tetrahydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (5e)

Cream solid; M. P. 275-2780C. IR (vmax) : 3320, 3107, 2361, 1538, 1442, 1382 cm-1; 1H

NMR (300MHz, DMSO-d6): δ (ppm): 2.13 (s, 3H, CH3), 5.28 (s, 1H,CH), 6.85 (s, 1H, Ar-H),

8.70 (d, 2H, Ar-H), 10.94 (s, 2H, NH), 13C NMR=(75MHz ,DMSO-d6): δ (ppm): 10.50,

25.09, 93.34, 101.99, 115.91, 133.06, 136.89, 138.33, 159.10, 163.90, 173.47 , HRMS : mass

calculated for [C12H10N6O2S] =302.311 [m/z] ; Obs. Mass= 302.306 [m/z] Anal.Calcd for

C12H10N6O2S: C (47.68%), H (3.33%), N(27.80%), Found C (47.62%),H (3.29%),N ( 27.75%)

(Fig. S17, S18, S18, S19)

(Table 3, Entry 6): 3-methyl-4-(3-chlorophenyl)-7-thioxo-4,6,7,8-

tetrahydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (5f)

White solid; M. P. 235-2370C. IR (vmax): 1585, 2821, 3413 cm-1; 1H NMR (300MHz, DMSO-

d6) : δ (ppm): 2.20 (s, 3H, CH3), 5.50 (s, 1H, CH), 7.09-7.16 (m, 2H, Ar-H), 7.21-7.23 (d, 1H,

4

Ar-H), 7.47-7.50 (d, 1H, J = 9 Hz, Ar-H), 8.17 (s, 1H, NH), 11.13 (s, 1H, NH), 13C NMR=

(75MHz, DMSO-d6): δ (ppm): 10.42, 30.64, 95.67, 104.42, 126.66, 128.20, 130.00, 130.40,

132.89, 139.61, 142.87, 159.33, 163.90, 173.06 , Anal.Calcd for C15H11ClN4O2S : C (51.95%),

H( 3.20%), N(16.16%), Found: C(51.88%), H (3.15%),N (16.10%) (Fig. S20, S21, S22)

(Table 3, Entry 7): 3-methyl-4-(2-chlorophenyl)-7-thioxo-4,6,7,8-

tetrahydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (5g)

White solid; M. P. 238-2400C. IR (vmax) : 3287, 3015, 1681, 1586, 1341 cm-1; 1H NMR

(300MHz, DMSO-d6) : δ (ppm): 2.21 (s, 3H, CH3), 5.49 (s, 1H, CH), 7.06-7.19 (q, 3H, Ar-H),

7.43-7.45 (d, 1H, J = 6 Hz ,Ar-H), 13C NMR= (75MHz DMSO-d6): δ (ppm): 10.60, 30.61,

126.13, 127.41, 129.54, 130.58, 133.19, 163.79, 173.11, Anal.Calcd for C15H11ClN4O2S : C

(51.95%), H( 3.20%), N (16.16%), Found: C (51.86%), H (3.18%), N (16.13%) (Fig. S23,

S24, S25)

(Table 3, Entry 8): 3-methyl-4-(2-nitrophenyl)-7-thioxo-4,6,7,8-

tetrahydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (5h)

Cream solid; M. P. 244-2450C. IR (vmax) : 3346, 3019, 2351, 1578, 1477 cm-1; 1H NMR

(300MHz, DMSO-d6) : δ (ppm): 2.22 (s, 3H, CH3), 5.78 (s, 1H, CH), 7.29-7.47 (m, 4H, Ar-

H), 10.01 (s, 2H, NH), 13C NMR=(75MHz DMSO-d6) : δ = 10.26, 28.55, 90.79, 105.08,

123.90, 127.54, 130.08, 131.46, 134.75, 144.09, 150.11, 151.54, 159.55, 165.18 ; Anal.Calcd for

C15H11N5O4S: C (50.42%), H (3.10%) N (19.60%), Found: C (50.34%), H, (3.05%) N

(19.46%).(Fig. S26, S27, S28)

(Table 3, Entry 9): 4-(3-hydroxyphenyl)-3-methyl-7-thioxo-4,6,7,8-

tetrahydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (5i)

White solid; M. P. 252-2540C. IR (vmax) : 3300, 3219, 2874 cm-1; 1H NMR (300MHz,

DMSO-d6) (Fig.31): δ (ppm): 2.18 (s, 1H, CH3), 5.30 (s, 1H, CH), 6.53-6.56 (d, 2H, J = 9 Hz,

5

Ar-H), 6.81-6.84 (d, 2H, J = 9 Hz ,Ar-H), 11.18( s, 2H, NH) 13C NMR= (75MHz DMSO-

d6) : δ (ppm):10.44, 30.52, 56.72, 96.69, 105.75, 114.93, 127.99, 132.83, 142.40, 155.23, 159.43,

164.04, 164.64, 172.99, Anal.Calcd for C15H12N4O3S: C (54.87%), H (3.68%), N (17.66%),

Found: C (54.84%), H (3.64%), N (17.63%) (Fig. S29, S30, S31)

(Table 3, Entry 10): 4-(2-hydroxyphenyl)-3-methyl-7-thioxo-4,6,7,8-

tetrahydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (5j)

White solid; M. P. 248-2500C. IR (vmax) : 1612, 2987, 3079, 3183, 3239 cm-1; 1H NMR

(300MHz, DMSO-d6) : δ (ppm): 2.18 (s, 1H, CH3), 3.43-3.48 (d, 1H, OH), 5.30 (s, 1H, CH),

6.54-6.57 (d, 2H, J = 9 Hz, Ar-H), 6.82-6.85 (d, 1H, J = 9 Hz Ar-H), 11.25 ( s, 2H, NH), 13C

NMR=(75MHz, DMSO-d6) : δ (ppm): 10.44, 30.52, 96.63, 105.68, 114.95, 128.01, 132.95,

142.26, 155.25, 159.45, 163.96, 173.00, Anal.Calcd for C15H12N4O3S: C (54.87%) H (3.68%) N

(17.66%), Found: C (54.83%), H (3.65%), N (17.64%) (Fig.S32, S33, S34)

(Table 3, Entry 11): 3-methyl-4-(4-nitrophenyl)-7-thioxo-4,6,7,8-

tetrahydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (5k)

Yellow solid; M. P. mp 218-2200C. IR (vmax) : 3334, 3185, 1657, 1517 cm-1; 1H NMR

(300MHz, DMSO-d6) : δ (ppm): 2.26 (s, 3H, CH3), 5.48 (s, 1H, CH), 7.23-7.30 (d, 2H, J = 9

Hz ,Ar-H), 8.04-8.11 (d, 2H, J = 9 Hz, Ar-H),11.56 (s, 2H, NH), 13C NMR= (75MHz,

DMSO-d6) : δ (ppm): 10.29, 18.75, 31.56, 56.60, 95.69, 96.16, 104.75, 123.68, 128.16, 128.37,

144.39, 145.75, 146.13, 150.74, 158.84, 163.99, 173.42, 173.63, (Anal.Calcd for C15H11N5O4S:

C (50.42%), H (3.10%) N(19.60%), Found: C (50.40%), H (3.05%), N(19.50) (Fig.S35, S36,

S37)

(Table 3, Entry 12): 3-methyl-4-(4-chlorophenyl)-7-thioxo-4,6,7,8-

tetrahydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (5l)

6

White solid; M. P. mp 216-2180C. IR (vmax) : 3395, 3317, 2875, 1583, 1517 cm-1; 1H NMR

(300MHz, DMSO-d6) : δ (ppm): 2.20 (s, 3H, CH3), 5.36 (s, 1H, CH), 7.01-7.04 (d, 2H, J = 9

Hz, Ar-H), 7.12-7.15 (d, 2H, J = 9 Hz, Ar-H), 8.05 (s, 1H, NH), 11.19 (s, 2H, NH ),

Anal.Calcd for C15H11ClN4O2S : C (51.95%), H (3.20%), N (16.16%), Found: C (51.90%), H

(3.16%) N (16.11%) (Fig. S38, S39)

IR spectra of 5a

Fig. S1

1HNMR of 5a

7

Fig. S2

13CNMR of 5a

Fig. S3

Mass Spectra of 5a

8

Fig.S4

IR spectra of 5b

Fig.S5

1HNMR of 5b

9

Fig. S6

13CNMR of 5b

Fig. S7

Mass spectra of 5b

10

Fig. S8

IR spectra of 5c

Fig. S9

1HNMR of 5c

11

Fig. S10

13CNMR of 5c

Fig. S11

Mass Spectra of 5c

12

Fig. S12

IR spectra of 5d

Fig. S13

1HNMR of 5d

13

Fig. S14

13CNMR of 5d

Fig. S15

Mass spectra of 5d

14

Fig. S16

IR spectra of 5e

Fig. S17

1HNMR of 5e

15

Fig. S18

13CNMR of 5e

Fig. S19

Mass Spectra of 5e

16

Fig. S20

Mass Spectra of 5f

Fig. S21

1HNMR of 5f

17

Fig. S22

13CNMR of 5f

Fig. S23

IR spectra of 5g

18

Fig. S24

1HNMR of 5g

Fig. S25

13CNMR of 5g

19

Fig. S25

IR spectra of 5h

Fig. S26

1HNMR of 5h

20

Fig. S27

13CNMR of 5h

Fig. S28

IR spectra of 5i

21

Fig. S29

1HNMR of 5i

Fig. S30

13CNMR of 5i

22

Fig. S31

IR Spectra of 5j

Fig. S32

1HNMR of 5j

23

Fig. S33

13CNMR of 5j

Fig. S34

IR spectra of 5k

24

Fig. S35

1HNMR of 5k

Fig. S36

13CNMR of 5k

25

Fig. S37

IR Spectra of 5l

Fig. S38

1HNMR of 5i

26

Fig. S39

27