Indian Journal of Chemistry Vol. 428, August 2003, pp. 193 1- 1936

Synthesis of novel naphtho[2, I-b ]furopyrimidine deri vati yes

K M Mahadevan, V P Yaidya* & H M Yagdevi

Department of Chemistry, Kuvempu University , Jnana Sahyadri, Shankaraghalla 577 451 , Dis!: Shimoga, Karnataka, Indi a

Received 8 AugLisl 2002; accepled (revised) I May 2003

2-Acyl-3-ami nonaphtho[2, I-bJfurans 2a-c are converted into corresponding oximes 3a-c,whi ch on reaction with ch loroacetyl chloride in the presence of triethyl ami ne yield 2-chloromethyl-4-alkyl/ary lnaphtho[2, I -b lfuro[3.2-dJpyrimidine-3-oxides 4a-c. Acylation of compounds 2a-c furnish 2-acy l-3-acylamidonaphtho[2. I-blfurans 5a-f, which un-dergo ring closure, on reacting with hydraz ine hydrate and produce 2-alkyl/aryl-3,4-dihydro-3-amino-4-hydroxy-4-alky l/aryl-naphtho[2, l -bJfuro[3,2-djpyrimidines 6a-f. Compounds 6a-f when refluxed with formic ac id undergo ring open-ing and rearrangement sim ultaneously to give 2-acyl-3-(3' -alkyl/aryl- I' ,2',4'-triazol-4'-yl)naphtho[2, I-b ]furans 7a-f. The compounds synthesized have been screened for antimicrobiaL anthe lmintic and anti -inflammatory activity .

Pyrimidine based heterocycles are of interest as po-tential bioactive molecules and exhibit antimicrobial, antimicotic, antiviral, antiplatelet activities and also act as enzyme inhibitors l.9• Also, naphtho[2,I-blfuran derivatives synthesized in our laboratory , have been shown to possess antimicrobial, anti-inflammatory, analgesic and anthelmintic activities

,o. '3 . These results

prompted us to annelate naphtho[2, I-b ]furan to pyrimidine ring and evaluate their antimicrobial, anthelmintic and anti-inflammatory activity of the resulting heterocycles.

The required starting material, 2-hydroxy-l-naph-thonitrile 1 was synthesized from 2-hydroxy-l-naph-thaldehyde by a novel approach. 2-Hydroxy-l-naph-thaldehyde on reaction with hydroxylamine hydro-chloride gave the corresponding oxime, which on treatment with acetic anhydride, instead of undergo-ing dehydration, underwent cyclisation and produced naphtho[2, I-b ]isoxazole as an oil. The IR spectrum of this compound was conspicuous by the absence of absorption band due to both -OH and -CHO stretch-ing frequencies. IH NMR spectrum of isoxazole ex-hibited only one signal as multiplet at 8 7.01-8 .3 ppm integrating for seven protons. This oil , without further purification, when reacted with sodium ethoxide fol-lowed by acidification gave 2-hydroxy-l-naphthoni-trile in an excellent yield. The IR spectrum of 1 exhib-ited sharp absorption band at 2225 cm·1 due to C=N . The I H NMR spectrum substantiated the structure assigned to 1, which ex hibited a multiplet at 8 7.1 2-8.0 ppm due to six aromatic protons and a singlet at 8 10.61 ppm due to -OH proton .

The synthesis of 2-acetyl-3-aminonaphtho[2, I-b]-furan 2a from 2-hydroxy-l-naphthonitrile has already been reported from our laboratory". By using simil ar method, 2-benzoyl-3-aminonaphtho[2,l-b ]furan 2b and 2-(4-hydroxybenzoyl)-3-aminonaphtho[2, I-b]-furan 2c were synthesized by the reaction of 2-hydroxy-l-naphthonitrile with phenacyl bromide and 4-hydroxyphenacyl bromide respectively . In this case also condensation and Thorpe-Zigler cyclization oc-curred in a single step (Scheme I) .

13C NMR and mass spectra of 2a were recorded as additional evidence to the structure assigned. In the broad band decoupled I3C spectrum of 2a, a small peak at 189.17 ppm was ass igned to carbonyl carbon atom. The remaining small peaks appearing at 8 153.04, 141.09, 136.27, 130.32, 128.83 and 114.14 were attributed to C2', C8a. C4a. C2. C 1 and C3' carbon atoms, which are quaternary carbon atoms. The large peaks appearing at 8 131.28, 129.61, 127 .71 124.89 and 122.07 were assigned to C4, Cs, C8, C6 and C7 carbon atoms of naphthalene ring respectively. As expected C3 of naphthalene nucleus exhibited a large peak at 113 .27 ppm. Methyl carbon atom exhibited a medium peak upfield at 25.86 ppm.

The reaction of 2a-c with hydroxylamine hydro-chloride yielded corresponding oximes 3a-c, which on treatment with chloroacetyl chloride in acetone and in the presence of catalytic amount of triethyl amine un-derwent simultaneous acy lation and ring closure to produce 2-chloromethyl-4-alky/arylnaphtho[2, I-b ]furo-pyrimidine-3-oxides 4a-c. The formation of such 3-oxides under these conditions seemed quite reason-able, since similar single step conversion of

1932 INDI AN J. CHEM .. SEC B. AUGUST 2003

CHO

~ ___ OH

~

NH2 NHpH

/ N-OH EtOH 0 ---

3a-c R 2a-c R

1 CICH2COCI Acetone/Et3N

Ny-CH2CI

..-:: N" 0

4a-c R

N f" N~N

\ R1

.... 0 7a-f

R

5a-f R

H

-H2O OHC-N"

H-N3

N \ I R1

.... 0

R

Ny R1

N", 6a-f HO NH2

R

l~oOH

Scheme I

2-aminobenzophenones into quinazoline-3-oxide I4

and also cyclization of oximes to N-oxides are de-scribed in the literaturels.

The IR spectrum of 4a exhibited absorption bands in the region 1300- 1350 cm-I which could be attrib-uted to N---70 stretching f requency. In IH NMR spec-

trum of 4a, a singlets appearing at 8 1.2 and 4.0 were attributed to CH 3 and - CH2 protons respectivel y, whereas remaining aromati c protons appeared as a multiplet at 8 7.1-8.4.

It has been shown that O-acetamido benzophe-nones react readil y with hydrazine hydrate to produce 3-ami no-4-hydrox y-4-arylquinazo lenes 16- 18 which on reaction with fo rmic acid undergo transformati on to the corresponding 2- tri azo ly l benzophenones. This fact stimulated our interest in biheterocyc les of naph-tho[2, I-b ]furan with triazoly l ring system at 3-position. To accompli sh thi s, the compounds 2a-c were acy lated using appropri ate ac id anhydrides or acid chlorides under suitable reacti on conditions to

obtain compounds 5a-f. These compounds when re-acted with hydrazine hydrate resulted in the formation of 2-alkyl/aryl-3,4-dihydro-3-amino-4-hydroxy-4-al ky l/ary lnaphtho[2, I-b ]furo[3,2-d]pyrimidi nes 6a-f. The main diagnostic feature of these compounds was the absence of absorption peak due to carbony l group in their IR spectra. Appearance of new absorption bands at 3300-3400,1620 and 1580 cm-I due to - H2, - OH, C= and C=C stretching frequencies respec-tively confirmed the .assigned structure. Further ev i-dence for the proposed structure was obtained from IH NMR spectrum of 6a, which exhibited singlets at 81.2 and 2.3 due to protons of two -CH3 groups. The protons of -NH2 group appeared as a broad si nglet at 8 5.5 (D20 exchangeable), whereas - OH proton (D20 exchangeable) appeared as a singlet at 8 4.7. The aromatic protons appeared as a multiplet at 8 7.3-8 .3.

When compound 6a was dissolved in formic acid and heated at reflux for 3-4 hr, a mu lticomponent mixture was resulted, from thi s 39% of new com-

MAHADEY AN el al.: NAPHTHO[2, I -bjFUROPYRIMIDrNE DERry ATrYES 1933

pound 7a was isolated by column chromatography (Silica gel, 60-1 20 mesh, Solvent - chloroform: ethyl acetate, 9: 1). The IR spectrum of 7a-f exhibited a strong absorption band around 1638-1645 cm-I due to C=O group. In the 'H NMR spectrum of 7a signals due to - NH2 and -OH protons were conspicuously absent. Instead new singlets appeared at 8 1.6 and 2.6, which were attributed to methyl group attached to triazolyl ring and methyl group of -CO-CH3 respec-ti vely. A multiplet at 8 7.2-8 :5 integrated for seven protons was due to 6 aromatic protons and a proton of triazolyl ring. On the bas is of IR and IH NMR data and also in analogy with earlier observations, the compound 7a was identified as 2-acetyl-3-(3'-methyl-I' ,2' ,4'-triazol-4'-yl)naphtho[2, I-b ]furan. The conver-sion of Sa t07a was supposed to follow the mecha-nism as shown in Scheme I. Similarly, other com-pounds 6b-f were converted into the respecti ve 2-acyl-3-triazolylnaphtho[2, I-b] furans 7b-f by the action of formic acid (Table I). The characterization data of compounds 2a-c, 3a-c, 4a-c, Sa-f, 6a-f and 7a-f are given in Table I.

Experimental Section Melting points were determined in open capillary

tubes and are uncorrected. Purity of the compounds was checked by TLC on silica gel G. IH and 13C NMR spectra (300 MHz) were recorded on a Bruker supercon IT NMR instrument using TMS as internal standard (chemical shifts in 8, ppm); IR spectra on a Perkin Elmer 157 Infrared spectrophotometer (v ll1ax cm-,); and mass spectra on a Jeol IMS-O 300 Mass spectrometer operating at 70 e V.

2-Hydroxy-l-naphthonitrile 1. A mixture of 2-hydroxy-I-naphthaldoxime (20 g) and aceti c anhy-dride (20 mL) was refl uxed fo r 30 min . Acetic anhy-dride was removed by distillation under reduced pres-sure and the dark coloured dense liquid of naph-tho[ I ,2-d] isoxazole was treated with freshly prepared sodium ethoxide [prepared by adding freshly cut dry sodium (20 g) in to abso lute ethanol (100 mL) at O°C °c]. The mixture was sti rred for 30 min at room tem-perature and poured into ice-water. On acidification with dil. HCI , it gave 2-hydroxy- I-naphthonitrile as light brown solid, which was collected and recrystal-li zed from ethanol, yie ld 17.5 g (98%), m.p .72°C.

2-Acyl-3-aminonaphtho[2,1-b ]furans 2a-c. A mixture of 1 (0.0 I mole) in dry acetone (50 mL), an-hydrous potassium carbonate (5 g) and chloroacetone (0.01 mole) was refluxed for 8 hr. The potassium car-bonate was filtered off and from the filtrate acetone

was removed under reduced pressure to obtain the product 2a as solid, which was recrystallized from aq. OMF. The other compounds 2b-c were also prepared similarly by using appropriate phenacy l bromides. 2a ; MS : mlz 225(M+), 210, 182, 154, 127, 77 ; 2b; IR (KBr): 3327,3345 (-NH2)' 1691 cm·I(C=O); IH NMR (COCl3): 6.4 (brs, -NH2)' 8 7.3-8.2 (m, 11 H, ArH); 2c; IR (KBr): 3441,3250 (-OH and -NH2), 1709 cm-I

(C=O); IH NMR (COCb): 6.3 (brs, -NH2) ' 6.5 (brs, -OH), 7 .1-8.3 (m, lO H, ArH) .

Oximes of 2-acyl-3-aminonaphtho[2,1-b ]furans 3a-c. Hydroxylamine hydrochloride (0.0 1 mole) was added to a solution of 2a (O.Olmole) in ethanol (80 mL) followed by the addition of aqueous potassium hydroxide (10 %, 5 mL). The mixture was heated on a steam-bath for 2 hr, cooled to room temperature and poured in to ice-water (500 mL). The crude product thus obtained was filtered, dried and recrystallized from abso lute ethanol.

Similarly, compounds 3b-c were obtained from 2b-c. 2-Chloromethyl-4-alkyVarylnaphtho[2,1-b ]furo-

[3,2-d]pyrimidine-3-oxides 4a-c. Chloroacetyl chlo-ride (0.01 mole) was added dropwi se with stirring to a warmed solution of 3a (0.01 mole) in acetone (50 mL) and a triethyl amine (1 mL). The mixture was allowed to stand overnight at room temperature and concentrated in vacuum. The residue was recrystal-lized from acetone to obtain 4a. MS: mlz 298 (M+) , 282 (100%), 247 (33.3%),206, 178, 127,77.

Compounds 4b-c were prepared similarly from 3b-c.

2-Acyl-3-acylamidonaphtho[2,1-b ]furans Sa-f. A well stirred suspension of 2a (0.01 mole) in aqueous sodium hydrox ide (10 %, 30 mL) was treated with ace-tyl chloride ( 10 mL) in portions. After stirring the reac-tion mixture for 20 mjn at room temperature, the sol id separated was collected and washed with water. Pure sample was obtained by crystallization from ethanol.

Similarly, compounds Sb-f were prepared from 2b-c using appropriate anhydrides or ac id chlorides.

2-AlkyVaryl-3,4-dihydro-3-amino-4-hydroxy-4-alkyVarylnaphtho[2,1-b ]furo[3,2-d] pyrimidines 6a-f. A mi xture of Sa-f (0.0 1 mole) and hydrazine hydrate (0.0 1 mole) in absolute ethanol (50 mL) was refluxed for 8 hr on a water-bath. The resulting reac-tion mi xture was poured into ice-water and the ye llow solid thus separated on washing with water gave the products 6a-f, wh ich were recrystalli zed from suitab le solvent. 6b; IR (KBr): 3350, 3325 (-OH and -NH2) , 1605 cm-' (C=N); 'H NMR (COCb): 83.5 (brs, -OH), 6. 15 (brs , -NH2), 7.0-8.3 (m, II H, ArH ); 6c;

1934 INDIAN 1. CHEM., SEC B, AUGUST 2003

Table I--Characterization data of compounds 2a-c, 3a-c, 4a-c, 5a-f, 6a-f and 7a-f.

Compd R R, Mol. Yield m.p Found %(Calcd) formula (%) °C C H N

2a CH3 C'4HIIN02 80 130 74.66 4.88 6.22 (74.52 4.80 6.20)

2b C6HS C'9H U N02 90 155 79.4 4.52 4.87 (79.20 4.47 4.81)

2c 4-0H-CoHs C'9H I.1 NO) 85 168 75 .24 4.29 4.62 (75.20 4.22 4.58)

3a CH) C'4H'2N20 2 60 145 70.00 5.00 11.66 (69.67 4.89 11.50)

3b C6HS C '9H'4N20 2 65 180 75.4 4.63 9.20 (75 .23 4.60 9.17)

3c 4-0H-CoHs C'9H '4N20 3 60 178 71.64 4.40 8.80 (7 1.54 4.37 8.78)

4a CH) C '6HIIN20 2CI 70 202 64.4 23.69 9.39 (64.22 23.63 9.33)

4b C6HS C2, H u N20 2C1 55 210 70.00 3.61 7.77 (69.65 3.60 7.71)

4c 4-0H-C6HS C2,H IJN2O)C1 60 195 67.02 3.45 7.44 (67 .00 3.34 7.38)

Sa CH) CH) C'6H' 3NO) 60 160 71.91 4 .82 5.24 (7 1.87 4 .80 5.20)

5b C6HS CH) C2,H,sNO) 75 170 76.59 4.55 4.25 (76.52 4.45 4.20)

5c 4-0H-C6HS CH3 C2,H, sN04 50 195 73.04 4.34 4.05 (73.00 4.24 4.00)

5d CH) C6HS C2,H13NO) 70 203 77.06 3.97 4.28 (77.00 3.90 4.22)

5e C6Hs C6HS C26H, sN03 60 221 80.20 3.85 3.59 (80.00 3.80 3.56)

Sf 4-0H-C6HS C6HS C26H, sN04 60 228 77.03 3.70 3.45 (77.00 3.68 3.44)

6a CH3 CH) C'6H,sN)0 2 45 250 68.32 5.33 14.96 (68.22 5.30 14.93)

6b C6HS CH) C2,H17N)0 2 50 234 73.46 4.95 12.24 (73 .38 4.91 12.19)

6c 4-0H-C6HS CH) C2,H17N)03 40 237 70.19 4.73 11.69 (70.14 4.70 11.63)

6d CH) C6Hs C2,H 17N30 2 60 236 73.46 4 .95 12.24 (73.43 4 .90 12.19)

6e C6HS C6HS C26H'9N30 2 70 252 77.03 4.69 10.37 (77 .00 4.65 10.34)

6f 4-0H-C6Hs C6HS C26H'9N)0 3 65 264 74.10 4 .51 9.97 (74.00 4.48 9.91)

7a CH) CH3 C 17H13N)0 2 50 218 70.10 4.46 14.43 (70.00 4.42 14.38)

7b CoHs CH3 C22H, sN30 2 60 189 74.78 4.24 11.89 (74.67 4.20 11 .85)

7c 4-0H-C6HS CH3 Cn H, sN30 3 45 210 71 .54 4.06 11 .38 (71.50 4.00 11.32)

7d CH3 C6HS Cn H, sN30 2 55 232 74.78 4.24 11 .89 (74.72 4.20 11.86)

7e C6HS C6HS C27H' 7N)0 2 70 248 78.07 4.09 10.12 (78.00 4.00 10.09)

7f 4-0H-C6HS C6Hs C27 H I7 N)0 3 60 257 75. 17 3.94 9.74 (75.12 3.88 9.70)

MAHADEV AN el al.: NAPHTHO[2, I-bjFUROPYRIMIDINE DERIVATIVES 1935

IR · (KBr): 3330, 3341 (-OH, and -NH2), 1609 cm I(C=N); IH NMR (CDCl3): 8 3.S (brs, -OH), 6.3 (brs, -NH2), 6.5 (brs, -OH phenolic), 7.0-S .3 ppm (m, 1OH, ArH).

2-Acyl-3-(3'-methyl-l' ,2' ,4'-triazol-4'-yl)naphtho-[2,1-b ]furans 7a-f. A suspension of 6a (0.01 mole) in formic acid (30 rnL) was refluxed for 3 hr and the reaction mixture was allowed to cool for 2 hr, then poured into ice-cold water (500 rnL). The crude prod-uct was filtered and recrystallized from suitable sol-vent to give 7a. Compounds 7b-f were prepared simi-larly by using 6b-f. 7b; IR (KBr): 1696 cm·1 (C=O); IH NMR (CDCI3): 82.0 (s, 3H, CH3), 8 7.I-S.6 (m, 12H, ArH); 7c; IR (KBr) : 3445 (-OH), 1710 cm-I

(C=O); IH NMR (CDCI3): 8 2.1 (s, 3H, CH3), 6.5 (brs,-OH phenolic), 7 .0-S .5 (m, I1H, ArH).

Antimicrobial activity All the newly synthesized compounds were screened

for antibacterial activity against both gram-positive, S. aureus and gram-negative, K. pneumoniae bacteria and antifungal activity against C. albicans and A. niger ac-cording to cup plate method 10 at a concentration of 0.005 mole/rnL. Streptomycin and Gressofulvin were used as standard for comparison of antibacterial and antifungal activity, respecti vely. Solvent DMF was used as control. The results of screening are given in Table II. The com-pounds 2b, 3c, Sb, Sd and 6c were found to be more acti ve against S. aureus and the compounds 2b, 3c, Sd, 6c, 7a, 7c and 7e were found to exhibit more activity against K. pneumoniae. The compounds 4a, Sc, 6c, 6f, 7f, and 7d against C. albicans and compounds 3c, 4b, Sd, 6b, 6d, 6e, 7a and 7b against A. niger exhibited sig-nificant antifungal activity.

Anthelmintic activity Anthelmintic activi ty of the compounds was evalu-

ated on earthworms (Pheritima posthuma, Order-Annelida, Class-Oligochaeta) by following the re-ported method I I. Mebendazole was used as standard for compari son. The tes t compounds and standard drug were used at a concentration of 100 mg in 0.1 % Tween-SO (25 mL) suspension. The results of evalua-tion are presented in Table II. The compounds 2a, Sd, 6d, 6c, 7a and 7c were found to possess more anthelmintic acti vi ty than the standard.

Antiinflammatory activity Some selected compounds were screened for anti -

inflammatory acti vi ty by Carrageenan induced paw oedema method 19 on albino rats (Wistar strain).

Table II-Antimicrobial and anthelmintic acti vi ti es of compounds 2a-c, 3a-c, 4a-c, Sa-f and 7a-f.

Compd Ant ibacterial activity Antifungal activity Anthelmintic (Zone of inhibition (Zone of inhibition activi ty

in mm *) in mm*) (i n min)

S.aur-eus

Kpneu-moniae

Ca/hi- Aniger Para- Death cans lys is

2a 7

2b 16

2c 15

3a 9

3b

3c 17

4a 13

4b 8 4c

Sa

Sb

Sc

Sd

Se

Sf

6a

6b

6c

6d

6e

6f

7a

7b

7c

7d

7e

7f

Saline

Std

7

15

13

15

13

4

9

16

9

12

6

8 10

12

14

34

15

18

17

31

17

20

14

23

33

18

24

34

27

29

37

27

30

23

32

27

26

13 24 110

06 19 100 100

90 120

23 22 80 130

11 18

9 48 80 100

34 26 90 120

17 45 100

23

33

06

16

17

26

28

34

26

27

35

34

27

13

26

27

18

31

28

33

33

45

14

30

44

16

12

24

13

24

100

90

11 0

100

90

100

130

160

120

60

11 0

90

20

60

90

130

120

140

120

95

130

120

11 0

165

180

150

90

80

11 0

90

100

110

*Inc ludi ng diameter of the we ll. Control (DMF) = No ac ti vity

Compd

Control Std

4a

4b

6a

6b 7a

Table III-Antiinflammatory ac ti vity of some selec ted compounds

Dose Diffe rence in paw volume

mg/kg afte r 3hr ± S.E.M. 1.24 ± 0.0204

40 0.28 ± 0 .060

100 OA I ± 0.0126

100 0.70 ± 0.0190

100 0.32±0.0 135

100 0.68 ± 0 .0089

100 0 .36 ± 0 .0 152

% Protection

77Al

66.93

43.54

74.19

45.16

70.96

Values are mean ± S.E.M, Index for anti-infl ammatory acti vity study, Method: Carrageenan induced paw oedema, Animal s: Al-bino rats, No of animals per group: 6 ( 150- 120 g), Route of ad-min istration: Oral , Contro l: Twee n-80 (0. 1 %), Standard drug: Ibuprofen, SEM : Standard Error Mean.

1936 INDIAN J. CHEM., SEC B, AUGUST 2003

Measurement of paw volume was carried by using plethysmometer. Ibuprofen was used as standard for comparison. The results of screening are summarised in Table III. The compound 6a was found to exhibit almost equipotent activity when compared to standard drug. Whereas the remaining compounds were found to be less active.

Acknowledgement

The authors are thankful to Professor and Chair-man , Department of Chemistry, Kuvempu University for providing laboratory facilities . The authors are also thankful to the Head, RSIC, Indian Institute of Science, Bangalore for spectral data, to Mr Maruthi, Dept. of Biotechnology, Kuvempu University, Shankaraghatta for his help in carrying out biological activities.

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