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Reactions of B e n z o f u r a n s , V *

Formylat ion and Brominat ion of 2 , 3 - D i p h e n y l b e n z o f u r a n

0 . H . H I S H M A T

National Research Centre, Dokki, Cairo, A. R. Egypt

and

A . H . A B D - E L - R A H M A N

Faculty of Science, Mansoura University, Mansoura, A. R. Egypt

(Z. Naturforsch. 31b, 1138-1141 [1976]; received February 11, 1976)

2,3-Diphenylbenzofuran, Benzofurans, Formylation, Bromination

VILSMEIER-HAACK formylation of 2,3-diphenylbenzofuran (la) gave the 5,6-diformyl derivative (lb). Huang-Minion reduction of lb yielded the 5,6-dimethyl derivative (lc). Oxidation of 1 c followed by hydrolysis the 2-hydroxy-4,5-dimethylbenzophenone (2 b) was obtained.

Condensation of lb with primary amines gave the corresponding Schiff bases (3a-j). l a on bromination gave 5-bromo-2,3-diphenylbenzofuran (1 d), which on hydrolysis via

oxidation yielded 2-hydroxy-5-bromobenzophenone (2d), ld was also obtained by condensation of benzoin and p-bromoplienol in presence of sulphuric acid.

Conrad-Limpach reaction of 5-methoxy-6-amino-2,3-diphenylbenzofuran (le) and ethyl acetoacetate gave 2,3-diphenyl-7-methyl-5-methoxy-9-hydroxy[2,3-f]furoquinoline via the azomethine (4).

I t has been reported that some alkylated, nitrated and halogenated benzofurans possess parasiticidal activity against triehromones vaginalis, entamoeba dysenteriae and syphaera obvelata 1 - 3 . Both Schiff bases of 2-ethyl-3-formylbenzofuran and their reduced products show hypotensive activity4 . Thus, the synthesis o f some derivatives of the benzofuran series has now been undertaken in order to obtain some derivatives o f potential biological action.

It has been reported that G A T T E R M A N formylation of 3-phenyl-6-methoxybenzofuran led to the forma-tion o f the 2-formyl derivative5 - 7 . Similarly V I L S M E I E R - H A A C K formylation of 6- or 5-methoxy-3-methylbenzofuran gave the 2-formyl derivatives8. On the other hand formylation of 5- and 6-methoxy-2,3-diphenylbenzofuran gave the 6- and 5-formyl derivatives respectively9 . Also F R I E D E L - C R A F T

acetylation of 2,3-diphenylbenzofuran gave 6-acetyl

* Part I V : O. H . HISHMAT, A . H . ABD-EL-RAHMAN, and E. M. KANDEEL, Indian J. Chem., in press.

Requests for reprints should be sent to Prof. Dr. O. H. HISHMAT, Natural Products Laboratory, National Res. Centre, Dokki, Cairo. Egypt.

derivative1 0 , while b y using excess o f acetyl chloride the triacetyl derivative was obtained1 1 .

In the present work 2,3-diphenylbenzofuran ( l a ) was synthesized b y another method with higher purity than that prepared by M O R T I M E R et al.12. Whereas l a has been prepared1 2 f rom benzoin and phenol in presence o f boric acid and the m.p . was reported 123 °C, we have synthesised it by using benzoin, phenol and sulphuric acid, in 9 0 % yield, m.p . 130 °C.

Formylation of l a according to V I L S M E I E R -

H A A C K 1 3 b y using dimethyl formamide and phos-phorus oxychloride in excess gave 5,6-diformyl-2,3-diphenylbenzofuran (lb). The structure of l b was confirmed b y its H U A N G - M I N L O N reduction1 4 , b y using hydrazine hydrate and diethylene glycol 5,6-dimethyl-2,3-diphenylbenzofuran1 5 (lc) was obtained. Oxidation o f l c with chromic-acetic acid mixture yielded 2-benzoyloxy-4,5-dimethylbenzo-phenone (2a). Alkaline hydrolysis o f 2a gave the known2-hydroxy-4,5-dimethylbenzophenone(2b)1 6 . The infrared spectrum of l b reveals a band at 1698 c m - 1 characteristic for an aromatic - C H O group1 7 a .

O. H. HISHMAT-A. H. ABD-EL-RAHMAN • REACTIONS OF BENZOFURANS 1139

HGC H5C6CO R' XX

2 a : R = C O C 6 H 5 ;

R ' = R " = C H 3

2 b : R = H ; R ' = R " = C H 3

l a : R = R ' = H l b : R = R ' = C H O l c : R = R ' = C H 3

l d : R = B r ; R ' = H l e : R = O C H 3 ; R ' = N H 2 2c : R = C O C 6 H 5 ;

R ' = B r ; R " = H 2d: R = R " = H ;

R ' = B r

Condensation o f 1 b with the primary amines: ani-line, £>-toluidine, o-toluidine, p-anisidine, o-anis-idine, p-nitroaniline, o-nitroaniline, £>-chloroaniline, p-bromoaniline and butylamine gave the cor-responding Schiff bases 3a - i 1 8 .

HsCs-̂

Hsc6-

3a : R=CeH5 3 b : R = C 6 H 4 C H 3 - P

3 c : R = C 6 H 4 C H 3 - O

3 d : R = C 6 H 4 O C H 3 - P

3 e : R = C 6 H 4 O C H 3 - o

CH=NR

3 f : R = C 6 H 4 N 0 2 v 3 g : R = C 6 H 4 N 0 2 - o 3 h : R = C 6 H 4 C l - p 3 i : R = C 6 H 4 B r - p 3 j : R = C 4 H 9

Taking 3 a, 3 e and 3 i as an example, the infrared spectra of those compounds show bands at about 1660,1650 and 1670 c m - 1 respectively characteristic for C = N group1 7 b , and show the absence of the carbonyl group (aldehyde group)1 7 a .

Whereas O F F E N B E R G et al.19 has reported that bromination of 2,3-diphenylbenzofuran (1 a) yielded the 6-bromo derivative m.p . 127 °C, we found that l a on bromination under the same experimental conditions gave the 5-bromo derivative ( l d ) m.p . 99 °C. This is in agreement with the finding o f S M I T H 20 who found that coumarilic acid ethyl ester on bromination yielded the 5 -bromo derivative. Also bromination o f 6-methoxy-2,3-diphenylbenzo-furan 2 1 yielded the 5-bromo derivative. Oxidation o f 1 d followed b y hydrolysis gives the known 2-hydroxy-5-bromobenzophenone (2d)22. 2d, pre-pared by B L A T T (m.p. 110 ° C ) 2 2 . While 2-hydroxy-4-bromobenzophenone known in the literature22 is reported to melt at 85 °C.

As condensation of hydroquinone 2 3 and p-cresol2 4

with benzoin leads to the formation of 5 -hydroxy and 5-methyl-2,3-diphenylbenzofuran, respectively.

W e have condensed p-bromophenol with benzoin in presence of sulphuric acid to form 5-bromo-2,3-diphenylbenzofuran which proved to be identical to our compound ld (m.p. and mixed m.p. ) .

The furoquinoline 5 has been successfully achieved from 5-methoxy-6-amino-2,3-diphenylbenzofuran2 1

( l e ) according to C O N R A D - L I M B A C H reaction2 5 by condensation of 1 e with ethyl acetoacetate to give the azomethine 4. Cyclization o f 4 by heat in diphenyl ether gave the furoquinoline (5).

HSC6̂ p^0CH3 H5C- ^ /0CH 3

CH3 C2H5 JL II

CH3

Experimental Melting points are not corrected. Infrared spectra

were carried out on Unicam S. P. 1000 spectro-photometer.

Preparation of 2,3-diphenylbenzofuran (la) 100 g of benzoin and 150 g of phenol was heated

on an oil bath at 120-140 °C till fusion, then leave to cool. Add 225 ml o f sulphuric acid (200 ml of 7 3 % sulphuric acid and 25 ml of water) and heat again at 120-140 °C for 20 minutes, then leave to cool, wash the solid so obtained with water and with 100 ml of 1 0 % sodium hydroxide, crystallise f rom ethanol to give white needles m.p . 130 °C, yield is ca. 9 0 % . It proved to be identical with an authentic sample1 2 (mixed m.p. ) .

5,6-Diformyl-2,3-diphenylbenzofuran (1 b) To a solution of 3 g l a in 10 ml of dimethyl-

formamide was added to 5 ml o f phosphorus oxy -chloride in small portions. Heat on a boiling water bath for 10 hours, then decompose the reaction mixture by boiling with a saturated solution of sodium acetate for 15 minutes. Extract the organic layer with benzene and wash with water, then evaporate the solvent to give white needless f rom n-hexan, m.p . 58 °C, yield is ca. 8 0 % . Analysis for C22H14O3

Calcd C 80.98 H 4.29, Found C 80.92 H 4 . 1 5 .

5,6-Dimethyl-2,3-diphenylbenzofuran (1 c) Reflux a mixture of 4.4 g o f l b and 1.5 ml of

hydrazine hydrate in 10 ml of diethylene glycol for 15 minutes. Cool and add 1.6 g o f potassium hydroxide, then heat again at boiling for 30 minutes. Leave to cool, filter to give 5,6-dimethyl-2,3-di-phenylbenzofuran1 5 as white crystals f rom ethanol, m.p . 154 °C, yield is ca. 7 3 % (mixed m.p . with an authentic15 sample give no depression).

O. H. HISHMAT-A. H. ABD-EL-RAHMAN • REACTIONS OF BENZOFURANS 1140

2-Benzoyloxy-4,5-dimethylbenzophenone (2 a) 0.4 g o f 1C is added to a hot solution of 0.4 g of

chromic anhydride in 20 ml of glacial acetic acid. Add another 0.15 g of chromic anhydride and reflux for 30 minutes, dilute with water (20 ml) and leave to cool, then filter, the sohd so obtained was crystalhsed f rom w-hexan as white crystals, m.p . 65 °C, yield is ca. 5 5 % . Analysis for C22H18O3

Calcd C 80.00 H 5.76, Found C 79.73 H 5.52.

2-Hydroxy-4,5-dimethylbenzophenone (2 b) 9 b was obtained by reflux 1 g of 2 a with 0.25 g

o f potassium hydroxide in 150 ml of ethanol for 1 hour. Concentrate the solvent to about 10 ml, then pour on water (75 ml). Leave to cool and acidify with concentrated hydrochloric acid to give 2b 1 6 in yield 6 4 % from ethanol m .p . identical with an authentic specimen.

Preparation of Schiff bases 3 a - j General procedure

Reflux a mixture of 0.05 mole of 1 b and 0.05 mole of the appropriate amine for 3 hours. The reaction mixture was left to cool, filter and crystallise from ethanol (see Table I) .

5-Bromo-2,3-diphenylbenzofuran (1 d) To a mixture of 1 g of 1 a in 60 ml of carbon

tetrachloride, is added 0.46 g bromine (excess) in 10 ml of carbontetrachloride. Leave at room tem-perature for 24 hours, then evaporate the solvent under reduced pressure. The oily residue is crystal-lised f rom n-hexan as yellow needles, m.p . 99 °C, yield is ca. 8 3 % . Analysis for CioH^BrO

Calcd C 68.77 H 3.72 Br 22.92, Found C 68.53 H 3.61 Br 23.11. l d is also obtained by condensation of 100 g of

benzoin and 150 g of p-bromophenol as in case of 1 a which proved to be identical to our compound l d (m.p. and mixed m.p . ) yield is ca. 8 5 % .

2-Benzoyloxy-5-bromobenzophenone (2 c) Oxidation of 1 g o f 1 d with chromic-acetic acid

mixture as in case of 2a gave a solid ( 6 0 % yield), crystallised from w-hexan as white crystals, m.p . 87 °C. Analysis for CwHizBrOz

Calcd C 62.99 H 3.41 Br 20.99, Found C 63.21 H 3.51 Br 21.29.

2-Hydroxy-5-bromobenzophenone (2d) Similarly, 2 c is hydrolysed with potassium

hydroxide in ethanol to give the known 2-hydroxy-5-bromobenzophenone 2 2 f r om ethanol, m .p . and mixed m.p . 110 °C in 6 5 % yield.

2,3-Diphenyl-5-methoxy-7-methyl-9-hydroxy[2,3-f ] -furoquinoline (5)

A mixture o f 1 g of 5-methoxy-6-amino-2,3-diphenylbenzofuran2 1 ( l c ) and 1 m l o f freshly distilled ethyl acetoacetate in 25 ml of methylene chloride and 0.5 ml o f concentrated hydrochloric acid was left at room temperature for 36 hours. Then evaporate the solvent under reduced pressure, dissolved in 100 ml o f benzene and filter then evaporate the solvent to give the azomethine 4 as white crystals m . p . 238 °C f rom acetone, yield is ca. 80%.

Analysis for C27H25NO4 Calcd C 75.88 H 5.76 N 3.27, Found C 75.76 H 5.49 N 3.43.

Cyclisation of the azomethine 4 1 g of the azomethine 4 in dissolved in 25 ml of

diphenylether, then add slowly while heating another 25 ml of diphenyl ether boil and stir well for 20 minutes. Then leave to cool for 18 hours, filter to give 2,3-diphenyl-5-methoxy-7-methyl-9-hydroxy-[2,3-f] furoquinoline (5) as white crystals f rom cycle hexan, m .p . 195 °C, yield is ca. 6 5 % . Analysis for C25H19NO3

Calcd C 78.74 H 4.98 N 3.67, Found C 78.92 H 4.73 N 3.52.

Table I.

Analysis Compound m.p. Yield Mol. Calcd Found Compound

[°C] [%] formula C H N C H N

3 a 154 75 C34H24N2O 85.71 5.04 5.88 85.51 5.16 5.73 3b 140 80 C36H28N2O 85.71 5.55 5.55 85.62 5.27 5.23 3 c 150 73 C36H28N20 85.71 5.55 5.55 85.88 5.68 5.43 3 d 165 68 C36H28N2O3 80.59 5.22 5.22 80.21 5.11 5.32 3e 169 81 C36H28N2O3 80.59 5.22 5.22 80.23 5.32 4.98 3 ! 62 75 C34H22N4O5 72.08 3.89 9.89 72.34 3.64 9.56

148 83 C34H22N4O5 72.08 3.89 9.89 71.81 3.98 9.65 3 h 160 76 C 3 4 H 2 2 C l 2 N 2 0 74.86 4.04 5.15 74.66 4.21 5.35* 3 i 164 65 C34H22Br2N20 64.35 3.47 4.42 64.53 3.22 4.54** Bj 94 62 C30H32N2O 82.57 7.34 6.42 82.23 7.51 6.34

Calcd. for Cl 13.05, found 13.35%; ** Calcd. for Br 25.25, found 25.43°(

O. H. HISHMAT-A. H. ABD-EL-RAHMAN • REACTIONS OF BENZOFURANS 1141

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