6-BROMO-2-PHENYLDIHYDRO-I ::3-BENZOXAZINE-4-ONE. 23

1~1.-6-Bromo - 2 -phenyZdihydro-l : 3 - benxoxaxine-4-one and Related Derivatives,

By ERNEST CHISLETT HUGHES and ARTHUR WALSH TITHERLEY.

IN a previous paper (Trans., 1910, 97, 1368) the authors described a series of chlorederivatives in connexion with the study of the action of chlorine on 2-phenyldihydro-l : 3-benzoxazine-4-one (I). The behaviour of the latter compound with bromine has now been examined, and it has been found that simple bromination occurs in the benzene nucleus, yielding 6-bromo-Z-phenyldihydro-l : 3-benz- oxazine-4-one (11), whilst no substitution of the 2-hydrogen atom takes place such as occurs in the corresponding experiments with chlorine ; that is, the expected unsaturated derivative, 6-bromo- 2-phenyl-1 : 3-benzoxazine4-one (VI), is not produced. This com- pound, however, can be obtained by submitting 6-bromo-2-phenyl- dihydro-1 : 3-benzoxazine-4-one (11) to the action of chlorine instead of to the further action of bromine, when in benzotrichloride solution at l l O o substitution occurs a t position 2, yielding the inter- mediate 2-chloro-6-bromo-derivative (VIII), which immediately loses hydrogen chloride as in the case of the 2 : 6-dichloro-compound (Zoc. cit . ) . It is evident that the hydrogen atom at position 2 is readily affected by chlorine, but not by bromine. Further, the unsaturated ring compound (VI) has been synthetically prepared from 0-benzoyl-5-bromoaalicylamide (V) (obtained by pyridine benzoylation of 5-bromosalicylamide, IV) by the same dehydration method aa that used in the preparation of the corresponding 6-chloro- compound. Further, the constitution of the dihydro-compound (11) has been confirmed by its independent synthesis from 5-bromo- salicylamide (IV) and benzaldehyde. The properties of the two bromo-oxazone compounds (I1 and VI) are in every respect similar to those of the corresponding chloro-derivatives, and whilst 6-bromo- 2-phenyldihydro-1 : 3-benzoxazine-4-0110 (11) on treatment with

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24 HUGHES AND TITHERLEY : 6-BROMO-2-PHENY LDIEIY DRO-

pyridine and alkali yields a labile syn-benzylidene-5-bromosalicyl- amide (111), and with boiling dilute alkali, benzaldehyde and 5-bromosalicylamide, 6-brome2-phenyl-1 : 3-benzoxazine-4-one (VI) is converted by treatment with alkali (or acid) into N-benzoyl- 5-bromosalicylamide (VII), which on further hydrolysis gives 5-bromosalicylamide and benzoic acid. The same reversible re- arrangement phenomena have been observed between 0- and N-benzoyl-5-bromosalicylamides (V and VII) as between the corre- sponding 5-chloro-derivatives a nd 0- and N-benzoylsalicylamides. The above relations are expressed in the scheme:

(I. ) 2-Phenyldihydro- (11. ) 6-Bromo-2-phenyl- (111.) syn-Benzylidane- 1 : S-benzoxazine- dihydro-1 : 3-benz- 5 - bromosalicyl- 4-One. oxazine - 4 - one amide.

(m. p. 223").

/ /" Br/\/co*NH2

Br/\/'OoNH2 + O:CHph Benzoylation I t ____, 1 1 \/\.OH \/\O*COPh

(IV. ) 5-Bromosalicylamide (V. ) 0- Benzo yl- 5 -bromosalicylamide (m. p. 238"). (m. p. 154").

GO CO*NH*COPh HZ.0 Brf\f -+ Br/\ \N

\/\OH 1 "CPh

c' \/v

(VI.) 6-Bromo-2-pheiiyl- ( V I I.) N-Benzoyl-5-bromo- 1 : 3-benzoxazine-

4-0ne (m. p. 208"). 249"). salicylamide (m. p.

t-HCI

co co B r / \ A N H

I I ICHPh 0

B ~ ( ) / \ N H C1

\A/ /CClPh +- 0

\/\ (VIII.) Not isolated. (I1

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1 : 3-BENZOXAZINE-4-ONE AND RELATED DERIVATIVES. 25

EXPERIMENTAL.

6-Brom-2-phenyldihydro-l : 3-b enzoxazine-4-one, C,H, Br< COgrH

0-C HPB'

(1) Bromination of 2-Phenyldihydro-l : 3-b enzoxazine-4-one.- Bromination proceeds easily in the cold, but owing to a secondary reaction, in which some water appears to be produced, a considerable quantity of bromosalicylamide and benzaldehyde is formed as a by-product. A solution of 10 grams of 2-phenyldihydrel : 3-benz- oxazine-4-one in chloroform was gradually treated with 5.2 grams of bromine; the red colour rapidly disappeared, and a pale yellow solid separated (4-5 grams), which, after two hours, was collected and recrystallised from alcohol. It melted at 235O, gave a strong violet colour with ferric chloride, dissolved with slight fluorescence in sodium hydroxide, and was identified as 5-bromosalicylamide. (Found, N = 6.45 ; Br. = 36.68. Calc., N = 6.48 ; Br = 37.03 per cent.)

From the chloroform filtrate, which contained impure benz- aldehyde, 6-bromo - 2 - phenyldihydro - 1 : 3 - benzoxazine-4-one (4.6 grams) was isolated as a pale yellow solid by evaporation and digestion with cold dilute sodium hydroxide. It was obtained pure, by recrystallisation from hot benzene, in fine, colourless needles, melting at 223O: 0.3506, by Kjeldahl's method, required 11.2 C.C. NIlO-HCl. N =4*42. 0.2186 gave 0.1340 AgBr. Br = 26.08.

C,,H,,O,NBr requires N = 4.61 ; Br = 26-31 per cent. The compound is sparingly soluble in cold alcohol, benzene, or

acetone, moderately so in cold chloroform, and readily soluble in hot alcohol or benzene, from both of which it crystallises well on cooling. It is readily decomposed on warming with dilute sodium hydroxide, giving benzaldehyde.

(2) Condensation of 5-Bromosalicylamide and 23enzaldehyde.- The requisite 5-bromosalicylamide (described by Kauschke, J . pr. Chem., 1895, [ii], 51, 211) was obtained by adding 60 grams of bromine gradually to a boiling solution of 50 grams of salicylamide in 1500 C.C. of chloroform. A vigorous reaction took place, the colour of the bromine disappearing immediately, and a copious precipitate of the bromclderivative being formed. The chloroform was finally distilled off in order to remove the hydrogen bromide, which proved troublesome unless eliminated at this stage, and the solid collected and washed with a iittle ether. After recrystallisation from alcohol, it melted at 238O (Kauschke gives 232O). The con- densation of 5-bromosalicylamide and benzaldehyde was easily

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26 HUGHES AND TITHERLEY 6-BROMO-Z-PHENYLDIHYDRO-

effected. Five grams of bromosalicylamide were dissolved by warming in 20 C.C. of benzaldehyde, and 0.5 C.C. of alcoholic hydrogen chloride added. After heating a t looo for a few minutes and allowing to cool slowly, 6-bromo-2-phenyldihydro-l : 3-benz- oxazineQone separated, practically pure, as a thick mass of colour- less crystals (6 grams), which were collected and washed with a little alcohol and ether. It melted a t 219O, and, after re- crystallisation from alcohol, at 223O. The substance was identical in every respect with that obtained by the bromination method, and a mixture of the two melted at 223O : 0.4666, by Kjeldahl’s method, required 15.5 C.C. N/lO-HCI. N=4.64. 0-4104 gave 0.2540 AgBr. B r = 26.34.

C,,H,,O,NBr requires N =4*61; Br = 26.31 per cent.

syn-BenzyZidene-5-bromosalicylamide, C,H,Br<~~N:CHPh . Two grams of 6-brome2-phenyldihydro-l : 3-benzoxazine-kone in

30 grams of pyridine were shaken with 20 C.C. of 10 per cent. sodium hydroxide for half an hour, after which time the bright yellow colour first produced had disappeared. The solution was diluted with water to 750 c.c., and acidified at Oo with dilute hydro- chloric acid. The resulting thick, white, amorphous precipitate, consisting of the syn-bromclderivative, was collected, repeatedly washed with water, and dried on porous porcelain in a vacuum. The melting point (100--150°) was indefinite, and it was not found possible to crystallise the compound without rearrangement t o the cyclic isomeride, but it was practically pure, as shown by its properties and analysis. 0.5166, by Kjeldahl’s method, required 17.2 C.C. N/10-HCI. N =4*66. 0.1952 gave 0.1238 AgBr. Br=26.67.

C, ,H, ,O~Br requires N = 4.61 ; Br = 26.31 per cent.

The yield was quantitative :

syn-Benzylidene-5-bromosalicylamide is very sparingly soluble in solvents in the cold, whilst in the hot in rearranges. On melting, it also rearranges in the course of about forty-five seconds to 6-bromo-2-phenyldihydro-1 : 3-benzoxazine-4-one, which solidifies in the tube, and then melts at 219-220°.

co-E 6-Bromo-2-phenyl-l : 3-b enzoxazhe-4-one, C,HsBr< O-CPh. 1. Preparation from 6-Brom-2-phenyldihydro-l : 3-6 enz-

oxazine-4-one.

The action of bromine on 6-bromcl2-phenyldihydro-l : 3-benz- oxazine-4-one was examined under a variety of conditions, but in

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1 : 3-BENZOXAZINE-4-OME AND RELATED DERIVATIVES. 27

no case could the desired 6-bromo-2-phenyl-l : 3-benzoxazinekone be isolated. The action in all citses led t o fission of the ring, with production of 5-brom~alicylamide. Chlorine, however, gave the desired result. Eight grams of 6-brome2-phenyldihydrel: 3-benz- oxazin&-one, dissolved in the minimum quantity of benzotri- chloride at l l O o , were treated with a rapid current of dry chlorine for one hour. On cooling, a mass of fine needles separated, con- sisting of 6-bromo-2-phen yl-l : 3-b enzoxazine4-0ne, which, after washing with benzene, melted at 202O, and on recrystallisation from benzene at 207O. The yield was 5 grams, and the product was identical in all respects with that obtained by method 2 (see below) : 0’4078, by Kjeldahl’s method, required 13.7 C.C. N / 10-HCI. N = 4.67. 0.4022 gave 0’2522 AgBr. Br = 26.68.

C,,H,O,NBr requires N = 4.64 ; Br = 26-50 per cent.

2. Preparation from 0-Benaoy 2-5-6 romosalic ylamide.

The method employed was similar to that adopted by Titherley (Trans., 1910, 97, 208), using anisole w a solvent. A very slow stream of dry hydrogen chloride was passed into a solution of 2 grams of 0-benzoyl-5-bromosdicylamide (p. 28) in 10 C.C. of anisole at 150° contained in a, small distilling flak. The anisole slowly distilled off, carrying with it the water formed in the reaction. The resulting yellow syrup, which solidified on cooling, was digested with 50 C.C. of dry boiling benzene. This left a quantity of N-benzoyl-5-bromosalicylamide (0.2 gram), and the filtrate, on cooling, deposited 6-bromo-2-phenyl-l : 3-benzoxazine-4-one in a practically pure condition (1 gram), melting at 2 0 7 O . On re- crystallisation from benzene, it wm obtained in small, white needles, melting at 208O: 0.1770, by Kjeldahl’s method, required 6.0 C.C. N / 10-HCI. N = 4.75, 0.1330 gave 0.0814 AgBr. Br=26-04.

C,,H,O,NBr requires N = 4-64 ; Br = 26.50 per cent. The compound is sparingly soluble in cold alcohol, acetone, or

benzene, but readily so in the hot solvents, and it is moderately soluble in cold chloroform. It is not acted on by coId dilute sodium hydroxide, but with strong aqueous or alcoholic ammonia, it gives bright orange needles like the corresponding chlorclderivative. Dilute acids in the cold do not affect the bromo-derivative, but in hot alcoholic solution the ring undergoes disruption with addition of water, yielding N-benzoyl-5-bromosalicylamide (m. p. 240°), which separates as a voluminous mass, the yield being quantitative. This N-benzoyl derivative waa identical with the product obtained by the rearrangement of O-benzoyl-5-bromosaIic@mide (p. 28), and a.

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28 6-BROMO-2:PHENYLDIHYDRO-1 : 3-BENZOXAZINE-4-ONE.

mixture of the two melted at 240°, It gave the following figures on analysis : 0.3648, by Kjeldahl’s method, required 11.5 C.C. N / 10-HCl. N =4*41. 0.1810 gave 0*1080 AgBr. Br = 25.53.

C,,Hl0O3NBr requires N = 4.38 ; Br = 25.00 per cent.

CO*NH, 0 - B enzo y Z-5- b romosalic ylamide, C,H3Br<o. COPh

A solution of 10 grams of 5-bromosalicyIamide in 40 grams of pyridine (dried over barium oxide) was treated with 10 grams of benzoyl chloride with continued shaking. The temperature was kept a t -15O during the addition, which occupied one and a-half hours, and the resulting bright red mixture was kept at -15O for a further hour. It was then treated with 50 C.C. of dry ether, the ethereal pyridine solution decanted off, and the yellow, solid mass treated with dilute sulphuric acid at Oo. An insoluble buff powder remained, consisting of the crude 0-benzoyl derivative, which, after washing with water and ether, weighed 10 grams. On recrys- tallisation from boiling toluene, it separated in fine, colourlesB, glistening needles, melting a t 1 5 4 O : 0.6488, by Kjeldahl’s method, required 20.3 C.C. iV/ 10-HCl. N = 4.38, 0.4528 gave 0.2620 AgBr. Br = 24-73.

C14E,,0,NBr requires N = 4-38 ; Br = 25.00 per cent. 0-Benzoyl-5-bromosalicylamide is sparingly soluble in the usual

solvents. I n boiling alcohol it dissolves, but almost immediately rearranges to the N-benzoyl isomeride (m. p. 238O), which separates on cooling slightly.

The same rearrangement occurs on melting, the liquid at 154O setting in about forty-five seconds to the solid N-benzoyl derivative, which then melts at. 240O.

N-BenzoyZ-5-bromosalicylamide, C,H,Br<OH CO*NH*COPh.

Two grams of 0-benzoyl-5-bromosalicylamide were dissolved in the least possible quantity of boiling alcohol, and the solution diluted to 200 C.C. with water at 80°. The temperature was then kept a t the boiling point for a few minutes, when a thick, curdy precipitate of the pure N-benzoyl derivative, melting a t 248*, was obtained. On recrystallisation from pure acetic acid, the melting point was raised to 249O: 0.4526, by Kjeldahl’s method, required 14.2 C.C. N/lO-HCI. N = 4.39. 0.3142 gave 0.1842 AgBr. Br = 24.95.

C,,E,,O,NBr requires N = 4-38 ; Br = 25-00 per cent.

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KOMPPA : SYNTHESIS OF CAMPHORIC ACID. 29

N-BcnzoyZ-5-bromsaZicyZamide is very sparingly soluble in all the usual solvents, hot or cold. It may, however, be recrystallised from acetic acid if the operation be carried out fairly rapidly to avoid rearrangement. It gives intense yellow sodium and ammonium salts, which are sparingly soluble in water, from which, on acidification, the substance is precipitated in a colourless, gelatinous form.

Rearrangement.-One gram of the N-benzoyl derivative was boiled with 25 C.C. of glacial acetic acid for four hours. On cooling, 0.2 gram of unchanged substance separ'ated out, and on diluting the filtrate with water, 0.5 gram of 0-benzoyl-5-bromosalicylamide was obtained (m. p. 150°), which, on recrystallisation from toluene, melted at 1 5 4 O . It was completely identical in all its properties with the synthetic product.

ORGANIC LABOR ATOlLP, UNIVERSITY OF LIVERPOOL.

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