Alkylating A g e n t s and M a n n i c h Reaction. Chemistry Department, Faculty of Science, Cairo University, Egypt

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1 Reactions w i t h l P h e n y l t h i o h y d a n t o i n. Preparation of 5 A r y l a z o l p h e n y l t h i o h y d a n t o i n, their Reactions towards Alkylating A g e n t s and M a n n i c h Reaction F. SHALABY, H. DABOUN, a n d S. S. M. BOGHDAD Chemistry Department, Faculty of Science, Cairo University, Egypt (Z. Naturforsch. 1b, 8589 [197]; received January 19, 197) lphenylthiohydantoin, Alkylating Agents, Amines, Mannich Reaction lphenylthiohydantoin reacted with aryldiazonium salts to give the corresponding 5arylazolphenylthiohydantoin ( l a f ). On alkylation of l a, b, f with different alkyl halides, the corresponding alkylmercapto derivatives (2 a f ) were obtained. 2 a was hydrolysed with a mixture of ethanolhydrochloric acid to give 5phenylazolphenyl hydantoin (). Treatment of 2 a, d with amines gave the products a h. a when refluxed with a mixture of acetichydrochloric acid, the product was obtained. l a, b reacted with formaldehyde and appropriate amine to give the corresponding Mannich bases 5 a k. Also lphenylthiohydantoin when exposed to the Mannich reaction, ae were obtained. a when treated with benzenediazonium chloride, the colour substance 5 a was separated. Recently, thiohydantoin1 and lphenylthiohydantoin2 were prepared by refluxing hydantoin and 1phenylhydantoin with phosphorus pentasulphide in dioxane. Under controlled conditions, thiohydantoin was found to react smoothly with aromatic aldehydes in glacial acetic acid to give the corresponding arylidene derivatives2; while difficulty occurred when Nl substituted hydantoin and lphenylthiohydantoin2 condensed with aromatic aldehydes to give unsaturated hydantoin derivatives. The arylazo derivatives (laf) gave the correct analytical data and they disolved in dilute aqueous sodium hydroxide solution (2%). The introduction of the electron withdrawing arylazo group in C5 position activated the hydantoin ring as well as the thione group; so on alkylation of the compounds 1 a, b, f, with different alkyl halides in the presence of aqueous sodium hydroxide and ethanol yielded the corresponding alkylmercapto derivatives (2 af) in quantitative yields. ArNNCH n this paper we report the coupling of 1phenyl thiohydantoin with aryldiazonium salts to give the coloured arylazo derivatives (laf). ArN=NCH PhN 2a: 2b: 2c: 2d: 2e: 2f: OS PhN^ /NH 1 l a : AR=CH5 l b : AR=PCl CH l c : A T = O N 0 2 CH l d : AR=OCH C^m l e : AR=MCH CH l f : AR=PCH CH Requests for reprints should be sent to Prof. Dr. F. SHALABY, Chemistry Department, Faculty of Science, Cairo University, Cairo, Egypt. CSR N 0 2 A r = C H 5 ; R = CH R = C 2 H 5 R = CH 2 C H 5 A r = p C l C H; R = C 2 H 5 A r = p C H CH; R = C 2 H 5 A r = p C H C H ; R = CH 2 C H 5 When 2a was refluxed with a mixture of ethanolhydrochloric acid, till the odour of methane thiol could not be detected, the methylmercapto group present at position underwent cleavage thereby yielding 5phenylazolphenylhydantoin (), which was identical with authentic sample. Dieses Werk wurde im Jahr 201 vom Verlag Zeitschrift für Naturforschung in Zusammenarbeit mit der MaxPlanckGesellschaft zur Förderung der Wissenschaften e.v. digitalisiert und unter folgender Lizenz veröffentlicht: Creative Commons NamensnennungKeine Bearbeitung.0 Deutschland Lizenz. This work has been digitalized and published in 201 by Verlag Zeitschrift für Naturforschung in cooperation with the Max Planck Society for the Advancement of Science under a Creative Commons AttributionNoDerivs.0 Germany License. Zum ist eine Anpassung der Lizenzbedingungen (Entfall der Creative Commons Lizenzbedingung Keine Bearbeitung ) beabsichtigt, um eine Nachnutzung auch im Rahmen zukünftiger wissenschaftlicher Nutzungsformen zu ermöglichen. On it is planned to change the License Conditions (the removal of the Creative Commons License condition no derivative works ). This is to allow reuse in the area of future scientific usage.

2 8 A. F. A. S H A L A B Y ET AL. R E A C T O N S W T H 1 P H E N Y L T H 0 H Y D A N T O N thiohydantoin was regenerated when 5 a was hydrolysed with boiling concentrated hydrochloric Our study was extended towards the action of Mannich reaction on lphenylthiohydantoin, On fusion of 2 a with benzylamine and/or 2 a, d which when treated with formaldehyde and the with the primary aromatic amines at 1010 C appropriate amine under the above experimental (bath temperature) till the odour of the evolved conditions, the free methylene group did not enter alkane thiol could not be detected, the corresponding into reaction while the N position due to its 5arylazosubstitutediminohydantoins ( ah) favourable location between the carbonyl group as were obtained. well as the activating thione group, entered into ArNNCH C=NR reaction yielding the corresponding Mannich bases C H 5 N=NCH C0 PhN^. /NH PhNL a: b: c: d: e: f: g: h: Ar = C H 5 : Ar^CeHs; Ar = pcl Ar=pCl Ar=pCl.NH ArNNCH C=S PhN. PHN. c 0 NCH2NHR a: b: R=CH5 R=PCl CH d: R = O C H c: e: R=oN02CH R = M C H C C H H The products ae gave pale yellow colour when treated with concentrated sulphuric The structure of the products ae is inferred from the facts that they gave the correct analytical values also when a was treated with a cold solution of benzenediazonium chloride, the previously prepared 5a was obtained. Also when a was refluxed with a concentrated hydrochloric acid lphenylthiohydantoin was regenerated. Experimental Melting points are uncorrected. NCH 2 NHR o Ar=pCl Ar=pCl Ar=pCl Ar=pCl Ar=pCl Ar=pCl CH2 OS A R = CH 2 C H 5 R = CH5 R = och C H R=roCH C H R = p C H CH CH; R = CH5 CH; R = o C H CH C H ; R = pch C H The coloured compounds ah gave the correct analytical values. a was hydrolysed with a mixture of hot acetichydrochloric acid yielding 5phenylazolphenylhydantoin (). t was reported that the Mannich bases of 2thiohydantoin derivatives were synthesised and tested as pharmacological active compounds5. When 5arylazothiohydantoin derivatives (la,b) were allowed to condense with formaldehyde and the appropriate amine in ethanol under the Mannich reaction conditions7; in each case one product was isolated and the Mannich bases 5 ak were obtained. 5a: 5b: oc: 5d: 5e: 5f: 5g: 5h: 5i: 5j: 5k: ae. 5 R = CH5 R = pcl C H R = on0 2 C H R = och C H R = P C H CH CH; R = CH5 CH; R = P C l CH C H ; R = on0 2 C H C H ; R = och C H C H ; R =?nch C H C H ; R = pch C H Compounds 5 ak gave the correct analytical values and gave red colour with concentrated sulphuric They are insoluble in aqueous sodium hydroxide solution (2%). 5Phenylazolphenyl Preparation (laf) of 5arylazolphenylthiohydantoin General procedure: The aromatic amine (0.008 mole) dissolved in concentrated hydrochloric acid ( ml) and water ( ml) was cooled to 0 C and then treated with a cold solution of sodium nitrite (0. g) in water ( ml). The diazotized amine was added gradually to an icecold solution of 1. g 1phenylthiohydantoin2 dissolved in 50 ml ethanol containing 2. g of sodium acetate. After the addition was completed, the reaction mixture wtas left aside in a cold chest for 1 hour. The product separated was filtered off, washed with water and crystalhsed from acetic acid (cf. Table ). The 5arylazo derivatives (1 af), listed in Table, are red in colour, soluble in sodium hydroxide (2%), and give deep red colour with concentrated sulphuric

3 F. A. S H A L A B Y ET AL. R E A C T O N S W T H 1 P H E N Y L T H 0 H Y D A N T 0 N 87 Table. 5Arylazolphenylthiohydantoin. Com m.p. Formula la lb lc ld le lf C15H12ONS C15H11ONSC* C15HUON5S CHONS CHONS CHONS * Cl: Calcd 10.7; Found 10.8%. of alkyl halides on 1 a, b, f To each of 1 a, b, f (0.02 mole) in 0 ml of sodium hydroxide and ethanol (0 ml) was added the appropriate alkyl halide (0.022 mole). The reaction mixture was stirred for 0 minutes and then left overnight at room temperature. The solid obtained was collected by filtration and recrystallised from ethyl alcohol (cf. Table ). The alkylmercapto derivatives (2af), listed in Table, are insoluble in sodium hydroxide (2%) and give red colour with concentrated sulphuric of concentrated hydrochloric acid on 2 a 1010 C for 2 hours till the odour of the thiol could not be detected, then left aside to cool at room temperature. The sohd obtained was washed with alcohol and collected by filtration and crystalhsed from ethyl alcohol (cf. Table ). The 5arylazosubstitutediininohydantoins (ah), hsted in Table, are all coloured. They give yellow colour with concentrated sulphuric of acetichydrochloric acid mixture on a a (0.5 g) in a mixture of acetic acid (10 ml) and concentrated hydrochloric acid (10 ml) was refluxed for hours, allowed to cool at room temperature. The sohd (0. g) which separated, was filtered off and crystalhsed from dimethylformamide as 5phenylazolphenylhydantoin (), m.p. 05 C (melting point and mixed melting point determination). 0.5g of 2a in a mixture of ethanol (20 ml) and concentrated hydrochloric acid (5 ml) was refluxed till the odour of the evolved methane thiol could not be detected. The reaction mixture was left to cool at room temperature, and the solid (0. g) Mannich reaction with 5arylazolphenylthioobtained was collected by filtration and crystallised hydantoin (la,b) from dimethylformamide, m. p. 05 C, and identified To a suspension of each of la,b (0.01 mole) and as 5phenylazolphenylhydantoin () by melting the appropriate amine (0.011 mole) in ethyl alcohol point and mixed melting point determination. (50 ml) was added 0% aqueous formaldehyde (1.1 ml). The reaction mixture was heated on steam of aromatic amines on alkylmercapto bath for 2 hours. The reaction mixture was conderivatives (2 a, d) centrated to half its volume and left aside overnight A mixture of each of 2 a, d (0.005 mole) and the at room temperature. The sohd product so obtained appropriate primary aromatic amine ( mole) was filtered and crystalhsed from ethyl alcohol was mixed well and heated in an oilbath at {cf. Table V). Table. 5Arylazolphenylalkylmercaptohydantoin. Com m.p. 2a 2b 2c 2d 2e 2! Formula C 1 H ON S C17H1ONS C22Hi8ONS C17H15ONSC* C8H18ONS C2H20ONS * Cl: Calcd 9.90; Found 10.0%

4 88 A. F. S H A L A B Y ET AL. R E A C T O N S W T H 1 P H E N Y L T H 0 H Y D A N T O N Table. 5Arylazolphenyliminohydantoin derivatives. Compound m.p. [ CJ Form vila a b c d e f * 252* 278* C21H17ON5 C 2 2H 19 ON 5 C2iHON5C1** C 2 2H 18 0N 5 C1*** C 2 2H 18 0N 5 C1**** g h * Crystallised from ethyl alcohol (85%); ** Cl: Calcd 9.11; Found 9. 2 % ; *** Cl: Calcd 8.80; Found 8. 9 % ; **** Cl: Calcd 8.80; Found 8.8%. Table V. 5Arylazolphenylarylaminomethylthiohydantoin. Com m.p. Formula Chlorine 5a 5b 5c od 5e 5! g 5h ai 5j 5k S C22H8ON5SC1 C22H18ONS C2H21ON5S C2N2iON5S C22H8ON5SC1 C22H7ON5SC12 C22H70NSC1 C2H20ON5SC1 C 2 H 20 ON 5 SC C 2 H 20 ON 5 SC The Mannichbases 5 ak, listed in Table V, are coloured compounds, give red colour with concentrated sulphuric They are insoluble in sodium hydroxide (2%) of concentrated hydrochloric acid on 5 a A mixture of 0.5 g of 5 a and 10 ml of concentrated hydrochloric acid was refluxed for 10 minutes and allowed to cool. The sohd (0. g) which separated, was filtered off and crystallised from acetic acid, m.p. 21 C and identified as 5phenylazolphenylthiohydantoin (la) by melting point and mixed melting point determination. Mannich reaction with lphenylthiohydantoin To a suspension of 1.92 g of lphenylthiohydantoin2 (0.01 mole) and the appropriate amine (0.01 mole) in ethyl alcohol (50 ml) was added 0% aqueous formaldehyde (1.1 ml). The reaction mixture was worked up as above and the solid obtained was crystalhsed from alcohol (cf. Table V) The Mannichbases ae, listed in Table V, give pale yellow colour with concentrated sulphuric They are insoluble in sodium hydroxide (2%) of benzenediazonium chloride on a To a cold solution of a (2.97 g; 0.01 mole) in 70 ml of ethanol containing g of sodium acetate, was added dropwise the diazonium chloride solution prepared from 0.9 g of aniline. After the addition was completed, the reaction mixture was left aside for one hour, filtered and crystalhsed from ethyl alcohol, m.p. 18 C (2.5 g). t was identified as 5a by melting point and mixed melting point. of concentrated hydrochloric acid on a A mixture of 1 g of a and 20 ml of concentrated hydrochloric acid was refluxed for 10 minutes, allowed to cool, the solid (0. g) so obtained was filtered and crystallised from alcohol as colourless crystals of 1 pheny 1thiohydantoin, m.p. 201 C (melting point and mixed melting point determination) 2.

5 A. F. A. SHALABY ET AL. REACTONS WTH 1 PHENYLTHOHYDANTON 89 Table V. lphenylarylaminomethylthiohydantoin. Analysis Com m.p. Formula a CH15ONS b 22 0 C1HiONSC1* c 188 CH0NS d 19 5 C7H7ONS e 177 C7H7ONS * Cl: Calcd 10.71; Found 10.%. 1 A. P. GRSCHUK, S. N. BARANOV, T. E. GORZDRA, and. D. KOMARTSA, Zh. Prikl. Khim. 0 (), [197] (Russ); C. A. 7, 1189c [197]. 2 A. F. A. SHALABY, H. A. DABOUN, and S. S. M. BOGHDAD, Z. Naturforsch. 29B, 9910 [197]. H. L. WHEELER and C. HOFFMANN, Amer. Chem. J. 5, 8 [1911]. A. F. A. SHALABY, H. A. DABOUN, and M. A. ABDEL Azrz, ndian J. Chem. 12, 577 [197]. 5 A. ZEJC, Diss. Pharm. Pharmacol. 20 (5), 507 [198]; C. A. 70, 7780a [199]. V. G. ZUBENKO, Farm. Zh. (Kiev). 2 (2), 18 [199] (Ukrain); C. A. 71, 128k [199]. 7 F. F. BLCKE, "Org. Reactions," Vol., pp. 01, John Wiley and Sons, New York 192.