The synthesis of seven undescribed 0-ethyl-S-[(2-N-methyl-
N-arylamino)ethyl] methylphosphonothioates (compounds I-VII)
and their methosulphates (compounds VIII-XIV) is presented
together with their physicochemical characteristics.
From N,N-dimethylarylamines were prepared N-methyl-N-(
2-hydroxyethyl)arylamines which with phosphorus oxychloride
gave the corresponding N-methyl,N-(2-chloroethyl)arylamines. By
reacting them with sodium 0-ethyl methylphosphonothioate the substances I-VII were obtained. The substances VIII-XIV were
obtained by quaternization of substance I-VII with dimethylsulphate.
As intermediate products the following new compounds were
1synthetized: N-methyl- N-(2-hydroxyethyl)m-methoxyphenylamine,
N-methyl- N-(2-hydroxyethyl)p-methoxyphenylamine, N-methylN-(
2-chloroethyl)m-methoxyphenylamine and N-methyl- N-(2-
-chloroethyl)p-methoxyphenylamine

M. Orlov

M. Ćosić

Z. Binenfeid

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CROATICA CHEMICA ACTA CCACAA 45 (4) 561-567 (1973) CCA-801 YU ISSN 0011-1643 547.435 Original Scientific Paper Aromatic Phosphoryl Thiocholines. II*. Syntheses and Physicochemical Properties M. Casie, M. Orlov, and Z. Binenfeid Institute for Technical and Medical Protection, 11000 Belgrade, Serbia, and Chemical Plant Chromos-Katran-Kutrilin, 41000 Zagreb, Croatia, Yugoslavia Received April 26, 1973 The synthesis of seven undescribed 0-ethyl-S-[(2-N-methyl--N-arylamino)ethyl] methylphosphonothioates (compounds I-VII) and their methosulphates (compounds VIII-XIV) is presented together with their physicochemical characteristics. From N,N-dimethylarylamines were prepared N-methyl-N--(2-hydroxyethyl)arylamines which with phosphorus oxychloride gave the corresponding N-methyl,N-(2-chloroethyl)arylamines. By reacting them with sodium 0-ethyl methylphosphonothioate the sub-stances I-VII were obtained. The substances VIII-XIV were obtained by quaternization of substance I-VII with dimethyl-sulphate. As intermediate products the following new compounds were 1synthetized: N-methyl- N-(2-hydroxyethyl)m-methoxyphenylamine, N-methyl- N-(2-hydroxyethyl)p-methoxyphenylamine, N-methyl-N-(2-chloroethyl)m-methoxyphenylamine and N-methyl- N-(2--chloroethyl)p-methoxyphenylamine. During the last years several representatives of a new group of biologi-cally active aromatic phosphorylthioethylalkylaryl amines have been described. Kabachnik et al.1 synthetized 0,0-diethyl[S-(2-N-methyl-N-arylamino)ethyl] thiophosphorothioates: C2HsO"' /" 0 p C2HsO / "' SCH2CH2NC6H4R I CHa with R = H, -CH3, -OCH3 , -Cl in p and m position and their methosulpha~ . tes. Studying the kinetics of their alkaline hydrolysis, the authors1 found these compounds to be very stable, the tertiary compounds being more stable than the quaternary ones. Brestkin et al.2 studied the kinetics of cholinesterase inhi-biHon, and at the same time focussed their attention upon the influence of the aryl radical on the biological properties of these compounds. For that reason it was of interest to synthetize the derivatives of the phosphonic acid corresponding to the general formula: * Part I: ref. 3. 562 ivr. cosrc ET AL. CH3"' / 0 p C2HsO / """ SCH2CH2NCaH4R I CH3 with R = H, -CH3 , -OCH3 , -Cl in m and p position and the methosulphate of their dimethylammonium analogues in order to learn how the quaternization of the nitrogen atom, aromatic nuclei and the position of different ring sub-stituents influence their biological activity.3 The starting material 0-ethyl methylthiophosphonic acid was synthetized by the method of Pelchovicz and coworkers.4 The N-rnethyl N-(2-hydroxyethyl) -arylamines were prepared by the method of Nagusk'i and Yosimoto5 used for the synthesis of the unsubstituted N-methyl N-(2-hydroxyethyl)phenylamine: heating (CHa)2NCaH4R + ClCH2CH20H ----+ HOCH2CH2NCaH4R + CH3Cl I CH a The corresponding N-methyl-N-(2-chloroethyl)arylamines were obtained by rthe reaction of POC13 with the above mentioned hydroxy compounds6. The syntheses of 0-ethyl S-[(2-N-rmethyl-N-arylamino)ethyljmethylphos-phonothioates were performed by reacting sodium 0-ethyl methylphospho-nothioate and corresponding N-methyl-(2-chloroethyl) arylamines: Under the conditions mentioned the reaction is a bimolecular nucleophilic substitution (SN2) in which the nucleophile is the sulphur atom of the sodium 0 -ethyl methylphosphonothioate7• In the syntheses of 0-ethyl S-[(2-N-methyl--N-ary1amino)ethyl]methylphosiphonothioates the S-alkylated products were always obtained because the reaction was performed with a weak electrophile in a protonated solvent which does favor S-alkylation. 0-Ethyl S-[(2-N,N--dimethylarylammonium)ethyl]methyl phosphonothioate methosulphates were prepared by methylating the corre3ponding tertiary compounds with the equi-molecular quantity of dimethylsulphate using the method of Volkova et aI.8 In relation to the analogous thiocholine compounds with alkyl groups on the nitrogen atom9 , the syntheses of the described tertiary compounds and the methylation process are of longer duration. Probably this can be attributed to the presence of the aromatic radical on the nitrogen atom, which slows down the described reactions by enhancing the thermochemical stability. Resonance effects from the aromatic ring are likely to cause the diminished reactivity of the described aromatic compounds in relation to the corresponding aliphatic ones. AROMATIC PHOSPHORYL THIOCHOLINES 563 EXPERIMENTAL 0-Ethyl methylthiophosphonic acid was obtained in 700/o yield from methylthio-phosphonic dichloride, ethanol and potassium hydroxyde4 as yellowish oil b. p. 80 °c (0.3 mmHg), ni; = 1.4910 [lit.4 87-93 (0.55 mmHg); nijl = 1.4927]. N-M ethyl,N-(2-hydroxyethyl)-arylamines5 The mixture of N,N-dimethylalkylarylamine (2 mol) and ethylenechlorhydrine (2 mol) was refluxed for 5-15 h under constant stirring at 190-200 '°C until no more methyl chloride was formed. The reaction time was dependent on the ring substituent. The described products were isolated from 1he reaction mixture by fractionated vacuum distiliation. In this manner N-methyl,N-(2-hydroxyethyl)-phenylamine and the corresponding m-methyl, p-methyl, m-chloro, and p-chloro phenylamines were prepared. N-Methyl,N-(2-hydroxyethyl)-m-methoxyphenylamine. - The mixture of N,N--dimethyl-m-methoxyphenylamine (2 mol) and ethylenechlorhydrine (2 mol) was refluxed for 15 h at 200 °c. After vacuum distillation the yellowish oil with a b. p. 100-106 °c (0.08 mmHg), n~ = 1.5620, was obtained in 700/o yield. Anal. C10H15N02 (181.24) calc'd.: C 66.28; H 8.34; N 7.700/o found: C 66.48; H 8.24; N 7.360/o' N-Methyl,N-(2-hydro.xyethyl) p-methoxyphenylamine. - N,N-Dimethyl-p-metho-xyphenylamine (2 mol) was added to ethylenechlorhydrine (2 mol) and the mixture was refluxed for 12 h at 195 °c. After vacuum distillation the yellowish oil with a b. p . 160-161° (0.1 mmHg), n~ = 1.5560, was obtained in 700/o yield. Anal. C10H 15N02 (181.24) calc'd.: C 66.28; H 8.34; N 7.700/o found: C 66.50; H 8.20; N 7.300/o N-M ethyl,N-(2-chloroethyl)-arylamines6 Corresponding N-methyl-N-(2-hydroxyethyl)-arylamine (1.3 mol) was dissolved in 200 ml of dried benzene in a 500 ml flask and, phosphorus oxychloride (0.65 mol) added drop by drop at 15 °c. The reaction mixture was then heated for 1 h in a water bath at 80 °c, cooled to room temperature and poured into cooled water (500 ml). Under continuous cooling a 100/o sodium hydroxide solution was then added (to pH= 7.5). The separated oil layer was extracted twice with benzene (100 ml) and the extract kept overnight on anhydrous sodium sulphate. After filtration the benzene was evaporated and the remainder distilled in vacuum. In this manner N-methyl,N-(2-chloroethyl)-phenyl amine and the corresponding m-methyl, - m--chloro, p-methyl and p-chlorophenyl amines were prepared. N-Methyl,N-(2-chloroethyl) m-methoxyphenylamine. - After vacuum distillation a clear oil, b. p. 110-12 °c (0.13 mmHg), n~ = 1.5590 in 480/o yield was obtained. Anal. C10H 14ClNO (199.69) calc'd.: C 60.04 : H 7.01; N 7.020/o found: C 60.24; H 6.83; N 6.950/o N-Methyl,N-(2-chloroethyl) p-methoxyphenylami ne. - A clear oil, b. p. 122-5 °C (1.5 mmHg), n~ = 1.5540 in 620/o yield was obtained. Anal. C10H14ClNO (199.69) calc'd.: C 60.04; H 7.01; N 7.020/o found: C 59.80; H 7.01; N 7.000/o 0-Ethyl S-[(2-N-methyl,N-arylamino)ethyl]methyl phosphonothioates (I-VII) In a 250 ml flask fitted with a mechanical stirrer, condenser, dropping funnel and thermometer 0-ethyl methylthiophosphonic acid (0.2 mol) was placed, and under constant stirring a 50/o solution of sodium in anhydrous ethanol was added drop by drop until a phenolphtalein colour change. Corresponding N-methyl-N-(2--chloroethyl) arylamine (0.2 mol) was added drop by drop at 40-50 °c under No. R I I H II m-CHs III p-CH3 IV m-OCH3 V p-OCH3 VI m-Cl VII I p-Cl TABLE I 0-Ethyl S-[2-N-methyl,N-arylamino)ethyl] methylphosphonotioates b. p./°C (p/mmHg) 162 (8 x 10-2 ) 150 (10-3) 148 (10-3) 165-8 (10-3) 170-5 (10-3) 160-5 (10-3) 160-3 (10-3) 25 nD 1.5590 1.5550 1.5535 1.5603 1.5570 1.5707 1.5695 CHs 0 "" ,I CHs p / "" I C2HsO S CH2CH2 N · CaH4R d25 4 I MRD I calc. J found 9 r£1 H <:> :>< ;;--Calc'd c I H I N I I C I :o1n: J p 1.1430 I 76.94 I 77.351 48 152.231 7.40 I 5.13111.25152.431 7.60 I 5.40 I 10.95 1.1136 I 82.55 I 82.56 50 -54.55 7.93 4.62 I 10.68 54.33 I 7.71 I 4.87 I 10.78 1.1241 I 82.55 I 81.95 I 57 1.1576 I 84.11 I 84.75 I 36 51.47 I 7.31 I 4.60 I 10.21 1.1556 I 84.11 I 84.50 I 35 1.2176 I 82.64 I 82.94 I 21 46.83 J 6.22 I 4.55 I 10.06 1.2256 I 82.64 I 82.29 I 35 54.07 7.88 4.37 10.38 51.22 7.22 4.25 9.92 51.35 7.41 4.34 10.05 46.70 I 6.21 I 4.42 I 9.98 46.65 6.09 4.58 9.82 <:J1 0) H>- ~ 0 0 [fl ...... 0 t"l "'" :i:. r No. VIII IX x XI XII XIII XIV AROMATIC PHOSPHORYL THIOCHOLINES TABLE II 0-Ethyl S- [2-N,N-dimethylarylammonium)ethyl]methylphosphonothioate methosulphate R YIELD I Calc'd. Found O/a I I I I I I c H N p c H N 42.10 6.56 3.81 7.76 42.33 6.67 3.87 m-CH3 85 43.05 7.07 3.29 43.50 6.83 3.38 7.49 p-CH3 78 43.70 6.99 3.05 m -OCH3 70 41.35 6.68 3.00 41.70 6.57 3.25 9.25 p-OCHa 73 41.50 6.87 3.05 m-Cl 47 38.38 5.53 3.15 38.74 5.81 3.22 7.13 p-Cl* 69 38.44 5.66 3.32 • m. p. 114 •c. 565 I p 7.58 7.19 7.46 9.07 9.21 6.90 7.26 continuous stirring, and heated and stirred at 70-80 °c for additional 8-14 h. The sodium chloride which separates during the reaction was filtered off and ethanol evaporated from the filtrate. The residual oil was washed with water and separated. The water layer was added to the rest of the crude product. The mixture was dried overnight on anhydrous sodium sulphate. After filtration, benzene was evaporated in vacuo and the oily residue was redistilled in high vacuum. The data for compounds I-VII are summarized in Table I. Infrared spectra of compounds I-VII show characteristic absorption maxima which correspond to the vibrations between phosphorus and neighboring atoms: 1220- 1245 (P=O); 775-780 of low intensity (P-0); 1030-1040 (P-O-CH2); 735- 745 (P-C); 530-540 (P-S); 1300-1305 (P-CH3); ,.., 1160 and 960 of low intensity (P-OCH2); 900 and 880-885 cm-1 (P-CH3 »rocking«). As well as these absorption bands in the spectra, there exist other vibration bands characterizing the type and position of substituerits in the benzene r,ing. The unsubstituted derivative absorbs at 690 and 755 cm-1, the m-substituted at 750-775 cm·1 and the p-substituted at 810-820 cm·1• · 1 : I ' The NMR spectra of the compounds I-VII are characterized by the fact that the common part of the molecule gave similar spectra (shape and position of the signals). So the P-CH3 in all the spectra in the region -c = 8.30-8.42 gave a doublet (because of coupling with phosphorus, JHP = 16 Hz), the CH3 from the ethoxy group gave a triplet -c = 8.60-8.78), the CH2 group from the ethoxy group gave a multiplet because of coupling with the CH3 group and phosphorus (-c = 5.6-6.3), with a center at -c = 6.0. The S-CH2 gave an unresolved multiplet (-c = 6.6-7.5) with a center at -c = 7.2, the N-CH2 gave also a multiplet (r = 6.2-6.7) with a center at -c = 6.6. The position of the N- CH3 singlet depends on the kind of benzene ring substituent. The protons of the benzene ring gave characteristic resonance signals, the shape of the signal depends on the substituent position. The multiplet of p-substituted 566 M. COSIC ET AL. compounds is a symmetrical AA'BB' quartet and the m-substituted compounds gave an unsymmetrical signal. The compounds I-VII are colorless or yellowish liquids with a high boiling point. They are soluble in most organic solvents and practically insoluble in water. 0-Ethyl S-[(2-N,N-dimethylarylammonium)ethyljmethyl-phosphonothioate methosulphates (VIII-XIV) 0-Ethyl S-[(2-N-methyl-N-arylamino)ethyl]methyl phosphonothioate (0.2 m ol) was dissolved in anhydrous benzene (25-30 ml) and under stirring, freshly distilled dimethyl sulphate (0.02 mol) was added. The reaction ended and the two layers separated during this operation. The solvent was decanted and the operation repeated pressure (18 mm Hg) and the residue was dissolved in abs. ethanol (10-15 ml) or abs. chloroform. To the solution, dried ether (100-150 ml) was added and a dense oil separated during this operation. The solvent was decented and the operatrion r epeated three times. The solvent was then evaporated in vacuo. The last residues of the solvents disappeared by heating the oily or crystalline substance for 3 h in vacuo (0.05-1 mmHg) at 50-60 °C. The data for compounds VIII-XIV are given in Table II. The IR spectra of the compounds VIII-XIV have three very intensive and large vibration bands: 1230 (P =O) , 1030 (P-O-CH2), and 750-770 (P-C) cm-1 which prove that these links become more strongly polarized because of the quaternization. The other bands are of diminished intensity. The NMR spectra of the compounds VIII-XIV differ from those of the compounds I-VII insofar that the singlet corresponding to the NCH3 group is shifted + to a lower magnetic field corresponding by its ,intensity to N(CH3)a. At a somewhat higher magnetic field of this singlet there appeared a singlet which is characteristic for the CHs group from CHaS04-. The compounds VIII-XIV are very dense oils excluding the compound XIV which is crystalline. Because of their high polarity all of them dissolve well in water and are insoluble in nonpolar organic solvents. Acknowledgment. The authors wish to thank to Dr. D. Jeremie for interpretation of NMR spectra, and B. Videkanic for technical assistance. REFERENCES 1. N. E. Tep 1 o v , N. N. Godo vi k o v , and M. J. Kaba ch n i k , Zh. Obshch. Khim. 35 (1965) 1658. 2. A. P . Brest kin, J. L. Bu k , R. J . Vo 1 k ova, N. N. Godo vi k o v , M. J. Kaba ch n i k, and N. E. Tep 1 o v , Dok!. Akad. Nauk SSSR, 163 (1965) 365. 3. M . Cos i c, B. Bosko vi c, and Z. Bin en f e 1 d, Acta Pharm. Jugoslav. 23 (1973) 9. 4.. Z. Pe 1 ch o vi ch, H. L e ad er, S. C o hen, and D. B a 1 de rm an, J. Chem. Soc. (1962) 3824. 5. G. Nag us k i, and S. Yo s i mot o, J . Chem. Soc. Jap. 73 (1952) 331. 6. R. Anker and A. Cook, J . Chem. Soc. (1944) 490. 7. M. J. Kaba ch n i k , T. A. Mast r ju k ova, E. J. Mat ros o v, and B. Fiser, Zh. Strukt. Khim. 6 (1965) 691. 8. R. J. Volkova, N. N. Godovikov, and M. J . Kabachnik, Vop. Med. Khim. (1961) 250. 9. L. E. Tamm e 1 in, Sv. Kem. Tidskr. 70 (1958) 157. IZVOD Aromatski fosforiltioholini. II. Sinteza i fizikalno-kemijske osobine M. Casie, M. Orlov i Z. Binenfeld Opisana je sinteza sedam dosad neopisanih O-etil-S-(2-metil-N-arilamino)etil metiltiofosfonata {spojevi I-VII) i njihovih metosulfata(spojevi VIII-XIV) i prika-zane njihove fizikalno-kemijske karakteristike. AROMATIC PHOSPHORYL THIOCHOLINES 567 Iz N,N-dimetilarilamina pripremljeni su N-metil- N-(2-hidroksietil)arilamini koji sa POCh daju odgovarajuce N-metil- N- (2-kloretil)arilamine koji reakcijom sa na-trijumovom soli 0-etilmetiltiofosfonske kiseline daju supstance I-VII. Njihovom kvaternizacijom dimetilsulfatom dobijaju se spojevi VIII-XIV. U toku ovih s inteza pripravljeni su jo.s i ovi dosada neopisani spojevi: N-metil-N-(2-hidroksietil) m-metoksifenilamin, N-metil- N-(2-hidroksietil)p-metoksi-fenilamin , N-metil- N-(2-kloretil)m-metoksifenilamin i N-metil-N-(2-kloretil)p-meto-ksifenilamin. INSTITUT ZA TEHNICKO-MEDICINSKU ZASTITU, 11000 BEOGRAD i KEMIJSKI KOMBINAT CHROMOS-KATRAN-KUTRILIN, 41000 ZAGREB Primljeno 26. travnja 1973. 

English

Aromatic Phosphoryl Thiocholines. II. Syntheses and Physicochemical Properties

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CROATICA CHEMICA ACTA CCACAA 45 (4) 561-567 (1973) CCA-801 YU ISSN 0011-1643 547.435 Original Scientific Paper Aromatic Phosphoryl Thiocholines. II*. Syntheses and Physicochemical Properties M. Casie, M. Orlov, and Z. Binenfeid Institute for Technical and Medical Protection, 11000 Belgrade, Serbia, and Chemical Plant Chromos-Katran-Kutrilin, 41000 Zagreb, Croatia, Yugoslavia Received April 26, 1973 The synthesis of seven undescribed 0-ethyl-S-[(2-N-methyl--N-arylamino)ethyl] methylphosphonothioates (compounds I-VII) and their methosulphates (compounds VIII-XIV) is presented together with their physicochemical characteristics. From N,N-dimethylarylamines were prepared N-methyl-N--(2-hydroxyethyl)arylamines which with phosphorus oxychloride gave the corresponding N-methyl,N-(2-chloroethyl)arylamines. By reacting them with sodium 0-ethyl methylphosphonothioate the sub-stances I-VII were obtained. The substances VIII-XIV were obtained by quaternization of substance I-VII with dimethyl-sulphate. As intermediate products the following new compounds were 1synthetized: N-methyl- N-(2-hydroxyethyl)m-methoxyphenylamine, N-methyl- N-(2-hydroxyethyl)p-methoxyphenylamine, N-methyl-N-(2-chloroethyl)m-methoxyphenylamine and N-methyl- N-(2--chloroethyl)p-methoxyphenylamine. During the last years several representatives of a new group of biologi-cally active aromatic phosphorylthioethylalkylaryl amines have been described. Kabachnik et al.1 synthetized 0,0-diethyl[S-(2-N-methyl-N-arylamino)ethyl] thiophosphorothioates: C2HsO"' /" 0 p C2HsO / "' SCH2CH2NC6H4R I CHa with R = H, -CH3, -OCH3 , -Cl in p and m position and their methosulpha~ . tes. Studying the kinetics of their alkaline hydrolysis, the authors1 found these compounds to be very stable, the tertiary compounds being more stable than the quaternary ones. Brestkin et al.2 studied the kinetics of cholinesterase inhi-biHon, and at the same time focussed their attention upon the influence of the aryl radical on the biological properties of these compounds. For that reason it was of interest to synthetize the derivatives of the phosphonic acid corresponding to the general formula: * Part I: ref. 3. 562 ivr. cosrc ET AL. CH3"' / 0 p C2HsO / """ SCH2CH2NCaH4R I CH3 with R = H, -CH3 , -OCH3 , -Cl in m and p position and the methosulphate of their dimethylammonium analogues in order to learn how the quaternization of the nitrogen atom, aromatic nuclei and the position of different ring sub-stituents influence their biological activity.3 The starting material 0-ethyl methylthiophosphonic acid was synthetized by the method of Pelchovicz and coworkers.4 The N-rnethyl N-(2-hydroxyethyl) -arylamines were prepared by the method of Nagusk'i and Yosimoto5 used for the synthesis of the unsubstituted N-methyl N-(2-hydroxyethyl)phenylamine: heating (CHa)2NCaH4R + ClCH2CH20H ----+ HOCH2CH2NCaH4R + CH3Cl I CH a The corresponding N-methyl-N-(2-chloroethyl)arylamines were obtained by rthe reaction of POC13 with the above mentioned hydroxy compounds6. The syntheses of 0-ethyl S-[(2-N-rmethyl-N-arylamino)ethyljmethylphos-phonothioates were performed by reacting sodium 0-ethyl methylphospho-nothioate and corresponding N-methyl-(2-chloroethyl) arylamines: Under the conditions mentioned the reaction is a bimolecular nucleophilic substitution (SN2) in which the nucleophile is the sulphur atom of the sodium 0 -ethyl methylphosphonothioate7• In the syntheses of 0-ethyl S-[(2-N-methyl--N-ary1amino)ethyl]methylphosiphonothioates the S-alkylated products were always obtained because the reaction was performed with a weak electrophile in a protonated solvent which does favor S-alkylation. 0-Ethyl S-[(2-N,N--dimethylarylammonium)ethyl]methyl phosphonothioate methosulphates were prepared by methylating the corre3ponding tertiary compounds with the equi-molecular quantity of dimethylsulphate using the method of Volkova et aI.8 In relation to the analogous thiocholine compounds with alkyl groups on the nitrogen atom9 , the syntheses of the described tertiary compounds and the methylation process are of longer duration. Probably this can be attributed to the presence of the aromatic radical on the nitrogen atom, which slows down the described reactions by enhancing the thermochemical stability. Resonance effects from the aromatic ring are likely to cause the diminished reactivity of the described aromatic compounds in relation to the corresponding aliphatic ones. AROMATIC PHOSPHORYL THIOCHOLINES 563 EXPERIMENTAL 0-Ethyl methylthiophosphonic acid was obtained in 700/o yield from methylthio-phosphonic dichloride, ethanol and potassium hydroxyde4 as yellowish oil b. p. 80 °c (0.3 mmHg), ni; = 1.4910 [lit.4 87-93 (0.55 mmHg); nijl = 1.4927]. N-M ethyl,N-(2-hydroxyethyl)-arylamines5 The mixture of N,N-dimethylalkylarylamine (2 mol) and ethylenechlorhydrine (2 mol) was refluxed for 5-15 h under constant stirring at 190-200 '°C until no more methyl chloride was formed. The reaction time was dependent on the ring substituent. The described products were isolated from 1he reaction mixture by fractionated vacuum distiliation. In this manner N-methyl,N-(2-hydroxyethyl)-phenylamine and the corresponding m-methyl, p-methyl, m-chloro, and p-chloro phenylamines were prepared. N-Methyl,N-(2-hydroxyethyl)-m-methoxyphenylamine. - The mixture of N,N--dimethyl-m-methoxyphenylamine (2 mol) and ethylenechlorhydrine (2 mol) was refluxed for 15 h at 200 °c. After vacuum distillation the yellowish oil with a b. p. 100-106 °c (0.08 mmHg), n~ = 1.5620, was obtained in 700/o yield. Anal. C10H15N02 (181.24) calc'd.: C 66.28; H 8.34; N 7.700/o found: C 66.48; H 8.24; N 7.360/o' N-Methyl,N-(2-hydro.xyethyl) p-methoxyphenylamine. - N,N-Dimethyl-p-metho-xyphenylamine (2 mol) was added to ethylenechlorhydrine (2 mol) and the mixture was refluxed for 12 h at 195 °c. After vacuum distillation the yellowish oil with a b. p . 160-161° (0.1 mmHg), n~ = 1.5560, was obtained in 700/o yield. Anal. C10H 15N02 (181.24) calc'd.: C 66.28; H 8.34; N 7.700/o found: C 66.50; H 8.20; N 7.300/o N-M ethyl,N-(2-chloroethyl)-arylamines6 Corresponding N-methyl-N-(2-hydroxyethyl)-arylamine (1.3 mol) was dissolved in 200 ml of dried benzene in a 500 ml flask and, phosphorus oxychloride (0.65 mol) added drop by drop at 15 °c. The reaction mixture was then heated for 1 h in a water bath at 80 °c, cooled to room temperature and poured into cooled water (500 ml). Under continuous cooling a 100/o sodium hydroxide solution was then added (to pH= 7.5). The separated oil layer was extracted twice with benzene (100 ml) and the extract kept overnight on anhydrous sodium sulphate. After filtration the benzene was evaporated and the remainder distilled in vacuum. In this manner N-methyl,N-(2-chloroethyl)-phenyl amine and the corresponding m-methyl, - m--chloro, p-methyl and p-chlorophenyl amines were prepared. N-Methyl,N-(2-chloroethyl) m-methoxyphenylamine. - After vacuum distillation a clear oil, b. p. 110-12 °c (0.13 mmHg), n~ = 1.5590 in 480/o yield was obtained. Anal. C10H 14ClNO (199.69) calc'd.: C 60.04 : H 7.01; N 7.020/o found: C 60.24; H 6.83; N 6.950/o N-Methyl,N-(2-chloroethyl) p-methoxyphenylami ne. - A clear oil, b. p. 122-5 °C (1.5 mmHg), n~ = 1.5540 in 620/o yield was obtained. Anal. C10H14ClNO (199.69) calc'd.: C 60.04; H 7.01; N 7.020/o found: C 59.80; H 7.01; N 7.000/o 0-Ethyl S-[(2-N-methyl,N-arylamino)ethyl]methyl phosphonothioates (I-VII) In a 250 ml flask fitted with a mechanical stirrer, condenser, dropping funnel and thermometer 0-ethyl methylthiophosphonic acid (0.2 mol) was placed, and under constant stirring a 50/o solution of sodium in anhydrous ethanol was added drop by drop until a phenolphtalein colour change. Corresponding N-methyl-N-(2--chloroethyl) arylamine (0.2 mol) was added drop by drop at 40-50 °c under No. R I I H II m-CHs III p-CH3 IV m-OCH3 V p-OCH3 VI m-Cl VII I p-Cl TABLE I 0-Ethyl S-[2-N-methyl,N-arylamino)ethyl] methylphosphonotioates b. p./°C (p/mmHg) 162 (8 x 10-2 ) 150 (10-3 ) 148 (10-3 ) 165-8 (10-3 ) 170-5 (10-3 ) 160-5 (10-3 ) 160-3 (10-3 ) 25 nD 1.5590 1.5550 1.5535 1.5603 1.5570 1.5707 1.5695 CHs 0 "" ,I CHs p / "" I C2HsO S CH2CH2 N · CaH4R d25 4 I MRD I calc. J found 9 r£1 H <:> :>< ;;--Calc'd c I H I N I I C I :o1n: J p 1.1430 I 76.94 I 77.351 48 152.231 7.40 I 5.13111.25152.431 7.60 I 5.40 I 10.95 1.1136 I 82.55 I 82.56 50 -54.55 7.93 4.62 I 10.68 54.33 I 7.71 I 4.87 I 10 .78 1.1241 I 82.55 I 81.95 I 57 1.1576 I 84.11 I 84.75 I 36 51.47 I 7.31 I 4.60 I 10.21 1.1556 I 84.11 I 84.50 I 35 1.2176 I 82.64 I 82.94 I 21 46.83 J 6.22 I 4.55 I 10.06 1.2256 I 82.64 I 82.29 I 35 54.07 7.88 4.37 10.38 51.22 7.22 4.25 9.92 51.35 7.41 4.34 10.05 46.70 I 6.21 I 4.42 I 9.98 46.65 6.09 4.58 9.82 <:J1 0) H>- ~ 0 0 [fl ...... 0 t"l "'" :i:. r No. VIII IX x XI XII XIII XIV AROMATIC PHOSPHORYL THIOCHOLINES TABLE II 0-Ethyl S- [2-N,N-dimethylarylammonium)ethyl]methylphosphonothioate methosulphate R YIELD I Calc'd. Found O/a I I I I I I c H N p c H N 42.10 6.56 3.81 7.76 42.33 6.67 3.87 m-CH3 85 43.05 7.07 3.29 43.50 6.83 3.38 7.49 p-CH3 78 43.70 6.99 3.05 m -OCH3 70 41.35 6.68 3.00 41.70 6.57 3.25 9.25 p-OCHa 73 41.50 6.87 3.05 m-Cl 47 38.38 5.53 3.15 38.74 5.81 3.22 7.13 p-Cl* 69 38.44 5.66 3.32 • m. p. 114 •c. 565 I p 7.58 7.19 7.46 9.07 9.21 6.90 7.26 continuous stirring, and heated and stirred at 70-80 °c for additional 8-14 h. The sodium chloride which separates during the reaction was filtered off and ethanol evaporated from the filtrate. The residual oil was washed with water and separated. The water layer was added to the rest of the crude product. The mixture was dried overnight on anhydrous sodium sulphate. After filtration, benzene was evaporated in vacuo and the oily residue was redistilled in high vacuum. The data for compounds I-VII are summarized in Table I. Infrared spectra of compounds I-VII show characteristic absorption maxima which correspond to the vibrations between phosphorus and neighboring atoms: 1220- 1245 (P=O); 775-780 of low intensity (P-0); 1030-1040 (P-O-CH2); 735- 745 (P-C); 530-540 (P-S); 1300-1305 (P-CH3); ,.., 1160 and 960 of low intensity (P-OCH2); 900 and 880-885 cm-1 (P-CH3 »rocking«). As well as these absorption bands in the spectra, there exist other vibration bands characterizing the type and position of substituerits in the benzene r,ing. The unsubstituted derivative absorbs at 690 and 755 cm-1, the m-substituted at 750-775 cm·1 and the p-substituted at 810-820 cm·1• · 1 : I ' The NMR spectra of the compounds I-VII are characterized by the fact that the common part of the molecule gave similar spectra (shape and position of the signals). So the P-CH3 in all the spectra in the region -c = 8.30-8.42 gave a doublet (because of coupling with phosphorus, JHP = 16 Hz), the CH3 from the ethoxy group gave a triplet -c = 8.60-8.78), the CH2 group from the ethoxy group gave a multiplet because of coupling with the CH3 group and phosphorus (-c = 5.6-6.3), with a center at -c = 6.0. The S-CH2 gave an unresolved multiplet (-c = 6.6-7.5) with a center at -c = 7.2, the N-CH2 gave also a multiplet (r = 6.2-6.7) with a center at -c = 6.6. The position of the N- CH3 singlet depends on the kind of benzene ring substituent. The protons of the benzene ring gave characteristic resonance signals, the shape of the signal depends on the substituent position. The multiplet of p-substituted 566 M. COSIC ET AL. compounds is a symmetrical AA'BB' quartet and the m-substituted compounds gave an unsymmetrical signal. The compounds I-VII are colorless or yellowish liquids with a high boiling point. They are soluble in most organic solvents and practically insoluble in water. 0-Ethyl S-[(2-N,N-dimethylarylammonium)ethyljmethyl-phosphonothioate methosulphates (VIII-XIV) 0-Ethyl S-[(2-N-methyl-N-arylamino)ethyl]methyl phosphonothioate (0.2 m ol) was dissolved in anhydrous benzene (25-30 ml) and under stirring, freshly distilled dimethyl sulphate (0.02 mol) was added. The reaction ended and the two layers separated during this operation. The solvent was decanted and the operation repeated pressure (18 mm Hg) and the residue was dissolved in abs. ethanol (10-15 ml) or abs. chloroform. To the solution, dried ether (100-150 ml) was added and a dense oil separated during this operation. The solvent was decented and the operatrion r epeated three times. The solvent was then evaporated in vacuo. The last residues of the solvents disappeared by heating the oily or crystalline substance for 3 h in vacuo (0.05-1 mmHg) at 50-60 °C. The data for compounds VIII-XIV are given in Table II. The IR spectra of the compounds VIII-XIV have three very intensive and large vibration bands: 1230 (P =O) , 1030 (P-O-CH2), and 750-770 (P-C) cm-1 which prove that these links become more strongly polarized because of the quaternization. The other bands are of diminished intensity. The NMR spectra of the compounds VIII-XIV differ from those of the compounds I-VII insofar that the singlet corresponding to the NCH3 group is shifted + to a lower magnetic field corresponding by its ,intensity to N(CH3)a. At a somewhat higher magnetic field of this singlet there appeared a singlet which is characteristic for the CHs group from CHaS04-. The compounds VIII-XIV are very dense oils excluding the compound XIV which is crystalline. Because of their high polarity all of them dissolve well in water and are insoluble in nonpolar organic solvents. Acknowledgment. The authors wish to thank to Dr. D. Jeremie for interpretation of NMR spectra, and B. Videkanic for technical assistance. REFERENCES 1. N. E. Tep 1 o v , N. N. Godo vi k o v , and M. J. Kaba ch n i k , Zh. Obshch. Khim. 35 (1965) 1658. 2. A. P . Brest kin, J. L. Bu k , R. J . Vo 1 k ova, N. N. Godo vi k o v , M. J. Kaba ch n i k, and N. E. Tep 1 o v , Dok!. Akad. Nauk SSSR, 163 (1965) 365. 3. M . Cos i c, B. Bosko vi c, and Z. Bin en f e 1 d, Acta Pharm. Jugoslav. 23 (1973) 9. 4.. Z. Pe 1 ch o vi ch, H. L e ad er, S. C o hen, and D. B a 1 de rm an, J. Chem. Soc. (1962) 3824. 5. G. Nag us k i, and S. Yo s i mot o, J . Chem. Soc. Jap. 73 (1952) 331. 6. R. Anker and A. Cook, J . Chem. Soc. (1944) 490. 7. M. J. Kaba ch n i k , T. A. Mast r ju k ova, E. J. Mat ros o v, and B. Fiser, Zh. Strukt. Khim. 6 (1965) 691. 8. R. J. Volkova, N. N. Godovikov, and M. J . Kabachnik, Vop. Med. Khim. (1961) 250. 9. L. E. Tamm e 1 in, Sv. Kem. Tidskr. 70 (1958) 157. IZVOD Aromatski fosforiltioholini. II. Sinteza i fizikalno-kemijske osobine M. Casie, M. Orlov i Z. Binenfeld Opisana je sinteza sedam dosad neopisanih O-etil-S-(2-metil-N-arilamino)etil metiltiofosfonata {spojevi I-VII) i njihovih metosulfata(spojevi VIII-XIV) i prika-zane njihove fizikalno-kemijske karakteristike. AROMATIC PHOSPHORYL THIOCHOLINES 567 Iz N,N-dimetilarilamina pripremljeni su N-metil- N-(2-hidroksietil)arilamini koji sa POCh daju odgovarajuce N-metil- N- (2-kloretil)arilamine koji reakcijom sa na-trijumovom soli 0-etilmetiltiofosfonske kiseline daju supstance I-VII. Njihovom kvaternizacijom dimetilsulfatom dobijaju se spojevi VIII-XIV. U toku ovih s inteza pripravljeni su jo.s i ovi dosada neopisani spojevi: N-metil-N-(2-hidroksietil) m-metoksifenilamin, N-metil- N-(2-hidroksietil)p-metoksi-fenilamin , N-metil- N-(2-kloretil)m-metoksifenilamin i N-metil-N-(2-kloretil)p-meto-ksifenilamin. INSTITUT ZA TEHNICKO-MEDICINSKU ZASTITU, 11000 BEOGRAD i KEMIJSKI KOMBINAT CHROMOS-KATRAN-KUTRILIN, 41000 ZAGREB Primljeno 26. travnja 1973. 

Aromatic Phosphoryl Thiocholines. II. Syntheses and Physicochemical Properties

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