REACTION OF Π-DEFICIENT AROMATIC HETEROCYCLES WITH AMMONIUM POLYHALIDES. n'.HALOGENATION OF PHENOTHIAZINE WITH BENZYLTRIETHYLAMMONIUM (BTEA) POLYHALIDES. a Radu Custelceanu \ Mircea Vlassa\ I. A. Silberg a *, MonicazyxwvutsrqponmlkjihgfedcbaUTSRPONMJIHFEDCB Szφke a. Sonn I. Fδrca§b and Monica Culeab "Babe§­Bolyai University" , Faculty of Chemistry and Chemical Engineering, str.Arany Janos 11, R0­3400 ­ Cluj­Napoca, Romania. b Institute of Isotopic and Molecular Technology, R0­3400­Cluj­Napoca 5, PO Box 700 ABSTRACT : The reactions of phenothiazine with benzyltriethylammonium polyhalides under mild, non­ toxic conditions yield halogenophenothiazines and, for the first time to our knowledge, charge­transfer complexes with mixed halogenes of the type phenothiazine Cl x I y . INTRODUCTION Halogenation with quaternary ammonium polyhalides has been widely applied since 1987 in the class of aliphatic and aromatic compounds (2) but it was seldom used for heterocyclic compounds, except for thiophene (3) and acridine derivatives (1). Due to the fact that the results obtained by us (4) using BTEA in halogenation of acridine and acridone compounds were better, from a synthetic point of view, comparatively with classical methods, we extended our study to phenothiazines, in view of the practical importance of this class of substances. So far, a great variety of reagents have been used for the halogenation of phenothiazinesgee .g . molecular chlorine (4­7), CuCl2 (8,9), N a N 0 2 and HCl (10), SOCl2 (11), PC15 (12,13), HCl in the presence of either nitrous vapors (14) or H 2 0 2 (15) for chlorination ; bromine (6,16,17) N a N 0 2 and HBr (10) or CuBr 2 (18) for bromination. Iodination with molecular iodine leads only to charge­transfer complexes with paramagnetic and semiconducting properties (19­22). Similar compounds with bromine (23­25) or mixed halogens ( Brx I y ) (26) were also prepared. 317 Vol. 3, No. 4, 1997 Reaction of II-deficient Aromatic Hetercycles with Ammonium Plyhalides III. Halogenation of Phenothiazines with Benzyltriethylammonium (beta) polyhalides EXPERIMENTAL The elemental analyses for C, Ν and halogens were within ± 0.4 % of the theoretical values for the new compounds resulted from reaction e and g (see Table). M.p. were uncorrected. Mass spectra were recorded on a Varian MAT 311 instrument, ESR spectra on a Radiopan 253 SE/X instrument at a modulation of 100 kHz, IR spectra were recorded, in pellets, on an Unicam SP 200 G instrument and UV­ VIS spectra, in CH2CI2 solution, on a Carl Zeiss Specord spectrometer. The reactions were monitored by TLC using benzene:ether 4:1 as eluent and visualisation was done with iodine. BTEA polyhalides were prepared according to literature data (1). 3,7-Dibromophenothiazine A mixture of phenothiazine (0.2 g, lmmol), BTEABr 3 (0.9 g, 2 mmols) and methanol (15 mL) was refluxed for 6 hrs. The reaction mixture was cooled and the resulted precipitate was filtered and washed 0 withTIHECBA CH2CI2 yielding 0.2 g (56%) of 3,7­dibromophenothiazine, m.p.=198­199 °C [lit. C 193 and 206 ( 6 a, 16)] MS: m/e M+ 355/ 357/ 359. 1,3,7,9,-Tetrabromophenothiazine A mixture of phenothiazine (0.2g, 1 mmol), BTEABr 3 (3.6 g, 8 mmols) and acetic acid (25 mL) was refluxed for 2 hrs. The reaction mixture was then cooled, the precipitate filtered and washed with acetone yielding 0.4 g (78%) of 1,3,7,9­tetrabromophenothiazine, m.p.=269­272 0 C [lit. 0 C 272­273 (16)]. M.S. : m/e M" 511/ 513/ 515/ 517/ 519. (3-Chlorophenothiazine)2. ICb A mixture of phenothiazine (0.2g, 1 mmol ), BTEAICLt ( 0.92g, 2 mmols) and acetic acid (20 mL) was magnetically stirred at room temperature for 7 hrs. Subsequently the reaction mixture was filtered and the precipitate was washed with acetic acid yielding 0.2 g (57%) of compound (3­chlorophenothiazine)2 . ICb. M.p.= 136­137 °C. 1,3,7,9-Tetrachlorophenothiazine A mixture of phenothiazine (0.2 g, 1 mmol), B TEA I CI 4 (1.84 g, 4 mmols) and acetic acid (20 mL) was magnetically stirred at room temperature for 20 hrs, then it was filtered and the precipitate washed with acetone, yielding 0.25 g of crude product, m.p=222­226 °C. After recrystallization from 0 nitrobenzene, 0.2 g of pure 1,3,7,9­tetrachlorophenothiazine were obtained, m p . p. =230­231° C [lit. C 235(15)]. M. S. : m/e M* 335/ 337 / 339 / 341/ 343. 3,7-Dichlorophenothiazine.ICb A mixture of phenothiazine (0.2 g, 1 mmol), BTEAIC12 (1.6 g, 4 mmols) and acetic acid (20 mL) was magnetically stirred for 24 hrs., then it was filtered yielding 0.1 g of crude product. After recrystallization from benzene, 0.06 g (12%) of 3,7­dichlorophenothiazine ICl? were obtained, m.p.=150­ 154 °C. M.S. : m/e M" 499/ 501/ 503/ 505/ 507 ; 367 ( \ f ­ 232). Heterocyclic R. Custelcenau, Μ. Vlassa, et αϊ. Communications RESULTS Halogenation with BTEA polyhalides demonstrated that there still are some unexplored possibilities. The results of halogenation of phenothiazine with benzyltriethylammonium tribromide (BTEABr3), dichloroiodate (BTEAICb) and tetrachloroiodate (BTEAICLt) are summarized in Table. Table. Halogenation of phenothiazine (1) with BTEA polyhalides in acetic acid (reaction a,c,d,e,f and g) or methanol (reaction b). Reaction a BTEABr3 Moelcular ratio BTEAY :1 1 b BTEABr3 2 3 ­bromo­phenothiazine* 3,7­dibromo­phenothiazine* 3,7­dibromo­phenothiazine c BTEABr3 8 1,3,7,9­tetrabromo­phenothiazine d BTEAICU 1 e f BTEAICI4 BTEAICU 2 4 3­chloro­phenothiazine* 3,7­dichloro­phenothiazine* (3­chloro­phenothiazine)2. ICI3 1,3,7,9­tetrachlorophenothiazine BTEAY Products 4 3,7­dichlorophenothiazine. ICI3 BTEAICb g Unseparatec products, detected by mass spectrometry and TLC m.p. (lit. m.p.) °C yield 198­199 (193 then 206) (6a, 16) 269­272 (272­273) (16) 56 136­137 230­231 (235) (15) 150­154 57 59 % 78 12 DISCUSSION Due to the high reactivity of phenothiazine toward electrophilic reagents, selective halogenation leading to 3­chloro or 3­bromo derivatives was not possible ( see Table reaction a and d). However, these reagents allowed us to obtain 3,7­dibromo­ (see Table reaction b), 1,3,7,9­tetrabromo­ (see Table reaction c) or 1,3,7,9­tetrachlorophenothiazine (see Table reaction f) with yields comparable with classical methods but under milder and non­toxic conditions. Besides, the same reagents led to the two new compounds (see Table reaction e and g). So we isolated two charge­transfer complexes of phenothiazine with ICI3. Elemental analysis suggested a (3­chloro­phenothiazine)2.ICl3 structure for compound resulted from reaction e. The same structure is also consistent with IR spectra (VNH = 3260 cm"1) and its chemical behavior; thus refluxing in acetic acid for 5 minutes a mixture of 3­chloro­ and 3,7­dichlorophenothiazine was detected by TLC (see Scheme). The visible spectra in CH2C12 exhibits absorptions at 468 and 565 nm characteristic for the phenothiazinyl cation radicals (27). This fact, correlated with the intense ESR signal in solid state Vol. 3, No. 4, 1997 Reaction of II-deficient Aromatic Hetercycles with Ammonium Plyhalides III. Halogenation of Phenothiazines with Benzyltriethylammonium (beta) polyhalides (singlet, g = 1.990, DH = 13.8 Gauss) points out an advanced transfer of the electrons from the phenothiazine to IC13 . On standing a few hours in CH 2 Cl2 , the above mentioned compound was converted into the so­called "green product" with visible absorptions at 468 and 640 nm, reaction which is also specific for cation radicals of phenothiazine (27). • Η Elemental analysis for compound obtained from reaction g agrees with the formula phenothiazine. ICI3. The mass spectra shows the molecular peak at m/e 499 and another peak at m/e 267 (NT­ 232) indicating the dichlorophenothiazinyl fragment. The spectral data also support this assumption; Vnh = 3260 cm"1 in IR, in pellet; λ™* = 296, 364, 448, 660 nm, in UV­ VIS spectra , in CH2C12 ; singlet, g = 1.989, DH = 20.2 Gauss, in ESR spectra in solid state. R. Custelcenau, Μ. Vlassa, et al. Heterocyclic Communications Unfortunately we did not succeed to prepare, with good yields, mixed halogenophenothiazine using these reagents. Thus, after 30 hours of refluxing in methanol of 2­chlorophenothiazine with BTEABr3 (1:1 molar ratio), 80% of starting material was recovered. CONCLUSION The reaction of phenothiazine with BTEA polyhalides, which take place under mild and non­toxic condition, allowing to obtain halogenophenothiazine derivatives with yields comparable with those of classical methods. Further, is it to be noted that with these reagents was possible to obtain, for the first time, charge­transfer complexes with mixed halogenes of the type phenothiazine . Clx I y . REFERENCES (1) M. Vlassa, I. Α Silberg, R A. Custelceanu and M. Culea, Synth.Commun. 25, 3493, (1955) (2) S. Kajigaeshi, T. Kakinami, T. Okamoto, N. Nakamura and M. Fujikawa, Bull Chem. Soc. Jpn. 60. 4187,(1987) (3) T. Okamoto, T. Kakinami, N. Fujimoto and S. Kajigaeshi, Bull. Chem Soc. Jpn. 64,2566,(1991) (4) C. Bodea and M.yvutsrponmlkjihgedcbaVUTSRPMLKJIHGFDCBA Rδileanu, Studii Cercet. Chim. (Cluj), Romania, 9 , 159 (1958); C.A 55 , 15497e (1961) (5) C. Bodea and M. Rδileanu, Liebigs Ann. Chem. 620 , 88 (1959) (6) a. C. Bodea, M. Terdic and I. A. Silberg. Liebigs Ann. Chem. _673 , 113 (1964); b. C. Bodea and M. Terdic, Studii Cercet. Chim. (Cluj), Romania, 14 , 113 (1963); C.A. 59 , 11477 h (1963) (7) C. Bodea and I. A. Silberg, Rev. Roum. Chim. 9 , 425, (1964) (8) C. Bodea and I. A. Silberg, Rev. Roum. Chim. 10, 887, (1965) (9) I. A Silberg, V. Fδrca§an and M. Diudea, J. Prakt. Chem. 318 , 393 (1976) (10) I. A. Silberg and M. Diudea, Rev. Roum. Chim. 25 , 1239 (1980) (11) M. Fujimoto, Bull. Chem. Soc. Jpn. 32 , 480 (1959) (12) M. Strell and M. Rupprecht, German Patent 938.669 ; C. A. 53 , 8173 a (1959) (13) R. Kupka, Ph. D. Thesis, M٧nchen University, M٧nchen, Germany, 1951, citated in C.Bodea and I. A. Silberg, Advances in Heterocyclic Chem. Academic Press, vol.9, pp.398 321 Vol. 3, No. 4, 1997 Reaction of II-deficient Aromatic Hetercycles with Ammonium Plyhalides III. Halogenation of Phenothiazines with Benzyltriethylammonium (beta) polyhalides (14) O. Unger and R. A. Hoffmann, Ber. Deut. Chem. Ges. 29 , 1362 (1896) (15) Η. J. Page, S. Smiles, J. Chem. Soc., 97 , 1115 (1910) (16) C. Bodea, M. Terdic and I. A. Silberg, Liebigs Ann. Chem. 631 , 194 (1960) (17) I. Yoshikazu, S. Takehico and M. Enchiro, Nippopn Kagacu Kaishi (Japan) 3 , 437 (1979) (18) M. Diudea and I. A. Silberg, J. prakt. Chem. 324 , 769 ( 1982) (19) A. Brau, J. R Fragers and F. Guttmann, Electrochim. Acta 17 , 1803 (1972) (20) S. Chan, C. M. Cooley and H. Keyzer, Tetahedron Lett. (1975), 1193 (21) F. Guttmann, J. Chem. Phys. 46 , 1969 ( 1967) (22) A E. Szent­Gyorgy, I. Irenburg and S. L. Baird, Proc. Natl. Acad. Sei. U. S. 46 , 1444 (1960) (23) S. N. Bhat and H. Kuroda, Bull. Chem. Soc. Jpn. 4 6 , 3585 (1963) (24) S. Doi, Y. Matsunaga, Bull. Chem. Soc. Jpn. 48 , 3447 (1975) (25) I. A Silberg, Ph. D. Thesis, Cluj­Napoca, Romania, 1970 (26) Y. Matsunaga and M. Shono, Bull. Chem. Soc. Jpn. 43 , 2007 (1970) (27) C. Bodea, I. A. Silberg, Advanced in Heterocyclic Chemistry, Academy Press, 1969, vol. 9, pp. 322­440 R e c e i v e d o n April 10, 1 9 9 7 322