J . Org. Chem., Vol. 40, No. 16,1975 2307
Diepoxides of Pyrene and Dibenz[a, hlanthracene (7)I. Granoth and A. Kalir, J. Org. Chem., 38,841 (1973). (8)I. Belsky, H. Dodiuk, and Y. Shvo, J. Org. Chem., 39,989 (1974). (9)E. D. Bergmann and M. Rabinovitz, J. Org. Chem., 25,828 (1960). (10)F. Bergmann and A. Kalmus, J. Am. Chem. Soc., 76,4137(1954). (11) J. F. Liebman and T. H. Vanderspurt, J. Nuorine Chem., 2, 413 (19721973). (12)T-L. Ho, Chem. Rev., 75, l(1975).
(13)R. F. Zurcher in “Nuclear Magnetic Resonance In Chemistry”,B. Pesce, Ed., Academic Press, New York, N.Y., 1965,p 45. (14)I. Granoth, A. Kalir, 2. Pelah, and E. D. Bergmann, Tetrahedron, 26,813 (1970). (15)F. L. Pattison, R. R. Fraser, J. C. Middleton, J. C. Schneider, and J. B. Stothers, Can. J. Techno/.,34, 21 (1956). (16)I. Granothand H. J. Pownall, J. Org. Chem., 40,2088 (1975).
Synthesis of Diepoxides and Diphenol Ethers of Pyrene and Dibenz[ a,h]anthracene S. C. Agarwal and B. L. Van Duuren* Laboratory of Organic Chemistry and Carcinogenesis, Institute of Environmental Medicine, New York University Medical Center, New York, New York 10016 Received March 18, 1975 The diepoxides, 4,5,9,10-diepoxytetrahydropyrene and 5,6,12,13-diepoxytetrahydrodibenz[a,h]anthracene, were synthesized from the parent hydrocarbons via their respective diozonides and tetraaldehydes. Both epoxides were converted to diphenols; because of the instability of the diphenols they were converted to and characterized as phenol ethers. The two diphenol ethers derived from diepoxydibenz[a,h]anthracene were characterized as 5,1%dimethoxydibenz[a,h]anthracene and 6,13-dimethoxydibenz[a,h]anthracene.All of these compounds are new with the exception of 5,12-dimethoxydibenz[a,h] anthracene. These epoxides and their diphenols are important in chemical carcinogenesis studies. Naphthalene epoxide is the first aromatic hydrocarbon epoxide to be synthesized and shown to be a metabolite in a biological system.1 Since then a number of monoepoxides of carcinogenic hydrocarbons have been synthesized;2 recently the synthesis of the monoepoxide of the noncarcinogenic hydrocarbon, pyrene, was also r e p ~ r t e d The . ~ metabolism of both pyrene and the carcinogen dibenz[a,h] anthracene has been studied in detail4 and several phenolic metabolites of both hydrocarbons have been r e p ~ r t e dThe .~ definitive isolation of their mono- or diepoxides from in vivo or in vitro biological systems has, however, not been a c c ~ m p l i s h e dI. t~has been shown, however, that 5,6-epoxydibenz[a,h]anthracene has weak tumor-inducing activity.6 The continued interest in mechanism of action and metabolism of aromatic hydrocarbons7 prompted the synthesis of diepoxides of pyrene and of the carcinogen dibenz[a,h]anthracene, since these diepoxides are expected to play a role in the biologic activity of the hydrocarbons. In the present work, the phenol ethers formed from the diepoxides upon acid-catalyzed rearrangement and methylation are described and compared with the known metabolic products. The general procedure of Newman and Blums was used to convert the dialdehydes to the epoxides using Mark’s reagent,g i.e., tris(dimethy1amino)phosphine. The required precursor for the synthesis of 5,6,12,13-diepoxytetrahydrodibenz[a,h] anthracene isp- terpheny1-2,2’,5’,2’’-tetracarboxaldehyde (I), which has been reported.1° However, the reported product was not identical with the completely characterized product obtained in this work. Ozonization of a dilute solution of dibenz[a,h]anthracene in anhydrous CHZC12 a t -70’ with 2 molar equiv of ozone gave predominantly the 5,6,12,13-diozonide of the parent hydrocarbon. This was shown by the alkaline hydrogen peroxide oxidation of the diozonide to the known 2,2’,5’2’’-tetracarboxyp - terpheny1.l0 The diozonide on reduction with sodium iodide in acetic acid afforded an aldehyde, mp 234-236O, in good yield. The product reported earlierlO had mp >360°. Based on its uv absorption at 296 and 233 nm, ir bands a t 3.46, 3.61, and 5.93 w , mass spectrum and C, H analysis it
was characterized as the tetraaldehyde 1. When refluxed with tris(dimethy1amino)phosphine in dry benzene, the tetraaldehyde was converted to the diepoxide 2, the structure of which was confirmed by spectral and combustion analyses. Additional support for its structure was provided by the comparison of its ultraviolet spectrum with that of 5,6,12,13-tetrahydrodiben~[a,h]anthracene.~~ In both compounds there is restricted rotation of the benzene rings and therefore they have similar uv absorption spectra which are, however, quite different from that of p-terphenyl. The acid-catalyzed rearrangement of the diepoxide 2 could lead to three isomeric diphenols, i.e., 6,13-dihydroxy, 5,13-dihydroxy-, and 5,12-dihydroxydibenz[a,h]anthracene. Two of the methyl ethers derived from these phe-
1
2
3
5
4
6
2308
J,Org. Chem., Vol. 40,No. 16,1975
nols have been described earlier.12 They are the 5,12 and 5,13 isomers; the reported melting points of the two methyl ethers are 304-305 and 285-287O, respectively. T h e diepoxide was refluxed in HC1-acetone followed by methylation with dimethyl sulfate and potassium carbonate. The phenol ethers were separated by silica gel column chromatography followed by fractional crystallization. Two phenol ethers were obtained: the previously unknown 6,13-dimethoxy isomer, mp 271-273’, was obtained in good yield along with the previously characterized 5,12-dimethoxy isomer,12 mp 303-305O, as the minor product. The new 6,13-dimethyl ether was characterized by its C, H analysis, ir, uv, and mass spectrum. None of the diphenols mentioned above have been detected as metabolites of dibenz[a,hlanthracene, although the presence of 6,13,dihydroxydibenz[a,h] anthracene as a possible metabolite has been suggested.12J3 Pyrene diepoxide 4 was synthesized by the same series of reactions as that described above for dibenz[a,h]anthracene. Biphenyl-2,2’,6,6’-tetracarboxaldehyde (3) was obtained in good yield by ozonolysis of pyrene followed by sodium iodide-acetic acid reduction of the intermediate ozonide. Its structure was confirmed by elemental and spectral analyses. The tetraaldehyde was cyclized to 4 in 19.3% yield. A mass spectral parent ion, rnle 234, and the absence of hydroxyl and carbonyl infrared absorptions as well as its uv absorption pattern, confirmed its structure as 4,5,9,10diepoxytetrahqdropyrene. The uv absorption“spectrum was very similar to that of 9,lO-epoxyphenanthrene synthesized in this laboratory using the previously described method.8 An analytically pure sample of 4 could be obtained only when freshly redistilled Mark’s reagent was used for this reaction. Acid-catalyzed rearrangement of 4 and subsequent methylation gave two isomeric methyl ethers, 5 and 6, mp 250-252 and 153-155’, respectively; these two isomers were separated by fractional crystallization. The higher melting isomer has a uv spectrum very similar to that of pyrene. The positions of the methoxy groups in the two isomers has yet to be determined. The synthesis of 4,9-dihydroxypyrene has been reported;14 however, the characterization of the compound was incomplete. Neither of the diphenols of pyrene has been identified as metabolites of the hydrocarbon in laboratory ani mal^.^ As a part of this work, the fluorescence excitation and emission spectra of all fluorescent compounds were obtained (Table 11),as additional information in the spectroscopic characterization of new compounds. In the course of these measurements it was observed that the diepoxides readily undergo photochemical rearrangement, presumably to the corresponding oxepins, as was observed earlier in the case of the monoepoxide of ~ y r e n e . ~These * oxepins are, to our knowledge, unknown compounds and they were not investigated further in the course of this work. With the renewed interest in aromatic hydrocarbon metabolism and improved analytical methods now available for the isolation of metabolites of aromatic hydrocarbons in vivo and/or in vitro, it is expected that the compounds described in this report will be of great interest to workers in chemical carcinogenesis. Furthermore, as bifunctional alkylating agents these epoxides are of particular interest because it is known that among aliphatic epoxides the bifunctional epoxides are frequently carcinogenic, whereas their monofunctional analogs are inactivee6
Experimental Section Melting points were taken on a Thomas-Hoover capillary apparatus and are uncorrected. Infrared spectra were determined in KBr pellets, using a Perkin-Elmer Model 421 spectrophotometer, and ultraviolet spectra (Table I) were obtained with a Cary Model
Agarwal and Van Duuren 14.Proton magnetic resonance spectra were recorded only of those compounds which were sufficiently soluble in the commonly available NMR solvents using a Varian Model A-60A spectrometer. A custom-designed multipurpose luminescence spectr~photometerl~ was used to record the fluorescence excitation and emission spectra (Table 11). Corrected emission spectra were recorded in quantum units and corrected excitation spectra in energy units. All fluorescence measurements were made by use of 5-nm slits on the excitation and emission monochromators. The mass spectra were obtained from the Morgan Schaffer Corp., Montreal, Canada. The samples were introduced through a direct inlet in most cases. The ozonizer used was a Welsbach Corp. Model T-408.Microanalyses were performed by Spang Microanalytical Laboratory, Ann Arbor, Mich. TLC was carried out on precoated silica gel G plates; spots were visualized with short- and long-wavelength uv lamps. Most of the compounds reported are sensitive to photooxidation and precautions were taken to prevent such degradation. p-Terphenyl-2,2’,5f,2”.tetracarboxaldehyde (1). Dibenz[a,h]anthracene (1.13 g), dissolved in dry CHzClz (350 ml), was cooled to -7OO and treated with ozonized oxygen until approximately 2 molar equiv of ozone had been added. The crude ozonide precipitated during the addition of the second molar equivalent of ozone. The reaction mixture was immediately flushed with nitrogen, allowed to warm to room temperature, and concentrated to -100 ml in a rotary evaporator under reduced pressure. Powdered sodium iodide (8g) and glacial acetic acid (60 ml) were added to the white slurry with stirring. The clear reddish-brown solution was kept at 4O for 24 hr in a N2 atmosphere. The liberated iodine was reduced with aqueous sodium thiosulfate (10%). The mixture was extracted with an excess of CHzClz, and the extract was washed with aqueous sodium carbonate (10%) and then with water. The extract was dried over anhydrous MgS04 and evaporated to dryness to yield a white residue which crystallized from CHnClz-hexane as creamy-white needles (0.820 g, 59%): mp 234236’ (lit.lo mp >360°); ir 3.46,3.61 (C-H stretch), 5.93 Fm (C=O stretch); mass spectrum m/e 342 (parent ion). Anal. Calcd for CznHi404: C, 77.18;H, 4.12.Found: C, 76.69;H, 4.22.TLC, Rf 0.66 in CHzCIz-acetone (9.75:0.25). A part of the ozonide was oxidized by heating its suspension in ethanol with Hz02 (30%) and sodium hydroxide solution.l0 The solution was acidified and extracted with ether. The ether extract on concentration yielded colorless crystals, mp 310-314O dec. It was terphenyl by direct comparidentified as 2,2’,5’,2’’-tetracarboxy-pison with an authentic sample (mixture melting point, ir, uv). 5,6,12,13-Diepoxy-5,6,12,13-tetrahydrodibenz[ a,b]anthracene (2). The tetraaldehyde, structure 1 (0.5 g), was dissolved in heated dry benzene (100ml) and freshly distilled tris(dimethy1amino)phosphine (0.6ml) was added to the solution. The mixture was refluxed in a Nz atmosphere for 25 min and then evaporated to near dryness in a rotary evaporator under reduced pressure. Filtration and washing of the residue with benzene-hexane (1:l)left colorless needles of the diepoxide (0.36 g, 80%): mp 192-193O dec; ir 6.71,6.98,8.36,9.81,11.85,13.5 1.1; mass spectrum m/e 310 (parent ion). Anal. Calcd for C22H14O2: C, 85.14;H, 4.55.Found: C, 84.85; H, 4.57. TLC, Rf 0.84 in cyclohexane-dioxane (64). This compound was sparingly soluble in most organic solvents. The diepoxide was stable at -loo and could be stored unchanged at -10’ in the dark for several months but it is sensitive to light. 5J2-Dirnethoxy- and 6,13-Dirnethoxydibenz[a,b]anthracene. Concentrated HCl(1.0 ml) was added to the above diepoxide (0.650g) in acetone (400ml) and the solution was refluxed for 0.5 hr in a Nz atmosphere. The reaction mixture was concentrated to a small volume (-5 ml). Acetone (100 ml, dried over KzCOs), dimethyl sulfate (1.0 ml), and anhydrous KzC03 (5.0g) were added immediately and the mixture was refluxed for 18 hr. The reaction mixture was filtered and washed with an excess of dry acetone and the solvent was removed by distillation under reduced pressure. The pale yellow residue was chromatographed on a Florisil column and eluted with hexane-benzene (8:2v/v). The fractions having Rf 0.54 in hexane-CHzClz (64) were combined and evaporated to dryness. Fractional crystallization of the pale yellow residue (0.380 g) from CHzC12 yielded two crops of product. The first crop (70 mg) was crystallized several times from benzene, colorless plates (30mg): mp 303-305O (lit.12 for 5,12-dimethoxydibenz[a,h]anthracene, mp 304-305O); ir 6.16, 6.24, 6.68,6.83,6.95,7.16,7.35 rm; mass spectrum mle 338 (parent ion). Anal. Calcd for Cz4H1802: C, 85.18;H, 5.36.Found: C, 85.04;H, 5.39. The second crop on rechromatography on silica gel using CHzClz-hexane (2:8)and recrystallization from a CHzClz-hexane mixture gave pale yellow plates (100 mg): mp 268-270O; ir 6.19,
J. Org. Chem., Vol. 40, No. 16,1975 2309
Diepoxides of Pyrene and Dibenzla, hlanthracene
Table I Ultraviolet Absorption Spectra Compd
XmaXt
p -Terphenyl -2,2', 5', 2"-tetracarboxaldehyde (1)" 5,6,12,13 -Diepoxy -5,6,12,13 - tetrahydrodibenz[a,h]anthracene (2)" 5,6,12,13 -Tetrahydrodibenz[a,h]anthracene* 5,12-Dimethosydibenz[a,h]anthracenec (cf. uv of dibenz[a, h ]anthracene 16) 6,13-Dimetho.xydibenz[a,h]anthracened Biphenyl -2,2',6,6'-tetracarboxaldehyde (3)" 4,5,9,10 -Dieploxy -4,5,9,10 -tetrahydropyrene
nm (EtOH)
233, 296 (sh) 215,231 (sh), 247, 256, 291 (sh), 304,318,334 241,250, 278 (sh), 290,302,320,332 224,257, 278 (sh), 291,302,325,336,352 (€46, 644, 18,590,43,940,82,810,107,822,16,731, 11,830,8619) 225,273, 296,302,322,333, 350 (40,560, 36,504,77,064,76,557,20,111,15,210,13,182) 233 (sh), 254 (sh), 298 264 (sh), 270,287, 300
(4 )" Phenanthrene epoxidee Dimethoxypyrene, mp 250-252"
266,277, 287,300 (sh) 234,243, 255,265,276, 298 (sh), 311, 325,341, 357,376 (41,134,73,797,14,060,27,248, 46,286,5240, 11,091, 23,405,30,304,5414, 6200) 220,230 (sh), 240, 255, 266 (sh), 275,298 (sh), Dimethoxypyrene, mp 153-155" 305,319,330,350, 376 (27,335,34,060, 52,400,20,174,18,340,25,152,10,480,8733, 11,440,19,300, 18,602,1746) a Because of insolubility in many organic solvents, 6 values could not be calculated. b Registry no., 153-31-1. c Registry no., 55400-91-4. d Registry no., 55400-92-5. e Registry no., 585-08-0.
Table I1 Fluorescence Excitation and Emission Spectra Compd
5,6,12,13-Diepoxy-5,6,12,13tetrahydrodibenz [a,h]anthracene (2) 5,12-Dimethoxydibenz [a,k ] anthracene 6,13-Dimethoxydibenz[a,h]anthracene Dimethoxypyrene, mp 250252" Dimethoxypyrene, mp 153155" a Concentration not determined.
Solvent and concn
Cyclohexane, satd soln," deoxygenated Ethanol, 0.04 pg/ ml, deoxygenated Ethanol, 0.04 pg/ ml, deoxygenated Ethanol, 0.03 pg/ ml, deoxygenated Ethanol, 0.03 pg/ ml, deoxygenated
6.24,6.44,6.66,6.85,6.95,7.14,7.26 pm; mass spectrum m/e 338 (parent ion), Anal. Calcd for C24H1802: C, 85.18;H, 5.36.Found: C, 85.16;H, 5.30. Biphenyl-2,2f,6,6f-tetracarboxaldehyde (3). Pyrene (2.02g) in dry CHzClz (400ml) was ozonized using 2 molar equiv of ozone. Powdered sodium iodide (16 g) and glacial acetic acid (120 ml) were added after concentrating the solution. The reaction mixture was worked up as described for 1 and this gave a pale-yellow product which was purified by silica gel column chromatography with CHZC12 as eluent. The eluate on concentration and addition of hexane yielded colorless flakes (1.04g, 39.4%): mp 154-156O (1it.l' mp 162-163O); ir 3.48,3.52,3.62,3.66 (C-H stretch), 5.95 pm (C=O stretch); NMR (CDC13) S 8.2 (m, 6 H, aromatic), 9.86(s, 4 H, -CHO). Anal. Calcd for C16H1004: C, 72.18;H, 3.78.Found: C, 72.24;H, 3.89.TLC, Rf 0.75in CHzClpCH30H (19.5:0.5). 4,5,9,10-Diepoxy-4,5,9,lO-tetrahydropyrene (4). The tetraaldehyde (3, 0.5g) in dry benzene (30ml) was refluxed with tris(dimethy1amino)phosphine (0.5 ml) for 0.5 hr. On cooling, lightbrown needles (0 085 g, 19.3%), mp 206-208O dec, were obtained. The product was recrystallized from dioxane as colorless needles, without change in melting point. It was sparingly soluble in most organic solvents, TLC, R,P 0.64in cyclohexane-dioxane (1:l). It 8.11,9.512.2, , 12.8pm; mass spectrum mle 234 (parshowed ir 6.93, ent ion). Anal. Calcd for C16H1002: C, 82.04;H, 4.30.Found C,
Excitation maxima, nm
232 (sh), 244 (sh), 253, 290 (sh), 302,318, 336 253,281 (sh), 290,302, 326 (sh), 337 (sh), 357, 375 (sh) 272,295,302,319 (sh), 418, 332,349,388 243,264, 275,310 (sh), 324,339,353 (sh) 240, 255,274, 303 (sh), 320 (sh), 355,348
Emission wavelength, nm
Emission maxima, nm
Excitation wavelength, nm
355
338,355,372, 390 (sh)
334
400
400,423,449, 480 (sh)
300
418
408 (sh), 419, 437 (sh) 377,396,417, 440 (sh) 378,399,419, 445 (sh)
295
396 376
275 274
81.89;H, 4.40.The diepoxide rearranged to a mixture of phenols when subjected to vacuum sublimation at 175O (0.2 mm). Acid-Catalyzed Rearrangement of Pyrene Diepoxide to Phenols and Their Subsequent Methylation (5, 6). Pyrene diepoxide (0.4g) in dry acetone (300ml) waa refluxed with concentrated HC1 (0.5ml) for 0.25 hr. The reaction mixture was worked up and methylated with dimethyl sulfate as described above. The pale-yellow residue [Rf 0.58,CHzClz-hexane (4:6)]obtained after eluting the silica gel column with CHzClz-hexane (4:6v/v) mixture gave two crops on fractional crystallization from CHZClz-hexane. The first crop crystallized from CHzClz as colorless plates (0.099): mp 250-252O;ir 6.26,6.32,6.66,6.84,7.00,7.14,8.0,8.84 km; mass spectrum mle 262 (parent ion). Anal. Calcd for Cl~H1402:C, 82.42; H, 5.38.Found: C, 82.38;H, 5.38. The second crop was rechromatographed on silica gel and recrystallized from CH2Clphexane as white flakes (0.123g): mp 153-155O;ir 6.16,6.26,6.30,6.45,6.68,7.25,7.30,7.95,9.25 pm; mass spectrum mle 262 (parent ion); NMR (CDC13) 8 4.12(s, 6 H, 2-OCH3), 7.2,8.0,8.6(s,2H, m, 4 H, d, 2 H, aromatic). Anal. Calcd for C18H1402: C, 82.42;H, 5.38.Found: C, 82.49;H,5.37.
Acknowledgment. This work was supported by USPHS Center Grant ES-00260from the National Institute of En-
2310 J . Org. Chem., Vol. 40, No. 16,1975
Taguchi and Mushika
vironmental Health Sciences and Center Grant CA 13343 from the National Cancer Institute. Registry No.-1, 55400-86-7;2, 55400-87-8;3, 4371-26-0;4, 55400-88-9;5, 55400-89-0;6, 55400-90-3;dibenz[a,h]anthracene, 53-70-3; dimethyl sulfate, 77-78-1. References and Notes (1)
(a) D. M. Jerina, J. W. Daly, B. Wltkop, P. Zaltrman-Nlrenberg, and S . Udenfriend, J. Am. Chem. Soc., 00, 8525 (1968); (b) 6iochemlstry, 9, 147 (1970).
(a)E. Boyland and P. Sims, 6iOChem. J., 97, 7 (1965); (b)S. H. Goh and R . G. Harvey, J. Am. Chem. SOC.,95, 242 (1973); (c)P. Dansette and D. M. Jerina, ibM., 98, 1224 (1974). (3) (a) B. L. Van Duuren, G. Wltz, and S. C. Agarwal, J. Org. Chem., 30, 1032 (1974); (b) H. Cho and R. G. Harvey, Tetrahedron Lett., 1491 (1974), and ref 2c.
(2)
(4) D. B. Clayson, :'Chemical Carcinogenesis", Little, Brown and Co., Boston, Mass., 1962, p 166. (5)D. M. Jerlna and J. W. Daly. Science, 185, 573 (1974). (6) B. L. Van Duuren, Ann. N. Y. Acad. Sci., 183, 633 (1969). (7) D. M. Jerina, "Chemical Carcinogenesis", Part A, P. 0. Ts'o and J. A. Di Paolo, Ed., Marcel Dekker, New York, N.Y., 1974, p 289. (8) M. S. Newman and S. Blum, J. Am. Chem. Soc., 86,5598 (1964). (9) V. Mark, J. Am. Chem. Soc., 85, 1884 (1963). (10) E. J. Moriconi,W. F. O'Connor, W. J. Schmltt, 0. W. Cogswell, and B. P. Furer, J. Am. Chem. Soc., 82, 3441 (1960). (11) W. Lijinsky, J. Org. Chem., 28, 3230 (1961). (12) J. A. Labudde and C. Heldelberger, J. Am. Chern. Soc., 80, 1225 (1958). (13) E. Boyland, A. A. Levl, E. H. Mawson, and E. Roe, 8iOChem. J., 39, 184 (1941). (14) R. Weitzenbbck, Monatsh. Chem., 34, 193 (1913). (15) S. Cravltt and B. L. Van Duuren, Chem. insfrum., 1, 71 (1968). (16) M. S. Newman and W. Hung, J. Org. Chem., 30, 3950 (1974), and ref 2a. (17) L. F. Fieser and F. Novello, J. Am. Chem. SOC.,82, 1855 (1940). 9
Synthetic Studies on Phosphorylating Reagent. 11.' 2-( N,N-Dialkylamino)-4-nitrophenylPhosphate and Its Use in the Synthesis of Phosphate Esters Yoshihiko Taguchi and Yoshitaka Mushika* Research Laboratory of Applied Biochemistry, Tanabe Seiyaku Co., Ltd., 16-89,Kashima-3-chome, Yodogawa-ku, Osaka, 532,Japan Received March 10,1975 2-(N,N-Dimethylamino)-4-nitrophenyl phosphate (6a) and 2-(N,N-diethylamino)-4-nitrophenylphosphate (6b) were prepared from 2-amino-4-nitrophenol (4)via three steps. These compounds were activatable in situ by
the addition of an acidic catalyst and showed moderate phosphorylating ability toward various alcohols. By the comparison of their reactivities in the reaction with benzyl alcohol, 6a was shown to be a better phosphorylating agent than 6b. It reacted readily with an alcohol having an unprotected amino group to give the aminoalkyl phosphate without unfavorable formation of the phosphoroamidate. Reaction with a mercapto alcohol under the same condition gave the S-hydroxyalkylphosphorothioate as the main product. In previous papers,l-a we have reported the synthesis of a new phosphorylating reagent, 2-chloromethyl-4-nitrophenyl phosphorodichloridate (I), having an activatable protecting group and its use in the preparation of alkyl phosphates. It was shown that the reagent is very useful for the preparation of the valuable alkyl dihydrogen phosphates and dialkyl hydrogen phosphates from the corresponding alcohols. However, it could not be utilized in the phosphorylation of amino alcohols because of reaction with the amino group. Recently, with a view to developing a milder reagent which could be used in the phosphorylation of amino alcohols, the reactivity of the inner salt of 1-(2-dihydrogenphosphoroxy-5-nitrobenzy1)pyridiniumhydroxide (3) was investigated.l This reagent derived from 1 showed reduced activity and reacted satisfactorily with a tert -amino substituted alcohol to afford the tert -aminoalkyl phosphate. However, phosphorylation of alcohols which have secondary and primary amino groups resulted in the unfavorable formation of the phosphoroamidate. Another disadvantage of the reagent is its low reactivity and necessity of an excess of alcohol for completion of the reaction. In the present study, with an aim to develop a more versatile reagent, 2-(N,N-dialkylamino)-4-nitrophenylphosphate (6) was designed as a new phosphorylating agent on the following assumptions. The 2-(N,N-dialkylamino)-4nitrophenyl group would function as a protecting group a t the first stage, because the strong electron-withdrawing power of the nitro group, which exerts phosphorylating ability, is compensated by the electron-releasing effect of the dialkylamino group. However, upon addition of acidic catalyst the dialkylamino group would be converted into
the positively charged ammonium group, which would enhance the electrophilicity of the phosphoryl group. Thus the reaction with a nucleophile such as alcohol and thiol would proceed smoothly. At the same time, it was expected that selective phosphorylatian of the hydroxy group in an amino alcohol would be possible because of protonation of the amino group of the reactant under the conditions used. While Amery and Corbett' obtained 2-(N,N-dimethylamino)-4-nitrophenol (5a) from 2-aminoanisole via three steps, we have attempted the preparation of 2-(N,N-dialkylamino)-4-nitrophenoi by the selective dialkylation of 2amino-4-nitrophenol (4). Alkylation of 4 with 2.5 molar quantities of methyl or ethyl iodide in the presence of triethylamine proceeded successfully to give the corresponding 2-(N,N-dialkylamino)-4-nitrophenol hydrochlorides 5a,b in 58 and 19% yield, respectively (Chart I). In these al-
Chart I
4
Sa, R=CH,I b, R=C>H,
6a, R = C H J
b, R=C,H,
