The Chlorination of Certain Purinones with Phosphorus Oxychloride in the Presence of Tertiary Amines
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THE CHLORINATION OF CERTAIN PURINONES WI'fH PHOSPHORUS OXYCHLORIDE IN THE PRESENCE OF TERTIARY AMINES by ROLAND KENITH ROBINS \ ·' A THESIS subnltted to OREGON STATE, COLLEGE 1n partial fulfillment of the requirements tor the degree or DOCTOR OF PHILOSOPHY June 1952 lPlROYlEr Redacted for Privacy lrcfsor ff fmfrtrf In fir;r cf Ltr Redacted for Privacy Redacted for Privacy Uril5! of ofuArlr orltil.t Redacted for Privacy lha f 0mftrtr ililErof ftr ltbrrt, lr nrrrrrrlril ItDr0 try feltrrat fr Bct0nr AOKNO LEOOEMENT The author wishes to express his deepest gratitude to his wife, Lesaa, for her personal sacrifice and efforts ·which have contri buted greatly to the sucoeas of this work. The author wishes also to express thanks to Dr. Bert E. Christensen for h1s valuable assistance throughout the course of this research. TABLE OF CONTENTS Page Discussion • • • • • • • • • • • • • • • • • • • 1 Experimental • • • • • • • • • • • • • • • • • .. 13 Summary • • • • • • ., • • • • • • • • • • ,. • ., 28 Bibliography • • • • • • • • • • • • • • • • • • 29 LIST OF FIGURES Figure 1 • • • • • • • • • • • • • • • • • • • • 5 • Figure 2 • • • • • • ,. • • • • • • • •••••• 9 THE CHLORINATION OF CERTAIN PURINONES WITH PHOSPHORUS OXYCHLORIDE IN THE PRESENCE OF TERTIARY AMINES Since Baddiley and Topham (2, p.678) first re• ported using dimethylaniline in the chlorination or barbituric acid with phosphorus oxychloride, the use or a mixture or this tertiary amine and phosphorus oxy chloride has found extensive application in the prep aration ot numerous chloropyrimidinea . Because of the close chemical relationship of pyrimidine and purine derivatives, it aeemed quite logical that thia ·reaction could well be extended to the preparation of the rather inaooeaaible chloropur1nes. These chloropurinea could then serve as valuable inter mediates in the preparation or synthetic nucleoaidea I (7, pp.833-838). It was for this reason that a study • of the behavior of the reaction mixture ot dimethyl• aniline, phosphorus oxychloride, and uric acid was undertaken. It was hoped that the main reaction pro duct would be 2,6,8-triohloropurine. Preliminary experiments were not very promising. Short periods of reaction time commonly employed in the preparation of chloropyrtm1dinea were found to have little effect in chlorinating the purine ring. Moat of the uric acid was recovered unchanged. Longer periods of reaction time resulted in yielding a phosphorylated 2 product insoluble in dilute hydrochloric acid and a pro duct containing phosphorus which was soluble in dilute mineral acids. The acid insoluble material proved to be a complex phosphorylated, partially chlorinated purine derivative which defied all attempts of further purifi· cation and thus could not be further identified. The other phosphorus containing compound was readily pur ified and ave a sharp melting po1nt (m.p. 20g-211°). Since the nature of this latter product was not immed iately apparent, the compound was subjected to further investigation. Chemical analysis showed the empirical formula to be C16H21N202P• This data suggested that reaction bad probably occurred between dtmethylaniline and phos• phorus oxychloride. Repeated exper~ents of long reac tion time 1n the absence of uric acid gave the same product, although it was noted that the yield was much greater even in the presence of only catalytic amounts of uric acid. Because of the fact that this compound could well shed considerable 11 ht on the direction that the reao 1on was taking, a systematic study of the structure of this compound was undertaken. According to the literature Bourneuf (5, pp.l808 1823) phosphorylated d1methylan1line under pressure with 3 phosphorus oxychloride and obtained an alkali-soluble product, C1sH21N202P, melting point 199° (capillary), 249° (block). Bourneuf (5, pp.l808-1823) also obtained from the same reaction mixture, three alkali-insoluble side products, tetramet~yldiaminodiphenylmethane (m.p. 90°), the oxide of hexamethyltr1am1notriphenylphosphine (m.p. 2620), and its hydrate (m.p. 318°). The analyt ical data given for the aide products were very ques tionable, suggesting impure samples, while the position ot phosphorylation in no case had been determined. D1methylanil1ne bas likewise been phosphorylated with phosphorus trichloride by a number of investi ators (5, pp.l808·1815; 15, P•20J 17, pp.745-748) who iso lated d1methylam1nophenylphoaphinoua acid trom the reaction mixture, but in no instance established the position ot phosphorylation. Judging by the properties and the analytical data it seemed apparent that the product obtained in this labora.tory (C1sH21N202P) and that reported by Bourneuf (5, pp.l808-1823) with the same empirical formula were identical. However, in view of' the uncertainty re.. gard1ng the position of phosphorylation and the dis crepancies in the .melting point in what appeared to be the same product, this problem was subjected to fUrther investigation. 4 Bis(~-chlorophenyl)phosphinio acid was prepared by the method of Kos olapoft (12, p.2983), and in turn converted to bis(~- om inophenyl) phos ph1n1o acid by well established procedures described by Bauer (3, p.2138). Attempts to convert this comp ound to the d1methylamino derative were, however, unsuccessful. Attempts to prepare a Grignard reagent from ~-bromodimethylaniline, to be used as an intermediate in the synthesis of bis(It-dimethylaminophenyl)phos ph1nic acid (I, Figure 1), failed. In view of these experiments, e._-d1methylaminophenyll1thium was pre pared and used according to the directions of Kosolapott (12, p.2983) for synthesizing arylphosphinic acids using the Grignard reagent. The E_•dimethylam1nophenyl 11th1um reacted readily with phosphorus oxychloride by this procedure to yield alkali-soluble bis(e._•dimethyl aminophenyl)phosphinic acid {m.p. 208-210°) (I, Figure 1) which was judged to be identical with our original reaction product cl6H21N2o2P on the basis of mixed melting point tests. An alkali-insoluble by-product was also isolated which on the basis of analytical data and synthesis was found to be tris(~-dimethylaminophenyl)• phosphine oxide (III, Figure 1), which was probably the same as the hexamethyltriaminotriphenylphosphine oxide described by Bourneuf. 5 ~(CHah N(CHah POCJ, 0P-OH 0 0 N(CHa)2 II PCI,/ ~POC I, . / N(CHah "' N(CHah 0 0 Li JPOCI, N(CHah H,o. (CH,J,No 00 0N(CHah III FIGURE I. REACTION ScHEME 6 The reaction of phosphorus trichloride and di methy-laniline as de ... cribed by Bourneuf (5, pp . l808 1815) and Raudn1tz (17, pp.745-748) as repeated in this laboratory. The two products obt ined, b1s (dimethylaminophen11)phosph1noua acid and tris(di methylam1nophenyl}phosph1ne ere oxidized with three per cent hydrogen peroxide. The two oxidation pro ducts were found to be identical with b1s(~- d1methyl am1nophenyl)phosph1n1c acid (I, Figure 1) and tris (~-d1methylam1nophenyl)phosphine oxide (III, Figure 1) respectively. This proved that phosphorylation of d1methylan111ne with phosphorus trichloride also takes place in the para position. It was thus shown that when d1methylanil1ne, phosphorus oxychloride, and uric acid were refluxed for lon periods. necessary to achieve even a small amount of chlorination of the purine nucleus that considerable phosphorylation of the dimethylan111ne took place in the ~ position and only a very small amount of the desired 2,6,8-triehloropurine could be isolated. Recently, Davoll and Lowy (6, p.2936) report an isolation of only 16-25 per cent yield of trichloro• purine from uric acid using d1methylan111ne and phos phorus oxychloride as a chlorinating mixture . 7 In search for a anerslly useful method of ob• tainin chlor•opurino.a from the eorresponding purinones a number of routine chlorinations using other tertiary amines were attemp ted. In the 11 ht of the previous work, triethylamine was chosen as the .first tertiary run1ne to be substituted .for d1methyle.n111ne in the reaction mixture. Since triethylamine contained no , "phenyl" group, phosphorylation of the phenyl nucleus as a major side reaction was 1mpoesible. In the course of th1s work it was discovered that in the pre.sence of a limited amount or tr1ethyl• amine, uric acid was oonver•ted to 8-ohloroxanthine in yields of from 30-40 per cent; by the substitu tion of mono-potassium salt or uric acid the yields were consistently abotre SO per cent, These results · were interesting since in the usual chlorination it is the e... position which is the last to be chlorin• ated (9, p.2220). When these experiments were extended to the use of excess triethylamine coupled with longer reaction time, it was discovered that the reaction not only .. chlorinated the purine nucleus but the triethylamine proceeded to ammonate the r1n • Uric acid under these conditions gave a produet, c9H11NsC1 2, (I, Figure 2, R =C2H5) instead of the expected tr1ehloropurine. 8 It thus appeared that the p~oduet contained a diethyl amino-subetituent. In order to determine the position of this substituent a second synthesis was undertaken. Tri chloropurine was treated with diethylamine; this gave a product which was found to be identical to (! 1 R : C2H5 .Figure 2). The reaction of a secondary amine with tr1chloropurine has not boen previously described, but 2,6-dichloro-7•methylpurine (l, p.l272) has been re• • ported to yield 2•chloro- 6-d1ethylam1no•7•methylpur1ne upon treatment with diethylamine. Since the 6- posi~ tion 1s known to be the most reactive 1n trichloro purine it seemed highly likely that the d1ethylam1no