MASATERU MIYANO AND S A B U FUNAHASHI R~
3522 [CONTRIBUTION FROM THE
VOl. 77
LABORATORY O F BIOCHEMISTRY, FACULTY OF AGRICULTURE, NAGOYA UNIVERSITY]
Synthesis of Organic Phosphorus Compounds. I. p-Substituted Benzyl Esters BY MASATERU MEYANO AND S A B U R FUNAHASHI ~ RECEIVED JULY 15, 1954 Di-p-bromobenzyl, di-p-chlorobenzyl and di-p-xylyl phosphite were synthesized The chlorophosphondtes derived froin them were found to be characteristic phosphorylating agents for amines and alcohols.
Phosphoric acid esters and amides, compounds of great biochemical significance, have been prepared by the reaction of diphenyl or dibenzyl chlorophosphonate with a tertiary base followed by hydrogenolysis of the protecting groups. Brig1 and Muller' synthesized diphenyl chlorophosphonate; dibenzyl chlorophosphonate2 has been used for the preparation of nucleotides and nucleotide coenzymes b y Todd, et al.3 Since this reagent has some disadvantages, we have studied some di- (p-substituted benzyl) chlorophosphonates (11). The substituted benzyl esters,
especially the p-bromo and p-chloro, are crystallized more easily than the corresponding non-substituted esters; it is advantageous to remove the catalyst pois'on by crystallizing the intermediate before hydrogenation. Since the mechanism of the alkaline hydrolysis of phosphoric acid esters is that of bimolecular substitution, p-halobenzyl groups would be expected to be hydrolyzed more easily. Thus, while dibenzyl phosphite was converted to dibenzyl phosphate in 88% yield5 in the following reaction, the p-halobenzyl groups were hydrolyzed completely under these conditions, and even under more moderate conditions considerable hydrolysis occurred. The p-xylyl group was not hydrolyzed by alkali. C)
+
(c~H~cH~o)~P-H c e l l 0
II
+ Z N ~ O H+
(CsHsCHnO)?P-OSa
+ CHCI, + NaCl + HzO
Baddiley, et u Z . , ~ reported that the hydrogenolysis of the p-bromobenzyl group was very slow, but we found that the @-bromobenzyl and p-xylyl groups were hydrogenolyzed a t a satisfactory rate, and the p-chlorobenzyl group a t a somewhat slower rate. Unexpectedly, p-substituted halogen ;~lsowas hydrogenolyzed under our conditions to give the halogen acid which, although i t accelerates hydrogenolysis of the benzyl group, will deconipose some unstable phosphorus compounds. Monoethyl phosphate was synthesized from dip-bromobenzyl chlorophosphonate. Several amidophosphonates including the anilino(1V) and cyclo(1) P. Brig1 a n d H. hldller, B e y . . 73, 2123 (1938). (2) F. R.Atherton, H. T . Openshaw a n d A. R. Todd, J Chem. SOL.
382 (184.5) (3) A . R . T o d d , el ai., ibid.,46 (1954). I - 1 ) F R. .4therton, H T. Howard and A. R . T o d d . ibid, 1107 I IN8). ( . 5 ) V. h I . Clark and A . R . Tcidd, i b z d , 2030 (1950). !(i) 1 Badrliley, V. 11. C l a r k . J J. llichalski a n d A . R.'r,xld i b i i i . S I 3 (194!)).
hexylamino(V) compounds also were synthesized. Amidophosphonates of strong bases such as cyclohexylamine or ammonia could be obtained directly from phosphites in the following reaction, while weak bases such as aniline did not react; thus, ani0 II
(XCsH4CHz0)2P-H
+ CCI4 + 2XH2K --+ 0
,/
(XCsHdCH2O)zP-XHR
+ CHC13 + SHzR.HC1
linophosphonate was prepared by the reaction of chlorophosphonate and aniline. This result was very similar to non-substituted dibenzyl p h o ~ p h i t e . ~
Experimental Melting points are not corrected ;hialytic,tl value? ,ire given in Table I. b-Substituted Benzyl Alcohols.--p-Lirornobenzvl and pchiorobenzyl alcohols &re prepared 'from the Corresponding chlorides which were refluxed for 10 hours with a slight excess of potassium acetate in aqueous ethanol and for an additional 8 hours with potassium hydroxide in aqueous ethanol; i n . p . ' s 77" and 73-74', respectively. p-Xylyl alcohol was obtained by hydrolysis of p-xylyl chloride with sodium carbonate followed by recrystallization from petroleum ether; m.p. 59'. These alcohols should be free from o-isomer for use in the following reaction. Di-(p-substituted benzyl) Phosphites.-A mixture of 0.764 mole of the p-substituted benzyl alcohol and 0.825 mole of dimethylaniline dissolved in 250 ml. of benzene its added to a stirred solution of 34 ml. of phosphorus trichloride in 250 ml. of benzene; the temperature was maintained a t 8-10" by cooling in a n ice-bath and moisture was excluded. -4fter 20 minutes stirring, water (100 ml.) was added carefully followed by vigorous stirring for a n additional 30 minutes. n'hite platelets crystallized; they were filtered, washed with 100 ml. of water, dried over phosphorus pentoxide. The combined filtrates and washings was separated in two layers; the upper layer was washed with 100 ml. of 5% aqueous potassium carbonate solution and 100 ml. of water, dried (calcium chloride) and concentrated t o 150 ml. under reduced pressure, a second crop of crystals was obtained when light petroleum ether ( b . p . 60-90') was added. Still more crop \vas obtained from the mother liquor which was concentrated and set aside in a refrigerator for several d a y s . The crude product can be recrystallized from alcohol, cyclohexane or benzene. Di-(p-substituted benzyl! Ch1orophosphonates.--To 0.00955 mole of the di-()-substituted benzyl) phosphite suspended in 2.5 nil. of carbon tetrachloride wits added 0.XO ml. (0.0098~5 mole) of sulfuryl chloride drop by drop whilc the mixture \vas shaken in an ice-bath. The gases evolved, the excess sulfuryl chloride and most of the solvent were removed under reduced pressure a t room temperature. The resulting sirup in the proper solvent was used immediately without further purification. Di-(p-substituted benzyl) Amidophosphonates.-The anilinophosphonates were prepared by the addition of 2.0 ml. of aniline to a cold carbon tetrachloride solution of the di-phalobenzyl chlorophosphonate (prepared from 0.01 mole of the corresponding phosphite); the c!-clohexS.laminophosphonates by the addition of 2.5 ml. (0.0218 mole) of cyclohexylamine to a cold solution of 0.01 mole of the phosphite .~ .~
171 1' ( 1 $1 %.;I.
~I < , A t h e r t u n , I1 'I' ~
Olien4iaw aud A I< 'l'opCK BrCsH4CH20 .,,>pc:,
--H2S04
NaBr
(1) Department of Agricultural Chemistry, T o k y o University. (2) J. Baddiley, V. M. C l a r k , J. J. hlichalski and A . R. T o d d , J . C h e m . Soc.. 81.5 (1949). (3) V . h l Clark an,I h. I < , 'rodPP
