2584
~ORIAIUNICilTIONSTO THE
EDITOR
Vol. 80
METHYLATION OF ALCOHOLS WITH Found: C, 54.85; H, 7.90; N, 10.35) and as the DIAZOMETHANE dipotassium salt (A nul. Calcd. for Cl2HI2O5P2K2 : C, 33.64; H,2.99; N. 6.93. Found: C,35,.40; H, Siu: Methylation of alcohols by the IVillianison sytl3.06; Lu, 7.14) in yields of about 60%. This substrate I1 underwent no spontaneous thesis requires strongly basic conditions and there hydrolysis a t pH 4.0 to pH 11.5 after two hours a t is no satisfactory general methylation procedure 37". It slowly liberated aniline a t pH 3.5 and did so effective under neutral or mildly acidic conditions. more rapidly at pH 2.5. Aniline was measured I n principle, diazomethane with a n acidic catalyst colorimetrically.6 The evidence, moreover, clearly should methylate alcohols, b u t the usual protonic indicates t h a t no hydrolysis of the pyrophosphate, acid, such as hydrochloric acid, is unsatisfactory P-0-P, bond had occurred under any of these because i t is itself methylated with diazomethane. conditions and t h a t liberation of aniline in acid re- Fluoroboric acid, however, promised to serve as a sulted solely from phosphamide, P-N, bond cleav- useful catalyst since it would be consumed in reacage. If hydrolysis of the pyrophosphate bond tion with diazoinethane only by some proces: inabove pH 4.0 had occurred phenylphosphoroamidic volving rupture of a B-F bond.' This expectation acid (111) would be formed. This product 111' is was indeed realized and a novel method has been essentially completely hydrolyzed after 30 minutes developed for methylation of alcohols in high yields at pH 4.0, conditions a t which the substrate I1 under mild conditions. Methylations of alcohols were carried out in diethyl ether or methylene chloride a t 0-23" in thc presence of 0.6-8 mole per cent. of fluoroboric acid. Methyl ethers of simple primary or unhindered secondary alcohols thus were formed rapidly in 84OSyoyields. Moderately hindered secondary alcoI, R = C6HjCHa hols and tertiary alcohols reacted more slowly, 11, R = H yields were lower and methylation was accompanied gives no hydrolysis. Thus I11 can be assayed for. by some polymethylene formation, minimized a t Cleavage of the pyrophosphate bond in I1 below lower temperatures. Typical cases were n-octanol p H 4.0 is measurable simply by assay for inorganic ( S i % ) , cyclohexanol (927,), chol orthophosphate. These assays showed that in- cholestanol (98yG), 3-cholestanol significant amounts of either phenylphosphoro- phenylcarbinol (307;) and t-amyl Competition experiments s h o w amidic acid I11 or inorganic phosphate were prothe rates of primary, secondary and tertiary butyl duced above or below p H 4.0, respectively. As regards stability to spontaneous hydrolysis alcohols = 2,.2:1.3:1.0 and ,3 (equatorial) and cy this substrate I1 is, therefore, eminently satisfac- (axial) cholestanol = 1.3: l . Clearly, these acidtory for enzymatic work. Extracts of intestine catalyzed methylations lack high steric selectivity. with high alkaline phosphatase activity8 active Triphenylcarbinol and isoborneol could not be against various phosphamidesg were significantly methylated by this method. The new reagent provides a unique tool for the active against this substrate 11. Preliminary results, however, suggest t h a t the methylation of certain alcohols containing other active enzyme is not alkaline phosphatase since sensitive groups. For example, testosterone and maximum hydrolysis occurred a t a new p H between desoxycorticosterone have been converted directly 7.6-8.0, and of the two intestinal extracts studied to their inethyl ether:---a dificult, if not impossible, the partially purified one was significantly more ac- transformation by any previously axrailable direct tive against @-glycerol phosphate and P-napthyl methods. Testosterone methyl ether, which docs phosphate than i t was against the substrate 11. not appear to have been described before, melts a t The relationship of this "pyrophospharnidase" to 127-1%i.,j0, [ a ] , > C H C ' a +106.3" (found: C,7!).%1 ; phosphamidase and its distribution in tissues are H, 0.71; OCH::, 10.3). Ascorbic acid gave a hitherto unknown trimethyl ether, 1n.p. 09.3-101 ', under study t h a t will be reported later. Acknowledgments.-This work was s u j p r t e c i ( Q ) ? ~ D 33" (HYO) ; C, 49.48; H , 6.49;OCH3, 4%.:3; by a research grant ( N o . C-2130) from the Sational which we consider to be 2,3,6-triiiiethylascorbic Institutes of Health, U.S. Public Health Service. acid on the basis 01 its oxidation with weakly The authors also gratefully acknowledge assistance alkaline periodate, and by its infrared and ultrafrom A h . Phyllis R. Kaplan and Mr. Harold violet spectra and the changes in the latter in the presence of dilute alkali. Sominer. Fluoroboric acid also has been s1~ow.n to catDEPARTMEKT OF CHEMISTRY E L r a r x BOGER alyze the othern-ise sluggish reaction of weakly BRANDEIS UNIVERSITY ORRIE52. FRIEDMAN acidic phenols with diazomethane. Estradiol was lV.4LTHAM 54, >IASSACHUSETTS thus converted t o the dimethyl ether i n Slyc yield RECEIVEE JANWART 22, tR68 urider Conditions which, although forcillg, gave 110 reaction a t all in the absence of thc catalyst. ( t i ) F. hIichael and J . Schierhcrlt, Rev., 89, 1089 (1952). Other meakly acidic phenols of PI
