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CON~IUNICATIONS TO THE
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use of the A17*20-21-hydroxygroup2 as a precursor rectly in 50-i570 yield. Alternatively, 50Yc acetic for the dihydroxyacetone chain. T h e latter acid at 100" for seven hours, followed by acetylamethod has been particularly useful for the syn- tion and chromatography, has given the correthesis of alkyl homologs of cortisone and hydro- sponding 21-acetate in 50-6076 yields. cortisone because of its applicability to baseThese B M D derivatives have been subjected to catalyzed alkylations. Both of these methods a variety of reaction conditions without damage t o have intrinsic limitations for some applications, the protected side chain : e.g., alkylations, acylahowever. tions, dioxolanations, brominations, oxidations, h new type of protecting group has been found reductions, and acid catalyzed rearrangements. and consists of two formaldehyde units bridging I n all cases the spiroketal function remains essenC I ~C , 20 and ( 2 2 1 . I t results from acid-catalyzed tially untouched. Details of these transformations condensation of a lia,2l-dihydroxy-30-ketopreg-d l be the subject of future communications from nane with formaldehyde in the presence of a strong these laboratories. R. E. BEYLER acid. Once formed the bismethylenedioxy funcR . M. MORIARTY tion can be removed by fairly vigorous treatment MERCKSHARP& DOHME RESEARCH LABORATORIES FRAXCES HOFFMAN with acids. L. €3. SARETT RAHWAY, S.J. For example, 50 g. of cortisone in 2000 ml. of RECEIVED FEBRUARY 13, 1958 chloroform was stirred with 500 ml. of formalin (37% aqueous formaldehyde) and 500 ml. of conDEMONSTRATION OF AN ATOM TRANSFER centrated hydrochloric acid for 48 hours to yield 39.5 g. of lT,20;20,21-bismethylenedioxy-4-preg- PROCESS BY ELECTRON SPIN RESONANCE' nene-3,ll-dione n1.p. 242-250". Similarly hydro- Sir: cortisone, prednisone, prednisolone, Sa-fluorohyThe electron spin resonance spectrum of a dilute drocortisone (properties listed in Table I) and a solution of the sodium ketyl of benzophenone in number of other steroids have given bismethylene- 1,2-dimethoxyethane consists of more than eighty dioxy (BMD) derivatives. hyperfine components in a span of about 2s oersteds. \%?bile we have not yet made a complete TABLEI analysis of the spectrum, we have determined by PROPERTIES O F 17,20;20,21-BISMETHYLENEDIOXY comparison with the spectra of the corresponding STEROIDS lithium and potassium ketyls t h a t a splitting by Yield, hI.p., C, H C, H Steroid w ,' 'C. [ ~ I D C H C I I Calcd. Found the nuclear moment of N a Y 3 (spin 3 / 3 ) occurs. The magnitude of this splitting is about 1 oersted Cortisone BMD 70 238-261 +82 68.63 68.70 or about 2.8 megacycles per second. The fact 7.51 7.38 t h a t i t occurs indicates t h a t each ketyl molecule Hydrocortisone 50 217-222 +26 68.29 68.01 retains its sodium atom for a time -3 X lo-.; BMD 7 . 9 7 7.97 second or longer. 60 211-217 t 5 7 68.98 68.60 Prednisone BMD I n the presence of benzophenone an exchange re7.05 7.11 action occurs. The over-all reaction is NaOC60 270-274 -20 68.63 68.37 Prednisolone (C6H6)2 OC(C&)2 = OC(C&)2 f NaOCBhID 7.51 7.70 (CfiH5)2. The question whether the reaction pro9e-Fluorohydro70 930-260 +30 65.38 65.74 ceeds by transfer of sodium atoms or by separate cortisone BSID or 7.39 fj89 and uncorrelated transfers of electrons and sodium ions may be answered by the electron spin reso285-290 nance method. Should each unpaired electron inI n general, the B M D compounds are highly teract with the nuclear magnetic moments of crystalline, high melting solids which are much less many sodium atoms as well as with the moments of polar than the parent steroid as evidenced by solu- many protons as the exchange reaction proceeds bility and chromatographic behavior. The molec- t h e resonance spectrum would collapse into a ular rotation change from the dihydroxyacetone single line. On the other hand, if each electron to the bismethylenedioxy side chain is in a levoro- carries its sodium nucleus with i t during many extatory direction (LUD -390 to -490"). X1- changes (atom transfer), the spectrum would colthough two stereoisomers a t Cz0 are theoretically lapse into four lines, each line corresponding to one possible, one isomer has been isolated in all in- of the four possible orientations of the sodiunl stances. The spiroketal grouping is quite stable to nuclei. acid. For example, cortisone B N D survives I n the presence of benzophenone a t -2 31 we 1.25 3 hydrochloric acid in methanol for 1X observe the latter possibility ; the original spectrum hours a t SO",or 1 &Ysulfuric acid in SOY0 methanol of more than eighty lines has collapsed into four for 11 hours under reflux. equally intense lines with separation 1.1 oersteds. Removal of the bisniethylenedioxy function to Our observations are compatible with a second orreform the dihydroxyacetone side chain is best ac- der rate constant for the exchange K >_ 5 X 10' complished with aqueous organic acids such as for- liter mole-' sec.-l. a t a concentration of benzomic or acetic acid. Heating the B M D derivative phenone -2 111 the mean life of each ketyl molein GOYc formic acid a t steam-bath temperature for cule t ~ ( 10-8 second while the mean time of ten to thirty minutes gives the parent steroid di-
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