COMMUNICATIONS TO THE EDITOR
Sept. 20, 1964
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identified by comparing i t with an authentic sample.' 1-trans-3-Pentadiene reacts faster than the czs isomer. The unreacted 1,a-pentadiene was found t o be rich in the cis isomer. The reaction of isoprene with ethylene at 20' gave 4-methyl-l,4-hexadiene (one geometrical isomer), b.p. nZ0D 1.4248, and 5-methyl-l,4-hexadiene, 88-89', b.p. 88-89', 12% 1.4256, in a ratio of 6:4. As the re(10) P. Gray and A . Williams, Chcm. Rcu., I S , 239 (1959). (1 1) National Science Foundation Cooperative Fellow, 1963-1964 action temperature was raised, the ratio approached DEPARTMENT OF CHEMISTRY CHEVESWALLING 1: 1. The terminal double bonds of 4-methyl- and 5HAVEMEYER HALL MORTON J. G I B I A N ~ ~ methyl-l,4-hexadiene were reduced by diisobutylCOLUMBIA UNIVERSITY aluminum hydride t o afford one geometrical isomer NEW YORK, N E W YORK 10027 of 3-methyl-2-hexene and 2-meth~l-2-hexene,~ reRECEIVED JULY 15, 1964 spectively. A mixture of geometrical isomers of 3methyl-2-hexene was prepared by the Wittig reaction Stereospecific Synthesis of 1,I-Dienes of 2-pentanone with ethylidenetriphenylphosphorane. The isomers were separated by gas chromatography Sir: using a squalane column (4 m.) a t 60'. The infrared We wish to report the novel synthesis of 1,4-dienes spectrum and gas chromatographic retention time of I1 and 111by the reaction of 1,3-dienes I with ethylene the first eluted component were identical with those of in the presence of a catalyst consisting of iron comthe reduction product of 4-methyl- 1,4-hexadiene. pounds and organoaluminum compounds. This reInvestigation of its geometry is underway. RI Rz In a similar way, the reaction of 2,3-dimethyl-1,3I 1 butadiene with ethylene gave 4,5-dimethyl-1,4-hexaCHz=C-C=CHRa + CHFCHZ --f diene, b.p. 119-120°, nZ0D1.4408. I The steric course and orientation of the reaction are being investigated. A detailed description of these reactions will be published later. I1
104 kcal."J suggests that the energetics of hydrogen abstraction by the benzophenone triplet and the tbutoxy radical must be very similar. We are extending our experiments to other substrates and triplet states of other ketones and find, for example, that the acetophenone triplet shows similar but significantly different selectivities.
RI Rz I
I
CH~-C=C-CHR~-CH=CH~ I11
R1,Ra, R3
=
H or CHs
action affords either of the possible geometrical isomers of the 1,4-dienesselectively. In a typical example, 25 ml. of toluene, 0.003 mole of iron(II1) acetylacetonate, 0.012 mole of triethylaluminum, and 0.6 mole of 1,3-butadiene were placed in a stainless steel autoclave (100 ml.). The resulting mixture was stirred for 1.5 hr. a t 30' under ethylene pressure (40 kg./cm.2). After the usual work-up, the reaction products were separated by preparative gas chromatography. l-cis-4-Hexadiene, b.p. 66.5', nZ0D 1.4147, was obtained in 35% yield and identified by comparison of its infrared spectrum and gas chromatographic retention time with an authentic sample.' In addition, small amounts of 2,4-hexadiene and 1,3hexadiene were obtained. For 1,3-pentadiene and isoprene, there are two possible sites of addition. The reaction of 1,3-pentadiene with ethylene a t 50' afforded 3-methyl-1-cis-4-hexadiene, b.p. 83O, nZ0D 1.4169, and l-czs-4-heptadiene, b.p. 93', nZoD1.4209, in a ratio of 7:3, ;.e., ethylene adds more easily to the 4- position of 1,3-pentadiene than to the 1- position. The terminal double bond of the former compound was reduced by addition of an equivalent amount of diisobutylalumirium hydride, followed by hydrolysis to give 4-methyl-cis-2-hexene. The absence of the trans isomer2 was confirmed by gas chromatographic analysis. The latter compound was (1) Mixtures of c i s and trans isomel-s of l,4-hexadiene and 1.4-heptadiene were prepared by the known method [ B . H . Shoemaker and C. E . Board, J . A m . Chem. S O C ,OS, 1503 11531)1. The c i s isomers of both 1,4-dienes were separated by gas chromatography using a silver nitrate-henzyi cyanide column (2 5 m . ) . (2) F. J . Soday and C.E . Board, ibid., 66, 3293 (1933).
(3) M . D. Sutherland, ibid., 76, 5944 (1953).
BASICRESEARCH LABORATORIES TOYO RAYONCo., LTD. KAMAKURA, JAPAN RECEIVED JULY 21, 1964
Go HATA
An Approach to an Improved Antiinflammatory Steroid. The Synthesis of 118,l'I-Dihydroxy-3,20-dione-l,4-pregnadien-2 1-yl
2-Acetamido-2-deoxy-~-~-glucopyranoside Sir : When cortisone is used in the treatment of inflammation, a number of effects also occur which are undesirable in this therapy, such as negative nitrogen balance, osteoporosis, adrenal atrophy, formation of ulcers, and retention of sodium chloride. Numerous synthetic steroids have been prepared2 in an attempt to obtain a therapeutically active drug which will not cause these side effects. However, mineralocorticoid activity is the only effect, undesired in antiinflammatory therapy, which has been dissociated. It seemed possible to reduce all of these side effects if an inactive steroid could be prepared which is preferentially converted into an active drug a t the site of its therapeutic action. Connective tissue has an active metabolism of hyaluronic acid.3 An indication of higher activity of 8D-glucuronidase in the synovial fluid of joints from patients with rheumatoid arthritis than in liver was given by Ballet.* Very recently a striking increase ( 1 ) The authors are indebted to Drs. G . Boxer and K. Meyer for many Ftimulating discussions. ( 2 ) I. H . Sarett, A. A. Patchett, and S . L . Steelman, Fortschr ArrneimilId'orsch., 6, 1 1 (1963). (3) See, P . z . , E. Buddecke, Angcw. C h c m , 74, 663 (15GO) ( 4 ) A . J . Ballet, J . F . Goodwin, and A . K . Brown, J C f i n Znsest., 38, 451 (1959).
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Vol. 86
in 8-N-acetylglucosaminidase levels was reported for levels of I1 reported above. Whether these favorable the synovial fluid of patients suffering from severe results can be duplicated in man cannot be ascertained rheumatoid arthritis6 without prolonged clinical studies. We envisaged that 11~,17-dihydroxy-3,20-dione-1,4MERCKSHARP& DOHME RALPHHIRSCHMANN pregnadien-2 1-y 1 2-acetamido-2-deoxy-~-~-glucopyran- RESEARCH LARORATORIES ROBERTG. STRACHAN OF MERCK & Co., INC. DIVISION P. BUCHSCHACHER oside (I) should show antiinflammatory activity only RAHWAY, KEWJERSEY L. H. SARETT after cleavage by /3-N-acetylglucosaminidase, because MERCKINSTITUTE FOR S. L. STEELMAN cortisol 2 1-methyl and hexadecyl ethers possess subTHERAPEUTIC RESEARCH K. SILBER stantially no systemic cortisone-like activity.6 Lack of RAHWAY, NEWJERSEY systemic activity of I, in conjunction with preferential RECEIVED JULY31, 1964 enzymatic cleavage at the inflamed site, should cause I t o be an effective but relatively nontoxic antiinflammatory agent. Radical Anions as Intermediates in Substitution Reactions. Carbon Alkylation of Nitroparaffin Salts The Koenigs-Knorr condensation of prednisolone (11) with 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-a-~Sir: glucopyranosyl chloride led to 118,17-dihydroxy-3,20Nitroparaffin salts normally undergo oxygen alkyla2-acetamido-3,4,6-tri-0- tion on treatment with alkyl halides.' However, indione- 1,4-pregnadien-21-yl acety~-2-deoxy-~-~-g~ucopyranoside ( I I I ) , m.p. 246stances are known in which the result is carbon alkyla248'; [ a ] " D +36" (c I , CHCla);' ::A: 243 mp (log tion. Thus, when p-nitrobenzyl chloride is treated c 4.17). Anal. Found: C, 60.98; H, 7.02. Methwith a salt of 2-nitropropane an 83-95% yield of [ ( Y ] ~ ~ Df66' anolysis afforded I , m.p. 1S3-184'; the carbon alkylate is With o-nitro( c 1, MeOH); "A':: 243 mp (log c 4.19). Anal. benzyl chloride a 37-46y0 yield of the carbon alkylate Found: C, 62.13; H , 7.47; N, 2.28. Incubation of I is isolated. Significantly, m-nitrobenzyl chloride gives with ~-N-acetylglucosaminidase7gave the theoretical no carbon amount of 11. As expected, the addition of 2-acetK' R' 0 amido-2-deoxy-~-g~uconolactone inhibited the enzyK"CH2X I . I +/ R-C-NOZ ----+ R-C--NO2 or R-C=N matic hydrolysis.8 Unlike prednisolone phosphate, I \ I was not rapidly converted into prednisolone after CHzR" OCHsR', parenteral. injection into a rat or dog. When plasma I I1 levels of I I were determined after intravenous adminIn 1961 it was established that the uniqueness of the istration of I , the blood levels of 11 never reached more p-nitrobenzyl system depends not only on the pthan one-fifth those obtained after the subcutaneous nitro group but also on the leaving group; the more injection of an equimolar amount of prednisolone 21easily displaced the leaving group the less carbon phosphate. Incubation of tritiated I9 with sera and alkylate is produced.2 For example, p-nitrobenzyl joint fluids of two arthritic patients'O resulted in more chloride gives 92y0 carbon alkylation while p-nitroenzymatic hydrolysis per unit volume in the joint benzyl iodide gives an 86% yield of the oxygen alkylfluids than in the Sera and this difference was particuate. In contrast, the unsubstituted benzyl system larly striking (17-fold) in a severely ill patient." shows no leaving-group effect; the reactions of benzyl Compound I was tested in the rat in the granuloma chloride, bromide, iodide, or tosylate with the lithium inhibition assay after subcutaneous administration. salt of 2-nitropropane all give 82-84y0 yields of benzalI t showed eight-tenths of the antiinflammatory podehyde. It was proposed2 that oxygen alkylation, the tency of an equimolar dose of 11. Indices for undeusual mode of reaction of a nitroparaffin anion, derives sired effects were, however, considerably smaller simply from nucleophilic displacement by the oxygen (two-tenths that of I1 for body weight loss, threeof the anion on the benzylic carbon but that in the ptenths that of I1 for thymus involution, and fournitrobenzyl series, with a difficultly displaced leaving tenths that of I1 for ACTH inhibition). A very group, a second mode of attack by the nitroparaffin striking separation of an undesired effect was observed anion has a chance to compete and i t is this second in a standard ulcerogenic assayT2in the rat, where I process which is productive of carbon alkylation. had
