DECEMBER, 19(i2 yellow solution after about 1 min. The solution waa cooled in ice water, and the crystals which formed were filtered and dried in air (evaporation of the solution and addition of ether may be needed to promote crystallization). The rod-shaped crystals turned red a t 100" and decomposed a t 170'. These physical properties agree with those reported for alloxan .I1 Further evidence of the product's being uric acid was obtained from positive color reactions observed, as follows. A sodium hydroxide solution of the compound gave a redhrown precipitate with phosphotungstic acid and hydrochloric acid.'* A sodium carbonate solution of the compound reduced silver nitrate paperI3 and gave a blue precipitate with phosphomolybdic acid.14 An authentic sample of uric acid was obtained and used as a comparison throughout this identification. 1-Methyl-5-carbethoxy-4-N '-methylureido-2-oxyimidazo1e.-Ethyl a-chloro-b,p-diethoxyacrylate (4.4 g . , 20.0 mmoles) and 1.7 g . (23 mmoles) of dry methylurea in a 50-ml. flat-bottomed distilling flask protected from moisture were heated to 102'. After having been stirred magnetically for approximately 5 rnin., the mixture became homogeneous, and after another 15 min., ethanol began to distill; reaction apparently was complete a t the end of 0.5 hr. A clear light yellow oil remained which was poured into cold water and crystallized after standing for several hours a t 5 " . The product was filtered, washed with ether, and dried in air to give 2.0 g. of product, 72%, based on urea taken. An analytical sample, prepared by recrystallizing twice from water, melted a t 158-159'. Anal. Calcd. for CgH140Sd: C, 44 62; H , 5.82; N , 23.12. Found: C,44..53; H , 5.69; N , 23.24. The structure of the imidazole was shown by its conversion to 1,7-dimethyluric acid. The imidazole (1.4 g., 5.8 moles) was dissolved in 6.5 ml. of 870 potassium hydroxide solution (9.3 mmoles of KOH). The solution was heated a t 60" for 2 rnin., cooled, and diluted with 15 ml. water before acidification with glacial acetic acid. The white precipitate was filtered, washed with 10 ml. of ethanol, 10 ml. of ether, and dried in air. The yield was 0.65 g. (57%). The product sublimed rapidly a t 360-365" and melted with decomposition ahout 382' (Biltz reports 287" as the melting point of 1,7-dimethyluric acid16); it had the same properties aa 1,7-dimethyluric acid prepared in the next section. Direct Preparation of 1,7-Dimethyluric Acid.-Ethyl achloro-B,@-diethoxyacrylate(4.4 g., 20.0 mmoles) and 1.7 g. (30.0 mmoles) of dry methylurea were condrnsed by heating a t 105' for 25 min. (2 ml. of ethanol was collected). To the reaction mixture was added 21 ml. of 8% potassium hydroxide solution a t 50"; the mixture was stirred 2 min. and added to 20 ml. uf water. Cooling to room temperature and acidification with glacial acetic acid causes a colorless solid to separate which was filtered, washed with water, ethanol, and ether, and dried in air. The yield was 1.68 g . (747,, calculated as 1,7-dimethyluric acid, based on urea taken). This product sublimed rapidly at 350-365" and melted with decomposition a t 382". Identification of the product as 1,7-dimethyluric acid was confirmed by analysis and by the preparation of the 5chloro-l,7-dimethy1-A4~g-isnuric acid derivative. Ana2. Calcd. for C7HR03N4: C, 42.86; H, 4.11; 3 , 28.57. Found: C, 42.82 H, 4.11; N , 28.62. 5-Chloro-1 ,7-dimethyl-A4~9-isouricAcid .-One-half gram (2.5 mmoles) of dry dimethyluric acid was suspended in 7 ml. of dry chloroform. Chlorine gas was bubbled through the suspension a t a rapid rate for 10 min. while cooling in an ice-salt bath. No solution occurred but a gradual transformation from the granular suspension t o a white gummy ( 1 1 ) H. Ailte and M. IIeyn, Ann., 413, 60 (1916).
(12) B. e. Schoendorff, Pfluegers Arch. ges. Physiol., 62, 30 (1896). (13) H. Schiff, Ann., 109,65 (1859). (14) Offer, Zenlr. Phyeiol., 8, 801 11894-1895) [Reilstein 26, 521 (1937)l. (15) H. Bilte and P. Damrn, A n n . , 413, 142 (1916).
SOTES
4635
solid occurred. Chlorine flow was discontinued, dry air waa drawn through the mixture, and the product waa filtered and washed with dry chloroform and ether. The yield was 0.2 g. of a solid which melted a t 130" with decomposition, 34% of the expected isouric acid. Biltz and Damm report a melting point a t 131' with decomposition for 5-chloro-1,7-dimethyl-A4~g-isouric acid.16 Anal. Calcd. for C7H702N4Cl: C, 36.45; H, 3.06; N, 24.29; C1, 15.37. Found: C, 36.62; H, 2.98; K , 24.20; C1, 15.26. (16) H. Riltz and P. Darnm, ibid., 413, 137 (1916).
A New Synthesis of Quinuclidine STANLEY LEONARD AND SAMUEL ELKIN Department of Chemistry, School of Pharmacy, Temple University, Philadelphia 40, Pennsylvania Received April 2'7, 1962
Quinuclidine (1-azabicyclo [2.2.2]octane) was first synthesized in 1909 by Loffler and Stiezel.' 4hiethylpyridine reacted with formaldehyde to form, among other substances, 4-(&hydroxyethyl)pyridine. Reduction and subsequent replacement of the hydroxyl group with iodine, using hydriodic acid, gave 4-(&iodoethyl)piperidine; the latter was converted to quinuclidine by dilute alkali. However, the authors failed to isolate quinuclidine in a pure state. Meisenheimer, et followed the same route and obtained quinuclidine in the form of colorless crystals, m.p. 154'; yielding a picrate, m.p. 27.5'. Brown and Eldred3 utilized the approach of Meisenheimer. The former started with 4-bydroxyethylpyridine rather than with y-picoline. The authors also increased the yield of quinuclidine by improving the method of isolation. Wawzonek, et ~ l . converted , ~ N-bromo- and Nchloro-4-ethylpiperidine into quinuclidine by irradiating first with ultraviolet light in S5yo sulfuric acid a t temperatures ranging from 0-23' and then treating with alkali. This synthesis was simultaneously discovered by Lukes and fer le^.^ Clemo and Metcalfe6 heated ethylpiperidine 4carboxylate, ethyl chloroacetate, and potassium carbonate for four hours at 110-115' and obtained Thp ethylpiperidine - 1-acetate 4 -carboxylate. Dieckmann reaction followed by hydrolysis and decarboxylation gave 2-ketoquinuclidine. Wolff or Clemenson reduction gave quinuclidine. ( 1 ) K. Loffler and F. Stiezel, Be?.. 42, 124 (1909). (2) J. Meisenheimer, J . Neresheimer, and W. Schneider, Ann., 420,
191 (1920). (3) H. C. Brown and N . R . Eldred, J . Am. Chem. Soc., 71, 448 (1949). (4) S. Wauaonek. RI. F. Nelson, and P. S. Thelen, ibid., 73, 2806 (1951). ( 5 ) R. Lukes and M. Ferles, Collection Czech. Chem. Commun., 16, 416 (1951); Chem. Abst?., 47, 21770 (1953). (6) C. R . Clerno and T. P. Metoaife, J . Chem. Soc., 1989 (1937).
NOTES
4636
Ishiguro, et al.,' passed K,n'-bis(2-hydroxyethy1)piperazine into an evacuated vessel containing silicon oxide-alumina a t 325' during six hours. Ultimate treatment with p-nitrophenol gave 1,4diazabicyclo [2.2.2]octane bis(pnitropheno1ate). Prelog, et C L ~ .treated , ~ tetrahydropyran-4-propionic acid with sodium azide and obtained 4-(2-aminoethyl) tetrahydropyran. Treatment with hydrogen bromide at 100' for seven hours gave 3-(2-aminoethyl)-l,5-dibromopentanehydrobromide which with sodium hydroxide gave quinuclidine. Prelogg approached the synthesis of quinuclidine from another direction. The methods he developed were based on the action of ammonia under pressure at 100-120' on aliphatic tribromides and on alkali treatment of dibromoalkylamines. Rubtsov and Volskova'O prepared 2-(l-benzoyl4-piperidy1)ethyl bromide. This compound, upon treatment with hydrogen bromide and ultimate refluxing with sodium hydroxide, gave quinuclidine, which was isolated as the picrate. Quinuclidine was prepared in this laboratory by the vapor phase dehydration over alumina of commericially available 4-hydroxyethylpiperidine. Purification of the product was conveniently acheived by sublimation. Experimental 4-Hydroxyethylpiperidine,1140 g., was distilled a t 8So/ 0.1 mm. The vapors were passed through a column (18 X 0.5 in.) packed with dried alumina. The column temperature was maintained a t 400-450" in a muffle furnace. The diGtillate was poured into a Dry Ice-acetone mixture, whereupon a solid precipitated. Filtration yielded 20 g. of a white product and atarting material. The residue, after being dried in a vacuum desiccator for 5 min. at 30" and then sublimed, gave 11.2 g. of quinuclidine, m.p. 156" (sealed tube); reported m.p., 154°,2156".12 Picrate from alcohol, m.p. 278O, reported m.p. 274O,*274-275O." i l n a l . Calcd. for C13H16X407 (quinuclidine picrate): C, 45.88; H, 4.74; N, 16.47. Found: C,46.27; H , 4.72; N, 16.15. (7) T. Ishiguro. et al., J. Pharm. Soc. Japan, 7 6 , 1370 (1955): Chem. Abstr., 5 0 , 10106f (1956). ( 8 ) V. Prelog, E. Cerkonvikov, a n d G. Ustricev, Ann., 636, 37 (1930). (9) V. Prelog, U.S. P a t e n t 2,192,840: Chem. Abstr., 34, 4396 (1940). (10) M. V. Rubtsov a n d V. A. Volskova, Zh. Obshch. Khim., 19, 1378 (1949); Chern. Abstr.. 44, 1981g (1950). (11) Reilly Tar and Chemical Co., Indianapolis, Ind. (12) I. Heilbron. "Dictionary of Organic Compounds," Val. IX. Oxford University Press, New York, N. Y., 1953, p. 312.
VOL.27
Air Force program being conducted in this laboratory to develop new hydrocarbon fuels. Khromov, et ~ 1 reported . ~ that ~ 1-chloro-1-methylcyclohexane reacts with its Grignard reagent when heated in the presence of cuprous chloride and copper turnings to yield the expected coupling product 1,l'dimethylbicyclohexyl. They indicated difficulty in removing unsaturated impurities from their final product, and found it necessary to distil, chromatograph on silica gel, and finally redistil to obtain a pure product, described as having b.p. 99.5-100°/5 mm., T Z ~ O D 1.4920, d2O 0.9045, MRD calcd. for C14H2e:62.45; found: 62.32. Our work, following their procedure, has led to the isolation of a different hydrocarbon. Instrumental evaluation has demonstrated that our product, a solid melting a t 42-43', and not the material described by Khromov and co-workers, is, in fact, 1,l'-dimethylbicyclohexyl. I n addition to Khromov's method, we have also used the coupling procedure employing methylmagnesium bromide and cobaltous salts described by Kharasch and his co-workers.2" Low-boiling products resulting from disproportionation and free radical fragmentation account for about 9095% of the yield by either synthetic method. These products, principally methylcyclohexane and methylcyclohexene, were not separated from the solvent. After removal of these low-boiling compounds, both synthetic methods produced three principal coupling products in approximately equal amounts, as demonstrated by vapor phase chromatography (v.P.c.). In order of increasing retention time these components will be designated A, B, and C. Careful fractionation enabled us to isolate the highest boiling component of this triad, C, as a solid in reasonable purity. Recrystallization from ethanol yielded the hydrocarbon in a t least 99 area % purity by V.P.C. Compound C has been shown to be 1,l'-dimethylbicyclohexyl, and A and B are probably l-methyl1 - cyclohexylcyclohexane and 1 - methyl - 1cyclohexylcyclohexene-2 or -3, respectively.
A HqC
Isolation and Identification of
1,l'-Dimethylbicyclohexyl SHIRLEY A. LIEBMAN, PAUL F. DONOVAN, AXD STANLEY D. KOCH^
CH3 C
B @H3
+
(CH3
Monsanto Research Corporation, Boston, Massachusetts Received M a y 1, 1962
The preparation of a small amount of 1,l'dimethylbicyclohexyl was required as a part of an
(1) To whom correspondence should be addressed. (2) (a) S. I. Khromov, D. A. Kondrat'ev, E. S. Balenkova, and B. A. Kazanskil, Dokl. Akad. Nauk S S S R , 109, 109 (1956): (b) M. 9. Kharasch, F. Engelmann, a n d W. H. Urry, J . Am. Chem. Soc., 66, 365 (1944).
