Notes - The Journal of Organic Chemistry (ACS Publications)

Notes guanidino-4-methylquinazoline hydrochloride (III.HC1), prepared for comparison from o-aminoacetophenone hydrochloride and dicyandianiide according to the procedure of Theiling and McKee.6 Proof that the by-product is correctly represented by 11, rather than by the alternative structure IV, was secured by the unambiguous synthesis depicted in Chart I. Acetylation of 3,4-~ylidine,~ followed by reaction with chloroacetyl chloride in the presence of aluminum chloride according to the procedure of Kunckell and Schneider,’ yielded 2-acetamido-w-chloro-4,5-dimethylacetophenone, the structure of which was con-

Quinazolines. 11. 2-Guanidino-4,6,7trimethylquinazoline as a By-product in the Three-Component Synthesis of 4,6-Diamino2,2-dimethyl-l-(3,4-xylyl)-1,2-dihydro-striazine’!2 ANDREROSOWSKY, HELJOKANGUR PROTOPAPA, AND EDWARD J. MODEST

?’he Children’s Cancer Research Foundation, and the Department of Pathology, Harvard Medical School at The Children’s Hospital, Boston, Massachusetts Received August 10, 1964

A high-melting, biologically active substance, identified as 3-guanidino-1-methylbenzo[flquinazoline hydrochloride,2 was isolated in these laboratories as a byproduct in the three-component synthesis3r4 of 4,6diamin0-2,2-dimethyl-l-(Znaphthyl)-l ,2-dihyd r o-s-t r iazine from 2-naphthylamine hydrochloride, dicyandiamide, and acetone. We now wish to describe the only other anomalous guanidinoquinazoline by-product that we have encountered thus far in our considerable experience with the three-component dihydrotriazine synthesis. Careful work-up of the reaction mixture from the condensation of 3,4-xylidine hydrochloride with dicyandiamide and acetone revealed that the desired three-component synthesis product, 4,6-diamino-2,2dimethyl-l-(3,4-xyly1)-1,2-dihydro-s-triazine (I . HCl), was accompanied by a small quantity (13 Compound V, the hitherto unreported “acetone anil” of 3,4-xylidine, was prepared by condensation with acetone in the presence of iodine.lOtll That the structure of this substance is V, and not the sterically less-favored cyclization product VI, was shown by its n.m.r. spectrum (only two peaks in the aromatic region a t T 3.18 and 3.83, corresponding to the C-5 and C-8 protons, respectively, in V). It should be emphasized that, among the numerous arylamines employed in these laboratories for the three-component dihydrotriazine s y n t h e s i ~ ,only ~ , ~ two, 2-naphthylamine and 3,4-xylidine, have given isolable quantities of guanidinoquinazoline by-products. Nevertheless, we believe that path B may be a more common side reaction than is now apparent and that it may escape detection in most instances because it is a low-yield process. I n certain cases the two-component synthesisl*may actually be a more desirable approach, since it obviates the possibility of “acetone anil” formation (path B). This point was illustrated, in the present work, by the preparation of 1.HCl from VI1 HC1 and acetone in 84y0yield without by-product formation. The various factors affecting the degree to which guanidinoquinazoline formation can be expected to compete with dihydrotriaeine formation in the three-component synthesis are currently under study and will be discussed in a future report. Experimentall‘ 4,6-Diamino-2 ,2-dimethyl-1-(3 ,4-xylyl)-l ,Z-dihydro-s-triazine mixture of

( I ) . A . Standard Three-Component Synthesis.-A (13) J. P. Brown, Chem. Ind. (London). 233 (1980).

3,4-xylidine (72.7 g., 0.6 mole), dicyandiamide (54 g., 0.6 4 mole) concentrated hydrochloric acid (50 ml., 0.6 mole), and acetone (300 ml.) was stirred magnetically for 5.5 hr. under reflux and then at room temperature overnight. A golden yellow solution was obtained in 10 min. and colorless solid began to form shortly thereafter. After refrigeration of the reaction mixture for approximately 4 hr., the solid was collected and washed with acetone. The small colorless prisms (89.6 g., 53%) melted a t 211-218’ and gave a negative biguanide test (no precipitate with alkaline copper ammonium ~ u l f a t e ) . ~ JFour ~ crystallizations from 20% ethanol removed traces of II.HC1 and afforded I.HC1 as colorless shiny prismatic plates, m.p. 189-191’. The ultraviolet absorption spectrum of I.HC1 showed Amsx in mp ( e ) a t pH 1: 233-236plateau (5920), 271 inflection(720); a t pH 10: 241 (11,040), 271 (920); in EtOH: 244 (12,730). Anal. Calcd. for CI~H1~N6.HCI.O.5H20:C, 53.69; H , 7.28; C1, 12.19; N, 24.09. Found: C, 53.19; H, 7.33; C1, 12.27; N , 24.10. For the preparation of I free base, a solution of 4 g. of oncecrystallized 1,HCl in 30 ml. of water waa brought to pH 11 with 5 N sodium hydroxide a t room temperature. Small colorless prismatic crystals were obtained (1.93 g., 57%) of n1.p. 153-198’. According to the melting point and ultraviolet absorption spectrum, this solid was contaminated with a small amount of 11. The volume of the original mother liquor was therefore reduced to 25 ml. a t room temperature, and after overnight refrigeration a second crop of colorless thick prismatic rods (0.26 g., 7.7?&)was obtained of m.p. 140-147’. Two crystallizations of this solid from 95qb ethanol afforded I as small colorless prismatic rods, m.p. 131-133’. Anal. Calcd. for C18H18N6:C, 63.64; H , 7.81; N, 28.55. Found: C,63.48; H, 7.78; N, 28.69. Another crop (0.6 g., 180/0)of crude I free base, contaminated with a small amount of 11, was obtained from the original aqueous wash upon evaporation to dryness a t room temperature; the total crude yield of I was 83y0. (14) Ultraviolet absorption spectra were measured with a Cary Model 11 spectrophotometer. Spectra at pH 1 were taken in 0.1 N hydrochloric acid and a t pH 10 in 0.05 M sodium carbonate-sodium borate buffer. Infrared spectra were taken in potassium bromide disks with a Perkin-Elmer Model 137B double-beam recording spectrophotometer (sodium chloride prism). N.m.r. spectra were measured in carbon tetrachloride or deuteriochloroform with a Varian A-60 instrument, with tetramethylsilane as the internal reference. Unless otherwise stated, analytical samples were dried at 70-100° for 17 hr. in vacuo over phosphorus pentoxide. Melting points were determined at Z0/min. in sealed Pyrex capillary tubes in a modified WagnerMeyer melting point apparatus [E. C. Wagner and J. F. Meyer, Ind. Eng. Chem., Anal. Ed., 10, 584 (1938)l and are corrected wherever possible. Decomposition points are not reproducible unless conditions are rigidly controlled. Microchemical analyses were performed by Scandinavian Microanalytical Laboratory, Herlev, Denmark, and by Galbreith Laboratories. Knoxville, Tenn.

JANUARY1965

NOTES

The impure crop melting a t 153-198" was extracted with hot water to remove most of the I still present, and the remaining solid (0.57 g.) was washed with ether and crystallized twice from %yoethanol. The pale yellow prisms (0.06 g.) were identical with I1 obtained from other runs (vide infra). B. Two-Component Synthesis.-A mixture of N1-(3,4-xylyl)biguanide hydrochloride (i'II.HC1) (12.1 g., 0.05 mole), concentrated hydrochloric acid (2.1 ml., 0.025 mole), and acetone (100 ml.) was stirred under reflux for 2 days, and a t room temperature for a n additional 4 days, a t which time a negative biguanide test indicated completion of the reaction. The solid was collected and washed with acetone. The yield of small colorless prisms was 11.8 g. (847,), m.p. 189-200'. Crystallization'of 9 g. from 25 ml. of water afforded colorless prismatic plates, 4.3 g., Two more crystallizations from water gave m.p. 204-209'. colorless thin prismatic plates (II.HC1) which melted a t 189-191' after having been dried in vacuo for 1 week over phosphorus pentoxide a t 106'. Anal. Calcd. for Cl,HlaNr.HCl.0.5H~O: C, 53.69: H , 7.28; ._ .- NJ24.09. Found: C, 54.03, 54.05; H,7.14, 7.24; N, 24.16. 2-Guanidino-4,6,7-trimethylquinazolne (11). A. Modified Three-Component Synthesis.-A mixture of 3A-xylidine (12.1 g., 0.1 mole), dicyandiamide (9.0 g., 0.11 mole), concent)ratedhydrochloric acid (8.4 ml., 0.1 mole), and acetone (60 ml.) was stirred under reflux for 1.5 hr. An additional 2.5 ml. (0.03 mole) of concentrated hydrochloric acid was added, and reflux was resumed for 1 hr. The clear solution was refrigerated overnight and the solid ( I I ' H C I ) was collected, washed with acetone, and dried in vacuo a t 65"; crude yield 1.21 g. (4.6y0). Crystallization of 100 mg. from 2 ml. of water afforded a colorless powder, m.p. 314-315" dec. A pale greenish precipitate was observed on addition of alkaline copper ammonium sulfate,2 and a positive Sakaguchi reaction was obtained.* Anal. Calcd. for Cl~H15N5.HC1.0.75H~O:C, 51.54; H, 6.35; N, 25.18. Found: C, 51.71; H,6.40; N, 24.57. On prolonged refrigeration, the original filtrate yielded several crops of solids (combined weight 5.28 g.), which appeared, on the basis of infrared spectra and biguanide tests, to consist mainly of 4,6-diamino-2,2-dimethyl-l-(3,4xylyl)-1,2-dihydro-s-triazinehydrochloride (I.HC1). The mother liquor gave a positive biguanide test, indicating' the presence of Nl-(3,4-xylyl)biguanide hydrochloride (VII.HC1). B. Reaction of 3,4-Xylidine "Acetone A d " with Dicyandiamide.-A solution of 12.1 g. (0.1 mole) of 3,4-xylidine and 1 g. of iodine in 65 ml. of anhydrous acetone was refluxed for 24 hr. and the acetone was removed in VUCUO. The dark oily residue was dissolved in 130 ml. of benzene and the solution was extracted with several portions of 10% aqueous sodium thiosulfate (400 ml. total), rinsed with distilled water, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. A solution of dicyandiamide (8.5 g., 0.1 mole) and concentrated hydrochloric acid (12.5 ml., 50% excess) in 5oy0 ethanol (100 ml.) was added. to the semicrystalline residue (V), and the mixture was stirred under reflux for 2 hr. A heavy precipitate formed upon cooling to room temperature. After overnight refrigeration the product was collected and washed with water and acetone. The offwhite solid (14.8 g., 54%) melted a t 316-319' dec. Another crop (5.4 g., 19yo) of solid waa obtained from the combined mother liquor and wash upon concentration to approximately one-half the original volume; total crude yield 20.2 g. (73%). A solution of 14.7 g. of crude product in 160 ml. of 20% ethanol was treated with Darcol6 and concentrated to approximately 80 ml. After overnight refrigeration the solid was collected, washed with acetone, and dried in a vacuum oven a t 50' for 5 hr.; yield 12.6 g. Two more crystallizations from 20% ethanol afforded II.HC1 as small colorless prismatic needles, m.p. 316-317" dec. Anal. Calcd. for ClzH15Nb,HC1.0.5H20:C, 52.45; H , 6.241 C1, 12.90; N, 25.49. Found: C, 52.52, 52.30; H , 6.13, 6.16: C1, 13.04; N, 25.65. For the preparation of I1 free base, a solution of 1 g. of II.HC1 in 35 ml. of 35y0 ethanol was brought to p H 11 with 5 N sodium hydroxide and cooled. The product was collected and washed with water and acetone: small off-white prismatic rods (0.74 g., 89%), m.p. 262-263" dec. Two crystallizations from 95% ethanol afforded I1 free base as nearly colorless prismatic rods: m.p. 259-260' dec.; Amax in mp ( e ) a t pH 1: 249 (65,860), 328

(3930); a t pH 10: 250 (39,800), 264 (30,260), 282 inflection (13,640), 341 (4010); in EtOH: 249 (57,600), 264 inflection (18,510), 331 (3390), 340 plateau (3930); a t pH 13: 264 and 346 only, no peak at 249-250. Anal. Calcd. for Cl2Hl6N5:C, 62.86; H, 6.59; N, 30.55. Found: C, 62.90; H, 6.56; N , 30.52. Acidification of an ethanolic solution of I1 free base with hydrochloric acid yielded II.HC1 identical with the material obtained in procedures and B. In another run, 3,4-xylidine "acetone anil" was prepared from 2.42 g. (0.02 mole) of 3,4-xylidine as described in the preceding experiment. A solution of the crude, partly crystalline product in 30 ml. of 50% ethanol was treated with Darco and concentrated to 10 ml. Overnight refrigeration gave 2,2,4,6,7-pentamethyl 1,2-dihydroquinoline (3,4-xylidine "acetone mil") (V), 2.28 g. (57%), m.p. 63-65'. Two further crystallizations from 50% ethanol afforded slightly off-white, thin prismatic plates, m.p. 64-65', which were dried for 5 days over phosphorus pentoxide in a closed evacuated drying pistol a t room temperature; , , ,A in mp ( e ) a t pH 1: 222 inflection (17,480), 264 (11,700), 294 inflection (970); a t pH 10: 228 (30,110), 265 inflection (3070); 330 (3330); in EtOH: 231 (32,660), 265 inflection (2760), 339 (3070). Anal. Calcd. for ClrH19N: C, 83.53; H, 9.51; N, 6.96. Found: C, 83.60; H,9.55; N , 6.97. The 7-values for the n.m.r. spectrum (in carbon tetrachloride) of V [8.82 (singlet), 8.04 (doublet,) 7.88 (singlet), 6.75 (broad), 4.80 (broad), 3.83 (singlet), 3.18 (singlet); relative peak areas 6 :3 :6 : 1 : 1 :1 : 11 correspond to gem-dimethyl, vinyl methyl, aromatic methyl, amine, vinyl and aromatic protons, respectively. Except for the additional aromatic methyl peak a t 7 7.83, theabove spectrum conforms well to that reported by Elliott and Yates11" for aniline "acetone anil." C. Fusion of 2-Amino-4,5-dimethylacetophenonewith Dicyandiamide.-3,4-Xylidine was acetylated in excess acetic anhydridea and the resulting 3,4-xylidide (colorless prismatic needles, yield 86%, m.p. 97-100", 1it.O m.p. 96-98') was dried for 4 hr. at 4Cb50' in vacuo and used without purification for the preparation of 2-acetamidow-chloro-4,5-dimethylacetophenone (pale orange flat prismatic needles, yield 96%, m.p. 166-168", lit.'r8 m.p. 166-167") by condensation with chloroacetyl chloride and aluminum chloride in carbon disulfide.' Acid hydrolysis and dehalogenation with zincBfurnished 2-amino-4,5-dimethylacetophenone (pale yellow thin prismatic rods, yield 9375, m.p. 125127', lit.Bm.p. 125-126'). A mixture of the latter compound (1.0 g., 6.1 mmoles), dicyandiamide (0.24 g., 2.8 mmoles), and concentrated hydrochloric acid (0.51 ml., 6.1 mmoles) was heated in an oil bath for 4 hr. at 137-140' (internal temperature) while a gentle stream of nitrogen was passed through the reaction system. The nearly solid product was dissolved in 50 ml. of boiling water containing a few drops of hydrochloric acid, and the solution was treated with Darco. Concentration to 8 ml. under reduced pressure, acidification to pH 1 with hydrochloric acid, and refrigeration produced 0.31 g. (40%) of nearly colorless prismatic needles. One crystallization from 10% ethanol containing a few drops of hydrochloric acid afforded colorless prismatic needles, m .p. 316317' dec. These crystals of II.HC1 were shown, on the basis of their melting point and mixture melting point (316-317' dec.), and ultraviolet and infrared absorption spectra, to be identical with those prepared by procedure A. The n.m.r. spectrum (in deuteriochloroform) of 2-acetamido-wchloro-4,5-dimethylacetophenoneshowed 7 7.76 (singlet), 7.70 (singlet), 7.65 (siflglet), 5.19 (singlet), 2.60 (singlet), 2.37 (singlet); relative peak areas3:3:3:2:1:1. 2-Guanidino-4-methylquinazolineHydrochloride (III,HCl).A sample of III.HCI, m.p. 319-321' dec. (lit.5 m.p. 319-320" dec.), was prepared from o-aminoacetophenone hydrochloride and dicyandiamide according to the procedure of Theiling and M C K ~ The ~ . free ~ base I11 was prepared in the manner used for 11. The ultraviolet absorption spectrum of I11 showed, , ,A in mh ( e ) a t pH 1: 245 (58,080), 264 inflection (5800), 323 (2960); a t pH 10: 245 (28,810), 261 (24,180), 338 (3210); in EtOH: 245 (42,760), 266 (18,5601,284 (11,940), 292 inflection (10,990), 327331 plateau (27201,339 (2940). NI-(3,4-Xylyl)biguanide Hydrochloride (VII.HC1).--ZTI.HCI was prepared from 3,4-xylidine hydrochloride and dicyandiamide by a modification of the procedure of King and T ~ n k i n and ,~ melted a t 223-224" (lit.gm.p. 225226').

(15) Darco G-60 activated carbon. itlaa Chemiral Industries, Inc., Wilmington. Del.

287

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288

Acknowledgment.-The authors are indebted to Dr. James H. Gunnerson, Mr. Leo McCready, and Mr. Michael Botchan for their assistance in the measurement of infrared and ultraviolet absorption spectra.

Transformations in the 1,lo-Phenanthroline Series E. J. COREY,A. L. BORROR, AND THOMAS FOGLIA Departments of Chemistry, Harvard University, Cambridge, Massachusetts, and Drexel Institub of Technology, Philadelphia, Pennsylvania Received September 16, 1964

In conjunction with a study of metal ion coordination with 1,lO-phenanthroline derivatiyes and macrocycles derived therefrom we have investigated some of the properties and reactions of 1,lo-phenanthroline 1-oxide (I). This substance, which had been prepared previously by Maerker and Case in 26.5y0 yield,' is now readily available (70-8070 yields) using a modified procedure described herein. The N-oxide is a tan solid, soluble in cold water, pK, = 6.6 at 22', significantly more basic than 1,lO-phenanthroline2 (pKa = 4.8) or pyridine 1-oxide3 (PKa = 0.8). 1,lo-Phenanthroline 1-oxide allows the introduction of a cyano group into the 2-position of the phenanthroline ring system. Treatment of the 1-oxide with benzoyl chloride and potassium cyanide at room temperature furnished 2-cyano-1,IO-phenanthroline (11) in good yield. Hydrolysis of I1 under basic conditions gave 1,l0-phenanthroline-2-carboxylicacid (111), a hitherto unknown and very useful substance. It is interesting

VOL.30

ring system nitrates to give 5-nitro-1 ,lo-phenanthroline in 90% yield.6 The apparent lack of reactivity of the N-oxide toward electrophilic substitution was reinvestigated. With potassium nitrate in sulfuric acid as a nitrating medium, the N-oxide was actually found to afford a mononitro compound in about 10% yield a t 90'. The low yield was not improved by increasing the reaction temperature or time. The product of the reaction was assigned the structure 4-nitro-1 ,lo-phenanthroline 1-oxide (IV) from the following observations. (1) The nitro group is very labile and is replaced by chloride when the compound is heated to reflux in concentrated hydrochloric acid to give 4-chloro-1,lOphenanthroline 1-oxide (V).' (2) Reaction of IV with phosphorus trichloride in refluxing chloroform resulted in both deoxygenation and replacement of the nitro group by chlorine. The product, 4-chloro-1,lO-phenanthroline, had been prepared previously* by a different method. In agreement with the previous reports we found the compound to be hygroscopic, but the melting

VI

J

I

I1

I11

t o note that the observed reaction takes precedence over the Reissert reaction4 at C-9,N-10. The latter course would require the attachment of benzoyl to K-10 which is sterically unfavorable. In addition it should be noted that we have found 1,lO-phenanthroline itself not to undergo the Reissert reaction under the conditions useful for quinolines. Although ?\'-oxides in general are nitrated readily,6 1,lO-phenanthroline 1-oxide has been reported to fail to undergo nitration.' On the other hand, the parent (1) G . M. Maerker and F. H. Case, J . A n . Chem. Soc., 80, 2745 (1958). (2) T . S. Lee, I. M. Kolthoff, and D . L. Leusing, zbtd., 70, 2348 (1948). (3) H . H. Jaffe and G . 0. Doak. Ibzd., 77, 4441 (1955). (4) See W. E. McEwen and R. L. Cobb. Chem. Rev.. I O , 511 (1955). ( 5 ) E. Ochlal. J . Org. Chem., 18, 534 (1953).

point which we observed was 163-165' (lit.8 m.p. 180-230'). Hawkins and co-workersgrecently repeated the original preparation, successfully purified the comThe pound, and reported a melting point of 165-166'. picrate of our specimen had m.p. 203-204' (reported originally for the picrate of 4-chloro-1,lO-phenanthroline,8m.p. 203-206'). The conditions which effect the conversion of 1,lOphenanthroline to the 5-nitro derivativea (150-160°, mixture of concentrated nitric and sulfuric acid) lead to gross degradation of 1,IO-phenanthroline N-oxide. At lower temperatures the N-oxide is converted to the 4-nitro derivative ih low yield and an insoluble acidic by-product is formed in considerable amount. Our experience with N-oxide I confirms its exceptional unreactivity under the ordinary conditions of electrophilic substitution for aza-aromatic N-oxides. In all probability this effect stems from the relatively great stability of the conjugate acid of I and the consequence that the concentration of free unprotonated I, a much (6) G. F. Smith and F. W. Cagle, {bid., 19, 781 (1947). (7) Nitro groups para to an N-oxide function are known to induce facile nucleophilic displacement. See H. J. den Hertog and W. P. Comb& Rec. /Tau. chim., 70, 581 (1951). (8) H. R. Snyder and H. E. Freier, J . A m . Chem. Soc., 68, 1320 (1946). (9) C. J. Hawkins. H. Dueaell, and W. F. Pickering, A n d . Chim. Acta. S I , 257 (1961).

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NOTES

more reactive species in electrophilic substitution, must be exceedingly small under the usual conditions of electrophilic substitution. The relative stability of the protonated form of 1,lo-phenanthroline 1-oxide, which is probably due to hydrogen bonding as shown in VI1 and recent paperslOlll

with a type GK 2026C electrode. Duplicate titration of a 0.0185 M solution of N-oxide with 0.1 N HCl gave a pK, value of 6.63 f 0.02 a t 22'. No correction for ionic strength was made. Determination of the ultraviolet and visible spectra in aqueous solution gave Amax 264, 309, 322 (sh), and 365 mp (log e 4.42, 3.68, 3.59, and 3.28, respectively). Transition Metal Complexes of 1,lO-Phenanthroline 1-Oxide. A. Bis-1 ,lo-phenanthroline 1-Oxide Copper(I1) Chloride Dihydrate.-To a solution of 80 mg. (0.408 mmole) of 1,lO-phenanthroline 1-oxide in 10 MI. of 95% ethanol was added a solution of 27.5 mg. (0.205 mmole) of cupric chloride in 5 ml. of ethanol. The mixture was allowed to stand a few hours and then filtered. The collected material was dried in vacuo a t 60' to yield 77 mg. (66.5%) of green solid. Anal. Calcd. for (CIZHIIN;~O)Z.CUC~~.~HZO: C, 51.21; H , 3.58; N,9.95. Found: C, 51.01; H,3.78; N,9.94. B . Bis-1 ,lo-phenanthroline 1-Oxide Nickel(I1) Chloride Hemihydrate.-To a solution of 500 mg. (2.55 mmoles) of 1,lOphenanthroline 1-oxide in 12 ml. of ethanol was added 294 mg. (1.23 mmoles) of NiClZ.6H20dissolved in 20 ml. of ethanol. The solution was warmed slightly on the steam bath and allowed to stand a few hours. The yellowish orange solid was collected by suction filtration and dried in vacuo a t 60" to give 585 mg. (89%) of material. Anal. Calcd. for ( C I ~ H E N Z ~ ) Z . N ~ C ~ C,Z 54.41; . ~ . ~ H, HZO: 3.23; N, 10.55. Found: C, 54.80; H,3.52; N , 10.30. C. Bis-1,lO-phenanthroline 1-Oxide Cobalt(I1) Chloride.To a solution of 500 mg. (2.55 mmoles) of 1,lO-phenanthroline 1-oxide in 65 ml. of ethanol was added 312 mg. (1.32 mmoles) of CoCl2.6HZOdissolved in 30 ml. of ethanol. The solution waa warmed on the steam bath and allowed to stand for a few hours. The orange solid was collected by suction filtration and dried in vacuo a t 60" to give 575 mg. (85y0)of material. Anal. Calcd. for ( C I Z H E N ~ O ) ~ . C OC, C I ~55.38; : H , 3.08; N, 10.75. Found: C, 55.43; H,3.33; N, 10.74. These complexes were- water soluble. Their ultraviolet and visible spectra in aqueous solution gave absorption maxima and extinction coefficients identical with 1,IO-phenanthroline 1-oxide provided complete dissociation to the N-oxide and metal ions was assumed. Complexes giving the same spectra and comparable analyses also were obtained when the N-oxide to metal chloride mixing ratio was 6: 1. 2-Cyano-1 ,IO-phenanthro1ine.-A solution consisting of 2.98 g. (0.0148 mole) of 1,lO-phenanthroline 1-oxide and 3.0 g. of potassium cyanide dissolved in 50 ml. of water was stirred magnetically while 3.0 ml. of benzoyl chloride was added dropwise. The total addition required 15 min. and the reaction was stirred for an additional 15 min. The precipitated solid wati collected by suction filtration, washed with water, and dried. Crystallization from ethanol afforded 2.15 g. (71yc) of light tan needles, m.p. 233-234'. Further recrystallization from ethanol raised the melting point to 237-238". Anal. Calcd. for C I S H ~ N C, ~ : 76.07; H , 3.44; N, 20.48. Found: C,75.81; H,3.65; N,20.34. 2-Carboxy-l,lO-phenanthroline.-To a solution of 1.O g. (0.0049 mole) of 2-cyano-l,l0-phenanthrolinein 10 ml. of 95Tc ethanol was added a solution of 0.8 g. of sodium hydroxide in 5 ml. of water and the mixture was refluxed for 2 hr. (evolution of ammonia ceased). The solution was cooled to room temperature and made slightly acidic with concentrated hydrochloric acid. The solvent was removed in vacuo. The residue was heated in 10 ml. of water on the steam bath and filtered. The light tan product was crystallized from ethanol to yield 0.87 g. (76y0) of white solid, m.p. 209-210' dec. The compound hydrates readily and attempts to dry it completely were unsuccessful. Anal. Calcd. for C I S H ~ N ~ O ~ . ~ . C, ~ ~ 63.28; H Z O : H , 4.29; N, 11.35. Found: C,63.24; H,4.32; N, 11.26. A picrate was prepared and recrystallized from aqueous methanol. Analysis indicates that the picrate is formed by combination of 2 moles of carboxylic acid and 1 mole of picric acid. The picrate melts a t 230-231 dec. Anal. Calcd. for (C,,H,NZO2),C,HSN3Oi:C, 56.72; H , 2.83; N;14.47. Found: C, 57.07; H , 2.92; N, 14.13. 4-Nitro-1,lO-phenanthroline1-Oxide.-To a solution of 2.0 g. (0.0102 mole) of l,l0-phenanthroline 1-oxide in 10 ml. of concentrated sulfuric acid (sp. gr. 1.84) was added 1.1 g . of potassium nitrate and the mixture was heated on the steam bath for 1 hr. An additional 1.1 g. of potassium nitrate was added and the

6

+

w on the preparation and characterization of several complexes containing pyridine 1-oxide as a ligand, suggested that 1,lo-phenanthroline 1-oxide might function as a chelate with oxygen and nitrogen serving as coordination sites. Solid complexes of 1,lo-phenanthroline with copper, nickel, and cobalt chlorides were prepared by mixing ethanolic solutions of the S-oxide and the metal chloride. The ligand to metal ratio was varied from 2 : 1 to 6 : 1 but in each case the same complex precipitated from solution and analysis indicated a ligand metal ratio of 2 : 1 corresponding to the general formula C12HBK:20:2MC12. nHzO. These complexes were not unusually stable and like the pyridine N-oxide complexes they dissociated in water and regenerated the N-oxide and metal ions; the ultraviolet and visible spectra of aqueous solutions of the complexes gave absorption maxima and extinction coefficients identical in all respects with that determined for the pure N-oxide. Experimental'2 1,lO-Fjhenanthroline 1-Oxide.-To a solution of 10.0 g. (0.0505 mole) of 1,lO-phenanthroline monohydrate in 60 ml. of glacial acetic acid was added 6.0 ml. of 30% hydrogen peroxide. The temperature of the solution was maintained a t 70-75' for 3 hr. after which an additional 6.0 ml. of hydrogen peroxide was added and the heating continued for 3 hr. The solution was concentrated to a volume of approximately 15 ml. using a rotary evaporator; 15 ml. of water was added and the concentration was continued to a volume of approximately 10 ml. The mixture was neutralized with a sodium carbonatewater paste. The solid mass was extracted repeatedly with several portions of chloroform and the extracts were evaporated. The resulting residue was dried in an oven a t 50', ground to a fine powder, and reextracted with chloroform. The combined chloroform extracts were dried over sodium sulfate, boiled with decolorizing charcoal, and evaporated to give 7-8 g . (7C-807c) of 1,lO-phenanthroline 1oxide, m.p. 176-179'. Crystallization from chlorobenzene gave fine pale yellow needles, m.p. 180-181'. The compound had been prepared previously by Maerker and Case' in 23.6% yield (crude product). These workers report m.p. 179-180' for the pure compound. The picrate of 1,lo-phenanthroline 1-oxide waa prepared by the addition of a saturated aqueous solution of picric acid to an aqueous solution of the N-oxide. The picrate melts at 201-203" after recrystallization from ethanol. The pK. of 1,lO-phenanthroline 1-oxide waa determined by potentiometric titration using a Radiometer p H meter equipped (10) J. V. Quagliano, J. Fujita, G . Frana, D . J. Phillips, J. A. Walmsley, and S. Y. Tyree, J . Am. Chem. Soc., 88, 3770 (1961). (11) R. L. Carlin. ibid.. 88, 3773 (1961). (12) Melting points were determined with a capillary melting point apparaturr and are uncorrected. Infrared spectra were obtained with a PerkinElmer Infracord by the potaesium bromide pellet method. Analyses were by Pascher Microanalytical Laboratory, Bonn, Germany, by Alfred Bernhardt Microanalytical Laboratory, Miilheim, Germany, and by Scandinavian Microanalytical Laboratory, Copenhagen, Denmark. 1,lO-Phenanthroline wae obtained from Aldrich Chemical Co., Milwaukee, Wis. Ultraviolet and visible spectra were with a Bausch and Lomb Spectronic 505.

289

O

290

NOTES

heating continued for 1 hr. The mixture was poured into 25 g. of ice and neutralized with solid sodium carbonate. The solution was extracted with chloroform. The chloroform extracts were dried and the chloroform was removed by evaporation. The residue weighed 1.5 g. The residue was stirred with 20 ml. of water, filtered, and dissolved in dilute sulfuric acid. Neutralization with ammonium hydroxide gave a yellow solid which was collected by suction filtration and dried. Crystallization from a chloroform-ether mixture gave 0.24 g. (10%) of material, m.p. 160" dec. Anal. Calcd. for Cl2H,X3O3:C, 59.74; H , 2.93; N, 17.42. Found: C,59.70; H,2.99; N, 17.28. The ammoniacal filtrate from the above reaction was evaporated to dryness. The residue was extracted with chloroform. Removal of the chloroform and examination of the infrared spectrum of the residue indicated that it was mainly unchanged 1,lOphenanthroline 1-oxide. When the nitration was carried out a t 11G115" a 10% yield of 4-nitro-1,lO-phenanthroline1-oxide was again obtained. 4-Chloro-1,lo-phenanthroline 1-Oxide.-A solution of 150 mg. (0.625 mmole) of 4-nitro-1,lO-phenanthroline1-oxide in 10 ml. of 50y0 hydrochloric acid was refluxed for 18 hr. The mixture was cooled, neutralized with solid sodium carbonate, and repeatedly extracted with chloroform. The chloroform extracts were dried over sodium sulfate and the solvent was removed. The yield of pale yellow solid was 100 mg. (69.5%). Recrystallization from benzene furnished the analytical sample, m.p. 139-141'. The compound gave a positive test for chlorine. Anal. Calcd. for C,zH,C1N20: C, 62.42; H , 3.03; N, 12.12. Found: C, 62.30; H , 3.24; N, 12.11. 4-Chloro-l,lO-phenanthroline.-To a solution of 0.5 g. (2.07 mmoles) of 4-nitro-1 ,IO-phenanthroline 1-oxide in 15 ml. of chloroform was added dropwise a solution of freshly distilled phosphorus trichloride in 5 ml. of chloroform. A precipitate formed which dissolved upon heating. The reaction mixture was refluxed for 2 hr. The solution was cooled, poured onto crushed ice, and treated with solid sodium carbonate. The chloroorm was separated and the aqueous layer was extracted with several portions of chloroform. The chloroform extracts were dried and the chloroform was evaporated. The pinkish solid that remained proved t o be an acid salt. The salt was dissolved in water and neutralized with ammonium hydroxide; the resulting solution was extracted with chloroform. Drying and removal of the solvent furnished 0.283 g. (63.5%) of white solid, m.p. 159-162". Recrystallization from benzene raised the melting point to 163-165'. Because of the hygroscopic nature of the compound it was converted to a picrate for analytical purposes. The picrate gave a positive test for chloride. Anal. Calcd. for C18H1&1N507: C, 48.71; H, 2.27; N, 15.78. Found: C,48.65; H , 2.42; N, 15.69. Nitration and Degradation of 1,lO-Phenanthroline in NitricSulfuric Acid.--To 5 ml. of concentrated sulfuric acid (sp. gr. 1.84) was added, with cooling, 2.35 g. (0.012 mole) of 1,lO-phenanthroline 1-oxide. The mixture was heated on an oil bath to 85-90" during the addition of 1.75 g. of concentrated nitric acid (Spectrograde 1.42). The addition required 40 min.; the reaction was maintained a t 85-90' for an additional 3.5 hr. After 2.5 hr. an orange solid began to precipitate from solution. The mixture was cooled and poured onto 45 g. of ice. Neutralization with sodium carbonate followed by filtration gave 0.6 g. of an orange solid. The compound was extremely insoluble in most organic solvents, but could be crystallized from aqueous dimethylformamide. The crystallized material melted a t 210-215" dec. and shoaed infrared bands a t 3500 (OH?), 1710 (C=O?), 1550 (NOz?), and 1360 em.-' (XOz). The compound was insoluble in mineral acids and only sparingly soluble in base. Anal. Found: C, 54.37; H , 2.70; N, 16.87. The aqueous filtrate from the above reaction was extracted with chloroform. Removal of the chloroform by evaporation gave 0.1 g. of 4-nitro-1,lO-phenanthroline1-oxide, identified by melting point and infrared spectrum.

Acknowledgment.-This work was supported in part by the National Science Foundation (G14473) and a Drexel Institute of Technology Faculty Research Grant.

VOL. 30 Addition Reactions of Substituted 1,4-Cyclohexadienes. I.

3,3,6,6-Tetramethyl-l,4-~yclohexadiene'~ F. W. GRANT,^^ R. W. GLEASON, AND C. H. BUSHWELLER

Departments of Chemistry, Hamilton College, Clinton, New York, and Middlebury College, Middlebury, Vermont Received September 8,1964

Bicyclo [2.2.1Iheptadiene and bicyclo [2.2.2]octadiene are known to undergo a variety of 1,5-honioconjugate addition reactions2 Recognizing the unique disposition of the double bonds in these conipounds and the spectral evidence demonstrating interaction between them,4 it was, nonetheless, of interest to determine whether homoconjugate addition might be induced in the related 1,4-cyclohexadiene (I) or its derivatives. Double-bond interaction in I has been inferred from its ultraviolet absorption ~ p e c t r u m . ~An unsuccessful attempt in this direction was reported by van Tamelen5 who reinvestigated the controlled Prevost addition of iodine and silver benzoate to I6 and confirmed that the major product was correctly described as the 1,2addition product, cyclohexene 4,5-dibenzoate. He extended this work to include the controlled bromination of I which resulted in 4,5-dibromocyclohexene. No trace of a homoconjugate addition product was noted in either case. Earlier reports pertinent to this problem have described the halogenation of l-methyl-,' 1,2-dimeth~l-,~ 1,2-dichlor0-,~and perfluoro-l,4-~yclohexadiene'~ but in none of these cases were homoconjugate addition products isolated, although this possibility may not have been fully explored in the analysis of minor products.

V,R=H VI, R = COCH3

VI1

Our interest has been in derivatives of I substituted at the 3- and 6-positions where bulky cis and equatorially oriented groups might be expected to favor (1) (a) Taken in part from the Master's Thesis of C. H. B., Middlebury College, 1963. (b) Department of chemistry, Hamilton College, Clinton, N. Y. (2) A 8ummary of pertinent publications is found in ref. 3 and should include the work of A . Gagneux and C. A. Grob, Helu. Chim. Acta, 42, 1753; 2008 (1959). (3) W. Reusch, M. Russell, and C. Dzurella, J . Orp. Chem., 29, 2448 (1964). (4) C. F. Wilcox, Jr., S. Winstein. and W. McMillan, J . A m . Chem. Soc.. 81,5450 (1980). (5) E. E. van Tamelen, J . A m . Chem. SOC.,7 1 , 1704 (1955). (8) G. E.McCasland and E. C. Horswill, ibid., 76, 1654 (1954). (7) F. A. Haak and J. B. Wibaut, Rec. trau. cham., 69,1382 (1950). (8) W. Hltckel and U. Worffel, Chem. Ber., 88, 338 (1955). (9) R. Riemschneider, Monaleh., 86, 101 (1955). (10) D. E. Evans and J. C. Taylor, J . Chem. Soc., 3779 (1954).

JANUARY1965

NOTES

291

carbon), a broad singlet a t 5.63 (ring hydrogen at the maximum "folding" of the ring system and, therefore, iodine substituted carbon), and a complex series of a high probability of interaction between double bands at 7.6-8.7 (remaining hydrogens). The relative bonds. The synthesis and properties of compounds peak intensities of these four sets of hydrogens were of this type will be the subject of a future communifound to be 4.8 : 1.0 : 1.0 :6.2, respectively. The evication. dence is consistent with that expected of the homoconGeminal substitution at the 3- and 6-positions of I jugate addition product (IV). should have an inhibitory effect on the "folding" Our synthesis of I1 was carried out prior to the of the ring system and it appears from an examination published account of Reusch, et u Z . , ~ and, while following of models that the compound which forms the subject of this paper, 3,3,6,6-tetramethyl-l,4-~yclohexadiene the same general lines, differs sufficiently in detail and result to warrant inclusion in the Experimental section. (11),is very nearly planar in this respect. No evidence These authors obtained a 10% yield of a 10: 1 mixture of r-system interaction has been noted in its ultraviolet of I1 and p-xylene as products of the pyrolysis of the spectrum. a trans diacetate (VI) a t 350'. Upon increasing the We have found that Prevost addition of iodine and temperature to 410°, p-xylene was obtained in 90% silver benzoate to I1 proceeds by 1,Zaddition to yield 4-iodo-3,3,6,6-tetramethylcyclohexene 5-benzoate (111) yield as the only identified product. In our hands, in 68% yield with no evidence of a homoconjugate the pyrolysis of a 1:l mixture of the cis and trans addition product. Presumably because of steric diacetates (VI) at 520 f 5' resulted in the formation factors, I11 failed to react further with silver benzoate of I1 (25%), VI1 (23%), p-xylene (373, and the reto form the 4,5-dibenzoate. The structure of I11 was covery of 10% VI. Titration of the crude pyrolysis confirmed by elemental analysis and from infrared product indicated a 63% yield of acetic acid. The and n.m.r. spectral considerations. A strong band a t repyrolysis of VI1 under the same conditions resulted in 764 cm.-' has been attributed to vinyl hydrogen in a 41% yield of 11. the infrared spectrum of 113and we believe this to be The structure of I1 was confirmed by catalytic reassociated with a weaker absorption at 796 cm.-l. l5 by formaduction to 1,1,4,4-tetramethylcyclohexane, Both of these bands are present but attenuated in tion of a tetrabromide (n.m.r.l6: methyl hydrogens a t 111. Olefinic unsaturation was also evident in abT 8.43 and ring hydrogens at 5.29 in the ratio 3.0: 1.0, sorptions a t 1650 and 3017 cm.-'. Conventional tests respectively), and from its n.m.r. spectrumlB (methyl for unsaturation such as bromination or oxidation with hydrogens a t r 8.96 and vinyl hydrogens at 4.60 permanganate required sufficiently vigorous conditions in the ratio 3.0: 1.0, respectively). The latter result to be ambiguous. These observations parallel those confirms an earlier finding.3 of McCasland and Horswil16on the addition reactions of The failure of I and several derivatives to react with cyclohexene 4,5-dibenzoate. The n.m.r. spectrum of maleic anhydridels,17 tetracyanoethylene,18 and azo111" in deuteriochloroform contained a complex dicarboxylic ester19n20 in the Diels-Alder sense is paralmultiplet a t r 1.7-2.6 (phenyl hydrogens), a set of three leled in the lack of reactivity of the first two dieneopeaks at 8.72, 8.85, and 8.90 (ratio: 1.0:1.0:2.0, philes and ethyl acetylene dicarboxylate with I1 under methyl hydrogens), and seven peaks near 5 (ring a wide variety of Diels-Alder conditions. hydrogens). The relative weights of these three sets of hydrogens were 5.0: 12.2:3.8, respectively. The Experimental21 seven peaks near r 5 constituted two AB quadruplets 2,2,5,5-Tetramethylcyclohexane-l,3-diol(V) .-This material with one accidental superposition. The second, third, was prepared by the lithium aluminum hydride reduction of 60.0 fourth, and fifth peaks from the low-field side were g. of dimethyldimedon.22 The cis diol (13.6 g., 22%, m.p. 201assigned to the vinyl protons a t C-1 and C-2 ( r 4.68 203", lit.2220.5-206") and trans diol (29.3 g., 47%, m.p. 105107', lit.22107-108") were separated by fractional crystallization and 4.54, J = 10 c.P.s.) and the first, third, sixth, and from chloroform. seventh are assigned to the C-4 and C-5 protons ( r 2,2,5,5-Tetramethylcyclohexane 1,3-Diacetate (VI).-To a 4.48and5.44, J = 12c.p.s.9. stirred solution of 20.2 g. of the cis diol in 250 ml. of dry ether To our knowledge, the Prevost reaction has not containing 48 ml. of pyridine waa added 20.0 g. of acetyl chloride previously been employed in a homoconjugate addidropwise. After refluxing for 3 hr. the cooled reaction mixture waa poured into 1 1. of ice-water containing 48 ml. of acetic acid. tion reaction13and it was, therefore, of interest to estabThe ether layer was separated, washed with 10% aqueous acetic lish that the reaction of iodine, silver benzoate, and acid, water, 1% aqueous sodium carbonate, and water and dried bicyclo [2.2.1Iheptadiene proceeded in this sense. A over sodium sulfate. Evaporation left a residue which waa single crystalline product was isolated in 37% yield and crystallized from ligroin ( 3 5 4 0 " ) to give 23.4 g. (78%) of the its structure was inferred from its elemental analysis cis diacetate, m.p. 84-86', lit.2283.5-84.5'. Using an identical procedure, 38.9 g. of trans diol was converted to 41.0 g. (70%) of and n.m.r. spectrum.ll The latter showed no vinyl trans diacetate, m.p. 63-66", lit.2264-66'. hydrogen peak such as appears in the spectrum of 3,3,6,6-Tetramethyl-1,4-cyclohexadiene(11).-Approximately bicyclo[2.2.l]heptene at 7 4.06.14 The spectrum consisted of a complex multiplet a t T 1.9-2.8 (phenyl (15) G. Chiurdoglu and A. Maquestiau. Bull. soc. chim. Belges, 68, 357 hydrogens), an unsymmetrical triplet at 5.14 (J = (1 954). 2 c.P.s.) (ring hydrogen at the benzoxy-substituted (16) We are indebted to Professor W. R . Moore of the Massachusetts (11) We are indebted to Professor E. H. White of the Johns Hopkins Yniversity for this spectrum and its interpretation. (12) We have been unable to find a precedent for this unusually large coupling constant in a related environment. (13) A general review of the Prevost and related reactions is given by C. V. Wilson. [email protected], 9, 339 (1957). (14) G. V. D. Tiers, "N. M . R. Summary," Central Research Department, Minnesota Mining and Manufacturing Company, St. Paul, Minn.

Institute of Technology for this spectrum. (17) R. Riemschneider, Z. Naturforsch., bb, 48 (1951). (18) D . T. Longone and G. L. Smith, Tetrahedron Letters, 205 (1962). (19) B. Fransus and J. H. Surridge, J . Org. Chem., 9 1 , 1951 (1962). (20) B . Fransus, ibid., 98, 2954 (1963). (21) All melting points and boiling points are uncorrected. Microanalyses were performed by Galbraith Laboratories, Knoxville, Tenn., or C. F. Geiger. Ontario, Calif. (22) A. Allen, R . Sneeden, and J. Colvin, J . Chem. Soc.. 557 (1958).

292

VOL. 30

NOTES

equal weights of the cis and trans diacetates (VI, 41 g.) were pyrolyzed a t 520 + 5" by the procedure of Bailey and Kingsas Premelted VI was added with dry nitrogen (4 ml./min.) a t the rate of 0.2-0.3 g./min. to the reaction chamber which consisted of a 14 X 310 mm. Vycor tube packed with allwin. Pyrex helices. By titration of the crude pyrolysate with base, 0.20 mole (63%) of acetic acid waa estimated. The pyrolysate was taken up in ether, washed repeatedly with 1% aqueous sodium carbonate, dried over sodium sulfate, and evaporated to a residue which was fractionally distilled to yield 6.0 g. (287,) of crude 11, b.p. 130-134" (750 mm.). Fractional vacuum distillation of the residue resulting from the above distillation resulted in the recovery of 4.2 g. (10%) of VI, b.p. 130-138" (6-7 mm.), and 7.0g. (23%) of a pale yellow liquid, b.p. 88.5-95.0' (6-7 mm.), which was unsaturated to bromine in carbon tetrachloride and had an infrared spectrum consistent with its formulation as 3,3,6,6-tetramethylcyclohexene 4-acetate (peaks a t 1740 and 1030 cm.-l). Repyrolysis of 5.3 g. of this acetate resulted in 1.5 g. (41%) of 11. p-Xylene was detected as an impurity in crude I1 by gas-liquid chromatography and comparison of its infrared spectrum with that of an authentic sample. The gas chromatographic peak area ratio of I1 to p-xylene waa found to be 10: 1. An analytical sample of I1 was obtained by gas-liquid chromatography over a 7-ft. column of 30yc silicone oil 550 on base-washed Chromosorb P, b.p. 132-133" (750 mm.), 12% 1.4367. Anal. Calcd. for C10H16: C, 88.16; H , 11.84. Found: C, 88.31; H , 11.68. Bromination of I1 in carbon tetrachloride for 45 min. a t 27" resulted in a tetrabromide which was crystallized from ethanol t o m.p. 69.0-69.5". Anal. Calcd. for C1oHl6Br4: C, 26.35; H , 3.54; Br, 70.12. Found: C,26.41; H , 3.76; Br, 69.99. Catalytic hydrogenation of I1 with Adams catalyst in glacial acetic acid resulted in the absorption of 99.2% of the theoretical volume of hydrogen. 1,1,4,4-Tetramethylcyclohexanewaa isolated and purified by fractional distillation, b.p. 146-148" (750 mm.), n% 1.4237, d25 0.7747; lit.15 b.p. 152.6-153.3", n% 1.4258, dzo 0.7754. 4-Iodo-3,3,6,6-tetraethylcyclohexene5-Benzoate (III).-A solution of 2.5 g. of iodine in 20 ml. of dry benzene was added in portions with shaking to 2.3 g. of freshly prepared dry powdered silver benzoate.*' To this solution was added, all a t once, 1.5 g. of 11. After 1 hr. at reflux the solution was cooled and filtered; the filtrate waa washed with water, 10% sodium bisulfite solution, 107, sodium carbonate solution, and water. After drying over sodium sulfate the solution was evaporated to a clear sirup which crystallized from methanol to yield 2.60 g. (68% bssed on iodine) of a white crystalline product, m.p. 78-81'. Repeated recrystallization from ligroin (35-60") raised t,his to m.p. 80.581.5'. Anal. Calcd. for CllH21102: C, 53.17; H , 5.51; I , 33.03; mol. wt. ( h a t ) , 384. Found: C, 53.14; H, 5.48; I , 33.16; mol. wt. (Fiast), 374. This substance failed to decolorize warm (50") solutions of 370 bromine in carbon tetrachloride, bromine water, or 1yopotassium permanganate in acetone over 5-min. periods relative to blank reagents. I t also failed to react with a threefold excess of silver benzoate in refluxing dry benzene over an 85-hr. period. 3-Iodotricyclo12.2.1 . O Z 4heptane 5-Benzoate (IV).--The reaction was carried out as described above using 3.0 g. of dry powdered silver benzoate, 3.3 g. of iodine, and 4.6 g. of freshly distilled bicyclo[2.2.l]heptadiene,b.p. 89" (753 mm.). Crystallization of the clear, sirupy product from methanol and then ligroin (35-60") resulted in 1.25 g. (37% based on iodine) of a white crystalline product, m.p. 65-68'. Repeated recrystallization from ligroin raised the melting point to 67.549.0". Anal. Calcd. for C1,HlJOz: C, 49.45; H , 3.85; I , 37.33. Found: C, 49.54; H , 3.81; I , 37.11. Attempted Diels-Alder Reactions of I1.-Maleic anhydride tetracyanoethylene, and ethyl acetylene dicarboxylate were added to equal weights of I1 with and without solvent a t temperatures from 37 to 150' and for periods of 1-24 hr. Thin layer chromatography and infrared analysis failed to indicate adduction. (23) W.J. Bailey and C. King, J . Ore. Chem., 21, 858 (1956). (24) B. I. Halperin, H. B. Donahoe, J. Kleinberg, and C. A. Vanderwerf, J . Org. Chem., 17,623(1952).

Acknowledgment.-F. W. G. and C. H. B. gratefully acknowledge partial support from the Petroleum Research Fund of the American Chemical Society, Grant 528-B.

Alkylations of Ketone and Aldehyde Phenylhydrazones by Means of Alkali Amides in Liquid Ammonia to Form N-Alkyl Derivatives WILLIAMG. KENYON' A N D CHARLES R. HAUSER

Department of Chemistry, Duke University, Durham, North Carolina Received August do, 1964

Alkylations of benzaldehyde phenylhydrazone to form N-alkyl derivatives have previously been effected with alkyl halides by means of sodamide in benzene, but the details were not given.2 We have effected alkylations of this phenylhydrazone and of certain ketone phenylhydrazones (I) by means of sodamide or potassium amide in liquid ammonia to form the N-alkyl derivatives I1 (eq. 1, Table I). R C&

*

b-NNHCeH5 I

R 1. MNHm (lis. NH6) _______+

2. R'X

R'

CeH~b=NhiCaHa (1)

I1

Interestingly, the color of the intermediate anion of benzophenone phenylhydrazone was dark red, similar to that of the diphenylmethide ion. This suggests that resonance form I I I b makes some contribution to the structure of the anion, though the contribution of IIIa may be more important. (CsHs)zC=N--NCsHs IIIa

(CsHs)z&N=NCsHs IIIb

t )

That the products were the N-alkyl derivatives, not the possible C-alkyl derivatives, was supported by the essential agreement of their melting points with the reported values, analysis in certain cases, and by independent syntheses of the N-benzyl derivatives of benzaldehyde and benzophenone phenylhydrazones (eq. 2). R

b +

T6H6

CsHs 4 HtN CsHs +11 R = H or CSHS; R' = CsHaCH,

(2)

Table I shows that the alkylations of the phenylhydrazones I to form the N-alkyl derivatives I1 (eq. 1) were realized in good to excellent yields (69-92%). This method appears more convenient than that represented by eq. 2, which has been reported difficult to effect.2*aOnly the condensation of benzophenone with N-methylphenylhydrazine seems to have been realized previously in good yield (71%) and this required a (1) Union Carbide and Carbon Chemicals Co. Fellow, 1961-1963. (2) P. Grsmmaticakis, Compt. rend., 409, 994 (1939). (3) F.Bovini. Atli accod. nor. Lincei. M e n . C l a w Sci. pa. mat. e nat., Ser rr, ss,460 (1913).

NOTES

JANUARY1965

293

TABLE I ALKYLATIONS OF PHENYLHYDRAZONES I" TO FORM I1 1, R

IIR'X

M

R

M.p.,

R'

Yield, %

OC.

Found

H C6HICHzC1 Na H CeHbCHz 92'*' 109-110 CHa CeH,CHzCl K CHa CeH,CHz 69' 57-58 779 76-79 CsH, CHJ K CeH, CHa 93"~ K CEH, n-C4HeBr CEH, n-CaHeBr 52-54' CeH C&,CH,Cl Na CaH, CEH~CHZ 85* 108-109 CeH, CsHbCHzC1 K CeH, CEH,CH~ gob 108-109' a According to eq. 1. 90-min. reaction period. Combined yield from two crops. Ref. 2. 30-min. reaction Busch and K. Schmidt, J . prakt. Chem., 129, 151 (1931). 1-hr. reaction period. Ref. 4. 3-hr. reaction period. j for Cz3HZlN2: C, 84.10; H, 7.37; N, 8.53. Found: C, 84.03; H, 7.42; N, 8.66. Ref. 3. Anal. Calcd. for 86.15; H, 6.12; N, 7.73. Found: C,86.45; H,6.24; N,8.15.

'

2-day reaction period. The two condensations represented in eq. 2 were accomplished by us after a 20-hr. reaction period in yields of only 40 and 78%, respectively; these yields are appreciably lower than those obtained even after a much shorter reaction period according to eq. 1 (see Table I). Moreover, certain N-alkylphenylhydrazines are not readily available. Experimental' The benzaldehyde phenylhydrazone,O acetophenone phenylh y d r a ~ o n e ,and ~ benzophenone phenylhydrazones used in this study were prepared according to literature procedures and were recrystallized. The acetophenone phenylhydrazone should be freshly prepared. Alkylations of Phenylhydrazones 1.-To a stirred suspension of 0.025 mole of sodamidee in 500 ml. of commercial, anhydrous, liquid ammonia or to a stirred solution of 0.025-0.1 mole of potassium amide1° in 250-500 ml. of commercial, anhydrous, liquid ammonia was added 1 mole equiv. of finely ground phenylhydrazone I . The solutions of the resulting alkali salts (see Table I ) were colored brownish yellow, orange-tan, and blood red, respectively. After 10-15 min., 1 mole equiv. of the appropriate halide in 15-20 ml. of anhydrous ether was added; the color of the solution changed and a precipitate formed. After stirring for the appropriate length of time (see footnotes b, e , g, and i in Table I ) , a slight excess of 1 mol. equiv. of ammonium chloride was added. The ammonia was allowed to evaporate, and the residue was taken up in ether and water. The layers were separated. The ethereal layer was washed with saturated sodium chloride solution and combined with two ethereal extracts of the aqueous layer treated in the same manner. I n the experiment with methyl iodide the ethereal solution was also washed with saturated sodium bisulfate to remove any iodine that might have been formed. The ethereal solution was dried over anhydrous magnesium sulfate and the solvent was removed. The residues were recrystallized from ethanol. Condensations of N-Benzyl-N-phenylhydrazine Hydrochloride with Carbonyl Compounds to Form I1 (Eq. 2). A. With Benzaldehyde.-A solution of 1.06 g. (0.01 mole) of benzaldehyde and 2.35 g. (0.01 mole) of N-benzyl-N-phenylhydrazine hydrochloride in 5 ml. of pyridine and 45 ml. of ethanol was refluxed for 20 hr. according to a current method for the preparation of oximes.ll There was obtained 2.32 g. (78%) of benzaldehyde benzylphenylhydrazone, m.p. 106-108° after recrystallieation from ethanol. Upon admixture with the product melting at 109-110" obtained according to eq. 1, the melting point was 10&1G9°. The infrared spectra of the two samples were identical. (4) W. Schlenkand E. Bergmann, Ann., 469,315 (1928). (5) Analyses are b y Dr. Ing. Schoeller, Kronach. West Germany, and Galbraith Microanalytical Laboratories. Knoxville, Tenn. Melting points (Mel-Temp capillary melting point apparatus) are uncorrected. (6) K. A. Jensen and B. Bak, J . p r a k f . Chem., 161, 167 (1938). (7) R. L. Shriner. W. C. Ashley, and E. Welch, "Organic Syntheses," Coll. Vol. 111. John Wiley and Sons. Inc., New York, N. Y . , 1955, p. 725. (8) S. G. Cohen and C. H. Wang, J . A m . Chem. Soc.. 7 7 , 3628 (1955). (9) See C. R. Hauser, F. W. Swamer, and J. T. Adams. Oru. Reactions, 8, 122 (1954). (10) See R. 9.Yost and C. R. Hauser, J . A m . Chem. SOC.,69, 2325 (1947). (11) See A. Brodhag and C. R. Hauser, ibid.. 77, 3024 (1955).

Lit. l l l d

58' 81*

... 105-106k 105-106' period, f M. Anal. Calcd. Czaz2N2: C l

B. With Benzophenone.-The reaction involving 0.91 g. (0.005 mole) of benzophenone, 1.18 g. (0.005 mole) of N-benzylN-phenylhydrazine hydrochloride in 5 ml. of pyridine, and 45 ml. of ethanol, refluxed for 20 hr. ae described above, yielded 0.72 g. (40%) of benzophenone benaylphenylhydrazone, m.p. and m.m.p 106-108" after recrystallization from ethanol.

The Asinger Reaction with 1-Methyl-4-piperidone ROBERTE. LYLE,RICHARD M U N K AND , ~ LAURENCE LADD

Department of Chemistry, University of New Hampshire, Durham, New Hampshire Received September 8, 1964

The discovery that p- and 7-mercaptoamines provided some protection against ionizing radiation2 caused an interest in the synthesis of 3- and 4-mercaptopiperidines. The preparation of these compounds by nucleophilic displacements of halogen from 3- and 4-halopiperidines was complicated by the discovery that the former underwent rearrangement with ring contractiona while the latter underwent rupture of the ring' during solvolysis reactions. Using a gem-dithiol as intermediate, the synthesis of 1-met hyl-4-mercap topiperidine was accomplished,6but a similar route to 1-methyl-3-mercaptopiperidine was not successful. The formation of thiazolines by the Asinger reaction6OBaseemed to offer an alternate approach to these compounds from l-methyl-4piperidone, provided that the intermediate thiazoline could be hydrolyzed to give a derivative of l-methyl-3mercapto-4-piperidone. 1-Methyl-4-piperidone (1) gave a mildly exothermic reaction with sulfur and ammonia to form a compound having the properties expected for the thiazoline 2a. (1) On leave from the Pliva Pharmaceutical Co., 1962-1963. (2) Z. M. Bacq, A. Herve, J. Lecompte, P . Fischer, J. Blavier, G. Dechamps, H. LeBihan, and P. Praset, Arch. Intern. Phyeiol., 69, 442 (1951); D. G. Doherty and W. T. Burnett, Proc. SOC.E z p t . Biol. Med., 89, 312 (1955). (3) R . Fuson and C. Zirkle, J . A m . Chem. Soc., TO, 2760 (1948); J. Biel, L. G. Abood, W. K. Hoya, H. A. Leiser, P. A. Nuhfer, and E. F . Kluchesky, J . Oru. Chem., 46, 4096 (19131); E. G . Brain, F. P. Doyle, and M. D. Mehts, J . Chem. Soc., 622 (1961). (4) C. A. Grob. BUZZ. aoc. chim. (France), 1360 (1960); S. Archer, T. R . Lewis, and B. Zenitr. J . A m . Chem. SOC.,80, 958 (1958). (5) R . E. Lyle and H. Barrera, J . 070. Chem., 47, 641 (1962). (6) F. Asinger. el ol., Ann., 604, 37 (1957); 606, 67 (19E7): 610, 1 , 25, 33, 49 (1957); 619, 145, 169 (1958): 627, 195 (1959); 674, 103, 134, 156, 179 (1964). (6a) NOTEADDEDI N PROOF.-The Asinger reaction with 1-methyl-4-piperidone (1) has been reported by F . Aainger, W. Shiifer, and H . W. Beckeri ibid., 674, 57 (1964).

NOTES

294

The n.m.r. and infrared spectra eliminated other doublebond isomers from consideration. A dihydrochloride (2) was formed by treatment of 2a with anhydrous hydrogen chloride. The infrared spectrum of the salt 2 showed that salt formation had occurred with the two piperidine nitrogens and not with the thiazoline nitrogen. Because of the difficulty of introducing a positive charge on the thiazoline nitrogen, hydrolysis of the ring was difficult. A reaction time of 6 hr. under reflux with concentrated hydrochloric acid was required to cause rupture of the thiazoline ring. This hydrolysis gave 1 molar equiv. of 1-methyl-4-piperidone and the 1,4-dithiadiene 3. The n.m.r. spectrum of 3 showed a multiplet at 2.1-2.6 p.p.m. with a relative intensity of 8 corresponding to the “ethano” protons, a singlet a t 2.30 p.p.m. for the resonance of the NCHI, and a triplet (J = 2.5 c.P.s.) a t 2.96 p.p.m. for the methylene flanked by the nitrogen and a double bond. Splitting results from spin-spin interaction with the allylic methylene hydrogens.

2a 2, dihydrochloride

It was reasoned that reduction of the thiazoline 2 to the thiazolidine would permit hydrolysis of the ring to produce l-methyl-4-amino-3-mercaptopiperidineand 1methyl-4-piperidone (1). The successful reduction of thiamine chloride’ and numerous imines* with complex metal hydrides led to a study of these reductions with 2a. Sodium borohydride gave no reaction. Lithium aluminum hydride caused reduction of the double bond, but hydrogenolysis of the thiazolidine ring may have occurred in a manner similar to that described by Eliel and co-workersg to give 4. Since the product of this reaction was not purified the structure cannot be considered proven.

Experimental 1,6’-Dimethyl-2 ’,4’,5‘,6‘,7 ’,7a’-hexahydrospiro [piperidine4,2 ’-thiazolo[5,4-c]pyridine] Dihydrochloride (2).-A suspension

(7) G. F. Bovicino and D . J. Hennessy, J . Am. Chrm. SOC.,7 @ ,6325 (1957). (8) P. Ceratti and H. Schmid, Helu. Chim. Acta, 46, 1992 (1962); F. J. Evans, G . G . Lyle, J. Watkins, and R . E. Lyle, J . Org. Cham., 11, 1553 (1962). (9) E. L. Eliel. E. W. Della, and M. M. Rogic, ibid., 17,4712 (1962).

VOL. 30

of 6.0 g. of sulfur in 40.0 g. of 1-methyl-4-piperidone (1) was stirred and cooled with ice while ammonia gas was bubbled through the mixture. The temperature of the reaction was maintained between 40-50”. The introduction of ammonia was continued until the last traces of sulfur disappeared, usually about 2 hr. The excess ammonia was removed by reducing the pressure over the reaction mixture. The warm, viscous liquid was diluted with 200 ml. of 50% potassium carbonate solution, and the mixture was extracted with five 100-ml. portions of ether. The ether solution was dried over potassium carbonate, filtered, and treated with hydrogen chloride. -4 yellow precipitate of 1,6’-dimet,hyl[5,4-c]2’,4’,5’,6’,7‘,7a’- hexahydrospiro [piperidine-4,2’-thiazolo pyridine] dihydrochloride ( 2 ) formed immediately. The solid was removed by filtration, washed with ether, and dried under reduced pressure over calcium chloride to give 53.5 g. of 2 , m.p. 2OCk205’ dec. An analytical sample was prepared by recrystallization from a mixture of ethanol and isopropyl alcohol. The analytical sample melted a t 240-241’. Anal. Calcd. for Cl?H23C12N3S: C, 46.15, H , 7.37. Found: C, 46.01; H, 7.23. The base, 1,6’-dimethyl- 2’,4’,5’,6’,7’,7a’-hexahydrospiro[piperidine-4,2’-thiazolo[5,4-c]pyridine] (2a) was isolated by distillation of the reaction mixture from above, or waa formed in quantitative yield from the dihydrochloride 2 by neutralization with potassium carbonate solution. The base thus formed was purified by distillation under reduced pressure, and the fraction, b.p. 198-202’ a t 16 mm., was taken as 2a. That no structural change had occurred on conversion of the dihydrochloride to the base could be shown by treatment of the oil with hydrogen chioride and re-forming 2, the dihydrochloride, with a melting point of 240-242 ’. Anal. Calcd. for C12H21N3S:C, 60.25; H , 8.78; S, 13.39. Found: C, 60.30; H, 9.03; S, 13.40. Hydrolysis of 1,6’-Dimethyl-2 ’,4’,5’,6‘,7’,7a’-hexahydrospiro[piperidine4,2’-thiazol0[5,4-~]pyridine] Dihydrochloride (2).A mixture of 26.0 g. of 2 in 100 ml. of concentrated hydrochloric acid was heated under mild reflux for 6 hr. The excess hydrochloric acid was removed by distillation under reduced pressure and the residue was diluted with water. Potassium carbonate was added until a saturated solution was obtained, and, the mixture was extracted with ether. The ether solution was dried over potassium carbonate. Distillation of the ether solution gave approximately 1 molar equiv. of l-methyl-4-piperidone, identified by infrared spectrum, and an intractable residue. The eulfurcontaining product was isolated by saturating the dried ether extrart with hydrogen chloride and separating the salt which precipitated by filtration. After drying in a vacuum desiccator, the salt was dissolved in water, and the solution waa saturated with potassium carbonate. The oil which separated was taken up in ether. Evaporation of ether gave an oil which solidified on cooling overnight to give 6.3 g. (30y0 based on structure 3) of solid, m.p. 88-90’. Recrystallization of the solid from petroleum ether (b.p. 30-60’) gave an analytical sample, m.p. 9394O. dnal. Calcd. for CLZHlBNZS2: C, 56.65; H, 7.13. Found: C, 56.66; H , 7.41. Reduction of 2a with Lithium Aluminum Hydride.-To a stirred suspenaion of 5 g. of lithium aluminum hydride in tetrahydrofuran, was added 20 g. of 2a dropwise. The mixture was heated under reflux for 3 hr. and decomposed with water. The organic layer was separated and the inorganic precipitate was washed with tetrahydrofuran and ether. The organic layers were combined, dried, and concentrated by distillation. The residue was dissolved in ether, and the solution deposited a small amount of solid, m.p. 113-115”, on standing overnight. This solid gave positive nitroprusside and lead acetate tests for mercaptans. The infrared spectrum and elemental analyses led to the tentative assignment of structure of l-methyl-3-mercapto-4(1-methyl-4-piperidy1amino)piperidine(4). Anal. Calcd. for C12H21N3S: C, 59.27; H, 10.29. Found: C, 58.49; H , 10.23.

Acknowledgment.-The authors wish to express appreciation to the Medical Corps of the U. S. Army for partial support of the research with Contract DA49-193-MD-2034.

NOTES

JANUARY 1965

295

A New R o u t e t o A1~3*5('0)-Estratriene-3-thiol~ a n d Related Compounds RINALDO GARDIAND CESAREPEDRALI

Vister Research Laboratories, Casatenovo ( C o m ) ,Italy Received July 84, 1964

The availability of 19-norsteroids from 10-methyl steroids by the syntheses recently developed in several laboratories' prompted a reinvestigation of their conversion in ring A aromatic steroids. I n pursuing our studies on the aromatization of p,r-disubstituted 3keto-19-norsteroids , we have devised a simple route to IIa,R=O;R'=CBHsCHz 3-thioestrogens. b, R = 0; R ' = CH3CHz As previously r e p ~ r t e d ,19-nor-3-ketones ~,~ functionC,R = 0; R'= Dalized a t either C-5 and C-10 or C-5 and C-6 undergo d , R = K.-H o H ; R'=CsHsCHz. ready aromatization to phenolic steroid 3-ethers by treatment with acids in alcoholic solvents. The alkoxy e,R=O; R ' = H moieties of the ethers originate from the medium. It .H f, R = q O H : R ' = H could be reasonably assumed that the same reaction carried out in the presence of mercaptans would have given the corresponding sulfide^.^ A1~3~5(1D)-estratrien-17-one (IIa) with sodium in liquid Actually, 5~,lO~-oxido-19-norandrostane-3,17-dioneammonia gave rise to a thiol promptly recognized as (Ia), 3 refluxed in acetone with thiobenzyl alcohol and 3-mer~apto-A~~~~~(~~)-estratrien-l7-one (3-thioestrone) hydrochloric acid, gave 3-ben~ylmercapto-A'*~~~(~~)(IIe) by its typical ultraviolet and infrared absorptions. estratrien-17-one (IIa) in good yield. The product A more prolonged treatment of IIa, as well as the rewas easily identified by its elemental analysis, infrared ductive cleavage of benzyl thio ether IId, yielded 3spectrum, and ultraviolet spectrum which had a thioestradiol (IIf). The latter, also obtained by maximum a t 258 mp characteristic of an aromatic NaBH4 reduction of IIe, was characterized as the disulfide.6 Finally, desulfurization of I I a with Raney sulfide, which proved to be identical with the product nickel afforded A 5 ( l0)-estra trien- 17-one (111). Sulreported by Hecker. fide IIa was also obtained in a quite similar manner from 5 CY,6a-oxido- 19-norandrostane-3 ,17-dione biscyExperimentall] cloethylene ketal (IV).8 3-Benzylmercapto-A1~~~s~10~-estratrien-17-one (IIa). A.-A Treatment of Ia with ethylmercaptan or cyclopentylsolution of 500 mg. of 5@,10@-oxido-19-norandrostane-3,17-dione mercaptan in the presence of hydrochloric acid yielded (Ia), in a mixture of 10 ml. of acetone and 4 ml. of benzyl mercaptan was treated with 2 drops of concentrated hydrochloric ethylsulfide I I b or cyclopentylsulfide IIc, respectively, acid and refluxed for 1 hr. The mixture was then cooled and the as expected. acetone was removed under vacuum. The oily residue was Likewise, acid-catalyzed aromatization of 5&10/3treated with 50 ml. of 1 N sodium hydroxide and the mixture was oxido-19-norandrostan-l7~-ol-3-one (Ib)9 in acetoneextracted with ether. The ethereal extracts were washed with water and dried, and the solvent was removed to give a residue, benzyl mercaptan gave 3-benzylmer~apto-A'~~*~(~~)which was chromatographed on alumina. Elution with ether estratrien-170-01 (IId), which was also prepared by afforded 425 mg. of 3-benzylmer~spto-A~J~~~~o)-estratrien-l7-one NaBH4reduction of IIa. (Ha), m.p. 125-127", which on recrystallization from methanol Benzyl sulfides IIa and IId appeared to be suitable 258 mp (6 melted a t 131-132': [ a ] D +117O (CHCI,);; : A intermediates for the preparation of free A193.5(1'J)- 8700); v:::' 1733, 1590, 1558, 1498 (shoulder), 1258, 1050, 808, 770, 715, and 691 c m . 3 . estratriene-3-thiols. Easy debenzylation of benzyl Anal. Calcd. for C26H280S: C, 79.74; H , 7.49; S, 8.52. thioethers is well known, hydrogenolysis by metals Found: C, 79.63; H , 7.46;S, 8.62. in liquid ammonia being the procedure of choice. '0 B.-5a,6aY-Oxido-19-norandrostane-3,17-dionebiscycloethylAccordingly, brief treatment of 3-benzylmercaptoene ketal (IV)8(500 mg.), treated with benzyl mercaptan accord1v

!

(1) (a) R. Gardi and C. Pedrali, Qazz. chim. ital, 91, 129 (1961); 98, 614 (1963); (b) M. Akhtar and D. H. R. Barton, J. A m . Chem. Soc., 84, 1496 (1962); (0) A. Bowers, R. Villotti, J. A. Edwards, E. Denot, and 0. Halpern, ibzd., 84, 3204 (1962); (d) K. Heusler, J. Kalvoda, C. Meystre, H. Ueberwasser, P. Wieland, G. Anner, and A. Wettstein,, Etpsrientia, 18, 464 (1962). (2) Preparation of 3-thioestradiol from the Corresponding 3-amine has been recently described by E. Hecker. Ber., 96,977 (1962). (3) R. Gardi. C. Pedrali, and A. Ercoli, Gam. chim. %tal.,98, 1503 (1963). (4) R. Gardi and C. Pedrali, Stemzde, 0 , 387 (1963). (5) This was supported also by a consideration on the reaction mechanism, which very likely involves. as key steps, alcohol addition to protonated ketone and subsequent water removal.8 (6) Cf.E. A. Fehnel and M. Carmack. J . A m . Chem. Soc.. 71, 84 (1949). (7) E. Caapi, E. Cullen, and P. K. Grover, J. Chem. SOC.,212 (1963). (8) R. Gardi, C. Pedrali, and A. Ercoli, G a m chim. ztal., 98, 525 (1963). (9) J. P. Ruelas, J. i r i a r t e , F. Kincl, and C. Djerassi, J . Org. Chem., 08, 1744 (1958).

ing to the above procedure, yielded 360 mg. of IIa: m.p. 130131", [ a ] D +117O (CHC13),.Az:H and Y:::' as reported above. By reaction of 5~,10@-oxido-19-norandrostane-3,17-dione (Ia) with ethyl mercaptan and with cyclopentyl mercaptan, carried out according to the above described procedure, the following compounds were prepared. 3-Ethylmer~apto-A~~~~~~~o)-estratrien-l7-one (IIb) had m.p. 93-94'; [ a ]+146" ~ (CHCI,);" : :A 258 mp (€8800); 1736, 1593, 1556, 1498 (shoulder) 1256, 1049, 821, and 776 cm.-'.

v:::'

(10) Cf.R. H. Sifferd and V. du Vigneaud, J. Bioi. Chem.. 108, 753 (1935); J. Baddilly and E. M. Thain, J . Chem. Soc., 800 (1952); e/. also Biochem. Prep., I , 93 (1957). (11) Melting points are uncorrected. The ultraviolet spectra were determined on an Optica CFI spectrophotometer and the infrared spectra on a Perkin-Elmer Model 21 instrument. We are indebted t o Dr. Sergio Cairoli for the microanalyses.

296

NOTES

VOL. 30

Anal. Calcd. for CzaHz80S: C, 76.38; H, 8.33; S, 10.20. 107.5"'a; [ a ] ~ +78" (dioxane); 214 mp (e 22,000), 242 Found: C, 76.55; H , 8.38; S, 10.35. NaoH 265 mp (e 16,600)'; :::Y 3550,2520, (9800), and 286 (980); A",:" 3-Cyclopentylmer~apto-A~~3~~(~o)-estratrien-l7-one (IIc) had 1592, 1556, 1496, 1244, 1065, 1049, 1005, 809, and 770 cm.-'. ~ (CHCl,); 260-261 mp (e m.p. 102-103O; [ a ] +131" Anal. Calcd. for C18Hz40S: C , 74.95; H, 8.39; S, 11.12. 8900); '":v 1733, 1590, 1556, 1496 (shoulder) 1258, 1046, 809, Found: C, 75.06; H , 8.27; S, 10.98. and 770 cm.-'. B.-Benzyl sulfide IId, reduced as above, yielded IIf identical with the product prepared according to A. Anal. Calcd. for C23H3~OS:C, 77.91; H, 8.53; S, 9.04. C.-3-Thioestrone (IIe, 250 mg.) was reduced with 50 mg. of Found: C, 78.20; H, 8.48; 9, 9.22. sodium borohydride in aqueous tetrahydrofuran for 8 hr. a t 3-Benzylmer~apto-A~~~~~(~~)-estratrien-17p-01 (IId). A.-A solution of 500 mg. of S~,lO~-oxido-l9-norandrostan-l7~-01-3-room temperature. Isolation and purification of the product with the aforementioned care afforded 200 mg. of IIf, m.p. 106one (Ib) in a mixture of 10 ml. of acetone and 4 ml. of benzyl 107.5", [P]D +78.5" (dioxane), identical with the product premercaptan was treated with 2 drops of concentrated hydrochloric pared according to A and B. acid and refluxed for 1 hr. The mixture was then cooled and the 17p-Hydr0xy-A~~~~~(~~)-estratrien-3-yl Disulfide.-A solution product was isolated as described for IIa. The crude product of 50 mg. of 3-thioestradiol (IIf) in ethanol (2 ml.) was treated (410 mg.), recrystallized from methanol and dried under vacuum with LL solution of 100 mg. of FeCl3.6H*0in ethanol (1 ml.) and a t 80" for 5 hr., afforded 360 mg. of benzyl sulfide IId: m.p. 107allowed to stand a t room temperature for 2 hr. Dilution with 108"; [P]D +58" (CHCI,); 258 mp (e 8300); 3540, water gave a crude product, which was recrystallized from meth1588, 1556, 1496 (shoulder) 1038, 1005, 806, 768, 714, and 690 ~ anol to give 40 mg. of the disulfide: m.p. 194-196°2; [ a ] +96" cm.?. 235-240 mp (e 22,000); v:.":"' 3410, 1590, 1500 (dioxane);" : :A Anal. Calcd. for C~sHs~OS: C, 79.31; H, 7.99; S, 8.47. (shoulder), 1245,1132, 1068,1050,1005,876,808, and 769 cm.-l. Found: C, 79.18; H , 8.03; S, 8.58. Anal. Calcd. for C~~H,BOZSZ: C , 75.21; H, 8.07; S, 11.16. B.-Sodium borohydride (50 mg.) in 2 ml. of water was added Found: C, 74.97; H , 8.18; S, 11.08. to a solution of 250 mg. of 3-thioestrone benzyl ether (IIa) in 10 Reduction of the product with sodium in liquid ammonia in the ml. of tetrahydrofuran and the whole was stirred a t room temconventional manner gave 3-thioestradiol. perature for 8 hr. Water was added and the mixture was extracted with ether. After washing the collected extracts with (13) Heckerz reported for IIf partially different data: m.p. 98-100°; water, evaporation of the solvent yielded 45 mg. of IId, m.p. 96hmax 241 mp (( 9350), 273.5 (1330), and (295) (750); ?:A: NaoH 267 m p (c 16,000); ~2:: 3356 and 2551 cm.-'. 98", which after crystallization from methanol and careful drying showed m.p. 107-108", [P]D +58" (CHCl,), and v:::' as reported above. A1~3J(10)-Estratrien-17-one (111).-Raney nickel W2 (2 ml.) The Aldol Condensation of Methylene was added to a solution of 280 mg. of 3-thioestrone benzyl ether (IIa) in 10 ml. of absolute ethyl alcohol and the mixture was Ris(ethy1 sulfone). A Novel Synthesis of heated under reflux for 8 hr. After cooling, the catalyst was reBenzofurans moved by filtration and washed with ethyl alcohol; afterwards the solution was evaporated t o give 148 mg. of a product, m.p. 135-137". Two recrystallizations from methanol yielded A1r3N10)MARVINL. OFTEDAHL, JOSEPH W. BAKER,AND estratrien-17-one (111): m.p. 139-140"; [ P ] D +166" (dioxane)'Z; MARTINW. DIETRICH hEtOH ma, 214 mp (e 8200), 267 (470), and 274 (490); '":Y 1735, 1601, 1574, 1494, 1050, 815, 750, and 741 cm.-'. Research Department, Organic Chemicals Division, Anal. Calcd. for CI8H220: C, 84.99; H, 8.72. Found: C , Monsanto Company, St. Louis, Missouri 63177 85.25; H , 8.72. 3-Mer ~apto-A~~~~~(~0)-estratrien-l7-one (3-Thioestrone) (IIe) Received August 14, 1964 To 120 ml. of anhydrous liquid ammonia contained in a flask cooled in a Dry Ice-acetone bath, sufficient metallic sodium was added so that the blue color finally persisted for a t least 10 min. Although a few 1,l-bisalkylsulfonyl-1-alkenes(2) (about 200 mg.) . The air was displaced by nitrogen and a soluare tion of 600 mg. of 3-benzylmer~apto-A~~~~~(~o)-estratrien-17-oneknownl1t2a Knoevenagel condensation3 between a methylenebis(alky1 sulfone) and an aldehyde which (IIa) in a mixture of 20 ml. of anhydrous ether and 10 ml. of anhydrous dioxane (both solvents were freed of peroxides) was proceeds directly to 1,1-bisalkylsulfonyl-1-alkeneshas rapidly added. The blue color disappeared and was regenerated not been described. The P-hydroxy sulfones ( l ) , the by the addition of a small amount of sodium. The mixture was RCH(OH)CH(S0zEt)t RCH=C( S0zEt)z then stirred for 10 min. and the reaction was terminated with am1 2 monium chloride. The cooling bath was removed and the ammonia was allowed to evaporate. After dilution with ice-cold expected intermediates by this procedure, are known water and acidification with diluted hydrochloric acid the mixture was extracted with peroxide-free ether. The ether extract was to undergo the retro-aldol reaction common to such washed with 3y0 sodium bicarbonate solution and then with substances. 1 , 4 However, it was anticipated that the water until neutral, dried with anhydrous magnesium sulfate, efficient removal of water from the reaction and the and concentrated under vacuum. The crude product, 360 mg., use of a catalyst of the type recommended by Copea m.p. 20&202", was purified by dissolution in 0.5 N sodium would suppress this side reaction. Accordingly, when hydroxide and reprecipitation with diluted hydrochloric acid. Crystallization from acetone gave IIe (needles), m.p. 205-207"; an equimolar mixture of aldehyde and methylenebis[P]D +164" (dioxane);" : : :A 213mp (e23,200), 242 (10,300), and (ethyl sulfone) (3) was heated in refluxing toluene in 285 (1070); A:LN NaoH 265 mp (e 16,000); ~2::' 2520 (very weak), the presence of a trace of piperidine acetate, the de1732, 1591, 1556, 1493, 1253, 1116, 1047, 1002, 807, and 769 sired l ,l-bis(ethylsulfonyl)-2-substitutedethylenes were cm.-'. obtained in moderate yield (Table I). Anal. Calcd. for C18HzzOS: C, 75.48; H , 7.74; S, 11.20. Found: C, 75.51; H, 7.73; S, 11.36. When salicylaldehydes were employed in the re3-Thioestradiol (IIf). A.-Benzyl sulfide (IIa, 600 mg.) was action sequence, a slight excess of the equimolar quantreated with sodium in liquid ammonia as reported for the pre(1) D. L. MacDonald and H. 0. L. Fischer, J . Am. Chem. SOC.,74, 2087 paration of IIe, except that the reaction time was extended to 1 (1952). hr. The reduction gave 340 mg. of 3-thioestradiol (IIf), m.p. (2) L. C. Rinzema, J. Stoffelsma, and J. F. Arens, Rec. t w u . chim., 78, 97-99", which, after purification as reported for IIe (taking care 354 (1959); A. L. Barney, U. S. Patent 2,641,594 (June 9, 1953). of using solvents freed of peroxides), recrystallization from hexane, (3) E. Knoevensgel, Ber., 18, 172 (1896); Si, 730 (1898); A. C. Cope, and drying a t 80" under vacuum for 10 hr., showed m.p. 106J . Am. Chem. Soc., OS, 2327 (1937).

v:::'

.-

(4) E. Rothstein. J . Chem. Soc., 684 (1934); H . J. Backer, et al., Rec. trou. chim., 70, 365 (1951); L. Housh and T. J . Taylor, J . Chem. Soc., 970 (12) For 111, lit.' m.p. 135-136'.

[ a ]+400°(?) ~

(dioxane).

(1956).

NOTES

JANUARY1965

297

TABLEI 1,1-BIB(ETHYLSULFONY L)-ZX-ETHYLENES R--CH=C( SO2CHzCHs)z Yield.

R

M.P., O C .

Calcd.. 7%

r

%"

Formula

Phenylb 96-97 29 16.5 3,PDichlorophenyl 121-122 4-Nitrophenyl 180-181 48 38 n-Heptyl 180-187 (0.3)' a Corrected for unchanged starting material.

CuHieOi% CizHi~C120& CIZHI&OBS~ CisH2eOSz Lit 2 m.p. 92-93'.

tity of piperidine was employed as catalyst in order to neutralize the phenolic hydroxyl group in the aldehyde. Completion of this reaction resulted in the elimination of one of the ethylsulfonyl groups as ethanesulfinic acid and the formation of a 2-ethylsulfonylbenzofuran (4) in good yield. Application of the reaction to a variety of substituted salicylaldehydes indicated the cyclization to be general for the salicylaldehydes. The ethylsulfonylbenzofurans were characterized by means of elemental analysis and infrared and nuclear magnetic resonance spectra (Tables I1 and 111). The n.m.r. spectra were particularly useful for structure determinations, yielding data that were readily interpreted by first-order methods. The scission of the carbon-sulfur bond in sulfones with the resultant format,ion of a sulfinic acid is well known.&' The formation of ethanesulfinic acid in the course of forming 4 from a salicylaldehyde and 3 was established by means of a color test for sulfinic acidss on the aqueous extracts of the cyclization reaction mixtures. The 2-ethylsulfonylbenzofurans 4 probably arise via the reaction sequence shown. Following the initial condensation-dehydration sequence, intramolecular attack of the phenolate anion upon the carbon bearing the sulfone group results in ring closure with the concomitant elimination of ethanesulfinic acid, yielding 4. Any pathway to 4 involving attack of phenolate or piperidine a t the olefinic position p to the sulfone groups in 5 is improbable because of the geometry of 5 and the fact that the phenolate anion can supply electrons to the sulfone olefin, offsetting the strong inductive effect of the sulfone groups 5a-5b and materially reducing the tendency of 5 to add nucleophiles.

J.

C

H

50 0 5 59 403 395 43 2 4 54 5 0 3 844 Chlorine.

S

Found, %--

X

C

n

49 8 5 63 19 8c 40 5 4 16 4 20d 43 3 4 65 19 2 207 50 4 8 60 Nitrogen. e B.p., 'C. (mm.).

S

18 9 20 9

X

19 6' 4 OOd

The cyclization proceeded with equal facility and comparable yields when triethylamine was employed as the catalyst and no reaction occurred when piperidine acetate was used. The benzofuran 4 may be obtained; but in much lower yield, if less than an equimolar quantity of piperidine is employed, indicating the importance of neutralizing the phenolic hydroxyl group. Attempts to isolate the intermediate o-hydroxy-/3-bis(ethylsulfonyl)styrenewere unsuccessful. Experimental Melting points were determined on a Fisher-Johns melting point apparatus and are corrected. Appropriate analytical and spectroscopic data may be found in Tables I , 11, and 111. Methylenebis(ethy1 sulfone) (3) was prepared by peracetic acid oxidation of methylenebis(ethy1 sulfide) .et 10 1 ,l-Bis (ethylsulfony1)-2-Substituted Ethylenes (2) .-A toluene solution, 0.5 M each in the appropriate aldehyde and 3, was treated with a small quantity of piperidine acetate (1-3 g./mole of reactants) and heated a t reflux in a flask fitted with a DeanStark trap. Upon completion of the reaction, as indicated by the cessation of water evolution, the reaction mixture was freed of toluene a t reduced pressure. The product was purified either by distillation or by recrystallization from isopropyl alcohol. Substituted 2-Ethylsulfonylbenzofurans (4).-A toluene solution, 0.5 M each in the appropriate salicylaldehyde and 3, was treated with 1.1 times the equimolar quantity of piperidine and heated at reflux in a flask fitted with a Dean-Stark trap. Upon completion of the reaction (cessation of water evolution), the mixture was freed of solvent a t reduced pressure. The oily or semisolid residue was dissolved in the minimum amount of boiling isopropyl alcohol and the resulting solution was treated with an amount of glacial acetic acid slightly in exress of the quantity of piperidine used to catalyze the condensation. The aciditied mixture was decolorized with activated charcoal, and rtllowed to cool. The resulting crystalline product was purified by recrystallization from isopropyl alcohol. The presence of ethanesulfinic acid was indicated by trituration of a portion of the oily reaction residue (after removal of the solvent) with water. The water layer was collected and treated with a hydrochloric acid solution of ferric chloride as described by Feigl.8 The resulting precipitate indicated the presence of sulfinic arid in the reaction mixture. When 3,5-dichlorosalicylaldehydewas treated with 3 as described above, but with 1.1 times the equimolar quantity of triethylamine as the catalyst, 5,7-dichloro-2-ethylsulfonylbenzofuran was obtained in 657, yield. The yield of this compound

-

4 (5) G. W. Fenton and C. K. Ingold, J . Chem. Soc.. 705 (1930). (6) A. W.Johnson, Chem. Ind. (London), 1119 (1963). (7) 6. Hilnig and 0. Boes, Ann., 679, 28 (1963). (8) F. Feigl, "Spot Tests in Organic Chemistry,' translated by R. E. Oesper, Elaevier Publishing Co., New York. N. Y.,1956, p. 251.

(9) H. Bbhme, Ber.. 69B,1610 (1936). (10) Although a procedure for this oxidation with hydrogen peroxide employing glacial aretic acid as the solvent has been described,Qwe found that treatment of the pure dithioacetal (b.p. 81-82' at 20 mm.) with an equivalent amount of peracetic acid without a solvent gave pure 8 (m.p. 102-103°), which crystallized from the reaction mixture in 75% yield. As with all peracid-sulfide oxidations, efficient cooling and control of the addition rate was necessary to moderate the strongly exothermic reaction.

VOL. 30

NOTES

298

TABLE I1

ÐYLSULFONYLBENZOFURANS

"'-QJJ-

sozcH2cHa

Rz Yield, Ri

Rl

H

H H H H KO2

c1 Br NO2 H

c1

a

c1

Chlorine.

M.P.,

*

OC.

%

91-92 59,5 123-124 54 113-114 39 181-182 22 187-188 25 141-142 62 Bromine. Nitrogen.

Formula

CioHio0~S CioHgClOaS CloHsBrOsS CIOHBNOKS C~OHBNOKS CioHdXhS

Calcd.. %S

C

H

57.1 49.1 41.5 47.0 47.0 43.0

4.79 3.71 3 14 3.55 3.55 2.89

TABLE I11 N.M.R.PROPERTIES OF SCBSTITCTED 2-ETHYLSULFONYLBENZOFURANSa

15.2 13.0 11.1

12.6 12.6 11.5

-Found,

'70

X

C

H

S

14.5" 27.6b 5.4gC 5.49" 25.4"

57.2 49.0 41.6 47.3 47.2 43.0

4.87 3.87 3.22 3.58 3.78 2.88

15.0 13.1 10.8 13.0 12.3 11.2

7

X

14.4" 27.gb

5.2ZC 5.62" 25.6"

Attempts to cyclize 3,5-dichlorosalicylaldehyde employing a small amount of piperidine acetate (10 g./mole of aldehyde) resulted in no detectable reaction and 927, of 3 was recovered unchanged.

Acknowledgment.-We are indebted to Mr. D. R. Beasecker and his staff for the elemental analyses and to Mr. Alan Tharp for assistance in the infrared measurements. Substituent

Chemical shift*-Assignment

6 (p.p.m.)C

Coupling constant, J (C.P.8.)

None

7.94 (s) Hs 7 . 3 (m) H4, H5, H.5, H7 3.13 (9) -CHZ1.28 ( t ) -CHs 5-Chloro 8.39 (s) Ha 8.05 (d, d ) H4 J4.5 = 1.8 7.65 ( m ) He, H7 J47 = 0.8 3.32 ( 9 ) -CHzJ67 = 8.2 1.39 ( t ) -CHI 5-Bromo 7.99 (s) H3 7.78(m) HI 7.32 ( m ) H.5, H7 J e 7 = 9.0 3.17 ( 9 ) -CHr 1.32 ( t ) -CH; 5-Nitro 8.95(d) H4 J4.5 = 2 . 3 8 . 5 4 ( d ,d ) He Js7 = 9 . 9 8.49 (s) HI 7 . 8 7 (d, d ) H7 J47 = 0.8 3.38(q) -CHr 1.43 ( t ) -CHI 7-Nitro 8.54 (s) HI 8.40 ( m ) H4, He J d g = Js.5 = 8 . 5 7.70 ( t ) Ha 3.32 (4) -CHr 1.42 ( t ) -CHI 5,7-Dichloro 8.36 (s) HJ 7.85(d) H4 J4.5 = 1.9 7.55(d) He 3.27 (4) -CHz1.38 ( t ) -CHI a Spectra were obtained in deuteriochloroform solution containing internal tetramethylsilane (TMS). A Varian HR-60 high resolution n.m.r. spectrometer operating a t 60 Mc./eec. was employed. Spectra were calibrated by the audiofrequency side-band technique [J. T. Arnold and M. E. Packard, J. Chem. Phys., 19, 1608 (1951)l utilizing a frequency counter. Referred to internal TMS. s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. was 62y0 when piperidine was employed as the catalyst (Table 11). The use of 0.1 the equimolar amount of piperidine in the cyclization of 3,5-dichlorosalicylaldehydewith 3 resulted in the isolation of 5,7-dichloro-2-ethylsulfonylbenzofuranin only 11.7% yield and the recovery of 55y0 of unchanged 3.

The Addition of Alcohols to Dicyandiamide. A Correction of the Literature GUYD. DIANA,ETHELS. ZALAY,A N D ROYAL A. CUTLER,JR.

Sterling-Winthrop Research Institute, Rensselaer, New York Received August 4, 1964

Among the methods claimed as being useful for the synthesis of 1-amidino-3-alkylureas is the one published by Dutta and Ray.' The procedure, as reported, involved the addition of an alcohol to dicyandiamide in the presence of copper acetate. The resulting chelate salt was treated with ammonium sulfate which precipitated the insoluble copper ammonium sulfate salt of the alleged 1-amidino-3-alkylurea. Treatment with hydrogen sulfide produced the free base. The authors suggested that a rearrangement occurred by which the 1-amidino-0-alkylurea originally formed (I) was transformed into the compounds in question (11).

[

+ ROH +

XH IH 1

NHz NH -OR

+

I

8" B

NHt NH -NH-R

I1

We have now shown unequivocally that the compounds prepared by Dutta and Ray are, in fact, not the 1-amidino-3-alkylureas (11) but rather the 0alkylureas (I). A search of the literature revealed a method of synthesizing 1-amidino-3-alkylureas (11) which was unambiguous. This method involved the reaction (1) R. L. D u t t a and P. Ray, J. Indian Chem. Soc., 86, 499 (1959). (2) F. H. S. Curd, D. G. Davey, and D. N. Richardson, J. Chem. Soc., 1732 (1949).

JANUARY

NOTES

1965

of guanidine hydrochloride with an isocyanate in the presence of sodium and acetone and yielded the amidinourea as the free base.

iH

NHz NHz.HCI

+ R-N=C=O

Na d acetone

NH

0

eti:

NH2 --NH

-NH-R

We repeated this work with the n-butyl and nhexyl homologs, converted each to the sulfate salt, and made a direct comparison of each with the sulfate salt of the corresponding n-butyl and n-hexyl homologs prepared by the method of Dutta and Ray. From this examination it was obvious that the two procedures yielded entirely different compounds. In order to determine further the nature of the compounds produced by Dutta and Ray, we examined the work of Kawano and 0 d 0 . ~ Although Kawano and Odo did not cite the work of the Indian workers, they did publish a similar procedure but concluded that the products obtained therefrom were l-amidino0-alkylureas which they isolated as the hydrochlorides. In order to clarify the problem, we prepared l-amidino-3-0-ethylurea hydrochloride by the method of Kawano and 0 d 0 , ~converted it to the corresponding sulfate, and compared it directly with the product obtained by the method described by Dutta and Ray. The two compounds were identical and showed no mixture melting point depression. Hence it was concluded from the foregoing experiments that the compounds obtained by the latter workers, from the reaction of alcohols on dicyandiamide, were indeed the 1-amidino-0-alkylureas (I) and not 1-amidino-3-alkylureas (11) as originally claimed. It is of interest to note the difference in ability of the 1-amidino-0-alkylureas (I) to form metal chelates compared with the 1-amidino-3-alkylureas (11). Thus, Dutta and Ray reported that their compounds (which were actually 1-amidino-0-alkylureas) formed metal chelates,1~5-* and made use of this fact in their isolation. Our repetition of this work substantiated these observations. I n contrast, however, we have found that the 1-amidino-3-alkylureas (11) do not form metal chelates. Ray and Saha* have postulated that biguanides, which readily form metal complexes, have a chelated structure represented by 111. An analogous structure (IV) can be assigned to the 1-amidino-3-0-alkylureas.

r

l!? I11 (3) K. Kawano a n d K. Odo, Yukz Gosea Kagaku Kyokai Sha, 20, 568 (1962); Index Chemacus, 6, 21383 (1962). (4) K. KawanoBnd K. Odo, J . Chem. SOC.J a p a n , 8 2 , 1672 (1961). ( 5 ) R. L. D u t t a s n d P. R a y , J. Indaan Chem. SOC.,8 6 , 567 (1949). (6) R. L. D u t t a , ibzd., 87, 499, 565, 573, 789 (1960). (7) P. Ray, Chem. Rev., 61. 313 (1961). ( 8 ) R. L. D u t t a and S. Lahiry, J . Indian Chem. Soc., 88, 689 (1961).

299

Kundu and observed that l-amidino-3phenylurea, which has the phenyl substituent adjacent to the -CO- group, does not form metal complexes. This loss of chelating ability was attributed to the decrease in the basicity of the nitrogen bearing the aryl group. As noted above, however, this inability to form complexes was also observed to be true when an alkyl substituent, such as butyl or hexyl, was in this position. Slotta and Tschesche12have made a similar observation in the case of 1-amidino-3-methylurea. On the other hand, when the phenyl group is attached to the nitrogen adjacent to the >C=NH, the complexing power is unhindered. Thus, l-phenylaniidinourea (V) produced a pink precipitate when treated with ammoniacal copper sulfate.

WHCNHCNH II II NH 0

V

It would appear, therefore, that the difference in metal-complexing ability of the 3-amidino-1-substituted ureas is due not to the degree of basicity of these compounds but rather to steric factors operating between the metal and the nitrogen atoms with which it complexes. Thus, 1-substituted-amidino ureas (e.g., V) can contribute two unsubstituted nitrogen atoms for complexing with a metal ( e . g . , formula VI), whereas 1-amidino-3-substituted ureas have only one unsubstituted nitrogen atom to offer for complexing ( e . g . , VII). Interference between R and the metal atom in VI1 could explain the inability of 3-amidino-lsubstituted ureas to form metal complexes.1s

VI

VI1 Experimental"

1-Amidino-0-butylurea Sulfate.-This compound was prepared according to the procedure of Dutta and Ray' using 25 g. (0.297mole) of dicyandiamide, 25 g. of copper acetate, and 300 ml. of n-butyl alcohol to give 15 g. of product which, after crystallization from methanol-acetone, melted a t 134-136'. This was in agreement with the literature value (137-138').' 1-Amidino-3-butylurea Sulfate.-l-Amidino-3-butylurea waa prepared according to the procedure described by Curd2 using 3.2 g. (0.137g.-atom) of sodium, 14.3 g. (0.149mole) of guanidine hydrochloride, and 7.5 g. (0.138mole) of butyl isocyanate. The free base was not purified but was converted to the sulfate, in the following manner, in order to compare the product directly with the material prepared by Dutta. An ethereal solution of the crude base was cooled in an ice bath and neutralized by the dropwise addition of sulfuric acid whereupon an oil separated. The ether was decanted, fresh ether was added, and the mixture was cooled. On standing for several days, crystals appeared, yielding 1.5 g., m.p. 180-195" (9) P. R.ay and H. Saha, ihid., 14, 670 (1937). (10) N. Kundu and P. R a y , ibid., 29, 811 (1952). (11) P. Ray, ibid., 82, 141 (1955). (12) K. H. Slotta and R. Tschesche. Ber., 62, 1390 (1929). (13) We would like t o thank the referie for his suggestions on the clarifi-

cation of this argument. (14) All melting points, unless otherwise specified, are corrected. grateful t o Mr. K. D. Fleisoher and staff for analytical services.

We are

NOTES

300

(uncor.). After several recrystallizations from methanol-ether, an analytical sample was obtained, m.p. 197-198". Anal. Calcd. for CsHlrN40~0.5H~S04: N, 27.05; S, 7.74. Found: N, 27.09; S, 7.92. This material produced a melting point depression when mixed with the 1-amidino-0-butylurea sulfate prepared above. 1-Amidino-0-hexylurea Sulfate.-The material obtained by the procedure of Dutta and Ray1 had a melting point of 132135'. l-Amidino-3-hexylurea.-The free base was prepared by the procedure of Curd,2 m.p. 91-92'. The sulfate was prepared by treatment of a methanolic solution of base with ethereal sulfuric acid until the solution was slightly acidic. The solvent was removed in vacw, and the oily residue was dissolved in isopropyl alcohol. The addition of ether precipitated the sulfate, m.p. 128-129' (uncor.). Further recrystallization from isopropyl alcohol-ether raised the melting point to 131-134'. Anal. Calcd. for C8H18N40.0.5H&304:C, 40.83; H , 8.14; N, 23.81. Found: C, 41.11; H , 8.09; N, 24.01. A mixture melting point with the 1-amidino-0-hexylurea sulfate prepared above produced a depression. 1-Amidino-0-ethylurea Sulfate. A.-The compound was prepared by the procedure of Dutta and Ray.l As prepared by us it had a melting point of 165-166' which differed from that reported in the literature (137-138'). This experiment was repeated with the same results. B.-1-Amidino-0-ethylurea hydrochloride was synthesized by the procedure of Kawana,' m.p. 162-163' (uncor.), in agreement with the latter workers' melting point. The hydrochloride was converted to the sulfate in the following manner. Amberlite IRA-400 resin (20 9.) was slurried with distilled water, put into a chromatographic column, washed with 2 N sulfuric acid until the eluent produced a negative chloride test, and then washed with distilled water to neutrality. 1-Amidino-0-ethylurea hydrochloride (2 g.) was dissolved in 95% ethanol (25 ml.) and passed through the column. Ethanol (100 ml.) was added and the solution was collected and evaporated to yield a white solid which was dissolved in 20 ml. of 95y0 ethanol. Acetone was added (20 ml.), whereupon a white solid formed, m.p. 16g167". A mixture melting point with the material obtained by the method of Dutta and Ray1showed no depression.

The Rearrangement of 1-Piperidinemethanethiol Esters EDWARD E. SMISSMAN AND

JOHN

R. J. SORENSON~

Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas Received July 8Y,196'4

I n an attempt to characterize a compound believed to be the hydrochloride salt of l-piperidinemethanethiol acetate (Ia) it was converted to the free base (IIa). On distillation a clear liquid was obtained which gave an incorrect analysis for the desired product. An investigation of the nuclear magnetic resonance (n.m.r.) and infrared spectra of the distillate indicated the product to be 1-acetylpiperidine (111s). This was confirmed by comparison with an authentic sample.

I

I1 a,

R = CH3-

+

(CHZS),

b, R = (1) National Institutes of Health Predoctoral Fellow, 1963-1964.

VOL.30

To expand on this study a convenient synthesis for the acetyl and benzoyl esters Ia and I b from l-piperidinemethanethiol hydrochloride (IV) was devised. The parent compound, IV, prepared by the method of Binz and Pence, was heated with the corresponding thiolcarboxylic acid to afford the desired compound and hydrogen sulfide.

Q\>

H' HS

c1-

'

IV

The rearrangement of the thiol esters was effected by refluxing the free base in benzene. A plausible explanation for this facile rearrangement can be depicted as follows.

+

(CHFS)

Experimental3

1-Piperidinemethanethiol Acetate Hydrochloride (Ia).-To 16.7 g. (0.1 mole) of 1-piperidinemethanethiolhydrochloride (IV) was added 55.0 g. (0.72 mole) of thiolacetic acid and the mixture was heated a t steam-bath temperature for 3 hr. The reaction mixture was allowed to cool and then added to 500 ml. of anhydrous ether. The resulting precipitate was collected and washed twice with ether. The white solid was recrystallized from absolute alcohol to give 16.4 g. (79%) of the desired compound: m.p. 169" dec.; 5.85 p ; n.m.r. 150 (9, -CH,), 269 (s, NCHZS), 197 (m, NCHZ), and 104 (m, CCH,) C.P.S. in

DzO .

Anal. Calcd. for CsHl&lNOS: C, 45.82; H , 7.68; N, 6.67; S, 15.29. Found: C, 45.90; H , 7.42; N, 6.78; S, 14.78. 1-PiperidinemethanethiolBenzoate Hydrochloride (Ib) .-A suspension of 10.0 g. (0.06 mole) 1-piperidinemethanethiol hydrochloride (IV) and 25.0 g. (0.18 mole) of thiolbenzoic acid in 50 ml. of dichloromethane was heated a t steam-bath temperature for 1.5 hr. The dichloromethane was removed and the residue was poured into 500 ml. of anhydrous ether. The resulting precipitate was collected and redissolved in a minimum amount of dichloromethane. This solution was dropped slowly into 250 ml. of anhydrous ether. After repeating this procedure three times, 10.2 g. (63%) of the desired material, a crystalline solid, m.p. 158" dec., was obtained. Decomposition of this material occurred somewhat during the purification procedure with enough' impurity being formed to prohibit an accurate elemental analysis. The structure was established by spectral comparison with 1piperidinemethanethiol acetate hydrochloride (Ia). I b showed 5.95 p ; n.m.r. 477 and 484 (d, ortho =CH-), 456 (m, meta and para =CH-), 288 (E, NCHZS),190 (m, NCHZ),and 117 (m, CCHs) C.P.S. in DCCl,. 1-PiperidinemethanethiolAcetate (IIa) and 1-Piperidinemethanethiol Benzoate (IIb) .-Aqueous solutions of l-piperidinemethanethiol acetate hydrochloride (Ia) and l-piperidinemethanethiol benzoate hydrochloride (Ib) were made basic with saturated sodium bicarbonate solution. These solutions were then extracted with ether and the extracts were dried over anhydrous magnesium sulfate, The ether was removed in vacuo without the use of heat; the free bases were examined by n.m.r. and infra(2) A. Binz a n d L. H. Pence, J . A m . Chem. Soc., SI, 3134 (1939). (3) Melting points were obtained on a calibrated Kofler micro hot stage and a Thomas-Hoover Unimelt and are corrected. Infrared d a t a were recorded on Beckman IR5 and 1R8 spectrophotometers. Nuclear magnetic resonance d a t a were recorded on a Varian Associates Model A-60 spectrophotometer using T M S as the internal standard. Microanalyses were conducted by Drs. G. Weiler e n d F. B. Strauss, Oxford, England.

30 1

JANUARY 1965

NOTES

red. IIa showed XE'f,"'8 5.95 p ; n.m.r. 140 (s, -CHa), 271 (9, NCHZS), 144 (m, NCH2), and 89 (m, CCHd C.P.S. in CCh; 6.00 p ; n.m.r. 479 and 486 (d, ortho =CH-), I I b showed ?!A: 287 (s, NCHZS), 150 (m, 449 (m, meta and para =CH-), NCHZ),and 87 (m, CCH2) C.P.S. in CCh. Rearrangement of 1-Piperidinemethanethiol Acetate (IIa) to 1-Acetylpiperidine (IIJa).-A solution of 7.6 g. (0.044 mole) of 1-piperidinemethanethiol acetate (IIa) in 25 ml. of benzene was prepared. The solution was heated for 12 hr. The residue on distillation afforded 2.18 g. (60%) of I-acetylpiperidine, b.p. 56-60" a t 1.O mm. (1it.d b.p. 226-227' a t 760 mm.). The infrared and n.m.r. spectra of this substance were identical with those of an authentic sample: 6.14 p ; n.m.r. 117 (s, -CH3), 205 (m, NCHz),and 96 (m, CCH2)c.p.5. in cc14. Rearrangement of 1-Piperidinemethanethiol Benzoate (IIb) to 1-Benzoylpiperidine (IIIb).-The same procedure was used in the rearrangement of IIa. A solution of 8.2 g. (0.034 mole) of 1-piperidinemethanethiol benzoate (IIb) afforded 3.30 g. (5Oojoi of 1-benzoylpiperidine, b.p. 118-120' a t 1.0 mm., m.p. 46-47 (lit.4b.p. 320-321' a t 760 mm., m.p. 48'). The mixture melting point, infrared, and n.m.r. spectra of this substance were identical with those of an authentic sample: A;"'* 6.18 p ; n.m.r. 439 (s, all =CH-), 206 (m, NCHZ), and 94 (m. CCH2) C.P.S. in CC14. Polymeric Thiof0rmaldehyde.-The undistillable residue obtained in the rearrangement of I I a and I I b was recrystallized from CHCI,. The yield was 0.98 g. (48%) of a mixture of polymeric forms of thioformaldehyde, m.p. 136145', in the rearrangement of 11s and 0.71 g. (45y0) in the rearrangement of I I b [lit.5 m.p. 175-176" for (CH2S),, m.p. 216" for (CHZS)~].No attempt was made to isolate trithiane from the mixture or to characterize the other thioformaldehyde polymers.

cally to an alkylmagnesium alkoxide, obtained from reaction of 1 mole of a dialkylmagnesium with either 1 mole of a ketone or 1 mole of a tertiary alcohol produced much greater proportions of by-products from enolization and reduction on reaction with simple ketone~.~ This latter result was observed only when the alkylmagnesium alkoxide reagent was free from magnesium halide. One interpretation of these results is that all of the reactions in the presence of magnesium halide as well as reactions employing an excess of a dialkylmagnesium each involve the same organomagnesium species, perhaps a dialkylmagnesium, as the actual reacting species, whereas reactions with halide-free alkylmagnesium alkoxides involve a different reacting specjes which may be either an alkylmagnesium alkoxide or some more complex structure. To examine this hypothesis further we have examined the n.m.r. spectra of various organomagnesium reagents, a study to be reported elsewhere, and have studied the stereochemical course of additions of various methylmagnesium derivatives to a ketone to learn if differences could be detected. This latter study, reported here, utilized the reaction of various methylmagnesium derivatives with 4-t-butylcyclohexanone (1) to form the cis- (2) and trans-carbinols (3).4 In this reaction we wished to take advan-

Acknowledgment.-The authors gratefully acknowledge the support of this project by the National Institutes of Health Grants 1-F1-GM 14, 467-01A2, and RG-9254.

N

0

l

(CHs)3C

. CHaMgz 2. H20

H

1

(4) "Dictionary of Organic Compound&" 1. M . Heilbron, et. a l . , Ed., Oxford University Press, New York, N. Y., 1953. (5) A. Wohl, Ber., 19, 2344 (1886).

H

The Chemistry of Carbanions. VII. The Stereochemistry of Addition of Various Methylmagnesium Reagents' HERBERT 0. HOUSEAND WILLIAML. RESPESS

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 0.9139 Received August 91,1964

Earlier studies2.3 of additions of organomagnesium compounds to ketones had demonstrated that dialkylmagnesium compounds are more reactive than alkylmagnesium halides (Grignard reagents). Either organometallic reactant, when in excess, produces the same proportion of addition product to by-products resulting from enolization or reduction. However, the organometallic reagent, corresponding stoichiometri(1) This research h s s been supported by research grants from the National Institutes of Health (R. G . 8761) and the National Science Foundation (G-25214). (2) (a) J. G. Aston and S. A. Bernhard, Nature, 166, 485 (1950); (b) D. 0. Cowan a n d H. S. Mosher. J . O w . Chem., 97, 1 (1962); 98, 204 (1963): (0) M . Anteunis. ibid.. 96, 4214 (1961); 27, 596 (1962); M. Anteunis and R. D'Hollander, Tetrahedron Letfera. No. 96, 1275 (1962); (d) N . M. Bikales a n d E. I. Decker, Can. J . Chem.. 41, 1329 (1963); (e) A . Kirrmann, M. Vallino, a n d J. F. Fauvarque, Bull. uoc. chim. France, 1408 (1963). (3) (a) H. 0. House, D. D . Traficante. and R. A. Evans, J . Orp. Chem., 28, 348 (1963); (b) H. 0. House a n d D. D . Traficante, i6id., 98, 355 (1963); (0) H. 0. House a n d H. W. Thompson, ibid., 28, 360 (1963).

1 2

(cis, m.p. 70-71')

H 3 (trans, m.p. 96.5-97')

tage of the seemingly valid generalization5 that use of a more hindered cyclohexanone derivative or use of a more hindered organometallic reagent can be expected to increase the proportion of the cyclohexanol isomer with an axial hydroxyl function and an equatorial alkyl group (corresponding to 2). From the proportions of isomers 2 and 3 formed we might hope to learn whether the reacting species derived from various methylmagnesium reagents were different. The results of this study are summarized in Table I which lists the average values obtained from two or more determinations. All reaction mixtures obtained from organomagnesium reagents in the presence of magnesium bromide or with excess dimethylmagnesium yielded predominantly a mixture of alcohols 2 and 3 with little enolization (as measured by the amount of ketone 1 recovered). The products of these reactions contained 55-65% of the axial alcohol 2. From reaction mixtures containing the halide-free methylmagnesium salt of 3-methyl-3-pentano1, a large amount (4) (a) B. Cross and G . H. Whitham, J . Chem. Soc., 3892 (1960); (b) C. H . DePuy and R. W. King, J . A m . Chem. Soc., 88, 2743 (1961) : ( c ) W. J . Houlihan, J . Org. Chem., 27, 3860 (1962); (d) H. Favre and D. Gravel, Can. J . Chem., 89, 1548 (1961). (5) (a) G. J u s t and R. Nagarajsn, Ezperienfia, 18, 402 (1962); (b) G. F. Hennion a n d F. X.O'Shea [ J . A m . Chrm. Soc., 80, 614 (1958)Jfound t h a t addition of ethylmagnesium bromide to 1 gave product containing 73Y0 of the product with an axial hydroxyl function (corresponding to 2). whereas use of methylmagnesium bromide produced a mixture containing 55-60% of the corresponding isomer 9 (ref. 4 and this study).

302

NOTES

VOL. 30

TABLE I REACTION OF 4-&BUTYLCYCLOHEXANONE WITH METHYLMAQNESIUM DERIVATIVES Ketone, mmoles

Magnesium derivative (mmoles)

9.2 7.8 7.8 4.2 8.3 8.3

MeMgBr (37) MezMg (15.5) MezMg (15.5) Me2Mg (8.5) MeMgBr (33) MeMgBr (33)

Additive (mmoles)

...

... MgBa (15.6) MgBrz (10.8) EtrCO-Et (16.5) Et&-Me (16.5)

I 7.8

MQMg (15.5)

7.8

MezMg (15.5)

OH EtrCO-Et (15.5) MgBrz (15.6) Et&-Me( 15.5)

Volume of s o h , ml.

Yield of alcohol, %

37 31 31 28.6 33 33

94-96 83 92-93 95-97 89-94 88-93

31 31

87-9 1 28-30

Recovery of ketone, %

...

Composition of aloohol --mixturen% cis % trans

...

60 65 60 61 55 57

40 35 40 39 45 43

2-4 48-51'

60 73

40 27

8-9

... ... ...

+

I

OH 7.8 MezMg (15.5) Et-CO-Et (15.5) 31 23-30 46-52* 75 25 a Average values from two or more runs are listed. The individual values obtained did not differ from these average values by more than f 2 % . See the Experimental section for a description of other products present.

of enolization was observed as measured by the amount of recovered ketone 1 and by the formation of higher molecular weight products from aldol condensation (see Experimental). The alcohol product contained 73-7575 of the axial alcohol 2. Although the stereochemical differences observed in these reactions are not large, the results are compatible with our early suggestion3 that the reacting species in halide-free solutions of alkylmagnesium alkoxides is not the same as the reacting species derived from Grignard reagents or dialkylmagnesium compounds. The data would suggest that the reacting species obtained from the alkylmagnesium alkoxide has the greater steric bulk. Experimentale Preparation of Reagents .-Ethereal solutions of methylmagnesium bromide, dimethylmagnesium (from dimethylmercury) , and magnesium bromide (from ethylene dibromide) were prepared and standardized as previously described.3 Reaction of 14.02 g. (0.163 mole) of 3-pentanone with 250 ml. of an ethereal solution containing 0.330 mole of methylmagnesium bromide yielded, after the usual isolation procedure and fractional distillation, 10.06 g. (60%) of pure73-methyl-3-pentano1, b.p. 120-121 ', n Z 51.4158 ~ [lit.8b.p. 120-123", , ~ Z S D 1.41531, infrared0 absorption 3610 and 3450 c m . 3 (unassocd. and assocd. 0-H). Ethereal solutions of methylmagnesium 3-methyl-3-pentoxide (or its equivalent) were obtained by adding 1 molar equiv. of either 3pentanone or 3-methyl-3-pentanol to an ethereal solution containing either 1 molar equiv. of dimethylmagnesium or 2 molar equiv. of methylmagnesium bromide. The resulting solutions were stirred under nitrogen for 1 hr. prior to use. Pure74-t-butylcyclohexanone, b.p. 61-62' (0.1 mm.), m.p. 46-48' (lit.lo m.p. 47.5-48.5"), infrared@absorption 1730 cm.-l (C=O), n.m.r.Q absorption 8 0.92 (singlet, 9H, CH,) and 1.3-2.5 (broad multiplet, SH), was obtained by oxidation of the commercially available mixture of 4-t-butylcyclohexanols with chromic acid in acetic acid. The reaction of 4-t-butylcyclohexanone with an ethereal solution of methylmagnesium iodide a t room temperature (6) All melting points are corrected and all boiling points are uncorrected. Unless otherw.ise stated magnesium sulfate was employed a s a drying agent' T h e infrared spectra were determined with a Perkin-Elmer, Model 237, infrared recording spectrophotometer fitted with a grating. T h e n.m.r. spectra were determined a t 60 hIc. with a Varian, Model A-60, n.m.r. spectrometer. T h e microanalyses were performed by Dr. s. M. Nagy a n d his associates and b y the Scandinavian Microanalytical Laboratory. (7) A gas chromatography column packed with 20 M Carbowax suspended o n ground firebrick was employed for this analysis. (8) W. G . Young a n d I. D . Webb, J. A m . Chem. Soc., 78, 780 (1951). (9) Determined in carbon tetrachloride solution. (10) S. Winstein a n d N . J. Holness. J . A m . Chem. S o c . , 7 7 , 5562 (1955).

for 2 hr., followed by the usual isolation procedure, yielded, after sublimation (25" a t 0.1 mm.), 6497, of a mixture" of the stereoChroisomeric l-methyl-4-t-butylcyclohexanols,m.p. 55-58'. matography of 2.2 g. of this mixture on 150 g. of Merck midwashed alumina separated 1.04 g. of the cis alcohol (first eluted with benzene-ether mixtures), m.p. 68-70', and 0.969 g. of the trans alcohol (second eluted with benzene-ether mixtures), m.p. 95-96'. Recrystallization of each of these fractions from aqueous methanol afforded the cis isomer as white needles, m.p. 70-71' (lit.4cm.p. 71°), and the trans isomer as white prisms, m.p. 96.5-97" (lit.4c3dm.p. 97-98'). The pure7 cis isomer (eluted first on gas chromatography) has infrared absorption9 a t 3610 and 3480 cm.-l (0-H).with n.m.r. singleW a t 6 0.88 (9H) and a t 1.21 (3H) as well as broad absorption in the region 1.2-1.9 (9H). The pure7 trans isomer (eluted second on gas chromatography) has infrared peaks@a t 3605 and 3350-3450 cm.? (OH) with n.m.r. singlets' a t 8 0.88 (9H) and a t 1.23 (3H) and broad absorption in the region 1&2.0 (9H). Quantitative Reactions of Methylmagnesium Derivatives with 4-t-Butylcyclohexanone.-All reactions were run under a nitrogen atmosphere. For the gas chromatographic analyses,'s calibration curves were prepared from mixtures of known composition containing the various reactants and products. An ethereal solution containing ketone was added to an ethereal solution of the methylmagnesium derivative containing any additives specified in Table I. During the addition the reaction mixture was cooled by use of an ice bath. After the addition was complete, the reaction mixture was stirred for 1 hr. and then a weighed amount of durene was added as an internal standard and the mixture was hydrolyzed with saturated aqueous ammonium chloride. The ether layer and ether washings of the aqueous phase were combined, dried, concentrated under a Vigreux column, and analyzed. The results are summarized in Table I in which molar quantities from a representative run are cited with the range of yields obtained and the average composition of the product mixture. I n none of the experiments cited did the composition of an individual run differ from the average value by more than f 2 % . The material balances obtained were of the order of 90% for all of the reactions studied except the last two listed in Table I. In these cases where enolization (Ieading to recovery of the starting ketone after hydrolysis) was the predominant reaction, approximately 80% of the reactants were accounted for as recovered ketone or alcohol products. The reaction mixtures from a number of these runs were combined and distilled to separate a lowboiling fraction, b.p. 38-39' (16 mm.), composed largely of 3methyl-3-pentanol as judged from its infrared spectrum. The (11) A thin layer chromatographic plate coated with silica gel was employed for this analysis. T h e eluent was 2 : 1 (by volume) petroleum e t h e r ethyl ether. (12) Determined a s a solution in deuteriochloroform. (13) A column packed with General Electric silicone gum, No. XE-60, suspended on Chromosorb W was employed.

JANUARY1965

NOTES

residue from this distillation was sublimed (25" a t 0.1 mm.) for 48 hr. to separate the bulk of the volatile products, 4-t-butylcyclohexanone and the stereoisomeric 4-t-butyl-1-methylcyclohexanols. The residue from this sublimation was recrystallized from cyclohexane to separate a white crystalline solid melting over the range 139-190' which exhibited a single broad peak when examined by gas ~hromatography.1~Since we were unsuccessful in obtaining a single pure substance from the high molecular weight material, the spectra of the mixture were examined. The mixture has infrared absorption'5 a t 3580 and 3450 em.-' (unassocd. and assocd. OH) with no absorption in the 6-r region attributable to a carbonyl function. The n.m.r. spectrumlz has a singlet a t 6 0.82 (CH,-C+) with broad, partially resolved absorption in the region 1&1.8 but no evidence of absorption a t lower field indicative of vinyl protons. The mass spectrumla was particularly informative, exhibiting the highest peak a t m/e = 306 ( M + ) with high mass fragment peaks a t 291 (M - l 5 ) , 288 ( M - 18), 273 ( M - 15 - 18, abundant), 249 ( M - 57, abundant), and 231 (M - 57 - 18, abundant), and an intense peak a t m/e = 5 7 . These data are most easily accommodated by one or more of the stereoisomers of the structure 4 which would be expected to arise by an initial aldol condensation of 4-t-butylcyclohexanone with itself to form the ketone 5 followed by reaction with the methylmagnesium species present in solution.

Froni the reaction between diethylmagnesium and benzonitrile in tetrahydrofuran, when the ratio of available ethyl groups to benzonitrile was 1 or smaller, 1,3diphenyl-2-met hyl- 1,5-propanedione (I) and &methyl2,4,6-triphenylpyriniidine (111) were isolated. From the same reactants in ethyl ether a substance which appears to be X-(a-ethylbenza1)benzamidine (11) as well as the pyrimidine (111) were isolated. I was assumed

303

0

Ph

0

II

Ph -C-CH-C-Ph

I

II

Ph-C=N-C=N-H

I

CH3 1

II Ph

CH34

N

PhANAPh I11

to have formed by hydrolysis of the corresponding bisketiniine salt initially formed in the reaction mixture. The origin of the bisketiiiiine salt is reasonably represented as an aldol-type of condensation in the "nitrogen syst,em." To our knowledge this type of reaction has (14) A column packed with silicone gum, No. SE-30,suspended on Chromosorb W was employed. (15) Determined a s a solution in chloroform. (16) Determined with a C E C , Model 21-103, mass spectrometer.

Some New Condensation Products in the Reaction of Diethylmagnesium with Benzonitrile ALFREDA. SCALA,'& NORBERT M. B I K A L E SAND ,~~ ERNEST I. B E C K E R ~ ~ Polytechnic Institute of Brooklyn, Brooklyn, New York 11801 Received August 10, 1964

We wish to report three new condensation products been observed only once previously. EctorslOb has from the reaction of diethylmagnesium with benzonitrile. isolated 3,4,5-triphenyl-A2-pyrazolineas a product in While condensation products are well known in the the reaction of berizyliiiagnesium chloride with benzoreactions of alkylmagnesium compounds with nitriles, nitrile. I t is likely that this product is formed by atthese have heretofore been observed only when either tack of a salt similar to B upon another molecule of the nitrile2 or the Grignard reagent3 is unsaturated or benzonitrile, followed by cyclization. when t'he nitrile contains active a-hydrogen a t o n ~ s . ~ - ~ Formation of the benzamidine, 11, is readily underTrinierization of the nitrile to form an s-triazine has stood as arising from the addition of A to a second molealso been ~ b s e r v e d . ~ cule of benzonitrile to give a new salt D.11 Hydrolysis (1) (a) This material was abstracted from part of the doctoral dissertations of D gives 11.

of N. M. B. (1961) and A. A. S. (1965) presented to the Faculty of the Polytechnic Institute of Brooklyn in partial fulfillment of the requirements of their Ph.D. degrees. (b) T o whom inquiries should be sent. (2) H. R. Henze and L. R . Swett, J . A m . Chem. Soc., 7 8 , 4918 (1951). (3) H. R. Henze, G . L. Sutherland. and G. D. Edwards, ibid., 78, 4915 (1951). (4) M. S. Kharasch and 0. Reinmuth, "Grignard Reactions of Nonmetallic Substances," Prentice-Hall Co., Inc., New York, N. Y., 1954, pp. 774776, 782-783. (5) C. R . Hauser and W. J. Humphlett, J . Org. Chem., 16, 359 (1950). (6) J. Decombe, Compl. rend., 184, 2542 (1952). (7) M. Pretot and J. Decombe. ibid., 244, 1512 (1957). (8) F. F. Blicke and E . P. Tsao, J . A m . Chem. Soc.. 7 6 , 6587 (1953). (9) J. D. Citron and E. I. Becker, Can. J . Chem., 41, 1260 (1963).

Ph A

PhCN

-+-

HzO

PhC=YI

u (10) (a) T h e second valence of magnesiumis unspecified. (b) E . Ectors, Bull. eoc. chim. Belgee., 8 8 , 146 (1924). (11) J. J. Ritter and R . D. Anderson [ J . O r g . Chem., 24, 208 (1959)l assumed a similar type of condensation in the polymerization of benzonitrile with sodium.

NOTES

304

111 may be visualized as an addition of D to a third molecule of benzonitrile followed by cyclization, with the loss of ammonia.I2 Ph D

Ph

PhCN

+Ph-C=N-h=N-&=N-Mg

+ I11 + NH3

VOL.30

The white solid weighed 3.6 g. (187,) and melted at 139-140'. An analytical sample obtained by recrystallization from aqueous The infrared spectrum methanol melted a t 140.0-140.4°. showed bands at 3310 and 3470 (N-H) and a t 1575-1650 em.-' (C=N-Ph). Anal. Calcd. for Cl&N2: c, 81.32; H, 6.83; N , 11.86. Found: C, 80.89, 81.32, 80.88; H , 6.97, 7.11, 6.88; N, 11.54, 11.69, 11.62.

h~H5 Experimental

1,3-Diphenyl-2-methy1-1,3-propanedione ( I ).-Diethylmagnesium (5.8 mmoles) and benzonitrile (27.0 mmoles) in 32 ml. of tetrahydrofuran were allowed to react in a closed reaction vessel for 1 week a t room temperature, followed by heating on a steam bath for 40 hr. The brick red solution was decomposed in saturated ammonium chloride and extracted with ether. The ether solution was then extracted with 10% sodium bisulfite. After decomposition of the bisulfite solution, extraction with ether, and evaporation of the ether, a solid residue was obtained, which was recrystallized from 1: 1 hexane-pentane to give 0.22 g. (18.3% based on benzonitrile) of colorless product melting a t 81.0-82.3'. An analytical sample prepared by recrystallization from ethanol melted a t 83.4-84.7" (lit.la m.p. 82.584'). Anal. Calcd. for C&&: C, 80.65; H , 5.92. Found: C, 80.88, 80.86; H , 5.99, 5.73. The infrared absorption spectrum contained a doublet a t 1689 and 1667 cm.-l. The n.m.r. spectrum contained a quartet a t T 5.74-5.76 ( J = 5.9 c.p.6.) and a doublet a t 8.458.56 (J = 5.9 c.p.8.). The aromatic proton absorption appeared as two multiplets a t T 2.15-2.38 and 2.66-2.85. The relative areas of the quartet, doublet, and two aromatic multiplets were 1:3 :4 :6, respectively. The melting point of I was not depressed when admixed with an authentic sample of I prepared by the alkylation of dibenzoylmethane with methyl iodide. S-Methy1-2,4,6-triphenylpyrimidine(III).-The ether layer which remained after the extraction with sodium bisulfite in the preparation of I was concentrated to 30 ml. and, upon addition of 50 ml. of methanol, the crude solid precipitated, m.p. 167175". Recrystallization from ether afforded 0.98 g. (34.4% based on benzonitrile) of colorless crystals, m.p. 179.G180.3". An additional recrystallization from ether gave the analytical sample, m.p. 180.0-181.4" (lit.12 m.p. 182'). Anal. Calcd. for C23H18?;2: C, 85.68; H, 5.63; E, 8.69. Found: C, 85.85; H , 5.72; N,8.27. The n.m.r. spectrum contained a singlet a t T 7.70 as well as multiplets in the aromatic region a t 1.68-1.76, 2.42-2.63, and 2.66-2.90. The relative areas of these peaks were 3:2:4:9, respectively. The infrared absorption spectrum contained a strong peak a t 1538 cm.-'. A gas which was evolved when the reaction vessel above w a ~ opened was isolated on a vacuum manifold and identified as ethane by vapor phase chromatography on a Perkin-Elmer Vapor Fraktometer Model 154 using a J column. The retention time was identical with that of authentic ethane a t 25'. N-(a-Ethylbenza1)benzamidine (11). A.-To the diethylmagnesi~m1~81~ prepared from 14.2 g. (0.130 mole) of ethyl bromide and 1.6 g. (0.065 g.-atom) of magnesium in 200 ml. of ethyl ether, there was added 6.7 g . (0.065 mole) of benzonitrile. The solution turned yellow and a slight precipitate developed. After stirring the reaction mixture for 2 days a t room temperature, 20 ml. of water was added and the mixture was filtered. The combined organic layers were evaporated to dryness. Distillation of the residue afforded 8.2 g. (0.062 mole, 95%) of propiophenone ~ [lit.16b.p. 101.5ketimine, b.p. 92-96" (7.3 mm.), n Z 21.5475 102.5" (13.5mm.), nZ21)1.54761.

B.-The above reaction was run with 0.085 mole of diethylmagnesium and 0.17 mole of benzonitrile ( 1 ethyl group/benzonitrile). After decomposition of the reaction mixture in water, it was extracted with ether. Upon evaporation of the ether, crystals were obtained which were white after washing with ether. (12) R. hl. Anker and h. H. Cook [ J . Chem. Soc.. 323 (1941)l isolated 2-ethyl-2.4,6-triphenyl-l,Z-dihydrotriaeine from the reaction between ethyllithium and benzonitrile. \\'hen they heated the heterocycle a t 250300O. it was converted t o 111. (13) R. D.hhell. ibid., 928 (1901). (14) S. J. Stofer and E. I. Becker, J . O w . Chem., 87, 1868 (1962). (15) R. Kullmann. Compt. rend., 281, 866 (1950). (16) C. Moureu and G . Mignonac, ibid., 166, 1801 (1913).

Attempts to prepare this compound from benzamidine and propiophenone failed. When the mother liquor from the above preparation was distilled i n vacuo, 2.9 g. (13%) of propiophenone, b.p. 35-36' (8 mm.), n Z 6 D 1.6293, was isolated. The nondistillable residue was a thick, orange oil which hardened to a glass upon standing. The glass was insoluble in water, 5% sodium bicarbonate, 570 sodium hydroxide, 6 N NaOH, and 2 N HC1, but it did dissolve in concentrated hydrochloric acid. Trituration of the "glass" with methanol dissolved the orange material leaving white crystals, m.p. 182-183". The infrared spectrum of this material was identical with that of 111. 1-(2,4-Dinitrophenyl)-3,5-diphenyl-4-me~ylpyrazole .-A solution of I, 0.886 g. (3.72 mmoles), in 50 ml. of ethanol was combined with a hot solution of 0.737 g. (3.68 mmoles) of 2,4-dinitrophenylhydrazine in 150 ml. of ethanol containing 10 ml. of concentrated hydrochloric acid. After cooling, 1.21 g. of yellow solid, m.p. 18@182", was obtained by filtration. Recrystallization from 175 ml. of ethanol afforded 1.09 g. (67.0%) of yellow An analytical sample, prepared by crystals, m.p. 183.2-185.0'. recrystallization from ethanol, melted a t 183.3-185.1 '. Anal. Calcd. for C&16?;/404: c , 65.99; H , 4.03; N , 13.99. Found: C, 65.91; H , 3.65; N , 13.76.

Acknowledgment.-We acknowledge the generous support of part of this work by the National Science Foundation under its Grant G-14558 (A. A. S.) and by the American Cyanamid Company (N. M. B.). We also acknowledge the synthesis of 1,3-diphenyl-2methyl-1,3-propanedione by Mr. William Greenberg.

Halogenation of Aromatic Compounds by N-Bromo- and N-Chlorosuccinimide under Ionic Conditions FRANK L. LAMBERT, WILLIAMD. ELLIS,A N D RONALD J. PARRY Department of Chemistry, Occidental College, Los Angeles, California 90041 Received July by, 1964

In the extensive literature involving N-halosuccinimides and related N-halo compounds, there appears to have been only one investigation of ring substitution by N-haloimides or -amides in aromatic compounds not containing highly active groups.' Schmid2 found that benzene and toluene gave fair yields of their respective monobromo derivatives with N-bromosuccinimide (NBS) and aluminum chloride, but poor yields (together with polysubstituted products) following long reflux with NBS and zinc or iron(II1) chlorides, or wi h NBS and concentrated sulfuric acid. Our work in which t-butyl hypochlorite was used in aqueous sulfuric acid to attack aromatic compounds resulted in excellent yields of ring-chlorinated prodU C ~ but S , ~announcement of the results was anticipated aromatic compounds without hydroxy or amino groups or their (1) derivatives. (2) H. Sohmid, Helu. Chzm. Acta. 99, 1144 (1946). (3) We thank Paul J. Shlicta, Ted W. Reid, David A. Keefer. and Jerry D. Albert for extensive experimental work in developing this area, and the National Science Foundation for its support under G-2386 and under the Undergraduate Research Participation Program (G-1226).

JANUARY1965 by the publication of parallel findings by Harvey and Norman.' However, this experience with t-butyl hypochlorite led us to consider the potentially analogous behavior of the more readily available N-bromo- (NBS) and N-chlorosuccinimides (NBS) . We have found that rapid aromatic substitution resulting in excellent yields of product takes place under easily attainable experimental conditions. Polyhalogenation is nil or very low and no benzylic substitution occurs when toluene is the substrate. The results are presented in Table I. TABLE I AROMATIC HALOGENATION BY N-BROMOAND N-CHLOROSUCCINIMIDE IN AQUEOUS SULFURIC ACID Aromatic compd.

305

NOTES

Halogenating agent

-Reaction condn.Temp., Time? HZSOI" hr. OC.

Yield of product:

%

81d 45-55 1 : 4 3 75 NBS 90d 50-55 1:l 2 NBS 0.42 83d 50-55 1:l NBS 0.42 2 50-55 1:l Br2 64' 65-70 1:l 2 5 NCS 95, 65-70 1:4 2 5 Toluene NBS 1 93f 70-80 1:l NCS 94, 50-55 1 : l 2 25 Chlorobenzene NBS 59f 60-65 2:l 4 NCS 80f 80-85 2 : l 2.25 NCS 85-90 1:l 3 700 Nitrobenzene NBS b Time a Ratio of concentrated H2S0, to water by volume. that the reaction mixture was stirred. Actual reaction may have been completed within 30 min. in all, except for nitroPer cent of theoretical. benzene; cf. Experimental section. Dihalo derivative less than 1% yield. 6 Dihalo derivative less than 0.6% yield. f No dihalo product (from toluene) or polyhalo (from chlorobenzene) detected in V.P.C. analysis. 0 Determined by V.P.C. on a 6 ft. X 0.25 in. column of Apiezon L on 60-80-mesh Chromosorb regular. No dihalo product. Benzene

Although modest attempts were made to obtain adequate product yields, no exhaustive investigation of optimum conditions was carried out because of the generally excellent results noted in Table I. More dilute acid usually resulted in lower quantities of product. Portionwise addition of the NBS or NCS to the reaction mixture over a period of hours gave equal or better yields but was obviously less convenient than the simple mixing of all reagents a t one time. The bleach test described in the Experimental section afforded a convenient indication of the progress of the reaction. The isomer distribution of the products of reactions involving toluene and chlorobenzene is given in Table 11. Although the isomer distributions are consistent with halogenation a t 25' by (H20X)+ or Cl+,5it is patently fallacious to draw strong mechanistic conclusions from this correlation. Certainly, the actual halogenating moiety is not free halogen; the experiments using bromine in sulfuric acid gave very small amounts of product (Table I). The active agent could possibly be the protonated N-halo compound as has been suggested for N-chloromorpholine.6 Further study is necessary to establish the mechanism of the reaction. (4) D. R . Harvey and R . 0. C. Norman, J . Chem. Soc., 3604 (1961). (5) Leading references are given by L. M. Stock and H . C. Brown, Aduan. Phvs. OW. Chem., 1, 34 (1963). ( 6 ) M . D. Carr and B. D. England, Proc. Chem. Soe., 350 (1958).

TABLE I1 ISOMER DISTRIBUTION IN

THE HALOGENATION OF AROMATIC COMPOUNDS BY N-HALOSUCCINIMIDES IN AQUEOUS SULFURIC ACID

Compd.

Halogenating agent

--homer ratioortho mela para

Analytical method

67 2 31 a 65 1 34 a 39.4 1 . 5 59.1 b Chlorobenzene 41.3 1 . 4 57.3 b Determined by V.P.C. on a 12 ft. X 0.25 in. column of a p proximately 10% tricreayl phosphate on 60-80-mesh Chromosorb regular. meta and para isomers were not resolved. mChlorotoluene was determined by infrared analysis using the 8 6 @ ~ m . -band, ~ and m-bromotoluene by using the 830-, 765-, and 679-cm.-1 bands. b Determined by V.P.C. on a 12 ft. X 0.25 in. column of 5y0 diisodecyl phthalate and 5% Bentone on 60-80-meah Chromosorb W. Toluene

NBS NCS NBS NCS

Because of the ready availability and convenience of use of the halogenating agents, simple reaction conditions, short reaction time, absence of large amounts of free bromine or chlorine, and generally excellent yields of monohalo derivatives, this process of ring substitution with N-haloimides (and presumably Nhaloamides) under ionic conditions recommends itself for a wide variety of aromatic halogenations. Experimental General Procedure.-In a 500-ml. three-necked Morton flask, which was heated by a water bath and fitted with thermometer, condenser, and Teflon blade stirrer, was placed 200 ml. of sulfuric acid, diluted as noted in Table I. After 100 ml. of the aromatic compound had been poured in and the temperature adjusted as desired, 0.16 mole of NBS or NCS was added to the vigorously stirred reaction mixture.' The temperature usually rose 2-10' above that of the water bath for a few minutes. The progress of the reaction could be followed more accurately by use of potassium iodide-starch paper. When a drop of the reaction mixture was placed on the paper, a blue-black spot immediately appeared. Within a few seconds to a minute, the center of the blackened area bleached toward white. When this effect was no longer observed (after 15 min. for toluene, 2 hr. for nitrobenzene), the reaction was assumed to be nearly complete.* However, in all cases except those noted in Table I , stirring was continued for a t least 1 hr longer. The 25-min. reaction time (with benzene) was based on the results of the bleach test; the yield of product obtained in this experiment compared with those wherein longer reaction times were used indicates that the test is of adequate utility in following the progress of the reaction. Work-up of the reaction mixture was by obvious methods: separation of layers, washing of the organic layer with base and water,O and finally distillation through a simple 2-ft. tantalum helix column a t atmospheric pressure. Isomer distribution analyses were made by V.P.C. analysis of the solvent-stripped product in a Research Specialties instrument fitted with katharometer detector and employing the columns noted in Table 11. Because the m- and p-halotoluenes were not resolved on the columns available, a solvent-free fraction of the product was analyzed for concentration of the meta isomer using a neat sample in a Perkin-Elmer 237 infrared spectrophotometer a t the band positions stated in Table 11. Infrared (7) Vigorous agitation was essential. Slow stirring, even in a Morton flask, decreased yields of product by a third or more. (8) The bleaching of the blue-black starch-iodine complex may be caused by the N-halosuccinimides themselves in dilute sulfuric acid or by the halogenating agents derived from them. Whichever is the case, when bleaching no longer occurs, little (if any) potential or free halogenating agent remains in the reaction mixture and, thus, little or no further halogenation can be expected. (9) I n one experiment involving nitrobenzene and NBS, bromine vapors were noted during the final distillation despite supposedly adequate washing. A subeequent preparation was shaken with ammonium hydroxide after the sodium hydroxide wash and no such difficulties were experienced.

NOTES

306

and V.P.C.results were corroborated by examining mixtures of known composition of the pure halo aromatics involved. Chemicals.-Practical N-bromosuccinimide (Arapahoe) or purified NBS (Matheson Coleman and Bell) gave equivalent yields of product as did practical or purified N-chlorosuccinimide (Matheson Coleman and Bell) after allowance for inert content. Of the substances used as standards in the V.P.C. or infrared analyses, o-bromochlorobenzene was synthesized by the standard procedurelo; all other chemicals were White Label Eastman or reagent grade Matheson Coleman and Bell products whose purity was established by V.P.C. and/or infrared examination.

VOL. 30

type of product obtained. The reaction is quite rapid at room temperature, being complete in less than 1 niin. The following mechanism is suggested to account for the formation of the observed product. II II

4- -CN

S

0 II Ph- C -0- -Ph

I

CN

(10) J. L. Hartwell, “Organic Syntheses,” Coll. Vol. 111, E. C. Homing, E d . , John Wiley a n d Sons, Inc.. New York. N. Y., 1955,p. 185.

B 7CN,

Ph-C-0-

Reaction of Benzil with Cyanide Ion i n Dimethyl Sulfoxide

Ph

-

77

+

Ph-C-C-Ph

I

0 0II I Ph-C-C-Ph

JOHNC. TRISLER A N D JERRYL. F R Y E ~

Ph-&-O-C-Ph

I

-

Department of Chemistry, Louisiana Polytechnic Institute, Ruston, Louisiana Ph-C-C-Ph

I Ph -C-0 I

A number of reports concerning the cleavage of ben-

CN

zil by cyanide ion has appeared in the literature. Jourdan2 and more recently Kwart and Baevsky3 reported that cleavage products in alcoholic solution are benzaldehyde and the corresponding benzoic ester. (PhC0)Z

I

CN

Acknowledgment.-We thank Mr. James P. Hardy for preliminary experimental work and the National Science Foundation for its support by Grants G-12126 (J. P. H.), GE-987 (R. J. P.), and GE-2797 (W. D. E.) for Undergraduate Science Education.

Received September 8, 1964

0 0II I Ph-C-C-Ph

0 0 Ph-C-C-Ph

CN

II 0

-0 Ph-k%-Ph

I

-C-Ph

Ph-C-0-C-Ph

I !

CN

I

II

0

-CN + ROH + PhCHO + PhCOzR

Dilthey and Scheidt4 observed that the benzilic acid rearrangement is inhibited by cyanide ion and that cleavage products, benzoic acid and benzaldehyde, are obtained. Dakin and Haringtons found that benzil is converted to benzaniide and benzaldehyde by alcoholic ammonium cyanide. Other aromatic a-diketones were observed to exhibit similar behavior. Weiss6has shown that a mixture of benzoin and benzil can be separated by taking advantage of the facile cleavage of benzil by cyanide ion in aqueous ethanol at room temperature. Benzoin is also cleaved by cyanide ion, but under more vigorous conditions’; the reaction is carried out in refluxing aqueous ethanol and for a longer period of time than that required for benzil cleavage. Although cleavage of benzil by cyanide ion in protic solvents has been extensively studied, to our knowledge an investigation of the reaction in an aprotic solvent’ has not been made. With this thought in mind benzil was treated with sodium cyanide in dimethyl sulfoxide and trans-CY,a’-stilbenediol dibenzoate (11)was obtained as the cleavage product. Thus, it is seen that a change froni protic to aprotic solvent causes a change in the (1) Taken in part froni the M.S.Thesis of J . L. F. (2) F. Jourdan, Ber.. 16,659 (1883). (3) H.K a a r t and h‘l. Baevsky. J . Am. Chem. Soc., 80,580 (1958). (4) W.Dilthey and P. Scheidt, J . prakt. Chem., 141, 125 (1935). (5) H.D. Dakin and C. R. Harington, J . Biol. Chem., 66,487 (1923). (6) M. Weiss and M. Appel. J . Am. Chem. Soc., T O , 3666 (1948). (7) J. S. Ruck and W.S. Ide, ibid.. 69, 2784 (1931).

Reaction steps 1 and 2 in alcoholic solution have been established by the work of Kwart and Baevsky. These investigators proposed that step 2 is followed by neutralization of anion I with subsequent cleavage to benzoic ester and benzaldehyde as shown in eq. 6. Ph-C-0--C-Ph

1

I

I

+ ROH +

CN Ph-C-0-R

H

+ Ph-CHO + -CN

(6)

I t is seen that in an aprotic solvent reaction step 6 is not likely to occur. In dimethyl sulfoxide a proton is not readily available and, since this solvent has a tendency to greatly enhance nucleophilic activity,* anion I would be expected to attack the available electrophile which is another inolecule of benzil. Actually steps 4 and 5 are quite similar to step 2 with the exception that cleavage is accompanied by the loss of cyanide ion and forination of the stable coinpound 11. In addition to accounting for the observed product in a logical manner, the suggested inechanisni tends to further support the mechanism proposed by Kwart and Baevsky3 for the cleavage reaction in alcoholic solution. Reports concerning ala’-stilbenediol dibenzoate usually refer to the isomer melting at l5g0, “isobenzil’J, ( 8 ) 4 . J. Parker, Quart. Rev. (London), 16, 163 (1962).

JANUARY 1965

NOTES

with no reference to whether the compound has a cis or trans configuration. Staudinger and Binkert'O reported the preparation of stilbenediol dibenzoate, m.p. 159', along with a small quantity of a material melting at 185-187' from the reaction of benzoyl chloride with the potassium salt of stilbenediol. The material melting a t the higher temperature was said to be "probably the a-compound". More recently Ried and Ked1' referred to the higher melting compound as trans-stilbenediol dibenzoate. The compound was formed in low yield (1%) from the reaction of the benzoin-piperidine Mannich base with benzoyl chloride in pyridine. Blake, Coates, and TateI2 reported the compound melting at 159' as cis-stilbenediol dibenzoate. We have found that both isomers of a,a'-stilbenediol dibenzoate are conveniently prepared by first reducing benzil with potassium metal in refluxing benzene followed by the addition of benzoyl chloride to the reaction mixture. Presumably the potassium salt of stilbenediol is formed prior to the addition of benzoyl chloride. lo Separation of the two isomers is easily accomplished by taking advantage of the fact that the cis isomer is considerably more soluble than the trans isomer in benzene.

hot benzene. The combined filtrates, after being concentrated to 20 ml. and allowed to cool, afforded 1.53 g. (36% yield) of trans-a,a '-stilbenediol dibenzoate (II), m.p. 189' (from benzene), m.p. 188.5-189'. The filtrate remaining after isolation of the trans isomer was evaporated and the residue was triturated with aqueous acetone yielding 1.60 g. (38% yield) of cis-a,a'-stilbenediol dibenzoate, m.p. 158-159" (from 95% ethanol), lit.lo m.p. 159'.

Experimentalla Starting Materials.-Sodium cyanide was commercial material of the highest available purity and was dried for several hours a t 100' under vacuum prior to use. Benzil, m.p. 94-95', was obtained commercially and was used without further purification. Dimethyl sulfoxide1' wad dried with Molecular Sieves and in some cases distilled from calcium hydride ( 1 mm.).16 Other materials were of reagent grade and were used as obtained. Benzil and Sodium Cyanide in Dimethyl Sulfoxide.-Sodium cyanide, 0.49 g. (0.01 mole), was heated with stirring in 80 ml. of dimethyl sulfoxide to 70" under a nitrogen atmosphere. After most of the solute had dissolved, the solution was allowed to cool slowly to room temperature at which time 2.10 g. (0.01 mole) of benzil was added in one portion. The solution instantly became dark brown in color and after a reaction time of 1 min. was poured into cold water. The resulting aqueous suspension was acidified and extracted with ether. The ether solution was washed with water, extracted with sodium bicarbonate solution, washed again with water, dried, and evaporated. The residue, on trituration with ethanol, afforded 1.65 g. (78y0 yield) of trans-a,a'stilbenediol dibenzoate (II), m.p. 189" (from benzene), lit." m.p. 188.5-189'. On admixture with an authentic sample no depression in melting point was observed. Anal. Calcd. for C ~ B H ~ ~C,O ~ 79.89; : H, 4.79. Found: C, 79.55; H, 5.15. The sodium bicarbonate layer was acidified and extracted with ether from which was obtained 0.10 g. of benzoic acid, m.p. 121-122" (from water). Preparation of cis- and trans-a,a'-Stilbenediol Dibenzoate .Potassium metal, 0.78 g. (0.02 g.-atom), waa placed in a flask containing 50 ml. of anhydrous benzene. The flask was heated while being stirred in an atmosphere of nitrogen, t o the boiling point of the solvent. Benzil, 2.10 g. (0.01 mole), in 25 ml. of benzene was added slowly. When addition was complete the brown solution was stirred for 30 min. followed by the addition of 2.3 ml. (0.02 mole) of benzoyl chloride in 15 ml. of benzene. After stirring for an additional 15 min. the hot reaction mixture was filtered and the inorganic residue was extracted twice with (9) M . S. Kharaach. W. Nudenburg, and 9. Archer, J. A m . Chem. Soc., 6 6 , 495 (1943); M. Gomberp and W. E. Bachmann. ibid., 48, 2584 (1927); G. Scheuing and A. Heusle, Ann., 4 4 0 , 7 2 (1924); H. Klinger and L. Schmits, Ber.. 34, 1277 (1891), and references cited therein. (10) H. Staudinper and A. Binkert. Helu. Chim. Acta, 6 , 703 (1922). (11) W. Ried and G. Keil, A n n . , 616, 96 (1958). (12) D. Blake. G. E. Coates. and J. M. Tate. J. Chem. Soc., 618 (1961). (13) Melting points are uncorrected. Elemental analysis was carried out by Swarskopff Microanalytical Laboratories, Woodside 77, N. Y. (14) We gratefully acknowledge a free sample of dimethyl sulfoxide from Crown Zellerbach Corp., Camas, Wash. (15) E. J. Carey and M. Chaykovsky, J. A m . Chem. Soc., 84, 866 (1962).

307

A New Microbiological Steroid Reaction A. J. MANSON, R. E. SJOQREN, AND M. RIANO Sterling-Winthrop Research Institute, Rensselaer, New YOrk Received September 1, 196.4

During an investigation' of the action of various microorganisms on 2-hydroxymethylene-3-keto steroids,2 it was observed that when these substrates were submitted to the enzymatic action of Rhizopus stolonifer (also known as Rhizopus nigricans) an unusual reduction of the P-hydroxy-a$-unsaturated ketone to a @-hydroxy ketone occurred in preference to the more characteristic reactions of this microorganism ( i ~ . hydroxylation). , This Note reports the microbial reduction of 17a-ethinyll7-hydroxy-2-hydroxymethyleneandrost-4-en-3-one(I) and the pertinent chemical evidence in support of the assignment of structure 11.

n

(1) M. Riano, et at.,to be published. (2) The preparation of these compounds is reported by A. J. Manson, F. W. Stonner. H. C. Neumann, R. G . Christiansen, R. L. Clarke, J . H.

Ackerman, D. F. Page, J. W. Dean, D. K. Phillips, G. 0. Potts, A. Arnold, A. L. Beyler, and R. 0. Clinton, J . Med. Chem., 6 , 1 (1963), and references cited therein.

308

NOT=

17a-Ethinyl-17-hydroxy-2 - h y d r o x y m e t h y 1en eandrost-4-en-3-one (I) was incubated with R. stolonifer ATCC 12939(-) in a medium containing commercial dextrose, Edamine,3 and corn steep liquor for 38 hr. a t 27'. The major product of this reaction, which after purification was obtained in a 10% yield, was assigned structure I1 on the basis of its elemental analysis and its infrared, n.m.r. and ultraviolet spectra (see Experimental), This structure was rigorously proved by the following chemical evidence. Acetylation of I1 with acetic anhydride in pyridine yielded the monoacetate 111, which on treatment with sodium bicarbonate in aqueous methanol at room temperature afforded 17a-ethinyl17-hydroxy-2-methyleneandrost-4-en-3-one (IV). The structure of IV was confirmed by the comparison of the infrared and n.m.r. spectra with those of an authentic sample prepared from 17a-ethinyl-17-hydroxyandrost-4-en-3-one via the Mannich base V by the procedure of Carrington and c o - ~ o r k e r s . ~Therefore the microbial reduction product must be 17a-ethinyl-17hydroxy-2-hydroxymethylandrost-4-en-3-one(11). The configuration of the hydroxymethyl group of I1 is assumed to be equatorial (ie., the more stable isomer) due to conditions of its isolation. This assumption is supported by the observation that the infrared spectrum of I1 shows a ketone maximum at 6.05 pt(CHCl3), an unusually high wave length suggestive of a hydroxycarbonyl interaction5 which could only occur if the hydroxymethyl group is in the equatorial configuration. Furthermore, intramolecular hydrogen bonding is indicated by the fact that the relative intensities of the absorption bands of the two hydroxyl groups a t 2.76 and 2.83 p (CCI,) are not altered by dilution of the solution (c 0.004, 0.002, and 0.0002 M ) . Consistent with this line of thought is the normal absorption of the A 4 3 ketone of the monoacetate 111a t 5.98 p (CHClB). Prior to this Note th eonly reported microbiological reduction of a p-hydroxy-a,@-unsaturated ketone or its tautomer was the reduction of p-ketobutyraldehyde to d-1,3-butanediol by yeast.6 Furthermore, it is noteworthy that R. stolonifer is generally associated with oxidative rather than reductive types of microbiological reactions.'

VOL. 30 The cooled solution was inoculated with a 72-hr. vegetative growth of R. stolonzfer ATCC 12939( -). (This inoculum was prepared by incubating an aerated 10% suspension of the organism in 1 1. of the above sterile nutrient solution contained in ten 500-ml. Erlenmeyer flasks on a shaker rotating a t 210 r.p.m. a t 26".) The culture was allowed to grow for 21 hr. at 27" with an air supply of 3 l./min. and while agitated a t 400 r.p.m. After this period of time, a solution of 4 g. of 17a-ethinyl-17-hydroxy-2hydroxymethyleneandrost-4-en-3-one ( I ) *in 10 ml. of dimethylformamide was added to the culture under aseptic conditions and fermentation was continued under identical conditions for another 38 hr. The fermentation broth was then adjusted to pH 2 by the addition of 6 N hydrochloric acid and extracted twice with 20-1. portions of methylene dichloride. The combined extracts were concentrated on a steam bath under reduced pressure to a volume of ca. 2 l., washed with 2% sodium bicarbonate solution and water, dried (Na2S04), filtered, and concentrated to dryness to afford 1.55 g. of a residue. The crude product was subjected to chroniatography on 50 g. of silica gel. Elution with 5-60% ethyl acetate in ether gave 0.82 g. of colorless solid, which was recrystallized from ethyl acetate. The pure 17a-ethinyl-17hydroxy-2a-hydroxymethylandrost-4-en-3-one(0.41 g.) formed colorless needles: m.p. 164-165"; [ a ] +38.8"; ~ A,, 242 mp ( e 14,400); A,, 2.94 (OH), 4.74 ( c = c ) , 6.06 and 6.18 p (A4+ ketone); : : :A 2.76 (C-17 OH) and 2.83 (bonded OH); 6.05 p ( C 4 ) ; &" (lo'%, CDCla), 1.28 ((3-18 CH,), 1.80 (C-19 I CHI), 3.12 (GCH), 4.30 (-CH,O-), and 6.30 p.p.m. (-CI

CH=). Anal. Calcd. for C22H3003: C, 77.16; H , 8.83. Found: C, 77.17; H, 8.83. I n a control experiment, in which only the microorganism was omitted, no amount of I1 could be demonstrated by careful thin layer chromatography. 2a-Acetoxymethyl-l7~-ethinyl-l7-hydroxyandrost-4-en-3-one (111).-17a-Ethinyl-l7-hydroxy-2~-hydroxymethylandrost4 -en%one (11, 174 mg.) was dissolved in a mixture of 0.5 ml. of pyridine and 1 ml. of acetic anhydride. After standing for 4 hr. a t room temperature the mixture was quenched in ice-water and the precipitated material was collected, air dried, and recrystallized from ether-hexane. The monoacetate (78 mg.) had a m.p. 8689'; [ a ]+20.2; ~ Amax 241 mp ( e 12,600); A,, 2.88 (OH), 3.04 (=CH), 4.75 (C=C), 5.74 ( C = O of acetate), and 5.98 and 6.19 p (A4-3-ketone); 5.75 ( C 4 of acetate) and 5.98 p (A4-% ketone). Anal. Calcd. for C2aH8204: C, 74.97; H , 8.39. Found: C, 74.67; H , 8.49.

17~-Ethinyl-17-hydroxy-2-methyleneandrost-4-en-3-one (IV). A. From 2~-Acetoxyethyl-l7~-ethinyl-l7-hydroxyandrost-4-en3-one (III).-A solution of 0.60 g. of I11 in 25 ml. of methanol wae added to a solution of 1.2 g. of potassium bicarbonate in 100 ml. of 80% aqueous methanol. After 30 hr. a t room temperature the mixture was concentrated to a small volume under reduced pressure. The residue was mixed with 50 ml. of water and extracted Experimentala with ethyl acetate. The extract was dried (Na*SOI),filtered, and evaporated to dryness. There remained an oil which was dis17~-Ethinyl-l7-hydroxy-2a-hydroxyethylandrost-4-en-3-0ne solved in a minimum amount of ethyl acetate. On the addition (II).-A nutrient solution, prepared from 500 g. of commercial of hexane to this solution, a solid precipitate (0.30 g.) was obdextrose (Cerelose), 200 g. of Edamine,I 50 nil. of corn steep tained. Thin layer chromatography (silicon dioxide-ethyl aceliquor, and tap water ( q . s . 10 1.) was placed in a 14-1. fermentation tate) of this solid revealed two spots of equal intensities as detank and the solution was sterilized for 45 min. a t 15-lb. pressure. tected by sulfuric acid treatment followed by heat. One of these spots had a Rf value that was identical with that of the RI value of 17a-ethinyl-17-hydroxy-2a-hy.droliymethylandrost-4-en-3-one. (3) An enzymatic digest of lactalbumin obtained from Sheffield Farms' New York, N . Y . The other, less polar spot, was assumed to be the title compound. (4) T. R. Carrington, A. G. Long, and A. F. Turner, J . Chem. Soc., 1572 The crude mixture wae subjected to chromatography on 40 g. of (1982). The synthesis of I V by still another method (i.e., aldol condenmFlorisil. Elution with 10% ether in benzene gave a series of tion of the corresponding 2-ethoxyoxalyl derivative and formaldehyde) was fractions which was combined,(0.05 g.) and recrystallized from recently reported by D . D . Evans, D. E. Evans, G . 9. Lewis, and P. J. ethyl acetate and pentane to afford 170-ethinyl-17-hydroxy-2Palmer, ibid., 4312 (1963). methyleneandrost-4-en-3-oneas colorless, rectangular plates: (5) (a) R. N. Jones, P. Humphries, F. Herling, and K . Dobriner, J . A m . m.p. 184-185"; [ a ]=~ 70.0 (C=O, 4%); Ama, 260 mp ( e Chem. Soc., 74, 2820 (1952); (b) A. C. Huitric and W. D. Kumler, ibid.. 13,900); A, 2.90 (OH), 4.75 (C=C), and 6.00 and 6.15 p (A47 8 , 1147 (1956). (6) S. Grzycki, Biochem. 2.. 466, 195 (1933). 3-ketone); b,,, (12% C D C ~ I )1.45 , (C-18 CH,), 1.67 ((2-19 CHI),

+

(7) S. C. Prescott and C. G. Dunn, Industrial Microbiology, 3rd Ed., McGraw-Hill Book Co.. Inc., New York, N. Y., 1959, Chapter 44. ( 8 ) All melting points are corrected. Except as noted, rotations were measured in chloroform (e -1) solution at 25O, ultraviolet spectra in 95% ethanol (Cary), and infrared spectra in a KBr disk (Perkin-Elmer 21). Nuclear magnetic resonance spectra were determined on a Varian A-60 spectrometer using tetramethylsilane a8 an external standard and the signal assignments were consistent with the observed intensities and line shapes.

3.04 (=CH), 5.80 and 6.50 (=CH*), and 6.42 p.p.m. (-CCH=).@

I

(9) Cf. assignment of n.m.r. signals for 2-methylene-17a-methyltestoeterone, J. A. Edwards, M. C. Calzada and A. Bowers, J . Med. Chem., 6, 178 (1963).

NOTES

JANUARY 1965 Anal. Cslcd. for CzzH~02: C, 81.44; H, 8.70. Found: C, 81.66; H , 8.45. B. From l7c~-Ethmyl-l7-hydroxyandrost-4-en-3-one ma Mannich Reaction.-A solution of 14.0 g. of 17a-ethiny1-17-hydroxyandrost-4-en-3-one, 7 .O ml. of 40% aqueous formaldehyde, and 7.0 g. of dimethylamine hydrochloride in 300 ml. of acetic acid was heated in a nitrogen atmosphere a t 80"for 1 hr. Thereaction mixture wag poured into 2 1. of ice-cold water. The resultant precipitate was collected on a filter and dried. This material (1.04 9.) proved to be recovered starting material. The filtrate was made neutral with saturated sodium bicarbonate solution and extracted with methylene dichloride. The organic extract was washed with saturated salt solution, dried (NaB04),filtered, and evaporated to dryness under reduced pressure to afford 14 g. of a solid. (Purification of a small sample of this base by recrystallization from methylene dichloride was unsuccessful, probably owing to ita ready decomposition to the 2-methylene derivative.) The crude Mannich base was decomposed to the 2-methylene derivative by subjecting it to chromatography on 400 g. of Florisil. Elution with methylene dichloride-ether ( 1 : l ) gave 3.69 g. of crude 2-methylene derivative, m.p. 167-174', which was ehown by thin layer chromatography to be partly contaminated with starting material. The crude product was subjected to a Becond purification by chromatography on 300 g. of Florisil. Elution with benzene-ether (9 :1) and two recrystallizations from acetone afforded 1.02 g. of pure 17~~ethinyl-l7-hydroxy-2-methyleneandrost-4-en-3-one as colorless plates, m.p. 182-184", undepressed upon admixture with the sample prepared by method A. The infrared and n.m.r. spectra of this sample were identical with those of the sample prepared by method A.

Acknowledgment.-The authors are indebted to Dr. F. C. Nachod, Miss C. M. Martini, and Mr. M. Priznar for spectral determinations, and to Mr. K. D. Fleischer and staff for analytical services.

The Alkaloids of Tabernanthe iboga. IX.' e O The Structures of the Ibogaline Derivatives, Kisantine and Gabonine W. I. TAYLOR Research Department, Ciba Pharmaceutical Company, Division of Ciba Corporation, Summit, New Jersey

309

138

I

Figure 1.-Tabernanthine

oxindole (above) and kisantine (11) (below).

methoxyoxindole itself [Amax mp ( E ) , 264 (7440) and sh 299 (3600); vgzb 1710 and 1680 ~ m . - ~ ] . 'This conclusion is borne out in the p.m.r. spectrum8 which showed the presence of a strong singlet peak a t 3.9 (2-MeO), two singlet peaks at 7.1 and 6.56 (two uncoupled aromatic protons), a singlet at 9.1 (NH), and the characteristic set of peaks a t ca. 1 p.p.n~.for the CH3 of the ethyl moiety. Me0

) ? J T J H &

Me0

H

M Me0

I1

I

Meyl*

Me0

H

I11

Six years ago we reported2the isolation of twelve alkaloids from Tabernanthe iboga Baillon and determined the structures of nine of them.3 Of the remaining three bases, which had been obtained in very small amounts, kimvuline has been shown to be identical with iboxygaine4 and now kisantine and gabonine are recognized to be oxidation products of ibogaline (I),5which contain the oxindole (11) and the o-acetamidoacetophenone (111) chromophores, respectively. Kisantine (11) [Amax mp ( E ) , 213 (31,700), 268270 (6270) and sh 296 (4710); vZ$d 1670 cm.-'] has spectral properties in agreement for a 5,6-dimethoxyoxindole chromophore; cf. carapanaubine6 or 5,6-di-

Confirmation of these conclusions were obtained from a comparison of the mass spectrag of tabernanthine oxindolea and kisantine (Figure 1) which differ only in respect to those peaks which contain the extra methoxyl group. Gabonine has an ultraviolet absorption spectrum [A, mp ( E , calcd. for monomer), 250 (24,020), 283 (6620), and 348-350 (5530)l similar to that recorded for N-ethoxalyl-o-aminoacetophenonelO and almost superimposable upon that of 2-acetamido-4,5-dimethoxybenzaldehyde [Amax mp (e), 251 (35,200), 290 (9640), and 344 (7990)l. The p.m.r. spectrum' showed the expected singlet peaks a t 10.15 (NH), 8.1 and 7.0 (the two aromatic protons), 3.95 and 3.90 (the two MeO), and the eet of peaks ca. 1 p.p.m. (CH3 of an ethyl group).

(1) Part VIII. M. F. Bartlett, D. F. Dickel, R. C. Maxfield, L. E. Paszek, and A . F. Smith, J . A m . Chem. Soc., 81, 1932 (1959). (2) D. F . Dickel, C. L. Holden, R. C. Maxfield, L. E. Paszek, and W. I . Taylor, ibid., 80, 123 (1958). (3) M. F. Bartlett. D . F. Dickel, and W. I. Taylor, ibid., 80, 126 (1958). (4) R . Goutarel, F. Percheron, and iM.-M. Janot, Compt. rend., 346, 279 (1958). Iboxygaine (sample from M.-M. Janot) gives an undepressed mixture melting point and a superimpossble infrared spectrum in Nujol with kimvuline. (5) N. Neuss, J . Ore. Chem., 24, 2047 (1959). (6) B. Gilbert, J. A. Brisaolew, N . Finch, W. I. Taylor, H . Budsikiewicz, J. M. Wilson, and C. Djerassi, ibid., 86, 1523 (1963).

(7) These and other simple oxindoles [G. N. Walker, J . A m . Chem. Soc., 7 7 , 3845 (1955)l show two strong bands in the carbonyl region not shown b y their 3,3-disubstituted derivatives, e.g., the oxindole alkaloids; ref. 6 and N . Finch and W. 1. Taylor, ibid., 84, 3871 (1962), and references therein. (8) The p.1n.r. spectra were run in deuteriochloroform on a Varian A-60 using tetramethylsilane as an internal standard. The shifts are reported in parts per million using the tetramethylsilane signal as reference. (9) The mass spectra were determined for us through the kindness of Dr. C . Djerassi. (10) R . Goutarel, M.-M. Janot, V. Prelog, and W. I. Taylor, Hels. Chim. Acta, 99, 150 (1950).

Received March 6, 1964

NOTES

310

In the infrared spectrum gabonine had a set of peaks in Nujol at 1595, 1620, and 1672 cm.-' (broad) in good agreement with the model (1595, 1610, 1650, and 1680 cm. -l). An attempt was made to prove the validity of these conclusions by ring closure to a 4-quinolinol (cf. ring closure of the analogous yohimbine derivative") ; the compound remained unchanged as also did the related ozonolysis product of voacangine.'* A Dreiding model of the tetracyclic system (left-hand monomeric unit of IV) derived from ibogaline showed that the preferred configuration of the ten-membered ring was not favorable for ring closure (cf. an analogous situation for vobasine13). It may well be that the formation of iboquine by autooxidation of ibogaine does not proceed via a ring-opened intermediate. When the mass spectrum of gabonine was run the molecular ion was found to be exactly twice what was expected, viz., 2 x 372; hence, it is a t least a dimer. The paucity of gabonine and the rareness of ibogaline makes the attempted preparation of the former from the latter impossible for the moment, and structure IV for gabonine is put forward as a working hypothesis only.

IV

In view of the known ease of autooxidation of the iboga-class indole^,^^^ the possibility exists that kinsantine and gabonine may be artefacts isolated instead of ibogaline, which we never detected. (11) B. Witkop and S. Goodwin, J. A m . Chem. Soc., 76, 3371 (1953). (12) F. Walls, 0. Collera, and A. Sandoval, Tetrahedron, 2, 173 (1958). (13) M.P. Cava, S. K. Talspatra, J. A. Weisbach, B. Douglas, and G . 0. Dudek, Tetrahedron Letters, 53 (1963).

A S t u d y of Anodic Acetoxylation Potentials' M. LEUNG,J. HERZ,A N D H. W. SALZBERG Department of Chemistry, City College of the University of New York, New York SI, New York Received May 66,1964

The Kolbe electrochemical reaction is usually con~ i d e r e d ~to * ~proceed ~ ~ * according to the free-radical mechanism that is shown in the equation following, 2 R C 0 0 - - 2e

+ 2 R C 0 0 . + 2C02

+ 2R +

R2

(1)

though attempts to make use of the Kolbe reaction for alkylation have not been particularly successful. (1) Work was performed at the City College of the City University of New York. (2) B. C. L. Weedon, "Advances in Organic Chemistry," Vol. 1, Interscience Publishers, Inc., New York, N. Y . , 1960,pp. 1-34. (3) E. S. Gould, "Mechanism and Structure,'' Holt, Rinehart, and Winston, New- York, N . Y . , 1959, p. 689. ( 4 ) C. Walling, "Free Radicals in Solution." John Wiley and Sons, Inc., New York, N. Y.. 1957: (a) pp. 58f.3-582; (b) pp. 491-493.

VOL.

30

Trinitrotoluene has been methylated to trinitroxylene6 and pyridine alkylated to isomeric methylpyridines'j and phenylpyridines,'~s all, however, in low yield. Several acyloxylations have also been reported, the acetoxylation of a n i ~ o l e ,furan,g ~ and naphthalene. lo These acyloxylations have been ~ o n s i d e r e dto~ occur ~~~~ by attack of the acetoxy radical upon the substrate before decarboxylation could occur. Our studies indicate, however, that, a t least in the case of the formation of naphthyl acetate, the reaction probably does not proceed via the formation of an acetoxy radical which then adds to the naphthalene. Instead, the naphthalene molecule is first oxidized to a radical carbonium ion which then reacts further, according to the following scheme.

Experimental We first repeated the work of Linstead, et a1.10 They reported a 24y0 yield of or-naphthyl acetate, which, however, they did not isolate. They hydrolyzed and acidified the crude product and recovered the naphthol from the steam distillate. We looked for but were not able to detect any methylnaphthalenes in either the crude reaction mixture or the steam distillate, by column chromatography. We noted no anodic gas evolution, even a t current densities up to 1 amp./cm.2. Since the acetoxy radical is highly unstable11~~~ either these radicals were not formed or they reacted before they could decompose. The half-life of the acetoxy radical is estimated" to be of the order of 10-s-lO-lo seconds and even if the electric field exerted a stabilizing influence, it is difficult to see how the naphthalene could react with all of the radicals before they could decompose. We then investigated the electrochemical behavior of the naphthalene-acetic acid system and other related hydrocarbon-acetic acid systems. No attempt was made to isolate and determine the reaction products, which could not have been present in more than milligram quantities. No solution was electrolyzed long enough to consume more than about 0.1% of the organic reductant. Current density-anode potential measurements were made in solutions of potassium acetate, ammonium acetate, and zinc chloride, in anhydrous acetic acid, with and without added benzene, anthracene, and naphthalene. Anode potentials were measured using an interrupter technique to eliminate ohmic drop. The current was interrupted with an electronic circuit for 20-mec. intervals every millisecond and the potential was determined from the voltage-time trace on a calibrated oscilloscope. The current was measured from the potential fall across a resistor in series with the circuit. The cathode was a silver plate coated with silver chloride to avoid the evolution of hydrogen. The anode was a 1 . 2 - ~ m . ~ piece of bright platinum. (Later results using platinized titanium agreed with those on platinum.) The reference electrode was a silver-silver chloride wire. All solutions were saturated with respect to KCI or ZnC12. The cell was a 5 X 30 cm. Pyrex glass tube into which ground glass joints were sealed to admit the solution and to hold the three electrodes. The electrodes were sealed into the glass. The joints were fitted with Teflon sleeves to avoid the use of greases but were not completely airtight. However, the deliberate addition of enough water to a previously anhydrous solution to make it about 0.25 M with respect to water increased the potentials a t (5) L. F. Fieser, R . C. Clapp, and W. H. Daudt, J. A m . Chem. SOC.,64, 2052 (1942). (6) 5. Goldsohmidt and M. Minsinger, Chem. Ber., 87, 956 (1954). (7) F. Fichter and H. Stenal, Helu. Chim. Acta, 22, 974 (1939). (8) P.J. Bunyan and D. H. Hey, J. Chem. Soc.. 3787 (1960). (9) C. L. Wilson and W. T. Lippincott, J. Electrochem. Soc.. 108, 672 (1956). (IO) R. P. Linstead. J. C. Lunt, B. C. L. Weedon. and B. R. Shephard, J. Chem. Soc., 3824 (1952). (11) w. Braun, L. Rajkenbuch, and F. R. Eirich, J. Phys. Chem., 66, 1591 (1962).

NOTES

JANUARY1965 low current density by only about 5 mv. and had no noticeable effect a t high current densities. Since the effects of the organic solutes were a t least an order of magnitude greater, the small amounts of moisture diffusing in through the joints or admitted during addition of the solute would be negligible. Nevertheless, as far as practicable, moisture was excluded and the reagents were dried. The acetic acid was refluxed overnight with acetic anhydride and distilled directly into the cell, as required. The salts used were ZnClt and mixtures of KCl with either potassium or ammonium acetate. The salts were Baker’s analyzed grade, used directly with no purification other than drying. They were dehydrated by heating in situ a t 150-190’ a t 10 mm. for e t least 0.5 hr. Benzene (C.P.) was used without further purification. Anthracene (C.P.) was sublimed before use. The naphthalene was U.S.P. grade, sometimes used without further purification, sometimes sublimed, and sometimes column chromatographed. The purification had no apparent effect on the results of the naphthalene runs. Current-voltage measurements were made with each salt-acid solution until reproducible results were obtained. The cell was then opened and a sample of the organic reductant was quickly added. Moisture admitted during the addition of reductant is estimated, from the humidity of the air and the cell moles. dimensions, to be, a t most, The first few measurements made in each solution were usually irreproducible and with low results. However, on continuous passage of current, potentials rose and the results became reproducible. The higher the current, the shorter the time required for the potential to rise to reproducible values. This effect probably results from a clean up, either of the solution or of the electrode surface. (Pre-electrolysis with an auxiliary electrode was not practical because organic electrolysis products would have been formed.) The time taken for the current and voltage to reach steady-state values varied from solution to solution and depended on current density. Most measurements took between 5 and 20 min. per point. During that time interval, the current fell slightly and the potential rose. The curves were reproducible to +25 mv. a t higher current densities, or better than 2%.

311

t

0.6

L A . -

I-I-I~LLLL-LIVVLL

-4

-b

-6

-3

1

-2

Log amp./om.a.

Figure 1.

-5

-4

-3

-2

Log amp./cm.z.

Figure 2.

Results and Discussion Figure 1 shows some typical voltage-log current density curves for solutions of saturated ammonium acetate (B) and saturated potassium acetate (A). (Overvoltages could not be calculated since there were no data for the computation of the hypothetical acetate ion-acetate radical and naphthalene-naphthalene ion electrodes.) The results are in good agreement, allowing for the higher acetate ion concentration in the ammonium acetate solutions. The close correspondence of the upper plateaus is to some extent coincidental, since reproducibility from solution to solution is not that good. h’evertheless, it seems probable that the lower plateau corresponds to the oxidation of the acetate ion and the upper plateau corresponds to the oxidation of the molecular acetic acid. (There is some oxidation of the platinum, as reported by Conway.’* Small amounts of acid-resistant material were deposited a t the anode during the electrolysis.) The shapes of the curves, including the characteristic hysteresis loops are in agreement with the results reported by Conway12 for solutions of anhydrous formic acid-potassium formate and trifluoroacetic acid-potassium trifluoroacetate. Figure 2 compares a typical voltage-log current density curve for acetic acid-potassium acetate (B) with the results obtained on addition of benzene (A) or naphthalene (C) or anthracene (D) to the solution. It may be noted that the addition of benzene raised the potential somewhat while the addition of naphthalene (12) B. Conway and M. Dzieciuch, Proc. Chem. Soc., 121 (1962).

” 0.6 t

i

... -

-5

-4

-3

-2

Log amp./om.z.

Figure 3.

or anthracene lowered the potential sharply. The words “lowered the potential” can be taken literally because several times the organic reductant was added while the current was running under steady-state conditions and within seconds the potential dropped by 0.40.8 v. The order of ease of oxidation is the same as that reported by LundI3 and by Pysh and Yang14 and the 0.4-g. difference observed between the oxidation potentials of anthracene and naphthalene agrees very well with the 0.47-13 and the O.45-v.l4 differences obtained in a different system using a different technique (Le., vibrating and rotating microelectrodes in acetonitrile us. stationary steady-state macroelectrodes in acetic acid.) Results observed but not graphed indicate that curve C, for naphthalene, crosses curve B a t lowcurrent densities, in the amp./cm.2 range, indicating that naphthalene requires a higher oxidation potential than acetate ion but that naphthalene is probably more strongly adsorbed and displaces acetate ion from the surface. Figure 3 shows the results obtained with ZnClz in acetic acid, with (curve B) and without (curve A) added (13) H.Lund, Acta Chem. Scand., 11, 1323 (1957). (14) E.S. Pysh and N. C. Yang, J. A m . Chem. Soc.. 86, 2124 (1963).

NOTES

312

naphthalene. Again, the naphthalene lowered the oxidation potential sharply. The results of Figure 3 cannot be compared with those of Figure 2 since differences in chloride concentration change the potentials of the reference electrode. In all of the runs with organic reductants, a critical current density was reached, above which the potential rose to the value observed in the absence of the organic material. Potentials in this region fluctuated and the critical current density, a t concentrations of 0.1 M or less, varied from 1 to 5 X amp./cm.2. Since the previous investigators'O worked at current densities several orders of magnitude greater than ours, there must have been a t least three reacting species being simultaneously oxidized under their experimental conditions, namely acetate ions, the acetic acid molecules, and the organic reductant. The concentration of unoxidized organic reactant must have been practically zero.

Conclusions Since naphthalene is preferentially oxidized a t the electrode, the formation of naphthyl acetate would proceed via the formation of a naphthalene radical ion, rather than an acetoxy radical. This is in agreement with the mechanism suggested by Eberson. l5 The absence of methylnaphthalene and of anode gas, in any significant amounts, under the experimental conditions of Linstead'O is probably due to the naphthalene being oxidized to the radical ion, which then reacts further a t potentials below those required for the formation of acetoxy radicals. Further work is now in progress, on a preparative scale. Acknowledgment.-We thank the donors of the Petroleum Research Fund, administered by the American Chemical Society, for their generous support of this work. We wish also to thank the National Science Foundation for financial assistance to Miss Leung and to Mr. Herz, under the National Science Foundation Student Research Participation program. We wish also to thank Engelhardt Industries for their gift of several platinized titanium electrodes. (15) L. Eberson, Acta Chem. Scand., 11, 2004 (1963).

Coumarin-3-carboxylic Acids L. L. WOODS AND JOHN SAPP Department of Chemistry, Texas Smthern University, Houston, Texas 77004 Received August 1 1 , 1964

Although the method for preparing coumarin-3-carboxylic acids using basic catalysts has been known for a considerable number of years, lv2 many of the simpler compounds have not been prepared, and none have been synthesized using malononitrile as one of the reactants in such a procedure. In this report a procedure for the preparation of coumarin-3-carboxylic acids is given in which malononi(1) E. Knoevenagel, Eer., 91, 2619 (1898). ( 2 ) E. Knoevenagel. i b i d . , S I , 4461 (1904).

VOL.30

trile is condensed with aldehydes or ketones in the presence of piperidine and described as method A. Three of the acids were also prepared by the Knoevenage11t2procedure (method B) for comparison. The yields by our method (method A) are somewhat better than those of Knoevenagel which were in the range of 80%. The compounds prepared in the I-IV series are described in Table I.

Efforts were made to prepare the 4-phenyl derivative of IV by reacting 2,4-dihydroxybenzophenone with malononitrile, with diethyl malonate, and with malonic acid in the presence of piperidine. In all cases a reaction occurred, but either during the formation of the compound or during the hydrolysis the compound was decarboxylated, negating our attempt to ascertain what effect an electrophilic group in position 4 would exert on a powerfully fluorescent compound such as compound IV. Of primary interest to us is the fluorescence of the coumarins, which in this series is most pronounced in compound IV. In view of the low but definite fluorescence levels in compounds 1-111 it appears that the conclusion of Seshadria that a hydroxyl group must be present in a coumarin for it to fluoresce is in considerable error. Table I1 gives the fluorescence in quinine reference units (g.r.u.), the ultraviolet absorption characteristics, and the p-bromophenacyl derivatives of the compounds of the I-IV series. Experimental' Preparation of Members of I-IV Series. Method A,-To a mixture consisting of 0.1 mole of malononitrile and 0.1 mole of the aldehyde or ketone was slowly added, with shaking, to 20 ml. of piperidine. If the mixture did not become hot and the mass become homogeneous, it was gently heated on a hot plate until homogeneity was obtained. The mixture, after cooling, was treated with 100 ml. of 6 N hydrochloric acid, chilled, and filtered. The precipitate was refluxed for 18 hr. in 100 ml. of 9 N hydrochloric acid. After chilling the mixture, it was filtered and the precipitate was dried in air. Analytical samples were obtained either by recrystallizing the compounds twice from benzene-heptane mixtures or by dissolving the compound in ethyl acetate and then precipitating the compound with heptane. The process was repeated in either case for a second recrystallization. Method B.-One-tenth of a mole of the aldehyde or ketone was mixed with 0.1 mole of diethyl malonate followed by 20 ml. of piperidine. The mixtures were warmed on a hot plate, if necessary, to produce complete solution of the reactants. Acidification, hydrolysis, and purification of the compounds were effected in the same manner as in method A. Compounds which were prepared by both methods were proven to be identical by mixture melting points and by their infrared spectra. Preparation of p-Bromophenacyl Derivatives of I-IV Series.One gram each of the coumarin acid, 2',4-dibromoacetophenone, (3) (a) S. Rangaswami and T. R. Seshadri, Proc. Indian Acad. Sei., 14A, 375 (1940); Chem. Absfr.. 88, 3526 (1941). The reference in R. C. Elderfield's, "Heterocyclic Compounds," Vol. 4 , p. 193, ie in error as to the year of publication of the above article. (b) See also C. E. Wheelock, J . Am. Chem. Soc.. 81, 1348 (1959). on fluorescence in coulnarins. (4) Analyses were performed by Dr. Karl Tiedcke, 705 George Street,

Teaneck, N. J. point blocks.

All melting points were taken on Fischer-Johns melting

JANUARY 1965

313

NOTES TABLE I COUMARIN-3-CARBOXYLIC ACIDS

Aldehyde or ketone used

Compd."

Method used

Yield,

%

M.P., "C.

Formula

%-

-Carbon, Calcd.

-Chlorine, %Calcd. Found

-Hydrogen, %Calcd. Found

Found

63,16 63.34 3 . 1 8 3.38 100 CloHeOi 190-191 A, B I Salicylaldehyde 2.24 15.78 15.94 53.47 53.69 2.24 100 CloHaClOi 214-215 A,B I1 5-Chlorosalicylaldehyde I11 2'-Hydroxyacetophenone A 194.5-196 44 CuH804 64.70 64.50 3.94 4.14 IV 2,4-Dihydroxybenzaldehyde A, B 264-265 85 CloHsOs 58.26 57.99 2.93 3.14 a I, 3-carboxycoumarin, lit.2 m.p. 187-188"; 11, 3-carboxy-6-chlorocoumarin; 111, 3-carboxy-Pmethylcoumarin; IV, 3-carboxy-7hydroxycoumarin, P. C. Mitter and S. K. Saha [ J .Indian Chem. Soc., 11,257 (1934); Chenz. Abstr., 28,5069 (1934)] reported m.p. 262'.

TABLE I1 SPECTRAL CHARACTERISTICS AND p-BROMOPHENACYL DERIVATIVES OF I-IV SERIES Compd.

Q.r.u."

Ultraviolet absorption, mpb (log

e)

pBromophenacy1 ester formula

-Bromine, Calcd.

M.p., OC.

%-

I I1 I11

0.432 267.4 (3.90)) 300.5 (4.02) ClsH1lBrOs 122-123 20.68 1.16 295 (4.00)) 340 (3.85) ... ... ... 2.30 266.4 (3.84), 302.3 (4.03) C19H13BrO6 151-152 19.91 IV 196.6 263.7 (3.56), 346 (4.14) ClsHllBrOs 122-123.5 19.81 a See L. L. Woods and J. Sapp, J . Chem. Eng. Data, 8, 235 (1963), for the method of calculating quinine reference units. were run on a Bausch and Lomb 505 spectrophotometer in Spectrograde methanol.

and calcium carbonate were refluxed together for 90 min. in 50 ml. of absolute ethanol. The mixture was then filtered while boiling hot. The filtrate was diluted with an equal volume of water, chilled for 2-3 hr. in the freezer, and the precipitate was collected and recrystallized twice from absolute ethanol.

in Alkylaminotriphenylphosphonium Salts GURDIAL SINQH~' AND HANS ZIMMER~~

Department of Chemistry, University of Cincinnati, Cincinnati 21, Ohio

( PhsP-N-R)+X-

I

H I

The results obtained in the present investigation (Table I, Figure 1) can be conveniently discussed under the following two headings. TABLE I INFRARED DATAOF ALKYLAMINOTRIPHENYLPHOSPHONIUM SALTS (PhaP-N-R)+X-

Received September 1 , 196.4

---N-H 7

Participation of N-H in hydrogen bonding to anions had been studied quite extensively' in the recent years. Most work in this field has been done with ammonium and Larsson4 obtained evidence salts.2 Fujita, et of hydrogen bonding of the type N-H . . .anion from the lowering of the N-H stretching frequency in hexammine cobalt(II1) complexes. Most recently, similar studies on hexammine and pentammine complexes of chromium(II1) have been reported.s No hydrogen bond studies in alkylaminotriphenylAs phosphonium salts (I) have been reported. recently, some alkylaminotriphenylphosphonium salts, such as chlorides,e bromides,' iodides,' and tetra(1) (a) Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Mass. (b) To whom correspondence should be directed. (2) G. Gray and T. C. Waddington, Trans. Faraday Soc., 68, 901 (1957); A. Tramer. Compt. rend.. 349, 2755 (1959); P. Sauvageau and C. Sandorfy, Can. J. Chem., 88, 1901 (1960): G. Tsouoaris, Acta Cryat., 14, 917 (1961). (3) J. Fujita, K. Nakamoto, and M. Kobayashi, J. A m . Chem. Soc., 7 8 , 3295 (1956). (4) R. Larsson, Acta Chem. Scand., 16, 2460 (1962). (5) N. Tanaka, M. Kamada, J. Fujita, and E. Kyuno, E d . Chem. 8 o c . Japan, 37, 222 (1964).

... 19.49 19.67 Spectra

fluoroborates,s became available to us, it was decided to investigate systematically the possible presence of N-H . . . anion-type hydrogen bond in them. This report deals with the results of the investigation and their interpretation.

Acknowledgment.-The authors acknowledge with thanks the financial support of the Robert A. Welch Foundation for this investigation.

N-H Stretching Frequency

Found

20.97

R CHs CaHs CH(CHs)i C(CHa)a

c1-

2945 2942 2938 2934

stretching frequency, om.

-x

Br 2950 2948 2946 2941

--

-1-7

1-

BF4-

2954 2952 2952 2948

3294 3278 3257 3241

Effect of the Anion.-Alkylaminotriphenylphosphonium salts possess a secondary N-H group. It is well known that the free N-H moiety of the secondary amines absorbs in the 3500-3200-cm. -l r e g i ~ nwhereas, ,~ if N-H participates in hydrogen bonding, its absorption is shifted to a lower frequency and the absorption band becomes b r ~ a d e r . ~This , ~ ~is actually what was observed especially in the case of alkylaminotriphenylphosphonium chlorides, bromides, and iodides (Figure (6) H. Zimmer and G. Singh, Anum. Chem., 71, 574 (1963); Anocw. Chem., Intern. Ed. E n d . , 3, 395 (1964). (7) H. Zimmer and G. Singh, J. Orp. Chem., 28, 483 (1963). (8) H. Zimmer and G. Singh, ibzd., 39,3412 (1964). (9) L. J. Bellamy, "The Infrared Spectra of Complex Molecules," 2nd Ed., John Wiley and Sons, Inc., New York,N. Y.,1958, p. 215. (10) G. C. Pimental and A. L. MoClellan. "The Hydrogen Bond," Reinhold Publishing Corp., New York, N. Y., 1960, p. 75.

314

VOL.30

NOTES

om.-'.

Figure 1.-N-H Stretching frequency in alkylaminotriphenylphosphonium salts, (PhSPNHR)+X-. Concentration in chloroform: a-d, 0.1 mole; e, 0.05 mole.

N-H-stretching frequency, cm. -I

Figure 2.-N-H Stretching frequency in alkylaminotriphenylphosphonium tetrafluoroborates as a function of the number of methyl groups on N-a-carbon atom.

1). From the data recorded in Table I two points are quite clear. Firstly, except in the case of tetrafluoroborates, there is a significant lowering of N-H stretching frequency as compared to that of a free secondary N-H group. Secondly, in any row of Table I the shift in the stretching frequency of N-H is in the order of BF4-