Diuretics. II. Alkoxymercuration by Mixed Anion Salts of Mercury

Diuretics. II. Alkoxymercuration by Mixed Anion Salts of Mercury. Calvert W. Whitehead, John J. Traverso. J. Am. Chem. Soc. , 1958, 80 (9), pp 2182–...
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CALVERT W. ~VFIITEI-IEAD A N D JOHN J. TRAVERSO

2182

wasorepeated with p-aminobenzoic acid; yield 70%, m.p. 208 Anal. Calcd. for CIIHIONO~: N , 0.85. Found: N, 6.76.

Vol. 80

Table 11, and from ethyl N-allylcarbamylphenoxyacetates in Table 111. The other products are listed below.

.

N-( 3-Acetoxymercuri-2-~-methoxyethoxypropyl)-phthali-

p-( 2-P-Hydroxyethoxy-3-hydroxymercuributyrylainino)- mide, yield 9 g. (887,), m.p. 109'. Anal. Calcd. for CISphenylacetic Acid.-To 15 nil. of ethylene glycol was added H,.He;\'Oe: C. 36.75: H . 3.72: N. 2.69. Found: C , 36.70: 1 g. (0.01 mole) of p-crotonylnminophenylacetic acid and 1.5 g. (0.01 mole) of mercuric acetate. The resulting solution was allowed to stand for 5 days. The white solid that had separated was collected and washed with methanol and then with ether; yield 2 g. (50y6), m.p. 205' dec. A n d . Calcd. for C I J € ~ & I ~ S O BHg, : 40.53. Found: H g , 40.23. N-( 3-Hydroxymercuri-2-~-hydroxyethoxypropyl)-N'succinylurea Sodium Salt.-Twenty grams (0.1 mole) of S-allyl-N'-succinylureas was dissolved in 40 ml. of ethylene glycol. Thirty-two grams (0.1 mole) of mercuric acetate was added and stirred. The reaction was exothermic and there was a strong odor of acetic acid. After standing for two days a t room temperature, a sample was completely miscible in water and did not turn dark when made basic a i t h sodium hydroxide. The excess ethylene glycol was distilled a t 0.1 mm. and a t a bath temperature of 120'. The remaining sirup was dissolved in methanol, clarified with carbon and filtered. Ether was added and the mercurial precipitated as an oil. The nil was separated, dissolved in a minimum amount of distilled water, and carefully neutralized with sodium hydroxide to a pH of 7.5. The water was evaporated under reduced pressure to give a 60% yield of white solid. Anal. Calcd. for Cl0H17HgN2Sa07: Hg, 40.90. Found: Hg, 40.80. General Method for the Mercuration of Ethyl p-Allyloxybenzoate,g Ethyl p-(N-Allylcarbamy1)-phenoxyacetate, Ethyl o-(N-Allylcarbamy1)-phenoxyacetate, N-Allylphthalimide,lO a-Allylbenzhydrol11 and Methyl Chamate.--A mixture of 6.4 g. (0.02 mole) of mercuric acetate and 0.02 mole of the allylic compound or of methyl cinnamate was stirred in 10-25 ml. of the appropriate alcohol (methyl Cellosolve, ethyl Cellosolve, butyl Cellosolve, B-chloroethanol, ethyl lactate, ethylene glycol, ethanol or methanol) or in 25 ml. of water. The mixture dissolved and after standing for 2-5 days a t room temperature the product crystallized. This was collected and purified by recrystallization from ethyl acetate or a mixture of ethyl acetate and petroleum ether. The mercurials from ethyl p-allyloxybenzoate are listed in (8) D. E. Peareon and bl. V. Sigal, J r , J . Org. Chew.. 16, 1055 (1050). (9) 1,. Claisen and 0. Eisleb, A n n . , 401, 96 (1913). (10) T.B. Johnson and D. B. Jones, Am. Chenz. J . , 45, 349 (1911). (11) H.Gilman and J. H. McGlumphy, B d f . SOL. chim., 4s. 1322 (1").

' N-~3-Acktoxymercuri-Z-p-hydroxyethoxypropyl)-phthalimide, yield 9.5 g. (95'%), m.p. 126". Anal. Calcd. for CI6Hl7HgN06: C, 35.50; H, 3.37; N. 2.77. Found: C, 35.57; H , 3.52; N, 2.92. 4-Acetoxymercuri-l , 1-diphenyl-3-p-hy droxyethoxybutanol-I, yield 4.5 g. (41%), m.p. 114.5'. Anal. Calcd. for C20HuHg06: C , 44.07; H, 4.44. Found: C , 44.26; H, 4.48. 4-Acetoxymercuri-1 ,l-diphenyl-3-methoxybutanol-l, yield 7.2 g. (TO%), m.p. 135.6-136". Anal. Calcd. for CISHZZHgO(: Hg, 38.95. Found: Hg, 38.40. Methyl 2-hydroxymercuri-3-p-hydroxyethoxyhydrocinnamate, yield 6.9 g. (78%), m.p. 216-218' dec. Anal. Calcd. for C12HleHgO~:Hg, 45.40. Found: Hg, 45.70. Methyl 2-acetoxymercuri-3-p-methoxyethoxyhy&oc~amate, yield 7.9 g. (SO'%), m.p. 97". Anal. Calcd. for Cl6HPOHgO~:C, 36.30; H , 4.05. Found: C, 36.28; H, 3.97. Methyl 2-acetoxymercuri-3-p-chloroethoxyhydrocinnamate, yield 7.5 g. (75%), recrystallized from ethanol, m.p. 124". Anal. Calcd. for ClaH17C1HgOb: C, 33.48; H, 3.42. Found: C, 32.92; H, 3.34. Ethyl m-(3-Acetoxymercuri-2-p-hydroxyethoxypropyl)-~hydroxybenzoate.-Two grams (0.011 mole) of ethyl mallyl-p-hydroxyben~oate~ and 3.18 g. (0.01 mole) of mercuric acetate were dissolved in 5 ml. of ethylene glycol and allowed to stand a t room temperature for three days. Ether was added and the product precipitated. The precipitate was crystallized from a mixture of ethyl acetate and petroleum ether; yield 4 g. (77%), m.p. 99-100'. Anal. Calcd. for CleH~Hg07: Hg, 38.03. Found: Hg, 37.82. Ethyl m-(3-Acetoxymercuri-2-methoxy)-~-hydroxybenzoate.-The procedure in the above paragraph was repeated using methanol rather than ethylene glycol; yield 50%, m.p. 124-125'. Anal. Calcd. for Cld&~HgOs: Hg, 40.25. Found: Hg, 40.22.

2-Acetoxymercuri-S-carbethoxy-2,3-dihydrobenzofurane. -The procedure described in the above paragraph was used with the exception that ethylene glycol was replaced with ethanol, methyl Cellosolve, or benzyl alcohol. The yields varied from 14-50Q/0, m.p. 114-116'. Anal. Calcd. for C14Hl~Hg06: Hg, 43.01. Found: Hg, 42.95. IXDIANAPOLIS, INDIANA

-

[CONTRIBUTION

Diuretics.

FROM THE

LILLYRESEARCH LABORATORIES]

11. Alkoxymercuration by Mixed Anion Salts of Mercury BY CALVERT W. WHITEHEAD AND JOHN J. TRAVERSO RECEIVEDOCTOBER 21, 1957

Alkoxymercuration of allylamides by means of mixed anion salts of mercury furnished a convenient and direct synthesis of twenty-one new mercurial diuretics.

Normal mercuric salts of mineral acids, with few exceptions, are not suitable for the alkoxymercuration of olefins. This is due to the insolubility of some mercuric salts and to the instability of the mercury-olefin adduct in the presence of mineral acid.' Mixed anion salts of XHgOCOCH3, where X is a mineral acid anion, are moderately soluble in water and the common alcohols and yield predominantly HgX+ and CH3C02- ions in solution. Alkoxymercuration of allylic compounds by means (1) J. Chatt, Chrm. Revs., 48, 13 (1951).

of these mixed anion salts yielded the new mercurials RCH2CH(OR')CHzHgX (111) reported here. Mixed anion salts of mercury were prepared from mercuric acetate and each of the following normal salts : mercuric chloride, mercuric bromide, mercuric iodide, mercuric nitrate and mercuric thiocyanate. The mixed anion salts were established as discrete crystalline compounds by observing that their X-ray patterns were completely different from the patterns of the starting normal salts. The allylic compounds I employed

ALKOXYMERCURATION BY ANIONSALTS OF MERCURY

May 5 , 1958

2183

RCHzHC.,

of 0.01 to 0.05 mole (3.18 to 15.9 g.) of mercuric acetate and an equal molar amount of mercuric chloride, mercuric broI HzC’ mide, mercuric iodide, mercuric nitrate or mercuric thiocyanate was added to 100-200 ml. of the appropriate solvent. The solvents that were used were methanol, ethanol, f-CH8COzwater, methyl Cellosolve, ethyl Cellosolve and ethylene glyI col. The resulting mixed mercuric salts were not isolated RCHzCHOR’ H+ XHgOCOCHa when used in the mercuration reactions but allowed to react I with the allylamides as they existed either suspended or disI1 I11 CHzHgX X = C1, Br, I, SCN or KO3 R ’ = H, CHs, CtHb or CH30- solved in the solvent. The crystalline mixed anion salts were obtained from methanol by partial evaporation of the (CHZ,? solvent. These were recrystallized from methanol and R is given in Tables I, I1 and I11 their X-ray powder patterns determined.s N-Allylalkanesulfonddes (Table I).-The appropriate in the mercuration studies were allylamides of alkanesulfonyl chloride7 was added dropwise while stirring alkanesulfonic acids, alkanesulfamic acids, hydan- to an ether solution containing one mole equivalent of toic acid, hippuric acid and 1,3-dimethyluracil-5- allylamine or X-methylallylamine and one mole equivalent carboxylic acid. Two other amide-like derivatives, of pyridine. The molar quantities of the reactants varied N-dylurea and 3-allyl-5-carbethoxy-1-methyl-from 0.1 mole to 2.83 moles. After one hour the ether s o h was washed with water and dried over magnesium suluracil also were used. The allylamides were pre- tion fate. In the case the water-soluble N-methyl derivatives, pared from acid chlorides or esters by conventional the ether solution of was cooled and the pyridine hydrochloride methods. The two uracils were obtained by collected on a filter. The ether was evaporated and the product distilled through a Vigreux column. methods previously reported.2 N,N-Dialkyl-N’-allylsulfamates (Table I).-One-half The mercurials I11 were obtained by allowing mole of the aDDronriate N.N-dialkvlsulfamyl chlorides.0 the mixed salts to react with the allylamides in was added dropwise, with stkring, to 57 g. (1.0 mole) of alcoholic or aqueous solution. A number of these allylamine dissolved in 500 ml. of ether. The ether was mercurials were titrated in 66% aqueous N,N- washed with water and dried over magnesium sulfate. The dimethylformamide. Several were sufficiently sol- ether was evaporated and the product was distilled. of N-Ally1alkanesulfonddes.-One-tenth uble to be titrated in water. Titrations of the type moleMercuration of the N-allylalkanesulfonamide was added to 0.1 mole RHgX OH- S RHgOH X- (eq. l.)]all con- of chloromercuric acetate (see preparation of mercuric salts) formed very closely to the calculated theoretical in 200 ml. of distilled water. The resulting solution was curve. Attempts to determine the ionization con- warmed on the steam-bath to approximately 60’ and then to stand at room temperature for 4 days. This stant of the hydroxymercuri form in water were allowed same procedure was repeated with 0.1 mole of bromomercomplicated by the fact that the slope of the titra- curic acetate in water. The prodqcts from N-allylmethanetion curve is distinctly greater than the theoretical sulfonamide and N-allylethanesulfonamide crystallized from slope derived from a reaction of the type RHgOH solution, were collected and recrystallized from ethanol (Table 11). The products from N-allylbutanesulfonamide, H++RHg+ HzO (eq.2.).* K-allyl-N-methylbutanesulfonamideand N-allyl-N-methylSeveral authors4J have selected the p H of half- methanesulfonamide could not be induced to crystallize and conversion without comment concerning the slope therefore could not be Characterized. When mercurations of N-allylalkanesulfonamides were carried out in methanol of their titration curves. ethanol the Droducts senarated as -gums and could not be For this reason the results are expressed in Table or crystallized. IV as the apparent equilibrium constant for eq. 1. Mercuration of N.N-Dialkvl-N’-allv1sulfamates.-The defined as the molarity ratio (X-)/(OH-) a t procedure used here was e x a c t l i t h e s a i e as that described half-conversion. From the average of several de- above for the mercuration of the N-allylalkanesulfonamides. only mercurated product that could be crystallized and terminations of pH = f(OH-) in 66% dimethyl- The characterized was obtained from N-( allylsulfamy1)-morforniamide the constant in the following expression pholine (Table 11). Products from the other allylsulfawas determined: pH - log (OH-) = 16.8 f 0.1. mates were sirups or plastics. Hydantoic Acid Allylamide.-Two hundred and fifty It is interesting that the quantity (X-)/(OH-) is of allylamine was added to 132 g. of methyl hyabout the same in water and 66% dimethylform- milliliters dantoate’o and boiled under reflux for 24 hours. The examide for the halide compounds that were titrated cess allylamine was distilled under reduced pressure. The in both solvents, but that it is much greater in the remaining solid product was recrystallized from ethanol; non-aqueous solvent for the thiocyanate com- yield 140 g., m.p. 167-168’. Anal. Calcd. for C6HllN302: C , 45.85; H , 7.05; N , pounds. More favorable solvation of the thiocyanate ion by dimethylformamide and of the 26.74. Found: C, 46.94; H, 7.29; N, 26.51. Mercuration of Hydantoic Acid Allylamide.-Fifteen and halide ions by water, although not demonstrated grams (0.1 mole) of hydantoic acid allylamide independently, would seem to be a reasonable ex- seven-tenths was added to 0.1 mole of chloromercuric acetate in 200 ml. planation. of methanol, to 0.1 mole of bromomercuric acetate in 100 Acknowledgment.-The authors thank W. B. ml. of methanol, to 0.1 mole of thiocyanatomercuric acetate Brown, H. L. Hunter, G. Maciak and Miss Gloria in 400 ml. of methanol and to 0.1 mole of chloromercuric acetate in 200 ml. of water. The mixtures were agitated Beckman for the microanalyses; Harold Boaz until the solids dissolved. The products crystallized from for the titrations and their interpretations; R. R. the solutions after standing for 12 hours a t room temperaPfeiffer and Miss Ann Van Camp for the X-ray ture. Each mercurial was collected on a filter and recrysfrom methanol (Table 11). data; and Max Sigal, Jr., for valuable suggestions. tallized Mercuration of N-Ally1hippuramide.-Five and fiveHgX + f RCHZCH=CH2

+

+

+

+

Experimental Preparation of Mixed Anion Mercuric Salts.-A

mixture

(2) C. W. Whitehead, THIS JOURNAL, 74, 4267 (1952). (3) A study of the equilibria of R H g + in water is in progress.

(4) R. L. Rowland, THIS JOURNAL, 74,5482 (1952),curve 1 in Fig. 2. ( 5 ) T. D. Waugh, H. F. Walton and J. A. Laswick, J. P h y s . Chcm., 69, 395 (l955), curves l a and l b in Fig. 1.

( 6 ) The d , A. and I / I i values for the mixed salts may be obtained by writing the authors. (7) Supplied by Distillation Products Industries, Rochest8:r 3, N.Y. (8) L. F. Andrieth and M. von Rrauchitsch, J. Ore. Chcin., 21, 427 (1955). (9) L. Deniville, Bull. soc. ckim. F r o n r r , 151 3, 2143 (1936). (10) C. Harries and h l . Weiss. A n % . ,327, 365 (1903).

2184

CALVERT

w. W H I T E H E A D AND JOHN

Vol. 80

J. TRAVERSO

TABLE I S-~~LLYLALKAXESULFOXAMIDES

AND N,N-DIALKYL-S'-ALLYLSL?LFAMATES,

B.p.

R

R'

CH3 CHa CzHj (CH3)2S CPHS( CH8)S CaHZN' C3H80X"

H CH3

CaH 9 (C?Hs)?S IZ-C~HS Pyrrolidiiiu.

Formula

C4H sNOzS CaHiiNOiS CBH~ISODS CsHi2X202S C6Hi4S~08 C:HiaXzOzS CjH14xz03S

H H H I1 H I3

12-

H 5

CH3 kIorplio1iiio.

c

OC.

hfm.

103 92 117-120 110 100 135 130"

0.7 .5 .5 .5 .5

RS02NR'CH,CH=CH, Sitrogen, Calcd.

Yield. yo

i? 43 70 9 40 52

-

. I

50

CjH1SN02S 114 1.5 68 C~HI~N~OZS 10(1 0.5 5.5 CsHi7N02S 110 .5 30 Nelting point. T-alues for carboll. e i-alucs for hgdrugeii.

10.35 9.39 9.41 17.06 14.57 14.72 40.76'' 6.84' 7.90 14.57 7.32

YO

Found

10.47 9.31 9.47 17.37 14.76 14.59 40. 94d 6.86" I . 12 14.76 7.37

--

TABLE I1 RSIICH1CH( OR')CH?HgX 10

1 2 3 4 5 6

7 8 9 10 11

Iletl; yield ,;.I g . (