using a procedure previously described.5 The partition coefficient was calculated from the concentration of aryl compound in each phase (ratio of octanol solubility to aqueous phase solubility). Molecular Orbital Theory Calculations.-The matrix equations for Huckel molecular orbital treatment of the aryl x-electron framework were solved with the use of an IBhl 1130 computer. Coulomb and bond integrals were obtained from Streitwieser.6 Methyl substituents were treated as heteroatoms. Charge density (Qr) and electrophilic superdelocalizability (8,) values for aryl atoms were calculated from the appropriate equations also given by Streitwieser.'j Acknowledgment.-This work was supported in part by grants from The John -4.Hartford Foundation and A. H. Robins Company. The authors wish to express their appreciation to l l r , John Howell for assistance in computer programming, and the Department of Biometry for providing computational services. ( 5 ) K. S. Rogers, Pwc. Soc. E z p f l . Bid. M e d . . 130, 1140 (1969). (6) A. Streitaieser, Jr., "Molecular Orbital Theory for Organic Chemists,'' J o h n Wiley and Sons, Inc., New York, N. Y . , 1961, pp 52-330.
Iodinated Derivatives of Histamine and N-Acetylhistamine MINEKOTOMINAGA" Deparlment of Biochemistry, C'niversity of Campinas, Campinas, S.P., Brazil BND
ANTONIOC. h1.
PAIVAlb
Department of Biophysics and Physiology, Escola Paulista de Medicina, Siio Paulo, S.P., Brazil Received March 11, 1969
Although it has been reported that histamine loses its biological activity by reaction with iodine, probably by iodinat'ion,2and kinetic studies have indicated iodine substitution in its imidazole ring, iodinated derivatives of histamine have not yet been described. With the purpose of obtaining authentic iodinated derivatives for the chromatographic estimation of reaction products in studies of the kinetics of iodinat'ion of histamine and N-acetylhistamine, the following compounds were prepared: 5-iodohistamine dihydrochloride, 2,j-diiodohistamine, N-acetyl-5-iodohistamine, and N-acetyl-2,5diiodohistamine. The position of the iodine atom in the imidazole ring of these compounds was determined from their nmr spectra. The limited iodination of histamine resulted in only one of the two possible isomers of monoiodohistamine, in which the iodine atom is in the 5 position, in analogy with what' has been reported for monoiodoimida~ole~~ and monoiodohist'idine.4b None of the four compounds described here showed any spasmogenic activity upon the isolated guinea pig (1) (a) With a predoctoral research grant from the FundaoZo de Amparo A Pesquisa do Estado de Sea Paulo, Brazil. (b) T o whom inquiries should be sent. (2) A . C. M.Paiva and T. B. Paiva, Anais Acad. Brasil. Cienc., 8 0 , XLVI (19 58). (3) L. Schutte, P. P. Kluit, and E. Havinga, Tetrahedron S u p p l . , 7 , 296 (1966). (4) (a) A. Grimison and J.
Uensusan and M.
693
NOTES
July 1969
H. Ridd, J . Chem. Soc., 3019 (1959); (b) H. B.
S. R. Naider,
Biochemistry, 6 , 12 (1967).
ileum in doses up to lo4 times higher than an effective concentration of histamine on the same preparation. Slight antihistaminic activity was present only in X acetyl-2,5-diiodohistamine and in 2,5-diiodohistamine. The latter was the more active of the two; at a concentration of 2 x 10-8 M it caused 50% reversible inhibition of the contraction produced by 5.5 X 10-6 M histamine on the isolated guinea pig ileum. Experimental Section Microanalyses for C, H, N, I, and C1 were performed by Galbraith Laboratories, Inc., Knoxville, Tenn.6 Melting points were determined on the Kofler micro melting point apparatus and are reported uncorrected. Nmr spectra were obtained a t 60 hIc on a Varian T-60 or a Perkin-Elmer R-10 spectrometer, using D20 as the solvent and MetCO-de as an internal standard. Tlc was performed on silica gel G (E. Merck, A.G., Darmstadt) plates and the solvent system most adequate for separation of the iodinated compounds was n-BuOH saturated with 9 S NH40H, in which histamine had an R f value of 0.08. Biological act,ivity was tested by four-point assays on the isolated guinea pig ileum using histamine as standard. Antihistaminic activity was tested by the inhibition of response to histamine using acetylcholine as a control for specificity. 5-Iodohistamine Dihydroch1oride.-A solution of 2.0 g of histamine dihydrochloride in 200 ml of 0.5 'V NaOH and 100 ml of n-C&, was cooled in an ice bath, and 2.76 g of 1, dissolved in 300 ml of n-C&4 was added dropwise (90 min) with vigorous stirring. The stirring was continued for 10 min after t'he addition of I,, and then 0.56 g of KIOI, dissolved in 20 ml of HzO and 10 ml of concentrated HC1, was added, followed by the extraction of 1 2 with n-C6H14. The solution was concent'rated to dryness in vacuo at, 35". The residue was suspended in 200 ml of absolute EtOH and 10 ml of concentrated HC1 and refluxed for 30 min. The addition of a large volume of MezCO produced a white voluminous precipitate which was collected and, after charcoal decolorizing, crystallized from 1\Ie2CO-H20 as the dihydrochloride, yielding 1.5 g (45%) of a white solid that melted a t 211-213" dec and was very soluble in H20, sparingly soluble in EtOH, and insoluble in S\lezCO. This product gave only one spot on tlc with Rf 0.33. Anal. (C6HJNa.2HC1) C, H, N, C1, I. 2,5-Diiodohistamine.-To 1.0 g of histamine dihydrochloride, dissolved in 200 ml of 0.25 A7 NaOH and 100 ml of n-Cs&c, was added 3.04 g of 12 dissolved in 240 ml of n-C&,, as described in t,he preceding section. After addition of 0.50 g of KIOI, dissolved in 20 ml of H20 and 5 ml of concentrated HCl, IZwas removed by extraction with n-C6Hl4 and the solution was concentrated in vacuo, a t 35", to 35 ml. When the p H was brought t o 9 by addition of concentrated NH,OH a yellowish precipitate was formed. This was purified by repeated dissolution in concentrated HCl, treatment with charcoal, and precipitation by adding concentrated NH4OH to bring the pH to 9, yielding 0.85 g (43%) of a white powder that melted a t 163-164" dec, and gave one spot on tlc with Ri 0.52. Anal. (C:H,IZN~)C, H, N ; I: calcd, 69.93; found, 69.44. N-Acetylhistamine was prepared according to van der SIerwe,6a but the mixture of histamine and AczO was not refluxed, which prevented darkening of the product and afforded better yields. The light yellow oily residue, obtained after evaporation of the solvent, was dissolved in absolute EtOH and passed through a column of neutral alumina. On concent,ration of the eluate white crystals were obtained in a yield of 73%. The product melted a t 145147' (lit.eb mp 147-148') and gave one spot on tlc with Rf 0.47. N-Acetyl-5-iodohistamine.-The reaction of 1.0 g of K-acetylhistamine with 1.66 g of I, was performed as described above. After addition of KIOa, extraction of 1 2 , and concentrat,ion in vacuo, a t 40°, to 10 ml, alkalinization to pH 8 produced a white precipitate that was repeatedly dissolved in HzO and reprecipitated by adjusting to pH 8. The final product, obtained in a yield of 0.78 g (44%), melted a t 188-190', and gave one spot on tlc with Ri 0.66. Anal. ( C ~ H I J N ~ OC,) H, I, N. ( 5 ) Where analyses are indicated only by symbols of t h e elements analytical results obtained for those elements were within *0.4% of t h e theoretical value. (6) (a) P. van der Merwe, 2. Physiol. Chem., 177, 308 (1928): ( b ) H. Tabor and E. &losettip, J . Bid. Chem., 180, 703 (1949).
N-Acetyl-2,5-diiodohistamine. -The reavl ioii of 0.6 g of N-aretylhistamine with 1.52 g of 1 2 was performed as described for the other compounds. After addition of KIOI and extraction of I,, alkalinization to pH 8 produced a white voluminous prrcbipitate. The compound was obtained i i i a final yield of 0.45 g (84cc), melted at 214-216", arid gave one spot o r i tlr w i t h Rt 0.80. .InaZ. (C,ETqT?SaO.H20)C, H, I, S .
Acknowledgments.-We \I ihh t o thank Professor5 1'. C. 1;crreira arid 31. llotidome for valuable advice : ~ n d help in thc preparation of ?;-:icet?-lhistamiiir., I'rofes5or T. B. I'aiva for the biological I l l r . A. Hashimoto for the determination of nmr ipec tra. Sy-nthesesof Benzoniorphan and Related Compounds. 11.' The Debenzylation of Quaternary Ammonium Salts with Thiopheno12
aniinoi1iuni salts w ~ r econfirniccl by iiiicioan:il Quite natiircilly, benzyl phenyl ttiioethcr') arid 01' . phenyl thioether16mere detected 3s by-product 1i i ihiz ww, SaOH is thought to react n-ith an cquiiiiolar ;mount ot tliiopheiiol (cj. reaction 9 in 'I':ible 11) i i i the first place, and the resulting thiophmo\idc :tiiir)ri i. ail efiectivc riucleophile but r i o t k caiihe Hofmann degradatioii. an application of this method, :I rnoclificd syiiof pentazocine (I), I s Iianiely, 1, 2 , ~ ~ ; ~ . ~ , ~ j - l i e x : ~ - X - hydroxy- 2,6- methmo-B,11-dimethyl - 3 - (3,:4di~i~ethyl:tll~l)-~~-berizazocine, :I very effect ivc ;ui:i1getic agerii \Tit11 no dependencr liability. hay bwn invp.1 igatcd. 111 the previouh paper,' WP Iiu~cz.tlre:~tl~. I cyorted thc syntheses of sever:il quaternnry :irnmoniuni \:ilt\ (I1 IV) which were important intermedi:itca 101. ~)c~it:tzocine.lye also have reported t h a t iliv I diicstivc dcheiizylation of IV hy cdtulytic liytlrogcii:I. I I o n nff orded t hr expected pentazocine. but simult:incou* i d u c t i o n of thc double bond occ~urrcd. S o t prihingly. t r e a t r w n t of tn o tiuat e r n x y :iniiiiooiiiiii salts (I1 aiid 111) with thiophenol in aqucous S:iOH Olliy \..I: rlr tilcA of 117~t iHordecl :i mixturcx ut I (51.0 iormcd i i i ,X.i' 6 ( ig of 17.' with o\w- - o c l j i i n i t I i j o p l i c ~ i i oxidc in a n orgtliiic solvent. lis
(1-
'
YUI-
T. I< uai
li. KIGis i n 1, AI. Him \ & I , N. WAGLISLMI, K. 11-\[CIS II< i, \VI1 0. Kus 1x1 \
I A ~ I ,
f'liarmaccut Lcal Instztule, Tohokz~Cnzwrszfy, Aobayama, Sendai, Japun, and Research Laboralor ies, G e l a n Pharrnaceutical Company Ltcl , Sakurushinmachi, Setagayaliri, Tokyo, Japun
12cceizecl Febi itar y 3, 1969
Shamma and his comorliei*s3had successfully eniployed sodium thiophenoxide in the demethylation of a variet,y of quaternary salts and proposed that the reaction proceeded by Ss2-type displacement. I n view of the fact that the benzyl or allyl are much better leaving groups than methyl in riucleophillic displacement, we have investigated the selective K-debenzylation or S-deallylation of a number of quaternary animonium salts with t'hiophenol in the presence of 5-20?;> aqueous KaOH. From various K-benzylammonium salts with other S-alkyl groups, the corresponding debenzylated tertiary amines were obtained selectively as shown in Table I. The cleavage of C--X single bond by pyrolysis4 or by treatment with inorganic salts containing S5 has been ltriorvri in the case of both allylic and benzylic s&s. Therefore, an investigation was made whether either selective debenzylation or deallylation would occur in the several K-allyl-N-benzylammoniuin salts and a greater ratio of deallylatiori to debenzylatiori was observed in all cases in Table 11. A11 the tertiary amines obtained in Tables I and I1 wort found to be identical with authentic samples as free bases and/or their salts by mixture melting point, ir spectral, arid tlc compari~ons.4-~4The unknown ( 1 ) P a r t I : T. Iiainetani, li. l\igasa\ra. 11. Iiiiragi, T. Hayasaka, N. \\agatsiirna, and K. K a k i . Heterocyclic Chrm.. 6 , 43 (1969). 12) This forms p a r t CC S V of studies on t h e Syntheses of Heteror , y c l i o Compounds. One part of this work is reported: T. Rametani, li. Kigasawa. .\I. Hiirari, h-. Wagatsuma. a n d K. Wakisaka, Tetrahedron Letter,-, 635 (186Y). ( 3 ) 11. Shamma, N. C. Ueno. and J. h'. Kemar, i b i d . , 1375 (1966). (4) U. R. Tarbelland J . R. Vaiighan, Jr., J . A m . Chem. Soc., 65, 231 (1943). ( 5 ) €1. It, Snyder and J. C. Speck, ibid., 61, 668, 2895 (1939). 16)T. 'I'iiornson and T. S.Stevens, .I. Chem. Soc., 1932 (1932). 17) .I. .L. Harltrop and D. A. H. Taylor, i b i d . , 108 (1951). ( 8 ) .I. I.. D u n n and T. S.Stevens, tbtd., 1Y26 (1932). ( 9 ) A I'artheil and H. von Broich, Ber., 30, 618 (1897). 1 1 0 ! T. .J. King, J . Chem. Soc.. 8YS (1951). (11) .J. V. Rraun, Ber., 37, 2920 (1904); 1;. Ilasse and I nant1 ,I.
Ilird. .I. .\fed, Chvni., 7, 123 [19R4!. (19) All melting points and boiling point8 were not corrected.
(,
