3290
COMRIUNIC.\TIOP;S
TO TIIE
EDITOR
1'01. 7!1
of ribonuclease, of the 661-non-exchangeable hydrogens 7.17, are aromatic and 45.07,are on ali])hatic carbon atoms attached only to other aliphatic carbons. Of the remaining protons, 19.0% are on a carbons, 8.1% are on carbons attached to carboxyls and amides, 6.0Co are on carbons with hydroxyl substituents, 5.47, are on carbons attached to sulfur, 4.2% are on carbons bonded to positively charged nitrogen, 3.97, are on carbons attached to aromatic nuclei, and 1.2Y0 are on carbons bound to amide nitrogen. All of these categories could reasonably be expected to give rise to peaks between the extremes, but their positions in peaks I1 and 111 cannot be assigned with certainty at this time.
dicate an unsubstituted cyclopentadienyl The ultraviolet spectrum of this ketone is highly characteristic in that i t shows no rnaximuni near 225 or 270 mpL,regions where maxima have been shown to occur for ketones conjugated with the ferrocene nucleus.' Such spectral behavior is reasonable for a compound of this structure since the stereochemistry of the 3-carbon bridge prevents coplanarity, and thus conjugation, of the carbonyl with the adjacent ring. y-Ferrocenylbutyric acid3 (Ib, n = 3), wlieri treated with either polyphosphoric acid or trifluoroacetic anhydride, gave as the major product the homoannular cyclized ketone, 1,2-(a-ketotetramethylene)-ferrocenej8m p . 85.4--85.7", Xxnax 9 6 , 270 mp, 6226 17,600, €2'0 7,300, infrared bands: COSTRIBUTION S o . 1448 FROX THE 1679, 1281, 1109, 1003 cm.-l. Anal. Calcd. for STERLISG CHEMISTRY LABORATORY h l A R T I S SAUNDERS VALEUSIVERSITY ilRSOLD n ' I S H S I A C~H14Fe0: C, 66.19; H , 5.55; rnol. wt., 254. r E I V HAVES, COSNEC.TICUT J O H N G. KIRKWOOD Found: C, 66.59; H , 5.69; mol. wt., 256 (ebull., butanone). RECEIVED MAE.20, 1957 ~ either 6-Ferrocenylvaleric acid3 (IC, = ~ 1 )with polyphosphoric acid or trifluoroacetic anhydride, gave the homoannular product, l,%(a-ketopentaFERROCENE BRIDGING AND methylene)-ferrocene, m.p. 63.5-66.5", Xmax 227, HOMOANNULAR CYCLIZATIONS' 269 mp> 6227 15,500, cZ69 7,400, infrared bands: Sir: 1655, 1290, 1110, 1004 ern.-'. Anal. Calcd. for The question of homoannular vs. heteroannular C16HIBFeO: C, 67.19; H, 6.02; mol. wt., 268. intramolecular acylation in substituted ferrocenes Found: C, 66.99; H , 6.18; mol. wt., 314 (ebull., has been raised recently by Nesmeyanov.* lye butanone). The shift in the infrared carbonyl wish to report here examples of both of these types band to lower frequencyg and the reduction in the of cyclizations from suitable a-ferrocenylaliphatic extinction coefficient in the ultraviolet spectrum,l'' acids: (I), together with an instance of intermo- when compared to similar spectral features of the lecular acylation, and to present evidence that the lower, homologous, ketone from IIb, containing a product obtained from these ferrocenyl aliphatic 6-membered ring, are in agreement with like shifts acids is determined by the length of the poly- found between the corresponding 7- and G-memmethylene chain separating the ferrocene nucleus bered benzocyclanones.9,10 from the carboxyl group. The principal product from the treatment of eferrocenylcaproic acid3 (Id, n = 5 ) with polyphosphoric acid was a red-brown solid, apparently polymeric,l1insoluble in usual organic solvents, decomposing slowly above 200". The material exhibits strong infrared ketonic absorption (1 Mi0 B-Ferrocenylpropionic acid3 (Ia, n = 2 ) , when cm.-'), weaker carboxyl absorption (1725, 2400, treated with polyphosphoric acid, gave hetero- 2620 an.-') and gives analytical data consistent annular cyclization to the bridged compound with those for a condensation trimer, as H[CI(,HS1,1 '-(a-ketotrimethylene)-ferro~ene,~ m.p. 144144.5°.5 Anal. Calcd. for C13H12FeO: C, 65.03; Fe(CH2)6C0]30H,though i t is more likely a mixH , 5.04; Fe. 23.26; mol. wt., 240. Found: C, ture of compounds of varying molecular weight. G4.50; H, 5.04;Fe, 23.98; rnol. wt. 281 (ebull., Anal. Calcd. for C48H56Fe304:C, 66.68; 13, benzene), 324 (ebull., butanone). The infrared 6.53; Fe, 19.35. Found: C, 66.76;H, 6.58; 17e, spectrum contains ketone bands a t 1652 and 1266 18.95. cm.-l, but no bands near 1110 or 1004 crn.-l. (6) \I. Rosenblum, P h . D . Thesis, Harvard University, Auk'n4t, Presence of 1110 and 1004 cm.-' bands would in- 1053. (1) Presented in p a r t a t t h e 1 3 1 s t Meeting of t h e American Chemical Society, Miami, Florida, April 7-12, 1957; cf. Abstracts, p. 46-0.
(2) A . N.Xesmeyanov, N. A. Volkenau and V. D. Vilchevskaya. Doklady A k a d . Xarrk S . S . S . R . , 111, 362 (1956). (3) R. L. Rioehart, Jr., R. J. Curby, Jr., and P. E. Sokol, THIS J O U R N A L , 79, in press (1967). (-1) Ferrocene substituents o n t h e same cyclopentadienyl ring are numbered "1, 2 , 3 , " etc., as in t h e benzenoid compounds, while substituents o n t h e second cydopentadienyl ring are indicated b y a n accent, as "l', Z', 3'"' etc. [cf., e.g., P. L. Pauson, THISJ O U R N A L , 76, 2187 (1951)l. ( 5 ) Woodward and Csendes obtained what is apparently t h e same compound (m.p. 141-142O) from treatment of p-ferrocenylpropionic acid with trifluoroacetic anhydride, though t h e ketone was incompletely characterized ( R . B. Woodward and E. Csendes, personal comninuication: cf. ref. G , Appendix).
(7) K . L. Kinehart, Jr., IC. L. l l o t z and S. Moon, THIS J O t W ~ . ¶ l r , 79, 2749 (1957). (8) Nesmeyanovz has recently assigned a di-homoannular .triicture similar t o this t o t h e polyphosphoric acid cyclization p i u i l u c t f r c m 1,l'-ferrocenedibutyric acid. (9) IT', 1T. Schubert and \V. A . Sweeney, THIS J O U R S A I . , 77, ,41i? (1055).
(10) G. D. Hedden and R'. G. Brown, i b i d . , 75, 3744 (1053). (11) Homoannular cyclization of I d would require t h e furmation of a n 8-membered ring expected t o form with difficulty. A simi1;illv difficult cyclization would be antjcipated fioni fetrocenylacetic acidP (I, 71 = l i , which must give eithel a highly strained 4-membered benzocyclobutanone ring or a ?-carbon hridge, for which t h e interannular distance probably is too great.'2 I n pieliminary experiments in Iic~lyphosphoricacid, no ketonic product has been obtained. ( 3 2 ) P I ' . Eilnnd s n d i< P c ; > i n k y ,T I X I ~SO I T R N A X7. ,4 , 4971 (1952); J I). Uuuitz oud I. I: iJr,,d, .Y
COMMUNICATIONS TO THE EDITOR
June 20, 1957
This work was supported in part by a grant from the Research Corporation. DEPARTMENT OF CHEMISTRY CHEMICAL ENGISEERING OF ILLINOIS VXIVERSITY KENNETH L. RINEHART,JR. URBANA, ILLINOIS ROXALD J. CURBY, JR.
AND
RECEIVED APRIL29, 1957
3291
saturated compounds and which upon catalytic hydrogenation give the desired 3-aralkyl-4-hydroxycoumarins. I n a recent paper Ziegler and Roszmanns reported the synthesis of 3-substituted benzyl-4hydroxycoumarins by condensing 4-hydroxycoumarin and substituted benzyl alcohols directly using phosphorus oxychloride as the catalyst and solvent.
A NEW SYNTHETIC APPROACH TO SOME
OH
3-ARALKYL-4-HYDROXYCOUMARTNS'
?H
R'
Sir : Since the introduction of the anticoagulant Dicumarol@, 3,3'-methylenbis-(4-hydroxycoumarin) for clinical purposes,2 interest in the synthesis of new 3-substituted-4-hydroxycoumarins and in new methods of synthesizing them has been maintained. While the reactivity of the 3-position of 4-hydroxycoumarin (I) is well known, the direct alkylation of the 3-position of 4-hydroxycoumarin with reactive halides under acidic conditions has not been reported. Grussner6 had reported the alkylation of 4-hydroxycoumarins with reactive allyl and substituted allyl bromides under alkaline conditions. This method leaves much to be desired with respect to the yields obtained (usually 10-15y0) and the scope of the procedure. 394,6
I
I1
I I I-XI1
We have found that 4-hydroxycoumarin (I) can be alkylated readily in the 3-position by heating it in the molten state with certain reactive aralkyl halides (11) a t temperatures of 130-180". The 3aralkyl-4-hydroxycoumarins (111-XII) are readily isolated in the pure state and usually in very good yields. Alkylation of 4-hydroxycoumarin with certain aralkyl bromides (11) (or chlorides) in the molten state (length of heating period and temperature vary depending on the bromide used) gave 3-aral-
TABLE I 3-SlJBSTITUTED-4-HYDROXYCOUMARINS R
R'
M&p.,O C.
Yield,
%
Formula
Carbon, % Calcd. Found
Hydrogen, % Calcd. Found
I11 Phenylb H 197-200 53 C16H1203 IV o-Methylphenyl H 202-206 95 C17H1403 76.7 76.8 5.3 5.4 V o-Chlorophenyl H 229-232 28 Cl~HliClO3 67.0 66.6 3.8 4.1 VI Benzyl' H 195-198 82 C17H1403 VI1 97" C17H1603 CHs 201-202 Phenyld VI11 Phenyld"'f C2Hj 175-177 98 C15H1603 IX Phenylf n-C3H7 191-194 95 CigH1803 X Phenyl' ~ - C ~ H I , 179-180 97 C2oH2003 XI Phenyl n-CeH11 148-149 96 CaiHa203 78.4 78.1 6.8 6.8 80.3 4.9 5.0 XI1 Phenyl Phenyl 177-178 99 C22H1703 80.5 Melting points are uncorrected. * I. M. Heilbron and D. W. Hill, J . Chem. SOC.,1705 (1927), report a m.p. of 205'. H. Pauli and K. Lockemann, Ber., 48, 28 (1915), report a m.p. 205-206". H. Junek and E. Ziegler, Monatsh., 87, 218 (1955), report a m.p. 202" and a yield of ca. 10% for VI1 and a m.p. 175-176' for VIII. a F. Litvan and W. Stoll, U. S. Patent 2,647,681, Aug. 11, 1953, report a m.p. 179'. f A. Grussner and B. Hegediis (see ref. 7) report a m.p. 179-180' for VIII, a m.p. of 201-202' for IX, a m.p. 178-180" for X, no yields were reported.
Recently Griissner and Hegedus' reported a novel, mutiple-step procedure for the preparation of 3-aralkyl-4-hydroxycoumarins, in which organometal compounds are condensed with 3-acyl-4hydroxycoumarins to form tertiary carbinols which are in turn dehydrated to the corresponding un( 1 ) Published with t h e approval of t h e Director of the Wisconsin Agricultural Experiment Station. Supported in part by t h e Research Committee of t h e Graduate School from funds supplied by t h e Wisconsin Alumni Research Foundation. (2) K. P. Link, The Harvey Lecttcre Series, 89, 162 (1943-1944). 66, (3) M. Ikawa, M . A. S t a h m a n n a n d K. P. Link, THISJOURNAL, 902 (1944). (4) C. F. Huehner and K. P. Link, ibid., 67, 99 (1945). (5) H . R. Eisenhauer a n d K . P. Link, ibid., 75, 2044 (1953). (6) A. Grussner, "Jubilee Volume," F. Hoffman-La Roche a n d Co., Ltd., Basle, 1946, p. 238. (7) A. Griissner and B. Hegedds, U. S. Patent 2,723,276, Nov. 8, 1955.
kyl-4-hydroxycoumarins (111-XII) in good yields. The physical and analytical data for the compounds reported herein are in the table. Benzylation of the 3-position of 4-hydroxycoumarin by heating with benzyl ~-toluenesulfonateQ in the molten state a t 100-120° gave 3-benzyl-4hydroxycoumarin (111) in 15y0yield. The synthesis of some of the 3-aralkyl-4-hydroxycoumarins listed here by the older procedures would be very tedious if indeed i t could be realized.lO.ll The recent method of Griissner and ( 8 ) E. Ziegler and U. Roszmann, Monatsh., 88, 25 (1957). (9) J. K. Kochi and G. S. Hammond, THISJOURNAL, 75, 3443 (1953), report t h e preparation of benzyl p-toluenesulfonate. (10) R . C. Elderfield, "Heterocyclic Compounds," John Wiley and Sons, Inc., New York, N. Y . , 1951, pp. 174-194. (11) H . Simonis, "Die Cumaxine," Ferdinand Enke, Stuttgart, 1916, pp. 200-205.
