Synthesis of some tetrahydronaphthyl- and flavanyl-coumarins

摘要

1190 J.C.S. Perkin ISynthesis of So me Tetra hyd rona pht hyl- and Flavan yl -cou ma r i nsBy (the late) Roy S. Shadbolt and (in part) David R. Woodward," Agricultural Research Laboratories, Sorex(London) Ltd., Halebank, Widnes, Cheshire WA8 8NS(in part) Peter J. Birchwood, Ward, Blenkinsop and Co. Ltd., Halebank, Widnes, Cheshire WA8 8NSThe synthesis is described of a number of 3- 3-(p-substituted pheny1)-I ,2,3,4-tetrahydro-1 -naphthyl -4-hydroxy-coumarins (7) and 3-(4'-substituted flavan-4-yl)-4-hydroxycoumarins (1 7). many of which show outstandingactivity as anticoagulants against both Warfarin-sensitive and Warfarin-resistant rats. The final stage in thesyntheses involves the reaction of either 3-(p-substituted phenyl) -1.2.3.4-tetrahydro-1 -naphthols (6) or 4'-substituted flavan-4-01s (1 6) with 4-hydroxycoumarin to give the products (7) or (1 7), respectively, as mixtures ofstereoisomers.A NUMBER of 3-3-(@substituted phenyl)-l,2,3,4-tetra- afforded the malonic acids (4) in moderate yields,hydro-l-naphthyl-4-hydroxycoumarins have been re- together with alkali-insoluble products.In the casesported recently,l* many of which show outstanding where the alkali-insoluble products were investigated,activity against both Warfarin-sensitive and Warfarin- they were identified as substituted stilbenes (8)-( 10).resistant rats. The syntheses of these and related The malonic acids (4) could be decarboxylated bycompounds are described below. heating to 200 "C to give the corresponding butyrict 4 1a; R1=H, R2=p-Phb; R1=H, R2=p-(4-C1C6H4) k; R'=H, R2=p -hexylc ; R1=H, R2=p-(4-BrC6Hf,) 1; R'=H, R2=p-cyclohexyld; R'=H, R2=p-Ph0 m; R'=H, R2=p -dodecyle; R'=H, Rz=p-(4- BrCcH~e0) n; R'=H, R2=3,4-CH2tj; R~=H, ~ * = p -BU'f ; R'=H, RZ=p-PhCH2 0; RLH, R+C~g; R 1 =H, R 2 =p-Me p; R'=H, R2=p-Brh ; R'=H, R*=p-Pr" 4; R1=CL, R2=p-Phi ; R'=H, R2=p-Pri r; R'=Me, R2=p-PhSCHEME 1 Reagents: i, AlCI,; ii, NaBH,; iii, PBr,; iv, NaCH(CO,Et),, -OH; v, polyphosphoric acid; 14, 4-hydroxy-coumarin ;vii, PBr3,4-hydroxycoumarinThe ketones (1) (Scheme 1) were readily prepared bytreatment of a suitable aromatic compound with theappropriate phen ylace t yl chloride under Friedel-Craf t sconditions, and were reduced to the correspondingalcohols (2) with sodium borohydride. The alcohols (2)on treatment with phosphorus tribromide gave thebromoethanes (3) which, although unstable, on heatingwith diethyl sodiomalonate followed by hydrolysis,B.P.Appl. 024685/1978.M. R. Hadler and R. S . Shadbolt, Nature, 1976. 253. 276.M. R. Hadler, R. Redfern, and F. P. Rowe, J . Hygiene, 1975,4 R. B. Rennison and M. R. Hadler, J. Hygiene, 1976,74,449.4, 441.acids (11)-(13). Heating the malonic acids (4) or thederived butyric acids with polyphosphoric acid gave thedihydronaphthalenones ( 5 ) . Although this cyclisationcould give rise to either 3-@-substituted pheny1)-3,4-dihydronaphthalen-l(2H)-ones or 3-($-substituted benz1976 1191y1)indan-l-ones, it has been shown5 that in reactionsof this type six-membered rings are formed in preferenceto five-membered rings.Also, the carbonyl stretchingbands in the i.r. spectra of the products occurred atca. 1 880 cm-l, characteristic of 3,4-dihydronaphthalen-l(2H)-ones (the corresponding absorption for sub-stituted indanones occurs at ca. 1 720 cm-l).Reduction of the dihydronaphthalenones (5) withsodium borohydride afforded the tetrahydronaphthols(6), which may exist as cis- or trans-isomers. It hasbeen suggested ' 9 8 that reduction of 3,4-dihydro-3-met a1 h ydride gives cis- 1,2,3,4-tet rahydro-3-phenyl- 1 -naphthol (6; R1 = R2 = H). In 1,2,3,4-tetrahydro-3-phenyl- l-naphthols, the alicyclic ring is assumed to beheld in a half-chair conformation with the 3-substituentoccupying an equatorial position (Figure).phenylnaphthalen-l(2H)-one (5 ; R1 = R2 = H) byFIGUREIn the 1H n.m.r.spectrum of 3-(9-bromopheny1)-1,2,3,4-tetrahydro-l-naphthol (6p) (CDCl, ; after D,Oexchange) the l-H signal occurs as an apparent quartetcentred at T 5.1 with a width of 17 Hz. If the l-H ispseudo-axial, the width of the quartet 899 will be thesum of an axial-axial and an axial-equatorial coupling,that is ca. 16 Hz, whereas if the l-H is pseudo-equatorialthe width will be the sum of an equatorial-axial and anequatorial-equatorial coupling, that is ca. 7 Hz. Thissuggests that the l-H is pseudo-axial and that the con-figuration in the compound is 1,3-cis.The lH n.m.r. spectrum (CD,),SO of 3-(biphenyl-4-yl) - 1,2,3,4-tetrahydro- l-naphthol (6a) obtained byreduction of 3-(biphenyl-4-yl)-3,4-dihydronaphthalen-l(2H)-one (Sa) with sodium borohydride shows the l-Hsignal as a singlet with W, ca.20 Hz ( T 5.2), whereas thel-H band in the spectrum of the tetrahydro-l-naphthol(6a) obtained by reduction with aluminium isopropoxideappears as a singlet with Wa ca. 12 Hz (T 5.25). TheWi values 9~10 of the 1-H absorptions suggests the formerproduct to be the 1,3-cis-isomer, and, although the valuefor the latter is slightly high, since the two products areisomers the latter must be the 1,3-trurts-isomer.In these lH n.m.r. spectra, the OH absorption occursas a doublet centred at t 6.62 (J 6.5 Hz) for the cis-isomer and as a doublet at T 6.84 (J 5 Hz) for the tram-isomer. Since it has been shownll that in substitutedW.S. Johnson, Org. Reactions, 1944, 2, 114.I. Lednicer and C. R. Hauser, J . Amer. Chem. SOL, 1958, 80,J. W. Clark-Lcwis and V. Nair, Austral. J . Chem., 1967, 20,3409.0 1 978 S. Mitsui, A. Kasahara, and K. Hanava, Bull. Chem. Soc.cyclohexanols an axial OH signal occurs at higher field(Z 0.21-0.27) than that of an equatorial OH, and thatthe coupling constant between the 1-OH and I-H isgreater for the isomer where the OH is equatorial, thissubstantiates the proposed assignments.By analogy, the remaining 3-substituted 1,2,3,4-tetra-hydro-l-naphthols (6), prepared by reduction withsodium borohydride, are probably cis-isomers.3-Benzyl-4-hydroxycoumarins may be prepared 12' l3by heating substituted benzyl alcohols or halides with4-hydroxycoumarin.The tetrahydronaphthylcou-marins (7) were prepared by heating the tetrahydro-naphthols (6) with 4-hydroxycoumarin at 100-170",or by conversion of the tetrahydronaphthol (6) intothe corresponding l-bromotetrahydronaphthalene withphosphorus tribromide, followed by treatment with 4-hydroxycoumarin at 130-140 "C. The former reactionresults in the formation of larger amounts of by-products,and in both cases the purified products (7) are mixtures(t.1.c.) of two components believed to be cis- and trans-isomers. In the cases of 3-3-(bipheny1-4-~1)-1,2,3,4-t et rahydro- 1 -napht hyll-4- hydroxycoumarin (7a) and3-3- (4'-chloro biphenyl-4-y1)- 1,2,3,4- tet rahydro-l-naph-thyl-4-hydroxycoumarin (7b), the respective isomerswere isolated by chromatography and gave satisfactoryelemental analyses and almost identical U.V.spectra.The product (7a), obtained by heating cis- or trams-3- (biphenyl-4-yl) - 1,2,3,4-t et rahydro-1 -naphthol (6a) with4-hydroxycoumarin, contained approximately equalquantities of the two isomers (RF 0.55 and 0.65 onsilica in chloroform), whereas conversion of either thecis- or the trans-tetrahydronaphthol (6a) into thebromo-compound and subsequent treatment with 4-hydroxycoumarin gave a product consisting pre-dominantly of one isomer (RF 0.55).The lH n.m.r. spectrum of one isomer ( R F 0.55) inCDCI, shows the l-H signal as a double doublet centredat T 4.89. The couplings are 6 and 11 Hz, hence thel-H is axial. This isomer is therefore assigned thecis-configuration (cj.Figure). The spectrum of theother isomer (RF 0.65) in CDCI, shows the l-H signal asa triplet centred a t T 4.78 with J ca. 4 Hz. Thisindicates that the l-H is equatorial and hence theisomer has the tram-configuration (cf. Figure).The major by-product from the reaction of 3-(bi-phenyl-4-yl) - 1,2,3 ,amp;tet rah ydro-1 -napht hol (6a) with 4-hydroxycoumarin was isolated and identified as 2-(bi-phenyl-4-yl) -1,2-di hydronapht halene, resulting from de-hydration. The major by-products from the synthesesof the other tetrahydronaphthylcoumarins (7) andflavanylcoumarins (17) are probably the analogous2-substituted 1,2-dihydronaphthalenes or flav-3-enes.9 L. M. Jackman and S. Sternhell, 'Application of NuclearMagnetic Resonance Spectroscopy in Organic Chemistry,'Pergamon, London, 1969, p.288.l o E. W. Garbisch, jun., J . Org. Chem., 1962, 27, 4249.l1 C. P. Rader, J . Amer. Chem. Soc., 1966,88, 1713.12 E. Enders, ' Chemie der Pflangenschutz und Schadlings-bekampfungsmittel,' ed. R. Wegler, Springer-Verlag, Berlin,1970, DP. 614-643. r . Japan, 1968, 41, 2526. 19 -H.*R. Hudson, Synthesis, 1969, 1121192 J.C.S. Perkin IThe chalcones (14) (Scheme 2), prepared by alkali-catalysed condensations of appropriately substitutedacetophenones and benzaldehydes, rearranged on heatingwith sodium acetate in ethanol to give the flavan-4-ones(15). Reduction of the flavan-4-ones (15) with sodiumborohydride gave the flavan-4-01s (16), believed to havethe amp;-configuration (i) by analogy with the tetrahydro-l-naphthols, and (ii) because reduction of flavan-4-onewith sodium borohydride has been reported14 to yieldcis-flavan-4-01.Treatment of the flavan-4-01s (16) with4-hydroxycoumarin gave the flavanylcoumarins (17) asmixtures (t.1.c.) of two components which are believedto be cis- and trans-isomers.... 111-F-(16 1( 1 7 )a; R' = H, R ~ = Hb; R' = H, R2= PhC ; R ' = H, R 2 = CLd; R ' = CL, R2 = PhSCHEME 2 Reagents: i, NaOAc; ii, NaBH,;iii, 4-hydroxycoumarinEXPERIMENTALT.1.c. was carried out on Merck silica gel (5 554) or onMerck alumina (5 550) and the products were detected byusing a U.V. lamp. Column chromatography was carriedout on Merck silica gel 60 (7 734) or on B.D.H.neutralalumina. ' Chloroform ' as used for chromatographycontained 1 ethanol. lH N.m.r. spectra were recordedwith a Varian A-60 or HA-100 spectrometer with tetra-methylsilane as internal standard. 1.r. spectra wererecorded for Nujol mulls with a Unicam SP 200 spectro-photometer (NaCl optics). U.V. spectra were recorded forsolutions in methanol with a Unicam SP 800 spectrophoto-meter. Yields quoted are those before recrystallisation,and those for solid products obtained from oils are overallyields from the previously characterised intermediate.Products which are described as oils consisted largely of onecomponent (t.1.c.) and were used directly in subsequentreactions. M.p.s are of analytically pure samples. Ana-t For details of Supplementary Publications see Notice toAuthors No.7, J.C.S. Perkin I , 1975, Index issue.14 R. Bognar, A. L. Tokes, and M. Rakosi, Acta Chim. Acad.Sci. Hung, 1973, 79, 357.15 M. Delaville, Compt. rend., 1927, 184, 463.16 E. R. Bockstahler and D. L. Wright, J. Amer. Ckem. SOC.,1949, 71, 3760.17 N. P. Buu-HoI and R. Royer, Rec. Trav. chim., 1966,85, 251.18 E. E. Turner, J . Chem. SOC., 1916,107,1462.19 A. Friedman, N. Gugig, L. Mehr, and E. I. Becker, J . Org.Chem., 1959, 24, 516.lytical data for new compounds were within accepted limitsfor C and H, and are available as Supplementary PublicationNo. SUP 21714 (4 pp.).?Ketones (1).-The ketones (la),ls (ld),16 (lf),17 (lg),l*(lj),lg (lm),20 (ln),17 (10),~1 ( 1 ~ ) ~ ~ ~ (lr),23 were preparedby literature methods.General Procedzkre.-Aluminium chloride (0.52 mol) wasadded in portions to a stirred mixture of the phenylacetylchloride (0.5 mol), the aromatic compound (0.5 mol), anddichloromethane (300 ml) below 10 "C.The mixture wasstirred for 16 h, then added to ice-hydrochloric acid, andextracted with chloroform ; the extract was washed (H,O),dried, and evaporated to give the prodzkct (Table 1).TABLE 1Ketones (1)Yield Recryst.Product () solvent M.p. ("C)65 A 172-1 7351 A 180-18357 B 118-121C 56-59 8673 D 36-3873 C 54-57E 1 0 7-1 0970 F 191-194(1b)(lc)( le)(1h)Pi)( 11) (W(W 81a A, EtOAc; B, EtOH; C, hexane; D, light petroleum (b.p.40-60') ; E, light petroleum (b.p. 80-100') ; F, HOAc.Alcohols (2) .-Sodium borohydride (0.5 mol) was addedin portions with stirring to a suspension of the ketone (1)(0.5 mol) in ethanol (500 ml).The clear solution (ifnecessary the solution was heated to 60 "C until clear) wasstirred for 1 h, diluted with water, and extracted withchloroform. The extract was washed (H,O), dried, andevaporated, and the solid was collected with light petroleumand/or recrystallised to give the 1-(p-szkbstituted Phenyl)-2-phenylethanol (Table 2).Bromoethanes (3) .-Phosphorus tribromide (0.25 mol)was added dropwise over 1 h to a solution of the alcohol(2) (0.5 mol) in dichloromethane (500 ml) below 10 "C. Thesolution was stirred for 2 h a t 20 "C, then washed withice-water, dried, and evaporated. In most cases theresidue was used directly in the subsequent reaction owingto the unstable nature of the product. The 1-bromo-l-(p-substituted phenyl)-2-phenylethanes which were characterisedwere collected and recrystallised (Table 2).Two examplesillustrate the instability of the bromoethanes. (i) In thesynthesis of the malonic acids (4) a solid was obtainedwhich was insoluble in dichloromethane-water. This solidwas combined with that remaining at the end of the alkalinehydrolysis and was identified as the substituted stilbeneresulting from dehydrobromination. The following werecharacterised: 4-phenylstilbene ( 8 ) , m.p. 211-213' (lit.,24209') ; 4-(p-~hZouophenyl)stilbene (9), m.p. 237-239" (Found :C, 82.45; H, 5.3. C2,H,,C1 requires C, 82.55; H, 5.2);4-chlorostilbene (lo), m.p.125-127" (lit.,,, 129") (ii) anattempt to recrystallise 1 -bromo- 1 -( 4'-chlorobiphenyl-4-y1)-20 Neth. Appl. 640038/1964.21 D. Y. Curtin and M. C. Crew, J . Amev. Chem. SOC., 1954,78,22 I. L. Kotlyarevskii and N. I. Popova, Izvest. Akad. Nauk23 N . P. Buu-HOT, Nguyen-Hoan, and R. Royer, Bull. SOC.24 F. Bergmann and J. Weizman, J . Urg. Chem., 1944, 9, 415.26 F. Bergmann, J. Weizman, and D. Schapero, J . Urg. Chem.,3719.S.S.S.R., Ser. khim.. 1967, 208.chim. France, 1947, 84.1944, 9, 40819762-phenylethane (3b) from ethanol gave 1-(4'-chlo~obifihe~yZ-4-yZ)- l-ethoxy-2-$henylethane, m.p. 88-90' from lightpetroleum (b.p. 80-100') (Found: C, 78.3; H, 6.1; C1,10.3. C,,H,,C10 requires C, 78.5; H, 6.3; Cl, 10.5).MaZonic Acids (4).-The bromoethane (3) (0.1 mol) wasadded to a solution prepared from sodium hydride (60 ;0.1 mol) , dimethylformamide (80 ml), and diethyl malonate(0.1 mol), and the mixture was stirred at 90 "C for 16 h.3-(p-Substituted Phenyl) -4-phenylbzdyric A amp;amp;.--The (19-substituted phenyl-2-phenylethy1)malonic acid (4) washeated at 200 'C until evolution of carbon dioxide ceased.3-p-Phenoxyphenyl-4-fihenylbutyric acid ( 1 1 ) was obtainedin 70 yield by chromatography on silica in chloroform(RF 0.2); m.p.105-106" from light petroleum (b.p.SO-SO0) (Found: C, 79.1; euro;3, 6.1. C,,H200, requiresC, 79.5; H, 6.0).TABLE 2Alcohols (2) Bromoethanes (3) Malonic acids (4)A c c A I 3 r *Yield Recryst.Yield Recryst. Yield Recrys t.Product () solvent M.p. ("C) Product (yo) solvent M.p. ("C) Product (yo) solvent M.p. ('C)1(2a) 98 A 107-108 (3a) 92 A 100-101 (4a) 75 B 199-201(2b) 98 B 134.5-135.5 (3b) 80 D 105- 107 (4b) 30 176-178(Oil) (4d) 27 A-B 154-157(Oil) (4f) 43 A-B 163-164(4h) 68 A-B 173-174A 141-143 (3c) 80 A 1 1 3-1 1 5 ( 4 ~ ) 39 B-E 18758-63 (4e) 70 A-B 176-17866-69 ( 3 4 ::bsol; :t A(2e) 99(Oil) (3f)(Oil) b (3g)(2f)(28)(Oil) (3h)(2i) 39 (31)66-70 (31)(2h) 87 A(2j) 89 A(Oil) (3k)(2m) 90 D(2x1) 72 E 47-48 ( 3 4(20) 70 A 50-52.5 * (30)(2P) (Oil) b (3P)(2q) 97 129-130.5 (3q) 90 A(2r) (Oil) (3r) 80A, light petroleum (b.p. 80-100') ; B, EtOAc; C, hexane; D, light petroleum (b.p. 60-80") ; E, light petroleum (b.p.40-60') ;Lit. m.p. 52.5-82-83 (3e) 85 C(Oil) (4g) 70 B 180(Oil)(Oil) (41) 51 A-B 170(Oil) (4i) 38 A-B 180(Oil) (4k) 41 167-15952-56 (41) 50 A-B 189-190 80-83 (31) 80 A49-63 ( 3 4 (Oil) (4m) 65 A-B 156-157(an) 35 A-B 180-181 (Oil}(2k) ( 21) 95 c(Oil) (40) 53 168-170(Oil) (4p) 70 A-B 172-173172-1 74162115 ( 4 4 ;; I;12 7-1 28 (4r) A-BF, C,H,.53.6' (A. Feldstein and C. A. VanderWerf, J . Amer. Chetem. Soc., 1954, 76, 1626).b Lit. m.p. 69-70' (D. S. Noyce, D. R. Hartter, and F. B. Miles, J . Amer. Chem. Soc., 1968,90, 3794).d Decomposed with CO, evolution.TABLE 3Dihydronaphthalenones (5) Tetrahydronaphthols (6)I L r -l Yield Recryst. Yield Recryst.Product (yo) R F a solvent 0 M.p. ("C) vco/cm-l Product () solvent 5 M.p.("C)80 (A,B) 0.9 F 92-94 1675 (64 60 K 15955 (A,C) 0.5 155-157 1 675 (6b)( 5 446 D-G 156-1 58 (64( 5b)b (S,D) 0.6 (Oil) (6d)(5c)21 (S,D) 0.4 F-H 1 3 6-1 38 1675 ( 6 4(5d)(5e)92 (6g) 36 (S,D) 0.5 J (5f)(5g)(S,D) 0.5 (Oil) 1680 (6i)(5h)(5;)(S,D) 0.5 (Oil) 1685 (6j) 37(6k) (A,D) 0.8 (Oil)(51)( 5 4b (S,D) 0.8 (Oil) (an)(A,E) 0.2 99-106 1675 (60)( 5 4(50)(5P) 60 (A,E) 0.3 E 127-1 30 1676 (6P)(5r) 12 (A,D) 0.7 D-G 13 8-1 40 1670 (6r)150-152 9571 K 149-15249 F 80-8277 79-82(Oil)92(S.D) 0.4 (Oil) (6f) 26(Oil) (6h) 14 1 1 4-1 1 5J30 FG 99-10121 G 1 03- 1 0665-66108-11266-70(S,D) 0.51675 (61) 94 iM(S,D) 0.5 I 111-113(5k) 25(51) 79(5q) (S,D) 0.5 (Oil) (6q) 6537-40 1 690 (6m) 89(Oil)44 F 101-102.582 F 104-108F-L 161-162K 165-166O S, silica: A, alumina; B, CH,Cl,; C, CC1,:CHCl; D, C,H,; E, CCl,; F, light petroleum (b.p.80-100"); G, light petroleumb Prepared by cyclisa- (b.p. 6O-SO0) ; H, EtOAc; I, hexane; J, light petroleum (b.p. 40-60") ; K, EtOH; L, CHC1,; M, MeOH.tion of the 3-(p,-substituted phenyl) -4-phenylbutyric acid.Water and dichloromethane were added and the mixturewas filtered. The dichloromethane layer was separated,washed (H,O), dried, and evaporated. Sodium hydroxide(0.4 mol), water (200 ml), and ethanol (200 ml) were addedto the residue and the mixture was heated on a steam bathfor 6 h, while the ethanol distilled off. The mixture wasfiltered, acidified, and extracted with ethyl acetate, andthe extract was washed (H,O) and evaporated.Theresidue was collected with light petroleum (b.p. 60-80')or recrystallised to give the l-(p-substituted fihenyl) -2-fihenyZethyZmaZonic acid (Table 2 ) .3-4-(fi-Bromophenoxy)phenyl-4-phenylbutyric acid (12)was obtained as a gum and used without purification.4-PhenyZ-3-(5,6,7, S-tetrahydro-2-nafihthyZ) butyric acid (13)was obtained (73) by chromatography on silica in ethylacetate (RF 0.89); m.p. 91.5' from light petroleum (b.p.SO-lOO') (Found: C, 81.2; H, 7.9. C,,H,,O, requiresC, 81.6; H, 7.5).Dihydronaphthdemnes (5) .-The malonic acid (4) or thederived butyric acid ( 11)-( 13) and polyphosphoric acid(5 parts by weight) were stirred at 160-170 "C for 1 h.The mixture was cooled to 100 "C and toluene was added1194 J.C.S.Perkin Ifollowed cautiously by water. The toluene layer wasseparated, washed (H,O), dried, and evaporated. Theresidue was purified by chromatography to give the 3-(p-substituted phenyZ)-3,4-dihydronaphthaZen- 1 (2H) -one (TableTetrahydronapJztJzoZs (6) .-The dihydronaphthalenones (5)were reduced with sodium borohydride in the same way asthe ketones (1). The 3-(p-substituted phenyl)-lI2,3,4-tetva-hydro-l-naphthols (Table 3) are believed t o have the cis-configuration.The tetra-hydronaphthol (6) (20 mmol) and 4-hydroxycoumarin (20mmol) were heated together a t 160-170 "C for 1 h. Thecooled residue was purified by chromatography on silica(eluant benzene and then chloroform). The initial fractionscontained a by-product which, in the one case examinedin the preparation of the tetrahydronaphthylcouniarin(7a)J, was identified as 2-(biphenyZ-4-yZ)-l,2-dihydronapJ~tha-Zene (39), m.p.96-99" from light petroleum (b.p. 80-lOO"), IZp 0.93 (silica; benzene) (Found: C, 93.5; H, 6.6.C2,H1, requires C, 93.6; H, 6.4); T CIICI,; 100 MHz2.34-3.20 (13 H, m, aromatic), 3.47 (1 H, q, J 3 , 4 10, J2,*6.10-6.42 (1 H, m, H-2), and 6.82-7.14 (2 HI m, H-1).Fractions containing two components having R~)F 0.4-0.7(silica; chloroform), and believed to be the cis- and trans-isomers, were evaporated to give the 3-3-($-substitutedphenyl)-l,2,3,4-tetrahydro-l-naphthyl-4-hydroxycoumarin(Table 4).TABLE 4Tetrahydronaphthylcoumarins (7)3).Tetrahydronaphtlzylcoumarins (7) .-Method A .or J 4 , 5 3 Hz, H-4), 4.00 (1 H, 9, J 3 .4 10, J 2 . 3 3.5 Hz, H-3),MethodAAAAAABABBAABABBAAYield203238142013291849504825471236372311() RF0.55, 0.650.80, 0.700.56, 0.650.56, 0.610.58, 0.670.60, 0.670.54, 0.610.61, 0.670.52, 0.580.58, 0.620.62, 0.670.62, 0.670.52, 0.580.650.1, 0.22 b0.51, 0.610.42, 0.58Recryst .=solventAAABACADD1)DAD13EAAAM.p. ("C)215-217233-237228-230200- 2 0 1199-20175-851 69- 1 70102-1 06100- 104164-167109-1 11170-1 741 10-1 1 1206-20719 7-201210-213255-256230-2320 Silica ; chloroform. 6 Silica ; 1,1,2-trichloroethylene.A, EtOAc; B, Me,CO; C, light petroleum (b.p.100-120") ;D, light petroleum (b.p. 80-100') ; E, Et20.Method B . Phosphorus tribromide (7.4 mmol) wasadded dropwise to a stirred solution of the tetrahydro-naphthol (6) (20 mmol) in dichloromethane (50 ml) below10 "C. After 2 h the solution was washed (ice-water),dried, and evaporated. In another experiment, the residuewas recrystallised to give 3-(biphenyl-4-yl)-l-bromo-1,2,3,4-tetrahydronaphthalene (70), m.p. 133-135" (decomp.)(from ethyl acetate) (Found: C, 72.55; H, 5.4. C,,H,,Brrequires C, 72.8; H, 5.3) . 4-Hydroxycoumarin (20mmol) was added to the residue and the mixture washeated at 140 OC for 0.3 h. The cooled residue was chro-26 L. Bauer, A. J. Birch, and W.E. Hillis, Chenz. and Ind., 1954,433.matographed on silica (chloroform) t o give the product(Table 4).Separation of the Isomers of Tetrahydronaphthylcoumarins(7) .-(i) 3-3-(BiphenyZ-4-yZ)-l, 2,3,4-tetrahydro-l-naphthy4-4-hydroxycoumarin (7a). The isomers were separated bypreparative t.1.c. on silica (multiple development withbenzene). The bands were extracted with ethyl acetate togive two isomers: (a) R p 0.18 (silica; benzene), m.p.228-229" (from ethyl acetate), hx. 257 ( E 27 000) and309 nm (12 300) (Found: C, 83.6; H, 5.4. C3,H,,03requires C, 83.8; H, 5.4); and (b) RF 0.24 (silica;benzene), m.p. 200-202" (from ethyl acetate), A,, 257(E 26 500) and 309 nm (12 300) (Found: C, 83.7; H, 5.5).(ii) 3-3-(4'-ChZorobiPhenyZ-4-yZ)-lI 2,3,4-tetrahydro-l-naph-thy~-4-hydroxycoumarin (7b).The isomers were separatedby column chromatography on silica chloroform-1, 1,2-trichloroethylene (1 : l) to give two isomers: (a) RF 0.80(silica ; chloroform), m.p. 222-225" (from ethyl acetate),Anmx. 265.5 (E 41 800) and 308 nm (15 100) (Found: C , 77.5;H, 5.0. C3,H2,C103 requires C, 77.8; HI 4.8); and (b)R p 0.70 (silica; chloroform), m.p. 233-234' (from ethylacetate), LL 265.5 (E 36 900) and 309 nm (14 100) (Found:C, 77.5; H, 5.1).2-Hydroxy-4'-PhenyZchalcone ( 14b) .--o-Hydroxyaceto-phenone (8.8 g, 65 mmol), biphenyl-4-carbaldehyde (1 1.8 g ,65 mmol), ethanol (250 ml), and aqueous sodium hydroxide(50; 40 ml) were stirred for 4 h, and the solution wasacidified t o give the chalcone (95), m.p.148-150" frombenzene-light petroleum (b.p. 80-100deg;) (Found ; C,83.9; H, 5.2. C21H160, requires C, 84.0; H, 5.3).5-CJa1oro-2-hydroxy-4'-~henyZchaZcone (14d) was obtainedsimilarly (95) from 5'-chloro-2'-hydroxyacetophenone;m.p. 120" from light petroleum (b.p. 80-100deg;) (Found:C, 75.1; H, 4.7.Flavan-4-01 (16a) was prepared by reduction of flavan-4-one with sodium borohydride and had m.p. 143-145'(lit.,26 146").4'-Chloroflavan-4-oI (1 6c) .-4'-Chloroflavan-4-one 27 wasreduced with sodium boroliydride to give the flavanol(66), m.p. 160-162" from light petroleum (b.p. 100-120") (Found: C, 68.9; H, 5.2. C,,H,,C10, requires C,69.1 : H, 5.0).4'-PhenyZflavan-4-oZ ( 1 6b) .-2-Hydroxy-4'-plienylchal-cone (20.6 g, 69 mmol), sodium acetate (6.4 g), and ethanol(475 ml) were heated under reflux for 16 h.The solutionwas evaporated and the residue partitioned betweenchloroform and water. The chloroform layer was separatedand the solvent removed. Chromatography of the residueon alumina (benzene) gave crude 4'-phenylflavan-4-one(11.8 g, 39 mmol), which was reduced with sodium boro-hydride to give the3avanoZ (6.5 g, 31y0), m.p. 173.5-175"(Found: C, 83.5; H, 5.8. C,,H,,O, requires C, 83.4; H,6.0).Similarly 5-chloro-2-hydroxy-4'-plienylchalcone was con-verted into 6-chZoro-4'-phenyl~auan-4-oZ (1 6d) (32), m.p.173-175" (from ethanol) (Found: C, 74.7; H, 5.1.C21H,,C10, requires C, 74.8; H, 5.1).FZavanyZcoumarins (17) .-The flavanol (1 6) and 4-liydroxycoumarin (equimolar amounts) were heated at160-170" for 1 h, and the residue was chromatographedon silica (chloroform) to give, as mixtures of two com-ponents believed to be cis- and trans-isomers, the following:(a) 3-(4'-chZoro~7avan-4-yZ)-4-hydroxycoumarin (17c) (25) ,27 Peng Li Cheng, P. Fournari, and J. Tirouflets, Bull. SOC.chim. France, 1963, 2248.C2,H,,C102 requires C, 75.4; HI 4.5)1976 1195m.p. 9(t-110" from light petroleum (b.p. 100-120deg;),RF 0.49 and 0.61 (Found: C, 71.3; H, 4.6. C2,H,,CI04requires C, 71.2; H, 4.3) ; (b) 3-(6-chZoro-4'-~henyZ$avan-4-yZ)-4-2iydrox3/couuvtarin (17d) (25), m.p. 230-232" (fromethyl acetate), RF 0.41 and 0.51 (Found: C, 75.2; H, 4.6.C,oH,,C104 requires C, 74.9; H, 4.4).3- (Fbazran-4-yZ)-4-hydroxycouvpzarin ( 17a) .-Water (0.17ml), sulphuric acid (0.45 ml), and flavan-4-01 (5.5 g, 23mmol) were added to a stirred suspension of 4-hydroxy-coumarin (4.0 g , 24 mmol) in acetic acid (12.5 ml) at 100 "C.After 0.5 h the mixture was diluted with water and ex-tractetl with ethyl acetate. The extract was washed (H,O),dried, and evaporated. Chromatography of the residueon silica (chloroform) gave the fluvanyZcounzariE (0.74 g8), RF 0.50, m.p. 178-180" from light petroleum (b.p.100-120") (Found: C , 77.7; H, 4.8. C24H1804 requiresC, 77.8; H, 4.9).3-(4'-PhenyZflavan-4-yZ)-4-hydroxycoumar~n ( 17b) was ob-tained similarly (1 1 yo), m.p. 207-210" (from ethyl acetate),R p 0.41 and 0.51 (Found: C, 80.4; H, 5.1. C,,H,,O,requires C, 80.7; H, 5.0).We thank Mr. M. R. Hadler for advice and encourage-ment, Mrs. M. Heyes for technical assistance, and ProfessorJ. A. Elvidge, University of Surrey, for interpretation ofsome of the n.m.r. spectra.5/1984 Received, 10th October, 1976