A novel rearrangement reaction: single-step conversion of 2-(6-carboxy-3-oxoheptyl)-3,4-dihydro-6-methoxynaphthalen-1 (2H)-one into 1-(3-carboxybutyl)-2-(2-carboxyethyl)-3,4-dihydro-6-methoxynaphthalene

摘要

J. CHEM. SOC. PERKIN TRANS. I 1983 211 A Novel Rearrangement Reaction : Single-step Conversion of 2-(6-Carboxy-3-oxoheptyl)-3,4-di hydro-6-methoxynaphthalen-l(2H)-oneinto 1-(3-Carboxybutyl)-242-carboxyethyl)-3,4-dihydro-6-methoxy-naphthalene Susheel Durani and Randhir S. Kapil * Central Drug Research Institute, Lucknow 226001, India The synthesis of 2-(2-carboxyethyl) -1 -(3-carboxypropyl) -3,4-dihydro-6-methoxynaphthalene (28) and the homologous diacid (30) has been achieved in a single step from the 2-(6-carboxy-3-oxoalkyl)-3,4-di hydro-6- methoxynaphthalen-l(2H) -ones (22) and (24),respectively, via a novel acid-catalysed cyclisation-rearrangement reaction. The structure of the diacids (28) and (30) is supported by the high resolution mass spectrometric data of their respective dimethyl esters (29) and (31 ).The aromatic methoxy-group and the carboxy-function at C-6 in the side chain are critical for the rearrangement, but not for the cyclisation, part of the reaction. Based on this and other observations a mechanism for this novel rearrangement reaction has been proposed. The dihydronaphthalene derivatives (29) and (31) were required for possible elaboration into 13,14-seco-estradiol analogues. The synthesis of these molecules was envisaged via a Robinson annelation reaction between 3,4-dihydro-6- methoxynaphthalen-l(2H)-one and suitable chain elements (c), followed by an appropriate fragmentation of the resulting tricyclic system (b), as outlined in Scheme 1. During the course of exploratory work on this route, we came across a novel rearrangement reaction, which led to a facile synthesis of the required diesters (29) and (31).Thus, the 1-tetralone derivatives (22) and (24) carrying suitable chain elements at C-2, when refluxed briefly with acetic acid-dilute hydrochloric acid, furnished the required diacids (28) and (30) respectively, in ca. 30 yield. The present paper describes this unprecedented rearrangement reaction and deals with the elaboration of its mechanism. The tetralone derivatives (22) and (24) were synthesised by two different routes. Michael addition of 2-formyl-3,4-dihydro-6-methoxynaphthalen-1(2H)-one (1) on the enone ester (4),furnished the adduct (16), which on treatment with aqueous sodium hydroxide followed by ethereal diazo-methane, furnished the ester (23) via the crystalline diketo-acid (22).Alternatively, condensation of the quarternary ammo- nium iodide (3) with diethyl P-oxopimelate (10) according to the procedure of Brown et aZ.,'n2 furnished the diketo-ester (19) in high yield. Hydrolysis of (19) with barium hydroxide in aqueous ethanol, followed by decarboxylation, gave the diketo-acid (22) in moderate yield, along with 2-(2-carboxy- ethyl)-3,4-dihydro-6-methoxynaphthalen-l(2H)-one as the ketonic hydrolysis product. For the synthesis of the appropriate a-methyl-substituted diketo-acid (24), the enone ester (8) and j3-keto-ester (1 l), were required as the starting materials. For their synthesis, the Michael adduct (1 3) of diethyl methylmalonate and ethyl acrylate, prepared according to Floyd and Miller,j was subjected to controlled saponification followed by decarboxy- lation to obtain the half ester (S), carrying the methyl group adjacent to its ester function.Reaction of (5) with thionyl chloride brought about a rearrangement to furnish ethyl 5-chloro-2-methyl-5-oxopentanoate(6) and ethyl 5-chloro-4- methyl-5-oxopentanoate (7), as a mixture of products. It is known that half esters of unsymmetrically substituted SUC-cinic and glutaric acids react with thionyl chloride in a similar manner,4d furnishing ester acid chlorides as a mixture of two isomers. The mixture of acid chlorides (6)and (7) was con- verted into the 1,3-enones (8) and (9), and the 0-keto-esters a ROzC vnIU Scheme 1 (11) and (12), according to the procedure reported for the enone (4) and diethyl fboxopimelate,8 respectively, from methyl glutaryl chloride.The enones and the P-keto-esters were found to be 3 : 2 mixtures on the basis of their n.m.r. data and g.1.c. analysis. Attempted resolution of these mix- tures by fractional distillation proved abortive. The sub- sequent reactions were, therefore, carried out with the mixtures as such. Michael condensation of 3,4-dihydro-2-formylnaphthalen-l(2H)-one (1) with enones (8) and (9) furnished the adducts (17) and (18), which upon treatment with aqueous sodium hydroxide afforded the diketo-acids (24) and (26), as a mix- ture. Along the alternative route, condensation of the diesters (11) and (12) with the quarternary ammonium iodide (3) gave a mixture of the adducts (20) and (21).Hydrolysis and decarboxylation of these adducts furnished the diketo-acids (24) and (26), which on esterification furnished compounds (25) and (27) as a mixture. In the n.m.r. spectrum of these esters, the isomeric methyl groups appear as two separate J. CHEM. SOC. PERKIN TRANS. I 1983 63 (4) R1= vinyl, R2 = R3= H, R4= Me (5) R' = OH, R2 = H, R3= Me, R4= Et (6) R1= C1, R2 = H, R3= Me, R4= Et (7) R1= CI, R2 = Me, R3= H, R4= Et (8) R1= vinyl, R2 = H, R3= Me, R4= Et (9) R' = vinyl, R2 = Me, R3= H, R4= Et (10) R' = Et02CCH2, R2 = R3= H, R4= Et (11) R' = Et02CCH2,R2 = H, R3= Me, R4= Et (12) R' = Et02CCH2,R2 = Me, R3= H, R4= Et (14) R' = H, R2 = Me (15) R' = Me, R2 = H 0 CO~R~ (16) R1= CHO, R2 = R3= R4= H, R5= Me (17) R1= CHO, R2 = R3= H, R4= Me, R5= Et (18) R' = CHO, R2 = R4= H, R3= Me, R5= Et (19) R1= R3= R4= H, RZ= C02Me, R5= Et (20) R1= R3= H, R2 = C02Et,R4= Me, R5= Et (21) R1= R4= H, R2= C02Et,R3= Me, R5= Et (22) R' = R2 = R3= R4= R5= H (23) R1 = R2 = R3= R4= H, R5= Me (24) R1 = RZ= R3= R5= H, R4= Me (25) R1 = R2= R3 = H, R4= Rs= Me (26) R1 = R2 = R4= R5= H, R3= Me (27)R1 = R2 = R4= H, R3 = R5= Me C02R2 COzR2 (28) R' = R2 = H (29) R1= H, R2 = Me (30) R' = Me, R2 = H (31) R1= R2 = Me (291 R = H (311 R = Me r 1' -MeOH+ Me m/r 245.1187 m/~2 13.09 4 4 ( 9 7 If fOm (29 50 from ( 29 1and ( 311 m/z 213.0916 (93)from(311 C15H1703 C1LH1302 Scheme 2 As the next step of the original scheme, cyclisation of the diketo-carboxy-derivatives,such as (22), was attempted.In one such attempt, the acid (22) or its ester (23) was refluxed for 2h in acetic acid-dilute hydrochloric acid. Work-up of the reaction mixture led to the isolation of a crystalline compound in 33 yield, which was characterised as the diacid (28). Treatment of this compound (28) with ethereal diazomethane gave the diester (29). The disappearance of the i.r. bands at 1672, 1710, and 1 735 cm-', characteristic for the diketo-ester (23), and the appearance of the band at 1 700 cm-' for the acid (28) and at 1 735 cm-' for the ester (29) indicated that the transformation had utilized the keto- groups of the starting material.The appearance of a six-proton singlet at T 6.28 in the n.m.r. spectrum of compound (29) indicated it to be a dimethyl diester, and consequently compound (28) to be a diacid. More conclusive support for the structure of the diester (29) was forthcoming from its mass fragmentation pattern (see later). The mixture of isomeric diketo-acids (24) and (26) was next subjected to the rearrangement reaction. This resulted in the transformation of the monoacid (24) into the required diacid (30), while the isomer (26) was recovered unchanged. Treat- ment of the reaction product with ethereal diazomethane, followed by chromatography over a column of silica gel, led to the isolation of the diester (31) and the diketo-ester (27) as pure products.The n.m.r. spectrum of the diester (31) was in accordance with its homology with the diester (29), with its methyl ester functions appearing as two separate singlets at 7 6.33 and 6.37 and its at-methyl residue appearing as a doublet at r 8.82. The diketo-ester (27) was found to be identical with the previously- obtained mixture of (25) and (27) on the basis of t.1.c. as well as n.m.r., except for the doublet at t 8.94 in case of the mixture, which was thus assigned to the isomer (25). Mass Fragmentation Pattern of the Diesters (29) and (31).-In the high resolution mass spectrum, the diesters (29) and (31) showed prominent M+ ions at m/z 346.1781 (C20H2605, 94) and m/z 360.1950 (CZ1H2805,loo), respectively.A prominent peak at m/z 171, common to both the compounds doublets, centred at t 8.94 and 8.89. The latter signal was and corresponding to elemental composition ClzHl was subsequently found to correspond to the undesired isomer rationalised as indicated in Scheme 2. (27), which constituted 60 of the mixture. The origins of the peaks at m/z 273 and 287 for compounds J. CHEM. SOC. PERKIN TRANS. I 1983 213 r OMe 1’ R +C02Me (29) R =H (311 R= Me McLaf f er t y rearrangement 1. Me0 m/z 199.11 26 ( 34 ) from ( 291 m/z 172.0866(22)from (29) m/z 199.1126 ( 3 2o/o 1from ( 3 1 1 m/z 172.086 6( 15 If rom( 3 11 C1LH150 c15H120 Scheme 3 R202C R Pco2Me+ R’ I R’ ‘‘ R20 (291 R=H m/z 259 (311 R=Me 10 from (291 (32) R’ = R~ = H (34) R’=HJR2 =Me 6 from(311 (33) R‘ =OMeJR2 =Me (35) R’ = OMe, R2 =Me Y 1.Et02C R’ SR2‘ MeO MeO@@)I m/z 165.0961(40)from(29) m/z 171.0824 (100°/a1from(291 (36) R’ = H R2 = CH2CO2Et mh 185.0979 (45 ) from( 31 1 m/z 171.0808 ( 97 “/o 1 from (31 (37) R’ = OMe, R2 = C02Et C13H130 C12HllO Scheme 4 (29) and (31), respectively, and their common ion peaks at m/z 172 and 199, have been rationalised as shown in Scheme 3. An a-cleavage of the side chain at C-1 and formation of the ion peaks at m/z 245 and 213, as shown in Scheme 4, appears (38) R’ = H (40) R’= H to be the major mode of fragmentation for (29) as well as (31).(39) R’ =Me (41) R’= Me Mechanism of the Rearrangement Reaction.-Treatment for the rearrangement reaction, individually or as a mixture, of the diketoester (23) with 30 methanolic hydrochloric furnished the diacid (28), in ca. 30 yield. The diketo-ester acid for 2 h at room temperature furnished the isomeric (37), with its side chain shortened by one carbon atom, was cyclised keto-esters (33) and (33, in 80 overall yield. next synthesised by condensation of diethyl P-oxoadipate Compounds (33) and (35) when subjected to the conditions with the quaternary ammonium iodide (3), and was subjected 214 J. CHEM. SOC. PERKIN TRANS. I 1983 silica gel or alumina plates and by g.1.c. on a Varian Aerograph 1800 instrument. Ether refers to diethyl ether RYC002Hthroughout.MeO' 22) R=H 24) R = Me II/CO2" /1/CO2"R R (30)R = Me Scheme 5 to the rearrangement reaction. This resulted in formation of the isomeric tricyclic keto-acids (38) and (40), as the sole identifiable products, in ca. 70 overall yield. The des- methoxy-diketo-ester (36), synthesised in the usual manner starting from the tetralone derivative (2) and diethyl p-oxopimelate, when subjected to the conditions for the re- arrangement reaction, furnished the crystalline diketo-acid (32).while the mother-liquor, on esterification and chromato- graphy, furnished the isomeric tricyclic keto-ester (34)and an additional amount of (32)as its methyl ester. The cyclised materials, together accounting for ca.80 of the reaction product, were the only identifiable products formed in this reaction as well. From these experimental observations it is apparent that the rearrangement reaction proceeds in two steps, viz., cyclisation followed by a rearrangement. The aromatic methoxy-group and the carboxy-function at C-6 in the side chain are, understandably, not important for the first step, but are crucial for the rearrangement. Based on these observ- ations, the mechanism outlined in Scheme 5 has been pro- posed for the rearrangement reaction. Experimental The n.m.r. spectra were recorded on a Varian A-60D instru-ment in CDCl, solution, unless otherwise stated, using tetramethylsilane as internal reference. The mass spectra were recorded on a Hitachi RMU-6E mass spectrometer fitted with a direct inlet system, and high resolution mass spectra on a Jeol JMS-OlSG-2instrument.The i.r. spectra were recorded on Perkin-Elmer 337 or 177 grating instruments, either as KBr films or as neat samples, and the U.V. spectra on a Perkin-Elmer 202 automatic recording spectrophotometer. Homo-geneity of the compounds was checked by t.1.c. either on Diethyl 2-Ethoxycarbonyf-2-methyfgfutarate (1 3).-To a suspension of diethyl methylmalonate (24 ml) and sodium ethoxide prepared from sodium metal (0.55 g) and absolute ethanol (12ml) in dry ether (200ml), ethyl acrylate (16.5 ml) was added cautiously and the reaction mixture refluxed for 4 h. It was then cooled and acidified with aqueous AcOH (2; 100 ml) and extracted with ether (3 x 100 ml).The combined organic layer was washed with water (2 x 100 ml), dried (Na2S04) and ,concentrated. The residue was dis- tilled under reduced pressure to furnish the triester (13)(32 g), b.p. 145 "C at 3 mmHg; vmax.1735 cm-' (C02Et); r 5.60-6.15 (6 H, m, C02CH2CH3), 7.65-7.95 (4 H, m, CH2CH2),8.66 (3 H, m, CH,), and 8.78 (9 H, t, J 7.0 Hz, C02CH2CH3). Ethyl Hydrogen 2-Methylglutarate (3.-A solution of the triester (13) (55 g) in absolute ethanol (750ml) was refluxed with KOH pellets (30g) for 2.5 h. Most of the ethanol was removed under reduced pressure and the residue dissolved in water (700ml), acidified with ~M-HC~and extracted with ether (3 x 200 ml). The combined ethereal layer was washed with water (3 x 200 ml), dried (Na2S04) and concentrated.The crude product was decarboxylated by heating at 150 "C at 20 mmHg for 2 h and finally distilled to give the half-ester (5) (28 g), b.p. 144-145 "C at 8 mmHg; vmx. 1735 (C02Et) and 1 710 cm-I (C02H); r 5.84 (4 H, q, J 7.0 Hz, CO2CN2- CH3), 7.40-8.10 (4 H, m, CH2CH2),8.62 (3 H, s, CH,), and 8.77 (6 H, t, J 7.0 Hz,C02CH2CHj). Ethyl 5-Chloro-2-methyl-5-oxopentanoate(6) and Ethyl 5-chloro-4-methyl-5-oxopentanoate(7).-A mixture of the foregoing ester (16 g) was treated with thionyl chloride (48 g) according the described procedure: to afford a mixture of the acid chlorides (6)and (7) (15.2 g), b.p. 87-89 "C; v,,,. 1 795 (COCl) and 1 735 cm-I (C0,Et). Ethyl 2-Methyl-5-oxohept-6-enoate (8)and Ethyl 4-Methyl-5-oxohept-6-enoate(9).-The preceding mixture of isomeric acid chlorides (6) and (7)(I5 g) was converted into a mixture of the isomeric vinyl ketones (8) and (9) (9 g) according to the procedure described in ref.7 for the methyl ester (4),b.p. 80-82 "Cat 1 mmHg; vmx. 1735 (C0,Et) and 1675 cm-I (vinyl ketone); T 3.404.18 (3 H, m, COCHCH2), 5.95 (2H, m,COCH2CH3),7.30-8.55 (5 H, m, 2-, 3-, 4-H),8.82(3 H, m,C02CH2CH3),8.84 and 8.92 f3 H, 2 d,J 7.0Hz, CH(C02- Et)CH3 and COCHCH,. Diethyl6-Methyl-3-oxopimefate(1 1) and Diethyf 4-Methyl-3-oxopimelate (1 2).-The mixture of acid chlorides (6)and (7)(110 g) were first treated with ethyl acetoacetate in the pre- sence of sodium ethoxide and then with ammonia according to the described procedure to give the 0-ketoesters (11)and (12) (16 g), via the diketo-diesters (14) and (15), b.p.,.5122-125 "Cat 1.5 mmHg; v,, 1 725 cm-I (C02Et and CO); r 5.84 and 5.91 (4H, 2q, J 7.0 Hz, 2 C02CH2CH3),6.51 and 6.61 (2 H, 2 s, COCH2C02Et),7.10-8.50 (5 H, m, 4-,5-, and 6-H),and 8.60-9.20 (9 H, m, 2 C02CH2CH3 and isomeric CH3); g.1.c.column 3 SE-30 on chromosorb W(HP); carrier gas, nitrogen; temp. 180 "C retention time 7.0 min (40) and 7.5 min (60). 2-FormyI-3,4-dihydro-6-methoxy-2-(6-methoxycarbonyl-3-ox.ohexyl)naphthalen-l(2H)-one (1 6).-To a cooled mixture of 3,4-di hydro-2- hydroxymet hylene-6-met hoxy naph t halen- J. CHEM. SOC. PERKIN TRANS. I 1983 215 l(2H)-one lo (3 g) and vinyl ketone (4)(2.3g), triethylamine bh, CO,H), 2.03(1 H, d, J9.0Hz, ArH, m to OCH,), 6.9 4-, 6'-, 2-, 3-,and 4-H), 8.80 and 8.89(0.25ml) was added and the reaction mixture stirred at room 8.50 (14H, m, 1'-, 2f-, temperature for 16 h.It was diluted with ether (100ml), 3 H, 2d, J 7.0Hz,CH(C02H)CH3 and COCHCH3. washed with aqueous NaHCO, (5; 2 x 25 ml), ~M-HC~ (25ml), and finally with water (2 x 50 ml), dried (Na2S04) and concentrated. The residue was passed through a short column of silica gel, eluting with benzene, to give the substituted tetralone (16) (4.2 g), as a yellow oil; vmax,1 740 (C02Me), 1 727(CHO), 1 712(CO), and 1 670cm-' (ArCO); T 0.26 (1 H, s, CHO), 1.98 (1 H, d, J 9.0Hz,ArH, m to OCH,), 2.95-3.30 (2 H, m, ArH, o to OCH,), 6.11(3 H, s, OCH,), 6.30(3 H,s, C02CH3), and 6.85-8.45 (14H, m, lf-, 2f-,4f-,5'-, 6'-,3-,and 4-H).2-(6-Carboxy-3-oxohexyl)-3,4-dihydro-6-methoxynaph-thalen-l(2H)-one (22).-A mixture of the ester (16)(1.1 g) and aqueous NaOH (2~;25 ml) was stirred at room temper- ature for 24 h. It was then diluted with water (125ml) and extracted with ether (2x 50 ml). The aqueous layer was cooled to 0 "C and acidified with ~M-HC~ to give a pre-cipitate, which was filtered off, dried (P205)in vacuo and crystallised from benzene to afford the diketo-acid (22) (0.9g), m.p. 1-141 "C; vmaX.1712 (CO), 1690 (C02H), and 1 660cm-' (ArCO); T 0.50 (1 H, bh, C02H), 1.97(1 H, d, J 9.0 Hz, ArH, m to OCH,), 2.93-3.35 (2 H, m, ArH, o to OCH3), 6.12 (3 H, s, OCH3), and 6.85-8.35 (15 H, m, I/-, 2f-,4f-, 2-,3-,and 4-H) (Found: C, 67.85;H, 7.15.6f-, C18H2205requires C, 67.91;H, 6.97).3,4-Dihydro-6-methoxy-2-(6-methoxycarbonyl-3-oxohexyl)-naphthalen-l(2H)-one (23).--A solution of the acid (22)(150mg) in methanol-ether (1 : 4;10 ml) was treated with ethereal diazomethane prepared from 1 g of nitrosomethyl- urea at 5 "C. After being kept at room temperature for 1 h, the excess of diazomethane and ether was evaporated off and the residual oil was purified by passing it through a column of silica gel in benzene to furnish the diketo-ester(23) as an oil (148mg); vmx. 1735 (C02Me), 1710 (CO), and 1 672cm-' (ArCO); m/z332 (M+);T 1.99(1 H, d, J 9.0 Hz, ArH, m,to OCH,), 2.95-3.30 (2 H, m, ArH, o to OCH,), 6.12(3 H, s, OCH,), 6.30(3 H, s, C02CH3), and 6.85-8.35 (15 H, m, lf-,2f-, 6'-, 2-, 3-,and 4-H) (Found: C, 68.95;4f-, H, 7.45.C19H2405requires C, 68.66;H, 7.28).2-Formyl-2-(6-ethoxycarbonyl-6-methyl-3-oxohexyl)-3,4-dihydro-6-methoxynaphthalen-l(2H)-one(17) and 2-Formyl- 2-(6-ethoxycarbonyl-4-methyl-3-oxohexyl)-3,4-dihydro-6-methylnaphthalen-l(2H)-one(18).-A mixture of 3,bdihydro- 2-hy droxymethylene-6-methoxynaphthalen-1(2H)-one (1) (5 g), the vinyl ketones (8)and (9)(4.5g) and triethylamine (0.5 ml) was allowed to react for 16 h at room temperature and then worked up as described earlier for the ester (16)to give the mixture of substituted 1-tetralones (17)and (18) (7.6 g)as an oil; vmax.1 735 (C02Et), 1 727 (CHO), 1 712 (CO), and 1670 cm-I (ArCO); T 0.6 (1 H, s, CHO), 2.10 (1 H, d, J 9.0Hz, ArH, m to OCH,), 3.10-3.45 (2H, m, ArH, o to OCHj), 5.95 (2 H, 9, J 7.0Hz, C02CH,CH,), 6.20(3 H, S, OCH,), 6.90-8.50 (13 H, m, lf-, 2f-,4'-,6'-,3-,and 4-H), 8.80(3H, t, C02CH2CH3), 8.91and 8.963H, 2d, COCHCH, and CH(C02Et)CH3.3,4--Dihydro-6-methoxy-2-(6-methoxycarbonyl-6-methyl-3 oxohexyl)naphthalen-l(2H)-one (25) and 3,4-Dihydro-6-methoxy-2-(6-methoxycarbonyl-4-methyl-3-0xohexy1)naphtha-len-l(2H)-one(27).-The preceding mixture (1.5g) was esteri- fied by treatment with a solution of ethereal diazomethane prepared from 3 g of nitrosomethylurea as described earlier for the acid (22)to give the esters (25)and (27)as an oil (1.6 g); vmx. 1 735(C02Me), 1 710 (CO), and 1 672cm-' (ArCO); r 2.03(1 H, d, J9.0Hz, ArH, mto OCH,), 3.06-3.40 (2H, m, o to OCH3), 6.17 (3 H,s,OCH,), 6.34(3H,s,C02CH3), ArH, 6.85-8.45 (14H,m, 1'-, 2f-, 6'-,2-, 3-,and 4-H), 8.85and4f-, 8.89 3H, 2d, J 7.0 Hz, CH(C02Me)CH3 and COCHCH,.2-(2,6- Dimethoxycarbonyl-3 -oxohexyl)3,4-dihydr0-6-methoxynaphthalen-l(2H)-one(19).-A solution of the p-keto-ester (10)(10g) in absolute methanol (20ml) was added into a stirred solution of sodium methoxide prepared from Na metal (1.2g) in absolute methanol (20ml) at room temperature. Most of the solvent was removed under reduced pressure and the residue, suspended in dry dioxan (300ml), was treated with the methiodide (3) (20g) and the reaction mixture stirred at 80 "C for 8 h.After most of the solvent had been removed under reduced pressure, cold ~M-HC~(500 ml) was added to the residue which was then extracted with ether (3x 150 ml). The combined organic layer was washed with water (2x 200 ml), dried (Na2S04) and concentrated. The residual oil was filtered through a short column of silica gel in benzene to furnish the diketo-diester (19) (16 g) as an oil; vmX 1 735(C02Me), 1 712(CO), and 1 670 cm-' (ArCO); mlz 390 M+; T 2.05 (1 H, d, J 9.0 Hz, ArH, m to OCH,), 3.08-3.40 (2 H, m, ArH, o to OCH,), 6.12(3 H, s, OCHJ. 6.25 and 6.30 (6 H, 2 s, C02CH3), and 6.85-8.35 (14 H, m. 1'-, 2f-,4'-,6'-, 2-, 3-, and 4-H). Hydrolysis and Decarboxylation of the Ester (1 9).-A suspension of compound (19) (950 mg) and Ba(OH), (6g) in methanol-water (1 : 2; 20 ml) was refluxed for 45 min.It was then cooled in ice, acidified with ~M-HC~ and extracted with ether (3 x 50 ml). The combined ethereal layer was washed with water (2x 50 ml), dried (Na2S04) and con- centrated. The residual oil (760mg) was pyrolysed by heating at 150 "C and finally crystallised from benzene to give the acid (22) (250 mg), m.p. 140-141 "C. The mother-liquor was taken up in methanol-ether (1 : 4;10,ml) and treated with a solution of ethereal diazomethane (prepared from 1 g of nitrosomethylurea) at 5 "C for 1 h. Evaporation of the solvent and chromatography of the crude concentrate over a column of silica gel eluting with benzene, afforded the diketo- ester (23)(1 20 mg) and 3,4-dihydro-6-methoxy-2-(2-methoxy-carbonylethyl)naphthalen-l(2H)-one (140 mg), m.p.88-89 "C; vmX. 1720 (C02Me) and 1665 cm-' (CO); T 2.03 (1 H, d, J 8.0 Hz, ArH, m to OCH3), 3.07-3.3'8 (2 H, m, ArH, o to OCH,), 6.15(3 H, s, OCH3), 6.32 (3 H, s, COz-CH,), and 6.80-8.50 (9 H, m, lf-, 2'-,2-, 3-, and 4-H) (Found: C, 68.3; H, 6.9.C15H1804 requires C, 68.70;H, 6.87). 2-(6-Carboxy-6-methyl-3-oxohexyl)-3,4-dil~ydro-6-methoxy-naphthalen-l(2H)-one (24) and 2-(6-Carboxy-4-methyl-3-oxohexyl)-3,4-dihydro-6-methoxynaphthalen-1(2H)-one (26).-The foregoing mixture (3 g) was deformylated and saponified as described earlier for the ester (16)to give the isomeric diketo-acids (24)and (26)as a mixture (2.4g); v,, 1 712(CO, C02H), and 1 660cm-I (ArCO); r 0.53 (1 H, 2-(2,6-Diethoxycarbonyl-6-methylhexyl)-3,4-dihydro-6-methoxynaphthalen-l(2H)-one (20) and 2-(2,6-Diethoxy-carbonyl-4-methylhexyl)-3,4-dihydro-6-methoxynaphthalen-1-(2H)-one(21).-Finely cut sodium metal (0.75g) was taken up in dry dioxan (200ml) and absolute ethanol 15 ml) was added and the reaction mixture stirred at room temperature until the formation of sodium ethoxide was complete.A solution of the 216 P-keto-esters (1 1) and (12) (9 g) in dry dioxan (50 ml) was then added into it in one portion, followed by the methiodide (3) (12 g), and the reaction mixture was refluxed for 8 h. Most of the solvent was then removed under reduced pressure and the resi- due treated with cold aqueous AcOH (10; 150 ml).It was then extracted with ether (2 x 200 ml), the combined ethereal layer washed with water (3 x 100 ml), dried (Na2S04) and con- centrated. The residual oil was purified by passing it through a column of silica gel, eluting with benzene, to give the diketo- diesters (20) and (21) as a mixture (13 g); vmx. 1 732 (C02Et), 1 712 (CO), and 1 670 cm-’ (ArCO); z 2.05 (1 H, d, J 9.0 Hz, ArH, rn to OCH3), 3.10-3.45 (2 H, m, ArH, o to OCH,), 5.60-6.25 (4 H, m, 2 C02CH2CH3), 6.18 (3 H, s, OCH,), 6.9(r-8.50 (12 H, m, 1’-, 2’-, 4‘-, 6’-, 2-, 3-, and 4-H), and 8.60-9.30 (9 H, m, 2 C02CH2CH3 and side chain CH,). Hydrolysis and Decarboxylation of the Diesters (20) and (21).-The hydrolysis and pyrolytic decarboxylation of compounds (20) and (21) (1 g) was carried out as described earlier for the diester (19).Chromatography of the crude reaction product over a column of silica gel, eluting with ethyl acetate-benzene (1 : 5), furnished the isomeric diacids (24) and (26) (0.3 g) as a mixture. 2-(2-Carboxyethyl)-1-(3-carboxypropyl)-6-methoxy-3,4-dihydronaphthalene (28).-A solution of the acid (22) (500 mg) or the ester (23) (540 mg) in AcOH, HCI, and HzO (4 : 2 : 1, v/v; 16 ml) was heated at 120 “C for 2 h, poured over crushed ice (100 g) and extracted with ethyl acetate (3 x 50 ml). The combined organic layer was washed with water (3 x 30 ml), dried (Na2S04) and concentrated. The residue was crystallised from ethyl acetate-benzene to furnish the diacid (28) (164 mg), m.p. 159-162 “C; vmx.1700 cm-I (C0J-i); A,,,. (MeOH) 277 and 224 nm; T -0.20 (2, bh,2COzH),2.72(1 H,d,J9.0Hz,ArH,mtoOCH3),3.10-3.0 (2 H, m, ArH, o to OCH,), 6.19 (s, 3 H, ArOCH,), and 7.10-8.50 (14 H, m, l”, 3’-, lf’-,2”-, 3-, and 4-H) (Found: C, 67.7; H, 7.1. Cl8Hz2O5 requires C, 67.91; H, 6.97). 3,4-Dihydro-6-methoxy-2-(2-methoxycarbonylethyl)-1-(3-methoxycarbonylpropy1)naphthalene (29).-A solution of the diacid (28) (80 mg) in methanol-ether (1 : 4; 10 ml) was treated with a solution of ethereal diazomethane prepared from 750 mg of nitrosomethylurea at 5 “C for 1 h. After the solvent had been evaporated off, the residual oil was subjected to chromatography over a column of silica gel, eluting with benzene, to give the diester (29) (80 mg) as an oil; vmax.1 727 cm-I (COzMe); A,,,.(MeOH) 277 and 224 nm; m/z 346 (94, M+), 344 (32), 315 (ll), 273 (19), 259 (lo), 245 (50), 227 (lo), 214 (17), 213 (97), 199 (34), 197 (16), 185 (40),173 (lo), 172 (22), 171 (loo), 153 (ll), 141 (ll), 128 (13), and 115 (1 1); T 2.72 (1 H, d, J 9.0 Hz, ArH, m to OCH3), 3.10-3.30 (2 H, m, ArH, o to OCH,), 6.18 (3 H, s, ArOCH,), 6.30 (6 H, s, 2 CO,CH,), and 7.10-8.50 (14 H, m, 1’-, 2’-, 3’-, l”, 2”-, 3-, and 4-H). 3,4-Dihydro-6-methoxy-1-(3-methoxycarbonylbutyl)-2-(2-methoxycarbonylethy1)naphthalene (3l).-A mixture of the isomeric acids (24) and (26) (500 mg) or the esters (25) and (27) (530 mg) was subjected to the reaction conditions described earlier for compound (22) to obtain an oil, which was esterified by similar treatment with diazomethane.The crude product, on chromatography over a column of silica gel eluting with benzene with an increasing proportion of ethyl acetate, furnished the diester (31) (90 mg), as an oil; v,,, 1735 cm-’ (COzMe); m/z 360 (loo, M+), 358 (30), 330 (24), 329 (ll), 287 (13), 259 (6), 245 (50), 227 (14), 214 (16), 213 (93), 199 (32), 197 (lo), 186 (lo), 185 (45), 172 (15), J. CHEM. SOC. PERKIN TRANS. I 1983 171 (97),153 (8), 141 (8), 128 (9) and 115 (12); T 2.83 (1 H, d, J 9.0 Hz, ArH, m to OCH,), 3.20-3.40 (2 H, m, ArH, o to OCH,), 6.25 (3 H, s, ArOCH,), 6.33 (3 H, s, C02CH3), 6.37 (3 H, s, C02CH3), 7.20-8.50 (13 H, m, 1’-, 3’-, 1”-, 2”-, 3-, and 4-H), and 8.82 (3 H, d, J 7.0 Hz, CH,), and the diketo- ester (27) (210 mg); vmx.1735 (CO2Me), 1710 (CO), and 1 673 cm-I (ArCO); m/z 346 (M+);T 2.03 (1 H, d, J 9.0 Hz, ArH, rn to OCH3), 3.06-3.40 (2 H, m, ArH, o to OCH3), 6.17 (3 H, s, ArOCH,), 6.34 (3 H, s, COzCH3), 6.85-8.45 (14 H, m, 1’-, 2’-, 4’-, 6’-, 2-, 3-, and 4-H), and 8.89 (3 H, d, J 7.0 Hz, COCHCH,). Reaction of the Ester (23) with Methanolic Hydrochloric Acid.-A solution of the diketo-ester (23) (475 mg) in meth- anolic HC1 (15, 20 ml) was kept at room temperature for 4 h, after which time t.1.c. indicated complete disappearance of the starting material. It was then concentrated under reduced pressure and the residue was taken up in ether (100 ml); the ethereal layer was washed with water (3 x 50 ml), dried (NaZSO4), and concentrated.The crude concentrate, when subjected to chromatography on a column of silica gel, eluting with benzene in increasing proportions of ethyl ace- tate, furnished the enone (35) (150 mg) as an oil; vnlax.1 725 (C02Me) and 1 665 cm-I (conjugated ketone); A,,,. (MeOH) 314, 242, and 218sh nm; m/z 314 (M+);T(CCI,) 2.63 (1 H, d, J9.0 Hz, ArH, m to OCH3), 3.25-3.55 (2 H, m, ArH, o to OCH,), 6.30 (3 H, s, OCH3), 6.34 (3 H, s, CO2CH3), and 7.10-8.40 (13 H, m, 1’-, 2’-, 1-, 2-, 9-, lo-, and 1Oa-H), and its isomer (33) (170 mg) as an oil; v,,,,. 1 725 (COZMe) and 1705 cm-’ (CO); h,,,,, (MeOH) 276 and 222 nm; m/z 314 (M+); ~(Ccl,) 2.99 (1 H, d, J 9.0 Hz, ArH, m to OCH,), 3.30-3.60 (2 H, m, ArH, o to OCH,), 6.32 (3 H, s, OCH,), 6.38 (3 H, s, CO2CH3), and 6.60-8.33 (13 H, m, 1’-, 2‘-, 1-, 2-, 4-, 9-, and 10-H).Rearrangement Reaction of the Isomeric Esters (33) and (35).-A solution of the esters (33) and (35) (230 mg) in AcOH, HzO, and HCI (4 : 2 : 1, v/v; 10 ml) was refluxed for 2 h. It was then poured over crushed ice (50 g) and extracted with ethyl acetate (2 x 50 ml). The ethyl acetate extract was washed with water (3 x 25 ml), dried (Na2SO4) and con- centrated. The crude oil, on crystallisation from ethyl acetate- benzene afforded the diacid (28) (70 mg), m.p. 159-162 “C. 2-(23-Diethoxycarbonyl-3-oxopentyl)-3,4-dihydro-6-methoxynaphthalen-l(2H)-one (37).-Condensation of the methiodide (3) (4.5 g) with diethyl p-oxoadipate lL (3 g) in the presence of sodium ethoxide (prepared from 340 mg of sodium metal) according to the procedure described for the diester (19), furnished the diketo-diester (37) (2.5 g) as an oil; vmax.1 735 (COzEt), 1 710 (CO), and 1 675 cm-I (ArCO); m/z 404 (M+);‘I: 2.05 (1 H, d, J 9.0 Hz, ArH, m to OCH,), 3.10-3.45 (2 H, m, ArH, o to OCH,), 5.84 and 5.90 (4 H, 2 q, J7.0 Hz, 2C02CHZCH,), 6.35 (3 H, S, OCH3), 6.90-8.22 (12 H, m, 1’-, 2’-, 4‘-, 5‘-, 2-, 3-, and 4-H), and 8.73 (6 H, t, J 7.0 Hz, 2 COzCHzCH3).Attempted Rearrangement Reaction of the Diester (37).-A solution of compound (37) (450 mg) in AcOH, HCl, and H20 (4 : 2 : 1, v/v; 20 ml) was refluxed for 3 h. It was then poured over crushed ice (100 g) and extracted with ethyl acetate (2 x 100 ml). The organic layer was washed with water (3 x 50 ml), dried (Na2SO4) and concentrated to give a viscous brown oil (360 mg) which was taken up in methanol- ether (1 : 1; 20 ml), and then treated with ethereal diazo- methane (5; 10 ml) at 0 “C for 3 h.The solvent was eva- porated off and the residue subjected to chromatography over a column of silica gel, eluting with benzene, to give the J. CHEM. SOC. PERKIN TRANS. I 1983 enone (39) (104 mg); vmx 1728 (C02Me) and 1 655 cm-' (conjugated ketone); h,,,. (MeOH) 314, 242 and 218sh nm; T 2.67 (1 H, d, J 9.0 Hz, ArH, m to OCH3), 3.15-3.45 (2 H, m, ArH, o to OCH3), 6.53 (2 H, br s, 1'-H), and 7.05- 8.75 (9 H, m, 1-, 2-, 9-, lo-, and 10a-H), and its isomer (41) (84 mg); vmax. 1732 (C02Me) and 1712 cm-' (CO); hmX. (MeOH) 276 and 222 nm; r 2.65-3.45 (3 H, m, ArH), 6.22 (3 H, s, OCH,), 6.38 (3 H, s, C02CH3), and 6.85-7.95 (11 H, m, 1'-, 1-, 2-, 4-, 9-, and 10-H).Alkaline Hydrolysis of the Methyl Esters (39) and (41).- Compounds (39) and (41) were hydrolysed individually by refluxing them with ethanolic KOH (20). Most of the solvent was removed under reduced pressure and the residue was taken up in water, acidified with cold ~M-HC~, and then extracted with ethyl acetate. The organic layer was washed with water, dried (Na2S04) and concentrated. The residue, on crystallization from benzene, afforded the acid (38), m.p. 149-150 "C; v,,,. 1 700 (C02H) and 1 655 cm-' (conjugated ketone); kmx. (MeOH) 315, 242, and 218sh nm; r 0.33 (1 H, bh, D20exchangeable, C02H), 2.57 (1 H, d, J 9.0 Hz, ArH, m to OCH3), 3.05-3.40 (2 H, m,ArH, o to OCH3), 6.20 (3 H, s, OCH,), 6.50 (2 H, br d, 1'-H), and 7.05-8.50 (9 H, m, 1-, 2-, 9-, lo-, and 10a-H) (Found: C, 71.2; H, 6.35.CI7Hl8O4 requires C, 71.31; H, 6.34), and its isomer (a), m.p. 128-130 "C; vmx. 1710 cm-' (CO, COOH); kmx. (MeOH) 272 and 222 nm; r 2.65-3.45 (3 H, m, ArH), 5.10 (1 H, bh, D20 exchangeable, C02H), 6.22 (3 H, s, OCH,), and 6.50-8.10 (11 H, m, 1'-, 1-, 2-, 4-, 9-, and 10-H) (Found: C, 71.65; H, 6.2. C17H19O4 requires C, 71.31; H, 6.34). 2-( 2,6- Diethoxycarbonyl-3-oxohexyl)-3,4-dihydronaphthalen-l(2H)-one (36).-Condensation of the methiodide (2) (10 g)with dimethyl P-oxopimelate * (9 g) in the presence of sodium methoxide (prepared from 690 mg of sodium metal) according to the procedure described earlier for compound (19) gave the diketo-diester (36) (11 g) as an oil; vmx.1732 (C02Me), 1 710 (CO), and 1 678 cm-' (ArCO); mfz 360 (M+);r 1.95-2.22 (1 H, m, 8-H), 2.50-3.10 (3 H, m, 5-, 6-, and 7-H), 6.00-6.50 (1 H, m, 2'-H), 6.32 (3 H, s, CO?), 6.42 and 6.44 (3 H, 2 s, C02CH3), and 6.80-8.50 (13 H, m, 1'-, 4'-, 6'-, 2-, 3-, and 4-H). Attempted Rearrangement of the Diester (36).-A solution of compound (36) (3 g) in AcOH, HCl, and HzO (4 : 2 : 1, v/v; 50 ml) was refluxed for 3 h. Work-up gave a viscous acidic material (2.6 g) which, upon cry stallisation from benzene-hexane, furnished the enone-acid (32) (1.05 g), m.p. 119.5-121 "C; vmx. 1700 cm-' (CO, COOH); h,, (MeOH) 265,226, and 222 nm; r 0.33 (1 H, bh, D20exchange-able, C02H), 2.00-3.00 (4 H, m, ArH), and 7.00-8.30 (13 H, m, 1'-, 2'-, 1-, 2-, 4-, 9-, and 10-H) (Found: C, 75.9; H, 6.7.C17HlaOJ requires C, 75.53; H, 6.71). A solution of the mother-liquor (800 mg) in methanol- ether (1 : 1; 10 ml) was treated with ethereal diazomethane (5; 5 ml) at 0 "C for 2 h. Evaporation of the solvent and chromatography of the crude oil over a column of silica gel eluting with benzene furnished the enone-ester (34) (150 mg); vmax. 1735 (C02Me) and 1 660 cm-' (conjugated ketone); r 2.50-3.00 (4 H, m, ArH), 6.46 (3 H, s, C02CH3), 6.90- 8.50 (13 H, m, 1'-, 2'-, 1-, 2-, 9-, lo-, and 1Oa-H) and the methyl ester of the acid (32) (270 mg). Acknowledgement We are grateful to Dr. Nitya Anand for his keen interest in this study. References 1 E. Brown, J. Touet, and M. Ragault, Bull. SOC. Chim. Fr., 1972, 212. 2 E. Brown, M. Ragault, and J. Touet, Bull. SOC.Chim. Fr., 1971, 2195. 3 D. E. Floyd and S. E. Miller, J. Org. Chem., 1951, 16, 882. 4 J. Cason, J. Am. Chem. SOC.,1947,69, 1548. 5 S. Stallberg-Stenhagen,J. Am. Chem. SOC.,1947, 69, 2568. 6 J. E. H. Hancock and R. P. Linstead, J. Chem. SOC.,1953, 3490. 7 L. B. Barkley, W. S. Knowles, H. Raffelson, and Q. E. Thompson, J. Am. Chem. SOC.,1956,78,4111. 8 M. Guha and D. Nasipuri, Org. Synth., 1962, 42, 41. 9 R. F. Naylor, J. Chem. SOC.,1947, 1 106. 10 D. K. Banerjee, S. Chatterjee, C. N. Pillai, and M. V. Bhatt, J. Am. Chem. SOC.,1956,78, 3169. 11 D. Nasipuri and P. R. Mukherjee, J. Chem. SOC.,Perkin Trans. 2, 1975,464. Received 7th January 1982; Paper 21022