Regioselectivity in the reductive cleavage of pyrogallol derivatives: reductive electrophilic substitution of acetals of 2,3-dimethoxyphenol

摘要

J. CHEM. SOC. PERKIN TRANS. I 1995 26 1 Regioselectivity in the Reductive Cleavage of Pyrogallol Derivatives: Reductive Elect rophi I ic Substitution of Acetals of 2,3-Di met hoxyp henol Ugo Azzena,' Giovanni Melloni and Luisa Pisano Dipartimento di Chimica, Universita di Sassari, via Vienna 2, I-07 7 00 Sassari, Italy Acetals of 2,3-dimethoxyphenol were used as the starting materials for the transformation of 1.2.3-trioxygenated benzenes into various 1-oxygenated-2,3-dicarbon-substituted benzenes, via regio-selective reductive electrophilic substitution of the 2-methoxy group, followed by conversion into the corresponding triflates and a Pd-catalysed cross-coupling reaction. The regioselectivity of the reductive cleavage is ascribed to twisting of the leaving methoxy group out of the plane of the aromatic ring by the two ortho substituents.According to this methodology, a new synthesis of lunularic acid is presented. The reductive cleavage of carbon-oxygen bonds of aryl ethers is a topic of current interest, and several recent papers are devoted to the investigation of this reaction. We have recently reported that the reductive cleavage of 1,2,3-tnmethoxybenzene and its 5-substituted derivatives with alkali metals in tetrahydrofuran (THF) affords almost quantitative demethoxylation in the 2-position. The reaction proceeds uiu the intermediate formation of the corresponding 2,6-dimethoxyaryl carbanions, thus dis- closing a new and efficient approach to the synthesis of 2- and 2,5-substituted resorcinol dimethyl ethers.* In order to obtain more detailed information on the factors affecting the regioselectivity of this reaction, we have investigated the reductive cleavage of other derivatives of pyrogallol, and we now describe an extension of the above mentioned procedure allowing the transformation of derivatives of 1,2,3-trioxygenated benzene into l-oxygenated-2,3-dicarbon-substituted aromatics.To this end, we have investigated the reductive electrophilic substitution of acetals of 2,3-dimethoxy- phenol, compounds 1 and 2, planning to complete the reaction sequence through successive selective hydrolysis of the acetal group, transformation of the 2,3-disubstituted phenols thus obtained into the corresponding triflates, and a Pd-catalysed cross-coupling reaction of the last compound with nucleophilic reagents (Scheme I).A previous report concerning the regioselective reductive electrophilic substitution of 1,2-dimeth-oxy-3-(methoxymethoxy)benzene1 has already a~peared.~ OMe I I1MeObOP -Woe-Ill MeO,amp;OH bsol; 1 P=MOM 2 PI 2-THP bsol; 3 E=HorD,P=MOM 4 E=HorD,P=Z-THP 5 E=Me,P=MOM 6 E=Bu,P=MOM 7 E=BU,P=Z-THP 8 E= CONEtP, P = MOM 0 E= COpMe. P= MOM 10 E = COPh, P= MOM E 19 E=Me,R=Ph 20 E= CONEt2,R = Me 21 E = CO,Me, R = CfCPh 22 E 3:COiMe, R = C:CbOMe-p bsol; 11 E=Me 12 E=Bu 13 E=CONEtp14 E=COamp;k 15 E=COPh E 16 E=Me 17 E-CONEtP 18 E=C02Me Scheme 1 Reagents: i, K, THF; ii, EX; iii, HCI, MeOH; iv, (Tf),O,pyridine; v, PdL,, R,M.MOM = methoxyrnethyl, 2-THP = tetra-hydropyran-2-yl. As a complementary approach, we have investigated the reductive cleavage of l-methoxy-2,3-(methylenedioxy)benzene 25: indeed, reductive dealkoxylation at the 2-position of OR compound 25 should lead, after aqueous work-up, to the formation of 3-methoxyphenol26 (Scheme 2),5 whilst trapping with electrophiles of the (supposed) 2,6-dialkoxy-substituted carbanionic intermediate should afford 2-substituted-3-methoxyphenols. I M+ fo-M+ -Meooo 25 CHsO + -O226 Y Scheme 2 Reagents: i, 2 M; ii, water Results Two different acetalic groups, ie.,methoxymethyl (MOM) and 2-tetrahydropyranyl (THP), were chosen to protect the phen- olic function of 1,2-dimethoxyphenol during reduction with alkali metals in aprotic solvents.Accordingly, 1,2-dimethoxy-3- (methoxymethoxy)benzene 1 and 2,3-dimethoxyphenyl tetra- hydropyran-2-yl ether 2, were synthesized in good yields by known method^.^.' For comparison purposes, I-methoxy-3-(methoxymethoxy)benzene 3, I-methoxy-2-(methoxymeth-oxy)benzene 23, 3-methoxyphenyl tetrahydropyran-2-yl ether 4 and 2-methoxyphenyl tetrahydropyran-2-yl ether 24,were prepared analogously from the corresponding phenols. 1-Methoxy-2,3-(methylenedioxy)benzene25 was synthesized 262 J. CHEM. soc. PERKIN TRANS. I 1995 Table 1 Reductive cleavage of compounds 1 and 2' Time Yieldb D' Entry Compound Metal Solvent (t/h) Product () (I 1 1 K THF 7 3 90 ND 2 1 K THF 12 3 90 ND' 3 1 K THF 17 3 91 90 4 5 1 1 K Na THF THF 48 24 3 3 87 20 * 90 ND' 6 1 Li THF 24 3 53 J ND' 7 1 K isooctane 24 3 51d 90 8 9 1 2 K K Et,O THF 24 6 3 4 84 89 78 5 90 10 2 Na THF 24 4 86 ND' ~~~~ Reactions were run at room temperature in the presence of 3 mol equiv.of metal. * Isolated yield, unless otherwise indicated. Deuterium incorporation determined by 'H NMR spectroscopic monitoring of the percentage of deuterium incorporation at the 2-position (see Experimental section). Determined by 'H NMR spectroscopy; no other product, aside from starting material, was detected to any considerable extent. ND = Not determined. Formation of considerable amounts of phenolic compounds was observed.in 60 yield by the reaction of 3-methoxybenzene-1 ,2-diol with CH2Br, under basic phase-transfer reaction conditions.* Reductive Cleavage Reactions.-These reactions were carried out under Ar at room temperature in the presence of the freshly cut metal. Selected results are reported in Table 1. The results of D,O-quenching experiments, carried out to check the formation of carbanionic intermediates, are also reported in Table 1. The regioselective demethoxylation in the 2-position of compound 1 can be conveniently performed by the action of potassium metal (3 mol equiv.) in anhydrous THF at room temperature for 12 h. Quenching of the reaction mixture with water or with anhydrous EtOH (caution!) afforded l-methoxy- 3-(methoxymethoxy)benzene 3 in good yield (Table 1, entry 2); D,O-quenching showed almost quantitative formation of the corresponding arylpotassium derivative.This carbanion appears to be stable under the reaction conditions for a long time (Table 1, entries 3 and 4). Reductive cleavage with sodium metal was by far less effective, and led to recovery of the starting material to a high extent (Table 1, entry 5), whilst reductive cleavage with lithium metal afforded a high percentage of unidentified phenolic products (Table 1, entry 6). Besides THF, 2,2,4-trimethylpentane (isooctane) and diethyl ether were tested as solvents for the reductive cleavage of compound 1 with potassium metal. Demethoxylation at the 2-position was observed in both cases: however, only moderate conversion took place in isooctane after 24 h reaction time (Table 1, entry 7), whilst a relatively low amount of the intermediate carbanion was evidenced in Et20 (Table 1, entry 8).No other products of dealkoxylation, such as t-methoxy-2- (methoxymethoxy)benzene 23 or 1,2-dimethoxybenzene, were detected in the reaction mixtures, by either GLC or 'H NMR (300 MHz) spectroscopy (estimated error 5).Reductive cleavage of compound 2 with potassium metal in THF afforded a similar result: acetal 4, the product of regioselective demethoxylation at the 2-position, was obtained in good yield after 6 h at room temperature. Again, the reaction proceeded through the almost quantitative intermediate form- ation of the 2,6-disubstituted aryl carbanion (Table 1, entry 9). When compound 2 was treated with sodium metal in THF, compound 4 was formed in only 8 yield in 24 h (Table 1, entry 10).At variance with these results, reduction of the methylene- dioxy derivative 25 with potassium metal in THF at room temperature for 24 h afforded a relatively complex reaction mixture eqn. (l): starting material was recovered to a high extent (32), together with a mixture of phenolic products containing the desired 3-methoxyphenol 26, in low yield ( 20, as estimated by 'H NMR spectroscopy). By treatment with sodium metal, the reductive cleavage occurred practically not at all, and compound 25 was recovered unchanged after 24 h. These results showed the uselessness of this synthetic approach; accordingly, the reductive cleavage of acetal25 was not further investigated.* ?+H2""-6" 25 ?H Reductive Electrophilic Substitution.-The reductive electro- philic substitution reactions (Scheme 1) were run in THF using potassium metal as the reducing agent.Reductions of compound 1 were run at room temperature for 12-18 h, while compound 2 was similarly reduced within 6 h. The results are reported in Table 2. Inspection of Table 2 shows that alkylation with primary alkyl halides was achieved under mild reaction conditions: an excess (3mol equiv.) of methyl iodide was added at 0 "C to the reaction mixture obtained by the action of potassium metal on compound 1; after stirring of the mixture for 1 h, standard work-up afforded 1-methoxy-3-methoxymethoxy-2-methylben-zene 5 in satisfactory yield, as well as a small amount of the product of reductive demethoxylation (Table 2, entry 1).A similar result was obtained by employing butyl iodide as an electrophile, starting from either substrate 1 or 2: the 2-butyl- substituted aromatics 6 and 7 were obtained in 57 and 60 yield, respectively (Table 2, entries 2 and 3).1 In contrast, quenching of the reaction mixture obtained by reductive cleavage of compound 1with isopropyl iodide did not * No products of bimolecular recombination of the liberated form- aldehyde with aromatic anions (or radical anions) were detected. ?Quenching of the mixture obtained by the reductive cleavage of compound 1 with butyl bromide afforded compound 6 in 55 yield.J. CHEM. SOC. PERKIN TRANS. 1 1995 Table 2 Reductive electrophilic substitution of compounds 1 and 2 Temp. Time Entry Compound Electrophile (T,C) (t/h) Product, E Yield 1 1 Me1 0 1 5, Me 75 2 1 BuI 0 24 6, Bu 57 3 2 BuI 0 2 7, Bu 60 4 1 Pr'I 0 24 3, H 88 5 1 CICONEtz -40 2.5 8, CONEt, 50' 6 1 CIC0,Me -40 2.5 9,C02Me 66 7 1 ClCOPh -40 1 10, COPh 51' Isolated yield, unless otherwise indicated. * No other product, aside from 3 or 4, was detected to any considerable extent. Yield determined on the corresponding phenol, after acidic hydrolysis of the acetal moiety. Table 3 Cross-coupling reactions Compound Catalyst (molx) R"M (mol equiv.) Solvent Temp. (T/OC) Time (0) Product Field ()I 16 17 18 18 Pd(PPh3)4 (5) PdCI,(PPh,), (20) PdCI,(PPhJ, (5) PdC12(PPh3)2(5) PhB(OH)2' (2) SnMe,d (3) PhC=CHe (1.5) ArCKH'sf (1.5) DME DMF DMF DMF 85 120 90 90 5 8 16 14 19 (80) 20 (49) 21 (90) 22 (85) = = a DME I ,3-dimethoxyethane, DMF dimethylformamide.Isolated yields. In the presence of both 6.5 mol equiv. of 2 rnol dm-' Na,CO, and 3 rnol equiv. of LiCI. In two portions, according to ref. 3a,and in the presence of both 8 mol. equiv. of LiCl and 0.6 rnol equiv. of PPh,. In the presence of 4.5rnol equiv. of Et3N. Ar = 4-(MeO)C,H4. afford the desired alkyl-substituted derivative, but only the catalysed cross-coupling reaction of an electron-poor and product of reductive demethoxylation, compound 3 (Table 2, hindered triflate such as 17 with an organostannane usually entry 4).Similar results were previously observed during requires a small amount of catalyst and no addition of the attempted reductive electrophilic substitution of 1,2,3-trimeth-phosphinic ligand.3e On the other hand, we obtained a oxybenzene and its 5-substituted derivatives with secondary satisfactory yield of the desired amide only under reaction alkyl halides.* conditions which are typical of electron-rich triflates.3n The carbanionic intermediate generated by the reductive cleavage of compound 1 with potassium metal was successfully Synthetic Applications.-As an application of the above trapped also with several carboxyl derivatives; N,N-diethyl-2-reported methodology to the synthesis of natural products and methoxy-6-(methoxymethoxy)benzamide8, methyl 2-methoxy-analogues, acetylenes 21 and 22 were hydrogenated at room 6-(methoxymethoxy)benzoate 9 and 2-methoxy-6-(methoxy-temperature and ambient pressure to afford methyl 2-methoxy-methoxy)benzophenone 10 were obtained in satisfactory yields 6-(2-phenylethyl)benzoate27 and methyl 2-methoxy-6-2-(4'-upon quenching with an excess (3 mol equiv.) of N,N-methoxypheny1)ethylbenzoate 28, respectively (Scheme 3).diethylcarbamoyl chloride, methyl chloromethanoate and Basic hydrolysis of the ester 28 afforded 2-methoxy-6-2-(4'-benzoyl chloride, respectively (Table 2, entries 5-7). methoxyphenyl)ethylbenzoic acid 29, the dimethyl ether of lunularic acid, a growth inhibitor found in Lunuluriu cruciuta.lo Synthesisof TriJates.-Mild acidic hydrolysis of compounds Conversion of compound 28 into lunularic acid has already 510 (0.6 mol dm-3 HCl in methanol; room temp.; 1 h) allowed been described.lob the removal of the acetal protecting group; the corresponding phenols 11-15 were obtained in almost quantitative yields. Phenols 1S15 were also prepared in high yield by acidic hydrolysis of compounds 8-10, respectively, with 3 mol dm-3 HC1 in aqueous propan-2-01 overnight at room temperature.c Under the last reaction conditions, acetals 5 and 6 afforded 111 Ar Arcomplex reaction mixtures. 5: jAr Ar According to a known procedure," reaction of phenols 11,13 27 Ar = Ph, Wo yield 87 yield and 14 with trifluoromethanesulfonic anhydride in pyridine 28 k I C,H,OMep, afforded the triflates 1618 in 7040 yield.21 amp;=Ph 29 Ar = CeH40Mep,85 yield22 Ar CeH,OMep Cross-coupling Reactions.-To test the flexibility of the Scheme 3 Reagents and conditions: i, H,, PdlC, 1 atm, room temp.;proposed methodology, triflates 1618 were allowed to react ii, KOH, aq. EtOH, reflux with different coupling reagents in the presence of a Pd catalyst (Scheme I). According to this procedure compounds 19-22, were obtained. Reaction conditions and yields are reported in Discussion Table 3. The synthetic procedure described herein shows the feasibility Good yields were obtained in the cross-coupling reactions of transforming derivatives of 1,2,3-trioxygenated benzene into involving phenylboronic acid or acetylenes as the coupling l-oxygenated-2,3-dicarbon-substitutedaromatics, and repre-reagents, while a somewhat lower yield was obtained in the sents a considerable extension of our previous results with 1,2,3-synthesis of the amide 20, an intermediate in the synthesis of trimethoxybenzene and its 5-substituted homologues.2 several isoco~marins.~It is interesting to observe that the The main features of this highly regioselective reductive conditions needed in this last case are unusual.Indeed, the Pd-electrophilic substitution are the following: (i) easy access to the starting materials; (ii) high regioselectivity due to ipso-substitution of the 2-methoxy group; (iii) the reaction condi- tions allow the introduction of several functionalities which are, in principle, not stable to reduction with alkali metals.Our reaction represents a useful alternative to the known metal- lation of 1-methoxy-3-(methoxymethoxy)benzene 3 and of 3-methoxyphenyl tetrahydropyran-2-yl ether 4 with alkyl- lithium derivatives, followed by reaction with electrophiles. Indeed, the high regioselectivity observed in the synthetic procedure described herein competes well with the results obtained in these metallation reactions.* As already observed, the key step in the proposed reaction sequence is the regioselective reductive cleavage of suitable acetals of 2,3-dimethoxybenzene; this finding deserves a mech- anistic comment. Indeed, it is worth noting that this procedure allows the regioselective removal of the 2-methoxy group in the presence of either a methoxymethoxy or a tetrahydropyran-2-yl group. This is at variance with previous reports showing that the reductive cleavage of aryhxygen bonds is more easily obtained with methoxymethyl 'Jor tetrahydropyran-2-yl aryl ethers than with the methyl ethers, and supports the hypothesis of Maercker concerning the relationship between the conformation of the ether linkage and the regioselectivity of the C-0 bond scission under electron-transfer conditions.As in the case of 1,2,3-trimethoxybenzene,the high regioselectivity observed in the reductive cleavage of compounds 1 and 2 can be reasonably attributed, besides the relative stability of the resulting aromatic car bani on^,^^'^ to twisting of the leaving methoxy group out of the plane of the aromatic ring, this being caused by the two ortho substituents. Such an hypothesis is further supported by the results obtained in the reductive cleavage of the methylenedioxy derivative 25; indeed, when the alkoxy substituent in the 2- position is forced into a conformation almost coplanar with the aromatic ring, reductive cleavage of the 1,2,3-trioxybenzene derivative is no longer regioselective.Experimental M.p.s were measured on a Biichi 510 melting point apparatus and are uncorrected. B.p.s refer to the temperature of the air- bath (Kugelrohr distillation). Solvents were distilled from Na/K alloy under N, immediately prior to use. All products and reagents were of the highest commercial quality from freshly opened containers and were used without further purification.Deuterium oxide was 99.8 isotopic purity. Silica gel 60 (particle sizes 40-63 p) supplied by ICN was employed for flash chromatography. 'H NMR (300 MHz) and 13C NMR (75 MHz) spectra were measured on a Varian VX 300 for samples in CDCI3 solution with tetramethylsilane as internal standard. J-Values are in Hz. Deuterium incorporation was calculated as reported in ref. 2 (estimated error -= 5). IR spectra were recorded on a Perkin-Elmer 983 spectrometer for samples in CCI, solution. Elemental analyses were performed by the Microanalytical Laboratory of the Dipartimento di Chimica, Universita di Sassari. Preparation of Acetals 14, 225.-Compounds 1, 3 and 23 were prepared according to ref. 6; compounds 2,4 and 24 were prepared as reported in ref.7. Compound 25 was synthesized as described in ref. 8. All products were purified by distillation in vacuo and stored under Ar in a refrigerator. The products were characterised as follows. * Metallation of 3-methoxyphenol 26, with Bu'Li-Bu'OLi (2:1) (LICLIOR) is a non-regioselective reaction; see ref. 12, metallation of compound 26 with BuLi is also non-regioselective; see ref. 11. J. CHEM. SOC. PERKIN TRANS. I 1995 1,2-Dimethoxy-3-(methoxyrnethoxy)benzene1. Liquid, b.p. 95 "Cjl mmHg; SH 3.51 (3 H, s, MeOCH,), 3.87 (6 H, s, 2 x MeO), 5.22 (2 H, s, CH,), 6.63 (1 H, dd, J 8.5 and 1.5, ArH), 6.79 (1 H, dd, J 8.5 and 1.5, ArH) and 6.98 (1 H, t, J 8.5, ArH).2,3-Dirnethoxyphenyl tetrahydropyran-2-yl ether 2. Liquid, b.p. 135 "C/l mmHg; BH 1.55-2.06 (6 H, m, 3 x CH,), 3.56 3.66 (1 H, m, HCHO), 3.85 (3 H, s, MeO), 3.88 (3 H, s, MeO), 3.92-4.02 (1 H, m, HCHO), 5.43 (1 H, t, J 3.0, CHO,), 6.61 (1 H, d,J8.0, ArH), 6.80(1 H, d,JX.O, ArH)and6.96(1 H, d, J 8.0, ArH). 1-Methoxy-3-(rnethoxymethoxy)benzene 3. Liquid, b.p. 80 OCjl mmHg (lit.,6 123-123.5 "Cj17 mmHg); BH 3.48 (3 H, s, MeOCH,), 3.79 (3 H, s, MeO), 5.17 (2 H, s, CH2), 6.55 (1 H, ddd,J8.0,2.5and 1.O,ArH),6.61 (1 H, t,J2.5,ArH),6.64(1 H, ddd,J8.0,2.5andl.O,ArH)and7.19(lH,t,J8.0,ArH). 3-Methoxyphenyl tetrahydropyran-2-yl ether 4. Liquid, b.p. 115 "Cjl mmHg (lit.," 108-110 "CjO.02 mmHg); 6, 1.56-2.08 (6 H, m, 3 x CH,), 3.55-3.65 (1 H, m, HCHO), 3.79 (3 H, s, MeO), 3.85-3.95 (1 H, m, HCHO), 5.41 (1 H, t, J3.5, HCO,), 6.55(1H,dd,J8.Oandl.O,ArH),6.60-6.70(2H,m,2x ArH) and 7.18 (1 H, d, J 8.0, ArH).l-Methoxy-2-(methoxyrnethoxy)benzene 23. Liquid, b.p. 75 OC/l mmHg (lit.," 110-110.5 "Cj8 mmHg); 6, 3.51 (3 H, s, MeOCH,), 3.87(3 H, s, MeO), 5.22(2 H, s,CH,),6.84-6.94(2 H, m, 2 x ArH), 6.967.02 (1 H, m, ArH) and 7.12-7.18 (1 H, m, ArH). 2-Methoxyphenyl tetrahydropyran-2-yl ether 24. Liquid, b.p. 12OoC/1 mmHg;SH 1.562.14(6H, m, 3 x CHJ, 3.55-3.65(1 H, m, HCHO), 3.85 (3 H, s, MeO), 3.954.06 (1 H, m, HCHO), 5.39 (1 H, t, J3.5, HCO,), 6.84-7.02 (3 H, m, 3 x ArH) and 7.13 (1 H, dd, J 8.0 and 1.5, ArH). l-Methoxy-2,3-(methylenedioxy)benzene25.Liquid which solidified upon storage, b.p. 60 OCjl mmHg (1it.,l6 52 "CjO.2 mmHg);SH3.90(3H,s,MeO),5.95(2H,s,CH2),6.53(2H,d,J 8.5, 2 x ArH) and 6.78 (1 H, t, J8.5, ArH). The above compounds were further characterised by acidic hydrolysis (0.6 mol dm-3 HCI in MeOH; room temp; 1 h) to the corresponding known phenols. General Procedure for the Reductive Cleavage of Acetals 1, 2 and 25.-Reductive cleavage reactions were performed as reported in refs. 2 and 17, starting with 2.5-5 mmol of the appropriate substrate and 3 mol equiv. of the freshly cut metal. The mixture was stirred at room temperature for the time indicated (Table l), then was chilled to 0 "C, quenched by slow dropwise addition of water (caution!) and extracted with diethyl ether.The organic phase was washed successively with saturated aq. NaHC03 and water, dried (K,C03) and evaporated to afford the crude liquid products, which were recognised by comparison with known samples. In the case of compound 25, the aqueous phase was acidified with conc. HCl, stirred at room temperature for 1 h, and extracted with Et,O (4 x 10 cm3). The organic phase was dried (K,C03), and evaporated to afford a crude mixture which was characterised by GLC and 'H NMR spectroscopy. D,O quenching was performed as described in ref. 2. General Procedure for the Reductive Electrophilic Substitution of Acetals 1 and 2.-Reduction of the appropriate acetal was performed as described above. The reaction mixture was chilled to the reported temperature, the appropriate amount of the electrophile dissolved in anhydrous THF (5 cm3) was added dropwise, and the resulting mixture was stirred for several hours (Table 2).The reaction was quenched by slow dropwise addition of water (caution!) and worked up as reported above to afford the crude liquid products, which were characterised as follows. J. CHEM. SOC. PERKIN TRANS. I 1995 1-Methoxy-3-methoxymethoxy-2-methylbenzene5. Oil, puri- fied by flash chromatography CH,CI,-hexane (1 : l); dH2.13 (3 H, s, MeAr), 3.48 (3 H, s, MeOCH2), 3.82 (3 H, s, MeO), 5.19 upon storage, m.p. 134136OC; purified by flash chro-matography ethyl acetate-hexane (2:8); BH 3.51 (3 H, s, Me), 6.42(1H,dd,J8.5andl.O,ArH),6.65(1H,dd,J8.5andl.O, ArH), 7.38 (1 H, t, J 8.5, ArH), 7.41 (2 H, td, J 7.0 and 1.5, (2H,s,CH2),6.57(1H,d,J8.5,ArH),6.72(1H,d,J8.5,ArH)2 x ArH),7.5l(lH,tt,J7.5andlS,ArH),7.62(2H,dt,J7.0and 7.09 (1 H, t, J 8.5, ArH).2-Butyl-1-rnerhoxy-3-(methoxymethoxy)benzene6. Oil, puri- fied by flash chromatography CH,CI,-hexane (1 : l); SH0.92 (3 H, t, J 7.0, MeCH,), 1.28-1.54 (4 H, m, MeCH,CH,), 2.66 (2 H, t, J 7.0, CH2Ar), 3.48 (3 H, s, MeOCH,), 3.81 (3 H, s, MeO), 5.17 (2 H, s, CH,O), 6.56 (1 H, d, 58.0, ArH), 6.71 (1 H, d, J8.0, ArH) and 7.08 (1 H, t, J8.0, ArH). 2-Butyl-3-methoxyphenyl tetrahydropyran-2-yl ether 7. Oil, purified by flash chromatography ethyl acetate-hexane (0.5:9.5);6, 0.93 (3 H, t, 57.0, MeCH,), 1.24-2.16 (10 H, m, 5 x CH,), 2.60-2.68 (2 H, m, CH,Ar), 3.47-3.62 (1 H, m, HCHO), 3.80(3 H,s,MeO), 3.82-3.88(1 H,m, HCHO), 5.42(1 H, t, J3.5, HCO,), 6.54(1 H, d,J8.5,ArH),6.76(1 H,d,J8.5, ArH) and 7.07 (1 H, t, J 8.5, ArH).Methyl 2-methoxy-6-(methoxymethoxy)benzoate9. Oil, puri- fied by flash chromatography ethyl acetate-hexane (7 :3); SH 3.46 (3 H, s, MeOCH,), 3.82 (3 H, s, MeOAr), 3.92 (3 H, s, MeOCO), 5.17 (2 H, s,CH,), 6.60 (1 H, d, J8.5, ArH), 6.76 (1 H, d,J8.5,ArH)and7.27(1 H,t,J8.5,ArH). Compounds 5-7 and 9 were further characterised by acidic hydrolysis to the corresponding phenols (see below). Crude N,N-diethyl-2-methoxy-6-(methoxymethoxy)benzamide8 and 2-methoxy-6-(methoxymethoxy)benzophenone 10 were not characterised, but were directly hydrolysed to the corres-ponding phenols.General Procedure for the Acidic Hydrolysis of Compounds 5-10.-The appropriate acetal(2-3 mmol) was added under Ar to a stirred 0.6 mol dm-3 solution of HCI in MeOH obtained by adding AcCl (1 cm3) to MeOH (20 cm3) chilled to 0 OC. The mixture was stirred at room temperature for 1 h, diluted with water (20 cm3), and the MeOH was evaporated off under reduced pressure. The resulting mixture was extracted with Et,O (4 x 20 cm3). The organic phase was dried (CaCI,) and evaporated to afford the crude product which was characterised as follows. 3-Methoxy-2-methylphenol11. Oil which solidified upon storage, m.p. 33-34 "C (lit.," 33-36 "C); purified by flash chromatography ethyl acetate-hexane (3 :7); 6, 2.12 (3 H, s, MeAr), 3.80 (3 H, s, MeO), 5.32 (1 H, br s, OH), 6.44 (2 H, t, J 8.5, 2 x ArH) and 7.00 (1 H, t, J 8.5, ArH); vjcm-' 3610 and 3462.2-Butyl-3-merhoxyphenol 12. Oil, b.p. 175 OCj20 mmHg; purified by flash chromatography ethyl acetate-hexane-acetic acid (10: 10 : I); 6, 0.92 (3 H, t, J 8.0, MeCH,), 1.25-1.48 (4 H, and 1,5,2 x ArH) and 10.62 (1 H, br s, OH); vlcm-' 3384 and 1625 (Found: C, 74.0; H, 5.5. C14H1203 requires C, 73.67; H, 5.31). Synthesis of TriJ7uoromethanesulfonates1618.-These com-pounds were synthesized according to a general procedure described in ref. 3c. Crude products were purified by flash chromatography and characterised as follows. 3-Methoxy-2-methylphenyl trijhoromethanesulfonate 16. Pale yellow oil, purified by flash chromatography ethyl acet- ate-hexane (7 :3); SH 2.22 (3 H, s, MeAr), 3.85 (3 H, s, MeO), 6.85 (2 H, t, J8.0,2 x ArH) and 7.21 (1 H, t, J8.0, ArH);Sc 9.5, 55.9,109.6,113.2(q,Jl), 118,6(q,J318), 120.2,127.0, 148.8and 159.0 (Found: C, 40.4; H, 3.5.C,H,F,O,S requires C, 40.00; H, 3.36). 2-Diethylcarbamoyl-3-methoxyphenyl triJ7uoromethanesul-fonate 17. Pale yellow oil, which solidified upon storage, m.p. 56 "C; purified by flash chromatography ethyl acetate-hexane (6:4); SH 1.09 (3 H, t, J 7.0, MeCH,), 1.25 (3 H, t, J 7.0, MeCH,), 3.12-3.21 (2 H, m, MeCH,), 3.28-3.42 (1 H, m, HCHMe), 3.76-3.90(1 H,m, HCHMe), 3.85 (3 H, s, MeO),6.92 (1 H, d, J9.0, ArH), 6.96 (1 H, d, J9.0, ArH) and 7.38 (1 H, t, J 9.0, ArH);S, 12.4,13.5,38.7,42.8,56.1,110.6,113.3(q,Jl), 118.4 (4, J 318), 120.7, 130.4, 145.8, 156.9 and 162.5; vjcm-' 1645 (Found: C, 43.8, N, 4.2, H, 4.7.C13H16F3N05S requires C, 43.93; N, 3.93; H, 4.53). Methyl 2-methoxy-6-(tri~7uoromethanesulfonyl)benzoate18. Pale yellow oil, purified by flash chromatography ethyl acet- ate-hexane (3:7); SH 3.88 (3 H, s, MeOAr), 3.93 (3 H, s, MeOCO), 6.95 (2 H, t, J9.0, 2 x ArH) and 7.44 (1 H, t, J9.0, ArH);Sc52.8,56.5, 111.3, 113.4(q,Jl), 118.5(q,J318), 132.1, 146.8, 158.3, 158.4 and 163.6; vjcm-' 1743 (Found: C, 37.8; H, 2.9. C10H9F306S requires C, 38.22; H, 2.89). Cross-coupling Reactions.-Cross-coupling reactions were carried out according to known procedures. Reaction con- ditions and yields are reported in Table 3.The products were characterised as follows. 3-Methoxy-2-methylb@henyl 19. Synthesized according to a procedure described in ref. 3b; pale yellow oil, b.p. 12OoC/1 mmHg; purified by flash chromatography CH,Cl,-hexane (1 :9);SH 2.13 (3 H, S, MeAr), 3.85 (3 H, S, MeO), 6.86 (2 H, t, J 8.0, 2 x ArH), 7.19 (1 H, t, J 8.0, ArH) and 7.26-7.44 (5 H, m, Ph);Sc 13.3,55.5, 108.8, 122.2, 124.3, 125.9, 126.7, 128.0, 129.3, m, MeCH,CH,), 2.62(2H, t,J8.0, CH,Ar), 3.79(3 H, s, MeO), 141.8, 143.3 and 157.9 (Found: C, 84.9; H, 7.3. CI4Hl40 4.91(lH,brs.OH),6.42(1H,d,J8.0,ArH),6.46(1H,d,J8.0,requires C, 84.81; H, 7.12). ArH)and7.01(lH,t,J8.0,ArH);S,14.0,22.7,22.9,31.4,55.6, N,N-Diethyl-2-methoxy-6-methylbenzamide20. Synthesized 103.2, 108.2, 117.1, 126.6, 154.2and 158.6;v/cm-'3609and3407 (Found: C, 72.9; H, 8.7.C,,H,,02 requires C, 73.30; H, 8.95). N,N-Diethyl-2-hydroxy-6-methoxybenz~~nide13. Oil which solidified upon storage, m.p. 137-139 "C (lit.," 139-140 "C); purified by flash chromatography ethyl acetate-hexane-acetic acid (10: 10: l); 6, 1.00-1.30 (6 H, br m, 2 x MeCH,), 3.15- 3.70(4H, brm, 2 x CH,), 3.78 (3 H, s, MeO), 6.39(1 H, d,J8.0, ArH),6.54(1 H,d7J8.0,ArH), 7.12(1 H, t,J8.0,ArH)and7.96 (1 H, br, s. OH). Methyl 2-hydroxy-6-methoxybenzoate14. Oil which solidi- fied upon storage, m.p. 4345 OC (lit.,2o 40-42 "C); purified by flash chromatography ethyl acetate-hexane (3: 7); 6, 3.86 (3 H, s, MeOAr), 3.96 (3 H, s, MeOCO), 6.42 (1 H, d, J 8.5, ArH), 6.60(1 H,d,J8.5,ArH),7.34(1H,t,J8.5,ArH)and11.51(1H, br s, OH): v!cm-' 3279, 1696 and 1660.2-Hydro.xy-6-methoxybenzophenone15. Oil which solidified according to a procedure described in ref. 3a; pale yellow oil, b.p. 145 "C/l mmHg (lit.," 99-100 "C/0.13 mmHg); purified by flash chromatography ethyl acetate-hexane (7 : 3); 6, 1.02 (3 H, t, J 7.0, MeCH,), 1.25 (3 H, t, J7.0, MeCH,), 2.24 (3 H, s, MeAr), 3.11 (2 H, q, J 7.0, MeCH,), 3.32-3.48 (1 H, m, HCHMe), 3.72-3.86 (1 H, m, HCHMe), 3.79 (3 H, s, MeO), 6.73(1H,d,J8.0,ArH),6.80(1H,d,J8.0,ArH)and7.19(1H, t, J 8.0, ArH); vjcm-' 1628. Methyl 2-merhoxy-6-(phenylethynyI)benzoate21. Synthesized according to a procedure described in ref. 21; pale yellow oil, purified by flash chromatography CH,C12-hexane (7 : 3); 6, 3.86(3H,s,MeOAr), 3.97(3H,s,MeOCO),6.92(1 H,dd,J8.5 and0.5,ArH),7.16(1H,dd,J8.5and0.5,ArH),7.31-7.38(4H, m, 4 x ArH) and 7.47-7.51 (2 H, m, 2 x ArH); v/cm-' 2200 and 1730 (Found: C, 76.4; H, 5.3.C1,H,,03 requires C, 76.67; H, 5.30). 266 Methyl 2-methoxy-6-(4-rnethoxyphenyl)ethyny~benzoate 22. Synthesized according to a procedure described in ref. 21; pale yellow oil which solidified upon storage, m.p. 113- I 15 OC (from hexane); purified by flash chromatography CH,CI,-hexane (6 :4); BH 3.82 (3 H, s, MeOAr), 3.85 (3 H, s, MeOAr), 3.97 (3 H, s, MeOCO), 6.84-6.92 (3 H, m, 3 x ArH), 7.13 (1 H, dd, J 8.0 and 1.O, ArH), 7.32 (1 H, t, J 8.0, ArH) and 7.38-7.46 (2 H, m, 2 x ArH); Bc 52.4, 55.3, 56.0, 85.0, 93.0, 110.9, 114.0, 114.8, 122.5, 124.0, 125.7, 130.5, 133.1, 156.1, 159.8 and 167.5; v/crn-' 2210 and 1739 (Found: C, 72.6; H, 5.15.C,,H,,O, requires C, 72.96; H, 5.44). Methyl 2-Methoxy-6-(2-phenylethyl)benzoate 27.40111-pound 21 (0.26 g, 0.97 rnmol) was dissolved in acetic acid (5 cm3) and hydrogenated at room temperature and ambient pressure in the presence of 10 Pd/C (45 mg) during 12 h. The mixture was filtered, diluted with water (40cm3), and extracted with CHZCl2 (4 x 20 cm3). The organic phase was washed successively with water (3 x 20 cm3) and saturated aq. NaHCO, (2 x 20 cm3), and dried (CaCl,). Evaporation of the solvent, and flash chromatography ethyl acetate-hexane (2:8), afforded pure compound 27 (0.220 g, 83) as a pale yellow oil which solidified upon storage; m.p.7678 "C; BH 2.84-2.88 (4 H, m, 2 x CH2), 3.83 (3 H, s, MeOAr), 3.93 (3 H, s, MeOCO), 6.79 (2 H, dd, J 8.0 and 3.0,2 x ArH) and 7.12-7.34 (6 H, rn, 6 x ArH);B, 35.8,37.6, 52.2, 55.9, 108.7, 121.6, 126.0, 128.4, 130.4, 140.2, 141.5, 156.4and 168.8; vjcm-' 1733 (Found: C, 75.2; H, 6.7. C,,Hl,03 requires C, 75.53; H, 6.71). 2-Methoxy-6-2-(4-rnethoxyphenyl)ethylbenzoicAcid 29.-Compound 22 (0.450 g, 1.5 mmol) was dissolved in acetic acid (5 cm3tEtOH (30 cm3) and hydrogenated according to the above procedure. Crude product 28 (0.400 g, 87), a pale yellow oil which solidified upon storage, was dissolved in water (5 cm3)-EtOH (5 an3)containing 7 mol equiv. of KOH (0.51 g, 9.1 mmol). The mixture was stirred at reflux temperature for 4 days, then was chilled to room temperature, diluted with water (20 cm3), and the EtOH was evaporated off under reduced pressure.The resulting mixture was extracted with CH,Cl, (4 x 20 cm3) and the extract was dried (CaCl,). Evaporation of the solvent, and flash chromatography ethyl acetate-hexane (4: 6), afforded pure title acid 29 (0.320 g, 85) as a pale yellow oil, m.p. 105-106 OC (from toluene-hexane) (lit.,"* 102-103 "C); 6, 2.82-3.06 (4 H, m, 2 x CH,), 3.76 (3 H, s, MeO), 3.89(3H,s,MeO),6.76-6.86(4H,m,4x ArH), 7.11 (2H,d,J 8.5, 2 x ArH), 7.31 (1 H, t, J8.5, ArH) and 10.41 (1 H, br s, C0,H); BC 36.4, 36.8, 55.2, 56.1, 108.9, 113.7, 121.7, 122.4, 129.3, 131.0, 133.7, 141.5, 156.7, 157.8 and 172.6; vjcm-' 3510, 3069 and 1700.J. CHEM. soc. PERKIN TRANS. 1 1995 Acknowledgements Financial support from MURST, Roma (60 and 40 funds) is gratefully acknowledged. References 1 See, for example: (a) X. Martin, J. Marquet and J. M. Llunch, J. 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Chem., 1983,48, 1935. 20 R. J.Bass,B.J. BanksandM.Snarey, TetrahedronLett.,1980,21,769. 21 Q.-Y. Chen and Z.-Y. Yang, Tetrahedron Left., 1986,27, 1171. Paper 4/03207A Received 31st May 1994 Accepted 15th September 1994