Reaction of 4-chlorocoumarin with organometallic reagents. Synthesis of trialkylbenzopyrans, 4-chlorobenzopyrans, 4-alkylcoumarins ando-hydroxyphenylprop-2-ynyl alcohols

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1992 Reaction of 4-Chlorocoumarin with Organometallic Reagents. Synthesis of Trial kyl benzopyra ns, 4-C hlorobenzopyrans, 4-AI kylcou ma ri ns and 0-Hydroxyphenyl prop-2-ynyl Alcohols Angel Alberola, Blanca Calvo, Alfonso Gonzalez Ortega * and Rafael Pedrosa Departamento de Quimica Organica, Universidad de Valladolid, 47005 Valladolid, Spain 4-Chlorocoumarin has been shown to be a highly versatile starting material when treated with organometallic reagents. Thus, it has allowed the selective synthesis either directly, or through simple additional transformations, of 4-alkylcoumarins (with R,CuLi in Et,O, or Pr'Mg Br in THF), 2-chloro-2-(0- hydroxyphenyl)allyl alcohols or their 4-chloro-2H-1 -benzopyran derivatives (with RMgX in THF), 2-(o-hydroxyphenyl)prop-2-ynyt alcohols (when non-acid hydrolysis were used in the latter reactions) and 2,2,4-trialky1-2H-l -benzopyrans (when excess of RMgX or R,AI reagents were used).As a part of a more general project directed to the synthesis of formation of compound 2 into compound 3 was observed halogeno-2H- 1-benzopyrans, we have studied the behaviour of (except for MeMgI) when longer reaction times were used. the 4-chlorocoumarin 1 towards organometallic reagents. The However, in toluene, diethyl ether or THF at 25 "C,for one hour presence of the halogen at C-4 modifies the reactivity of the or more and molar ratio 8/1, the major product was compound heterocycle, making it more sensitive to variations in experi- 3,which was obtained in moderate to very good yield (51-83).mental conditions than are the 3-halogenocoumarins. The Complex mixtures of products were obtained when different reaction of 4-chlorocoumarin with organometallic derivatives experimental conditions were employed (Table 1). Nevertheless, (RMgX, R,A1, RLi, R,CuLi) can lead to a complex mixture of the isolation and purification of compound 2 was possible only compounds (Scheme l), depending on the nature of the organo- by recrystallization from the crude reaction mixture where they metallic reagent, the reaction and the hydrolysis conditions. were formed in high yield. Attempts at purification by other methods (including flash chromatography) transformed com- Reactions with Magnesium Derivatives.-Primary alkylmag-pound 2 into dehydrochlorination 5, or cyclization 8 products.nesium halides (R = methyl, ethyl, propyl or butyl) allowed This behaviour was also observed for compounds 3,which auto- selective preparation of compound 2 or 3. Thus, when the transformed readily into 2,2,4-trialky1-2H-l-benzopyrans9. It is reactions were carried out in THF (tetrahydrofuran), at 0 "Cfor noteworthy that the hydrolytic conditions are crucial to obtain a maximum of 1 h, and molar ratio RMgX/l, 5/1, a good yield 2 and 3 in good yields; thus using cold saturated aqueous (7249) of compound 2 was obtained, whereas the trans- NH,Cl (or a very dilute acidic solution and ice) followed by H + WH00 Cl CI A R 1 2 3 4 RR + q H + HWH0 OH 5 6 7 + CI A A 8 9 10 qR CI 0 11 12 Scbeme 1 a R = H, b R = Me,c R = Et, d R = Pr, e R = Bu, f R =Pri, g R = Bu'.Reagents: i, RM;ii, H,O.Table 1 Reaction of compound 1 with Grignard derivatives RMgX Solvent T/"C tlh l/RM MeMgI PhMe 0 2 Et,O 0 2 THF 0 2 EtMgI PhMe 25 2 Et20 25 2 THF 0 2 EtMgBr PhMe 25 1 Et20 25 1 THF 25 1 THF 0 1 THFb 0 1 PrMgBr PhMe 25 1 PhMe 0 1 Et20 25 1 Et,O 0 1 THF 25 0.5 THF 0 1 THF 0 1 BuMgBr PhMe 25 1 PhMe 0 1 Et20 25 1 THF 25 1 THF 0 I Pr'MgBr PhMe 25 1 PhMe 0 1 Et20 25 0.5 EtZO -50' 20 Et20 0 1 THF 25 0.5 THF -50' 20 THF 0 1 THF 0 1 THFd 25 1 Et20 -50 0.5 THF -50 0.5 Yields in all tables were calculated from NMR spectra of the reaction mixture.to room temp. Test negative (THF-benzophenoneNa, colourless solution). J. CHEM. SOC. PERKIN TRANS. 1 1992 ~ ~~ ~ Product ( Yield) 2 3 10 5b 3f(30) Sf(28)3f(79) 3f(50) 3f(75) 31(40) Sf(65) 1Of (79) 1Of (80) 1Of (69) Aqueous hydrolysis. 30 min at -50 "C,and then allowed to warm immediate work-up and removal of the solvent under reduced pressure at room temp. allowed the syntheses of the mentioned products. The behaviour of isopropylmagnesium bromide towards 1 was different from that shown by primary magnesium deriv- atives. The most important difference is the possibility to obtain 4-alkylcoumarin 1Of (1,4-addition-elimination)in very good yield (69-80), in diethyl ether or THF at -50 "C. In this case the bis-addition was the predominant process at temperatures higher than 0 "C,and the best yield (85) for 2f was obtained in toluene, instead of THF.The reason for this behaviour is that the competing 1P-addition process does not take place in this solvent,'-5 and the lower reactivity of the isopropylmagnesium bromide allows a better control of the reaction leading to compound 13 (Scheme 2). Unfortunately, other secondary alkylmagnesium derivatives, such as sec-butyl- or cyclopentyl-magnesium bromides yielded 4-alkyl coumarins in very low yields. Monitoring of the reactions showed that trialkyl derivatives 3 may be obtained either through 10 (for Pr'MgBr), or through the alkoxides 13 (for RMgBr; R = Et, Pr, Bu) (Scheme 2). The latter possibility opened a versatile path to trisubstituted benzo- pyrans with different alkyl groups attached to C-2 and C-4. Thus, these substrates can be obtained from compound 1 simply by appropriately changing the organometallic reagent used in each step (Scheme 3) (Table 2).1 1CI 13 1. il c10 3 Scheme 2 Reagents: i, RM; ii, H,O On the other hand, although 3-(o-hydroxyphenyl)prop-2-ynyl alcohols 5 could be formed by dehydrohalogenation during the reaction,6 their ratios in the final mixtures are highly dependent on the conditions of hydrolysis. Thus, derivatives 5 were obtained as major compounds (58-79) (after column chromatography) when the reactions were hydrolysed only by water, whereas quenching the reaction mixture with acetic acid J.CHEM. SOC. PERKIN TRANS. I 1992 3 R=W 9 R=R' 14 R = Et, R'= BU 15 R=Et,R'=Bu 16 R=Bu,R'=Et 17 R=Bu,W=Et Scheme 3 Reagents: i, RMgX; ii, H20, iii, R'MgX Table 2 Reaction of compounds 2 with RM 2 RM Solvent " t/h Product ( yield) 2b Me,AI CH2C12 20 2c zc EtMgBr Et,AI Et20 PhMe 12 20 2c 2e 2e 2e 2e BuMgBrBuMgBr BuMgBr EtMgBr Bu,Al Et,O Et,O PhMe Et20 PhMe 12 12 12 12 20 ~~~~ " The reactions were carried out at 25 "C; molar ratio 2/RM: 1/4. Table 3 Reaction of compound 1 with R,AI RM Solvent " T/T" 1/RM Products ( yield) Me,Al PhMe 25 3b (-1CH,Cl, 25 9b (49) CH,C12 25 9b (65) Et,AI PhMe 0 PhMe 25 CH,Cl, 25 CH,Cl, -50b Et,O 25 THF 25 Bu,AI PhMe -50b PhMe 0 PhMe 25 Bu',AI PhMe -50b PhMe 0 PhMe 25 Bu',Al-H PhMe -50 1 /6 2a (78) PhMe -50 112.5 lla (SO) PhMe 25 113 2a (75) Et,O -50 1/2.5 lla (40), 1 (45) " The reactions were carried out for 20 h.30 min at -50 "C, and then allowed to warm to room temp. led to mixtures of compounds 2,s and, in some cases, 7. These results suggest that the dehydrohalogenation process mainly occurs during, or after, hydrolysis in non-acidic conditions. Reactions with Organoaluminium Derivatives.-The control of the reactions of aluminium derivatives with 1is more difficult than the above reported with Grignard reagents. Thus, from a practical point of view, it is more convenient to have the reaction at 25 "C,to obtain products 3or 4. In this case triethyl- and tributyl-aluminium, in toluene, led to compound 3 in very good yields (68-85); but triisobutylaluminium, more sterically demanding and with a high reductive character, yielded a mixture of the alkylation-reduction compound 4 as major (52- 65), and the double reduction product 2a as minor component 3077 Table 4 Reaction of compound 1 with lithium derivatives RLi Solvent T/"C l/RLi t/h Products ( yield) ~ BuLi PhMe 25 1/4 Et,O -50 1/4 Et20 25 1/4 THF 25 1/4 MeLi Et,O -50 1/6 2 Et20 -50 1/4 2 Et,O -50" 1/6 12 THF -50 1/6 2 THF -50 1/4 2 " 30 min at -50 "C, and then allowed to warm to room temp.Table 5 Reaction of compounds 1 and 10 with organocuprates Coumarin R,CuLi Solvent" T"/T Products ( yield) 1 Me,CuLi Et,O -50 lob (90) Me2CuLi THF -20 lob (65) Me,CuLi Et,O -50 lob (85) Me,CuLi THF -20 lob (69) Bu2CuLi Et,O -50 1Oe (48), 2e (15) Bu,CuLi Et,O -50 1Oe (65) Bu,CuLi THF -50 1Oe (70) BuCu Et,O -50 1Oe(->10b Me,CuLi Et20 -50 lob (95) 10b Bu,CuLi Et20 -50 10b (90) 1Oe Me,CuLi Et20 -50 1Oe (95) 1Oe Me,CuLi Et20 -50 1Oe (87) " The reactions were carried out in molar ratio l/R,CuLi, 1/3 for 2 h.Boron trifluoride-diethyl ether complex was used. (10-34) (Table 3). The reductive character of these organo- metallic reagents increases in diethyl ether or THF, but their reactivity towards coumarins decreases,' making the reactions impossible from a synthetic point of view. Since trimethylaluminium is less reactive than triethyl- or tributyl-aluminium, the reaction had to be carried out in refluxing toluene.However, after 3 h, only a complex mixture of products was obtained. The trimethylbenzopyran 9b, which could not be obtained using MeMgI, could however be syn- thesized in moderate yield (65) when the reaction was carried out in CH2C12. The reaction of compound 1 with DIBAH, at room temp. yielded compound 2a. Nevertheless, at lower temperatures (-50 "C, 2 h, l/DIBAH, 1/2.5), the product obtained was lla, which is very unstable and was isolated after purification as chromone 12a. Reactions with Lithium Derivatives.-Lithium derivatives re- act by 1,2-addition, but in our case they did not lead preferen- tially to the expected dialkyl derivatives 2 (Table 4). Instead, the dehydrochlorination product 5e was obtained as major com- pound (25-60) in the reactions of 1with butyllithium.On the other hand, methyllithium reacted with 1 to give o-hydroxyphenylacetylene 6 as major compound. This degrad- ation product did not appear either in the reactions with other organometallics, or with butyllithium. Although compound 6 could be formed during the reaction, the main amount must be formed during the hydrolysis, since it diminished or disappeared when the reaction mixture was subjected to acetolysis. Reactions with 0rganocuprates.-Lithium dimethyl- and di- butyl-cuprates and their boron trifluoride-diethyl ether com- plexes reacted with 4-chlorocoumarin 1, giving very good yields of 4-methylcoumarin 10b (90) and 4-butylcoumarin 1Oe (65), respectively.Compounds 10 are stable in excess of the reagent, and they are probably formed by c~pulation,~ instead of 1,4-addition-eliminationprocess. Conversely, alkylcuprates which react better than lithium dialkylcuprates with a-P-unsaturated esters by a 1,4-addition process,' reacted with compound 1 leading to compound 10 in low yield (Table 5). Conclusion.+-Chlorocoumarin has been shown to be a very useful substrate in its reactions with organometallic reagents; both by its versatility in the introduction of different sub- stituents, and by the nature of the reaction products. Provided that strict control of the reaction conditions is achieved, these otherwise cumbersome and uninteresting reactions become useful synthetic procedures.Experimental M.p.s were measured on a Leit Laborlux D microscope with a heating device and are uncorrected. The b.p.s correspond to the oven temperature in a kugelrohr Buchi GKR-51. NMR spectra were recorded on Bruker AC80 spectrometer and chemical shifts are given downfield from SiMe, as internal standard, J values are given in Hz. Mass spectra were measured on Hewlett- Packard 5988A mass spectrometer. The starting material 4-chlorocoumarin was prepared as pre- viously described. Reactionof Compound1 with Organocuprates. Synthesis of 4-Methyl-1-benzopyran-2-one10b and 4-Butyl-1-benzopyran-2-one 10e.-A magnetically stirred solution of organocuprate or boron trifluoride-diethyl ether complex (1.6mmol) in the appropriate solvent (Table 5) (20cm3) under N, was cooled to -50 "C, and a solution of compound 1 (0.2g, 1.1 mmol) in dry solvent (20cm3) was added dropwise.The mixture was stirred for 60min, and quenched with saturated aq. NH,Cl (15cm3). The product was extracted with Et,O (3 x 20 cm3), and the extract was washed sequentially with water and brine. The organic layer was chromatographed on silica gel with methyl- ene chlorine as eluent, to yield the compounds 10b (0.14 g, 80) and 1Oe (0.15g, 64).4-Methyl-1-benzopyran-2-one 10b m.p. 81-82 "C (lit.," 82"C) (Found: C, 74.8;H, 4.85. Calc. for CloH,O,: C, 75.0;H, 5.0); 6,(80 MHz; CDCl,) 2.51 (3H, d, J l), 6.18 (1 H, q, J 1) and 6.85-7.61 (4 H, m). 4-Butyl- 1-benzopyran-2-one 10e m.p. 68.5-69.5"C (lit.,' 67-68"C) (Found: C, 77.35;H, 6.8.Calc.for C13HldO2: C, 77.2;H, 7.0);6,(80 MHz; CDCl,) 0.99 (3 H, td, J 6, l), 1.09-1.98 (4 H, m), 2.77 (2 H, m),6.26 (1 H, t, J 1) and 7.12-7.61(4 H, m); m/z 202 (M', 20) and 160 (100). Reactionof Compound1 with Organomagnesium, Organolith- ium and Organoaluminium Compounds. General Procedure.- To a magnetically stirred solution of 4-chlorocoumarin 1 (5.5 mmol) in the appropriate solvent (100cm3) was added dropwise (30min) the organometallic compound under nitrogen (see Tables 1, 3 and 4). At the end of the reaction (monitored by TLC), the mixture was hydrolysed. The organic layer was decanted, dried (MgS04) and the solvent was eliminated under reduced pressure at room temp. The conditions of hydrolysis and the methods of purification depend on the desired product, and are given below.(a) 1,l-Dialkyl-3-chloro-3-(o-hydroxyphenyl)prop-2-en-1-01s 2. The reaction was hydrolysed with saturated aqueous NH,Cl, and the product was isolated and purified by recrystallization from C14C or CHCl, from the reaction mixture. (6)1,1,3-Trialkyl-3-(o-hydroxyphenyl)prop-2-en-1-01s 3. The reaction mixture was quenched with ice-water, and acidified until metallic hydroxides were just dissolved, followed by J. CHEM. SOC. PERKIN TRANS. 1 1992 neutralization with NaHCO,. The compounds were purified by recrystallization from toluene-hexane, 1/20or by flash chrom- atography on silica gel with CH2C12 as eluent. It was not possible to purify compound 3e by recrystallization, and it was transformed into 2,2,4-trialkyl-2H-1-benzopyran 9e, when subjected to distillation.(c) 1,l-Dialkyl-3-(o-hydroxyphenyl)prop-2-yn-1-01s 5. The re- action mixture was hydrolysed with water at room temp. The title compounds were purified by column chromatography on silica gel, with CH2C12-Et,O: 20/1as eluent. (d)2,2-Dialkyl-4-chloro-2H-1-benzopyrans8. The concen-trate of the reaction was heated under reflux with silica gel ( x 3 w/w) l1 for 1 h. The title compounds 8 were purified by column chromatography on silica gel, with hexane as eluent. (e)2,2,4-Trialkyl-2H-l-benzopyrans9.After concentration of the reaction mixture of 1,1,3-trialkyl-3-(o-hydroxyphenyl)prop-2-en-1-01s3, the concentrate was treated as described in (d).The physical and spectral characteristics of the products, the optimized experimental conditions, and chemical yields are given below. (E)-3-Chloro-3-(o-hydroxyphenyl)prop-2-en-1-01 2a. (DIBAH, PhMe, -50 "C, 72) m.p. 74.5-75.5"C (Found: C, 58.3;H, 4.75.C,H,ClO, requires C, 58.6;H, 4.9);6,(80 MHz; CDCl,) 3.95 (2 H, d, J 7), 6.22 (1 H, t, J 7) and 6.72-7.28(4 H, m); m/z168(M+ + 2 -H20, 17), 166 (M+ -H20,55) and 165 (100). (E)-4-Chloro-4-(o-hydroxyphenyl)-2-methylbut-3-en-2-ol2b. (MeMgI, THF, 0 "C, 75) m.p. 106-107 "C (Found: C, 62.2;H, 6.4. C,,H,,ClO, requires C, 62.1;H, 6.2); 6,(80 MHz; CDCl,) 1.26 (6 H, s), 6.29 (1 H, s) and 6.78-7.33(4 H, m); m/z 196(M+ + 2 -H,O, 479,194(M+ -H,O, 11)and 179 (100).(E)-1-Chloro-3-ethyl-1-en-3-012c.1-(o-hydroxypheny1)pent-(EtMgBr, THF, 0 "C, 69); m.p. 94-95 "C (Found: C, 64.8; H, 7.3.C13H1,C102 requires C, 64.9;H, 7.1); 6,(80 MHz; CDCl,) 0.87 (6 H, t, J7),1.52 (4H, m), 6.20 (1 H, s) and 6.78-7.25(4 H, m); m/z242 (M+ + 2, l), 268 (M', 1)and 71 (100). (Z)-3-Ethyl-5-(o-hydroxyphenyl)hept-4-en-3-013c. (EtMgBr, PhMe, 25 "C, 77) m.p. 77.8-78.8"C (Found: C, 76.7;H, 9.65. C15H22O2 requires C, 76.9;H, 9.5);aH(8OMHz; CDCl,) 0.97 (9H, m), 1.48 (4 H, q, J7),2.25 (2H, qd, J7, l), 5.58 (1H, t, J 1) and 6.79-7.21(4 H, m); m/z 216 (M+ -H20,3) and 187 (100).0-Hydroxyphenyl)-4-propylnon-(2)-6-( 5-en-4-01 3d. (PrMgBr, Et,O, 25 "C, 73) b.p. 140-145 "C (2mmHg) (the title compound decomposed to 2,2,4-tripropyl-2H-1-benzopyran 9d); 6,(80 MHz; CDCl,) 0.97 (9 H, m), 1.05-1.72 (10 H, m), 2.20 (2H,td,J7,1),5.58(1H,t,Jl)and6.83-7.18(4H,m);m/z216 (M+ -H20,2) and 215 (100). (Z)-5-Butyl-7-(0-hydroxyphenyl)undec-6-en-5-01 3e. (Bu, Al, PhMe, 25 "C, 79) yellow oil (the compound decomposed to J. CHEM. SOC. PERKIN TRANS. 1 1992 2,2,4-tributyl-2H-l-benzopyrun9e); 6,(80 MHz; CDC1,) 0.80-1.26 (9 H, m), 1.28-1.62 (16 H, m), 2.15-2.42 (2 H, m), 5.59 (1 H, m) and 6.7G7.14 (4 H, m); m/z 300 (M+ -H20, 6) and 243 (100).(Z)-~-(O-ffydro.uyphenyl)-3-isopropyl-2,7-dimethylhept-4-en-3-013f. (Pr'MgBr, Et20, 25 "C, 75) m.p.93.6-94.6 "C (Found: C, 78.1; H, 10.4. C18H2802 requires C, 78.2; H, 10.2); 6,(80 MHz; CDCI,) 0.66-0.99 (12 H, m), 0.94 (16 H, d, J7), 1.83 (2 H, m), 2.39 (1 H, sept d, J 7, l), 5.42 (1 H, d, J 1) and 6.50-7.21 (4 H, m); m/: 258 (M+ -H20, 2) and 71 (100). (Z)-6-(o-HydroxyphenyZ)-2,8-dimethyfnon-5-en-4-o14g.(Bu',-Al, PhMe, 25 "C, 61) m.p. 93.6-94.6 "C (lit.," 93-94 "C) (Found: C, 80.8; H, 10.2. Calc. for C1,HZ6O2: C, 80.9; H, 10.3); 6,(80 MHz; CDCl,) 0.62-1.12 (12 H, m), 1.21-2.05 (4 H, m), 2.23 (2 H, m), 4.15 (1 H, dt, J9,7), 5.49 (1 H, d, J9) and 6.59-7.1 1 (4 H, m); mi= 244 (M+ -H20, 9) and 187 (100).4-(o-Hydroxypheny1)-2-methylbut-3-yn-2-o15b. (MeMgI, PhMe, 0 "C, 64) m.p. 131-132 "C (Found: C, 75.1; H, 6.7. C, ,H1 202requires C, 75.0; H, 6.9); aH(80MHz; CDCl,) 1.65 (6H,s),6.70-6.93(2H,m)and 7.12-7.32(2H,m);m/z 176(M+, 14) and 158 (100). 3-Ethy/-1-(o-hydroxypheny1)pent- 1 -yn-3-ol 5c. (EtMgBr, THF, 0 T, 67) m.p. 72.3-73.3 "C (Found: C, 76.25; H, 7.85. Ct ,H 602requires C, 76.4; H, 7.9); 6,(80 MHz; CDCl,) 1.08 (6 H, t, J 7), 1.78 (4 H, q, J 7) and 6.69-7.30 (4 H, m); m/z 204 (M+, 7) and 186 (100). 1-(o-Hydro.~~~phenl)-3-propylhex-1 -yn-3-01 5d. (PrMgBr, THF, O"C, 60) m.p. 6647°C (Found: C, 77.7; H, 8.5. C15H2,Oz requires C, 77.55; H, 8.7); 6,(80 MHz; CDCl,) 0.96 (6 H, t, J 7), 1.45-1.83 (8 H, m) and 6.71-7.33 (4 H, m); m/z 232 (M+, 4) and 43 (100).3-Butyl-l-(o-hydroxyphenyl)hept-l-yn-3-ol9.(BuMgBr, PhMe, 0 "C, 59) m.p. 63.5-64.5 "C (Found: C, 78.6; H, 9.15. C1 7H2402 requires C, 78.4; H, 9.3); 6,(80 MHz; CDC13) 0.90- 1.08 (6 H, m), 1.15-1.70 (12 H, m) and 6.71-7.32 (4 H, m); m/z 260 (M +,1) and 203 (100). l-(o-Hydroxyphenyl)-3-isopropyl-4-methyl-pent-l-yn-3-01 5f. (Pr'MgBr, THF, 0 "C, 60) m.p. 100.5-101.5 "C (Found: C, 77.65; H, 8.6. C15H2,02 requires C, 77.55; H, 8.7); 6,(80 MHz; CDCl,) 1.08 (6 H, d, J7), 1.10 (6 H, d, J7), 2.05 (2 H, sept, J7) and 6.70-7.32 (4 H, m); m/z 232 (M +,1) and 198 (100). o-Hydroxyphenylacetylene6. (MeLi, Et,O, -50 "C, 60) b.p. 79-82 "C (20 mmHg) lit.,', 74.5 (15 mmHg); dH(80MHz; CDCI,) 3.45 (1 H, s),6.65-7.65 (4 H, m); m/z 119 (M+ + 1,8) and 118 (Mf, 100).1 -one 7b.3-Hydroxy- 1 -(o-hydroxyphenyl)-3-methyfbutun-(MeMgI, THF, 0 "C, 60) Hydrolysed with AcOH, purified by chromatography with PhMe as eluent; b.p. 105-110 "C (1.5 mmHg) (Found: C, 68.15; H, 7.4, C 1H 1403 requires C, 68.0; H, 7.3); 6,(80 MHz; CDCl,) 1.36 (6 H, s), 3.16 (2 H, S) and 6.78- 7.79 (4 H, m); m/z 194 (M', 5) and 121 (100). 4-Chloro-2,2-dimethyl-2H-1 -benzopyran 8b. (MeMgI, THF, 0 "C, 70) b.p. 98-100 "C (1.5 mmHg) (Found: C, 67.6; H, 5.6. C H 'ClO requires C, 67.9; H, 5.7); 6,(80 MHz; CDCl,) 1.44 (6 H, s), 5.71 (1 H, s) and 6.70-7.51 (4 H, m); m/z 196 (M' + 2, 373,194 (M', 10) and 170 (100). 4-Chloro-2,2-diethyl-2H-1 -benzopyrun 8c (EtMgBr, THF, 0 "C, 65) b.p.100-105 "C (1.5 mmHg) (Found: C, 70.0; H, 6.6. Cl3HI5C10 requires C, 70.1; H, 6.8); 6,(80 MHz; CDCl,) 0.93 (6 H, t, J7), 1.56-1.86 (4 H, m), 5.62 (1 H, s) and 6.70-7.46 (4 H, m); m/z 224 (M+ + 2, l), 222 (M', 3) and 193 (100). 4-Chloro-2,2-dipropyl-2H-1 -benzopyran 8d. (PrMgBr, THF, 0 "C, 61) b.p. 105-110 "C (0.9 mmHg) (Found: C, 72.0; H, 7.5. C15H19CI0 requires C, 71.8; H, 7.6); 6,(80 MHz; CDCl,) 0.80-1.31 (6 H, m), 1.37-1.79 (8 H, m), 5.64 (1 H, s) and 6.68-7.46 (4 H, m); m/z 196 (M' + 2, 5), 194 (M', 15) and 207 (100). 4-Chloro-2,2-dibutyl-2H-1 -benzopyran 8e. (BuMgBr, THF, 0 "C, 70) b.p. 135-139 "C (2 mmHg) (Found: C, 73.4; H, 8.5. C17H2,C10 requires C, 73.2; H, 8.3); 6,(80 MHz; CDCI,) 0.73-1.05 (6 H, m), 1.05-1.94 (12 H, m), 5.63 (1 H, s) and 6.67- 7.45 (4 H, m);m/z 196 (M+ + 2,1), 194 (M+, 3) and 221 (100).2,2,4- Trimerhyl-2H- l-benzopyrun 9b. (Me,Al, Cl,CH2, 25 "C, 62) b.p. 60-65 "C (1 mmHg) lit.,14 63-65 "C (1 mmHg) (Found: C, 82.55; H, 8.2. Calc. for C12H14O: C, 82.7; H, 8.0); (SO MHz; CDC13) 1.39 (6 H, s), 1.98 (3 H, d, J l), 5.39 (1 H, q, J 1) and 6.74-7.20 (4 H, m); m/z 174 (M', 49) and 159 (100). 2,2,4-Tripropyl-2H- 1-Den:mpyran 9d. (PrMgBr, Et,O, 25 "C, 70) b.p. 120-125 "C (1.3 mmHg) (Found: C, 83.6; H, 9.9. CI8H2,O requires C, 83.7; H, 10.1); 6,(80 MHz; CDCl,) 0.80-1.05 (9 H, m), 1.26-1.71 (10 H, m), 2.36 (2 H, t, J 7), 5.26 (1 H, t, J 1) and 6.70-7.17 (4 H, m); m/z 258 (M+, 2) and 215 (100). 2,2,4- Tributyl-2H-1 -benzopyrun 9e.(Bu,Al, PhMe, 25 "C, 75) b.p. 145-150 "C (1.5 mmHg) (Found: C, 83.8; H, 10.6. C21H32O requires C, 83.95; H, 10.7); aH(80MHz; CDCl,) 0.95 (9 H, m), 1.15-1.71 (16 H, m), 2.45 (2 H, t, J7), 5.27 (1 H, s) and 6.63-7.19 (4 H, m); m/z 300 (M', 6) and 243 (100). 4-Isopropyl-l-benzopyran-2-one 1Of. (Pr'MgBr, Et,O, -50 "C, 78) b.p. 85-90 "C (0.9 mmHg) lit.,' 85-90 "C (0.9 mmHg) (Found: C, 76.75; H, 6.2. Calc. for C,,HI2O2: C, 76.6; H, 6.4); 6,(80 MHz; CDCl,) 1.31 (6 H, d, J 7), 3.30 (1 H, m), 6.27 (1 H, d, J 1) and 7.05-7.6 1 (4 H, m); m/z 188 (M +,5 1) and 145 (100). 4-Chloro-2H- l-benzopyran-2-01 1la. (DIBAH, PhMe, -50 "C, 75) 6H(80 MHz; CDCl,) 5.85 (1 HA, JAB 4), 5.95 (lHB, JAB 4) and 6.82-7.95 (4 H, m); this compound is unstable and during the purification it is transformed into 4H- l-benzopyran- 4-one 12a.l' (Z)-3-Ethyl-5-(o-hydroxyphenyf)non-4-en-3-o114.Character-ized as the cyclization product 4-butyl-2,2-diethyl-2H- 1 -benzo- pyran 15; the reaction mixture of 2c with BuMgBr (Table 2) was subjected to a work-up as described in the paragraph (d).After chromatographic separation, 15 was obtained in (68); b.p. 140-145 "C (1.5 mmHg) (Found: C, 83.65; H, 9.7. Cl7HZ4O requires C, 83.55; H, 9.9); S,(80 MHz; CDC1,) 0.75-0.94 (9 H, m), 1.61-1.22 (8 H, m), 2.33 (2 H, t, J7), 5.60 (1 H, t, J 1) and 6.77-7.27 (4 H, m); m/z 244 (M+, 3) and 215 (100). (Z)-5-Butyl-3-(o-hydroxyphenyl)non-3-en-5-of16. Character-ized as the cyclization product 2,2-dibutyl-4-ethyl-2H- l-benzo- pyran 17;the reaction mixture of 2e with EtMgBr (Table 2) was subjected to a work-up as described in the paragraph (d).After chromatographic separation, 17 was obtained in (63); b.p. 145-150°C (1.7 mmHg) (Found: C, 84.0; H, 10.5. C19H28O requires C, 83.8; H, 10.4); 6,(80 MHz; CDCl,) 0.86-1.98 (9 H, m), 1.20-1.61 (12 H, m), 2.27-2.54 (2 H, m), 5.26 (1 H, t, J 1) and 6.67-7.17 (4 H, m); m/z 272 (Mf,l) and 215 (100). Acknowledgements Authors are gratefully indebted to the Junta de Castilla y Leon by financial support of this work. References 1 A. Alberola, B. Calvo, A. Gonzalez, M. Vicente and S. G. Granda, J. Chem. SOC., Perkin Trans. 1, 1991,203. 2 R.W. Ticle,T. Melton and J. A. Elvidge,J.Chem. SOC., Perkin Trans. 1, 1974,596. 3 Chr. Ivanov and A. Bojilova, Synthesis, 1974,708. 4 G. A. Holmber, Acta Chem. Scand., 1961,15, 1255. 5 I. Renvall, Acta Acad. Aboensis, Math. Phys., 1969, 29, 1 (Chem. Absrr., 1970,72,66737 p). 6 H. Newmann and D. Seebach, Chem. Ber., 1978,111,2785. 7 E. J. Corey and I. Kuwajima, J.Am. Chem. SOC., 1970,92,395. 8 Y. Yamamoto, S. Yamamoto, H. Yatagai, Y. Ishihara and K. Maruyama, J. Org. Chem., 1982,4?, 119. J. CHEM. SOC. PERKIN TRANS. 1 1992 9 D. P. Spalding, H. S. Mosher and F. C. Withmore, J. Am. Chem. SOC., 14 J. J. Talley, Synthesis, 1983, 845. 1950,72,5338. 15 B. Fohlish, Chem. Ber., 1971, 104. 10 E.H. Woodrukk, Org. Synth., 1944,24,69. 11 A. Alberola, A. G. Ortega, R. Pedrosa, J. L. Perez and J. F. Rodriguez, J. Heterocvcl. Chem., 1983,20,715. 12 A. Alberola, F. Alonso and A. Gonzalez, An. Quim., 1982,7, 15. Paper 2/03578B 13 V. Prey, Monatsh. Chem., 1949, 80, 790 (Chem. Abstr., 1950, 44, Received 7th July 1992 7795). Accepted 17th July 1992