Catalytic Asymmetric Cyclocarbonylation of o-Isopropenylphenols: Enantioselective Synthesis of Six-Membered Ring Lactones Chune Dong and Howard Alper* Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
[email protected] Received January 13, 2004
Cyclocarbonylation of o-isopropenylphenols with CO (500 psi) and H2 (100 psi), using Pd(OAc)2 and (+)-DIOP as the chiral catalyst, in CH2Cl2 affords 3,4-dihydro-4-methylcoumarins in 60-85% yield and in up to 90% enantiomeric excess. The stereoselectivity is influenced by the structure of the chiral phosphine ligands and substrates, as well as by the reaction conditions. Introduction Asymmetric synthesis is an important strategy for the preparation of chiral intermediates that are crucial in agrochemical and pharmaceutical industries1. Recent developments in asymmetric cyclocarbonylation reactions, using chiral transition metal catalysts, are promising; for example, the enantioselective lactonization of unsaturated alcohols provides optically active fivemembered ring lactones in high enantiomeric excess.2 Despite the high enantioselectivities observed in the catalytic cyclocarbonylation of allylic alcohols, no success has been achieved so far in the asymmetric catalytic synthesis of enantiomerically enriched six-membered ring bicyclic lactones. The transition-metal-catalyzed carbonylation of alcohols to lactones has been well documented in the literature.3 We have previously reported palladium-catalyzed carbonylation reactions,4 in which the cyclocarbonylation of allylphenols catalyzed by palladium, leads to five-, six-, and seven-membered ring lactones in high yield, and the (1) Doyle, M. P. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH Publishers: New York, 2000; p 191. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994. (c) Lin, G. Q.; Li, Y. M.; Chan, A. S. C. Principles and Applications of Asymmetric Synthesis; Wiley: New York, 2001. (2) (a) Alper, H.; Hamel, N. J. Chem. Soc., Chem. Commun. 1990, 135. (b) Cao, P.; Zhang, X. M. J. Am. Chem. Soc. 1999, 121, 7708. (c) Yu, W. Y.; Bensimon, C.; Alper, H. Chem. Eur. J. 1997, 3, 417. (3) For recent syntheses of lactones, see: (a) Yoneda, E.; Zhang, S. W.; Zhou, D. Y.; Onitsuka, K.; Takahashi, S. J. Org. Chem. 2003, 68, 8571. (b) Ma, S. M.; Wu, B.; Zhao, S. M. Org. Lett. 2003, 5, 4429. (c) Magriotis, P. A. Angew. Chem., Int. Ed. 2001, 40, 4377. (d) Yoneda, E.; Kaneko, T.; Zhang, S. W.; Onitsuka, K.; Takahashi, S. Org. Lett. 2000, 2, 441. (e) Jiang, Z. X.; Qing, F. L. Tetrahedron Lett. 2001, 42, 9051. (f) Qing, F. L.; Jiang, Z. X. Tetrahedron Lett. 2001, 42, 5933. (g) Gregory, C. P. J.; Christopher, S. P. M.; Patricia, H.; Christopher, J. M. J. Org. Chem. 2001, 66, 7487. (h) Yoneda, E.; Zhang, S. W.; Onitsuka, K.; Takahashi, S. Tetrahedron Lett. 2001, 42, 5459. (i) Vasapollo, G.; Scarpa, A.; Mele, G.; Ronzini, L.; El Ali, B. Appl. Organomet. Chem. 2000, 14, 739. (j) Vasapollo, G.; Mele, G.; Maffei, A.; Del Sole, R. Appl. Organomet. Chem. 2003, 17, 835. (k) Vasapollo, G.; Mele, G.; El Ali, B. J. Mol. Catal. A: Chem. 2003, 204-205, 97. (l) Maffei, A.; Mele, G.; Ciccarella, G.; Vasapollo, G.; Crisafulli, C.; Scire, S.; La Mantia, F. Appl. Organomet. Chem. 2002, 16, 543.
distribution of the products depends on the nature of the catalyst systems. For example, six-membered ring lactones are predominately formed by using palladium acetate and dppb under 500 psi of CO and 100 psi of H2 (eq 1).5
On the basis of the above work, we subsequently explored the highly regioselective and enantioselective synthesis of optically active six-membered ring lactones by using appropriate chiral ligands and palladium sources. Herein we describe the first example of asymmetric cyclocarbonylation of a series of isopropenylphenols with CO and H2 resulting in the formation of 3,4-dihydro-4methylcoumarins, which are important building blocks for the synthesis of some natural and biologically active compounds.6 (4) (a) Brunner, M.; Alper, H. J. Org. Chem. 1997, 62, 7565. (b) El Ali, B.; Alper, H. Synlett 2000, 161. (c) Yu, W. Y.; Alper, H. J. Org. Chem. 1997, 62, 5684. (d) El Ali, B.; Alper, H. Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley Interscience: New York, 2002; Vol. 2, p 2333. (e) Antebi, S.; Arya, P.; Manzer, L. E.; Alper, H. J. Org. Chem. 2002, 67, 6623. (f) Xiao, W. J.; Alper, H. J. Org. Chem. 2001, 66, 6229. (g) Larksarp, C.; Alper, H. J. Org. Chem. 2000, 65, 2773. (h) Orejon, A.; Alper, H. J. Mol. Catal. A: Chem. 1999, 143, 137. (5) El Ali, B.; Okuro, K.; Vasapollo, G.; Alper, H. J. Am. Chem. Soc. 1996, 118, 4264. (6) (a) The Total Synthesis of Natural Products; Apsimon, J., Ed.; Wiley: New York, 1983; Vol. 5, p 93. (b) Barton, D.; Nakanishi, K.; Meth-Cohn, O. In Comprehensive Natural Products Chemistry; Elsevier Science Ltd.: Oxford, 1999; Vol. 8, p 378. (c) Dictionary of Natural Products, 1st ed.; Buckingham, J., Ed.; Chapman & Hall: New York, 1994.
10.1021/jo040109f CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/19/2004
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FIGURE 1. Chiral phosphine ligands. TABLE 1. Palladium-Catalyzed Asymmetric Cyclocarbonylation of 1a to 2a Using Different Chiral Diphosphine Ligandsa
entry 1 2 3 4 5 6 7 8 9 10 11 12 13
ligand (mol %)
Pd(OAc)2 (mol %)
solvent
(+)-Tol-BINAP (4) (+)-DIOP (4) (+)-DIOP (8) (+)-DIOP (8) (-)-BPPM (4) (-)-DDPP (4) (-)-Me-DuPHOS (4) (-)-NORPHOS (4) (+)-Trost ligand (4) (+)-DIOP (8) (+)-DIOP (8) (+)-DIOP (8) (+)-DIOP (4)
1 1 2 2 1 1 1 1 1 2 2 2 1
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 THF benzene toluene CH2Cl2
yield (%)
ee (%)b
52 83 85 85 85
53 85 90 87c 30
56 78 82 75
62 50 55 81d
a Reaction conditions: o-isopropenylphenol (1 mmol), Pd(OAc) , 2 ligand, CO 500 psi, H2 100 psi, 5 mL of solvent, 100 °C, 48 h; % ee was determined by means of capillary GC using a Supelco β-Dex 120 (0.25 mm × 0.25 µm) column. b (S) configuration was assigned to 2a by comparison of the sign of the specific rotation with the reference value.9 c Using Pd2(dba)3.CHCl3 as catalyst. d 80 °C, 72 h.
Results and Discussion Initial studies focused on examining the feasibility of asymmetric cyclocarbonylation and optimizing reaction conditions that could be applied to a variety of phenols to achieve high stereoselectivity. o-Isopropenylphenol (1a) was chosen as the model substrate for this study. The reaction conditions used previously for palladiumcatalyzed asymmetric cyclocarbonylation of 2-vinylanilines were employed in the present case.7 The catalyst for the enantioselective cyclocarbonylation of 1a was prepared in situ by treatment of palladium acetate with a chiral diphosphine ligand (Figure 1) under nitrogen atmosphere at room temperature. The resulting complex (7) Dong, C.; Alper, H. Tetrahedron: Asymmetry 2004, 15, 35.
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FIGURE 2. Cyclocarbonylation of o-isopropenylphenols.
was used to catalyze the carbonylation of 1a under 500 psi of carbon monoxide and 100 psi of hydrogen at 100 °C in CH2Cl2, affording the corresponding 3,4-dihydro4-methylcoumarin (2a) in high regioselectivity. The results of the asymmetric cyclocarbonylation of 1a to 2a by using palladium acetate and a variety of chiral diphosphine ligands (Figure 1) are summarized in Table 1. Among all the chiral ligands examined, (S,S)-(+)-oisopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane ((+)-DIOP) was found to be the best for this reaction, affording the lactone in 83% yield and 85% ee, respectively, by using 1 mol % of Pd(OAc)2 and 4 mol % of (+)-DIOP. In contrast with (+)-DIOP, (+)-Tol-BINAP was less effective, giving the optically active 3,4-dihydro4-methylcoumarin in 52% yield and 53% ee. (-)-BPPM showed higher activity but poor enantioselectivity for the reaction of 1a, with only 30% ee for 2a. No cyclocarbonylation occurred at all when the palladium-catalyzed reaction was performed in the presence of (-)-DDPP, (-)Me-DuPHOS, (-)-NORPHOS, or (+)-Trost ligand (1R,2R)(+)-1,2-diaminocyclohexane-N,N′-bis(2′-diphenylphosphinobenzoyl). Therefore (+)-DIOP was chosen as the chiral ligand for further optimization. We found that the amount of catalyst has an effect on the enantioselectivity. When Pd(OAc)2 and (+)-DIOP were increased to 2 mol
Cyclocarbonylation of o-Isopropenylphenols TABLE 2. Asymmetric Cyclocarbonylation of o-Isopropenylphenols in the Presence of Pd(OAc)2/(+)-DIOPa entry
phenols
products
1 2 3 4 5 6 7
1a 1b 1c 1d 1e 1f 1g
2a 2b 2c 2d 2e 2f 2g
temp (°C)
yield (%)b
ee (%)c
100 115 100 110 110 120 120
85 65 75 80 84 80 85
90 85 60 55 35 30 15d
a Reaction conditions: o-isopropenylphenol (1 mmol), Pd(OAc) 2 (0.02 mmol), (+)-DIOP (0.08 mmol), CO (500 psi), H2 (100 psi), CH2Cl2 (5 mL), 48 h. b Isolated yield. c Percent ee was measured by means of GC using Supelco β-Dex 120 (0.25 mm × 0.25 µm) column. d Percent ee was determined by chiral HPLC with Chiralpak AS column. The absolute configurations of 2b-g were not determined.
% and 8 mol %, respectively, the enantiomeric excess of 2a increased to 90% (entry 3). The effect of varying solvents was also examined. The reaction works well in dichloromethane (85% yield, 90% ee) but less so in THF (56% yield, 62% ee), benzene (78% yield, 50% ee), and toluene (82% yield, 55% ee). Under the same condition, performing the reaction at 80 °C for 72 h, 2a was obtained in 75% yield and 81% ee (entry 13). The reaction conditions optimized above were then applied to other isopropenylphenols (Figure 2), and the results are presented in Table 2. Substrates 1a, 1c, and 1e were synthesized according to literature procedures
by Grignard reaction of the corresponding 2-hydroxyacetophenone with methylmagnesium bromide, followed by dehydration.8a-c Isopropenylphenols 1b, 1d, 1f, and 1g were prepared by Wittig reaction of methyltriphenylphosphonium bromide with the corresponding acetophenone.8d,e Overall, the asymmetric cyclocarbonylation of isopropenylphenol gave chiral dihydro-4-methylcoumarin in high yield and in modest to good enantioselectivity. The results indicated that the structure of the substrate has a significant influence on the enantioselectivity of the reaction. Cyclocarbonylation of 2-isopropenylphenol (1a) gave 3,4-dihydro-4-methylcoumarin in 85% yield and 90% ee (entry 1). A more sterically hindered substrate such as 1-isopropenyl-2-naphthol (1b) decreased the rate of reaction, affording the corresponding lactone in 65% yield and in slightly lower (85% ee) enantioselectivity. The nature of the substituent on the phenyl ring had a significant effect on the enantioselectivity, although the yield of the reaction was not sensitive to the presence of different substituents. For example, cyclocarbonylation of 6-methoxyl-o-isopropenylphenol (1c) produced 5-methoxyl-3,4-dihydro-4-methyl-coumarin in 75% yield and 60% ee (entry 3), and the reaction of 5-bromo-isopropenylphenol (1d) afforded the lactone in 80% yield and in 55% ee (entry 4). However, 5-methyl-o-isopropenylphenol (1e) gave 5-methyl-3,4-dihydro-4-methylcoumarin in 84% yield and in only 35% ee. Lactonization of phenols bearing electron-withdrawing groups at the 3 and 5 positions of the phenyl ring (1f, 1g) provided lactones in lower % ee, and a slightly higher reaction temperature
SCHEME 1. Proposed Mechanism for Asymmetric Cyclocarbonylation of Isopropenylphenol by Palladium Acetate and (+)-DIOP
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was required to achieve comparable yields. In the case of 1f, the cyclocarbonylation reaction proceeded smoothly at 120 °C, giving the lactone in 80% yield and 30% ee, while only 15% ee was obtained when 1g was used as the substrate. A possible mechanism for the cyclocarbonylation reaction is illustrated in Scheme 1. First, a palladium(0) complex is formed, followed by oxidative addition of the palladium complex to the O-H bond of substrate 1a affording palladium hydride A. Subsequent coordination of the carbon-carbon double bond to the palladium hydride leads to intermediate B. Intramolecular hydropalladation of the latter generates two diastereoisomers C and D. Finally, carbon monoxide insertion to the Pd-C bond followed by reductive elimination would give the six-membered lactone. The enantiodiscrimination step is presumed to be the intramolecular hydropalladation. Steric interaction in the transition states between the chiral ligand and the organic entity bound to the palladium center is an important factor that can largely determine the enantioselectivity. In the experiment using (+)-DIOP as chiral ligand, the chirality of this diphosphine ligand governs the position of the phenyl rings on the phosphorus atom, which is the major element of steric interaction between the chiral diphosphine and the substrate. As to intermediates C and D, in the case of intramolecular hydropalladation, the formation of C is expected to be favored as a result of lower steric interaction between the methyl group and the phenyl ring, which are present in the cyclization of D; therefore C can react further to form the lactone (S)-2a after subsequent reductive elimination. In conclusion, we have developed the first enantioselective palladium-catalyzed asymmetric cyclocarbonylation reaction of o-isopropenylphenols to form enantiomeric enriched lactones in good yields and enantioselectivities. This cyclocarbonylation method provides an alternative route to synthesize chiral six-membered ring lactones. The latter are very useful building blocks for the synthesis of some natural and bioactive molecules.
Experimental Section Representative Procedure for Cyclocarbonylation of o-Isopropenylphenols. A mixture of 1.0 mmol of o-isopropenylphenol, 0.02 mmol of palladium acetate, and 0.08 mmol of (+)-DIOP was dissolved in 5 mL of dry CH2Cl2 and placed in an autoclave. The autoclave was purged, pressurized with CO (500 psi) and H2 (100 psi), and heated at 100 °C for 48 h. The reaction was cooled to room temperature, filtered through silica gel, and concentrated by rotary evaporation. The pure products were isolated by silica gel chromatography using ethyl acetate/hexane 1:5 as eluant. 3,4-Dihydro-4-methylcoumarin, 2a. Colorless oil, [R]22D ) -31.0 (c 1.05, CHCl3). IR (neat): ν 1772 (cm-1). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ 1.30(d, 3H, J ) 6.9 Hz), (8) (a) Baker, W.; Curtis, R. F.; Mcomie, J. F. W. J. Chem. Soc. 1952, 1774. (b) Dhekne, V. V.; Kulkarni, B. D.; Rao, A. S. Indian J. Chem. 1977, 15B, 755. (c) Weller, D. D.; Stirchak, E. P.; Weller, D. L. J. Org. Chem. 1983, 48, 4597. (d) Molina, P.; Alajarin, M.; Vidal, A.; SanchezAndrala, P. J. Org. Chem. 1992, 57, 929. (e) Zhang, H. C.; Huang, W. S.; Pu, L. J. Org. Chem. 2001, 66, 481. (9) Stephan, E.; Rocher, R.; Aubouet, J.; Pourcelot, G.; Cresson, P. Tetrahedron: Asymmetry 1994, 1, 41.
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2.55 (dd, 1H, J ) 7.1 Hz), 2.80 (dd, 1H, J ) 5.5 Hz), 3.16 (t, 1H, J ) 6.3 Hz), 7.03 (t, 1H, J ) 9.4 Hz), 7.10 (d, 1H, J ) 7.4 Hz), 7.18-7.23 (m, 2H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ 20.3, 29.8, 37.2, 117.0, 124.6, 126.5, 127.8, 128.2, 151.2, 168.4. MS (m/z): 162 [M+]. HRMS (EI): calcd for C10H10O2 162.0681, found 162.0656. 3,4-Dihydro-4-methyl-benzocoumarin, 2b. Colorless crystal, mp ) 138-139 °C, [R]22D ) +7.6 (c 0.81, CHCl3). IR (neat): ν 1766 (cm-1). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ 1.36 (d, 3H, J ) 7.2 Hz), 2.90 (d, 2H, J ) 6.0 Hz), 3.83 (t, 1H, J ) 6.7 Hz), 7.22 (d, 1H, J ) 9.7 Hz), 7.45 (t, 1H, J ) 7.5 Hz), 7.56 (t, 1H, J ) 6.9 Hz), 7.75 (d, 1H, J ) 8.9 Hz), 7.84 (d, 1H, J ) 8.0 Hz), 7.90 (d, 1H, J ) 8.5 Hz). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ 20.1, 26.6, 36.1, 117.6, 120.7, 122.4, 125.1, 127.2, 128.8, 128.9, 130.3, 131.0, 148.5, 168.1. MS (m/z): 212 [M+]. HRMS (EI): calcd for C14H12O2 212.0837, found 212.0839. 5-Methoxyl-3,4-dihydro-4-methylcoumarin, 2c. Colorless powder, mp ) 90-91 °C, [R]22D ) -13.6 (c 2.01, CHCl3). IR (neat): ν 1776 (cm-1). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ 1.17(d, 3H, J ) 7.1 Hz), 2.70 (d, 2H, J ) 4.8 Hz), 3.45-3.51(m, 1H), 3.84(s, 3H), 6.65 (dd, 2H, J ) 4.8 Hz), 7.16 (t, 1H, J ) 8.3 Hz). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ 20.0, 24.8, 36.5, 56.1, 106.7, 109.9, 116.7, 128.6, 152.2, 156.7, 168.7. MS (m/z): 192 [M+]. HRMS (EI): calcd for C11H12O3 192.0786, found 192.0769. 6-Bromo-3,4-dihydro-4-methylcoumarin, 2d. Colorless oil, [R]22D ) +1.2 (c 1.77, CHCl3). IR (neat): ν 1770 (cm-1). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ 1.31 (d, 3H, J ) 7.0 Hz), 2.55 (dd, 1H, J ) 7.4 Hz), 2.81 (dd, 1H, J ) 5.5 Hz), 3.16 (q, 1H, J ) 6.0 Hz), 6.91(dd, 1H, J ) 2.0 Hz), 7.34 (d, 2H, J ) 7.3 Hz),. 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ 19.6, 29.4, 36.3, 117.1, 118.7, 129.4, 129.9, 131.2, 150.3, 167.5. MS (m/z): 242 [M+]. HRMS (EI): calcd for C10H9O2Br 239.9786, found 239.9770. 5-Methyl-3,4-dihydro-4-methylcoumarin, 2e. White crystals, mp ) 37-39 °C, [R]22D ) -6.0 (c 1.01, CHCl3). IR (neat): ν 1764 (cm-1). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ 1.29 (d, 3H, J ) 7.0 Hz), 2.31 (s, 3H), 2.51 (dd, 1H, J ) 7.1 Hz), 2.79 (dd, 1H, J ) 5.5 Hz), 3.11 (q, 1H, J ) 6.7 Hz), 6.91 (d, 1H, J ) 8.1 Hz), 7.00 (d, 2H, J ) 12 Hz). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ 19.9, 20.8, 29.5, 36.9, 116.7, 126.9, 127.5, 128.7, 134.2, 149.1, 168.6. MS (m/z): 176 [M+]. HRMS (EI): calcd for C11H12O2 176.0837, found 176.0810. 6,8-Dibromo-3,4-dihydro-4-methylcoumarin, 2f. White powder, mp ) 141-142 °C, [R]22D ) +2.04 (c 1.03, CHCl3). IR (neat): ν 1809 (cm-1). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ 1.31 (d, 3H, J ) 7.0 Hz), 2.55 (dd, 1H, J ) 7.1 Hz), 2.82 (dd, 1H, J ) 5.4 Hz), 3.16 (q, 1H, J ) 6.4 Hz), 7.28 (s, 1H), 7.62(s, 1H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ 19.7, 30.1, 36.1, 111.8, 117.1, 128.6, 131.2, 134.4, 147.5, 166.2. MS (m/z): 320 [M+]. HRMS (EI): calcd for C10H8O2Br2 317.8891, found 317.8911. 6,8-Dichloro-3,4-dihydro-4-methylcoumarin, 2g. Colorless oil, [R]22D ) +2.24 (c 1.07, CHCl3). IR (neat): ν 1770 (cm-1). 1H NMR (300 MHz, CDCl , 25 °C, TMS): δ 1.32 (d, 3H, J ) 3 7.0 Hz), 2.61 (dd, 1H, J ) 7.1 Hz), 2.85 (dd, 1H, J ) 5.4 Hz), 3.17 (q, 1H, J ) 6.7 Hz), 7.10(s, 1H), 7.33(s, 1H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ 19.6, 30.0, 36.1, 122.9, 125.0, 128.8, 129.5, 130.8, 145.9, 166.2. MS (m/z): 230 [M+]. HRMS (EI): calcd for C10H8O2Cl2 229.9901, found 229.9877.
Acknowledgment. We are grateful to the Natural Sciences and Engineering Research Council of Canada for support of this research. Supporting Information Available: 1H and 13C NMR spectra of compounds 2a-g. This material is available free of charge via the Internet at http://pubs.acs.org. JO040109F
