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Short and stereoselective synthesis of polysubstituted cyclohexanones
Tetrahedron 60 (2004) 9149–9153
Short and stereoselective synthesis of polysubstituted cyclohexanones Jon K. F. Geirsson,* Liney Arnadottir and Stefan Jonsson Department of Chemistry, Science Institute, University of Iceland, Dunhaga 3, IS-107 Reykjavik, Iceland Received 28 May 2004; revised 29 June 2004; accepted 23 July 2004 Available online 26 August 2004
Abstract—Two equivalents of dimethyl 1,3-acetonedicarboxylate reacted with a,b-unsaturated aldehydes to form novel polysubstituted cyclohexanones 2 in an efficient one-step procedure. The reactions proceeded at room temperature in the presence of catalytic amount of sodium methoxide, affording the products in high yields in a remarkably stereoselective manner. The products are of possible biological interest. q 2004 Elsevier Ltd. All rights reserved.
1. Introduction Polysubstituted cyclohexanones and cyclohexanols are widespread structural subunits in biologically active compounds, and related molecules have been used as starting materials in the synthesis of pharmaceuticals1,2 and in natural product syntheses.3–6 As part of a research programme aimed at exploring the chemical and biological properties of bicyclo[3.3.1]nonan-3-ones 1,7,8 we observed that the base-catalyzed reaction between an a,b-unsaturated aldehyde and dimethyl 1,3-acetonedicarboxylate to yield 1, suffered from the concomitant formation of the polysubstituted cyclohexanones 2 (Scheme 1). In particular, the formation of 2 was a persisting problem when the
reaction was scaled up (e.g. from 0.5 to 5–10 g). In occasional instances 2 was the only product isolated. The simplicity and the stereoselectivity of the reaction prompted us to search for reaction conditions that would maximize the yields of the cyclohexanones 2. Similar stereoselectivity has recently been observed in the condensation of dimethyl 1,3-acetonedicarboxylate with pentane2,3-dione.9 A probable pathway for the formation of 2 is outlined in Scheme 2, proposing the intermediate formation of the conjugated derivative 3 as a result of an 1,2-addition of dimethyl 1,3-acetonedicarboxylate to the a,b-unsaturated aldehyde. The intermediate 3 undergoes an 1,4-addition with a second molecule of the keto diester with an ensuing ring closure of the symmetrical intermediate 4. The proposed formation of the bicyclo[3.3.1]nonan-3-ones 1 has been incorporated in Scheme 2 for comparative purposes.10 Accordingly, products 1 are probably formed by an initial 1,4-addition of the keto diester to the unsaturated aldehyde to form a cyclohexenone derivative as an intermediate. 2. Results and discussion
Scheme 1. The preparation of 1 and 2.
Keywords: 1,3-Acetonedicarboxylate; Polysubstituted cyclohexanones; Stereoselective reaction; Claisen condensation. * Corresponding author. Tel.: C354-525-4800; fax: C354-552-8911; e-mail: [email protected] 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.07.061
In accordance with the rationalizations set forth in Scheme 2 we were searching for reaction conditions that would favor an initial 1,2-addition of the keto diester to the a,bunsaturated aldehyde. In short, the best results with respect to the formation of 2 were obtained by stirring a methanol solution of the reactants for 24 h at ambient temperature in the presence of 4–5% of sodium methoxide. Using 2% NaOMe resulted in a slower reaction without improvement of yield and using 8–10% NaOMe resulted in decreased
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analytical and spectroscopic purposes. The formation of 2 could be largely suppressed by refluxing the methanol solution of dimethyl 1,3-acetonedicarboxylate and an a,bunsaturated aldehyde in the presence of 20 mol% of lithium methoxide. This afforded the bicyclo[3.3.1]nonan-3-ones 1 in 50–70% yield. It has been reported recently that the yields of 1 can be substantially increased by stirring the reactants in THF for 5–6 days at room temperature in the presence of TBAF or piperidine.10 The intermediate formation of 3 was not detected at any time during the reaction. In order to corroborate the proposed mechanism displayed in Scheme 2, the conjugated model compounds 5 and 6, depicted in Scheme 3, were synthesized according to the procedure described by Moorhoff.11 Both compounds, 5 and 6, were subjected to the reaction conditions that had been optimized for the formation of 2 (4% sodium methoxide in methanol, ambient temperature). The reactions were monitored with TLC and the conjugated starting materials had disappeared after 5–6 h of stirring. In case of 5 no identifiable products could be isolated, and that concurs with our findings that the reaction between dimethyl 1,3-acetonedicarboxylate and crotonaldehyde did not yield 2. Compound 6 yielded the cyclohexanone derivative 7 which corresponds to 2.
Scheme 2. Proposed pathways for the formation of 1 and 2.
yields. The results are summarized in Table 1. The products 2 were only sparingly soluble in methanol at ambient temperature, which simplified the purification procedure in case of a concomitant formation of 1. Methanol was used as the recrystallization solvent in order to obtain samples for Table 1. Preparation of cyclohexanones 2
Compound 2a 2b 2c 2d 2e 2f 2g 2h 2i
2j
R Ethyl Isopropyl Phenyl 4-Methoxyphenyl 2-Methoxyphenyl 4-Chlorophenyl 2-Chlorophenyl 4-Nitrophenyl 2-Nitrophenyl
Yield (%) 68 62 80 46 39 73 76 73 79
Scheme 3. The reaction of 5 and 6 with dimethyl 1,3-acetonedicarboxylate.
The stereochemistry proposed for 2a–j is displayed in Scheme 4 using 2b as an example. It is based on the observation that the signal assigned to H-6 appeared as doublet with JZ12.0 Hz, and the signal for H-4 appeared as dd with JZ12.0, 1.5 Hz. A third signal at d 3.96 was assigned to H-5 and exhibited a td with JZ12.0, 8.8 Hz. This led to the assignment of axial dispositions for all three protons. As noted above, the signal for H-4 appeared as dd with the smaller coupling constant of JZ1.5 Hz being due to a long range coupling between H-4 and the hydroxyl proton of the C-3 hydroxyl. This indicated that both the hydroxyl group and the H-4 are in axial dispositions, supporting the proposed relative configuration at C-3 depicted in Scheme 4. The hydroxyl group is probably hydrogen bonded to an oxygen atom of the ester group at
96 Scheme 4. Proposed stereochemistry of 2b with the largest groups in equatorial dispositions.
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C-2, which might provide the conformational homogeneity to allow detectable long range coupling. An analogous argument was used to define the stereochemistry of 2a–j. A long range coupling between the hydroxyl proton of the C-3 hydroxyl and H-4 was observed in all cases. Such long range coupling involving a hydroxyl proton, although presumably rare, has been described in the literature.12,13 It is worth mentioning that the hydroxyl proton of the cyclohexanone 7 did not display a long range coupling, and for that reason the relative configuration at C-3 could not be determined with NMR. Moreover, a signal at d 2.85, assigned to H-4, appeared as d with JZ5.1 Hz, suggesting an equatorial disposition for that proton. The structures of 2a–j were determined by their spectroscopic and analytical data, and furthermore the structure of 2b was confirmed unambiguously by single crystal X-ray analysis (see ORTEP drawing, Fig. 1).14 The hydroxyl group at the C-3 carbon took axial orientation, and the distance between the hydroxyl (O-2) proton and the ester oxygen (O-7) of the ester group at the C-4 carbon was ˚ , that can be attributed as a weak hydrogen bonding. 2.49 A Moreover, it is noteworthy that the crystal structure of 2b does not have the hydroxyl proton in an orientation favorable for a long range coupling with H-4.
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aldehydes in a remarkably stereoselective reaction. The protocol appears to be of general validity, representing an expedient access to moderately complex molecules from simple starting materials. Work is currently being undertaken in our laboratory to further explore the chemistry of these compounds.
3. Experimental 3.1. General information The 1H and 13C NMR spectra were recorded in CHCl3 at 250 and 62.9 MHz respectively, unless otherwise cited. Chemical shifts are reported in ppm with respect to residual CHCl3 at 7.26 downfield from tetramethylsilane, and coupling constants are given in hertz. When appropriate, 2D COSY (H/H and C/H) and DEPT experiments were employed to delineate the stereostructures. Elemental analyses were carried out at the University of Iceland, and at the University of London. Melting points were determined in open capillaries and are uncorrected. Analytical TLC was performed by using 0.25 mm coated silica gel plates with F-254 indicator. Visualization was accomplished by UV light. 3.2. General procedure To a stirred solution of sodium (0.04 mmol) and dimethyl 1,3-acetonedicarboxylate (2.2 mmol) in methanol (10 mL) was added slowly an a,b-unsaturated aldehyde (1.0 mmol in methanol, 2 mL). The mixture was stirred at room temperature until the aldehyde had disappeared, as monitored by TLC (dichloromethane–ethyl acetateZ 10:1). The crystals were filtered off, washed with methanol and dried under vacuum. If necessary, the crystals could be recrystalized from methanol. The yields in Table 1 always refer to the recrystallized products. If the filtrate was concentrated and refrigerated over night, an additional small amount of crystals could often be obtained, sometimes contaminated by the bicyclo[3.3.1]nonan-3-one 1. All new compounds reported here were characterized on the basis of complementary spectral data (1H and 13C NMR, elemental analysis). The structure of 2b was confirmed unambiguously by X-ray analysis.
Figure 1. X-ray crystal structure of 2b.
The exclusive formation of 2a–j with the hydroxyl group at C-3 in an axial disposition is of interest. In spite of the absence of the rigorous data, it might be assumed that the stereodifferentiation occurs in the ring-closure step, i.e. in the transformation of 4 to 2 in Scheme 2. This transformation takes place, arguably, in a chair-like transition state with the participating carbonyl oxygen occupying a pseudoaxial disposition leaving the pseudoequatorial position for the larger –CH2CO2Me group. In summary, a short and efficient procedure is described for the synthesis of polysubstituted cyclohexanones from dimethyl 1.3-acetonedicarboxylate and a,b-unsaturated
3.2.1. 5-(1-Butenyl)-3-hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]cyclohexanone (2a). Prepared from 2-pentenal as a white solid in 68% yield: mp 140–141 8C; 1H NMR (CDCl3) d 0.88 (t, JZ 7.5 Hz, 3H), 1.92 (qdd, JZ7.5, 6.5, 1.2 Hz, 2H), 2.71 (AB system, nAZ2.63 ppm, nBZ2.79 ppm, JABZ17.6 Hz, 2H), 3.17 (dd, JZ12.0, 1.5 Hz, 1H), 3.34 (dd, JZ12.0, 0.6 Hz, 1H), 3.59 (dt, JZ8.7, 12.0 Hz, 1H), 3.67 (s, 3H), 3.699 (s, 3H), 3.701 (s, 3H), 3.78 (s, 3H), 4.33 (d, JZ0.6 Hz, 1H), 4.47 (d, JZ1.5 Hz, 1H (D2O-exchangeable)), 5.16 (ddt, JZ 15.3, 8.7, 1.2 Hz, 1H), 5.67 (dt, JZ15.3, 6.5 Hz, 1H); 13C NMR (CDCl3) d 13.6 (q), 25.4 (t), 41.2 (d), 42.4 (t), 51.8 (q), 51.9 (q), 52.1 (q), 52.6 (q), 52.9 (d), 61.5 (d), 61.8 (d), 74.7 (s), 126.1 (d), 137.6 (d), 167.6 (s), 169.8 (s), 170.5 (s, 2C), 197.7 (s). Anal. calcd for C19H26O10: C, 55.07; H, 6.32. Found: C, 55.10; H, 6.35.
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3.2.2. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]-5-(3-methyl-1-butenyl)cyclohexanone (2b). Prepared from 4-methyl-2-pentenal as a white solid in 62% yield: mp 137–138 8C; 1H NMR (CDCl3) d 0.89 (d, JZ6.7 Hz, 6H), 2.12–2.25 (m, 1H), 2.74 (AB system, nAZ2.67 ppm, nBZ2.81 ppm, JABZ17.6 Hz, 2H), 3.18 (dd, JZ11.9, 1.5 Hz, 1H), 3.34 (dd, JZ11.5, 0.6 Hz, 1H), 3.61 (td, JZ11.9, 8.8 Hz, 1H), 3.69 (s, 3H), 3.717 (s, 3H), 3.722 (s, 3H), 3.80 (s, 3H), 4.35 (d, JZ0.6 Hz, 1H), 4.52 (d, JZ1.5 Hz, 1H (D2O-exchangeable)), 5.13 (ddd, JZ15.2, 8.8, 1.1 Hz, 1H), 5.61 (dd, JZ15.2, 7.0 Hz, 1H); 13 C NMR (CDCl3) d 22.6 (2C), 31.4, 41.7, 42.8, 52.3, 52.4, 52.6, 53.1, 53.4, 62.0, 62.2, 75.2, 124.3, 143.7, 168.0, 170.2, 170.9, 171.0, 196.2. Anal. calcd for C20H28O10: C, 56.07; H, 6.59. Found: C, 56.36; H, 6.51. 3.2.3. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]-5-(2-phenyl-1-ethenyl)cyclohexanone (2c). Prepared from cinnamaldehyde as a white solid in 80% yield: mp 179–180 8C; 1H NMR (CDCl3) d 2.77 (AB system, nAZ2.70 ppm, nBZ2.84 ppm, JABZ17.8 Hz, 2H), 3.33 (dd, JZ11.9, 1.8 Hz, 1H), 3.49 (dd, JZ12.5, 0.4 Hz, 1H), 3.66 (s, 3H), 3.71 (s, 3H), 3.73 (s, 3H), 3.82 (s, 3H), 3.88 (ddd, JZ12.5, 11.9, 9.0 Hz, 1H), 4.44 (d, JZ0.4 Hz, 1H), 4.56 (d, JZ1.8 Hz, 1H (D2O-exchangeable)), 5.92 (dd, JZ15.8, 9.0 Hz, 1H), 6.57 (d, JZ15.8 Hz, 1H), 7.24–7.32 (m, 5H); 13C NMR (CDCl3) d 41.5, 42.3, 52.0, 52.1, 52.4, 52.7, 52.9, 61.1, 61.9, 74.9, 126.3, 126.5 (2C), 128.0, 128.5 (2C), 134.5, 136.2, 167.4, 169.8, 170.2, 170.6, 197.5. Anal. calcd for C23H26O10: C, 59.74; H, 5.67. Found: C, 59.78; H, 5.68. 3.2.4. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]-5-[2-(p-methoxy)phenyl-1ethenyl]cyclohexanone (2d). Prepared from p-methoxycinnamaldehyde as a white solid in 46% yield: mp 142– 143 8C; 1H NMR (CDCl3) d 2.76 (AB system, nAZ 2.68 ppm, nBZ2.84 ppm, JABZ17.7 Hz, 2H), 3.31 (dd, JZ12.0, 1.6 Hz, 1H), 3.47 (d, JZ12.0 Hz, 1H), 3.65 (s, 3H), 3.70 (s, 3H), 3.73 (s, 3H), 3.75–3.90 (partly obscured signal, 1H), 3.79 (s, 3H), 3.81 (s, 3H), 4.42 (s, 1H), 4.54 (d, JZ1.6 Hz, 1H (D2O-exchangeable)), 5.77 (dd, JZ15.7, 9.0 Hz, 1H), 6.50 (d, JZ15.7 Hz, 1H), 6.82 (apparent d, JZ 8.7 Hz, 2H), 7.23 (apparent d, JZ8.7 Hz, 2H); 13C NMR (CDCl3) d 41.6, 42.3, 51.96, 52.04, 52.3, 52.79, 52.83, 55.3, 61.3, 61.9, 74.8, 113.9 (2C), 124.0, 127.7 (2C), 129.0, 133.8, 159.5, 167.4, 169.8, 170.3, 170.6, 197.6. Anal. calcd for C24H28O11: C, 58.53; H, 5.73. Found: C, 58.72; H, 5.70. 3.2.5. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]-5-[2-(o-methoxyphenyl)-1ethenyl]cyclohexanone (2e). Prepared from o-methoxycinnamaldehyde as a white solid in 39% yield: mp 146– 147 8C; 1H NMR (CDCl3) d 2.77 (AB system, nAZ 2.70 ppm, nBZ2.84 ppm, JABZ17.7 Hz, 2H), 3.32 (dd, JZ12.0, 1.5 Hz, 1H), 3.49 (d, JZ12.0 Hz, 1H), 3.68 (s, 3H), 3.72 (s, 3H), 3.73 (s, 3H), 3.87 (td, JZ12.0, 8.9 Hz, 1H), 3.81 (s, 3H), 3.82 (s, 3H), 4.42 (s, 1H), 4.55 (d, JZ 1.5 Hz, 1H (D2O-exchangeable)), 5.93 (dd, JZ15.8, 8.9 Hz, 1H), 6.85 (d, JZ15.8 Hz, 1H), 6.83 (d, JZ8.1 Hz, 1H), 6.89 (d, JZ8.0 Hz, 1H) 7.17–7.30 (m, 2H); 13C NMR (CDCl3) d 41.9, 42.4, 52.0, 52.1, 52.3, 52.8, 53.0, 55.4, 61.4, 61.9, 74.8, 110.8, 120.4, 125.5, 126.96, 127.05, 129.0, 129.6,
156.8, 167.4, 169.8, 170.4, 170.6, 197.7. Anal. calcd for C24H28O11: C, 58.53; H, 5.73. Found: C, 58.64; H, 5.62. 3.2.6. 5-[2-(p-Chlorophenyl)-1-ethenyl]-3-hydroxy-2,4,6 tris(methoxycarbonyl)-3 [(methoxycarbonyl)methyl]cyclohexanone (2f). Prepared from p-chlorocinnamaldehyde as a white solid in 73% yield: mp 153–154 8C; 1H NMR (acetone-d6) d 2.60 (d, JZ17.3 Hz, 1H), 2.94 (d, JZ 17.3 Hz, 1H), 3.34 (dd, JZ11.9, 1.4 Hz, 1H), 3.59 (s, 3H), 3.62 (s, 3H), 3.65 (s, 3H), 3.73 (s, 3H), 3.79 (td, JZ11.9, 8.9 Hz, 1H), 4.02 (dd, JZ11.9, 0.6 Hz, 1H), 4.52 (d, JZ 0.6 Hz, 1H), 4.61 (d, JZ1.4 Hz, 1H (D2O-exchangeable)), 6.19 (dd, JZ15.9, 8.9 Hz, 1H), 6.51 (d, JZ15.9 Hz, 1H), 7.32 (apparent d, JZ8.7 Hz, 2H), 7.40 (apparent d, JZ 8.7 Hz, 2H); 13C NMR (acetone-d6) d 41.3, 41.7, 50.8 (2C), 51.00, 51.4, 52.0, 59.7, 61.8, 74.2, 127.4 (2C), 128.0, 128.1 (2C), 131.9, 135.0, 156.5, 167.3, 168.9, 169.5, 169.7, 197.7. Anal. calcd for C23H25ClO10: C, 55.59; H, 5.07. Found: C, 55.58; H, 5.20. 3.2.7. 5-[2-(o-Chlorophenyl)-1-ethenyl]-3-hydroxy-2,4,6tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]cyclohexanone (2g). Prepared from o-chlorocinnamaldehyde as a white solid in 76% yield: mp 157–158 8C; 1H NMR (CDCl3) d 2.77 (AB system, nAZ2.71 ppm, nBZ 2.83 ppm, JABZ17.8 Hz, 2H), 3.34 (dd, JZ12.0, 1.7 Hz, 1H), 3.50 (dd, JZ12.1, 0.5 Hz, 1H), 3.71 (s, 3H), 3.73 (s, 3H), 3.75 (s, 3H), 3.82 (s, 3H), 3.93 (ddd, JZ12.1, 12.0, 9.0 Hz, 1H), 4.44 (d, JZ0.5 Hz, 1H), 4.59 (d, JZ1.7 Hz, 1H (D2O-exchangeable)), 5.89 (dd, JZ15.6, 9.0 Hz, 1H), 6.94 (d, JZ15.6 Hz, 1H), 7.14–7.21 (m, 2H), 7.28–7.36 (m, 2H); 13 C NMR (CDCl3) d 41.6, 42.3, 52.0, 52.2, 52.5, 52.7, 52.8, 61.1, 61.9, 74.9, 126.8, 127.1, 129.0, 129.5, 129.6, 131.1, 133.1, 134.7, 167.3, 169.8, 170.2, 170.6, 197.3. Anal. calcd for C23H25ClO10: C, 55.59; H, 5.07. Found: C, 55.64; H, 5.34. 3.2.8. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]-5-[2-(p-nitrophenyl)-1-ethenyl]cyclohexanone (2h). Prepared from p-nitrocinnamaldehyde as a white solid in 73% yield: mp 161–162 8C; 1H NMR (CDCl3) d 2.77 (AB system, nAZ2.70 ppm, nBZ2.84 ppm, JABZ17.8 Hz, 2H), 3.38 (dd, JZ12.0, 1.7 Hz, 1H), 3.51 (d, JZ12.2 Hz, 1H), 3.67 (s, 3H), 3.72 (s, 3H), 3.74 (s, 3H), 3.83 (s, 3H), 3.95 (ddd, JZ12.2, 12.0, 9.0 Hz, 1H), 4.46 (s, 1H), 4.59 (d, JZ1.7 Hz, 1H (D2O-exchangeable)), 6.11 (dd, JZ15.8, 9.0 Hz, 1H), 6.64 (d, JZ15.8 Hz, 1H), 7.43 (apparent d, JZ8.8 Hz, 2H), 8.16 (apparent d, JZ8.8 Hz, 2H); 13C NMR (CDCl3) d 36.2, 37.2, 46.9, 47.0, 47.1, 47.4, 47.8, 55.4, 56.8, 69.8, 116.9 (2C), 121.9 (2C), 126.1, 127.5, 137.3, 142.1, 162.1, 164.69, 164.71, 165.4, 191.9. Anal. calcd for C23H25NO12: C, 54.44; H, 4.97; N, 2.76. Found: C, 54.18; H, 5.30; N, 2.60. 3.2.9. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]-5-[2-(o-nitrophenyl)-1-ethenyl]cyclohexanone (2i). Prepared from o-nitrocinnamaldehyde as a white solid in 79% yield: mp 155–156 8C; 1H NMR (CDCl3) d 2.78 (AB system, nAZ2.72 ppm, nBZ2.83 ppm, JABZ17.8 Hz, 2H), 3.37 (dd, JZ12.0, 1.8 Hz, 1H), 3.50 (dd, JZ12.5, 0.6 Hz, 1H), 3.74 (s, 3H), 3.76 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H), 3.97 (ddd, JZ12.5, 12.0, 8.9 Hz, 1H), 4.44 (d, JZ0.6 Hz, 1H), 4.60 (d, JZ1.8 Hz, 1H
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(D2O-exchangeable)), 5.88 (dd, JZ15.5, 8.9 Hz, 1H), 7.03 (d, JZ15.5 Hz, 1H), 7.35–7.45 (m, 2H), 7.55 (td, JZ7.7, 1.2 Hz, 1H), 7.96 (dd, JZ8.1, 1.2 Hz, 1H); 13C NMR (CDCl3) d 41.7, 42.7, 52.4, 52.8, 52.9, 53.1, 53.3, 61.4, 62.3, 75.3, 125.0, 129.0, 129.6, 131.0, 132.2, 132.9, 133.7, 148.0, 167.7, 170.3, 170.5, 171.0, 197.6. Anal. calcd for C23H25NO12: C, 54.44; H, 4.97; N, 2.76. Found: C, 54.28; H, 5.24; N, 2.78.
gratefully acknowledged. The authors thank Dr. A. Mishnev for the X-ray crystallographic determination.
3.2.10. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3[(methoxycarbonyl)methyl]-5-(2-methyl-1-propenyl)cyclohexanone (2j). Prepared from 3-methyl-2-butenal as a white solid in 96% yield: mp 149–150 8C; 1H NMR (CDCl3) d 1.63 (d, JZ1.2 Hz, 3H), 1.66 (d, JZ1.2 Hz, 3H), 2.70 (AB system, nAZ2.62 ppm, nBZ2.79 ppm, JABZ17.6 Hz, 2H), 3.11 (dd, JZ11.8, 1.6 Hz, 1H), 3.28 (dd, JZ11.8, 0.6 Hz, 1H), 3.65 (s, 3H), 3.69 (s, 3H), 3.70 (s, 3H), 3.78 (s, 3H), 3.94 (td, JZ11.8, 10.3 Hz, 1H), 4.36 (d, JZ0.6 Hz, 1H), 4.53 (d, JZ1.6 Hz, 1H (D2O-exchangeable)), 4.82 (dm, JZ 10.3 Hz, 1H); 13C NMR (CDCl3) d 18.1 (q), 25.8 (q), 37.5 (d), 42.4 (t), 51.8 (q), 51.9 (q), 52.1 (q), 52.7 (q), 53.1 (d), 61.6 (d), 61.8 (d), 74.8 (s), 122.0 (d), 138.1 (s), 167.7 (s), 170.0 (s), 170.5 (s), 170.6 (s), 197.9 (s). Anal. calcd for C19H26O10: C, 55.07; H, 6.32. Found: C, 54.92; H, 6.18.
1. Niwas, S.; Kumar, S.; Bhaduri, A. P. Indian J. Chem. 1984, 23B, 599. 2. Jotterand, N.; Vogel, P. Synlett 1998, 1237. 3. Hauser, F. M.; Pogany, S. A. Synthesis 1980, 814. 4. Pietrusiewicz, K. M.; Salamon˜czyk, I. J. Org. Chem. 1988, 53, 2837. 5. Mehta, G.; Reddy, D. S. J. Chem. Soc., Perkin Trans. 1 1998, 2125. 6. Laval, G.; Audran, G.; Galano, J.-M.; Monti, H. J. Org. Chem. 2000, 65, 3551. 7. Geirsson, J. K. F.; Johannesdottir, J. F. J. Org. Chem. 1996, 61, 7320. 8. Geirsson, J. K. F. In Recent Research Developments in Organic Chemistry; Transworld Research Network: 1998; Vol. 2, p 609. 9. Williams, R. V.; Gadgil, V. R.; Vij, A.; Cook, J. M.; Kubiak, G.; Huang, Q. J. Chem. Soc., Perkin Trans. 1 1997, 1425. 10. Aoyagi, K.; Nakamura, H.; Yamamoto, Y. J. Org. Chem. 1999, 64, 4148. 11. Moorhoff, C. M. Synthesis 1997, 685. 12. Kingsbury, C. A.; Egan, R. S.; Perun, T. J. J. Org. Chem. 1970, 35, 2913. 13. Muceniece, D.; Zandersons, A.; Lusis, V. Bull. Soc. Chim. Belg. 1997, 106, 467. 14. Crystallographic data for 2b has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 168881. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: C44-1223-336033 or e-mail: [email protected]).
3.2.11. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3methyl-5-(2-methyl-1-propenyl)cyclohexanone (7). White crystals; 1H NMR (CDCl3) d 1.31 (s, 3H), 1.67 (d, JZ1.3 Hz, 3H), 1.69 (d, JZ1.3 Hz, 3H), 2.85 (d, JZ 5.1 Hz, 1H), 3.70 (s, 3H), 3.75 (s, 3H), 3.81 (s, 3H), 3.85 (ddd, JZ12.2, 9.8, 5.1 Hz, 1H), 4.01 (dd, JZ12.2, 0.6 Hz, 1H), 4.24 (d, JZ0.6 Hz, 1H), 4.57–4.64 (br s, 1H (D2Oexchangeable)), 4.76 (dm, JZ9.8 Hz, 1H); 13C NMR (CDCl3) d 18.1, 25.9, 26.6, 36.9, 51.9, 52.0, 52.5, 54.7, 58.3, 61.0 75.1, 120.8, 137.6, 168.7, 171.0, 172.8, 199.8. Analytically pure sample was not obtained. Acknowledgements Financial support from the Icelandic Science Foundation is
References and notes
Short and stereoselective synthesis of polysubstituted cyclohexanones Jon K. F. Geirsson,* Liney Arnadottir and Stefan Jonsson Department of Chemistry, Science Institute, University of Iceland, Dunhaga 3, IS-107 Reykjavik, Iceland Received 28 May 2004; revised 29 June 2004; accepted 23 July 2004 Available online 26 August 2004
Abstract—Two equivalents of dimethyl 1,3-acetonedicarboxylate reacted with a,b-unsaturated aldehydes to form novel polysubstituted cyclohexanones 2 in an efficient one-step procedure. The reactions proceeded at room temperature in the presence of catalytic amount of sodium methoxide, affording the products in high yields in a remarkably stereoselective manner. The products are of possible biological interest. q 2004 Elsevier Ltd. All rights reserved.
1. Introduction Polysubstituted cyclohexanones and cyclohexanols are widespread structural subunits in biologically active compounds, and related molecules have been used as starting materials in the synthesis of pharmaceuticals1,2 and in natural product syntheses.3–6 As part of a research programme aimed at exploring the chemical and biological properties of bicyclo[3.3.1]nonan-3-ones 1,7,8 we observed that the base-catalyzed reaction between an a,b-unsaturated aldehyde and dimethyl 1,3-acetonedicarboxylate to yield 1, suffered from the concomitant formation of the polysubstituted cyclohexanones 2 (Scheme 1). In particular, the formation of 2 was a persisting problem when the
reaction was scaled up (e.g. from 0.5 to 5–10 g). In occasional instances 2 was the only product isolated. The simplicity and the stereoselectivity of the reaction prompted us to search for reaction conditions that would maximize the yields of the cyclohexanones 2. Similar stereoselectivity has recently been observed in the condensation of dimethyl 1,3-acetonedicarboxylate with pentane2,3-dione.9 A probable pathway for the formation of 2 is outlined in Scheme 2, proposing the intermediate formation of the conjugated derivative 3 as a result of an 1,2-addition of dimethyl 1,3-acetonedicarboxylate to the a,b-unsaturated aldehyde. The intermediate 3 undergoes an 1,4-addition with a second molecule of the keto diester with an ensuing ring closure of the symmetrical intermediate 4. The proposed formation of the bicyclo[3.3.1]nonan-3-ones 1 has been incorporated in Scheme 2 for comparative purposes.10 Accordingly, products 1 are probably formed by an initial 1,4-addition of the keto diester to the unsaturated aldehyde to form a cyclohexenone derivative as an intermediate. 2. Results and discussion
Scheme 1. The preparation of 1 and 2.
Keywords: 1,3-Acetonedicarboxylate; Polysubstituted cyclohexanones; Stereoselective reaction; Claisen condensation. * Corresponding author. Tel.: C354-525-4800; fax: C354-552-8911; e-mail: [email protected] 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.07.061
In accordance with the rationalizations set forth in Scheme 2 we were searching for reaction conditions that would favor an initial 1,2-addition of the keto diester to the a,bunsaturated aldehyde. In short, the best results with respect to the formation of 2 were obtained by stirring a methanol solution of the reactants for 24 h at ambient temperature in the presence of 4–5% of sodium methoxide. Using 2% NaOMe resulted in a slower reaction without improvement of yield and using 8–10% NaOMe resulted in decreased
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analytical and spectroscopic purposes. The formation of 2 could be largely suppressed by refluxing the methanol solution of dimethyl 1,3-acetonedicarboxylate and an a,bunsaturated aldehyde in the presence of 20 mol% of lithium methoxide. This afforded the bicyclo[3.3.1]nonan-3-ones 1 in 50–70% yield. It has been reported recently that the yields of 1 can be substantially increased by stirring the reactants in THF for 5–6 days at room temperature in the presence of TBAF or piperidine.10 The intermediate formation of 3 was not detected at any time during the reaction. In order to corroborate the proposed mechanism displayed in Scheme 2, the conjugated model compounds 5 and 6, depicted in Scheme 3, were synthesized according to the procedure described by Moorhoff.11 Both compounds, 5 and 6, were subjected to the reaction conditions that had been optimized for the formation of 2 (4% sodium methoxide in methanol, ambient temperature). The reactions were monitored with TLC and the conjugated starting materials had disappeared after 5–6 h of stirring. In case of 5 no identifiable products could be isolated, and that concurs with our findings that the reaction between dimethyl 1,3-acetonedicarboxylate and crotonaldehyde did not yield 2. Compound 6 yielded the cyclohexanone derivative 7 which corresponds to 2.
Scheme 2. Proposed pathways for the formation of 1 and 2.
yields. The results are summarized in Table 1. The products 2 were only sparingly soluble in methanol at ambient temperature, which simplified the purification procedure in case of a concomitant formation of 1. Methanol was used as the recrystallization solvent in order to obtain samples for Table 1. Preparation of cyclohexanones 2
Compound 2a 2b 2c 2d 2e 2f 2g 2h 2i
2j
R Ethyl Isopropyl Phenyl 4-Methoxyphenyl 2-Methoxyphenyl 4-Chlorophenyl 2-Chlorophenyl 4-Nitrophenyl 2-Nitrophenyl
Yield (%) 68 62 80 46 39 73 76 73 79
Scheme 3. The reaction of 5 and 6 with dimethyl 1,3-acetonedicarboxylate.
The stereochemistry proposed for 2a–j is displayed in Scheme 4 using 2b as an example. It is based on the observation that the signal assigned to H-6 appeared as doublet with JZ12.0 Hz, and the signal for H-4 appeared as dd with JZ12.0, 1.5 Hz. A third signal at d 3.96 was assigned to H-5 and exhibited a td with JZ12.0, 8.8 Hz. This led to the assignment of axial dispositions for all three protons. As noted above, the signal for H-4 appeared as dd with the smaller coupling constant of JZ1.5 Hz being due to a long range coupling between H-4 and the hydroxyl proton of the C-3 hydroxyl. This indicated that both the hydroxyl group and the H-4 are in axial dispositions, supporting the proposed relative configuration at C-3 depicted in Scheme 4. The hydroxyl group is probably hydrogen bonded to an oxygen atom of the ester group at
96 Scheme 4. Proposed stereochemistry of 2b with the largest groups in equatorial dispositions.
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C-2, which might provide the conformational homogeneity to allow detectable long range coupling. An analogous argument was used to define the stereochemistry of 2a–j. A long range coupling between the hydroxyl proton of the C-3 hydroxyl and H-4 was observed in all cases. Such long range coupling involving a hydroxyl proton, although presumably rare, has been described in the literature.12,13 It is worth mentioning that the hydroxyl proton of the cyclohexanone 7 did not display a long range coupling, and for that reason the relative configuration at C-3 could not be determined with NMR. Moreover, a signal at d 2.85, assigned to H-4, appeared as d with JZ5.1 Hz, suggesting an equatorial disposition for that proton. The structures of 2a–j were determined by their spectroscopic and analytical data, and furthermore the structure of 2b was confirmed unambiguously by single crystal X-ray analysis (see ORTEP drawing, Fig. 1).14 The hydroxyl group at the C-3 carbon took axial orientation, and the distance between the hydroxyl (O-2) proton and the ester oxygen (O-7) of the ester group at the C-4 carbon was ˚ , that can be attributed as a weak hydrogen bonding. 2.49 A Moreover, it is noteworthy that the crystal structure of 2b does not have the hydroxyl proton in an orientation favorable for a long range coupling with H-4.
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aldehydes in a remarkably stereoselective reaction. The protocol appears to be of general validity, representing an expedient access to moderately complex molecules from simple starting materials. Work is currently being undertaken in our laboratory to further explore the chemistry of these compounds.
3. Experimental 3.1. General information The 1H and 13C NMR spectra were recorded in CHCl3 at 250 and 62.9 MHz respectively, unless otherwise cited. Chemical shifts are reported in ppm with respect to residual CHCl3 at 7.26 downfield from tetramethylsilane, and coupling constants are given in hertz. When appropriate, 2D COSY (H/H and C/H) and DEPT experiments were employed to delineate the stereostructures. Elemental analyses were carried out at the University of Iceland, and at the University of London. Melting points were determined in open capillaries and are uncorrected. Analytical TLC was performed by using 0.25 mm coated silica gel plates with F-254 indicator. Visualization was accomplished by UV light. 3.2. General procedure To a stirred solution of sodium (0.04 mmol) and dimethyl 1,3-acetonedicarboxylate (2.2 mmol) in methanol (10 mL) was added slowly an a,b-unsaturated aldehyde (1.0 mmol in methanol, 2 mL). The mixture was stirred at room temperature until the aldehyde had disappeared, as monitored by TLC (dichloromethane–ethyl acetateZ 10:1). The crystals were filtered off, washed with methanol and dried under vacuum. If necessary, the crystals could be recrystalized from methanol. The yields in Table 1 always refer to the recrystallized products. If the filtrate was concentrated and refrigerated over night, an additional small amount of crystals could often be obtained, sometimes contaminated by the bicyclo[3.3.1]nonan-3-one 1. All new compounds reported here were characterized on the basis of complementary spectral data (1H and 13C NMR, elemental analysis). The structure of 2b was confirmed unambiguously by X-ray analysis.
Figure 1. X-ray crystal structure of 2b.
The exclusive formation of 2a–j with the hydroxyl group at C-3 in an axial disposition is of interest. In spite of the absence of the rigorous data, it might be assumed that the stereodifferentiation occurs in the ring-closure step, i.e. in the transformation of 4 to 2 in Scheme 2. This transformation takes place, arguably, in a chair-like transition state with the participating carbonyl oxygen occupying a pseudoaxial disposition leaving the pseudoequatorial position for the larger –CH2CO2Me group. In summary, a short and efficient procedure is described for the synthesis of polysubstituted cyclohexanones from dimethyl 1.3-acetonedicarboxylate and a,b-unsaturated
3.2.1. 5-(1-Butenyl)-3-hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]cyclohexanone (2a). Prepared from 2-pentenal as a white solid in 68% yield: mp 140–141 8C; 1H NMR (CDCl3) d 0.88 (t, JZ 7.5 Hz, 3H), 1.92 (qdd, JZ7.5, 6.5, 1.2 Hz, 2H), 2.71 (AB system, nAZ2.63 ppm, nBZ2.79 ppm, JABZ17.6 Hz, 2H), 3.17 (dd, JZ12.0, 1.5 Hz, 1H), 3.34 (dd, JZ12.0, 0.6 Hz, 1H), 3.59 (dt, JZ8.7, 12.0 Hz, 1H), 3.67 (s, 3H), 3.699 (s, 3H), 3.701 (s, 3H), 3.78 (s, 3H), 4.33 (d, JZ0.6 Hz, 1H), 4.47 (d, JZ1.5 Hz, 1H (D2O-exchangeable)), 5.16 (ddt, JZ 15.3, 8.7, 1.2 Hz, 1H), 5.67 (dt, JZ15.3, 6.5 Hz, 1H); 13C NMR (CDCl3) d 13.6 (q), 25.4 (t), 41.2 (d), 42.4 (t), 51.8 (q), 51.9 (q), 52.1 (q), 52.6 (q), 52.9 (d), 61.5 (d), 61.8 (d), 74.7 (s), 126.1 (d), 137.6 (d), 167.6 (s), 169.8 (s), 170.5 (s, 2C), 197.7 (s). Anal. calcd for C19H26O10: C, 55.07; H, 6.32. Found: C, 55.10; H, 6.35.
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3.2.2. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]-5-(3-methyl-1-butenyl)cyclohexanone (2b). Prepared from 4-methyl-2-pentenal as a white solid in 62% yield: mp 137–138 8C; 1H NMR (CDCl3) d 0.89 (d, JZ6.7 Hz, 6H), 2.12–2.25 (m, 1H), 2.74 (AB system, nAZ2.67 ppm, nBZ2.81 ppm, JABZ17.6 Hz, 2H), 3.18 (dd, JZ11.9, 1.5 Hz, 1H), 3.34 (dd, JZ11.5, 0.6 Hz, 1H), 3.61 (td, JZ11.9, 8.8 Hz, 1H), 3.69 (s, 3H), 3.717 (s, 3H), 3.722 (s, 3H), 3.80 (s, 3H), 4.35 (d, JZ0.6 Hz, 1H), 4.52 (d, JZ1.5 Hz, 1H (D2O-exchangeable)), 5.13 (ddd, JZ15.2, 8.8, 1.1 Hz, 1H), 5.61 (dd, JZ15.2, 7.0 Hz, 1H); 13 C NMR (CDCl3) d 22.6 (2C), 31.4, 41.7, 42.8, 52.3, 52.4, 52.6, 53.1, 53.4, 62.0, 62.2, 75.2, 124.3, 143.7, 168.0, 170.2, 170.9, 171.0, 196.2. Anal. calcd for C20H28O10: C, 56.07; H, 6.59. Found: C, 56.36; H, 6.51. 3.2.3. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]-5-(2-phenyl-1-ethenyl)cyclohexanone (2c). Prepared from cinnamaldehyde as a white solid in 80% yield: mp 179–180 8C; 1H NMR (CDCl3) d 2.77 (AB system, nAZ2.70 ppm, nBZ2.84 ppm, JABZ17.8 Hz, 2H), 3.33 (dd, JZ11.9, 1.8 Hz, 1H), 3.49 (dd, JZ12.5, 0.4 Hz, 1H), 3.66 (s, 3H), 3.71 (s, 3H), 3.73 (s, 3H), 3.82 (s, 3H), 3.88 (ddd, JZ12.5, 11.9, 9.0 Hz, 1H), 4.44 (d, JZ0.4 Hz, 1H), 4.56 (d, JZ1.8 Hz, 1H (D2O-exchangeable)), 5.92 (dd, JZ15.8, 9.0 Hz, 1H), 6.57 (d, JZ15.8 Hz, 1H), 7.24–7.32 (m, 5H); 13C NMR (CDCl3) d 41.5, 42.3, 52.0, 52.1, 52.4, 52.7, 52.9, 61.1, 61.9, 74.9, 126.3, 126.5 (2C), 128.0, 128.5 (2C), 134.5, 136.2, 167.4, 169.8, 170.2, 170.6, 197.5. Anal. calcd for C23H26O10: C, 59.74; H, 5.67. Found: C, 59.78; H, 5.68. 3.2.4. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]-5-[2-(p-methoxy)phenyl-1ethenyl]cyclohexanone (2d). Prepared from p-methoxycinnamaldehyde as a white solid in 46% yield: mp 142– 143 8C; 1H NMR (CDCl3) d 2.76 (AB system, nAZ 2.68 ppm, nBZ2.84 ppm, JABZ17.7 Hz, 2H), 3.31 (dd, JZ12.0, 1.6 Hz, 1H), 3.47 (d, JZ12.0 Hz, 1H), 3.65 (s, 3H), 3.70 (s, 3H), 3.73 (s, 3H), 3.75–3.90 (partly obscured signal, 1H), 3.79 (s, 3H), 3.81 (s, 3H), 4.42 (s, 1H), 4.54 (d, JZ1.6 Hz, 1H (D2O-exchangeable)), 5.77 (dd, JZ15.7, 9.0 Hz, 1H), 6.50 (d, JZ15.7 Hz, 1H), 6.82 (apparent d, JZ 8.7 Hz, 2H), 7.23 (apparent d, JZ8.7 Hz, 2H); 13C NMR (CDCl3) d 41.6, 42.3, 51.96, 52.04, 52.3, 52.79, 52.83, 55.3, 61.3, 61.9, 74.8, 113.9 (2C), 124.0, 127.7 (2C), 129.0, 133.8, 159.5, 167.4, 169.8, 170.3, 170.6, 197.6. Anal. calcd for C24H28O11: C, 58.53; H, 5.73. Found: C, 58.72; H, 5.70. 3.2.5. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]-5-[2-(o-methoxyphenyl)-1ethenyl]cyclohexanone (2e). Prepared from o-methoxycinnamaldehyde as a white solid in 39% yield: mp 146– 147 8C; 1H NMR (CDCl3) d 2.77 (AB system, nAZ 2.70 ppm, nBZ2.84 ppm, JABZ17.7 Hz, 2H), 3.32 (dd, JZ12.0, 1.5 Hz, 1H), 3.49 (d, JZ12.0 Hz, 1H), 3.68 (s, 3H), 3.72 (s, 3H), 3.73 (s, 3H), 3.87 (td, JZ12.0, 8.9 Hz, 1H), 3.81 (s, 3H), 3.82 (s, 3H), 4.42 (s, 1H), 4.55 (d, JZ 1.5 Hz, 1H (D2O-exchangeable)), 5.93 (dd, JZ15.8, 8.9 Hz, 1H), 6.85 (d, JZ15.8 Hz, 1H), 6.83 (d, JZ8.1 Hz, 1H), 6.89 (d, JZ8.0 Hz, 1H) 7.17–7.30 (m, 2H); 13C NMR (CDCl3) d 41.9, 42.4, 52.0, 52.1, 52.3, 52.8, 53.0, 55.4, 61.4, 61.9, 74.8, 110.8, 120.4, 125.5, 126.96, 127.05, 129.0, 129.6,
156.8, 167.4, 169.8, 170.4, 170.6, 197.7. Anal. calcd for C24H28O11: C, 58.53; H, 5.73. Found: C, 58.64; H, 5.62. 3.2.6. 5-[2-(p-Chlorophenyl)-1-ethenyl]-3-hydroxy-2,4,6 tris(methoxycarbonyl)-3 [(methoxycarbonyl)methyl]cyclohexanone (2f). Prepared from p-chlorocinnamaldehyde as a white solid in 73% yield: mp 153–154 8C; 1H NMR (acetone-d6) d 2.60 (d, JZ17.3 Hz, 1H), 2.94 (d, JZ 17.3 Hz, 1H), 3.34 (dd, JZ11.9, 1.4 Hz, 1H), 3.59 (s, 3H), 3.62 (s, 3H), 3.65 (s, 3H), 3.73 (s, 3H), 3.79 (td, JZ11.9, 8.9 Hz, 1H), 4.02 (dd, JZ11.9, 0.6 Hz, 1H), 4.52 (d, JZ 0.6 Hz, 1H), 4.61 (d, JZ1.4 Hz, 1H (D2O-exchangeable)), 6.19 (dd, JZ15.9, 8.9 Hz, 1H), 6.51 (d, JZ15.9 Hz, 1H), 7.32 (apparent d, JZ8.7 Hz, 2H), 7.40 (apparent d, JZ 8.7 Hz, 2H); 13C NMR (acetone-d6) d 41.3, 41.7, 50.8 (2C), 51.00, 51.4, 52.0, 59.7, 61.8, 74.2, 127.4 (2C), 128.0, 128.1 (2C), 131.9, 135.0, 156.5, 167.3, 168.9, 169.5, 169.7, 197.7. Anal. calcd for C23H25ClO10: C, 55.59; H, 5.07. Found: C, 55.58; H, 5.20. 3.2.7. 5-[2-(o-Chlorophenyl)-1-ethenyl]-3-hydroxy-2,4,6tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]cyclohexanone (2g). Prepared from o-chlorocinnamaldehyde as a white solid in 76% yield: mp 157–158 8C; 1H NMR (CDCl3) d 2.77 (AB system, nAZ2.71 ppm, nBZ 2.83 ppm, JABZ17.8 Hz, 2H), 3.34 (dd, JZ12.0, 1.7 Hz, 1H), 3.50 (dd, JZ12.1, 0.5 Hz, 1H), 3.71 (s, 3H), 3.73 (s, 3H), 3.75 (s, 3H), 3.82 (s, 3H), 3.93 (ddd, JZ12.1, 12.0, 9.0 Hz, 1H), 4.44 (d, JZ0.5 Hz, 1H), 4.59 (d, JZ1.7 Hz, 1H (D2O-exchangeable)), 5.89 (dd, JZ15.6, 9.0 Hz, 1H), 6.94 (d, JZ15.6 Hz, 1H), 7.14–7.21 (m, 2H), 7.28–7.36 (m, 2H); 13 C NMR (CDCl3) d 41.6, 42.3, 52.0, 52.2, 52.5, 52.7, 52.8, 61.1, 61.9, 74.9, 126.8, 127.1, 129.0, 129.5, 129.6, 131.1, 133.1, 134.7, 167.3, 169.8, 170.2, 170.6, 197.3. Anal. calcd for C23H25ClO10: C, 55.59; H, 5.07. Found: C, 55.64; H, 5.34. 3.2.8. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]-5-[2-(p-nitrophenyl)-1-ethenyl]cyclohexanone (2h). Prepared from p-nitrocinnamaldehyde as a white solid in 73% yield: mp 161–162 8C; 1H NMR (CDCl3) d 2.77 (AB system, nAZ2.70 ppm, nBZ2.84 ppm, JABZ17.8 Hz, 2H), 3.38 (dd, JZ12.0, 1.7 Hz, 1H), 3.51 (d, JZ12.2 Hz, 1H), 3.67 (s, 3H), 3.72 (s, 3H), 3.74 (s, 3H), 3.83 (s, 3H), 3.95 (ddd, JZ12.2, 12.0, 9.0 Hz, 1H), 4.46 (s, 1H), 4.59 (d, JZ1.7 Hz, 1H (D2O-exchangeable)), 6.11 (dd, JZ15.8, 9.0 Hz, 1H), 6.64 (d, JZ15.8 Hz, 1H), 7.43 (apparent d, JZ8.8 Hz, 2H), 8.16 (apparent d, JZ8.8 Hz, 2H); 13C NMR (CDCl3) d 36.2, 37.2, 46.9, 47.0, 47.1, 47.4, 47.8, 55.4, 56.8, 69.8, 116.9 (2C), 121.9 (2C), 126.1, 127.5, 137.3, 142.1, 162.1, 164.69, 164.71, 165.4, 191.9. Anal. calcd for C23H25NO12: C, 54.44; H, 4.97; N, 2.76. Found: C, 54.18; H, 5.30; N, 2.60. 3.2.9. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3-[(methoxycarbonyl)methyl]-5-[2-(o-nitrophenyl)-1-ethenyl]cyclohexanone (2i). Prepared from o-nitrocinnamaldehyde as a white solid in 79% yield: mp 155–156 8C; 1H NMR (CDCl3) d 2.78 (AB system, nAZ2.72 ppm, nBZ2.83 ppm, JABZ17.8 Hz, 2H), 3.37 (dd, JZ12.0, 1.8 Hz, 1H), 3.50 (dd, JZ12.5, 0.6 Hz, 1H), 3.74 (s, 3H), 3.76 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H), 3.97 (ddd, JZ12.5, 12.0, 8.9 Hz, 1H), 4.44 (d, JZ0.6 Hz, 1H), 4.60 (d, JZ1.8 Hz, 1H
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(D2O-exchangeable)), 5.88 (dd, JZ15.5, 8.9 Hz, 1H), 7.03 (d, JZ15.5 Hz, 1H), 7.35–7.45 (m, 2H), 7.55 (td, JZ7.7, 1.2 Hz, 1H), 7.96 (dd, JZ8.1, 1.2 Hz, 1H); 13C NMR (CDCl3) d 41.7, 42.7, 52.4, 52.8, 52.9, 53.1, 53.3, 61.4, 62.3, 75.3, 125.0, 129.0, 129.6, 131.0, 132.2, 132.9, 133.7, 148.0, 167.7, 170.3, 170.5, 171.0, 197.6. Anal. calcd for C23H25NO12: C, 54.44; H, 4.97; N, 2.76. Found: C, 54.28; H, 5.24; N, 2.78.
gratefully acknowledged. The authors thank Dr. A. Mishnev for the X-ray crystallographic determination.
3.2.10. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3[(methoxycarbonyl)methyl]-5-(2-methyl-1-propenyl)cyclohexanone (2j). Prepared from 3-methyl-2-butenal as a white solid in 96% yield: mp 149–150 8C; 1H NMR (CDCl3) d 1.63 (d, JZ1.2 Hz, 3H), 1.66 (d, JZ1.2 Hz, 3H), 2.70 (AB system, nAZ2.62 ppm, nBZ2.79 ppm, JABZ17.6 Hz, 2H), 3.11 (dd, JZ11.8, 1.6 Hz, 1H), 3.28 (dd, JZ11.8, 0.6 Hz, 1H), 3.65 (s, 3H), 3.69 (s, 3H), 3.70 (s, 3H), 3.78 (s, 3H), 3.94 (td, JZ11.8, 10.3 Hz, 1H), 4.36 (d, JZ0.6 Hz, 1H), 4.53 (d, JZ1.6 Hz, 1H (D2O-exchangeable)), 4.82 (dm, JZ 10.3 Hz, 1H); 13C NMR (CDCl3) d 18.1 (q), 25.8 (q), 37.5 (d), 42.4 (t), 51.8 (q), 51.9 (q), 52.1 (q), 52.7 (q), 53.1 (d), 61.6 (d), 61.8 (d), 74.8 (s), 122.0 (d), 138.1 (s), 167.7 (s), 170.0 (s), 170.5 (s), 170.6 (s), 197.9 (s). Anal. calcd for C19H26O10: C, 55.07; H, 6.32. Found: C, 54.92; H, 6.18.
1. Niwas, S.; Kumar, S.; Bhaduri, A. P. Indian J. Chem. 1984, 23B, 599. 2. Jotterand, N.; Vogel, P. Synlett 1998, 1237. 3. Hauser, F. M.; Pogany, S. A. Synthesis 1980, 814. 4. Pietrusiewicz, K. M.; Salamon˜czyk, I. J. Org. Chem. 1988, 53, 2837. 5. Mehta, G.; Reddy, D. S. J. Chem. Soc., Perkin Trans. 1 1998, 2125. 6. Laval, G.; Audran, G.; Galano, J.-M.; Monti, H. J. Org. Chem. 2000, 65, 3551. 7. Geirsson, J. K. F.; Johannesdottir, J. F. J. Org. Chem. 1996, 61, 7320. 8. Geirsson, J. K. F. In Recent Research Developments in Organic Chemistry; Transworld Research Network: 1998; Vol. 2, p 609. 9. Williams, R. V.; Gadgil, V. R.; Vij, A.; Cook, J. M.; Kubiak, G.; Huang, Q. J. Chem. Soc., Perkin Trans. 1 1997, 1425. 10. Aoyagi, K.; Nakamura, H.; Yamamoto, Y. J. Org. Chem. 1999, 64, 4148. 11. Moorhoff, C. M. Synthesis 1997, 685. 12. Kingsbury, C. A.; Egan, R. S.; Perun, T. J. J. Org. Chem. 1970, 35, 2913. 13. Muceniece, D.; Zandersons, A.; Lusis, V. Bull. Soc. Chim. Belg. 1997, 106, 467. 14. Crystallographic data for 2b has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 168881. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: C44-1223-336033 or e-mail: [email protected]).
3.2.11. 3-Hydroxy-2,4,6-tris(methoxycarbonyl)-3methyl-5-(2-methyl-1-propenyl)cyclohexanone (7). White crystals; 1H NMR (CDCl3) d 1.31 (s, 3H), 1.67 (d, JZ1.3 Hz, 3H), 1.69 (d, JZ1.3 Hz, 3H), 2.85 (d, JZ 5.1 Hz, 1H), 3.70 (s, 3H), 3.75 (s, 3H), 3.81 (s, 3H), 3.85 (ddd, JZ12.2, 9.8, 5.1 Hz, 1H), 4.01 (dd, JZ12.2, 0.6 Hz, 1H), 4.24 (d, JZ0.6 Hz, 1H), 4.57–4.64 (br s, 1H (D2Oexchangeable)), 4.76 (dm, JZ9.8 Hz, 1H); 13C NMR (CDCl3) d 18.1, 25.9, 26.6, 36.9, 51.9, 52.0, 52.5, 54.7, 58.3, 61.0 75.1, 120.8, 137.6, 168.7, 171.0, 172.8, 199.8. Analytically pure sample was not obtained. Acknowledgements Financial support from the Icelandic Science Foundation is
References and notes