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Synthesis of spirane-bridged rigidified oxalkyl cyclopentadienyl ligands
Tetrahedron 61 (2005) 6829–6835
Synthesis of spirane-bridged rigidified oxalkyl cyclopentadienyl ligands Mette Lene Falck-Pedersen and Kjell Undheim* Department of Chemistry, University of Oslo, N-0315 Oslo, Norway Received 2 March 2005; revised 11 April 2005; accepted 28 April 2005
Abstract—Methods for the preparation of constrained spirane-bridged oxalkyl indenyl ligands are described. The cis,cis-a,a 0 -spirane derivatives were synthesised in several steps from spiro[4.4]nonane-1,6-dione. Carbylation was achieved by Wittig methenylation. A subsequent stereoselective hydroboration by 9-BBN followed by peroxide treatment furnished the corresponding cis-methanol. Further manipulations provided the cis-carboxylic ester, which in a double Grignard reaction with a,a 0 -dichloro-o-xylene, furnished the corresponding indenyl derivative. The final products were cis,cis-a-(2-indenyl)-a 0 -(methoxy or methoxymethyl)spiro[4.4]nonanes. q 2005 Elsevier Ltd. All rights reserved.
1. Introduction Ligands for ansa-semimetallocenes may have a coordinating heteroatom in a side-chain tethered to a cyclopentadienyl unit. The heteroatom may be an oxygen in the form of an ether or a carbonyl group,1,2 or a nitrogen in the form of an amino group.3 We herein describe some oxa derivatives. The heteroatom in the bidentate ligand influences the electronic and steric properties of the metal center by intramolecular coordination. The reversible blocking of a vacant metal site in this manner will stabilise a highly reactive center in catalytic reactions with an increase in lifetime of the catalyst system. Preparation of chiral catalyst systems, however, is hampered by the fluctuation of the cyclopentadienyl unit, which makes it difficult to obtain the rigid chiral environment required for asymmetric transformations.4 This report describes construction of some rigidified bidentate spirane-bridged ligands with an ether oxygen in the side-chain. The commonly used ethylene spacer between the cyclopentadienyl and the alkoxy units in ansa semimetallocenes has been replaced in the spiranes by a three- or four-atom bridge, but the spacing of the a,a 0 -functional groups in the rigid spirane scaffold is appropriate for metal coordination. Small ring spiranes are rigid structures with the two rings fixed in an orthogonal relationship through the common spiro atom. Substituents are rigidly fixed in corresponding configurational relationships. We describe synthesis of Keywords: Cyclopentadienyl ligands; Oxaligands; Wittig reactions; Stereoselective hydroboration; Indenylation. * Corresponding author. Tel.: C47 22 85 55 21; fax: C47 22 85 55 07; e-mail: [email protected] 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.04.075
derivatives of the spiro[4.4]nonane system as an extension of earlier studies of spirane systems.5–7 The target molecules have the cyclopentadienyl unit embedded in the indenyl system as shown for the cis,cis-disubstituted spiranes A and B in Scheme 1.
Scheme 1.
2. Results and discussion The target compounds were to have a 2-indenyl and an ether function in the adjacent a,a 0 -positions in the spirane scaffold, structures A and B in Scheme 1. The indenyl function was to be introduced by a double Grignard reaction of the intermediate carboxylic ester derivatives 6 and 14 which were prepared as shown in Schemes 2 and 3. The spirane substrate 1 in Scheme 2 was available from spiro[4.4]nonane-1,6-dione essentially as described.8 The silyl group at the secondary alcohol function in the substrate was removed with TBAF in THF. The alcohol 2 was subsequently O-methylated by MeI with NaH as base. Stereochemical control in the preparation of the cis-alcohol 4 was achieved by hydroboration with the bulky 9-BBN reagent. Adduct formation occurs at the less shielded face
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Scheme 2.
Scheme 3.
which forces the methylene side-chain carbon into a spirane cis-configuration despite the higher steric repulsion. Hydrogen peroxide treatment subsequently provided the alcohol 4 with the cis-configuration which is a requirement for coordination to a metal in a semi-metallocene arrangement. Only the cis,cis-isomer spirane 4 was detected and was isolated in 81% yield. A subsequent oxidation with sodium periodate–ruthenium trichloride gave the corresponding carboxylic acid 5 in good yield. The acid was converted into its methyl ester 6 with the silyl modified diazomethane reagent TMSCHN2. Synthesis of the second carboxylate substrate 14 for indenylation is shown in Scheme 3. The methylene substrate 1 was regio- and stereoselectively hydroborated by the bulky 9-BBN reagent, and hydroxylated by alkaline hydrogen peroxide to provide the cis-methanol 7. Attempts to O-methylate the free hydroxyl group in the methanol 7 by a reaction with methyl iodide in the presence of a base
resulted in extensive silyl group migration from the secondary alcohol to the primary alcohol group for steric reasons. The migration presumably proceeds by iodide effected desilylation followed by resilylation at the primary alcohol function under the applied reaction conditions. Removal of the silyl group protection by treatment with TBAF provided the diol 8 with a primary and a secondary alcohol function. Differentiation between these hydroxyl functions for preparation of the desired O-methylation was successful. In our best conditions for selective methylation of the primary alcohol function, methyl iodide together with sodium hydride in cold THF provided chemoselectively the desired methyl ether 9 in 78% yield. A subsequent PCC oxidation of the remaining hydroxyl function yielded the ketone 10 in 92% yield. A Wittig reaction was used to convert the ketone to the methylene derivative 11. A commercially available dry mixture of methyl(triphenyl)phosphonium bromide–sodamide in THF was used for the methenylation, yield 86%. For the hydroxylation, 9-BBN
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Scheme 4.
was used to effect stereocontrolled hydroboration. A subsequent reaction with alkaline hydrogen peroxide furnished the cis-methanol 12. Oxidation of the alcohol with the NaIO4–RuCl3$H2O reagent provided the carboxylic acid 13 in high yield. The latter was converted into its methyl ester 14 by treatment with the silyl modified diazomethane reagent TMS–diazomethane. The preparation of the targeted half-sandwich ligands 16 and 18 is shown in Scheme 4. The cyclopentadiene unit in these structures is part of the indene ring system. The key reaction for construction of the indene ring was a double Grignard reaction with the bismagnesium derivative from a,a 0 -dichloro-o-xylene. In the preparation of the bis(Grignard) reagent from a,a 0 -dichloro-o-xylene and magnesium, the recommended powdered magnesium (50 mesh) was used.9 The cyclic alcohol 15 was isolated in 49% yield. A subsequent treatment with p-toluenesulfonic acid led to water elimination and isolation of the 2-indenyl derivative 16 in 80% yield. In a similar series of reactions, the spirane ester 14 and the bis(Grignard) reagent provided the cyclised alcohol 17 in 51% yield. Water elimination effected by p-toluenesulfonic acid catalysis furnished the indenyl target 18 in 72% yield. The products 16 and 18 have the same cis,cis-configuration as was established in the
formation of their precursors 4, 7 and 12. The assigned relative configuration is also in accord with the transformations shown in Scheme 5. The methyl ether 16 in its reaction with trimethylsilyl iodide suffered demethylation and a subsequent addition of the hydroxy function to the indenyl double bond. The product was the five-membered bridged spirane 19 in high yield, 91%. Assignment of the structure was supported by NMR data. In a similar manner the methyl ether 18 provided the six-membered bridged spirane 20 in 83% yield.
3. Conclusion This report describes the preparation of cis,cis-a,a 0 substituted and constrained spirane-bridged oxalkyl– indenyl ligands in several steps from spiro[4.4]nonane1,6-dione. Carbylation was achieved by Wittig methenylation. A subsequent stereoselective hydroboration by 9-BBN followed by peroxide treatment furnished the corresponding cis-methanol which was transformed into the cis-carboxylic ester. A double Grignard reaction between the ester and a,a 0 -dichloro-o-xylene, furnished the corresponding indenyl derivative. The final products were cis,cis-a-(2-indenyl)-a 0 -(methoxy or methoxymethyl)spiro[4.4]nonanes.
4. Experimental 4.1. General 1
Scheme 5.
H NMR spectra were recorded in CDCl3 at 300 or 200 MHz with a Bruker DPX 300 or DPX 200 spectrometer. The 13C NMR spectra were recorded in CDCl3 at 75 or 50 MHz. Chemical shifts are reported in ppm using residual CHCl3 (7.24 ppm) and CDCl3 (77 ppm) as references. J-Values are given in Hz. Mass spectra under electronimpact conditions (EI) were recorded at 70 eV ionising potential; methane was used for chemical ionisation (CI). The spectra are presented as m/z (% rel. int.). IR spectra were recorded on a Nicolet Magna 550 spectrometer using liquid film or ATR (attenuated total reflectance).
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Dry THF was distilled from sodium and benzophenone under argon. Dry dichloromethane and NMP were distilled from calcium hydride. Dry DMF was distilled from BaO. 4.1.1. cis-Spiro[4.4]nonane-6-methylen-1-ol (2). A solution of cis-1-tert-butyldimethylsilyloxyspiro[4.4]nonane-6-methylene (1)8 (1.00 g, 3.76 mmol) and TBAF (1 M in THF, 7.52 mL, 7.52 mmol) in dry THF (20 mL) under argon was stirred at room temperature overnight. Water was added and the pH adjusted to 4.5 with acetic acid before the solution was extracted with EtOAc, washed with water and brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 5:1; yield 526 mg (92%) of a colourless oil. HRMS: M 152.1209. Calcd for C10H16O: 152.1201. IR (film) n cmK1 3393 (br), 2955, 2926, 2872, 2856; 1H NMR (CDCl3): d 1.4–2.4 (12H, m, CH2), 3.51 (1H, d, JZ 4.7 Hz, CH), 4.89 (1H, s, CHH), 5.10 (1H, s, CHH); 13C NMR (CDCl3): d 21.4 (CH2), 22.7 (CH2), 32.5 (CH2), 34.0 (CH2), 35.6 (CH2), 38.8 (CH2), 58.9 (C), 76.7 (CH), 107.4 (CH), 155.6 (C); MS (EI): 152 (M, 1%), 134 (41), 119 (30), 108 (86), 95 (47), 93 (60), 81 (42), 79 (47). 4.1.2. cis-1-Methoxyspiro[4.4]nonane-6-methylene (3). NaH (50% in oil, 316 mg, 6.58 mmol) was added to a solution of cis-spiro[4.4]nonane-6-methylen-1-ol (2) (500 mg, 3.29 mmol) in dry THF (30 mL) and dry DMF (10 mL) at 0 8C under argon. The solution was stirred at 0 8C for 2 h before MeI (1.401 g, 9.87 mmol) was added. The reaction mixture was stirred overnight at room temperature and evaporated. Diethyl ether was added and the solution was washed with water (4!) and brine, dried (MgSO4) and the filtrate evaporated. The crude product was purified by flash chromatography on silica gel using hexane/ EtOAc 10:1; yield: 519 mg (95%) of a colourless oil. HRMS: M 166.2635. Calcd for C11H18O: 166.2633. IR (film) n cmK1 3079, 2953, 2873, 2819, 1118; 1H NMR (CDCl3): d 1.43–1.87 (10H, m, CH2), 2.34–2.38 (2H, m, CH2), 3.20 (3H, s, OCH3), 4.89 (1H, br s, CHH]), 4.95 (1H, br s, CHH]); 13C NMR (CDCl3): d 20.8 (CH2), 22.6 (CH2), 30.3 (CH2), 34.3 (CH2), 36.9 (CH2), 39.7 (CH2), 56.7 (C), 57.4 (CH3), 88.8 (CH), 106.8 (CH2), 154.4 (C); MS (EI): m/z (%) 166 (M, 4%), 134 (100), 119 (60), 106 (36), 93 (30), 91 (48), 79 (43), 71 (67). 4.1.3. cis,cis-6-Methoxyspiro[4.4]nonane-1-methanol (4). 9-BBN (0.5 M in hexane) (7.23 mL, 3.61 mmol) was added with a syringe to a solution of cis-1-methoxyspiro[4.4]nonane-6-methylene (3) (300 mg, 1.81 mmol) in dry THF (10 mL) under argon. The solution was stirred at 80 8C for 5 h and cooled to 0 8C. NaOH (4 mL, 2 M) and H2O2 (4 mL, 35%) were added, and the solution was stirred at room temperature for 30 min. Ethyl acetate was added, the solution washed with brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 3:1; yield: 283 mg (85%) of a colourless oil. IR (film) n cmK1 3412 (br), 2954, 2874, 2820, 1110; 1H NMR (CDCl3): d 1.2–2.1 (13H, m, CH2 and CH), 3.24 (3H, s, OCH3), 3.31–3.40 (1H, m, CHH), 3.50 (1H, br s, CHO), 3.57–3.67 (1H, m, CHH); 13C NMR (CDCl3): d 20.0 (CH2), 22.1 (CH2), 28.1 (CH2), 29.5 (CH2), 36.0 (CH2), 36.5 (CH2), 48.7 (CH), 55.3 (OCH3), 57.5 (C), 65.1 (CH2O),
87.8 (CHO); MS (CI-CH4): m/z (%) 185 (MCH, 2%), 165 (5), 151 (6), 136 (12), 135 (100), 134 (8), 133 (11), 121 (6). 4.1.4. cis,cis-6-Methoxyspiro[4.4]nonane-1-carboxylic acid (5). RuCl3$H2O (9 mg, 0.04 mmol) was added to a solution of cis,cis-6-methoxyspiro[4.4]nonane-1-methanol (4) (150 mg, 0.82 mmol) and NaIO4 (567 mg, 2.65 mmol) in CCl4 (1.5 mL), MeCN (1.5 mL) and H2O (2.5 mL) at room temperature. The reaction mixture was stirred for 5 h at room temperature and CH2Cl2 added. The water layer was extracted with CH2Cl2 (3!). The combined organic solutions were dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using EtOAc; yield 125 mg (78%) of a colourless oil. HRMS: M 198.1256. Calcd for C11H18O3: 198.1250; IR (film) n cmK1 3500–2500 (br), 2959, 2873, 1732, 1698; 1H NMR (CDCl3): d 1.3–2.3 (13H, m, CH2 and CH), 3.12 (3H, s, CH3), 3.49 (1H, br s, CH), 10.6 (1H, br s, CO2H); 13C NMR (CDCl3): d 21.3 (CH2), 24.1 (CH2), 28.8 (CH2), 30.4 (CH2), 36.6 (CH2), 37.4 (CH2), 50.8 (CH), 55.8 (CH3), 59.2 (C), 87.9 (CH), 181.2 (CO); MS (EI): m/z (%) 198 (M, 35%), 180 (23), 166 (32), 121 (57), 120 (64), 111 (65), 93 (36), 71 (100). 4.1.5. Methyl cis,cis-6-methoxyspiro[4.4]nonane-1-carboxylate (6). TMSCHN 2 (2 M in hexane, 0.6 mL, 1.2 mmol) was added to a solution of cis,cis-6-methoxyspiro[4.4]nonane-1-carboxylic acid (5) (120 mg, 0.61 mmol) in hexane (3.5 mL) and MeOH (1 mL) at room temperature. The solution was stirred at room temperature for 1 h and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 8:1; yield 97 mg (76%) of a colourless oil. HRMS: M 212.1412. Calcd for C12H20O3: 212.1419. IR (film) n cmK1 2956, 2873, 2819, 1732, 1154; 1H NMR (CDCl3): d 1.2–2.0 (12H, m, CH2), 2.62 (1H, dd, JZ5.0, 7.9 Hz, CH), 3.10 (3H, s, CH3), 3.42 (1H, br s, CH), 3.61 (3H, s, CH3); 13C NMR (CDCl3): d 21.3 (CH2), 24.4 (CH2), 28.7 (CH2), 30.8 (CH2), 37.1 (CH2), 37.5 (CH2), 50.3 (CH), 51.3 (CH3), 56.1 (CH3), 59.2 (C), 87.8 (CH), 176.1 (CO); MS (EI): m/z (%) 212 (M, 45%), 180 (37), 152 (25), 151 (13), 121 (100), 120 (83), 111 (81), 93 (37). 4.1.6. cis,cis-6-tert-Butyldimethylsilyloxyspiro[4.4]nonane-1-methanol (7). 9-BBN (0.5 M in hexane) (13 mL, 6.54 mmol) was added with a syringe to a solution of cis-1-tert-butyldimethylsilyloxyspiro[4.4]nonane-6methylene9 (1) (870 mg, 3.27 mmol) in dry THF (50 mL) under argon. The solution was stirred at 70 8C for 4 h and cooled to 0 8C. NaOH (6 mL, 2 M) and H2O2 (6 mL, 35%) were added. The resultant solution was stirred at room temperature for 30 min. Ethyl acetate was added and the solution was washed with brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 3:1; yield: 750 mg (81%) of a colourless oil. HRMS: M 227.1477. Calcd for C12H23O2Si (MKtBu): 227.1467. IR (film) n cmK1 3381 (br), 2954, 2930, 2860, 1251; 1H NMR (CDCl3): d 0.10 (3H, s, CH-3), 0.11 (3H, s, CH3), 0.90 (9H, s, CH3), 1.2–2.0 (13H, m, CH2 and CH), 3.33–3.44 (1H, m, CHH), 3.60–3.72 (1H, m, CHH), 3.97 (1H, t, JZ6.3 Hz, CH); 13C NMR (CDCl3): d K4.0 (CH3), K3.4 (CH3), 18.7 (C), 19.1 (CH2), 22.1 (CH2), 26.4 (CH3), 28.5 (CH2), 32.8
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(CH2), 35.1 (CH2), 36.8 (CH2), 47.8 (CH), 56.4 (C), 64.7 (CH2), 79.0 (CH); MS (CI-CH4) m/z (%): 285 (MCH, 7%), 153 (6), 151 (5), 136 (12), 135 (100), 133 (6), 93 (3), 75 (7). 4.1.7. cis,cis-6-Hydroxyspiro[4.4]nonane-1-methanol (8). A solution of cis,cis-6-tert-butyldimethylsilyloxyspiro[4.4]nonane-1-methanol (7) (186 mg, 0.65 mmol) and TBAF (1 M in THF, 1.3 mL, 1.3 mmol) in dry THF (10 mL) under argon was stirred overnight at room temperature. Water was added to the solution and the pH adjusted to 4.5 with acetic acid. The solution was extracted with EtOAc, washed with water and brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 1:4; yield 102 mg (92%) of a colourless oil. (Found C, 70.29; H, 10.37. Calcd for C10H18O2: C, 70.55; H, 10.66%). HRMS: M 170.1302. Calcd for C10H18O2: 170.1307; IR (film) n cmK1 3285 (br), 2953, 2874, 1443, 1049; 1H NMR (CDCl3): d 1.2–2.1 (13H, m, CH2 and CH), 3.46 (1H, dd, JZ3.2, 10.6 Hz, CHH), 3.66 (1 H, t, JZ10.6 Hz, CHH), 4.00 (1H, t, JZ3.5 Hz, CH), 4.5 (2 H, br s, OH); 13C NMR (CDCl3): d 20.5 (CH2), 22.0 (CH2), 29.1 (CH2), 33.3 (CH2), 33.8 (CH2), 35.6 (CH2), 48.2 (CH), 59.1 (C), 65.4 (CH2), 78.3 (CH); MS (EI) m/z (%):170 (M, 1%), 134 (52), 122 (43), 108 (100), 95 (49), 93 (67), 81 (58), 79 (66). 4.1.8. cis,cis-6-Methoxymethylspiro[4.4]nonane-1-ol (9). NaH (60% in oil, 55 mg, 1.37 mmol) was added to a solution of cis,cis-6-hydroxyspiro[4.4]nonane-1-methanol (8) (233 mg, 1.37 mmol) in dry THF (10 mL) under argon at 0 8C. The suspension was stirred at 0 8C for 2 h before MeI (234 mg, 1.64 mmol) was added. The solution was stirred at 0 8C for 2 h, evaporated and the crude product was purified by flash chromatography on silica gel using hexane/EtOAc 5:1; yield 197 mg (78%) of a colourless oil. IR (film) n cmK1 3486 (br), 2954, 2876, 1117, 1099; 1H NMR (CDCl3): d 1.2– 2.0 (13H, m, CH2 and CH), 3.15–3.38 (2H, m, CH2), 3.30 (3H, s, CH3), 3.80 (1H, br s, CHO), 4.15 (1H, s, OH); 13C NMR (CDCl3): d 19.8 (CH2), 21.1 (CH2), 28.3 (CH2), 32.1 (CH2), 32.3 (CH2), 34.7 (CH2), 45.5 (CH), 58.7 (CH3), 59.3 (C), 76.1 (CH2), 78.0 (CH); MS (EI): m/z (%) 184 (M, 3%), 152 (30), 134 (100), 119 (26), 108 (95), 93 (58), 81 (62), 79 (69). 4.1.9. cis-6-Methoxymethylspiro[4.4]nonan-1-one (10). cis,cis-6-Methoxymethylspiro[4.4]nonane-1-ol (9) (197 mg, 1.07 mmol) and PCC (462 mg, 2.14 mmol) were stirred in dry CH2Cl2 (10 mL) under argon at room temperature overnight. A small amount of silica gel was added to the solution and the mixture was evaporated to dryness. The residue was added on top of a silica gel column and the product isolated after flash chromatography using hexane/EtOAc 10:1; yield: 180 mg (92%) of a colourless oil. HRMS: M 182.1313. Calcd for C11H18O2: 182.1307; IR (film) n cmK1 2951, 2869, 1731, 1450, 1098; 1H NMR (CDCl3): d 1.2–2.3 (13H, m, CH2 and CH), 3.05–3.26 (2H, m, CH2O), 3.12 (3H, s, CH3O); 13C NMR (CDCl3): d 20.3 (CH2), 25.7 (CH2), 30.3 (CH2), 38.0 (CH2), 39.4 (CH2), 40.5 (CH2), 50.3 (CH), 56.9 (C), 58.3 (CH3), 73.5 (CH2), 220.8 (CO); MS (EI): m/z (%) 182 (M, 8%), 150 (71), 122 (34), 121 (29), 94 (45), 93 (42), 84 (46), 45 (100). 4.1.10. cis-1-Methoxymethylspiro[4.4]nonane-6-methylene (11). A dry mixture of methyltriphenylphosphonium bromide and sodamide (2.25 g, 5.49 mmol) was dissolved in
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dry THF (10 mL) under argon and the medium stirred at room temperature for 15 min before cis-6-methoxymethylspiro[4.4]nonan-1-one (10) (500 mg, 2.75 mmol) in dry THF (10 mL) was added with a syringe. The solution was stirred at 70 8C overnight. A small amount of silica gel was added to the solution and the mixture evaporated to dryness. The residue was added on top of a silica gel column and the product isolated after flash chromatography using hexane/ EtOAc 10:1; yield: 425 mg (86%) of a colourless oil. (Found: C, 80.11; H, 11.05. Calcd for C12H20O: C, 79.94; H, 11.18%). HRMS: M 180.1517. Calcd for C12H20O: 180.1514. IR (film) n cmK1 3071, 2950, 2871, 1646, 1101; 1H NMR (CDCl3): d 1.5–1.9 (11H, m, CH2 and CH), 2.32–2.34 (2H, m, CH2), 3.06–3.24 (2H, m, CH2), 3.26 (3H, s, CH3), 4.67 (1H, br s, CHH]), 4.90 (1H, br s, CHH]); 13 C NMR (CDCl3): d 22.6 (CH2), 23.5 (CH2), 29.9 (CH2), 34.4 (CH2), 40.0 (CH2), 42.4 (CH2), 47.6 (CH), 54.9 (C), 58.6 (CH3), 75.7 (CH2), 105.0 (CH2), 156.8 (C); MS (EI): m/z (%) 180 (M, 2%), 149 (37), 148 (25), 135 (100), 133 (20), 107 (14), 105 (20), 93 (27). 4.1.11. cis,cis-6-Methoxymethylspiro[4.4]nonane-1methanol (12). 9-BBN (0.5 M in hexane) (10.22 mL, 5.11 mmol) was added with syringe to a solution of cis-1methoxymethylspiro[4.4]nonane-6-methylene (11) (460 mg, 2.56 mmol) in dry THF (30 mL) under argon. The solution was stirred at 80 8C for 5 h and cooled to 0 8C. NaOH (5 mL, 2 M) and H2O2 (5 mL, 35%) were added and the solution was stirred at room temperature for 30 min. Diethyl ether was added and the solution was washed with brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 1:2; yield: 382 mg (75%) of a colourless oil. HRMS: (M -H2O) 180.1522. Calcd for C12H20O: 180.1514; IR (film) n cmK1 3374 (br), 2952, 2876, 1452, 1105; 1H NMR (CDCl3): d 1.2–1.8 (14H, m, CH2 and CH), 2.83 (1H, br s, OH), 2.96–3.02 (1H, m, CHH), 3.15–3.24 (1H, m, CHH), 3.23 (3H, s, OCH3), 3.38–3.41 (1H, m, CHH), 3.63– 3.67 (1H, m, CHH); 13C NMR (CDCl3): d 19.2 (2!CH2), 27.2 (CH2), 27.6 (CH2), 35.4 (CH2), 35.5 (CH2), 45.2 (CH), 48.1 (CH), 54.6 (C), 58.5 (CH3), 62.9 (CH2), 73.7 (CH2); MS (CI-CH4): m/z (%) 199 (MCH, 94%), 181 (15), 150 (12), 149 (100), 148 (24), 136 (18), 135 (30), 93 (10). 4.1.12. cis,cis-6-Methoxymethylspiro[4.4]nonane-1-carboxylic acid (13). A mixture of cis-6-methoxymethylspiro[4.4]nonane-1-methanol (12) (433 mg, 2.19 mmol) and NaIO4 (1.521 g, 7.10 mmol) in CCl4 (4 mL), MeCN (4 mL) and H2O (6 mL) was stirred at room temperature for 5 h. CH2Cl2 was added, the layers separated and the water layer extracted with CH2Cl2 (3!). The combined organic solutions were dried (MgSO4), evaporated and the crude product purified by filtration through a silica gel plug using EtOAc; yield 390 mg (84%) of a colourless oil. The crude acid product was used as such in the subsequent synthesis of its methyl ester. HRMS: M 212.1415: calcd for C12H20O3: 212.1412. 1H NMR (CDCl3): d 1.4–2.0 (12H, m, CH2), 2.15–2.22 (1H, m, CH), 2.53–2.56 (1H, m, CH), 3.10–3.17 (1H, m, CHH), 3.25 (3H, s, CH3), 3.33–3.38 (1H, m, CHH), 11.00 (1H, br s, CO2H); 13C NMR (CDCl3): d 20.2 (CH2), 20.7 (CH2), 27.5 (CH2), 29.8 (CH2), 35.8 (CH2), 36.4 (CH2), 45.2 (CH), 50.7 (CH), 56.0 (C), 58.3 (CH3), 74.3 (CH2),
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181.6 (CO); MS (EI): m/z (%) 212 (M, 4%), 180 (41), 167 (23), 166 (42), 135 (37), 121 (100), 120 (28), 93 (31). 4.1.13. Methyl cis,cis-6-methoxymethylspiro[4.4]nonane-1-carboxylate (14). TMSCHN2 (2 M in hexane, 1.84 mL, 3.68 mmol) was added to a solution of the crude acid product from above cis,cis-6-methoxymethylspiro[4.4]nonane-1-carboxylic acid (13) (390 mg, 1.84 mmol) in hexane (14 mL) and MeOH (4 mL) at room temperature. The solution was stirred for 1 h at room temperature and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 5:1; yield 201 mg (48%) of a colourless oil. HRMS: M 226.1550: calcd for C13H22O3: 226.1569; IR (film) n cmK1 2951, 2874, 1735, 1434, 1362; 1H NMR (CDCl3): d 1.3–1.8 (12H, m, CH2), 2.07–2.13 (1H, m, CH), 2.47–2.50 (1H, m, CH), 3.02 (1H, dd, JZ7.7, 9.4 Hz, CHH), 3.17 (3H, s, CH3), 3.17–3.23 (1H, m, CHH), 3.56 (3H, s, CH3); 13C NMR (CDCl3): d 20.3 (CH2), 20.8 (CH2), 27.6 (CH2), 29.8 (CH2), 36.2 (CH2), 36.6 (CH2), 45.4 (CH), 50.5 (CH), 50.9 (CH3), 56.0 (C), 58.4 (CH3), 74.3 (CH2), 176.3 (CO); MS (EI): m/z (%) 226 (M, 4%), 209 (31), 208 (34), 180 (77), 148 (40), 135 (33), 121 (100), 120 (42). 4.1.14. cis,cis-1-Methoxy-6-(2-hydroxyindan-2-yl)spiro[4.4]nonane (15). 1,2-Dibromoethane (one drop) was added to a suspension of Mg (124 mg, 5.10 mmol) in dry THF (2 mL) under argon and the mixture heated briefly to initiate a vigorous reaction. The THF was removed under vacuum after 15 min and fresh THF (3 mL) was added. A solution of a,a 0 -dichloro-o-xylene (226 mg, 1.29 mmol) in THF (20 mL) was added slowly to the Mg suspension at room temperature over 1 h. The reaction was stirred at room temperature for 12 h, cooled to K78 8C, and a solution of methyl cis,cis-6-methoxyspiro[4.4]nonane-1-carboxylate (6) (80 mg, 0.38 mmol) in THF (6 mL) added over 20 min. The mixture was allowed to warm to room temperature. After 4 h at room temperature, water (5 mL) was added slowly, the mixture filtered, and the THF was removed under vacuum. EtOAc and aqueous 1 M NH4Cl were added to the residue and the two layers were separated. The organic solution was washed with water (2!) and brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 5:1; yield 53 mg (49%) of a colourless oil. HRMS: M 286.1943. Calcd for C19H26O2: 286.1933. IR (film) (cmK1 3387 (br), 3020, 2951, 2873, 1059; 1H NMR (CDCl3): d 1.3–2.3 (13H, m, CH2 and CH), 2.97–3.17 (4H, m, CH2), 3.30 (3H, s, OCH3), 3.60 (1H, d, JZ3.6 Hz, CH), 5.55 (1H, s, OH), 7.10–7.23 (4H, m, Ph); 13C NMR (CDCl3): d 19.3 (CH2), 21.4 (CH2), 27.7 (CH2), 28.7 (CH2), 36.8 (CH2)n, 39.4 (CH2), 46.1 (CH2), 48.1 (CH2), 55.0 (CH), 55.4 (CH3), 57.7 (C), 82.5 (CH), 86.6 (C), 124.46 (CH), 124.56 (CH), 126.02 (CH), 126.14 (CH), 142.0 (C), 142.2 (C); MS (EI): m/z (%) 286 (M, 10%), 181 (50), 149 (13), 132 (29), 122 (46), 121 (100), 105 (28), 104 (31). 4.1.15. cis,cis-1-Methoxy-6-(2-indenyl)spiro[4.4]nonane (16). cis,cis-1-Methoxy-6-(2-hydroxyindan-2-yl)spiro[4.4]nonane (15) (53 mg, 0.19 mmol) and p-TsOH$H2O (18 mg, 0.093 mmol) were dissolved in CH2Cl2 (3 mL) and the solution stirred at room temperature for 2 h. The solvent was evaporated and the crude product was purified by flash
chromatography on silica gel using hexane/EtOAc 15:1; yield 40 mg (80%) of a colourless oil. (Found C, 85.29; H, 9.22. Calcd for C19H24O: C, 85.03; H, 9.01%). HRMS: M 268.1838. Calcd for C19H24O: 268.1827. IR (film) n cmK1 3387 (br), 3054, 3017, 2956, 2873, 1461; 1H NMR (CDCl3): d 1.4–2.0 (13H, m, CH2 and CH), 3.00 (3H, s, CH3), 3.17 (1H, d, JZ3.8 Hz, CH), 3.32–3.57 (2H, m, CH2), 6.51 (1H, s, CH), 7.09–7.39 (4H, m, Ph); 13C NMR (CDCl3): d 20.4 (CH2), 22.0 (CH2), 28.0 (CH2), 32.0 (CH2), 34.2 (CH2), 35.9 (CH2), 42.5 (CH2), 47.5 (CH), 55.6 (CH3), 60.2 (C), 88.2 (CH), 119.7 (CH), 123.1 (CH), 123.2 (CH), 125.4 (CH), 126.0 (CH), 143.1 (C), 146.0 (C), 155.2 (C); MS (EI): m/z (%) 268 (M, 59%), 236 (100), 155 (81), 142 (76), 141 (36), 129 (30), 128 (33), 115 (33). 4.1.16. cis,cis-6-Methoxymethyl-1-(2-hydroxyindan-2yl)spiro[4.4]nonane (17). 1,2-Dibromoethane (one drop) was added to a suspension of Mg (86 mg, 3.54 mmol) in dry THF (2 mL) under argon and the mixture heated briefly to initiate a vigorous reaction. The THF was removed under vacuum after 15 min and fresh THF (3 mL) was added. A solution of a,a 0 -dichloro-o-xylene (308 mg, 1.76 mmol) in THF (30 mL) was added slowly to the Mg suspension at ambient temperature over 1 h. The reaction was stirred for an additional 12 h, cooled to K78 8C, and a solution of methyl cis,cis-6-methoxymethylspiro[4.4]nona-1-carboxylate (14) (200 mg, 0.88 mmol) in THF (15 mL) was added over 20 min. The mixture was allowed to warm to ambient temperature and kept at this temperature for 3.5 h before water (5 mL) was added slowly. The mixture was filtered, the THF removed at reduced pressure, EtOAc and aqueous 1 M NH4Cl added, and the two layers separated. The organic solution was washed with water (2!) and brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/ EtOAc 5:1; yield 135 mg (51%) of a colourless oil. (Found C, 80.13; H, 9.59. Calcd for C20H28O2: C, 79.96; H, 9.39%). HRMS: M 300.2077. Calcd for C20H28O2: 300.2089. IR (film) n cmK1 3408 (br), 2954, 2877, 1735, 1459; 1H NMR (CDCl3): d 1.5–1.7 (12H, m, CH2), 2.24–2.26 (1H, m, CH), 2.40–2.42 (1H, m, CH), 2.8–3.1 (4H, m, CH2), 3.22–3.37 (2H, m, CH2), 3.32 (3H, s, CH3), 4.12 (1H, s, OH), 7.11– 7.24 (4H, m, Ph); 13C NMR (CDCl3): d 18.9 (CH2), 20.1 (CH2), 28.2 (CH2), 28.8 (CH2), 35.8 (2!CH2), 44.9 (CH2), 45.4 (CH2), 49.3 (CH), 52.5 (CH), 56.5 (C), 58.5 (CH3), 75.5 (CH2), 84.8 (C), 124.8 (2!CH), 126.09 (CH), 126.11 (CH), 141.1 (C), 142.7 (C); MS (EI): m/z (%) 300 (M, 4%), 282 (32), 268 (10), 250 (21), 195 (57), 163 (23), 136 (31), 135 (100). 4.1.17. cis,cis-6-Methoxymethyl-1-(2-indenyl)spiro[4.4]nonane (18). cis,cis-6-Methoxymethyl-1-(2-hydroxyindan2-yl)spiro[4.4]nonane (17) (135 mg, 0.45 mmol) and p-TsOH$H2O (43 mg, 0.22 mmol) were dissolved in CH2Cl2 (5 mL) and stirred at room temperature for 5 h. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel using hexane/ EtOAc 15:1; yield 91 mg (72%) of a colourless oil. (Found C, 85.31; H, 9.11. Calcd for C20H26O: C, 85.06; H, 9.28%). HRMS: M 282.1981. Calcd for C20H26O: 282.1984; IR (film) n cmK1 2951, 2922, 2873, 1461, 1110; 1H NMR (CDCl3): d 1.4–2.1 (13H, m, CH2 and CH), 2.82 (1H, d, JZ 7.1 Hz, CH), 3.04 (1H, t, JZ9.7 Hz, CHHO), 3.13 (3H, s,
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CH3), 3.30–3.41 (3H, m, CH2 and CHHO), 6.55 (1H, s, CH), 7.11–7.40 (4H, m, Ph); 13C NMR (CDCl3): d 20.3 (CH2), 20.7 (CH2), 27.4 (CH2), 32.9 (CH2), 37.2 (CH2), 38.0 (CH2), 41.4 (CH2), 46.2 (CH), 48.5 (CH), 56.8 (C), 58.5 (CH3), 73.2 (CH2), 120.0 (CH), 123.2 (CH), 123.6 (CH), 126.2 (CH), 126.4 (CH), 142.8 (C), 145.5 (C), 153.4 (C); MS (EI): m/z (%) 282 (M, 17%), 250 (64), 169 (38), 168 (32), 155 (76), 142 (100), 141 (45), 129 (38). 4.1.18. cis,cis-1,6-[1-Oxaethano-2-spiro(2,3-dihydroinden-2-yl)]spiro[4.4]nonane (19). TMSI (52 mg, 0.26 mmol) was added with a syringe to a solution of cis,cis-1-methoxy-6-(2-indenyl)spiro[4.4]nonane (16) (35 mg, 0.13 mmol) in dry CH2Cl2 (5 mL) under argon at room temperature. The solution was stirred at this temperature for 2 h and evaporated. The crude product was purified by flash chromatography using hexane/EtOAc 15:1; yield 30 mg (91%) of a colourless oil. (Found C, 85.15; H, 8.58.Calcd for C18H22O: C, 84.99; H, 8.72%). HRMS: M 254.1664.Calcd for C18H22O: 254.1671; IR (film) n cmK1 3021, 2946, 2863, 1483, 1041; 1H NMR (CDCl3): d 1.45–1.88 (12H, m, CH2), 2.38–2.40 (1H, m, CH), 2.86–3.09 (4H, m, CH2), 4.01 (1H, d, JZ4.6 Hz, CH), 7.10–7.21 (4H, m, Ph); 13C NMR (CDCl3): d 24.8 (CH2), 27.3 (CH2), 29.2 (CH2), 33.6 (CH2), 38.9 (CH2), 39.4 (CH2), 41.9 (CH2), 46.6 (CH2), 60.1 (CH), 63.1 (C), 89.4 (CH), 94.5 (C), 124.3 (CH), 124.7 (CH), 126.2 (CH), 126.3 (CH), 141.1 (C), 142.1 (C); MS (EI): m/z (%): 254 (M, 100%), 225 (25), 149 (20), 132 (45), 121 (19), 115 (12), 105 (19), 104 (25). 4.1.19. cis,cis-1,6-[2-Oxapropano-1-spiro(2,3-dihydroinden-2-yl)]spiro[4.4]nonane (20). TMSI (92 mg, 0.46 mmol) was added with a syringe to a solution of cis,cis-6-methoxymethyl-1-(2-indenyl)spiro[4.4]nonane (18) (65 mg, 0.23 mmol) in dry CH2Cl2 (5 mL) under argon at room temperature. The solution was stirred at this temperature for 3 h and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/
6835
EtOAc 20:1; yield 51 mg (83%) of a colourless oil. HRMS: M 268.1830.Calcd for C19H24O: 268.1827. IR (film) n cmK1 3020, 2943, 2860, 1485, 1079; 1H NMR (CDCl3): d 1.4–2.0 (12H, m, CH2), 2.24–2.32 (1H, m, CH), 2.64–2.87 (2H, m, CH2), 2.97–3.11 (3H, m, CH2 and CH), 3.37 (1H, dd, JZ 8.9, 6.5 Hz, CHH), 3.89 (1H, dd, JZ8.8, 7.7 Hz, CHH), 6.89–7.19 (4H, m, Ph); 13C NMR (CDCl3): d 22.9 (CH2), 28.1 (CH2), 31.1 (CH2), 34.3 (CH2), 34.8 (CH2), 35.2 (CH2), 36.1 (CH2), 42.1 (CH2), 43.9 (CH), 54.7 (CH), 64.0 (C), 71.7 (CH2), 96.7 (C), 124.2 (CH), 124.4 (CH), 126.0 (CH), 126.1 (CH), 142.7 (C), 143.7 (C); MS (EI): m/z (%): 268 (M, 100%), 155 (22), 152 (30), 151 (88), 145 (20), 142 (30), 116 (39), 115 (31).
References and notes 1. Van der Zeijden, A. A. H.; Mattheis, C.; Fro¨hlich, R. Organometallics. 1997, 16, 2651–2658. 2. Miyazawa, A.; Kase, T.; Hashimoto, K.; Choi, J.-c.; Sakakura, T.; Ji-zhu, J. Macromolecules 2004, 37, 8840–8845. 3. (a) McKnight, A. L.; Waymouth, R. M. Chem. Rev. 1998, 98, 2587–2598. (b) Van Leusen, D.; Beetstra, D. J.; Hessen, B.; Teuben, J. H. Organometallics 2000, 19, 4084–4089. 4. van der Zeijden, A. A. A.; Mattheis, C. J. Organomet. Chem. 1999, 584, 274–285. 5. Aburel, P. S.; Rømming, C.; Ma, K.; Undheim, K. J. Chem. Soc., Perkin Trans. 1 2001, 1458–1472. 6. Falck-Pedersen, M.-L.; Undheim, K. Tetrahedron 1999, 55, 8525–8538. 7. Rolandsgard, M.; Baldawi, S.; Sirbu, D.; Bjørnstad, V.; Rømming, C.; Undheim, K. Tetrahedron 2005, 61, 4129–4140. 8. Yuan, P.; Plourde, R.; Shoemaker, M. R.; Moore, C. L.; Hansen, D. E. J. Org. Chem. 1995, 60, 5360–5364. 9. Ellis, W. W.; Hollis, T. K.; Odenkirk, W.; Whelan, J.; Ostrander, R.; Rheingold, A. L.; Bosnich, B. Organometallics 1993, 12, 4391–4401.
Synthesis of spirane-bridged rigidified oxalkyl cyclopentadienyl ligands Mette Lene Falck-Pedersen and Kjell Undheim* Department of Chemistry, University of Oslo, N-0315 Oslo, Norway Received 2 March 2005; revised 11 April 2005; accepted 28 April 2005
Abstract—Methods for the preparation of constrained spirane-bridged oxalkyl indenyl ligands are described. The cis,cis-a,a 0 -spirane derivatives were synthesised in several steps from spiro[4.4]nonane-1,6-dione. Carbylation was achieved by Wittig methenylation. A subsequent stereoselective hydroboration by 9-BBN followed by peroxide treatment furnished the corresponding cis-methanol. Further manipulations provided the cis-carboxylic ester, which in a double Grignard reaction with a,a 0 -dichloro-o-xylene, furnished the corresponding indenyl derivative. The final products were cis,cis-a-(2-indenyl)-a 0 -(methoxy or methoxymethyl)spiro[4.4]nonanes. q 2005 Elsevier Ltd. All rights reserved.
1. Introduction Ligands for ansa-semimetallocenes may have a coordinating heteroatom in a side-chain tethered to a cyclopentadienyl unit. The heteroatom may be an oxygen in the form of an ether or a carbonyl group,1,2 or a nitrogen in the form of an amino group.3 We herein describe some oxa derivatives. The heteroatom in the bidentate ligand influences the electronic and steric properties of the metal center by intramolecular coordination. The reversible blocking of a vacant metal site in this manner will stabilise a highly reactive center in catalytic reactions with an increase in lifetime of the catalyst system. Preparation of chiral catalyst systems, however, is hampered by the fluctuation of the cyclopentadienyl unit, which makes it difficult to obtain the rigid chiral environment required for asymmetric transformations.4 This report describes construction of some rigidified bidentate spirane-bridged ligands with an ether oxygen in the side-chain. The commonly used ethylene spacer between the cyclopentadienyl and the alkoxy units in ansa semimetallocenes has been replaced in the spiranes by a three- or four-atom bridge, but the spacing of the a,a 0 -functional groups in the rigid spirane scaffold is appropriate for metal coordination. Small ring spiranes are rigid structures with the two rings fixed in an orthogonal relationship through the common spiro atom. Substituents are rigidly fixed in corresponding configurational relationships. We describe synthesis of Keywords: Cyclopentadienyl ligands; Oxaligands; Wittig reactions; Stereoselective hydroboration; Indenylation. * Corresponding author. Tel.: C47 22 85 55 21; fax: C47 22 85 55 07; e-mail: [email protected] 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.04.075
derivatives of the spiro[4.4]nonane system as an extension of earlier studies of spirane systems.5–7 The target molecules have the cyclopentadienyl unit embedded in the indenyl system as shown for the cis,cis-disubstituted spiranes A and B in Scheme 1.
Scheme 1.
2. Results and discussion The target compounds were to have a 2-indenyl and an ether function in the adjacent a,a 0 -positions in the spirane scaffold, structures A and B in Scheme 1. The indenyl function was to be introduced by a double Grignard reaction of the intermediate carboxylic ester derivatives 6 and 14 which were prepared as shown in Schemes 2 and 3. The spirane substrate 1 in Scheme 2 was available from spiro[4.4]nonane-1,6-dione essentially as described.8 The silyl group at the secondary alcohol function in the substrate was removed with TBAF in THF. The alcohol 2 was subsequently O-methylated by MeI with NaH as base. Stereochemical control in the preparation of the cis-alcohol 4 was achieved by hydroboration with the bulky 9-BBN reagent. Adduct formation occurs at the less shielded face
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Scheme 2.
Scheme 3.
which forces the methylene side-chain carbon into a spirane cis-configuration despite the higher steric repulsion. Hydrogen peroxide treatment subsequently provided the alcohol 4 with the cis-configuration which is a requirement for coordination to a metal in a semi-metallocene arrangement. Only the cis,cis-isomer spirane 4 was detected and was isolated in 81% yield. A subsequent oxidation with sodium periodate–ruthenium trichloride gave the corresponding carboxylic acid 5 in good yield. The acid was converted into its methyl ester 6 with the silyl modified diazomethane reagent TMSCHN2. Synthesis of the second carboxylate substrate 14 for indenylation is shown in Scheme 3. The methylene substrate 1 was regio- and stereoselectively hydroborated by the bulky 9-BBN reagent, and hydroxylated by alkaline hydrogen peroxide to provide the cis-methanol 7. Attempts to O-methylate the free hydroxyl group in the methanol 7 by a reaction with methyl iodide in the presence of a base
resulted in extensive silyl group migration from the secondary alcohol to the primary alcohol group for steric reasons. The migration presumably proceeds by iodide effected desilylation followed by resilylation at the primary alcohol function under the applied reaction conditions. Removal of the silyl group protection by treatment with TBAF provided the diol 8 with a primary and a secondary alcohol function. Differentiation between these hydroxyl functions for preparation of the desired O-methylation was successful. In our best conditions for selective methylation of the primary alcohol function, methyl iodide together with sodium hydride in cold THF provided chemoselectively the desired methyl ether 9 in 78% yield. A subsequent PCC oxidation of the remaining hydroxyl function yielded the ketone 10 in 92% yield. A Wittig reaction was used to convert the ketone to the methylene derivative 11. A commercially available dry mixture of methyl(triphenyl)phosphonium bromide–sodamide in THF was used for the methenylation, yield 86%. For the hydroxylation, 9-BBN
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6831
Scheme 4.
was used to effect stereocontrolled hydroboration. A subsequent reaction with alkaline hydrogen peroxide furnished the cis-methanol 12. Oxidation of the alcohol with the NaIO4–RuCl3$H2O reagent provided the carboxylic acid 13 in high yield. The latter was converted into its methyl ester 14 by treatment with the silyl modified diazomethane reagent TMS–diazomethane. The preparation of the targeted half-sandwich ligands 16 and 18 is shown in Scheme 4. The cyclopentadiene unit in these structures is part of the indene ring system. The key reaction for construction of the indene ring was a double Grignard reaction with the bismagnesium derivative from a,a 0 -dichloro-o-xylene. In the preparation of the bis(Grignard) reagent from a,a 0 -dichloro-o-xylene and magnesium, the recommended powdered magnesium (50 mesh) was used.9 The cyclic alcohol 15 was isolated in 49% yield. A subsequent treatment with p-toluenesulfonic acid led to water elimination and isolation of the 2-indenyl derivative 16 in 80% yield. In a similar series of reactions, the spirane ester 14 and the bis(Grignard) reagent provided the cyclised alcohol 17 in 51% yield. Water elimination effected by p-toluenesulfonic acid catalysis furnished the indenyl target 18 in 72% yield. The products 16 and 18 have the same cis,cis-configuration as was established in the
formation of their precursors 4, 7 and 12. The assigned relative configuration is also in accord with the transformations shown in Scheme 5. The methyl ether 16 in its reaction with trimethylsilyl iodide suffered demethylation and a subsequent addition of the hydroxy function to the indenyl double bond. The product was the five-membered bridged spirane 19 in high yield, 91%. Assignment of the structure was supported by NMR data. In a similar manner the methyl ether 18 provided the six-membered bridged spirane 20 in 83% yield.
3. Conclusion This report describes the preparation of cis,cis-a,a 0 substituted and constrained spirane-bridged oxalkyl– indenyl ligands in several steps from spiro[4.4]nonane1,6-dione. Carbylation was achieved by Wittig methenylation. A subsequent stereoselective hydroboration by 9-BBN followed by peroxide treatment furnished the corresponding cis-methanol which was transformed into the cis-carboxylic ester. A double Grignard reaction between the ester and a,a 0 -dichloro-o-xylene, furnished the corresponding indenyl derivative. The final products were cis,cis-a-(2-indenyl)-a 0 -(methoxy or methoxymethyl)spiro[4.4]nonanes.
4. Experimental 4.1. General 1
Scheme 5.
H NMR spectra were recorded in CDCl3 at 300 or 200 MHz with a Bruker DPX 300 or DPX 200 spectrometer. The 13C NMR spectra were recorded in CDCl3 at 75 or 50 MHz. Chemical shifts are reported in ppm using residual CHCl3 (7.24 ppm) and CDCl3 (77 ppm) as references. J-Values are given in Hz. Mass spectra under electronimpact conditions (EI) were recorded at 70 eV ionising potential; methane was used for chemical ionisation (CI). The spectra are presented as m/z (% rel. int.). IR spectra were recorded on a Nicolet Magna 550 spectrometer using liquid film or ATR (attenuated total reflectance).
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Dry THF was distilled from sodium and benzophenone under argon. Dry dichloromethane and NMP were distilled from calcium hydride. Dry DMF was distilled from BaO. 4.1.1. cis-Spiro[4.4]nonane-6-methylen-1-ol (2). A solution of cis-1-tert-butyldimethylsilyloxyspiro[4.4]nonane-6-methylene (1)8 (1.00 g, 3.76 mmol) and TBAF (1 M in THF, 7.52 mL, 7.52 mmol) in dry THF (20 mL) under argon was stirred at room temperature overnight. Water was added and the pH adjusted to 4.5 with acetic acid before the solution was extracted with EtOAc, washed with water and brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 5:1; yield 526 mg (92%) of a colourless oil. HRMS: M 152.1209. Calcd for C10H16O: 152.1201. IR (film) n cmK1 3393 (br), 2955, 2926, 2872, 2856; 1H NMR (CDCl3): d 1.4–2.4 (12H, m, CH2), 3.51 (1H, d, JZ 4.7 Hz, CH), 4.89 (1H, s, CHH), 5.10 (1H, s, CHH); 13C NMR (CDCl3): d 21.4 (CH2), 22.7 (CH2), 32.5 (CH2), 34.0 (CH2), 35.6 (CH2), 38.8 (CH2), 58.9 (C), 76.7 (CH), 107.4 (CH), 155.6 (C); MS (EI): 152 (M, 1%), 134 (41), 119 (30), 108 (86), 95 (47), 93 (60), 81 (42), 79 (47). 4.1.2. cis-1-Methoxyspiro[4.4]nonane-6-methylene (3). NaH (50% in oil, 316 mg, 6.58 mmol) was added to a solution of cis-spiro[4.4]nonane-6-methylen-1-ol (2) (500 mg, 3.29 mmol) in dry THF (30 mL) and dry DMF (10 mL) at 0 8C under argon. The solution was stirred at 0 8C for 2 h before MeI (1.401 g, 9.87 mmol) was added. The reaction mixture was stirred overnight at room temperature and evaporated. Diethyl ether was added and the solution was washed with water (4!) and brine, dried (MgSO4) and the filtrate evaporated. The crude product was purified by flash chromatography on silica gel using hexane/ EtOAc 10:1; yield: 519 mg (95%) of a colourless oil. HRMS: M 166.2635. Calcd for C11H18O: 166.2633. IR (film) n cmK1 3079, 2953, 2873, 2819, 1118; 1H NMR (CDCl3): d 1.43–1.87 (10H, m, CH2), 2.34–2.38 (2H, m, CH2), 3.20 (3H, s, OCH3), 4.89 (1H, br s, CHH]), 4.95 (1H, br s, CHH]); 13C NMR (CDCl3): d 20.8 (CH2), 22.6 (CH2), 30.3 (CH2), 34.3 (CH2), 36.9 (CH2), 39.7 (CH2), 56.7 (C), 57.4 (CH3), 88.8 (CH), 106.8 (CH2), 154.4 (C); MS (EI): m/z (%) 166 (M, 4%), 134 (100), 119 (60), 106 (36), 93 (30), 91 (48), 79 (43), 71 (67). 4.1.3. cis,cis-6-Methoxyspiro[4.4]nonane-1-methanol (4). 9-BBN (0.5 M in hexane) (7.23 mL, 3.61 mmol) was added with a syringe to a solution of cis-1-methoxyspiro[4.4]nonane-6-methylene (3) (300 mg, 1.81 mmol) in dry THF (10 mL) under argon. The solution was stirred at 80 8C for 5 h and cooled to 0 8C. NaOH (4 mL, 2 M) and H2O2 (4 mL, 35%) were added, and the solution was stirred at room temperature for 30 min. Ethyl acetate was added, the solution washed with brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 3:1; yield: 283 mg (85%) of a colourless oil. IR (film) n cmK1 3412 (br), 2954, 2874, 2820, 1110; 1H NMR (CDCl3): d 1.2–2.1 (13H, m, CH2 and CH), 3.24 (3H, s, OCH3), 3.31–3.40 (1H, m, CHH), 3.50 (1H, br s, CHO), 3.57–3.67 (1H, m, CHH); 13C NMR (CDCl3): d 20.0 (CH2), 22.1 (CH2), 28.1 (CH2), 29.5 (CH2), 36.0 (CH2), 36.5 (CH2), 48.7 (CH), 55.3 (OCH3), 57.5 (C), 65.1 (CH2O),
87.8 (CHO); MS (CI-CH4): m/z (%) 185 (MCH, 2%), 165 (5), 151 (6), 136 (12), 135 (100), 134 (8), 133 (11), 121 (6). 4.1.4. cis,cis-6-Methoxyspiro[4.4]nonane-1-carboxylic acid (5). RuCl3$H2O (9 mg, 0.04 mmol) was added to a solution of cis,cis-6-methoxyspiro[4.4]nonane-1-methanol (4) (150 mg, 0.82 mmol) and NaIO4 (567 mg, 2.65 mmol) in CCl4 (1.5 mL), MeCN (1.5 mL) and H2O (2.5 mL) at room temperature. The reaction mixture was stirred for 5 h at room temperature and CH2Cl2 added. The water layer was extracted with CH2Cl2 (3!). The combined organic solutions were dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using EtOAc; yield 125 mg (78%) of a colourless oil. HRMS: M 198.1256. Calcd for C11H18O3: 198.1250; IR (film) n cmK1 3500–2500 (br), 2959, 2873, 1732, 1698; 1H NMR (CDCl3): d 1.3–2.3 (13H, m, CH2 and CH), 3.12 (3H, s, CH3), 3.49 (1H, br s, CH), 10.6 (1H, br s, CO2H); 13C NMR (CDCl3): d 21.3 (CH2), 24.1 (CH2), 28.8 (CH2), 30.4 (CH2), 36.6 (CH2), 37.4 (CH2), 50.8 (CH), 55.8 (CH3), 59.2 (C), 87.9 (CH), 181.2 (CO); MS (EI): m/z (%) 198 (M, 35%), 180 (23), 166 (32), 121 (57), 120 (64), 111 (65), 93 (36), 71 (100). 4.1.5. Methyl cis,cis-6-methoxyspiro[4.4]nonane-1-carboxylate (6). TMSCHN 2 (2 M in hexane, 0.6 mL, 1.2 mmol) was added to a solution of cis,cis-6-methoxyspiro[4.4]nonane-1-carboxylic acid (5) (120 mg, 0.61 mmol) in hexane (3.5 mL) and MeOH (1 mL) at room temperature. The solution was stirred at room temperature for 1 h and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 8:1; yield 97 mg (76%) of a colourless oil. HRMS: M 212.1412. Calcd for C12H20O3: 212.1419. IR (film) n cmK1 2956, 2873, 2819, 1732, 1154; 1H NMR (CDCl3): d 1.2–2.0 (12H, m, CH2), 2.62 (1H, dd, JZ5.0, 7.9 Hz, CH), 3.10 (3H, s, CH3), 3.42 (1H, br s, CH), 3.61 (3H, s, CH3); 13C NMR (CDCl3): d 21.3 (CH2), 24.4 (CH2), 28.7 (CH2), 30.8 (CH2), 37.1 (CH2), 37.5 (CH2), 50.3 (CH), 51.3 (CH3), 56.1 (CH3), 59.2 (C), 87.8 (CH), 176.1 (CO); MS (EI): m/z (%) 212 (M, 45%), 180 (37), 152 (25), 151 (13), 121 (100), 120 (83), 111 (81), 93 (37). 4.1.6. cis,cis-6-tert-Butyldimethylsilyloxyspiro[4.4]nonane-1-methanol (7). 9-BBN (0.5 M in hexane) (13 mL, 6.54 mmol) was added with a syringe to a solution of cis-1-tert-butyldimethylsilyloxyspiro[4.4]nonane-6methylene9 (1) (870 mg, 3.27 mmol) in dry THF (50 mL) under argon. The solution was stirred at 70 8C for 4 h and cooled to 0 8C. NaOH (6 mL, 2 M) and H2O2 (6 mL, 35%) were added. The resultant solution was stirred at room temperature for 30 min. Ethyl acetate was added and the solution was washed with brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 3:1; yield: 750 mg (81%) of a colourless oil. HRMS: M 227.1477. Calcd for C12H23O2Si (MKtBu): 227.1467. IR (film) n cmK1 3381 (br), 2954, 2930, 2860, 1251; 1H NMR (CDCl3): d 0.10 (3H, s, CH-3), 0.11 (3H, s, CH3), 0.90 (9H, s, CH3), 1.2–2.0 (13H, m, CH2 and CH), 3.33–3.44 (1H, m, CHH), 3.60–3.72 (1H, m, CHH), 3.97 (1H, t, JZ6.3 Hz, CH); 13C NMR (CDCl3): d K4.0 (CH3), K3.4 (CH3), 18.7 (C), 19.1 (CH2), 22.1 (CH2), 26.4 (CH3), 28.5 (CH2), 32.8
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(CH2), 35.1 (CH2), 36.8 (CH2), 47.8 (CH), 56.4 (C), 64.7 (CH2), 79.0 (CH); MS (CI-CH4) m/z (%): 285 (MCH, 7%), 153 (6), 151 (5), 136 (12), 135 (100), 133 (6), 93 (3), 75 (7). 4.1.7. cis,cis-6-Hydroxyspiro[4.4]nonane-1-methanol (8). A solution of cis,cis-6-tert-butyldimethylsilyloxyspiro[4.4]nonane-1-methanol (7) (186 mg, 0.65 mmol) and TBAF (1 M in THF, 1.3 mL, 1.3 mmol) in dry THF (10 mL) under argon was stirred overnight at room temperature. Water was added to the solution and the pH adjusted to 4.5 with acetic acid. The solution was extracted with EtOAc, washed with water and brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 1:4; yield 102 mg (92%) of a colourless oil. (Found C, 70.29; H, 10.37. Calcd for C10H18O2: C, 70.55; H, 10.66%). HRMS: M 170.1302. Calcd for C10H18O2: 170.1307; IR (film) n cmK1 3285 (br), 2953, 2874, 1443, 1049; 1H NMR (CDCl3): d 1.2–2.1 (13H, m, CH2 and CH), 3.46 (1H, dd, JZ3.2, 10.6 Hz, CHH), 3.66 (1 H, t, JZ10.6 Hz, CHH), 4.00 (1H, t, JZ3.5 Hz, CH), 4.5 (2 H, br s, OH); 13C NMR (CDCl3): d 20.5 (CH2), 22.0 (CH2), 29.1 (CH2), 33.3 (CH2), 33.8 (CH2), 35.6 (CH2), 48.2 (CH), 59.1 (C), 65.4 (CH2), 78.3 (CH); MS (EI) m/z (%):170 (M, 1%), 134 (52), 122 (43), 108 (100), 95 (49), 93 (67), 81 (58), 79 (66). 4.1.8. cis,cis-6-Methoxymethylspiro[4.4]nonane-1-ol (9). NaH (60% in oil, 55 mg, 1.37 mmol) was added to a solution of cis,cis-6-hydroxyspiro[4.4]nonane-1-methanol (8) (233 mg, 1.37 mmol) in dry THF (10 mL) under argon at 0 8C. The suspension was stirred at 0 8C for 2 h before MeI (234 mg, 1.64 mmol) was added. The solution was stirred at 0 8C for 2 h, evaporated and the crude product was purified by flash chromatography on silica gel using hexane/EtOAc 5:1; yield 197 mg (78%) of a colourless oil. IR (film) n cmK1 3486 (br), 2954, 2876, 1117, 1099; 1H NMR (CDCl3): d 1.2– 2.0 (13H, m, CH2 and CH), 3.15–3.38 (2H, m, CH2), 3.30 (3H, s, CH3), 3.80 (1H, br s, CHO), 4.15 (1H, s, OH); 13C NMR (CDCl3): d 19.8 (CH2), 21.1 (CH2), 28.3 (CH2), 32.1 (CH2), 32.3 (CH2), 34.7 (CH2), 45.5 (CH), 58.7 (CH3), 59.3 (C), 76.1 (CH2), 78.0 (CH); MS (EI): m/z (%) 184 (M, 3%), 152 (30), 134 (100), 119 (26), 108 (95), 93 (58), 81 (62), 79 (69). 4.1.9. cis-6-Methoxymethylspiro[4.4]nonan-1-one (10). cis,cis-6-Methoxymethylspiro[4.4]nonane-1-ol (9) (197 mg, 1.07 mmol) and PCC (462 mg, 2.14 mmol) were stirred in dry CH2Cl2 (10 mL) under argon at room temperature overnight. A small amount of silica gel was added to the solution and the mixture was evaporated to dryness. The residue was added on top of a silica gel column and the product isolated after flash chromatography using hexane/EtOAc 10:1; yield: 180 mg (92%) of a colourless oil. HRMS: M 182.1313. Calcd for C11H18O2: 182.1307; IR (film) n cmK1 2951, 2869, 1731, 1450, 1098; 1H NMR (CDCl3): d 1.2–2.3 (13H, m, CH2 and CH), 3.05–3.26 (2H, m, CH2O), 3.12 (3H, s, CH3O); 13C NMR (CDCl3): d 20.3 (CH2), 25.7 (CH2), 30.3 (CH2), 38.0 (CH2), 39.4 (CH2), 40.5 (CH2), 50.3 (CH), 56.9 (C), 58.3 (CH3), 73.5 (CH2), 220.8 (CO); MS (EI): m/z (%) 182 (M, 8%), 150 (71), 122 (34), 121 (29), 94 (45), 93 (42), 84 (46), 45 (100). 4.1.10. cis-1-Methoxymethylspiro[4.4]nonane-6-methylene (11). A dry mixture of methyltriphenylphosphonium bromide and sodamide (2.25 g, 5.49 mmol) was dissolved in
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dry THF (10 mL) under argon and the medium stirred at room temperature for 15 min before cis-6-methoxymethylspiro[4.4]nonan-1-one (10) (500 mg, 2.75 mmol) in dry THF (10 mL) was added with a syringe. The solution was stirred at 70 8C overnight. A small amount of silica gel was added to the solution and the mixture evaporated to dryness. The residue was added on top of a silica gel column and the product isolated after flash chromatography using hexane/ EtOAc 10:1; yield: 425 mg (86%) of a colourless oil. (Found: C, 80.11; H, 11.05. Calcd for C12H20O: C, 79.94; H, 11.18%). HRMS: M 180.1517. Calcd for C12H20O: 180.1514. IR (film) n cmK1 3071, 2950, 2871, 1646, 1101; 1H NMR (CDCl3): d 1.5–1.9 (11H, m, CH2 and CH), 2.32–2.34 (2H, m, CH2), 3.06–3.24 (2H, m, CH2), 3.26 (3H, s, CH3), 4.67 (1H, br s, CHH]), 4.90 (1H, br s, CHH]); 13 C NMR (CDCl3): d 22.6 (CH2), 23.5 (CH2), 29.9 (CH2), 34.4 (CH2), 40.0 (CH2), 42.4 (CH2), 47.6 (CH), 54.9 (C), 58.6 (CH3), 75.7 (CH2), 105.0 (CH2), 156.8 (C); MS (EI): m/z (%) 180 (M, 2%), 149 (37), 148 (25), 135 (100), 133 (20), 107 (14), 105 (20), 93 (27). 4.1.11. cis,cis-6-Methoxymethylspiro[4.4]nonane-1methanol (12). 9-BBN (0.5 M in hexane) (10.22 mL, 5.11 mmol) was added with syringe to a solution of cis-1methoxymethylspiro[4.4]nonane-6-methylene (11) (460 mg, 2.56 mmol) in dry THF (30 mL) under argon. The solution was stirred at 80 8C for 5 h and cooled to 0 8C. NaOH (5 mL, 2 M) and H2O2 (5 mL, 35%) were added and the solution was stirred at room temperature for 30 min. Diethyl ether was added and the solution was washed with brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 1:2; yield: 382 mg (75%) of a colourless oil. HRMS: (M -H2O) 180.1522. Calcd for C12H20O: 180.1514; IR (film) n cmK1 3374 (br), 2952, 2876, 1452, 1105; 1H NMR (CDCl3): d 1.2–1.8 (14H, m, CH2 and CH), 2.83 (1H, br s, OH), 2.96–3.02 (1H, m, CHH), 3.15–3.24 (1H, m, CHH), 3.23 (3H, s, OCH3), 3.38–3.41 (1H, m, CHH), 3.63– 3.67 (1H, m, CHH); 13C NMR (CDCl3): d 19.2 (2!CH2), 27.2 (CH2), 27.6 (CH2), 35.4 (CH2), 35.5 (CH2), 45.2 (CH), 48.1 (CH), 54.6 (C), 58.5 (CH3), 62.9 (CH2), 73.7 (CH2); MS (CI-CH4): m/z (%) 199 (MCH, 94%), 181 (15), 150 (12), 149 (100), 148 (24), 136 (18), 135 (30), 93 (10). 4.1.12. cis,cis-6-Methoxymethylspiro[4.4]nonane-1-carboxylic acid (13). A mixture of cis-6-methoxymethylspiro[4.4]nonane-1-methanol (12) (433 mg, 2.19 mmol) and NaIO4 (1.521 g, 7.10 mmol) in CCl4 (4 mL), MeCN (4 mL) and H2O (6 mL) was stirred at room temperature for 5 h. CH2Cl2 was added, the layers separated and the water layer extracted with CH2Cl2 (3!). The combined organic solutions were dried (MgSO4), evaporated and the crude product purified by filtration through a silica gel plug using EtOAc; yield 390 mg (84%) of a colourless oil. The crude acid product was used as such in the subsequent synthesis of its methyl ester. HRMS: M 212.1415: calcd for C12H20O3: 212.1412. 1H NMR (CDCl3): d 1.4–2.0 (12H, m, CH2), 2.15–2.22 (1H, m, CH), 2.53–2.56 (1H, m, CH), 3.10–3.17 (1H, m, CHH), 3.25 (3H, s, CH3), 3.33–3.38 (1H, m, CHH), 11.00 (1H, br s, CO2H); 13C NMR (CDCl3): d 20.2 (CH2), 20.7 (CH2), 27.5 (CH2), 29.8 (CH2), 35.8 (CH2), 36.4 (CH2), 45.2 (CH), 50.7 (CH), 56.0 (C), 58.3 (CH3), 74.3 (CH2),
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181.6 (CO); MS (EI): m/z (%) 212 (M, 4%), 180 (41), 167 (23), 166 (42), 135 (37), 121 (100), 120 (28), 93 (31). 4.1.13. Methyl cis,cis-6-methoxymethylspiro[4.4]nonane-1-carboxylate (14). TMSCHN2 (2 M in hexane, 1.84 mL, 3.68 mmol) was added to a solution of the crude acid product from above cis,cis-6-methoxymethylspiro[4.4]nonane-1-carboxylic acid (13) (390 mg, 1.84 mmol) in hexane (14 mL) and MeOH (4 mL) at room temperature. The solution was stirred for 1 h at room temperature and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 5:1; yield 201 mg (48%) of a colourless oil. HRMS: M 226.1550: calcd for C13H22O3: 226.1569; IR (film) n cmK1 2951, 2874, 1735, 1434, 1362; 1H NMR (CDCl3): d 1.3–1.8 (12H, m, CH2), 2.07–2.13 (1H, m, CH), 2.47–2.50 (1H, m, CH), 3.02 (1H, dd, JZ7.7, 9.4 Hz, CHH), 3.17 (3H, s, CH3), 3.17–3.23 (1H, m, CHH), 3.56 (3H, s, CH3); 13C NMR (CDCl3): d 20.3 (CH2), 20.8 (CH2), 27.6 (CH2), 29.8 (CH2), 36.2 (CH2), 36.6 (CH2), 45.4 (CH), 50.5 (CH), 50.9 (CH3), 56.0 (C), 58.4 (CH3), 74.3 (CH2), 176.3 (CO); MS (EI): m/z (%) 226 (M, 4%), 209 (31), 208 (34), 180 (77), 148 (40), 135 (33), 121 (100), 120 (42). 4.1.14. cis,cis-1-Methoxy-6-(2-hydroxyindan-2-yl)spiro[4.4]nonane (15). 1,2-Dibromoethane (one drop) was added to a suspension of Mg (124 mg, 5.10 mmol) in dry THF (2 mL) under argon and the mixture heated briefly to initiate a vigorous reaction. The THF was removed under vacuum after 15 min and fresh THF (3 mL) was added. A solution of a,a 0 -dichloro-o-xylene (226 mg, 1.29 mmol) in THF (20 mL) was added slowly to the Mg suspension at room temperature over 1 h. The reaction was stirred at room temperature for 12 h, cooled to K78 8C, and a solution of methyl cis,cis-6-methoxyspiro[4.4]nonane-1-carboxylate (6) (80 mg, 0.38 mmol) in THF (6 mL) added over 20 min. The mixture was allowed to warm to room temperature. After 4 h at room temperature, water (5 mL) was added slowly, the mixture filtered, and the THF was removed under vacuum. EtOAc and aqueous 1 M NH4Cl were added to the residue and the two layers were separated. The organic solution was washed with water (2!) and brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/EtOAc 5:1; yield 53 mg (49%) of a colourless oil. HRMS: M 286.1943. Calcd for C19H26O2: 286.1933. IR (film) (cmK1 3387 (br), 3020, 2951, 2873, 1059; 1H NMR (CDCl3): d 1.3–2.3 (13H, m, CH2 and CH), 2.97–3.17 (4H, m, CH2), 3.30 (3H, s, OCH3), 3.60 (1H, d, JZ3.6 Hz, CH), 5.55 (1H, s, OH), 7.10–7.23 (4H, m, Ph); 13C NMR (CDCl3): d 19.3 (CH2), 21.4 (CH2), 27.7 (CH2), 28.7 (CH2), 36.8 (CH2)n, 39.4 (CH2), 46.1 (CH2), 48.1 (CH2), 55.0 (CH), 55.4 (CH3), 57.7 (C), 82.5 (CH), 86.6 (C), 124.46 (CH), 124.56 (CH), 126.02 (CH), 126.14 (CH), 142.0 (C), 142.2 (C); MS (EI): m/z (%) 286 (M, 10%), 181 (50), 149 (13), 132 (29), 122 (46), 121 (100), 105 (28), 104 (31). 4.1.15. cis,cis-1-Methoxy-6-(2-indenyl)spiro[4.4]nonane (16). cis,cis-1-Methoxy-6-(2-hydroxyindan-2-yl)spiro[4.4]nonane (15) (53 mg, 0.19 mmol) and p-TsOH$H2O (18 mg, 0.093 mmol) were dissolved in CH2Cl2 (3 mL) and the solution stirred at room temperature for 2 h. The solvent was evaporated and the crude product was purified by flash
chromatography on silica gel using hexane/EtOAc 15:1; yield 40 mg (80%) of a colourless oil. (Found C, 85.29; H, 9.22. Calcd for C19H24O: C, 85.03; H, 9.01%). HRMS: M 268.1838. Calcd for C19H24O: 268.1827. IR (film) n cmK1 3387 (br), 3054, 3017, 2956, 2873, 1461; 1H NMR (CDCl3): d 1.4–2.0 (13H, m, CH2 and CH), 3.00 (3H, s, CH3), 3.17 (1H, d, JZ3.8 Hz, CH), 3.32–3.57 (2H, m, CH2), 6.51 (1H, s, CH), 7.09–7.39 (4H, m, Ph); 13C NMR (CDCl3): d 20.4 (CH2), 22.0 (CH2), 28.0 (CH2), 32.0 (CH2), 34.2 (CH2), 35.9 (CH2), 42.5 (CH2), 47.5 (CH), 55.6 (CH3), 60.2 (C), 88.2 (CH), 119.7 (CH), 123.1 (CH), 123.2 (CH), 125.4 (CH), 126.0 (CH), 143.1 (C), 146.0 (C), 155.2 (C); MS (EI): m/z (%) 268 (M, 59%), 236 (100), 155 (81), 142 (76), 141 (36), 129 (30), 128 (33), 115 (33). 4.1.16. cis,cis-6-Methoxymethyl-1-(2-hydroxyindan-2yl)spiro[4.4]nonane (17). 1,2-Dibromoethane (one drop) was added to a suspension of Mg (86 mg, 3.54 mmol) in dry THF (2 mL) under argon and the mixture heated briefly to initiate a vigorous reaction. The THF was removed under vacuum after 15 min and fresh THF (3 mL) was added. A solution of a,a 0 -dichloro-o-xylene (308 mg, 1.76 mmol) in THF (30 mL) was added slowly to the Mg suspension at ambient temperature over 1 h. The reaction was stirred for an additional 12 h, cooled to K78 8C, and a solution of methyl cis,cis-6-methoxymethylspiro[4.4]nona-1-carboxylate (14) (200 mg, 0.88 mmol) in THF (15 mL) was added over 20 min. The mixture was allowed to warm to ambient temperature and kept at this temperature for 3.5 h before water (5 mL) was added slowly. The mixture was filtered, the THF removed at reduced pressure, EtOAc and aqueous 1 M NH4Cl added, and the two layers separated. The organic solution was washed with water (2!) and brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/ EtOAc 5:1; yield 135 mg (51%) of a colourless oil. (Found C, 80.13; H, 9.59. Calcd for C20H28O2: C, 79.96; H, 9.39%). HRMS: M 300.2077. Calcd for C20H28O2: 300.2089. IR (film) n cmK1 3408 (br), 2954, 2877, 1735, 1459; 1H NMR (CDCl3): d 1.5–1.7 (12H, m, CH2), 2.24–2.26 (1H, m, CH), 2.40–2.42 (1H, m, CH), 2.8–3.1 (4H, m, CH2), 3.22–3.37 (2H, m, CH2), 3.32 (3H, s, CH3), 4.12 (1H, s, OH), 7.11– 7.24 (4H, m, Ph); 13C NMR (CDCl3): d 18.9 (CH2), 20.1 (CH2), 28.2 (CH2), 28.8 (CH2), 35.8 (2!CH2), 44.9 (CH2), 45.4 (CH2), 49.3 (CH), 52.5 (CH), 56.5 (C), 58.5 (CH3), 75.5 (CH2), 84.8 (C), 124.8 (2!CH), 126.09 (CH), 126.11 (CH), 141.1 (C), 142.7 (C); MS (EI): m/z (%) 300 (M, 4%), 282 (32), 268 (10), 250 (21), 195 (57), 163 (23), 136 (31), 135 (100). 4.1.17. cis,cis-6-Methoxymethyl-1-(2-indenyl)spiro[4.4]nonane (18). cis,cis-6-Methoxymethyl-1-(2-hydroxyindan2-yl)spiro[4.4]nonane (17) (135 mg, 0.45 mmol) and p-TsOH$H2O (43 mg, 0.22 mmol) were dissolved in CH2Cl2 (5 mL) and stirred at room temperature for 5 h. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel using hexane/ EtOAc 15:1; yield 91 mg (72%) of a colourless oil. (Found C, 85.31; H, 9.11. Calcd for C20H26O: C, 85.06; H, 9.28%). HRMS: M 282.1981. Calcd for C20H26O: 282.1984; IR (film) n cmK1 2951, 2922, 2873, 1461, 1110; 1H NMR (CDCl3): d 1.4–2.1 (13H, m, CH2 and CH), 2.82 (1H, d, JZ 7.1 Hz, CH), 3.04 (1H, t, JZ9.7 Hz, CHHO), 3.13 (3H, s,
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CH3), 3.30–3.41 (3H, m, CH2 and CHHO), 6.55 (1H, s, CH), 7.11–7.40 (4H, m, Ph); 13C NMR (CDCl3): d 20.3 (CH2), 20.7 (CH2), 27.4 (CH2), 32.9 (CH2), 37.2 (CH2), 38.0 (CH2), 41.4 (CH2), 46.2 (CH), 48.5 (CH), 56.8 (C), 58.5 (CH3), 73.2 (CH2), 120.0 (CH), 123.2 (CH), 123.6 (CH), 126.2 (CH), 126.4 (CH), 142.8 (C), 145.5 (C), 153.4 (C); MS (EI): m/z (%) 282 (M, 17%), 250 (64), 169 (38), 168 (32), 155 (76), 142 (100), 141 (45), 129 (38). 4.1.18. cis,cis-1,6-[1-Oxaethano-2-spiro(2,3-dihydroinden-2-yl)]spiro[4.4]nonane (19). TMSI (52 mg, 0.26 mmol) was added with a syringe to a solution of cis,cis-1-methoxy-6-(2-indenyl)spiro[4.4]nonane (16) (35 mg, 0.13 mmol) in dry CH2Cl2 (5 mL) under argon at room temperature. The solution was stirred at this temperature for 2 h and evaporated. The crude product was purified by flash chromatography using hexane/EtOAc 15:1; yield 30 mg (91%) of a colourless oil. (Found C, 85.15; H, 8.58.Calcd for C18H22O: C, 84.99; H, 8.72%). HRMS: M 254.1664.Calcd for C18H22O: 254.1671; IR (film) n cmK1 3021, 2946, 2863, 1483, 1041; 1H NMR (CDCl3): d 1.45–1.88 (12H, m, CH2), 2.38–2.40 (1H, m, CH), 2.86–3.09 (4H, m, CH2), 4.01 (1H, d, JZ4.6 Hz, CH), 7.10–7.21 (4H, m, Ph); 13C NMR (CDCl3): d 24.8 (CH2), 27.3 (CH2), 29.2 (CH2), 33.6 (CH2), 38.9 (CH2), 39.4 (CH2), 41.9 (CH2), 46.6 (CH2), 60.1 (CH), 63.1 (C), 89.4 (CH), 94.5 (C), 124.3 (CH), 124.7 (CH), 126.2 (CH), 126.3 (CH), 141.1 (C), 142.1 (C); MS (EI): m/z (%): 254 (M, 100%), 225 (25), 149 (20), 132 (45), 121 (19), 115 (12), 105 (19), 104 (25). 4.1.19. cis,cis-1,6-[2-Oxapropano-1-spiro(2,3-dihydroinden-2-yl)]spiro[4.4]nonane (20). TMSI (92 mg, 0.46 mmol) was added with a syringe to a solution of cis,cis-6-methoxymethyl-1-(2-indenyl)spiro[4.4]nonane (18) (65 mg, 0.23 mmol) in dry CH2Cl2 (5 mL) under argon at room temperature. The solution was stirred at this temperature for 3 h and evaporated. The crude product was purified by flash chromatography on silica gel using hexane/
6835
EtOAc 20:1; yield 51 mg (83%) of a colourless oil. HRMS: M 268.1830.Calcd for C19H24O: 268.1827. IR (film) n cmK1 3020, 2943, 2860, 1485, 1079; 1H NMR (CDCl3): d 1.4–2.0 (12H, m, CH2), 2.24–2.32 (1H, m, CH), 2.64–2.87 (2H, m, CH2), 2.97–3.11 (3H, m, CH2 and CH), 3.37 (1H, dd, JZ 8.9, 6.5 Hz, CHH), 3.89 (1H, dd, JZ8.8, 7.7 Hz, CHH), 6.89–7.19 (4H, m, Ph); 13C NMR (CDCl3): d 22.9 (CH2), 28.1 (CH2), 31.1 (CH2), 34.3 (CH2), 34.8 (CH2), 35.2 (CH2), 36.1 (CH2), 42.1 (CH2), 43.9 (CH), 54.7 (CH), 64.0 (C), 71.7 (CH2), 96.7 (C), 124.2 (CH), 124.4 (CH), 126.0 (CH), 126.1 (CH), 142.7 (C), 143.7 (C); MS (EI): m/z (%): 268 (M, 100%), 155 (22), 152 (30), 151 (88), 145 (20), 142 (30), 116 (39), 115 (31).
References and notes 1. Van der Zeijden, A. A. H.; Mattheis, C.; Fro¨hlich, R. Organometallics. 1997, 16, 2651–2658. 2. Miyazawa, A.; Kase, T.; Hashimoto, K.; Choi, J.-c.; Sakakura, T.; Ji-zhu, J. Macromolecules 2004, 37, 8840–8845. 3. (a) McKnight, A. L.; Waymouth, R. M. Chem. Rev. 1998, 98, 2587–2598. (b) Van Leusen, D.; Beetstra, D. J.; Hessen, B.; Teuben, J. H. Organometallics 2000, 19, 4084–4089. 4. van der Zeijden, A. A. A.; Mattheis, C. J. Organomet. Chem. 1999, 584, 274–285. 5. Aburel, P. S.; Rømming, C.; Ma, K.; Undheim, K. J. Chem. Soc., Perkin Trans. 1 2001, 1458–1472. 6. Falck-Pedersen, M.-L.; Undheim, K. Tetrahedron 1999, 55, 8525–8538. 7. Rolandsgard, M.; Baldawi, S.; Sirbu, D.; Bjørnstad, V.; Rømming, C.; Undheim, K. Tetrahedron 2005, 61, 4129–4140. 8. Yuan, P.; Plourde, R.; Shoemaker, M. R.; Moore, C. L.; Hansen, D. E. J. Org. Chem. 1995, 60, 5360–5364. 9. Ellis, W. W.; Hollis, T. K.; Odenkirk, W.; Whelan, J.; Ostrander, R.; Rheingold, A. L.; Bosnich, B. Organometallics 1993, 12, 4391–4401.