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Synlett 2003(14): 2151-2154  
DOI: 10.1055/s-2003-42064
LETTER
© Georg Thieme Verlag Stuttgart · New York

New Two-Step Synthesis of Azulene-1-carboxylic Esters Using Lithium Trimethylsilyldiazomethane

Yoshiyuki Hari, Shunkichi Tanaka, Yasuta Takuma, Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Fax: +81(52)8363439; e-Mail: aoyama@phar.nagoya-cu.ac.jp;
Further Information

Publication History

Received 12 August 2003
Publication Date:
07 October 2003 (online)

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Abstract

Lithium trimethylsilyldiazomethane successfully reacted with various ethyl or tert-butyl 4-aryl-2-oxobutanoates to yield 2,3-dihydroazulene-1-carboxylic esters via alkylidene carbene intermediates, and the resulting 2,3-dihydroazulenes were easily converted to the corresponding azulene-1-carboxylic esters by oxidation with chemical manganese dioxide.

Key words

alkylidene carbenes - azulenes - chemical manganese dioxide - diazo compounds - lithium trimethylsilyldizaomethane

    References

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7

Selected data for the synthesized azulene analogues 2a-g.
Compound 2a: 1H NMR (CDCl3): δ = 1.27 (3 H, d, J = 7 Hz), 2.63 (4 H, s), 4.17 (2 H, q, J = 7 Hz), 5.80-6.03 (4 H, m), 7.40 (1 H, d, J = 12 Hz). HRMS (EI) calcd for C13H14O2: 202.0994. Found: 202.0995. Compound 2b: 1H NMR (CDCl3): δ = 1.48 (9 H, s), 2.58 (4 H, s), 5.74-5.97 (4 H, m), 7.33 (1 H, d, J = 12 Hz). HRMS (EI) calcd for C15H18O2: 230.1307. Found: 230.1313. Compound 2c: 1H NMR (CD2Cl2): δ = 1.34 (9 H, s), 1.71 (3 H, s), 2.43 (4 H, s), 5.64-5.71 (2 H, m), 5.76 (1 H, d, J = 12 Hz), 7.18 (1 H, d, J = 12 Hz). HRMS (EI) calcd for C16H20O2: 244.1463. Found: 244.1461. Compound 2d: 1H NMR (CD2Cl2): δ = 1.37 (9 H, s), 2.48 (4 H, s), 3.45 (3 H, s), 5.16 (1 H, d, J = 9 Hz), 5.71-5.81 (2 H, m), 7.36 (1 H, d, J = 13 Hz). HRMS (EI) calcd for C16H20O3: 260.1410. Found: 260.1412. Compound 2e: 1H NMR (CD2Cl2): δ = 1.28 (9 H, s), 2.38 (4 H, s), 5.48 (1 H, d, J = 9 Hz), 5.76 (1 H, dd, J = 2, 13 Hz), 5.89 (1 H, dd, J = 2, 9 Hz), 7.09 (1 H, d, J = 13 Hz). HRMS (EI) calcd for C15H17ClO2: 264.0917. Found: 264.0919. Compound 2f: 1H NMR (CD2Cl2): δ = 1.34 (9 H, s), 2.12 (1 H, t, J = 8 Hz), 2.59 (1 H, t, J = 8 Hz), 6.66 (1 H, d, J = 12 Hz), 7.02-7.31 (2 H, m), 11.30 (1 H, d, J = 12 Hz). HRMS (EI) calcd for C16H17F3O2: 298.1181. Found: 298.1183. Compound 2g: 1H NMR (CD2Cl2): δ = 1.20 (3 H, d, J = 7 Hz), 1.46 (9 H, s), 2.14-2.21 (1 H, m), 2.65-2.82 (2 H, m), 5.76-5.99 (4 H, m), 7.34 (1 H, d, J = 12 Hz). HRMS (EI) calcd for C16H20O2: 244.1463. Found: 244.1461.

8

When 1,2-dimethoxyethane was used as a solvent, the reaction gave a complex mixture.

9

Typical Procedure: To a stirred solution of diisopropyl-amine (114 mg, 1.0 mmol) in Et2O (4 mL) was added dropwise n-BuLi (1.56 M in hexane solution, 0.64 mL, 1.0 mmol) at -78 °C under N2, and the mixture was stirred for 10 min. TMSCHN2 (1.33 M n-hexane solution, 0.75 mL, 1.0 mmol) was further added dropwise, and the mixture was stirred for 20 min. A solution of 1b (134 mg, 0.5 mmol) in Et2O (1 mL) was added dropwise. The mixture was stirred at -78 °C for 3 h, then heated under reflux for 7 h. After being quenched with H2O (3 mL) at 0 °C, the mixture was extracted with EtOAc (30 mL × 3). The organic extracts were washed with H2O (80 mL) and sat. brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (n-hexane:Et2O = 20:1) to give 2b (68 mg, 60%) as a brown wax.

10

tert-Butyl 4-aryl-2-oxobutanoates 1c-f were prepared by the reaction of 2-arylethylmagnesium bromides, prepared from 2-arylethyl bromides and magnesium, with di-tert-butyl oxalate according to the literature on the synthesis of 1b, see: Dao D. H., Kawai Y., Hida K., Hornes S., Nakamura K., Ohno A.; Bull. Chem. Soc. Jpn.; 1998, 71: 425

11

This compound was prepared from hydrolysis of 2a followed by condensation with dimethylamine.

14

This compound was prepared by the reaction of a Grignard reagent, prepared from 2-phenyl-1-propyl bromide and magnesium, with di-tert-butyl oxalate.

15

Typical Procedure: A mixture of 2b (59 mg, 0.26 mmol), CMD (890 mg, 40 equiv) in CH2Cl2 (3 mL) was stirred for 6 h. The mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (n-hexane:EtOAc = 30:1) to give 4b (31 mg, 52%) as a violet wax.

16

Selected data for the synthesized azulene analogues 4a-g.
Compound 4a: 1H NMR (CDCl3): δ = 1.45 (3 H, t, J = 7 Hz), 4.43 (2 H, d, J = 7 Hz), 7.30 (1 H, d, J = 4 Hz), 7.44 (1 H, t, J = 10 Hz), 7.55 (1 H, t, J = 10 Hz), 7.80 (1 H, t, J = 10 Hz), 8.38 (1 H, d, J = 4 Hz), 8.46 (1 H, d, J = 10 Hz), 9.66 (1 H, d, J = 10 Hz). HRMS (EI) calcd for C13H12O2: 200.0837. Found: 200.0837. Compound 4b: 1H NMR (CDCl3): δ = 1.67 (9 H, s), 7.27 (1 H, d, J = 7 Hz), 7.41 (1 H, t, J = 10 Hz), 7.50 (1 H, t, J = 10 Hz), 7.76 (1 H, t, J = 10 Hz), 8.33 (1 H, d, J = 4 Hz), 8.43 (1 H, d, J = 10 Hz), 9.63 (1 H, d, J = 10 Hz). HRMS (EI) calcd for C15H16O2: 228.1150. Found: 228.1148. Compound 4c: 1H NMR (CDCl3): δ = 1.65 (9 H, s), 2.71 (3 H, s), 7.18 (1 H, d J = 4 Hz), 7.31 (1 H, d, J = 10 Hz), 7.40 (1 H, d, J = 10 Hz), 8.20 (1 H, d, J = 4 Hz), 8.28 (1 H, d, J = 10 Hz), 18.92 (1 H, d, J = 10 Hz). HRMS (EI) calcd for C16H18O2: 242.1307. Found: 242.1316. Compound 4d: 1H NMR (CDCl3): δ = 2.07 (9 H, s), 4.00 (3 H, s), 6.81-6.87 (2 H, m), 7.00-7.15 (1 H, m), 8.04 (1 H, d, J = 4 Hz), 8.28 (1 H, d, J = 11 Hz), 9.48 (1 H, d, J = 11 Hz). HRMS (EI) calcd for C16H18O3: 258.1256. Found: 258.1258. Compound 4e: 1H NMR (CDCl3): δ = 1.65 (9 H, s), 7.28 (1 H, d J = 4 Hz), 7.51 (1 H, dd, J = 2, 10 Hz), 7.60 (1 H, dd, J = 2, 11 Hz), 8.23 (1 H, d, J = 10 Hz), 8.28 (1 H, d, J = 4 Hz), 9.43 (1 H, d, J = 10 Hz). HRMS (EI) calcd for C15H15ClO2: 262.0761. Found: 262.0766. Compound 4f: 1H NMR (CDCl3): δ = 1.67 (9 H, s), 7.30-7.33 (1 H, m), 7.40 (1 H, d, J = 4 Hz), 7.67 (1 H, d, J = 10 Hz), 7.75 (1 H, d, J = 10 Hz), 8.48 (1 H, d, J = 4 Hz), 9.69 (1 H, d, J = 10 Hz). HRMS (EI) calcd for C16H15F3O2: 296.1024. Found: 296.1028. Compound 4g: 1H NMR (CDCl3): δ = 1.65 (9 H, s), 2.62 (3 H, s), 7.34 (1 H, t, J = 10 Hz), 7.38 (1 H, t, J = 10 Hz), 7.71 (1 H, t, J = 10 Hz), 8.15 (1 H, s), 8.32 (1 H, d, J = 10 Hz), 9.53 (1 H, d, J = 10 Hz). HRMS (EI) calcd for C16H18O2: 242.1307. Found: 242.1307.