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

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

• 1a Ito S. Nomura A. Morita N. Kabuto C. Kobayashi H. Maejima S. Fujimori K. Yasunami M. J. Org. Chem.  2002,  67:  7295 
• 1b Pham W. Weissleder R. Tung CH. Angew. Chem. Int. Ed.  2002,  19:  3659 
• 1c Waele VD. Schmidhammer U. Mrozek T. Daub J. Riedle E. J. Am. Chem. Soc.  2002,  124:  2438 
• 1d Tanaka Y. Shigenobu K. Cardiovasc. Drug Rev.  2001,  19:  297 ; and references cited therein
• 1e Ito S. Inabe H. Okujima T. Morita N. Watanabe M. Imafuku K. Tetrahedron Lett.  2000,  40:  8343 
• Recent constructional methods of the azulene skeleton, see:
• 2a Rekka E. Chrysselis M. Siskou I. Kourounakis A. Chem. Pharm. Bull.  2002,  50:  904 
• 2b Nagel M. Hansen H.-J. Synlett  2002,  692 
• 2c Yokoyama R. Ito S. Watanabe M. Harada N. Kabuto C. Morita N. J. Chem. Soc., Perkin Trans. 1  2001,  2257 
• 2d Brown DG. Hoye TR. Brisbois RG. J. Org. Chem.  1998,  63:  1630 
• 2e Yasunami M. Miyoshi S. Kanegae N. Takase K. Bull. Chem. Soc. Jpn.  1993,  66:  892 
• 3 Very recently, a synthetic method of azulenes bearing substituents on both the five- and seven-membered rings via rhodium-mediated carbene intermediate has been reported. See: Kane JL. Shea KM. Crombie AL. Danheiser RL. Org. Lett.  2001,  3:  1081 
• 4a Miyabe R. Shioiri T. Aoyama T. Heterocycles  2002,  57:  1313 
• 4b Sakai A. Aoyama T. Shioiri T. Tetrahedron Lett.  2000,  41:  6859 
• 4c Sakai A. Aoyama T. Shioiri T. Tetrahedron  1999,  55:  3687 
• 4d For a review, see: Shioiri T. Aoyama T. Science of Synthesis   Vol. 4:  Fleming I. Ley SV. Georg Thieme Verlag; Stuttgart: 2001.  p.569 
• 4e See also: Shioiri T. Aoyama T. J. Synth. Org. Chem. Jpn.  1996,  54:  918 
• 5 Ogawa H. Aoyama T. Shioiri T. Synlett  1994,  757 
• 6 Aoyama T. Sonoda N. Yamauchi M. Toriyama K. Anzai M. Aodo A. Shioiri T. Synlett  1998,  35 
• For reviews, see:
• 12a Stang P. Chem. Rev.  1978,  78:  383 
• 12b Kirmse W. Angew. Chem., Int. Ed. Engl.  1997,  36:  1164 
• 13 First report on the cyclopentene synthesis by the reaction of ketones with TMSC(Li)N₂, see: Ohira S. Okai K. Moritani T. Chem. Commun.  1992,  721 

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.