From Phenols to Azulenes: An Extended and Versatile Route to Polyalkylated Azulenes with Variable Substitution Patterns at the Seven- and Five-membered Ring

Abstract

Polyalkylated azulenes can easily be prepared from polyalkylphenyl propiolates which are transformed by dynamic gas phase thermo-isomerization (DGPTI) into polyalkylcyclohepta[b]furan-2(2H)-ones. The latter react thermally with enol ethers or enamines to the corresponding azulenes. The enamines may be generated in situ from corresponding aminals, especially, in cases where it is difficult to obtain the pure enamines due to their high reactivity.

Key words

azulene syntheses - polyalkylated azulenes - cyclohepta[b]furan-2(2H)-ones - enamine formation in situ

References

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• 4a Nagel M. Hansen H.-J. Helv. Chim. Acta  2000,  83:  1022 
• 4b

  In addition, several grams of 4,8-dimethylcyclohepta[b]furan-2(2H)-one(12b) were prepared analogously as described from 2,6-dimethylphenyl prop-2-ynoate(9b). Selected spectroscopic data of 9b (colorless solid): ¹H NMR (300 MHz, CDCl₃): 7.06 (br s, 3 H); 3.03 (s, 1 H), 2.18 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): 150.3 (s, C=O), 147.2 (s, arom. C-O), 129.9 [s, C(2′,6′)], 128.7 [d, C(3′,5′)], 126.5 [d, C(4)], 76.5 [d, C(3)], 74.0 [s, C(2)], 16.1 (q, o-CH₃). Data of 12b: ¹H NMR (300 MHz, CDCl₃): 6.93 (d, J = 8.9 Hz, 1 H); 6.84 (d, J = 11.4 Hz, 1 H); 6.67 (dd, J = 8.9, 9.9 Hz, 1 H); 5.57 (s, 1 H); 2.40 (s, 3 H); 2.28 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): 168.0, 152.4, 151.7, 137.5 (4 s), 134.6, 133.4, 127.8 (3 d), 125.0 (s), 95.5 (d), 23.2, 18.6 (2 q).

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  See also ref. [1f] [3]

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• 10i

  Cf. also the discussion in ref. [3] .

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• 14 Carlson R. Nilsson A. Strömqvist M. Acta Chem. Scand., Ser. B  1983,  37:  7 
• 16a The well-established Ziegler-Hafner procedure, starting from the corresponding trimethylpyrylium salt and sodium cyclopentadienide, delivers optimized yields of 20 in the order of 45-65%: Hafner K. Kaiser H. Liebigs Ann. Chem.  1958,  618:  140 
• 16b cf. also: Org. Synth. Coll. Vol. V   J. Wiley and Sons; New York: 1964.  p.1088-1091  
• 16c For NMR data, see also: Braun S. Kinkeldei J. Tetrahedron  1977,  33:  1827-1832  ; and references therein.
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• 17 Hafner"s synthesis (cf. ref.^16a) leads to badly separable mixtures of 1,4,6,8- and 2,4,6,8-tetramethylazulene (23, and 25, respectively): Anderson AG. Anderson RG. Hollander GT. J. Org. Chem.  1965,  30:  131 ; cf. also ref.^5c
• For further literature, including spectroscopic characterizations, see:
• 18a Chen Y. Kunz RW. Uebelhart P. Weber RH. Hansen H.-J. Helv. Chim. Acta  1992,  75:  2447 
• 18b Fallahpour RA. Hansen H.-J. Helv. Chim. Acta  1992,  75:  2210 
• 18c Rippert AJ. Ph. D. Thesis   University of Zürich; Switzerland: 1994. 
• For the preparation of pyrrolidine enamines from aminals cf.:
• 20a Mannich G. Davidsen H. Ber. Deutsch. Chem. Ges.  1936,  69:  2106 
• 20b Opitz G. Hellmann H. Schubert HW. Liebigs Ann. Chem.  1959,  623:  112 
• 20c Igarashi M. Tada M. J. Heterocyclic Chem.  1995,  32:  807 ; and references therein
• 20d

  In situ aminal thermolysis (general method): Finely powdered, dry K₂CO₃ (1.2-2 mol equiv) was suspended in toluene, and pyrrolidine (2 mol equiv) was added. The aldehyde (1 mol equiv) was added with stirring at 0-5 °C and the suspension stirred for 12 h at r.t. (inert gas atmosphere). After filtration (or centrifugation) the slightly yellowish ‘aminal solutions’ were used without further purification. The cyclohepta[b]furan-2(2H)-ones 12 were dissolved in TEGDME (or NMP or toluene, respectively) and heated with stirring together with about 5-7 mol equiv of the ‘aminal solution’ to 120-140 °C in a stainless steel autoclave or Schlenk flask, respectively. Within 12-36 h the mixture changed the color from yellow to reddish brown and finally to violet with a slight evolution of gas (CO₂). The formation of the azulenes was monitored by TLC analyses after acidic work-up of aliquot parts of the product mixture. Finally, the mixtures were poured in diluted HCl solution (pH ca. 4-5) and the organic phase dissolved in hexane. The intensely blue-green to red-violet colored organic layers were washed several times with diluted HCl solutions and brine, and filtered through a pad of silica gel or alox. The now blue or violet organic phases were dried (NaSO₄) and the solvent removed. The azulenes were subsequently purified by column chromatography on alox (basic, act. IV) or on silica gel with hexane as eluent.

• 21a Hafner K. Angew. Chem.  1958,  70:  419 
• 21b Hafner K. Stephan A. Bernhard C. Liebigs Ann. Chem.  1961,  650:  42 
• 21c Hafner K. Stephan A. Bernhard C. Liebigs Ann. Chem.  1961,  650:  62 

13

Typical procedure for the synthesis of 2-isopropyl-4,8-dimethylazulene (vetivazulene or elemazulene, 16): In a thick-walled 15 mL Pyrex tube, equipped with a srew cap and a magnetic stirrer, 300 mg to 500 mg of 4,8-dimethylcyclohepta[b]furan-2(2H)-one (12b) were dissolved in 10 mL of either a mixture of anhyd toluene and t-BuOH (ca. 3:1 to 1:1, to enhance the solubility of 12b) or pure t-BuOH. Then, 1.5-2.5 mL of enamine 15 (prepared according to ref. [14] ) were added, and the tube was sealed and heated in an oil bath to 120-130 °C for 12-16 h with stirring. During this time, the color of the reaction mixture changed from orange to reddish brown or dark violet. The formation of the violet azulene 16 was directly monitored by TLC analyses of aliquot parts of the mixture (alox plates, eluant hexane). Samples were taken from the tube after cooling to r.t. (a small pressure relief was observed, due to the evolution of equimolar amounts of CO₂ during the reaction).
Work-up: The reaction mixture was poured into about 50 mL of hexane and washed several times with water (to hydrolyze the excess of non-reacted enamine), successively with 5% HCl solution, and sat. NaHCO₃ solution. After evaporation of the volatile components in vacuo the dark-colored oily residue was filtered through a pad of aluminium oxide (or SiO₂) with hexane as eluant. The violet filtrate was collected, dried on MgSO₄ and concentrated. After purification by column chromatography on aluminium oxide with hexane as eluant, azulene 16 was obtained as blue-violet oil (GC purity > 95%) in typical yields of 70-80% (cf. also the similar general procedure in ref. [20d] ). Selected spectroscopic data of 16: ¹H NMR (300 MHz, CDCl₃): 7.34 [t, J = 10.2 Hz, H-C(6)]; 7.25 [s, H-C(1,3)]; 7.07 [d, J = 10.2 Hz, H-C(5,7)]; 3.30 [sept, J = 6.9 Hz, 1 H, iPr-C(2)]; 2.88 [s, H₃C-C(4,8)]; 1.43 (d, J = 6.9 Hz, 6 H, iPr-C(2)). ¹H NMR (300 MHz, C₆D₆): 7.33 (s, 2 H); 7.11 (t, J = 10.0 Hz, 1 H), 6.83 (d, J = 10.2 Hz, 2 H); 3.29 (sept, J = 6.9 Hz, 1 H); 2.65 (s, 6 H); 1.45 (d, J = 6.9 Hz, 6 H).¹³C NMR (75 MHz, CDCl₃): 158.0 [C(2)], 144.6 [C(4,8)], 137.7 [C(3a,8a)], 133.5 [C(6)], 125.5 [C(5,7)], 113.5 [C(1,3)], 30.1 [d, iPr-C(2)], 24.5 [Me-C(4,8)], 24.0 [q, iPr-C(2)]. EI-MS: 199.0 (22), 198.0 (92, M^+·), 182.9 (100, M - 15), 168.0 (55, M - 30), 165.0 (47, M - 43).

15

Preparations of azulenes 17 and 35 were performed analogously to the procedure described in ref. [13] Selected spectroscopic data of 2-isopropyl-4,6,8-trimethylazulene (17) (reddish-violet oil): ¹H NMR (300 MHz, CDCl₃): 7.17 (s, 2 H); 7.00 (s, 2 H), 3.26 (sept, J = 6.9 Hz, 1 H); 2.83 (s, 6 H); 2.28 (s, 3 H); 1.41 (d, J = 6.9 Hz, 6 H).¹H NMR (300 MHz, C₆D₆): 7.32 (s, 2 H); 6.82 (s, 2 H); 3.30 (sept, 1 H); 2.67 (s, 6 H); 2.30 (s, 3 H); 1.47 (d, J = 6.9 Hz, 6 H). ¹³C NMR (75 MHz, CDCl₃): 156.5, 144.1, 143.5 136.2 (4 s), 127.2 (d), 113.4 (s), 29.9 (d), 28.4, 24.8, 23.9 (3 q). EI-MS: 212.0 (87, M^+·), 197.0 (100, M - 15). Data of 2-isopropyl-4,5,7,8-tetramethylazulene (35) (dark-blue solid): ¹H NMR (300 MHz, CDCl₃): 7.50 (s, 1 H); 7.14 (s, 2 H), 3.25 (sept, J = 6.9 Hz, 1 H); 2.72 (s, 6 H); 2.51 (s, 6 H); 1.41 (d, J = 6.9 Hz, 6 H).¹H NMR (300 MHz, C₆D₆): 7.37 (s, 3 H); 3.34 (sept, 1 H); 2.58 (s, 6 H); 2.30 (s, 6 H); 1.50 (d, J = 6.9 Hz, 6 H). ¹³C NMR (75 MHz, CDCl₃): 157.2, 142.6 (2 s), 139.7 (d), 138.6, 130.2 (2 s), 111.7, 30.0 (2 d), 26.8, 23.9, 21.1 (3 q). EI-MS: 226.0 (100, M^+·), 211.0 (65, M - 15).

19

Cf. ref. [1g] and references cited therein.

22

For azulene formation from 12e by cycloaddition with itself or with other cyclohepta[b]furan-2(2H)-ones such as 12a or 12c, see ref. [1f]

23

Data of selected azulenes: For 14, 33 and 34, see ref. [4] . NMR data (standard conditions: 300/75.5 MHz, in CDCl₃/TMS): 1,4,6,8-Tetramethylazulene(23): (violet-blue cyrstals) ¹H NMR: 7.44 [d, ³ J {H-C(3)} = 4 Hz, H-C(2)]; 7.24 [d, ³ J {H-C(2)} = 4 Hz, H-C(3)]; 6.86 [br s, H-C(5,7)]; 3.02 [s, CH₃-C(8)]; 2.81 [s, CH₃-C(4)]; 2.56 [br s, 6 H, CH₃-C(1), CH₃-C(6)]. ¹³C NMR: 147.1 [C(8)], 145.7 [C(6)]; 144.9 [C(4)]; 136.7 [C(3a)]; 136.5 [C(2)]; 132.9 [C(8a)]; 127.7 [C(7)]; 126.8 [C(1)]; 125,6 [C(5)]; 114.6 [C(3)]; 28.4 [CH₃-C(8)]; 27.7 [CH₃-C(6)]; 25.3 [CH₃-C(4)]; 19.7 [CH₃-C(1)]. EI-MS (GC-MS): 184 (100, M^+·), 169 (85, [M - CH₃]^+·). 2,4,6,8-Tetramethylazulene (25): (blue-violet crystals) ¹H NMR: 7.12 [s, H-C(1,3)]; 7.02 [s, H-C(5,7)]; 2.82 [s, H₃C-C(4,8)]; 2.61, 2.598 [2 s, H₃C-C(6), H₃C-C(2)]. ¹³C NMR: 145.0, 144.0, 143.0, 136.5 [4 q, C(2,3a/8a,4/8,6)]; 127.2 [d, H-C(5/7)]; 116.3 [d, H-C(5/7)]; 28.4 [q, H₃ C-C(6)]; 24.8 [q, H₃ C-C(4/8)]; 16.4 [q, H₃ C-C(2)]. EI-MS (GC-MS): 184 (100, M^+·), 169 (65, [M - CH₃]^+·). 2-Ethyl-4,6,8-trimethylazulene (28): ¹H NMR (taken from the 1:1 mixture with known 27): 7.12 [ s , H-C(1,3)]; 6.99 [(H-C(5,7)]; 3.03 [q, J = 7.4 Hz,
Me-CH ₂-C(2)]; 2.81 [s, CH₃-C(4,8)]; 2.60 [s, CH₃-C(6)]; 1.32 [t, J = 7.4 Hz, CH ₃-CH₂-C(2)]. EI-MS (GC-MS): 198 (100, M ⁺ ), 183 (75, [M - CH₃]⁺ ). 1-Ethyl-4,6,8-trimethylazulene (30): ¹H NMR: 7.52 [d, ³ J = 4 Hz, H-C(2)]; 7.28 [d, J = 4 Hz, H-C(3)]; 6.86 [br s, H-C(5,7)]; 3.25 (q, J = 7.4 Hz, H ₂CCH₃); 2.98, 2.80, 2.53 (3 s, 3 CH₃); 1.36 (t, J = 7.4 Hz, H₂CCH ₃). ¹³C NMR: 146.7, 145.6, 144.9, 136.8 (4s, arom C); 134,6 [d, H-C(2)]; 133.8 132.0 (2 s, arom. C); 128.1, 125.9, 115.1 (3 d, H-C); 28.4, 27.5, 25.5 (3 q, CH₃); 25.3 (t, CH ₂CH₃); 17.1 (q, CH₃). EI-MS (GC-MS): 198 (35, M^+·), 183 (100, [M - CH₃]^+·). 1-Isopropyl-4,6,8-trimethylazulene (32): (blue oil) ¹H NMR: 7.69 [d, J = 4.2 Hz, H-C(2)]; 7.33 [d, J = 4.2 Hz, H-C(3)]; 6.98, 6.88 [2 s, H-C(5), H-C(7)]; 3.91 [sept, J = 6.7 Hz, H-C(CH₃)₂]; 3.03, 2.82, 2.54 (3 s, 3 CH₃); 1.38 [d, J = 6.7 Hz, H-C(CH ₃)₂]. ¹³C NMR: 146.2, 145.3, 144.8, 139.2, 136.7 (5 s), 131.8 (d), 130.9 (s); 128.5, 126.0, 115.5 (3 d, arom C-H); 28.5 [d, H-C(CH₃)₂]; 28.3, 28.1, 26.0, 25.9, 25.6 (5 q, CH₃). EI-MS (GC-MS): 212 (25, M^+·), (100, [M - CH₃]^+·). 4,5,7,8-Tetramethylazulene (36) (blue oil): ¹H NMR: 7.70 [t, J = 4.0 Hz, H-C(2)]; 7.66 [s, H-C(6)]; 7.39 [d, J = 4.0 Hz, H-C(1,3)]; 2.83 (s, 2 CH₃); 2.60 (s, 2 CH₃). ¹³C NMR: 144.8 [s, C(3a,8a)]; 141,3 [d, H-C(6)]; 138.4 [s, C(4,8)]; 133.3 [d, H-C(2)]; 130,2 [s, C(5,7)]; 114.2 [d, H-C(1,3)]; 26.8, 21.4 (2 q). EI-MS (GC-MS): 184 (100, M^+·), 169 (85, [M - CH₃]^+·). 1,4,5,7,8-Pentamethylazulene (37): ¹H NMR: 7.60 [d, J = 4.1 Hz, H-C(2)]; 7.37 [d, J = 4.1 Hz, H-C(3)]; 2.79, 2.60, 2.54 (3 s, CH₃); 2.33 (s, 2 CH₃). ¹³C NMR: 146.6, 143.8 [2 q, C(3a), C(8a)]; 140.8 [d, H-C(6)]; 140.0 (q, arom C); 138.1 [d, H-C(2)]; 136.5, 134.7, 130.0, 128.9 (4 q, arom C), 114.1 [d, H-C(3)]; 27.2, 26.4, 23.1, 21.4, 20.5 (5 q, CH₃). 1-Isopropyl-4,5,7,8-tetramethylazulene (38): (dark blue oil) ¹H NMR: 7.72 [d, J = 4.4 Hz, H-C(2)]; 7.44 [s, H-C(6)]; 7.27 [d, J = 4.4 Hz, H-C(3)]; 3.80 [sept, J = 6.9 Hz, H-C(CH₃)₂]; 2.83, 2.76 (2 s, CH₃); 2.51 (s, 2 CH₃); 1.37 [d, J = 6.7 Hz, H-C(CH ₃)₂]. EI-MS (GC-MS): 226 (30, M^+·), 211 (100, [M - CH₃]^+·). 4,5,6,7,8-Pentamethylazulene (40) [1f] (blue crystals): ¹H NMR: 7.56 [t, J = 4.3 Hz, H-C(2)]; 7.25 [d, J ˜ 4 Hz, H-C(1,3)]; 2.84 (br s, 6 H, 2 CH₃); 2.52 (s, 3 H, CH₃); 2.47 (s, 6 H, 2 CH₃). ¹³C NMR: 145.3, 144.4, 137.6 (3 s); 132.1 [d, C(2)]; 130.5 (s); 113.9 [d, C(1,3)]; 24.5, 22.7, 22.5 (3 q). 1,4,5,6,7,8-Hexamethylazulene (39): (blue-violet oil) ¹H NMR: 7.20 [d, J = 3.9 Hz, H-C(2)]; 6.99 [d, J = 3.9 Hz, H-C(3)]; 2.75, 2.70, 2.68, 2.37 (4 s, 4 CH₃); 2.33 (br s, 2 CH₃).