Conformationally Flexible C ₃-Symmetric 1,3-Oxazoles as Molecular Scaffolds

Dedicated to Professor Leo Paquette on the occasion of his 81^st birthday

Abstract

Flexible-arm, C ₃-symmetric tris-oxazoles are synthesized for their applications in supramolecular chemistry and materials science. The C ₃-symmetry is introduced starting from 1,3,5-trimethylbenzene and carrying out threefold reactions at each stage of the synthesis. The applicability of these tris-oxazoles is demonstrated by transforming a representative example into a highly fluorescent material. This is accomplished by conjugation with an aromatic moiety via palladium(0)-catalyzed direct arylation at C-2 of the oxazole. A unique molecular arrangement in the crystal structure is observed.

Key words

C ₃-symmetric molecules - 1,3-oxazoles - tris-aromatic aldehydes - van Leusen synthesis - fluorescent materials

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• 18 1,3,5-Tris[(2-formyl-6-methoxy)phenyloxymethyl)-2,4,6-trimethylbenzene (2e); Typical Procedure To a stirred solution of a 2-hydroxy-3-methoxybenzaldehyde (0.23 g, 1.5 mmol) in acetone was added K₂CO₃ (0.62 g, 4.5 mmol) followed by 1,3,5-tris(bromomethyl)-2,4,6-trimethylbenzene (1) (0.2 g, 0.5 mmol). The resulting mixture was stirred at r.t. for 3 h. On completion of the reaction (TLC), the acetone was evaporated to a small volume followed by the addition of cold H₂O. The solid thus obtained was filtered and recrystallized from EtOH to give pure tris-aromatic aldehyde 2e. Yield: 0.18 g (70%); white solid; mp 208 °C. IR (KBr): 2841, 1693, 1583, 1481, 1359, 1265, 1249, 1209 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.45 (s, 9 H, –CH₃), 3.96 (s, 9 H, –OCH₃), 5.45 (s, 6 H, –OCH₂–), 7.12–7.20 (m, 6 H), 7.39 (dd, J ₁ = 7.2 Hz, J2 = 2.0 Hz, 3 H), 10.15 (s, 3 H, –CHO). ¹³C NMR (100 MHz, CDCl₃): δ = 16.0 (–CH₃), 56.0 (–OCH₃), 77.0 (–OCH₂), 118.1, 119.0, 123.2, 129.9, 132.1, 140.3, 151.4, 153.6, 190.9 (–CHO). Anal. Calcd for C₃₆H₃₆O₉: C, 70.57; H, 5.92. Found: C, 69.91; H, 6.79.
• 19 van Leusen AM, Hoogenboom BE, Siderius H. Tetrahedron Lett. 1972; 2369
• 20 1,3,5-Tris[6-methoxy-2-(1,3-oxazol-5-yl)phenyloxymethyl]-2,4,6-trimethylbenzene (3e); Typical Procedure To a two-necked round-bottomed flask were added tris-aldehyde 2e (0.1 g, 0.16 mmol), p-toluenesulfonylmethyl isocyanide (TosMIC) (0.13 g, 0.65 mmol), K₂CO₃ (0.16 g, 1.2 mmol) and MeOH. The resulting mixture was heated at reflux temperature for 3–4 h. On completion of the reaction (TLC), the MeOH was evaporated under reduced pressure and the residue was purified by column chromatography on silica (EtOAc–hexanes, 6:4 to 8:2) to give the corresponding tris-1,3-oxazole 3e. Yield: 0.07 g (60%); white solid; mp 210 °C. IR (KBr): 2939, 2834, 1589, 1560, 1503, 1471, 1265 cm^–1. ¹H NMR (100 MHz, CDCl₃): δ = 2.45 (s, 9 H, –CH₃), 3.94 (s, 9 H, –OCH₃), 5.31 (s, 6 H, –OCH₂–), 6.97 (dd, J ₁ = 8.2 Hz, J ₂ = 1.2 Hz, 3 H), 7.13 (t, J = 8.0 Hz, 3 H), 7.30 (s, 3 H, oxazole H), 7.35 (dd, J ₁ = 8.2 Hz, J ₂ = 1.2 Hz, 3 H), 7.87 (s, 3 H, –N=CH–, oxazole H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.1 (–CH₃), 55.9 (–OCH₃), 70.0 (–OCH₂), 112.4, 118.2, 122.1, 123.9, 125.7, 132.5, 139.5, 145.1, 153.1. HRMS (Q-TOF MS ES+): m/z [M]⁺ calcd for C₄₂H₃₉N₃O₉: 729.2686; found: 729.2677.
• 21 Crystal data for compound 3a (CCDC 1403715): C₃₉H₃₃N₃O₆ (M = 639.68): triclinic space group P-1 (no. 2), a = 11.0751(12) Å, b = 11.1638(12) Å, c = 13.9139(15) Å, α = 100.558(2)°, β = 108.883(2)°, γ = 98.899(2)°, V = 1557.3(3) Å³, Z = 2, T = 294.15 K, μ(MoKα) = 0.093 mm^–1, D_calc  = 1.364 g/mm³, 18425 reflections measured (3.2 ≤ 2θ ≤ 56.1), 7290 unique (R _int = 0.0235) which were used in all calculations. The final R ₁ was 0.0659 [>2σ(I)] and wR ₂ was 0.1933 (all data).
• 22 For similar coupling under microwave conditions, see: Besselievre F, Mahuteau-Betzer F, Grierson DS, Piguel S. J. Org. Chem. 2008; 73: 3278
• 23 1,3,5-Tris[4-(2-phenyl-1,3-oxazol-5-yl)phenyloxymethyl]-2,4,6-trimethylbenzene (4) To a two-necked round-bottomed flask were added compound 3a (0.1 g, 0.19 mmol), bromobenzene (0.14 g, 0.86 mmol), K₂CO₃ (1.6 g, 1.15 mmol), Pd(OAc)₂ (6 mg, 15 mol%), CuI (0.10 g, 0.57 mmol) and DMF (4 mL). The resulting mixture was degassed and then heated to 150 °C and stirred under an N₂ atm for 3 h. On completion of the reaction (TLC), the solids were removed by filtration through Celite^® followed by washing with CH₂Cl₂. The filtrate and washings were evaporated under vacuum and the residue purified by column chromatography on silica (EtOAc–hexanes, 3:7) to afford tris(2-phenyl-1,3-oxazol-5-yl) 4. Yield: 0.05 g (35%); white solid; mp: 187 °C. IR (KBr): 2923, 1612, 1499, 1242, 1176 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.52 (s, 9 H, –CH₃), 5.20 (s, 6 H, –OCH₂–), 7.13 (d, J = 8.8 Hz, 6 H), 7.37 (s, 3 H, oxazole H), 7.50 (d, J = 7.6 Hz, 9 H), 7.72 (d, J  = 9.2 Hz, 6 H), 8.12 (dd, J ₁ = 7.8 Hz, J ₂ = 2.0 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.0 (–CH₃), 65.1 (–OCH₂), 115.1, 121.2, 122.1, 125.8, 126.1, 127.5, 128.8, 130.1, 131.6, 139.5, 151.2 and 159.3 (oxazole carbons), 160.6 (Ar–O–). HRMS (Q-TOF MS ES+): m/z [M + H]⁺ calcd for C₅₇H₄₆N₃O₆: 868.3387; found: 868.2813; m/z [M + Na]⁺ calcd for C₅₇H₄₅N₃O₆Na: 890.3206; found: 890.2594.