Mild, Efficient, and Highly Regioselective Synthesis of 2,6-Diiodobenzaldehyde Derivatives

Abstract

An efficient and versatile synthesis of 2,6-diiodobenzaldehydes via highly regioselective metal–iodine exchange (MIE) of 5-substituted 1,2,3-triiodobenzenes is reported. The nature of substituents (R) on the phenyl has a large influence on the reactivity of reaction but not on the regioselectivity. The regioselectivity of the MIE can be controlled by the use of ethyl formate as a formylating agent providing only the internal benzaldehyde derivatives in excellent site-selectivity. The best reactivity and the highest isolated yields were furnished with products bearing electron-rich substituents. Several chemical transformations of the target compound as a valuable precursor in synthesis were also demonstrated providing the desired derivatives in good isolated yields. This report discloses a protocol for the synthesis of 2,6-diiodobenzaldehyde derivatives that is scalable, general in scope, and indeed difficult to be made by other means.

Keywords

2,6-diiodobenzaldehydes - Grignard reactions - regioselectivity - metal–iodine exchange - substituent effect - Suzuki–Miyaura cross-coupling - nucleophilic addition

• References and Notes

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• 16 General Procedure for the MIE Reaction between 5-Substituted 1,2,3-Triiodobenzenes and Ethyl FormateA flame-dried round-bottom flask was charged with 5-substituted 1,2,3-triiodobenzene (1.02 mmol, 1.0 equiv.) and 10 mL of freshly dried THF. The mixture was cooled down under argon gas to –78 °C. 2 M solution of isopropylmagnesium chloride (1.15 mmol, 1.1 equiv.) was added dropewise over 1 h. The solution was stirred for 30 min at the same temperature. Ethyl formate (1.53 mmol, 1.50 equiv.) was added and the mixture left to warm up overnight. Saturated NH₄Cl (20 mL) was added, and the reaction mixture was extracted with diethyl ether (2 × 50 mL). Organic layers were combined, washed with brine, dried with Na₂SO₄, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography (5% EtOAc/hexane) to yield the pure desired product.2,6-Diiodobenzaldehyde (6_A)Yellow solid (261 mg, 71% yield). Mp 58–60 °C. IR (cast film): 3026, 3008, 2913, 2887, 1715, 1613, 1598, 983, 864 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.78 (s, 1 H), 8.01 (d, 2 H, J = 7.8 Hz), 6.86 (t, 1 H, J = 7.8 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 195.7, 141.6, 135.6, 134.6, 97.5. HRMS (ESI): m/z calcd for C₇H₅I₂O [M + H]⁺: 358.8430; found: 358.8425.4-Fluoro-2,6-diiodobenzaldehyde (7_A)Yellow solid (192 mg, 50% yield). Mp 91–93 °C. IR (cast film): 3028, 3004, 2979, 2846, 1719, 1642, 1599, 976, 817, 688, 524 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.73 (s, 1 H), 7.80 (d, 2 H, J = 7.4 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 194.5, 164.5, 161.8, 131.3 131.29, 129.2 129.0, 97.7, 97.6. HRMS (ESI): m/z calcd for C₇H₄FI₂O [M + H]⁺: 376.8336; found: 376.8331.4-Chloro-2,6-diiodobenzaldehyde (8_A)Yellow solid (312 mg, 78% yield). Mp 65–67 °C. IR (cast film): 3012, 3004, 2941, 2876, 1709, 1621, 1587, 1008, 867, 726, 553 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.72 (s, 1 H), 8.05 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.7, 141.1, 139.7, 133.5, 97.4. HRMS (ESI): m/z calcd for C₇H₄ClI₂O [M + H]⁺: 392.8040; found: 392.8033.4-Bromo-2,6-diiodobenzaldehyde (9_A)Yellow solid (201 mg, 45% yield). Mp 101–103 °C. IR (cast film): 3024, 3004, 2943, 2869, 1706, 1607, 1587, 943, 634 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.70 (s, 1 H), 8.19 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.8, 143.8, 134.0, 128.3, 97.6. HRMS (ESI): m/z calcd for C₇H₄BrI₂O [M + H]⁺: 436.7535; found: 436.7528.2,6-Diiodo-4-methylbenzaldehyde (10_A)Yellow solid (288 mg, 76% yield). Mp 130–132 °C. IR (cast film): 3031, 3010, 3004, 2953, 2896, 1713, 1621, 1589, 981, 736 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.76 (s, 1 H), 7.86 (s, 2 H), 2.31 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 195.5, 146.1, 142.5, 132.2, 98.0, 20.5. HRMS (ESI): m/z calcd for C₈H₇I₂O [M + H]⁺: 372.8586; found: 372.8584.2,6-Diiodo-4-methoxybenzaldehyde (11_A)Yellow solid (317 mg, 80% yield). Mp 83–85 °C. IR (cast film): 3027, 3011, 2945, 2879, 1713, 1621, 1587, 1207, 1186, 873, 736 cm^–1. ¹H NMR (400MHz, CDCl₃): δ = 9.71 (s, 1 H), 7.59 (s, 2 H), 3.86 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.8, 162.6, 127.8, 126.7, 99.4, 56.2. HRMS (ESI): m/z calcd for C₈H₇I₂O₂ [M + H]⁺: 388.8535; found: 388.8529.Methyl 4-formyl-3,5-diiodobenzoate (12_A)Yellow solid (280 mg, 66% yield). Mp 76–78 °C. IR (cast film): 3031, 3015, 2983, 2907, 1741, 1716, 1627, 1583, 1207, 1131, 867, 627 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.78 (s, 1 H), 8.61 (s, 2 H), 3.96 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 195.2, 163.5, 142.1, 139.4, 134.9, 96.1, 53.2. HRMS (ESI): m/z calcd for C₉H₇I₂O₃ [M + H]⁺: 416.8485; found: 416.8477.2-Chloro-6-iodobenzaldehyde (13_A)Yellow solid (209 mg, 77% yield). Mp 80–82 °C. IR (cast film): 3021, 3002, 2937, 2889, 1719, 1641, 1599, 867, 764, 537 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 10.19 (s, 1 H), 7.94 (d, 1 H, J = 8.0 Hz), 7.48 (d, 1 H, J = 8.0 Hz), 7.13 (t, 1 H, J = 7.9 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 191.7, 140.1, 136.9, 134.1, 133.1, 131.2, 96.4. HRMS (ESI): m/z for C₇H₅ClIO [M + H]⁺: 266.9074; found: 266.9067.2-Bromo-6-iodobenzaldehyde (14_A)Yellow solid (238 mg, 75% yield). Mp 87–89 °C. IR (cast film): 3019, 3004, 2983, 2876, 1714, 1607, 1596, 861, 584 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 10.05 (s, 1 H), 7.98 (d, 1 H, J = 8.0 Hz), 7.68 (d, 1 H, J = 8.0 Hz), 7.03 (t, 1 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 193.1, 140.9, 134.6, 134.4, 134.4, 125.4, 96.5. HRMS (ESI): m/z for C₇H₅BrIO [M + H]⁺: 310.8568; found: 310.8564.