Development of a Dual Fries–Claisen Rearrangement Strategy

Abstract

In this paper we describe the development and application of a sequential Fries–Claisen rearrangement strategy as a new route for annelation on an aromatic ring. We demonstrate the potential utility of this protocol through the synthesis of a pyranonaphthoquinone target.

Key words

annelation - pericyclic reaction - rearrangement - Fries - Claisen

• References and Notes


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• 7 General Procedure for the Fries–Claisen Rearrangements: Claisen Rearrangement of 8 4-(Allyloxy)-8-(benzyloxy)naphthalen-1-yl dimethyl carbamate (8, 1.0 g, 2.65 mmol) was heated under reflux in mesitylene (10 mL) for 24 h. The solvent was removed under reduced pressure to yield a tarry brown solid. The crude solid was dissolved in hexanes (30 mL) and placed under reduced pressure in order to azeotropically remove any residual mesitylene. The resulting solid was filter-washed with cold hexane (30 mL) to yield 9 as a dark brown solid (793 mg, 79%); mp 89–91 °C. IR (thin film, CH₂Cl₂): 3416, 1634, 1262 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.58, 2.75, 3.26 (2 H, d, J = 6.4 Hz), 5.10 (2 H, s), 5.11–5.12 (1 H, m), 5.15 (1 H, q, J = 2.0 Hz), 5.90–5.97 (1 H, m), 6.14 (1 H, s), 6.74 (1 H, s), 6.82 (1 H, d, J = 7.6 Hz), 7.20 (1 H, t, J = 8.4 Hz), 7.36–7.49 (5 H, m), 7.65 (1 H, d, J = 8.4 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 34.3, 35.7, 36.4, 70.7, 106.5, 115.0, 116.2, 119.1, 120.1, 121.5, 125.0, 126.9, 128.0, 128.2, 128.5 (2 C), 129.2, 136.2, 137.0, 139.6, 147.0, 154.4, 156.3. HRMS–FAB: m/z calcd for C₂₃H₂₃NO₄: 377.1627; found: 377.1621 [M⁺].Fries Rearrangement of 12 4-(Allyloxy)-8-(benzyloxy)-1-methoxy-N,N-dimethyl-2-naphthamide (12, 1.68 g, 4.30 mmol) was heated to 160 °C in mesitylene, and the reaction was monitored by ¹H NMR analysis. After 3 h the mesitylene was removed by eva-poration under reduced pressure. The crude tarry brown solid was dissolved in hexanes and placed under reduced pressure in order to azeotropically remove any residual mesitylene. This process was repeated three times to give a light brown solid which was chromatographed on silica gel, eluting with light PE–EtOAc (1:1), to give 13 as a white solid (1.28 g, 76%); mp 169–170 °C. IR (ATR): 1594, 1570, 1261, 1058 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 2.82 (3 H, s), 3.16 (3 H, s), 3.24 (1 H, dd, J = 7.2, 16.2 Hz), 3.37 (1 H, dt, J = 1.8, 16.2 Hz), 3.73 (3 H, s), 5.12–5.18 (2 H, m), 5.22 (2 H, q, J = 12.0 Hz), 5.87–5.99 (1 H, m), 6.22 (1 H, s), 6.92 (1 H, d, J = 7.8 Hz), 7.31–7.43 (4 H, m), 7.54 (2 H, d, J = 6.9 Hz), 7.81 (1 H, dd, J = 0.6, 8.4 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 32.3, 34.6, 38.5, 63.7, 71.3, 108.2, 115.2, 116.2, 117.1, 119.7, 126.0, 127.5 (2 C), 127.8, 128.5 (2 C), 128.7, 129.0, 135.6, 137.0, 145.8, 146.8, 155.0, 169.4. HRMS (EI, CI): m/z calcd for C₂₄H₂₅NO₄: 392.1856; found: 392.1853 [MH⁺]
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