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. 2012 Mar 16;14(6):1616-9.
doi: 10.1021/ol300364s. Epub 2012 Mar 2.

Nickel-catalyzed cross-coupling of chromene acetals and boronic acids

Thomas J A Graham  1 , Abigail G Doyle
Affiliations

Nickel-catalyzed cross-coupling of chromene acetals and boronic acids

Thomas J A Graham et al. Org Lett. .

Abstract

A modular and highly efficient protocol for the synthesis of 2-aryl- and heteroaryl-2H-chromenes is described. Under base-free conditions, readily accessible 2-ethoxy-2H-chromenes undergo C(sp(3))-O activation and C(sp(3))-C bond formation in the presence of an inexpensive nickel catalyst and boronic acids. This new strategy enables broad access to 2-substituted-2H-chromenes and has been applied to the late-stage incorporation of complex molecules, including the pharmaceuticals loratidine and indomethacin methyl ester.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Pharmacologically active and photochromic chromene derivatives.
Figure 2
Figure 2
Scope of Ni-catalyzed coupling of aryl- and heteroarylboronic acids with 2-ethoxy-2H-chromene 1a.a a General conditions (yields are the average of two runs, 0.50 mmol scale): Ni(cod)2 (10 mol %), PPh3 (10 mol %), 0.02 M, 23 or 40 °C. b10 mmol scale, Ni(cod)2 (5 mol %), PPh3 (5 mol %), 0.20 M, 40 °C, 14 h. c8:1 rr. dNi(cod)2 (10 mol %), PPh3 (30 mol %), 100 °C. eBoronic acid prepared from the chloride, see Supporting Information for details. f0.10 mmol, one run. gContains PPh3 as a minor impurity.
Figure 3
Figure 3
Scope of 2-ethoxy-2H-chromenes.a a Conditions (yields are the average of two runs, 0.50 mmol): Ni(cod)2 (10 mol %), PPh3 (10 mol %), 0.02 M, 40 °C. bNi(cod)2 (10 mol %), PPh3 (30 mol %), 100 °C (one run).
Scheme 1
Scheme 1
Synthetic Strategies for Chromene Synthesis

  1. Feasibility independent of electronic/steric properties of reaction partners

  2. First example of Suzuki–Miyaura cross-coupling with allylic acetals

Scheme 2
Scheme 2
Late-Stage Chromene Acetal Couplinga aConditions: (a) acetal 1a, 2 equiv of aryl boronic acid, Ni(cod)2 (10 mol %), PPh3 (30 mol %), dioxane/t-AmOH (10:1), 100 °C; see Supporting Information for further details.
See this image and copyright information in PMC

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