Synlett 2019; 30(07): 787-791
DOI: 10.1055/s-0037-1611228
letter
© Georg Thieme Verlag Stuttgart · New York

A Cascade Suzuki–Miyaura/Diels–Alder Protocol: Exploring the Bifunctional Utility of Vinyl Bpin

David L. Cain
a   EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK   Email: aw260@st-andrews.ac.uk
,
Calum McLaughlin
b   WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK
,
John J. Molloy
b   WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK
,
Cameron Carpenter-Warren
a   EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK   Email: aw260@st-andrews.ac.uk
,
Niall A. Anderson
c   GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road Stevenage, Hertfordshire, SG1 2NY, UK
,
a   EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK   Email: aw260@st-andrews.ac.uk
› Author Affiliations
Industrial CASE studentship awarded from EPSRC and GlaxoSmithKline.
Further Information

Publication History

Received: 07 September 2018

Accepted: 30 September 2018

Publication Date:
24 October 2018 (online)


Published as part of the Special Section 10th EuCheMS Organic Division Young Investigator Workshop

Abstract

Cascade reactions are an important strategy in reaction ­design, allowing streamlining of chemical synthesis. Here we report a cascade Suzuki–Miyaura/Diels–Alder reaction, employing vinyl Bpin as a bifunctional reagent in two distinct roles: as an organoboron nucleo­phile for cross-coupling and as a Diels–Alder dienophile. Merging these two reactions enables a rapid and operationally simple synthesis of functionalized carbocycles in good yield. The effect of the organoboron subtype on Diels–Alder regioselectivity was investigated and postsynthetic modifications were carried out on a model substrate. The potential for a complementary Heck/Diels–Alder process was also assessed.

Supporting Information

 
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  • 29 General Experimental Procedure for the Tandem Suzuki–Miyaura/Diels–Alder Reaction Pd(OAc)2(4 mol%), SPhos (8 mol%), vinyl (pseudo)halide (1 equiv), vinyl Bpin (5–7 equiv), and K3PO4(3 equiv) were weighed into an oven-dried microwave vial. The reaction vessel was then capped and purged with N2 before the addition of 1,4-dioxane (0.125 M) and H2O (5 equiv). The reaction mixture was heated at 50 °C with stirring. After 1 h the temperature was increased to 150 °C, and the reaction mixture was stirred for 23 h. The reaction mixture was allowed to cool to room temperature, vented, and de-capped. The reaction mixture was diluted with EtOAc (20 mL) and passed through a layer of Celite, eluting with EtOAc. The filtrate was concentrated under reduced pressure. THF (0.25 M) was added to the crude residue, and the solution was cooled to 0 °C before the addition of H2O2 (30% w/v, 20 equiv) and 2 M NaOH (4 equiv) sequentially. After 5 min the reaction mixture was allowed to warm to room temperature and was stirred for 1 h. The mixture was quenched with Na2S2O3 at 0 °C until effervescence ceases and diluted with sat. aq. NH4Cl. The organics were extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to afford the desired products. Compound 4a Prepared according to General Procedure using 6-methoxy-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (77.0 mg, 0.25 mmol, 1 equiv), Pd(OAc)2 (2.2 mg, 0.01 mmol, 4 mol%), SPhos (8.2 mg, 0.02 mmol, 8 mol%), vinyl Bpin (192 mg, 1.25 mmol, 5 equiv), K3PO4 (159 mg, 0.75 mmol, 3 equiv), 1,4-dioxane (2 mL, 0.125 M) and H2O (22.5 μL, 1.25 mmol, 5 equiv), then aqueous H2O2 (30% w/v, 500 μL, 5 mmol, 20 equiv), 2 M NaOH (500 μL, 1 mmol, 4 equiv), and THF (1 mL). After the reaction was complete, the reaction mixture was subjected to the purification method outlined in the General Procedure (silica gel, 0–60% EtOAc in PE 40–60°) to afford the desired mixture of products as a yellow oil (41.3 mg, 72%, 3:1 r.r.). The major regioisomer was separated by column chromatography (ca. 95% purity). Data for the Major Regioisomer IR (film): νmax = 3364 (br), 2914, 2847, 2830, 1605, 1493, 1456, 1279, 1253, 1231, 1034 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.51 (dd, J = 8.8, 6.0 Hz, 1 H), 6.71 (dd, J = 8.8, 2.5 Hz, 1 H), 6.60 (d, J = 2.6 Hz, 1 H), 6.07–6.02 (m, 1 H), 4.04–3.95 (m, 1 H), 3.79 (s, 3 H), 2.95–2.75 (m, 2 H), 2.61–2.54 (m, 1 H), 2.52–2.39 (m, 1 H), 2.23–2.10 (m, 2 H), 2.02–1.94 (m, 1 H), 1.54–1.49 (m, 1 H), 1.46–1.36 (m, 1 H). 13C NMR (101 MHz, CDCl3): δ = 158.7, 138.0, 135.7, 127.1, 125.1, 115.5, 113.4, 112.9, 67.7, 55.4, 40.7, 36.7, 36.1, 31.2, 30.5. HRMS: m/z calcd for [M + H]+ (C15H19O2): 231.1380; found: 231.1378.