Isolera prime

All starting materials and reagents were purchased from commercially available sources and used without further purification, with exception of CH₂Cl₂, which was purified on a solvent purification system prior to reactions.^{14 1}H NMR shifts are measured using the solvent residual peak as the internal standard (CHCl₃ δ 7.26), and reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, dd = doublet of doublet, q = quartet, m = multiplet), coupling constant (Hz), integration. ¹³C NMR shifts are measured using the solvent residual peak as the internal standard (CDCl₃ δ 77.16), and reported as chemical shifts. Infrared (IR) spectral bands are characterized as broad (br), strong (s), medium (m), and weak (w). Mass spectra were recorded on a spectrometer by electrospray ionization (ESI) technique and time-of-flight (TOF) mass analyzer Microwave reactions were performed via the Biotage® Intiator (External IR Temperature Sensor). Where noted, reaction products were purified via silica gel chromatography using a Biotage® Isolera Prime, with Biotage® SNAP 10g cartridges, in a solvent system of ethyl acetate in hexane.

Rhodium(II) acetate dimer (3.1 mg, .007 mmol) was added to a 2–5 mL microwave vial containing 5-methoxy-1,3-benzodioxole²⁰ (500 μL, 4 mmol). A solution of ethyl diazoacetate (143 μL, 1 mmol) in 5-methoxy-1,3-benzodioxole (125 μL, 1 mmol) was added dropwise into the stirring rhodium acetate solution over the course of 20 minutes. At the conclusion of addition, the mixture was allowed to stir at rt overnight. The crude mixture was then loaded onto a SiliaSep 25 g flash silica gel column and subjected to column chromatography (Biotage Isolera Prime, solvent gradient: 0% EtOAc in hexane (40 CV); 0–4% EtOAc in hexane (8 CV); 4–5% EtOAc in hexane (2 CV); 5% EtOAc in hexane (2 CV); 5–6% EtOAc in hexane (1 CV); 6% EtOAc in hexane (4 CV)). Product fractions were concentrated in vacuo to yield 24 as a yellow oil (88.5 mg, 37% yield). ¹H NMR (400 MHz, CDCl₃) δ 6.32 (d, J = 9.5 Hz, 1H), 5.69 (dd, J = 14.3, 1.7 Hz, 2H), 5.53 (s, 1H), 5.33 (dd, J = 9.5, 7.1 Hz, 1H), 4.31 – 4.14 (m, 2H), 3.63 (s, 3H), 3.32 (d, J = 7.1 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.0, 144.4, 140.3, 136.4, 116.9, 110.7, 98.4, 88.6, 61.3, 57.1, 49.9, 14.3. IR (thin film, KBr) 3427 (br), 2918 (m), 1743 (s), 1628 (s), 1314 (m), 1177 (m), 1033 (w), 742 (w) cm⁻¹. HRMS (ESI-TOF) m/z [M + H]⁺ calc’d for C₁₂H₁₅O₅⁺: 239.0914. Found: 239.0915.

Rhodium(II) acetate dimer (4 mg, .009 mmol) was added to a 2–5 mL microwave vial containing 1,2-dimethoxybenzene (675 μL, 5.28 mmol). A solution of ethyl diazoacetate (139 μL, 1.32 mmol) in 1,2-dimethoxybenzene (169 μL, 1.32 mmol) was added dropwise into the stirring rhodium acetate solution over the course of 20 minutes. At the conclusion of addition, the mixture was allowed to stir at rt overnight. The crude mixture was then loaded onto a SiliaSep 12 g flash silica gel column and subjected to column chromatography (Biotage Isolera Prime, solvent gradient: 3% EtOAc in hexane (20 CV); 3–6% EtOAc in hexane (5 CV); 6% EtOAc in hexane (7 CV); 6–12% EtOAc in hexane (5 CV)). Product fractions were concentrated in vacuo to yield 8 as a yellow oil (66 mg, 22% yield), with ¹H NMR data consistent with previously reported data.^{10 1}H NMR (400 MHz, CDCl₃) δ 5.34 (dd, J = 4.3, 2.5 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.59 (s, 6H), 2.82 – 2.76 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H), 0.76 (t, J = 3.9 Hz, 1H).

To a solution of 13/14 (20 mg, 0.0714mmol, 1 eq) in CDCl₃ (1 mL, 0.9 M) was added dimethyl acetylenedicarboxylate (16a, 100 μL, 0.814 mmol, 11 eq). The reaction was subjected to microwave irradiation at 150 °C for 2 h, and immediately purified by chromatography (Biotage Isolera Prime, SiliCycle SiliaSep 25 g silica gel, 40-63 μm 60 Å, solvent gradient: 0-25% EtOAc in hexanes (500 mL)). Product fractions were concentrated en vacuo to yield 15a as a pale, yellow oil (38 mg, 95% yield). R_f = 0.53 in 25% ethyl acetate. IR (thin film, KBr): 2956 (w), 2843 (w), 1716 (s), 1654 (w), 1614 (m), 1438 (m), 1379 (w), 1281 (b), 1146 (w), 1069 (s), 1005 (m), 933 (w), 902 (w), 878 (w), 847 (w), 812 (w), 787 (w), 766 (w), 700 (w), 6309 (w) cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 6.15 (d, J = 4.9 Hz, 1H), 5.39 (d, J = 4.9 Hz, 1H), 3.79 (d, J = 6.4 Hz, 6H), 3.56 (s, 3H), 1.59 (s, 3H). ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 188.2, 163.1, 162.1, 146.5, 146.4, 143.1, 114.4, 94.0, 78.2, 55.1, 52.8. 52.8, 16.2. HRMS (ESI-TOF)m/z: [M+H]⁺ calc’d for C₁₃H₁₅O₇⁺ : 283.0812 Found: 283.0817