The Diels-Alder reaction is one of the most popular transformations for organic chemists to generate molecular complexity efficiently. Surprisingly, little is known about its industrial application for the synthesis of pharmacologically active ingredients, agrochemicals, and flavors and fragrances. This Review highlights selected examples, with a focus on large-scale applications (>1 kg) from a process research and development perspective.

The combination of catalytic amounts of [Pd(PPh3)4], copper thiophene-2-carboxylate (CuTC) and [Ph2PO2][NBu4] allowed a series of exigent Stille-Migita reactions to be performed with high yields; as the protocol is fluoride free, a variety of O-silyl and C-silyl groups remained intact.

General. NMR spectra were recorded with a Bruker DPX 300, AV 400, or DMX 600 spectrometer in the solvents indicated; chemical shifts (δ) are given in ppm relative to TMS, coupling constants (J) in Hertz. The solvent signals were used as references and the chemical shifts converted to the TMS scale (CDCl 3 : δ C = 77.0 ppm; residual CHCl 3 in CDCl 3 : δ H = 7.24 ppm; CD 2 Cl 2 : δ C = 53.8 ppm; residual CH 2 Cl 2 in CD 2 Cl 2 : δ H = 5.32 ppm). Where indicated, the signal assignments are unambiguous; the numbering scheme is arbitrary and is shown in the inserts. The assignments are based upon 1D and 2D spectra recorded using the following pulse sequences from the Bruker standard pulse program library: DEPT; COSY (cosygs and Negishi carboalumination: Preparation of vinyl iodide 25.A solution of AlMe 3 (2.0 M in heptane, 21.2 mL, 42.4 mmol) was added to a suspension of Cp 2 ZrCl 2 (4.64 g, 15.9 mmol) in 1,2-dichloroethane (70 mL). After stirring for 0.5 h, a solution of alkyne 24 (3.56 g, 10.57 mmol) in 1,2-dichloroethane (15 mL) was added dropwise. The resulting yellow solution was stirred for 24 h at ambient temperature before the mixture was cooled to −20°C and a solution of iodine (16.10 g, 63.5 mmol) in THF (60 mL) was slowly added. After stirring for 20 min at −20°C and 30 min at 0°C, the reaction was carefully quenched with water (10 mL). A sat. aq. Na 2 SO 3 solution was then added and the layers were separated. The aqueous phase was extracted twice with CH 2 Cl 2 (40 mL each), the combined organic extracts were washed with brine, dried over MgSO 4 and evaporated. .7, 135.7, 134.0, 129.7, 127.8, 75.4, 61.8, 39.9, 37.7, 27.0, 20.5, 19.6, 19.3 was added dropwise to a solution of epoxide 7 (7.6 g, 30.84 mmol) in toluene (25 mL) at −78°C over the course of 1 h. The temperature was then raised to −40°C and stirring continued for 4 h before the reaction was carefully quenched at −60°C with a solution of tBuOH in THF (1:1, 25 mL). The resulting mixture was poured into an icecold solution of Rochelle's salt (85g in 250 mL water) and vigorously stirred for 2 h until a clear separation of the phases was reached. The aqueous layer was extracted with tert-butyl methyl ether, the combined organic phases were dried over Na 2 SO 4 and evaporated, and the residue was purified by flash chromatography (hexanes:EtOAc, 1:1) to give product 8 as a

General. NMR spectra were recorded with a Bruker DPX 300, AV 400, or DMX 600 spectrometer in the solvents indicated; chemical shifts (δ) are given in ppm relative to TMS, coupling constants (J) in Hertz. The solvent signals were used as references and the chemical shifts converted to the TMS scale (CDCl 3 : δ C = 77.0 ppm; residual CHCl 3 in CDCl 3 : δ H = 7.24 ppm; CD 2 Cl 2 : δ C = 53.8 ppm; residual CH 2 Cl 2 in CD 2 Cl 2 : δ H = 5.32 ppm). Where indicated, the signal assignments are unambiguous; the numbering scheme is arbitrary and is shown in the inserts. The assignments are based upon 1D and 2D spectra recorded using the following pulse sequences from the Bruker standard pulse program library: DEPT; COSY (cosygs and Negishi carboalumination: Preparation of vinyl iodide 25.A solution of AlMe 3 (2.0 M in heptane, 21.2 mL, 42.4 mmol) was added to a suspension of Cp 2 ZrCl 2 (4.64 g, 15.9 mmol) in 1,2-dichloroethane (70 mL). After stirring for 0.5 h, a solution of alkyne 24 (3.56 g, 10.57 mmol) in 1,2-dichloroethane (15 mL) was added dropwise. The resulting yellow solution was stirred for 24 h at ambient temperature before the mixture was cooled to −20°C and a solution of iodine (16.10 g, 63.5 mmol) in THF (60 mL) was slowly added. After stirring for 20 min at −20°C and 30 min at 0°C, the reaction was carefully quenched with water (10 mL). A sat. aq. Na 2 SO 3 solution was then added and the layers were separated. The aqueous phase was extracted twice with CH 2 Cl 2 (40 mL each), the combined organic extracts were washed with brine, dried over MgSO 4 and evaporated. .7, 135.7, 134.0, 129.7, 127.8, 75.4, 61.8, 39.9, 37.7, 27.0, 20.5, 19.6, 19.3 was added dropwise to a solution of epoxide 7 (7.6 g, 30.84 mmol) in toluene (25 mL) at −78°C over the course of 1 h. The temperature was then raised to −40°C and stirring continued for 4 h before the reaction was carefully quenched at −60°C with a solution of tBuOH in THF (1:1, 25 mL). The resulting mixture was poured into an icecold solution of Rochelle's salt (85g in 250 mL water) and vigorously stirred for 2 h until a clear separation of the phases was reached. The aqueous layer was extracted with tert-butyl methyl ether, the combined organic phases were dried over Na 2 SO 4 and evaporated, and the residue was purified by flash chromatography (hexanes:EtOAc, 1:1) to give product 8 as a