Stig D. Friis, Rolf H. Taaning, Anders T. Lindhardt, and Troels Skrydstrup* Supporting Information

Transcription

1 Stig D. Friis, Rolf H. Taaning, Anders T. Lindhardt, and Troels Skrydstrup* The Center for Insoluble Protein Structures (inspin), Department of Chemistry and the Interdisciplinary Nanoscience Center, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark. Supporting Information S1

2 1. General Methods S3 2. Synthesis of Silacarboxylic acids S4 3. Decarbonylation experiments S6 4. Palladium catalyzed carbonylative couplings S13 5. NMR spectra S17 6. Gas yield calculation example S30 7. Gas release data S31 S2

3 1. General Methods Dry solvents were prepared according to standard literature procedures, 1 all other chemicals were used as received from the suppliers unless mentioned. Starting materials were made according to literature. Flash column chromatography was carried out on silica gel 60 ( mesh). 1 H- and 13 C-NMR spectra were recorded at 400 MHz and 100 MHz, respectively using a Varian Mercury 400 spectrometer. Chemical shifts are reported in ppm relative to the solvent residual peak, 2 using the following peak pattern abbreviations: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; pent, pentet; sext, sextet; sept, septet; m, multiplet; dd, doublet of doublets; dt, doublet of triplets; ddd, doublet of doublet of doublets; ddt, doublet of doublet of triplets, and td, triplet of doublets. HRMS was recorded on a LC TOF (ES) or a microtof-q. 1 Perrin, D.; Armarego, W. Purification of Laboratory Chemicals 3rd Ed, Pergamon Press, Gottlieb, H. E., Kotlyar V., Nudelman A. J. Org. Chem. 1997, 62, S3

4 2. Synthesis of Silacarboxylic acids Dimethyl(phenyl)silacarboxylic acid (1) Small pieces of lithium (100 mg, 14 mmol) were added to dry THF (5 ml) under argon. Chlorodimethyl(phenyl)silane (0.50 ml, 3.0 mmol) was added via syringe and the reaction stirred under argon. After 5 h the resulting black solution was transferred to a dry flask under argon and cooled to -78 C. The argon atmosphere was exchanged for CO 2 using a balloon and the reaction was stirred like this for 20 min before the cold bath was removed. After having warmed to room temperature, the reaction mixture was slowly poured into a separation funnel with 1 M aqueous HCl (30 ml) and CH 2 Cl 2 (25 ml). After phase separation the aqueous phase was extracted with CH 2 Cl 2 (2 25 ml). The combined organic phase was dried over MgSO 4, filtered and concentrated in vacuo to give a brown solid. The crude product was purified by flash column chromatography using 5% Et 2 O and 0.5% HCO 2 H in pentane as eluent, and yielded the title compound 1 as colorless needles (427 mg, 79%). 1 H NMR (400 MHz, CDCl 3 ) (ppm) (br s, 1H), 7.63 (dd, J = 7.6 Hz, 1.6 Hz, 2H), (m, 3H), 0.56 (s, 6H). 13 C NMR (100 MHz, CDCl 3 ) (ppm) 193.2, (2C), 133.1, 130.3, (2C), (2C). HRMS: C 9 H 12 O 2 Si [M+Na + ]; calculated: , found: Methyldiphenylsilacarboxylic acid (2) Small pieces of lithium (750 mg, 108 mmol) were added to dry THF (60 ml) under argon. Chloro(methyl)diphenylsilane (5.0 ml, 24 mmol) was slowly added and the reaction was stirred for 5 h. The resulting black solution was transferred to a dry flask under argon and cooled to -78 C. After exchanging the argon atmosphere with CO 2 the reaction was stirred under CO 2 for 20 min. The cold bath was removed and the reaction mixture was allowed to warm to room temperature, still being under CO 2. The reaction was then slowly added to a stirring mixture of 1 M aqueous HCl (125 ml) and pentane (20 ml) and following phase separation the aqueous phase was extracted with CH 2 Cl 2 (4 20 ml). Drying of the combined organic phase over MgSO 4, filtration and concentration in vacuo gave a slightly yellow solid. Recrystallization from n-heptane afforded the title compound 2 as colorless square crystals (4.43 g, 77%). 1 H NMR (400 MHz, CDCl 3 ) (ppm) (br s, 1H), 7.67 (dd, J = 8.0 Hz, 1.6 Hz, 4H), (m, 6H), 0.84 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) (ppm) 190.4, (4C), (2C), (2C), (4C), HRMS: C 14 H 14 O 2 Si [M+Na + ]; calculated: , found: S4

5 tert-butyldiphenylsilacarboxylic acid (3) Small pieces of lithium (200 mg, 29 mmol) were added to dry THF (15 ml) under argon, followed by slow addition of tert-butylchlorodiphenylsilane (1.0 ml, 3.8 mmol). After having stirred for 5 h, the resulting black solution was transferred to a dry flask under argon and cooled to -78 C. The argon atmosphere was exchanged with CO 2 using a balloon and the reaction was stirred under CO 2 for 20 min, before the cold bath was removed. After having warmed to room temperature, the reaction was slowly poured into a stirring mixture of 1M aqueous HCl (40 ml) and pentane (10 ml). After phase separation the aqueous phase was extracted with CH 2 Cl 2 (3 15 ml). Drying of the combined organic phase with MgSO 4, filtration and concentration in vacuo resulted in a slightly yellow solid. Recrystallization from n-heptane afforded the desired product 3 as colorless needles (847 mg, 77%). 1 H NMR (400 MHz, CDCl 3 ) (ppm) 7.71 (dd, J = 8.0 Hz, 1.6 Hz, 4H), (m, 6H), 1.21 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) (ppm) 188.8, (4C), (2C), (2C), (4C), 27.3 (3C), HRMS: C 17 H 20 O 2 Si [M+Na + ]; calculated: , found: [ 13 C]-Methyldiphenylsilacarboxylic acid (11) Small pieces of lithium (1.0 g, 144 mmol) were added to dry THF (120 ml) under argon. Chloro(methyl)diphenylsilane (11.0 ml, 52.2 mmol) was slowly added and the reaction was stirred for 6 h. The resulting black solution was transferred to a dry flask under argon and cooled to -78 C. Vacuum was applied to the flask before 13 CO 2 from a pressurized container (loading pressure 2.36 atm, loading temperature 300K, cylinder volume 461 ml, 44.2 mmol) was added. After 20 min a balloon with argon was put on the reaction flask and the reaction was stirred overnight at -78 C. After 16 h the brown solution was slowly added to a cold stirred mixture of 1M HCl (200 ml) and pentane (30 ml) via cannula. After phase separation the aqueous phase was extracted with CH 2 Cl 2 (3 50 ml). Drying of the combined organic phase over MgSO 4, filtration and concentration in vacuo afforded the crude product. This was purified by recrystallization from n-heptane to give the title product 11 as colorless square crystals (10.7 g, 99%). 1 H NMR (400 MHz, CDCl 3 ) (ppm) (br s, 1H), (m, 4H), (m, 6H), 0.84 (d, J = 2.4 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) (ppm) ( 13 C-enriched), (d, J = 0.9 Hz, 4C), (d, J = 4.9 Hz, 2C), (2C), (4C), -5.2 (d, J = 4.6 Hz). HRMS: C CH 14 O 2 Si [M+Na + ]; calculated: , found: S5

6 Gas release [%] 3. Decarbonylation experiments Gas volume measurements, General Procedure A Silacarboxylic acid CO precursor (0.5 mmol) and activator (0.55 mmol) was weighed into a crimp cap vial. This was closed and connected to a gasvolumeter (Figure 1), through the septum via a needle. The water level was noted, before the addition of solvent (2.0 ml) to the vial and lowering into heat bath if required. Monitoring of the water level over time with continuous alignment of the water level in the two tubes, give a time resolved measure of gas evolution. When the water level was constant in time, the heat bath, if one was used, was removed and the reaction was allowed to cool to room temperature. The water level was again noted, giving a measure of the complete gas evolution of the reaction, excluding gas expansion due to heating. Finally the gas volumes were converted into amount of CO utilizing the ideal gas equation and plotted as percentage of the theoretical amount of CO against time. 3,4 Figure 1. Gas-volumeter Dimethyl(phenyl)silacarboxylic acid (1), with KF in dioxane at 60 C General procedure A was employed using KF and CO precursor 1 in dioxane. Heating the reaction to 60 C afforded a 90 % gas yield. Gas release complete at 12 min with KF in Dioxane, 60 C Heat bath removed at Final volume measured at 25 min 30 min Time [min] 3 The atmospheric pressure measured by the National Danish Whether Service (DMI) at the time and place of the experiment was used. 4 A calculation example is shown later in the Supporting Information. S6

7 Gas release [%] Gas release [%] Gas release [%] Methyldiphenylsilacarboxylic acid (2), with KF in dioxane at 40 C General procedure A was employed using KF and CO precursor 2 in dioxane. Heating the reaction to 40 C afforded a 95 % gas yield. Gas release complete at 10 min Heat bath removed at 20 min Final volume measured at 25 min 2 with KF in Dioxane, 40 C Time [min] tert-butyldiphenylsilacarboxylic acid (3), with KF in dioxane at 40 C General procedure A was employed using KF and CO precursor 3 in dioxane. Heating the reaction to 40 C afforded a 97 % gas yield. Gas release complete at 20 min Heat bath removed at 30 min Final volume measured at 35 min 3 with KF in Dioxane, 40 C Time [min] Methyldiphenylsilacarboxylic acid (2), with KF in DMF at rt General procedure A was employed using KF and CO precursor 2 in dioxane. Stirring the reaction at room temperature afforded a 94 % gas yield with KF in DMF, rt Gas release complete at Final volume measured at 1 min 5 min Time [min] S7

8 Gas release [%] Gas release [%] Gas release [%] Methyldiphenylsilacarboxylic acid (2), with KF in THF at 40 C General procedure A was employed using KF and CO precursor 2 in THF. Heating the reaction to 40 C afforded a 96 % gas yield. Gas release complete at 5 min Heat bath removed at 12 min Final volume measured at 20 min 2 with KF in THF, 40 C Time [min] Methyldiphenylsilacarboxylic acid (2), with KF in PEG5000 at 70 C General procedure A was employed using KF and CO precursor 2 in poly(ethylene glycol) methyl ether (1.0 g). Heating the reaction to 70 C afforded a 94 % gas yield. Gas release complete at 20 min Heat bath removed at 35 min Final volume measured at 50 min 2 with KF in PEG5000, 70 C Time [min] Methyldiphenylsilacarboxylic acid (2), with KF in water at 70 C General procedure A was employed using KF and CO precursor 2 in water. Heating the reaction to 70 C afforded a 41 % gas yield with KF in Water, 70 C Gas release complete at Heat bath removed at Final volume measured at 20 h 23 h 24 h Time [h] S8

9 Gas release [%] Gas release [%] Gas release [%] Methyldiphenylsilacarboxylic acid (2), with TBAF in dioxane at rt CO precursor 2 (121 mg, 0.50 mmol) was weighed into a crimp cap vial and dissolved in dioxane (2.0 ml). After closing the vial and connection of the gas-volumeter, 1M TBAF in THF (0.55 ml, 0.55 mmol) was added and the gas evolution was monitored over time. When the expansion seized a 100 % gas yield resulted. Gas release complete at 1 min 2 with TBAF in Dioxane, rt Time [min] Final volume measured at 5 min Methyldiphenylsilacarboxylic acid (2), with CsF in dioxane at rt General procedure A was employed using CsF and CO precursor 2 in dioxane. Stirring the reaction at room temperature afforded a 94 % gas yield with CsF in Dioxane, rt Gas release complete at Final volume measured at 7 min 16 min Time [min] Methyldiphenylsilacarboxylic acid (2), with MeOK in dioxane at 40 C General procedure A was employed using MeOK and CO precursor 2 in dioxane. Heating the reaction to 40 C afforded a 97 % gas yield with MeOK in Dioxane, 40 C Gas release complete at Heat bath removed at Final volume measured at 7 min 15 min 25 min Time [min] S9

10 Gas release [%] Gas release [%] Gas release [%] Methyldiphenylsilacarboxylic acid (2), with t-buok in dioxane at 40 C General procedure A was employed using t-buok and CO precursor 2 in dioxane. Heating the reaction to 40 C afforded a 86 % gas yield with t-buok in Dioxane, 40 C Gas release complete at Heat bath removed at Final volume measured at 5 min 150 min 180 min Time [min] Methyldiphenylsilacarboxylic acid (2), with MePh 2 SiOK in dioxane at 40 C Modified general procedure A was employed, using MePh 2 SiOK and CO precursor 2 in dioxane. The reaction was setup in a glovebox due to the hygroscopic nature of MePh 2 SiOK. Heating the reaction to 40 C afforded a 99 % gas yield with MePh 2 SiOK in Dioxane, 40 C Gas release complete at Heat bath removed at Final volume measured at 10 min 20 min 30 min Time [min] Methyldiphenylsilacarboxylic acid (2), with 0.5 eq. of KF in dioxane at 40 C Modified general procedure A was employed using CO precursor 2, but only 0.5 equivalents of KF in dioxane. Heating the reaction to 40 C afforded a 94 % gas yield with 0.5 eq KF in Dioxane, 40 C Gas release complete at Heat bath removed at Final volume measured at 20 min 60 min 70 min Time [min] S10

11 Gas release [%] Gas release [%] Gas release [%] Methyldiphenylsilacarboxylic acid (2), with 0.25 eq. of KF in dioxane at 40 C Modified general procedure A was employed using CO precursor 2, but only 0.25 equivalents of KF in dioxane. Heating the reaction to 40 C afforded a 94 % gas yield with 0.25 eq KF in Dioxane, 40 C Gas release complete at Heat bath removed at Final volume measured at 30 min 35 min 45 min Time [min] Methyldiphenylsilacarboxylic acid (2), with 0.1 eq. of KF in dioxane at 40 C Modified general procedure A was employed using CO precursor 2, but only 0.1 equivalents of KF in dioxane. Heating the reaction to 40 C afforded a 92 % gas yield with 0.1 eq KF in Dioxane, 40 C Gas release complete at Heat bath removed at Final volume measured at 120 min 130 min 150 min Time [min] Methyldiphenylsilacarboxylic acid (2), with 0.05 eq. of KF in dioxane at 40 C Modified general procedure A was employed using CO precursor 2, but only 0.05 equivalents of KF in dioxane. Heating the reaction to 40 C afforded a 78 % gas yield with 0.05 eq KF in Dioxane, 40 C Gas release complete at Heat bath removed at Final volume measured at 48 h 66 h 67 h Time [h] S11

12 N-hexyl-4-methoxybenzamide (4) This method is representative for aminocarbonylations yielding 4. In a glovebox under argon, in a two chamber system (Figure 2). 5 Methyldiphenylsilacarboxylic acid (2) (82 mg, 0.34 mmol) and KF (21 mg, 0.36 mmol) were weighed into chamber A. Pd(dba) 2 (14 mg, 0.02 mmol), PPh 3 (13 mg, 0.05 mmol), and 4-iodoanisole (117 mg, 0.50 mmol) were weighed into chamber B followed by the addition of dry dioxane (3 ml), triethylamine (139 L, 1.0 mmol), and 1-hexylamine (132 L, 1.0 mmol). Lastly, dry dioxane (3 ml) was added to chamber A, the system was closed, and heated to 80 C. After 16 h the reaction mixture in chamber B was concentrated in vacuo and the product purified by flash column chromatography in 20% EtOAc in pentane. The product was isolated as a pale yellow solid (80 mg, 100%). 1 H NMR (400 MHz, CDCl 3 ) (ppm) 7.72 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.02 (br s, 1H), 3.84 (s, 3H), 3.43 (q, J = 6.0 Hz, 2H), (m, 2H), (m, 6H), 0.89 (t, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) (ppm) 167.0, 161.9, (2C), 127.2, (2C), 55.3, 40.1, 31.5, 29.7, 26.7, 22.5, HRMS: C 14 H 21 NO 2 [M+H + ]; calculated: , found: Figure 2. Two chamber system 5 Hermange, P.; Lindhardt, A. T.; Taaning, R. H.; Bjerglund, K.; Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, S12

13 4. Palladium catalyzed carbonylative couplings Methyl 5-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)-2-(methoxymethoxy)benzoate (5) In a glovebox under argon, in a two chamber system.5 methyldiphenylsilacarboxylic acid (2) (182 mg, 0.75 mmol) and KF (48 mg, 0.83 mmol) were weighed into chamber A. Pd(dba) 2 (14 mg, 0.02 mmol), PPh 3 (13 mg, 0.05 mmol), and methyl 5-iodo-2-(methoxymethoxy)benzoate (162 mg, 0.50 mmol) were weighed into chamber B followed by the addition of dry dioxane (3.0 ml), triethylamine (139 L, 1.0 mmol), and cyclopropyl(piperazin-1-yl)methanone (154 mg, 1.0 mmol). Lastly dry dioxane (3.0 ml) was added to chamber A, the system was closed and heated to 70 C. After 16 h the reaction mixture in chamber B was concentrated in vacuo. Purification by flash column chromatography using 0-1.5% MeOH in EtOAc yielded the title compound as a colorless wax (156 mg, 82%). 1 H NMR (400 MHz, CDCl 3 ) (ppm) 7.87 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 5.27 (s, 2H), 3.87 (s, 3H), 3.67 (br s, 8H), 3.50 (s, 3H), 1.71 (br s, 1H), (m, 2H), (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) (ppm) 172.3, 169.3, 165.6, 157.9, 132.5, 130.9, 128.0, 121.1, 115.9, 94.8, 56.4, 52.2, 45.2 (2C, br), 42.1 (2C, br), 11.0, 7.6 (2C). HRMS: C 19 H 24 N 2 O 6 [M+H + ]; calculated: , found: Cyclopropylmethyl quinoline-8-carboxylate (6) In a glovebox under argon, in a two chamber system.5 Methyldiphenylsilacarboxylic acid (2) (181 mg, 0.75 mmol) and KF (48 mg, 0.82 mmol) were weighed into chamber A. Pd(OAc) 2 (4.6 mg, 0.02 mmol), dcpp 2HBF 4 (13.6 mg, 0.02 mmol), quinolin-8-yl 4-methylbenzenesulfonate (150 mg, 0.50 mmol), K 2 CO 3 (138 mg, 1.0 mmol), and 4Å MS (100 mg) were then weighed into chamber B followed by addition of cyclopropylmethanol (122 L, 1.5 mmol) and dry toluene (0.5 ml). Lastly dry toluene (0.5 ml) was added to chamber A, the system was closed, and heated to 90 C for 16 h. The content of chamber B was filtered through celite with EtOAc and concentrated in vacuo to give at yellow liquid. The desired product was isolated as a colorless solid (85 mg, 75%) after flash column chromatography using 20% EtOAc in pentane. 1 H NMR (400 MHz, CDCl 3 ) (ppm) 9.06 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.19 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 8.06 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 7.94 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.58 (dd, J = 8.4 Hz, 7.2 Hz, 1H), 7.46 (dd, J = 8.4 Hz, 4.0 Hz, 1H), 4.32 (d, J = 7.2 Hz, 2H), (m, 1H), (m, 2H), (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) (ppm) 167.7, 151.4, 145.5, 136.1, 131.9, 131.1, 130.2, 128.4, 125.5, 121.5, 70.2, 9.9, 3.4 (2C). HRMS: C 14 H 13 NO 2 [M+Na + ]; calculated: , found: S13

14 Ethyl 4-(2-oxo-2-(pyrrolidin-1-yl)acetyl)benzoate (7) In a glovebox under argon, in a two chamber system.5 methyldiphenylsilacarboxylic acid (2) (365 mg, 1.50 mmol) and KF (94 mg, 1.62 mmol) were weighed into chamber A, and Pd(t-Bu 3 P) 2 (5.5 mg, 0.01 mmol) were weighed into chamber B. Dry THF (5.0 ml) was then added to chamber B, followed by ethyl 4-iodobenzoate (138 mg, 0.50 mmol), pyrrolidine (100 L, 1.22 mmol), and DBU (150 L, 2.01 mmol). Dry THF (1.0 ml) was then added to chamber A and the system was closed. After having stirred at room temperature for 2 h, the content of chamber B was concentrated in vacuo. Purification by flash column chromatography using 30% Et 2 O in pentane, yielded the title compound 7 as a slightly yellow solid (124 mg, 91%). 1 H NMR (400 MHz, CDCl 3 ) (ppm) 8.14 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 4.40 (q, J = 7.2 Hz, 2H), 3.66 (t, J = 7.2 Hz, 2H), 3.44 (t, J = 6.8 Hz, 2H), 1.97 (t, J = 7.2 Hz, 2H), 1.95 (t, J = 6.8 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) (ppm) 190.6, 165.4, 164.1, 136.1, 135.4, (2C), (2C), 61.5, 46.7, 45.4, 25.9, 23.9, HRMS: C 15 H 17 NO 4 [M+Na + ]; calculated: , found: (E)-3-(3,4-Dimethoxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (8) In a glovebox under argon, in a two chamber system.5 methyldiphenylsilacarboxylic acid (2) (182 mg, 0.75 mmol) and KF (4.4 mg, 0.08 mmol) were weighed into chamber A. [Pd(cinnamyl)Cl] 2 (6.5 mg, 0.01 mmol) and 4-iodoanisole (118 mg, 0.50 mmol) were weighed into chamber B. Dry dioxane (1.8 ml) was added to chamber B followed by CataCXium A stock solution (200 L, mmol) in dioxane, 3,4-dimethoxystyrene (148 L, 1.00 mmol), and dicyclohexylmethylamine (321 L, 1.50 mmol). Dioxane (2.0 ml) was then added to chamber A, the system was closed, and heated to 95 C. After 40 h the reaction mixture of chamber B was concentrated in vacuo. The title compound 8 was isolated as a pale yellow solid (116 mg, 77%) after flash column chromatography using 0-70 % Et 2 O in pentane. 1 H NMR (400 MHz, CDCl 3 ) (ppm) 8.02 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 15.6 Hz, 1H), 7.39 (d, J = 15.6 Hz, 1H), 7.21 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.87 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) (ppm) 188.7, 163.2, 151.2, 149.2, 144.1, 131.3, (2C), 128.0, 122.9, 119.8, (2C), 111.1, 110.0, 56.0, 55.9, HRMS: C 18 H 18 O 4 [M+H + ]; calculate: , found: (4-Methoxyphenyl)hept-2-yn-1-one (9) In a glovebox under argon, in a two chamber system.5 methyldiphenylsilacarboxylic acid (2) (291 mg, 1.20 mmol) and CsF (201 mg, 1.32 mmol) were weighed into chamber A. PdCl 2 (PPh 3 ) 2 (28 mg, 0.04 mmol) and 4-iodoanisole (188 mg, 0.80 mmol) were weighed into chamber B. Water (1.0 ml) was then added to chamber B followed by triethylamine (335 L, 2.40 mmol) and 1-hexyne (138 L, 1.20 mmol). Lastly dry S14

15 dioxane (1.0 ml) was added to chamber A, the system was closed, and stirred at room temperature for 16 h. The reaction mixture from chamber B was then poured into water (10 ml) and extracted with CH 2 Cl 2 (4 15 ml). Drying of the combined organic phase over MgSO 4, filtration and concentration in vacuo followed by flash column chromatography in 0-3.5% EtOAc in pentane afforded the title compound 9 as a slightly yellow liquid (143 mg, 82 %). 1 H NMR (400 MHz, CDCl 3 ) (ppm) 8.10 (d, J = 9.2 Hz, 2H), 6.94 (d, J = 9.2 Hz, 2H), 3.88 (s, 3H), 2.49 (t, J = 7.2 Hz, 2H), (m, 2H), (m, 2H), 0.96 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) (ppm) 176.9, 164.2, (2C), 130.3, (2C), 95.9, 79.6, 55.5, 29.9, 22.1, 18.9, HRMS: C 14 H 16 O 2 [M+H + ]; calculated: , found: N-Methyl-4-((E)-1-methyl-4-oxo-3-phenylazetidin-2-yl)benzamide (10) In a glovebox under argon, in a two chamber system.5 methyldiphenylsilacarboxylic acid (2) (113 mg, 0.47 mmol) and KF (29 mg, 0.51 mmol) were weighed into chamber A. Pd 2 (dba) 3 (6.9 mg, mmol), (E)-N-methyl-4-((methylimino)methyl)benzamide (57 mg, 0.32 mmol), and potassium (E)-2- benzylidene-1-tosylhydrazin-1-ide (211 mg, 0.68 mmol) were weighed into chamber B, followed by the addition of 1,2- dichloroethane (5.0 ml). Lastly 1,2-dichloroethane (2.0 ml) was added to chamber A, the system was closed, and heated to 60 C. After 24 h chamber B was concentrated. Flash column chromatography in % EtOAc in pentane afforded the desired product as a colorless solid (59 mg, 62%). 1 H NMR (400 MHz, CDCl 3 ) (ppm) 7.83 (d, J = 8.4 Hz, 2H), (m, 7H), 6.38 (br d, J = 4.0 Hz, 1H), 4.48 (d, J = 2.0 Hz, 1H), 4.12 (m, 1H), 3.01 (d, J = 4.8 Hz, 3H), 2.86 (d, J = 0.8 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) (ppm) 168.2, 167.5, 140.8, 135.1, 134.6, (2C), (3C), (2C), (2C), 65.9, 64.9, 27.2, HRMS: C 18 H 18 N 2 O 2 [M+Na + ]; calculated: , found: [ 13 C]-3-(Cyclopentyloxy)-N-(3,5-dichloropyridin-4-yl)-4-methoxybenzamide (12) In a glovebox under argon, in a two chamber system.5 [ 13 C]-methyldiphenylsilacarboxylic acid (11) (122 mg, 0.50 mmol) and KF (32 mg, 0.55 mmol) were weighed into chamber A. Pd(OAc) 2 (6.7 mg, 0.03 mmol), CataCXium A (21.5 mg, 0.06 mmol), 2-(cyclopentyloxy)-4-iodo-1-methoxybenzene (191 mg, 0.60 mmol), and 3,5-dichloropyridin-4-amine (98 mg, 0.60 mmol) were weighed into chamber B, followed by addition of dry toluene (3.0 ml) and DBU (179 L, 1.20 mmol). Lastly dry toluene (2.0 ml) was added to chamber A, the system was closed and heated to 70 C. After 21 h the content of chamber B was concentrated under reduced pressure. Purification by flash column chromatography with increasing polarity from 20% EtOAc in pentane to 1% MeOH in EtOAc afforded the carbon-13 labeled title compound as a colorless solid (141 mg, 74%). 1 H NMR (400 MHz, CDCl 3 ) (ppm) 8.52 (s, 2H), 7.86 (s, 1H), (m, 2H), 7.90 (d, J = 8.0 Hz, 1H), 4.84 (sept, J = 3.2 Hz, 1H), 3.91 (s, 3H), (m, 6H), (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) (ppm) ( 13 C-enriched), 153.8, (2C), (d, J = S15

16 5.3 Hz), 140.3, (2C), (d, J = 68.9 Hz), (d, J = 2.6 Hz), (d, J = 3.0 Hz), (d, J = 5.3 Hz), 80.6, 56.0, 32.6 (2C), 23.9 (2C). HRMS: C CH 18 Cl 2 N 2 O 3 [M+H + ]; calculated: , found: [ 13 C]-1-(4-Benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (13) In a glovebox under argon, in a two chamber system.5 [ 13 C]-methyldiphenylsilacarboxylic acid (11) (365 mg, 1.50 mmol) and KF (96 mg, 1.65 mmol) were weighed into chamber A. Pd(t-Bu 3 P) 2 (5.2 mg, 0.01 mmol), tert-butyl 3-iodo-1H-indole-1-carboxylate (173 mg, 0.50 mmol), and phenyl(piperazin-1-yl)methanone (287 mg, 1.51 mmol) were weighed into chamber B followed by addition of dry THF (5.0 ml) and DBU (150 L, 1.00 mol). Lastly dry THF (2.0 ml) was added to chamber A, the system was closed, and stirred at room temperature. After 43 h the reaction mixture of chamber B was transferred to a flask and CH 2 Cl 2 (10 ml) was added. TFA (8.0 ml) was then slowly added and the reaction was stirred at room temperature for 2h, before it was slowly added to a saturated solution of NaHCO 3 (100 ml). After phase separation the aqueous phase was extracted with CH 2 Cl 2 (3 30 ml), the combined organic phase was dried over MgSO 4, filtered, and concentrated in vacuo. Purification by flash column chromatography in 0-2% MeOH in EtOAc yielded the desired product as a colorless solid (125 mg, 68%). 1 H NMR (400 MHz, DMSO-d 6 ) (ppm) (br s, 1H), 8.21 (s, 1H), 8.13 (d, J = 6.4 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.43 (m, 5H), 7.28 (m, 2H), (m, 8H). 13 C NMR (100 MHz, DMSO-d 6 ) (ppm) (d, J = 64.6 Hz ( 13 C-enriched)), 169.3, (d, J = 64.6 Hz ( 13 C-enriched)), (d, J = 8.5 Hz), (d, J = 3.5 Hz), 135.5, 129.7, (2C), (2C), (t, J =2.4 Hz), 123.7, 122.7, 121.0, (dd, J = 67.7 Hz, 15.8 Hz) 112.7, 45.5 (2C, br), 40.6 (2C, br). HRMS: C C 2 H 19 N 3 O 3 [M+H + ]; calculated: , found: S16

17 5. NMR Spectra S17

18 S18

19 S19

20 S20

21 S21

22 S22

23 S23

24 S24

25 S25

26 S26

27 S27

28 S28

29 S29

30 6. Gas yield calculation example The gas volume was calculated using simple geometry. V = gas volume d = water level at the give time d 0 = water level at t = 0, before addition of solvent r = 0.71 cm (inner radius of the gas volumeter glass tube) V solvent = solvent volume added Using the ideal gas equation the amount of CO generated was calculated. n CO = amount of gas p = atmospheric pressure, as given by the National Danish Whether Service (DMI) at the time and place of the experiment. V = gas volume R = ml hpa K -1 mmol -1 (gas constant) T = laboratory temperature The gas yield in percent was then calculated S30

31 7. Gas release data 1 with KF in dioxane, 60 C Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S31

32 2 with KF in dioxane, 40 C Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S32

33 3 with KF in dioxane, 40 C Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S33

34 with KF in DMF, rt Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S34

35 2 with KF in THF, 40 C Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S35

36 2 with KF in PEG5000, 70 C Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S36

37 S37

38 2 with KF in water, 70 C Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S38

39 2 with TBAF in dioxane, rt Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S39

40 2 with CsF in dioxane, rt Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S40

41 2 with MeOK in dioxane, 40 C Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S41

42 2 with t-buok in dioxane, 40 C Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S42

43 2 with MePh 2 SiOK in dioxane, 40 C Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S43

44 2 with 0.5 eq KF in dioxane, 40 C Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S44

45 2 with 0.25 eq KF in dioxane, 40 C Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S45

46 2 with 0.1 eq KF in dioxane, 40 C Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S46

47 2 with 0.05 eq KF in dioxane, 40 C Pressure [hpa] Temperature [K] m silacarboxylic acid [mg] n silacarboxylic acid [mmol] Time [min] Water level [cm] Volume [ml] n CO [mmol] Gas yield [%] S47