Supporting Information

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1 Supporting Information A General, Activator-Free Palladium-Catalyzed Synthesis of Arylacetic and Benzoic Acids from Formic Acid Lin Wang, Helfried Neumann, and Matthias Beller* anie_ _sm_miscellaneous_information.pdf

2 Table of Contents General Considerations... 2 Experimental Sections Synthesis and characterization of new ligands (L2, L8 and L9) Procedure for synthesis of L General procedure for synthesis of L8 and L Optimizing the reaction conditions for Pd-catalyzed carbonylation of 1a with formic acid Kinetic research for the Pd-catalyzed carbonylation with formic acid General procedure for Pd-catalyzed carbonylation of arylethyl halides with formic acid Synthesis of Diclofenac sodium from the reaction of 2k with 2,6-dichlorobenzenamine The influence of base on carbonylation of aryl bromide General procedure for Pd-catalyzed carbonylation of aryl bromides with formic acid Optimizing the reaction conditions for Pd-catalyzed carbonylation of aryl chloride with formic acid General procedure for Pd-catalyzed carbonylation of aryl chlorides with formic acid Pd-catalyzed carbonylation of benzyl or aryl halides with formic acid under open conditions Pd-catalyzed decomposition of formic acid General procedure The GC-MS spectra The Pd-catalyzed carbonylation reaction with CO gas The mercury drop experiment NMR spectra References

3 General Considerations All chemicals were purchased from Sigma-Aldrich, Strem, Acros, TCI or Alfa Aesar and used as received unless stated otherwise. Solvents (Anhydrous and under inert atmosphere) were collected from the solvent purification system and used under standard schlenk technique. Liquid bases were distilled and stored under argon. NMR spectra were recorded on Bruker Avance 300 and Bruker ARX 400 spectrometers. Chemical shifts (ppm) are given relative to solvent: references for DMSO-D 6 were 2.51 ppm and 3.37 (H 2O) ( 1 H NMR) and ppm ( 13 C NMR); references for C 6D 6 were 7.15 ppm ( 1 H NMR) and ppm ( 13 C NMR) Multiplets were assigned as s (singlet), d (doublet), t (triplet), q (quartet), p (pentet) dd (doublet of doublet), m (multiplet) and br. s (broad singlet). Unless otherwise stated, yields refer to isolated yields, estimated to be >95% pure according to 1 H-NMR spectroscopy or GC. All measurements were carried out at room temperature unless otherwise stated. Electron impact (EI) mass spectra were recorded on AMD 402 mass spectrometer (70 ev). Gas chromatography analysis was performed on an Agilent HP-7890A instrument with a FID detector and HP-5 capillary column (polydimethylsiloxane with 5% phenyl groups, 30 m, 0.32 mm i.d., 0.25 μm film thickness) using argon as carrier gas. The products were isolated from the reaction mixture by column chromatography on silica gel 60, mm, mesh (Merck). 2

4 Experimental Sections 1. Synthesis and characterization of new ligands (L2, L8 and L9). Among the 9 kinds of ligands used in this work, the commercial available L3, L6 and L7 purchased from Sigma-Aldrich and used as soon as received; L1, L4 and L5 were synthesized based on the literature [1], [2], the NMR and High Resolution Mass Spectra accord with the reported data; L2, L8 and L9 are reported for the first time, the process of synthesis and characterization data are showed following. 1.1 Procedure for synthesis of L2 To a Schlenk flask equipped with magnetic stirring bar, freshly distilled furan (7.2 ml, 99.2 mmol) and 22.4 ml THF was added. At - 78 o C, 7.93 ml hexane solution of n-buli (2.5M, mmol) was dropped slowly. The mixture was stirred at the same temperature for 10 min and then continued to be stirred at 0 o C for 30 min. Afterwards, the reaction was warmed to room temperature and kept stirring for 2.5 h. At this time, the solution of 2-furanyllithium was obtained. To this solution, t-bupcl 2 (3.3 g, mmol) was added dropwise at -78 o C. The resulting suspension was kept stirring at room temperature overnight followed by filtration and collection of the filtrate. After removal of volatile substance, the chlorophosphine (2-furyl(t-Bu)PCl) was obtained in the yield of 77% by distilled under reduce pressure (0.58 mbar, o C). On the other hand, Grignard reagent of α, α'-dichloro-o-xylene was produced from the reaction of α, α'-dichloro-o-xylene (1.21 g, 6.9 mmol) with activated magnesium powder (0.675 g, 27.8 mmol, heated to 90 o C for 1 h under vacuum and activated by I 2). At room temperature, a solution of α, α'-dichloro-o-xylene in 70 ml of THF was slowly added dropwise with the syringe pump. The mixture was stirred overnight followed by filtration from unreacted magnesium powder. The content of Grignard reagent was determined by titration. The yield of desired product is 91%. With these two components in hand, the final product L2 was synthesized as follows: Chlorophosphine (2-furyl(t-Bu)PCl, 1.6 g, 8.66 mmol) were dissolved in 10 ml of THF under argon in a 250 ml three-necked flask with reflux condenser and cooled to -60 C. Then 55 ml of the Grignard solution (0.063M, 3.46 mmol) were slowly added dropwise at this temperature with the syringe pump. The mixture was allowed to warm to room temperature overnight and a clear yellow solution was obtained. To complete the reaction, the mixture was heated for 1 hour under reflux. After cooling, 1 ml of H 2O was added and the solution decolorizes and became milky cloudy. After removal of THF under high vacuum, 10 ml of water and 10 ml of ethyl ether were added thereto and two homogeneous, clear phases were obtained, which could be readily separated. The aqueous phase was extracted with ethyl ether (10 ml 3). After drying the organic phase with Na 2SO 4, the ether was removed in a high vacuum. The solid was dissolved in 5 ml MeOH with warming on the water bath and filtered through Celite. At -28 C, L2 was obtained in the yield of 57%. 1 H NMR (400 MHz, C 6D 6): δ 1.20(d, J 3 H,P = 11.8 Hz, 18H, C(CH3) 3), 3.52 (m, 2H, CH2), 4.33 (dd, J 2 H,P = 13.3 Hz, J 2 H,H = 4.3 Hz, 2H, CH2), 5.93 (m, 2H, furyl), 6.50 (m, 2H, furyl), 6.79 (m, 2H, C 6H4), 6.89 (m, 2H, furyl), 7.26 (m, 2H, C 6H4). 13 C{ 1 H } NMR (100 MHz, C 6D 6): δ (J 1 C,P = 8 Hz, C(CH 3) 3), (J 1 C,P = 8 Hz, C(CH 3) 3), (J 2 C,P = 14 Hz, C(CH 3) 3), (J 1 C,P = 11 Hz, CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (J = 4 Hz, C Ar), (C Ar), (C Ar), (C Ar), (C Ar). 31 P{ 1 H } NMR (162 MHz, C 6D 6) δ General procedure for synthesis of L8 and L9 Firstly, benzylmagnesium chloride was synthesized from the reaction of benzyl chloride with activated magnesium powder (0.675 g, 27.8 mmol, heated to 90 o C for 1 h under vacuum and activated by I 2). At room temperature, a 70 ml THF solution of benzyl chloride (1.8 g, 13.9 mmol) was slowly added dropwise with the syringe pump. The mixture was stirred overnight followed by filtration from unreacted magnesium powder. The content of Grignard reagent was determined by titration. The yield of desired product is 96%. 3

5 To a 10 ml THF solution of chlorophosphine (2-Py(t-Bu) PCl or 2-furyl(t-Bu)PCl) (7.73 mmol), 58 ml THF solution of benzylmagnesium chloride was added dropwise with the syringe pump at -60 o C. The mixture was allowed to warm to room temperature overnight. To complete the reaction, the mixture was heated for 1 hour under reflux. After cooling, 1 ml of H 2O was added and the solution decolorizes and became milky cloudy. After removal of THF under high vacuum, 10 ml of water and 10 ml of ethyl ether were added thereto and two homogeneous, clear phases were obtained, which could be readily separated. The aqueous phase was extracted with ethyl ether (10 ml 3). After drying the organic phase with Na 2SO 4, the ether was removed in a high vacuum. The solid was dissolved in 5 ml MeOH with warming on the water bath and filtered through Celite. At -28 C, L8 or L9 was obtained. L8: Yield, 84%. 1 H NMR (300 MHz, C 6D 6): δ 1.06 (d, J 3 H,P = 9 Hz, 18H, C(CH3) 3), 2.96 (dd, J 2 H,P = 12 Hz, J 2 H,H = 3 Hz, 1H, CH2), 4.10 (dd, J 2 H,P = 12 Hz, J 2 H,H = 3 Hz, 1H, CH2), 6.55 (m, 1H, Py), 6.84 (m, 1H, Py), 6.96 (m, 1H, Py), 7.70 (m, 2H, C 6H4), 7.24 (m, 1H, Py), 7.36 (m, 2H, C 6H4), 8.58 (m, 1H, Py). 13 C{ 1 H } NMR (75 MHz, C 6D 6): δ (J 2 C,P = 14 Hz, C(CH 3) 3), (J 1 C,P = 17.2 Hz, C(CH 3) 3), (J 1 C,P = 14 Hz, CH 2), (C Ar), (J = 3 Hz, C Ar), (J = 1.5 Hz, C Ar), (J = 6.8 Hz, C Ar), (J = 42.8 Hz, C Ar), (J = 10.5 Hz, C Ar), (J = 10.5 Hz, C Ar), (J = 3 Hz, C Ar), (J = 20.2 Hz, C Ar). 31 P{ 1 H } NMR (121.5 MHz, C 6D 6) δ L9: Yield, 75%. 1 H NMR (300 MHz, C 6D 6): δ 1.07 (d, J 3 H,P = 12 Hz, 18H, C(CH3) 3), 2.86 (dd, J 2 H,P = 12 Hz, J 2 H,H = 3 Hz, 1H, CH2), 3.46 (dd, J 2 H,P = 12 Hz, J 2 H,H = 3 Hz, 1H, CH2), 5.98 (m, 1H, furyl), 6.50 (m, 1H, furyl), 6.95 (m, 1H, furyl), 7.06 (m, 2H, C 6H4), 7.13 (m, 2H, C 6H4), 7.27 (m, 1H, furyl). 13 C{ 1 H } NMR (75 MHz, C 6D 6): δ (J 2 C,P = 13.5 Hz, C(CH 3) 3), (J 1 C,P = 13.5 Hz, C(CH 3) 3), (J 1 C,P = 13.5 Hz, CH 2), (J = 7.5 Hz, C Ar), (J = 26.2 Hz, C Ar), (J = 3 Hz, C Ar), (J = 1.5 Hz, C Ar), (J = 7.5 Hz, C Ar), (J = 7.5 Hz, C Ar), (C Ar), (J = 38.2 Hz, C Ar). 31 P{ 1 H } NMR (121.5 MHz, C 6D 6) δ Optimizing the reaction conditions for Pd-catalyzed carbonylation of 1a with formic acid. Table S1. Optimizing the reaction conditions for carbonylation of 1a with formic acid in the presence of Pd(OAc)2 and L1. a Entry Solvent Base Cat. (mol%) Cat.: L Temp. ( o C) Conv. (%) Yield of 2a (%) b Yield of 2a (%) b 1 toluene TMEDA 0.5 1: dioxane TMEDA 0.5 1: < H2O TMEDA 0.5 1: <5 <5 4 DMF TMEDA 0.5 1: DMF NEt : DMF DBU 0.5 1: DMF TMEDA 1 1: DMF TMEDA : DMF TMEDA 0.5 1: DMF TMEDA 0.5 1: DMF TMEDA 0.5 1: < DMF TMEDA 0.5 1:4 60 < DMF TMEDA 0.5 1: a. Reaction conditions: 1a (1 mmol), formic acid (0.5 ml, 13 mmol), Pd(OAc)2, L1, base (1 mmol), in solvent (1.5 ml) for 24 h. b. Isolated yields. 4

6 Figure S1. The relation between yield of 2a (%) with equivalent of TMEDA. Solvent influenced the reaction of Pd-catalyzed carbonylation of 1a significantly. In general, the solvent with strong polarity such as DMF benefited the production of 2a. In contrast, when toluene was used as solvent, there were no desired product 2a found after reaction (Table S1, Entries 1-4). TMEDA is the best base for this reaction. Stronger bases such as DBU are much inferior to TMEDA because of their acceleration for by-product 2a (Table S1, Entries 5 and 6). Similarly, too much loading of TMEDA also goes against the generation of 2a (Figure S1). Interestingly, increasing the loading of catalyst led to decreasing yield of 2a (Table S1, Entry 7). In this case, the yield of by-product increased, which indicated that Pd(OAc) 2/L1 are able to catalyze the simple nucleophilic substitution reaction as well. In order to obtain 2a in good yield, the reaction should be heated to at least 115 o C. 3. Kinetic research for the Pd-catalyzed carbonylation with formic acid. The kinetic research for Pd-catalyzed carbonylation of different substrates is showed in Figure S2. The carbonylation of 1a was much faster than the one of 1l: In 60 min, the conversion of the former reaction reached almost 100% with the 78% yield of desired product 2a while the latter reaction needed 240 min to complete. In the further study, we found that at the beginning the amount of CO was low, which indicated: 1) For some substrates such as 1a, low pressure CO is enough for carbonylation while higher pressure is necessary for the other substrates; 2) by-product may be produced at the initial stage when CO was just generated in low pressure. 5

7 Figure S2. The relation between yield of 2a and 2l (%) with reaction time (min). 4. General procedure for Pd-catalyzed carbonylation of arylethyl halides with formic acid. Under the protection of argon, a 25 ml reaction tube was charged with Pd(OAc) 2 (0.005 mmol), L1 (0.02 mmol) and equipped with a stirring bar. Then 1.5 ml DMF was dropped to dissolve the catalyst followed by the addition of TMEDA (1 mmol) and substrate (1 mmol). At last, formic acid was added into the mixture, which was moderately exothermic at the beginning. The reaction was heated to 115 o C for 12 h. After cooling down to room temperature, gas was released carefully. Pure product could be obtained by column chromatography on silica gel (general eluent: hexane/ethylacetate = 2:1) or CombiFlush. Isolated yield: 81%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 2.29 (s, 3H, CH3), 3.52 (s, 2H, CH2), (m, 3H, Ar), 7.21 (m, 1H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 3), (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 9H 10O 2: 150.1; found: Isolated yield: 72% for benzyl chloride and 84% for benzyl bromide. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 3.57 (s, 2H, CH2), (m, 3H, Ar), (m, 2H, Ar), (s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 8H 8O 2: 136.1; found:

8 Isolated yield: 80%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 2.24 (s, 3H, CH3), 3.59 (s, 2H, CH2), (m, 4H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 3), (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 9H 10O 2: 150.1; found: Isolated yield: 73%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 3.49 (s, 2H, CH2), 3.74 (s, 3H, OCH3), 6.88 (d, J = 9 Hz, 2H, Ar), 7.18 (d, J = 9 Hz, 2H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 2), (OCH 3), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 9H 10O 3: 166.1; found: Isolated yield: 76%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 1.17 (t, J = 7.5 Hz, 3H, CH3), 2.58 (q, J = 7.5 Hz, 2H, CH2), 3.52 (s, 2H, CH2), 7.16 (m, 4H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 3), (CH 2), (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 10H 12O 2: 164.1; found: Isolated yield: 75%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 1.20 (d, J = 7.5 Hz, 6H, CH3), 2.87 (septet, J = 7.5 Hz, 1H, CH), 3.52 (s, 2H, CH2), (m, 4H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 3), (CH), (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 11H 14O 2: 178.1; found: Isolated yield: 72%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 1.28 (s, 9H, CH3), 3.52 (s, 2H, CH2), 7.18 (d, J = 9 Hz, 2H, Ar), 7.34 (d, J = 9 Hz, 2H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 3), (C(CH 3) 3), (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 12H 16O 2: 192.1; found: Isolated yield: 71%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 3.58 (s, 2H, CH2), (m, 2H, Ar), (m, 2H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 2), (J = 21 Hz, C Ar), (J = 8.2 Hz, C Ar), (J = Hz, F- C Ar), (C=O). MS (EI) calculated for C 8H 7FO 2: 154.0; found:

9 Isolated yield: 70%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 3.63 (s, 2H, CH2), (m, 2H, Ar), (m, 2H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 2), (J = 21 Hz, C Ar), (J = 15.8 Hz, C Ar), (J = 3.8 Hz, C Ar), (J = 7.5 Hz, C Ar), (J = 3.8 Hz, C Ar), (J = Hz, F-C Ar), (C=O). MS (EI) calculated for C 8H 7FO 2: 154.0; found: Isolated yield: 53%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 3.60 (s, 2H, CH2), (m, 2H, Ar), (m, 2H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 2), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 8H 7ClO 2: 170.0; found: Isolated yield: 50%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 3.72 (s, 2H, CH2), (m, 2H, Ar), (m, 2H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 8H 7ClO 2: 170.0; found: Isolated yield: 71%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 3.76 (s, 2H, CH2), (m, 3H, Ar), (m, 4H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 12H 10O 2: 186.1; found: Isolated yield: 75%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 4.06 (s, 2H, CH2), (m, 4H, Ar), (m, 3H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 12H 10O 2: 186.1; found: Isolated yield: 73%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 3.62 (s, 2H, CH2), (m, 3H, Ar), (m, 2H, Ar), (m, 4H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 14H 12O 2: 212.1; found:

10 Isolated yield: 76%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 3.67 (s, 2H, CH2), (m, 9H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 14H 12O 2: 212.1; found: Isolated yield: 75%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 3.51 (s, 2H, CH2), (m, 9H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 14H 12O 2: 212.1; found: Isolated yield: 26%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 2.26 (s, 3H, CH3), 2.51 (mix with signal of DMSO-D 6, 2H, CH2), 2.78 (t, J = 7.5 Hz, 2H, CH2), (m, 4H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 3), (CH 2), (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 10H 12O 2: 164.1; found: Isolated yield: 46%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 3.81 (s, 2H, CH2), 5.38 (s, CH2), (m, 4H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 2), (OCH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 9H 8O 2: 148.1; found: Synthesis of Diclofenac sodium from the reaction of 2k with 2,6-dichlorobenzenamine The method to synthesize Diclofenac sodium based on the literature [ref]: Under the argon atmosphere, a 100 ml Schlenk tube equipped with stirring bar was charged with 2k (3 mmol), 2,6-dichlorobenzenamine (15 mmol), K 2CO 3 (6 mmol), KI (3 mmol), I 2 (2 mmol) and 20 ml DMF. The mixture was stirred fully and heated to reflux for 12 h. After cooling down to room temperature, the mixture was filtered and the residue was washed with water (5 ml 3). To the combined solution of filtrate with washing solution, n- butanol was added. The solvent was removed by distillation under reduced pressure and the residue was washed with chloroform followed by dissolution with water. Subsequently, the mixture are acidified with 2 N HCl and extracted with chloroform. The solvent of extract was then removed and the residue was re-dissolved by EtOH. To the organic solution, 2 N aqueous NaOH was added and the mixture was refluxed for 4 h. At last, the solution was cooled in an ice bath to precipitate crystals. Purer product could be obtained by recrystallization with water. Yield: 31%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 3.42 (s, 2H, CH2), 6.27 (m, 1H, Ar), ), 6.75 (m, 1H, Ar), ), 6.94 (m, 1H, Ar), 7.07 (m, 2H, Ar), 7.45 (m, 2H, Ar), (br.s, 1H, NH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 2), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). m.p o C. 9

11 6. The influence of base on carbonylation of aryl bromide The reaction conditions for carbonylation of aryl bromides are similar to the one of benzyl halides except the loading of base. As showed in Figure S3, the optimized loading of TMEDA is 0.25 equivalents, which is much lower than the case in the carbonylation of benzyl halides. Figure S3. The relation between yield of 4f (%) with equivalent of TMEDA. 7. General procedure for Pd-catalyzed carbonylation of aryl bromides with formic acid. Under the protection of argon, a 25 ml reaction tube was charged with Pd(OAc) 2 (0.005 mmol), L1 (0.02 mmol) and equipped with a stirring bar. Then 1.5 ml DMF was dropped to dissolve the catalyst followed by the addition of TMEDA (0.25 mmol) and substrate (1 mmol). At last, formic acid (0.5 ml) was added into the mixture, which was moderately exothermic at the beginning. The reaction was heated to 115 o C for 24 h. After cooling down to room temperature, gas was released carefully. Pure product could be obtained by column chromatography on silica gel (general eluent: hexane/ethylacetate = 2:1). Isolated yield: 93%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 3.81 (s, 2H, OCH3), 6.88 (d, J = 9 Hz, 2H, Ar), 8.00 (d, J = 9 Hz, 2H, Ar); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (OCH 3), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 8H 8O 3: 152.1; found: Isolated yield: 92%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ (m, 2H, Ar), (m, 1H, Ar), (m, 2H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 7H 6O 2: 122.0; found:

12 Isolated yield: 85%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 7.58 (d, J = 9 Hz, 2H, Ar), 7.94 (d, J = 9 Hz, 2H, Ar); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 7H 5ClO 2: 156.0; found: Isolated yield: 80%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ (m, 2H, Ar), (m, 2H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (d, J 2 C,F = 21.8 Hz, C Ar), (d, J 4 C,F = 3 Hz, C Ar), (d, J 3 C,F = 9 Hz, C Ar), (d, J 1 C,F = 249 Hz, C Ar), (C=O). MS (EI) calculated for C 7H 5FO 2: 140.0; found: Isolated yield: 72%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ (m, 2H, Ar), (m, 2H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (C Ar), (C N), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 8H 5NO 2: 147.0; found: Isolated yield: 80%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 7.86 (d, J = 9 Hz, 2H, Ar), 8.14 (d, J = 9 Hz, 2H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (C Ar), (q, J 2 C,F = 3.8 Hz, C Ar), (C Ar), (q, J 1 C,F = 31.5 Hz, CF 3), (C Ar), (C=O). MS (EI) calculated for C 8H 5F 3O 2: 190.0; found: Isolated yield: 75%. 1 H NMR (300MHz, DMSO-D 6, ppm): δ 6.82 (d, J = 9 Hz, 2H, Ar), 7.80 (d, J = 9 Hz, 2H, Ar), (br.s, 1H, OH), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 7H 6O 3: 138.0; found: Isolated yield: 47%. 1 H NMR (300MHz, DMSO-D 6, ppm): (m, 3H, Ar), 8.02 (d, J = 9 Hz, 1H, Ar), 8.16 (d, J = 9 Hz, 2H, Ar), 8.88 (d, J = 9 Hz, 1H, Ar),13.15 (s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 11H 8O 2: 172.1; found:

13 Isolated yield: 90%. 1 H NMR (300MHz, DMSO-D 6, ppm): (m, 2H, Ar), (m, 4H, Ar), 8.63 (s, 1H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 11H 8O 2: 172.1; found: Isolated yield: 83%. 1 H NMR (300MHz, DMSO-D 6, ppm): (m, 3H, Ar), (m, 4H, Ar), 8.04 (d, J = 9 Hz, 2H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C Ar), (C=O). MS (EI) calculated for C 13H 10O 2: 198.1; found: Optimizing the reaction conditions for Pd-catalyzed carbonylation of aryl chloride with formic acid. Table S2. Optimizing the reaction conditions for carbonylation of 5f with formic acid in the presence of Pd(OAc)2 and L1. a Entry Solvent Base (equiv.) Cat. (mol%) Cat.: L Temp. ( o C) Yield of 4f (%) b 1 DMF TMEDA (0.25) 0.5 1: DMF TMEDA (0.25) 1 1: DMF TMEDA (0.25) 3 1: DMF TMEDA (0.25) 5 1: CH3CN TMEDA (0.25) 3 1:4 130 <5 6 DMF+H2O (3:1) TMEDA (0.25) 3 1:4 130 <5 7 DMF TMEDA (0.5) 3 1: DMF TMEDA (1) 3 1: DMF NaOtBu (0. 5) 3 1:4 130 <5 10 DMF TMEDA (0.25) 3 1: DMF TMEDA (0.25) 3 1:2 130 <5 12 DMF TMEDA (0.25) 3 1: DMF TMEDA (0.25) 3 1: a. Reaction conditions: 5f (1 mmol), formic acid (0.5 ml, 13 mmol), Pd(OAc)2, L1, base, in solvent (1.5 ml) for 24 h. b. Isolated yields. 9. General procedure for Pd-catalyzed carbonylation of aryl chlorides with formic acid. Under the protection of argon, a 25 ml reaction tube was charged with Pd(OAc) 2 (0.03 mmol), L1 (0.12 mmol) and equipped with a stirring bar. Then 1.5 ml DMF was dropped to dissolve the catalyst followed by the addition of TMEDA (0.25 mmol) and substrate (1 mmol). At last, formic acid (0.5 ml) was added into the mixture, which was moderately exothermic at the beginning. The reaction was heated to 130 o C for 24 h. After cooling down to room temperature, gas was released carefully. Pure product could be obtained by column chromatography on silica gel (general eluent: hexane/ethylacetate = 2:1). The NMR data of 4f, 4e, 4d which were produced from the carbonylation reaction of aryl chlorides are in accord with the ones with aryl bromides as substrates. Therefore, the NMR data of above compounds are not shown here. Isolated yield: 60%. 1 H NMR (300MHz, DMSO-D 6, ppm): 2.64 (s, 3H, CH3), 8.06 (br.s, 4H, Ar), (br.s, 1H, COOH); 13 C{ 1 H} NMR (75 MHz, DMSO-D 6, ppm): δ (CH 3), (C Ar), (C Ar), (C Ar), (C Ar), (COOH), (C=O). MS (EI) calculated for C 9H 8O 3: 164.0; found:

14 10. Pd-catalyzed carbonylation of benzyl or aryl halides with formic acid under open conditions. Scheme S1. Pd-catalyzed carbonylation of benzyl or aryl halides with formic acid under open conditions. B A C (a) (b) Figure S4. Pd-catalyzed carbonylation reaction with formic acid using two compartments: After 0 h (a) and 24 h (b). A so-called open-system experiment was performed to proof the in situ formation of CO (Scheme S1). The device is shown in Figure S4, (a). Tube A is the reaction tube, in which Pd(OAc) 2 (0.005 mmol), L1 (0.04 mmol), TMEDA (1 mmol for benzyl chlorides and 0.25 mmol for aryl bromides), substrate (1 mmol) and HCOOH (0.5 ml) were dissolved by 1.5 ml DMF and stirred for 24 h at 115 o C. The generated gas was collected by tube C with a balloon. Tube A and tube C were connected by rubber tube B. (Tube B and tube c were at room temperature.) The system pressure maintained in accordance with atmospheric pressure. For all reactions (Scheme S1, equation 1 to equation 4), the phenomena were similar: At the beginning of the reaction, there was no gas produced so that the balloon was flat. As the reaction progressed, the balloon expended gradually. After 24 h, the tube A was cooled down to room temperature and the balloon of tube B became fuller (Figure 4, b). Under the open conditions, the yields of desired products (2a, 2b, 2l and 4a) dropped significantly while more by-products such as benzyl formats and hydrodechlorination products were detected. More specifically, for carbonylation of 1a and 1b (Scheme S1, equations 1 and 2), the coupling products (2a, 40% and 2b, 37%, respectively) became the major products. Meanwhile, the carbonylation of 1l under open conditions resulted in 2l and hydrodechlorination by-product 2l in the yields of 22% (2l) and 38% 13

15 (2l ), respectively (Scheme S1, equation 3). As for the carbonylation of aryl bromide 3a, the reaction suffered from poor conversion (39%) while the yield of acid product was only 34% (Scheme S1, equation 4). From these series of open-conditions reactions, two conclusions could be given: 1) The carbonylation reactions do not undergo the cross-coupling process involving the C-H activation of formic acid; 2) during the reaction, some gas was generated. Related high pressure of gas benefits the carbonylation of both benzyl and aryl halides. From the following experiment, we can confirm the major ingredient of gas is CO. 11. Pd-catalyzed decomposition of formic acid General procedure Under the protection of argon, a 25 ml autoclave equipped by mechanical stirring bar was charged with Pd(OAc) 2 (0.01 mmol), L1 (0.04 mmol), TMEDA (0.5 mmol), formic acid or deuterated formic acid (13 mmol) and 3 ml DMF. The mixture was intensive stirred and heated to 115 o C. The pressure in autoclave was monitored during the reaction period. After 18 h, the reaction was stopped and cooled down to room temperature. The gas components were tested by GC-MS The GC-MS spectra 14

16 GC-MS spectrum for decomposition of HCOOH 15

17 GC-MS spectrum for decomposition of HCOOD 16

18 GC-MS spectrum for decomposition of DCOOH 17

19 12. The Pd-catalyzed carbonylation reaction with CO gas Scheme S2. Pd-catalyzed carbonylation of 1a with CO gas. To a vial (12 ml reaction volume) which was charged with Pd(AcO) 2 (0.005 mmol) and equipped with a septum, a small cannula and a stirring bar, L1 (0.02 mmol), DMF (1.5 ml), TMEDA (1 mmol), 1a (1 mmol) were added. After addition of 0.4 ml H 2O or 4 mmol HCOOH, the vials were placed in an alloy plate which was transferred to a 300 ml autoclave (4560 series from Parr Instruments ) under an argon atmosphere. The autoclave was flushed three times with CO and then pressurized to 10 bar CO. The reaction was kept stirring at 115 o C for 24 h. After cooling down to room temperature, CO was released carefully. Pure product could be isolated by Combi-Flush, which was used to determine the yield. CO (10 bar) /H 2O (0.4 ml) was tested instead of formic acid in the Pd-catalyzed carbonylation of 1a (Scheme S2). As a result, the desired product 2a was only obtained in the yield of 12%. When H 2O was replaced by 4 equivalents HCOOH, the yield of 2a was improved up to 74%, which indicated that formic acid played a role as the nucleophile in addition to the CO-surrogate. 13. The mercury drop experiment Scheme S3. Mercury drop experiment for Pd-catalyzed carbonylation reaction with formic acid. Under the protection of argon, a 25 ml reaction tube was charged with Pd(OAc) 2 (0.005 mmol), L1 (0.02 mmol) and equipped with a stirring bar. Then 1.5 ml DMF was dropped to dissolve the catalyst followed by the addition of TMEDA (1 mmol),1a (1 mmol), formic acid (0.5 ml) and a drop of mercury. The reaction was heated to 115 o C for 12 h. After cooling down to room temperature, gas was released carefully. Via GC with hexadecane as standard, the yield of product 2a was detected as 77%. 18

20 NMR spectra 1 H NMR (300 MHz, C 6D 6, ppm) 31 P{ 1 H } NMR (121.5 MHz, C 6D 6, ppm) 19

21 1 H NMR (300 MHz, C 6D 6, ppm) 13 C{ 1 H } NMR (75 MHz, C 6D 6, ppm) 20

22 31 P{ 1 H } NMR (121.5 MHz, C 6D 6, ppm) 1 H NMR (300 MHz, C 6D 6, ppm) 21

23 13 C{ 1 H } NMR (75 MHz, C 6D 6, ppm) 31 P{ 1 H } NMR (121.5 MHz, C 6D 6, ppm) 22

24 1 H NMR (300 MHz, C 6D 6, ppm) 13 C{ 1 H } NMR (75 MHz, C 6D 6, ppm) 23

25 31 P{ 1 H } NMR (121.5 MHz, C 6D 6, ppm) 24

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55 References [1] K. Dong, X. Fang, S. Gülak, R. Franke, A. Spannenberg, H. Neumann, R. Jackstell, M. Beller, Nat. Commun [2] K. Dong, R. Sang, J. Liu, R. Razzaq, R. Franke, R. Jackstell, M. Beller, Angew. Chem. 2017, 129,