Supporting Information

Transcription

1 Supporting Information Suzuki-Miyaura Cross-Coupling of Heteroaryl Halides and Arylboronic Acids in Continuous-Flow Timothy oël* and Andrew J. Musacchio Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.

2 1. General Reagent Information All reactions were carried out using reagent grade solvents, and all solutions were prepared under an argon atmosphere. Aryl halides, potassium phosphate tribasic, tetrabutylammonium bromide (TBAB) and anhydrous 1-methyl-2-pyrrolidinone (MP) were purchased from Sigma-Aldrich chemical company and were used as received. Aryl boronic acids were purchased from Frontier Scientific or Sigma-Aldrich and were used as received. L1 and L2 were purchased from Strem Chemicals. L3 was synthesized according to a literature procedure. [1] Precatalysts P1-3 [2] and P4 [3] were prepared according to literature procedures. Reaction solutions were prepared in screw-cap, ovendried volumetric flasks. For the continuous-flow experiments, one solution was prepared, which contained aryl halide, aryl boronic acid, XPhos precatalyst P4, toluene and MP. Reagents that were solids were added to the volumetric flasks that were then evacuated and refilled with argon. This process was repeated a total of 3 times. Liquid reagents were added by syringe and the solutions were made up to the desired volume with toluene. The other solutions were made up as stock solutions. A first stock solution contained 4.83 g of TBAB dissolved in deionized water (150 ml). A second stock solution contained g of K 3 PO 4 dissolved in deionized water (150 ml). Both the 0.1 M TBAB stock solution and the 4.0 M K 3 PO 4 stock solution were degassed by performing several evacuation/argon refill cycles under sonication and stored under argon prior to use. These solutions were loaded into syringes and attached to syringe pumps. 2. General Analytical Information All compounds were characterized by 1 H MR, 13 C MR and IR spectroscopy. Copies of the 1 H and 13 C spectra can be found at the end of the Supporting Information. uclear Magnetic Resonance spectra were recorded on a Bruker 400 MHz instrument. All 1 H MR are reported in δ units, parts per million (ppm), and were measured relative to the signals for residual chloroform (7.26 ppm) in the deuterated solvent, unless otherwise stated. All 13 C MR are reported in ppm relative to deuterochloroform (77.23 ppm), SI 2

3 unless otherwise stated, and all were obtained with 1H decoupling. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. All IR spectra were taken on a Perkin Elmer 2000 FTIR. All GC analyses were performed on a Agilent 6890 gas chromatograph with an FID detector using a J & W DB-1 column (10 m, 0.1 mm ID). Elemental analyses were performed by Atlantic Microlabs Inc., orcross, GA. 3. Experimental setup The equipment configuration that was used for the Suzuki-Miyaura cross-coupling reactions is described in Figure S1. Two Harvard Apparatus PHD2000 syringe pumps were used to deliver reagents from ormject plastic syringes to the reactor. On one syringe pump, a 10 ml syringe with aryl chloride, aryl boronic acid and XPhos precatalyst P4 in MP/toluene was mounted. On the second syringe pump, a 5 ml syringe 0.1 M aq. TBAB solution and another 5 ml syringe containing 4.0M aq. K 3 PO 4 solution were mounted. The packed bed reactor had a volume of 400 µl (10 cm length, cm ID, packing µm stainless steel spheres) and was assembled according to a literature procedure. [4] The tubing from the syringes to the reactor was made out of PFA capillary tubing (1/16 OD x 500 µm ID) and all fluidic connections were made using either 1/4-28 flat bottomed flangeless fittings or coned fittings (IDEX Health and Science). The mixing tee s used in this work were made out of TEFZEL (ETFE) (500 µm ID) and purchased from IDEX Health and Science. The packed bed reactor was submerged in an oil bath. The bath temperature was monitored via a thermocouple and maintained with a Waage immersion heater controlled by a J-KEM Scientific Gemini PID controller. Upon exiting the reactor, the reaction stream was quenched by a stream of H 2 O and EtOAc. These two streams were delivered by two Chromtech P-1500 dual stainless steel piston HPLC pumps. The diluted reaction stream was then fed to a GILSO FC 204 fraction collector. SI 3

4 Syringe 1: Aryl halide, Aryl boronic acid XPhos precatalyst, MP/toluene Syringe 3: 4M aq. K 3 PO 4 HPLC Pumps: EtOAc/H 2 O quench Syringe 2: 0.1 M aq. TBAB Packed-Bed Reactor 90 C Fraction Collection Figure S1. Microreactor setup for the continuous-flow synthesis of palladium-catalyzed Suzuki-Miyaura cross-coupling reactions 4. Workup and yields Samples were collected in test tubes and were diluted with equal amounts of ethyl acetate and water and vigorously mixed. An aliquot of the organic phase was filtered through a short plug of silica gel and analyzed by GC. In certain cases, the phases were separated and the water phase was extracted in total 3 times with ethyl acetate. The organic phases were combined and concentrated in vacuo. The crude material was purified by column chromatography via Biotage SP4 (silica-packed 25 g 100 g snap column; eluting with hexanes and 0-50% ethyl acetate). 5. Typical Procedure to Obtain Isolated Yields An oven-dried screw-top volumetric flask (10.00 ml) that was fitted with a Teflon screw-cap, was charged with aryl halide (5 mmol), aryl boronic acid (7.5 mmol) and XPhos precatalyst (19.7 mg, 25 µmol). The vessel was evacuated and backfilled with argon (this process was repeated a total of 3 times) and toluene (2.0 ml) was added via syringe and MP was added to make the solution volume 10 ml. This solution was loaded into a ormject plastic syringe and fitted to a syringe pump. Stock solutions of aqueous TBAB (0.1 M) and aqueous K 3 PO 4 (4.0 M) were loaded into ormject plastic SI 4

5 syringes (5 ml) and fitted to a second syringe pump. The different solutions were flowed through the microfluidic system, as diagrammed in Figure S1, with the appropriate flow rates to give the different residence times. When exciting the reactor, the reaction was quenched with ethyl acetate and water. The flow rate of the ethyl acetate stream and water stream are both 200 µl/min. Typically, each experiment is preceded by a flush in order to ensure steady-state data collection. ext, a sample was collected in order to obtain exactly 2 mmol of product. The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography via Biotage SP4 (silicapacked 50 g snap column; eluting with hexanes and 0-50% ethyl acetate). 6. Experimental Procedures for Examples Described in Figure 3 F F MeO 2-(2,4-difluorophenyl)-6-methoxypyridine (1a). Following the typical procedure, a syringe (10 ml solution) was loaded with 2-chloro-6-methoxypyridine (600 µl, 5 mmol), 2,4-difluorophenylboronic acid (1.18 g, 7.5 mmol), XPhos precatalyst P4 (19.7 mg, 25 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (600 µl/min total flow rate) to give a residence time of 40 seconds. A sample was collected for 400 seconds (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 0-10% ethyl acetate) to give the title compound as a off-white solid (412 mg, 93%), mp = C. 1 H MR (400 MHz, SI 5

6 CDCl 3 ) δ: 8.11 (dt, J = 6.8, 8.9 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.37 (dd, J = 2.0, 7.6 Hz, 1H), (m, 1H), (m, 1H), 6.68 (d, J = 8.2 Hz, 1H), 3.98 (s, 3H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 164.5, 164.4, 163.9, 162.3, 162.2, 162.0, 161.9, 159.8, 159.7, 149.6, 149.5, 139.3, 132.2, 132.1, 132.1, 132.0, 123.7, 123.7, 123.6, 123.5, 117.1, 117.0, 112.0, 111.9, 111.8, 111.7, 109.9, 104.8, 104.6, 104.5, 104.3, 53.4 ppm. IR (neat, cm -1 ): 1578, 1507, 1465, 1430, 1404, 1265, 1142, 1025, 971, 793. Anal. Calcd. for C 12 H 9 F 2 O: C, 65.16; H, Found: C, 65.17; H, MeO OMe 2,4-dimethoxy-5-(pyridin-2-yl)pyrimidine (1b). Following the typical procedure, a syringe (10 ml solution) was loaded with 2-chloropyridine (470 µl, 5 mmol), 2,4- dimethoxypyrimidine-5-boronic acid (1.38 g, 7.5 mmol), XPhos precatalyst P4 (19.7 mg, 25 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 60 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 30-50% ethyl acetate) to give the title compound as a off-white solid (402 mg, 93%), mp = C. 1 H MR (400 MHz, CDCl 3 ) δ: 8.82 (s, 1H), (m, 1H), 7.74 (td, J = 1.0, 8.0 Hz, 1H), 7.62 (dt, J = 1.0, 8.0 Hz, 1H), 7.12 (ddd, J = 1.0, 5.0, 8.0 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 168.3, 165.1, 159.9, 151.9, 149.7, 136.3, 124.0, 122.2, 114.7, 55.1, 54.2 ppm. IR (neat, cm -1 ): 1611, 1560, 1488, 1467, 1403, 1384, 1287, 1080, 1004, 800. Anal. Calcd. for C 11 H 11 3 O 2 : C, 60.82; H, Found: C, 60.54; H, SI 6

7 O 3-(furan-3-yl)-pyridine (1c). [5] Following the typical procedure, a syringe (10 ml solution) was loaded with 3-chloropyridine (480 µl, 5 mmol), furan-3-boronic acid (840 mg, 7.5 mmol), XPhos precatalyst P4 (59.0 mg, 75 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 60 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 15-30% ethyl acetate) to give the title compound as a brown oil (268 mg, 92%). 1 H MR (400 MHz, CDCl 3 ) δ: 8.72 (dd, J = 0.8, 2.2 Hz, 1H), 8.45 (dd, J = 1.6, 4.8 Hz, 1H), 7.73 (t, J = 1.0 Hz, 1H), 7.71 (td, J = 1.9, 7.9 Hz, 1H), 7.47 (t, J = 1.6 Hz, 1H), 7.25 (ddd, J = 0.8, 4.8, 7.9 Hz, 1H), 6.66 (dd, J = 0.9, 1.9 Hz, 1H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 148.2, 147.2, 144.3, 139.1, 133.2, 128.6, 123.8, 123.4, ppm. IR (neat, cm -1 ): 1508, 1417, 1163, 1063, 1026, 923, 873, 784, 707, 598. S F 2-fluoro-5-(thiophen-3-yl)pyridine (1d). Following the typical procedure, a syringe (10 ml solution) was loaded with 5-bromo-2-fluoropyridine (520 µl, 5 mmol), 3- thienylboronic acid (960 mg, 7.5 mmol), XPhos precatalyst P4 (19.7 mg, 25 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 SI 7

8 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 60 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 0-10% ethyl acetate) to give the title compound as a orange oil (358 mg, 99%). 1 H MR (400 MHz, CDCl 3 ) δ: (m, 1H), (m, 1H), (m, 2H), 7.25 (dd, J = 1.4, 5.0 Hz, 1H), 6.87 (dd, J = 3.0, 8.5 Hz, 1H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 163.8, 161.5, 145.1, 145.0, 139.0, 139.0, 137.5, 129.8, 129.7, 127.2, 125.8, 121.3, 109.7, ppm. IR (neat, cm -1 ): 3102, 1588, 1531, 1482, 1399, 1337, 1252, 867, 806, 782. Anal. Calcd. for C 9 H 6 FS: C, 60.32; H, Found: C, 60.37; H, F Me 6-(6-fluoropyridin-3-yl)-2-methylquinoline (1e). Following the typical procedure, a syringe (10 ml solution) was loaded with 6-bromo-2-methylquinoline (1.11 g, 5 mmol), 6-fluoro-3-pyridinylboronic acid (1.1 g, 7.5 mmol), XPhos precatalyst P4 (19.7 mg, 25 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 60 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with SI 8

9 hexanes and 20-50% ethyl acetate) to give the title compound as a off-white solid (460 mg, 97%), mp = C. 1 H MR (400 MHz, CDCl 3 ) δ: 8.49 (d, J = 2.4 Hz, 1H), (m, 3H), 7.86 (d, J = 2.0 Hz, 1H), 7.80 (dd, J = 2.1, 8.8 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.0 (dd, J = 3.0, 8.5 Hz, 1H), 2.73 (s, 3H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 164.6, 162.2, 159.9, 147.6, 146.3, 146.2, 140.1, 140.0, 136.5, 134.4, 134.4, 134.4, 134.0, 129.9, 128.6, 126.8, 125.7, 123.0, 110.0, 109.6, 25.6 ppm. IR (neat, cm -1 ): 3063, 1592, 1489, 1405, 1385, 1254, 1014, 883, 829, 602. Anal. Calcd. for C 15 H 11 F 2 : C, 75.62; H, Found: C, 75.74; H, O 1-(furan-3-yl)isoquinoline (1f). Following the typical procedure, a syringe (10 ml solution) was loaded with 1-chloroisoquinoline (820 mg, 5 mmol), furan-3-boronic acid (840 mg, 7.5 mmol), XPhos precatalyst P4 (19.7 mg, 25 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 60 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 5-15% ethyl acetate) to give the title compound as a brown oil (351 mg, 90%). 1 H MR (400 MHz, CDCl 3 ) δ: 8.52 (d, J = 5.7 Hz, 1H), 8.30 (dd, J = 0.8, 8.2 Hz, 1H), 7.92 (dd, J = 0.8, 1.5 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.66 (dd, J = 1.5, 6.8, 8.2 Hz, 1H), (m, 3H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 153.2, 143.3, 142.6, 142.5, 136.9, 130.2, 127.6, 127.3, 127.0, 126.8, 125.5, 119.9, ppm. IR (neat, cm -1 ): 1622, 1583, 1552, 1507, SI 9

10 1158, 926, 874, 819, 686, 666. Anal. Calcd. for C 13 H 9 O: C, 79.98; H, Found: C, 79.70; H, S 5-(benzo[b]thiophen-3-yl)pyrimidine (1g). Following the typical procedure, a syringe (10 ml solution) was loaded with 5-bromopyrimidine (795 mg, 5 mmol), benzo[b]thien- 3-ylboronic acid (1.34 g, 7.5 mmol), XPhos precatalyst P4 (39.3 mg, 50 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 60 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 20-40% ethyl acetate) to give the title compound as a off-white solid (411 mg, 97%), mp = C. 1 H MR (400 MHz, CDCl 3 ) δ: 9.23 (s, 1H), 8.94 (s, 2H), (m, 1H), (m, 1H), 7.51 (s, 1H), (m, 2H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 157.9, 156.3, 140.9, 137.2, 130.8, 130.2, 126.1, 125.3, 125.3, 123.4, ppm. IR (neat, cm -1 ): 3066, 2921, 1563, 1549, 1433, 1409, 1193, 838, 751, 724. SI 10

11 Boc tert-butyl 2-(pyrimidin-2-yl)-1H-pyrrole-1-carboxylate (1h). Following the typical procedure, a syringe (10 ml solution) was loaded with 2-chloropyrimidine (458 mg, 4 mmol), 1-Boc-pyrrole-2-boronic acid (1.33 g, 6 mmol), XPhos precatalyst P4 (32.0 mg, 40.7 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 75 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 0-30% ethyl acetate) to give the title compound as a brown oil (428 mg, 87%). 1 H MR (400 MHz, CDCl 3 ) δ: 8.70 (d, J = 4.9 Hz, 2H), 7.32 (dd, J = 1.7, 3.2 Hz, 1H), 7.10 (t, J = 4.9 Hz, 1H), 6.72 (dd, J = 1.7, 3.2 Hz, 1H), 6.23 (t, J = 3.2 Hz, 1H), 1.37 (s, 9H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 161.3, 156.8, 149.5, 132.9, 125.2, 118.5, 118.2, 110.9, 84.1, 27.8 ppm. IR (neat, cm -1 ): 2080, 1745, 1568, 1552, 1416, 1398, 1316, 1156, 801, 735. Anal. Calcd. for C 13 H 15 3 O 2 : C, 63.66; H, Found: C, 63.92; H, MeO O OMe 2-(dibenzo[b,d]furan-4-yl)-4,6-dimethoxypyrimidine (1i). Following the typical procedure, a syringe (10 ml solution) was loaded with 2-chloro-4,6- SI 11

12 dimethoxypyrimidine (699 mg, 4 mmol), 4-(dibenzofuranyl)boronic acid (1.27 g, 6 mmol), XPhos precatalyst P4 (15.7 mg, 20 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 75 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 0-30% ethyl acetate) to give the title compound as a off-white solid (576 mg, 94%), mp = C. 1 H MR (400 MHz, CDCl 3 ) δ: 8.46 (dd, J = 1.3, 7.7 Hz, 1H), 8.04 (dd, J = 1.3, 7.7 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), (m, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 6.02 (s, 1H), 4.12 (s, 6H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 171.7, 162.1, 156.7, 155.0, 128.6, 127.5, 126.1, 123.9, 123.3, 123.0, 122.9, 122.7, 120.7, 112.1, 88.2, 54.3 ppm. IR (neat, cm -1 ): 1594, 1567, 1466, 1383, 1275, 1192, 1160, 1049, 841, 747. Anal. Calcd. for C 18 H 14 2 O 3 : C, 70.58; H, Found: C, 70.63; H, Me S Me 2,5-dimethyl-3-(thiophen-3-yl)pyrazine (1j). Following the typical procedure, a syringe (10 ml solution) was loaded with 3-chloro-2,5-dimethylpyrazine (713 mg, 5 mmol), 3- thienylboronic acid (960 mg, 7.5 mmol), XPhos precatalyst P4 (19.7 mg, 25 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate SI 12

13 flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 60 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 10-30% ethyl acetate) to give the title compound as a brown oil (372 mg, 98%). 1 H MR (400 MHz, CDCl 3 ) δ: 8.17 (s, 1H), 7.55 (dd, J = 1.3, 3.0 Hz, 1H), 7.41 (dd, J = 1.3, 5.0 Hz, 1H), 7.30 (dd, J = 3.0, 5.0 Hz, 1H), 2.57 (s, 3H), 2.45 (s, 3H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 150.2, 147.8, 147.7, 141.4, 139.9, 128.5, 125.7, 125.6, 23.1, 21.2 ppm. IR (neat, cm -1 ): 2922, 1534, 1448, 1376, 1341, 1158, 852, 800, 764, 655. Anal. Calcd. for C 10 H 10 2 S: C, 63.13; H, Found: C, 62.85; H, S 3-(thiophen-3-yl)quinoline (1k). Following the typical procedure, a syringe (10 ml solution) was loaded with 3-chlorothiophene (465 µl, 5 mmol), 3-quinolineboronic acid (1.3 g, 7.5 mmol), XPhos precatalyst P4 (39.3 mg, 50 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 60 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 15-30% ethyl acetate) to give the title compound as a off-white solid (388 mg, 92%), mp = C. 1 H MR (400 MHz, CDCl 3 ) δ: 9.17 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), (m, 1H), 7.62 (dd, J = 1.2, 2.9 Hz, 1H), (m, 1H), 7.49 (dd, J = 1.2, 2.9 Hz, 1H), 7.45 (dd, J = 2.8, 5.0 Hz, 1H) SI 13

14 ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 149.7, 147.4, 139.1, 132.2, 129.5, 129.4, 128.9, 128.3, 128.1, 127.3, 127.2, 126.3, ppm. IR (neat, cm -1 ): 3092, 2924, 1570, 1497, 903, 787, 775, 745, 653, 618. Anal. Calcd. for C 13 H 9 S: C, 73.90; H, Found: C, 73.96; H, S COOMe noct methyl 4-(3-octylthiophen-2-yl)benzoate (1l). Following the typical procedure, a syringe (10 ml solution) was loaded with 2-bromo-3-octylthiophene (1.1 ml, 5 mmol), 4-methoxycarbonylphenylboronic acid (1.35 g, 7.5 mmol), XPhos precatalyst P4 (19.7 mg, 25 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 60 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 0-5% ethyl acetate) to give the title compound as a yellow oil (602 mg, 91%). 1 H MR (400 MHz, CDCl 3 ) δ: 8.06 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 5.2 Hz, 1H), 6.97 (d, J = 5.2 Hz, 1H), 3.91 (s, 3H), 2.65 (d, J = 7.9 Hz, 2H), 1.59 (pent, J = 7.0 Hz, 2H), (m, 10H), 0.86 (t, J = 7.0 Hz, 3H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 166.9, 139.9, 139.7, 136.7, 130.0, 129.9, 129.2, 128.8, 124.8, 52.2, 32.0, 31.0, 29.6, 29.5, 29.4, 28.9, 22.8, 14.2 ppm. IR (neat, cm -1 ): 2925, 2855, 1726, 1607, 1435, 1276, 1180, 1111, 856, 772. Anal. Calcd. for C 20 H 26 O 2 S: C, 72.69; H, Found: C, 72.55; H, SI 14

15 Me F S OMe 3-(4-fluoro-2-methoxyphenyl)-4-methylthiophene (1m). Following the typical procedure, a syringe (10 ml solution) was loaded with 3-bromo-4-methylthiophene (560 µl, 5 mmol), 4-fluoro-2-methoxyphenylboronic acid (1.28 g, 7.5 mmol), XPhos precatalyst P4 (19.7 mg, 25 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 60 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 0-5% ethyl acetate) to give the title compound as a yellow oil (391 mg, 88%). 1 H MR (400 MHz, CDCl 3 ) δ: (m, 2H), 7.01 (dd, J = 1.0, 3.0 Hz, 1H), (m, 2H), 3.79 (s, 3H), 2.14 (s, 3H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 164.6, 162.2, 158.3, 158.2, 139.1, 137.8, 132.2, 132.1, 123.8, 122.1, 122.0, 120.9, 106.9, 106.7, 99.4, 99.1, 55.7, 15.0 ppm. IR (neat, cm -1 ): 2924, 1603, 1506, 1547, 1506, 1456, 1281, 1152, 947, 792. Anal. Calcd. for C 12 H 11 FOS: C, 64.84; H, Found: C, 64.80; H, O F O 4-(benzo[d][1,3]dioxol-5-yl)-1-(4-fluorophenyl)-1H-pyrazole (1n). Following the typical procedure, a syringe (10 ml solution) was loaded with 4-bromo-1-(4- SI 15

16 fluorophenyl)-1h-pyrazole (1.21 g, 5 mmol), 3,4-(methylenedioxy)phenylboronic acid (1.24 g, 7.5 mmol), XPhos precatalyst P4 (59.0 mg, 75 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 60 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 0-10% ethyl acetate) to give the title compound as a light-brown solid (501 mg, 89%), mp = C. 1 H MR (400 MHz, CDCl 3 ) δ: 7.95 (s, 1H), 7.86 (s, 1H), (m, 2H), (m, 2H), (m, 2H), 6.81 (d, J = 7.7 Hz, 1H), 5.95 (s, 2H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 162.6, 160.1, 148.4, 146.9, 138.9, 136.6, 126.2, 125.1, 123.2, 121.0, 120.9, 119.3, 116.6, 116.4, 109.0, 106.6, ppm. IR (neat, cm -1 ): 1515, 1505, 1492, 1394, 1251, 1227, 1043, 935, 834, 813. Anal. Calcd. for C 16 H 11 F 2 O 2 : C, 68.08; H, Found: C, 68.27; H, OMe Me O 5-(6-methoxypyridin-3yl)-2-methylbenzo[d]oxazole (1o). Following the typical procedure, a syringe (10 ml solution) was loaded with 5-chloro-2-methylbenzoxazole (844 mg, 5 mmol), 6-methoxy-3-pyridinylboronic acid (1.15 g, 7.5 mmol), XPhos precatalyst P4 (19.7 mg, 25 µmol), toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a SI 16

17 residence time of 3 minutes. A sample was collected for 60 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 15-30% ethyl acetate) to give the title compound as a off-white solid (462 mg, 96%), mp = C. 1 H MR (400 MHz, CDCl 3 ) δ: 8.33 (d, J = 2.6 Hz, 1H), 7.72 (dd, J = 2.6, 8.6 Hz, 1H), (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 1.8, 8.4 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 3.92 (s, 3H), 2.59 (s, 3H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 164.8, 163.7, 150.7, 145.3, 142.5, 137.8, 134.7, 130.1, 123.6, 117.6, 111.0, 110.6, 53.7, 14.7 ppm. IR (neat, cm -1 ): 1603, 1576, 1505, 1472, 1437, 1383, 1270, 1210, 1020, 813. Anal. Calcd. for C 14 H 12 2 O 2 : C, 69.99; H, Found: C, 69.77; H, Experimental Procedures for Examples Described in Figure 4 MeO S 2-methoxy-6-(thiophen-3-yl)-pyridine (2a). Following the typical procedure, a syringe (10 ml solution) was loaded with 2-chloro-6-methoxypyridine (600 µl, 5 mmol), 3- thienylboronic acid (960 mg, 7.5 mmol), XPhos precatalyst P4 (2.0 mg, 2.5 µmol), XPhos L1 (1.2 mg, 2.5 µmol) toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (80 µl/min total flow rate) to give a residence time of 5 minutes. A sample was collected for 100 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 0-10% ethyl acetate) to give the title SI 17

18 compound as a light yellow oil (380 mg, 99%). 1 H MR (400 MHz, CDCl 3 ) δ: 7.92 (dd, J = 1.1, 3.0 Hz, 1H), 7.66 (dd, J = 1.1, 5.0 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.35 (dd, J = 3.0, 5.0 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 4.02 (s, 3H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 163.7, 150.9, 142.2, 139.2, 126.2, 126.1, 123.4, 112.7, 108.9, 53.2 ppm. IR (neat, cm -1 ): 2948, 1577, 1466, 1305, 1247, 1151, 1023, 845, 781, 682. Anal. Calcd. for C 10 H 9 OS: C, 62.80; H, Found: C, 63.07; H, Me O CF 3 4-(furan-2-yl)-6-methyl-2-(trifluoromethyl)-quinoline (2b). Following the typical procedure, a syringe (10 ml solution) was loaded with 6-methyl-2-(trifluoromethyl)- quinolin-4-yltrifluoromethanesulfonate (1.80 g, 5 mmol), 2-furanylboronic acid (839.2 mg, 7.5 mmol), XPhos precatalyst P4 (7.9 mg, 10 µmol), XPhos L1 (4.8 mg, 10 µmol) toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (80 µl/min total flow rate) to give a residence time of 5 minutes. A sample was collected for 100 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 0-10% ethyl acetate) to give the title compound as a light brown solid (451 mg, 82%), mp = C. 1 H MR (400 MHz, CDCl 3 ) δ: 8.19 (s, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.84 (s, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.56 (dd, J = 1.5, 8.7 Hz, 1H), 6.98 (d, J = 3.4 Hz, 1H), 6.60 (dd, J = 1.8, 3.4 Hz, 1H), 2.52 (s, 3H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 150.4, 147.3, 147.0, 147.0, 146.6, 146.3, 144.6, 139.4, 137.0, 132.9, 130.5, 126.0, 124.9, 124.3, 123.3, 120.5, 117.8, 114.2, 114.2, 113.3, 112.4, 22.3 ppm. IR SI 18

19 (neat, cm -1 ): 1585, 1505, 1486, 1354, 1270, 1173, 1134, 1102, 983, 741. Anal. Calcd. for C 15 H 10 F 3 O: C, 64.98; H, Found: C, 64.94; H, O O S 7-(thiophen-2-yl)-4H-chromen-4-one (2c). Following the typical procedure, a syringe (10 ml solution) was loaded with 4-oxo-4H-chromen-7-yltrifluoromethanesulfonate (1.47 g, 5 mmol), 2-thienylboronic acid (960.0 mg, 7.5 mmol), XPhos precatalyst P4 (7.9 mg, 10 µmol), XPhos L1 (4.8 mg, 10 µmol) toluene (2 ml) dissolved in MP. A second syringe (5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (80 µl/min total flow rate) to give a residence time of 5 minutes. A sample was collected for 100 minutes (2 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 0-40% ethyl acetate) to give the title compound as a yellow solid (382 mg, 84%), mp = C. 1 H MR (400 MHz, CDCl 3 ) δ: 8.08 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 6.0 Hz, 1H), (m, 2H), 7.36 (d, J = 3.4 Hz, 1H), 7.32 (d, J = 5.0 Hz, 1H), 7.04 (t, J = 3.4 Hz, 1H), 6.24 (d, J = 6.0 Hz, 1H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 177.1, 156.9, 155.4, 141.9, 139.8, 128.6, 127.2, 126.5, 125.4, 123.5, 122.9, 114.3, ppm. IR (neat, cm -1 ): 1643, 1623, 1427, 1349, 1237, 1162, 867, 816, 738, 713. Anal. Calcd. for C 13 H 8 O 2 S: C, 68.40; H, Found: C, 68.29; H, SI 19

20 8. Experimental Procedures for Examples Described in Figure 5 S 6-(thiophen-3-yl)-quinoline (3a). Following the typical procedure, a syringe (25 ml solution) was loaded with 6-chloroquinoline (2.05 g, 12.5 mmol), 3-thienylboronic acid (2.4 g, mmol), XPhos precatalyst P4 (49.2 mg, 62.5 µmol), toluene (5 ml) dissolved in MP. A second syringe (12.5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (12.5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 5 hours (10 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 0-20% ethyl acetate) to give the title compound as a brown solid (1.95 g, 92%), mp = C. 1 H MR (400 MHz, CDCl 3 ) δ: 8.84 (dd, J = 1.6, 4.2 Hz, 1H), (m, 2H), (m, 2H), 7.55 (dd, J = 1.3, 2.8 Hz, 1H), 7.47 (dd, J = 1.3, 5.0 Hz, 1H), 7.40 (dd, J = 2.8, 5.0 Hz, 1H), 7.34 (dd, J = 4.2, 8.3 Hz, 1H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 150.3, 147.7, 141.5, 136.2, 134.0, 130.1, 128.8, 128.7, 126.8, 126.5, 124.5, 121.7, ppm. IR (neat, cm -1 ): 1700, 1653, 1559, 1540, 1385, 1122, 886, 844, 792, 667. Anal. Calcd. for C 13 H 9 S: C, 73.90; H, Found: C, 73.86; H, SI 20

21 MeO OMe F 3 C 2,4-dimethoxy-5-(5-(trifluoromethyl)pyridin-2-yl)pyrimidine (3b). Following the typical procedure, a syringe (25 ml solution) was loaded with 2-chloro-5- (trifluoromethyl)pyridine (2.27 g, 12.5 mmol), 2,4-dimethoxypyrimidine-5-boronic acid (3.45 g, mmol), XPhos precatalyst P4 (49.2 mg, 62.5 µmol), toluene (5 ml) dissolved in MP. A second syringe (12.5 ml solution) was loaded with 0.1 M aqueous TBAB solution. A third syringe (12.5 ml solution) was loaded with 4.0 M aqueous K 3 PO 4 solution. These syringes were fitted to syringe pumps as described in Figure S1. The reagents were flowed through the reactor (400 µl) with the appropriate flow rates (133.3 µl/min total flow rate) to give a residence time of 3 minutes. A sample was collected for 5 hours (10 mmol). The organic layer was separated and the aqueous layer was extracted 3 more times with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (silica gel, eluting with hexanes and 0-30% ethyl acetate) to give the title compound as a off-white solid (2.77 g, 97%), mp = C. 1 H MR (400 MHz, CDCl 3 ) δ: 8.96 (s, 1H), 8.81 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 4.03 (s, 3H), 3.98 (s, 3H) ppm. 13 C MR (100 MHz, CDCl 3 ) δ: 168.4, 165.6, 160.7, 155.2, 146.4, 146.4, 146.3, 146.3, 133.5, 133.5, 133.4, 125.1, 124.9, 124.5, 123.3, 122.4, 113.3, 55.2, 54.4 ppm. IR (neat, cm -1 ): 1598, 1566, 1547, 1466, 1403, 1377, 1327, 1110, 1080, Anal. Calcd. for C 12 H 10 F 3 3 O 2 : C, 50.53; H, Found: C, 50.81; H, SI 21

22 9. References: [1] Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, [2] Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, [3] Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, [4] aber, J. R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2010, 49, [5] Bhayana, B.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2009, 11, SI 22

23 10. 1 H MR and 13 C MR spectra: F F MeO 1a SI 23

24 F F MeO 1a SI 24

25 MeO OMe 1b SI 25

26 MeO OMe 1b SI 26

27 O 1c SI 27

28 O 1c SI 28

29 S F SI 29

30 S F 1d SI 30

31 F Me 1e SI 31

32 F Me 1e SI 32

33 O 1f SI 33

34 O 1f SI 34

35 S 1g SI 35

36 S 1g SI 36

37 Boc 1h SI 37

38 Boc 1h SI 38

39 MeO O OMe 1i SI 39

40 MeO O OMe 1i SI 40

41 Me S Me 1j SI 41

42 Me S Me 1j SI 42

43 S 1k SI 43

44 S 1k SI 44

45 COOMe S noct 1l SI 45

46 COOMe S noct 1l SI 46

47 Me F S OMe 1m SI 47

48 Me F S OMe 1m SI 48

49 O F O 1n SI 49

50 O F O 1n SI 50

51 OMe Me O 1o SI 51

52 OMe Me O 1o SI 52

53 MeO S 2a SI 53

54 MeO S 2a SI 54

55 O Me CF 3 2b SI 55

56 O Me CF 3 2b SI 56

57 O O S 2c SI 57

58 O O S 2c SI 58

59 S 3a SI 59

60 S 3a SI 60

61 MeO OMe F 3 C 3b SI 61

62 MeO OMe F 3 C 3b SI 62