Supporting Information © Wiley-VCH 2007 69451 Weinheim, Germany Electronic Effects on the Selectivity of Pd-Catalyzed C-N Bond- Forming Reactions Using Biarylphosphine Ligands: The Competitive Roles of Binding and Acidity, and the Exploitation of Electronic Effects to Achieve a Reversal of Chemoselectivity

Mark R. Biscoe, Timothy E. Barder, and Stephen L. Buchwald*

Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge Massachusetts 02139

General. All reactions were carried out under an argon atmosphere or in a nitrogen- filled , unless otherwise noted. THF, Et2O, CH2Cl2 and toluene were purchased from J.T. Baker in CYCLE-TAINER® -delivery kegs and vigorously purged with argon for 2 h. The were further purified by passing them under argon pressure through two packed columns of neutral alumina (for THF and Et2O) or through neutral alumina and copper (II) oxide (for toluene and CH2Cl2). p-Anisidine and p-toluidine were each purified by sublimation prior to use. p-Dimethylaminoaniline (Aldrich) was used as received and stored in a nitrogen-filled glovebox at –20 °C. All other amines were purified by distillation from CaH2. Anhydrous chlorobenzene, DME, and dioxane

(Aldrich) were purged with argon for 1 h and stored in a nitrogen-filled glovebox. PdCl2 was received as a gift from BASF. SPhos was synthesized according to reference 1. Unless otherwise stated, commercially-available materials were used without further purification.

All new compounds were characterized by 1H NMR, 13C NMR, and low resolution mass spectroscopy and/or X-ray crystallography. Copies of the 1H and 13C NMR are attached for all new compounds. Nuclear Magnetic Resonance spectra were recorded on a Bruker 400 or 600 MHz instrument. All 1H NMR experiments are reported in δ units, parts per million (ppm), and were measured relative to the signals for residual (7.26 ppm), methylene chloride (5.32 ppm) or benzene (7.16 ppm) in the deuterated solvents. All 13C NMR spectra are reported in ppm relative to deuterochloroform (77.23 ppm), deuteromethylene chloride (54.00 ppm) or deuterobenzene (128.39 ppm), and all were obtained with 1H decoupling. All 31P NMR spectra are reported in ppm relative to

H3PO4 (0 ppm – external standard). All GC analyses were performed on a Hewlett-

S1 Packard 6890 gas chromatograph with an FID detector using a 25 m x 0.20 mm capillary column with cross-linked methyl siloxane as the stationary phase.

Standard Procedure for Measurement of Relative Amine Binding to 1:

1 (10 mg, 7.75 x10-3 mmol) was dissolved in toluene (0.5 mL). All binding constants were measured relative to morpholine and/or dibutylamine. Known amounts of aliphatic amine or aniline and morpholine or dibutylamine (each of which were in at least 5-fold excess) were added to the solution of 1 in toluene. After the addition of the amines, the reaction mixture was stirred at room temperature for 10 min. Relative binding was determined by the intensity of signals in the corresponding 31P NMR spectrum (unlocked, D1 = 5 s, room temperature). The molarities of the two amines involved in the measurement were calculated and the measured integrals were corrected for the difference in initial concentrations. Each measurement was performed in duplicate (See below for a representative spectrum of each run).

Procedure for the Measurement of the Absolute Binding of Aniline to 1:

1 [10 mg, 7.75 x10-3 mmol (1.6 x 10-2 mmol of SPhosPd(Ph)Cl monomer)] was dissolved in toluene (0.75 mL). Aniline (7.3 µL, 8 x10-2 mmol) was added to the solution of 1, which was then allowed to stir for 10 min. Kbinding = [1•aniline]/{[1][aniline]}. Equilibrium concentrations were calculated after measuring ratio of bound 1 to free 1 using 31P NMR spectroscopy (unlocked, D1 = 5 s, room temperature). Two separate measurements resulted in binding constants of 3.31 M-1 and 3.47 M-1.

Standard Procedure for the Measurement of Selectivity Using Neutral Amines:

Precatalyst 1 (7 mg, 0.005 mmol) was transferred to an oven-dried screw-top . The test tube was transferred to a nitrogen-filled glovebox. PhCl (20 µL, 0.2 mmol), Amine 1 (1 mmol) and Amine 2 (1 mmol) were added to the test tube via syringe. Toluene (1 mL) was added to the test tube via syringe and the solution was stirred until homogeneous. To a separate vial, NaOt-Am (44 mg, 0.4 mmol) was added. After dissolving in toluene (1 mL), the NaOt-Am solution was transferred to the reaction tube. The test tube was sealed with a screw cap and stirred for 4 h at room temperature.

S2 Outside the glovebox, the reaction solution was poured into a separatory containing saturated aqueous NH4Cl (20 mL) and EtOAc (20 mL). The organic layer was analyzed by (calibrated) to obtain relative ratios of phenylated amines. All amines were competed against morpholine. The anilines were competed against PhNH2 to re-check accuracy of selectivity values.

Standard Procedure for Formation of Lithium Amides:

Amine (10 mmol) was added to a 50 mL round bottom flask containing hexane (15 mL) under argon. The mixture was cooled to 0 °C, then n-BuLi (8 mmol) was added dropwise via syringe. The solution was stirred for 30 minutes and transferred to a nitrogen-filled glovebox. The precipitated solid (80-90% yield) was collected via suction filtration on a fritted filter. The lithium amides were stored in a -20 °C freezer inside the glovebox.

Standard Procedure for the Measurement of Selectivity Using Lithium Amides:

In a nitrogen-filled glovebox, lithium amide 1 (0.5 mmol) and lithium amide 2 (0.5 mmol) were transferred to a screw-top test tube. Dioxane or DME (2 mL) was added to the test tube containing the lithium amides. The DME solutions became homogeneous and transparent, while the dioxane solutions remained turbid. 1 (4 mg, 0.0025 mmol) was added to a separate vial, followed by chlorobenzene (10 µL, 0.1 mmol). This mixture was dissolved in dioxane or DME (1 mL) and transferred to the test tube containing the solution of lithium amides. The test tube was sealed with a screw cap and stirred for 8 h at room temperature inside the glovebox. Outside the glovebox, the reaction solution was poured into a separatory funnel containing saturated aqueous

NH4Cl (20 mL). The neutralized solution was then extracted with EtOAc (20 mL). The organic layer was analyzed by gas chromatography (calibrated) to obtain relative ratios of phenylated amines.

SPhos Palladium(II) Phenyl Chloride Propylamine [SPhosPd(Ph)(Cl)H2NC3H8] (2):

PCy SPhos = 2 SPhosPd MeO OMe N Cl H2

S3 SPhos (0.5 g, 1.22 mmol) was added to a 25 mL Schlenk tube. In a nitrogen-filled 2 glovebox, Me2Pd(tmeda) (0.31 g, 0.1.22 mmol) was added to a vial and dissolved in chlorobenzene (4 mL). This solution was transferred to the Schlenk tube. n-Propylamine (1 mL) was added to the Schlenk tube, which was then sealed with a Teflon cap and heated to 55 °C for 2 h outside of the glove box. The solvent was removed under reduced pressure. The remaining solid was dissolved in CH2Cl2 (2 mL), and hexane (100 mL) was then added. After sitting in a –20 °C freezer for 2 days, 0.71 g (85%) fine, off- white crystals formed from the solution. A crystal suitable for X-ray diffraction was grown by vapor diffusion of pentane into a toluene solution of 2 at -20 °C. 1H NMR

(400 MHz, CD2Cl2): δ 7.46 (m, 1H), 7.24-7.37 (m, 2H), 7.04-7.11 (m, 3H), 6.94-6.96 (m, 1H), 6.75-6.79 (m, 3H), 6.65 (d, 2H, J=7.6 Hz), 3.39 (s, 6H), 2.45 (m, 4H), 2.22 (m, 2H), 1.95 (m, 3H), 1.44-1.70 (m, 13H), 1.15 (m, 2H), 1.00 (m, 3H), 0.81 (t, 3H, J=7.4 Hz). 13 C NMR (100 MHz, CD2Cl2): δ 158.26, 154.51, 139.09, 139.06, 136.82, 136.69, 136.28, 136.25, 133.67, 133.59, 129.68, 129.39, 129.03, 128.81, 128.79, 127.11, 125.56, 125.45, 122.88, 119.39, 104.24, 56.10, 55.72, 45.29, 36.77, 36.53, 31.97, 30.15, 28.25, 28.15, 28.03, 27.93, 26.88, 26.60, 26.11, 11.36 (observed complexity results from C-P coupling 31 and dynamic molecular behavior). P NMR (162 MHz, tol-d8): δ 45.6.

References:

1) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685. 2) de Graaf, W.; Boersma, J.; Smeets, W. J. J.; Spek, A. L.; van Koten, G. Organometallics 1989, 8, 2907.

S4 NMR Spectra:

SSPPhhoossPPdd NN Cl H Cl H2

1 H NMR of 2 in CD2Cl2

SPhosPd SPhosPd N Cl NH2 Cl H

13 C NMR of 2 in CD2Cl2

S5 SPhosPd N Cl H2 SPhosPd N Cl H

31 P NMR of 2 in tol-d8

31 Entire P NMR spectra (C6D6) for Figure 2.

Cl HNBu2 SPhosPd PdSPhos excess Cl

S6 NH2 Cl SPhosPd PdSPhos Cl excess

Cl NH2 SPhosPd PdSPhos Cl HNBu2 1.2 equiv 1.2 equiv 0.5 equiv

S7 Representative 31P NMR spectra for relative binding studies in Table 1

SPhosPd SPhosPd NBu N 2 Cl H Cl H NBOC

SPhosPd SPhosPd NBu N 2 Cl H Cl H O

S8 SPhosPd SPhosPd NBu2 N Cl H Cl H

SPhosPd SPhosPd N Me NBu 2 Cl Cl H H H

S9 SPhosPd NBu2 Cl H

SPhosPd N Cl H H

SPhosPd SPhosPd N OMe NBu 2 Cl Cl H H H

S10 SPhosPd NBu SPhosPd 2 N NMe Cl H 2 Cl H H

SPhosPd NBu2 Cl H

SPhosPd N t-Bu Cl H H

S11 SPhosPd SPhosPd N s-Bu NBu Cl 2 H H Cl H

SPhosPd N SPhosPd Cl H N(CH2CH2OMe)2 O Cl H

SPhos oxide

S12 Gaussian 03, Revision B.05, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; and Pople, J. A.; Gaussian, Inc., Wallingford CT, 2004.

S13 MeO

MeO

P Cl P Pd Pd Ar Cl

X-ray crystal structure of 1 (thermal ellipsoids at 30% probability)

S14 H2 Cl N Pd P OMe

MeO

X-ray crystal structure of 2 (thermal ellipsoids at 30% probability)

S15