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Supporting Information

Parameterization of phosphine ligands demonstrates enhacement of nickel catalysis via remote

steric effects

Kevin Wu and Abigail G. Doyle

Department of Chemistry, Princeton University Frick Chemical Laboratory, Princeton, NJ 08544 USA

E-mail: [email protected]

TABLE OF CONTENTS

A) General Considerations ....................................................................................................... 1 B) Preparation of Ligand Precursors ...................................................................................... 2 C) Ligand Preparation ............................................................................................................. 4 D) Reaction Optimization, Control Experiments, and NMR Timepoint Studies ................. 17 E) Synthesis of Starting Materials ......................................................................................... 20 F) Suzuki Arylation of Benzylic Acetals and Characterization ............................................ 23 G) Ligand Parameter Generation and Data .......................................................................... 41 H) DFT Generated Steric Parameters ................................................................................... 54 I) X-Ray Crystallography Details ........................................................................................... 67 J) R Source Code for Plotting and Regression Analysis ....................................................... 89 K) Coordinates for Computed Structures .............................................................................. 89 L) NMR Spectra ...................................................................................................................... 89

A) General Considerations General information. Unless otherwise noted, reactions were performed with rigorous exclusion of air or moisture. Argon-flushed stainless steel cannulae or gas-tight syringes were used to transfer air- and moisture-sensitive reagents. Solvent was freshly distilled/degassed prior to use unless otherwise noted. Reactions were monitored by LCMS gas chromatography or NMR spectrometry. Organic solutions were concentrated under reduced pressure using a rotary evaporator (30 C, 99%) was refluxed over sodium, distilled, and degassed before being stored in a nitrogen-filled glove box over activated 4 sieves. Pentane (Fisher, HPLC grade) was stored over activated sieves and degassed before being stored in a nitrogen-filled glovebox over activated 4 sieves. All other solvents (toluene, diethyl ether, hexanes, tetrahydrofuran) were HPLC grade, degassed for 30 minutes, and dried by passing through a neutral alumina column.2 Deuterated solvents were purchased from Aldrich (dichloromethane-d2 and

1 Graham, T. J. A.; Shields, J. D.; Doyle, A. G. Chem. Sci. 2011, 2, 980984. 2 Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 15181520.

2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

SUPPLEMENTARY INFORMATIONDOI: 10.1038/NCHEM.2741

NATURE CHEMISTRY | www.nature.com/naturechemistry 1

http://dx.doi.org/10.1038/nchem.2741

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toluene-d8) and Cambridge Isotopes (benzene-d6 and chloroform-d1) degassed and stored activated 4 sieves in a nitrogen-filled glovebox. Ni(cod)2 was purchased from Strem and stored at 40 C in a

nitrogen-filled glovebox.

PCy3, PCy2Ph, PCyPh2, PiPrPh2, PtBu3, PPh3, and IMesCl (1,3-Bis(2,6-diisopropylphenyl)imidazolium

chloride) were purchased from Sigma-Aldrich and stored in a nitrogen-filled glovebox. PCyCl2, PCy2Cl

and PtBuCl2 were purchased from Strem and stored and dispensed in a nitrogen-filled glovebox.

Instrumentation. Proton nuclear magnetic resonance (1H NMR) spectra, carbon nuclear magnetic

resonance (13C NMR) spectra, and phosphorus nuclear magnetic resonance (31P NMR) spectra were

recorded on a Bruker 500 AVANCE spectrometer (500, 125, and 200 MHz, respectively). Chemical shifts

for proton are reported in parts per million (ppm) downfield from tetramethylsilane and are referenced to

residual protium in the NMR solvent (CDCl3 = 7.26, C6D6 = 7.16). Chemical shifts for carbon are

reported in ppm downfield from tetramethylsilane and are referenced to the carbon resonances of the

solvent residual peak (CDCl3 = 77.16, C6D6 = 128.06). Chemical shifts for phosphorus are reported in

ppm and are referenced to triphenylphosphine oxide shift. Fluorine nuclear magnetic resonance (19F

NMR) spectra were recorded on a Varian Inova 300 (282 MHz) or 400 (376 MHz) spectrometer;

chemical shifts are reported in parts per millions and are referenced to CFCl3 ( 0 ppm). NMR data are

presented as follows: chemical shift ( ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,

p = pentet, m = multiplet, br = broad), coupling constant in Hertz (Hz), integration. FT-IR spectra were

recorded on a Perkin-Elmer Paragon 500 and are reported in terms of frequency of absorption (cm1).

Reversed-phase liquid chromatography/mass spectrometry (LC/MS) was performed on an Agilent 1260

Infinity analytical LC and Agilent 6120 Quadrupole LC/MS system, using electrospray

ionization/atmospheric-pressure chemical ionization (ESI/APCI), and UV detection at 254 and 280 nm.

Statistical analyses were carried out in Microsoft Windows 8.1 Professional. Microsoft Excel was used

for data collection and preliminary organization.

Statistical analysis. The R statistical program (version 3.2.3) 3 was used as a platform for statistical

analysis and graphical visualization. Packages for statistical analysis included the MASS,4 boot,5 and

caret6 packages, and the ggplot27 package was used for graphical visualization. The foreach and parallel

package was used for multicore acceleration of certain mathematical calculations.

The RStudio IDE (Version 0.99.891, RStudio Inc.) was the development environment used for R analysis.

B) Preparation of Ligand Precursors

2,4-6-tribromo-2-iodobenzene. 2,4,6-Tribromobenzenamine (8.00 g, 24.3 mmol) was dissolved in

concentrated sulfuric acid (Volume: 20 mL) and cooled to 0 C using an ice bath. A concentrated solution

3 R Core Team. R: A language and environment for statistical computing; R Foundation for Statistical Computing:

Vienna, Austria, 2015. 4 Venables, W. N.; Ripley, B. D. Modern Applied Statistics with S; Fourth ed.; Springer: New York, 2002. 5 Canty, A.; Ripley, B. boot: Bootstrap R (S-Plus) Functions; R package version 1.3-17 ed., 2015. 6 Kuhn, M. Caret: Classification and Regression Training; R package version 6.0-68 ed., 2016. 7 Wickham, H. ggplot2: Elegant Graphics for Data Analysis; Springer-Verlag: New York, 2009.

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of Sodium nitrite (3.68 g, 53.4 mmol) in water was added in portions and the reaction was allowed to stir

at 0 C for 3.5 hours. The mixture was then poured onto an ice/water slurry in an Erlenmeyer funnel,

followed by the immediate addition of potassium iodide (24.2 g, 146 mmol) in ice cold water.

The mixture was then transferred to a separation funnel and extracted with ethyl acetate (5 x 20 mL). The

combined organic layers were rinsed with saturated aqueous NaHSO3 (5 x 20 mL), water (3 x 20 mL),

and brine. The solution was then dried over magnesium sulfate, filtered, and concentrated under reduced

pressure to yield the crude product as a brownish solid. The presence of the desired product was

confirmed by 1H NMR, and the product was purified by recrystallization from hot ethanol.

1,3,5-tribromo-2-iodobenzene (7.03 g, 15.9 mmol, 65 % yield) was isolated from initial recrystallization

as a bright orange solid. The spectra were consistent with the previously reported information.8

5'-bromo-2,2'',4,4'',6,6''-hexaisopropyl-1,1':3',1''-terphenyl.9 A solution of degassed 2-bromo-1,3,5-

triisopropylbenzene (4.02 mL, 15.9 mmol) in THF (30 mL) was prepared in an oven-dried rbf equipped

with a PTFE stirbar. Activated magnesium turnings (0.772 g, 31.8 mmol) were prepared by reaction with

1,2-dibromoethane (0.05 mL) in THF (10 mL) under nitrogen in an oven-dried rbf equipped with a PTFE

stirbar and a reflux condenser. The magnesium flask was heated with a heat gun until the solution began

to reflux, and then 2 mL of the aryl bromide was added to initiate the reaction. After initiation, the

remainder of the bromide solution was added dropwise over a period of 30 minutes, while the reaction

was heated to reflux in an oil bath after about half the solution was added. The flask containing the aryl

halide was rinsed with THF (2 x 5 mL) and the mixture was refluxed overnight.

1,3,5-tribromo-2-iodobenzene (2.00 g, 4.54 mmol) was loaded into an oven-dried rbf equipped with a

PTFE stirbar and degassed by 3x evacuation/refill cycles. THF (30 mL) was then added and the iodide

was added dropwise to the refluxing organomagnesium mixture over 30 minutes, and the flask was rinsed

with THF (2 x 5 mL). The resulting mixture was then refluxed for 4h and then allowed to cool to room

temperature and the solution was decanted onto ice cold aqueous HCl (30 mL, 10% wt).

The aqueous layer was then diluted with water (15 mL). The aqueous layer was extracted with diethyl

ether (3 x 60 mL) and the combined organic layers were washed sequentially with saturated aqueous

Na2S2O3 (30 mL), water (30 mL), and dried over magnesium sulfate. The resulting mixture was then

filtered and concentrated under reduced pressure to yield the crude product.

The crude product was purified by recrystallization from diethyl ether and ethanol. A minimum of diethyl

ether was added to dissolve the crude product under heating, followed by the addition of 5 to 8x the

volume of ethanol while heating. The mixture was then allowed to cool slowly to room temperature and

sit overnight. The white crystalline powder was then collected by vacuum filtration and rinsed with EtOH

(2 x 5 ml).

8 Stoll, R. S.; Peters, M. V.; Kuhn, A.; Heiles, S.; Goddard, R.; Buhl, M.; Thiele, C. M.; Hecht, S. J. Am. Chem Soc.

2009, 131, 357-367. 9 Jung, B.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 1490-1493.

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5'-bromo-2,2'',4,4'',6,6''-hexaisopropyl-1,1':3',1''-terphenyl (1.39 g, 2.48 mmol, 55 % yield) was isolated

from recrystallization as a white solid. The observed spectra matched the reported information.

C) Ligand Preparation

General Procedure A: For diarylalkylphosphine synthesis.

The synthesis of diarylalkylphosphines proceeds through the following procedure:

A solution of tert-butyllithium (4.05 equiv, 1.7 M in pentane) was added via syringe to an oven-dried

Schlenk flask under nitrogen equipped with a PTFE stirbar. The solution was then cooled to 78 C and

an equal volume of diethyl ether was added and the solution stirred for 5 minutes, followed by the

dropwise addition via syringe of aryl bromide (ArBr) (2.05 equiv) in diethyl ether (prepared separately in

a round-bottom flask under N2 with the equal amount of diethyl ether as in the Schlenk flask). The flask

containing the aryl bromide was rinsed with diethyl ether. The solution was then allowed to stir for 1 hour

at 78 C to facilitate lithium-halogen exchange.

Dichloro(alkyl)phosphine (PAlkCl2) (1.00 equiv) in diethyl ether was then added dropwise via syringe.

The cooling bath was allowed to expire slowly, thus facilitating a slow warming to room temperature

overnight while the reaction was allowed to stir vigorously. The progression of the reaction was

monitored by 31P NMR spectroscopy of aliquots. Complete consumption of the alkyldichlorophosphine

(AlkPCl2, shows up at 180-200 ppm) and the intermediate phosphine monohalide (AlkPArX, where X

may be Br or Cl, 40-60 ppm) indicate complete conversion.

Upon complete conversion to the desired phosphine, the reaction flask was cooled to 0 C and nitrogen-

sparged saturated aqueous ammonium chloride solution (15 mL) was added dropwise via syringe to the

reaction. The ice bath was removed and the mixture was extracted in the reaction flask with diethyl ether

under N2 (3 x 15 mL). This extraction was performed on the benchtop using degassed diethyl ether and

solvents were transferred using syringes. Oxygen intrusion (and subsequent phosphine oxide formation)

can be minimized by fully degassing all solvents by either sparging with nitrogen for a minimum of 15

minutes or freeze-pump-thaw (3 cycles). The organic layers were transferred by syringe to a nitrogen-

filled flask with flame-dried magnesium sulfate. The flask was then brought into the glovebox for vacuum

filtration into a Schlenk flask equipped with a PTFE stirbar. The filter was rinsed with diethyl ether (2 x

15 mL) and the filtrate was concentrated under reduced pressure.

The crude product was recrystallized from degassed ethanol or ethanol/methanol (~3 mL of alcohol per

expected gram of phosphine) added in the glovebox. Heating of the solvent could be accomplished by

removing the Schlenk flask from the glovebox, attaching it to a Schlenk line, and using a heat gun. The

flask was put into the glovebox freezer (35 C) for storage overnight before collection of the solid

product via vacuum filtration under nitrogen.

While the solid forms of these ligands are stable in air and do not change after 1 month of storage on the

bench, they will decompose upon heating in a melting point apparatus or in non-degassed solvents.

Ligands that take the form of oils are air sensitive. HRMS and IR analyses were done in air, in non-

degassed solvents due to practical limitations.

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General Procedure B: For monoarylalkylphosphine synthesis.

The synthesis of monoarylalkylphosphines proceeds through the following procedure: A solution of tert-

butyllithium (2.00 equiv, 1.7 M in pentane) was added via syringe to an oven-dried Schlenk flask under

nitrogen equipped with a PTFE stirbar. The solution was then cooled to 78 C and an equal volume of

diethyl ether was added and the solution stirred for 5 minutes, followed by the dropwise addition via

syringe of aryl bromide (ArBr) (1.00 equiv) in diethyl ether (prepared separately in a round-bottom flask

under N2 with the equal amount of diethyl ether as in the Schlenk flask). The flask containing the aryl

bromide was rinsed with diethyl ether. The solution was then allowed to stir for 3 hours to facilitate

lithium-halogen exchange at 78 C. (NOTE: Complete lithium-halogen exchange is critical to a

successful outcome. Excess or remaining tert-butyllithium will outcompete the aryllithium during

addition to the phosphine.)

Dialkyl(chloro)phosphine (PAlk2Cl) (1.00 equiv) in diethyl ether was then added dropwise via syringe

and the cooling bath was removed. The reaction was allowed to warm to room temperature with stirring

vigorously overnight. The progression of the reaction was monitored by 31P NMR spectroscopy of

aliquots. Complete consumption of the phosphine monohalide (40-60 ppm) indicates complete

conversion.

Upon complete consumption of the monochlorophosphine, the reaction flask was cooled to 0 C and

nitrogen-sparged saturated aqueous ammonium chloride solution (15 mL) was added dropwise via syringe

to the reaction. The ice bath was removed and the mixture was extracted in the reaction flask with diethyl

ether under N2 (3 x 15 mL). This extraction was performed on the benchtop using degassed diethyl ether

and solvents were transferred using syringes. Oxygen intrusion (and subsequent phosphine oxide

formation) can be minimized by fully degassing all solvents by either sparging with nitrogen for a

minimum of 15 minutes or freeze-pump-thaw (3 cycles). The organic layers were transferred by syringe

to a nitrogen-filled flask with flame-dried magnesium sulfate. The flask was then brought into the

glovebox for vacuum filtration into a Schlenk flask equipped with a PTFE stirbar. The filter was rinsed

with diethyl ether (2 x 15 mL) and the filtrate was concentrated under reduced pressure.

The crude product was recrystallized from degassed ethanol or ethanol/methanol (~3 mL of alcohol per

expected gram of phosphine) added in the glovebox. Heating of the solvent could be accomplished by

removing the Schlenk flask from the glovebox, attaching it to a Schlenk line, and using a heat gun. The

flask was put into the glovebox freezer (35 C) for storage overnight before collection of the solid

product via vacuum filtration under nitrogen.

While the solid forms of these ligands are stable in air and do not change after 1 month of storage on the

bench, they will decompose upon heating in a melting point apparatus or in non-degassed solvents.

Ligands that take the form of oils are air sensitive. HRMS and IR analyses were done in air, in non-

degassed solvents due to practical limitations.

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cyclopentylbis(3,5-di-tert-butylphenyl)phosphine (L16). Prepared with general procedure A. A

solution of tert-butyllithium (6.35 mL, 10.8 mmol) was added via syringe to an oven-dried Schlenk flask

equipped with a PTFE stirbar. The solution was then cooled to 78 C and an equal volume of diethyl

ether (6 mL) was added and the solution stirred for 5 minutes, followed by the dropwise addition of 1-

bromo-3,5-di-tert-butylbenzene (1.49 g, 5.53 mmol) in diethyl ether (6 mL). The solution was then

allowed to stir for 30 minutes at 78 C. Dichloro(cyclopentyl)phosphine (0.450 g, 2.63 mmol) in diethyl

ether (6 mL) was then added dropwise and the cooling bath was removed. The reaction was allowed to

warm to room temperature with stirring overnight.


sparged saturated aqueous ammonium chloride solution (15 mL) was added dropwise to the reaction. The

ice bath was removed and the mixture was extracted with diethyl ether under N2 (3 x 15 mL). The organic

layers were transferred by syringe to a nitrogen-filled flask with MgSO4. The flask was then brought into

the glovebox for vacuum filtration and recrystallization with EtOH.

Cyclopentylbis(3,5-di-tert-butylphenyl)phosphine (0.815 g, 1.70 mmol, 65 % yield) was isolated as a

white crystalline solid. 1H NMR (500 MHz, Benzene-d6): 7.72 (dd, J = 7.6, 1.9 Hz, 4H), 7.52 (t, J = 1.9 Hz, 2H), 2.78 (td, J =

8.5, 7.1 Hz, 1H), 2.02 1.88 (m, 2H), 1.85 1.71 (m, 2H), 1.71 1.60 (m, 2H), 1.56 1.43 (m, 2H), 1.28

(s, 36H).

13C NMR (125 MHz, Benzene-d6): 150.68 (d, J = 6.5 Hz), 139.10 (d, J = 14.1 Hz), 128.04 (d, J = 19.7

Hz), 122.65, 37.14 (d, J = 10.2 Hz), 35.06, 31.63, 31.61 (d, J = 20.0 Hz), 26.94 (d, J = 7.1 Hz).

31P NMR (120 MHz, Benzene-d6): 1.32.

HRMS (ESI-TOF, for C33H51P+, [M]+): Observed: 478.37287 m/z, calculated: 478.37284 m/z.

IR (may contain some P=O, cm-1): 2955, 2868, 1591, 1476, 1421, 1393, 1362, 1248, 1187, 1144, 896,

710.

cyclohexylbis(3,5-di-tert-butylphenyl)phosphine (L13). Prepared with general procedure A. A

solution of tert-butyllithium (2.61 mL, 4.43 mmol) was added via syringe to an oven-dried Schlenk flask

under nitrogen equipped with a PTFE stirbar. The solution was then cooled to 78 C and an equal

volume of diethyl ether (3 mL) was added and the solution stirred for 5 minutes, followed by the

dropwise addition of 1-bromo-3,5-diisopropylbenzene (0.547 g, 2.27 mmol) in diethyl ether (3 mL). The

solution was then allowed to stir for 2 hours at 78 C. Dichloro(cyclohexyl)phosphine (0.200 g, 1.081

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mmol) in diethyl ether (3 mL) was then added dropwise and the cooling bath was removed. The reaction

was allowed to warm to room temperature with stirring overnight.





the glovebox for vacuum filtration and concentration under reduced pressure.

Upon filtration and concentration under reduced pressure, the crude product was recrystallized from

degassed ethanol under N2 in a Schlenk flask. Heating was done on a Schlenk line outside of the

glovebox. Upon cooling to room temperature, the Schlenk flask was then brought into the glovebox and

kept in a 35 C freezer until crystallization. The product was collected by vacuum filtration under

nitrogen and then dried under vacuum.

Cyclohexylbis(3,5-di-tert-butylphenyl)phosphine (0.225 g, 0.457 mmol, 40% yield, corrected) was

isolated as a white crystalline solid with 4% of phosphine oxide impurity that was not removed by

recrystallization. This ligand was used without additional purification.

1H NMR (500 MHz, Benzene-d6): 7.78 (dd, J = 7.6, 1.9 Hz, 4H), 7.56 7.51 (m, 2H), 2.45 (tdt, J =

11.7, 6.2, 3.2 Hz, 1H), 2.00 (d, J = 13.7 Hz, 2H), 1.70 (dt, J = 12.9, 3.5 Hz, 2H), 1.60 1.38 (m, 3H), 1.28

(s, 36H), 1.24 1.08 (m, 3H). Note: NMR solvent shows diethyl ether from glovebox atmosphere.


Hz), 122.88, 37.05 (d, J = 10.9 Hz), 35.06, 31.63, 30.27 (d, J = 15.5 Hz), 27.26 (d, J = 10.7 Hz), 26.82.

31P NMR (200 MHz, Benzene-d6): 1.88. (4% impurity of phosphine oxide at 31.68 ppm)



791, 711.

dicyclopentyl(2,2'',4,4'',6,6''-hexaisopropyl-[1,1':3',1''-terphenyl]-5'-yl)phosphine (L17). Prepared

according to general procedure B. A solution of tert-butyllithium (1.068 mL, 1.816 mmol) was added

via syringe to an oven-dried Schlenk flask under nitrogen equipped with a PTFE stirbar. The solution was

then cooled to 78 C and an equal volume of diethyl ether (2 mL) was added and the solution stirred for

5 minutes, followed by the dropwise addition of 5'-bromo-2,2'',4,4'',6,6''-hexaisopropyl-1,1':3',1''-

terphenyl (0.500 g, 0.890 mmol) in diethyl ether (2 mL). The solution was then allowed to stir for 3 hours

at 78 C. Chlorodicyclopentylphosphine (0.182 g, 0.890 mmol) in diethyl ether (1 mL) was then added

dropwise and the cooling bath was removed. The reaction was allowed to warm to room temperature

overnight with stirring. An aliquot was analyzed by 31P NMR for presence of the monochlorophosphine.

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nitrogen-sparged saturated aqueous ammonium chloride solution (15 mL) was added dropwise to the

reaction. The ice bath was removed and the mixture was extracted with diethyl ether under N2 (3 x 15

mL). The organic layers were transferred by syringe to a nitrogen-filled flask with MgSO4. The flask was

then brought into the glovebox for vacuum filtration.




kept in a 35 C freezer until crystallization. The product was collected by vacuum filtration under

nitrogen and then dried under vacuum.

Dicyclopentyl(2,2'',4,4'',6,6''-hexaisopropyl-[1,1':3',1''-terphenyl]-5'-yl)phosphine (0.280 g, 0.430 mmol,

48 % yield) was isolated as a white solid.

1H NMR (500 MHz, Benzene-d6): 7.51 (dd, J = 6.5, 1.6 Hz, 2H), 7.22 (s, 4H), 7.08 (d, J = 1.3 Hz, 1H),

2.99 (apparent hept, J = 7.4 Hz, 4H) [split by diastereotopic CH3 groups], 2.90 (apparent hept, J = 7.7 Hz,

2H) [split by diastereotopic CH3 groups], 2.07 (pd, J = 7.8, 2.8 Hz, 2H), 1.92 1.78 (m, 2H), 1.70 1.35

(m, 14H), 1.31 (apparent d, J = 6.9 Hz, 12H) [diastereotopic CH3 groups], 1.27 1.20 (m, 24H)

[diastereotopic CH3 groups].

13C NMR (125 MHz, Benzene-d6): 148.16 (2C), 146.52 (4C), 140.34 (2C, d, J = 6.9 Hz), 137.84 (1C,

d, J = 19.9 Hz), 137.21 (2C), 133.56 (2C, d, J = 18.5 Hz), 131.69 (1C), 120.41 (4C), 36.25 (2C, d, J =

12.0 Hz), 34.58 (2C), 30.77 (2C, d, J = 20.9 Hz), 30.63 (4C), 30.16 (2C, d, J = 11.2 Hz), 26.70 (2C, d, J =

7.4 Hz), 26.01 (2C, d, J = 5.4 Hz), 24.27 24.06 (8C, m), 24.01 (4C). (Total: 46C)



IR (may contain some P=O, cm-1): 2959, 2869, 1608, 1460, 1361, 1138.

dicyclopentyl(phenyl)phosphine (L8). A solution of bromocyclopentane (3.03 mL, 28.4 mmol) in

diethyl ether (16 mL) was added dropwise to activated magnesium (0.869 g, 35.8 mmol) under nitrogen

in an oven-dried rbf equipped with a PTFE stirbar. The reaction was placed in a room temperature water

bath to prevent exotherm during reaction intiation. The flask containing the alkyl halide was rinsed with

diethyl ether (2 x 2 mL). The reaction was then stirred at room temperature for 2 h.

The Grignard reagent was then added dropwise to a solution of dichloro(phenyl)phosphine (1.52 mL, 11.2

mmol) in diethyl ether (20 mL) under nitrogen in an oven-dried Schlenk flask equipped with a PTFE

stirbar at 45 C. The solution was then allowed to warm to room temperature by expiration of the dry ice

bath and stirred overnight at room temperature.

Upon reaction completion as monitored by 31P NMR, degassed saturated aqueous ammonium chloride (10

mL) was added slowly to quench any remaining Grignard and the aqueous layer was extracted with

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diethyl ether (3 x 10 mL). The combined organic layers were then dried over magnesium sulfate, filtered

in the glovebox, and concentrated under reduced pressure.

The crude product was then purified by vacuum distillation at ~100 C at 250 mtorr. The distillate was

quickly transferred to the glovebox after purging the atmosphere with nitrogen.

Dicyclopentyl(phenyl)phosphine (0.745 g, 3.02 mmol, 26 % yield) was isolated as a clear viscous oil with

~5% of the phosphine oxide by 31P NMR.

1H NMR (500 MHz, Benzene-d6): 7.57 (tt, J = 6.8, 1.7 Hz, 2H), 7.22 7.09 (m, 3H), 2.13 1.99 (m,

2H), 1.91 1.80 (m, 2H), 1.68 1.42 (m, 10H), 1.42 1.25 (m, 4H).


Hz), 128.23, 37.66 (d, J = 11.3 Hz), 31.47 (d, J = 21.3 Hz), 31.22 (d, J = 13.4 Hz), 26.99 (d, J = 7.7 Hz),

26.06 (d, J = 6.4 Hz).

31P NMR (200 MHz, Benzene-d6): 41.63 (P=O), 1.07.

HRMS (ESI-TOF, for C16H23P+, [M]+): Observed: 246.15305 m/z, calculated: 246.15374 m/z

IR (may contain some P=O, cm-1): 2951, 2868, 1435, 1389, 1360, 1139, 1070, 906, 745, 698.

cyclopentyldiphenylphosphine (L10). A solution of bromocyclopentane (1.35 mL, 12.7 mmol) in

diethyl ether (16 mL) was added dropwise to activated magnesium (0.388 g, 15.9 mmol) under nitrogen

in an oven-dried rbf equipped with a PTFE stirbar. The reaction was placed in a room temperature water

bath to prevent exotherm during reaction intiation. The flask containing the alkyl halide was rinsed with

diethyl ether (2 x 2 mL). The reaction was then stirred at room temperature for 2 h.

The Grignard reagent was then added dropwise to a solution of chlorodiphenylphosphine (1.79 mL, 9.97

mmol) in diethyl ether (20 mL) under nitrogen in an oven-dried Schlenk flask equipped with a PTFE

stirbar at 45 C. The solution was then allowed to warm to room temperature by expiration of the dry ice

bath and stirred overnight at room temperature.

Upon reaction completion as monitored by 31P NMR, degassed saturated aqueous ammonium chloride (10

mL) was added slowly to quench any remaining Grignard and the aqueous layer was extracted with

diethyl ether (3 x 10 mL). The combined organic layers were then dried over magnesium sulfate, filtered

in the glovebox, and concentrated under reduced pressure.

The crude product was then purified by vacuum distillation at ~100 C at 250 mtorr. The distillate was

quickly transferred to the glovebox after purging the atmosphere of nitrogen.

Cyclopentyldiphenylphosphine (2.14 g, 8.42 mmol, 84 % yield) was isolated as a clear, viscous oil with

about ~4% of the phosphine oxide as observed by 31P NMR.

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1H NMR (500 MHz, Benzene-d6): 7.51 (tt, J = 7.0, 1.6 Hz, 4H), 7.14 7.03 (m, 6H), 2.42 (hextet, J =

8.0 Hz, 1H), 1.77 1.63 (m, 2H), 1.64 1.47 (m, 4H), 1.47 1.33 (m, 2H).

13C NMR (125 MHz, Benzene-d6): 139.61 (d, J = 15.2 Hz), 133.32 (d, J = 18.7 Hz), 128.26, 128.18 (d,

J = 6.5 Hz), 35.93 (d, J = 9.3 Hz), 30.95 (d, J = 20.3 Hz), 26.37 (d, J = 7.4 Hz).

31P NMR (200 MHz, Benzene-d6): 31.28 (P=O), 3.70.


IR (may contain some P=O, cm-1): 2985, 2870, 1437, 1387, 1139, 721, 697.

Cyclopentyldimesitylphosphine (L12). Prepared with general procedure A. A solution of tert-

butyllithium (4.64 mL, 7.89 mmol) was added via syringe to an oven-dried Schlenk flask under nitrogen

equipped with a PTFE stirbar. The solution was then cooled to 78 C and an equal volume of diethyl

ether (7 mL) was added and the solution stirred for 5 minutes, followed by the dropwise addition of 2-

bromo-1,3,5-trimethylbenzene (0.671 mL, 4.39 mmol) in diethyl ether (7 mL). The solution was then








the glovebox for vacuum filtration and concentration under reduced pressure.

The crude product took the form of a white solid, which was recrystallized by heating with hot ethanol

under nitrogen and then cooling in a 35 C freezer in the glovebox. The product was collected by

vacuum filtration under nitrogen, rinsed with ethanol, and then dried under vacuum.

Cyclopentyldimesitylphosphine (0.125 g, 0.369 mmol, 21 % yield) was isolated as a white solid.

1H NMR (500 MHz, Benzene-d6): 6.82 (d, J = 2.3 Hz, 4H), 3.52 (pd, J = 7.5, 6.0 Hz, 1H), 2.59 (s,

12H), 2.19 (s, 6H), 1.93 1.61 (m, 6H), 1.60 1.47 (m, 2H).


Since this ligand was ineffective in the reaction, no additional characterization was performed.

S-11

cyclopentylbis(3,5-dimethylphenyl)phosphine (L14). Prepared with general procedure A. A solution

of tert-butyllithium (5.57 mL, 9.47 mmol) was added via syringe to an oven-dried Schlenk flask equipped

under nitrogen with a PTFE stirbar. The solution was then cooled to 78 C and an equal volume of

diethyl ether (6 mL) was added and the solution stirred for 5 minutes, followed by the dropwise addition

of 1-bromo-3,5-dimethylbenzene (0.89 g, 4.80 mmol) in diethyl ether (6 mL). The solution was then




Upon complete conversion to the desired phosphine as monitored by 31P NMR, the reaction flask was

cooled to 0 C and nitrogen-sparged saturated aqueous ammonium chloride solution (15 mL) was added

dropwise to the reaction. The ice bath was removed and the mixture was extracted with diethyl ether

under N2 (3 x 15 mL). The organic layers were transferred by syringe to a nitrogen-filled flask with

MgSO4. The flask was then brought into the glovebox for vacuum filtration and concentration under

reduced pressure.

The crude product took the form of a white solid, which was recrystallized by heating with hot ethanol

under nitrogen and then cooling in a 35 C freezer in the glovebox. The product was collected by

vacuum filtration under nitrogen, rinsed with ethanol, and then dried under vacuum.

Cyclopentylbis(3,5-dimethylphenyl)phosphine (0.520 g, 1.68 mmol, 72 % yield) was isolated as a white

solid.

1H NMR (500 MHz, Benzene-d6): 7.43 7.34 (m, 4H), 6.80 6.71 (m, 2H), 2.76 2.53 (m, 1H), 2.09

(s, 12H), 1.92 1.77 (m, 2H), 1.74 1.57 (m, 4H), 1.57 1.41 (m, 2H).


Hz), 130.60, 36.14 (d, J = 9.3 Hz), 31.55 (d, J = 20.6 Hz), 26.89 (d, J = 7.1 Hz), 21.36.



IR (may contain some P=O, cm-1): 2986, 2870, 2159, 1449, 1387, 1360, 1139, 1074.

S-12

bis(3,5-bis(trifluoromethyl)phenyl)(cyclopentyl)phosphine (L15). Bis(3,5-

bis(trifluoromethyl)phenyl)chlorophosphine (0.800 g, 1.62 mmol) was weighed out into an oven-dried

Schlenk flask equipped with a PTFE stirbar in a N2 filled glovebox. Copper(I) chloride (6.4 mg, 0.065

mmol) was added, followed by diethyl ether (Volume: 7.00 mL). The Schlenk flask was then sealed with

a septum and removed from the glovebox. The reaction was then cooled to 0 C and

cyclopentylmagnesium bromide (2.03 mL, 2.03 mmol) was added dropwise to the reaction mixture. The

cooling bath was removed and the solution allowed to stir overnight at 23 C. The reaction was then

quenched with N2 sparged saturated aqueous ammonium chloride at 0 C.

The mixture was extracted with Et2O (3 x 10 mL) and the combined layers were dried over MgSO4 under

N2 in a septum sealed flask. The flask was then brought into the glovebox and filtered. The solvent was

then removed under high vacuum to give the crude product.




kept in a 35 C freezer until crystallization. The product was collected by vacuum filtration, rinsed with

ethanol, and then dried under vacuum.

Bis(3,5-bis(trifluoromethyl)phenyl)(cyclopentyl)phosphine (0.075 g, 0.143 mmol, 8.8 % yield) was

isolated as a orange solid.

1H NMR (500 MHz, Benzene-d6): 7.73 (d, J = 5.8 Hz, 4H), 7.63 (s, 6H), 1.86 (h, J = 7.9 Hz, 1H), 1.50

1.18 (m, 6H), 1.17 1.04 (m, 2H).

13C NMR (125 MHz, Benzene-d6): 141.69 (d, J = 22.9 Hz), 133.01 (d, J = 19.0 Hz), 132.09 (qd, J =

33.3, 6.1 Hz), 123.53 (q, J = 273.3 Hz), 123.20 (p, J = 3.9 Hz), 34.72 (d, J = 10.2 Hz), 30.66 (d, J = 20.7

Hz), 26.57 (d, J = 7.2 Hz).


19F NMR (282 MHz, Benzene-d6): 62.77.

Since this ligand was ineffective in the reaction, no additional characterization was performed.

(cyclopentylmethyl)bis(3,5-di-tert-butylphenyl)phosphine (L18). Prepared according to a variation of

general procedure A. Cyclopentylmethyl phosphine dihalide (MeCypPX2, with X consisting of a

mixture of bromide and chloride) was prepared from the addition of cyclopentylmethyl magnesium

bromide (1.15 equiv) to phosphorous trichloride (1.00 equiv) at -78 C in diethyl ether. Magnesium salts

were removed via filtration through celite in the glovebox, the filtrate was concentrated under vacuum,

and the MeCypPX2 was used in the reaction without further purification.

S-13

A solution of tert-butyllithium (4.95 ml, 8.42 mmol) was added via syringe to an oven-dried Schlenk flask

equipped with a PTFE stirbar. The solution was then cooled to -78 C and an equal volume of diethyl

ether (5 ml) was added and the solution stirred for 5 minutes, followed by the dropwise addition of 1-

bromo-3,5-di-tert-butylbenzene (1.161 g, 4.31 mmol) in diethyl ether (5 ml). The solution was then

allowed to stir for 30 minutes. The cyclopentylmethyl phosphine dihalide (1.00 equiv) in diethyl ether (5

ml) was then added dropwise and the cooling bath was removed. The reaction was allowed to warm to

room temperature with stirring overnight. The reaction was monitored for completion by 31P NMR.


cooled to 0 C and nitrogen-sparged saturated aqueous ammonium chloride solution (15 mL) was added

dropwise to the reaction. The ice bath was removed and the mixture was extracted with diethyl ether

under N2 (3 x 15 mL). The organic layers were transferred by syringe to a nitrogen-filled flask with

MgSO4. The flask was then brought into the glovebox for vacuum filtration and concentration under

reduced pressure.

The crude product took the form of a viscous oil, which was recrystallized by adding an ethanol/methanol

(3:1) mixture in the glovebox, heating mixture under nitrogen, and then cooling in a 35 C freezer in the

glovebox. The product was collected by vacuum filtration under nitrogen, rinsed with ethanol, and then

dried under vacuum.

(cyclopentylmethyl)bis(3,5-di-tert-butylphenyl)phosphine (0.250 g, 0.446 mmol, 22 % yield, 88% pure

by 31P NMR) was isolated as a white solid.

1H NMR (500 MHz, Benzene-d6): 7.70 (d, J = 7.7, 1.9 Hz, 4H), 7.54 7.49 (m, 2H), 2.42 2.29 (m,

2H), 2.16 2.04 (m, 1H), 1.97 1.86 (m, 2H), 1.60 1.50 (m, 2H), 1.42 1.33 (m, 4H), 1.27 (s, 36H).


Hz), 122.35, 38.01 (d, J = 12.6 Hz), 36.24 (d, J = 14.3 Hz), 34.71, 34.37 (d, J = 8.4 Hz), 31.24, 24.96.

31P NMR (200 MHz, Benzene-d6): -16.39.

HRMS (ESI-TOF, for C34H54P+, [M+H]+): Observed: 493.39543 m/z, calculated: 493.39631 m/z.


1202, 1131, 896, 872, 710.

cyclohexylbis(4-methoxyphenyl)phosphine (L19). Prepared according to general procedure A. A

solution of tert-butyllithium (5.02 ml, 8.54 mmol) was added via syringe to an oven-dried Schlenk flask

equipped with a PTFE stirbar. The solution was then cooled to -78 C and an equal volume of diethyl

ether (5 ml) was added and the solution stirred for 5 minutes, followed by the dropwise addition of 1-

bromo-4-methoxybenzene (0.808 g, 4.32 mmol) in diethyl ether (5 ml). The solution was then allowed to

stir for 2 hours. dichloro(cyclohexyl)phosphine (0.390 g, 2.108 mmol) in diethyl ether (5 ml) was then

added dropwise and the cooling bath was removed. The reaction was allowed to warm to room

temperature with stirring overnight.

S-14


cooled to 0 C and nitrogen-sparged saturated ammonium chloride solution (15 ml) was added dropwise

to the reaction. The ice bath was removed and the mixture was extracted with diethyl ether under N2 (3 x

15 ml). The organic layers were transferred by syringe to a nitrogen-filled flask with MgSO4. The flask

was then brought into the glovebox for vacuum filtration and concentration under reduced pressure.

The crude product took the form of a white, amorphous solid, which was recrystallized by the addition of

degassed ethanol in the glovebox, heating under nitrogen, and then cooling in a -35 C freezer in the

glovebox. The product was collected by vacuum filtration under nitrogen, rinsed with degassed ethanol,

and dried under vacuum.

cyclohexylbis(4-methoxyphenyl)phosphine (0.520 g, 1.584 mmol, 75 % yield) was isolated as a white

solid.

1H NMR (500 MHz, Benzene-d6): 7.61 7.46 (m, 4H), 6.83 6.70 (m, 4H), 3.26 (s, 6H), 2.17 (tdd, J =

11.6, 6.6, 3.3 Hz, 1H), 1.90 1.78 (m, 2H), 1.74 1.64 (m, 2H), 1.63 1.54 (m, 1H), 1.44 1.29 (m,

2H), 1.29 1.13 (m, 3H).

13C NMR (125 MHz, Benzene-d6): 160.34, 135.08 (d, J = 20.9 Hz), 128.91 (d, J = 13.2 Hz), 114.06 (d,

J = 7.7 Hz), 54.30, 36.27 (d, J = 9.1 Hz), 29.75 (d, J = 16.3 Hz), 26.80 (d, J = 11.2 Hz), 26.47 (d, J = 1.3

Hz).

31P NMR (200 MHz, Benzene-d6): -8.14.

HRMS (ESI-TOF, for C34H54P+, [M+H]+): Observed: 329.16721 m/z, calculated: 329.16704 m/z.


1176, 1094, 1030, 824, 796.

tert-butylbis(3,5-di-tert-butylphenyl)phosphine (L20). Prepared according general procedure A. A

solution of tert-butyllithium (10.49 ml, 17.83 mmol) was added via syringe to an oven-dried Schlenk

flask equipped with a PTFE stirbar. The solution was then cooled to -78 C and an equal volume of

diethyl ether (10 ml) was added and the solution stirred for 5 minutes, followed by the dropwise addition

of 1-bromo-3,5-di-tert-butylbenzene (2.489 g, 9.25 mmol) in diethyl ether (5 ml). The solution was then

allowed to stir for 30 minutes. tert-butyldichlorophosphine (0.700 g, 4.40 mmol) in diethyl ether (5 ml)

was then added dropwise and the cooling bath was removed. The reaction was allowed to warm to room

temperature with stirring overnight. The reaction was monitored for completion by 31P NMR.


cooled to 0 C and nitrogen-sparged saturated ammonium chloride solution (15 ml) was added dropwise

to the reaction. The ice bath was removed and the mixture was extracted with diethyl ether under N2 (3 x

15 ml). The organic layers were transferred by syringe to a nitrogen-filled flask with MgSO4. The flask

was then brought into the glovebox for vacuum filtration and concentration under reduced pressure.

S-15

The crude product took the form of a white, amorphous solid, which was recrystallized by the addition of

degassed ethanol in the glovebox, heating under nitrogen, and then cooling in a -35 C freezer in the

glovebox. The product was collected by vacuum filtration under nitrogen, rinsed with degassed ethanol,

and dried under vacuum.

tert-butylbis(3,5-di-tert-butylphenyl)phosphine (0.830 g, 1.778 mmol, 40.4 % yield) isolated as a white

crystalline solid.

The spectra matched the literature information.10

dicyclohexyl(2,2'',4,4'',6,6''-hexaisopropyl-[1,1':3',1''-terphenyl]-5'-yl)phosphine (S-L1). Prepared

according to general procedure B. A solution of tert-butyllithium (3.14 mL, 5.34 mmol) was added via

syringe to an oven-dried Schlenk flask under nitrogen equipped with a PTFE stirbar. The solution was

then cooled to 78 C and an equal volume of diethyl ether (2 mL) was added and the solution stirred for

5 minutes, followed by the dropwise addition of 5'-bromo-2,2'',4,4'',6,6''-hexaisopropyl-1,1':3',1''-

terphenyl (1.50 g, 2.67 mmol) in diethyl ether (2 mL). The solution was then allowed to stir for 3 hours at

78 C. Chlorodicyclohexylphosphine (0.653 g, 2.80 mmol) in diethyl ether (1 mL) was then added

dropwise and the cooling bath was removed. The reaction was allowed to warm to room temperature with

stirring. After 1 hour, an aliquot was analyzed by 31P NMR for presence of the monochlorophosphine.


nitrogen-sparged saturated aqueous ammonium chloride solution (15 mL) was added dropwise to the

reaction. The ice bath was removed and the mixture was extracted with diethyl ether under N2 (3 x 15

mL). The organic layers were transferred by syringe to a nitrogen-filled flask with MgSO4. The flask was

then brought into the glovebox for vacuum filtration and concentration under reduced pressure.

The crude product was analyzed by 31P and 1H NMR to mostly desired product. The crude product was

the recrystallized from hot degassed ethanol (~4 mL solvent) and cooled in the glovebox freezer at 35 C

for 3 hours, followed by vacuum filtration in the glovebox and rinsed with cold (35 C) degassed ethanol

to give the purified product. The product was then dried under high vacuum in the glovebox.

Dicyclohexyl(2,2'',4,4'',6,6''-hexaisopropyl-[1,1':3',1''-terphenyl]-5'-yl)phosphine (1.21 g, 1.78 mmol, 66

% yield) was isolated as a white powder.

1H NMR (500 MHz, Benzene-d6): 7.49 (dd, J = 6.5, 1.6 Hz, 2H), 7.22 (s, 5H), 7.09 (q, J = 1.4 Hz, 1H),

3.01 (apparent hept, J = 7.1 Hz, 4H) [split by diastereotopic CH3 groups], 2.90 (apparent hept, J = 7.1 Hz,

2H) [split by diastereotopic CH3 groups], 1.90 (d, J = 8.7 Hz, 4H), 1.81 1.66 (m, 4H), 1.66 1.53 (m,

10 McAtee, J. R.; Yap, G. P. A.; Watson, D. A. J. Am. Chem. Soc. 2014, 136, 10166-10172.

S-16

4H), 1.31 (apparent d, J = 6.9 Hz, 12H) [diastereotopic CH3 groups], 1.26 1.19 (m, 24H)

[diastereotopic CH3 groups], 1.20 1.02 (m, 9H).

13C NMR (125 MHz, Benzene-d6): 148.56, 146.91, 140.65 (d, J = 7.0 Hz), 137.57, 135.10 (d, J = 21.5

Hz), 134.66 (d, J = 19.1 Hz), 132.09, 120.83, 34.96, 32.59 (d, J = 14.0 Hz), 31.05, 30.54 (d, J = 17.3 Hz),

29.20 (d, J = 6.8 Hz), 27.50 (d, J = 12.4 Hz), 27.18 (d, J = 6.7 Hz), 27.03, 24.68 24.44 (m), 24.40.



IR (cm-1): 2984, 2870, 2002, 1608, 1449, 1382, 1361, 1298, 1139, 1074, 939, 876, 856.

Ligand S-L1 gave results comparable to L17 in the standard acetal coupling to yield 1.

L16-AuCl Complex (S-1). Chloro(dimethyl sulfide)gold(I) (0.075 g, 0.255 mmol) and

cyclopentylbis(3,5-di-tert-butylphenyl)phosphine (0.122 g, 0.255 mmol) were weighed out in the

glovebox into a flame-dried Schlenk flask equipped with a PTFE stirbar. The flask was then sealed with a

septum and removed from the glovebox. Dichloromethane (1 ml) was added and the reaction was stirred

overnight at 23 C.

The product was then collected by evaporation of the solvent, and the crude product analyzed by 31P and 1H NMR. The 31P NMR of the product showed no free phosphine remaining. A crystal suitable for X-Ray

crystallography was grown from slow evaporation from dichloromethane.

31P NMR (121 MHz, Chloroform-d): 45.49. Contains a small amount of phosphine oxide due to

oxidation in non-degassed NMR solvent.

The CIF file and the corresponding checkCIF file are attached. No level A or B errors were detected.

The structure was deposited into the Cambridge Structural Database: CCDC 1520891

S-17

D) Reaction Optimization, Control Experiments, and NMR Timepoint Studies

Screening reactions were conducted on 0.03 mmol scale, in 1 mL of total solvent (0.03M). A stock

solution of benzaldehyde dimethyl acetal (1.0 equiv) and 2-fluorobiphenyl (0.4 equiv) was prepared in the

glovebox in the solvent of choice, as well as separate stock solutions of Ni(cod)2 or other Ni source (15

mol%) [prepare no earlier than 5 minutes before addition to ligand, will decompose in glovebox] and of

para-fluorophenyl boroxine (0.6 equiv), and the solutions were stirred vigorously in the glovebox. The

ligand (30 mol% for monodentate, 15 mol% for bidentate) was weighed out into individual reaction

vessels (2-dram vials, equipped with a PTFE stirbar, and threads coated with PTFE tape) dissolved in

solvent, and then the Ni stock solution was added. The ligand was stirred with the nickel source for 30

minutes, and then followed by the sequential addition of acetal and boroxine stock solutions. IMesCl

deprotonated in situ by prestirring with NaOtBu (1.25 equiv relative to the imidazolinium salt) to IMes.

The reaction vessels were then sealed with a PTFE septum cap, wrapped with electrical tape, and brought

outside of the glovebox. The reactions were allowed to stir at the designated temperature and time. At the

same time, 1H NMR of the stock solution was used to determine the relative ratio of the acetal and

fluorinated standard.

After the designated reaction times, the reactions were then cooled to room temperature. An aliquot was

passed through a plug of celite and then diluted with chloroform-d for 19F NMR analysis.

Solvent, ligand and reaction condition evaluation at 70 C.

entry solvent ligand yield (%)a

1 dioxane PPh3 trace

2 dioxane PCy3 14

3 DMF PCy3 0

4 hexanes PCy3 41

5 toluene PCy3 36

6 toluene PCy2Ph 35

7 toluene PCyPh2 18

8 toluene PiPrPh2 18

9 toluene DPEPhos 4

10 toluene PtBuPh2 3

11 dioxane PCy3b 0

12 toluene PCy3c 8

13 toluene 7.5% Ni(cod)2 and 15%

PCy3

28

14 toluene 15% PCy3 7

S-18

15 toluene no catalyst 0

aDetermined by 19F NMR with 2-flurobiphenyl as a quantitative internal standard. bUsing NiCl2glyme in place of Ni(cod)2. cReaction run at 40 C.

Additional optimization studies using commercial ligands (NHCs, bidentate phosphines) did not lead to

high yield.

Concentration evaluation at 60 C.

entry concentration yield (%)a

1 0.4 M 55

2 0.2 M 68

3 0.1 M 80

4 0.05 M 81

5 0.04 M 76

6 0.03 M 72

7 0.02 M 67

8 0.01 M 44

aDetermined by 19F NMR with 2-flurobiphenyl as a quantitative internal standard.

Diminished reaction efficiency is observed at higher concentrations. Below 0.1 M, the reaction yield is

relatively insensitive to concentration. However, some boroxines are insoluble at higher concentrations,

so 0.03 M was used as the standard concentration for most reactions.

Unsuccessful Substrates.

Some acetals and boroxines did not give the desired coupling product when subject to the optimized

conditions. A representative few are shown below. Efforts to develop successful coupling conditions for

these susbstrates (particularly the heterocyclic boroxines) are ongoing.

NMR timepoint studies.

S-19

NMR timepoints were set up on the 0.06 mmol scale, in 1 mL of toluene (0.06M). A stock solution of

benzaldehyde dimethyl acetal (1.0 equiv) and 2-fluorobiphenyl (0.4 equiv) was prepared in the glovebox

in the solvent of choice, as well as separate stock solutions of Ni(cod)2 (15 mol%) [prepare no earlier than

5 minutes before addition to ligand, will decompose even in glovebox] and of para-fluorophenyl boroxine

(0.6 equiv), and the solutions were stirred vigorously in the glovebox. The ligand was weighed out into

individual reaction vessels (2-dram vials, equipped with a PTFE stirbar, and threads coated with PTFE

tape) dissolved in solvent, and then the Ni stock solution was added. The ligand was stirred with the

nickel source for 30 minutes, and then followed by the sequential addition of acetal and boroxine stock

solutions. 0.4 mL of the reaction solution was then removed and dispensed into a J-Young NMR tube,

followed by the addition of 0.4 mL of benzene-d6 as a NMR solvent.

The reaction was then monitored by 19F NMR during the specified time. 1H NMR from the stock solution

was used to determine the initial ratio of the acetal and fluorinated standard.

S-20

E) Synthesis of Starting Materials

Benzaldehyde dimethyl acetals were prepared according to a literature procedure.11 Aldehyde (1.0 equiv)

was weighed out into a threaded tube equipped with a PTFE stirbar. Trimethylorthoformate (4.0 equiv)

was then added to the reaction mixture, followed by the addition of para-tolylsulfonic acid (0.08 equiv) as

the catalyst. The tube was then sealed with a PTFE septum cap and heated at 100 C for 16 h.

Upon completion of the reaction and cooling to room temperature, triethylamine (5 mL) was added to the

reaction mixture to completely quench to acid catalyst and the reaction was allowed to stir for 5 minutes.

The solution was then filtered through celite and concentrated under reduced pressure. The crude product

was then dissolved in a small amount of hexanes and filtered through a plug of basic alumina. The

resulting filtrate was concentrated to yield purified product, which was used in the coupling reactions.

1-(dimethoxymethyl)-2-methoxybenzene (acetal for 10)12, 1-(dimethoxymethyl)-4-methoxybenzene

(acetal for 11)12, 1-(dimethoxymethyl)-4-fluorobenzene (acetal for 12)12, 2-

(dimethoxymethyl)naphthalene (acetal for 13)12, and 5-(dimethoxymethyl)benzo[d][1,3]dioxole (acetal

for 14)13, all matched the literature spectra. 2-(diethoxymethyl)furan (acetal for 15) was used as received

from commercial sources, as well as acetals 20 and 22.

1-methoxyisochroman (16). To a solution of DDQ (2.152 g, 9.48 mmol) in CH2Cl2 (Volume: 50 mL)

under N2 atmosphere was added methanol (0.30 g, 9.9 mmol) and isochroman (0.99 mL, 7.9 mmol)

sequentially. The reaction was then allowed to stir for 18 h at room temperature. The reaction was

quenched by the addition of saturated sodium bicarbonate (60 mL) and then filtered through celite. The

celite was rinsed with CH2Cl2 and the layers separated. The aqueous layer was extracted with CH2Cl2 (2 x

30 mL). The combined aqueous layers were washed with saturated sodium bicarbonate, brine, and dried

over Na2SO4. The solvent was removed under reduced pressure.

The product was purified by flash chromatography (Biotage 100g cartridge, hexanes:EtOAc 10:1 Product

Rf ~ 0.65, SM Rf ~ 0.70).

1-methoxyisochroman (0.50 g, 3.1 mmol, 39 % yield) was isolated as a thick, viscous oil.

The spectral data matched the literature information.14

11 Zhang, M.; Wang, Y.; Yang, Y.; Hu, X. Adv. Synth. Catal. 2012, 354, 981-985. 12 Krebs, A.; Bolm, C. Synlett 2011, 2011, 671-673. 13 Napolitano, E.; Giannone, E.; Fiaschi, R.; Marsili, A. J. Org. Chem. 1983, 48, 3653-3657. 14 Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198-7199.

S-21

1-methoxy-1,3-dihydroisobenzofuran (18). To a solution of DDQ (2.83 g, 12.5 mmol) in CH2Cl2

(Volume: 50 mL) under N2 atmosphere was added methanol (0.400 g, 12.48 mmol) and Phthalan (1.14

mL, 10.4 mmol) sequentially. The reaction was then allowed to stir for 36 h at room temperature.

The reaction was quenched by the addition of saturated sodium bicarbonate (60 mL) and then filtered

through celite. The celite was rinsed with CH2Cl2 and the layers separated. The aqueous layer was

extracted with CH2Cl2 (2 x 30 mL). The combined aqueous layers were washed with saturated sodium

bicarbonate, brine, and dried over Na2SO4. The solvent was removed under reduced pressure.

1-methoxy-1,3-dihydroisobenzofuran (0.75 g, 5.0 mmol, 48 % yield) was isolated as a clear, colorless oil.


2-phenyl-1,3-dioxane (24). Indium triflate (0.074 g, 0.13 mmol) was added to a mixture of

(dimethoxymethyl)benzene (1.97 mL, 13.1 mmol) and trimethylene glycol (1.04 mL, 14.5 mmol) in a

threaded tube equipped with a PTFE stirbar. The tube was then capped and stirred at room temperature

for 30 minutes. The glycol was then removed under reduced pressure and the remaining residue was

passed through a plug of basic alumina. The plug was rinsed several times with pentane and the solvent

was removed under reduced pressure to provide the final product.

2-phenyl-1,3-dioxane (2.19 g, 13.3 mmol, quantitative yield) was isolated as a clear, colorless oil.


(diisopropoxymethyl)benzene (26). Powdered 5 molecular sieves in a 100 mL rbf were dried under

high vacuum. i-PrOH (Volume: 40 mL) was then added to the flask, followed by benzaldehyde (1.50 g,

14.1 mmol) and 4-methylbenzenesulfonic acid (0.12 g, 0.71 mmol). The reaction was then allowed to stir

overnight at rt. The solution was then treated with triethylamine (6 mL) and filtered through celite to yield

the desired product.

(Diisopropoxymethyl)benzene (2.7 g, 13 mmol, 92 % yield) was isolated as a clear, colorless, oil.


15 Smith, B. M.; Kubczyk, T. M.; Graham, A. E. Tetrahedron 2012, 68, 7775-7781.

S-22

(((phenylmethylene)bis(oxy))bis(methylene))dibenzene (28). Indium trifluoride (0.081 g, 0.471 mmol)

were added to a threaded tube equipped with a PTFE stirbar. Toluene (Volume: 20 mL) was then added to

dissolve the components, followed by benzaldehyde (0.958 mL, 9.42 mmol) and phenylmethanol (1.950

mL, 18.85 mmol). The reaction was then sealed by with a Teflon cap and heated at 70 C for 4 hours.

Upon completion of reaction, triethylamine (2 mL) was added and the reaction was filtered over a pad of

celite. The pad was then rinsed several times with ethyl acetate and the combined filtrate was

concentrated under reduced pressure. The crude product was then passed through a plug of basic alumina,

rinsing with hexanes.

The product after crude showed a significant amount of aldehyde and alcohol remaining by 1H NMR. The

alcohol and alcohol were removed under vacuum distillation over potassium carbonate (0.1 torr at 80 C),

and the remaining residue was taken up in hexanes and passed through an alumina plug. The solvent was

removed under reduced pressure and the product was determined to be pure by 1H NMR.

(((Phenylmethylene)bis(oxy))bis(methylene))dibenzene (0.35 g, 1.15 mmol, 12 % yield) was isolated as a

clear, colorless oil.


(bis(neopentyloxy)methyl)benzene (30). Benzaldehyde (1.92 mL, 18.9 mmol), neopentylalcohol (4.06

mL, 37.7 mmol), and toluenesulfonicacid monohydrae (0.036 g, 0.19 mmol) were added to a round

bottom flask equipped with a PTFE stirbar under nitrogen. Benzene (Volume: 50 mL) was added and a

Dean-Stark apparatus equipped with a condenser attached to the flask.

The reaction was then heated at reflux overnight. The residual acid was then quenched by the addition of

triethylamine (5 mL), and the mixture was then poured into a separatory funnel, rinshed with water, and

dried over potassium carbonate. The mixture was then filtered and concentrated under vacuum to give the

crude product. The 1H NMR of the crude product showed the desired product as well as some of the

unreacted alcohol and benzaldehyde.

The crude product was purified by fractional distillation under high vacuum. The impurities distilled at 55

C at 0.2 torr, and the product distilled at 89 C at 0.2 torr.

(Bis(neopentyloxy)methyl)benzene (0.610 g, 2.31 mmol, 12 % yield) was isolated as a clear, colorless oil.


16 Madabhushi, S.; Mallu, K. K. R.; Chinthala, N.; Beeram, C. R.; Vangipuram, V. S. Tet. Lett. 2012, 53, 697-701. 17 Kwart, H.; Silver, P. A. J. Org. Chem. 1975, 40, 3019-3026.

S-23

F) Suzuki Arylation of Benzylic Acetals and Characterization

General coupling procedure.

The acetal (0.3 mmol) was weighed out into a flame-dried vial equipped with a PTFE stirbar. The vial

was then evacuated, refilled (3x) and brought into the glovebox. In the glovebox, the reaction was then

dissolved with toluene (2 mL).

Ni(cod)2 (0.012 g, 0.045 mmol) and L17 (0.059 g, 0.090 mmol) were weighed out into a flame-dried

Schlenk flask equipped with a PTFE stirbar. The catalyst mixture was then dissolved under toluene (7

mL) and allowed to stir for 10 minutes. The acetal solution was then added and the vial was rinsed with

toluene (2 x 1 mL). The boroxine (0.180 mmol) is then added to the reaction vessel, it is sealed, and

brought outside of the glovebox. Note: Threaded tubes with a PTFE coated threading and PTFE septa can

be used as alternative reaction vessels. The exclusion of air from the reaction is critical, however. This

can be achieved by greasing ground glass joints and lining threading with PTFE tape.

The reaction was allowed to stir at 70 C for 16 h (typical). Some substrates may have slightly different

optimal temperatures, although in general good reactivity is obtained at 70 C.

The reaction was worked up by addition of saturated aqueous ammonium chloride solution. In certain

cases, 30% aqueous hydrogen peroxide with additional water was used instead to oxidize remaining

ligand. The mixture was then stirred vigorously for 10 minutes and the organic layer separated. The

aqueous layer is then extracted with diethyl ether (2 x 5 mL). The combined organic layers were then

dried over magnesium sulfate, filtered, and concentrated under reduced pressure.

The crude product can be purified by prep TLC or column chromatography. 90:10

Pentane:Dichloromethane or 1:1 Hexanes:Toluene generally are the most successful solvent systems for

purifying the diaryl ether products, which can be quite non-polar.

1-fluoro-4-(methoxy(phenyl)methyl)benzene (2). Prepared using the general coupling procedure.

(Dimethoxymethyl)benzene (0.046 g, 0.3 mmol) was weighed out into a flame-dried vial equipped with a

PTFE stirbar. The vial was then evacuated, refilled (3x), and brought into the glovebox. In the glovebox,

the reaction was then dissolved with toluene (2 mL).




toluene (2 x 1 mL). 2,4,6-tris(4-fluorophenyl)-1,3,5,2,4,6-trioxatriborinane (0.066 g, 0.180 mmol) was

then added to the reaction vessel, it was sealed, and brought outside of the glovebox.

S-24

The reaction was allowed to stir at 70 C for 16 h.

The reaction was worked up by addition of a solution of saturated aqueous ammonium chloride. The

mixture was then stirred vigorously for 10 minutes and the organic layer was separated. The aqueous

layer was then extracted with diethyl ether (2 x 5 mL). The combined organic layers was then dried over

magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by

prep TLC (90:10 Pentane:Dichloromethane).

1-fluoro-4-(methoxy(phenyl)methyl)benzene (0.053 g, 0.245 mmol, 82 % yield) was isolated as a clear,

colorless oil.

The spectral data was consistent with the previously reported information.18

1-(methoxy(phenyl)methyl)-4-(trifluoromethyl)benzene (3). Prepared using the general coupling

procedure. (Dimethoxymethyl)benzene (0.046 g, 0.30 mmol) was weighed out into a flame-dried vial

equipped with a PTFE stirbar. The vial was then evacuated, refilled (3x), and brought into the glovebox.

In the glovebox, the reaction was then dissolved with toluene (2 mL).




toluene (2 x 1 mL). 2,4,6-tris(4-(trifluoromethyl)phenyl)-1,3,5,2,4,6-trioxatriborinane (0.093 g, 0.180

mmol) was then added to the Schlenk flask and it was sealed and removed from the glovebox.


The reaction was worked up by filtration through a plug of silica gel and rinsing with dichloromethane.

The product was purified by flash chromatography (90:10 Pentane:DCM).

1-(methoxy(phenyl)methyl)-4-(trifluoromethyl)benzene (0.071 g, 0.267 mmol, 89 % yield) was isolated

as a clear, colorless oil.


1-methoxy-4-(methoxy(phenyl)methyl)benzene (4). Prepared using the general coupling procedure.


18 Arendt, K. M.; Doyle, A. G. Angew. Chem. Int. Ed. 2015, 54, 9876-9880.

S-25






toluene (2 x 1 mL).




layer was then extracted with diethyl ether (2 x 5 mL). The combined organic layers was then dried over

magnesium sulfate, filtered, and concentrated under reduced pressure. The product was purified by prep

TLC (1:1 Hexanes:Toluene).

1-methoxy-4-(methoxy(phenyl)methyl)benzene (0.018 g, 0.079 mmol, 26 % yield) was isolated as a



2-(methoxy(phenyl)methyl)naphthalene (5). Prepared using the general coupling procedure.







toluene (2 x 1 mL). 2,4,6-tri(naphthalen-2-yl)-1,3,5,2,4,6-trioxatriborinane (0.083 g, 0.180 mmol) was

then added to the Schlenk flask and it was sealed and removed from the glovebox.


The reaction was worked up by the addition of 30% hydrogen peroxide in water and diluted with

additional water. The mixture was then stirred vigorously for 10 minutes before the layers were allowed

to settle and the organic layer separated. The aqueous mixture was then extracted with diethyl ether (2 x 5

mL) and the combined organic layers were dried over magnesium sulfate. The drying agent was then

removed by filtration and the solution was concentrated under reduced pressure. The crude product was

then purified by prep TLC (5:1 Hexanes:Et2O).

2-(methoxy(phenyl)methyl)naphthalene (0.042 g, 0.169 mmol, 56 % yield) was isolated as a clear,

colorless oil.

19 Muramatsu, W.; Nakano, K. Org. Lett. 2014, 16, 2042-2045.

S-26

The spectral data matched the reported information.18

ethyl 3-(methoxy(phenyl)methyl)benzoate (6). Prepared using the general coupling procedure.







toluene (2 x 1 mL). Triethyl 3,3',3''-(1,3,5,2,4,6-trioxatriborinane-2,4,6-triyl)tribenzoate (0.095 g, 0.180









Ethyl 3-(methoxy(phenyl)methyl)benzoate (0.074 g, 0.274 mmol, 91 % yield) was isolated as a clear

colorless oil.

1H NMR (500 MHz, Chloroform-d): 8.07 8.04 (m, 1H), 7.93 (dq, J = 7.7, 1.2 Hz, 1H), 7.54 (dt, J =

7.7, 1.6 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.37 7.31 (m, 4H), 7.29 7.23 (m, 1H), 5.29 (s, 1H), 4.37 (q,

J = 7.1 Hz, 2H), 3.39 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H).

13C NMR (125 MHz, Chloroform-d): 166.75, 142.79, 141.75, 131.37, 130.85, 128.90, 128.74, 128.22,

127.91, 127.12, 85.21, 61.23, 57.29, 14.57.

HRMS (ESI-TOF, for C16H15O2+, [M-OMe]+): Observed: 239.10729 m/z, calculated: 239.10720 m/z.

IR (cm-1): 2985, 2871, 1715, 1606, 1587, 1493, 1450, 1392, 1366, 1277, 1180, 1140, 1082, 1023, 973,

919, 814, 742, 701.

1-(methoxy(phenyl)methyl)-3,5-dimethylbenzene (7). Prepared using the general coupling procedure.


S-27






toluene (2 x 1 mL). 2,4,6-tris(3,5-dimethylphenyl)-1,3,5,2,4,6-trioxatriborinane (0.071 g, 0.180 mmol)

was then added to the Schlenk flask and it was sealed and removed from the glovebox.








1-(methoxy(phenyl)methyl)-3,5-dimethylbenzene (0.037 g, 0.163 mmol, 55 % yield) isolated as a clear

oil.

1H NMR (500 MHz, Chloroform-d): 7.38 7.28 (m, 4H), 7.28 7.20 (m, 1H), 6.96 (s, 2H), 6.88 (s,

1H), 5.17 (s, 1H), 3.38 (s, 3H), 2.29 (s, 6H).


85.75, 57.25, 21.57.

HRMS (ESI-TOF, C16H17O+, [M-H]+): Observed: 225.12821 m/z, calculated: 225.12794 m/z.

IR (cm-1): 2927, 2820, 1604, 1493, 1451, 1421, 1324, 1264, 1185, 1094, 1073, 1029, 972, 910, 844, 698

2-(methoxy(phenyl)methyl)-1,3,5-trimethylbenzene (8). Prepared using the general coupling

procedure. (Dimethoxymethyl)benzene (0.046 g, 0.3 mmol) was weighed out into a flame-dried vial

equipped with a PTFE stirbar. The vial was then evacuated, refilled (3x), and brought into the glovebox.

In the glovebox, the reaction was then dissolved with toluene (2 mL).




toluene (2 x 1 mL). 2,4,6-trimesityl-1,3,5,2,4,6-trioxatriborinane (0.079 g, 0.180 mmol) was then added to

the Schlenk flask and it was sealed and removed from the glovebox.


S-28






then purified by prep TLC (30:1 Hexanes:EtOAc)

2-(methoxy(phenyl)methyl)-1,3,5-trimethylbenzene (0.041 g, 0.171 mmol, 57 % yield) was isolated as a


1H NMR (500 MHz, Chloroform-d): 7.32 7.17 (m, 5H), 6.86 (s, 2H), 5.82 (s, 1H), 3.36 (d, J = 1.4

Hz, 3H), 2.30 (s, 3H), 2.22 (s, 6H).


79.98, 56.41, 20.93, 20.57.

HRMS (ESI-TOF, for C16H17+, [M-OMe]+): Observed: 209.13279 m/z, calculated: 209.13248 m/z.

IR (cm-1): 2924, 2816, 1610, 1493, 1449, 1378, 1324, 1164, 1125, 1092, 1066, 1029, 1017, 970, 935,

849, 803, 725, 697.

4-(methoxy(phenyl)methyl)dibenzo[b,d]furan (9). Prepared using the general coupling procedure.

(Dimethoxymethyl)benzene (0.046 g, 0.30 mmol) was weighed out into a flame-dried vial equipped with

a PTFE stirbar. The vial was then evacuated, refilled (3x), and brought into the glovebox. In the glovebox,





toluene (2 x 1 mL). 2-(dibenzo[b,d]furan-3-yl)-4,6-bis(dibenzo[b,d]furan-4-yl)-1,3,5,2,4,6-

trioxatriborinane (0.105 g, 0.180 mmol) was then added to the Schlenk flask and it was sealed and

removed from the glovebox.

The reaction was then allowed to stir at 60 C for 16 h. This particular boroxine was initially insoluble,

but gradually dissolved during the course of the reaction.

The product was then purifed by prep TLC, (1:1 Hexanes:Toluene, Rf ~0.4).

4-(methoxy(phenyl)methyl)dibenzo[b,d]furan (0.067 g, 0.232 mmol, 77 % yield) was isolated as a clear,

colorless oil.

1H NMR (500 MHz, Chloroform-d): 7.86 (dd, J = 7.7, 1.4 Hz, 1H), 7.78 (dd, J = 7.6, 1.3 Hz, 1H),

7.53 (d, J = 8.3 Hz, 1H), 7.48 (t, J = 8.2 Hz, 3H), 7.38 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.31 7.22 (m,

3H), 7.21 7.14 (m, 2H), 5.93 (s, 1H), 3.42 (s, 3H).

S-29


124.59, 124.32, 124.28, 123.10, 122.78, 120.72, 119.76, 111.84, 79.71, 57.37.

HRMS (ESI-TOF, C19H13O+, [M-OMe]+): Observed: 257.09727 m/z, calculated: 257.09664 m/z.

IR (cm-1): 3060, 3030, 2929, 2820, 1602, 1587, 1493, 1450, 1421, 1324, 1266, 1184, 1115, 1069, 1029,

843, 752, 697.

1-methoxy-2-(methoxy(4-(trifluoromethyl)phenyl)methyl)benzene (10). Prepared using the general

coupling procedure. 1-(dimethoxymethyl)-2-methoxybenzene (0.055 g, 0.3 mmol) was weighed out into a

flame-dried vial equipped with a PTFE stirbar. The vial was then evacuated, refilled (3x), and brought

into the glovebox. In the glovebox, the reaction was then dissolved with toluene (2 mL).













1-methoxy-2-(methoxy(4-(trifluoromethyl)phenyl)methyl)benzene (0.052 g, 0.176 mmol, 59 % yield)

was isolated as a clear, colorless oil.

1H NMR (500 MHz, Chloroform-d): 7.53 (q, J = 8.4 Hz, 4H), 7.43 (dd, J = 7.6, 1.7 Hz, 1H), 7.29

7.19 (m, 1H), 6.98 (td, J = 7.5, 1.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 5.73 (s, 1H), 3.82 (s, 3H), 3.39 (s,

3H).

13C NMR (125 MHz, Chloroform-d): 156.69, 146.47, 129.90, 129.42 (q, J = 32.2 Hz), 128.94, 127.31,

126.84, 125.30 (q, J = 3.8 Hz), 124.44 (q, J = 272.0 Hz), 121.12, 110.75, 78.36, 57.37, 55.60.

19F NMR (282 MHz, Chloroform-d): 62.43.

HRMS (ESI-TOF, for C15H13F3O+, [M-OMe]+): Observed: 265.08357 m/z, calculated: 265.08402 m/z

IR (cm-1): 2938, 2826, 1618, 1600, 1491, 1465, 1450, 1416, 1323, 1286, 1243, 1162, 1117, 1090, 1066,

1049, 1028, 815, 754.

S-30

1-methoxy-4-(methoxy(4-(trifluoromethyl)phenyl)methyl)benzene (11). Prepared using the general

coupling procedure. 1-(dimethoxymethyl)-4-methoxybenzene (0.055 g, 0.3 mmol) was weighed out into a

flame-dried vial equipped with a PTFE stirbar. The vial was then evacuated, refilled (3x), and brought

into the glovebox. In the glovebox, the reaction was then dissolved with toluene (2 mL).





mmol) was then added. The Schlenk flask was sealed and removed from the glovebox.




layer was then extracted with diethyl ether (2 x 5 mL). The combined organic layers were then dried over

magnesium sulfate, filtered, and concentrated under reduced pressure. The product was purified by

prep TLC (1:1 Hexanes:Toluene).

1-methoxy-4-(methoxy(4-(trifluoromethyl)phenyl)methyl)benzene (0.054 g, 0.182 mmol, 61 % yield)

was isolated as a clear, colorless oil.

1H NMR (500 MHz, Chloroform-d): 7.57 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.25 7.19

(m, 2H), 6.90 6.83 (m, 2H), 5.24 (s, 1H), 3.79 (s, 3H), 3.37 (s, 3H).

13C NMR (125 MHz, Chloroform-d6): 159.48, 146.70, 133.51, 129.65 (q, J = 32.3 Hz), 128.55,

127.09, 125.52 (q, J = 3.8 Hz), 124.37 (q, J = 272.0 Hz), 114.18, 84.53, 57.15, 55.48.

19F NMR (282 MHz, Chloroform-d): 62.47.

HRMS (ESI-TOF, for C15H12F3O+, [M-OMe]+): Observed: 265.08364 m/z, calculated: 265.08402 m/z.

IR (cm-1): 2986, 2871, 1612, 1511, 1325, 1248, 1133, 1093, 1066, 1035.

1-fluoro-4-(methoxy(4-(trifluoromethyl)phenyl)methyl)benzene (12). Product was prepared via the

general coupling procedure. 1-(dimethoxymethyl)-4-fluorobenzene (0.051 g, 0.3 mmol) was weighed out

into a flame-dried vial equipped with a PTFE stirbar. The vial was then evacuated, refilled (3x), and

brought into the glovebox. In the glovebox, the reaction was then dissolved with toluene (2 mL).

S-31












then purified by prep TLC (10% DCM in Pentanes, Rf ~ 0.6).

1-fluoro-4-(methoxy(4-(trifluoromethyl)phenyl)methyl)benzene (0.062 g, 0.220 mmol, 73 % yield) was

isolated as a clear, colorless oil.

1H NMR (500 MHz, Chloroform-d): 7.59 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 7.7 Hz, 2H), 7.33 7.25

(m, 2H), 7.07 6.97 (m, 2H), 5.26 (s, 1H), 3.37 (s, 3H).

13C NMR (126 MHz, Chloroform-d): 162.54 (d, J = 246.4 Hz), 146.12, 137.24 (d, J = 3.2 Hz), 129.95

(q, J = 32.3 Hz), 128.87 (d, J = 8.2 Hz), 127.17, 125.65 (q, J = 3.8 Hz), 124.29 (q, J = 272.0 Hz), 115.72

(d, J = 21.5 Hz), 84.27, 57.28.

19F NMR (282 MHz, Chloroform-d): 62.53, 114.39 (tt, J = 8.6, 5.2 Hz).

HRMS (ESI-TOF, for C14H9F3+, [M-OMe]+): Observed: 253.06391 m/z, calculated: 253.06404 m/z.

IR (cm-1): 2988, 2939, 2872, 1717, 1604, 1508, 1415, 1323, 1281, 1224, 1123, 1089, 1065, 1017, 824,

749, 703

2-(methoxy(4-(trifluoromethyl)phenyl)methyl)naphthalene (13). Product was prepared via the general

coupling procedure. 2-(dimethoxymethyl)naphthalene (0.061 g, 0.3 mmol) was weighed out into a flame-

dried vial equipped with a PTFE stirbar. The vial was then evacuated, refilled (3x), and brought into the

glovebox. In the glovebox, the reaction was then dissolved with toluene (2 mL).





mmol) was then added. The Schlenk flask was sealed and removed from the glovebox.




S-32




then purified by prep TLC (10:1 Pentane:DCM, Rf ~ 0.55).

2-(methoxy(4-(trifluoromethyl)phenyl)methyl)naphthalene (0.082 g, 0.259 mmol, 86 % yield) was

isolated as a clear, colorless oil.

1H NMR (500 MHz, Chloroform-d): 7.88 7.78 (m, 5H), 7.59 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2

Hz, 2H), 7.51 7.47 (m, 1H), 7.39 (dd, J = 8.5, 1.7 Hz, 1H), 5.45 (s, 1H), 3.44 (s, 3H).

13C NMR (125 MHz, Chloroform-d): 1

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