SU PPLEMENTARY INFORMATION - Nature · I. General Information & Reaction Setup ... discolored TfCl was purified by passing through a small pad of basic alumina. ... (λ = 214–258

Table of Contents

I. General Information & Reaction Setup II. Direct Trifluoromethylation of Aromatics & Heteroaromatics III. Direct Trifluoromethylation of Biologically Active Molecules IV. Emission Quenching Experiments V. Cyclic Voltammetry Measurements VI. NMR Spectra

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SUPPLEMENTARY INFORMATIONdoi:10.1038/nature10647

Supplementary Information

I. General Information.

Commercial reagents were purified prior to use following the guidelines of Perrin and

Armarego.1 As a precaution due to its moisture sensitivity, triflyl chloride (TfCl) is transferred to

a Schlenk tube upon purchase and stored in a refrigerator. However, the reaction appears to

tolerate several equivalents of water or alcohol with only moderate decrease in efficiency.

Occasionally, discolored TfCl was purified by passing through a small pad of basic alumina. All

solvents were purified by column according to the method of Grubbs.2 Organic solutions were

concentrated under reduced pressure on a Büchi rotary evaporator. Chromatographic purification

of products was accomplished using force-flow chromatography on Aldrich silica gel according

to the method of Still.3 Thin-layer chromatography (TLC) was performed on Aldrich 250 µm

silica gel plates. TLC visualization was performed by fluorescence quenching, KMnO4 or iodine

stain. All yields reported are averages of at least two experimental runs. 1H and 19F NMR spectra were recorded on a Varian Inova 400 (400 MHz and 376 MHz,

respectively) or Bruker 500 (500 MHz) and are referenced relative to residual CDCl3 proton

signals at δ 7.27 ppm and CFCl3 (δ 0.0 ppm) respectively. Data for 1H and 19F NMR are reported

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

= multiplet, b = broad, ap = apparent), integration, coupling constant (Hz) and assignment. 13C

spectra were recorded on a Bruker 500 (126 MHz) and are referenced relative to CDCl3 at δ

77.23 ppm. Data for 13C NMR are reported in terms of chemical shift and multiplicity where

appropriate. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are

reported in terms of frequency of absorption (cm-1). High Resolution Mass spectra were

obtained from the Princeton University Mass Spectral Facility. Supercritical fluid

chromatography (SFC) was performed at a preparatory-scale on a Berger equipped with a diode

array UV detector (λ = 214–258 nm) by Lotus Separations, LLC at Princeton University.

(1) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals; 3rd ed., Pergamon Press, Oxford, 1988. (2) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics, 1996, 15, 1518. (3) Still, W. C.; Kahn, M.; Mitra, A. J. J. Org. Chem. 1978, 43, 2923.


SUPPLEMENTARY INFORMATIONRESEARCHdoi:10.1038/nature10647

Reaction Set-up

In a typical experiment, a variety of fluorescent light fixtures may be used, including

aquarium lights, flashlights, work lamps, and compact fluorescent light bulbs of varying power

output. Ultimately, a 26 W compact fluorescent light bulb (daylight GE Energy Smart™1600

lumens) was chosen because of the combination of its intense luminosity and compact size.

Placing the light source approximately 2 cm from the reaction ensured efficient photo-excitation.

Parallel reactions (up to 16 at a time) for substrate evaluation and optimization are easily set-up

by cutting a test tube rack in half and removing the center.

26 W Fluorescent

Light Bulbs Reaction Set-Up:

Vials Arranged in Half a Test Tube Rack



II. Direct Trifluoromethylation of Aromatics & Heteroaromatics

General Procedure A − Trifluoromethylation of electron rich heteroarenes

five-atom

heteroarenesCF3 heteroarenes

Y

XCF3

Y

X

Ru(phen)3Cl2 1 (1%)

CF3SO2Cl (2 eq)

K2HPO4, MeCN, 23 °C

26 W light

An oven-dried 17 × 60 mm (8 mL) borosilicate vial4 was equipped with a magnetic stir

bar, Ru(phen)3Cl25 (3.6 mg, 0.01 equiv), and K2HPO4 (261 mg, 3 equiv).6,7 The vial was fitted

with a silicone septa screw cap and degassed by quickly alternating vacuum evacuation and

argon backfill (×3) before MeCN (4 mL, 0.125 M) and the heteroarene (0.5 mmol, 1 equiv) were

added by syringe. The resulting solution was degassed by alternating vacuum evacuation at -78

°C then allowing solution to warm to room temperature under argon (×3). The triflyl chloride

(106.5 µL, 2 equiv) was added by syringe and the vial was sealed with parafilm and placed

approximately 2 cm from a 26 W compact fluorescent light bulb.8 Slower stirring (< 4000 rpm)

is preferred to allow more light penetration into the heterogeneous solution. After 24 hours,9 the

reaction was either (i) quenched with water (2 mL) and extracted with Et2O (×2) and CH2Cl2

(×1), and the combined organic layers were dried over MgSO4 or (ii) concentrated directly onto

celite in vacuo. The crude material was then purified by column chromatography on silica gel

using the noted solvent mixture to furnish the desired trifluoromethyl product.

4 Kimble Article No. 60942A-8, Sample Vials (or Fisher Scientific Catalog # 03-340-47A) 5 Ru(phen)3Cl2xH2O was purchased from Aldrich (CAS: 207802-45-7; Product ID: 343714) 6 The hygroscopic K2HPO4 is regularly oven-dried and stored in a desiccator before use. 7 The arene may also be added here as a solid; or as a liquid, it may be added after the solvent, as indicated. 8 26-W GE DayLight Energy Smart™(1600 lumens) Spiral CFL Bulb, 2-Pack (Product ID: GE 85397) 9 The reaction may be easily monitored by 19F NMR using C6F6 as an internal standard.



General Procedure B − Trifluoromethylation of electron deficient heteroarenes

6-atomheterocycles

CF3 heteroarenes

BA

C

B

C

A CF3

Ir(dF•ppy)3 (2%)

CF3SO2Cl (4 eq)

K2HPO4, MeCN, rt

26 W light

This procedure is identical to General Procedure A except for the use of twice the loading

of triflyl chloride (213 µL, 4 equiv) and an iridium photocatalyst with a longer lived excited

state, Ir(Fppy)310

(7.6 mg, 0.02 equiv).

General Procedure C − Trifluoromethylation of arenes

K2HPO4, MeCN, rt

26 W light

Ir(dF•ppy)3 (1%)

CF3SO2Cl (2 eq) CF3H

CF3 arenesC-H arenes

R R

This procedure is identical to General Procedure A except for the use of an iridium

photocatalyst with a longer lived excited state, Ir(Fppy)3 (3.8 mg, 0.01 equiv).

Characterization of volatile compounds – Preparatory TLC

For volatile compounds (those that are evaporated on the rotary evaporator), reactions

were performed in CD3CN and characterized or the crude mixture was subjected directly to

preparatory thin layer chromatography (prep TLC) using the noted solvent mixture to furnish the

desired trifluoromethyl product which was then extracted from silica with CD3CN.

10 Ir(Fppy) 3 was purchased from Aldrich (CAS: 264906-16-3; Product ID: 682594). It may also be prepared by the following method: Tamayo, A. B., Alleyne, B. D., Djurovich, P. I., Lamansky, S., Tsyba, I., Ho, N. N., Bau, R., and Thompson, M. E. J. Am. Chem. Soc., 2003, 125, 7377–7387



Functional Group Compatibility – Special Precautions

• Alkyl amines must be protected in situ with the addition of 1.2 equiv of HCl (any source

of HCl may be used to protect the nitrogen lone pair from photocatalytic oxidation)

Me MeHN

ON

Me

Me

4

CF3-lidocaine78% (2:1)CF3

Ir(Fppy)3 2 (1%)CF3SO2Cl (2 eq)

K2HPO4, MeCN, 23 °C26 W light

oxidative decomposition

CF3SO2Cl (2 eq)

The addition of 1.2 equiv of HCl provides in situ protection of the amine

Standard photoredox conditions are not amenable to alkyl amines

Ir(Fppy)3 2 (1%)


Me MeHN

ON

Me

Me

Me MeHN

ON

Me

Me

1.2 equiv HCl

• Pyridines are sometimes problematic due to competitive protonation, which inhibits

quantitative conversion, especially as the reaction progresses. We devised two solutions

to address this challenge through the use of either pyridines or triflyl chloride in excess.

pyridines



N

CF3

Me Me

48%

NMe Me

unreacted SM

N

CF3

Me Me

pyridines


Employing excess triflyl chloride (or inverse stoichiometry) is necessary for pyridines

N

CF3

Me Me

73%

N

CF3

Me Me

•HCl

Standard conditions for 6-membered heteroaromatics hindered by pyridine basicity




Substrate Scope – Characterization

NMe

CF3

1-methyl-2-(trifluoromethyl)pyrrole (Table 1a, entry 1). Prepared following general

procedure A using N-Me-pyrrole (44.4 μL, 0.5 mmol). After 24 hours, the reaction mixture (94%

yield by 19F NMR) was purified by prep TLC using 15% Et2O in petroleum ether to provide the

title compound. IR (thin film) 3101, 2981, 2874, 1461, 1355, 1295, 1239, 1212 cm-1; 1H NMR

(500 MHz, CD3CN) δ 6.89 (s, 1H), 6.61 (dd, J = 1.9, 0.9 Hz, 1H), 6.13 (t, J = 3.1 Hz, 1H), 3.75

(s, 3H); 13C NMR (126 MHz, CD3CN) δ 136.9 (q, J2 = 27.7 Hz), 127.3, 121.5 (q, J1 = 265.3 Hz),

111.2 (q, J3 = 3.5 Hz), 106.7, 34.0; 19F NMR (376 MHz, CDCl3) δ -59.7 (s); HRMS (ESI-TOF)

calculated for C6H6F3NO [M+OH]+ m/z 165.0402, found 165.0409.

NBoc

CF3

tert-butyl 2-(trifluoromethyl)pyrrole-1-carboxylate (Table 1a, entry 2). Prepared following

general procedure A using N-Boc-pyrrole (83.6 μL , 0.5 mmol). After 12 hours, the reaction

mixture (78% yield by 19F NMR) was purified by prep TLC using 10% Et2O in petroleum ether

to provide the title compound. IR (thin film) 3312, 2964, 2879, 1516, 1474, 1386, 1285, 1174

cm-1; 1H NMR (500 MHz, CD3CN) δ 7.52 (dd, J = 3.0, 1.9 Hz, 1H), 6.86 (dd, J = 1.5, 0.8 Hz,

1H), 6.30 (t, J = 3.3 Hz, 1H), 1.62 (s, 9H); 13C NMR (126 MHz, CD3CN) δ 146.8, 126.1 (q, J4 =

1.9 Hz), 120.7 (q, J2 = 30.1 Hz), 120.4 (q, J1 = 265.3 Hz), 117.6 (q, J3 = 4.6 Hz), 109.4, 85.3,

26.5; 19F NMR (376 MHz, CDCl3) δ -59.2 (s); HRMS (ESI-TOF) calculated for C10H12F3NO2

[M]+ m/z 235.0820, found 235.0811.



NH

CF3

2-(trifluoromethyl)pyrrole (Table 1a, entry 3). Prepared following general procedure A using

pyrrole (34.7 μL, 0.5 mmol). After 8 hours, the reaction mixture (88% yield by 19F NMR) was

purified by prep TLC using 10% Et2O in petroleum ether to provide the title compound. IR (thin

film) 3417, 2937, 2851, 1342, 1295, 1129 cm-1; 1H NMR (500 MHz, CD3CN) δ 10.96 (bs, 1H),

6.96 (s, 1H), 6.58 (s, 1H), 6.19 (s, 1H); 13C NMR (126 MHz, CD3CN) δ 136.8 (q, J2 = 27.1 Hz),

121.4 (q, J1 = 264.8 Hz), 109.2 (q, J3 = 3.0 Hz), 108.0, 106.9; 19F NMR (376 MHz, CDCl3) δ -

59.8 (s); HRMS (ESI-TOF) calculated for C5H4F3N [M]+ m/z 135.0296, found 135.0288.

NH

CF3F3C

2,5-bis(trifluoromethyl)pyrrole (Table 1a, entry 4). Prepared following general procedure A

using pyrrole (34.7 μL , 0.5 mmol) and triflyl chloride (3 equiv). After 24 hours, the reaction

mixture (91% yield by 19F NMR) was purified by prep TLC using 10% Et2O in petroleum ether

to provide the title compound. IR (thin film) 3404, 2974, 2844, 1358, 1246, 1183 cm-1; 1H NMR

(500 MHz, CD3CN) δ 10.93 (bs, 1H), 6.71 (d, J = 2.6 Hz, 2H); 13C NMR (126 MHz, CD3CN) δ

126.59 (d, J1 = 274.7 Hz), 122.63 (d, J2 = 24.4 Hz), 117.0; 19F NMR (376 MHz, CDCl3) δ -61.2

(s); HRMS (ESI-TOF) calculated for C6H3F6N [M]+ m/z 203.0170, found 203.0183.



OCF3Me

2-methyl-5-(trifluoromethyl)furan (Table 1a, entry 5). Prepared following general procedure

A using 2-methyl furan (45.1 μL, 0.5 mmol). After 24 hours, the reaction mixture (87% yield by 19F NMR) was purified by prep TLC using 10% Et2O in petroleum ether to provide the title

compound. IR (thin film) 2974, 2866, 1352, 1221, 1202 cm-1; 1H NMR (500 MHz, CD3CN) δ

6.88 (d, J = 1.9 Hz, 1H), 6.22 (dd, J = 2.4, 0.8 Hz, 1H), 2.37 (s, 3H); 13C NMR (126 MHz,

CD3CN) δ 155.9, 138.8 (q, J2 = 24.5 Hz), 119.2 (q, J1 = 265.1 Hz), 113.1 (q, J3 = 2.9 Hz), 106.7,

12.2; 19F NMR (376 MHz, CDCl3) δ -64.9 (s); HRMS (ESI-TOF) calculated for C6H5F3O [M]+

m/z 150.0293, found 150.0296.

SCF3Me

2-methyl-5-(trifluoromethyl)thiophene (Table 1a, entry 6). Prepared following general

procedure A using 2-methyl thiophene (48.4 μL, 0.5 mmol). After 48 hours, the reaction mixture

(82% yield by 19F NMR) was purified by prep TLC using 10% Et2O in petroleum ether to

provide the title compound. IR (thin film) 2976, 2869, 1330, 1211, 1246 cm-1; 1H NMR (500

MHz, CD3CN) δ 7.39 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 2.4, 1.2 Hz, 1H), 2.56 (s, 3H); 13C NMR

(126 MHz, CD3CN) δ 145.0, 129.2 (q, J3 = 3.9 Hz), 127.1 (q, J2 = 38.0 Hz), 125.4, 122.5 (q, J1 =

266.9 Hz), 13.9; 19F NMR (376 MHz, CDCl3) δ -56.1 (s); HRMS (ESI-TOF) calculated for

C6H5F3S [M]+ m/z 166.0064, found 166.0068.



OCF3Me

Me

2,3-dimethyl-5-(trifluoromethyl)furan (Table 1a, entry 7). Prepared following general

procedure A using 2,3-dimethyl furan (52.4 μL, 0.5 mmol). After 24 hours, the reaction mixture

(80% yield by 19F NMR) was purified by prep TLC using 10% Et2O in petroleum ether to


MHz, CD3CN) δ 6.78 (s, 1H), 2.28 (s, 3H), 2.00 (s, 3H); 13C NMR (126 MHz, CD3CN) δ 147.6,

138.8 (q, J2 = 21.8 Hz), 119.3 (q, J1 = 264.9 Hz), 115.4, 115.0 (q, J3 = 2.7 Hz), 10.1, 8.3; 19F

NMR (376 MHz, CDCl3) δ -64.9 (s); HRMS (ESI-TOF) calculated for C7H7F3O [M]+ m/z

164.0449, found 164.0458.

SCF3

Me

5

3-methyl-2-(trifluoromethyl)thiophene (Table 1a, entry 8). Prepared following general

procedure A using 3-methyl thiophene (48.3 μL, 0.5 mmol). After 24 hours, the reaction mixture

(76% yield, 2:1 r.r. by 19F NMR) was purified by prep TLC using 10% Et2O in petroleum ether

to provide the title compound. IR (thin film) 2981, 2872, 1352, 1217, 1254 cm-1; 1H NMR (500

MHz, CD3CN) δ 7.57 (d, J = 5.0 Hz, 1H), 7.04 (d, J = 4.0 Hz, 1H), 2.41 (d, J = 1.4 Hz, 3H); 13C

NMR (126 MHz, CD3CN) δ 140.5 (q, J3 = 3.1 Hz), 136.8 (q, J2 = 30.2 Hz), 131.3, 127.5 (q, J4 =

1.2 Hz), 123.2 (q, J1 = 268.0 Hz), 12.9; 19F NMR (376 MHz, CDCl3) δ -55.3 (s); HRMS (ESI-

TOF) calculated for C6H5F3S [M]+ m/z 166.0064, found 166.0076.



N

SCF3

Me

4-methyl-5-(trifluoromethyl)thiazole (Table 1a, entry 9). Prepared following general

procedure A using 4-methyl thiazole (45.5 μL, 0.5 mmol), 4% photocatalyst, and triflyl chloride

(8 equiv). After 72 hours, the reaction mixture (70% yield by 19F NMR) was purified by prep

TLC using 10% Et2O in petroleum ether to provide the title compound. IR (thin film) 2964,

2873, 1356, 1204, 1193 cm-1; 1H NMR (500 MHz, CD3CN) δ 8.18 (s, 1H), 1.76 (s, 3H); 13C

NMR (126 MHz, CD3CN) δ 161.5, 147.5 (q, J3 = 3.2 Hz), 136.9 (q, J2 = 27.6 Hz), 118.5 (q, J1 =

270.1 Hz), 14.6; 19F NMR (376 MHz, CDCl3) δ -54.1 (s); HRMS (ESI-TOF) calculated for

C5H4F3NS [M]+ m/z 167.0017, found 167.0025.

O

CF3

Me

3-methyl-2-(trifluoromethyl)benzofuran (Table 1a, entry 10). Prepared following general

procedure A using benzofuran (66 mg, 0.5 mmol). After 48 hours, the reaction mixture was

purified by flash chromatography using 1% Et2O in petroleum ether to provide the title

compound (84 mg, 84% yield) as a white solid. IR (thin film) 2920, 2850, 1379, 1325, 1171 cm-

1; 1H NMR (500 MHz, CDCl3) δ 7.61 (d, 1H, J = 7.8 Hz), 7.52 (d, 1H, J = 8.3 Hz), 7.44 (t, 1H, J

= 7.7 Hz), 7.33 (t, 1H, J = 7.5 Hz), 2.45 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 154.0, 138.5 (q,

J2 = 39.6 Hz), 128.4, 127.0, 123.4, 120.5 (q, J1 = 268.5 Hz), 120.7, 118.3 (q, J3 = 2.8 Hz), 111.9,


m/z 200.0449, found 200.0444.



NH

CF3

3

2-(trifluoromethyl)indole (Table 1a, entry 11). Prepared following general procedure A using

indole (58.6 mg, 0.5 mmol). After 24 hours, the reaction mixture was purified by flash

chromatography using 20% Et2O in petroleum ether to provide the title compound (67 mg, 72%

yield, 4:1 r.r.) as a white solid. IR (thin film) 3309, 2922, 2860, 1359, 1286, 1104 cm-1; 1H NMR

(500 MHz, CDCl3) δ 8.37 (bs, 1H), 7.71 (d, 1H, J = 7.9 Hz), 7.44 (d, 1H, J = 8.0 Hz), 7.35 (t,

1H, J = 7.6 Hz), 7.22 (t, 1H, J = 7.5 Hz), 6.95 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 132.2,

122.7 (q, J2 = 10.0 Hz), 120.9, 118.2, 117.3, 116.2 (q, J4 = 9.4 Hz), 107.8, 107.7 (q, J1 = 262.2

Hz), 100.4 (q, J3 = 5.0 Hz); 19F NMR (376 MHz, CDCl3) δ -60.9 (s); HRMS (ESI-TOF)

calculated for C9H6F3N [M]+ m/z 185.0452, found 185.0457.

NAc

CF3

2

3-(trifluoromethyl)-N-acylindole (Table 1a, entry 12). Prepared following general procedure

A using N-acyl indole (80 mg, 0.5 mmol). After 24 hours, the reaction mixture was purified by

flash chromatography using 10% Et2O in petroleum ether to provide the title compound (92 mg,

81% yield, 3:1 r.r.) as a clear oil. IR (thin film) 3388, 2995, 2873, 1369, 1299, 1155 cm-1; 1H

NMR (500 MHz, CDCl3) (1:1 rotamers) δ 8.31 (s, 1H), 7.90 (s, 1H), 7.22 (ap t, J = 8.4 Hz, 2H),

7.15 (d, J = 25.7 Hz, 2H), 7.13 (d, J = 10.7 Hz, 2H), 7.09 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.6 Hz,

1H), 1.88 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 135.68 (d, J = 312.8 Hz), 127.18 (d, J = 123.5

Hz), 126.22 (s), 123.50 (d, J = 128.6 Hz), 122.42 (q, J1 = 269.1 Hz), 121.06 (d, J = 153.4 Hz),

119.52 (d, J = 60.0 Hz), 118.94 (s), 111.13 (d, J = 39.9 Hz), 30.46 (dd, J = 5.8, 2.9 Hz); 19F

NMR (376 MHz, CDCl3) δ -60.2 (s); HRMS (ESI-TOF) calculated for C11H8F3NO [M]+ m/z

227.0558, found 227.0561.



N

N CF3

OMe

2-methoxy-3-(trifluoromethyl)pyrazine (Table 1b, entry 1). Prepared following general

procedure B using 2-methoxypyrazine (48.3 μL, 0.5 mmol). After 24 hours, the reaction mixture

was purified by flash chromatography using 25% Et2O in petroleum ether to provide the title

compound (73 mg, 82% yield) as a clear oil. IR (thin film) 2977, 2860, 1382, 1350, 1174 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.36 (d, J = 1.5 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 4.11 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 158.0, 144.5, 135.1, 132.3 (q, J2 = 36.2 Hz), 120.9 (q, J1 = 274.2

Hz), 54.5; 19F NMR (376 MHz, CDCl3) δ -68.3 (s); HRMS (ESI-TOF) calculated for C6H5F3N2O

[M]+ m/z 178.0354, found 178.0361.

N

N CF3

Me

Me

2,5-dimethyl-3-(trifluoromethyl)pyrazine (Table 1b, entry 2). Prepared following general

procedure B using 2,5-dimethylpyrazine (54.6 μ L, 0.5 mmol). After 24 hours, the reaction

mixture was purified by flash chromatography using 25% Et2O in petroleum ether to provide the

title compound (69 mg, 78% yield) as a clear oil. IR (thin film) 2987, 2871, 1384, 1169 cm-1; 1H

NMR (500 MHz, CD3CN) δ 8.47 (s, 1H), 2.61 (s, 3H), 2.57 (s, 3H); 13C NMR (126 MHz,

CD3CN) δ 151.3, 150.2, 142.1, 137.9 (d, J2 = 34.0 Hz), 122.3 (q, J1 = 273.3 Hz), 19.1, 19.0; 19F

NMR (376 MHz, CDCl3) δ -66.2 (s); HRMS (ESI-TOF) calculated for C7H7F3N2 [M]+ m/z

176.0561, found 176.0565.



N

N

Me

CF3

Me

3,5-dimethyl-2-(trifluoromethyl)pyrazine (Table 1b, entry 3). Prepared following general

procedure B using 2,6-dimethylpyrazine (54.1 mg, 0.5 mmol). After 24 hours, the reaction



NMR (500 MHz, CDCl3) δ 8.33 (s, 1H), 2.64 (s, 3H), 2.32 (s, 3H); 13C NMR (126 MHz, CDCl3)

δ 152.5, 150.6, 139.8, 136.4 (d, J2 = 28.6 Hz), 120.2 (q, J1 = 276.2 Hz), 19.9, 17.6; 19F NMR

(376 MHz, CDCl3) δ -65.9 (s); HRMS (ESI-TOF) calculated for C7H7F3N2 [M]+ m/z 176.05613,

found 176.0518.

N

N CF3

ClCl

3,5-dichloro-2-(trifluoromethyl)pyrazine (Table 1b, entry 4). Prepared following general

procedure B using 2,6-dichloropyrazine (74.5 mg, 0.5 mmol). After 48 hours, the reaction



NMR (500 MHz, CDCl3) δ 9.56 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 148.7, 146.8 (q, J3 = 4.0

Hz), 140.1, 122.9 (q, J2 = 26.0 Hz), 102.1 (q, J1 = 271.3 Hz); 19F NMR (376 MHz, CDCl3) δ -

66.8 (s); HRMS (ESI-TOF) calculated for C5HCl2F3N2 [M]+ m/z 215.9469, found 215.9476.



N

CF3

Me Me

2,6-dimethyl-3-(trifluoromethyl)pyridine (Table 1b, entry 5). Prepared following general

procedure B using 2,6-lutidine (58.2 μL, 0.5 mmol), 4% photocatalyst, and triflyl chloride (8

equiv). After 72 hours, the reaction mixture (73% yield by 19F NMR) was purified by prep TLC

using 20% Et2O in petroleum ether to provide the title compound. IR (thin film) 2977, 2866,

1380, 1350, 1145 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.53 (d, 1H, J = 8.3 Hz), 7.78 (d, 1H, J =

8.3 Hz), 3.02 (s, 3H), 2.93 (s, 3H); 13C NMR (126 MHz, CD3CN) δ 155.2 (q, J3 = 5.2 Hz), 147.4,

140.9 (d, J2 = 23.6 Hz), 126.6, 124.1 (d, J1 = 272.6 Hz), 121.5, 20.6 (q, J4 = 4.7 Hz), 20.2; 19F

NMR (376 MHz, CDCl3) δ -62.3 (s); HRMS (ESI-TOF) calculated for C8H8F3N [M]+ m/z

175.0609, found 175.0612.

HN

N

CF3

O

5-(trifluoromethyl)pyrimidin-4(3H)-one (Table 1b, entry 6). Prepared following general

procedure B using pyrimidin-4(3H)-one (48.0 mg, 0.5 mmol). After 24 hours, the reaction


title compound (61 mg, 74% yield) as a white solid. IR (thin film) 3075, 2973, 2865, 1668,

1561, 1510, 1329, 1134 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.38 (s, 1H), 8.34 (s, 1H); 13C NMR

(126 MHz, CDCl3) δ 160.0, 154.9 (q, J3 = 4.9 Hz), 152.3, 121.9 (q, J1 = 272.0 Hz), 118.3 (q, J2 =

31.8 Hz); 19F NMR (376 MHz, CDCl3) δ -65.8 (s); HRMS (ESI-TOF) calculated for C5H3F3N2O

[M]+ m/z 164.01975, found 164.0222.



N

N

Me

CF3

Me

Me

OH

2-isopropyl-6-methyl-5-(trifluoromethyl)pyrimidin-4-ol (Table 1b, entry 7). Prepared

following general procedure B using 2-isopropyl-6-methyl-pyrimidin-4-ol (76.1 mg, 0.5 mmol).

After 72 hours, the reaction mixture was purified by flash chromatography using 30% Et2O in

petroleum ether to provide the title compound (94 mg, 85% yield) as a white solid. IR (thin film)

3109, 2936, 2823, 1740, 1593, 1558, 1489, 1397, 1272, 1181, 1123 cm-1; 1H NMR (500 MHz,

CDCl3) δ 11.60 (bs, 1H), 2.46 (dd, 3H, J = 2.7 Hz, 5.5 Hz), 1.90 (s, 6H), 1.36 (bs, 1H); 13C NMR

(126 MHz, CDCl3) δ 166.2 (q, J3 = 1.0 Hz), 162.6, 159.7, 123.3 (q, J1 = 273.7 Hz), 113.6 (q, J2 =

30.6 Hz), 66.2, 31.1, 23.8 (q, J4 = 3.3 Hz); 19F NMR (376 MHz, CDCl3) δ -58.6 (d); HRMS

(ESI-TOF) calculated for C9H10F3N2O [M]+ m/z 218.0667, found 218.0675.

N

N

Me

MeS

CF3

4-methyl-2-(methylthio)-5-(trifluoromethyl)pyrimidine (Table 1b, entry 8). Prepared

following general procedure B using 4-methyl-2-(methylthio)pyrimidine (69.6 μL, 0.5 mmol).

After 72 hours, the reaction mixture was purified by flash chromatography using 20% Et2O in

petroleum ether to provide the title compound (75 mg, 72% yield) as a clear oil. IR (thin film)

2991, 2872, 1583, 1496, 1301, 1210 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.64 (s, 1H), 2.64 (q,

3H, J = 1.3 Hz), 2.62 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 176.2, 165.9, 153.9 (q, J3 = 5.4

Hz), 123.8 (q, J1 = 272.1 Hz), 118.4 (q, J2 = 32.4 Hz), 22.4 (q, J4 = 1.4 Hz), 14.26; 19F NMR (376

MHz, CDCl3) δ -62.2 (s); HRMS (ESI-TOF) calculated for C7H7F3N2S [M]+ m/z 208.0282,

found 208.0280.



N

N

OMe

OMeMeO

CF3

2,4,6-trimethoxy-5-(trifluoromethyl)pyrimidine (Table 1b, entry 9). Prepared following

general procedure B using 2,4,6-trimethoxypyrimidine (85.1 mg, 0.5 mmol). After 24 hours, the

reaction mixture was purified by flash chromatography using 5% Et2O in petroleum ether to

provide the title compound (102 mg, 86% yield) as a white solid. IR (thin film) 2962, 1564,

1502, 1475, 1381, 1303, 1199 cm-1; 1H NMR (500 MHz, CDCl3) δ 3.93 (s, 3H), 3.90 (d, 3H, J2 =

20.9 Hz), 3.83 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 172.7, 169.7, 164.9 (q, J3 = 7.7 Hz), 128.2

(q, J1 = 271.2 Hz), 89.1 (q, J2 = 34.2 Hz), 54.8 (d, J = 60.8 Hz), 54.8, 53.9; 19F NMR (376 MHz,

CDCl3) δ -56.4 (s); HRMS (ESI-TOF) calculated for C8H9F3N2O3 [M]+ m/z 238.0565, found

238.0560.

N

Me

CF3

Me Me

2,4,6-trimethyl-3-(trifluoromethyl)pyridine (Table 1b, entry 10). Prepared following general

procedure B using 2,4,6-collidine (66.3 μL, 0.5 mmol), 4% photocatalyst, and triflyl chloride (8

equiv). After 72 hours, the reaction mixture (81% yield by 19F NMR) was purified by prep TLC

using 15% Et2O in petroleum ether to provide the title compound. IR (thin film) 2987, 2870,

1429, 1382, 1164 cm-1; 1H NMR (500 MHz, CD3CN) δ 7.65 (s, 1H), 3.01 (dd, 3H J = 3.0, 6.2),

2.86 (s, 3H), 2.70 (dd, 3H J = 3.0, 6.2); 13C NMR (126 MHz, CD3CN) δ 157.7, 155.5, 152.7,

136.8 (q, J2 = 27.5 Hz), 128.7, 124.8 (q, J1 = 301.0 Hz), 20.8 (q, J = 4.0 Hz), 18.1, 18.0; 19F

NMR (376 MHz, CDCl3) δ -56.5 (s); HRMS (ESI-TOF) calculated for C9H10F3N [M]+ m/z

189.0765, found 189.0764.



N

CF3

OMe5

2-methoxy-3-(trifluoromethyl)pyridine (Table 1b, entry 11). Prepared following general

procedure B using 2-methoxypyridine (52.6 μL, 0.5 mmol). After 48 hours, the reaction mixture

(78% yield, 3:1 r..r by 19F NMR) was purified by prep TLC using 7% Et2O in petroleum ether to


MHz, CD3CN) δ 8.36 (d, J = 3.9 Hz, 1H), 7.89 (dd, J = 7.5, 1.0 Hz, 1H), 7.00 (dd, J = 7.2, 5.3

Hz, 1H), 4.07 (s, 3H); 13C NMR (126 MHz, CD3CN) δ 160.9, 136.4 (q, J3 = 4.8 Hz), 123.0 (q, J1

= 271.6 Hz), 115.9, 113.3 (q, J2 = 33.0 Hz), 104.3, 54.1; 19F NMR (376 MHz, CDCl3) δ -64.4 (s);

HRMS (ESI-TOF) calculated for C7H6F3NO [M]+ m/z 177.04015, found 177.0404.

N

Me

CF3

OMe

2-methoxy-4-methyl-5-(trifluoromethyl)pyridine (Table 1b, entry 12). Prepared following

general procedure B using 2-methoxy-4-methyl pyridine (61.5 μL, 0.5 mmol). After 24 hours,

the reaction mixture was purified by prep TLC using 10% Et2O in petroleum ether to provide the

title compound (75 mg, 78% yield). IR (thin film) 2977, 2862, 1382, 1351, 1113 cm-1; 1H NMR

(500 MHz, CDCl3) δ 8.14 (d, J = 5.2 Hz, 1H), 6.78 (d, J = 5.1 Hz, 1H), 4.02 (s, 3H), 2.49 (dd, J

= 6.6, 3.3 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 161.9, 149.6, 149.1, 124.6 (q, J1 = 274.5 Hz),

120.6, 112.0 (q, J2 = 31.1 Hz), 54.3, 21.1 (q, J3 = 3.9 Hz); 19F NMR (376 MHz, CDCl3) δ -54.7

(s); HRMS (ESI-TOF) calculated for C8H8F3NO [M]+ m/z 191.0558, found 191.0558.



NO CF3

Me

1-methyl-5-(trifluoromethyl)-2-pyridinone (Table 1b, entry 13). Prepared following general

procedure B using N-Me-2-pyridinone (49.2 μL, 0.5 mmol). After 24 hours, the reaction mixture

was purified by flash chromatography using 35% Et2O in petroleum ether to provide the title

compound (77 mg, 87% yield) as a clear oil. IR (thin film) 2989, 2870, 1694, 1381, 1286, 1259,

1157 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.10 (d, J = 6.1 Hz, 1H), 4.86 (d, J = 6.1 Hz, 1H), 4.26

(q, J = 6.9 Hz, 1H), 3.24 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 157.1, 135.7 (q, J3 = 5.5 Hz),

127.6 (q, J2 = 31.8 Hz), 122.0 (q, J1 = 280.2 Hz), 66.2 (q, J3 = 30.0 Hz), 44.6, 36.3; 19F NMR

(376 MHz, CDCl3) δ -66.5 (s); HRMS (ESI-TOF) calculated for C7H6F3NO [M]+ m/z 177.0401,

found 177.0422.

O

CF3

O Me

Me

4,6-dimethyl-5-(trifluoromethyl)-2-pyranone (Table 1b, entry 14). Prepared following

general procedure B using 4,6-dimethyl-2-pyranone (62.1 mg, 0.5 mmol). After 24 hours, the


provide the title compound (86 mg, 90% yield) as a white solid. IR (thin film) 2979, 2863, 1718,

1645, 1557, 1437, 1388, 1372, 1350, 1270, 1202 1147 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.96

(s, 1H), 2.36 (dd, J = 5.4, 2.7 Hz, 3H), 2.29 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 164.1, 158.3

(q, J3 = 1.4 Hz), 158.2 (q, J3 = 1.4 Hz), 123.2 (q, J1 = 273.9 Hz), 111.0 (q, J2 = 31.1 Hz), 108.4,

20.8 (q, J4 = 3.6 Hz), 19.9; 19F NMR (376 MHz, CDCl3) δ -58.5 (s); HRMS (ESI-TOF)

calculated for C8H7F3O2 [M]+ m/z 192.0398, found 192.0416.



O

CF3

O

Me Me

2,6-dimethyl-3-(trifluoromethyl)-4-pyranone (Table 1b, entry 15). Prepared following

general procedure B using 2,6-dimethyl-4-pyranone (62.1 mg, 0.5 mmol). After 24 hours, the


provide the title compound (85 mg, 88% yield) as a clear oil. IR (thin film) 3082, 2927, 2849,

1672, 1630, 1399, 1335, 1276, 1208, 1168, 1128 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.70 (s,

1H), 2.24 (s, 3H), 2.12 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 182.4 (q, J3 = 1.6 Hz), 170.2,

121.8 (q, J1 = 283.9 Hz), 105.8, 99.8, 59.4 (q, J2 = 25.4 Hz), 29.9 (q, J4 = 1.6 Hz), 20.8; 19F NMR

(376 MHz, CDCl3) δ -64.6 (s); HRMS (ESI-TOF) calculated for C8H7F3O2 [M]+ m/z 192.0398,

found 192.0425.

CF3

1,1,1-trifluorotoluene (Table 1c, entry 1). Prepared following general procedure C using

analytically pure benzene (44.4 μL, 0.5 mmol) in d-MeCN. After 24 hours, the reaction mixture

was analyzed directly by 19F NMR (74% yield). 1H NMR (500 MHz, CD3CN) δ 7.73 (d, J = 7.8

Hz, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.60 (t, J = 7.7 Hz, 2H); 13C NMR (126 MHz, CD3CN) δ

132.0, 128.7, 124.7 (q, J3 = 3.9 Hz), 124.2 (q, J1 = 271.2 Hz), 117.0; 19F NMR (376 MHz,

CDCl3) δ -63.6 (s).



NHBoc

CF3

tert-butyl 2-(trifluoromethyl)phenylcarbamate (Table 1c, entry 2). Prepared following

general procedure C using N-Boc aniline (96.6 mg, 0.5 mmol). After 24 hours, the reaction

mixture (80% yield, 3:1 o/p by 19F NMR) was purified by flash chromatography using 10% Et2O

in petroleum ether to provide the title compound as a clear oil. IR (thin film) 3115, 2927, 2842,

1590, 1552, 1436, 1264 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J = 8.3 Hz, 1H), 7.59 (d, J

= 7.9 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.82 (bs, 1H), 1.55 (s, 9H); 13C

NMR (126 MHz, CDCl3) δ 152.6, 136.2 (q, J3 = 1.5 Hz), 132.8, 126.0 (q, J3 = 5.4 Hz), 124.2 (q,

J1 = 272.8 Hz), 123.0, 122.4, 118.9 (q, J2 = 29.3 Hz), 81.3, 28.2; 19F NMR (376 MHz, CDCl3) δ -

61.3 (s); HRMS (ESI-TOF) calculated for C12H14F3NO2 [M]+ m/z 261.0977, found 261.0988.

OMe

CF3

2-(trifluoromethyl)anisole (Table 1c, entry 3). Prepared following general procedure C using

anisole (54.3 μ L, 0.5 mmol). After 24 hours, the reaction mixture was purified by flash


yield, 2:1 o/p) as a clear oil and a mixture separable by prep SFC. IR (thin film) 2920, 2802,

1379, 1322, 1079 cm-1; Ortho-CF3 anisole: 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.4 Hz,

1H), 7.43 (t, J = 7.9 Hz, 1H), 6.97 – 6.91 (m, 2H), 3.84 (s, 3H); 13C NMR (126 MHz, CDCl3) δ

157.5, 133.3, 127.1 (q, J3 = 5.3 Hz), 123.7 (q, J1 = 272.2 Hz), 120.0, 118.7 (q, J2 = 30.7 Hz),

111.9, 55.9; 19F NMR (376 MHz, CDCl3) δ -62.9 (s); Para-CF3 anisole: 1H NMR (500 MHz,

CDCl3) δ 7.48 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 3.78 (s, 3H); 13C NMR (126 MHz,

CDCl3) δ 162.0, 126.9 (q, J3 = 3.7 Hz), 124.5 (q, J1 = 270.9 Hz), 122.8 (q, J2 = 32.5 Hz), 114.0,


m/z 176.0449, found 176.0439.



SMe

CF3

2-(trifluoromethyl)-S-methylthioanisole (Table 1c, entry 4). Prepared following general

procedure C using S-methylthioanisole (58.7 μ L, 0.5 mmol). After 24 hours, the reaction


title compound (70 mg, 73% yield, 2:1 o/p) as a clear oil and a mixture separable by prep SFC.

IR (thin film) 2934, 2817, 1395, 1278, 1164 cm-1; Ortho-CF3 thioanisole: 1H NMR (500 MHz,

CDCl3) δ 7.64 (t, J = 7.4 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.36 (t, J =

7.6 Hz, 1H), 2.60 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -62.8 (s); Para-CF3 thioanisole: 1H

NMR (500 MHz, CDCl3) δ 8.11 (d, J = 4.8 Hz, 2H), 6.74 (d, J = 4.6 Hz, 2H), 3.99 (s, 3H); 13C

NMR (126 MHz, CDCl3) δ 161.8, 149.1 (q, J3 = 3.9 Hz), 124.4 (q, J1 = 274.4 Hz), 120.4, 111.8

(q, J2 = 31.2 Hz), 54.1; 19F NMR (376 MHz, CDCl3) δ -63.2 (s); HRMS (ESI-TOF) calculated

for C8H8F3OS [M+OH]+ m/z 208.0170, found 208.0169.

Me

CF3

MeMe

1,3,5-trimethyl-2-(trifluoromethyl)benzene (Table 1c, entry 5). Prepared following general

procedure C using 1,3,5-mesitylene (69.6 μL, 0.5 mmol). After 24 hours, the reaction mixture

(70% yield by 19F NMR) was purified by flash chromatography using 3% Et2O in petroleum

ether to provide the title compound as a clear oil. IR (thin film) 2909, 2857, 1383, 1321, 1120

cm-1; 1H NMR (500 MHz, CDCl3) δ 6.82 (s, 2H), 2.49 – 2.30 (m, 9H); 13C NMR (126 MHz,

CDCl3) δ 140.1, 137.3 (dd, J3 = 4.1, 1.9 Hz), 130.9, 127.7 (q, J2 = 28.5 Hz), 125.5 (q, J1 = 276.5

Hz), 21.75 (dq, J4 = 93.9, 4.5 Hz), 20.9; 19F NMR (376 MHz, CDCl3) δ -54.3 (s).



Me

Br

Me

CF3

2-bromo-1,3-dimethyl-4-(trifluoromethyl)benzene (Table 1c, entry 6). Prepared following

general procedure C using 2-bromo xylene (66.6 μL, 0.5 mmol) in d-MeCN. After 24 hours, the

reaction mixture (75% yield, 4:1 r.r by 19F NMR) was purified by flash chromatography using

1% Et2O in petroleum ether to provide the title compound as a clear oil. IR (thin film) 2951,

2885, 1382, 1317, 1223, 1119 cm-1; 1H NMR (500 MHz, CD3CN) δ 7.59 (d, J = 8.1 Hz, 1H),

7.32 (d, J = 8.0 Hz, 1H), 2.57 (s, 3H), 2.50 (s, 3H); 13C NMR (126 MHz, CD3CN) δ 143.0,

139.4, 129.3, 127.7, 126.9 (q, J2 = 29.8 Hz), 124.2 (q, J3 = 6.1 Hz), 123.9 (q, J1 = 265.7 Hz),

23.4, 19.2 (q, J4 = 2.4 Hz); 19F NMR (376 MHz, CDCl3) δ -61.5 (s); HRMS (ESI-TOF)

calculated for C9H8BrF3 [M]+ m/z 251.9762, found 251.9730.

Me

CF3

Me

Meta-xylene (Table 1c, entry 7). Prepared following general procedure C using meta-xylene

(61.7 μL, 0.5 mmol) in d-MeCN. After 24 hours, the reaction mixture was analyzed directly by 19F NMR (77% yield, 2:1 r.r.). IR (thin film) 2934, 2873, 1381, 1316, 1133 cm-1; 1H NMR (500

MHz, CD3CN) δ 7.37 (d, J = 7.9 Hz, 1H), 7.23 (s, 1H), 7.20 (d, J = 7.8 Hz, 1H), 2.46 (s, 3H),

2.38 (s, 3H); 13C NMR (126 MHz, CD3CN) δ 144.4, 140.8 (q, J3 = 4.1 Hz), 138.9 (q, J2 = 27.4

Hz), 134.3, 131.9, 128.2, 126.7 (q, J1 = 272.3 Hz), 23.0, 22.2; 19F NMR (376 MHz, CDCl3) δ -

60.8 (s).



MeCF3Me

Ortho-xylene (Table 1c, entry 8). Prepared following general procedure C using ortho-xylene

(60.3 μL, 0.5 mmol) in d-MeCN. After 24 hours, the reaction mixture was analyzed directly by 19F NMR (72% yield, 2:1 r.r.). IR (thin film) 2928, 2862, 1379, 1320, 1127 cm-1; 1H NMR (500

MHz, CD3CN) δ 7.54 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 2.39

(s, 3H), 2.37 (s, 3H); 13C NMR (126 MHz, CD3CN) δ 138.9 (q, J3 = 3.1 Hz), 137.6, 133.3 (q, J4 =

0.8 Hz), 129.6, 127.8 (q, J2 = 28.6 Hz), 125.5 (q, J3 = 3.7 Hz), 124.7 (q, J1 = 273.0 Hz), 19.0,

18.4; 19F NMR (376 MHz, CDCl3) δ -62.0 (s); HRMS (ESI-TOF) calculated for C9H7F3 [M]+ m/z

172.0500, found 172.0503.

Me

CF3MeO

MeO

3

1,2-dimethoxy-4-methyl-5-(trifluoromethyl)benzene (Table 1c, entry 9). Prepared following

general procedure C using 3,4-dimethoxy toluene (71.8 μ L, 0.5 mmol). After 24 hours, the

reaction mixture (92% yield, 5:1 o/p by 19F NMR) was purified by flash chromatography using

5% Et2O in petroleum ether to provide the title compound as a clear oil. IR (thin film) 2922,

2852, 1521, 1405, 1356, 1288, 1127 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.07 (s, 1H), 6.73 (s,

1H), 3.91 (s, 3H), 3.89 (s, 3H), 2.42 (d, J = 1.7 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 150.8,

146.4, 129.8 (q, J3 = 1.9 Hz), 124.7 (q, J1 = 272.7 Hz), 120.6 (q, J2 = 30.3 Hz), 114.4, 109.0 (q, J3

= 5.6 Hz), 56.1, 56.0, 19.0 (q, J4 = 1.9 Hz); 19F NMR (376 MHz, CDCl3) δ -60.5 (s); HRMS

(ESI-TOF) calculated for C10H11F3O2 [M]+ m/z 220.0711, found 220.0731.



CF3

BF3K

O

O

6-(trifluoromethyl)3,4-benzo[1,3]dioxole)potassium trifluoroborate (Table 1c, entry 10).

Prepared following general procedure C using 3,4-benzo[1,3]dioxole)potassium trifluoroborate

(114.0 mg, 0.5 mmol) in d-MeCN. After 24 hours, the reaction mixture was analyzed directly by 19F NMR (74% yield, 2:1 r.r.). IR (thin film) 2954, 2871, 1471, 1382, 1309, 1263 cm-1; 1H NMR

(500 MHz, CD3CN) δ 6.09 (s, 1H), 5.96 (s, 1H), 1.83 (dt, J = 4.9, 2.4 Hz, 2H); 13C NMR (126

MHz, CD3CN) δ 152.2, 146.4, 119.6 (q, J2 = 4.4 Hz), 109.8, 107.9 (q, J1 = 270.6 Hz), 105.0 (dd,

J3 = 7.4, 3.7 Hz), 103.8, 29.6; 19F NMR (376 MHz, CDCl3) δ -59.0 (s); HRMS (ESI-TOF)

calculated for C8H6BF6KO [M]+ m/z 282.0053, found 282.0037.

Me

Me CF3

2-(trifluoromethyl)-para-xylene (Table 1c, entry 11). Prepared following general procedure C

using para-xylene (61.7 μL, 0.5 mmol) in d-MeCN. After 24 hours, the reaction mixture was

analyzed directly by 19F NMR (77% yield). IR (thin film) 2925, 2861, 1373, 1322, 1227, 1161

cm-1; 1H NMR (500 MHz, CD3CN) δ 7.50 (s, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 7.8 Hz,

1H), 2.45 (s, 3H), 2.38 (s, 3H); 13C NMR (126 MHz, CD3CN) δ 134.3, 133.0 (q, J = 1.8 Hz),

132.3, 128.5, 127.5 (q, J = 28.1 Hz), 125.7 (q, J = 5.6 Hz), 121.5 (q, J = 276.3 Hz), 29.6, 17.6 (q,

J = 2.1 Hz); 19F NMR (376 MHz, CDCl3) δ -62.4 (s).



OMe

MeO CF3

1,4-dimethoxy-2-(trifluoromethyl)benzene (Table 1c, entry 12). Prepared following general

procedure C using 1,4-dimethoxy benzene (69.1 μL, 0.5 mmol). After 24 hours, the reaction


title compound (88 mg, 85% yield) as a clear oil. IR (thin film) 3101, 2912, 2868, 1378, 1315,

1264, 1102 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.11 (d, J = 3.0 Hz, 1H), 7.02 (dd, J = 9.0, 3.0

Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H); 13C NMR (126 MHz, CDCl3) δ

152.9, 151.5 (q, J3 = 1.6 Hz), 123.4 (q, J1 = 272.4 Hz), 119.3 (q, J2 = 31.0 Hz), 118.1, 113.5,

112.8 (q, J3 = 5.4 Hz), 56.6, 55.9; 19F NMR (376 MHz, CDCl3) δ -62.8 (s); HRMS (ESI-TOF)

calculated for C9H9F3O2 [M]+ m/z 206.0555, found 206.0546.

OMe

CF3Me3Si

4-trimethylsilyl-2-(trifluoromethyl)anisole (Table 1c, entry 13). Prepared following general

procedure C using 4-trimethylsilyl anisole (97.2 μL, 0.5 mmol). After 24 hours, the reaction


title compound (94 mg, 76% yield) as a clear oil. IR (thin film) 2989, 2870, 1392, 1265, 1142

cm-1; 1H NMR (500 MHz, CDCl3) δ 7.67 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 8.2 Hz,

1H), 3.91 (s, 3H), 0.27 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 159.1 (q, J3 = 1.4 Hz), 139.6,

132.8 (q, J3 = 5.1 Hz), 132.3, 125.0 (q, J1 = 272.6 Hz), 119.2 (q, J2 = 30.2 Hz), 112.5, 56.9, 0.0; 19F NMR (376 MHz, CDCl3) δ -62.7 (s); HRMS (ESI-TOF) calculated for C11H15F3OSi [M]+ m/z

248.0844, found 248.0838.



OMe

Me CF3

4-methyl-2-(trifluoromethyl)anisole (Table 1c, entry 14). Prepared following general

procedure C using para-methoxy toluene (63.0 μ L, 0.5 mmol). After 24 hours, the reaction

mixture (85% yield, 4:1 r.r. by 19F NMR) was purified by flash chromatography using 5% Et2O


1260, 1149 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.45 (s, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.08 (d, J

= 7.4 Hz, 1H), 3.88 (s, 3H), 2.34 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 155.0 (q, J3 = 3.7 Hz),

133.8, 129.4, 126.8 (q, J3 = 5.4 Hz), 123.7 (d, J1 = 271.2 Hz), 121.8 (d, J2 = 28.4 Hz), 112.1,

55.3, 29.6; 19F NMR (376 MHz, CDCl3) δ -63.0 (s); HRMS (ESI-TOF) calculated for C9H9F3O

[M]+ m/z 190.0606, found 190.0612.

Me

CF3tBu

3

4-tert-butyl-2-(trifluoromethyl)toluene (Table 1c, entry 15). Prepared following general

procedure C using para-tert-butyl toluene (86.4 μL, 0.5 mmol). After 24 hours, the reaction

mixture (78% yield, 5:1 r.r. by 19F NMR) was purified by flash chromatography using 2% Et2O


1301, 1119 cm-1; 1H NMR (500 MHz, CDCl3) δ δ 7.71 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.29 (d,

J = 7.9 Hz, 1H), 2.53 (s, 3H), 1.40 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 148.9, 133.5 (q, J3 =

1.6 Hz), 131.7, 128.6 (q, J3 = 0.7 Hz), 126.2 (q, J2 = 25.7 Hz), 125.0 (q, J1 = 282.4 Hz), 122.6 (q,

J3 = 5.6 Hz), 34.5, 31.2, 18.8 (q, J4 = 2.0 Hz); 19F NMR (376 MHz, CDCl3) δ -61.8 (s).



III. Direct Trifluoromethylation of Biologically Active Molecules.

N

N

O

F3C

O

Me

Me

1,3-dimethyl-5-(trifluoromethyl)pyrimidine-2,4-dione (Figure 3a, CF3-methyluracil).

Prepared following general procedure C using 1,3-dimethyl uracil (70.1 mg, 0.5 mmol). After

24 hours, the reaction mixture was purified by flash chromatography using 25-100% Et2O in

petroleum ether to provide the title compound (96 mg, 92% yield) as a clear oil. IR (thin film)

3355, 2981, 2876, 1717, 1671, 1460, 1381, 1326, 1211 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.67

(s, 1H), 3.49 (s, 3H), 3.37 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 158.7, 151.0, 143.5 (q, J3 = 5.8

Hz), 122.0 (q, J1 = 269.8 Hz), 104.2 (d, J2 = 32.8 Hz), 37.9, 28.1; 19F NMR (376 MHz, CDCl3) δ

-64.2 (s); HRMS (ESI-TOF) calculated for C7H7F3N2O2 [M]+ m/z 208.0460, found 208.0477.

CF3

MeO

MeO

O

5,6-dimethoxy-7-(trifluoromethyl)-1-indanone (Figure 3a, CF3-Aricept® precursor).

Prepared following general procedure C using 5,6-dimethoxy-indanone (96.1 mg, 0.5 mmol) and

triflyl chloride (1.1 equiv). After 24 hours, the reaction mixture was purified by flash


yield) as a clear oil. IR (thin film) 2989, 2870, 1712, 1585, 1477, 1436, 1345, 1322, 1301, 1276

cm-1; 1H NMR (500 MHz, CDCl3) δ 7.09 (s, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.08 (td, J = 5.5, 2.6

Hz, 2H), 2.58 – 2.47 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 205.2, 154.4 (q, J3 = 2.3 Hz),

153.5, 145.6, 133.4, 124.0 (q, J1 = 274.6 Hz), 122.0 (d, J2 = 31.0 Hz), 109.0, 61.8, 56.3; 19F NMR

(376 MHz, CDCl3) δ -57.7 (s); HRMS (ESI-TOF) calculated for C12H11F3O3 [M]+ m/z 260.0660,

found 260.0657.



O

O

CF3

2-phenyl-3-(trifluoromethyl)-4-chromenone (Figure 3a, CF3-flavone). Prepared following

general procedure C using flavone (111 mg, 0.5 mmol). After 24 hours, the reaction mixture was

purified by flash chromatography using 10-25% Et2O in petroleum ether to provide the title

compound (123 mg, 85% yield) as a clear oil. IR (thin film) 1659, 1624, 1572, 1465, 1449,

1382, 1324, 1222, 1189, 1125 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.28 (dd, J = 8.3, 1.5 Hz, 1H),

7.75 (dd, J = 7.0, 1.6 Hz, 1H), 7.63 – 7.57 (m, 3H), 7.54 (d, J = 7.5 Hz, 2H), 7.48 (d, J = 8.2 Hz,

2H); 13C NMR (126 MHz, CDCl3) δ 174.5, 167.1 (q, J3 = 2.3 Hz), 155.5, 134.8, 132.4, 131.5,

128.6, 128.6, 128.5, 128.4, 126.3, 126.2, 123.3, 122.7 (q, J1 = 273.9 Hz), 118.0, 113.2 (q, J2 =

29.2 Hz); 19F NMR (376 MHz, CDCl3) δ -56.6 (s); HRMS (ESI-TOF) calculated for C16H9F3O2

[M]+ m/z 290.0555, found 290.0583.

H

O

OMe

OMe

CF3

2

3,4-dimethoxy-5-(trifluoromethyl)benzaldehyde (Figure 3b, CF3-methylvanillin). Prepared

following general procedure B using methylvanillin (83.1 mg, 0.5 mmol). After 48 hours, the


provide the title compound (96 mg, 82% yield, 5:1 r.r.) as a clear oil. IR (thin film) 2990, 2870,

1687, 1594, 1463, 1393, 1360, 1304, 1226 cm-1; 1H NMR (500 MHz, CDCl3) δ 10.30 (dd, J =

4.0, 1.9 Hz, 1H), 7.65 (s, 1H), 7.21 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H); 13C NMR (126 MHz,

CDCl3) δ 187.9 (dd, J = 5.3, 2.6 Hz), 152.9, 151.3, 127.4, 125.6 (q, J2 = 32.8 Hz), 123.8 (q, J1 =

273.9 Hz), 110.2, 108.3 (q, J3 = 5.9 Hz), 56.5 (t, J = 5.4 Hz), 56.4; 19F NMR (376 MHz, CDCl3)

δ -54.0 (s); HRMS (ESI-TOF) calculated for C10H9F3O3 [M]+ m/z 234.0504, found 234.0512.



Me

O

OH

Me

Me

CF3

2

2-(4-isobutyl-3-(trifluoromethyl)phenyl)propanoic acid (Figure 3b, CF3-ibuprofen).

Prepared following general procedure B using ibuprofen (103 mg, 0.5 mmol). After 48 hours,

the reaction mixture was purified by flash chromatography using 40% Et2O in petroleum ether to

provide the title compound (107 mg, 78% yield, 1.4:1 r.r.) as a clear oil. IR (thin film) 3240,

2978, 2870, 1447, 1382, 1350, 1299, 1175 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.67 (dd, J =

105.5, 15.9 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.16 (dd, J = 58.7, 8.0 Hz, 1H), 4.17 (dq, J = 14.2,

7.1 Hz, 1H), 2.65 (dd, J = 26.9, 7.2 Hz, 1H), 2.47 (dd, J = 25.0, 7.2 Hz, 1H), 1.89 (ddt, J = 39.6,

19.4, 6.7 Hz, 1H), 1.54 (tdd, J = 11.1, 8.1, 4.5 Hz, 3H), 1.00 – 0.82 (m, 6H); 13C NMR (126

MHz, CDCl3) δ 179.9, 141.1, 132.9, 128.6, 128.0 (d, J2 = 29.4 Hz), 127.3, 124.7 (d, J3 = 10.4

Hz), 124.4 (q, J1 = 274.0 Hz), 44.8, 40.5, 30.1, 22.3, 19.2, 18.1; 19F NMR (376 MHz, CDCl3) δ -

59.3 (s); HRMS (ESI-TOF) calculated for C14H17F3O2 [M]+ m/z 274.1181, found 274.1192.



Me MeHN

ON

Me

Me

4CF3

2-(diethylamino)-N-(2,6-dimethyl-4-(trifluoromethyl)phenyl)acetamide (Figure 3b,

CF3-lidocaine). Prepared following general procedure C using lidocaine (117.2 mg, 0.5 mmol)

with the addition of 1.2 equivalent of HCl (any source of HCl can be used to protect the lone pair

of the nitrogen from photocatalytic oxidation). After 48 hours, the reaction mixture was purified

by base-treated prep TLC using 10% MeOH in CH2Cl2 to provide the title compound (118 mg,

78% yield, 2:1 r.r.). IR (thin film) 3340, 2977, 2899, 1717, 1352, 1127 cm-1; 1H NMR (500

MHz, CD3CN) δ 9.01 (broad d, J = 29.3 Hz, 1H), 7.43 (dd, J = 144.8, 8.1 Hz, 1H), 7.19 – 7.07

(m, 1H), 4.26 (dd, J = 34.8, 4.7 Hz, 2H), 3.33 (ddd, J = 14.4, 6.3, 4.5 Hz, 4H), 2.33 (d, J = 20.1

Hz, 3H), 2.24 (s, 3H), 1.35 (t, J = 7.3 Hz, 6H); 13C NMR (126 MHz, CD3CN) δ 162.9, 140.5,

136.8 (q, J3 = 3.7 Hz), 134.3, 133.0, 127.7 (q, J3 = 3.0 Hz), 127.2, 126.5 (q, J2 = 29.5 Hz), 124.3

(q, J1 = 272.6 Hz), 52.5, 49.4, 17.8, 17.3, 8.4; 19F NMR (376 MHz, CDCl3) δ -61.5 (s); HRMS

(ESI-TOF) calculated for C15H20ClF3N2O [M]+ m/ z 336.1216, found 336.1222.



NNH

O OH OH

OH

O

F

F3C

2

4'

Me Me

(3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(4-trifluoromethylphenylcarbamoyl)-

1-pyrrole-3,5-dihydroxyheptanoic acid (Figure 3c, CF3-Lipitor®). Prepared following general

procedure C using Lipitor® (140 mg, 0.25 mmol). After 24 hours, the reaction mixture was

purified by prep TLC using 10% MeOH in CH2Cl2 to provide the title compound (116 mg, 74%

yield, 1:1:1 r.r.) as a clear oil. Lotus Separations, LLC at Princeton University performed further

separation of the three regioisomers via preparatory-scale supercritical fluid chromatography

(SFC). IR (thin film) 3345, 2978, 2868, 1381, 1162, 1154 cm-1; 1H NMR (500 MHz, CDCl3) δ

9.91 (s, 1H, CO2H), 7.53 (d, J = 7.8 Hz, 2H), 7.32 – 7.16 (m, 5H), 7.12 – 6.97 (m, 6H), 6.77 (bs,

1H, NH), 4.84 (bs, 2H, OH), 4.06 – 3.87 (m, 2H), 3.87 – 3.63 (m, 2H), 3.54 (d, J = 3.9 Hz, 1H),

3.24 (dt, J = 14.1, 7.0 Hz, 1H), 2.03 (dd, J = 15.1, 4.0 Hz, 1H), 1.87 (dd, J = 15.1, 8.0 Hz, 1H),

1.54 (dd, J = 30.3, 24.9 Hz, 2H), 1.48 – 1.29 (m, 6H), 1.25 – 1.13 (m, 1H); 13C NMR (126 MHz,

CDCl3) δ 162.32, 143.28, 132.79, 132.55, 131.92, 131.85, 131.20 (d, J1 = 120.2 Hz), 131.06,

130.59, 130.08 (q, J2 = 25.9 Hz), 129.61, 128.83, 128.12, 127.96, 127.34, 126.93, 126.18 (q, J3 =

3.2 Hz), 125.88 (q, J1 = 264.4 Hz), 125.34, 124.33, 124.24, 120.57, 120.06, 119.98, 116.22 (d, J2

= 21.9 Hz), 74.27, 68.48, 62.38, 51.75, 37.44, 34.21, 18.07, 16.84, 16.73; pure isomer A: 19F

NMR (376 MHz, CDCl3) δ -61.4 (s, 3F), 113.9 (s, 1F); pure isomer B: 19F NMR (376 MHz,

CDCl3) δ -62.4 (s, 3F), 114.0 (s, 1F); pure isomer C: 19F NMR (376 MHz, CDCl3) δ -62.9 (s,

3F), 114.1 (s, 1F); HRMS (ESI-TOF) calculated for C34H32F4N2O5 [M-2H]+ m/z 624.2247, found

624.2254.



IV. Emission Quenching Experiments.

Emission intensities were recorded using a Perkin Elmer LS50 Luminescence spectrometer. All

Ru(phen)3Cl2 solutions were excited at 460 nm and the emission intensity at 595 nm was

observed. In a typical experiment, a 2.5 × 10-3 M solution of Ru(phen)3Cl2 in acetonitrile was

added to the appropriate amount of quencher in a screw-top 1.0 cm quartz cuvette. After

degassing with a stream of nitrogen for 10 minutes, the emission spectrum of the sample was

collected.

Figure S1: Ru(phen)3Cl2 Emission Quenching

Summary of quenching experiments:

Quencher Stern-Volmer constant

Triflyl chloride 22.17 2-methyl furan 0.37

anisole 0.28 benzene 0.07

2,6-lutidine 0.33



V. Cyclic Voltammetry (CV) Measurements.

CV data was measured using a BAS 100B/W electrochemical analyzer, Pt working and auxiliary

electrodes, Ag/AgCl reference electrode, a 0.1 M LiClO4 in acetonitrile electrolyte solution, a

substrate concentration of 0.025 M, and a sweep rate of 25 mV/s.

Figure S2: Cyclic Voltammogram of Triflyl Chloride x-axis (V)

VI. NMR Spectra

1H and 13C NMR spectra are included below for all isolated compounds.



NBoc

CF3



NBoc

CF3



O

CF3

Me



O

CF3

Me



NH

CF3

3



NH

CF3

3



NAc

CF3

2



NAc

CF3

2



N

N CF3

OMe



N

N CF3

OMe



N

N CF3

ClCl



N

N CF3

ClCl



HN

N

CF3

O



HN

N

CF3

O



N

N

Me

CF3

Me

Me

OH



N

N

Me

CF3

Me

Me

OH



N

N

Me

MeS

CF3



N

N

Me

MeS

CF3



N

N

OMe

OMeMeO

CF3



N

N

OMe

OMeMeO

CF3



NO CF3

Me



NO CF3

Me



O

CF3

O Me

Me



O

CF3

O Me

Me



O

CF3

O

Me Me



O

CF3

O

Me Me



NHBoc

CF3



NHBoc

CF3



OMe

CF3



OMe

CF3



OMe

CF3



OMe

CF3



SMe

CF3



SMe

CF3



Me

CF3

MeMe



Me

CF3

MeMe



Me

Br

Me

CF3



Me

Br

Me

CF3



Me

CF3MeO

MeO

3



Me

CF3MeO

MeO

3



CF3

BF3K

O

O



CF3

BF3K

O

O



Me

Me CF3



Me

Me CF3



OMe

MeO CF3



OMe

MeO CF3



OMe

CF3Me3Si



OMe

CF3Me3Si



OMe

Me CF3



OMe

Me CF3



Me

CF3tBu

3



Me

CF3tBu

3



N

N

O

F3C

O

Me

Me



N

N

O

F3C

O

Me

Me



CF3

MeO

MeO

O



CF3

MeO

MeO

O



O

O

CF3



O

O

CF3



H

O

OMe

OMe

CF3

2



H

O

OMe

OMe

CF3

2



Me

O

OH

Me

Me

CF3

2



Me

O

OH

Me

Me

CF3

2



NNH

O OH OH

OH

O

F

F3C

2

4'

Me Me



NNH

O OH OH

OH

O

F

F3C

2

4'

Me Me



Documents

SU PPLEMENTARY INFORMATION - Nature · I. General Information & Reaction Setup ... discolored TfCl was purified by passing through a small pad of basic alumina. ... (λ = 214–258