Supporting Information Chlorodifluoromethyl Phenyl Sulfone

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Supporting Information

Chlorodifluoromethyl phenyl sulfone: a novel non-ODS- based difluorocarbene reagent for O- and N- difluoromethylations

Ji Zhenga, Ya Lia, Laijun Zhanga, Jinbo Hu*.a, Gerrit Joost Meuzelaarb, and Hans-Jürgen Federselb aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China; and bGlobal Process R&D, Södertälje site, AstraZeneca, SE-151 85 Södertälje, Sweden

General. Unless otherwise mentioned, reagents were purchased from commercial sources and used as received. The solvent THF was distilled from sodium. High-resolution mass data were recorded on a high-resolution mass spectrometer in the EI , ESI or MALDI mode. 1H

NMR spectra were recorded at 300 MHz in CDCl3 and were referenced to residual CHCl3 19 or to tetramethylsilane (TMS). F NMR spectra were recorded at 282 MHz using CFCl3 13 as external standard. C NMR spectra were recorded at 75, 100 or 125 MHz in CDCl3. All chemical shifts are reported in δ parts per million and coupling constants are in hertz.

PhSO2CF2H, PhSO2CF2Br, PhSO2CF2I, PhSO2CF3 were prepared by using the known procedures.1

Preparation of chlorodifluoromethyl phenyl sulfone (2). Method A: Under N2 atmosphere, into a 500 mL three-neck flask containing N-chlorosuccinimide (16.0 g, 120 o mmol), PhSO2CF2H (3) (6.7 g, 35 mmol) and THF (140 mL) at −78 C, was added LHMDS (90 mmol, dissolved in 60 mL of THF) dropwise via a needle over a period of 18 min, followed by stirring at −78oC for additional 2 h. Then the reaction was quenched o by adding excess amount of saturated NH4Cl (aqueous solution) at −78 C, followed by extraction with diethyl ether. The organic phase was washed with brine and then dried over anhydrous MgSO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography using a mixture of ethyl acetate and petroleum ether (1:30, v/v) as eluent to give product 2 (6.3 g; yield: 79%) as a colorless liquid. IR (film): 3073, 1585, 1451, 1365, 1190, 1120, 1079, -1 1 930, 757, 719, 684, 657, 606, 582, 551, 428 cm . H NMR (CDCl3, 300 MHz): δ 7.67 (t,

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19 J = 16.2 Hz, 2H), 7.84 (t, J = 15.3 Hz, 1H), 8.05 (d , J = 8.1 Hz, 2H). F NMR (CDCl3, 13 282 MHz): δ -63.0 (s, 2F). C NMR(CDCl3, 125 MHz): δ 136.3, 131.2, 130.8, 129.7, 126.4 (t, J = 333.6 Hz). MS (EI, m/z, %): 226 (M+, 0.57), 77 (100.00). HRMS (EI): calcd. for C7H5F2O2ClS: 225.9667; Found: 225.9670. Method B: (a) Under N2 atmosphere, thioanisole (4) (15.86 g, 114 mmol), tetrachloromethane (10 mL), and PCl5 (0.53 g, 2.5 mmol) were added into a 100-L three- neck flask equipped with a magnetic stirrer, a condensor with a gas outlet on the top, and a septum. With vigorous stirring of the solution at rt, chlorine gas was bubbled slowly into the mixture via a teflon needle. Immediately, an exothermic reaction occurred and HCl gas evolved, which was collected and neutralized by NaOH solution through the gas outlet. After the mixture was stirred for 1 h, the reaction mixture was further stirred at 80oC for 10 h (with chlorine gas was keeping passing through the reaction mixture). The progress of the chlorination process was monitored by 1H NMR until all of the thioanisole was consumed. Then CH2Cl2 (20 mL) was added, and the mixture was washed with H2O and saturated NaHCO3 aqueous solution. The separated organic phase was further washed with brine and dried over anhydrous MgSO4. After filtration and removal of the solvent under vacuum, trichloromethyl phenyl sulfide (5) was obtained through fractional vaccum distillation (bp: 86-87oC/1mmHg): 22.56 g (99.18 mmol, 87% yield). (b) Into a 250-mL round-bottom teflon flask, was added a magnetic stirrer and 50 g of Olah’s reagent (molar ratio: HF/pyridine = 10:1). Thereafter, trichloromethyl phenyl sulfide 5 (10 g, 44.15 mmol) was slowly added to the HF-pyridine solution at 20oC, and a gas-outlet was placed on the top of the reaction flask for the purpose of HCl gas collection. The reaction mixture was stirred for 4 h at rt, and the progress of fluorination was monitored by 19F NMR. After the reaction was finished, the reaction mixture was poured into iced water, and extracted with cold CH2Cl2 (200 mL x 3). The combined organic phase was washed with cold saturated NaHCO3 aqueous solution and brine, successively. After drying over MgSO4 and solvent removal, crude chlorodifluoromethyl phenyl sulfide (6) (19F NMR: δ -27 ppm, (s)) was obtained (purity > 94%, determined by NMR). The impurities were mainly PhSCF3 and PhSCClF2. (c) To a 250-mL round-bottom flask with a magnetic stirrer containing the above- obtained crude product (6), were added CH3CN (75 mL), CCl4 (75 mL), H2O (150 mL), NaIO4 (40 g) and ruthenium trichloride hydrate (150 mg). The resulting mixture was stirred at rt for 10 h. The completion of the reaction was monitored by 19F NMR. Thereafter, 150 mL of water was added, and the resulting reaction mixture was extracted with ether (150 mL x 2). The combined organic phase was washed successively with saturated NaHCO3 and NaCl solutions. After drying over anhydrous MgSO4 and solvent removal, the crude product 2 was further purified by silica gel column chromatography (pet ether/ethyl acetate = 50:1 v/v) to give 8.153 g chlorodifluoromethyl phenyl sulfone as a colorless liquid (96% purity, determined by 1H and 19F NMR; the main impurity was

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1 19 PhSO2CF3), yield for 2 steps: 78%. The H and F NMR data showed that the product was identical to compound 2 prepared via preparative method A (see above).

We applied this chlorodifluoromethyl phenyl sulfone sample 2 (with 4% PhSO2CF3 impurity) in the O- and N-difluoromethylation reactions, and found that it worked equally well as pure compound 2.

Typical procedure for difluoromethylation using chlorodifluoromethyl phenyl sulfone (2). Into a pressure tube containing a mixture of 1-naphthol (7n) (144 mg, 1.0 mmol), chlorodifluoromethyl phenyl sulfone 2 (521 mg, 2.3 mmol), CH3CN (7 mL) and a magnetic stirrer, was added aqueous KOH (25 wt.%, 2 mL, ca. 11 mmol). The pressure tube was then sealed with a cap. The reaction mixture was stirred at 50 oC for 5 h. After cooling to RT, the mixture was extracted with Et2O (25 mL x 3), and the combined organic layers were dried over anhydrous MgSO4. After the removal of solvents under vacuum, the crude product was further purified by silica gel column chromatography to give product 8n as a colorless liquid, yield: 79% (153 mg). Colorless liquid. 1H

NMR(CDCl3, 300 MHz): δ 6.67 (t, J = 73.8 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.56 (t, J = 8.1 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.86 (t, J = 5.1 Hz, 1H), 19 8.19 (t, J = 5.4 Hz, 1H). F NMR (CDCl3, 282 MHz): δ -79.83 (d, J = 74.8 Hz, 2F). The characterization data was consistent with reference.10

Characterization date for the isolated compounds:

19 1-(Difluoromethoxy)benzene (8a): F NMR (CDCl3, 282 MHz): δ -82.71 (d, J = 75.3 Hz, 2F). The characterization data were consistent with those reported in reference.5

1 1-(Difluoromethoxy)-2-iodobenzene (8b): Colorless liquid. H NMR (CDCl3, 300 MHz): δ 6.52 (t, J = 73.2 Hz, 1H), 6.96 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 9.0Hz, 1H), 7.35 (t, J = 19 8.1 Hz, 1H), 7.85(d, J = 8.1Hz, 1H). F NMR (CDCl3, 282 MHz): δ -81.36 (d, J = 72.8 Hz, 2F). The characterization data was consistent with reference.10

1 1-(Difluoromethoxy)-4-iodobenzene (8c): Colorless liquid. H NMR (CDCl3, 300 MHz): δ 6.48 (t, J = 73.5 Hz, 1H), 6.89 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 9.0Hz, 2H). 19F NMR

(CDCl3, 282 MHz): δ -81.18 (d, J = 73.6 Hz, 2F). The characterization data was consistent with reference.2

1 1-Bromo-4-(difluoromethoxy)benzene (8d): Colorless liquid. H NMR (CDCl3, 300 MHz): δ 6.49 (t, J = 73.5 Hz, 1H), 7.02 (d, J = 12.0 Hz, 2H), 7.48 (d, J = 15.0 Hz, 2H). 19 F NMR (CDCl3, 282 MHz): δ -81.60 (d, J = 73.1 Hz, 2F). The characterization data were consistent with those reported previously.2

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1 1-Chloro-4-(difluoromethoxy)benzene (8e): Colorless liquid. H NMR (CDCl3, 300 MHz): δ 6.48 (t, J = 73.2 Hz, 1H), 7.08 (d, J = 12.0 Hz, 2H), 7.33 (d, J = 11.7 Hz, 2H). 19 F NMR (CDCl3, 282 MHz): δ -81.58 (d, J = 73.1 Hz, 2F). The characterization data was consistent with previous report.3

1 1-(Difluoromethoxy)-2-nitrobenzene (8f): Yellow liquid. H NMR (CDCl3, 300MHz): δ 6.63 (t, J = 147.0 Hz, 1H), 7.39 (t, J = 6.0 Hz, 2H), 7.63 (t, J = 9.1 Hz, 1H), 7.93 (d, J = 19 7.8 Hz, 1H). F NMR (CDCl3, 282 MHz): δ -82.01 (d, J = 73.4 Hz, 2F). The characterization data was consistent with previous report.4

1 1-(Difluoromethoxy)-4-nitrobenzene (8g): Yellow liquid. H NMR (CDCl3, 300 MHz): δ 6.63 (t, J = 72.0 Hz, 1H), 7.26 (d, J = 9.0 Hz, 2H), 8.26 (d, J = 15.3 Hz, 2H). 19F NMR

(CDCl3, 282 MHz): δ -82.49 (d, J = 71.7 Hz, 2F). The characterization data was consistent with reference.5

1-tert-Butyl-4-(difluoromethoxy)benzene (8h): Colorless liquid. IR (film): 2967, 1608, -1 1 1513, 1382, 1231, 1137 cm . H NMR (CDCl3, 300 MHz): δ 6.48 (t, J = 74.8 Hz, 1H), 19 7.04 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 9.3 Hz, 2H), 1.31 (s, 9H). F NMR (CDCl3, 282 13 MHz): δ -80.37 (d, J = 73.4, 2F). C NMR (CDCl3, 125 MHz): δ 149.0, 148.4, 126.7, 119.1, 116.2 (t, J = 257.3 Hz), 34.4, 31.4. MS (EI, m/z, %): 200 (M+, 13.11), 185

(100.00). Anal. calcd. for C11H14F2O: C, 65.98; H, 7.05; Found: C, 65.84; H, 7.35.

o 1 1-(Difluoromethoxy)-3-phenylbenzene (8i): White solid, mp. 26-28 C. H NMR (CDCl3, 300 MHz): δ 7.56 (t, J = 6.9 Hz, 4H), 7.44 (t, J = 7.8 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 19 7.19 (d, J = 8.4 Hz, 2H), 6.55 (t, J = 73.8 Hz, 1H). F NMR (CDCl3, 282 MHz): δ -81.07 (d, J = 71.7 Hz, 2F). The characterization data was consistent with reference.10

19 1-(difluoromethoxy)-2-methoxybenzene (8j): F NMR (CDCl3, 282MHz): δ -82.69 (d, J = 72.7, 2F).

1 2,4-Dichloro-1-(difluoromethoxy)benzene (8k): Colorless liquid. H NMR (CDCl3, 300 MHz): δ 6.51(t, J = 73.1 Hz, 1H), 7.17-7.26 (m, J = 29.2 Hz, 2H), 7.46 (d , J = 2.5 Hz, 19 1H). F NMR (CDCl3, 282 MHz): δ -81.68 (d, J = 71.1 Hz, 2F). The characterization data was consistent with previous report.6

1,3,5-Tribromo-2-(difluoromethoxy)benzene (8l): White solid. Mp. 65-66oC; 1H NMR 19 (CDCl3, 300 MHz): δ 7.74 (s, 2H), 6.59 (t, J = 73.8 Hz, 1H). F NMR (CDCl3, 282 MHz): δ -81.31 (d, J = 71.7 Hz, 2F). The characterization data was consistent with reference.10

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(E)-1-Difluoromethoxy-4-styrylbenzene (8m): White solid. Mp. 95-96 oC. 1H NMR

(CDCl3, 300 MHz): δ 7.51 (d, J = 8.4 Hz, 4H), 7.37 (d, J = 7.8 Hz, 2H), 7.27 (t, J = 6.9 19 Hz, 1H), 7.10 (d, J = 9.9 Hz, 4H), 6.52 (t, J = 73.5 Hz, 1H). F NMR (CDCl3, 282 MHz): δ -82.53 (d, J = 74.7 Hz, 2F). The characterization data was consistent with reference.10

1 1-(Difluoromethoxy)naphthalene (8n): Colorless liquid. H NMR(CDCl3, 300 MHz): δ 6.67 (t, J = 73.8 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.56 (t, J = 8.1 Hz, 2H), 7.71 (d, J = 8.4 Hz, 1H), 7.86 (t, J = 5.1 Hz, 1H), 8.19 (t, J = 5.4 Hz, 1H). 19 F NMR (CDCl3, 282 MHz): δ -79.83 (d, J = 74.8 Hz, 2F). The characterization data was consistent with reference.10

1 2-(difluoromethoxy)naphthalene (8o): Colorless liquid. H NMR (CDCl3, 300 MHz): δ 6.63 (t, J = 74.1 Hz, 1H), 7.25-7.30 (m, J = 15.0 Hz, 1H), 7.44-7.54 (m, J = 30.0 Hz, 3H), 19 7.79-7.86 (m, J = 23.6 Hz, 3H). F NMR (CDCl3, 282 MHz): δ -79.83 (d, J = 74.8 Hz, 2F). The characterization data was consistent with previous reports.5,6

8-(Difluoromethoxy)quinoline (8p): White solid, m.p. 70-73oC. IR (film): 3097, 1584, 1452, 1362, 1189, 1120, 1077, 931, 760, 719, 685, 655, 582, 551, 429 cm-1. 1H NMR

(CDCl3, 300 MHz): δ 7.10 (t, J = 75.3 Hz, 1H), 7.46-7.53 (m, 3H), 7.69-7.72 (m, 1H), 19 8.21 (d, J = 10.2 Hz, 1H), 8.98 (d, J = 6.0 Hz, 1H). F NMR (CDCl3, 282 MHz): δ - 13 81.85 (d, J = 73.9 Hz, 2F). C NMR(CDCl3, 125MHz): δ 150.5, 147.0, 136.2, 129.7, 126.4, 125.3, 122.0, 119.8, 119.0, 116.5 (t, J = 258 Hz). MS (EI, m/z, %): 195 (M+, 7.00),

129 (100.00). Anal. calcd. for C10H7F2ON: C, 61.25; H, 3.68; N, 9.92; Found: C, 61.54; H, 3.62; N, 7.18.

1-(Difluoromethyl)-1H-benzo[d]imidazole (13a): White solid, m.p. 40-41 oC. 1H NMR

(CDCl3, 300MHz): δ 7.34 (t, J = 60.3 Hz, 1H), 7.36-7.43 (m, 2H), 7.60-7.63 (m, 1H), 19 7.84-7.87 (m, 1H), 8.14 (m, 1H). F NMR (CDCl3, 282 MHz): δ -93.7 (d, J = 61.1, 2F). The characterization data was consistent with previous report.9

1-(Difluoromethyl)-2-phenyl-1H-imidazole (13b): White solid, m.p. 67-68 oC . 1H NMR

(CDCl3, 300 MHz): δ 7.07 (t, J = 59.9 Hz, 1H), 7.23 (s, 1H), 7.40 (s, 1H), 7.50-7.53 (m, 19 3H), 7.58-7.62 (m, 2H). F NMR (CDCl3, 282 MHz): δ -90.44 (d, J = 59.7, 2F). The characterization data was consistent with previous report.8

o 1 1-Difluoromethyl-1H-benzotriazole (13c): White solid, mp. 38–40 C. H NMR (CDCl3, 300 MHz): δ 7.48–7.53 (m, 1H), 7.62–7.67 (m, 1H), 7.83 (d, J = 8.5Hz, 1H), 7.86 (t, J = 19 58.3 Hz, 1H, CHF2), 8.14–8.16 (m, 1H). F NMR (CDCl3, 282 MHz): δ -103.1 (d, J = 58.3 Hz, 2F). The characterization data was consistent with previous report.7

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4-Benzoyl-2-(difluoromethyl)-3-methyl-1-phenyl-1,2-dihydropyrazol-5-one (13d): White solid, m.p. 44 oC. IR (KBr): 1641, 1599, 1552, 1505, 1469, 1386, 1309, 1250, 1151, 1088, 1041, 935, 906, 869, 800, 767, 733, 693, 661, 488 cm-1. 1H NMR (CDCl3, 300 MHz): δ 2.23 (s, 3H), 6.73 (t, J = 73.0 Hz, 1H), 7.39-7.44 (m, 1H), 7.47-7.54 (m, 4H), 7.58-7.68 19 (m, 3H), 7.80-7.83 (m, 2H). F NMR (CDCl3, 282 MHz): δ -82.82 (d, J = 74.0 Hz, 2F). 13 C NMR (CDCl3, 125 MHz): δ 15.0, 109.8, 112.7, 116.3 (t, J = 269.0 Hz), 123.7, 128.3, 128.6, 129.3, 129.2, 133.0, 137.0, 138.4, 149.7. MS (ESI, m/z): 329.2 ( M++H+), HRMS + + (ESI) calcd. For C18H14F2N2O2: ( M +H ): 328.1023; Found: 328.1096.

2-(Difluoromethyl)-1-phenylpyrazolidin-3-one (13e): Colorless liquid. IR (film): 2932, 2270, 1686, 1651, 1601, 1503, 1407, 1350, 1254, 1141, 1084, 751, 693, 658 cm-1. 1H

NMR (CDCl3, 300 MHz): δ 3.02 (t, J = 9.8 Hz, 2H), 3.83 (t, J = 9.8 Hz, 2H), 6.84-6.89 (m, 1H), 6.92-6.98 (m, 2H), 7.11 (t, J = 72.1 Hz, 1H), 723-7.29 (m, 2H). 19F NMR 13 (CDCl3, 282 MHz): δ -87.11 (d, J = 72.2 Hz, 2F). C NMR (CDCl3, 125 MHz): δ 30.5, 50.5, 114.2 (t, J = 259.3 Hz), 114.3, 119.7, 129.1, 148.0, 156.6. MS (EI, m/z, %): 212 + (M , 31.63), 77 (100.00). HRMS (EI): calcd. for C10H10F2N2O: 212.0761; Found: 212.0770.

1-Bromo-3-chloro-5-(difluoromethoxy)benzene (16): Colorless liquid. IR (film): 1588, -1 1 1574, 1429, 1380, 1222, 1123, 1060, 938, 850, 780, 667, 419, 410 cm . H NMR (CDCl3, 300 MHz): δ 6.42 (t, J = 72.7 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 7.13 (d, J = 1.9 Hz, 1H), 19 13 7.29-7.31 (m, 1H). F NMR (CDCl3, 282 MHz): δ -81.67 (d, J = 71.8 Hz, 2F). C NMR (CDCl3, 125 MHz): δ 115.3 (t, J = 264.6 Hz), 119.2, 121.5, 123.0, 128.7, 135.9, 151.6. + MS (EI, m/z, %): 256 (M , 59.27), 208 (100.00). HRMS (EI): calcd. for C7H4F2ClBrO: 255.9102; Found: 255.9103. EA: calcd. for C7H4F2ClBrO: C, 32.66; H, 1.57; Found: C, 33.5; H, 1.76.

2-(3-Chloro-5-(difluoromethoxy)phenyl)-1,3-dioxolane (17): Colorless liquid. IR (film): 3089, 2894, 1590, 1453, 1381, 1308, 1268, 1177, 1121, 1051, 1001, 970, 942, 861, 687, -1 1 550, 471 cm . H NMR (CDCl3, 300 MHz): δ 4.31-4.43 (m, 4H), 6.09 (s, 1H), 6.82 (t, J 19 = 73.2 Hz, 1H), 7.45 (s, 1H), 7.64 (s, 1H). F NMR (CDCl3, 282 MHz): δ -80.97 (d, J = 13 73.6 Hz, 2F). C NMR (CDCl3, 125 MHz): δ 65.4, 102.2, 115.6 (t, J = 261.7 Hz), 115.8, 120.6, 123.8, 135.2, 141.9, 151.6. MS (EI, m/z, %): 250 (M+, 16.33), 73 (100.00). Anal. calcd. for C10H9F2ClO3: C, 47.92; H, 3.62; Found: C, 48.04; H, 3.71.

______References: 1. (a) Prakash, G. K. S.; Hu, J.; Olah, G. A.; Org. Lett. 2003, 5, 3253–3256; and the references cited therein. (b) Prakash, G. K. S.; Hu, J.; Wang,Y.; Olah, G. A. Org. Lett. 2004, 6, 4315–4317.

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2. Shelyazhenko, S. V.; A Fialkov, Y.; Yagupol'skii, L. M. J. Org. Chem. USSR (Engl.Transl). 1992, 28, 1317–1324. 3. (a) Langlois, B. R. J. Fluorine Chem. 1988, 41, 247–262. (b) Rico, I.; Wakselman, C. Tetrahedron. 1981, 37, 24, 4209–4214. 4. Xiao, W.; Krishnan, R.; Lin, Y.-I.; Santos. E.; Delos, F.; Kuck, N. A. et al, J. Pharm. Sci. 1989, 78, 7, 585–588. 5. Chen, Q.-Y.; Wu, Sh.-W. J. Fluorine Chem. 1989, 44, 433–440. 6. Miller, T. J. Org. Chem. 1960, 25, 2009–2012. 7. Lyga, J. W.; Patera, R. M. J. Fluorine Chem. 1998, 92, 141–146. 8. Bissky, G.; Roeschenthaler, G.-V.; Lorka, E.; Barten, J.; Medebielle, M.; Staninets, V.; Vasilij, K.; Alexander, A. J. Fluorine Chem. 2001, 109, 173–182. 9. Jonczyk, A.; Nawrot, E.; Kisielewski, M. J. Fluorine Chem. 2005, 126, 1587–1591. 10. Zhang,L.; Zheng, J.; Hu, J.; J. Org. Chem.. 2006, 71, 9845-9848.

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1H, 13C, and 19F NMR spectra of all new products

O F S Cl O F

1 2 H NMR (CDCl3)

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O F S Cl O F

19 2 F NMR (CDCl3)

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O F S Cl O F

13 2 C NMR (CDCl3)

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HF2CO

1 8h H NMR (CDCl3)

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HF2CO

19 8h F NMR (CDCl3)

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HF2CO

13 8h C NMR (CDCl3)

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OCF2H 1 8p H NMR (CDCl3)

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OCF2H 19 8p F NMR (CDCl3)

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OCF2H 13 8p C NMR (CDCl3)

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H F F N N

O O 1 13d H NMR (CDCl3)

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H F F N N

O O 19 13d F NMR (CDCl3)

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H F F N N

O O 13 13d C NMR (CDCl3)

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H F F N O N

1 13e H NMR (CDCl3)

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H F F N O N

19 13e F NMR (CDCl3)

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H F F N O N

13 13e C NMR (CDCl3)

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Cl Br

OCF2H 1 16 H NMR (CDCl3)

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Cl Br

OCF2H 19 16 F NMR (CDCl3)

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Cl Br

OCF2H 13 16 C NMR (CDCl3)

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O Cl O

OCF2H 1 17 H NMR (CDCl3)

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O Cl O

OCF2H 19 17 F NMR (CDCl3)

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O Cl O

OCF2H 13 17 C NMR (CDCl3)

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1H and 19F NMR spectra of all (known) liquid products

OCF2H 1 8b H NMR (CDCl3)

7.865 7.838 7.375 7.350 7.348 7.322 7.259 7.257 7.254 7.173 7.145 6.993 6.989 6.967 6.962 6.938 6.763 6.762 6.758 6.519 6.517 6.513 6.274 6.272 1.549 1.546 1.253 -0.001 -0.005

0.96 0.98 0.98 0.99 1.00

8 6 4 2 0 PP

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OCF2H 19 8b F NMR (CDCl3)

-80.789 -81.049

-75 -80 -85 -90 PP

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I OCF2H

1 8c H NMR (CDCl3)

7.681 7.678 7.658 7.652 7.256 6.901 6.874 6.724 6.722 6.480 6.477 6.235 6.232 1.544 1.540 1.253

2.00 2.00

1.09

8 6 4 2 0 PP

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I OCF2H

19 8c F NMR (CDCl3)

-81.037 -81.297

-70 -75 -80 -85 -90 PP

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Br OCF2H

1 8d H NMR (CDCl3)

7.495 7.489 7.479 7.473 7.466 7.262 7.042 7.031 7.003 6.731 6.486 6.241 1.579 -0.001

2.00 2.03

0.95

8 7 6 5 4 3 2 1 0 PP

33 Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2007

Br OCF2H

19 8d F NMR (CDCl3)

-81.473 -81.734

-78 -80 -82 -84 -86 PP

34 Supplementary Material (ESI) for Chemical Communications This journal is © The Royal Society of Chemistry 2007

Cl OCF2H

1 8e H NMR (CDCl3)

7.347 7.341 7.339 7.323 7.316 7.308 7.261 7.098 7.088 7.058 6.728 6.483 6.238 1.578 -0.000

2.00 1.97

0.95

7 6 5 4 3 2 1 0 PP

Cl OCF2H

19 8e F NMR (CDCl3)

-81.446 -81.707

-77 -78 -79 -80 -81 -82 -83 -84 -85 -86 PP

OCF2H

NO2

1 8f H NMR (CDCl3)

952 . 7 7.945 7.941 7.924 7.918 7.913 7.662 7.656 7.649 7.635 7.628 7.609 7.603 7.597 7.420 7.417 7.390 7.373 7.365 7.362 7.263 7.257 6.871 6.865 6.628 6.622 6.385 6.378 1.561 1.555 1.427 1.422 1.252 -0.000 -0.007

2.01

1.01 0.97 1.00

8 7 6 5 4 3 2 1 0 PP

OCF2H

NO2

19 8f F NMR (CDCl3)

-81.882 -82.144

-76 -78 -80 -82 -84 -86 -88 PP

O2N OCF2H

1 8g H NMR (CDCl3)

8.290 8.282 8.267 8.258 8.249 8.239 7.274 7.263 7.253 7.244 6.876 6.867 6.856 6.636 6.626 6.615 6.396 6.387 6.380 6.375 1.557 1.258 0.000 -0.010

2.18 1.99

1.00

8 6 4 2 0 PP

O2N OCF2H

19 8g F NMR (CDCl3)

-82.365 -82.620

-76 -78 -80 -82 -84 -86 -88 PP

OCF2H Cl

Cl 1 8k H NMR (CDCl3)

7.468 7.461 7.271 7.262 7.242 7.235 7.203 7.174 6.760 6.516 6.272 1.578 -0.001

2.15

0.93 1.00

8 7 6 5 4 3 2 1 0 PP

OCF2H Cl

Cl 19 8k F NMR (CDCl3)

-81.989 -82.247

-77 -78 -79 -80 -81 -82 -83 -84 -85 PP

OCF2H

1 8n H NMR (CDCl3)

8.204 8.190 8.172 7.879 7.873 7.862 7.857 7.847 7.719 7.691 7.589 7.571 7.567 7.555 7.547 7.540 7.523 7.445 7.418 7.392 7.253 7.251 7.207 7.182 6.912 6.665 6.419 1.537 1.535 1.254 -0.001 -0.004

1.99

1.00 1.01 1.02 1.02 1.00 1.00

8 7 6 5 4 3 2 1 0 PP

OCF2H

19 8n F NMR (CDCl3)

-79.701 -79.968

-74 -76 -78 -80 -82 -84 -86 -88 PP

OCF2H

1 8o H NMR (CDCl3)

7.857 7.826 7.807 7.781 7.533 7.510 7.490 7.484 7.459 7.435 7.296 7.289 7.266 7.260 7.249 6.869 6.622 6.376 1.542 -0.001

3.01 3.04

1.24 1.00

8 7 6 5 4 3 2 1 0 PP

OCF2H

19 8o F NMR (CDCl3)

-80.425 -80.690

-77 -78 -79 -80 -81 -82 -83 -84 -85 -86 PP