Facile Preparation of 2-Iodophenyl Trifluoromethanesulfonates: Superior Aryne Precursors

Abstract

A comparative study of 3-methoxyaryne precursors ­revealed 2-iodo-3-methoxyphenyl triflate as the most effective in nonpolar solvent. Use of Hoppe’s N-isopropyl carbamate allows for the systematic preparation of a variety of 2-iodophenyl triflates via a ­directed ortho-lithiation-iodination-decarbamation sequence. These steps are possible without isolation of the intermediate ­iodophenyl carbamates.

Key words

arynes - carbamate - halogenation - iodophenyl triflate - metalations

References and Notes

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15

General Procedure for the Preparation of 2-Iodophenols 11-20
To a solution of the carbamate (2.5 mmol) dissolved in dry Et₂O (25 mL) under argon was added TMEDA (1.1 equiv, 2.75 mmol) at 0 °C. Then TMSOTf (1.1 equiv, 2.75 mmol) was slowly added to the solution and the reaction mixture was allowed to warm to r.t. over a period of 30 min. After cooling the solution to -78 °C, TMEDA (2.0 equiv, 5.0 mmol) was added followed by the dropwise addition of n-BuLi or t-BuLi (2.0-2.5 equiv, 5.0-6.2 mmol). The reaction mixture was stirred for 1 h and was then treated with I₂ (1.0 equiv, 2.5 mmol) dissolved in THF (3 mL). After reacting for 2 h, EtOH (0.25 mL) was added and the solvent was removed by rotary evaporation. The resultant residue was dissolved in EtOH (25 mL) and treated with 5 mL of aq 2 N NaOH (4 equiv, 10 mmol). The reaction proceeded for 2 h, after which the pH was adjusted to 6-8 with 2 N HCl. The aqueous layer was extracted with Et₂O (3 × 25 mL) and the combined organic layers were washed with a 1 M solution of Na₂S₂O₃ (25 mL), then dried and filtered. Upon concen-tration, the resulting residue was purified using flash chromatography (hexane-EtOAc, 95:5 to 9:1) affording the desired 2-iodophenol.

16

General Procedure for the Preparation of 2-Iodophenyl Triflates 21-30
To a -78 °C solution of 2-iodophenol (1.0 mmol) in CH₂Cl₂ (3 mL) was added anhydrous i-Pr₂NEt (1.25 mmol) and Tf₂O (1.25 mmol). After 10 min, the cooling bath was removed and the reaction mixture was allowed to warm to r.t. The reaction was quenched with H₂O (5 mL) after 1-2 h, and the aqueous phase was extracted with Et₂O (3 × 5 mL). The combined organic layers were dried and concentrated. The crude material was then purified by flash chromatog-raphy (100% hexane to hexane-EtOAc, 98:2) or recrystal-lized from hexane to afford the desired 2-iodophenyl triflate.

17

Compound 2: white solid, mp 54-55 °C. IR (neat): 3441 (m), 1734 (s), 1507 (m), 908 (m), 732 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.16 (t, J = 8.2 Hz, 1 H), 6.66 (dt, J = 5.0, 2.0 Hz, 2 H), 6.62 (t, J = 2.0 Hz, 1 H), 4.79 (d, J = 0.7 Hz, 1 H), 3.82 (dt, J = 13.2, 6.4 Hz, 1 H), 3.72 (s, 3 H), 1.16 (d, J = 6.5 Hz, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 160.3, 153.5, 152.0, 129.5, 113.8, 111.1, 107.5, 55.3, 43.4, 22.8. HRMS (EI): m/z [M]⁺ calcd for C₁₁H₁₅NO₃: 209.1052; found: 209.1056.

18

Compound 3: white solid, mp 105-106 °C. IR (neat): 3343 (m), 1739 (s), 1608 (m), 739 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 6.96 (d, J = 8.0 Hz, 1 H), 6.75 (s, 1 H), 6.71 (d, J = 8.0 Hz, 1 H), 4.97 (d, J = 4.0 Hz, 1 H,), 3.86 (td, J = 6.7, 13.1 Hz, 1 H), 3.81 (s, 3 H), 2.32 (s, 3 H), 1.20 (d, J = 6.5 Hz, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 153.5, 151.1, 137.6, 136.0, 122.7, 120.9, 113.1, 55.7, 43.3, 22.7, 21.2. HRMS (EI): m/z [M]⁺ calcd for C₁₂H₁₇NO₃: 223.1208; found: 223.1210.

19

Compound 5: white solid, mp 151-152 °C. IR (neat): 3391 (m), 1738 (s), 1502 (s), 847 (w), 746 (s) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.55 (d, J = 7.5 Hz, 4 H), 7.42 (t, J = 7.4 Hz, 2 H), 7.33 (t, J = 7.1 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 2 H), 4.89 (d, J = 4.9 Hz, 1 H), 3.91 (dd, J = 12.8, 6.3 Hz, 1 H), 1.24 (d, J = 6.3 Hz, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 153.6, 150.4, 140.5, 138.3, 128.7, 127.9, 127.1, 127.0, 121.8, 43.4, 22.8. HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₇NO₂: 255.1259; found: 255.1259.

21

Compound 7: white solid, mp 123-124 °C. IR (neat): 3326 (br), 1739 (s), 1495 (s), 845 (s), 746 (s) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.04 (td, J = 8.6, 16.7 Hz, 4 H), 4.98 (s, 1 H), 3.87 (dd, J = 6.5, 13.1 Hz, 1 H), 1.20 (d, J = 6.4 Hz, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 159.7 [d, J(CF) = 243.2 Hz], 153.6, 146.8 [d, J(CF) = 2.6 Hz], 122.9 [d, J(CF) = 8.4 Hz], 115.6 [d, J(CF) = 23.4 Hz], 43.4, 22.7. HRMS (EI): m/z [M]⁺ calcd for C₁₀H₁₂FNO₂: 197.0852; found: 197.0853.

22

Compound 8: white solid, mp 85-86 °C. IR (neat): 3433 (m), 1601 (s), 1508 (m), 748 (s) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.29 (dd, J = 8.3, 15.3 Hz, 1 H), 6.91 (ddd, J = 6.0, 8.1, 6.6 Hz, 3 H), 4.84 (d, J = 0.9 Hz, 1 H), 3.89 (qd, J = 6.6, 13.4 Hz, 1 H), 1.24 (d, J = 6.6 Hz, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 162.7 [d, J(CF) = 246.6 Hz], 153.0, 151.9 [d, J(CF) = 11.0 Hz], 129.8 [d, J(CF) = 9.4 Hz], 117.2 [d, J(CF) = 2.0 Hz], 112.0 [d, J(CF) = 21.1 Hz], 109.5 [d, J(CF) = 24.3 Hz], 43.4, 22.7. HRMS (EI): m/z [M]⁺ calcd for C₁₀H₁₂FNO₂: 197.0852; found: 197.0850.

23

Compound 9: white solid, mp 119-120 °C. IR (neat): 3316 (br), 1739 (s), 1535 (s), 814 (m), 700 (s) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.36 (m, 3 H), 7.25 (d, J = 7.0 Hz, 1 H), 4.93 (d, J = 3.9 Hz, 1 H), 3.81 (qd, J = 13.5, 6.6 Hz, 1 H), 1.15 (d, J = 6.6 Hz, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 153.0, 151.1, 131.6 [q, J(CF) = 32.8 Hz], 129.6, 125.1, 125.1, 123.6 [q, J(CF) = 272.3 Hz], 121.7 [d, J(CF) = 3.7 Hz], 118.7 [dd, J(CF) = 3.6 Hz, J = 7.4 Hz], 43.5, 22.6. HRMS (EI): m/z [M]⁺ calcd for C₁₁H₁₂F₃NO₂: 247.0820; found: 247.0824.

24

Compound 10: white solid, mp 88-89 °C. IR (neat): 3339 (br), 1743 (s), 1490 (s), 804 (m), 743 (s) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.46 (m, 2 H), 7.41 (s, 1 H), 7.36 (d, J = 7.3 Hz, 1 H), 4.89 (d, J = 4.6 Hz, 1 H), 3.90 (qd, J = 6.7, 13.4 Hz, 1 H), 1.25 (d, J = 6.5 Hz, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 153.05, 151.1, 131.6 [q, J(CF) = 32.7 Hz], 129.6, 125.1, 123.6 [q, J(CF) = 272.3 Hz], 121.79 [d, J(CF) = 3.6 Hz], 118.7 [dd, J(CF) = 7.3, 3.5 Hz], 43.5, 22.6. HRMS (EI): m/z [M]⁺ calcd for C₁₁H₁₂F₃NO₂: 247.0820; found: 247.0822.

26

Compound is commercially available.

31

Compound 21: recrystallization from hexane, white solid, mp 79-80 °C. IR (neat): 3053 (m), 2987 (w), 1600 (m), 1573 (w), 1456 (m), 1423 (m), 1326 (m), 1265 (s), 1245 (m), 1218 (s), 1160 (m), 1139 (m), 1083 (m), 1059 (m), 1020 (w), 968 (m), 895 (m), 826 (m), 810 (m), 740 (s) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 6.54 (d, J = 2.45 Hz, 1 H), 6.42 (d, J = 2.47 Hz, 1 H), 3.88 (s, 3 H), 3.82 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 161.8, 160.4, 151.4, 118.6 [q, J(CF) = 318.5 Hz], 99.8, 98.1, 71.4, 56.8, 55.8. HRMS (EI): m/z [M]⁺ calcd for C₉H₈F₃IO₅S: 411.9089; found: 411.9106.

32

Compound 23: viscous liquid. IR (neat): 2946 (w), 1590 (s), 1504 (s), 1461 (s), 1421 (m), 1301 (m), 1211 (m), 1133 (m), 1041 (m), 946 (m), 873 (m), 836 (m), 798 (m), 769 (m) cm^-1. ¹H NMR (360 MHz, CDCl₃): δ = 7.23 (dd, J = 0.6, 1.8 Hz, 1 H), 6.77 (d, J = 1.3 Hz, 1 H), 3.84 (s, 3 H), 2.30 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 151.1, 140.7, 138.1, 131.6, 122.5, 118.7 [q, J(CF) = 321.0 Hz], 89.5, 56.1, 20.9. HRMS (EI): m/z [M]⁺ calcd for C₉H₈F₃IO₄S: 395.9140; found: 395.9142.

34

Compound 25: recrystallization from hexane, white needles, mp 41-42 °C. IR (neat): 2925 (w), 1583 (s), 1469 (s), 1425 (s), 1375 (m), 1247 (m), 1213 (s), 1172 (m), 1137 (m), 1031 (m), 885 (m), 833 (m), 798 (m), 761 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 8.10 (d, J = 2.2 Hz, 1 H), 7.60 (dd, J = 2.2, 8.6 Hz, 1 H), 7.53 (td, J = 1.8, 3.3 Hz, 1 H), 7.46 (td, J = 1.6, 15.0 Hz, 2 H), 7.46 (d, J = 1.6, 4.8 Hz, 1 H), 7.42 (td, J = 1.9, 4.8 Hz, 1 H), 7.38 (d, J = 8.6 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 149.5, 143.0, 139.1, 137.9, 129.1, 128.6, 128.5, 127.2, 122.0, 118.7 [q, J(CF) = 321.0 Hz], 89.4. HRMS (EI): m/z [M]⁺ calcd for C₁₃H₈F₃IO₃S: 427.9191; found: 427.9190.

35

Compound 26: liquid. IR (neat): 2960 (w), 1569 (s), 1461 (s), 1428 (s), 1371 (m), 1214 (m), 1174 (m), 1137 (m), 1101 (m), 1031 (m), 883 (m), 821 (m), 790 (m), 763 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.90 (d, J = 2.5 Hz, 1 H), 7.40 (dd, J = 2.5, 8.8 Hz, 1 H), 7.25 (d, J = 8.9 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 148.9, 140.0, 134.6, 130.1, 122.6, 118.6 [q, J(CF) = 320.7 Hz], 89.6. HRMS (EI): m/z [M]⁺ calcd for C₇H₃ClF₃IO₃S: 385.8488; found: 385.8497.

36

Compound 27: liquid. IR (neat): 2985 (w), 1588 (s), 1474 (s), 1428 (s), 1250 (m), 1226 (m), 1139 (m), 1029 (m), 907 (m), 856 (m), 817 (m), 734 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.61 (dd, J = 3.0, 7.3 Hz, 1 H), 7.29 (dd, J = 4.6, 9.1 Hz, 1 H), 7.14 (ddd, J = 3.0, 7.3, 9.1 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 160.8 [d, J(CF) = 254.0 Hz], 146.5 [d, J(CF) = 3.4 Hz], 127.5 [d, J(CF) = 25.6 Hz], 122.9 [d, J(CF) = 9.2 Hz], 118.7 [q, J(CF) = 320.6 Hz], 116.9 [d, J(CF) = 23.7 Hz], 89.4 [d, J(CF) = 8.8 Hz]. HRMS (EI): m/z [M]⁺ calcd for C₇H₃F₄IO₃S: 369.8772; found: 369.8778.

37

Compound 28: viscous liquid. IR (neat): 3154 (w), 1577 (m), 1457 (s), 1428 (s), 1281 (w), 1248 (m), 1220 (s), 1139 (s), 1096 (w), 1035 (w), 975 (s), 906 (s), 835 (m), 787 (m), 725 (s) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.43 (dt, J = 8.4, 6.1 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 1 H), 7.11 (ddd, J = 8.3, 7.2, 1.2 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 163.0 [d, J(CF) = 252.6 Hz], 151.0 [d, J(CF) = 4.5 Hz], 130.7 [d, J(CF) = 9.0 Hz], 118.7 [q, J(CF) = 320.7 Hz], 117.7 [d, J(CF) = 2.8 Hz], 115.3 [d, J(CF) = 24.2 Hz], 79.2 [d, J(CF) = 29.5 Hz]. HRMS (EI): m/z [M]⁺ calcd for C₇H₃F₄IO₃S: 369.8784; found: 369.8783.

38

Compound 29: recrystallization from hexane, white needles, mp 37-38 °C. IR (neat): 3154 (w), 1606 (s), 1479 (s), 1430 (s), 1398 (m), 1323 (m), 1246 (m), 1221 (m), 1140 (m), 1181 (m), 1080 (m), 1023 (m), 906 (m), 829 (m), 808 (m), 735 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 8.08 (d, J = 8.3 Hz, 1 H), 7.54 (d, J = 1.3 Hz, 1 H), 7.38 (dd, J = 8.3, 1.7 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 150.3, 141.6, 132.9 [q, J(CF) = 34.2 Hz], 126.1 [q, J(CF) = 3.5 Hz], 122.7 [q, J(CF) = 272.9 Hz], 119.1 [q, J(CF) = 3.6 Hz], 118.7 [q, J(CF) = 320.8 Hz], 94.1 [d, J(CF) = 0.9 Hz]. HRMS (EI): m/z [M - Tf]⁺ calcd for C₇H₃F₃IO: 286.9181; found: 286.9175.

39

Compound 30: recrystallization from hexane, white needles, mp 39-40 °C. IR (neat): 2985 (w), 1430 (s), 1399 (m), 1323 (m), 1265 (m), 1246 (m), 1221 (m), 1180 (m), 1139 (m), 1080 (m), 1023 (m), 906 (m), 808 (m), 729 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 8.08 (dd, J = 8.3, 0.5, Hz, 1 H), 7.54 (d, J = 1.4 Hz, 1 H), 7.38 (dd, J = 8.3, 1.3 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 150.3, 141.6, 132.8 [q, J(CF) = 34.2 Hz], 126.1 [q, J(CF) = 3.5 Hz], 122.7 [q, J(CF) = 272.7 Hz], 119.1 [q, J(CF) = 3.3 Hz], 118.6 [q, J(CF) = 320.7 Hz], 94.1. HRMS (EI): m/z [M - Tf]⁺ calcd for C₇H₃F₃IO: 286.9181; found: 286.9192.