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.

arynes - carbamate - halogenation - iodophenyl triflate - metalations

References and Notes

1a Matsumoto T. Hosoya T. Katsuki M. Suzuki K. Tetrahedron Lett.  1991,  32:  6735 

1b Matsumoto T. Hosoya T. Suzuki K. J. Am. Chem. Soc.  1992,  114:  3568 

1c Hosoya T. Takashiro E. Matsumoto T. Suzuki K. J. Am. Chem. Soc.  1994,  116:  1004 

1d Hamura T. Hosoya T. Yamaguchi H. Kuriyama Y. Tanabe M. Miyamoto M. Yasui Y. Matsumoto T. Suzuki K. Helv. Chim. Acta  2002,  85:  3589 

2a Himeshima Y. Sonoda T. Kobayashi H. Chem. Lett.  1983,  12:  1211 

2b Peña D. Escudero S. Pérez D. Guitián E. Castedo L. Angew. Chem. Int. Ed.  1998,  37:  2659 

2c Peña D. Pérez D. Guitián E. Castedo L. J. Am. Chem. Soc.  1999,  121:  5827 

3 Uchiyama M. Miyoshi T. Kajihara Y. Sakamoto T. Otani Y. Ohwada T. Kondo Y. J. Am. Chem. Soc.  2002,  124:  8514 

The successful formation of 2-methoxybenzyne by dehydro-halogenation of 3-chloroanisole at temperatures < -95 °C has been reported:

4a Iwao M. J. Org. Chem.  1990,  55:  3622 

4b Kaelin DE. Lopez OD. Martin SF. J. Am. Chem. Soc.  2001,  123:  6937 

5 For a seminal study of benzyne generation from ortho-dihalobenzenes using organolithium reagents, see: Gilman H. Gorsich RD. J. Am. Chem. Soc.  1957,  79:  2625 

6a Adejare A. Miller DD. Tetrahedron Lett.  1984,  25:  5597 

6b Grunewald GL. Kolar AJ. Palanki MSS. Paradkar VM. Reitz TJ. Sall DJ. Org. Prep. Proced. Int.  1990,  22:  747 

7a Giles RGF. Sargent MV. Sianipar H. J. Chem. Soc., Perkin Trans. 1  1991,  1571 

7b Giles RGF. Hughes AB. Sargent MV. J. Chem. Soc., Perkin Trans. 1  1991,  1581 

7c Baker RW. Baker TM. Birkbeck AA. Giles RGF. Sargent MV. Skelton BW. White AH. J. Chem. Soc., Perkin Trans. 1  1991,  1589 

8 The 2-iodophenyl tosylate reportedly serves as an efficient aryne precursor upon treatment with isopropylmagnesium chloride and warming in the presence of a nucleophile: Lin W. Ilgen F. Knochel P. Tetrahedron Lett.  2006,  47:  1941 

9a Srebnik M. Mechoulam R. Yona I. J. Chem. Soc., Perkin Trans. 1  1987,  1423 

9b Doad GJS. Barltrop JA. Petty CM. Owen TC. Tetrahedron Lett.  1989,  30:  1597 

9c Thomsen I. Torssell KBG. Acta Chem. Scand.  1991,  45:  539 

9d Barluenga J. Gonzàlez JM. García-Martín MA. Campos PJ. Asensio G. J. Org. Chem.  1993,  58:  2058 

9e Yonezawa S. Komurasaki T. Kawada K. Tsuri T. Fuji M. Kugimiya A. Haga N. Mitsumori S. Inagaki M. Nakatani T. Tamura Y. Takechi S. Taishi T. Ohtani M. J. Org. Chem.  1998,  63:  5831 

9f Yang SG. Kim YH. Tetrahedron Lett.  1999,  40:  6051 

9g Denieul MR. Laursen B. Hazell R. Skrydstup T. J. Org. Chem.  2000,  65:  6052 

9h Mukaiyama T. Kitagawa H. Matsuo J. Tetrahedron Lett.  2000,  41:  9383 

9i Narender N. Srinivasu P. Kulakarni SJ. Raghavan KV. Synth. Commun.  2002,  32:  2319 

9j Jereb M. Zupan M. Stavber S. Chem. Commun.  2004,  2614 

9k Krishna Mohan KVV. Narender N. Kulkarni SJ. Tetrahedron Lett.  2004,  45:  8015 

9l Patil BR. Bhusare SR. Pawar RP. Vibhute YB. Tetrahedron Lett.  2005,  46:  7179 

10 Kauch M. Hoppe D. Synthesis  2006,  1578 

11a Kauch M. Hoppe D. Can. J. Chem.  2001,  79:  1736 

11b Kauch M. Snieckus V. Hoppe D. J. Org. Chem.  2005,  70:  7149 

12 MacPhee JA. Panaye A. Dubois JE. Tetrahedron  1978,  34:  3553 

13 Sloan CP. Cuevas JC. Quesnelle C. Snieckus V. Tetrahedron Lett.  1988,  29:  4685 

14 Sanz R. Castroviejo MP. Fernández Y. Fañanás FJ. J. Org. Chem.  2005,  70:  6548 

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.

20 Patonay T. Patonay-Peli E. Mogyorodi F. Synth. Commun.  1990,  20:  2865 

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.

25 Weeratunga G. Jaworskasobiesiak A. Horne S. Rodrigo R. Can. J. Chem.  1987,  65:  2019 

26

Compound is commercially available.

27 Varma PS. Yasodhoda KM. J. Indian Chem. Soc.  1939,  16:  477 

28 Finger GC. Gortatowski MJ. Shiley RH. White RH. J. Am. Chem. Soc.  1959,  81:  94 

29 Mylari BL. Armento SJ. Beebe DA. Conn EL. Coutcher JB. Dina MS. O’Gorman MT. Linhares MC. Martin WH. Oates PJ. Tess DA. Withbroe GJ. Zembrowski WJ. J. Med. Chem.  2005,  48:  6326 

30 Selliah R. Dantanarayana A. Haggard K. Egan J. Do EU. May JA. J. Labelled Compd. Radiopharm.  2001,  44:  173 

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.

33 Qing FL. Fan J. Sun HB. Yue XJ. J. Chem. Soc., Perkin Trans. 1  1997,  3053 

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.