Synthesis of Enantiopure 2,5-Dihydro-3-iodofurans and Substituted 3-Iodofurans by Iodocyclization of 4-Hydroxy-1,2-alkadienyl Carbamates

Abstract

Enantiopure cis-2,5-dihydro-3-iodofurans and substitute­d 3-iodofurans were prepared by iodine-induced cyclization­ of enantiopure syn-4-hydroxy-1,2-alkadienyl carbamate­s. These products represent highly functionalized intermedi­ates which can be readily elaborated, for example, in transitio­n metal-catalyzed cross-coupling reactions.

Key words

furans - 2,5-dihydrofurans - stereoselective cyclization - enantiopure allenes - iodine

References

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• 2a Diederich F. Stang PJ. Metal-Catalyzed Cross-coupling Reactions   Wiley-VCH; Weinheim: 1998. 
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• 10a Dowle MD. Davies DI. Chem. Soc. Rev.  1979,  8:  171 
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• 11 Shingu K. Hagishita S. Nakagawa M. Tetrahedron Lett.  1967,  4371 
• X-ray crystal structure analysis of 7a: formula C₃₄H₄₁IN₂O₃, M = 652.59, colorless crystal, 0.35 × 0.30 × 0.30 mm, a = 13.950(1), b = 15.173(1), c = 15.538(1) Å, V = 3288.8(4) ų, ρ_calc = 1.318 g cm^{- 3}, µ = 10.07 cm^{- 1}, empirical absorption correction via SORTAV (0.719 T 0.752), Z = 4, orthorhombic, space group P ₂₁₂₁₂₁ (No. 19), λ = 0.71073 Å, T = 198 K, ω and φ scans, 21235 reflections collected (±h, ±k, ±l), [(sinθ/λ)] = 0.66 Å^{- 1}, 7690 independent (R_int = 0.034) and 6050 observed reflections [I 2σ(I)], 366 refined parameters, R = 0.041, ωR ² = 0.088, max. residual electron density 0.80 (-0.97) e Å^{- 3}, Flack parameter -0.03(2), hydrogens calculated and riding. Data set was collected with KappaCCD diffractometer, equipped with a rotating anode generator Nonius FR591. Programs used: data collection COLLECT (Nonius B.V., 1998), data reduction Denzo-SMN:
• 12a Otwinowski Z. Minor W. Methods Enzymol.  1997,  276:  307 
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• 12f Graphics SCHAKAL: Keller E. SCHAKAL   Universität Freiburg; Germany: 1997. 
• 12g

  Crystallogaphic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC-204009. Copies of the data can be obtained free of charge on application to The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: int. code [phone], e-mail: [e-mail]].

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1

X-ray structure analysis.

8

Zimmermann, M.; Hoppe, D., manuscript in preparation.

9

Typical Experimental Procedure and Spectral Data for 7 and 8:
NaI (1.1 equiv) was added to 4-hydroxy-1,2-alkadienyl carbamate 5 or 6 (1.0 equiv) in CH₂Cl₂-MeOH (3:1, 8 mL/mmol) under an Ar atmosphere at 0 °C in the dark. N-Chlorosuccinimide (1.0 equiv) in CH₂Cl₂ was added dropwise within 5 min. The solution was allowed to stir for 5 min at r.t. and diluted with Et₂O. The organic phase was washed with sat NaHCO₃ solution (1 ×), sat Na₂S₂O₃ solution (1 ×) and brine (1 ×). The organic phase was dried (MgSO₄), concentrated in vacuo and the residue purified by flash column chromatography [SiO₂, Et₂O-pentane, 5%(vol) Et₃N]. To remove the triethylamine, the collected fraction was washed with sat NH₄Cl solution (2 ×), dried (MgSO₄), and concentrated in vacuo to give the 2,5-dihydro-3-iodofurans 7 and 8, respectively.
7a: mp 140 °C (Et₂O); R_f = 0.59 (Et₂O-petroleum ether, 1:5); [α]_D ²⁰ = -4.2 (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ = 0.62 (br d, 6 H), 1.25 (s, 3 H), 1.28 (br s, 6 H), 2.93-2.99 (m, 1 H), 3.10-3.20 (m, 2 H), 3.39-3.57 (m, 2 H), 3.39, 4.14 (each d, ² J = 13.2 Hz, 4 H), 4.40-4.43 (m, 1 H), 6.73-6.77 (m, 1 H), 7.16-7.39 (m, 15 H); ¹³C NMR (100 MHz, CDCl₃): δ = 14.4, 20.5, 28.8, 45.9, 55.4, 60.2, 86.1, 88.3, 103.2, 125.9, 127.0, 128.1, 128.4, 129.7, 129.9, 139.9, 148.1, 152.9; Anal. Calcd for C₃₄H₄₁IN₂O₃ (652.61): C, 62.57; H, 6.33; N, 4.29. Found: C, 62.53; H, 6.34; N, 4.08.
8a: mp 111 °C (Et₂O); R_f = 0.33 (Et₂O-petroleum ether, 1:5); [α]_D ²⁰ = -1.4 (c 1.00, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 1.23 (br d, 12 H), 1.44 (s, 3 H), 2.58, 2.88 (each dd, ² J = 14.7 Hz, ³ J = 4.4 Hz, ³ J = 9.5 Hz, 2 H), 3.16 (ddd, ³ J = 1.1 Hz, ³ J = 4.4 Hz, ³ J = 9.5 Hz, 1 H), 3.62, 3.92 (each d, ² J = 14.1 Hz, 4 H), 3.86-4.01 (m, 2 H), 5.19-5.25 (m, ³ J = 1.1 Hz, 1 H), 6.86-6.89 (m, 1 H), 6.90-7.28 (m, 15 H); ¹³C NMR (100 MHz, CDCl₃): δ = 14.5, 21.1, 32.1, 46.1, 54.2, 59.0, 85.9, 87.5, 105.0, 125.7, 126.6, 127.9, 128.0, 128.6, 129.5, 139.9, 140.1, 147.6, 153.9; Anal. Calcd for C₃₄H₄₁IN₂O₃ (652.61): C, 62.57; H, 6.33; N, 4.29. Found: C, 62.59; H, 6.44; N, 4.40.
7b: mp 134 °C (Et₂O); R_f = 0.61 (Et₂O-petroleum ether = 1:5); [α]_D ²⁰ = -86.6 (c 1.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ = 0.63 (br d, ³ J = 54.1 Hz, 6 H), 0.93, 0.99 (each d, ³ J = 6.6 Hz, 6 H), 1.26 (br s, 6 H), 1.34 (s, 3 H), 1.51, 1.91 (each ddd, ² J = 13.2 Hz, ³ J = 3.6 Hz, ³ J = 4.3 Hz, ³ J = 10.0 Hz, ³ J = 10.9 Hz, 2 H), 1.79 (m, ³ J = 4.3 Hz, ³ J = 6.6 Hz,
³ J = 10.0Hz, 1 H), 2.88 (ddd, ³ J = 54.1 Hz, ³ J = 3.8 Hz,
³ J = 10.9 Hz, 1 H), 3.28, 3.96 (each d, ² J = 13.1 Hz, 4 H), 3.44 (br d, ³ J = 6.6 Hz, 2 H), 4.67-4.71 (m, ³ J = 3.8 Hz, 1 H), 6.71-6.74 (m, 1 H), 7.15-7.31 (m, 10 H); ¹³C NMR (75 MHz, CDCl₃): δ = 14.6, 20.5, 21.9, 24.2, 24.9, 31.4, 45.1, 55.1, 55.4, 86.0, 89.4, 103.2, 126.7, 127.9, 129.9, 140.4, 148.5, 153.0; Anal. Calcd for C₃₁H₄₃IN₂O₃ (618.59): C, 60.19; H, 7.01; N, 4.53. Found: C, 60.09; H, 6.86; N, 4.39.
8b: mp 155 °C (Et₂O); R_f = 0.32 (Et₂O-petroleum ether = 1:5); [α]_D ²⁰ = -55.2 (c 1.00, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ = 0.39, 0.81 (each d, ³ J = 6.8 Hz, 6 H), 0.64, 1.65 (each ddd, ² J = 14.4 Hz, ³ J = 2.5 Hz, ³ J = 2.6 Hz, ³ J = 10.7 Hz, ³ J = 11.0 Hz, 2 H), 1.22 (d, ³ J = 6.8 Hz, 12 H), 1.57 (s, 3 H), 1.80-1.99 (m, ³ J = 2.6 Hz, ³ J = 6.8 Hz, ³ J = 10.7 Hz, 1 H), 2.83 (ddd, ³ J = 1.2 Hz, ³ J = 2.5 Hz, ³ J = 11.0 Hz, 1 H), 3.49, 3.99 (each d, ² J = 13.9 Hz, 4 H), 3.69-4.07 (m, ³ J = 6.8 Hz, 2 H), 5.19-5.24 (m, ³ J = 1.2 Hz, 1 H), 6.79-6.84 (m, 1 H), 7.15-7.39 (m, 10 H); ¹³C NMR (75 MHz, CDCl₃): δ = 14.6, 21.1, 21.8, 23.6, 24.2, 34.8, 46.1, 54.4, 54.7, 85.2, 86.6, 104.9, 126.8, 128.1, 129.1, 140.5, 147.6, 154.2; Anal. Calcd for C₃₁H₄₃IN₂O₃ (618.59): C, 60.19; H, 7.01; N, 4.53. Found: C, 59.95; H, 7.14; N, 4.33.
7c: mp 64 °C (Et₂O); R_f = 0.65 (Et₂O-petroleum ether = 1:5); [α]_D ²⁰ = +34.3(c 1.00, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ = 0.00 (s, 9 H), 0.61 (br d, 6 H), 1.28 (br. s, 6 H), 2.96, 3.07 (each dd, ² J = 12.8 Hz, ³ J = 4.1 Hz, ³ J = 11.1 Hz, 2 H), 3.33 (dt, ³ J = 3.4 Hz, ³ J = 4.1 Hz, ³ J = 11.1 Hz, 1 H), 3.33-3.50 (m, 2 H), 3.50, 4.15 (d, ² J = 13.6 Hz, 4 H), 4.66 (dd, ⁴ J = 2.8 Hz, ³ J = 3.4 Hz, 1 H), 6.68 (d, ⁴ J = 2.8 Hz, 1 H), 7.13-7.34 (m, 15 H); ¹³C NMR (75 MHz, CDCl₃): δ = -1.6, 20.5, 30.2, 45.8, 55.2, 62.6, 93.2, 99.7, 104.9, 125.9, 126.9, 128.2, 128.4, 129.4, 130.1, 139.8, 140.3, 151.3, 152.9; Anal. Calcd for C₃₆H₄₇IN₂O₃Si (710.76): C, 60.83; H, 6.67; N, 3.94. Found: C, 61.01; H, 6.57; N, 3.58.
8c: mp = 122 °C (Et₂O); R_f = 0.47 (Et₂O-petroleum ether = 1:5); [α]_D ²⁰ = -27.3 (c 1.00, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ = 0.00 (s, 9 H), 1.22 (br. s, 12 H), 2.57, 2.94 (each dd, ² J = 14.7 Hz, ³ J = 3.8 Hz, ³ J = 11.0 Hz, 2 H), 3.28 (ddd, ³ J = 1.5 Hz, ³ J = 3.8 Hz, ³ J = 11.0 Hz, 1 H), 3.71, 3.85 (each d, ² J = 14.9 Hz, 4 H), 3.77-4.08 (m, 2 H), 5.45 (dd, ³ J = 1.5 Hz, ⁴ J = 1.2 Hz, 1 H), 6.79 (d, ⁴ J = 1.2 Hz, 1 H), 6.95-7.32 (m, 15 H); ¹³C NMR (75 MHz, CDCl₃): δ = -1.2, 21.1, 32.5, 46.1, 53.9, 59.7, 93.1, 98.6, 106.9, 126.0, 126.5, 127.9, 128.1, 128.4, 129.8, 140.1, 140.2, 151.2, 153.8; Anal. Calcd for C₃₆H₄₇IN₂O₃Si (710.76): C, 60.83; H, 6.67; N, 3.94. Found: C, 61.09; H, 6.46; N, 3.69.

13

Typical Experimental Procedure and Spectral Data for 11: I₂ (1.1 equiv) was added to 4-hydroxy-1,2-alkadienyl carbamate 4 (1.0 equiv) in DMSO-H₂O (6:1, 9 mL/mmol) under an Ar atmosphere. The mixture was stirred at 90 °C for 3 h. The solution was allowed to cool and diluted with Et₂O. The organic phase was washed with H₂O (2 ×), sat Na₂SO₃ solution (1 ×), H₂O (1 ×) and brine (1 ×). The organic layer was dried (Na₂SO₄), concentrated in vacuo and the residue purified by flash column chromatography (SiO₂, pentane). As some 3-iodofurans 11 are sensitive to air, they were stored in the freezer under Ar.
11a: R_f = 0.78 (Et₂O-petroleum ether, 1:1); ¹H NMR (300 MHz, C₆D₆): δ = 0.47 (s, 9 H), 1.25 (d, ³ J = 6.9 Hz, 6 H), 3.13 (sept, ³ J = 6.9 Hz, 1 H), 7.24 (s, 1 H); ¹³C NMR (75 MHz, C₆D₆): δ = 0.8, 21.9, 28.6, 70.5, 113.3, 144.9, 166.9; Anal. Calcd for C₁₀H₁₇IOSi (308.23): C, 38.97; H, 5.56. Found: C, 39.03; H, 5.66.
11b: R_f = 0.66 (Et₂O-petroleum ether, 1:1); ¹H NMR (300 MHz, C₆D₆): δ = 0.41 (s, 9 H), 2.13 (s, 3 H), 7.19 (s, 1 H); ¹³C NMR (75 MHz, C₆D₆): δ = 0.0, 14.1, 70.2, 114.6, 144.3, 158.0; Anal. Calcd for C₈H₁₃IOSi (280.18): C, 34.29; H, 4.68. Found: C, 34.37; H, 4.75.
11c: R_f = 0.70 (Et₂O-petroleum ether, 1:1); ¹H NMR (300 MHz, C₆D₆): δ = 0.36 (s, 9 H), 7.44-7.13 (m, 6 H); ¹³C NMR (75 MHz, C₆D₆): δ = 0.4, 71.0, 116.7, 127.6, 128.2, 128.4, 131.9, 145.6, 160.5; Anal. Calcd. for C₁₃H₁₅IOSi (342.25): C, 45.62; H, 4.42. Found: C, 45.85; H, 4.58.
11d: R_f = 0.71 (Et₂O-petroleum ether, 1:1); ¹H NMR (300 MHz, C₆D₆): δ = 0.49 (s, 9 H), 1.29 (d, ³ J = 6.9 Hz, 6 H), 2.19 (s, 3 H), 3.13 (sept, ³ J = 6.9 Hz, 1 H); ¹³C NMR (75 MHz, C₆D₆): δ = 0.8, 13.0, 22.1, 28.6, 69.4, 110.9, 151.4, 165.1; Anal. Calcd for C₁₁H₁₉IOSi (322.26): C, 41.00; H, 5.94. Found: C, 40.59; H, 6.13.
11e: R_f = 0.74 (Et₂O-petroleum ether, 1:1); ¹H NMR (300 MHz, C₆D₆): δ = 0.46 (s, 9 H), 2.17 (s, 3 H), 2.19 (s, 3 H); ¹³C NMR (75 MHz, C₆D₆): δ = 0.0, 12.4, 14.2, 68.9, 115.2, 150.9, 156.0; MS (EI, 70 eV): m/z (%) = 294(100), 288(93), 185(15), 152(22), 109(11), 73(28); HRMS (EI) calcd for C₉H₁₅IOSi (294.20): 293.9936. Found: 293.9932.
11f: R_f = 0.71 (Et₂O-petroleum ether, 1:1); ¹H NMR (300 MHz, C₆D₆): δ = 1.17 (d, ³ J = 6.9 Hz, 6 H), 1.85 (s, 3 H), 2.82 (sept, ³ J = 6.9 Hz, 1 H), 7.15 (s, 1 H); ¹³C NMR (75 MHz, C₆D₆): δ = 11.0, 21.5, 27.4, 72.9, 115.7, 143.0, 156.3; MS (EI, 70 eV): m/z (%) = 250(51), 235(100), 127(2), 108(8), 80(13); HRMS (EI) calcd for C₈H₁₁IO (250.08): 249.9854. Found: 249.9844.
11g: R_f = 0.64 (Et₂O-petroleum ether, 1:1); ¹H NMR (300 MHz, C₆D₆): δ = 2.09 (s, 3 H), 7.66-7.57 and 7.33-7.15 (m, 6 H); ¹³C NMR (75 MHz, C₆D₆): δ = 12.9, 75.2, 119.4, 126.4, 128.0, 129.2, 131.8, 144.4, 149.8; Anal. Calcd for C₁₁H₉IO (284.09): C, 46.51; H, 3.19. Found: C, 46.38; H, 3.07.
11h: R_f = 0.74 (Et₂O-petroleum ether, 1:1); ¹H NMR (300 MHz, C₆D₆): δ = 1.23 (d, ³ J = 6.9 Hz, 6 H), 1.90 (s, 3 H), 2.19 (s, 3 H), 2.87 (sept, ³ J = 6.9 Hz, 1 H); ¹³C NMR (75 MHz, C₆D₆): δ = 10.3, 12.2, 20.4, 25.9, 70.1, 114.5, 148.6, 153.0; Anal. Calcd for C₉H₁₃IO (264.10): C, 40.93; H, 4.96. Found: C, 40.96; H, 4.94.
11i: R_f = 0.66 (Et₂O-petroleum ether, 1:1); ¹H NMR (300 MHz, CDCl₃): δ = 1.03 (s, 9 H), 1.74 (s, 3 H), 4.62 (s, 2 H), 7.31-7.45 and 7.63-7.69 (m, 11 H); ¹³C NMR (75 MHz, CDCl₃): δ = 11.0, 19.7, 27.1, 57.5, 72.3, 120.6, 128.1, 130.1, 133.7, 136.0, 144.2, 149.7; Anal. Calcd for C₂₂H₂₅IO₂Si (476.42): C, 55.46; H, 5.29. Found: C, 55.43; H, 5.59.
11j: R_f = 0.68 (Et₂O-petroleum ether, 1:1); ¹H NMR (300 MHz, C₆D₆): δ = 0.97 (t, ³ J = 7.0 Hz, 3 H), 1.61-1.73 (m, 2 H), 2.61 (t, ³ J = 8.0 Hz, 2 H), 7.11-7.30 and 7.66-7.71 (m, 6 H); ¹³C NMR (75 MHz, C₆D₆): δ = 14.1, 23.3, 28.5, 73.9, 113.0, 123.4, 127.8, 128.9, 131.4, 144.3, 149.6; Anal. Calcd. for C₁₃H₁₃IO (312.15): C, 50.02; H, 4.20. Found: C, 49.92; H, 4.01.