Highly Efficient 4-O-Alkylations of Tetronic Acids Involving Oxyphosphonium Intermediates

Abstract

4-Alkoxy-5H-furan-2-ones were prepared in fair to high yields by regioselective 4-O-alkylation of tetronic acids with stoi­chiometric amounts of primary and secondary alcohols. This approach involves the intermediacy of (5-oxo-2,5-dihydrofuran-3-yloxy) phosphonium trifluoromethanesulfonates, which were generated in situ on reaction of tetronic acids with triphenylphosphonium anhydride trifluoromethanesulfonate (Hendrickson’s reagent).

tetronic acids - alkylations - regioselectivity - phosphonium ions - Mitsunobu reaction

References

1a Steel PG. Chem. Commun.  1999,  2257 

1b Roush WR. Barda DA. Tetrahedron Lett.  1997,  38:  8781 

1c Rossin R. Jones PR. Murphy PJ. Worsley WR. J. Chem. Soc., Perkin Trans. 1  1996,  1323 

1d Pattenden GJ. Fortsch. Chem. Org. Naturst.  1978,  35:  133 

For leading references, see:

2a Schobert R. Siegfried S. Synlett  2000,  686 

2b Sato T. Koji Y. Otera J. Synlett  1995,  843 

2c Hoffmann HM. Schmidt B. Wolff S. Tetrahedron  1989,  45:  6113 ; and references cited therein

3 Bajwa JS. Anderson RC. Tetrahedron Lett.  1990,  31:  6973 

4 Tahir H. Hindsgaul O. J. Org. Chem.  2000,  65:  911 

5 Martin SF. Dodge JA. Tetrahedron Lett.  1991,  32:  3017 ; and references cited therein

6 Analogous side reactions are well known for Mitsunobu esterifications with hindered alcohols. For a detailed mechanistic discussion, see: Hughes DL. Reamer RA.
J. Org. Chem.  1996,  61:  2967 

7 Hendrickson JB. In Encyclopedia of Reagents for Organic Synthesis   Vol. 8:  Paquette LA. Wiley; Chichester: 1995.  p.5405 

8 Hendrickson JB. Singer M. Hussoin MS. J. Org. Chem.  1993,  58:  6913 

9

Typical Procedure for the 4-O-Alkylation of Tetronic Acids:
To a stirred solution of triphenylphosphine oxide (584 mg, 2.1 mmol) in CH₂Cl₂ (2 mL) at 0 °C was added dropwise trifluoromethanesulfonic anhydride (168 µL, 1.0 mmol). After 15 min, when the reagent had precipitated, a solution of tetronic acid (100 mg, 1.0 mmol) and i-Pr₂NEt (174 µL, 1.0 mmol) in CH₂Cl₂ (3 mL) was added. After the colorless precipitate had dissolved, the respective alcohol (1.0-1.2 mmol) was added dropwise, followed by i-Pr₂NEt (209 µL, 1.25 mmol). Then the reaction mixture was allowed to warm to r.t. and stirred for 20 h, before it was concentrated under reduced pressure. The crude product was purified by flash chromatography.

10

4-Methoxy-5 H -furan-2-one ( 5a): Colourless crystals. Mp 48 °C (Lit.: [16] 63 °C). ¹H NMR (500 MHz, CDCl₃): δ = 3.92 (s, 3 H, CH₃), 4.64 (d, 2 H, J = 1.1 Hz, 5-H), 5.12 (t, 1 H, J = 1.1 Hz, 3-H). 4-Benzyloxy-5 H -furan-2-one ( 5b): Colourless crystals. Mp 90 °C (Lit.: [16] 103-104 °C). ¹H NMR (400 MHz, CDCl₃): δ = 4.65 (d, 2 H, J = 1.3 Hz, 5-H), 5.06 (s, 2 H, CH₂O), 5.18 (t, 1 H, J = 1.3 Hz, 3-H), 7.35-7.44 (m, 5 H, H_arom).
4-Allyloxy-5 H -furan-2-one ( 5c): Colourless oil. IR(film): ν = 3123, 1778, 1745, 1627 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 4.58 (dt, 2 H, J = 1.3, 5.8 Hz, CH₂O), 4.66 (d, 2 H, J = 1.1 Hz, 5-H), 5.11 (t, 1 H, J = 1.1 Hz, 3-H), 5.40 (ddd, 1 H, J = 1.2, 2.4, 10.5 Hz, CH=CH ₂), 5.43 (ddd, 1 H, J = 1.2, 3.1, 17.3 Hz, CH=CH ₂), 5.98 (ddt, 1 H, J = 5.8, 10.5, 17.2 Hz, CH=CH₂). ¹³C NMR (125 MHz, CDCl₃): δ = 67.9 (C-5), 73.2 (CH₂O), 89.5 (C-3), 120.3 (CH=CH₂), 130.2 (CH=CH₂), 173.3 (C-2), 178.3 (C-4). MS (CI, CH₅ ⁺): m/z (%) = 141(100) [M + H⁺]. Anal. Calcd for C₇H₈O₃ (140.1): C, 60.00; H, 5.75. Found: C, 59.98; H, 5.88.
4-Octyloxy-5 H -furan-2-one ( 5d): Colourless oil. IR (KBr): ν = 3124, 1778, 1747 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.82 (t, 3 H, J = 7.1 Hz, CH₃), 1.16-1.39 (m, 10 H, CH₂), 1.68-1.77 (q, 2 H, J = 6.7 Hz, CH ₂CH₂O), 3.99 (t, 2 H, J = 6.7 Hz, CH₂O), 4.85 (d, 2 H, J = 1.1 Hz, 5-H), 5.38 (t, 1 H, J = 1.1 Hz, 3-H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.3 (C-8′), 22.6 (C-7′), 25.6 (C-3′), 28.4 (C-4′/C-5′), 29.1 (C-2′), 31.7 (C-6′), 67.9 (C-5), 73.1 (C-1′), 88.7 (C-3), 173.6 (C-2), 179.6 (C-4). MS (70 eV): m/z = 212 [M⁺]. Anal. Calcd for C₁₂H₂₀O₃: C, 67.89; H, 9.50. Found: C, 67.89; H, 9.58.
4-Isopropoxy-5 H -furan-2-one ( 5e): [17] Colourless oil. ¹H NMR (500 MHz, CDCl₃): δ = 1.39 (d, 6 H, J = 6.2 Hz, CH₃), 4.44 (sept, 1 H, J = 6.2 Hz, CH), 4.60 (d, 2 H, J = 1.1 Hz, 5-H), 5.03 (t, 1 H, J = 1.1 Hz, 3-H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.3 [(CH₃)₂], 68.2 (C-5), 76.6 (CH), 88.5 (C-3), 173.9 (C-2), 178.3 (C-4).
( R )-4-(1-Methylheptyloxy)-5 H -furan-2-one ( 5f): Colourless oil. [α]_D ²⁰ = +1.6 (c 1.08, CH₂Cl₂). IR(film): ν = 3118, 2932, 2858, 1775, 1749, 1625 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 0.89 (t, 3 H, J = 7.0 Hz, CH ₃ CH₂), 1.19-1.44 [m, 10 H, CH₃(CH ₂ )₅], 1.35 (d, 1 H, J = 6.1 Hz, CH ₃ CH), 1.61 (m, 1 H, CH ₂ CH), 1.74 (m, 1 H, CH ₂ CH), 4.27 (qt, 1 H, J = 6.1, 7.0 Hz, CH), 4.58 (dt, 1 H, J = 1.1, 16.4 Hz, 5-H), 4.63 (dt, 1 H, J = 1.1, 16.4 Hz, 5-H), 5.02 (t, 1 H, J = 1.1 Hz, 3-H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.0 (C-8′), 19.0 (C-1′), 22.8 (C-7′), 25.1 (C-4′), 29.0 (C-5′), 31.6 (C-6′), 35.6 (C-3′), 68.1 (C-5), 80.5 (C-2′), 88.3 (C-3), 174.0 (C-2), 178.7 (C-4). MS (CI, CH₄): m/z = 213 [M + H⁺]. Anal. Calcd for C₁₂H₂₀O₃ (212.3): C, 67.89; H, 9.50; Found: C, 67.79; H, 9.76.
4- tert -Butoxy-5 H -furan-2-one ( 5g): Colourless crystals. Mp 88-90 °C. IR (KBr): ν = 3120, 1740, 1612 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.50 (s, 9 H, CH₃), 4.55 (d, 2 H, J = 1.2 Hz, 5-H), 5.09 (t, 1 H, J = 1.2 Hz, 3-H). MS (CI, CH₄): m/z = 157 [M + H⁺]. HRMS: m/z calcd for C₈H₁₃O₃ [M + H⁺]: 157.0865. Found: 157.0832.
( RS )-4-Methoxy-5-methyl-5 H -furan-2-one ( 5h): Colourless crystals. Mp 36 °C (Lit.: [18] 30-32 °C). ¹H NMR (500 MHz, CDCl₃): δ = 1.46 (d, 3 H, J = 6.7 Hz, CH₃), 3.89 (s, 3 H, OCH₃), 4.83 (dq, 1 H, J = 0.9, 6.7 Hz, 5-H), 5.05 (d, 1 H, J = 0.9 Hz, 3-H). ¹³C NMR (100 MHz, CDCl₃): δ = 17.8 (CH₃), 59.5 (CH₃O), 75.3 (C-5), 88.0 (C-3), 172.5 (C-2), 183.5 (C-4).
( RS )-4-Benzyloxy-5-methyl-5 H -furan-2-one ( 5i): Colourless crystals. Mp 74 °C (Lit.: [16] 72 °C). IR (KBr): ν = 3121, 2980, 1750, 1621 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.49 (d, 3 H, J = 6.8 Hz, CH₃), 4.88 (dq, 1 H, J = 0.9, 6.8 Hz, 5-H), 5.05 (d, 1 H, J = 11.6 Hz, CH₂O), 5.08 (d, 1 H, J = 11.6 Hz, CH₂O), 5.11 (d, 1 H, J = 0.9 Hz, 3-H), 7.35-7.45 (m, 5 H, H_arom). MS (CI, CH₄): m/z = 205 [M + H⁺]. Anal. Calcd for C₁₂H₁₂O₃ (204.2): C, 70.58; H, 5.92. Found: C, 70.48; H, 5.82.
( RS )-4-Allyloxy-5-methyl-5 H -furan-2-one ( 5j): Colourless oil. IR(film): ν = 3119, 1755, 1633 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.48 (d, 3 H, J = 6.8 Hz, CH₃), 4.55 (dt, 2 H, J = 1.4, 5.7 Hz, CH₂O), 4.85 (q, 1 H, J = 6.8 Hz, 5-H), 5.04 (s _br 1 H, 3-H), 5.39 (ddd, 1 H, J = 1.0, 2.2, 10.4 Hz, CH=CH ₂), 5.42 (ddd, 1 H, J = 1.1, 2.6, 17.3 Hz, CH=CH ₂), 5.97 (ddt, 1 H, J = 5.7, 10.4, 17.3 Hz, CH=CH₂). ¹³C NMR (100 MHz, CDCl₃): δ = 17.8 (CH₃), 73.1 (CH₂O), 75.4 (C-5), 88.8 (C-3), 120.1 (CH=CH₂), 130.3 (CH=CH₂), 172.5 (C-2), 182.0 (C-4). MS (CI, CH₄): m/z = 155 [M + H⁺]. HRMS: m/z calcd for C₈H₁₀O₃ (EI): 154.0630. Found: 154.0669.

11 Compound (S)-5f was prepared from butynoate 8 and (S)-2-octanol as indicated in Scheme 4 according to a recently reported procedure. The enantiomeric purity of this product (97.2% ee)12 was almost equivalent to that of starting (S)-2-octanol (97.6% ee): Paintner FF. Metz M. Bauschke G. Synthesis  2002,  869 

12 The enantiomeric purity of products 5f was determined indirectly. Successive treatment of 5f with LiAlH₄ (1.0 equiv, THF, -78 °C to r.t.) and 0.01 M HCl (1.0 equiv, r.t.) afforded 2-octanol in 95% yield. Subsequent derivatization with (S)-naproxen® chloride (5 equiv, CH₂Cl₂, Δ) according to Spahn led to the corresponding 2-octyl esters. The ratio of diastereomers was determined by GC from the crude reaction product: Spahn H. Arch. Pharm. (Weinheim, Ger.)  1988,  321:  847 

13 Crich D. Dyker H. Tetrahedron Lett.  1989,  475 

14 Maeda H. Koide T. Maki T. Ohmori H. Chem. Pharm. Bull.  1995,  43:  1076 

15 Saylik D. Horvath MJ. Elmes PS. Jackson WR. Lovel CG. Moody K. J. Org. Chem.  1999,  64:  3941 

16 Pollet P. Gelin S. Tetrahedron  1978,  34:  1453 

17 Zimmer H. Amer A. Pham CV. Grob Schmidt D. J. Org. Chem.  1988,  53:  3368 

18 Gawronski JK. Chen QH. Geng Z. Huang B. Martin MR. Mateo AI. Brzostowska M. Rychlewska U. Feringa BL. Chirality  1997,  9:  537