A One-Pot, Base-Free Annelation Approach to - American Chemical

Taylor, Kitson and Wood

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A One-Pot, Base-Free Annelation Approach to α-Alkylidene-γ-Butyrolactones

Russell R. A. Kitson and Richard J. K. Taylor*

Department of Chemistry, University of York, Heslington, York YO10 5DD, UK. [email protected]

and

John L. Wood,

Department of Chemistry, Colorado State University, Fort Collins, CO 80523-1872, USA.

Table of Contents

Page

1.

General Experimental

S1

2.

Literature Preparations

S2

3.

Experimental Procedures

S3

3.1

Methylene Series

S3

3.2

Alkylidene/Arylidene series

S9

4.

References

S13

5.

Spectral Data

S13

1. General Experimental. 1

H NMR, 13C NMR and 31P NMR spectra were recorded at 400 MHz, 100 Hz and 162

MHz respectively. All spectral data was acquired at 295 K. Chemical shifts are quoted in parts per million (ppm) using the residual solvent peak as an internal standard (1H NMR 7.26 ppm for CHCl3 and

13

C NMR 77.0 ppm for CDCl3).

Coupling constants (J) are reported in Hz. Multiplicity abbreviations used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br. (broad). Signal assignments were accomplished via analysis of COSY, NOESY, HSQC and HMBC experiments where necessary. Infrared spectra were recorded using NaCl plates. Low and high-


S2

resolution mass spectra were obtained for all novel compounds using electrospray ionization (ESI) and chemical ionization (CI, using ammonia gas). Melting points were determined using open capillary tubes and are uncorrected.

Thin layer

chromatography (TLC) was performed using silica gel 60F254 precoated aluminumbacked plates. The compounds were visualized using UV light (254 nm) and the stain specified.

Flash chromatography was performed at medium pressure using dry

packed silica gel 35-70 µm, 60 Å with the eluant specified. Petroleum ether is the fraction with b.p. 40-60 °C. 1,4-Dioxane and tetrahydrofuran were distilled from sodium-benzophenone ketyl radical immediately before use.

Water refers to

deionised water. Except where specified, all reagents were purchased from commercial sources and were used without further purification.

2. Literature Preparations. Bestmann’s ylide (triphenylphosphoranylideneketene) 12 was either purchased from Sigma-Aldrich or synthesized from methoxycarbonylmethylene)triphenylphosphorane using an organic synthesis procedure.1 4-Hydroxy-2-cyclohexenone 16 was prepared according to the procedure described by Danishefsky and Simoneau.2 4-Hydroxy-4methylcyclohexa-2,5-dienone 25 was prepared according to the procedure described by Taylor and co-workers.3 4-Hydroxy-5,5-dimethyl-2-cyclopentenone4 27 was prepared via a novel Piancatelli rearrangement5 from 2-(furan-2-yl)-propan-2-ol. 5hydroxy(5H)furan-2-one 29 was prepared according to the procedure described by Lee, Garst and co-workers.6

4-Hydroxy-cyclohept-2-enone 31 was prepared

according to the procedure described by Toste and co-workers.7 Methyl (E)-4hydroxybut-2-enoate 33 was prepared according to the procedure described by Craig and Reader.8

4-(2-Hydroxypropan-2-yl)cyclohex-2-enone9

35 was prepared

according to the procedure described by Kobayashi and William10 with subsequent deprotection of the TES group by heating to reflux in acetone with PPTS overnight.


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3. Experimental Procedures.

3.1 Methylene Series.

Preparation of 3-(Phosphoranylidene)tetrahydrobenzofuran-2,5(3H,6H)-dione 17

Triphenylphosphoranylideneketene1 12 (Bestmann’s ylide) (240 mg, 0.795 mmol, 1.0 equiv.), handled under an atmosphere of argon, was added in one portion to a stirred solution of 4-hydroxycyclohex-2-enone2 16 (89 mg, 0.795 mmol, 1.0 equiv.) in 1,4dioxane (16 mL, 0.05M) at rt under argon and the resulting solution was heated to reflux for 7 h. The solvent was removed in vacuo to afford the title compound 17 (374 mg, quantitative yield) as a yellow foam. No further purification possible (N.B. fairly rapidly degrades e.g. on silica). Data for 17: TLC Rf 0.26 (9:1 EtOAc/MeOH, det: p-Anisaldehyde/∆, Red); IR (Neat) ῦ (cm-1) 2923 (m), 2853 (m), 1764 (s), 1724 (s), 1438 (s), 1178 (m), 1119 (s), 722 (s), 694 (s); 1HNMR (400 MHz, CDCl3) δ (ppm) 7.67-7.56 (9H, m, HC (9+11)), 7.52-7.47 (6H, m, HC (10)), 4.94 (1H, dddd, J = 8.7, 4.7, 4.5, 0.7 Hz, HC-O (7a)), 3.38-3.33 (1H, m, HC (3a)), 2.64 (1H, dddd, J = 18.1, 11.3, 5.6, 0.7 Hz, H2C (6)), 2.29 (1H, ddd, J = 13.8, 4.7, 0.3 Hz, H2C (4)), 2.19 (1H, dddd, J = 18.1, 5.2, 4.5, 0.3 Hz, H2C (6)), 2.12 (1H, dd, J = 13.8, 4.5 Hz, H2C (4)), 1.95 (1H, ddd, J = 15.1, 5.6, 0.4 Hz, H2C (7)), 1.64 (1H, ddd, J = 15.1, 5.2, 0.3 Hz, H2C (7)); 13CNMR (100 MHz, CDCl3) δ (ppm) 213.1 (C=O (5)), 175.0 (d, JHP = 20.6 Hz, C=O (2)), 134.5 (d, JHP = 10.4 Hz, CH (9)), 132.6 (d, JHP = 3.0 Hz, CH (11)), 129.1 (d, JHP = 12.4 Hz, CH (10)), 125.5 (d, JHP = 91.7 Hz, C (8)), 73.8 (d, JHP = 12.8 Hz, O-CH (7a), 44.8 (CH2 (7), 40.3 (d, JHP = 12.0 Hz, CH (3a), 37.7 (d, JHP = 134.6 Hz, C (3), 33.5 (CH2 (6), 25.7 (CH2 (4); 31P{1H}NMR (162 MHz, CDCl3) δ 15.1 (s); MS (ESI) m/z (species, %) 415 ([M+H]+, 100); HRMS calculated for C26H24O3P [M+H]+ requires 415.1458; found 415.1465 (1.7 ppm error).


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General Procedure 1: Preparation of α-Methylene-γ-butyrolactones. Preparation of 3-Methylenetetrahydrobenzofuran-2,5-dione 18

Triphenylphosphoranylideneketene1 12 (Bestmann’s ylide) (54 mg, 0.178 mmol, 1.05 equiv.), handled under an atmosphere of argon, was added in one portion to a stirred solution of 4-hydroxycyclohex-2-enone2 16 (19 mg, 0.169 mmol, 1.0 equiv.) in 1,4dioxane (3.4 mL, 0.05M) at rt under argon and the resulting solution was heated to reflux for 5.5 h. The septum was removed and paraformaldehyde (51 mg, 1.696 mmol, 10 equiv.) was added in one portion, rapidly replacing the septum once the addition was complete. The mixture was then heated to reflux for 30 min before being cooled and the solvent was removed in vacuo. The residue was purified by flash column chromatography on SiO2 eluting with 1:1 petrol/EtOAc → 1:2 petrol/EtOAc to afford the title compound 18 (24 mg, 86%) as a colourless solid. Data for 18: mp 107.5-108.5 °C (lit. mp 107.5-108.5 °C11); 1H NMR (400 MHz, CDCl3) δ (ppm) 6.34 (1 H, d, J = 2.9 Hz, H2C (8)), 5.62 (1 H, d, J = 2.7 Hz, H2C (8)), 5.00 (1 H, ddd, J = 8.6, 4.2, 1.6 Hz, HC-O (7a)), 3.59 (1 H, ddddd, J = 11.9, 8.6, 6.3, 2.9, 2.7 Hz, HC (3a)), 2.70 (1 H, dd, J = 16.4, 6.3 Hz, H2C (4)), 2.57 (1 H, dd, J = 16.4, 5.0 Hz, H2C (4)), 2.33-2.16 (4 H, m, H2C (6+7)). Data is consistent with that reported in the literature.11

(3aR7aR, 3aS7aS)-7a-Methyl-3-methylene-3a,7a-dihydro-3H,4H-benzofuran-2,5dione 26

Taylor, Kitson and Wood The

reaction

was

performed

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to

general

procedure

1

using

triphenylphosphoranylideneketene1 12 (67 mg, 0.220 mmol, 1.05 equiv.), 4-hydroxy4-methylcyclohexa-2,5-dienone3 25 (26 mg, 0.210 mmol, 1.0 equiv.), 1,4-dioxane (4.2 mL) and paraformaldehyde (63 mg, 2.097 mmol, 10 equiv.), differing only in that the acylation/conjugate addition was kept at reflux for 15 h. Following concentration in vacuo, the residue was purified by flash column chromatography on SiO2 eluting with 1:2 petrol/EtOAc to afford the title compound 11 (34 mg, 91%) as a colourless solid. Data for 26: mp 148-150 °C (dec.) (lit. mp 148-150 °C (dec.)11); 1H NMR (400 MHz, CDCl3) δ (ppm) 6.59 (1 H, dd, J = 10.4, 1.8 Hz, HC (7)), 6.30 (1 H, d, J = 3.4 Hz, H2C (8)), 5.98 (1 H, d, J = 10.4 Hz, HC (6)), 5.58 (1 H, d, J = 2.8 Hz, H2C (8)), 3.32-3.38 (m, 1 H, HC (3a)), 2.83-2.86 (m, 2 H, H2C (4)), 1.74 (s, 3 H, H3C (9)). Data is consistent with that reported in the literature.11

6,6-Dimethyl-3-methylenetetrahydro-2H-cyclopenta[b]furan-2,5(3H)-dione 28

The reaction was performed according to general procedure 1 using using triphenylphosphoranylideneketene1 12 (23 mg, 0.075 mmol, 1.05 equiv.), 4-hydroxy5,5-dimethylcyclopent-2-enone4 27 (9 mg, 0.071 mmol, 1.0 equiv.), 1,4-dioxane (1.4 mL) and paraformaldehyde (21 mg, 0.714 mmol, 10 equiv.), differing only in that the acylation/conjugate addition was kept at reflux for 15 h. Following concentration in vacuo, the residue was purified by flash column chromatography on SiO2 eluting with 1:1 petrol/EtOAc to afford the title compound 28 (9 mg, 70%) as a colourless solid. Data for 28: mp 86-87 °C (lit. mp 86-87 °C11); 1H NMR (400 MHz, CDCl3) δ (ppm) 6.31 (1 H, d, J = 1.9 Hz, H2C (7)), 5.75 (1 H, d, J = 1.7 Hz, H2C (7)), 4.63 (1 H, d, J = 6.3 Hz, HC-O (6a)), 3.71 (1 H, ddddd, J = 10.9, 6.3, 6.0, 1.9, 1.7 Hz, HC (3a)), 3.00 (1 H, dd, J = 19.6, 10.9 Hz, H2C (4)), 2.21 (1 H, dd, J = 19.6, 6.0 Hz, H2C (4)), 1.18


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(3 H, s, H3C (8)), 1.11 (1 H, s, H3C (8)). Data is consistent with that reported in the literature.11

3-Methylenedihydrofuro[2,3-b]furan-2,5(3H,6aH)-dione 30

The reaction was performed according to general procedure 1 using using triphenylphosphoranylideneketene1 12 (57 mg, 0.189 mmol, 1.05 equiv.), 5hydroxy(5H)furan-2-one6 29 (18 mg, 0.180 mmol, 1.0 equiv.), 1,4-dioxane (3.6 mL) and paraformaldehyde (54 mg, 1.800 mmol, 10 equiv.), differing only in that the acylation/conjugate addition was performed at rt for 5 d. Following concentration in vacuo, the residue was purified by flash column chromatography on SiO2 eluting with 1:1 petrol/EtOAc to afford the title compound 30 (15 mg, 54%) as a colourless solid. Data for 30: mp 87-88 °C; TLC Rf 0.44 (EtOAc, det: KMnO4/∆); IR (Neat) ῦ (cm-1) 2962 (m), 2920 (m), 2850 (m), 1770 (s), 1748 (s), 1260 (m), 1158 (w), 1080 (m), 1012 (m), 977 (w), 799 (m); 1HNMR (400 MHz, CDCl3) δ (ppm) 6.53 (1H, d, J = 2.7 Hz, H2C (7), 6.35 (1H, d, J = 6.2 Hz, HC-(O)2 (6a), 5.90 (1H, d, J = 2.4 Hz, H2C (7), 3.91 (1H, ddddd, J = 10.7, 6.2, 3.5, 2.7, 2.4 Hz, HC (3a), 3.13 (1H, dd, J = 18.5, 10.7 Hz, H2C (4), 2.64 (1H, dd, J = 18.5, 3.5 Hz, H2C (4); 13CNMR (100 MHz, CDCl3) δ (ppm) 172.6 (C=O (5)), 167.3 (C=O (2)), 135.4 (C (3)), 127.4 (CH2 (7)), 100.8 ((O)2CH (6a)), 38.2 (CH (3a)), 34.5 (CH2 (4); MS (ESI) m/z (species, %) 155 ([M+H]+, 16), 177 ([M+Na]+, 12); HRMS calculated for C7H7O4 [M+H]+ requires 155.0339; found 155.0341 (1.3 ppm error).

3-Methylenehexahydro-2H-cycloheptafuran-2,5(3H)-dione 32


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The reaction was performed according to general procedure 1 using using triphenylphosphoranylideneketene1 12 (40 mg, 0.133 mmol, 1.05 equiv.), 4hydroxycyclohept-2-enone7 31 (16 mg, 0.127 mmol, 1.0 equiv.), 1,4-dioxane (2.5 mL) and paraformaldehyde (38 mg, 1.269 mmol, 10 equiv.), differing only in that the acylation/conjugate addition was kept at reflux for 15 h. Following concentration in vacuo, the residue was purified by flash column chromatography on SiO2 eluting with 1:2 petrol/EtOAc to afford the title compound 32 (16 mg, 70%) as a colourless solid. Data for 32: mp 87-88 °C (lit. mp 87-88 °C11); 1H NMR (400 MHz, CDCl3) δ (ppm) 6.36 (1 H, d, J = 2.7 Hz, H2C (9)), 5.70 (1 H, d, J = 2.4 Hz, H2C (9)), 4.71 (1 H, ddd, J = 9.5, 7.9, 3.8 Hz, HC-O (8a)), 3.37 (1 H, ddddd, J = 11.6, 7.9, 4.5, 2.7, 2.4 Hz, HC (3a)), 2.82 (1 H, dd, J = 13.0, 11.6 Hz, H2C (4)), 2.56 (1 H, dd, J = 13.0, 4.5 Hz, H2C (4)), 2.51 (2 H, t, J = 7.5 Hz, H2C (6)), 2.21 (1 H, dddd, J = 16.9, 7.5, 3.8, 2.1 Hz, H2C (7)), 2.08-1.92 (2 H, m, H2C (7+8)), 1.65-1.54 (1 H, m, H2C (8)). Data is consistent with that reported in the literature.11

Methyl-(4-methylidene-5-oxotetrahydrofuran-3-yl)acetate 34

The reaction was performed according to general procedure 1 using using triphenylphosphoranylideneketene1 12 (25 mg, 0.081 mmol, 1.05 equiv.), (E)-methyl4-hydroxybut-2-enoate8 33 (9 mg, 0.078 mmol, 1.0 equiv.), 1,4-dioxane (1.6 mL) and paraformaldehyde (23 mg, 0.776 mmol, 10 equiv.), differing only in that the acylation/conjugate addition was kept at reflux for 15 h. Following concentration in vacuo, the residue was purified by flash column chromatography on SiO2 eluting with


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2:1 petrol/EtOAc to afford the title compound 34 (9 mg, 68%) as a colourless oil. Data for 34: 1H NMR (400 MHz, CDCl3): δ (ppm) 6.30 (1 H, d, J = 2.5 Hz, H2C (6)), 5.65 (1 H, d, J = 2.5 Hz, H2C (6)), 4.61 (1 H, dd, J = 9.0, 9.0 Hz, H2C (2)), 4.04 (1 H, dd, J = 9.0, 6.0 Hz, H2C (2)), 3.70 (3 H, s, H3C-O (9)), 3.54–3.43 (1 H, m, HC (3)), 2.74 (1 H, dd, J = 17.0, 5.5 Hz, H2C-O (7)), 2.56 (1 H, dd, J = 17.0, 9.5 Hz, H2C (7)); 13

C NMR (100 MHz, CDCl3): δ (ppm) 171.2 (C=O (8)), 169.9 (C=O (5)), 136.9, (C

(4)), 122.8 (CH2 (6)), 70.8 (O-CH2 (2)), 52.0 (O-CH3 (9)), 37.9 (CH2 (7)), 34.9 (CH (3)). Data is consistent with that reported in the literature.11 1,1-Dimethyl-4-methylenetetrahydro-1H-isochromene-3,6(4H,7H)-dione 36

The reaction was performed according to general procedure 1 using using triphenylphosphoranylideneketene1 12 (37 mg, 0.123 mmol, 1.05 equiv.), 4-(2hydroxypropan-2-yl)cyclohex-2-enone9 35 (18 mg, 0.117 mmol, 1.0 equiv.), 1,4dioxane (2.3 mL) and paraformaldehyde (35 mg, 1.169 mmol, 10 equiv.), differing only in that the acylation/conjugate addition was kept at reflux for 60 h. Following concentration in vacuo, the residue was purified by flash column chromatography on SiO2 eluting with 1:2 petrol/EtOAc to afford the title compound 36 (16 mg, 66%) as a colourless solid. Data for 36: mp 126-127 °C (lit. mp 126-127 °C11); 1H NMR (400 MHz, CDCl3): δ (ppm) 6.67 (1 H, d, J = 2.5 Hz, H2C (9)), 5.74 (1 H, d, J = 2.5 Hz, H2C (9)), 3.59-3.53 (1 H, m, HC (4a)), 2.82 (1 H, ddd, J = 15.0, 2.5, 2.5 Hz, H2C (5)), 2.64 (1 H, ddd, J = 15.0, 5.5, 0.5 Hz, H2C (5)), 2.46-2.38 (1 H, m, H2C (7)), 2.38-2.28 (1 H, m, H2C (7)), 2.20-2.11 (2 H, m, H2C (8) and HC (8a)), 1.75-1.66 (1 H, m, H2C (8)), 1.56 (3 H, s, H3C (10)), 1.44 (3 H, s, H3C (10)). Data is consistent with that reported in the literature.11


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3.2 Alkylidene/Arylidene Series.

(E)-3-Benzylidenetetrahydrobenzofuran-2,5(3H,6H)-dione 20

The reaction was performed according to general procedure 1 using using triphenylphosphoranylideneketene1 12 (54 mg, 0.178 mmol, 1.05 equiv.), 4hydroxycyclohex-2-enone2 16 (19 mg, 0.170 mmol, 1.0 equiv.) and 1,4-dioxane (3.4 mL) differing only in that benzaldehyde (0.026 mL, 0.254 mmol, 5 equiv.) was added in one portion via syringe instead of paraformaldehyde and the Wittig olefination was performed at reflux for 2 d. Following concentration in vacuo, the residue was purified by flash column chromatography on SiO2 eluting with 1:1 petrol/EtOAc to afford the title compound 20 (20 mg, 49%) as a pale yellow solid. Data for 20: mp 130.5-131.5 °C (lit. mp 130.5-131.5 °C11); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.59 (1 H, d, J = 2.5 Hz, HC (8)), 7.47-7.40 (5 H, m, HC (10+11+12)), 5.01-4.95 (1 H, m, HC-O (7a)), 4.06 (1 H, ddd, J = 15.0, 7.0, 2.5 Hz, HC (3a)), 2.72 (1 H, dd, J = 16.0, 7.0 Hz, H2C (4)), 2.50 (1 H, dd, J = 16.0, 7.0 Hz, H2C (4)), 2.48-2.41 (1 H, m, H2C (6)), 2.36-2.27 (3 H, m, H2C (6+7)). Data is consistent with that reported in the literature.11

(E)-3-(4-Methoxybenzylidene)tetrahydrobenzofuran-2,5(3H,6H)-dione 21


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The reaction was performed according to general procedure 1 using using triphenylphosphoranylideneketene1 12 (57 mg, 0.188 mmol, 1.05 equiv.), 4hydroxycyclohex-2-enone2 16 (20 mg, 0.179 mmol, 1.0 equiv.) and 1,4-dioxane (3.6 mL) differing only in that anisaldehyde (0.109 mL, 0.122 mmol, 5 equiv.) was added in one portion via syringe instead of paraformaldehyde and the Wittig olefination was performed at reflux for 5 d. Following concentration in vacuo, the residue was purified by flash column chromatography on SiO2 eluting with 1:1 petrol/EtOAc to afford the title compound 21 (17 mg, 35%) as a yellow solid. Data for 21: mp 98-99 °C; TLC Rf 0.53 (EtOAc, det: p-Anisaldehyde/∆, green); IR (Neat) ῦ (cm-1) 2957 (m), 1743 (s), 1716 (s), 1644 (m), 1602 (s), 1513 (m), 1306 (w), 1259 (m), 1173 (m), 1028 (w); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.53 (1 H, d, J = 2.3 Hz, HC (8)), 7.41 (2 H, d, J = 8.9 Hz, HC (10)), 6.94 (2 H, d, J = 8.9 Hz, HC (11)), 4.96 (1 H, dddd, J = 7.8, 4.9, 4.9, 4.9 Hz, HC-O (7a)), 4.01 (1 H, dddd, J = 7.8, 7.0, 6.8, 2.3 Hz, HC (3a)), 3.84 (3 H, s, H3C-O (13)), 2.74 (1 H, dd, J = 15.9, 6.8 Hz, H2C (6)), 2.53 (1 H, dd, J = 15.9, 7.0 Hz, H2C (6)), 2.48-2.43 (1 H, m, H2C (4)), 2.35-2.29 (3 H, m, H2C (4+7)); 13

C NMR (100 MHz, CDCl3): δ (ppm) 209.4 (C=O (5)), 172.0 (C=O (2)), 161.7, (C-O

(12)), 138.8 (C (8)), 132.3 (CH (10)), 126.0 (C (9)), 124.7 (C (3)), 114.8 (CH (11)), 74.2 (O-CH (7a)), 55.3 (O-CH3 (13)), 38.5 (CH2 (6)), 36.1 (CH (3a)), 33.2 (CH2 (4)), 25.6 (CH2 (7)); MS (CI) m/z (species, %) 273 ([M+H]+, 100), 290 ([M+ NH4]+, 77); HRMS calculated for C16H20NO4 [M+NH4]+ requires 290.1392; found 290.1392 (0.1 ppm error). Data is consistent with that reported in the literature.11 Single crystal diffraction data (X-Ray) was recorded from a crystal of dimensions 0.22 × 0.22 × 0.17 mm grown by dissolving 21 in the minimum CH2Cl2 and layering with hexane. After 2 weeks, yellow cubes were obtained.

(E)-3-(4-0itrobenzylidene)tetrahydrobenzofuran-2,5(3H,6H)-dione 22


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The reaction was performed according to general procedure 1 using using triphenylphosphoranylideneketene1 12 (51 mg, 0.161 mmol, 1.05 equiv.), 4hydroxycyclohex-2-enone2 16 (18 mg, 0.169 mmol, 1.0 equiv.) and 1,4-dioxane (3.2 mL) differing only in that p-nitrobenzaldehyde (121 mg, 0.804 mmol, 5 equiv.) was added in one portion instead of paraformaldehyde and the Wittig olefination was performed at reflux for 8 h. Following concentration in vacuo, the residue was purified by flash column chromatography on SiO2 eluting with 2:1 petrol/EtOAc to afford the title compound 22 (31 mg, 67%) as a yellow solid. Data for 22: mp 87-88 °C; TLC Rf 0.60 (EtOAc, det: KMnO4/∆); IR (Neat) ῦ (cm-1) 2956 (m), 2851 (m), 1749 (s), 1709 (s), 1650 (w), 1599 (m), 1345 (s), 1234 (m), 1189 (m), 1025 (m), 851 (w); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.30 (2 H, d, J = 8.8 Hz, HC (11)), 7.64 (1 H, d, J = 2.5 Hz, HC (8)), 7.61 (2 H, d, J = 8.8 Hz, HC (10)), 5.04 (1 H, ddd, J = 7.9, 5.1, 5.1 Hz, HC-O (7a)), 4.08 (1 H, dddd, J = 7.9, 7.0, 7.0, 2.5 Hz, HC (3a)), 2.69 (1 H, dd, J = 15.9, 6.9 Hz, H2C (6)), 2.49-2.43 (1 H, m, H2C (4)), 2.44 (1 H, dd, J = 15.9, 7.0 Hz, H2C (6)), 2.39-2.31 (3 H, m, H2C (4+7));

13

C NMR (100 MHz, CDCl3): δ

(ppm) 208.1 (C=O (5)), 170.5 (C=O (2)), 148.5, (N-C (12)), 139.7 (C (9)), 136.2 (CH (8)), 132.1 (C (3)), 130.6 (CH (10)), 124.6 (CH (11)), 74.5 (O-CH (7a)), 38.7 (CH2 (4)), 36.0 (CH (3a)), 33.0 (CH2 (6)), 25.6 (CH2 (7)); MS (ESI) m/z (species, %) 288 ([M+H]+, 100), 310 ([M+ Na]+, 80); HRMS calculated for C15H14NO5 [M+H]+ requires 288.0866; found 288.0858 (2.9 ppm error).

(E)-3-(3,4,5-Trimethoxybenzylidene)tetrahydrobenzofuran-2,5(3H,6H)-dione 23

The reaction was performed according to general procedure 1 using using triphenylphosphoranylideneketene1 12 (51 mg, 0.161 mmol, 1.05 equiv.), 4hydroxycyclohex-2-enone2 16 (18 mg, 0.169 mmol, 1.0 equiv.) and 1,4-dioxane (3.2 mL) differing only in that 3,4,5-trimethoxybenzaldehyde (121 mg, 0.804 mmol, 5 equiv.) was added in one portion instead of paraformaldehyde and the Wittig olefination was performed at reflux for 4 d. Following concentration in vacuo, the


S12

residue was purified by flash column chromatography on SiO2 eluting with 2:1 petrol/EtOAc to afford the title compound 22 (30 mg, 60%) as a yellow solid. Data for 22: mp 141.5-142.5 °C (lit. mp 141.5-142.5 °C11); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.48 (1 H, d, J = 2.4 Hz, HC (8)), 6.66 (2 H, s, HC (10)), 5.48 (1 H, ddd, J = 9.6, 7.4, 2.4 Hz, HC-O (7a)), 4.01 (1 H, ddddd, J = 14.8, 7.4, 6.8, 6.8, 2.4 Hz, HC (3a)), 3.88 (3 H, s, H3C-O (13)), 3.85 (6 H, s, H3C-O (14)), 2.74 (1 H, dd, J = 15.8, 6.8 Hz, H2C (4)), 2.59 (1 H, dd, J = 15.8, 6.8 Hz, H2C (4)), 2.49-2.41 (1 H, m, H2C (6)), 2.35-2.29 (3 H, m, H2C (6+7)). Data is consistent with that reported in the literature.11

3-Hexylidenetetrahydrobenzofuran-2,5(3H,6H)-dione 24

The reaction was performed according to general procedure 1 using using triphenylphosphoranylideneketene1 12 (45 mg, 0.150 mmol, 1.05 equiv.), 4hydroxycyclohex-2-enone2 16 (16 mg, 0.143 mmol, 1.0 equiv.) and 1,4-dioxane (2.9 mL) differing only in that hexanal (0.088 mL, 0.714 mmol, 5 equiv.) was added in one portion via syringe instead of paraformaldehyde and the Wittig olefination was performed at reflux for 3 d. Following concentration in vacuo, the residue was purified by flash column chromatography on SiO2 eluting with 4:1 petrol/EtOAc→1:1 petrol/EtOAc to the title compound 24 (24 mg, 71%), a 1:1 mixture of inseparable diastereoisomers as a colourless oil. Data for 24: TLC Rf 0.26 (9:1 EtOAc/MeOH, det: KMnO4/∆); IR (Neat) ῦ (cm-1) 2956 (m), 2851 (m), 1749 (s), 1709 (s), 1650 (w), 1599 (m), 1345 (s), 1234 (m), 1189 (m), 1025 (m), 851 (w); 1H NMR (400 MHz, CDCl3): δ (ppm) 6.79 (1 H, ddd, J = 7.4, 7.4, 2.4 Hz, HC (8-Z)), 6.16 (1 H, ddd, J = 7.8, 7.8, 2.4 Hz, HC (8-E)), 4.95-4.85 (1 H, m, HC-O (7a-E+Z)), 3.58-3.49 (1 H, m, HC (3a-E+Z)), 2.70 (1 H, dddd, J = 15.6, 7.5, 4.0, 2.1 Hz, H2C (4-E+Z)), 2.63 (1 H, ddd, J = 15.6, 7.6, 6.1 Hz, H2C (4-E+Z)), 2.54-2.37 (2 H, m, H2C (6-E+Z)), 2.35-2.12 (4 H, m, H2C (9+7-E+Z)), 1.48-1.23 (6 H, m, H2C (10+11+12-E+Z)), 0.89-0.83 (3 H, m, H3C (13-E+Z));

13

C NMR (100 MHz, CDCl3): δ (ppm) 208.9 (C=O (5-E)), 208.8


S13

(C=O (5-Z)), 170.1, (C=O (2-E)), 169.1 (C=O (2-Z)), 147.0 (CH (8-E)), 143.9 (CH (8-Z)), 128.6 (C (3-E)), 126.9 (C (3-Z)), 74.1 (O-CH (7a-E)), 73.7 (O-CH (7a-Z)), 42.0 (CH2 (4-E)), 41.0 (CH2 (4-Z)), 37.1 (CH (3a-E)) 35.2 (CH (3a-Z)), 33.6 (CH2 (6E)), 33.5 (CH2 (6-Z)), 31.4 (CH2 (11-E)), 31.3 (CH2 (11-Z)), 29.5 (CH2 (9-E)), 28.5 (CH2 (9-Z)), 28.0 (CH2 (10-E)), 27.4 (CH2 (10-Z)), 26.4 (CH2 (7-E)), 25.9 (CH2 (7-Z)), 22.4 (CH2 (12-E)), 22.3 (CH2 (12-Z)), 13.9 (CH3 (13-E)), 13.8 (CH3 (13-Z)); MS (ESI) m/z (species, %) 254 ([M+NH4]+, 100), 237 ([M+H]+, 97). Data is consistent with that reported in the literature.11

4. References 1.

Schobert, R. Org. Synth. 2005, 82, 140.

2.

Danishefsky, S. J.; Simoneau, B. J. Am. Chem. Soc. 1989, 111, 2599-2604.

3.

McKillop, A.; McLaren, L.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 1994, 2047-2048.

4.

Pohmakotr, M.; Popuang, S.; Chancharunee, S. Tetrahedron Lett. 1989, 30, 1715-1718.

5.

Piancatelli, G.; Scettri, A.; Barbadoro, S. Tetrahedron Lett. 1976, 39, 35553558.

6.

Lee, G. C. M.; Syage, E. T.; Harcourt, D. A.; Holmes, J. M.; Garst, M. E. J. Org. Chem. 1991, 56, 7007.

7.

Staben, S. T.; Linghu, X.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 1265812659.

8.

Craig, D.; Reader, J. C. Tetrahedron Lett. 1990, 31, 6585.

9.

Uliss, D. B.; Handrick, G. R.; Dalzell, H. C.; Razdan, R. K. J. Am. Chem. Soc. 2002, 100, 2929.

10.

William, A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67, 8771.

11.

Edwards, M. G.; Kenworthy, M. N.; Kitson, R. R. A.; Scott, M. S.; Taylor, R. J. K. Angew. Chem. Int. Ed. 2008, 47, 1935; Edwards, M. G.; Kenworthy, M. N.; Kitson, R. R. A.; Scott, M. S.; Whitwood, A. C.; Taylor, R. J. K. Eur. J. Org. Chem. 2008, 4769.

5. Spectral Data

2

2

D

2

D

D

&+&O

D

3K 3 3K

SSPW

(&; 0+] &'&O

+ 2

Taylor, Kitson and Wood S14

D

SSPW

2

3K 3 3K

2

D

2

(&; 0+] &'&O

D &'&O

D


2

2

2

D

D

2

D

D

SSPW

&+&O

(&; 0+] &'&O

+ 2


SSPW

(&; 0+] &'&O

2

2

D

D

2

2

D

&'&O

D



S18

SSPW

0H2

(&; 0+] &'&O

2

D

2

D

2

D

&'&O

D



S20

SSPW

21

(&; 0+] &'&O

2

D

2

D

2

D

&'&O

D


A One-Pot, Base-Free Annelation Approach to - American Chemical

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