A one-pot, base-free annelation approach to α-alkylidene- γbutyrolactones

Article abstract of DOI:10.1021/ol902191d

A novel annelation procedure has been developed for the conversion of γ-hydoxy enones into a-alkylidene-y-butyrolactones. This one-pot method utilizes the Bestmann ylide (triphenylphosphoranylideneketene) and proceeds by way of acylation followed by an in

Full text of DOI:10.1021/ol902191d

Taylor, Kitson and Wood
S1
A OneꢀPot, BaseꢀFree Annelation Approach to αꢀAlkylideneꢀγꢀButyrolactones
Russell R. A. Kitson and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK.
rjkt1@york.ac.uk
and
John L. Wood,
Department of Chemistry, Colorado State University, Fort Collins, CO 80523-1872,
USA.
Table of Contents
Page
S1
1.
2.
3.
General Experimental
Literature Preparations
Experimental Procedures
S2
S3
3.1
3.2
Methylene Series
S3
Alkylidene/Arylidene series
S9
4.
5.
References
S13
S13
Spectral Data
1. General Experimental.
1H 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 13C 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 highꢀ

Taylor, Kitson and Wood
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 aluminumꢀ
backed 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 35ꢀ70 ꢁm, 60 Å with the eluant specified. Petroleum ether is the
fraction with b.p. 40ꢀ60 °C. 1,4ꢀDioxane and tetrahydrofuran were distilled from
sodiumꢀbenzophenone 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
SigmaꢀAldrich or synthesized from methoxycarbonylmethylene)triphenylphosphorane
using an organic synthesis procedure.1 4ꢀHydroxyꢀ2ꢀcyclohexenone 16 was prepared
according to the procedure described by Danishefsky and Simoneau.2 4ꢀHydroxyꢀ4ꢀ
methylcyclohexaꢀ2,5ꢀdienone 25 was prepared according to the procedure described
by Taylor and coꢀworkers.3 4ꢀHydroxyꢀ5,5ꢀdimethylꢀ2ꢀcyclopentenone4 27 was
prepared via a novel Piancatelli rearrangement5 from 2ꢀ(furanꢀ2ꢀyl)ꢀpropanꢀ2ꢀol. 5ꢀ
hydroxy(5H)furanꢀ2ꢀone 29 was prepared according to the procedure described by
Lee, Garst and coꢀworkers.6 4ꢀHydroxyꢀcycloheptꢀ2ꢀenone 31 was prepared
according to the procedure described by Toste and coꢀworkers.7 Methyl (E)ꢀ4ꢀ
hydroxybutꢀ2ꢀenoate 33 was prepared according to the procedure described by Craig
and Reader.8 4ꢀ(2ꢀHydroxypropanꢀ2ꢀyl)cyclohexꢀ2ꢀenone9 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.

Taylor, Kitson and Wood
S3
3. Experimental Procedures.
3.1 Methylene Series.
Preparation of 3ꢀ(Phosphoranylidene)tetrahydrobenzofuranꢀ2,5(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 4ꢀhydroxycyclohexꢀ2ꢀenone2 16 (89 mg, 0.795 mmol, 1.0 equiv.) in 1,4ꢀ
dioxane (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: pꢀAnisaldehyde/ꢂ, Red); IR (Neat) ῦ (cmꢀ1) 2923 (m), 2853 (m), 1764 (s), 1724
(s), 1438 (s), 1178 (m), 1119 (s), 722 (s), 694 (s); 1HNMR (400 MHz, CDCl3) δ (ppm)
7.67ꢀ7.56 (9H, m, HC (9+11)), 7.52ꢀ7.47 (6H, m, HC (10)), 4.94 (1H, dddd, J = 8.7,
4.7, 4.5, 0.7 Hz, HCꢀO (7a)), 3.38ꢀ3.33 (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, OꢀCH (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).

Taylor, Kitson and Wood
S4
General Procedure 1: Preparation of αꢀMethyleneꢀγꢀbutyrolactones. Preparation of
3ꢀMethylenetetrahydrobenzofuranꢀ2,5ꢀdione 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 4ꢀhydroxycyclohexꢀ2ꢀenone2 16 (19 mg, 0.169 mmol, 1.0 equiv.) in 1,4ꢀ
dioxane (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.
1
Data for 18: mp 107.5ꢀ108.5 °C (lit. mp 107.5ꢀ108.5 °C11); H 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, HCꢀO (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)), 2.33ꢀ2.16 (4 H, m, H2C (6+7)). Data is consistent with that
reported in the literature.11
(3aR7aR, 3aS7aS)ꢀ7aꢀMethylꢀ3ꢀmethyleneꢀ3a,7aꢀdihydroꢀ3H,4Hꢀbenzofuranꢀ2,5ꢀ
dione 26

Taylor, Kitson and Wood
S5
The reaction was performed according to general procedure
1
using
triphenylphosphoranylideneketene1 12 (67 mg, 0.220 mmol, 1.05 equiv.), 4ꢀhydroxyꢀ
4ꢀmethylcyclohexaꢀ2,5ꢀdienone3 25 (26 mg, 0.210 mmol, 1.0 equiv.), 1,4ꢀdioxane
(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
1
solid. Data for 26: mp 148ꢀ150 °C (dec.) (lit. mp 148ꢀ150 °C (dec.)11); H 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)), 3.32ꢀ3.38 (m, 1 H, HC (3a)), 2.83ꢀ2.86 (m, 2 H, H2C (4)), 1.74 (s, 3 H, H3C (9)).
Data is consistent with that reported in the literature.11
6,6ꢀDimethylꢀ3ꢀmethylenetetrahydroꢀ2Hꢀcyclopenta[b]furanꢀ2,5(3H)ꢀdione 28
The reaction was performed according to general procedure 1 using using
triphenylphosphoranylideneketene1 12 (23 mg, 0.075 mmol, 1.05 equiv.), 4ꢀhydroxyꢀ
5,5ꢀdimethylcyclopentꢀ2ꢀenone4 27 (9 mg, 0.071 mmol, 1.0 equiv.), 1,4ꢀdioxane (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 86ꢀ87 °C (lit. mp 86ꢀ87 °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, HCꢀO (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

Taylor, Kitson and Wood
S6
(3 H, s, H3C (8)), 1.11 (1 H, s, H3C (8)). Data is consistent with that reported in the
literature.11
3ꢀMethylenedihydrofuro[2,3ꢀb]furanꢀ2,5(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.), 5ꢀ
hydroxy(5H)furanꢀ2ꢀone6 29 (18 mg, 0.180 mmol, 1.0 equiv.), 1,4ꢀdioxane (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 87ꢀ88 °C; TLC Rf 0.44 (EtOAc, det: KMnO4/ꢂ); IR (Neat) ῦ (cmꢀ1)
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, HCꢀ(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
13
Hz, H2C (4), 2.64 (1H, dd, J = 18.5, 3.5 Hz, H2C (4); CNMR (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)2ꢀ
CH (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).
3ꢀMethylenehexahydroꢀ2Hꢀcycloheptafuranꢀ2,5(3H)ꢀdione 32

Taylor, Kitson and Wood
S7
The reaction was performed according to general procedure 1 using using
triphenylphosphoranylideneketene1 12 (40 mg, 0.133 mmol, 1.05 equiv.), 4ꢀ
hydroxycycloheptꢀ2ꢀenone7 31 (16 mg, 0.127 mmol, 1.0 equiv.), 1,4ꢀdioxane (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 87ꢀ88 °C (lit. mp 87ꢀ88 °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, HCꢀO (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)), 2.08ꢀ1.92 (2 H, m, H2C (7+8)), 1.65ꢀ1.54 (1 H, m, H2C (8)). Data is
consistent with that reported in the literature.11
Methylꢀ(4ꢀmethylideneꢀ5ꢀoxotetrahydrofuranꢀ3ꢀyl)acetate 34
The reaction was performed according to general procedure 1 using using
triphenylphosphoranylideneketene1 12 (25 mg, 0.081 mmol, 1.05 equiv.), (E)ꢀmethylꢀ
4ꢀhydroxybutꢀ2ꢀenoate8 33 (9 mg, 0.078 mmol, 1.0 equiv.), 1,4ꢀdioxane (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

Taylor, Kitson and Wood
S8
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, H3CꢀO (9)), 3.54–3.43 (1 H, m, HC (3)),
2.74 (1 H, dd, J = 17.0, 5.5 Hz, H2CꢀO (7)), 2.56 (1 H, dd, J = 17.0, 9.5 Hz, H2C (7));
13C 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 (OꢀCH2 (2)), 52.0 (OꢀCH3 (9)), 37.9 (CH2 (7)), 34.9 (CH
(3)). Data is consistent with that reported in the literature.11
1,1ꢀDimethylꢀ4ꢀmethylenetetrahydroꢀ1Hꢀisochromeneꢀ3,6(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.), 4ꢀ(2ꢀ
hydroxypropanꢀ2ꢀyl)cyclohexꢀ2ꢀenone9 35 (18 mg, 0.117 mmol, 1.0 equiv.), 1,4ꢀ
dioxane (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 126ꢀ127 °C (lit. mp 126ꢀ127 °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)), 3.59ꢀ3.53 (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)), 2.46ꢀ2.38 (1 H, m, H2C (7)), 2.38ꢀ2.28
(1 H, m, H2C (7)), 2.20ꢀ2.11 (2 H, m, H2C (8) and HC (8a)), 1.75ꢀ1.66 (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

Taylor, Kitson and Wood
S9
3.2 Alkylidene/Arylidene Series.
(E)ꢀ3ꢀBenzylidenetetrahydrobenzofuranꢀ2,5(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.), 4ꢀ
hydroxycyclohexꢀ2ꢀenone2 16 (19 mg, 0.170 mmol, 1.0 equiv.) and 1,4ꢀdioxane (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
130.5ꢀ131.5 °C (lit. mp 130.5ꢀ131.5 °C11); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.59
(1 H, d, J = 2.5 Hz, HC (8)), 7.47ꢀ7.40 (5 H, m, HC (10+11+12)), 5.01ꢀ4.95 (1 H, m,
HCꢀO (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)), 2.48ꢀ2.41 (1 H, m, H2C
(6)), 2.36ꢀ2.27 (3 H, m, H2C (6+7)). Data is consistent with that reported in the
literature.11
(E)ꢀ3ꢀ(4ꢀMethoxybenzylidene)tetrahydrobenzofuranꢀ2,5(3H,6H)ꢀdione 21

Taylor, Kitson and Wood
S10
The reaction was performed according to general procedure 1 using using
triphenylphosphoranylideneketene1 12 (57 mg, 0.188 mmol, 1.05 equiv.), 4ꢀ
hydroxycyclohexꢀ2ꢀenone2 16 (20 mg, 0.179 mmol, 1.0 equiv.) and 1,4ꢀdioxane (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 98ꢀ99
°C; TLC Rf 0.53 (EtOAc, det: pꢀAnisaldehyde/ꢂ, green); IR (Neat) ῦ (cmꢀ1) 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, HCꢀO (7a)), 4.01 (1 H, dddd, J = 7.8, 7.0, 6.8, 2.3 Hz, HC (3a)),
3.84 (3 H, s, H3CꢀO (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)), 2.48ꢀ2.43 (1 H, m, H2C (4)), 2.35ꢀ2.29 (3 H, m, H2C (4+7));
13C NMR (100 MHz, CDCl3): δ (ppm) 209.4 (C=O (5)), 172.0 (C=O (2)), 161.7, (CꢀO
(12)), 138.8 (C (8)), 132.3 (CH (10)), 126.0 (C (9)), 124.7 (C (3)), 114.8 (CH (11)),
74.2 (OꢀCH (7a)), 55.3 (OꢀCH3 (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 (XꢀRay) 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)ꢀ3ꢀ(4ꢀꢁitrobenzylidene)tetrahydrobenzofuranꢀ2,5(3H,6H)ꢀdione 22

Taylor, Kitson and Wood
S11
The reaction was performed according to general procedure 1 using using
triphenylphosphoranylideneketene1 12 (51 mg, 0.161 mmol, 1.05 equiv.), 4ꢀ
hydroxycyclohexꢀ2ꢀenone2 16 (18 mg, 0.169 mmol, 1.0 equiv.) and 1,4ꢀdioxane (3.2
mL) differing only in that pꢀnitrobenzaldehyde (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 87ꢀ88
°C; TLC Rf 0.60 (EtOAc, det: KMnO4/ꢂ); IR (Neat) ῦ (cmꢀ1) 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, HCꢀO (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)), 2.49ꢀ2.43 (1 H, m, H2C (4)), 2.44 (1 H, dd, J = 15.9,
13
7.0 Hz, H2C (6)), 2.39ꢀ2.31 (3 H, m, H2C (4+7)); C NMR (100 MHz, CDCl3): δ
(ppm) 208.1 (C=O (5)), 170.5 (C=O (2)), 148.5, (NꢀC (12)), 139.7 (C (9)), 136.2 (CH
(8)), 132.1 (C (3)), 130.6 (CH (10)), 124.6 (CH (11)), 74.5 (OꢀCH (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)ꢀ3ꢀ(3,4,5ꢀTrimethoxybenzylidene)tetrahydrobenzofuranꢀ2,5(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.), 4ꢀ
hydroxycyclohexꢀ2ꢀenone2 16 (18 mg, 0.169 mmol, 1.0 equiv.) and 1,4ꢀdioxane (3.2
mL) differing only in that 3,4,5ꢀtrimethoxybenzaldehyde (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

Taylor, Kitson and Wood
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 141.5ꢀ142.5 °C (lit. mp 141.5ꢀ142.5 °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, HCꢀO (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, H3CꢀO (13)), 3.85 (6 H, s, H3CꢀO (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)), 2.49ꢀ2.41 (1 H, m, H2C
(6)), 2.35ꢀ2.29 (3 H, m, H2C (6+7)). Data is consistent with that reported in the
literature.11
3ꢀHexylidenetetrahydrobenzofuranꢀ2,5(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.), 4ꢀ
hydroxycyclohexꢀ2ꢀenone2 16 (16 mg, 0.143 mmol, 1.0 equiv.) and 1,4ꢀdioxane (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/ꢂ); IR (Neat) ῦ (cmꢀ1) 2956 (m), 2851 (m), 1749 (s), 1709 (s), 1650 (w),
1
1599 (m), 1345 (s), 1234 (m), 1189 (m), 1025 (m), 851 (w); H NMR (400 MHz,
CDCl3): δ (ppm) 6.79 (1 H, ddd, J = 7.4, 7.4, 2.4 Hz, HC (8ꢀZ)), 6.16 (1 H, ddd, J =
7.8, 7.8, 2.4 Hz, HC (8ꢀE)), 4.95ꢀ4.85 (1 H, m, HCꢀO (7aꢀE+Z)), 3.58ꢀ3.49 (1 H, m,
HC (3aꢀE+Z)), 2.70 (1 H, dddd, J = 15.6, 7.5, 4.0, 2.1 Hz, H2C (4ꢀE+Z)), 2.63 (1 H,
ddd, J = 15.6, 7.6, 6.1 Hz, H2C (4ꢀE+Z)), 2.54ꢀ2.37 (2 H, m, H2C (6ꢀE+Z)), 2.35ꢀ2.12
(4 H, m, H2C (9+7ꢀE+Z)), 1.48ꢀ1.23 (6 H, m, H2C (10+11+12ꢀE+Z)), 0.89ꢀ0.83 (3 H,
13
m, H3C (13ꢀE+Z)); C NMR (100 MHz, CDCl3): δ (ppm) 208.9 (C=O (5ꢀE)), 208.8

Taylor, Kitson and Wood
S13
(C=O (5ꢀZ)), 170.1, (C=O (2ꢀE)), 169.1 (C=O (2ꢀZ)), 147.0 (CH (8ꢀE)), 143.9 (CH
(8ꢀZ)), 128.6 (C (3ꢀE)), 126.9 (C (3ꢀZ)), 74.1 (OꢀCH (7aꢀE)), 73.7 (OꢀCH (7aꢀZ)),
42.0 (CH2 (4ꢀE)), 41.0 (CH2 (4ꢀZ)), 37.1 (CH (3aꢀE)) 35.2 (CH (3aꢀZ)), 33.6 (CH2 (6ꢀ
E)), 33.5 (CH2 (6ꢀZ)), 31.4 (CH2 (11ꢀE)), 31.3 (CH2 (11ꢀZ)), 29.5 (CH2 (9ꢀE)), 28.5
(CH2 (9ꢀZ)), 28.0 (CH2 (10ꢀE)), 27.4 (CH2 (10ꢀZ)), 26.4 (CH2 (7ꢀE)), 25.9 (CH2 (7ꢀZ)),
22.4 (CH2 (12ꢀE)), 22.3 (CH2 (12ꢀZ)), 13.9 (CH3 (13ꢀE)), 13.8 (CH3 (13ꢀZ)); 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.
2.
3.
Schobert, R. Org. Synth. 2005, 82, 140.
Danishefsky, S. J.; Simoneau, B. J. Am. Chem. Soc. 1989, 111, 2599ꢀ2604.
McKillop, A.; McLaren, L.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1
1994, 2047ꢀ2048.
4.
5.
6.
7.
Pohmakotr, M.; Popuang, S.; Chancharunee, S. Tetrahedron Lett. 1989, 30,
1715ꢀ1718.
Piancatelli, G.; Scettri, A.; Barbadoro, S. Tetrahedron Lett. 1976, 39, 3555ꢀ
3558.
Lee, G. C. M.; Syage, E. T.; Harcourt, D. A.; Holmes, J. M.; Garst, M. E. J.
Org. Chem. 1991, 56, 7007.
Staben, S. T.; Linghu, X.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 12658ꢀ
12659.
8.
9.
Craig, D.; Reader, J. C. Tetrahedron Lett. 1990, 31, 6585.
Uliss, D. B.; Handrick, G. R.; Dalzell, H. C.; Razdan, R. K. J. Am. Chem. Soc.
2002, 100, 2929.
10.
11.
William, A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67, 8771.
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

Taylor, Kitson and Wood
S14
ꢇ ꢏꢍ
ꢅ ꢇꢏ
ꢅ ꢏꢏ
ꢇ ꢏꢎ
ꢇ ꢏꢎ
ꢐꢇ ꢇꢅ
ꢅ ꢇꢋ
ꢅ ꢇꢇ
ꢋ ꢏꢈ
ꢏ ꢅꢋ

Taylor, Kitson and Wood
S15
ꢋ ꢈ ꢊ
ꢉ ꢉ ꢊ
ꢇ ꢉ ꢋ ꢊ
ꢌ ꢉ ꢏ ꢊ
ꢉ ꢌ ꢇ ꢊ
ꢌ ꢌ ꢇ ꢊ
ꢏ ꢌ ꢌ ꢊ
ꢋ ꢋ ꢉ ꢊ
ꢏ ꢋ ꢉ ꢊ
ꢇ
ꢍ
ꢅ ꢈ ꢊ
ꢅ ꢈ ꢊ
ꢇ
ꢅ
ꢅ ꢈ ꢍ ꢊ
ꢅ ꢈ ꢍ ꢊ
ꢎ
ꢎ
ꢅ ꢉ ꢈ ꢊ
ꢅ ꢉ ꢈ ꢊ
ꢌ
ꢅ ꢉ ꢉ ꢊ
ꢅ ꢉ ꢉ ꢊ
ꢍ
ꢅ
ꢅ ꢋ ꢌ ꢊ
ꢅ ꢋ ꢊ
ꢅ
ꢈ ꢅ ꢉ ꢊ

Taylor, Kitson and Wood
S16
ꢇꢎꢉ
ꢇꢎꢈ
ꢇꢎꢋ
ꢇꢎꢈ
ꢇꢎꢉ
ꢇꢎ

Taylor, Kitson and Wood
S17
ꢉ ꢊ ꢌ
ꢈ ꢉ ꢎ ꢌ
ꢎ
ꢅ ꢇ ꢇ ꢌ
ꢊ
ꢊ
ꢅ ꢈ ꢋ ꢌ
ꢅ ꢉ ꢌ
ꢉ
ꢍ
ꢅ ꢍ ꢋ ꢌ
ꢅ ꢋ ꢈ ꢌ

Taylor, Kitson and Wood
S18

Taylor, Kitson and Wood
S19
ꢎ ꢈ ꢌ
ꢈ ꢉ ꢉ ꢌ
ꢅ ꢉ ꢎ ꢌ
ꢉ ꢏ ꢌ
ꢉ
ꢌ
ꢈ ꢍ ꢊ ꢌ
ꢏ
ꢍ
ꢇ
ꢅ ꢅ ꢊ ꢌ
ꢅ ꢈ ꢊ ꢌ
ꢅ ꢈ ꢎ ꢌ
ꢉ
ꢏ
ꢅ ꢉ ꢈ ꢌ
ꢅ ꢉ ꢏ ꢌ
ꢍ
ꢇ
ꢅ ꢎ ꢅ ꢌ
ꢅ ꢍ ꢈ ꢌ
ꢊ
ꢈ ꢇ ꢋ ꢌ

Taylor, Kitson and Wood
S20

Taylor, Kitson and Wood
S21
ꢏ ꢈ ꢊ
ꢇ ꢍ ꢍ ꢊ
ꢇ ꢍ ꢏ ꢊ
ꢋ ꢍ ꢉ ꢊ
ꢋ ꢌ ꢊ
ꢏ
ꢏ
ꢅ
ꢈ
ꢋ
ꢅ ꢈ ꢌ ꢊ
ꢅ ꢍ ꢇ ꢊ
ꢅ ꢍ ꢈ ꢊ
ꢅ ꢍ ꢏ ꢊ
ꢅ ꢍ ꢎ ꢊ
ꢅ ꢌ ꢉ ꢊ
ꢅ ꢋ ꢇ ꢊ
ꢅ
ꢈ ꢇ ꢉ ꢊ