Suzuki cross-coupling reactions of γ-alkylidenebutenolides: Application to the synthesis of vulpinic acid

Article abstract of DOI:10.1021/jo049780a

α-Hydroxy-γ-alkylidenebutenolides were efficiently functionalized by Suzuki cross-coupling reactions via the corresponding enol triflates. The natural product vulpinic acid was prepared by this methodology.

Full text of DOI:10.1021/jo049780a

Su zu k i Cr oss-Cou p lin g Rea ction s of γ-Alk ylid en ebu ten olid es:
Ap p lica tion to th e Syn th esis of Vu lp in ic Acid
Zafar Ahmed and Peter Langer*
Institut fu¨r Chemie und Biochemie der Ernst-Moritz-Arndt Universita¨t Greifswald, Soldmannstr. 16,
D-17487 Greifswald, Germany
peter.langer@uni-greifswald.de
Received February 7, 2004
R-Hydroxy-γ-alkylidenebutenolides were efficiently functionalized by Suzuki cross-coupling reactions
via the corresponding enol triflates. The natural product vulpinic acid was prepared by this
methodology.
γ-Alkylidenebutenolides are present in a variety of
pharmacologically relevant natural products and natural
product analogues.1 We have recently reported the func-
tionalization of the R-carbon atom of γ-alkylidenebuteno-
lides, readily available by cyclization of 1,3-bis-silyl enol
ethers2,3 with oxalyl chloride,4 by Stille cross-coupling
reactions.5,6 Very recently, Le Gall et al. reported a
related approach, based on the Suzuki reaction, and its
application to the synthesis of an analogue of norbadione
A and of a pulvinic acid derivative.7 This publication
prompted us to report our own findings in this area. We
report the functionalization of a variety of γ-alkylideneb-
utenolides by Suzuki reactions and the application of this
methodology to the synthesis of vulpinic acid. The latter
belongs to the pharmacologically relevant class of pulvi-
nic acid natural products which have been isolated from
lactone moieties. Our approach allows a regioselective
synthesis of pulvinic acids, since the aryl substituents
of the latter are introduced independently from each
other. From a practical viewpoint, the method is straight-
forward and the starting materials are readily available.
Resu lts a n d Discu ssion
Triflate 3a was prepared from butenolide 2a 4b in good
yield. The Suzuki reaction of 3a with phenylboronic acid
afforded the γ-alkylidenebutenolide 4a (Scheme 1). Op-
timal yields were obtained by application of standard
reaction conditions used also by Le Gall et al. (3 mol %
Pd(PPh3)4, 1.5 equiv of K3PO4, dioxane, reflux).7 Surpris-
ingly, all attempts to prepare 4a by Stille cross-coupling
reactions proved unsuccessful. The Suzuki reaction of 3a
with p-methoxyphenyl-, p-tolyl-, and p-chlorophenyl-
boronic acid afforded the butenolides 4b, 4c, and 4d ,
respectively (Table 1). Butenolide 4e was prepared by
reaction of 3a with 2-thienylboronic acid. The high
diastereomeric purity (E/Z > 98:2) of the exocyclic double
bond of 2a and 3a was not reduced during the Suzuki
reaction, due to the higher thermodynamic stability of
the E- compared to the Z-configured isomer.4b
a variety of terrestric sources such as mushrooms.8,9
A
number of regioselective8d and unselective8a,c syntheses
of unsymmetrical pulvinic acids have been reported.1,8
For example, pulvinic acids are available by cleavage of
pulvinic lactones.8a However, mixtures of regioisomeric
products were obtained for unsymmetrical derivatives,
due to the very similar chemical environment of the two
* To whom correspondence should be addressed. Fax: (+49) 3834-
864461.
Triflate 3b was prepared from ethyl-substituted buteno-
lide 2b. The reaction of 3b with phenylboronic acid
afforded butenolide 4f. The application of the Stille
reaction was again not successful. The reaction of 2-thie-
nylboronic acid with triflate 3c, prepared from methoxy-
(1) Reviews: (a) Rao, Y. S. Chem. Rev. 1976, 76, 625. (b) Pattenden,
G. Prog. Chem. Nat. Prod. 1978, 35, 133. (c) Gill, M.; Steglich, W. Prog.
Chem. Org. Nat. Prod. 1987, 51, 1. (d) Knight, D. W. Contemp. Org.
Synth. 1994, 1, 287. (e) Negishi, E.-i.; Kotora, M. Tetrahedron 1997,
53, 6707. (f) Bru¨ckner, R. Chem. Commun. 2002, 141.
(2) (a) Krohn, K.; Ostermeyer, H.-H.; Tolkiehn, K. Chem. Ber. 1979,
112, 2640. (b) Chan, T.-H.; Brownbridge, P. J . Am. Chem. Soc. 1980,
102, 3534. (c) Simoneau, B.; Brassard, P. Tetrahedron 1986, 14, 3767.
(d) Molander, G. A.; Cameron, K. O. J . Am. Chem. Soc. 1993, 115,
830.
(3) For a review of 1,3-bis-silyl enol ethers, see: Langer, P: Synthesis
2002, 441.
(4) (a) Langer, P.; Stoll, M. Angew. Chem. 1999, 111, 1919; Angew.
Chem., Int. Ed. 1999, 38, 1803. (b) Langer, P.; Schneider, T.; Stoll, M.
Chem. Eur. J . 2000, 6, 3204.
(8) For syntheses of vulpinic acid and derivatives, see, for example:
(a) Pattenden, G.; Pegg, N. A.; Kenyon, R. W. J . Chem. Soc., Perkin
Trans. 1 1991, 2363 and references therein. (b) Ramage, R.; Griffiths,
G. J .; Sweeney, J . N. A. J . Chem. Soc., Perkin Trans. 1 1984, 1547. (c)
Weinstock, J .; Blank, J . E.; Oh, H.-J .; Sutton, B. M. J . Org. Chem.
1979, 44, 673. (d) Knight, D. W.; Pattenden, G. J . Chem. Soc., Chem.
Commun. 1976, 660. (e) Wikholm, R. J .; Moore, H. W. J . Am. Chem.
Soc. 1972, 94, 6152.
(5) Langer, P.; Eckardt, T.; Schneider, T.; Go¨bel, C.; Herbst-Irmer,
R. J . Org. Chem. 2001, 66, 2222.
(9) Isolation: (a) A° kermark, B. Acta Chem. Scand. 1961, 15, 1695.
(b) Stachel, H.-D. Arch. Pharm. Ber. Dtsch. Pharm. Ges. 1963, 296,
479. (c) Emmerich, R.; Giez, I.; Lange, O. L.; Proksch, P. Phytochemistry
1993, 33, 1389. (d) Duncan, C. J . G.; Cuendet, M.; Fronczek, F. R.;
Pezzuto, J . M.; Mehta, R. G.; Hamann, M. T.; Ross, S. A. J . Nat. Prod.
2003, 66, 103. (e) Quang, D. N.; Hashimoto, T.; Nukada, M.; Yamamoto,
I.; Tanaka, M.; Takaoka, S.; Asakawa, Y. Chem. Pharm. Bull. 2003,
51, 330.
(6) For cross-coupling reactions of related butenolides, see: (a)
Siegel, K.; Bru¨ckner, R. Chem. Eur. J . 1998, 4, 1116. (b) Goerth, F.;
Umland, A.; Bru¨ckner, R. Eur. J . Org. Chem. 1998, 1055.
(7) Desage-El Murr, M.; Nowaczyk, S.; Le Gall, T.; Mioskowski, C.;
Amekraz, B.; Moulin, C. Angew. Chem. 2003, 115, 1327; Angew. Chem.,
Int. Ed. 2003, 42, 1289.
10.1021/jo049780a CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/23/2004
J . Org. Chem. 2004, 69, 3753-3757
3753

Ahmed and Langer
SCHEME 1. Syn th esis of bu ten olid es 4a
SCHEME 2. Tota l Syn th esis of Vu lp in ic Acid (13)a
a
Key: (i) Me3SiOTf (0.3 equiv), CH2Cl2, -78 f +20 °C; (ii) Tf2O,
pyridine, -78 f -10 °C; (iii) Pd(PPh3)4 (3 mol %), K3PO4 (1.5
equiv), dioxane, reflux.
TABLE 1. Syn th esis of Bu ten olid es 4a -j by Su zu k i
Cr oss-Cou p lin g Rea ction s
4
R1
R2
R3
R4
% (3)a % (4)a E/Zb
a
b
c
d
e
f
g
h
i
H
H
H
H
H
Et
H
OMe Ph
52
64
73
75
58
53
61
54
<2:98
<2:98
1:1
>98:2
>98:2
>98:2
>98:2
>98:2
<2:98
<2:98
H
H
H
H
H
H
OMe p-(MeO)C6H4
OMe p-MeC6H4
OMe p-ClC6H4
OMe 2-thienyl
OEt Ph
76
61
65
87
70
OMe
OMe 2-thienyl
-(CH2)3- OEt Ph
-(CH2)4- OMe Ph
-(CH2)9- OEt Ph
87
95
76
j
a
b
Yields of isolated products. Configuration of the exocyclic
double bond (by 1H NMR).
a
Key: (i) (1) LDA, THF, (2) 5 (0.5 equiv), -78 f +20 °C; (ii)
Me3SiCl, NEt3, toluene, 20 °C; (iii) (1) LDA, THF, -78 °C, (2)
Me3SiCl, -78 f +20 °C; (iv) oxalyl chloride, Me3SiOTf (0.3 equiv),
CH2Cl2, -78 f +20 °C; (v) Tf2O, pyridine, -78 f -10 °C; (vi)
PhB(OH)2, Pd(PPh3)4 (3 mol %), K3PO4 (1.5 equiv), dioxane, reflux;
(vii) BBr3 (4 equiv), CH2Cl2, 0 °C.
substituted butenolide 2c,5 gave butenolide 4g. The
geometry of the Z-configured exocyclic double bond, which
is thermodynamically favored due to the steric influence
of the substituent R1, was not changed during the
synthesis of butenolides 4f and 4g. The 5,6-, 5,7-, and
5,12-bicyclic butenolides 2d -f were prepared by cycliza-
tion of the cyclic 1,3-bis-silyl enol ethers 1d -f with oxalyl
chloride.10 The butenolides were transformed into the
corresponding triflates 3d -f. The Suzuki cross coupling
reaction of 3d -f with phenylboronic acid afforded the
bicyclic butenolides 4h -j. The Suzuki reactions were
carried out in 53-87% yields.
The synthesis of vulpinic acid was studied next (Scheme
2). The reaction of esters 5 and 6 gave the â-ketoester 7.
1,3-Bis-silyl enol ether 9 was prepared from 7 in two
steps via silyl enol ether 8. The TMSOTf-catalyzed
cyclization of 9 with oxalyl chloride afforded the novel
E-configured γ-alkylidenebutenolide 10 which was trans-
formed into the triflate 11. The configuration of the
exocyclic double bond of 10 is derived from the fact that
vulpinic acid (13) is isolated in the correct stereochemical
form. The Suzuki reaction of 11 with phenylboronic acid
afforded 12 in good yield. The configuration of the
exocyclic double bond, which was established by NOESY
experiments, proved again stable under the conditions
of the Suzuki reaction. Treatment of butenolide 12 with
BBr3 chemoselectively afforded vulpinic acid (13). The
spectroscopic data of 13 are identical to those reported
in the literature.8a
In summary, we have reported the synthesis of a
variety of butenolides by functionalization of the R-hy-
droxy group of γ-alkylidenebutenolides by Suzuki cross-
coupling reactions. The natural product vulpinic acid was
prepared. Most of the cross coupling reactions reported
herein could not be realized by application of our recently
published Stille approach. Our current studies are di-
rected toward the application of the methodology reported
herein to the synthesis of other butenolide natural
products.
Exp er im en ta l Section
Gen er a l Com m en ts. All solvents were dried by standard
methods, and all reactions were carried out under an inert
1
atmosphere. For the H and 13C NMR spectra the deuterated
solvents indicated were used. Mass spectral data (MS) were
obtained using the electron ionization (70 eV) or the chemical
ionization technique (CI, H2O). For preparative-scale chroma-
(10) Langer, P.; Eckardt, T.; Stoll, M.; Karime´, I.; Mu¨ller, P.; Saleh,
N. N. R. Eur. J . Org. Chem. 2001, 3657.
3754 J . Org. Chem., Vol. 69, No. 11, 2004

Suzuki Cross-Coupling Reactions of γ-Alkylidenebutenolides
tography silica gel (60-200 mesh) was used. Melting points
are uncorrected. Butenolides 2a -f and 3c were prepared by
published procedures.4b,5,10
(44), 95 (52), 55 (83), 29 (47). Anal. Calcd for C18H23O7SF3
(440.43): C, 49.08; H, 5.26. Found: C, 49.29; H, 4.95.
Gen er a l P r oced u r e for th e Syn th esis of Bu ten olid es
(4) by Su zu k i Rea ction s. A dioxane solution of triflate 3 (1.0
equiv), boronic acid (1.3 equiv), K3PO4 (1.5 equiv), and Pd-
(PPh3)4 (3 mol %) was refluxed for 4 h. A saturated aqueous
solution of ammonium chloride was added. The organic and
the aqueous layers were separated, and the latter was
extracted (3×) with ether. The combined organic layers were
dried (Na2SO4) and filtered, and the filtrate was concentrated
in vacuo. The residue was purified by chromatography (silica
gel, EtOAc/hexane).
4a . Starting with triflate 3a (125 mg, 0.41 mmol), phenyl-
boronic acid (65 mg, 0.53 mmol), K3PO4 (140 mg, 0.65 mmol),
and Pd(PPh3)4 (14 mg, 0.012 mmol), 4a was isolated as a yellow
solid (60 mg, 63%): mp 117 °C; 1H NMR (300 MHz, CDCl3) δ
3.82 (s, 3 H, OCH3), 5.92 (d, 1 H, J ) 0.9 Hz, dCH), 7.26-
7.47 (m, 3 H, ArH), 7.90-8.00 (m, 2 H, ArH), 8.47 (d, 1 H, J
) 0.9 Hz, dCH); 13C NMR (75 MHz, CDCl3) δ 52.0 (CH3), 101.2,
127.8 (2C, CH), 128.4 (C), 129.0 (2C), 130.9, 132.1 (CH), 134.8,
159.4, 165.8, 166.9 (C); IR (KBr) ν 1776 (s), 1710 (s), 1648 (s),
1447 (m), 1374 (m), 1258 (s), 1217 (w) cm-1; MS (EI, 70 eV)
m/z 230 (M+, 100), 199 (60), 170 (70), 102 (92), 70 (60), 51 (8).
Anal. Calcd for C13H10O4 (230.21): C, 67.82; H, 4.37. Found:
C, 67.63; H, 4.70.
4b. Starting with triflate 3a (131 mg, 0.43 mmol), 4-meth-
oxyphenylboronic acid (71 mg, 0.47 mmol), K3PO4 (137 mg,
0.64 mmol), and Pd(PPh3)4 (15 mg, 0.012 mmol), 4b was
isolated as a yellow solid (82 mg, 73%): mp 94-95 °C; 1H NMR
(300 MHz, CDCl3) δ 3.82 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3),
5.87 (s, 1 H, dCH), 6.97 (dd, 2 H, J ) 1.9, 7.0 Hz, ArH), 7.98
(dd, 2 H, J ) 2.1, 6.9 Hz, ArH), 8.33 (s, 1 H, dCH); 13C NMR
(75 MHz, CDCl3) δ 51.9, 55.4 (CH3), 100.3, 114.5 (2C, CH),
121.8 (C), 129.4 (2C), 134.3 (CH), 159.7, 161.8, 166.0, 167.2
(C); IR (KBr) ν 833 (m), 1084 (m), 1144 (m), 1253 (s), 1510
(m), 1605 (s), 1646 (m), 1716 (m), 1781 (s) cm-1; MS (EI, 70
eV) m/z 260 (M+, 100), 229 (30), 200 (20), 132 (27), 70 (17), 28
(17). Anal. Calcd for C14H12O5 (260.24): C, 64.61; H, 4.65.
Found: C, 64.20; H, 4.90.
Gen er a l P r oced u r e for th e P r ep a r a tion of Tr ifla tes
(3). To a dichloromethane solution of butenolide 2 (1.0 equiv)
were added triflic anhydride (1.2 equiv) and pyridine (2.0
equiv) at -78 °C. The solution was allowed to warm to -10
°C within 4 h. The product was isolated by rapid chromatog-
raphy (silica gel, dichloromethane) of the reaction mixture.
3a . Starting with butenolide 2a (1.90 g, 11.17 mmol), triflic
anhydride (2.26 mL, 13.41 mmol), and pyridine (1.80 mL, 22.35
mmol), 3a was isolated as a yellow solid (1.71 g, 51%): mp 66
°C; 1H NMR (300 MHz, CDCl3) δ 3.83 (s, 3 H, OCH3), 6.10 (d,
1 H, J ) 0.5 Hz, dCH), 8.20 (d, 1 H, J ) 0.5 Hz, dCH); 13C
NMR (75 MHz, CDCl3) δ 52.5 (CH3), 106.5 (CH), 118.4 (q, J )
319.1, CF3), 125.3 (CH), 140.6, 155.0, 159.2, 164.5 (C); IR (KBr)
ν 752 (w), 848 (w), 1058 (s), 1137 (m), 1223 (s), 1241 (s), 1440
(s), 1662 (m), 1723 (m), 1819(s) cm-1; MS (EI, 70 eV) m/z 302
(M+, 7), 207 (22), 125 (22), 70 (100), 60 (17). Anal. Calcd for
C8H5O7SF3 (302.17): C, 31.80; H, 1.66; S, 10.60. Found: C,
32.39; H, 1.72; S, 11.24.
3b. Starting with butenolide 2b (245 mg, 1.15 mmol), triflic
anhydride (0.23 mL, 1.38 mmol), and pyridine (0.18 mL, 1.38
mmol), 3b was isolated as a yellow oil (299 mg, 75%): 1H NMR
(300 MHz, CDCl3) δ 1.31 (t, 3 H, J ) 7.8 Hz, CH3), 1.34 (t, 3
H, J ) 7.2 Hz, CH3), 2.61 (q, 2 H, J ) 7.8 Hz, CH2), 4.30 (q, 2
H, J ) 7.2 Hz, OCH2), 5.71 (s, 1 H, dCH); 13C NMR (75 MHz,
CDCl3) δ 12.8, 14.2 (CH3), 17.2, 61.6 (CH2), 102.9 (CH), 118.4
(q, J ) 319.3 Hz, CF3), 135.4, 147.6, 152.2, 159.6, 162.2 (C);
IR (KBr) ν 1810 (s), 1726 (m), 1663 (w), 1434 (s), 1238 (s), 1134
(m), 1034 (s), 817 (m), 608 (w) cm-1; MS (EI, 70 eV) m/z 344
(M+, 2), 299 (44), 211 (23), 183 (44), 137 (40), 97 (20), 70 (100),
29 (61). Anal. Calcd for C11H11O7SF3 (344.25): C, 38.37; H,
3.22; S, 9.31. Found: C, 38.68; H, 3.46; S, 9.76.
3d . Starting with butenolide 2d (0.80 g, 3.56 mmol), triflic
anhydride (0.72 mL, 4.28 mmol), and pyridine (0.58 mL, 7.13
mmol), 3d was isolated as a yellow oil (1.11 g, 87%): 1H NMR
(300 MHz, CDCl3) δ 1.46 (t, 3 H, J ) 7.2 Hz, CH3), 1.95 (quint,
2 H, J ) 6.3 Hz, CH2), 2.69 (t, 2 H, J ) 6.0 Hz, CH2), 2.81 (t,
2 H, J ) 6.6 Hz, CH2), 4.32 (q, 2 H, J ) 7.2 Hz, OCH2); 13C
NMR (75 MHz, CDCl3) δ 14.0, (CH3), 21.2, 22.0, 24.5, 61.6
(CH2), 116.6, 118.2 (q, J ) 319.1 Hz, CF3), 131.2, 143.3, 147.5,
160.3, 163.5 (C); IR (KBr) ν 2986 (w), 1803 (s), 1710 (s), 1657
(m), 1436 (s), 1375 (m), 1263 (s), 1137 (s), 1094 (m), 1063 (s),
815 (m), 763 (m) cm-1; MS (EI, 70 eV) m/z 356 (M+, 9), 311
(16), 195 (99), 148 (73), 121 (35), 84 (64), 49 (84), 32 (100).
Anal. Calcd for C12H14O7SF3 (356.27): C, 40.45; H, 3.11.
Found: C, 40.80; H, 3.21.
4c. Starting with triflate 3a (140 mg, 0.46 mmol), 4-tolyl-
boronic acid (81 mg, 0.59 mmol), K3PO4 (157 mg, 0.73 mmol),
and Pd(PPh3)4 (16 mg, 0.013 mmol), 4c was isolated as a light
yellowish solid (85 mg, 75%): mp 110 °C; 1H NMR (300 MHz,
CDCl3) δ 2.40 (s, 3 H, CH3), 3.82 (s, 3 H, OCH), 5.90 (s, 1 H,
dCH), 7.27 (d, 2 H, J ) 7.2 Hz, ArH), 7.89 (dd, 2 H, J ) 1.5
Hz, 6.3 Hz, ArH), 8.42 (s, 1 H, dCH); 13C NMR (75 MHz,
CDCl3) δ 21.6, 52.0, (CH3), 100.8 (CH), 125.7 (C), 127.8 (2C),
129.8 (2C), 131.5 (CH), 134.8, 141.6, 159.6, 165.9, 167.1 (C);
IR (KBr) ν 3543 (w), 3436 (w), 3086 (w), 2952 (w), 1781 (s),
1650 (s), 1609 (m), 1438 (m), 1253 (s), 1223 (m), 1147 (s), 1080
3e. Starting with butenolide 2e (0.50 g, 2.23 mmol), triflic
anhydride (0.45 mL, 2.67 mmol), and pyridine (0.36 mL, 4.46
mmol), 3e was isolated as a pink solid (0.76 g, 95%): mp 64-
65 °C; 1H NMR (300 MHz, CDCl3) δ 1.85-1.98 (m, 4 H, CH2),
2.75 (t, 2 H, J ) 5.4 Hz, CH2), 2.83 (t, 2 H, J ) 6.3 Hz, CH2),
3.87 (s, 3 H, OCH3); 13C NMR (75 MHz, CDCl3) δ 22.9, 25.3,
26.1, 28.5 (CH2), 52.9 (CH3), 118.3 (q, J ) 319.12, CF3), 124.8,
134.5, 145.3, 147.1, 159.5, 166.2 (C); IR (KBr) ν 2941 (w), 1788
(s), 1735 (s), 1634 (w), 1440 (s), 1266 (m), 1238 (s), 1137 (s),
1134 (m), 1093 (m), 1050 (s), 860 (m), 618 (m) cm-1; MS (EI,
70 eV) m/z 356 (M+, 10), 325 (18), 195 (100), 163 (87), 135 (27),
95 (29), 70 (27). Anal. Calcd for C12H11O7SF3 (356.27): C, 40.45;
H, 3.11; S, 9.00. Found: C, 40.68; H, 3.13; S, 8.64.
(s), 1034 (m), 951 (m), 859 (m), 826 (s), 751 (w), 527 (w) cm-1
;
MS (EI, 70 eV) m/z 244 (M+, 100), 213 (50), 184 (60), 156 (9),
115 (48), 70 (59). Anal. Calcd for C14H12O4 (244.24): C, 68.84;
H, 4.95. Found: C, 68.92; H, 5.03.
4d . Starting with triflate 3a (120 mg, 0.39 mmol), 4-chloro-
phenylboronic acid (79 mg, 0.50 mmol), K3PO4 (132 mg, 0.62
mmol), and Pd(PPh3)4 (14 mg, 0.011 mmol), 4d was isolated
as a yellow solid (60 mg, 58%): mp 154 °C; 1H NMR (300 MHz,
CDCl3) δ 3.83 (s, 3 H, OCH3), 5.95 (s, 1 H, dCH), 7.46 (d, 2 H,
J ) 8.7 Hz, ArH), 7.95 (d, 2 H, J ) 8.7 Hz, ArH), 8.48 (s, 1 H,
dCH); 13C NMR (75 MHz, CDCl3) δ 52.1 (CH3), 101.7 (CH),
126.8 (C), 129.1 (2C), 129.4, (2C), 132.3 (CH), 133.6, 137.2,
159.1, 165.7, 166.7 (C); IR (KBr) ν 3089 (w), 2952 (w), 1800
(s), 1777 (s), 1722 (s), 1650 (s), 1598 (m), 1434 (m), 1380 (m),
1254 (s), 1143 (s), 1085 (s), 959 (m), 843 (m) cm-1; MS (EI, 70
eV) m/z 264 (M+, 100), 233 (58), 204 (38), 193 (7), 148 (10),
136 (59), 70 (68), 28 (30). Anal. Calcd for C13H9O4Cl (260.66):
C, 58.99; H, 3.42. Found: C, 58.64; H, 3.67.
3f. Starting with butenolide 2f (212 mg, 0.68 mmol), triflic
anhydride (0.14 mL, 0.81 mmol), and pyridine (0.11 mL, 1.36
mmol), 3f was isolated as a yellow oil (230 mg, 76%): 1H NMR
(300 MHz, CDCl3) δ 1.37 (t, 3 H, J ) 7.2 Hz, CH3), 1.43-1.69
(m, 10 H, CH2), 2.44-2.49 (m, 2 H, CH2), 2.63-2.69 (m, 2 H,
CH2), 4.35 (q, 2 H, J ) 7.2 Hz, OCH2); 13C NMR (75 MHz,
CDCl3) δ 14.1 (CH3), 19.7, 20.2, 23.5, 23.6, 24.4, 25.6, 25.7,
25.9, 26.5, 62.1 (CH2), 118.4 (q, J ) 319.3 Hz, CF3), 126.0,
135.3, 142.1, 146.2, 159.2, 165.9 (C); MS (EI, 70 eV) m/z 440
(M+, 2), 395 (46), 307 (52), 279 (95), 233 (100), 205 (85), 148
4e. Starting with triflate 3a (128 mg, 0.42 mmol), 2-thio-
pheneboronic acid (70 mg, 0.54 mmol), K3PO4 (143 mg, 0.67
mmol), and Pd(PPh3)4 (15 mg, 0.012 mmol), 4e was isolated
as a yellow solid (53 mg, 53%): mp 104 °C; 1H NMR (300 MHz,
J . Org. Chem, Vol. 69, No. 11, 2004 3755

Ahmed and Langer
CDCl3) δ 3.82 (s, 3 H, OCH3), 5.91 (s, 1 H, dCH), 7.16 (dd, 1
H, J ) 5.1 Hz, 3.9 Hz, dCH), 7.56 (dd, 1 H, J ) 0.91 Hz, 5.1
Hz, dCH), 7.91 (dd, 1 H, J ) 0.9 Hz, 3.9 Hz dCH), 8.24 (s, 1
H, dCH); 13C NMR (75 MHz, CDCl3) δ 52.0 (CH3), 101.2, 128.1,
128.6 (CH), 129.7 (C), 130.5, 130.7 (CH), 131.0, 159.8, 165.8,
166.3 (C); IR (KBr) ν 3190 (w), 2952 (w), 1795 (s), 1781 (s),
1706 (s), 1643 (s), 1586 (m), 1435 (m), 1254 (s), 1139 (s), 1077
(m), 1042 (m), 840 (m), 732 (m) cm-1; MS (EI, 70 eV) m/z 236
(M+, 29), 219 (22), 205 (15), 130 (80), 107 (18), 88 (25), 70 (30),
43 (58), 28 (100). Anal. Calcd for C11H8O4S (236.24): C, 55.92;
H, 3.41, S 13.57. Found: C, 55.85; H, 3.80, S 13.24.
4f. Starting with triflate 3b (146 mg, 0.42 mmol), phenyl-
boronic acid (67 mg, 0.55 mmol), K3PO4 (143 mg, 0.67 mmol),
and Pd(PPh3)4 (15 mg, 0.012 mmol), 4f was isolated as a
colorless solid (70 mg, 61%): mp 94-95 °C; 1H NMR (300 MHz,
CDCl3) δ 1.30 (t, 3 H, J ) 7.8 Hz, CH3), 1.36 (t, 3 H, J ) 7.2
Hz, CH3), 2.66 (q, 2 H, J ) 7.8 Hz, CH2), 4.31 (q, 2 H, J ) 7.2
Hz, OCH2), 5.59 (s, 1 H, dCH), 7.44-7.55 (m, 5 H, ArH); 13C
NMR (75 MHz, CDCl3) δ 14.1, 14.2 (CH3), 18.3, 61.1 (CH2),
98.2 (CH), 128.4 (C), 128.8 (2C), 128.9(2C), 129.7 (CH), 130.0,
152.4, 156.5, 163.6, 167.2 (C); IR (KBr) ν 2983 (m), 1780 (s),
1716 (s), 1655 (s), 1370 (m), 1297 (m), 1241 (m), 1188 (s), 1150
(s), 1044 (m), 967 (s), 864(w), 702 (m) cm-1; MS (EI, 70 eV)
m/z 272 (M+, 46), 226 (100), 198 (62), 129 (45), 114 (60), 91
(22), 70 (49), 43 (30), 29 (44). Anal. Calcd for C16H16O4
(273.58): C, 70.34; H, 6.36. Found: C, 70.33; H, 6.50.
4j. Starting with triflate 3f (125 mg, 0.28 mmol), phenyl-
boronic acid (45 mg, 0.36 mmol), K3PO4 (95 mg, 0.44 mmol),
and Pd(PPh3)4 (11 mg, 0.008 mmol), 4j was isolated as a
1
colorless solid (73 mg, 70%): mp 149 °C; H NMR (300 MHz,
CDCl3) δ 1.38 (t, 3 H, J ) 7.2 Hz, CH3), 1.42-1.48 (m, 10 H,
CH2), 1.57-1.65 (m, 2 H, CH2), 1.68-1.74 (m, 2 H, CH2), 2.48-
2.59 (m, 2 H, CH2), 2.68-2.71 (m, 2 H, CH2), 4.36 (q, 2 H, J )
7.2 Hz, OCH2), 7.38-7.49 (m, 5 H, ArH); 13C NMR (75 MHz,
CDCl3) δ 14.4 (CH3), 19.8, 20.4, 24.2, 24.9, 25.0, 25.8, 26.0,
26.1, 28.8, 62.0 (CH2), 128.9, (2C, CH), 129.3 (C), 129.3 (2C,
CH), 129.6 (C), 129.8 (CH), 131.3, 146.6, 150.8, 167.5, 167.7
(C); IR (KBr) ν 2937 (s), 2874 (w), 1761 (s), 1722 (s), 1471 (m),
1309 (m), 1213 (m), 1160 (w), 1130 (w), 1090 (w), 1027 (w),
702 (w) cm-1; MS (EI, 70 eV) m/z 368 (M+, 27), 322 (21), 294
(34), 277 (25), 212 (22), 115 (36), 91 (18), 55 (23), 28 (100).
Anal. Calcd for C23H28O4 (368.47): C, 74.97; H, 7.66. Found:
C, 74.51; H, 7.88.
Syn th esis of â-Ketoester 7. The reaction was carried out
analogously to a known procedure.7 To a stirred solution of
LDA (58.0 mmol) in THF (150 mL) was added methyl phenyl-
acetate (8.10 mL, 57.6 mmol) at -78 °C. After the solution
was stirred for 1 h, methyl methoxyacetate (3.00 g, 28.8 mmol)
was added. The temperature of the solution was allowed to
rise to 20 °C during 12 h. A saturated aqueous solution of NH4-
Cl was added, the layers were separated, and the aqueous
layer was extracted with dichloromethane (3 × 150 mL). The
combined organic layers were dried (Na2SO4) and filtered, and
the solvent of the filtrate was removed in vacuo. The residue
was purified by chromatography (silica gel, hexane/EtOAc) to
give 7 as a colorless oil (4.58 g, 67%): 1H NMR (300 MHz,
CDCl3) δ 3.35 (s, 3 H, OCH3), 3.74 (s, 3 H, OCH3), 3.86 (s, 1 H,
CH), 4.08 (s, 2 H, CH2), 7.31-7.36 (m, 5 H, ArH); MS (EI, 70
eV) m/z 222 (M+, 100). Anal. Calcd for C12H14O4 (222.24): C,
64.85; H, 6.35. Found: C, 64.55; H, 6.58.
Syn th esis of Silyl En ol Eth er 8. The reaction was carried
out analogously to a known procedure.4b To a stirred benzene
solution (10 mL) of 7 (4.50 g) was added triethylamine (4.50
mL, 32.4 mmol). After the solution was stirred for 2 h,
trimethylchlorosilane (4.60 mL, 36.4 mmol) was added. After
the solution was stirred for 72 h, the solvent was removed in
vacuo and to the residue was added hexane (100 mL) to give
a suspension. The latter was filtered under argon atmosphere.
The filtrate was distilled in vacuo to give 8 as a colorless oil
(5.00 g, 84%). The compound was used directly after its
preparation: 1H NMR (300 MHz, CDCl3) δ ) 0.08 (s, 9 H, CH3),
3.26 (s, 3 H, OCH3), 3.44 (s, 3 H, OCH3), 3.77 (s, 2 H, CH2),
7.21-7.39 (m, 5 H, ArH).
4g. Starting with triflate 3c (150 mg, 0.45 mmol), 2-thio-
pheneboronic acid (75 mg, 0.58 mmol), K3PO4 (153 mg, 0.72
mmol), and Pd(PPh3)4 (16 mg, 0.013 mmol), 4g was isolated
1
as a yellow solid (65 mg, 54%): mp 94-95 °C; H NMR (300
MHz, CDCl3) δ 3.83 (s, 3 H, OCH3), 4.04 (s, 3 H, OCH3), 5.72
(s, 1 H, dCH), 7.13 (dd, 1 H, J ) 5.1 Hz, 3.6 Hz, dCH), 7.51
(dd, 1 H, J ) 0.91 Hz, 5.1 Hz, dCH), 7.57 (dd, 1 H, J ) 0.9
Hz, 3.6 Hz, dCH); 13C NMR (75 MHz, CDCl3) δ 52.1, 61.2
(CH3), 97.0 (CH), 106.7(C), 127.4, 129.0, 130.1 (CH), 130.5,
151.5, 160.5, 163.6, 166.0 (C); IR (KBr) ν 3087 (w), 2948 (w),
1782 (s), 1718 (s), 1653 (s), 1627 (m), 1511 (w), 1436 (m), 1365
(m), 1203 (m), 1172 (m), 1124 (m), 1022 (m), 842 (m), 724 (m)
cm-1; MS (EI, 70 eV) m/z 266 (M+, 100), 235 (13), 206 (25),
150 (38), 123 (39), 70 (42), 28 (67). Anal. Calcd for C12H10O5S
(266.27): C, 54.12; H, 3.78, S 12.04. Found: C, 54.59; H, 3.96,
S 12.24.
4h . Starting with triflate 3d (250 mg, 0.70 mmol), phenyl-
boronic acid (111 mg, 0.91 mmol), K3PO4 (238 mg, 1.12 mmol),
and Pd(PPh3)4 (24 mg, 0.021 mmol), 4h was isolated as a light
yellow solid (130 mg, 65%): mp 138-139 °C; 1H NMR (300
MHz, CDCl3) δ 1.38 (t, 3 H, J ) 7.2 Hz, CH3), 1.91 (quint, 2
H, J ) 6.3 Hz, CH2), 2.67 (t, 2 H, J ) 6.0 Hz, CH2), 2.91 (t, 2
H, J ) 6.3 Hz, CH2), 4.34 (q, 2 H, J ) 7.2 Hz, OCH2), 7.40-
7.49 (m, 3 H, ArH), 7.63-7.67 (m, 2 H, ArH); 13C NMR (75
MHz, CDCl3) δ 14.3 (CH3), 22.3, 22.5, 24.6, 61.4 (CH2) 111.6,
124.6 (C), 128. 7 (2C), 128.7 (2C), 129.2 (CH), 129.3, 148.3,
151.9, 165.0, 168.2 (C); MS (EI, 70 eV) m/z 284 (M+, 92), 238
(83), 210 (100), 183 (19), 114 (50), 77 (9), 29 (10). Anal. Calcd
for C17H16O4 (284.31): C, 71.81; H, 5.67. Found: C, 72.02; H,
5.40.
Syn th esis of Bis-Silyl En ol Eth er 9. The reaction was
carried out analogously to a known procedure.4b To a stirred
THF solution (100 mL) of LDA (20.4 mmol, 1.5 equiv) was
added 8 (4.00 g, 13.6 mmol) at -78 °C. After the solution was
stirred for 1 h, trimethylchlorosilane (2.57 mL, 20.4 mmol) was
added. The solution was allowed to warm to room temperature
during 12 h with stirring. The solvent was removed in vacuo,
and to the residue was added hexane (100 mL) to give a
suspension. The latter was filtered under argon atmosphere.
The filtrate was distilled in vacuo to give 9 as a colorless oil
(4.50 g, 90%): The compound was used directly after its
4i. Starting with triflate 3e (150 mg, 0.42 mmol), phenyl-
boronic acid (68 mg, 0.54 mmol), K3PO4 (143 mg, 0.67 mmol),
and Pd(PPh3)4 (15 mg, 0.012 mmol), 4i was isolated as a light
yellow solid (105 mg, 87%): mp 115-116 °C; 1H NMR (300
MHz, CDCl3) δ 1.82 (quint, 2 H, J ) 6.0 Hz, CH2), 1.94 (quint,
2 H, J ) 6.0 Hz, CH2), 2.76 (t, 2 H, J ) 6.0 Hz, CH2), 2.89 (t,
2 H, J ) 6.0 Hz, CH2), 3.88 (s, 3 H, OCH3), 7.40-7.50 (m, 5 H,
ArH); 13C NMR (75 MHz, CDCl3) δ 23.5, 26.3, 26.9, 27.0 (CH2),
52.7 (CH3), 118.2 (2C, C), 128.6 (2C, CH), 129.1 (C), 129.2,
129.3 (2C, CH), 151.1, 152.1, 167.4, 167.8 (C); IR (KBr) ν 2949
(m), 1763 (s), 1696 (s), 1627 (m), 1440 (m), 1306 (m), 1272 (m),
1
preparation. H NMR (300 MHz, CDCl3) δ 0.04 (s, 9 H, CH3),
0.31 (s, 9 H, CH3), 3.41 (s, 3 H, OCH3), 3.56 (s, 3 H, OCH3),
5.63 (s, 1 H, dCH), 7.22-7.35 (m, 5 H, ArH).
Syn th esis of Bu ten olid e 10. The reaction was carried out
analogously to a known procedure.4b To a CH2Cl2 solution (120
mL) of oxalyl chloride (0.70 mL, 7.8 mmol) and of 1,3-bis-
(trimethylsilyloxy)-1,3-diene 9 (2.20 g, 6.0 mmol) was added
a CH2Cl2 solution (5 mL) of Me3SiOTf (0.6 mL, 3.6 mmol) at
-78 °C. The temperature of the reaction mixture was allowed
to rise to 20 °C during 12 h. After the mixture was stirred for
2 h at 20 °C, a saturated aqueous solution of NaCl was added.
The aqueous layer was separated and extracted with CH2Cl2.
The combined organic layers were washed with an aqueous
solution of HCl (10%), dried (Na2SO4), and filtered. The solvent
1220 (w), 1131 (m), 1060 (m), 949 (m), 789 (w), 701 (w) cm-1
;
MS (EI, 70 eV) m/z 284 (M+, 44), 252 (79), 224 (100), 196 (18),
168 (15), 128 (12), 114 (28), 91 (10), 59 (6). Anal. Calcd
for C17H16O4 (284.31): C, 71.81; H, 5.67. Found: C, 71.69; H,
5.76.
3756 J . Org. Chem., Vol. 69, No. 11, 2004

Suzuki Cross-Coupling Reactions of γ-Alkylidenebutenolides
of the filtrate was removed in vacuo, and the residue was
purified by column chromatography (silica gel, hexane/EtOAc)
to give 10 as a yellow solid (900 mg, 54%): 1H NMR (300 MHz,
CDCl3) δ ) 3.84 (s, 3 H, OCH3), 4.18 (s, 3 H, OCH3), 7.31-
7.56 (m, 5 H, ArH), 12.93 (s, 1 H, OH); MS (EI, 70 eV) m/z 276
(M+, 100). Anal. Calcd for C14H12O6 (276.25): C, 60.87; H, 4.38.
Found: C, 60.62; H, 4.52.
Syn th esis of Tr ifla te 11. The synthesis was carried out
according to the procedure given for the synthesis of triflates
3. Starting with butenolide 10 (520 mg), triflic anhydride (0.38
mL), and pyridine (0.3 mL), 11 (469 mg, 61%) was isolated as
a colorless solid: mp 118 °C; 1H NMR (300 MHz, CDCl3) δ
3.89 (s, 3 H, OCH3), 4.30 (s, 3 H, OCH3), 7.42 (dd, 2 H, J ) 5.2
Hz, 2.0 Hz, ArH), 7.58-7.61 (m, 3 H, ArH); 13C NMR (75 MHz,
CDCl3) δ 53.0, 61.1 (CH3), 114.2, 118.3 (q, J ) 319.9 Hz, CF3),
120.8 (C) 128.9 (2C), 129.3 (2C, CH), 130.0 (C), 130.2 (CH),
137.1, 155.5, 160.0, 165.6 (C); IR (KBr) ν 2960 (w), 1799 (s),
1736 (s), 1662 (s), 1646 (s), 1426 (s), 1366 (m), 1332 (m), 1203
(s), 1137 (m), 1089 (s), 1048 (s), 803 (m), 625 (m) cm-1; MS
(EI, 70 eV) m/z 408 (M+, 38), 275 (25), 219 (100), 191 (97), 145
(21), 89 (34), 28 (62). Anal. Calcd for C15H11O8SF3 (408.30):
C, 44.12; H, 2.71. Found: C, 44.22; H, 2.88.
167.7 (C); IR (KBr) ν 1775 (s), 1730 (s), 1622 (m), 1494 (w),
1449 (w), 1429 (w), 1368 (m), 1303 (m), 1231 (s), 1159 (m),
1042 (s), 934 (m), 698 (m) cm-1; MS (EI, 70 eV) m/z 336 (M+,
100), 249 (20), 219 (50), 191 (43), 176 (13), 145 (18), 89 (54),
77 (12). Anal. Calcd for C20H16O5 (336.34): C, 71.42; H, 4.79.
Found: C, 71.64; H, 4.83.
Syn th esis of Vu lp in ic Acid (13). To a CH2Cl2 solution (20
mL) of 12 (75 mg, 0.22 mmol) was added BBr3 (0.09 mL, 0.89
mmol) at 0 °C, and the mixture was stirred for 2 h at 0 °C. An
aqueous solution of HCl (5%) was added. The aqueous layer
was separated and extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were dried (Na2SO4) and filtered, and
the solvent of the filtrate was removed in vacuo. The residue
was purified by column chromatography (silica gel, hexane/
EtOAc) to give 13 as a light yellow solid (45 mg, 63%). The
spectroscopic data of 13 are identical to those reported for
vulpinic acid in the literature:8a 1H NMR (300 MHz, CDCl3) δ
3.86 (s, 3 H, OCH3), 7.25-7.46 (m, 8 H, ArH), 8.11-8.14 (m,
2 H, ArH), 13.76 (s, 1 H, OH); 13C NMR (75 MHz, CDCl3) δ
54.5 (CH3), 105.2, 115.8 (C), 127.9 (2C), 128.1 (2C), 128.4 (2C),
128.6 (CH), 128.9 (C), 129.9 (2C, CH), 131.9, 154.9, 160.2,
165.9, 171.7 (C); IR (KBr) ν 3435 (m), 2959 (w), 2564 (w), 1771
(s), 1679 (w), 1612 (s), 1438 (s), 1306 (s), 1071 (s), 955 (m),
692 (w) cm-1; MS (EI, 70 eV) m/z 322 (M+, 29), 290 (85), 234
(15), 145 (80), 89 (100). Anal. Calcd for C19H14O5 (322.31): C,
70.80; H, 4.37. Found: C, 70.35; H, 4.50.
Syn th esis of Bu ten olid e 12. The synthesis was carried
out according to the procedure given for the synthesis of
butenolides 4.
1. Starting with triflate 11 (140 mg, 0.34 mmol), phenyl-
boronic acid (55 mg, 0.44 mmol), K3PO4 (116 mg, 0.54 mmol),
and Pd(PPh3)4 (12 mg, 0.01 mmol), 12 was isolated as a light
yellow solid (100 mg, 86%): mp 138-139 °C; 1H NMR (300
MHz, CDCl3) δ 3.78 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 7.34-
7.69 (m, 10 H, ArH); 13C NMR (75 MHz, CDCl3) δ 52.8, 61.3
(CH3), 108.2, 116.3, 128.3 (C), 128.5 (2C), 128.8 (2C), 129.0,
129.1 (2C), 129.4, 129.9 (2C, CH), 131.0, 141.4, 162.6, 167.0,
Ackn owledgm en t. Financial support from the Deut-
sche Forschungsgemeinschaft and from the government
of Mecklenburg-Vorpommern (scholarship for Z.A.) is
gratefully acknowledged.
J O049780A
J . Org. Chem, Vol. 69, No. 11, 2004 3757