Efficient synthesis of γ-alkylidenetetronic esters by sequential lewis acid catalyzed [3 + 2] cyclizations and palladium-catalyzed cross-coupling reactions

Article abstract of DOI:10.1021/jo005565s

A new approach for the synthesis of γ-alkylidenetetronic acids and esters is reported which involves Me₃SiOTf-catalyzed, regio- and stereoselective cyclization of 4-alkoxy-1,3-bis(trimethylsilyloxy)-1,3-butadienes with oxalyl chloride. The α-hydroxy group of the butenolides is efficiently functionalized by palladium-catalyzed cross-coupling reactions via the corresponding enol triflates.

Full text of DOI:10.1021/jo005565s

2222
J . Org. Chem. 2001, 66, 2222-2226
Efficien t Syn th esis of γ-Alk ylid en etetr on ic Ester s by Sequ en tia l
Lew is Acid Ca ta lyzed [3 + 2] Cycliza tion s a n d
P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin g Rea ction s
Peter Langer,* Tobias Eckardt, and Toni Schneider
Institut fu¨r Organische Chemie der Georg-August-Universita¨t Go¨ttingen,
Tammannstrasse 2, 37077 Go¨ttingen, Germany
Cornelia Go¨bel and Regine Herbst-Irmer
Institut fu¨r Anorganische Chemie der Georg-August-Universita¨t Go¨ttingen,
Tammannstrasse 4, 37077 Go¨ttingen, Germany
planger@uni-goettingen.de
Received J uly 4, 2000
A new approach for the synthesis of γ-alkylidenetetronic acids and esters is reported which involves
Me3SiOTf-catalyzed, regio- and stereoselective cyclization of 4-alkoxy-1,3-bis(trimethylsilyloxy)-
1,3-butadienes with oxalyl chloride. The R-hydroxy group of the butenolides is efficiently function-
alized by palladium-catalyzed cross-coupling reactions via the corresponding enol triflates.
Sch em e 1. Syn th esis of th e γ-Alk ylid en etetr on ic
Ester s 4a -d
Many natural products, such as pulvinic or pinastric
acid, belong to the pharmacologically relevant substance
class of γ-alkylidenetetronic acid derivatives.1,2 These
heterocycles have been used as building blocks in natural
product syntheses, for example, in an approach3 to the
spirocyclic fragment of the antibiotic chlorotricolide.4 The
preparation of γ-alkylidenetetronic acid derivatives from
ascorbic acid requires several steps and has the dis-
advantage that no additional substituents can be intro-
duced at the exocyclic double bond and at the butenolide
moiety.5a In addition, regioselective protection of the two
hydroxy groups of ascorbic acid derivatives is problematic
and requires additional steps.5b,c We have recently re-
ported6 the first Lewis acid catalyzed cyclizations of 1,3-
bis(trimethylsilyloxy)-1,3-butadienes, electroneutral 1,3-
dicarbonyl dianion equivalents,7 with oxalyl chloride to
give γ-alkylidenebutenolides. Herein, we wish to report
full details of a significant extension of this methodology
to the synthesis of γ-alkylidenetetronic acid derivatives.8
In addition, we report, to our knowledge, the first
Ta ble 1. Syn th esis of γ-Alk ylid en etetr on ic Ester s 4a -d
entry
R1
R2
2a (%)
3a (%)
4a (%)
δb (ppm)
a
b
c
d
a
Me
Me
Allyl
Bn
OMe
Me
OEt
OEt
92
93
93
95
88
72
82
86
85
72
54
70
5.44
5.52
5.42
5.43
* To whom correspondence should be addressed. Fax: 0049 (0) 551
399475.
(1) Reviews: (a) Rao, Y. S. Chem. Rev. 1976, 76, 625. (b) Pattenden,
G. Prog. Chem. Nat. Prod. 1978, 35, 133. (c) Knight, D. W. Contemp.
Org. Synth. 1994, 1, 287. (d) Negishi, E.-i.; Kotora, M. Tetrahedron
1997, 53, 6707.
Isolated yields (Z/E > 98:2 for 4a -d ). Chemical shift (1H
b
NMR) of the proton of the exocyclic double bond of 4a -d .
palladium-catalyzed cross-coupling reactions of R-hy-
droxy-γ-alkylidenetetronic esters.
(2) (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.
(c) Enders, D.; Dyker, H.; Leusink, F. R. Chem. Eur. J . 1998, 4, 311.
(3) Poss, A. J .; Brodowski, M. H. Tetrahedron Lett. 1989, 2505.
(4) Ireland, R. E.; Varney, M. D. J . Org. Chem. 1986, 51, 635.
(5) (a) Khan, M. A.; Adams, H. Synthesis 1995, 687. (b) Nihro, Y.;
Sogawa, S.; Izumi, A.; Sasanori, A.; Sudo, T.; Miki, T.; Matsumoto,
H.; Satoh, T. J . Med. Chem. 1992, 35, 1618. (c) For regioselective
alkylations, see: Beifuss, U.; Kunz, O.; Aguado, G. P. Synlett 1999,
147.
(6) (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. (c) Langer, P.; Eckardt, T.; Stoll, M. Org.
Lett. 2000, 2991. (d) Langer, P.; Saleh, N. N. R. Org. Lett. 2000, 3333.
(7) (a) Krohn, K.; Ostermeyer, H.-H.; Tolkiehn, K. Chem. Ber. 1979,
112, 2640-2649. (b) Chan, T.-H.; Brownbridge, P. J . Am. Chem. Soc.
1980, 102, 3534. (c) Molander, G. A.; Cameron, K. O. J . Am. Chem.
Soc. 1993, 115, 830.
Resu lts a n d Discu ssion
Commercially available methyl 4-methoxyacetoacetate
1a and the known 1,3-diketone 1b9 were converted into
the silyl enol ethers 2a ,b and subsequently treated with
LDA and Me3SiCl at -78 °C to give the 1,3-bis(tri-
methylsilyloxy)-1,3-butadienes 3a ,b (Scheme 1).10 The
Me3SiOTf-catalyzed cyclization of 3a ,b with oxalyl chlo-
ride resulted in regioselective formation of the Z-config-
ured γ-alkylidenetetronic esters 4a ,b in good yields
(Table 1). The application of our recently published
(8) Parts of this work have been published as
communication: Langer, P.; Eckardt, T. Synlett 2000, 844.
a
preliminary
(9) Brisson, C.; Brassard, P. J . Org. Chem. 1981, 46, 1810.
(10) Simoneau, B.; Brassard, P. Tetrahedron 1986, 14, 3767.
10.1021/jo005565s CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/09/2001

Synthesis of γ-Alkylidenetetronic Esters
J . Org. Chem., Vol. 66, No. 7, 2001 2223
Ta ble 2. Op tim iza tion of th e Syn th esis of th e γ-Alk ylid en etetr on ic Ester 8a
entry
catalyst (mol %)
additive (equiv)
T (°C)
solvent
t (h)
yield (8a )a
1
2
3
4
5
6
7
Pd(OAc)2 (10)b
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
LiCl (3.0)
LiCl (3.0)
CsF (3.0), LiCl (0.1)
60-80
20
20
20
20
DMF
THF
THF
THF
THF
THF
THF
48
48
48
48
48
24
24
0
6
7
Pd2dba3‚CHCl3 (10)c
Pd2dba3‚CHCl3 (10)c
Pd2dba3‚CHCl3 (10)c
Pd2dba3‚CHCl3 (10)c
0
LiCl (3.0)
LiCl (3.0)
LiCl (3.0)
41
42
40
20
55
a
b
Isolated yield. PPh3 (60 mol %) was added. c P(2-furyl)3 (20-40 mol %) was added.
Sch em e 2. Syn th esis of γ-Alk ylid en etetr on ic
Sch em e 3. Syn th esis a n d Cr oss-Cou p lin g
Rea ction s of En ol Tr ifla tes 7a ,b
Acid 6
dianion methodology6a for the synthesis of γ-alkylidene-
butenolides to the preparation of 4a -d proved unsuc-
cessul, since the dianions of 1a -d could not be gener-
ated.11 The structure and the Z-configuration of 4a were
independently confirmed by X-ray crystallography (Fig-
ure 1, Supporting Information).
The free γ-alkylidenetetronic acid 6 was prepared from
tetronic ester 4d as depicted in Scheme 2.8 The benzyl
protecting group could be chemoselectively removed from
5b, whereas deprotection of 5a resulted in decomposition
under a variety of conditions.
Ta ble 3. P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin g Rea ction s
of Tr ifla tes 7a ,b
7
8
R1
R2
R3
R
yielda (%)
a
a
a
a
a
a
b
b
b
b
a
a
b
c
d
e
f
g
h
i
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
OMe
OMe
OMe
OMe
OMe
OMe
OEt
OEt
OEt
OEt
Ph
Ph
2-furyl
-CtCPh
Me
-CHdCH2
Ph
p-MeOC6H4
2-furyl
Bu
Me
Bu
Me
Me
Bu
Me
Me
Bu
Me
34
42
46
35
37
37
46
57
61
30
-CtCPh
We next focused on the functionalization of the R-car-
bon of the γ-alkylidenetetronic esters by palladium-
catalyzed cross-coupling reactions. The butenolides 4a
and 4d were transformed by trifluoromethanesulfonic
anhydride/pyridine into the corresponding triflates 7a
and 7b, respectively. Our first attempts to induce a
palladium-catalyzed cross-coupling reaction of triflate 7a
with tributylphenylstannane using Pd(OAc)2 as the
catalyst were unsuccessful.13,14 The use of Pd(PPh3)4
resulted in formation of the desired coupling product 8a ,
however, in only low yield. The initial problems can be
explained by the low reactivity of hindered, electron-rich
enol triflates toward palladium-catalyzed cross-coupling
reactions.15,16
a
Isolated yields.
We have eventually found that optimal yields were
obtained when Pd2dba3‚CHCl3 (10-20 mol %) in the
presence of LiCl (3.0 equiv) and P(2-furyl)3 (20-40 mol
%) was used (Scheme 3, Table 2).17 Related conditions
have been previously employed by Bru¨ckner et al. in
butenolide syntheses.2b It was difficult to isolate the
product in pure form, since Bu3SnCl could not be com-
pletely removed. However, the problem could be solved
by the use of Me3SnPh (rather than Bu3SnPh), which
resulted in formation of water-soluble Me3SnCl.
Palladium-catalyzed cross-coupling of triflate 7a with
trimethylphenylstannane, tributyl(2-furyl)stannane, tri-
methyl(phenylalkynyl)stannane, tetramethylstannane,
and tributylvinylstannane afforded the γ-alkylidene-
tetronic esters 8a -e in acceptable yields (Table 3). Stille
couplings of the benzyloxy-substituted triflate 7b were
next studied: reaction of 7b with trimethylphenylstan-
nane, trimethyl(p-tolyl)stannane, tributyl(2-furyl)stan-
nane, and trimethyl(phenylalkynyl)stannane gave the
γ-alkylidenetetronic esters 8f-i in acceptable yields.
In summary, we have developed a conceptually new
approach to γ-alkylidenetetronic esters by a [3 + 2]
(11) For an account of the regioselectivity of deprotonations of
R-alkoxy and R-acyloxy ketones, see: Paquette, L. A.; O’Neil, S. V.;
Guillo, N.; Zeng, Q.; Young, D. G. Synlett 1999, 1857.
(12) Beck, G.; J endralla, H.; Kessler, K. Synthesis 1995, 1014.
(13) (a) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Scott, W. J .; McMurry, J . E. Acc. Chem. Res. 1988, 21, 47.
(14) For Stille reactions of enol triflates, see: (a) Echavarren, A.
M.; Stille, J . K. J . Am. Chem. Soc. 1987, 109, 5478. (b) Echavarren, A.
M.; Stille, J . K., J . Am. Chem. Soc. 1988, 110, 1557.
(15) (a) Heck, R. F. Palladium Reagents in Organic Synthesis;
Academic Press: New York. (b) Trost, B. M.; Verhoeven, T. R. In
Comprehensive Organometallic Chemistry; Wilkinson, G., Ed.; Perga-
mon Press: Oxford, 1982; Vol. 8. (c) de Meijere, A.; Meyer, F. E. Angew.
Chem. 1994, 106, 2473; Angew. Chem., Int. Ed. Engl. 1994, 33, 2379.
(16) For Stille reactions of hindered, electron-rich 2,6-dimethoxyaryl-
triflates, see: Saa´, J . M.; Martorell, G.; Garc´ıa-Raso, A. J . Org. Chem.
1992, 57, 678.
(17) For the first use of Pd2dba3 and P(2-furyl)3 in Stille reactions,
see: Farina, V.; Baker, S. R.; Benigni, D. A.; Hauck, S. I.; Sapino, C.,
J r. J . Org. Chem. 1990, 55, 5833.

2224 J . Org. Chem., Vol. 66, No. 7, 2001
Langer et al.
minimum transmission, 0.9728 and 0.9466; refinement method,
full-matrix least-squares on F2; data/restraints/parameters,
2956/1/265; GOF, 1.166; final R indices [I > 2σ(I)], R1 ) 0.0628,
wR2 ) 0.1445; R indices (all data), R1 ) 0.0790, wR2 ) 0.1515;
extinction coefficient, 0.0075(14); largest difference peak and
cyclization-Stille coupling strategy. A free γ-alkylidene-
tetronic acid was prepared from the corresponding ben-
zoate ester by chemoselective debenzylation. The γ-alkyl-
idenetetronic acid derivatives reported herein are of
pharmacological relevance and represent analogues of
pulvinic acid and related natural products.
hole, 0.346 and -0.313 e‚Å-3
.
4-Meth oxy-5-[Z-(a cetylm eth ylid en e]-3-h yd r oxy-2-fu r a -
n on e (4b). Starting with diene 3b (405 mg, 1.48 mmol), 4b
was isolated as a colorless solid (196 mg, 72%): mp 82 °C; 1H
NMR (acetone-d6, 300 MHz) δ 2.35 (s, 3 H, COCH3), 4.20 (s, 3
H, OCH3), 5.52 (s, 1 H, CH); 13C NMR (acetone-d6, 75 MHz)
δC 31.04 (COCH3), 59.82 (OCH3), 104.25 (CH), 125.03, 142.84,
151.48 (OCC), 164.48 (OCO), 194.97 (CO); IR (KBr) v˜ 3565,
3164, 1783, 1693, 1623, 1464, 1424, 1364, 1271, 1195, 1117,
1086, 1033, 1011 cm-1; MS (EI, 70 eV) m/z 184 (M+, 71), 169
(100), 141 (35), 128 (72), 113 (90), 85 (48). The exact molecular
mass m/z ) 184.0371 ( 2 mD (M+) was confirmed by HRMS
(EI, 70 eV). Anal. Calcd for C8H8O5: C, 52.18; H, 4.38. Found:
C, 52.38; H, 4.32.
4-Allyloxy-5-[Z-(e t h oxyca r b on ylm e t h ylid e n e ]-3-h y-
d r oxy-2-fu r a n on e (4c). Starting with diene 3c (1.63 mmol,
0.54 g), 4c was isolated as a colorless oil (212 mg, 54%): 1H
NMR (acetone-d6, 250 MHz) δ 1.24 (t, J ) 7.1 Hz, 3 H,
OCH2CH3), 4.17 (q, J ) 7.1 Hz, 2 H, OCH2CH3), 4.94-5.04
(m, 2 H, OCH2CHCH2), 5.21-5.51 (m, 3 H, dCH-, OCH2CHd
CH2), 6.01-6.19 (m, 1 H, OCH2CHdCH2); 13C NMR (acetone-
d6, 50 MHz) δC 14.48 (OCH2CH3), 60.83 (OCH2CH3), 72.59
(OCH2CHdCH2), 95.03 (CHCdO), 119.02 (OCH2CH)CH2),
125.39 (C), 133.53 (OCH2CHdCH2), 141.24, 153.10 (C), 163.30,
164.94 (CdO); MS (CI, NH3) m/z 240 (100, M+).
4-Ben zyloxy-5-[Z-(eth oxyca r bon ylm eth ylid en e)]-3-h y-
d r oxy-2-fu r a n on e (4d ). Starting with 4-benzyloxy-1,3-bis-
(trimethylsilyloxy)-1,3-diene 3d (1.5 mmol), 4d was isolated
as a colorless solid (302 mg, 70%): mp 67-69 °C; 1H NMR
(acetone-d6, 250 MHz) δ 1.23 (t, J ) 6 Hz, 3 H, CH3), 2.85 (br,
1 H, OH), 4.15 (q, J ) 6 Hz, 2 H, OCH2CH3), 5.43 (s, 1 H,
CCHCO), 5.55 (s, 2 H, CH2Ph), 7.30-7.55 (m, 5 H, Ph); 13C
NMR (acetone-d6, 50 MHz) δC 14.42 (CH3), 60.81 (OCH2CH3),
73.61 (OCH2Ph), 95.06 (CCHCO), 125.63 (C), 128.77, 129.15,
129.30 (CH, Ph), 136.91, 141.32, 153.10 (C), 163.30, 164.88
(CO); MS (EI, 70 eV) m/z 290 (M+, 100). Anal. Calcd for
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-
tography silica gel (60-200 mesh) was used. Melting points
are uncorrected. Elemental analyses were performed at the
microanalytical laboratory of the University of Go¨ttingen.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of γ-Alk yl-
id en etetr on ic Ester s 4a -d . To a CH2Cl2 solution (30 mL)
of oxalyl chloride (1.5 mmol, 0.13 mL) were added the 1,3-bis-
(trimethylsilyloxy)-1,3-diene (1.5 mmol) and a CH2Cl2 solution
(7 mL) of Me3SiOTf (0.45 mmol) at -78 °C. The solution was
warmed within 6 h to 20 °C and stirred for 14 h at 20 °C. A
saturated aqueous solution of brine was added and the
aqueous layer was extracted with ether (4 × 200 mL). The
combined organic layers were dried (MgSO4) and filtered, and
the filtrate was concentrated in vacuo. The residue was
purified by chromatography (silica gel, ether/petroleum ether
) 1:10 f 1:3).
4-Meth oxy-5-[Z-(m eth oxyca r bon ylm eth ylid en e]-3-h y-
d r oxy-2-fu r a n on e (4a ).6b Starting with 1,4-dimethoxy-1,3-
bis(trimethylsilyloxy)-1,3-butadiene 3a (436 mg, 1.50 mmol),
tetronic ester 4a was isolated as a colorless solid (255 mg,
85%): mp 87 °C; 1H NMR (MeOH-d4, 250 MHz) δ 3.75 (s, 3 H,
OCH3), 4.18 (t, 3 H, CO2CH3), 5.44 (s, 1 H, CH). 13C NMR
(MeOH-d4, 62.5 MHz) δC 52.14 (OCH3), 59.86 (CO2CH3), 94.29
(CH), 126.31, 142.53, 154.34 (C), 165.57, 165.70 (CO). IR (KBr)
v˜ 3208, 3082, 2877, 1795, 1682, 1466, 1442, 1372, 1348, 1302,
1195, 1119, 1089, 1024 cm-1; MS (EI, 70 eV) m/z 200 (M+, 61),
169 (50), 140 (30), 113 (64), 85 (42), 69 (100). The exact
molecular mass m/z ) 200.0320 ( 2 mD (M+) was confirmed
by HRMS (EI, 70 eV). Anal. Calcd for C8H8O6: C, 48.01; H,
4.03. Found: C, 47.71;, H, 4.28.
C
15H14O6: C, 62.07; H, 4.86. Found: C, 62.32; H, 4.63.
3-Ben zoyloxy-4-ben zyloxy-5-[Z-(eth oxyca r bon ylm eth -
ylid en e)]-2-fu r a n on e (5b). To a pyridine solution (30 mL)
of 4d (100 mg, 0.34 mmol) was added benzoyl chloride (0.14
mL, 1.14 mmol) at 0 °C. After the solution was stirred for 24
h at 0 °C, the mixture was poured into a saturated aqueous
solution of NaHCO3. The organic layer was extracted with
water (3 × 40 mL), dried (Na2SO4), and filtered, and the filtrate
was concentrated in vacuo to give 5b as a colorless solid (126
mg, 93%): 1H NMR (CDCl3, 250 MHz) δ 1.33 (t, J ) 7 Hz, 3
H, OCH2CH3), 4.27 (q, J ) 7 Hz, 2 H, OCH2CH3), 5.38 (s, 2 H,
OCH2Ph), 5.77 (s, 1 H, CHCdO), 7.26-7.39 (m, 5 H, Ph), 7.51-
7.63 (m, 2 H, Ph), 7.67-7.78 (m, 1 H, Ph), 8.05-8.15 (m, 2 H,
Ph); 13C NMR (CDCl3, 75.5 MHz) δC 14.12 (OCH2CH3), 61.08
(OCH2CH3), 73.95 (OCH2Ph), 98.21 (CHCdO), 126.99, 127.58,
128.53, 128.79, 128.81, 129.16 (CH, Ph), 130.57, 133.96, 134.66
(C-3, Ph), 149.77, 152.07 (C-4, C-5), 161.76, 162.78, 163.02 (Cd
O); MS (EI, 70 eV) m/z 394 (M+, 20). Anal. Calcd for C22H18O7:
C, 67.00; H, 4.60. Found: C, 66.65; H, 4.74.
X-r a y Str u ctu r e An a lysis.18-21 For the data collection, a
Stoe-Siemens-Huber four-circle diffractometer equipped with
a Siemens SMART CCD area detector using graphite-mono-
chromated Mo KR radiation was used. The structures were
solved by direct methods (SHELXS) and refined by full-matrix
2
least-squares techniques against Fo (SHELXL-97). All non-
hydrogen atoms were refined anisotropically. A riding model
starting from calculated positions was employed for the
hydrogen atoms bond to carbon, while the hydrogen bond to
O(3) was refined freely.
Cr ysta l d a ta of 4a : empirical formula, C16H16O12; formula
weight, 400.29; T ) 133(2) K; wavelength, 0.71073 Å; crystal
system, monoclinic; space group, P2(1)/c; unit cell dimensions,
a ) 13.013(2) Å, b ) 16.890(2) Å, c ) 7.6550(10) Å, â )
90.55(2)°; V ) 1682.4(4) Å3; Z ) 4; density (calcd), 1.580 Mg/
m3; absorption coefficient, 0.139 mm-1; F(000): 832; crystal
size, 0.40 × 0.30 × 0.20 mm3; θ range for data collection, 2.88-
25.02°; index ranges, 15 e h e 15, 0 e k e 20, 0 e l e 9;
reflections collected, 21221; independent reflections, 2956
[R(int) ) 0.0724]; completeness to θ ) 25.02°, 99.9%; absorp-
tion correction, semiempirical from equivalents; maximum and
3-Ben zoyloxy-5-[Z-(eth oxyca r bon ylm eth ylid en )]-4-h y-
d r oxy-2-fu r a n on e (6). See ref 8.
4-Meth oxy-5-[Z-(m eth oxycar bon ylm eth yliden e)]-3-(tr i-
flu or om eth a n esu lfon yloxy)-2-fu r a n on e (7a ). To a CH2Cl2
solution (10 mL) of 4a (213 mg, 1.06 mmol) were added
pyridine (168 mg, 2.12 mmol) and trifluoromethane sulfonic
anhydride (330 mg, 1.17 mmol) at -78 °C. The solution was
warmed within 4 h to -10 °C. The mixture was purified by
chromatography (silica gel, CH2Cl2) to give 7a as a slight
yellow oil (276 mg, 78%): 1H NMR (CDCl3, 250 MHz) δ 3.82
(s, 3 H, OCH3), 4.31 (s, 3 H, OCH3), 5.82 (s, 1 H, CHCO2CH3);
13C NMR (CDCl3, 50 MHz) δC 52.33, 60.67, 100.15, 114.08,
117.45 (q, CF3), 148.08, 155.05, 159.71, 162.54 (C); MS (70 eV,
EI) m/z 331 (M+, 19). The exact molecular mass m/z ) 331.9814
( 2 mD (M+) was confirmed by HRMS (EI, 70 eV).
(18) COLLECT, Data Collection Software; Nonius B.V., Nether-
lands, 1998.
(19) Otwinowski, Z.; Minor, W. Processing of X-ray Diffraction Data
Collected in Oscillation Mode, in Methods in Enzymology; Carter, C.
W., Sweet, R. M., Eds.; Academic Press: New York, 1997; Vol. 276,
Macromolecular Crystallography, Part A, pp 307-326.
(20) Sheldrick, G. M. Acta Crystallogr. Sect. A 1990, 46, 467.
(21) Sheldrick, G. M. SHELXL-97 (Release 97-2), University of
Go¨ttingen, Germany, 1997.

Synthesis of γ-Alkylidenetetronic Esters
J . Org. Chem., Vol. 66, No. 7, 2001 2225
4-Ben zyloxy-5-[Z-(eth oxyca r bon ylm eth ylid en e)]-3-(tr i-
flu or m eth a n su lfon yloxy)-2-fu r a n on e (7b). Compound 7b
was prepared according to the procedure given for the prepa-
ration of 7a . Starting with 4d (100 mg, 0.34 mmol), 7b was
isolated as a slight yellow oil (121 mg, 83%): 1H NMR (CDCl3,
250 MHz) δ 1.31 (t, J ) 7 Hz, 3 H, CH3), 4.26 (q, J ) 7 Hz, 2
H, OCH2CH3), 5.51 (s, 2 H, OCH2Ph), 5.83 (s, 1 H, CHCO2Et),
7.40-7.47 (m, 5 H, Ph); 13C NMR (CDCl3, 50 MHz) δC 14.03
(OCH2CH3), 61.40 (OCH2CH3), 75.27 (OCH2Ph), 100.63 (CHCO2-
Et), 114.35 (C-3), 124.71 (q, CF3), 128.30, 129.01, 129.78 (CH,
Ph), 132.85 (C, Ph), 148.15, 154.17 (C), 159.75, 162.05 (CO);
MS (EI, 70 eV) m/z 422 (M+, 8), 377 (20), 289 (6), 91 (100).
The exact molecular mass m/z ) 422.0283 ( 2 mD (M+) was
confirmed by HRMS (EI, 70 eV).
molecular mass m/z ) 284.0685 ( 2 mD (M+) for C16H12O5 was
confirmed by HRMS (EI, 70 eV).
4-Met h oxy-5-[Z-2-(m et h oxyca r b on ylm et h ylid en e)]-3-
m eth yl-2-fu r a n on e (8d ): To a degassed THF solution (5 mL)
of triflate 7a (0.46 mmol, 154 mg) were added Pd2dba3‚CHCl3
(10 mol %, 48 mg), P(2-furyl)3 (40 mol %, 43 mg), and LiCl
(1.38 mmol, 59 mg). After the mixture was stirred for 5 min,
tetramethylstannane (0.60 mmol, 0.08 mL) was added. After
the resulting mixture was stirred for 24 h at 20 °C, a saturated
aqueous KF solution (200 mL) was added. The aqueous layer
was extracted with ether (4 × 150 mL), the organic layer was
dried (MgSO4) and filtered, and the solvent of the filtrate was
removed in vacuo. The residue was purified by chromatogra-
phy (silica gel, ether/petroleum ether ) 1:4) to give 8d as a
yellow solid (34 mg, 37%): 1H NMR (CDCl3, 250 MHz) δ 2.17
(s, 3 H, CH3), 3.82 (s, 3 H, OCH3), 4.32 (s, 3 H, OCH3), 5.82 (s,
1 H, CHCO2CH3); 13C NMR (CDCl3, 75 MHz) δC 8.04 (CH3),
52.35 (OCH3), 59.36 (OCH3), 96.28 (CH), 102.80, 152.72, 160.22
(C), 164.20, 169.85 (CO); MS (70 eV, EI) m/z 198 (M+, 41), 167
(100), 97 (32), 83 (44). The exact molecular mass m/z )
198.0528 ( 2 mD (M+) for C9H10O5 was confirmed by HRMS
(EI, 70 eV).
4-Met h oxy-5-[Z-2-(m et h oxyca r b on ylm et h ylid en e)]-3-
vin yl-2-fu r a n on e (8e): To a degassed THF solution (7 mL)
of triflate 7a (0.45 mmol, 150 mg) were added Pd2dba3‚CHCl3
(10 mol %, 47 mg), P(2-furyl)3 (20 mol %, 21 mg), and LiCl
(1.35 mmol, 57 mg). After the mixture was stirred for 5 min,
tributylvinylstannane (0.54 mmol, 0.16 mL, d ) 1.086 g/mL)
was added. After the resulting mixture was stirred for 24 h at
20 °C, a saturated aqueous KF solution (200 mL) was added.
The aqueous layer was extracted with ether (4 × 150 mL),
the organic layer was dried (MgSO4) and filtered, and the
filtrate was concentrated in vacuo. The residue was purified
by chromatography (2 ×, silica gel, ether/petroleum ether )
1:4) to give 8e as a yellow solid (36 mg, 37%). Tributylchloro-
stannane could not be completely removed from the product:
1H NMR (acetone-d6, 250 MHz) δ 3.78 (s, 3 H, OCH3), 4.21 (s,
3 H, OCH3), 5.54 [d, J ) 11 Hz, 1 H, HCdCH-H(cis)], 5.63 (1
H, CHCO2CH3), 6.26 [d, J ) 18 Hz, 1 H, HCdCH-H(trans)],
6.72 [dd, J ) 18, 11 Hz, 1 H, HCdCH2); 13C NMR (CDCl3, 62.5
MHz) δC 51.97, 60.67 (OCH3), 96.03 (dCHCO2Me), 104.42 (C),
121.93, 122.77 (HCdCH2, CHdCH2), 151.55, 160.30, 163.82,
166.26 (C). Tributylchlorstannane could not be completely
removed.
4-Ben zyloxy-5-[Z-2-(et h oxyca r b on ylm et h ylid en e)]-3-
p h en yl-2-fu r a n on e (8f). To a degassed THF solution of
triflate 7b (0.24 mmol, 100 mg) were added Pd2dba3‚CHCl3
(10 mol %, 25 mg), P(2-furyl)3 (40 mol %, 22 mg), and LiCl
(0.72 mmol, 30 mg). After the mixture was stirred for 5 min,
trimethylphenylstannane (0.26 mmol, 70 mg) was added. After
the resulting mixture was stirred for 24 h at 20 °C, a saturated
aqueous KF solution (200 mL) was added. The aqueous layer
was extracted with ether (4 × 150 mL), the organic layer was
dried (MgSO4) and filtered, and the filtrate was concentrated
in vacuo. The residue was purified by chromatography (silica
gel, ether/petroleum ether ) 1:4) to give 8f as a yellow solid
(38 mg, 46%): 1H NMR (CDCl3, 250 MHz) δ 1.33 (t, J ) 7.1
Hz, 3 H, OCH2CH3), 4.28 (q, J ) 7.1 Hz, 2 H, OCH2CH3), 5.03
(s, 2 H, OCH2Ph), 5.75 (s, 1 H, CHCO2Et), 7.08-7.11 (m, 2 H,
Ph), 7.31-7.34 (m, 3 H, Ph), 7.43-7.45 (m, 5 H, Ph); 13C NMR
(CDCl3, 75.5 MHz) δC 14.21 (OCH2CH3), 61.04 (OCH2CH3),
74.72 (OCH2Ph), 96.75 (CHCdO), 109.08 (C-3), 127.79, 128.51,
128.70, 129.03, 129.33, 130.11 (CH, Ph), 128.05, 134.26 (C, Ph),
152.21 (C-4), 161.22 (C-5), 163.45, 167.39 (CdO); MS (70 eV,
EI) m/z 350 (M+, 20), 332 (28), 304 (8), 276 (4), 145 (6), 91
(100). The exact molecular mass m/z ) 350.1154 ( 2 mD (M+)
was confirmed by HRMS (EI, 70 eV). Anal. Calcd for
4-Me t h oxy-5-[Z-(m e t h oxyca r b on ylm e t h ylid e n e )]-3-
p h en yl-2-fu r a n on e (8a ). To a thoroughly degassed THF
solution (7 mL) of triflate 7a (0.30 mmol, 101 mg) were added
Pd2dba3‚CHCl3 (5 mol %, 16 mg), P(2-furyl)3 (20 mol %, 14 mg),
and LiCl (39 mg, 300 mol %). After the mixture was stirred
for 5 min, trimethylphenylstannane (0.37 mmol, 0.086 mL)
was added. After the resulting mixture was stirred for 24 h at
20 °C, water (100 mL) was added. The aqueous layer was
extracted with ether (4 × 100 mL), and the organic layer was
dried (MgSO4), filtered and the solvent of the filtrate was
removed in vacuo. The residue was purified by chromatogra-
phy to give 8a as a yellow solid (33 mg, 42%): 1H NMR
(acetone-d6, 250 MHz) δ 3.82 (2 × s, 2 × 3 H, 2 × OCH3), 5.73
(s, 1 H, CHCO2CH3), 7.43 (s, 5 H, Ph); 13C NMR (CDCl3, 62.5
MHz) δC 52.08 (OCH3), 61.04 (OCH3), 96.21 (CH), 107.89 (C),
127.85 (C), 128.40 129.18, 130.23 (CH, Ph) 151.95, 162.18,
163.91 (C, CO, OCOC), 167.46 (CO); MS (70 eV, EI) m/z 260
(M+, 100), 177 (15), 57 (27). The exact molecular mass m/z )
260.0685 ( 2 mD (M+) was confirmed by HRMS (EI, 70 eV).
4-Meth oxy-5-[Z-(m eth oxyca r bon ylm eth ylid en e)]-3-(2-
fu r yl)-2-fu r a n on e (8b). To a degassed THF solution (5 mL)
of triflate 7a (0.59 mmol, 196 mg) were added Pd2dba3‚CHCl3
(5 mol %, 31 mg), P(2-furyl)3 (20 mol %, 27 mg), and LiCl (1.80
mmol, 75 mg). After the mixture was stirred for 5 min, tributyl-
(2-furyl)stannane (0.71 mmol, 0.24 mL) was added. After the
resulting mixture was stirred for 24 h at 20 °C, a saturated
aqueous KF solution (100 mL) was added. The aqueous layer
was extracted with ether (4 × 150 mL), the organic layer was
dried (MgSO4) and filtered, and the solvent of the filtrate was
removed in vacuo. The residue was purified by chromatogra-
phy (using a 1 cm KF layer on the top of the column) and by
subsequent washing with petroleum ether to give 8b as a
yellow solid (68 mg, 46%): 1H NMR (CDCl3, 250 MHz) δ 3.82
(s, 3 H, OCH3), 4.20 (s, 3 H, OCH3), 5.75 (s, 1 H, CHCO2CH3),
6.55 (dd, J ) 3.6 Hz, J ) 1.8 Hz, 1 H, 4′-H), 7.03 (dd, J ) 3.4
Hz, J ) 0.8 Hz, 1 H, 3′-H), 7.56 (dd, J ) 1.8 Hz, 0.8 Hz, 1 H,
5′-H); 13C NMR (CDCl3, 75 MHz) δC 52.01, 61.95 (OCH3), 96.54,
99.60, 111.98, 113.53, 142.26, 143.93, 152.14, 159.60, 163.72,
165.74; MS (70 eV, EI) m/z 250 (M+, 100), 219 (11), 135 (15),
107 (23). Anal. Calcd for C12H10O6 (250.2): C, 57.61; H, 4.03.
Found: C, 57.26; H, 3.94.
4-Met h oxy-5-[Z-2-(m et h oxyca r b on ylm et h ylid en e)]-3-
(p h en yleth yn yl)-2-fu r a n on e (8c). To a degassed THF solu-
tion (5 mL) of triflate 7a (0.83 mmol, 277 mg) were added
Pd2dba3‚CHCl3 (5 mol %, 43 mg), P(2-furyl)3 (20 mol %, 39 mg),
and LiCl (300 mol %, 106 mg). After the mixture was stirred
for 5 min, trimethyl(phenylethynyl)stannane (1.00 mmol, 265
mg) was added. After the resulting mixture was stirred for 24
h at 20 °C, a saturated aqueous KF-solution (200 mL) was
added. The aqueous layer was extracted with ether (4 × 150
mL), the organic layer was dried (MgSO4) and filtered, and
the filtrate was concentrated in vacuo. The residue was
purified by chromatography (silica gel, ether/petroleum ether
) 1:3) to give 8c as a yellow solid (83 mg, 35%): 1H NMR
(CDCl3, 250 MHz) δ 3.81 (s, 3 H, OCH3), 4.49 (s, 3 H, OCH3),
5.70 (s, 1 H, CHCO2CH3), 7.28-7.57 (m, 5 H, Ph); 13C NMR
(CDCl3, 75 MHz) δC 52.15, 60.26 (OCH3), 91.07 (C), 96.94 (CH),
98.70, 121.73 (C), 128.49, 129.43 (2 × CH, Ph), 131.47 (C),
131.51 (CH, Ph), 151.33, 163.47, 164.95, 165.18 (C); MS (70
eV, EI) m/z 284 (M+, 100), 234 (16), 113 (21). The exact
C
21H18O5: C, 71.99; H, 5.18. Found: C, 72.20; H, 5.02.
4-Ben zyloxy-5-[Z-2-(et h oxyca r b on ylm et h ylid en e)]-3-
(4-m eth oxyp h en yl)-2-fu r a n on e (8g). To a THF solution of
triflate 7b (0.24 mmol, 100 mg) were added Pd2dba3‚CHCl3
(10 mol %, 25 mg), P(2-furyl)3 (40 mol %, 22 mg), and LiCl
(0.72 mmol, 30 mg). After the mixture was stirred for 5 min,
trimethyl(4-methoxyphenyl)stannane (0.26 mmol, 70 mg) was
added. After the resluting mixture was stirred for 24 h at 20

2226 J . Org. Chem., Vol. 66, No. 7, 2001
Langer et al.
°C, a saturated aqueous KF solution (200 mL) was added. The
aqueous layer was extracted with ether (4 × 100 mL), the
organic layer was dried (MgSO4) and filtered, and the filtrate
was concentrated in vacuo. The residue was purified by
chromatography (silica gel, ether/petroleum ether ) 1:4) to give
8g as a yellow solid (52 mg, 57%): 1H NMR (CDCl3, 250 MHz)
δ 1.33 (t, J ) 7.2 Hz, 3 H, OCH2CH3), 3.85 (s, 3 H, OCH3),
4.27 (q, J ) 7.1 Hz, 2 H, OCH2CH3), 5.05 (s, 2 H, OCH2Ph),
5.70 (s, 1 H, CHCdO), 6.90-6.99 (m, 2 H, Ph), 7.12-7.23 (m,
EI) m/z 340 (M+, 4), 322 (4), 294 (8), 215 (6), 204 (5), 91 (100).
The exact molecular mass m/z ) 340.0947 ( 2 mD (M+) for
C19H16O6 was confirmed by HRMS (EI, 70 eV).
4-Ben zyloxy-5-[Z-2-(et h oxyca r b on ylm et h ylid en e)]-3-
(p h en yleth yn yl)-2-fu r a n on e (8i). To a THF solution of
triflate 7b (0.24 mmol, 100 mg) were added Pd2dba3‚CHCl3
(10 mol %, 25 mg), P(2-furyl)3 (40 mol %, 22 mg), and LiCl
(0.72 mmol, 30 mg). After the mixture was stirred for 5 min,
trimethyl(phenylethynyl)stannane (0.26 mmol, 70 mg) was
added. After the resulting mixture was stirred for 24 h at 20
°C, water (100 mL) was added. The aqueous layer was
extracted with ether (4 × 100 mL), the organic layer was dried
(MgSO4) and filtered, and the filtrate was concentrated in
vacuo. The residue was purified by chromatography to give 8i
as a yellow solid (27 mg, 30%): 1H NMR (acetone-d6, 250 MHz)
δ 1.25 (t, J ) 7.1 Hz, 3 H, CH3), 4.20 (q, J ) 7.1 Hz, 2 H,
OCH2CH3), 5.65 (s, 1 H, CHCO2Et), 6.00 (s, 2 H, OCH2Ph),
7.24-7.59 (m, 10 H, Ph); 13C NMR (CDCl3, 62.9 MHz) δC 14.43
(CH3), 61.31 (OCH2CH3), 75.41 (OCH2Ph), 79.91, 91.02 (C,
alkyne), 97.51 (CHCdO), 100.01 (C-3), 129.01, 129.47, 129.58,
129.77, 130.37, 132.26 (CH, Ph), 135.85 (C, Ph), 152.51, 152.56
(C-4, C, Ph), 163.46 (C-5), 166.25, 167.89 (CdO); MS (70 eV,
EI) m/z 374 (M+, 4), 328 (8), 301 (18), 165 (12), 113 (6), 91
(100). The exact molecular mass m/z ) 374.1154 ( 2 mD (M+)
for C23H18O5 was confirmed by HRMS (EI, 70 eV).
2 H, Ph), 7.27-7.36 (m, 3 H, Ph), 7.38-7.49 (m, 2 H, Ph); 13
C
NMR (CDCl3, 62.9 MHz) δC 14.20 (OCH2CH3), 55.34 (OMe),
60.98 (OCH2CH3), 74.48 (OCH2Ph), 96.38 (CHCdO), 109.59
(C-3), 127.71, 127.86, 128.41, 128.46, 128.99, 131.28 (CH, Ph),
131.61, 134.41 (C, Ph), 152.41 (C-4), 160.35 (C-5), 163.49,
167.58 (CdO); MS (70 eV, EI) m/z 380 (M+, 18). The exact
molecular mass m/z ) 380.1260 ( 2 mD (M+) for C22H20O6 was
confirmed by HRMS (EI, 70 eV).
4-Ben zyloxy-5-[Z-2-(et h oxyca r b on ylm et h ylid en e)]-3-
(2-fu r yl)-2-fu r a n on e (8h ). To a THF solution of triflate 7b
(0.24 mmol, 100 mg) were added Pd2dba3‚CHCl3 (10 mol %,
25 mg), P(2-furyl)3 (40 mol %, 22 mg), and LiCl (0.72 mmol,
30 mg). After the mixture was stirred for 5 min, tributyl(2-
furyl)stannane (0.26 mmol, 0.08 mL, d ) 1.139) was added.
After the resulting mixture was stirred for 24 h at 20 °C, water
(100 mL) was added. The aqueous layer was extracted with
ether (4 × 100 mL), the organic layer was dried (MgSO4) and
filtered, and the filtrate was concentrated in vacuo. The
residue was purified by chromatography (silica gel, ether/
petroleum ether ) 1:3), and subsequent washing of the product
with petroleum ether to give 8h as a yellow solid (50 mg, 61%):
1H NMR (CDCl3, 250 MHz) δ 1.31 (t, J ) 7.1 Hz, 3 H,
OCH2CH3), 4.25 (q, J ) 7.1 Hz, 2 H, OCH2CH3), 5.45 (s, 2 H,
OCH2Ph), 5.72 (s, 1 H, CHCdO), 6.58 (dd, J ) 3.5 Hz, J ) 1.8
Hz, 1 H, 4′-H), 7.06 (dd, J ) 3.5 Hz, J ) 0.7 Hz, 1 H, 5′-H),
7.27-7.39 (m, 5 H, Ph), 7.61 (dd, J ) 1.8 Hz, J ) 0.7 Hz, 1 H,
3′-H); 13C NMR (CDCl3, 62.9 MHz) δC 14.15 (OCH2CH3), 60.96
(OCH2CH3), 76.31 (OCH2Ph), 97.13 (CHCdO), 100.75 (C-3),
112.19, 113.70 (C-3′, C-4′, furane), 128.18, 128.74, 129.07 (CH,
Ph), 134.61 (C-5′, furane), 142.68, 144.08 (C-4, C, Ph), 152.46,
158.32 (C-5, C-2′, furane), 163.25, 165.69 (CdO); MS (70 eV,
Ack n ow led gm en t. P.L. thanks Professor A. de
Meijere for his support. Financial support from the
Fonds der Chemischen Industrie (Liebig-scholarship
and funds for P.L.) and the Deutsche Forschungsge-
meinschaft is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Details of the struc-
ture determination for 4a including atomic coordinates, H-
atom coordinates, bond distances and bond angles, and an
ORTEP plot. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O005565S