A Novel Access to γ-Alkylidenebutenolides: Sequential Stille Couplings of Dibromomethylenebutenolides

Article abstract of DOI:10.1055/s-2003-44997

γ-(Dibromomethylene)butenolide (2) and β-bromo-γ- (bromomethylene)butenolide (Z-5), both of which obtained from dibromolevulinic acid (6) in a single step, underwent Pd-catalyzed couplings with phenyl- or styryltributylstannane giving mono-bromobutenolides with excellent stereo- and regiocontrol. A second Stille coupling or the reduction with Zn dust led to bromine-free γ-alkylidenebutenolides as single stereoisomers.

Full text of DOI:10.1055/s-2003-44997

LETTER
321
A Novel Access to g-Alkylidenebutenolides: Sequential Stille Couplings of
Dibromomethylenebutenolides
A
a
N
ovel
Access to
c
g
-
Alkylide
h
nebutenolide
i
s
m Sorg,a Konrad Siegel,b Reinhard Brückner*a
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität, Albertstr. 21, 79104 Freiburg, Germany
Fax +49(761)2036100; E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
b
Bayer Health Care AG, PH-OP-ELB-CE-VF, Building 64, 42096 Wuppertal, Germany
Received 2 October 2003
butenolides stereoselectively – a theme of ongoing
interest for ourselves11 and others.12
Abstract: g-(Dibromomethylene)butenolide (2) and b-bromo-g-
(bromomethylene)butenolide (Z-5), both of which obtained from
dibromolevulinic acid (6) in a single step, underwent Pd-catalyzed
couplings with phenyl- or styryltributylstannane giving mono-
bromobutenolides with excellent stereo- and regiocontrol. A second
Stille coupling or the reduction with Zn dust led to bromine-free g-
alkylidenebutenolides as single stereoisomers.
The isomeric 1,3-dibromo‘diene’ Z-5 (Scheme 2) under-
went stepwise Stille couplings,1b too, the order of attack
being Z>E (or !>" in Scheme 2). This opened another
stereoselective route to g-alkylidenebutenolide, as also
described in this communication. These couplings, while
unprecedented for ‘genuine’ 1,3-dibromodienes 3, resem-
ble couplings with diene-1,3-diyl bistriflates 413 (Sono-
gashira), 1,3-dibromobenzene14 (Stille), 3,5-dibromo-a-
pyrone15 (Stille), or 5,7-dibromoquinoline16 (Suzuki).
Key words: catalysis, palladium, regioselective C,C coupling,
stereoselective C,C coupling, unsaturated lactone
Pd-catalyzed C,C-couplings between alkenes or organo-
metallic compounds on one side and alkenyl or aryl
halides or triflates (or occasionally fluorosulfonates or
even tosylates) on the other side have become indispens-
able tools in organic synthesis.1 Pd-catalyzed C,C-cou-
plings with multifunctional substrates which proceed
stepwise and regioselectively are synthetically particular-
ly attractive. Accordingly, a series of substrates has been
explored in this context,2 a well-studied case being Pd-
catalyzed carbofunctionalizations of gem-dibromoolefins
1 (Scheme 1). Being conveniently accessible by the
Corey–Fuchs reaction3 of aldehydes, such dibromoolefins
with trisubstituted C=C bonds are known to undergo se-
quential C,C-coupling with various organometallics4–9 or
olefins.10 Each reagent replaces the bromine atoms in the
2.
?
1.
Br
TfO
Br
( )n
Ry
E- or Z-3
O
Br
1.
TfO
2.
Br
O
E-4a (n = 1)
E-4b (n = 2)
Z-5
?
Scheme 2
order E>Z (or !>" as shown in Scheme 1). Reported gem-Dibromoolefin 2 and 1,3-dibromo‘diene’ Z-5 were
here is the first gem-dibromoolefin 2 with a tetrasubsti- prepared in 189617 from easily accessible dibromolevulin-
tuted C=C bond which Stille-couples1b in a stepwise man- ic acid (6)18 by treatment with 2:1 concd H2SO4/oleum
ner. The preferred coupling is Z>E (or !>", according and conc. H2SO4, respectively (Scheme 3).19 We prepared
to Scheme 1). Investigating these couplings meant devel- 2 and Z-5 reproducibly and without the respective isomer
oping a novel method for synthesizing g-alkylidene- being formed under the following conditions: the combi-
nation 50–60 °C/6 minutes provided 220 in 28% yield
whereas room temperature/20 °C to 85 °C/30 minutes fur-
2.
1.
nished Z-5 in 41% yield.21 Both syntheses worked on a 5
g scale, too, albeit less efficiently (24% for 2 and 35% for
Z-5).
Br
Br
Br
Br
R
Due to the inertness of organotin compounds towards air,
water, many reaction conditions, and often even purifica-
tion by chromatography on silica gel,22 we chose trans-
O
O
1
2
23
24
1.
2.
PhCH=CHSnBu3 and PhSnBu3 as coupling partners.
The catalyst was Pd(dba)2 to which AsPh3 was added
according to established protocols.25 Treating gem-di-
bromide 2 or 1,3-dibromide Z-5 with approximately
stoichiometric amounts of one stannane and, after
chromatography, with 1.3–1.6 equivalents of the other
stannane furnished the stereopure biscoupling products
Scheme 1
SYNLETT 2004, No. 2, pp 0321–0325
Advanced online publication: 16.12.2003
DOI: 10.1055/s-2003-44997; Art ID: G26303ST
© Georg Thieme Verlag Stuttgart · New York
0
2.
0
2.
2
0
0
4

322
A. Sorg et al.
LETTER
Ph
Ph
Br
2'
2'
1'
4
4
OH
O
O
E-8
Ph
Br
O O
O
O
a)
b)
E-7
6
Br
a)
b)
Br
Br
O
Ph
Br
O
2'
O
4
O
Br
Z-5
2
O
Br
O
O
O
Scheme 3 Reagents and conditions: a) Oleum/concd H2SO4
(v/v = 2:1), 50–60 °C, 6 min; 28%; b) concd H2SO4, r.t., 20 min,
→ 85 °C, 30 min; 41%.
Ph
E-9
Z-9
c)
4
E- or Z-7 starting from 2 (Scheme 4), or, starting from Z-
5, the biscoupling products Z-13 or Z-17 as pure regioiso-
mers (Scheme 5). These previously unknown g-alky-
lidenebutenolide are isomers and were obtained in 59%,
67%, 47%, and 43% yield, respectively. Their structural
assignments posed a stereochemistry question – which
biscoupling product of Scheme 4 is E-7 and which is Z-7?
– and a regiochemistry question – which biscoupling
product of Scheme 5 is Z-13 and which is Z-17? When
these were answered26 it was clear that the reactivities of
the bromine atoms in the underlying dibromides 2 and Z-
5 were !>" (cf. Scheme 1 and Scheme 2).
Br
Br
1'
d)
O
O
Br
O
O
2
Z-10
e)
4
Br
Ph
Br
O
Ph
O
O
O
E-11
Z-11
f)
g)
The same conclusions with regard to stereochemistry, re-
giochemistry, and differential bromine reactivity were
drawn from NMR analyses27 of three of the immediate
precursors of the above-mentioned biscoupling products:
4
Ph
Ph
1'
O
O
O
O
monocoupling product Z-9 (from
2
and trans-
Ph
E-12
PhCH=CHSnBu3, Scheme 4; 67% yield), monocoupling
product Z-1428 (from Z-5 and trans-PhCH=CHSnBu3,
Scheme 5; 52% yield), and monocoupling product Z-16
(from Z-5 and PhSnBu3, Scheme 5; 47% yield).
Z-7
Scheme 4 Reagents and conditions: a) PhSnBu3 (1.41 equiv),
Pd(dba)2 (0.05 equiv), AsPh3 (0.23 equiv), THF, 65 °C, 8 h; 88%; b)
Zn dust (1.20 equiv), HOAc (1 drop), THF, r.t., sonication, 35 min;
77%, E:Z = 90:10; c) trans-PhCH=CHSnBu3 (1.17 equiv), Pd(dba)2
(0.06 equiv), AsPh3 (0.20 equiv),THF, 65 °C, 7 h; 67%; d) HSnBu3
(1.10 equiv), Pd(PPh3)4 (0.10 equiv), THF, 65 °C; 3 h, 51%; e)
PhSnBu3 (1.11 equiv), Pd(dba)2 (0.05 equiv), AsPh3 (0.20 equiv),
THF, 65 °C, 8 h; 84%; f) trans-PhCH=CHSnBu3 (1.52 equiv),
Pd(dba)2 (0.06 equiv), AsPh3 (0.20 equiv), THF, 65 °C, 6 h; 80%; g)
Zn dust (2.90 equiv), HOAc (1 drop), THF, r.t., sonication, 1 h; 79%,
E:Z = 98:2.
Bromobutenolide Z-1129 – which is the monocoupling
product from 2 and PhSnBu3 (84% yield) – was indistin-
1
guishable from stereoisomer E-11 by H NMR spectros-
copy since the resonances of the phenyl ring overlapped
with d4-H. Ancillary evidence came from the stereochemi-
cal assignment of bromobutenolide Z-10. This was ob-
tained by coupling the same dibromoolefin 2 in the
presence of Pd(PPh3)4 with HSnBu3 (51% yield; method:
ref.30) rather than with the previously used PhSnBu3 (→Z-
11). Enhanced absorption of 1¢-H10 (d = 6.11 ppm in
CDCl3) while irradiating 4-H10 (d = 7.38 ppm) confirmed
the Z-configuration.31
noteworthy that the debrominations of the (a-bromo-
alkylidene)butenolides Z-9 and Z-11 proceed with 90%
and 98% retention of configuration, respectively. Thus,
the latter reductions appear to proceed chiefly via Zndust
-
In all monocoupling products (Z-9 and Z-11 of Scheme 4,
Z-14 and Z-16 of Scheme 5) the bromine atom could be
replaced by hydrogen through sonication with Zn dust and
a drop of HOAc in THF.32 This led to a third series of
g-alkylidenebutenolides, namely to compounds E-8
(77%; E:Z = 90:10, inseparable by flash-chromatography
on silica gel22), E-12 (79%; E:Z = 98:2), Z-8 (78%; no
E-isomer detected), and Z-12 (86%; no E-isomer de-
tected), respectively (Scheme 4 and Scheme 5).33 It is
bonded rather than via free alkenyl radicals. Two previous
syntheses of 834 and 1235 had delivered E:Z mixtures while
a third one had led to 12 Z-selectively, too.36
In summary, we have developed new routes to g-alkyl-
idenebutenolides with uniform and predictable stereo-
structures and three different substitution patterns: with a
tetrasubstituted C1¢ = Cg bond and no b-substituent (E-
and Z-7, Z-9, Z-11), with a trisubstituted C1¢ = Cg bond
Synlett 2004, No. 2, 321–325 © Thieme Stuttgart · New York

LETTER
A Novel Access to g-Alkylidenebutenolides
323
Ph
Acknowledgment
4
1'
We are indebted to the ‘Fonds der Chemischen Industrie’ for a
stipend for K. S. and for financial support and express our gratitude
to Melanie Waldrich for technical assistance.
O
O
O
O
Ph
Ph
Z-8
Z-13
References
a) b)
(1) General references: (a) Tsuji, J. Palladium Reagents and
Catalysis: Innovations in Organic Synthesis; John Wiley:
Chichester, 1995. (b) Farina, V.; Krishnamurthy, V.; Scott,
W. J. Org. React. 1997, 50, 1. (c) Negishi, E.-i.; Liu, F. In
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.;
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998, 1–42.
(d) Mitchell, T. N. In Metal-Catalyzed Cross-Coupling
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Weinheim, 1998, 167–197. (e) Boudier, A.; Bromm, L. O.;
Lotz, M.; Knochel, P. Angew. Chem. Int. Ed 2000, 39, 4414;
Angew. Chem. 2000, 112, 4584. (f) Poli, G.; Giambastiani,
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(h) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew.
Chem. Int. Ed. 2001, 40, 4544; Angew. Chem. 2001, 113,
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(2) See for example: (a) 2,4-Dibromothiazole: Bach, T.;
Heuser, S. J. Org. Chem. 2002, 67, 5789; and literature cited
therein. (b) 2,3-Dibromofuran-5-carboxylate: Bach, T.;
Krüger, L. Synlett 1998, 1185; and literature cited therein.
(c) 2-Bromo-1-cyclohexenyl triflate (in contrast to 1,2-
dibromocyclohexene): Voigt, K.; von Zezschwitz, P.;
Rosauer, K.; Lansky, A.; Adams, O.; Reiser, O.; de Meijere,
A. Eur. J. Org. Chem. 1998, 1521. (d) and: von Zezschwitz,
P.; Petry, F.; de Meijere, A. Chem.–Eur. J 2001, 7, 4035; and
literature cited therein. (e) 1,2-Dibromobenzene: Wegener,
H. A.; Scott, L. T.; de Meijere, A. J. Org. Chem. 2003, 68,
883; and literature cited therein. (f) 3,4-Dibromo- and 2,3-
dichloro-2(5H)-furanone: Bellina, F.; Anselmi, C.; Martina,
F.; Rossi, R. Eur. J. Org. Chem. 2003, 2290; and literature
cited therein.
Ph
Br
1'
3' 2'
O
O
Br
O
O
Ph
Z-14
c)
iso-14
Br
Br
O
Br
cf.31
O
O
O
Z-5
d)
15
Ph
O
Br
3
3
1'
1'
Br
O
Ph
O
O
f)
Z-16
iso-16
e)
Ph
4
1'
(3) (a) Dibromomethylenation: Ramirez, F.; Desai, N. B.;
McKelvie, N. J. Am. Chem. Soc. 1962, 84, 1745. (b) Br,Li
exchange/rearrangement: Köbrich, G.; Trapp, H.; Flory, K.;
Drischel, W. Chem. Ber. 1966, 99, 689. (c) Sequential
dibromomethylenation/Br,Li exchange/rearrangement:
Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(4) With organomagnesiums: (a) Minato, A.; Suzuki, K.;
Tamao, K. J. Am. Chem. Soc. 1987, 109, 1257; gem-
dichloroalkenes. (b) Bryant-Friedrich, A.; Neidlein, R.
Synthesis 1995, 1506. (c) Braun, M.; Rahematpura, J.;
Bühne, C.; Paulitz, T. C. Synlett 2000, 1070.
O
O
Z-17
Ph
Ph
O
O
Z-12
Scheme 5 Reagents and conditions: a) PhSnBu3 (1.60 equiv),
Pd(dba)2 (0.06 equiv), AsPh3 (0.20 equiv), THF, 65 °C, 9 h; 90%; b)
Zn dust (1.28 equiv), HOAc (2 drops), THF, r.t., sonication, 1 h; 78%;
c) trans-PhCH=CHSnBu3 (1.20 equiv), Pd(dba)2 (0.06 equiv), AsPh3
(0.20 equiv), THF, 65 °C, 3 h; 52%; d) PhSnBu3 (1.07 equiv),
Pd(dba)2 (0.05 equiv), AsPh3 (0.20 equiv), THF, 65 °C, 9 h; 47%; e)
trans-PhCH=CHSnBu3 (1.29 equiv), Pd(dba)2 (0.05 equiv), AsPh3
(0.22 equiv), THF, 65 °C, 7 h; 91%; f) Zn dust (1.50 equiv), HOAc (2
drops), THF, r.t., sonication, 45 min; 86%.
(5) With organozincs: (a) Ref.4a (gem-dichloroalkenes).
(b) Minato, A. J. Org. Chem. 1991, 56, 4052. (c) Panek, J.
S.; Hu, T. J. Org. Chem. 1997, 62, 4912. (d) Ogasawara,
M.; Ikeda, H.; Hayashi, T. Angew. Chem. Int. Ed. 2000, 39,
1042; Angew. Chem. 2000, 112, 1084. (e) Shi, J.-c.; Zeng,
X.; Negishi, E.-i. Org. Lett. 2003, 5, 1825.
(6) With organocoppers: (a) Uenishi, J.; Matsui, K.; Ohmiya, H.
J. Organomet. Chem. 2002, 653, 141. (b) Uenishi, J.;
Matsui, K. Tetrahedron Lett. 2001, 42, 4353.
and no b-substituent (E- and Z-8, E- and Z-12), and with a
trisubstituted C1¢ = Cg bond and one b-substituent (Z-13,
Z-14, Z-16, Z-17).37 Bromobutenolide Z-10 obtained by
the stereoselective reduction of dibromobutenolide 2 is a
useful starting material for the synthesis of Z-configured
g-alkylidenebutenolides.38
(7) With organozirconiums: Xu, C.; Negishi, E.-i. Tetrahedron
Lett. 1999, 40, 431.
Synlett 2004, No. 2, 321–325 © Thieme Stuttgart · New York

324
A. Sorg et al.
LETTER
(8) With organoborons: (a) Roush, W. R.; Brown, B. B.;
Drozda, S. E. Tetrahedron Lett. 1988, 29, 3541. (b) Roush,
W. R.; Moriarty, K. J.; Brown, B. B. Tetrahedron Lett. 1990,
31, 6509. (c) Baldwin, J. E.; Chesworth, R.; Parker, J. S.;
Russell, A. T. Tetrahedron Lett. 1995, 36, 9551. (d) Roush,
W. R.; Koyama, K.; Curtin, M. L.; Moriarty, K. J. J. Am.
Chem. Soc. 1996, 118, 7502. (e) Roush, W. R.; Reilly, M.
L.; Koyama, K.; Brown, B. B. J. Org. Chem. 1997, 62,
8708. (f) Hanisch, I.; Brückner, R. Synlett 2000, 374.
(g) Shen, W. Synlett 2000, 737. (h) Frank, S. A.; Chen, H.;
Kunz, R. K.; Schnaderbeck, M. J.; Roush, W. R. Org. Lett.
2000, 17, 2691.
(9) With organotins: (a) Shen, W.; Wang, L. Tetrahedron Lett.
1998, 39, 7625. (b) Shen, W.; Wang, L. J. Org. Chem. 1999,
64, 8873.
(10) (a) Ma, S.; Xu, B.; Ni, B. J. Org. Chem. 2000, 65, 8532.
(b) Moller, B.; Undheim, K. Eur. J. Org. Chem. 2003, 332.
(11) (a) Brückner, R. Chem. Commun. 2001, 141. (b) Brückner,
R. Curr. Org. Chem. 2001, 5, 679.
(12) (a) Knight, D. W. Contemp. Org. Synth. 1994, 1, 287.
(b) Negishi, E.-i.; Kotora, M. Tetrahedron 1997, 53, 6707.
(c) Rossi, R.; Bellina, F. In Targets in Heterocyclic Systems:
Chemistry and Properties, Vol. 5; Attanasi, O. A.; Spinelli,
D., Eds.; Società Chimica Italiana: Roma, 2002, 169–198.
(d) Carter, N. B.; Nadany, A. E.; Sweeney, J. B. J. Chem.
Soc., Perkin Trans. 1 2002, 2324.
(13) Brückner, R.; Suffert, J. Synlett 1999, 657; and literature
cited therein.
(14) Dubois, E.; Beau, J.-M. J. Chem. Soc., Chem. Commun.
1990, 1191.
(24) Method: Gilman, H.; Rosenberg, S. D. J. Am. Chem. Soc.
1953, 75, 2507.
(25) (a) Farina, V. Pure Appl. Chem. 1996, 68, 73. (b)Entwistle,
D. A.; Jordan, S. I.; Montgomery, J.; Pattenden, G. Synthesis
1998, 603. (c) Amatore, C.; Bahsoun, A. A.; Jutand, A.;
Meyer, G.; Ntepe, A. N.; Ricard, L. J. Am. Chem. Soc. 2003,
125, 4212.
(26) The stereochemical problem was clarified by the (albeit
small) NOE observed at 2¢-H (d = 7.28 ppm in CDCl3) while
irradiating 4-H (d = 8.02 ppm) of the isomer labeled E-7.
The regiochemistry problem was solved by the occurrence
2
2
of two vicinal Csp -H/Csp -H couplings (J = 11.7 Hz, 15.8
Hz) for the olefinic protons of the isomer designated Z-13 as
contrasting with only one such coupling (J = 16.1 Hz) in the
isomer designated Z-17. The same answer came from the
occurrence of one olefinic 1H NMR singlet in Z-13 (d = 6.21
ppm) as opposed to two such singlets in Z-17 (d = 6.28 and
6.31 ppm).
(27) The differentiation of compound Z-9 from stereoisomer E-9
followed from irradiating 4-H (d = 7.87 ppm in CDCl3) and
the resulting increase of absorption by 2¢-H (d = 7.07 ppm).
Butenolide Z-14 was distinguished from the isomeric
structure iso-14 by the occurrence of two olefinic 3-bond
H,H couplings (J1¢,2¢ = 11.4 Hz, J3¢,2¢ = 15.8 Hz) rather than
one. Monocoupling product Z-16 was differentiated from
regioisomer iso-16 by an NOE experiment: irradiation of
ortho-H (d = 7.78–7.83 ppm in CDCl3) enhanced only the
absorption by 1¢-H (d = 6.36 ppm) and not by 1¢-H and 3-H
as expected for iso-16.
(28) (Z)-4-Bromo-5-(trans-3-phenyl-2-propenylidene)-2(5H)-
(15) Kim, W.-S.; Kim, H.-J.; Cho, C.-G. Tetrahedron Lett. 2002,
43, 9015.
(16) Trecourt, F.; Mallet, M.; Mongin, F.; Quéguiner, G.
Tetrahedron 1995, 51, 11743.
furanone (Z-14): 1H NMR (300 MHz, CDCl3): d = 6.30 (d,
J1¢,2¢ = 11.4 Hz, 1¢-H), 6.37 (s, 3-H), 6.93 (d, J3¢,2¢ = 15.8 Hz,
3¢-H), 7.25–7.41 (m, 2¢-H, 2 × meta-H, para-H), 7.50–7.53
(m, 2 × ortho-H). 13C NMR (125.7 MHz, CDCl3): d = 114.51
(C-1¢), 119.11 (C-3), 121.01 (C-2¢), 127.40 (2 × Cortho),
128.92 (2 × Cmeta), 129.41 (Cpara), 136.11 and 136.19 (C-4,
Cipso), 140.13 (C-3¢), 147.23 (C-5), 166.64 (C-2). Anal.
Calcd for C13H9BrO2 (276.5): C, 56.34; H, 3.27. Found: C,
56.36; H, 3.19.
(17) Wolff, L.; Rüdel, F. Liebigs Ann. 1896, 294, 183; Structural
assignments: Ref.19(2); ref.19b (Z-5).
(18) Manny, A. J.; Kjelleberg, S.; Kumar, N.; de Nys, R.; Read,
R. W.; Steinberg, P. Tetrahedron 1997, 51, 15813.
(19) (a) Koch, H.; Pirsch, J. Monatsh. Chem. 1962, 93, 661.
(b) Wells, P. R. Aust. J. Chem. 1963, 16, 165.
(29) (Z)-5-(1-Bromo-1-phenylmethylene)-2(5H)-furanone (Z-
11): 1H NMR (300 MHz, CDCl3): d = 6.31 (d, J3,4 = 5.6 Hz,
3-H), 7.41–7.49 (m, C6H5 and 4-H). 13C NMR (75.4 MHz,
CDCl3): d = 110.88 (C-1¢), 120.80 (C-3), 128.75 and 130.11
(2 × Cortho, 2 × Cmeta), 130.23 (Cpara), 135.39 (Cipso), 140.88
(C-4), 149.10 (C-5), 168.46 (C-2). Anal. Calcd for
C11H7BrO2 (250.5): C, 52.62; H, 2.81. Found: C, 52.66; H,
2.70.
(20) 5-(Dibromomethylene)-2(5H)-furanone (2): 3,5-
Dibromolevulinic acid (6; 4.77 g, 17.4 mmol), oleum (18
mL, 65% SO3), and concentrated H2SO4 (9 mL) were stirred
at 50–60 °C for 6 min. The solution was poured on ice and
extracted with CH2Cl2 (3 × 30 mL). The combined organic
extracts were dried (Na2SO4) and evaporated under reduced
pressure. After flash chromatography on silica gel22
(cyclohexane:EtOAc 15:1→5:1) compound 2 (1.22 g, 28%)
was obtained as a slightly yellow solid (mp 132–134 °C). 1H
NMR (300 MHz, CDCl3): d = 6.41 (d, J3,4 = 5.6 Hz, 3-H),
7.67 (d, J4,3 = 5.6 Hz, 4-H).
(21) (Z)-4-Bromo-5(bromomethylene)-2(5H)-furanone (Z-5):
3,5-Dibromolevulinic acid (6; 912 mg, 3.33 mmol) and
concentrated H2SO4 (20 mL) were stirred at r.t. for 20 min
and at 85 °C for 30 min. The solution was poured on ice and
extracted with CH2Cl2 (3 × 30 mL). The combined organic
extracts were dried (Na2SO4) and evaporated under reduced
pressure. After flash chromatography on silica gel22
(cyclohexane:EtOAc 15:1→5:1) compound Z-5 (346 mg,
41%) was obtained as a slightly yellow solid (mp 96–97 °C).
1H NMR (300 MHz, CDCl3): d = 6.41 (s, 1¢-H), 6.50 (s, 3-
H).
(30) (a) Uenishi, J.; Kawahama, R.; Shiga, Y.; Yonemitsu, O.
Tetrahedron Lett. 1996, 37, 6759. (b) Uenishi, J.;
Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1996,
61, 5716. (c) Uenishi, J.; Kawahama, R.; Yonemitsu, O.;
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(31) While we debrominated 1,1-dibromoolefin 2 using
Pd(PPh3)4 and HSnBu3 (→Z-10, Scheme 4) the same
reagents30 or variations thereof [Pd(PPh3)4/HSiEt3 or
HSi(SiMe3)3 or NH4HCO2; Pd(dba)2 or NiCl2(PPh3)2/
HSnBu3] failed to reduce 1,3-dibromodiene Z-5 due to
inertness (15 was not formed, Scheme 5).
(32) Method, albeit without sonication: (a) Villa, M. J.; Lete, E.;
Badia, D.; Dominguez, E. J. Chem. Res., Synop. 1987, 418.
(b) Farmer, E. H.; Healey, A. T. J. Chem. Soc. 1927, 1060.
(33) The C1¢ = Cg configuration of debromination product E-8
followed from the NOE’s induced by irradiating, in CDCl3
solution, 4-H (d = 7.84 ppm): The absorption of 1¢-H
(d = 6.50 ppm) remained unaltered while the absorption of
2¢-H (d = 7.02 ppm) increased. In Z-8 an analogous
(22) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
(23) Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem. 1983,
48, 4634.
Synlett 2004, No. 2, 321–325 © Thieme Stuttgart · New York

LETTER
A Novel Access to g-Alkylidenebutenolides
325
assignment was impossible because the resonances of 4-H
(37) Alternative ways to alkylidenebutenolides of this
and 2¢-H overlapped. The C1¢ = Cg configurations of the
debromination products E-12 and Z-12 were established by
the absence(presence) of an NOE at 1¢-H (d = 6.81 ppm and
d = 6.03 ppm, respectively, in CDCl3) when irradiating 4-H
(d = 7.82 ppm and d = 7.49 ppm, respectively).
substitution pattern: (a) Negishi, E.-i.; Kotora, M. Synthesis
1997, 121. (b) Boukouvalas, J.; Lachance, N.; Ouellet, M.;
Trudeau, M. Tetrahedron Lett. 1998, 39, 7665. (c) Rousset,
S.; Thibonnet, J.; Abarbri, M.; Duchêne, A.; Parrain, J.-L.
Synlett 2000, 260.
(34) Xu, D.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 4686.
(35) Pohmakotr, M.; Tuchinda, P.; Premkaisorn, P.; Reutrakul,
V. Tetrahedron 1998, 54, 11297.
(36) Rousset, S.; Abarbri, M.; Thibonnet, J.; Duchêne, A.;
Parrain, J.-L. Org. Lett. 1999, 1, 701.
(38) (a) Sorg, A. Dissertation (in progress) (b) Brückner, R.;
Siegel, K.; Sorg, A. In Strategies and Tactics in Natural
Product Synthesis, Vol. 5; Harmata, M., Ed.; Elsevier/
Academic Press: Orlando, in press.
Synlett 2004, No. 2, 321–325 © Thieme Stuttgart · New York