Synthesis of butenolides as seed germination stimulants

Article abstract of DOI:10.1016/j.tetlet.2008.03.024

Syntheses of a series of novel butenolides as seed germination stimulants are described. The key steps include the cyclization reaction of enamine 4 to form a pyran ring, the efficient halogenating reaction and the selective lithiation reaction of butenolides.

Full text of DOI:10.1016/j.tetlet.2008.03.024

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2922–2925
Synthesis of butenolides as seed germination stimulants
Kingmo Sun, Yuzhong Chen, Ty Wagerle, David Linnstaedt, Martin Currie,
Preston Chmura, Ying Song, Ming Xu *
DuPont Crop Protection, Stine/Haskell Research Center, PO Box 30, Bidg 300, Newark, DE 19714, USA
Received 30 January 2008; revised 3 March 2008; accepted 5 March 2008
Available online 8 March 2008
Abstract
Syntheses of a series of novel butenolides as seed germination stimulants are described. The key steps include the cyclization reaction
of enamine 4 to form a pyran ring, the efficient halogenating reaction and the selective lithiation reaction of butenolides.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
O
R
3
O
O
EtO
EtOOC
1
The butenolide, 3-methyl-2H-furo[2,3-c]pyran-2-one (1),
has recently been identified as a constituent of smoke. It
has been shown to possess unique germination properties
at extraordinarily low concentrations, as low as 10ꢀ9 M,
and has therefore been postulated to play a role in field
and forest restoration following fires.1 The synthesis of 1
has recently been reported, however, we sought an alter-
nate synthesis for our analog program directed at struc-
ture–activity studies.2 Here we report a new synthesis to
the plant-derived butenolide 1 as well as the synthesis of
analogs of formula 2 (Fig. 1).
O
O
7
O
NMe2
Me2N
5
3
4
Fig. 2.
To accomplish this we envisioned a strategy that utilized
a ring closure of compound 4, or its equivalent aldehyde, to
form the pyran ring of butenolide 3 (Fig. 2). Enamine 4 is
readily available from the known butenolide 5.3
O
O
O
O
R1
2. Results and discussion
Enamine 4 was readily prepared by simply heating
butenolide 5 with excess N,N-dimethylformamide dimethyl
acetal and removing the methanol generated by distillation
(Scheme 1). Without further purification, 4 was converted
to aldehyde 6 by treatment with 1.0 M aqueous HCl afford-
ing compound 6 in 60% yield over two steps.4 Cyclization
of aldehyde 6 in the mixed solvents THF/CF3COOH/
H2O (20:2:1) resulted in butenolide 8 in 29% yield. In con-
trast cyclization of aldehyde 6 in the solvent mixture
CF3COOH/dioxane (3.75:1) provided the decarboxylated
O
O
R2
1
2
Fig. 1.
*
Corresponding author. Tel.: +1 302 366 5706; fax: +1 302 366 5738.
E-mail address: ming.xu@usa.dupont.com (M. Xu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.024

K. Sun et al. / Tetrahedron Letters 49 (2008) 2922–2925
2923
O
O
O
EtO
O
8
e
c
O
O
O
O
O
O
EtO
b
EtO
a
O
O
EtO
O
NMe2
NMe2
Me2N
O
5
6
4
d
f
O
O
O
7
Scheme 1. Reagents and conditions: (a) Me2NCH(OMe)2; (b) HCl, THF, 60% for two steps; (c) THF/CF3COOH/H2O; 29%; (d) dioxane/CF3COOH,
32%; (e) THF/CF3COOH/H2O; 15% for two steps; (f) CF3COOH/H2O, 15% for two steps.
butenolide 7 in 32% yield.5 Butenolides 7 and 8 could also
be prepared directly from the freshly prepared enamine 4
although in the significantly lower yield of 15%.6
via direct metalation as shown in Scheme 3. Treament of
13a with LHMDS in THF at ꢀ78 °C followed by quench-
ing with trimethylsilyl chloride, afforded 14b (R = H,
R2 = SiMe3) in 50% yield. The structure of 14b was unam-
biguously confirmed by X-ray structural analysis.11 Appli-
cation of this procedure with different substrates of
compounds 13 or 1 (R = H, Br or Me) provided the corre-
sponding analogs of 14. These results are summarized in
Table 2. In addition, the chemical yield was improved from
50% to 90% by mixing substrate 13a with the TMSCl prior
to the addition of LHMDS as can be seen in Table 2 by
comparison of entries 2 and 6. A similar result was
obtained with substrate 1 (R = CH3, Table 2, entry 5).
Alternatively, the palladium catalyzed coupling of iodide
14a with a variety of boronic acids or organotin reagents
also allowed for preparation of derivatives at the 7-
position.
In conclusion, we have demonstrated a very efficient
route to butenolides 7 and 8. The halogenation of 7 opens
the door to various butenolide analogs for SAR explora-
tion, including the preparation of the natural seed germina-
tion stimulant 1. The selective lithiation of 13 or 1 allows
for the preparation of a variety of derivatives. Some of
these analogs have shown germination activity equivalent
to butenolide 1.
Introduction of substituents at the 3-position of com-
pound 7 was accomplished as shown in Scheme 2. Treat-
ment of 7 with NBS in ethanol at room temperature7
provided the corresponding bromide 9b in excellent yield.
Chloride 9a and iodide 9c were obtained via the same pro-
cedure using NCS or NIS in good yield. With the haloge-
nated compounds 9 in hand, various functional groups
could be introduced. For example, the trifluoromethyl ana-
log 10 was obtained by treatment of 9c with trifluro-
methyltriethylsilane in the presence of copper iodide and
potassium fluoride in NMP according to the literature
procedure.8 Introduction of electrophilic groups was
accomplished by reaction of bromide 9b or iodide 9c with
an alkyllithium or alkylmagnesium halide to form an orga-
nometallic intermediate, followed by quenching with an
electrophile R3X.9 Alternatively, the palladium catalyzed
coupling reaction of 9b or 9c with boronic acids or tin
reagents provided analogs 12 in moderate to good yield.10
The natural butenolide 1 could be prepared by either
method (Table 1, entries 2 and 5).
In order to introduce substituents at the 7-position of
compound 13 or 1 an interesting method was developed

2924
K. Sun et al. / Tetrahedron Letters 49 (2008) 2922–2925
Table 2
O
O
R3
Electrophilic substitution of compounds 13
Entry
Substrate
R2X
Product
Yield (%)
1
2
3
4
5
6
13a (R = H)
13a (R = H)
13a (R = H)
13b (R = Br)
1 (R = CH3)
13a (R = H)
I2
14a (R2 = I)
35
50
30
10
90
90
TMSCl
ClCOOMe
TMSCl
TMSCl
TMSCl
14b (R2 = SiMe3)
14c (R2 = COOMe)
14d (R2 = SiMe3)
14e (R2 = SiMe3)
14b (R2 = SiMe3)
O
11
c
O
O
O
O
O
O
X
CF3
Acknowledgments
a
b
We would like to thank Gavin R. Flematti and Kingsley
W. Dixon from the University of Western Australia for
helpful discussions. We also wish to thank Tom Stevenson
and George Lahm for their invaluable synthesis discussion
and Will Marshall for the X-ray analysis of compound 14b.
O
O
O
7
9a X: Cl
9b X: Br
9c X: I
10
References and notes
d
O
R4
1. (a) Flematti, G. R.; Ghisalberti, E. L.; Dixon, K. W.; Trengove, R. D.
Science 2004, 305, 977; (b) Van Staden, J.; Jager, A. K.; Light, A. K.;
Burger, B. V. South African J. Bot. 2004, 70, 654–659.
O
2. (a) Flematti, G. R.; Ghisalberti, E. L.; Dixon, K. W.; Trengove, R. D.
Tetrahedron Lett. 2005, 46, 5719–5721; (b) Flematti, G. R.; Goddard-
Borger, E. D.; Merritt, D. J.; Ghisalberti, E. L.; Dixon, K. W.;
Trengove, R. D. J. Agric. Food Chem. 2007, 55, 2189–2194; (c)
Goddard-Borger, E. D.; Ghisalberti, E. L.; Stick, R. V. Eur. J. Org.
Chem. 2007, 3925–3934; (d) Matsuo, N.; Nagasawa, A.; Mae, M.;
PCT Int. Appl., WO 2007102615, 2007; (e) Matsuo, N.; Nagasawa,
A.; Mae, M. Chem. Abstr. 2007, 147, 365476.
3. Haefliger, W.; Petrzilka, T. Helv. Chim. Acta 1966, 49, 1937–1950.
4. Procedure to prepare enamine 4 and aldehyde 6: Ethyl 4-methyl-2-
oxo-2,5-dihydro-furan-3-carboxylate (1.5 g, 8.82 mole) and dimethyl-
formamide dimethylacetal (30 mL) were combined and heated under
stirring in a round bottom flask with a distillation apparatus equipped
with a vacuum jacketed vigreux column. The temperature at the
distillation head gradually rose to 105 °C over the course of about 2 h.
The reaction mixture in the round bottom flask was cooled to room
O
12
Scheme 2. Reagents and conditions: (a) (i) NCS, EtOH, 8a, 70%; (ii) NBS,
EtOH, 8b, 90%; (iii) NIS, EtOH, 8c, 60%; (b) CF3SiEt3, KF, CuI, 1-methyl-
2-pyrrolidinone, 50%; (c) n-BuLi, THF, ꢀ78 °C, R3X; (d) Pd(OAc)2, S-
Phos, K3PO4, R4B(OH)2, toluene; or Pd(PPh3)4, LiCl, R4SnBu3, toluene.
S-Phos: 2-dicyclohexylphosphino-20,60-dimethoxybiphenyl.
Table 1
Electrophilic substitution of compounds 9
Entry
Substrate
Reactant
Product
Yield
(%)
(R3X or R4X)
temperature, and concentrated under reduced pressure with
a
1
2
3
4
5
6
7
8
9c
9b
9b
9c
9b
9b
9b
9b
CF3SiEt3
MeI
TMSCl
10
1 (R3 = Me)
11b (R3 = SiMe3)
11c (R3 = CHOHPh)
1 (R4 = Me)
12b (R4 = Et)
12c (R4 = CHCH2)
12d (R4 = Ph)
45
20
20
10
90
55
60
85
Rotovap at room temperature to give compound 4 (2.7 g, containing
small amounts of dimethylformamide and DMF-dimethylacetal. This
material was used fresh for the subsequent reaction without further
purification.). 1H NMR (CDCl3) d 1.36 (t, J = 7.2 Hz, 3H), 2.98 (s,
6H), 3.23 (s, 6H), 4.31 (q, J = 7.2 Hz, 2H), 5.77 (d, J = 13 Hz, 1H),
6.22 (s, 1H), 7.15 (d, J = 13 Hz, 1H). To ethyl 5-dimethylamino-
methylene-4-(2-dimethylamino-vinyl)-2-oxo-2,5-dihydro- furan-3-car-
boxylate (7.5 g, crude product freshly prepared from 4.25 g (25 mmol)
of ethyl 4-methyl-2-oxo-2,5-dihydro-furan-3-carboxylate as described
above) in tetrahydrofuran (50 mL) under stirring, hydrochloric acid
(1 N, 30 mL) was added. The reaction mixture was further stirred at
room temperature for 2 h and concentrated under reduced pressure
with the use of a room temperature bath. The residue thus obtained
was purified with a silica gel column eluted with dichloromethane and
methanol mixtures (from dichloromethane to methanol/dichloro-
methane: 10/90) to give compound 6 as a foam (3.8 g, 60% from ethyl
4-methyl-2-oxo-2,5-dihydro-furan-3-carboxylate). TLC Rf = 0.28
(MeOH/CH2Cl2, 1:9). This material was kept in a refrigerator to
avoid decomposition. A sample of this material was recrystallized
from benzene and showed no decomposition at room temperature
over a week. 1H NMR (CDCl3) d 1.35 (t, J = 7.2 Hz, 3H), 3.25 (bs,
3H), 3.43 (bs, 3H), 3.94 (d, J = 1.2 Hz, 2H), 4.33 (q, J = 7.2 Hz, 2H),
6.36 (s, 1H), 9.66 (t, J = 1.2 Hz, 1H).
PhCHO
MeB(OH)2
EtB(OH)2
CH2@CHSnBu3
PhB(OH)2
9
9c
12e (R4 = 2-furan)
80
SnBu3
O
O
O
R
R
O
O
a
O
O
R2
13a R = H
14
13b R = Br
1 R = Me
Scheme 3. Reagents and conditions: (a) LHMDS, THF, ꢀ78 °C, R2X.
5. Procedure for butenolides 7 and 8 from aldehyde 6: Dioxane (400 ml)
and trifluoroacetic acid (1500 ml) were combined and stirred. When
LHMDS: lithium bis(trimethylsilyl)amide.

K. Sun et al. / Tetrahedron Letters 49 (2008) 2922–2925
2925
the exotherm subsided, the mixture was warmed to 90 °C. Ethyl 5-
dimethylaminomethylene-2-oxo-4-(2-oxo-ethyl)-2,5-dihydro-furan-3-
carboxylate (20 g, solid) was added in one portion with good
mechanical stirring. The temperature of the reaction was controlled
between 92 and 95 °C. The reaction was stopped at 13 minutes by
quickly cooling in a dry-ice/acetone bath to below room temperature.
The reaction mixture was concentrated on a rotovap with a high
vacuum oil pump at 25 °C. The residue was directly applied to a silica
gel column and eluted with hexanes then with hexanes/ethyl acetate
mixtures to give butenolide 7 (3.46 g, 32%). TLC Rf = 0.26 (EtOAc/
stirred at room temperature for one hour and then refluxed for 30
minutes. The reaction mixture was concentrated under reduced
pressure at room temperature. The residue thus obtained was
dissolved in a small amount of dichloromethane and applied to the
top of a silica gel column, eluted with ethyl acetate and hexane
mixtures (ethyl acetate/hexane from 1/1 to 2/1) to give butenolide 7
(0.175 g, 14.6% from ethyl 4-methyl-2-oxo-2,5-dihydro-furan-3-car-
boxylate). Ethyl 5-dimethylaminomethylene-4-(2-dimethylamino-vinyl)-
2-oxo-2,5-dihydro- furan-3-carboxylate (5 g, crude product freshly
prepared from 2.78 g (16.3 mmol) of ethyl 4-methyl-2-oxo-2,5-
dihydro-furan-3-carboxylate as described above) in a mixture of
trifluoroacetic acid (25 mL), water (12.5 mL), and tetrahydrofuran
(125 mL) was stirred at room temperature for 2 h and then warmed to
reflux. The reaction was closely monitored with NMR and TLC
(methanol (5%) to dichloromethylene (95%)). After 3 h of heating, the
reaction mixture was cooled and concentrated under reduced pressure
at room temperature to a thick residue. This residue was dissolved in a
small amount of dichloromethane and purified with a silica gel
column eluted with ethyl acetate and hexane mixtures (ethyl acetate/
hexane from 1/5 to 2/1) to give butenolide 8 (0.51 g, 15% from ethyl
4-methyl-2-oxo-2,5-dihydro-furan-3-carboxylate).
hexanes, 1:1); mp 103–105 °C; 1H NMR (CDCl3)
d 5.42 (d,
J = 1.2 Hz, 1H), 6.66 (d, J = 5.4 Hz, 1H), 7.43 (d, J = 5.4 Hz, 1H),
7.55 (d, J = 1.2 Hz, 1H). Ethyl 5-dimethylaminomethylene-2-oxo-
4-(2-oxo-ethyl)-2,5-dihydro-furan-3-carboxylate (1.5 g, 5.93 mmol)
was dissolved in a mixture of tetrahydrofuran (37 mL), trifluoroacetic
acid (3.7 mL) and water (1.9 mL) and warmed to reflux with stirring.
The reaction was closely monitored with NMR and TLC (methanol/
dichloromethylene: 1/19). After 2 h of heating, the reaction mixture
was cooled to room temperature and concentrated under reduced
pressure with the use of a bath at room temperature. The residue
thus obtained was dissolved in a small amount of dichloromethane
and purified with a silica gel column eluted with ethyl acetate and
hexanes (ethyl acetate/hexanes from 1/5 to 2/1) to give butenolide 8
(0.36 g, 29.2%). TLC Rf = 0.13 (EtOAc/hexanes, 1:1); mp 131–
133 °C; 1H NMR (CDCl3) d 1.40 (t, J = 6.8 Hz, 3H), 4.38 (q,
J = 6.8 Hz, 2H), 7.53 (d, J = 5.2 Hz, 1H), 7.83 (d, J = 5.2 Hz, 1H),
7.91 (s, 1H).
7. Ge, P.; Kirk, K. L. J. Fluorine Chem. 1997, 84, 45–47.
8. Cottet, F.; Castagnetti, E.; Schlosser, M. Synthesis 2005, 798–803.
9. Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Vu, V. A.;
Knochel, P. Synthesis 2002, 565–569. and references cited therein.
10. Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2004, 43, 1871–1876 and references cited therein.
6. Procedure for butenolides 7 and 8 from enamine 4: To a mixture of
ethyl 5-dimethylaminomethylene-4-(2-dimethylamino-vinyl)-2-oxo-
2,5-dihydro-furan-3-carboxylate (2.9 g, crude product freshly
prepared from 1.5 g (8.82 mmol) of ethyl 4-methyl-2-oxo-2,5-dihy-
dro-furan-3-carboxylate as described above) and ice (10 g) cooled in
an external ice/water bath under stirring, trifluoroacetic acid (50 mL)
was added slowly maintaining the temperature of the reaction mixture
below 25 °C. After the addition, the reaction mixture was further
11. Crystallographic data for 14b: C10H12O3Si, from Et2O/hexane,
colorless, irregular block, ꢁ0.540 ꢂ 0.480 ꢂ 0.080 mm, monoclinic,
˚
˚
˚
Cc,
a = 7.676(6) A,
b = 22.260(19) A,
c = 6.979(6) A,
b =
3
˚
112.329(8)°, Vol = 1103.0(16) A , Z = 4, T = ꢀ100 °C, formula
weight = 208.29, density = 1.254 g/cm3, l(Mo) = 0.19 mmꢀ1
. The
details of the crystal data have been deposited with Cambridge
Crystal Data Centre as supplementary publication No. CCDC
676590.