A new Knoevenagel-type synthesis of fully substituted γ- hydroxybutenolides

Article abstract of DOI:10.1016/j.tetlet.2012.05.125

The synthesis of fully substituted γ-hydroxybutenolides is possible by a Knoevenagel-type ring condensation of α-methyleneketones and α-ketoesters under basic conditions. This novel transformation allowed the preparation of di-aryl/heteroaryl substituted hydroxyfuranones, such as 20 and 27, which are important intermediates for pyridazine fungicides. As it turned out, a whole range of different substituents, such as alkyl, cycloalkyl, aryl, heteroaryl and ester groups could be linked to the butenolide scaffold, demonstrating the broad scope of the novel cyclization.

Full text of DOI:10.1016/j.tetlet.2012.05.125

Tetrahedron Letters 53 (2012) 4117–4120
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new Knoevenagel-type synthesis of fully substituted c-hydroxybutenolides
⇑
Clemens Lamberth , Edouard Godineau, Tomas Smejkal, Stephan Trah
Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, CH-4332 Stein, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of fully substituted
c
-hydroxybutenolides is possible by a Knoevenagel-type ring conden-
Received 10 April 2012
Revised 23 May 2012
Accepted 25 May 2012
Available online 1 June 2012
sation of
a-methyleneketones and a-ketoesters under basic conditions. This novel transformation
allowed the preparation of di-aryl/heteroaryl substituted hydroxyfuranones, such as 20 and 27, which
are important intermediates for pyridazine fungicides. As it turned out, a whole range of different
substituents, such as alkyl, cycloalkyl, aryl, heteroaryl and ester groups could be linked to the butenolide
scaffold, demonstrating the broad scope of the novel cyclization.
Keywords:
Butenolide
Ó 2012 Elsevier Ltd. All rights reserved.
Furanone
Heterocycle
Knoevenagel reaction
Fungicide
Fully substituted 5-hydroxyfuran-2(5H)-ones are an important
class of butenolides, because several of its members exhibit a broad
range of biological activities. Some of these examples, which have
attracted a lot of attention recently, are the endothelin-A receptor
antagonist CI-1020 (PD156707, 1),1 the cyclooxygenase-2 inhibitor
22 and the plant growth inhibitor 3.3 In addition, such trialkylated
Three different methods for the synthesis of fully substituted
hydroxybutenolides have been described so far. One route employs
the base-catalysed aldol reaction of a -ketoester 4 with an alde-
c-
c
hyde 5, which after subsequent reflux under acidic conditions
undergoes water elimination, double bond isomerization and cycli-
zation to the
ond possibility is the one-pot conversion of an a-bromoketone 7
c
-hydroxybutenolide 6 (Scheme 1, route A).1,6 A sec-
or -arylated
c
-hydroxybutenolides have been used as intermedi-
ates for the synthesis of agrochemical seed germination inhibitors4
and fungicides (Fig. 1).5
and an acetic acid 8 into 9, which starts with an ester formation
of both educts, followed by an intramolecular aldol condensation
R2
R3
1. NaOMe
2. AcOH
O
CO2Me
R3
O
HO
R1
R2
H
O
1
O
(A)
(B)
R
R
+
+
O
O
O
O
O
O
S
5
4
6
Cl
O
O
1. Et3N
R2
R3
2. DBU
O
HO
HO
R1
3. air
OH
HO
R1
R3
2
O
O
O
O
O
O
1
2
Br
O
9
7
8
CI-1020
R2
R3
R2
HO
R3
O
AlBr3
O
(R1 = Ar)
O
HO
R1
R1
X
(C)
+
O
O
3
O
O
9
11
R1 = Ar: X = H
10
Figure 1. Biologically active fully substituted c-hydroxybutenolides.
R1 = Alk: X = Li or MgI
⇑
Corresponding author. Tel.: +41 62 866 0224; fax: +41 62 866 0860.
E-mail address: clemens.lamberth@syngenta.com (C. Lamberth).
Scheme 1. Different synthesis routes to fully substituted c-hydroxybutenolides.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.125

4118
C. Lamberth et al. / Tetrahedron Letters 53 (2012) 4117–4120
and an oxidative hydroxylation (route B).2,5,7 Finally, disubstituted
maleic anhydrides can be transformed into -hydroxyfuranones by
introduction of a third carbon substituent (route C). If this -sub-
trifluorobenzene (16), which are available in bulk amounts
(Scheme 2).
c
c
Therefore we were looking for an alternative synthesis possibil-
ity with a better potential for scalability. A shorter access to the re-
quired butenolide 20 from bulk chemicals was highly desirable.
We decided to reverse the methylene and carbonyl functions of
the reaction partners 15 and 19 and therefore synthesized 20 from
the methylketone 22 and ethyl 2,4,6-trifluorophenylglyoxylate
(23). Both intermediates could be obtained in one step from suit-
able starting materials. The 3-pyridinylacetone 22 was produced
by Stille coupling of 5-bromo-2-methoxypyridine (21) with isopro-
penyl acetate and tributyltin methoxide via the in situ generated
tributyltin enolate of acetone.9 The transformation of 1-bromo-
2,4,6-trifluorobenzene (17) with isopropylmagnesium chloride
and diethyloxalate directly delivered ethyl 2,4,6-trifluorophenyl-
stituent is aliphatic, it can be achieved via the addition of an orga-
nolithium or Grignard reagent to one of the C@O double bonds,4 if
it is aromatic, then Friedel–Crafts acylation reactions have been
described to deliver c
-hydroxybutenolides.8
Recently we have described the chemistry and biology of
special tetrasubstituted pyridazines, which are potent fungicides
against a broad range of plant pathogens, for example, Botrytis
cinerea (grey mould), Mycosphaerella graminicola (wheat leaf
blotch) and Alternaria solani (potato and tomato early blight).5
Their synthesis has been achieved via hydrazine-mediated ring
enlargement of c-hydroxybutenolides such as 20. Typically these
key intermediates carry a 2,4,6-trifluorophenyl ring in position 3
and a methyl function in position 5, position 4 is usually substi-
tuted by an aryl or heteroaryl group. We have prepared the
required butenolides by application of route B in Scheme 1, from
glyoxylate (23).10 This
verted with the methyl pyridylmethyl ketone 22 under basic
conditions to the desired -hydroxybutenolide 20 by a Knoevena-
gel-type condensation. Although such a transformation has never
a-ketoester could then be directly con-
c
an a-bromoketone, such as 15 and 2,4,6-trifluorophenylacetic acid
(19). This reliable three-step-one-pot reaction allowed the flexible
synthesis of many butenolides with several different substituents
linked to the broadly variable position 4. A weakness however,
been used before on purpose for the synthesis of monocyclic c-
hydroxyfuranones, the synthesis of spiro-11 or annelated12 bicyclic
systems has been reported in a similar manner. Furthermore, one
publication describes the reaction of 3-oxoglutarate with pyruvate
under physiological conditions in a citrate-phosphate buffer to a
is the availability of the required
a-bromoketone and the 2,4,6-
trifluorophenylacetic acid especially during scale-up, because both
have to be prepared in three steps each from the corresponding
benzoic acid or heteroarylcarboxylic acid, such as 12, and 1,3,5-
fumarate, which is structurally related to a c
-hydroxybutenolide.13
Compared to the well-known routes shown in Scheme 1, this new
Br2,
O
O
O
O
1. (COCl)2
2. MeONHMe
HBr,
O
AcOH
EtMgCl
91 %
N
OH
Br
96 %
80 %
N
O
F
N
O
N
O
F
O
N
15
14
13
12
+
F
O
O
O
F
F
F
EtO2CCH2CO2Et,
CuBr, NaOEt
OH
O
Br
F
Br2, FeCl3
97 %
HCl
O
78 %
F
F
F
F
F
19
18
17
16
1. NEt3
73 % 2. DBU
3. air
F
O
N
F
F
HO
O
O
20
DBU
47 %
H2=C(Me)OAc), Bu3SnOMe,
Pd(OAc)2, P(o-Tol)3
Br
O
O
80 %
O
N
O
F
N
22
21
+
F
O
F
F
O
Br
F
iPrMgCl, (CO2Et)2
62 %
F
17
23
Scheme 2. Different synthesis routes to the fully substituted c-hydroxybutenolide 20.

C. Lamberth et al. / Tetrahedron Letters 53 (2012) 4117–4120
4119
Table 2
Synthesis of
substituents
1. NaNO2, HBF4
2. H2C=C(Me)OAc
Cu2O, KOAc
c-hydroxybutenolides with alkyl, cycloalkyl, aryl, heteroaryl and ester
NH2
25 %
O
Br
R2
HO
R1
R3
Br
O
R1
DBU
24
25
O
R3
R2
+
O
HC CC(Me)2OH
1.
O
O
O
Pd(PPh3)2Cl2, CuI
2. NaOH
76 %
28a-d
29a-d
30a-d
Entry R1
R2
R3
Yielda (%)
1
2
3
4
Methyl
Cyclopropyl
5-Methylthien-2-yl Phenyl
2-Fluorophenyl 3-Methylphenyl
2,4-Dichlorophenyl sec-Butyl
4-Fluorophenyl Thienyl
42% 30a
38% 30b
O
Ethoxycarbonyl 51% 30c
4-Chlorophenyl 45% 30d
26
a
Isolated yield.
F
O
F
O
O
conditions of the novel Knoevenagel-type
c-hydroxybutenolide
F
condensation the desired target compound 27 (Scheme 3).
The reaction conditions, such as base, solvent and reaction tem-
perature for the ring condensation of c-hydroxybutenolide 27 have
, base
23
(see Table 1)
been broadly varied (Table 1). The best results have been obtained
with 1.5 equivalents of DBU in DMF at À20 °C.16 We screened a
variety of other organic or inorganic bases, such as DBN, Hünig’s
base, potassium tert-butylate, sodium hydroxide, etc., all of which
failed to deliver substantial amounts of 27. The replacement of the
base by an acid, such as sulfuric acid or p-toluenesulfonic acid did
not result in the formation of the desired product. Enamine catal-
ysis also proved unsuccessful to trigger the condensation reaction.
During the course of our optimization studies, we observed 23 to
be fairly sensitive to the presence of water. The addition of a dehy-
drating agent however failed to improve the yield.
F
F
F
HO
O
O
27
Scheme 3. Synthesis of the c-hydroxybutenolide 27.
Table 1
Influence of the base on the Knoevenagel-type synthesis of
c
-hydroxybutenolide 27
We tested the scope of this transformation by combination of
from 23 and 26 (Scheme 3)
diversely substituted arylacetones and
a-ketoesters. As it turned
Entry
Conditions
Yield (%)
out, it was possible to prepare -hydroxyfuranones 30a–d with a
c
1
2
3
4
5
6
7
8
9
K2CO3, 0 °C, DMF
6a
broad variety of carbon substituents in positions 3, 4 and 5 (Table
2). In addition to the already applied electron-withdrawing 2,4,6-
trifluorophenyl group at position 3, it was also possible to link alkyl
(entry 1), heteroaryl (entry 2), ester (entry 3) and para-substituted
aryl (entry 4) to the ring carbon adjacent to the carbonyl group of
the lactone. At carbon atom 5, which also carries the hydroxyl
function, different alkyl (entry 1), cycloalkyl (entry 2), heteroaryl
(entry 3) and aryl groups (entry 4) could be installed.17
NaHMDS, À78 °C, DMF
Decomp.
NaOH, 0 °C, DMF
5a
NaOMe, 0 °C, DMF
KOtBu, 0 °C, DMF
NEt3, 0 °C, DMF
5a
4a
No reaction
No reaction
No reaction
39b
EtN(iPr)2, 0 °C, DMF
DBN, À20 to 20 °C, DMF
DBU (1.5 equiv), 0 °C, DMF
DBU (1.5 equiv), À20 °C, DMF
DBU, MgSO4, À10 °C, DMF
10
11
45b
In conclusion, we have developed a new synthesis of fully
18c
substituted
nagel-type ring condensation of benzyl or heteroarylmethyl ke-
tones with -ketoesters. The good availability and the broad
c-hydroxybutenolides, which depends on the Knoeve-
a
Yield estimated by UPLC analysis using 4-tert-butylbiphenyl as internal
standard.
a
b
Isolated yield.
Yield estimated by 1H NMR using 1,3,5-trimethoxybenzene as internal standard.
c
variability of these required cyclization partners are a clear advan-
tage of the novel synthesis route, as well as the ability to control
the regiochemistry of the ring closure reaction.
References and notes
method opens a completely new way for the efficient, short-step
synthesis of fully substituted -hydroxybutenolides.
c
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Reisdorph, B. R.; Plummer, M. S.; Sharipour, A.; Lee, C.; Cheng, X.-M.; Walker, D.
We decided to apply this new reaction in the preparation of other
-hydroxybutenolides and to study it in more detail. The furanone
c
27 is the key intermediate of the synthesis pathway to a highly
active pyridazine fungicide and therefore an attractive synthesis
target. Based on the new reaction methodology, it was possible to
prepare 27 in only a few steps from 4-bromoaniline (24). This start-
ing material was converted into the corresponding diazonium salt,
which was then linked to isopropenyl acetate via a Meerwein-type
arylation to obtain 4-bromobenzyl methyl ketone (25).14 Its palla-
dium-catalysed Sonogashira coupling with dimethyl ethynyl carbi-
nol and subsequent acetone cleavage15 delivered 26, which gave by
reaction with ethyl 2,4,6-trifluorophenylglyoxylate (23) under the

4120
C. Lamberth et al. / Tetrahedron Letters 53 (2012) 4117–4120
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procedure
for
the
synthesis
of
fully
substituted
c
-hydroxybutenolides: DBU (1.1 g, 7.3 mmol) was added dropwise to
a
2. Black, W. C.; Brideau, C.; Chan, C.-C.; Charleson, S.; Cromlish, W.; Gordon, R.;
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Schneiter, P. Bioorg. Med. Chem. 2012, 20, 2803–2810.
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solution of 4-ethynylbenzyl methyl ketone (26, 0.8 g, 4.8 mmol) in 3 ml of
N,N-dimethylformamide at 0 °C under an argon atmosphere. The mixture
was stirred for further 15 min at 0 °C, then
a solution of ethyl 2,4,6-
trifluorophenylglyoxylate (23, 1.3 g, 5.3 mmol) in 3 ml of N,N-dimethyl-
formamide was added very slowly and the reaction mixture was kept for
12 h at 0 °C. Subsequently it was quenched by addition of 2 ml of ethanol and
3.5 ml of 4 M aqueous sodium hydroxide, then the obtained solution was
stirred for 15 min and washed with diethyl ether. The aqueous phase was
acidified to pH 1 with concentrated aqueous hydrochloride acid and extracted
with diethyl ether. The organic layer was dried over sodium sulfate and
purified by chromatography on silica gel to obtain 4-(4-ethynylphenyl)-5-
hydroxy-5-methyl-3-(2,4,6-trifluorophenyl)-5H-furan-2-one
(27,
0.6 g,
1.9 mmol, 39%); mp 186–188 °C. 1H NMR (400 MHz, CDCl3): d (ppm) = 1.71
(s, 3H), 3.24 (s, 1H), 6.67 (t, 1H), 6.82 (t, 1H), 7.43 (d, 2H), 7.51 (d, 2H). LC-MS:
tR = 1.83 min, m/z = 345 [M+1].
17. Further spectroscopic data:
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Tetrahedron Lett. 2003, 44, 8869–8871.
Compound 20: 1H NMR (400 MHz, CDCl3): d (ppm) = 1.84 (s, 3H), 3.97 (s, 3H),
6.70 (t, 1H), 6.76 (d, 1H), 6.85 (t, 1H), 7.82 (dd, 1H), 8.40 (d, 1H). LC–MS:
tR = 1.69 min, m/z = 352 [M+1].
10. Dumeunier, R.; Lamberth, C.; Trah, S. (Syngenta AG), PCT application WO 2009/
127612, Priority 14.4.2008, Publication 22.10.2009.
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3112–3122.
Compound 30a: 1H NMR (400 MHz, CDCl3): d (ppm) = 0.69–0.76 (m, 3H), 0.85
(t, 1H), 1.08 (d, 1H), 1.19–1.27 (m, 3H), 1.64 (s, 3H), 2.25 (q, 1H), 4.36 (br s, 1H),
7.31–7.40 (m, 2H), 7.52 (s, 1H). LC–MS: tR = 1.85 min, m/z = 315 [M+1].
Compound 30b: 1H NMR (400 MHz, CDCl3): d (ppm) = 0.93–0.98 (m, 1H), 1.20
(d, 1H), 1.31 (t, 1H), 1.62–1.69 (m, 1H), 2.26 (q, 1H), 6.97 (t, 2H), 7.06–7.38 (m,
3H), 7.75 (dd, 1H), 8.11 (t, 1H), 16.57 (br s, 1H). LC–MS: tR = 1.50 min, m/z = 317
[M+1].
Compound 30c: 1H NMR (400 MHz, CDCl3): d (ppm) = 1.12 (t, 3H), 2.48 (s, 3H),
4.19 (q, 2H), 6.65 (d, 1H), 7.12 (br s, 1H), 7.34–7.50 (m, 6H). LC–MS:
tR = 1.46 min, m/z = 345 [M+1], 300 [MÀOEt].
Compound 30d: 1H NMR (400 MHz, CDCl3): d (ppm) = 2.19 (s, 3H), 4.07 (br s,
1H), 6.98–7.07 (m, 3H), 7.10 (d, 2H), 7.16 (t, 1H), 7.28–7.43 (m, 5H), 7.69 (t,
1H). LC–MS: tR = 1.92 min, m/z = 395 [M+1].