Efficient synthesis of novel γ-substituted γ-butenolides by Lewis acid catalyzed addition of metal enolates of active methylene compounds to mucohalic acids

Article abstract of DOI:10.1021/jo050538t

Lewis acid catalyzed addition of active methylene compounds to mucochloric acid (1) and mucobromic acid (2) affording Knoevenagel aldol adducts, γ-substituted γ-butenolides, has been explored. Catalytic efficiencies of various Lewis acids have been compar

Full text of DOI:10.1021/jo050538t

Efficient Synthesis of Novel γ-Substituted γ-Butenolides by Lewis
Acid Catalyzed Addition of Metal Enolates of Active Methylene
Compounds to Mucohalic Acids
Ji Zhang,* Koushik Das Sarma, Timothy T. Curran, Daniel T. Belmont, and
James G. Davidson
Chemical Research and Development, Pfizer Global Research & Development, Ann Arbor Laboratories,
Pfizer, Inc., 2800 Plymouth Road, Ann Arbor, Michigan 48105
ji.zhang@pfizer.com
Received March 16, 2005
Lewis acid catalyzed addition of active methylene compounds to mucochloric acid (1) and mucobromic
acid (2) affording Knoevenagel aldol adducts, γ-substituted γ-butenolides, has been explored.
Catalytic efficiencies of various Lewis acids have been compared. Indium acetate (0.25-5 mol %)
was found to be the most efficient catalyst.
Introduction
There has been a continuous interest in developing
efficient and convenient methods for the synthesis of
γ-butenolides1 because these subunits are found in many
natural products, as well as in a number of synthetic drug
candidates with diverse biological activities (Figure 1).2
Mucohalic acids (1 and 2, Figure 2) are two inexpensive,
commercially available, and highly functionalized start-
ing materials. The unique disposition of various func-
tionalities makes them interesting building blocks for
molecules of interest. However, they have remained
FIGURE 1. Natural and synthetic compounds with the
γ-butenolide subunit.
* To whom correspondence should be addressed. Fax: +1-734-622-
3294. Tel: +1- 734-622-3940.
(1) (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 14370. (b) Boye, A. C.; Meyer, D.; Ingison, C. K.; French, A. N.;
Wirth, T. Org. Lett. 2003, 5, 2157. (c) Dangel, B. D.; Johnson, J. A.;
Sames, D. J. Am. Chem. Soc. 2001, 123, 8149. (d) Morizawa, Y.;
Hiyama, T.; Nazoki, H. Tetrahedron Lett. 1981, 22, 2297. (e) Evans,
P. A.; Kennedy, L. J. Org. Lett. 2000, 2, 2213. (f) Takimoto, M.;
Kawamura, M.; Mori, M. Org. Lett. 2003, 5, 2599. (g) Pearson, A. J.;
Mesaros, E. F. Org. Lett. 2002, 4, 2001.
(2) (a) Meresse, P.; Dechaux, E.; Monneret, C.; Bertounesque, E.
Curr. Med. Chem. 2004, 11, 2443.(b) Vogel, K.; Sterling, J.; Herzig,
Y.; Nudelman, A. Tetrahedron 1996, 52, 3049. (c) Bo¨hm, C.; Reiser, O.
Org. Lett. 2001, 3, 1315. (d) Pohmakotr, M.; Harnying, W.; Tuchinda,
P.; Reutrakul, V. Helv. Chim. Acta 2002, 85, 3792. (e) Avedissian, H.
A.; Sinha, S. C.; Yazbak, A.; Sinha, A.; Neogi, P.; Sinha S. C.; Keinan,
E. J. Org. Chem. 2000, 65, 6035. (f) Sinha, S. C.; Sinha, S. C.; Keinan,
E. J. Org. Chem. 1999, 64, 7067. (g) Ito, C.; Itoigawa, M.; Katsuno, S.;
Omura, M.; Tokuda, H.; Nishino, H.; Furukawa, H. J. Nat. Prod. 2000,
63, 1218. (h) Lattmann, E.; Ayuko, W. O.; Kinchinaton, D.; Langley,
C. A.; Singh, H.; Karimi, L.; Tisdale, M. J. J. Pharm. Pharmacol. 2003,
55, 1259.
FIGURE 2. Mucochloric and mucobromic acids and related
compounds.
underutilized in organic synthesis presumably as a result
of the difficulty in the selective manipulation of the
functional groups and their poor stability under basic
conditions. In an effort to establish the relative reactivity
10.1021/jo050538t CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/21/2005
5890
J. Org. Chem. 2005, 70, 5890-5895

Novel γ-Substituted γ-Butenolides
TABLE 1. ZnCl2-Catalyzed Knoevenagel Aldol
Condensation with Mucochloric Acida
among the functional groups, we have recently reported
regioselective amination, etherification, reductive ami-
nation, arylation, allylation, and C-C bond formation by
Mukaiyama aldol reaction of mucohalic acids.3 To further
explore mucohalic acid chemistry, this paper reports
Lewis acid catalyzed Knoevenagel aldol addition of active
methylene compounds to mucohalic acids to afford γ-func-
tionalized γ-butenolides.
The Knoevenagel condensation is one of the most
useful and classical methods for C-C bond formation in
organic synthesis.4 Usually a catalytic amount of am-
monia or amine base is employed to promote the con-
densation of aldehyde or ketone with active methylene
compounds. The use of Lewis acid to catalyze this
reaction has begun to receive some attention in recent
years but is still in its infancy.5 All of these reports
utilized simple aromatic aldehydes or ketones as the
carbonyl component and the active methylene compounds
lacked diversity. Also, there are few reported efforts to
reduce the Lewis acid loading in this type of reaction.
The instability of mucohalic acids under basic conditions
prompted us to focus on Lewis acid catalyzed C-C bond
forming reactions at the C-4 positions of mucohalic acids.6
Results and Discussion
We initiated our study with 1 using diethyl malonate
as the active methylene compound and ZnCl2 as the
Lewis acid.7 Refluxing a mixture of 1 and ZnCl2 (10 mol
%) in toluene with water removal in a Dean-Stark
condenser over 16 h resulted in 82% isolated yield of 3.
It is interesting to note that because of the unique
disposition of the carboxylic acid group the aldol adduct
cyclized (dehydration) and the isolated product is 3 not
4 (Figure 2). Similar observations were made during the
reductive amination of mucohalic acids where R,â-
unsaturated γ-butyrolactam was isolated.3
Without doubt, connecting mucohalic acid, a versatile
building block, to a very useful and inexpensive three-
carbon building block, diethyl malonate, is more mean-
ingful.8 The initial exciting result prompted us to explore
different active methylene compounds that resulted in
the isolation of Knoevenagel-type aldol addition products
a Reaction conditions: 10 mmol each of 1 and R1CH2R2, 0.1
equiv of ZnCl2, 50 mL of PhMe, refluxed for 16 h with water
separation by Dean-Stark. b Products were isolated and purified
by silica gel chromatography and characterized c The reaction was
done for 24 h d Product crystallized out from the reaction mixture
upon cooling
in good to excellent isolated yields (Table 1). Interest-
ingly, the use of Meldrum’s acid afforded the Doebner
product via acetonide cleavage and decarboxylation
(entry 7).9 Though the yields were satisfactory, in some
cases it was difficult to isolate the products from uncon-
verted starting material (entries 2, 3, 5, 7 and 8) because
of the close polarity of 1 and the corresponding products.
Also, the reaction condition was not suitable for 2 as
significant decomposition occurred at times. Our effort
to reduce the amount of ZnCl2 from 10 mol % was not
successful because of longer reaction time and incomplete
conversion.
For the future development of a chiral Lewis acid
catalyst for chiral butenolide formation, it would be
necessary to reduce the catalyst amount.10 Therefore, we
decided to investigate the effect of various Lewis acids
on these transformations. It is known that a Lewis acid
(3) (a) Zhang, J.; Blazecka, P. G.; Belmont, D.; Davidson, J. G. Org.
Lett. 2002, 4, 4559. (b) Zhang, J.; Blazecka, P. G.; Davidson, J. G. Org.
Lett. 2003, 5, 553. (c) Blazecka, P. G.; Belmont, D.; Curran, T.; Pflum,
D.; Zhang, J. Org. Lett. 2003, 5, 5015. (d) Zhang, J.; Blazecka, P. G.;
Berven, H.; Belmont, D. Tetrahedron Lett. 2003, 44, 5579. (e) Angell,
P.; Zhang, J.; Belmont, D.; Curran, T.; Davidson, J. G. Tetrahedron
Lett. 2005, 46, 2029.
(4) Tietze, L. F.; Beifuss, U. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: New York, Oxford, 1991;
Vol. 2, p 341.
(5) (a) Rao, P. S.; Venkataratnam, R. V. Tetrahedron Lett. 1991, 32,
5821. (b) Narsaiah, A. V.; Nagaiah, K. Synth. Commun. 2003, 33, 3825.
(c) Prajapati, D.; Sandhu, J. S. Chem. Lett. 1992, 1945. (d) Harjani, J.
R.; Nara, S. J.; Salunkhe, M. M. Tetrahedron Lett. 2002, 43, 1127. (e)
Appendino, G.; Cravotto, G.; Minassi, A.; Palmisano, G. Eur. J. Org.
Chem. 2001, 3711.
(6) Base-catalyzed condensations between mucohalic acids and
active methylene compounds have been reported previously with poor
yield (2-45%). See: Mowry, D. T. J. Am. Chem. Soc. 1953, 75, 1909
and correction at J. Am. Chem. Soc. 1954, 76, 6417.
(7) Initial results were presented in part at the 225th ACS National
Meeting, New Orleans, LA, March 23-27, 2003.
(8) (a) Nguyen, R.-V.; Yao, X.-Q.; Bhole, D. S.; Li, C.-J. Nano Lett.
2005, ASAP. (b) Yao, X.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 6884.
(c) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc.
2004, 126, 4526.
(9) Doebner, O. Ber. 1900, 33, 2140.
(10) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-
VCH: New York, 2000.
J. Org. Chem, Vol. 70, No. 15, 2005 5891

Zhang et al.
TABLE 2. Effect of Lewis Acids on Knoevenagel Aldol
Condensation with Mucochloric Acida
chloride and indium acetate, especially In(OAc)3, are
superior to In(OTf)3. Unlike indium chloride, In(OAc)3
seldom received attention in organic synthesis until
recently. For example, Li reported that using In(OAc)3
to promote Grignard-type reactions,13 aldol reactions, and
Mannich-type reactions in water and protic solvents.14
Recently Hosomi reported In(OAc)3-catalyzed 1,4-reduc-
tion with PhSiH3 in ethanol at ambient temperature.15
In our study, we found that the loading of indium acetate
can be as low as 1% and still give excellent yield of
butenolide 4 (entry 19, HPLC conversion 100%, isolated
yield 95%).
We have optimized the reaction on a larger scale (16.8
g of 1, 100 mmol) and found this procedure is reliable
and robust. Under air, a mixture of 1 (16.8 g, 100 mmol),
diethyl malonate (16 g, 100 mmol), and In(OAc)3 (0.25
mol %, 0.07 g) in reagent grade toluene (50 mL) was
heated to reflux for 14 h, and water was removed via a
Dean-Stark trap to afford butenolide 3 in 92% isolated
yield.16 Regarding the relatively nontoxic nature of the
catalyst, its ease of handling, and the easy availability
and low cost of both starting materials, it is difficult to
envision a more ideal process in terms of green chemistry
principles, experimental ease, practicality, and efficiency.
These In(OAc)3 conditions were found to be general and
efficient for the use of a variety of other active methylene
compounds such as alkyl cyanoacetate, ethyl malonate
monoamide, and ethyl nitroacetate (Table 3). With 5%
In(OAc)3 as catalyst, the reactions typically completed
within 8 h and in some cases even faster (entry 11, 2.5
h). As a result of shorter reaction times, it became
practical for more hindered substrates (entry 7). The yield
was 10% lower with diethyl chloromalonate and ZnCl2
(entry 5, Table 1) compared to that with In(OAc)3 (entry
6, Table 3). It is also important to note that ZnCl2 failed
to yield any product with ethyl malonate monoamide and
ethyl nitroacetate. Interestingly, neither In(OAc)3 nor
ZnCl2 gave any product with acetyl acetone or ethyl
acetoacetate under these reaction conditions.
entry
Lewis acid
ZnCl2
Zn(OTf)2
BiCl3
Mg(OTf)2
Sc(OTf)3
Yb(OTf)3
AlCl3
mol %
% of 3 at 8 hb
1
10
5
10
5
5
5
80
2
19
3
32
4
7
5
60
6
72
7
10
5
68
8
CoCl2
ZrCl4
0
9
5
90
10
11
12
13
14
15
16
17
18
In(ClO4)3‚H2O
In(OTf)3
InBr3
5
45
5
52
5
71
InF3
5
63
InCl3
10
5
100 (3 h)
99 (6 h)
99
InCl3
InCl3
1
In(OAc)3
In(OAc)3
5
100 (5.5 h)
1
100 (95)c
a Reaction conditions: 10 mmol each of 1 and CH2(CO2Et)2, LA,
50 mL of PhMe refluxed with water separation by Dean-Stark.
b Measured by HPLC. c Isolated yield.
FIGURE 3. Side product and suggested In-enolate.
greatly shifts the tautomeric equilibrium between enol
and keto forms and often favors the enol form by
chelation. The enolate of an active methylene compound
is responsible for its reactivity as a nucleophile. Thus,
the reaction between 1 and diethyl malonate was per-
formed using different Lewis acids (Table 2). Surpris-
ingly, the best result was obtained with InCl3 and
In(OAc)3. Yields were lower with other In(III) salts, such
as InBr3, InF3, and In(ClO4)3. A substantial amount (10-
20%) of the ethyl ether 12 formed when In(OTf)3, Sc-
(OTf)3, or In(ClO4)3‚H2O was used as Lewis acid, pre-
sumably by hydrolysis of diethyl malonate and subsequent
etherification of 1. Though ZrCl4 resulted in a good con-
version, it is not very suitable from a practical standpoint
because of its hygroscopic and corrosive nature.
Reactions between mucobromic acid 2 and active
methylene compounds were found as effective as with 1
(Table 3). Simple malonates work well and gave the
desired product with excellent isolated yield (entry 1).
For a monosubstituted malonate such as diethyl methyl
malonate (entry 5), the reaction time was longer (12 h)
and the yield was lower (78%) using 2 compared to that
with 1, presumably as a result of steric hindrance caused
by a larger Br atom at the â-position. Nevertheless, In-
(OAc)3 proved to be milder than ZnCl2 in promoting this
transformation.
The indium(III) salt, considered to be a novel, water-
tolerant, and green Lewis acid, has received significant
attention in recent years.11 The most-utilized In(III)
Lewis acids are indium chloride and indium triflate.
Recently Nakamura and co-workers reported indium
triflate catalyzed addition of active methylene compounds
to 1-alkynes, where it was suggested that the formation
of indium enolate (13, Figure 3) is essential for the
catalytic cycle.12 In this study, we found both indium
On the basis of the experimental results and known
literature examples, a possible reaction pathway is given
(Figure 4). An indium enolate generated from indium
acetate and an active methylene compound is critical for
the catalytic cycle. The released acetic acid is useful to
enrich activated species 24. The role In(OAc)3 plays is
perhaps 3-fold: (a) generating indium enolate, (b) gen-
erating acetic acid, and (c) catalyzing the dehydration to
(13) Wei, C.; Li, C.-J. Green Chem. 2002, 4, 39.
(14) Wang, M.; Yang, X.-F.; Li, C.-J. Eur. J. Org. Chem. 2003, 998.
(15) Miura, K.; Yamada, Y.; Tomita, M.; Hosomi, A. Synlett 2004,
1985.
(16) With 0.5 mol % In(OAc)3, the reaction was over in 7 h and the
isolated yield was 96%.
(11) (a) Babu, G.; Perumal, P. T. Aldrichimica Acta 2000, 33, 16.
(b) Frost, C. G.; Hartley, J. P. Mini-Rev. Org. Chem. 2004, 1, 1. (c)
Ranu, B. C. Eur. J. Org. Chem. 2000, 2347.
(12) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc.
2003, 125, 13002.
5892 J. Org. Chem., Vol. 70, No. 15, 2005

Novel γ-Substituted γ-Butenolides
TABLE 3. In(OAc)3 Catalyzed Knoevenagel Aldol Condensation with Mucohalic Acidsa
a Reaction conditions: 10 mmol each of 1/2 and R1CH2R2, 0.05 equiv of In(OAc)3, and 50 mL of PhMe, reluxed with water separation
by Dean-Stark. b Products were isolated and purified by silica gel chromatography and characterized. c Product crystallized out from
the reaction mixture upon cooling.
a Knoevenagel aldol reaction as the reaction product
remains at the aldol product stage.18
Conclusions
In summary, we have developed a simple, efficient, and
highly practical method to promote the Knoevenagel aldol
reaction where mucohalic acids are used as starting
material, giving γ-functionalized γ-butenolides in good
to excellent yield. Indium acetate turned out to be a novel,
green Lewis acid to promote this reaction for addition of
diverse types of active methylene compounds such as
dialkyl malonate, alkyl cyanoacetate, ethyl malonate
monoamide, and ethyl nitroacetate to mucochloric acid.
FIGURE 4. Proposed catalytic cycle.
To the best of our knowledge, this is the first report of a
Knoevenagel aldol condensation reaction catalyzed by In-
(OAc)3. We have been able to minimize the consumption
form the butenolide 3. It is easy to understand why
indium triflate is not as good as indium acetate because
the free CF3SO3H is a strong acid that can catalyze (with
help from indium triflate) the hydrolysis of diethyl
malonate, thus forming the side product 12. Because the
Knoevenagel condensation product, 4, was not formed
(when diethyl methyl malonate was used, it is impossible
to form 4 or the diene-acid17), we consider this reaction
(17) It is unlikely to form diene-acids such as 4 even when R1 ) H
because these types of compounds are very unstable with heat and
expected to undergo decarboxylation that would produce other side
products. See: Al-Hakim, A.; Haines, A. H. Tetrahedron Lett. 1982,
23, 5295.
(18) Marumoto, S.; Kogen, H.; Naruto, S. Chem. Commun. 1998,
2253.
J. Org. Chem, Vol. 70, No. 15, 2005 5893

Zhang et al.
62.5, 61.2, 53.8, 26.8, 14.2, 9.4. Anal. Calcd for C13H16Cl2O6:
C, 46.04; H, 4.75; Cl, 20.91. Found: C, 46.00; H, 4.66; Cl, 21.07.
(3,4-Dichloro-5-oxo-2,5-dihydro-furan-2-yl)-acetic Acid
(10). 1H NMR (400 MHz, DMSO-d6) δ: 12.89 (br. S, 1H), 7.11
(s, 1H), 3.62 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ: 167.6,
165.9, 147.9, 124.0, 92.7, 41.7. IR (KBr): 3001, 2910, 1794,
1702, 1637 cm-1. Anal. Calcd for C6H4Cl2O4: C, 34.15; H, 1.91.
Found: C, 33.51; H, 1.70.
of In(OAc)3 to 0.25 mol % and establish the efficiency of
this methodology by performing the reaction at larger
scale. Further investigations, including extension of the
use of these building blocks and indium enolates in
organic synthesis and exploring the generality of this
methodology with diverse carbonyl compounds, will be
reported in due course.
Octyl Cyano-(3,4-dichloro-5-oxo-2,5-dihydro-furan-2-
yl)-acetate (11, diastereomeric mixture). 1H NMR (400
MHz, CDCl3) δ: 5.56 (d, J ) 2.53 Hz, 70% of 1H), 5.53 (d, J )
3.51 Hz, 30% of 1H), 4.30 (t, J ) 6.92 Hz, 1H), 4.26 (m, 1H),
4.16 (m, 1H), 1.69 (m, 2H), 1.30 (m, 10H), 0.86 (br t, J ) 8.0
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 163.1, 161.9, 161.3,
147.4, 124.6, 110.5, 78.3, 68.9, 40.7, 31.91, 29.3, 28.4, 25.8, 22.8,
14.3. Anal. Calcd for C15H19Cl2NO4: C, 51.74; H, 5.50; N, 4.02;
Cl, 20.36. Found: C, 51.61; H, 5.39; N, 4.03; Cl, 20.25.
3,4-Dichloro-5-ethoxy-5H-furan-2-one (12).19 1H NMR
(400 MHz, CDCl3) δ: 5.79 (s, 1H), 3.89 (m, 1H), 3.79 (m, 1H),
1.30 (t, J ) 7.13 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 163.4,
147.7, 124.5, 101.0, 66.3, 15.1. LRMS (GC) m/z: 196 (M+)
Diethyl 2-(3,4-Dibromo-5-oxo-2,5-dihydro-furan-2-yl)-
Experimental Section
All reactions were carried out under nitrogen atmosphere
unless otherwise noted.
General Procedure for Compounds 3, 4-9, 11-18, and
21-23. A mixture of mucohalic acid (10 mmol), In(OAc)3 (0.5
mmol), and the active methylene compound (10 mmol) in 50
mL of toluene was refluxed with water separation in a Dean-
Stark condenser. The reaction mixture was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography using ethyl acetate/hexanes as eluent.
General Procedure for Compounds 10 and 19. A
mixture of mucohalic acid (10 mmol), In(OAc)3 (0.5 mmol), and
the active methylene compound (10 mmol) in 50 mL of toluene
was refluxed. No water separation was observed in the Dean-
Stark condenser. The reaction mixture was filtered hot and
concentrated to half. The product crystallized out upon cooling.
Procedure for Compound 20. Similar to the procedure
for 10 and 19 except that the product did not crystallize out.
The reaction mixture was cooled to room temperature, and 50
mL of tbutyl methyl ether was added to it. The organic phase
was sequentially washed with 2 N HCl (2 × 10 mL) and brine
(10 mL), dried over anhydrous Na2SO4, and filtered, and the
filtrate was concentrated under high vacuum to yield the
desired product of sufficiently high purity.
1
malonate (14). H NMR (400 MHz, CDCl3) δ: 5.55 (d, J )
4.30 Hz, 1H), 4.26 (m, 2H), 4.21 (m, 2H), 3.96 (d, J ) 4.30 Hz,
1H), 1.29 (t, J ) 7.23, 3H), 1.23 (t, J ) 7.13, 3H). 13C NMR
(100 MHz, CDCl3) δ: 165.4, 165.1, 164.2, 144.5, 117.0, 81.7,
62.9, 62.7, 53.1, 14.2. Anal. Calcd for C11H12Br2O6: C, 33.03;
H, 3.02; Br, 39.95. Found: C, 33.38; H, 2.75; Br, 39.61.
Diisopropyl 2-(3,4-Dichloro-5-oxo-2,5-dihydro-furan-2-
1
yl)-malonate (15). H NMR (400 MHz, CDCl3) δ: 5.55 (d, J
) 4.10 Hz, 1H), 5.08 (m, 2H), 3.89 (d, J ) 4.10 Hz, 1H), 1.25
(d, J ) 6.25 Hz, 6H), 1.22 (m, 6H). 13C NMR (100 MHz, CDCl3)
δ: 164.5, 163.8, 149.8, 122.8, 79.1, 70.9, 70.8, 53.2, 21.8, 21.7.
Anal. Calcd for C13H16Cl2O6: C, 46.04; H, 4.75. Found: C,
45.79; H, 4.76.
Diethyl 2-(3,4-Dichloro-5-oxo-2,5-dihydro-furan-2-yl)-
malonate (3). 1H NMR (400 MHz, CDCl3) δ: 5.56 (d, J ) 4.49
Hz, 1H), 4.23 (m, 4H), 3.93 (d, J ) 4.49 Hz, 1H), 1.25 (m, 6H).
13C NMR (100 MHz, CDCl3) δ: 165.0, 164.2, 149.7, 122.9, 79.0,
62.9, 52.9, 14.1. Anal. Calcd for C11H12Cl2O6: C, 42.47; H, 3.89.
Found: C, 42.39; H, 3.79.
Diisopropyl 2-(3,4-Dibromo-5-oxo-2,5-dihydro-furan-
1
2-yl)-malonate (16). H NMR (400 MHz, CDCl3) δ: 5.53 (d,
J ) 3.91 Hz, 1H), 5.10 (m, 1H), 5.03 (m, 1H), 3.90 (d, J ) 3.91
Hz, 1H), 1.25 (d, J ) 6.25 Hz, 6H), 1.22 (d, J ) 6.25 Hz, 3H),
1.21 (d, J ) 6.25 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 165.5,
164.7, 163.8, 144.8, 116.9, 81.8, 70.9, 70.6, 53.4, 21.7. Anal.
Calcd for C13H16Br2O6: C, 36.48; H, 3.77; Br, 37.33. Found:
C, 36.85; H, 3.71; Br, 37.31.
Benzyl Ethyl 2-(3,4-Dichloro-5-oxo-2,5-dihydro-furan-
2-yl)-malonate (5, diastereomeric mixture). 1H NMR (400
MHz, CDCl3) δ: 7.35 (m, 5H), 5.58 and 5.57 (d, J ) 3.51 Hz,
1H), 5.20 (m, 2H), 4.23 (m, 2H), 3.99 and 3.94 (d, J ) 4.48 Hz,
total 1H), 1.22 (m, 3H). 13C NMR (100 MHz, CDCl3) δ: 165.4,
165.0, 164.1, 144.6, 134.6, 129.1, 128.9, 128.7, 123.0, 78.9, 68.5,
63.0, 62.9, 52.9, 52.8, 14.1. Anal. Calcd for C16H14Cl2O6: C,
51.50; H, 3.78; Cl, 19.00. Found: C, 51.68; H, 3.65; Cl, 19.20.
Dibenzyl 2-(3,4-Dichloro-5-oxo-2,5-dihydro-furan-2-yl)-
Benzyl Ethyl 2-(3,4-Dibromo-5-oxo-2,5-dihydro-furan-
2-yl)-malonate (17). 1H NMR (400 MHz, CDCl3) δ: 7.35 (m,
5H), 5.56 (m, 1H), 5.20 (m, 2H), 4.20 (m, 2H), 4.01 (d, J )
4.09 Hz, 1H), 1.24 (m, 3H). 13C NMR (100 MHz, CDCl3) δ:
165.4, 165.0, 164.1, 144.6, 134.6, 129.1, 128.9, 128.7, 117.0,
81.7, 68.5, 68.3, 63.0, 62.8, 53.1, 52.9, 14.1. HRMS (ESI) calcd
for C16H14Br2NaO6 482.9055 (M + Na+), found 482.9039.
Diethyl 2-(3,4-Dibromo-5-oxo-2,5-dihydro-furan-2-yl)-
2-methyl-malonate (18). 1H NMR (400 MHz, CDCl3) δ: 5.77
(s, 1H), 4.25 (m, 4H), 1.43 (s, 3H), 1.27 (t, J ) 7.13 Hz, 6H).
13C NMR (100 MHz, CDCl3) δ: 167.6, 167.3, 165.3, 144.7,
116.8, 85.5, 63.0, 57.0, 15.3, 14.1. Anal. Calcd for C12H14-
Br2O6: C, 34.81; H, 3.41; Br, 38.60. Found: C, 34.54; H, 3.18;
Br, 38.80.
(3,4-Dibromo-5-oxo-2,5-dihydro-furan-2-yl)-acetic Acid
(19). 1H NMR (400 MHz, DMSO-d6) δ: 12.95 (br. s, 1H), 7.08
(s, 1H), 3.60 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ: 167.7,
165.9, 144.4, 118.5, 95.0, 41.7. IR (KBr): 2997, 2952, 1784,
1763, 1717 cm-1. Anal. Calcd for C6H4Br2O4: C, 24.03; H, 1.34.
Found: C, 24.65; H, 1.08.
1
malonate (6). H NMR (400 MHz, CDCl3) δ: 7.33 (m, 6H),
7.27 (m, 4H), 5.56 (d, J ) 4.48 Hz, 1H), 5.20 (d, J ) 1.75 Hz,
2H), 5.15 (s, 2H), 4.03 (d, J ) 4.48 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ: 164.7, 164.6, 149.4, 134.5, 128.9, 128.8, 128.7,
123.0, 78.9, 68.6, 52.8. Anal. Calcd for C21H16Cl2O6: C, 57.95;
H, 3.71; Cl, 16.29. Found: C, 57.61; H, 3.51; Cl, 16.54.
Diethyl 2-(3,4-Dichloro-5-oxo-2,5-dihydro-furan-2-yl)-
1
2-methyl-malonate (7). H NMR (400 MHz, CDCl3) δ: 5.74
(s, 1H), 4.23 (m, 4H), 1.43 (s, 3H), 1.26 (m, 6H). 13C NMR (100
MHz, CDCl3) δ: 167.2, 164.4, 150.1, 123.4, 83.0, 63.0, 62.8,
56.7, 15.4, 14.1. Anal. Calcd for C12H14Cl2O6: C, 44.33; H, 4.34.
Found: C, 44.45; H, 4.18.
Diethyl 2-Chloro-2-(3,4-dichloro-5-oxo-2,5-dihydro-fu-
1
ran-2-yl)-malonate (8). H NMR (400 MHz, CDCl3) δ: 6.02
(s, 1H), 4.37 (m, 4H), 1.34 (m, 6H). 13C NMR (100 MHz, CDCl3)
δ: 163.7, 162.6, 147.8, 125.1, 82.4, 70.8, 64.7, 14.1. Anal. Calcd
for C11H11Cl3O6: C, 38.23; H, 3.21; Cl, 30.78. Found: C, 38.53;
H, 2.96; Cl, 30.94.
2-(3,4-Dichloro-5-oxo-2,5-dihydro-furan-2-yl)-propion-
ic Acid (20, diastereomeric mixture). 1H NMR (400 MHz,
CDCl3) δ: 10.41 (br s, 1H), 6.93 (d, J ) 2.15 Hz, 90% of 1H),
6.91 (d, J ) 3.71 Hz, 10% of 1H), 3.66-3.59 (m, 1H), 1.57 (d,
J ) 7. 23 Hz, 10% of 3H), 1.53 (d, J ) 7.42 Hz, 90% of 3H). 13
C
Diethyl 2-(3,4-Dichloro-5-oxo-2,5-dihydro-furan-2-yl)-
2-ethyl-malonate (9). 1H NMR (400 MHz, CDCl3) δ: 5.52 (s,
1H), 4.25 (m, 2H) 4.16 (m, 2H), 2.17 (m, 2H) 1.26 (t, J ) 7.24
Hz, 3H), 1.20 (t, J ) 7.23, 3H) 1.02 (t, J ) 7.52, 3H). 13C NMR
(100 MHz, CDCl3) δ: 169.7, 167.6, 166.8, 151.5, 122.6, 82.5,
NMR (100 MHz, CDCl3) δ: 174.6, 167.5, 147.0, 125.0, 91.8,
(19) Lattmann, E.; Kinchington, D.; Singh, H.; Merino, I.; Begum,
A.; Ayuko, W. O.; Tisdale, M. J. Pharm. Pharmacol. Lett. 2001, 11, 5.
5894 J. Org. Chem., Vol. 70, No. 15, 2005

Novel γ-Substituted γ-Butenolides
45.8, 13.5. LRMS (APCI) m/z: 224.9 [M - 1]-. HRMS (ESI)
calcd for C7H4ClO4 186.9798 ([{M - HCl} - H]-), found
186.9794.
80.0, 79.8, 63.3, 63.0, 52.6, 51.8, 14.0. Anal. Calcd for C9H9-
Cl2NO5: C, 38.32; H, 3.22; N, 4.97; Cl, 25.14. Found: C, 38.29;
H, 3.08; N, 4.88; Cl, 24.99.
Ethyl (3,4-Dichloro-5-oxo-2,5-dihydro-furan-2-yl)-ni-
tro-acetate (23, diastereomeric mixture). 1H NMR (400
MHz, CDCl3) δ: 5.75 (d, J ) 2.73 Hz, 60% of 1H), 5.71 (d, J )
4.09 Hz, 40% of 1H), 5.66 (d, J ) 2.73 Hz, 60% of 1H), 5.55 (d,
J ) 4.29 Hz, 40% of 1H), 4.37 (m, 2H), 1.31 (m, 3H). 13C NMR
(100 MHz, CDCl3) δ: 163.5, 159.7, 151.9, 123.9, 101.1, 84.9,
64.8, 14.0. LRMS (APCI) m/z: 284.0 (M-).
Octyl Cyano-(3,4-dibromo-5-oxo-2,5-dihydro-furan-2-
1
yl)-acetate (21). H NMR (400 MHz, CDCl3) δ: 5.54 (d, J )
2.54 Hz, 70% of 1H), 5.52 (d, J ) 3.32 Hz, 30% of 1H), 4.30 (t,
J ) 6.84 Hz, 1H), 4.25 (m, 1H), 4.18 (m, 1H), 1.71 (m, 2H),
1.27 (m, 10H), 0.87 (br t, J ) 8.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ: 164.2, 162.0, 161.4, 142.6, 118.4, 110.5, 81.1, 68.8,
68.6, 60.6, 41.2, 40.9, 31.9, 29.3, 28.5, 25.8, 22.8, 14.3. Anal.
Calcd for C15H19Br2NO4: C, 41.21; H, 4.38; N, 3.20; Br, 36.56.
Found: C, 41.32; H, 4.18; N, 3.16: Br, 36.79.
Acknowledgment. K.D.S. wishes to thank Pfizer,
Inc. for a postdoctoral fellowship.
Ethyl 2-(3,4-Dichloro-5-oxo-2,5-dihydro-furan-2-yl)-
malonamate (22, diastereomeric mixture). 1H NMR (400
MHz, CDCl3) δ: 5.74 (d, J ) 2.93 Hz, 60% of 1H), 5.67 (d, J )
3.91 Hz, 40% of 1H), 4.22 (m, 2H), 3.87 (d, J ) 3.91 Hz, 40%
of 1H), 3.80 (d, J ) 3.13 Hz, 60% of 1H), 1.30 (t, J ) 7.13 Hz,
40% of 3H), 1.22 (t, J ) 7.13 Hz, 60% of 3H). 13C NMR (100
MHz, CDCl3) δ: 167.3, 166.5, 166.1, 64.8, 150.9, 150.6, 123.3,
Supporting Information Available: 1H and 13C NMR
data of the compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO050538T
J. Org. Chem, Vol. 70, No. 15, 2005 5895