A new strategy for the synthesis of furan-3,4-dicarboxylic acid

Article abstract of DOI:10.1055/s-2002-31967

A facile route to furan-3,4-dicarboxylic acid is described. Dimethylmaleic anhydride (1) on NBS-bromination followed by aqueous KOH treatment gave bis(hydroxymethyl)maleic anhydride (3), which on intramolecular Mitsunobu ring closure followed by esterification and DDQ-oxidation furnished the desired esters of furan-3,4-dicarboxylic acid 7a/b.

Full text of DOI:10.1055/s-2002-31967

1010
SHORT PAPER
A New Strategy for the Synthesis of Furan-3,4-dicarboxylic Acid1
S
ynthesis of Furan
n
-3,4-dicarbo
i
xylic
A
l
cid M. Deshpande, Arvind A. Natu, Narshinha P. Argade*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Fax +91(20)5893153; E-mail: argade@dalton.ncl.res.in
Received 15 February 2002; revised 16 April 2002
98% yield. The isolated anhydride 3 was quite stable and
did not show any tendency for intramolecular/intermole-
cular dehydration, Michael addition and nucleophilic ring
opening of anhydride moiety. The anhydride 3 on in-
Abstract: A facile route to furan-3,4-dicarboxylic acid is de-
scribed. Dimethylmaleic anhydride (1) on NBS-bromination fol-
lowed by aqueous KOH treatment gave bis(hydroxymethyl)maleic
anhydride (3), which on intramolecular Mitsunobu ring closure fol-
lowed by esterification and DDQ-oxidation furnished the desired tramolecular Mitsunobu ring closure in THF at room
esters of furan-3,4-dicarboxylic acid 7a/b.
temperature followed by aqueous work up furnished di-
hydrofuran-3,4-dicarboxylic acid (5) in 91% yield. The
diacid 5 on reaction with methanol/ethanol and a catalytic
amount of sulfuric acid gave the corresponding esters
6a/b, respectively, in 88–90% yield. These esters 6a/b, in
presence of excess of DDQ in refluxing 1,4-dioxane,
Key words: 2,3-bis(bromomethyl)maleic anhydride, intramolecu-
lar Mitsunobu ring closure, DDQ-oxidation, furan-3,4-dicarboxylic
acid
The applications of furan-3,4-dicarboxylic acid and its es- furnished the desired 3,4-furandicarboxylic acid esters
ters have been well known in practice.2 They are used as 7a/b in 80–85% yield (Scheme). The overall yield of
starting materials in the synthesis of several bioactive nat- 7a/b in five-steps was 39–42% and the analytical and
ural products such as zargocic acid,3 confertin,4 aromati- spectral data obtained for 7a/b were in complete agree-
cin,5 lactral,6 freelingyne,7 biotin,8 nectriafurone9 and ment with the reported data.2,14c The present practical ap-
perrilin.9 They are also used in the synthesis of several proach to design 7 from suitably substituted dicarboxylic
pharmacologically useful molecules,10 preparation of acid/cyclic anhydride to generate furan ring has several
complexes with rare earth metal ions11 and as a potential advantages over others in the literature (furan to furan-
dienes in Diels–Alder reactions for the synthesis of sever- 3,4-dicarboxylic acid).
al novel heterocycles.12 The development of new facile
In our hands all our attempts to transfer 2 to dihydro-
pyrrole-3,4-dicarboxylic acid/dihydrothiophene-3,4-di-
synthetic routes to this potential building block is a chal-
lenging task.13–17 To date five multi-step synthesis of 7a/b
carboxylic acid (8a/b) using ammonia and sodium sulfide
are known in the literature via partial decarboxylation of
met with failure, and only polymeric/decomposed gums
were obtained. The conditions to obtain 8a/b from 2 are
still elusive to us and the work is in progress in our labo-
furan tetracarboxylic acid,13 thermal decomposition of
partially reduced Diels–Alder adduct of furan and acety-
lenedicarboxylic acid/ester,14 cyclisation of 1,4-dicarbon-
ratory.
yl systems,15 regioselective lithiation of 2-silylated-3-
In summary, starting from dimethylmaleic anhydride (1),
we have demonstrated an elegant 5-step practical ap-
proach to esters of furan-3,4-dicarboxylic acid 7a/b with
39–42% overall yield via two new anhydrides 2 and 3.
furoic acid16 and involving condensation of methyl glyco-
late with methyl acrylate as the key step.17 Very recently
we prepared the (bromomethyl)methylmaleic anhydride
and used it for synthesis of chaetomellic acid A,18a fulgen-
ic acid,18b heterocycles,18c maleic anhydride segment of
tautomycin,18d telfairic anhydride19 and graphenone.19
Now, we herein report the preparation of bis(bromometh-
yl)maleic anhydride (2) and its application for the new
synthesis of esters of furan-3,4-dicarboxylic acid 7a/b
(Scheme).
Melting points are uncorrected. The IR spectra were recorded on FT
IR-8400 IR spectrophotometer. The 1H NMR spectra were recorded
on Bruker ACF 200 NMR spectrometer (200 MHz). The 13C NMR
spectra were recorded on Bruker ACF 200 NMR spectrometer (50
MHz). The Mass spectra were recorded on Finnigan Mat 1020 mass
spectrometer at 70 eV. Column chromatographic separations were
done on ACME silica gel (60–120 mesh). Petroleum ether with a bp
range of 60–80 °C was used. Dimethylmaleic anhydride, Ph3P, di-
ethyl azodicarboxylate (DEAD) and dibenzoyl peroxide (DBP)
were obtained from Aldrich Chemical Co.
The reaction of dimethylmaleic anhydride (1) with excess
of NBS in the presence of catalytic amounts of dibenzoyl
peroxide in refluxing CCl4 gave the bis(bromomethyl)ma-
leic anhydride (2) in 62% yield. The dibromoanhydride 2
on treatment with 4 N aqueous KOH at room temperature
followed by acidification afforded exclusively the substi-
tution product bis(hydroxymethyl)maleic anhydride (3) in
Bis(bromomethyl)maleic Anhydride (2)
A mixture of dimethylmaleic anhydride (1; 5.04 g, 40 mmol), N-
bromosuccinimide (14.24 g, 80 mmol) and a catalytic amount of
dibenzoyl peroxide (200 mg, 0.83 mmol) in CCl4 (300 mL) was
gently refluxed for 12 h in a 500 mL round-bottom flask. The reac-
tion mixture was allowed to cool to r.t. and a second portion of N-
bromosuccinimide (14.24 g, 80 mmol) and dibenzoyl peroxide (200
mg, 0.83 mmol) was added and again the refluxing was continued
Synthesis 2002, No. 8, 04 06 2002. Article Identifier:
1437-210X,E;2002,0,08,1010,1012,ftx,en;Z03402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

SHORT PAPER
Synthesis of Furan-3,4-dicarboxylic Acid
1011
Scheme Reagents and conditions: i) NBS, DBP, CCl4, reflux, 24; ii) (a) aq KOH, r.t., 3 h, (b) H+/2 N HCl; iii) DEAD, TPP, THF, r.t., 3 h;
iv) ROH, H+/H2SO4, r.t., 24 h; v) DDQ, 1,4-dioxane, reflux, 24 h
for another 12 h. The mixture was left overnight at r.t. and then fil-
tered. The residue was washed with CCl4 (2 25 mL), the combined
organic layer was washed with H2O (2 100 mL), brine (100 mL),
then dried (Na2SO4) and concentrated in vacuo to furnish a thick
yellow oil. Chromatography of the oil on a silica gel column with
petroleum ether–EtOAc (8:2) as eluent gave the crude product (9.7
g) which was further purified by distillation using a Kugelrhor ap-
paratus. The first fraction (2.2 g) was a mixture of a small amount
of starting material and major portion of (bromomethyl)methylma-
leic anhydride, whereas the second fraction obtained at 145–150 °C/
2 mm was the pure dibromoanhydride 2; yield: 7.1 g (62%, 98% pu-
rity by 1H NMR); mp 84–86 °C [benzene–petroleum ether (1:3)].
THF (10 mL) in a dropwise fashion with continuous stirring at r.t.
and the reaction mixture was further stirred for 3 h. The mixture was
concentrated in vacuo and the residue was dissolved in aq 5%
NaHCO3 solution (25 mL). The aqueous layer was washed with
EtOAc (2 20 mL); subsequent acidification of the aqueous layer
with aq 2 N HCl followed by extraction with EtOAc (3 10 mL).
The organic extracts were washed with H2O (10 mL), brine (10
mL), dried (Na2SO4) and concentrated to furnish the pure product 5;
yield: 1.44 g (91%); mp 191–193 °C (EtOAc).
1H NMR (acetone-d6, 200 MHz): = 4.96 (s, 4 H), 8.75–9.75 (br s,
2 H).
13C NMR (DMSO-d6, 50 MHz): = 77.3, 139.9, 164.2.
IR (Nujol): 1784, 1664 cm–1.
1H NMR (CDCl3, 200 MHz): = 4.28 (s).
13C NMR (CDCl3, 50 MHz): = 15.1, 141.1, 162.7.
MS: m/z (%) = 158 (2), 140 (12), 112 (14), 96 (23), 84 (35), 69 (47),
66 (100), 55 (28).
Anal. Calcd for C6H6O5: C, 45.58; H, 3.83. Found: C, 45.76; H,
3.58.
MS: m/z (%) = 286 (9), 284 (21), 282 (9), 205 (93), 203 (100), 161
(36), 159 (39), 133 (58), 131 (59), 124 (22), 80 (83), 66 (85).
Dimethyl 2,5-Dihydrofuran-3,4-dicarboxylate (6a); Typical
Procedure
Anal. Calcd for C6H4Br2O3: C, 25.38; H, 1.42. Found: C, 25.62; H,
1.26.
A solution of 5 (790 mg, 5 mmol) in MeOH and H2SO4 (19:1, 20
mL) was stirred at r.t. for 24 h under N2 and the reaction mixture
was concentrated in vacuo. The residue was diluted with H2O and
extracted with EtOAc (3 25 mL). The combined organic layer was
washed with H2O (25 mL), brine (25 mL) and dried (Na2SO4). Con-
centration of organic layer in vacuo followed by silica gel column
chromatographic purification of the crude product using petroleum
ether–EtOAc (7:3) as eluent furnished the pure dimethyl ester 6a as
a thick oil; yield: 837 mg (90%).
Bis(hydroxymethyl)maleic Anhydride (3)
To an ice-cold solution of 4 N aq KOH (25 mL) was added bis(bro-
momethyl)maleic anhydride (2; 5.68 g, 20 mmol) and the mixture
was stirred at r.t. for 3 h. The mixture was slowly acidified with aq
2 N HCl and saturated with solid NaCl and stirred at r.t. for 30 min.
The aqueous layer was extracted with EtOAc (3 25 mL), the or-
ganic layer was washed with brine (25 mL) and dried (Na2SO4).
Concentration of the organic layer in vacuo gave pure 3; yield: 3.01
g (98%); mp 174–176 °C [benzene–petroleum ether (1:3)].
IR (neat): 1726, 1666, 1279 cm–1.
IR (Nujol): 3429, 1769, 1693 cm–1.
1H NMR (acetone-d6, 200 MHz): = 4.96 (s, 4 H), 8.00–9.00 (br s,
1H NMR (CDCl3, 200 MHz): = 3.82 (s, 6 H), 4.93 (s, 4 H).
13C NMR (CDCl3, 50 MHz): = 52.1, 76.3, 136.2, 162.4.
2 H).
Anal. Calcd for C8H10O5: C, 51.61; H, 5.41. Found: C, 51.86; H,
5.54.
13C NMR (acetone-d6, 50 MHz): = 77.7, 139.9, 164.4.
MS: m/z (%) = 158 (2), 140 (52), 113 (36), 112 (39), 96 (41), 95
(39), 91 (7), 84 (100), 69 (83), 66 (85), 55 (24).
Diethyl 2,5-Dihydrofuran-3,4-dicarboxylate (6b)
Similarly the diethyl ester was prepared from 5 (790 mg, 5 mmol)
using EtOH and H2SO4 (19:1, 20 mL); thick oil; yield: 941 mg
(88%).
Anal. Calcd for C6H6O5: C, 45.58; H, 3.83. Found: C, 45.73; H,
3.67.
IR (neat): 1726, 1666, 1273 cm–1.
1H NMR (CDCl3, 200 MHz): = 1.32 (t, J = 8 Hz, 6 H), 4.27 (q,
J = 8 Hz, 4 H), 4.93 (s, 4 H).
2,5-Dihydrofuran-3,4-dicarboxylic Acid (5)
To a solution of 3 (1.58 g, 10 mmol) and Ph3P (2.88 g, 11 mmol) in
THF (20 mL) was added a solution of DEAD (1.92 g, 11 mmol) in
Synthesis 2002, No. 8, 1010–1012 ISSN 0039-7881 © Thieme Stuttgart · New York

1012
A. M. Deshpande et al.
SHORT PAPER
13C NMR (CDCl3, 50 MHz): = 14.0, 61.4, 76.5, 136.2, 162.2.
References
MS: m/z (%) = 214 (2), 213 (8), 201 (4), 189 (19), 168 (35), 157 (7),
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Dimethyl Furan-3,4-dicarboxylate (7a); Typical Procedure
To a solution of 6a (744 mg, 4 mmol) in 1,4-dioxane (15 mL) was
added DDQ (2.724 g, 12 mmol) and the reaction mixture was re-
fluxed for 24 h. The mixture was concentrated in vacuo and the res-
idue was dissolved in EtOAc (30 mL), washed with H2O (15 mL),
brine (15 mL) and dried (Na2SO4). Concentration of organic layer
in vacuo followed by silica gel column chromatographic purifica-
tion of the crude product using petroleum ether–EtOAc (7.5:2.5) as
eluent furnished the pure dimethyl ester 7a; yield: 618 mg (84%);
mp 48–50 °C.
IR (Neat): 2955, 1736, 1286 cm–1.
1H NMR (CDCl3, 200 MHz): = 3.87 (s, 6 H), 7.95 (s, 2 H).
13C NMR (CDCl3, 50 MHz): = 51.9, 118.2, 148.7, 162.0.
MS: m/z (%) = 184 (23), 153 (100), 123 (70), 95 (5), 69 (4), 59 (10),
53 (10).
Anal. Calcd for C8H8O5: C, 52.18; H, 4.38. Found: C, 52.27; H,
4.34.
Diethyl Furan-3,4-dicarboxylate (7b)
Similarly reaction of 6b (856 mg, 4 mmol) on DDQ oxidation
(2.724 g, 12 mmol) furnished 7b as a thick oil; yield: 687 mg (81%).
IR (neat): 2951, 1732, 1281 cm–1.
1H NMR (CDCl3, 200 MHz): = 1.32 (t, J = 8 Hz, 6 H), 4.33 (q,
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Acknowledgement
A. M. D. thanks CSIR, New Delhi, for the award of a fellowship. N.
P. A. thanks Department of Science & Technology, New Delhi for
financial support. We thank Dr. K. N. Ganesh, Head, Division of
Organic Chemistry (Synthesis), for constant encouragement.
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Synthesis 2002, No. 8, 1010–1012 ISSN 0039-7881 © Thieme Stuttgart · New York