A facile synthesis of fulgenic acid via base induced 1,4- dehydrobromination of (bromomethyl)methylmaleic anhydride

Article abstract of DOI:10.1055/s-1999-3558

A facile synthesis of fulgenic acid (1) via 1,4-dehydrobromination of (bromomethyl)methylmaleic anhydride (2) using aqueous KOH, t-BuOK in THF, and NaH in benzene in 60-85% yield is described. The newly synthesized (hydroxymethyl)methylmaleic anhydride (3) also underwent smooth 1,4- elimination in the presence of aqueous KOH to yield 1.

Full text of DOI:10.1055/s-1999-3558

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Sachin G. Deshpande, Narshinha P. Argade*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Fax +91(20)5893153
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Dedicated to Dr. V. Balasubramaniyan on the occasion of his 66th birthday
$EVWUDFWꢊ A facile synthesis of fulgenic acid (ꢀ) via 1,4-dehydro-
bromination of (bromomethyl)methylmaleic anhydride (ꢋ) using
aqueous KOH, W-BuOK in THF, and NaH in benzene in 60–85%
yield is described. The newly synthesized (hydroxymethyl)methyl-
maleic anhydride (ꢁ) also underwent smooth 1,4-elimination in the
presence of aqueous KOH to yield ꢀ.
.H\ꢄ ZRUGVꢊ (bromomethyl)methylmaleic anhydride, base, 1,4-
elimination, fulgenic acid
Butadiene-2,3-dicarboxylic acid (Fulgenic acid, ꢀ) has
been used in studies2 on the mechanism of action of vita-
min B12, in Diels–Alder reactions,3 and in the preparation
of optically pure 2,3-dimethyl succinic acid isomers by
asymmetric catalytic reduction,4 while the corresponding
Reagents and conditions: i) (a) 4 N aq KOH, reflux, 12 h, (b)H+/
H2SO4 (60–65%); ii) (a) -BuOK, THF, r.t., 4 h, (b) H+/H2SO4 (80–
85%); iii) (a) NaH, benzene, reflux, 4 h, (b) H+/H2SO4 (80–85%); iv)
(a) 4 N aq KOH, r.t., 5 h, (b) H+/H2SO4 (86%); v) Ac2O, H+/H2SO4,
r.t., 1 h, (93%)
fulgenic anhydride has been recently used in the prepara-
tion of tailor-made polymers with material characteris-
tics,5 such as photochromic light transmissible articles for
optical memories and displays. Five alternate synthesis of
fulgenic acid (ꢀ) have been reported in the literature.3,6–9
The first low-yield synthesis involves6 a pyrolysis of the
dimethyl ester of cyclohexene-1,2-dicarboxylic acid at
700–800oC. A second five-step synthesis with low overall
yield based on the pyrolysis of dimethyl α,α-dimethyldi-
acetyltartrate with two 1,2-elimination reactions at 490oC
as a key step has been described.7 The third four-step syn-
thesis with 10% overall yield3 employs, pyrolysis of 1,1’-
[2,3-bis(ethoxycarbonyl)tetramethylene]dipiperidinium
dichloride under 1 Torr pressure at 100oC involving dou-
ble 1,2-elimination reactions. The fourth one-pot synthe-
sis with 90% yield8 involves pyrolysis of a diester of
cyclobutene-1,2-dicarboxylic acid under high vacuum at
420oC. A fifth five-step synthesis with 37% overall yield
has been described9 starting from triethyl prop-3-ene-
1,1,2-tricarboxylate with two oxidative 1,2-eliminations
of phenylselenyl moieties using ozone.
smooth allylic substitution to furnish, the unknown (hy-
droxymethyl)methylmaleic anhydride (ꢁ) in 86% yield.
The spectral data for ꢁ revealed that the hydroxy anhy-
dride exists in its free form and does not show any tenden-
cy to undergo intramolecular Michael addition to form
oxirane or oxetane type of derivatives. The hydroxy anhy-
dride ꢁ was acylated at room temperature using acetic an-
hydride in the presence of a catalytic amount of
concentrated H2SO4 and further characterized as (ace-
toxymethyl)methylmaleic anhydride (ꢆ) (93%). The an-
hydrides ꢋ and ꢁ on refluxing with aqueous KOH gave
fulgenic acid (ꢀ) in 60–65% yield via 1,4-elimination. In
both the cases the elimination must be taking place on the
dipotassium salt of (hydroxymethyl)methylmaleic acid in
basic aqueous medium. In another reaction the anhydride
ꢋꢄon treatment with excess of W-BuOK in THF at room
temperature gave ꢀ inꢄ80–85% yield by abstracting the al-
lylic H-atom followed by intramolecular 1,4-elimination
of the allylic bromo atom. Similarly, the anhydride ꢋꢄon
reaction with sodium hydride in refluxing benzene also
furnished the fulgenic acid (ꢀ) in 80–85% yield involving
1,4-elimination of the allylic bromo atom. Amongst all the
above mentioned conversions of ꢋ to ꢀ, the reaction in
benzene using NaH was more clean to handle, as the for-
Recently, we prepared10 the (bromomethyl)methylmaleic
anhydride (ꢋ),11a by NBS bromination of dimethylmaleic
anhydride,11b for the synthesis10 of chaetomellic acid A
anhydride. We reasoned that the bromoanhydride ꢋ would
be a potential precursor for the synthesis of fulgenic acid
(ꢀ), via base induced 1,4-elimination12 of the allylic bro-
mo atom and we herein report a facile approach to ꢀ
(Scheme).
The (bromomethyl)methylmaleic anhydride (ꢋ) on treat-
ment with aqueous KOH at room temperature, underwent
Synthesis 1999, No. 8, 1306–1308 ISSN 0039-7881 © Thieme Stuttgart · New York

6+257ꢄ3$3(5
A Facile Synthesis of Fulgenic Acid via Base Induced 1,4-Dehydrobromination
ꢀꢁꢂꢌ
dried (Na2SO4). Concentration of the organic layer in vacuo fol-
lowed by silica gel column chromatographic purification of the res-
idue using a mixture of petroleum ether/EtOAc (3:1) gave pure ꢁ;
yield: 1.22 g (86%); mp 54–56oC.
IR (nujol): ν = 3255, 1800, 1760, cm−1.
1H NMR (CDCl3, 200 MHz): δ = 2.22 (s, 3 H), 2.40 (br s ,1 H), 4.63
(d , - = 2 Hz, 2 H).
mation of polymeric impurities was not observed in this
reaction. The analytical and spectral data obtained for ꢀ
were in agreement with the reported data.3,7–9
In summary, we have demonstrated a base-induced facile
synthesis of fulgenic acid (ꢀ) starting from (bromometh-
yl)methylmaleic anhydride (ꢋ) with 60–85% yields, em-
ploying an 1,4-elimination of hydrobromic acid.
13C NMR (CDCl3, 50 MHz): δ = 9.9, 55.2, 141.3, 143.4, 165.7,
166.3.
Melting points are uncorrected. Column chromatographic separa-
tions were done on ACME silica gel (60–120 mesh). KOBu-W and
NaH (60% dispersion in mineral oil) were obtained from Aldrich
Chemical Co. Petroleum ether used had bp 60-80 °C.
MS: Pꢇ] = 142, 124, 113, 98, 85, 69, 55.
Anal. Calcd for C6H6O4 (142.1): C, 50.71; H, 4.26; Found: C, 50.78;
H, 4.33.
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A solution of ꢁ (284 mg, 2 mmol) in Ac2O (3 mL), was stirred at r.t.
in presence of catalytic amount of concd H2SO4 for 1 h. The mixture
was diluted with Et2O (30 mL), washed with brine (2 × 10 mL) and
dried (Na2SO4). Concentration of organic layer in vacuo followed
by silica gel column chromatographic purification of the residue us-
ing a mixture of petroleum ether/EtOAc (85:15) gave pure ꢆꢄ(thick
oil);ꢄyield:ꢄ344 mg (93%).
Method A:ꢄA solution of (bromomethyl)methylmaleic anhydride
(ꢋ; 1.03 g, 5 mmol) or (hydroxymethyl)methylmaleic anhydride (ꢁ;
710 mg, 5 mmol) in 4 N aq KOH (12.5 mL) was gently refluxed for
12 h. The mixture was allowed to cool to r.t. and slowly acidified to
pH 2, with 6 N H2SO4 (10 mL). The aqueous layer was extracted
with Et2O (3 × 20 mL) and the combined organic layer was washed
with brine and dried (Na2SO4). The concentration of organic layer
in vacuo at r.t. followed by silica gel column chromatographic puri-
fication of the residue using a mixture of petroleum ether/EtOAc
(6:4) gave pure ꢀ; yield: 430 to 460 mg (60–65%). [The aqueous
layer on further extraction with EtOAc (3 × 10 mL) gave small
amount (5–10%) of polymeric white colour residue].
IR (neat): ν = 1860, 1825, 1775, 1685 cm−1.
1H NMR (CDCl3, 200 MHz): δ = 2.13 (s, 3 H), 2.21 (s, 3 H), 4.97
(s, 2 H).
13C NMR (CDCl3, 75 MHz): δ = 9.5, 20.0, 54.9, 137.0, 144.4,
163.7, 165.1, 169.8.
Method B: To a slurry of W-BuOK (2.80 g, 25 mmol) in THF (15
mL) was added a solution of the anhydride ꢋ (1.03 g, 5 mmol) in
THF (10 mL) at r.t. withꢄconstant stirring under argon atmosphere.
The mixture was further stirred for 4 h and diluted with Et2O (25
mL), brine (10 mL), and then slowly acidified with 6 N H2SO4 (5
mL). The organic layer was separated and the aqueous layer was
MS: Pꢇ] = 184, 142, 124, 113, 98, 67.
Anal. Calcd for C8H8O5 (184.2): C, 52.18; H, 4.38; Found: C, 52.39;
H, 4.51.
further extracted with Et2O (3 × 15 mL). The combined organic lay- $FNQRZOHGJHPHQW
er on usual work up and silica gel column chromatographic purifi-
cation gave pure ꢀ; yield: 570 to 600 mg (80–85%).
N. P. A. thanks D. S. T., New Delhi, for the financial support under
the Young-Scientist Scheme. We thank Dr. K. N. Ganesh, Head,
Division of Organic Chemistry (Synthesis), for constant encourage-
ment.
Method C: To a slurry of mineral oil free NaH (600 mg, 25 mmol)
in benzene (15 mL) was added a solution of anhydride ꢋꢄ(1.03 g, 5
mmol) in benzene (10 mL) under argon atmosphere and the mixture
was refluxed under stirring for 4 h. The reaction was allowed to
reach r.t. and diluted with Et2O (25 mL), brine (10 mL), and then
slowly acidified with 6 N H2SO4 (5 mL). The organic layer was sep-
arated and the aqueous layer was further extracted with Et2O (3 ×
15 mL). The combined organic layer on usual workup followed by
silica gel column chromatographic purification gave pure ꢀ; yield:
570 to 600 mg (80–85%). Recrystallization from acetone plus chlo-
roform mixture (1:9) gave analytically pure sample of ꢀ; mp 186–
188oC (Lit.8a mp 184–187oC); Rf 0.51 (MeOH/EtOAc, 1:1).
5HIHUHQFHV
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&KHPꢈꢀ6RFꢈꢉꢀ3HUNLQꢀ7UDQV. ꢅ ꢀꢎꢏꢍ, 413.
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IR (nujol): ν = 3145, 1675, 1615 cm−1.
1H NMR (acetone-G6, 200 MHz): δ = 5.88 (d, - = 1.5 Hz, 2 H), 6.22
(d, - = 1.5 Hz, 2 H).
13C NMR (DMSO-G6, 50 MHz): δ = 126.4, 140.1, 167.0.
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MS: Pꢇ] = 142, 124, 98, 80, 69.
(4) Muramatsu, H.; Kawano, H.;ꢀIshii, Y.; Saburi, M.; Uchida, Y.
-ꢈꢀ&KHPꢈꢀ6RFꢈꢉꢀ&KHPꢈꢀ&RPPXQ. ꢀꢎꢏꢎ, 769.
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ꢀꢎꢎꢌ, ꢂꢅꢁ, 178 925.
Anal. Calcd for C6H6O4 (142.1): C, 50.71; H, 4.26; Found: C, 50.49;
H, 4.52.
ꢁꢇ+\GUR[\PHWK\OꢇꢆꢇPHWK\OIXUDQꢇꢋꢅꢍꢇGLRQHꢄꢈꢁꢉꢄ
To an ice-cold solution of 4 N aq KOH (10 mL) was added, (bro-
momethyl)methylmaleic anhydride (ꢋ;ꢄ2.05 g, 10 mmol) and the
mixture was stirred at r.t. for 5 h. The mixture was slowly acidified
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Synthesis 1999, No. 8, 1306–1308 ISSN 0039-7881 © Thieme Stuttgart · New York

ꢀꢁꢂꢏ
S. G. Deshpande, N. P. Argade
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Article Identifier:
1437-210X,E;1999,0,08,1306,1308,ftx,en;Z01099SS.pdf
Synthesis 1999, No. 8, 1306–1308 ISSN 0039-7881 © Thieme Stuttgart · New York