Efficient synthesis of 2,3,4-trisubstituted furans from the reaction of activated acetylenes with ethyl bromopyruvate in the presence of enaminones

Article abstract of DOI:10.1007/s00706-008-0858-8

The reaction of dialkyl acetylenedicarboxylates or diaroylacetylenes with ethyl bromopyruvate in the presence of enaminones led to 2-ethyl 3,4-dialkyl 4-bromo-4,5-dihydro-2,3,4-furantricarboxylates or ethyl 3,4-diaroyl-4-bromo-4,5- dihydro-2-furancarboxyl

Full text of DOI:10.1007/s00706-008-0858-8

Monatsh Chem 139, 945–948 (2008)
DOI 10.1007/s00706-008-0858-8
Printed in The Netherlands
Efficient synthesis of 2,3,4-trisubstituted furans from the reaction of activated
acetylenes with ethyl bromopyruvate in the presence of enaminones
Issa Yavari, Zinatossadat Hossaini, Maryam Sabbaghan
Chemistry Department, Tarbiat Modares University, Tehran, Iran
Received 12 November 2007; Accepted 20 November 2007; Published online 21 April 2008
# Springer-Verlag 2008
Abstract The reaction of dialkyl acetylenedicarboxy-
lates or diaroylacetylenes with ethyl bromopyruvate
in the presence of enaminones led to 2-ethyl 3,4-dia-
lkyl 4-bromo-4,5-dihydro-2,3,4-furantricarboxylates
or ethyl 3,4-diaroyl-4-bromo-4,5-dihydro-2-furancar-
boxylate in excellent yields. These compounds are
quantitatively converted to the corresponding 2,3,4-
trisubstituted furans by 4-dimethylaminopyridine.
Results and discussion
As part of our current studies on the development of
new routes in heterocyclic synthesis [18–21], we
report an efficient synthesis of 2,3,4-trisubstituted
furans. Thus, the reaction of dialkyl acetylenedicar-
boxylates 1a–1c or diaroylacetylenes 1d–1e [22, 23],
with ethyl bromopyruvate [2] in the presence of en-
aminones 3 [24] led to 2-ethyl 3,4-dialkyl 4-bromo-
4,5-dihydro-2,3,4-fur-tricarboxylates 4a–4c or ethyl
3,4-diaroyl-4-bromo-4,5-dihydro-2-furoates 4d–4e,
in excellent yields. These compounds are quantitative-
ly converted to the corresponding 2,3,4-trisubstituted
furans 5 by 4-dimethylaminopyridine (Scheme 1).
The structures of compounds 4a–4e and 5a–5e
were apparent from their mass spectra, which dis-
played in each case, the molecular ion peak at the
appropriate m=z values. The 1H and 13C NMR spec-
troscopic data, as well as IR spectra, are in agree-
Keywords Ethyl bromopyruvate; Activated acetylenes; Tri-
substituted furans; Enaminone.
Introduction
Highly substituted furans play an important role
in organic chemistry, not only as key structural
units in many natural products, common subunits
in pharmaceuticals [1–7], fragrances [8], and flavors
[9], but also as useful building blocks in synthetic
chemistry [10–14]. They have also found utility
as synthetic intermediates or synthons for numer-
ous functional groups, inter alia, carboxylic acids,
ꢀ-keto-esters, and aromatics [15]. For this reason,
the efficient synthesis of multiply substituted furans
continues to attract the interest of synthesis chemists
[16, 17].
1
ment with the proposed structures. The H NMR
spectrum of 4a exhibited two singlets (ꢁ ¼ 3.59
and 3.80 ppm) arising from the methoxy proton,
along with two doublets (ꢁ ¼ 4.44 ppm) and 4.64
(2JHH ¼ 10.8 Hz) for the diastereotopic methylene
protons. The carbonyl groups resonances in the 13C
NMR spectra of 4a appear at ꢁ ¼ 160.0, 162.1, and
171.5 ppm. The mass spectrum of 4a displayed the
molecular ion peak at m=z ¼ 337, which is consistent
with the 1:1 adduct of ethyl bromopyruvate and 1a.
Correspondence: Issa Yavari, Chemistry Department, Tarbiat
Modares University, PO Box 14115-175, Tehran, Iran.
E-mail: yavarisa@modares.ac.ir
1
The H NMR spectrum of 5a exhibited three
singlets for methoxy (ꢁ ¼ 3.60 and 3.75 ppm) and

946
I. Yavari et al.
Scheme 1
methine (ꢁ ¼ 7.53 ppm) protons, along with char-
acteristic signals of the ethoxy group. The 13C
signals of carbonyl groups in 5a appear at ꢁ ¼
161.9, 168.6, and 168.7 ppm. The mass spec-
trum of 4a displayed the molecular ion peak at
m=z ¼ 256.
Scheme 2

Efficient synthesis of 2,3,4-trisubstituted furans
947
2-Ethyl 3,4-diethyl 4-bromo-4,5-dihydro-2,3,4-furantri-
Mechanistically, it is conceivable that the reaction
involves the initial formation of a 1,3-dipolar inter-
mediate [25] 6 between the enaminone and the elec-
tron-deficient acetylenic compound, which reacts
with the carbonyl group of 2 to generate 7. This
intermediate undergoes a Darzens-type reaction to
produce 8, which losses the enaminone moiety via
9 to generate 10. Electrocyclization of 10 leads to 4,
which is converted to 5 by loss of HBr in the pres-
ence of 4-dimethylaminopyridine (Scheme 2).
In conclusion, the reaction of dialkyl acetylene-
dicarboxylates or diaroylacetylenes with 2 in the
presence of enaminones led to 4-bromo-4,5-dihy-
dro-furan derivatives, in excellent yields. In the pres-
ence of 4-dimethylaminopyridine, these compounds
are quantitatively converted to 2,3,4-trisubstituted
furans. The present procedure has the advantage that
the reaction is performed under neutral conditions,
and the starting material can be used without any
activation or modification.
carboxylate (4b, C13H17BrO7)
Yellow oil, yield 0.54g, 75%; IR (KBr): ꢂꢀ¼ 1734, 1730,
1725, 1634, 1575 cmꢀ1; EI-MS: m=z (%) ¼ 367 (Mþ2, 15),
365 (Mþ, 15), 320 (5), 285 (76), 230 (64), 135 (58), 45 (100);
3
3
1H NMR: ꢁ ¼ 0.98 (t, J ¼ 7.5, Me), 1.04 (t, J ¼ 7.3, Me),
3
3
1.12 (t, JHH ¼ 7.2, Me), 3.99 (q, J ¼ 7.2, OCH2), 4.03 (q,
3J ¼ 7.5, OCH2), 4.14 (q, 3J ¼ 7.3, OCH2), 4.32 (d, 2J ¼ 10.8,
CH), 4.51 (d, J ¼ 10.8, CH) ppm; 13C NMR: ꢁ ¼ 13.5 (Me),
2
13.7 (Me), 13.8 (Me), 60.1 (OCH2), 61.9 (OCH2), 62.3
(OCH2), 82.0 (CH2), 82.1 (C), 113.0 (C), 158.4 (C), 161.6
(C¼O), 162.1 (C¼O), 171.4 (C¼O) ppm.
2-Ethyl 3,4-di(tert-butyl)4-bromo-4,5-dihydro-2,3,4-
furantricarboxylate (4c, C17H25BrO7)
Yellow oil, yield 0.66g, 78%; IR (KBr): ꢂꢀ¼ 1730, 1725,
1720, 1636, 1579 cmꢀ1; EI-MS: m=z (%) ¼ 423 (Mþ2, 15),
421 (Mþ, 15), 376 (76), 341 (46), 364 (82), 348 (65), 275 (64),
1
73 (34), 57 (100), 45 (84); H NMR: ꢁ ¼ 1.39 (3Me), 1.46
3
(t, J ¼ 7.2, Me), 1.51 (3Me), 4.16–4.29 (m, OCH2), 4.43 (d,
2J ¼ 10.7, CH), 4.62 (d, 2J ¼ 10.7, CH) ppm; 13C NMR:
ꢁ ¼ 13.9 (Me), 27.8 (3Me), 28.0 (3Me), 62.8 (OCH2), 81.1
(CH2), 81.6 (C), 82.6 (CMe3), 84.1 (CMe3), 112.2 (C), 158.6
(C), 161.1 (C¼O), 164.2 (C¼O), 172.1 (C¼O) ppm.
Experimental
2-Ethyl 3,4-dibenzoyl-4-bromo-4,5-dihydro-2,3,4-furan-
tricarboxylate (4d, C21H17BrO5)
Dibenzoylacetylene was prepared according to Refs. [22, 23].
Other chemicals were purchased from Fluka and used without
further purification. Melting points were measured on an
Electrothermal 9100 aparatus. Elemental analyses for the C
and H were performed using a Heraeus CHN-O-Rapid ana-
lyzer. The results agreed favorably with the calculated values.
Mass spectra were recorded on a Finnigan-Mat 8430 spec-
trometer operating at an ionization potential of 70eV. IR
spectra were measured on a Shimadzu IR-460 spectrometer.
1H, and 13C NMR spectra were measured with a Bruker DRX-
500 Avance spectrometer at 500.1 and 125.8MHz.
Yellow powder, yield 0.64 g, 74%; IR (KBr): ꢂꢀ¼ 1726, 1660,
1635, 1563, 1506, 1434 cmꢀ1. EI-MS: m=z (%) ¼ 431 (Mþ2,
5), 429 (Mþ, 5), 384 (82), 352 (46), 349 (58), 324 (66), 219
1
3
(35), 45 (64), 105 (100); H NMR: ꢁ ¼ 1.16 (t, JHH ¼ 7.3,
3
2
Me), 4.21 (q, J ¼ 7.3, OCH2), 4.41 (d, J ¼ 10.5, CH), 4.63
2
3
(d, J ¼ 10.5, CH), 7.41 (t, J ¼ 7.2, 2CH), 7.47–7.63 (m, 4
CH), 7.88 (d, 3J ¼ 7.3, 2CH). 8.07 (d, 3J ¼ 7.3, 2CH) ppm; 13
C
NMR: ꢁ ¼ 13.8 (Me), 63.0 (OCH2), 81.7 (CH2), 82.0 (C),
120.9 (C), 128.2 (2CH), 128.5 (2CH), 128.7 (2CH), 129.5
(2CH), 132.1 (CH), 134.0 (CH), 136.1 (C), 139.2 (C), 154.6
(C), 168.7 (C¼O), 187.6 (C¼O), 194.4 (C¼O) ppm.
General procedure for the preparation of 4
2-Ethyl 3,4-di(4-methylbenzoyl)-4-bromo-4,5-dihydro-2,3,4-
furantricarboxylate (4e, C23H21BrO5)
To a stirred solution of 2 mmol dialkyl acetylenedicarboxylate
or diaroyl acetylene and 0.390 g ethyl bromopyruvate (2mmol)
in 15 cm3 of CH2Cl2 was added the 2 mmol enaminone at
room temperature. The reaction mixture was then stirred for
24h. The solvent was removed under reduced pressure, and
the residue was purified by column chromatography (SiO2;
n-hexane:AcOEt, 9:1) to afford 4.
Orange powder, yield 0.73 g, 80%; IR (KBr): ꢂꢀ¼ 1732, 1697,
1638, 1575, 1432 cmꢀ1; EI-MS: m=z (%) ¼ 459 (Mþ2, 10),
457 (Mþ, 10), 412 (66), 377 (56), 337 (85), 217 (64), 120
(34), 45 (100); 1H NMR: ꢁ ¼ 1.32 (t, 3J ¼ 7.2, Me), 2.38 (Me),
3
2
2.43 (Me), 4.28 (q, J ¼ 7.2, OCH2), 4.39 (d, J ¼ 10.6, CH),
4.63 (d, 2J ¼ 10.6, CH), 7.19 (d, 3J ¼ 7.2, 2CH), 7.29 (d,
3J ¼ 7.2, 2CH), 7.77 (d, 3J ¼ 7.2, 2CH), 7.93 (d, 3J ¼ 7.2,
2CH) ppm; 13C NMR: ꢁ ¼ 14.1 (Me), 21.4 (Me), 22.1 (Me),
63.4 (OCH2), 82.5 (CH2), 83.1 (C), 121.1 (C), 127.1 (2CH),
128.5 (2CH), 130.6 (2CH), 130.9 (2CH), 133.6 (C), 138.5 (C),
1143.0 (C), 143.4 (C), 154.2 (C), 161.7 (C¼O), 189.1 (C¼O),
193.2 (C¼O) ppm.
2-Ethyl 3,4-dimethyl 4-bromo-4,5-dihydro-2,3,4-furantri-
carboxylate (4a, C11H13BrO7)
Yellow oil, yield 0.55 g, 81%; IR (KBr): ꢂꢀ¼ 1735, 1733,
1729, 1636, 1582 cmꢀ1; EI-MS: m=z (%) ¼ 339 (Mþ2, 5),
337 (Mþ, 5), 306 (66), 292 (64), 275 (85), 257 (62), 45 (84),
3
31 (100); 1H NMR: ꢁ ¼ 1.17 (t, J ¼ 7.2, Me), 3.59 (s, OMe),
3
2
3.80 (s, OMe), 4.21 (q, J ¼ 7.2, CH2O), 4.44 (d, J ¼ 10.8,
2
CH), 4.64 (d, JHH ¼ 10.8, CH) ppm; 13C NMR: ꢁ ¼ 13.8
General procedure for the preparation of 5
(Me), 51.6 (OMe), 52.9 (OMe), 63.1 (OCH2), 81.9 (CH2),
82.2 (C), 111.9 (C), 158.3 (C), 160.0 (C¼O), 162.1 (C¼O),
171.5 (C¼O) ppm.
To a stirred solution of 2 mmol 4 in 15cm3 CH2Cl2 was added
the 2 mmol 4-dimethylaminopyridine at room temperature.
The reaction mixture was then stirred for 12h. The solvent

948
I. Yavari et al.
was removed under reduced pressure, and the residue was
purified by column chromatography (SiO2; n-hexane:AcOEt,
10:1) to afford 5.
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2-Ethyl 3,4-dimethyl 2,3,4-furantricarboxylate (5a, C11H12O7 )
Yellow oil, yield 0.43 g, 84%; IR (KBr): ꢂꢀ¼ 1732, 1730,
1727 cmꢀ1; EI-MS: m=z (%) ¼ 256 (Mþ, 10), 225 (64), 211
1
3
(82), 194 (64), 45 (86), 31 (100); H NMR: ꢁ ¼ 1.16 (t, J ¼
3
7.2, Me), 3.60 (OMe), 3.75 (OMe), 4.19 (q, J ¼ 7.2, OCH2),
7.53 (s, CH) ppm; 13C NMR: ꢁ ¼ 13.7 (Me), 51.5 (OMe), 53.0
(OMe), 62.9 (OCH2), 112.5 (C), 117.9 (C), 154.6 (C), 158.5
(CH), 161.9 (C¼O), 168.6 (C¼O), 168.7 (C¼O) ppm.
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2-Ethyl 3,4-diethyl 2,3,4-furantricarboxylate (5b, C13H16O7)
Yellow oil, yield 0.44 g, 78%; IR (KBr): ꢂꢀ¼ 1730, 1725,
1720 cmꢀ1; EI-MS: m=z (%) ¼ 284 (Mþ, 15), 239 (76),
ꢁ ¼ 0.97 (t, 3J ¼ 7.5, Me), 1.09 (t, 3J ¼ 7.3, Me), 1.14 (t,
3J ¼ 7.2, Me), 3.82 (q, 3J ¼ 7.2, OCH2), 3.90 (q, 3J ¼ 7.5,
OCH2), 4.12 (q, 3J ¼ 7.3, OCH2), 7.32 (s, CH) ppm; 13C
NMR: ꢁ ¼ 13.4 (Me), 13.6 (Me), 13.8 (Me), 61.1 (OCH2),
61.7 (OCH2), 62.3 (OCH2), 111.5 (C), 113.1 (C), 153.2 (C),
159.1 (CH), 161.6 (C¼O), 168.1 (C¼O), 169.4 (C¼O) ppm.
1
194 (85), 149 (54), 135 (62), 90 (62), 45 (100); H NMR:
10. Benassi R (1996) In: Katritzky AR, Rees CW, Scriven
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2-Ethyl 3,4-di(tert-butyl)- 2,3,4-furantricarboxylate
(5c, C17H24O7)
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Yellow oil, yield 0.56 g, 82%; IR (KBr): ꢂꢀ¼ 1725, 1720,
1715 cmꢀ1; EI-MS: m=z (%) ¼ 340 (Mþ, 5), 295 (34), 283
(86), 267 (64), 194 (54), 146 (46), 73 (98), 45 (64), 57
(100); H NMR: ꢁ ¼ 1.15 (t, J ¼ 7.2, Me), 1.32 (3Me), 1.48
(3 Me), 4.26 (q, 3J ¼ 7.2, OCH2), 7.42 (s, CH) ppm; 13C
NMR: ꢁ ¼ 14.2 (Me), 27.5 (3Me), 27.8 (3Me), 62.5 (OCH2),
82.3 (CMe3), 83.1 (CMe3), 111.2 (C), 113.6 (C), 154.2 (C),
157.9 (CH), 162.0 (C¼O), 163.9 (C¼O) 166.3 (C¼O) ppm.
1
3
Ethyl 3,4-dibenzoyl-2-furoate (5d, C21H16O5)
Yellow oil, yield 0.59 g, 85%; IR (KBr): ꢂꢀ¼ 1725, 1668,
1654 cmꢀ1; EI-MS: m=z (%) ¼ 348 (Mþ, 5), 303 (56), 271
(85), 243 (86), 45 (46), 105 (100); 1H NMR: ꢁ ¼ 1.16 (t,
3
3J ¼ 7.3, Me), 4.21 (q, J ¼ 7.3, OCH2), 6.20 (s, CH), 7.36
(t, 3J ¼ 7.2, 2CH), 7.40–7.65 (m, 4CH), 7.85 (d, 3J ¼ 7.3,
2CH), 8.12 (d, 3J ¼ 7.3, 2CH) ppm; 13C NMR: ꢁ ¼ 13.7 (Me),
63.5 (OCH2), 117.9 (C), 121.2 (C), 128.2 (2CH), 128.5 (2CH),
128.7 (2CH), 129.5 (2CH), 132.1 (CH), 134.0 (CH), 136.1
(C), 139.2 (C), 154.6 (C), 159.4 (CH), 169.7 (C¼O), 188.6
(C¼O), 191.2 (C¼O) ppm.
Ethyl 3,4-di(4-methylbenzoyl)-2-furoate (5e, C23H20O5)
Yellow oil, yield 0.69 g, 92%; IR (KBr): ꢂꢀ¼ 1727, 1690,
1665 cmꢀ1; EI-MS: m=z (%) ¼ 376 (Mþ, 15), 331 (74),
1
256 (85), 136 (62), 120 (100); 45 (82); H NMR: ꢁ ¼ 1.32
(t, 3J ¼ 7.2, Me), 2.38 (Me), 2.43 (Me), 4.28 (q, 3J ¼ 7.2,
3
3
OCH2), 6.17 (s, CH), 7.19 (d, J ¼ 7.2, 2CH), 7.29 (d, J ¼
3
3
7.2, 2CH), 7.77 (d, J ¼ 7.2, 2CH), 7.93 (d, J ¼ 7.2, 2CH)
ppm; 13C NMR: ꢁ ¼ 14.1 (Me), 21.4 (Me), 22.1 (Me), 63.4
(OCH2), 119.4 (C), 121.1 (C), 127.1 (2CH), 128.5 (2CH),
130.6 (2CH), 130.9 (2CH), 135.2 (C), 133.6 (C), 138.5 (C),
143.0 (C), 154.2 (C), 158.9 (CH), 162.5 (C¼O), 190.1 (C¼O),
192.8 (C¼O) ppm.