Synthesis of furan and dihydrofuran derivatives via Feist–Benary reaction in the presence of ammonium acetate in aqueous ethanol

Article abstract of DOI:10.1007/s10593-016-1854-2

[Figure not available: see fulltext.] An efficient synthesis of dihydrofurans and furans by a reaction between 1,3-dicarbonyl compounds and ethyl bromopyruvate, ethyl 2-chloroacetoacetate, or 3-chloroacetylacetone in the presence of ammonium acetate in aq

Full text of DOI:10.1007/s10593-016-1854-2

DOI 10.1007/s10593-016-1854-2
Chemistry of Heterocyclic Compounds 2016, 52(3), 161–164
Synthesis of furan and dihydrofuran derivatives via Feist–Benary
reaction in the presence of ammonium acetate in aqueous ethanol
Maryam Ghazvini1*, Ashraf Sadat Shahvelayati 2, Ali Sabri1, Fatemeh Zeinali Nasrabadi1
1 Department of Chemistry, Payame Noor University,
P.O. Box: 19395-4697, Tehran, Iran; e-mail: m.ghazvini@damavand.tpnu.ac.ir
2 Department of Chemistry, Islamic Azad University Shahr-e Rey Branch,
P.O. Box: 144-18155, Tehran, Iran; e-mail: avelayati@yahoo.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(3), 161–164
Submitted December 2, 2015
Accepted after revision February 22, 2016
X
O
O
p-TSA
PhMe, 80°C
NH4OAc
EtOH–H2O, 80°C
+
O
R2
R2
R2
O
O
R1
R1 = CO2Et, R2 = H; R1 = Me, R2 = CO2Et, COMe
R1
R1
HO
O
O
An efficient synthesis of dihydrofurans and furans by a reaction between 1,3-dicarbonyl compounds and ethyl bromopyruvate, ethyl
2-chloroacetoacetate, or 3-chloroacetylacetone in the presence of ammonium acetate in aqueous ethanol is described. When the reaction
was performed with a phenacyl bromide, O-alkylation of 1,3-dicarbonyl compounds occurred without cyclization.
Keywords: 1,3-dicarbonyl compounds, dihydrofuran, ethyl bromopyruvate, furan, phenacyl bromide, Feist–Benary reaction.
The Feist–Benary reaction involves condensation of
1,3-dicarbonyl compounds with α-halo ketones to produce
substituted furans.1,2 However, running the reaction under
modified conditions allowed the isolation of a dihydrofuran
intermediate. Several groups studied the mechanism and
scope of this so-called ''interrupted'' Feist–Benary reac-
tion.3,4 Most publications concerning this reaction have
been aimed at studying its catalytic asymmetric version
with particular emphasis of the diastereoselectivity and
enantioselectivity issues.4b,c,5–8 Furans, as well as di- and
tetrahydrofurans are constituents of many natural products
arising from plants and marine organisms with promising
biological activities.9–12
As a part of the recent trend of developing new methods
of heterocyclic synthesis in water,13–15 we wish to report an
efficient synthesis of functionalized dihydrofurans and
furans by the reaction of 1,3-dicarbonyl compounds 1a–d
with α-halo ketones in the presence of ammonium acetate
in aqueous ethanolic solution. The reaction of 1,3-
dicarbonyl compounds 1a–d with ethyl bromopyruvate (2)
thus led to dihydrofurans 3a–d in good yields (Scheme 1).
The isolation of products in this method is easier than in
other described methods, and the reaction is more
environment-friendly because of solvent used (aqueous
ethanol); in addition, the yields of the products are higher.
Compounds 3a–d were converted to the corresponding
furan derivatives 4a–d in the presence of p-toluenesulfonic
acid (p-TSA).
However, under similar conditions the reactions of
α-halo ketones, 3-chloropentane-2,4-dione (5a) and methyl
2-chloro-3-oxobutanoate (5b), with 1,3-dicarbonyl com-
pounds 1b–d led directly to fused furan derivatives 6a–e in
good yields (Scheme 2). The structures of compounds 3a–d,
1
4a–d, 6a–e were confirmed by IR, H and 13C NMR
spectroscopy and mass spectrometry.
Under similar conditions the reaction of 4'-bromo-
phenacyl bromides (7) with 1,3-dicarbonyl compounds
1b,c led to esters 8a,b (Scheme 3).
Structure of the isolated products 8a,b was determined
on the basis of their elemental analyses, as well as their IR,
1H and 13C NMR spectroscopy and mass spectrometry data.
1
The H NMR spectrum of compound 8a in CDCl3 showed
five sharp singlets arising from C(CH3)2 (1.10 ppm), CH2
(2.23, 2.44, and 5.10 ppm), and methine (5.20 ppm)
protons.
The proposed mechanism of this reaction is presented in
Scheme 4. The reaction likely starts as a C-acylation of
enolate 9 with the formation of a 1:1 adduct 10 between the
1,3-dicarbonyl compound 1 and α-halo ketones 2, 5.
Adduct 10 undergoes intramolecular cyclization to produce
dihydrofurans of type 3, which are converted to furans by
elimination of H2O. In the case of phenacyl bromide 7, its
carbonyl group is involved in resonance with the aryl ring,
thus the nucleophilic attack is directed towards α-carbon of
compound 1. Thus, steric factors might lead to a pre-
ferential O-alkylation of enolate 9 to give ethers 8.
0009-3122/16/52(3)-0161©2016 Springer Science+Business Media New York
161

Chemistry of Heterocyclic Compounds 2016, 52(3), 161–164
Scheme 1
Scheme 2
Br
NH4OAc
+
O
EtOH–H2O, 80°C, 4 h
O
O
O
CO2Et
1a–d
2
O
O
p-TSA
PhMe, 80°C, 6 h
CO2Et
HO CO2Et
O
3a–d
4a–d
1,3-Dicarbonyl
compound
Dihydrofuran
Furan
O
O
Me
Me
O
Me Me
Me
Me
O
O
O
HO
1a
Me Me
1b
EtO2C
4a (89%)
CO2Et
3a (88%)
Me
Me
Me
Me
O
O
CO2Et
CO2Et
O
O
O
O
HO
O
O
3b (97%)
4b (96%)
O
O
CO2Et
HO
CO2Et
4c (87%)
O
O
1c
3c (88%)
Me
N
Me
N
O
O
O
O
O
Me
O
Me
O
N
N
N
N
Me
Me
CO2Et
CO2Et
HO
O
O
1d
3d (93%)
4d (91%)
Scheme 3
Scheme 4
O
O
R
R
Br
O
NH OAc
+
4
1b,c
EtOH–H O, 80°C, 4 h
2
O
Br
7
Br
8a R = Me (85%)
bR = H (55%)
162

Chemistry of Heterocyclic Compounds 2016, 52(3), 161–164
The reaction between 1,3-dicarbonyl compounds and
3.43 (3H, s, CH3); 3.58 (3H, s, CH3); 4.39 (2H, q, 3J = 7.1,
OCH2); 7.80 (1H, s, CH). 13C NMR spectrum, δ, ppm:
14.6, 29.0, 29.9 (3CH3); 61.8 (OCH2); 94.9, 119.0, 150.6
(3C); 143.7 (CH); 156.8, 156.9, 161.3 (3C=O). Mass
spectrum, m/z (Irel, %): 252 [M]+ (100), 195 (91), 167 (77),
123 (28), 95 (46), 66 (46). Found, %: C 52.32; H 4.71;
N 11.21. C11H12N2O5. Calculated, %: C 52.38; H 4.80;
N 11.11.
Preparation of fused furans 6a–e (General method).
A mixture of the 1,3-dicarbonyl compound 1b–d (2 mmol)
and ammonium acetate (0.14 g, 2 mmol) in EtOH–H2O,
7:3, (5 ml) was stirred at 80°C for 1 h. Then α-halo ketone
5a,b (2 mmol) was added and the stirring was continued at
80°C for additional 3 h. The solvent was removed under
reduced pressure, and the viscous residue was purified by
column chromatography using hexane–AcOEt, 4:1, as
eluent.
α-halo ketones in the presence of ammonium acetate in
aqueous ethanol leads, depending on the structure of the
α-halo ketone, to highly substituted dihydrofurans or furans,
or open-chain O-alkylation products. For the purpose of
synthesizing furan derivatives, the simplicity of this
procedure makes it an interesting alternative to complex
multistep approaches in view the environment-friendly
conditions and availability of the starting materials.
Experimental
IR spectra were recorded on a Shimadzu IR-460 spectro-
meter in KBr. 1H and 13C NMR spectra were recorded on a
Bruker Avance DRX-300 instrument (300 and 75 MHz,
respectively) in acetone-d6 (compounds 6a,d) or CDCl3
(other compounds) with TMS as internal standard. Electron
ionization mass spectra were recorded on a Finnigan MAT
8430 mass spectrometer operating at an ionization potential
of 70 eV. Elemental analyses were carried out on a Heraeus
CHN-O-Rapid analyzer. Melting points were determined
on an Electrothermal 9100 apparatus. Preparative column
chromatography was performed on silica gel (Merck 230–
400 mesh). All chemicals were purchased from Fluka and
used without further purification.
Preparation of dihydrofuran-3-carboxylates 3a–d
(General method). A mixture of the 1,3-dicarbonyl
compound 1 (2 mmol) and ammonium acetate (0.14 g,
2 mmol) in EtOH–H2O, 7:3 (5 ml) was stirred at 80°C for
about 1 h. Then ethyl bromopyruvate (2) (0.39 g, 2 mmol)
was added to the reaction mixture, and the stirring was
continued for 3 h. The solvent was removed under reduced
pressure, and the viscous residue was purified by column
chromatography using n-hexane–AcOEt, 4:1, as eluent.
Products 3a–c have been reported previously.4b
2-Acetyl-3,6,6-trimethyl-6,7-dihydrobenzofuran-4(5H)-
one (6a). Yield 0.36 g (83%), white powder, mp 132–134°C.
IR spectrum, ν, cm–1: 2938, 1683, 1661, 1591, 1226, 1113,
1
676. H NMR spectrum, δ, ppm (J, Hz): 1.15 (6H, s,
2CH3); 2.40 (2H, s, CH2); 2.51 (2H, s, CH2); 2.85 (3H, s,
CH3); 2.89 (3H, s, CH3). 13C NMR spectrum, δ, ppm: 10.9,
27.9, 28.9 (4CH3); 38.1, 53.1 (2CH2); 35.3; 121.4; 129.0;
149.0; 167.7; 189.2 (C=O); 195.0 (C=O). Mass spectrum,
m/z (Irel, %): 220 [M]+ (2), 177 (81), 121 (100), 82 (43), 55
(33), 43 (53). Found, %: C 71.17; H 7.19. C13H16O3.
Calculated, %: C 70.89; H 7.32.
Ethyl 3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrobenzo-
furan-2-carboxylate (6b). Yield 0.38 g (76%), white
powder, mp 72–74°C. IR spectrum, ν, cm–1 : 2957, 1716,
1
1672, 1457, 1242, 1144, 766. H NMR spectrum, δ, ppm
(J, Hz): 1.15 (6H, s, 2CH3); 1.44 (3H, t, 3J = 7.1, CH2CH3);
2.39 (2H, s, CH2); 2.57 (3H, s, CH3); 2.79 (2H, s, CH2);
3
Ethyl 5-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,6-
hexahydrofuro[2,3-d]pyrimidine-5-carboxylate (3d). Yield
0.5 g (93%), white powder, mp 166–168°C. IR spectrum,
ν, cm–1: 3438, 2924, 2359, 1644, 1463, 1388, 1114.
4.39 (2H, q, J = 7.1, CH2O). 13C NMR spectrum, δ, ppm:
10.7, 14.7, 28.8 (4CH3); 38.0, 53.1 (2CH2); 61.3 (OCH2);
35.3; 121.0; 129.9; 140.9; 159.8; 168.3 (C=O); 194.9
(C=O). Mass spectrum, m/z (Irel, %): 250 [M]+ (2), 177
(88), 121 (100), 82 (45), 55 (36), 41 (36). Found, %:
C 67.27; H 7.20. C14H18O4. Calculated, %: C 67.18; H 7.25.
Ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-
2-carboxylate (6c). Yield 0.32 g (72%), white powder, mp
87–89°C (mp 88–90°C,4g mp 93–94°C (ligroin)16).
IR spectrum, ν, cm–1: 2921, 1714, 1674, 1455, 1218, 771.
3
1H NMR spectrum, δ, ppm (J, Hz): 1.34 (3H, t, J = 6.9,
CH2CH3); 3.30 (3H, s, CH3); 3.40 (3H, s, CH3); 4.19 (1H,
br. s, OH); 4.36–4.39 (2H, m, CH2O); 4.84 (1H, d, 2J = 9.9)
2
and 5.12 (1H, d, J = 9.9, CH2). 13C NMR spectrum,
δ, ppm: 14.4, 28.2, 29.8 (3CH3); 63.7 (OCH2); 80.2 (CH2);
84.4, 91.7, 151.7 (3C); 159.3, 164.2, 171.9 (3C=O). Found, %:
C 48.63; H 5.51; N 10.51. C11H14N2O6. Calculated, %:
C 48.89; H 5.22; N 10.37.
3
1H NMR spectrum, δ, ppm (J, Hz): 1.41 (3H, t, J = 7.1,
3
CH2CH3); 2.17–2.21 (2H, m, CH2); 2.53 (2H, t, J = 6.4,
3
Preparation of furan-3-carboxylates 4a–d (General
method). p-Toluenesulfonic acid (0.34 g, 0.5 mmol) was
added to a stirred solution of compound 3a–d (2 mmol) in
toluene (10 ml). The reaction mixture was stirred at 80°C
for 6 h. The solvent was removed under reduced pressure,
and the residue was separated by column chromatography
using hexane–AcOEt, 6:1, as eluent. Products 4a–c have
been reported previously.4b
CH2); 2.57 (3H, s, CH3); 2.94 (2H, t, J = 6.8, CH2); 4.39
(2H, q, 3J = 7.1, CH2O). 13C NMR spectrum, δ, ppm: 10.7,
14.7 (2CH3); 22.5, 24.1, 38.8 (3CH2); 61.3 (OCH2); 122.1;
130.1; 140.1; 160.0; 169.0 (C=O); 195.5 (C=O). Mass
spectrum, m/z (Irel, %): 222 [M]+ (56), 194 (60), 166 (45),
83 (45), 57 (100). Found, %: C 64.89; H 6.30. C12H14O4.
Calculated, %: C 64.85; H 6.35.
2-Acetyl-3-methyl-6,7-dihydrobenzofuran-4(5H)-one
(6d). Yield 0.27 g (71%), white powder, mp 114–116°C.
IR spectrum, ν, cm–1: 2922, 1734, 1677, 1218, 766.
1H NMR spectrum, δ, ppm (J, Hz): 2.19–2.21 (2H, m,
Ethyl 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro-
[2,3-d]pyrimidine-5-carboxylate (4d). Yield 0.46 g (91%),
white powder, mp 140–142°C. IR spectrum, ν, cm–1: 3434,
2925, 1747, 1671, 1524, 1260, 1101, 1017. 1H NMR
3
CH2); 2.42 (3H, s, CH3); 2.47 (2H, t, J = 7.5, CH2); 2.50
3
3
spectrum, δ, ppm (J, Hz): 1.40 (3H, t, J = 7.1, CH2CH3);
(3H, s, CH3); 2.97 (2H, t, J = 6.0, CH2). 13C NMR
163

Chemistry of Heterocyclic Compounds 2016, 52(3), 161–164
spectrum, δ, ppm: 9.9, 22.3 (2CH3); 23.6, 26.9, 38.4
(mp 182–183°C17). IR spectrum, ν, cm–1: 1701, 1637, 1392,
1
(3CH3); 123.1; 128.9; 154.6; 169.2; 188.3 (C=O); 194.0
(C=O). Mass spectrum, m/z (Irel, %): 192 [M]+ (53), 149
(64), 71 (53), 57 (100), 43 (75). Found, %: C 68.85; H 6.39.
C11H12O3. Calculated, %: C 68.74; H 6.29.
1222. H NMR spectrum, δ, ppm (J, Hz): 2.00–2.08 (2H,
3
3
m, CH2); 2.38 (2H, t, J = 7.6, CH2); 2.50 (2H, t, J = 6.2,
CH2); 5.14 (2H, s, CH2O); 5.28 (1H, s, CH); 7.67 (2H, d,
3
3J = 7.7, H Ar); 7.79 (2H, d, J = 7.7, H Ar). 13C NMR
Ethyl 1,3,5-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrobenzo-
furo[2,3-d]pyrimidine-6-carboxylate (6e). Yield 0.37 g
(69%), white powder, mp 158–160°C. IR spectrum, ν, cm–1:
spectrum, δ, ppm: 21.5, 29.1, 37.1 (3CH2); 70.1 (OCH2);
104.1 (CH); 129.7; 132.8; 130.0; 132.8; 177.2; 191.3
(C=O); 199.8 (C=O). Mass spectrum, m/z (Irel, %): 310
[M(81Br)]+ (25), 308 [M(79Br)]+ (27), 185 [81BrC6H4CO]+
(98), 183 [79BrC6H4CO]+ (100), 157 (13), 155 (16). Found,
%: C 54.29; H 4.32. C14H13BrO3. Calculated, %: C 54.39;
H 4.24.
1
2924, 1683, 1636, 1344, 770. H NMR spectrum, δ, ppm
3
(J, Hz): 1.41 (3H, t, J = 7.1, CH2CH3); 2.65 (3H, s, CH3);
3.40 (3H, s, CH3); 3.62 (3H, s, CH3); 4.39 (2H, q, 3J = 7.1,
CH2O). 13C NMR spectrum, δ, ppm: 10.8, 14.7, 28.5, 31.8
(4CH3); 61.5 (OCH2); 131.6, 137.0, 150.9, 156.1 (C Ar);
158.8, 158.9, 170.2 (3C=O). Mass spectrum, m/z (Irel, %):
266 [M]+ (100), 209 (91), 181 (77), 137 (28), 109 (46), 80
(46). Found, %: C 54.22; H 5.45; N 10.41. C12H14N2O5.
Calculated, %: C 54.13; H 5.30; N 10.52.
References
1. Mross, G.; Holtz, E.; Langer, P. J. Org. Chem. 2006, 71,
8045.
2. Dunlop, A. P.; Hurd, C. D. J. Org. Chem. 1950, 15, 1160.
3. Calter, M. A.; Zhu, C. Org. Lett. 2002, 4, 205.
4. (a) Cantlon, I. J. ; Cocker, W.; Mcmurry, T. B. H.
Tetrahedron 1961, 15, 46. (b) Ranu, B. C.; Adak, L.;
Banerjee, S. Tetrahedron Lett. 2008, 49, 4613. (c) Calter, M. A.;
Philips, R. M.; Flaschenriem, C. J. Am. Chem. Soc. 2005, 127,
14566. (d) Jin, Y.; Liu, X. Y.; Jing, L. L.; He, W.; Sun, X. L.;
Zhang, S. Y. Chirality 2007, 19, 386. (e) Shafiee, A.;
Shekarchi, M.; Ellahiyan, F.; Akbarzadeh, T. J. Heterocycl.
Chem. 2003, 40, 427.
Preparation of open-chain adducts 8a,b (General
method). A mixture of the 1,3-dicarbonyl compound 1b,c
(2 mmol) and ammonium acetate (0.14 g, 2 mmol) in EtOH–
H2O, 7:3 (3 ml) was stirred at 80°C for about an hour. Then
4'-bromophenacyl bromide (7) (0.56 g, 2 mmol) was added
to the reaction mixture and the stirring was continued for 3
h. The solvent was removed under reduced pressure, and
the viscous residue was purified by column
chromatography using hexane–AcOEt, 6:1, as eluent.
2-[2-(4-Bromophenyl)-2-oxoethoxy]-5,5-dimethylcyclo-
hex-2-enone (8a). Yield 0.57 g (85%), white powder, mp
177–179°C (mp 182–183°C17). IR spectrum, ν, cm–1: 1709,
1601, 1383, 1208. 1H NMR spectrum, δ, ppm (J, Hz): 1.10
(6H, s, 2CH3); 2.23 (2H, s, CH2); 2.44 (2H, s, CH2); 5.10
5. Chen, H.; Jiang, R.; Wang, Q. F.; Sun, X. L.; Luo, J.;
Zhang, S. Y. Chin. Chem. Lett. 2010, 21, 167.
6. Calter, M. A.; Korotkov, A. Org. Lett. 2011, 13, 6328.
7. Calter, M. A.; Korotkov, A. Org. Lett. 2015, 17, 1385.
8. Sinha, D.; Biswas, A.; Singh, V. K. Org. Lett. 2015, 17, 3302.
9. Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
10. Lee, J.; Li, J. H.; Oya, S.; Snyder, J. K. J. Org. Chem. 1992,
57, 5301.
11. Kubo, I.; Lee, Y.-W.; Balogh-Nair, V.; Nakanishi, K.;
Chapya, A. J. Chem. Soc., Chem. Commun. 1976, 22, 949.
12. Schulte, G.; Scheuer, P. J.; McConnell, O. Helv. Chim. Acta
1980, 63, 2159.
13. Yavari, I.; Sabbaghan, M. Synth. Commun. 2007, 37, 1791.
14. Yavari, I.; Sirouspour, M. ; Souri, S.; Nasiri, F.; Djahaniani, H.
Mendeleev Commun. 2005, 15, 120.
15. Yavari, I.; Hosseini, N.; Moradi, L.; Mirzaei, A. Tetrahedron
Lett. 2008, 49, 4239.
3
(2H, s, CH2O); 5.20 (1H, s, CH); 7.65 (2H, d, J = 8.5,
3
H Ar); 7.77 (2H, d, J = 8.5, H Ar). 13C NMR spectrum,
δ, ppm: 28.6 (2CH3); 33.0 (C); 42.9, 51.1 (2CH2); 70.2
(OCH2); 102.8 (CH); 129.7; 132.7; 129.9; 133.1; 175.4;
191.3 (C=O); 199.6 (C=O). Mass spectrum, m/z (Irel, %):
338 [M(81Br)]+ (19), 336 [M(79Br)]+ (18), 323
[M(81Br)–CH3]+ (43), 321 [M(79Br)–CH3]+ (41), 185
[81BrC6H4CO]+ (100), 183 [79BrC6H4CO]+ (98), 157 (13),
155 (13). Found, %: C 56.88; H 5.16. C16H17BrO3. Calcu-
lated, %: C 56.99; H 5.08.
16. Stetter, H.; Lauterbach, R. Chem. Ber. 1960, 93, 603.
17. Ibata, T.; Miyauchi, K.; Nakata, S. Bull. Chem. Soc. Jpn.
1979, 52, 3467.
3-[2-(4-Bromophenyl)-2-oxoethoxy]cyclohex-2-enone
(8b). Yield 0.34 g (55%), white powder, mp 179–181°C
164