A novel α-isocyanoacetamide-based three-component reaction for the synthesis of dialkyl 2-acyl-5-aminofuran-3,4-dicarboxylates

Article abstract of DOI:10.1039/c0ob00979b

α-Isocyanoacetamides, acyl chlorides and dialkylacetylenedicarboxylates undergo a smooth multicomponent reaction to produce dialkyl 2-acyl-5-aminofuran-3,4-dicarboxylates in good yield. The scope and mechanism of this new multicomponent transformation are

Full text of DOI:10.1039/c0ob00979b

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PAPER
A novel a-isocyanoacetamide-based three-component reaction for the
synthesis of dialkyl 2-acyl-5-aminofuran-3,4-dicarboxylates†
Riccardo Mossetti, Diego Caprioglio, Giampiero Colombano, Gian Cesare Tron and Tracey Pirali*
Received 3rd November 2010, Accepted 14th December 2010
DOI: 10.1039/c0ob00979b
a-Isocyanoacetamides, acyl chlorides and dialkylacetylenedicarboxylates undergo a smooth
multicomponent reaction to produce dialkyl 2-acyl-5-aminofuran-3,4-dicarboxylates in good yield. The
scope and mechanism of this new multicomponent transformation are discussed.
chloride (1a), 2-isocyano-1-morpholinopropan-1-one (2a) and
dimethyl acetylenedicarboxylate (DMAD; 3a) as test substrates,
furan 4a was isolated in 74% yield without the need for column
chromatography (Scheme 1).
Introduction
Substituted furan rings can be broadly found in many natural
products, as well as in pharmaceutically-relevant substances.1
Besides the biological relevance of these compounds, furans
have been extensively used as versatile building blocks in syn-
thetic chemistry, thanks to their proclivity to undergo Diels–
Alder cycloadditions, oxidations/reductions and hydrolysis trans-
formations.2 For these reasons, the search for novel and pragmatic
methodologies for the synthesis of furans is actively pursued.
In recent years, there has been considerable interest in the
Scheme 1 Synthesis of furan 4a.
development of efficient synthetic routes that allow the facile
assembly of substituted furans under mild reaction conditions
from simple and readily available starting materials, making
their use feasible for a combinatorial approach.3 In this context,
isocyanide-based multicomponent reactions play a preeminent
role over classical linear syntheses.4 Three main approaches can
be identified in the isocyanide-based multicomponent synthesis
of tetrasubstituted furans developed so far. The first is based on a
cycloaddition between a zwitterionic species, generated by reacting
an isocyanide with an activated alkyne, and an electrophilic
species.5 The second involves the formation of a carbonylic a,b-
unsaturated compound followed by a [4+1] cycloaddition with an
isocyanide,6 while the third concerns a 1,3-dipolar cycloaddition
between oxazoles, generated by reacting isocyanoacetamides with
electrophilic reagents, and activated acetylenes.7
The following optimized experimental procedure was used:
to a solution of a-isocyanoacetamide (1.0 equiv.) in dry
dichloromethane is added triethylamine (1.0 equiv.). A solution
of acyl chloride (1.0 equiv.) in dry dichloromethane is then added
dropwise over aperiodof 10min, andthe reaction is stirredatroom
temperature for 1 h in an atmosphere of nitrogen. Dry toluene
and dialkylacetylene dicarboxylate (1.0 equiv.) are then added,
and the reaction stirred under reflux overnight. The volatiles are
evaporated under reduced pressure, and the solid washed with
diethyl ether and filtered to give the desired furan.
A plausible reaction scenario is depicted in Scheme 2. The
acyl chloride reacts with triethylamine, forming the corresponding
ketene, which is then trapped by the isocyanide to produce the
Results and discussion
In connection with our ongoing study on the reactivity of a-
isocyanoacetamides with acyl chlorides,8 we report herein a
novel three-component synthesis of scarcely represented9 2-acyl-5-
aminofurans by reacting acyl chlorides, a-isocyanoacetamides and
dialkyl acetylenedicarboxylates. Using 3-cyclopentylpropanoyl
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farma-
cologiche, Universita` degli Studi del Piemonte Orientale “A. Avogadro”,
Via Bovio 6, 28100, Novara, Italy. E-mail: tracey.pirali@pharm.unipmn.it;
Fax: +39 0321375853; Tel: +39 0321375821
† Electronic supplementary information (ESI) available: See DOI:
10.1039/c0ob00979b
Scheme 2 Proposed reaction mechanism.
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Table 1 Furans from a-isocyanoacetamides, acyl chlorides and dialkylacetylenedicarboxylates
R1
R2
R3
R4
Product
Yield (%)
CH2Cyclopentyl
C4H9
CH3
CH3
CH2Ph
CH2Cyclopentyl
CH2Ph
CH2Cyclopentyl
CH2Ph
CH2Cyclopentyl
C4H9
C4H9
–(CH2)2–O–(CH2)2–
–(CH2)4–
–(CH2)5–
–(CH2)2–O–(CH2)2–
–(CH2)2–O–(CH2)2–
–CH3
–(CH2)5–
–(CH2)4–
–CH3
–(CH2)5–
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
tBu
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
74
62
79
65
59
67
68
57
69
74
73
75
60
72
61
55
CH2Ph
CH2Ph
–(CH2)5–
–(CH2)2–O–(CH2)2–
–(CH2)2–O–(CH2)2–
–CH3
–(CH2)5–
–(CH2)4–
CH3
CH2Ph
CH2Ph
C4H9
CH2Ph
nitrilium ion. Subsequent cyclization and proton transfer lead to
the 2-acyl-5-aminooxazole, prone to react with an activated alkyne
toform a 2-acyl-5-aminofuran bya[4+2]cycloadditionanda[4+2]
cycloreversion,9 with the loss of a molecule of acetonitrile.10
The role of the leaving group in the cycloreversion step was
explored. The best results in terms of reaction time, yield,
atom economy and purification were achieved when acetonitrile
was the leaving group (Scheme 3). Interestingly, when unsub-
stituted isocyanoacetamide 2b was used, it failed to give the
desired furan scaffold, although it can react with acyl chlorides
to afford 2-acyl-5-aminooxazoles.8 For this reason, a-methyl-
substituted a-isocyanoacetamides were preferentially used. They
were synthesized by the solventless aminolysis of methyl 2-
isocyanopropanoate with secondary amines.11
The overall sequence includes six chemical reactions that follow
one other in a single one-pot process, with the loss of only a
molecule of acetonitrile and a molecule of hydrochloric acid. The
ease of isolation of the products makes this procedure amenable to
combinatorial exploitation, as well as the presence of a carbonyl
group and two carboxyl moieties giving the possibility for further
modifications.
Experimental section
Commercially available reagents and solvents were used without
further purification. Dichloromethane was dried by distillation
˚
from P2O5 and stored over activated molecular sieves (4 A).
Toluene was dried by distillation from sodium and stored over
˚
activated molecular sieves (4 A). When needed, the reactions were
performed in oven-dried glassware under a positive pressure of
dry nitrogen.
Melting points were determined in open glass capillaries with
a Stuart scientific SMP3 apparatus and are uncorrected. All the
compounds were checked by IR (FT-IR THERMO-NICOLET
1
AVATAR), H and 13C APT (JEOL ECP 300 MHz) and mass
Scheme 3 A comparison between variously substituted a-isocyano-
acetamides.
spectrometry (Thermo Finningan LCQ-deca XP-plus) equipped
with an ESI source and an ion trap detector. Chemical shifts are
reported in part per million (ppm). Column chromatography was
performed on silica gel (Merck Kieselgel 70–230 mesh ASTM)
using the indicated eluents. Thin layer chromatography (TLC)
was carried out on 5 ¥ 20 cm plates with a layer thickness of
0.25 mm (Merck Silica gel 60 F254). When necessary, they were
developed with KMnO4. Elemental analysis (C, H, N) of all the
new compounds were within 0.4% of the calculated values.
The generality of this novel transformation was next examined.
Four acyl chlorides, three dialkyl acetylenedicarboxylates and
four isocyanoacetamides were used, affording sixteen dialkyl
2-alkanoyl-5-(alkylamino)furan-3,4-dicarboxylates (4a–p) in 55–
79% yield (Table 1).
It has to be stressed that no chromatographic procedure was
necessary for the purification of the furan products, but they were
easily isolated in high purity by ether washing and filtration.
a-Isocyanoacetamides 2a–f
Conclusions
2-Isocyano-1-(pyrrolidin-1-yl)ethanone (2b). Methyl isocy-
anoacetate (1 equiv.) is reacted with pyrrolidine (1 equiv.) to
give the a-isocyanoacetamide 2b according to the previous
literature.11
In conclusion, we have documented a straightforward synthesis
of dialkyl 2-acyl-5-aminofuran-3,4-dicarboxylates, displaying four
points of diversity and an unprecedented substitution pattern.
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◦
75%, dH(300 MHz, CDCl3) 4.15 (2 H, s), 3.31 (2 H, m), 3.22 (2
H, m), 1.84 (2 H, m), 1.73 (2 H, m); dC(75 MHz, CDCl3) d 161.6,
160.4, 47.3, 46.8, 45.8, 26.8, 24.8; m/z 139 (M + H)+
2-Isocyano-3-phenyl-1-(pyrrolidin-1-yl)propan-1-one (2c). The
subsequent alkylation, in the presence of caesium hydroxide,
gives the a-substituted a-isocyanoacetamide 2c according to
the previous literature.12 The volatiles are evaporated under
reduced pressure and the crude material is purified by column
chromatography on silica by using PE/EtOAc 7 : 3 as the eluent
to give the desired a-isocyanoacetamide 2c.
yellow solid; mp = 93–95 C; (found: C, 61.16; H, 6.99; N 3.56;
C20H27NO7 requires C, 61.06; H, 6.92; N 3.56%); nmax(neat)/cm-1
2950, 1744, 1708, 1668, 1565, 1450, 1232, 749; dH(300 MHz,
CDCl3) 3.91 (3 H, s), 3.80 (4 H, m), 3.71 (3 H, s), 3.67 (4 H, m),
2.62 (2 H, t, J 7.4), 1.76–1.43 (9 H, m), 1.06 (2 H, m); dC(75 MHz,
CDCl3) 188.6, 165.6, 163.2, 161.5, 140.2, 128.6, 95.2, 67.6, 54.0,
52.9, 49.5, 40.9, 38.7, 33.7, 31.1, 26.3; m/z 394 (M + H)+.
Dimethyl 2-cyclopentyl-5-hexanoylfuran-3,4-dicarboxylate (4b).
The crude material is purified by diethyl ether washing and
filtration to give furan 4b (62%) as a yellow amorphous solid
(found: C, 61.68; H, 7.28; N 4.00; C18H25NO6 requires C, 61.52;
H, 7.17; N 3.99%); nmax(neat)/cm-1 1741, 1705, 1570, 1232, 732;
dH(300 MHz, CDCl3) 3.87 (3 H, s), 3.65 (7 H, m), 2.55 (2 H, t, J
3.4), 1.92 (4 H, quint, J 3.3), 1.59 (2 H, quint, J 7.1), 1.25 (4 H,
m), 0.81 (3 H, t, J 7.1); dC(75 MHz, CDCl3) d 188.3, 165.9, 163.3,
160.0, 139.5, 129.2, 92.5, 53.9, 52.4, 51.0, 39.1, 32.5, 26.5, 24.6,
23.5, 15.0; m/z 352 (M + H)+.
70%, dH(300 MHz, CDCl3) 7.28 (5 H, m), 4.40 (1 H, t, J 7.4), 3.45
(3 H, m), 3.20 (2 H, m), 3.00 (1 H, m), 1.80 (4 H, m); dC(75 MHz,
CDCl3) d 163.8, 160.0, 136.0, 130.1, 129.5, 128.3, 57.9, 47.4, 47.3,
39.8, 26.8, 24.7; m/z 251 (M + Na)+
General procedure for the preparation of isocyanoacetamides 2a,
2d, 2e and 2f. Methyl-2-isocyanopropanoate (1 equiv.) is reacted
with the amine (1 equiv.) to give the a-isocyanoacetamide. The
reaction is stirred at room temperature overnight. The volatiles
are evaporated under reduced pressure and the crude material is
purified by column chromatography on silica by using petroleum
ether/EtOAc as the eluent to give the a-isocyanoacetamide.
Dimethyl 2-piperidin-1-yl-5-propionylfuran-3,4-dicarboxylate
(4c). The crude material is purified by diethyl ether washing and
filtration to give furan 4c (79%) as a yellow solid; mp = 83–85 ◦C
(found: C, 59.30; H, 6.59; N 3.98; C16H21NO6 requires C, 59.43;
H, 6.55; N 4.33%); nmax(neat)/cm-1 1741, 1706, 1568, 1198, 734;
dH(300 MHz, CDCl3) 3.79 (3 H, s), 3.59 (3 H, s), 3.47 (4 H, m),
2.55 (2 H, q, J 7.1), 1.56 (4 H, m), 1.00 (5 H, m); dC(75 MHz,
CDCl3) 189.1, 166.0, 163.4, 161.9, 139.5, 128.9, 94.2, 54.1, 52.9,
50.6, 32.6, 26.9, 25.2, 8.70; m/z 346 (M + Na)+.
2-Isocyano-1-morpholinopropan-1-one
(2a). Eluent:
PE/
EtOAc 4 : 6, 64%, light yellow oil, dH(300 MHz, CDCl3) 4.46 (1
H, q, J 6.6), 3.71–3.25 (8 H, m), 1.42 (3 H, br d); dC(75 MHz,
CDCl3) d 165.4, 159.7, 67.6, 67.2, 50.5, 47.2, 43.9, 19.8; m/z 169
(M + H)+.
Dimethyl 2-morpholin-4-yl-5-propionylfuran-3,4-dicarboxylate
(4d). The crude material is purified by diethyl ether washing and
filtration to give furan 4d (65%) as a brown solid; mp = 159–161 ◦C
(found: C, 55.46; H, 5.95; N 4.20; C15H19NO7 requires C, 55.38;
H, 5.89; N 4.31%); nmax(neat)/cm-1 1750, 1731, 1567, 1448, 1226;
dH(300 MHz, CDCl3) 3.93 (3 H, s), 3.81 (4 H, m), 3.72 (3 H, s),
3.67 (4 H, m), 2.68 (2 H, q, J 7.4), 1.39 (3 H, t, J 7.4); dC(75 MHz,
CDCl3) 189.3, 165.8, 163.3, 161.5, 140.1, 128.4, 95.3, 67.6, 54.3,
53.1, 49.5, 32.7, 9.94; m/z 348 (M + Na)+.
2-Isocyano-1-(pyrrolidin-1-yl)propan-1-one (2d). Eluent: PE/
EtOAc 4 : 6, 65%, white solid, mp = 85–86 ◦C, dH(300 MHz,
CDCl3) 4.35 (1 H, q, J 6.6), 3.57 (1 H, m), 3.42 (3 H, m), 2.08–1.80
(4 H, m), 1.53 (3 H, d, J 6.6); dC(75 MHz, CDCl3) d 164.8, 159.2,
52.1, 47.8, 47.7, 27.2, 25.0, 19.5; m/z 153 (M + H)+.
2-Isocyano-1-(piperidin-1-yl)propan-1-one (2e). Eluent: PE/
EtOAc 5 : 5, 65%, light yellow solid, mp = 91–92 ◦C, dH(300 MHz,
CDCl3) 4.47 (1 H, q, J 6.9), 3.57–3.22 (4 H, m), 1.63–1.40 (9 H);
dC(75 MHz, CDCl3) d 164.8, 159.2, 50.7, 47.9, 44.8, 27.0, 26.4,
25.2, 22.0; m/z 167 (M + H)+.
Dimethyl
2-(3-phenylpropanoyl)-5-piperidin-1-ylfuran-3,4-
dicarboxylate (4e). The crude material is purified by diethyl
ether washing and filtration to give furan 4e (59%) as a light
brown solid; mp = 118–120 ◦C (found: C, 62.85; H, 5.84; N 3.55;
C21H23NO7 requires C, 62.83; H, 5.78; N 3.49%); nmax(neat)/cm-1
1750, 1707, 1569, 1275, 1259, 764, 749; dH(300 MHz, CDCl3)
7.30–7.08 (5 H, m), 3.92 (3 H, s), 3.78 (4 H, m), 3.72 (3 H, s), 3.64
(4 H, m), 2.96 (4 H, m); dC(75 MHz, CDCl3) 188.1, 165.8, 163.4,
161.7, 142.4, 140.0, 130.0, 129.8, 129.0, 127.6, 95.6, 67.8, 54.5,
53.3, 49.6, 41.5, 31.0; m/z 424 (M + Na)+.
N-Benzyl-2-isocyano-N-methylpropanamide (2f). Eluent: PE/
EtOAc 7 : 3, 58%, light yellow oil, dH(300 MHz, CDCl3) 7.40–7.11
(5 H, m), 4.63–4.47 (3 H, m), 2.98 (3 H, s), 1.60 (3 H, d, J 6.63);
dC(75 MHz, CDCl3) 165.1, 158.1, 135.6, 134.8, 127.6, 125.7, 51.2,
49.2, 34.3, 18.1; m/z 203 (M + H)+.
General procedure for the preparation of 2-acyl-5-aminofuranes
4a–p
To
a
solution of a-isocyanoacetamide (1 equiv.) in dry
Dimethyl
2-[benzyl(methyl)amino]-5-(3-cyclopentylpro-
dichloromethane, triethylamine (1 equiv.) is added. A solution
of acyl chloride (1 equiv.) in dry dichloromethane is added drop
wise in a period of ten minutes and the reaction is stirred at room
temperature for 1 h in an atmosphere of nitrogen. Dry toluene
and dialkylacetylene dicarboxylate (1 equiv.) are added and the
reaction is stirred under reflux overnight. The volatile is evaporated
under reduced pressure and the solid is washed with diethyl ether
and filtered. Alternatively, the crude material is purified by column
chromatography on silica by using petroleum ether/EtOAc as
eluent to give furan 4.
panoyl)furan-3,4-dicarboxylate (4f). The crude material is
purified by diethyl ether washing and filtration to give furan 4f
(67%) as a light yellow solid; mp = 125–127 ◦C (found: C, 67.30;
H, 6.85; N 3.21; C24H29NO6 requires C, 67.43; H, 6.84; N 3.28%);
n
max(neat)/cm-1 1747, 1706, 1569, 668; dH(300 MHz, CDCl3) 7.26
(5 H, m), 4.79 (2 H, m), 3.93 (3 H, s), 3.70 (3 H, s), 3.12 (3 H, s),
2.61 (2 H, t, J 7.4), 1.75–1.38 (9 H, m), 1.04 (2 H, m); dC(75 MHz,
CDCl3) 188.9, 166.0, 162.0 (2C), 137.3, 130.3, 129.3 (2C), 129.0
(2C), 94.8, 57.7, 54.4, 53.1, 41.1, 39.6, 39.0, 33.9, 31.5, 26.6; m/z
450 (M + Na)+.
Dimethyl 2-(3-cyclopentylpropanoyl)-5-morpholin-4-ylfuran-
3,4-dicarboxylate (4a). The crude material is purified by diethyl
ether washing and filtration to give furan 4a (74%) as a light
Dimethyl
2-(3-phenylpropanoyl)-5-piperidin-1-ylfuran-3,4-
dicarboxylate (4g). The crude material is purified by diethyl
ether washing and filtration to give furan 4g (68%) as a light
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yellow solid; mp = 87–88 ◦C (found: C, 66.01; H, 6.28; N 3.42;
C22H25NO6 requires C, 66.15; H, 6.31; N 3.51%); nmax(neat)/cm-1
1746, 1704, 1569, 1449, 1259, 1227, 733; dH(300 MHz, CDCl3)
7.19 (5 H, m), 3.90 (3 H, s), 3.70 (3 H, s), 3.56 (4 H, m), 2.94 (4 H,
m), 1.64 (6 H, m); dC(75 MHz, CDCl3) 187.0, 165.5, 163.0, 161.5,
141.9 (2C), 139.0, 129.4, 129.2, 127.0, 94.0, 53.8, 52.5, 50.2, 40.8,
30.5, 26.4, 24.8; m/z 422 (M + Na)+.
Diethyl
2-morpholin-4-yl-5-propionylfuran-3,4-dicarboxylate
(4m). The crude material is purified by diethyl ether washing
and filtration to give furan 4m (60%) as a white solid; mp =
142–143 ◦C (found: C, 58.50; H, 7.29; N 3.69; C18H27NO7 requires
C, 58.52; H, 7.37; N 3.79%); nmax(neat)/cm-1 1738, 1691, 1569,
1441, 1209, 1064, 668; dH(300 MHz, CDCl3) 4.38 (2 H, q, J 7.1),
4.18 (2 H, q, J 7.1), 3.80 (4 H, m), 3.67 (4 H, m), 2.67 (2 H, q, J
7.4), 1.38 (3 H, t, J 7.1), 1.26 (3 H, t, J 7.1), 1.13 (3 H, t, J 7.4);
dC(75 MHz, CDCl3) 186.7, 162.8, 160.6, 159.1, 137.8, 126.2, 92.7,
65.2, 60.9, 59.5, 47.0, 30.3, 12.9, 12.8, 6.3; m/z 376 (M + Na)+.
Dimethyl
2-(3-cyclopentylpropanoyl)-5-pyrrolidin-1-ylfuran-
3,4-dicarboxylate (4h). The crude material is purified by diethyl
ether washing and filtration to give furan 4h (57%) as a white
amorphous solid (found: C, 63.71; H, 7.33; N 3.90; C20H27NO6
requires C, 63.64; H, 7.21; N 3.71%); nmax(neat)/cm-1 1750, 1707,
1569, 1219, 749; dH(300 MHz, CDCl3) 3.89 (3 H, s), 3.68 (7 H,
m), 2.60 (2 H, t, J 7.4), 1.94 (4 H, quint, J 3.03), 1.79–1.42 (11 H,
m); dC(75 MHz, CDCl3) 188.4, 165.9, 163.3, 160.0, 139.5, 129.2,
92.5, 53.9, 52.4, 51.0, 40.8, 40.7, 33.4, 31.2, 26.5, 26.1; m/z 440
(M + Na)+.
Dimethyl
2-(3-phenylpropanoyl)-5-piperidin-1-ylfuran-3,4-
dicarboxylate (4n). The crude material is purified by column
chromatography on silica by using petroleum ether/EtOAc 7 : 3
as the eluent give furan 4n (72%) as a yellow oil (found: C, 66.99;
H, 6.35; N 3.11; C27H29NO6 requires C, 69.96; H, 6.31; N 3.02%);
n
max(neat)/cm-1 1739, 1701, 1568, 1212, 1075, 698; dH(300 MHz,
CDCl3) 7.40–7.18 (10 H, m), 4.78 (2 H, s), 4.41 (2 H, q, J 7.1),
4.16 (2 H, q, J 7.1), 3.08 (3 H, s), 2.90 (4 H, m), 1.38 (3 H, t, J
7.1), 1.22 (3 H, t, J 7.1); dC(75 MHz, CDCl3) 186.2, 164.3, 162.0,
161.0, 141.2, 138.5 (2C), 136.2, 129.0, 128.7, 128.6, 128.1, 127.9,
126.3, 94.2, 62.2, 60.8, 56.5, 40.2, 38.3, 29.9, 14.2 (2C); m/z 486
(M + Na)+.
Dimethyl
2-[benzyl(methyl)amino]-5-(3-phenylpropanoyl)-
furan-3,4-dicarboxylate (4i). The crude material is purified
by column chromatography on silica by using petroleum
ether/EtOAc 7 : 3 as the eluent to give furan 4i (69%) as a yellow
oil (found: C, 69.01; H, 5.70; N 3.33; C25H25NO6 requires C, 68.95;
H, 5.79; N 3.22%); nmax(neat)/cm-1 1742, 1706, 1569, 1453, 1218,
750; dH(300 MHz, CDCl3) 7.25 (10 H, m), 4.78 (2 H, s), 3.94 (3 H,
s), 3.71 (3 H, s), 3.09 (3 H, s), 2.94 (m, 4 H); dC(75 MHz, CDCl3)
186.4, 164.8, 162.4, 161.8, 141.2, 138.5 (2C), 136.2, 129.3, 128.7,
128.5, 128.2, 127.9, 126.4, 93.5, 56.6, 53.2, 52.0, 40.3, 38.3, 29.9;
m/z 458 (M + Na)+.
Dimethyl 2-(3-cyclopentylpropanoyl)-5-piperidin-1-ylfuran-3,4-
dicarboxylate (4j). The crude material is purified by diethyl ether
washing and filtration to give furan 4j (74%) as a white solid; mp =
81–83 ◦C (found: C, 64.30; H, 7.41; N 3.50; C21H29NO6 requires C,
64.43; H, 7.47; N 3.58%); nmax(neat)/cm-1 1750, 1731, 1718, 1275,
764, 749; dH(300 MHz, CDCl3) 3.92 (3 H, s), 3.72 (3 H, s), 3.60
(4 H, m), 2.63 (2 H, t, J 7.4),1.81–1.48 (15 H, m), 1.09 (2 H, m);
dC(75 MHz, CDCl3) 189.0, 166.2, 163.6, 162.1, 139.9, 129.2, 94.7,
54.3, 53.0, 50.9, 41.1, 38.9, 33.9, 31.4, 27.0, 26.6, 25.4; m/z 414
(M + Na)+.
Diethyl
2-(3-phenylpropanoyl)-5-piperidin-1-ylfuran-3,4-
dicarboxylate (4o). The crude material is purified by diethyl
ether washing and filtration to give furan 4o (61%) as a yellow
solid; mp = 62–64 ◦C (found: C, 67.53; H, 6.90; N 3.30; C24H29NO6
requires C, 67.43; H, 6.84; N 3.28%); nmax(neat)/cm-1 1740, 1700,
1560, 1216, 1192, 1087, 699; dH(300 MHz, CDCl3) 7.22 (5 H, m),
4.37 (2 H, q, J 7.1), 4.18 (2 H, q, J 7.1), 3.57 (4 H, m), 2.96 (4
H, m), 1.66 (4 H, m), 1.36 (3 H, t, J 7.1), 1.26 (3 H, t, J 7.1);
dC(75 MHz, CDCl3) 186.8, 164.9, 162.6, 161.5, 141.9 (2C), 139.0,
129.3, 129.2, 126.9, 94.3, 62.8, 61.2, 50.2, 40.8, 30.5, 26.4, 24.7,
14.9, 14.8; m/z 450 (M + Na)+.
Di-tert-butyl
2-hexanoyl-5-pyrrolidin-1-ylfuran-3,4-
dicarboxylate (4p). The crude material is purified by diethyl
ether washing and filtration to give furan 4p (55%) as a light
yellow solid; mp = 98–100 C (found: C, 66.00; H, 8.40; N 3.11;
◦
C24H37NO6 requires C, 66.18; H, 8.56; N 3.22%); nmax(neat)/cm-1
1734, 1697, 1559, 1242, 1160, 1140, 749, 668; dH(300 MHz,
CDCl3) 3.60 (4 H, m), 2.62 (2 H, t, J 7.4), 1.95 (4 H, m), 1.60 (9
H, s), 1.49 (9 H, s), 1.29 (6 H, m), 0.87 (3 H, t, J 6.3); dC(75 MHz,
CDCl3) 188.4, 164.0, 163.2, 159.4, 139.8, 130.9, 95.1, 84.3, 82.7,
51.1, 39.7, 32.9, 29.7, 29.6, 26.8, 25.2, 23.8, 15.3; m/z 458 (M +
Na)+.
Diethyl
2-hexanoyl-5-piperidin-1-ylfuran-3,4-dicarboxylate
(4k). The crude material is purified by diethyl ether washing and
filtration to give furan 4k (73%) as an orange solid; mp = 56–58 ◦C
(found: C, 64.25; H, 7.99; N 3.68; C21H31NO6 requires C, 64.10;
H, 7.94; N 3.56%); nmax(neat)/cm-1 1714, 1701, 1560, 1222, 1193,
1084, 668; dH(300 MHz, CDCl3) 4.35 (2 H, q, J 7.3), 4.15 (2 H,
q, J 7.1), 3.57 (4 H, m), 2.59 (2 H, t, J 7.4), 1.61 (8 H, m), 1.34 (3
H, t, J 7.3), 1.27 (4 H, m), 1.23 (3 H, t, J 7.1), 0.84 (3 H, t, J 6.8);
dC(75 MHz, CDCl3) 186.7, 162.8, 160.6, 159.1, 137.8, 126.2, 92.7,
65.2, 60.9, 59.5, 47.0, 30.3, 12.9, 12.8, 6.3; m/z 394 (M + H)+.
Notes and references
1 (a) F. M. Dean, Advances in Heterocyclic Chemistry, ed. A. R. Katrizky,
Academic Press, New York, 1982, vol. 30, pp. 167–238; (b) F. M. Dean
and M. V. Sargent, in Comprehensive Heterocyclic Chemistry, ed. C. W.
Bird and G. W. H. Cheeseman, Pergamon Press, New York, 1984, vol.
4, part 3, pp. 531–598.
2 (a) B. H. Lipshutz, Chem. Rev., 1986, 86, 795–819; (b) H. N. C. Wong,
P. Yu and C. Y. Yick, Pure Appl. Chem., 1999, 71, 1041–1044; (c) H. K.
Lee, K. F. Chan, C. W. Hui, H. K. Yim, X. W. Wu and H. N. C Wong,
Pure Appl. Chem., 2005, 77, 139–143; (d) J. Raczko and J. Jurczak, in
Studies in Natural Products Chemistry, ed. Atta-ur-Rahman, Elsevier,
1995, vol. 16, pp. 639–685.
Diethyl
2-hexanoyl-5-morpholin-4-ylfuran-3,4-dicarboxylate
(4l). The crude material is purified by diethyl ether washing and
filtration to give furan 4l (75%) as a light yellow solid; mp =
125–127 ◦C (found: C, 67.68; H, 7.30; N 3.51; C20H29NO7 requires
C, 60.74; H, 7.39; N 3.54%); nmax(neat)/cm-1 1706, 1569, 668;
dH(300 MHz, CDCl3) 4.38 (2 H, q, J 7.1), 4.18 (2 H, q, J 7.1),
3.81 (4 H, m), 3.68 (4 H, m), 2.6 (2 H, t, J 7.1), 1.64 (2 H, quint, J
7.1), 1.38 (3 H, t, J 7.1), 1.30 (4 H, m), 1.27 (3 H, t, J 7.1), 0.87 (3
H, t, J 6.8); dC(75 MHz, CDCl3) 189.0, 165.9, 163.4, 161.8, 138.3,
129.2, 96.2, 68.2, 63.9, 62.4, 50.0, 40.0, 33.2, 25.2, 24.2, 15.9, 15.8,
15.7; m/z 418 (M + Na)+.
3 For an overview on recent developments in furan synthesis, see: (a) S.
F. Kirsch, Org. Biomol. Chem., 2006, 4, 2076–2080; (b) X. L. Hou, H.
Y. Cheung, T. Y. Hon, P. L. Kwan, T. H. Lo, S. Y. Tong and H. N. C.
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9 To the best of our knowledge, the only dialkyl 2-acyl-5-aminofuran-
3,4-dicarboxylates reported to date have been described by the Doyle
and Padwa group. This skeleton was synthesized by reacting a
rhodium-catalyzed cycloaddition between DMAD and an isomunch-
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 1627–1631 | 1631
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