Synthesis of highly functionalised 2-aminofurans

Article abstract of DOI:10.1070/MC2004v014n01ABEH001860

The reaction of alkyl isocyanides and dimethyl 2-oxo-3-arylidenesuccinates leads to highly functionalised aminofuran derivatives in good yields.

Full text of DOI:10.1070/MC2004v014n01ABEH001860

Mendeleev Commun., 2004, 14(1), 38–39
Synthesis of highly functionalised 2-aminofurans
Issa Yavari,* Hoorieh Djahaniani and Loghman Moradi
Department of Chemistry, University of Tarbiat Modarres, P.O. Box 14115-175, Tehran, Iran.
Fax: +98 21 800 6544; e-mail: isayavar@yahoo.com
DOI: 10.1070/MC2004v014n01ABEH001860
The reaction of alkyl isocyanides and dimethyl 2-oxo-3-arylidenesuccinates leads to highly functionalised aminofuran derivatives
in good yields.
Furans are common substructures in numerous natural products,
such as kallolides1 and combranolides.2 Polysubstituted furans
play an important role in organic chemistry not only due to their
presence as key structural units in many natural products and in
important pharmaceuticals,3 but also they can be employed as
building blocks in synthetic organic chemistry. Many strategies
have been developed for the preparation of furans.4 As part of
our current studies5 on the development of new routes to hetero-
cyclic systems, we now report an efficient synthetic route to
aminofurans using alkyl isocyanides and 2-oxo-3-arylidene-
succinates 1. Thus, the reaction between alkyl isocyanides and
1 at ambient temperature in dichloromethane leads to 2-amino-
furan derivatives 3a–g in 70–90% yields (Scheme 1). Com-
pound 1, which is readily available,6 possesses a highly polarised
carbon–carbon double bond.7,8 Therefore, it is expected to be a
strong Michael acceptor.
to assume that compounds 3a–g result from the addition of
alkyl isocyanides to the polarised olefinic system of 1. Then,
the carbon atom of the isocyanide moiety is attacked by the
oxygen atom of enolate ion 4 to form compound 5. Such an
‡
1H and 13C NMR spectra were measured with a Bruker DRX-500
AVANCE instrument with CDCl3 as a solvent at 500.1 and 125.7 MHz,
respectively. Mass spectra were recorded on a Finnigan-Matt 8430 mass
spectrometer operating at an ionization potential of 70 eV.
Typical experimental procedure for the preparation of 3a–g: to a mag-
netically stirred solution of 0.49 g of dimethyl 2-oxoarylidenesuccinate
(2 mmol) in 10 ml of CH2Cl2 was added dropwise at –10 °C for 10 min
0.16 g of tert-butyl isocyanide (2 mmol). The reaction mixture was then
allowed to warm up to room temperature and stand for 24 h. The solvent
was removed under a reduced pressure, and the residue was separated by
silica gel column chromatography (Merck 230-400 mesh) using n-hexane–
ethyl acetate (5:1) as an eluent.
3a: yield 0.23 g (70%), yellow oil. 1H NMR (CDCl3) d: 1.50 (s,
CMe3), 3.71 and 3.92 (2s, 2OMe), 6.90 (s, NH), 7.32–7.72 (m, Ph).
13C NMR (CDCl3) d: 29.12 (CMe3), 50.69 and 51.97 (2OMe), 52.01
(CMe3), 88.23 (C3 furan), 124.30 and 128.65 (5CH), 127.55 (C4 furan),
129.10 (Cipso), 141.27 (C5 furan), 162.02 (N–C–O), 165.17 and 166.18
(2C=O, ester). IR (KBr, n/cm–1): 3325 (NH), 1728 and 1671 (C=O). MS,
m/z (%): 331 (M+, 60), 275 (75), 243 (30), 211 (25), 105 (90), 77 (30),
57 (30), 41 (30). Found (%): C, 65.30; H, 6.41; N, 4.25. Calc. for
C18H21NO5 (%):C, 65.24; H, 6.39; N, 4.23.
Ar
CO2Me
O
R
Ar
CO2Me
R
N
C
N
CO2Me
O
CO2Me
H
1a–f
2a,b
3a–g
1 a Ar = phenyl
b Ar = 3-nitrophenyl
c Ar = 4-nitrophenyl
2 a R = But
b R = Bz
3b: yield 0.32 g (85%), mp 148–150 °C. 1H NMR (CDCl3) d: 1.52 (s,
CMe3), 3.79 and 3.97 (2s, 2OMe), 6.92 (s, NH), 7.53 (t, CH, 3JHH 8.1 Hz),
7.81 (t, CH, 3JHH 7.9 Hz), 8.07 (dd, CH, 3JHH 8.1 Hz, 4JHH 1.2 Hz), 8.35
4
(d, CH, JHH 1.6 Hz). 13C NMR (CDCl3) d: 29.84 (CMe3), 51.31 and
d Ar = 4-chlorophenyl
e Ar = 1-naphthyl
f Ar = 2-furyl
52.90 (2OMe), 53.00 (CMe3), 88.87 (C3 furan), 115.79 (C4 furan), 118.92,
121.64, 129.45 and 129.80 (4CH), 130.75 (Cipso), 138.53 (C5 furan),
148.65 (C–NO2), 161.71 (N–C–O), 164.71 and 165.38 (2C=O, ester).
IR (KBr, n/cm–1): 3300 (NH), 1727 and 1667 (C=O). MS, m/z (%): 376
(M+, 25), 320 (80), 288 (75), 256 (60), 150 (75), 134 (30), 104 (30), 76
(25), 57 (90), 41 (75). Found (%): C, 57.51; H, 5.39; N, 7.46. Calc. for
C18H20N2O7 (%): C, 57.44; H, 5.36; N, 7.44.
Yield
70%
85%
88%
3 a Ar = phenyl, R = But
b Ar = 3-nitrophenyl, R = But
c Ar = 4-nitrophenyl, R = But
d Ar = 4-chlorophenyl, R = But 75%
3c: yield 0.33 g (88%), mp 174–176 °C. 1H NMR (CDCl3) d: 1.52 (s,
e Ar = 1-naphthyl, R = But
f Ar = 1-naphthyl, R = Bz
g Ar = 2-furyl, R = But
70%
90%
70%
3
CMe3), 3.79 and 3.96 (2s, 2OMe), 6.97 (s, NH), 7.60 (d, CH, JHH
8.5 Hz), 8.21 (d, CH, 3JHH 8.5 Hz). 13C NMR (CDCl3) d: 29.78 (CMe3),
51.43 and 53.04 (2OMe), 53.13 (CMe3), 89.63 (C3 furan), 117.51 (C4
furan), 123.93 and 124.39 (4CH), 134.98 (Cipso), 138.33 (C5 furan),
145.96 (C–NO2), 161.92 (N–C–O), 164.56 and 165.50 (2C=O, ester).
IR (KBr, n/cm–1): 3420 (NH), 1721 and 1676 (C=O). MS, m/z (%): 376
(M+, 25), 320 (80), 288 (80), 256 (30), 151 (80), 134 (25), 104 (25), 57
(50), 41 (30). Found (%): C, 57.48; H, 5.40; N, 7.45. Calc. for C18H20N2O7
(%): C, 57.44; H, 5.36; N, 7.44.
Scheme 1
The reaction of dimethyl 2-oxo-3-arylidenesuccinates 1 with
tert-butyl or benzyl isocyanide proceeded spontaneously at
room temperature in dichloromethane and produced dimethyl
5-alkylamino-4-aryl-2,3-furandicarboxylates 3a–g.† The struc-
tures of compounds 3a–g were deduced from their elemental
3d: yield 0.25 g (75%), mp 91–93 °C. 1H NMR (CDCl3) d: 1.48 (s,
CMe3), 3.77 and 3.90 (2s, 2OMe), 6.83 (s, NH), 7.33 (d, CH, 3JHH 8.4 Hz),
8.45 (d, CH, 3JHH 8.4 Hz). 13C NMR (CDCl3) d: 29.87 (CMe3), 51.20 and
52.70 (2OMe), 52.83 (CMe3), 88.55 (C3 furan), 113.70 (C4 furan),
125.75 and 128.98 (4CH), 127.74 (C–Cl), 133.32 (Cipso), 140.30 (C5
furan), 161.57 (N–C–O), 164.91 and 165.87 (2C=O, ester). IR (KBr,
n/cm–1): 3315 (NH), 1729 and 1675 (C=O). MS, m/z (%): 365 (M+, 90),
309 (90), 277 (50), 245 (40), 139 (60), 57 (50). Found (%): C, 59.13; H,
5.48; N, 3.80. Calc. for C18H20ClNO5 (%): C, 59.10; H, 5.51; N, 3.83.
3e: yield 0.27 g (70%), yellow oil. 1H NMR (CDCl3) d: 1.43 (s, CMe3),
3.65 and 3.81 (2s, 2OMe), 6.97 (s, NH), 7.43–8.10 (m, C10H7). 13C NMR
(CDCl3) d: 29.94 (CMe3), 51.20 and 52.25 (2OMe), 52.78 (CMe3), 87.56
(C3 furan), 116.08 (C4 furan), 125.17, 125.60, 126.15, 126.59, 128.48,
and 129.71 (7CH), 126.70, 131.46, and 133.74 (3C), 142.97 (C5 furan),
162.50 (N–C–O), 165.10 and 165.42 (2C=O, ester). IR (KBr, n/cm–1):
3385 (NH), 1717 and 1667 (C=O). MS, m/z (%): 381 (M+, 90), 325 (75),
261 (90), 155 (90), 127 (60), 57 (50), 41 (50). Found (%): C, 69.30; H,
6.11; N, 3.64. Calc. for C22H23NO5 (%): C, 69.28; H, 6.08; N, 3.67.
1
analyses, mass spectra, H and 13C NMR and IR spectroscopic
data.‡ The 1H NMR spectrum of 3a exhibited three single sharp
lines readily recognised as arising from tert-butyl (d 1.52 ppm)
and methoxy (d 3.79 and 3.97 ppm) protons. A singlet (d
6.92 ppm) is observed for the NH group, and the phenyl moiety
gave rise to characteristic signals in the aromatic region of the
spectrum. The proton-decoupled 13C NMR spectrum of 3a
showed 13 distinct resonances in agreement with the proposed
structure.
A plausible mechanism for the formation of 2-aminofuran
derivatives 3a–g is indicated in Scheme 2. On the basis of the
well-established chemistry of isocyanides,9–13 it is reasonable
†
When the reaction of 1a and 2a was carried out in the presence of
dimethyl acetylenedicarboxylate or dibenzoylacetylene, compound 3a and
the unchanged acetylenic compound were isolated.
– 38 –

Mendeleev Commun., 2004, 14(1), 38–39
12 H. M. Walborsky and M. P. Periasamy, in The Chemistry of Functional
R
N
C
Groups, Supplement C, eds. S. Patai and Z. Rappoport, Wiley, New
York, 1983, ch. 20, p. 835.
13 S. Marcaccini and T. Torroba, Org. Prep. Proced. Int., 1993, 25, 141.
RN
Ar
O
CO Me
2
O
3
Ar
CO Me
CO Me
2
2
CO Me
2
4
5
Scheme 2
addition product may tautomerise under the reaction conditions
employed and produce compound 3.
In summary, we have found an efficient synthetic method for
the preparation of highly functionalised 2-aminofurans. This
method carries the advantage that not only the reaction is per-
formed under neutral conditions, but also the starting materials
and reagents can be mixed without any activation or modification.
Received: 3rd November 2003; Com. 03/2186
3f: yield 0.37 g (90%), mp 122–124 °C. 1H NMR (CDCl3) d: 3.66 and
3.83 (2s, 2OMe), 4.59 (d, CH2, 3JHH 6.2 Hz), 7.13 (t, NH, 3JHH 6.2 Hz),
7.30–7.88 (m, C10H7 and Ph). 13C NMR (CDCl3) d: 46.21 (CMe3), 51.29
and 52.25 (2OMe), 87.44 (C3 furan), 116.50 (C4 furan), 125.07, 125.54,
126.10, 126.68, 127.29, 127.70, 128.40, 128.47, 128.84, and 129.82
(12CH), 126.40, 131.61, 133.68, and 137.94 (4C), 143.25 (C5 furan),
162.16 (N–C–O), 164.81 and 165.10 (2C=O, ester). IR (KBr, n/cm–1):
3345 (NH), 1721 and 1667 (C=O). MS, m/z (%): 415 (M+, 90), 324 (40),
264 (25), 155(80), 91 (90). Found (%): C, 72.30; H, 5.11; N, 3.40. Calc.
for C25H21NO5 (%): C, 72.28; H, 5.09; N, 3.37.
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3g: yield 0.22 g (70%), red oil. H NMR (CDCl3) d: 1.43 (s, CMe3),
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(2OMe), 52.90 (CMe3), 87.57 (C3 furan), 107.20, 111.34, and 142.50
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– 39 –