Reaction between alkyl isocyanides and dibenzoylacetylene in the presence of strong NH-acids: Synthesis of highly functionalized aminofurans

Article abstract of DOI:10.1016/S0040-4020(03)00990-6

Protonation of the highly reactive 1:1 intermediates produced in the reaction between alkyl isocyanides and dibenzoylacetylene by saccharin, phthalimide, or 4-methyl-5-nitroimidazole, leads to vinylnitrilium cations, which undergo carbon-centered Michael

Full text of DOI:10.1016/S0040-4020(03)00990-6

Tetrahedron 59 (2003) 6083–6086
Reaction between alkyl isocyanides and dibenzoylacetylene
in the presence of strong NH-acids: synthesis of highly
functionalized aminofurans
*
Issa Yavari, Abdolali Alizadeh, Mohammad Anary-Abbasinejad and Hamid R. Bijanzadeh
Department of Chemistry, University of Tarbiat Modarres, P.O. Box 14115-175, Tehran, Iran
Received 28 February 2003; revised 27 May 2003; accepted 19 June 2003
Abstract—Protonation of the highly reactive 1:1 intermediates produced in the reaction between alkyl isocyanides and dibenzoylacetylene
by saccharin, phthalimide, or 4-methyl-5-nitroimidazole, leads to vinylnitrilium cations, which undergo carbon-centered Michael type
addition with the conjugate base of the NH-acid to produce highly functionalized aminofuran derivatives.
q 2003 Elsevier Ltd. All rights reserved.
Polysubstituted furans play an important role in organic
chemistry not only due to their presence as key structural
units in many natural products1 and in important pharma-
ceuticals,2 but they can also be employed in synthetic
chemistry as building blocks. For this reason the synthesis
of polysubstituted furans continues to attract the interest of
many synthetic chemists. The formation of a carbon–
carbon bond at the a-position to a nitrogen atom is of
importance for the elaboration of amines and, in particular,
the synthesis of nitrogen-containing natural products and
biologically active compounds.3 We now report an efficient
synthetic route to polysubstituted furans using dibenzoyl-
acetylene and alkyl isocyanides in the presence of a
NH-acid such as saccharin, phthalimide or 4-methyl-5-
nitroimidazole. Thus, the reaction between dibenzoyl-
acetylene and alkyl isocyanides in the presence of hetero-
cyclic NH-acids at ambient temperature in dry diethyl ether,
leads to highly functionalized aminofurans.
Scheme 1.
The reaction of dibenzoylacetylene with alkyl isocyanides
in the presence of phthalimide, proceeded spontaneously at
room temperature in dry diethyl ether and produced 2-[4-
1H and 13C NMR spectroscopic data, as well as IR spectra,
benzoyl-5-(alkylamino)-2-phenyl-3-furyl]-1H-isoindole-
are in agreement with the proposed structures. Partial
1,3-(2H)-dione (2) and 2-{(Z)-1-benzoyl-2-[(alkylimino)-
assignments of the NMR chemical shifts are given in
methyl]-3-oxo-3-phenyl-1-propenyl}-1H-isoindole-1,3-
Section 1.
(2H)-dione (3) in a 2:1 ratio (Scheme 1).
On the basis of the well-established chemistry of iso-
The nature of these compounds as 1:1:1 adducts was
apparent from their mass spectra, which displayed, in each
cyanides4–8 it is reasonable to assume that diaminofurans 2
and imines 3 result from nucleophilic addition of alkyl
isocyanides to dibenzoylacetylene and subsequent protona-
case, the molecular ion peak at appropriate m/z values. The
tion of the 1:1 adduct by the NH-acid. Then, the positively
Keywords: alkyl isocyanides; dibenzoylacetylene; keteneimine; 4-methyl-
charged ion 4 is attacked by the anion of the NH-acid to
5-nitroimidazole; phthalimide; saccharin.
produce the keteneimine 5, which cyclizes, under the
reaction condition employed, to produce the aminofuran 2,
*
Corresponding author. Tel.: þ98-21-8006631; fax: þ98-21-8006544;
e-mail: isayavar@yahoo.com
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00990-6

6084
I. Yavari et al. / Tetrahedron 59 (2003) 6083–6086
Scheme 2.
or undergoes 1,3-hydrogen shift to produce the imine
derivative 3 (Scheme 2).
potential interest. The present method carries the advantage
that not only is the reaction performed under neutral
conditions, but also the starting materials and reagents can
be mixed without any activation or modification.
Under the reaction conditions given for phthalimide, only
one product was isolated from the reaction mixture of
4-methyl-5-nitroimidazole, tert-butyl isocyanide and
dibenzoylacetylene. Structure 2c was assigned to the
isolated product on the basis of its elemental analyses and
IR, 1H NMR and 13C NMR spectra. The 1H NMR spectrum
of 2c showed (besides signals for the phenyl groups) four
signals for tert-butyl, methyl, methine, and NH protons. The
13C NMR of this product showed 19 signals in agreement
with the suggested structure.
1. Experimental
Melting points were measured on an Electrothermal 9100
apparatus. Elemental analyses for C, H, and N were
performed using a Heraeus CHN-O-Rapid analyzer. IR
spectra were recorded as KBr discs on a Shimadzu IR-460
1
spectrometer. H and 13C, NMR spectra were obtained at
500.1 and 125.7 MHz, respectively, on a BRUKER DRX
500-AVANCE FT-NMR instrument with CDCl3 as solvent.
Compounds dibenzoylacetylene,9,10 4-methyl-5-nitro-
imidazole11 and 2-benzoylimidazole12 were prepared
according to the published procedures. The reagents and
solvents used in this work were obtained from Fluka (Buchs,
Switzerland) and used without further purification.
1.1. General procedure
To a magnetically stirred solution of dibenzoylacetylene
(2 mmol) and the NH-acid compound (2 mmol) in 10 mL
dry diethyl ether was added a mixture of alkyl isocyanide
(2 mmol) in 5 mL dry diethyl ether at room temperature.
The reaction mixture was then allowed to stir for 24 h. The
solvent was removed under reduced pressure, and the
residue was separated by silica gel (Merck 230–240 mesh)
column chromatography using hexane–ethyl acetate
mixture as eluent.
From the reaction of saccharin with dibenzoylacetylene in
the presence of tert-butyl or cyclohexyl isocyanide, only
one product was isolated from the reaction mixtures
(Scheme 3). Structures 2d and 2e were assigned to the
isolatedproductsonthe basis oftheirelementalanalyses, mass
spectra, and IR, 1H NMR and 13C NMR spectroscopic data.
In summary, we have found a simple and efficient method
for the preparation of some functionalized aminofurans of
1.1.1. 2-[4-Benzoyl-5-(tert-butylamino)-2-phenyl-3-
furyl]-1H-isoindole-1,3-(2H)-dione (2a). Yellow crystals,
0.27 g, yield 60%, mp 227–2308C. IR (KBr) (nmax, cm21):
3348 (N–H), 1775 and 1714 (CO–N–CO), 1618 (CvO).
Anal. calcd for C29H24N2O4 (464.5): C, 74.99; H, 5.21; N,
6.03%. Found: C, 74.8; H, 5.3; N, 6.0%. 1H NMR
(500 MHz, CDCl3): dH¼1.60 (9H, s, CMe3), 6.72 (t,
3
3JHH¼7.3 Hz, CH arom), 6.89 (t, JHH¼7.5 Hz, 2CH
3
arom), 7.20 (t, JHH¼7.6 Hz, CH arom), 7.22 (d,
3
3JHH¼7.6 Hz, 2CH arom), 7.26 (t, JHH¼7.5 Hz, 2CH
3
arom), 7.38 (d, JHH¼7.8 Hz, 2CH arom), 7.65 (m, 4CH
arom), 8.78 (s, N–H). 13C NMR (125.7 MHz, CDCl3):
Scheme 3.
dC¼29.82 (Me3C), 52.98 (CMe3), 97.38 and 110.90 (2C of

I. Yavari et al. / Tetrahedron 59 (2003) 6083–6086
6085
furan), 123.40 (2CH4,7 of C6H4), 124.29, 126.07, 127.59,
127.68, 128.51, 128.62, 128.80, 131.68, 134.07, 140.42
(2C6H5 and C6H4), 140.49 (C–O), 162.83 (N–C–O),
166.71 (2CvO), 188.77 (CvO). MS, m/z (%): 465
(Mþþ1, 7), 464 (Mþ, 22), 409 (12), 408 (53), 407 (21),
303 (4), 260 (6), 232 (2), 197 (2), 148 (12), 106 (7), 105
(100), 76 (15), 54 (10).
and 32.55 (5CH2 of cyclohexyl), 61.79 (N–CH), 124.20 and
128.35 (2CH arom), (128.48 C2 of propenyl), 120.66,
129.03, 131.23, 132.89, 133.64, 135.14, 136.37, 136.69,
141.54 (2C6H5 and C6H4), (C1 of propenyl), 150.75
(NvCH), 165.87 (2CvO), 189.15 and 193.84 (2CvO).
MS, m/z (%): 491 (Mþþ1, 14), 490 (Mþ, 37), 408 (24), 385
(18), 304 (16), 303 (59), 263 (100), 246 (60), 219 (19), 205
(9), 147 (10), 130 (16), 105 (100), 76 (11).
1.1.2. 2-{(Z)-1-Benzoyl-2-[(tert-butylimino)-methyl]-3-
oxo-3-phenyl-1-propenyl}-1H-isoindole-1,3 (2H)-dione
(3a). Pale yellow crystals, 0.17 g, yield 38%, mp 169–
1718C. IR (KBr) (nmax, cm21): 1771 and 1704 (CO–N–
CO), 1679 (CvO), 1651 (CvN), 1616 (CvC). Anal. calcd
for C29H24N2O4 (464.5): C, 74.99; H, 5.21; N, 6.03%.
Found: C, 74.6; H, 5.1; N, 6.0%. 1H NMR (500 MHz,
CDCl3): dH¼1.90 (9H, s, Me3C), 7.12 (s, NvCH), 7.35 (t,
3JHH¼7.5 Hz, 2CH arom), 7.44–7.53 (m, 4CH arom), 7.75
(d, 3JHH¼7.6 Hz, 2CH arom), 7.85 (m, 2CH arom), 7.98 (m,
2CH arom), 8.06 (d, 3JHH¼7.50 Hz, 2CH arom). 13C NMR
(125.7 MHz, CDCl3): dC¼29.29 (Me3C), 59.19 (CMe3),
124.44 (2CH arom), 127.59 (C2 of propenyl), 128.32,
128.60, 128.67, 128.94, 131.55, 132.73, 133.64, 135.16,
136.52, 136.67 (2C6H5 and C6H4), 138.22 (C1 of propenyl),
152.00 (CvN), 166.00 (2CvO), 189.30 and 194.05
(2CvO). MS, m/z (%): 464 (Mþ, 2), 333 (7), 318 (20),
278 (8), 277 (31), 230 (6), 148 (10), 147 (43), 129 (13), 105
(100), 83 (13), 76 (18), 75 (11).
1.1.5. [2-(tert-Butylamino)-4-(4-methyl-5-nitro-1H-imi-
dazol-1-yl)-5-phenyl-3-furyl]-phenyl) methanone (2c).
Yellow powder, 0.42 g, yield 95%, mp 163–1678C. IR
(KBr) (nmax, cm21): 3265 (N–H), 1618 (CvO), 1549
(CvN), 1490 and 1353 (NO2). Anal. calcd for C25H24N4O4
(444.5): C, 67.55; H, 5.44; N, 12.60%. Found: C, 67.5; H,
1
5.5; N, 12.7%. H NMR (500 MHz, CDCl3): dH¼1.62 (s,
3
Me3C), 2.17 (s, N–CH3), 6.98 (d, JHH¼8.1 Hz, 2CH
3
arom), 7.07 (d, JHH¼7.7 Hz, 2CH arom), 7.13 (t,
3JHH¼7.4 Hz, 2CH arom), 7.20 (s, NvCH–N), 7.21–7.30
(m, 4CH arom), 8.94 (s, N–H). 13C NMR (125.7 MHz,
CDCl3): dC¼10.70 (N–CH3), 29.70 (Me3C), 53.43 (CMe3),
97.21 and, 113.55 (2C of furan), 123.61 and, 125.44 (4CH of
C6H5), 127.07 (N–CvN), 127.93, 128.56, 129.35, 130.30,
131.46 (2C6H5), 134.77 (C2H of imidazole), 138.98 (C6H5),
139.03 and 144.77 (C4 and C5 of imidazole), 162.83 (N–C–
O), 188.42 (CvO). MS, m/z (%): 445 (Mþþ1, 4), 444 (Mþ,
18), 388 (34), 353 (11), 337 (23), 328 (13), 283 (53), 204
(33), 183 (25), 128 (13), 106 (6), 105 (100), 76 (49), 54 (5).
1.1.3. 2-[4-Benzoyl-5-(cyclohexylamino)-2-phenyl-3-
furyl]-1H-isoindole-1,3-(2H)-dione (2b). Yellow powder,
0.29 g, yield 60%, mp 238–2438C. IR (KBr) (nmax, cm21):
3340 (N–H), 1770 and 1710 (CO–N–CO), 1632 (CvO).
Anal. calcd for C31H26N2O4 (490.5): C, 75.90; H, 5.34; N,
5.71%. Found: C, 75.9; H, 5.3; N, 5.7%. 1H NMR
(500 MHz, CDCl3): dH¼1.46–2.14 (m, 5CH2 of cyclo-
hexyl), 3.91 (1H, m, CH of cyclohexyl), 6.73 (t,
1.1.6. 2-[4-Benzoyl-5-(tert-butylamino)-2-phenyl-3-
furyl]-1H-1,2-benzisothiazole-1,1,3 (2H)-trione (2d).
Yellow needles, 0.47 g, yield 95%, mp 273–2758C. IR
(KBr) (nmax, cm21): 3235 (N–H), 1738 (CvO), 1621
(CvO), 1365 and 1184 (SO2). Anal. calcd for
C28H24N2O5S (500.6): C, 67.18; H, 4.83; N, 5.60%.
Found: C, 67.2; H, 4.9; N, 5.6%. 1H NMR (500 MHz,
CDCl3): dH¼1.58 (9H, s, CMe3), 6.90 (t, 3JHH¼6.2 Hz, CH
3
3JHH¼7.1 Hz, CH arom), 6.89 (t, JHH¼7.3 Hz, 2CH
3
3
arom), 7.19–7.28 (m, 5CH arom), 7.38 (d, JHH¼7.3 Hz,
arom), 7.00 (t, JHH¼6.1 Hz, 2CH arom), 7.23 (t,
3
3
2CH arom), 7.65 (s, 4CH arom), 8.46 (d, JHH¼6.7 Hz
3JHH¼5.8 Hz, CH arom), 7.29 (t, JHH¼6.4 Hz, 2CH
N–H). 13C NMR (125.7 MHz, CDCl3): dC¼24.52 (2CH2),
25.40 (CH2), 33.30 (2CH2), 51.12 (N–CH), 96.79 and
111.06 (2C of furan), 123.39, 124.45, 126.05, 127.58,
127.72, 128.49, 128.60, 128.71, 131.72, 134.01, 140.21
(2C6H5 and C6H4), 140.54 (C–O), 162.53 (N–C–O),
166.72 (2CvO), 188.73 (CvO). MS, m/z (%): 491
(Mþþ1, 15), 490 (Mþ, 45), 489 (2), 409 (16), 408 (39),
407 (25), 357 (11), 303 (14), 200 (14), 172 (10), 148 (21),
129 (15), 106 (23), 105 (100), 82 (16), 76 (79), 52 (26).
arom), 7.40 (d, JHH¼6.4 Hz, 2CH arom), 7.56 (d,
3
3JHH¼6.7 Hz, 2CH arom), 7.66 (s, CH arom), 7.76 (s,
2CH arom), 7.98 (s, CH arom), 8.68 (s, N–H). 13C NMR
(125.7 MHz, CDCl3): dC¼29.83 (Me3C), 53.01 (CMe3),
97.54 and 106.54 (C4 and C3 of furan), 120.92, 125.02,
125.32, 126.74, 127.20, 127.32, 127.94, 128.40, 128.73,
129.41, 134.04, 134.89, 137.61 (2C6H5 and C6H4), 140.41
(C–O), 143.27 (C6H4), 158.70 (N–C–O), 163.02 (CvO),
189.33 (CvO). MS, m/z (%): 500 (Mþ, 7), 445 (6), 444
(24), 443 (21), 276 (4), 275 (18), 247 (2), 197 (3), 169 (4),
106 (6), 105 (100), 76 (20), 54 (6).
1.1.4. 2-{(Z)-1-Benzoyl-2-[(cyclohexylimino)methyl]-3-
oxo-3-phenyl-1-propenyl}-1H-isoindole-1,3-(2H)dione
(3b). Pale yellow crystals, 0.17 g, yield 35%, mp 157–
1598C. IR (KBr) (nmax, cm21): 1770 and 1705 (OC–N–
CO), 1681 (CvO), 1654 (CvO), 1600 (CvC), 1588
(CvN). Anal. calcd for C31H26N2O4 (490.5): C, 75.90; H,
5.34; N, 5.71%. Found: C, 75.6; H, 5.4; N, 5.7%. 1H NMR
(500 MHz, CDCl3): dH¼1.10–1.33 (m, 5CH2), 3.26 (m,
1.1.7. 2-[4-Benzoyl-5-(cyclohexylamino)-2-phenyl-3-
furyl]-1H-1,2-benzisothiazole-1,1,3 (2H)-trione (2e).
Orange powder, 0.47 g, yield 90%, mp 237–2408C. IR
(KBr) (nmax, cm21): 3285 (N–H), 1731 (N–CvO), 1633
(CvO), 1333 and 1185 (SO2). Anal. calcd for
C30H26N2O5S (526.6): C, 68.42; H, 4.98; N, 5.32%.
Found: C, 68.5; H, 5.1; N, 5.3%. 1H NMR (500 MHz,
CDCl3): dH¼1.1–2.16 (5CH2 of cyclohexyl), 3.90 (m,
3
N–CH), 7.22 (s, NvCH), 7.37 (t, JHH¼7.4 Hz, 2CH
3
arom), 7.45 (t, JHH¼7.4 Hz, 2CH arom), 7.50 (t,
3
3
3JHH¼8.2 Hz, CH arom), 7.52 (t, JHH¼8.2 Hz, CH
N–CH), 6.92 (t, JHH¼7.3 Hz, CH arom), 7.00 (t,
3
3
arom), 7.78 (d, JHH¼7.7 Hz, 2CH arom), 7.86 (m, 2CH
3JHH¼7.5 Hz, 2CH arom), 7.24 (t, JHH¼6.8 Hz, CH
3
3
arom), 7.98 (m, 2CH arom), 8.08 (d, JHH¼7.5 Hz, 2CH
arom), 7.30 (t, JHH¼7.5 Hz, 2CH arom), 7.42 (t,
arom). 13C NMR (125.7 MHz, CDCl3): dC¼23.28, 25.38
3JHH¼7.6 Hz, 2CH arom), 7.56 (d, JHH¼7.9 Hz, 2CH
3

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I. Yavari et al. / Tetrahedron 59 (2003) 6083–6086
3. Katritzky, A. R.; Strah, S.; Belyakor, S. A. Tetrahedron 1998,
54, 7167.
arom), 7.68 (m, CH arom), 7.78 (m, 2CH arom), 7.99 (m,
CH arom), 8.34 (s, N–H). 13C NMR (125.7 MHz, CDCl3):
dC¼24.47 (CH2), 25.39 (2CH2), 33.27 (CH2), 33.31 (CH2),
51.12 (CH), 96.87 and 106.76 (C4 and C3 of furan), 120.94,
125.18, 125.32, 126.79, 127.23, 127.28, 127.93, 128.43,
128.64, 129.40, 134.01, 134.84, 137.65 (2C6H5 and C6H4),
140.45 (C–O), 143.05 (C6H4), 158.73 (N–C–O), 162.00
(CvO), 189.22 (CvO). MS, m/z (%): 527 (Mþþ1, 7), 526
(Mþ, 17), 525 (Mþ21, 2), 444 (7), 443 (7), 370 (12), 289
(11), 288 (45), 287 (53), 275 (32), 106 (18), 105 (100), 82
(27), 76 (61), 52 (54).
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