Synthesis and dynamic NMR study of functionalized 1-(3-furyl)-1H-indole-2, 3-diones

Article abstract of DOI:10.1007/s00706-006-0576-z

Protonation of the highly reactive 1:1 intermediates produced in the reaction between alkyl(aryl) isocyanides and dibenzoylacetylene by isatin, leads to vinylnitrilium cations, which undergo carbon-centered Michael-type addition with the conjugate base of

Full text of DOI:10.1007/s00706-006-0576-z

Monatshefte fu¨r Chemie 138, 107–110 (2007)
DOI 10.1007/s00706-006-0576-z
Printed in The Netherlands
Synthesis and Dynamic NMR Study of Functionalized
1-(3-Furyl)-1H-indole-2,3-diones
ꢀ
Issa Yavari , Zinatossadat Hossaini, and Maryam Sabbaghan
Department of Chemistry, Tarbiat Modarres University, Tehran, Iran
Received June 19, 2006; accepted (revised) July 11, 2006; published online January 22, 2007
# Springer-Verlag 2007
Summary. Protonation of the highly reactive 1:1 intermedi-
ates produced in the reaction between alkyl(aryl) isocyanides
Results and Discussion
The reaction proceeded spontaneously at room tem-
and dibenzoylacetylene by isatin, leads to vinylnitrilium cat-
ions, which undergo carbon-centered Michael-type addition
with the conjugate base of the NH-acid to produce highly
functionalized 1-(3-furyl)-1H-indole-2,3-diones. A dynamic
NMR effect is observed in the 1H NMR spectra of these com-
pounds as a result of restricted rotation around the single bond
linking the indole moiety and the furan system. The free-energy
perature and produced 2 in excellent yield (Scheme 1).
The nature of these compounds as 1:1:1 adducts was
apparent from their mass spectra, which displayed,
in each case, the molecular ion peak at appropriate
m=z values. The 1H and 13C NMR spectroscopic data,
as well as IR spectra, are in agreement with the pro-
posed structures.
of activation (ꢀG#) for this process is 69–71 ꢁ 2 kJmolꢂ1
.
Keywords. Dibenzoylacetylene; Isatin; Alkyl(aryl) isocya-
nides; Dynamic NMR.
On the basis of the well-established chemistry of
isocyanides [3–6], it is reasonable to assume that
compound 3 results from nucleophilic addition of 1
to DBA and subsequent protonation of the 1:1 adduct
by isatin. Then, the positively charged ion 3 is at-
tacked by the anion of the NH-acid 4 to produce the
keteneimine 5, which cyclizes, under the reaction con-
dition employed, to produce 2 (Scheme 2).
Introduction
Polyfunctionalized furans play an important role in
organic chemistry not only due to their presence as
key structural units in many natural products [1] and
in important pharmaceuticals [2], but they can also be
employed in synthetic chemistry as building blocks.
For this reason, the synthesis of polysubstituted fu-
rans continues to attract the interest of many synthetic
chemists. We now report an efficient synthetic route to
polyfunctionalized furans using dibenzoylacetylene
(DBA) and alkyl(aryl) isocyanides in the presence of
isatin. Thus, the reaction between isocyanides 1 and
DBA in the presence of isatin at ambient temperature
in dry diethyl ether leads to 1-(3-furyl)-1H-indole-
2,3-diones 2.
1
The H NMR spectrum of 2a in CDCl3 showed
a singlet at ꢀ ¼ 0.79 ppm for the tert-butyl group.
Because of restricted rotation around the Ar–N bond
in these molecules, the CH2 protons and the two
methyl groups of the CMe2 moiety are diastereotopic.
Thus, the CMe2 group exhibits two sharp singlets at
ꢀ ¼ 1.18 and 1.21ppm while the methylene protons ap-
pear as an AB system at ꢀ ¼ 1.49ppm (JAB ¼ 15.0 Hz).
1
The H and 13C NMR spectra of 2b–2d are similar
to those for 2a except for the alkylamino moieties.
The methylene protons of the benzyl group in 2b are
diasterotopic and exhibit an ABX (JAB ¼ 14.2 Hz,
JAX ¼ JBX ¼ 6.2 Hz, ꢀA ¼ 4.52 ppm, ꢀB ¼ 4.56 ppm)
system.
ꢀ
Corresponding author. E-mail: yavarisa@modares.ac.ir

108
I. Yavari et al.
Scheme 1
Scheme 2
pffiffiffi
Compounds 2a–2c exhibit atropisomerism at am-
protons and using the expression k ¼ ꢁꢀꢂ= 2 [7],
the first-order rate constant (k) was calculated (see
Table 1).
bient temperature because of hindered rotation around
the carbon–nitrogen bond linking the isatin moiety
and the furan ring system.
This becomes evident from the 1H NMR spectrum
of 2a in CDCl3 solution. At 20ꢃC several sharp sig-
nals are present which become broad near 50ꢃC (see
Fig. 1). Increasing the temperature leads to coalesce-
nce of the methyl and methine signals.
Although an extensive lineshape analysis in rela-
tion to the dynamic NMR effect observed for 2a was
not undertaken in the present work, the variable tem-
perature spectra are sufficient to calculate the free-
energy barrier of activation for the restricted C–N
bond rotation. From the coalescence of the methyl
Application of the absolute rate theory with a
transmission coefficient of 1 gives a free energy of
activation (ꢀG#) of 71 ꢁ 2 kJ molꢂ1 for 2a, where all
known sources of errors are estimated and included
[8]. Similar dynamic NMR effects were observed for
the methylene protons of compounds 2b and 2c.
Also 2d will exhibit atropisomerism, it is just not
visible in NMR.
In conclusion, the presented one-pot reaction leads
to highly functionalized 1-(3-furyl)-1H-indole-2,3-
diones. A dynamic NMR effect is observed in the
1H NMR spectra of these compounds as a result of

Functionalized 1-(3-Furyl)-1H-indole-2,3-diones
109
General Procedure for the Preparation of 1H-Indole-
2,3-diones 2
To a magnetically stirred solution of 0.48g DBA (2mmol) and
0.30g isatin (2mmol) in 10cm3 CH2Cl2 were added 2 mmol
of the alkyl(aryl) isocyanide at room temperature. The re-
action mixture was then stirred for 30 h. The solvent was
removed under reduced pressure and the viscous residue
was purified by column chromatography on silica gel (Merck
230–400 mesh) using n-hexane: EtOAc (3:1) as eluent to give
the product.
1-[4-Benzoyl-2-phenyl-5-[(1,1,3,3-tetramethylbutyl)amino]-
3-furyl]-1H-indole-2,3-dione (2a, C33H32N2O4)
Orange powder, mp 166–168ꢃC; yield 0.96g, 92%. IR (KBr):
ꢂꢁ¼ 3465, 1733, 1678, 1653, 1596cmꢂ1; 1H NMR (500 MHz,
CDCl3): ꢀ ¼ 0.79 (s, CMe3), 1.18 (s, CH3), 1.21 (s, CH3), 1.49
(dd, JAB ¼ 15.0Hz, CH2), 6.65 (d, J ¼ 7.2Hz, CH), 7.05 (t,
J ¼ 7.3Hz, 2CH), 7.08 (d, J ¼ 7.1 Hz, CH), 7.16 (t, J ¼ 7.9 Hz,
2CHmeta of C6H5), 7.26 (s, N–H), 7.35 (t, J ¼ 7.4 Hz, 2CHmeta
of C6H5), 7.45 (t, J ¼ 7.2 Hz, CHpara of C6H5), 7.51 (t,
J ¼ 7.2 Hz, CHpara of C6H5), 7.64 (d, J ¼ 7.3 Hz, 2CHortho of
C6H5), 7.87 (d, J ¼ 7.5Hz, 2CHortho of C6H5) ppm; 13C NMR
(125.7MHz, CDCl3): ꢀ ¼ 29.7 (CH3), 30.1 (C), 31.6 (3CH3),
31.9 (CH3), 55.0 (CH2), 63.0 (C–N), 93.4 and 110.8 (2C
of furan), 122.9 (2CH of C6H4), 123.3, 124.5, 126.5, 127.7,
128.5, 128.9, 129.5, 131.2, 137.6, 141.4 (2C6H5 and C6H4),
150.6 (C–O), 159.9 (N–C–O), 164.0 (C¼O), 180.2 and
185.9 (2C¼O) ppm; MS (EI, 70 eV): m=z (%) ¼ 520 (Mþ,
10), 262 (25), 184 (15), 146 (10), 105 (100), 77 (45), 57
(100), 41 (42).
1
Fig. 1. Variable temperature 500 MHz H NMR spectra of
2a in CDCl3
restricted rotation around the single bond linking the
indole moiety and the furan system.
1-[4-Benzoyl-5-(benzylamino)-2-phenyl-3-furyl]-
1H-indole-2,3-dione (2b, C32H22N2O4)
Yellow powder, mp 180–182ꢃC; yield 0.84 g, 84%; IR (KBr):
ꢂꢁ¼ 3335, 1730, 1663, 1595 cmꢂ1
;
1H NMR (500 MHz,
Experimental
CDCl3): ꢀ ¼ 4.54 (ABX, JAB ¼ 14.2Hz, JAX ¼ JBX ¼ 6.2 Hz,
ꢀA ¼ 4.52, ꢀB ¼ 4.56), 6.93 (d, J ¼ 7.1Hz, CH), 7.13 (t,
J ¼ 7.2Hz, 2CH), 7.16 (d, J ¼ 7.3 Hz, CH), 7.19 (t, J ¼ 7.7 Hz,
2CHmeta of C6H5), 7.25 (t, J ¼ 7.8 Hz, 3CHmeta), 7.31 (t,
J ¼ 7.2Hz, 2CHortho), 7.41 (t, J ¼ 7.7 Hz, 2CHpara of C6H5),
7.45 (t, J ¼ 7.4 Hz, CHpara), 7.53 (d, J ¼ 7.4 Hz, 2CHortho of
C6H5), 7.64 (d, J ¼ 7.2Hz, 2CHortho of C6H5), 8.19 (s, N–H)
ppm; 13C NMR (125.7MHz, CDCl3): ꢀ ¼ 44.3 (CH2–N), 94.3
and 110.6 (2C of furan), 122.5 (2CH of C6H4), 124.3, 125.5,
126.5, 127.6, 128.5, 128.9, 129.0, 132.7, 134.1, 135.8, 136.3,
137.0 (3C6H5 and C6H4), 146.9 (C–O), 152.1 (N–C–O), 161.8
(C¼O), 188.8 and 197.2 (2C¼O) ppm; MS (EI, 70eV):
DBA was prepared according to Refs. [9, 10]. Other chemicals
were purchased from Fluka and used without further purifica-
tion. Melting points were measured on an Electrothermal 9100
aparatus. Elemental analyses for C, H, and N were performed
using a Heraeus CHN-O-Rapid analyzer. The results agreed
favorably with the calculated values. Mass spectra were re-
corded on a FINNIGAN-MAT 8430 spectrometer operating at
an ionization potential of 70 eV. 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 125.8 MHz.
1
Table 1. Selected H chemical shifts (500 MHz) and activation parameters of 2a–2c in CDCl3
ꢀMe
ꢀMe
ꢀ
ꢀ
CHb
CHa
ꢀG#
kJ molꢂ1
Tc=K
ꢀꢂ=Hz
kc=sꢂ1
ppm
ppm
ppm
ppm
328
333
323
325
1.18
1.21
15
15
20
25
33
33
45
56
2a
1.46
4.52
4.47
1.49
4.56
4.52
71 ꢁ 2
69 ꢁ 2
69 ꢁ 2
2b
2c

110
I. Yavari et al.: Functionalized 1-(3-Furyl)-1H-indole-2,3-diones
m=z (%) ¼ 498 (Mþ, 5), 146 (25), 106 (65), 105(100), 91 (34),
References
77 (85), 57 (45).
[1] Lipshutz BH (1986) Chem Rev 86: 795
[2] Nakanishi K (1974) Natural Products Chemistry;
Kodansha: Tokyo
[3] Ugi I (1982) Angew Chem Int Ed Engl 21: 810
[4] Walborsky HM, Periasamy MP, The Chemistry of Func-
tional Groups; Patai S, Rappoport Z (1983) Eds Wiley:
New York,; Suppl. C, p 835 Chapter 20
Ethyl 2-[[3-benzoyl-4-(2,3-dioxo-2,3-dihydro-1H-indol-
1-yl)-5-phenyl-2-furyl]amino]acetate (2c, C29H22N2O6)
Pale yellow powder, mp 159–161ꢃC; yield 0.84 g, 85%; IR
(KBr): ꢂꢁ¼ 3410, 1729, 1685, 1624 cmꢂ1. 1H NMR (500MHz,
CDCl3): ꢀ ¼ 1.32 (t, J ¼ 7.2 Hz, CH3), 4.29 (q, J ¼ 7.1 Hz,
OCH2), 4.49 (ABX, JAB ¼ 13.0Hz, JAX ¼ JBX ¼ 6.5 Hz,
ꢀA ¼ 4.47, ꢀB ¼ 4.52), 6.96 (d, J ¼ 7.1 Hz, CH), 7.01 (t,
J ¼ 7.2 Hz, 2CH), 7.04 (d, J ¼ 7.3 Hz, CH), 7.12 (t, J ¼ 7.5 Hz,
2CHmeta of C6H5), 7.31 (t, J ¼ 7.8Hz, 2CHmeta of C6H5), 7.50
(t, J ¼ 7.3 Hz, CHpara of C6H5), 7.53 (t, J ¼ 7.3 Hz, CHpara of
C6H5), 7.60 (d, J ¼ 7.5 Hz, 2CHortho of C6H5), 7.63 (d,
J ¼ 7.6 Hz, 2CHortho of C6H5), 8.79 (t, J ¼ 5.6 Hz,
NH. . .O¼C) ppm; 13C NMR (125.7MHz, CDCl3): ꢀ ¼ 14.2
(Me), 44.2 (CH2–N), 62.0 (OCH2), 94.2 and 111.6 (2C of
furan), 123.4 (2CH of C6H4), 124.3, 125.5, 126.5, 127.8,
128.3, 128.5, 129.0, 131.4, 138.6, 140.2 (C6H5 and C6H4),
150.1 (C–O), 158.1 (N–C–O), 164.9 and 168.6 (2C¼O),
181.5 and 189.1 (2C¼O) ppm; MS (EI, 70 eV): m=z
(%) ¼ 494 (Mþ, 4), 449 (38), 405 (62), 391 (54), 376 (21),
303 (18), 232 (28), 197 (8), 146 (68), 105(100), 76 (30), 57 (70).
[5] Marcaccini S, Torroba T (1993) Org Prep Proced Int 25:
141
[6] (a) Yavari I, Hazeri N, Maghsoodlou MT, Moradi AJ
(2001) Chem Res (S) 272; (b) Yavari I, Adib M, Sayahi
MH (2002) J Chem Soc, Perkin Trans 1 2343;
(c) Yavari I, Anari-Abbasinejadand M, Alizadeh A
(2002) Monatsh Chem l33: 1221; (d) Yavari I, Alizadeh
A, Anary-Abbasinejad M, Bijanzadeh HR (2003) Tetra-
hedron 59: 6083; (e) Yavari I, Djahaniani H, Nasiri F
(2003) Tetrahedron 59: 9409; (f) Maghsoodlou MT,
Yavari I, Nasiri F, Djahaniani H, Razmjoo Z (2003)
Monatsh Chem 134: 1585; (g) Yavari I, Habibi A,
Hosseini-Tabatabaei MR (2003) Monatsh Chem 134:
1651; (h) Yavari I, Djahaniani H, Nasiri F (2004) Synthe-
sis 679; (i) Yavari I, Habibi A (2004) Synthesis 989;
(j) Yavari I, Djahaniani H, Nassiri F (2004) Coll Czech
Chem Commun 69: 1499; (k) Mosslemin MH, Yavari I,
Anary-Abbasinejad M, Nateghi MR (2004) J Fluorine
Chem 125: 1497; (l) Yavari I, Nasiri F, Djahaniani H
(2004) Molecular Diversity 8: 431; (m) Yavari I, Moradi
L, Nasiri F, Djahaniani H (2005) Mendeleev Commun
15: 156; (n) Yavari I, Djahaniani H, Moradi L (2004)
Mendeleev Commun 14: 38; (o) Yavari I, Djahaniani H,
Nasiri F (2004) Mendeleev Commun 14: 214
[7] Gu
1-[4-Benzoyl-5-(tert-butylamino)-2-phenyl-3-furyl]-
1H-indole-2,3-dione (2d, C29H24N2O4)
Orange powder, mp 174–176ꢃC; yield 0.78 g, 84%; IR (KBr):
ꢂꢁ¼ 3380, 1732, 1680, 1606cmꢂ1
;
1H NMR (500MHz,
CDCl3): ꢀ ¼ 1.64 (s, 9H, CMe3), 6.66 (d, J ¼ 7.3 Hz, CH),
7.01 (t, J ¼ 7.4 Hz, 2CH), 7.04 (d, J ¼ 7.4 Hz, CH), 7.14 (t,
J ¼ 7.7 Hz, 2CHmeta of C6H5), 7.25 (t, J ¼ 7.8 Hz, 2CHmeta of
C6H5), 7.41 (t, J ¼ 7.2 Hz, CHpara of C6H5), 7.47 (t,
J ¼ 7.3 Hz, CHpara of C6H5), 7.54 (d, J ¼ 7.5 Hz, 2CHortho of
C6H5), 7.63 (d, J ¼ 7.6 Hz, 2CHortho of C6H5), 8.79 (s, N–H)
ppm; 13C NMR (125.7 MHz, CDCl3): ꢀ ¼ 29.8 (CMe3), 53.3
(CMe3), 95.4 and 111.8 (2C of furan), 123.9 (2CH of C6H4),
124.3, 125.5, 126.5, 127.7, 128.0, 128.1, 129.0, 130.2, 138.6,
140.0 (C6H5 and C6H4), 150.6 (C–O), 157.9 (N–C–O), 163.0
(C¼O), 181.2 and 188.9 (2C¼O) ppm; MS (EI, 70 eV): m=z
(%) ¼ 464 (Mþ, 10), 409 (25), 408 (53), 407 (35), 303 (10),
260 (25), 232 (15), 197 (10), 105 (100), 76 (15), 57 (10).
¨nther H (1995) NMR Spectroscopy, 2nd ed, Wiley,
New York, Chapter 9
[8] Anet FAL, Anet R (1975) In: Cotton FA, Jackman LM
(eds) Dynamic Nuclear Magnetic Resonance Spectros-
copy. Academic Press, New York, p 543
[9] Skattebol L, Jones ERH, Whiting MC (1963) Org Synth
Coll Vol 4: 792
[10] Bowden K, Heilbron IM, Jones ERH, Weedon BC
(1946) J Chem Soc 39