Synthesis of functionalized 5H-spiro[furan-2,2'-indene]-1',3',5-triones from primary amines, acetylenic esters and ninhydrin

Article abstract of DOI:10.1007/s13738-011-0061-4

An effective route to functionalized 5H-spiro[ furan-2,2'-indene]-1',3',5- triones is described via tandem reaction of primary amines, acetylenic esters and ninhydrin. Iranian Chemical Society 2012.

Full text of DOI:10.1007/s13738-011-0061-4

J IRAN CHEM SOC (2012) 9:503–506
DOI 10.1007/s13738-011-0061-4
ORIGINAL PAPER
Synthesis of functionalized 5H-spiro[furan-2,20-indene]-10,30,5-
triones from primary amines, acetylenic esters and ninhydrin
•
Issa Yavari Samira Arab-Salmanabadi
•
Ali Aminkhani
Received: 19 August 2011 / Accepted: 2 December 2011 / Published online: 13 January 2012
Ó Iranian Chemical Society 2012
Abstract An effective route to functionalized 5H-spir-
o[furan-2,20-indene]-10,30,5-triones is described via tandem
reaction of primary amines, acetylenic esters and ninhydrin.
purification. Melting points were obtained uncorrected
using an Electrothermal-9100 apparatus. IR spectra were
recorded with a Shimadzu IR-460 spectrometer. 1H and 13
C
NMR spectra were recorded with a Bruker DRX-300
Avance instrument using CDCl3 as the deuterated solvent
containing tetramethylsilane as internal standard, at 300
and 75 MHz, respectively; d in parts per million, J in hertz.
EI-MS (70 eV) mass spectra were obtained with a Finnigan-
MAT-8430 mass spectrometer in m/z. Elemental analyses
(C, H, N) were obtained with a Heraeus CHN-O-Rapid
analyzer.
Keywords Spiro compound ꢀ Primary amine ꢀ Acetylenic
ester ꢀ Ninhydrin ꢀ Tandem reaction
Introduction
Spiro compounds having cyclic structures fused at a central
carbon are of interest due to their interesting conformational
features and their structural implications on biological sys-
tems [1]. The asymmetric characteristic of the molecule due
to the chiral spiro carbon is one of the important criteria of the
biological activities. The presence of the sterically con-
strained spiro structure in various natural products also adds
to the interest in the investigations of spiro compounds [2–5].
We recently reported the formation of novel spiro
compounds via the reaction of indane-1,3-dione with
Huisgen’s zwitterions formed in situ from N-heterocycles
and activated acetylenes via cyclization [5, 6].
General procedure for the preparation of compound 4
To a stirred solution of amine 1 (2 mmol) and the acety-
lenic ester 2 (2 mmol) in toluene (10 mL), was added
ninhydrin (3, 0.32 g, 2 mmol) at rt, then refluxed for 5–8 h.
After completion of the reaction [TLC (AcOEt/hexane 1:4)
monitoring], the solvent was removed under reduced
pressure, and the residue was purified by column chroma-
tography [silica gel (230–400 mesh; Merck), hexane/
AcOEt 5:1: pure product].
Methyl 4-(ethylamino)-10,5-dioxo-10,30-dihydro-5H-
Experimental
spiro[furan-2,20-indene]-3-carboxylate (4a)
Chemicals and apparatus
Yellow oil, yield: 0.24 g (76%). IR (KBr): 3,352 (N–H),
1,784, 1,723, 1,689, 1,645 (C=O) cm-1. EI-MS: m/z
(%) = 315 (M?, 6), 227 (16), 171 (14), 105 (100), 59 (91),
58 (11), 44 (66), 29 (34). Anal. Calcd. for C16H13NO6
(315.28): C, 60.95; H, 4.16; N, 4.44%. Found: C, 61.31; H,
Amines 1, acetylenic esters 2, and ninhydrin (3) were
obtained from Merck and were used without further
1
3
4.11; N, 4.38%. H NMR: d = 1.30 (3H, t, J = 7.2 Hz,
Me), 3.44 (3H, s, MeO), 3.86 (2H, q, 3J = 7.2 Hz, CH2N),
6.78 (1 H, br s, NH), 7.97–8.11 (4H, m, 4CH). 13C NMR:
d = 16.6 (Me), 29.6 (CH2N), 51.9 (MeO), 109.4 (C), 120.3
I. Yavari (&) ꢀ S. Arab-Salmanabadi ꢀ A. Aminkhani
Department of Chemistry Science and Research Branch,
Islamic Azad University, Tehran, Iran
e-mail: yavarisa@modares.ac.ir
123

504
J IRAN CHEM SOC (2012) 9:503–506
Methyl 4-(cyclohexylamino)-10,30,5-trioxo-10,30-dihydro-
5H-spiro[furan-2,20-indene]-3-carboxylate (4e)
(C), 124.6 (2CH), 137.3 (2CH), 141.5 (2C), 148.7 (C),
166.7 (C=O), 170.3 (C=O), 194.0 (2C=O).
Ethyl 4-(ethylamino)-10,30,5-trioxo-10,30-dihydro-5H-
Yellow oil, yield: 0.28 g (75%). IR (KBr): 3,350 (N–H),
1,781, 1,721, 1,695, 1,647 (C=O) cm-1. EI-MS: m/z
(%) = 369 (M?, 9), 227 (17), 225 (32), 105 (100), 98 (80),
83 (46), 73 (88). Anal. Calcd. for C20H19NO6 (369.37): C,
65.03; H, 5.18; N, 3.79%. Found: C, 65.42; H, 5.13; N,
spiro[furan-2,20-indene]-3-carboxylate (4b)
Yellow oil, yield: 0.24 g (72%). IR (KBr): 3,355 (N–H),
1,783, 1,720, 1,692, 1,649 (C=O) cm-1. EI-MS: m/z
(%) = 329 (M?, 11), 227 (17), 185 (14), 105 (100), 58
(11), 44 (70), 73 (91), 29 (46). Anal. Calcd. for C17H15NO6
(329.30): C, 62.00; H, 4.59; N, 4.25%. Found: C, 61.75; H,
1
3.73%. H NMR: d = 1.37–2.19 (10 m, 5CH2), 3.43 (3H,
s, MeO), 4.43 (1H, m, CHN), 6.77 (1 H, br s, N–H),
7.96–8.11 (4H, m, 4CH). 13C NMR: d = 24.9 (CH2), 25.6
(CH2), 29.6 (CH2), 34.9 (CH2), 51.8 (MeO), 54.7(CHN),
109.5 (C), 120.6 (C), 124.6 (2CH), 137.2 (2CH), 141.4
(2C), 148.7 (C), 166.7 (C=O), 170.1 (C=O), 194.0 (2C=O).
1
3
4.51; N, 4.20%. H NMR: d = 0.89 (3H, t, J = 7.2 Hz,
Me), 1.29 (3H, t, 3J = 6.8, Me), 3.86 (2H, q, 3J = 7.2 Hz,
3
CH2N), 4.20 (2H, q, J = 6.8 Hz, CH2O), 6.78 (1 H, br s,
N–H), 7.96–8.10 (4H, m, 4CH). 13C NMR: d = 14.2 (Me),
16.4 (Me), 29.5 (CH2N), 61.0 (CH2O), 109.1 (C), 120.1
(C), 124.5 (2CH), 137.2 (2CH), 141.3 (2C), 148.4 (C),
166.5 (C=O), 170.1 (C=O), 194.2 (2C=O).
Ethyl 4-(cyclohexylamino)-10,30,5-trioxo-10,30-dihydro-5H-
spiro[furan-2,20-indene]-3-carboxylate (4f)
Yellow oil, yield: 0.27 g (70%). IR (KBr): 3,346 (N–H),
1,785, 1,720, 1,691, 1,645 (C=O) cm-1. EI-MS: m/z
(%) = 383 (M?, 8),239 (16), 227 (18), 112 (11), 105 (100),
104 (22), 98 (87), 83 (46), 73 (88). Anal. Calcd. for
C21H21NO6 (383.39): C, 65.79; H, 5.52; N, 3.65%. Found:
Methy 4-(butylamino)-10,30,5-trioxo-10,30-dihydro-5H-
spiro[furan-2,20-indene]-3-carboxylate (4c)
Yellow oil, yield: 0.29 g (85%). IR (KBr): 3,356 (N–H),
1,785, 1,725, 1,691, 1,646 (C=O) cm-1. EI-MS: m/z
(%) = 343 (M?, 11), 227 (13), 199 (8), 105 (90), 104 (7),
86 (19), 72 (100), 59 (98), 57 (17).Anal. Calcd. for
C18H17NO6 (343.33): C, 62.97; H, 4.99; N, 4.08%. Found:
1
C, 65.51; H, 5.45; N, 3.60%. H NMR: d = 1.27 (3H, t,
3J = 6.8 Hz, Me), 1.36-2.35 (10H, m, 5CH2), 4.20 (2H, q,
3J = 6.8 Hz, CH2O), 4.43 (1H, m, CHN), 6.78 (1 H, br s,
N–H), 7.34–8.20 (4H, m, 4CH).13C NMR: d = 14.2 (Me),
24.5 (CH2), 25.4 (CH2), 29.7 (CH2), 34.8 (CH2),
61.7(CH2O), 54.8 (CHN), 109.4 (C), 120.6 (C), 124.4
(2CH), 137.3 (2CH), 141.2 (2C), 148.6 (C), 166.8 (C=O),
170.3 (C=O), 194.2 (2C=O).
1
C, 62.61; H, 4.92; N, 4.01%. H NMR: d = 0.98 (3H, t,
3J = 7.2 Hz, Me), 1.44 (2H, m, CH2), 1.64 (2H, m, CH2),
3
3.43 (3H, s, MeO), 3.83 (2H, t, J = 7.2 Hz, CH2N), 6.78
(1 H, br s, N–H), 7.96–8.11 (4H, m, 4CH). 13C NMR:
d = 14.1 (Me), 14.5 (CH2), 33.3 (CH2), 42.8 (CH2N), 51.9
(MeO), 109.2 (C), 120.2 (C), 124.6 (2CH), 137.3 (2CH),
141.5 (2C), 148.7 (C), 163.7 (C=O), 170.3 (C=O), 194.1
(2C=O).
Methyl 4-(benzylamino)-10,30,5-trioxo-10,30-dihydro-5H-
spiro[furan-2,20-indene]-3-carboxylate (4g)
Yellow oil, yield: 0.30 g (80%). IR (KBr): 3,351 (N–H),
1,786, 1,724, 1,690, 1,648 (C=O) cm-1. EI-MS: m/z
(%) = 337 (M?, 12), 233 (31), 227 (21), 120 (13), 105
(100), 104 (65), 91 (71), 59 (88). Anal. Calcd. for
C21H15NO6 (377.35): C, 66.84; H, 4.01; N, 3.71%. Found:
C, 66.51; H, 3.96; N, 3.65%.1H NMR: d = 3.43 (3H, s,
MeO), 5.04 (2H, d, 3J = 6.2 Hz, CH2N), 6.75 (1H, br s, N–
H), 7.34–8.12 (9H, m, 9CH).13C NMR: d = 48.6 (CH2N),
52.0 (MeO), 109.7 (C), 120.9 (C), 124.7 (2CH), 128.1
(2CH), 128.3 (CH), 129.3 (2CH), 137.3 (2CH), 138.0 (C),
141.5 (2C), 148.7 (C), 166.7 (C=O), 170.2 (C=O), 193.8
(2C=O).
Ethyl 4-(butylamino)-10,30,5-trioxo-10,30-dihydro-5H-
spiro[furan-2,20-indene]-3-carboxylate (4d)
Yellow oil, yield: 0.28 g (78%). IR (KBr): 3354 (N–H),
1,786, 1,725, 1,689, 1,647 (C=O) cm-1. EI-MS: m/z
(%) = 357 (M?, 9), 227 (25), 213 (11), 105 (96), 104 (20),
86 (24), 73 (92), 72 (100), 57 (22).Anal. Calcd. for
C19H19NO6 (357.36): C, 63.86; H, 5.36; N, 3.92%. Found:
1
C, 63.55; H, 5.30; N, 3.86%. H NMR: d = 0.97 (3H, t,
3J = 7.2 Hz, Me), 1.29 (3H, t, 3J = 6.9 Hz, Me), 1.43 (2H,
3
m, CH2), 1.63 (2H, m, CH2), 3.89 (2H, t, J = 7.2 Hz,
3
CH2N), 4.20 (2H, q, J = 6.9 Hz, CH2O), 6.77 (1 H, br s,
N–H), 7.96–8.11 (4H, m, 4CH). 13C NMR: d = 14.1 (Me),
14.2 (Me), 14.6 (CH2), 33.4 (CH2), 42.9 (CH2N), 61.2
(CH2O), 109.3 (C), 120.2(C), 124.3 (2CH), 137.6 (2CH),
141.5 (2C), 148.5 (C), 163.6 (C=O), 170.5 (C=O), 194.2
(2C=O).
Ethyl 4-(benzylamino)-10,30,5-trioxo-10,30-dihydro-5H-
spiro[furan-2,20-indene]-3-carboxylate (4h)
Yellow oil, yield: 0.30 g (78%). IR (KBr): 3,356 (N–H),
1,785, 1,728, 1,691, 1,650 (C=O) cm-1.EI-MS: m/z
123

J IRAN CHEM SOC (2012) 9:503–506
505
(%) = 391 (M?, 9), 247 (19), 227 (14), 119 (18), 105
(100), 104 (34), 91 (69), 73 (84). Anal. Calcd. for
C22H17NO6 (391.37): C, 67.51; H, 4.38; N, 3.58%. Found:
C, 67.32; H, 4.31; N, 3.52%.1H NMR: d = 1.29 (3H, t,
3J = 6.8 Hz, Me), 4.12 (2H, q, 3J = 6.8 Hz, Me), 5.01
(2H, d, 3J = 6.2 Hz, CH2N), 6.70 (1 H, br s, N–H),
7.30–8.13 (9H, m, 9CH).13C NMR: d = 14.2 (Me),
48.7(CH2N), 62.1 (MeO), 109.5 (C), 120.8 (C), 124.8
(2CH), 128.0 (2CH), 128.3 (CH), 129.5 (2CH), 137.4
(2CH), 138.2 (C), 141.4 (2C), 148.6 (C), 166.8 (C=O),
170.0 (C=O), 193.5 (2C=O).
(377.35): C, 66.84; H, 4.01; N, 3.71%. Found: C, 66.52; H,
3
3.94; N, 3.65%.1H NMR: d = 1.14 (3H, t, J = 6.8 Hz,
3
Me), 4.09 (2H, q, J = 6.8 Hz, CH2O), 6.69 (1 H, br s,
N–H), 7.20–8.14 (9H, m, 9CH).13C NMR: d = 14.1 (Me),
61.4 (CH2O), 109.3 (C), 120.4 (C), 123.3 (2CH), 124.6
(2CH), 126.8 (CH), 129.1 (2CH), 137.6 (2CH), 139.5 (C),
141.4 (2C), 145.2 (C), 165.7 (C=O), 170.3 (C=O), 193.8
(2C=O).
Methyl 4-(benzo[d]thiazol-2-ylamino)-10,30,5-trioxo-10,30-
dihydro-5H-spiro[furan-2,20-indene]-3-carboxylate (4k)
Pale yellow crystals, mp 165–167 °C, yield: 0.29 g (71%).
IR (KBr): 3,356 (N–H), 1,785, 1,724, 1,693
(C=O) cm-1.EI-MS: m/z (%) = 420 (M?, 27), 276 (11),
227 (17), 162 (23), 149 (65), 134 (62), 105 (100), 73 (51).
Anal. Calcd. for C21H12N2O6S(420.39): C, 60.00; H, 2.88;
Methyl 10,30,5-trioxo-4-(phenylamino)-10,30-dihydro-5H-
spiro[furan-2,20-indene]-3-carboxylate (4i)
Yellow oil, yield: 0.26 g (73%). IR (KBr): 3,355 (N–H),
1,784, 1,726, 1,693, 1,651 (C=O) cm-1.EI-MS: m/z
(%) = 363 (M?, 8), 227 (23), 219 (14), 105 (100), 104
(17), 99 (54), 77 (89), 59 (61). Anal. Calcd. for C20H13NO6
(363.32): C, 66.12; H, 3.61; N, 3.86%. Found: C, 66.59; H,
3.52; N, 3.80%.1H NMR: d = 3.45 (3H, s, MeO), 6.78 (1
H, br s, N–H), 7.23–8.14 (9H, m, 9CH).13C NMR:
d = 52.3 (MeO), 109.1 (C), 120.2 (C), 123.1 (2CH), 124.4
(2CH), 126.7 (CH), 129.2 (2CH), 137.4 (2CH), 139.8 (C),
141.6 (2C), 145.3 (C), 165.5 (C=O), 170.1 (C=O), 193.3
(2C=O).
1
N, 6.66%. Found: C, 59.75; H, 2.83; N, 6.61%. H NMR:
d = 3.70 (3H, s, MeO), 6.86 (1 H, br s, N–H), 7.17–8.19
(8H, m, 8CH).13C NMR: d = 52.3 (MeO), 114.0 (C),
118.3 (CH), 121.8 (CH), 122.1 (C), 125.3 (CH), 124.5
(CH), 125.8 (2CH), 130.8 (C), 133.0 (2CH), 141.2 (2C),
148.7 (C), 153.2 (C), 167.2 (C=O), 170.3 (C=O), 174.5
(C=N), 196.5 (2C=O).
Results and discussion
Ethyl 10,30,5-trioxo-4-(phenylamino)-10,30-dihydro-5H-
As part of our continuing interest in the construction of
novel heterocycles [7–10], we now report the results of our
studies involving the reactions of enamines derived from
primary amines 1 and dialkyl acetylenedicarboxylates 2 in
the presence of ninhydrin (3), which constitutes a synthesis
of functionalized 5H-spiro[furan-2,20-indene]-10,30,5-tri-
ones 4 (Scheme 1).
spiro[furan-2,20-indene]-3-carboxylatee (4j)
Yellow oil, yield: 0.26 g (70%). IR (KBr): 3,353 (N–H),
1,784, 1,726, 1,693. 1,652 (C=O) cm-1.EI-MS: m/z
(%) = 405 (M?, 10), 233 (18), 227 (23), 105 (100), 104
(43), 92 (70), 77 (78), 73 (54). Anal. Calcd. for C21H15NO6
Scheme 1
O
O
CO2R'
O
O
Toluene
rt; 5-8 h
C
R
NH2
+
O
+
C
NHR
CO2R'
O
O
CO2R'
Yield %
R'
R
1a: R = Et
1b: R = n-Bu
1c: R = c-Hexyl
1d: R = Bn
1e: R = Ph
2a: R' = Me
2b: R' = Et
3
76
72
85
78
75
70
80
78
73
70
71
Me
Et
Me
Et
Me
Et
Me
Et
4a Et
4b Et
4c n-Bu
4d n-Bu
4e c-Hexyl
c-Hexyl
4g Bn
4h Bn
4f
Me
Et
Me
4i
4j
Ph
Ph
4k Benzo[d]thiazol-2-yl
123

506
J IRAN CHEM SOC (2012) 9:503–506
Scheme 2
O
RNH
O
3
CO2R'
2
+
1
CHCO2R'
R'O2C
CO2R'
NHR
O
5
6
O
O
imine-enamine
O
OH
O
OH
OR' tautomerization
_
R'OH
OR'
4
CO2R'
NR
O
CO2R'
NHR
O
7
8
1
The H NMR spectrum of 4a exhibited two singlets for
methoxy (d = 3.44 ppm) and NH (d = 6.78 ppm) protons.
The Et-N and phenyl groups showed characteristic multi-
plets in the appropriate regions of the spectrum. Com-
pounds 4 possess Cs symmetry. Thus, the ninhydrin residue
exhibits a complex AA’XX’ spin system for the aromatic
protons. The 1H-decoupled 13C NMR spectrum of 4a
showed 12 distinct resonances which further confirmed the
proposed structure. The ninhydrin residue shows only five
13C resonances due to the presence of Cs symmetry in 4.
The 1H NMR and 13C NMR spectra of 4b–4k were similar
to those for 4a except for the ester and alkyl(aryl)amino
moieties.
esters and ninhydrin. Simple mixing of the starting mate-
rials and the potential diversity of this type of reaction are
the advantages of this procedure.
References
1. R. Pradhan, M. Patra, A.K. Behera, B.K. Mishra, R.K. Behera,
Tetrahedron 62, 779 (2006)
2. N. Srivastav, A. Mittal, A. Kumar, Chem. Comm. 28, 493 (1992)
3. F. Matloubi-Moghaddam, L. Hojabri, S. Taheri, P. Pirani, J. Iran.
Chem. Soc. 7, 781 (2010)
4. A. Alizadeh-Karsalary, M.R. Mohammadizadeh, A.R. Hasa-
ninejad, A.A. Mohammadi, A.R. Karimi, J. Iran. Chem. Soc. 7,
45 (2010)
5. S.V. Patel, M.P. Patel, R.G. Patel, J. Iran. Chem. Soc. 2, 220
(2005)
6. I. Yavari, A. Mirzaei, L. Moradi, S. Hosseini, Tetrahedron Lett.
49, 2355 (2008)
7. I. Yavari, A. Mirzaei, L. Moradi, G. Khalili, Tetrahedron Lett. 51,
396 (2010)
8. I. Yavari, A. Mirzaei, L. Moradi, Helv. Chim.Acta 89, 2825
(2006)
9. I. Yavari, G. Khalili, Helv. Chim.Acta 93, 277 (2010)
10. I. Yavari, A. Mirzaei, L. Moradi, G. Khalili, Tetrahedron Lett. 51,
396 (2010)
A plausible pathway may be advanced to rationalize
product formation (Scheme 2). Presumably, the enamino-
ester intermediate 5 is attacked by 3 to furnish the inter-
mediate 6, which undergoes proton-transfer reaction to
produce imine derivative 7. This intermediate undergoes
imine-enamine tautomerization to generate 8, which is
converted to 4 by elimination of R’OH.
In conclusion, we have demonstrated a one-pot synthesis
of functionalized 5H-spiro[furan-2,20-indene]-10,30,5-tri-
ones via tandem reaction of primary amines, acetylenic
123