Multi-component reaction of amines, alkyl propiolates, and ninhydrin: An efficient protocol for the synthesis of tetrahydro-dihydroxy-oxoindeno[1,2-b] pyrrole derivatives

Article abstract of DOI:10.1055/s-2006-926327

A new protocol for the synthesis of a series of tetrahydrodihydroxy- oxoindeno[1,2-b]pyrrole from simple primary amines, alkyl propiolates, and ninhydrin was developed. The key step in the synthesis is an efficient three-component reaction of an amine wit

Full text of DOI:10.1055/s-2006-926327

SHORT PAPER
765
Multi-Component Reaction of Amines, Alkyl Propiolates, and Ninhydrin:
An Efficient Protocol for the Synthesis of Tetrahydro-dihydroxy-oxoinde-
no[1,2-b]pyrrole Derivatives
S
ynthesis
a
of
T
etrahyd
v
ro-dihydroxy
a
-oxoinde
n
d
o[1,2-
b
]pyrrole
D
e
A
rivative
s
zizian,*a Farhad Hatamjafari,b Ali Reza Karimi,c Masoud Shaabanzadehb
a
Chemistry Department, Faculty of Sciences, Shahid Beheshty University, 1983963113, Tehran, Iran
E-mail: j-azizian@cc.sbu.ac.ir
b
c
Chemistry Department, Science and Research Campus, Islamic Azad University, P. O. Box 19395-1775, Tehran, Iran
Chemistry Department, Faculty of Sciences, Islamic Azad University, P. O. Box 31485-313, Karaj, Iran
Received 4 July 2005; revised 14 September 2005
cosidases and exhibit bactericidal, antidiabetic, and anti-
viral activities,3,4 making these compounds good lead
compounds for the development of new drugs for the
treatment of viral infections, cancer, and diabetes.3,4 Con-
Abstract: A new protocol for the synthesis of a series of tetrahydro-
dihydroxy-oxoindeno[1,2-b]pyrrole from simple primary amines,
alkyl propiolates, and ninhydrin was developed. The key step in the
synthesis is an efficient three-component reaction of an amine with
an alkyl propiolate to give a 3-amino acrylate derivative, which then sequently, the development of general and facile methods
reacts with ninhydrin.
for the synthesis of such compounds is an active field of
research.4–7 For example the tetrahydro-dihydroxy-oxoin-
Key words: tetrahydro-dihydroxy-oxoindeno[1,2-b]pyrrole deriv-
atives, multicomponent reaction, cyclization
deno[1,2-b]pyrrole system is of interest in connection
with the search for potential oral hypoglycemic agents.8
As part of our general interest in MCRs,9 our ongoing re-
search programs in the area of heterocyclic compounds
containing nitrogen,9,10 and due to the resultant pharmaco-
logical interest in polyhydroxylated alkaloids, herein we
report an efficient three-component method for the con-
struction of new tetrahydro-dihydroxy-oxoindeno[1,2-
b]pyrroles, via condensation of amines, alkyl propiolates,
and ninhydrin (Scheme 1).
Despite recent advances in molecular biology and the
progress in combinatorial synthetic methodology, the rate
of introduction of new pharmaceuticals has decreased
markedly over the past two decades.1a Structural diversity
in a focused collection of potential therapeutics is be-
lieved to increase the positive hit rate. Most pharmaceuti-
cals in use are still small synthetic organic molecules that
often contain a heterocyclic ring.1a–c However, the range
of easily accessible and suitably functionalized heterocy-
clic building blocks for the synthesis of structurally di-
verse libraries is rather limited. The development of new,
rapid, and clean synthetic routes toward focused libraries
of such compounds is therefore of great importance to
both medicinal and synthetic chemists.1 Undoubtedly, the
most efficient strategies involve multicomponent reac-
tions (MCRs), which have become a powerful tool for the
rapid introduction of molecular diversity.2 Consequently,
the design and development of MCRs for the generation
of heterocycles have received increased interest.2a
In order to prove that b-aminoacrylates 5 exist as interme-
diates in this reaction, compound 5e (Z/E, 6:4) was syn-
thesized separately by the condensation of benzyl amine
and methyl propiolate, and then reacted with 3. The result-
ing product was identical to that formed in the three-com-
ponent procedure.
The reaction was carried out by the simple addition of one
equivalent of primary amine to one equivalent of alkyl
propiolate in water, followed by the addition of one equiv-
alent of ninhydrin; the reaction was complete within six
hours at room temperature affording 4a–e (Table 1).
The 1H NMR spectra revealed only one diastereomer, for
Polyhydroxylated alkaloids are interesting heterocycles
that can act as powerful and selective inhibitors of gly-
example, the 1H NMR spectrum of 4a exhibited one triplet
O
R1
O
COOR1
OH
HN
H2O
H2O
OH
OH
COOR1
HO
2
+
R
NH2
+
r.t.
r.t.
N
R2
COOR2
H
O
1
2
5
3
4
Scheme 1
SYNTHESIS 2006, No. 5, pp 0765–0767
x
x
.
x
x
.2
0
0
6
Advanced online publication: 07.02.2006
DOI: 10.1055/s-2006-926327; Art ID: Z12805SS
© Georg Thieme Verlag Stuttgart · New York

766
J. Azizian et al.
SHORT PAPER
IR (KBr): 1652, 1719 (C=O) cm–1.
Table 1 Three-Component Synthesis of Some Novel Tetrahydro-
dihydroxy-oxoindeno[1,2-b]pyrroles
1H NMR (CDCl3, 300 MHz): d = 0.96 (t, 3J = 7.14 Hz, 3 H, CH3),
1.27 (t, 3J = 7.50 Hz, 3 H, CH3), 1.23–1.73 (m, 4 H, CH2CH2), 3.46,
3.72 (m, 2 H, NCH2), 4.20 (q, 3J = 7.14 Hz, 2 H, OCH2), 4.26, 4.53
(2 br s, 2 H, OH), 7.24 (s, 1 H, C=CH), 7.53–7.90 (m, 4 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 14.11, 14.94 (2 × CH3), 20.46,
32.46, 44.15, 59.78 (4 × CH2), 84.53, 95.44 (2 × COH), 97.27,
124.33, 125.03, 130.70, 135.59, 136.19, 147.79, 148.80 (Ar,
C=CH), 165.39, 198.04 (2 × C=O).
Entry
R1
Et
R2
Product
4a
Yields (%)
1
2
3
4
5
Bn
96
89
82
85
87
Et
n-Bu
c-Hexyl
c-Hexyl
Bn
4b
Me
Et
4c
MS: m/z (%) = 331 (M+, 10), 285 (30), 258 (55), 186 (60), 105
(100), 77 (60), 41 (50).
4d
Me
4e
Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39; N, 4.23. Found: C,
65.20; H, 6.25; N, 4.20.
Methyl 1-Cyclohexyl-1,3a,4,8b-tetrahydro-3a,8b-dihydroxy-4-
oxoindeno[1,2-b]pyrrole-3-carboxylate (4c)
Yield: 82%; light-yellow crystalline solid; mp 155–156 °C.
IR (KBr): 1679, 1722 (C=O) cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.37–2.18 (m, 10 H, CH2), 3.72 (s,
3 H, OCH3), 3.80 (s, 1 H, NCH), 4.24, 4.42 (2 br s, 2 H, 2 × OH),
7.26 (s, 1 H, C=CH), 7.34–7.90 (m, 4 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 26.51, 31.32, 36.56 (3 × CH2),
51.13 (CH), 53.94 (CH3), 84.33, 95.69 (2 × COH), 96.76, 123.85,
125.08, 130.78, 135.25, 136.42, 147.04, 148.04 (ArH, C=CH),
165.69, 197.92 (2 × C=O).
at (1.24 ppm) and one quartet (4.17 ppm) corresponding
to the ethyl group and two broad singlets (4.39 and 4.56
ppm) for the hydroxyl groups. On top of this, two doublets
at 4.63 and 4.92 ppm are readily attributable to the meth-
ylene protons, along with multiplets at 7.03–7.91 corre-
1
sponding to the alkene and aromatic protons. The H
decoupled 13C NMR spectrum of 4a showed 19 distinct
resonances, in agreement with the proposed structure.
In summary, the MCR described herein provides a simple
and direct entry into a number of interesting novel tetrahy-
dro-dihydroxy-oxoindeno[1,2-b]pyrrole derivatives that
may be of value in medicinal chemistry as oral hypogly-
cemic agents.
MS: m/z (%) = 343 (M+, 10), 284 (20), 228 (100), 104 (66), 76 (60),
55 (100).
Anal. Calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08. Found: C,
66.40; H, 6.10; N, 4.05.
Mps were measured on an Electrothermal 9100 apparatus and are
uncorrected. IR spectra were measured on a Shimadzu IR-470 spec-
trophotometer. 1H NMR and 13C NMR spectra were determined on
Bruker 300 DRX AVANCE instrument at 300 and 75 MHz, respec-
tively. Elemental analyses were performed using a Heraeus CHN-
O-Rapid analyzer.
Ethyl 1-Cyclohexyl-1,3a,4,8b-tetrahydro-3a,8b-dihydroxy-4-
oxoindeno[1,2-b]pyrrole-3-carboxylate (4d)
Yield: 85%; yellow crystalline solid; mp 147–148 °C.
IR (KBr): 1679, 1722 (C=O) cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.26 (t, 3J = 6.90 Hz, 3 H, CH3),
1.36–2.17 (m, 10 H, CH2), 3.87 (s, 1 H, NCH), 4.17 (q, 3J = 7.10 Hz,
2 H, OCH2), 4.47, 4.78 (2 br s, 2 H, 2 × OH), 7.33 (s, 1 H, C=CH),
7.51–7.88 (m, 4 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 18.73 (CH3), 26.51, 31.31, 34.41,
58.78 (4 × CH2), 53.85 (CH), 84.31, 95.69 (COH), 96.70, 123.84,
124.14, 125.02, 130.72, 135.56, 136.35, 146.78 (ArH, C=CH),
165.40, 197.93 (2 × C=O).
Ethyl 1-Benzyl-1,3a,4,8b-tetrahydro-3a,8b-dihydroxy-4-oxoin-
deno[1,2-b]pyrrole-3-carboxylate (4a); Typical Procedure
BnNH2 (0.107 g, 1 mmol) in H2O (10 mL) was added to ethyl pro-
piolate (0.098 g, 1 mmol). The mixture was stirred for 1 h, then nin-
hydrin (0.178 g, 1 mmol) was added and stirring was continued at
r.t. for a further 6 h. The solid formed was removed by filtration and
recrystallized (EtOH) to give 4a.
Yield: 96%; light-red crystalline solid; mp 139–140 °C.
IR (KBr): 1647, 1736 (C=O) cm–1.
MS: m/z (%) = 365 (M+, 10), 284 (24), 228 (100), 104 (66), 76 (60),
55 (100).
Anal. Calcd for C20H23NO5: C, 67.21; H, 6.49; N, 3.92. Found: C,
67.15; H, 6.45; N, 3.90.
3
1H NMR (CDCl3, 300 MHz): d = 1.24 (t, J = 7.2 Hz, 3 H, CH3),
4.17 (q, 3J = 7.2 Hz, 2 H, OCH2), 4.39, 4.56 (2 br s, 2 H, OH), 4.63,
4.92 (2 d, 3J = 6.9 Hz, 2 H, NCH2), 7.03 (s, 1 H, C=CH), 7.22–7.91
(m, 9 H, ArH).
Methyl 1-Benzyl-1,3a,4,8b-tetrahydro-3a,8b-dihydroxy-4-ox-
oindeno[1,2-b]pyrrole-3-carboxylate (4e)
Yield: 87%; light-yellow crystalline solid; mp 137–138 °C.
IR (KBr): 1648, 1727 (C=O) cm–1.
1H NMR (CDCl3, 300 MHz): d = 3.66 (s, 3 H, OCH3), 4.52, 4.70 (2
br s, 2 H, OH), 4.66, 4.88 (2 d, 3J = 7.2 Hz, 2 H, NCH2), 7.04 (s, 1
H, C=CH), 7.22–7.89 (m, 9 H, ArH).
13C NMR (CDCl3, 75 MHz): d = 48.36 (CH2), 51.21 (CH3), 48.31,
59.91 (2 × CH2), 84.58, 95.50 (2 × COH), 98.17, 124.53, 125.14,
128.63, 128.78, 129.44, 130.87, 135.54, 136.36, 136.41, 147.70,
149.27 (Ar, C=CH), 165.61, 148.04 (C=O).
13C NMR (CDCl3, 75 MHz): d = 14.89 (CH3), 48.31, 59.91 (2 ×
CH2), 84.62, 95.49 (2 × COH), 98.44, 124.55, 125.07, 128.55,
128.72, 129.40, 130.83, 135.58, 136.29, 136.57, 147.73, 149.03
(Ar, C=CH), 165.27, 198.03 (2 × C=O).
MS: m/z (%) = 365 (M+, 4), 274 (20), 228 (80), 91 (100), 55 (44).
Anal. Calcd for C21H19NO5: C, 69.03; H, 5.24; N, 3.83. Found: C,
69.10; H, 5.20; N, 3.75.
Ethyl 1-Butyl-1,3a,4,8b-tetrahydro-3a,8b-dihydroxy-4-oxoin-
deno[1,2-b]pyrrole-3-carboxylate (4b)
Yield: 89%; yellow crystalline solid; mp 142–143 °C.
MS: m/z (%) = 351 (M+, 10), 260 (20), 228 (40), 91 (100), 76 (16),
50 (10).
Synthesis 2006, No. 5, 765–767 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Tetrahydro-dihydroxy-oxoindeno[1,2-b]pyrrole Derivatives
767
Anal. Calcd for C20H17NO5: C, 68.37; H, 4.88; N, 3.99. Found: C,
68.30; H, 4.80; N, 3.95.
(4) White, J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am. Chem.
Soc. 1998, 120, 7359; and references cited therein.
(5) Denmark, S. E.; Hurd, A. R. J. Org. Chem. 2000, 65, 2875;
and references cited therein.
(E/Z)-Methyl 3-(Benzylamino)acrylate (5e)
1H NMR (CDCl3, 300 MHz): d = 3.60 (s, 3 H, Z-CH3), 3.67 (s, 3 H,
E-CH3), 4.20 (d, 3J = 5.70 Hz, 2 H, Z-CH2), 4.30 (d, 3J = 5.30 Hz, 2
H, E-CH2), 4.53 (d, 3J = 7.90 Hz, 1 H, Z-CH=CH), 4.75 (d,
3J = 13.50 Hz, 1 H, E-CH=CH), 7.02 (dd, 3J = 7.90, 7.30 Hz, 1 H,
Z-CH=CH), 7.07 (dd, 3J = 13.10, 7.50 Hz, 1 H, E-CH=CH), 7.22–
7.45 (m, 5 H, Z/E-ArH), 7.65 (br s, 1 H, Z-NH), 7.50 (br s, 1 H, E-
NH).
(6) Denmark, S. E.; Herbert, B. J. Org. Chem. 2000, 65, 2887;
and references cited therein.
(7) (a) Nemr, A. E. Tetrahedron 2000, 56, 8579. (b) White, J.
D.; Hrnciar, P. J. Org. Chem. 2000, 65, 9129. (c) Pearson,
W. H.; Hines, J. V. J. Org. Chem. 2000, 65, 5785.
(8) (a) Chatterjie, N.; Shapiro, R.; Quo, S. G.; Stephani, R. A.
Tetrahedron Lett. 1975, 30, 2535. (b) De, A. U.; Saha, B. P.
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Huffman, J. C. J. Heterocycl. Chem. 1995, 32, 33.
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594.
Anal. Calcd for C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C,
69.01; H, 6.79; N, 7.20.
(9) (a) Azizian, J.; Mohammadi, A. A.; Karimi, A. R.;
Mohammadizadeh, M. R. J. Org. Chem. 2005, 70, 350.
(b) Azizian, J.; Karimi, A. R.; Mohammadi, A. A. Synth.
Commun. 2003, 33, 383. (c) Azizian, J.; Karimi, A. R.;
Arefrad, H.; Mohammadi, A. A.; Mohammadizadeh, M. R.
Mol. Diversity 2003, 6, 223. (d) Azizian, J.; Mohammadi,
A. A.; Karimi, A. R. Synth. Commun. 2003, 33, 415.
(e) Azizian, J.; Karimi, A. R.; Mohammadi, A. A.;
Mohammadizadeh, M. R. Synthesis 2004, 2263.
(10) (a) Azizian, J.; Karimi, A. R.; Kazemizadeh, Z.;
Mohammadi, A. A.; Mohammadizadeh, M. R. Synthesis
2005, 1095. (b) Azizian, J.; Karimi, A. R.; Kazemizadeh, Z.;
Mohammadi, A. A.; Mohammadizadeh, M. R. J. Org. Chem.
2005, 70, 1471. (c) Azizian, J.; Morady, A. V.; Jadidi, K.;
Mehrdad, M.; Sarrafi, Y. Synth. Commun. 2000, 30, 537.
(d) Azizian, J.; Soozangarzadeh, S.; Jadidi, K. Synth.
Commun. 2001, 31, 99. (e) Azizian, J.; Asadi, A.; Jadidi, K.
Synth. Commun. 2001, 31, 1. (f) Azizian, J.; Jadidi, K.;
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(g) Azizian, J.; Sarrafi, Y.; Mehrdad, M.; Jadidi, K. Indian J.
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Acknowledgment
We gratefully acknowledge the financial support from the Research
Council of Science and Research, Islamic Azad University.
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Synthesis 2006, No. 5, 765–767 © Thieme Stuttgart · New York