One-pot synthesis of tetrahydroindeno[1,2-b]pyrrolo-3-carboxylates derivatives

Article abstract of DOI:10.1002/jhet.835

Tetrahydroindeno [1,2-b]pyrrole-3-carboxylate were synthesized in a one-pot procedure by the reaction of 1,3-dicarbonyl and activated carbonyl compounds such as benzyl or ninhydrin in ethanol/water in the presence of ammonium acetate. Copyright

Full text of DOI:10.1002/jhet.835

March 2012
One-Pot Synthesis of Tetrahydroindeno[1,2-b]pyrrolo-3-
carboxylates Derivatives
413
Javad Azizian,* Fatemeh Sheikholeslami, Javad Hosseini,
Mohammadkazem Mohammadi, and Behrooz Mirza
Department of Chemistry, Science and Research Campus, Islamic Azad University,
Ponak Branch, Tehran, Iran
*E-mail: j-azizian@cc.sbu.ac.ir
Received October 3, 2010
DOI 10.1002/jhet.835
Published online 21 November 2011 in Wiley Online Library (wileyonlinelibrary.com).
Tetrahydroindeno [1,2-b]pyrrole-3-carboxylate were synthesized in a one-pot procedure by the
reaction of 1,3-dicarbonyl and activated carbonyl compounds such as benzyl or ninhydrin in ethanol/
water in the presence of ammonium acetate.
J. Heterocyclic Chem., 49, 413 (2012).
INTRODUCTION
biocidal profile remarkably [21]. Therefore, we investi-
gated a MCR of 1,3-dicarbonyl 1 and ninhydrin 2 in the
presence of ammonium acetate in EtOH/H2O as a sol-
vent, which afforded tetrahydroindeno [1,2-b]pyrrole-3-
carboxylate derivatives in good isolated yields (Scheme
1). The procedure was simple and easy to handle. Struc-
tures of compounds 3a–3d were assigned by IR, 1H
Multicomponent reactions (MCRs), with three or more
reactants combining in a one-pot procedure to give a sin-
gle product, have become increasingly popular during the
last decade [1–4]. They are economically and environmen-
tally advantageous because multistep syntheses produce
considerable amounts of waste mainly due to complex iso-
lation procedures often involving expensive, toxic, and
hazardous solvents after each step. MCRs are perfectly
suited for combinatorial library synthesis, and thus are
finding increased use in the discovery process for new
drugs and agrochemicals [5]. They provide a powerful tool
toward the one-pot synthesis of diverse and complex com-
pounds as well as small and drug-like heterocycles [6].
Polysubstituted pyrroles are molecular frameworks having
immense importance in material science [7]. They have
been also used as antioxidants [8], antibacterial [9,10], ion-
otropic [11,12], antitumor [13], anti-inflammatory [14,15],
and antifungal agents [16]. Moreover, they are a highly
versatile class of intermediates in the synthesis of natural
products as well as in heterocyclic chemistry [17].
1
NMR, 13C NMR, and mass spectral data. The H NMR
spectrum of 3a exhibited a triplet and singlet at d ¼
1.35 (3J ¼ 7.1) and d ¼ 2.21 ppm for the methyl pro-
tons, along with characteristic signals for the methoxy
protons at (d ¼ 4.61 and 4.72 ppm). The carbonyl group
resonances in the 13C NMR spectra of 3a appear at
165.7 and 190.1 ppm. The mass spectra of 3a displayed
the molecular ion peak at 289.
A tentative mechanism for this transformation is pro-
posed in Scheme 2. It is conceivable that, the reaction
involves the initial formation of enaminones 4 between
1,3-dicarbonyls 1 with ammonium acetate. Enaminones
that is formed in EtOH/H2O; react with carbonyl group
of 2 and produced 5. Cyclization of this intermediate
leads to the compound 3.
As part of our research on the development of new
synthetic methods in heterocyclic chemistry [18–20],
herein, we describe an efficient synthesis of functional-
ized tetrahydroindeno [1,2-b]pyrrole-3-carboxylate 3 via
the reaction of 1,3-dicarbonyls 1 and ninhydrin 2 in the
presence of ammonium acetate in EtOH/H2O as a sol-
vent (Scheme 1).
Under similar conditions, the reaction of 1,3-dicar-
bonyl 1 with another activated carbonyl compounds
such as benzyl or acenaphthoquinone in the presence of
ammonium acetate in EtOH/H2O led to tetrahydroindeno
[1,2-b]pyrrole-3-carboxylate derivatives in good yields
(see Table 1).
In summary, the reaction of 1,3-dicarbonyls and acti-
vated carbonyl compounds such as ninhydrin, benzyl, or
acenaphthoquinone in the presence of ammonium ace-
tate in EtOH/H2O as a solvent, which afforded tetrahy-
droindeno [1,2-b]pyrrole-3-carboxylate derivatives in
RESULTS AND DISCUSSION
The presence of two or more different heterocyclic
moieties in a single molecule often enhances the
C
V
2011 HeteroCorporation

414
J. Azizian, F. Sheikholeslami, J. Hosseini, M. Mohammadi, and B. Mirza
Vol 49
Scheme 1
15.3 (Me), 27.9 (Me), 85.8 (COH), 92.1 (COH), 106.4 (C),
123.5, 124.6, 130.4, 135.1, 136.3, 150.2 (C), 163.4 (C¼¼O),
196.5 (C¼¼O) ppm. EI-MS: 259 (Mþ,40), 241 (60), 227
(90),199 (35), 104 (50), 76 (33). Anal. Calcd for C14H13NO4
(259.259): C, 64.85, H, 5.05, N, 5.40; Found: C, 63.78, H,
5.11, N, 5.9%.
Ethyl2-ethioxt-3a,8b-dihydroxy-4-oxo-1,3a,4,8b-tetrahydroin-
deno[1,2-b]-pyrrolo-3carboxylate (3c). Yellow powder, mp
200–202ꢀC, yield: 0.38g (60%). IR (KBr) (mmax/cmꢁ1):
3200,1772, 1726, 1514, 1260 cmꢁ1
.
1H NMR: 1.3 (s, 6 H, 2
3
3
Me), 3.77 (t, 2 H, JHH ¼ 7.5 Hz, OCH2), 4.18 (t, 2 H, JHH
¼ 7.5 Hz, OCH2),4.56(s, OH), 4.70(s,OH), 5.5 (s,1H,NH),
7.74(1H), 7.89(2H), 8.08(1H)ppm. 13C NMR: 14.1(Me),
14.5(Me), 60.2 (OCH2), 65.3 (OCH2), 82.4 (OCH2), 95.2
(OCH2), 109.1 (C), 122.7, 124.4, 129.2,133.4, 135.5,136.6,
140.2, 165.4 (C¼¼O), 173.2(C¼¼O) ppm.. EI-MS: 319 (Mþ,15),
301(60), 273 (88), 245 (78), 218 (25), 104 (50), 76 (33). Anal.
Calcd for C16H17NO6 (319.31): C, 60.12, H, 5.32, N, 4.38;
Found: C, 59.48, H, 5.12, N, 4.51%.
excellent yields. The present procedure has the advant-
age that the reaction is performed under neutral condi-
tions, and the starting material can be used without any
activation or modification.
3-Acetyl-3a,8b-dihydroxy-2-phenyl-3a,8b-dihydroindeno[1,2-
b]-pyrrol-4(1H)-one (3d). Yellow powder, yield: mp 144–
146ꢀC, 0.57 g (90%). IR (KBr) (mmax/cmꢁ1): 3648, 3462,
EXPERIMENTAL
All the chemicals used in this work were purchased from
Fluka (Buchs, Switzerland) and were used without further puri-
fication. Melting points were measured on an Electrothermal-
9100 apparatus. IR spectra were recorded with a Shimadzu IR-
460 spectrometer. 1H and 13C NMR spectra were measured
with a BRUKER DRX-500 AVANCE spectrometer at 500.1 and
125.7 MHz, respectively. 1H and 13C NMR spectra were
obtained for solutions in CDCl3 using tetramethylsilane (TMS)
or 85% H3PO4 as external standard; d in parts per million, J in
hertz. EI-mass spectrometer (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.
General procedure. To a stirred solution of 1,3-dicarbonyls
(2 mmol) in EtOH/H2O (10:1) as a solvent (10 mL) was added
ammonium acetate (2 mmol). After 30 min, a solution of acti-
vated carbonyl compounds (2 mmol) in EtOH/H2O (3 mL)
was added slowly, and the mixture was refluxed for 7–10 h.
The solvent was removed under reduced pressure, and the resi-
due was purified by column chromatography (SiO2; n-hexane/
AcOEt 8:1) to afford the pure title compounds.
3217, 1731, 1715, 1602, 1548, 1472, 899, 701 cmꢁ1 1H
.
NMR: 1.65 (s, 3 H, Me), 3.51(s, 2OH), 5.74 (s, NH), 7.37 (2
H), 7.5 (3 H), 7.6(1 H), 7.81(2 H), 7.91(1 H) ppm. 13C NMR:
30.1 (Me), 85.2 (C), 92.4 (C), 115.1, 118.2, 119.3, 124.9,
125.2, 128.8, 129.3, 131.1, 132.4, 134.5,135.1, 137.4, 142.5,
150.1, 175.2 (C¼¼O), 190 (C¼¼O) ppm. EI-MS: 321 (Mþ, 20),
303 (62), 289 (90), 226 (78), 213 (45), 186 (35), 104 (50), 76
(40). Anal. Calcd for C19H15NO4 (321.3): C, 70.9, H, 4.66, N,
4.35; Found: C, 70.5, H, 4.20, N, 4.27%.
Ethyl 4,5-dihydroxy-2-methyl-4,5-diphenyl-4,5-dihydro-
1H-pyrrole-3carboxylate (6a). Pale yellow powder, mp 119–
120ꢀC, yield: 0.64 g (95%). IR (KBr) (mmax/cmꢁ1): 3353,
3056, 2398, 1734, 1713, 1682, 1602, 1191, 1088, cmꢁ1
.
1H
3
NMR: 1.01 (t, 3 H, JHH ¼ 7.1 Hz, Me), 2.37 (s, 3 H, Me),
3
4.09 (q, 2 H, JHH ¼ 5.7 Hz, OCH2), 5.2 (s, OH), 7.09–7.3
(m,10 H), 9.02(s, 1 H, NH) ppm. 13C NMR: 14.2 (Me), 30.3
(Me), 59.5 (OCH2), 61.1, 62.2, 113.2, 123.3, 126.3, 127.1,
127.9, 128.3, 128.4, 128.8,128.9, 130.3, 131.1, 133.6, 136.3,
151.7, 170 (C¼¼O) ppm. EI-MS: 339 (Mþ, 15), 321 (58), 293
(90), 275 (95), 248 (25), 171 (30), 76 (25). Anal. Calcd for
C20H21NO4 (339.4): C, 70.78, H, 6.19, N, 4.12; Found: C,
69.89, H, 7.21, N, 4.87%.
Ethyla,8b-dihydroxy-2-methyl-4-oxo-1,3a,4,8b-tetrahydroin-
deno[1,2-b]-pyrrolo-3carboxylate (3a). Yellow crystal, mp:
152–154ꢀC, yield: 0.53 g (92%). IR (KBr) (mmax/cmꢁ1): 3403,
1-(4,5-Dihydroxy-2-methyl-4,5-diphenyl-4,5-dihydro-1H-
pyrrol-3yl)-1-ethanone (6b). Yellow powder, mp132–134ꢀC,
yield: 0.49 g (80%). IR (KBr) (mmax/cmꢁ1): 3412,1733, 1685,
1716, 1650, 1564, 1480, 1379, 1326, 1208, 1140 cmꢁ1
.
1H
3
NMR: 1.35 (t, 3 H, JHH ¼ 7.1 Hz, Me), 2.21 (s, 3 H, Me),
3
1559, 1522, 1187, 1090, 830 cmꢁ1 1H NMR: 1.87 (s, 3 H,
.
4.26 (t, 2 H, JHH ¼7.4 Hz, OCH2), 4.61 (s, OH), 4.72 (s,
3
OH), 5.67 (s, NH), 7.56 (t,1 H, JHH ¼3.3 Hz), 7.78 (d, 2 H,
Me), 2.37 (s, 3 H, Me), 4.12 (s, OH), 4.2 (s, OH), 4.32 (s,
NH), 7.09–7.62 (m, 10 H) ppm. 13C NMR: 22.0 (Me), 30.6
(Me), 66.7, 80.6, 122.7, 123.3, 127.1,127.2, 127.3, 127.6,
128.3, 128.9, 131.3,131.2, 132.1, 135.7, 136.7,151.2, 197.1
3
3JHH ¼3.7 Hz,), 7.87 (d,1 H, JHH ¼7.6 Hz) ppm. 13C NMR:
14.1 (Me), 14.4 (Me), 58.6 (CH2O), 85.4, 91.9, 96.1, 123.47,
124.75, 130.32, 135.5, 135.86, 150.5, 159.92 (C), 165.7
(C¼¼O), 190.1 (C¼¼O) ppm. EI-MS: 289 (Mþ,30), 271 (62),
243(92), 225 (97), 198 (30), 104(40),76 (30). Anal. Calcd for
C15H15NO5 (289.3): C, 62.27, H, 5.22, N, 4.84; Found: C,
61.23, H, 5.32, N, 4.43%.
Scheme 2
3-Acetyl-3a,8b-dihydroxy-2-methyl-3a,8b-dihydroindeno[1,2-
b]-pyrrol-4(1H)-one (3b). White powder, mp 215–218ꢀC,
yield: 0.46 g (90%). IR (KBr) (mmax/cmꢁ1): 3361, 3271, 1709,
1603, 1578, 1482, 1441, 1385 cmꢁ1 1H NMR: 2.23 (s, 3 H,
.
Me), 2.40 (s, 3 H, Me), 4.12(s, OH), 4.15(s, OH), 4.26 (s,
NH), 7.59–7.62 (t, 1H),7.79 (1H), 7.81 (2 H) ppm. 13C NMR:
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DOI 10.1002/jhet

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One-Pot Synthesis of Tetrahydroindeno[1,2-b]pyrrolo-3-carboxylates Derivatives
415
Table 1
Tetrahydroindeno[1,2-b]pyrrole-3-carboxylate derivatives.
Activated carbonyl
compound
Yield
(%)
Entry
1,3-dicarbonyl
Product
1
95
2
3
4
5
6
7
8
80
65
80
60
87
90
85
1
(C¼¼O) ppm. EI-MS: 309 (Mþ, 35), 291 (60), 277 (88), 250
(48), 173 (50), 76 (30). Anal. Calcd for C19H19NO3 (309.3):
C, 73.70, H, 6.14, N, 4.52; Found: C, 72.5, H, 6.38, N, 4.92%.
1-(4,5-Dihydroxy-2,4,5-triphenyl-4,5-dihydro-1H-pyrrol-3yl)-
1-ethanone (6c). Yellow powder,mp 140–142ꢀC, yield: 0.48 g
(65%). IR (KBr) (mmax/cmꢁ1): 3319, 3180, 1911, 1594, 1570,
1733, 1685, 1522,1370,1187, 1090, 1014, 830 cmꢁ1. H NMR:
3
1.19 (t, 3 H, JHH ¼7.08 HZ, Me), 2.25 (s, 3H, Me), 4.04 (q,
3
2H, JHH ¼ 7.12 HZ,CH2O), 4.61 (s, 2OH), 7.18–7.35 (8 H-
Ar), 10.74 (s, NH) ppm.13C NMR: 13.7(Me), 26.2 (Me), 59.1
(CH2O),
61.4 (COH), 114.1, 117. 2, 127.5, 128.01, 128.8, 129.06,
131.5, 132.1, 132.2, 132.9, 135. 6, 137.03, 150.1, 155.0, 165.1
(C¼¼O), 169.5 (C¼¼O) ppm. EI-MS: 408 (Mþ, 30), 390 (59), 362
(88), 344 (98), 317(30), 111(40). Anal. Calcd for C20H19Cl2NO4
(408.3): C, 58.83, H, 4.69, N, 3.43: Found: C, 57.5, H, 4.25, N,
3.60
1324, 1261, 1092, 1025, 802 cmꢁ1 1H NMR: 2.06 (s, 3 H,
.
Me), 5.19 (s, OH), 5.76 (s, OH), 7.25–7.91 (15H-Ar), 10.22 (s,
NH) ppm. 13C NMR: 23.3 (Me), 76.9 (COH), 92.7 (COH),
111.0, 118.2, 122.2, 124.3, 125.4, 126.1, 127.5 (3C), 127.7,
128.6 (3C), 128.7, 129.1, 130.0, 131.2 (3C), 140.5, 189.9
(C¼¼O) ppm. EI-MS: 371 (Mþ, 25), 353 (50), 339 (90), 312
(38), 235(60), 76 (40). Anal. Calcd for C24H21NO3 (371.4): C,
77.53, H, 5.65, N, 3.76; Found: C, 77.19, H, 5.38, N, 3.79%.
Ethyl4,5-bis(4-chlorophenyl)-4,5-dihydroxy-2-methyl-4,5-
dihydro-1H-pyrrole-3-carboxylate (6d). Yellow powder,mp
122–124ꢀC, yield: 0.65 g (80%). IR (KBR) (vmax/cmꢁ1): 3412,
Ethyl6b,9a-dihydroxy-8-methyl-7,9a-dihydro-6bH-acenaph-
tho[1,2-b]-pyrrole-9-carboxylate (7a). Yellow powder, mp
169–171ꢀC, yield: 0.37 g (60%). IR (KBR) (vmax/cmꢁ1): 3412,
1733, 1685, 1522, 1370,1187, 1090, 1014, 830 cmꢁ1
.
1H
3
NMR: 1.48 (t, 3 H, JHH ¼ 7.0 HZ, Me), 2.23 (s, 3H, Me),
3
4.25 (q, 2H, JHH ¼ 7.12 HZ, OCH2), 4.1(s, OH), 4.4 (s, OH),
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J. Azizian, F. Sheikholeslami, J. Hosseini, M. Mohammadi, and B. Mirza
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5.4 (s, NH), 7.12–7.82 (6H-Ar) ppm.13C NMR: 13.7 (Me),
13.5 (Me), 17.0 (Me), 59.4 (CH2O), 90.4 (COH), 95.0 (COH),
110.3, 116.1, 117. 2, 124.7, 126.5, 127.5, 128.1, 132.2, 139.1,
140.0, 144.1, 166.7 (C¼¼O) ppm. EI-MS: 311 (Mþ, 25), 293
(49), 265 (85), 247 (95), 220(33). Anal. Calcd for C18H17NO4
(311.3): C, 69.44, H, 5.50, N, 4.49: Found: C, 68.97, H, 5.39,
N, 4.87.
C19H17NO3 (337.3): C, 74.00, H, 5.57, N, 4.55; Found: C,
73.45, H, 5.29, N, 4.21%.
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1-[6b,9a-dihydroxy-8-methyl-7,9a-dihydro-6bH-acenaph-
tho[1,2-b]-pyrrol-9-yl]-1-ethanone (7b). White powder, mp
177–181ꢀC, yield: 0.48 g (87%). IR (KBr) (mmax/cmꢁ1): 3422,
[3] Balme, G.; Bossharth, E.; Monteiro, N. Eur J Org Chem
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1773, 1726, 1581, 1436, 1383, 1023, 776 cmꢁ1 1H NMR:
.
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2.21 (s, 3 H, Me), 2.40 (s, 3 H, Me), 5.19 (s, OH), 5.38 (s,
OH), 5.6 (s, NH), 7.54–7.86 (m, 6 H) ppm. 13C NMR: 16.7
(Me), 29.7 (Me), 89.8 (C-OH), 97.42 (C-OH), 112.0 (C),
119.5, 121.2, 124.3, 125.3, 128.9, 129.4, 131.5, 136.4, 143.5,
146.6, 161.8, 192.7 (C¼¼O) ppm. EI-MS: 281 (Mþ, 19), 263
(70), 249 (90), 222 (38). Anal. Calcd for C17H15NO3 (281.3):
C, 72.52, H, 5.37, N, 4.97; Found: C, 71.77, H, 5.11, N,
4.66%.
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Ethyl3a,11b-dihydroxy-2-methyl-3a,11b-dihydro-1H-diben-
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190ꢀC, yield: 0.60 g (90%). IR (KBr) (mmax/cmꢁ1): 3766,
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3431, 17, 1726, 1690, 1629,1443, 1337,1205, 1028, 745 cmꢁ1
.
3
1H NMR: 1.33 (t, 3 H, JHH ¼ 7.2 Hz, Me), 2.38 (s, 3 H,
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J.; Wurziger, H. Eur J Med Chem 1993, 28, 129.
3
Me), 4.38 (q, 2 H, JHH ¼ 7.1 Hz, CH2O), 5.31(s, OH), 5.43
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(s, OH), 5.8 (s, NH), 7.39–7.54 (m, 4 H, H-Ar), 7.62 (t, 1 H,
3
3JHH ¼ 7.1 Hz, 1 H), 7.78 (t, 1 H, JHH ¼ 7.3 Hz, CH), 7.93
3
3
(d,1 H, JHH ¼ 7.9 Hz, CH), 7.97 (d, 1 H, JHH ¼ 7.8 Hz,
CH) ppm. 13C NMR: 14.4 (Me), 18.1 (Me), 62.2 (CH2O), 75.3
(COH), 98.2 (COH), 108.0 (C), 119.2, 124.9, 125.5, 126.6,
127.4, 128.9, 130.0, 130.3, 130.4, 133.3, 134.0, 137.1, 164.4,
168.3 (C¼¼O) ppm. EI-MS: 337 (Mþ, 42), 319 (53), 291 (94),
273 (98), 246(41). Anal. Calcd for C20H19NO4 (337.3): C,
71.14, H, 5.67, N, 4.15; Found: C, 70.69, H, 5.41, N, 4.9%.
1-(3a,11b-dihydroxy-2-methyl-3a-11b-dihydro-1H-dibenzo[e,
g]indol-3-yl)-1-ethanone (8b). Orange powder, mp 198–200ꢀC,
yield: 0.52 g (85%). IR (KBr) (mmax/cmꢁ1): 3367, 1726, 1660,
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1383, 1195, 1157, 1083, 745 cmꢁ1 1H NMR: 2.38 (s, NH),
.
2.5 (s, 6 H, 2 Me), 5.31(s, OH), 5.43 (s, OH), 7.38–7.56 (m, 4
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3
3
H-Ar), 7.62 (t, 1 H, JHH ¼ 7.7 HZ, H-Ar), 7.75 (d, 1 H, JHH
¼ 6.4 Hz, H-Ar), 7.95 (t, 2 H, JHH ¼ 8.5 Hz, HAr) ppm. 13C
3
NMR: 14.4 (Me), 18.1 (Me), 75.3 (C), 98.2 (C), 108.0 (C),
119.2, 124.9, 125.5, 126.6, 127.4, 128.9, 130.0, 130.3, 130.4,
133.3, 134.0, 137.1, 164.4, 192.3 (C¼¼O) ppm. EI-MS:
307(Mþ, 37), 289 (57), 275 (30), 248 (38). Anal. Calcd for
[21] Ji, S. J.; Wang, S. Y.; Zhang, Y.; Loh, T. P. Tetrahedron
2004, 60, 2051.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet