Synthesis of pyrrole-fused chromanones via one-pot multicomponent reactions

Article abstract of DOI:10.1016/j.tet.2013.01.085

We have developed one-pot method for the synthesis of functionalized novel pyrrole-fused chromanones. A variety of 5-hydroxy-N-substituted-2H- dihydrochromeno[3,4-c]pyrrole-2-ones were obtained in moderate to good yields via condensation of 2-hydroxybenzaldehydes and ethyl acetoacetate with isocyanides in ethanol. The proof of the structure relies on analytical investigation and X-ray crystallography. These reactions presumably proceed via reaction of the in situ generated 3-acetyl-2H-chromen-2-one intermediates with isocyanides through Michael addition/intramolecular cyclization/oxidation tandem sequences.

Full text of DOI:10.1016/j.tet.2013.01.085

Tetrahedron 69 (2013) 3054e3060
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of pyrrole-fused chromanones via one-pot
multicomponent reactions
,
a
b
Mehdi Ghandi a , Ali-Tabatabaei Ghomi , Maciej Kubicki
*
a School of Chemistry, College of Science, University of Tehran, Tehran, PO Box 14155 6455, Iran
b Faculty of Chemistry, Adam Mickiewicz University in Poznan, Umultowska 89b, 61-614 Poznan, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed one-pot method for the synthesis of functionalized novel pyrrole-fused chroma-
nones. A variety of 5-hydroxy-N-substituted-2H-dihydrochromeno[3,4-c]pyrrole-2-ones were obtained
in moderate to good yields via condensation of 2-hydroxybenzaldehydes and ethyl acetoacetate with
isocyanides in ethanol. The proof of the structure relies on analytical investigation and X-ray crystal-
lography. These reactions presumably proceed via reaction of the in situ generated 3-acetyl-2H-chro-
men-2-one intermediates with isocyanides through Michael addition/intramolecular cyclization/
oxidation tandem sequences.
Received 4 November 2012
Received in revised form 10 January 2013
Accepted 28 January 2013
Available online 12 February 2013
Keywords:
3-Acetyl-2H-chromen-2-ones
Isocyanides
Ó 2013 Elsevier Ltd. All rights reserved.
Dihydrochromeno[3,4-c]pyrrole-1,4-dione
Tandem reactions
1. Introduction
a novel antagonist of the ETB receptor),7 and azaspirene (4, a novel
angiogenesis inhibitor)8 (Fig. 1).
The so-called multicomponent reactions (MCRs) are one-pot
processes in which at least three or more different simple sub-
strates react for the preparation of target materials.1 These re-
actions, which have gained much attention over the past years,
frequently occur not through a single-step procedure, but rather by
several sequential steps or multicomponent cascade or domino
reactions.2 Simplicity, greater efficiency and atom economy with
generation of molecular complexity and diversity in a one-pot
transformation are some advantages of these reactions. As an im-
portant subclass of MCRs, the isocyanide based multicomponent
reactions (IMCRs) are processes in which an isocyanide is used as
one of the starting materials in order to obtain new compounds.3
The pioneering work of Ugi is the most popular IMCR in which
a carboxylic acid, a primary amine, an aldehyde, and an isocyanide
react in a one-pot manner to afford an N-substituted acyl amino-
amide containing four independently varying groups.4
The known properties of heterocycles containing the 5-
hydroxy-3-pyrrolin-2-one moieties along with the documented
A number of isolated biologically active natural products are
known to contain the 5-hydroxy-3-pyrrolin-2-one moiety. These
include fusarin C (1, potent mycotoxin),5 epolactaene (2, effective in
promoting neural outgrowth and arresting the cell cycle at the G0/
G1 phase in a human neuroblastoma cell line),6 oteromycin (3,
* Corresponding author. Tel.: þ98 21 61112250; fax: þ98 21 66495291; e-mail
addresses: ghandi@khayam.ut.ac.ir, meh.ghandi@gmail.com (M. Ghandi).
Fig. 1. Structures of fusarin C (1), epolactaene (2), oteromycin (3), and azaspirene (4).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.085

M. Ghandi et al. / Tetrahedron 69 (2013) 3054e3060
3055
multiple biological activities of coumarins in treating various can-
cer, cardiovascular, and rheumatic diseases9 prompted us to un-
dertake a study on the synthesis of novel heterocyclic scaffolds
containing the 5-hydroxy-3-pyrrolin-2-one motif, fused with
chromanones. Based on the known participation method of
the in situ generated quinone methides obtained from 4-
hydroxycoumains and aldehydes in a [4þ1] cycloaddition reaction
with isocyanides,10 we decided to carry out the similar [4þ1] cy-
cloaddition of the in situ generated 3-acetyl-2H-chromen-2-ones
with isocyanides as a convenient alternative to the synthesis of
coumarin-based heterocycles. Herein, we report the synthesis of
novel 2-hydroxy-N-substituted-2H-dihydrochromeno[3,4-c]pyr-
role-2-ones via a one-pot, three component reaction of a variety of
2-hydroxybenzaldehydes with ethyl acetoacetate and tert-butyl,
cyclohexyl or 1,1,3,3-tetramethylbutyl isocyanides in ethanol.
Scheme 3. One-pot synthesis of 2ael from 3aed and isocyanides.
We propose the following mechanistic consideration to account
for the formation of hydroxyamide 2a on the basis of the previously
reported works (Scheme 4).12 Upon the formation of 2-aminofuran
(I1) as the initially generated product, it may combine with triplet
oxygen quite rapidly to afford hydroperoxide I2 and molozonide I3,
respectively. Similar to that of the known classical ozonalysis re-
action, I3 may be fragmented to compound I4. Rapid conversion of
I4, affords I5 and finally hydroxyamide 2a by the well-known pro-
cess of disproportionation.13
The effect of introducing either a strong electron-donating
(EDG) or electron-withdrawing group (EWG) into the salicylalde-
hyde ring is to decrease the product yields (entries 7 to 12, Table 1).
On the other hand, whereas unsubstituted salicylaldehydes afford
the corresponding products in highest yields (entries 1 to 3, Table
1), those bearing modest electron-withdrawing groups produce
a less pronounced reduction in yields (entries 4 to 6, Table 1). This
behavior supports the suggested mechanism for the formation of
the initially generated product I1 (Scheme 3) if the isocyanide ad-
dition to the double bond of 1a (first step, Scheme 3), or the sub-
sequent cyclization process (second step, Scheme 3) becomes rate
limiting for EDGs and EWGs, respectively. Therefore, obtaining
lower yields of 2gel is anticipated.
2. Results and discussion
3-Acetyl-2H-chromen-2-one (1a) was used for our early in-
vestigation. Indeed, 2a was isolated as the sole reaction product
upon treatment of 1a with an equimolar amount of tert-butyl iso-
cyanide in EtOH at reflux within 16 h (Scheme 1).
Scheme 1. Formation of 2a from the reaction of 1a with tert-butyl isocyanide.
Our later studies revealed that 2a could be synthesized in a one-
pot reaction if 1a prepared in situ from piperidine-catalyzed con-
densation of salicylaldehyde (3a) with ethyl acetoacetate in EtOH at
reflux within 4 h, is treated with an equimolar amount of tert-butyl
isocyanide at reflux within 16 h (Scheme 2). Therefore, the utility of
3-acetyl-2H-chromen-2-one (1a) in the initial reaction was
confirmed.
3. Conclusion
In conclusion, a one-pot, three component reaction for the syn-
thesis of pyrrole-fused chromanone derivatives was described. Overall,
a number of 5-hydroxy-N-substituted-2H-dihydrochromeno[3,4-c]
pyrrole-2-ones were obtained in moderate to good yields via con-
densation of 2-hydroxybenzaldehydes and ethyl acetoacetate with
isocyanides in ethanol. These new structures broaden the chromenone
scaffolds and many of them may represent interesting
pharmacophores.
4. Experimental section
4.1. General information
All commercially available chemicals and reagents were pur-
chased from Merck Chemical Company and used without further
purification. Melting points were determined with an Electrother-
mal model 9100 apparatus and are uncorrected. IR spectra were
recorded on a Shimadzu 4300 spectrophotometer, in cmꢀ1. 1H and
13C NMR spectra were recorded on a Bruker DRX-500-AVANCE
spectrometer at 500 (1H) and 125 MHz (13C) using CDCl3 as sol-
vent and with the residual solvent signal as internal reference
(CDCl3, 7.24 and 77.0 ppm). Mass spectra of the products were
obtained with an HP (Agilent technologies) 5937 Mass Selective
Detector. Elemental analyses were carried out by a CHN-Rapid
Heraeus elemental analyzer (Wellesley, MA).
Scheme 2. One-pot synthesis of 2a from 3a.
This new method was then applied to
a range of 2-
hydroxybenzaldehydes (3aed) and tert-butyl, cyclohexyl or
1,1,3,3-tetramethylbutyl isocyanides (Scheme 3, Table 1). The
structures of 2ael were deduced by elemental analysis, MS, IR, 1H
NMR, and 13C NMR spectroscopy. For example, part of the 1H NMR
spectrum of 2b exhibited characteristic Me and OH signals at d 1.89
(3H, s) and 3.05 (1H, s), respectively. The 1H-decoupled 13C NMR
spectrum of 2b showed 16 distinct signals, including two charac-
teristic peaks at
d
160.4 and 163.8 due to two C]O groups, in
4.2. Representative procedure for the synthesis of 2ael
agreement with the proposed structure. Unambiguous evidence for
the proposed structure of 2b was finally obtained by single crystal
X-ray diffraction analysis (Fig. 2).11
To a stirring solution of piperidine (0.170 g, 20 mol %) in EtOH
(10 mL) was added 2-hydroxybenzaldehyde derivative (1.0 mmol)

3056
M. Ghandi et al. / Tetrahedron 69 (2013) 3054e3060
Table 1
Results obtained for the formation of 2ael
Entry
Aldehyde
Isocyanide
Product
Yield (%)
1
(Me)3CeNC
64
1a
2a
2
3
4
5
65
65
62
63
1a
2b
2c
2d
1a
(Me)3CeNC
1b
1b
2e
6
63
1b
2f

M. Ghandi et al. / Tetrahedron 69 (2013) 3054e3060
3057
Table 1 (continued )
Entry
Aldehyde
Isocyanide
Product
Yield (%)
7
(Me)3CeNC
49
1c
2g
8
50
1c
2h
9
55
1c
2i
10
52
1d
2j
11
59
1d
2k
12
60
1d
2l

3058
M. Ghandi et al. / Tetrahedron 69 (2013) 3054e3060
4.2.1. 2-tert-Butyl-3-hydroxy-3-methyl-2,3-dihydrochromeno[3,4-c]
pyrrole-1,4-dione (2a). White solid (184 mg, 64%); mp 171e173 ꢁC;
[found: C, 66.49; H, 6.18; N, 4.67. C16H17NO4 requires C, 66.89; H,
5.96; N, 4.88%]; Rf (33% EtOAc/hexane) 0.40; nmax (KBr) 3411 (OH),
1731 (C]O), 1683 (C]O) cmꢀ1
; dH (400 MHz, CDCl3) 1.66 (9H, s,
CMe3), 2.64 (3H, s, Me), 3.16 (1H, s, OH), 7.36e7.40 (2H, m, Ar),
7.60e7.64 (1H, m, Ar), 8.60 (1H, dd, J 5.2, 2.0 Hz, Ar); dC (100 MHz,
CDCl3), 22.9 (Me), 26.2 (CMe3), 52.9 (CMe3), 88.2 (C3), 109.4, 122.2,
123.4,128.2,129.4 (Ar),140.5 (C3a),145.4 (C9b),150.5 (Ar),160.4 (C]
O), 163.4 (C]O); m/z (EI, 70 eV) 287 (8, Mþ), 272 (20), 215 (86), 97
(20), 58 (100%).
4.2.2. 2-Cyclohexyl-3-hydroxy-3-methyl-2,3-dihydrochromeno[3,4-
c]pyrrole-1,4-dione (2b). White solid (203 mg, 65%); mp
173e175 ꢁC; [found: C, 68.69; H, 6.18; N, 4.67. C18H19NO4 requires C,
68.99; H, 6.11; N, 4.47%]; Rf (33% EtOAc/hexane) 0.41; nmax (KBr)
Fig. 2. X-ray crystal structure of compound 2b.
Scheme 4. Proposed mechanism for the formation of 2a.
and ethyl acetoacetate (0.130 g, 1.0 mmol) and the mixture was
heated at reflux for 4 h. Isocyanide (1.0 mmol) was then added and
the mixture was heated at reflux for another 16 h. After completion
as indicated by TLC, the solvent was removed under reduced
pressure and the residue was purified by column chromatography
(SiO2, eluent: 1:3 n-hexane/EtOAc) to afford the products 2ael.
3474 (OH), 1723 (C]O), 1694 (C]O) cmꢀ1
; dH (400 MHz, CDCl3),
1.20e2.50 (10H, m, 5CH2 of cyclohexyl), 1.89 (3H, s, Me), 2.80 (1H, s,
OH), 3.50 (1H, m, CHN of cyclohexyl), 7.36e7.40 (2H, m, Ar),
7.60e7.64 (1H, m, Ar), 8.60 (1H, dd, J 6.4, 1.6 Hz, Ar); dC (100 MHz,
CDCl3), 22.7 (Me), 25.2, 26.2, 26.3, 30.0, 30.0 (CH2), 52.8 (CHN of
cyclohexyl), 88.2 (C3), 114.9, 125.1, 125.8, 132.2, 133.4 (Ar), 137.3

M. Ghandi et al. / Tetrahedron 69 (2013) 3054e3060
3059
(C3a), 145.5 (C9b), 150.5 (Ar), 160.4 (C]O), 163.8 (C]O); m/z (EI,
70 eV) 314 (17, Mþþ1), 296 (80), 215 (60), 98 (100), 56 (80%).
163.4 (C]O); m/z (EI, 70 eV) 332 (8, Mþ), 318 (33), 260 (100), 191
(20), 58 (36%).
4.2.3. 3-Hydroxy-3-methyl-2-(2,4,4-trimethylpentan-2-yl)-2,3-
dihydrochromeno[3,4-c]pyrrole-1,4-dione (2c). White solid (223 mg,
65%); mp 150e152 ꢁC; [found: C, 69.56; H, 7.18; N, 4.17. C20H25NO4
requires C, 69.95; H, 7.34; N, 4.08%]; Rf (33% EtOAc/hexane) 0.43;
4.2.8. 2-Cyclohexyl-3-hydroxy-3-methyl-8-nitro-2,3-dihydrochro-
meno[3,4-c]pyrrole-1,4-dione (2h). Brownish solid (179 mg, 50%);
mp 169e170 ꢁC; [found: C, 60.39; H, 4.99; N, 7.77. C18H18N2O6 re-
quires C, 60.33; H, 5.06; N, 7.82%]; Rf (33% EtOAc/hexane) 0.36; nmax
nmax (KBr) 3274 (OH), 1717 (C]O), 1642 (C]O) cmꢀ1
;
dH (400 MHz,
(KBr) 3417 (OH), 1692 (C]O), 1649 (C]O) cmꢀ1
; dH (400 MHz,
CDCl3), 1.07 (9H, S, CMe3), 1.65 (6H, s, CMe2), 1.78 (2H, s, CH2), 2.64
(3H, Me), 3.17 (1H, s, OH), 7.36e7.40 (2H, m, Ar), 7.60e7.64 (1H, m,
Ar), 8.60 (1H, dd, J 8.40, 6.4, 1.6 Hz, Ar); dC (100 MHz, CDCl3), 22.9
(Me), 27.9, 31.0 (CMe2), 31.6, 31.7 (CMe3), 54.0 (CCH2C), 57.7 (CMe2),
88.2 (C3), 109.3, 122.2, 123.4, 128.2, 129.4 (Ar), 140.5(C3a), 145.5
(C9b),150.5 (Ar),160.4, 163.4 (C]O); m/z (EI, 70 eV) 343 (8, Mþ), 272
(20), 215 (86), 97 (20), 58 (100%).
CDCl3),1.20e2.50 (10H, m, 5CH2 of cyclohexyl) 1.89 (3H, s, Me), 2.78
(1H, s, OH), 3.47e3.54 (1H, m, CHN of cyclohexyl), 7.55 (1H, d,
J¼9.2 Hz, Ar), 8.52e8.61 (2H, m, Ar); dC (100 MHz, CDCl3), 22.7 (Me),
25.2, 26.2, 26.3, 30.0, 30.1 (CH2), 52.9 (CHN of cyclohexyl), 88.3 (C3),
122.2, 123.4, 128.2, 129.3 (Ar), 140.5 (C3a), 144.4(C9b), 145.5, 157.4
(Ar), 160.4 (C]O), 163.4 (C]O); m/z (EI, 70 eV) 358 (8,Mþ), 344
(35), 260 (100), 191 (20), 58 (35%).
4.2.4. 8-Bromo-2-tert-butyl-3-hydroxy-3-methyl-2,3-dihydrochro-
meno[3,4-c]pyrrole-1,4-dione (2d). White solid (226 mg, 62%); mp
183e185 ꢁC; [found: C, 52.69; H, 4.18; N, 3.67. C16H16Br NO4 re-
quires C, 52.48; H, 4.40; N, 3.82%]; Rf (3% EtOAc/hexane) 0.50; nmax
4.2.9. 3-Hydroxy-3-methyl-8-nitro-2-(2,4,4-trimethylpentan-2-yl)-
2,3-dihydrochromeno[3,4-c]pyrrole-1,4-dione (2i). Brownish solid
(213 mg, 55%); mp 154e155 ꢁC; [found: C, 61.72; H, 6.12; N, 7.27.
C20H24N2O6 requires C, 61.84; H, 6.23; N, 7.21%]; Rf (33% EtOAc/
(KBr) 3279 (OH), 1715 (C]O), 1639 (C]O) cmꢀ1
;
dH (400 MHz,
hexane) 0.37; nmax (KBr) 3390 (OH), 1672, 1659 (C]O) cmꢀ1
; dH
CDCl3), 1.66 (9H, s, CMe3), 2.07 (3H, s, Me), 3.06 (1H, s, OH), 7.28
(1H, d, J 9.0 Hz, Ar), 7.71 (1H, dd, J¼9.0, 2.4 Hz, Ar), 8.83 (1H, d,
J¼2.4 Hz, Ar); dC (100 MHz, CDCl3), 22.9 (Me), 26.2, (CMe3), 52.9
(CMe3), 88.3 (C3), 122.2, 123.4, 128.2, 129.4, 134.3 (Ar), 135.4 (C3a),
145.5 (C9b), 150.4 (Ar), 160.31 (C]O), 163.3 (C]O); m/z (EI, 70 eV)
(400 MHz, CDCl3), 1.07 (9H, s, CMe3), 1.65 (6H, s, CMe2), 1.78 (2H, s,
CH2), 2.65 (3H,s, Me), 3.17 (1H, s, OH), 7.55 (1H, d, J¼6.0 Hz, Ar),
8.52e8.61 (2H, m, Ar); dC (100 MHz, CDCl3), 22.9 (Me), 27.9, 31.0
(CMe2), 31.6, 31.7 (CMe3), 54.0 (CCH2C), 57.7 (CMe3), 88.2 (C3),
122.2, 123.4, 128.2, 129.4 (Ar) 140.5 (C3a), 144. 4(C9b), 145.5, 157.5
(Ar), 160.3, 163.4 (C]O); m/z (EI, 70 eV) 388 (8, Mþ), 332 (35), 318
(33), 260 (100), 191 (20), 58 (35%).
367 (Mþþ2 [81Br], 15), 365 (Mþ
[
79Br], 15), 350 (43), 295 (68), 223
(17), 58 (100%).
4.2.5. 8-Bromo-2-cyclohexyl-2,3-dihydro-3-hydroxy-3-methylchro-
meno[3,4-c]pyrrole-1,4-dione (2e). Greenish solid (246 mg, 63%);
mp 189e190 ꢁC; [found: C, 55.49; H, 4.41; N, 3.47. C18H18Br NO4
requires C, 55.12; H, 4.63; N, 3.57%]; Rf (33% EtOAc/hexane) 0.53;
4.2.10. 2-tert-Butyl-3-hydroxy-6-methoxy-3-methyl-2,3-dihydroch-
romeno[3,4-c]pyrrole-1,4-dione (2j). Greenish solid (165 mg, 52%);
mp 189e190 ꢁC; [found: C, 64.49; H, 6.11; N, 4.47. C17H19NO5 re-
quires C, 64.34; H, 6.03; N, 4.41%]; Rf (33% EtOAc/hexane) 0.25;
nmax (KBr) 3335 (OH), 1736, 1660 (C]O) cmꢀ1
;
dH (400 MHz,
nmax (KBr) 3317 (OH), 1752, 1675 (C]O) cmꢀ1
; dH (400 MHz,
CDCl3), 1.20e2.50 (10H, m, 5CH2 of cyclohexyl) 1.89 (3H, s, Me),
2.80 (1H, s, OH), 3.50 (1H, m, CHN of cyclohexyl), 7.28 (1H, d,
J¼8.8 Hz, Ar), 7.71 (1H, dd, J¼8.8, 2.4 Hz, Ar), 8.83 (1H, d,
J¼2.4 Hz, Ar); dC (100 MHz, CDCl3), 22.7 (Me), 25.2, 26.2, 26.3,
30.0, 30.1 (CH2), 52.8 (CHN of cyclohexyl), 88.2 (C3), 114.9, 120.4,
127.1, 127.8, 133.4 (Ar), 137.3 (C3a), 145.5 (C9b), 150.5 (Ar), 160.4
(C]O), 163.8 (C]O); m/z (EI, 70 eV) 395 (Mþþ2 [81Br], 18), 393
CDCl3), 1.66 (9H, s, CMe3), 2.64 (3H, s, Me), 3.16 (1H, s, OH), 4.0
(3H, s, OMe), 7.29 (1H, d, J¼8.4 Hz, Ar), 7.69e7.72 (1H, dd, J¼7.6,
2.8 Hz, Ar), 8.83 (1H, d, J¼1.2 Hz, Ar); dC (100 MHz, CDCl3), 22.9
(Me), 26.2, 52.9 (CMe3), 55.9 (OMe), 88.2 (C3), 112.4, 122.2, 128.2,
129.4, 137.3 (C3a), 144.5 (C9b), 147.5, 150.5 (Ar), 160.4, 163.4 (C]O);
m/z (EI, 70 eV) 317 (8, Mþ), 302 (35), 245 (80), 114 (34), 97 (35), 58
(100%).
(Mþ 79Br], 18), 376 (34), 295 (80), 98 (100), 56 (75%).
[
4.2.11. 2-Cyclohexyl-3-hydroxy-6-methoxy-3-methyl-2,3-dihydroch-
romeno[3,4-c]pyrrole-1,4-dione (2k). Greenish solid (202 mg, 59%);
mp 209e210 ꢁC; [found: C, 66.49; H, 6.11; N, 4.07. C19H21NO5 re-
quires C, 66.46; H, 6.16; N, 4.08%]; Rf (33% EtOAc/hexane) 0.26; nmax
4.2.6. 8-Bromo-3-hydroxy-3-methyl-2-(2,4,4-trimethylpentan-2-yl)-
2,3-dihydrochromeno[3,4-c]pyrrole-1,4-dione (2f). Greenish solid
(265 mg, 63%); mp 174e175 ꢁC; [found: C, 56.49; H, 5.71; N, 3.37.
C20H24BrNO4 requires C, 56.88; H, 5.73; N, 3.32%]; Rf (3% EtOAc/
hexane) 0.52; nmax (KBr) nmax 3295 (OH), 1710 (C]O), 1665 (C]O)
(KBr) 3347 (OH), 1742, 1685 (C]O) cmꢀ1
; dH (400 MHz, CDCl3),
1.20e2.50 (10H, m, 5CH2 of cyclohexyl) 1.89 (3H, s, Me), 2.80 (1H, s,
OH), 3.47e3.54 (1H, m, CHN of cyclohexyl), 4.00 (3H, s, OMe), 7.28
(1H, d, J¼7.2 Hz, Ar), 7.71 (1H, dd, J¼7.2, 2.4 Hz, Ar), 8.82 (1H, d,
J¼2.4 Hz, Ar); dC (100 MHz, CDCl3), 22.7 (Me), 25.2, 26.2, 26.3, 30.0,
30.1 (CH2), 52.9 (CHN of cyclohexyl), 58.2 (OMe), 88.2 (C3), 114.9,
120.4, 127.1, 127.8, 133.4 (Ar) 137.3 (C3a), 145.4 (C9b), 150.4 (Ar),
160.4, 163.9 (C]O); m/z (EI, 70 eV) 343 (8, Mþ), 329 (50), 245 (100),
175 (28), 98 (70), 56 (32%).
cmꢀ1
; dH (400 MHz, CDCl3), 1.07 (9H, s, CMe3), 1.65 (6H, s, CMe2),
1.78 (2H, s, CH2), 2.64 (3H, s, Me), 3.17 (1H, s, OH), 7.28 (1H, d,
J¼9.2 Hz, Ar), 7.71 (1H, dd, J¼9.2, 2.4 Hz, Ar), 8.83 (1H, d, J¼2.4 Hz,
Ar); dC (100 MHz, CDCl3), 22.9 (Me), 27.9, 31.0 (CMe2), 31.6, 31.7
(CMe3), 54.0 (CCH2C), 57.7 (CMe3), 88.2 (C3), 122.2, 123.4, 128.2,
129.4, 134.3 (Ar), 135.5 (C3a), 145.5 (C9b), 150.5 (Ar), 160.3 (C]O),
163.3 (C]O); m/z (EI, 70 eV) 423 (Mþþ2 [81Br], 8), 421 (Mþ
[
79Br],
8), 366 (15), 350 (43), 295 (68), 58 (100%).
4.2.12. 3-Hydroxy-6-methoxy-3-methyl-2-(2,4,4-trimethylpentan-2-
4.2.7. 2-tert-Butyl-3-hydroxy-3-methyl-8-nitro-2,3-dihydrochromeno
[3,4-c]pyrrole-1,4-dione (2g). Brownish solid (163 mg, 49%); mp
159e160 ꢁC; [found: C, 57.49; H, 4.71; N, 8.47. C16H16 N2O6 re-
quires C, 57.83; H, 4.85; N, 8.43%]; Rf (33% EtOAc/hexane) 0.35;
yl)-2,3-dihydrochromeno[3,4-c]pyrrole-1,4-dione
(2l). Greenish
solid (224 mg, 60%); mp 174e175 ꢁC; [found: C, 67.43; H, 7.23; N,
3.66. C21H27NO5 requires C, 67.54; H, 7.29; N, 3.75%]; Rf (33% EtOAc/
hexane) 0.27; nmax (KBr) 3317 (OH),1712, 1695 (C]O) cmꢀ1
; dH
nmax (KBr) 3395 (OH), 1706 (C]O), 1639 (C]O) cmꢀ1
;
dH
(400 MHz, CDCl3), 1.07 (9H, s, CMe3), 1.65 (6H, s, CMe2), 1.78 (2H, s,
CH2), 2.65 (3H, s, Me), 3.10 (1H, s, OH), 4.00 (3H, s, OMe), 7.28 (1H, d,
J¼7.6 Hz, Ar), 7.71 (1H, dd, J¼7.6, 2.4 Hz, Ar), 8.83 (1H, d, J¼2.4 Hz,
Ar); dC (100 MHz, CDCl3), 22.9 (Me), 27.9, 31.0 (CMe2), 31.6, 31.7
(CMe3), 54.0 (CCH2C), 57.7 (CMe3), 59.7 (OMe), 88.3 (C3), 112.4,
(400 MHz, CDCl3), 1.66 (9H, s, CMe3), 2.64 (3H, s, Me), 3.16 (1H, s,
OH), 7.55 (1H, d, J¼8.0 Hz, Ar), 8.52e8.61 (2H, m, Ar); dC (100 MHz,
CDCl3), 22.9 (Me), 26.2, 52.9 (CMe3), 88.2 (C3), 122.2, 123.4, 128.2,
129.4 (Ar) 140.5 (C3a), 144.5 (C9b) 145.5, 157.4 (Ar), 160.4 (C]O),

3060
M. Ghandi et al. / Tetrahedron 69 (2013) 3054e3060
6. Kakeya, H.; Onozawa, C.; Sato, M.; Arai, K.; Osada, H. J. Med. Chem. 1997, 40,
391e394.
7. Singh, S. B.; Goetz, M. A.; Jones, E. T.; Bills, G. F.; Giacobbe, R. A.; Herram, L.;
Stevens- Miles, S.; Williams, D. A., Jr. J. Org. Chem. 1995, 60, 7040e7042.
8. Asami, Y.; Kakeya, H.; Onose, R.; Yoshida, A.; Matsuzaki, H.; Osada, H. Org. Lett.
2002, 4, 2845e2848.
122.2, 128.2, 129.4 (Ar) 137.3 (C3a), 144.5 (C9b) 147.5, 150.5 (Ar),
160.3, 163.4 (C]O); m/z (EI, 70 eV) 374 (33, Mþþ1), 302 (35), 245
(80), 114 (34), 97 (35), 58 (100%).
Acknowledgements
9. (a) Che, C.; Li, S.; Jiang, X.; Quan, J.; Lin, S.; Yang, Z. Org. Lett. 2010, 12,
4682e4685; (b) Casley-Smith, J. R. Br. J. Exp. Pathol. 1975, 56, 439e443; (c)
Fylaktakidou, K.; Hadjipavlou-Litina, D.; Litinas, K.; Nicolaides, D. Curr. Pharm.
Des. 2004, 30, 3813e3833; (d) Neichi, T.; Koshihara, Y.; Mutora, S. I. Biochim.
Biophys. Acta 1983, 753, 130e132; (e) Kimura, Y.; Okuda, H.; Arichi, S.; Baba, K.;
Kozawa, M. Biochim. Biophys. Acta 1985, 834, 224e229; (f) Craven, P. A.;
Pfanstiel, J.; De Rubertis, F. R. J. Clin. Invest. 1986, 77, 850e859; (g) Ozaki, Y.;
Ohashi, T.; Niwa, Y. Biochem. Pharmacol. 1986, 35, 3481e3488; (h) Paya, M.;
Halliwell, B.; Hoult, J. R. S. Biochem. Pharmacol. 1992, 44, 205e214; (i) Mora, A.;
Paya, M.; Rios, J. L.; Alcaraz, M. J. Biochem. Pharmacol. 1990, 40, 793e797.
10. (a) Nair, V.; Menon, R. S.; Vinod, A. U.; Viji, S. Tetrahedron Lett. 2002, 43,
2293e2295; (b) Obata, N.; Takizawa, T. Tetrahedron Lett. 1969, 10, 3403e3406;
(c) Ito, Y.; Kato, H.; Saegusa, T. J. Org. Chem. 1982, 47, 741e743; (d) Gambarayan,
N. P.; Rokhlin, E. M.; Zeifmann, Y. V.; Simonyan, L. A.; Knunyans, I. L. Dokl. Akad.
Nauk SSSR 1966, 166, 864e868; (e) Rigby, J. H.; Qabar, M. N. J. Am. Chem. Soc.
1991, 113, 8975e8976; (f) Kollenz, G.; Ott, W.; Ziegler, E.; Peters, K.; v.
Schnering, H. G.; Quast, H. Liebigs Ann. Chem. 1980, 1801e1805; (g) Ott, W.;
Kratky, C. .; Seiler, P. Liebigs Ann. Chem. 1980, 1711e1717; (h) Ott, W.; Kollenz, G.;
Peters, K.; Peters, E.-M.; v. Schnering, H. G.; Quast, H. Liebigs Ann. Chem. 1983,
635e641.
The authors acknowledge the University of Tehran for financial
support of this research.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.01.085.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References and notes
1. (a) Liang, B.; Kalidindi, S.; Porco, J. A., Jr.; Stephenson, C. R. J. Org. Lett. 2010, 12,
572e575; (b) Ganem, B. Acc. Chem. Res. 2009, 42, 463e472; (c) Cui, S. L.; Lin, X.
F.; Wang, Y. G. Org. Lett. 2006, 8, 4517e4520.
11. Crystallographic data for 2b have been deposited at the Cambridge Crystal-
lographic Data Centre with the deposition number CCDC 907693. Copies of
these data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/re-
trieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, UK; fax: 44 1223 336 033; or e-mail: deposit@
ccdc.cam.ac.uk).
12. (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; Choi, H.-S. J. Am. Chem.
Soc. 2002, 124, 2190e2201; (b) Quai, M.; Frattini, S.; Vendrame, U.; Mondoni,
M.; Dossena, S.; Cereda, E. Tetrahedron Lett. 2004, 45, 1413e1416; (c) Adib, M.;
Mahdavi, M.; Alizadeh Noghania, M.; Bijanzadeh, H. R. Tetrahedron Lett. 2007,
48, 8056e8059; (d) Ghandi, M.; Asgari, P.; Taheri, A.; Abbasi, A. Cent. Eur. J.
Chem. 2010, 8, 899e905.
2. Kriis, K.; Ausmees, K.; Pehk, T.; Lopp, M.; Kanger, T. Org. Lett. 2010, 12,
2230e2233.
3. (a) Shaw, A. Y.; Xu, Z.; Hulme, C. Tetrahedron Lett. 2012, 53, 1998e2000; (b)
Ghandi, M.; Zarezadeh, N.; Taheri, A. Tetrahedron Lett. 2012, 53, 3353e3356; (c)
Ghandi, M.; Zarezadeh, N.; Taheri, A. Tetrahedron Lett. 2011, 52, 1228e1232; (d)
Soleimani, E.; Zainali, M. J. Org. Chem. 2011, 76, 10306e10311; (e) Kaim, L. E.;
Grimaud, L.; Patil, P. Org. Lett. 2011, 13, 1261e1263; (f) Shaabani, A.; Ghadari, R.;
Sarvary, A.; Rezayan, H. J. Org. Chem. 2009, 74, 4372e4374; (g) Domling, A.
Chem. Rev. 2006, 106, 17e89; (h) Nair, V.; Menon, R. S.; Beneesh, P. B.;
Sreekumar, V.; Bindu, S. Org. Lett. 2004, 6, 767e769.
4. Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8e20.
5. Song, Z.; Cox, R. J.; Lazarus, C. M.; Simpson, T. J. ChemBioChem 2004, 5,
1196e1203.
13. Smith, L. L.; Kulig, M. J. J. Am. Chem. Soc. 1976, 98, 1027e1029.