One-pot three-component synthesis of functionalized spirolactones by means of reaction between aromatic ketones, dimethyl acetylenedicarboxylate, and N-heterocycles

Article abstract of DOI:10.1016/j.tet.2011.09.017

A simple and convenient one-pot multi-component reaction has been described for the synthesis of functionalized spirolactones. This strategy demonstrated three-component reaction between aromatic ketones (11H-indeno[1,2-b]quinoxalin- 11-one) and dimethyl acetylenedicarboxylate (DMAD) in the presence of N-heterocycles, such as pyridine, quinoline, and isoquinoline in CH ₂Cl₂ at ambient temperature without use of any catalyst or activator.

Full text of DOI:10.1016/j.tet.2011.09.017

Tetrahedron 67 (2011) 8492e8495
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot three-component synthesis of functionalized spirolactones by means
of reaction between aromatic ketones, dimethyl acetylenedicarboxylate,
and N-heterocycles
,
a
b
a
Malek Taher Maghsoodlou a , Sayyed Mostafa Habibi-Khorassani , Abbas Moradi , Nourallah Hazeri ,
*
Amir Davodi a, Seyed Sajad Sajadikhah a
a Department of Chemistry, University of Sistan and Baluchestan, PO Box 98135-674, Zahedan, Iran
b Department of Chemistry, University of Birjand, PO Box 97175-615, Birjand, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 May 2011
Received in revised form 15 August 2011
Accepted 6 September 2011
Available online 12 September 2011
A simple and convenient one-pot multi-component reaction has been described for the synthesis of
functionalized spirolactones. This strategy demonstrated three-component reaction between aromatic
ketones (11H-indeno[1,2-b]quinoxalin-11-one) and dimethyl acetylenedicarboxylate (DMAD) in the
presence of N-heterocycles, such as pyridine, quinoline, and isoquinoline in CH2Cl2 at ambient temper-
ature without use of any catalyst or activator.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Spirolactone
N-Heterocycle
DMAD
Multi-component reaction
1. Introduction
2. Results and discussion
The development of simple synthesis routes for widely used
organic compounds using readily available reagents is one of the
most important tasks in organic chemistry.1 Heterocyclic systems
with oxygen, nitrogen, sulfur, and other heteroatoms in five and
six-membered rings are of interest due to their pharmaceutical and
biological activities, such as anti-inflammatory, cardiotonic, ino-
tropic, antihypertensive, antimicrobial, and antibacterial proper-
ties.2e9 In this respect, spiro compound and specially spirolactone
derivatives have been reported as anti-convulsants10 and antitu-
morals.11,12 As a results, a number methods have been describing
novel synthesis for spiro compounds.13ꢀ23
First, the aromatic ketones (11H-indeno[1,2-b]quinoxalin-11-
one) 1 were synthesized according to previous work,30 by means
of reaction between ninhydrin (2,2-dihydroxyindane-1,3-dione)
and 1,2-diaminobenzene derivatives (Scheme 1).
Scheme 1. Synthesis of 11H-indeno[1,2-b]quinoxalin-11-one derivatives.30
In continuation of our work on multi-component reactions,24e29
we now describe a one-pot, three-component synthesis of new
functionalized spirolactones 4 from reaction between aromatic
ketones 1, dimethyl acetylenedicarboxylate (DMAD) 2 and N-het-
erocycles 3, such as pyridine, quinoline, and isoquinoline in high to
excellent yields.
The reaction of aromatic ketones 1 and DMAD 2 in the presence
of N-heterocycles 3 proceeds smoothly in CH2Cl2 at ambient tem-
perature to produce spirolactones 4 in high to excellent yield
(Scheme 2). The results are summarized in Table 1. It is noteworthy
that the reaction in the presence of pyridine and/or isoquinoline (as
a N-heterocycle) generates only one diastereoisomer, while with
quinoline produce two diastereoisomers. Our attempt to separate
these diastereoisomers was unsuccessful (Scheme 3).
The structures of the products 4aef were deduced by IR, 1H
NMR, and 13C NMR spectroscopy. The mass spectra of these
* Corresponding author. E-mail address: mt_maghsoodlou@yahoo.com
(M.T. Maghsoodlou).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.017

M.T. Maghsoodlou et al. / Tetrahedron 67 (2011) 8492e8495
8493
R
a 1,3-dipolar intermediate 5 between N-heterocycle 3 and DMAD 2,
which reacts with the carbonyl group of aromatic ketone 1 for
generating intermediate 6. Cyclization of the intermediate 6 leads
to the intermediate 7, next the reaction between intermediate 7
and methoxy anion generate the spirolactone 4.
R
R
OMe
O
N
O
R
N
R
CO Me
N
R
R
R
R
CH2Cl2
rt, 6 h
O
N
MeO C
+
+
N
R
R
CO Me
N
3. Conclusion
R
2
3
4
1
Scheme 2. Synthesis of spirolactone 4.
In summary, we demonstrated an effective one-pot three-
component approach for the synthesis of spirolactone derivatives
via the reaction between the aromatic ketones (11H-indeno[1,2-b]
quinoxalin-11-one), DMAD and N-heterocycles, such as pyridine,
quinoline, and isoquinoline in CH2Cl2 at ambient temperature in
high to excellent yields. The present procedure has the advantage
that, not only is the reaction performed under neutral conditions,
but also the substances can be mixed without any activation or
modification.
Table 1
Synthesis of spirolactone 4 in the presence of various N-Heterocycle compounds
Entry
1
R1
R2
N-heterocycle
Product
Yielda (%)
H
H
4a
91
N
N
4. Experimental
4.1. General
2
Me
Me
4b
89
Melting points and IR spectra were taken on an Electrothermal
9100 apparatus and a JASCO FT-IR-460 plus spectrometer, re-
spectively. Elemental analyses for C, H, and N were performed using
a Heraeus CHN-O-Rapid analyzer at Iranian Central Research of Pe-
troleum Company. The 1H and 13C NMR spectra were recorded on
a Bruker (Rheinstetten, Germany) DRX-250 and 300 Avanve in-
strumentwithCDCl3 assolvent and using TMS asinternal referenceat
250, 300, 62.9, and 75 MHz, respectively. The mass spectra were
recorded on a shimadzu GCeMS-QP5050 mass spectrometer, oper-
ating at an ionizationpotential of 70 eV. All reagents and solvent were
obtained from Merck (Darmastadt, Germany), Acros (Geel, Belgium),
and Fluka(Buchs, Switzerland), and usewithout further purifications.
3
4
5
H
H
4c
4d
4e
90
87
84
N
N
Me
H
Me
H
N
N
6
Me
Me
4f
81
4.2. General procedure for synthesis of spirolactone 4
a
Isolated yields.
To a stirred solution of aromatic ketone 1 (1 mmol) and N-het-
erocycle 3 (1 mmol) in CH2Cl2 (10 mL) was added dropwise
a mixture of DMAD 2 (1 mmol) in CH2Cl2 (2 mL) at ambient tem-
perature over 15 min. The mixture was allowed to stir for 6 h. After
completion of the reaction (monitored by TLC), the solvent was
removed under reduced pressure and the residue was washed with
cold ethanol to afford pure product 4.
4.2.1. Methyl 4-(2-methoxypyridin-1(2H)-yl)-5-oxo-5H-spiro[furan-
2,110-indeno[1,2-b]quinoxaline]-3-carboxylate (4a). Yellow powder,
yield 0.413 g (91%). [Found: C, 69.08; H, 4.26; N, 9.33. C26H19N3O5
requires C, 68.87; H, 4.22; N, 9.27%]; Rf (50% EtOAc/hexane) 0.54;
mp: 167e169 ꢁC. IR (KBr) (lmax, cmꢀ1): 2945, 3057 (CH), 1700 and
1735 (C]O). 1H NMR (250 MHz, CDCl3): 3.16 (3H, s, OCH3), 4.00 (3H,
s, OCH3), 5.36 (1H, m, CHdihydropyridine), 5.53 (1H, m, CHdihydropyridine),
6.24 (1H, m, CHdihydropyridine), 6.46 (1H, d, J¼7.5, CHdihydropyridine),
7.01 (H, s, CH), 7.46 (5H, m, 5CH), 8.07 (1H, d, J¼7.5, CHdihydropyridine),
8.16 (2H, m, 2CH). 13C NMR (62.9 MHz, CDCl3): 51.4, 53.3 (2OCH3),
79.4 (Cspiro), 80.0, 101.6 (2CH), 107.4 (C), 116.5, 123.3, 123.6, 124.8,
125.0, 128.8, 129.2, 129.8, 130.3 (9CH), 132.0, 138.4 (2C), 142.2 (CH),
142.7 (C),145.7 (CH),146.5,147.2,154.0,161.7 (4C),163.6,163.8 (2C]
O). MS (m/z, %): 453 (Mþ, 29), 421 (5), 394 (16), 362 (100).
Scheme 3. Two diastereoisomers of spirolactones 4e and 4f.
compounds displayed molecular ion peaks at the appropriate m/z
values and initial fragmentation involves the loss of the side chains.
For example, the 1H NMR spectrum of 4a exhibited two singlets at
d
3.16 and 4.00 ppm for methoxy groups. The hemiaminal proton of
4a was observed at
d 6.46 ppm as doublet with coupling constant
3J¼7.5 Hz. The other dihydropyridine protons and the aromatic
protons resonance appeared as mixture of singlets, doublets, trip-
lets or multiplets around
d
5.36e8.16 ppm. The 13C NMR spectrum
of compound 4a showed 26 distinct resonances consistent with the
spirolactone structure. The characteristic signal for the spiro carbon
4.2.2. Methyl 4-(2-methoxypyridin-1(2H)-yl)-70,80-dimethyl-5-oxo-
5H-spiro[furan-2,110-indeno[1,2-b]quinoxaline]-3-carboxylate
(4b). Yellow powder, yield 0.430 g (89%). [Found: C, 69.99; H, 4.80;
N, 8.78. C28H23N3O5 requires C, 69.84; H, 4.81; N, 8.73%]; Rf (50%
EtOAc/hexane) 0.61; mp: 169e172 ꢁC. IR (KBr) (lmax, cmꢀ1): 2951
(CH), 1709 and 1739 (C]O). 1H NMR (250 MHz, CDCl3): 2.48 (6H, s,
was observed at
d 79.4 ppm.
Although the mechanism of this reaction has not been estab-
lished experimentally, the proposed mechanism for the formation
of these spirolactones 4 is illustrated in Scheme 4. It is reasonable to
assume that the spirolactone 4 results from the initial formation of

8494
M.T. Maghsoodlou et al. / Tetrahedron 67 (2011) 8492e8495
R
R
O
R
R
N
R
N
R
OMe
CO2Me
R
R
R
R
O
R
1
+
N
R1
R2
MeO2C
N
CO2Me
CO2Me
R
CO2Me
N
3
2
5
6
R
R
R
OMe
N
O
R
O
MeO2C
4
N
R1
R2
N
7
Scheme 4. The proposed mechanism for synthesis of spirolactone 4.
2CH3), 3.13 (3H, s, OCH3), 4.00 (3H, s, OCH3), 5.35 (1H, m, CHdihy-
dropyridine), 5.51 (1H, m, CHdihydropyridine), 6.22 (1H, m, CHdihydropyr-
idine), 6.46 (1H, d, J¼7.25, CHdihydropyridine), 7.00 (1H, s, CH), 7.49 (3H,
m, 3CH), 7.82 (1H, s, CH), 7.88 (1H, s, CH), 8.11 (1H, d, J¼6.5, CHdi-
hydropyridine). 13C NMR (62.9 MHz, CDCl3): 20.1, 20.2 (2CH3), 51.4,
53.3 (2OCH3), 79.5 (Cspiro), 79.9, 101.4 (2CH), 107.5 (C), 116.5 (CH),
121.3 (C), 122.0 (CH), 123.0 (C), 124.9, 125.0, 128.5 (3CH), 129.1 (C),
130.1 (CH), 131.5 (C), 139.1, 140.1 (2CH), 141.1, 145.3 (2C), 147.0 (CH),
150.9, 153.0, 160.8 (3C), 163.6, 163.8 (2C]O). MS (m/z, %): 481 (Mþ,
11), 449 (3), 422 (4), 389 (39), 312 (13), 128 (47), 77 (100).
4.2.5. Methyl 4-(2-methoxyquinolin-1(2H)-yl)-5-oxo-5H-spiro[fu-
ran-2,110-indeno[1,2-b]quinoxaline]-3-carboxylate
(4e). Yellow
powder, yield 0.424 g (84%). [Found: C, 71.78; H, 4.25; N, 8.33.
C30H21N3O5 requires C, 71.56; H, 4.20; N, 8.35%]; mp: 216e220 ꢁC. IR
(KBr) (lmax, cmꢀ1): 3064 and 2951 (CH), 1714 and 1740 (C]O). NMR
data for the major isomer (55%).1H NMR (300 MHz, CDCl3): 3.26 (3H, s,
OCH3), 3.92 (3H, s, OCH3), 5.94 (1H, m, CHdihydroquinoline), 6.50 (1H, d,
J¼4.3, CHdihydroquinoline), 6.87 (1H, d, J¼9.7, CHdihydroquinoline), 7.08 (2H,
m, 2CH), 7.26e8.24 (10H, m, 10CH). 13C NMR (75 MHz, CDCl3): 52.0,
53.2 (2OCH3), 79.9 (CH), 81.0 (Cspiro), 114.3, 118.5 (2CH), 121.7 (C),
122.5, 122.5, 123.7, 124.7, 128.7, 129.6, 129.7, 129.8, 130.2, 131.6, 132.5
(11CH), 135.8 (C), 136.8 (CH), 141.4, 142.1, 142.1, 142.6, 143.6, 146.4,
153.8, 161.2 (8C), 163.7, 164.4 (2C]O). NMR data for the minor isomer
(45%). 1H NMR (300 MHz, CDCl3): 3.24 (3H, s, OCH3), 3.89 (3H, s,
OCH3), 5.94 (1H, m, CHdihydroquinoline), 5.99 (1H, d, J¼4.3, CHdihy-
droquinoline), 6.83 (1H, d, J¼9.7, CHdihydroquinoline), 7.08 (2H, m, 2CH),
7.26e8.24 (10H, m, 10CH). 13C NMR (75 MHz, CDCl3): 52.0, 53.2
(2OCH3), 79.9 (CH), 81.0 (Cspiro), 115.3, 117.9 (2CH), 121.2 (C), 122.1,
122.7, 124.3, 128.6, 128.9, 129.1, 129.2, 129.9, 130.4, 130.6, 132.1, 132.4
(12CH), 138.1, 140.8, 141.4, 142.1, 143.2, 144.6, 147.1, 156.45, 161.2 (9C),
164.1, 164.7 (2C]O). MS: (m/z, %): 503 (Mþ, 9), 443 (7), 412 (4), 314
(9), 128 (100).
4.2.3. Methyl
4-[1-methoxyisoquinolin-2(1H)-yl]-5-oxo-5H-spiro
(4c). Yellow
[furan-2,110-indeno[1,2-b]quinoxaline]-3-carboxylate
powder, yield 0.454 g (90%). [Found: C, 71.67; H, 4.18; N, 8.31.
C30H21N3O5 requires C, 71.56; H, 4.20; N, 8.35%]; Rf (50% EtOAc/
hexane) 0.58; mp: 190e193 ꢁC. IR (KBr) (lmax, cmꢀ1): 2949 (CH),
1708 and 1734 (C]O). 1H NMR (250 MHz, CDCl3): 3.19 (3H, s,
OCH3), 4.03 (3H, s, OCH3), 5.87 (1H, d, J¼7.5, CHdihydroisoquinoline),
6.51 (1H, d, J¼7.5, CHdihydroisoquinoline), 7.02 (1H, s, CH), 7.11 (3H, m,
3CH), 7.56 (6H, m, 6CH), 8.17 (3H, m, 3CH). 13C NMR (62.9 MHz,
CDCl3): 51.5, 53.4 (2OCH3), 79.9 (Cspiro), 80.8, 105.1 (2CH), 122.6
(C), 123.4, 123.9, 125.2 (3CH), 126.3 (CH), 127.0, 127.8 (2CH), 128.9
(C), 129.0, 129.4 (2CH), 129.7 (C), 129.8, 130.0, 130.4 (3CH), 132.2,
137.9 (2C), 141.3 (CH), 142.2, 145.5 (2C), 147.4 (CH), 153.9, 162.2
(2C), 163.7, 163.9 (2C]O). MS (m/z, %): 503 (Mþ, 2), 444 (10), 412
(13), 128 (14), 42 (100).
4.2.6. Methyl 4-(2-methoxyquinolin-1(2H)-yl)-70,80-dimethyl-5-oxo-
5H-spiro[furan-2,110-indeno[1,2-b]quinoxaline]-3-carboxylate
(4f). Yellow powder, yield 0.453 g (85%). [Found: C, 72.59; H,
4.80; N, 7.96. C30H21N3O5 requires C, 72.30; H, 4.74; N, 7.91%];
mp: 217e220 ꢁC. IR (KBr) (lmax, cmꢀ1): 2920, 2920 (CH), 1721 and
1741 (C]O). NMR data for the major isomer (60%). 1H NMR
(300 MHz, CDCl3): 2.49 (6H, s, 2CH3), 3.23 (3H, s, OCH3), 3.90 (3H,
s, OCH3), 5.93 (1H, m, CHdihydroquinoline), 6.49 (1H, d, J¼4.4, CHdi-
hydroquinoline), 6.85 (1H, d, J¼9.5, CHdihydroquinoline), 7.03e8.11 (10H,
m, 10CH). 13C NMR (75 MHz, CDCl3): 20.2, 20.5 (2CH3), 51.9, 53.2
(2OCH3), 79.8 (CH), 81.0 (Cspiro), 114.3, 118.5, 122.1 (3CH), 122.6
(C) 124.5, 129.0, 129.2, 129.7, 130.7, 132.0 (6CH), 136.0, 136.1, 136.4
(3C), 136.5 (CH), 139.5 (C), 140.9 (CH) 141.3, 14.5, 141.7, 141.9 (4C),
143.5 (CH), 146.3, 148.3, 156.1 (3C), 163.7, 164.4 (2C]O). NMR
data for the minor isomer (40%). 1H NMR (300 MHz, CDCl3): 2.51
(6H, s, 2CH3), 3.20 (3H, s, OCH3), 3.87 (3H, s, OCH3), 5.93 (1H, m,
CHdihydroquinoline), 5.99 (1H, d, J¼4.4, CHdihydroquinoline), 6.82 ( H, d,
J¼9.5, CHdihydroquinoline), 7.03e8.11 (10H, m, 10CH). 13C NMR
(75 MHz, CDCl3): 20.2, 20.3 (2CH3), 51.9, 53.2 (2OCH3), 79.8 (CH),
4.2.4. Methyl 4-(1-methoxyisoquinolin-2(1H)-yl)-70,80-dimethyl-5-
oxo-5H-spiro[furan-2,110-indeno [1,2-b]quinoxaline]-3-carboxylate
(4d). Yellow powder, yield 0.463 g (87%). [Found: C, 72.55; H,
4.77; N, 7.93. C30H21N3O5 requires C, 72.30; H, 4.74; N, 7.91%]; Rf
(50% EtOAc/hexane) 0.63; mp: 205e207 ꢁC. IR (KBr) (lmax, cmꢀ1):
2950, 3037 (CH), 1703 and 1737 (C]O). 1H NMR (250 MHz, CDCl3):
2.50 (3H, s, CH3), 2.52 (3H, s, CH3), 3.16 (3H, s, OCH3), 4.03 (3H, s,
OCH3), 4.86 (1H, d, J¼7.5, CHdihydroisoquinoline), 6.50 (1H, d, J¼7.5,
CHdihydroisoquinoline), 7.01 (1H, s, CH), 7.14 (3H, m, 3CH), 7.7 (4H, m,
4H), 7.87 (1H, s, CH), 8.00 (1H, s, CH), 8.27 (1H, m, CH). 13C NMR
(62.9 MHz, CDCl3): 20.2, 20.3 (2CH3), 51.4, 53.4 (2OCH3), 80.0
(Cspiro), 80.8, 105.1, 123.4, 123.9, 125.2 (5CH), 126.3 (C) 127.0, 127.7,
129.2, 129.4 (4CH), 129.7, 130.5, 132.4 (3C), 139.9, 140.3, 145.5 (3CH),
147.5, 155.0, 161.6 (3C), 163.7, 163.9 (2C]O). MS (m/z, %): 530
(MþꢀH, 11), 499 (3), 472 (5), 128 (100), 76 (30).

M.T. Maghsoodlou et al. / Tetrahedron 67 (2011) 8492e8495
8495
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