An unexpected route toward the synthesis of spiro-benzo[b]acridine-furan derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.05.107

A facile and straightforward procedure for the synthesis of spiro-benzo[b]acridine-6,2′-furan derivatives via the reaction between benzo[b]acridine-6,11-dione, electron-deficient acetylenic compounds, and an isocyanide is described. The benzo[b]acridine-6,11-dione is obtained from the reaction between 2-(aminomethyl)aniline and 2-hydroxynaphthalene-1,4-dione via an unexpected reaction pathway. The products are synthesized in medium to high yields and no complicated purification is required.

Full text of DOI:10.1016/j.tetlet.2012.05.107

Tetrahedron Letters 53 (2012) 4018–4021
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An unexpected route toward the synthesis of spiro-benzo[b]acridine-furan
derivatives
⇑
Rahim Ghadari, Fatemeh Hajishaabanha, Mojtaba Mahyari, Ahmad Shaabani , Hamid Reza Khavasi
Department of Chemistry, Shahid Beheshti University, G. C., PO Box 19396-4716, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
A facile and straightforward procedure for the synthesis of spiro-benzo[b]acridine-6,20-furan derivatives
via the reaction between benzo[b]acridine-6,11-dione, electron-deficient acetylenic compounds, and an
isocyanide is described. The benzo[b]acridine-6,11-dione is obtained from the reaction between 2-(ami-
nomethyl)aniline and 2-hydroxynaphthalene-1,4-dione via an unexpected reaction pathway. The
products are synthesized in medium to high yields and no complicated purification is required.
Ó 2012 Elsevier Ltd. All rights reserved.
Article history:
Received 2 April 2012
Revised 6 May 2012
Accepted 24 May 2012
Available online 30 May 2012
Keywords:
Spiro-benzo[b]acridine-6,20-furan
Hetero-Diels–Alder
Heterocycle
Multicomponent reaction
Isocyanide
Spiro compounds are of importance from a biological and phar-
maceutical point of view and they show different activities such as
antimycobacterial,1 inhibition of the rabbit muscle 26S protea-
some,2 and act as an MDM2-p53 inhibitor providing a new and
promising strategy toward cancer treatment.3 Examples have been
used effectively to treat different types of human tumor cells.4
Some examples are active toward doxorubicin- and cis-platin-
resistant human tumor cells, as reported by Gomez-Monterrey
et al.5 Modulation of the activity of p53 has also been reported.
This behavior led to cell death which is crucial to inhibition of tu-
mor development.6 Anti-influenza A virus activity via modulation
of the dynamic of the M2 proton channel has also been reported.7
These compounds are promising replacements for amantadine
which exhibits side effects on the central nervous system and
due to increased drug resistance by the virus. Fungicidal,8 antima-
larial activity,9 HIV-1 reverse transcriptase dimerization inhibitor
properties,10 and anticancer properties (including multi-drug resis-
tant cancers)11 have been reported for compounds containing this
moiety. Spiro compounds are also important due to their interest-
ing structural and physical properties. Bent ladder-type hexaphen-
ylenes with spiro-linkages have been used as blue emitters.12
Chiral and flexible metal-organic frameworks using bifunctional
spiro linkers have been synthesized by Gedrich et al.13 Some com-
pounds with high Tg values have showed promising photo-physical
properties and they are very good candidates for use in
optoelectronics.14 Phosphorescent organic light-emitting diodes
(PHOLEDs) have also been synthesized based on spiro systems.15
As a result of the above-mentioned properties of spiro com-
pounds, different methods for their synthesis have been introduced.
For example, a synthesis via a one-pot, two-step, three-component
reaction has been reported by Zhuang.16 In addition, the use of NiCl2
or CoCl2 as the catalyst under microwave irradiation conditions,17
Fischer carbene complexes,18 ultrasound-assisted combinatorial
synthesis,19 organocatalytic approaches,20 palladium-catalyzed
synthesis,21 a domino Knoevenagel/Michael/cyclization sequence
catalyzed by cupreine,22 Pd-catalyzed intramolecular ipso-Friedel–
Crafts allylic alkylation of phenols,23 domino Stetter-aldol–Michael
and Stetter-aldol–Aldol reactions,24 and other methods25–28 have
been reported.
As part of our studies on MCRs,29–32 a procedure for the synthe-
sis of pyran derivatives 5 via a two-step reaction between CH-acid
3, dialkyl acetylenedicarboxylates [such as dimethyl acetylenedi-
carboxylate (DMAD)] and an isocyanide was designed. Initially,
the possibility of the synthesis of compound 3 from the reaction
of 2-(aminomethyl)aniline (1) and 2-hydroxynaphthalene-1,4-
dione (2) in acetic acid at room temperature was examined. Anal-
ysis of the spectroscopic data led us to conclude that the desired
product 3 was not obtained; instead the reaction proceeded via
an unexpected route yielding compound 4. With compound 4 in
hand, the multicomponent reaction between active-carbonyl
compound 4, electron-deficient acetylenic compounds, and an iso-
cyanide was examined (Scheme 1).
In a pilot experiment, benzo[b]acridine-6,11-dione (4), diethyl
acetylenedicarboxylate (7, R = Et), and benzyl isocyanide (8,
⇑
Corresponding author.
E-mail address: a-shaabani@cc.sbu.ac.ir (A. Shaabani).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.107

R. Ghadari et al. / Tetrahedron Letters 53 (2012) 4018–4021
4019
CO2R
R'
NH
RO2C
N
N
OH
N
O
N
O
O
5
3
DMAD,
isocyanide
OH
NH2
AcOH
+
O
O
RO2C
N
R'
NH2
N
RO2C
N
O
1
2
4
6
O
Scheme 1. Planned reaction for the synthesis of pyran derivatives versus the unexpected pathway toward the spiro-compounds.
O
O
RO2C
RO2C
N
R'
N
CH3CN
rt, 24 h
O
+
RO2C
CO R
+ R'
2
N
N
8
7
4
R = methyl, ethyl, t-butyl
6a-h
67-88%
O
R' = cyclohexyl, t-butyl, 1,1,3,3-tetramethylbutyl, benzyl
Scheme 2. Synthesis of spiro-benzo[b]acridine-6,20-furan derivatives.
R0 = Bn) in CH3CN were stirred at room temperature for 24 h. After
completion of the reaction, the precipitated product was separated
by filtration, washed with n-hexane, and recrystallized from EtOH/
H2O to afford product 6a in 88% yield. To explore the scope of this
reaction, different electron-deficient acetylenic compounds and
various alkyl, aryl, and alicyclic isocyanides were employed
(Scheme 2) to afford a range of diverse spiro-benzo[b]acridine-
6,20-furans (Table 1).
the case of pathway II, a hetero-Diels–Alder reaction between
intermediate 13 and compound 2 produces the intermediate 14,
which after dehydration, affords dione 15. Finally, the product 4
is obtained via oxidation of intermediate 15.
To distinguish the preferred pathway (I or II), the reaction
shown in Scheme 5 was run. Analysis of the reaction medium after
24 h showed that the desired product had been produced. This
indicated that the reaction proceeded via a hetero-Diels–Alder
mechanism to produce intermediate 17, which underwent two
successive oxidations in the reaction medium to produce the final
product. This finding leads us to conclude that the preferred path-
way to produce benzo[b]acridine-6,11-dione is via route II.
In summary, a simple and efficient synthetic procedure has
been developed for the synthesis of functionalized spiro-benzo
[b]acridine-6,20-furan derivatives from readily available starting
materials. The reported approach has advantages including a sim-
ple work-up, clean production of the products, and good functional
group tolerance. As spiro-containing compounds possess biological
activities, we hope the described procedure might be of interest to
those seeking novel synthetic approaches for medicinal chemistry.
The structures of the products were deduced from their IR, 1H
NMR, 13C NMR, and mass spectroscopic data. As an example, the
1H NMR spectrum of compound 6a showed two triplets
(J = 7.0 Hz) at 0.81 and 1.32 ppm for two CH3 groups and two quar-
tets at 3.82 and 4.40 ppm for two CH2 moieties (J = 7.0 Hz). The
protons of the N–CH2 moiety were observed as an ABq pattern at
4.65 ppm and the aromatic protons and C@CH occurred at 7.22–
8.40 and 9.34 ppm, respectively. The 1H-decoupled 13C NMR
spectrum of 6a showed 31 distinct resonances in agreement with
the proposed structure. The mass spectra of these compounds dis-
played molecular ion peaks at the appropriate m/z values. Finally,
the structure of product 6a was confirmed unambiguously by
single-crystal X-ray analysis (Fig. 1).
Although the mechanistic aspects of the above-mentioned reac-
tion for the synthesis of these spiro compounds have not been ex-
plored experimentally, a reasonable mechanism can be suggested
(Scheme 3). The initial step involves the reaction between the elec-
tron-deficient acetylenic compound 7 with isocyanide 8 to produce
the intermediate Huisgen zwitterion 9. Attack of 9 on compound 4
leads to intermediate 10, which after intramolecular cyclization,
yields the desired products 6a–h.
As mentioned previously, the designed reaction for the synthe-
sis of compound 3 did not occur as expected and benzo[b]acridine-
6,11-dione (4) was obtained instead via an unexpected pathway.
Two suggested pathways for the formation of compound 4 are pre-
sented in Scheme 4. It is conceivable in route I, that the initial
event is the formation of intermediate 12 by attack of compound
2 on 2-(aminomethyl)anilium salt 11. In the next step, intermedi-
ate 15 is obtained by an intramolecular condensation reaction. In
Preparation of benzo[b]acridine-6,11-dione (4)
To a magnetically stirred solution of 2-(aminomethyl)aniline (1)
(0.12 g, 1 mmol) in AcOH (5 mL), was added 2-hydroxynaphtha-
lene-1,4-dione (2) (0.34 g, 2 mmol). The reaction was stirred for
24 h and the precipitated product was separated by filtration and
washed with distilled H2O (10 mL). The product was obtained as
a dark yellow powder (0.19 g, 73%); mp >270 °C. IR (KBr) cmꢀ1
:
1688, 1665, 1616, 1578, 1489, 1380, 1345. 1H NMR (300.13 MHz,
DMSO-d6) d: 7.84–8.42 (8H, m, H-Ar), 9.31 (1H, s, CH). 13C NMR
(62.90 MHz, DMSO-d6) d: 27.4, 28.3, 29.8, 54.6, 83.7, 83.8, 124.5,
126.8, 127.6, 127.7, 128.7, 128.9, 129.3, 130.5, 130.6, 131.0,
133.7, 135.5, 137.9, 138.7, 149.4, 153.9, 182.3. MS m/z: 259 (M+,
100), 231 (74), 203 (72), 176 (19), 150 (8), 127 (10), 101 (28), 76
(37), 50 (22). Anal. Calcd for C17H9NO2: C, 78.76; H, 3.50; N, 5.40.
Found: C, 78.72; H, 3.40; N, 5.36.

4020
R. Ghadari et al. / Tetrahedron Letters 53 (2012) 4018–4021
Table 1
Table 1 (continued)
Synthesized spiro-benzo[b]acridine-6,20-furan derivatives
Entry
R
R0
Product
Yield
(%)
Entry
R
R0
Product
Yield
(%)
O
O
O
O
O
N
O
N
O
O
t-
Bu
1,1,3,3-
Tetramethylbutyl
6h
79
O
6a
Et
Bn
88
O N
O
N
O
O
O
N
O
6b
Et
Cyclohexyl
67
O
O N
O
O
O
N
O
O N
t-
Bu
6c
Cyclohexyl
73
O
O
O
O
N
N
O
O
6d
Me Bn
70
O N
O
Figure 1. ORTEP diagram of product 6a (CCDC 871537).
O
O
O
O
Preparation of diethyl 50-(benzylimino)-11-oxo-50H,11H-
6e
Me Cyclohexyl
75
O
N
spiro[benzo[b]acridine-6,20-furan]-30,40-dicarboxylate (6a);
typical procedure
O
To a magnetically stirred solution of benzo[b]acridine-6,11-
dione (4) (0.26 g, 1 mmol) in CH3CN (10 mL), was added diethyl
acetylenedicarboxylate (0.17 g, 1 mmol) and benzylisocyanide
(0.12 g, 1 mmol). The resulting mixture was stirred at room tem-
perature for 24 h. After completion of the reaction (monitored by
TLC), the precipitated product was separated by filtration, washed
with n-hexane (5 mL), and recrystallized from EtOH/H2O (3/2) to
afford the desired product as a yellow powder (0.48 g, 88%); mp
157–158 °C. IR (KBr) cmꢀ1: 3443, 3058, 3033, 2975, 2892, 1731,
1671, 1591, 1495, 1457, 1376, 1339. 1H NMR (300.13 MHz,
DMSO-d6) d: 0.81 (3H, t, J = 7.0 Hz, O–CH2CH3), 1.32 (3H, t,
J = 7.0 Hz, O–CH2CH3), 3.82 (2H, q, J = 7.0 Hz, O–CH2CH3), 4.40
(2H, q, J = 7.0 Hz, O–CH2CH3), 4.65 (2H, ABq, J = 15.2 Hz, N–CH2),
7.22–8.40 (13H, m, H-Ar), 9.34 (1H, s, CH). 13C NMR
(100.64 MHz, DMSO-d6) d: 9.3, 10.1, 47.4, 58.3, 58.6, 81.8, 120.3,
122.9, 123.5, 123.7, 123.8, 124.5, 124.6, 124.8, 125.1, 126.4,
126.8, 129.7, 131.5, 132.3, 133.3, 134.0, 135.3, 141.3, 145.0,
150.2, 154.0, 155.2, 157.3, 177.9, 202.7. MS m/z: 546 (M+, 8), 441
O
O
O
N
N
O
6f
Et
t-Bu
80
O
O
O N
O
O
O
t-
Bu
6g
t-Bu
84
O N
O

R. Ghadari et al. / Tetrahedron Letters 53 (2012) 4018–4021
4021
R'
RO2C
RO2C
N
CO2R
RO2C
O
O
N
O
N
+
RO2C
CO2R
N R'
6a-h
N
4
R'
8
9
7
10
O
Scheme 3. Suggested mechanism for the synthesis of spiro-benzo[b]acridine-6,20-furan derivatives 6a–h.
O
O
H
O
O
NH3
NH2
2
O
-NH3
O
I
NH2 O
11
NH2
NH2
H+
N
12
-H2O
[O]
4 O
O
O
O
O
II
1
-H2O
NH
HO
N
H
N
OH
2
13
15
O
14
O
Scheme 4. Proposed pathways for the synthesis of benzo[b]acridine-6,11-dione (4).
O
O
O
O
[O]
NH2 AcOH
rt, 24 h
16
O
N
NH
N
H
NH2
4
17
O
Scheme 5. Reaction used to distinguish the pathway of the reaction to give compound 4.
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We gratefully acknowledge financial support from the Research
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