A rapid and simple diversity-oriented synthesis of novel 3-amino-2′-oxospiro [benzo[c]pyrano[3,2-a]phenazine-1,3′-indoline]- 2-carbonitrile/carboxylate derivatives via a one-pot, four-component domino reaction

Article abstract of DOI:10.1016/j.tetlet.2013.04.082

An efficient regio- and chemoselective method for the synthesis of novel 3-amino-2′-oxospiro[benzo[c]pyrano[3,2-a]phenazine-1,3′-indoline] -2-carbonitrile/carboxylate derivatives has been developed via the one-pot, four-component domino coupling of 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamines, isatins, and malononitrile/cyanoacetic ester in the presence of DABCO under reflux conditions in excellent yields. The merit of this cascade formation of two CN bonds/Knoevenagel condensation/Michael addition/cyclization sequence is highlighted by its high atom-economy, excellent yields, efficiency of producing five new bonds (two C-N, two C-C, and one C-O), and one stereocenter in a single operation.

Full text of DOI:10.1016/j.tetlet.2013.04.082

Accepted Manuscript
A rapid and simple diversity-oriented synthesis of novel 3-amino-2’-oxospiro
[benzo[c]pyrano[3,2-a]phenazine-1,3’-indoline]-2-carbonitrile/carboxylate de‐
rivatives via a one-pot, four-component domino reaction
Gholam Hossein Mahdavinia, Maryam Mirzazadeh, Behrouz Notash
PII:
S0040-4039(13)00677-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.04.082
TETL 42850
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
3 September 2012
10 April 2013
19 April 2013
Please cite this article as: Mahdavinia, G.H., Mirzazadeh, M., Notash, B., A rapid and simple diversity-oriented
synthesis of novel 3-amino-2’-oxospiro [benzo[c]pyrano[3,2-a]phenazine-1,3’-indoline]-2-carbonitrile/carboxylate
derivatives via a one-pot, four-component domino reaction, Tetrahedron Letters (2013), doi: http://dx.doi.org/
10.1016/j.tetlet.2013.04.082
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
A rapid and simple diversity-oriented
synthesis of novel 3-amino-2'-oxospiro
[benzo[c]pyrano[3,2-a]phenazine-1,3'-
indoline]-2-carbonitrile/carboxylate
derivatives via a one-pot, four-component
domino reaction
Leave this area blank for abstract info.
Gholam Hossein Mahdavinia, Maryam Mirzazadeh, Behrouz Notash
O
R2
R1
R2
NH2
NH2
OH
Z
R1
HN
N
O
X
O
N
(10 mol%)
DABCO
O
CN
X
EtOH / reflux
Z
H2N
O
O
N
H

A rapid and simple diversity-oriented synthesis of novel 3-amino-2'-oxospiro
[benzo[c]pyrano[3,2-a]phenazine-1,3'-indoline]-2-carbonitrile/carboxylate
derivatives via a one-pot, four-component domino reaction
Gholam Hossein Mahdaviniaa, Maryam Mirzazadeha, Behrouz Notashb
aDepartment of Chemistry, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran
bChemistry Department, Shahid Beheshti University, G. C., Evin, Tehran 1983963113, Iran
Abstract:
An efficient regio- and chemoselective method for the synthesis of novel 3-amino-2'-
oxospiro[benzo[c]pyrano[3,2-a]phenazine-1,3'-indoline]-2-carbonitrile/carboxylate derivatives
has been developed via the one-pot, four-component domino coupling of 2-hydroxynaphthalene-
1,4-dione, benzene-1,2-diamines, isatins and malononitrile/cyanoacetic ester in the presence of
DABCO under reflux conditions in excellent yields. The merit of this cascade formation of two
C=N bonds/Knoevenagel condensation/Michael addition/cyclization sequence is highlighted by
its high atom-economy, excellent yields, efficiency of producing five new bonds (two C-N, two
C-C and one C-O), and one stereocenter in a single operation.
Keywords: One-pot, Four-component, DABCO, Regioselective, Domino reaction, Diversity-
oriented synthesis.
The development of the design and synthesis of new diverse polycyclic heterocycles with
potential medicinal and biological activity has become an important area of research in organic,
combinatorial, and medicinal chemistry.1 To achieve this aim, diversity-oriented synthesis
(DOS) is a useful tool.2 DOS provides the synthetic means for the combination of functionally
and regiochemically diverse small molecules, particularly those possessing skeletons resembling
those found in natural products or drug-like molecules.3 Multicomponent reactions (MCRs) and
multicomponent domino reactions (MDR), due to their productivity, lower costs, minimum
waste production, simple execution, shorter reaction times, structural diversity, environmentally
friendliness and high degrees of atom economy, whilst avoiding complicated purification
operations and allowing savings of both solvents and reagents, are important tools in
combinatorial and DOS chemistry.4-13

Indoles,14 phenazines15 and pyrans16 are very important classes of heterocyclic compounds. The
indole and indoline ring systems are widely distributed structural frameworks that are present in
a number of pharmaceuticals and natural products.17 Phenazine systems are of particular
importance as they belong to privileged medicinal scaffolds with highly pronounced antimalarial,
trypanocidal, fungicidal, and antiplatelet activities.18 The heterocyclic pyran ring system and its
derivatives are usually structural subunits in a variety of important natural compounds, including
carbohydrates, alkaloids, polyether antibiotics, pheromones, and iridoids.19 While phenazines,
indoles and pyrans have attracted significant attention, the preparation of compounds
incorporating all of these motifs (Figure 1) has not been reported. We therefore sought to
develop a simple and versatile procedure for the combinatorial synthesis of a spiro-substituted
pyranophenazine-indoline library for biological screening.
Indole
HN
N
O
N
X
Phenazine
H2N
O
Pyran
Figure 1.
As part of our continuing interest in the development of new synthetic methods in heterocyclic
chemistry,20 guided by the observation that the presence of two or more different heterocyclic
moieties in a single molecule often enhances the biological properties remarkably, we herein
report
a
new four-component reaction for the synthesis of
3-amino-2'-
oxospiro[benzo[c]pyrano[3,2-a]phenazine-1,3'-indoline]-2-carbonitrile/ carboxylate derivatives.
This reaction proceeds under reflux conditions in the absence of strong acids or metal catalysts
(Scheme 1).
We began this study by subjecting benzo[a]phenazin-5-ol (6) [prepared from 2-
hydroxynaphthalene-1,4-dione (1) and benzene-1,2-diamine (2a)18] and isatin (3a) to reaction
with malononitrile (4a) in AcOH under reflux conditions (Scheme 2).

O
O
R1
R2
NH2
NH2
OH
R1
2a: R1=H, R2=H
2b: R1=CH3, R2=H
2c: R1=CH3, R2=CH3
1
R2
N
Z
N
N
(10 mol%)
N
O
Z
O
EtOH / reflux
CN
X
O
N
HN
NH2
H
X
O
5a-k
3a: Z=H
3b: Z=Br
3c: Z=Cl
4a: X=CN
4b: X=CO2Et
Scheme 1.
Unfortunately, the desired product was not obtained. We next examined this reaction in the
absence and presence of several additives in ethanol as the solvent. No reaction occurred in the
absence additives. Additives such as CAN and NH4Cl resulted in trace yields, but L-proline and
DABCO catalyzed reaction in moderate yields (25% and 35%). When DABCO was used in
CH3CN as the solvent in this reaction system, the yield of the product was improved
significantly. The best result (98% yield) was obtained when DABCO was used in CH3CN at
reflux (Table 1).
N
OH
O
N
N
various conditions
CN
CN
O
O
N
N
HN
H
NH2
O
NC
6
3
4
5
Scheme 2.
Table 1. One-pot, three-component synthesis of 2-amino-2'-oxospiro[benzo[c]pyrano[2,3-a]phenazine-1,3'-
indoline]-3-carbonitrile under various conditions.
Entry
Catalyst (mol %)
Solvent
Conditions
120 °C
reflux
Time
12 h
12 h
12 h
12 h
12 h
12 h
Yield(%)
--
1
2
3
4
5
6
--
--
--
AcOH
EtOH
EtOH
EtOH
EtOH
--
CAN (20)
NH4Cl (20)
L-proline (20)
DABCO (20)
reflux
trace
trace
25
reflux
reflux
reflux
35

7
8
9a
DABCO (20)
DABCO (10)
DABCO (10)
CH3CN
CH3CN
EtOH
reflux
reflux
reflux
20 min
45 min
10 min
98
95
98
a
One-pot, four-component reaction: 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamine, isatin and
malononitrile
To minimize the steps required for formation of the product and to simplify the procedure, 2-
hydroxynaphthalene-1,4-dione (1) and benzene-1,2-diamine (2a) were first stirred at reflux for 5
minutes in the presence of DABCO as the catalyst, to give an orange solid. Next, isatin (3a) and
malononitrile (4a) were added and the mixture was heated under reflux conditions for 10
minutes. The desired product was obtained as a yellow solid in 98% yield. This two-step
procedure allowed the one-pot four-component reaction to be controlled, thereby avoiding the
necessity to separate intermediates (6), as well as time-consuming and costly purification
processes.
Having optimized the conditions, various symmetrical and unsymmetrical benzene-1,2-diamines
(2a-c) and 2-hydroxynaphthalene-1,4-dione (1) were condensed with isatins 3a-c and
malononitrile (or cyanoacetic ester) (4a, b) in the presence of DABCO to afford the
corresponding spiro-benzopyranophenazine-indoline products (5a-k) (Scheme 1). The results
(Table 2) show that the desired products were obtained in excellent yields.
Table 2. DABCO-catalyzed synthesis of 3-amino-2'-oxospiro[benzo[c]pyrano[3,2-a]phenazine-1,3'-
indoline]-2-carbonitrile/carboxylate derivatives.
Benzene-
Isatin
Malono
Time
(min)
10
Yield
(%)
98
Mp
Product
1,2-diamine
derivative
derivative
4a
(°C)
317 (dec.)
268 (dec.)
338 (dec.)
307 (dec.)
343 (dec.)
315 (dec.)
274 (dec.)
335 (dec.)
336 (dec.)
362 (dec.)
350 (dec.)
2a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
3a
3a
3b
3b
3c
3a
3a
3b
3c
3b
3c
5a
5b
5c
5d
5e
5f
15
100
100
97
4b
10
4a
10
4b
15
99
4a
15
97
4a
10
95
4b
5g
5h
5i
15
100
100
96
4a
15
4a
15
4a
5j
10
97
4a
5k

Our synthesis of
3-amino-2'-oxospiro[benzo[c]pyrano[3,2-a]phenazine-1,3'-indoline]-2-
carbonitrile/carboxylate derivatives 5, using the above conditions, was based on the following
considerations: (1) 2-hydroxynaphthalene-1,4-dione (1), possessing three electrophilic centers,
has proven to be an important building block for the construction of various heterocyclic
frameworks; (2) 2-hydroxynaphthalene-1,4-dione (1) is converted into the corresponding
benzo[a]phenazin-5-ol 6 on reaction with benzene-1,2-diamines S-2; (3) 2-hydroxynaphthalene-
1,4-dione (1) is converted into the corresponding benzo[a]phenazine-5-ol (6) molecules (major
and minor isomers) on reaction with unsymmetrical benzene-1,2-diamines US-2; (4) isatin (3)
can be easily attacked by the carbon nucleophilic center of malononitrile leading to Knoevenagel
condensation products (intermediate A in Scheme 4) finally; (5) the Knoevenagel products
attacked by benzo[a]phenazine-5-ol (6) leading to the 3-amino-2'-oxospiro[benzo[c]pyrano[3,2-
a]phenazine-1,3'-indoline]-2-carbonitrile/carboxylate derivatives (5) are useful for drug design
and synthesis (see Scheme 3).
HN
O
O
CN
N
N
O
+
N
NH2
NH2
N
NC
N
H
CN
H2N
O
HO
3
4
6
S-2
5
O
O
Me
OH
Me
N
N
N
N
1
HO
6-Major
Me
NH2
NH2
HO
6-Minor
US-2
CN
CN
CN
4
O
4
O
CN
O
O
N
H
N
H
3
3
Me
HN
HN
Me
O
O
N
N
N
N
NC
H2N
NC
O
H2N
O
5-Major
5-Minor

Scheme 3.
Scheme 3 shows that when we used an unsymmetrical (monosubstituted) benzene-1,2-diamine
1
regioselectivity was observed. Figure 2 shows the H NMR spectrum of 3-amino-12-methyl-2'
oxospiro[benzo[c]pyrano[3,2-a]phenazine-1,3'-indoline]-2-carbonitrile (5f). The signal at δ
10.80 (0.56 H, NH indole) is due to the major isomer and the signal at δ 10.77 (0.41 H, NH
indole) is related to the minor isomer.
1
Figure 2. The H NMR (400 MHz, DMSO-d6) signals of the major and minor isomers of 3-amino-12-methyl-2'
oxospiro[benzo[c]pyrano[3,2-a]phenazine-1,3'-indoline]-2-carbonitrile (5f).
In order to elucidate the structure of these compounds, we determined the structure of compound
(5a) by X-ray crystallography.21 The ORTEP diagram of (5a) and selected bond lengths, bond
angles and torsion angles are presented in Figure 3.

Figure 3. ORTEP diagram of 5a. Thermal ellipsoids at 30% probability level.
Methanol and DMSO solvent molecules have been omitted for clarity. Selected bond
lengths
(Å):
O(1)-C(2)
1.224(4),
O(2)-C(12)
1.389(4),
O(2)-C(11)
1.356(4), N(2)-C(10) 1.155(5), C(9)-C(10) 1.416(5), N(1)-C(2) 1.361(5), C(9)-C(11)
1.361(5), N(3)-C(11) 1.334(5), C(1)-C(21) 1.515(5), C(1)-C(9) 1.518(5), C(1)-C(8)
1.531(5), C(1)-C(2) 1.565(5), N(4)-C(20) 1.330(5), N(5)-C(19) 1.338(4), N(3)-C(11)
1.334(5); Selected bond angles (º): N(2)-C(10)-C(9) 178.6(4), C(21)-C(1)-C(9)
108.4(3), C(21)-C(1)-C(8) 116.4(3), C(9)-C(1)-C(8) 111.2(3), C(21)-C(1)-C(2)
112.3(3), C(9)-C(1)-C(2) 107.0(3), C(8)-C(1)-C(2) 101.1(3), C(11)-O(2)-C(12)
118.6(3); Selected torsion angles (º): N(4)-C(20)-C(21)-C(1) 4.5(5), C(21)-C(1)-
C(8)-C(7) 60.8(5), O(2)-C(12)-C(13)-C(14) 0.1(5).
In summary, we have developed a convenient, efficient, chemoselective, regioselective, one-pot,
four-component domino synthesis of 3-amino-2'-oxospiro[benzo[c]pyrano[3,2-a]phenazine-1,3'-
indoline]-2-carbonitrile/carboxylate derivatives involving the formation of C-N, C-O, C-C bonds

and two spiro rings in the presence of DABCO in ethanol under reflux conditions. The
advantages of this synthesis are the use of an inexpensive and readily available catalyst, a
convenient one-pot operation, short reaction times of 10-15 min, easy work-up, excellent yields
of products and reduced waste production without the use of any strong acids or metal
promoters.
General procedure for the synthesis of compounds 5a-k.
DABCO (10 mol%) was added to a mixture of 2-hydroxynaphthalene-1,4-dione (1) (1 mmol),
benzene-1,2-diamine (2) (1 mmol) in EtOH (10 mL). The resulting mixture was refluxed for 5
min. Next, isatin (3) (1 mmol) and malononitrile/ethyl cyanoacetate (4) (1 mmol) were added
and the mixture refluxed for the appropriate amount time (Table 2). After completion of the
reaction, the progress of which was monitored by TLC (EtOAc/n-hexane 2:1), the mixture was
cooled to room temperature. Then, precipitated product was filtered and washed with H2O (10
mL) and EtOH (5 mL) to afford the desired product. The products were found to be sufficiently
pure that no further purification was necessary.
3-Amino-2'-oxospiro[benzo[c]pyrano[3,2-a]phenazine-1,3'-indoline]-2-carbonitrile (5a):
o
Yellow powder; mp: 317 C; IR (KBr, cm-1): 3464, 3240, 2185, 1719, 1659, 1593, 1374, 1293,
1
1066, 751, 677; H NMR (400 MHz, DMSO-d6): δ 6.73 (t, 1H, J=7.6 Hz, ArH), 6.9 (d, 1H,
J=7.2 Hz, ArH), 7.02 (d, 1H, J=7.6 Hz, ArH), 7.16 (t, 1H, J=7.2 Hz, ArH), 7.53 (s, 2H, NH2),
7.69-7.70 (m, 1H, ArH), 7.87-7.89 (m, 2H, ArH), 7.99-8.05 (m, 2H, ArH), 8.24-8.26 (m, 1H,
13
ArH), 8.50 (d, 1H, J=7.6 Hz, ArH), 9.25 (d, 1H, J=8.0 Hz, ArH), 10.83 (s, 1H, NH); C NMR
(100 MHz, DMSO-d6): δ 56.49, 57.66, 109.67, 110.82, 118.26, 118.57, 122.13, 122.99, 123.95,
125.38, 125.96, 128.45, 128.81, 129.54, 130.31, 130.74, 131.01, 131.34, 136.16, 139.87, 140.47,
140.79, 141.58, 143.34, 148.02, 159.89, 179.59; Anal. Calcd for C27H15 N5O2: C, 73.46; H, 3.42;
N, 15.86. Found: C, 73.38; H, 4.39; N, 15.88.

References and notes
[1] (a) Schreiber, S. L. Science 2000, 287, 1964; (b) Thompson, L. A. Curr. Opin. Chem.
Biol. 2000, 4, 324; (c) Trost, B. M.; Angew. Chem., Int. Ed. Engl. 1995, 34, 259; (d)
Tietze, L. F. Chem. Rev. 1996, 96, 115; (e) Trost, B. M. Science 1991, 254, 1471; (f) Zhu
J.-P.; Bienaymé, H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2005, p. 1499;
(g) Singh, M. S.; Nandi, G. C.; Samai, S. Green Chem. 2012, 14, 447; (h) Wen, L.-R.; Li,
Z.-R.; Li, M.; Cao, H. Green Chem. 2012, 14, 707.
[2] (a) Burke, M. D.; Schreiber, S. L. Angew. Chem. Int. Ed. 2004, 43, 46; (b) Spring, D. R.
Org. Biomol. Chem. 2003, 1, 3867; (c) Strausberg, R. L.; Schreiber, S. L. Science 2003,
300, 294.
[3] Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
[4] Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321.
[5] (a) Lin, C. H.; Chen, J. R.; Yang, D. Y. J. Comb. Chem. 2010, 12, 119; (b) Neogi, S.;
Roy, A.; Naskar, D. J. Comb. Chem. 2010, 12, 75.
[6] Rhoden, C. R. B.; Rivera, D. G.; Kreye, O.; Bauer, A. K.; Westermann, B.; Wessjohann,
L. A. J. Comb. Chem. 2009, 11, 1078.
[7] Shaabani, A.; Ghadari, R.; Ghasemi, S.; Pedarpour, M.; Rezayan, A. H.; Sarvary, A.; Ng,
S. W. J. Comb. Chem. 2009, 11, 956.
[8] Shaabani, A.; Maleki, A.; Hajishaabanha, F.; Mofakham, H.; Seyyedhamzeh, M.;
Mahyari, M.; Ng, S. W. J. Comb. Chem. 2010, 12, 186.
[9] Thirumurugan, P.; Nandakumar, A.; Muralidharan, D.; Perumal, P. T. J. Comb. Chem.
2010, 12, 161.
[10] Wang, K.; Kim, D. B.; Domling, A. J. Comb. Chem. 2010, 12, 111.
[11] Zeng, L. Y.; Cai, C. J. Comb. Chem. 2010, 12, 35.
[12] Zhou, H. Y.; Zhang, W.; Yan, B. J. Comb. Chem. 2010, 12, 206.
[13] Kumaravel, K.; Vasuki, G. Curr. Org. Chem. 2009, 13, 1820.
[14] Houlihan, W. J.; Remers, W. A.; Brown, R. K. Indoles: Part I; Wiley: New York, NY,
1992.
[15] Laursen, J. B.; Nielsen, J. Chem. Rev. 2004, 104, 1663.

[16] Green, G. R.; Evans, J. M.; Vong, A. K. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1995,
Vol. 5, p 469.
[17] Sundberg, R. J. The Chemistry of Indoles; Academic: New York, NY, 1996.
[18] Wang, S.-L.; Wu F.-Y.; Cheng, C.; Zhang G.; Liu, Y.-P.; Jiang, B.; Shi, F.; Tu, S.-J. ACS
Comb. Sci. 2011, 13, 135 and references cited therein.
[19] Tietze L. F.; Kettschau G. Top. Curr. Chem. 1997, 189,12
[20] (a) Rostamizadeh, Sh.; Amani, M. A.; Mahdavinia, G. H.; Amiri, G.; Sepehrian, H.;
Ebrahimi, S. Synthesis 2010, 1356; (b) Mahdavinia, G. H.; Amani, M. A.; Sepehrian, H.
Chin. J. Chem. 2012, 30, 703.
[21] X-Ray data for 5a: C30H25N5O4S, M = 551.62, monoclinic system, space group P21/c, a =
17.019(3), b = 9.2544(19), c = 17.092(3) Å, β= 91.48(3) o, V= 2691.1(9) Å3, Z= 4, Dcalc
=
1.361 g.cm-3, μ(Mo-Kα)= 0.167 mm-1, T = 120(2) K, crystal size of 0.3 x 0.27 x 0.2 mm3.
The X-ray diffraction measurements were made on a STOE IPDS-2T diffractometer with
graphite monochromated Mo-Kα radiation. The structure was solved using SHELXS.
The structure refinement and data reduction was carried out with SHELXL using the X-
STEP32 suite of programs.22 The non-hydrogen atoms were refined anisotropically by
full matrix least-squares on F2 values to final R1= 0.0760, wR2 = 0.1606 and S = 1.117
with 380 parameters using 4715 independent reflections. Hydrogen atoms attached to
nitrogen and oxygen atoms were located in a difference Fourier map and refined
isotropically. All other hydrogen atoms were added in idealized positions. The
crystallographic information file has been deposited with the Cambridge Crystallographic
Data Centre, CCDC 920546.
[22] X-STEP32 Version1.07b, X-ray structure evaluation package, 2000, Stoe&Cie,
Darmstadt, Germany.

O
X
O
NH
N
N
X
3
CN
H
4
CN
NH
N
N
N
O
CN
X
HN
O
X
NH
N
R
OH
CN
X
X
OH
R
H
-H2O
CN
O
X
X
H
HN
NC
R
NC
R
O
CN
A
NH
N
O
N
NH
X
O
N
NH
R
O
N
O
O
OH
N
R
H2N
OH
+
-2H2O
R
H2N
OH
N
R
N
N
-H+
2
1
6
+H+
R
R
X
O
NH
H
N
O
N
R
N
X
X
O
NH2
O
NH2
5