A convenient approach to the design and synthesis of indolo[3,2-c]coumarins via the microwave-assisted Cadogan reaction

Article abstract of DOI:10.1016/j.tetlet.2013.08.030

3-(4,5-Dimethoxy-2-nitrophenyl)coumarins bearing various substituents on the benzene ring of the coumarin system have been prepared from salicylaldehydes and 2-(4,5-dimethoxy-2-nitrophenyl)acetonitrile by means of the Perkin condensation. Further cyclization of these 3-aryl coumarins through the microwave-assisted Cadogan reaction afforded the corresponding indolo[3,2-c]coumarins in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.08.030

Accepted Manuscript
A convenient approach to the design and synthesis of indolo[3,2-c]coumarins
via the microwave-assisted Cadogan reaction
Roman A. Irgashev, Arseny A. Karmatsky, Pavel A. Slepukhin, Gennady L.
Rusinov, Valery N. Charushin
PII:
S0040-4039(13)01383-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.030
TETL 43392
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 June 2013
18 July 2013
7 August 2013
Please cite this article as: Irgashev, R.A., Karmatsky, A.A., Slepukhin, P.A., Rusinov, G.L., Charushin, V.N., A
convenient approach to the design and synthesis of indolo[3,2-c]coumarins via the microwave-assisted Cadogan
reaction, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.030
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Graphical abstract
________________________________________________________________________________
A convenient approach to the design and synthesis of indolo[3,2-c]coumarins via the microwave-assisted
Cadogan reaction
Roman A. Irgashev*, Arseny A. Karmatsky, Pavel A. Slepukhin, Gennady L. Rusinov, Valery N. Charushin
________________________________________________________________________________________________________________________
∗ Corresponding author. Fax: +7 343 369 30 58;
e-mail: irgashev@ios.uran.ru

A convenient approach to the design and synthesis
of indolo[3,2-c]coumarins via the microwave-assisted Cadogan reaction
Roman A. Irgasheva,*, Arseny A. Karmatskya, Pavel A. Slepukhina,
Gennady L. Rusinova,b, Valery N. Charushina,b
aI. Postovsky Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences, S. Kovalevskoy Str., 22, Ekaterinburg, 620041, Russia
bUral Federal University named after the First President of Russia B.Eltsin, Mira St. 19, Ekaterinburg, 620002, Russia
A B S T R A C T
3-(4,5-Dimethoxy-2-nitrophenyl)coumarins bearing various substituents on the benzene ring of the
coumarin system have been prepared from salicylaldehydes and 2-(4,5-dimethoxy-2-
nitrophenyl)acetonitrile by means of the Perkin condensation. Further cyclization of these 3-aryl
coumarins through the microwave-assisted Cadogan reaction afforded the corresponding
indolo[3,2-c]coumarins in good to excellent yields.
Keywords: Indolo[3,2-c]coumarins, 3-Aryl coumarins, Salicylaldehydes, Cadogan reaction,
Microwave-assisted synthesis, Reductive cyclization
The deoxygenation of C-nitroso- or C-nitro-substituted (hetero)arenes by the action of
trivalent phosphorus-containing compounds (e.g. triethyl phosphite and triphenylphosphine) occurs
via the Cadogan reaction.1 When conducted in an intramolecular sense, N-containing heterocycles
are formed. It has been assumed that the transformation takes place through a nitrene-type
intermediate (Scheme 1).2 The Cadogan reaction is a simple and convenient synthetic route to
indoles, carbazoles, and other condensed derivatives of pyrroles, imidazoles, pyrazoles and
triazoles.3
(Het)Ar1
(Het)Ar
(Het)Ar1
(Het)Ar1
3
(Het)Ar
(Het)Ar
3
2
(Het)Ar1
(Het)Ar
Scheme 1. The formal mechanism for the Cadogan reaction
2

This reaction has been improved by using microwave irradiation instead of conventional reflux for
several hours. This has led to reduced reaction times of two minutes at best, and increased yields of
the major products.4 Although a number of aromatic and heteroaromatic nitro compounds have been
used successfully in the Cadogan cyclization, there are no reports in the literature on using
coumarin derivatives in this reaction.
Figure 1. Bioactive coumarins
Coumarins represent an important family of oxygen-containing fused heterocycles, which are
widely distributed in Nature, especially in plants. Natural coumarins and their synthetic analogs
exhibit a wide range of physiological activities, such as anti-oxidant,5a antifungal,5b antihelmintic,5c
anticoagulant (warfarin),5d antibacterial (novobiocin)5e and antiviral5f properties, including anti-
HIV5g (lamellarines) and anti-HCV5h activities (Figure 1). Also, coumarin derivatives are important
as fluorescent indicators, optical brighteners and photosensitizers or dyes for lasers and DSSC (dye-
sensitized solar cell).6,7 The development of novel synthetic approaches to coumarin derivatives is
of significant synthetic importance.
Indolo[3,2-c]coumarins [chromeno[4,3-b]indol-6(11H)-ones] are nitrogen-containing analogs
of naturally occurring compounds known as coumestans (benzofuro[3,2-c]chromen-6-one), examp-
les of which include coumestrol, wedelolactone and plicadin, which are found in various plants
(Figure 2).
OH
OH
OH
O
O
OH
O
OH
O
O
O
Me
Me
HO
O
O
MeO
O
O
coumestrol
wedelolactone
plicadin
Figure 2. Naturally occurring coumestans
3

Since many coumestans possess estrogenic,8a antitumor8b and antihepatotoxic8c activities, the
development of synthetic approaches to new derivatives and close structural analogues of
coumestans, as well as elucidation of their pharmacological properties are worthwhile.
In this paper, we report a novel and convenient synthetic approach to indolo[3,2-c]coumarins
based on the microwave-assisted Cadogan cyclization of 3-(2-nitroaryl)-substituted coumarins.
2
3
Scheme 2. Synthetic routes to indolo[3,2-c]coumarins
It should be noted that a number of synthetic routes to indolo[3,2-c]coumarins have been
described in the literature, including copper-catalyzed cyclization of 2-(2-halophenyl)indole-3-
carboxylic acids 1,9a palladium-catalyzed carbonylation/lactonization of 2-(2-acetoxyphenyl)-3-
iodoindoles 2,9b thermal cyclization of 4-azido-3-arylcoumarins 3,9c and dehydrogenation of 4-
amino-3-arylcoumarins 49d (Scheme 2). These methods utilize derivatives of coumarin and indole,
which have to be prepared in several steps. In contrast, our approach to the synthesis of indolo[3,2-
c]coumarins can be realized in two steps from commercially available reagents. As a result of the
Perkin condensation of salicylaldehydes 5a-h with 2-(4,5-dimethoxy-2-nitrophenyl)acetonitrile, a
number of 3-(4,5-dimethoxy-2-nitrophenyl)coumarins 6a-h have been obtained.10 This
transformation was carried out in ethanol in the presence of piperidine as the catalyst, and the
intermediate imines A were hydrolyzed with sulfuric acid without isolation (see Scheme 3, Table
1). Coumarins 6a-g were obtained in 83–98% yields and required no further purification after
1
filtration (purity assessed by H NMR). An exception was coumarin 6h for which crystallization
from DMF was necessary to obtain the target product, albeit in a relatively low yield of 27%.
4

Scheme 3. Synthesis of coumarins 6a-h
Table 1. Yields and melting points of coumarins 6
Salicylaldehyde
R1
H
OMe
OMe
H
Br
H
H
H
R2
H
H
Br
OMe
Br
Cl
R3
H
H
H
H
H
H
H
Coumarin
Yield (%)
Mp (°C)
232 – 233
236 – 237
254 – 255
232 – 234
237 – 238
274 – 275
278 – 280
282 – 284
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
98
94
92
87
83
85
95
27
5g
5h
Br
6g
6h
Benzo[f]
The starting 2-(4,5-dimethoxy-2-nitrophenyl)acetonitrile required for the Perkin condensation
was prepared by nitration of homoveratronitrile with nitric acid in glacial acetic acid.11 Attempts to
synthesize coumarins 6 by means of the Perkin condensation of salicylaldehydes with ethyl 2-(4,5-
dimethoxy-2-nitrophenyl)acetate in the presence of piperidine as the catalyst failed, even with a
stronger base, such as potassium tert-butoxide. The structures of coumarins 6 were confirmed by
1
elemental analysis and H, 13C NMR and IR spectroscopy. However, the 13С NMR spectra of
coumarins 6f,g could not be obtained due to the poor solubility of these compounds in deuterated
solvents. The structures of coumarins 6 were established unequivocally by X-ray crystallographic
analysis, performed on compound 6a (Figure 3).12
Figure 3. Mercury13 representation of the X-ray crystal structure of 6a.
Thermal ellipsoids at 50% probability.
5

The second step in the synthesis of indolo[3,2-c]coumarins was reductive cyclization of
compounds 6. We decided to study the microwave-assisted Cadogan reaction for the synthesis of
indolo[3,2-c]coumarins 7, as it was reported earlier that the use of the microwave-assisted technique
was effective for various substrates.4b The results obtained demonstrate that the microwave-assisted
Cadogan reaction was successful for the preparation of compounds 7. Optimization of the
temperature, time, and solvents was performed on the synthesis of coumarin 7a.
Triphenylphosphine or triethyl phosphite were used as reducing agents in these transformations (see
Table 2 and Scheme 4).
Scheme 4. The Cadogan cyclization of coumarin 6a
Table 2. Optimization of the conditions for MW-assisted Cadogan cyclization
Entry
Solvent
Time
(min)
5
Yield (%) with
Ph3Pa
Yield (%) with
(EtO)3Pa
1
2
3
4
5
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
DMF
(6a/7a)b
(6a/7a)b
10
25
25
25
41
54
0
67
61
0
Diglyme
68
71
a 1 mmol of 6a, 3 mmol of Ph3P or (EtO)3P and 2.5 ml of an appropriate solvent were used
b A mixture of 6a and 7a was obtained with low conversion of the starting material
It was found that indolo[3,2-c]coumarin 7a was formed in the highest yield when the reaction
mixture was heated at 200 °С for 25 minutes in diglyme under microwave irradiation (Table 2,
entry 5). The yields of 7a were slightly different when triphenylphosphine or triethyl phosphite
were used under the same reaction conditions.
The optimized conditions for the preparation of 7a were used for the synthesis of other
indolo[3,2-c]coumarins 7.14 However, triphenylphosphine proved to be unsuitable for the syntheses
of 7c-e. Instead, these compounds were obtained in good yields when triethyl phosphite was used as
the reducing agent. Indeed, triethyl phosphite proved to be a more effective reagent for cyclization
of coumarins 6. The exception was coumarin 6h, which did not undergo cyclization in the presence
of triethyl phosphite (see Scheme 5 and Table 3).
6

Scheme 5. Synthesis of indolo[3,2-c]coumarins 7 via the Cadogan cyclization
Table 3. Yields of indolo[3,2-c]coumarins 7 with Ph3P and (EtO)3P.
Coumarin
R1
R2
R3
Indolo[3,2-
Yield (%) with
Yield (%) with
c]coumarin
Ph3P
68
68
0
0
0
61
64
58
(EtO)3P
71
6a
6b
6c
6d
6e
6f
H
OMe
OMe Br
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
7a
7b
7c
7d
7e
7f
86
92
89
73
82
83
0
OMe
Br
Cl
Br
6g
6h
7g
7h
Benzo[f]
It should be noted that indolo[3,2-c]coumarins 7a-h were obtained in good to excellent yields
and in analytically pure form without the need for further purification. All products 7 had very low
solubility in a majority of organic solvents, while their melting points exceeded 350 ˚C.
Two methods for the further modification of indolo[3,2-c]coumarin 7a have been studied.
Demethylation of compound 7a was performed with 48% hydrobromic acid under reflux to give the
corresponding dihydroxy derivative 8. 11-Substituted compounds 9a,b were isolated in moderate
yields via alkylation of indolo[3,2-c]coumarin 7a. This synthesis was carried out in DMF at room
temperature in the presence of sodium tert-butoxide as the base (Scheme 6).
Scheme 6. Modifications of indolo[3,2-c]coumarin 7a
The structure of benzylated derivative 9a was confirmed by X-ray crystallography (Figure
4).15 This analysis provided indirect proof for the structures of indolo[3,2-c]coumarins 7, in addition
to the 1H and 13C NMR spectral data and elemental analyses.
7

Figure 4. Mercury13 representation of the X-ray crystal structure of 9a.
Thermal ellipsoids at 50% probability.
In summary, we have developed a convenient and highly efficient two-step synthesis of
indolo[3,2-c]coumarins from commercially available salicylaldehydes by means of the Perkin
condensation, followed by microwave-assisted Cadogan cyclization. Further studies on the use of
this approach for the synthesis of other 3-(hetero)arylcoumarins containing a nitro group on the 3-
(hetero)aryl substituent are in progress.
Acknowledgments
This work was supported by the Ural Branch of the Russian Academy of Sciences (Grants № 12-P-
3-1014, 12-P-3-1030, 12-T-3-1025 and 12-T-3-1031), the State Program for the Supporting of
Leading Scientific Schools of the Russian Federation (grant NSh 5505.2012.3), the Russian
Foundation for Basic Research (research projects No. 12-03-31574-mol_a, 13-03-96049-r_ural_a),
and the Ministry of Education and Science of the Russian Federation (projects № 8430 and 8634).
8

References and notes
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Proc. Chem. Soc. 1962, 361; (с) Bunyan, P. J.; Cadogan, J. I. G. Proc. Chem. Soc. 1962, 78.
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3. Cadogan, J. I. G.; Mackie, R. K. Chem. Soc. Rev., 1974, 3, 87 – 137.
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Creencia, E.C.; Kosaka, M.; Muramatsu, T.; Kobayashi, M.; Iizuka, T.; Horaguchi, T. J.
Heterocycl. Chem. 2009, 46, 1309 – 1317.
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T. J. Enzyme Inhib. Med. Chem. 2005, 20, 333 – 340; (c) Mahmoud, Z. F.; Sarg, T. M.; Amer, M.
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1975, 64, 1995 – 1998. (e) Pereira, N. A.; Pereira, B. M. R.; Nascimento, M. C.; Parente, J. P.;
Mors, W. B. Planta Med. 1994, 60, 99 – 100; (f) Hwu, J. R.; Singha, R.; Hong, S. C.; Chang, Y. H.;
Das, A. R.; Vliengen, I.; De Clercq, E.; Neyts, J. Antiviral Res. 2008, 77, 157 – 162; (g) Reddy, M.
V. R.; Rao, M. R.; Rhodes, D.; Hansen, M.; Rubins, K.; Bushman, F. D.; Venkateswarlu, Y.;
Faulkner, D. J. J. Med. Chem. 1999, 42, 1901 – 1907; (h) Neyts, J.; De Clercq, E.; Singha, R.;
Chang, Y. H.; Das, A. R.; Chakraborty, S. K.; Hong, S. C.; Tsay, S.-C.; Hsu, M.-H.; Hwu, J. R. J.
Med. Chem. 2009, 52, 1486 – 1490.
6. (a) Lee, K. S.; Kim, H. J.; Kim, G. H.; Shin, I.; Hong, J. I. Org. Lett. 2008, 10, 49 – 51; (b) Zhao,
Y.; Zheng, Q.; Dakin, K.; Xu, K.; Martinez, M. L.; Li, W.-H. J. Am. Chem. Soc. 2004, 126, 4653 −
4663; (c) Woodroofe, C. C.; Won, A. C.; Lippard, S. J. Inorg. Chem. 2005, 44, 3112 − 3120.
7. (a) Hara, K.; Wang, Z. S.; Sato, T.; Furube, A.; Katoh, R.; Sugihara, H.; Dan-Oh, Y.; Kasada, C.;
Shinpo, A.; Suga, S. J. Phys. Chem. B 2005, 109, 15476 – 14582; (b) Hara, K.; Sato, T.; Katoh, R.;
Furube, A.; Ohga, Y.; Shinpo, A.; Suga, S.; Sayama, K.; Sugihara, H.; Arakawa, H. J. Phys. Chem.
B 2003, 107, 597 – 606; (c) Hara, K.; Tachibana, Y.; Ohga, Y.; Shinpo, A.; Suga, S.; Sayama, K.;
Sugihara, H.; Arakawa, H. Sol. Energy Mater. Sol. Cells 2003, 77, 89 – 103.
8. (a) Kuiper, G. G.; Lemmen, J. G.; Carlsson, B.; Corton, J. C.; Safe, S. H.; van der Saag, P. T.;
van der Burg, B.; Gustafsson, J. A. Endocrinology, 1998, 139, 4252 – 4263; (b) Sarveswaran, S.;
Gautam, S. C.; Ghosh, J. Int. J. Oncol. 2012, 41, 2191 – 2199; (c) Wong, S.M.; Antus, S.;
Gottsegen, A.; Fessler, B.; Rao, G. S.; Sonnenbichler, J.; Wagner, H. Arzneimittelforschung 1988,
38, 661 – 665.
9. (a) Thasana, N.; Worayuthakarn, R.; Kradanrat, P.; Hohn, E.; Young, L.; Ruchirawat, S. J. Org.
Chem. 2007, 72, 9379 – 9382; (b) Yao, T.; Yue, D.; Larock, R. C. J. Org. Chem. 2005, 70, 9985 –
9

9989; (c) Stadlbauer, W.; Laschober, R.; Kappe, T. Monatsh. Chem. 1991, 122, 853 – 861. (d)
Stadlbauer, W.; Kappe, T. Monatsh. Chem. 1984, 115, 467 – 476.
10. General procedure for the preparation of coumarins 6. Piperidine (0.03 ml, 5 mol%) was added
to a warm solution of the appropriate salicylaldehyde 5 (5 mmol) and 2-(4,5-dimethoxy-2-
nitrophenyl)acetonitrile (1.12 g, 5 mmol) in EtOH (10 ml). The resulting solution was refluxed with
stirring for 5 h. The mixture was treated with a solution of concentrated H2SO4 (0.55 ml) in EtOH
(2 ml) and refluxed with stirring for 2 h. The obtained precipitate was filtered, washed with EtOH
(10 ml), hot H2O (40 ml) and finally with EtOH (10 ml), and dried at 100 °C.
3-(4,5-Dimethoxy-2-nitrophenyl)coumarin (6a). Yellow crystals. IR (KBr): 3040, 3004, 2947,
1
2851, 1717, 1512, 1335, 1278, 1222, 1069, 875, 757 cm–1; H NMR (400 MHz, DMSO-d6) δ 3.93
(s, 3H, MeO), 3.94 (s, 3H, MeO), 7.25 (s, 1H), 7.41 − 7.46 (m, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.65 –
7.70 (m, 1H), 7.73 (s, 1H), 7.80 (dd, J = 7.7, 1.3 Hz, 1H), 8.24 (s, 1H); 13C NMR (126 MHz,
DMSO-d6) δ 56.2, 56.5, 107.9, 114.3, 116.1, 119.1, 123.9, 124.9, 126.8, 128.6, 132.0, 140.2, 140.6,
148.6, 152.8, 152.9, 159.0; Anal. Calcd for C17H13NO6: C, 62.39; H, 4.00; N, 4.28. Found: C,
62.29; H, 3.93; N, 4.27.
11. Walker, G. N. J. Am. Chem. Soc., 1955, 77, 3844 – 3850.
12. Crystal data for 9a: Yellow crystals 0.25×0.12×0.04 mm, θ < 28.28o, 7428 reflections were
collected, 3624 independent reflections (Rint 0.0181), completeness 98.9%. Crystal is triclinic, space
group P-1, a= 6.6935(9) Å, b= 7.5212(7) Å, c= 15.399(2) Å, α= 76.398(10), β= 82.687(11)o, γ=
81.040(10)o, μ= 0.113 mm-1. The SHELXTL program16 was used for solution and structure
refinement. The details of the refinement and the final R indices: R1= 0.0354 [I>2σ(I)], wR2=
0.0880 [I>2σ(I)], R1= 0.0696 (all data), wR2= 0.0927 (all data), S= 1.001. Deposition number
CCDC 939607 contains the supplementary crystallographic data for this structure. These data can
be obtained free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
13. Mercury 3.1, available from http://www.ccdc.cam.ac.uk/mercury/.
14. General procedure for the preparation of indolo[3,2-c]coumarins [chromeno[4,3-b]indol-
6(11H)-ones] 7. The appropriate coumarin 6 (1 mmol), Ph3P (3 mmol, 0.8 g) or (EtO)3P (3 mmol,
0.5 ml) and diglyme (2.5 ml) were placed in a reaction vessel. The resulting suspension was
irradiated17 with stirring at 200 °C (250 W) for 25 min. The mixture was cooled and the product
was filtered, washed with diglyme (3 ml) and EtOH (10 ml), and dried at 110 °C.
8,9-Dimethoxychromeno[4,3-b]indol-6(11H)-one (7a). Light cream powder. IR (KBr): 3201, 3001,
1
2958, 2839, 1704, 1669, 1511, 1486, 1454, 1294, 1207, 1152, 1107, 1017, 842, 752, 537 cm–1; H
NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H, MeO), 3.89 (s, 3H, MeO), 7.15 (s, 1H), 7.42 – 7.53 (m,
10

13
3H), 7.54 – 7.61 (m, 1H), 8.15 (dd, J = 7.8, 1.1 Hz, 1H), 12.79 (s, 1H, NH); C NMR (126 MHz,
DMSO-d6) δ 55.7, 55.8, 95.7, 100.2, 101.7, 113.5, 116.9, 117.0, 122.0, 124.2, 129.8, 132.1, 139.9,
146.5, 148.5, 152.1, 158.0; Anal. Calcd for C17H13NO4: C, 69.15; H, 4.44; N, 4.74. Found: C,
69.39; H, 4.57; N, 4.74.
15. Crystal data for 9a: White crystals 0.25×0.20×0.15 mm, θ < 26.37o, 5235 reflections were
collected, 4315 independent reflections (Rint 0.0293), completeness 96.7%. Crystals belong to the
triclinic space group P-1, a= 7.9538(10) Å, b= 10.5329(17) Å, c= 14.242(2) Å, α= 68.751(12)o, β=
87.641(15)o, γ= 80.276(12)o, μ= 0.080 mm-1. The SHELXTL program16 was used for solution and
structure refinement. The details of the refinement and the final R indices: R1= 0.0512 [I>2σ(I)],
wR2= 0.1475 [I>2σ(I)], R1= 0.1351 (all data), wR2= 0.1518 (all data), S= 1.001. Deposition number
CCDC 939608 contains the supplementary crystallographic data for this structure. These data can
be obtained free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
16. Sheldrick, G. M. Acta Cryst. Sect. A. 2008, 64, 112 – 122.
17. Microwave experiments were carried out in a Discover unimodal microwave system (CEM,
USA) with a working frequency of 2.45 GHz and the power of microwave radiation ranged from 0
to 300 W. The reactions were carried out in a 10 ml reaction tube fitted with a Teflon stopper. The
temperature of the reaction was monitored with an internal IR sensor located on the external surface
of the reaction vessel.
11

Graphical abstract
_____________________________________________________________________________________________
A convenient approach to the design and synthesis of indolo[3,2-c]coumarins via the microwave-assisted
Cadogan reaction
Roman A. Irgashev*, Arseny A. Karmatsky, Pavel A. Slepukhin, Gennady L. Rusinov, Valery N. Charushin
_____________________________________________________________________________________________
12