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A greener, facile and scalable synthesis of indole derivatives in water: reactions of indole-2,3-diones with 1,2-difunctionalized benzene
Tetrahedron Letters 53 (2012) 6236–6240
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A greener, facile and scalable synthesis of indole derivatives in water: reactions of indole-2,3-diones with 1,2-difunctionalized benzene Renuka Jain ⇑, Kanti Sharma, Deepak Kumar Department of Chemistry, University of Rajasthan, Jaipur 302 004, India
a r t i c l e
i n f o
Article history: Received 23 July 2012 Revised 3 September 2012 Accepted 5 September 2012 Available online 13 September 2012 Keywords: Indole-2,3-diones 1,2-Difunctionalized benzene Tetrabutylammonium bromide Aqueous micellar media Eco-friendly synthesis
a b s t r a c t An efficient, facile and greener protocol for the synthesis of indole derivatives viz., 30 H-spiro[indole3,20 -[1,3]benzothiazole]-2(1H)-ones, 6H-indolo[2,3-b]quinoxalines and 3-(2-hydroxy-phenylimino)1,3-dihydro-indol-2-ones, by the reactions of indole-2,3-diones with 1,2-difunctionalized benzene using tetrabutylammonium bromide (TBAB), as a surfactant under aqueous micellar media is described. This methodology has advantages of simple handling, mild reaction conditions and high yields of products in shorter reaction time as well as environmentally benign synthesis. Ó 2012 Elsevier Ltd. All rights reserved.
In recent years, the main aims of green chemistry are the development of cleaner and more benign chemical processes by replacement of volatile and hazardous reagents and solvents with environmentally benign materials and thus increase of process selectivity.1,2 Organic synthesis in water is both environmentally and economically benign because of the cheap, non-inflammable, nontoxic, safe to use and unique physical and chemical properties such as the network of hydrogen bond, the large surface tension, high specific heat capacity and high polarity which often increases its reactivity and selectivity that cannot be obtained in organic solvents.1c,3 Further, due to poor solubility of organic molecules in water, it provides an easy approach for the separation of hazardous organic reagents, by-products and catalysts from the aqueous phase.4 Therefore, in the past decade, aqueous-mediated reactions have been extensively pursued due to their efficient, atom-economy and green credentials.5 Recently, surfactants (surface-active reagents) have attracted considerable interest in organic synthesis because of their high catalytic activity and benign character in the context of green chemistry. Introduction of surfactants in aqueous medium has been proved to increase the reactivity of aqueous mediated reactions via the formation of vesicular cavities or micelles with hydrophobic core and hydrophilic corona at ambient conditions. The catalytic use of micellar surfactants in water is widespread and has been studied in detail for a number of different reactions in aque-
⇑ Corresponding author. Tel.: +91 141 2742048. E-mail address: [email protected] (R. Jain). 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.09.013
ous medium which provides an alternative synthetic approach under aqueous conditions.6 Indole-2,3-dione commonly known as isatin and its derivatives possess interesting biological activities and are widely used as a precursor for many natural products.7 Furthermore, compounds possessing this heterocyclic nucleus have been isolated from plants also.8 The heterocyclic spiro-oxindole framework is a privileged structure motif that forms the core of a large family of natural products with interesting biological and structural properties (Fig. 1). Spiro-oxindole ring system and its derivatives exhibit numerous types of biological activities such as antimicrobial, antitumor, antileukemic and anticonvulsant as well as found to be potent nonpeptide inhibitors of the p53-MDM2 interaction.9 These have also been reported to act as aldose reductase, poliovirus and rhinovirus 3C-proteinase inhibitors.10 A published report’s survey revealed that the synthesis of indole derivatives by the reactions of indole-2,3-diones with 1,2-difunctionalized benzene has been carried out using different solvents and catalysts.11 However, in these reported methods, most of the synthetic approaches are associated with harsh reaction conditions, using environmentally black-listed solvents, prolonged reaction time and tedious isolation procedure with poor yields. Therefore, it appeared to be of interest to develop eco-friendly, facile and more practical procedure for the synthesis of these important heterocyclic derivatives. Considering the significance of surfactants and in our continuous ongoing efforts to develop new efficient protocol for the synthesis of bioactive heterocycles employing green tools from readily available building blocks,12 herein we report for the first
R. Jain et al. / Tetrahedron Letters 53 (2012) 6236–6240
O
H
O SCH3
N
HN
N S
N O
MeO
O
H N H
Spirobrassinin
Spirotryprostatin A
NH
N Bu-i
O
O
O
N H
OH
N H
Elacomine
Horsfiline
Figure 1. Examples of oxindole moiety containing natural products.
time, a green, efficient and new procedure for the synthesis of indole derivatives in aqueous micellar media using tetrabutylammonium bromide, as a surfactant in water. The choice of an appropriate reaction medium is of essential importance for a successful synthesis. In our initial investigation, the reaction of indole-2,3-dione 1a, and 2-aminothiophenol 2, as a model substrate was investigated to establish the feasibility of the strategy and optimize the reaction conditions. Various solvents such as methanol, ethanol (neutral/acidic) as well as water with/ without surfactant were screened and optimized. The best results that is excellent yields in shorter reaction time were obtained in aqueous medium with surfactants where there was no requirement for a further purification process like column chromatography. We have carried out the reactions at different temperatures using different concentrations of the surfactant and the data are presented in Table 1, from which it is clear that the rate of reaction increased continuously with increase of the catalyst concentration upto 15 mol % without any considerable difference on a further increase of the catalyst concentration. It was observed that the concentration of the catalyst plays a significant role in controlling the rate of the reaction and it was concluded that among the various
Table 1 Synthesis of 4a under different reaction conditionsa Entry
Solvent
Temperature (°C)
Reaction time (h)
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12
MeOH EtOH (neutral) EtOH (acidic) Water Water/TBABc Water/TBABc Water/TBABc Water/TBABc Water/TBABc Water/TBABd Water/TBABe Water/TBABf
Reflux Reflux Reflux Reflux RT 60 80 100 Reflux 60 60 60
4 5 4 3 6 0.5 0.5 0.5 0.5 0.5 0.5 0.5
58 56 58 72 84 84 81 80 77 81 89 90
a Reaction conditions: 1.0 mmol of indole-2,3-dione 1a and o-aminothiophenol 2 was used. b Isolated yield. c TBAB (10 mol %). d TBAB (5 mol %). e TBAB (15 mol %). f TBAB (20 mol %).
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amounts of the catalyst studied, 15 mol % of TBAB was found to be the best at 60 °C temperature, in aqueous condition. It was observed that on introduction of TBAB followed by stirring, the initially floating reactants in the mixture converted to a yellowish-brown turbid emulsion (Fig. 2a), which implies that there was the formation of micelle like colloidal aggregates. Indeed, the light microscopic observation of the emulsion dispersion formed from indole-2,3-dione, 2-aminothiophenol and TBAB in distilled water revealed that spherical particles were formed (Fig. 2b).13 It is assumed that most of the organic substrates are concentrated in the spherical particles, which act as a hydrophobic reaction site and result in the rapid reaction in water. The catalytic effect of micellar TBAB in these reactions may be explained as follows. Indole-2,3-diones as well as 1,2-difunctionalized benzene molecules are hydrophobic in aqueous medium. In the micellar solution, the organic substrates which are hydrophobic, escape from water molecule towards the hydrophobic core of micelle droplets where the reaction occurred more easily. The hydrophobic interior of the micelles rapidly excludes the water molecules generated during the reaction, thus shifting the equilibrium towards the product side.14 The above explanation is schematically presented in Figure 3. The synthesis of compounds 4a–c have been performed by taking indole-2,3-diones 1a–c (1.0 mmol), 2-aminothiophenol 2 (1.0 mmol) and tetrabutylammonium bromide (15 mol %) in distilled water. The reaction has been carried out by stirring the reaction mixture at 60 ± 2 °C until completion of the reaction as evidenced by TLC (Scheme 1 and Table 2).15 Initially, the b-carbonyl group of 1 reacts with the amino group of 2 leading to the formation of intermediate 3, this is followed by the nucleophillic attack of the thiol group (presence of more acidic hydrogen on thiol group) on the b-carbon leading to the formation of 4 by the removal of a water molecule. The isolated products 4 were characterized on the basis of their IR, 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis. The IR spectrum of 4b showed absorptions at 3320 and 1712 cm1 indicative of the –NH and carbonyl functionality of benzothiazole moiety and oxindole ring, respectively. The 1H NMR spectrum of 4b exhibited two sharp singlets arising from the proton of –NCH3 of oxindole (d 3.20 ppm) and –NH group of benzothiazole (d 7.26 ppm) along with characteristic signals with appropriate chemical shifts and coupling constants for the eight H-atoms of the two aromatic moieties. In the 13C NMR spectrum the signal at d 74.0 ppm indicates the presence of a quaternary carbon atom with spiro linkage. The carbon atoms of the –NCH3 and carbonyl group of the oxindole ring resonated at d 26.5 and 175.2 ppm, respectively. The mass spectrum of 4b displayed a
Figure 2. (a) Reaction mixture of the indole-2,3-dione (1a), o-aminothiophenol (2) and TBAB in distilled water. (b) Optical micrograph of the reaction mixture (scale bar = 25 lm).
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R. Jain et al. / Tetrahedron Letters 53 (2012) 6236–6240
O N H
S
O
NH
+
H2N
N H
O
+ H2O
HS
Hydrophobic interior Hydrophilic exterior
: TBAB Figure 3. Micelles-promoted green synthesis of 30 H-Spiro[indole-3,20 -[1,3]benzothiazole]-2(1H)-one.
H O
TBAB (15 mol%) Water, 60 °C
H2 N
O
HS
N R
1a-c
S
HO
+ N R
S
-H2O
N H O
O
N R
3a-c
2
NH
4a-c
R = H, CH3, CH2Ph Scheme 1. Synthesis of 30 H-spiro[indole-3,20 -[1,3]benzothiazole]-2(1H)-ones 4a–c.
Table 2 Synthesis of 30 H-spiro[indole-3,20 -[1,3]benzothiazole]-2(1H)-one derivatives 4a–ca
Table 3 Synthesis of 6H-indolo[2,3-b]quinoxaline derivatives 7a–ca
Entry
Product
R
Temperature (°C)
Reaction time (min)
Yieldb (%)
Entry
Product
R
Temperature (°C)
Reaction time (min)
Yieldb (%)
1 2 3
4a 4b 4c
H CH3 CH2Ph
60 60 60
30 35 50
89 85 83
1 2 3
7a 7b 7c
H CH3 CH2Ph
60 60 60
50 40 50
85 83 83
a Reaction conditions: 1.0 mmol of indole-2,3-diones 1a–c and o-aminothiophenol 2, TBAB (15 mol %) and distilled water (5.0 mL) was used. b Isolated yield.
a Reaction conditions: 1.0 mmol of indole-2,3-diones 1a–c and o-phenylenediamine 5, TBAB (15 mol %) and distilled water (5.0 mL) was used. b Isolated yield.
molecular ion peak (M+) at m/z 268.3, which is 18 mass units (H2O) lower than that of a 1:1 adduct of 1-methyl-indole-2,3-dione and
o-aminothiophenol which further supported the formation of cycloadduct 4b.15
O
TBAB (15 mol%) Water, 60 °C
H2 N
HO
H N
+ N R
O
H2 N
N R
5
O H2 N
6a-c Scheme 2. Synthesis of 6H-indolo[2,3-b]quinoxalines 7a–c.
N
-2H2O N R
N
7a-c
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R. Jain et al. / Tetrahedron Letters 53 (2012) 6236–6240
O
TBAB (15 mol%) Water, 60 °C
H2N
HO
H N
+ O
N R
HO
N R
8
O
N
-H2O
HO
9a-c
N R
O HO
10a-c
Scheme 3. Synthesis of 3-(2-hydroxy-phenylimino)-1,3-dihydro-indol-2-ones 10a–c.
Table 4 Synthesis of 3-(2-hydroxy-phenylimino)-1,3-dihydro-indol-2-one derivatives 10a–ca Entry
Product
R
Temperature (°C)
Reaction time (min)
Yieldb (%)
1 2 3
10a 10b 10c
H CH3 CH2Ph
60 60 60
45 40 40
86 84 85
a Reaction conditions: 1.0 mmol of indole-2,3-diones 1a–c and o-aminophenol 8, TBAB (15 mol %) and distilled water (5.0 mL) was used. b Isolated yield.
O
TBAB(15mol%) Water, 60 °C
HO
+ N R
O
No reaction
HO
11 Scheme 4.
Encouraged by this success, we have extended this protocol to another 1,2-difunctionalized benzene which is o-phenylenediamine 5 under similar conditions as optimized (Scheme 2 and Table 3). Several investigations of the reactions between indole-2,3-diones and o-phenylenediamine in various solvents have been carried out and found that the solvent used in the reaction can shift the reaction towards the formation of different products.7,11a,16 When this reaction was performed in optimized condition, we found that there was the formation of quinoxaline derivatives 7a–c instead of spiro cycloadduct which was confirmed by the 13C NMR spectrum in which no signals due to C@O of oxindole ring and spiro carbon were observed while a peak at 1620 cm1 due to the presence of C@N appeared.17 It is well known that ammonia reacts with the b-carbonyl of indole-2,3-dione to give the adduct at lower temperatures.18 The analogous intermediates 6a–c would give a preferable explanation of the formation of 7a–c. The reaction of the amino group with the a-carbonyl of the 6a–c, followed by the removal of two molecule of water would give 7a–c. The structure of products 7 was characterized on the basis of their spectral and elemental analyses. The IR spectrum of the product 7b showed a peak at 1620 cm1 due to C@N group in the tetracyclic ring system. In the IR spectrum, the disappearance of two C@O of the oxindole ring along with the appearance of a signal due to C@N further proved the formation of quinoxaline derivatives instead of a spiro cycloadduct. In the 1H NMR spectrum, Hatoms of the –NCH3 group of the oxindole ring appeared at d 2.94 ppm as a singlet along with characteristic signals with appropriate chemical shift and coupling constant for the eight protons of the two aromatic moieties. In the 13C NMR, the C-atom of –NCH3 of oxindole ring resonated at d 30.0 ppm along with aromatic signals. In the mass spectrum, molecular ion peak (M+) appeared at m/z 233.2, which is 36 mass units (2 H2O) lower than that of a 1:1
adduct of the reactant and further confirmed the formation of product 7b.17 On a similar protocol, we next investigated other 1,2-difunctionalized benzene, o-aminophenol 8 where interesting results were obtained. In this case there was the formation of Schiff’s bases, 3-(2-hydroxy-phenylimino)-1,3-dihydro-indol-2-ones 10a– c only in excellent yields instead of spiro or other condensed products (Scheme 3 and Table 4). The formation of the products 10a–c was explained as amino group of 8 reacts with b-carbonyl of indole-2,3-diones affording intermediates 9a–c, which on the removal of one molecule of water gave 3-(2-hydroxy-phenylimino)-1,3-dihydro-indol-2-ones. On the other hand the formation of spiro derivatives was ruled out due to the presence of less acidic hydrogen of the hydroxyl group and also the possibility of the condensed product was ruled out due to the presence of –OH group in the product. The chemical structure of the products was proven on the basis of their spectral data. The IR spectrum of the 10a showed a broad signal at 3100–3295 cm1 due to –NH and –OH along with signals at 1722 and 1618 cm1 due to C@O and C@N groups, respectively. The absorption band at 1290 cm1 is attributed to the phenolic C– O stretching vibration.19 Further, when this methodology was applied for 1,2-dihydroxy benzene 11, the reaction was not successful in the all optimized conditions (Scheme 4). In conclusion, an efficient, facile and straightforward green protocol for the synthesis of indole derivatives has been developed by using TBAB, as a surfactant in aqueous medium for the first time. The reactions of indole-2,3-diones with various 1,2-difunctionalized benzene viz., o-aminothiophenol, o-phenylenediamine and o-aminophenol afford 30 H-spiro[indole-3,20 -[1,3]benzothiazole]2(1H)-ones, 6H-indolo[2,3-b]quinoxalines and 3-(2-hydroxy-phenylimino)-1,3-dihydro-indol-2-ones, respectively while a reaction does not take place with 1,2-dihydroxy benzene. Acknowledgements Authors are grateful to CSIR and UGC, New Delhi, India for financial assistance. References and notes 1. (a) Li, C.-J. Chem. Rev. 2005, 105, 3095; (b) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209; (c) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751; (d) Solhy, A.; Elmakssoudi, A.; Tahir, R.; Karkouri, M.; Larzek, M.; Bousmina, M.; Zahouily, M. Green Chem. 2010, 12, 2261; (e)Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic & Professional: London, 1998; (f) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1988. 2. (a) Lancester, M. Green Chemistry: An Introductory Text; Royal Society of Chemistry: Cambridge, 2002; (b) Tan, J.-N.; Li, H.; Gu, Y. Green Chem. 2010, 12, 1772. 3. (a) Yorimitsu, H.; Shinokubo, H.; Oshima, K. Synlett 2002, 5, 674; (b) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275; (c) Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492; (d) Breslow, R.; Maitra, U. Tetrahedron Lett. 1984, 25, 1239; (e) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816. 4. (a) Dolzhenko, A. V.; Pastorin, G.; Dolzhenko, A. V.; Chui, W. K. Tetrahedron Lett. 2009, 50, 2124; (b) Panda, S. S.; Jain, S. C. Synth. Commun. 2011, 41, 729.
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R. Jain et al. / Tetrahedron Letters 53 (2012) 6236–6240
5. (a) Ma, N.; Jiang, B.; Zhang, G.; Tu, S.-J.; Walter, W.; Li, G. Green Chem. 2010, 12, 1357; (b) Jiang, B.; Li, C.; Shi, F.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G. J. Org. Chem. 2010, 75, 2962; (c) Ganem, B. Acc. Chem. Res. 2009, 42, 463; (d) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072; (e) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861; (f) Lindstrom, U. M.; Andersson, F. Angew. Chem., Int. Ed. 2006, 45, 548; (g) Candeias, N. R.; Branco, L. C.; Gois, P. M. P.; Afonso, C. A. M.; Trindade, A. F. Chem. Rev. 2009, 109, 2703; (h) Shapiro, N.; Vigalok, A. Angew. Chem., Int. Ed. 2008, 47, 2849. 6. (a) Selke, R.; Holz, J.; Riepe, A.; Borner, A. Chem. Eur. J. 1998, 4, 769; (b) Blagoeva, I. B.; Toteva, M. M.; Ouarti, N.; Ruasse, M. F. J. Org. Chem. 2001, 66, 2123; (c) Firouzabadi, H.; Iranpoor, N.; Garzan, A. Adv. Synth. Catal. 2005, 347, 1925; (d) Shiri, M.; Zolfigol, M. A. Tetrahedron 2009, 65, 587; (e) Kobayashi, S.; Hachiya, I. J. Org. Chem. 1994, 59, 3590; (f) Larpent, C.; Bernard, E.; Menn, F. B.; Patin, H. J. Mol. Catal. A: Chem. 1997, 116, 227; (g) Selke, R.; Holz, J.; Riepe, A.; Borner, A. Chem. d Eur. J. 1998, 4, 769; (h) van den Broeke, L. J. P.; de Bruijn, V. G.; Heijnen, J. H. M.; Keurentjes, J. T. F. Ind. Eng. Chem. Res. 2001, 40, 5240. 7. Da Silva, J. F. M.; Garden, S. J. C.; Pinto, A. J. Braz. Chem. Soc. 2001, 12, 273. 8. Kamano, Y.; Zhang, H. P.; Ichihara, Y.; Kizu, H.; Komiyama, K.; Pettit, G. R. Tetrahedron Lett. 1995, 36, 2783. 9. (a) Kornet, M. J.; Thio, A. P. J. Med. Chem. 1976, 19, 892; (b) Bhaskar, G.; Arun, Y.; Balachandran, C.; Saikumar, C.; Perumal, P. T. Eur. J. Med. Chem. 2012, 51, 79; (c) Gomez-Monterrey, I.; Bertamino, A.; Porta, A.; Carotenuto, A.; Musella, S.; Aquino, C.; Granata, I.; Sala, M.; Brancaccio, D.; Picone, D.; Ercole, C.; Stiuso, P.; Campiglia, P.; Grieco, P.; Ianelli, P.; Maresca, B.; Novellino, E. J. Med. Chem. 2010, 53, 8319; (d) Wang, S.; Malek, S.; Long, J.; Ouillette, P. PCT Int. Appl. WO 2011127058 A2 20111013, 2011.; (e) Basavaiah, D.; Reddy, R. K. Org. Lett. 2007, 9, 57. 10. Skiles, J. W.; Mc Neil, D. Tetrahedron Lett. 1990, 31, 7277. 11. (a) Popp, F. D. J. Heterocycl. Chem. 1969, 6, 125; (b) Karali, N.; Guzel, O.; Ozsoy, N.; Ozbey, S.; Salman, A. Eur. J. Med. Chem. 2010, 45, 1068; (c) Alam, Y. A.; Nawwar, G. A. M. Heteroatom Chem. 2002, 13, 207; (d) Dowlatabadi, R.; Khalaj, A.; Rahimian, S.; Montazeri, M.; Amini, M.; Shahverdi, A.; Mahjub, E. Synth. Commun. 2011, 41, 1650. 12. (a) Jain, R.; Sharma, K.; Kumar, D. Tetrahedron lett. 2012, 53, 1993; (b) Jain, R.; Sharma, K.; Kumar, D. Helv. Chim. Acta 2012. http://dx.doi.org/10.1002/ hlca.2012,00,168; (c) Jain, R.; Sharma, K.; Kumar, D. J. Heterocycl. Chem. 2011. http://dx.doi.org/10.1002/jhet.1071; (d) Jain, R.; Yadav, T.; Kumar, M.; Yadav, A. K. Synth. Commun. 2011, 41, 1889; (e) Jain, R.; Yadav, T.; Kumar, M.; Yadav, A. K. J. Heterocycl. Chem. 2010, 47, 603; (f) Yadav, A. K.; Kumar, M.; Yadav, T.; Jain, R. Synlett 2010, 5, 712; (g) Yadav, A. K.; Kumar, M.; Yadav, T.; Jain, R. Tetrahedron Lett. 2009, 50, 5031; (h) Yadav, A. K.; Manju, M.; Kumar, M.; Yadav, T.; Jain, R. Tetrahedron Lett. 2008, 49, 5724. 13. (a) Watanabe, Y.; Sawada, K.; Hayashi, M. Green Chem. 2010, 12, 384; (b) Shinde, P. V.; Kategaonkar, A. H.; Shingate, B. B.; Shingare, M. S.; Beilstein, J. Org. Chem. 2011, 7, 53; (c) Manabe, K.; Mori, Y.; Wakabayashi, T.; Nagayama, S.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 7202. 14. Wang, L.-M.; Jiao, N.; Qiu, J.; Yu, J.-J.; Liu, J.-Q.; Guo, F.-L.; Liu, Y Tetrahedron 2010, 1, 339. 15. Typical experimental procedure for synthesis of 4a: To a mixture of indole-2,3dione 1a (1.0 mmol) and o-aminothiophenol 2 (1.0 mmol) in distilled water (5.0 mL), was added TBAB (0.0483 g, 15 mol %). This reaction mixture was
16. 17.
18. 19.
allowed to stir magnetically at 60 °C. Progress of the reaction was monitored by TLC (Pet. ether–ethyl acetate = 4:1) and visualization was accomplished in an iodine chamber. After completion of the reaction, the solid obtained was collected by filtration and washed with warm water. The crude product, so obtained was purified by crystallization with ethanol to afford pure product. Spectral data of representative compounds: 30 H-Spiro[indole-3,2’-[1,3]benzothiazole]-2(1H)-one 4a (Table 2, entry 1): Light yellow solid; mp 220–222 °C; IR (KBr, cm1): 3310, 3195, 1705, 1465, 758; 1H NMR (300 MHz, DMSO-d6): d 6.65–6.74 (m, 2H, Ar-H), 6.88 (t, 1H, J = 7.8 Hz, Ar-H), 6.94 (d, 1H, J = 7.2 Hz, Ar-H), 7.03 (t, 1H, J = 7.2 Hz, Ar-H), 7.22–7.30 (m, 1H, Ar-H), 7.49 (d, 1H, J = 7.2 Hz, Ar-H), 7.54 (s, 1H, NH, D2O exchangeable), 7.57 (d, 1H, J = 6.9 Hz, Ar-H), 9.96 (s, 1H, NH, D2O exchangeable); 13C NMR (75 MHz, DMSO-d6): 73.9, 109.0, 109.7, 119.2, 120.5, 122.1, 124.3, 124.8, 125.0, 129.5, 129.6, 140.3, 145.7, 176.3; MS (m/z): 254.3; Anal. Calcd for C14H10N2OS: C, 66.06; H, 3.93; N, 11.01. Found; C, 66.18; H, 3.85; N, 11.12. 1-Methyl-30 H-spiro[indole-3,20 -[1,3]benzothiazole]-2(1H)-one 4b (Table 2, entry 2): Light yellow solid; mp 162–164 °C; IR (KBr, cm1): 3320, 1712, 1470, 755; 1 H NMR (300 MHz, DMSO-d6): d 3.20 (s, 3H, N-CH3), 6.70 (d, 1H, J = 7.8, Ar-H), 6.81 (t, 1H, J = 7.8 Hz, Ar-H), 6.82–6.94 (m, 1H, Ar-H), 6.99 (d, 1H, J = 7.2 Hz, ArH), 7.02 (dd, 1H, J = 7.6, 1.2 Hz, Ar-H), 7.12 (d, 1H, J = 7.8 Hz, Ar-H), 7.26 (s, 1H, NH, D2O exchangeable), 7.36 (d, 1H, J = 6.9 Hz, Ar-H), 7.61 (t, 1H, J = 7.8 Hz, ArH); 13C NMR (75 MHz, DMSO-d6): 26.5, 74.0, 108.5, 110.9, 121.4, 121.6, 123.6, 123.7, 125.1, 125.9, 129.7, 130.7, 142.4, 145.3, 175.2; MS (m/z): 268.3; Anal. Calcd for C15H12N2OS: C, 67.08; H, 4.47; N, 10.43. Found; C, 66.97; H, 4.58; N, 10.49. (a) Popp, F. D. Adv. Heterocycl. Chem. 1975, 18, 1; (b) Bergman, J.; Engqvist, R.; Stalhandske, C.; Wallberg, H. Tetrahedron 2003, 59, 1033. General procedure for synthesis of 7a: A mixture of indole-2,3-dione 1a (1.0 mmol), o-phenylenediamine 5 (1.0 mmol), TBAB (0.0483 g, 15 mol %) and distilled water (5.0 mL) was taken in a round bottom flask. The reaction was performed in the same way as described above. Spectral data of representative compounds: 6H-indolo[2,3-b]quinoxaline 7a (Table 3, entry 1): Yellow solid; mp 290–292 °C; IR (KBr, cm1): 3095–3200, 1620, 1455, 756; 1H NMR (300 MHz, DMSO-d6): d 7.35 (t, 1H, J = 7.8 Hz, Ar-H), 7.52–7.79 (m, 1H, Ar-H), 8.10 (dd, 2H, J = 7.8, 1.2 Hz, Ar-H), 8.32 (dd, 2H, J = 6.6, 1.5 Hz, Ar-H), 8.44 (d, 2H, J = 7.8 Hz, Ar-H), 11.61 (s, 1H, NH, D2O exchangeable); 13C NMR (75 MHz, DMSO-d6): 112.1, 118.9, 120.9, 122.6, 126.1, 127.1, 128.6, 131.1, 131.3, 138.1, 139.7, 140.0, 144.2, 145.7; MS (m/z): 219.2; Anal. Calcd for C14H9N3: C, 76.64; H, 4.10; N, 19.16. Found; C, 76.51; H, 4.17; N, 19.07. 6-Methyl-6H-indolo[2,3-b]quinoxaline 7b (Table 3, entry 2): Yellow solid; mp 148-150 °C; IR (KBr, cm1): 1620, 1460, 758; 1H NMR (300 MHz, DMSO-d6): d 2.94 (s, 3H, N-CH3), 6.69 (d, 1H, J = 7.8 Hz, Ar-H), 6.75 (d, 1H, J = 7.8 Hz, Ar-H), 7.25–7.41 (m, 3H, Ar-H), 7.45 (d, 1H, J = 7.2, Hz, Ar-H), 7.74 (d, 1H, J = 7.2 Hz, Ar-H), 8.38 (dd, 1H, J = 7.8, 1.2 Hz, Ar-H); 13C NMR (75 MHz, DMSO-d6): 30.0, 110.7, 114.8, 115.2, 117.4, 118.6, 121.2, 123.4, 127.9, 129.4, 131.5, 131.6, 131.8, 149.4, 155.7; MS (m/z): 233.2; Anal. Calcd for C15H11N3: C, 77.18; H, 4.71; N, 18.01. Found; C, 77.26; H, 4.63; N, 18.13. Reissert, A.; Hoppmann, H. Ber. 1924, 57B, 972. Hassaan, A. M.; Kalifa, M. A.; Shehata, A. Z. Bull. Soc. Chim. Belg. 1995, 104, 121.
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
A greener, facile and scalable synthesis of indole derivatives in water: reactions of indole-2,3-diones with 1,2-difunctionalized benzene Renuka Jain ⇑, Kanti Sharma, Deepak Kumar Department of Chemistry, University of Rajasthan, Jaipur 302 004, India
a r t i c l e
i n f o
Article history: Received 23 July 2012 Revised 3 September 2012 Accepted 5 September 2012 Available online 13 September 2012 Keywords: Indole-2,3-diones 1,2-Difunctionalized benzene Tetrabutylammonium bromide Aqueous micellar media Eco-friendly synthesis
a b s t r a c t An efficient, facile and greener protocol for the synthesis of indole derivatives viz., 30 H-spiro[indole3,20 -[1,3]benzothiazole]-2(1H)-ones, 6H-indolo[2,3-b]quinoxalines and 3-(2-hydroxy-phenylimino)1,3-dihydro-indol-2-ones, by the reactions of indole-2,3-diones with 1,2-difunctionalized benzene using tetrabutylammonium bromide (TBAB), as a surfactant under aqueous micellar media is described. This methodology has advantages of simple handling, mild reaction conditions and high yields of products in shorter reaction time as well as environmentally benign synthesis. Ó 2012 Elsevier Ltd. All rights reserved.
In recent years, the main aims of green chemistry are the development of cleaner and more benign chemical processes by replacement of volatile and hazardous reagents and solvents with environmentally benign materials and thus increase of process selectivity.1,2 Organic synthesis in water is both environmentally and economically benign because of the cheap, non-inflammable, nontoxic, safe to use and unique physical and chemical properties such as the network of hydrogen bond, the large surface tension, high specific heat capacity and high polarity which often increases its reactivity and selectivity that cannot be obtained in organic solvents.1c,3 Further, due to poor solubility of organic molecules in water, it provides an easy approach for the separation of hazardous organic reagents, by-products and catalysts from the aqueous phase.4 Therefore, in the past decade, aqueous-mediated reactions have been extensively pursued due to their efficient, atom-economy and green credentials.5 Recently, surfactants (surface-active reagents) have attracted considerable interest in organic synthesis because of their high catalytic activity and benign character in the context of green chemistry. Introduction of surfactants in aqueous medium has been proved to increase the reactivity of aqueous mediated reactions via the formation of vesicular cavities or micelles with hydrophobic core and hydrophilic corona at ambient conditions. The catalytic use of micellar surfactants in water is widespread and has been studied in detail for a number of different reactions in aque-
⇑ Corresponding author. Tel.: +91 141 2742048. E-mail address: [email protected] (R. Jain). 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.09.013
ous medium which provides an alternative synthetic approach under aqueous conditions.6 Indole-2,3-dione commonly known as isatin and its derivatives possess interesting biological activities and are widely used as a precursor for many natural products.7 Furthermore, compounds possessing this heterocyclic nucleus have been isolated from plants also.8 The heterocyclic spiro-oxindole framework is a privileged structure motif that forms the core of a large family of natural products with interesting biological and structural properties (Fig. 1). Spiro-oxindole ring system and its derivatives exhibit numerous types of biological activities such as antimicrobial, antitumor, antileukemic and anticonvulsant as well as found to be potent nonpeptide inhibitors of the p53-MDM2 interaction.9 These have also been reported to act as aldose reductase, poliovirus and rhinovirus 3C-proteinase inhibitors.10 A published report’s survey revealed that the synthesis of indole derivatives by the reactions of indole-2,3-diones with 1,2-difunctionalized benzene has been carried out using different solvents and catalysts.11 However, in these reported methods, most of the synthetic approaches are associated with harsh reaction conditions, using environmentally black-listed solvents, prolonged reaction time and tedious isolation procedure with poor yields. Therefore, it appeared to be of interest to develop eco-friendly, facile and more practical procedure for the synthesis of these important heterocyclic derivatives. Considering the significance of surfactants and in our continuous ongoing efforts to develop new efficient protocol for the synthesis of bioactive heterocycles employing green tools from readily available building blocks,12 herein we report for the first
R. Jain et al. / Tetrahedron Letters 53 (2012) 6236–6240
O
H
O SCH3
N
HN
N S
N O
MeO
O
H N H
Spirobrassinin
Spirotryprostatin A
NH
N Bu-i
O
O
O
N H
OH
N H
Elacomine
Horsfiline
Figure 1. Examples of oxindole moiety containing natural products.
time, a green, efficient and new procedure for the synthesis of indole derivatives in aqueous micellar media using tetrabutylammonium bromide, as a surfactant in water. The choice of an appropriate reaction medium is of essential importance for a successful synthesis. In our initial investigation, the reaction of indole-2,3-dione 1a, and 2-aminothiophenol 2, as a model substrate was investigated to establish the feasibility of the strategy and optimize the reaction conditions. Various solvents such as methanol, ethanol (neutral/acidic) as well as water with/ without surfactant were screened and optimized. The best results that is excellent yields in shorter reaction time were obtained in aqueous medium with surfactants where there was no requirement for a further purification process like column chromatography. We have carried out the reactions at different temperatures using different concentrations of the surfactant and the data are presented in Table 1, from which it is clear that the rate of reaction increased continuously with increase of the catalyst concentration upto 15 mol % without any considerable difference on a further increase of the catalyst concentration. It was observed that the concentration of the catalyst plays a significant role in controlling the rate of the reaction and it was concluded that among the various
Table 1 Synthesis of 4a under different reaction conditionsa Entry
Solvent
Temperature (°C)
Reaction time (h)
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12
MeOH EtOH (neutral) EtOH (acidic) Water Water/TBABc Water/TBABc Water/TBABc Water/TBABc Water/TBABc Water/TBABd Water/TBABe Water/TBABf
Reflux Reflux Reflux Reflux RT 60 80 100 Reflux 60 60 60
4 5 4 3 6 0.5 0.5 0.5 0.5 0.5 0.5 0.5
58 56 58 72 84 84 81 80 77 81 89 90
a Reaction conditions: 1.0 mmol of indole-2,3-dione 1a and o-aminothiophenol 2 was used. b Isolated yield. c TBAB (10 mol %). d TBAB (5 mol %). e TBAB (15 mol %). f TBAB (20 mol %).
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amounts of the catalyst studied, 15 mol % of TBAB was found to be the best at 60 °C temperature, in aqueous condition. It was observed that on introduction of TBAB followed by stirring, the initially floating reactants in the mixture converted to a yellowish-brown turbid emulsion (Fig. 2a), which implies that there was the formation of micelle like colloidal aggregates. Indeed, the light microscopic observation of the emulsion dispersion formed from indole-2,3-dione, 2-aminothiophenol and TBAB in distilled water revealed that spherical particles were formed (Fig. 2b).13 It is assumed that most of the organic substrates are concentrated in the spherical particles, which act as a hydrophobic reaction site and result in the rapid reaction in water. The catalytic effect of micellar TBAB in these reactions may be explained as follows. Indole-2,3-diones as well as 1,2-difunctionalized benzene molecules are hydrophobic in aqueous medium. In the micellar solution, the organic substrates which are hydrophobic, escape from water molecule towards the hydrophobic core of micelle droplets where the reaction occurred more easily. The hydrophobic interior of the micelles rapidly excludes the water molecules generated during the reaction, thus shifting the equilibrium towards the product side.14 The above explanation is schematically presented in Figure 3. The synthesis of compounds 4a–c have been performed by taking indole-2,3-diones 1a–c (1.0 mmol), 2-aminothiophenol 2 (1.0 mmol) and tetrabutylammonium bromide (15 mol %) in distilled water. The reaction has been carried out by stirring the reaction mixture at 60 ± 2 °C until completion of the reaction as evidenced by TLC (Scheme 1 and Table 2).15 Initially, the b-carbonyl group of 1 reacts with the amino group of 2 leading to the formation of intermediate 3, this is followed by the nucleophillic attack of the thiol group (presence of more acidic hydrogen on thiol group) on the b-carbon leading to the formation of 4 by the removal of a water molecule. The isolated products 4 were characterized on the basis of their IR, 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis. The IR spectrum of 4b showed absorptions at 3320 and 1712 cm1 indicative of the –NH and carbonyl functionality of benzothiazole moiety and oxindole ring, respectively. The 1H NMR spectrum of 4b exhibited two sharp singlets arising from the proton of –NCH3 of oxindole (d 3.20 ppm) and –NH group of benzothiazole (d 7.26 ppm) along with characteristic signals with appropriate chemical shifts and coupling constants for the eight H-atoms of the two aromatic moieties. In the 13C NMR spectrum the signal at d 74.0 ppm indicates the presence of a quaternary carbon atom with spiro linkage. The carbon atoms of the –NCH3 and carbonyl group of the oxindole ring resonated at d 26.5 and 175.2 ppm, respectively. The mass spectrum of 4b displayed a
Figure 2. (a) Reaction mixture of the indole-2,3-dione (1a), o-aminothiophenol (2) and TBAB in distilled water. (b) Optical micrograph of the reaction mixture (scale bar = 25 lm).
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R. Jain et al. / Tetrahedron Letters 53 (2012) 6236–6240
O N H
S
O
NH
+
H2N
N H
O
+ H2O
HS
Hydrophobic interior Hydrophilic exterior
: TBAB Figure 3. Micelles-promoted green synthesis of 30 H-Spiro[indole-3,20 -[1,3]benzothiazole]-2(1H)-one.
H O
TBAB (15 mol%) Water, 60 °C
H2 N
O
HS
N R
1a-c
S
HO
+ N R
S
-H2O
N H O
O
N R
3a-c
2
NH
4a-c
R = H, CH3, CH2Ph Scheme 1. Synthesis of 30 H-spiro[indole-3,20 -[1,3]benzothiazole]-2(1H)-ones 4a–c.
Table 2 Synthesis of 30 H-spiro[indole-3,20 -[1,3]benzothiazole]-2(1H)-one derivatives 4a–ca
Table 3 Synthesis of 6H-indolo[2,3-b]quinoxaline derivatives 7a–ca
Entry
Product
R
Temperature (°C)
Reaction time (min)
Yieldb (%)
Entry
Product
R
Temperature (°C)
Reaction time (min)
Yieldb (%)
1 2 3
4a 4b 4c
H CH3 CH2Ph
60 60 60
30 35 50
89 85 83
1 2 3
7a 7b 7c
H CH3 CH2Ph
60 60 60
50 40 50
85 83 83
a Reaction conditions: 1.0 mmol of indole-2,3-diones 1a–c and o-aminothiophenol 2, TBAB (15 mol %) and distilled water (5.0 mL) was used. b Isolated yield.
a Reaction conditions: 1.0 mmol of indole-2,3-diones 1a–c and o-phenylenediamine 5, TBAB (15 mol %) and distilled water (5.0 mL) was used. b Isolated yield.
molecular ion peak (M+) at m/z 268.3, which is 18 mass units (H2O) lower than that of a 1:1 adduct of 1-methyl-indole-2,3-dione and
o-aminothiophenol which further supported the formation of cycloadduct 4b.15
O
TBAB (15 mol%) Water, 60 °C
H2 N
HO
H N
+ N R
O
H2 N
N R
5
O H2 N
6a-c Scheme 2. Synthesis of 6H-indolo[2,3-b]quinoxalines 7a–c.
N
-2H2O N R
N
7a-c
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R. Jain et al. / Tetrahedron Letters 53 (2012) 6236–6240
O
TBAB (15 mol%) Water, 60 °C
H2N
HO
H N
+ O
N R
HO
N R
8
O
N
-H2O
HO
9a-c
N R
O HO
10a-c
Scheme 3. Synthesis of 3-(2-hydroxy-phenylimino)-1,3-dihydro-indol-2-ones 10a–c.
Table 4 Synthesis of 3-(2-hydroxy-phenylimino)-1,3-dihydro-indol-2-one derivatives 10a–ca Entry
Product
R
Temperature (°C)
Reaction time (min)
Yieldb (%)
1 2 3
10a 10b 10c
H CH3 CH2Ph
60 60 60
45 40 40
86 84 85
a Reaction conditions: 1.0 mmol of indole-2,3-diones 1a–c and o-aminophenol 8, TBAB (15 mol %) and distilled water (5.0 mL) was used. b Isolated yield.
O
TBAB(15mol%) Water, 60 °C
HO
+ N R
O
No reaction
HO
11 Scheme 4.
Encouraged by this success, we have extended this protocol to another 1,2-difunctionalized benzene which is o-phenylenediamine 5 under similar conditions as optimized (Scheme 2 and Table 3). Several investigations of the reactions between indole-2,3-diones and o-phenylenediamine in various solvents have been carried out and found that the solvent used in the reaction can shift the reaction towards the formation of different products.7,11a,16 When this reaction was performed in optimized condition, we found that there was the formation of quinoxaline derivatives 7a–c instead of spiro cycloadduct which was confirmed by the 13C NMR spectrum in which no signals due to C@O of oxindole ring and spiro carbon were observed while a peak at 1620 cm1 due to the presence of C@N appeared.17 It is well known that ammonia reacts with the b-carbonyl of indole-2,3-dione to give the adduct at lower temperatures.18 The analogous intermediates 6a–c would give a preferable explanation of the formation of 7a–c. The reaction of the amino group with the a-carbonyl of the 6a–c, followed by the removal of two molecule of water would give 7a–c. The structure of products 7 was characterized on the basis of their spectral and elemental analyses. The IR spectrum of the product 7b showed a peak at 1620 cm1 due to C@N group in the tetracyclic ring system. In the IR spectrum, the disappearance of two C@O of the oxindole ring along with the appearance of a signal due to C@N further proved the formation of quinoxaline derivatives instead of a spiro cycloadduct. In the 1H NMR spectrum, Hatoms of the –NCH3 group of the oxindole ring appeared at d 2.94 ppm as a singlet along with characteristic signals with appropriate chemical shift and coupling constant for the eight protons of the two aromatic moieties. In the 13C NMR, the C-atom of –NCH3 of oxindole ring resonated at d 30.0 ppm along with aromatic signals. In the mass spectrum, molecular ion peak (M+) appeared at m/z 233.2, which is 36 mass units (2 H2O) lower than that of a 1:1
adduct of the reactant and further confirmed the formation of product 7b.17 On a similar protocol, we next investigated other 1,2-difunctionalized benzene, o-aminophenol 8 where interesting results were obtained. In this case there was the formation of Schiff’s bases, 3-(2-hydroxy-phenylimino)-1,3-dihydro-indol-2-ones 10a– c only in excellent yields instead of spiro or other condensed products (Scheme 3 and Table 4). The formation of the products 10a–c was explained as amino group of 8 reacts with b-carbonyl of indole-2,3-diones affording intermediates 9a–c, which on the removal of one molecule of water gave 3-(2-hydroxy-phenylimino)-1,3-dihydro-indol-2-ones. On the other hand the formation of spiro derivatives was ruled out due to the presence of less acidic hydrogen of the hydroxyl group and also the possibility of the condensed product was ruled out due to the presence of –OH group in the product. The chemical structure of the products was proven on the basis of their spectral data. The IR spectrum of the 10a showed a broad signal at 3100–3295 cm1 due to –NH and –OH along with signals at 1722 and 1618 cm1 due to C@O and C@N groups, respectively. The absorption band at 1290 cm1 is attributed to the phenolic C– O stretching vibration.19 Further, when this methodology was applied for 1,2-dihydroxy benzene 11, the reaction was not successful in the all optimized conditions (Scheme 4). In conclusion, an efficient, facile and straightforward green protocol for the synthesis of indole derivatives has been developed by using TBAB, as a surfactant in aqueous medium for the first time. The reactions of indole-2,3-diones with various 1,2-difunctionalized benzene viz., o-aminothiophenol, o-phenylenediamine and o-aminophenol afford 30 H-spiro[indole-3,20 -[1,3]benzothiazole]2(1H)-ones, 6H-indolo[2,3-b]quinoxalines and 3-(2-hydroxy-phenylimino)-1,3-dihydro-indol-2-ones, respectively while a reaction does not take place with 1,2-dihydroxy benzene. Acknowledgements Authors are grateful to CSIR and UGC, New Delhi, India for financial assistance. References and notes 1. (a) Li, C.-J. Chem. Rev. 2005, 105, 3095; (b) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209; (c) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751; (d) Solhy, A.; Elmakssoudi, A.; Tahir, R.; Karkouri, M.; Larzek, M.; Bousmina, M.; Zahouily, M. Green Chem. 2010, 12, 2261; (e)Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic & Professional: London, 1998; (f) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1988. 2. (a) Lancester, M. Green Chemistry: An Introductory Text; Royal Society of Chemistry: Cambridge, 2002; (b) Tan, J.-N.; Li, H.; Gu, Y. Green Chem. 2010, 12, 1772. 3. (a) Yorimitsu, H.; Shinokubo, H.; Oshima, K. Synlett 2002, 5, 674; (b) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275; (c) Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492; (d) Breslow, R.; Maitra, U. Tetrahedron Lett. 1984, 25, 1239; (e) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816. 4. (a) Dolzhenko, A. V.; Pastorin, G.; Dolzhenko, A. V.; Chui, W. K. Tetrahedron Lett. 2009, 50, 2124; (b) Panda, S. S.; Jain, S. C. Synth. Commun. 2011, 41, 729.
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5. (a) Ma, N.; Jiang, B.; Zhang, G.; Tu, S.-J.; Walter, W.; Li, G. Green Chem. 2010, 12, 1357; (b) Jiang, B.; Li, C.; Shi, F.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G. J. Org. Chem. 2010, 75, 2962; (c) Ganem, B. Acc. Chem. Res. 2009, 42, 463; (d) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072; (e) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861; (f) Lindstrom, U. M.; Andersson, F. Angew. Chem., Int. Ed. 2006, 45, 548; (g) Candeias, N. R.; Branco, L. C.; Gois, P. M. P.; Afonso, C. A. M.; Trindade, A. F. Chem. Rev. 2009, 109, 2703; (h) Shapiro, N.; Vigalok, A. Angew. Chem., Int. Ed. 2008, 47, 2849. 6. (a) Selke, R.; Holz, J.; Riepe, A.; Borner, A. Chem. Eur. J. 1998, 4, 769; (b) Blagoeva, I. B.; Toteva, M. M.; Ouarti, N.; Ruasse, M. F. J. Org. Chem. 2001, 66, 2123; (c) Firouzabadi, H.; Iranpoor, N.; Garzan, A. Adv. Synth. Catal. 2005, 347, 1925; (d) Shiri, M.; Zolfigol, M. A. Tetrahedron 2009, 65, 587; (e) Kobayashi, S.; Hachiya, I. J. Org. Chem. 1994, 59, 3590; (f) Larpent, C.; Bernard, E.; Menn, F. B.; Patin, H. J. Mol. Catal. A: Chem. 1997, 116, 227; (g) Selke, R.; Holz, J.; Riepe, A.; Borner, A. Chem. d Eur. J. 1998, 4, 769; (h) van den Broeke, L. J. P.; de Bruijn, V. G.; Heijnen, J. H. M.; Keurentjes, J. T. F. Ind. Eng. Chem. Res. 2001, 40, 5240. 7. Da Silva, J. F. M.; Garden, S. J. C.; Pinto, A. J. Braz. Chem. Soc. 2001, 12, 273. 8. Kamano, Y.; Zhang, H. P.; Ichihara, Y.; Kizu, H.; Komiyama, K.; Pettit, G. R. Tetrahedron Lett. 1995, 36, 2783. 9. (a) Kornet, M. J.; Thio, A. P. J. Med. Chem. 1976, 19, 892; (b) Bhaskar, G.; Arun, Y.; Balachandran, C.; Saikumar, C.; Perumal, P. T. Eur. J. Med. Chem. 2012, 51, 79; (c) Gomez-Monterrey, I.; Bertamino, A.; Porta, A.; Carotenuto, A.; Musella, S.; Aquino, C.; Granata, I.; Sala, M.; Brancaccio, D.; Picone, D.; Ercole, C.; Stiuso, P.; Campiglia, P.; Grieco, P.; Ianelli, P.; Maresca, B.; Novellino, E. J. Med. Chem. 2010, 53, 8319; (d) Wang, S.; Malek, S.; Long, J.; Ouillette, P. PCT Int. Appl. WO 2011127058 A2 20111013, 2011.; (e) Basavaiah, D.; Reddy, R. K. Org. Lett. 2007, 9, 57. 10. Skiles, J. W.; Mc Neil, D. Tetrahedron Lett. 1990, 31, 7277. 11. (a) Popp, F. D. J. Heterocycl. Chem. 1969, 6, 125; (b) Karali, N.; Guzel, O.; Ozsoy, N.; Ozbey, S.; Salman, A. Eur. J. Med. Chem. 2010, 45, 1068; (c) Alam, Y. A.; Nawwar, G. A. M. Heteroatom Chem. 2002, 13, 207; (d) Dowlatabadi, R.; Khalaj, A.; Rahimian, S.; Montazeri, M.; Amini, M.; Shahverdi, A.; Mahjub, E. Synth. Commun. 2011, 41, 1650. 12. (a) Jain, R.; Sharma, K.; Kumar, D. Tetrahedron lett. 2012, 53, 1993; (b) Jain, R.; Sharma, K.; Kumar, D. Helv. Chim. Acta 2012. http://dx.doi.org/10.1002/ hlca.2012,00,168; (c) Jain, R.; Sharma, K.; Kumar, D. J. Heterocycl. Chem. 2011. http://dx.doi.org/10.1002/jhet.1071; (d) Jain, R.; Yadav, T.; Kumar, M.; Yadav, A. K. Synth. Commun. 2011, 41, 1889; (e) Jain, R.; Yadav, T.; Kumar, M.; Yadav, A. K. J. Heterocycl. Chem. 2010, 47, 603; (f) Yadav, A. K.; Kumar, M.; Yadav, T.; Jain, R. Synlett 2010, 5, 712; (g) Yadav, A. K.; Kumar, M.; Yadav, T.; Jain, R. Tetrahedron Lett. 2009, 50, 5031; (h) Yadav, A. K.; Manju, M.; Kumar, M.; Yadav, T.; Jain, R. Tetrahedron Lett. 2008, 49, 5724. 13. (a) Watanabe, Y.; Sawada, K.; Hayashi, M. Green Chem. 2010, 12, 384; (b) Shinde, P. V.; Kategaonkar, A. H.; Shingate, B. B.; Shingare, M. S.; Beilstein, J. Org. Chem. 2011, 7, 53; (c) Manabe, K.; Mori, Y.; Wakabayashi, T.; Nagayama, S.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 7202. 14. Wang, L.-M.; Jiao, N.; Qiu, J.; Yu, J.-J.; Liu, J.-Q.; Guo, F.-L.; Liu, Y Tetrahedron 2010, 1, 339. 15. Typical experimental procedure for synthesis of 4a: To a mixture of indole-2,3dione 1a (1.0 mmol) and o-aminothiophenol 2 (1.0 mmol) in distilled water (5.0 mL), was added TBAB (0.0483 g, 15 mol %). This reaction mixture was
16. 17.
18. 19.
allowed to stir magnetically at 60 °C. Progress of the reaction was monitored by TLC (Pet. ether–ethyl acetate = 4:1) and visualization was accomplished in an iodine chamber. After completion of the reaction, the solid obtained was collected by filtration and washed with warm water. The crude product, so obtained was purified by crystallization with ethanol to afford pure product. Spectral data of representative compounds: 30 H-Spiro[indole-3,2’-[1,3]benzothiazole]-2(1H)-one 4a (Table 2, entry 1): Light yellow solid; mp 220–222 °C; IR (KBr, cm1): 3310, 3195, 1705, 1465, 758; 1H NMR (300 MHz, DMSO-d6): d 6.65–6.74 (m, 2H, Ar-H), 6.88 (t, 1H, J = 7.8 Hz, Ar-H), 6.94 (d, 1H, J = 7.2 Hz, Ar-H), 7.03 (t, 1H, J = 7.2 Hz, Ar-H), 7.22–7.30 (m, 1H, Ar-H), 7.49 (d, 1H, J = 7.2 Hz, Ar-H), 7.54 (s, 1H, NH, D2O exchangeable), 7.57 (d, 1H, J = 6.9 Hz, Ar-H), 9.96 (s, 1H, NH, D2O exchangeable); 13C NMR (75 MHz, DMSO-d6): 73.9, 109.0, 109.7, 119.2, 120.5, 122.1, 124.3, 124.8, 125.0, 129.5, 129.6, 140.3, 145.7, 176.3; MS (m/z): 254.3; Anal. Calcd for C14H10N2OS: C, 66.06; H, 3.93; N, 11.01. Found; C, 66.18; H, 3.85; N, 11.12. 1-Methyl-30 H-spiro[indole-3,20 -[1,3]benzothiazole]-2(1H)-one 4b (Table 2, entry 2): Light yellow solid; mp 162–164 °C; IR (KBr, cm1): 3320, 1712, 1470, 755; 1 H NMR (300 MHz, DMSO-d6): d 3.20 (s, 3H, N-CH3), 6.70 (d, 1H, J = 7.8, Ar-H), 6.81 (t, 1H, J = 7.8 Hz, Ar-H), 6.82–6.94 (m, 1H, Ar-H), 6.99 (d, 1H, J = 7.2 Hz, ArH), 7.02 (dd, 1H, J = 7.6, 1.2 Hz, Ar-H), 7.12 (d, 1H, J = 7.8 Hz, Ar-H), 7.26 (s, 1H, NH, D2O exchangeable), 7.36 (d, 1H, J = 6.9 Hz, Ar-H), 7.61 (t, 1H, J = 7.8 Hz, ArH); 13C NMR (75 MHz, DMSO-d6): 26.5, 74.0, 108.5, 110.9, 121.4, 121.6, 123.6, 123.7, 125.1, 125.9, 129.7, 130.7, 142.4, 145.3, 175.2; MS (m/z): 268.3; Anal. Calcd for C15H12N2OS: C, 67.08; H, 4.47; N, 10.43. Found; C, 66.97; H, 4.58; N, 10.49. (a) Popp, F. D. Adv. Heterocycl. Chem. 1975, 18, 1; (b) Bergman, J.; Engqvist, R.; Stalhandske, C.; Wallberg, H. Tetrahedron 2003, 59, 1033. General procedure for synthesis of 7a: A mixture of indole-2,3-dione 1a (1.0 mmol), o-phenylenediamine 5 (1.0 mmol), TBAB (0.0483 g, 15 mol %) and distilled water (5.0 mL) was taken in a round bottom flask. The reaction was performed in the same way as described above. Spectral data of representative compounds: 6H-indolo[2,3-b]quinoxaline 7a (Table 3, entry 1): Yellow solid; mp 290–292 °C; IR (KBr, cm1): 3095–3200, 1620, 1455, 756; 1H NMR (300 MHz, DMSO-d6): d 7.35 (t, 1H, J = 7.8 Hz, Ar-H), 7.52–7.79 (m, 1H, Ar-H), 8.10 (dd, 2H, J = 7.8, 1.2 Hz, Ar-H), 8.32 (dd, 2H, J = 6.6, 1.5 Hz, Ar-H), 8.44 (d, 2H, J = 7.8 Hz, Ar-H), 11.61 (s, 1H, NH, D2O exchangeable); 13C NMR (75 MHz, DMSO-d6): 112.1, 118.9, 120.9, 122.6, 126.1, 127.1, 128.6, 131.1, 131.3, 138.1, 139.7, 140.0, 144.2, 145.7; MS (m/z): 219.2; Anal. Calcd for C14H9N3: C, 76.64; H, 4.10; N, 19.16. Found; C, 76.51; H, 4.17; N, 19.07. 6-Methyl-6H-indolo[2,3-b]quinoxaline 7b (Table 3, entry 2): Yellow solid; mp 148-150 °C; IR (KBr, cm1): 1620, 1460, 758; 1H NMR (300 MHz, DMSO-d6): d 2.94 (s, 3H, N-CH3), 6.69 (d, 1H, J = 7.8 Hz, Ar-H), 6.75 (d, 1H, J = 7.8 Hz, Ar-H), 7.25–7.41 (m, 3H, Ar-H), 7.45 (d, 1H, J = 7.2, Hz, Ar-H), 7.74 (d, 1H, J = 7.2 Hz, Ar-H), 8.38 (dd, 1H, J = 7.8, 1.2 Hz, Ar-H); 13C NMR (75 MHz, DMSO-d6): 30.0, 110.7, 114.8, 115.2, 117.4, 118.6, 121.2, 123.4, 127.9, 129.4, 131.5, 131.6, 131.8, 149.4, 155.7; MS (m/z): 233.2; Anal. Calcd for C15H11N3: C, 77.18; H, 4.71; N, 18.01. Found; C, 77.26; H, 4.63; N, 18.13. Reissert, A.; Hoppmann, H. Ber. 1924, 57B, 972. Hassaan, A. M.; Kalifa, M. A.; Shehata, A. Z. Bull. Soc. Chim. Belg. 1995, 104, 121.