Selective synthesis of 4,5-dihydroimidazo- and imidazo[1,5-a]quinoxalines via modified Pictet–Spengler reaction

Accepted Manuscript Selective synthesis of 4,5-dihydroimidazo- and imidazo[1,5-a]quinoxalines via modified Pictet-Spengler reaction Akhilesh Kumar Verma, Rajeev Ranjan Jha, V. Kasi Sankar, Raj Pal Singh PII: DOI: Reference:

S0040-4039(13)01425-1 http://dx.doi.org/10.1016/j.tetlet.2013.08.052 TETL 43415

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Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

4 July 2013 13 August 2013 17 August 2013

Please cite this article as: Verma, A.K., Jha, R.R., Kasi Sankar, V., Singh, R.P., Selective synthesis of 4,5dihydroimidazo- and imidazo[1,5-a]quinoxalines via modified Pictet-Spengler reaction, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.052

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Selective synthesis of 4,5-dihydroimidazoand imidazo[1,5-a]quinoxalines via modified Pictect-Spengler reaction

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Akhilesh K. Verma, Rajeev R. Jha, V. Kasi Sankar and Raj P. Singh

1

Tetrahedron Letters journal homepage: www.elsevier.com

Selective synthesis of 4,5-dihydroimidazo- and imidazo[1,5-a]quinoxalines via modified Pictet-Spengler reaction Akhilesh Kumar Vermaa*, Rajeev Ranjan Jhaa, V. Kasi Sankara and Raj Pal Singhb a b

Synthetic Organic Chemistry Organic Research Laboratory, Department of Chemistry, University of Delhi Centre for Fire, Explosive & Environment Safety (DRDO), Timarpur, Delhi 110054, India

ARTICLE INFO

ABSTRACT

Article history: Received Received in revised form Accepted Available online

An efficient tandem approach for the selective synthesis of 4,5-dihydroimidazo[1,5a]quinoxalines 6a–g and imidazo[1,5-a]quinoxalines 7a–h by the reaction of 2-imidazolyl anilines 4a–c with aryl aldehydes 5a–k under mild reaction condition is described. Introduction of electron releasing alkyl groups in substrates 4a–b was found to be instrumental for the success of the reaction.

Keywords: Pictet-Spengeler, Quinoxaline Tandem Cyclization Lewis-Acid

2009 Elsevier Ltd. All rights reserved.

Nitrogen containing heterocycles are important class of compounds due to their presence in natural products and biologically active pharmaceuticals.1 Among these heterocycles, imidazoquinoxalines play an important role in medicinal chemistry due to its significant biological activities like anticancer,2 anti-HIV agent,3a glucagon receptor antagonists,3b and angiotensin receptor activity.3c They are also used for the synthesis of GABA benzodiazepines receptor agonists/ antagonists4 and for other therapeutic applications (Figure 1).5

GAB A inhibitors

A1 and A2a adenosines

anti-tumor agents

Figure 2. General strategy of the Pictet-Spengler reaction.

BMS-238497 kinase inhibitor

Figure 1. Selected examples of biologically active imidazo[1,5-a] quinoxalines.

From synthetic point of view, the opportunity to prepare biologically important heterocyclic molecules in limited steps under mild reaction condition is an exciting goal for every modern organic chemist. Although number of methods are available for the synthesis of simple substituted quinoxalines,6–7 limited work has been done for the synthesis of polycyclic quinoxalines especially imidazo[1,5-a]quinoxalines.8–9 Pictet-Spengler reaction involves the condensation of an aldehyde with appropriate amine to form an imine, final cyclization between a sufficiently reactive aromatic moiety and activated iminium ion results in a new carbon-carbon bond, forming a heterocyclic ring (Figure 2). 10

Scheme 1. Synthesis of tetrahydropyrazino[1,2-a]indoles, and indolo-/pyrrolo[1,2-a]quinoxalines using Pictet-Spengler strategy.

In recent years we have successfully applied Pictet-spengler strategy for the synthesis of 1,2,3,4-tetrahydropyrazino[1,2a]indoles, and indolo-/pyrrolo[1,2-a]quinoxalines (Scheme 1, eq. i & ii). During our investigation, we observed that the reactions were successful only with the electron-rich substrates (eq. i & ii). When we tried to synthesize imidazo[1,5-a]quinoxalines using electron-deficient 2-(1H-imidazol-1-yl)aniline (4c), we failed to obtain the desired product (Scheme 1, eq. iii ). This led us to

2

Tetrahedron

conclude that for the success of Pictet-Spengler reaction a sufficiently active aryl substrate is essential. Based on our previous studies using activated substrates,12-14 we hypothesized that the use of alkyl substituted imidazole amines 4a–b might offer a possibility for the synthesis of substituted imidazo-fused quinoxalines (Scheme 2).

allowed to run for 2 h, product 6a (reduced form) was formed selectively in 88% yield (entry 11). Further decrease in the reaction time (from 2 h to 1 h) decreased the yield of the product 6a (entry 12). The yield of the product 6a remained same when reaction was carried out using 15 mol % of p-TsOH (entry 13); however decrease in catalyst loading adversely affected the yield of the product 6a (entry 14). Other Lewis acid such as FeCl3 and ZnCl2 was found inferior for the transformation (entries 15–16). Lower yield of the product was obtained in the absence of benzotriazole (entries 17–18). After various reaction conditions were screened, 10 mol % of p-TsOH in toluene was found to be most effective for the selective formation of products 6a and 7a (entries 9 and 11). Table 1. Optimization of the reaction conditionsa

Scheme 2. Designed strategy for the synthesis of imidazo[1,5-a] quinoxalines 6, 7.

In continuation of our interest in the synthesis of fused heterocycles by using benzotriazole methodology12-13 and alkyne chemistry,14 herein we wish to report our study on the selective synthesis of dihydroimidazo[1,5-a]quinoxalines 6a–g and imidazo[1,5-a]quinoxalines 7a–h in good to excellent yields by using modified Pictet-Spengler reaction (Scheme 2). 2-Imidazolylarylamines 4a–c required for the reactions were obtained in quantitative yields by the reduction of corresponding nitro derivatives 3a–c using 10% palladium charcoal. The nitro compounds 3a–c were prepared by the reaction of commercially available 2-fluoronitrobenzene 2, with substituted imidazoles 1a– c using NaOH in DMSO at room temperature (Scheme 3).

Scheme 3. Preparation of 2-imidazolylarylamines 4a–c.

To identify the optimal condition for the reaction, various Lewis acids and organic solvents were examined in the reaction of 2-(2ethyl-4-methyl-1H-imidazol-1-yl)aniline 4a with 4-bromobenzaldehyde (Table 1). When amine 4a (0.5 mmol) was allowed to react with 1.0 equiv of 5a using 10 mol % of AlCl3, 1.0 equiv of benzotriazole in 2.0 mL of CH2Cl2 at 25oC for 0.5 h, dihydroimidazo[1,5-a]quinoxaline (6a) was obtained in 45% yield (Table 1, entry 1). An increase in the reaction time from 0.5 to 1 h and then to 2 h afforded the product 6a (reduced form) in 56 and 75% yields respectively (entries 2–3). When reaction was further allowed to stir for 5 h, product 6a was obtained in 65% yield along with the oxidized form of imidazoquinoxaline 7a in 10% yield (entry 4). We observed that increase in the reaction time (12 h), leads to the formation of auto-oxidized product 7a over reduced product 6a [entry 5, compare 6a (15%) vs 7a (55%)]. Similar result was obtained when CHCl3 was used as a solvent (entry 6). When THF was used as a solvent, the product 6a and 7a were obtained in 11% and 69% yields, respectively (entry 7). Surprisingly, when toluene was used as the solvent, only product 7a (oxidized) was formed in 81% yield (entry 8). Use of p-TsOH as the catalyst improved the yield of the desired product 7a (entry 9). Decrease in reaction time from 12 h to 5 h, afforded the mixture of 6a (reduced form) and 7a (oxidized form) in 59 and 30% yields respectively (entry 10). When reaction was

Time Yieldb(%) (h) 6a 7a 1 CH2Cl2 AlCl3/10 0.5 45 00 2 CH2Cl2 AlCl3/10 1.0 56 00 3 CH2Cl2 AlCl3/10 2.0 75 00 4 CH2Cl2 AlCl3/10 5.0 65 10 5 CH2Cl2 AlCl3/10 12.0 15 55 6 CHCl3 AlCl3/10 12.0 17 56 7 THF AlCl3/10 12.0 11 69 8 Toluene AlCl3/10 12.0 00 81 9 Toluene p-TsOH/10 12.0 00 86 10 Toluene p-TsOH/10 5.0 59 30 11 Toluene p-TsOH/10 2.0 88 00 12 Toluene p-TsOH/10 1.0 59 00 13 Toluene p-TsOH/15 2.0 88 00 14 Toluene p-TsOH/0.5 2.0 61 00 15 Toluene FeCl3/10 2.0 29 00 16 Toluene ZnCl2/10 2.0 48 00 17 Toluene p-TsOH/10 2.0 69c 00 18 Toluene p-TsOH/10 12.0 00 72c a Reactions were performed using 0.6 mmol of aldehyde 5a, 0.5 mmol of benzotriazole, 0.5 mmol of amine 6a in 2.0 mL solvent at 25 °C unless otherwise noted. b Isolated yield. c Reaction without benzotriazole. Entrya

Solvent

Catalyst (mol %)

Having determined the optimal reaction conditions (Table 1, entries 9 and 11), we investigated the scope of the developed chemistry by employing a variety of substituted aldehydes with amines 4a–c. To our delight, a wide range of substituted aldehydes reacted well and provided the desired products 4,5dihydroimidazo[1,5-a]quinoxalines 6a–g,15 and imidazo[1,5a]quinoxalines 7a–h in good to excellent yields (Table 2). Aldehydes with electron-withdrawing groups afforded the products in better yields than electron-releasing ones. Amine 4a bearing electron-releasing ethyl and methyl groups provided the desired products in higher yields in comparison to amine 4b (Table 2, entries1–6 vs entries 7–15); however reaction of amine 4c (without any electron-releasing group) fails to afford the desired cyclized product 7i (entry 16). Presence of electronreleasing group at C-2 and C-4 position of 4a–b increases the electron-density on C-5 position of the imidazole ring, which facilitates the nucleophilic attack of C-5 position of the imidazole ring to iminium cation (Figure 3, i). The suggested mechanism involves the formation of transient intermediate X in the presence of a p-TsOH and benzotriazole, which forms the iminium ion Y by the facile removal of benzotriazole. The intermediate Y undergoes intramolecular C–C bond formation and generates 3° carbocation

3 ion Z which aromatized to furnish the dihydroimidazoquinoxalines 6 (Figure 3, ii). Dihydroquinoxalines were auto-oxidized in the presence of air after 8–10 h,17 and provided the oxidized form of imidazoquinoxalines 7.

13

4b

5k

7f

82b

14

4b

5e

7g

78b

15

4b

5c

7h

75b

5a

7i

-

Table 2. Scope of the reactiona,b Entrya

Amine

Aldehyde

Product

Yield (%)c

1 5a

6a

88a

4a

2

4a

5b

6b

90a 16

3

4a

5c

6c

86a

4

4a

5d

6d

84a

5

4a

5e

6e

85a

6

4a

5f

6f

80a

5g

6g

77a

7a

86b

7

4c Reactions were performed using 0.6 mmol of aldehyde 5, 1.0 equiv of benzotriazole, 10 mol % of p-TsOH and 0.5 mmol of amine 4 in 2.0 mL of toluene at 25 °C for 2 h, unless otherwise noted. b 25 °C for 10–12 h. c Isolated yield. a

4b

8

4a

5a

Figure 3. (i) Effect of electron-releasing group on the reactivity of imidazole ring. (ii) Possible mechanism.

9

4a

5h

7b

88b

10

4a

5i

7c

80b

11

4b

5b

7d

83b

12

4b

5j

7e

82b

Figure 4. ORTEP diagram of imidazoquinoxaline 6b

The formation of cyclized products 6a–g was fully characterized by 1H, 13C NMR and mass spectroscopic data. The disappearance of the peak at ~6.6 ppm of the C-5 position of the imidazole amine 4, and appearance of a new characteristic peaks at ~5.6 ppm in 1H NMR, 53.4 ppm in 13C NMR in the product 6, confirmed the structure of the cyclized compound. The structure of the cyclized products was further supported by the X-ray

4

Tetrahedron

crystallographic analysis of 6b.16 The oxidized imidazoquinoxalines 7a–h were supported by the disappearance of the characteristic N-CH proton at ~5.6 ppm in 1H NMR, and shifting of the N-CH carbon from 53.4 ppm to deshielding region in 13C NMR. In conclusion we have demonstrated, a general and efficient method for the selective synthesis of oxidized and reduced form of imidazo[1,5-a]quinoxalines by modified PictetSpengler reaction under mild conditions in good yields. The reactions were facilitated by the presence of electron-releasing group in substrate 4a–b. The developed approach expands the application of Pictet-Spengler reaction for the synthesis of imidazo-fused quinoxalines, which are of great importance in medicinal chemistry. Further investigations to expand the reaction scope are ongoing and will be reported in due course.

Acknowledgments We thank DU-DST PURSE Grant for the financial support and USIC University of Delhi for the use of Instrumentation facility. R.R.J is thankful to CSIR for the Fellowship. Supplementary Material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.04. 125. References and notes 1. (a) Chen, P.; Barrish, J. C.; Iwanowicz, E.; Lin, J.; Bednarz, M. S.; Chen, B. Tetrahedron Lett. 2001, 42, 4293; (b) Gribble, G. W. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. S. V., Eds.; Pergamon Press: New York, 1996, 2, 207. 2. Alleca, S.; Corona, P.; Lorigo, M.; Paglietti, G.; Loddo, R.; Mascia, V.; Busonera, B.; La Colla, P. Il Farmaco, 2003, 58, 639 and references therein. 3. (a) Patel, M.; Mc Hugh, R. J.; Cordova, B. C.; Klabe, R. M.; EricksonVitanen, S.; Trainor, G. L.; Rodger, J. D. Bioorg. Med. Chem. Lett. 2000, 10, 1729; (b) Guillon, J.; Dallemagne, P.; Pfeiffer, B.; Renard, P.; Manechez, D.; Kervran, A.; Rault, S. Eur. J. Med. Chem, 1998, 33, 293; (c) Kim, K. S.; Qian, L.; Bird, J. E.; Dickinson, K. E. J.; Moreland, S.; Schaeffer, T. R.; Waldron, T. L.; Delaney, C. L.; Weller, H. N.; Miller, A. V. J. Med. Chem. Soc. 1951, 73, 5687. 4. (a) Jacobsen, E. J.; Stelzer, L. S.; Belonga, K. L.; Carter, D. B.; Im, W. B.; Sethy, V. H.; Tang, A. H.; VonVoigtlander, P. F.; Petke, J. D. J. Med. Chem. 1996, 39, 3820; (b) Davey, D. D.; Erhardt, P. W.; Cantor, E. H.; Greenberg, S. S.; Ingebretsen, W. R.; Wiggins, J. J. Med. Chem. 1991, 34, 2671; (c) Colltta, V.; Cecchi, L.; Catarzi, D.; Filacchioini, G.; Martini, C.; Tacchi, P.; Lucacchini, A. Eur. J. Med. Chem. 1995, 30, 133. 5. (a) Sakata, G.; Makino, K.; Kurasawa, Y. Hetrocycles, 1998, 27, 2481; (b) Seitz, L. E.; Suling, W. J.; Reynolds, R. C. J. Med. Chem. 2002, 45, 5604; (c) Gzit, A.; App, H.; Mcmohan, G.; Chen, J.; Levtzki, A.; Bohmer, F. D. J. Med. Chem. 1996, 39, 2170; (d) Ali, M. M.; Ismail, M. M. F.; El-Gaby, M. S. A.; Zahran, M. A.; Ammar, Y. A. Molecules, 2000, 5, 864; (e) Campiani, G.; Nacci, V.; Corelli, F.; Anzini, M. Synth. Commun.1991, 21, 1567. 6. (a) Venkatesh, C.; Singh, B.; Mahata, P. K.; Ila, H.; Junjappa, H. Org. Lett. 2005, 7, 2169; (b) Juncai, F.; Yang, L.; Qinghua, M.; Bin, L. Synth. Commun. 1998, 28, 193; (c) Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K. Chem. Commun. 2003, 2286; (d) Kaupp, G.; Naimi-Jamal, M. R. Eur. J. Org. Chem. 2002, 8, 1368; (e) Chen, P.; Barrish, J. C.; Iwanowicz, E.; Lin, J.; Bednarz, M. S.; Chen, B. C. Tetrahedron Lett. 2001, 42, 4293; (f) Soderberg, B. C. G.; Wallace, J. M.; Tamariz, J. Org. Lett. 2002, 4, 1339; (g) Suginome, M.; Collet, S.; Ito, Y. Org. Lett. 2002, 4, 351; (h) Mukhopadhyay, R.; Kundu, N. G. Tetrahedron Lett. 2000, 41, 9927; (i) Bunce, R. A.; Herron, D. M.; Ackerman, M. L. J. Org. Chem. 2000, 65, 2847; (j) Banik, B. K.; Banik, I.; Hackfeld, L.; Becker, F. F. Heterocycles, 2002, 56, 467; (k) Goswami, S.; Adak, A. K. Chem. Lett. 2003, 32, 678. 7. (a) Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Mantellini, F.; Santeusanio, S. Synlett 2003, 1183. (b) Tanaka, K.; Takahashi, H.; Takimoto, K.; Sugita, M.; Mitsuhashi, K. J. Heterocycl. Chem. 1992, 29, 771. (c) Popat, K. H.; Nimavat, K. S.; Thaker, K. M.; Joshi, H. S. J. Ind.

Chem. Soc. 2003, 80, 709. (d) Rao, K. V. S.; Subrahmanyam, M. Chem. Lett. 2002, 234. (e) Reeves, J. T.; Fandrick, D. R.; Tan, Z.; Song, J. J.; Lee, H.; Yee, N. K.; Senanayake, C. H. J. Org. Chem. 2010, 75, 992. 8. (a) Raines, S.; Chai, S. Y.; Palopoli, F. P. J. Heterocycl. Chem., 1976, 13, 711; (b) Zhang, X. C.; Huang, W. Y. Tetrahedron Lett. 1997, 38, 4827 and refrences therein; (c) Veeraraghavan, S.; Popp, F. D. J. Heterocycl. Chem. 1981, 18, 775; (d) Kim, H. S.; Kurasawa, Y.; Yoshii, C.; Masuyama, M.; Takada, A.; Okamoto, Y. J. Heterocycl. Chem. 1990, 27, 1115; (e) Cheeseman, G. W. H.; Rafiq, M. J. Chem. Soc(C), 1971, 2732. 9. (a) Atfah, A.; Abu-Shuheil, M. Y.; Hill, J. Tetrahedron, 1990, 46, 6483; (b) Yi, C. S.; Yun, S. Y. J. Am. Chem. Soc. 2005, 127, 17000; (c) Kundu, B.; Sawant, D.; Chhabra, R. J. Comb. Chem. 2005, 7, 317. 10. (a) Gonzalez, J. F.; Cuesta, E.; Avendano, C. Tetrahedron, 2004, 60, 6319; (b) Yu, J.; Wearing, X. Z.; Cook, J. M. Tetrahedron Lett. 2003, 44, 543; (c) Cutter, P. S.; Miller, R. B.; Schore, N. E. Tetrahedron, 2002, 58, 1471; (d) Singh, K.; Deb, P. K.; Venugopalan, P. Tetrahedron, 2001, 57, 7939; (e) Cox, E. D.; Hamaker, L. K.; Yu, P.; Czerwinski, K. M.; Deng, L.; Bennett, D. W.; Cook, J. M. J. Org. Chem. 1997, 62, 44; (f) Kametani, T.; Iida, H.; Shinbo, M.; Endo, T. Chem. Pharm. Bull. 1968, 16, 949; (g) Kametani, T.; Kigasawa, K.; Hiiragi, M.; Ishimaru, H. J. Chem. Soc. C 1971, 2632; (h) Stuart, K.; Woo-Ming, R. Heterocycles 1975, 3, 223; (i) Von Strandtmann, M.; Puchalski, C.; Shavel, J. J. Med. Chem. 1964, 7, 141; (j) Brown, R. T.; Chapple, C. L. J. Chem. Soc., Chem. Commun. 1973, 886; (k) Srinivasan, N.; Ganesan, A. J. Chem.Soc. Chem. Commun. 2003, 916; (l) Tsuji, R.; Nakagawa, M.; Nishida, A. Tetrahedron Asymmetry. 2003, 14, 177; (m) Jiang, W.; Sui, Z.; Chen, X. Tetrahedron Lett. 2002, 43, 8941; (n) Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 4685; (o)Yamada, H.; Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.; Nakgawa, M. J. Org. Chem. 1998, 63, 6348; (p) Waldmann, H.; Schmidt, G.; Jansen, M.; Geb, J. Tetrahedron 1994, 50, 11865; (q) Feng, X.; Lancelot, J. C.; Gillard, A. C.; Landelle, H.; Rault, S. J. Heterocycl. Chem. 1998, 35, 1313; (r) Grigg, R.; MacLachlan, W. S.; MacPherson, D. T.; Sridharan, V.; Suganthan, S.; Pett, M. T.; Zhang, J. Tetrahedron 2000, 56, 6585; (s) Ducrot, P.; Rabhi, C., Thal, C. Tetrahedron 2000, 56, 2683. 11. Verma, A. K.; Jha, R. R.; Shankar, V. K.; Aggarwal, T.; Singh, R. P. Eur. J. Org. Chem. 2011, 6998. 12. Katritzky, A. R.; Lan, X. F.; Yang, J. Z.; Denisko, O. V. Chem. Rev. 1998, 98, 409. 13. (a) Katritzky, A. R.; Verma, A. K.; He, H.; Chandra, R. J. Org. Chem. 2003, 68, 4938; (b) Tiwari, R. K.; Singh, D.; Singh, J.; Yadav, V.; Phatak, A. K.; Dabur, R.; Chhillar, A.; Singh, R.; Sharma, G. L.; Chandra, R.; Verma, A. K. Bioorg. Med. Chem. Lett. 2006, 413; (c) Tiwari, R. K.; Singh, D.; Singh, J.; Chhillar, A.; Chandra, R.; Verma, A. K. Eur. J. Med. Chem. 2006, 41, 40; (d) Tiwari, R. K.; Singh, J.; Singh, D.; Verma, A. K.; Chandra, R. Tetrahedron 2005, 61, 9513; (e) Chaudhary, P.; Kumar, R.; Verma, A. K.; Singh, D.; Yadav, J.; Chillar, A.; Sharma, G. L.; Chandra, R. Bioorg. Med. Chem. 2006, 14, 1819 14. (a) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock, R. C. Angew. Chem. Int. Ed. 2009, 48, 1138; (b) Verma, A. K.; Joshi, M.; Singh, V. P. Org. Lett. 2011, 13, 1630; (c) Rustagi, V.; Aggarwal, T.; Verma, A. K. Green Chem. 2011, 13, 1640; (d) Verma, A. K.; Shukla, S. P.; Singh, J.; Rustagi, V. J. Org. Chem., 2011, 76, 5670. (e) Verma, A. K.; Kotla, S. K. R.; Choudhary, D.; Patel, M.; Tiwari, R. J. Org. Chem. 2013, 78, 4386; (f) Shukla, S. P.; Tiwari, R. K.; Verma, A. V. J. Org. Chem. 2012, 77, 10382; (g) Verma, A. K.; Jha, R. R.; Chaudhary, R.; Tiwari, R. K.; Reddy, K. S. K.; Danodia, A. J. Org. Chem. 2012, 77, 8191; (h) Rustagi, V.; Tiwari, R.; Verma, A. K. Eur. J. Org. Chem. 2012, 4590. 15. General procedure for the synthesis of 6a. To a well-stirred solution of 4a (0.5 mmol) in dry toluene (2.0 mL), benzotriazole (0.5 mmol), aldehyde 5a (0.6 mmol) and p-TsOH (10 mol %) were added to a round bottom flask. The reaction mixture was stirred for 1–2 h at 25 °C till the disappearance of starting material. The reaction mixture was extracted with DCM and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and obtained product was further purified by column chromatography. The formation of product was confirmed by the 1H, 13C NMR and mass spectroscopic analysis. Yellow needles; mp 174–176 oC; 1H NMR (300 MHz, CDCl3) δ 7.47 (t, J = 8.3 Hz, 3H), 7.19 (d, J = 8.4 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.91 (t, J = 7.2 Hz, 1H), 6.81–6.79 (m, 1H), 5.43 (s, 1H), 4.30 (brs, 1H), 3.07 (q, J = 7.5 Hz, 2H), 1.85 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 146.0, 140.1, 136.5, 131.9, 131.8, 130.2, 129.1, 125.9, 124.7, 123.3, 122.1, 119.7, 117.8, 116.3, 53.9, 23.5, 12.6, 12.1. HRMS (ESI): [M+H+] Calcd for C19H18BrN3: 367.0684; found: 367.0689. 16. CCDC 947885 (6b) contains the supplementary crystallographic data for this paper and can be obtained free of charge from the Cambridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/request/cif. 17. Supporting information

SUPPORTING INFORMATION Selective synthesis of 4,5-dihydroimidazo- and imidazo[1,5-a]quinoxalines via modified Pictet-Spengler reaction Akhilesh K. Verma,*a Rajeev R. Jha,a V. Kasi Sankara and Raj P. Singhb a

Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India. b

Centre for Fire, Explosive & Environment Safety, Timarpur, Delhi -110054 E-Mail address: [email protected]

S.NO. Table of contents

Page No

1.

General Experimental

S2-S2

2.

S2-S3

6.

General procedure for the synthesis of substituted 1-(2-nitrophenyl)1H-imidazole (3a–c) General procedure for the synthesis of substituted 1-(2aminophenyl)-1H-imidazole (4a–c) General procedure for the synthesis of dihydroimidazo[1,5a]quinoxaline (6a–g) General procedure for the synthesis of substituted phenylimidazo[1,5-a]quinoxaline(7a–h) Crystallographic study of compounds 6b

7.

References

S11-S11

8.

Control Experiment

S12-S12

9.

Copies of 1H NMR and 13C NMR

S13-S46

3. 4. 5.

S1

S3-S4 S4-S7 S7-S10 S10-S11

(A) General Experimental 1

H and

13

C NMR spectra were recorded using a Bruker Avance 300 MHz NMR

spectrometer. The chemical shifts are referenced to signals at 7.26 and 77.0 ppm, respectively, CdCl3 is solvent with TMS as the internal standard. High resolution mass spectra (HR-MS) were obtained on a Waters Micromass Q-Tof Micro instrument. Melting points were measured with a BÜCHI B-545 melting point instrument and were uncorrected. TLC was performed by using commercially prepared 100–400 mesh silica gel plates (GF254) and visualization was effected at 254 nm. All reagents and solvents were purchased as reagent grade and used without further purification. (B) General procedure for the synthesis of substituted 1-(2-nitrophenyl)-1H-imidazole (3a–c). To a well-stirred solution of N- heterocycles 1a–c (1.0 mmol) in 1.0 ml of DMSO, NaOH (1.0 equiv) and 2-floronitrobenzene 2 was added slowly. The reaction mixture was stirred vigorously for 1–1.5 h at r. t. till no more starting material was detectable by TLC analysis. After that reaction mixture was extracted with ethyl acetate and water and dried over Na2SO4. The solvent was evaporated in vacuo and the crude was purified by column chromatography (hexane and ethylacetate) to afford the desired product in good yields. Compounds 3b–c was previously reported.1

2-Ethyl-4-methyl-1-(2-nitrophenyl)-1H-imidazole(3a). The product was obtained as a yellow needles; Yield 80%; mp 58–60 °C: 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J = 8.1Hz, 1H), 7.75 (t, J = 7.5Hz, 1H), 7.65 (t, J = 7.5Hz, 1H), 7.43 (d, J = 7.8Hz, 1H), 6.61 (s, 1H), 2.41 (q, J = 7.5 Hz, 2H), 2.23 (s, 3H), 1.20 (t, J = 7.5 Hz, 3H); 13

C NMR (75 MHz, CDCl3): δ 149.3, 146.2, 137.2, 133.4, 130.9, 130.0, 129.7, 124.9,

116.5, 20.0, 13.2, 11.8. HRMS (ESI): [M+H+] Calcd for C12H13N3O2: 231.1008; found: 231.1010.

S2

4-Methyl-1-(2-nitrophenyl)-1H-imidazole (3b). This compound is previously reported. 1c

1-(2-Nitrophenyl)-1H-imidazole(3c). This compound is previously reported.1c

(C) General procedure for the synthesis of substituted 1-(2-aminophenyl)-1Himidazole (4a–c). To a well-stirred solution of alkyl substituted 1-(2-nitrophenyl)-1Himidazole 3a–c (1.0 mmol) in 25 ml of absolute ethanol, of 10% Pd/C (20 mol %) was added. The reaction mixture was stirred for 2–3 h at r. t. under hydrogen atmosphere at 45 psi. Then the reaction mixture was filtered with aid of celite and the filtrate was evaporated in vacuo to obtain the desired amines. Compounds 4b–c was previously reported.1

2-(2-Ethyl-4-methyl-1H-imidazol-1-yl)phenylamine(4a). The product was obtained as a cololess needles; Yield 81%; mp 128–130 oC: 1H NMR (300 MHz, CDCl3): δ 7.25–7.19 (m, 1H), 7.06–7.04 (m, 1H), 6.82–6.76 (m, 2H), 6.60 (s, 1H), 3.61 (s, 2H), 2.53–2.46 (q, J = 7.7Hz, 2H), 2.26 (s, 3H), 1.25–1.15 (m, 3H);

13

C NMR (75 MHz,

CDCl3): δ 149.8, 142.8, 137.2, 129.8, 128.1, 123.3, 118.2, 116.2, 115.9, 20.2, 13.6, 12.3. HRMS (ESI): [M+H+] Calcd for C12H15N3: 201.1266; found: 201.1270.

2-(4-Methyl-1H-imidazol-1-yl)aniline (4b). This compound is previously reported.

1

S3

2-(1H-Imidazol-1-yl)aniline (4c). This compound is previously reported.1 (D) General procedure for the synthesis of dihydroimidazo[1,5-a]quinoxaline (6a– g). To a well-stirred solution of 2-(2-Ethyl-4-methyl-1H-imidazol-1-yl)aniline 4a or 2-(4Methyl-1H-imidazol-1-yl)aniline 4b or 2-(1H-Imidazol-1-yl)aniline 4c (0.5 mmol), in dry toluene (2.0 ml), benzotrazole (0.5 mmol) and aldehyde 5a–g (0.6 mmol) was added followed by addition of catalytic amount of p-TsOH (10 mol %). The reaction was stirred for 1–2 h at 25 °C till no more starting material was detectable by TLC analysis. After that reaction mixture was extracted with DCM and water. The organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated in vacuo and the needles obtained were purified by column chromatography (hexane and ethylacetate) to afford the desired product in good yields.

4-(4-Bromophenyl)-1-ethyl-3-methyl-4,5-dihydroimidazo[1,5a]quinoxaline (6a). The product was obtained as a off white needles; Yield 88%; mp 174–176 oC: 1H NMR (300 MHz, CDCl3): δ 7.47 (t, J = 8.3 Hz, 3H), 7.19 (d, J = 8.4 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.91 (t, J = 7.2 Hz, 1H), 6.81–6.79 (m, 1H), 5.43 (s, 1H), 4.30 (brs, 1H), 3.07 (q, J = 7.5 Hz, 2H), 1.85 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 146.0, 140.1, 136.5, 131.9, 131.8, 130.2, 129.1, 125.9, 124.7, 123.3, 122.1, 119.7, 117.8, 116.3, 53.9, 23.5, 12.6, 12.1. HRMS (ESI): [M+H+] Calcd for C19H18BrN3: 367.0684; found: 367.0689.

1-Ethyl-3-methyl-4-(4-nitrophenyl)-4,5-dihydroimidazo[1,5a]quinoxaline (6b). The product was obtained as a yellow needles; Yield 90%; mp 190– 192 oC: 1H NMR (300 MHz, CDCl3): δ 8.14 (d, J = 8.7 Hz, 2H), 7.50–7.42 (m, 3H), 7.06 S4

(t, J = 7.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 5.58 (s, 1H), 4.51 (brs, 1H), 3.06 (q, J = 7.4 Hz, 2H), 1.91 (s, 3H), 1.44 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 148.5, 147.6, 146.4, 135.7, 130.4, 128.0, 126.1, 124.5, 124.0, 122.4, 120.0, 117.8, 116.4, 53.4, 23.5, 12.6, 12.0. HRMS (ESI): [M+H+] Calcd for C19H18N4O2: 334.1430; found: 334.1432.

4-(2,4-Dichlorophenyl)-1-ethyl-3-methyl-4,5-dihydroimidazo[1,5a]quinoxaline (6c). The product was obtained as a yellow needles; Yield 86%; mp 215– 217 oC: 1H NMR (300 MHz, CDCl3): δ 7.48 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.05–6.96 (m, 2H), 6.90–6.84 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.72–6.69 (dd, J = 6.6 and 1.2 Hz, 1H), 5.88 (d, J = 1.2 Hz, 1H), 4.68 (brs, 1H), 3.13 (q, J = 7.2 Hz, 2H), 1.98 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 146.4, 136.7, 135.4, 134.3, 133.1, 130.5, 129.9, 129.5, 127.4, 126.0, 124.6, 121.8, 119.9, 117.7, 116.8, 49.8, 23.6, 12.2, 12.0. HRMS (ESI): [M+H+] Calcd for C19H17Cl2N3: 357.0800; found: 357.0806.

4-(3-Chlorophenyl)-1-ethyl-3-methyl-4,5-dihydroimidazo[1,5a]quinoxaline (6d). The product was obtained as a pale yellow needles; Yield 84%; mp 140–142 °C.

1

H NMR (300 MHz, CDCl3): δ 7.47 (d, J = 8.1 Hz, 1H), 7.30 – 7.23 (m,

3H), 7.17 – 7.15 (m, 1H), 7.07–7.02 (m, 1H), 6.92–6.86 (m, 1H), 6.80–6.78 (m, 1H), 5.43 (s, 1H), 4.33 (brs, 1H), 3.05 (q, J = 7.5 Hz, 2H), 1.85 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H); 13

C NMR (75 MHz, CDCl3): δ 146.0, 143.1, 136.4, 134.6, 130.3, 130.0, 128.3, 127.6,

125.9, 125.5, 124.6, 123.1, 119.7, 117.8, 116.3, 54.0, 23.5, 12.6, 12.0. HRMS (ESI): [M+H+] Calcd for C19H18ClN3: 323.1189; found: 323.1191.

S5

1-Ethyl-3-methyl-4-(3-nitrophenyl)-4,5-dihydroimidazo[1,5a]quinoxaline (6e). The product was obtained as a orange needles; Yield 85%; mp 168– 170 °C: 1H NMR (300 MHz, CDCl3): δ 8.20–8.12 (m, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.06 (t, J = 7.2 Hz, 1H), 6.91 (t, J = 7.1 Hz, 1H), 6.83 (d, J = 6.6 Hz, 1H), 5.59 (s, 1H), 4.46 (brs, 1H), 3.06 (q, J = 7.5 Hz, 2H), 1.89 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H);

13

C NMR (75 MHz, CDCl3): δ 148.4, 146.4, 143.4, 135.8, 133.4, 130.4, 129.8,

126.1, 124.6, 123.1, 122.6, 122.2, 120.1, 117.6, 116.5, 53.5, 23.5, 12.6, 12.0. HRMS (ESI): [M+H+] Calcd for C19H18N4O2: 334.1430; found: 334.1435.

1-Ethyl-4-(3-methoxyphenyl)-3-methyl-4,5-dihydroimidazo[1,5a]quinoxaline (6f). The product was obtained as a white needles; Yield 80%; mp 142– 144 °C: 1H NMR (300 MHz, CDCl3): δ 7.39 (d, J = 8.0 Hz, 1H), 7.18–7.12 (m, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.82–6.70 (m, 5H), 5.33 (s, 1H), 4.24 (brs, NH), 3.66 (s, 3H), 2.97 (q, J = 7.3Hz, 2H), 1.76 (s, 3H), 1.36 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 159.9, 145.8, 142.5, 136.9, 130.0, 129.7, 125.8, 124.7, 123.7, 119.7, 119.5, 117.8, 116.2, 113.6, 112.9, 55.1, 54.5, 23.4, 12.5, 12.1. HRMS (ESI): [M+H+] Calcd for C20H21N3O: 319.1685; found: 319.1688.

4-(4-Methoxyphenyl)-3-methyl-4,5-dihydroimidazo[1,5-a]quinoxaline (6g). The product was obtained as a off white needles; Yield 77%; mp 90–92 oC: 1H NMR (300 MHz, CDCl3): δ 7.94 (s, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.24 (d, J = 7.2 Hz, 2H), 7.00 (d, J = 7.5 Hz, 1H), 6.83 (m, 3H), 6.72 (d, J = 7.5 Hz, 1H), 5.51 (s, 1H), 4.23 (brs, 1H), 3.79 (s, 3H), 1.79 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 159.5, 136.0, 135.3, S6

133.3, 133.1, 130.1, 129.2, 128.7, 127.8, 126.2, 122.4, 119.0, 115.5, 114.9, 114.0, 55.2, 53.8, 12.7. HRMS (ESI): [M+H+] Calcd for C18H17N3O: 291.1372; found: 291.1379.

(E) General procedure for the synthesis of substituted phenylimidazo[1,5a]quinoxaline(7a–h). To a well-stirred solution of 2-(2-Ethyl-4-methyl-1H-imidazol-1yl)aniline 4a or 2-(4-Methyl-1H-imidazol-1-yl)aniline 4b or 2-(1H-Imidazol-1-yl)aniline 4c (0.5 mmol), in dry toluene (2.0 ml), benzotrazole (0.5 mmol) and aldehyde 5a–c, 5e, 5h–k (0.6 mmol) was added followed by addition of catalytic amount of p-TsOH (10 mol %). The reaction was stirred for 10–12 h at r. t. till no more starting material was detectable by TLC analysis. After that reaction mixture was extracted with DCM and water. The organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated in vacuo and the needles obtained were purified by column chromatography (hexane and ethyl acetate) to afford the desired product in good yields.

4-(4-Chlorophenyl)-1-ethyl-3-methylimidazo[1,5-a]quinoxaline(7a). The product was obtained as a yellow needles; Yield 86%; mp 175–177 oC: 1H NMR (300 MHz, CDCl3): δ 8.13–8.09 (m, 1H), 8.03–7.95 (m, 1H), 7.59–7.46 (m, 6H), 3.44 (q, J = 7.4 Hz, 2H), 2.13 (s, 3H), 1.59 (t, J = 7.5 Hz, 3H);

13

C NMR (75 MHz, CDCl3): δ

154.4, 145.7, 137.2, 136.6, 135.8, 135.7, 130.08, 130.01, 128.7, 127.6, 126.9, 126.3, 121.3, 115.7, 25.05, 16.2, 11.7. HRMS (ESI): [M+H+] Calcd for C19H16BrN3: 365.0528; found: 365.0529.

1-Ethyl-4-(4-fluorophenyl)-3-methylimidazo[1,5-a]quinoxaline (7b). The product was obtained as a pale yellow needles; Yield 88%; mp 171–173 oC: 1H NMR (300 MHz, CDCl3): δ 8.14–8.10 (m, 1H), 8.00–7.96 (m, 1H), 7.64–7.59 (m, 2H), 7.56–7.47 (m, 2H), 7.28–7.20 (m, 2H), 3.43 (q, J = 7.5 Hz, 2H), 2.12 (s, 3H), 1.59 (t, J = 7.5 Hz, 3H);

13

C NMR (75 MHz, CDCl3): δ 161.9, 155.3, 145.6, 137.3, 135.8, 134.3, S7

130.6, 130.5, 130.0, 127.4, 126.9, 126.2, 121.4, 115.6, 115.3, 25.0, 16.1, 11.7. HRMS (ESI): [M+H+] Calcd for C19H16FN3: 305.1328; found: 305.1331.

1-Ethyl-3-methyl-4-p-tolylimidazo[1,5-a]quinoxaline(7c).

The

o

1

product was obtained as a pale-yellow needles; Yield 80%; mp 146–148 C; H NMR (400 MHz, CDCl3): δ 8.09–7.97 (m, 2H), 7.47–7.45 (m, 4H), 7.31 (d, J = 7.2 Hz, 2H), 3.42 (q, J = 7.0 Hz, 2H), 2.44 (s, 3H), 2.10 (s, 3H), 1.57 (t, J = 7.2Hz, 3H);

13

C (100

MHz, CDCl3): δ 156.5, 145.4, 139.4, 137.4, 135.9, 135.3, 129.9, 129.0, 128.4, 127.1, 126.8, 126.1, 121.5, 115.6, 25.0, 21.4, 16.1, 11.7. HRMS (ESI): [M+H+] Calcd for C20H19N3: 301.1579; found: 301.1582.

3-Methyl-4-(4-nitrophenyl)imidazo[1,5-a]quinoxaline (7d). The product was obtained as a pale yellow needles; Yield 83%; mp 126–128 °C; 1H NMR (300 MHz, CDCl3): δ 8.60 (s, 1H), 8.31 (d, J = 8.3 Hz, 2H), 8.00 (d, J = 8.7 Hz, 2H), 7.67–7.65 (m, 1H), 7.45–7.39 (m, 1H), 7.27–7.22 (m, 1H), 6.96 (s, 1H), 2.29 (s, 3H);

13

C (75 MHz,

CDCl3): δ 158.6, 149.5, 144.0, 140.9, 138.2, 137.5, 131.8, 129.7, 128.4, 127.9, 125.0, 124.1, 119.2, 116.8, 13.6. HRMS (ESI): [M+H+] calcd for C17H12N4O2: 304.0960; found: 304.0960.

4-(3-Methylimidazo[1,5-a]quinoxalin-4-yl)benzonitrile(7e) The product was obtained as a colorless needles; Yield 82%; mp 80–82 °C: 1H NMR (400 MHz, CDCl3): δ 8.01–7.92 (m, 2H), 7.74 (dd, J = 5.1 and 1.5 Hz, 2H), 7.67 (d, J = 1.2 Hz, 1H), 7.44–7.36 (m, 2H), 7.24–7.22 (m, 1H), 6.95 (s, 1H), 2.29 (d, J = 0.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 159.1, 144.1, 139.3, 138.1, 137.5, 132.9, 132.6, 131.7, 129.8, 129.4, S8

128.4, 127.7, 125.0, 119.2, 118.2, 116.8, 114.9, 13.6. HRMS (ESI): [M+H+] Calcd for C18H12N4: 284.1062; found: 284.1064.

3-Methyl-4-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]quinoxaline(7f). The product was obtained as a pale yellow needles; Yield 82%; mp 102–104 °C; 1H NMR (400 MHz, CDCl3): δ 7.95 (d, J = 8.1 Hz, 2H), 7.72–7.68 (m, 2H), 7.43–7.34 (m, 3H), 7.20 (d, J = 14.1 Hz, 1H), 6.96 (s, 1H), 2.29 (s, 3H); 13C (75 MHz, CDCl3): δ 159.7, 144.4, 138.7, 138.1, 137.5, 133.4, 133.0, 131.6, 129.2, 128.3, 127.4, 125.8, 124.9, 121.9, 119.4, 116.8, 13.6. HRMS (ESI): [M+H+] Calcd for C18H12F3N3: 327.0983; found: 327.0986.

3-Methyl-4-(3-nitrophenyl)imidazo[1,5-a]quinoxaline(7g).

The

product was obtained as a light yellow needles; Yield 78%; mp 110–112 °C; 1H NMR (300 MHz, CDCl3): δ 8.35–8.32 (m, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.4 Hz, 2H), 7.45–7.37 (m, 3H), 7.21 (d, J = 7.2 Hz, 1H), 6.98 (s, 1H), 2.29 (s, 3H);

13

C (75

MHz, CDCl3): δ 158.6, 148.6, 144.2, 138.2, 137.4, 137.3, 133.8, 131.6, 130.0, 128.4, 127.6, 126.1, 125.0, 124.1, 119.3, 116.8, 13.9. HRMS (ESI): [M+H+] Calcd for C17H12N4O2: 304.0960; found: 304.0965.

4-(2,4-Dichlorophenyl)-3-methylimidazo[1,5-a]quinoxaline(7h). The product was obtained as a pale yellow needles; Yield 75%; mp 82–84 °C: 1H NMR (300 MHz, CDCl3): δ 8.04 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 2.1 S9

Hz, 1H), 7.43–7.36 (m, 2H), 7.35–7.29 (m, 1H), 7.23–7.20 (m, 1H), 6.94 (t, J = 0.9 Hz, 1H), 2.29 (d, J = 0.9 Hz, 3H); 13C (75 MHz, CDCl3): δ 156.8, 144.7, 138.3, 138.0, 137.5, 136.6, 131.7, 131.3, 129.8, 129.7, 128.4, 127.9, 127.4, 124.9, 119.6, 116.9, 13.1. HRMS (ESI): [M+H+] Calcd for C17H11Cl2N3: 327.0330; found: 327.0335. Table I. Crystallographic data and structure refinement for compounds 6b The crystal evaluation and data collection were performed at 173 K on a Bruker CCD1000 diffractometer with Mo Kα (λ = 0.71073 Å) radiation. A multi-scan correction was applied. The structure was solved by the direct methods using SIR-92 and refined by fullmatrix least-squares refinement techniques on F2 using SHELXL972. The hydrogen atoms were placed into the calculated positions and included in the last cycles of the refinement. All calculations were done using Wingx software package3. Crystallographic data for the structures 6b reported in this Letter have been deposited with the Cambridge Crystallographic Data Centre as supplementary publications CCDC 947885. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223 336 033; e-mail: [email protected]). 6b Empirical formula

C19H18N4O2

Formula weight

334.37

Temperature

173(2) K

Wavelength

0.71073 Å

Crystal system

Monoclinic

Space group

P 21/n

a

8.694(3) Å

b

20.560(7) Å

c

9.211(3) Å

α

90°

β

103.339(6)°

γ

90°

Volume

1602.1(9) Å3 S10

Z

4

Density (calculated)

1.386 Mg/m3

Absorption coefficient

0.093 mm-1

F(000)

704

Crystal size

0.47 x 0.45 x 0.38 mm3

Theta range for data collection

1.98 to 28.33° --11 ≤ h ≤ 11, -27≤ k ≤ 27, -12 ≤ l ≤

Index ranges

12 Reflections collected

14121

Independent reflections

2834 [R(int) = 0.0374]

Completeness to theta = 28.33°

95.8 %

Absorption correction

Multi-scan

Max. and min. transmission

0.9655 and 0.9575

Refinement method

Full-matrix least-squares on F2

Data / restraints / parameters

3831 / 0 / 231

Goodness-of-fit on F2

1.032

Final R indices [I>2sigma(I)]a, b

R1 = 0.0511, wR2 = 0.1152

R indices (all data)

R1 = 0.0746, wR2 = 0.1276

Largest diff. peak and hole a

0.105 and -0.115 e.Å-3

R = ∑(║Fo│– │Fc║)/∑│Fo│; bRW = {∑[w(Fo2 ─ Fc2)2]/∑[w(Fo2)2]}1/2

(F) References: 1. Verma, A. K.; Jha, R. R.; Shankar, V. K.; Aggarwal, T.; Singh, R. P. Eur. J. Org. Chem. 2011, 6998. 2. Sheldrick, G. M. Acta Cryst., 2008, A64, 112-122. 3. Farrugia, L. J. WinGX Version 1.80.05, An integrated system of Windows Programs for the Solution, Refinement and Analysis of Single Crystal X-Ray Diffraction Data; Department of Chemistry, University of Glasgow (1997-2009).

S11

(G) Control Experiment: To validate the formation of oxidized product we have performed the control experiment. When reaction of 4a with 5a was carried out in presence of inert (nitrogen) atmosphere, only reduced product 6a was obtained in 88% yield; however when we allowed reaction for 18 h in inert atmosphere same result was obtained (Scheme S-I , eq. i). We observed that when reaction was carried-out in air, oxidized product 7a was obtained after 12 h (Scheme S-I, ii). When solid compound 6a was kept for longer period of time under inert atmosphere; oxidized product 7a was not observed (Scheme SI, eq. iii); however when we left the compound in open air, compound 6a was slowly get oxidized into 7a (Scheme SI, eq. iii).

2005, 6

1

Scheme Sl. Control Experiment for the conformation of Oxidized Product

3-9518. Tetrahedron, 2005, 61, 951

S12

(H) Copies of 1H NMR and 13C NMR 1

H NMR

3a

S13

13

C NMR

3a

S14

1

H NMR

4a

S15

13

C NMR

4a

S16

1

H NMR

6a

S17

13

C NMR

6a

1

H NMR S18

6b

S19

13

C NMR

6b

1

H NMR S20

6c

13

C NMR S21

6c

1

H NMR S22

6d

13

C NMR S23

6d

1

H NMR S24

6e

13

C NMR S25

6e

13

C NMR S26

6f

13

C NMR S27

6f

1

H NMR S28

6g

S29

13

C NMR

6g

1

H NMR S30

7a

13

C NMR S31

7a

1

H NMR S32

7b

S33

13

C NMR

7b

1

H NMR S34

7c

13

C NMR S35

7c

S36

1

H NMR

7d

S37

13

C NMR

7d

1

H NMR S38

7e

13

C NMR S39

7e

1

H NMR S40

7f

13

C NMR S41

7f

S42

1

H NMR

7g

S43

13

C NMR

7g

S44

1

H NMR

7h

S45

13

C NMR

7h

S46