Polar [3 + 2] cycloaddition of isatin-3-imines with electrophilically activated heteroaromatic N-ylides: Synthesis of spirocyclic imidazo[1,2-a]pyridine and isoquinoline derivatives

Tayebeh Sattaei Mokhtari; Mohammad Seifi; Vahid Saheb; Hassan Sheibani

doi:10.1016/j.arabjc.2015.05.023

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Original article

12 (

); 2937-2942

doi:

10.1016/j.arabjc.2015.05.023

Polar [3 + 2] cycloaddition of isatin-3-imines with electrophilically activated heteroaromatic N-ylides: Synthesis of spirocyclic imidazo[1,2-a]pyridine and isoquinoline derivatives

Tayebeh Sattaei Mokhtari^{^a}, Mohammad Seifi^{^b}, Vahid Saheb^{^b}, Hassan Sheibani^{^b,⁎}

a Department of Chemistry, Islamic Azad University, Jiroft Branch, Jiroft, Iran

b Department of Chemistry, Shahid Bahonar University of Kerman, Kerman 76169, Iran

⁎Corresponding author. Tel./fax: +98 341 322 2033. hsheibani@mail.uk.ac.ir (Hassan Sheibani)

Received: 2013-11-24, Accepted: 2015-5-31, Published: 2015-12-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Abstract

A new synthesis of spiro[imidazo[1,2-a]pyridine-2,3′-indoline]-2′-ones 3a-f and spiro[imidazo[1,2-a]isoquinoline-2,3′-indolin]-2′-ones 5a-d, respectively by polar [3 + 2] cycloaddition reactions of isatin-3-imines with pyridinium and isoquinolinium ylides which are derived from 2-bromoacetophenone, 2,4′-dibromoacetophenone or methyl bromoacetate is described. These cycloaddition reactions consist of the nucleophilic attack of the heteroaromatic N-ylides on isatin-3-imine derivatives. The salient features of these processes include operational simplicity, high yields, and easily accessible starting materials. In addition, Density Functional Theory (DFT) calculations at the M06–2X/6–31 + G(d) level have been performed to investigate the possible transition states and products. The theoretical results are in good agreement with the experimental findings and show that the product 3a is the most stable product and is formed through a kinetically feasible pathway.

Keywords

Pyridinium and isoquinolinium ylides

Isatin-3-imines

Spiro[imidazo[1,2-a]pyridine-2,3′-indoline]-2′-ones

Spiro[imidazo[1,2-a]isoquinoline-2,3′-indolin]-2′-ones

Polar [3 + 2] cycloaddition

Show Related Articles from PubMed

1 Introduction

Spirocyclic systems containing one carbon atom common to two rings are structurally interesting (Sannigrahi, 1999). The presence of the sterically constrained spiro structure in various natural products also adds to the interest in the investigations of spiro compounds (Srivastav et al., 1992). These compounds represent an important class of naturally occurring substances characteristic by their highly pronounced biological properties such as anticancer agents (Young-Won et al., 2008; Wen-Liang et al., 2007), antibacterial agents (Hyeong-Beom et al., 2007), anticonvulsant agents (Krzysztof et al., 2008; Jolanta et al., 2006), antituberculosis agents (Chande et al., 2005), anti-Alzheimer’s agents (Masakazu et al., 2001), and antimicrobial agents (Thadhaney et al., 2010). Consequently, many synthetic methodologies have been developed for constructing these spirocycles, most of which were based on cycloaddition or condensation reactions (Prakash et al., 2012; Feldman and Karatjas, 2006). For example the synthesis of spiro neutral products such as (±)-welwitindolinone A isonitrile I and (±)-brevianamide A II has been reported by Wood and Williams respectively (Reisman et al., 2008; Miller and Williams, 2009).

In the past few years a growing interest in the chemistry of imidazo[1,2-a] pyridines and isoquinolines has been developed due to the extent of their applications in pharmacological science (Wisniewska et al., 2012; Hayakawa et al., 2007; Singhaus et al., 2010 ). Indeed they are known for their antibacterial (Al-Tel et al., 2011), antiviral (Gueiffier et al., 1996,1998), anti-inflammatory (Flores et al., 2012), antiulcer (Katsura et al.,1992), antitubercular (Moraski et al., 2012), anticancer (Ducray et al., 2011), antiparasitic (Martínez et al., 2010) and antiprotozoa (Ismail et al., 2004) activities. Nitrogen-containing heterocyclic compounds, are of high industrial interest for applications as intermediates to produce pharmaceuticals, herbicides, fungicides, dyes, etc (Pozharskii et al., 1997). The conjugated heterocyclic N-ylides have been known as a subgroup of mesomeric betaines (Ollis and Stanforth, 1985), widely used as building blocks for the synthesis of fused heterocyclic systems and natural products, due to its 1,3-dipolar character (Padwa, 1984) that allows cycloaddition processes to take place efficiently. Today, cycloimmonium ylides are involved in a wide range of synthetically useful reactions, mainly in the field of heterocyclic chemistry (Tewari and Dubey, 1980). The pyridinium ylides were known as one of the special ammonium ylides, which can react with alkenes substituted with electron-withdrawing groups to give the corresponding cyclopropanes and the pyridine group has been utilized as a leaving group in intermolecular reactions (Kojima et al., 2000, 2006). However the 1,3-dipolar cycloaddition of heteroaromatic N-ylides, such as isoquinolinium ylides with electron-deficient alkynes and alkenes are released to pyrolo[2,1-a]isoquinoline derivatives (Domling and Ugi, 2000; Yan et al., 2007; Han et al., 2011 ). In view of our general interest in the development of synthesis of heterocyclic compounds (Seifi et al., 2013; Seifi and Sheibani, 2013a,b ), we now report a new synthesis of compounds 3a–f and 5d–d by the 1,3-dipolar cyclization reactions of pyridinium and isoquinolinium ylides with 3-(phenylimino)indoline-2-one and 5-bromo-3-(phenylimino)indoline-2-one in excellent yields. Also, density function theory (DFT) calculations are carried out to explore the possible transition states and minimum energy structures of the title reaction.

2 Experimental section

Melting points were measured on a Electrothermal-9100 apparatus and are uncorrected. IR spectra were recorded on a Brucker FT-IR Tensor 27 infrared spectrophotometer. ¹H NMR and spectra were recorded on a Avance III 400 or 300 MHz Bruker spectrometer. ¹³C NMR spectra were recorded on the same instruments at 100 or 75 MHz using TMS as an internal standard respectively. Mass spectra were measured on a GCMS-QP1000 EX spectrometer at 70 eV. Elemental analyses were performed using a Heracus CHN-O-Rapid analyzer. The 3-(phenylimino)indoline-2-one and 5-bromo-3-(phenylimino)indoline-2-one were known and prepared according to a general procedure (Sridhar et al., 2001). Pyridinium and isoquinolinium salts were prepared according to a literature procedure (Hazra et al., 2011).

2.1

2.1 General procedure for the preparation of compounds 3a–f and 5a–d in acetonitrile

A solution of pyridinium salts (1a–c) or isoquinolinium salts (4a, c) (2 mmol), 3-(phenylimino)indoline-2-one (2a) or 5-bromo-3-(phenylimino)indoline-2-one (2b) (2 mmol) and triethylamine (0.2 mL) in acetonitrile (20 mL) was stirred at room temperature for about 60 min (the progress of the reaction being monitored by TLC and using n-hexane/ethyl acetate as an eluent). The solvent was diluted with 50 mL of water and the resulting precipitate was collected with filtration. The crude product was recrystallized with dichloromethane/n-hexane to give the pure solid sample for analysis.

2.2

2.2 Spectral data for selected compounds

2.2.1

2.2.1 3-Benzoyl-1-phenyl-3,8a-dihydro-1H-spiro[imidazo[1,2-a]pyridine-2,3′-indolin]-2′-one (3a)

Green crystals; yield: 95%; mp 178–181 °C; IR (KBr) νmax (cm⁻¹): 3170 (NH-amid), 1741, 1651(C⚌O), 1608, 1590 (C⚌C). ¹H NMR (400 MHz, DMSO-d6, ppm): 10.99 (s, 1H, N—CH⚌), 8.35 (s, 1H, NH), 7.60–6.32 (m, 18H, Ar, CH⚌CH), 5.80 (s, 1H, N—CH—N). ¹³C NMR (100 MHz, DMSO-d6, ppm): 163.51 (C⚌O), 158.46 (N—C⚌O), 155.01, 152.84, 150.57, 149.03, 147.01, 145.70, 134.46, 134.20, 129.63, 128.33, 125.38, 124.96, 124.47, 122.78, 122.32, 121.72, 119.07, 117.25, 115.68, 111.57 (N—C—N), 110.80 (spiro carbon). MS (m/z): 419 (M⁺) (3), 368 (4), 264 (4), 222 (90), 194 (100), 167 (24), 139 (4), 105 (16), 77 (51), 51 (23). Anal. calcd. for C₂₇H₂₁N₃O₂: C, 77.31; H, 5.05; N, 10.00%. Found: C, 77.02; H, 4.87; N, 9.69%.

2.2.2

2.2.2 3-Benzoyl-5′-bromo-1-phenyl-3,8a-dihydro-1H-spiro[imidazo[1,2-a]pyridine-2,3′-indolin]-2′-one (3b)

Green crystals; yield: 92%; mp 190 °C (decompose); IR (KBr) νmax (cm⁻¹): 3251 (NH), 1740, 1651 (C⚌O), 1608 (C⚌C). ¹H NMR (400 MHz, DMSO-d6, ppm): 11.16 (s, 1H, N—CH⚌), 8.57 (s, 1H, NH), 7.51–6.34 (m, 17H, Ar, CH⚌CH), 5.50 (s, 1H, N—CH—N). ¹³C NMR (100 MHz, DMSO-d6, ppm): 167.85 (C⚌O), 154.07 (N—C⚌O), 150.19, 149.58, 147.44, 146.02, 145.50, 136.48, 136.25, 129.66, 128.29, 127.56, 125.28, 125.02, 124.88, 119.25, 117.32, 117.13, 113.55, 113.51, 112.87, 112.76 (N—C—N), 108.67 (spiro carbon). MS (m/z): 497 (M⁺) (2), 396 (3), 368 (3), 302 (61), 274 (100), 245 (6), 192 (19), 166 (25), 116 (11), 105 (9), 90 (11), 77 (75), 51 (41). Anal. calcd. for C₂₇H₂₀BrN₃O₂: C, 65.07; H, 4.04; N, 8.43%. Found: C, 64.72; H, 3.86; N, 8.09%.

2.2.3

2.2.3 3-(4-Bromobenzoyl)-1-phenyl-3,8a-dihydro-1H-spiro[imidazo[1,2-a]pyridine-2,3′-indolin]-2′-one (3c)

Green crystals; yield: 92%; mp 165 °C (decompose); IR (KBr) νmax (cm⁻¹): 3173 (NH), 1747, 1651 (C⚌O), 1612, 1589 (C⚌C). ¹H NMR (400 MHz, DMSO-d6, ppm): 11.01 (s, 1H, N—CH⚌), 8.74 (s, 1H, NH), 7.50–6.33 (m, 17H, Ar, CH⚌CH), 5.42 (s, 1H, N—CH—N). ¹³C NMR (100 MHz, DMSO-d6, ppm): 163.45, 154.95, 150.53, 146.94, 134.44, 134.18, 131.20, 129.59, 128.28, 127.89, 127.62, 126.09. 125.34, 124.91, 124.42, 122.75, 122.29, 121.70, 119.02, 117.19, 115.65, 111.50 (N—C—N), 110.72 (spiro carbon). MS (m/z): 497 (M⁺) (2), 393 (5), 368 (17), 313 (20), 264 (17), 222 (33), 194 (70), 161 (25), 118 (26), 97 (44), 79 (100), 57 (87).

2.2.4

2.2.4 5′-Bromo-3-(4-bromobenzoyl)-1-phenyl-3,8a-dihydro-1H-spiro[imidazo[1,2-a]pyridine-2,3′-indolin]-2′-one (3d)

Green crystals; yield: 90%; mp 187 °C (decompose); IR (KBr) νmax (cm⁻¹): 3253 (NH), 1740, 1652 (C⚌O), 1608, 1588 (C⚌C). ¹H NMR (400 MHz, DMSO-d6, ppm): 11.16 (s, 1H, N—CH⚌), 8.59 (s, 1H, NH), 7.52–6.34 (m, 16H, Ar, CH⚌CH), 5.48 (s, 1H, N—CH—N). ¹³C NMR (100 MHz, DMSO-d6, ppm): 165.26, 154.08, 150.19, 146.03, 139.69, 136.48, 136.25, 133.74, 131.42, 129.66, 128.29, 127.56, 125.28, 125.02, 124.88, 123.37, 121.59, 119.26, 117.32, 117.13, 113.55, 112.87 (N—C—N), 110.02 (spiro carbon). MS (m/z): 577 (M⁺) (2), 475 (3), 422 (5), 368 (2), 302 (57), 274 (100), 245 (6), 192 (19), 166 (23), 116 (12), 90 (10), 77 (64), 51(32). Anal. calcd. for C₂₇H₁₉Br₂N₃O₂: C, 56.18; H, 3.32; N, 7.28%. Found: C, 55.85; H, 3.09; N, 6.94%.

2.2.5

2.2.5 Methyl 2′-oxo-1-phenyl-3,8a-dihydro-1H-spiro[imidazo[1,2-a]pyridine-2,3′-indoline]-3-carboxylate (3e)

Orange crystals; yield: 92%; mp 215–218 °C; IR (KBr) νmax (cm⁻¹): 3174 (NH), 1748 (C⚌O), 1648 (C⚌O), 1612, 1594 (C⚌C). ¹H NMR (400 MHz, DMSO-d6, ppm): 11.00 (s, 1H, NCH⚌), 8.66 (s, 1H, NH), 7.60–6.32 (m, 13H, Ar, CH⚌CH), 5.76 (s, 1H, N—CH—N), 3.67 (s, 3H, CH₃). ¹³C NMR (100 MHz, DMSO-d6, ppm): 163.66, 158.42, 154.71, 150.53, 149.34, 146.80, 145.63, 134.43, 129.78, 128.28, 125.33, 124.80, 122.83, 121.88, 119.11, 117.19, 115.70, 111.48 (N—C—N), 110.74 (spiro carbon), 54.92 (OCH₃). MS (m/z): 373 (M⁺) (3), 369 (2), 274 (5), 222 (87), 194 (100), 167 (22), 118 (9), 90 (11), 77 (42), 51 (20). Anal. calcd. for C₂₂H₁₉N₃O₃: C, 70.76; H, 5.13; N, 11.25%. Found: C, 70.42; H, 3.96; N, 10.89%.

2.2.6

2.2.6 Methyl 5′-bromo-2′-oxo-1-phenyl-3,8a-dihydro-1H-spiro[imidazo[1,2-a]pyridine-2,3′-indoline]-3-carboxylate (3f)

Orange crystals; yield: 90%; mp 240 °C (decompose); IR (KBr) νmax (cm⁻¹): 3257 (NH), 1740, 1649 (C⚌O), 1608, 1590 (C⚌C). ¹H NMR (400 MHz, DMSO-d6, ppm): 11.15 (s, 1H, NCH⚌), 8.78 (s, 1H, NH), 7.52–6.33 (m, 12H, Ar, CH⚌CH), 5.44 (s, 1H, N—CH—N), 3.66 (s, 3H, CH₃). ¹³C NMR (100 MHz, DMSO-d6, ppm): 162.97, 154.07, 150.18, 145.96, 138.81, 136.47, 136.24, 129.65, 128.29, 127.56, 125.28, 125.02, 123.36, 119.26, 117.28, 117.13, 113.52, 112.87 (N—C—N), 104.86 (spiro carbon), 53.27 (OCH₃). MS (m/z): 451 (M⁺) (2), 368 (4), 302 (59), 274 (100), 245 (6), 192 (20), 166 (27), 116 (12), 90 (12), 77 (74), 51 (37).

2.2.7

2.2.7 3-Benzoyl-1-phenyl-3,10b-dihydro-1H-spiro[imidazo[2,1-a]isoquinoline-2,3′-indolin]-2′-one (5a)

Orange crystals; yield: 93%; mp 154 °C (decompose); IR (KBr) νmax (cm⁻¹): 3259 (NH), 1739, 1664 (C⚌O), 1618, 1597 (C⚌C). ¹H NMR (400 MHz, DMSO-d6, ppm): 10.82 (s, 1H, NCH⚌), 8.96 (s, 1H, NH), 7.78–6.51 (m, 20H, Ar, CH⚌CH), 5.39 (s, 1H, N—CH—N). ¹³C NMR (100 MHz, DMSO-d6, ppm): 163.45 (C⚌O), 154.94, 150.53, 146.94, 138.37, 135.42, 134.43, 134.17, 133.70, 132.11, 129.58, 128.73, 128.28, 127.94, 127.14, 125.79, 125.33, 125.09, 124.91, 123.31, 122.75, 122.29, 121.69, 119.02, 117.19, 111.50 (N—C—N), 100.42 (spiro carbon). MS (m/z): 469 (M⁺) (3), 414 (3), 358 (9), 298 (3), 264 (10), 159 (10), 129 (4), 105 (100), 77 (65), 51 (14). Anal. calcd. for C₃₁H₂₃N₃O₂: C, 79.30; H, 4.94; N, 8.95%. Found: C, 79.02; H, 4.78; N, 8.59%.

2.2.8

2.2.8 3-Benzoyl-5′-bromo-1-phenyl-3,10b-dihydro-1H-spiro[imidazo[2,1-a]isoquinoline-2,3′-indolin]-2′-one (5b)

Orange crystals; yield: 92%; mp 160 °C (decompose); IR (KBr) νmax (cm⁻¹): 3253 (NH), 1740, 1664 (C⚌O), 1611, 1579 (C⚌C). ¹H NMR (400 MHz, DMSO-d6, ppm): 11.17 (s, 1H, NCH⚌), 8.52 (s, 1H, NH), 7.97–6.87 (m, 19H, Ar, CH⚌CH), 5.57 (s, 1H, N—CH—N). ¹³C NMR (100 MHz, DMSO-d6, ppm): 168.09), 154.07, 150.19, 146.03, 138.47, 138.37, 136.47, 136.25, 135.44, 133.69, 132.11, 129.65, 128.81, 128.73, 128.29, 127.94, 127.56, 127.19, 125.79, 125.27, 125.09, 123.30, 119.26, 117.13, 113.53, 112.87 (N—C—N), 100.41 (spiro carbon). MS (m/z): 547 (M⁺) (2), 475 (7), 425 (2), 385 (3), 358 (8), 300 (4), 254 (8), 213 (6), 164 (4), 129 (9), 105 (100), 77 (63), 51 (10). Anal. calcd. for C₃₁H₂₂BrN₃O₂: C, 67.89; H, 4.04; N, 7.66%. Found: C, 67.51; H, 3.76; N, 7.19%.

2.2.9

2.2.9 Methyl 2′-oxo-1-phenyl-3,10b-dihydro-1H-spiro[imidazo[2,1-a]isoquinoline-2,3′-indoline]-3-carboxylate (5c)

Orange crystals; yield: 93%; mp 175 °C (decompose); IR (KBr) νmax (cm⁻¹): 3243 (broad, OH enol form and NH), 1748, 1652 (C⚌O), 1615, 1591 (C⚌C). ¹H NMR (400 MHz, DMSO-d6, ppm): 11.00 (s, 1H, NCH⚌), 8.75 (s, 1H, NH), 7.50–6.33 (m, 15H, Ar, CH⚌CH), 5.40 (s, 1H, N—CH—N), 3.67 (s, 3H, CH₃). ¹³C NMR (100 MHz, DMSO-d6, ppm): 163.45, 154.94, 150.53, 146.94, 137.29, 134.53, 134.17, 129.58, 128.75, 128.28, 125.33, 124.91, 124.42, 122.74, 122.28, 121.69, 119.67, 119.02, 117.19, 115.65, 111.50, 111.45 (N—C—N), 110.72 (spiro carbon), 53.92 (OCH₃). MS (m/z): 423 (M⁺) (4), 412 (12), 368 (11), 313 (12), 255 (10), 236 (22), 222 (60), 194 (100), 167 (23), 129 (99), 93 (35), 77 (76), 51 (35).

2.2.10

2.2.10 Methyl 5′-bromo-2′-oxo-1-phenyl-3,10b-dihydro-1H-spiro[imidazo[2,1-a]isoquinoline-2,3′-indoline]-3-carboxylate (5d)

Orange crystals; yield: 90%; mp 250 °C (decompose); IR (KBr) νmax (cm⁻¹): 3258 (NH), 1740, 1650 (C⚌O), 1609, 1590 (C⚌C). ¹H NMR (400 MHz, DMSO-d6, ppm): 11.15 (s, 1H, NCH⚌), 8.84 (s, 1H, NH), 7.52–6.34 (m, 14H, Ar, CH⚌CH), 5.55 (s, 1H, N—CH—N), 3.68 (s, 3H, CH₃). ¹³C NMR (100 MHz, DMSO-d6, ppm): 165.09, 154.07, 150.19, 146.03, 140.78, 136.25, 134.41, 131.38, 129.66, 128.29, 127.56, 125.28, 125.03, 124.88, 119.88, 119.26, 117.30, 117.13, 113.54, 112.87, 112.77 (N—C—N), 110.33 (spiro carbon), 53.71 (OCH₃). MS (m/z): 501 (M⁺) (2), 431 (5), 368 (7), 302 (57), 274 (100), 245 (6), 192 (20), 166 (27), 129 (9), 116 (13), 90 (12), 77 (75), 51 (36). Anal. calcd. for C₂₆H₂₀BrN₃O₃: C, 62.16; H, 4.01; N, 8.36%. Found: C, 61.85; H, 3.78; N, 8.01%.

3 Results and discussions

In the present work, we report a new synthesis of compounds 3a–f and 5a–d, which are prepared by the reaction of isatin-3-imines 2a, b with pyridinium and isoquinolinium ylides under mild conditions at ambient temperature in excellent yields. In order to optimize the reaction conditions, we used some polar and non polar solvents in the reaction of pyridinium or isoquinolinium bromides with 3-(phenylimino)indoline-2-one 2a in the presence of triethylamine or potassium carbonate as a base. The results are shown in Table 1. It is noteworthy to mention that the polar solvents such as acetonitrile and dichloromethane, which afford better yields than toluene as a nonpolar solvent, and acetonitrile and triethylamine are the most effective solvent and base respectively.

Table 1 Solvent and base effects on the reaction of pyridinium or isoquinolinium bromides with 3-(phenylimino)indoline-2-one 2a.

Compound, No.	Solvent	Base	Time (min)	Yield (%)
3a	Acetonitrile	Et₃N	60	95
3a	Acetonitrile	K₂CO₃	67	90
3a	Toluene	Et₃N	80	82
3a	Toluene	K₂CO₃	90	80
3a	CH₂Cl₂	Et₃N	65	90
3a	CH₂Cl₂	K₂CO₃	75	88
5a	Acetonitrile	Et₃N	60	93
5a	Acetonitrile	K₂CO₃	65	90
5a	Toluene	Et₃N	77	85
5a	Toluene	K₂CO₃	85	82
5a	CH₂Cl₂	Et₃N	70	90
5a	CH₂Cl₂	K₂CO₃	75	87

Isatin-3-imines 2a, b which are prepared by reacting isatins and aniline, are interesting electrophilic reagents for synthesis of spiro compounds. Pyridinium ylides I which were prepared in situ from the pyridinium salts 1a–c, were stirred with isatin-3-imines 2a and b in CH₃CN at room temperature to give spiro compounds 3a–f by the 1,3-dipolar cyclization reaction in excellent yields (Scheme 1).

1,3-Dipolar cyclization reaction of pyridinium ylides I with isatin-3-imines (2a, b).

The pyridinium ylides were known as one of special ammonium ylides, which can react with alkenes substituted with electron-withdrawing groups to give the corresponding cyclopropanes and the pyridine group has been utilized as a leaving group in intermolecular reactions (Kojima et al., 2006). However the 1,3-dipolar cycloaddition reactions of pyridinium ylides with various perfluoroalkenes, perfluoroazaolefins and trifluoroacetonitrile to synthesize monofluoro or trifluoromethyl substituted heterocycles, such as pyrazolo[1,2-a]pyridines and indolizines have been reported (Fang et al., 2004). According to Scheme 1, we find that the reaction of pyridinium ylides I with isatin-3-imines 2a, b that bear imine group as electron-withdrawing released only spiro compounds (3a–f). Under the same conditions when the isoquinolinium ylides which were prepared in situ from the reaction of isoquinolinium bromides (4a, c) were treated with isatin-3-imines (2a, b), spiro derivatives 5a–d via 1,3-dipolar cycloaddition reactions were obtained in excellent yields (Scheme 2).

Reaction of isoquinolinium bromides (4a, c) with isatin-3-imines (2a, b).

To confirm the structure of products 3 and 5, DFT calculations at the M06-2X/6-31G∗ (Zhao and Truhlar, 2008) level of theory are performed to optimize the geometries for the possible transition states (TS1 and TS2) and products 4 and 3a which were released from the reaction of 2-oxo-2-phenyl-1-(pyridin-1-ium-1-yl)ethan-1-ide (Ia) with 3-(phenylimino)indolin-2-one (2a). The relative energies of these species are depicted in Fig. 1.

Relative energies of the stationary points arising from the reaction of I with 2a computed at the M06-2X/6-31+G(d).

As it is seen, the most stable product is 3a with the relative energy of −102.5 kJ mol⁻¹. The calculations reveal that 3a is formed via a concerted mechanism (TS1 in Fig. 1) with the very low barrier height of 5.2 kJ mol⁻¹. Therefore, it is a kinetically feasible reaction pathway. It is found that a barrier height of 187.8 kJ mol⁻¹ (TS2 in Fig. 1) should be surmounted for the formation of 4. The relative energy of the product 3a is −69.9 kJ mol⁻¹. As a result, the latter product is not important from both kinetics and thermodynamics stand points.

The structure of compounds 3a–f and 5a–d was determined on the basis of their elemental analyses, mass spectrum, ¹H and ¹³C NMR and IR spectroscopic data. Only one product was obtained in each case.

4 Conclusions

In summary, we have investigated the [3 + 2] cycloaddition reaction between heteroaromatic N-ylides, such as pyridinium or isoquinolinium ylides with 3-(phenylimino)indoline-2-one and 5-bromo-3-(phenylimino)indoline-2-one which lead to the formation of corresponding spiro[imidazo[1,2-a]pyridine-2,3′-indoline]-2′-one and spiro[imidazo[1,2-a]isoquinoline-2,3′-indolin]-2′-one derivatives respectively. Prominent among the advantages of these reactions are high conversions, short reaction times and cleaner reaction profiles. Further expansion of the synthesis of spiro compounds with potential biological activity is in progress in our laboratory.

Acknowledgment

The authors express appreciation to the Shahid Bahonar University of Kerman Faculty Research Committee for its support of this investigation.

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Ducray R., Simpson I., Jung F.H., Nissink J.W.M., Kenny P.W., Fitzek M., Walker G.E., Ward L.T., Hudson K., . Bioorg. Med. Chem. Lett.. 2011;21:4698.
Fang X., Wu Y.M., Deng J., Wang S.W., . Tetrahedron. 2004;60:5487.
Feldman K.S., Karatjas A.G., . Org. Lett.. 2006;8:4137.
Flores Y.K.M., Aldrete M.E.C., Zamora H.S., Basurto J.C., Camargo M.E.M., . Med. Chem. Res.. 2012;21:775.
Gueiffier A., Lhassani M., Elhakmaoui A., Snoeck R., Andrei G., Chavignon O., Teulade J.C., Kerbal A., Essassi E.M., Debouzy J.C., Witvrouw M., Blache Y., Balzarini J., Clercq E.D., Chapat J.P., . J. Med. Chem.. 1996;39:2856.
Gueiffier A., Mavel S., Lhassani M., Elhakmaoui A., Snoeck R., Andrei G., Chavignon O., Teulade J.C., Witvrouw M., Balzarini J., Clercq E.D., Chapat J.P., . J. Med. Chem.. 1998;41:5108.
Han Y., Hou H., Fu Q., Yan C.G., . Tetrahedron. 2011;67:2313.
Hayakawa M., Kaizawa H., Kawaguchi K., Ishikawa N., Koizumi T., Ohishi T., Yamano M., Okada M., Ohta M., Tsukamoto S., Raynaud F.I., Waterfield M.D., Parker P., Workman P., . Bioorg. Med. Chem.. 2007;15:403.
Hazra A., Mondal S., Maity A., Naskar S., Saha P., Paira R., Sahu K.B., Paira P., Ghosh S., Sinha C., Samanta A., Banerjee S., Mondal N.B., . Eur. J. Med. Chem.. 2011;46:2132.
Hyeong-Beom, P., Hyun, J.N., Hee, H.J., Hoon, C.J., Hoon, C.J., Jung-Hyuck, C., Ho, Y.K., Chang-Hyun, O., 2007. 340, 530
Ismail M.A., Brun R., Wenzler T., Tanious F.A., Wilson W.D., Boykin D.W., . J. Med. Chem.. 2004;47:3658.
Jolanta O., Krzysztof K., Ewa T., . Pharmacol. Rep.. 2006;58:207-214.
Katsura K., Nishino S., Inoue Y., Tomoi M., Takasugi H., . Chem. Pharm. Bull.. 1992;40:371.
Kojima S., Fujitomo K., Shinohara Y., Shimizu M., Ohkata K., . Tetrahedron Lett.. 2000;41:9847.
Kojima S., Suzuki M., Watanabe A., Ohkata K., . Tetrahedron Lett.. 2006;47:9061.
Krzysztof K., Jolanta O., Malgorzata D., . Eur. J. Med. Chem.. 2008;43:53.
Martínez M.L., Zamora H.S., Aldrete M.E.C., Ferrara J.G.T., Basurto J.C., Ochoa C.M., . Med. Chem. Res.. 2010;21:1.
Masakazu, F., Kenji, H., Jiro, K., 2001. Int. Pat. WO/2001/066546.
Miller K.A., Williams R.M., . Chem. Soc. Rev.. 2009;38:3160.
Moraski G.C., Markley L.D., Chang M., Cho S., Franzblau S.G., Hwang C.H., Boshoff H., Miller M.J., . Bioorg. Med. Chem.. 2012;20:2214.
Ollis D.W., Stanforth S.P., . Tetrahedron. 1985;41:2239.
Padwa A., . 1,3-Dipolar Cycloaddition Chemistry. New York: Wiley-Interscience; 1984.
Pozharskii A.F., Soldatenkov A.T., Katritzky A.R., . Heterocycles in Life and Society. New York: Wiley; 1997.
Prakash C.R., Raja S., Saravanan G., . Chinese Chem. Lett.. 2012;23:541.
Reisman S.E., Ready J.M., Weiss M.M., Hasuoka A., Hirata M., Tamaki K., Ovaska T.V., Smith C.J., Wood J.L., . J. Am. Chem. Soc.. 2008;130:2087.
Sannigrahi M., . Tetrahedron. 1999;55:9007.
Seifi M., Sheibani H., . Arkivoc. 2013;iv:191.
Seifi M., Sheibani H., . Lett. Org. Chem.. 2013;10:478.
Seifi M., Alinaghizadeh F., Sheibani H., . Scientia Iranica. 2013;20(6(C2)):1.
Singhaus R.R., Bernotas R.C., Steffan R., Matelan E., Quinet E., Nambi P., Feingold I., Huselton C., Wilhelmsson A., Goos-Nilsson A., Wrobel J., . Bioorg. Med. Chem. Lett.. 2010;20:521.
Sridhar S.K., Saravanan M., Ramesh A., . Eur. J. Med. Chem.. 2001;36:615.
Srivastav N., Mittal A., Kumar A., . J. Chem. Soc. Chem. Commun. 1992:493.
Tewari R.S., Dubey A.K., . J. Chem. Eng. Data. 1980;25:91.
Thadhaney B., Sain D., Pernawat G., Talesara G.L., . Indian J. Chem.. 2010;49B:368.
Wen-Liang W., Tian-Jiao Z., Hong-Wen T., Zhen-Yu L., Yu-Chun F., Qian-Qun G., Wei Ming Z., . Chem. Biodivers. 2007;4:2913.
Wisniewska J.M., Rodl C.B., Kahnt A.S., Buscato E.L., Ulrich S., Tanrikulu Y., Achenbach J., Rorsch F., Grosch S., Schneider G., Cinatl J.J., Proschak E., Steinhilber D., Hofmann B., . Biochem. Pharmacol.. 2012;83:228.
Yan C.G., Cai X.M., Wang Q.F., Wang T.Y., Zheng M., . Org. Biomol. Chem.. 2007;5:945.
Young-Won C., Angela S., Bao-Ning S., Quiwen M., Hee-Byung C., Soedarsono R., Leonardus K., Agus R., Norman F., Steven S., Douglas K., . J. Nat. Prod.. 2008;71:390.
Zhao Y., Truhlar D.G., . Theory Chem. Acc.. 2008;120:215.

Introduction

Experimental section

General procedure for the preparation of compounds 3a–f and 5a–d in acetonitrile
Spectral data for selected compounds

Results and discussions

Conclusions

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[1] Al-Tel T.H., Al-Qawasmeh R.A., Zaarour R., . Eur. J. Med. Chem.. 2011;46:1874.

[2] Chande M.S., Verma R.S., Barve P.A., Khanwelkar R.R., Vaidya R.B., Ajaikumar K.B., . Eur. J. Med. Chem.. 2005;40:1143.

[3] Domling A., Ugi I., . Angew. Chem. Int. Ed.. 2000;39:3168.

[4] Ducray R., Simpson I., Jung F.H., Nissink J.W.M., Kenny P.W., Fitzek M., Walker G.E., Ward L.T., Hudson K., . Bioorg. Med. Chem. Lett.. 2011;21:4698.

[5] Fang X., Wu Y.M., Deng J., Wang S.W., . Tetrahedron. 2004;60:5487.

[6] Feldman K.S., Karatjas A.G., . Org. Lett.. 2006;8:4137.

[7] Flores Y.K.M., Aldrete M.E.C., Zamora H.S., Basurto J.C., Camargo M.E.M., . Med. Chem. Res.. 2012;21:775.

[8] Gueiffier A., Lhassani M., Elhakmaoui A., Snoeck R., Andrei G., Chavignon O., Teulade J.C., Kerbal A., Essassi E.M., Debouzy J.C., Witvrouw M., Blache Y., Balzarini J., Clercq E.D., Chapat J.P., . J. Med. Chem.. 1996;39:2856.

[9] Gueiffier A., Mavel S., Lhassani M., Elhakmaoui A., Snoeck R., Andrei G., Chavignon O., Teulade J.C., Witvrouw M., Balzarini J., Clercq E.D., Chapat J.P., . J. Med. Chem.. 1998;41:5108.

[10] Han Y., Hou H., Fu Q., Yan C.G., . Tetrahedron. 2011;67:2313.

[11] Hayakawa M., Kaizawa H., Kawaguchi K., Ishikawa N., Koizumi T., Ohishi T., Yamano M., Okada M., Ohta M., Tsukamoto S., Raynaud F.I., Waterfield M.D., Parker P., Workman P., . Bioorg. Med. Chem.. 2007;15:403.

[12] Hazra A., Mondal S., Maity A., Naskar S., Saha P., Paira R., Sahu K.B., Paira P., Ghosh S., Sinha C., Samanta A., Banerjee S., Mondal N.B., . Eur. J. Med. Chem.. 2011;46:2132.

[13] Hyeong-Beom, P., Hyun, J.N., Hee, H.J., Hoon, C.J., Hoon, C.J., Jung-Hyuck, C., Ho, Y.K., Chang-Hyun, O., 2007. 340, 530

[14] Ismail M.A., Brun R., Wenzler T., Tanious F.A., Wilson W.D., Boykin D.W., . J. Med. Chem.. 2004;47:3658.

[15] Jolanta O., Krzysztof K., Ewa T., . Pharmacol. Rep.. 2006;58:207-214.

[16] Katsura K., Nishino S., Inoue Y., Tomoi M., Takasugi H., . Chem. Pharm. Bull.. 1992;40:371.

[17] Kojima S., Fujitomo K., Shinohara Y., Shimizu M., Ohkata K., . Tetrahedron Lett.. 2000;41:9847.

[18] Kojima S., Suzuki M., Watanabe A., Ohkata K., . Tetrahedron Lett.. 2006;47:9061.

[19] Krzysztof K., Jolanta O., Malgorzata D., . Eur. J. Med. Chem.. 2008;43:53.

[20] Martínez M.L., Zamora H.S., Aldrete M.E.C., Ferrara J.G.T., Basurto J.C., Ochoa C.M., . Med. Chem. Res.. 2010;21:1.

[21] Masakazu, F., Kenji, H., Jiro, K., 2001. Int. Pat. WO/2001/066546.

[22] Miller K.A., Williams R.M., . Chem. Soc. Rev.. 2009;38:3160.

[23] Moraski G.C., Markley L.D., Chang M., Cho S., Franzblau S.G., Hwang C.H., Boshoff H., Miller M.J., . Bioorg. Med. Chem.. 2012;20:2214.

[24] Ollis D.W., Stanforth S.P., . Tetrahedron. 1985;41:2239.

[25] Padwa A., . 1,3-Dipolar Cycloaddition Chemistry. New York: Wiley-Interscience; 1984.

[26] Pozharskii A.F., Soldatenkov A.T., Katritzky A.R., . Heterocycles in Life and Society. New York: Wiley; 1997.

[27] Prakash C.R., Raja S., Saravanan G., . Chinese Chem. Lett.. 2012;23:541.

[28] Reisman S.E., Ready J.M., Weiss M.M., Hasuoka A., Hirata M., Tamaki K., Ovaska T.V., Smith C.J., Wood J.L., . J. Am. Chem. Soc.. 2008;130:2087.

[29] Sannigrahi M., . Tetrahedron. 1999;55:9007.

[30] Seifi M., Sheibani H., . Arkivoc. 2013;iv:191.

[31] Seifi M., Sheibani H., . Lett. Org. Chem.. 2013;10:478.

[32] Seifi M., Alinaghizadeh F., Sheibani H., . Scientia Iranica. 2013;20(6(C2)):1.

[33] Singhaus R.R., Bernotas R.C., Steffan R., Matelan E., Quinet E., Nambi P., Feingold I., Huselton C., Wilhelmsson A., Goos-Nilsson A., Wrobel J., . Bioorg. Med. Chem. Lett.. 2010;20:521.

[34] Sridhar S.K., Saravanan M., Ramesh A., . Eur. J. Med. Chem.. 2001;36:615.

[35] Srivastav N., Mittal A., Kumar A., . J. Chem. Soc. Chem. Commun. 1992:493.

[36] Tewari R.S., Dubey A.K., . J. Chem. Eng. Data. 1980;25:91.

[37] Thadhaney B., Sain D., Pernawat G., Talesara G.L., . Indian J. Chem.. 2010;49B:368.

[38] Wen-Liang W., Tian-Jiao Z., Hong-Wen T., Zhen-Yu L., Yu-Chun F., Qian-Qun G., Wei Ming Z., . Chem. Biodivers. 2007;4:2913.

[39] Wisniewska J.M., Rodl C.B., Kahnt A.S., Buscato E.L., Ulrich S., Tanrikulu Y., Achenbach J., Rorsch F., Grosch S., Schneider G., Cinatl J.J., Proschak E., Steinhilber D., Hofmann B., . Biochem. Pharmacol.. 2012;83:228.

[40] Yan C.G., Cai X.M., Wang Q.F., Wang T.Y., Zheng M., . Org. Biomol. Chem.. 2007;5:945.

[41] Young-Won C., Angela S., Bao-Ning S., Quiwen M., Hee-Byung C., Soedarsono R., Leonardus K., Agus R., Norman F., Steven S., Douglas K., . J. Nat. Prod.. 2008;71:390.

[42] Zhao Y., Truhlar D.G., . Theory Chem. Acc.. 2008;120:215.

Polar [3 + 2] cycloaddition of isatin-3-imines with electrophilically activated heteroaromatic N-ylides: Synthesis of spirocyclic imidazo[1,2-a]pyridine and isoquinoline derivatives

Abstract

Abstract

Keywords

Pyridinium and isoquinolinium ylides

Isatin-3-imines

Spiro[imidazo[1,2-a]pyridine-2,3′-indoline]-2′-ones

Spiro[imidazo[1,2-a]isoquinoline-2,3′-indolin]-2′-ones

Polar [3 + 2] cycloaddition

1 Introduction

2 Experimental section

2.1 General procedure for the preparation of compounds 3a–f and 5a–d in acetonitrile

2.2 Spectral data for selected compounds

2.2.1 3-Benzoyl-1-phenyl-3,8a-dihydro-1H-spiro[imidazo[1,2-a]pyridine-2,3′-indolin]-2′-one (3a)

2.2.2 3-Benzoyl-5′-bromo-1-phenyl-3,8a-dihydro-1H-spiro[imidazo[1,2-a]pyridine-2,3′-indolin]-2′-one (3b)

2.2.3 3-(4-Bromobenzoyl)-1-phenyl-3,8a-dihydro-1H-spiro[imidazo[1,2-a]pyridine-2,3′-indolin]-2′-one (3c)

2.2.4 5′-Bromo-3-(4-bromobenzoyl)-1-phenyl-3,8a-dihydro-1H-spiro[imidazo[1,2-a]pyridine-2,3′-indolin]-2′-one (3d)

2.2.5 Methyl 2′-oxo-1-phenyl-3,8a-dihydro-1H-spiro[imidazo[1,2-a]pyridine-2,3′-indoline]-3-carboxylate (3e)

2.2.6 Methyl 5′-bromo-2′-oxo-1-phenyl-3,8a-dihydro-1H-spiro[imidazo[1,2-a]pyridine-2,3′-indoline]-3-carboxylate (3f)

2.2.7 3-Benzoyl-1-phenyl-3,10b-dihydro-1H-spiro[imidazo[2,1-a]isoquinoline-2,3′-indolin]-2′-one (5a)

2.2.8 3-Benzoyl-5′-bromo-1-phenyl-3,10b-dihydro-1H-spiro[imidazo[2,1-a]isoquinoline-2,3′-indolin]-2′-one (5b)

2.2.9 Methyl 2′-oxo-1-phenyl-3,10b-dihydro-1H-spiro[imidazo[2,1-a]isoquinoline-2,3′-indoline]-3-carboxylate (5c)

2.2.10 Methyl 5′-bromo-2′-oxo-1-phenyl-3,10b-dihydro-1H-spiro[imidazo[2,1-a]isoquinoline-2,3′-indoline]-3-carboxylate (5d)

3 Results and discussions

4 Conclusions

Acknowledgment

References

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