Subscribe to RSS
DOI: 10.1055/s-0036-1589496
Synthesis of Chromenoimidazoles, Annulated with an Azaindole Moiety, through a Base-Promoted Domino Reaction of Cyanomethyl Quaternary Salts
Publication History
Received: 15 February 2017
Accepted after revision: 20 February 2017
Publication Date:
04 April 2017 (online)
Abstract
The reactivity of N-cyanomethyl quaternary salts of 4-, 5- and 7-azaindoles towards salicylic aldehydes has been studied. The interaction of azaindolium salts with salicylic aldehydes proceeds as a base-promoted domino reaction, giving the corresponding chromenoimidazopyrrolopyridines. In the case of the 7-(cyanomethyl)-7-azaindolium salt, the reaction was found to be more sensitive, but the use of the 1-methyl-substituted salt allowed the synthesis of the desired compounds, incorporating the heterocyclic core of isogranulatimide C, a marine natural product.
#
Key words
azaindoles - domino reaction - isogranulatimides - iminium salts - chromenoimidazoles - microwaveImidazoles annulated with a pyrrolopyridine (azaindole) moiety are known for their antiviral[1] and antitumor[2] activities. An imidazopyrrolopyridine fragment appears in the isogranulatimides (Figure [1]), marine natural products isolated from the Brazilian ascidian Didemnum granulatum, which show high inhibitory activity against the G2 DNA damage checkpoint, the kinases Chk1 (IC50 = 0.1 μM) and GSK-3 beta[3] and various other kinases.[4] Their analogues also exhibit high antiproliferative[5] and Chk1 inhibition[6] activities.
Imidazoles annulated with chromenes A (Figure [1]) have recently been characterized as cytotoxic agents against HCT116 cancer cells due to their ability to induce cell cycle arrest and apoptosis without significant effects on normal cells.[7]
Synthetic approaches toward the imidazopyrrolopyridine core of isogranulatimides are usually based on the construction of the pyridine ring.[8] The current project involves the preparation of imidazopyrrolopyridines fused with a chromene moiety through a base-promoted domino reaction of isomeric N-(cyanomethyl)azaindolium salts with o-hydroxybenzaldehydes, creating the imidazole and pyran cycles in an effective manner.[9]
Recently, preliminary studies of 6-(cyanomethyl)pyrrolo[2,3-c]pyridinium salt reactivity showed the possibility of transforming such salts into chromenoimidazopyrrolopyridines, incorporating the heterocyclic core of isogranulatimide A (Scheme [1]).[10] The potential of this reaction in the construction of different isomeric chromenoimidazopyrrolopyridines, among other things comprising the isogranulatimide C heterocyclic core, is the subject of this paper.
First, N-(cyanomethyl)azaindolium salts 1–3 were prepared by alkylation of the corresponding heterocycles with chloroacetonitrile or bromoacetonitrile in acetonitrile (Scheme [2]). The yields for compounds 2 and 3 were 80% and 83%, respectively; the 1H-7-azaindole, which is the least nucleophilic in the azaindole series, was alkylated to give 1a in 79% yield. In the case of 1-methyl-1H-7-azaindole, the steric hindrance of the methyl group necessitated the use of the more reactive bromoacetonitrile, to provide quaternary salt 1b in 61% yield.
The reaction of 7-(cyanomethyl)-7-azaindolium salt 1a with salicylic aldehydes under the conditions earlier optimized for the 6-azaindolium salt did not result in the formation of the target polycyclic product of the domino process, but gave coumaryl-substituted 7H-7-azaindoles 4a–c (Scheme [3]). The structure of compound 4a was determined by 1H, 13C and 15N NMR spectroscopy using 2D COSY, TOCSY, NOESY, HSQC, edited HSQC, HMBC, long-range HMBC, and 15N HMBC experiments (for details, see the Supporting Information). A possible reason for this reaction pathway is initial deprotonation of N-1 and formation of the anhydrobase of the azaindole. In the absence of a positive charge on N-7 of the azaindole, the reaction loses its driving force, the intermediate B is hydrolyzed, and the final cyclization does not occur (Scheme [3]). In an effort to overcome the problem, 7-(cyanomethyl)-1-methyl-7-azaindolium bromide (1b) was tested in the analogous reaction. Despite the absence of N-H in salt 1b and the impossibility of forming anhydrobases, the process still followed the undesired pathway, giving compounds 5a–d. It was hypothesized that performing the reaction under water-free conditions might avoid the hydrolysis of the imine intermediate. Therefore, the reaction was carried out in MeOH or DMF under argon atmosphere in the presence of different desiccants, including molecular sieves, and anhydrous magnesium and copper sulfate, and employing anhydrous sodium carbonate and alternative bases, but it still resulted in the formation of hydrolysis product 5a (Table [1], entries 1–6). Presumably, the water formed during the condensation is enough for the hydrolysis to proceed. Fortunately, performing the reaction under microwave (MW) irradiation in absolute ethanol, with molecular sieves and anhydrous potassium carbonate, eventually led to the formation of the desired products 6a–c in moderate yields (Scheme [3]).
The use of DBU (Table [1], entries 12–15) or ammonium acetate (Table [1], entry 16) as base, or isopropyl alcohol as solvent (Table [1], entry 10), was less effective than potassium carbonate in ethanol (Table [1], entry 7). The modest yields may be associated with the instability of the products 6 under the reaction conditions and the reduction of the reaction times, achieved under microwave conditions, explains the success of the microwave approach.
The optimized conditions were utilized to examine the scope of the reaction of 5-azaindolium salt 2 (Scheme [4]). Thus, annulated pyrrolopyridines 7a–e were synthesized in 70–87% yield. The preparation of compounds 7 was not as sensitive to the presence of water and the reaction time; for instance, compound 7a was produced in 64% yield after reflux for 8 hours with ammonium acetate in a water–methanol mixture.
The optimized conditions were also employed to examine the reactivity of 4-(cyanomethyl)-4-azaindolium salt 3 in the domino process. Thus, it was shown that the reaction proceeded analogously, giving isomeric chromenoimidazopyrrolopyridines 8a–d (Scheme [5]).
The proposed reaction mechanism is as follows: (a) Knoevenagel condensation of the salicylic aldehyde with the quaternary pyrrolopyridine salt followed by (b) nucleophilic cyclization of the phenolate anion, another (c) nucleophilic cyclization, and (d) aromatization of the imidazole to yield the target product (Scheme [6]).
In conclusion, we have studied the domino reaction of 4-, 5- and 7-azaindolium salts with substituted salicylic aldehydes. The target chromenoimidazopyrrolopyridines were formed in all cases, providing a reliable route towards analogues of the isogranulatimide marine natural products family.
Starting azaindoles and aldehydes were purchased from commercial sources (7-azaindole CAS 271-63-6, 5-azaindole CAS 271-34-1, 4-azaindole CAS 272-49-1, chloroacetonitrile CAS 107-14-2, bromoacetonitrile CAS 590-17-0, salicylaldehyde CAS 90-02-8, 5-bromosalicylaldehyde CAS 1761-61-1, 2-hydroxy-5-methoxybenzaldehyde CAS 672-13-9, 2-hydroxy-1-naphthaldehyde CAS 708-06-5, 3-ethoxysalicylaldehyde CAS 492-88-6, 3,5-dichlorosalicylaldehyde CAS 90-60-8) and were used without any additional purification. 1-Methyl-7-azaindole was prepared according to a literature procedure.[11] Solvents were distilled and dried according to standard procedures. 1H and 13C NMR spectra were acquired on 400 or 600 MHz spectrometers and referenced to the residual signals of the solvent. The solvent for NMR samples was DMSO-d 6 or CDCl3 with a few drops of TFA. Chemical shifts are reported in parts per million (δ/ppm) and coupling constants in hertz (J/Hz). The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; br s, broad singlet. IR spectra were made on an Infralum FT-801; wavelengths are reported in reciprocal centimeters (λmax/cm–1). Mass spectra were recorded with a Shimadzu LCMS-8040 triple quadrupole liquid chromatograph–mass spectrometer and MALDI spectra with a Bruker Autoflex Speed instrument in a positive ion reflection mode using solid-state UV laser and EI techniques. Microwave-assisted reactions were carried out in a Monowave 300 reactor (Anton Paar GmbH); the reaction temperature was monitored by an IR sensor. Standard 10-mL G10 reaction vials, sealed with silicone septa, were used for the microwave irradiation experiments. Reaction progress was monitored by TLC and the spots were visualized under UV light (254 or 365 nm). Column chromatography was performed using silica gel (230–400 mesh) and MeOH–CH2Cl2 mixtures in different proportions as the mobile phase. Melting points were determined on an SMP-10 apparatus and are uncorrected.
#
7-(Cyanomethyl)-1H-pyrrolo[2,3-b]pyridin-7-ium Chloride (1a)
A solution of 7-azaindole (2 g, 17 mmol) with excess chloroacetonitrile (1.61 mL, 25.5 mmol, 1.5 equiv) in MeCN (5 mL) in a closed vial was placed into a microwave reactor, where it was heated at 140 °C for 30 min. The precipitate was collected by filtration, washed with MeCN (3 × 5 mL) and dried under air to give a gray solid; yield: 2.587 g (79%); mp 203 °С.
IR (KBr): 3123–2710, 1617, 1469, 1346, 1107, 886, 810, 738 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 6.34 (s, 2 Н, СН2), 7.02 (d, J = 3.4 Hz, 1 Н), 7.71–7.73 (m, 1 H), 8.03 (d, J = 3.4 Hz, 1 H), 8.85 (d, J = 7.7 Hz, 1 H), 8.87 (d, J = 6.2 Hz, 1 H).
13С NMR (100 MHz, DМSО-d 6): δ = 43.3, 104.1, 113.9, 116.5, 127.1, 130.5, 136.6, 138.9, 139.0.
ESI-MS: m/z = 158 [M – Cl]+.
Anal. Calcd for C9H8ClN3 (193.63): C, 55.83; H, 4.16; N, 21.70. Found: C, 55.90; H, 4.11; N, 21.78.
#
7-(Cyanomethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-7-ium Bromide (1b)
To a solution of 1-methyl-7-azaindole (1.194 g, 9 mmol) in MeCN (4 mL) was added excess bromoacetonitrile (0.940 mL, 13.5 mmol, 1.5 equiv). The reaction mixture was stirred under reflux for 24 h. The precipitate was collected by filtration, washed with MeCN (3 ×) and dried under air to give a gray solid; yield: 1.190 g (52%); mp 194 °С.
IR (KBr): 3118, 3062, 2916, 2260, 1617, 1589, 1505, 1400, 1353, 1244, 1115, 806, 722, 592 cm–1.
1Н NMR (400 MHz, DМSО-d 6): δ = 4.35 (s, 3 H), 6.50 (s, 2 H), 7.04 (d, J = 3.3 Hz, 1 H), 7.73 (t, J = 7.3 Hz, 1 H), 7.92 (d, J = 3.3 Hz, 1 H), 8.80 (d, J = 6.5 Hz, 1 H), 8.85 (d, J = 7.8 Hz, 1 H).
13С NMR (100 MHz, DМSО-d 6): δ = 37.1, 43.7, 103.2, 114.9, 116.5, 128.9, 136.9, 137.9, 138.7, 139.6.
ESI-MS: m/z = 172 [M – Br]+.
Anal. Calcd for C10H10BrN3 (252.12): C, 47.64; H, 4.00; N, 16.67. Found: C, 47.87; H, 3.93; N, 16.60.
#
Compounds 4 and 5; General Procedure
To a solution of salt 1a or 1b (0.991 mmol) and the corresponding aldehyde (0.991 mmol) in a MeOH–H2O mixture (1:1, 4 mL) was added NH4OAc (0.991 mmol) at reflux. The reaction mixture was stirred under reflux for 3 h. Upon reaction completion, the solvent was evaporated under reduced pressure and the product was isolated by silica gel column chromatography (MeOH–CH2Cl2, 1:100 to 1:10).
#
3-(7H-Pyrrolo[2,3-b]pyridin-7-yl)-2H-chromen-2-one (4a)
Yellow solid; yield: 0.07 g (27%); mp 142 °С (dec).
IR (KBr): 3098, 1726, 1608, 1272, 1048, 761, 737 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 6.68 (d, J = 2.7 Hz, 1 Н, H-3′), 7.12 (t, J = 6.9 Hz, 1 Н, H-5′), 7.51 (t, J = 7.2 Hz, 1 H, H-6), 7.62 (d, J = 8.3 Hz, 1 H, H-8), 7.65 (d, J = 2.7 Hz, 1 H, H-2′), 7.80 (t, J = 7.6 Hz, 1 H, H-7), 7.88 (dd, J = 7.6, 1.4 Hz, 1 H, H-5), 8.21 (d, J = 6.2 Hz, 1 H, H-6′), 8.36 (d, J = 7.6 Hz, 1 H, H-4′), 8.71 (s, 1 Н, H-4).
13С NMR (100 MHz, DМSО-d 6): δ = 101.5 (C-3′), 108.8 (C-5′), 116.6 (C-8), 118.2 (C-8a), 125.4 (C-6), 126.8 (C-3), 129.6 (C-5), 130.4 (C-3a′), 131.4 (C-6′), 132.5 (C-4′), 133.5 (C-7), 141.8 (C-4), 145.0 (C-2′), 148.0 (C-7a′), 153.2 (C-4a), 157.0 (C-2).
EI-MS: m/z (%) = 263 (20), 262 (100) [M]+, 261 (24), 235 (12), 234 (67), 206 (24), 205 (42), 145 (96), 131 (11), 118 (18), 103 (24), 102 (11), 90 (14), 89 (43), 76 (12), 63 (17).
Anal. Calcd for C16H10N2O2 (262.27): C, 73.27; H, 3.84; N, 10.68. Found: C, 73.44; H, 3.76; N, 10.58.
#
6-Bromo-3-(7H-pyrrolo[2,3-b]pyridin-7-yl)-2H-chromen-2-one (4b)
Yellow solid; yield: 0.119 g (35%); mp 240 °С (dec).
IR (KBr): 3071, 2921–2853, 1726, 1539, 1341, 1268, 1147, 1048, 928, 721 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 6.68 (d, J = 2.8 Hz, 1 Н), 7.09–7.13 (m, 1 Н), 7.61 (d, J = 8.8 Hz, 1 Н), 7.64 (d, J = 2.8 Hz, 1 H), 7.95 (dd, J = 8.8, 2.2 Hz, 1 H), 8.13 (d, J = 2.2 Hz, 1 H), 8.16 (d, J = 6.1 Hz, 1 H), 8.36 (d, J = 7.4 Hz, 1 H), 8.63 (s, 1 Н).
13С NMR (100 MHz, CDCl3 + TFA): δ = 104.7, 116.4, 118.3, 118.9, 119.2, 124.9, 128.2, 130.8, 132.1, 135.8, 138.4, 139.4, 139.6, 143.5, 152.7, 156.4.
EI-MS: m/z (%) = 340 (100) [M]+, 339 (19), 312 (79), 223 (59), 205 (29), 204 (13), 177 (10), 167 (23), 130 (26), 118 (27), 117 (15), 91 (10), 89 (19), 88 (21), 76 (10), 75 (11), 63 (12), 62 (11).
Anal. Calcd for C16H9BrN2O2 (341.16): C, 56.33; H, 2.66; N, 8.21. Found: C, 56.44; H, 2.60; N, 8.15.
#
6-Methoxy-3-(7H-pyrrolo[2,3-b]pyridin-7-yl)-2H-chromen-2-one (4c)
Yellow solid; yield: 0.120 g (42%); mp 150 °С (dec).
IR (KBr): 3165, 3104–3046, 2994–2838, 1720, 1580, 1488, 1344, 1269, 1149, 1050, 729 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 3.85 (s, 3 Н, OCH3), 6.68 (d, J = 2.8 Hz, 1 Н), 7.10–7.12 (m, 1 Н), 7.39 (dd, J = 9.0, 2.8 Hz, 1 H), 7.42 (d, J = 2.8 Hz, 1 H), 7.57 (d, J = 9.0 Hz, 1 H), 7.65 (d, J = 2.8 Hz, 1 H), 8.20 (d, J = 6.8 Hz, 1 H), 8.35 (d, J = 6.2 Hz, 1 Н), 8.62 (s, 1 Н).
13С NMR (150 MHz, DМSО-d 6): δ = 55.9, 101.4, 108.7, 111.4, 117.7, 118.7, 120.9, 126.9, 130.3, 131.3, 132.3, 141.5, 145.0, 147.5, 148.0, 156.1, 157.0.
EI-MS: m/z (%) = 293 (14), 292 (70) [M]+, 265 (19), 264 (100), 249 (19), 221 (22), 193 (19), 192 (15), 176 (12), 175 (97), 146 (10), 131 (10), 119 (36), 118 (14), 103 (11), 76 (11).
Anal. Calcd for C17H12N2O3 (292.29): C, 69.86; H, 4.14; N, 9.58. Found: C, 69.99; H, 4.01; N, 9.45.
#
1-Methyl-7-(2-oxo-2H-chromen-3-yl)-1H-pyrrolo[2,3-b]pyridin-7-ium Bromide (5a)
Beige solid; yield: 0.160 g (45%); mp 179 °С (dec).
IR (KBr): 3078, 3005, 1716, 1604, 1258, 1052, 808, 761, 728 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 3.80 (s, 3 H, CH3), 7.12 (d, J = 3.8 Hz, 1 H, H-3′), 7.59 (t, J = 7.6 Hz, 1 H, H-6), 7.68 (d, J = 8.3 Hz, 1 H, H-8), 7.85 (t, J = 7.0 Hz, 1 H, H-5′), 7.90 (m, 1 H, H-7), 7.93 (d, J = 3.2 Hz, 1 H, H-2′), 7.96 (d, J = 7.6 Hz, 1 H, H-5), 8.73 (d, J = 6.4 Hz, 1 H, H-6′), 8.98 (d, J = 8.3 Hz, 1 H, H-4′), 9.01 (s, 1 H, H-4).
13С NMR (100 MHz, DМSО-d 6): δ = 36.4 (CH3), 103.2 (C-3′), 116.1 (C-5′), 116.9 (C-8), 117.3 (C-4a), 125.0 (C-3), 125.8 (C-6), 128.2 (C-3a′), 130.6 (C-5), 134.7 (C-7), 136.5 (C-2′), 137.6 (C-7a′), 139.6 (C-6′), 140.1 (C-4′), 144.4 (C-4), 153.6 (C-8a), 157.3 (C-2).
MS (MALDI): m/z = 277 [M – Br]+.
Anal. Calcd for C17H13BrN2O2 (357.21): C, 57.16; H, 3.67; N, 7.84. Found: C, 57.01; H, 3.52; N, 7.77.
#
7-(6-Bromo-2-oxo-2H-chromen-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-7-ium Bromide (5b)
Orange solid; yield: 0.095 g (22%); mp 125 °С (dec).
IR (KBr): 3091, 2922–2853, 1742, 1598, 1449–1409, 1354, 1253, 1160–1046, 818, 723 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 3.80 (s, 3 H, CH3), 7.12 (d, J = 3.4 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.83 (dd, J = 7.8, 6.7 Hz, 1 H), 7.92 (d, J = 3.4 Hz, 1 H), 8.04 (dd, J = 8.8, 2.5 Hz, 1 H), 8.24 (d, J = 2.5 Hz, 1 H), 8.68 (dd, J = 6.7, 1.0 Hz, 1 H), 8.92 (s, 1 H), 8.97 (dd, J = 7.8, 1.0 Hz, 1 H).
13С NMR (100 MHz, DМSО-d 6): δ = 36.6, 103.5, 116.3, 117.4, 119.3, 119.3, 126.0, 128.5, 132.5, 136.7, 137.1, 137.7, 139.5, 140.4, 143.3, 152.9, 157.1.
MS (MALDI): m/z = 355 [M – Br]+.
Anal. Calcd for C17H12Br2N2O2 (436.10): C, 46.82; H, 2.77; N, 6.42. Found: C, 46.98; H, 2.72; N, 6.33.
#
1-Methyl-7-(3-oxo-3H-benzo[f]chromen-2-yl)-1H-pyrrolo[2,3-b]pyridin-7-ium Bromide (5c)
Dark gray solid; yield: 0.130 g (32%); mp 176 °С (dec).
IR (KBr): 3210, 3095–2843, 1660, 1619–1580, 1493, 1451–1413, 1357, 1261–1222, 1048, 890, 832, 729, 588 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 3.82 (s, 3 H, CH3), 7.16 (d, J = 3.3 Hz, 1 H), 7.75 (d, J = 7.5 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 2 H), 7.90 (t, J = 7.0 Hz, 1 H), 7.95 (d, J = 3.3 Hz, 1 H), 8.20 (d, J = 8.1 Hz, 1 H), 8.49 (d, J = 8.8 Hz, 2 H), 8.81 (d, J = 5.1 Hz, 1 H), 9.02 (d, J = 7.7 Hz, 1 H), 9.91 (s, 1 H).
13С NMR (100 MHz, DМSО-d 6): δ = 36.6, 103.3, 104.8, 112.1, 116.2, 116.7, 122.5, 124.2, 126.9, 128.2, 129.1 (2 C), 130.2, 136.3, 136.6, 137.6, 140.0, 140.2, 141.2, 154.3, 157.3.
ESI-MS: m/z = 327 [M – Br]+.
Anal. Calcd for C21H15BrN2O2 (407.27): C, 61.93; H, 3.71; N, 6.88. Found: C, 62.09; H, 3.60; N, 6.69.
#
7-(6,8-Dichloro-2-oxo-2H-chromen-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-7-ium Bromide (5d)
Yellow solid; yield: 0.197 g (47%); mp 118 °С (dec).
IR (KBr): 3092–3020, 2954–2767, 1737, 1619, 1527, 1447–1410, 1357, 1232, 1048, 808, 727 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 4.04 (s, 3 H, CH3), 7.00 (d, J = 3.4 Hz, 1 H), 7.45 (d, J = 2.8 Hz, 1 H), 7.50 (s, 1 H), 7.60 (d, J = 2.8 Hz, 1 H), 7.66 (dd, J = 7.6, 6.2 Hz, 1 H), 7.84 (d, J = 3.4 Hz, 1 H), 8.66 (d, J = 5.5 Hz, 1 H), 8.78 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, DМSО-d 6): δ = 36.6, 102.6, 115.4, 116.3, 121.3, 124.2, 125.7, 127.6, 130.4, 131.2, 134.9, 136.0, 136.8, 137.7, 139.9, 153.9, 163.6.
ESI-MS: m/z = 345 [M – Br]+.
Anal. Calcd for C17H11BrCl2N2O2 (426.09): C, 47.92; H, 2.60; N, 6.57. Found: C, 48.12; H, 2.70; N, 6.50.
#
Compounds 6; General Procedure
A solution of salt 1b (0.13 g, 0.516 mmol) and the corresponding aldehyde (0.512 mmol) in anhyd EtOH (4 mL) with K2CO3 (0.173 g, 2.2 equiv) in a closed vial was placed into a microwave reactor, where it was heated at 150 °C for 7 min. Upon reaction completion, the mixture was diluted with H2O (8 mL) and EtOH (3 mL), and the formed precipitate was collected by filtration, washed with an EtOH–H2O mixture (7:8) (3 × 3 mL) and dried under air.
#
1-Methyl-1,12-dihydrochromeno[2′,3′:4,5]imidazo[1,2-a]pyrrolo[3,2-e]pyridine (6a)
Brown solid; yield: 0.076 g (54%); mp 148 °С.
IR (KBr): 3500–2841, 1625, 1561, 1490, 1454–1422, 1368, 1285, 1249, 1224, 799, 755, 707, 656 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 4.14 (s, 3 H, CH3), 4.68 (s, 2 H, CH2), 6.54 (d, J = 2.6 Hz, 1 H), 7.14–7.19 (m, 4 H), 7.30 (t, J = 7.3 Hz, 1 H), 7.45 (d, J = 7.0 Hz, 1 H), 7.55 (d, J = 9.2 Hz, 1 H).
13С NMR (100 MHz, DМSО-d 6): δ = 28.2, 38.2, 96.3, 102.3, 107.7, 113.6, 116.8, 119.1, 120.5, 123.2, 125.4, 127.9, 129.2, 130.5, 140.7, 149.9, 150.2.
ESI-MS: m/z = 276 [M + Н]+.
Anal. Calcd for C17H13N3O (275.31): C, 74.17; H, 4.76; N, 15.26. Found: C, 74.06; H, 4.83; N, 15.20.
#
10-Methoxy-1-methyl-1,12-dihydrochromeno[2′,3′:4,5]imidazo[1,2-a]pyrrolo[3,2-e]pyridine (6b)
Brown solid; yield: 0.074 g (47%); mp 188 °С.
IR (KBr): 3655–2837, 1709, 1624–1568, 1495–1369, 1284–1210, 1035, 794, 720, 655 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 3.77 (s, 3 H, CH3), 4.14 (s, 3 H, CH3), 4.64 (s, 2 H, CH2), 6.54 (d, J = 3.3 Hz, 1 H), 6.87 (dd, J = 8.8, 2.8 Hz, 1 H), 7.03 (d, J = 2.8 Hz, 1 H), 7.11–7.16 (m, 3 H), 7.54 (d, J = 8.8 Hz, 1 H).
13С NMR (100 MHz, DМSО-d 6): δ = 28.6, 38.2, 55.4, 95.9, 102.2, 107.7, 113.6, 114.1, 114.2, 117.5, 119.7, 120.4, 125.4, 129.2, 140.7, 144.1, 150.2, 154.8.
ESI-MS: m/z = 306 [M + Н]+.
Anal. Calcd for C18H15N3O2 (305.34): C, 70.81; H, 4.95; N, 13.76. Found: C, 70.59; H, 4.99; N, 13.69.
#
8-Ethoxy-1-methyl-1,12-dihydrochromeno[2′,3′:4,5]imidazo[1,2-a]pyrrolo[3,2-e]pyridine (6c)
Brown solid; yield: 0.058 g (36%); mp 149 °С.
IR (KBr): 3624–2845, 1708–1567, 1500–1423, 1270, 1209, 1115–1000, 793, 760, 721, 655 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 1.42 (t, J = 7.0 Hz, 3 H, CH3), 4.10–4.13 (m, 5 H, OCH2 CH3, NCH3), 4.68 (s, 2 H, CH2), 6.54 (d, J = 2.9 Hz, 1 H, H-3), 6.97–6.99 (m, 2 H, H-11, H-9), 7.05 (t, J = 7.7 Hz, 1 H, H-10), 7.13 (d, J = 2.9 Hz, 1 H, H-2), 7.16 (d, J = 9.1 Hz, 1 H, H-4), 7.56 (d, J = 9.1 Hz, 1 H, H-4).
13С NMR (100 MHz, DМSО-d 6): δ = 14.7 (CH2 CH3), 28.4 (CH2), 38.2 (NCH3), 64.0 (CH2CH3), 96.2 (C-12a), 102.2 (C-3), 107.7 (C-5), 111.5 (C-11), 113.6 (C-3a), 119.8 (C-8a), 120.5 (C-4), 121.6 (C-9), 122.8 (C-10), 125.4 (C-2), 129.2 (C-13a), 140.1 (C-11a), 140.7 (C-6a), 147.2 (C-8), 149.9 (C-7a).
ESI-MS: m/z = 320 [M + Н]+.
Anal. Calcd for C19H17N3O2 (319.36): C, 71.46; H, 5.37; N, 13.16. Found: C, 71.34; H, 5.46; N, 13.05.
#
5-(Сyanomethyl)-1H-pyrrolo[3,2-c]pyridin-5-ium Chloride (2)
To a solution of 5-azaindole (1 g, 8.5 mmol) in MeCN (5 mL) was added chloroacetonitrile (0.8 mL, 12.75 mmol). The reaction mixture was stirred under reflux for 6 h. The precipitate was collected by filtration, washed with MeCN (3 × 5 mL) and dried under air to give a gray solid; yield: 1.31 g (80%); mp 212–214 °С.
IR (KBr): 3203–2541, 1893, 1778, 1636, 1602, 1523, 1484, 1417, 1361, 1334, 1276, 1240, 1139, 924, 816, 729 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 6.10 (s, 2 H), 7.11 (d, J = 3.3 Hz, 1 H), 8.03 (d, J = 3.3 Hz, 1 H), 8.13 (d, J = 7.0 Hz, 1 H), 8.67 (d, J = 7.0 Hz, 1 H), 9.60 (s, 1 H), 13.62 (br s, 1 H).
13С NMR (150 MHz, DМSО-d 6): δ = 46.2, 104.6, 110.3, 115.3, 124.8, 133.8, 134.3, 139.7, 141.3.
ESI-MS: m/z = 158 [M – Cl]+.
Anal. Calcd for C9H8ClN3 (193.63): C, 55.83; H, 4.16; N, 21.70. Found: C, 55.97; H, 4.08; N, 21.80.
#
4-(Cyanomethyl)-1H-pyrrolo[3,2-b]pyridin-4-ium Chloride (3)
To a solution of 4-azaindole (1 g, 8.5 mmol) in MeCN (5 mL) was added chloroacetonitrile (0.8 mL, 12.75 mmol). The reaction mixture was stirred under reflux for 6 h. The precipitate was collected by filtration, washed with MeCN (3 ×) and dried under air to give a beige solid; yield: 1.358 g (83%); mp 226–228 °С.
IR (KBr): 3013–2573, 1637, 1583, 1462, 1384, 1342, 1286, 1237, 1168, 1131, 900, 822, 796, 764, 598 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 6.34 (s, 2 H), 7.21 (d, J = 3.1 Hz, 1 H), 7.78 (dd, J = 6.2, 1.5 Hz, 1 H), 8.46 (d, J = 3.1 Hz, 1 H), 8.74 (d, J = 7.6 Hz, 1 H), 9.00 (d, J = 6.2 Hz, 1 H).
13С NMR (150 MHz, DМSО-d 6): δ = 43.9, 96.2, 114.3, 117.2, 129.4, 132.7, 137.0, 138.3, 138.4.
ESI-MS: m/z = 158 [M – Cl]+.
Anal. Calcd for C9H8ClN3 (193.63): C, 55.83; H, 4.16; N, 21.70. Found: C, 55.95; H, 4.06; N, 21.75.
#
Compounds 7 and 8; General Procedure
A solution of salt 2 or 3 (0.110 g, 0.57 mmol) and the corresponding aldehyde (0.512 mmol) in anhyd EtOH (4 mL) with K2CO3 (0.173 g, 2.2 equiv) in a closed vial was placed into a microwave reactor, where it was heated at 150 °C for 7 min. Upon reaction completion, the mixture was diluted with H2O (10 mL), and the formed precipitate was collected by filtration, washed with EtOH (2 × 3 mL) and with H2O (1 × 3 mL), and dried under air.
#
3,7-Dihydrochromeno[2′,3′:4,5]imidazo[1,2-a]pyrrolo[3,2-c]pyridine (7a)
Beige solid; yield: 0.104 g (79%); mp 276–278 °С (dec).
IR (KBr): 3157–2695, 1778, 1722, 1649, 1427, 1392, 1369, 1327, 1212, 881, 750, 733 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 4.30 (s, 2 H, CH2), 6.71 (br s, 1 H, H-1), 7.13–7.19 (m, 3 H, H-10, H-4, H-11), 7.30 (t, J = 7.6 Hz, 1 H, H-9), 7.35 (t, J = 2.8 Hz, 1 H, H-2), 7.39 (d, J = 7.6 Hz, 1 H, H-8), 7.88 (d, J = 7.6 Hz, 1 H, H-5), 11.63 (s, 1 H, NH).
13С NMR (100 MHz, DМSО-d 6): δ = 27.7 (CH2), 96.1 (С-3a), 100.1 (C-1), 101.1 (C-4), 112.9 (C-13a), 117.3 (C-11a), 117.9 (C-11), 118.6 (C-5), 123.1 (C-10), 123.7 (C-2), 127.8 (C-9), 130.5 (C-8, C-13b), 136.7 (C-6a), 149.1 (C-12a), 151.4 (C-7a).
ESI-MS: m/z = 262 [M + Н]+.
Anal. Calcd for C16H11N3O (261.28): C, 73.55; H, 4.24; N, 16.08. Found: C, 73.45; H, 4.34; N, 15.96.
#
9-Bromo-3,7-dihydrochromeno[2′,3′:4,5]imidazo[1,2-a]pyrrolo[3,2-c]pyridine (7b)
Light brown solid; yield: 0.13 g (75%); mp >300 °C.
IR (KBr): 3157–2721, 1649, 1472, 1427, 1393, 1320, 1113, 874, 820, 732 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 4.31 (s, 2 H), 6.70 (s, 1 H), 7.17 (m, 2 Н), 7.35 (s, 1 H), 7.47 (dd, J = 8.3, 1.7 Hz, 1 H), 7.60 (s, 1 H), 7.85 (d, J = 7.4 Hz, 1 H), 11.65 (s, 1 H).
13С NMR (100 MHz, DМSО-d 6): δ = 22.7, 95.8, 100.2, 101.4, 112.9, 114.6, 118.1, 119.6, 121.5, 123.9, 130.6, 133.0, 136.8, 148.9, 150.6, 155.9.
ESI-MS: m/z = 340 [M + H]+.
Anal. Calcd for C16H10BrN3O (340.18): C, 56.49; H, 2.96; N, 12.35. Found: C, 56.36; H, 2.99; N, 12.30.
#
9-Methoxy-3,7-dihydrochromeno[2′,3′:4,5]imidazo[1,2-a]pyrrolo[3,2-c]pyridine (7c)
Light brown solid; yield: 0.130 g (87%); mp >300 °С.
IR (KBr): 3155–2834, 1651, 1491, 1434, 1368, 1197, 1040, 802, 730 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 3.77 (s, 3 Н), 4.26 (s, 2 H), 6.70 (s, 1 H), 6.89 (d, J = 8.3 Hz, 1 H), 6.93 (s, 1 H), 7.14 (m, 2 Н), 7.34 (s, 1 H), 7.85 (d, J = 7.4 Hz, 1 H), 11.62 (s, 1 H).
13С NMR (100 MHz, DМSО-d 6, 45 °C): δ = 23.8, 55.1, 95.4, 99.8, 100.7, 112.6, 113.6, 114.3, 117.7, 117.8, 119.0, 123.4, 130.3, 136.4, 145.1, 149.2, 154.6.
ESI-MS: m/z = 292 [M + H]+.
Anal. Calcd for C17H13N3O2 (291.31): С, 70.09; H, 4.50; N, 14.42. Found: С, 69.95; H, 4.67; N, 14.32.
#
3,7-Dihydrobenzo[5′,6′]chromeno[2′,3′:4,5]imidazo[1,2-a]pyrrolo[3,2-c]pyridine (7d)
Gray solid; yield: 0.134 g (84%); mp 293–296 °С (dec).
IR (KBr): 3209, 3116, 3049, 2981, 2821, 1661, 1596, 1583, 1518, 1427, 1390, 1310, 1224, 741 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 4.58 (s, 2 H), 6.75 (s, 1 H), 7.24 (d, J = 7.4 Hz, 1 H), 7.38 (s, 1 Н), 7.44 (d, J = 8.3 Hz, 1 H), 7.54 (d, J = 7.4 Hz, 1 H), 7.70 (d, J = 7.4 Hz, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.98 (d, J = 7.4 Hz, 1 H), 8.04 (d, J = 8.3 Hz, 1 H), 8.08 (d, J = 7.4 Hz, 1 H), 11.69 (s, 1 H).
13С NMR (100 MHz, DМSО-d 6): δ = 21.0, 97.0, 100.2, 101.3, 111.2, 113.0, 118.2, 118.5, 123.0, 123.8, 124.6, 127.0, 128.2, 128.6, 129.9, 130.6, 132.3, 136.8, 148.7, 148.9.
ESI-MS: m/z = 312 [M + H]+.
Anal. Calcd for C20H13N3O (311.34): C, 77.16; H, 4.21; N, 13.50. Found: C, 77.03; H, 4.30; N, 13.39.
#
11-Ethoxy-3,7-dihydrochromeno[2′,3′:4,5]imidazo[1,2-a]pyrrolo[3,2-c]pyridine (7e)
Beige solid; yield: 0.109 g (70%); mp 299–304 °С (dec).
IR (KBr): 3160–2837, 1655, 1574, 1470, 1422, 1393, 1326, 1262, 1199, 1082, 877, 753, 711 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 1.41 (br s, 3 Н), 4.09 (m, 2 H), 4.28 (s, 2 H), 6.68 (s, 1 H), 6.91 (d, J = 6.6 Hz, 1 H), 6.96 (d, J = 6.6 Hz, 1 Н), 7.02 (d, J = 6.6 Hz, 1 H), 7.16 (d, J = 5.8 Hz, 1 H), 7.35 (s, 1 H), 7.86 (d, J = 6.6 Hz, 1 H), 11.71 (s, 1 H).
Due to the poor solubility of 7e, the 13C NMR spectrum could not be recorded. The use of a CDCl3–TFA mixture as solvent led to compound degradation.
ESI-MS: m/z = 306 [M + H]+.
Anal. Calcd for C18H15N3O2 (305.34): C, 70.81; H, 4.95; N, 13.76. Found: C, 70.75; H, 4.99; N, 13.70.
#
3,12-Dihydrochromeno[2′,3′:4,5]imidazo[1,2-a]pyrrolo[2,3-e]pyridine (8a)
Beige solid; yield: 0.077 g (57%); mp 280–283 °С (dec).
IR (KBr): 3186–2723, 1643, 1569, 1429, 1207, 888, 751 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 4.69 (s, 2 H, CH2), 6.83 (br s, 1 H, H-1), 7.13–7.15 (m, 2 H, H-9, H-5), 7.17 (d, J = 8.1 Hz, 1 H, H-4), 7.30 (t, J = 7.4 Hz, 1 H, H-10), 7.41–7.43 (m, 2 Н, H-2, H-11), 7.46 (d, J = 9.2 Hz, 1 H, H-8), 11.67 (br s, 1 H, NH).
13С NMR (100 MHz, DМSО-d 6): δ = 24.2 (CH2), 94.2 (C-1), 97.9 (C-12a), 108.6 (C-5), 113.2 (C-8), 117.4 (C-4), 118.7 (C-7a), 122.4 (C-13a), 123.3 (C-9), 123.5 (C-2), 124.3 (C-3a), 128.0 (C-10), 130.7 (C-11), 137.4 (C-5a), 150.0 (C-6a), 151.5 (C-11a).
ESI-MS: m/z = 262 [M + H]+.
Anal. Calcd for C16H11N3O (261.28): C, 73.55; H, 4.24; N, 16.08. Found: C, 73.42; H, 4.31; N, 15.99.
#
10-Bromo-3,12-dihydrochromeno[2′,3′:4,5]imidazo[1,2-a]pyrrolo[2,3-e]pyridine (8b)
Beige solid; yield: 0.103 g (56%); mp >300 °С.
IR (KBr): 3188–2733, 1635, 1470, 1429, 1247, 1210, 789, 696 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 4.70 (s, 2 H), 6.78 (s, 1 H), 7.13–7.17 (m, 2 H), 7.43–7.47 (m, 3 H), 7.62 (s, 1 H), 11.69 (br s, 1 H).
13С NMR (100 MHz, DМSО-d 6): δ = 23.9, 94.1, 97.4, 108.5, 113.3, 114.6, 119.6, 121.5, 122.3, 123.5, 124.1, 130.7, 132.9, 137.3, 149.6, 150.7.
ESI-MS: m/z = 340 [M + H]+.
Anal. Calcd for C16H10BrN3O (340.18): C, 56.49; H, 2.96; N, 12.35. Found: C, 56.40; H, 3.01; N, 12.29.
#
10-Methoxy-3,12-dihydrochromeno[2′,3′:4,5]imidazo[1,2-a]pyrrolo[2,3-e]pyridine (8c)
Beige solid; yield: 0.070 g (47%); mp 273–276 °С (dec).
IR (KBr): 3188–2639, 1638, 1494–1430, 1429, 1199, 883, 712 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 3.77 (s, 3 Н), 4.67 (s, 2 H), 6.81 (d, J = 2.8 Hz, 1 H), 6.89 (dd, J = 8.9, 3.0 Hz, 1 H), 6.98 (d, J = 2.8 Hz, 1 H), 7.13 (m, 2 H), 7.41 (d, J = 2.5 Hz, 1 H), 7.44 (d, J = 9.1 Hz, 1 H), 11.67 (br s, 1 H).
13С NMR (100 MHz, DМSО-d 6): δ = 24.5, 55.4, 94.1, 97.5, 108.4, 113.1, 114.1, 114.5, 118.1, 119.3, 122.2, 123.4, 124.2, 137.2, 145.2, 150.1, 154.9.
ESI-MS: m/z = 292 [M + H]+.
Anal. Calcd for C17H13N3O2 (291.31): С, 70.09; H, 4.50; N, 14.42. Found: С, 69.98; H, 4.58; N, 14.38.
#
3,14-Dihydrobenzo[5′,6′]chromeno[2′,3′:4,5]imidazo[1,2-a]pyrrolo[2,3-e]pyridine (8d)
Beige solid; yield: 0.070 g (44%); mp 273–276 °С (dec).
IR (KBr): 3432–2713, 1643, 1576, 1428–1396, 1311, 1230, 802, 707 cm–1.
1Н NMR (600 MHz, DМSО-d 6): δ = 4.56 (s, 2 H), 6.75 (d, J = 2.5 Hz, 1 H), 7.24 (d, J = 7.0 Hz, 1 H), 7.37 (d, J = 2.5 Hz, 1 H), 7.44 (d, J = 9.1 Hz, 1 H), 7.55 (d, J = 7.4 Hz, 1 H), 7.70 (t, J = 7.4 Hz, 1 H), 7.95 (d, J = 9.1 Hz, 1 H), 7.99 (d, J = 8.2 Hz, 1 H), 8.05 (d, J = 8.2 Hz, 1 H), 8.08 (d, J = 7.0 Hz, 1 H), 11.68 (br s, 1 H).
13С NMR (100 MHz, DМSО-d 6): δ = 20.9, 96.9, 100.2, 101.3, 111.2, 112.9, 118.2, 118.5, 123.0, 123.8, 124.6, 126.9, 128.2, 128.6, 129.9, 130.7, 132.3, 136.9, 148.7, 148.9.
ESI-MS: m/z = 312 [M + H]+.
Anal. Calcd for C20H13N3O (311.34): C, 77.16; H, 4.21; N, 13.50. Found: C, 77.09; H, 4.25; N, 13.42.
#
#
No conflict of interest has been declared by the author(s).
Acknowledgment
This work was financially supported by the Ministry of Education and Science of the Russian Federation through the program to improve the competitiveness of RUDN University among the world’s leading research and education centers in 2016–2020. The financial support of the Russian Foundation for Basic Research (grant # 16-53-540004-Viet_а) and Vietnam Academy of Science and Technology is gratefully acknowledged.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0036-1558972.
- Supporting Information
-
References
- 1 Chezal J.-M, Paeshuyse J, Gaumet V, Canitrot D, Maisonial A, Lartigue C, Gueiffier A, Moreau E, Teulade J.-C, Chavignon O, Neyts J. Eur. J. Med. Chem. 2010; 45: 2044-2044
- 2 Hranjec M, Pavlovi G, Marjanovi M, Kralj M, Karminski-Zamola G. Eur. J. Med. Chem. 2010; 45: 2405-2405
- 3 Moraes EC, Meirelles GV, Honorato RV, de Souza TA. C. B, de Souza EE, Murakami MT, de Oliveira PS. L, Kobarg J. Molecules 2015; 20: 1176-1176
- 4a Jiang X, Zhao B, Britton R, Lim LY, Leong D, Sanghera JS, Zhou B.-B, Piers E, Andersen RJ, Roberge M. Mol. Cancer Ther. 2004; 3: 1221-1221
- 4b Roberge M, Berlinck RG. S, Xu L, Anderson HJ, Lim LY, Curman D, Stringer CM, Friend SH, Davies P, Vincent I, Haggarty SJ, Kelly MT, Britton R, Piers E, Andersen RJ. Cancer Res. 1998; 58: 5701-5701
- 4c Hènon H, Conchon E, Hugon B, Messaoudi S, Golsteyn RM, Prudhomme M. Anti-Cancer Agents Med. Chem. 2008; 8: 577-577
- 5 Lavrard H, Salvetti B, Mathieu V, Rodriguez F, Kiss R, Delfourne E. ChemMedChem 2015; 10: 607-607
- 6 Hugon B, Anizon F, Bailly C, Golsteyn RM, Pierré A, Léonce S, Hickman J, Pfeiffer B, Prudhomme M. Bioorg. Med. Chem. 2007; 15: 5965-5965
- 7 Lima CF, Costa M, Proenca MF, Pereira-Wilson C. Eur. J. Pharm. Sci. 2015; 72: 34-34
- 8a Piers E, Britton R, Andersen RJ. J. Org. Chem. 2000; 65: 530-530
- 8b Sanchez-Martinez C, Shih C, Faul MM, Zhu G, Paal M, Somoza C, Li T, Kumrich CA, Winneroski LL, Xun Z, Brooks HB, Patel BK. R, Schultz RM, DeHahn TB, Spencer CD, Watkins SA, Considine E, Dempsey JA, Ogg CA, Campbell RM, Anderson BA, Wagner J. Bioorg. Med. Chem. Lett. 2003; 13: 3835-3835
- 8c Delfourne E. Tetrahedron Lett. 2011; 52: 6560-6560
- 8d Salvetti B, Lavrard H, Delfourne E. Tetrahedron Lett. 2014; 55: 6560-6560
- 9a Voskressensky LG, Festa AA, Sokolova EA, Varlamov AV. Tetrahedron 2012; 68: 5498-5498
- 9b Voskressensky LG, Festa AA, Sokolova EA, Khrustalev VN, Varlamov AV. Eur. J. Org. Chem. 2012; 6124-6124
- 9c Voskressensky LG, Sokolova EA, Festa AA, Khrustalev VN, Van Tuyen N, Anh LT, Varlamov AV. Chem. Heterocycl. Compd. 2013; 49: 484-484
- 9d Voskressensky LG, Sokolova EA, Festa AA, Varlamov AV. Tetrahedron Lett. 2013; 54: 5172-5172
- 10 Voskressensky LG, Storozhenko OA, Festa AA, Khrustalev VN, Dang TT. A, Nguyen VT, Varlamov AV. Tetrahedron Lett. 2015; 56: 6475-6475
- 11 Mahadevan I, Rasmussen M. Tetrahedron 1993; 49: 1331-1331
For our studies on the construction of fused chromenoimidazoles, see:
-
References
- 1 Chezal J.-M, Paeshuyse J, Gaumet V, Canitrot D, Maisonial A, Lartigue C, Gueiffier A, Moreau E, Teulade J.-C, Chavignon O, Neyts J. Eur. J. Med. Chem. 2010; 45: 2044-2044
- 2 Hranjec M, Pavlovi G, Marjanovi M, Kralj M, Karminski-Zamola G. Eur. J. Med. Chem. 2010; 45: 2405-2405
- 3 Moraes EC, Meirelles GV, Honorato RV, de Souza TA. C. B, de Souza EE, Murakami MT, de Oliveira PS. L, Kobarg J. Molecules 2015; 20: 1176-1176
- 4a Jiang X, Zhao B, Britton R, Lim LY, Leong D, Sanghera JS, Zhou B.-B, Piers E, Andersen RJ, Roberge M. Mol. Cancer Ther. 2004; 3: 1221-1221
- 4b Roberge M, Berlinck RG. S, Xu L, Anderson HJ, Lim LY, Curman D, Stringer CM, Friend SH, Davies P, Vincent I, Haggarty SJ, Kelly MT, Britton R, Piers E, Andersen RJ. Cancer Res. 1998; 58: 5701-5701
- 4c Hènon H, Conchon E, Hugon B, Messaoudi S, Golsteyn RM, Prudhomme M. Anti-Cancer Agents Med. Chem. 2008; 8: 577-577
- 5 Lavrard H, Salvetti B, Mathieu V, Rodriguez F, Kiss R, Delfourne E. ChemMedChem 2015; 10: 607-607
- 6 Hugon B, Anizon F, Bailly C, Golsteyn RM, Pierré A, Léonce S, Hickman J, Pfeiffer B, Prudhomme M. Bioorg. Med. Chem. 2007; 15: 5965-5965
- 7 Lima CF, Costa M, Proenca MF, Pereira-Wilson C. Eur. J. Pharm. Sci. 2015; 72: 34-34
- 8a Piers E, Britton R, Andersen RJ. J. Org. Chem. 2000; 65: 530-530
- 8b Sanchez-Martinez C, Shih C, Faul MM, Zhu G, Paal M, Somoza C, Li T, Kumrich CA, Winneroski LL, Xun Z, Brooks HB, Patel BK. R, Schultz RM, DeHahn TB, Spencer CD, Watkins SA, Considine E, Dempsey JA, Ogg CA, Campbell RM, Anderson BA, Wagner J. Bioorg. Med. Chem. Lett. 2003; 13: 3835-3835
- 8c Delfourne E. Tetrahedron Lett. 2011; 52: 6560-6560
- 8d Salvetti B, Lavrard H, Delfourne E. Tetrahedron Lett. 2014; 55: 6560-6560
- 9a Voskressensky LG, Festa AA, Sokolova EA, Varlamov AV. Tetrahedron 2012; 68: 5498-5498
- 9b Voskressensky LG, Festa AA, Sokolova EA, Khrustalev VN, Varlamov AV. Eur. J. Org. Chem. 2012; 6124-6124
- 9c Voskressensky LG, Sokolova EA, Festa AA, Khrustalev VN, Van Tuyen N, Anh LT, Varlamov AV. Chem. Heterocycl. Compd. 2013; 49: 484-484
- 9d Voskressensky LG, Sokolova EA, Festa AA, Varlamov AV. Tetrahedron Lett. 2013; 54: 5172-5172
- 10 Voskressensky LG, Storozhenko OA, Festa AA, Khrustalev VN, Dang TT. A, Nguyen VT, Varlamov AV. Tetrahedron Lett. 2015; 56: 6475-6475
- 11 Mahadevan I, Rasmussen M. Tetrahedron 1993; 49: 1331-1331
For our studies on the construction of fused chromenoimidazoles, see: