Spiro-condensation of 5-methoxycarbonyl-1H-pyrrole-2,3-diones with cyclic enoles to form spiro substituted furo[3,2-c]-coumarins and quinolines

Abstract

Highly efficient spiro-condensation enabling cyclic enoles to act as 1,3-bis-nucleophiles in reaction with pyrrole-2,3-diones acting as 1,2-bis-electrophiles was developed. The corresponding furo[3,2-c]coumarins and furo[3,2-c]quinolines containing a spiro pyrrole fragment were obtained in high yields.

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Introduction

Natural products containing furo[3,2-c]coumarin¹ and furo[3,2-c]quinolone² fragments have been the subject of great interest due to their important biological properties. For example, phyto-alkaloids hypocrolide A, glaumacidine, coumestrol (coumestan), and their synthetic analogs demonstrated promising antimitotic, antiprolifirative and cytotoxic activities (Scheme 1). Not surprisingly, development of new synthetic routes to these scaffolds is of great interest for modern synthetic and medicinal chemistry. Herein we wish to disclose the results of our synthetic studies towards spiro analogs of furo[3,2-c]coumarins and furo[3,2-c]quinolones. The featured synthetic strategy is based on highly selective electrophilic reactions of 1H-pyrrole-2,3-diones.

Scheme 1

Results and discussion

Due to their high reactivity and pronounced electrophilic properties 1H-pyrrole-2,3-diones are often employed as useful building blocks allowing for efficient incorporation of a nitrogen containing five-membered heterocyclic unit in the structure of a target molecule. Such approach has found application in total synthesis of natural alkaloids.³ The installation of additional electron-withdrawing groups (such as acyl, alkoxycarbonyl or 1,2-dicarbonyl moieties) at C-4 and C-5 of the pyrrole ring may further increase synthetic versatility of these compounds. Diverse reactions of such 4,5-disubstituted 1H-pyrrole-2,3-diones can be used for expeditious assembly of various fused and bridged, polyheterocyclic scaffolds, often hardly available or unavailable by other methods.⁴ Furthermore, the installation of an ester function at C-5 provides an additional electrophilic moiety in multistep cascade reactions with bis-nucleophilic reagents, offering easy access towards functionalized spiro-pyrroles (Scheme 2). Thus, we previously demonstrated the reaction of 5-methoxycarbonyl-1H-pyrrole-2,3-diones 1 with 1,3-N,N-bis-nuclephiles, such as urea derivatives 2 to yield derivatives of 1,3,6-triazaspiro[4,4]nonane 3 (Scheme 2, path A).⁵ Similarly, utilization of enamines 4 as 1,3-C,N-bisnucleophiles afforded products with 1,7-diazaspiro[4,4]nonane scaffold 5 (Scheme 2, path B).^6,7 A detailed investigation of this transformation revealed that both acyclic⁶ and cyclic⁷ enamines can be readily employed as bis-nucleophiles, providing facile access to annulated functionalized spiranes 5 with increased molecular complexity. At the same time, to the best of our knowledge, related spiro-condensations of monocyclic 1H-pyrrole-2,3-diones 1 with enoles 6 (Scheme 2, path C) is still unknown. We envisioned that such a process, if successful, might serve for efficient preparation of 7-oxa-1-azaspiro[4,4]nonanes 7, including spiro-derivatives of furo[3,2-c]coumarins and furo[3,2-c]quinolones.

Scheme 2

To this end we envisioned that stable enol forms such as 4-hydroxycoumarine (6a, X = O) and 4-hydroxyquinolin-2(1H)-ones (6b, X = NMe; 6b, X = NPh) could serve as suitable precursors for the designed transformation. Indeed, enolate 8 generated in the presence of catalytic base is expected to perform a conjugate addition across the highly electrophilic vinylogous amide moiety in pyrroledione 1. The resulting enolate 9 is anticipated to undergo a proton transfer to produce less basic enolate 10, which is well suited for an intramolecular 5-exo-trig cyclization affecting the ester function at C-5 and providing target structure 11 (Scheme 3).

Scheme 3

To evaluate this idea we carried out the reaction of methyl 3-benzoyl-4,5-dioxo-1-phenyl-4,5-dihydro-1H-pyrrole-2-carboxylate (1a, Ar¹ = Ph, Ar² = Ph) with 4-hydroxy-2H-chromen-2-one (6a). It was observed that an equimolar mixture of these starting materials when refluxed in toluene in the presence of catalytic amounts of triethylamine (10 mol%) engaged in a quick reaction. The distinct purple color of pyrroledione faded away and the colorless product 11aa crystallized directly from the reaction mixture after cooling it down to −10 °C. This furo-coumarine was obtained as the sole product in good yield (68%, Table 1, entry 1). Reactions of other 4-aroyl-5-methoxycarbonyl pyrrolediones with 6a also proceeded uneventfully, affording the corresponding furo[3,2-c]coumarins very efficiently (Table 1, entries 2–8). Reactions involving enolates generated from 4-hydroxy-2-quinolones 6b, c were carried out under the same conditions and also afforded the corresponding spiro furo[3,2-c]quinolones as sole products, albeit in somewhat lower yields (Table 1, entries 9–13). Formation of these structures was unambiguously confirmed by X-ray crystallography of compounds 11ba (Fig. 1) and 11db (Fig. 2).

Table 1 Spiro-condensation of 4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones 1 with cyclic enoles 6

#	1	6	X	Ar^1	Ar^2	11	Yield^a, %
a Isolated yields of purified compounds 11.
1	1a	6a	O	Ph	Ph	11aa	68
2	1b	6a	O	4-MeOC6H4	Ph	11ba	70
3	1c	6a	O	Ph	4-MeOC6H4	11ca	84
4	1d	6a	O	Ph	4-MeC6H4	11da	80
5	1e	6a	O	4-MeC6H4	Ph	11ea	76
6	1f	6a	O	4-MeC6H4	4-MeC6H4	11fa	78
7	1g	6a	O	Ph	4-ClC6H4	11ga	67
8	1h	6a	O	Ph	4-BrC6H4	11ha	76
9	1c	6b	NMe	Ph	4-MeOC6H4	11cb	68
10	1d	6b	NMe	Ph	4-MeC6H4	11db	69
11	1a	6c	NPh	Ph	Ph	11ac	56
12	1g	6c	NPh	Ph	4-ClC6H4	11gc	59
13	1i	6c	NPh	4-BrC6H4	4-MeC6H4	11ic	67

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Fig. 1 ORTEP drawing of compound 11ba: showing 50% probability amplitude displacement ellipsoids (CCDC # 1486439†).

Fig. 2 ORTEP drawing of compound 11db: showing 50% probability amplitude displacement ellipsoids and a molecule of disordered crystallized solvent (acetonitrile) (CCDC # 1486440†).

We wondered, if the featured spiro-condensation would proceed selectively in more complex substrates, possibly allowing for alternative reaction pathways. For example, reaction of pyrrolediones 12 bearing a cinnamoyl substituent at C-4, with bis-nucleophilic enolates should proceed through intermediate 14, which could in principle undergo a second-fold enolexo-6-endo-trig Michael addition reaction to furnish different spiro scaffold 15 (Scheme 4). In our recent report we disclosed that in reactions of 4-cinnamoyl-pyrrole-2,3-diones 12 with five-membered cyclic enolates this process was prevalent.⁸ Interestingly, in the presence of six-membered enolates, generated from heterocyclic precursors 6a–c the reaction did not take this alternative route at all, proceeding instead via a “normal” 5-exo-trig lactonization pathway to afford the corresponding furo[3,2-c]coumarins and furo[3,2-c]quinolones 13 as sole products (Scheme 4, Table 2).

Scheme 4

Table 2 Spiro-condensation of 4-cinnamoyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones 12 with cyclic enoles 6

#	12	6	X	Ar^1	Ar^2	13	Yield^a, %
a Isolated yields of purified compounds 13.
1	12a	6a	O	Ph	4-MeC6H4	13aa	67
2	12a	6b	NMe	Ph	4-MeC6H4	13ab	75
3	12b	6b	NMe	Ph	4-MeOC6H4	13bb	78
4	12c	6b	NMe	4-MeOC6H4	4-MeOC6H4	13cb	77
5	12b	6c	NPh	Ph	4-MeOC6H4	13bc	65
6	12d	6c	NPh	4-MeOC6H4	4-MeC6H4	13dc	62

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Next, we investigated the reactivity of 4,5-dimethoxycarbonyl-1H-pyrrole-2,3-diones 16. After initial Michael addition of cyclic enolate 8, these substrates should provide intermediate 18, which can undergo the subsequent intramolecular nucleophilic attack involving one of the two available ester groups (Scheme 5). We were pleased to discover that these reactions also proceeded chemoselectively according to 5-exo-trig pathway, providing γ-lactones 17 as sole products in high yields (Table 3, entries 1–6). The alternative 6-exo-trig pathway was not realized at all, and the corresponding δ-lactones 18 were not detected in the reaction mixtures (Scheme 5).

Scheme 5

Table 3 Spiro-condensation of 4,5-dimethoxycarbonyl-1H-pyrrole-2,3-diones 16 with cyclic enoles 6

#	16	6	X	Ar^1	17	Yield^a, %
a Isolated yields of purified compounds 17.
1	16a	6a	O	CH2Ph	17aa	83
2	16b	6a	O	Ph	17ba	84
3	16c	6a	O	4-MeC6H4	17ca	81
4	16a	6c	NPh	CH2Ph	17ac	79
5	16b	6c	NPh	Ph	17bc	69
6	16c	6c	NPh	4-MeC6H4	17cc	64

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Conclusions

We have developed a novel cascade transformation combining an intermolecular conjugate addition of stabilized cyclic enolate (4-hydroxycoumarin or 4-hydroxy-2-quinolone) across a highly electrophilic vinylogous amide moiety of pyrrole-2,3-dione, and subsequent lactonization involving intramolecular nucleophilic attack of O-enolate at the ester substituent at C-5. The corresponding spiro furo[3,2-c]coumarins and furo[3,2-c]quinolones were formed as sole products in good yields. Remarkably, the introduction of competitive electrophilic substituents at C-4, such as cinnamoyl or methoxycarbonyl groups, did not divert the reaction from the described mechanistic route.

Experimental part

¹H and ¹³C NMR spectra were recorded on a Bruker Avance-III spectrometer (400 or 100 MHz, respectively) equipped with BBO probe in CDCl₃ or DMSO-d₆ using TMS as internal standard. IR spectra were recorded with a Perkin–Elmer Spectrum Two spectrometer from mulls in mineral oil. Melting points were measured with Stuart smp30 apparatus. X-ray crystallography was performed on Xcalibur Ruby diffractometer. The mass spectra were recorded on an Waters UPLC-MS instrument equipped with an ESI MS Xevo TQD detector. Elemental analyses were carried out on Vario MICRO Cube analyzer. Starting 5-methoxycarbonyl 1H-pyrrole-2,3-diones 1a–i, 12a–d, and 16a–c were obtained as described in literature sources,⁹ N-methyl- and N-phenyl-4-hydroxy-2-quinolones 6b, c were also prepared according to literature procedures.¹⁰ Anhydrous toluene was obtained by heating at reflux with molten sodium followed by distillation in under an atmosphere of dry nitrogen. Other reagents and solvents were purchased from commercial vendors and were used as received.

3′-Benzoyl-4′-hydroxy-1′-(4-methoxyphenyl)-2H,4H-spiro[furo[3,2-c]chromene-3,2′-pyrrole]-2,4,5′(1′H)-trione (11ca, typical procedure)

A solution of 4-hydroxycoumarin 6a (162 mg, 1.00 mmol), methyl 3-benzoyl-1-(4-methoxyphenyl)-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylate 1c (365 mg, 1.00 mmol), and Et₃N (10 mg, 0.10 mmol) in anhydrous toluene (5 mL) was stirred at reflux for 1.5 h until purple color of pyrroledione faded away, and the solid precipitate formed. Then the reaction mixture was cooled to −10 °C, and the resulted precipitate was filtered off, washed with hexane and recrystallized from toluene/chloroform (2 : 1) to afford 11ca (416 mg, 84%) as a colorless crystals, mp 240–242 °C (dec.). ¹H NMR (400 MHz, CDCl₃) δ 7.88–7.85 (m, 2H, Ar), 7.76–7.71 (m, 1H, Ar), 7.67–7.53 (m, 2H, Ar), 7.48–7.31 (m, 4H, Ar), 7.19–7.13 (m, 2H, Ar), 6.87–6.83 (m, 2H, Ar), 3.74 (s, 3H, OMe); ¹³C NMR (100 MHz, CDCl₃) δ 188.9, 169.7, 166.2, 165.4, 160.5, 156.1, 155.9, 150.4, 136.5, 134.9, 133.9, 129.6, 129.0, 128.6, 125.8, 125.1, 123.9, 117.7, 116.6, 115.5, 110.3, 100.9, 70.0, 55.6; IR (NaCl, cm⁻¹): 3408, 1848, 1736, 1707, 1676, 1652; MS: found 496.17; calcd for C₂₈H₁₈NO₈ (M + H)⁺ 496.10; EA: found C 67.84, H 3.45, N 2.86; calcd for C₂₈H₁₇NO₈ (495.44): C 67.88, H 3.46, N 2.83.

3′-Benzoyl-4′-hydroxy-1′-phenyl-2H,4H-spiro[furo[3,2-c]chromene-3,2′-pyrrole]-2,4,5′(1′H)-trione (11aa)

Yield 316 mg (68%), mp 237–239 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.89–7.85 (m, 2H, Ar), 7.73 (ddd, J = 7.9, 1.6, 0.5 Hz, 1H, Ar), 7.65–7.53 (m, 2H, Ar), 7.46–7.40 (m, 2H, Ar), 7.38–7.30 (m, 5H, Ar), 7.27–7.24 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 188.9, 169.6, 166.0, 165.4, 156.0, 155.9, 150.4, 136.5, 134.9, 133.9, 133.5, 130.2, 129.8, 129.6, 128.6, 127.5, 125.1, 123.9, 117.7, 116.7, 110.3, 100.8, 69.7 ppm. IR (NaCl, cm⁻¹): 3413, 1851, 1744, 1711, 1674, 1648; MS: found 466.15; calcd for C₂₇H₁₆NO₇ (M + H)⁺ 466.09; EA: found C 69.64, H 3.23, N 3.04; calcd for C₂₇H₁₅NO₇ (465.42): C 69.68, H 3.25, N 3.01.

4′-Hydroxy-3′-(4-methoxybenzoyl)-1′-phenyl-2H,4H-spiro[furo[3,2-c]chromene-3,2′-pyrrole]-2,4,5′(1′H)-trione (11ba)

Yield 347 mg (70%), mp 251–252 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.92–7.87 (m, 2H, Ar), 7.78–7.71 (m, 1H, Ar), 7.77 (ddd, J = 8.4, 7.5, 1.6 Hz, 1H, Ar), 7.41–7.23 (m, 7H, Ar), 6.97–6.92 (m, 2H, Ar), 3.87 (s, 3H, OMe); ¹³C NMR (100 MHz, CDCl₃) δ 186.9, 169.7, 166.0, 165.4, 164.6, 156.0, 155.9, 148.9, 134.9, 133.7, 132.3, 130.2, 129.7, 129.2, 127.5, 125.1, 123.9, 177.7, 117.1, 114.1, 110.3, 100.9, 65.9, 55.7; IR (NaCl, cm⁻¹): 3428, 1848, 1737, 1717, 1671, 1651; MS: found 496.19; calcd for C₂₈H₁₈NO₈ (M + H)⁺ 496.10; EA: found C 67.83, H 3.46, N 2.84; calcd for C₂₈H₁₇NO₈ (495.44): C 67.88, H 3.46, N 2.83.

3′-Benzoyl-4′-hydroxy-1′-(4-tolyl)-2H,4H-spiro[furo[3,2-c]chromene-3,2′-pyrrole]-2,4,5′(1′H)-trione (11da)

Yield 383 mg (80%), mp 203–205 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.92–7.87 (m, 2H, Ar), 7.78–7.71 (m, 1H, Ar), 7.68–7.53 (m, 2H, Ar), 7.48–7.40 (m, 2H, Ar), 7.37–7.30 (m, 2H, Ar), 7.19–7.06 (m, 4H, Ar), 2.21 (s, 3H, Me); ¹³C NMR (100 MHz, CDCl₃) δ 188.9, 169.7, 166.1, 165.4, 156.0, 155.9, 150.5, 140.1, 136.5, 134.9, 133.9, 130.8, 130.8, 129.6, 128.6, 127.3, 125.0, 123.9, 117.7, 116.6, 110.3, 100.9, 69.8, 21.3; IR (NaCl, cm⁻¹): 3441, 1851, 1724, 1708, 1674, 1646; MS: found 480.19; calcd for C₂₈H₁₈NO₇ (M + H)⁺ 480.11; EA: found C 70.12, H 3.56, N 2.94; calcd for C₂₈H₁₇NO₇ (479.44): C 70.15, H 3.57, N 2.92.

4′-Hydroxy-3′-(4-methylbenzoyl)-1′-phenyl-2H,4H-spiro[furo[3,2-c]chromene-3,2′-pyrrole]-2,4,5′(1′H)-trione (11ea)

Yield 364 mg (76%), mp 229–231 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.81–7.71 (m, 3H, Ar), 7.63 (ddd, J = 8.4, 7.5, 1.6 Hz, 1H, Ar), 7.41–7.30 (m, 5H, Ar), 7.28–7.21 (m, 4H, Ar), 2.40 (s, 3H, Me); ¹³C NMR (100 MHz, CDCl₃) δ 188.4, 169.7, 166.1, 165.4, 156.0, 155.9, 149.9, 145.2, 134.9, 133.8, 133.5, 130.2, 129.8, 129.8, 129.4, 127.5, 124.9, 123.9, 117.7, 117.0, 110.2, 100.7, 69.7, 22.0; IR (NaCl, cm⁻¹): 3420, 1854, 1713, 1673, 1648; MS: found 480.18; calcd for C₂₈H₁₈NO₇ (M + H)⁺ 480.11; EA: found C 70.11, H 3.55, N 2.92; calcd for C₂₈H₁₇NO₇ (479.44): C 70.15, H 3.57, N 2.92.

4′-Hydroxy-3′-(4-methylbenzoyl)-1′-(4-tolyl)-2H,4H-spiro[furo[3,2-c]chromene-3,2′-pyrrole]-2,4,5′(1′H)-trione (11fa)

Yield 385 mg (78%), mp 259–260 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.80–7.71 (m, 3H, Ar), 7.63 (ddd, J = 8.3, 7.5, 1.6 Hz, 1H, Ar), 7.38–7.29 (m, 2H, Ar), 7.27–7.22 (m, 3H, Ar), 7.17–7.11 (m, 3H, Ar), 2.40 (s, 3H, Me), 2.29 (s, 3H, Me); ¹³C NMR (100 MHz, CDCl₃) δ 188.3, 169.8, 166.0, 165.3, 155.9, 149.8, 145.1, 140.0, 134.8, 133.9, 130.8, 129.8, 129.4, 127.3, 125.0, 123.9, 117.7, 116.7, 110.4, 101.0, 69.8, 22.0, 21.3; IR (NaCl, cm⁻¹): 3438, 1848, 1723, 1673, 1646; MS: found 494.23; calcd for C₂₉H₂₀NO₇ (M + H)⁺ 494.12; EA: found C 70.54, H 3.86, N 2.85; calcd for C₂₉H₁₉NO₇ (493.47): C 70.59, H 3.88, N 2.84.

3′-Benzoyl-1′-(4-chlorophenyl)-4′-hydroxy-2H,4H-spiro[furo[3,2-c]chromene-3,2′-pyrrole]-2,4,5′(1′H)-trione (11ga)

Yield 335 mg (67%), mp 233–235 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.88–7.84 (m, 2H, Ar), 7.77 (dd, J = 7.9, 1.6 Hz, 1H, Ar), 7.70–7.62 (m, 1H, Ar), 7.58 (t, J = 7.4 Hz, 1H, Ar), 7.45 (t, J = 7.7 Hz, 2H, Ar), 7.40–7.30 (m, 4H, Ar), 7.20 (dd, J = 9.1, 2.4 Hz, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 188.8, 169.6, 165.9, 165.6, 156.0 (2C), 150.0, 136.4, 136.0, 135.2, 134.1, 132.0, 130.5, 129.6, 128.9, 128.7, 125.2, 124.0, 117.8, 116.9, 110.2, 100.5, 69.6; IR (NaCl, cm⁻¹): 3464, 1849, 1737, 1709, 1680, 1656; MS: found 500.17; calcd for C₂₇H₁₅ClNO₇ (M + H)⁺ 500.05; EA: found C 64.83, H 2.80, Cl 7.12, N 2.81; calcd for C₂₇H₁₄ClNO₇ (499.86): C 64.88, H 2.82, Cl 7.09, N 2.80.

3′-Benzoyl-1′-(4-bromophenyl)-4′-hydroxy-2H,4H-spiro[furo[3,2-c]chromene-3,2′-pyrrole]-2,4,5′(1′H)-trione (11ha)

Yield 413 mg (76%), mp 235–236 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.88–7.83 (m, 2H, Ar), 7.77 (dd, J = 7.9, 1.6 Hz, 1H, Ar), 7.66 (ddd, J = 8.9, 7.5, 1.6 Hz, 1H, Ar), 7.58 (ddd, J = 8.7, 2.5, 1.2 Hz, 1H, Ar), 7.52–7.41 (m, 4H, Ar), 7.39–7.33 (m, 2H, Ar), 7.16–7.11 (m, 2H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 188.8, 169.6, 165.8, 165.6, 156.0, 156.0, 149.9, 136.4, 135.2, 134.1, 133.5, 132.6, 129.6, 129.1, 128.7, 125.2, 124.1, 124.0, 117.8, 116.9, 110.2, 100.5, 69.6; IR (NaCl, cm⁻¹): 3473, 1848, 1738, 1709, 1678, 1654; MS: found 544.18; calcd for C₂₇H₁₅BrNO₇ (M + H)⁺ 544.00; EA: found C 59.54, H 2.61, Br 14.73, N 2.57; calcd for C₂₇H₁₄BrNO₇ (544.31): C 59.58, H 2.59, Br 14.68, N 2.57.

3′-Benzoyl-4′-hydroxy-1′-(4-methoxyphenyl)-5-methyl-2H-spiro[furo[3,2-c]quinoline-3,2′-pyrrole]-2,4,5′(1′H,5H)-trione (11cb)

Yield 345 mg (68%), mp 243–244 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.92–7.84 (m, 3H, Ar), 7.66 (ddd, J = 8.8, 7.2, 1.6 Hz, 1H, Ar), 7.56–7.47 (m, 1H, Ar), 7.42–7.28 (m, 4H, Ar), 7.22–7.14 (m, 2H, Ar), 6.85–6.80 (m, 2H, Ar), 3.74 (s, 3H, Me), 3.63 (s, 3H, OMe); ¹³C NMR (100 MHz, CDCl₃) δ 188.9, 171.2, 166.0, 161.0, 160.2, 157.7, 150.2, 141.9, 136.9, 133.5, 133.5, 129.7, 129.1, 128.5, 126.4, 124.2, 122.8, 116.6, 115.2, 115.1, 110.5, 105.6, 70.9, 55.5, 29.4; IR (NaCl, cm⁻¹): 3429, 1838, 1738, 1727, 1659, 1630; MS: found 509.21; calcd for C₂₉H₂₁N₂O₇ (M + H)⁺ 509.13; EA: found C 68.44, H 3.93, N 5.56; calcd for C₂₉H₂₀N₂O₇ (508.49): C 68.50, H 3.96, N 5.51.

3′-Benzoyl-4′-hydroxy-5-methyl-1′-(4-tolyl)-2H-spiro[furo[3,2-c]quinoline-3,2′-pyrrole]-2,4,5′(1′H,5H)-trione (11db)

Yield 339 mg (69%), mp 257–259 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.92–7.82 (m, 3H, Ar), 7.68 (ddd, J = 8.8, 7.2, 1.6 Hz, 1H, Ar), 7.54–7.49 (m, 1H, Ar), 7.40–7.26 (m, 4H, Ar), 7.18–7.09 (m, 4H, Ar), 3.62 (s, 3H, Me), 2.28 (s, 3H, C₆H₄Me); ¹³C NMR (100 MHz, DMSO-d₆) δ 188.5, 171.7, 165.6, 159.2, 156.6, 153.8, 141.0, 138.7, 136.6, 133.6, 133.1, 131.4, 130.2, 128.9, 128.2, 126.6, 122.8 (2C), 116.0, 115.4, 108.9, 105.4, 69.4, 28.9, 20.5; IR (NaCl, cm⁻¹): 3449, 1837, 1738, 1659, 1634; MS: found 493.21; calcd for C₂₉H₂₁N₂O₆ (M + H)⁺ 493.14; EA: found C 70.64, H 4.08, N 5.73; calcd for C₂₉H₂₀N₂O₆ (492.49): C 70.73, H 4.09, N 5.69.

3′-Benzoyl-4′-hydroxy-1′,5-diphenyl-2H-spiro[furo[3,2-c]quinoline-3,2′-pyrrole]-2,4,5′(1′H,5H)-trione (11ac)

Yield 303 mg (56%), mp 261–263 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.89–7.81 (m, 3H, Ar), 7.62–7.46 (m, 4H, Ar), 7.45–7.28 (m, 8H, Ar), 7.23 (d, J = 7.2 Hz, 1H, Ar), 7.15–7.12 (m, 1H, Ar), 7.03 (d, J = 7.7 Hz, 1H, Ar), 6.67 (d, J = 8.6 Hz, 1H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 189.1, 171.1, 166.0, 161.6, 157.6, 150.3, 143.0, 136.9, 136.6, 134.2, 133.6, 133.0, 130.4, 129.9, 129.6, 129.5, 129.4, 129.2, 128.8, 128.6, 127.6, 123.7, 123.0, 116.9, 110.2, 105.8, 70.6; IR (NaCl, cm⁻¹): 3443, 1835, 1732, 1718, 1637, 1626; MS: found 541.21; calcd for C₃₃H₂₁N₂O₆ (M + H)⁺ 541.14; EA: found C 73.29, H 3.71, N 5.20; calcd for C₃₃H₂₀N₂O₆ (540.53): C 73.33, H 3.73, N 5.18.

3′-Benzoyl-1′-(4-chlorophenyl)-4′-hydroxy-5-phenyl-2H-spiro[furo[3,2-c]quinoline-3,2′-pyrrole]-2,4,5′(1′H,5H)-trione (11gc)

Yield 339 mg (59%), mp 229–231 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.90–7.84 (m, 3H, Ar), 7.62–7.48 (m, 4H, Ar), 7.42 (ddd, J = 7.3, 4.7, 1.0 Hz, 3H, Ar), 7.37–7.22 (m, 5H, Ar), 7.16–7.10 (m, 1H, Ar), 7.07–7.01 (m, 1H, Ar), 6.69 (d, J = 8.5 Hz, 1H, Ar); ¹³C NMR (100 MHz, CDCl₃) δ 189.0, 170.9, 165.9, 161.7, 157.6, 149.8, 143.0, 136.8, 136.5, 135.6, 133.8, 133.2, 132.7, 130.4, 130.2, 129.6, 129.5, 129.2, 129.0, 128.8, 128.6, 123.8, 123.2, 117.0, 116.8, 110.2, 105.3, 70.6; IR (NaCl, cm⁻¹): 3400, 1841, 1734, 1651, 1622; MS: found 575.23; calcd for C₃₃H₂₀ClN₂O₆ (M + H)⁺ 575.10; EA: found C 68.89, H 3.46, Cl 6.11, N 4.80; calcd for C₃₃H₁₉ClN₂O₆ (574.97): C 68.94, H 3.33, Cl 6.17, N 4.87.

3′-(4-Bromobenzoyl)-4′-hydroxy-5-phenyl-1′-(4-tolyl)-2H-spiro[furo[3,2-c]quinoline-3,2′-pyrrole]-2,4,5′(1′H,5H)-trione (11ic)

Yield 362 mg (67%), mp 272–274 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 8.0 Hz, 1H, Ar), 7.76 (d, J = 8.3 Hz, 2H, Ar), 7.60–7.47 (m, 3H, Ar), 7.42–7.36 (m, 3H, Ar), 7.28–7.11 (m, 6H, Ar), 7.05 (d, J = 7.0 Hz, 1H, Ar), 6.69 (d, J = 8.7 Hz, 1H, Ar), 2.33 (s, 3H, Me); ¹³C NMR (100 MHz, CDCl₃) δ 188.2, 177.1, 165.7, 161.7, 157.6, 151.1, 142.9, 139.8, 136.5, 135.8, 133.0, 131.8, 131.3, 130.7, 130.4, 130.4, 129.9, 129.5, 129.3, 128.8, 128.5, 127.8, 123.7, 123.1, 120.1, 117.1, 116.3, 110.3, 105.8, 70.5, 21.4; IR (NaCl, cm⁻¹): 3449, 1836, 1735, 1660, 1616; MS: found 633.15; calcd for C₃₄H₂₁BrN₂O₆ (M + H)⁺ 633.07; EA: found C 64.36, H 3.39, Br 12.43, N 4.37; calcd for C₃₄H₂₁BrN₂O₆ (633.45): C 64.47, H 3.34, Br 12.61, N 4.42.

3′-Cinnamoyl-4′-hydroxy-1′-(4-tolyl)-2H,4H-spiro[furo[3,2-c]chromene-3,2′-pyrrole]-2,4,5′(1′H)-trione (13aa)

Yield 339 mg (67%), mp 236–237 °C (dec.), colorless crystals. ¹H NMR (400 MHz, DMSO-d₆) δ 11.25 (br. s, 1H, OH), 7.88–7.83 (m, 2H, Ar + CH=CH), 7.75–7.57 (m, 5H, Ar + CH=CH), 7.55–7.39 (m, 4H, Ar + CH=CH), 7.25 (d, J = 7.3 Hz, 2H, Ar + CH=CH), 7.02 (d, J = 7.4 Hz, 2H, Ar + CH=CH), 2.24 (s, 3H, Me); ¹³C NMR (100 MHz, DMSO-d₆) δ 182.0, 170.9, 165.8, 163.5, 157.6, 155.2, 154.8, 143.1, 139.1, 135.4, 133.4, 131.2, 130.8, 130.6, 129.1, 128.5, 126.6, 125.6, 123.3, 117.5, 115.6, 109.3, 101.8, 67.9, 20.6; IR (NaCl, cm⁻¹): 3420, 1843, 1716, 1670, 1642; MS: found 506.25; calcd for C₃₀H₂₀NO₇ (M + H)⁺ 506.12; EA: found C 71.36, H 3.73, N 2.79; calcd for C₃₀H₁₉NO₇ (505.48): C 71.28, H 3.79, N 2.77.

3′-Cinnamoyl-4′-hydroxy-5-methyl-1′-(4-tolyl)-2H-spiro[furo[3,2-c]quinoline-3,2′-pyrrole]-2,4,5′(1′H,5H)-trione (13ab)

Yield 389 mg (75%), mp 276–277 °C (dec.), colorless crystals. ¹H NMR (400 MHz, DMSO-d₆) δ 7.83–7.75 (m, 2H, Ar + CH=CH), 7.67–7.60 (m, 5H, Ar + CH=CH), 7.49–7.34 (m, 4H, Ar + CH=CH), 7.18 (d, J = 8.1 Hz, 2H, Ar + CH=CH), 7.04–6.99 (m, 2H, Ar + CH=CH), 3.59 (s, 3H, Me), 2.21 (s, 3H, C₆H₄Me); ¹³C NMR (100 MHz, DMSO-d₆) δ 181.9, 171.8, 165.6, 158.9, 156.5, 156.5, 142.9, 140.9, 138.6, 134.2, 133.4, 131.5, 130.7, 130.1, 129.0, 128.3, 126.5, 123.4, 122.8, 122.7, 116.4, 115.9, 109.0, 106.1, 68.7, 28.8, 20.4; IR (NaCl, cm⁻¹): 3437, 1841, 1728, 1667, 1639; MS: found 519.35; calcd for C₃₁H₂₃N₂O₆ (M + H)⁺ 519.16; EA: found C 71.76, H 4.21, N 5.43; calcd for C₃₁H₂₂N₂O₆ (518.53): C 71.81, H 4.28, N 5.40.

3′-Cinnamoyl-4′-hydroxy-1′-(4-methoxyphenyl)-5-methyl-2H-spiro[furo[3,2-c]quinoline-3,2′-pyrrole]-2,4,5′(1′H,5H)-trione (13bb)

Yield 417 mg (78%), mp 297–298 °C (dec.), colorless crystals. ¹H NMR (400 MHz, DMSO-d₆) δ 7.83–7.75 (m, 2H, Ar + CH=CH), 7.74–7.51 (m, 5H, Ar + CH=CH), 7.49–7.36 (m, 4H, Ar + CH=CH), 7.07–7.00 (m, 2H, Ar + CH=CH), 6.97–6.92 (m, 2H, Ar + CH=CH), 6.31 (br. s, 1H, OH), 3.68 (s, 3H, OMe), 3.60 (s, 3H, Me); ¹³C NMR (100 MHz, DMSO-d₆) δ 181.9, 171.8, 165.8, 159.3, 159.0, 156.7, 156.6, 142.9, 140.9, 134.2, 133.4, 130.7, 129.0, 128.3, 126.4, 123.4, 122.8, 122.7, 116.4, 116.0, 114.9, 109.1, 106.1, 68.9, 55.2, 28.8; IR (NaCl, cm⁻¹): 3456, 1839, 1728, 1662, 1639; MS: found 535.28; calcd for C₃₁H₂₃N₂O₇ (M + H)⁺ 535.15; EA: found C 69.78, H 4.02, N 5.23; calcd for C₃₁H₂₂N₂O₇ (534.52): C 69.66, H 4.15, N 5.24.

4′-Hydroxy-1′-(4-methoxyphenyl)-3′-(3-(4-methoxyphenyl)acryloyl)-5-methyl-2H-spiro[furo[3,2-c]quinoline-3,2′-pyrrole]-2,4,5′(1′H,5H)-trione (13cb)

Yield 435 mg (77%), mp 281–282 °C (dec.), colorless crystals. ¹H NMR (400 MHz, DMSO-d₆) δ 7.83–7.75 (m, 2H, Ar + CH=CH), 7.68–7.48 (m, 5H, Ar + CH=CH), 7.42–7.38 (m, 1H, Ar + CH=CH), 7.08–6.98 (m, 4H, Ar + CH=CH), 6.97–6.92 (m, 2H, Ar), 3.81 (s, 3H, OMe), 3.68 (s, 3H, OMe), 3.60 (s, 3H, Me); ¹³C NMR (100 MHz, DMSO-d₆) δ 181.9, 171.8, 165.8, 161.5, 159.3, 159.2, 156.6, 155.9, 143.0, 140.9, 133.4, 130.3, 128.3, 126.8, 126.4, 122.8, 122.7, 120.9, 116.8, 115.9, 114.9, 114.6, 109.1, 106.1, 68.9, 55.3, 55.2, 28.8; IR (NaCl, cm⁻¹): 3431, 1839, 1730, 1658, 1629; MS: found 565.27; calcd for C₃₂H₂₅N₂O₈ (M + H)⁺ 565.16; EA: found C 67.99, H 4.32, N 4.94; calcd for C₃₂H₂₄N₂O₈ (564.55): C 68.08, H 4.29, N 4.96.

3′-Cinnamoyl-4′-hydroxy-1′-(4-methoxyphenyl)-5-phenyl-2H-spiro[furo[3,2-c]quinoline-3,2′-pyrrole]-2,4,5′(1′H,5H)-trione (13bc)

Yield 388 mg (65%), mp 290–291 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 7.9 Hz, 1H, Ar + CH=CH), 7.75–7.26 (m, 12H, Ar + CH=CH), 7.25–7.21 (m, 3H, Ar + CH=CH), 7.07 (d, J = 7.4 Hz, 1H, Ar + CH=CH), 6.84 (d, J = 8.9 Hz, 2H, Ar + CH=CH), 6.71 (d, J = 8.7 Hz, 1H, Ar + CH=CH), 3.75 (s, 3H, OMe); ¹³C NMR (100 MHz, CDCl₃) δ 183.4, 171.2, 166.0, 161.5, 160.3, 157.7, 144.7, 142.9, 136.7, 134.8, 132.9, 130.9, 130.4, 129.5, 129.3, 129.1, 129.1, 129.0, 128.9, 126.6, 123.7, 123.7, 123.1, 117.9, 117.0, 115.2, 110.4, 105.4, 70.1, 55.6; IR (NaCl, cm⁻¹): 3423, 1839, 1716, 1667, 1639; MS: found 597.28; calcd for C₃₆H₂₅N₂O₇ (M + H)⁺ 597.17; EA: found C 72.39, H 4.01, N 4.76; calcd for C₃₆H₂₄N₂O₇ (596.60): C 72.48, H 4.06, N 4.70.

4′-Hydroxy-3′-(3-(4-methoxyphenyl)acryloyl)-5-phenyl-1′-(4-tolyl)-2H-spiro[furo[3,2-c]quinoline-3,2′-pyrrole]-2,4,5′(1′H, 5H)-trione (13dc)

Yield 440 mg (62%), mp 272–273 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.88 (dd, J = 8.0, 1.3 Hz, 1H, Ar + CH=CH), 7.72–7.36 (m, 8H, Ar + CH=CH), 7.29–7.09 (m, 6H, Ar + CH=CH), 7.05 (d, J = 7.7 Hz, 1H, Ar + CH=CH), 6.87 (d, J = 8.8 Hz, 2H, Ar + CH=CH), 6.70 (d, J = 8.6 Hz, 1H, Ar + CH=CH), 3.83 (s, 3H, OMe), 2.29 (s, 3H, Me); ¹³C NMR (100 MHz, CDCl₃) δ 183.2, 171.2, 166.0, 162.2, 161.4, 157.7, 144.7, 142.9, 139.6, 136.7, 132.8, 131.5, 130.8, 130.5, 130.4, 130.4, 129.4, 129.3, 128.9, 127.5, 127.4, 123.7, 123.0, 121.3, 117.0, 114.7, 110.4, 106.5, 70.0, 55.6, 21.3; IR (NaCl, cm⁻¹): 3443, 1846, 1737, 1662, 1637; MS: found 611.33; calcd for C₃₇H₂₇N₂O₇ (M + H)⁺ 611.18; EA: found C 72.71, H 4.25, N 4.63; calcd for C₃₇H₂₆N₂O₇ (610.62): C 72.78, H 4.29, N 4.59.

Methyl 1′-benzyl-4′-hydroxy-2,4,5′-trioxo-1′,5′-dihydro-2H,4H-spiro[furo[3,2-c]chromene-3,2′-pyrrole]-3′-carboxylate (17aa)

Yield 359 mg (83%), mp 222–224 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 8.70 (br. s, 1H, OH), 7.74–7.65 (m, 2H, Ar), 7.45–7.33 (m, 2H, Ar), 7.14–7.06 (m, 5H, Ar), 4.49 (dd, J = 4.53, 4.70 Hz, 2H, CH₂), 3.72 (s, 3H, OMe); ¹³C NMR (100 MHz, CDCl₃) δ 168.9, 164.1, 164.0, 163.0, 157.8, 155.9, 155.1, 135.0, 133.0, 129.2, 128.8, 128.7, 125.1, 123.4, 117.7, 110.2, 108.2, 101.5, 65.6, 52.8, 46.0; IR (NaCl, cm⁻¹): 3202, 1843, 1714, 1678, 1662, 1650; MS: found 434.15; calcd for C₂₃H₁₆NO₈ (M + H)⁺ 434.09; EA: found C 63.71, H 3.46, N 3.28; calcd for: C₂₃H₁₅NO₈ (433.37): C 63.75, H 3.49, N 3.23.

Methyl 4′-hydroxy-2,4,5′-trioxo-1′-phenyl-1′,5′-dihydro-2H,4H-spiro[furo[3,2-c]chromene-3,2′-pyrrole]-3′-carboxylate (17ba)

Yield 352 mg (84%), mp 206–208 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 8.62 (br. s, 1H, OH), 7.72–7.65 (m, 2H, Ar), 7.43–7.27 (m, 5H, Ar), 7.24–7.19 (m, 2H, Ar), 3.79 (s, 3H, OMe); ¹³C NMR (100 MHz, CDCl₃) δ 169.5, 164.7, 163.4, 163.1, 157.6, 156.0, 155.6, 135.1, 133.8, 130.2, 129.7, 127.6, 125.2, 123.6, 117.9, 110.1, 108.0, 101.1, 68.1, 52.9; IR (NaCl, cm⁻¹): 3279, 1837, 1738, 1716, 1645; MS: found 420.14; calcd for C₂₂H₁₄NO₈ (M + H)⁺ 420.07; EA: found C 62.91, H 3.06, N 3.38; calcd for C₂₂H₁₃NO₈ (419.35): C 63.01; H 3.12; N 3.34.

Methyl 4′-hydroxy-2,4,5′-trioxo-1′-(4-tolyl)-1′,5′-dihydro-2H,4H-spiro[furo[3,2-c]chromene-3,2′-pyrrole]-3′-carboxylate (17ca)

Yield 351 mg (81%), mp 210–212 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.71–7.64 (m, 2H, Ar), 7.43–7.33 (m, 2H, Ar), 7.17–7.07 (m, 4H, Ar), 6.30 (wide s, 1H, OH), 3.77 (s, 3H, OMe), 2.27 (s, 3H, Me); ¹³C NMR (100 MHz, CDCl₃) δ 169.6, 164.7, 163.7, 163.1, 157.4, 156.0, 155.6, 140.0, 135.0, 130.9, 130.8, 127.4, 125.1, 123.7, 117.9, 110.1, 107.9, 101.2, 68.3, 52.8, 21.3; IR (NaCl, cm⁻¹): 3148, 1852, 1743, 1722, 1692, 1652; MS: found 434.18; calcd for C₂₃H₁₆NO₈ (M + H)⁺ 434.09; EA: found C 63.71, H 3.46, N 3.28; calcd for C₂₃H₁₅NO₈ (433.37): C 63.75, H 3.49, N 3.23.

Methyl 1′-benzyl-4′-hydroxy-2,4,5′-trioxo-5-phenyl-1′,4,5,5′-tetrahydro-2H-spiro[furo[3,2-c]quinoline-3,2′-pyrrole]-3′-carboxylate (17ac)

Yield 401 mg (79%), mp 244–246 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 8.72 (br. s, 1H, OH), 7.80 (dd, J = 8.0, 1.4 Hz, 1H, Ar), 7.62–7.44 (m, 4H, Ar), 7.31 (td, J = 7.7, 0.9 Hz, 1H, Ar), 7.22–7.05 (m, 7H, Ar), 6.74 (d, J = 8.6 Hz, 1H, Ar), 4.57 (s, 2H, CH₂), 3.70 (s, 3H, OMe); ¹³C NMR (100 MHz, CDCl₃) δ 170.3, 164.3, 163.2, 160.9, 157.7, 157.2, 142.9, 136.5, 134.2, 133.1, 130.4, 129.4, 129.5, 129.3, 129.1, 129.0, 128.6, 128.3, 123.3, 123.1, 117.0, 110.1, 108.6, 106.1, 66.6, 52.6, 45.9; IR (NaCl, cm⁻¹): 3448, 1835, 1732, 1712, 1697, 1651, 1632; MS: found 509.28; calcd for C₂₉H₂₁N₂O₇ (M + H)⁺ 509.13; EA: found C 68.43, H 3.93, N 5.54; calcd for C₂₉H₂₀N₂O₇ (508.49): C 68.50, H 3.96, N 5.51.

Methyl 4′-hydroxy-2,4,5′-trioxo-1′,5-diphenyl-1′,4,5,5′-tetrahydro-2H-spiro[furo[3,2-c]quinoline-3,2′-pyrrole]-3′-carboxylate (17bc)

Yield 341 mg (69%), mp 255–256 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 8.77 (br. s, 1H, OH), 7.81 (ddd, J = 8.0, 1.5, 0.5 Hz, 1H, Ar), 7.63–7.49 (m, 3H, Ar), 7.45 (ddd, J = 8.8, 6.6, 3.0 Hz, 1H, Ar), 7.36–7.23 (m, 7H, Ar), 7.03 (ddd, J = 6.4, 2.9, 1.5 Hz, 1H, Ar), 6.72 (d, J = 7.3 Hz, 1H, Ar), 3.77 (s, 3H, OMe); ¹³C NMR (100 MHz, CDCl₃) δ 170.9, 163.7, 163.3, 161.2, 157.6, 157.4, 143.0, 136.5, 134.0, 133.2, 130.5, 130.5, 129.8, 129.5, 129.3, 129.2, 128.8, 127.7, 123.5, 123.2, 117.1, 110.0, 108.4, 105.9, 69.0, 52.7; IR (NaCl, cm⁻¹): 3183, 1836, 1741, 1713, 1671, 1650, 1639; MS: found 495.22; calcd for C₂₈H₁₉N₂O₇ (M + H)⁺ 495.12; EA: found C 68.09, H 3.63, N 5.74; calcd for C₂₈H₁₈N₂O₇ (494.46): C 68.02, H 3.67, N 5.67.

Methyl 4′-hydroxy-2,4,5′-trioxo-5-phenyl-1′-(4-tolyl)-1′,4,5,5′-tetrahydro-2H-spiro[furo[3,2-c]quinoline-3,2′-pyrrole]-3′-carboxylate (17cc)

Yield 325 mg (64%), mp 259–261 °C (dec.), colorless crystals. ¹H NMR (400 MHz, CDCl₃) δ 8.74 (wide s, 1H, OH), 7.81 (dd, J = 8.0, 1.3 Hz, 1H, Ar), 7.65–7.49 (m, 3H, Ar), 7.45 (ddd, J = 8.7, 7.2, 1.6 Hz, 1H, Ar), 7.34–7.22 (m, 2H, Ar), 7.18–7.01 (m, 5H, Ar), 6.74 (d, J = 8.6 Hz, 1H, Ar), 3.76 (s, 3H, OMe), 2.28 (s, 3H, Me); ¹³C NMR (100 MHz, CDCl₃) δ 170.9, 163.8, 163.3, 161.1, 157.7, 157.5, 143.0, 139.5, 136.6, 133.1, 131.6, 130.5, 130.5, 129.6, 129.2, 128.8, 127.6, 123.5, 123.1, 117.1, 110.1, 108.3, 106.0, 69.0, 52.6, 21.3; IR: ν = 3188, 1840, 1733, 1708, 1650, 1639; MS: found 509.25; calcd for C₂₉H₂₁N₂O₇ (M + H)⁺ 509.13; EA: found C 68.59, H 3.91, N 5.53; calcd for C₂₉H₂₀N₂O₇ (508.49): C 68.50, H 3.96, N 5.51.

Acknowledgements

Financial support for this work was provided by Ministry of Education and Science of the Russian Federation (project # 965).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, physico-chemical and spectral data. CCDC 1486439 and 1486440. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra16889b

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