HETEROCYCLES

Short Paper | Special issue | Vol. 86, No. 2, 2012, pp. 1507-1516
Received, 19th June, 2012, Accepted, 21st August, 2012, Published online, 4th September, 2012.
DOI: 10.3987/COM-12-S(N)42

■ Reactions of 3-[Bis(methylthio)methylene]-2(3H)-imidazo[1,2-a]pyridinones with Quinolinium and Isoquinolinium N-Unsubstituted Aminides

Akikazu Kakehi,* Takashi Abe, Hiroyuki Suga, and Kennosuke Itoh

Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, 4-17-1 Wakasato, Nagano 380-8553, Japan

Abstract

1,3-Dipolar cycloadditions of 3-[bis(methylthio)methylene]- 2(3H)-imidazo[1,2-a]pyridinones with quinolinium and isoquinolinium N-unsubstituted aminides were investigated and the corresponding spiro[imidazo[1,2-a]pyridine-3,3’-pyrazolo[1,5-a]quinoline] and spiro[imidazo[1,2-a]pyridine-3,3’-pyrazolo[5,1-a]isoquinoline] derivatives were formed by way of the elimination of methanethiol from the primary adducts.

Ketene dithioacetals substituted with electron-withdrawing group(s) are excellent electrophiles and dipolarophiles and their reactions with various substrates were documented.2-4 Recently, we reported a synthesis of 3-[bis(methylthio)methylene]-2(3H)-imidazo[1,2-a]pyridinones (1) which are novel heterocyclic ketenedithioacetals conjugated with a carbonyl group, and their transformations to 2H-pyrano[2’,3’:4,5]imidazo[1,2-a]pyridin-2-ones (2)5 and ethyl 2’,3’-dihydro-2-methylthio-2’,4-dioxospiro-
[2-cyclopentene-1,3’-imidazo[1,2-a]pyridine]-3-carboxylates (3) (see Figure 1).6 We were particularly interested in the formation of the spiro compounds 3 because a structurally similar 2,3-dihydrospiro[imidazo[1,2-a]pyridine-3,2’-indan]-2-one (4, ZSET1446) has been reported to act as an Alzheimer’s disease progression inhibitor and cognitive enhancer.7-9 Therefore, we next planned to prepare new 2(3H)-imidazo[1,2-a]pyridinone derivatives having a spiro-fused five-membered heterocycle at the 3-position from the 1,3-dipolar cycloadditions of 1 with appropriate reagents. After some elaboration for such 1,3-dipoles we found that 1 smoothly reacted with the title compounds. We report here the syntheses of 2-methylthio-2-oxo-2,3,3’,3a’-tetrahydrospiro[imidazo[1,2-a]pyridine-3,3’-pyrazolo-[1,5-a]quinoline] and 2-methylthio-2-oxo-2,3,3’,3a’-tetrahydrospiro[imidazo[1,2-a]pyridine-3,3’-pyrazolo[5,1-a]isoquinoline] derivatives in the reactions of 3-[bis(methylthio)methylene]-2(3H)-imidazo[1,2-a]pyridinones (1) with quinolinium and isoquinolinium N-unsubstituted aminides.

Since we earlier reported the 1,3-dipolar cycloadditions of 3-[bis(methylthio)methylene]-2(3H)-indolizinones whose structure is closely similar to that of 3-[bis(methylthio)methylene]-2(3H)-imidazo[1,2-a]pyridinones (1),4 we examined the reactions of 1a—c with monocyclic and bicyclic pyridiniumN-unsubstituted aminides. The reactions of 1a—c with 1-aminopyridinium iodide in the presence of a base did not afford any significant product, but those with 1-aminoquinolinium mesitylenesulfonate (5a) and 1-aminoisoquinolinium mesitylenesulfonate (5b) in the presence of excess potassium carbonate in THF at room temperature proceeded with the elimination of methanethiol to provide the corresponding products 6a—c, 7a,b and 7c+8c (its ratio 10:1) respectively. (Scheme 1)

Interestingly, compound 7c was converted to 8c during the recrystallization from CHCl3-hexane or on standing at room temperature. On the other hand, similar reaction of 1a with pyridinium monosubstituted methylide such as pyridinium 1-(ethoxycarbonyl)methylide or 1-phenacylide did not provide good results.
Elemental analyses and HRMS data for products 6a—c, 7a,b, and 8c were in accord with our proposed compositions and their IR spectra of 6a—c, and 7a,b exhibited a characteristic carbonyl band of the 2(3H)-imidazo[1,2-a]pyridinone at 1698—1701 cm-1. In 1H-NMR spectra of 6a—c and 7a—c the signal (δ 2.50—2.55) of sole methylthio group and that (δ 5.65—5.70 for 6a—c and δ 6.07—6.12 for 7a—c) for the 3a’-proton attached on the sp3-carbon were distinctly indicated.10 In addition the large high field shift (1.71—1.88 ppm) of the 5-proton in 6a—c and 7a—c compared with that in 1a—c was observed.5 This fact strongly supported the presence of the spiro structure at the 3-position of the 2(3H)-imidazo[1,2-a]pyridinone skeleton in 6a—c and 7a—c, because the lower chemical shifts of the 5-proton in 1a—c was mainly derived from the deshielding effect by the 3-exo-methylene group. The final structures of 6a—c and 7a—c were decided by the X-ray analysis of one compound 6a. The ORTEP drawing of 6a is shown in Figure 2.11

On the other hand, the 1H-NMR spectrum of 8c in CDCl3 significantly changed the chemical shifts depending upon their concentrations. For example, the 1H-NMR spectrum in 3.79×10-3 mol/L of 8c showed the signals at δ 2.34 (3H, s, 3’-Me), 2.40 (3H, s, 5’-Me), 2.73 (3H, s, SMe), 7.11 (1H, d, J=7.3 Hz, 6-H), 7.47 (1H, br s, 4’-H), 7.54 (1H, ddd, J=8.2, 8.1, 1.4 Hz, 9-H), 7.59 (1H, ddd, J=8.2, 7.7, 1.4 Hz, 8-H), 7.72 (1H, br d, J=7.7 Hz, 7-H), 8.16 (1H, br s, 6’-H), 8.21 (1H, J=7.3 Hz, 5-H), 8.31 (1H, br s, NH), and 9.20 (1H, br d, J=8.1 Hz, 10-H) and that in 9.30×10-2 mol/L exhibited the corresponding signals at δ 2.30, 2.37, 2.71, 7.06, 7.42, 7.49, 7.55, 7.67, 8.08, 8.20, 8.59, 9.11. Like this all methine and methyl protons of 8c showed the high field shifts (0.01-0.09 ppm) with the increase of the concentration but only amino proton a larger low field shift (0.28 ppm). The origins of such high or low field shifts for the proton signals of 8c is unclear but they may be considered the shielding effect by the intermolecular arene-arene interactions to their methine and methyl protons12 and the deshielding effect by the hydrogen bonding of the amino group respectively. In addition the presences of three sp3-carbons and an amino group could be also confirmed in the C13-NMR and IR spectra of 8c. Though we first considered the structure of 8c as isoquinolinium aminide 12 (see Scheme 2) formed by the retro-1,5-dipolar cyclization of 7c, these spectral evidences refused the structure 12 and suggested an alternative structure 8c. The structure 8c was finally confirmed by the X-ray analysis and the ORTEP drawing is shown in Figure 3.

The possible mechanisms for these reactions are shown in Scheme 2. There are two possible routes for the formation of cycloadducts 6a—c and 7a—c. First is path A in which products 6a—c and 7a—c were formed via the 1,3-dipolar cycloadditions of 1a—c with quinolinium (9a) or isoquinolinium aminide (9b) generated in situ from the alkaline treatment of their salts 5a,b, followed by the elimination of one molecule of methanethiol from the primary adducts 10. The second is path B in which the same products were given through the nucleophlic addition of the aminide nitrogen of 9a,b to the positive carbon of ketenedithioacetals 1a—c, the elimination of a methanethiol from the primary adducts 11, and then the 1,5-dipolar cyclization of the corresponding quinolinium or isoquinolinium

N-vinylaminides 12. We believe that above reactions proceeded by way of path A since it is known that the 1,5-dipolar cyclization of pyridinium (2,2-disubstituted vinyl)aminide derivatives is generally difficult to take place under such mild conditions.13-16 However, we do not completely refuse the alternative route (path B) for the formation of spiro compounds 6a—c and 7a―c since the extremely high electrophilicity of ketenedithioacetals conjugated with electron-withdrawing group(s) is well documented.2,3,5,6 The transformation from 7c to 8c can be interpreted by the aromatization of the 4,5-dihydropyrazole ring in 7c, followed by the 1,3-shift of the amino proton in the resulting 1,2-dihydropyridine 13.
The pharmaceutical activity for these spiro compounds 2, 6 and 7 is now in screening.

EXPERIMENTAL
Melting points were measured with a Yanagimoto micromelting point apparatus and were not corrected. Microanalyses were carried out on a Perkin-Elmer 2400 elemental analyzer. The 1H-NMR and 13C-NMR spectra were determined with a JEOL JNM-LA400 (1H: 400 MHz and 13C: 100.4 MHz) spectrometer in deuteriochloroform with tetramethylsilane used as the internal standard; the chemical shifts are expressed in δ values. The IR and HRMS spectra were taken with JASCO FT/IR-5300 IR spectrophotometers and Agilent 6520 Accurate-Mass Quadrupole Time-of-Flight (Q-TOF) LC/MS.

Reaction of 3-[bis(methylthio)methylene]-2(3H)-imidazo[1,2-a]pyridinones with quinolinium or isoquinolinium aminides. General method. A mixture of 3-[bis(methylthio)methylene]-2(3H)-imidazo[1,5-a]pyridinones (1, 1 mmol), 1-aminoquinolinium (5a, 0.344g (1 mmol)) or 1-aminoisoquinolinium mesitylenesulfonate (5b, 0.344g (1 mmol)), and potassium carbonate (5g) in THF (30 mL) was stirred at room temperature until the disappearance of 1 was confirmed by TLC monitoring. The resulting mixture was then filtered to remove insoluble inorganic substances and the filtrate was concentrated at reduced pressure. The residue was separated by column chromatography on alumina using chloroform as an eluent. The yellow fractions were combined and concentrated at reduced pressure. Recrystallization from CHCl3-hexane gave the corresponding adducts 6a—c and 7a,b, but the reaction of 1c with 5b afforded a 10:1 mixture of 7c and 8c after the column chromatographic separation and the recrystallization of its crude products from the same solvent afforded only 8c. The same compound 8c could be also obtained on standing of cycloadduct 7c at room temperature. These results and some properties of products (6a—c, 7a—c, and 8c) are as follows:
2’-Methylthio-2-oxo-2,3,3’,3a’-tetrahydrospiro[imidazo[1,2-a]pyridine-3,3’-pyrazolo[1,5-a]quinoline] (6a): 50% (from 1a and 5a), 2 h (reaction time), yellow prisms (from CHCl3-hexane), mp 165—166 oC. IR (KBr) cm-1: 1626, 1698. 1H-NMR δ: 2.55 (3H, s, SMe), 5.19 (1H, dd, J = 10.0, 2.3 Hz, 4’-H), 5.69 (1H, dd, J = 2.3, 2.3 Hz, 3a’-H), 6.51 (1H, dd, J = 10.0, 2.3 Hz, 5’-H), 6.60 (1H, ddd, J = 6.8, 6.8, 1.0 Hz, 6-H), 6.83 (1H, ddd, J = 7.6, 7.3, 1.2 Hz, 7’-H), 7.02 (1H, dd, J = 7.3, 1.2 Hz, 6’-H), 7.17 (1H, br d, J = 6.8 Hz, 5-H), 7.21—7.27 (2H, m, 8-H, 8’-H), 7.38 (1H, br d, J = 8.1 Hz, 9’-H), 7.67 (1H, ddd, J = 9.1, 6.8, 1.0 Hz, 7-H). 13C NMR (CDCl3) δ: 14.27, 68.65, 79.79, 112.30, 112.92, 113.66, 113.81, 118.63, 119.93, 127.72, 130.09, 130.24, 134.93, 138.48, 142.84, 147.49, 166.37, 181.63. C18H15N4OS (M+H)+: Calcd; 335.0961 (Found; 335.0968). Anal. Calcd for C18H14N4OS: C, 64.65; H, 4.22; N, 16.75. Found C, 64.40; H, 4.12; N, 16.63.
8-Methyl-2’-methylthio-2-oxo-2,3,3’,3a’-tetrahydrospiro[imidazo[1,2-a]pyridine-3,3’-pyrazolo[1,5-a]quinoline] (6b): 73% (from 1b and 5a), 2 h (reaction time), yellow prisms (from CHCl3-hexane), mp 97—98 oC. IR (KBr) cm-1: 1618, 1701. 1H-NMR δ: 2.43 (3H, s, 8-Me), 2.54 (3H, s, SMe), 5.19 (1H, dd, J = 10.0, 2.3 Hz, 4’-H), 5.70 (1H, dd, J = 2.3, 2.3 Hz, 3a’-H), 6.50 (1H, dd, J = 10.0, 2.3 Hz, 5’-H), 6.53 (1H, dd, J = 6.8, 6.8 Hz, 6-H), 6.82 (1H, ddd, J = 7.6, 7.3, 1.2 Hz, 7’-H), 7.02 (1H, dd, J = 7.3, 1.2 Hz, 6’-H), 7.06 (1H, br d, J = 6.8 Hz, 5-H), 7.24 (1H, ddd, J = 8.1, 7.6, 1.2 Hz, 8’-H), 7.38 (1H, br d, J = 8.1 Hz, 9’-H), 7.48 (1H, br d, J = 6.8 Hz, 7-H). 13C NMR (CDCl3) δ: 14.44, 17.32, 68.76, 80.52, 112.09, 113.03, 114.16, 118.82, 119.97, 126.50, 127.83, 130.21, 131.27, 138.74, 141.11, 147.76, 166.45, 181.78 (one carbon is overlapping). C19H17N4OS (M+H)+: Calcd; 349.1118 (Found; 349.1122). Anal. Calcd for C19H16N4OS: C, 65.50; H, 4.63; N, 16.08. Found C, 65.47; H, 4.51; N, 15.89.
6,8-Dimethyl-2’-methylthio-2-oxo-2,3,3’,3a’-tetrahydrospiro[imidazo[1,2-a]pyridine-3,3’-pyrazolo[1,5-a]quinoline] (6c): 48% (from 1c and 5a), 16 h (reaction time), yellow needles (from CHCl3-hexane), mp 101—103 oC. IR (KBr) cm-1: 1635, 1701. 1H-NMR δ: 2.10 (3H, s, 6-Me), 2.40 (3H, s, 8-Me), 2.54 (3H, s, SMe), 5.20 (1H, dd, J = 10.0, 2.3 Hz, 4’-H), 5.65 (1H, dd, J = 2.3, 2.3 Hz, 3a’-H), 6.50 (1H, dd, J = 10.0, 2.3 Hz, 5’-H), 6.83 (1H, ddd, J = 7.6, 7.3, 1.2 Hz, 7’-H), 6.86 (1H, br s, 5-H), 7.04 (1H, dd, J = 7.3, 1.2 Hz, 6’-H), 7.25 (1H, ddd, J = 8.1, 7.6, 1.2 Hz, 8’-H), 7.34 (1H, br s, 7-H), 7.39 (1H, br d, J = 8.1 Hz, 9’-H). C20H19N4OS (M+H)+: Calcd; 363.1274 (Found; 363.1284). Anal. Calcd for C20H18N4OS: C, 66.28; H, 5.01; N, 15.46. Found C, 66.32; H, 4.79; N, 15.35.
2’-Methylthio-2-oxo-2,3,3’,3a’-tetrahydrospiro[imidazo[1,2-a]pyridine-3,3’-pyrazolo[5,1-a][isoquinoline] (7a): 41% (from 1a and 5b), 1 h (reaction time), yellow prisms (from CHCl3-hexane), mp 176—178 oC. R (KBr) cm-1: 1626, 1701. 1H-NMR δ: 2.51 (3H, s, SMe), 5.44 (1H, d, J = 7.6 Hz, 8’-H), 6.12 (1H, s, 3a’-H), 6.41 (1H, ddd, J = 6.8, 6.8, 1.0 Hz, 6-H), 6.52 (1H, br d, J = 7.6 Hz, 4’-H), 6.84 (1H, dt, J = 7.6, 1.2 Hz, 5’-H), 6.88 (1H, d, J = 7.6 Hz, 9’-H), 6.96 (1H, dd, J = 7.6, 1.2 Hz, 7’-H), 7.05 (1H, br d, J = 6.8 Hz, 5-H), 7.08 (1H, br t, J = 7.6 Hz, 6’-H), 7.19 (1H, br d, J = 9.2 Hz, 8-H), 7.54 (1H, ddd, J = 9.2, 6.8, 1.0 Hz, (7-H). 13C NMR (CDCl3) δ: 14.23, 69.08, 82.02, 100.02, 112.44, 116.06, 122.86, 124.62, 125.28, 126.51, 128.75, 129.51, 132.18, 133.88, 142.68, 148.00, 166.85, 182.69. C18H15N4OS (M+H)+ : Calcd; 335.0961 (Found; 335.0968). Anal. Calcd for C18H14N4OS: C, 64.65; H, 4.22; N, 16.75. Found C, 64.51; H, 4.21; N, 16.66.
8-Methyl-2’-methylthio-2-oxo-2,3,3’,3a’-tetrahydrospiro[imidazo[1,2-a]pyridine-3,3’-pyrazolo[5,1-a]isoquinoline] (7b): 87% (from 1b and 5b), 3 h (reaction time), yellow prisms (from CHCl3-hexane), mp 158—159 oC. IR (KBr) cm-1: 1622, 1698. 1H-NMR δ:2.50 (3H, s, SMe), 5.42 (1H, d, J = 7.6 Hz, 8’-H), 6.12 (1H, s, 3a’-H), 6.41 (1H, ddd, J = 6.8, 6.8, 1.0 Hz, 6-H), 6.52 (1H, br d, J = 7.6 Hz, 4’-H), 6.84 (1H, ddd, J = 7.6, 7.6, 1.2 Hz, 5’-H), 6.88 (1H, d, J = 7.6 Hz, 9’-H), 6.96 (1H, dd, J = 7.6, 1.2 Hz, 7’-H), 7.05 (1H, br d, J = 6.8 Hz, 5-H), 7.08 (1H, br t, J = 7.6 Hz, 6’-H), 7.19 (1H, br d, J = 9.2 Hz, 8-H), 7.54 (1H, ddd, J = 9.2, 6.8, 1.0 Hz, (7-H). 13C NMR (CDCl3) δ: 14.28, 17.32, 69.05, 82.60, 99.95, 112.18, 123.07, 124.69, 125.23, 126.39, 128.67, 129.58, 130.98, 132.27, 141.06, 148.10, 166.76, 182.68. C19H17N4OS (M+H)+ : Calcd; 349.1118 (Found; 349.1124). Anal. Calcd for C19H16N4OS: C, 65.50; H, 4.63; N, 16.08. Found C, 65.38; H, 4.67; N, 15.89.

6,8-Dimethyl-2’-methylthio-2-oxo-2,3,3’,3a’-tetrahydrospiro[imidazo[1,2-a]pyridine-3,3’-pyrazolo[5,1-a]isoquinoline] (7c): 42% (from 1c and 5b), 24 h (reaction time), yellow prisms. 1H-NMR δ: 1.95 (3H, S, 6-Me), 2.38 (3H, s, 8-Me), 2.50 (3H, s, SMe), 5.43 (1H, d, J = 7.6 Hz, 8’-H), 6.07 (1H, s, 3a’-H), 6.48 (1H, br d, J = 7.6 Hz, 4’-H), 6.73 (1H, br s, 5-H), 6.81 (1H, ddd, J = 7.6, 7.6, 1.2 Hz, 5’-H), 6.89 (1H, d, J = 7.6 Hz, 9’-H), 6.94 (1H, dd, J = 7.6, 1.2 Hz, 7’-H), 7.06 (1H, br t, J = 7.6 Hz, 6’-H), 7.21 (1H, br s, 7-H).17 13C NMR (CDCl3) δ: 14.13, 16.99, 17.21, 69.00, 82.81, 100.02, 122.42, 123.21, 124.61, 125.18, 125.65, 126.41, 128.71, 128.90, 129.74, 132.33, 144.04, 148.29, 165.20, 182.74.
2-Methylthiopyrazolo[5,1-a]isoquinoline-1-[N-(3,5-dimethylpyridin-2-yl)]carboxamide (8c): 4% (from 1c and 5b), 24 h (reaction time), colorless prisms (from CHCl3-Et2O), mp 183—184 oC. IR (KBr) cm-1: 3192, 1665. 1H-NMR δ (3.79×10-3 mol/L): 2.34 (3H, s, 3’-Me), 2.40 (3H, s, 5’-Me), 2.73 (3H, s, SMe), 7.11 (1H, d, J = 7.3 Hz, 6-H), 7.47 (1H, br s, 4’-H), 7.54 (1H, ddd, J = 8.2, 8.1, 1.4 Hz, 9-H), 7.59 (1H, ddd, J = 8.2, 7.7, 1.4 Hz, 8-H), 7.72 (1H, br d, J = 7.7 Hz, 7-H), 8.16 (1H, br s, 6’-H), 8.21 (1H, d, J = 7.3 Hz, 5-H), 8.31 (1H, br s, NH), 9.20 (1H, br d, J = 8.1 Hz, 10-H). 1H-NMR δ (9.30×10-2 mol/L): 2.30 (3H, s, 3’-Me), 2.37 (3H, s, 5’-Me), 2.71 (3H, s, SMe), 7.06 (1H, d, J = 7.3 Hz, 6-H), 7.42 (1H, br s, 4’-H), 7.49 (1H, ddd, J = 8.2, 8.1, 1.4 Hz, 9-H), 7.55 (1H, ddd, J = 8.2, 7.7, 1.4 Hz, 8-H), 7.67 (1H, br d, J = 7.7 Hz, 7-H), 8.08 (1H, br s, 6’-H), 8.20 (1H, d, J = 7.3 Hz, 5-H), 8.59 (1H, br s, NH), 9.11 (1H, br d, J = 8.1 Hz, 10-H). 13C NMR (CDCl3) δ (9.30×10-2 mol/L): 15.23, 17.72, 18.45, 109.06, 113.56, 123.52, 125.47, 126.92, 127.02, 127.84, 128.56, 129.06, 130.15, 131.38, 139.38, 140.47, 146.19, 147.19, 150.15, 162.55. C20H19N4OS (M+H)+: Calcd; 363.1274 (Found; 363.1280). Anal. Calcd for C20H18N4OS: C, 66.28; H, 5.01; N, 15.46. Found C, 66.11; H, 5.00; N, 15.43.

Crystallography of 2’-Methylthio-2-oxo-2,3,3’,3a’-tetrahydrospiro[imidazo[1,2-a]pyridine-3,3’-pyrazolo[1,5-a]quinoline] (6a). A single crystal (0.92×0.52×0.04 mm) grown from ethanol was used for the unit-cell determinations and data collection by a Rigaku AFC5S four-circle diffractometer with graphite-monochromated MoKα radiation (λ=0.71069 Å). Crystal data of 6a: C18H14N4OS; M=334.39; monoclinic, space group P21/a (#14), Z=4 with a=14.523 (14) Å, b=7.22 (3) Å, c=15.600 (18) Å, β=99.65o (8); V=1611.7 (64) Å3, and Dcalc.=1.378 g/cm3. All calculations were performed using CrystalStructure.18 The structure was solved by a direct method (SIR92).19 The non-hydrogen atoms were refined anisotropically, and the hydrogen atoms were attached at the idealized position and not refined. The final R- and Rw-factors after full-matrix least-squares refinements were 0.074 and 0.055 for 1230 (I>2.00σ(I)) observed reflections, respectively.
Crystallography of 2-Methylthiopyrazolo[5,1-a]isoquinoline-1-[N-(3,5-dimethylpyridin-2-yl)]carboxamide (8c). A single crystal (0.20×0.20×0.40 mm) grown from CHCl3-hexane was used for the unit-cell determinations and data collection by a Bruker D8 goniometer with graphite-monochromated MoKα radiation (λ = 0.71069 Å). Crystal data of 8c: C20H18N4OS; M = 362.45; orthorhombic, space group Pbca (#61), Z = 8 with a = 16.5134 (10) Å, b = 8.9284 (5) Å, c = 23.6791 (14) Å; V = 3503.9 (4) Å3, and Dcalc = 1.374 g/cm3. All calculations were performed using Bruker SHELXTL Software Package. The structure was solved by a direct method (SHELXL-97).20 The non-hydrogen atoms were refined anisotropically, and the hydrogen atoms were attached at the idealized position and not refined. The final R- and Rw-factors after full-matrix least-squares refinements were 0.035 and 0.088 for 3667 (I>2.00σ(I)) observed reflections, respectively.

References

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12. In this case the intramolecular arene-arene interaction of 8c is negligible because the amide linkage holds usually a Z-form as seen in the X-ray structure (See Figure 3).
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14. Y. Tamura, Y. Miki, Y. Sumida, and M. Ikeda, J. Chem. Soc., Perkin Trans. 1, 1973, 2580. CrossRef
15. A. Kakehi, S. Ito, T. Funahashi, and Y. Ota, J. Org. Chem., 1976, 41, 1570. CrossRef
16. Y. Tominaga, S. Hidaki, Y. Matsuda, and G. Kobayashi, Yakugaku Zasshi, 1984, 104, 440.
17. Elemental analysis for this compound 7c could not be performed because of its smooth transformation to isoquinolinium N-vinylaminide 8c.
18. CrystalStructure 3.8: Crystal Structure Analysis Package, Rigaku and Rigaku/MSC (2000—2006). 9009 New Trails Dr. The Woodlands TX 77381 USA.
19. SIR92: A. Altmare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. Burla, G. Polridori, and M. Camalli, J. Appl. Cryst., 1994, 27, 435. CrossRef
20. SHELXL-97: G. M. Sheldrick, Acta Cryst., 2008, A64, 112.