HETEROCYCLES

Paper | Special issue | Vol. 84, No. 2, 2012, pp. 753-764
Received, 24th June, 2011, Accepted, 4th August, 2011, Published online, 15th August, 2011.
DOI: 10.3987/COM-11-S(P)50

■ Molecular Recognition of 2-(Arylmethylthio)indolizine Derivatives through an Intramolecular Arene-π (Cation) Interaction

Akikazu Kakehi,* Kennosuke Itoh, Hiroyuki Suga, Nobuhiro Yamaguchi, Takashi Abe, Yohei Yuda, and Haruka Katsumata

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

Abstract

Some 2-(arylmethylthio)indolizines bearing ethoxycarbonyl and/or cyano group(s) at the 1- and 3-positions were synthesized and their conformations were investigated by 1H-NMR spectra and X-ray analyses. Interestingly, it was indicated that the sulfide linkages in 2-(1-naphthylmethylthio)indolizine derivatives in CDCl3 solution are mainly present in gauche conformations and the intramolecular arene-π (cation) interactions reflect the electrophilic reactivity of the 1- and 3-substituents.

INTRODUCTION
In recent years, we reported interesting intramolecular arene-arene and arene-π interactions in some model compounds in which various aryl rings or double and triple bonds are combined with a thieno[3,4-b]indolizine ring at the 3-position through a sulfide spacer.2-6 From these studies we made clear that the gauche forms of the sulfide linkage are more stable than the anti one and one gauche form having some favorable interaction as described above is predominant in the solution state, though the differences in the energies between these gauche and anti forms are small and these forms are capable of being present in their crystalline states. In a continuation of this work we are next interested in applying this type of interaction to molecular recognition, in particular, the discrimination between two functional groups which are similar. We selected diethyl indolizine-1,3-dicarboxylate and indolizine- 1,3-carbonitriles as model compounds (See Figure 1) because their two ethoxycarbonyl and cyano groups are not distinguishable with ease by usual 1H-NMR or IR spectra. In addition the pyrrole ring of the indolizine skeleton in the crystal structure did not indicate the distinct bond alteration as shown in form B in Figure 1 and the 1- and 3-positions toward the 2-position has similar structural data.7 However, the order (3-CN>1-CN>3-CO2Et>1-CO2Et) for the electrophilic reactivity of the ester carbonyl and cyano groups at the 1- and 3-positions in some reactions is evident except that of diethyl 6,8-dimethylindolizine-1,3-dicarboxylate in which the steric promotion to the 1-ethoxycarbonyl group by the 8-methyl one is present.8-11 In general, a more reactive electron-withdrawing group in a molecule has a larger LUMO coefficient than a less reactive one and the intramolecular arene-π (cation) interaction between an aryl ring and the more reactive group should be larger than the other.

We expected that the gauche conformations (G1 and G2) of title compounds would become more stable than the anti one (A1) in the solution state because of the presence of a favorable arene-π (cation) interaction and it can be easily detected by observing the shielding or deshielding effect of a proper aryl ring onto the 1- or 3-substituent and vice versa. In this paper we report the preparation of the title and related compounds and their conformational analyses by 1H-NMR spectra and X-ray analyses.

RESULTS AND DISCUSSION
We selected phenyl and 1-naphthyl groups as the aryl group in the 2-substituent of the title compounds and examined the possibility of these shielding effects. From the consideration of these molecular structures using Dreiding models it was indicated that the overlap of the phenyl ring on the ethoxy group of the ester function at the 1- (G2 form) or 3-position (G1 form) is less effective but that of the 1-naphthyl ring is adequate. These models 4a―i, and related compounds 4j―o were prepared in 31―73% yields by the S-alkylations of pyridinium 1-(2-arylmethylthio-2-thioxo)ethylide (1a―i) with ethyl bromoacetate (2a) or bromoacetonitirile (2b), followed by alkaline treatment and dehydrogenation of the corresponding pyridinium salts 3a―o. (Scheme 1)

Elemental analyses for products 4a—o were in accord with our proposed compositions and their IR spectra exhibited characteristic aromatic ester carbonyl band(s) at 1676—1699 cm-1 or a cyano one at 2197—2213 cm-1. In addition, the carbonyl band for the 1-ethoxycarbonyl group in compounds 4c,f,l was observed at higher region (1705—1725 cm-1).8,9 The UV-VIS spectra of 2-(arylmethylthio)indolizines (4a—o) were nearly parallel to those for respect 2-(methylthio)indolizines and significant bathochromic shifts and an remarkable increase in their molar extinction coefficients were not observed.12 The 1H-NMR spectral data of 2-(arylmethylthio)- 4a—o and the corresponding 2-(methylthio)indolizine derivatives 5a—l (Figure 2) are shown in Table 1. In the 1H-NMR and 13C-NMR spectra of 4a—o the signals for any other conformer could not be detected.13 As expected, the shielding effect to one ethoxy group in the 1H-NMR spectra of diethyl 2-(benzylthio)indolizine-1,3-

dicarboxylates (4a—c) was considerably small (δ 0.06—0.09 ppm) in comparison to those of diethyl 2-(methylthio)indolizine-1,3-dicarboxylates (5a—c). On the other hand, the shielding effect to one ethoxy group in diethyl 2-(1-naphthylmethylthio)indolizine- 1,3-dicarboxylates (4d—f) was larger (δ 0.16—0.37 ppm) and the signals due to the C-2’, C-3’, and C-4’ protons (see Figure 1) on the naphthyl ring also appeared at higher magnetic regions. Interestingly, both ethoxy proton signals in 6,8-dimethyl derivative 4f changed significantly to indicate the coexistence of the G1 and G2 conformers. In the 1H-NMR spectra of 2-(1-naphthylmethylthio)indolizine-1,3-dicarbonitriles (4g—i) the reduction or absence of the shielding effect to the C-2’, C-3’, and C-4’ protons on the naphthyl ring in 4g—i was observed. The fact that 4d,e and 4g—i have the G1 conformation could be determined by the X-ray analyses of 4e,h and the ORTEP drawing for 4e is shown in Figure 3.14

As seen in this figure the naphthyl moiety (arene) overlapped with the carbonyl function (π) in the 3-ethoxycarbonyl group. Similarly the naphthyl ring in 4h faced to the 3-cyano group. The torsion angles (C2-S-C2(2)-C1’) of 4e,h were 56.8(4) and 59.5(3) oC respectively and these values closely resemble the ideal one (60 oC). The conformations of the ethyl 1-cyano-2- (1-naphthylmethylthio)indolizine-3-carboxylates 4j—l and ethyl 3-cyano-2-(1- naphthylmethylthio)indolizine-1-carboxylates 4m—o were deduced by comparing their 1H-NMR spectra with those of 4d,e,g—i and 5d,e,g—i. For example, the signals of the 3-ethoxycarbonyl group in 4j—l shifted to higher magnetic fields (δ 1.22—1.27 and 4.15—4.27) than those (δ 1.46—1.47 and 4.46—4.48) of 5g—i to indicate the contribution of the G1 form, but the shielding effect was smaller than that of 4d,e and the high-field shifts to the C-2’, C-3’, and C-4’ protons on the naphthyl ring of 4j,k was almost not observed. All of the chemical shifts for the naphthyl ring protons of 4j,k are parallel to those of 4g—i. This fact seems to indicate the comparatively weak contribution of the G1 form and the larger one of the G2 form in 4j,k. Similarly, the high-field shift to the 1-ethoxycarbonyl group of 4m,n was almost not observed and the predominant presence of the G1 form was suggested. However, the 1H-NMR spectra of compounds 4l,o exhibited significant high-field shifts of the C-2’ proton and the ethoxyl protons, and the presence of the arene-π (cation) interaction between the 1-naphthyl ring and the ester carbonyl group was shown.
This trend (3-CN>1-CN>3-Es>1-Es) of the arene-π (cation) interaction shown here coincided well with the order of the electrophilic reactivity of indolizine derivatives bearing electron withdrawing groups at the 1- and 3-positions. 8,9 Furthermore, the increase in the reactivity of the 1-ethoxycarbonyl group by the 8-methyl group as seen in ethyl 6,8-dimethylindolizine-1-carboxylate derivatives 4f,o was also in accord with our previous experimental results, 8,11 though it does not mean the exclusive nucleophilic attack on the 1-ethoxycarbonyl group in these molecules. The increased reactivity of the 3-ethoxycarbonyl group in ethyl 1-cyano-6,8-dimethylindolizine-3-carboxylate (4l) has not been observed until now but an example in which the 3-acetyl group of 3-acetyl-2-ethoxycarbonylmethylthio- 6,8-dimethylindolizine-1-carbonitrile reacted under the alkaline conditions to provide the corresponding ethyl 9-cyano-3,6,8-trimethylthieno[2,3-b]indolizine-2-carboxylate was described.8
In summary, we have synthesized some 2-(1-naphthylmethylthio)indolizines having ethoxycarbonyl and/or cyano group(s) at the 1- and 3-positions and showed that the order of the reactivity of these substituents can be predicted by analyzing the intramolecular arene-π (cation) interaction.

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 deuteriochloroform25 with tetramethylsilane used as the internal standard; the chemical shifts are expressed in δ values. The IR spectra were taken with JASCO FT/IR-5300 IR spectrophotometers.
Preparation of pyridinium 1-[2-(arylmethylthio)-2-thioxo]ethanides Pyridinium methylides employed here were prepared according to the procedure described by Tominaga et al.15 The results and some properties of new pyridinium methylides (1c,f,i) are as follows:
3,5-Dimethylpyridinium 1-(1-ethoxycarbonyl-2-benzylthio-2-thioxo)ethanides (1c): 66% (from 1-ethoxycarbonylmethyl-3,5-dimethylpyridinium chloride, carbon disulfide, and benzyl bromide), yellow needles (from CHCl3-Et2O), mp 226—227 oC. IR (KBr) cm-1: 1644. 1H-NMR δ: 1.17 (3H, t, J=7.1 Hz, OCH2CH3), 2.52 (6H, s, 3-, 5-Me), 4.14 (2H, q, J=7.1 Hz, OCH2CH3), 4.57 (2H, s, SCH2), 7.20 (1H, m, 4’-H), 7.27 (2H, m, 3’-H), 7.43 (2H, m, 2’-H), 7.92 (1H, br s, 4-H), 8.14 (2H, br s, 2-, 6-H). Anal. Calcd for C19H21NO2S2: C, 63.48; H, 5.89; N, 3.90. Found: C, 63.77; H, 5.71; N, 3.79.
3,5-Dimethylpyridinium 1-[1-ethoxycarbonyl-2-(1-naphthylmethylthio)-2-thioxo]ethanides (1f): 57% (from 1-ethoxycarbonylmethyl-3,5-dimethylpyridinium chloride, carbon disulfide, and 1-chloromethylnaphthalene), yellow needles (from CHCl3- Et2O), mp 234—235 oC. IR (KBr) cm-1: 1640. 1H-NMR δ: 1.11 (3H, t, J=7.1 Hz, OCH2CH3), 2.53 (6H, s, 3-, 5-Me), 4.08 (2H, q, J=7.1 Hz, OCH2CH3), 5.01 (2H, s, SCH2), 7.38 (1H, q, J=7.1, 8.1 Hz, naphthyl-H), 7.45 (1H, m, naphthyl-H), 7.50 (1H, m, naphthyl-H), 7.60 (1H, (br d, J=6.8 Hz, naphthyl-H), 7.74 (1H, br d, J=8.5 Hz, naphthyl-H), 7.82 (1H, br d, J=7.6 Hz, naphthyl-H), 7.93 (1H, br s, 4-H), 8.17 (2H, br s, 2-, 6-H), 8.21 (1H, br d, J=8.3 Hz, naphthyl-H). Anal. Calcd for C23H23NO2S2: C, 67.45; H, 5.66; N, 3.42. Found: C, 67.44; H, 5.78; N, 3.31.
3,5-Dimethylpyridinium 1-[1-cyano-2-(1-naphthylmethylthio)-2-thioxo]ethanides (1i): 60% (from 1-cyanomethyl-3,5-dimethylpyridinium chloride, carbon disulfide, and 1-chloromethylnaphthalene), yellow needles (from CHCl3- Et2O), mp 203—204 oC. IR (KBr) cm-1: 2166. 1H-NMR δ: 2.51 (6H, s, 3-, 5-Me), 5.10 (2H, s, SCH2), 7.40 (1H, q, J=7.1, 8.1 Hz, naphthyl-H), 7.49 (1H, m, naphthyl-H), 7.54 (1H, m, naphthyl-H), 7.63 (1H, (br d, J=7.1 Hz, naphthyl-H), 7.77 (1H, br d, J=8.3 Hz, naphthyl-H), 7.84 (1H, br d, J=7.6 Hz, naphthyl-H), 7.85 (1H, br s, 4-H), 8.19 (1H, br d, J=8.1 Hz, naphthyl-H), 8.58 (2H, br s, 2-, 6-H). Anal. Calcd for C21H18N2S2: C, 69.58; H, 5.01; N, 7.73. Found: C, 69.66; H, 5.01; N, 7.64.
Preparation of 2-(arylmethylthio)indolizine 4a—o and 2-(methylthio)indolizine derivatives 5a—l. General method. A mixture of pyridinium 1-(2-arylmethylthio-2-thioxo)ethanides (1, 2 mmol) or pyridinium 1-(2-methylthio-2-thioxo)ethanides (2 mmol), and ethyl bromoacetate 2a or bromoacetonitrile 2b (2.2 mmol) in CHCl3 (20 mL) was kept at rt under occasional stirring until the disappearance of pyridinium methylide was detected by TLC monitoring (1-2 days). After S-alkylation was completed, the resulting solution was concentrated at reduced pressure and the residue was washed three times with 10 mL portions of ether to remove unaltered alkylating agent. Without further purification the resulting pyridinium salt was dissolved in CHCl3 (30 mL) and the solution was treated with DBU (0.40 g, 2.6 mmol) under stirring in an ice bath for 10 min and then with chloranil (0.492 g, 2 mmol) under the same conditions for a further 4—6 h. The reaction mixture was concentrated at reduced pressure and the residue was separated by column chromatography on alumina using CHCl3 as an eluent. The pale yellow CHCl3 layers of product (4) were combined and concentrated at reduced pressure. Recrystallization of the crude product from EtOH afforded the corresponding 2-(arylmethylthio)indolizines 4 or 2-(methylthio)indolizines 5. 1H-NMR spectral data for products (4a—o) and (5a—l) are listed in Table 1, and the other data for new compounds (4a—o) and (5c,f,i,l) are as follows:
Diethyl 2-(benzylthio)indolizine-1,3-dicarboxylate (4a): 40% (from 1a and ethyl bromoacetate (2a), colorless needles, mp 52—53 oC. IR (KBr) cm-1: 1699, 1674. UV-Vis (nm (log ε), CHCl3): 282 (4.18), 322 (3.94), 334 (3.95). 13C NMR (CDCl3) δ: 14.44, 14.60, 41.35, 60.15, 60.73, 107.97, 114.13, 117.53, 119.34, 125.40, 126.79, 127.45, 128.06, 128.78, 130.76, 138.00, 138.50, 161.27, 163.65. Anal. Calcd for C21H21NO4S: C, 65.78; H, 5.52; N, 3.65. Found: C, 65.82; H, 5.48; N, 3.38.
Diethyl 2-benzylthio-7-methylindolizine-1,3-dicarboxylate (4b): 52% (from 1b and 2a), colorless needles, mp 114—115 oC. IR (KBr) cm-1: 1699, 1676. UV-Vis (nm (log ε), CHCl3): 285 (4.30), 324 (4.10), 336 (4.09). 13C NMR (CDCl3) δ: 14.41, 14.57, 41.35, 60.00, 60.55, 106.72, 116.63, 116.92, 117.89, 126.71, 126.88, 127.98, 128.72, 130.70, 136.69, 138.03, 139.02, 140.55, 161.27, 163.84. Anal. Calcd for C22H23NO4S: C, 66.48; H, 5.83; N, 3.52. Found: C, 66.48; H, 5.90; N, 3.46.
Diethyl 2-benzylthio-6,8-dimethylindolizine-1,3-dicarboxylate (4c): 73% (from 1c and 2a), colorless needles, mp 67—69 oC. IR (KBr) cm-1: 1705, 1682. UV-Vis (nm (log ε), CHCl3): 265 (4.31), 340 (4.05), 354 (4.02). 13C NMR (CDCl3) δ: 14.32, 14.51, 18.49, 19.42, 41.88, 60.43, 61.28, 114.16, 115.30, 123.19, 123.25, 125.82, 126.88, 127.90, 127.65, 128.14, 128.77, 132.96, 137.82, 161.20, 166.25. Anal. Calcd for C23H25NO4S: C, 67.13; H, 6.12; N, 3.40. Found: C, 67.10; H, 6.29; N, 3.27.
Diethyl 2-(1-naphthylmethylthio)indolizine-1,3-dicarboxylate (4d): 54% (from 1d and 2a), colorless needles, mp 185—187 oC. IR (KBr) cm-1: 1698. UV-Vis (nm (log ε), CHCl3): 283 (4.41), 289 (shoulder), 335 (shoulder), 350 (shoulder). 13C NMR (CDCl3) δ: 14.21, 14.59, 39.32, 60.21, 60.65, 107.98, 114.17, 117.77, 119.41, 124.32, 125.03, 125.44, 125.51, 125.74, 127.00, 127.48, 127.88, 128.46, 130.82, 131.60, 133.77, 133.81, 138.54, 161.27, 163.74. Anal. Calcd for C25H23NO4S: C, 69.26; H., 5.35; N, 3.23. Found: C, 69.17; H, 5.36; N, 3.31.
Diethyl 7-methyl-2-(1-naphthylmethylthio)indolizine-1,3-dicarboxylate (4e): 41% (from 1e and 2a), colorless prisms, mp 119—121 oC. IR (KBr) cm-1: 1691, 1674. UV-Vis (nm (log ε), CHCl3): 286 (4.41), 338 (shoulder), 353 (shoulder). 13C NMR (CDCl3) δ: 14.22, 14.61, 21.54, 39.37, 60.10, 60.52, 106.77, 116.72, 117.20, 118.01, 124.34, 125.03, 125.49, 125.71, 126.95, 127.84, 128.46, 130.84, 131.62, 133.78, 133.90, 136.75, 139.12, 161.32, 163.97 (one carbon is overlapping). Anal. Calcd for C26H25NO4S: C, 69.78; H, 5.63; N, 3.13. Found: C, 69.81; H, 5.62; N, 3.10.
Diethyl 6,8-dimethyl-2-(1-naphthylmethylthio)indolizine-1,3-dicarboxylate (4f): 40% (from 1f and 2a), colorless needles, mp 138—140 oC. IR (KBr) cm-1: 1725, 1671. UV-Vis (nm (log ε), CHCl3): 277 (shoulder), 289 (shoulder), 340 (4.04), 354 (4.01). 13C NMR (CDCl3) δ: 14.21, 14.34, 18.48, 19.38, 39.70, 60.32, 61.26, 114.30, 115.49,123.16, 123.22, 124.20, 125.05, 125.48, 125.72, 125.76, 126.89, 127.01, 127.57, 127.87, 128.43, 131.50, 132.91, 133.57, 133.75, 161.14, 166.28. Anal. Calcd for C27H27NO4S: C, 70.26; H, 5.90; N, 3.03. Found: C, 70.22; H, 6.01; N, 2.96.
2-(1-Naphthylmethylthio)indolizine-1,3-dicarbonitrile (4g): 54% (from 1g and 2b), colorless needles, mp 210—213 oC. IR (KBr) cm-1: 2207. UV-Vis (nm (log ε), CHCl3): 273 (4.36), 291 (shoulder), 320 (shoulder), 350 (shoulder). 13C NMR (CDCl3) δ: 37.68, 88.90, 100.37, 110.71, 113.46, 115.58, 117.65, 123.48, 125.01, 125.69, 125.90, 126.39, 126.80, 127.77, 128.64, 128.89, 131.04, 131.16, 134.36, 139.25. Anal. Calcd for C21H13N3S: C, 74.31; H, 3.86; N, 12.38. Found: C, 74.21; H, 3.80; N, 12.32.
7-Methyl-2-(1-naphthylmethylthio)indolizine-1,3-dicarbonitrile (4h): 31% (from 1h and 2b), colorless needles, mp 214 oC. IR (KBr) cm-1: 2211. UV-Vis (nm (log ε), CHCl3): 274 (shoulder), 283 (4.14), 332 (shoulder). 13C NMR (CDCl3) δ: 21.48, 37.72, 87.44, 99.74, 111.05, 113.85, 116.30, 118.19, 123.59, 125.04, 125.11, 125.93, 126.45, 127.80, 127.81 ,128.69, 128.90, 131.20, 133.82, 134.31, 138.77, 139.78. Anal. Calcd for C22H15N3S: C, 74.76; H, 4.28; N, 11.89. Found: C, 74.52; H, 4.46; N, 11.95.
6.8-Dimethyl-2-(1-naphthylmethylthio)indolizine-1,3-dicarbonitrile (4i): 32% (from 1i and 2b), colorless needles, mp 190—191 oC. IR (KBr) cm-1: 2213. UV-Vis (nm (log ε), CHCl3): 275 (4.35), 291 (shoulder), 329 (shoulder). 13C NMR (CDCl3) δ: 18.12, 18.19, 37.96, 88.61, 100.67, 111.11, 115.29, 121.72, 123.64, 125.06, 125.91, 126.38, 127.79, 128.45, 128.65, 128.83, 130.03, 131.29, 131.36, 133.84, 133.91, 137.32 (one carbon is overlapping). Anal. Calcd for C23H17N3S: C, 75.18; H, 4.66; N, 11.44. Found: C, 75.39; H, 4.62; N, 11.26.
Ethyl 1-cyano-2-(1-naphthylmethylthio)indolizine-3-carboxylate (4j): 56% (from 1d and 2b), colorless needles, mp 155—157 oC. IR (KBr) cm-1: 2209, 1680. UV-Vis (nm (log ε), CHCl3): 273 (shoulder), 283 (4.51), 331 (3.98), 345 (shoulder). 13C NMR (CDCl3) δ: 14.30, 36.81, 60.87, 87.44, 114.44, 114.74, 115.52, 116.35, 123.86, 125.10, 125.71, 126.11, 126.16, 127.62, 128.13, 128.46, 128.55, 131.41, 131.86, 133.75, 134.28, 140.43, 160.39. Anal. Calcd for C23H18N2O2S: C, 71.48; H, 4.69; N, 7.25. Found: C, 71.62; H, 4.66; N, 7.14.
Ethyl 1-cyano-7-methyl-2-(1-naphthylmethylthio)indolizine-3-carboxylate (4k): 61% (from 1e and 2b), colorless needles, mp 147—149 oC. IR (KBr) cm-1: 2209, 1680. UV-Vis (nm (log ε), CHCl3): 275 (shoulder), 283 (4.51), 332 (shoulder), 345 (shoulder). 13C NMR (CDCl3) δ: 14.30, 21.19, 36.75, 60.71, 86.01, 113.79, 115.03, 117.23, 123.88, 125.08, 125.86, 126.08, 127.50, 127.59, 128.40, 128.52, 131.41, 131.92, 133.72, 134.17, 137.81, 140.89, 160.40. Anal. Calcd for C24H20N2O2S: C, 71.98; H, 5.03; N, 6.99. Found: C, 71.67; H, 5.09; N, 7.25.
Ethyl 1-cyano-6,8-dimethyl-2-(1-naphthylmethylthio)indolizine-3-carboxylate (4l): 64% (from 1f and 2b), colorless needles, mp 167—169 oC. IR (KBr) cm-1: 2209, 1686. UV-Vis (nm (log ε), CHCl3): 277 (4.40), 286 (4.40), 331 (shoulder), 347 (shoulder). 13C NMR (CDCl3) δ: 14.17, 18.44, 18.64, 38.02, 60.75, 88.90, 115.90, 117.04, 123.96, 124.09, 124.60, 125.00, 125.63, 125.97, 127.07, 127.32, 128.26, 128.49, 129.45, 131.39, 132.49, 132.79, 133.74, 137.66, 160.49. Anal. Calcd for C25H22N2O2S: C, 72.44; H, 5.35; N, 6.76. Found: C, 72.53; H, 5.45; N, 6.57.
Ethyl 3-cyano-2-(1-naphthylmethylthio)indolizine-1-carboxylate (4m): 34% (from 1g and 2a), colorless needles, mp 155—157 oC. IR (KBr) cm-1: 2201, 1697. UV-Vis (nm (log ε), CHCl3): 280 (4.46), 321 (shoulder), 352 (shoulder). 13C NMR (CDCl3) δ: 14.56, 36.78, 60.41, 98.83, 105.67, 112.95, 114.68, 119.95, 123.90, 124.96, 125.14, 125.79, 126.24, 126.47, 127.73, 128.53, 128.58, 131.54, 131.83, 133.79, 135.28, 138.29, 162.98. Anal. Calcd for C23H18N2O2S: C, 71.48; H, 4.69; N, 7.25. Found: C, 71.55; H, 4.74; N, 7.14.
Ethyl 3-cyano-7-methyl-2-(1-naphthylmethylthio)indolizine-1-carboxylate (4n): 49% (from 1h and 2a), colorless needles, mp 197—200 oC. IR (KBr) cm-1: 2197, 1682. UV-Vis (nm (log ε), CHCl3): 278 (4.52), 324 (shoulder). 13C NMR (CDCl3) δ: 14.58, 21.67, 36.73, 60.29, 98.09, 104.31, 113.24, 117.17, 118.54, 123.91, 124.32, 125.11, 125.76, 126.21, 127.69, 128.47, 128.54, 131.51, 131.86, 133.76, 135.25, 138.10, 138.72, 163.17. Anal. Calcd for C24H20N2O2S: C, 71.98; H, 5.03; N, 6.99. Found: C, 72.04; H, 4.89; N, 7.07.
Ethyl 3-cyano-6,8-dimethyl-2-(1-naphthylmethylthio)indolizine-1-carboxylate (4o): 38% (from 1i and 2a), colorless needles, mp 151—153 oC. IR (KBr) cm-1: 2204, 1712. UV-Vis (nm (log ε), CHCl3): 279 (4.34), 317 (shoulder), 331 (4.02). 13C NMR (CDCl3) δ: 14.34, 17.99, 20.28, 38.63, 61.24, 99.77, 111.01, 112.70, 120.91, 123.91, 124.39, 125.07, 125.70, 126.05, 127.547, 128.41, 128.54, 128.80, 129.35, 130.17, 131.41, 132.30, 133.81, 134.23, 164.01. Anal. Calcd for C25H22N2O2S: C, 72.44; H, 5.35; N, 6.76. Found: C, 72.43; H, 5.25; N, 6.87.
Diethyl 6,8-dimethyl-2-(methylthio)indolizine-1,3-dicarboxylate (5c): 81% (from 3,5-dimethylpyridinium 1-(1-ethoxycarbonyl-2-methylthio-2-thioxo)ethanide and 2a), colorless needles, mp 51—52 oC. IR (KBr) cm-1: 1719, 1669. UV-Vis (nm (log ε), CHCl3): 267 (4.31), 338 (4.03), 354 (4.01). 13C NMR (CDCl3) δ: 14.30, 14.43, 18.47, 19.42, 19.89, 60.56, 61.38, 112.79, 114.36, 123.06, 123.26, 126.69, 127.76, 128.59, 133.03, 161.24, 166.58. Anal. Calcd for C17H21NO4S: C, 60.88; H, 6.31; N, 4.18. Found: C, 60.90; H, 6.33; N, 4.13.
6,8-Dimethyl-2-(methylthio)indolizine-1,3-dicarbonitrile (5f): 66% (from 3,5-dimethylpyridinium 1-(1-cyano-2-methylthio-2-thioxo)ethanide and 2b), colorless needles, mp 224—226 oC. IR (KBr) cm-1: 2213. UV-Vis (nm (log ε), CHCl3): 268 (4.50), 327 (4.03). 13C NMR (CDCl3) δ: 17.74, 18.12, 18.17, 86.73, 98.33, 111.71, 115.29, 121.73, 125.70, 128.26, 130.15, 137.11, 137.46. Anal. Calcd for C13H11N3S: C, 64.71; H, 4.59; N, 17.41. Found: C, 64.61; H, 4.50; N, 17.60.
Ethyl 1-cyano-6,8-dimethyl-2-(methylthio)indolizine-3-carboxylate (5i): 60% (from 3,5-dimethylpyridinium 1-(1-ethoxycarbonyl-2-methylthio-2-thioxo)ethanide and 2b), pale yellow needles, mp 123—125 oC. IR (KBr) cm-1: 2207, 1686. UV-Vis (nm (log ε), CHCl3): 274 (4.48), 283 (4.50), 332 (4.01). 13C NMR (CDCl3) δ: 14.39, 17.93, 18.42, 18.68, 60.87, 86.09, 113.80, 117.36, 124.08, 124.44, 126.76, 129.62, 136.15, 138.01, 160.53. Anal. Calcd for C15H16N2O2S: C, 62.48; H, 5.59; N, 9.71. Found: C, 62.39; H, 5.58; N, 9.68.
Ethyl 3-cyano-6,8-dimethyl-2-(methylthio)indolizine-1-carboxylate (5l): 73% (from 3,5-dimethylpyridinium 1-(1-cyano-2-methylthio-2-thioxo)ethanide and 2a), colorless needles, mp 98—100 oC. IR (KBr) cm-1: 2201, 1709. UV-Vis (nm (log ε), CHCl3): 270 (4.53), 330 (4.04). 13C NMR (CDCl3) δ: 14.38, 17.94, 18.25, 20.63, 61.11, 96.89, 10869, 113.53, 12090, 124.11, 128.58, 129.93, 134.31, 134.73, 163.82. Anal. Calcd for C15H16N2O2S: C, 62.48; H, 5.59; N, 9.71. Found: C, 62.26; H, 5.45; N, 9.49.

Crystallography of diethyl 7-methyl-2-(1-naphthylmethylthio)indolizine-1,3-dicarboxylate (4e). A single crystal (1.00×0.22×0.14 mm) grown from EtOH 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 4e: C26H25NO4S; M=447.55; triclinic, space group P-1 (#2), Z=2 with a=10.628 (5) Å, b=14.634 (5) Å, c=8.435 (5) Å, α=95.36o (4), β=106.86o (4), γ=110.25o (2); V=1150.2 (9) Å3, and Dcalc.=1.292 g/cm3. All calculations were performed using CrystalStructure.16 The structure was solved by a direct method (SIR88).17 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 0.062 and 0.049 for 2523 (I>2.00s(I)) observed reflections, respectively.
Crystallography of 7-methyl-2-(1-naphthylmethylthio)indolizine-1,3-dicarbonitrile (4h). A single crystal (0.68×0.24×0.20 mm) grown from EtOH 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 4h: C22H15N3S; M=353.44; monoclinic, space group P21/c (#14), Z=4 with a=7.56 (4) Å, b=13.79 (4) Å, c=17.05 (5) Å, β=95.5o (5); V=1769.3 (122) Å3, and Dcalc.=1.327 g/cm3. All calculations were performed using CrystalStructure.16 The structure was solved by a direct method (SIR88).17 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 0.058 and 0.041 for 1716 (I>2.00s(I)) observed reflections, respectively.

References

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13. In 1H-NMR spectra of 4f,l at -50 oC in CDCl3 no signal for other conformers was detected.
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