HETEROCYCLES

Paper | Special issue | Vol. 82, No. 2, 2011, pp. 1251-1266
Received, 25th June, 2010, Accepted, 16th August, 2010, Published online, 17th August, 2010.
DOI: 10.3987/COM-10-S(E)72

■ A New Synthetic Approach to Some Functionalized Cycl[3.2.2]azine Derivatives

Hideyuki Muranaka, Akikazu Kakehi,* 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

Dehydrogenation of some ethyl 4-oxo-1H-8,8a-dihydro-1,4- thiazino[3,4,5-cd]indolizine-1-carboxylates with 2,3-dichloro-5,6-dicyano-1,4- benzoquinone (DDQ) were examined. No simply dehydrogenated products such as 4-oxo-1H- and 4-oxo-8H-1,4-thiazino[3,4,5-cd]indolizines or their full conjugated enol forms could be obtained, but ethyl cycl[3.2.2]azine-1- carboxylates were directly obtained via the cyclization and the subsequent desulfurization of the 4H-1,4-thiazine ring in the dehydrogenated intermediates.

INTRODUCTION
Aromaticity is a very important concept in organic chemistry. The fact that planar cyclic polyenes containing (4n+2)π electrons have an aromatic character from Hückel rules2,3 is widely known and applied to the syntheses of various aromatic compounds. In contrast, the difficulty of generating planar cyclic polyenes having an anti-aromatic 4nπ system and the instability of such compounds are also well known. We have previously reported the smooth generation of bicyclic intermediates such as pyrido[2,1-c]-1,4-thiazine intermediates (A) (see Figure 1) having an anti-aromatic 12π electron system and their efficient transformation to aromatic indolizine derivatives (C) via the intramolecular cyclization followed by the rearrangement or the desulfurization depending upon the nature of the R1 substituent in the tricyclic thiirane intermediates (B).4-7 In connection with this reaction it is readily imaginable that the 4,6-tethered pyrido[2,1-c]-1,4-thiazines should be potential intermediates for cycl[3.2.n]azine derivatives such as (E) whose preparative routes are limited.8,9 We have also described the formation of some functionalized 4(1H)-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizinone derivatives (F), which are prospective precursors for the 4,6-tethered pyrido[2,1-c]-1,4-thiazines (D), from the reaction of (Z)-3-[mercapto(methylthio)methylene]-2(3H)-indolizinones with various alkyl halides in the presence of a base.10-12 Hence, we were interested in the dehydrogenation of compounds such as (F), because the subsequent vinylogous keto-enol tautomerization of the resulting 4-oxo-1H- (H) and/or 4-oxo-8H-1,4-thiazino[3,4,5-cd]indolizines (G) may lead to the full-conjugated 1,4-thiazino[3,4,5-cd]indolizin-4-ols (D) which in turn provide the corresponding cycl[3.2.2]azines (E). In this paper we report the syntheses of some functionalized cycl[3.2.2]azine derivatives from the dehydrogenation of ethyl 3-alkylthio-4-oxo-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylate derivatives.

RESULTS AND DISCUSSION
Preparation of 4(1H)-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizinone derivatives (3 and 4).
We first selected ethyl 3-alkylthio-4-oxo-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylates (3 and 4) as the substrates in the expectation of their high solubility and easy handling in this dehydrogenation because of the low yields and low solubility of the 1-cyano compounds.12 The required 4-oxo-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine derivatives were obtained as the trans- 3a-n and cis-mixtures 4a-n at the 1- and 8a-positions from the reactions of (Z)-3-[alkylthio(mercapto)methylene]-2(3H)-indolizinones (1a-n)13,14 with ethyl bromoacetate (2) in the presence of 2-equivalents of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) at 50 °C for 10 min. In these reactions the trans isomers 3a-n were always formed predominantly (Scheme 1). Our attempts to separate the trans-cis mixtures to perspective isomers by column chromatography were unsuccessful because of their similar solubility. However, we decided to use the trans-cis mixtures (3a-n and 4a-n) in the subsequent reactions, because both dehydrogenation reactions should form the same products such as 4(8H)-1,4-thiazino[2,3,4-cd]indolizinones (6) and 1,4-thiazino[3,4,5-cd]indolizin-3-ols (7) or the enantiomeric pair in 4(1H)-1,4-thiazino[3,4,5-cd]indolizinones (5) (see Scheme 2).
The predominant formation of the trans derivatives 3a-n over the cis ones 4a-n was unexpected for us since we have previously observed the formation of only the cis derivatives 4a,e,h in the reaction of 1a,e,h with 2 in the presence of small excess DBU at room temperature for 12 h.12 Considering the stability of these compounds, however, it can be thought that the use of excess base at a higher temperature promoted the transformation from the less stable cis derivatives 4a-n, in which the 1-ethoxycarbonyl group occupies the pseudo-axial position, to more stable trans ones 3a-n, in which the same group holds the pseudo-equatorial position, during the base-catalyzed isomerization of the active 1-methine proton.

The structural assignment for compounds 3a-n and 4a-n was accomplished by some physical and spectral means and by the comparison with those of the known substances 4a,e,h.12 Their elemental analyses were in accord with our proposed compositions, and the IR spectra showed the absorption bands at 1618-1624 and 1720-1737 cm-1 due to saturated ester carbonyl group(s) and an enone carbonyl one, respectively. The assignment of the trans and cis configurations for compounds 3a-n and 4a-n was made by comparing the coupling constants between each 1-methine proton and the 8a-proton in their 1H-NMR spectra (Table 1), since it is already known that the trans coupling constant is ca. 10.0 Hz and fairly larger than the cis coupling constant (ca. 2.0 Hz).10-12 In addition, the NOE measurement of compound 3a confirmed the signal position of the 8-H (axial), because the irradiation to the 1-H (axial, δ 4.21) increased the intensity of a multiplet signal at δ 2.52. Thus, the alternative signal appeared at δ 2.83 was confirmed to be the 8-H (equatorial). The analyses of the proton signals for other compounds 3b‒n and 4b‒n were performed on the analogy of these findings.

Preparation of cycl[3.2.2]azines.
In contrast to the smooth dehydrogenation of 1,9a-dihydropyrido[2,1-c]-1,4-thiazine derivatives such as (A) with DDQ or chloranil in an ice bath, the treatment of 4(1H)-8,8a-dihydro-1,4-thiazino[3,4,5-cd]- indolizinones (3a‒n and 4a‒n) with the same dehydrogenating agents in chloroform in the range from 0 oC to the reflux temperature did not provide any expected dehydrogenated compounds such as 4(1H)- (5), 4(8H)-1,4-thiazino[3,4,5-cd]indolizinones (6), and/or their full conjugated enol forms (7). The formation of a new product was confirmed when the dehydrogenation of 3a+4a with DDQ was examined in dioxane/toluene at 80 oC, but its conversion was very slow. Hence, the reactions at higher temperatures were examined, and we found that ethyl 3-hydroxy-2-(methylthio)cycl[3.2.2]azine- 1-carboxylate (8a) involving a small amount of its keto form (9a) was directly obtained in 36 or 46% yield from the reaction in N,N-dimethyformamide or N-methyl-2-pyrrolidone at 150‒170 °C, respectively. The yield was slightly improved when 2,4,6-collidine was used as a solvent and the reaction temperature was raised to 180 °C. The treatment of 3b‒g,l‒n + 4b‒g,l‒n with DDQ under the optimized reaction conditions gave the corresponding cycl[3.2.2]azine derivatives (8b‒g,l‒n + 9b‒g,l‒n) in 16‒51% yields. On the other hand, similar reactions of 3h‒k+4h‒k bearing the 5-methyl group did not provide the expected products 8h‒k+9h‒k because of their thermal instability. To improve these yields and the stability of these products 8a‒n+9a‒n, acetic anhydride was added into the reaction solutions of 3a‒n+4a‒n and DDQ to afford the corresponding ethyl 3-acetoxycycl[3.2.2]azine-1-carboxylate derivatives (10a‒n) in 10‒65% yields respectively. These results are shown in Scheme 2.
The structural assignments for compounds 8a‒g,l‒n + 9a‒g,l‒n and 10a‒n were carried out by their elemental analyses, HRMS, and IR and 1H-NMR spectral analyses. In particular, their HRMS and elemental analyses were completely in accord with the compositions for the dehydrogenated and desulfurized structures in comparison with those of the materials 3a‒n+4a‒n. The IR spectra of 8a‒g,l‒n + 9a‒g,l‒n and 10a‒n showed an α,β-unsaturated ester carbonyl band at 1655‒1686cm-1. The 1H-NMR spectra (see Table 2) of these products 8a‒g,l‒n + 9a‒g,l‒n showed the disappearance of the saturated 1-, 8-, and 8a-proton characteristics of 4(1H)-8,8a-dihydrothiazinoindolizinones 3a‒n+4a‒n and the new appearance of the three aromatic protons with an ABC pattern. Interestingly, the 1H-NMR spectra of these products in DMSO-d6 exhibited only the proton signals for the enol forms 8a‒g,l‒n, while those in CDCl3 indicated the proton signals both for the keto-enol mixtures 8a‒g,l‒n+9a‒g,l‒n. For example, the spectrum in DMSO-d6 showed only the signals of 8a due to the 5-, 6-, and 7-protons on the cycl[3.2.2]azine ring at δ 7.77 (1H, d, J = 7.9 Hz), 7.84 (1H, t, J = 7.9 Hz), and 8.01 (1H, d, J = 7.9 Hz) respectively, together with a hydroxy proton (δ 10.77

(1H, br s)), ethoxy protons (δ 1.42 (3H, t, J = 7.1 Hz) and 4.38 (2H, q, J = 7.1 Hz)), methylthio protons (δ 2.96 (3H, s)) and aromatic protons (δ 7.37 (2H) 7.54 (1H), and 7.77 (2H)). On the other hand, that in CDCl3 exhibited the characteristic proton signals of minor 9a at inter alia δ 4.95 (1H, s, 4-H), 6.78 (1H, dd, J = 7.1 Hz, 5-H), 7.46 (1H, q, J = 7.1, 8.9 Hz, 6-H), and 7.86 (1H, d, J = 8.9 H, 7-Hz), together with the proton signals for major 8a. The ratio of 8a to 9a in CDCl3 was 88 : 12. The keto-enol tautomerism between 8l and 9l was also observed in the 1H-NMR measurement in CDCl3, but the ratio (5<95) of 8l to 9l reversed. As expected, the O-acetylated cycl[3.2.2]azines 10a‒n are stable crystalline substances and the signal patterns and the chemical shifts of the skeletal

protons in their 1H-NMR spectra in CDCl3 were very similar to those of 8a‒g,l‒n in DMSO-d6. The X-ray analysis of one compound 10i finally confirmed this structure. The ORTEP drawing15 is shown in Figure 2.

Mechanistically, there seemed to be no problem in the desulfurization from a 4H-1,4-thiazine form having an unstable 8π electron system in the above reactions. However, we could not show the positions of the first dehydrogenation, because we could not obtain any intermediates such as 4(1H)- 5 and/or 4(8H)-1,4-thiazino[3,4,5-cd]indolizinone 6.
In summary we have developed a novel approach to functionalized cycl[3.2.2]azine derivatives which are not easily available by other methods, though their yields were low to moderate.

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 spectra were determined with a Bruker AMX-500 (1H: 500MHz) spectrometer in deuteriochloroform or DMSO-d6 with tetramethylsilane used as the internal standard; the chemical shifts are expressed in δ values. The IR and HRMS spectra were taken with NICOLET AVATAR320 Fourier transform infrared spectrophotometer and Agilent 6520 Accurate-Mass Quadrupole Time-of-Flight (Q-TOF) LC/MS.
Preparation of 3-[(alkylthio)mercaptomethylene]-2(3H)-indolizinones (1a‒n). General Method. An ethanolic solution (50 mL) of the corresponding 1-(ethoxycarbonylmethyl)pyridium bromide (17.5 mmol) was treated with DBU (36.8 mmol) under stirring at 60 °C for 15 min. After cooling to room temperature, carbon disulfide (18.4 mmol) was added to this reaction solution and the resulting mixture was allowed to react under stirring for 5 min. Alkylating reagent such as dimethyl sulfate, diethyl sulfate, benzyl bromide, and ethyl bromoacetate was then added and allowed to react under stirring at room temperature for 90 min. The separated precipitates were collected by suction, dried, and recrystallized from CH2Cl2-Et2O to give the corresponding 3-[(alkylhio)mercapto-
methylene]-2(3H)-indolizinones (1a‒n).
The physical and spectral data of known compounds 1a (46%), 1b (31%), 1e (55%), 1h (43%), and 1l (65%) were in accord with those reported previously by us, and some data for new compounds 1c,d,f,g,i‒k,m,n are as follows.
(Z)-3-[(Benzylthio)mercaptomethylene]-1-phenyl-2(3H)-indolizinone (1c): 72% (from 2-benzyl-1-(ethoxycarbonylmethyl)pyridinium bromide, CS2, and benzyl bromide), red prisms, mp 125‒126 °C. IR (KBr) cm-1: 1581 (CO), 2510 (SH). 1H-NMR (CDCl3): 4.74 (2H, s, CH2Ph), 6.81 (1H, dt, J = 7.0, 1.4 Hz, 6-H), 7.20‒7.52 (10H, m, 7-H, 8-H, and aryl-H ), 7.60‒7.66 (2H, m, aryl-H), 9.40 (1H, d, J = 7.1 Hz, 5-H), 12.85 (1H, br s, SH). Anal. Calcd for C22H17NOS2: C, 70.37; H, 4.56; N, 3.73. Found: C, 70.21; H, 4.38; N, 3.59. Positive ion ESI-HRMS Calcd for C22H17NOS2 [M+H]+: 376.0824. Found m/z 376.0828.
(Z)-3-[(Ethoxycarbonylmethylthio)mercaptomethylene]-1-phenyl-2(3H)-indolizinone (1d): 76% (from 2-benzyl-1-(ethoxycarbonylmethyl)pyridinium bromide, CS2, and ethyl bromoacetate), red powder, mp 104‒105 °C. IR (KBr) cm-1: 1582 (CO), 1742 (CO), 2619 (SH). 1H-NMR (CDCl3): 1.33 (3H, t, J = 7.1 Hz, OCH2CH3), 4.28 (2H, q, J = 7.1 Hz, OCH2CH3), 4.35 (2H, s, SCH2), 6.89 (1H, dt, J = 7.1, 1.4 Hz, 6-H), 7.24‒7.68 (7H, m, 7-H, 8-H, and aryl-H), 9.45 (1H, d, J = 7.1 Hz, 5-H), 12.52 (1H, br s, SH). Anal. Calcd for C19H17NO3S: C,61.43; H, 4.61; N, 3.77. Found: C, 61.40; H, 4.74; N, 3.61. Positive ion ESI-HRMS Calcd for C19H17NO3S2 [M+H]+: 372.0723. Found m/z 372.0726.
1-(p-Chlorophenyl)-(Z)-3-[(ethylthio)mercaptomethylene]-2(3H)-indolizinone (1f): 78% (from 2-(p-chlorobenzyl)-1-(ethoxycarbonylmethyl)pyridinium bromide, CS2, and diethyl sulfate), brown prisms, mp 119‒120 °C. IR (KBr) cm-1: 1581 (CO), 2813 (SH). 1H-NMR (CDCl3): 1.49 (3H, t, J = 7.5 Hz, SCH2CH3), 3.54 (2H, q, J = 7.5Hz, SCH2CH3), 6.88 (1H, dt, J = 7.0, 1.4 Hz, 6-H), 7.25‒7.31 (1H, m, 7-H), 7.43 (2H, d, J = 8.5 Hz, aryl-H), 7.55‒7.61 (3H, m, aryl-H), 9.49 (1H, d, J = 7.1 Hz, 5-H), 12.97 (1H, br s, SH). Anal. Calcd for C17H14ClNOS2: C, 58.70; H, 4.06; N, 4.03. Found: C, 58.82; H, 4.07; N, 3.87. H Positive ion ESI-HRMS Calcd for C17H14ClNOS2 [M+H]+: 348.0278. Found m/z 348.0289.
1-(p-Chlorophenyl)-(Z)-3-[(benzylthio)mercaptomethylene]-2(3H)-indolizinone (1g): 76% (from 2-(p-chlorobenzyl)-1-(ethoxycarbonylmethyl)pyridinium bromide, CS2, and benzyl bromide), orange prisms, mp 137‒138 °C. IR (KBr) cm-1: 1580 (CO), 2508 (SH). 1H-NMR (CDCl3): 4.76 (2H, s, SCH2Ph), 6.83 (1H, dt, J = 7.0Hz, 1.4 Hz, 6-H), 7.23‒7.50 (9H, m, 7-H, 8-H, and aryl-H), 7.57 (2H, d, J = 8.6 Hz, aryl-H), 9.39 (1H, d, J = 7.0 Hz, 5-H), 12.88 (1H, br s, SH). Anal. Calcd for C22H16ClNOS2: C, 64.46; H, 3.93; N, 3.42. Found: C, 64.19; H, 3.91; N, 3.42. Positive ion ESI-HRMS Calcd for C22H16ClNOS2 [M+H]+: 410.0434. Found m/z 410.0437.
(Z)-3-[(Ethylthio)mercaptomethylene]-1-methyl-2(3H)-indolizinone (1i): 36% (from 2-ethyl-1- (ethoxycarbonylmethyl)pyridinium bromide, CS2, and diethyl sulfate), orange prisms, mp 156‒158 °C. IR (KBr) cm-1: 1592 (CO), 2546 (SH). 1H-NMR (CDCl3): 1.47 (3H, t, J = 7.4 Hz, SCH2CH3), 2.17 (3H, s, 1-Me), 3.52 (2H, q, J = 7.2Hz, SCH2CH3), 6.77 (1H, dt, J = 7.0, 1.6 Hz, 6-H), 7.19‒7.30 (2H, m, 7-H and 8-H), 9.38 (1H, d, J = 7.0Hz, 5-H), 12.61 (1H, br s, SH). Anal. Calcd for C12H13NOS2: C, 57.34; H, 5.21; N, 5.57. Found: C, 57.64; H, 5.16; N, 5.31. Positive ion ESI-HRMS Calcd for C12H13NOS2 [M+H]+: 252.05113. Found m/z 252.0519.
(Z)-3-[(Benzylthio)mercaptomethylene]-1-methyl-2(3H)-indolizinone (1j): 62% (from 2-ethyl-1- (ethoxycarbonylmethyl)pyridinium bromide, CS2, and benzyl bromide), orange prisms, mp 134‒135 °C. IR (KBr) cm-1: 1596 (CO), 2588 (SH). 1H-NMR (CDCl3): 2.17 (3H, s, 1-Me), 4.75 (2H, s, SCH2Ph), 6.72 (1H, dt, J = 7.0, 1.6 Hz, 6-H), 7.15‒7.50 (7H, m, 7-H, 8-H and aryl-H ), 9.29 (1H, d, J = 7.0Hz, 5-H), 12.52 (1H, br s, SH). Anal. Calcd for C17H15NOS2: C, 65.15; H, 4.82; N, 4.47. Found: C, 65.40; H, 4.77; N, 4.27. Positive ion ESI-HRMS Calcd for C17H15NOS2 [M+H]+: 314.06678. Found m/z 314.0675.
(Z)-3-[(Ethoxycarbonylmethylthio)mercaptomethylene]-1-methyl-2(3H)-indolizinone (1k): 46% (from 2-ethyl-1-(ethoxycarbonylmethyl)pyridinium bromide, CS2, and ethyl bromoacetate), orange prisms, mp 125‒126 °C. IR (KBr) cm-1: 1596 (CO), 1732 (CO), 2662 (SH). 1H-NMR (CDCl3): 1.32 (3H, t, J = 7.1 Hz, ), 2.16 (3H, s, 1-Me), 4.26 (2H, q, J = 7.1 Hz, ), 4.33 (2H, s, SCH2), 6.77‒6.83 (1H, m, 6-H), 7.23‒7.31 (2H, m, 7-H and 8-H), 9.34 (1H, d, J = 7.0Hz, 5-H), 12.22 (1H, br s, SH). Anal. Calcd for C14H15NO3S2: C, 54.35; H, 4.89; N, 4.53. Found: C, 54.58; H, 4.84; N, 4.34. Positive ion ESI-HRMS Calcd for C14H15NO3S2 [M+H]+: 310.0566. Found m/z 310.0574.
1-Ethyl-(Z)-3-[(ethylthio)mercaptomethylene]-2(3H)-indolizinone (1m): 38% (from 1-ethoxycarbonylmethyl-2-propylpyridinium bromide, CS2, and diethyl sulfate), red prisms, mp 59‒61 °C. IR (KBr) cm-1: 1589 (CO), 2612 (SH). 1H-NMR (CDCl3): 1.21 (3H, t, J = 7.5Hz), 1.47 (3H, t, J = 7.4Hz), 2.68 (2H, q, J = 7.5Hz), 3.52 (2H, q, J = 7.4Hz), 6.77 (1H, dt, J = 7.0, 1.5Hz, 6-H), 7.18‒7.33 (2H, m, 7-H and 8-H), 9.39 (1H, d, J = 7.1Hz, 5-H), 12.60 (1H, br s, SH). Anal. Calcd for C13H15NOS2: C, 58.84; H, 5.70; N, 5.28. Found: C, 58.87; H, 5.55; N, 4.98. Positive ion ESI-HRMS Calcd for C13H15NOS2 [M+H]+: 266.0667. Found m/z 266.0676.
1-Ethyl-(Z)-3-[(benzylthio)mercaptomethylene]-2(3H)-indolizinone (1n): 44% (from 1-ethoxycarbonylmethyl-2-propylpyridinium bromide, CS2, and benzyl bromide), red prisms, mp 98‒99 °C. IR (KBr) cm-1: 1589 (CO), 2640 (SH). 1H-NMR (CDCl3): 1.21 (3H, t, J = 7.6Hz, 1-CH2CH3), 2.68 (2H, q, J = 7.6 Hz, 1-CH2CH3), 4.74 (2H, s, SCH2Ph), 6.71 (1H, dt, J = 6.9, 1.4 Hz, 6-H), 7.15‒7.49 (7H, m, 7-H, 8-H, and aryl-H ), 9.29 (1H, d, J = 7.2 Hz, 5-H), 12.51 (1H, br s, SH). Anal. Calcd for C18H17NOS2: C, 66.02; H, 5.23; N, 4.28. Found: C, 66.26; H, 5.13; N, 4.14. Positive ion ESI-HRMS Calcd for C18H17NOS2 [M+H]+ 328.0824. Found m/z 328.0825.

Preparation of 4(1H)-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizinone derivatives (3a‒n and 4a‒n). General method. A chloroform solution (40 mL) of 3-(mercaptomethylene)-2(3H)-indolizinone (1, 8.4 mmol) and ethyl bromoacetate (2, 16.9 mmol) was treated with DBU (16.9 mmol) at 50 °C for 10 min. The mixture was diluted with CHCl3 and washed with 2N-HCl twice. The organic layer was dried over MgSO4 and concentrated at reduced pressure. The residue was purified by column chromatography on silica gel using hexane-EtOAc as an eluent. Evaporation of the solvent and recrystallization from Et2O to provide the corresponding 4(1H)-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizinone derivatives(4a‒n) as cis/trans mixtures.
The 1H-NMR spectra for compounds 3a‒n and 4a‒n are shown in Table 1 and the other data are as follows.
Ethyl 3-methylthio-4-oxo-5-phenyl-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylate (3a+4a): 59% (from 1a and 2), red powder. IR (KBr) cm-1: 1618 (CO), 1736 (CO). Anal. Calcd for C20H19NO3S2: C, 62.31; H, 4.97; N, 3.63. Found: C, 62.11; H, 5.03; N, 3.57.
Ethyl 3-ethylthio-4-oxo-5-phenyl-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylate (3b+4b): 49% (from 1b and 2), red powder. IR (KBr) cm-1: 1623 (CO), 1724 (CO). Anal. Calcd for C21H21NO3S2: C, 63.13; H, 5.30; N, 3.51. Found: C, 63.09; H, 5.23; N, 3.25.
Ethyl 3-benzylthio-4-oxo-5-phenyl-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylate (3c+4c(trace)): 23% (from 1c and 2), red powder, mp 164‒166 °C (3c). IR (KBr) cm-1: 1618 (CO), 1732 (CO). Anal. Calcd for C26H23NO3S2: C, 67.65; H, 5.02; N, 3.03. Found: C, 67.81; H, 5.00; N, 2.90.
Ethyl 3-ethoxycarbonylmethylthio-4-oxo-5-phenyl-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylate (3d+4d(trace)): 34% (from 1d and 2), red powder, mp 105‒109 °C (3d). IR (KBr) cm-1: 1624 (CO), 1735 (CO). Anal. Calcd for C23H23NO5S2: C, 60.38; H, 5.07; N, 3.06. Found: C, 60.21; H, 5.29; N, 3.00.
Ethyl 5-(p-chlorophenyl)-3-methylthio-4-oxo-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylate (3e+4e): 55% (from 1e and 2), red powder. IR (KBr) cm-1: 1621 (CO), 1732 (CO). Anal. Calcd for C20H18ClNO3S2: C, 57.20; H, 4.32; N, 3.34. Found: C, 57.29; H, 4.41; N, 3.10.
Ethyl 5-(p-chlorophenyl)-3-ethylthio-4-oxo-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylate (3f+4f): 36% (from 1f and 2), red powder. IR (KBr) cm-1: 1623 (CO), 1721 (CO). Anal. Calcd for C21H20ClNO3S2: C, 58.12; H, 4.65; N, 3.23. Found: C, 58.29; H, 4.65; N, 2.95.
Ethyl 3-benzylthio-5-(p-chlorophenyl)-4-oxo-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1- carboxylate (3g+4g): 59% (from 1g and 2), red powder. IR (KBr) cm-1: 1615 (CO), 1729 (CO). Anal. Calcd for C26H22ClNO3S2: C, 62.96; H, 4.47; N, 2.82. Found: C, 63.11; H, 4.73; N, 2.52.
Ethyl 5-methyl-3-methylthio-4-oxo-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylate (3h+4h): 63% (from 1h and 2), red powder. IR (KBr) cm-1: 1616 (CO), 1720 (CO). Anal. Calcd for C15H17NO3S2: C, 55.71; H, 5.30; N, 4.33. Found: C, 55.77; H, 5.29; N, 4.21.
Ethyl 5-methyl-3-ethylthio-4-oxo-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylate (3i+4i): 73% (from 1i and 2), orange powder. IR (KBr) cm-1: 1621 (CO), 1729 (CO). Anal. Calcd for C16H19NO3S2: C, 56.95; H, 5.68; N, 4.15. Found: C, 56.89; H, 5.66; N, 4.04.
Ethyl 3-benzylthio-5-methyl-4-oxo-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylate (3j+4j): 72% (from 1j and 2), red powder. IR (KBr) cm-1: 1618 (CO), 1737 (CO). Anal. Calcd for C21H21NO3S2: C, 63.13; H, 5.30; N, 3.51. Found: C, 63.04; H, 5.41; N, 3.22.
Ethyl 3-ethoxycarbonylmethylthio-5-methyl-4-oxo-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]- indolizine-1-carboxylate (3k+4k): 58% (from 1k and 2), red powder. IR (KBr) cm-1: 1616 (CO), 1736 (CO). Anal. Calcd for C18H21NO5S2: C, 54.67; H, 5.35; N, 3.54. Found: C, 54.53; H, 5.31; N, 3.59.
Ethyl 5-ethyl-3-methylthio-4-oxo-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylate (3l+4l(trace)): 70% (from 1l and 2), red prisms, mp 105‒108 °C (3l). IR (KBr) cm-1: 1618 (CO), 1736 (CO). Anal. Calcd for C16H19NO3S2: C, 56.95; H, 5.68; N, 4.15. Found: C, 57.01; H, 5.70; N, 4.07.
Ethyl 5-ethyl-3-ethylthio-4-oxo-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylate (3m+4m): 58% (from 1m and 2), red prisms. IR (KBr) cm-1: 1619 (CO), 1731 (CO). Anal. Calcd for C17H21NO3S2: C, 58.09; H, 6.02; N, 3.99. Found: C, 58.11; H, 6.05; N, 3.88.
Ethyl 5-ethyl-3-methylthio-4-oxo-1H-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizine-1-carboxylate (3n+4n): 30% (from 1n and 2), red prisms. IR (KBr) cm-1: 1618 (CO), 1725 (CO). Anal. Calcd for C22H23NO3S2: C, 63.90; H, 5.61; N, 3.39. Found: C, 63.99; H, 5.71; N, 3.15.

Preparation of 2-(alkylthio)cycl[3.2.2]azin-3-ol derivatives (8a‒n) and 3-Acetoxy-2-(alkylthio)cycl[3.2.2]azine derivatives. (10a‒n). General method A. A suspension of 4(1H)-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizinone (3+4, 1 mmol), DDQ (0.341g, 1.5 mmol), and 2,4,6-collidine (5 mL) was heated at 180 °C for 15 min. After cooling, the reaction mixture was diluted with AcOEt (30 mL) and 1N-HCl (30 mL). The separated precipitates were removed by suction. The organic layer which was collected using a separatory funnel was washed was then washed with 1N-HCl (30 mL). The organic layer was dried over MgSO4 and concentrated at reduced pressure. The residue was purified by column chromatography on silica gel using hexane-AcOEt as an eluent. Evaporation of the solvent and recrystallization from CH2Cl2-Et2O provided the corresponding 2-(alkylthio)cycl[3.2.2]azin-3-ol derivatives (8a‒n).
General method B. In these reactions, mixtures of 4(1H)-8,8a-dihydro-1,4-thiazino[3,4,5-cd]- indolizinone (3+4, 1 mmol), DDQ (0.341g, 1.5 mmol), acetic anhydride (0.49 mL), and 2,4,6-collidine (5 mL) were heated at 180 °C for 15 min. The same work-ups described above for the resulting reaction mixtures afforded the corresponding 3-Acetoxy-2-(alkylthio)cycl[3.2.2]azine derivatives (10a‒n).
General method B. In these reactions, mixtures of 4(1H)-8,8a-dihydro-1,4-thiazino[3,4,5-cd]indolizinone (3+4, 1 mmol), DDQ (0.341g, 1.5 mmol), acetic anhydride (0.49 mL), and 2,4,6-collidine (5 mL) were heated at 180 °C for 15 min. The same work-ups described above for the resulting reaction mixtures afforded the corresponding 3-Acetoxy-2-(alkylthio)cycl[3.2.2]azine derivatives (10a‒n).
The elemental analyses of some cycl[3.2.2]azin-3-ol derivatives (8h‒k) having the 4-methyl group were unsuccessful because of their thermal instability. Interestingly, the 1H-NMR measurements of these cycl[3.2.2]azin-3-ols (8a‒n) in CDCl3 indicated the presence of the keto type tautomers, 3(4H)-cycl[3.2.2]azin-3-ones (9a‒n), while those in DMSO-d6 exhibited only the enol forms 8a‒n.
The 1H-NMR spectral data for cycl[3.2.2]azine derivatives 8a‒n and 10a‒n are listed in Table 2 and the other results are as follows.
Ethyl 3-hydroxy-2-methylthio-4-phenylcycl[3.2.2]azine-1-carboxylate (8a): 51% (from 3a+4a), pale yellow powder, mp 86‒88 oC. IR (KBr) cm-1: 1665 (CO). 1H-NMR (CDCl3): 8a; 1.51 (3H, t, J = 7.1 Hz, OCH2CH3), 2.98 (3H, s, SMe), 4.49 (2H, q, J = 7.1 Hz, OCH2CH3), 6.27 (1H, br s, OH), 7.41, 7.58, and 7.69 (5H, aryl-H ), 7.49 (1H, d, J = 7.9 Hz, 5-H), 7.74 (1H, t, J = 7.9 Hz, 6-H), 8.07 (1H, d, J = 7.9 Hz, 7-H). 9a; 1.46 (3H, t, J = 7.1 Hz, OCH2CH3), 2.90 (3H, s, SMe), 4.44 (2H, q, J = 7.1 Hz, OCH2CH3), 4.95 (1H, s, 4-H), 7. 1‒7.4 (5H, aryl-H ), 6.78 (1H, d, J = 7.1 Hz, 5-H), 7.46 (1H, q, J = 7.1, 8.9 Hz, 6-H), 7.86 (1H, d, J = 8.9 Hz, 7-H). Positive ion ESI-HRMS Calcd for C20H18NO3S [M+H]+: 352.1002. Found m/z 352.1013. Anal. Calcd for C20H17NO3S+H2O: C, 65.02; H, 5.18; N, 3.79. Found: C, 65.18; H, 5.11; N, 3.69.
Ethyl 2-ethylthio-3-hydroxy-4-phenylcycl[3.2.2]azine-1-carboxylate (8b): 49% (from 3b+4b), pale yellow prisms, mp 53‒54 oC. IR (KBr) cm-1: 1664 (CO), 1686 (CO). Positive ion ESI-HRMS Calcd for C21H20NO3S [M+H]+: 366.1158. Found m/z 366.1158. Anal. Calcd for C21H19NO3S: C, 69.02; H, 5.24; N, 3.83. Found: C, 69.15; H, 5.22; N, 3.73.
Ethyl 2-benzylthio-3-hydroxy-4-phenylcycl[3.2.2]azine-1-carboxylate (8c): 36% (from 3c+4c), pale yellow powder, mp 65‒67 oC. IR (KBr) cm-1: 1686 (CO). Positive ion ESI-HRMS Calcd for C26H22NO3S [M+H]+: 366.1158. Found m/z 366.1158. Anal. Calcd for C26H21NO3S: C, 73.05; H, 4.95; N, 3.28. Found: C, 73.31; H, 4.97; N, 3.17.
Ethyl 2-ethoxycarbonylmethylthio-3-hydroxy-4-phenylcycl[3.2.2]azine-1-carboxylate (8d): 24% (from 3d+4d), pale brown powder, mp 119‒121 oC. IR (KBr) cm-1: 1686 (CO), 1697 (CO). Positive ion ESI-HRMS Calcd for C23H22NO5S [M+H]+: 424.1213. Found m/z 424.1217.
Ethyl 4-(p-chlorophenyl)-2-methylthio-3-hydroxycycl[3.2.2]azine-1-carboxylate (8e): 32% (from 3e+4e), yellow powder, mp 178‒180 oC. IR (KBr) cm-1: 1664 (CO). Positive ion ESI-HRMS Calcd for C20H17ClNO3S [M+H]+: 386.0612. Found m/z 386.0624. Anal. Calcd for C20H16ClNO3S: C, 62.25; H, 4.18; N, 4.21. Found: C, 62.55; H, 4.21; N, 3.53.
Ethyl 4-(p-chlorophenyl)-2-ethylthio-3-hydroxycycl[3.2.2]azine-1-carboxylate (8f): 44% (from 3f+4f), pale yellow powder, mp 156‒158 oC. IR (KBr) cm-1: 1656 (CO). Positive ion ESI-HRMS Calcd for C21H19ClNO3S [M+H]+: 400.1036. Found m/z 400.1031. Anal. Calcd for C21H18ClNO3S: C, 63.07; H, 4.54; N, 3.50. Found: C, 63.27; H, 4.62; N, 3.22.
Ethyl 4-(p-chlorophenyl)-2-benzylthio-3-hydroxycycl[3.2.2]azine-1-carboxylate (8g): 21% (from 3g+4g), red powder, mp 173‒174 oC. IR (KBr) cm-1: 1655 (CO). Positive ion ESI-HRMS Calcd for C26H21ClNO3S [M+H]+: 462.1192. Found m/z 462.1188. Anal. Calcd for C26H20ClNO3S: C, 67.60; H, 4.36; N, 3.03. Found: C, 67.61; H, 4.35; N, 2.78.
Ethyl 4-ethyl-2-methylthio-3-hydroxycycl[3.2.2]azine-1-carboxylate (8l): 24% (from 3l+4l), pale brown powder, mp 110‒111 oC. IR (KBr) cm-1: 1685 (CO). 1H-NMR (CDCl3). 8l; 0.90 (3H, t, J = 7.4 Hz, 4-CH2CH3), 1.45 (3H, t, J = 7.1 Hz, OCH2CH3), 1.9‒2.3 (2H, m, 4-CH2CH3), 2.92 (3H, s, SMe), 4.45 (2H, q, J = 7.1 Hz, OCH2CH3), 7.63 (1H, d, J = 7.8 Hz, 5-H), 7.79 (1H, q, J = 7.8, 8.3 Hz, 6-H), 8.09 (1H, d, J = 8.3 Hz, 7-H), 9.93 (1H, br s, OH). 9l; 0.98 (3H, t, J = 7.5 Hz, 4-CH2CH3), 1.49 (3H, t, J = 7.1 Hz, OCH2CH3), 1.9‒2.3 (2H, m, 4-CH2CH3), 2.95 (3H, s, SMe), 3.80 (1H, m, 4-H), 4.43 (2H, q, J = 7.1 Hz, OCH2CH3), 6.85 (1H, d, J=7.1 Hz, 5-H), 7.45 (1H, q, J = 7.1, 8.9 Hz, 6-H), 7.82 (1H, d, J = 8.9 Hz, 7-H). Positive ion ESI-HRMS Calcd for C16H18NO3S [M+H]+: 366.1158. Found m/z 366.1158. Anal. Calcd for C16H17NO3S: C, 63.35; H, 5.65; N, 4.62. Found: C, 63.35; H, 5.66; N, 4.53.
Ethyl 4-ethyl-2-ethylthio-3-hydroxycycl[3.2.2]azine-1-carboxylate (8m): 16% (from 3m+4m), pale yellow powder, mp 96‒97 oC. IR (KBr) cm-1: 1655 (CO). Positive ion ESI-HRMS Calcd for C17H19NO3SNa [M+Na]+: 340.0979. Found m/z 340.0978.
Ethyl 2-benzylthio-4-ethyl-3-hydroxycycl[3.2.2]azine-1-carboxylate (8n): 24% (from 3n+4n), pale brown powder, mp 108‒110 oC. IR (KBr) cm-1: 1676 (CO). Positive ion ESI-HRMS Calcd for C21H20NO3S [M+H]+: 380.1315. Found m/z 380.1324.
Ethyl 3-acetoxy-2-methylthio-4-phenylcycl[3.2.2]azine-1-carboxylate (10a): 65% (from 3a+4a), yellow prisms, mp 196‒198 oC. IR (KBr) cm-1: 1690 (CO), 1769 (CO). Positive ion ESI-HRMS Calcd for C22H20NO4S [M+H]+: 394.1108. Found m/z 394.1110. Anal. Calcd for C22H19NO4S: C, 67.16; H, 4.87; N, 3.56. Found: C, 67.15; H, 4.83; N, 3.61.
Ethyl 3-acetoxy-2-ethylthio-4-phenylcycl[3.2.2]azine-1-carboxylate (10b): 53% (from 3b+4b), yellow needles, mp 171‒172 oC. IR (KBr) cm-1: 1692 (CO), 1769 (CO). Positive ion ESI-HRMS Calcd for C23H22NO4S [M+H]+: 408.1264. Found m/z 408.1267. Anal. Calcd for C23H21NO4S: C, 67.79; H, 5.19; N, 3.44. Found: C, 67.91; H, 5.05; N, 3.46.
Ethyl 3-acetoxy-2-benzylthio-4-phenylcycl[3.2.2]azine-1-carboxylate (10c): 26% (from 3c+4c), orange prisms, mp 152‒153 oC. IR (KBr) cm-1: 1679 (CO), 1770 (CO). Positive ion ESI-HRMS Calcd for C28H24NO4S [M+H]+: 470.1421. Found m/z 470.1421. Anal. Calcd for C28H23NO4S: C, 71.62; H, 4.94; N, 2.98. Found: C, 71.36; H, 4.78; N, 2.81.
Ethyl 3-acetoxy-2-ethoxycarbonylmethylthio-4-phenylcycl[3.2.2]azine-1-carboxylate (10d): 23% (from 3d+4d), pale yellow powder, mp 124‒125 oC. IR (KBr) cm-1: 1688 (CO), 1747 (CO), 1785 (CO). Positive ion ESI-HRMS Calcd for C25H24NO6S [M+H]+: 466.1319. Found m/z 466.1325. Anal. Calcd for C25H23NO6S: C, 64.50; H, 4.98; N, 3.01. Found: C, 64.69; H, 4.89; N, 2.84.
Ethyl 3-acetoxy-4-(p-chlorophenyl)-2-(methylthio)cycl[3.2.2]azine-1-carboxylate (10e): 49% (from 3a+4a), pale yellow needles, mp 192‒194 oC. IR (KBr) cm-1: 1686 (CO), 1773 (CO). Positive ion ESI-HRMS Calcd for C22H19ClNO4S [M+H]+: 428.0718. Found m/z 428.0725. Anal. Calcd for C22H18ClNO4S: C, 61.75; H, 4.24; N, 3.27. Found: C, 61.71; H, 4.29; N, 3.17.
Ethyl 3-acetoxy-4-(p-chlorophenyl)-2-(ethylthio)cycl[3.2.2]azine-1-carboxylate (10f): 56% (from 3f+4f), pale yellow needles, mp 145‒146 oC. IR (KBr) cm-1: 1697 (CO), 1773 (CO). Positive ion ESI-HRMS Calcd for C23H21ClNO4S [M+H]+: 442.0874. Found m/z 442.0874. Anal. Calcd for C23H20ClNO4S: C, 62.51; H, 4.56; N, 3.17. Found: C, 62.69; H, 4.70; N, 3.08.
Ethyl 3-acetoxy-4-(p-chlorophenyl)-2-(benzylthio)cycl[3.2.2]azine-1-carboxylate (10g): 18% (from 3a+4a), pale yellow needles, mp 197‒198 oC. IR (KBr) cm-1: 1686 (CO), 1773 (CO). Positive ion ESI-HRMS Calcd for C28H23ClNO4S [M+H]+: 504.1031. Found m/z 504.1034. Anal. Calcd for C28H22ClNO4S: C, 66.73; H, 4.40; N, 2.78. Found: C, 66.78; H, 4.49; N, 2.72.
Ethyl 3-acetoxy-4-methyl-2-(methylthio)cycl[3.2.2]azine-1-carboxylate (10h): 10% (from 3h+4h), pale yellow needles, mp 145‒146 oC. IR (KBr) cm-1: 1682 (CO), 1764 (CO). Positive ion ESI-HRMS Calcd for C17H18NO4S [M+H]+: 332.0958. Found m/z 332.0951. Anal. Calcd for C17H17NO4S: C, 61.62; H, 5.17; N, 4.23. Found: C, 61.61; H, 5.18; N, 4.22.
Ethyl 3-acetoxy-2-ethylthio-4-methylcycl[3.2.2]azine-1-carboxylate (10i): 11% (from 3i+4i), pale yellow needles, mp 129‒130 oC. IR (KBr) cm-1: 1673 (CO), 1774 (CO). Positive ion ESI-HRMS Calcd for C18H20NO4S [M+H]+: 346.1108. Found m/z 346.1117. Anal. Calcd for C18H19NO4S: C, 62.59; H, 5.54; N, 4.06. Found: C, 62.66; H, 5.55; N, 3.98.
Ethyl 3-acetoxy-2-benzylthio-4-methylcycl[3.2.2]azine-1-carboxylate (10j): 15% (from 3j+4j), pale yellow needles, mp 133‒135 oC. IR (KBr) cm-1: 1678 (CO), 1764 (CO). Positive ion ESI-HRMS Calcd for C23H22NO4S [M+H]+: 408.1264. Found m/z 408.1271. Anal. Calcd for C23H21NO4S: C, 67.79; H, 5.19; N, 3.44. Found: C, 67.76; H, 5.17; N, 3.32.
Ethyl 3-acetoxy-2-ethoxycarbonylmethylthio-4-methylcycl[3.2.2]azine-1-carboxylate (10k): 17% (from 3k+4k), yellow needles, mp 115‒116 oC. IR (KBr) cm-1: 1680 (CO), 1739 (CO), 1773 (CO). Positive ion ESI-HRMS Calcd for C20H22NO6S [M+H]+: 404.1162, Found m/z 404.1167. Anal. Calcd for C20H21NO6S: C, 59.54; H, 5.25; N, 3.47. Found: C, 59.62; H, 5.21; N, 3.43.
Ethyl 3-acetoxy-4-ethyl-2-(methylthio)cycl[3.2.2]azine-1-carboxylate (10l): 43% (from 3l+4l), yellow needles, mp 111‒112 oC. IR (KBr) cm-1: 1679 (CO), 1762 (CO). Positive ion ESI-HRMS Calcd for C18H20NO4S [M+H]+: 346.1108. Found m/z 346.1112. Anal. Calcd for C18H19NO4S: C, 62.59; H, 5.54; N, 4.06. Found: C, 62.88; H, 5.42; N, 3.90.
Ethyl 3-acetoxy-4-ethyl-2-(ethylthio)cycl[3.2.2]azine-1-carboxylate (10m): 38% (from 3m+4m), yellow prisms, mp 97‒98 oC. IR (KBr) cm-1: 1697 (CO), 1759 (CO). Positive ion ESI-HRMS Calcd for C19H22NO4S [M+H]+: 360.1264. Found m/z 360.1266. Anal. Calcd for C19H21NO4S: C, 63.49; H, 5.89; N, 3.90. Found: C, 63.80; H, 5.76; N, 3.71.
Ethyl 3-acetoxy-2-benzylthio-4-ethylcycl[3.2.2]azine-1-carboxylate (10n): 23% (from 3n+4n), orange prisms, mp 125‒126 oC. IR (KBr) cm-1: 1678 (CO), 1769 (CO). Positive ion ESI-HRMS Calcd for C24H24NO4S [M+H]+: 422.1421. Found m/z 422.1428. Anal. Calcd for C24H23NO4S: C, 68.39; H, 5.50; N, 3.32. Found: C, 68.69; H, 5.34; N, 3.18.

Crystallography of ethyl 3-acetoxy-2-ethylthio-4-methylcycl[3.2.2]azine-1-carboxylates (10i). A single crystal (0.18×0.32×0.68 mm) grown from CH2Cl2–Et2O was used for the unit-cell determinations and the data collection by a Rigaku AFC5S four-circle diffractometer with graphite-monochromated MoKa radiation (l = 0.71069 Å). Crystal data of 10i: C18H19NO4S; M = 345.41; monoclinic, space group P21/c (#14), Z = 4 with a = 9.63 (2) Å, b = 19.14 (3) Å, c = 9.99 (2) Å, β = 109.91o (15); V = 1731 (7) Å3, and Dcalc. = 1.326 g/cm3. All calculations were performed using CrystalStructure.16 The structure was solved by a direct method (SIR).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 0.064 and 0.047 for 1288 (I>2.00(I)) observed reflections, respectively.

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