HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 7, 2009, pp. 1777-1786
Received, 5th February, 2009, Accepted, 12th March, 2009, Published online, 13th March, 2009.
DOI: 10.3987/COM-09-11677

■ Reaction of 1-Azabicyclo[1.1.0]butane with Activated Amides

Kazuhiko Hayashi,* Eiko Kujime, Hajime Katayama, Shigeki Sano, and Yoshimitsu Nagao

College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyama-ku, Nagoya 463-8521, Japan

Abstract

1-Azabicyclo[1.1.0]butane (ABB, 1) reacted with 3-acyl-1,3-thiazolidine-2-thiones (7,11a—m) in the presence of a catalytic amount of Mg(OTf)2 to give the corresponding 2-(1-acylazetidin-3-yl)thio-1,3-thiazolines (8,12a—m). It was hypothesized that this reaction is primarily influenced by a steric bulkiness of acyl groups in 3-acyl-1,3-thiazolidine-2-thiones. Resulting compounds (8, 12k) were readily converted to thiols (13,14), and azetidine-3-thiol hydrochloride (15), which is the key intermediate of 1-(1,3-thiazolin-2-yl)azetidine-3-thiol hydrochloride (4) useful for the preparation of a new oral 1β-methylcarbapenem antibiotic L-084, was obtained quantitatively by hydrolysis of 14.

INTRODUCTION
1-Azabicyclo[1.1.0]butanes have proved to be a unique molecule bearing a highly strained bicyclic structure, and are synthetically useful for the preparation of azetidine derivatives.1,2 In the last two decades, numerous reactions have been described in which 1-azabicyclo[1.1.0]butanes were explored as versatile reagents.1-3 However, the synthetic utility of unsubstituted 1-azabicyclo[1.1.0]butane (ABB, 1), which must be useful for the preparation of various 3-monosubstituted and 1,3-disubstituted azetidines, has rarely been reported because of its synthetic difficulty related to its remarkably strained structure.1,2 These azetidine moieties have often been found in many natural products4 and biologically active compounds such as carbapenems4 and new quinolone antibiotics.5
In this context, we established an efficient synthetic method of ABB (1) starting from allylamine (2) via 2,3-dibromopropylamine hydrobromide (3),5 and reported its application to the syntheses of various 3-substituted azetidines.7 Additionally, the resulting azetidines were converted to 1-(1,3-thiazolin-2-yl)azetidine-3-thiol hydrochloride (4), which was exploited for the synthesis of a new oral 1β-methylcarbapenem antibiotic L-084,5,7,8 an energetic material 1,3,3-trinitroazetidine (TNAZ, 5),2,8 and a new quinolone derivatives (6),9 as shown in Scheme 1. In the present study, we observed that the reaction of ABB (1) with activated amides results in electrophilic addition of the amides to afford 1,3-disubstituted azetidines, and this reaction is promoted by some Lewis acids. Herein, we focus on the reaction of ABB (1) with 3-acyl-1,3-thiazolidine-2-thiones as activated amides,10 and report the results of our studies.

RESULTS AND DISCUSSION
A THF solution of ABB (1), obtained by treatment of 3 with n-BuLi at -78 ºC in THF followed by codistillation with THF,5,7 was used for the reaction with 3-acyl-1,3-thiazolidine-2-thiones. First, 3-benzoyl-1,3-thiazolidine-2-thione (7) was allowed to react with a small excess of ABB (1) under reflux for 15 h, and 2-(1-benzoylazetidin-3-yl)thio-1,3-thiazoline (8) was generated in poor yield, as shown in Scheme 2 and Table 1 (entry 1). The addition of the catalytic amount of Lewis acid improved the reaction, and Mg(OTf)2 was most effective (entries 2―6). Room temperature was selected as the reaction temperature from the results of entries 6―8. The compound 1-(1-benzoylazetidin-3-yl)-1,3-thiazolidine-2-thione (9) was not obtained under any of the conditions employed (Scheme 2). In this reaction, the benzoyl group activated by a Lewis acid may initiate attack of the N1 position of the strained molecule ABB (1), followed by cleavage of the highly strained N1-C3 σ-bond,2,11 and the sulfur atom of 1,3-thiazolidine-2-thionyl anion (10) then reacts with the cationic C3 position, as shown in Scheme 3.
Table 2 shows representative results of the reaction of ABB (1) with various 3-acyl-1,3-thiazolidine-2-thiones (11a―m) at room temperature in the presence of Mg(OTf)2. All reactions proceeded to give the corresponding products 12a―m. In the case of the reaction with 11a―h,

para-substituted compounds 11e―h showed a higher yield than the ortho-substituted compounds 11a―d regardless of any electronic effect of the substituent on the aromatic ring (entries 1―8). The yield of the reaction with 3-(2-naphthoyl)-1,3-thiazolidine-2-thiones (11j) was higher than that of the reaction with 3-(1-naphthoyl)-1,3-thiazolidine-2-thiones (11i) (entries 9,10). The compound 11m afforded 12m in poor yield, compared with 11k and 11l (entries 11―13). From these results, it was estimated that this reaction with 11a―m is mainly influenced not by an electronic effect but by the steric bulkiness of the acyl groups in 3-acyl-1,3-thiazolidine-2-thiones (11a―m).

Subsequently, the reaction of products 8 and 12k with hydrochloric acid in MeOH were carried out under reflux, and thiols 13 and 14 were obtained in 80% and 75% yield, respectively (Scheme 4). To the best of our knowledge, 1-acylazetidine-3-thiols such as 13 and 14 have not been reported. This method is efficient for the synthesis of 1-acylazetidine-3-thiol derivatives. Further, the resulting compound 14 was readily hydrolyzed with 3N HCl to afford azetidine-3-thiol hydrochloride (15), which is the key intermediate of 4 (Scheme 1), in quantitative yield.

In conclusion, we demonstrated the reaction of ABB (1) with 3-acyl-1,3-thiazolidine-2-thiones (7, 11a-m). The reaction was promoted by a Lewis acid, and 2-(1-acylazetidin-3-yl)thio-1,3-thiazolines (8, 12a-m) were obtained. The resulting compounds (8, 12k) were readily converted to thiols (13, 14), respectively. The compound (14) was hydrolyzed quantitatively to give 15, which is the key intermediate of 4 useful for the preparation of L-084.

EXPERIMENTAL
All melting points were measured using a Yanaco micro melting point apparatus and are uncorrected. IR spectra were obtained on a JASCO FT/IR-420 or JASCO FT/IR-4100 IR Fourier transform spectrometer. 1H-NMR spectra were recorded on a JEOL JNM-ECA500 (500 MHz) spectrometer. 13C-NMR spectra were recorded on a JEOL JNM-ECA500 (125 MHz) spectrometer with complete proton decoupling. Chemical shifts are given in δ values (ppm) using tetramethylsilane (TMS) as an internal standard. Electron spray ionization (ESI)-MS were recorded on a Waters LCT Premier spectrometer. All reactions were monitored by TLC employing 0.25-mm silica gel plates (Merck 5715; 60 F254). Column chromatography was carried out on silica gel [Kanto Chemical 60N (spherical, neutral); 63-210 µm]. All reagents were used as purchased.
THF solution of 1-azabicyclo[1.1.0]butane (ABB, 1)5,7,8
A hexane solution of n-BuLi (2.64 mol/L, 94.7 ml, 252 mmol) was added dropwise to a suspension of 3 (25.0 g, 83.9 mmol) in THF (250 mL) at -78 ºC under nitrogen, and the mixture was stirred at -78 ºC　for 1 h. The reaction was then quenched with 50% KOH and distilled at 80 ºC. The resulting THF solution was dried over K2CO3 and filtered. The filtrate was adjusted to the 500 mL volume with THF. This THF solution of ABB (1, ca. 0.14 mol/L) was used in the following reactions.
Typical procedure for the preparation of 2-(1-benzoylazetidin-3-yl)thio-1,3-thiazoline (8) (Table 1)
To a solution of 3-benzoyl-1,3-thiazolidine-2-thione (7, 139 mg, 0.621 mmol) and ABB (1, ca. 0.14 mol/L in THF, 5.0 mL, ca. 0.70 mmol) in THF was added Mg(OTf)2 (20 mg, 0.062 mmol) at 0 ºC. After being stirred at room temperature for 1.5 h, the reaction mixture was evaporated in vacuo to give a residue, which was purified by column chromatography on silica gel with n-hexane – AcOEt (1 : 2, v/v) to afford 8 (113 mg, 65%).
2-(1-Benzoylazetidin-3-yl)thio-1,3-thiazoline (8): Colorless needles (Et2O); mp 92―92.5 ºC; 1H-NMR (500 MHz, CDCl3) δ: 3.40 (2H, t, J = 8.0 Hz), 4.10―4.30 (2H, m), 4.17 (2H, td, J = 8.0, 2.3 Hz), 4.43 (1H, tt, J = 8.0, 5.5 Hz), 4.56―4.78 (2H, m), 7.41 (2H, t, J = 7.4 Hz), 7.47 (1H, t, J = 7.4 Hz), 7.62 (2H, d, J = 7.4 Hz); 13C-NMR (125 MHz, CDCl3) δ: 33.9, 35.7, 54.8, 61.0, 64.4, 127.9, 128.4, 131.2, 132.7, 163.3, 170.4; IR (KBr) 1629, 1565, 1446, 1400, 1002, 792, 717, 695 cm-1; ESI-MS Calcd for
C13H14N2OS2 MW 279.0626, Found m/z 279.0626 (M+ + H).
Typical procedure for the preparation of 2-(1-acylazetidin-3-yl)thio-1,3-thiazoline 12 (Table 2)
To a solution of 3-(2-methyl)benzoyl-1,3-thiazolidine-2-thione (9k, 60 mg, 0.37 mmol) and ABB (1, ca.
0.14 mol/L in THF, 3.0 mL, ca. 0.42 mmol) in THF was added Mg(OTf)2 (12 mg, 0.037 mmol) at 0 ºC. After being stirred at room temperature for 1.5 h, the reaction mixture was evaporated in vacuo to give a residue, which was purified by column chromatography on silica gel with n-hexane – AcOEt (1 : 2, v/v) to CHCl3 – MeOH (10 :1, v/v) to afford 10k (46 mg, 57%).
2-[1-(2-Methylbenzoyl)azetidin-3-yl]thio-1,3-thiazoline (12a): Colorless oil. 1H-NMR (500 MHz, CDCl3) δ: 2.40 (3H, s), 3.39 (2H, td, J = 8.0, 2.3 Hz), 3.83―3.92 (1H, m), 4.11―4.19 (1H, m), 4.15 (2H, t, J = 8.0 Hz), 4.32―4.41 (2H, m), 4.55―4.62 (1H, m), 7.16―7.26 (3H, m), 7.29 (1H, td, J = 7.5, 1.7 Hz); 13C-NMR (125 MHz, CDCl3) δ: 19.3, 33.4, 35.6, 54.2, 59.0, 64.2, 125.6, 126.6, 129.7, 130.8, 133.4, 135.5, 163.6, 171.3; IR (neat) 2945, 2877, 1643, 1570, 1415, 742 cm-1; ESI-MS Calcd for C14H17N2OS2 MW 293.0782, Found m/z 293.0784 (M+ + H).
2-[1-(2-Methoxybenzoyl)azetidin-3-yl]thio-1,3-thiazoline (12b): Colorless oil. 1H-NMR (500 MHz, CDCl3) δ: 3.38 (2H, td, J = 8.0, 2.9 Hz), 3.86 (3H, s), 3.89―3.94 (1H, m), 4.09―4.14 (1H, m), 4.16 (2H, t, J = 8.0 Hz), 4.36―4.45(2H, m), 6.91 (1H, d, J = 7.4 Hz), 6.98 (1H, t, J = 7.4 Hz), 7.37 (1H, t, J = 7.4 Hz), 7.38 (1H, d, J = 7.4 Hz); 13C-NMR (125 MHz, CDCl3) δ: 33.5, 35.6, 54.6, 55.7, 58.4, 64.2, 111.2, 120.8, 123.3, 129.2, 131.5, 156.0, 163.9, 168.9; IR (neat) 2943, 2879, 1633, 1570, 1464, 1441, 1248, 1022, 756 cm-1; ESI-MS Calcd for C14H17N2O2S2 MW 309.0731, Found m/z 309.0730 (M+ + H).
2-[1-(2-Chlorobenzoyl)azetidin-3-yl]thio-1,3-thiazoline (12c): Colorless oil. 1H-NMR (500 MHz, CDCl3) δ: 3.39 (2H, td, J = 8.0, 2.3 Hz), 3.87―3.94 (1H, m), 4.10―4.19 (1H, m), 4.15 (2H, t, J = 8.0 Hz), 4.35―4.45 (2H, m), 4.56―4.65 (1H, m), 7.23―7.42 (4H, m); 13C-NMR (125 MHz, CDCl3) δ: 33.4, 35.6, 54.5, 58.3, 64.2, 127.0, 128.4, 129.8, 130.5, 130.8, 133.6, 163.3, 167.8; IR (neat) 2945, 2877, 1651, 1568, 1423, 1059, 748 cm-1; ESI-MS Calcd for C13H14ClN2OS2 MW 313.0236 Found m/z 313.0238 (M+ + H).
2-[1-(2-Nitrobenzoyl)azetidin-3-yl]thio-1,3-thiazoline (12d): Pale yellow oil. 1H-NMR (500 MHz, CDCl3) δ: 3.39 (2H, td, J = 8.0, 4.6 Hz), 3.85 (1H, dd, J = 9.2, 5.5 Hz), 4.12―4.22 (1H, m), 4.15 (2H, t, J = 8.0 Hz), 4.33 (1H, dd, J = 9.2, 8.0 Hz), 4.46 (1H, tt, J = 8.0, 5.5 Hz), 4.67 (1H, dd, J = 10.9, 8.0 Hz), 7.45 (1H, d, J = 7.8 Hz), 7.59 (1H, t, J = 7.8 Hz), 7.70 (1H, t, J = 7.8 Hz), 8.15 (1H, d, J = 7.8 Hz); 13C-NMR (125 MHz, CDCl3) δ: 33.5, 35.6, 54.9, 58.5, 64.3, 124.7, 128.5, 130.4, 130.7, 134.2, 145.9, 163.2, 167.7; IR (neat) 2947, 2877, 1651, 1574, 1531, 1485, 1427, 1348, 760 cm-1; ESI-MS Calcd for C13H13N3NaO3S2 MW 346.0296, Found m/z 346.0300 (M+ + Na).
2-[1-(4-Methylbenzoyl)azetidin-3-yl]thio-1,3-thiazoline (12e): Colorless needles (THF–n-hexane); mp
140―141 ºC; 1H-NMR (500 MHz, CDCl3) δ: 2.38 (3H, s), 3.40 (2H, t, J = 8.0 Hz), 4.09―4.29 (2H, m), 4.17 (2H, t, J = 8.0 Hz), 4.42 (1H, tt, J = 8.0, 5.4 Hz), 4.55―4.78 (2H, m), 7.21 (2H, d, J = 8.0 Hz), 7.52 (2H, d, J = 8.0 Hz); 13C-NMR (125 MHz, CDCl3) δ: 21.4, 33.9, 35.6, 54.8, 61.0, 64.3, 127.9, 129.0, 129.8, 141.6, 163.6, 170.4; IR (KBr) 2939, 1624, 1568, 1415, 833, 750 cm-1; ESI-MS Calcd for C14H17N2OS2
MW 293.0782, Found m/z 293.0780 (M+ + H).
2-[1-(4-Methoxybenzoyl)azetidin-3-yl]thio-1,3-thiazoline (12f): Colorless plates (THF–n-hexane); mp 116―117 ºC; 1H-NMR (500 MHz, CDCl3) δ: 3.40 (2H, t, J = 8.0 Hz), 3.86 (3H, s), 4.08―4.32 (2H, m), 4.17 (2H, t, J = 8.0 Hz), 4.42 (1H, tt, J = 8.0, 5.5 Hz), 4.53―4.81 (2H, m), 6.88―6.96 (2H, m), 7.57―7.66 (2H, m); 13C-NMR (125 MHz, CDCl3) δ: 33.9, 35.6, 54.8, 55.3, 61.2, 64.2, 113.6, 124.9, 129.8, 161.9, 163.8, 170.0; IR (KBr) 2941, 1606, 1574, 1423, 1402, 1257, 1028, 845, 764 cm-1; ESI-MS Calcd for C14H17N2O2S2 MW 309.0731, Found m/z 309.0738 (M+ + H).
2-[1-(4-Chlorobenzoyl)azetidin-3-yl]thio-1,3-thiazoline (12g): Pale yellow needles (THF–n-hexane); mp 109.5―110.5 ºC; 1H-NMR (500 MHz, CDCl3) δ: 3.40 (2H, t, J = 8.0 Hz), 4.09―4.27 (2H, m), 4.17 (2H, t, J = 8.0 Hz), 4.43 (1H, tt, J = 8.0, 5.5 Hz), 4.54―4.77 (2H, m), 7.39 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz); 13C-NMR (125 MHz, CDCl3) δ: 33.9, 35.6, 54.8, 61.1, 64.0, 128.7, 129.3, 131.0, 137.4, 164.1, 169.2; IR (KBr) 2945, 1608, 1564, 1439, 1090, 841, 746 cm-1; ESI-MS Calcd for C13H14ClN2OS2 MW 313.0236, Found m/z 313.0235 (M+ + H).
2-[1-(4-Nitrobenzoyl)azetidin-3-yl]thio-1,3-thiazoline (12h): Pale yellow powder (THF–n-hexane); mp 140―142 ºC; 1H-NMR (500 MHz, CDCl3) δ: 3.41 (2H, t, J = 8.0 Hz), 4.12―4.27 (2H, m), 4.17 (2H, td, J = 8.0, 3.4 Hz), 4.45 (1H, tt, J = 8.0, 5.5 Hz), 4.58―4.76 (2H, m), 7.79 (2H, d, J = 8.6 Hz), 8.28 (2H, d, J = 8.6 Hz); 13C-NMR (125 MHz, CDCl3) δ: 33.8, 35.6, 54.9, 60.9, 64.2, 123.7, 128.9, 138.5, 149.3, 163.5, 168.0; IR (KBr) 2949, 1620, 1599, 1562, 1520, 1439, 1348, 843, 714 cm-1; ESI-MS Calcd for C13H14N3O3S2 MW 324.0477, Found m/z 324.0483 (M+ + H).
2-[1-(1-Naphthoyl)azetidin-3-yl]thio-1,3-thiazoline (12i): Colorless oil. 1H-NMR (500 MHz, CDCl3) δ: 3.37 (2H, td, J = 8.0, 4.0 Hz), 3.86 (1H, dd, J = 9.2, 5.2 Hz), 4.13 (2H, t, J = 8.0 Hz), 4.26 (1H, dd, J = 10.6, 5.2 Hz), 4.33 (1H, dd, J = 9.2, 8.0 Hz), 4.39 (1H, tt, J = 8.0, 5.2 Hz), 4.70 (1H, dd, J = 10.6, 8.0 Hz), 7.47 (1H, dd, J = 8.0, 6.9 Hz), 7.51―7.61 (3H, m), 7.87 (1H, d, J = 8.0 Hz), 7.90 (1H, d, J = 8.0 Hz), 8.14 (1H, d, J = 8.0 Hz); 13C-NMR (125 MHz, CDCl3) δ: 33.5, 35.5, 54.6, 59.2, 64.2, 124.8, 125.2, 125.4, 126.4, 127.2, 128.4, 129.7, 130.4, 131.3, 133.6, 163.6, 170.7; IR (neat) 2945, 2877, 1643, 1570, 1425, 1385, 795, 779, 752 cm-1; ESI-MS Calcd for C17H17N2OS2 MW 329.0782, Found m/z 329.0782 (M+ + H).
2-[1-(2-Naphthoyl)azetidin-3-yl]thio-1,3-thiazoline (12j): Colorless plates (THF–n-hexane); mp 120.5―121.5 ºC; 1H-NMR (500 MHz, CDCl3) δ: 3.40 (2H, t, J = 8.0 Hz), 4.12―4.37 (2H, m), 4.17 (2H, td, J = 8.0, 1.7 Hz), 4.46 (1H, tt, J = 8.0, 5.0 Hz), 4.62―4.86 (2H, m), 7.51―7.62 (2H, m), 7.71 (1H, dd, J = 8.6, 1.8 Hz), 7.83―7.96 (3H, m), 8.11 (1H, s); 13C-NMR (125 MHz, CDCl3) δ: 34.0, 35.6, 54.9, 61.2, 64.3, 124.4, 126.7, 127.6, 127.8, 128.3, 128.4, 128.8, 130.0, 132.5, 134.5, 163.6, 170.5; IR (KBr) 2924, 1631, 1608, 1568, 1444, 1423, 823, 775, 760 cm-1; ESI-MS Calcd for C17H16N2NaOS2 MW 351.0602, Found m/z 351.0582 (M+ + Na).
2-(1-Acetylazetidin-3-yl)thio-1,3-thiazoline (12k): Colorless plates (THF–n-hexane); mp 63―64 ºC; 1H-NMR (500 MHz, CDCl3) δ: 1.87 (3H, s), 3.41 (2H, t, J = 8.0 Hz), 3.93 (1H, dd, J = 9.7, 5.2 Hz), 4.07 (1H, dd, J = 8.9, 5.2 Hz), 4.19 (2H, td, J = 8.0, 2.3 Hz), 4.36 (1H, tt, J = 8.0, 5.2 Hz), 4.41 (1H, dd, J = 9.7, 8.0 Hz), 4.58 (1H, dd, J = 8.9, 8.0 Hz); 13C-NMR (125 MHz, CDCl3) δ: 18.8, 32.7, 35.7, 54.1, 58.2, 64.4, 163.4, 170.5; IR (KBr) 2945, 2877, 1631, 1567, 1463 cm-1; ESI-MS Calcd for C8H13N2OS2 MW 217.0469, Found m/z 217.0477 (M+ + H).
2-(1-Formylazetidin-3-yl)thio-1,3-thiazoline (12l): Colorless oil. 1H-NMR (500 MHz, CDCl3) δ: 3.42 (2H, t, J = 8.0 Hz), 3.93―4.00 (1H, m), 4.09―4.13 (1H, m), 4.19 (2H, t, J = 8.0 Hz), 4.42―4.51 (2H, m), 4.57―4.64 (1H, m), 8.00 (1H, s); 13C-NMR (125 MHz, CDCl3) δ: 34.6, 35.7, 53.9, 55.8, 64.3, 161.9, 163.1; IR (neat) 2945, 1663, 1568, 1418, 1363 cm-1; ESI-MS Calcd for C7H10N2NaOS2 MW 225.0132, Found m/z 225.0133 (M+ + Na).
2-(1-tert-Butoxycarbonylazetidin-3-yl)thio-1,3-thiazoline (12m): Colorless oil. 1H-NMR (500 MHz, CDCl3) δ: 1.44 (9H, s), 3.40 (2H, t, J = 8.0 Hz), 3.88 (2H, dd, J = 9.5, 4.9 Hz), 4.19 (2H, t, J = 8.0 Hz), 4.26―4.39 (3H, m); 13C-NMR (125 MHz, CDCl3) δ: 28.3, 33.2, 35.6, 37.7, 55.6, 57.3, 64.4, 79.8, 155.9, 163.6; IR (neat) 2976, 2883, 1703, 1568, 1456, 1392, 1367, 1157 cm-1; ESI-MS Calcd for C11H19N2O2S2 MW 275.0888, Found m/z 275.0869 (M+ + H).
1-Benzoylazetidine-3-thiol (13)
To a solution of 2-(1-benzoylazetidin-3-yl)thio-1,3-thiazoline (8, 167 mg, 0.600 mmol) in MeOH (6 mL) was added dropwise 3N HCl (0.6 mL) at rt. After the mixture was refluxed for 1 h, the reaction mixture was concentrated in vacuo and then extracted with AcOEt. The extract was dried over anhydrous MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane – AcOEt (1 : 1, v/v) to afford 13 (92 mg, 80%).
1-Benzoylazetidine-3-thiol (13): Colorless plates (THF–n-hexane); mp 73.5―75 ºC; 1H-NMR (500 MHz, CDCl3) δ: 2.08 (1H, d, J = 8.0 Hz), 3.77―3.86 (1H, m), 4.00―4.23 (2H, m), 4.60―4.73 (2H, m), 7.42 (2H, t, J = 7.5 Hz), 7.47 (1H, t, J = 7.5 Hz), 7.61 (2H, d, J = 7.5 Hz); 13C-NMR (125 MHz, CDCl3) δ: 27.6, 59.4, 63.8, 127.8, 128.4, 131.2, 132.7, 170.2; IR (KBr) 2947, 2866, 2501, 1611, 1574, 1448, 1431, 795, 716 cm-1; ESI-MS Calcd for C10H12NOS MW 194.0640, Found m/z 194.0631 (M+ + H).
1-Acetylazetidine-3-thiol (14)
To a solution of 2-(1-acetylazetidin-3-yl)thio-1,3-thiazoline (12k, 2.16 g, 10.0 mmol) in MeOH (100 mL) was added dropwise 1N HCl (10 mL) at rt. After the mixture was refluxed for 40 min, the reaction mixture was concentrated in vacuo, and then extracted with AcOEt. The extract was dried over anhydrous MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane – AcOEt (1 : 2, v/v) to CHCl3 – MeOH (10 : 1, v/v) to afford 14 (979 mg, 75%).
1-Acetylazetidine-3-thiol (14): Colorless oil. 1H-NMR (500 MHz, CDCl3) δ: 1.86 (3H, s), 2.06 (1H, d, J = 8.0 Hz), 3.74 (1H, qt, J = 8.0, 5.7 Hz), 3.85 (1H, dd, J = 9.7, 5.7 Hz), 3.98 (1H, dd, J = 8.6, 5.7 Hz), 4.44 (1H, dd, J = 9.7, 8.0 Hz), 4.54 (1H, dd, J = 8.6, 8.0 Hz); 13C-NMR (125 MHz, CDCl3) δ: 18.8, 26.5, 58.6, 61.1, 170.4; IR (neat) 2501, 1611, 1574, 1448, 1431, 795, 716 cm-1; ESI-MS Calcd for C5H10NOS MW 132.0483, Found m/z 132.0486 (M+ + H).
Azetidine-3-thiol hydrochloride (15)5(b),7
1-Acetylazetidiene-3-thiol (14, 39 mg, 0.30 mmol) was dissolved in 3N HCl (3 mL), and the acidic solution was refluxed for 30 min. The reaction mixture was washed with AcOEt and evaporated in vacuo to afford 15 (37 mg, 99%).
Azetidine-3-thiol hydrochloride (15): Colorless oil. 1H-NMR (500 MHz, CDCl3) δ: 3.93―4.09 (3H, m), 4.38―4.45 (2H, m); 13C-NMR (125 MHz, CDCl3) δ: 30.8, 57.4; IR (neat) 3734, 3649, 2972, 1541, 1457 cm-1; ESI-MS Calcd for C3H7NNaS MW 112.0197, Found m/z 112.0196 (M+ - HCl + Na).

ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Scientific Reserch (C) (20550102) from the Japan Society for the Promotion of Science.

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