PDF icon Download PDF
Synlett 2003(2): 0166-0172
DOI: 10.1055/s-2003-36802
LETTER
© Georg Thieme Verlag Stuttgart · New York

Isothiazole Ring Formation with Substituted 2-Alkylthio-3-acyl-4-quinolinone Using O-(Mesitylenesulfonyl)hydroxylamine (MSH)

Jong Hee Choi, Eun Bok Choi, Chwang Siek Pak*
Korea Research Institute of Chemical Technology, Yusung-Ku Jang-Dong 100, Taejeon, 305-600, Korea
Fax: +82(42)8600307; e-Mail: cspak@krict.re.kr;
Further Information

Publication History

Received 9 December 2002
Publication Date:
22 January 2003 (online)

   Permissions and Reprints All articles of this category
Preview

Abstract

Isothiazole ring skeleton was formed by the treatment of substituted 2-alkylthio-3-acyl-4-quinolinone with O-(mesitylenesulfonyl)hydroxylamine(MSH). A mixture of alkyl transferred 3-methyl-9-alkyl-4,9-dihydroisothiazolo[5,4-b]quinolin-4-one as a major product and dealkylated 3-methyl-4,9-dihydroisothiazolo[5,4-b]quinolin-4-one as a minor product was obtained from unsubstituted 2-alkylthio-3-acyl-4-quinolinone in the presence of K2CO3. When 2 equivalents of MSH were used in the absence of K2CO3 only dealkylated product was obtained in quantitative yield.

Key words

imine - electrophilic addition - cyclizations - isothiazole - O-(mesitylenesulfonyl)hydroxyl amine

18

X-ray crystal structure analysis of 2a and 3f: Atomic coordinates, bond lengths [Å] and angles [deg], anisotropic displacement parameters, hydrogen coordinates, torsion angles [deg] have been deposited at Cambridge Crystallographic Data Centre 12, Union Road. Cambridge. CB2 1EZ, UK. Under deposition number CCDC 192773 for 2a,CCDC 192772 for 3f (Fax: +44(1223)336033, E-mail:deposit@ccdc.cam.ac.uk).

19

Representative Procedure: To a stirred solution of (1a) (300 mg, 1.28 mmol) in DMF (3 mL) was added K2CO3 (442 mg, 3.2 mmol). After Stirring for 30 min at r.t., MSH (304 mg, 1.41 mmol) was added in small portion during the period of 1 h. The mixture was stirred at r.t. for 4 h. The solvent was distilled off, and the residue was partitioned between EtOAc (500 mL) and H2O (80 mL). The organic layer was separated, washed with brine (50 mL), and dried with anhyd MgSO4. After filtering MgSO4, the solvent was evaporated under vacuum to give a mixture of crude products (267 mg) which was separated by column chromatography (hexanes:EtOAc = 3:1) to afford 3,9-dimethyl-9H-isothiazolo[5,4-b]quinolin-4-one (2a) (162 mg, 55%), 3-methyl-9H-isothiazolo[5,4-b]quinolin-4-one (3a) (83mg, 30%) and 2,4,6-trimethyl-benzenesufonic acid methyl ester (22 mg, 8%). (2a) Yield: 55%, Yellow solid,
Rf = 0.41 (CH2Cl2:MeOH = 30:1), mp 199-200 °C.
1H NMR (300 MHz, CDCl3): δ = 8.56-8.51 (m, 1 H),
7.79-7.70 (m, 1 H), 7.46-7.37 (m, 2 H), 3.84 (s, 3 H), 2.89 (s, 3 H).13C NMR (125 MHz, CDCl3): δ = 174.16, 170.24, 168.23, 140.61, 133.17, 127.51, 125.60, 123.29, 118.99, 113.69, 38.46, 21.09. MS: m/z = 230 (M+), 215, 197, 184, 169. HRMS (EI): calcd for C12H10N2O1S1: 230.0517.
Found: 230.0520. Anal. Calcd for C12H10N2O1S1: C, 62.59; H, 4.38; N, 12.16; S, 13.92. Found: C, 62.61; H, 4.41; N, 12.55; S, 13.83. (3a) Yield: 30%, Yellow solid, Rf = 0.08 (hexanes:EtOAC = 3:1), mp 342-344 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 12.75 (s, 1 H), 8.25-8.22 (m, 1 H), 7.78-7.71 (m, 1 H), 7.53-7.49 (m, 1 H), 7.40-7.33 (m, 1 H), 2.72 (s, 3 H).13C NMR (125 MHz, DMSO-d 6): δ = 173.75, 165.97, 165.24, 140.07, 133.20, 125.93, 123.55, 122.93, 118.64, 117.60, 20.35. MS: m/z = 216 (M+), 199, 183, 170, 161. HRMS (EI): calcd for C11H8N2O1S1: 216.0360. Found: 216.0357. 2,4,6-Trimethyl-benzenesufonic Acid Methyl Ester: Yield: 8%, Yellow oil, Rf = 0.76 (hexanes:EtOAc = 3:1). 1H NMR (200 MHz, CDCl3): δ = 6.99 (s, 2 H), 3.70 (s, 3 H), 2.63 (s, 6 H), 2.32 (s, 3 H). MS: m/z = 214 (M+), 196, 182, 174, 165, 149.

20

1H NMR was run in Bruker AMX 500MHz in DMF-d 7. A mixture of MSH (22 mg) and 1a (12 mg) in 1mL of DMF-d 7 was used and the spectrum was run at an interval of 5 min up to 1 h. After 12th run 3 h, 1 d, 3 d interval spectrum was obtained.

21

In order to prepare GCMS sample for low boiling material, reaction was run under the standard condition. After 2 h, low boiling cut was collected using dry ice-acetone trap. The sample was analyzed in HP 5890 series II (GC) and HP5971 series MSD (mass detector). Conditions: capillary column DB-wax 30m × 0.25 mm (0.25 µm film thickness), ion source temperature 200 °C, injection temperature 250 °C: oven temperature 35 °C to ca. 240 °C programmed 10 °C/min, retention time: 2.08 min HCO2Me, 3.47 min MeOH.

27

Methylthio group of quinolinone 1a was removed by Raney nickel to provide 3-acyl-4-quinolinone (8) and acyl group of 1a was removed by treatment with trifluoro acetic acid as solvent to give 2-methylthio-4-quinolinone (9). Reaction of 8 or 9 with MSH did not proceed after overnight stirring under the same condition.