HETEROCYCLES

Short Paper | Special issue | Vol. 88, No. 2, 2014, pp. 1573-1579
Received, 26th July, 2013, Accepted, 14th August, 2013, Published online, 22nd August, 2013.
DOI: 10.3987/COM-13-S(S)96

■ Preparation of New Heptafulvenes and the Related Compounds Derived from 2H-Cyclohepta[d]thiazol-2-one and -2-thione

Ohki Sato,* Nobuhiro Ando, and Tatsuro Toma

Department of Chemistry, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570 , Japan

Abstract

2H-Cyclohepta[d]thiazol-2-one reacted with dimethyl malonate in the presence of sodium hydride to generate the 6- and 4-adducts, which were oxidized by DDQ to afford a 2-thiazolone-fuzed heptafulvene and a tricyclic compound, respectively. The reaction of 2H-cyclohepta[d]thiazol-2-thione under the same addition conditions gave the similar 6- and 4-adducts. Oxidation of each separated adducts afforded the corresponding regioisomeric heptafulvene disulfides with thiazole rings, respectively.

2H-Cyclohepta[d]thiazol-2-one (1) and the sulfur analogue, -2-thione (2) are classified as non-benzenoid aromatics, and their chemical and physical properties are of interest because of their polarized structure similar to that of azulenes. Although some preparation methods1,2 and cycloaddition reactions3,4 of 1 were reported, no attempt for the reaction with nucleophiles is known so far as we are aware. In this manuscript, we report the reactions of 1 and 2 with dimethyl malonate in the presence of sodium hydride and the successive oxidation that furnish new thiazolone/thiazole-fused heptafulvene systems. Heptafulvenes with electron-deficient substituents are stable compounds and their highly polarized properties have attracted attention for chemists, however, their synthetic methods have not been much investigated.5-9

A reaction of 1 and dimethyl malonate with sodium hydride generated a mixture of 3a and 3b, adducts at the 6- and 4-positions, respectively. In this reaction, the 8-adduct (3c) was not formed. The calculated heats of formation using DFT method (B3LYP/6-31G*)10 supported these results to a certain extent (3a: 0 kcal/mol, 3b: +2.6 kcal/mol, 3c: +52.6 kcal/mol). When the mixture was oxidized by DDQ, 3a afforded a thiazolone-fuzed heptafulvene, 6-[di(methoxycarbonyl)methylene]-3H-cyclohepta[d]thiazol-2-one (4a, 33% from 1), whereas 3b produced not a heptafulvene (4b) but a tricyclic compound, methyl 2,3-dioxo-1-thia-2a-azacyclopent[cd]azulene-4-carboxylate (5, 41% from 1).

The mixture of 3a and 3b were able to separate by recrystallization (hexane-CH2Cl2). Treatment of separated 3b with DDQ at room temperature formed 4-substituted cycloheptathiazol-2-one (6b, 67%), which was a tautomer of unstable 4b (6b: 0 kcal/mol, 4b: +71 kcal/mol by B3LYP/6-31G*). The intramolecular cyclization of isolated 6b was accomplished under thermal conditions to give 5 (75%).

The synthetic heptafulvene (4a) was an orange solid [155-156 °C (dec.)]. The 1H NMR spectrum showed four protons at δ 6.70, 6.90, 7.08 and 7.31 as a seven-membered ring moiety and a singlet peak at δ 3.68 as CO2Me moieties (chemically equivalent six protons). A NH proton was also observed at δ 11.23. The 13C NMR spectrum showed thirteen carbons involving three kinds of carbonyl ones (δ 166.3, 166.4 and 169.7). IR and MS spectra gave N-H and C=O stretching peaks (ν 3025, 1748, 1740, 1690) and a molecular ion peak [m/z 294 (MH+)]. The tricyclic compound (5) was a yellow solid [284-285 °C (dec.)]. The 1H NMR spectrum showed four protons at δ 7.63, 7.86, 8.08 and 8.66 with appropriate coupling constants (J = 11.2 and/or 9.4 Hz) as a seven-membered ring moiety and a singlet peak at δ 3.79 (CO2Me, 3H). The 13C NMR spectrum showed three kinds of carbonyl carbons (δ 158.8, 162.8 and 163.7) within the twelve ones. IR and MS spectra gave three kinds of C=O stretching peaks (ν 1755, 1736 and 1705) and a molecular ion peak [m/z 262 (MH+)]. Together with elemental analysis results of 4 and 5, those spectral data supported their structures. Physical data of the intermediates 3a, 3b and 6b were also consistent with their proposed structures, respectively.
We next focused on the chemical properties of 2H-cyclohepta[d]thiazol-2-thione (2), the sulfur analogue of 1. Preparation of 2 (75%) was carried out by the thermal reaction of 1 with Lawesson’s reagent.11,12 2 was a reddish black solid [mp 141-142 °C (dec.)] and the structure was confirmed by the measurement of instrumental analysis data.

The reaction of 2 under same addition conditions in the case of 1 afforded the 4- and 6-adducts 7a (35%) and 7b (48%), which were separated by recrystallization. The 8-adduct (7c) was not formed in a similar manner as described above. Oxidation of isolated 7a with 0.5 mol eq. of DDQ at room temperature might produce not a heptafulvene monomer (9a) but a disulfide (8a) as a mixture of diastereoisomers. In the case of 7b, the product might be a disulfide (8b), which was neither a tricyclic compound (10) nor 4-substituted cycloheptathiazol-2-thione (11b). The crude 8a or 8b was oxidized by further 1.0 mol eq. of DDQ to afford a heptafulvene disulfide, bis{[6-di(methoxycarbonyl)methylene]cyclohepta[d]thiazol- 2-yl} disulfide [12a, a reddish orange solid; 173-174 °C (dec.), 63% from 7a] or a 4-regioisomer (12b, red needles; mp 86-87 °C, 84% from 7b), respectively. The structures of 7a, 7b, 12a and 12b were confirmed by the measurement of instrumental analysis data.
In conclusion, we have succeeded in the preparation of new thiazolone/thiazole-fuzed heptafulvenes derived from 2H-cyclohepta[d]thiazol-2-one (1) and -2-thione (2). Further work, aimed at the electrochemical properties arising from the contribution of their polarized structures and their chemical transformations toward the construction of functional compounds, is in progress.

EXPERIMENTAL
Mps were determined with a Laboratory Devices MEL-TEMP apparatus and are uncorrected. 1H and 13C NMR spectra (SiMe4 as the internal standard) were obtained with Bruker AV500, AM400, AV300, AC300 and/or AC200 spectrometers. IR spectra were obtained with a Perkin Elmer System 2000 FT instrument. MS spectra were obtained with a JEOL JMS700AM spectrometer. Unless otherwise stated the spectra were taken in the following solvents/media: IR, KBr; 1H and 13C NMR, CDCl3; MS spectra were taken at 70 eV by electron impact (EI) and/or fast atom bombardment (FAB) method. The progress of reactions was followed by TLC method using Merck Silica gel 60F254.
Preparation of a heptafulvene (4a) and a tricyclic compound (5): To a solution of 11 (130 mg, 8.0 x 10-1 mmol) in dry THF (5.0 mL), a mixture of dimethyl malonate (1.2 mol eq.) and sodium hydride (1.2 mol eq.) in dry THF (1.0 mL) was added at 0 °C under N2. The solution was stirred for 4 h at rt. The reaction mixture was quenched with sat. aq. NH4Cl and the aqueous layer was extracted with CH2Cl2. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to give a mixture of crude 3a and 3b. To a solution of the mixture in benzene (6.0 mL), DDQ (1.0 mol eq.) was added and the reaction mixture was refluxed for 1 h. The solvent was removed and the residue was purified by SiO2 column chromatography and/or recrystallization (hexane-CH2Cl2) to give 4a (77 mg, 33%) and 5 (96 mg, 41%). The mixture of 3a and 3b was able to separate by recrystallization (hexane-CH2Cl2). A benzene (1.0 mL) solution of separated 3a (10 mg, 3.4 x 10-2 mmol) and DDQ (1.0 mol eq.) was stirred for 2 h at rt under Ar. After removal of the solvent in vacuo, the residue was purified by SiO2 column chromatography to give 4a (6.8 mg, 68%). A benzene (2.0 mL) solution of separated 3b (30 mg, 1.0 x 10-1 mmol) and DDQ (1.0 mol eq.) was stirred for 2 h at rt under Ar and the solvent was removed. The resulting crude materials were recrystallized with benzene-hexane to give 6b (20 mg, 67%). A benzene (1.0 mL) solution of 6b (10 mg, 3.4 x 10-2 mmol) was refluxed for 2 h under Ar and the resulting solid was purified by recrystallization (hexane-CH2Cl2) to give 5 (6.7 mg, 75%).
6-Adduct (3a): colorless crystals; mp 160 °C (dec.); 1H NMR δ 2.79 (dt, J = 11.2, 6.0 Hz, 1H), 3.77 (s, 6H), 3.80 (d, J = 11.2 Hz, 1H), 5.24 (dd, J = 9.6, 6.0 Hz, 1H), 5.44 (dd, J = 9.6, 6.0 Hz, 1H), 6.34 (d, J = 9.6 Hz, 1H), 6.37 (d, J = 9.6 Hz, 1H), 9.61 (br.s, 1H); 13C NMR δ 38.3, 52.8 (2C), 53.2, 116.6, 119.3, 119.8, 120.6, 123.6, 132.6, 168.3 (2C), 172.2; IR (KBr) ν 3130, 1738, 1644 cm-1; MS (FAB, NBA) m/z 296 (MH+). Anal. Calcd for C13H13NO5S: C, 52.87; H, 4.44; N, 4.74. Found: C, 52.71; H, 4.29; N, 4.78.
4-Adduct (3b): colorless needles; mp 110 °C (dec.); 1H NMR δ 3.49 (d, J = 11.2 Hz, 1H), 3.68 (s, 3H), 3.72 (s, 3H), 4.25 (dd, J = 11.2, 8.5 Hz, 1H), 5.54 (t like, J = 10.4 Hz, 1H), 6.26 (m, 1H), 6.40-6.50 (m, 2H), 9.21 (br.s, 1H); 13C NMR δ 37.2, 49.7, 52.9, 53.1, 113.3, 121.4, 123.1, 124.8, 127.0, 128.3, 167.3, 168.0, 174.0; IR (KBr) ν 3152, 1759, 1733, 1675 cm-1; MS (FAB, NBA) m/z 296 (MH+). Anal. Calcd for C13H13NO5S: C, 52.87; H, 4.44; N, 4.74. Found: C, 52.91; H, 4.26; N, 4.83.
Heptafulvene (4a): an orange solid; mp 155-156 °C (dec.); 1H NMR (DMSO-d6) δ 3.68 (s, 6H), 6.70 (d, J = 12.5 Hz, 1H), 6.90 (d, J = 12.5 Hz, 1H), 7.08 (dd, J = 12.5, 2.2 Hz, 1H), 7.31 (dd, J = 12.5, 2.2 Hz, 1H), 11.23 (br.s, 1H); 13C NMR (DMSO-d6) δ 52.19, 52.21, 113.9, 122.9, 124.1, 126.1, 129.5, 131.9, 137.8, 148.0, 166.3, 166.4, 169.7; IR (KBr) ν 3025, 1748, 1740, 1690 cm-1; MS (FAB, NBA) m/z 294 (MH+). Anal. Calcd for C13H11NO5S: C, 53.24; H, 3.78; N, 4.78. Found: C, 53.06; H, 3.75; N, 4.84.
Tricyclic compound (5): a yellow solid; mp 284-285 °C (dec.); 1H NMR (DMSO-d6) δ 3.79 (s, 3H), 7.63 (dd, J = 11.2, 9.4 Hz, 1H), 7.86 (dd, J = 11.2, 9.4 Hz, 1H), 8.08 (d, J = 11.2 Hz, 1H), 8.66 (d, J = 11.2 Hz, 1H); 13C NMR (DMSO-d6) δ 51.0, 102.0, 130.0, 131.6, 132.5, 133.9, 138.4, 139.8, 145.5, 158.8, 162.8, 163.7; IR (KBr) ν 1755, 1736, 1705 cm-1; MS (FAB, Thiogly.) m/z 262 (MH+). Anal. Calcd for C12H7NO4S: C, 55.17; H, 2.70; N, 5.36. Found: C, 55.16; H, 2.59; N, 5.43.
4-Substituted cycloheptathiazol-2-one (6b): yellow crystals; mp 135 °C (dec.); 1H NMR δ 3.80 (s, 6H), 6.17 (s, 1H), 7.49-7.59 (m, 2H), 8.01-8.04 (m, 1H), 8.06-8.10 (m, 1H); 1H NMR (benzene-d6) δ 3.27 (s, 6H), 6.09 (t like, J = 10 Hz, 1H), 6.35 (s, 1H), 6.37 (t like, J = 10 Hz, 1H), 6.52 (d lile, J = 10 Hz, 1H), 7.78 (d like, J = 10 Hz, 1H); 13C NMR δ 53.3 (2C), 56.7, 128.4, 131.5 (2C), 135.1, 137.2, 141.3, 168.1, 171.7 (2C), 177.7; IR (KBr) ν 1742, 1677 cm-1; MS (FAB, NBA) m/z 294 (MH+). Anal. Calcd for C13H11NO5S: C, 53.24; H, 3.78; N, 4.78. Found: C, 53.18; H, 3.62; N, 4.84.
Preparation of cycloheptathiazol-2-thione (2): A mixture of 1 (326 mg, 2.0 mmol) and Lawesson’s reagent (0.5 mol eq.) in benzene (20 mL) was refluxed for 4 h under Ar. After removal of the solvent in vacuo, the resulting crude material was purified by SiO2 column chromatography to give 2 (270 mg, 75%). The purification should be carried out rapidly because of some lability of 2 in solution.
Cycloheptathiazol-2-thione (2): a reddish black solid; mp 141-142 °C (dec.); 1H NMR δ 7.50-7.56 (m, 2H), 7.76-7.83 (m, 1H), 7.95-7.98 (m, 1H), 8.07 (d like, J = 11 Hz, 1H); 13C NMR δ 128.7, 132.8, 137.6, 138.2, 141.3, 165.5, 172.9, 206.3; IR (KBr) ν 1218 cm-1; MS (EI) m/z 179 (M+); HRMS (EI) Calcd for C8H5NS2: 178.9863. Found: 178.9860.
Preparation of heptafulvene disulfides (12a and 12b): To a solution of 2 (90 mg, 5.0 x 10-1 mmol) in dry THF (3.0 mL), a mixture of dimethyl malonate (1.2 mol eq.) and sodium hydride (1.2 mol eq.) in dry THF (3.0 mL) was added at 0 °C under Ar. The solution was stirred for 4 h at rt. The reaction mixture was quenched with sat. aq. NH4Cl and the aqueous layer was extracted with CH2Cl2. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to give a mixture of crude 7a and 7b. The mixture was separated and purified by recrystallization (hexane-CH2Cl2) to give 7a (54 mg, 35%) and 7b (75 mg, 48%). A benzene (1.0 mL) solution of isolated 7a (15 mg, 4.8 x 10-2 mmol) and DDQ (0.5 mol eq.) was stirred for 2 h at rt under Ar and the solvent was removed. 1H NMR spectrum of the resulting residue suggested a formation of 8a as a mixture of diastereoisomers [δ 2.92-2.98 (m, 2H), 3.73 (d like, J = 11 Hz, 2H), 3.75 (s, 12H), 5.51 (m, 2H), 5.58 (m, 2H), 6.69 (d like, J = 10 Hz, 2H), 6.89 (d like, J = 10 Hz, 2H)]. DDQ (further 1.0 mol eq.) was added to a benzene (1.0 mL) solution of the residue and the reaction mixture was stirred for 14 h at rt under Ar. After removal of the solvent in vacuo, the resulting crude material was purified by SiO2 column chromatography to give 12a (9.3 mg, 63% from 7a). A benzene solution (1.0 mL) of isolated 7b (30 mg, 9.6 x 10-2 mmol) and DDQ (total 1.5 mol eq.) was stirred for 14 h at rt under Ar. After removal of the solvent in vacuo, the residue was purified by SiO2 column chromatography to give 12b (25 mg, 84% from 7b). The reaction of 7b with DDQ (0.5 mol eq.) at rt for 2 h in benzene gave the similar results in the case of 7a, which suggested a formation of 8b as a mixture of diastereoisomers by the 1H NMR measurement [δ 3.59 (s, 6H), 3.74 (s, 6H), 3.92 (d, J = 11.0 Hz, 1H), 3.94 (d, J = 11.0 Hz, 1H), 4.07 (dd, J = 11.0, 6.6 Hz, 1H), 4.11 (dd, J = 11.0, 6.6 Hz, 1H), 5.71 (dd like, J = 10, 7 Hz, 2H), 6.17-6.23 (m, 2H), 6.49-6.60 (m, 2H), 6.81 (d like, J = 11 Hz, 2H)].
6-Adduct (7a): brown crystals; mp 106 °C (dec.); 1H NMR δ 2.82 (dt, J = 11.2, 6.3 Hz, 1H), 3.77 (s, 6H), 3.79 (d, J = 11.2 Hz, 1H), 5.36 (dd, J = 9.6, 6.3 Hz, 1H), 5.54 (dd, J = 9.6, 6.3 Hz, 1H), 6.40 (d like, J = 9.6 Hz, 2H), 10.08 (br.s, 1H); 13C NMR (DMSO-d6) δ 38.5, 53.1 (3C), 116.8, 119.3, 121.5, 125.3, 127.4, 140.2, 168.6 (2C), 187.5; IR (KBr) ν 3050, 1737, 1058 cm-1; MS (FAB, NBA) m/z 312 (MH+). Anal. Calcd for C13H13NO4S2: C, 50.14; H, 4.21; N, 4.50. Found: C, 50.32; H, 4.18; N, 4.71.
4-Adduct (7b): a brown solid; mp 94 °C (dec.); 1H NMR δ 3.52 (d, J = 11.4 Hz, 1H), 3.69 (s, 3H), 3.74 (s, 3H), 4.37 (dd, J = 11.4, 8.5 Hz, 1H), 5.59 (t like, J = 10 Hz, 1H), 6.26-6.31 (m, 1H), 6.41-6.56 (m, 2H), 11.17 (br.s, 1H); 13C NMR δ 36.8, 49.9, 53.2, 53.4, 120.8, 123.1, 123.2, 128.2, 128.5, 131.3, 167.2, 167.7, 189.7; IR (KBr) ν 2995, 1750, 1725, 1063 cm-1; MS (FAB, NBA) m/z 312 (MH+). Anal. Calcd for C13H13NO4S2: C, 50.14; H, 4.21; N, 4.50. Found: C, 49.86; H, 4.05; N, 4.43.
Heptafulvene disulfide (12a): a reddish orange solid; 173-174 °C (dec.); 1H NMR δ 3.79 (s, 3H), 3.81 (s, 3H), 6.83 (d, J = 12.3 Hz, 1H), 7.08 (d, J = 12.3 Hz, 1H), 7.21 (dd, J = 12.3, 2.0 Hz, 1H), 7.29 (dd, J = 12.3, 2.1 Hz, 1H); 13C NMR δ 52.4, 52.5, 118.7, 124.9, 128.9, 130.0, 130.7, 140.4, 147.4, 155.7, 166.0, 166.4, 166.7; IR (KBr) ν 1722, 1682 cm-1; MS (FAB, NBA) m/z 617 (MH+). Anal. Calcd for C26H20N2O8S4: C, 50.64; H, 3.27; N, 4.54. Found: C, 50.49; H, 3.20; N, 4.58.
Heptafulvene disulfide (12b): red needles; mp 86-87 °C; 1H NMR δ 3.78 (s, 3H), 3.80 (s, 3H), 6.48-6.59 (m, 2H), 6.86 (d like, J = 10 Hz, 1H), 8.05 (d like, J = 10 Hz, 1H); 13C NMR δ 52.1, 52.3, 119.0, 122.9, 129.8, 130.6, 131.0, 141.1, 143.3, 149.3, 164.6, 165.9, 168.4; IR (KBr) ν 1716, 1695 cm-1; MS (FAB, NBA) m/z 617 (MH+). Anal. Calcd for C26H20N2O8S4.CH2Cl2: C, 46.22; H, 3.16; N, 3.99. Found: C, 46.45; H, 3.04; N, 4.11.

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