HETEROCYCLES

Short Paper | Regular issue | Vol. 85, No. 12, 2012, pp. 3007-3013
Received, 11th September, 2012, Accepted, 24th October, 2012, Published online, 30th October, 2012.
DOI: 10.3987/COM-12-12584

■ One-Pot Synthesis of 2-(1,4-Dihydro-2H-3,1-benzothiazin-2-ylidene)propanedioic Acid Derivatives by the Reaction of 2-(1-Bromoalkyl)phenyl Isothiocyanates with Propanedioic Acid Derivatives Using Sodium Hydride

Kazuhiro Kobayashi* and Kosuke Ezaki

Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

An efficient one-pot procedure for the preparation of 2-(1,4-dihydro-2H-3,1-benzothiazin-2-ylidene)propanedioic acid derivatives from 2-(1-bromoalkyl)phenyl isothiocyanates with propanedioic (malonic) acid derivatives, such as propanedinitrile, ethyl cyanoacetates, 3-oxo-3-(pyrrolidin-1- yl)propanenitrile and diethyl propanedioate, has been developed. The reactions are carried out in the presence of two equivalents of sodium hydride at –20 ˚C to give the desired products.

2-(1,4-Dihydro-2H-3,1-benzothiazin-2-ylidene)propanedioic acid derivatives are attractive heterocycles as some compounds having the 1,4-dihydro-2H-3,1-benzothiazin-2-ylidene structure have been reported to possess pharmacological activities.1 However, few general methods for the preparation of 2-(1,4-dihydro-2H-3,1-benzothiazin-2-ylidene)propanedioic acid derivatives have been elaborated, though a synthesis of ethyl 2-cyano-2-(4-oxo-1,4-dihydro-2H-3,1-benzothiazin-2-ylidene)acetate by the reaction of ethyl 2-isothiocyanatobenzoate with methyl cyanoacetates in the presence of Et3N has been reported by Basheer and Rappoport.2 In this article, we wish to describe a facile one-pot procedure for the synthesis of 2-(1,4-dihydro-2H-3,1-benzothiazin-2-ylidene)propanedioic acid derivatives by the reaction of 2-(1-bromoalkyl)phenyl isothiocyanates with propanedioic (malonic) acid derivatives using sodium hydride as a base under mild conditions.
The one-pot synthesis was conducted by the process depicted in Scheme 1. The starting isothiocyanates (1) were easily obtained by benzylic bromination of commercially available 2-alkylphenyl isothiocyanates with N-bromosuccinimide (NBS). Compounds (1) were allowed to react with propanedioic acid derivatives, such as propanedinitrile, ethyl cyanoacetate, 3-oxo-3-(pyrrolidin-1-yl)- propanenitrile and diethyl propanedioate, in the presence of two equivalents of sodium hydride in DMSO/THF at –20 ˚C. The stabilized carbanions, generated from propanedioic acid derivatives and the first equivalent of sodium hydride, attack on the isothiocyanato carbon to generate the intermediates (2). Then, the second equivalent of sodium hydride abstracts the methine proton, activated by the two electron withdrawing groups and the thiocarbonyl group, to generate the dianion intermediates (3). Intramolecular substitution of bromide with thioenolate sulfur provides 1-sodio-3,1-benzothiazine intermediates (4). The usual aqueous workup and subsequent recrystallization of the crude products afforded the desired products (5). The results are compiled in Table 1. For example, the reaction of 2-(bromomethyl)phenyl isothiocyanate (1a) with propanedinitrile proceeded cleanly and smoothly to yield the corresponding desired product (5a) in good yield (Entry 1). At a higher temperature (0 ˚C) a rather complicated mixture of products was obtained and the yield of the desired product (5a) dropped to 22% (data not shown in Table 1). The reactions in THF using two equivalents of sodium hydride and in DMSO/THF using an equivalent of sodium hydride both gave considerably complicated reaction mixtures as judged by TLC analyses. Although ethyl cyanoacetate, 3-oxo-3-(pyrrolidin-1-yl)propanenitrile, and diethyl propanedioate are also usable in the reactions with 1a, the yields of the corresponding products (5b-d) were moderate (Entries 2-4, respectively).

The use of 2-bromomethyl-4-chlorophenyl isothiocyanate (1b) provided the corresponding products (5f-h) in yields comparable to those of using 1a (Entries 6–8). While the reaction of 2-bromomethyl-4-methoxyphenyl isothiocyanate (1c) with propanedinitrile led to the formation of rather intractable mixture of products, from which only moderate yield of the expected product (5i) was isolated (Entry 9), that using 2-(1-bromoethyl)phenyl isothiocyanate (1d) proceeded uneventfully to give the corresponding products (5j) in relatively good yield (Entry 10).

When the reaction was carried out using ethyl cyanoacetate or 3-oxo-3-(pyrrolidin-1-yl)propanenitrile, only E-isomer was obtained in each case (Entries 2, 3, 7, and 8). As depicted in Figure 1, this exclusive formation of E-isomers ascribed to the stabilization due to the hydrogen bonding between the NH hydrogen and the carbonyl oxygen in each case. As can be seen in EXPERIMENTAL section, the C=O stretching bands of these products are observed at considerably decreased wavenumbers and the chemical shifts of NH protons appear in much lower magnetic field (δ 12.23–13.60) than those of 2-(1,4-dihydro-2H-3,1-benzothiazin-2-ylidene)propanedinitriles (5a, 5f, 5i, and 5j). Ethyl 3-oxobutanoate proved to be usable in the present reaction, but the reaction with 1a provided the product (5e) as a mixture of stereoisomers in much lower yields than those using the above propanedioic acid derivatives (Entry 5).

In conclusion, we have developed an efficient one-pot synthesis of 2-(1,4-dihydro-2H-3,1-benzothiazin- 2-ylidene)propanedioic acid derivatives by the reaction of 2-(1-bromoalkyl)phenyl isothiocyanates with propanedioic acid derivatives under mild reaction conditions. Notable advantages of the present method are: i) simplicity of the procedure, ii) mild reaction conditions, and iii) easy availability of the starting materials.

EXPERIMENTAL
All melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are uncorrected. IR spectra were recorded with a Perkin–Elmer Spectrum65 FTIR spectrophotometer. 1H NMR spectra were recorded using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 500 MHz or a JEOL LA400FT NMR spectrometer operating at 400 MHz. 13C NMR spectra were recorded using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 125 MHz. High-resolution MS spectra (DART, positive) were measured by a Thermo Scientific Exactive spectrometer. TLC was carried out on Merck Kieselgel 60 PF254. Column chromatography was performed using WAKO GEL C-200E. All of the organic solvents used in this study were dried over appropriate drying agents and distilled prior to use.
Starting Materials. 1-Bromomethyl-2-isothiocyanatobenzene (1a)3 and 3-oxo-3-(pyrrolidin-1- yl)propanenitrile4 were prepared according to the appropriate reported procedures. All other chemicals used in this study were commercially available.
1-Bromoalkyl-2-isothiocyanatobenzenes (1b), (1c), and (1d). These compounds were prepared from the respective 1-alkyl-2-isothiocyanatobenzenes according to the procedure reported for the preparation of 1a from 1-isothiocyanato-2-methylbenzene.3
1-Bromomethyl-5-chloro-2-isothiocyanatobenzene (1b):5 yield: 67%; a white solid; mp 57–59 ˚C (hexane–CH2Cl2); IR (KBr) 2069 cm–1; 1H NMR (500 MHz, CDCl3) δ 4.45 (s, 2H), 7.21 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 8.4, 2.3 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H). Anal. Calcd for C8H5BrClNS: C, 36.60; H, 1.92; N, 5.33. Found: C, 36.58; H, 1.93; N, 5.16.
1-Bromomethyl-2-isothiocyanato-5-methoxybenzene (1c): yield: 57%; a white solid; mp 74–76 ˚C (hexane–CH2Cl2); IR (KBr) 2135, 1608 cm–1; 1H NMR (500 MHz, CDCl3) δ 3.82 (s, 3H), 4.47 (s, 2H), 6.83 (dd, J = 9.2, 3.1 Hz, 1H), 6.90 (d, J = 3.1 Hz, 1H), 7.20 (d, J = 9.2 Hz, 1H). Anal. Calcd for C9H8BrNOS: C, 41.88; H, 3.12; N, 5.43. Found: C, 41.68; H, 3.19; N, 5.30.
1-(1-Bromoethyl)-2-isothiocyanatobenzene (1d): yield: 60%; a colorless liquid; Rf 0.50 (hexane); IR (KBr) 2097 cm–1; 1H NMR (500 MHz, CDCl3) δ 1.99 (d, J = 6.9 Hz, 3H), 5.38 (q, J = 6.9 Hz, 1H), 7.19–7.25 (m, 3H), 7.48–7.51 (m, 1H). Anal. Calcd for C9H8BrNS: C, 44.64; H, 3.33; N, 5.78. Found: C, 44.58; H, 3.38; N, 5.71.
Typical Procedure for the Preparation of 2-(1,4-Dihydro-2H-3,1-benzothiazin-2-ylidene)malonic Acid Derivatives (5). 2-(1,4-Dihydro-2H-3,1-benzothiazin-2-ylidene)-1,3-propanedinitrile (5a). To a stirred suspension of NaH (60% in mineral oil; 80 mg, 2.0 mmol) in DMSO–THF (6 mL; 1:2, v/v) at –20 ˚C was added CH2(CN)2 (66 mg, 1.0 mmol) dropwise. After evolution of H2 gas had ceased, compound (1a) (0.23 g, 1.0 mmol) was added, and then stirring was continued for 30 min at the same temperature before saturated aqueous NH4Cl (15 mL) was added. The mixture was extracted with AcOEt (3 × 10 mL) and the combined extracts were washed with water (2 × 10 mL) and brine (10 mL), dried (Na2SO4), and concentrated by evaporation. The residual solid was recrystallized from hexane–CH2Cl2 to give 5a (0.17 g, 82%); a white solid; mp 223–225 ˚C; IR (KBr) 3247, 3212, 2217, 2197, 1624 cm–1; 1H NMR (400 MHz, CDCl3) δ 4.01 (s, 2H), 7.11 (d, J = 7.8 Hz, 1H), 7.23–7.26 (m, 2H), 7.36–7.40 (m, 1H), 8.64 (br, 1H); 13C NMR (CDCl3) δ 28.47, 50.06, 113.79 (two overlapped Cs), 118.13, 119.98, 126.36, 127.69, 129.64, 135.23, 168.63. HR MS (DART, positive). Calcd for C11H8N3S (M+H): 214.0439. Found: m/z 214.0425. Anal. Calcd for C11H7N3S: C, 61.95; H, 3.31; N, 19.70. Found: C, 61.91; H, 3.34; N, 19.62.
Ethyl (E)-2-Cyano-2-(1,4-dihydro-2H-3,1-benzothiazin-2-ylidene)acetate (5b): a pale-yellow solid; mp 127–129 ˚C (hexane–CH2Cl2); IR (KBr) 3286, 3223, 2203, 1649, 1611 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.36 (t, J = 7.3 Hz, 3H), 3.99 (s, 2H), 4.29 (q, J = 7.4 Hz, 2H), 7.02 (d, J = 7.8 Hz, 1H), 7.17–7.19 (m, 2H), 7.30–7.34 (m, 1H), 12.23 (br s, 1H); 13C NMR (CDCl3) δ 14.28, 27.93, 61.13, 73.32, 116.93, 118.31, 119.44, 125.65, 127.57, 129.19, 135.36, 166.73, 167.61. HR MS (DART, positive). Calcd for C13H13N2O2S (M+H): 261.0697. Found: m/z 261.0681. Anal. Calcd for C13H12N2O2S: C, 59.98; H, 4.56; N, 10.76. Found: C, 60.01; H, 4.64; N, 10.49.
(E)-2-(1,4-Dihydro-2H-3,1-benzothiazin-2-ylidene)-3-oxo-3-(pyrrolidin-1-yl)propanenitrile (5c): a pale-yellow solid; mp 185–187 ˚C (hexane–CH2Cl2); IR (KBr) 3284, 2184, 1611, 1575 cm–1; 1H NMR (500 MHz, CDCl3) δ 1.91–1.95 (m, 4H), 3.56 (br s, 2H), 3.81 (br s, 2H), 3.96 (s, 2H), 6.99 (dd, J = 7.6 Hz, 1H), 7.11–7.16 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 13.50 (br s, 1H); 13C NMR (CDCl3) δ 23.92, 26.74, 28.16, 47.20, 48.85, 73.74, 118.45, 119.23, 120.08, 124.94, 127.31, 128.97, 136.05, 165.80, 166.03. HR MS (DART, positive). Calcd for C15H16N3OS (M+H): 286.1014. Found: m/z 286.1024. Anal. Calcd for C15H15N3OS: C, 63.13; H, 5.30; N, 14.73. Found: C, 63.08; H, 5.29; N, 14.70.
Diethyl 2-(1,4-Dihydro-2H-3,1-benzothiazin-2-ylidene)-1,3-propandioate (5d): a pale-yellow solid; mp 76–79 ˚C (hexane–CH2Cl2); IR (KBr) 3254, 1666, 1640, 1602 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.33 and 1.34 (2t, J = 7.3 Hz each, combined 6H), 3.78 (s, 2H), 4.26 and 4.28 (2q, J = 7.3 Hz each, combined 4H), 6.98 (d, J = 7.8 Hz, 1H), 7.08–7.15 (m, 2H), 7.27 (d, J = 7.8 Hz, 1H), 12.59 (br s, 1H); 13C NMR (CDCl3) δ 14.01, 14.22, 28.31, 60.34, 60.83, 93.39, 118.13, 121.12, 124.42, 126.88, 128.55, 136.52, 164.02, 166.89, 168.49. HR MS (DART, positive). Calcd for C15H18NO4S (M+H): 308.0956. Found: m/z 308.0972. Anal. Calcd for C15H17NO4S: C, 58.61; H, 5.57; N, 4.56. Found: C, 58.71; H, 5.82; N, 4.60.
Ethyl 2-(1,4-Dihydro-2H-3,1-benzothiazin-2-ylidene)-3-oxobutanoate (5e): a mixture of stereoisomers (E:Z = ca. 1:9); a pale-yellow solid; mp 96–112 ˚C; IR (KBr) 3276, 1692, 1614 cm–1; 1H NMR (500 MHz, CDCl3) δ 1.37 and 1.39 (2t, J = 6.9 Hz each, combined 3H), 2.43 (s, 0.3H), 2.47 (s, 2.7H), 3.69 (s, 0.2H), 3.79 (s, 1.8H), 4.31 and 4.34 (2q, J = 6.9 Hz each, combined 2H), 7.03 (d, J = 8.0 Hz, 1H), 7.13–7.17 (m, 2H), 7.27–7.31 (m, 1H), 13.22 (br s, 1H); 13C NMR (CDCl3) δ 14.30, 28.29, 28.86, 30.60, 31.60, 60.48, 60.78, 102.31, 103.09, 118.30, 118.97, 121.00, 125.15, 125.49, 126.92, 128.27, 128.61, 135.96, 167.45, 167.94, 196.03. HR MS (DART, positive). Calcd for C14H16NO3S (M+H): 278.0851. Found: m/z 278.0837. Anal. Calcd for C14H15NO3S: C, 60.63; H, 5.45; N, 5.05. Found: C, 60.42; H, 5.62; N, 5.02.
2-(6-Chloro-1,4-dihydro-2H-3,1-benzothiazin-2-ylidene)-1,3-propanedinitrile (5f): a yellow solid; mp 253–255 ˚C (hexane–THF); IR (KBr) 3243, 3199, 2220, 2199, 1622 cm–1; 1H NMR (500 MHz, CDCl3) δ 3.98 (s, 2H), 7.04 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.36 (dd, J = 8.4, 2.3 Hz, 1H), 8.54 (br s, 1H); 13C NMR (DMSO-d6) δ 26.95, 50.11, 114.32, 115.90, 121.01, 123.77, 127.17, 128.52, 129.45, 135.18, 167.99. HR MS (DART, positive). Calcd for C11H7ClN3S (M+H): 248.0049. Found: m/z 248.0068. Anal. Calcd for C11H6ClN3S: C, 53.34; H, 2.44; N, 16.96. Found: C, 53.23; H, 2.52; N, 16.81.
Ethyl (E)-2-(6-Chloro-1,4-dihydro-2H-3,1-benzothiazin-2-ylidene)-2-cyanoacetate (5g): a pale-yellow solid; mp 135–136 ˚C (hexane–CH2Cl2); IR (KBr) 3171, 2213, 1653, 1612 cm–1; 1H NMR (500 MHz, CDCl3) δ 1.35 (t, J = 7.6 Hz, 3H), 3.95 (s, 2H), 4.29 (q, J = 7.6 Hz, 2H), 6.96 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.30 (dd, J = 8.4, 2.3 Hz, 1H), 12.27 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 14.28, 27.71, 61.34, 74.16, 119.47, 121.06, 127.56, 128.67, 129.23, 130.61, 134.11, 166.20, 167.57. HR MS (DART, positive). Calcd for C13H12ClN2O2S (M+H): 295.0308. Found: m/z 295.0323. Anal. Calcd for C13H11ClN2O2S: C, 52.97; H, 3.76; N, 9.50. Found: C, 52.90; H, 3.82; N, 9.43.
(E)-2-(6-Chloro-1,4-dihydro-2H-3,1-benzothiazin-2-ylidene)-3-oxo-3-(pyrrolidin-1-yl)propanenitrile (5h): a pale-yellow solid; mp 204–206 ˚C (hexane–CH2Cl2); IR (KBr) 3385, 2187, 1614, 1567 cm–1; 1H NMR (500 MHz, CDCl3) δ 1.91–1.95 (m, 4H), 3.55–3.81 (m, 4H), 3.92 (s, 2H), 6.92 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.4, 2.3 Hz, 1H), 13.60 (br s, 1H); 13C NMR (CDCl3) δ 25.15, 26.75, 27.93, 47.69, 49.29, 74.38, 118.89, 119.59, 121.64, 127.30, 128.99, 129.84, 134.77, 165.56, 165.63. HR MS (DART, positive). Calcd for C15H15ClN3OS (M+H): 320.0624. Found: m/z 320.0614. Anal. Calcd for C15H14ClN3OS: C, 56.33; H, 4.41; N, 13.14. Found: C, 56.26; H, 4.48; N, 13.08.
2-(6-Methoxy-1,4-dihydro-2H-3,1-benzothiazin-2-ylidene)-1,3-propanedinitrile (5i): a white solid; mp 250–251 ˚C (hexane–CH2Cl2); IR (KBr) 3254, 3212, 2217, 2200, 1626 cm–1; 1H NMR (500 MHz, CDCl3) δ 3.82 (s, 3H), 3.96 (s, 2H), 6.75 (d, J = 2.3 Hz, 1H), 6.90 (dd, J = 8.4, 2.3 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 8.70 (br s, 1H); 13C NMR (DMSO-d6) δ 27.54, 48.26, 55.56, 112.51, 114.10, 114.81, 116.38, 120.59, 123.19, 129.60, 157.11, 167.31. HR MS (DART, positive). Calcd for C12H10N3OS (M+H): 244.0544. Found: m/z 244.0551. Anal. Calcd for C12H9N3OS: C, 59.24; H, 3.73; N, 17.27. Found: C, 59.13; H, 3.81; N, 17.22.
2-(4-Methyl-1,4-dihydro-2H-3,1-benzothiazin-2-ylidene)-1,3-propanedinitrile (5j): a pale-yellow solid; mp 215–217 ˚C (hexane–CHCl3); IR (KBr) 3245, 3208, 2219, 2195, 1620 cm–1; 1H NMR (500 MHz, DMSO-d6) δ 1.47 (d, J = 7.6 Hz, 3H), 4.56 (q, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 11.89 (br s, 1H); 13C NMR (DMSO-d6) δ 21.88, 37.08, 49.74, 114.64, 116.21, 119.75 (two overlapped Cs), 126.17, 126.53, 128.72, 134.99, 166.37. HR MS (DART, positive). Calcd for C12H10N3S (M+H): 228.0595. Found: m/z 228.0587. Anal. Calcd for C12H9N3S: C, 63.41; H, 3.99; N, 18.49. Found: C, 63.16; H, 4.01; N, 18.19.

ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research (C) 22550035 from Japan Society for the Promotion of Science. We thank Mrs. Miyuki Tanmatsu of our university for recording mass spectra and performing combustion analyses.

References

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