Synthesis of fluorine-containing 1,3-thiazine derivatives from primary polyfluoroalkanethioamides

Journal of Fluorine Chemistry 168 (2014) 105–110

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Synthesis of fluorine-containing 1,3-thiazine derivatives from primary polyfluoroalkanethioamides Sergiy S. Mykhaylychenko, Nadiia V. Pikun, Eduard B. Rusanov, Yuriy G. Shermolovich * Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5, Murmanska, 02094, Kiev, Ukraine

A R T I C L E I N F O

A B S T R A C T

Article history: Received 30 July 2014 Received in revised form 4 September 2014 Accepted 7 September 2014 Available online

New fluorine-containing 1,3-thiazine derivatives were obtained by the reactions of primary polyfluoroalkanethioamides with methyl vinyl ketone and ethyl acrylate in the presence of boron trifluoride etherate. The outcome of the reactions depends on the type of a,b-unsaturated carbonyl compound and the polyfluoroalkyl chain length. Hydrolysis of the obtained 1,3-thiazines leads to the formation of thioester derivatives. ß 2014 Elsevier B.V. All rights reserved.

Keywords: Fluorinated thioamide Methyl vinyl ketone Ethyl acrylate 1,3-thiazine Thioester

1. Introduction

2. Results and discussion

One of the most intensively developing directions in the chemistry of biologically active heterocycles is the synthesis of their fluorinated derivatives [1]. One of the most widely used methods of their preparation consists of the application of simple and reactive acyclic fluorinated compounds (building-blocks) [2]. Previously we have shown that amides of polyfluoroalkanethiocarboxylic acids can serve as such building-blocks. The use of these compounds allowed obtaining polyfluoroalkyl-substituted 1,2,4thiadiazoles, 1,3-thiazolidineones, imidazolines, pyrimidines, 1,3diazepines and thiopyranes [3]. In the present work we studied the possibility of using primary amides of polyfluoroalkanethiocarboxylic acids 1 for the synthesis of fluorine-containing 1,3-thiazine derivatives. It was reported previously that non-fluorinated thioamides react with a,bunsaturated aldehydes, ketones, esters and keto esters under neutral, basic (Et3N, NaHCO3) and acidic conditions (dry HCl, boron trifluoride etherate) to give the corresponding 1,3-thiazines bearing hydroxyl group at the 4 position [4–13]. Some of the prepared 1,3-thiazines are promising compounds in the search for new antitubercular [10] and skin-depigmenting [11] agents.

We found that polyfluoroalkanethioamides 1a,b bearing heptafluoropropyl and tetrafluoroethyl groups reacted with methyl vinyl ketone and boron trifluoride etherate in dichloromethane at room temperature. After the work-up with a saturated NaHCO3 aqueous solution, new 5,6-dihydro-4=-1,3thiazin-4-ols 2a,b were obtained (Scheme 1). In the case of the reaction of trifluorothioacetamide 1c with methyl vinyl ketone and boron trifluoride etherate, the corresponding heterocycle 2F was not isolated. Probably, compound 2F is not stable and instead of it, thioester 3c was obtained after the treatment of the reaction mixture with a saturated NaHCO3 aqueous solution (Scheme 1). 1,3-Thiazine derivatives 2a,b are more stable in aqueous alkaline medium that allows to isolate them, and are easily hydrolyzed under acidic conditions (HCl conc.) to give the corresponding thioesters 3a,b (Scheme 1). The structure of 5,6-dihydro-4=-1,3-thiazin-4-ol 2a was confirmed by single crystal X-ray diffraction (Fig. 1). In the asymmetric unit two independent molecules are arranged in chains along ob directions of O–H. . .O hydrogen bonds with the following parameters: O(1A)–H(1A) 0.68(3) A˚, O(1A). . .O(1B) 2.766(2) A˚, O(1A)– H(1A). . .O(1B) 176(3)8; O(1B)–H(1B) 0.66(3) A˚, O(1A). . .O(1B) 2.753(2) A˚, O(1B) –H(1B). . .O(1A) 168(3)8. Both molecules exhibit identical twist conformation for the central six-membered cycles. NMR (1H, 13C, 19F), IR and MS data are in good agreement with the structures of the compounds 2a,b and 3a–c. In the 13CNMR

* Corresponding author. Tel.: +38 044 2928312; fax: +38 044 5732643. E-mail addresses: [email protected], [email protected] (Y.G. Shermolovich). http://dx.doi.org/10.1016/j.jfluchem.2014.09.006 0022-1139/ß 2014 Elsevier B.V. All rights reserved.

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1. BF3·Et2O, CH2Cl2, r.t. 2. NaHCO3 aq. RF = C3F7, H(CF2)2 RF

O

S NH2

1a-c

S

RF

HCl aq.

N

RF

O S

Me OH

O Me

C3F7: 2a (45%) H(CF2)2: 2b (86%)

C3F7: 3a (64%) H(CF2)2: 3b (95%)

Me BF3·Et2O, CH2Cl2, r.t. RF = CF3

S

F3C N

Me OH

NaHCO3 aq.

F3C

O S

O Me

3c (71%)

2c Scheme 1. Reactions of polyfluoroalkanethioamides 1a–c with methyl vinyl ketone.

spectra of 3a–c, the signals in the ranges of 205.4–205.7 ppm and 185.1–189.9 ppm were attributed to the carbonyl groups of ketone and thioester functions, respectively. In contrast to methyl vinyl ketone, ethyl acrylate reacted with thioamides 1a–c in the presence of boron trifluoride etherate more slowly (15 days at room temperature). After the treatment of the reaction mixture with a saturated NaHCO3 aqueous solution, new fluorine-containing 1,3-thiazinan-4-ones 6a–c were isolated by column chromatography (Scheme 2). The formation of 1,3-thiazinan-4-ones probably proceeds via elimination–addition of ethanol involving intermediates 4, 5. Compounds 6a–c are relatively stable in aqueous alkaline medium and are easily hydrolyzed under acidic conditions. Treatment of 6a–c with HCl (conc.) at room temperature results in the formation of thioester derivatives 7a–c (Scheme 3). The possible reaction scheme includes elimination of ethanol from 6a to c catalyzed by HCl with its subsequent addition to 5 giving intermediate 4. Hydrolysis of the latter leads to acyclic imine 8 which is converted into 7a–c under acidic conditions. Compounds 7a–c are also formed upon heating 1,3-thiazinane-4-ones 6a–c

with boron trifluoride etherate in toluene followed by the treatment of the reaction mixture with water. The structure of 1,3-thiazinan-4-one 6c was confirmed by single crystal X-ray diffraction (Fig. 2). It was found that in the asymmetric unit, two independent molecules are arranged in the dimer by pair of N–H. . .O hydrogen bonds with the following parameters: N(1A)–H(1A) 0.74(3) A˚, N(1A). . .O(2B) 2.881(3) A˚, N(1A)–H(1A)–O(2B) 170(3)8; N(1B)–H(1B) 0.73(3) A˚, N(1B). . .O(2A) 2.888(3) A˚, N(1B)–H(1B)–O(2A) 172(3)8. The molecules exhibit different conformations for the central sixmembered cycles. In the molecule labeled by a letter A, sixmembered cycle has twist conformation; in the molecule B, the conformation looks like a half-boat. NMR (1H, 13C, 19F), IR and MS data of the compounds 7a–c and 6a–c are in good agreement with the proposed structures. In the 13 CNMR spectra of 7a–c, the signals in the ranges of 171.0– 171.1 ppm and 184.8–189.6 ppm were attributed to the carbonyl groups of ester and thioester functions, respectively. Noteworthy that only two examples of fluorine-containing 1,3thiazinane-4-ones are described in the literature (Fig. 3). These

Fig. 1. A perspective view and labeling scheme for the molecules of 2a. Selected bond lengths (A˚) and angles (8): S(1A)–C(1A) 1.754(2), N(1A)–C(1A) 1.265(3), S(1B)–C(1B) 1.752(2), N(1B)–C(1B) 1.265(3), N(1A)C(1A)S(1A) 131.3(2), N(1B)C(1B)S(1B) 130.9(2).

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Scheme 2. Reactions of polyfluoroalkanethioamides 1a–c with ethyl acrylate.

derivatives were prepared by the reaction of fluorinated imines with 3-mercaptopropionic acid and cysteine [14,15]. Among the obtained thioesters, the derivative 7c was described in [16], which was used for the synthesis of the corresponding trifluoromethyl sulfide. In conclusion, we have shown that the outcome of the reactions of primary polyfluoroalkanethioamides with methyl vinyl ketone and ethyl acrylate in the presence of boron trifluoride etherate depends on the type of a,b-unsaturated carbonyl compound and the polyfluoroalkyl chain length. The reactions involving polyfluoroalkanethioamides and methyl vinyl ketone afforded 5,6dihydro-4H-1,3-thiazin-4-ols except for trifluorothioacetamide, while the use of ethyl acrylate allowed obtaining 1,3-thiazinan-4ones. Hydrolysis of the obtained fluorine-containing heterocyclic compounds 2a,b and 6a–c gave thioester derivatives.

instrument at 100.62 MHz, and 19F NMR spectra – on a spectrometer Varian Gemini 200 instrument at 188.14 MHz. Tetramethysilane (1HNMR: d = 0.00 ppm), CHCl3 (13CNMR: d = 77.16 ppm), C6F6 (19F NMR: d = –162.9 ppm) were used as internal standards for 1H, 13C and 19F NMR spectra. Mass spectra were obtained on a Hewlett Packard HP GC/MS 5890/5972 instrument (EI, 70 eV). IR spectra were recorded on a Bruker Vertex 70 spectrometer in KBr pellets or in thin layer. The elemental analyses were carried out at the Analytical Laboratory of the Institute of Organic Chemistry, National Academy of Sciences of Ukraine. Melting points were measured on a Boe¨tius heating block. Silica gel Merck 60 (40–63 mm) was used for column chromatography. TLC was performed on Macherey–Nagel Polygram1 Sil G/UV254 plates and visualized by exposure to UV-light or iodine vapor. All solvents were dried and distilled by standard procedures prior to use.

3. Experimental 3.1. General

3.2. General procedure for the reaction of polyfluoroalkanethioamides (1a–c) with methyl vinyl ketone

1 HNMR spectra were recorded on a Varian VXR-300 instrument at 299.94 MHz, 13C{1H} NMR spectra – on a Bruker Avance 400

Methyl vinyl ketone (20.0 mmol) was added to a solution of the corresponding polyfluoroalkanethioamide (1a–c) (10.0 mmol) in

Scheme 3. Acid hydrolysis of 1,3-thiazinan-4-ones 6a–c.

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CFAFB), 127.2 (m, 2F, CF2). 13CNMR (CDCl3, d ppm): 23.5 (s, SCH2CH2), 26.6 (s, CH3), 29.0 (s, SCH2CH2), 82.3 (s, Cq), 108.7 (tqm, 1 JC,F = 288.5 Hz, 2JC,F = 34.9 Hz, CF3CF2CF2), 110.2 (tt, 1JC,F = 260.8 Hz, 2 JC,F = 29.5 Hz, CF3CF2CF2), 117.8 (qt, 1JC,F = 288.0 Hz, 2JC,F = 34.4 Hz, CF3), 157.7 (t, 2JC,F = 27.7 Hz, C5 5N). GC–MS, m/z: 299 [M]+. Anal. calcd for C8H8F7NOS: C, 32.11, H, 2.69; N, 4.68; S, 10.72. Found: C, 32.13; H, 2.73; N, 4.70; S, 10.73.

Fig. 2. A perspective view and labeling scheme for the molecules of 6c. Selected bond lengths (A˚) and angles (8): S(1A)–C(1A) 1.820(2), N(1A)–C(1A) 1.435(3), S(1B)–C(1B) 1.829(2), N(1B)–C(1B) 1.435(3), N(1B)C(1B)S(1B) 113.6(2), N(1A)C(1A)S(1A) 113.5(2).

dry dichloromethane (15 mL). To this solution BF3
Et2O (10.0 mmol) was added and the reaction mixture was stirred at room temperature for 4 days. In the case of the isolation of compounds (2a) and (3c), the reaction mixture was washed with a saturated aqueous solution of NaHCO3 (15 mL) and water (2  15 mL). The aqueous phase was additionally washed with dichloromethane (2  10 mL). Combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by fractional distillation to obtain (2a) and by chromatography on silica gel (eluent: mixture (8:2) of hexane-ethyl acetate) to obtain (3c). In the case of the isolation of compound (2b), the precipitate formed was filtered off, dissolved in ethyl acetate, and washed with a saturated aqueous NaHCO3 solution (15 mL), water (2  15 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: mixture (8:2) of hexane and ethyl acetate) giving 1,3-thiazin-4-ol (2b). 3.2.1. 2-(2,2,3,3,4,4,4-Heptafluoropropyl)-4-methyl-5,6-dihydro-4H1,3-thiazin-4-ol (2a) Yield: 45%. Colorless crystals. Rf = 0.38 (hexane/ethyl acetate 8:2); mp 47–48 8C (from hexane). 1HNMR (CDCl3, d ppm): 1.43 (s, 3H, CH3), 1.75 (m, 1H, CH), 2.05 (m, 1H, CH), 2.66 (bs, 1H, OH), 3.16 (m, 2H, CH2S). 19F NMR (CDCl3, d ppm): 81.4 (m, 3F, CF3), 114.3 (dm, 2JF,F = 275.2 Hz, 1F, CFAFB), 116.0 (dm, 2JF,F = 275.2 Hz, 1F,

Fig. 3. The known examples of fluorine-containing 1,3-thiazinane-4-ones. Captions to the schemes for the article

3.2.2. 2-(1,1,2,2-Tetrafluoroethyl)-4-methyl-5,6-dihydro-4H-1,3thiazin-4-ol (2b) Yield: 86%. Yellow liquid. Rf = 0.29 (hexane/ethyl acetate 8:2). IR (cm 1): 3393 (OH), 1616 (C5 5N). 1HNMR (CDCl3, d ppm): 1.41 (s, 3H, CH3), 1.68 (m, 1H, CH), 2.03 (m, 1H, CH), 3.05–3.25 (m, 2H, CH2S), 6.18 (tt, 2JH,F = 53.1 Hz, 3JH,F = 5.4 Hz, 1H, HCF2CF2). 19F NMR (CDCl3, d ppm): 119.6 (dm, 2JF,F = 279.8 Hz, 1F, CFAFB), 121.8 (dm, 2JF,F = 279.8 Hz, 1F, CFAFB), 139.5 (ddm, 2JF,F = 245.5 Hz, 2 JF,H = 53.1 Hz, 1F, CFACFBH), 141.3 (ddm, 2JF,F = 245.5 Hz, 2 13 JF,H = 53.1 Hz, 1F, CFACFBH). CNMR (CDCl3, d ppm): 23.1 (s, SCH2CH2), 26.9 (s, CH3), 29.3 (s, SCH2CH2), 81.9 (s, Cq), 109.6 (tt, 1 JC,F = 250.6 Hz, 2JC,F = 32.7 Hz, HCF2), 110.8 (tt, 1JC,F = 255.0 Hz, 2 JC,F = 26.7 Hz, CF2), 154.9 (t, 2JC,F = 29.2 Hz, C5 5N). GC–MS, m/z: 231 [M]+. Anal. calcd for C7H9F4NOS: C, 36.36, H, 3.92; N, 6.06; S, 13.87. Found: C, 36.40; H, 3.85; N, 6.02; S, 13.80. 3.2.3. S-3-Oxobutyl 2,2,2-trifluoroethanethioate (3c) Yield: 71%. Yellow liquid. bp 39–40 8C (0.08 mmHg). 1HNMR (CDCl3, d ppm): 2.18 (s, 3H, CH3), 2.86 (t, 3JH,H = 6.6 Hz, 2H, SCH2CH2), 3.23 (t, 3JH,H = 6.6 Hz, 2H, SCH2CH2). 19F NMR (CDCl3, d ppm): 74.4 (s, 3F, CF3). 13CNMR (CDCl3, d ppm): 22.9 (s, SCH2CH2), 29.8 (s, CH3), 42.1 (s, SCH2CH2), 115.6 (q, 1JC,F = 290.5 Hz, CF3), 185.1 (q, 2JC,F = 40.1 Hz, COS), 205.7 (s, COMe). GC–MS, m/z: 200 [M]+. Anal. calcd for C6H7F3O2S: C, 36.00, H, 3.52; S, 16.02. Found: C, 35.92; H, 3.68; S, 16.12. 3.3. Hydrolysis of 1,3-thiazin-4-ols (2a,b) Concentrated hydrochloric acid (36%) (0.8 mmol) was added to a solution of the corresponding 1,3-thiazin-4-ol (2a,b) (0.4 mmol) in acetone (10 mL). The reaction mixture was stirred at room temperature for 3 days. The precipitate formed was filtered off. The solvent was evaporated in vacuo. The residue was dissolved in dichloromethane and washed with water (2  15 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: mixture (8:2) of hexane and ethyl acetate) to give the corresponding thioester (3a,b). 3.3.1. S-3-Oxobutyl 2,2,3,3,4,4,4-heptafluorobutanethioate (3a) Yield: 64%. Yellow liquid. Rf = 0.69 (hexane/ethyl acetate 8:2). 1 HNMR (CDCl3, d ppm): 2.19 (s, 3H, CH3), 2.85 (t, 3JH,H = 6.6 Hz, 2H, SCH2CH2), 3.25 (t, 3JH,H = 6.6 Hz, 2H, SCH2CH2). 19F NMR (CDCl3, d ppm): 81.7 (m, 3F, CF3), 118.7 (m, 2F, CF2), 127.8 (m, 2F, CF2). 13 CNMR (CDCl3, d ppm): 23.2 (s, SCH2CH2), 29.6 (s, CH3), 42.0 (s, SCH2CH2), 105.4–122.1 (m, CF3CF2CF2), 186.8 (t, 2JC,F = 30.2 Hz, COS), 205.4 (s, COMe). GC–MS, m/z (rel. int.): 300 [M]+. Anal. calcd for C8H7F7O2S: C, 32.01, H, 2.35; S, 10.68. Found: C, 32.15; H, 2.37; S, 10.72. 3.3.2. S-3-Oxobutyl 2,2,3,3-tetrafluoropropanethioate (3b) Yield: 95%. Yellow liquid. Rf = 0.58 (hexane/ethyl acetate 8:2). IR (cm 1): 1710, 1682 (CO, COS). 1HNMR (CDCl3, d ppm): 2.19 (s, 3H, CH3), 2.84 (t, 3JH,H = 6.5 Hz, 2H, SCH2CH2), 3.22 (t, 3JH,H = 6.5 Hz, 2H, SCH2CH2), 6.04 (tt, 2JH,F = 52.8 Hz, 3JH,F = 5.1 Hz, 1H, HCF2). 19F NMR (CDCl3, d ppm): 123.3 (m, 2F, CF2), 138.9 (dt, 2 JF,H = 52.8 Hz, 3JF,F = 9.2 Hz, 2F, HCF2). 13CNMR (CDCl3, d ppm): 22.7 (s, SCH2CH2), 29.8 (s, CH3), 42.3 (s, SCH2CH2), 108.9 (tt,

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JC,F = 252.2 Hz, 2JC,F = 33.5 Hz, HCF2), 109.4 (tt, 1JC,F = 264.0 Hz, JC,F = 28.6 Hz, CF2), 189.9 (t, 2JC,F = 30.5 Hz, COS), 205.5 (s, COMe). GC–MS, m/z: 232 [M]+. Anal. calcd for C7H8F4O2S: C, 36.21, H, 3.47; S, 13.81. Found: C, 36.15; H, 3.52; S, 13.86.

calcd for C7H10F3NO2S: C, 36.68, H, 4.40; N, 6.11; S, 13.99. Found: C, 36.75; H, 4.49; N, 6.04; S, 13.83.

3.4. General procedure for the reaction of polyfluoroalkanethioamides (1a–c) with ethyl acrylate

Concentrated hydrochloric acid (36%) (0.8 mmol) was added to a solution of the corresponding 1,3-thiazinan-4-one (6a–c) (0.4 mmol) in acetone (10 mL). The reaction mixture was stirred at room temperature for 4 days. The precipitate formed was filtered off. The solvent was evaporated in vacuo. The residue was dissolved in dichloromethane and washed with water (2  15 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a mixture (8:2) of hexane and ethyl acetate to give the corresponding product (7a–c).

2

Ethyl acrylate (30.0 mmol) was added to a solution of the corresponding polyfluoroalkanethioamide (1a–c) (10.0 mmol) in toluene (15 mL). To this solution BF3
Et2O (10.0 mmol) was added. The reaction mixture was stirred at room temperature for 15 days and then it was washed with saturated aqueous NaHCO3 solution (15 mL) and water (2  15 mL). Aqueous phase was additionally washed with dichloromethane (2  10 mL). Combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel affording 1,3-thiazinan-4-one (6a–c). 3.4.1. 2-Ethoxy-2-(2,2,3,3,4,4,4-heptafluoropropyl)-1,3-thiazinan-4one (6a) It was purified by chromatography on silica gel, eluting with a mixture (1:1) of petroleum ether and ethyl acetate. Yield: 25%. Yellow oil. Rf = 0.74 (petroleum ether/ethyl acetate 1:1). IR (cm 1): 3195 (d, NH), 1679 (C5 5O). 1HNMR (C6D6, d ppm): 0.91 (t, 3 JH,H = 7.0 Hz, 3H, OCHACHBCH3), 1.79 (m, 1H, CH), 2.09 (m, 3H, 3  CH), 3.18 (m, 1H, OCHACHBCH3), 3.52 (m, 1H, OCHACHBCH3), 6.84 (bs, 1H, NH). 19F NMR (CDCl3, d ppm): 81.0 (s, 3F, CF3), 115.4 (dm, 2JF,F = 272.9 Hz, 1F, CFAFB), 118.9 (dm, 2JF,F = 272.9 Hz, 1F, CFAFB), 122.1 (m, 2F, CF2). 13CNMR (CDCl3, d ppm): 14.4 (s, OCH2CH3), 23.3 (s, SCH2CH2), 33.2 (s, SCH2CH2), 59.7 (s, OCH2CH3), 95.7 (t, 2JC,F = 27.6 Hz, Cq), 110.5–121.7 (m, CF3CF2CF2), 173.3 (s, C5 5O). GC–MS, m/z: 329 [M]+. Anal. calcd for C9H10F7NO2S: C, 32.83, H, 3.06; N, 4.25; S, 9.74. Found: C, 32.75; H, 3.15; N, 4.13; S, 9.68. 3.4.2. 2-Ethoxy-2-(1,1,2,2-tetrafluoroethyl)-1,3-thiazinan-4-one (6b) It was purified by chromatography on silica gel, eluting with a mixture (6:4) of petroleum ether and ethyl acetate. Yield: 29%. Yellow oil. Rf = 0.42 (petroleum ether/ethyl acetate 6:4). IR (cm 1): 3193 (d, NH), 1677 (C5 5O). 1HNMR (C6D6, d ppm): 0.89 (t, 3 JH,H = 7.2 Hz, 3H, OCHACHBCH3), 1.83 (m, 1H, CH), 2.05–2.20 (m, 3H, 3  CH), 3.23 (m, 1H, OCHACHBCH3), 3.52 (m, 1H, OCHACHBCH3), 5.82 (tt, 2JH,F = 53.1 Hz, 3JH,F = 4.8 Hz, 1H, HCF2CF2), 7.24 (bs, 1H, NH). 19F NMR (CDCl3, d ppm): 124.4 (dm, 2 JF,F = 268.9 Hz, 1F, CFACFB), 129.9 (dm, 2JF,F = 268.9 Hz, 1F, CFACFB), 135.7 (m, 2F, HCF2). 13CNMR (CDCl3, d ppm): 14.6 (s, OCH2CH3), 23.2 (s, SCH2CH2), 33.4 (s, SCH2CH2), 59.4 (s, OCH2CH3), 94.6 (dd, 2JC,FA = 26.5 Hz, 2JC,FB = 26.5 Hz, Cq), 109.6 (tt, 1 JC,F = 251.7 Hz, 2JC,F = 31.8 Hz, HCF2), 114.2 (tt, 1JC,F = 259.7 Hz, 2 JC,F = 26.9 Hz, CF2), 173.2 (s, C5 5O). GC–MS, m/z: 261 [M]+. Anal. calcd for C8H11F4NO2S: C, 36.78, H, 4.24; N, 5.36; S, 12.27. Found: C, 36.70; H, 4.31; N, 5.32; S, 12.20. 3.4.3. 2-Ethoxy-2-(trifluoromethyl)-1,3-thiazinan-4-one (6c) It was purified by chromatography on silica gel, eluting with a mixture (8:2) of petroleum ether and ethyl acetate. Yield: 50%. Colorless crystals. mp 114–115 8C (from hexane). Rf = 0.29 (petroleum ether/ethyl acetate 8:2). IR (KBr, cm 1): 3146 (d, NH), 1695 (C5 5O). 1HNMR (CDCl3, d ppm): 1.26 (t, 3JH,H = 7.0 Hz, 3H, OCHACHBCH3), 2.76 (m, 2H, CH2), 2.87 (m, 1H, CH), 3.10 (m, 1H, CH), 3.67 (m, 1H, OCHACHBCH3), 3.89 (m, 1H, OCHACHBCH3), 7.08 (bs, 1H, NH). 19F NMR (CDCl3, d ppm): 85.0 (s, 3F, CF3). 13CNMR (CDCl3, d ppm): 14.8 (s, OCH2CH3), 23.8 (s, SCH2CH2), 33.5 (s, SCH2CH2), 59.9 (s, OCH2CH3), 92.6 (q, 2JC,F = 33.8 Hz, Cq), 122.7 (q, 1 JC,F = 286.0 Hz, CF3), 172.1 (s, C5 5O). GC–MS, m/z: 229 [M]+. Anal.

3.5. Hydrolysis of 1,3-thiazinan-4-ones (6a–c)

3.5.1. Ethyl 3-(2,2,3,3,4,4,4-heptafluorobutanoylthio)propanoate (7a) Yield: 75%. Yellow liquid. Rf = 0.69 (hexane/ethyl acetate 8:2). 1 HNMR (CDCl3, d ppm): 1.28 (t, 3JH,H = 7.2 Hz, 3H, OCH2CH3), 2.70 (t, 3 JH,H = 6.6 Hz, 2H, SCH2CH2), 3.32 (t, 3JH,H = 6.6 Hz, 2H, SCH2CH2), 4.18 (q, 3JH,H = 7.2 Hz, 2H, OCH2CH3). 19F NMR (CDCl3, d ppm): 81.7 (m, 3F, CF3), 118.7 (m, 2F, CF2), 127.7 (m, 2F, CF2). 13CNMR (CDCl3, d ppm): 14.1 (s, OCH2CH3), 24.6 (s, SCH2CH2), 33.4 (s, SCH2CH2), 61.3 (s, OCH2CH3), 108.1–119.2 (m, CF3CF2CF2), 171.0 (s, COOEt), 186.6 (t, 2 JC,F = 30.2 Hz, COS). GC–MS, m/z: 330 [M]+. Anal. calcd for C9H9F7O3S: C, 32.73, H, 2.75; S, 9.71. Found: C, 32.70; H, 2.70; S, 9.82. 3.5.2. Ethyl 3-(2,2,3,3-tetrafluoropropanoylthio)propanoate (7b) Yield: 63%. Yellow liquid. Rf = 0.67 (hexane/ethyl acetate 8:2). IR (cm 1): 1732, 1685 (CO, COS). 1HNMR (CDCl3, d ppm): 1.28 (t, 3 JH,H = 7.2 Hz, 3H, OCH2CH3), 2.69 (t, 3JH,H = 6.9 Hz, 2H, SCH2CH2), 3.29 (t, 3JH,H = 6.9 Hz, 2H, SCH2CH2), 4.16 (q, 3JH,H = 7.2 Hz, 2H, OCH2CH3), 6.04 (tt, 2JH,F = 52.8 Hz, 3JH,F = 5.1 Hz, 1H, HCF2CF2). 19F NMR (CDCl3, d ppm): 123.4 (m, 2F, CF2), 138.9 (dm, 2 JF,H = 52.8 Hz, 2F, HCF2). 13CNMR (CDCl3, d ppm): 14.2 (s, OCH2CH3), 24.1 (s, SCH2CH2), 33.5 (s, SCH2CH2), 61.3 (s, OCH2CH3), 108.8 (tt, 1JC,F = 252.2 Hz, 2JC,F = 33.3 Hz, HCF2), 109.4 (tt, 1 JC,F = 263.6 Hz, 2JC,F = 28.7 Hz, CF2), 171.1 (s, COOEt), 189.6 (t, 2 JC,F = 31.0 Hz, COS). GC–MS, m/z: 262 [M]+. Anal. calcd for C8H10F4O3S: C, 36.64, H, 3.84; S, 12.23. Found: C, 36.71; H, 3.96; S, 12.31. 3.5.3. Ethyl 3-(2,2,2-trifluoroacetylthio)propanoate (7c) Yield: 82%. Yellow liquid. bp 35–36 8C (0.08 mmHg). Rf = 0.71 (hexane/ethyl acetate 8:2). IR (cm 1): 1733, 1704 (CO, COS). 1 HNMR (CDCl3, d ppm): 1.28 (t, 3JH,H = 7.2 Hz, 3H, OCH2CH3), 2.71 (t, 3JH,H = 6.8 Hz, 2H, SCH2CH2), 3.30 (t, 3JH,H = 6.8 Hz, 2H, SCH2CH2), 4.19 (q, 3JH,H = 7.2 Hz, 2H, OCH2CH3). 19F NMR (CDCl3, d ppm): 76.6 (s, 3F, CF3). 13CNMR (CDCl3, d ppm): 14.1 (s, OCH2CH3), 24.3 (s, SCH2CH2), 33.4 (s, SCH2CH2), 61.3 (s, OCH2CH3), 115.6 (q, 1 JC,F = 290.8 Hz, CF3), 171.0 (s, COOEt), 184.8 (q, 2JC,F = 40.1 Hz, COS). GC–MS, m/z: 230 [M]+. Anal. calcd for C7H9F3O3S: C, 36.52, H, 3.94; S, 13.93. Found: C, 36.61; H, 4.02; S, 13.81. 3.6. X-ray structure determination for (2a) 3.6.1. Crystal data C8H8F7NOS, M 299.21, monoclinic, space group P21/c, a = 13.3915(3), b = 6.4818(2), c = 26.1699(6) A˚, b = 97.234(1)8, V = 2253.49(10)A˚3, Z = 8, dc = 1.764 g cm 3, m = 0.37 mm 1, F(000) = 1200, crystal size ca. 0.10  0.24  0.44 mm3. 3.6.2. Data collection All crystallographic measurements were performed at room temperature on a Bruker Smart Apex II diffractometer operating in

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the v and w scans mode. The intensity data were collected within the range of 1.53  u  30.568 using Mo-Ka radiation (l = 0.71078 A˚). The intensities of 21,953 reflections were collected (4889 unique reflections, Rmerg = 0.0369). 3.6.3. Structure solution and refinement The structure was solved by direct methods and refined by the fullmatrix least-squares technique in the anisotropic approximation for non-hydrogen atoms using the Bruker SHELXTL program package [17]. All hydrogen atoms were refined isotropically. In the refinement, 4889 reflections were used. Convergence was obtained at R1 = 0.0547 and wR2 = 0.1064 for all reflection and R1 = 0.0413 and wR2 = 0.1011, GOF = 1.064 for observed (3904 reflections with I  2s(I), 389 parameters; observed/variable ratio 10.0; the largest and minimal peaks in the final difference map 1.29 and –0.29 e/A˚3, weighting scheme is as follows: v = 1/[s2(Fo2) + (0.0506P)2 + 1.37P], where C = (Fo2 + 2Fc2)/3). Full crystallographic details have been deposited at Cambridge Crystallographic Data Centre (CCDC). Any request to the CCDC for these materials should quote the full literature citation and reference number CCDC 1016919. 3.7. X-ray structure determination for (6c) 3.7.1. Crystal data C7H10F3NO2S, M 229.22, triclinic, space group P-1, a = 7.0009(2), b = 12.5322(4), c = 12.6099(4) A˚, a = 66.170(2), b = 87.033(2), g = 79.029(2)8, V = 993.15(5)A˚3, Z = 4, dc = 1.533 g cm 3, m = 0.346 mm 1, F(000) = 472, crystal size ca. 0.07  0.30  0.42 mm3. 3.7.2. Data collection All crystallographic measurements were performed at room temperature on a Bruker Smart Apex II diffractometer operating in the v and w scans mode. The intensity data were collected within the range of 1.77  u  28.548 using Mo-Ka radiation (l = 0.71078 A˚). The intensities of 15833 reflections were collected (4957 unique reflections, Rmerg = 0.0345). 3.7.3. Structure solution and refinement The structure was solved by direct methods and refined by the full-matrix least-squares technique in the anisotropic approximation for non-hydrogen atoms using the Bruker SHELXTL program package [17]. All CH hydrogene atoms were placed at calculated positions and refined as ‘riding’ atoms, NH hydrogene vich is involved in H-bonding were found in Fourier synthesis and refined isotropically. In the refinement 4957 reflections were used.

Convergence was obtained at R1 = 0.0935 and wR2 = 0.1496, for all reflection and R1 = 0.0517 and wR2 = 0.1274, GOF = 1.024 for observed (2986 reflections with I  2s(I), 261 parameters; observed/variable ratio 11.4; the largest and minimal peaks in the final difference map 0.41 and –0.34 e/A˚3, weighting scheme is as follows: v = 1/[s2(Fo2) + (0.061P)2 + 0.4109P], where C = (Fo2 + 2Fc2)/3). Full crystallographic details have been deposited at Cambridge Crystallographic Data Centre (CCDC). Any request to the CCDC for these materials should quote the full literature citation and reference number CCDC 1016920. Acknowledgments We thank Dr. V. V. Trachevsky, Joint Usage Centre of Radiospectroscopy (Kiev), NAS of Ukraine, for recording the 13CNMR spectra. References [1] (a) J.T. Welch, S. Eswarakrishnan (Eds.), Fluorine in Bioorganic Chemistry, John Wiley & Sons, New York, 1991; (b) T. Hiyama, Organofluorine Compounds: Chemistry and Applications, Springer, Berlin, 2000; (c) A.A.Yu. Gakh, G. Shermolovich, Curr. Top. Med. Chem. 14 (2014) 952–965. [2] F.A. Davis, P.N. Kasu, Org. Prep. Proc. Int. 31 (1999) 125–157. [3] (a) V.M. Timoshenko, A.V. Rudnichenko, A.V.Yu. Tkachenko, G. Shermolovich, Russ. J. Org. Chem. 41 (2005) 268–271; (b) A.V. Rudnichenko, V.M.Yu. Timoshenko, G. Shermolovich, J. Fluor. Chem. 125 (2004) 439–444; (c) A.V.Yu. Rudnichenko, G. Shermolovich, Synth. Commun. 37 (2007) 459–465; (d) S.S. Mykhaylychenko, N.V.Yu. Pikun, G. Shermolovich, J. Fluor. Chem. 140 (2012) 76–81. [4] G.C. Barett, S.H. Eggers, T.R. Emmerson, G. Lowe, J. Chem. Soc.. (1964) 788–792. [5] V.G. Nenaidenko, A.V. Sanin, M.V. Lebedev, E.S. Balenkova, Zh. Org. Khim. 31 (1995) 783–785. [6] M. Bakasse, M. Rambaud, J. Bourrigaud, J. Villieras, G. Dugway, Synth. Commun. 18 (1988) 1043–1059. [7] A. Boussouffi, J.-L. Parrain, P. Hudhomme, G. Duguay, Tetrahedron 50 (1994) 12609–12624. [8] S. Hoff, A.P. Blok, Recl. Trav. Chim. Pays-Bas 92 (1973) 631–640. [9] X. Huang, L. Yu, Z.-H. Chen, Synth. Commun. 35 (2005) 1253–1261. [10] M. Koketsu, K. Tanaka, Y. Takenaka, C.D. Kwong, H. Ishihara, Eur. J. Pharm. Sci. 15 (2002) 307–310. [11] S.K. Ha, M. Koketsu, M. Lee, E. Moon, S.-H. Kim, T.-J. Yoon, S.Y. Kim, J. Pharm. Pharmacol. 61 (2009) 1653–1657. [12] D.M. Green, A.G. Long, P.J. May, A.F. Turner, J. Chem. Soc. (1964) 766–783. [13] M.W. Notzel, T. Labahn, M. Es-Sayed, A. De Meijere, Eur. J. Org. Chem. 16 (2001) 3025–3030. [14] M.S. Raasch, J. Heterocycl. Chem. 11 (1974) 587–593. [15] Yu.V. Rassukana, Synthesis (2011) 3426–3428. [16] (a) T. Billard, N. Roques, B.R. Langlois, J. Org. Chem. 64 (1999) 3813–3820; (b) B.R. Langlois, T. Billard, J.-C. Mulatier, C. Yezeguelian, J. Fluor. Chem. 128 (2007) 851–856. [17] G.M. Sheldrick, Acta Crystallogr. A 64 (2008) 112–122.