Primary polyfluoroalkanethioamides as mild thioacylating reagents for alkyl amines and α-amino acid esters

Accepted Manuscript Title: Primary polyfluoroalkanethioamides as mild thioacylating reagents for alkyl amines and ␣-amino acid esters Author: Nadiia V. Pikun Sergiy S. Mykhaylychenko Irine B. Kulik Yuriy G. Shermolovich PII: DOI: Reference:

S0022-1139(16)30057-4 http://dx.doi.org/doi:10.1016/j.jfluchem.2016.03.005 FLUOR 8745

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FLUOR

Received date: Revised date: Accepted date:

16-2-2016 11-3-2016 15-3-2016

Please cite this article as: Nadiia V.Pikun, Sergiy S.Mykhaylychenko, Irine B.Kulik, Yuriy G.Shermolovich, Primary polyfluoroalkanethioamides as mild thioacylating reagents for alkyl amines and rmalpha-amino acid esters, Journal of Fluorine Chemistry http://dx.doi.org/10.1016/j.jfluchem.2016.03.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Primary polyfluoroalkanethioamides as mild thioacylating reagents for alkyl amines and α-amino acid esters

Nadiia V. Pikuna, Sergiy S. Mykhaylychenkoa, Irine B. Kulikb and Yuriy G. Shermolovicha*

a

Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5, Murmanska, 02094, Kiev, Ukraine. b Institute of Bioorganic Chemistry & Petrochemistry, National Academy of Sciences of Ukraine, 1, Murmanska, 02660, Kiev, Ukraine. * Corresponding author. Tel.: +38 044 2928312; fax: +38 044 5732643. E-mail address: [email protected] (Yuriy G. Shermolovich)

Graphical abstract Transamidation reaction of primary polyfluoroalkanethioamides with alkyl amines and αamino acid esters was studied.

O R1 S RF HN R

R NH 2

S RF NH 2

OR 2

R1

S

NH 2 RF

N H

OR 2 O

R F = CF 3 , HCF2 CF 2

Highlights

1



Transamidation reactions of primary polyfluoroalkanethioamides with alkyl

amines and α-amino acid esters were studied  

Synthesis of new 3,3,4,4-tetrafluoropyrrolidine-2,5-dithione was performed The synthesis method of new fluorinated N-thioacyl derivatives of α-

amino acids esters was proposed.

Abstract – New fluorinated N-alkylthioamides were obtained by the transamidation reactions of primary amides of polyfluoroalkanethiocarboxylic acids with alkyl amines. Thionation of 2,2,3,3-tetrafluorosuccinamide with P4S10 in the presence of hexamethyldisiloxane gave 3,3,4,4tetrafluoropyrrolidine-2,5-dithione. The latter compound and primary polyfluoroalkanethioamides were shown to react with α-amino acid esters under mild conditions affording their new polyfluoroalkanethioyl derivatives. Keywords: fluorinated thioamide; transamidation; thioacylation agent; amino acid; thiopeptide

1. Introduction Thioamides have found a wide variety of synthetic applications over the past decades [1]. The investigations of polyfluoroalkanethioamides performed during the recent years revealed a significant synthetic potential of these compounds due to the diversity of their transformations involving polyfluoroalkyl and thiocarbonyl groups [2]. The products of these transformations exhibit a broad spectrum of biological activity [3–7]. In the literature, there are a number of publications on the methods of synthesis of polyfluoroalkanethioamides bearing different substituents at the nitrogen atom and polyfluoroalkyl substituents of different lengths. The most used methods employed for the preparation of fluorinated thioamides are based on the thionation of the corresponding amides by P4S10 as well as on using polyfluoro aliphatic nitriles and esters, thioesters or halides of polyfluoroalkanethiocarboxylic acids [8–10]. These methods involve the use of toxic and gaseous compounds or 2

low available reagents and high temperatures. In the present work, we investigated the possibility of application of available primary polyfluoroalkanethioamides 1 as mild thioacylating reagents for the synthesis of N-substituted polyfluorinated thioamides and chemical modification of amino acid esters. 2. Results and discussion Previously

we

have

shown

polyfluoroalkanethiocarboxylic acids 1a,b

that

primary

amides

of

reacted with 1,2-, 1,3-, and 1,4-

diaminoalkanes giving the corresponding heterocyclic compounds (Scheme 1). The reactions were accompanied by the elimination of hydrogen sulfide and ammonia [11, 12].

We have found that in contrast to diaminoalkanes, primary aliphatic amines reacted selectively with thioamides 1a,b at room temperature without the elimination of hydrogen sulfide leading to the formation of transamidation products – N-substituted thioamides 2a-c (Scheme 2).

Less nucleophilic p-toluidine did not react with thioamides 1a,b under the same conditions or upon heating at 100°C. Reaction of thioamides 1a,b with morpholine did not proceed selectively and gave a mixture of compounds according to the 19F NMR data of the reaction mixtures. The obtained results allowed us to conclude that the reactions of polyfluoroalkanethioamides with alkyl amines can serve as a method of synthesis of various fluorine-containing N-alkyl thioamides. It should be noted that the described reactions proceed under milder conditions as compared to the similar reactions of non-fluorinated thioamides with 3

alkyl amines which require heating at elevated temperatures (70−110°C) [13−16]. This may cause the elimination of hydrogen sulfide from primary thioamide, which is a commonly occurring side product in such type of reactions, or the formation of amidine via an alternative reaction pathway. To

extend

the

scope

of

transamidation

reaction

of

polyfluoroalkanethioamides 1a,b, we examined the possibility of using these compounds as thioacylating agents for α-amino acid esters. It was found that thioamides 1a,b smoothly reacted with esters of α-amino acids (L-alanine, Lphenylalanine,

D-tryptophane)

at

room

temperature

affording

polyfluoroalkanethioyl derivatives 3a-f, which were isolated in 51–84% yields after column chromatography (Scheme 3). Compounds 3a-f were obtained in the optically active form; it is suggested that no racemization occurred during the reaction.

From the obtained results (Schemes 2 and 3), it can be concluded that the use of primary polyfluoroalkanethioamides as N-thioacylating agents is advantageous since they are more readily available compounds as compared to other derivatives of polyfluoroalkanethiocarboxylic acids – thioesters, dithioesters, and thioacyl halides. Their preparation requires several steps that results in a decrease of the overall yields. In addition, the reactions between the fluorinated thioacyl chlorides and amines do not proceed in a selective manner giving complex mixtures (unpublished results from our laboratory). Compounds 3c,d were treated with an aqueous solution of NaOH to give the optically active water-soluble sodium salts 4a,b which can be used to evaluate the biological activity (Scheme 4).

It should be noted that the described transformations (Scheme 3) may give access to thiopeptides which have attracted interest as synthetic targets. It is known 4

that the replacement of the peptide bond by a thiopeptide bond or the introduction of fluorine atoms to the α-carbon atom may lead to a significant change in biological activity of the peptide compounds [17, 18]. In particular, fluorinated substituents (CF, CF2, HCF2) have been used as an isosteric analog of the amide functionality [19, 20]. In order to prepare the polyfluoro-substituted thiopeptide analogs containing a thioamide linkage in the middle of the chain, thioamides of polyfluorinated dicarboxylic acids can be used. For this purpose, we performed thionation of 2,2,3,3-tetrafluorosuccinamide 5 [21] with P4S10 in the presence of hexamethyldisiloxane (HMDSO) which resulted in the formation of

3,3,4,4-

tetrafluoropyrrolidine-2,5-dithione 6 (Scheme 5).

The reaction of 3,3,4,4-tetrafluoropyrrolidine-2,5-dithione 6 with an excess (2.6 equiv.) of methyl L-phenylalaninate afforded compound 7 representing a dipeptide analog containing the thiocarbonyl groups and fluorine atoms in the middle of the chain (Scheme 6).

In

conclusion,

we

have

shown

that

primary

amides

of

polyfluoroalkanethiocarboxylic acids can be mild thioacylating reagents for alkyl amines and α-amino acid esters. The described thioacylation reactions open up possibilities for the synthesis of fluorinated thiopeptide analogs. 3. Experimental 3.1. General

5

1

H and 19F NMR spectra were recorded on a Varian VXR-300 instrument at

299.94 MHz and 282.20 MHz, respectively. 13C NMR spectra were recorded on a Bruker Avance 400 instrument at 100.62 MHz. Tetramethysilane (1H NMR: δ = 0.00 ppm), CHCl3 (13C NMR: δ = 77.16 ppm), C6F6 (19F NMR: δ = –162.9 ppm) were used as internal standards for 1H,

13

C, and

19

F NMR spectra. LC–MS data

were obtained using an ADSI MS, Agilent 1100\DAD\MSD VL G1965 instrument (ESI, 70 eV). GC–MS data were obtained using a Hewlett Packard HP GC/MS 5890/5972 instrument (EI, 70 eV). Optical rotation was measured on an automatic Anton Paar MCP 300 polarimeter. 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 Boёtius heating block. Silica gel Merck 60 (70–230 μm) was used for column chromatography. TLC was performed on Macherey–Nagel Poly-gram® 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. 3.2. General procedure for the reaction of primary polyfluoroalkanethioamides (1a,b) with primary amines. Amine (2.0 mmol) was added to a solution of polyfluoroalkanethioamide (1a,b) (1.0 mmol) in chloroform (15 mL). The reaction mixture was stirred at room temperature for 4 days. Then the solvent was evaporated in vacuo and the crude product was purified by column chromatography on silica gel to give the corresponding thioamide (2a−c). 3.2.1. N-Propyl-2,2,2-trifluoroethanethioamide (2a) It was purified by chromatography on silica gel, eluting with a mixture (8:2) of hexane and ethyl acetate. Yield: 72%. Yellow liquid. Rf = 0.65 (hexane/ethyl acetate 8:2). 1H NMR (CDCl3, δ ppm): 1.02 (t, 3JH,H = 7.2 Hz, 3H, CH3), 1.75 (m, 2H, CH2), 3.65 (m, 2H, NCH2), 8.13 (bs, 1H, NH). 19F NMR (CDCl3, δ ppm): 6

−70.6 (s, CF3). 13C NMR (CDCl3, δ ppm): 11.3 (s, CH3), 20.8 (s, CH2), 47.4 (s, NCH2), 117.4 (q, 1JC,F = 280.1 Hz, CF3), 183.2 (q, 2JC,F = 35.5 Hz, C=S). GC–MS, m/z: 171 [M]+. Anal. Calcd for C5H8F3NS: C, 35.08; H, 4.71; N, 8.18; S, 18.73. Found: C, 35.12; H, 4.75; N, 8.23; S, 18.72. 3.2.2. N-Propyl-2,2,3,3-tetrafluoropropanethioamide (2b) It was purified by chromatography on silica gel, eluting with a mixture (8:2) of hexane and ethyl acetate. Yield: 70%. Yellow oil. Rf = 0.67 (hexane/ethyl acetate 8:2). 1H NMR (CDCl3, δ ppm): 0.98 (t, 3JH,H = 7.2 Hz, 3H, CH3), 1.75 (m, 2H, CH2), 3.65 (m, 2H, NCH2), 6.48 (tt, 2JH,F = 53.4 Hz, 3JH,F = 5.7 Hz, 1H, HCF2), 8.14 (bs, 1H, NH). 19F NMR (CDCl3, δ ppm): −120.9 (m, 2F, CF2), −140.4 (dm, 2JF,H = 53.4 Hz, 2F, HCF2). GC–MS, m/z: 203 [M]+. Anal. Calcd for C6H9F4NS: C, 35.46; H, 4.46; N, 6.89; S, 15.78. Found: C, 35.48; H, 4.52; N, 6.73; S, 15.80. 3.2.3. N-Benzyl-2,2,3,3-tetrafluoropropanethioamide (2c) It was purified by chromatography on silica gel, eluting with hexane. Yield: 65%. Yellow oil. Rf = 0.36 (hexane). 1H NMR (CDCl3, δ ppm): 4.72 (d, 3JH,H = 5.2 Hz, 2H, CH2), 6.38 (tt, 2JH,F = 53.0 Hz, 3JH,F = 5.6 Hz, 1H, HCF2), 7.17−7.33 (m, 5H, Ph), 8.22 (bs, 1H, NH).

19

F NMR (CDCl3, δ ppm): −120.9 (m, 2F, CF2),

−140.2 (dm, 2JF,H = 53.0 Hz, 2F, HCF2). 13C NMR (CDCl3, δ ppm): 49.6 (s, CH2), 109.6 (tt, 1JC,F = 252.6 Hz, 2JC,F = 32.2 Hz, HCF2), 111.2 (tt, 1JC,F = 260.6 Hz, 2JC,F = 28.2 Hz, CF2), 128.2 (s, 2 × CH Ph), 128.6 (s, CH Ph), 129.1 (s, 2 × CH Ph), 134.4 (s, Cq Ph), 185.7 (t, 2JC,F = 23.1 Hz, C=S). GC–MS, m/z: 251 [M]+. Anal. Calcd for C10H9F4NS: C, 47.80; H, 3.61; N, 5.57; S, 12.76. Found: C, 47.82; H, 3.65; N, 5.57; S, 12.78. 3.3. General procedure for the reaction of primary polyfluoroalkanethioamides (1a,b) with α-amino acid esters.

7

Amino

acid

ester

(1.3

mmol)

was

added

to

a

solution

of

polyfluoroalkanethioamide (1a,b) (1.0 mmol) in chloroform (10 mL). The reaction mixture was stirred at room temperature for 4 days. Then the solvent was evaporated in vacuo and the crude product was purified by column chromatography on silica gel to give the corresponding polyfluoroalkanethioyl derivative (3a−f).

3.3.1 tert-Butyl (2,2,2-trifluoroethanethioyl)-L-alaninate (3a) It was purified by chromatography on silica gel, eluting with a mixture (9:1) of hexane and ethyl acetate. Yield: 56%. Pale-yellow solid, mp 85−86°C. [α]D20 −94˚ (c = 1, MeOH). Rf = 0.48 (hexane/ethyl acetate 9:1). 1H NMR (CDCl3, δ ppm): 1.43−1.61 (m, 12H, C(CH3)3 + CHCH3), 4.81 (m, 1H, CH), 8.55 (bs, 1H, NH). 19F NMR (CDCl3, δ ppm): −71.2 (s, CF3). 13C NMR (CDCl3, δ ppm): 16.3 (s, CH3), 28.1 (s, C(CH3)3), 53.9 (s, CH), 83.9 (s, C(CH3)3), 117.3 (q, 1JC,F = 278.7 Hz, CF3), 170.6 (s, C=O), 182.4 (q, 2JC,F = 31.1 Hz, C=S). MS, m/z: 256 [M−H]−. Anal. Calcd for C9H14F3NO2S: C, 42.02; H, 5.48; N, 5.44; S, 12.46. Found: C, 42.10; H, 5.52; N, 5.47; S, 12.37. 3.3.2 tert-Butyl (2,2,3,3-tetrafluoropropanethioyl)-L-alaninate (3b) It was purified by chromatography on silica gel, eluting with a mixture (9:1) of hexane and ethyl acetate. Yield: 73%. Yellow oil. [α]D20 −40˚ (c = 1, MeOH). Rf = 0.66 (hexane/ethyl acetate 9:1). 1H NMR (CDCl3, δ ppm): 1.44−1.62 (m, 12H, C(CH3)3 + CHCH3), 4.83 (m, 1H, CH), 6.44 (tt, 2JH,F = 53.1 Hz, 3JH,F = 5.6 Hz, 1H, HCF2), 8.72 (bs, 1H, NH). 19F NMR (CDCl3, δ ppm): −121.0 (m, 2F, CF2), −140.2 (dm, 2JF,H = 53.1 Hz, 2F, HCF2). 13C NMR (CDCl3, δ ppm): 16.3 (s, CH3), 28.0 (s, C(CH3)3), 53.8 (s, CH), 83.8 (s, C(CH3)3), 109.7 (tt, 1JC,F = 252.8 Hz, 2JC,F = 31.9 Hz, HCF2), 111.2 (tt, 1JC,F = 261.1 Hz, 2JC,F = 27.7 Hz, CF2), 170.3 (s, C=O), 185.2

8

(t, 2JC,F = 23.7 Hz, C=S). MS, m/z: 288 [M−H]−. Anal. Calcd for C10H15F4NO2S: C, 41.52; H, 5.23; N, 4.84; S, 11.08. Found: C, 41.58; H, 5.27; N, 4.92; S, 11.12. 3.3.3. Methyl (2,2,2-trifluoroethanethioyl)-L-phenylalaninate (3c) It was purified by chromatography on silica gel, eluting with a mixture (9:1) of hexane and ethyl acetate. Yield: 76%. Yellow oil. [α]D20 +101˚ (c = 1, MeOH). Rf = 0.43 (hexane/ethyl acetate 9:1). 1H NMR (CDCl3, δ ppm): 3.25 (dd, 2JH,H= 14.1 Hz, 3JH,H = 5.3 Hz, 1H, CHAHB), 3.46 (dd, 2JH,H= 14.1 Hz, 3JH,H = 5.3 Hz, 1H, CHAHB), 3.81 (s, 3H, OCH3), 5.26 (m, 1H, CH), 7.05 (m, 2H, Ph), 7.29 (m, 3H, Ph), 8.29 (bs, 1H, NH).

19

F NMR (CDCl3, δ ppm): −71.1 (s, CF3).

13

C NMR

(CDCl3, δ ppm): 35.4 (s, CH2), 53.0 (s, CH), 58.2 (s, OCH3), 117.2 (q, 1JC,F = 279.9 Hz, CF3), 127.8 (s, CH Ph), 128.9 (s, 2 × CH Ph), 129.2 (s, 2 × CH Ph), 134.5 (s, Cq Ph), 170.2 (s, C=O), 182.7 (q, 2JC,F = 36.4 Hz, C=S). MS, m/z: 290 [M−H]−. Anal. Calcd for C12H12F3NO2S: C, 49.48; H, 4.15; N, 4.81; S, 11.01. Found: C, 49.52; H, 4.17; N, 4.90; S, 11.07. 3.3.4. Methyl (2,2,3,3-tetrafluoropropanethioyl)-L-phenylalaninate (3d) It was purified by chromatography on silica gel, eluting with a mixture (9:1) of hexane and ethyl acetate. Yield: 84%. Yellow oil. [α]D20 +44˚ (c = 1, MeOH). Rf = 0.43 (hexane/ethyl acetate 9:1). 1H NMR (CDCl3, δ ppm): 3.24 (dd, 2JH,H = 13.9 Hz, 3JH,H = 5.1 Hz, 1H, CHAHB), 3.43 (dd, 2JH,H= 13.9 Hz, 3JH,H = 5.1 Hz, 1H, CHAHB), 3.76 (s, 3H, OCH3), 5.30 (m, 1H, CH), 6.45 (tt, 2JH,F = 53.1 Hz, 3JH,F = 5.7 Hz, 1H, HCF2), 7.04 (m, 2H, Ph), 7.28 (m, 3H, Ph), 8.49 (bs, 1H, NH).

19

F

NMR (CDCl3, δ ppm): −119.6 (dm, 2JF,F = 254.2 Hz, 1F, CFAFB), −122.0 (dm, 2JF,F = 254.2 Hz, 1F, CFAFB), −140.0 (dm, 2JF,H = 53.1 Hz, 2F, HCF2).

13

C NMR

(CDCl3, δ ppm): 35.7 (s, CH2), 53.0 (s, CH), 58.1 (s, OCH3), 109.7 (tt, 1JC,F = 253.8 Hz, 2JC,F = 31.5 Hz, HCF2), 111.1 (tt, 1JC,F = 262.2 Hz, 2JC,F = 29.4 Hz, CF2), 127.8 (s, CH Ph), 129.0 (s, 2 × CH Ph), 129.3 (s, 2 × CH Ph), 134.5 (s, Cq Ph), 170.1 (s, C=O), 185.7 (t, 2JC,F = 23.4 Hz, C=S). GC–MS, m/z: 323 [M]+. Anal.

9

Calcd for C13H13F4NO2S: C, 48.29; H, 4.05; N, 4.33; S, 9.92. Found: C, 48.32; H, 4.12; N, 4.37; S, 9.95. 3.3.5. Methyl (2,2,2-trifluoroethanethioyl)-D-tryptophanate (3e) It was purified by chromatography on silica gel, eluting with a mixture (7:3) of hexane and ethyl acetate. Yield: 57%. Brown oil. [α]D20 −41˚ (c = 1, MeOH). Rf = 0.50 (hexane/ethyl acetate 7:3). 1H NMR (CDCl3, δ ppm): 3.47 (dd, 2JH,H= 15.2 Hz, 3JH,H = 4.6 Hz, 1H, CHAHB), 3.66 (dd, 2JH,H = 15.2 Hz, 3JH,H = 4.6 Hz, 1H, CHAHB), 3.75 (s, 3H, OCH3), 5.33 (m, 1H, CH), 6.97 (s, 1H, indolyl), 7.12 (t, 3JH,H = 7.5 Hz, 1H, indolyl), 7.21 (t, 3JH,H = 7.5 Hz, 1H, indolyl), 7.37 (d, 3JH,H = 7.5 Hz, 1H, indolyl), 7.47 (d, 3JH,H = 7.5 Hz, 1H, indolyl), 8.15 (bs, 1H, NH), 8.38 (bs, 1H, NH). 19F NMR (CDCl3, δ ppm): −71.1 (s, CF3). 13C NMR (CDCl3, δ ppm): 25.4 (s, CH2), 53.1 (s, CH), 58.7 (s, OCH3), 108.7 (s, Cq indolyl), 111.5 (s, CH indolyl), 117.3 (q, 1JC,F = 279.9 Hz, CF3), 118.3 (s, CH indolyl), 120.1 (s, CH indolyl), 122.7 (s, CH indolyl), 123.1 (s, CH indolyl), 127.4 (s, Cq indolyl), 136.2 (s, Cq indolyl), 170.4 (s, C=O), 182.8 (q, 2JC,F = 35.8 Hz, C=S). MS, m/z: 329 [M−H]−. Anal. Calcd for C14H13F3N2O2S: C, 50.90; H, 3.97; N, 8.48; S, 9.71. Found: C, 50.92; H, 3.95; N, 8.45; S, 9.77. 3.3.6. Methyl (2,2,3,3-tetrafluoropropanethioyl)-D-tryptophanate (3f) It was purified by chromatography on silica gel, eluting with a mixture (8:2) of hexane and ethyl acetate. Yield: 51%. Yellow oil. [α]D20 −33˚ (c = 1, MeOH). Rf = 0.35 (hexane/ethyl acetate 8:2). 1H NMR (CDCl3, δ ppm): 3.40 (dd, 2JH,H= 14.8 Hz, 3JH,H = 4.6 Hz, 1H, CHAHB), 3.53 (dd, 2JH,H= 14.8 Hz, 3JH,H = 4.6 Hz, 1H, CHAHB), 3.64 (s, 3H, OCH3), 5.27 (m, 1H, CH), 6.40 (tt, 2JH,F = 53.1 Hz, 3JH,F = 5.7 Hz, 1H, HCF2), 6.87 (s, 1H, indolyl), 7.06 (t, 3JH,H = 7.5 Hz, 1H, indolyl), 7.14 (t, 3JH,H = 7.5 Hz, 1H, indolyl), 7.28 (d, 3JH,H = 7.5 Hz, 1H, indolyl), 7.41 (d, 3JH,H = 7.5 Hz, 1H, indolyl), 8.05 (bs, 1H, NH), 8.52 (bs, 1H, NH). 19F NMR (CDCl3, δ ppm): −120.7 (m, 2F, CF2), −139.9 (dm, 2JF,H = 53.1 Hz, 2F, HCF2).

13

C NMR

(CDCl3, δ ppm): 25.8 (s, CH2), 53.0 (s, CH), 57.9 (s, OCH3), 108.6 (s, Cq indolyl), 10

109.7 (tt, 1JC,F = 252.7 Hz, 2JC,F = 31.7 Hz, HCF2), 111.1 (tt, 1JC,F = 261.3 Hz, 2JC,F = 28.6 Hz, CF2), 111.5 (s, CH indolyl), 118.4 (s, CH indolyl), 120.0 (s, CH indolyl), 125.6 (s, CH indolyl), 123.2 (s, CH indolyl), 127.3 (s, Cq indolyl), 136.2 (s, Cq indolyl), 170.3 (s, C=O), 185.6 (t, 2JC,F = 23.5 Hz, C=S). MS, m/z: 361 [M−H]−. Anal. Calcd for C15H14F4N2O2S: C, 49.72; H, 3.89; N, 7.73; S, 8.85. Found: C, 49.80; H, 3.92; N, 7.78; S, 8.90. 3.4. General procedure for the preparation of sodium salts (4a,b) A solution of NaOH (0.04 g, 1.0 mmol) in water (10 mL) was added to the corresponding amino acid derivative (3c,d) (1.0 mmol). The reaction mixture was stirred at room temperature for 12 h and washed with dichloromethane (2 × 10 mL). Then water was evaporated under pressure and the residue was dried in vacuo (0.08 mm Hg) at 40°C giving the corresponding sodium salt (4a,b). 3.4.1. Sodium (2,2,2-trifluoroethanethioyl)-L-phenylalaninate (4a) Yield: 42%. Yellow oil. [α]D20 +130˚ (c = 1, H2O). 1H NMR (DMSO-d6, δ ppm): 2.89 (m, 1H, CHAHB), 3.01 (m, 1H, CHAHB), 4.55 (m, 1H, CH), 7.00−7.31 (m, 5H, Ph). 19F NMR (DMSO-d6, δ ppm): −68.5 (s, CF3). MS, m/z: 276 [M−Na]−. Anal. Calcd for C11H9F3NNaO2S: C, 44.15; H, 3.03; N, 4.68; S, 10.72. Found: C, 44.20; H, 3.11; N, 4.70; S, 10.75. 3.4.2. Sodium (2,2,3,3-tetrafluoropropanethioyl)-L-phenylalaninate (4b) Yield: 51%. Yellow solid, mp 170−172ºC. [α]D20 +81˚ (c = 1, H2O). 1H NMR (DMSO-d6, δ ppm): 3.11 (dd, 2JH,H= 13.4 Hz, 3JH,H = 5.0 Hz, 1H, CHAHB), 3.38 (dd, 2JH,H= 13.4 Hz, 3JH,H = 5.0 Hz, 1H, CHAHB), 4.37 (m, 1H, CH), 6.88 (tt, 2

JH,F = 52.5 Hz, 3JH,F = 5.7 Hz, 1H, HCF2), 7.01−7.20 (m, 5H, Ph).

19

F NMR

(DMSO-d6, δ ppm): −117.7 (dm, 2JF,F = 256.0 Hz, 1F, CFAFB), −118.9 (dm, 2JF,F = 256.0 Hz, 1F, CFAFB), −138.9 (m, 2F, HCF2). 13C NMR (DMSO-d6, δ ppm): 36.5 (s, CH2), 61.2 (s, CH), 106.8−113.7 (m, HCF2CF2), 127.3 (s, CH Ph), 128.8 (s, 2 × 11

CH Ph), 129.1 (s, 2 × CH Ph), 136.6 (s, Cq Ph), 176.5 (s, C=O), 185.7 (t, 2JC,F = 23.4 Hz, C=S). MS, m/z: 308 [M−Na]−. Anal. Calcd for C12H10F4NNaO2S: C, 43.51; H, 3.04; N, 4.23; S, 9.68. Found: C, 43.57; H, 3.05; N, 4.27; S, 9.72. 3.5. Thionation of of 2,2,3,3-tetrafluorosuccinamide (5) Phosphorus pentasulfide (8.26 g, 18.6 mmol) and hexamethyldisiloxane (HMDSO) (4.83 g, 29.8 mmol) were added to a suspension of 2,2,3,3tetrafluorosuccinamide (5) (3.50 g, 18.6 mmol) in toluene (80 mL). The reaction mixture was stirred 18 h at 120°C; the reaction was followed by

19

F NMR,

monitoring the disappearance of the starting amide peak in the precipitate. The mixture was cooled to room temperature. Solid material was filtered off and washed with diethyl ether (20 mL). Solvents and excess of HMDSO were removed in vacuo. The residue was fractionated in vacuo (0.08 mm Hg) giving 3,3,4,4tetrafluoropyrrolidine-2,5-dithione (6). 3.5.1. 3,3,4,4-Tetrafluoropyrrolidine-2,5-dithione (6) Yield: 55%. Yellow oily liquid, bp 92−94°C (0.08 mm Hg).

19

F NMR

(CDCl3, δ ppm): −116.5 (s, 2 × CF2). 13C NMR (CDCl3, δ ppm): 107.7 (tt, 1JC,F = 263.3 Hz, 2JC,F = 23.9 Hz, 2 × CF2), 188.9 (t, 2JC,F = 33.9 Hz, 2 × C=S). MS, m/z: 202 [M−H]−. Anal. Calcd for C4HF4NS2: C, 23.65; H, 0.50; N, 6.89; S, 31.56. Found: C, 23.67; H, 0.68; N, 6.91; S, 31.59. 3.6. Reaction of 3,3,4,4-tetrafluoropyrrolidine-2,5-dithione (6) with methyl Lphenylalaninate Methyl L-phenylalaninate (0.47 g, 2.6 mmol) was added to a solution of 3,3,4,4-tetrafluoropyrrolidine-2,5-dithione (6) (0.20 g, 1.0 mmol) in chloroform (10 mL). The reaction mixture was stirred at room temperature for 4 days. Then the solvent was evaporated in vacuo and the crude product was purified by column 12

chromatography on silica gel, eluting with a mixture (8:2) of hexane and ethyl acetate to afford the compound (7). 3.6.1. Dimethyl N,N’-(2,2,3,3-tetrafluorobutanedithioyl)bis(L-phenylalaninate) (7) Yield: 71%. Yellow oil. [α]D20 +25˚ (c = 1, MeOH). Rf = 0.56 (hexane/ethyl acetate 7:3). 1H NMR (CDCl3, δ ppm): 3.18−3.40 (m, 4H, 2 × CH2), 3.75 (s, 6H, 2 × CH3), 5.19−5.33 (m, 2H, 2 × CH), 7.00−7.19 (m, 4H, 2 × CH Ph), 7.00−7.19 (m, 4H, 4 × CH Ph), 7.22−7.45 (m, 6H, 6 × CH Ph), 8.35 (bs, 2H, 2 × NH). 19F NMR (CDCl3, δ ppm): −109.6 (dm, 2JF,F = 253.0 Hz, 2F, 2 × CFAFB), −111.1 (dm, 2JF,F = 253.0 Hz, 2F, 2 × CFAFB). 13C NMR (CDCl3, δ ppm): 35.9 (s, 2 × CH2), 52.8 (s, 2 × CH), 58.6 (s, 2 × OCH3), 111.3 (tt, 1JC,F = 263.8 Hz, 2JC,F = 31.2 Hz, CF2CF2), 127.7 (s, 2 × CH Ph), 128.9 (s, 4 × CH Ph), 129.3 (s, 4 × CH Ph), 134.8 (s, 2 × Cq Ph), 170.1 (s, 2 × COOCH3), 184.1 (t, 2JC,F = 26.2 Hz, 2 × C=S). MS, m/z: 545 [M+H]+, 543 [M−H]−. Anal. Calcd for C24H24F4N2O4S2: C, 52.93, H, 4.44; N, 5.14; S, 11.78. Found: C, 52.95; H, 4.48; N, 5.09; S, 11.74. References 1. (a) R. N. Hurd, G. DeLaMater, Chem. Rev. 61 (1961) 45−86. (b) K. A. Petrov, L. N. Andreev, Russ. Chem. Rev. 40 (1971) 505–524. (c) N. G. Zabirov, F. M. Shamsevaleev, R. A. Cherkasov, Russ. Chem. Rev. 60 (1991) 1128–1145. (d) T. S. Jagodzinski, Chem. Rev. 103 (2003) 197–227. 2. (a) S. S. Mykhaylychenko, J.-P. Bouillon, Yu. G. Shermolovich, J. Fluorine Chem. 130 (2009) 878–885. (b) S. S. Mykhaylychenko, N. V. Pikun, Yu. G. Shermolovich, Tetrahedron Lett. 52 (2011) 4788–4791. (c) S. S. Mykhaylychenko, N. V. Pikun, Yu. G. Shermolovich, J. Fluorine Chem. 140 (2012) 76–81. (d) N. V. Pikun, S. S. Mykhaylychenko, E. B. Rusanov, Yu. G. Shermolovich, Russ. J. Org. Chem. 42 (2013) 1572–1579. 3. C. B.Vicentini, G. Forlani, M. Manfrini, C. Romagnoli, D. Mares, J. Agric. Food Chem. 50 (2002) 4839−4845. 4. R. H. Rynbrandt, E. E. Nishizawa, D. P. Balogoyen, A. R. Mendoza, K. A. Annis, J. Med. Chem. 24 (1981) 1507−1510. 5. J. Zhu, H. Xie, S. Li, Z. Chen, Y. Wu, J. Fluorine Chem. 132 (2011) 306−309. 13

6. J. Zhu, H. Xie, S. Li, Z. Chen, Y. Wu, Org. Lett. 12 (2010) 2434−2436. 7. K.-L. Yu, A. F. Torri, G. Luo, C. Cianci, K. Grant-Young, S. Danetz, L. Tiley, M. Krystal, N. A. Meanwell, Bioorg. Med. Chem. Lett. 12 (2002) 3379–3382. 8. Yu. G. Shermolovich, N. V. Pikun, Ukr. Khim. Zh. 79 (2013) 59–73. 9. F. Laduron, C. Nyns, Z. Janousek, H. G. Viehe J. prakt. Chem. 339 (1997) 697–707. 10. E. Pfund, T. Lequeux, S. Masson, M. Vazeux, Org. Lett. 4 (2002) 843–846. 11. A. V. Rudnichenko, E. I. Kaminskaya, Yu. G. Shermolovich, Zh. Org. Farm. Khim. 4 (2006) 38−40. 12. A. V. Rudnichenko, Yu. G. Shermolovich, Synth. Commun. 37 (2007) 459−465. 13. M. J. Schlatter, J. Am. Chem. Soc. 64 (1942) 2722. 14. M. Haddad, F. Dahan, J. P. Legros, L. Lopez, M. T. Boisdon, J. Barrans, J. Chem. Soc., Perkin Trans. 2 (1992) 671−678. 15. U. Pathak, S. Bhattacharyya, S. Mathur, RSC Adv. 5 (2015) 4484−4488. 16. A. Ojeda-Porras, D. Gamba-Sánchez, Tetrahedron Lett. 56 (2015) 4308−4311. 17. E. Pfund, S. Masson, M. Vazeux, T. Lequeux, J. Org. Chem. 69 (2004) 4670−4676. 18. E. Pfund, T. Lequeux, S. Masson, M. Vazeux, A. Cordi, A. Pierre, V. Serre, G. Hervé, Bioorg. Med.Chem. 13 (2005) 4921−4928. 19. E. Yang, M. R. Reese, J. M. Humphrey, Org. Lett. 14 (2012) 3944–3947. 20. G. S.Garrett, T. J. Emge, S. C. Lee, E. M. Fischer, K. Dyehouse, J. M. McIver, J. Org. Chem. 59 (1991) 4823–4826 21. E. C. Stump, M. M. Guy, J. Sutton, G. Westmoreland, J. Chem. Eng. Data 9 (1964) 249.

14

H2N

NH2

N RF N H

S

[10, 11]

H2N

NH2

N RF

RF NH2 1a,b

-NH3 -H2S

HN H2N

NH2

N RF HN

RF = CF3 (a), HCF2CF2 (b)

Scheme 1. Reactions of polyfluoroalkanethioamides 1a,b with diaminoalkanes.

S R NH2

RF NH2

CHCl3, rt -NH3

1a,b

S RF HN R 2a-c

RF = CF3

Alk = n-Pr

2a

(72%)

RF = HCF2CF2

Alk = n-Pr

2b

(70%)

RF = HCF2CF2

Alk = Bn

2c

(65%)

Scheme 2. Reactions of polyfluoroalkanethioamides 1a,b with primary aliphatic amines.

15

O H3C

O tBu S

NH 2 RF

CH 3 N H

O tBu O

R F = CF 3 3a (56%) R F = HCF 2CF 2 3b (73%) O OCH 3 NH 2

S RF NH 2

S N H

RF

CHCl3, rt

1a,b

OCH 3 O

R F = CF3 3c (76%) R F = HCF2 CF 2 3d (84%)

O OCH 3 HN

NH

NH 2

S RF

N H

OCH 3 O

R F = CF 3 3e (57%) R F = HCF 2CF 2 3f (51%)

Scheme 3. Reactions of polyfluoroalkanethioamides 1a,b with α-amino acid esters.

Ph

S RF

OMe

N H

O

Ph

S

NaOHaq. RF

N H

3c,d

ONa O

4a,b RF = CF3

4a (42%)

RF = HCF2CF2 4b (51%)

Scheme 4. Preparation of sodium salts 4a,b.

16

F F

O

H2N

NH2 O

S

F

P4S10/ Me3Si-O-SiMe3

F

PhMe, reflux

F

NH

F F

F

5

S 6 (55%)

Scheme 5. Thionation of 2,2,3,3-tetrafluorosuccinamide 5.

S

F

O

F NH F F

S

O

CHCl3, rt Ph

OMe

MeO

NH2

Ph

6

F F

H N S

F F

Ph

S N H

OMe O

7 (71%)

Scheme 6. Reaction of 3,3,4,4-tetrafluoropyrrolidine-2,5-dithione 6 with methyl Lphenylalaninate.

17