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Russian Chemical Bulletin, International Edition, Vol. 66, No. 6, pp. 1116—1121, June, 2017

Synthesis of ethyl α-nitro-β-trifluoromethyl acrylate and β-trifluoromethyl-substituted tryptophan analogs and their plant growth regulating activity O. Yu. Fedorovskii,a A. Yu. Volkonskii,a A. S. Golubev,a Yu. Ya. Spiridonov,b and N. D. Chkanikova aA.

N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 ul. Vavilova, 119991 Moscow, Russian Federation. Fax: +7 (499) 135 5085. E-mail: [email protected] bAll-Russian Research Institute of Phytopathology, 5 ul. Institut, Bol´shie Vyazemy, 143050 Moscow region, Russian Federation

Ethyl -nitro--trifluoromethyl acrylate was synthesized by nucleophile-catalyzed reaction of ethyl nitroacetate with excess trifluoroacetaldehyde methyl hemiacetal and subsequent dehydration of the intermediate alcohol with P2O5. The synthesized nitro olefin regioselectively reacts with the substituted indoles to give fluorinated 3-indolyl-2-nitrobutyrates, which were converted into the corresponding -trifluoromethyl-substituted tryptophan analogs via the nitro group reduction followed by saponification of the ethoxycarbonyl group. In the step of synthesis of amino ester, the 2-methylindole derivative was resolved into diastereomers, which were transformed to the corresponding acids separately. It was found that the synthesized -trifluoromethyltryptophans have plant-growth regulating activity apparently attributable to their metabolic transformations into substituted -trifluoromethylindol-3-ylacetic acids. Key words: ethyl -nitro--trifluoromethyl acrylate, -trifluoromethyl-substituted tryptophan analogs.

Conjugated nitro olefins are recognized as very reactive electrophiles widely used in the synthesis of organic compounds of various classes.1—3 Introduction of the functional groups into nitroalkenes widen the scope of their synthetic applications and variety of the target products. For instance, introduction of the carbalkoxy substituent in the geminal position (to the nitro group) of nitro alkenes open prospects to -amino acids.4—6 The presence of the fluorinated fragment at the -position of -amino acids affected their metabolism.7 To date, numerous synthetic approaches to -nitroalkyl esters bearing -alkyl, -aryl, and -hetaryl substituents have been reported.8—15 However, we found no data on -perfluoroalkyl-substituted -nitroacrylic esters. In the present work, we described a two-step synthesis of ethyl 2-nitro-3-trifluoromethyl acrylate (1) (a mixture of E/Z-isomers) by the reaction of ethyl nitroacetate (2) with excess trifluoroacetaldehyde methyl hemiacetal 3 (was used as a mixture with trifluoroacetaldehyde monohydrate (4)) in the presence of nucleophilic catalyst (Na2CO3, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)) followed by dehydration of intermediate nitro alcohol 5 (obtained as a 1.2 : 1.0 diastereomeric mixture) with P2O5 (Scheme 1). The synthesized trif luoromethyl-substituted nitro aclylate E,Z-1 quantitatively reacts with indole derivatives 6a—d giving the corresponding fluorinated 3-indolyl-2-

Scheme 1

nitrobutyrates 7a—d (as the diastereomeric mixtures in the ratio of (~1.1—1.5) : 1.0 for 7a—c and of ~2.0 : 1.0 for 7d) (Scheme 2). Compounds 7a—d were converted into -amino acid esters 8a—d by the reduction with zinc in acetic acid. The ester groups of compounds 8a—c were hydrolyzed to give "free" -trifluoromethyl-substituted tryptophan analogs 9a—c* as racemic mixtures (see Scheme 2). * N-Acetyl- and N-carbobenzyloxy--trifluoromethyltryptophans have been previously described.16,17

Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1116—1121, June, 2017. 1066-5285/17/6606-1116 © 2017 Springer Science+Business Media, Inc.

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Scheme 2

Compounds 6—9 R1 a H b OMe c Br d H

R2 H H H Me

Reagents and conditions: i. CH2Cl2, 0—5 C; ii. Zn, AcOH; iii. 1) NaOH, H2O, 2) HCl.

We succeeded in separation of 2-methylindole derivative, amino ester 8d, into diastereomers 8dA and 8dB by silica gel column chromatography (see Experimental). Subsequent saponification of diastereomers 8dA and 8dB results in diastereomerically pure (de  97%) -trifluorinated tryptophan analogs 9dA and 9dB (Scheme 3). Scheme 3

Reagents and conditions: 1) NaOH, H2O, 2) HCl.

It is known18,19 that both L- and D-forms of tryptophan are the sources of indol-3-ylacetic acid (IAA), an important plant growth regulating hormone. Indol-3-ylacetic acid stimulates seed germination and promotes root formation. However, direct large-scale application of IAA is limited by its low stability to peroxidase-catalyzed oxidation.20 This problem can be solved by either using metabolic precursors of IAA or synthetizing its derivatives more stable to enzymatic oxidation. Patent21 claimed the practical value of derivatives of 2-trifluoromethyl-2-(indol-3-yl)acetic acid (10) stable to peroxidase-catalyzed oxidation. High efficiency of these compounds was demonstrated by Kato and co-workers.20 Assuming that compounds 9a—d will transform into fluorinated IAA derivatives 10 in plants similarly to tryptophan, we decided to estimate the effects of the synthesized -trifluoromethyltryptophans on seed germination and root development.

Growth regulating activity of the tryptophan derivatives 9a—d was tested on corn. The experiments were carried out using Petri dishes. The effects of the compounds at a dose of 100 mg per 1 ton of seed were estimated determining both the sprout height and root length. The measurements were performed on the 7th day of the seed imbibition at 25 C on wet filter pater. The obtained results are summarized in Table 1. Table 1 shows that all compounds have strong effect on the root development exerting also some effect on the sprout elongation. The highest activity was found for 5-unsubstituted tryptophan derivative 9a, which is a probable precursor of -trifluoromethylindol-3-ylacetic acid (10; R1 = R2 = H). Table 1. Effects of substituted -trifluoromethyltryptophans 9a—d (at a dose of 100 mg per 1 ton of seeds) on the lengths of the corn sprout and roots Compound

9a 9b 9c 9db

Sprouts

Roots

Height /cm

Elongation (%)a

Length /cm

Elongation (%)a

3.7 3.9 3.6 3.9

8.8 14.7 5.9 14.7

9.3 8.2 7.6 8.4

43.1 26.2 16.9 29.2

a  Elongations of the sprouts and roots are given as percentage relative to the control (water). Height of the sprouts and lengths of the roots in the control sample was 3.4 and 6.5 cm, respectively. b A diastereomeric mixture.

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In summary, in the present work we developed preparative procedure to ethyl -nitro--trifluoromethyl acrylate and demonstrated the possibility of its derivatization and diastereomeric resolution to obtain diastereomers with high diastereomeric excess (de ≥ 97%) on the step of the synthesis of amino ester. The synthesized tryptophan analogs stimulate corn germination. Experimental 1H NMR spectra were run on a Bruker AvanceTM400 instrument (working frequency of 400.13 MHz). The proton chemical shifts were measured relative to the residual solvent signal ((CDCl3 7.26 and (DMSO-d6) 2.50) and referenced to SiMe4. 19F NMR spectra were recorded on a BrukerAvanceTM400 instrument (working frequency of 376.50 MHz) without proton decoupling. The 19F NMR shifts were measured relative to trifluoroacetic acid (an internal standard) and referenced to CFCl3. Raman spectrometry was performed with Ramanor HG-2S x and LabRAM spectrometers. Electron impact (70 eV) mass spectra were obtained with a Finnigan Polaris Q instrument equipped with an ion trap. The samples were introduced via either the direct inlet or the chromatographic inlet system. Mass spectra of compounds 7c, 8c, and 9c bearing the bromide atoms are given for the ions containing the 79Br isotopes. Electrospray ionization (ESI) high resolution mass spectrometry was carried out with a Bruker micrOTOF II instrument22 operating in positive (capillary voltage of 4500 V) and negative (capillary voltage of 3200 V) ion modes. Operating mass range was m/z 50—3000 Da, calibration was either internal or external (Electrospray Calibrant Solution, Fluka). The samples were introduced via a syringe inlet as a solution in MeCN, MeOH, and water at flow rate of 3 L min–1. Nebulizer gas was nitrogen (flow rate of 4 L min–1), inlet temperature was 180 C. Column chromatography was performed with Merck Kieselgel 60 (0.06—0.20 mm). The reaction course and purity of the products were monitored by TLC on precoated Merck Kieselgel 60 F254 plates using petroleum ether (b.p. 40—70 C), ethyl acetate, isopropanol, and acetic acid for the development. Ethyl nitroacetate 2 and trifluoroacetaldehyde methyl hemiacetal 3 (mixture with monohydrate 4) were synthesized as earlier described.23,24 The substituted indoles 6a—d, DBU, solvents, and other commercially available reagents were purified if required following the standard procedures. Ethyl 4,4,4-trifluoro-2-nitrobut-2-enoate (1). A mixture of ethyl nitroacetate 2 (3.92 g, 29.5 mmol), methyl hemiacetal 3 (20.10 g, 157 mmol based on the total of all trifluoroacetaldehyde derivatives; molar ratio 3  :  4  5.1  :  1.0), and DBU (0.200 g, 1.32 mmol) was kept at room temperature for 24 h until the ethyl nitroacetate conversion of ≥95% was achieved. The reaction mixture was neutralized by addition of concentrated H2SO4 (0.140 g). The low-boiling components were distilled in vacuo (1 Torr) at ≤40 C into a receiver cooled to –78 C.* The residue was dissolved in CH2Cl2, washed with water, dried with MgSO4, and concentrated in vacuo. Crude alcohol 5 was mixed with P2O5 (19.7 g, 139 mmol) and the mixture was heated at ≤150 C under vacuum of 10 Torr to collect the fraction with b.p. 65—69 C

* Methyl hemiacetal 3 (a mixture with hydrate 4) was recovered by distillation of a low-boiling fraction and was used for the next synthesis.

Fedorovskii et al.

(10 Torr). Nitroolefin 1 was obtained in the yield of 3.33 g (53%), light yellow mobile liquid with pungent smell, purity of ≥99%, the isomeric ratio E : Z = 1.8 : 1.0. After distillation at 10 Torr almost stopped, vacuum was lowered to 1 Torr and acrylate 1 (0.58 g) was collected into a receiver cooled to –78 C; purity of 60—65%, the isomeric ratio E : Z = 0.8 : 1.0. This fraction was repeatedly distilled over a fresh portion of P2O5 to obtain additionally 0.15 g (2%) of olefin 1, b.p. 68—71 C (10 Torr), purity ≥96%, the isomeric ratio E : Z = 0.8 : 1.0. Overall yield of nitroacrylate 1 was 3.48 g (55%). E-Isomer. 1H NMR, (CDCl3), : 7.14 (q, 1 H, CH, J = 7.0 Hz); 4.47 (q, 2 H, CH2, J = 7.2 Hz); 1.40 (t, 3 H, CH3, J = 7.2 Hz). 19F NMR (CDCl3),: –60.46 (d, CF3, J = 6.9 Hz). MS (EI, 70 eV), m/z (Irel (%)): 214 [M + H]+ (38.1); 186 [M – OEt]+ (11.8); 123 [C4H2F3O]+ (10.1); 105 [C3F4]+ (10.1); 91 [C3HF2O]+ (36.8); 75 [C3HF2]+ (24.5); 74 [CNO3]+ (50.8); 53 [C3HO]+ (100); 45 [C2H5O]+ (25.1); 30 [NO]+ (58.9); 29 [C2H5]+ (36.1); 27 [C2H3]+ (32.9). Z-Isomer. 1H NMR (CDCl ),  6.77 (q, 1 H, CH, J = 6.9 Hz); 4.43 (q, 2 H, 3 CH2, J = 7.2 Hz); 1.38 (t, 3 H, CH3, J = 7.2 Hz). 19F NMR (CDCl3), : –61.63 (d, CF3, J = 6.9 Hz). MS (EI, 70 eV), m/z (Irel (%)): 214 [M + H]+ (57.7); 186 [M – OEt]+ (18.6); 123 [C4H2F3O]+ (27.0); 91 [C3HF2O]+ (63.5); 75 [C3HF2]+ (26.0); 74 [CNO3]+ (67.2); 53 [C3HO]+ (100); 45 [C2H5O]+ (20.1); 30 [NO]+ (66.9); 29 [C2H5]+ (46.0); 27 [C2H3]+ (41.8). Raman spectra of E/Z-isomeric mixture (E : Z = 2.9 : 1.0), /cm–1: 1341 (v.s), 1377 (m), 1563 (m, NO2); 1696 (s), 1750 (s, C=C, C=O). Found (%): C, 33.81; H, 2.72; F, 26.68; N, 6.39. C6H6F3NO4. Calculated (%): C, 33.82; H, 2.84; F, 26.74; N, 6.57. Ethyl 4,4,4-trifluoro-3-hydroxy-2-nitrobutanoate (5). A mixture of ethyl nitroacetate 2 (4.29 g, 32.2 mmol), methyl hemiacetal 3 (25.55 g, 200 mmol based on the total of all trifluoroacetaldehyde derivatives; molar ratio 3 : 4 ≈ 5.4 : 1.0), and anhydrous Na2CO3 (0.057 g, 0.54 mmol) was stirred at room temperature for 24 h until the ethyl nitroacetate conversion of ≥95% was achieved. The reaction mixture was neutralized by addition of concentrated HCl (0.108 g) and the low-boiling fraction was distilled in vacuo (1 Torr) at ≤40 C into a receiver cooled to –78 C.* The residue was dissolved in CH2Cl2, washed with water, dried with MgSO4, and concentrated in vacuo. Vacuum distillation of the residue afforded ester 5 in the yield of 6.59 g (89%), colorless moderately viscous liquid, b.p. 71—75 C (1 Torr), purity ≥98%, the diastereomeric ratio of 1.2 : 1.0. Major diastereomer. 1H NMR (neat), : 5.94 (d, 1 H, CHNO2, J = 6.3 Hz); 5.38 (br.m, 1 H, CHCF3); 5.07 (d, 1 H, OH, J = 8.2 Hz);** 4.72 (q, 2 H, CH2, J = 7.2 Hz); 1.67 (t, 3 H, CH3, J = 7.0 Hz). 19F NMR (neat), : –76.34 (d, CF , J = 5.7 Hz). Minor diaste3 reomer. 1H NMR (neat),  5.90 (d, 1 H, CHNO2, J = 4.9 Hz); 5.50 (br.m, 1 H, CHCF3); 5.11 (d, 1 H, OH, J = 7.9 Hz);** 4.74 (q, 2 H, CH2, J = 7.2 Hz); 1.68 (t, 3 H, CH3, J = 7.0 Hz). 19F NMR (neat), : –76.68 (d, CF , J = 6.4 Hz). Raman spec3 trum of the diatereomeric mixture, /cm–1: 1359 (v.s), 1377 (s), 1575 (m, NO2), 1752 (s, C=O). MS (EI, 70 eV), m/z (Irel (%)): 232 [M + H]+ (27.3); 214 [M – OH]+ (6.2); 186 [M – OEt]+ (12.5); 157 [M – C2H4 – NO2]+ (33.9); 139 [M – EtOH – NO2]+ (100); 134 [M – CF3 – CO]+ (76.0); 71 [C3H3O2]+ (45.4); 69 [CF3]+ (45.4). Found (%): C, 31.03; H, 3.44; F, 24.51; * Methyl hemiacetal 3 (a mixture with hydrate 4) was recovered by distillation of a low-boiling fraction and was used for the next synthesis. ** Positions ( 4—6) and coupling (d or br.s) of this signal significantly depend on the mixture compositions.

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Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017

N, 6.02. C 6H 8F 3NO 5. Calculated (%): C, 31.18; H, 3.49; F, 24.66; N, 6.06. Ethyl 4,4,4-trifluoro-3-(1H-indol-3-yl)-2-nitrobutanoate (7a). To a solution of indole 6a (0.585 g, 0.005 mmol) in CH2Cl2 (35 mL), a solution of alkene 1 (1.065 g, 0.005 mol) in CH2Cl2 (2 mL) was added at 0—5 C over 1 h. After the reaction completion (24 h, TLC monitoring), the reaction mixture was concentrated in vacuo maintaining the bath temperature at ≤45 C. The obtained product was used in the next step without further purification. Yield of chromatographically pure 7a was 1.6 g (97%), yellow-brown oil. According to NMR spectroscopy data, compound 7a is a mixture of diastereomers in a 1.0 : 0.83 ratio. Major diastereomer. 1H NMR (DMSO-d6), : 0.69 (t, 3 H, CH2CH3, J = 7.0 Hz); 3.75 (q, 2 H, CH2CH3, J = 7.0 Hz); 5.05 (m, 1 H, CF3CH, JF,H = 8.3); 5.77 (d, 1 H, NO2CH, J = 10.2 Hz); 7.26—7.69 (m, 5 H, Ar); 8.35 (br.s, 1 H, NH). 19F NMR (DMSO-d6), : –69.07 (d, CF3, JF,H = 8.3 Hz). Minor diastereomer. 1H NMR (DMSO-d6), : 1.34 (t, 3 H, CH2CH3, J = 7.0 Hz); 4.35 (q, 2 H, CH2CH3, J = 7.0 Hz); 4.93 (m, 1 H, CF3CH, JF,H = 9.2 Hz); 5.78 (d, 1 H, NO2CH, J = 10.2 Hz); 7.26—7.69 (m, 5 H, Ar); 8.35 (br.s, 1 H, NH). 19F NMR (DMSO-d6), : –67.03 (d, CF3, JF,H = 8.3 Hz). MS (EI, 70 eV), m/z (Irel (%)): 330 [M]+ (62); 284 [C14H13F3NO2]+ (67); 211 [C11H8F3N]+ (100). Ethyl 4,4,4-trifluoro-3-(5-methoxy-1H-indol-3-yl)-2-nitrobutanoate (7b) was synthesized similarly to compound 7a. Yellow oil, Rf 0.75 (development with chloroform—ethyl acetate, 9 : 1). Yield 98%. According to NMR spectroscopy data, compound 7b is a mixture of diastereomers in a 1.0  :  0.82 ratio. Major diastereomer. 1H NMR (DMSO-d6), : 0.73 (t, 3 H, CH2CH3, J = 7.0 Hz); 3.79 (q, 2 H, CH2CH3, J = 7.0 Hz); 3.91 (s, 3 H, MeO); 5.02 (m, 1 H, CF3CH); 5.74 (d, 1 H, NO2CH, J = 5.7 Hz); 6.93 (d, 1 H, H(7), J = 8.8 Hz); 7.11 (dd, 1 H, H(6), J = 7.1 Hz, J = 2.0 Hz); 7.25 (m, 2 H, ArH(4), ArH(2)); 8.27 (br.s, 1 H, NH). 19F NMR (DMSO-d6), : –67.93 (d, CF3, JF,H = 8.6 Hz). Minor diastereomer. 1H NMR (DMSO-d6), : 1.35 (t, 3 H, CH2CH3, J = 7.0 Hz); 4.37 (q, 2 H, CH2CH3, J = 7.0 Hz); 3.91 (s, 3 H, MeO); 4.88 (m, 1 H, CF3CH); 5.78 (d, 1 H, NO2CH, J = 5.5 Hz); 6.93 (d, 1 H, ArH(7), J = 8.8 Hz); 7.11 (dd, 1 H, ArH(6), J = 7.1 Hz, J = 2.0 Hz); 7.25 (m, 2 H, ArH(4), ArH(2), Ar); 8.27 (br.s, 1 H, NH). 19F NMR (DMSO-d6), : –65.95 (d, CF3, JF,H = 8.6 Hz). MS (EI, 70 eV), m/z (Irel (%)): 360 [M]+ (81); 314 [C15H15F3NO3]+ (76); 241 [C12H9F3NO]+ (100). Ethyl 3-(5-bromo-1H-indol-3-yl)-4,4,4-trifluoro-2-nitrobutanoate (7c) was synthesized similarly to compound 7a. Yellowbrown oil, Rf 0.4 (development with petroleum ether—ethyl acetate, 7 : 3). Yield 98%. According to NMR spectroscopy data, compound 7c is a mixture of diastereomers in a 0.97 : 1.0 ratio. Major diastereomer. 1H NMR (CDCl3), : 1.35 (t, 3 H, CH2CH3, J = 7.2 Hz); 4.35 (q, 2 H, CH2CH3, J = 7.2 Hz); 4.85 (m, 1 H, CF3CH); 5.73 (d, 1 H, O2NCH, J = 10.3 Hz); 7.21—7.38 (m, 3 H, Ar); 7.82 (br.s, 1 H, ArH(2)); 8.39 (br.s, 1 H, NH). 19F NMR (CDCl3), : –65.96 (br.s, CF3). Minor diastereomer. 1H NMR (CDCl3), : 0.79 (t, 3 H, CH2CH3, J = 7.0 Hz); 3.79 (q, 2 H, CH2CH3, J = 7.0 Hz); 4.98 (m, 1 H, CF3CH); 5.71 (d, 1 H, O2NCH, J = 9.8 Hz); 7.21—7.38 (m, 3 H, Ar); 7.82 (br.s, 1 H, ArH(2)); 8.39 (br.s, 1 H, NH). 19F NMR (CDCl3), : –67.91 (br.s, CF3). MS (EI, 70 eV), m/z (Irel (%)): 407.9 [M]+ (34); 362.1 [C12H7BrF3N2O3 + H]+ (48); 211.2 [C11H8F3N]+ (100); 210.2 [C9H8BrN + H]+ (82). Ethyl 4,4,4-trifluoro-3-(2-methyl-1H-indol-3-yl)-2-nitrobutanoate (7d) was synthesized similarly to compound 7a. Yellow-

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brown oil, Rf 0.6 (development with chloroform—ethyl acetate— petroleum ether, 1  :  1  :  3). Yield 92%. According to NMR spectroscopy data, compound 7d is a mixture of diastereomers in a 1.96 : 1.0 ratio. Major diastereomer. 1H NMR (CDCl3), : 0.61 (t, 3 H, CH2CH3, J = 7.0 Hz); 2.49 (s, 3 H, ArCH3); 3.73 (q, 2 H, CH2CH3, J = 7.0 Hz); 4.89 (br.m, 1 H, CF3CH); 6.06 (br.d, 1 H, O2NCH); 7.13—7.39 (m, 3 H, Ar); 7.52 (br.d, 1 H, ArH(4), J = 5.4 Hz); 8.09 (br.s, 1 H, NH). 19F NMR (CDCl3), : –67.57 (br.s, CF3). Minor diastereomer. 1H NMR (CDCl3), : 1.39 (t, 3 H, CH2CH3, J =7.0 Hz); 2.48 (s, 3 H, C(2)CH3); 4.39 (q, 2 H, CH2CH3, J = 7.0 Hz); 4.74 (br.m, 1 H, CF3CH); 6.05 (br.d, 1 H, O2NCH); 7.13—7.39 (m, 3 H, Ar); 7.55 (br.d, 1 H, ArH(4)), J = 7.6 Hz); 8.09 (br.s, 1 H, NH). 19F NMR (CDCl3), : –65.04 (br.s, CF3). MS (EI, 70 eV), m/z (Irel (%)): 344 [M]+ (64); 225 [C12H10F3N]+ (100). Ethyl 2-amino-4,4,4-trifluoro-3-(1H-indol-3-yl)-butanoate (8a). To a vigorously stirred solution of compound 7a (0.31 g, 0.97 mmol) in AcOH (25 mL), activated zinc25 (2 g, 0.031 mol) was added by portions at room temperature over 30 min. After the reaction completion (1 h, TLC monitoring), the unreacted zinc was removed by filtration and washed on the filter with ethanol (2×30 mL). The filtrate was concentrated in vacuo (~20 mm Hg, bath temperature ≤45 C). The residue was dissolved in distilled water (120 mL) and treated with K2CO3 until pH 8—10 was reached. The oil formed was extracted with ethyl acetate (3×50 mL). The combined extract was dried with sodium sulfate and filtered through a 1 cm silica gel pad applied on a fritted funnel (200 mesh). Concentration of the filtrate in vacuo (~20 mm Hg, bath temperature ≤45 C) and subsequent coevaporation of the residue with CH2Cl2 (2×30 mL) to remove water traces afforded 0.17 g (59%) of compound 8a. Yellow oil, Rf 0.15 (development with chloroform—ethyl acetate, 85 : 15). According to NMR spectroscopy data, compound 8a is a mixture of diastereomers in a 1.0  :  0.94 ratio. Major diastereomer. 1H NMR (DMSO-d ), : 0.83 (t, 3 H, CH CH , J = 7.0 Hz); 6 2 3 2.1 (br.s, 2 H, NH2); 3.84 (q, 2 H, CH2CH3, J = 7.0 Hz); 4.15—4.36 (m, 2 H, the CF3CH and NH2CH proton signals overlap); 6.97—7.57 (m, 5 H, Ar); 11.18 (br.s, 1 H, NH). 19F NMR (DMSO-d6), : –63.76 (d, CF3, JF,H = 8.3 Hz). Minor diastereomer. 1H NMR (DMSO-d6), : 1.08 (t, 3 H, CH2CH3, J = 7.0 Hz); 2.1 (br.s, 2 H, NH2); 3.97 (q, 2 H, CH2CH3, J = 7.0 Hz); 4.15—4.36 (m, 2 H, the CF3CH and NH2CH proton signals overlap); 6.97—7.57 (m, 5 H, Ar); 11,28 (br.s, 1 H, NH). 19F NMR (DMSO-d ), : –65.88 (d, CF , J 6 3 F,H = 8.3 Hz). MS (EI, 70 eV), m/z (Irel (%)): 300 [M + H]+ (7); 227 [C11H10F3N2]+ (12); 198 [C10H7F3N]+ (100). Ethyl 2-amino-4,4,4-trifluoro-3-(5-methoxy-1H-indol-3-yl) butanoic acid (8b) was synthesized similarly to compound 8a. Yellow-brown oil, Rf 0.3 (development with petroleum ether— ethyl acetate—ethanol, 14 : 5 : 1). Yield 63%. According to NMR spectroscopy data, compound 8b is a mixture of diastereomers in a 0.75 : 1.0 ratio. Major diastereomer. 1H NMR (DMSO-d6), : 0.88 (t, 3 H, CH2CH3, J = 7.0 Hz); 3.76 (s, 3 H, MeO); 3.82—4.27 (m, 4 H, the CH2CH3, CF3CH, and NH2CH proton signals of both diastereomers overlap); 6.76 (dd, 1 H, ArH(6), 3J = 8.6 Hz, 4J = 2.2 Hz); 7.07 (d, 1 H, ArH(4), J = 1.6 Hz); 7.26 (d, 1 H, ArH(7), J = 8.6 Hz); 7.32 (d, 1 H, ArH(4), 4J = 1.9 Hz); 11.04 (br.s, 1 H, NH). 19F NMR (DMSO-d ), : 6 –63.89 (br.s, CF3). Minor diastereomer. 1H NMR (DMSO-d6), : 1.08 (t, 3 H, CH2CH3, J = 7.0 Hz); 3.75 (s, 3 H, MeO); 3.82—4.27 (m, 4 H, the CH2CH3, CF3CH, and NH2CH proton signals of both diastereomers overlap); 6.78 (dd, 1 H, ArH(6),

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= 8.6 Hz, 4J = 2.2 Hz); 7.02 (d, 1 H, ArH(2)), J = 1.9 Hz); 7.28 (d, 1 H, ArH(7), J = 8.6 Hz); 7.44 (d, 1 H, ArH(4), J = 1.9 Hz); 11.11 (br.s, 1 H, NH). 19F NMR (DMSO-d6), : –65.92 (br.s, CF3). MS (EI, 70 eV), m/z (Irel (%)): 330 [M]+ (4); 228 [C11H9F3NO]+ (100). Ethyl 2-amino-3-(5-bromo-1H-indol-3-yl)-4,4,4-trifluorobutanoate (8c) was synthesized similarly to compound 8a. Yellowbrown oil, Rf 0.3 (development with chloroform—ethyl acetate, 7 : 3). Yield 73%. According to NMR spectroscopy data, compound 8c is a mixture of diastereomers in a 1.0 : 0.92 ratio. Major diastereomer. 1H NMR (CDCl3), : 1.24 (t, 3 H, CH2CH3, J = 7.0 Hz); 1.74 (br.s, 2 H, NH2); 3.92—4.34 (m, 4 H, the CH2CH3, CF3CH, and NH2CH proton signals of both diastereomers overlap); 7.21—7.77 (m, 4 H, Ar); 8.45 (br.s, 1 H, NH). 19F NMR (CDCl3), : –65.98 (d, CF3, JF,H = 9.2 Hz). Minor diastereomer. 1H NMR (CDCl3), : 1.15 (t, 3 H, CH2CH3, J = 7.0 Hz); 1.74 (br.s, 2 H, NH2); 3.92—4.34 (m, 4 H, the CH2CH3, CF3CH, and NH2CH proton signals of both diastereomers overlap); 7.21—7.77 (m, 4 H, Ar); 8.39 (br.s, 1 H, NH). 19F NMR (CDCl3), : –63.51 (d, CF3, JF,H = = 9.2 Hz). MS (EI, 70 eV), m/z (Irel (%)): 377.8 [M]+ (3); 379 [M + H]+ (12); 277.1 [C10H6BrF3N + H]+ (100); 276.1 [C10H6BrF3N]+ (67). Ethyl 2-amino-4,4,4-trifluoro-3-(2-methyl-1H-indol-3-yl) butanoate (8d) was synthesized similarly to compound 8a. Yellowbrown oil, Rf 0.25 for 8dA and Rf 0.30 for 8dB (development with petroleum ether—ethyl acetate, 3 : 2). Yield 66%. According to NMR spectroscopy data, the isomer ratio 8dA : 8dB = 0.47 : 1.0. Resolution of isomer mixture 8d (1.1 g) with preparative TLC (elution with petroleum ether—ethyl acetate, 3 : 2) afforded 0.3 g of diastereomer 8dA and 0.7 g of diastereomer 8dB. Major diastereomer 8dB. 1H NMR (DMSO-d6), : 0.57 (t, 3 H, CH2CH3, J = 7.0 Hz); 2.31 (s, 3 H, CH3); 3.64 (q, 2 H, CH2CH3, J = 7.0 Hz); 3.90 (pent, 1 H, CF3CH, JF,H = 10.5 Hz, JH,H = = 10.3 Hz); 4.17 (d, 1 H, NH2CH, J = 10.5 Hz); 6.91—7.12 (m, 2 H, ArH(5), ArH(6)); 7.22 (d, 1 H, ArH(7), J = 7.6 Hz); 7.45 (d, 1 H, ArH(4), J = 7.9 Hz); 11.03 (br.s, 1 H, NH). 19F NMR (DMSO-d6), : –61.67 (d, CF3, JF,H = 8.3 Hz). MS (EI, 70 eV), m/z (Irel (%)): 315.2 [M + H]+ (4); 212.2 [C11H9F3N]+ (100). Minor diastereomer 8dA. 1H NMR (DMSO-d6), : 1.21 (t, 3 H, CH2CH3, J = 7.0 Hz); 2.36 (s, 3 H, CH3); 3.93—4.18 (m, 4 H, the CH2CH3, CF3CH, and NH2CH proton signals overlap); 6.91—7.05 (m, 2 H, ArH(5), ArH(6)); 7.26 (d, 1 H, ArH(7), J = 7.9 Hz); 7.59 (br.s, 1 H, ArH(4)); 11.20 (br.s, 1 H, NH). 19F NMR (DMSO-d ), : –64.68 (br.s, CF ). MS (EI, 70 eV), 6 3 m/z (Irel (%)): 315 [M + H]+ (4); 212 [C11H9F3N]+ (100). 2-Amino-4,4,4-trifluoro-3-(1H-indol-3-yl)butanoic acid (9a). To a vigorously stirred solution of ester 8a (0.51 g, 0.0017 mol) in THF (15 mL), a solution of NaOH (0.5 g, 0.0125 mol) in water (10 mL) was added. The reaction mixture was refluxed for 3 h, cooled down, and concentrated in vacuo (~20 mm Hg, bath temperature ≤45 C). The residue was dissolved in distilled water (15 mL), cooled to 5 C, and neutralized by the dropwise addition of 18% aqueous HCl (pH monitoring using universal indicator paper). At pH close to neutral, amino acid 9a was formed in the solution. Compound 9a was extracted with ethyl acetate— diethyl ether (1 : 1, 3×15 mL), the combined organic layers were dried with sodium sulfate, and concentrated in vacuo to dryness. The residue was co-evaporated with dichloromethane (2×30 mL) to remove the traces of water and ethyl acetate. The obtained powder was washed with anhydrous diethyl ether (2×15 mL), the organic phase was decanted. Drying the residue in vacuo afforded

Fedorovskii et al.

0.35 g (76%) of compound 9a. Light beige powder, m.p. 147—152 C, Rf 0.25 (development with ethyl acetate—isopropanol—acetic acid, 3 : 1 : 1). According to NMR spectroscopy data, compound 9a is a mixture of diastereomers in a 1.49 : 1.0 ratio. Major diastereomer. 1H NMR (DMSO-d6), : 3.82 (br.s, 1 H, NH2CH); 4.72 (m, 1 H, CF3CH); 6.99—7.61 (m, 5 H, Ar); 11.39 (br.s, 1 H, NH). 19F NMR (DMSO-d6), : –66.75 (br.s, CF3). Minor diastereomer. 1H NMR (DMSO-d6), : 3.77 (d, 1 H, NH2CH, J = 4.1 Hz); 4.43 (m, 1 H, CF3CH); 6.99—7.61 (m, 5 H, Ar); 11.34 (br.s, 1 H, NH). 19F NMR (DMSO-d6), : –63.81 (br.s, CF3). MS (EI, 70 eV), m/z (Irel (%)): 272.0 [M]+ (3); 198.1 [C10H7F3N]+ (100). MS (ESI), found: m/z 273.0845 [M + H]+, C12H11F3N2O2. Calculated: M = 273.0845. 2-Amino-4,4,4-trifluoro-3-(5-methoxy-1H-indol-3-yl)butanoic acid (9b) was synthesized similarly to compound 9a in the yield of 63%. Light beige powder, m.p. 137—140 C, Rf 0.25 (development with ethyl acetate—isoropanol—acetic acid, 3 : 1 : 1). According to NMR spectroscopy data, 9b is a mixture of diastereomers in a 0.99  :  1.00 ratio. Major diastereomer. 1H NMR (DMSO-d ), : 3.77 (s, 3 H, OCH ); 4.28 (d, 1 H, 6 3 NH2CH, J = 5.1 Hz); 4.61—4.78 (m, 2 H, the CF3CH proton signals of both diastereomers overlap); 6.75—7.45 (m, 4 H, the signals of both diastereomers overlap, Ar); 11.30 (br.s, 1 H, NH). 19F NMR (DMSO-d ), : –66.42 (d, CF , J = 5.5 Hz). Minor 6 3 diastereomer. 1H NMR (DMSO-d6), : 3.75 (s, 3 H, OCH3); 4.14 (d, 1 H, NH2CH, J = 3.8 Hz); 4.61—4.78 (m, 2 H, the CF3CH proton signals of both diastereomers overlap); 6.75—7.46 (m, 4 H, the signals of both diastereomers overlap, Ar); 11.30 (br.s, 1 H, NH). 19F NMR (DMSO-d6), : –64.86 (br.s, CF3). MS (EI, 70 eV), m/z (Irel (%)): 302 [M]+ (3); 256 [M – COOH + H]+ (3); 228 [C11H9F3NO]+ (100); 213 [M – C2H4NO2 + CH 3] + (14). MS (ESI), found: m/z 303.0951 [M + H] +, C13H13F3N2O3. Calculated: M = 303.0962. 2-Amino-3-(5-bromo-1H-indol-3-yl)-4,4,4-trifluorobutanoic acid (9c) was synthesized similarly to compound 9a in the yield of 69%. Light beige powder, m.p. 155—160 C, Rf 0.25 (development with ethyl acetate—isopropanol—acetic acid, 3  :  1  :  1). According to NMR spectroscopy data, compound 9c is a mixture of diastereomers in a 1.0 : 1.57 ratio. Major diastereomer. 1H NMR (DMSO-d6), : 4.01 (d, 1 H, NH2CH, J = 3.2 Hz); 4.72 (m, 1 H, CF3CH); 7.21—7.56 (m, 3 H, Ar); 7.80 (br.s, 1 H, ArH(2)); 11.66 (br.s, 1 H, NH). 19F NMR (DMSO-d6), : –66.56 (d, CF3, JF,H = 8.3 Hz). Minor diastereomer. 1H NMR (DMSO-d6), : 4.15 (d, 1 H, NH2CH, J = 5.1 Hz); 4.56 (m, 1 H, CF3CH); 7.21—7.56 (m, 3 H, Ar); 7.80 (br.s, 1 H, ArH(2)); 11.66 (br.s, 1 H, NH). 19F NMR (DMSO-d6), : –64.67 (br.s, CF3). MS (EI, 70 eV), m/z (Irel (%)): 350 [M]+ (4); 351 [M + H]+ (14); 276 [C10H6BrF3N]+ (84); 278 [C10H7BrF3N + H]+ (100). MS (ESI), found: m/z 350.9951 [M + H]+. C12H10BrF3N2O2. Calculated: M = 350.9950. 2-Amino-4,4,4-trifluoro-3-(2-methyl-1H-indol-3-yl)butanoic acid (9dA) (minor diastereomer) was synthesized similarly to compound 9a in the yield of 80%. White powder tinged with light grey, m.p. 145—151 C, Rf 0.25 (development with ethyl acetate—isopropanol—acetic acid, 3 : 1 : 1). 1H NMR (DMSO-d6), : 2.38 (s, 3 H, CH3); 4.07 (d, 1 H, NH2CH, J = 7.3 Hz); 4.17 (br.m, CF3CH); 6.96—7.58 (m, 4 H, Ar); 11.25 (br.s, 1 H, NH). 19F NMR (DMSO-d ), : –64.35 (br.s, CF ). MS (EI, 70 eV), 6 3 m/z (Irel (%)): 286 [M]+ (3); 240 [M – COOH + H]+ (4); 212 [C11H9F3N]+ (100); 192 [M – C6H4 + H2O]+ (12); 143 [C10H9N]+ (8). MS (ESI), found: m/z 287.1002 [M + H]+, C13H13F3N2O2. Calculated: M = 287.1001.

Tryptophane analoges as plant growth regulators

Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017

2-Amino-4,4,4-trifluoro-3-(2-methyl-1H-indol-3-yl)butanoic acid (9dB) (major diastereomer) was synthesized similarly to compound 9a in the yield of 76%. White powder tinged with light grey, m.p. 167—172 C, Rf 0.25 (development with ethyl acetate—isopropanol—acetic acid, 3 : 1 : 1). 1H NMR (DMSO-d6), : 2.34 (s, 3 H, CH3); 4.06—4.13 (m, 2 H, the NH2CH and CF3CH proton signals overlap); 6.93—7.52 (m, 4 H, Ar); 11.14 (s, 1 H, NH, Ar). 19F NMR (DMSO-d6), : –62.33 (br.s, CF3). MS (EI, 70 eV), m/z (Irel (%)): 286 [M]+ (2); 240 [M – COOH + + H]+ (2); 212 [M – C2H4NO2]+ (100); 192 [M – C6H4 + H2O]+ (9); 172 [M – C2HF3O2]+ (7); 143 [C10H9N]+ (8); 115 [C8H5N]+ (5). MS (ESI), found: m/z 287.1002 [M + H]+, C13H13F3N2O2. Calculated: M = 287.1001.

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Received March 3, 2017; in revised form March 30, 2017