Synthetical Application of Alkyl 2-isothiocyanatocarboxylates. A Simple Synthesis of 5-Substituted-3-amino-2-thioxo-4-imidazolidinones (3-Amino-2-thiohydantoins)

Abstract

The title 3-amino-2-thiohydantoins 3 has been prepared in very good yields by the reaction of alkyl isothiocynatocarboxylates 1 with hydrazine hydrate.The synthesis of starting isothiocyanates as well as spectral data of 3-aminothiohydantoins and alkyl isothiocyanatocarboxylates has been presented.

Introduction

In the last twenty years, much interest has been focused on the synthesis of N-aminoheterocycles, since this class of compounds has interesting biological properties. Numerous heterocyclic compounds having a thiourea or a thiosemicarbazide moiety have been found to be active as agrochemicals [1,2,3]. As a part of our research in the synthesis of novel heterocycles derived from α-aminoacids we have found a very simple way leading to the 3-aminothiohydantoins.

The title compounds of the general formula 3 are novel, except for 3b (R=H), which has been postulated as a product of sodium ethoxide catalyzed cyclization of the thiosemicarbazide 2b [4], or by thermal cyclization of the compound 2b [5]. Gut et all. [6], relying mainly on infrared spectral evidence, showed that 6-oxo-3-thioxo-hexahydro-1,2,4-triazine prepared by Gante and Lautsch [7] is in reality 3-amino-2-thiohydantoin 3b. 3-Acetamino-2-thiohydantoin was prepared as a side product of the thermal cyclization of 1-Acetylamino-4-ethoxycarbonylmethyl-3-thiosemicarbazide in dimethylformamide [8]. N-substituted derivatives of 3-aminothiohydantoins can be prepared by the reaction of α-chlorocarboxylic acid hydrazides with potassium thiocyanate in acetonitrile proceeding via thiocyanates and isothiocynates, respectively [9,10].

Results and discussion

The general method of preparation 3b-i is based on the reaction of alkyl 2-isothiocyanatocarboxylates 1 with the hydrazine hydrate (Scheme 1). This method allows preparation of title compounds 3 starting from α-aminoacids, which are subsequently transformed to isothiocyanates 1. As it has been stated in our previous paper, isothiocyanatocarboxylates are mostly stable and good accessible compounds [11].

Isothiocyanate 1d prepared by the thiophosgene method [11] is until now an unknown compound. ¹H-, and ¹³C-NMR spectra of 1d-i, have not been reported yet (

Table 1. Spectral Data of Isothiocyanates 1.

Product	[α]22 (g /100ml)	IR (cm-1)	1H NMR (CDCl3/TMS) δ (ppm), J (Hz)	13C NMR (CDCl3/TMS) δ (ppm)
	n - hexane
1dc	±	2081, 1750b	1.06 (s, 9H, (CH3)3C), 3.81 (s, 3H, OCH3), 3.96 (s, 1H, H-2)	26.5 (CH3), 36.8 (C(CH3)3), 68.9 (OCH3), 136.1 (NCS), 167.8 (C=O)
1e	-26.2° (0,29)	2054, 1740a	2.98 (dd, J = 11.2, 5.5, H-3a), 3.04 (dd, 1H, J = 11.2, 5.5, H-3b), 3.75 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.75 (dd, 1H, 2 x J = 4.9, H-2)	36.9 (C-3), 52.0, 53.2 (2xOCH3), 55.1 (C-2), 139.0 (NCS), 167.4, 168.9 (2xC=0)
1f	-32.4° (0.37)	2085, 1740b	2.16 (m, 1H, H-3a), 2.30 (m, 1H, H-3b), 2.53 (m, 2H, H-4), 3.71 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.44 (dd, 1H, 2 x J = 4.9, H-2)	28.2 (C-4), 29.4 (C-3), 51.6, 53.0 (2xOCH3), 58.2 (C-2), 137.8 (NCS), 166.2, 171.9 (2xC=O)
1g	±	2052, 1749	1.25 (t, 3H, J = 7.1, OCH2CH3), 4.21 (q, 2H, J = 7.1, OCH2CH3, 5.26 (s, 1H, H-2 ), 7.42-7.98 (m, 5Harom.)	14.0 (OCH2CH3), 62.9 (OCH2), 62.9 (C-2), 126.8, 129.1, 129.3 (Carom.), 131.0 (C-1’arom.), 139.8 (NCS), 167.4 (C=O)
1h	±	2110, 2170, 1742, 1732a	1.27 (t, 3H, J = 7.2, OCH2CH3), 3.23 (dd, 1H, J = 4.8, 13.7, H-3a), 3.11 (dd, 1H, J = 8.2, 13.7, H- 3b), 4.22 (q, 2H, J = 7.2, OCH2CH3), 4.44 (dd, 1H, 2 x J = 4.8, H-2), 7.21-7.35 (m, 5H, Harom)	14.1 (OCH2CH3), 39.7 (C-3), 60.9 (C-2), 62.6 (OCH2), 127.6, 128.8, 129.4, (3xCarom.), 135.1 (C-1’arom.), 138.0 (NCS), 167.9 (C=O)
1i	-35.3° (0.45)	2064, 1760, 1749a	1.29 (t, 3H, J = 7.2, OCH2CH3), 3.07 (dd, 1H, J = 7.8, 14.0, H-3a), 3.17 (dd, 1H, J = 4.8, 14.0, H-3b), 4.21 (q, 2H, 2 x J = 7.2, OCH2CH3), 4.41 (dd, 1H, 2 x J = 4.7, H-2), 6.79 (d, 2H, J = 8.4, Harom), 7.09 (d, 2H, J = 8.4, Harom.)	14.1 (OCH2CH3), 38.9 (C-3), 61.1 (C-2), 62.7 (OCH2), 115.7 (C-2’,6’), 127.1 (C-1’), 130.7 (C-3’,5’arom.), 137.9 (NCS), 155.1 (C-4’), 168.1 (C=O)

a-CHCl₃ solution b-KBr disc/film c-yield 21%, b.p.29°C/0.09 mbar

). The reaction of isothiocyanates with hydrazine hydrate is stopped in the case of 1b on the stage of 4-ethoxycarbonylmethylthiosemicarbazide 2b either by cooling to laboratory temperature, or by the reflux of isothiocyanate 1b and hydrazine hydrate in ethanol. Compound 2b cyclised to 3b when heated to its melting, or by a short reflux (1 minute) in ethanol in the presence of a subequimolar amount of sodium ethanolate. A longer reflux (0.5 hour) with an equimolar amount of sodium ethanolate led to the sodium carboxylatemethythiosemicarbazide or carboxymethylthiosemicarbazide 2a, respectively. The Conversion of 2d to 3d was carried out and monitored in an NMR tube without isolation of 3d. In all other cases 3-amino-2-thiohydantoins 3 were isolated, without thiosemicarbazide intermediate 2. Our attempts to prepare 2c, e-i by change of temperature (0° C) or by change of the solvent (diethyl ether) failed. Compound 3c crystallized with difficulties and a prolonged standing upon crystallization from ethanol-diethyl ether was necessary.

The physicochemical data 3-aminothiohydantoins 3 are summarized in the

Table 2. Spectral data of 3-Aminothiohydantoins 3.

Product	[α]22 (g / 100 ml)	UV (MeOH) λm (nM)	IR (cm-1)	1H NMR (DMSO-d6/TMS) δ (ppm), J (Hz)	13C NMR (DMSO d6/TMS) δ (ppm)
					C-2,4,5	others
3b	-	239.5 (3.84)	3283, 3179, 3135, 1742, 1514	4.08 (s, 2H, CH2), 4.96 (s, 2H, NH2), 10.06 (bs, 1H, NH)	183.55 169.42 46.99	_
3c	+3.7° (0.4) MeOH	234.0 (3.48) 264.0 (3.97)	3304, 3240, 3210, 1741, 1507	1.46 (d, 3H, J = 7.1, CH3), 4.09 (dq, 1H , J = 7.1, 1.3, CH), 9.65 (bs, 1H, NH)	182.63 172.47 53.09	16.21
3d	+	_	_	0.94 (s, 9H, (CH3)3C)), 3.73 (s, 2H, NH2), 3.89 (s, 1H, CH), 10.27 (bs, 1H, NH)	183.10 170.49 65.59	34.91 25.27
3e	-25.4° (0.45) 4% HCl	235.8 (3.85) 264.8 (4.35)	3360, 3230, 1744, 1729	2.81 (d, 2H, J = 5.1, CH2), 3.60 (s, 3H, OCH3), 4.43 (dd, 1H, 2 x J = 5.4, CH), 4.98 (s, 2H, NH2), 10.18 (bs, 1H, NH)	183.40 170.73 53.75	169.23 51.74 34.41
3f	-25.3° (0.27) 4% HCl	235.8 (3.83) 264.6 (4.32)	3343, 3240, 3196, 1740, 1732, 1501	1.9 (m, 2H, CCH2), 2.43 (m, 2H, CH2CO), 3.60 (s, 3 H, OCH3), 4.23 (dd, 1H, 2 x J = 5.4, CH), 4.98 (s, 2H, NH2), 10.29 (bs, 1H, NH)	183.0 172.25 56.29	171.35 51.44 28.46 26.04
3g	+	270.0 (4.17)	3324, 3248, 3162, 1757, 1518	5.08 (s, 2H, NH), 5.38 (s, 1H, CH), 7.45 - 7.26 (m, 5H, Harom.), 10.70 (bs, 1H, NH)	183.30 170.22 60.59	134.40 128.76 127.57 126.88
3h	+	238.0 (3.78) 266.0 (4.25)	3308, 3235, 3179, 1736, 1510	3.05 (dd, 1H, J = 14.1, 6.1, CHH), 3.21 (dd, 1H, J =14.3, 4.4, CHH), 3.30 (s, 2H, NH2), 4.31 (dd, 1H, J = 6.1, 4.3, CH), 7.20-7.43 (m, 5H, H arom.), 9.90 (bs, 1H, NH)	182.66 170.78 58.16	134.91 129.4 128.11 126.77 35.83
3i	+12.0° (0.14) 4% HCl	226.7 (4.04) 266.2 (4.26)	3435, 3299, 3237, 3177, 1724, 1514	2.47 (m, 2H, CH2), 4.42 (m, 1H, CH), 4.83 (s, 1H, NH2), 6.60 (d, 2H, J = 8.5, Harom. ), 6.92 (d, 2H, J = 8.4, H arom.), 9.28 (s, 1H, OH), 10.25 (bs, 1H, NH)	182.61 170.90 58.48	156.09 130.42 124.80 114.96 35.02

and

Table 3. Physicochemical data and Mass spectra of 3-Aminothiohydantoins 3.

Product	mp (°C) Yield (%)	Moleculare Formula a M.W.	MS m/z (%)
3b	159 – 160 80	C3H5N3OS 131.15	131 (M+., 100), 103 (47), 74 (20), 73 (5), 72 (11), 60 (6), 55 (4), 47 (5), 45 (10), 43 (13), 34 (41), 33 (14)
3c	161 – 163 70	C4H7N3OS 145.18	145 (M+., 100), 117 (27), 86 (17), 74 (13), 60 (8), 44 (56)
3e	152 – 154 72	C6H9N3O3S 203.22	203 (M+., 100), 175 (13), 172 (14), 171 (6), 144 (20), 143 (16), 130 (11), 116 (5), 113 (30), 112 (9), 102 (96), 101 (25), 86 (22), 85 (29), 75 (24), 74 (39), 70 (39), 60 (26), 59 (42), 58 (8), 57 (16), 55 (34), 54 (5), 43 (46)
3f	160 – 61 75	C7H11N3O3S 217.34	217 (M+., 100), 186 (18), 185 (49), 158 (5), 144 (11), 143 (15), 126 (11), 116 (11), 114 (5), 102 (8), 98 (17), 84 (60), 75 (9), 74 (12), 59 (5), 56 (13), 55 (13)
3g	157 – 158 80	C9H9N3OS 207.25	207 (M+., 100), 205 (7), 179 (20), 148 (47), 147 (27), 118 (14), 106 (58), 104 (14), 102 (5), 91 (8), 90 (15), 89 (5), 79 (8), 77 (10), 74 (15), 51 (6)
3h	234 – 235 75	C10H11N3OS 221.28	221 (M+., 61), 193 (26), 163 (5), 162 (5), 131 (7), 130 (13), 128 (13), 121 (6), 120 (64), 119 (5), 118 (5), 117 (17), 116 (20), 106 (45), 104 (13), 103 (16), 102 (12), 92 (23), 91 (100), 89 (5), 86 (5), 78 (8), 77 (17), 75 (18), 65 (23), 63 (6), 51 (12), 50 (6)
3i	210 – 212 64	C10H11N3O2S 237.27	237 (M+., 12), 131 (10), 122 (9), 108 (9), 107 (100), 77 (5)

^a Satisfactory microanalyses obtained: C± 0.3, H± 0.2, N±0.3, S± 0.4

. Structural assignment of isothiocyanates 1 and 3-aminothiohydantoins 3 is based on spectroscopic data (IR, ¹H, ¹³C NMR, mass spectrometry ) (Table 1, Table 2 and Table 3).

In summary, we have synthesized in novel and facile way 3-aminothiohydantoins 3 and a new isothiocyanate 1d.

Experimental

Hydrazine hydrate, thiophosgene, glycine, l-α-alanine, dl-tert-leucine, l-aspartic acid, l-glutamic acid, dl-phenylglycine, dl-phenylalanine, l-tyrosine were purchased from Fluka. Solvents were purified, dried and distilled. Melting points (uncorrected) were determined on a Boetius hot plate. Chromatography: TLC: Silica gel 60 F₂₅₄ (Merck). Column chromatography: Silica gel 60, mesh size 0.04 - 0.0630 mm (Merck). Elemental analyses were obtained using Carlo Erba CHNS-OEA 1108 - Elemental Analyzer. Optical rotation values were measured on a Perkin Elmer P 241 polarimeter. IR spectra were recorded using a Philips FTIR PU 9800 spectrometer, with only selected peaks reported. UV spectra were measured in MeOH solution and were recorded on a Specord UV-VIS M-40 (Zeiss Jena) instrument. Mass spectra were recorded on a AEI MS 902 S electron ionization spectrometer (EI = 70eV). ¹H NMR (300 MHz) and ¹³C NMR (75 MHz) spectra were recorded on a Varian VXR 300. Spectra were internally referenced to TMS. Peaks are reported in ppm down field of TMS. ¹³C NMR peak assignments were made by DEPT editing of the spectra.

General metod for preparation of isothiocyanates 1b-i

A solution of the requiste amino ester hydrochloride (1g) in water (10ml) was mixed with chloroform (10ml) and a stock solution of thiophosgene (1.05 mol-equivalent) was added under stirring with simultaneous addition of a reagent neutralizing the hydrogen chloride, liberated during the reaction (NaHCO₃). The addition was carried out at such rate as to maintain the coloration of the reaction mixture due to an excess of thiophosgene. After the carbon dioxide evolution had ceased, the chloroform layer was separated, washed successively with 0.1_M-HCl (2 × 10 ml) and water (3 × 10ml), dried over sodium sulphate and taken down at 25°C. The oily residue was distilled under diminished pressure, or, alternatively, the solid compound was crystallized from a suitable solvent [11] (Tab.1).

Ethoxycarbonylmethylthiosemicarbazide (2b)

Yield 95%, mp. 172°-174° C, lit.[5] 171° C, Elemental anal. for C₅H₁₁N₃O₂S (M 177.24), calc. / found %C 33,88 / 33.76, %H 6.26 / 6.31, %N 23.71 / 23.67, %S 18.09 / 18.07 .

MS (70eV) m/z (%): 177 (M⁺., 96), 132 (13), 131 (100), 118 (10), 115 (6), 104 (30), 103 (47), 102 (5), 90 (12), 75 (26), 74 (41), 73 (14), 72 (81), 70 (5), 62 (7), 60 (28), 59 (15), 56 (5), 55 (17), 46 (22), 45 (44), 44 (38), 43 (37), 42 (22), 41 (13).

IR (KBr, cm^-1) : 3351, 3312, 3271, 3215, 1750, 1632, 1545, 1497, 1398, 1206, 1375, 1341, 1296, 1240, 1208.

¹H-NMR (DMSO-d₆ / TMS) : 1.18 (t, J = 7.1, 3H, CH₃), 3.27 (s, 4.07 (q, J = 7.1, 2H, OCH₂), 4.21 (d, J = 3.0, 2H, CH₂NH), 4.48 (br, 2H, NH₂), 8.11 (t, J = 3.0, 1H, NH-CH₂), 8.89 (s, 1H, NH-N).

¹³C-NMR (DMSO-d₆ / TMS): 14.1 (CH3), 44.7 (CH2NH), 60.2 (CH2O), 169.8 ( C=O), 181.9 (C=S).

Methoxycarbonyl-t-butylmethylthiosemicarbazide (2d)

Yield 60%, m.p. 108° - 111°C,

MS (70eV) m/z (%): 219 (M⁺., 54), 188 (14), 187 (24), 184 (10), 160 (12), 159 (12), 146 (8), 144 (10), 131 (24), 128 (18), 115 (20), 112 (10), 99 (14), 90 (12), 89 (18), 88 (28), 86 (74), 84 (28), 73 (20), 72 (42), 69 (36), 58 (44), 57 (64), 56 (32), 55 (28), 41 (60), 37 (42), 35 (100), 32 (100). IR (KBr, cm^-1): 3368, 3316, 3295, 2972, 2959, 1730 cm^-1.

¹H-NMR (DMSO-d₆ / TMS) : 0.95 (s, 9H, (CH₃)₃C), 3.65 (s, 3H, OCH₃), 4.70 (br, 2H, NH₂), 4.79 (d, 1H, J = 9.3, CH), 7.91 (d, 1H, J = 9.3, NH-CH), 9.05 (s, 1H, NH-N).

¹³C-NMR (DMSO-d₆ / TMS) : 26.53, 34.31, 51.55, 63.56, 171.5, 181.3

3-Aminothiohydantoin (3b)

Method A: 0.44 g (3 mM ) of 2b is heated (160° C) under vacuum (0.1 mbar) for 0.5 hours. The dark solid afforded after recrystallization from ethanol (charcoal) 0.12 g (36%) of gray crystals, mp. 159-160° C, with satisfactory spectral data ( Table 2).

Method B: 1.64g (9.2 mM ) of 2b was dissolved in ethanol (50 ml) under reflux, water solution of sodium hydroxide (0.1g in 2 ml H₂O) was added , reaction mixture was after 1 minute cooled to 50° C, acidified by diluted HCl (1:10) to pH 6.5. Purification of the reaction mixture with active charcoal and crystallization afforded 0.4 g (33%) of 3b, mp 156 -158° C. Recrystallisation from methanol gave sample with mp.159 -160° (TLC: CHCl₃ / MeOH 9:1, R_f 0.27) having satisfactory elemental analysis data and identical spectral data as the compound 3b prepared by the method A.

3-Aminothiohydantoins 3; General procedure

A solution of hydrazin hydrate 80% (0.62 g, 11 mM ) in MeOH or EtOH (3 mL) was added dropwise to an intensively stirred cooled solution (0° C) of the appropriate isothiocyanate 1b-i (10 mM) in diethyl ether (20 mL). The mixture was stirred for 30 minutes at laboratory temperature (22°C) and then allowed to stand in refrigerator (4°C) for 2 hours. The precipitate was separated by suction filtration, and washed by Et₂O. Recrystallization from EtOH / Et₂O resulted in white crystals (Table 2, Table 3).