Thiocyanation of α-amino carbonyl compounds for the synthesis of aromatic thiocyanates

Abstract

A procedure for K₂S₂O₈-mediated thiocyanation of α-amino carbonyl compounds has been developed for the synthesis of aromatic thiocyanates. A series of α-amino carbonyl compounds have been investigated, and the desired products are obtained in 74%–93% yields. This strategy has the advantages of simple reaction conditions without use of a transition-metal catalyst, high regioselectivity, and high efficiency. Moreover, we found that arylamine thiocyanates can also be obtained from α-amino carbonyl compounds and potassium thiocyanate in the presence of CoCl₂·6H₂O, I₂, and dimethyl sulfoxide through the cleavage of the C–N bond. To explore the reaction mechanism, we designed several control experiments and proposed a possible mechanism using the experimental results and related literature reports.

Keywords

α-amino carbonyl compounds aromatic thiocyanates thiocyanation reaction

Introduction

As an important structural unit, the α-amino carbonyl fragment exists in numerous natural products and pharmaceutical compounds,^1–7 and it is a versatile precursor for the synthesis of various heterocyclic compounds.^8–14 Glycine, the simplest α-amino carbonyl compound, is one of the essential amino acids in the human body. Besides, amoxicillin and clopidogrel demonstrate the application of α-amino carbonyl compounds in medicine and provide resistance to some diseases. α-Amino carbonyl compounds are involved in many reactions, the most important among which are the reactions with nucleophiles, which include alcohols,¹⁵ thiols,¹⁵ amines,^16,17 phosphites,^18,19 nitromethane,²⁰ ketones,²¹ 1,3-dicarbonyl compounds,^22–24 (hetero) arenes,^25–31 and others.

To the best of our knowledge, there are no reports on the thiocyanation of α-amino carbonyl compounds. Organic thiocyanates are well known in the area of organosulfur chemistry and have become a hot research field in organic synthetic chemistry, since they are not only the substructures or building blocks of bioactive natural products^32–35 but also versatile synthetic precursors for the synthesis of sulfur-containing compounds such as thiols,^36,37 thioethers,^38,39 and disulfides.^40,41 Therefore, it is worthwhile to develop a simple and efficient method to achieve the thiocyanation of α-amino carbonyl compounds for the synthesis of organic thiocyanates.

As a continuation of our research on α-functionalized carbonyl compounds,^{17,20,42–48} herein, we describe a straightforward synthesis of aromatic thiocyanates through K₂S₂O₈-mediated thiocyanation of α-amino carbonyl compounds using KSCN as the thiocyanation reagent (Scheme 1A). Moreover, we can prepare arylamine thiocyanates from α-amino carbonyl compounds and KSCN in the presence of CoCl₂·6H₂O, I₂, and dimethyl sulfoxide (DMSO) through the cleavage of the C–N bond (Scheme 1B). The α-amino carbonyl compounds can be easily fabricated from ketones and amines^49,50 and are used as raw materials for the synthesis of a wide range of compounds.⁵¹

Scheme 1.

Thiocyanation of α-amino carbonyl compounds.

Results and discussion

We began the investigation using 2-(methyl(phenyl)amino)-1-phenylethan-1-one (1a) and KSCN (2) as model substrates (Table 1). The desired product 3a was obtained in 28% yield using PhI(OAc)₂ (3 equiv.) and CH₃CN (2 mL) in a sealed tube at room temperature for 16 h (entry 1). This result greatly encouraged us to further explore the reaction. First, we investigated different oxidants for the reaction, including DTBP (di-tert-butylperoxide), TBHP (tert-butyl hydroperoxide, 70% in water), DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), K₂S₂O₈, and O₂. The oxidant K₂S₂O₈ was the best, giving the product in 87% yield (entries 2–6). Solvents often have a large effect on reactions, so we screened the effect of different solvents on the reaction. Common solvents such as DMF (N,N-dimethylformamide), DMSO, CHCl₃, EtOH, 1,4-dioxane, and toluene were selected for this reaction. Among them, the reaction using CHCl₃ or toluene was better, but it was still inferior to the use of acetonitrile (entries 7–12). Next, we explored the effect of the amount of K₂S₂O₈ on the reaction. As the amount of K₂S₂O₈ increased, the corresponding yield also increased, and the yield reached a maximum when K₂S₂O₈ (3 equiv.) was used (entries 13–15). Besides, when the amount of KSCN was increased from 1 equiv. to 4 equiv., the corresponding yield was also increased, up to 93% (entries 16–18). When NH₄SCN was selected as the SCN reagent, the yield of 3a was reduced to 76% (entry 19). The temperature had a great effect on the reaction, and as the temperature increased, the yield decreased, mainly due to the formation of by-products (entries 20 and 21). Therefore, the optimal conditions for the reaction are 1a (1 equiv.), 2 (4 equiv.), K₂S₂O₈ (3 equiv.), and CH₃CN (2 mL) in a sealed tube at room temperature for 16 h (entry 18).

Table 1.

Optimization of reaction conditions.^a


Entry	[SCN] (equiv.)	Oxidant (equiv.)	Solvent	Yield (%)^b
1	KSCN (3)	PhI(OAc)₂ (3)	CH₃CN	28
2	KSCN (3)	DTBP (3)	CH₃CN	Trace
3	KSCN (3)	TBHP (3)	CH₃CN	12
4	KSCN (3)	DDQ (3)	CH₃CN	73
5	KSCN (3)	K₂S₂O₈ (3)	CH₃CN	87
6	KSCN (3)	O₂ (balloon)	CH₃CN	0
7	KSCN (3)	K₂S₂O₈ (3)	DMF	54
8	KSCN (3)	K₂S₂O₈ (3)	DMSO	31
9	KSCN (3)	K₂S₂O₈ (3)	CHCl₃	80
10	KSCN (3)	K₂S₂O₈ (3)	EtOH	9
11	KSCN (3)	K₂S₂O₈ (3)	Dioxane	45
12	KSCN (3)	K₂S₂O₈ (3)	Toluene	82
13	KSCN (3)	K₂S₂O₈ (1)	CH₃CN	54
14	KSCN (3)	K₂S₂O₈ (2)	CH₃CN	81
15	KSCN (3)	K₂S₂O₈ (4)	CH₃CN	87
16	KSCN (1)	K₂S₂O₈ (3)	CH₃CN	51
17	KSCN (2)	K₂S₂O₈ (3)	CH₃CN	70
18	KSCN (4)	K₂S₂O₈ (3)	CH₃CN	93
19	NH₄SCN (4)	K₂S₂O₈ (3)	CH₃CN	76
20^c	KSCN (4)	K₂S₂O₈ (3)	CH₃CN	85
21^d	KSCN (4)	K₂S₂O₈ (3)	CH₃CN	71

Reaction conditions: 1a (0.2 mmol), KSCN, oxidant, and solvent (2 mL) in a sealed tube at room temperature for 16 h.

Isolated yields based on 1a.

At 50 °C.

At 80 °C.

Bold figure represents the best conditions.

With the optimal conditions in hand, we then investigated the substrate scope of the transformation (Table 2). First, we screened the substituents on the aromatic ring of the 1-arylethanone moiety. For the substrates bearing electron-withdrawing substituents on the aromatic ring, including F–, Cl–, I–, CF3–, CN–, and NO₂– at the p-position, the protocol was applicable, and the corresponding products were obtained in moderate to good yields (3b–3g). In the cases of substrates having electron-withdrawing substituents at the m- or o-position, the desired products were also obtained in good yields (3h–3j). By comparing the yields of 3c, 3h, and 3j, it was deduced that steric effects have little effect on the reaction. For the substrates bearing electron-donating substituents such as methyl (1k and 1m) and methoxy (1l), these substituents were also tolerated under the reaction conditions.

Table 2.

Substrate scope for the reaction.^a,b.

Reaction conditions: 1 (0.2 mmol), 2 (0.8 mmol), K₂S₂O₈ (0.6 mmol), and CH₃CN (2 mL) in a sealed tube at room temperature for 16 h.

Isolated yields based on 1.

Moreover, we explored the reactivity of α-amino carbonyl compounds having substituents on the nitrogen atom. The reaction can proceed smoothly when other alkyl groups are attached to the nitrogen atom, such as ethyl, n-butyl, allyl, and benzyl (3o–3r). It is worth noting that the carbon–carbon double bond of allyl is not affected during the reaction (3q). For the substrate having an aromatic group at the nitrogen atom (3s), the method was successful and the corresponding product was obtained in moderate yield. Unfortunately, 1-phenyl-2-(phenylamino)ethan-1-one was not applicable to the reaction. When ethyl N-methyl-N-phenylglycinate (1t) and 2-(methyl(phenyl)amino) acetonitrile (1u) were chosen as the substrates, the corresponding products 3t and 3u were obtained in good yields, which further increased the scope of the reaction.

Furthermore, we found that arylamine thiocyanates can also be obtained from α-amino carbonyl compounds and KSCN. After screening, the catalyst system CoCl₂·6H₂O (10 mol%)/I₂ (2 equiv.)/DMSO was shown to be the best combination. Then, we investigated the substrate scope of this transformation (Table 3). For the carbonyl moiety, regardless of whether an electron-donating or electron-withdrawing group was attached to the benzene ring, the product 4a was obtained in moderate yields. For the amino moiety, when a substituent is attached to the ortho or meta position of the benzene ring, the target product can also be obtained in a moderate yield (4b–e). Unfortunately, as the alkyl chain on the nitrogen atom increases, the reaction efficiency decreases. When 2-(n-butyl(phenyl)amino)-1-phenylethan-1-one was used as the substrate, the target product 4g was only obtained in a low yield.

Table 3.

Substrate scope for the synthesis of arylamine thiocyanates.^a,b.

Reaction conditions: 1 (0.3 mmol), 2 (0.3 mmol), CoCl₂·6H₂O (10 mol%), I₂ (0.6 mmol), and DMSO (2 mL) in a sealed tube at 80 °C for 16 h.

Isolated yields based on 1.

To explore the reaction mechanism, several control experiments were carried out (Scheme 2). When the radical inhibitor TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was added to the reaction under the optimal conditions, the product 3a was obtained in 84% yield (Scheme 2A). When the radical inhibitor BHT (2,6-di-tert-butyl-4-methylphenol) was added, the yield of 3a was almost unaffected (Scheme 2B). These two results indicate that the reaction might not be a radical process and may involve an ionic pathway. Moreover, when compound 5 was chosen as the substrate instead of 1a, none of the products 3a or 6 were detected (Scheme 2C). When 3a was chosen as the substrate in the presence of CoCl₂·6H₂O, I₂, and DMSO, product 4a was obtained in 67% yield and benzoylformic acid was detected by gas chromatography–mass spectrometry (GC-MS; Scheme 2D).

Scheme 2.

Control experiments.

Based on these experimental results and previous reports,^52–60 a possible mechanism for the thiocyanation of α-amino carbonyl compounds is proposed (Scheme 3). Initially, ⁺SCN is formed from the KSCN by the oxidant and adds to the substrate 1a to afford intermediate I. The intermediate I is unstable and converts into the product 3a by losing a hydrogen ion. The product 4a was obtained from 3a under the conditions of cobalt catalyst, I₂, and DMSO.

Scheme 3.

Possible mechanism.

Conclusion

In conclusion, we have demonstrated a novel procedure for the synthesis of aromatic thiocyanates through K₂S₂O₈-mediated thiocyanation of α-amino carbonyl compounds. This strategy has the advantages of simple reaction conditions without the use of a transition-metal catalyst, high regioselectivity, and high efficiency. Moreover, arylamine thiocyanates can also be obtained from α-amino carbonyl compounds and potassium thiocyanate in the presence of cobalt catalyst, I₂, and DMSO through the cleavage of the C–N bond. These reactions expand further the use of α-amino carbonyl compounds in organic synthesis. Studies to gain insights into the reaction mechanism and application of the protocol for the synthesis of bioactive molecules are currently underway.

Experimental section

General information

Commercially available reagents were purchased from commercial suppliers and used without further purification. Reactions were monitored by thin-layer chromatography (TLC). Flash column chromatography was performed over silica gel (200–300 mesh). ¹H and ¹³C NMR spectra were recorded on a 400 MHz NMR plus spectrometer using residue solvent peaks as internal standards. High-resolution mass spectra were obtained using a GCT time of flight (TOF) instrument with the electron ionization (EI) source. Melting points are uncorrected.

General procedure for the synthesis of product 3

To a sealed tube were added α-amino carbonyl compound 1 (0.2 mmol), KSCN (0.8 mmol), K₂S₂O₈ (0.6 mmol), and CH₃CN (2 mL). Then, the tube was stirred at room temperature for 16 h. After completion of the reaction, the resulting mixture was concentrated in vacuo and purified by column chromatography on silica gel (petroleum ether/ethyl acetate) to afford the desired product 3.

2-(Methyl(4-thiocyanatophenyl)amino)-1-phenylethan-1-one (3a): White solid, 93% yield (52 mg), m.p. = 145–146 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J = 5.6 Hz, 2H), 7.62–7.66 (m, 1H), 7.50–7.53 (m, 2H), 7.39 (d, J = 7.2 Hz, 2H), 6.63 (d, J = 7.2 Hz, 2H), 4.83 (s, 2H), 3.13 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 195.0, 150.7, 134.9, 134.4, 133.9, 128.9, 127.7, 113.2, 112.3, 107.7, 58.4, 39.7; high resolution mass spectrometry (HRMS) (EI): m/z [M]⁺ calcd for C₁₆H₁₄N₂OS: 282.0822, found: 282.0824.

1-(4-Fluorophenyl)-2-(methyl(4-thiocyanatophenyl)amino)ethan-1-one (3b): White solid, 85% yield (51 mg), m.p. = 160–162 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.99–8.02 (m, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.16–7.20 (m, 2H), 6.62 (d, J = 6.8 Hz, 2H), 4.79 (s, 2H), 3.11 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 193.4, 166.0 (d, J = 203.7 Hz), 150.7, 134.3, 131.3 (d, J = 2.9 Hz), 130.4 (d, J = 7.2 Hz), 116.1 (d, J = 17.3 Hz), 113.2, 112.3, 107.7, 58.3, 39.6; HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₃FN₂OS: 300.0728, found: 300.0723.

1-(4-Chlorophenyl)-2-(methyl(4-thiocyanatophenyl)amino)ethan-1-one (3c): White solid, 83% yield (52 mg), m.p. = 156–157 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J = 7.2 Hz, 2H), 7.49 (d, J = 7.2 Hz, 2H), 7.39 (d, J = 6.8 Hz, 2H), 6.62 (d, J = 7.2 Hz, 2H), 4.78 (s, 2H), 3.11 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 193.9, 150.6, 140.4, 134.4, 133.2, 129.3, 129.1, 113.2, 112.3, 107.9, 58.4, 39.7; HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₃ClN₂OS: 316.0432, found: 316.0436.

1-(4-Iodophenyl)-2-(methyl(4-thiocyanatophenyl)amino)ethan-1-one (3d): White solid, 89% yield (72 mg), m.p. = 163–164 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 6.8 Hz, 2H), 7.67 (d, J = 6.4 Hz, 2H), 7.38 (d, J = 7.2 Hz, 2H), 6.61 (d, J = 6.8 Hz, 2H), 4.76 (s, 2H), 3.11 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 194.5, 150.6, 138.2, 134.4, 134.1, 129.0, 113.2, 112.3, 107.9, 102.0, 58.3, 39.6; HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₃IN₂OS:407.9788, found: 407.9789.

2-(Methyl(4-thiocyanatophenyl)amino)-1-(4-(trifluoromethyl)phenyl)ethan-1-one (3e): Light yellow solid, 86% yield (60 mg), m.p. = 143–144 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J = 6.0 Hz, 2H), 7.79 (d, J = 6.4 Hz, 2H), 7.40 (d, J = 7.2 Hz, 2H), 6.63 (d, J = 7.2 Hz, 2H), 4.84 (s, 2H), 3.13 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 194.4, 150.5, 137.5, 135.1 (q, J = 26.0 Hz), 134.4, 128.1, 126.0 (q, J = 2.9 Hz), 123.4 (q, J = 216.6 Hz), 113.3, 112.2, 108.2, 58.7, 39.7; HRMS (EI): m/z [M]⁺ calcd for C₁₇H₁₃F₃N₂OS: 350.0696, found: 350.0691.

4-(N-Methyl-N-(4-thiocyanatophenyl)glycyl)benzonitrile (3f): Yellow solid, 78% yield (48 mg), m.p. = 151–152 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J = 6.8 Hz, 2H), 7.82 (d, J = 6.4 Hz, 2H), 7.40 (d, J = 7.2 Hz, 2H), 6.62 (d, J = 7.6 Hz, 2H), 4.82 (s, 2H), 3.12 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 194.2, 150.4, 137.7, 134.4, 132.8, 128.2, 117.6, 117.1, 113.3, 112.2, 108.4, 58.8, 39.7; HRMS (EI): m/z [M]⁺ calcd for C₁₇H₁₃N₃OS: 307.0772, found: 307.0766.

2-(Methyl(4-thiocyanatophenyl)amino)-1-(4-nitrophenyl)ethan-1-one (3g): Yellow solid, 74% yield (48 mg), m.p. = 162–163 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J = 6.8 Hz, 2H), 8.12 (d, J = 7.2 Hz, 2H), 7.40 (d, J = 7.2 Hz, 2H), 6.63 (d, J = 7.2 Hz, 2H), 4.85 (s, 2H), 3.13 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 194.1, 150.6, 150.4, 139.2, 134.4, 128.9, 124.1, 113.3, 112.2, 108.4, 58.9, 39.7; HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₃N₃O₃S: 327.0673, found: 327.0670.

1-(3-Chlorophenyl)-2-(methyl(4-thiocyanatophenyl)amino)ethan-1-one (3h): White solid, 89% yield (56 mg), m.p. = 127–128 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.93 (t, J = 1.2 Hz, 1H), 7.85–7.83 (m, 1H), 7.61–7.59 (m, 1H), 7.46 (t, J = 6.4 Hz, 1H), 7.38 (d, J = 7.2 Hz, 2H), 6.61 (d, J = 7.6 Hz, 2H), 4.79 (s, 2H), 3.11 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 193.9, 150.5, 136.3, 135.2, 134.3, 133.8, 130.2, 127.8, 125.7, 113.2, 112.3, 107.9, 58.5, 39.6; HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₃ClN₂OS: 316.0432, found: 316.0433.

1-(3-Bromophenyl)-2-(methyl(4-thiocyanatophenyl)amino)ethan-1-one (3i): White solid, 90% yield (65 mg), m.p. = 138–139 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.08 (t, J = 1.2 Hz, 1H), 7.88–7.89 (m, 1H), 7.74–7.76 (m, 1H), 7.37–7.41 (m, 3H), 6.61 (d, J = 7.6 Hz, 2H), 4.78 (s, 2H), 3.11 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 193.9, 150.5, 136.7, 136.5, 134.3, 130.8, 130.5, 126.2, 123.2, 113.2, 112.3, 107.9, 58.5, 39.6; HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₃BrN₂OS: 359.9927, found: 359.9921.

1-(2-Chlorophenyl)-2-(methyl(4-thiocyanatophenyl)amino)ethan-1-one (3j): White solid, 82% yield (52 mg), m.p. = 108–109 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.44–7.47 (m, 3H), 7.40 (d, J = 7.2 Hz, 2H), 7.33–7.37 (m, 1H), 6.65 (d, J = 7.6 Hz, 2H), 4.72 (s, 2H), 3.10 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 199.2, 150.4, 137.2, 134.3, 132.5, 130.9, 130.5, 129.1, 127.2, 113.2, 112.3, 107.9, 61.9, 39.6; HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₃ClN₂OS: 316.0432, found: 316.0430.

2-(Methyl(4-thiocyanatophenyl)amino)-1-(p-tolyl)ethan-1-one (3k): White solid, 88% yield (52 mg), m.p. = 131–133 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 6.4 Hz, 2H), 7.37 (d, J = 7.2 Hz, 2H), 7.31 (d, J = 6.4 Hz, 2H), 6.62 (d, J = 7.2 Hz, 2H), 4.79 (s, 2H), 3.11 (s, 3H), 2.44 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 194.5, 150.8, 144.8, 134.3, 132.4, 129.5, 127.8, 113.1, 112.3, 107.3, 58.2, 39.6, 21.6; HRMS (EI): m/z [M]⁺ calcd for C₁₇H₁₆N₂OS: 296.0978, found: 296.0975.

1-(4-Methoxyphenyl)-2-(methyl(4-thiocyanatophenyl)amino)ethan-1-one (3l): White solid, 75% yield (47 mg), m.p. = 125–126 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 4.77 (s, 2H), 3.89 (s, 3H), 3.11 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 193.4, 164.0, 150.8, 134.3, 130.0, 127.9, 114.0, 113.1, 112.4, 107.3, 58.0, 55.5, 39.7; HRMS (EI): m/z [M]⁺ calcd for C₁₇H₁₆N₂O₂S: 312.0927, found: 312.0926.

2-(Methyl(4-thiocyanatophenyl)amino)-1-(m-tolyl)ethan-1-one (3m): White solid, 86% yield (51 mg), m.p. = 107–109 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 6.0 Hz, 1H), 7.37–7.41 (m, 3H), 6.62 (d, J = 6.8 Hz, 2H), 4.81 (s, 2H), 3.12 (s, 3H), 2.43 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 195.1, 150.8, 138.8, 134.9, 134.6, 134.4, 128.7, 128.2, 124.8, 113.1, 112.4, 107.4, 58.4, 39.6, 21.3; HRMS (EI): m/z [M]⁺ calcd for C₁₇H₁₆N₂OS: 296.0978, found: 296.0976.

2-(Methyl(4-thiocyanatophenyl)amino)-1-(naphthalen-2-yl)ethan-1-one (3n): White solid, 76% yield (50 mg), m.p. = 128–129 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 7.90–8.02 (m 4H), 7.63–7.67 (m, 1H), 7.58–7.61 (m, 1H), 7.40 (d, J = 6.8 Hz, 2H), 6.67 (d, J = 7.6 Hz, 2H), 4.97 (s, 2H), 3.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 195.0, 150.8, 135.8, 134.4, 132.4, 132.2, 129.5, 129.4, 128.9, 127.9, 127.1, 123.3, 113.2, 112.4, 107.7, 58.5, 39.7; HRMS (EI): m/z [M]⁺ calcd for C₂₀H₁₆N₂OS: 332.0978, found: 332.0974.

2-(Ethyl(4-thiocyanatophenyl)amino)-1-phenylethan-1-one (3o): White solid, 80% yield (47 mg), m.p. = 134–135 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.99–8.01 (m 2H), 7.62–7.66 (m, 1H), 7.51–7.54 (m, 2H), 7.37 (d, J = 7.2 Hz, 2H), 6.57 (d, J = 7.6 Hz, 2H), 4.79 (s, 2H), 3.50 (q, J = 5.6 Hz, 2H), 1.24 (t, J = 5.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 194.9, 149.6, 134.9, 134.6, 133.8, 128.9, 127.7, 113.0, 112.4, 107.0, 56.4, 46.4, 12.2; HRMS (EI): m/z [M]⁺ calcd for C₁₇H₁₆N₂OS: 296.0978, found: 296.0973.

2-(Butyl(4-thiocyanatophenyl)amino)-1-phenylethan-1-one (3p): Light yellow solid, 84% yield (54 mg), m.p. = 87–88 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.99–8.01 (m 2H), 7.62–7.66 (m, 1H), 7.50–7.53 (m, 2H), 7.35 (d, J = 7.2 Hz, 2H), 6.56 (d, J = 7.2 Hz, 2H), 4.80 (s, 2H), 3.41 (t, J = 6.4 Hz, 2H), 1.61–1.68 (m, 2H), 1.34–1.42 (m, 2H), 0.97 (t, J = 6.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 194.8, 149.9, 134.8, 134.5, 133.8, 128.8, 127.7, 112.9, 112.4, 106.7, 56.8, 52.0, 29.3, 20.1, 13.8; HRMS (EI): m/z [M]⁺ calcd for C₁₉H₂₀N₂OS: 324.1296, found: 324.1291.

2-(Allyl(4-thiocyanatophenyl)amino)-1-phenylethan-1-one (3q): Light yellow solid, 85% yield (52 mg), m.p. = 73–75 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.99–8.01 (m 2H), 7.62–7.66 (m, 1H), 7.50–7.53 (m, 2H), 7.36 (d, J = 6.8 Hz, 2H), 6.59 (d, J = 7.2 Hz, 2H), 5.85–5.92 (m, 1H), 5.21–5.26 (m, 2H), 4.80 (s, 2H), 4.04–4.06 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 194.9, 150.1, 134.8, 134.3, 133.9, 132.7, 128.9, 127.7, 116.7, 113.4, 112.3, 107.6, 56.3, 54.3; HRMS (EI): m/z [M]⁺ calcd for C₁₈H₁₆N₂OS: 308.0978, found: 308.0982.

2-(Benzyl(4-thiocyanatophenyl)amino)-1-phenylethan-1-one (3r): Light yellow solid, 75% yield (54 mg), m.p. = 80–81 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.97–7.99 (m 2H), 7.63–7.66 (m, 1H), 7.50–7.53 (m, 2H), 7.34–7.38 (m, 4H), 7.27–7.31 (m, 3H), 6.63 (d, J = 7.2 Hz, 2H), 4.87 (s, 2H), 4.69 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 195.0, 150.8, 135.8, 134.4, 132.4, 132.2, 129.5, 129.4, 128.9, 127.9, 127.1, 123.3, 113.2, 112.4, 107.7, 58.5, 39.7; HRMS (EI): m/z [M]⁺ calcd for C₂₂H₁₈N₂OS: 358.1135, found: 358.1132.

2-(Methyl(3-methyl-4-thiocyanatophenyl)amino)-1-phenylethan-1-one (3s): White solid, 78% yield (46 mg), m.p. = 146–147 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.97–7.99 (m 2H), 7.62–7.66 (m, 1H), 7.50–7.53 (m, 2H), 7.39 (d, J = 6.8 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 6.47 (dd, J = 2.4, 6.8 Hz, 1H), 4.82 (s, 2H), 3.11 (s, 3H), 2.47 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 195.1, 151.3, 142.7, 136.0, 134.9, 133.8, 128.9, 127.7, 114.3, 111.9, 110.9, 107.4, 58.4, 39.6, 21.4; HRMS (EI): m/z [M]⁺ calcd for C₁₇H₁₆N₂OS: 296.0978, found: 296.0975.

Ethyl N-methyl-N-(4-thiocyanatophenyl)glycinate (3t): White solid, 83% yield (42 mg), m.p. = 78–79 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.42 (d, J = 7.6 Hz, 2H), 6.66 (d, J = 7.6 Hz, 2H), 4.18 (q, J = 6.0 Hz, 2H), 4.06 (s, 2H), 3.08 (s, 3H), 1.25 (t, J = 6.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.9, 150.4, 134.3, 113.2, 112.2, 108.1, 61.1, 54.0, 39.5, 14.1; HRMS (EI): m/z [M]⁺ calcd for C₁₂H₁₄N₂O₂S: 250.0771, found: 250.0776.

2-(Methyl(4-thiocyanatophenyl)amino)acetonitrile (3u): White solid, 86% yield (35 mg), m.p. = 120–122 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 4.22 (s, 2H), 3.07 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 149.0, 133.8, 115.2, 114.9, 112.1, 111.6, 41.4, 39.1; HRMS (EI): m/z [M]⁺ calcd for C₁₀H₉N₃S: 203.0512, found: 203.0511.

General procedure for the synthesis of product 4

To a sealed tube were added α-amino carbonyl compound 1 (0.3 mmol), KSCN (0.3 mmol), CoCl₂·6H₂O (10 mol%), I₂ (0.6 mmol), and DMSO (2 mL). Then, the tube was stirred at 80 °C for 16 h. After completion of the reaction, a Na₂S₂O₃ solution was added, and the resulting mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na₂SO₄, and concentrated in vacuo. The resulting mixture was purified by column chromatography on silica gel (petroleum ether/ethyl acetate) to afford the desired product 4.

N-Methyl-4-thiocyanatoaniline (4a):^52,54 Light yellow oil, 76% yield (37 mg); ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, J = 6.8 Hz, 2H), 6.58 (d, J = 7.2 Hz, 2H), 4.09 (s, 1H), 2.85 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 151.0, 134.7, 113.3, 112.6, 107.4, 30.2.

N,3-Dimethyl-4-thiocyanatoaniline (4b): Light yellow solid, 70% yield (37 mg), m.p. = 48–49 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, J = 7.2 Hz, 1H), 6.50 (d, J = 1.6 Hz, 1H), 6.43–6.41 (m, 1H), 4.03 (s, 1H), 2.83 (s, 3H), 2.48 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 151.6, 142.9, 136.3, 114.4, 112.2, 111.0, 107.1, 30.1, 21.1; HRMS (EI): m/z [M]⁺ calcd for C₉H₁₀N₂S: 178.0560, found: 178.0557.

3-Chloro-N-methyl-4-thiocyanatoaniline (4c): White solid, 67% yield (40 mg), m.p. = 57–59 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.42 (d, J = 6.8 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 6.48–6.46 (m, 1H), 4.27 (s, 1H), 2.82 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 152.0, 138.2, 135.4, 113.0, 112.1, 111.2, 106.1, 30.0; HRMS (EI): m/z [M]⁺ calcd for C₈H₇ClN₂S:198.0013, found:198.0011.

N,2-dimethyl-4-thiocyanatoaniline (4d): Light yellow solid, 68% yield (36 mg), m.p. = 51–52 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.36–7.34 (m, 1H),7.26–7.25 (m, 1H), 6.56 (d, J = 6.8 Hz, 1H), 3.91 (s, 1H), 2.90 (s, 3H), 2.11 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 149.1, 134.5, 132.8, 123.5, 112.7, 109.8, 106.9, 30.3, 17.1; HRMS (EI): m/z [M]⁺ calcd for C₉H₁₀N₂S: 178.0560, found: 178.0556.

2-Chloro-N-methyl-4-thiocyanatoaniline (4e): White solid, 53% yield (31 mg), m.p. = 52–53 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J = 2.0 Hz, 1H), 7.39–7.37 (m, 1H), 6.62 (d, J = 7.2 Hz, 1H), 4.70 (s, 1H), 2.92 (d, J = 3.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 146.8, 133.4, 133.3, 119.5, 111.8, 111.1, 107.4, 30.0; HRMS (EI): m/z [M]⁺ calcd for C₈H₇ClN₂S: 198.0013, found: 198.0011.

N-Ethyl-4-thiocyanatoaniline (4f):⁵² White solid, 36% yield (19 mg), m.p. = 55–56 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J = 6.8 Hz, 2H), 6.57 (d, J = 6.8 Hz, 2H), 3.97 (s, 1H), 3.16 (q, J = 5.6 Hz, 2H), 1.26 (t, J = 5.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 150.2, 134.7, 113.5, 112.6, 107.2, 37.9, 14.4.

Supplemental Material

Supporting_information_1 – Supplemental material for Thiocyanation of α-amino carbonyl compounds for the synthesis of aromatic thiocyanates

Supplemental material, Supporting_information_1 for Thiocyanation of α-amino carbonyl compounds for the synthesis of aromatic thiocyanates by Niannian Yi, Mingjing Ouyang, Huimin Liu, Miao Yan, Xiaoyong Wen, Yi Xiong and Bing Yi in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this paper.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this paper: This work was supported by the National Natural Science Foundation of China (No. 21772035) and the Provincial Natural Science Foundation of Hunan (No. 2019JJ50104).

ORCID iD

Niannian Yi

Supplemental material

Supplemental material for this article is available online.

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