Trifluoroacetic acid catalyzed thiophenylmethylation and thioalkylmethylation of lactams and phenols via domino three-component reaction in water

Abstract

An efficient one-pot trifluoroacetic acid catalyzed thiophenylmethylation and thioalkylmethylation of lactams, isatins and phenols via domino three-component coupling (3CC) with thiols and formaldehyde in water has been described. The developed protocol has wide substrate-scope for a variety of thiols, lactams and isatins. Utility of the protocol for ortho-/para-thiophenylmethylation of phenols indicated that reaction proceeds through in situ formation of a thiophenylmethylium cation intermediate. LC-ESIMS-based mechanistic investigation further confirmed formation of this intermediate. For isatins, the N- versus O-thiophenylmethylation was confirmed by recording the X-ray crystal structure of compound 4e. Thionaphthyl analog 3e exhibited significant antiproliferative activity in MCF-7 cells (IC₅₀ 8 μM) via apoptosis-induction.

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Introduction

Thiols are common building blocks in organic chemistry,¹ and play important roles in biological processes and are also used in cell imaging and protein labelling.² The thiophenylmethylation reaction finds wide utility in organic chemistry and in the total synthesis of natural products.³ Available protocols^3,4 involve use of organic solvents, and also the substrate-scope for these protocols has not been established.

The three-component coupling (3CC) of phenols with formaldehyde and styrene produced flavans 1 via [4 + 2]-Diels–Alder cycloaddition of in situ generated ortho-quinone methide with styrene.⁵ Further, the 3CC of phenols with formaldehyde and lactam gave amidoalkyl products 2 through Mannich-type condensation.⁶ As a continuation of these results, herein we investigated the reactivity of thiophenols in these 3CC reactions. This resulted in development of simple and efficient trifluoroacetic acid catalyzed one-pot protocol for thiophenylmethylation and thioalkylmethylation of lactams, isatins and phenols (Fig. 1). With the advances in green chemistry, development of reactions in aqueous media is gaining tremendous importance.⁷ The present protocol involves use of water as a reaction medium containing 0.1% TFA as a catalyst.

Fig. 1 Our previous work on phenols (reaction of phenols with formaldehyde and styrene/vinyl lactams) and the present work on thiols.

Results and discussion

The present study was initiated with the reaction of thiophenol 5a with formaldehyde 6 and N-vinyl caprolactam 7 in presence of 50% w/w silica–HClO₄ (Table 1, entry 1). In this reaction, thiophenylmethylated lactam 3a was formed and not the ortho-amidoalkyl product, as it was formed with phenols.⁶ Similar to our earlier reports,^6,8 it was noticed that the formation of product 3a proceeds via acid and heat mediated devinylation of N-vinyl lactam 7, which is followed by the 3CC of lactam with thiol 5a and formaldehyde 6. The preference of 3CC on SH-functionality over ortho-CH demonstrates higher nucleophilicity of SH- group than ortho-CH position in this reaction.

Table 1 Solvent and catalyst optimization studies^a

Entry	Reaction medium	Temp. (°C)	Time (h)	%Yield^b of 3a
a Reagents and conditions: thiol 5a (1.0 mmol), N-vinyl lactam 7 (1.2 mmol), formaldehyde 6 (3.0 mmol).b Isolated yield.c Optimized reaction condition.
1	50 mol% w/w silica–HClO4 in ACN	80	8	60
2	10 mol% AcOH	80	6	10
3	10 mol% HCOOH	80	6	30
4	10 mol% TFA	80	2	80
5	10% TFA in water	80	2	80
6	10% TFA in water	rt	1	0
7	10% TFA in water	rt	12	0
8	1% TFA in water	80	2	80
9	0.1% TFA in water	80	2	80
10	0.1% TFA in water	80	1	78
11^c	0.1% TFA in water	80	0.5	76
12	Water	80	24	0
13	Dioxane	80	12	0

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Next, the catalyst and solvent optimization study was carried out. The silica–HClO₄ catalyst produced 60% yield of product 3a in ACN; however no improvements in reaction yield was observed when further solvent optimization was carried out using other solvents such as DCM, MeOH and DMF. Next, the reaction in acetic acid and formic acid was investigated, which produced poor yields (10 and 30%, respectively) of product 3a (entries 2 and 3). In the presence of 10 mol% TFA, reaction moved efficiently producing 80% of the product (entry 4). Next, we attempted to use water as a reaction medium for this reaction. The use of 10% TFA in water produced 3a in excellent yield (entry 5). Further optimization of the TFA amount and reaction time (entries 5–11) indicated that 0.1% TFA in water at 80 °C for 30 min was able to produce desired product in good yield (entry 11). Continuation of reaction for additional time (entries 9 and 10) does not let to significant improvement in product yield. Thus, entry 11 was considered as optimized reaction condition. When the reaction was performed only in water, no product was formed (entry 12). As reported by Abdel-Ghany and coworkers,^4a we attempted this 3CC reaction in dioxane as a solvent without addition of any catalyst; however no product was formed (entry 13). When this reaction was carried out using lactam instead of N-vinyl lactam using optimized reaction conditions (entry 11), similar results were obtained. Since N-vinyl lactam undergoes acid and heat-mediated devinylation to produce lactam, which participates in thiophenylmethylation reaction, all further investigations were performed using lactams.

As the reaction also proceeded without water as a medium, it is clear that water only acts a reaction medium and do not participate in reaction mechanism.

The scope of this 3CC protocol was investigated for variety of aromatic and aliphatic thiols and various lactams. Results are shown in Fig. 2. The reaction proceeded smoothly with both aromatic as well as aliphatic thiols, producing 64–90% yields of thiophenyl/thioalkyl methylated products.

Fig. 2 Thiophenylmethylation and thioalkylmethylation of lactams (reaction time and yields are mentioned in the parentheses). Reagents and conditions: thiol 5 (1.0 mmol), lactam 8 (1.2 mmol), formaldehyde 6 (3.0 mmol), 0.1% TFA in water, 80 °C, 0.5–1 h.

The substitution of various electron-donating (3b, 3c, 3g, and 3h) as well as electron-withdrawing groups (3d, 3i, and 3n) on thiophenol was also well tolerated. Furthermore, the thionaphthol also participated well in this reaction producing corresponding thiophenylmethylated products in excellent yields (products 3e, 3j and 3o).

In case of lactams as well as isatins, there are two possible positions for alkylation. For lactams, it was possible to differentiate N- versus O-alkylation simply by checking the presence or absence of amidic carbonyl (–N–CO–) stretching frequency in IR spectrum. All alkylated products of lactams showed presence of stretching frequency of ∼1650 cm⁻¹ in IR spectrum indicating N-alkylation. Further, this observation was supported by ¹H and ¹³C NMR data.

Next we investigated the 3CC reaction of thiophenols 5 and formaldehyde 6 with isatins 9 as nucleophiles. Like lactams and N-vinyl lactams, the thiophenylmethylated isatins 4a–e were formed in excellent yields (Fig. 3). In this case, two possible positions for alkylation cannot be differentiated only with IR data as products contain additional –C=O group. Further, both possible products have similar expected NMR values. Thus, in order to confirm the structure of the obtained products, X-ray crystallography study for one of the analog 4e was carried out. The molecular conformation of 4e in crystals is shown in Fig. 4.

Fig. 3 Thiophenylmethylation of isatins. Reagents and conditions: thiol 5 (1.0 mmol), formaldehyde 6 (3.0 mmol), isatin 9 (1.2 mmol), 0.1% TFA in water, 80 °C, 15 min.

Fig. 4 The molecular conformation of 4e in crystals.

Next, the reactivity of thiophenol 5c with formaldehyde 6 and styrene 10 in presence of 50 mol% silica–HClO₄ was investigated. The silica–HClO₄ catalyst was chosen for this reaction, in order to follow the exactly same protocol as we reported earlier for phenols.⁵ The expected styrene-linked product 12 was not formed; instead a thiophenol dimer 11 was produced. The formation of thiophenol dimer 11 occurred presumably via formation of thiophenylmethylium cation intermediate I. The styrene 10 has not participated and not played any role in this reaction, which was further confirmed by performing control reaction (reaction in the absence of styrene 10). When this 3CC reaction was performed in presence of 0.1% TFA in water, it also led to formation of product 11 and not the thioflavan 12 (Fig. 5). This finding further suggested that nucleophilicity of SH is higher than ortho-CH.

Fig. 5 The 3CC reaction of thiophenol with formaldehyde and styrene. Reagents and conditions: thiophenol 5c (1.0 mmol), formaldehyde 6 (3.0 mmol), styrene 10 (1.2 mmol) and 50 mol% silica–HClO₄ in ACN was heated at 80 °C for 4 h. Similar results were observed when 0.1% TFA in water was used instead of silica–HClO₄ in ACN.

Further, in order to support the formation of intermediate I, and also to investigate the scope of this protocol for thiophenylmethylation of –CH activated phenols, the reaction of thiophenols with formaldehyde 6 and o-cresol 13 was studied. In this reaction, a pair of two products were formed, one with para-substituted o-cresols 14aa–14ba and other with ortho-/para-disubstituted o-cresols 14ab–14bb, the former being a major product. The occurrence of thiophenylmethylation at 4, 6-positions of o-cresol, indicates that the reaction sequence should be involving formation of thiophenylmethylium cation I, followed by subsequent electrophilic substitution on o-cresol at 4,6-positions (Fig. 6).

Fig. 6 Thiophenylmethylation of phenols. Reagents and conditions: thiophenol 5 (1.0 mmol) and formaldehyde 6 (3.0 mmol), o-cresol 13 (1.2 mmol), 0.1% TFA in water, 80 °C, 4 h.

Next, in order to confirm the formation of thiophenylmethylium cation I intermediate, the reaction between 4-methoxy thiophenol, formaldehyde and caprolactam was monitored by LC-ESIMS. The proposed mechanism for formation of N-thiophenylmethylated product 3c is depicted in Fig. 7b. The LCMS spectra depicted in Fig. 7a showed formation of thiophenylmethylium cation I with m/z 153 [M]⁺ at t_R 13.3 min, which eventually led to formation of product 3c (m/z 266 [M + H]⁺ at t_R 21.5 min). Apart from these peaks, LCMS analysis also indicated formation of lactam dimer 16 (m/z 239 [M + H]⁺ at 11.5 min), and interestingly an ortho-thioquinone methide II (m/z 153 [M + H]⁺ at 15.7 min), which further produced ortho-amidoalkyated product 15 (m/z 266 [M + H]⁺ at 20.9 min). The product 15 was formed in very minor amount, and thus could not be isolated. In order to rule out the possibility of formation of I through hydrolysis of product 3c, the HPLC analysis of the reaction mixture at different time intervals was carried out. The HPLC analysis (Fig. 7a insets) performed at 2 min, showed 41 : 42 ratio of I: 3c, which was further changed to 11 : 78 ratio at 30 min, indicating that the thiophenylmethylium cation I has been formed immediately after mixing reactants as an intermediate and not through the hydrolysis of product 3c. Further, we checked the stability⁹ of representative products 3h and 4a in LCMS mobile phase (0.1% formic acid in water; and acetonitrile) as well as in biological fluids (PBS, SGF and SIF) and both compounds were found to be stable after incubation at 37 °C for 30 min (see Section S8 of ESI‡).

Fig. 7 LC-ESIMS analysis to investigate the mechanism for thiophenylmethylation of lactam. (a) TIC chromatogram of crude reaction mixture recorded after 2 min of reaction time (insets: HPLC chromatogram of reaction mixture recorded at 2 and 30 min, respectively; UV 240 nm). (b) Scheme depicting various formation of various intermediates and products (c–h) MS spectrum of peaks eluted at t_R 3.8, 11.5, 13.3, 15.7, 20.9 and 21.5 min.

Based on the literature precedence on anticancer potential for this class of compounds,^4b all synthesized compounds were screened for cytotoxicity against a panel of cancer cell lines (results shown in ESI: Table S1‡). Analog 3e displayed cytotoxicity against MCF-7 cells with IC₅₀ value of 8 μM. The mechanistic investigation of compound 3e for cell cycle phase distribution, mitochondrial membrane potential (MMP) loss, and effect on apoptotic body formation in MCF-7 cells, revealed that the compound exhibits antiproliferative activity via MMP loss and induction of apoptosis in MCF-7 cells (see, ESI: Section S5‡).

Conclusion

In summary, results presented here indicated that phenols and thiophenols react differently via different intermediates and gives different types of products. The simple and efficient TFA-catalyzed protocol for thiophenylmethylation and thioalkylmethylation of lactams and phenols in aqueous medium has been described. The developed protocol has several advantages such as metal-free conditions, aqueous medium and broad substrate scope. Further, the LCMS-based mechanistic studies suggested that reaction proceeds through thiophenylmethylium cation intermediate. The naphthyl analog 3e displayed promising cytotoxic activity and induced apoptosis in breast cancer MCF-7 cells.

Experimental section

General information

All chemicals were obtained from Sigma-Aldrich Company and used as received. ¹H, ¹³C and DEPT NMR spectra were recorded on Brucker-Avance DPX FT-NMR 500 and 400 MHz instruments. Chemical data for protons are reported in parts per million (ppm) downfield from tetramethylsilane and are referenced to the residual proton in the NMR solvent (CDCl₃, 7.26 ppm). Carbon nuclear magnetic resonance spectra (¹³C NMR) were recorded at 125 MHz or 100 MHz: chemical data for carbons are reported in parts per million (ppm, δ scale) downfield from tetramethylsilane and are referenced to the carbon resonance of the solvent (CDCl₃, 77 ppm). ESIMS and HRMS spectra were recorded on Agilent 1100 LC-Q-TOF and HRMS-6540-UHD machines. IR spectra were recorded on Perkin-Elmer IR spectrophotometer. Melting points were recorded on digital melting point apparatus. LC-ESIMS analysis was carried out on Triple-Quad LC-MS/MS system (model 6410).

General procedure for thiophenyl/thioalkyl methylation of lactams and isatins

To the solution of substituted thiol (5a, 300 mg) in 0.1% TFA in water (5 mL) were added formaldehyde (6, 3 equiv.) and lactam (8, 1.2 mmol)/N-vinyl lactam (7, 1.2 mmol)/isatins (9, 1.2 mmol). The resulting reaction mixture was then refluxed at 80 °C for 15–60 min. Completion of the reaction was monitored by TLC (20% EtOAc in n-hexane). Reaction mixture was cooled to room temperature and was neutralized with saturated NaHCO₃ solution and extracted with with EtOAc (50 mL × 2). Combined organic layers were dried over anhydrous sodium sulphate and evaporated on vacuo rotavapor to get crude product. Crude products were purified by silica gel column chromatography using EtOAc: hexane to get amido alkylated products.

1-((Phenylthio)methyl)azepan-2-one (3a). Yield: 80%; light yellow oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.47 (d, J = 8.0 Hz, 2H), 7.32 (dd, J = 8.8 Hz, 2H), 7.24 (dd, J = 4, 4 Hz, 1H), 4.93 (s, 2H), 3.40 (t, J = 4.0 Hz, 2H), 2.49 (t, J = 4.0 Hz, 2H), 1.66–1.56 (m, 6H); ¹³C NMR (CDCl₃, 125 MHz): δ 176.0, 134.0, 130.8, 128.9, 126.9, 51.6, 48.7, 37.2, 29.8, 28.3, 23.2; IR (CHCl₃): ν_max 3308, 2927, 2854, 1726, 1648, 1478, 1439, 1419, 1257, 1083, 1025 cm⁻¹; ESIMS: m/z 236.1 [M + H]; HR-ESIMS: m/z 236.1102 calcd for C₁₃H₁₇NOS + H⁺ (236.1103).

1-((p-Tolylthio)methyl)azepan-2-one (3b). Yield: 82%; light yellow oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.33 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 4.83 (s, 2H), 3.34 (t, J = 8.0 Hz, 2H), 2.44 (t, J = 4.0 Hz, 2H), 2.28 (s, 3H), 1.62–1.53 (m, 6H); ¹³C NMR (CDCl₃, 125 MHz): δ 175.8, 137.0, 131.5, 130.3, 129.7, 52.3, 48.8, 37.1, 29.8, 28.4, 23.2, 21.0; IR (CHCl₃): ν_max 3435, 2927, 2855, 1649, 1492, 1476, 1442, 1419, 1351, 1336, 1256, 1228, 1191, 1138, 1089, 1042 cm⁻¹; ESI-MS: m/z 249.0 [M − H]⁻; HR-ESIMS: m/z 250.1264 calcd for C₁₄H₁₉NOS + H⁺ (250.1260).

1-((4-Methoxyphenylthio)methyl)azepan-2-one (3c). Yield: 88%; colorless oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.41 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 12.0 Hz, 2H), 4.79 (s, 2H), 3.77 (s, 3H), 3.35 (t, J = 4.0 Hz, 2H), 2.45 (t, J = 4.0 Hz, 2H), 1.65–1.56 (m, 6H); ¹³C NMR (CDCl₃, 125 MHz): δ 175.9, 159.4, 134.3, 124.2, 114.6, 55.2, 53.4, 49.1, 37.1, 29.8, 28.4, 23.3; IR (CHCl₃): ν_max 3849, 3740, 3684, 3665, 3308, 2927, 2854, 1726, 1648, 1591, 1493, 1442, 1419, 1284, 1244, 1191, 1029 cm⁻¹; ESI-MS: m/z 266.0 [M + H]⁺, 288.0 [M + Na]⁺; HR-ESIMS: m/z 266.1209 calcd for C₁₄H₁₉NO₂S + H⁺ (266.1209).

1-((4-Chlorophenylthio)methyl)azepan-2-one (3d). Yield: 78%; light yellow oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.32 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 4.82 (s, 2H), 3.32 (t, J = 4.0 Hz, 2H), 2.41 (t, J = 4.0 Hz, 2H), 1.58–1.48 (m, 6H); ¹³C NMR (CDCl₃, 125 MHz): δ 176.0, 133.0, 132.5, 132.0, 129.3, 51.6, 48.7, 37.2, 29.8, 28.4, 23.3; IR (CHCl₃): ν_max 3434, 2929, 2854, 1649, 1477, 1442, 1419, 1352, 1256, 1229, 1191, 1138, 1094, 1042, 1011 cm⁻¹; ESI-MS: m/z 270.0 [M + H]⁺; HR-ESIMS: m/z 270.071 calcd for C₁₃H₁₆ClNOS + H⁺ (270.0713).

1-((Naphthalen-6-ylthio)methyl)azepan-2-one (3e). Yield: 90%; brown oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.91 (s, 1H), 7.79 (m, 3H), 7.53–7.43 (m, 3H), 5.01 (s, 2H), 3.40 (t, J = 4.0 Hz, 2H), 2.48 (t, J = 4.0 Hz, 2H), 1.61–1.52 (m, 6H); ¹³C NMR (CDCl₃, 100 MHz): δ 176.0, 133.7, 132.1, 131.6, 129.1, 128.5, 128.1, 127.7, 127.4, 126.5, 126.0, 51.5, 48.8, 37.2, 29.8, 28.4, 23.2; IR (CHCl₃): ν_max 3308, 3049, 2927, 2853, 1726, 1647, 1500, 1478, 1442, 1418, 1351, 1257, 1132, 1073, 1041 cm⁻¹; ESI-MS: m/z 286.1 [M + H]⁺, 308.1 [M + Na]⁺; HR-ESIMS: m/z 286.1248 calcd for C₁₇H₁₉NOS + H⁺ (286.1260).

1-((Phenylthio)methyl)piperidin-2-one (3f). Yield: 80%; brown oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.47 (d, J = 8.0 Hz, 2H), 7.28–7.20 (m, 3H), 4.86 (s, 2H), 3.29 (t, J = 4.0 Hz, 2H), 2.28 (t, J = 4.0 Hz, 2H), 1.70–1.65 (m, 4H); ¹³C NMR (CDCl₃, 125 MHz): δ 169.6, 134.0, 131.3, 128.7, 127.0, 50.7, 46.7, 32.1, 22.7, 20.9; IR (CHCl₃): ν_max 3793, 3700, 3308, 2945, 2865, 1726, 1644, 1485, 1463, 1439, 1414, 1348, 1330, 1245, 1172, 1087, 1024 cm⁻¹; ESI-MS: m/z 222.0 [M + H]⁺; HR-ESIMS: m/z 222.0948 calcd for C₁₂H₁₅NOS + H⁺ (222.0947).

1-((p-Tolylthio)methyl)piperidin-2-one (3g). Yield: 82%; light yellow oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.37 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 4.82 (s, 2H), 3.33 (t, J = 4.0 Hz, 2H), 2.30 (m, 5H), 1.73 (m, 4H); ¹³C NMR (CDCl₃, 125 MHz): δ 176.0, 137.5, 132.2, 130.2, 129.7, 51.6, 46.9, 32.2, 22.9, 21.14, 21.10; IR (CHCl₃): ν_max 3435, 2944, 2866, 1647, 1488, 1462, 1443, 1415, 1348, 1330, 1282, 1245, 1171, 1089, 1043 cm⁻¹; ESI-MS: m/z 236.1 [M + H]⁺; HR-ESIMS: m/z 236.1109 calcd for C₁₃H₁₇NOS + H⁺ (236.1103).

1-((4-Methoxyphenylthio)methyl)piperidin-2-one (3h). Yield: 84%; light brown oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.42 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 4.75 (s, 2H), 3.78 (s, 3H), 3.33 (t, J = 4.0 Hz, 2H), 2.29 (t, J = 4.0 Hz, 2H), 1.74 (m, 4H); ¹³C NMR (CDCl₃, 125 MHz): δ 169.8, 159.6, 135.0, 124.1, 114.5, 55.2, 52.4, 47.0, 32.2, 22.9, 21.1; IR (CHCl₃): ν_max 3790, 3435, 2943, 2868, 1726, 1644, 1591, 1570, 1493, 1463, 1443, 1415, 1349, 1331, 1285, 1244, 1171, 1092, 1028 cm⁻¹; ESI-MS: m/z 252.1 [M + H]⁺; HR-ESIMS: m/z 252.1057 calcd for C₁₃ H₁₇NO₂S + H⁺ (252.1052).

1-((4-Chlorophenylthio)methyl)piperidin-2-one (3i). Yield: 82%; light yellow oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.33 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 4.78 (s, 2H), 3.26 (t, J = 4.0 Hz, 2H), 2.22 (t, J = 4.0 Hz, 2H), 1.67 (m, 4H); ¹³C NMR (CDCl₃, 125 MHz): δ 179.8, 133.1, 132.8, 132.5, 128.9, 50.8, 46.8, 32.2, 22.8, 21.1; IR (CHCl₃): ν_max 3435, 2946, 2867, 2345, 1729, 1646, 1572, 1477, 1463, 1443, 1414, 1388, 1348, 1331, 1283, 1245, 1172, 1157, 1093, 1011 cm⁻¹; ESI-MS: m/z 256.0 [M + H]⁺; HR-ESIMS: m/z 256.0557 calcd for C₁₂H₁₅ClNOS + H⁺ (256.0557).

1-((Naphthalen-3-ylthio)methyl)piperidin-2-one (3j). Yield: 89%; brown oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.93 (s, 1H), 7.76 (m, 3H), 7.53–7.41 (m, 3H), 4.95 (s, 2H), 3.28 (t, J = 4.0 Hz, 2H), 2.27 (t, J = 4.0 Hz, 2H), 1.65 (m, 4H); ¹³C NMR (CDCl₃, 125 MHz): δ 170.0, 133.6, 132.2, 131.5, 130.0, 128.8, 128.5, 127.7, 127.4, 126.6, 126.1, 50.8, 47.0, 32.3, 22.9, 21.1; IR (CHCl₃): ν_max 3435, 3051, 2945, 2866, 1644, 1588, 1485, 1462, 1414, 1348, 1330, 1281, 1246, 1172, 1132, 1090, 1071 cm⁻¹; ESI-MS: m/z 272.1 [M + H]⁺; HRMS: m/z 272.1110 calcd for C₁₆H₁₇NOS + H⁺ (272.1103).

1-((Phenylthio)methyl)pyrrolidin-2-one (3k). Yield: 72%; light yellow oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.44 (d, J = 8.0 Hz, 2H), 7.29–7.21 (m, 3H), 4.74 (s, 2H), 3.42 (t, J = 4.0 Hz, 2H), 2.28 (t, J = 4.0 Hz, 2H), 1.95 (m, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 174.8, 133.6, 130.8, 129.0, 127.1, 46.6, 45.8, 30.7, 17.5; IR (CHCl₃): ν_max 3435, 3055, 2920, 1686, 1582, 1482, 1460, 1437, 1419, 1289, 1252, 1157, 1024 cm⁻¹; ESI-MS: m/z 208.0 [M + H]⁺, 230.0 [M + Na]⁺; HR-ESIMS: m/z 208.0791 calcd for C₁₁H₁₃NOS + H⁺ (208.0790).

1-((p-Tolylthio)methyl)pyrrolidin-2-one (3l). Yield: 76%; light yellow oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.34 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 4.70 (s, 2H), 3.44 (t, J = 4.0 Hz, 2H), 2.32 (s, 3H), 2.31–2.25 (m, 2H), 1.96 (m, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 174.8, 137.5, 131.7, 129.8, 47.3, 45.9, 30.8, 29.7, 21.1, 17.6; IR (CHCl₃): ν_max 3308, 2920, 2851, 1690, 1492, 1460, 1418, 1289, 1252, 1157, 1090, 1040 cm⁻¹; ESI-MS: m/z 222.0 [M + H]⁺; HR-ESIMS: m/z 222.0948 calcd for C₁₂H₁₅NOS + H⁺ (222.0947).

1-((4-Methoxyphenylthio)methyl)pyrrolidin-2-one (3m). Yield: 80%; brown oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.40 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 4.63 (s, 2H), 3.78 (s, 3H), 3.45 (t, J = 4.0 Hz, 2H), 2.28 (t, J = 4.0 Hz, 2H), 1.97 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ 174.8, 159.6, 134.5, 123.6, 114.6, 55.2, 48.2, 45.9, 30.8, 17.6; IR (CHCl₃): ν_max 3435, 2924, 2837, 1688, 1591, 1570, 1494, 1460, 1420, 1325, 1286, 1245, 1174, 1104, 1028 cm⁻¹; ESI-MS: m/z 238.0 [M + H]⁺; HR-ESIMS: m/z 238.0892 calcd for C₁₂H₁₅NO₂S + H⁺ (238.0896).

1-((4-Chlorophenylthio)methyl)pyrrolidin-2-one (3n). Yield: 78%; light yellow oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.38 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 4.73 (s, 2H), 3.44 (t, J = 4.0 Hz, 2H), 2.31 (t, J = 4.0 Hz, 2H), 1.98 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ 175.0, 133.1, 132.15, 132.1, 129.1, 46.7, 46.6, 30.7, 17.5; IR (CHCl₃): ν_max 3434, 2920, 1687, 1477, 1460, 1419, 1289, 1251, 1158, 1094, 1011 cm⁻¹; ESI-MS: m/z 264.0 [M + Na]⁺; HR-ESIMS: m/z 264.0217 calcd for C₁₁H₁₂ClNOS + Na⁺ (264.0220).

1-((Naphthalen-3-ylthio)methyl)pyrrolidin-2-one(3o). Yield: 88%; light yellow oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.90 (s, 1H), 7.77 (m, 3H), 7.50–7.42 (m, 3H), 4.85 (s, 2H), 3.42 (t, J = 4.0 Hz, 2H), 2.26 (t, J = 4.0 Hz, 2H), 1.92 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz): δ 175.0, 133.7, 132.2, 131.1, 129.2, 128.6, 128.0, 127.7, 127.4, 126.6, 126.1, 46.5, 46.0, 30.8, 17.5; IR (CHCl₃): ν_max 3860, 3789, 3308, 3052, 2920, 1726, 1687, 1624, 1588, 1490, 1459, 1418, 1289, 1253, 1157, 1132, 1071, 1042 cm⁻¹; ESI-MS: m/z 258.0 [M + H]⁺, 280.0 [M + Na]⁺; HR-ESIMS: m/z 258.0941 calcd for C₁₅H₁₅NOS + H⁺ (258.0947).

1-((Benzylthio)methyl)azepan-2-one (3p). Yield: 70%; light yellow oil; ¹H NMR (CDCl₃, 400 MHz): δ 7.38–7.23 (m, 5H), 4.57 (s, 2H), 3.78 (s, 2H), 3.34 (t, J = 4.0 Hz, 2H), 2.48 (t, J = 4.0 Hz, 2H), 1.70–1.6 (m, 6H); ¹³C NMR (CDCl₃, 100 MHz): δ 175.4, 137.8, 127.9, 127.5, 126.0, 48.7, 47.5, 36.3, 34.6, 28.9, 27.5, 22.4; IR (CHCl₃): ν_max 3435, 3060, 3027, 2926, 2853, 1645, 1494, 1478, 1453, 1442, 1420, 1352, 1337, 1229, 1190, 1137, 1082, 1071, 1029 cm⁻¹; ESI-MS: m/z 250.1 [M + H]⁺, 272.1 [M + Na]⁺; HR-ESIMS: m/z 250.1259 calcd for C₁₄H₁₉NOS + H⁺ (250.1260).

1-((Butylthio)methyl)azepan-2-one (3q). Yield: 68%; light yellow oil; ¹H NMR (CDCl₃, 400 MHz): δ 4.55 (s, 2H), 3.45 (t, J = 4.0 Hz, 2H), 2.56 (m, 4H), 1.73–1.67 (m, 6H), 1.61–1.57 (m, 2H), 1.42–1.38 (m, 2H), 0.92 (t, 4.0 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ 176.1, 49.0, 48.3, 37.3, 31.7, 30.3, 29.9, 28.6, 23.5, 21.9, 13.7; IR (CHCl₃): ν_max 3789, 3682, 3435, 2928, 2856, 1648, 1442, 1420, 1352, 1257, 1228, 1190, 1138, 1082 cm⁻¹; ESI-MS: m/z 216.14 [M + H]⁺, 238.12 [M + Na]⁺; HR-ESIMS: m/z 216.1421 calcd for C₁₁H₂₁NOS + H⁺ (216.1417).

1-((Pentylthio)methyl)azepan-2-one (3r). Yield: 68%; light yellow oil; ¹H NMR (CDCl₃, 400 MHz): δ 4.55 (s, 2H), 3.45 (t, J = 4.0 Hz, 2H), 2.56–2.52 (m, 4H), 1.73–1.61 (m, 8H), 1.35 (m, 2H), 0.91 (t, J = 4.0 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ 176.3, 49.2, 48.4, 37.3, 31.0, 30.7, 29.9, 29.4, 28.5, 23.5, 22.3, 14.0; IR (CHCl₃): ν_max 3435, 2927, 2855, 1648, 1476, 1442, 1420, 1383, 1352, 1256, 1228, 1190, 1138, 1082, 1041 cm⁻¹; ESI-MS: m/z 230.15 [M + H]⁺; HR-ESIMS: m/z 230.1578 calcd for C₁₂H₂₃NOS + H⁺ (230.1573).

1-((Hexylthio)methyl)azepan-2-one (3s). Yield: 64%; light yellow oil; ¹H NMR (CDCl₃, 400 MHz): δ 4.55 (s, 2H), 3.45 (t, J = 4.0 Hz, 2H), 2.56 (m, 4H), 1.73–1.60 (m, 8H), 1.29–1.26 (m, 8H), 0.90 (t, J = 4.0 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ 176.2, 49.1, 48.3, 37.2, 31.3, 30.7, 29.9, 29.6, 28.5, 23.5, 22.5, 14.0; IR (CHCl₃): ν_max 3435, 2926, 2855, 1648, 1468, 1442, 1420, 1352, 1256, 1228, 1190, 1138, 1082, 1040 cm⁻¹; ESI-MS: m/z 230.15 [M + H]⁺, 266.15 [M + Na]⁺; HR-ESIMS: m/z 244.1723 calcd for C₁₃H₂₅NOS + H⁺ (244.1730).

1-(((4-Methoxyphenyl)thio)methyl)indoline-2,3-dione (4a). Yield: 95%; orange red solid; m.p. 109–111 °C; ¹H NMR (CDCl₃, 400 MHz): δ 7.63 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.13 (m, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 2H), 4.98 (s, 2H), 3.76 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 182.6, 160.6, 157.2, 149.4, 138.3, 136.2, 125.3, 124.1, 121.6, 117.7, 115.0, 112.0, 55.4, 45.8; IR (CHCl₃): ν_max 3447, 2921, 1738, 1611, 1590, 1493, 1469, 1363, 1339, 1286, 1267, 1171, 1094, 1022 cm⁻¹; ESI-MS: m/z 300 [M + H]⁺, 322 [M + Na]⁺; HR-ESIMS: m/z 300.0661 calcd for C₁₆H₁₃NO₃S + H⁺ (300.0689) and m/z 322.0478 calcd for C₁₆H₁₃NO₃S + Na⁺ (322.0508).

5-Bromo-1-(((4-methoxyphenyl)thio)methyl)indoline-2,3-dione (4b). Yield: 86%; orange red solid; m.p. 135–137 °C; ¹H NMR (CDCl₃, 400 MHz): δ 7.72 (M, 2H), 7.31 (d, J = 8 Hz, 2H), 6.92 (d, J = 12.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 2H), 4.96 (s, 2H), 3.77 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 181.4, 160.7, 156.5, 148.1, 140.4, 136.2, 128.0, 121.3, 118.8, 117.1, 115.1, 113.8, 55.3, 45.9; IR (CHCl₃): ν_max 3436, 2055, 1742, 1638, 1493, 1467, 1439, 1247, 1158, 1019 cm⁻¹; ESI-MS: m/z 377.9 [M + H]⁺, 399.9 [M + Na]⁺; HR-ESIMS: m/z 377.9782 calcd for C₁₆H₁₂BrNO₃S + H⁺ (377.9794).

1-(((4-Methoxyphenyl)thio)methyl)-5-nitroindoline-2,3-dione (4c). Yield: 85%; orange red solid; m.p. 180–181 °C; ¹H NMR (CDCl₃, 400 MHz): δ 8.54 (d, J = 8.0 Hz, 1H), 8.48 (s, 1H), 7.30–7.28 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 2H), 5.04 (s, 2H), 3.80 (s, 3H); IR (CHCl₃): ν_max 3436, 2920, 2064, 1749, 1615, 1531, 1494, 1475, 1340, 1247, 1163, 1018 cm⁻¹; ESI-MS: m/z 345.0 [M + H]⁺, 367.0 [M + Na]⁺; HR-ESIMS: m/z 345.0535 calcd for C₁₆H₁₂N₂O₅S + H⁺ (345.0540) and m/z 367.0359 calcd for C₁₆H₁₂N₂O₅S + Na⁺ (367.0359).

4-Chloro-1-(((4-methoxyphenyl)thio)methyl)indoline-2,3-dione (4d). Yield: 87%; orange red solid; m.p. 116–118 °C; ¹H NMR (CDCl₃, 400 MHz): δ 7.54 (d, J = 4.0 Hz, 1H), 7.40–7.30 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 6.86–6.77 (m, 3H), 4.94 (s, 2H), 3.77 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 181.1, 160.8, 157.1, 150.4, 144.7, 136.3, 132.6, 126.2, 124.3, 115.1, 114.6, 112.7, 55.3, 46.1; IR (CHCl₃): ν_max 3436, 2067, 1636, 1493, 1361, 1287, 1247, 1171, 1020 cm⁻¹; ESI-MS: m/z 334.0 [M + H]⁺, 355.9 [M + Na]⁺; HR-ESIMS: m/z 356.0101 calcd for C₁₆H₁₂ClNO₃S + Na⁺ (356.0110).

5-Fluoro-1-(((4-methoxyphenyl)thio)methyl)indoline-2,3-dione (4e). Yield: 94%; orange red solid; m.p. 103–104 °C; ¹H NMR (CDCl₃, 400 MHz): δ 7.35–7.29 (m, 4H), 6.99 (d, J = 4.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 2H), 4.98 (s, 2H), 3.77 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 182.0, 160.6, 158.5, 157.0, 145.4, 136.2, 124.8, 121.3, 118.3, 115.0, 113.4, 112.3, 55.3, 45.9; IR (CHCl₃): ν_max 3436, 2918, 1745, 1621, 1484, 1247, 1019 cm⁻¹; ESI-MS: m/z 318.0 [M + H]⁺, 340.0 [M + Na]⁺; HR-ESIMS: m/z 340.0429 calcd for C₁₆H₁₂FNO₃S + Na (340.0414).

Preparation of bis((4-methoxyphenyl)thio)methane (11).^4a

To the solution of thiophenol (5a, 1.0 mmol) in 0.1% TFA in water (5 mL) was added formaldehyde (6, 3 equiv.). The resulting reaction mixture was then refluxed at 80 °C for 6 h. The crude reaction mixture was purified by silica gel column chromatography using EtOAc: hexane as mobile phase to yield product 11. Yield: 72%; white solid; m.p. 67–68 °C; ¹H NMR (CDCl₃, 400 MHz): δ 7.30 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 8.0 Hz, 2H), 4.05 (s, 2H), 3.69 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 159.6, 134.5, 125.3, 114.6, 55.4, 44.5; IR (CHCl₃): ν_max 3436, 2920, 2833, 2040, 1633, 1590, 1492, 1461, 1438, 1284, 1244, 1196, 1094, 1026 cm⁻¹; ESI-MS: m/z 293.0 [M + H]⁺.

General procedure for thiophenylmethylation of phenols

To the solution of substituted thiophenol (5a–b, 1.0 mmol) in 0.1% TFA in water (5 mL) was added formaldehyde (6, 3 equiv.). The resulting reaction mixture was then refluxed at 80 °C for 30 min. The ortho-cresol (13, 2.0 mmol) was then added and reaction mixture was further stirred at 80 °C for 4 h. The reaction mixture was purified by silica gel column chromatography using EtOAc: hexane as mobile phase to yield pair of products, one with para-substituted o-cresols 14aa–14ba and other with ortho-/para-disubstituted o-cresols 14ab–14bb.

2-Methyl-4-((phenylthio)methyl)phenol (14aa). Yield: 55%; white solid; m.p. 68–70 °C; ¹H NMR (CDCl₃, 400 MHz): δ 7.31–7.29 (m, 2H), 7.26–7.22 (m, 2H), 7.18–7.14 (m, 1H), 7.04 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.0 (s, 1H), 4.03 (s, 2H), 2.18 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 153.1, 136.7, 131.7, 129.6, 129.3, 128.9, 127.6, 126.3, 124.2, 115.1, 38.5, 15.9; IR (CHCl₃): ν_max 3847, 3350, 3058, 2921, 2850, 2351, 2284, 1600, 1585, 1501, 1479, 1436, 1384, 1368, 1298, 1265, 1245, 1201, 1151, 1114, 1089, 1070, 1042, 1024 cm⁻¹.

2-Methyl-4,6-bis((phenylthio)methyl)phenol (14ab). Yield: 28%; light brown solid; m.p. 97–99 °C; ¹H NMR (CDCl₃, 400 MHz): δ 7.34–7.31 (m, 2H), 7.27–7.17 (m, 8H), 6.97 (s, 1H), 6.84 (s, 1H), 5.95 (s, 1H), 4.11 (s, 2H), 3.96 (s, 2H), 2.21 (s, 3H); ¹³C NMR (CDCl₃ 100 MHz): δ 152.2, 136.7, 134.5, 131.0, 130.7, 129.6, 129.0, 128.9, 128.8, 128.7, 127.1, 126.2, 125.4, 122.0, 38.4, 36.0, 15.9; IR (CHCl₃): ν_max 3445, 2921, 2852, 1619, 1480, 1438, 1019 cm⁻¹.

4-(((4-Chlorophenyl)thio)methyl)-2-methylphenol (14ba). Yield: 48%; light brown solid; m.p. 92–94 °C; ¹H NMR (CDCl₃, 400 MHz): δ 7.20 (m, 4H), 7.03 (s, J = 8.0 Hz, 1H), 6.95 (m, 1H), 6.66 (d, J = 8.0 Hz, 1H), 5.04 (s, 2H), 3.99 (s, 2H), 2.19 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ 152.3, 134.1, 131.4, 130.7, 130.3, 128.0, 126.7, 123.2, 114.1, 37.9, 14.9; IR (CHCl₃): ν_max 3745, 3324, 3024, 2927, 2854, 1601, 1506, 1474, 1442, 1426, 1387, 1366, 1298, 1270, 1260, 1249, 1208, 1179, 1151, 1112, 1095, 1007 cm⁻¹; ESI-MS: m/z 263.02 [M − H]⁻; HR-ESIMS: m/z 263.0298 calcd for C₁₄H₁₃ClOS–H⁻ (263.0303).

2,4-Bis(((4-chlorophenyl)thio)methyl)-6-methylphenol (14bb). Yield: 28%; light yellow sticky solid; ¹H NMR (CDCl₃, 400 MHz): δ 7.24–7.14 (m, 8H), 6.95 (s, 1H), 6.78 (s, 1H), 5.77 (s, 1H), 4.07 (s, 2H), 3.92 (s, 2H), 2.21 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 152.1, 135.0, 133.3, 132.9, 132.3, 132.28, 131.1, 131.0, 129.1, 128.9, 128.7, 128.6, 38.6, 35.9, 15.8; IR (CHCl₃): ν_max 3446, 2922, 1619, 1476, 1387, 1219, 1095, 1016 cm⁻¹.

X-ray crystallography of 5-fluoro-1-(((4-methoxyphenyl)thio)methyl)indoline-2,3-dione (4e)

Single crystals of 5-fluoro-1-(((4-methoxyphenyl)thio)methyl)indoline-2,3-dione 4e were obtained by slow evaporation at room temperature, from a mixture of methanol–water. The X-ray data was collected from a dry crystal mounted on an ‘Xcalibur, Sapphire3’, Oxford diffractometer. The crystal structure was solved by direct method using SHELXS-97 followed by full matrix anisotropic least square refinement using SHELXL-97.¹⁰ All the hydrogen atoms were located from difference Fourier map and refined isotropically. All the relevant crystallographic data collection parameters and structure refinement details for 4e is summarized in Table S4.‡ Bond lengths and bond angles are given in Table S5.‡

Crystal data for 4e: C₁₆ H₁₂F₁N₁O₃S₁, M = 317.33, monoclinic, space group: P2₁/c, a = 21.243 (5), b = 5.558 (5), c = 13.288 (5) Å, α = 90°, β = 107.615 (5)°, γ = 90°; V = 1495.3 (15) ų, Z = 4, D_c = 1.410 mg m⁻³, μ = 0.239 mm⁻¹, θ range: 3.65 to 26.0°, 5636 reflections measured, 2926 independent (R_int = 0.0492), 248 parameters. The structure was solved by direct methods and refined by full-matrix least-squares on F²; final R indices for 1337 observed reflections [I > 2σ (I)]: R₁ = 0.0652, wR₂ = 0.1593; maximal/minimum residual electron density: 0.199 and −0.176 e Å⁻³.‡

Acknowledgements

R. M. and R. S. are thankful to CSIR and DST for the award of Research Fellowships. SBB thanks Department of Science and Technology (DST, Govt. of India) for financial support under Fast-Track Scheme (grant no. SR/FT/CS-168/2011).

Notes and references

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4. (a) H. Abdel-Ghany, A. M. El-Sayed, A. Khodairy and H. Salah, Synth. Commun., 2001, 31, 2523–2535; (b) G. Ramachandran, N. S. Karthikeyan, P. Giridharan and K. I. Sathiyanarayanan, Org. Biomol. Chem., 2012, 10, 5343–5346; (c) M. Yamauchi, S. Katayama and T. Watanabe, Synthesis, 1982, 11, 935–936.
5. S. B. Bharate, R. Mudududdla, J. B. Bharate, N. Battini, S. Battula, R. R. Yadav, B. Singh and R. A. Vishwakarma, Org. Biomol. Chem., 2012, 10, 5143–5150.
6. R. Mudududdla, S. K. Jain, J. B. Bharate, A. P. Gupta, B. Singh, R. A. Vishwakarma and S. B. Bharate, J. Org. Chem., 2012, 77, 8821–8827.
7. (a) A. Chanda and V. V. Fokin, Chem. Rev., 2009, 109, 725–748; (b) M.-O. Simon and C.-J. Li, Chem. Soc. Rev., 2012, 41, 1415–1427.
8. S. B. Bharate, R. Mudududdla, R. Sharma and R. A. Vishwakarma, Tetrahedron Lett., 2013, 54, 2913–2915.
9. J. E. Coughlin, R. K. Pandey, S. Padmanabhan, K. G. O'Loughlin, J. Marquis, C. E. Green, J. C. Mirsalis and R. P. Iyer, Drug Metab. Dispos., 2012, 40, 970–981.
10. G. M. Sheldrick, Acta Crystallogr., Sect. A: Cryst. Phys., Diffr., Theor. Gen. Crystallogr., 2008, 64, 112–122.

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Footnotes

† IIIM Publication number IIIM/1643/2014.

‡ Electronic supplementary information (ESI) available: Spectroscopic data scans, biology data and protocols, LC-ESIMS data. CCDC 975544. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra47874b

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