Synthesis of ionic liquid-supported hypervalent iodine reagent and its application as a ‘catch and release’ reagent for α-substituted acetophenones

Abstract

A novel imidazolium-based ionic liquid-supported hypervalent iodine reagent has been synthesized and employed for a ‘catch and release’ strategy with substituted acetophenones to generate various α-substituted acetophenones in good to excellent yields. The use of an ionic liquid-supported hypervalent iodine reagent avoids chromatographic separation for the purification of α-substituted acetophenones and thus makes the method greener.

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Introduction

High-throughput screening relies on combinatorial chemistry techniques for the rapid production of a library of compounds with adequate purity. It is very challenging to improve the efficiency of the reaction and make the purification process simple and straightforward. Solid-phase organic synthesis (SPOS)^1–6 is a widely employed tool in combinatorial synthesis that has facilitated the synthesis of many pharmacologically important compounds and made the purification process more facile. Despite its great success, SPOS is associated with some serious drawbacks such as difficulties in the monitoring of the reaction, the need for extra steps, non-linear kinetics and heterogeneous reaction conditions. This has driven the re-evaluation of supported reagents and scavengers in combinatorial synthesis with the combined advantages of solid- and solution-phase chemistry.^7–10 The synthesis of polymer-,¹¹ polyethylene glycol (PEG)-^12–14 and silica-supported reagents^15–17 is tricky, and it is difficult to determine the amount of reagent that has been grafted on these supports. On the other hand, fluorous-supported reagents are expensive and need specialized solvents to carry out the reactions.^18–21

In recent years, ionic liquid-supported reagents^22–29 have gained considerable interest as promising alternative supported reagents due to their high loading capacity, tunable solubility, homogeneity and easy monitoring of the reaction by various analytical techniques such as NMR, IR and mass spectrometry. Several ionic liquid-supported reagents have been synthesized and used for different organic transformations (Fig. 1), for example, ionic liquid-supported methyl sulfoxide (1) has been used for the Swern oxidation of alcohols,³⁰ ionic liquid-supported tin reagent (2) has been used for Stille cross-coupling,^31–33 ionic liquid-supported triphenylphosphine³⁴ (3) has been used as a ligand in C–C coupling reactions, ionic liquid-supported iodobenzene diacetate (IL-IBD)³⁵ (4) has been used for the oxidation of alcohols and sulfides,³⁶ and ionic liquid-supported hydroxyl(tosyl)iodobenzene³⁷ (IL-HTIB) (5) has been used as a tosylating reagent. More recently, we have developed a self-stable and novel ionic liquid-supported sulfonyl azide (6) which has been successfully used as a diazo transfer reagent.³⁸

Fig. 1 Structure of selected ionic liquid-supported reagents.

Continuing our interest in functionalized ionic liquids,^38–42 we envisaged a new synthetic approach where ionic liquid-supported reagents can be employed in a “catch and release (CAR)” strategy. This strategy is a hybrid of scavenging and liquid phase synthesis, where the ionic liquid-supported reagent captures the required substrate and releases the desired product by subsequent reactions. HTIB is an important iodine(III) reagent for the oxytosylation and synthesis of heterocyclic compounds.^43–46 In this paper, we wish to report the synthesis of novel ionic liquid-supported hypervalent iodine reagent 11 and demonstrate its application in a “catch and release” strategy for the synthesis of α-substituted acetophenones.

Results and discussion

The synthesis of 11 was achieved from 2,3-dimethylimidazole (7) as shown in Scheme 1. Ionic liquid-supported sulfonic acid (9) was synthesized by the reaction of 7 with sultone (8), followed by acidification with trifluoromethane-sulfonic acid.⁴² The homogeneous solution of 9 in CH₃CN was added to a hot solution of iodobenzene diacetate (10), and the reaction mixture was kept at room temperature for one week to obtain 11. Several attempts were made by varying the reaction conditions to reduce the reaction time to no success, and the best yield of 11 was obtained in a week. The structure of 11 was unambiguously established by spectroscopic data such as ¹H, ¹³C NMR and high-resolution mass spectrometry (HRMS). The ¹H NMR spectrum of 11 showed doublets at δ 7.63 and 7.59 for imidazole protons, along with other aromatic and aliphatic protons. In the ¹³C NMR spectrum, the C₁ carbon of the phenyl ring attached to iodine resonated at δ 94.93 and the CF₃ carbon of CF₃SO₃⁻ resonated at δ 121.02 as a quartet, in addition to the other six aliphatic and seven aromatic carbons of the molecule. The molecular ion peak at m/z 453.0345 [M − CF₃SO₃]⁺ in the HRMS provided clear evidence towards the structure of 11.

Scheme 1 Synthesis of ionic liquid-supported hypervalent iodine.

After successful synthesis of 11, we explored its application as an α-sulfonating agent to capture substituted acetophenones. To optimize the reaction conditions, 4-chloroacetophenone (12a) was selected as a model substrate, and the reaction of 12a with 11 was examined under different reaction conditions as outlined in Table 1. It was found that 12a was completely captured in CH₃CN (Table 1, entry 10) using 2 equiv. of 11 at 80 °C after 12 h. The use of other solvents such as THF, CHCl₃ and [bmim][BF₄] did not result in the efficient capturing of 12a. Although the capturing efficiency was enhanced in solvent-free conditions (Table 1, entry 2 vs 8), the formation of an unidentified impurity was a major drawback under these conditions.

Table 1 Optimization of the reaction conditions to capture 12a using 11^a

Entry	Solvent	11 (mmol)	Temp. (°C)	Time (h)	Conversion^b (%)
a Reaction conditions: 12a (1 mmol), 11 (mmol as indicated in table), solvent (5 mL), Na2SO4 (0.5 mmol).b Determined based on recovered 12a.c No solvent.d An unidentified impurity was formed along with 13.
1	—^c	1	30	12	10
2	—^c	1	80	12	70^d
3	THF	1	Reflux	18	Traces
4	THF	2	Reflux	16	22
5	[bmim][BF4]	1	80	16	17
6	[bmim][BF4]	2	80	12	32
7	CHCl3	2	Reflux	14	50
8	CH3CN	1	80	12	51
9	CH3CN	2	30	12	27
10	CH3CN	2	80	12	100

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To confirm the identity of the product 13a, acetonitrile was evaporated and the reaction mixture was run through a short plug of silica using a dichloromethane–methanol mixture (95 : 5 v/v) as the eluent. The obtained pure product was analyzed by NMR and mass spectroscopic data. The appearance of a peak at δ 5.70 for the methylene protons attached to the ionic liquid-supported sulfonate group along with the other six aromatic and fourteen aliphatic protons in the ¹H NMR spectra, and the peak at δ 191.27 for the carbonyl group, along with the other carbons, in the ¹³C NMR showed that 12a was ‘captured’ by the ionic liquid. Finally, a peak at m/z 385.098, corresponding to molecular formula, C₁₇H₂₂ClN₂O₄S⁺ [M − CF₃SO₃]⁺ in the HRMS confirmed the structure of 13a.

To explore the generality of the reaction, acetophenones with both electron-withdrawing and electron-releasing groups were reacted with 11 to yield 13. Most of the substituted acetophenones reacted with 11 smoothly under the given conditions (Table 2), however in the case of 4-methoxy and 4-nitroacetophenones, a small amount of the corresponding benzoic acid (10–12%) was formed along with 13, which was removed by simple washing with diethyl ether.

Table 2 Synthesis of ionic liquid-supported sulfonates 13 using 11^a

Entry	Ar	Conversion^b (%)	Entry	Ar	Conversion^b (%)
a Reaction conditions: 12a–h (1.0 mmol), 11 (2.0 mmol), Na2SO4 (0.5 mmol), CH3CN (5.0 mL), 80 °C, 12 h.b Determined based on recovered acetophenone.c The corresponding benzoic acid was formed in 10–12% yield.
a	4-ClC6H4	100	e	4-CH3OC6H4	80^c
b	3-ClC6H4	100	f	C10H7	100
c	4-BrC6H4	90	g	4-NO2C6H4	80^c
d	4-CH3C6H4	90	h	C4H4S	100

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Next, we studied the ‘release’ of acetophenone from 13a using thiocyanate as the anion to give α-thiocyanato-β-ketones (14a). When 13a was treated with KSCN at room temperature for 4 h, the ionic liquid-supported substituted acetophenone was released cleanly with the thiocyanate ion without any side product. Simple extraction with hexane–ethyl acetate (7 : 3 v/v), followed by washing with water, gave 14a in 92% yield and high purity.

Encouraged with these systematic “catch and release” results for 12a, we focused our attention on developing a simple and straightforward, chromatograpy-free protocol for the synthesis of α-substituted acetophenones (14–16) from 12 (Table 3). Initially, 12a was treated with 11 in dry CH₃CN at 80 °C for 12 h in the presence of anhydrous Na₂SO₄. After completion of the reaction, the reaction mixture was filtered and CH₃CN was evaporated under reduced pressure. The residue containing ionic liquid-supported 4-chloroacetophenone (13a) was washed with diethyl ether and subsequently treated with KSCN at room temperature for 4 h. On completion of the reaction, the product was extracted with hexane–ethyl acetate (7 : 3 v/v), washed with water, dried with anhydrous Na₂SO₄ and concentrated to give 14a in 92% yield. The purity of 14a was over 98% as indicated by HPLC and NMR (see ESI†).

Table 3 Synthesis of α-substituted acetophenones (14–16) using 11 by the capture and release strategy^a

Entry	Ar	% Yield^b
		14	15	16
a Reaction conditions: 12 (1.0 mmol), 11 (2.0 mmol), Na2SO4 (0.5 mmol) CH3CN (5 mL), 80 °C, 12 h, followed by Nu (1.0 mmol), 30 °C, 4 h.b Isolated yields.
a	4-ClC6H4	92	90	68
b	3-ClC6H4	70	84	58
c	4-BrC6H4	80	67	46
d	4-CH3C6H4	76	62	52
e	4-CH3OC6H4	65	78	50
f	C10H7	90	92	68
g	4-NO2C6H4	65	70	51
h	C4H4S	75	76	55

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On establishing a simple and chromatography-free method for the synthesis of 14a, we utilized different acetophenones (12a–h) with three nucleophiles, –SCN, –N₃ and CH₃C₆H₄SO₂⁻, to obtain the corresponding β-substituted acetophenones 14, 15 and 16, respectively (Table 3). As indicated in Table 3, acetophenone with both electron-releasing and electron-withdrawing groups reacted smoothly. α-Thiocyanato-β-ketones (14) and α-azido-β-ketones (15) were obtained in good to excellent yield (62–92%), while β-ketosulfones (16) were obtained in moderate to good yield (46–68%). This may be attributed to their different nucleophilicity. It is worth mentioning that all the compounds were of high purity and no chromatographic separation was performed. The yields of the products (14–16) are based on the acetophenones after two steps. The purification method is simple and involves extraction with hexane–ethyl acetate (7 : 3 v/v) followed by washing with water and drying with anhydrous sodium sulfate.

Compared to the polymer-bound iodine(III) reagent,^47,48 the loading capacity is higher for the ionic liquid-supported reagent, and the reaction can be monitored easily by different spectroscopic techniques. The present method does not require an excess amount of nucleophile to “release” the products as is the case with the polymer-bound reagent, and purification of the products does not require chromatographic separation.

Conclusions

In summary, we have successfully developed an efficient and simple protocol for the synthesis of an ionic liquid-supported hypervalent iodine reagent, and its use has been demonstrated in the generation of α-substituted acetophenones through a “catch and release” strategy. The two-step protocol for the conversion of substituted acetophenones to α-substituted acetophenones involves no chromatographic separation and gives the product in good to excellent yield and high purity. The scope and utility of the developed ionic liquid-supported reagent is general and can be used for the synthesis of various substituted ketones and heterocyclic compounds.

Experimental

Synthesis of ionic liquid-supported hypervalent iodine (11)

Ionic liquid-supported sulfonic acid (13 mmol) and IBD (13 mmol) were dissolved in the minimum amount of CH₃CN in different conical flasks and heated on a hotplate. The warm ionic liquid-supported sulfonic acid solution was added to the flask containing IBD under hot conditions. The reaction mixture was kept aside for one week. Acetonitrile was removed by a rotary evaporator under reduced pressure, and the resulting mixture was washed with dry DCM (3 × 30 mL) to remove unreacted starting materials to obtain a thick yellow liquid (7.55 g, 96%). ¹H NMR (300 MHz, DMSO-d₆, CD₃OD) δ 8.22 (s, 1H), 7.76 (d, J = 1.1 Hz, 1H), 7.73 (d, J = 1.1 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.44–7.37 (m, 1H), 7.23–7.15 (m, 2H), 4.14 (t, J = 7.3 Hz, 2H), 3.76 (s, 3H), 2.64 (d, J = 7.5 Hz, 2H), 2.59 (s, 3H), 1.91–1.78 (m, 2H), 1.71–1.58 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 144.6, 137.5, 130.9, 128.0, 123.1, 122.6, 121.2, 121.0 (q, J_C–F = 320.25 Hz, OTf), 94.9, 50.7, 34.8, 28.4, 21.9, 9.2; HRMS (ESI-TOF) calculated for C₁₅H₂₂IN₂O₄S⁺: 453.0339, found: 453.0356 [M − CF₃SO₃]⁺.

Synthesis of ionic liquid-supported sulfonates (13a–h)

Acetophenone (1.0 mmol), 11 (2 mmol) and dry Na₂SO₄ (0.5 mmol) were added to CH₃CN (5 mL) and heated at reflux until the acetophenone was completely consumed. The reaction mixture was filtered, CH₃CN was removed under reduced pressure and the resulting reaction mixture was purified by silica-gel column chromatography (dichloromethane–methanol 3 : 1 as the eluent) to obtain the desired compound 13a–h.

13a: Off-white solid (272 mg, 51%); m.p.: 90–96 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 7.97 (d, J = 8.6 Hz, 2H), 7.70–7.60 (m, 4H), 5.70 (s, 2H), 4.19 (t, J = 6.7 Hz, 2H), 3.75 (s, 3H), 3.55 (t, J = 7.1 Hz, 2H), 2.60 (s, 3H), 1.94–1.70 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 191.2, 144.8, 139.5, 132.7, 130.2, 129.5, 122.8, 121.3, 121.1 (q, J_C–F = 320.25 Hz, OTf), 71.6, 49.3, 47.2, 35.1, 27.8, 20.3, 9.6; HRMS (ESI-TOF) calculated for C₁₇H₂₂ClN₂O₄S⁺: 385.0983, found: 385.0975 [M − CF₃SO₃]⁺.

13b: Yellow liquid (265 mg, 50%); ¹H NMR (300 MHz, DMSO-d₆) δ 8.01–7.97 (m, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.80 (dd, J = 8.0, 1.1 Hz, 1H), 7.67–7.62 (m, 3H), 5.74 (s, 2H), 4.19 (t, J = 6.9 Hz, 2H), 3.76 (s, 3H), 3.59–3.52 (m, 2H), 2.60 (s, 3H), 1.94–1.76 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 189.2, 142.8, 142.6, 133.7, 132.2, 129.3, 126.0, 124.9, 120.7, 119.2, 119.0 (q, J_C–F = 320.25 Hz, OTf), 69.6, 47.2, 45.1, 33.0, 25.8, 18.3, 7.5; HRMS (ESI-TOF) calculated for C₁₇H₂₂ClN₂O₄S⁺: 385.0983, found: 385.1015 [M − CF₃SO₃]⁺.

13c: Pale yellow solid (259 mg, 45%); m.p.: 83–96 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 7.92–7.86 (m, 2H), 7.83–7.77 (m, 2H), 7.65 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 5.70 (s, 2H), 4.19 (t, J = 6.8 Hz, 2H), 3.75 (s, 3H), 3.60–3.49 (m, 2H), 2.60 (s, 3H), 1.95–1.72 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 191.5, 144.9, 133.1, 132.5, 130.3, 128.7, 122.8, 121.3, 121.1 (q, J_C–F = 320.25 Hz, OTf), 71.6, 49.3, 47.2, 35.1, 27.8, 20.4, 9.6; HRMS (ESI-TOF) calculated for C₁₇H₂₂BrN₂O₄S⁺: 429.0478, found: 429.0512 [M − CF₃SO₃]⁺ and 431.0489 [M + 2 − CF₃SO₃]⁺.

13d: Yellow solid (231 mg, 45%); m.p.: 64–70 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (d, J = 8.2 Hz, 2H), 7.64 (dd, J = 8.9, 2.1 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 5.68 (s, 2H), 4.19 (t, J = 6.8 Hz, 2H), 3.76 (s, 3H), 3.63–3.48 (m, 2H), 2.60 (s, 3H), 2.40 (s, 3H), 1.96–1.78 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 191.6, 145.3, 144.9, 131.5, 129.9, 128.4, 122.8, 121.3, 121.1 (q, J_C–F = 320.25 Hz, OTf), 71.6, 49.3, 47.2, 35.1, 27.8, 21.7, 20.4, 9.6; HRMS (ESI-TOF) calculated for C₁₈H₂₅N₂O₄S⁺: 365.1530, found: 365.1555 [M − CF₃SO₃]⁺.

13e: Thick light brown liquid (211 mg, 40%); ¹H NMR (300 MHz, DMSO-d₆) δ 7.94 (d, J = 9.0 Hz, 2H), 7.63 (dd, J = 8.9, 2.1 Hz, 2H), 7.12–7.06 (m, 2H), 5.64 (s, 2H), 4.21–4.11 (m, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 3.56–3.47 (m, 2H), 2.59 (s, 3H), 1.95–1.78 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 190.4, 164.3, 144.8, 130.7, 126.8, 122.8, 121.3, 121.1 (q, J_C–F = 320.25 Hz, OTf), 114.6, 71.4, 56.1, 49.4, 47.2, 35.1, 27.8, 20.4, 9.5; HRMS (ESI-TOF) calculated for C₁₈H₂₅N₂O₅S⁺: 381.1479, found: 381.1504 [M − CF₃SO₃]⁺.

13f: Brown liquid (373 mg, 68%); ¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.16–7.95 (m, 4H), 7.76–7.62 (m, 4H), 5.88 (s, 2H), 4.21 (t, J = 6.7 Hz, 2H), 3.77 (s, 3H), 3.60 (t, J = 7.1 Hz, 2H), 2.61 (s, 3H), 2.02–1.70 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 192.0, 144.9, 135.9, 132.4, 131.3, 130.6, 130.0, 129.6, 129.1, 128.3, 127.7, 123.5, 122.8, 121.3, 121.3 (q, J_C–F = 320.25 Hz, OTf), 71.7, 49.3, 47.2, 35.1, 27.9, 20.4, 9.6; HRMS (ESI-TOF) calculated for C₂₁H₂₅N₂O₄S⁺: 401.1530, found: 401.1524 [M − CF₃SO₃]⁺.

13g: Brown solid (218 mg, 40%); m.p.: 85–90 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 8.39 (d, J = 8.7 Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H), 7.64 (dd, J = 7.5, 1.8 Hz, 2H), 5.78 (s, 2H), 4.19 (t, J = 6.7 Hz, 2H), 3.76 (s, 3H), 3.56 (t, J = 7.0 Hz, 2H), 2.60 (s, 3H), 1.98–1.73 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 191.5, 150.8, 144.9, 138.7, 129.9, 124.4, 122.8, 121.3, 121.2 (q, J_C–F = 320.25 Hz, OTf), 71.9, 49.3, 47.2, 35.1, 27.8, 20.3, 9.6; HRMS (ESI-TOF) calculated for C₁₇H₂₁N₃O₆S⁺: 395.1240, found: 395.1252 [M − CF₃SO₃]⁺.

13h: Thick light brown liquid (252 mg, 50%); ¹H NMR (300 MHz, DMSO-d₆) δ 8.14 (dd, J = 4.9, 0.7 Hz, 1H), 8.08–8.01 (m, 1H), 7.64 (dd, J = 8.2, 2.0 Hz, 2H), 7.32 (dd, J = 4.7, 4.0 Hz, 1H), 5.60 (s, 2H), 4.19 (t, J = 6.7 Hz, 2H), 3.75 (s, 3H), 3.60–3.47 (m, 2H), 2.59 (s, 3H), 1.95–1.71 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 185.4, 144.9, 140.0, 136.5, 134.5, 129.5, 122.8, 121.3, 121.1 (q, J_C–F = 320.25 Hz, OTf), 70.8, 49.4, 47.2, 35.1, 27.8, 20.4, 9.6; HRMS (ESI-TOF) calculated for C₁₅H₂₁N₂O₄S₂⁺: 357.0937, found: 357.0949 [M − CF₃SO₃]⁺.

General procedure for the synthesis of α-substituted acetophenones (14–16)

To a solution of substituted acetophenone (12) (1.0 mmol) and 11 (2.0 mmol) in CH₃CN, anhydrous Na₂SO₄ (0.5 mmol) was added and the resulting mixture was heated until the acetophenone was completely consumed (monitored by TLC). After completion of the reaction, the reaction mixture was filtered and CH₃CN was evaporated under reduced pressure. The residue was washed with ether (3 × 10 mL), and the viscous ionic liquid-supported sulfonate obtained (13) was treated with KSCN/NaN₃/CH₃C₆H₄SO₂Na (1.0 mmol) and stirred vigorously at room temperature under solvent-free conditions. After completion of the reaction, the product was extracted with hexane–ethyl acetate (3 × 10 mL, 7 : 3 v/v), leaving behind the ionic liquid 9 which is insoluble in this solvent mixture. Thus, the product was extracted in hexane–ethyl acetate and washed with water. The organic layers were dried over anhydrous sodium sulfate and concentrated to obtain the pure product (14–16) without chromatographic purification.

1-(4-Chlorophenyl)-2-thiocyanatoethanone (14a). Yellow solid (194 mg, 92%); m.p.: 132–137 °C (lit.⁴⁹ 133–135 °C); ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 4.70 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 189.69, 141.54, 132.29, 129.84, 129.59, 111.55, 42.66; HRMS (m/z) calculated for C₉H₇NClOS⁺: 211.9913, found: 211.9889 [M + H]⁺.

1-(3-Chlorophenyl)-2-thiocyanatoethanone (14b). Yellow solid (147 mg, 70%); m.p.: 84–86 °C (lit.⁴⁹ 68–70 °C); ¹H NMR (300 MHz, CDCl₃) δ 7.92 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 4.69 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 189.71, 135.64, 135.43, 134.73, 130.52, 128.51, 126.54, 111.42, 42.61; HRMS (m/z) calculated for C₉H₇NClOS⁺: 211.9913, found: 211.9892 [M + H]⁺.

1-(4-Bromophenyl)-2-thiocyanatoethanone (14c). Off-white solid (228 mg, 80%); m.p.: 143–144 °C (lit.⁵⁰ 140–143 °C); ¹H NMR (300 MHz, DMSO-d₆) δ 7.95 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 5.08 (s, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 192.12, 133.81, 132.49, 130.99, 128.97, 113.18, 42.01; HRMS (m/z) calculated for C₉H₇BrNOS: 255.9426, found: 255.9442 [M + H]⁺ and 257.9436 [M + H + 2]⁺.

2-Thiocyanato-1-tolylethanone (14d). White solid (145 mg, 76%); m.p.: 100–101 °C (lit.⁴⁹ 104–107 °C); ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J = 7.1 Hz, 2H), 7.32 (d, J = 6.8 Hz, 2H), 4.72 (s, 2H), 2.45 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 190.42, 146.09, 131.50, 129.85, 128.59, 112.02, 43.05, 21.85; HRMS (m/z) calculated for C₁₀H₁₀NOS⁺: 192.0478, found: 192.0503 [M + H]⁺.

1-(4-Methoxyphenyl)-2-thiocyanatoethanone (14e). Off-white solid (145 mg, 65%); m.p.: 121–123 °C (lit.⁴⁹ 120–122 °C); ¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 4.71 (s, 2H), 3.90 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 189.20, 164.82, 130.92, 126.95, 114.37, 112.17, 55.69, 42.95; HRMS (m/z) calculated for C₁₀H₁₀NO₂S⁺: 208.0427, found: 208.0423 [M + H]⁺.

1-(Naphthalene-2-yl)-2-thiocyanatoethanone (14f). Yellow solid (204 mg, 90%); m.p.: 104–109 °C (lit.⁵¹ 102–104 °C); ¹H NMR (300 MHz, CDCl₃) δ 8.40 (s, 1H), 8.09–7.80 (m, 4H), 7.73–7.48 (m, 2H), 4.83 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 190.78, 136.16, 132.28, 131.25, 130.83, 129.75, 129.56, 129.18, 127.97, 127.46, 123.31, 112.02, 43.11; HRMS (m/z) calculated for C₁₃H₁₀NOS⁺: 228.0478, found: 228.0463 [M + H]⁺.

1-(4-Nitrophenyl)-2-thiocyanatoethanone (14g). Off-white solid (101 mg, 65%); m.p.: 117–118 °C (lit.⁴⁹ 118–120 °C); ¹H NMR (300 MHz, DMSO-d6) δ 8.27 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H), 4.63 (s, 2H); ¹³C NMR (75 MHz, DMSO-d6) δ 184.81, 146.41, 133.53, 124.91, 119.62, 106.29, 37.67; HRMS (m/z) calculated for C₉H₇N₂O₃S⁺: 223.0172, found: 223.0184 [M + H]⁺.

2-Thiocyanato-1-(thiophen-2-yl)ethanone (14h). Yellow solid (166 mg, 75%); m.p.: 91–94 °C (lit.⁵² 89–91 °C); ¹H NMR (300 MHz, CDCl₃) δ 7.80 (dd, J = 4.3, 1.5 Hz, 2H), 7.24–7.19 (m, 1H), 4.57 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 183.37, 140.49, 136.17, 133.80, 128.79, 111.53, 41.65; HRMS (m/z) calculated for C₇H₆NOS₂⁺: 183.9985, found: 183.9978 [M + H]⁺.

2-Azido-1-(4-chlorophenyl)ethanone (15a). Colourless solid (175 mg, 90%); m.p. 66–69 °C (lit.⁵³ 65–67 °C); ¹H NMR (300 MHz, CDCl₃) δ 7.87 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 4.53 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 197.29, 140.81, 131.70, 129.38, 129.07, 65.42. HRMS (m/z) calculated for C₈H₇ClN₃O⁺: 196.0272, found: 196.0258 [M + H]⁺.

2-Azido-1-(3-chlorophenyl)ethanone (15b). Brown solid; (163 mg, 84%); m.p. 64–67 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.89 (s, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 4.54 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 192.11, 135.83, 135.40, 134.08, 130.33, 128.07, 125.99, 54.95; HRMS (m/z) calculated for C₈H₇ClN₃O⁺: 196.0272, found: 196.0284 [M + H]⁺.

2-Azido-1-(4-bromophenyl)ethanone (15C). Yellow solid (159 mg, 67%); m.p. 74–76 °C (lit.⁵⁴ 79.5–81 °C); ¹H NMR (300 MHz, CDCl₃) δ 7.77 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 4.53 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 192.33, 133.07, 132.36, 129.47, 129.40, 54.80; HRMS (m/z) calculated for C₈H₇BrN₃O⁺: 239.9767, found: 239.9756 [M + H]⁺ and 241.9687 [M + H + 2]⁺.

2-Azido-1-p-tolylethanone (15d). Off-white solid (108 mg, 62%); m.p.: 57–59 °C (lit.⁵³ 56–57 °C); ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 4.46 (s, 2H), 2.35 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 192.79, 145.18, 131.91, 129.65, 128.03, 54.77, 21.76; HRMS (m/z) calculated for C₉H₁₀N₃O⁺: 176.0818, found: 176.0834 [M + H]⁺.

2-Azido-1-(4-methoxyphenyl)ethanone (15e). Yellow solid (148 mg, 78%); m.p.: 65–67 °C (lit.⁵³ 67–68 °C); ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.43 (s, 2H), 3.81 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 190.63, 163.23, 129.26, 126.36, 113.14, 54.55, 53.52; HRMS (m/z) calculated for C₉H₁₀N₃O₂⁺: 192.0768, found: 192.0779 [M + H]⁺.

2-Azido-1-(naphthalene-2-yl)ethanone (15f). Yellow solid (194 mg, 92%); m.p.: 64–66 °C (lit.⁵⁵ 66–67 °C); ¹H NMR (300 MHz, CDCl₃) δ 8.40 (s, 1H), 8.01–7.87 (m, 4H), 7.61 (m, 2H), 4.70 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 193.15, 135.98, 132.38, 131.71, 129.81, 129.61, 129.09, 129.00, 127.92, 127.19, 123.31, 54.98; HRMS (m/z) calculated for C₁₂H₁₀N₃O⁺: 212.0818, found: 212.0788 [M + H]⁺.

2-Azido-1-(4-nitrophenyl)ethanone (15g). Brown solid (144 mg, 70%); m.p.: 91–93 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.37 (d, J = 1.9 Hz, 1H), 8.35 (d, J = 1.9 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 1.8 Hz, 1H), 4.63 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 192.05, 150.86, 138.71, 129.13, 124.20, 55.26; HRMS (m/z) calculated for C₈H₇N₄O₃⁺: 207.0513, found: 207.0496 [M + H]⁺.

2-Azido-1-(thiophen-2-yl)ethanone (15h). Colourless solid (100 mg, 76%); m.p.: 67–69 °C (lit.⁵⁶ 62–64 °C); ¹H NMR (300 MHz, DMSO-d₆) δ 8.04 (d, J = 37.0 Hz, 2H), 7.29 (m, 1H), 4.81 (s, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 188.08, 140.85, 136.16, 134.43, 129.37, 54.76; HRMS (m/z) calculated for C₆H₆N₃OS⁺: 168.0226, found: 168.0247 [M + H]⁺.

1-(4-Chlorophenyl)-2-tosylethanone (16a). Yellow solid (209 mg, 68%); m.p.: 139–140 °C (lit.⁵⁷ 136–138 °C); ¹H NMR (500 MHz, DMSO-d₆) δ 7.91 (dd, J = 6.7, 2.0 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.55 (dd, J = 6.7, 2.0 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 5.20 (s, 2H), 2.37 (s, 3H); ¹³C NMR (126 MHz, DMSO-d₆) δ 188.61, 145.32, 145.29, 134.77, 131.38, 130.15, 129.33, 129.30, 128.46, 62.84, 21.49; HRMS (m/z) calculated for C₁₅H₁₄ClO₃S⁺: 309.0347, found: 309.0338 [M + H]⁺.

1-(3-Chlorophenyl)-2-tosylethanone (16b). Pale yellow solid (178 mg, 58%); m.p.: 120–124 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.84 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.9 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 4.69 (s, 2H), 2.45 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 187.08, 145.62, 137.23, 135.56, 135.23, 134.20, 130.17, 129.93, 129.14, 128.58, 127.59, 63.69, 21.72; HRMS (m/z) calculated for C₁₅H₁₄ClO₃S⁺: 309.0347, found: 309.0337 [M + H]⁺.

1-(4-Bromophenyl)-2-tosylethanone (16c). Pale yellow solid (161 mg, 46%); m.p.: 135–140 °C (lit.⁵⁸ 144–146 °C); ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 4.68 (s, 2H), 2.44 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 187.29, 145.57, 135.58, 134.50, 132.20, 132.06, 130.82, 129.92, 128.55, 63.69, 21.73; HRMS (m/z) calculated for C₁₅H₁₄BrO₃S⁺: 352.9842, found: 352.9864 [M + H]⁺ and 354.9834 [M + H + 2]⁺.

1-p-Tolyl-2-tosylethanone (16d). Light yellow solid (149 mg, 52%); m.p.: 98–101 °C (lit.⁵⁹ 100–102 °C); ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 7.6 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 7.7 Hz, 2H), 4.61 (s, 2H), 2.36 (s, 3H), 2.35 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 187.68, 145.57, 145.31, 135.81, 133.38, 129.82, 129.56, 129.52, 128.61, 63.57, 21.80, 21.72; HRMS (m/z) calculated for C₁₆H₁₇O₃S⁺: 289.0893, found: 289.0914 [M + H]⁺.

1-(4-Methoxyphenyl)-2-tosylethanone (16e). Off-white solid (152 mg, 50%); m.p.: 120–121 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.94 (dd, J = 8.7, 1.6 Hz, 2H), 7.75 (d, J = 6.9 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 6.95 (dd, J = 8.7, 1.5 Hz, 2H), 4.66 (s, 2H), 3.89 (s, 3H), 2.44 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 186.34, 164.56, 145.27, 135.80, 131.93, 129.80, 128.91, 128.58, 114.07, 63.59, 55.62, 21.71; HRMS (m/z) calculated for C₁₆H₁₇O₄S⁺: 305.0842, found: 305.0858 [M + H]⁺.

1-(Naphthalene-2-yl)-2-tosylethanone (16f). Sticky yellow solid (220 mg, 68%); ¹H NMR (500 MHz, CDCl₃) δ 8.44 (s, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.90–7.84 (m, 2H), 7.80–7.75 (m, 2H), 7.68–7.55 (m, 2H), 7.34–7.28 (m, 2H), 4.86 (s, 2H), 2.40 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 190.54, 145.29, 135.83, 134.63, 133.93, 133.40, 130.86, 130.39, 129.83, 129.10, 128.76, 128.61, 126.86, 125.59, 124.28, 66.34, 21.70; HRMS (m/z) calculated for C₁₉H₁₇O₃S⁺: 325.0893, found: 325.0915 [M + H]⁺.

1-(4-Nitrophenyl)-2-tosylethanone (16g). Pale yellow solid (162 mg, 51%); m.p.: 139–144 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.32 (d, J = 8.8 Hz, 2H), 8.15 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 4.77 (s, 2H), 2.46 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 187.05, 150.84, 145.91, 139.97, 135.37, 130.51, 130.05, 128.51, 123.97, 64.09, 21.75; HRMS (m/z) calculated for C₁₅H₁₄NO₅S⁺: 320.0587, found: 320.0593 [M + H]⁺.

1-(Thiophenyl-2-yl)-2-tosylethanone (16h). Yellow liquid (154 mg, 55%); ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 3.5 Hz, 1H), 7.69 (d, J = 7.8 Hz, 3H), 7.27 (d, J = 8.0 Hz, 2H), 7.09 (t, J = 4.3 Hz, 1H), 4.54 (s, 2H), 2.37 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 180.32, 145.50, 143.22, 136.42, 135.49, 135.29, 129.89, 128.72, 128.64, 64.74, 21.74; HRMS (m/z) calculated for C₁₃H₁₃O₃S₂⁺: 281.0301, found: 281.0288 [M + H]⁺.

Acknowledgements

The authors sincerely thank the Council of Scientific and Industrial Research (CSIR), New Delhi for research funding [Grant No. 02(0115)/13/EMR-II]. MMK and SC thank CSIR for providing the research fellowship.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: copies of ¹H and ¹³C NMR for compounds 11, 13 and 14–16, and HPLC analysis of 14a. See DOI: 10.1039/c4ra00063c

‡ Both authors contributed equally

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