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Article

Brønsted Acidic Ionic Liquid Accelerated Halogenation of Organic Compounds with N-Halosuccinimides (NXS)

by
Dejan Vražič
1,
Marjan Jereb
2,
Kenneth K. Laali
3 and
Stojan Stavber
1,4,*
1
Laboratory for Organic and Bioorganic Chemistry, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia
2
Faculty for Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
3
Department of Chemistry, University North Florida, Science and Engineering Building, 1 UNF Drive, Jacksonville, FL 32224, USA
4
Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins CIPKeBiP, Jamova 39, 1000 Ljubljana, Slovenia
*
Author to whom correspondence should be addressed.
Molecules 2013, 18(1), 74-96; https://doi.org/10.3390/molecules18010074
Submission received: 15 November 2012 / Revised: 6 December 2012 / Accepted: 11 December 2012 / Published: 21 December 2012
(This article belongs to the Section Organic Chemistry)
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Abstract

:
The Brønsted-acidic ionic liquid 1-methyl-3-(4-sulfobutyl)imidazolium triflate [BMIM(SO3H)][OTf] was demonstrated to act efficiently as solvent and catalyst for the halogenation of activated organic compounds with N-halosuccinimides (NXS) under mild conditions with short reaction times. Methyl aryl ketones were converted into α-halo and α,α-dihaloketones, depending on the quantity of NXS used. Ketones with activated aromatic rings were selectively halogenated, however in some cases mixtures of α-halogenated ketone and ring-halogenated ketones were obtained. Activated aromatics were regioselectively ring halogenated to give mono- and dihalo-substituted products. The [BMIM(SO3H)][OTf] ionic liquid (IL-A) was successfully reused eight times in a representative monohalogenation reaction with no noticeable decrease in efficiency. An effective halogenation scale-up in this IL is also presented. The reactivity trend and the observed chemo- and regioselectiivities point to an ET process in these IL-promoted halofunctionalization reactions.

Graphical Abstract

1. Introduction

Halogenated organic compounds are highly versatile starting materials and intermediates in organic and organometallic chemistry and their production has been under constant investigation. The topic has been extensively reviewed [1,2,3,4]. Halogenation reactions are often associated with extensive waste production and relatively high process costs. Increasing environmental and climate changes urge the development of safer and “greener” synthetic pathways at reduced costs. The main reaction waste is usually the organic solvent used as reaction medium; moreover volatile organics have severe environmental and health issues.
N-halosuccinimides are very popular as halogen-transfer reagents [5,6,7,8,9]; however they are usually not reactive enough for direct halogenation and require a Lewis acid or a Brønsted acid catalyst. The catalysts employed are usually moisture sensitive, they are often metallic or strongly acidic, produce toxic waste, and are costly.
Halogenation of aromatic compounds in different ILs has been recently reviewed [10,11] and further studied [12]. Fluorination of arenes with F-TEDA-BF4 was examined in imidazolium-ILs [13]. Other earlier studies include chlorination of aromatics with trichloroisocyanuric acid in IL-A (Figure 1) [14], oxidative chlorination with HCl in [Hmim][NO3] [15], bromination of aromatics in tribromide-based ILs [16,17,18,19], iodination with I2/H2O2 in BMIM-IL [20], I2/F-TEDA-BF4 in imidazolium- and pyridinium-IL, also with I2 or MeI/Koser’s reagent in BMIM-IL [21], iodination of alcohols in [Hmim][HSO4] [22], and with N-iodosaccharin [23].
Brønsted-acidic ionic liquids such as [BMIM(SO3H)][OTf] [24] (IL-A) have attracted considerable attention as dual solvent/catalysts and were employed in diverse acid-catalyzed transformations [25,26,27,28,29,30].
In continuation of our previous studies on application of ionic liquids as solvents and catalysts in synthesis [31,32,33,34,35,36,37,38,39,40,41,42,43], we report on the utility of IL-A for halofunctionalization of organic molecules with NXS reagents.

2. Results and Discussion

Halogenation of acetophenone (1) with NIS, NBS and NCS was studied in IL-A and IL-B (Figure 1), and α-halogenation took place with all three reagents (Table 1). Iodination of 1 with 1.1 equiv. of NIS at 55 °C gave 2a with significantly higher conversion in IL-A than in IL-B; albeit with slightly lower selectivity (Table 1, entries 1 and 2). Similar results were obtained in bromination with NBS (entries 3 and 4). Bromination with 2.2 equiv. of NBS in IL-A resulted in quantitative dibromination, whereas in IL-B only monobromination took place (entries 5 and 6). Chlorofunctionalization with 1.1 equivalents of NCS in the both IL-A and IL-B gave 2c as the main product; whereas regioselectivity in IL-A changed after prolonged heating and 3c was obtained as the mayor product (entries 7–9). Reaction with 2.2 equiv. of NCS in IL-B gave 2c as major and 3c as minor products, whereas 3c was formed exclusively in IL-A (entries 10 and 11). The results confirm the superior catalytic effect of the Brønsted acidic IL-A.
Focusing on the effect of the structure of aryl methyl ketones 4 on halogenation with N-halosuccinimides in IL-A (Table 2), compound 4a was selectively converted into its α-iodo derivative 5a (entry 1). Functionalization of 4a with 1.1 equiv. of NBS was less selective, furnishing α-bromo- and α,α-dibromo- substituted ketones 6a and 7a (entry 2), while reaction with 2.2 equiv of NBS yielded 7a in excellent yield (entry 3). Chlorination with 2.2 equiv. of NCS selectively produced the α,α-dichloroketone 8a (entry 4).
Halogenation of 2-acetylthiophene (4b) yielded the α-iodoketone 5b regioselectively (entry 5). Reaction of 4b with NBS (1.1 equiv.) exhibited a similar level of selectivity as with 4a, forming the mono- and dibrominated products 6b and 7b (entry 6), and with 2.2 equiv. of NBS 7b in high yield. Functionalization with 2.2 equiv. of NCS selectively furnished the α,α-dichloroketone 8b (entry 8). Compound 4c was regioselectively converted to its α-iodoketone 5c with NIS in high yield (entry 9). Bromination with NBS was somewhat less selective than in the previous cases giving a mixture of α-bromo and α,α-dibromoketones 6c and 7c (entry 10), while with 2.2 equiv. of NBS 7c was selectively obtained in high yield (entry 11). The reaction temperatures were in 55–70 °C range, depending on the reactivity of the NXS reagent, and the reaction times varied from 10 to 150 minutes. It is noteworthy that no ring functionalization products were formed with ketones 4a, 4b and 4c, despite the additional activation of the aromatic ring with an EDG functionalization, which was obviously not enough for acetyl group deactivation of the aromatic part of the target.
Halofunctionalization of 4c with excess of NCS was studied in IL-A at 70 °C (Scheme 1). With 2.2 equiv. of NCS a mixture of 2,2-dichloro-1-(p-anisyl)ethanone (8c) and 2,2-dichloro-1-(3-chloro-4-methoxyphenyl)ethanone (9) was obtained in 58:42 ratio, respectively, and with 3.3 equiv. of NCS selectively compound 9 was formed in high yield as the sole product.
In the next phase of this study halofunctionalization of isomeric dimethoxyacetophenones 10, 14, 18 and trimethoxyacetophenone 25 were examined (Scheme 2, Scheme 3 and Scheme 4). Transformation of 10 with 1.1 equiv. of NBS furnished a mixture of α-bromoketone 12 and α,α-dibromo derivative 13, whereas with 2.2 equivalents of NBS, 13 was obtained as a sole product in high yield. Compound 10 was regioselectively converted into the α-iodoketone 11 with 1.1 equiv. NIS in good yield (Scheme 2).
Isomeric 2′,4′-dimethoxyacetophenone (14) exhibited different selectivity in reaction with 1.1 equiv. of NIS, forming a mixture of the α-iodoketone 15 as the major product along with 1-acetyl-5-iodo-2,4-dimethoxybenzene (16) and 2-iodo-1-(5-iodo-2,4-dimethoxyphenyl)ethanone (17) as minor products (Scheme 2). 2′,6′-Dimethoxyacetophenone (18) exhibited a similar reactivity trend as 14. Functionalization of 18 with 4.4 equiv. of NCS in IL-A selectively furnished 2,2-dichloro-1-(3,5-dichloro-2,6-dimethoxyphenyl)ethanone (21) in a good yield (Scheme 3). Reaction of 18 with 1.1 equiv. of NIS furnished a mixture of α-iodoketone 19 as major, and 2-iodo-1-(3-iodo-2,6-dimethoxyphenyl)ethanone (20) as minor product. Functionalization of 18 with 1.1 equiv. of NBS yielded the 3-bromo derivative 22 (as the main product), along with 2-bromo-1-(3-bromo-2,6-dimethoxyphenyl)ethanone (23) and 2,2-dibromo-1-(3,5-dibromo-2,6-dimethoxyphenyl)ethanone (24) as minor products. A similar reactivity trend was observed with 2.2 equiv. of NBS, forming 22 and 24 (but 23 was not formed). When 4.4 equiv. of NBS was employed, the tetrabromo-derivative 24 was isolated as the sole product in good yield.
2′,3′,4′-Trimethoxyacetophenone (25) was rapidly (within minutes) converted to the α-iodo derivative 26 with 1.1 equiv. of NIS (Scheme 4). Reaction of 25 with NBS gave a mixture of up to four compounds, depending on the quantity of the NBS. With 1.1 equiv. of NBS the α-bromoketone 27 was the main product, and α,α-dibromoketone 28, 2-bromo-1-(5-bromo-2,3,4-trimethoxyphenyl)ethanone (29) and tribromo-substituted ketone 30 were the minor products. With 2.2 equiv. of NBS 29 and 30 were the only isolated products (27 and 28 were not observed). Reaction of 25 with 3.3 equiv. of NBS exclusively yielded 30 in excellent yield (see Scheme 4).
To explore the potential utility of NXS/IL-A system in ring halogenation of activated arenes, halofunctionalization of anisole (31), 1,3-dimethoxybenzene (34), toluene (37), and 2-methylthiophene (40) were examined (Scheme 5).
Reaction of anisole (31) with 1.1 equiv. of NXS was highly para-selective, forming the corresponding iodo- 32a, bromo- 32b and chloro-derivative 32c (in 84-78% isolated yields) with no ortho-substitution being observed. Reaction of 31 with 2.2 equiv. of NXS selectively produced 2,4-dihaloanisoles 33a–c in high yields.
1,3-Dimethoxybenzene (34) was transformed with 2.2 equiv. of NIS, NBS and NCS into 2,4-dihalo-1,5-dimethoxybenzenes 35a–c in high yields. Transformation of 34 with 3.3 equiv. of NCS led to a dearomatization of the target molecule and the formation of 2,4,4-trichloro-5-methoxycyclohexa-2,5-dienone (36) in 84% yield. This compound is the result of chlorination of aromatic ring resulting primarily in 35c and further regioselective 1,4-addition-elimination process following ipso-chlorination and demethylation of the para-methoxy group, what was confirmed by an independent experiment and the structure of 36 unequivocally distinguished from the possibly formed isomeric 4,6,6-trichloro-3-methoxycyclohexa-2,4-dienone using 2D-NMR measurement techniques HSQC and HMBC (Figure 2). The also expected 1,3,5-trichloro-2,4-dimethoxybenzene was not formed probably because of substantial sterical hindrance between the two methoxy substituents on the aromatic ring.
Halogenation of toluene (37) with 1.1 equiv. of NXS gave 4- and 2-halotoluene. The ortho/para ratio with NIS was 42:58, whereas with NBS and NCS this ratio changed in favor of the ortho-isomer. A similar regioselectivity was reported in halogenation of toluene with NBS and NCS in the presence of FeCl3 [5].
2-Methylthiophene (40) was selectively converted into its 5-iodo derivative 41 in high yield with 1.1 equiv. of NIS. Reaction of 40 with NCS and NBS were also carried out successfully, however the isolated yields were low due to the volatility of the products.
Having discovered these highly efficient halofunctionalization reactions we then explored the possibility to make the process more economical through recycling and reuse of the IL. To explore this possibility, halogenation of acetophenone (1) with 1.1 equiv. of NIS was selected as a prototype reaction and the reaction was successfully repeated in reused/recycled IL-A for 8 cycles (Table 3) with no notable decrease in the conversions. To address the question of relative reactivity of the NXS reagent versus recycling and reuse, bromofunctionalization of 1 with 2.2 equivalents of NBS was examined (Table 3) over 5 repeated cycles, showing a gradual decrease in the dibromo derivative 3b with concomitant increase in monobromo product 2b. The data underscores the importance of IL-A as a promoter in these halogen-transfer reactions.
Finally to explore the feasibility to perform these reactions on larger scales than reported thus far, bromination of 1 was carried out on a 9 mmol scale (a 9 fold increase), by using 19.8 mmols of NBS, and 27 mmol of IL-A. The 2,2-dibromo-1-phenylethanone 3b was obtained in 90% isolated yield after 40 minutes at 70 °C.
Concerning a plausible mechanism for halofunctionalization with NXS/[BMIM(SO3H)][OTf] systems, previous studies [44,45,46,47] have shown that ring halogenations of activated aromatics with NIS, NBS and NCS proceed through an electron transfer (ET) pathway as the main reaction channel. Based on the fact that in the present study under the reaction conditions employed only activated aromatics could be halogenated, and considering the observed chemo- and regioselectivity patterns, in all probability the ET reaction pathway is also most likely operating in these reactions. The role of acidic IL as a catalyst is to enhance the electrophilic character of NXS reagents by additional polarization of N-X bond. In halogenation of phenyl methyl ketones the acidic IL could also act as enolization catalyst, accelerating electrophilic addition of halogen. With the studied ketones, side chain halogenation is the primary event with ring halogenation manifesting only when the ring is highly activated (two methoxy groups).

3. Experimental

3.1. General

All chemicals were purchased from commercial sources and used without further purification. Column chromatography was carried out using silica gel 60 (particle size: 0.063–0.2 mm) and preparative thin layer chromatography using PLC Silica gel 60 F254, 2 mm plates. Melting points were obtained with a Büchi 535 apparatus. For obtaining IR spectra on FTS3000-MX spectrometer, either a KBr pellet of the product was made or NaCl plates were used based on the physical state of product. NMR spectra were recorded on a Bruker Avance 300 DPX instrument (1H: 300 MHz, 13C: 75.5 MHz). The 1H spectra were referred to an internal standard (0 ppm for TMS) or to the residual 1H signal of CHCl3 at 7.26 ppm and for CD3COCD3 at 2.05 ppm (central line). The 13C spectra were referred to the residual signal of CDCl3 (77.0 ppm, central line) or CD3COCD3 (30.8 ppm, central line). Elemental analysis was performed on a Perkin-Elmer 2400-Series 2 apparatus.

3.2. Representative Procedure for Halogenation of Aromatic Compounds

To a stirred mixture of the aromatic compound (1 mmol) in ionic liquid (3 mmol), N-halo-succinimide (1.1–4.4 mmol) was added. The reaction mixture was stirred at 55, 70 or 85 °C until completion (monitored by TLC). The mixture was cooled to room temperature and washed three times with dichloromethane. The combined organic fractions were washed with aqueous Na2S2O3 and NaHCO3, dried over anhydrous Na2SO4 and filtered. Solvent was removed under reduced pressure and the crude reaction mixture was analyzed by 1H-NMR. Isolation of products from reaction mixtures was accomplished by preparative TLC or column chromatography and pure compounds were analyzed by NMR, MS and IR spectroscopy. Data for known compounds were verified from the literature while the new compounds were completely verified by spectroscopic data and C, H, N elemental analysis.
2-Iodo-1-phenylethanone (2a). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min, 55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, orange oil (86%), mp: lit [48] 33–35 °C; 1H-NMR (CDCl3): δ 8.03–7.97 (m, 2H), 7.64–7.57 (m, 1H), 7.54–7.45 (m, 2H), 4.37 (s, 2H); IR(NaCl): 3059, 2976, 2938, 1674, 1595, 1449, 1418, 1271, 1173, 1105, 1001, 791, 747, 703 cm−1; MS (ESI): 247.0 (M+H)+.
2-Bromo-1-phenylethanone (2b). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 20 min, 55 °C), preparative chromatography, SiO2, hexane/CH2Cl2 = 2.5/7.5, white solid (73%), mp: 46.8–48.2 °C (lit [49] 48.8–49.3 °C); 1H-NMR (CDCl3): δ 8.02–7.97 (m, 2H), 7.66–7.57 (m, 1H), 7.55–7.45 (m, 2H), 4.46 (s, 2H); IR (KBr): 3058, 3002, 2951, 1694, 1593, 1447, 1390, 1281, 1198, 991, 881, 746, 685, 623 cm−1; MS (ESI): 199.0 (M+H)+, 201.0 (M+2+H)+.
2-Chloro-1-phenylethanone (2c). One mmol of substrate, 3 mmol IL-B, 1.1 mmol NCS, r.t. = 30 min, 70 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, white solid (74%), mp: 53.2–54.2 °C (lit [50] 55 °C); 1H-NMR (CDCl3): δ 8.00–7.93 (m, 2H), 7.66–7.58 (m, 1H), 7.55–7.46 (m, 2H), 4.71 (s, 2H); IR (neat): 2951, 1692, 1595, 1580, 1448, 1397, 1209, 999, 769, 746, 685, 640 cm−1; MS (ESI): 155.0 (M+H)+, 157.0 (M+2+H)+.
2,2-Dibromo-1-phenylethanone (3b). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS, r.t. = 30 min, 70 °C, CC SiO2, CH2Cl2, white solid (82%), mp: 31.5–32.9 °C (lit [51] 33.5–34.5 °C); 1H-NMR (CDCl3): δ 8.13–8.04 (m, 2H), 7.69–7.60 (m, 1H), 7.57–7.46 (m, 2H), 6.70 (s, 1H); IR (KBr): 1693, 1587, 1445, 1267, 1198, 983, 797, 705, 678, 625 cm−1; MS (ESI): 276.9 (M+H)+, 278.9 (M+2+H)+, 280.9 (M+4+H)+.
2,2-Dichloro-1-phenylethanone (3c). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NCS, r.t. = 120 min, 70 °C, CC SiO2, CH2Cl2, yellow oil [52] (96%); 1H-NMR (CDCl3): δ 8.13–8.06 (m, 2H), 7.69–7.62 (m, 1H), 7.57–7.49 (m, 2H), 6.68 (s, 1H); IR (NaCl): 3065, 3008, 1705, 1595, 1449, 1278, 1222, 1182, 990, 932, 810, 774, 685, 654 cm−1; MS (ESI): 154.0 (M−Cl+H)+, 156.0 (M−Cl+2+H)+.
2-Iodo-1-(2-naphthyl)ethanone (5a). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min, 55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, yellow solid (84%), mp: 87.5–90.2 °C (lit [53] 87–87.5 °C); 1H-NMR (CDCl3): δ 8.54–8.51 (m, 1H), 8.06–7.96 (m, 2H), 7.94–7.87 (m, 2H), 7.67–7.54 (m, 2H), 4.49 (s, 2H); IR(KBr): 1661, 1622, 1464, 1368, 1285, 1231, 1144, 1123, 1094, 1020, 991, 866, 804, 750 cm−1; MS (ESI): 297.0 (M+H)+.
2-Iodo-1-(2-thienyl)ethanone (5b). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min, 55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, yellow oil [54] (80%); 1H-NMR (CDCl3): δ 7.80 (dd, J = 3.9 Hz, J = 1.0 Hz, 1H), 7.69 (dd, J = 4.9 Hz, J = 1.0 Hz, 1H), 7.16 (dd, J = 4.9 Hz, J = 3.9 Hz, 1H), 4.30 (s, 2H); IR (NaCl): 3089, 3036, 2972, 2936, 1650, 1514, 1412, 1355, 1280, 1164, 1099, 1061, 963, 858, 727 cm−1; MS (ESI): 252.9 (M+H)+.
1-(p-Anisyl)-2-iodoethanone (5c). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min, 55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, grey solid (80%), mp: 56.3–59.4 °C (lit [48] 57–59.5 °C); 1H-NMR (CDCl3): δ 7.97 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 4.31 (s, 2H), 3.89 (s, 3H); IR (KBr): 3032, 2972, 1656, 1601, 1568, 1508, 1454, 1422, 1288, 1257, 1173, 1099, 1016, 1001, 845, 754 cm−1; MS (ESI): 277.0 (M+H)+.
2-Bromo-1-(2-naphthyl)ethanone (6a). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 20 min, 55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, grey solid (66%), mp: 80.3–82.2 °C (lit [55] 78–79.5 °C); 1H-NMR (CDCl3): δ 8.54–8.50 (m, 1H), 8.07–7.96 (m, 2H), 7.96–7.87 (m, 2H), 7.68–7.54 (m, 2H), 4.58 (s, 2H); IR (KBr): 2999, 2948, 1690, 1624, 1591, 1468, 1385, 1175, 1159, 1127, 1028, 853, 812, 740, 680 cm−1; MS (ESI): 249.0 (M+H)+, 251.0 (M+2+H)+.
2-Bromo-1-(2-thienyl)ethanone (6b). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 10 min, 55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, yellow oil (72%), mp: lit [56] 31–33 °C; 1H-NMR (CDCl3): δ 7.81 (dd, J = 3.9 Hz, J = 1.0 Hz, 1H), 7.72 (dd, J = 4.9 Hz, J = 1.0 Hz, 1H), 7.17 (dd, J = 4.9 Hz, J = 3.9 Hz, 1H), 4.36 (s, 2H); IR (NaCl): 3098, 2942, 1652, 1514, 1412, 1355, 1287, 1194, 1110, 1061, 973, 939, 854, 727, 667 cm−1; MS (ESI): 204.9 (M+H)+, 206.9 (M+2+H)+.
2-Bromo-1-(p-anisyl)ethanone (6c). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 20 min, 55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, pale red (62%), mp: 68.4–69.7 °C (lit [56] 69–71 °C); 1H-NMR (CDCl3): δ 7.97 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 4.40 (s, 2H), 3.89 (s, 3H); IR (KBr): 2938, 1688, 1597, 1510, 1326, 1263, 1208, 1167, 1115, 1016, 986, 745, 685 cm−1; MS (ESI): 229.0 (M+H)+, 231.0 (M+2+H)+.
2,2-Dibromo-1-(2-naphthyl)ethanone (7a). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS, r.t. = 60 min, 70 °C, CC SiO2, CH2Cl2, white solid (94%), mp: 78.1–80.7 °C (lit [57] 100–101.5 °C); 1H-NMR (CDCl3): δ 8.67–8.63 (m, 1H), 8.13–8.07 (m, 1H), 8.04–7.87 (m, 3H), 7.70–7.56 (m, 2H), 6.86 (s, 1H); IR (KBr): 1682, 1620, 1587, 1358, 1273, 1182, 1153, 1119, 820, 733, 683, 623 cm−1; MS (ESI): 326.9 (M+H)+, 328.9 (M+2+H)+, 330.9 (M+4+H)+.
2,2-Dibromo-1-(2-thienyl)ethanone (7b). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS, r.t. = 30 min, 70 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, orange oil [58] (85%); 1H-NMR (CDCl3): δ 8.03–7.98 (m, 1H), 7.80–7.76 (m, 1H), 7.22–7.18 (m, 1H), 6.48 (s, 1H); IR (NaCl): 3098, 3013, 1669, 1512, 1411, 1354, 1279, 1179, 1065, 937, 858, 726, 665, 638 cm−1; MS (ESI): 282.9 (M+H)+, 284.9 (M+2+H)+, 286.8 (M+4+H)+.
2,2-Dibromo-1-(p-anisyl)ethanone (7c). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS, r.t. = 30 min, 70 °C, CC SiO2, CH2Cl2, white solid (91%), mp: 86.7–88.9 °C (lit [51] 93–94 °C); 1H-NMR (CDCl3): δ 8.08 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 6.66 (s, 1H), 3.90 (s, 3H); IR(KBr): 3032, 1674, 1597, 1566, 1504, 1420, 1314, 1263, 1202, 1177, 1146, 1020, 982, 845, 810, 761, 706, 683 cm−1; MS (ESI): 306.9 (M+H)+, 308.9 (M+2+H)+, 310.9 (M+4+H)+.
2,2-Dichloro-1-(2-naphthyl)ethanone (8a). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NCS, r.t. = 150 min, 70 °C, CC SiO2, CH2Cl2, yellow solid (86%), mp: 66.6–69.8 °C (lit [59] 80–80.5 °C); 1H-NMR (CDCl3): δ 8.68–8.62 (m, 1H), 8.13–8.06 (m, 1H), 8.04–7.87 (m, 3H), 7.71–7.56 (m, 2H), 6.83 (s, 1H); IR (KBr): 3059, 1699, 1626, 1596, 1466, 1357, 1282, 1219, 1175, 1125, 866, 824, 785, 742, 657 cm−1; MS (ESI): 239.0 (M+H)+, 241.0 (M+2+H)+.
2,2-Dichloro-1-(2-thienyl)ethanone (8b). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NCS, r.t. = 90 min, 70 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 3.5/6.5, orange oil [60] (67%); 1H-NMR (CDCl3): δ 8.02 (dd, J = 3.9 Hz, J = 1.0 Hz, 1H), 7.80 (dd, J = 4.9 Hz, J = 1.0 Hz, 1H), 7.21 (dd, J = 4.9 Hz, J = 3.9 Hz, 1H), 6.47 (s, 3H); IR (NaCl): 3100, 3007, 1682, 1512, 1409, 1356, 1277, 1240, 1217, 1188, 1067, 944, 858, 802, 720, 668 cm−1; MS (ESI): 194.9 (M+H)+.
2,2-Dichloro-1-(p-anisyl)ethanone (8c). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NCS, r.t. = 90 min, 70 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 3.5/6.5, white solid (36%), mp: 76.9–78.2 °C (lit [61] 78–79 °C); 1H-NMR (CDCl3): δ 8.08 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 6.63 (s, 1H), 3.90 (s, 3H); IR (KBr): 3028, 1683, 1600, 1568, 1506, 1422, 1318, 1298, 1265, 1236, 1175, 1024, 847, 795, 745, 646 cm−1; MS (ESI): 219.0 (M+H)+, 221 (M+2+H)+.
2,2-Dichloro-1-(3-chloro-4-methoxyphenyl)ethanone (9). One mmol of substrate, 3 mmol IL-A, 3.3 mmol NCS, r.t. = 180 min, 70 °C; preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5; white solid (76%); mp: 99.3–100.9 °C; 1H-NMR (CDCl3): δ 8.14 (d, J = 2.3 Hz, 1H), 8.05 (dd, J = 8.8 Hz, J = 2.3 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.57 (s, 1H), 4.00 (s, 3H); 13C-NMR (CD3COCD3): δ 185.7, 161.9, 133.1, 132.5, 127.0, 124.6, 114.3, 70.0, 58.2; IR (KBr): 2982, 1686, 1591, 1508, 1318, 1281, 1227, 1182, 1148, 1065, 1009, 824, 797, 750, 700, 631 cm−1; MS (ESI): 253.0 (M+H)+, 255.0 (M+2+H)+; HRMS: calcd for C9H8Cl3O2: 252.9590; found: 252.9601; Anal. Calcd for C9H7Cl3O2: C, 42.64; H, 2.78. Found: C, 42.92; H, 2.72.
2-Iodo-1-(3,4-dimethoxyphenyl)ethanone (11). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 15 min, 55 °C, preparative chromatography SiO2, CH2Cl2, yellow solid (69%), mp: 62.0–65.0 °C (lit [62] 65.2–66.2 °C); 1H-NMR (CDCl3): δ 7.62 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.33 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H); IR (KBr): 2934, 2837, 1652, 1583, 1514, 1451, 1425, 1273, 1231, 1154, 1095, 1019, 877, 810, 768, 748, 617 cm−1; MS (ESI): 307.0 (M+H)+.
2-Bromo-1-(3,4-dimethoxyphenyl)ethanone (12). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 60 min, 55 °C, preparative chromatography SiO2, CH2Cl2, white solid (63%), mp: 80.5–81.6 °C (lit [63] 80–81 °C); 1H-NMR (CDCl3): δ 7.62 (dd, J = 8.4 Hz, J = 1.9 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.41 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H); IR (KBr): 2966, 2940, 2843, 1682, 1586, 1515, 1466, 1420, 1283, 1244, 1155, 1020, 868, 798, 769, 683, 619 cm−1; MS (ESI): 259.0 (M+H)+, 261.0 (M+2+H)+.
2,2-Dibromo-1-(3,4-dimethoxyphenyl)ethanone (13). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS, r.t. = 120 min, 70 °C; column chromatography SiO2, CH2Cl2; white solid (87%); mp: 79.0–81.7 °C; 1H-NMR (CDCl3): δ 7.74 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.69 (s, 1H), 3.98 (s, 3H), 3.95 (s, 3H); 13C-NMR (CD3COCD3): 186.8, 156.9, 151.6, 126.2, 125.4, 113.7, 112.8, 57.4, 57.3, 43.3; IR (KBr): 3017, 2967, 2933, 2837, 1676, 1587, 1518, 1454, 1416, 1350, 1279, 1238, 1190, 1155, 1016, 881, 800, 756, 689, 621 cm−1; MS (ESI): 336.9 (M+H)+, 338.9 (M+2+H)+, 340.9 (M+4+H)+; HRMS: calcd for C10H11Br2O3: 336.9075; found: 336.9084.
2-Iodo-1-(2,4-dimethoxyphenyl)ethanone (15). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min, 55 °C, preparative chromatography SiO2, CH2Cl2, brown solid (34%), mp: 64.5–67.0 °C (lit [48] 55–57.5 °C); 1H-NMR (CDCl3): δ 7.91 (d, J = 8.8 Hz, 1H), 6.56 (dd, J = 8.8 Hz, J = 2.3 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 4.46 (s, 2H), 3.94 (s, 3H), 3.87 (s, 3H); IR (KBr): 3009, 2940, 2838, 1657, 1595, 1499, 1454, 1414, 1333, 1267, 1211, 1161, 1109, 1023, 984, 826, 610 cm−1; MS m/z (CI): 307.0 (M+H)+.
1-Acetyl-5-iodo-2,4-dimethoxybenzene (16). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min, 55 °C, preparative chromatography SiO2, CH2Cl2, grey solid (3%), mp: 130.3–134.0 °C (lit [48] 142–145 °C); 1H-NMR (CDCl3): δ 8.23 (s, 1H), 6.39 (s, 1H), 3.94 (s, 3H), 3.94 (s, 3H), 2.56 (s, 3H); IR (KBr): 1647, 1591, 1464, 1391, 1357, 1321, 1271, 1231, 1022, 830 cm−1; MS (ESI): 307.0 (M+H)+, HRMS: calcd for C10H12IO3: 306.9831; found: 306.9821.
2-Iodo-1-(5-iodo-2,4-dimethoxyphenyl)ethanone (17). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min, 55 °C; preparative chromatography SiO2, CH2Cl2); yellow solid (8%); mp: 145.8–148.6 °C; 1H-NMR (CDCl3): δ 8.32 (s, 1H), 6.41 (s, 1H), 4.42 (s, 2H), 4.00 (s, 3H), 3.97 (s, 3H); 13C-NMR (CD3COCD3): δ 192.0, 165.2, 163.6, 143.4, 120.4, 98.1, 76.4, 58.4, 57.8, 10.7; IR (KBr): 1635, 1585, 1464, 1403, 1389, 1329, 1262, 1213, 1017, 919, 818 cm−1; MS (ESI): 432.9 (M + H)+; HRMS: calcd for C10H11I2O3: 432.8798; found: 432.8788.
2-Iodo-1-(2,6-dimethoxyphenyl)ethanone (19). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min, 55 °C, preparative chromatography SiO2, CH2Cl2, yellow solid (47%), mp: 51.7–54.6 °C (lit [48] 58–60.5 °C); 1H-NMR (CDCl3): δ 7.31 (t, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 2H), 4.30 (s, 2H), 3.83 (s, 6H); IR (KBr): 2937, 2837, 1713, 1593, 1474, 1429, 1378, 1307, 1284, 1250, 1161, 1121, 1091, 980, 773, 722 cm−1; MS (ESI): 307.0 (M+H)+.
2-Iodo-1-(3-iodo-2,6-dimethoxyphenyl)ethanone (20). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min, 55 °C; preparative chromatography SiO2, CH2Cl2; yellow oil (10%); 1H-NMR (CDCl3): δ 7.75 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 8.8 Hz, 1H), 4.31 (s, 2H), 3.84 (s, 3H), 3.82 (s, 3H); 13C-NMR (CD3COCD3): δ 195.4, 159.9, 159.0, 143.0, 125.0, 111.8, 82.0, 64.5, 57.9, 11.1; IR (NaCl): 2967, 2938, 2838, 1694, 1574, 1462, 1433, 1395, 1282, 1244, 1165, 1084, 1003, 913, 805 cm−1; MS (ESI): 432.9 (M + H)+: HRMS: calcd for C10H11I2O3: 432.8798; found: 432.8788.
2,2-Dichloro-1-(3,5-dichloro-2,6-dimethoxyphenyl)ethanone (21). One mmol of substrate, 3 mmol IL-A, 4.4 mmol NCS, r.t. = 1080 min, 85 °C; preparative chromatography SiO2, hexane/CH2Cl2 = 1/1; white solid (65%); mp: 53.4–54.4 °C; 1H-NMR (CD3COCD3): δ 7.77 (s, 1H), 6.92 (s, 1H), 3.92 (s, 6H); 13C-NMR (CD3COCD3): δ 189.0, 154.8, 135.5, 129.7, 125.4, 72.5, 64.3; IR (KBr): 3016, 2946, 1738, 1568, 1462, 1414, 1214, 1070, 984, 926, 872, 818, 773, 714, 641 cm−1; Anal. Calcd for C10H8Cl4O3: C, 37.77; H, 2.54. Found: C, 37.89; H, 2.36.
1-Acetyl-3-bromo-2,6-dimethoxybenzene (22). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 10 min, 55 °C, preparative chromatography SiO2, CH2Cl2, yellow oil [64] (63%); 1H-NMR (CDCl3): δ 7.48 (d, J = 8.9 Hz, 1H), 6.61 (d, J = 8.9 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2.49 (s, 3H); IR(NaCl): 3004, 2940, 2873, 2839, 1707, 1580, 1464, 1401, 1351, 1285, 1240, 1219, 1183, 1092, 1007, 971, 910, 801, 689, 652 cm−1; MS (ESI): 259.0 (M+H)+, 261.0 (M+2+H)+.
2-Bromo-1-(3-bromo-2,6-dimethoxyphenyl)ethanone (23). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 10 min, 55 °C; preparative chromatography SiO2, CH2Cl2; yellow oil (8%); 1H-NMR (CDCl3): δ 7.54 (d, J = 8.9 Hz, 1H), 6.64 (d, J = 8.9 Hz, 1H), 4.36 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H); 13C-NMR (CD3COCD3): δ 194.5, 158.9, 156.4, 137.1, 125.7, 111.1, 109.4, 64.1, 57.9, 38.6; IR (NaCl): 2941, 1707, 1580, 1464, 1403, 1285, 1227, 1180, 1132, 1088, 1005, 916, 803 cm−1; MS (ESI): 336.9 (M+H)+, 338.9 (M+2+H)+, 340.9 (M+4+H)+; HRMS: calcd for C10H11Br2O3: 336.9075; found: 336.9082.
2,2-Dibromo-1-(3,5-dibromo-2,6-dimethoxyphenyl)ethanone (24). One mmol of substrate, 3 mmol IL-A, 4.4 mmol NBS, r.t. = 360 min, 85 °C; preparative chromatography SiO2, hexane/CH2Cl2 = 1/1); white solid (72%); mp: 54.9–57.6 °C; 1H-NMR (CD3COCD3): δ 8.05 (s, 1H), 6.88 (s, 1H), 3.90 (s, 6H); 13C-NMR (CD3COCD3): δ 188.5, 156.6, 140.9, 129.5, 114.4, 64.5, 45.2; IR (KBr): 3017, 2939, 1723, 1559, 1456, 1406, 1275, 1220, 1165, 1066, 982, 916, 799 615 cm−1; MS (ESI): 494.7 (M+2+H)+, 496.7 (M+4+H)+, 498.7 (M+6+H)+; HRMS: calcd for C10H9Br4O3: 492.7285; found: 492.7296; Anal. Calcd for C10H8Br4O3: C, 24.23; H, 1.63. Found: C, 24.37; H, 1.61.
2-Iodo-1-(2,3,4-trimethoxyphenyl)ethanone (26). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 60 min, 55 °C, preparative chromatography SiO2, CH2Cl2, yellow oil [63] (68%); 1H-NMR (CDCl3): δ 7.59 (d, J = 8.9 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H), 4.49 (s, 2H), 4.07 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H); IR (NaCl): 2941, 2840, 1661, 1587, 1493, 1464, 1410, 1287, 1212, 1096, 1005, 924, 881, 808, 697 cm−1; MS (ESI): 337.0 (M+H)+.
2-Bromo-1-(2,3,4-trimethoxyphenyl)ethanone (27). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 30 min, 55 °C, preparative chromatography SiO2, CH2Cl2, white solid [65] (44%), mp: 39.8–42.0 °C; 1H-NMR (CDCl3): δ 7.61 (d, J = 8.9 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 4.57 (s, 2H), 4.05 (s, 3H), 3.93 (s, 3H), 3.87 (s, 3H); IR (NaCl): 2941, 2843, 1680, 1589, 1493, 1464, 1410, 1294, 1213, 1099, 999, 809, 668 cm−1; MS (ESI): 289.0 (M+H)+, 291.0 (M+2+H)+.
2,2-Dibromo-1-(2,3,4-trimethoxyphenyl)ethanone (28). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 30 min, 55 °C; preparative chromatography SiO2, CH2Cl2; white solid (14%); mp: 42.9–44.6 °C; 1H-NMR (CDCl3): δ 7.64 (d, J = 9.0 Hz, 1H), 7.09 (s, 1H), 6.76 (d, J = 9.0 Hz, 1H), 4.08 (s, 3H), 3.94 (s, 3H), 3.87 (s, 3H); 13C-NMR (CD3COCD3): δ 188.2, 161.0, 155.5, 143.7, 128.8, 121.3, 109.9, 63.6, 62.0, 57.7, 46.5; IR (KBr): 3020, 2942, 1682, 1588, 1495, 1462, 1410, 1293, 1217, 1097, 989, 814, 687 cm−1; MS (ESI): 366.9 (M+H)+, 368.9 (M+2+H)+, 370.9 (M+4+H)+; HRMS: calcd for C11H13Br2O4: 366.9181; found: 366.9175; Anal. Calcd for C11H12Br2O4: C, 35.90; H, 3.29. Found: C, 36.29; H, 3.29.
2-Bromo-1-(5-bromo-2,3,4-trimethoxyphenyl)ethanone (29). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS, r.t. = 120 min, 70 °C; preparative chromatography SiO2, CH2Cl2; colorless oil (37%); 1H-NMR (CDCl3): δ 7.75 (s, 1H), 4.52 (s, 2H), 4.05 (s, 3H), 3.99 (s, 3H), 3.90 (s, 3H); 13C-NMR (CD3COCD3): δ 191.6, 157.3, 155.8, 149.2, 129.8, 128.0, 113.0, 63.2, 62.5, 62.5, 38.6; IR(NaCl): 3073, 2942, 1692, 1574, 1462, 1403, 1304, 1260, 1223, 1092, 1051, 995, 932, 889, 872, 791, 674 cm−1; MS (ESI): 366.9 (M+H)+, 368.9 (M+2+H)+, 370.9 (M+4+H)+; HRMS: calcd for C11H13Br2O4: 366.9181; found: 366.9186; Anal. Calcd for C11H12Br2O4: C, 35.90; H, 3.29. Found: C, 35.91; H, 3.15.
2,2-Dibromo-1-(5-bromo-2,3,4-trimethoxyphenyl)ethanone (30). One mmol of substrate, 3 mmol IL-A, 3.3 mmol NBS, r.t. = 120 min, 70 °C; preparative chromatography SiO2, hexane/CH2Cl2 = 1/9); yellow oil (88%); 1H-NMR (CD3COCD3): δ 7.70 (s, 1H), 7.22 (s, 1H), 4.11 (s, 3H), 4.00 (s, 3H), 3.94 (s, 3H); 13C-NMR (CD3COCD3): δ 187.6, 157.8, 155.5, 149.0, 130.4, 125.3, 113.2, 63.7, 62.6, 62.6, 45.9; IR (NaCl): 2943, 1690, 1574, 1463, 1403, 1304, 1258, 1216, 1090, 1047, 993, 797, 669 cm−1; MS (ESI): 444.8 (M+H)+, 446.8 (M+2+H)+, 448.8 (M+4+H)+, 450.8 (M+6+H)+; HRMS: calcd for C11H12Br3O4: 444.8286; found: 444.8291; Anal. Calcd for C11H11Br3O4: C, 29.56; H, 2.48. Found: C, 29.44; H, 2.27.
p-Iodoanisole (32a). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 20 min, 55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 7.5/2.5, white solid (84%), mp: 42.1–44.4 °C (lit [48] 47–49.5 °C); 1H-NMR (CDCl3): δ 7.55 (d, J = 9.0 Hz, 2H), 6.68 (d, J = 9.0 Hz, 2H), 3.78 (s, 3H); IR (KBr): 2965, 2936, 2835, 1584, 1481, 1450, 1285, 1244, 1173, 1026, 993, 807 cm−1.
p-Bromoanisole (32b). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 20 min, 55 °C, CC (SiO2, hexane, colorless oil [9] (81%); 1H-NMR (CDCl3): δ 7.37 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 3.78 (s, 3H); IR (NaCl): 3004, 2957, 2937, 2903, 2835, 1579, 1487, 1460, 1290, 1249, 1171, 1072, 1032, 1003, 822 cm−1.
p-Chloroanisole (32c). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NCS, r.t. = 30 min, 55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 7.5/2.5, colorless oil [66] (78%); 1H-NMR (CDCl3): δ 7.24 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 9.0 Hz, 1H), 3.79 (s, 3H); IR (NaCl): 3006, 2959, 2940, 2906, 2837, 1593, 1492, 1460, 1290, 1245, 1181, 1169, 1092, 1063, 1032, 824, 750, 686, 639, 626 cm−1.
2,4-Diiodoanisole (33a). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NIS, r.t. = 30 min, 70 °C, CC (SiO2, CH2Cl2, white solid (92%), mp: 65.8–67.0 °C (lit [67] 67.5–68.5 °C); 1H-NMR (CDCl3): δ 8.04 (d, J = 2.1 Hz, 1H), 7.58 (dd, J = 8.6 Hz, J = 2.1 Hz, 1H), 6.58 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H); IR (KBr): 1582, 1469, 1429, 1275, 1246, 1182, 1142, 1034, 866, 797, 656 cm−1.
2,4-Dibromoanisole (33b). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS, r.t. = 180 min, 85 °C, CC SiO2, hexane/CH2Cl2 = 7.5/2.5, white solid (90%), mp: 53.5–56.0 °C (lit [67] 61–62 °C); 1H-NMR (CDCl3): δ 7.67 (d, J = 2.3 Hz, 1H), 7.38 (dd, J = 8.8 Hz, J = 2.3 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H); IR (NaCl): 3080, 2973, 2936, 2835, 1574, 1476, 1456, 1379, 1289, 1250, 1052, 1020, 876, 804, 679, 619 cm−1.
2,4-Dichloroanisole (33c). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NCS, r.t. = 30 min, 70 °C, CC SiO2, hexane/CH2Cl2 = 7.5/2.5, colorless oil [66] (89%); 1H-NMR (CDCl3): δ 7.37 (d, J = 2.5 Hz, 1H), 7.19 (dd, J = 8.8 Hz, J = 2.5 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H); IR (NaCl): 3075, 3011, 2965, 2940, 2901, 2841, 1580, 1484, 1439, 1389, 1292, 1263, 1184, 1106, 1065, 1025, 870, 835, 805, 716, 642 cm−1.
1,5-Diiodo-2,4-dimethoxybenzene (35a). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NIS, r.t. = 20 min, 70 °C, column chromatography (SiO2, CH2Cl2, white solid (89%), mp: 193.6–196.5 °C (lit [68] 201–202 °C); 1H-NMR (CDCl3): δ 8.04 (s, 1H), 6.37 (s, 1H), 3.89 (s, 6H); IR (neat): 1568, 1556, 1458, 1452, 1428, 1357, 1275, 1207, 1177, 1034, 1014, 886, 813, 652 cm−1; MS (ESI): 389.9 (M)+.
1,5-Dibromo-2,4-dimethoxybenzene (35b). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NBS, r.t. = 30 min, 70 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, white solid (70%), mp: 135.5–138.4 °C (lit [69] 138–139 °C); 1H-NMR (CDCl3): δ 7.66 (s, 1H), 6.50 (s, 1H), 3.91 (s, 6H); IR (neat): 1579, 1570, 1487, 1463, 1432, 1367, 1287, 1208, 1175, 1061, 1052, 1019, 877, 864, 813, 805, 687, 680 cm−1.
1,5-Dichloro-2,4-dimethoxybenzene (35c). One mmol of substrate, 3 mmol IL-A, 2.2 mmol NCS, r.t. = 120 min, 70 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5, white solid (82%), mp: 111.6–114.2 °C (lit [70] 118–119 °C); 1H-NMR (CDCl3): δ 7.36 (s, 1H), 6.54 (s, 1H), 3.91 (s, 6H); IR (neat): 1738, 1578, 1492, 1466, 1454, 1428, 1374, 1295, 1229, 1206, 1171, 1085, 1021, 861, 804, 740 cm−1.
2,4,4-Trichloro-5-methoxycyclohexa-2,5-dienone (36). One mmol of substrate, 3 mmol IL-A, 3.3 mmol NCS, r.t. = 45 min, 70 °C; preparative chromatography SiO2, hexane/CH2Cl2 = 2.5/7.5; yellow solid (84%); mp: 114.6–116.2 °C; 1H-NMR (CDCl3): δ 7.13 (s, 1H), 5.65 (s, 1H), 3.94 (s, 3H); 13C-NMR (CD3COCD3): δ 178.3, 169.5, 139.7, 132.4, 101.2, 76.3, 59.3; IR (neat): 1738, 1657, 1595, 1459, 1347, 1269, 1217, 1156, 1034, 974, 934, 898, 838, 783, 698, 686, 608 cm−1; MS (ESI): 226.9 (M+H)+, 228.9 (M+2+H)+, 230.9 (M+4+H)+; HRMS: calcd for C7H6Cl3O2: 226.9433; found: 226.9431; Anal. Calcd for C7H5Cl3O2: C, 36.96; H, 2.22. Found: C, 37.13; H, 2.23.
p-Iodotoluene+o-Iodotoluene (38a, 39a). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 20 min, 55 °C, preparative chromatography SiO2, hexane/CH2Cl2 = 99.7/0.3, yellow oil [71] (49%); 1H-NMR (CDCl3): δ 7.80 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 4.1 Hz, 2H), 6.92 (d, J = 8.1 Hz, 2H), 6.90-6.82 (m, 1H), 2.43 (s, 3H), 2.29 (s, 3H).
p-Bromotoluene+o-Bromotoluene (38b, 39b). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NBS, r.t. = 20 min, 55 °C; 1H-NMR (CDCl3): δ 7.55–7.49 (m, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.29–7.14 (m, 2H), 7.08–6.99 (m, 3H), 2.40 (s, 3H), 2.30 (s, 3H) [72].
p-Chlorotoluene+o-Chlorotoluene (38c, 39c). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NCS, r.t. = 180 min, 70 °C; 1H-NMR (CDCl3): δ 7.37–7.31 (m, 1H), 7.25–7.07 (m, 7H), 2.39 (s, 3H), 2.32 (s, 3H) [73].
5-Iodo-2-methylthiophene (41). One mmol of substrate, 3 mmol IL-A, 1.1 mmol NIS, r.t. = 10 min, 55 °C, CC SiO2, hexane/CH2Cl2 = 7.5/2.5), yellow oil [74] (81%); 1H-NMR (CDCl3): δ 7.00 (d, J = 3.5 Hz, 1H), 6.44 (dq, J = 3.5 Hz, J = 0.9 Hz, 1H), 2.49 (d, J = 0.9 Hz, 3H).

3.3. Scale up Experiment

To a stirred mixture of acetophenone (1, 9 mmol, 1.08 g) in IL-A (27 mmol, 9.95 g), N-bromo succinimide (19.8 mmol, 3.52 g) was added. The reaction mixture was stirred at 70 °C for 40 min. Then the mixture was cooled to room temperature and washed three times with dichloromethane. The combined organic fractions were washed with aqueous Na2S2O3 and NaHCO3, dried over anhydrous Na2SO4 and filtered. Solvent was removed under reduced pressure and the crude reaction mixture was analyzed with 1H-NMR. Purification of crude reaction mixture by chromatography yielded 2.25 g (90%) of 3b.

3.4. Recycling/Reuse of IL-A in Iodination of Acetophenone (1) with NIS

To a stirred mixture of acetophenone (1, 1 mmol, 120 mg) in IL-A (3 mmol, 368 mg), N-iodo succinimide (1.1 mmol, 225 mg) was added. The reaction mixture was stirred at 55 °C for 10 minutes. Then the mixture was cooled to room temperature and washed three times with dichloromethane. The combined organic fractions were washed with aqueous Na2S2O3 and NaHCO3, dried over anhydrous Na2SO4 and filtered. Solvent was removed under reduced pressure and the crude reaction mixture was analyzed with 1H-NMR. Purification of crude reaction mixture with chromatography yielded 212 mg (86%) of 2a. The IL-A from reaction was dried under reduced pressure and reused.

4. Conclusions

In summary, the Brønsted acidic ionic liquid 1-methyl-3-(4-sulfobutyl)imidazolium triflate ([BMIM(SO3H)][OTf]; IL-A) exhibited a notable catalytic effect in the halofunctionalization of aromatics with NXS and transformations were significantly faster as compared to IL-B. Aryl methyl ketones were α- and α,α-dihalogenated with high selectivity and in respectable yields. In the case of methoxy-substituted acetophenones, competing ring halogenation occurred. Activated arenes were selectively mono- and dihalogenated. A noteworthy feature is exclusive para-halogenation of anisole with NXS/IL-A. Recycling and reuse of [BMIM(SO3H)][OTf] was demonstrated in a prototype iodination reaction in eight cycles with no decrease in the conversion. The catalytic role of IL-A in dibromination with NBS is manifested in higher mono- to dihalogenation ratios when the reaction is repeated in the used IL. The feasibility for scale-up was also demonstrated in a representative case.

Acknowledgments

The authors are grateful to the staff of the Mass Spectroscopy Centre at Jožef Stefan Institute for mass spectrometric measuraments and prof. B. Stanovnik for elemental analysis. The Slovenian Research Agency (contracts: Programme ARRS P1-0134, Young Researchers Fellowship ARRS 1000-08-310039, and USA/Si bilateral project BI-US/12-13-004) and European Regional Development Found (OP 13.1.1.2.02.0005) are acknowledged for financial support.

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Sample Availability: Samples of all the compounds except 16, 17, 20, 23, 28, 38a–c, 39a–c and 41 are available from the authors.
Molecules 18 00074 g001 550
Figure 1. Structure of investigated imidazolium-based ionic liquids IL-A and IL-B.
Figure 1. Structure of investigated imidazolium-based ionic liquids IL-A and IL-B.
Molecules 18 00074 g001
Molecules 18 00074 sch001 550
Scheme 1. Chlorination of 4′-methoxyacetophenone (4c) with NCS.
Scheme 1. Chlorination of 4′-methoxyacetophenone (4c) with NCS.
Molecules 18 00074 sch001
Molecules 18 00074 sch002 550
Scheme 2. Halofunctionalization of 3′,4′-dimethoxyacetophenone (10) and 2′,4′-dimethoxyacetophenone (14) with NXS reagents in [BMIM(SO3H)][OTf] (IL-A) medium a.
Scheme 2. Halofunctionalization of 3′,4′-dimethoxyacetophenone (10) and 2′,4′-dimethoxyacetophenone (14) with NXS reagents in [BMIM(SO3H)][OTf] (IL-A) medium a.
Molecules 18 00074 sch002
Molecules 18 00074 sch003 550
Scheme 3. Halofunctionalization of 2′,6′-dimethoxyacetophenone (18) with NXS reagents in [BMIM(SO3H)][OTf] (IL-A) medium a.
Scheme 3. Halofunctionalization of 2′,6′-dimethoxyacetophenone (18) with NXS reagents in [BMIM(SO3H)][OTf] (IL-A) medium a.
Molecules 18 00074 sch003
Molecules 18 00074 sch004 550
Scheme 4. Halofunctionalization of 2′,3′,4′-trimethoxyacetophenone (25) with NXS reagents in [BMIM(SO3H)][OTf] (IL-A) medium a.
Scheme 4. Halofunctionalization of 2′,3′,4′-trimethoxyacetophenone (25) with NXS reagents in [BMIM(SO3H)][OTf] (IL-A) medium a.
Molecules 18 00074 sch004
Molecules 18 00074 sch005 550
Scheme 5. Transformation of activated aromatic molecules with N-halosuccinimides (NXS) in [BMIM(SO3H)][OTf] (IL-A) a.
Scheme 5. Transformation of activated aromatic molecules with N-halosuccinimides (NXS) in [BMIM(SO3H)][OTf] (IL-A) a.
Molecules 18 00074 sch005
Molecules 18 00074 g002 550
Figure 2. Copies of 2D-NMR spectra for 2,4,4-trichloro-5-methoxycyclohexa-2,5-dienone (36).
Figure 2. Copies of 2D-NMR spectra for 2,4,4-trichloro-5-methoxycyclohexa-2,5-dienone (36).
Molecules 18 00074 g002
Table
Table 1. Halogenation of acetophenone 1 with N-halosuccinimides (NXS) in 1-butyl-3-methylimidazolium based ionic liquids a.
Table 1. Halogenation of acetophenone 1 with N-halosuccinimides (NXS) in 1-butyl-3-methylimidazolium based ionic liquids a.
Molecules 18 00074 i001
EntryXNXS (equiv.)ILT (°C)Reaction time (min)Conversion of 1 b (%)2 / 3
1I1.1IL-B551013100 / 0
2I1.1IL-A55109893 / 7
3Br1.1IL-B552022100 / 0
4Br1.1IL-A55209586 / 14
5Br2.2IL-B703060100 / 0
6Br2.2IL-A70301000 / 100
7Cl1.1IL-B70309785 / 15
8Cl1.1IL-A70304790 / 10
9Cl1.1IL-A70906315 / 85
10Cl2.2IL-B70309291 / 9
11Cl2.2IL-A70301000 / 100
a Reaction conditions: 1 mmol of 1, 1.1 or 2.2 mmol of NXS stirred in 3 mmol of IL; b Conversion determined by 1H-NMR.
Table
Table 2. The effect of aryl methyl ketone 4 structure on halofunctionalization with N-halosuccinimides (NXS) in [BMIM(SO3H)][OTf] (IL-A) a.
Table 2. The effect of aryl methyl ketone 4 structure on halofunctionalization with N-halosuccinimides (NXS) in [BMIM(SO3H)][OTf] (IL-A) a.
Molecules 18 00074 i002
EntryArReaction conditionsa
NXS (mmol) / T (°C) / t (min)		ProductsYield (%) b
5 or 67 or 8
1 Molecules 18 00074 i003NIS (1.1) / 55 / 10 5a94 (84)
2NBS (1.1) / 55 / 206a / 7a72 (66)19 (18)
3NBS (2.2) / 70 / 607a 96 (94)
4NCS (2.2) / 70 / 1508a 97 (86)
5 Molecules 18 00074 i004NIS (1.1) / 55 / 10 5b91 (80)
6NBS (1.1) / 55 / 106b / 7b75 (72)16 (15)
7NBS (2.2) / 70 / 307b 95 (85)
8NCS (2.2) / 70 / 608b 96 (67)
9 Molecules 18 00074 i005NIS (1.1) / 55 / 10 5c92 (80)
10NBS (1.1) / 55 / 206c / 7c71 (62)22 (20)
11NBS (2.2) / 70 / 307c 100 (91)
a Reaction conditions: 1 mmol of 4, 1.1 or 2.2 mmol of NXS stirred in 3 mmol of IL-A at 55–70 °C for 10 to 150 min; b Relative yields determined by 1H-NMR, values in the brackets refer to the yields of isolated pure products.
Table 3. The effect of [BMIM(SO3H)][OTf] (IL-A) recycling on transformation of acetophenone 1 with NXS reagents.
Table
 
 
Molecules 18 00074 i006
Repetition numberYield (%)
186
290
390
488
590
689
787
892
Table
 
 
Molecules 18 00074 i007
Repetition numberProduct distribution (2b:3b)
10:100
24:96
312:88
425:75
533:67

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MDPI and ACS Style

Vražič, D.; Jereb, M.; Laali, K.K.; Stavber, S. Brønsted Acidic Ionic Liquid Accelerated Halogenation of Organic Compounds with N-Halosuccinimides (NXS). Molecules 2013, 18, 74-96. https://doi.org/10.3390/molecules18010074

AMA Style

Vražič D, Jereb M, Laali KK, Stavber S. Brønsted Acidic Ionic Liquid Accelerated Halogenation of Organic Compounds with N-Halosuccinimides (NXS). Molecules. 2013; 18(1):74-96. https://doi.org/10.3390/molecules18010074

Chicago/Turabian Style

Vražič, Dejan, Marjan Jereb, Kenneth K. Laali, and Stojan Stavber. 2013. "Brønsted Acidic Ionic Liquid Accelerated Halogenation of Organic Compounds with N-Halosuccinimides (NXS)" Molecules 18, no. 1: 74-96. https://doi.org/10.3390/molecules18010074

APA Style

Vražič, D., Jereb, M., Laali, K. K., & Stavber, S. (2013). Brønsted Acidic Ionic Liquid Accelerated Halogenation of Organic Compounds with N-Halosuccinimides (NXS). Molecules, 18(1), 74-96. https://doi.org/10.3390/molecules18010074

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