2015, Vol.26 
b MOE Key Laboratory of Protein Sciences, Department of Pharmacology and Pharmaceutical Sciences, School of Medicine and School of Life Sciences, Tsinghua University, Beijing 100084, China
2-Chloro aromatic ketones serve as versatile building blocks for the synthesis of various heterocycles,such as derivatives of indazoles,derivatives of benzo[d]isoxazoles,derivatives of indoles,derivatives of quinolinone,derivatives of benzo[b]thiophenes and derivatives of benzo[d]isothiazoles,etc. [1]. Moreover,introducing chlorine atom on drug candidates is a commonly used strategy to modulate the bioactivities of these molecules [2].
Traditionally,there are mainly two approaches (Scheme 1) for the synthesis of 2-chloro aromatic ketones: (1) Early-stage introducing chlorine atom on the starting material for aromatic ketone synthesis [3],such as Friedel-Crafts acylation; (2) latestage introducing chlorine atom on the ketone molecules through functional group transformations,such as the widely used Sandmeyer reaction [4]. Both strategies rely on pre-functionalization of the starting material for aromatic ketone synthesis,which usually involve a multi-step process to assemble the targeted ketone molecules. In recent years,transition-metal-catalyzed C(sp2)-H activation reactions have received more and more attention,which are atom economic and step economic [5]. Inour continuous studies toward transition-metal-catalyzed C(sp2)- H halogenation reactions [6],we envisioned that 2-chloro aromatic ketones could be accessed through palladium-catalyzed ortho-selective C(sp2)-H chlorination of aromatic ketones under proper conditions (Scheme 1).
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| Scheme 1. Different approaches for the synthesis of 2-chloro aromatic ketones. | |
We chose benzophenone (1a) as the substrate to explore the reaction conditions (Table 1). The reaction was initiated with Pd(OAc)2 as catalyst,NCS as chlorination reagent,and DCE as solvent. After being stirred at 80 ℃ for 10 h,no desired chlorination product (1b) was observed and all of the starting material remained (entry 1). Based on our experience and understanding of weak coordination [7],we believed that suitable acid could possibly promote this reaction. Then we began to screen weak and strong acids. Delightfully,when 1.0 equiv. of TfOH was added,the desired chlorination product (1b) was obtained in 85% 1H NMR yield (entry 4),with minor amount of unknown side products. In contrast,AcOH and TFA were ineffective. Subsequential cooxidants screening found that the 1H NMR yield of (1b) could be further improved to 95% in the presence of K2S2O8 (entry 6). Na2S2O8 and (NH4)2S2O8 gave similar results (entry 5 and 7). Without palladium catalyst,there was no reaction (entry 8). Other palladium catalysts,such as Pd(MeCN)Cl2,gave relatively lowyields (entry 9). DCE was proved to be the better solvent. Other solvents,such PhMe,only gave 10% 1H-NMR yield (entry 10). The reaction could also proceed at 60 ℃ with a slightly lower 1H NMR yield (entry 12). In general,the reaction will proceed to completion with 10 mol% Pd(OAc)2,1.0 equiv. of TfOH,1.05 equiv. of NCS,1.05 equiv. of K2S2O8 in DCE within 10 h at 80 ℃.
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Table 1 Optimization of reaction conditions. |
Aromatic ketones (0.2 mmol,1.0 equiv.),NCS (0.21 mmol,1.05 equiv.),Pd(OAc)2 (0.01 mmol,0.05 equiv.) and K2S2O8 (0.21 mmol,1.05 equiv.) were dissolved in commercially available dichloroethane (1 mL). Then TfOH (0.2 mmol,1.0 equiv.) was added into the reaction solution. The reaction mixture was stirred at 80 ℃ for 3-30 h. After completion of the reaction,the mixture was cooled to room temperature and then saturated NaHCO3 aqueous solution was added to quench the reaction. The organiclayer was separated,dried over anhydrous Na2SO4 and concentrated on rotavapor under reduced pressure. Finally the residue was purified by silical gel column chromatography to give corresponding products.
2-(Chlorophenyl)(phenyl)methanone (1b): 1H NMR (400 MHz,CDCl3): δ 7.83-7.81 (m,2H),7.60 (t,1H,J = 7.6 Hz),7.49-7.42 (m,4H),7.39-7.37 (m,2H); 13C NMR (100 MHz,CDCl3): δ 195.4,138.8,136.7,133.8,131.5,131.2,130.2,129.3,128.8,126.8; LRMS (ESI) calcd. for C13H10ClO [M+H]+: 217.03,found 217.03.
1-(2-Chloro-4-methylphenyl)-2,2-dimethylpropan-1-one (2b): 1H NMR (400 MHz,CDCl3): δ 7.21 (s,1H),7.06 (d,1H,J = 7.96 Hz),7.02 (d,1H,J = 7.76 Hz),2.34 (s,3H),1.25 (s,9H); 13C NMR (100 MHz,CDCl3): δ 211.9,140.2,137.8,130.4,129.4,127.0,126.1,45.3,27.0,21.1; LRMS (ESI) calcd. for C12H16ClO [M+H]+: 271.08,found 271.25.
1-(2-Chloro-4-fluorophenyl)-2,2-dimethylpropan-1-one (3b): 1H NMR (400 MHz,CDCl3): δ 7.17-7.12 (m,2H),7.02-6.98 (m,1H),1.26 (s,9H); 13C NMR (100 MHz,CDCl3): δ 210.9,162.4 (d,J = 250 Hz),136.7 (d,J = 4.05 Hz),130.9 (d,J = 10.17 Hz),127.5 (d,J = 8.93 Hz),117.6 (d,J = 24.46 Hz),113.8 (d,J = 21.48 Hz),45.5,27.0; LRMS (ESI) calcd. for C11H13ClFO [M+H]+: 215.06,found 215.28.
1-(2,4-Dichlorophenyl)-2,2-dimethylpropan-1-one (4b): 1H NMR (400 MHz,CDCl3): δ 7.42 (d,1H,j = 1.7 Hz),7.28-7.26 (m,1H),7.09 (d,1H,J = 8.2 Hz),1.26 (s,1H); 13C NMR (100 MHz,CDCl3): δ 210.7,139.0,135.2,130.7,130.0,127.2,126.8,45.4,27.0; LRMS (ESI) calcd. for C11H13Cl2O [M+H]+: 231.03,found 231.98.
1-(4-Bromo-2-chlorophenyl)-2,2-dimethylpropan-1-one (5b): 1H NMR (400 MHz,CDCl3): δ 7.58 (d,1H,J = 1.68 Hz),7.41 (dd,1H,J = 1.72 Hz,J = 8.14 Hz),7.02 (d,1H,J = 8.16 Hz),1.25 (s,1H); 13C NMR (100 MHz,CDCl3): δ 210.6,139.5,132.8,130.8,129.6,127.4,122.9,45.4,26.9; LRMS (ESI) calcd. for C11H13BrClO [M+H]+: 274.98,found 274.12.
1-(2-Chloro-4-methoxyphenyl)-2,2-dimethylpropan-1-one (6b): 1H NMR (400 MHz,CDCl3): δ 7.07 (d,1H,J = 8.36 Hz),6.92 (s,1H),6.79 (d,1H,J = 7.88 Hz),3.18 (s,3H),1.25 (s,9H); 13C NMR (100 MHz,CDCl3): δ 211.3,160.1,132.9,130.6,127.0,115.2,112.2,55.6,45.3,27.0; LRMS (ESI) calcd. for C19H24ClO [M+H]+:227.08,found 227.96.
Adamantan-1-yl(2-chloro-3,5-dimethylphenyl)methanone (7b): 1H NMR (400 MHz,CDCl3):δ 7.04 (s,1H),6.72 (s,1H),2.34 (s,3H),2.30 (s,3H),2.04 (s,3H),1.95 (m,6H),1.75-1.68 (m,3H); 13C NMR (100 MHz,CDCl3): δ 211.8,140.5,136.8,136.0,131.7,126.3,124.4,47.3,38.5,36.6,28.1,21.0,20.2; LRMS (ESI) calcd. for C12H16ClO2 [M+H]+: 303.14,found 303.05.
Adamantan-1-yl(2-chloro-4-methylphenyl)methanone (8b): 1H NMR (400 MHz,CDCl3): δ 7.20 (s,1H),7.06 (d,1H,J = 7.72 Hz),6.99 (d,1H,J = 7.72 Hz),2.34 (s,3H),2.04 (s,3H),1.94 (m,6H),1.75-1.66 (m,6H); 13C NMR (100 MHz,CDCl3): δ 211.0,140.0,137.3,130.2,129.3,126.8,126.2,47.4,38.3,36.4,27.9,21.0; LRMS (ESI) calcd. for C18H22ClO [M+H]+: 289.13,found 289.41.
Adamantan-1-yl(2-chloro-5-methylphenyl)methanone (9b): 1H NMR (400 MHz,CDCl3): δ 7.26-7.24 (m,1H),7.09 (d,1H,J = 8.12 Hz),6.89 (s,1H),2.34 (s,3H),2.04 (s,3H),1.95-1.94 (d,6H,J = 2.08 Hz),1.72-1.71 (m,6H); 13C NMR (100 MHz,CDCl3): δ 211.3,140.2,136.3,130.5,129.6,126.9,126.4,47.4,38.4,36.6,28.1,21.1; LRMS (ESI) calcd. for C18H22ClO [M+H]+: 289.13,found 289.07.
2.3. General procedure for the preparation of 3-phenylbenzo[d]isoxazole (11)A mixture of aromatic ketone (1b,216 mg,1 mmol,1.0 equiv.),hydroxylamine hydrochloride (83.4 mg,1.2 mmol,1.2 equiv.) and sodium acetate trihydrate (163.3 mg,1.2 mmol,1.2 equiv.)dissolved in ethanol (5 mL) were refluxed for 24 h under Ar atmosphere. H2O was added to the mixture and the reaction mixture was extracted by ethyl acetate (8 mL 3 times). The combined organic phase was washed with brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography to give intermediate product (196.4 mg,85%).
A mixture of intermediate (21.4 mg,0.1 mmol,1.0 equiv.) and t-BuOK (22.4 mg,0.2 mmol,2.0 equiv.) in THF (3 mL) was refluxed for 10 h. H2O was added to the mixture and the reaction mixture was extracted by ethyl acetate (8 mL × 3). The combined organic phase was washed with brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography to give product (11,17.6 mg,88%). 1H NMR (400 MHz,CDCl3): δ 7.99-7.93 (m,3H),7.67-7.54 (m,5H),7.40- 7.37 (m,1H); 13C NMR (100 MHz,CDCl3): δ 164.0,157.4,130.4,129.9,129.3,129.1,128.2,124.0,122.4,120.6; LRMS (ESI) calcd. for C13H10NO [M+H]+: 196.07,found 196.04.
2.4. General procedure for the preparation of 3-phenyl-1-tosyl- 1H-indazole (12)Acetyl chloride (0.4 g,0.36 mL,5.1 mmol,5.1 equiv.) was added slowly to 4 mL EtOH at 0 ℃. Stirring was continued for 30 min at room temperature. (2-Chlorophenyl)(phenyl)methanone (1b,1.0 mmol,1.0 equiv.) was dissolved in ethanol (6 mL) and added to acidic EtOH-solution followed by addition of p-toluenesulfonylhydrazide (0.48 g,2.6 mmol,2.6 equiv.). The reaction was stirred overnight (18 h) at room temperature. The reaction was monitored by TLC. When the reaction completed,the reaction mixture was poured into water (10 mL). The obtained mixture was rotary evaporated until the complete removal of EtOH. The residue was extracted by EtOAc (8 mL × 3). The reactions were monitored by TLC,wherein the mixture was poured into water and the aqueous solution extracted with EtOAc. Combined organic layer was washed with water (20 mL) and brine (20 mL),dried over Na2SO4,filtered and concentrated on rotavapor under reduced pressure. Finally the residue was purified by silical gel column chromatography to give corresponding intermediate product (30.7 mg,80%).
A mixture of intermediate (38.4 mg,0.1 mmol,1 equiv.),PdCl2(dppf)•DCM (8.16 mg,0.01 mmol,0.1 equiv.),and t-BuOK (22.4 mg,0.2 mmol,2 equiv.) dissolved in dioxane (3 mL) was stirred at 80 ℃ for 6 h under Ar atmosphere. The reaction mixture was filtered through a pad of Celite and the filtrate was evaporated. The residue was purified by silica gel column chromatography eluting with hexane-ethyl acetate (8:1) to give product (12,29.6 mg,85%). 1H NMR (400 MHz,CDCl3): δ 8.27 (d,1 H,J = 8.48 Hz),7.94-7.90 (m,5H),7.58 (t,1H,J = 7.68 Hz),7.52- 7.47 (m,3H),7.37 (t,1H,J = 7.68 Hz),7.24 (t,3H,J = 8.12 Hz),2.34 (s,3H); 13C NMR (100 MHz,CDCl3): δ 151.8,145.4,142.0,134.8,131.6,129.9,129.7,129.2,129.0,128.4,127.8,124.6,124.5,121.8,113.8,21.8; LRMS (ESI) calcd. for C20H17N2O2S [M+H]+: 349.09,found 349.00.
3. Results and discussionWith the optimized conditions in hand,we began to study the substrates scope of this chlorination reaction. As displayed in Table 2,a variety of ketones were smoothly transformed into the corresponding 2-chloro aromatic ketones in good to excellent yields. To examine the functional groups tolerance of this reaction,a series of ketones with para-methyl,F,Cl,Br,and methoxyl groups,was prepared and examined (2a-6a). The results showed that this reaction could tolerate with either electron-donating functional groups (methyl and methoxyl group) or electronwithdrawing functional groups (F,Cl and Br). To further study the influence of substitution patterns to the reactivity,several ketones with para,meta,and ortho-methyl group,were tested (7a-10a). Both para and meta-methyl substituted ketones gave satisfactory yields (7b-9b). However,there was no reaction at all for ortho-methyl substituted ketone (10b),possibly due to the large steric hindrance between adamantly and methyl groups. It should be noted that air- or moisture-proof operations were not essential for this reaction.
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Table 2 Substrates scope for C–H chlorination of aromatic ketones. |
To further exemplify the synthetic utility of this chlorination reaction,two biologically important heterocyclic compounds were selected as synthetic targets. Compound (11) has fungistatic activity against Pestalotia annonicola [8]. Indazole derivatives are also important compounds in medicinal chemistry fields [9]. As shown in Scheme 2,derivatives of benzo[d]isoxazole and 1H-indazole were readily prepared from the chlorination compound (1b) in satisfactory yields by a nucleophilic addition and cyclization sequence [1, 10]. Additionally this method should be potentially used to late-stage modification of drugs with aryl ketone scaffold,such as Ketoprofen and Fenofibrate.
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| Scheme 2. Applications in heterocycle synthesis. Conditions: (a) 2 equiv. NH2OH•HCl, EtOH, reflux; (b) 2 equiv. t-BuOK, THF, reflux; (c) 5.1 equiv AcCl, 1 equiv. Ts-NHNH2,EtOH, reflux (d) 0.1 equiv. PdCl2(dppf)•DCM, 2 equiv. t-BuOK, dioxane, 80 ℃. | |
In summary,a convenient and efficient method for the preparation of 2-chloro aromatic ketones was developed. Chlorine atom was successfully introduced on the ketone molecules through palladium-catalyzed ortho-selective C(sp2)- H chlorination. This efficient approach toward 2-chloro aromatic ketones paved the way for the synthesis of various heterocycles. Moreover,this chlorination reaction had the potential for latestage modification of drug candidates and rapid access of drug analogs.
AcknowledgmentsThis work was supported by ‘973’ grant (Nos. 2011CB965300),NSFC (Nos. 21142008,21302106),Tsinghua University 985 Phase II funds and the Tsinghua University Initiative Scientific Research Program.
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