催化学报  2015, Vol. 36 Issue (1): 78-85   PDF (7329 KB)    
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郭腾龙
姜权彬
余立坤
余正坤
Synthesis of chalcones via domino dehydrochlorination/Pd(OAc)2-catalyzed Heck reaction
Tenglong Guoa, Quanbin Jianga, Likun Yub, Zhengkun Yua     
a Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning, China;
b Fertilizer Analysis Station of Technology Center, SINOPEC Baling Petrochemical Company, Yueyang 414003, Hunan, China
Received: 2014-08-22. Accepted: 2014-09-22. Published: 2015-01-20.
* Corresponding author.Tel/Fax: +86-411-84379227; E-mail: zkyu@dicp.ac.cn
Foundation Item:This work was supported by the National Natural Science Foundation of China (21272232).
Abstract: A new method has been developed for the cross-coupling of aryl halides with β-chloroalkyl aryl ketones and their ester and amide analogs through a domino dehydrochlorination/Pd(OAc)2-catalyzed Heck reaction sequence. The enone intermediates generated in situ reduced the occurrence of side reactions and therefore enhanced the efficiency of the reaction. This reaction exhibited good tolerance to various functional groups on both substrates and provides rapid access to a wide range of chalcone derivatives.
© 2014, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
Key words: β-Chloroalkyl aryl ketone     Heck reaction     Enone     Domino reaction     Chalcone    
经由Domino脱HCl/Pd(OAc)2催化的Heck反应合成查尔酮
郭腾龙a, 姜权彬a, 余立坤b, 余正坤a     
a 中国科学院大连化学物理研究所, 辽宁大连116023;
b 中国石化巴陵石化分公司技术中心化肥分析站, 湖南岳阳414003
收稿日期: 2014-08-22. 接受日期: 2014-09-22. 出版日期: 2015-01-20.
基金来源：国家自然科学基金(21272232).
*通讯联系人.余正坤, 电话/传真: (0411) 84379227; 电子信箱: zkyu@dicp.ac.cn
摘要：通过Domino脱HCl/Pd(OAc)2催化的Heck反应实现了β-氯代烷基芳基酮、酯和酰胺与卤代芳烃的交叉偶联反应, 高效合成了查尔酮类化合物. 利用原位生成烯酮为中间体进行反应的策略, 减少副反应的发生, 从而提高反应的效率. 该方法对各种官能团的容忍性好, 为从氯代烷烃出发直接合成查尔酮类化合物提供了一条新途径.
关键词： β-氯代烷基芳基酮     Heck反应     烯酮     Domino反应     查尔酮    

1. Introduction

Chalcones are an important class of biologically active compounds (Scheme 1) [1, 2], which have been reported to exhibit a wide range of pharmacological properties, including anticancer, anti-inflammatory, antioxidant, antimicrobial, and antiallergic activity [3]. Compounds belonging to this structural class are also recognized as important intermediates for the synthesis of heterocyclic systems [4, 5, 6] and functional materials [7, 8]. Chalcones are generally synthesized using a Claisen-Schmidt condensation [9]. However, the overall efficiency and functional group tolerance of this reaction are usually poor because of its requirement for strongly basic conditions. To overcome these limitations, several transition-mental-catalyzed cross- coupling reactions have been developed for the synthesis of chalcones, which can be conducted under relatively mild conditions [10, 11, 12, 13].

Scheme 1. Examples of bioactive chalcones.

The Pd-catalyzed Heck reaction is one of the most powerful methods for the arylation and vinylation of alkenes [14]. Although chalcones can be generated directly by the Heck-type cross-coupling of aryl halides with aryl vinyl ketones, there have been very few examples of this reaction in the literature [15, 16]. The main reason for the lack of publications in this area can be attributed to the poor stability of most aryl vinyl ketones (enones), which can decompose upon exposure to heat, light and oxygen during their preparation and storage. Multi-step procedures are therefore often required for the preparation of α,β-unsaturated carbonyl compounds starting from the corresponding saturated carbonyl compounds [17, 18]. For the synthesis of chalcones using enones as substrates, it is envisaged that a domino reaction sequence involving the in-situ generation of an enone followed by its cross- coupling with an aryl halide would provide facile access to a broad range of chalcones. The Pd-catalyzed cross-coupling reactions of propiophenones with aryl carboxylic acids [19] and (hetero)arenes [20] have been reported to afford chalcones via the in-situ generation of the corresponding enones. The decarboxylative arylation of benzoylacrylic acids has also been reported to provide access to chalcones in a similar manner [21]. Although these methods represent useful strategies for the synthesis of chalcones, their overall utility has been limited by their general requirement for high loadings of the catalysts and oxidants under relatively harsh conditions. We recently found that β-chloroalkyl aryl ketones and their ester and amide analogs could be used as precursors to α,β-unsaturated carbonyls in the Rh(I)-catalyzed conjugate addition by arylboronic acids [22], as well as the Pd-catalyzed, Cu-mediated synthesis of carbazoles [23]. As part of our ongoing research into the development of new domino reactions [24], we envisioned that in-situ generated enones could be employed in a Heck-type cross-coupling reaction under mild conditions without the addition of an oxidant. Herein, we report the development of a new method for the synthesis of chalcones by Pd-catalyzed formal sp2 C-X (X = I, Br) / sp3 C-Cl cross-coupling of aryl halides with β-chloroalkyl aryl ketones, and their ester and amide analogs.

2. Experimental

General considerations. All the aryl halides were purchased from commercial suppliers and used as provided without further purification. The β-chloroalkyl carbonyl compounds were either purchased from commercial suppliers or prepared according to the literature procedures [22]. Compounds 3a-3c [21], 3d [25], 3e and 3f [21], 3g [26], 3h [21], 3i [25], 3j [21], 3k [27], 3l [27], 3m [21], 3n [28], 5a and 5b [10], 5c [29], 5d [30], 5e [31], 5f and 5g [10], 5h and 5i [25], 5j [32], 5k [33], 5l [34], and 5m and 5n [35] are known compounds and the spectroscopic features of the materials synthesized in current study were found to be in good agreement with those reported in the literature. All of the solvents used in the current study were freshly distilled prior to use. 1H and 13C NMR spectra were recorded on a Bruker DRX-400 spectrometer (Bruker, German) and all the chemical shift values were measured relative to tetramethylsilane (TMS; δTMS = 0.00) or the residual chloroform peak of CDCl3 [δ (1H) = 7.26; δ (13C) = 77.16].

General procedure for the synthesis of chalcones - synthesis of chalcone 3a. A mixture of Pd(OAc)2 (4.5 mg, 0.02 mmol), PPh3 (11.2 mg, 0.04 mmol), iodobenzene (1a) (82 mg, 0.4 mmol), 3-chloropropiophenone (2a) (87 mg, 0.5 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (2.5 mL) was stirred under a N2 atmosphere at room temperature for 10 min, and then heated at 90 °C for 16 h. The reaction was then cooled to ambient temperature and diluted with CH2Cl2 (10 mL) before being filtered through a short pad of silica gel. The silica pad was rinsed with DCM (5 mL), and the combined filtrates were washed with brine (15 mL), dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure to give the crude product as a residue, which was purified by silica gel column chromatography eluting with a mixture of petroleum ether (60-90 °C)/EtOAc (v/v = 30:1).

(E)-Chalcone(3a) [21]. Yield 90%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 7.3 Hz, 2H, aromatic CH), 7.90 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.72 (dd, J = 6.3, 2.8 Hz, 2H, aromatic CH), 7.69-7.55 (m, 4H, aromatic CH and CH=CHCOPh), 7.52-7.46 (m, 3H, aromatic CH).

(E)-1-Phenyl-3-(p-tolyl)prop-2-en-1-one (3b) [21]. Yield 83%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.07-7.99 (m, 2H, aromatic CH), 7.80 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.61-7.46 (m, 6H, aromatic CH and CH=CHCOPh), 7.24 (t, J = X Hz, 2H, aromatic CH), 2.40 (s, 3H, CH3).

(E)-1-phenyl-3-(m-tolyl)prop-2-en-1-one (3c) [21]. Yield 84%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 7.4 Hz, 2H, aromatic CH), 7.85 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.58 (m, 4H, aromatic CH and CH=CHCOPh), 7.49 (d, J = 6.0 Hz, 2H, aromatic CH), 7.35 (t, 1H, aromatic CH), 7.28 (t, 1H, aromatic CH), 2.44 (s, 3H, CH3).

(E)-1-Phenyl-3-(o-tolyl)prop-2-en-1-one (3d) [25]. Yield 87%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 15.6 Hz, 1H, CH=CHCOPh), 8.08 (m, 2H, aromatic CH), 7.75 (d, J = 7.4 Hz, 1H, aromatic CH), 7.63 (t, J = X Hz, 1H, aromatic CH), 7.53 (m, 3H, aromatic CH and CH=CHCOPh), 7.35 (t, 1H, aromatic CH), 7.28 (m, 2H, aromatic CH), 2.52 (s, 3H, CH3).

(E)-3-(4-Methoxyphenyl)-1-phenylprop-2-en-1-one (3e) [21]. Yield 85%, white solid. 1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.1 Hz, 2H, aromatic CH), 7.79 (d, J = 15.6 Hz, 1H, CH=CHCOPh), 7.59 (m, 3H, aromatic CH), 7.50 (t, J = X Hz, 2H, aromatic CH), 7.42 (d, J = 15.6 Hz, 1H, CH=CHCOPh), 6.94 (d, J = 8.5 Hz, 2H, aromatic CH), 3.86 (s, 3H, OCH3).

(E)-3-(4-Chlorophenyl)-1-phenylprop-2-en-1-one (3f) [21]. Yield 86%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.00 (m, 2H, aromatic CH), 7.74 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.57 (m, 3H, aromatic CH), 7.49 (m, 3H, aromatic CH and CH=CHCOPh), 7.37 (d, J = 8.5 Hz, 2H, aromatic CH).

(E)-3-(2-Chlorophenyl)-1-phenylprop-2-en-1-one (3g) [26]. Yield 81%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 15.8 Hz, 1H, CH=CHCOPh), 8.02 (d, J = 7.2 Hz, 2H, aromatic CH), 7.75 (dd, J = 7.0, 2.4 Hz, 1H, aromatic CH), 7.59 (t, J = X Hz, 1H, aromatic CH), 7.50 (m, 3H, aromatic CH and CH=CHCOPh), 7.43 (m, 1H, aromatic CH), 7.32 (m, 2H, aromatic CH).

(E)-3-(4-fluorophenyl)-1-phenylprop-2-en-1-one (3h) [21]. Yield 91%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 7.3 Hz, 2H, aromatic CH), 7.77 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.66-7.56 (m, 3H, aromatic CH), 7.49 (m, 3H, aromatic CH and CH=CHCOPh), 7.10 (t, 2H, aromatic CH).

(E)-1-Phenyl-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one (3i) [25]. Yield 80%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 7.6 Hz, 2H, aromatic CH), 7.80 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.73 (d, J = 8.1 Hz, 2H, aromatic CH), 7.66 (d, J = 8.1 Hz, 2H, aromatic CH), 7.60 (m, 2 H, aromatic CH and CH=CHCOPh), 7.51 (t, J = 7.5 Hz, 2H, aromatic CH).

(E)-Methyl 4-(3-oxo-3-phenylprop-1-en-1-yl)benzoate (3j) [21]. Yield 79%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.08-7.98 (m, 4 H, aromatic CH), 7.79 (d, J = 15.7, 1H, CH=CHCOPh), 7.67 (dd, J = 8.3, 1.8 Hz, 2H, aromatic CH), 7.62-7.55 (m, 2H, aromatic CH and CH=CHCOPh), 7.49 (m, 2H, aromatic CH), 3.92 (s, 3H, CO2CH3).

(E)-4-(3-Oxo-3-phenylprop-1-en-1-yl)benzonitrile (3k) [27]. Yield 70%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 7.4 Hz, 2H, aromatic CH), 7.78-7.70 (m, 3H, aromatic CH and CH=CHCOPh), 7.68 (d, J = 8.6 Hz, 2H, aromatic CH), 7.64-7.57 (m, 2H, aromatic CH and CH=CHCOPh), 7.51 (t, 2H, aromatic CH).

(E)-3-(4-Nitrophenyl)-1-phenylprop-2-en-1-one (3l) [27]. Yield 58%, yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 8.7 Hz, 2H, aromatic CH), 8.04 (d, J = 7.3 Hz, 2H, aromatic CH), 7.81 (m, 3H, aromatic CH and CH=CHCOPh), 7.64 (m, 2H, aromatic CH and CH=CHCOPh), 7.53 (t, J = 7.6 Hz, 2H, aromatic CH).

(E)-3-(4-Acetylphenyl)-1-phenylprop-2-en-1-one (3m) [21]. Yield 51%, yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.01 (m, 4 H, aromatic CH), 7.80 (d, J = 15.8 Hz, 1H, CH=CHCOPh), 7.71 (d, J = 8.4 Hz, 2H, aromatic CH), 7.64-7.56 (m, 2H, aromatic CH and CH=CHCOPh), 7.50 (m, 2H, aromatic CH), 2.62 (s, 3H, CH3).

(E)-1-Phenyl-3-(thiophen-2-yl)prop-2-en-1-one (3n) [28]. Yield 75%, yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 7.6 Hz, 2H, aromatic CH), 7.94 (d, J = 15.3 Hz, 1H, CH=CHCOPh), 7.57 (t, J = X Hz, 1H, aromatic CH), 7.49 (t, J = X Hz, 2H, aromatic CH), 7.41 (d, J = 5.0 Hz, 1H, thienyl CH), 7.37-7.30 (m, 2H, thienyl CH and CH=CHCOPh), 7.11-7.03 (m, 1 H, thienyl CH).

(E)-3-Phenyl-1-(p-tolyl)prop-2-en-1-one (5a) [10]. Yield 83%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 8.2 Hz, 2H aromatic CH), 7.82 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.64 (m, 2H, aromatic CH), 7.55 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.41 (m, 3H, aromatic CH), 7.30 (d, J = 8.1 Hz, 2H, aromatic CH), 2.43 (s, 3H, CH3).

(E)-1-(4-Methoxyphenyl)-3-phenylprop-2-en-1-one (5b) [10]. Yield 89%, white solid. 1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 8.8 Hz, 2H, aromatic CH), 7.80 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.63 (m, 2H, aromatic CH), 7.55 (d, J = 15.6 Hz, 1H, CH=CHCOPh), 7.40 (m, 3H, aromatic CH), 6.97 (d, J = 8.8 Hz, 2H, aromatic CH), 3.86 (s, 3H, OCH3).

(E)-1-(3,4-Dimethylphenyl)-3-phenylprop-2-en-1-one (5c) [29]. Yield 83%, white solid. 1H NMR (400 MHz, CDCl3): δ = 7.80 (m, 3H, aromatic CH and CH=CHCOPh), 7.65 (m, 2H, aromatic CH), 7.55 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.46-7.39 (m, 3H, aromatic CH), 7.26 (d, J = 7.8 Hz, 1H, aromatic CH), 2.35 (d, J = 3.8 Hz, 6H, 2×CH3).

(E)-1-(2,4-Dimethylphenyl)-3-phenylprop-2-en-1-one (5d) [30]. Yield 84%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 7.57 (m, 2H, aromatic CH), 7.52 (d, J = 16.0 Hz, 1H, CH=CHCOPh), 7.47 (d, J = 7.6 Hz, 1H, aromatic CH), 7.40 (m, 3H, aromatic CH), 7.19 (d, J = 16.0 Hz, 1H, CH=CHCOPh), 7.10 (d, J = 9.1 Hz, 2H, aromatic CH), 2.46 (s, 3H, CH3), 2.39 (s, 3H, CH3).

(E)-1-(2,5-Dimethylphenyl)-3-phenylprop-2-en-1-one (5e) [31]. Yield 82%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 7.58 (m, 2H, aromatic CH), 7.48 (d, J = 16.1 Hz, 1H, CH=CHCOPh), 7.40 (m, 3H, aromatic CH), 7.31 (s, 1H, aromatic CH), 7.22-7.12 (m, 3H, aromatic CH and CH=CHCOPh), 2.41 (s, 3H, CH3), 2.38 (s, 3H, CH3).

(E)-1-(4-Chlorophenyl)-3-phenylprop-2-en-1-one (5f) [10]. Yield 86%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 8.4 Hz, 2H, aromatic CH), 7.81 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.64 (m, 2H, aromatic CH), 7.47 (m, 3H, aromatic CH and CH=CHCOPh), 7.41 (m, 3H, aromatic CH).

(E)-1-(4-Fluorophenyl)-3-phenylprop-2-en-1-one (5g) [10]. Yield 90%, pale yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.06 (dd, J = 8.7, 5.5 Hz, 2H, aromatic CH), 7.82 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.64 (m, 2H, aromatic CH), 7.51 (d, J = 15.7 Hz, 1H, CH=CHCOPh), 7.46-7.37 (m, 3H, aromatic CH), 7.17 (t, J = X Hz, 2H, aromatic CH).

(E)-3-Phenyl-1-(thiophen-2-yl)prop-2-en-1-one (5h) [25]. Yield 80%, yellow solid. 1H NMR (400 MHz, CDCl3): δ = 7.90-7.81 (m, 2H, thienyl CH and CH=CHCOPh), 7.70-7.60 (m, 3H, thienyl CH and aromatic CH), 7.40 (m, 4H, aromatic CH and CH=CHCOPh), 7.18 (t, J = 4.2 Hz, 1H, thienyl CH).

(E)-1-(Furan-2-yl)-3-phenylprop-2-en-1-one (5i) [25]. Yield 78%, yellow solid. 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 15.8 Hz, 1H, CH=CHCOPh), 7.63 (m, 3H, furyl CH and aromatic CH), 7.49-7.37 (m, 4H, aromatic CH and CH=CHCOPh), 7.32 (d, J = 3.3 Hz, 1H, furyl CH), 6.57 (dd, J = 3.4 and 1.5 Hz, 1H, furyl CH).

(E)-1-(1-Methyl-1H-indol-3-yl)-3-phenylprop-2-en-1-one (5j) [32]. Yield 85%, white solid. 1H NMR (400 MHz, CDCl3): δ = 8.54 (dd, J = 6.5, 2.3 Hz, 1H, indolyl CH), 7.80 (d, J = 15.6 Hz, 1H, CH=CHCOPh), 7.75 (d, J = 2.6 Hz, 1H, indolyl CH), 7.61 (d, J = 7.3 Hz, 2H, aromatic CH), 7.38 (m, 3H, aromatic CH), 7.34-7.25 (m, 4H, aromatic CH and CH=CHCOPh), 3.77 (s, 3H, NCH3).

m-Tolyl cinnamate (5k) [33]. Yield 79%, white solid. 1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 16.0 Hz, 1H, CH=CHCOOPh), 7.66-7.55 (m, 2H, aromatic CH), 7.44 (m, 3H, aromatic CH), 7.31 (t, J = 7.7 Hz, 1H, aromatic CH), 7.09 (d, J = 7.6 Hz, 1H, aromatic CH), 7.01 (d, J = 8.6 Hz, 2H, aromatic CH), 6.66 (d, J = 16.0 Hz, 1H, CH=CHCOOPh), 2.40 (s, 3H, CH3).

4-Chlorophenyl cinnamate (5l) [34]. Yield 77%, white solid. 1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 16.0 Hz, 1H, CH=CHCOOPh), 7.60 (m, 2H, aromatic CH), 7.45 (m, 3H, aromatic CH), 7.38 (d, J = 8.8 Hz, 2H, aromatic CH), 7.14 (d, J = 8.8 Hz, 2H, aromatic CH), 6.63 (d, J = 16.0 Hz, 1H, CH=CHCOOPh).

N-Methyl-N-(p-tolyl)cinnamamide (5m) [35]. Yield 90%, white solid. 1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 15.6 Hz, 1H, CH=CHCONAr), 7.29 (m, 5H), 7.22 (d, J = 8.0 Hz, 2H, aromatic CH), 7.10 (d, J = 8.1 Hz, 2H, aromatic CH), 6.39 (d, J = 15.6 Hz, 1H, CH=CHCONAr), 3.38 (s, 3H, NCH3), 2.40 (s, 3H, CH3).

N-(4-Chlorophenyl)-N-methylcinnamamide (5n) [35]. Yield 88%, white solid. 1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 15.5 Hz, 1H, CH=CHCONAr), 7.41 (d, J = 7.5 Hz, 2H, aromatic CH), 7.32 (m, 5H, aromatic CH), 7.18 (d, J = 7.5 Hz, 2H, aromatic CH), 6.35 (d, J = 15.5 Hz, 1H, CH=CHCONAr), 3.39 (s, 3H, NCH3).

3. Results and discussion
3.1. Optimization of the reaction conditions

The reaction of iodobenzene (1a) with a single equivalent of 3-chloropropiophenone (2a) was selected as a model reaction for the optimization of the reaction conditions. The model reaction was initially conducted in dioxane at 90 °C under a N2 atmosphere using 5 mol% Pd(OAc)2 as the catalyst, 10 mol% PPh3 as the ligand, and K3PO4 as the base, which gave the desired chalcone product 3a in a GC yield of 74% (Table 1, entry 1). Several other solvents were screened in the reaction, including MeCN, DMF, DMSO, PhCH3 and H2O, and DMF was found to provide the best results in terms of the yield of the chalcone product 3a (Table 1, entries 2-6). It is noteworthy that the reaction proceeded smoothly in H2O to form 3a in moderate yield (Table 1, entry 6). Having identified the optimum solvent, we proceeded to screen a series of different bases, including K2CO3, Na2CO3 and Cs2CO3 (Table 1, entries 7-10). Interestingly, K3PO4 and K2CO3 both worked more efficiently than Na2CO3, whereas the use of the stronger base Cs2CO3 failed to provide any of the desired products (Table 1, entry 9). Increasing the loading of 2a to 1.25 equiv. led to an increase in the isolated yield to 90% when K2CO3 was used as the base (Table 1, entry 11).In contrast, increasing the loading of 1a to 1.25 equiv. led to a slight decrease in the yield (Table 1, entry 12).

Table 1
Screening of conditions for the reaction of 1a with 2a.

Notably, only trace amounts of 4, formed from the dimerization of the in-situ generated enone—that is, the phenyl vinyl ketone from the dehydrochlorination of 2a—were detected during the optimization of this reaction.

3.2. Substrate scope

With the optimized conditions in hand, we proceeded to evaluate the scope of the reaction using a series of aryl halides (Table 2). Pleasingly, aryl iodides bearing an electron-donating group such as a methyl or methoxy group reacted smoothly with 2a to give the desired products 3b-3e in 83%-87% yields (Table 2, entries 2-5). Furthermore, compound 2a reacted with 4-, 3- and 2-iodotoluene to give the corresponding products in similar high yields, showing no obvious steric effect (Table 2, entries 2-4). Aryl iodides bearing weakly electron-withdrawing groups also reacted smoothly with 2a to afford the corresponding chalcone products 3f-3j in good to excellent yields (Table 2, entries 6-10). However, highly electron-deficient aryl iodides, such as 1k-1m, exhibited much lower levels of reactivity to give 3k-3m in moderate yields (Table 2, entries 11-13). 2-Iodothiophene also reacted smoothly under the optimized conditions to give 3n in 75% yield (Table 2, entry 14). Although aryl iodides reacted efficiently with 2a to give the corresponding chalcones, bromobenzene reacted slowly to form 3a in 33% yield (Table 2, entry 15). Furthermore, chlorobenzene failed to provide any of the desired product under the optimized conditions (Table 2, entry 16).

Table 2
Reactions of aryl halides with 2a.

The scope of the β-chloroalkyl carbonyl compounds was also explored by reacting a series of these compounds with iodobenzene (1a) under the optimized conditions (Table 3). The reactions of substituted 3-chloropropiophenones 2b-2h proceeded efficiently to afford the desired products 5a-5g in 82%-89% yields, with good functional group tolerance exhibited towards methyl, methoxy, chloro, and fluoro substituents on the phenyl ring (Table 3, entries 1-7). The corresponding thienyl, furyl, and indolyl derivatives of type 2 also exhibited good reactivity to give the corresponding products 5h-5j in 78-85% yields (Table 3, entries 8-10). Pleasingly, the ester and amide substrates 2l-2o also reacted smoothly under the optimized conditions to furnish 5k-5n (77%-90%), with the esters reacting more efficiently than the amides (Table 3, entries 11-14).

Table 3
Reactions of β-chloroalkyl carbonyl compounds with 1a.

Competition reactions were performed to determine the reactivity of the different substrates. An equimolar mixture of 1b and 1f was reacted with 2a to give a mixture of 3b/3f (mol/mol = 39:61; Eq. (1)), revealing that the presence of an electron-withdrawing substituent on the phenyl ring of the aryl iodide substrate provided a higher yield of the corresponding chalcone than the corresponding reaction with an electron-donating group. Treatment of 1a with an equimolar mixture of 2b and 2g under the same conditions led to a mixture of 5a and 5f (mol/mo = 41:59; Eq. (2)), demonstrating that an electron-withdrawing substituent on the aryl moiety of the β-chloroalkyl aryl ketone provided a higher yield of the corresponding chalcone than the corresponding reaction with an electron-donating group.

3.3. Mechanism

It has been confirmed that heating substrates such as 2 under basic conditions leads to formation of the corresponding enones [22, 23]. Interestingly, the reaction of phenyl vinyl ketone (6) with 1a under conditions similar to those developed in this study afforded 3a in 92% isolated yield (Eq. (3)), which suggested that enones such as 6 were being generated in situ from 2, and that enones could therefore be acting as intermediates in the current coupling reactions of 1 with 2.

Based on the results of this study, we have proposed a mechanism for this transformation, which is depicted in Scheme 2 for the reaction of 1a with 2a. Briefly, Pd(OAc)2 would be reduced by PPh3 to give a Pd(0) species, which would initiate the catalytic reaction. Oxidative addition of PhI to Pd(0) would lead to the formation of species A, which would react with enone 6 (generated in-situ from 2a) to produce π-complex B. Enone 6 would then undergo alkene insertion into the Pd-C bond to yield C, followed by β-hydride elimination to produce product 3a and the Pd(II) species D. The Pd(0) species would then be regenerated by the reductive elimination of HI from D in the presence of K2CO3 to complete the catalytic cycle.

Scheme 2. A proposed mechanism for the reaction of 1a with 2a.
4. Conclusions

In summary, a new reaction for the cross-coupling of aryl halides with β-chloroalkyl aryl ketones and their ester and amide analogs has been developed involving a domino dehydrochlorination/Pd(OAc)2-catalyzed Heck reaction with in-situ generated enones acting as the reaction intermediates. This new method provides rapid access to chalcones from readily available starting materials.

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