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Palladacycle-Catalyzed Deacetonative Sonogashira Coupling of Aryl Propargyl Alcohols with Aryl Chlorides Hao Hu, Fan Yang,* and Yangjie Wu* The College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, People’s Republic of China S Supporting Information *
ABSTRACT: An efficient and general protocol for the deacetonative Sonogashira coupling of aryl propargyl alcohols with aryl chlorides is described. The reaction proceeded smoothly with the catalyst system of palladacycle/Xphos. This result represents the first successful deacetonative Sonogashira version for electron-poor, electron-neutral, and even inactive sterically hindered electron-rich aryl chlorides.
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acetylenes with low yields.5d Recently, Tsai and co-workers described FeCl3-catalyzed one-pot Sonogashira−Hagihara coupling of aryl iodides with aryl propargyl alcohols.5f However, the substrate scope in the above-mentioned reports is mainly limited to aryl iodides and bromides, and successful examples for commercially available aryl chlorides remain rare. From the viewpoint of synthetic cost, developing a generally applicable catalytic system for aryl chlorides would be challenging but highly desirable (Scheme 1b). In recent years, our research group has focused on the catalytic application of a family of versatile palladacyclic catalysts: cyclopalladated ferrocenylimines (Figure 1).6 The
he Sonogashira reaction has been one of the most straightforward and efficient tools for C(sp)−C(sp2) bond-forming reactions, thereby dominating the synthesis of diaryl acetylenes.1 Significant progress has been achieved in the coupling of commercially available aryl chlorides by Buchwald, Fu, and others.2 However, this reaction still suffers from some limitations, especially the problem of poor tolerance to electron-poor terminal alkynes and generation of diynes as byproducts.3 To address these challenges, decarboxylative and deacetonative Sonogashira couplings have emerged as two promising alternatives within recent years.4,5 In particular, deacetonative coupling was first reported in 2001 by Chow’s group, who described a PdCl2(PPh3)2/CuI-catalyzed tandem catalytic reaction of aryl-2-methyl-3-butyn-2-ol with aryl bromides (Scheme 1a).5a Subsequently, significant progress Scheme 1. Synthesis of Unsymmetrical Diaryl Acetylenes via Catalytic Deacetonative Sonogashira Coupling
Figure 1. Palladacycle: cyclopalladated ferrocenylimine.
bulky alkylphosphine ligands were developed in Buchwald’s group and have been widely applied to the cross-coupling of aryl chlorides.2d Just recently, with the aid of the palladacycle and an alkylphosphine ligand, we realized the first successful decarboxylative Sonogashira reaction of alkynyl carboxylic acids with aryl chlorides in xylene/H2O.6g To further explore another alternative catalytic version of the traditional Sonogashira reaction, in this work we attempted to fulfill the palladacycle/ alkylphosphine-catalyzed deacetonative Sonogashira reaction of aryl propargyl alcohol with aryl chlorides to facilitate the industrial demand.
has been achieved by the groups of Kotschy, Shirakawa, Hua, and Tsai (Scheme 1a).5b−f Especially, Hua and co-workers developed the first deacetonative Sonogashira reaction of aryl chlorides using PdCl2(PCy3)2 as the catalyst. This protocol is quite effective for the synthesis of symmetrical diaryl acetylenes but provided only three examples for unsymmetrical diaryl © XXXX American Chemical Society
Received: July 10, 2013
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dx.doi.org/10.1021/jo4014657 | J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
Note
Generally, electronic and ortho-steric effects had no significant influence on this coupling, and the reactions could tolerate various functional groups such as MeO, NO2, MeOOC, CN, and CF3, leading to the desired products in good to excellent yields. Aryl chlorides bearing one ortho-sterically hindered group could be coupled with 4-phenyl-2-methyl-3-butyne-2-ol, leading to excellent isolated yields (Table 2, 3ea, 3fa, 3ia, and 3oa). Notably, even the more sterically hindered 2-chloro-mxylene gave a 99% isolated yield (Table 2, 3ga). Moreover, the reactions of some heteroaryl chlorides also smoothly generated the desired products in excellent yields (Table 2, 3sa, 3ta, 3ua, and 3va). Subsequently, experiments were directed at establishing the scope of aryl propargyl alcohols (Table 3). The results indicated that electronic and steric effects have no obvious influence. Notably, sterically hindered aryl propargyl alcohols possessing one or two ortho-sterically hindered groups could be efficiently converted into the corresponding products in moderate yields of 76%, 42%, and 58% (Table 3, 3hd, 3he, and 3hi, respectively). In addition, electron-withdrawing groups on the aryl ring did not hamper the coupling significantly, and the corresponding products were also obtained in yields of 78% and 75% (Table 3, 3hh and 3hj, respectively). To indicate the advantage of the deacetonative coupling reaction over the traditional Sonogashira coupling, competitive reactions of 4-chloroanisole (1h) with 2-methyl-4-(4-nitrophenyl)-3-butyn-2-ol (2j) and 1-ethynyl-4-nitrobenzene (4a) were finally performed (Scheme 2). The reaction of 2j generated the product 3hj in a yield of 75%, while the coupling reaction of 4a did not occur at all. These results indicate that the deacetonative coupling reaction can tolerate electron-poor alkynes well. Our previous reports have indicated that the palladacycle just behaves as a reservoir of catalytically active Pd(0) species.6d,g On the basis of these related reports, a possible mechanism is outlined in Scheme 3. Initially, a Pd(0) species is released from the palladacycle to form the catalytically active species Pd(0)L2 (I) with the alkylphosphine ligand. Next, oxidative addition of the aryl chloride (1) to Pd(0)L2 takes place to afford Pd(II) intermediate II. Subsequently, the reaction of intermediate II with the aryl propargyl alcohol occurrs, forming the Pd(II) intermediate III via a deacetonative step in the presence of K2CO3. Finally, the desired product 3 and active catalyst Pd(0)L2(I) are generated through reductive elimination of intermediate III to fulfill the catalytic cycle. We have developed a general and efficient method for the deacetonative Sonogashira coupling of aryl propargyl alcohols with aryl chlorides using palladacycle/Xphos as the catalyst system, affording symmetrical and unsymmetrical diaryl acetylenes in mostly good to excellent yields. Notably, this deacetonative coupling is applicable to electron-poor, electronneutral, and even inactive sterically hindered electron-rich aryl chlorides. Moreover, the reaction well tolerates electron-poor alkynes, for which the traditional Sonogashira reaction does not work.
We began the reaction conditions optimization with the reaction of chlorobenzene (1a) and 4-phenyl-2-methyl-3butyne-2-ol (2a) in DMF using Xphos as the ligand, and a relatively low but promising isolated yield of 48% was observed (Table 1, entry 1). Next, other solvents (e.g., DMA, DMSO, Table 1. Screening for Optimal Conditionsa
entry
ligand
solvent
base
yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16b 17c 18d 19e 20f 21g 22h
Xphos Xphos Xphos Xphos Xphos Xphos Xphos Xphos Xphos Xphos Xphos Xphos PPh3 Davephos Dppf Xphos Xphos Xphos Xphos Xphos Xphos Xphos
DMF DMA DMSO dioxane toluene CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN
K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K3PO4 KOH KF KOAc NaOH Na2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3
48 67 60 46 39 96 76
