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Journal of the American Chemical Society
Palladium(II)-Catalyzed Tandem Oxidative Acetoxylation/ortho C-H Activation/Carbocyclization of Arylallenes Javier Mazuela,± Debasis Banerjee,± and Jan‐E. Bäckvall* Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE‐10691, Stockholm, Sweden Supporting Information Placeholder ABSTRACT: Herein we report an example of tandem oxi‐ dative acetoxylation/carbocyclization of arylallenes 1 using Pd(OAc)2. The catalytic protocol is highly selective and pro‐ vides access to new C‐C and C‐O bonds leading to a carbocy‐ clization. The reaction proceeds via C‐H activation by Pd. Mechanistic investigations show that the C‐H activation is not the rate‐limiting step and indicate that the reaction proceeds via acetoxylation of the allene. Transition metal‐catalyzed C‐H bond functionalization for construction of new C‐C bonds in a selective and con‐ trolled manner is an actual challenge in organic synthesis 1 and has received significant attention in recent years. De‐ spite notable progress in this area, more practical and gen‐ eral applications of aryl C‐H bond activation still rely on the assistance of a heteroatom‐based neighboring functional 1 group, which often are difficult to remove or modify. Howev‐ er, an atom‐economic approach would be to utilize a direct‐ ing group directly involved in the functionalization in a tan‐ dem fashion, which intramolecularly induces an activation of 2 the ortho arene C‐H bond and leads to a carbocyclization. Transition metal‐catalyzed oxidative carbocyclizations have been identified as potential technologies for designing more complex structures occurring in various biologically 3 active natural products and pharmaceuticals. During the past decade, we have developed a number of highly regio‐, and stereoselective palladium‐catalyzed oxidative carbocycli‐ 4,5 zations of enallenes, dienallenes, allenynes and enynes. Some time ago we reported on the intramolecular Pd(II)‐ catalyzed oxidative carbocyclizations of dienallenes for the 5d,6 stereospecific formation of bicyclic systems (Scheme 1, a). A detailed mechanistic study revealed the participation of a (‐allyl)palladium species, which is attacked by a nucleophile to furnish the product. More recently we have also developed a novel Pd(II)‐catalyzed oxidative acetoxylation/carbo‐ cyclization protocol for allenynes to form acetoxylated vinyl‐ 7 allenes in a one pot operation (Scheme 1, b). 8 Up to date no carbocyclization process, is known where an allene moiety acts as directing group for intramolecular 2 aryl sp C‐H bond activation. We have now developed an oxidative palladium‐catalyzed protocol for tandem acetoxyla‐ tion/carbocyclization of arylallenes 1, where the allene moie‐ 2 ty forms a new C–C bond with the aryl via a sp C‐H bond 9 activation (Scheme 1, c). In our initial investigations we choose arylallene 1a as model substrate for the tandem carbocyclization/acetoxy‐
lation reactions using 5 mol % of Pd(OAc)2 in the presence of o 1.5 equiv of p‐benzoquinone (BQ) in acetic acid at 60 C. Under these conditions the desired carbocyclization product was obtained in 24% yield (Table 1, entry 1). An increase of the catalyst loading to 10 mol% of Pd(OAc)2 proved benefi‐ cial and afforded a 45% yield of 2a along with 18% yield of dimer 3a (Table 1, entry 2).
Scheme 1: Pd‐catalyzed intramolecular oxidative acetoxyla‐ tion/carbocyclization of dienallenes, allenynes and ar‐ ylallenes We next studied the influence of different Pd‐salts and additives on the model reaction. Use of other Pd(II)‐salts, such as the White catalyst ([1,2‐Bis(phenylsulfinyl)ethane]‐ palladium acetate), PdCl2 and Pd(TFA)2 did not lead to any improvement of the yield of 2a, whereas Pd(acac)2 resulted in a promising yield of 46% of 2a together with 16% yield of dimer 3a (Table 1, entries 3‐6). We therefore studied the influence of different additives on the carbocyclization reac‐ tion using Pd(OAc)2 as catalyst. Application of acridine (L1), triphenylphosphine (L) and racemic phosphoric acid (PA) inhibited the reaction (Table 1, entries 7‐9, see SI for details). On the other hand, the use of 2 equiv. of dimethylsulf‐ oxide (DMSO) as additive in combination with Pd(OAc)2 enhanced the formation of product 2a (60% yield) while in‐ hibiting the formation of the dimeric byproduct 3a (Table 1,
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Journal of the American Chemical Society
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4
Pd(acac)2(10)
5
PdCl2 (10)
‐
1.5
6
Pd(TFA)2 (10)
‐
1.5
12). The use of Pd(acac)2 as catalyst under these conditions gave a lower yield (Table 1, entry 13). Surprisingly, under the optimal reaction conditions, ex‐ amination of different co‐solvents (THF, 1,4‐dioxane, 1,2‐ dichloroethane, acetonitrile and toluene) showed that the use of acetic acid as the sole solvent is crucial for the carbo‐ cyclization/acetoxylation of 1a to occur (Table 1, entry 12 and Table S5, Supporting Information). Variation of the reaction temperature proved that 60 ºC is the optimal temperature for this protocol (Table 1, entries, 12, 14‐16). Control experiments showed that removal of either Pd(OAc)2 or BQ completely stopped the reaction (Table 1, entries 17‐18). After having established the optimized reaction condi‐ tion, we next explored the scope of the Pd(II)‐catalyzed tan‐ dem acetoxylation/carbocyclizations of arylallenes 1 (Table 2). Arylallenes with m‐Me‐ or p‐Me‐ substituents on the aromatic ring afforded 56 and 62% yield of 2c and 2d, respec‐ tively. However, o‐Me‐substituted arylallene resulted in a lower yield of 2b, which may be due to steric effects. The introduction of electron‐donating substituents led to a de‐ 3a, 2a, Yield Yield crease in the efficiency of the reaction (2e, 2f and 2g vs. 2a). [b] [b] Interestingly, in the case of m‐OMe substituted arylallene a [%] [%] mixture of two different regioisomers in a 6.5 : 1 ratio was 24 23 formed. Coordination of the neighboring OMe‐group should 45 18 facilitate the formation of the intermediate Pd‐species that leads to 2e. 40 17 Table 2. Pd(II)‐catalyzed tandem oxidative acetoxyla‐ 46 16 a,b tion/carbocyclization of arylallenes 0 ‐ 23 10
entries 10 and 11). Various electronically and sterically differ‐ ent DMSO derivatives were tested, which showed that DMSO was the best sulfoxide for this carbocyclization reac‐ tion (Table S1, Supporting Information). The oxidant also plays a crucial role for the selective Pd‐catalyzed carbocycli‐ zations. The use of different oxidants such as PhI(OAc)2, a series of substituted benzoquinones, or various metal salts (CuCl2, Cu(OAc)2, AgOAc, and Ag2O) in the presence of catalytic amounts of Pd(OAc)2 proved to be inefficient (Ta‐ ble Table 1. Optimization studies for Palladium(II)‐catalyzed a oxidative carbocyclizations
Entry
Pd‐cat. (mol%)
Additive
BQ equiv
1
Pd(OAc)2 (5)
‐
1.5
2
Pd(OAc)2 (10)
c
3
‐
1.5
‐
1.5
‐
1.5
7
Pd(OAc)2 (10)
L1
1.5
