Biaryl benzyl bromide

In the laboratory of J. Zhu, the synthesis of the fully functionalized 15-membered biaryl-containing macrocycle of RP 66453 was accomplished. One of the key steps in their approach was Corey s enantioselective alkylation of a glycine template with a structurally complex biaryl benzyl bromide. This benzyl bromide was prepared from the corresponding benzyl mesylate via the Finkelstein reaction using lithium bromide in acetone. 

Since ketone R)-16 was prepared in a non-selective way when an achiral imino enolate was alkylated, it was considered whether alkylation of chiral enolates, such as that of oxazoline 18, with benzyl bromide 14, would provide stereoselective access to the corresponding alkylation product 19 with R-configuration at C(8) (Scheme 4). Indeed, alkylation of 18 with 14 gave the biaryl 19 and its diastereoisomer almost quantitatively, in a 14 1 ratio. However, reductive hydrolysis using the sequence 1. MeOTf, 2. NaBH4, and 3. H30", afforded hydroxy aldehyde 20 in 25% yield at best. Furthermore, partial epimerization at C(8) occurred (dr 7.7 1). An alternative route, using chiral hydrazones, was even less successful. 

In 1993 Suzuki and colleagues described the palladium-catalyzed carbonylative coupling of aryl iodides with aryl boronic acids [13]. Various diarylketones were produced in high yields (Scheme 4.4). The choice of base and solvent was essential to obtain the desired ketones without biaryl by-products. The coupling of benzyl bromide was also described. In 1998 the group extended this methodology to aryl bromides and triflates [14]. In the case of aryl bromides, Nal or KI was required as an additive. The in situ transformation of aryl bromides to aryl iodides may be involved. 

Greaney et al. introduced the Heck reaction to the benzyne three-component coupling to prepare 1,2-functional-ized arenes 28 and 29. Alternatives to allyl chlorides as the initial carbopalladation electrophile were presented, that is, methyl bromoacetate and benzyl bromides, thus avoiding the formation of benzyne/benzyne/allyl by-products and therefore improving the efficiency of the reaction [39], When using aryl iodides as the electrophilic partners, highly functionalized biaryl compounds 30 are obtained (Scheme 3.20) [40]. 

Applications of the aforementioned methodology are also found in the total synthesis of plagiochin D to link a 16-membered biaryl system [47], as well as to the intramolecular cyclization of di-benzyl halides [45, 48]. Additional examples include dithienothiophene (40) from dithienyl bromide 39 [49] and carbazole 42 from diarylbromide 41 [50]. 

The synthetic route began with the synthesis of the bromide 147 by benzylation and ketalisation of the known aldehyde 146 (Scheme 20). Generation of the Grignard reagent followed by addition of chiral oxazoline 105 afforded the biaryls 148 and 149 in 64% yield and a ratio of 77 23 respectively along with 22% of the demethylated oxazoline 114. Quaterisation, base hydrolysis and reduction then gave the alcohol 150 which was converted into the acetamide 144 by... 

Proazaphosphatrane bases were used for palladium catalysed Stille reactions of aryl chlorides. These bases efficiently catalyse the coupling of electronically diverse aryl chlorides with an array of organotin reagents. The catalyst system based on benzyl (Bn)-proazaphosphatrane is active for the synthesis of sterically hindered biaryls. The use of the proazaphosphatrane allows room temperature coupling of aryl bromides and it also permits aryl triflates and vinyl chlorides to participate in Stille coupling [69] (Scheme 5.47). 

Unsymmetrical biaryh and diarylmethanes. Negishi et al have used a nickel-(0) complex or a palladium(0) complex as catalyst for the cross-coupling of aryl-or benzylzinc halides with aryl halides at room temperature to form biaryls or diarylmethanes. The zinc derivatives are prepared by reaction of aryl- or benzyl-lithium with zinc chloride or bromide. 

The left-hand allyl-benzyl ether intermediate 102 was prepared from 2,4-dichloropyrimidine (99) (Scheme 5.2). Thus, Suzuki coupling of 99 with boronic acid 100 proceeded smoothly to yield biaryl 101 in moderate yield. Alleviation of benzyl alcohol 101 with allyl bromide 94 under phase transfer conditions then provided the key left-hand fragment 102. 

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