Cross-coupling alkyl bromides

Recently, Caddick and Cloke have developed an extension of this procedure that allows the use of alkyl bromides as coupling partners. The basic changes consist of a stoichiometric amount of the bulkier KO Bu instead of KOMe to activate the borane, and the addition of AgOTf to the reaction mixture [119]. These results, although poor in terms of yield, clearly confirm that sp -sp Suzuki-Miyaura cross-couplings are possible and should be further developed (Scheme 6.35). 

Our third approach to 27 addressed the unavailability of 3-methoxy-2-cyclopentenone (31) in bulk quantities which necessitated the discovery of an alternative route (Scheme 7.7). Fortunately, the precursor to 31,1,3-cyclopentandione (35), was available in the required quantities and our efforts shifted to the use of this reagent Bromination of 35 with NBS, employing either KHC03 or KOH as the base, gave brominated dione 36 in 85% isolated yield. Unfortunately, direct cross-coupling of alkyl bromide 36 with boronic acid 12 under a variety of Suzuki-... 

The same ligand allowed the cross-coupling of various boronic acids (aryl, alkenyl, alkyl) with alkyl bromides in the system (Pd(OAc)2/PMe Bu2, BuOK. amyl alcohol, r.t.).411... 

In this method, Furstner converts N-BOC protected pyrrole to the 2,5-dibromo compound (122) with NBS and this is followed by metalation and carbomethoxylation with t-butyl lithium in THF and subsequent trapping of the metalated species with methyl chloroformate to yield a pyrrole diester (123). Bromination of this diester at positions 3 and 4 with bromine in water followed by Suzuki cross-coupling with 3,4,5-trimethoxyphenyl boronic acid yields the symmetrical tetrasubstituted pyrrole (125). Base-mediated N-alkylation of this pyrrole with 4-methoxyphenethyl bromide produces the key Boger diester (126) and thereby constitutes a relay synthesis of permethyl storniamide A (120). 

As well as alkenylstannanes [106-108], other classes such as a-heteroatom-substituted alkyltributylstannanes [109] and, more importantly, allylic stannanes [110, 111] also undergo these Sn-Cu transmetalations. Otherwise difficult to prepare, allylic copper reagents may, however, be obtained by treatment of allylic stannanes (produced in turn from organolithium, magnesium, or zinc organometallics) with Me2CuLi LiCN. They enter into cross-coupling reactions with alkyl bromides [110] or vinyl triflates (Scheme 2.52) [111]. 

Figure 3.47. Scope of Ni/49-catalyzed asymmetric cross-coupling of vinyl bromide with secondary alkyl Grignard reagents.

The sequential approach is also common in proposals written by synthetic chemists (a multistep synthesis is inherently step by step). Vyvyan (excerpt 13N), for example, proposes a strategy to synthesize a select group of heliannuols (alleo-pathic natural products isolated from the sunflower) in an optically pure form. One approach that he will explore involves enantioselective cross-coupling reactions between an alkyl zinc reagent and an aryl bromide. He begins with experiments that will utilize recently developed catalysts and produce products with known optical rotation data. Subsequent reactions are described that will lead potentially to the desired stereospecific heliannuols A and D. 

Once this process is explored with the model system to assess the level of enantioselectivity, we will then prepare alkyl zinc reagent 48 from 44 using standard methods - - and cross couple 48 to aryl bromide 18 using the appropriate chiral catalysts (Scheme 7). Although the acetonide stereocenter in 48 is somewhat remote from the coupling site, the stereocenter may serve to enhance the stereoselectivity of the cross-coupling process because the two possible products are diastereomers, not simply enantiomers. This reaction will produce 49 from (S)-48 and 30 from (R)-48 that can then be converted to epoxides 31 and 32 using standard methods. Epoxide 31 leads to heliannuol D 4 after base-promoted epoxide cyclization and deprotonation. Similarly, epoxide 32 leads to heliannuol A 1 after acid-promoted cyclization. 

In 1995 Soderquist and Ftirstner independently reported that alkynylborates 67, prepared in situ from 9-OMe-9-BBN and alkynylmetals, effectively cross-couple with aryl and alkyl bromides using a Pd catalyst under base-free conditions at 60 °G. Soderquist and co-workers also reported on the synthesis of alkynylborinates 68, which are easier to isolate (Figure... 

TABLE 8. Cross-coupling between aryl Grignard reagents and alkyl bromides... 

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