Miyaura reaction esters

For the synthesis of a cavitand functionalized with terpyridyl groups via rigid linkages, transition metal catalyzed cross-coupling reactions are especially well suited. Starting with the boronic acid ester 48 [65], attachment of the terpyridyl groups to the cavitand was realized by Suzuki-Miyaura reaction with the tetraiodo-cavitand 47 (Fig. 15). 

Suzuki-Miyaura reactions are perhaps the most widely employed palladium catalyzed cross-couplings in the realm of thiazole medicinal chemistry. They typically take place only when the thiazole is an electrophile in the transformation. The nucleophilic thiazole boronic acid or ester, especially at the 2-position, is relatively unstable and therefore difficult to prepare. The electrophiles namely the 2-, 4-, or 5-substituted halothiazoles are often readily accessible in terms of their synthetic ease or commercial availability. A remarkable application has been described by Jang et al. in the discovery... 

Although the SM reactions of haloferrocenes proceed rather slow, they are clean and chemoselective, providing the production of arylferrocenes which would be hardly accessible by other strategies. Several papers regarding improved and alternative technics for performing the Suzuki-Miyaura reactions have been published. A useful procedure involves transmetallation of (half amount) simple aryl halides with only 0.5 eq. of -BuLi, followed by quenching the resulted aryllithium reagent with trimethyl borate [88], Thus obtained arylboronic ester is coupled under the standard SM conditions method A) with an excess of parent aryl halide to furnish the symmetrical biaryl in fair yields. For example, 2-bromoanisole (218) was coupled by this way to afford 2,2 -dimethoxybiphenyl (92) in 56% yield [88], Scheme 36. 

In its original format, the Suzuki-Miyaura reaction involves the cross-coupling of an aryl or alkenyl haHde with a boronic acid or boronate ester in the presence of a base under Pd catalysis. 

Boronic acids and boronate esters serve a myriad of purposes, and the discovery of the Suzuki-Miyaura reaction facilitated the widespread interest and application of organoboron compounds. This palladium-catalyzed C-C bond forming reaction initiated renewed interest in the preparation of diversely functionalized boronic acids that would lead to valuable products. From this synthetic standpoint, Suzuki coupling reactions have been employed in the production of natural products and the preparation of materials of interest. " The search for interesting starting materials for the Suzuki reaction produced a series of methods to prepare boronic acids so these species could be exploited in further applications. These compounds... 

P-Substituted vinylboronic esters were isolated in fair to high yields from the coupling under classical Heck conditions of vinylBhg with (hetero)aryl iodides and bromides (Table 3.1, entries 1-3). A dienyl boronic ester was obtained by coupling of vinylBhg with a vinyl iodide derived from phenylgly-cine (entry 4). The preparation of a styryl boronic ester with a sulfonamide moiety is described in a patent (entry 5) this product was later used in a Suzuki-Miyaura reaction. ... 

Scheme 3.23 Suzuki-Miyaura reaction with a styryl boronic ester. (Adapted with permission from ref. 90 2013 American Chemical Society.)...

Few literature data allow a clear-cut comparison between different arylboronic esters under identical reaction conditions (Cu, Ni, Ru, Pd, ). Heise and coworkers tested the reactivity in Suzuki-Miyaura reactions of the three cyclic esters Bpin, Bhg, Bnpg under the same conditions. This reactivity clearly increases with decreasing steric hindrance (Scheme 3.35). For Ni-catalyzed Suzuki-Miyaura couplings also, the relative efficiencies of boronic esters of pinaeol and neopentylglycol, boronic acid and trifluoroborates were compared in a dedicated study. Parallel and competition experiments... 

The above examples show that the dioxaborinanes ArBhg and ArBnpg react in higher yields in Suzuki-Miyaura couplings than their Bpin counterparts, and hint that the use of pinacol as the protecting diol for boronic esters should not be so systematic in the context of Suzuki-Miyaura reactions. ... 

The most widely used cross-coupling arylation reaction is the Suzuki-Miyaura reaction (Scheme 1.10), which was first reported in 1979 [12, 26, 27]. The reaction involves transmetallation with an organoboron reagent that is usually a boronic acid or ester. No transmetallation occurs under neutral conditions only in the presence of a base, which is usually an alkaline earth metal alkoxide, although weak bases such as K COj can be used [12] (Scheme 1.10b). Pd(OAc)2 or Pdj(dba)3 are the common sources of Pd(0). In some circumstances, arenediazonium tetrafluoroborates have been used [12e]. Nickel complexes can be used under some circumstance instead of Pd. 

Coupling of (R)-IO and (R)-ll to (R)-12 is completed by the well-known Suzuki-Miyaura reaction where Pd(0) complex catalyzes the formation of the C-C bond (Sect. 6.3, Example 6.4). In the next step, the protecting group is eliminated and the C=C bond reduced by achiral Ir(I) complex to trans-(lR,4S)-14. It is important to note the wrong R configuration at the C(l) atom in this and the previous intermediate. Inversion of the configuration in (15,45)-15 is achieved by the Mitunobu reaction with diphenylphosphorylazide (dppa) as the source of nucleophilic azide ions in the presence of DBU. This reaction is the method of choice for the transformation of alcohols in many other functionalities, azides, esters, alkyl-aryl ethers, imides, sulfonamides, etc., and its mechanism is explained in considerable detail [21, 22]. 

An alternative method for the direct arylation of thiophenes via C-H bond functionalization is a one-pot C-H borylation/Suzuki-Miyaura reaction sequence (Scheme 16) [66]. The first step is the generation of the organoboron intermediates 33 and 36 from the thiophenes 32 and 35 by means of an iridium catalyst. The second step, the Suzuki-Miyaura cross-coupling, can be accomplished subsequently by adding an aryl bromide to the solution of crude boronate esters without the necessity to remove the spent iridium catalyst beforehand. 

Tetra(2-thienyl)ethylene (TTE) derivatives 122 can be synthesized by Suzuki-Miyaura reactions of a c -boronic ester 121 with differently functionalized bromothiophenes 120 (Scheme 49, Table 27) [342]. F/c-bis(pinacolatoboryl)ethyl-ene 121 can be isolated from the reaction of di(2-thienyl)acetylene with bis-pinacolato-diboron beforehand, but is subsequently employed as crude intermediate... 

The sulfonate ester 520 is able to release hydrogenated or deuterated compounds 528 by addition of HCO2H or DCO2D, triethylamine and Pd(OAC)2-dppp as the catalyst-ligand system. Carbon-carbon bond-forming reactions have also been combined with the simultaneous cleavage of the Hnker. Thus, the Mizoroki-Heck reaction as well as Suzuki-Miyaura reaction have been performed on solid phase and gave styrene 532 and biaryl systems 530, respectively (Scheme 80). 

Firooznia has reported the synthesis of 4-substituted phenylalanine derivatives via cross-coupling of protected (4-pinacolylboron)phenylalanine derivatives such as 61 with aryl and alkenyl iodides, bromides and triflates [44]. They have further shown that BOC derivatives of (4-pinacolylboron)phenylalanine ethyl ester 61 or the corresponding boronic acids undergo Suzuki-Miyaura reactions with a number of aryl chlorides in the presence of PdCl2(PCy)3 or NiCl2(dppf), respectively providing diverse sets of 4-substituted phenylalanine derivatives of type 62 [45]. This strategy has also been used for the synthesis of enantiomerically enriched 4-substituted phenylalanine derivatives (Scheme 3.28) [46]. 

The first example of asymmetric rhodium-catalyzed 1,4-addition of organoboron reagents to enones was described in 1998 by Hayashi and Miyaura. Significant progress has been made in the past few years. This asymmetric addition reaction can be carried out in aqueous solvent for a broad range of substrates, such as a,/ -unsaturated ketones, esters, amides, phosphonates, nitroalkenes. The enantioselectivity is always very high (in most cases over 90% ee). This asymmetric transformation provides the best method for the enantioselective introduction of aryl and alkenyl groups to the / -position of these electron-deficient olefins. 

The reaction of cyclic a,/ -unsaturated esters also proceeds with high enantioselectivity (97-98% ee) and yields (Scheme 35).110 Similar results for the asymmetric 1,4-addition to ct,/Tunsaturated esters have been independently reported by Miyaura and co-workers.111... 

No examples of such reactions have been disclosed. Displacement of halogens on the parent heterocycle through metal-catalyzed processes have surprisingly not been reported to our knowledge on the neutral heterocycle. Recently, Suzuki-Miyaura cross-coupling reactions of imidazolium bromide 113 with various boronic acids or esters were reported <2005T6207> to proceed in good yield, without deprotonation at the C-3 position (Scheme 35). 

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