Boronic acids heterocycles

The heterocyclic scaffolds are prepared from pyroglutamic acid [154, 155]. 1-aminoalkyl boronic acid pinanediol esters are readily available through a diastereoselective homologation with dichloromethyllithium, providing (5)-a-chloroboronic esters. Aminolysis of the chloride yielded... 

The interaction of PBA derivatives with molecular species having the above functional groups occurs optimally in the pH range of 8-9, but it is typically reversible at acid pH or in the presence of a high concentration of competing ligand. However, the heterocyclic boronic acid complex is relatively stable under optimal conditions of formation. 

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). 

Chemists working to develop new bioactive compounds try to be alert for new stable heterocycle platforms, but they can easily overlook some of the more, shall we say, exotic ones. When one thinks about the utility of boron in heterocyclic chemistry, the Suzuki cross-coupling reaction typically first comes to mind. In this valuable synthetic reaction <95CRV2457>, a boronic acid group is discarded under basic conditions during a Pd-catalyzed C-C bond formation. There are exceptions, of course, but few chemists appreciate that boron is an element that can be valuable to retain in a molecule so that its unique properties can be utilized. 

Li and Yue also reported the intermolecular palladium catalyzed cross coupling reactions of bromo quinoxalines 214 and 216 with aryl boronic acids and heterocyclic stannanes, respectively <99TL4507>. The Suzuki couplings (i.e., 214 215) required the use of a... 

For a recent review on heterocyclic boronic acids see Tyrrel, E. Brookes, P. Synthesis,... 

In an application of the Suzuki process, 2-chloroquinoline (141) has been converted into the condensed heterocycle 197 (Scheme 58) (89JHC1589). Thus, metalation, trimethyl borate quench, and hydrolysis affords the stable 3-boronic acid 195 which, upon subjection to cross coupling with ortho-iodo aniline in the presence of Pd(0) catalyst and base, affords the 3-arylquinoline 196. Acid catalysis converts this material into the in-dolo[2,3-f ]quinoline (197) in 35% overall yield. 

Nucleophiles other than hydride can be added to support-bound imines to yield amines. These include C,H-acidic compounds, alkynes, electron-rich heterocycles, organometallic compounds, boronic acids, and ketene acetals (Table 10.9). When basic reaction conditions are used, stoichiometric amounts of the imine must be prepared on the support (Entries 1-3, Table 10.9). Alternatively, if the carbon nucleophile is stable under acidic conditions, imines or iminium salts might be generated in situ, as, for instance, in the Mannich reaction. Few examples have been reported of Mannich reactions on insoluble supports, and most of these have been based on alkynes as C-nucleophiles. 

To expand the diversity of their libraries Brill et al.16 also modified various heterocycles by alkylation, acylation, or metal-mediated coupling reaction prior to resin capture. A remaining chloro substituent was still available for nucleophilic displacement or a palladium-mediated coupling reaction with anilines, phenols, and boronic acids on solid phase [see Fig. 10 for the preparation of purine derivative (62)]. 

The use of diamine derivatives in the three-component process leads to peptidomimetic heterocycles, such as 2-oxopiperazines (piperazinones) [58], benzopiperazi-nones [58] and benzodiazepines. In fact, the 2-oxopiperazines 89 can be obtained directly in one step via the reaction of a diamine 85 with glyoxylic acid 86 and a boronic acid 87 (Scheme 7.12) [58]. Presumably, the intermediate amino acids 88 can undergo a subsequent boronic acid-catalyzed lactamization [29] to afford 89. A two-step approach was used for the synthesis of benzopiperazinones (e.g. 96) [58]. 

In addition to forming known types of molecules in only a few steps, this process also enables the synthesis of a variety of novel structures and heterocycles with a high degree of molecular diversity. The commercial availability of an increasing number of structurally novel boronic acids and amine derivatives facilitates their further incorporation into the many types of products that can be synthesized. 

E. Tyrrell, P. Brookes, The Synthesis and Applications of Heterocyclic Boronic Acids, Synthesis 2003, 469 183. 

The Suzuki-Miyaura tactic carried out on solid support (Scheme 28) [52] provides routes to small libraries of condensed heterocycles. Thus, Merrifield resin with the LeznofF-linked bromobenzene derivative 78 undergoes cross-coupling under normal solution-phase conditions with boron pinacolate 79 or boronic acid 80, prepared by DoM, to afford phenan-thridines 81 or, via 82 and some manipulation, dibenzopyranones 83 in good yields and with high purities. The Stille solid-support reaction has also been successfully executed [53]. 

Coupling of aromatic heterocycles goes well. The 2-position of a pyridine is very electrophilic and not at all nucleophilic (Chapter 43) but couplings at this position are fine with either the halide or the boronic acid in that position. Clearly, it is a mistake to see either of these substituents as contributing a nucleophilic carbon . It is better to see the reaction as a coupling of two equal partners and the two substituents (halide and boronic acid) as a control element to ensure cross-coupling and prevent dimerization. In the second example potassium te t-butoxide was crucial as weaker and less hindered bases gave poor yields. 

Palladium-catalyzed processes are perhaps the most important developments in heterocyclic chemistry since CHEC-II and certainly since the original GHEG. The intermediates are never isolated, but, nonetheless, are essential to the transformations. Oxidative insertions of palladium (or less often, nickel, or iron), especially into bromo- or iodoazines, or triflates (prepared from -ols or - or -ones), or alternatively, the use of pyridine boronic acids, boronates, stannanes, silanes, and organmetallic species such as Grignard and zinc derivatives, form the basis of these methodologies. 

A C2-symmetric benzo [ Jfuran-containing heterocycle 108 was constructed by the palladium-catalyzed coupling reaction between the lactam-derived vinyl phosphates and benzo[ ]furan-2-boronic acid 101 (Equation 98) <2005TL3703>. 

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