Directed C-H borylation

Rhodium- and Ir-catalyzed C-H borylation of arenes are nowadays important pathways. The regioselectivity of the first successful reactions were chiefly under steric control (to the least hindered positions), often offering a simple access to positions (for instance position 5 of 1,3-dimethoxy-benzene) where installation of a halide group for Pd-catalyzed borylation is difficult. These successes prompted a promising development of strategies for directed C-H borylations. ... 

Direct borylation of hydrocarbons catalyzed by a transition metal complex has been extensively studied by several groups and has become an economical, efficient, elegant, and environmentally benign protocol for the synthesis of a variety of organoboron compounds. The Rh-, Ir-, Re-, and Pd-catalyzed C-/H borylation of alkanes, arenes, and benzylic positions... 

Initial reports on the borylation of alkanes using isolated transition-metal-boryl complexes date back to 1995, when Hartwig showed that Cp Re(CO)2(Bpin)2 converts pentane to 1-borylpentane with high regioselectivity. " The catalytic C-H borylation of alkanes with Cp Re(CO)3 using photochemical activation was demonstrated soon thereafter (equation 25). Also, an efficient thermal process that involves the use of rhodium catalysts has since been developed (equation 26). It is interesting to note that this methodology is not restricted to small molecules, but has recently been exploited for the direct side-chain functionalization of polyolefins. ... 

They found that combination of the Ir(T) catalyzed C-H borylation and Suzuki coupling sequence led to a two-step, one-pot C-H Suzuki arylation that enabled direct transformation of the N-Boc pyrrole to the C3 arylated intermediate in 78% yield. Following installation of the required acyl group, an application of their oxidative Pd-catalyzed C-H alkenylation reaction enabled formation of the key structural architecture of the natural deliver the natural product. The orthogonal selectivity characteristics displayed by these C-H functionalization processes makes possible iterative functionalization of the heteroaromatic pyrrole core. Utilization of the highly versatile C-H borylation - Suzuki coupling to install the aromatic functionality opens up possibilities of facile analogue synthesis via this route. 

A second interesting development uses traceless, sUyl-based directing groups as shown in Scheme 23.31. This strategy allows ortho-C-H borylation of phenols, arylamines, and alkylarenes... 

SCHEME 23.30 Directed ortho-C-H borylation with supported Ir catalyst. 

Once a CO has been lost, there are two possible mechanisms for the alkyl group transfer to boron (see below, where Beat = the boryl ligand). One is a direct insertion of the metal into R-H (step 2), and the other is a cr bond metathesis (step 3). The first possibility would require a reductive elimination (see Section 12.2.3) to form the alkylboronate ester (step 4). Both pathways would re-associate a CO to give the final organometallic product (step 5). The authors prefer the direct C-H activation, but this has yet to be proven. In summary, C-H activation and functionalization is an elusive process, one that hopefully will have further breakthroughs in the near future. 

C-H borylation of alkanes was first demonstrated by Hartwig using photochemical activation of Cp RefCOjj (Scheme 2.3) [51]. With irradiation from a 450 W medium-pressure Hanovia mercury arc lamp, alkylboronates are obtained by direct borylation of alkanes with pin2B2 in the presence of Cp Re(CO)j (2.4-5.0 mol%) and CO (2 atm). Pinacolborane is not effective for the borylation thus, one of two boron atoms participated in the catalytic cyde. All reactions resulted in high regiospecifidty for the functionalization of terminal primary carbons. 

The ready availability of arylboronates by an aromatic C-H borylation provides a synthetic link to the well-established palladium-catalyzed cross-coupling reactions, rhodium-catalyzed 1,4-addition to a,p-unsaturated carbonyl compounds, and other bond forming reactions using arylboronic esters (Scheme 2.12). Borylation of 1,3-dichlorobenzene with pinacolborane is followed directly by a cross-coupling reaction with methyl p-bromobenzoate for the synthesis of a biaryl product in 91% yield [60]. Pinacol esters of arylboronic acids react much slower than the free acids [62], but both derivatives achieve high isolated yields and comparable enantioselectivities (91% ee) in asymmetric 1,4-addition to N-benzyl crotonamides [63]. Borylation of arenes followed by oxidation of the C-B bond is synthetically equivalent to an aromatic C-H oxidation to phenols [64]. Oxidation of the resulting arylboronates with Oxone in a 1 1 acetone-water solution is completed within 10 min at room temperature. 

Borylation of the benzylic position of arenes via C—H functionalization has been achieved. Yu has also reported the ability construct C-B bonds via directed C—H functionalization of arylbenzamides catalyzed by Pd(II). Formation of carbon-carbon bonds between arenes and alkyltrifluoroborates, alkylstannanes, and alkyl halides has been reported. The incorporation of amino acid derived... 

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. 

Can the iridium chemistry tolerate substrates with primary alcohols Need to generate an aryltrifluoroborate salt Yes, a version of the iridium-catalyzed C—H borylation is tolerant to the presence of primary alcohols [75] A convenient precursor for the direct synthesis is not readily available. Try generating an arylboronic acid or arylboronate, and treat it with a solution of KHP [37, 38]. For arylboronates, a 4 1 THF/water mixture was successful [38]... 

The direct borylation of arenes was catalyzed by iridium complexes [61-63]. Iridium complex generated from [lrCl(cod)]2 and 2,2 -bipyridine (bpy) showed the high catalytic activity of the reaction of bis (pinaco la to) diboron (B2Pin2) 138 with benzene 139 to afford phenylborane 140 (Equation 10.36) [61]. Various arenes and heteroarenes are allowed to react with B2Pin2 and pinacolborane (HBpin) in the presence of [lrCl(cod)]2/bipyridne or [lr(OMe)(cod)]2/bipyridine to produce corresponding aryl- and heteroarylboron compounds [62]. The reaction is considered to proceed via the formation of a tris(boryl)iridium(lll) species and its oxidative addition to an aromahc C—H bond. 

Most current regioselective, catalytic functionalization of saturated C-H bonds [1-5] occurs by directed processes [6-13]. In these processes the catalyst or reagent docks at a functional group or reacts at C-H bonds that are located a to a heteroat-om, because these bonds are weaker than more distal ones [14]. Borylation of methyl C-H bonds complements the directed chemistry because it occurs at unactivated C-H bonds with regioselectivity that is independent of the position of the functional group in the reagent [15]. 

An iridium(l) complex, generated from l/2[Ir(OMe)(COD)]2 and 4,4 -di-/-butyl-2,2 -bipyridine (dtbpy), catalyzed the direct borylation of 2-substituted pyrroles in stoichiometric amounts relative to 2,2 -bi-l,3,2-dioxaborolane 785 in hexane at room temperature (Equation 188) <2003ASC1103>. The pyrrolylborates 786 from regioselective C-H activation at the 5-position were formed in high yields. Similar borylation of unsubstituted pyrrole with an equimolar amount of borolane 785 regioselectively provided 2,5-bis(boryl)pyrrole 787 (Equation 189). 

Although direct borylation of arenes in specific cases is possible and metal-catalyzed C H and C-X activation reactions provide new possibihties, most arylboranes are prepared from organometalhc precursors. In particular, monoborylated... 

---