Pinacol ester derivatives

Addition of a boron-boron bond across a carbon-carbon triple bond is known for some 40 years since the finding that diboron tetrahalides add to alkenes and alkynes in the absence of catalysts.36 Although the reaction seemed to be potentially attractive, the instability of diboron tetrahalides was the critical drawback for the practical use in synthesis. In 1993, much more stable pinacol ester derivative of diboron was found to add to alkynes in the presence of platinum catalysts such as Pt(PPh3)4, Pt(CH2=CH2)(PPh3)2, and Pt(CO)2(PPh3)2 (Figure 1, Scheme 2).37,38 Other... 

Diboration provides another means of obtaining organoboranes. Studies [30-36] have been focused on the diboration reactions of alkynes and olefins with pinacol ester derivatives catalyzed by Pd(0) and Pt(0) metal complexes. Interestingly, it has been shown that Pt (0) complexes catalyze cis addition of the B-B bond in pinacol ester derivatives to alkynes but not to olefins. On the other hand, Pd (0) complexes do not catalyze diboration reactions, neither for alkynes nor for olefins. 

Lewis acids and Bu4NI catalyzed allylboration with potassium allyl- and crotyltrifluoroborates (Equation (154)).30,40 620,621 The reaction of pinacol ester derivatives was very slow even at room temperature, but Sc(OTf)3 smoothly catalyzed the addition at — 78 °C with high diastereoselectivity (Equation (155)622 and (156)623,624). A palladium pincer complex catalyzed the addition of trifluoroborate to tosylimines (Equation (157)).625... 

Then, the scaffold 9 was reacted with 12 boronic acid pinacol ester derivatives (10a-101), yielding the corresponding 6-arylcoumarins, lla-111. Although the compounds with an electron-withdrawing group, such as nitro (lie), cyano (Hi), or methoxycarbonyl (llj), were obtained in relatively low yield (28%, 45%, and 46%, respectively), most of the reactions proceeded in moderate yield. Some functional groups on the phenyl group were rather easily transformed, as observed in the syntheses of 11m, lln, and llo. 

Scheme 20 Reactivity of 29 in Suzuki-Miyaura coupling of allylboronic acid pinacol ester derivatives...

Allylboronates prepared from simple diols display appreciable reactivity, but eyelie boronate derivatives prepared from 1,2- or 1,3-diols display considerably less. The commonly employed pinacol esters are among the least reactive members of this class. 2-Allyl-3-methyl-l,3,2-oxaza-... 

Borylated products derived from B2pin2 allow normal work up including chromatographic purification and are stable towards air. Pinacol esters are difficult to hydrolyze, but they may serve as coupling partners in the Suzuki Coupling and similar reactions without prior hydrolysis. 

The total synthesis of the proteasome inhibitor cyclic peptide TMC-95A was accomplished by. S.J. Danishefsky and co-workers. The biaryl linkage in the natural product was constructed by a Suzuki cross-coupling between an aryl iodide and an arylboronic ester derived from L-tyrosine. The required arylboronic pinacolate substrate was prepared using the Miyaura boration. The aryl iodide was exposed to b/s(pinacolato)diboron in the presence of a palladium catalyst and potassium acetate in DMSO. The coupling proceeded in high yield and no symmetrical biaryl by-product was observed. 

For a study of the dependence of reactivity of allylboronates on the diol unit, see W. R. Roush, L. Banfi, J. C. Park and L. K. Hoong, Tetrahedron Lett., 1989, 30, 7305. While pinacol esters are commonly employed owing to their stability, these derivatives are considerably less reactive than other esters. 

The pinacol rearrangement of sulfonate esters derived from a-hydroxy acetals proceeds by way of intermediate oxonium species, which upon hydrolysis are transformed to the corresponding esters. Sulfonate 24, prepared in optically pure form by classical resolution of the diastereomer-ic mixture obtained from reaction of (-)-camphorsulfonyl chloride with the racemic naph-thenyl alcohol, undergoes thermal [1,2] rearrangement to yield the corresponding ester29. 

Under modified Suzuki cross-coupling conditions the reaction of boronic acids 20a-c with 4-iodoanisole give protodeboronation as the main result, and triazolopyridines la,b are recovered from the reaction mixture in almost quantitative yield. The pinacol esters 21a, c give only protodeboronation, nevertheless the pinacol ester 21b under standard Suzuki-type conditions give better results furnishing protodeboronation, and also the heterobiaryl derivative, although only in low 5deld (20%). Such different reactivity is probably due to the better solubility and stability of the pinacol ester 21b. 

E)- and (Z)-(Fluoroalkenyl)boronate derivatives 712 and 714 have been prepared stereospecifically by the reaction of (E)- or (Z)-(2-fluoroalkenyl)iodonium salts 711 and 713 with [bis(4-fluorophenoxy)]alkylboranes, followed by transesterification to pinacol esters (Scheme 3.285). The mechanism of this reaction involves... 

The synthesis of dictyodendrins A and F was realized through a sequential C—H functionahzation strategy inclusive of an initial C3 arylation, a site-selective double C—H alkylation with an aryldiazoacetate derivative and a subsequent Suzuki-Miyaura cross-coupHng with indole-3-boronic acid pinacol ester 107 (2015JAC644). A formal 67r-electrocyc-lization of the resultant tetrasubstituted pyrrole 108 fashioned the required pyrrolo-[2,3-c]carbazole core (109) which was further elaborated to the targets. 

A systematic study for boronic acid replacements for N—H bond arylations has been investigated, and the outcome compares favorably to the O—H bond arylation reaction (Table 4.6) [17,41]. However, to date no catalytic in copper variations have been reported with these alternative aryl donors. The best donors are triarylborox-ines and boronic acid esters derived from 2,2 -dimethyl-l,3-propanediol and 1,3-propanediol and, as in the case of the O—H bond arylation, the pinacolate esters are poor aryl donors. Sodium tetraphenylborate is also an alternative phenyl donor in the copper] 11)-mediated, microwave-assisted N-arylation using KF-AI2O3 as heterogeneous base in the absence of solvent [30]. 

Benzo[l)]furan-6-carbonitrile and 6-cyanobenzo[l>]furan-2-boronic acid pinacol ester were prepared in the presence of Cu. (13SC1974) 2-Substituted benzo[ ]furans were synthesized by employing easily accessible A/-tosylhy-drazones and o-hydroxy or o-amino phenylacetylenes as substrates. (13OBC1490) One-pot access to either 2-naphthols or benzo[l>]furans via the aerobic Wacker-type oxidation/intramolecular aldol cyclization was accomplished. (13T1532 ) 5,5-Disubstituted-2,2 -bisbenzofuran derivatives were produced by treatment of 4-substituted-2-(2-trimethylsilylethynyl) phenyl tert-butyldimethylsilyl ether analogues with CuCl as a catalyst (13TL2655). 

Heterocyclic aromatic boronic acids, in particular pyridinyl, pyrrolyl, indolyl, thienyl, and furyl derivatives, are popular cross-coupling intermediates in natural product synthesis and medicinal chemistry. The synthesis of heterocyclic boronic acids has been reviewed recently [222], and will not be discussed in detail here. In general, these compounds can be synthesized using methods similar to those described in the above section for arylboronic acids. Of particular note, all three isomers of pyridineboronic acid have been described, including the pinacol ester of the unstable and hitherto elusive 2-substituted isomer, which is notorious for its tendency to pro-todeboronate [223]. Improvements and variants of the established methods for synthesizing heterocyclic boronic acids have been constantly reported [13, 182]. For example, a Hg-to-B transmetallation procedure was recently employed to synthesize a highly functionalized indolylboronic acid (entry 19, Table 1.3) [187]. 

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. 

The Pd-catalyzed reaction of such polyfunctional boronic esters like 21b with various aryl halides provides the desired cross-coupling products like 22 in high yields [10,11]. Interestingly, a one-pot reaction allowing the selective reaction with two electrophiles is possible. Thus, the treatment of the meta-iodophenyl boronic pinacol ester 18 with i-PrMgCl LiCl followed by a transmetallation to the copper derivative and subsequent reaction with 2-methyl-3-iodocyclohexenone provides the intermediate boronic ester 23 that after a Suzuki-Miyaura cross-coupling, furnishes the heterocyclic product 24 in 52% yield (Scheme 3.6) [11]. 

Yamamoto has reported the synthesis of (4-boronylphenyl)alanine (BPA), used dinically for treatment of malignant melanoma and brain tumors in neutron capture therapy by Pd-catalyzed coupling of triflate 47 with the diboron derivative 48 [22]. The boronic ester 49 could be easily cleaved by hydrogenolysis to give I-BPA 50 in 74% yield, whereas the corresponding pinacol ester yielded mixture... 

Boronic esters are easily prepared from a diol and the boronic acid with removal of water, either chemically or azeotropically. (See Chapter 2 on the protection of diols.) Sterically hindered boronic esters, such as those of pinacol, can be prepared in the presence of water. Boronic esters of simple unhindered diols are quite sensitive to water and hydrolyze readily. On the other hand, very hindered esters, such as the pinacol and pinanediol derivatives, are exceedingly difficult to hydrolyze and often require rather harsh conditions to achieve cleavage. 

Compound 51 was found to be unstable and difficult to purify, as described in the literature [93—95]. Therefore, 51 was not isolated, but was instead converted to the stable pinacol 1-acetamido-l-hexylboronate derivative 52. However, the acylated derivative 52 could not be purified by column chromatography as it was destroyed on silica gel and partially decomposed on alumina. Fortunately, we found that it dissolves in basic aqueous solution (pH > 11) and can then be extracted into diethyl ether when the pH of the aqueous layer is 5—6. Finally, pure 52 was obtained by repeated washing with weak acids and bases. It should be mentioned here that exposure to a strongly acidic solution, which also dissolves compound 51, results in its decomposition. Compared with other routes, the present two-step method involves mild reaction conditions (THF, ambient temperature) and a simple work-up procedure. It should prove very useful in providing an alternative access to a-aminoboronic esters, an important class of inhibitors of serine proteases. 

The benzylic free radical produced by the addition of the carbamoyl radical to the ethyl cinnamate molecule is more stable than the alternative radical alpha to the ester group. With such an orientation of addition to the a,p-unsaturated ester, this reaction should lead to derivatives of malonic acid. However, it has been found that the intermediate radical, being a stable benzylic free radical, fails to perform the subsequent abstraction of a hydrogen atom from formamide, and thus no chain-transfer step takes place. Instead of performing this step it favours the combination with a semi-pinacol radical, which is present in solution, to yield the hydroxy ester which subsequently lactonizes to give the major product of the reaction (67). 

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