Recent progress in the synthesis of pyridinylboronic acids and esters

Recent progress in the synthesis of (un)substituted pyridinylboronic acids and esters is reviewed. Five approaches to the synthesis of (un)substituted pyridinylboronic acids and esters are summarized: (1) halogen-metal exchange (HMe) and borylation, (2) metal-hydrogen exchange via directed ortho-metallation (D o M) followed by borylation, (3) palladium-catalyzed cross-coupling of halopyridines with tetraalkoxydiborane or dialkoxyhydroborane (4) iridium or rhodium catalyzed C-H or C-F borylation, and (5) [4+2] cycloadditions.


Introduction
Substituted pyridines are important components of many drugs and drug candidates.In recent years, the wide application of Suzuki-type cross-coupling reactions 1 has led to a rapid growth in the synthesis of heterocyclic boronic acids and esters and a concomitant rise in their use, utility, and flexibility in organic synthesis.An important sub-class of these heterocylic boronic acids and esters include pyridinylboronic acids and esters that are suitable for use in combinatorial approaches to drug design and discovery. 2ost pyridinylboronic acids and esters contain only one boronic acid substituent on the pyridine ring (general structure represented as 1).6-Pyridinylboronic acids are herein treated as 2-pyridinylboronic acids, and pyridinyl-5-boronic acids are treated as pyridinyl-3-boronic acids for the corresponding nitrogen-boron positions.Compounds bearing multiple boronic acids and esters on a pyridine ring have been observed in very limited cases, and only as 2,4-, 2,5-2,6-, and 3,5-disubstituted pyridinylboronic acids and esters (general structure represented as 2). 3,44][5][6][7] 2-Pyridinylboronic esters exhibit much greater stability than the corresponding acids.In addition, several air-and waterstable 2-pyridinylboronic esters have been developed and will be discussed later.
In 2003, Tyrrell and Brookes published a review on the synthesis of heterocyclic boronic acids, which included that of pyridinylboronic acids and esters. 8However, up until that time there had been only limited progress on the synthesis of pyridinylboronic acids and esters, and especially of 2-pyridinylboronic acids and esters.Since then, many articles have been published that report improved reactivity and selectivity of (un)substituted pyridinylboronic acids and esters, or improved stability of 2-pyridinylboronic acids and esters.Also, new approaches have been developed for the synthesis of (un)substituted pyridinylboronic acids and esters, which include transition metal-catalyzed C-H/C-F bond activation 9,10 and [4+2] cycloaddition chemistry. 11ecause of the importance of pyridines in organic synthesis, our aim here is to summarize these advances and to provide an up-to-date review on the synthesis of pyridinylboronic acids and esters based on the recent literature.

The synthesis of pyridinylboronic acids and esters
Thus far, there are five methods used in the synthesis of pyridinylboronic acids and esters: (1) the metal-halogen exchange of the corresponding pyridinyl halides followed by borylation using trialkylborates, (2) the metal-hydrogen exchange of the corresponding substituted pyridine under directed ortho-metallation (DoM) followed by borylation using trialkylborates, (3) palladiumcatalyzed cross coupling of halopyridines with tetraalkoxydiboron or dialkoxyhydroborane, (4) iridium-or rhodium-catalyzed C-H or C-F bond activation followed by borylation, and (5) [4+2] cycloaddition.

The synthesis of pyridinylboronic acids and esters by halogen-metal (Li, Mg or Sn) exchange / borylation
The halogen-metal exchange, followed by borylation, is the most fundamental method for the preparation of pyridinylboronic acids and esters, and still remains the least expensive and most reliable large-scale preparation method.Trimethyl borate B(OMe)3 (4a, R = R1 = Me), 8 triisopropyl borate B(Oi-Pr)3 (4b, R = R1 = i Pr), 8 tributyl borate B(OBu)3 (4c, R = R1 = n-Bu) 8,12 and tris(trimethylsilyl) borate B(OSiMe3)3 (4d, R = R1 = SiMe3) 13 are the most commonly used starting non-cyclic trialkylborates, while the most commonly used cyclic borates are MeO-Bpin (4e), 14 i PrO-Bpin (4f), 15 and MPB-O i Pr (4g). 16Under some circumstances, 5 was obtained as a stable intermediate and used directly for Suzuki coupling, 17 but it was generally transformed into a stable pyridinylboronic acid or ester via path A, B, or C prior to use in the coupling reaction.For example, most 3-pyridinylboronic acids and 4-pyridinylboronic acids are stable and can be obtained by quenching the reaction mixture with aqueous acid or base (path A in Scheme 1, via 4a-d, R = R1). 8[16] N Y X X = Cl, Br, I Y = H, FG(s) The general procedure for halogen-metal exchange (HMe) and borylation for the synthesis of pyridinylboronic acids and esters, FG(s) = Functional Group(s).
There are two general protocols employed that use the metal-halogen exchange, both of which typically use either an organolithium (RLi) or an organomagnesium halide (RMgX).The usual procedure often refers to the procedure where the addition of the organometal to the halopyridine occurs first and is followed by the addition of the trialkyl borate.The revised protocol often employs the in situ quench procedure, wherein the organometal is added to a cooled mixture of the halopyridine and trialkyl borate.The latter generally gives much better results when the halopyridine bears functional groups, such as esters and nitriles, that are incompatible with organometallic reagents. 18The organometal, solvent, and temperature also have a large effect on the borylation: different results were obtained using 3-bromopyridine under varying conditions. 192.1.2.The selectivity of halogen-metal (Li or Mg) exchange / borylation.9][20][21][22][23] With simple chloropyridines and fluoropyridines (3, Y = H; X = F or Cl) it was generally difficult to affect the metal-halogen exchange transformation.

The synthesis of pyridinediboronic acids via halogen-organotin (Sn) exchange of the corresponding pyridinyl halides and borylation.
Though not widely applied, the organotin and halogen exchange followed by BH3 borylation and hydrolysis is an alternative approach for the synthesis of pyridinylboronic acids and esters.Unlike the halogen-metal (Li or Mg) exchange which was followed by borate, the organotin-halogen exchange was followed by reaction with borane and subsequent hydrolysis.The organotin method provides a successful approach to the synthesis of pyridinediboronic acids and esters (Scheme 2).Scheme 2. The synthesis of pyridinediboronic acids via organotin pyridine.

The synthesis of pyridinylboronic acids and esters by directed ortho-metalation(DoM) and boronylation
Directed ortho-metalation (DoM) [43][44][45] followed by borylation with trialkylborate provides another approach for the synthesis of pyridinylboronic acids and esters bearing Directed Metalation Groups (DMGs).a.All metalations were carried out in THF, and at -78 ºC, except for Entry 7 (-50 ºC).b The products for Entries 1-13 are 3-pyridinylboronic acids (R1 = H) using path A. c The products for Entries 14-27 are 4-pyridinylboronic acids or esters.d Both Paths A and B were used.4-pyridinylboronic acids (R 1= H) were obtained using path A, pinacol esters were obtained using Path B.
Pyridinylboronic acids were obtained by quenching the reaction mixture with aqueous acid or base (path A), 24 while pyridinylboronic esters (generally the pinacol ester) were obtained by a "one-pot" procedure by the addition of an alkyldiol (e.g.pinacol) to the reaction mixture (path B). 25

Synthesis of pyridinylboronic acids and esters by palladium-catalyzed cross-coupling of halopyridines with tetraalkoxydiboron or dialkoxyhydroborane
The Suzuki-type cross-coupling method is widely used for the preparation of the majority of pyridinylboronic esters.It has a broad substrate scope and good tolerance for most functional groups.The general procedure is shown in (Scheme 4).Scheme 4. The general procedure of Pd-catalyzed Suzuki-coupling of halopyridines with tetraalkoxydiboron or dialkoxyhydroborane, FG(s) = Functional Group(s).
Bromopyridines (3, X = Br), iodopyridines (3, X = I) and chloropyridines (3, X = Cl) can all be used as suitable substrates.5][56][57][58][59][60][61][62] Other tetraalkoxydiboron compounds such as (neopentylglycolato)diboron (10) were also reported. 63Dialkoxyhydroborane compounds like (pinacolato)hydroborane (HBPin, 11) are occasionally reported as well. 64The Pd-catalyst and ligands play critical roles in the cross-coupling reaction, especially for chloropyridines. 56Compound 12 was found to be an effective ligand for the transformation of chloropyridines, where it can be used either directly as the ligand in the cross-coupling reaction, 56 or in preparation of the catalyst (e.g. 13, where L = 12). 57OAc is generally used as the base, as stronger bases (e.g.K3PO4 and K2CO3) may lead to side reactions such as homo-coupling. 56,57Dioxane, DMSO, and DMF are usually employed as solvents, and the duration and temperature of the reactions are variable. 57A summary of the literature results is presented in Table 3.   Scheme 5.The general procedure of iridium-or rhodium-catalyzed borylation of pyridines FG(s) = Fuctional Group(s).
Ligands play important roles in the yield and regioselectivity of iridium-and rhodiumcatalyzed C-H bond borylation reactions.[69][70][71][72][73][74][75] 2.4.2.The regioselectivity of the iridium-or rhodium-catalyzed C-H bond borylation.The regioselectivity of the borylation of 3 was also studied.4][75] The borylation selectivity with ligands 14b and 14d were observed to be different: borylation occurred in the position adjacent to the nitrogen atom in 14b ( R = tBu), but occurred at the 5-position (i.e.ortho to the methoxy groups) in 14d (R = OMe). 73 summary of the results of Ir-catalyzed C-H borylation described in the literature is provided in Table 4.

The synthesis of pyridinylboronic acids and esters by [4+2] cycloaddition
An alternative strategy to the synthesis of functionalized pyridinylboronic esters employs a [4+2] Diels-Alder-like cycloaddition with an alkynylboronate (19).Typical overall yields using this method were found to be between 62 and 88%.The regioselectivity varied from 20:1 to 1:2 for 20 / 21, depending on the substituents, R1 and R2, on the diene and dienophile.This strategy allows for a diverse range of intermediates to be generated in good yield. 11 Scheme 7. The [4+2] cycloaddition for the synthesis of substituted pyridinylboronic pinacol esters.

Conclusions
The methods described herein demonstrate that the preparation of pyridinylboronic acids can be achieved through diverse chemistry.This diversity provides flexibility in the functional groups present on the starting pyridines, as the limitations of one procedure may be overcome by the use of an alternative method.We wanted to provide an up-to-date review on the synthesis of pyridinylboronic acids and esters, given the rapid rise in the use of and types of boronic acids and esters in organic synthesis and the importance of these compounds in drug design and discovery..With the rapid development of new chemistry in recent years, new and effective approaches to the synthesis of functionalized pyridinylboronic acids and esters can be expected.

Table 1 .
The synthesis of 2-pyridinylboronic acids via halogen-metal exchange (H-Me) followed by borylation according to Scheme 1

Table 2 .
A summary of the reported results for the synthesis of pyridinylboronic acids and esters via directed ortho-metalation (DoM)/borylation from substituted pyridine (Scheme 3)

Table 3 .
A summary of (un)substituted pyridinylboronic acids and esters prepared from pyridinyl halides via a Pd-catalysed cross-coupling reaction (Scheme 4)

The general procedure of iridium-or rhodium-catalyzed C-H bond borylation.
Iridium-or rhodium-catalyzed borylation of pyridine or substituted pyridines via C-H activation is one of the most promising methods for the preparation of pyridinylboronic acids because of its high atom efficiency and because it can be conducted under mild reaction conditions compared with traditional halogen-metal exchange reactions.This method is generally applied to the synthesis of pyridinylboronic acid pinacol esters.The general procedure is shown in Scheme 5 where X represents H or a functional group at the 2'position.