The 2‐Pyridyl Problem: Challenging Nucleophiles in Cross‐Coupling Arylations

Abstract Azine‐containing biaryls are ubiquitous scaffolds in many areas of chemistry, and efficient methods for their synthesis are continually desired. Pyridine rings are prominent amongst these motifs. Transition‐metal‐catalysed cross‐coupling reactions have been widely used for their synthesis and functionalisation as they often provide a swift and tuneable route to related biaryl scaffolds. However, 2‐pyridine organometallics are capricious coupling partners and 2‐pyridyl boron reagents in particular are notorious for their instability and poor reactivity in Suzuki–Miyaura cross‐coupling reactions. The synthesis of pyridine‐containing biaryls is therefore limited, and methods for the formation of unsymmetrical 2,2′‐bis‐pyridines are scarce. This Review focuses on the methods developed for the challenging coupling of 2‐pyridine nucleophiles with (hetero)aryl electrophiles, and ranges from traditional cross‐coupling processes to alternative nucleophilic reagents and novel main group approaches.


Introduction
Pyridine derivatives are ac ommon structural motif in natural products [1] and have found applications in diverse fields,f rom functional materials (photovoltaics,l igands, dyes), [2] to agrochemistry [3] and medicinal chemistry ( Figure 1). [4] Thep yridine core ranks second out of the most used heterocycles in medicinal compounds, [4a] and bipyridines are frequently employed as ligands in coordination chemistry. [5] Ah istorical review of the first fifty years of the chemistry of 2,2'-bipyridines was recently reported by Housecroft and Constable. [6] Despite the clear importance of pyridines,their functionalisation remains challenging,particularly at the 2-position. In transition-metal-catalysed coupling chemistry,t he use of 2pyridyl derivatives as nucleophilic coupling partners has proved notoriously difficult in traditional cross-coupling reactions.T his challenge was coined the "2-pyridyl organometallic cross-coupling problem" by Fagnou and co-workers in 2005 (Scheme 1A). [7] Considering the popularity of the Suzuki-Miyaura cross-coupling (SMC), there is particular interest in improving the poor reaction success of 2-pyridyl boron nucleophiles.F or example,t he challenges of coupling 2-pyridyl boronates lead Rault and coworkers to tune their synthetic pathway to avoid such species while preparing Nemertelline. [8] Thee xtent of the 2-pyridyl problem is highlighted by the results of asurvey of the use of 2-pyridyl boron reagents in Suzuki chemistry,t aken from the Pfizer internal electronic Azine-containing biaryls are ubiquitous scaffolds in many areas of chemistry,a nd efficient methods for their synthesis are continually desired. Pyridine rings are prominent amongst these motifs.T ransition-metal-catalysed cross-coupling reactions have been widely used for their synthesis and functionalisation as they often provide aswift and tuneable route to related biaryl scaffolds.H owever,2-pyridine organometallics are capricious coupling partners and 2-pyridyl boron reagents in particular are notorious for their instability and poor reactivity in Suzuki-Miyaura cross-coupling reactions.T he synthesis of pyridine-containing biaryls is therefore limited, and methods for the formation of unsymmetrical 2,2'-bis-pyridines are scarce.This Review focuses on the methods developed for the challenging coupling of 2pyridine nucleophiles with (hetero)aryl electrophiles,and ranges from traditional cross-coupling processes to alternative nucleophilic reagents and novel main group approaches.  laboratory notebook:less than 8% of the reactions surveyed obtained ap roduct yield of at least 20 %. [9] Oxidative crosscouplings of two pyridyl nucleophiles are evidently underdeveloped for the same reasons (Scheme 1B). Given these challenges,i tf ollows that many innovative developments have emerged, and these are the focus of this Review.Anote on terminology;a lthough cross-coupling reactions are not traditional nucleophile + electrophile combinations,for pragmatic reasons,i nt his Review we will refer to aryl À metal species as the nucleophilic fragment, while aryl halides (or pseudohalides) will be referred to as the electrophile.
The2-pyridyl problem can be circumvented by the formal inversion of polarity of the coupling partners (Scheme 1D). 2-Halopyridines are excellent electrophilic partners,compatible with ar ange of cross-coupling conditions.I ndeed, experimental [10] and theoretical [11] results show that 2,3-and 2,4dihalopyridines react regioselectively at the position adjacent to the nitrogen, where the CÀXb ond has al ower bond dissociation energy.H owever,s uch an approach is less attractive in discovery chemistry as it fails to exploit the vast libraries of commercially available halogen-substituted arenes.F urthermore,t his reverse-polarity approach is not compatible with the preparation of non-symmetrical 2,2'bipyridines and other 2,2'-bis-azine-linked derivatives.
Thecross-coupling of two electrophiles,derived from the classical Ullmann reaction, [12] also offers an alternative to the 2-pyridyl problem (Scheme 1E). Since its first application to the synthesis of bipyridine in 1928, [13] numerous metalcatalysed Ullmann-type homocouplings have been developed for the synthesis of symmetrical 2,2'-bipyridines and bis-azine derivatives. [14] However,the reductive coupling of two different electrophiles remains difficult owing to selectivity issues. Cross-electrophile couplings leading to non-symmetric biheteroaryl compounds remain underdeveloped and do not yet represent ag eneral solution to the 2-pyridyl problem. [15] Direct arylation through palladium-catalysed CÀHactivation has emerged as an attractive alternative to classic crosscoupling reactions, [16] especially for heterocycles as the presence of the heteroatom activates as pecific C À Hb ond, increasing reactivity and regioselectivity. [17] Significant progress in this field has recently been made concerning the direct arylation of 2-pyridine derivatives (Scheme 1C). [18] Functionalised pyridines can also be obtained de novo,using carbonyl fragments (Scheme 1F). However,t his Review focuses on cross-coupling processes,w hich provide as wift and tuneable route to ab road range of scaffolds.R eactions involving 2pyridyl radical intermediates are not discussed in this Review.
Rather than discussing ab road range of heteroaromatic nucleophiles, [19,20] we have chosen to focus on 2-pyridyl nucleophiles as benchmark substrates.I ndeed, 2-pyridines are of prime importance and are notoriously one of the most challenging nucleophiles in cross-coupling reactions.Focusing on other heterocycles, [21] which are traditionally better performing nucleophiles,c an be misleading when making the appropriate choice of reagents and conditions for more challenging substrates.
This Review aims to provide ac ritical overview of the progress that has been made towards ageneral solution to the 2-pyridyl problem, ranging from traditional cross-coupling arylations to more recent developments.T he sections of this Review are organised by nucleophile type.T his discussion of innovative strategies developed for various 2-pyridyl nucleophiles should provide chemists with as et of resources and conditions applicable to ar ange of challenging heteroaromatic substrates.

2-Pyridylzinc (Zn)
Organozinc reagents can be obtained via direct, or transition-metal-catalysed, oxidative addition of zinc into carbon À halide bonds,transmetalation of metalated substrates with az inc source such as ZnCl 2 or ZnBr 2 ,o rb ydirect zincation of CÀHbonds. [22] These methods can be applied on multi-kilogram scale to 2-pyridyl substrates,w hich do not suffer from any particular instability compared to their carbocyclic analogues. [23] Negishi cross-coupling protocols developed for carbocyclic substrates [24] were adapted to 2pyridyl derivatives without major changes. [25] Ther elatively inexpensive catalyst Pd(PPh 3 ) 4 can be employed for the coupling of structurally simple 2-pyridylzinc reagents with awide variety of electrophiles,tolerating halides,amines and alcohols (Scheme 2). [26] Hapke and Lützen showed that Pd(P t Bu 3 ) 2 could be used to form 5-substituted 2,2'-bipyridines (9 examples,5 -90 % yield). [27] XPhos was subsequently found to be am ore efficient ligand [28] and was employed by Knochel, Buchwald and co-workers for coupling 2-pyridylzinc pivalate reagents. [29] By employing zinc pivalate as the zinc source, these substrates could be weighed under air with minimal loss of activity.Arange of functional groups such as esters, ketones,a mides,a nilines or nitriles were tolerated on the electrophile,but the pyridine core remained poorly functionalised (14 examples,60-98 %yield). TheBuchwald group also demonstrated that the use of their XPhos Pd G3-amido precatalyst (Scheme 3) provided much improved activity in Negishi cross-couplings. [30] Although the coupling was only applied to unsubstituted 2-pyridylzinc chloride,t hese mild reaction conditions allowed the coupling of al arge scope of challenging nucleophiles,s uch as 5-membered heterocycles bearing more than one heteroatom, or polyfluoro(hetero)aryl zinc reagents.
Organ and co-workers showed the remarkable efficiency of aN-heterocyclic carbene (NHC) ligand for the synthesis of sterically demanding tetra-ortho-substituted biaryls. [31] They demonstrated that this catalyst was also efficient for avariety of heterocyclic substrates,including 2-pyridylzinc bromide.
More recently,Liu and Wang developed adirect coupling of electron-deficient (hetero)arenes using iodonium salts. [32] Theb ase Zn(tmp)Cl·LiCl was selected to promote selective zincation. Subsequent coupling with iodonium salts under copper catalysis allowed adiverse scope of nucleophiles to be used (Scheme 4). No desired product was observed when the iodonium electrophile was replaced by its triflate or iodide equivalent. Thesynthetic utility of this method was illustrated by arapid synthesis of ahistone deacetylase inhibitor in 50 % overall yield from commercial 6-bromonicotinonitrile.

2-Pyridylstannanes (Sn)
2-Pyridylstannanes usually provide robust, scalable,a nd high yielding reactions with aryl halides. [21,33] 2-(Tributylstannyl)pyridine is commercially available,a nd 2-(trialkylstannyl)pyridyl derivatives can be obtained directly from 2bromopyridines using Sn 2 Bu 6 in ap alladium-catalysed process, [34] or via lithium/bromide exchange followed by quenching with trialkyltin chloride. [35] However,recent reports of tin-based cross-coupling methodologies involving 2-pyridyl substrates are scarce. [36] Theh igh toxicity of organotin compounds,t he difficulty associated with the removal of tin impurities from reaction mixtures,and the low tolerance of tin residues in biological assays explain the reduced focus in this area. Nevertheless,i ti si mportant to mention that 2-pyridylstannanes have been extensively used for the synthesis of nitrogen abundant molecules such as polypyridines, [37] complex polyazine molecules, [38] tert-pyridines, [39] and also medicinally relevant scaffolds such as analogues of the antitumour antibiotic lavandamycin [40] as well as natural products. [41] 2.3.

2-Pyridyl Grignard Reagents (Mg)
Although 2-pyridyl Grignard reagents have long been known and easily accessed via magnesium/halide exchange reactions, [42] their use in cross-coupling reactions has remained limited. [43] In 1982, Kumada, Suzuki and co-workers reported aN iCl 2 (dppp)-catalysed coupling of heterocyclic Grignard reagents with ar ange of heteroaromatic aryl halides. [44] However,t he formation of 2,2'-bipyridine only proceeded in 13 %y ield. In 2010, Ackermann, Schulzke and co-workers showed the unique ability of secondary phosphine oxides (SPOs) to promote the palladium-catalysed coupling of 2-pyridyl Grignard reagents with aryl halides. [45] In contrast, commonly employed phosphine and NHC ligands showed no or poor reactivity.C atalyst loading could be lowered to 1mol %[ Pd] using ap reformed catalyst (Scheme 5, Conditions B) but the combination of Pd 2 (dba) 3 and phosphine oxide ligand (1-Ad) 2 P(O)H was also successful (Conditions A). 2-Pyridylmagnesium bromide reacted in good to excellent yields with aromatic or heteroaromatic electrophiles (52-94 %y ield), and the pyridine nucleophile could be substituted at positions 4o r6without loss of reactivity.H owever,f unctional group tolerance remains limited.
Duan and co-workers reported the successful use of 2pyridyl Grignard reagents in the iron- [46] or cobalt-mediated [47] oxidative assembly of two aryl metal reagents using oxygen as an oxidant. Thet wo arylmetal reagents were assembled sequentially to form at itanate complex [HetAr(ArTi-(OR) 3 )M],a nd the reductive coupling was triggered by the addition of the iron or cobalt catalyst mixture under an oxygen atmosphere (Scheme 6). Both iron and cobalt protocols tolerated ar ange of aromatic and heteroaromatic substrates,b ut 2,2'-bis-azine-linked derivatives could not be obtained.

Couplings with Alternative Metal Reagents
In 2019, Schoenebeck demonstrated that novel organogermanes could provide as olution to the problem posed by unstable 2-pyridyl and polyfluoroaryl boronic acids in Suzuki reactions. [48] Key benefits identified in this work:a rylgermanes have low toxicity, [49] were easily synthesised from triethylgermanium chloride using Grignard reagents,a nd demonstrated high stability to both acid and base.T he reaction coupled aryl iodides or iodoniums chemoselectively to av ariety of aryl and heteroaryl germanes (Scheme 7). Yields were noticeably lower for the heteroaryl germanes compared to the carbocyclic variants.A lso,n oh eteroaryl electrophiles were coupled. Pentafluorophenyl germane coupled in excellent yields,h ighlighting the importance of this work for what would otherwise be ac hallenging SMC. Notably,u nder conventional palladium catalysis the organogermanes were unreactive,y et under Pd nanoparticle catalysis,w ith much lower catalyst loadings,h igh reactivity was shown. This,c oupled with the chemoselectivity for iodo electrophiles,lends well to an orthogonal synthetic approach as other reactive functional groups (BPin, Br, Cl, NO 2 ,O Tf) present on either coupling partner remained unscathed post reaction.
In 2012, Huo and co-workers presented zirconium nucleophiles as an alternative to organozinc reagents. [50] The heteroaromatic zirconium reagents were prepared in situ from oxidative addition of heteroaryl chlorides into Cp 2 ZrBu 2 .T he sole example of a2 -pyridyl zirconium coupling to an aryl bromide was obtained in moderate yield (56 %), thus further optimisation would be necessary to improve the applicability to the 2-pyridyl problem.
Arylalanes have gained popularity in C À Cb ond forming cross-coupling reactions but with limited extension to the 2pyridyl problem. In 2014, Zhou reported the cross-coupling of pyridyl or thienyl aluminium reagents with (hetero)aryl bromides and benzyl chlorides. [51] Thes cope was limited to unsubstituted heteroaryl alanes,a lbeit in very good yields (Scheme 8). 2-Pyridyl alanes coupled with consistently lower yields than the 3-pyridyl substrates,r eiterating the increased challenge associated with 2-pyridyl nucleophiles.The reaction could be scaled up with in situ aluminium reagent preparation (5 mmol, 90 %, 3-phenyl pyridine). 2,2'-Bis-azine could not be obtained, presumably due product inhibition of the catalyst.

2-Pyridylsilanes (Si)
Organosilanes can also be used as nucleophilic coupling partners in desilylative coupling reactions with aryl halides. Hiyama was the first to report ac ross-coupling involving 2pyridylsilane nucleophiles using an unstable dichloroethylsilyl group (Scheme 9a). [54] In 2005, Fort and co-workers reported the first stable and easy to handle 2-pyridyltrimethylsilanes suitable for the Hiyama couping (Scheme 9b). [55] However, the scope was limited to pyridines bearing an electronwithdrawing substituent to increase the polarisation of the C À Si bond, ap roblem that was solved by Whittaker and coworkers using as ilver additive. [56] This was further improved by Yoshida and his group by replacing am ethyl substituent with an allyl group on silicon (Scheme 9c). Anarrow scope of 2-aryl pyridines (8 examples,5 9-93 %y ield) was obtained without need for any fluoride source. [57] By analogy to the reported binding of CuI to 2-(allyldimethylsilyl)pyridine, [58] they proposed that the soft silver centre would bind to both pyridine and allyl moieties,while the hard oxygen atom would coordinate the silicon (Scheme 9d). Under these conditions, other silyl groups such as homoallyl-, vinyl-, and p-acetylbenzyl-dimethylsilyl provided low to moderate reactivity,while 2-(trimethylsilyl)pyridine remained unreactive,highlighting the poor polarisation of unactivated CÀSi bonds.
Ar ange of other conditions were also developed for 2pyridyltrimethylsilane substrates,h owever,t he substrate scope focused on the electrophile while the pyridine core remained poorly functionalised. [59] TheHiyama group showed that 2-pyridyltriethylsilanes could also be employed in ac opper-catalysed cross-coupling reaction with aryl halides (Scheme 10, conditions A). [60] Thes ame group subsequently reported ad ual Pd/Cu catalytic system which allowed the coupling of ar ange of silyl groups under milder conditions (Scheme 10, conditions B). [61] Thee fficiencyo ft hese couplings was demonstrated with al arge scope of heterocyclic substrates,aswell as challenging polyfluorocarbocyclic nucleophiles,but the pyridine scope was once again limited.
Smith and co-workers showed that isolation of the silane nucleophile could be circumvented by using elegant siliconbased transfer agents. [62] 2-Lithiopyridine could therefore be used directly as the nucleophilic coupling partner,a nd the transfer agents could be recovered and reused without loss of reactivity or cross-contamination. Together with the advancements in preparing heteroaryl silicon derivatives, [63] the Hiyama coupling appears as agood alternative to traditional organometallic reagents.U nfortunately,t he synthesis of 2pyridyl silanes still requires the use of organolithium reagents, and accessing functionalised 2-pyridyl silane substrates remains ac hallenge.

Problematic Suzuki-Miyaura Couplings
SMC reactions have emerged over recent decades as the favoured route for swift construction of C(sp 2 )ÀC(sp 2 )bonds, in both chemical industry and academia ( Figure 2). [9,64] The reason SMC has become the choice carbon À carbon bond forming methodology over more conventional organometallic cross-coupling is in part due to milder reaction conditions, broad functional group tolerance and use of less toxic and more stable boron-based nucleophiles. [65] Boron-nucleophiles have al ess polarised carbonÀmetal bond than classical organometallic reagents.T his generally allows better chemoselectivity and functional group tolerance. [66] Another factor in the widespread use of SMC reactions is the continued research and innovation into development of new catalysts and boron-reagents. [64b, 67] Additionally,t hese reactions have been developed alongside,a nd are compatible with, new emerging technologies,s uch as automation and microwave reactions. [68] Despite the wide-spread application of boronic acids in SMC processes,s ome boronic acids have notoriously poor reaction success due to their instability,b oth under storage and SMC conditions.T he most infamously unstable arylboronic acids with regards to protodeboronation are heteroaromatic (particularly 2-heteroaryl) and polyfluorinated phe-nyls ( Figure 3). [19] These motifs are valued in industry and academia, making the difficulties in coupling these nucleophiles more frustrating. Thecross-coupling of 2-pyridyl boron reagents is particularly challenging.M any reports using 2pyridyl boron nucleophiles show moderate to poor yields, limited scope of aryl or heteroaryl electrophiles,often require substrate specific optimisation, and employ boron reagents frequently prepared using organolithium chemistry. [65,69] As aresult, there is asizeable body of research into establishing general SMC conditions for efficient coupling of these reagents and investigating novel, more stable 2-pyridyl boron nucleophiles.Thus,the successful coupling of 2-pyridyl boron reagents has become ab enchmark for ar obust SMC reaction.
In designing workable SMC solutions to the 2-pyridyl problem, it is key to understand the challenges faced when coupling 2-pyridyl boronates,p articularly the innate propensity of these species to undergo protodeboronation. [67a] Reports from the Kuivila group in 1961 gave initial mechanistic insights into the pathway of protodeboronation of arylboronic acids and the factors that influence the rate of decomposition. [70] However,a st hese studies pre-date the SMC reaction, the importance of pH in affecting the rate of decomposition was less explored. In 2014, Perrin and coworkers published an investigation into base-promoted protodeboronation of electron-deficient (hetero)arylboronic acids. [71] Thereport concluded that alkaline conditions rapidly accelerate the decomposition of 2,6-dihalogen-substitued arylboronic acids.A lthough no 2-pyridyl boronic acids were studied, this highlighted the relationship between pH and the rate of protodeboronation.
Seminal work into understanding the instability of 2pyridyl boronic acid and boronates was reported by the group of Lloyd-Jones. [19] They investigated the pH-dependent rate of protodeboronation for 18 unstable boronic acids,a nd proposed ageneral kinetic model. [19a] 3-and 4-pyridyl boronic acids were found to undergo slow protodeboronation under heating and basic conditions (t 1/2 > 1week, pH 12, 70 8 8C), whereas 2-pyridyl and 5-thiazolyl boronic acids undergo rapid protodeboronation under heating and neutral conditions (t 1/   25-50 s, pH 7, 70 8 8C). Thef ast protodeboronation of 2pyridyl boronic acids was shown to not be accelerated by higher pH;instead, 2-pyridyl boronic acid was more stable at high pH (pH > 10) than under weakly acidic/basic conditions (pH 4-8). Lloyd-Jones details how 2-pyridyl boronic acids decompose via fragmentation of az witterionic intermediate, which is formed at am aximum rate between pH 4a nd 8 (Scheme 11). This species is more readily formed from 2pyridyl boronic acids than the 3-or 4-pyridyl analogues.T his is partially attributed to the stronger ylidic character and closer charge placement in the zwitterion formed with 2pyridyl substrates.Z witterionic fragmentation is strongly facilitated by the basic nitrogen adjacent to the boron, which stabilises the B(OH) 3 leaving group during CÀBb ond cleavage.A th igher pH this interaction is attenuated and protodeboronation is slower.T he presence of this stabilising interaction explains in part why 2-pyridyl species are especially prone to protodeboronation.
An electron-withdrawing substituent at the 6-position of 2-pyridyl boronic acid results in protodeboronation occurring within al ower pH range than for the unsubstituted 2pyridine. [19a] In addition, substituents at the 6-position are proposed to block coordination of the pyridyl nitrogen to the Pd centre,t hus preventing any reduction in catalytic activity from this interaction. [72] This is worth noting, as multiple reports discussed in Section 3.3 give noticeably higher yields when the 2-pyridyl nucleophile is 6-substituted.

Developments in Catalytic Systems
Prior to in-depth mechanistic understanding of protodeboronation, more active catalyst systems were employed as astrategy to circumvent boronate instability.SMC conditions were tailored to increase the rate of product formation, in order to outcompete protodeboronation. In the context of difficult SMC reactions the most notable families of ligands developed are bulky,e lectron-rich monophosphines (e.g. SPhos,X Phos,P Cy 3 ) , [73] and SPOs. [74] Another strategy to improve the efficiency of aSMC catalytic system is to employ ap recatalyst. There has been success in developing precatalysts that assist in enabling the use of milder conditions and/or shorter reaction times for the coupling of some challenging boronic acids such as polyfluorophenyls, [75] 5-membered heterocycles, [75][76] and ah andful of 6-membered heteroaromatic boronates. [76][77] However,use of these activated ligands and precatalyst systems alone does not provide ag eneral solution to the 2-pyridyl problem, although they are useful developments when used in conjunction with more stable boron-derived reagents. [75][76][77]

Copper Additives
Lewis acidic metals,s uch as copper, silver and zinc,h ave historically been useful additives in conventional crosscoupling reactions and have likewise had success in improving the yield of the SMC of particularly challenging nucleophiles. [78] In 2009, Deng,P aone and co-workers found that as toichiometric copper additive was key in achieving high yields of 2-arylpyridines when coupling various challenging 2heterocyclic pinacol boronates (Scheme 12 a). [79] However, for 6-substituted 2-pyridyl boronates,t he presence of copper was not necessary to obtain good yields.This is in line with the discussion of the relative stability of 6-substituted 2-pyridyl reagents in Section 3.1.
In 2011, Crowley and co-workers expanded the scope of this copper-assisted SMC by using S-Phos or X-Phos. [80] This shortened the reaction times and allowed the use of less reactive aryl chlorides (Scheme 12 b). Adrawback is that both methodologies require stoichiometric copper and at wo-fold excess of the boronate reagent to outcompete the competitive homocoupling of the 2-pyridyl species.H owever,c ommercially available boronate esters and ac heap Cu I source are used. Therefore,this approach does provide astraightforward solution to poor 2-pyridyl boronate reactivity.T he success of the copper additives reported here has been capitalised on in further reports using next-generation boronate reagents, discussed in Section 3.3.
Concerning the role of copper, the authors postulated that the 2-pyridyl boronate species first undergoes irreversible transmetalation to give a2 -pyridyl cuprate in situ (Figure 4.1). This cuprate is proposed to undergo more efficient transmetalation with the active Pd species than the parent boronate,a nd circumvents the potential for protodeboronation. This is similar to one of the proposed roles of copper salts in Stille reactions. [78d] However,i nt he aforementioned 2016 report from Lloyd-Jones,t he role of Lewis acid additives in preventing protodeboronation was extensively explored. [19a] Through NMR studies,i tw as observed that copper binds reversibly to the pyridine (Figure 4.2). This CuÀNc oordination reduces the proportion of the key zwitterion intermediate in the reaction mixture,w hich is responsible for protodeboronation. Thea uthors concluded that it is the reversible complexation of copper to the pyridyl nitrogen which attenuates protodeboronation and improves reaction success.Compared to other Lewis acids (Zn, Ag, Sr), copper additives have the greatest impact, likely as copper is more azaphilic.

Alternative Boronate Species
As well as tailoring SMC conditions,a nother key focus area is the development of more stable boron-derived reagents;o nes that are resistant to,o ru ndergo as lower rate of protodeboronation.Aplethora of next-generation organoboron nucleophiles have arisen over the last two decades ( Figure 5).
These next-generation boron-based reagents operate either as slow-release species or as more stable,d irect coupling partners. [66][67]81] In both approaches,t he Lewis acidity of the boron centre is reduced. Thes low-release strategy masks the boron centre,rendering it less reactive,and then, under the reaction conditions,the active boron species is released at ac ontrolled rate. [66][67]82] This approach ensures that the ratio of catalyst to active,unmasked boron reagent is high and favours transmetalation over protodeboronation. Theother, more recent approach is the development of stable boron nucleophiles that react directly in SMC reactions and do not hydrolyse to the boronic acid in situ. [66,81] There are multiple reviews discussing in depth the discovery,s ynthesis and development of various boronbased nucleophiles. [65,67,83] However,i nt his Review,w e focus on these species as applied to 2-pyridyl couplings.

Cyclic Triol and Triisopropyl Borate Salts
Aryl cyclic triolborates were first introduced for use in SMC by Miyaura in 2008. [84] An advantage of triol salts over boronic acids is that they are bench-stable complexes and are shown to be highly efficient in transmetalation. Miyaura established the use of these reagents in carbocyclic SMC couplings,b oasting al arge substrate scope.H owever,o nly one example of a2 -pyridyl cyclic triolborate was featured, and the addition of CuI (20 mol %) was needed to achieve ahigh yield (90 %).
In 2010, Miyaura published ar eport focusing on heteroaromatic triolborates in SMC. [85] Boronic acids that were challenging to couple under typical SMC conditions were shown to couple efficiently as triolborates using an aqueous base.Conditions were optimised for the SMC of 2-pyridyl, 3pyridyl or 2-thiophenyl triolborates,a nd as mall scope was established. More general conditions followed in 2011, however, the scope of 2-pyridyl substrates was again limited. [86] In 2012, Cefalo and co-workers reported asystem for coupling lithium triisopropyl-and triol-2-pyridylborate salts, involving dual addition of catalytic CuCl and stoichiometric ZnCl 2 to the Pd-mediated reaction. [78c] However,t he scope was small and low yielding. Notably,C u I additives again proved essential for improving the reaction in all these reports.
Tr aditionally the counterion for cyclic triolborates is potassium or lithium. [84][85][86] This limits solubility of these reagents in organic medium. In 2013, Yamamoto and coworkers introduced tetrabutylammonium (TBA) 2-pyridyltriolborate salts for use in SMC. [87] Ther ate of the transmetalation step was observed to be faster with the TBAs alt compared to other alkali metal counterions (Bu 4 N + > Cs + > K + > Na + > Li + ). This higher reactivity is what the authors reason enables the use of less activated aryl chlorides as the

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Reviews 11076 www.angewandte.org electrophiles.Indeed, alarge scope of 2-(hetero)arylpyridines has been shown, with good to excellent yields (Scheme 13). Notably,n ob ase was used. Instead, an amino ligand was employed in conjunction with ac opper additive.T his methodology is auseful addition to the tools for the 2-pyridyl problem, however,there are some drawbacks.Namely,there is poor atom economy in using TBAs alts,w hich are used in excess and are also non-commercially available fragments.
As previously discussed (Section 3.2.1.), copper helps to attenuate the major decomposition pathway of 2-pyridyl boronates. [19a, 79] Hence,t he use of ac opper additive in all these reports calls into question if the more efficient coupling of 2-pyridyl borates can be attributed to the cyclic triolborate or the copper.
In 2008, Billingsley and Buchwald presented ag eneral method for the SMC of 2-pyridyl triisopropyl borates (B(O i Pr) 3 )u sing SPO ligands. [74b] In this report, various 2pyridyl boron reagents were used and quantitative conversion was seen only when employing lithium 2-pyridyl À B(O i Pr) 3 reagents (Scheme 14). In order for aryl chlorides to be coupled, the bulkier and more electron-rich ligand 2 had to be used. Unlike the cyclic triolborate work, this system does not require aC ua dditive.P otukuchi and Ackermann similarly reported the reaction of various substituted 2-pyridylÀB-(O i Pr) 3 Li reagents with aryl bromides using SPO ligands,also without the aid of copper (19 examples,30-87 %). [88] Overall, methodologies utilising 2-pyridyl triisopropyland triol-borates require specific tuning to be of use as solutions to the 2-pyridyl problem, demanding large organic counterions,s pecific phosphine oxide ligands or metal additives.M oreover,t he primary routes to access these species proceed via the unstable parent boronic acid, or are functional group restricted as they involve lithiation. [74b, 85, 87-88]

N-Phenyldiethanolamine Boronates (PDEA)
In 2004, Hodgson and Salingue developed anovel aminostabilised boronate for 2-pyridyl couplings using aN-phenyldiethanolamine (PDEA) group. [89] PDEA boronates are stabilised by the intramolecular dative bond between the nitrogen and boron atoms.A saresult these reagents are stable to prolonged storage.T he authors showed that 2-pyridylÀB(PDEA) could be synthesised in ascalable,one-pot procedure from the 2-bromopyridine via the triisopropyl borate in good yields.I nt his report, the first SMC system specifically optimised for the coupling of 2-pyridyl À B-(PDEA) with aryl bromides and iodides was described. [89] A small scope of nine 2-arylpyridines was obtained in varied yields (10-89 %);n ob iheteroaryls were prepared. Addition of copper was essential, again challenging how much of the improved reaction efficacy is due to the stabilised boronate versus the Cu I salt.
In 2007, Steven and co-workers accessed am oderate scope of 2-aryl-pyridines (10 examples,4 7-84 %y ield) using B(PDEA) under similar conditions to those reported by Hodgson. [69a] Although only the unsubstituted 2-pyridine boronate was used, the improved conditions allowed the coupling of various less reactive heteroaromatic electrophiles. In 2010 Lützen and Gütz published am ore extensive investigation, [90] and arange of 2,2'-bipyridines were synthesised in comparable,o re ven better yields than the same products accessed using Negishi or Stille cross-coupling reactions (Scheme 15).
Theu se of 2-pyridyl PDEA boronates has been successfully adapted to solid support chemistry. [91] As before, acopper additive was essential.

N-Methyliminodiacetic Acid (MIDA) Boronates
In 2007, Burke and Gillis introduced the use of aboronic acid protected by the trivalent N-methyliminodiacetic acid (MIDA) ligand for use in iterative SMC. [92] Initially, B(MIDA) reagents were used as masking groups,b eing converted into the parent boronic acid on treatment with aqueous base.

Reviews
In 2009, Burke and co-workers drastically expanded the utility of B(MIDA) reagents by using them directly in SMC. [82b] As previously discussed, there is kinetic competition between in situ protodeboronation of unstable boronic acids and their cross-coupling.Asasolution Burke and co-workers devised a"slow-release" strategy.This denotes the controlled rate of formation of unstable boronic acids from (benchstable) B(MIDA) in situ. [67a] Thestabilising BÀNcoordination in B(MIDA), similarly seen in PDEA boronates, [89] is key for allowing the slow release to be achieved. MIDAb oronates hydrolyse quickly when treated with strong base such as NaOH (< 10 min at 23 8 8C).
[82b] Utilising aw eaker base, tailoring the solvent system, and controlling the reaction temperature enabled the hydrolysis of B(MIDA) to be moderated. This strategy was applied to ar ange of challenging boron nucleophiles,i ncluding the unsubstituted 2-pyridyl À B(MIDA) (Scheme 16 a). Thep roduct yields were dramatically higher using B(MIDA) compared to the boronic acid directly.I ns upport of the slow-release hypothesis, increasing the rate of B(MIDA) release through use of as trong base (aqueous NaOH) gave similar yields to direct use of the boronic acid. Notably,acopper additive was employed.
In 2012 Burke and co-workers reported aS MC system specifically tailored for 2-pyridyl MIDAb oronates,o ffering this as "the first general solution to the 2-pyridine problem". [93] Thecombination of aXPhos palladacycle G1 catalyst and copper diethanolamine (DEA) as an additive were found to be optimum. Thea uthors demonstrated the generality of these SMC conditions by obtaining alarge scope of biaryls in good yields,using both activated and deactivated (hetero)aryl halides and triflates (Scheme 16 b). Similar to the synthesis of previously described boron reagents,as calable method for preparing 2-pyridyl À B(MIDA) reagents was also detailed: accessing triisopropylborates via lithiation, followed by ligand exchange.
First reported by Lipshutz and co-workers in 2013, the use of ad esigner surfactant in the SMC of arylÀB(MIDA) enabled high product yields to be obtained under aqueous nanomicellar conditions at room temperature. [94] Micelle catalysis allows the coupling to run under mild conditions, theoretically in small apolar aggregates,therein avoiding fast protodeboronation. Although not the focus of the paper, preliminary studies showed 6-methoxy-2-pyridyl MIDAb oronates were amenable to micellar catalysis.
In 2017, Lipshutz reported the application of micellar catalysis directly to 6-substituted 2-pyridylÀB(MIDA). [72a] One of the proposed roles of Cu additives in SMC is that Cu coordinates the pyridyl nitrogen and prevents unproductive Pd À Ncoordination. [19a] Theauthors propose that, instead, PdÀNcoordination could be sterically blocked by asubstituent at the 6-position ( Figure 6). To maintain the versatility of this method, the authors demonstrated that the substituent placed in the 6-position of the 2-pyridyl boronate could be easily removed or further transformed after cross-coupling.
In addition to attenuating Pd À N(pyridine) coordination, computational data shows that an electronegative group in the 6-position promotes cross-couplings by reducing the rate of protodeboronation of the 2-pyridylboronic acids formed in situ. [72a] Thes cope of the reaction is broad, with ad iverse scope of 2-hetero(aryl)pyridines achieved (Scheme 17). Furthermore,n oh omocoupling of the B(MIDA) was observed. Thec ombination of micelle catalysis and the attenuation strategy was further developed by Novartis chemists in 2018, who reported amodest scope of biheteroaryls from the SMC of 6-chloro-2-pyridyl Bpin. [95] Ligand-free conditions have also been developed for the use of 2-pyridyl À B(MIDA), [96] however asubstituent in the 6position of the pyridine is required. [97]

Organotrifluoroborates
Potassium organotrifluoroborates (RÀBF 3 K) are another class of popular nucleophilic reagents for SMC reactions.

Angewandte Chemie
Reviews 11078 www.angewandte.org These reagents are air and moisture stable,a nd can be prepared easily from organoboron reagents and cheap potassium hydrogen fluoride (KHF 2 ). [83,98] Theu se of Ar À BF 3 Kr eagents in challenging SMC reactions was considerably advanced by the Molander group in the early 2000s. [99] In 2003, they demonstrated that many (hetero)aryl-aryl scaffolds could be constructed through coupling of (hetero)arylÀ BF 3 Kwith aryl halides under ligandless conditions.However, the group explicitly showed that the coupling of 2-pyridyltrifluoroborate reagents was unsuccessful.
Only in 2012 did Wu and co-workers report optimised conditions for the SMC of 2-pyridylÀBF 3 Kr eagents. [100] Similarly to other research into the 2-pyridyl problem using the SMC reaction, an electron-rich and bulky monophosphine ligand was used. Thea uthors report ab road range of 2-(hetero)arylpyridines synthesised in moderate to good yields (Scheme 18). Although the scope of the electrophilic partner is broad, only 6-substituted 2-pyridyl-trifluoroborates were coupled. Additionally,t here are innate disadvantages with these reagents;a ss alts they are often difficult to purify,t o progress through multi-step synthesis,a nd have limited solubility in organic media.
Studies of the cross-coupling of carbocyclic aryl À BF 3 K with aryl bromides show that the reaction proceeds via hydrolysis of the borate in situ (Scheme 19). [101] Theb oronic acid is the species that actively joins the catalytic cycle. [101a] Optimisation of the system is often necessary for each class of substrate,which is likely due to the need to balance the rate of hydrolysis with the rate of catalyst turnover,a ss een with MIDAb oronates. [101b] Thus,t he efficacyo fa ryl À BF 3 K reagents in achieving coupling where the analogous boronic acid is unstable is credited to the slow-release strategy. [67a] In principle,the slow-release approach appears apromising solution to the 2-pyridyl problem. However,outside of the previously discussed reports,e xamples of 2-pyridyl À B-(MIDA) and À BF 3 Kr eagents being used to prepare highly functionalised 2-arylpyridines are not common. Theu se of these 2-pyridyl boronic acid surrogates in synthesising bioactive structures has seen varying degrees of success. [102] 3.3.5. Anthranilamide (aam) Boronates Anthranilamide (aam)-substituted arylboranes were first introduced by Suginome and co-workers in 2011. [103] These aam units were originally developed as boron protecting groups,e nabling ab oron centre to be carried through multistep synthesis before being selectively deprotected to the boronic acid in the presence of acid. ArylÀB(aam) are reasonably moisture and air stable,a lthough they are more prone to hydrolysis than both the corresponding B(dan) and B(MIDA) reagents. [103] In 2019, arylÀB(aam) was first used directly in am icrowave-assisted SMC coupling by Yoshida and co-workers. [104] Theauthors propose that arylÀB(aam) acts as aslow-release reagent, releasing the active boronic acid in situ, thus removing the need for stepwise acidic deprotection. Indeed, the reaction is most efficient in an aqueous medium, whereas no reaction is observed under anhydrous conditions,t hus supporting the slow-release postulate.Asmall scope of 2arylpyridines were reported in high yields,a lbeit using elevated temperatures (Scheme 20). Notably,o nly 6-substituted-2-pyridyl À B(aam) reagents were used. Other heteroaryl À B(aam) reagents (2-thienyl and 2-furyl) were also shown to couple smoothly under these conditions.Although aweak base is employed, it is noteworthy that al arge excess is needed. In contrast to previous slow-release boronates, addition of Cu(OAc) 2 did not significantly promote the reaction.
To illustrate the stability of 2-pyridyl À B(aam) reagents, the authors noted that no decomposition was found in abatch of 6-methoxy-2-pyridylÀB(aam) stored at ambient temperature,1 .4 years after its synthesis.A lthough still in an ascent state of application to the 2-pyridyl problem, B(aam) reagents hold promise for further application.

1,8-Diaminonaphthalene (dan) Boronates
Another amino-stabilised boron reagent that has recently gained traction is the 1,8-diaminonaphthalene (dan)-protected arylboronic acid. Alike B(aam), dan boronates were originally introduced by Suginome and co-workers for use in iterative SMC reactions. [105] Originally developed as ab oronate masking group,the dan group was intended to make the reactive boron centre inert under SMC conditions.T he B(dan) reagent would then be subjected to as eparate acid deprotection step to reveal the active boron species. [105] Likely due to the donation of the diamino group nitrogen lone pair into the vacant p-orbital on boron, B(dan) reagents are considerably more stable than the corresponding aryl À B-(MIDA) towards hydrolysis. [103] Although introduced in 2007, arylÀB(dan) was not used directly in SMC reactions until 2020. [66,81] In these recent reports,a rylÀB(dan) is highlighted as stable with regards to protodeboronation. Unlike other slow-release boronates, B(dan) reacts directly in the SMC reaction and does not hydrolyse to the boronic acid in situ. Indeed, 11 BNMR studies confirm that the intact B(dan) species is transmetalation active. [66] Alongside various carbocyclic polyfluorophenyl substrates,S aito and co-workers reported as ingular example of 2-pyridyl À B(dan) coupling under SMC conditions (Figure 7). [81] Notably,2 -pyridyl À B(dan) and polyfluorophenyl À B(dan) reagents were demonstrated to be stable and easily purified by flash column chromatography.T he use of KO t Bu was key to reaction success,a si te nables the formation of the butoxide-borate complex, which is proposed to efficiently undergo transmetalation with palladium, as well as capturing the halide leaving group.N otably,a nhydrous conditions were favoured, further supporting that B(dan) is not hydrolysed to the boronic acid in situ.
Published concurrently with the above work, Tsuchimoto and Yoshida also showed the direct use of arylÀB(dan) in cross-coupling reactions. [66] Ther eaction conditions reported are similar and also require KO t Bu as the base for reaction success.The authors similarly cite the necessary generation of the shown active borate species.T he main difference is the use of am ore polar solvent and increased temperature, enabling am uch shorter reaction time.U nlike the report by Saito and co-workers,the scope featured multiple 2-pyridylÀ B(dan) substrates with varying substitution patterns,although high yields were only obtained for 6-substituted-2-pyridyl À B(dan) reagents (Scheme 21). Aryl À B(dan) reagents can be synthesised through similar methods to the other masked boronates described previously. [66,81,106] These reports present B(dan) as apromising complementary solution to the 2-pyridyl problem, and an alternative to slow-release boron reagents.H owever, the direct use of 2-pyridylÀB(dan) is still in its infancy, and exploration into more challenging 2-pyridyl couplings,p articularly hetero À hetero couplings,isy et to be seen.

Decarboxylative Cross-Couplings
Decarboxylation has been studied since the early 20th century, [107] with the very first decarboxylative cross-coupling documented by Nilsson in 1966. [108] Theb enefits of using carboxylate nucleophiles in coupling reactions are that they are readily available as well as cheap,g enerally non-toxic, stable at ambient temperature and can be considered agreen alternative to the corresponding sensitive and costly organometallic reagents.T hese advantages have attracted the scientific community,a nd the last few decades have seen many developments in decarboxylative cross-coupling chemistry. [109] Extending decarboxylative methodology to electron-deficient heteroaryl nucleophiles has proved challenging,e specially for pyridyl substrates.S tandard conditions can be applied to 3-pyridyl carboxylic acids,albeit with low yields, [110] however, 4-pyridyl carboxylic acids require tailored catalytic systems. [111] These difficulties pale in comparison to 2-pyridyl carboxylic acids,w hich have ap ropensity to protodecarboxylate. [112] Fora ne fficient decarboxylative cross-coupling process,p rotodecarboxylation needs to be avoided and the high activation barrier of the metal-mediated decarboxylation lowered (Scheme 22). In this section, efforts towards achieving this will be discussed.
Thefirst example of palladium-catalysed decarboxylative cross-couplings between 2-picolinic acids and (hetero)aryl bromides was presented by Wu and co-workers in 2013 (Scheme 23). [113] In this seminal work, the authors reasoned that ab identate ligand, with ar igid bite angle,h elped suppress homocoupled byproduct formation, however low yields were still attributed to this issue plus formation of protodecarboxylated pyridine.B oth silver and copper salts are commonly used additives in decarboxylative couplings;in this work copper(I) salts proved more efficient than silver salts.T he scope featured only unsubstituted picolinic acid as the carboxylate coupling partner, sterically hindered electrophiles and those with carbonyls gave reduced yields,and aryl bromides were required for effective coupling;iodides led to  Stoltz and co-workers presented as imilar dual Pd/Cucatalysed decarboxylative coupling using potassium picolinate as the nucleophile. [114] In this work, higher reaction temperatures (190 8 8C) were required to promote the challenging metal-mediated decarboxylation, however,t hese harsh conditions also led to significant byproduct formation. Although in these two formative works the biheteroaryl products were not obtained in high yields,2 -picolinic acids were shown to be viable 2-pyridyl nucleophiles.
An alternative approach was to use pyridine N-oxides, which are more reactive than pyridines (see section 5), with carboxylic acid functionality in the 2-position. Thef irst decarboxylative cross-coupling of picolinic acid N-oxides with aryl halides via bimetallic catalysis was reported by Hoarau and co-workers in 2014. [115] Couplings to heteroaryl halides gave products in moderate to good yields,w ith the scope not limited to unsubstituted pyridine N-oxides (Scheme 24). Although ah igh temperature (150 8 8C) was still required, the authors demonstrated ab roader range of substrates in higher yields than those shown in previous reports.A like the work by the groups of Wu and Stoltz, protodecarboxylation was found to be ad ominating side reaction in the Cu-mediated process.F urther mechanistic insight was gained computationally;increased interactions to the small copper metal centre significantly lowered the decarboxylation activation energy (E a )c ompared to silver (Scheme 24). This lowered E a led to accumulation of the easily protonated decarboxylated Cu-intermediate ( Scheme 22). Due to the tendency towards protodecarbox-ylation for the Cu system, higher yields were unsurprisingly observed with silver (Scheme 24). This process is reminiscent of the fast protodeboronation of 2-pyridyl boronic acids described in section 3.2.
While picolinic acid N-oxide is ac heap,c ommercially available substrate,the additional synthetic steps required to prepare more complex N-oxides that are not widely available are ad rawback. Furthermore,a ne xtra step is needed to deoxygenate the products after coupling,w hich makes the process more inefficient and less atom economical.
In 2017, Gooßen focused on decarboxylative crosscoupling of 3-fluoro-2-picolinic acid potassium salts;s ubsequent nucleophilic aromatic substitution could lead to other useful pharmacophores. [116] Unlike earlier work described in this Review,t he metal additive could be employed in substoichiometric amounts.H owever,h omocoupling and picolinic acid protodecarboxylation were once again key side reactions.I nterestingly,d uring reaction optimisation several phosphines underwent aryl group scrambling with the reagents after P À Cb ond cleavage to give 2-arylpyridine products.T his exact process was later exploited by McNally and will be discussed in Section 4.3. In general, the reaction was tolerant to abroad range of functionalised electrophiles, but coupling more inactive aryl chlorides instead of bromides substantially reduced yields.A like other decarboxylation work, acyl groups were not well tolerated (31-52 %) owing to interfering Cu coordination. Thed ecarboxylation operated with heterocyclic bromides in moderate to good yields (Scheme 25), and the scope was not limited to 3-fluoropicolinic acids,a lthough tailored reaction conditions were required for some substrates.U nsubstituted picolinic acids required extreme temperatures of 190 8 8C, comparable to the work of Stoltz, and resulted in poor yields (28-40 %). A substituent next to the carboxylate is known to facilitate the decarboxylation of benzoates, [117] but this finding also shows it is of importance for picolinates.A ny other substitution pattern on the picolinate resulted in no product formation.
Continued improvement in the environmental impact of these 2-pyridyl decarboxylative processes is necessary,such as lowering the temperature of metal-catalysed reactions and avoiding the use of undesirable polar aprotic solvents and bases (such as DMF,pyridine). [118]

Desulfinative Cross-Couplings
Desulfinative cross-couplings have been explored over the last few decades,primarily focusing on aryl sulfinates. [119] Conceptually,d esulfinative coupling processes are similar to decarboxylation. Sulfinate salts can be obtained through various methods,i ncluding oxidation of thiols,r eduction of sulfonyl chlorides and insertion of SO 2 into am etalated species (Mg or Li)b yu se of an organic SO 2 surrogate (e.g. DABSO). [120] Furthermore,s imilarly to carboxylates,m any sulfinate salts are inexpensive,c ommercially available and exhibit lower toxicity profiles [121] than traditional organometallic reagents.
Electron-poor heterocyclic sulfinate nucleophiles were underexplored in desulfinative cross-couplings until the Willis group reported pyridine-2-sulfinates as efficient alternatives to 2-pyridyl boronic derivatives in SMC (Scheme 28). [122] Couplings to less active and cheaper aryl chlorides were equally as efficient as those to the corresponding bromides, with the process producing high yields of pharmaceutically relevant heteroaryl pyridines that would have been challenging to synthesise by classical methods (38 examples,including coupled pyrimidines,q uinolines,p yrazines). In as econd report, the temperature of the reaction could be lowered to 120 8 8Co wing to the use of ab ulkier and more electron rich ligand, improving the functional group tolerance of the process. [123] This reduced reaction temperature demonstrates an advantage over decarboxylation.
Studies into the mechanism suggested that the potassium carbonate has two roles: [72b, 124] Thep otassium undergoes ac ation metathesis with the sodium sulfinate salt which facilitates the transmetalation step,while the carbonate traps the SO 2 byproduct and permits catalyst turnover. Alike the issues associated with picolinic acid decarboxylation, the nitrogen of the pyridine sulfinate strongly chelates to the Pd centre.L oss of SO 2 from this complex is turnover limiting (Scheme 26). Hence,high reaction temperatures,particularly for 2-pyridyl substrates,are required to overcome this strong k 2 N,O -chelation.
While pyridine-2-sulfinates are an excellent tool in forming medicinally relevant cross-coupled biaryl products,t hey are not without issue.B eing salts,t hey display purification and solubility issues in organic media, which can in turn limit their utility.I n2 018, the Willis group described allylsulfones acting as latent sulfinate reagents. [125] TheP dc atalyst has adual function;first, the sulfinate "unmasks" in situ through deallylation and then, the previously described desulfinative cross-coupling process follows (Scheme 27).
Thea llylsulfone demonstrated orthogonal reactivity to SMC and could withstand functional-group interconversions on the pyridine core highlighting the stability of this functionality.A sw ell as pyridyl nucleophiles,t he scope featured couplings of challenging 5-membered rings (pyrazoles,i midazole,i soxazole) and heterocyclic cores of medicinal agents (e.g. COX-2 inhibitors). TheW illis group desulfinative cross-couplings to form biheteroaryls are summarised in Scheme 28.

Main Group Ligand Couplings
In transition-metal catalysis,l igand scrambling and aryl transfer to phosphine ligands are often seen as side-reactions to be avoided rather than posing synthetic utility. [126] How-ever,t he formation of biheteroaryl products through phosphorus centres (phosphorus ligand couplings) has been reported as early as the 1940s.T hese early methods are mostly restricted to homocouplings and do not feature aset of conditions suitable to aw ide range of substrates. [127] Over recent years,this chemistry has had ar esurgence.
In 2018, McNally applied contractive phosphorus CÀC cross-coupling from CÀHp recursors to the 2-pyridyl problem. [128] Thekey step was the migration of one heterocycle to the ipso position of the second, around ac entral pentacoordinate P V atom (Scheme 29). Thereaction required aspecific addition sequence of reagents to ensure the pyridine was activated for nucleophilic addition as well as correct phosphonium salt formation. While CÀHp recursors are considered an atom-economical starting material, they often suffer from alack of regioselectivity in reactions.However, when no substituents were present on the pyridine ring, the reaction was completely selective for the 4-position, switching only to the 2-position when the 4-site was blocked. Functional groups, such as esters,t rifluoromethyl groups and halides,w ere tolerated to give ar ange of unsymmetrical biheteroaryl products,i ncluding 2,2'-bipyridines and complex drug molecules.H owever,o ther common functional groups performed poorly (alcohols,p henols and alkyl-substituted amides) because of their tendency to react with the strong acids employed. Additionally,p yridines and diazines with more than two EWGs or EDGs reacted poorly.
In order to further the utility of this P V contractive coupling methodology to the 2-pyridyl problem, McNally and co-workers returned in 2019 with an advancement. [129] Instead of the previous CÀHfunctionalisation approach, chloroazines and heteroaryl phosphines were used as substrates.The latter were prepared in as ingle step from the corresponding heteroaryl chloride (Scheme 30). Once isolated, the heteroaryl phosphines could undergo S N Ar with asecond heteroaryl chloride to generate ak ey bis-heteroarylphosphonium salt intermediate.S trong acids were required to protonate the pyridine nitrogen atoms,f orming aP V alkoxyphosphorane intermediate.
Themethodology was applied to abroad scope of biaryls. Improved regioselectivity from their 2018 work was demonstrated by the tolerance of C À Hinthe 4-position of 2-pyridine coupling partners.Unfortunately,key drawbacks are that the process requires strong acids and high reaction temperatures for many hours to result in mostly moderate yields of heterobiaryl products (Scheme 30). However,s ome scope examples would be challenging to obtain by classical organometallic chemistry.For example,comparing this P V approach to Stille and Negishi couplings to molecules containing multiple halides showed the P V route to be superior owing to its complete regioselectivity for the most S N Ar active halide.O rthogonality was explored, showing that the phosphine remained intact through aS MC.M ost importantly, placing PPh 2 at the 2-pyridyl position gave af ar higher yield of the 2,2'-bipyridine than methods with either the BF 3 Ksalt or BMIDA, which had also been previously developed as solutions for the 2-pyridyl problem.
In 2020, Qin and co-workers reported that oxidative crosscouplings of Grignard nucleophiles could be mediated by sulfinyl chlorides. [130] Thes equential assembly of two Grignard reagents leads to sulfuranes via sulfoxides (Scheme 31). Compared to the titanate work shown in Section 2.3, there is no need for added metal or oxygen to trigger the reductive elimination from the sulfurane complex. Although these sulfur(IV)-based coupling methods have been known since the 1980s, [14a] the novelty in the work of Qin and co-workers is the use of isopropylsulfinyl(IV) chloride.T his sulfur(IV) derivative could be conveniently prepared and stored at 4 8 8Cfor months without loss of reactivity,orcould be generated in situ using Herrmannsp rotocol. [131] Al arge scope of 2,2'-linked diazines (> 40 examples) was obtained in moderate to excellent yields (35-96 %y ield), and ar ange of functionalities including halides,a lkene,a lkynes,a cetals, esters,n itriles and amides were tolerated, owing to the high reaction rates and low temperatures needed for the coupling.
Utilisation of the chemistry of main group elements to perform cross-coupling reactions,r ather than relying on precious transition metals,c ould become ap opular area for synthetic chemists to explore, [132] especially as more sustainable and greener solutions are sought.

C À HA ctivation
Three categories of C À Ha ctivation are considered, depending on the nature of the pyridinesc oupling partner (Scheme 32): i) Double CÀHactivation or cross dehydrogenative coupling (CDC);i i) Coupling with an electrophile (mostly organohalides);i ii)Coupling with an ucleophile (such as Grignard or boron-based reagents).
C À H-activated coupling reactions with nucleophiles [133] will not be addressed here,a st he focus is on processes in which the pyridine group is not the electrophilic partner. While CDC does not use the pyridine moiety as anucleophile, it is also not used as an electrophile and is an interesting alternative solution to the 2-pyridyl problem. [134] This section is divided into 3subsections,focusing first on the activation of free pyridines,t hen N-oxides,a nd finally more recent developments of novel derivatives.

Pyridines
Direct C À Ha ctivation of pyridines is still an underdeveloped area, with only moderate success achieved so far, because of the need for harsh reaction conditions,l imited scopes and/or poor selectivity. [18b] As such, pyridines are often used as directing groups rather than reactive species in CÀH activation processes. Concerning direct pyridine homocoupling,t he symmetrical 2,2'-bipyridine motif has been achieved through various catalytic methods using Raney nickel, [135] Pd/C, [136] as well as ruthenium or tantalum complexes in stoichiometric [137] then sub-stoichiometric amounts. [138] These methods had several limitations,s uch as narrow scopes,h igh temperatures,a nd modest yields.
In 2013, ap alladium-catalysed oxidative cross-coupling was developed by Youand co-workers (Scheme 33). [139] In this reaction, both reagents coordinate to the palladium and the resulting complex undergoes reductive elimination, forming the desired product. As toichiometric quantity of oxidant, here as ilver salt, is required to oxidise the Pd 0 ,c losing the catalytic cycle.T he need for such al arge excess of the pyridine,used as both reagent and solvent, remains the main limitation. Alternatively,aRh III catalyst was used by Su and co-workers,b ut required the pyridine to carry an amide directing group to control the regioselectivity. [140] In 2016, Itami and co-workers coupled pyridines with benzoxazoles using an organohalide as the oxidant (Scheme 33). [141]

Coupling with an Electrophile
In 2008, Ellmann and co-workers used aR h I catalyst to form 2-arylpyridines from pyridines and aryl bromides (Scheme 34). [142] Substitution on the pyridine moiety was limited to simple alkyl chains and substitution vicinal to the nitrogen centre was needed in order to limit rhodium binding to the nitrogen. Excess of the pyridine reagent and high temperatures were the main limitations.N otably,u sing ap alladium catalyst instead leads to 3-arylation rather than the desired 2-arylation. [143] Scheme 32. CÀHactivation to solve the 2-pyridyl problem.

Pyridine N-Oxides
Replacing pyridines by their N-oxide derivatives has as ignificant number of advantages.T he oxide component serves as both an activating and directing group,lowering the acidity and free-energy barrier of the CÀHb ond on the Noxide compared to that of the corresponding pyridine, [144] thus enhancing the reactivity and the regioselectivity to the desired 2-position. [145] Furthermore,p yridine N-oxides are generally bench-stable solids and commercially available (or easily accessible by pyridine oxidation). However,t hey require an extra reduction step to yield the 2-arylpyridine moiety and often lead to significant amounts of the 2,6-diarylated product.

Cross Dehydrogenative Coupling
In 2008, Chang and co-workers developed adouble CÀH activation between pyridine N-oxides and unactivated arenes (Scheme 35). [146] Thereaction follows asimilar pathway as the CDC for pyridines (see Scheme 33). Theu nactivated arenes needed to be in large excess and were used as the solvent. A great many research groups have since developed variants of the same methodology,u sing activated heterocycles which circumvent the need for such an excess of substrate (Scheme 35). [147] Ac opper-assisted coupling between the N-oxide and an oxazole was developed by Miura and co-workers in 2015 (Scheme 36). [148] Thec opper has ad ual role,a ctivating the oxazole to add onto the N-oxide,then binding to the oxygen of the pyridine N-oxide and allowing re-aromatisation by deoxygenative elimination. While the scope is limited and the yields modest, this method allows for Pd-free arylation of the pyridine N-oxide in only 4hours without needing af urther reductive step.P yridine was used as an additive,p roviding evidence of the unreactive nature of pyridines to this CÀH activation.
AP d-free homocoupling of pyridine N-oxide was developed through the use of as trong base (Scheme 37). [149] Depending on whether or not copper acetate was added, the reaction would go through two different pathways:S N Ar (although it might be ar adical addition [150] )o racoppercatalysed oxidative coupling.While both pathways enable the homocoupling,t he S N Ar pathwaysf inal deoxygenative rearomatisation step produces an N-oxide rather than the N,N'dioxide.

Coupling with an Electrophile
In 2005, Fagnou and co-workers published the first example of C À Hactivation of pyridine N-oxides by developing ap alladium-catalysed cross-coupling between an aryl bromide and an N-oxide,with abroad scope,high yields,and complete regioselectivity at the 2-position (Scheme 38). [151] Steric and electronic effects did not significantly impact the yield and af urther Pd/C reduction allowed access to the desired 2-arylpyridines.T his synthetic methodology was extended to ab road scope of various N-oxides and coupling partners. [152] Regarding pyridine N-oxides,substitution at any position on the ring had little impact on yield, but regioselectivity issues appeared when the ring was substituted at the 3-or 5-positions.T zschucke and co-workers used these reaction conditions with 2-bromopyridines to form unsymmetrical bipyridines [153] and terpyridines (Scheme 38). [154] Them echanism was studied by the groups of Fagnou [155] and Hartwig. [156] It proceeds through ab imetallic palladium catalytic cycle,i nw hich the aryl halide and the pyridine Noxide each bind onto ad ifferent palladium complex. Tr ansmetalation and reductive elimination give the desired product, closing the catalytic cycle.T he presence (and regeneration) of acetate and tris(tert-butyl)phosphine are essential to the catalytic cycle,asboth bind to palladium to form reactive species (Scheme 39).
An alternative CÀHa ctivation of pyridine N-oxides was developed by the groups of Daugulis and You, replacing the palladium catalyst with ac heaper copper catalyst (Scheme 40). [157] When the 6-position was not blocked, diarylation could be observed.

Pyridinium Derivatives Coupled with an Electrophile
Building on Fagnousw ork, in 2008 Charette and coworkers replaced the pyridine N-oxide with aN -iminopyridinium ylide (Scheme 41). [158] As the amide functionality on the ylide is as tronger Lewis base-therefore ab etter direct-ing group-than the N-oxide,t his allows for an easier CÀH insertion. With only as mall excess of the ylide (1.5 vs. 4.0 equiv for the N-oxide), the arylation was performed on ab road scope with good yields.H owever, obtaining the Nfunctionalised pyridine requires two extra steps (methylation then reduction), rather than one in the case of the N-oxide. Contrary to pyridine N-oxides,only the unsubstituted ylide is commercially available and all others require synthesis.
Thenext year Wang, Hu and co-workers also modified the activating group,u sing N-phenacylpyridinium halides (Scheme 42). [159] Thea ctivating group on the pyridine is cleaved at the end of the reaction through enolisation, therefore no supplementary deprotection steps are necessary to obtain the 2-arylpyridine.H owever,alack of selectivity between the mono-and diarylated products was often observed.
Finally,Chen and co-workers developed avariation on the method, involving the use of at raceless activating group (Scheme 43). [160] Thep yridine undergoes in situ N-methylation to produce the methyl pyridinium, followed by copperassisted palladium-catalysed CÀHa ctivation and subsequent demethylation, yielding the desired diarylpyridines.T he diarylation is favoured over monoarylation by design rather than default yet unsymmetrical 2,6-disubstituted pyridines can still be obtained by prefunctionalising one of the positions. [161] Similar reaction conditions have also been applied to 2-picolinic acid derivatives for the synthesis of 2,6-diarylpyridines. [162] Scheme 39. Catalytic cycle for the CÀHa ctivation of pyridine N-oxides with electrophiles.

Conclusion
Thel andscape of 2-pyridyl nucleophiles was initially dominated by both tin and zinc reagents.T he former approach is now less commonly employed in arylation reactions due to toxicity issues,b ut the latter has seen considerable improvement with the advances in palladium catalysis and the development of highly efficient ligand systems.S uch progress has also enabled the use of other 2pyridyl nucleophiles,n amely silanes,G rignard reagents, germanes,alanes and indanes.
Tr aditionally the coupling of 2-pyridyl boronic acids was plagued with poor reaction success owing to their instability. However,t he popularity of SMC has led to considerable development of more efficient catalytic systems and new 2pyridyl boron nucleophiles.Innovative strategies,from stabilised, slow-release boronates to Lewis acid additives,h ave transformed the efficacyo f2 -pyridyl boron nucleophiles in SMC reactions.T he promising recent success of stable amino boronates (Bdan) shows there is still momentum in the quest for stable,yet reactive 2-pyridyl boron nucleophiles.
More recently,a lternative,n ovel nucleophiles have emerged as excellent solutions to the 2-pyridyl problem, such as sulfinate salts.While decarboxylation strategies show promise,i no rder to truly harness the abundance of green 2pyridyl carboxylate starting materials,further work is needed to elude undesirable side reactions.
Finally,direct CÀHactivation also offers asolution to the 2-pyridyl problem. Thep yridines poor results towards CÀH activation can be remedied by using the corresponding Noxides and related derivatives;h owever, their use requires added synthetic steps and can lead to over-arylation. Identifying abalance between reagent accessibility and significant, yet selective reactivity remains the main challenge of pyridine CÀHa ctivation.
It is important to note that the synthesis of 2-pyridyl nucleophiles is often limited. Many approaches require pyridyl nucleophiles to be synthesised via lithiation (e.g. alanes,g ermanes,b oronates and traditional organometallic reagents), which in turn constrains functional group tolerance on the reagent. Some modern methodologies,s uch as desulfinative,d ecarboxylative,P V contractive and organozirconium couplings,a re not restricted in this way.F uture efforts to improve efficacy,sustainability and functional group tolerance of both nucleophile synthesis and cross-coupling processes,w ill be necessary for increasing industrial application.
With these tools in hand, industrially important 2-pyridyl-(hetero)aryl frameworks are now more accessible than ever. We hope that the inventive strategies discussed herein should provide ar esource for both the 2-pyridyl problem and the coupling of other challenging heteroaromatic substrates.T he development of novel nucleophiles and cross-coupling conditions will continue and we hope that the chemistry explored in this Review proves auseful tool for future innovation.