Copper‐Catalyzed Borylative Couplings with C−N Electrophiles

Abstract Copper‐catalyzed borylative multicomponent reactions (MCRs) involving olefins and C−N electrophiles are a powerful tool to rapidly build up molecular complexity. The products from these reactions contain multiple functionalities, such as amino, cyano and boronate groups, that are ubiquitous in medicinal and process chemistry programs. Copper‐catalyzed MCRs are particularly attractive because they use a relatively abundant and non‐toxic catalyst to selectively deliver high‐value products from simple feedstocks such as olefins. In this Minireview, we explore this rapidly emerging field and survey the borylative union of allenes, dienes, styrenes and other olefins, with imines, nitriles and related C−N electrophiles.


Introduction
Building molecules that contain nitrogen is of great importance:a mines constitute 80 %o ft he bioactive targets used in drug discovery, [1] and the number of nitrile-containing drugs has been steadily increasing in recent decades. [2] In addition, the versatile reactivity of nitrogen-containing functional groups make them highly useful building blocks in synthesis.L ikewise,b oron-containing compounds are involved in 11 %o fC ÀCb ond forming reactions in process chemistry. [3] Thus,the union of nitrogen and boron-containing functional groups in defined molecular scaffolds is highly sought after. Indeed, to venture into underexplored regions of chemical space,n ovel disconnections of targets containing these important functionalities are needed. [4] Multicomponent reactions (MCRs) figure amongst the most promising strategies for addressing this challenge as they transform readily available feedstocks into complex structures in asingle step. [4b] In addition, due to their favorable atom and waste economies, [5] MCRs are ideal for the synthesis of bioactive targets. [6] Theneed to replace precious metals with more abundant and less toxic elements,such as copper, is apervading theme in contemporary synthesis. [7] Since the first reports by Hosomi and Miyaura at the turn of the century, [8] the copper-catalyzed borylation of C À Cm ultiple bonds,a long with the powerful extension of this methodology in MCRs,has been extensively studied. [9] Thea im of this Minireview is to highlight recent advances in copper-catalyzed borylative MCRs involving CÀ Ne lectrophiles and olefins for the synthesis of highly functionalized amines,n itriles and other nitrogen-containing products (Scheme 1).

Mechanistic Aspects in Copper-Catalyzed Borylative Couplings
Organocopper reagents can be generated in situ through borocupration of olefins,a nd then intercepted by C À N electrophiles (Scheme 2A). Acopper salt is first transformed into ac opper(I) alkoxide complex int-1 by treatment with base. [10] Tr ansmetallation then occurs between int-1 and ad iboron reagent 1,t ypically via s-bond metathesis (step A). [11] NHCs and phosphines are popular ligands in these processes,i nf act, the first isolated copper-boryl complexes int-2 featured NHCs as stabilizing ligands. [12] 1,2-Borocupration of an activated olefin 2 (internal, non-conjugated olefins are unreactive) [13] with int-2 produces the borylated organocopper complex int-3 (step B and Scheme 2B). [14] Ther egioselectivity and stereoselectivity of the borocupration is not easy to predict as both kinetic and thermodynamic factors must be taken into account. [13] Furthermore,i somerization [15] and rearrangement [14] can lead to epimerization [16] of the organocopper.F inally,r eaction with as uitable electrophile 3/4 delivers the product 5/6 (step C/D). Thec atalyst is regenerated using an equivalent of base and diboron, or by protonation of the product with an alcohol (step D). This simplified mechanism encompasses many of the transformations in this Minireview.A ss teps B and C determine the regio-and stereoselectivity of these reactions,t hey will be highlighted in the text when mechanistic evidence is available.
Copper-catalyzed borylative multicomponent reactions (MCRs) involving olefins and C À Nelectrophiles are apowerful tool to rapidly build up molecular complexity.T he products from these reactions contain multiple functionalities,s ucha sa mino,c yano and boronate groups,t hat are ubiquitous in medicinal and process chemistry programs.Copper-catalyzed MCRs are particularly attractive because they use arelatively abundant and non-toxiccatalyst to selectively deliver high-value products from simple feedstockssuch as olefins.In this Minireview,weexplore this rapidly emerging field and survey the borylative union of allenes,d ienes,s tyrenes and other olefins,w ith imines,nitriles and related C À Ne lectrophiles.

Copper-Catalyzed Borylative Couplings with Imines
Classical syntheses of amines often involve the addition of organometallic reagents to imines. [17] However,t hese reactions suffer from the inherent limitations associated with preformed organometallic reagents:c ryogenic temperatures,a ir and moisture sensitivity,s afety risks and pre-functionalized starting materials.Copper species are well known to modulate the reactivity of organometallic reagents [18] and can induce stereocontrol in additions to ketimines [19] and aldimines. [20] Theuse of copper catalysts to generate organocopper species in situ in MCRs is an attractive solution to the problems associated with stoichiometric organometallic reagents in amine synthesis.

Allenes
In an effort to circumvent the need for pre-formed allylmetal reagents in additions to imines, [21] Procter and coworkers [22] reported the first multicomponent copper-catalyzed borylative coupling of imines and allenes in 2016. Homoallylic amines 9 were formed from the addition of allylcopper complexes (e.g. int-6), formed in situ by borocupration of 1-monosubstituted or 1,1-disubstituted allenes 8,t o aldimines 7 (Scheme 3A). Ar ange of substituents on the imine were well tolerated, including electron-rich and electron-deficient (hetero)aromatic groups (to give 9a-e,S cheme 3B). Interestingly,X -ray and 11 BNMR analysis of the products revealed ad onor-acceptor interaction between the amine and the Bpin moiety (as illustrated in 9e). Ad ensity functional theory (DFT) study was performed to rationalize the observed anti-diastereoselectivity.A fter considering various possibilities,al owest energy pathway featuring a6membered, Zimmerman-Traxler-type transition-state TS1 from (Z)-allylcopper species int-6 and aldimine 7 was proposed.
Procter and co-workers [23] also reported an enantioselective variant of the reaction. By using the enantiopure NHC precursor L1 with CuI (5 mol %), excellent levels of stereoinduction and good to excellent yields were obtained (Scheme 3C). Importantly,s calability was achieved using alow catalytic loading (1 mol %) on a2gram scale,affording 10 a in almost quantitative yield, and with excellent diastereoand enantioselectivity.
These reports triggered the development of similar MCRs involving imine derivatives.F or example,t he Procter group [24a] used the approach to prepare quaternary a-amino acid derivatives 11 from ketiminoesters (Scheme 3D), for which an enantioselective variant has been reported by Chen et al. [24b] In addition, Zhang and co-workers [25] realized the enantioselective coupling of arylallenes with cyclic imines to access functionalized dibenzo-1,4-oxapines 12 (Scheme 3D).
In 2017, Hoveyda and co-workers [26] developed an enantioselective,c opper-catalyzed borylative coupling of allenes and N À Hketimines (Scheme 4A). Theinstability of ketimine electrophiles was cleverly managed by using the HCl salt of NÀHketimines 13,which were prepared through addition of an organolithium reagent to the corresponding nitrile and subsequent acidification. Using an enantiopure NHC ligand L2 with CuCl (5-10 mol %), the ketimine salts were combined with 1-substituted allenes 8 and B 2 pin 2 to give the desired products in good to excellent yields and excellent diastereoand enantioselectivities (Scheme 4B). In agreement with the studies of Procter and co-workers (Scheme 3B), DFT calculations supported am echanism involving as ix-membered transition state TS2 (Scheme 4C). They postulated that ac ombination of N!Na coordination and steric repulsion between the ligand and the Bpin moiety accounts for the high enantioselectivity of the transformation.

. Vinylarenes
In 2018, Kanai, Shimizu and co-workers [27] disclosed the first enantioselective copper-catalyzed borylative coupling of aldimines 15 and vinylarenes 16 using mesitylcopper (MesCu) as ap re-catalyst (Scheme 5A). [28] Notably,t hey were able to selectively access either anti-o rsyn-diastereomeric products by varying the chiral ligand (L3 a or L4). Aw ide range of products was obtained in high yields and high enantiomeric ratios (Scheme 5B). Provided that alarge excess (10 equiv) of vinylarene was used, aliphatic imines were also suitable candidates in spite of their potential to tautomerize to enamines.

. Direct Borylation of Imines
Theh ydroboration of imines affords important a-aminoboronic acids that are bio-isosteres of a-amino acids. [38] In 2013, Tian, Lin and co-workers [39] used N-benzoyl arylaldimines 38 to obtain a-amido boronic esters 39 in good yields and moderate enantioselectivities (Scheme 11 A,B). In 2015, Liao and co-workers [40] reported an improved coppercatalyzed enantioselective hydroboration of N-Boc aldimines 38 using ac hiral sulfoxide-phosphine ligand L9 (Scheme 11 A,C). Interestingly,t he absolute configuration of the resulting a-amido boronic esters 39 could be controlled by the copper counter ion (Scheme 11 C).
Thed irect borylation of imines has been used in related multicomponent reactions.I n2 019, Song and co-workers [41] reported the copper-catalyzed boroacylation of aldimines 40 (Scheme 12 A). Thet wo-step protocol involves formation of the iminium salt int-11 then copper-catalyzed borylation to yield the desired N-acylated a-amino boronic esters 42.T he process was efficient across aw ide range of aryl imines bearing alkyl and aryl N-substituents,a nd various aromatic and heteroaromatic acyl chlorides (Scheme 12 B). Thed irect conversion of aldehydes and amines through an in situ condensation/boroacylation sequence (to give 42 e and 42 f) was also possible.
Shortly after, Zhang,Luo,Hou and co-workers [42] reported ah ighly efficient copper-catalyzed borylative functionalization of aldimines involving CO 2 fixation (Scheme 12 A). Following borocupration of the aldimines,i ntramolecular N/ BL ewis pair formation was proposed to efficiently activate CO 2 (TS4;supported by DFT calculations), yielding versatile borocarbamate salts 43.T he methodology was applied to an extensive scope of aryl aldimines using only 1mol %o f ar eadily available NHC-ligated copper catalyst (Scheme 12 C). Finally,c arbamate-containing a-amino boronic esters 44 and 45 were generated upon treatment with amethylating agent or an acyl chloride.

Copper-Catalyzed Borylative Couplings with Nitriles
Thecyanationofolefins delivers versatile nitrile-containing products. [2] Electrophilic cyanating agents,s uch as Ncyano-N-phenyl-p-methylbenzenesulfonamide (NCTS 46 a), have emerged as as afer and more practical alternative to traditional cyanating reagents,such as hydrogen cyanide and cyanide salts. [43] They can be used to intercept nucleophilic organocopper species,a nd have recently featured as electrophilic partners in copper-catalyzed borylative MCRs.

Vinylarenes
In 2014, Yang and Buchwald [45] reported ac opper-catalyzed, regioselective borylative cyanation of 2-vinylnaphthalene derivatives 49 using NCTS 46 a (Scheme 14 A). The reaction displayed aclear selectivity for ortho-cyanation over benzylic cyanation( observed in less than 5%), and an exclusive preference for the most hindered ortho position (C1 vs.C 3). Substitution at the C6 position of the 2vinylnaphthalene derivatives was well tolerated (Scheme 14 B). Interestingly,d euterium labelling and crossover experiments showed an intramolecular transfer of the C1 deuterium of labelled 1-D-49 a to the benzylic position of 50 d.
Theo rigin of regioselectivity was studied by Yang and Liu [47] using DFT (Scheme 15). They proposed that benzylic cyanation is disfavored as ah igh energy 4-membered transition state TS6 is required, whereas the ortho-cyanation features am ore favorable six-membered TS (TS5 a and TS5 b). Thes electivity for C1 over C3 cyanationi n2vinylnaphthalene derivatives comes from al ower disruption of the aromaticity of the naphthalene system in TS5 a than in TS5 b.F acile 1,2-elimination of the copper tosylamide from int-14 then leads to ad earomatized intermediate.N ext, as previously demonstrated by Yang and Buchwald in ad euterium labeling experiment, rearomatization occurs by an intramolecular 1,3-migration of the C1 hydrogen via as ixmembered transition state TS7,f ollowed immediately by benzylic protonation TS8.
[a] MeOH was used as additive.
[b] standard procedure used then NaOH/H 2 O 2 ,overall yield shown for cyanodiboration and oxidation to the diol.
In 2018, Xiao,F ua nd co-workers [49] reported ac omplementary copper-catalyzed borylative benzylic cyanation of vinylarenes 49 (Scheme 17 A). Theu nprecedented regioselectivity was achieved by using dimethylmalononitrile (DMMN) 54,instead of NCTS derivatives 46,asthe electrophilic cyanating agent. Benzylic nitriles were obtained in good yields from aw ide range of vinylarenes,e ncompassing 2vinylnaphthalene and styrene derivatives (Scheme 17 B). Notably,t he presence of an allyl chain at the C1 position of 2-vinylnaphthalene did not lead to the Cope rearrangement seen by Yang.
Shortly after,b oth Huang and co-workers [51] and Li and co-workers [52] investigated the origin of the regiodivergency through DFT calculations (Scheme 18 C). They suggested that, due to the steric bulk of ligand L13,b orocupration occurs across the less hindered C4ÀC3 double bond to give the allyl copper species int-16 a followed by rearrangement to int-16 b.S ubsequent cyanation gives the 4,3-borocyanated product 56.C onversely,b orocupration occurs across C1ÀC2 with the less bulky ligand PCy 3 L14 due to the greater contribution of C1 to the LUMO,u ltimately leading to the 1,2-borocyanated isomer 57.

Addition Across Nitriles
In 2019, Hoveyda and co-workers [55] presented ab orylative coupling of allenes and nitriles to access primary alkylamines (Scheme 21 A). Thep rocess consists of two coppercatalyzed cycles:first, borocupration of 8 gives an allylcopper species that adds to nitriles 62,giving ketimine intermediates

Angewandte
Chemie (c.f. int-18). In asecond cycle,these intermediates are reduced to the desired amine 63 by ac opper hydride species. [56] Alkylallenes were coupled to ar ange of aromatic and aliphatic nitriles using L16 to afford syn-63 in good yields, with very good diastereo-and enantiocontrol (Scheme 21 A). Intramolecular N/B coordination was shown to be essential to activate the ketimine int-18 towards Cu À Hr eduction and to achieve excellent stereocontrol (TS9,Scheme 21 C). Through athree-step process, anti-63 products were obtained utilizing ligand L17 (Scheme 21 B). As spontaneous reduction does not occur with this system, Al(OTf) 3 was added to promote decoordination of the N/B pair and allow LiBH 4 reduction (TS10,Scheme 21 C).
Competition experiments (Scheme 21 D) showed that formation of the copper-hydride int-20,h ydrocupration of the allene 8 and addition of the resulting organocopper species (e.g. int-19 b)t ot he nitrile were all faster than the equivalent borylative process.Toavoid this undesired process, Hoveyda and co-workers used an excess of the polymeric silane,polymethylhydrosiloxane (PMHS), and afinely tuned mixture of alcohols to engage the copper hydride catalyst in an unproductive cycle (Scheme 21 D).

Angewandte
Chemie substituted and heteroaromatic styrene derivatives were not effective.Inaddition, an enantioselective functionalization of styrenes was developed with the chiral phosphine ligand L18 (Scheme 23 A,C).

Summary and Outlook
Thepast decade has seen significant progress made in the development of as uite of copper-catalyzed processes for the borofunctionalization of olefins using C À Ne lectrophiles. Numerous olefins,r anging from complex polyenes to simple styrene feedstocks,have been validated as coupling partners. Similarly,v arious CÀNi nputs have been utilized. Early transformations using achiral catalysts have rapidly evolved into highly enantioselective processes and the approach now allows efficient, catalytic access to important synthetic building blocks.
Anumber of challenges face this nascent area of research. Fore xample,c opper-catalyzed MCRs are still limited to activated alkenes and extension of this methodology to unactivated, "simple" alkenes remains ag oal for the future. Furthermore,afull understanding of the factors affecting regio-and stereoselectivity is needed and will aid our ability to predict reaction outcomes and to systematically develop new regio-and stereoselective borofunctionalizations.