Visible‐Light‐Driven Intermolecular Reductive Ene–Yne Coupling by Iridium/Cobalt Dual Catalysis for C(sp3)−C(sp2) Bond Formation

Abstract A new methodology to form C(sp3)−C(sp2) bonds by visible‐light‐driven intermolecular reductive ene–yne coupling has been successfully developed. The process relies on the ability of the Hantzsch ester to contribute in both SET and HAT processes through a unified cobalt and iridium catalytic system. This procedure avoids the use of stoichiometric amounts of reducing metallic reagents, which is translated into high functional‐group tolerance and atom economy.

The development of new methodologies for selective CÀC bond formation in ah ighly atom-economical way is one of the most relevant and evolving research areas in organic synthesis. [1] Particularly,t he transition-metal-catalyzed reductive coupling of easily available,i nexpensive, and bench-stable p components provides as traightforward route to achieve this goal. [2, 1b] However,t he available methodologies require stoichiometric amounts of metallicr eductants, such as Zn powder, silanes, boranes or Grignardr eagents.I nt his context, Chen et al. reportedi n2 002t he cobalt-catalyzed intermolecularr eductive couplingo fa lkynes with conjugated alkenes in a highly chemo-, regio-, and stereoselective fashion (Scheme 1a). [3] This pioneering result is significant, because typical cobalt-catalyzed CÀCr eactivities, such as cyclotrimerization [4a-c] and carbonylation, [4b-c] did not ensue. Notwithstanding the powero ft his approach, it struggles with low scope and the need of Zn powder in (super)stoichiometric amounts as reducing agent to generate active low-valent Co I species. Thus, the introduction of catalytic activation modes thata re environmentally benign and capable of achieving ah igherd egree of structuraldiversity are highly desirable in this topic.
Over the past decade,t he renowned field of photochemistry is retrieving ac entral role in synthetic endeavors. [5] Especially, the fast-moving area of photoredox catalysis has witnessed dramatic developments, which have enabled previously inaccessible or inefficientt ransformations. [6] Recently,R ovis et al. have explored the combination of photoredox catalysis with cobalt catalysis to access low-valent cobalt(I)o rc obalt(0) intermediates for the construction of arenes [7a] and in the hydroaminoalkylation of conjugatedd ienes. [7b-c] These cobalt intermediates are traditionally generated in situ by using strongr educing conditions, such as heterogeneousm etals or Grignard reagents,d ue to their synthetic challengea nd poor stability. [8, 2f] However,i nt heir study,atertiary amine is employed as as acrificial organic reductanti navisible-light-driven photoredox cycle, overcoming the problem of limited functional group tolerance. Later,Z hao, Wu et al. made use of this protocol for the hydrocarboxylation and carboxylationo fa lkynes using CO 2 . [9] Nevertheless, despite of its potential in CÀCb ond construction, this methodology has not been further developed.
Then, we turnedo ur attentiont oe asily accessible and bench-stable Hantzsch esters (HEs), [13] which over the last decadeh ave emerged as key electron [14] and proton [15] donors in av ariety of challenging photoredoxr eactions. HEs can be readily converted in to the corresponding pyridines by means of as tepwise pathway by either single electron transfer (SET) followed by hydrogen atom transfer (HAT) or vice versa. [16] Besides, their oxidative potential is typically0 .8-0.9 Vv ersus SCE, [17] suggesting that they have redox properties comparable to those of amines [18] (E 1/2 red = 0.8-1.0 vs. SCE). Gratifyingly, when using Hantzsch ester (HE) as organic reductant together with 4-(dimethylamino)pyridine (DMAP) as base, 3a/4 a were obtainedi na73 %y ield (entry 5). Other commercially available pyridines tested proved to be less effective than DMAP.I ncreasingt he PC loading to 2.0 mol %t he yield was improved to 80 %w ithouta ffecting the selectivity (entry 6). Te sts reactions in the absence of CoBr 2 ,P C, HE, DMAP,a nd Blue LED were performed proving that all the additives are required for the transformation (see Ta ble S3 in the Supporting Information).
By using these optimized conditions, the scope of this metallophotoredox reductivee ne-yne coupling was first evaluated for alkyl-alkyl substituted alkynes (Table 2). 2-Octyne in the presenceo fe thyl acrylate gave regioisomers 3a/4 a in good yield and moderate selectivity.H owever,w hen using tert-butyl acrylate,b oth yield and selectivity decrease (3b/4 b). It should be noticed that with ab ulky substituent, such as isopropyl at R 1 ,o nly product 3c was obtained albeit in lower yield (the bulkier tert-butyl substituent was unreactive under these conditions). Symmetric alkyne 4-octyne delivered 3d and 3e in 70 %a nd 43 %y ields, respectively.S ilyl ether protected alcohols were tolerated giving 3g/4 g in good yield and moderate selectivity.R emarkably,c ompound 4f waso btained as as ingle product in a6 5% yield probably due to steric hinderance.T he reactiona lso took place in the presence of an ester group giving 4h/3 h in moderate yield and selectivity. It should be noted that in this case, the regioselectivity shifts being 4h the major product, which can be associated to sterici mpediments as in 4f.
To gain insights into this transformation and propose ar ational reaction pathway,s omec ontrol experiments were carried out (Scheme 2). Firstly,t od etermine the protons ource.A s it is shown in Scheme 2a,w hen the reaction was performedi n CD 3 CN, no deuterated products were observed. Nevertheless, when the deuterated HE (11)w as employed, the corresponding deuterated products were obtained together with the deuterated form of the oxidized HE (Scheme 2b). Besides, Stern-Volmer quenching experiments reveal significant quenching interactions between the excited state of the photocatalyst and the HE (see Figure S5 in the Supporting Information). This indicates that the HE could act as both proton sourcea nd terminal reductant. Additionally,t he quantum yield (F)w as found to be 5%,w hich supports that ar adical-chain propagation mechanism is unlikely.M oreover, this is also in agreement with on/off experiments where the catalytic system is activated under irradiation and deactivated in darkness (see Figure S6 in the Supporting Information). Then, to prove that this process involves radicals, the reactionw as conducted in the presence of the radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO;S cheme 2c). In this case, the process was completely inhibited, which provides evidenceo fapossible initial electron transfer. [19] In light of the experimental data, as well as previous studies in metallophotoredox catalysis and intermolecular reductive ene-yne coupling, ap lausible mechanism was proposed in Scheme 3. First, aS ET process from the HE to the excited-state photocatalyst Ir III *m ight occur generating the radical cation A.T his reduction could be possible given their report-Scheme2.Mechanistic studies.  [7b, 16] Then, the Co II salt may be reduced in situ to Co I speciesb yt he photocatalyst. [7b] Next, consideringt hat the HE can contribute in both SET and HATp rocesses, [15c] ah ydrogen atom transfer from the radical cation A to Co I could afford the Co II ÀHc omplex. [20] Here, it is assumed that DMAP would facilitate the deprotonation of A to give B. [15c] The acrylate could undergo migratory insertion in to CoÀH giving the five-membered metallacycle C. [21] At this stage, depending on the nature of the alkyne, two different insertion paths into the CoÀCb ond could occur.T hus, when using alkyl-alkyl substituted alkynes, intermediate D could be generated (Path I), whereas for alkynesb earing one or two aromatic groups intermediate E might be formed (Path II). From these intermediates, as ubsequent reduction of Co III to Co II by the photocatalyst [7b] followed by af inal protonolysiss tep would deliver the corresponding productsand Co II back into the catalytic cycle. [3] In summary,w eh ave reported an ew methodt of orm C(sp 3 )ÀC(sp 2 )b onds by visible-light-driven intermolecularr eductive ene-yne coupling from commerciallya vailablea nd bench-stable alkynes and alkenes. This approach relies on the ability of the HE to contribute in both SET and HATp rocesses through the synergistic combinationo fp hotoredox and cobalt catalysis. The employment of very mild reaction conditions avoidingt he use of metallic reagents is translated into ab road functional-group tolerance. Besides, the proposed approach is in line with main goals in synthesis, such as atom-economy and sustainability principles highlighting the potentialo ft his transformation. Furthers tudies to expand the scope, as well as new synthetic applications, are currently underway.