Cascade Cross‐Coupling of Dienes: Photoredox and Nickel Dual Catalysis

Abstract Chemical transformations based on cascade reactions have the potential to simplify the preparation of diverse and architecturally complex molecules dramatically. Herein, we disclose an unprecedented and efficient method for the cross‐coupling of radical precursors, dienes, and electrophilic coupling partners via a photoredox‐ and nickel‐enabled cascade cross‐coupling process. The cascade reaction furnishes a diverse array of saturated carbo‐ and heterocyclic scaffolds, thus providing access to a quick gain in C−C bond saturation.


Introduction
Among the many different approaches to describe molecular complexity,C À Cb ond saturation index (Fsp 3 )h as recently been recognized as ak ey descriptor,o wing to the good correlation between clinical success and increasing saturation content. [1] Hence,t here has been an ever-increasing demand for the large and rapid increase of molecular complexity,enriched with saturated content, from simple and readily available feedstock chemicals in the field of medicinal chemistry. [2] An appealing method to meet this demand is based on free-radical cascade cyclizations,which are powerful and versatile methods for the construction of carbo-and heterocyclic ring systems found in drug molecules and natural products. [3] In the past several years,v isible light photocatalysis and nickel dual catalysis has emerged as apowerful tool in organic synthesis.I nt his context, the trapping of open-shell species (carbon-, nitrogen-, sulfur-, and phosphorus-based radicals) by various approaches has been thoroughly explored. [4] However,d espite the previous success of cascade radical cyclizations in radical chemistry,t heir application in photoredox-enabled cross-coupling reactions has not previously been exploited until very recently. [4s] On the other hand, the coupling of conventional preformed organometallics (Mg, Zn, and B) with aryl halide electrophiles has been reported in the field of cascade cyclization/cross-coupling. [5] However, the requirement of activated structures leads to low efficiency as well as poor step and atom economies.S ulfone functional groups are embedded in al arge number of pharmaceuticals, agrochemicals,a nd functional materials; [6] meanwhile the sulfone group is recognized as av ersatile building block in av ariety of carbon-carbon bond-forming reactions,s uch as fragment coupling and Julia olefination. [7] In our continuing efforts to expand the area of visible light photocatalysis,w e focus also on the development of efficient and practical methods for the synthesis of diverse sulfones under milder reaction conditions.H erein, we demonstrate that ad ual photoredox/nickel [4,8] -enabled cascade cross-coupling can forge two new CÀCb onds and one CÀS [9] bond using simple radical precursors,dienes,and electrophilic coupling partners. This transformation generates three bonds in one synthetic step and allows arapid increase of molecular complexity with respect to Fsp 3 from simple and commercially available feedstock chemicals.D ue to the mild nature of reaction conditions employed, avariety of functional groups are welltolerated making transition-metal-catalyzed reactions invaluable in the context of complex molecule synthesis.
Our proposed mechanism is shown in Scheme 1. Upon visible light irradiation, single electron transfer (SET) from the sodium sulfinate salt (for PhSO 2 C/PhSO 2 Na, E 1/2 red = + 0.5 Vv s. SCE in MeCN) [10] to the highly oxidizing excited state B of the photocatalyst (PC) would generate the sulfonyl free radical (PhSO 2 C)a long with the reduced form C of the photocatalyst. TheS -centered radical could add to ad iene, followed by ar adical cascade cyclization to deliver aC -centered radical, which would be then intercepted by Ni 0 species I to yield an alkyl-Ni I intermediate II.S ubsequent oxidative addition of an aryl halide Ar-X would form the Ni III complex III,which yields the desired coupled product as well as Ni I intermediate IV via reductive elimination. Lastly,t he nickel and photoredox catalytic cycles end up simultaneously, via asingle-electron-transfer event between Ni I intermediate and the reduced form C of the photocatalyst.
With the optimized reaction conditions in hand, we first examined the scope with respect to the diene component ( Table 2). Thetransformation was tolerant to awide range of electronically unbiased 1,6-dienes,w ith ester, ketone,a nd acetal functional groups being amenable to this coupling protocol (5-10,7 9-98 %y ield). Heteroatom-containing dienes such as diallyl amine and diallyl ether could be utilized, affording the corresponding highly functionalized pyrrolidine and tetrahydrofuran derivatives in similar efficiencya lbeit with lower diastereoselectivity (11 and 12,b oth 94 %y ield). In these cases,agood preference for the cis-3,4-disubstituted isomers was observed and no 6-endo products were detected. Thediastereoselectivities are consistent with previous reports on the stereochemistry of radical cyclizations,suggesting that the generation of the carbon-centered radical is independent of the nickel catalytic cycle.According to Baldwinsrules,we only observed the product resulting from the six-memberedring cyclization in the reaction of diallyldiphenylsilane. Several considerations such as bond lengths,S ie lectronic effects,a nd conformation of the transition states were proposed to explain the thermodynamically more favorable 6-endo-trig cyclization. [13] Moreover,t he reaction is not limited to 1,6-dienes.F or example,selective 1,4-difunctionalization took place in the case of conjugated 2,3-dimethyl-1,3butadiene,giving rise to ahighly substituted allylsulfone (14, 64 %). 2,5-Norbornadiene was transformed into adisubstituted tricyclic phenyl sulfone;t his outcome resulted from the rapid interconversion between the norbornenyl and nortricyclyl radicals,with the nortricyclyl radical being favored, and is also in good agreement with earlier work on norbornadiene radical chemistry. [14] Similarly,t he use of 1,5-cyclooctadiene allowed an impressive intramolecular cyclization prior to the cross-coupling,leading to the formation of bicyclicproduct 15 with excellent stereoselectivity (60 %).
Next, we examined the generality of the multicomponent cross-coupling with regard to the electrophilic coupling partner of this new reaction. As shown in Table 3, av ariety of (hetero)aryl halides performed well in this cross-coupling protocol. Fore xample,e lectron-deficient bromoarenes bearing ester,k etone,n itrile,a ldehyde,t rifluoromethyl, and fluoride were well tolerated (17-22 and 4,8 0-99 %y ield). Due to the relatively enhanced rate of oxidative addition of aryl bromide over aryl chloride,the cross-coupling took place chemoselectively to allow the chlorine group to be retained with opportunity for further synthetic elaboration (23,9 2% yield). In this context, it is also noteworthy that apinacolborate group can also be incorporated onto the arene ring (24, 97 %y ield). Next, several electron-neutral and electron-rich arenes containing alkyl, aryl, as well as amino functionalities were employed and gave the corresponding products in excellent yields (25-29,8 1-97 %y ield). Moreover,s ubstituents at the meta and ortho positions of the aromatic ring had no apparent effect on the efficiency of the coupling (30-34, 63-98 %y ield). Polycyclic aromatic bromides derived from phthalimide,i ndanone,a nd naphthalene also served as effective coupling partners,r esulting in excellent yields (35-37,8 6-97 %y ield). Heteroaromatic halides,w hich are common scaffolds in the preparation of medicinally relevant targets,s uch as pyridine,p yrimidine,q uinoline,i ndole,a nd thiophene are all effective electrophiles in this protocol (38-44,70-93 %yield). In addition, we were delighted to find that the current coupling can be further extended to the more abundant and diverse aryl chlorides.T his is remarkable considering that the use of aryl chlorides in Ni-catalyzed cross-couplings is difficult and rather underdeveloped. A range of aryl chlorides underwent the cascade cross-coupling to form the corresponding products with good efficiency (4, 17, 18,a nd 45-47,4 6-90 %y ield). Finally,w ed emonstrated the value of this new method for medicinal chemistry by the rapid incorporation of C À Cb ond saturated ring systems to
With the above success,wenext investigated adiverse set of either commercially available or readily accessible sulfinate salts to further highlight the versatility of this method. As indicated in Table 4, aw ide variety of neutral, electron-rich, and electron-poor benzene sulfinates were compatible with the optimized conditions (51-57,6 0-98 %y ield). Although the lithium sulfinate is anionic, the use of additional 2equiv Na 2 CO 3 was essential to achieve an efficient reaction under the standard conditions (5,92% yield). In the cases of linear and cycloalkyl sodium sulfinates,t he sulfonyl group was surprisingly preserved in contrast to the recent reports on desulfinative cross coupling with photoredox/Ni dual catalysis (58-60,74-98 %yield). [15] Moreover,heterocyclic derivatives such as pyridine-3-sulfinates and thiophene-3-sulfinates were all effective coupling partners in this protocol (61 and 62,7 1 and 92 %yield, respectively).
In order to gain more insight into the mechanism of the metalla-photoredox three-component-coupling protocol, we conducted some preliminary mechanistic experiments (Scheme 2). Firstly,weperformed cyclic voltammetry analysis with various aryl sulfinates.I nc omparison with the applied photocatalyst PC-I [Ir(dtbpy)(bpy) 2 ]PF 6 (E 1/2 [Ir *III /Ir II =+ 0.66 Vv s. SCE in CH 3 CN]), the SET oxidation is thermodynamically feasible regardless of the electronic nature of the substituent on the aryl ring of sulfinate salt. Thee lectron transfer step is promoted by the Ir III photocatalyst PC-I, which can be present as along-lived triplet excited state *PC-I (t 0 = 535.17 AE 1.54 ns,F igure S4) that can activate sodium 4cyanophenylsulfinate (3d). To conform the quenching of the 3* PC-I by 3d,s teady-state Stern-Volmer luminescence quenching experiments were carried out by the addition of different concentrations of 3d to 3* PC-I which displayed al inear correlation (Scheme 2a,b). Theq uenching study by time-resolved emission spectroscopy also revealed as imilar linear correlation where the excited-state lifetime of 3* PC-I is quenched by the different concentrations of 3d (Scheme 2b,c). Such al inear correlation in both steady-state and time-resolved experiments demonstrates that the quenching of excited-state 3* PC-I by 3d is dynamic in nature and further confirms that there is no ground-state association between the photocatalyst and 3d in solution. To shed more light on the underlying electron transfer event, the electron transfer (ET) rate constant k ET was determined by time-resolved emission measurements where the slope correlates with the ET rate constant k ET .Ak ET of (5.18 AE 0.23) 10 9 Lmol À1 s À1 was determined with ag ood linear fit by plotting the difference between the observed rate constant (k obs )a nd the groundstate recovery rate (k GSR )v ersus different concentrations of 3d (Scheme 2d). When the reaction mixture of diene 1,a ryl bromide 2b,a nd PhSO 2 Na was treated under the standard conditions in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO,1equiv) radical scavenger, no product was detected, implying that ar adical process is involved in the catalytic cycle (Scheme 3a). Importantly,o ur stoichiometric study with Ni II -ArCl (Scheme 3b)f ailed to give the corresponding cross-coupling product. This result indicates that aN i II -aryl species is not involved in the catalytic cycle, making the alternative catalytic Ni 0 /Ni II /Ni III pathway rather unlikely.Asaresult, our proposed mechanism involving first radical capture by Ni 0 followed by oxidative addition with aryl halides is more operative.The stereochemical outcome of the cyclization of sulfonyl-substituted 5-hexenyl radicals can be rationalized by using the chair-like transition state based on literature reports (Scheme 3c). [16] We assume that the cisfavored selectivity is partly due to the steric effect of X substituent. This consideration was supported by the fact that diallyl malonate ( Table 2, 5)g ave higher cis/trans ratio than the O-tethered diene ( Table 2, 11).
To highlight the robustness of the reaction, we carried out the synthesis of asulfone on apreparative scale (3 or 4mmol). Due to the higher cost of the iridium-based photocatalyst, we sought to use alternative sustainable organic photosensitizers. When we replaced iridium catalyst PC-I with carbazolyl dicyanobenzene PC-V under our optimal conditions,w e obtained the expected sulfonylarylation products 28, 65,a nd 67 in comparable good efficiency( Scheme 4a). To further demonstrate the synthetic utility of the present coupling method, sulfone 65 subjected to Julia olefination conditions to provide the E alkene 68 in good yield (Scheme 4b). [17] Moreover,t he allylic sulfone 67 could be desulfonylated to afford the allylarene 69 by Pd-catalyzed desulfonylation with LiEt 3 BH as reductant. [18] Scheme 3. Preliminary experiments on the reaction mechanism. a) Reaction inhibition with aradical scavenger.b )Stoichiometric study with Ni II -ArCl complex. c) Origin of the diastereoselectivity in CÀCb ond formation with 1,6-diene.

Conclusion
In conclusion, we have developed an unprecedented cascade cyclization/cross-coupling of various dienes with substituted sulfinates and aryl(hetero) halides via the photoredox and nickel synergistic catalysis.T he manifold forges three new bonds (one CÀSa nd two CÀCb onds) in one synthetic step and allows rapid increase of molecular complexity with respect to Fsp 3 from simple and commercially available feedstock chemicals.Avariety of carbo-and heterocyclic cores that are privileged motifs in pharmaceuticals,b ioactive molecules,a nd natural products can be accessed with moderate to excellent selectivities.W ea nticipate that these attributes will lead to brisk exploitation in the field of radical cascade/cross-coupling. In addition we performed aseries of mechanistic investigations which supported the proposed radical cyclization cross-coupling reaction pathway.