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. Author manuscript; available in PMC: 2022 Jul 8.
Published in final edited form as: Chem. 2021 Jul 8;7(7):1963–1974. doi: 10.1016/j.chempr.2021.06.007

Zirconium-Redox-Shuttled Cross-Electrophile Coupling of Aromatic and Heteroaromatic Halides

Ting-Feng Wu 1,4, Yue-Jiao Zhang 1,4, Yue Fu 3,4, Fang-Jie Liu 1, Jian-Tao Tang 1, Peng Liu 3,*, F Dean Toste 2,5,*, Baihua Ye 1,*
PMCID: PMC8492010  NIHMSID: NIHMS1716944  PMID: 34622088

SUMMARY

Transition metal-catalyzed cross-electrophile coupling (XEC) is a powerful tool for forging C(sp2)-C(sp2) bonds in biaryl molecules from abundant aromatic halides. While syntheses of unsymmetrical biaryl compounds through multimetallic XEC is of high synthetic value, selective XEC of two heteroaromatic halides remains elusive and challenging. Herein we report a homogeneous XEC method which relies on a zirconaaziridine complex as a shuttle for dual palladium catalyzed processes. The zirconaaziridine-mediated palladium (ZAPd) catalyzed reaction shows excellent compatibility with various functional groups and diverse heteroaromatic scaffolds. In accord with density functional theory (DFT) calculations, a redox-transmetallation between the oxidative addition product and the zirconaaziridine is proposed as the crucial elementary step. Thus, cross-coupling selectivity using a single transition metal catalyst is controlled by the relative rate of oxidative addition of Pd(0) into the aromatic halide. Overall, the concept of a combined reducing and transmetallating agent offers opportunities for development of transition-metal reductive coupling catalysis.

eTOC blurb

Heterocycles are ubiquitous in bioactive molecules. Construction of heteroaromatic scaffolds, which has mainly relied on classical cross-coupling reactions, remains challenging. Here, Ye, Toste and coworkers describe a complementary approach to these compounds using a cross-electrophile coupling (XEC) enabled by a dual palladium catalysis in the presence of zirconaaziridine as an aryl shuttling platform. High cross selectivity and functional group compatibilities highlights the utility of this protocol. Both DFT and experimental studies support redox-transmetallation as a crucial elementary step.

Graphical Abstract

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INTRODUCTION

Heterocycles represent privileged skeletons in a wide range of pharmaceuticals, natural products, agrochemicals and functional organic materials.1,2 Therefore, significant effort has been devoted towards the development of efficient methods for the synthesis of heteroaromatic arenes.3–17 These efforts gave rise to a number of transition metal catalyzed cross-coupling reactions, including those awarded the 2010 Nobel Prize in Chemistry.18 In general, cross-coupling reactions produce a carbon-carbon bond through the coupling of an organometallic fragment and an (heteroaryl)aryl halide or pseudohalide (Scheme 1A).19–23 A key elementary step in this process involves transfer of the group on the organometallic reagent to the transition metal catalyst, in an elementary process known as transmetallation.24 The breadth of organometallic reagents, including those derived from boron-, magnesium-, tin-, lithium- and zinc-carbon bonds, that undergo transmetallation has enabled the development of a diverse set of transition metal catalyzed cross-coupling reactions.25–29 However, prior to catalytic cross-coupling, these methods require preparation of the requisite transmetallating reagents, often from a more readily available (hetero) arylhalide through a formal reduction of the carbon-halogen bond.21 Attempts to render both the preparation of the organometallic reagent and the catalytic coupling reaction in a single operation have proven challenging and have generally resulted in protocols that require sequential metalation (borylation) and cross coupling via two steps in one pot.30–32

Scheme 1. Strategy for zirconaaziridine-mediated palladium (ZAPd)-catalyzed homo- and cross-electrophile coupling reactions.

Scheme 1.

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(A) Well-established cross couplings. (B) Ni-Pd bimetallic XEC catalysis reported by Weix. (C) Ni-Zr bimetallic homocoupling reported by Kishi. (D) Our approach of ZAPd-XEC catalysis.

Recently, multi-transition-metal catalyzed cross-electrophile coupling (XEC)33–38, single-electron transfer cross couplings39–41 and carbon-hydrogen functionalization reactions12 have emerged as attractive alternative approaches. In order to achieve selectivity between the two (pseudo)halide precursors and avoid homo-coupling, XEC approaches rely on the differences in relative rates for production of the organometallic reagent from the organic halide in an elementary step known as oxidative addition (formal reduction of the (hetero)arylhalide). Most commonly, two transition metal catalysts, Ni and Pd, are employed, with the former undergoing rapid oxidative addition and stoichiometric reduction (for example, zinc) to generate the required organometallic reagent prior to the palladium-catalyzed cross coupling event (Scheme 1B).33 Despite significant progress in this field, accessing heterocyclic compounds via direct XEC of two heteroaromatic (pseudo)halides remains a formidable challenge. In order to overcome this limitation several issues must be addressed, including the incompatibility of the heteroaromatic compounds with the organometallic coupling reagents and stoichiometric reducing agents, while maintaining selectivity for cross-coupling.16,31

Nevertheless, encouraged by the great value of heteroaromatic compounds, we sought an alternative platform for catalysis of both homo- and cross-electrophile couplings of readily available aromatic and heteroaromatic halides. In previously reported systems, selective in situ formation of one organometallic reagent under reductive coupling conditions requires that two electrophilic coupling partners have significantly different reactivities and has generally been addressed by employing two different transition metal catalysts.42,43 Moreover, transmetallation is pivotal to the success of these XEC reactions: first by reducing the initially produced organo-transition metal species to the organometallic cross-coupling partner and second in transferring the ligand of the resulting organometallic complex to catalytically active transition metal for the cross-coupling event.34,37 For example, in the elegant Ni/Pd catalyzed system developed by Weix, ligand exchange between two catalytically active transition-metal species involves a zinc reduction of an arylnickel species followed by transmetallation of the arylzinc intermediate to palladium (Scheme 1B).33,38 Similarly, Kishi et al. demonstrated that zirconocene and stoichiometric reducing agent (Mn) allowed for Ni-catalyzed homocoupling of aromatic halides (Scheme 1C).44 They proposed that this reaction proceeded through a mechanism involving transmetallation from arylnickel(II) to form an arylzirconium species and nickel(II) halides that were subsequent reduced by the stoichiometric metal to regenerate the active nickel(o) catalyst.

We were inspired by reports of redox-transmetallation45 from homogeneous organometallic complexes to consider the use of a homogenous organometallic complex as a soluble reducing agent that would also mediate rapid transmetallation from a kinetically formed (hetero)aryl-palladium(II) complex (Scheme 1D). Moreover, we envisioned that increasing the relative rate of the initial transmetallation/reduction event might preserve the selectivity imparted by the oxidative addition and allow for the use of a single transition metal catalyst in XEC. In this context, redox-transmetallation of (hetero)aromatic component is expected to be highly selective and proceed faster than subsequent conventional transmetallation and provide opportunities for the formation of the cross-coupled heteroaromatic-heteroaromatic products rather than competing homo-coupling adducts. We posited that zirconaaziridines (η2-imine zirconocene), first reported by Buchwald,46,47 would serve as potential candidates capable of undergoing redox-transmetallation, thus shuttling the heteroaryl group from Pd to Zr to form a (hetero)arylzirconocene complex that could participate in traditional transmetallation and cross-coupling. This strategy, which circumvents the use of reducing agents that might be incompatible with heteroaromatic compounds, would allow for high levels of XEC selectivity by modulating the relative rate of oxidative addition of palladium(o).48,49 On the basis of these hypotheses, we initiated our investigations of the combined zirconaaziridine/palladium (ZAPd) catalysis system in XEC reactions.

RESULTS & DISCUSSION

ZAPd-Homocoupling Reaction.

At the outset of the investigation, various reaction parameters were established for the simple homocoupling reaction of 2-bromoanisole mediated by Zr-1, prepared on gram scale from the commercially available Schwartz reagent46, and catalyzed by a phosphine-ligated palladium complex (see supplemental information, Tables S1–S6). P(tBu)3 and Q-Phos were identified as the best ligands for the formation of biaryl 1 while minimizing the formation of the simple arylhalide reduction product (Table S1). While aryl triflates were unreactive and aryl chlorides showed only modest productive reaction, both aryl bromides and iodides underwent smooth palladium-catalyzed homocoupling, setting the stage for further investigation of this catalyst system in reductive XEC (Table S2). Notably, zirconaaziridine was required for successful homocoupling, while the precursor zirconocene dichloride gave only low conversion of the starting arylbromide (Table S3). These initial studies also identified 80–100 °C and toluene as the optimal reaction temperature and solvent, respectively (Table S4 and S6).

With optimized reaction conditions for both homo- and cross-electrophile couplings in hand, we probed the generality of the ZAPd homocoupling protocol. Various substituted aromatic bromides were first examined in the electrophile homocoupling reactions. As depicted in Scheme 2A, substituted symmetrical biaryl derivatives 3–22 bearing alkyl, aryl, silyl, fluoro, trifluoromethyl, pentafluorosulfanyl, carboalkoxy, carboxamide, and amino groups were obtained in good to excellent yields (up to 99%). Notably, biaryl products 10 and 12 bearing synthetically useful boronate and cyano groups, respectively, were accessible despite the potential reactivity zirconaaziridines with these functional groups46. The construction of hindered C(sp2)-C(sp2) bonds required the use of P(tBu)3 as the ligand, which enabled the synthesis of 2,2’,6,6’-tetrasubstituted biaryl compounds 23–26 in good to excellent yields. These results demonstrate the simplicity and excellent functional group compatibility of the ZAPd catalyst system, and the potential of this protocol to complement traditional approaches to biaryl compounds, such as oxidative coupling8 and the Negishi cross-coupling reaction23,50. Next, we turned our attention to the scope of homo-electrophile couplings of heteroaromatic bromides that have proven challenging using these traditional methods (Scheme 2B). Nitrogen-coordinating electron-deficient pyridine, isoquinoline and pyrimidine underwent homocoupling to furnish 27–31 in excellent yields and without observation of pronounced catalyst deactivation. Homocoupling reactions of electronically different five-membered heteroaromatic bromides, including those based on oxazole, pyrazole and pyrrole, were also feasible affording 32–35. Moreover, the ZAPd homocoupling reaction of electron-deficient isoquinolinone, and 4,4’-dipyridone heterocycles showed slightly decreased yields in the formation of 36 and 37. On the other hand, biologically relevant heteroaromatic bromides, such as those based on thiophene, benzothiophene, furan, benzofuran, indoles and 7-azaindole, all underwent smooth coupling to afford 38–46 with similar reactivities. The breadth of these successful homocoupling of heteroaromatic halides encouraged us to investigate ZAPd catalyst platform to the challenging XEC of aromatics and heteroaromatics.

Scheme 2. Scope of ZAPd homocoupling of aryl and heteroaryl halides.

Scheme 2.

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Reaction conditions: Ar-Br (0.20 mmol), Zr-1 (0.20 mmol), Pd(dba)2 (10 μmol, 5.0 mol%), Q-Phos (20 μmol, 10.0 mol%), PhMe (2.0 mL, 0.10 M), 80 °C, 16 h. *PtBu3 was used instead of Q-Phos. (A) homocoupling of aromatic halides. (B) homocoupling of heteroaromatic halides.

ZAPd-Cross-electrophile coupling (XEC) Reaction.

Using the catalyst system described above, an equimolar (1 : 1) ratio of aryl bromide and iodide effectively underwent ZAPd-XEC with high selectivity (80%) in favor of the cross-coupled product 47. In contrast, a mixture of cross- and homo-coupled products was observed when aromatic compounds with the same carbon-halogen bond were employed (Table S7). A reexamination of the reaction parameters in the ZAPd-XEC reaction showed that the solvent, temperature, zirconaaziridine and ligand effects were similar to those found in the homocoupling reaction, with P(tBu)3 providing slightly improved yields and selectivity compared to Q-Phos (Tables S8–S13). With these studies we established Pd(PtBu3)2 (5.0 mol%) and additional P(tBu)3 (10.0 mol%) with two equivalents of Zr-1 as the conditions of choice. Conducting the ZAPd-XEC of 2-bromoanisole and iodobenzene with these parameters afforded the XEC adduct 47 in yield of 64% and cross-coupling selectivity of 81% (Scheme 3).

Scheme 3. Scope of ZAPd-XEC of aryl and heteroaryl halides.

Scheme 3.

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Reaction conditions: Ar1-Br (0.10 mmol), Ar2-I (0.10 mmol), Zr-1 (0.20 mmol), Pd(Pt-Bu3)2 (5.0 μmol, 5.0 mol%), Pt-Bu3 (10 μmol, 10.0 mol%), PhMe (1.0 mL, 0.10 M), 80 °C, 16 h. (A) cross electrophilic coupling of aromatic halides. (B) cross electrophilic coupling of heteroaromatic and aromatic halides.

Using these conditions, a wide range of unsymmetrical biaryl compounds (47–56), including those bearing boronic ester, trifluoromethyl, trimethylsilyl and carboxamide group, underwent the desired ZAPd-XEC reaction with cross-coupling selectivities of approximately 80% in most cases (Scheme 3A). Interestingly, compound 54 bearing a cyano group was isolated in yield of 72% despite in slightly lower selectivity (73%). The ZAPd-XEC of 4-iodoanisole to various heteroaromatic coupling partners was examined next (Scheme 3B). Cross-coupling with 6-methoxy pyridyl derivatives led to the formation of 57 and 58 with selectivities of 88% and 80%, respectively. Similar results were obtained when the pyridyl fragment was replaced with bromides derived from other heteroaromatic compounds frequently represented in pharmaceuticals (59–63). Notably, these examples retain excellent control in the generation of heteroaromatic-aromatic cross-coupling products (up to 92% selectivity). In addition, employing aryl iodides bearing trifluoromethyl (64), acetal (65) and boronate (66) substituents in the ZAPd-XEC reaction further demonstrates the potential synthetic value of this catalyst system.

Encouraged by aforementioned successful results, the unprecedented XEC between heteroaryl bromides and iodides was examined (Scheme 4). ZAPd-XEC of a 1:1 ratio of 2-iodothiophene with 3-bromoindole derivatives (67–69) revealed that the cross-coupling selectivity was influenced by the nature of indole substituents. More specifically, electronically neutral or electron-deficient variants gave excellent cross-coupling selectivities (up to 100%). Pleasingly, other indole and azaindole derivatives (70–72) were also amenable to the ZAPd-XEC reaction. Cross-coupling reactions were utilized to produce various combinations of heterocycles, including oxazole-thiophene 73, indole-pyrazole 74, indole-pyridine 75, indole-thiophene 76, furan-pyrazole 77, pyrrole-pyrazole 78 and pyrrole-pyridine 79, highlighting the breadth of the strategy. In addition, pyrazole 80 and pyridine 81 derivatives were also prepared using this method, although lower selectivities were observed. Finally, ZAPd-XEC reaction of substrates containing the challenging 2-pyridyl electrophilic fragment also successfully afforded the corresponding XEC products 82–85, albeit in diminished yields and moderate cross-coupling selectivities.

Scheme 4. Scope of ZAPd-XEC of two heteroaromatic halides.

Scheme 4.

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Reaction conditions: Ar1-Br (0.10 mmol), Ar2-I (0.10 mmol), Zr-1 (0.20 mmol), Pd(Pt-Bu3)2 (5.0 μmol, 5.0 mol%), Pt-Bu3 (10 μmol, 10.0 mol%), PhMe (1.0 mL, 0.10 M), 80 °C, 16 h.

Proposed Mechanism.

The proposed mechanism for ZAPd-XEC is outlined in Scheme 1D. At the outset, we considered whether the initial selectivity-determining oxidative addition might be performed by the stoichiometric zirconaaziridine complex. While the zirconium-mediated oxidative addition to arylhalides showed chemoselectivity consistent with that required for XEC (Scheme S1 and Table S14), examination of the reaction of 4-iodo-N-phenylpyrazole with zirconaaziridine at 60°C showed a dramatic acceleration in the conversion of the heteroarylhalide in the presence of catalytic amounts of bis(tri-t-butylphosphine)palladium(0) (see supplemental information, Scheme S2). Moreover, monitoring the reaction showed that zirconium-mediated consumption of the aryliodide was rapid, but product formation in the zirconium-mediated reaction was significantly slower in comparison to when the reaction was conducted under ZAPd-XEC conditions (Scheme 5A). More specifically, the zirconium-mediated palladium-catalyzed process showed rapid consumption (<1hr) of aryliodide with only small amounts of homocoupled product 2 formed within this time period (Case 1, see also Scheme S3 in supplemental information). Conversion of the arylbromide occurred after the aryliodide was consumed and was accompanied by generation of the heterocoupled product 47. In contrast, the reaction with zirconaaziridine, in absence of palladium catalyst showed slower consumption of the aryliodide, followed by slower reaction with the arylbromide, without significant formation of any coupled products (Case 2, see also Scheme S4). Little conversion and no product formation occurred in the absence of zirconaaziridine (Case 3, see also Scheme S5).

Scheme 5. Mechanistic studies.

Scheme 5.

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(A) Kinetic profile of coupling reactions with and without zirconaaziridine complex and palladium catalyst. (B) in situ observation of aryl zirconium intermediate by 1H-NMR spectroscopy.

Taken together, these results are most consistent with a mechanism of palladium-mediated oxidative addition to the aryliodide leading to an arylpalladium(II) intermediate that undergoes conversion to an arylzirconium species. Importantly, these arylzirconium intermediates do not undergo exchange reaction with arylhalides (Table S15), suggesting that the initially generated arylzirconium reflects the kinetic selectivity of the palladium-catalyzed oxidative addition. Moreover, methanolysis of the reaction mixture with CD3OD afforded 1-phenyl-1H-pyrazole in 49% yield with 80% deuterium incorporation at C4-position, consistent with the intermediacy of a Negishi-type heteroarylzirconium reagent51,52 that underwent protonolysis (Eq S22–S24 in supplemental information). On the basis of these experiments, we sought to obtain evidence for the postulated arylzirconium intermediate. To this end, the reaction of para-bromoanisole with zirconaaziridine, in the presence of catalytic amount of bis(tri-t-butylphosphine)palladium(0), was monitored by 1H-NMR (Scheme 5B, see also Scheme S9 and S10 in supplemental information). These conditions resulted in formation of the postulated arylzirconium intermediate, as confirmed by comparison with an authentic sample. Addition of bromopyrazole to the reaction mixture produced the desired coupling product, consistent with the viability of the arylzirconium intermediate in downstream Negishi-type coupling events. Similar experiments were performed with the homocoupling pathway for the formation of 4,4’-dimethoxybiphenyl 7 (see supplemental information). Importantly, these observations suggest that the redox-transmetallation proceeds faster than subsequent conventional transmetallation, thereby allowing for the observed XEC selectivity.

Having established that the initial oxidative addition is palladium mediated, we sought to explore the mechanism of the transmetallation event between the arylpalladium(II) halide intermediate and zirconaaziridine. In addition to furnishing an arylzirconium(IV) species for further Negishi-type cross coupling53, the reaction of the zirconaaziridine with the arylpalladium(II) halide must regenerate palladium(0), in the absence of exogenous reductant, for the subsequent oxidative addition. Experiments with deuterium labelled η2-imine zirconocene (Schemes S7 and S8) complexes suggest that redox chemistry leveraging the imine C-H bond, including those involving beta-hydrogen elimination, are not operative. Instead, drawing on the studies of Norton54, we favor a process in which a coordinately unsaturated Lewis-acidic palladium(II) complex reacts with the zirconaaziridine through a formal sigma-bond metathesis55. The bimetallic intermediate can then generate the requisite palladium(0) catalyst, the arylzirconocene intermediate and the imine without scrabbling of the imine C-H bond (see supplemental information, figures in Schemes S7–S8).

This proposed transmetallation mechanism is supported by computational studies through DFT calculations (see supplemental information for computational details and results for less favorable pathways). In “Pd Cycle 1” (Scheme 1D), oxidative addition of PhI to palladium(0) (TS5, ΔG‡ = 16.5 kcal/mol) forms phenylpalladium(II) iodide (86). We computed several possible transmetallation pathways of 86 with Zr-1 (Scheme S12). The lowest-energy pathway (Scheme 6A) follows a facial zirconaaziridine ring-opening via σ-bond metathesis with the Pd–I bond of 86 (TS1, ΔG‡ = 11.9 kcal/mol) to cleave the Zr–C bond in Zr-1 and generate a bimetallic intermediate 87. Alternative mechanisms for zirconaaziridine ring-opening, including backside- (TS6, ΔG‡ = 34.1 kcal/mol) and frontside-(TS7, ΔG‡ = 31.3 kcal/mol) bimolecular electrophilic substitutions, and σ-bond metathesis with the Pd–Ph bond of 86 (TS8, ΔE‡ = 27.1 kcal/mol) require higher activation barriers. In addition, a σ-bond metathesis process involving the Zr–N bond of Zr-1 is even less favorable (TS9, ΔG‡ = 52.4 kcal/mol). The higher activation energy for the Zr–N bond cleavage is consistent with the observation that the imine C–H(D) bonds were not scrambled (Scheme S8), because the C–H(D) scrambling would require a β-hydrogen elimination from the Zr–N bond cleavage intermediate. After the zirconaaziridine ring-opening, transmetallation of the phenyl group to zirconium occurs in two separate steps: intramolecular phenyl group transfer proceeds through TS2 (ΔG‡ = 20.5 kcal/mol) followed by a facial and irreversible syn E2-type elimination (TS3, ΔG‡ = 11.0 kcal/mol) to produce phenylzirconocene (Zr-2) and regenerate Pd(0) catalyst. Overall, the redox-transmetallation from Zr-1 to Zr-2 is exergonic by 16.0 kcal/mol. The exothermicity of the redox-transmetallation agrees with the aforementioned in situ detection of arylzirconium species (Schemes 5B). To form the final XEC product, Zr-2 undergoes transmetallation with LPdBr(Ph) formed in “Pd Cycle 2” with an activation free energy of 34.5 kcal/mol (see supplemental information for full details).

Scheme 6. Computational studies.

Scheme 6.

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(A) mechanism of redox transmetallation. (B) comparison of transmetallation activation energies.

Finally, to gain additional insight into the origin of the selectivity of the ZAPd-XEC coupling, we calculated the homo-coupling pathway via transmetallation between phenylpalladium(II) iodide (86) and phenylzirconium Zr-2 (Scheme 6B). The barrier to this traditional transmetallation (TS4, ΔG‡ = 29.5 kcal/mol) is 9.0 kcal/mol higher than that for the redox-transmetallation. This reactivity difference provides the likely reason for why XEC can be achieved: arylpalladium(II) species are more likely to engage in reaction with the zirconaaziridine than in traditional Negishi coupling with the in situ formed arylzirconium species. Therefore, the homo-coupling pathway is suppressed due to the lower barrier for redox-transmetallation.

CONCLUSION

In summary, we have elaborated a general and robust protocol for both catalytic homo- and cross-electrophile coupling of aromatic and heteroaromatic halides. It is noteworthy that the ZAPd-XEC methodology offers an entry into biologically relevant unsymmetrical heterocycles from the pool of available heteroaromatic halides. Excellent cross-selectivities together with tolerance of a wide range of functional groups highlight the potential of ZAPd-XEC. In particular, redox-transmetallation of zirconaaziridine with Ar-PdII-I, thus accumulating one Ar-Zr species for subsequent transmetallation, plays a crucial role in the control of XEC selectivity. More broadly, this process may provide new opportunities of exploring redox-shuttling using zirconaaziridine in other reductive transition metal-catalyzed processes.

EXPERIMENTAL PROCEDURES

Resource Availability

Lead Contact

Further information and requests for resources should be directed to and will be fulfilled by the Lead Contact, F. Dean Toste (fdtoste@berkeley.edu).”

Materials Availability

Full experimental details as well as detailed computational studies of reaction mechanisms can be found in the Supplemental Information.

Data and Code Availability

All data supporting this study are available in the Manuscript and Supplemental Information.

Supplementary Material

Supplemental Experimental Procedures
Table S16

Highlights.

Zirconaaziridine-mediated Pd-catalyzed cross-electrophile coupling reaction was developed.

Negishi-type aryl-Zr coupling reactants generated in situ by a redox-transmetallation.

XEC selectivity controlled by relative rate of Pd(0) oxidative addition into aryl halide.

The Bigger Picture.

Heteroaromatic compounds are privileged scaffolds in biologically relevant organic molecules and functional materials. While Negishi and Suzuki-Miyaura couplings are among the most powerful synthetic tools for assembly these structures, challenging and underdeveloped transition-metal catalyzed cross-electrophile coupling (XEC) of heteroaryl halides without in prior formation of organometallic reagents offers a synthetically valuable entry into these molecules. Herein, we disclose a protocol, involving homogeneous Pd-catalyzed zirconaaziridine redox-shuttled ZAPd-XEC of two heteroaromatic bromide and iodide. This platform provides high tolerance for diverse functional groups, excellent cross-selectivities and is controlled by a single Pd catalyst. The proposed redox-transmetallation in the ZAPd-XEC sets the stage for development of additional unprecedented transition-metal catalyzed processes.

ACKNOWLEDGMENTS

B. Y. gratefully acknowledge financial support from ShanghaiTech University startup funding and appreciate the support from Analytical Instrumentation Center (contract no. SPST-AIC10112914), SPST, ShanghaiTech University. F. D. T. thanks the National Institutes of General Medical (R35 GM118190) for financial support. P. L. thanks the National Science Foundation (CHE1654122) for financial support and Pitt CRC, XSEDE, and TACC for supercomputer resources. We thank Dr. Pavel A. Donets and Prof. Jie Zhao for helpful discussions.

Footnotes

DECLARATION OF INTERESTS

The authors declare no competing interests.

EXPERIMENT PROCEDURE

Full experimental procedures are provided in the Supplemental Information.

SUPPLEMENTAL INFORMATION

Document of Supplemental Information includes:

Supplemental Experimental Materials and Procedures, Schemes S1–S13, Tables S1–S15 and Figures S1–S191. Analytical Data and NMR-Spectra of synthesized compounds. Table S16: Cartesian coordinates and energies of all computed structures.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Experimental Procedures
NIHMS1716944-supplement-Supplemental_Experimental_Procedures.pdf (8.3MB, pdf)
Table S16
NIHMS1716944-supplement-Table_S16.xlsx (121KB, xlsx)

Data Availability Statement

All data supporting this study are available in the Manuscript and Supplemental Information.

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