Zirconium-redox-shuttled cross-electrophile coupling of aromatic and heteroaromatic halides

Article abstract of DOI:10.1016/j.chempr.2021.06.007

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 the synthesis of unsymmetrical biaryl compounds through multimetallic XEC is of high synthetic value, the 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 the development of transition metal reductive coupling catalysis.

Full text of DOI:10.1016/j.chempr.2021.06.007

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Article
Zirconium-redox-shuttled cross-electrophile
coupling of aromatic and heteroaromatic
halides
Ting-Feng Wu, Yue-Jiao Zhang,
ZAPd Cross-Electrophile Coupling
Yue Fu, ..., Peng Liu, F. Dean
Toste, Baihua Ye
Br
I
Pd
Zr
Pd
het
pengliu@pitt.edu (P.L.)
+
fdtoste@berkeley.edu (F.D.T.)
yebh@shanghaitech.edu.cn (B.Y.)
het
het
het
thf
Highlights
broad scope (85 examples)
redox-transmetallation
Cp
NTMS
Ph
A Zirconaaziridine-mediated Pd-
catalyzed cross-electrophile
coupling was developed
Zr
Cp
up to 100% XEC selectivity
diversified heteroaryl scaffolds
Buchwald’s reagent
Negishi-type aryl-Zr coupling
reactants generated in situ by a
redox transmetallation
I
Faster
oxidative addition
Pd
het
het
het
XEC selectivity controlled by
relative rate of Pd(0) oxidative
addition into aryl halide
Me3Si
Ph
N
Cp
Cp
Zr
ZAPd XEC
I
Pd
Ph
Pd
L
Zr
Br
redox-transmetallation
het
het
Heterocycles are ubiquitous in bioactive molecules. The construction of
heteroaromatic scaffolds, which mainly relies 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 dual palladium catalysis in the presence of zirconaaziridine as an aryl shuttling
platform. High cross selectivity and functional group compatibility highlight the
utility of this protocol. Both DFT and experimental studies support redox
transmetallation as a crucial elementary step.
Wu et al., Chem 7, 1963–1974
July 8, 2021 ª 2021 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2021.06.007

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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,
*
1,
F. Dean Toste,2,5, and Baihua Ye
*
*
SUMMARY
The bigger picture
Heteroaromatic compounds are
privileged scaffolds in biologically
relevant organic molecules and
functional materials. While
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 the synthesis of unsymmetri-
cal biaryl compounds through multimetallic XEC is of high synthetic
value, the 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 scaf-
folds. 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 the
development of transition metal reductive coupling catalysis.
Negishi and Suzuki-Miyaura
couplings are among the most
powerful synthetic tools for
assembling these structures,
challenging and underdeveloped
transition metal-catalyzed cross-
electrophile coupling (XEC) of
heteroaryl halides without 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 compounds. This platform
tolerates diverse functional
INTRODUCTION
Heterocycles represent privileged skeletons in a wide range of pharmaceuticals, nat-
ural products, agrochemicals, and functional organic materials.1,2 Therefore, a sig-
nificant effort has been devoted toward 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 that led to the
2010 Nobel Prize in Chemistry.18 In general, cross-coupling reactions produce a car-
bon-carbon bond through the coupling of an organometallic fragment and an (het-
eroaryl) aryl halide or pseudohalide (Scheme 1A).19–23 A key elementary step in this
process involves the transfer of the group on the organometallic reagent to the tran-
sition metal catalyst, in an elementary process known as transmetallation.24 The
breadth of organometallic reagents, including those derived from boron-, magne-
sium-, 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 the 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 organome-
tallic reagent and the catalytic coupling reaction in a single operation have proven
challenging and have generally resulted in protocols that require sequential metal-
ation (borylation) and cross-coupling via two steps in one pot.30–32
groups, provides excellent cross-
selectivities, and is controlled by a
single Pd catalyst. The proposed
redox transmetallation in the
ZAPd-XEC sets the stage for the
development of additional
unprecedented transition metal-
catalyzed processes.
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Recently, multi-transition metal-catalyzed cross-electrophile coupling (XEC),33–38
single-electron transfer cross-couplings,39–41 and carbon-hydrogen functionaliza-
tion reactions12 have emerged as attractive alternative approaches. In order to
achieve selectivity between the two (pseudo) halide precursors and to 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 formi-
dable challenge. In order to overcome this limitation, several issues must be ad-
dressed, including the incompatibility of the heteroaromatic compounds with the
organometallic coupling reagents and stoichiometric reducing agents, while main-
taining 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-electrophile coupling
and XEC of readily available aromatic and heteroaromatic halides. In previously re-
ported systems, selective in situ formation of one organometallic reagent under
reductive coupling conditions requires that two electrophilic coupling partners
have significantly different reactivities. This has generally been addressed by em-
ploying 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, by transferring the ligand of the resulting organometallic complex to cata-
lytically 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 the stoi-
chiometric reducing agent (Mn) allowed for Ni-catalyzed homocoupling of aromatic
halides (Scheme 1C).44 They proposed that this reaction proceeded through a mech-
anism involving transmetallation from arylnickel(II) to form an arylzirconium species
and nickel(II) halides that were subsequently reduced by the stoichiometric metal to
regenerate the active nickel(0) catalyst.
We were inspired by reports of redox-transmetallation45 from homogeneous organo-
metallic complexes to consider the use of a homogeneous organometallic complex
as a soluble reducing agent that would also mediate rapid transmetallation from a kinet-
ically formed(hetero)aryl-palladium(II) complex(Scheme1D). Moreover, weenvisioned
that increasingtherelative rateof theinitial transmetallation/reduction eventmightpre-
serve 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 the (hetero)
aromatic component is expected to be highly selective and to proceed faster than
the subsequent conventional transmetallation and provide opportunities for the forma-
tion of the cross-coupled heteroaromatic-heteroaromatic products, rather than
competing homocoupling adducts. We posited that zirconaaziridines (h2-imine zirco-
nocene), 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 transme-
tallation and cross-coupling. This strategy, which circumvents the use of reducing
1School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210,
China
2Department of Chemistry, University of
California and Chemical Sciences Division,
Lawrence Berkeley National Laboratory,
Berkeley, CA 94720, USA
3Department of Chemistry, University of
Pittsburgh, Pittsburgh, PA 15260, USA
4These authors contributed equally
5Lead contact
*Correspondence: pengliu@pitt.edu (P.L.),
fdtoste@berkeley.edu (F.D.T.),
yebh@shanghaitech.edu.cn (B.Y.)
https://doi.org/10.1016/j.chempr.2021.06.007
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A
D
B
C
Scheme 1. Strategy for zirconaaziridine-mediated palladium (ZAPd)-catalyzed homo- and cross-electrophile coupling reactions
(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.
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(0).48,49 On the basis of these hypotheses, we initiated our investigations of
the combined zirconaaziridine/palladium (ZAPd) catalysis system in XEC reactions.
RESULTS AND 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 reagent,46 and catalyzed
by a phosphine-ligated palladium complex (see supplemental information, Tables
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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 a
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 a low conversion of the starting aryl bromide (Table S3). These initial
studies also identified 80ꢀC–100ꢀC as the optimal reaction temperature and toluene
as the optimal solvent (Table S4 and S6).
With optimized reaction conditions for both homo-electrophile coupling and XEC 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, car-
boxamide, 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 groups.46 The construction of hindered C(sp2)–C(sp2) bonds
required the use of P(tBu)3 as the ligand, which enabled the synthesis of 2,20,6,60-tetra-
substituted biaryl compounds 23–26 in good to excellent yields. These results demon-
strate 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 reac-
tion.23,50 Next, we turned our attention to the scope of homo-electrophile coupling
of heteroaromatic bromides that have proven challenging using these traditional
methods (Scheme 2B). Nitrogen-coordinating electron-deficient pyridine, isoquino-
line, 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, andpyrrole, were alsofeasible, affording 32–35. Moreover,
the ZAPd-homocoupling reaction of the electron-deficient isoquinolinone, and 4,40-di-
pyridone 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 under-
went smooth coupling to afford 38–46 with similar reactivities. The breadth of these suc-
cessful homocoupling of heteroaromatic halides encouraged us to investigate the
ZAPd catalyst platform to the challenging XEC of aromatics and heteroaromatics.
ZAPd-cross-electrophile coupling (XEC) reaction
Using the catalyst system described earlier, 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 homocoupled products was
observed when aromatic compounds with the same carbon-halogen bond were em-
ployed (Table S7). A re-examination of the reaction parameters showed that the effects
of solvent, temperature, zirconaaziridine, and ligand on the outcome of the ZAPd-XEC
reaction were similar to those found in the homocoupling reaction, with P(tBu)3
providing slightly improved yields and selectivity compared with 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 a yield of 64% and cross-coupling selectivity of 81% (Scheme 3).
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A
B
Scheme 2. Scope of ZAPd homocoupling of aryl and heteroaryl halides
Reaction conditions: Ar-Br (0.20 mmol), Zr-1 (0.20 mmol), Pd(dba)2 (10 mmol, 5.0 mol %), Q-Phos
(20 mmol, 10.0 mol %), PhMe (2.0 mL, 0.10 M), 80ꢀC, 16 h. *PtBu3 was used instead of Q-Phos.
(A) Homocoupling of aromatic halides.
(B) Homocoupling of heteroaromatic halides.
Using these conditions, a wide range of unsymmetrical biaryl compounds (47–56),
including those bearing boronic ester, trifluoromethyl, trimethylsilyl, and carboxa-
mide groups, underwent the desired ZAPd-XEC reaction with cross-coupling selec-
tivities of approximately 80% in most cases (Scheme 3A). Interestingly, compound
54 bearing a cyano group was isolated in a yield of 72%, despite with 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 re-
placed with bromides derived from other heteroaromatic compounds frequently
represented in pharmaceuticals (59–63). Notably, these examples retain excellent
selectivity in favor of the heteroaromatic-aromatic cross-coupling products (up to
92% selectivity). In addition, employing aryl iodides bearing trifluoromethyl (64),
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Scheme 3. Scope of ZAPd-XEC of aryl and heteroaryl halides
Reaction conditions: Ar1-Br (0.10 mmol), Ar2-I (0.10 mmol), Zr-1 (0.20 mmol), Pd(Pt-Bu3)2 (5.0 mmol,
5.0 mol %), Pt-Bu3 (10 mmol, 10.0 mol %), PhMe (1.0 mL, 0.10 M), 80ꢀC, 16 h.
(A) Cross electrophilic coupling of aromatic halides.
(B) Cross electrophilic coupling of heteroaromatic and aromatic halides.
acetal (65), and boronate (66) substituents in the ZAPd-XEC reaction further demon-
strates the potential synthetic value of this catalyst system.
Encouraged by the aforementioned successful results, the unprecedented XEC be-
tween heteroaryl bromides and iodides was examined (Scheme 4). ZAPd-XEC with a
1:1 ratio of 2-iodothiophene and 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 de-
rivatives (70–72) were also amenable to the ZAPd-XEC reaction. Cross-coupling re-
actions 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 elec-
trophilic fragment also successfully afforded the corresponding XEC products 82–
85, albeit in diminished yields and moderate cross-coupling selectivities.
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
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Scheme 4. Scope of ZAPd-XEC of two heteroaromatic halides
Reaction conditions: Ar1-Br (0.10 mmol), Ar2-I (0.10 mmol), Zr-1 (0.20 mmol), Pd(Pt-Bu3)2 (5.0 mmol,
5.0 mol %), Pt-Bu3 (10 mmol, 10.0 mol %), PhMe (1.0 mL, 0.10 M), 80ꢀC, 16 h.
performed by the stoichiometric zirconaaziridine complex. While the zirconium-medi-
ated oxidative addition to arylhalides showed chemoselectivity consistent with that
required for XEC (Scheme S1; Table S14), examination of the reaction of 4-iodo-N-phe-
nylpyrazole with zirconaaziridine at 60ꢀC showed a dramatic acceleration in the conver-
sion of the heteroarylhalide in the presence of catalytic amounts of bis(tri-t-butylphos-
phine)palladium(0) (see supplemental information, Scheme S2). Moreover, monitoring
the reaction showed that zirconium-mediated consumption of the aryl iodide was rapid,
but the product formation in the zirconium-mediated reaction was significantly slower
than when the reaction was conducted under ZAPd-XEC conditions (Scheme 5A). More
specifically, the zirconium-mediated palladium-catalyzed process showed rapid con-
sumption (<1 h) of aryliodide with only small amounts of homocoupled product 2
formed within this time period (Case 1, see also Scheme S3). The conversion of the ar-
ylbromide occurred after the aryliodide was consumed and was accompanied by the
generation of the heterocoupled product 47. In contrast, the reaction with zirconaazir-
idine, in the absence of the palladium catalyst, showed slower consumption of the aryl
iodide, followed by slower reaction with the aryl bromide, 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).
Taken together, these results are most consistent with a mechanism of palladium-medi-
ated oxidative addition to the aryliodide leading to an arylpalladium(II) intermediate
that undergoes conversion to an arylzirconium species. Importantly, these arylzirco-
nium intermediates do not undergo exchange reactions 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
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A
B
Scheme 5. Mechanistic studies
(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.
mixture with CD3OD afforded 1-phenyl-1H-pyrazole in a 49% yield with 80% deuterium
incorporation at C4-position, consistent with the intermediacy of a Negishi-type heter-
oarylzirconium reagent51,52 that underwent protonolysis (Equations S22–S24). On the
basis of these experiments, we sought to obtain evidence for the postulated arylzirco-
nium intermediate. Tothisend, thereactionof para-bromoanisolewithzirconaaziridine,
in the presence of catalytic amount of bis(tri-t-butylphosphine)palladium(0), was moni-
tored by 1H-NMR (Scheme5B; see also Schemes S9 and S10). These conditions resulted
in the formation of the postulated arylzirconium intermediate, as confirmed by compar-
ison with an authentic sample. The addition of bromopyrazole to the reaction mixture
produced the desired coupling product, consistent with the viability of the arylzirco-
nium intermediate in downstream Negishi-type coupling events. Similar experiments
were performed with the homocoupling pathway for the formation of 4,40-dimethoxy-
biphenyl 7 (see supplemental information). Importantly, these observations suggest
that the redox transmetallation proceeds faster than the subsequent conventional
transmetallation, thereby allowing for the observed XEC selectivity.
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Having established that the initial oxidative addition is palladium mediated, we
sought to explore the mechanism of the transmetallation event between the arylpal-
ladium(II) halide intermediate and zirconaaziridine. In addition to furnishing an aryl-
zirconium(IV) species for further Negishi-type cross-coupling,53 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. Exper-
iments with deuterium-labeled h2-imine zirconocene (Schemes S7 and S8) com-
plexes 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 Norton,54 we favor a process in which a coordinately unsaturated Lewis-
acidic palladium(II) complex reacts with the zirconaaziridine through a formal
sigma-bond metathesis.55 The bimetallic intermediate can then generate the requi-
site palladium(0) catalyst, the arylzirconocene intermediate, and the imine, without
the scrabbling of the imine C–H bond (see supplemental information, figures in
Schemes S7 and 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 the ‘‘Pd Cycle 1’’ (Scheme 1D), oxidative
addition of PhI to palladium(0) (TS5, DGz = 16.5 kcal/mol) forms phenylpalladiu-
m(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 s-bond metathesis with the Pd–I bond of 86
(TS1, DGz = 11.9 kcal/mol) to cleave the Zr–C bond in Zr-1 and generate a bime-
tallic intermediate 87. Alternative mechanisms for zirconaaziridine ring opening,
including backside (TS6, DGz
= =
34.1 kcal/mol)- and frontside(TS7, DGz
31.3 kcal/mol)-bimolecular electrophilic substitutions, and s-bond metathesis
with the Pd–Ph bond of 86 (TS8, DEz = 27.1 kcal/mol) require higher activation bar-
riers. In addition, a s-bond metathesis process involving the Zr–N bond of Zr-1 is
even less favorable (TS9, DGz = 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 b-hydrogen elimination from the Zr–N bond cleavage intermediate. After
the zirconaaziridine ring opening, transmetallation of the phenyl group to zirco-
nium occurs in two separate steps: intramolecular phenyl group transfer proceeds
through TS2 (DGz = 20.5 kcal/mol), followed by a facial and irreversible syn E2-type
elimination (TS3, DGz = 11.0 kcal/mol) to produce phenylzirconocene (Zr-2) and
regenerate the 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 (Scheme
5B). To form the final XEC product, Zr-2 undergoes transmetallation with LPdBr(Ph)
formed in the ‘‘Pd Cycle 2’’ with an activation free energy of 34.5 kcal/mol (see sup-
plemental information for full details).
Finally, to gain an additional insight into the origin of the selectivity of the ZAPd-XEC
coupling, we calculated the homocoupling pathway via transmetallation between
phenylpalladium(II) iodide (86) and phenylzirconium Zr-2 (Scheme 6B). The barrier
to this traditional transmetallation (TS4, DGz = 29.5 kcal/mol) is 9.0 kcal/mol higher
than that for the redox transmetallation. This reactivity difference provides the likely
reason as to 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 homocoupling pathway is
suppressed due to the lower barrier for redox transmetallation.
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A
B
Scheme 6. Computational studies
(A) Mechanism of redox transmetallation.
(B) Comparison of transmetallation activation energies.
Conclusions
In summary, we have elaborated a general and robust protocol for both catalytic
homo-electrophile coupling and XEC of aromatic and heteroaromatic halides. It is
noteworthy that the ZAPd-XEC methodology offers an entry into biologically rele-
vant 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 subse-
quent transmetallation, plays a crucial role in the control of XEC selectivity. More
broadly, this process may provide new opportunities to explore redox-shuttling us-
ing 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 ful-
filled by the lead contact, F. Dean Toste (fdtoste@berkeley.edu).’’
1972 Chem 7, 1963–1974, July 8, 2021

ll
Article
Materials availability
Full experimental details as well as detailed computational studies of reaction mech-
anisms can be found in the supplemental information.
Data and code availability
All data supporting this study are available in the manuscript and supplemental
information.
Full experimental procedures are provided in the supplemental information.
SUPPLEMENTAL INFORMATION
Supplemental information can be found online at https://doi.org/10.1016/j.chempr.
2021.06.007.
ACKNOWLEDGMENTS
B.Y. gratefully acknowledges financial support from ShanghaiTech University startup
funding and appreciates the support from Analytical Instrumentation Center (con-
tract no. SPST-AIC10112914), SPST, ShanghaiTech University. F.D.T. thanks the Na-
tional 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. Do-
nets and Prof. Jie Zhao for helpful discussions.
AUTHOR CONTRIBUTIONS
B.Y. and F.D.T. conceived and directed the project. T.W. and Y.Z. carried out the
experiments with B.Y. providing guidance. F.-J.L. and J.-T.T. carried out the prepa-
ration of starting materials. Y.F. and P.L. studied the mechanisms using DFT calcula-
tions. B.Y., P.L., and F.D.T. wrote the manuscript with the input of all other authors.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: November 26, 2020
Revised: April 27, 2021
Accepted: June 8, 2021
Published: July 8, 2021
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