pubs.acs.

org/JACS Article

Merging Halogen-Atom Transfer (XAT) and Copper Catalysis for the

Modular Suzuki−Miyaura-Type Cross-Coupling of Alkyl Iodides and
Organoborons
Zhenhua Zhang,† Bartosz Górski,† and Daniele Leonori*
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ABSTRACT: We report here a mechanistically distinct approach to

achieve Suzuki−Miyaura-type cross-couplings between alkyl iodides
and aryl organoborons. This process requires a copper catalyst but,
in contrast with previous approaches based on palladium and nickel
systems, does not utilizes the metal for the activation of the alkyl
electrophile. Instead, this strategy exploits the halogen-atom-transfer
ability of α-aminoalkyl radicals to convert secondary alkyl iodides
into the corresponding alkyl radicals that then are coupled with aryl,
vinyl, alkynyl, benzyl, and allyl boronate species. These novel
coupling reactions feature a simple setup and conditions (1 h at
room temperature) and facilitate access to privileged motifs targeted
by the pharmaceutical sector.

■ INTRODUCTION
Among all cross-coupling approaches, the Nobel-Prize-winning
The cross-coupling strategies discussed above revolve
around the direct reaction of the nickel catalyst with an alkyl
Suzuki−Miyaura reaction has changed the way organic halide, which generally leads to the formation of transient
molecules are assembled.1 This process is widely used in radical species (Scheme 1B).9 While this might help in the case
both industrial and academic settings mostly due to its mild of difficult oxidative additions, it also means that the catalyst
conditions and the commercial availability of both organic properties need to be carefully balanced to enhance halide
halides and organoboron building blocks.2 However, while aryl activation without compromising the following elementary
halides are a benchmarked class of coupling partners, the steps such as transmetalation and reductive elimination.6a,10
utilization of alkyl halides is less straightforward. Under We recently speculated that a conceptually different strategy,
palladium catalysis, the slower rate of oxidative addition and where the metal catalyst is required to orchestrate the C−C
the increased chances of β-hydride elimination often render bond formation but not to activate the alkyl halide, might
these reactions difficult to implement.3 provide synthetic advantages toward the assembly of
Nickel catalysis has provided a workable solution to this challenging small-molecule building blocks. In this paper we
challenge through the use of catalysts supported by either report the realization of this goal and present a novel and
phenanthroline or aminoalcohol ligands.4 Other base metals general approach for the Suzuki−Miyaura-type cross-coupling
(mostly Fe and Co) have been successfully applied in Suzuki- between secondary alkyl iodides and a broad range of
type cross-coupling, but their reactivity is less general.5 Overall,
boronates. This method integrates α-aminoalkyl radical
despite significant success in the area, coupling with secondary
mediated halogen-atom transfer (XAT) with copper catalysis11
and unactivated alkyl electrophiles is still a relevant challenge,
as these processes are usually low yielding, especially when and provides a general entry into the modular assembly of
polar functionalities are present.6 Notwithstanding these challenging C(sp3)−C(sp2) as well as C(sp3)−C(sp3) and
challenges and often suboptimal yields, the synthetic value C(sp3)−C(sp) bonds.
provided by these coupling reactions makes them widely
applied by the pharmaceutical and agrochemical sectors, where Received: December 3, 2021
sp3-rich fragments have increased chances of biological activity Published: January 21, 2022
(Scheme 1A).7 The development of novel strategies increasing
our synthetic capacity for the assembly of these motifs has the
potential to affect the discovery and manufacture of materials
that ultimately can improve the quality of our lives.8

© 2022 American Chemical Society https://doi.org/10.1021/jacs.1c12649

1986 J. Am. Chem. Soc. 2022, 144, 1986−1992
Journal of the American Chemical Society pubs.acs.org/JACS Article

Scheme 1. (A) The Transition-Metal-Catalyzed (Mostly as the coupling partners. Starting from a [Cu(I)] catalyst,
Nickel) Cross-Coupling between Alkyl Halide and ground-state SET with a stoichiometric oxidant such as
Organoboron Building Blocks Is Often Used to Access sp3- cumO2TMS would deliver a Cu(II)] species that would
Rich Materials, (B) Current Methods Require the Nickel transmetalate with 2 and give the Ph−[Cu(II)] complex A.
Catalyst to Be Involved in the Halide Activation Step That The cumO• generated in the SET event would react with a
Can Be Challenging, and (C) This Work Exploits α- stoichiometric amine reagent to give, upon polarity-matched H
Aminoalkyl Radical-Mediated XAT to Activate the Halide atom transfer (HAT),15 the key nucleophilic α-aminoalkyl
and Uses a Copper Catalyst radical B. Polarity-accelerated XAT between B and 1 would
then be used to access the alkyl radical C, which could enter
the [Cu(I/II/III)]-catalytic cycle and trap A.16 This step
should deliver the alkyl,aryl−[Cu(III)] intermediate D, from
which reductive elimination is facile17 and should therefore
provide the cross-coupling product 3 while reinitiating the
catalytic cycle.
As was mentioned before, the key mechanistic difference
between this approach and other metal-mediated cross-
couplings is that the alkyl radical generation occurs in a
HAT/XAT loop that is dissected by the copper-based catalytic
cycle. This means that the alkyl halide does not need to engage
in direct SET with the metal, which can be difficult due to its
low reduction potential (for alkyl−I: Ered < −2 V vs SCE), or
enter its coordination sphere for subsequent abstraction (or
oxidative addition). This fundamental difference obviates the
need of a highly reducing catalyst, which we hoped might
translate into a broader substrate scope.
This proposal for the radical arylation of 1 was eventually
implemented using boronate 2a as the coupling partner
(prepared by addition of n-BuLi to 2c at −78 °C),
[Cu(CH3CN)4]PF6 as the catalyst, Et3N as the XAT promoter,
cumO2TMS as the oxidant, and 2,2,6,6-tetramethyl-3,5-
heptanedione (TMHD) as the ligand in a DMSO−THF
solvent mixture at room temperature (Scheme 2B, entry 1).18
Under these mild conditions, 3 was obtained in 72% yield in
just 1 h. The TMHD ligand was important to improve the
yield in this specific example (Scheme 2B, entry 2), but it was
not necessary for all the cross-couplings presented below. Less
activated organoborons (e.g., 2b−d) were evaluated, but they
did not lead to product formation (Scheme 2B, entry 3), which

■ RESULTS AND DISCUSSION

We and the Doyle group have recently reported that alkyl and
we propose might result from their lower ability to trans-
metalate with [Cu(II)] species.18
In the absence of [Cu(I)] catalyst or the oxidant, no
aryl iodides can be converted into the corresponding radicals reactivity took place (Scheme 2B, entry 4) while the exclusion
via α-aminoalkyl radical mediated XAT.12 This reactivity of Et3N provided 3 in 17% yield (Scheme 2B, entry 4). We
benefits from a polarized transition state where the α- were initially surprised by the success of this reaction, as the
aminoalkyl unit stabilizes charge transfer, which kinetically activation of 1 should not occur. An analysis of the crude
accelerates the halide abstraction. This blueprint for radical reaction mixture revealed the trace formation of Ph−I and
generation can be exploited in different settings, which include acetophenone. We propose that under these amine-free
the coupling of alkyl iodides with N-nucleophiles to assemble conditions other productive pathways based on SET oxidation
SN2-elusive C(sp3)−N bonds.13 This reactivity paradigm is of 2a to the corresponding Ph• and/or fragmentation of C to
possible by merging XAT with copper catalysis so that an alkyl Me• might be operating. These reactivities would generate
radical is generated and then captured by a copper-bound N XAT-active species that can homolytically activate 1 and lead
fragment. to product formation.18
In order to achieve C−C bond formation, we looked at the To obtain more details on the process, we ran some
Chan−Lam cross-coupling that has pioneered the ability of mechanistic studies. UV/vis absorption spectroscopy studies
aryl organoborons to undergo transmetalation with [Cu(II)] demonstrated that [Cu(CH3CN)4]PF6 is oxidized upon
species.14 We therefore envisaged that the merger of XAT with treatment with cumO2TMS (new absorption band at λ ≈
[Cu] catalysis might enable a hybrid type of cross-coupling, 650 nm)19 and that transmetalation with 2a might be
which would be of the Suzuki type in terms of retrosynthetic occurring (Scheme 2C-i). 11B NMR spectroscopy studies
disconnection but more Chan−Lam based in terms of were used to further support the transmetalation of 2a with
mechanism (Scheme 1C). [Cu(II)], as evidenced by the formation of BuB(pin) (Scheme
Our proposed pathway for such XAT-mediated and Cu- 2C-ii). The requirement of B to achieve XAT activation of 1
catalyzed arylation is illustrated in Scheme 2A using 3-iodo-N- was revealed by the fact that replacing Et3N for DABCO, an
Boc-azetidine 1 and the generic Ph-organoboron derivative 2 amine that can be oxidized but cannot lead to the formation of
1987 https://doi.org/10.1021/jacs.1c12649
J. Am. Chem. Soc. 2022, 144, 1986−1992
Journal of the American Chemical Society pubs.acs.org/JACS Article

Scheme 2. (A) Proposed Mechanism for the XAT-Mediated and Cu-Catalyzed Cross-Coupling of Alkyl Iodides and Aryl
Organoborons, (B) Reaction Optimization and Key Control Experiments, and (C) Selected Mechanistic Experiments

an α-aminoalkyl radical,20 led to 3 in 17% yield, which is functionalities. A similar trend was observed for the utilization
identical with the outcome observed under amine-free of meta- and ortho-substituted derivatives (13−17 and 18,
conditions (Scheme 2B, entry 6). Furthermore, the fact that respectively), which also included aryl chloride and bromide
a stoichiometric reaction of 1, 2a, and [Cu(I)] did not lead to functionalities that can be engaged in further modular
any product formation demonstrates that a putative Ph− diversifications.
[Cu(I)] intermediate is not able to activate the alkyl halide by Polysubstituted aryl boronates were screened next, and they
either SET or oxidative addition (Scheme 2C-iii). This clearly provided the desired products in good yields (19 and 20).
underscores the relevance of XAT as the alkyl iodide activation Electron-rich heteroaryl boronates were competent coupling
pathway. Finally, the thermal reaction of lauroyl peroxide 4 partners, and they enabled the introduction of medicinally
with 2a using a stoichiometric [Cu(II)] species gave 5 in 38% relevant benzofuran (21), bezothiophene (22), indole (23),
yield (Scheme 2C-iv). This experiment supports the and indazole (24) units, as well as thiophene (25), furan (26),
generation of a primary alkyl radical (O−O homolysis then pyrazole (27), and isoxazole (28). Pyridines are some of the
decarboxylation) that can intercept A and therefore enable the most prevalent motifs in bioactive leads,21 and pleasingly, our
coupling process.18 copper-catalyzed approach successfully engaged both C-3
With the optimized reaction conditions in hand, we (29−31) and C-4 (32) borylated derivatives.
evaluated the scope of the transformation using 1 as the Having benchmarked this reactivity on a diverse set of
model alkyl iodide (Scheme 3A). We started by evaluating aromatic coupling partners, we evaluated its feasibility with
para-substituted aryl boronates and found that a variety of respect to vinyl derivatives. Pleasingly, the utilization of several
substituents were tolerated, delivering the desired products in commercial boronic esters enabled, upon boronate formation,
good yields. These included substrates with electron-rich Me the introduction of vinyl (33) and styrenenyl (34) as well as
(6), OMe (7) and OEt (8) groups as well as electron- other mono- and disubstituted olefin (35−37 and 38, 39
withdrawing Cl (9), F (10), CF3 (11), and OCF3 (12) respectively) units in high yields. The initial results
1988 https://doi.org/10.1021/jacs.1c12649
J. Am. Chem. Soc. 2022, 144, 1986−1992
Journal of the American Chemical Society pubs.acs.org/JACS Article

Scheme 3. XAT-Mediated and Cu-Catalyzed Cross-Coupling of Alkyl Iodides and Aryl Organoborons: (A) Organoboron
Scope and Limitations and (B) Alkyl Iodide Scope and Limitations

a
cumO2Sit-BuPh was used in place of cumO2TMS. bcumO2TES was used in place of cumO2TMS. cReaction run with no TMHD. d10 mol % of
Cu(CH3CN)4PF6. e30 mol % of Cu(CH3CN)4PF6.

1989 https://doi.org/10.1021/jacs.1c12649
J. Am. Chem. Soc. 2022, 144, 1986−1992
Journal of the American Chemical Society

■
pubs.acs.org/JACS Article

demonstrated that alkynyl boronates are viable partners (40) CONCLUSIONS

to achieve C(sp3)−C(sp) bond formation, albeit in lower In conclusion, the results reported here demonstrate that α-
yields. aminoalkyl radical mediated halogen-atom transfer can be
The formation of C(sp3)−C(sp3) linkages via cross-coupling integrated with copper catalysis to enable the modular
strategies is still a challenging task. We were pleased to find assembly of C−C bonds. This reactivity provides a
that activated benzylic22 and allylic boronates performed well mechanistically distinct tactic to engage alkyl iodides in
under the reaction conditions, delivering 41−43 and 44 in general cross-coupling reactions with aryl, vinyl, alkynyl,
good yields. In terms of limitations, allenyl and unactivated benzyl, and allyl organborons. Future developments will be
alkyl boronates failed to to provide the desired products (45 aimed at engaging unactivated alkyl organometallic partners as
and 46). well as translating the chemistry into asymmetric settings.

■
Of the substrates presented in Scheme 3A, 8 and 38 have
been recently prepared by the pharmaceutical sector (8, 3 V- ASSOCIATED CONTENT
Biosciences;23 and 38, GSK24) by Ni-catalyzed Suzuki− * Supporting Information
sı
Miyaura cross-coupling on 1. The approach reported here The Supporting Information is available free of charge at
utilized the same iodide and provided the desired products in https://pubs.acs.org/doi/10.1021/jacs.1c12649.
higher yields. We hope this might highlight the complemen-
tarity that this strategy can provide to mainstream approaches Experimental procedures, optimization and mechanistic
in the case of challenging arylations. studies, and characterization data (PDF)
Evaluation of the alkyl iodide scope was performed using the
Ph−B(pin)-based boronate 2a as the coupling partner, which
revealed that a wide range of unactivated alkyl iodides can be
■ AUTHOR INFORMATION
Corresponding Author
engaged (Scheme 3B). This was showcased by the arylation of Daniele Leonori − Department of Chemistry, University of
several piperidine derivatives, either N-Boc protected (47 and Manchester, Manchester M13 9PL, U.K.; orcid.org/0000-
48) or part of a 2-aminopyrimidine unit (49, also on a 10 0002-7692-4504; Email: daniele.leonori@
mmol scale). The chemistry was then applied to the manchester.ac.uk
preparation of 50, which is an analogue of the alkaloid
nortropine. Other commercial small-molecule building blocks Authors
were successfully engaged, as demonstrated by the arylation of Zhenhua Zhang − Department of Chemistry, University of
4-iodo(thio)pyrans (51−53), 3-iodooxetane (54), and a Manchester, Manchester M13 9PL, U.K.
cyclobutene derivative (55) recently disclosed by Merck for Bartosz Górski − Department of Chemistry, University of
the preparation of trifluoromethylated cyclobutanes.25 Manchester, Manchester M13 9PL, U.K.
The coupling reactivity was compatible with ketone, acetal, Complete contact information is available at:
and ether functionalities (56−59), while the formation of 59 https://pubs.acs.org/10.1021/jacs.1c12649
and 60 demonstrated that HAT-labile benzylic positions are
tolerated. This chemoselectivity is noteworthy, considering the Author Contributions
ability of cumO• to promote HAT reactions on activated †
Z.Z. and B.G. contributed equally.
benzylic C(sp3)−H positions.26 Notes
Spirocycles are interesting chemotypes in drug development The authors declare no competing financial interest.

■
campaigns due to their high C(sp3) content.27 Pleasingly,
radical cross-couplings with several commercially available ACKNOWLEDGMENTS
iodides were high-yielding (61−65). Of these substrates, 63−
D.L. thanks the EPSRC for a Fellowship (EP/P004997/1), the
65 have been recently prepared by Janssen using Ni catalysis
European Research Council for a research grant (758427), and
on the corresponding iodides, albeit in lower yields and, in the
the Leverhulme Trust for an Award (Philip Leverhulme). Z.Z.
case of 65, as a mixture with the demethoxylated product,28
thanks the Marie Curie Actions for a Fellowship (840318).

■
which was not observed under our conditions.
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