Cobalt-Catalyzed C(sp2)-C(sp3) Suzuki-Miyaura Cross Coupling

Article abstract of DOI:10.1021/acs.orglett.0c02934

A cobalt-catalyzed method for the C(sp²)-C(sp³) Suzuki-Miyaura cross coupling of aryl boronic esters and alkyl bromides is described. Cobalt-ligand combinations were assayed with high-throughput experimentation, and cobalt(II) sources with trans-N,N′-dimethylcyclohexane-1,2-diamine (DMCyDA, L¹) produced optimal yield and selectivity. The scope of this transformation encompassed steric and electronic diversity on the aryl boronate nucleophile as well as various levels of branching and synthetically valuable functionality on the electrophile. Radical trap experiments support the formation of electrophile-derived radicals during catalysis.

Full text of DOI:10.1021/acs.orglett.0c02934

This is an open access article published under an ACS AuthorChoice License, which permits
copying and redistribution of the article or any adaptations for non-commercial purposes.
pubs.acs.org/OrgLett
Letter
Cobalt-Catalyzed C(sp2)−C(sp3) Suzuki−Miyaura Cross Coupling
Jacob R. Ludwig, Eric M. Simmons, Steven R. Wisniewski, and Paul J. Chirik*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02934
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A cobalt-catalyzed method for the C(sp2)−C(sp3)
Suzuki−Miyaura cross coupling of aryl boronic esters and alkyl
bromides is described. Cobalt−ligand combinations were assayed
with high-throughput experimentation, and cobalt(II) sources with
trans-N,N′-dimethylcyclohexane-1,2-diamine (DMCyDA, L1) pro-
duced optimal yield and selectivity. The scope of this trans-
formation encompassed steric and electronic diversity on the aryl
boronate nucleophile as well as various levels of branching and
synthetically valuable functionality on the electrophile. Radical trap
experiments support the formation of electrophile-derived radicals
during catalysis.
he transition-metal-catalyzed cross coupling of an
organoboron nucleophile and an organohalide (pseudo-
halide) electrophile, also known as the Suzuki−Miyaura
reaction, is one of the most widely used transformations in
synthetic chemistry (Scheme 1A).1 Broad functional group
removal following the catalytic reaction,3 distinguishing the
Suzuki−Miyaura variant from other types of couplings.4
Historically, palladium complexes have been the dominant
catalysts used for Suzuki−Miyaura reactions.2b,5 The emer-
gence of a detailed mechanistic picture has enabled the
evolution of specialized ligands,2a positioning palladium
catalysis as the state of the art for C(sp2)−C(sp2) coupling.
However, extending this approach to include C(sp3) coupling
partners has been problematic. Whereas some success has been
achieved with alkylboron nucleophiles,6 coupling to more
widely available alkyl electrophiles is limited by the SN2-type
pathways accessible to low-valent palladium catalysts.7 Addi-
tionally, competing β-hydrogen elimination (β-HE) from
intermediate palladium alkyls leads, in some cases, to
isomerized products.8
T
Scheme 1. Overview of Transition-Metal-Catalyzed Suzuki−
Miyaura Cross Coupling
First-row transition metals, by virtue of their distinct
electronic structures, often mitigate these challenges,9 and
effective methods have been developed for C(sp2)−C(sp3)
coupling that rely on more reactive organometallic nucleo-
philes.10 Although these methods generate valuable products,
many of the benefits associated with using neutral boron
reagents are lacking. Notable advancements have been made
with nickel- and copper-catalyzed coupling reactions using
organoboron coupling partners.10e−g One feature common
among late transition metals including palladium, nickel, and
copper is the facile transmetalation of neutral boron reagents
with metal-alkoxide intermediates; analogous reactivity with
Received: September 1, 2020
tolerance and high success rates have elevated Suzuki−Miyaura
coupling to a preferred method for C−C bond formation, in
particular, in pharmaceutical applications.2 The advantages of
organoboron nucleophiles include commercial availability,
convenient preparation, bench stability, and ease of byproduct
https://dx.doi.org/10.1021/acs.orglett.0c02934
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
Table 1. Optimization of Cobalt-Catalyzed C(sp2)−C(sp3) Suzuki−Miyaura Coupling of 1a and 2a
a
a
a
a
entry
[Co] (x)
ligand
base
solvent
conv. (%)
3a (%)
2a′ (%)
7
2a′′ (%)
b
1
2
CoCl2 (10)
KOMe
KOMe
KOMe
KOMe
KOMe
KOMe
KOMe
KOEt
KOMe
KOMe
KOMe
KOMe
KOMe
KOMe
KOMe
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
THF
dioxane
DMA
DMA
DMA
DMA
DMA
57
66
94
76
72
99
99
86
91
72
89
99
78
62
ND
26
31
61
37
33
59
49
38
35
37
28
69
0
23
22
14
28
19
7
22
34
6
3
32
5
83
ND
52
CoBr2 (10)
CoBr2 (10)
CoBr2 (10)
CoBr2 (10)
11
18
13
24
25
24
17
40
23
29
18
0
c
3
c
L1
L2
L3
4
5
6
c
L1CoBr2 (10)
L1CoBr2 (10)
L1CoBr2 (10)
L1CoBr2 (10)
L1CoBr2 (10)
L1CoBr2 (5)
L1CoBr2 (15)
L1CoBr2 (0)
L1CoBr2 (10)
L1CoBr2 (10)
d
7
8
9
10
11
12
13
e
14
11
5
ND
9
f
15
a
b
c
Yields and conversions measured by UPLC using 1,3,5-tri-tert-butylbenzene as an internal standard. 99.99% purity. For L1 and L2, the racemic
d
e
trans diastereomer was used. For the isolated precatalyst, L1CoBr2, the enantiopure (R,R) ligand was used. 1.5 equiv of base was used. PhB(OH)2
was used instead of PhB(neo). PhB(pin) was used instead of PhB(neo). ND = not determined. Cbz = benzyloxycarbonyl.
f
earlier transition metals is sometimes complicated by the
aggregation of alkoxide complexes.11 New methods that
employ Earth-abundant transition metals as catalysts with
organoboron coupling partners and common, readily used
bases are attractive to extend both the scope and utility of
C(sp2)−C(sp3) coupling as well as to provide a fundamental
understanding of what types of metal complexes promote the
transformation.
PhB(neo) 1a and 4-bromo-N-Cbz-piperidine 2a. (See the
Supporting Information for complete optimization details.) 2a
was chosen as the electrophile due to the prevalence of
piperidines in biologically active molecules16 and the ability of
the [N-Cbz] group to facilitate characterization.17 Further-
more, the cyclic nature of 2a makes it particularly prone to
elimination, suggesting that the optimal conditions for this
electrophile would likely extend to other alkyl bromides.
Application of the previously reported cobalt precatalysts
(Scheme 1B) for C(sp2)−C(sp2) coupling did not provide
synthetically useful amounts of the desired 4-aryl piperidine 3a
(Table S4); however, control experiments with cobalt(II) salts
in the absence of added ligand provided up to 31% yield of 3a
(Table 1). These observations raised concerns about trace
metal impurities; however, ultrapure (99.99%) CoCl2
performed similarly to CoBr2 (entries 1 and 2), and ICP-MS
analysis of each component of the reaction mixture established
that no other metal was present above 10 ppm (Tables S5 and
S7).
With the demonstration that cobalt was effective for
C(sp2)−C(sp3) coupling, a library of ligands10c was explored
to suppress the side reactions that produce 2a′ and 2a″ (Figure
S1, Tables S1−S3). In addition to reducing the overall yield
and efficiency of the reaction, side products like these, which
are common in cross-coupling reactions of this type, are often
problematic for the separation of byproducts from the desired
compound. High-throughput experimentation identified trans-
N,N′-dimethylcyclohexane-1,2-diamine (DMCyDA, L1) as an
optimal ligand for cross coupling, generating 3a in 61% yield
(entry 3). The cobalt(II) complex, (DMCyDA)CoBr2, was
prepared and provided similar results; therefore, it was used in
For cobalt, few methods have been reported that utilize
neutral organoboron coupling partners, and those that are
known have been exclusively applied to biaryl synthesis
(Scheme 1B). The first was reported by our laboratory in
2016 and relied on the well-defined cobalt(I) pincer complex,
(iPrPNP)CoCl, as a precatalyst for the coupling of a limited
selection of heteroaryl pinacol boronate esters and aryl
triflates.12 Subsequently, Duong and coworkers reported the
coupling of a broader range of aryl neopentyl glycol boronate
esters and (hetero)aryl halides using a terpyridine ligand
(PhTpy) and CoCl2 as a precatalyst mixture.13a Bedford has
also reported N-heterocyclic carbene-supported cobalt cata-
lysts for the coupling of alkyl-lithium-activated aryl boronic
esters with aryl chlorides and bromides.13b As interest grows in
molecules with increased C(sp3) content, specifically for
applications in medicinal chemistry14 and organic synthesis,15
so does motivation for new C(sp2)−C(sp3) cross coupling
methods. Here we describe the discovery of a diamine-ligated
cobalt precatalyst for the C(sp2)−C(sp3) Suzuki−Miyaura
coupling of arylboronic ester nucleophiles and alkyl bromide
electrophiles.
The discovery of a cobalt-catalyzed C(sp2)−C(sp3) Suzuki−
Miyaura reaction began with an investigation of the coupling of
B
https://dx.doi.org/10.1021/acs.orglett.0c02934
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 2. Scope of Cobalt-Catalyzed C(sp2)−C(sp3)
subsequent experiments for operational simplicity and
consistency (entry 6). Modest modifications to L1 such as
replacing the hydrogen on each nitrogen with an N-methyl
group (TMCyDA, L2)importantly, a ligand that has been
successfully used in previously reported, cobalt-catalyzed cross-
c
Suzuki−Miyaura Cross Coupling
18
coupling methods or the removal of the cyclohexane
backbone (DMEDA, L3) resulted in diminished yields of 37
and 33%, respectively (entries 4 and 5). Because the yields for
reactions with L2 and L3 are comparable to the yield for CoBr2
alone (31%, entry 2), inefficient complexation may be
responsible for the low yields; however, other effects might
also be operative.
With a suitable ligand identified, additional reaction
parameters were investigated. Relatively strong alkoxide bases
were required to promote cross coupling (entries 7 and 8), as
weaker phenoxide or silanolate derivatives resulted in
elimination with the former and overall poor conversion with
the latter (Table S8). The stoichiometry of the base also
proved important, as increasing the equivalents of KOMe from
1.25 to 1.5 had a deleterious effect on the formation of 3a with
increased elimination (entry 7).
Optimal cross coupling was observed with a slight excess of
aryl boron reagent 1a (1.5 equiv) relative to KOMe (1.25
equiv). This likely reduces the amount of base in solution,
thereby minimizing side products. An evaluation of common
solvents established DMA as optimal (entry 6), likely a result
of its high polarity that solubilizes all of the reaction
components. Ethereal solvents are widely used in other
cobalt-catalyzed cross coupling reactions;10c however, C−Br
reduction 2a′ was a significant side product in both THF and
1,4-dioxane, with 2a′ being the major product in THF (entries
9 and 10). Increasing the amount of the cobalt precursor to 15
mol % resulted in a modest improvement in yield (entries 11
and 12) and no coupling product was observed in the absence
of cobalt (entry 13). Finally, PhB(OH)2 and PhB(Pin), more
commonly encountered aryl boron reagents, afforded only
small amounts of 3a (entries 14 and 15), demonstrating the
unique efficacy of ArB(neo) reagents for transmetalation with
cobalt.
a
1
Yield determined by H NMR spectroscopy using mesitylene as an
b
internal standard. Diastereomeric ratio (dr) of 4:1 measured by
crude H NMR spectroscopy; major diastereomer shown. Yield of
isolated product shown unless otherwise stated.
c
1
With the optimized conditions established, the scope of the
cobalt-catalyzed cross coupling with various nucleophiles 1 and
electrophiles 2 was explored (Scheme 2). Reactivity trends
were determined for both 1 and 2 while keeping the other
coupling partner constant. Coupling products 3b−g derived
from a number of sterically and electronically differentiated
aryl B(neo) reagents were prepared. Specifically, sterically
demanding 2-methylphenyl 3b and 1-naphthyl 3c aromatic
rings were tolerated, along with alkoxy- (3g), phenoxy- (3d),
and trifluoromethyl-substituted (3f) arenes. Branched alkyl
electrophiles were effective partners, providing 3h−j in up to
73% yield. A set of electrophiles of constant chain length
between the site of C−C bond formation and a synthetically
versatile functional group provided products with an ester
(3k), a protected alcohol (3l), and a protected amine (3m),
each in good yield. The scope of this method was expanded to
include diversely functionalized coupling partners into the final
Suzuki products. Highlights include nucleophile- (3q) and
electrophile- (3p and 3s) derived heterocycles, adamantyl-19
(3o) and oxetane-20 (3p) based bioisosteres, and compounds
with functional groups that can be directly used for (−Ac 3n,
−CN 3o, and 3r), or deprotected prior to (−OTBS 3r and
−NBoc 3s), further synthetic manipulation.
The discovery of an effective C(sp2)−C(sp3) cross-coupling
method that is compatible with some common organic
functional groups inspired studies into the mechanism of the
reaction. Observation of the reduction product 2a′, derived
from the electrophile, suggested the intermediacy of radicals
that likely undergo competing H-atom abstraction. The
intermediacy of carbon-centered radicals is well established
for cross-coupling reactions using first-row transition-metal
catalysts including cobalt.10c Such intermediates are often
derived from organohalide halogen atom abstraction or single
electron transfer to some other type of activated C−X bond by
a reduced metal intermediate. A series of radical trap
experiments were performed to determine if radical inter-
mediates are formed in the present system. Cobalt-catalyzed
cross coupling of 4 with 6-bromo-1-hexene 5, a well-
established radical clock,21 produced a 7:1 mixture of cyclized
6a to linear 6b coupling products in 74% overall yield (Scheme
3A). This supports a pathway where the rate of direct radical
cross coupling to give linear product 6b is approximately the
same order of magnitude as the rate of initial radical cyclization
that occurs prior to C−C bond formation for cyclized product
6a.22 Intramolecular migratory insertion of the tethered alkene
of the Co-alkyl intermediate that occurs prior to reductive
C
https://dx.doi.org/10.1021/acs.orglett.0c02934
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 3. Experimental Support for Electrophile-Derived
Radical Intermediates in Cobalt-Catalyzed C(sp2)−C(sp3)
Suzuki−Miyaura Cross Coupling
Scheme 4. Reactivity and Selectivity of Aryl Borates in
Cobalt-Catalyzed Cross Coupling
a
Trace coupling product 3e detected by GC-MS. Yields of 3h and 10
determined by 1H NMR spectroscopy using mesitylene as an internal
standard.
a
Yield determined by GC-FID using dodecane as an internal
b
standard. Yield determined by 1H NMR spectroscopy using
1.25, then the preference for 3h decreased to 34% yield versus
20% for 10. Collectively, these experiments suggest that
coupling is favored with a more Lewis-acidic boron center.
In summary, a versatile cobalt-catalyzed C(sp2)−C(sp3)
Suzuki−Miyaura cross-coupling reaction has been developed.
While cobalt salts promoted the reaction, the introduction of
the diamine ligand DMCyDA, L1, significantly improved
selectivity for cross-coupling over side reactions. A substrate
scope compatible with common organic functional groups was
discovered. Radical clocks and trapping experiments support
the intermediacy of electrophile-derived radicals, and aryl
borates were shown to be competent nucleophilic coupling
partners. Future studies will focus on the development of new
catalysts with improved performance and will be coupled to
efforts to gain deeper insight into the mechanism of the
transformation.
mesitylene as an internal standard.
elimination could also account for the formation of 6a. To
distinguish these possibilities, an additional experiment was
conducted with 1,1-diphenylethylene,23 an established trap due
to the formation of a stabilized radical.24,25
Conducting the catalytic reaction of PhB(neo) and 1-
bromo-2-methylpropane in the presence of 1,1-diphenyl-
ethylene, addition products 7b and 7c were obtained, along
with the expected coupling product 7a, as the major
electrophile-containing products (Scheme 3B). Whereas direct
C−H abstraction by radical 7r yielded saturated product 7b,
alkene 7c constitutes the product of a formal alkyl Heck
reaction, a known pathway in cobalt catalysis.26 Taken
together, these results support the intermediacy of an
electrophile-derived radical during cobalt-catalyzed C(sp2)−
C(sp3) Suzuki−Miyaura cross coupling.
The role of borates was explored in the cobalt-catalyzed
reaction to gain insight into the nucleophile; the interaction of
KOMe with the arylboronate could generate this type of
intermediate under catalytic conditions. Duong and coworkers
have implicated borates as the reducing species for cobalt
precatalyst activation, although no direct evidence to support
these claims was reported.13 The potassium aryl borate 8a was
prepared from PhB(neo) and KOMe; 8a proved competent in
cobalt-catalyzed cross coupling, although a slightly lower yield
of 3e was obtained (Scheme 4A). With hydroxide-derived aryl
borate 8b, only trace 3e was obtained, likely as a result of
cobalt catalyst decomposition due to incompatibility with
[OH] groups.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02934.
Complete experimental procedures including general
considerations and characterization data and NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Paul J. Chirik − Department of Chemistry, Princeton University,
Princeton, New Jersey 08544, United States; orcid.org/
0000-0001-8473-2898; Email: pchirik@princeton.edu
With borates established as proficient coupling partners,
competition experiments with electronically differentiated aryl
boronates were conducted (Scheme 4B). The combination of
1.25 equiv of KOMe and 1.5 equiv each of the 4-carboxy 4-
and 4-methoxy 9-substituted aryl B(neo) reagents produced
the 4-carboxy coupling product 3h in 66% yield and the 4-
methoxy product 10 in 5% yield. Notably, if the same
conditions were used albeit with 2.5 equiv of KOMe instead of
Authors
Jacob R. Ludwig − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0001-8160-8736
Eric M. Simmons − Chemical Process Development, Bristol
Myers Squibb Company, New Brunswick, New Jersey 08903,
United States; orcid.org/0000-0002-3854-1561
D
https://dx.doi.org/10.1021/acs.orglett.0c02934
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(7) (a) Kambe, N.; Iwasaki, T.; Terao, J. Pd-Catalyzed Cross-
Coupling Reactions of Alkyl Halides. Chem. Soc. Rev. 2011, 40, 4937−
4947. (b) Campeau, L.-C.; Hazari, N. Cross-Coupling and Related
Reactions: Connecting Past Success to the Development of New
Reactions for the Future. Organometallics 2019, 38, 3−35.
Steven R. Wisniewski − Chemical Process Development, Bristol
Myers Squibb Company, New Brunswick, New Jersey 08903,
United States; orcid.org/0000-0001-6035-4394
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02934
(8) (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Advances in Transition
Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-
Organometallics as Reaction Partners. Chem. Rev. 2011, 111, 1417−
1492. (b) Luo, X.; Zhang, H.; Duan, H.; Liu, Q.; Zhu, L.; Zhang, T.;
Lei, A. Superior Effect of a π-Acceptor Ligand (Phosphine−Electron-
Deficient Olefin Ligand) in the Negishi Coupling Involving Alkylzinc
Reagents. Org. Lett. 2007, 9, 4571−4574.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.R.L. thanks the NIH for a Ruth L. Kirschstein National
Research Service Award (F32 GM137552). Sharla Wood
(BMS), Ziqing Lin (BMS), and Wei Ding (BMS) are gratefully
acknowledged for ICP-MS analysis, LC method development,
and HRMS analysis, respectively. Laura Wilson and Brandon
Kennedy of Lotus Separations are gratefully acknowledged for
the development and implementation of purification protocols
in various stages of the project. Financial support from the
National Institutes of Health (5R01GM121441) and BMS
through the Princeton Catalysis Initiative is acknowledged. We
thank Paul O. Peterson, Michael Schmidt, and Gregory
Beutner for helpful discussions.
(9) Diccianni, J. B.; Diao, T. Mechanisms of Nickel-Catalyzed Cross-
Coupling Reactions. Trends in Chemistry 2019, 1, 830−844.
(10) (a) Mako, T. L.; Byers, J. A. Recent Advances in Iron-Catalysed
Cross Coupling Reactions and Their Mechanistic Underpinning.
Inorg. Chem. Front. 2016, 3, 766−790. (b) Sears, J. D.; Neate, P. G.
N.; Neidig, M. L. Intermediates and Mechanism in Iron-Catalyzed
Cross-Coupling. J. Am. Chem. Soc. 2018, 140, 11872−11883.
(c) Cahiez, G.; Moyeux, A. Cobalt-Catalyzed Cross-Coupling
́
Reactions. Chem. Rev. 2010, 110, 1435−1462. (d) Guerinot, A.;
Cossy, J. Cobalt-Catalyzed Cross-Couplings between Alkyl Halides
and Grignard Reagents. Acc. Chem. Res. 2020, 53, 1351−1363.
(e) Hu, X. Nickel-Catalyzed Cross Coupling of Non-Activated Alkyl
Halides: A Mechanistic Perspective. Chem. Sci. 2011, 2, 1867−1886.
(f) Tobisu, M.; Chatani, N. Nickel-Catalyzed Cross-Coupling
Reactions of Unreactive Phenolic Electrophiles via C−O Bond
Activation. Top. Curr. Chem. 2016, 374, 41. (g) Thapa, S.; Shrestha,
B.; Gurung, S. K.; Giri, R. Copper-Catalysed Cross-Coupling: An
Untapped Potential. Org. Biomol. Chem. 2015, 13, 4816−4827.
(h) Huang, W.; Wan, X.; Shen, Q. Cobalt-Catalyzed Asymmetric
Cross-Coupling Reaction of Fluorinated Secondary Benzyl Bromides
with Lithium Aryl Boronates/ZnBr2. Org. Lett. 2020, 22, 4327−4332.
(11) Crockett, M. P.; Tyrol, C. C.; Wong, A. S.; Li, B.; Byers, J. A.
Iron-Catalyzed Suzuki−Miyaura Cross-Coupling Reactions between
Alkyl Halides and Unactivated Arylboronic Esters. Org. Lett. 2018, 20,
5233−5237.
REFERENCES
■
(1) (a) Suzuki, A. Cross-Coupling Reactions Of Organoboranes: An
Easy Way To Construct C−C Bonds (Nobel Lecture). Angew. Chem.,
Int. Ed. 2011, 50, 6722−6737. (b) Miyaura, N.; Suzuki, A. Palladium-
Catalyzed Cross-Coupling Reactions of Organoboron Compounds.
Chem. Rev. 1995, 95, 2457−2483. (c) Suzuki, A. Carbon−Carbon
Bonding Made Easy. Chem. Commun. 2005, 4759−4763. (d) Lennox,
A. J. J.; Lloyd-Jones, G. C. Transmetalation in the Suzuki−Miyaura
Coupling: The Fork in the Trail. Angew. Chem., Int. Ed. 2013, 52,
7362−7370.
(2) (a) Martin, R.; Buchwald, S. L. Palladium-Catalyzed Suzuki−
Miyaura Cross-Coupling Reactions Employing Dialkylbiaryl Phos-
phine Ligands. Acc. Chem. Res. 2008, 41, 1461−1473. (b) Han, F.-S.
Transition-Metal-Catalyzed Suzuki−Miyaura Cross-Coupling Reac-
tions: A Remarkable Advance from Palladium to Nickel Catalysts.
(12) Neely, J. M.; Bezdek, M. J.; Chirik, P. J. Insight into
Transmetalation Enables Cobalt-Catalyzed Suzuki−Miyaura Cross
Coupling. ACS Cent. Sci. 2016, 2, 935−942.
(13) (a) Duong, H. A.; Wu, W.; Teo, Y.-Y. Cobalt-Catalyzed Cross-
Coupling Reactions of Arylboronic Esters and Aryl Halides.
Organometallics 2017, 36, 4363−4366. (b) Asghar, S.; Tailor, S. B.;
Elorriaga, D.; Bedford, R. B. Cobalt-Catalyzed Suzuki Biaryl Coupling
of Aryl Halides. Angew. Chem., Int. Ed. 2017, 56, 16367−16370.
(14) (a) Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland:
Increasing Saturation as an Approach to Improving Clinical Success. J.
Med. Chem. 2009, 52 (21), 6752−6756. (b) Lovering, F. Escape from
Flatland 2: Complexity and Promiscuity. MedChemComm 2013, 4 (3),
515−519. (c) Dombrowski, A. W.; Gesmundo, N. J.; Aguirre, A. L.;
Sarris, K. A.; Young, J. M.; Bogdan, A. R.; Martin, M. C.; Gedeon, S.;
Wang, Y. Expanding the Medicinal Chemist Toolbox: Comparing
Seven C(sp2)-C(sp3) Cross-Coupling Methods by Library Synthesis.
ACS Med. Chem. Lett. 2020, 11, 597−604.
́
Chem. Soc. Rev. 2013, 42, 5270−5298. (c) Franzen, R.; Xu, Y. Review
on Green Chemistry − Suzuki Cross Coupling in Aqueous Media.
Can. J. Chem. 2005, 83, 266−272. (d) Maluenda, I.; Navarro, O.
Recent Developments in the Suzuki-Miyaura Reaction: 2010−2014.
̈
Molecules 2015, 20, 7528−7557. (e) Brown, D. G.; Bostrom, J.
Analysis of Past and Present Synthetic Methodologies on Medicinal
Chemistry: Where Have All the New Reactions Gone? J. Med. Chem.
2016, 59, 4443−4458. (f) Magano, J.; Dunetz, J. R. Large-Scale
Applications of Transition Metal-Catalyzed Couplings for the
Synthesis of Pharmaceuticals. Chem. Rev. 2011, 111, 2177−2250.
(3) (a) Fyfe, J. W. B.; Watson, A. J. B. Recent Developments in
Organoboron Chemistry: Old Dogs, New Tricks. Chem. 2017, 3, 31−
55. (b) Darses, S.; Genet, J.-P. Potassium Organotrifluoroborates:
New Perspectives in Organic Synthesis. Chem. Rev. 2008, 108, 288−
325. (c) Miyaura, N. Cross-Coupling Reaction of Organoboron
Compounds via Base-Assisted Transmetalation to Palladium(II)
Complexes. J. Organomet. Chem. 2002, 653, 54−57.
(15) (a) Choi, J.; Fu, G. C. Transition Metal−Catalyzed Alkyl-Alkyl
Bond Formation: Another Dimension in Cross-Coupling Chemistry.
Science 2017, 356, No. eaaf7230. (b) Fu, G. C. Transition-Metal
Catalysis of Nucleophilic Substitution Reactions: A Radical
Alternative to SN1 and SN2 Processes. ACS Cent. Sci. 2017, 3,
692−700.
(16) Goel, P.; Alam, O.; Naim, M. J.; Nawaz, F.; Iqbal, M.; Alam, M.
I. Recent Advancement of Piperidine Moiety in Treatment of Cancer-
A Review. Eur. J. Med. Chem. 2018, 157, 480−502.
(17) The N-Cbz group simultaneously provides a chromophore for
UV detection and a handle for mass spectrometry analysis that
supports compound identification by UPLC-MS.
́
(4) Cordovilla, C.; Bartolome, C.; Martínez-Ilarduya, J. M.; Espinet,
P. The Stille Reaction, 38 Years Later. ACS Catal. 2015, 5, 3040−
3053.
(5) Miyaura, N.; Yamada, K.; Suzuki, A. A New Stereospecific Cross-
Coupling by the Palladium-Catalyzed Reaction of 1-Alkenylboranes
with 1-Alkenyl or 1-Alkynyl Halides. Tetrahedron Lett. 1979, 20,
3437−3440.
(6) Wang, C.-Y.; Derosa, J.; Biscoe, M. R. Configurationally Stable,
Enantioenriched Organometallic Nucleophiles in Stereospecific Pd-
Catalyzed Cross-Coupling Reactions: An Alternative Approach to
Asymmetric Synthesis. Chem. Sci. 2015, 6, 5105−5113.
(18) (a) Ohmiya, H.; Yorimitsu, H.; Oshima, K. Cobalt(Diamine)-
Catalyzed Cross-Coupling Reaction of Alkyl Halides with Arylmag-
nesium Reagents: Stereoselective Constructions of Arylated Asym-
E
https://dx.doi.org/10.1021/acs.orglett.0c02934
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
metric Carbons and Application to Total Synthesis of AH13205. J.
Am. Chem. Soc. 2006, 128, 1886−1889. (b) Czaplik, W. M.; Mayer,
M.; Jacobi von Wangelin, A. Direct Cobalt-Catalyzed Cross-Coupling
Between Aryl and Alkyl Halides. Synlett 2009, 2009, 2931−2934.
(19) Mykhailiuk, P. K. Saturated Bioisosteres of Benzene: Where to
Go Next? Org. Biomol. Chem. 2019, 17, 2839−2849.
(20) (a) Bull, J. A.; Croft, R. A.; Davis, O. A.; Doran, R.; Morgan, K.
F. Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal
Chemistry. Chem. Rev. 2016, 116, 12150−12233. (b) Bhonde, V. R.;
O’Neill, B. T.; Buchwald, S. L. An Improved System for the Aqueous
Lipshutz−Negishi Cross-Coupling of Alkyl Halides with Aryl
Electrophiles. Angew. Chem., Int. Ed. 2016, 55, 1849−1853.
(21) Griller, D.; Ingold, K. U. Free-Radical Clocks. Acc. Chem. Res.
1980, 13, 317−323.
(22) Gao, K.; Yamakawa, T.; Yoshikai, N. Cobalt-Catalyzed
Chelation-Assisted Alkylation of Arenes with Primary and Secondary
Alkyl Halides. Synthesis 2014, 46, 2024−2039.
(23) Yan, X.-B.; Li, C.-L.; Jin, W.-J.; Guo, P.; Shu, X.-Z. Reductive
Coupling of Benzyl Oxalates with Highly Functionalized Alkyl
Bromides by Nickel Catalysis. Chem. Sci. 2018, 9, 4529−4534.
(24) Sun, C.-L.; Gu, Y.-F.; Wang, B.; Shi, Z.-J. Direct Arylation of
Alkenes with Aryl Iodides/Bromides through an Organocatalytic
Radical Process. Chem. - Eur. J. 2011, 17, 10844−10847.
(25) Whereas migratory insertion is also plausible, such a pathway
seems unlikely considering the steric profile of the alkene.
(26) Affo, W.; Ohmiya, H.; Fujioka, T.; Ikeda, Y.; Nakamura, T.;
Yorimitsu, H.; Oshima, K.; Imamura, Y.; Mizuta, T.; Miyoshi, K.
Cobalt-Catalyzed Trimethylsilylmethylmagnesium-Promoted Radical
Alkenylation of Alkyl Halides: A Complement to the Heck Reaction.
J. Am. Chem. Soc. 2006, 128, 8068−8077.
F
https://dx.doi.org/10.1021/acs.orglett.0c02934
Org. Lett. XXXX, XXX, XXX−XXX