A Pyridine–Pyridine Cross-Coupling Reaction via Dearomatized Radical Intermediates

Article abstract of DOI:10.1002/anie.201906267

A pyridine–pyridine coupling reaction has been developed between pyridyl phosphonium salts and cyanopyridines using B₂pin₂ as an electron-transfer reagent. Complete regio- and cross-selectivity are observed when forming a range of valuable 2,4′-bipyridines. Phosphonium salts were found to be the only viable radical precursors in this process, and mechanistic studies indicate that the process does not proceed through a Minisci-type coupling involving a pyridyl radical. Instead, a radical–radical coupling process between a boryl phosphonium pyridyl radical and a boryl-stabilized cyanopyridine radical explains the C?C bond-forming step.

Full text of DOI:10.1002/anie.201906267

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: A Pyridine-Pyridine Cross-Coupling Reaction via Dearomatized
Radical Intermediates.
Authors: John Luke Koniarczyk, Jacob W Greenwood, Juan Vicente
Alegre-Requena, Robert S Paton, and Andrew McNally
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906267
Angew. Chem. 10.1002/ange.201906267
Link to VoR: http://dx.doi.org/10.1002/anie.201906267
http://dx.doi.org/10.1002/ange.201906267

10.1002/anie.201906267
Angewandte Chemie International Edition
COMMUNICATION
A Pyridine-Pyridine Cross-Coupling Reaction via Dearomatized
Radical Intermediates.
‡§
J. Luke Koniarczyk+‡ , Jacob W. Greenwood+‡ , Juan V. Alegre-Requena‡ , Robert S. Paton
*
and Andrew McNally‡*
Abstract: A pyridine-pyridine coupling reaction has been developed
pathway. First, pyridyl radicals and the p-system of an
acceptor pyridine are electronically mismatched making
C–C bond formation kinetically prohibitive (Scheme 1C).
between pyridyl phosphonium salts and cyanopyridines using B2pin2
as an electron-transfer reagent. Complete regio- and cross-selectivity
are observed when forming a range of valuable 2,4’-bipyridines.
Phosphonium salts were found to be the only viable radical precursors
in this process, and mechanistic studies indicate that the process
does not proceed via Minisci-type coupling involving a pyridyl radical.
A – Minisci Reaction to Form Carbon-Carbon Bonds
direct C—H bond functionalization
R
amenable to various radical species
commonly used by medicinal chemists
Pyridyl
R
N
N
Instead,
a radical-radical coupling process between a boryl
phosphonium pyridyl radical and a boryl-stabilized cyanopyridine
radical explains the C–C bond-forming step.
Radical Coupling Partners
O
N
O
F
F
F
R
pyridine-pyridine
Minisci reactions are valuable processes for coupling
carbon-bearing groups to azaarenes and are characterized
by a mechanistic platform where carbon-centered radicals
add to a heteroaromatic p-system.[1] Diverse sets of
carbon-centered radicals and azaarene C–H precursors can
Minisci
Acyl
unknown
Alkyl
Aryl
Trifluoromethyl
B – This Work: Regioselective Pyridine-Pyridine Cross-Coupling
CN
N
PPh3
CN
OTf
R1
R2
B2pin2, NEt3
R1
be used interchangeably as coupling partners, including
R2
[1d]
room temperature
N
structurally complex variants (Scheme 1A).
Recent
N
N
advances, such as photoredox processes and new radical
precursors, have further improved the versatility of these
reactions, and they have been widely adopted by medicinal
chemists.[2-4] Within this reaction class, pyridine arylation
reactions have been demonstrated using a variety of aryl
radical precursors. However, no examples of cross-
coupling between two pyridines have been reported using
this manifold. The resulting bipyridines are common
motifs in pharmaceuticals and can be challenging to
prepare via metal-catalyzed cross-couplings.[5,6] We herein
report that pyridyl phosphonium salts selectively couple
with cyanopyridines using B2pin2 to facilitate electron
transfer (Scheme 1B). Bipyridines form with complete
control of regioselectivity and mechanistic studies reveal
an alternative coupling step to typical Minisci processes
involving dearomatized radical intermediates.
C – Challenges for Pyridine-Pyridine Minisci and Radical-Radical Couplings
Unproductive Reaction
Productive Reaction
NC
N
N
Bpin
N
N
X
Bpin
PPh3
Scheme 1. Limitations of Minisci reactions for pyridine-pyridine coupling and a
boron mediated method proceeding radical-radical coupling.
Brønsted acid activation of pyridines is common in
Minisci reactions and forming pyridinium ions could
further exacerbate the electronic incompatibility between
donor and acceptor heterocycles. Second, achieving cross-
selectivity between two different pyridines is challenging,
as pyridyl radicals can conceivably react at comparable
rates with their radical precursors and coupling partners.
This study reveals an alternative mechanistic platform
where the phosphonium group is not expelled to form a
pyridyl radical and, instead, bond-formation occurs
through a radical-radical coupling process involving a
boryl phosphonium radical and a boryl stabilized
cyanopyridine radical (Scheme 1C).
Two factors can account for pyridine-pyridine coupling
being unfavorable through a Minisci-type reaction
[*]
‡J. Luke. Koniaczyk, J. W. Greenwood, Dr. Juan V. Alegre-Requena,
Prof, Robert S. Paton and Prof. A. McNally
Department of Chemistry, Colorado State University
Fort Collins, Colorado, 80523 (USA).
E-mail: andy.mcnally@colostate.edu
Robert.Paton@colostate.edu
Our laboratory has shown that pyridines can be
converted into phosphonium salts in a 4-selective process
and participate in a range of subsequent transformations
proceeding through two-electron pathways.[7,8] We
questioned whether these reagents were also amenable to
open-shell pathways via single-electron reduction to
Homepage: mcnallygroup.org, www.patonlab.com
§Chemistry Research Laboratory, University of Oxford
Mansfield Road, Oxford, OX1 3TA (UK).
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201906267
Angewandte Chemie International Edition
COMMUNICATION
pyridyl radicals and hypothesized that a 4-position
pyridine borylation was feasible. Two reports from Li and
Jiao postulated that a persistent boryl radical forms from
4-substituted pyridines, such as cyano-derivatives (2a),
and B2pin2.[9] We speculated that reducing pyridyl
reaction time to 36 hours with product 4a then obtained in
excellent yield. No reaction occurred without including
B2pin2 and omitting NEt3 from the reaction decreased the
yield to 26% (see the Supporting Information for full
details). Next, other common precursors to carbon
centered radicals were examined (Scheme 2B). Under
optimized conditions, 2-phenylpyridines substituted with
halides, diazoniums, triflates, and pyridiniums were all
unsuccessful in forming 4a. Notably, 4-iodo-2-
A − Discovery and Optimization of a Pyridine-Pyridine Coupling Reaction
CN
PPh3
CN
Bpin
OTf
Photoredox
Catalysis
Ph
N
iPr2NEt, B2pin2
N
N
Ph
N
N
Ph
Table 2. Scope of Phosphonium Radical Precursors[a]
CH2Cl2
1a
2a
3
4a (unexpected)
CN
Results
Conditions[a]
Via
PPh3
CN
OTf
R
3
4a
CN
B2pin2, NEt3
R
N
h!, Ir(ppy)3
0%
0%
26%
N
1,2-dichloroethane
rt, 36 h
N
N
h!
12%
14%
No Photocatalyst
1
2a
4
N
Ph
N
Pyridyl
No Light
Pyridine
2,4’-Bipyridine
0%
1a’
2a’
Phosphonium Salt
Bpin
or Photocatalyst
CN
CN
B2pin2, NEt3
1,2-dichloroethane (0.2M)
36 hours, rt
Initial hypothesis:
Single-electron reduction of 1a
Minisci-type coupling of 1a’ with 2a’
Optimization:[b]
4b, X = OMe, 75%
4c, X = Bpin, 70%
4d, X = Cl, 51%
4e, X = I, 62%
X
4a, 97%
Me
N
N
B − Application of Other Radical Precursors
N
N
N
N
py
N
I
Br
N
N2
OTf
N
4f, 82%
OTf
Cl
CN
CN
CN
OMe
Cl
N
Ph
Ph
N
Ph
Ph
Ph
Cl
0%, 0%[c]
0%
0%[d]
0%
0%
N
N
N
N
N
4g, 30%
4h, 49%
4i, 34%
Scheme 2. (A) Attempted 4-borylation and unexpected bipyridine formation.
Yileds calculated by 1H NMR analysis [a] Initial reaction conditions: Ir(ppy)3 (1
mol %), iPr2EtN (2.5 equiv), 4-cyanopyridine (2.0 equiv), B2pin2 (1.0 equiv),
CH2Cl2 (0.1 M), 34-W Kessil blue LED, rt, 8 h. [b] 1a (1.0 equiv), 2 (2.0 equiv),
B2pin2 (1.0 equiv), NEt3 (1.25 equiv). (B) Alternative radical precursors: 1.0
equiv used in place of 1a under optimized conditions. py = pyridine. [c] Reaction
conditions: Ir(ppy)3 (1 mol %), iodopyridine (1.0 equiv), 2 (2.0 equiv), B2pin2 (1.0
equiv), NEt3 (1.25 equiv), 1,2-dichloroethane (0.2 M), rt, 36 h. [d] Diazo
compound decomposed under the reaction conditions.
CN
CN
N
F
Me
O
N
Ph
N
N
Ph
4k, 62%
4j, 65%
CN
N
CN
N
EtO2C
N
S
red
phosphonium salt 1a (Ep/2 = -1.51 V vs SCE) with
O
Ir(ppy)3 as a photocatalyst and iPr2EtN as a sacrificial
reductant would form a pyridyl radical (1a’) that could
react with the putative boryl radical and result in borylated
product 3 (Scheme 2). However, no borylation products
were observed and, instead, 2,4'-bipyridine 4a formed with
exclusive regioselectivity. Around the time of this finding,
further investigations revised the identity of the 4-
cyanopyridine-B2pin2 adduct to a delocalized radical in the
pyridine ring that may be capable of reducing 1a to pyridyl
radical 1a’.[9b,10] At this juncture, we hypothesized that a
Minisci-type coupling between 1a’ and pyridinium 2a’
had occurred and was specific to this reaction system (vide
infra).
N
N
4l, 65%
4m, 71%
F3C
CN
N
CN
N
Cl
Cl
O
N
H
N
N
MeO2S
4o, 44%[b]
4n, 82%
CF3
OAc
N
CN
N
CN
N
N
N
Me
AcO
Following the discovery, we set out to optimize the
coupling of 2-phenylpyridine phosphonium salt 1a and 4-
cyanopyridine 2a (Scheme 2A). The most significant
improvements came from changing the solvent to
dichloroethane, using NEt3 as a base and extending the
4q, 35%
4p, 75%
[a] Isolated yields of single regioisomers. Conditions: phosphonium 1 (1.0
equiv), 2a (2.0 equiv), B2pin2 (1.0 equiv), NEt3 (1.25 equiv), 1,2-dichloroethane
(0.2 M), rt, 36 h. [b] Yield determined by 1H NMR analysis.
This article is protected by copyright. All rights reserved.

10.1002/anie.201906267
Angewandte Chemie International Edition
COMMUNICATION
Table 3. Scope of Pyridine Acceptors[a]
phenylpyridine, which is known to generate pyridyl
radicals under photoredox conditions, was also
unsuccessful and further highlights the unique capacity of
pyridyl phosphonium salts to serve as coupling partners.[11]
PPh3
OTf
R
B2pin2, NEt3
Ph
R
N
1,2-dichloroethane
rt, 36 h
N
Ph
N
Next, the scope of pyridyl phosphonium salts was
examined (Table 2). A range of 2-aryl salts, including
functional groups amenable to further transformations, as
well as a 2-methyl salt, function effectively (4b-4f). A
chlorine atom is tolerated at the 2-position albeit in lower
yield (4g). Pyridines substituted at the 3-position are
compatible and coupled products are obtained in moderate
yield (4h & 4i). Fluorine atoms are accommodated as in
4j, derived from a 2,3-disubstituted salt. Azetidine rings
and heteroaromatics can also proceed through the reaction
without interference (4k & 4l). Finally, pharmaceuticals
and drug analogues were tested to demonstrate that
complex structures were applicable to the protocol;
examples 4m-4q show that a range of 2,4’-bipyridine
derivatives, with a range of functional groups, can be
formed with precise control of regioselectivity.
N
1a
Pyridyl
2
4
Pyridine
2,4’-Bipyridine
Phosphonium Salt
CN
CN
CN
Me
TMS
N
N
N
N
N
N
4r, 65%
4s, 55%
4t, 35%
Ph
Ph
Ph
CO2Me
CN
CN
OTBS
Me
CN
Me
Ph
N
N
N
N
N
N
4u, 71%
4v, 39%
4w, 48%[b]
Ph
Ph
Ph
CN
OCF3
S
CN
CN
CN
N
We then turned our attention to the scope of acceptor
pyridines and began with substituted cyanopyridines
(Table 3). Simple alkyl and silyl groups at the 3-position
are accommodated in products 4r-4t; single regioisomers,
apart from one example, were obtained despite the
possibility of C–C bond formation at other sites. Esters and
protected alcohols were also tolerated under the reaction
conditions, and substituted aromatic groups enable rapid
assembly of tri(hetero)aryl products (4u-4z). Tripyridyl
product 4aa demonstrates that site-selective coupling
occurs on cyano- over alkyl-substituted pyridines. A
substituent adjacent to the site of C–C bond formation is
tolerated, although steric effects appear to decrease yields
significantly (4ab). Despite assuming that a cyano group
is important for radical stabilization, a phosphonate ester
could also serve this role (4ac). Aryl groups at the 4-
position were not effective, however, an ester formed the
coupled product in low yields.[12]
N
N
N
N
N
4x, 53%
4y, 77%
4z, 73%
Ph
Ph
Ph
O
P
Me
CN
CN
EtO
OEt
N
Me
Me
N
N
N
N
N
N
4aa, 52%
4ab, 18%
4ac, 28%
Ph
Ph
Ph
EtO2C
N
F3C
CN
N
CN
S
O
N
N
N
Cl
4ad, 28%
4ae, 85%
CF3
[a] Isolated yields of single regioisomers. Conditions: phosphonium 1a (1.0
equiv), 2 (2.0 equiv), B2pin2 (1.0 equiv), NEt3 (1.25 equiv), 1,2-dichloroethane
(0.2 M), rt, 36 h. [b] 17:1 regiomeric ratio.
Inductively withdrawing groups, such as halides and
trifluoromethyl groups, at the 4-position were not effective
as coupling partners and support a pyridyl radical ion
intermediate as part of the reaction mechanism (vide
infra). Finally, complex phosphonium salts and acceptor
pyridines were shown as efficient coupling partners (4ad
& 4ae).
This article is protected by copyright. All rights reserved.

10.1002/anie.201906267
Angewandte Chemie International Edition
COMMUNICATION
A − Reaction Mechanism: Pyridyl Phosphonium Reduction
PPh3
We then performed a series of experiments to investigate
the mechanism of the reaction. First, a radical trapping
experiment was designed to provide evidence of an
intermediate pyridyl radical (Scheme 3A). When allyloxy-
substituted salt 5 was subjected to the reaction conditions
cyclized product 6 was not observed, and significant
amounts of bipyridine 4af formed. As 5-exo-trig radical
cyclizations in similar systems proceed with fast kinetics
(rate constants: 7.87 x 107 to 9.6 x 109 s-1),[13] this result
suggested that an alternative mechanism was operative.
Second, we considered that a putative pyridyl radical could
be reduced again to form a pyridyl anion, and that bond-
formation occurs via a two-electron pathway.
OTf
CN
CN
CN
1b
N
Homolytic
Cleavage
2a’’
ΔGrel
SET
Outer Sphere
N
N
N
Bpin
pinB
Bpin
= 0 kcal/mol
1
Int-1
CN
N
PPh3
Ph3P
OTf
CN
PPh3
OTf
N
N
O
B
O
SET
N
Inner
OTf
N
N
Sphere
Bpin
NC
2a
1b’’ Bpin
Int-2
2a’
1b’
ΔGrel = 1.6 kcal/mol
ΔGrel = 10.2 kcal/mol
ΔGrel = 31.9 kcal/mol
B − Reaction Mechanism: C–C Bond Formation via Radical-Radical Coupling
A − Radical Trapping Experiment
O
NC
NC
O
B
CN
PPh3
N
N
OTf
OTf
OTf
CN
PPh3
CN
N
N
O
PPh3
O
O
B2pin2, NEt3
N
N
1,2-dichloroethane
rt, 36 h
N
Me
N
Me
Me
N
N
Bpin
Bpin
B
TS-1
ΔGrel = 24.9 kcal/mol
CN
5
6 (not detected)
4af – 32%
O
2a’’
1b’’
O
ΔGrel = 0 kcal/mol
B − Anion Trapping Experiment
CN
CN
NC
O
O
Me
HO
OTf
Ph3P
N
OTf
PPh3
Me CN
Me
Air
–PPh3
NEt3
O
N
N
N
O
O
B2pin2, NEt3
H
H
N
Bpin
N
N
Bpin
PinB
1,2-dichloroethane
rt, 36 h
Me
N
N
Me
Me
N
N
Et3N Bpin
4
12
11
7
8 (not detected)
4ag – 39%
OTf
C − Alternative Mechanism to form the Radical Coupling Pair
Phosphonium
Radical Anion?
C
Cyclization Disfavored by Steric Interactions with +PPh3
O
CN
N
PPh3
CN
PPh3
OTf
OTf
CN
PPh3
Ph
Ph
Ph
Ph
Ph
OTf
Ph
Ph
Ph
Ph
B2pin2
P
P
P
Me
N
R
O
O
N
N
R
N
N
R
R
Bpin
pinB
Bpin
Bpin
N
Me
N
Me
N
2a
1b, R = H
Int-3, R = H, ΔGrel = 24.9 kcal/mol R = H, ΔGrel = –15.9 kcal/mol
Int-4, R = Me, ΔGrel = 25.9 kcal/mol R = Me, ΔGrel = –11.8 kcal/mol
1c, R = Me
D − Additive Study
CN
N
(Int-1, ΔGrel = 23.7 kcal/mol
2 x 2a’’, ΔGrel = –17.5 kcal/mol)
OTf
CN
X
PPh3
B2pin2, NEt3
Scheme 4. (A) SET reduction of pyridyl phosphonium ions; (B) Radical-radical
coupling between pyridyl boryl radical coupling partners; (C) Homolysis of a
heterodiboron complex to form the radical coupling pair. DFT computed Gibbs
energies were obtained for ground and transition state structures at the SMD-
ωB97X-D/Def2-QZVPP//ωB97X-D/def2-SVP level of theory.[14]
Ph
1,2-dichloroethane
rt, 36 h
N
Ph
N
N
Ph
N
9
X = H
1a
2a
4a
10 X = D
H
H
4a – 60%[a]
1a – 9%[a]
9 – 0%[a]
CO2Et
EtO2C
Me
4a – 0%[a]
9 – 7%[a]
10 – 72%[a]
D2O
via a pyridyl phosphonium radical anion (or a related
derivative) and the large phosphonium ion precludes
cyclization in both of the resonance forms shown in
Scheme 3C. Scheme 3D shows that pyridine-pyridine
coupling is only marginally perturbed by including a
Hantzsch ester and C–H abstraction had not occurred to
form 9. In the presence of D2O, phosphonium salt 1a is
largely converted into 9 and 10 (9:91) and no coupled
product was observed. Although we obtained useful
information from the experiments in Figure 1, the unusual
nature of the putative phosphonium pyridyl radical anion,
as well as the exact role of B2pin2 in the reaction, prompted
us to investigate the mechanism computationally.
N
H
Me
Scheme 3. (A) Pyridyl radical trap experiment; (B) Pyridyl anion trap
experiment; (C) Potential for radical ylides as intermediates and sterically
disfavoured cyclizations. (D) Effect of additives on the coupling process. [a]
Yield calculated by 1H NMR analysis of the crude reaction mixture using 1,3,5-
trimethoxybenzene as an internal standard.
However, ketone 7 showed no evidence of cyclization to
tertiary alcohol 8 and bipyridine 4af was again observed
as the major product (Scheme 3B). At this point, we
considered that C–C bond-formation could be occurring
This article is protected by copyright. All rights reserved.

10.1002/anie.201906267
Angewandte Chemie International Edition
COMMUNICATION
This work was supported from startup funds from Colorado State
University and partial support from the National Science
Foundation under Grant No. (1753087). We would like to
acknowledge Romeo Portillo from the Shores laboratory for his
valuable assitance running CV experiments. We acknoweldge the
RMACC Summit supercomputer, supported by the NSF (ACI-
1532235 and ACI1532236) and XSEDE through allocation
TGCHE180056.
Scheme 4 shows a proposed mechanism supported by
computational and spectroscopic studies. First, we
questioned how single-electron reduction of a pyridyl
phosphonium salt occurs. Li and Jiao proposed that two
equivalents of pyridine 2a react with B2pin2 to form Int-1,
and subsequent homolytic cleavage of the B–B bond
results in boryl radical adduct 2a’’ (Scheme 4A).[9,10] An
outer sphere single-electron transfer from 2a’’ to
phosphonium salt 1b would form phosphonium radical
anion 1b’ and 2a’. However, the process is endergonic by
ca. 30 kcal/mol and, therefore, thermodynamically
unfavorable. Alternatively, an inner sphere transfer via
bridged boronate complex Int-2 is feasible; the overall
process is endergonic (ca. 10 kcal/mol) due to the entropic
cost of forming Int-2, but subsequent electron transfer is
spontaneous.[9a,10c,10d] The cyanopyridine can then
disengage from the boron center and release boryl pyridyl
radical 1b’’ where most of the spin density is located at the
2- and 4-positions. Second, to determine the pathway for
C–C bond-formation, we modeled several combinations of
1b’’ with 2a and 2a’ via one and two-electron processes,
but none of these pathways were energetically feasible
(See SI for details). Instead, the most favorable pathway is
a radical-radical coupling of 1b’’ and boryl cyanopyridine
radical 2a’’to form adduct 11 (Scheme 4B). The process is
rendered irreversible by losing PPh3, and deborylation
likely occurs using NEt3 to form dearomatized
intermediate 12.[15] Opening the reaction vessel at the end
of the reaction results in a rapid color change, indicating
oxidation to bipyridine 4. We also considered that radical
pair 1b’’ and 2a’’ could arise directly from homolytic
cleavage of heterodiboron complexes (Scheme 4C). For
phosphonium salts without 2-position substitution,
forming Int-3 and subsequent generation of the radical
pair is energetically comparable to homodiboron complex
Int-1. Similarly, when a 2-substituent is present,
representing the majority of substrates in this study,
forming diboron complex Int-4 is thermodynamically
comparable.[16] In light of these results, we propose that
multiple pathways could result in the radical pair before
C–C bond-formation. Further details of the reaction
mechanism are described in the Supporting Information.
Keywords: Bipyridines • radical anions • phosphonium salts •
radical coupling • pyridine Minisci
[1]
[2]
For selected reviews on the Minisci reaction, see: a) F. Minisci, E.
Vismara, F. Fontana, Heterocycles 1989, 28, 489–519. b) F. Minisci, F.
Fontana, E. Vismara, J. Heterocycl. Chem. 1990, 27, 79–96. c) D. C.
Harrowven, B. J. Sutton, Prog. Heterocycl. Chem. 2005, 16, 27–53. d)
M. A. J. Duncton, MedChemComm 2011, 2, 1135.
a) J. Jin, D. W. C. MacMillan, Nature 2015, 525, 87–90. b) J. Jin, D. W.
C. MacMillan, Angew. Chem. Int. Ed. 2015, 54, 1565–1569; Angew.
Chem. 2015,127, 1585 –1589. c) D. A. DiRocco, K. Dykstra, S. Krska,
P. Vachal, D. V. Conway, M. Tudge, Angew. Chem. Int. Ed. 2014, 126,
4902–4906; Angew. Chem. 2014,126, 4902–4906 d) C. A. Huff, C. R.
D. Cohen, K. D. Dykstra, E. Streckfuss, D. A. DiRocco, S. W. Krska, J.
Org. Chem. 2016, 81, 6980–6987.
[3]
a) I. B. Seiple, S. Su, R. A. Rodriguez, R. Gianatassio, Y. Fujiwara, A. L.
Sobel, P. S. Baran, J. Am. Chem. Soc. 2010, 132, 13194–13196. b) J. K.
Matsui, D. N. Primer, G. A. Molander, Chem. Sci. 2017, 8, 3512–3522.
c) M. Presset, N. Fleury-Brégeot, D. Oehlrich, F. Rombouts, G. A.
Molander, J. Org. Chem. 2013, 78, 4615–4619.
[4]
[5]
T. Kino, Y. Nagase, Y. Ohtsuka, K. Yamamoto, D. Uraguchi, K. Tokuhisa,
T. Yamakawa, J. Fluor. Chem. 2010, 131, 98–105.
a) R. Capdeville, E. Buchdunger, J. Zimmermann A. Matter, Drug Discov.
2002, 1, 493–502. b) A. J. Roecker, S. P. Mercer, J. D. Schreier, C. D.
Cox, M. E. Fraley, J. T. Steen, W. Lemaire, J. G. Bruno, C. M. Harrell, S.
L. Garson, A. L. Gotter, S. V. Fox, J. Stevens, P. L. Tannenbaum, T.
Prueksaritanont, T. D. Cabalu, D. Cui, J. Stellabott, G. D. Hartman, S. D.
Young, C. J. Winrow, J. J. Renger, P. J. Coleman, ChemMedChem 2014,
9, 311–322. c) S. D. Martina, K. S. Vesta, T. L. Ripley, Ann.
Pharmacother. 2005, 39, 854–862.
[6]
a) T. Markovic, B. N. Rocke, D. C. Blakemore, V. Mascitti, M. C. Willis,
Chem. Sci. 2017, 8, 4437–4442. b) D. C. Blakemore, L. Castro, I.
Churcher, D. C. Rees, A. W. Thomas, D. M. Wilson, A. Wood, Nat. Chem.
2018, 10, 383–394. c) P. A. Cox, M. Reid, A. G. Leach, A. D. Campbell,
E. J. King, G. C. Lloyd-Jones, J. Am. Chem. Soc. 2017, 139, 13156–
13165.
[7]
[8]
a) E. Anders, F. Markus, Tetrahedron Lett. 1987, 28, 2675. b) E. Anders,
F. Markus, Chem. Ber. 1989, 122, 113–118. c) E. Anders, F. Markus,
Chem. Ber. 1989, 122, 119–122. d) M. Haase, H. Goerls, E. Anders,
Synthesis 1998, 1998, 195–200.
In conclusion, we report a pyridine-pyridine cross-
coupling reaction unique to heterocyclic phosphonium
salts. Mechanistic investigations point to a radical-radical
coupling reaction rather than a Minisci-type radical
pathway. Further study of the structure and properties of
pyridyl phosphonium radical anion derivatives are
ongoing in our laboratory.
a) R. G. Anderson, B. M. Jett, A. McNally, Tetrahedron 2017, 74, 3129–
3136. b) C. Patel, M. Mohnike, M. C. Hilton, A. McNally, Org. Lett.
2018, 20, 2607–2610. c) R. G. Anderson, B. M. Jett, A. McNally,
Angew. Chem. Int. Ed. 2018, 57, 12514-12518; Angew. Chem. 2018,
130, 12694–12698. d) M. C. Hilton, R. D. Dolewski, A. McNally, J. Am.
Chem. Soc. 2016, 138, 13806–13809. e) J. L. Koniarczyk, D. Hesk, A.
Overgard, I. W. Davies, A. McNally, J. Am. Chem. Soc. 2018, 140,
1990–1993.
Acknowledgements
This article is protected by copyright. All rights reserved.

10.1002/anie.201906267
Angewandte Chemie International Edition
COMMUNICATION
[9]
a) G. Wang, H. Zhang, J. Zhao, W. Li, J. Cao, C. Zhu, S. Li, Angew.
Chem. Int. Ed. 2016, 55, 5985–5989; Angew. Chem. 2016, 128, 6089–
6093. b) L. Zhang, L. Jiao, J. Am. Chem. Soc. 2017, 139, 607–610.
[10] a) L. Zhang, L. Jiao, Chem. Sci. 2018, 9, 2711–2722. b) J. Cao, G. Wang,
L. Gao, H, Chen, X. Liu, C. Xu, S. Li, Chem. Sci. 2019, 10, 2767–2772.;
c) J. Cao, G. Wang, L. Gao, X. Cheng, S. Li. Chem. Sci. 2018, 9, 3664–
3671 d) G. Wang, J. Cao, L. Gao, W. Chen, W. Huang, X. Cheng, S. Li,
J. Am. Chem. Soc. 2017, 139, 3904–3910.
[11] For examples see: a) R. A. Aycock, H. Wang, N. T. Jui, Chem. Sci. 2017,
8, 3121–3125. b) C. P. Seath, D. B. Vogt, Z. Xu, A. J. Boyington, N. T.
Jui, J. Am. Chem. Soc. 2018, 140, 15525–15534. c) S. Senaweera, J. D.
Weaver, J. Am. Chem. Soc. 2016, 138, 2520–2523. d) A. Singh, C. J.
Fennell, J. D. Weaver, Chem. Sci. 2016, 7, 6796–6802. e) C. Le, T. Q.
Chen, T. Liang, P. Zhang, D. W. C. MacMillan, Science 2018, 360, 1010–
1014.
[12] Bipyridine product formed in less than 10% yield based on 1H NMR
analysis when using ethyl isonicotinate as the acceptor pyridine (see
Supporting Information for details).
[13] a) J. W. Tye, Z. Weng, A. M. Johns, C. D. Incarvito, J. F. Hartwig, J. Am.
Chem. Soc. 2008, 130, 9971–9983. b) A. Annunziata, C. Galli, M.
Marinelli, T. Pau, Eur. J. Org. Chem. 2001, 7, 1323–1329. c) A. N.
Abeywickrema, A. L. J. Beckwith, J. Chem. Soc. Chem. Commun. 1986,
6, 464–465.
[14] This level of theory has been benchmarked for pyridyl phosphonium
species: M. C. Hilton, X. Zhang, B. T. Boyle, J. V. Alegre-Requena, J. R.
S. Paton, A. McNally, Science 2018, 362, 799–804. All computations
used Gaussian 16, rev B.01, Gaussian, Wallingord Inc. Further details
on computational methods employed are given in the ESI.
[15] Dearomatized intermediates are observable by in situ 1H NMR
spectroscopy and LCMS analysis of the reaction mixture. An example is
provided in the Supporting Information.
[16] We thank a reviewer for the suggestions on the reaction mechanism.
This article is protected by copyright. All rights reserved.

10.1002/anie.201906267
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
J. Luke Koniarczyk, Jacob. W.
Greenwood Dr. Juan V. Alegre-
Requena, Prof. Robert S. Paton Prof.
Andrew McNally*
Regio- and Cross-Selective Bipyridine Formation
CN
N
PPh3
CN
OTf
B2pin2
NEt3
R
R
Page No. – Page No.
N
N
N
A Pyridine-Pyridine Cross-Coupling
Reaction via Dearomatized Radical
Intermediates.
Text for Table of Contents
Radical-Radical Coupling
NC
N
Bpin
Bpin
N
PPh3
Pyridyl phosphonium salts react with cyanopyridines and B2pin2 to form 2,4-bipyridines with complete regiocontrol. Mechanistic
studies support a radical-radical coupling process between two boryl-stabilized pyridyl radical anions rather than a Minisci-type
pathway and the process is unique to pyridyl phosphonium salts.
This article is protected by copyright. All rights reserved.