A Unified Approach to Couple Aromatic Heteronucleophiles to Azines and Pharmaceuticals

Article abstract of DOI:10.1002/anie.201807322

Coupling aromatic heteronucleophiles to arenes is a common way to assemble drug-like molecules. Many methods operate via nucleophiles intercepting organometallic intermediates, via Pd-, Cu-, and Ni-catalysis, that facilitate carbon-heteroatom bond formation and a variety of protocols. We present an alternative, unified strategy where phosphonium salts can replicate the behavior of organometallic intermediates. Under a narrow set of reaction conditions, a variety of aromatic heteronucleophile classes can be coupled to pyridines and diazines that are often problematic in metal-catalyzed couplings, such as where (pseudo)halide precursors are unavailable in complex structures with multiple polar functional groups.

Full text of DOI:10.1002/anie.201807322

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: A Unified Approach to Couple Aromatic Heteronucleophiles to
Azines and Pharmaceuticals.
Authors: Ryan G Anderson, Brianna M Jett, 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.201807322
Angew. Chem. 10.1002/ange.201807322
Link to VoR: http://dx.doi.org/10.1002/anie.201807322
http://dx.doi.org/10.1002/ange.201807322

10.1002/anie.201807322
Angewandte Chemie International Edition
COMMUNICATION
A Unified Approach to Couple Aromatic Heteronucleophiles to
Azines and Pharmaceuticals.
Ryan G. Anderson, Brianna M. Jett and Andrew McNally*
Aromatic
heteronucleophiles
Abstract: Coupling aromatic heteronucleophiles to arenes is a
Exocyclic
OH
Endocyclic
common way to assemble drug-like molecules. Many methods
operate via nucleophiles intercepting organometallic intermediates,
via Pd-, Cu- and Ni-catalysis, that facilitate carbon-heteroatom bond-
formation and a variety of protocols. We present an alternative, unified
strategy where phosphonium salts can replicate the behavior of
N
SH
N
H
N
H
N
NHR
SeH
N
N
organometallic intermediates. Under
a narrow set of reaction
N
H
N
H
conditions, a variety of aromatic heteronucleophile classes can be
coupled to pyridines and diazines that are often problematic in metal-
catalyzed couplings, such as where (pseudo)halide precursors are
unavailable of in complex structures with multiple polar functional
groups.
+
Het-Hal
Het-PPh3
M =
P(V)
Pd, Ni, Cu
species
X
X
Y
Y
Ph
Ph
Aromatic heteronucleophiles can be classified as
exocyclic, and include phenols, thiophenols and anilines,
or endocyclic, such as pyrroles, indoles, imidazoles and
pyrazoles. These structures are fundamental building
blocks that are routinely coupled to other aromatic
compounds to make drug-like molecules. Coupling to
pyridines, quinolines and diazines is particularly relevant
as they are important pharmacophores and have resulted in
several marketed drugs. For example, azine–O–aryl and
azine–NR–aryl linkages are present in a large family of
kinase inhibitors and include therapeutics such as
sorafenib, gleevec and erlotinib.[1,2]
P
M
L
N
N
Ph
L
metal catalysis:
complex catalytic cycles
this work:
P-ligand coupling step
Y
Y
X
Y
N
or
N
N
using phosphonium salts:
simplified protocols
enhanced scope
complex heterocycles
Typical azine coupling stratiegies use SNAr reactions
and, most commonly, metal-catalyzed processes; in the
Scheme 1. Metal-catalyzed approaches to azines to aromatic
heteronucleophiles and a unified approach using phosphonium salts.
latter,
aromatic
heteronucleophiles
intercept
organometallic intermediates derived from oxidative
addition into heteroaryl (pseudo)halides or transmetalation
processes.[3-5] Carbon-heteroatom bond-formation occurs
by reductive elimination, but the success of these reactions
is dependent on all elementary steps of the complex
catalytic cycle. As a result, a multitude of catalytic
protocols exist varying in metal, ligand, base and other
reaction parameters. We envisioned an alternative, unified
strategy where heterocyclic phosphonium salts could serve
as equivalents to organometallic intermediates. In this
way, carbon-heteroatom bond-formation occurs by a
nucleophilic addition then phosphorus ligand-coupling
that approximates one subsection of a metal-catalysis
cycle.[6] We envisioned that this truncated mechanism
would enable multiple distinct nucleophiles to be
employed under a narrow set of reaction conditions and
simplify access to a range of coupled products.[7]
Furthermore, complex azine-containing structures can
often be problematic in metal-catalyzed processes because
of the limited availability of cross-coupling precursors and
the tendency of polar functional groups, often present in
these molecules, to interfere with catalytic processes.[8]
Herein, we show that this strategy has been successfully
executed by coupling seven classes of aromatic
heteronucleophiles to a range of pyridine and diazine
phosphonium salts.
[*]
Ryan G. Anderson, Brianna M. Jett, Prof. A. McNally
Department of Chemistry, Colorado State University
Fort Collins, Colorado, 80523 (USA).
Our laboratory has previously reported that a diverse set
of pyridines and diazines can be directly and selectively
converted into heterocyclic phosphonium salts from C–H
bond precursors.[9] The phosphonium ion then serves as a
generic functional handle and enables a range of
E-mail: andy.mcnally@colostate.edu
Homepage: mcnallygroup.org
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.201807322
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Cross-coupling of phenol to phosphonium salts: Optimization.[a], [b]
predominates (entries 7-9). While alkali decomposition of
phosphonium salts is known, the mechanism(s) of these
processes are not well resolved and are subject to ongoing
investigations in our laboratory.[12] Nevertheless, we were
confident that this optimization blueprint would also apply
to other classes of aromatic heteronucleophiles.
PPh3
OH
OPMP
H
NaH, solvent
temperature
OTf
equivs PMPOH
additive
Ph
N
N
Ph
N
Ph
1a
2a
2a’
OMe
T
[ºC]
Equiv
PMPOH
Additive
none
Yield
Yield [%][b]
2a’
Entry
Solvent
We next examined the scope of different classes of
aromatic heteronucleophiles in coupling reactions with 2-
phenylpyridine phosphonium salt 1a (Table 2). Phenol and
para-iodo phenol are tolerated in this protocol, with the C–
I bond in the latter being reactive in transition metal-
catalyzed processes (2b and 2c). However, the
withdrawing effect of halides reduces the yield of coupled
product in the reaction. Substituents in the ortho- and
meta-positions of phenols also provide coupled products
in reasonable yields (2d–2f). An advantage of this protocol
is that pKa effects can be exploited for chemoselective
reactions; the phenolic oxygen reacts preferentially in both
acetaminophen and a Boc-protected tyrosine (2g and 2h).
Thiophenol is a good nucleophile in this process, as are a
useful range of ortho-, meta- and para-substituented
derivatives (2i–2p). Coupling of hindered nucleophiles is
possible, such as the 2,6-disubstituted pattern in 2q.
Heteroaromatics, such as thiophenes, can be components
of the nucleophile (2r) and selenophenols are also
excellent coupling partners (2s). Anilines require a
modified reaction protocol; the nucleophile is
deprotonated at –78 ºC using n-BuLi, the phosphonium
salt is added and then the reaction is allowed to warm to
room temperature. Importantly, the nitrogen atom of the
aniline must be substituted; no product was obtained when
aniline was used as a nucleophile (2t) and we attribute this
result to an unwanted fragmentation reaction after the P(V)
intermediate is formed.[13] N-Methyl substituted systems
work well (2u and 2v) and an N-Bn group can serve as a
useful protecting group (2w). Indolines are also an
important class of molecules that are competent
nucleophiles (2x and 2y). Endocyclic aromatic
heteronucleophiles also proved to be well suited to the
strategy. Pyrrole formed coupled product 2z in good yield;
however, we were surprised to find that indole did not
undergo coupling (2aa). Our current hypothesis is that the
7-position C–H bond causes an unfavorable steric
interaction in the coupling transition state. We were
gratified to find that imidazoles and pyrazoles were
effective in this approach (2ab-2af) although a 1,2,4-
triazole did not result in any coupled product (not shown).
[%][b]
2a
1
2
3
4
23
THF
THF
THF
THF
1.1
1.1
1.1
1.5
0
3
87
83
59
40
23
40
40
15-crown-5
15-crown 5
36
15-crown-5 49
none 36
62
6
5
6
7
8
9
40
60
60
40
40
THF
THF
DME
1.5
1.5
1.5
15-crown-5 87
15-crown-5 76
15-crown-5 14
21
81
91
1,4-dioxane 1.5
DMF 1.5
none
1
[a] With 0.2 mmol 1a and equivs of NaH match equivs of para-methoxyphenol.
[b] Yields determined by 1H NMR analysis of the crude reactions using 1,3,5-
trimethoxybenzene as an internal standard.
subsequent bond-forming reactions.[10] Notably, the scope
of these reactions significantly expands the range of
heterocycles beyond typical functionalization reactions
such as halogenation or borylation.[11] While aliphatic
heteronucleophiles, such as alkoxides,[9a] are competent
coupling
partners,
we
found
that
aromatic
heteronucleophiles were not successful under the same
reactions conditions and highlight the challenges of using
new classes of coupling partners. As a representative case,
Table
1
shows that reacting 2-phenylpyridine
phosphonium salt 1a and sodium para-methoxyphenoxide
in THF at room temperature does not result in any of the
desired aryl-pyridyl ether product 2a (entry 1). Instead,
salt 1a partially decomposed to C–H compound 2a’.
Adding 15-crown-5 to the reaction resulted in a small
amount of the desired product 2a; raising the temperature
to 40 ºC and changing the equivalents of the nucleophile
to 1.5 increased conversion further (entries 2-4). Entry 5
shows that removing 15-crown-5 affects the reaction
profile with more C–H product formed. Conducing the
reaction at 60 ºC is the most effective protocol resulting in
in the most favorable ratio of 2a and 2a’ (entry 6). The
most significant byproducts of the reaction are
triphenylphosphine and triphenyl phosphine oxide that are
straightforward to remove by column chromatography.
The reaction performs well in DME, whereas 1,4-dioxane
is less efficient. Running the reaction in DMF resulted in
traces of the desired product 2a and C–H compound 2a’
Our attention turned to the scope of heterocyclic
phosphonium salts and, as seen in Table 2, various
aromatic heteronucleophiles can be coupled to pyridine
and diazine building blocks. It is important to note that all
phosphonium salts were prepared from C–H precursors in
a single step with complete control of regioselectivity in
the vast majority of cases (see Supporting Information for
This article is protected by copyright. All rights reserved.

10.1002/anie.201807322
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Scope of aromatic heteronucleophiles and heterocyclic phosphonium salts as coupling partners.
PPh3
YH
R'
Z
Salts 1 step from C–H
Pyridines 4-selective
OTf
R
NaH, THF
R
Y
R'
Z
X
R'
± 15-Crown-5, 0 ºC to 60 ºC
R
N
or
R'
or
N
X
N
H
Anilines: n-BuLi, THF
N
N
X
See supporting information
–78 ºC to RT
1
Y = O, S, N, Se
phenol scope
thiophenol scope
Z
HO
HO
Br
2i, Z = H, 83%
2j, Z = Cl, 73%
HS
OMe
HS
HS
HO
2b, Z = H, 70%
2k, Z = F, 78%
MeO
2d, 57%[b]
OMe
2c, Z = I, 60%
2l, Z = BPin, 69%
Z
Z
2o, 77%
2e, 52%[b]
2m, Z = OMe, 80%
2n, Z = Br, 84%
Me
HO
HO
HO
O
NHBoc
HS
OCF3
HS
Me
HS
HSe
OMe
N
H
Me
S
O
2g, 73%[b]
2f, 81%
2p, 52%
2q, 74%
2r, 69%
2s, 91%
2h, 59%
PPh3
OTf
aniline scope (n-BuLi, THF, –78 ºC to RT)
endocyclic nucleophiles
1a
Ph
N
Ph
N
N
N
H2N
MeHN
MeHN
OEt
N
H
N
H
N
H
H
2ab, 51%[c]
2ac, 25%[c]
2aa, 0%
2t, 0%
2u, 90%
2v, 81%
2z, 74%
Br
Me
H
N
H
N
Br
BnHN
N
N
N
N
H
Me
N
H
N
H
2w, 62%
2x, 68%
2y, 41%
2ad, 72%
2ae, 64%
2af, 37%
mono-substituted pyridines
disubstituted pyridines and quinolines
Me
Ph
Me
Ph
OPMP
N
SPh
N
SPh
OPMP
N
N
S
CN
CN
Ph
Ph
NC
NC
NC
F
F
N
N
N
N
N
N
2ar, 73%
2ag, 80%
2ah, 81%
2ai, 77%
2aj, 0%
2as, 63%
2at, 25%
S
Me
Ph
Ph
SPh
N
Me
SPh
N
N
Me
N
N
CN
N
OPMP
N
OMe
i-Pr
N
N
N
N
F3C
N
SPh
2au, 77%[b]
2av, 69%
2aw, 68%
2ax, 74%
2ak, 45%
2al, 82%
2am, 64%
CF3
CF3
CF3
diazines
CF3
OPMP
SPh
N
N
N
N
Br
Ph-4-OMe
N
N
N
N
N
N
N
N
Ph-4-OMe
N
OPMP
N
N
OPMP
N
MeS
N
N
2an, 80%
2ao, 71%
2ap, 76%[d]
2aq, 73%[e]
2ay, 87%
2az, 66%
2ba, 82%
2bb, 79%
[a] Yields of isolated products as single regioisomers are given. [b] Run in DME at 80 ºC. [c]KH and 18-crown-6 used. [d] Yield calculated by 1H NMR due to product
volatility [e] KH used.
details). Starting with mono-substituted pyridines: phenol, derivatives can be formed via this pathway. Disubstitution,
thiophenol and aniline nucleophiles can tolerate 3- such as 3,5-disubstituted pyridines are tolerated, as are 2,3-
substituents on the pyridine ring (2ag–2ai). An exception and 2,5-substitution patterns (2ar–2av). Quinolines are
is shown in diarylamine 2aj where no product was also effective substrates and can be coupled to phenols and
observed. Methoxy substituents at the 2-position of thiophenols (2aw and 2ax). Diazine salts were examined
pyridines result in moderate yields and 2,2-bipyridines are under this reaction protocol; pyrimidines work well as
competent substrates (2ak–2am). Blocking the 4-position partners (2ay–2ba) and functionalized quinoxaline 2bb
was obtained in good yield. Complex pyridines and
of pyridines results in salt formation at the 2-position;
examples 2an–2aq show that C–O and C–N bond
This article is protected by copyright. All rights reserved.

10.1002/anie.201807322
Angewandte Chemie International Edition
COMMUNICATION
Table 3. Scope of drug-like fragments and complex bioactive molecules.
PPh3
YH
Salts 1 step from C–H
Pyridines 4-selective
OTf
R
NaH, THF or DME
X
R
X
Y
R'
R
X
± 15-Crown-5, 0 ºC to 80 ºC
N
or
R'
or
N
H
N
Anilines: n-BuLi, THF
N
N
See supporting information
–78 ºC to RT
1
Y = O, S, Se, NR
exo- and endocyclic-coupled products, 2
drug-like fragments
N
Me
O
CF3
Ph
SPh
N
N
N
S
N
Me
N
N
2bf, 37%
N
N
Me
SPh
N
N
N
N
N
CF3
N
Ph
N
N
N
N
N
O
Ph
Me
F3C
Me
O
2bb
46%
N
2bg, 55%
2bc, 64%
2bd, 34%
2be, 65%
bioactive molecules
SPh
OMe
SePh
N
OMe
Cl
Cl
O
N
Me
O
O
N
O
N
O
NBn
N
N
CO2Et
N
O
CO2Et
from N-Bn varenicline
from pyriproxyfen
2bh, 50%
from loratadine
2bj, 90%
bepotastine derivative
2bk, 70%
2bi, 41%
MeO2S
MeN
OMe
N
N
Cl
N
N
S
N
OMe
Me
H
S
HN
N
OBn
N
N
Me
H
Me
N
Me
O
H
N
O
N
H
AcO
minor isomer
from
etoricoxib
from OBn-cinchonidine
from abiraterone acetate
from imatinib
2bo, 63%, 10:1 r.r.
NHAc
2bl, 54%
2bm, 61%
2bn, 48%
[a] Yields of isolated products as single regioisomers are given unless stated. [b] Ran in DME at 80 ºC
diazines are commonly found in medicinal chemistry on preferential reactivity with Tf2O during phosphonium
programs and we employed the phosphonium-mediated salt synthesis. We exploited our recently disclosed site-
process against a challenging set of drug-like fragments selective switching tactic in 2bg where selective C–P
and biologically active molecules (Table 3).[14] These bond-formation occurs on the pyrimidine system and then
molecules are problematic for traditional methods, coupled to an aniline.[10e] Para-methoxyphenol could also
particularly metal-catalyzed processes, due to the be coupled to a 1,2-oxazole-containing fragment (2bh).
difficulty in preparing halogenated precursors and the Second, we aimed to show that aromatic heteronucleophile
occurrence of polar functional groups that can disable coupling could be employed at advanced stages of drug
catalytic processes. Salts derived from triphenylphosphine development beyond fragment compounds.[16] To
were synthesized in each case due its widespread demonstrate this attribute, we chose a representative
availability, low cost, ease of salt purification and the selection of complex drugs, and other bioactive molecules,
consistently high regioselectivities observed.[15] First, we with a range of structural and functional diversity. Phenols
prepared six drug-like fragments that possess multiple can be coupled to pyriproxyfen, a pesticide, and a
functional groups and sites of reactivity. A pyrrole was protected version of the smoking cessation aid varenicline
coupled to a pyridine bearing a benzhydril center, and an (2bi and 2bj). Loratadine and a bepotastine analogue are
imidazole-substituted quinoline was formed without excellent coupling partners for thiophenols and
difficulty (2bc and 2bd). Site-selective C–S bond- selenophenols repectively (2bk and 2bl). Pyrrole can be
formation was possible in polyazines 2be and 2bf where coupled to benzyl-protected cinchonidine, and
a
thiophenol conjugate can be synthesized from the prostate
the 3-substituted pyridine is the favored heterocycle based
This article is protected by copyright. All rights reserved.

10.1002/anie.201807322
Angewandte Chemie International Edition
COMMUNICATION
convergent couplings between two complex coupling
partners and was exemplified by synthesizing a novel
kinase inhibitor. Simple protocols, readily available
reagents and applicability to pharmacogically-relevant
molecules make this approach useful for medicinal
chemists.
H
N
H
N
Sorafenib – tyrosine kinase inhibitor
O
O
N
Cl
– renal cell, hepatocellular and
thyroid carcinoma treatment
CF3
– ‘type II’ binding mode
O
pyridine binds
to ATP allosteric
binding site
– heteroaryl ether synthesized via SNAr
NHMe
Acknowledgements
Synthesis of a novel kinase inhibitor derivative
H
N
H
N
PPh3
We acknowledge support by start-up funds from Colorado State
University and from The National Institutes of Health under award
number R01 GM124094.
O
OTf
HO
Cl
3
CF3
N
CO2Me
(halide not commercial)
NaH, DME
15-Crown-5,
0 ºC to 80 ºC
Keywords: heteroatom coupling • pyridines • phosphonium salts
H
N
H
N
• late-stage • kinase inhibitors
O
O
N
Cl
[1]
P. Wu, T. E. Nielsen, M. H. Clausen, Trends Pharmacol. Sci. 2015, 36,
422.
CF3
[2]
[3]
L. N. Johnson, Q. Rev. Biophys. 2009, 42, 1.
2bq, 40%
CO2Me
For examples of SNAr reactions see: a) K. Walsh, H. F. Sneddon, C. J.
Moody, RSC Adv. 2014, 4, 28072; b) J. Liu, M. J. Robins, J. Am. Chem.
Soc. 2007, 129, 5962.
Scheme 2. Phosphonium coupling reactions to make novel kinase inhibitors.
[4]
For reviews see: a) D. S. Surry, S. L. Buchwald, Angew. Chem. Int. Ed.
2008, 47, 6338; b) P. Ruiz-Castillo, S. L. Buchwald, Chem. Rev. 2016,
116, 12564; c) J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534; d) M.
Kienle, S. R. Dubbaka, K. Brade, P. Knochel, Eur. J. Org. Chem. 2007,
2007, 4166; e) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A.-
M. Resmerita, N. K. Garg, V. Percec, Chem. Rev. 2011, 111, 1346; f) S.
V. Ley, A. W. Thomas, Angew. Chem. Int. Ed. 2003, 42, 5400; g) S.
Bhunia, G. G. Pawar, S. V. Kumar, Y. Jiang, D. Ma, Angew. Chem. Int.
Ed. 2017, 56, 16136; h) C.-F. Lee, Y.-C. Liu, S. S. Badsara, Chem. Asian.
J. 2014, 9, 706.
cancer drug abiraterone acetate (2bm and 2bn). Site-
selective processes were again exploited to make
functionalized derivatives of etoricoxib and gleevec (2bo
and 2bp) with the latter isolated as a 10:1 mixture of
regioisomers.
As a final demonstration of the utility of the coupling
process, we examined a convergent coupling reaction to
make a novel kinase inhibitor derivative that would be
challenging to access via conventional metal-catalyzed
cross coupling or SNAr reactions (Scheme 2). Sorafenib is
a marketed tyrosine kinase inhibitor that contains a
pyridine–O–aryl linkage (Scheme 2); in ‘type II binding’
the pyridine moiety occupies an allosteric pocket and
competes with ATP.[1,2,17,18] We envisioned a convergent
disconnection where a pyridylphosphonium salt could
react with phenol 3 that includes the diaryl urea moiety.
Scheme 2 shows a representative pyridine phosphonium
salt where the corresponding halide would be challenging
to prepare; coupling to phenol 3 proceeds in reasonable
yield to form 2bq and demonstrates that novel kinase
inhibitors can be rapidly synthesized via this approach.
[5]
For examples of recent light-driven processes see: a) E. B. Corcoran, M.
T. Pirnot, S. Lin, S. D. Dreher, D. A. DiRocco, I. W. Davies, S. L.
Buchwald, David, W. C. MacMillan, Science 2016, 353, 279; b) S. E.
Creutz, K. J. Lotito, G. C. Fu, J. C. Peters, Science 2012, 338, 647; c)
C.-H. Lim, M. Kudisch, B. Liu, G. M. Miyake, J. Am. Chem. Soc. 2018,
140, 7667; d) D. T. Ziegler, J. Choi, J. M. Muñoz-Molina, A. C. Bissember,
J. C. Peters, G. C. Fu, J. Am. Chem. Soc. 2013, 135, 13107; e) C. Uyeda,
Y. Tan, G. C. Fu, J. C. Peters, J. Am. Chem. Soc. 2013, 135, 9548; f) Y.
Tan, J. M. Muñoz-Molina, G. C. Fu, J. C. Peters, Chem. Sci. 2014, 5,
2831.
[6]
[7]
J. P. Finer, Ligand Coupling Reactions with Heteroaromatic Compounds,
Tetrahedron Organic Chemistry Series, Pergamon Press, Oxford, Vol.
18. Chap. 4.
A similar strategy involving stoichiometric palladium complexes has been
exploited for bioconjugation and fluorination reactions, see: a) E. V.
Vinogradova, C. Zhang, A. M. Spokoyny, B. L. Pentelute, S. L. Buchwald,
Nature 2015, 526, 687; b) E. Lee, A. S. Kamlet, D. C. Powers, C. N.
Neumann, G. B. Boursalian, T. Furuya, D. C. Choi, J. M. Hooker, T. Ritter,
Science 2011, 334, 639.
In summary, we have shown that pyridine and diazine
phosphonium salts can serve as coupling partners with
seven classes of aromatic heteronucleophiles. Advantages
of this strategy over conventional approaches include a
distinct scope of azine coupling partners, a simplified
mechanism and a narrow range of reaction conditions.
Applying this method to complex drug-like molecules is
also feasible and enables medicinal chemistry to rapidly
access valuable analogues. The method also enables
[8]
[9]
D. C. Blakemore, L. Castro, I. Churcher, D. C. Rees, A. W. Thomas, D.
M. Wilson, A. Wood, Nat. Chem. 2018, 10, 383.
a) M. C. Hilton, R. D. Dolewski, A. McNally, J. Am. Chem. Soc. 2016,
138, 13806; b) E. Anders, F. Markus, Tetrahedron Lett. 1987, 28, 2675;
c) E. Anders, F. Markus, Chem. Ber. 1989, 122, 113; d) E. Anders, F.
Markus, Chem. Ber. 1989, 122, 119; e) M. Haas, H. Goerls, E. Anders,
E. Synthesis 1998, 195.
[10] a) X. Zhang, A. McNally, Angew. Chem. Int. Ed. 2017, 56, 9833; b) J. L.
Koniarczyk, D. Hesk, A. Overgard, I. W. Davies, A. McNally, J. Am. Chem.
Soc. 2018, 140, 1990; c) Anderson, R. G.; Jett, B. M.; McNally, A.
Tetrahedron. 2018, 74, 3129; d) C. Patel, M. L. Mohnike, M. C. Hilton; A.
This article is protected by copyright. All rights reserved.

10.1002/anie.201807322
Angewandte Chemie International Edition
COMMUNICATION
McNally, Org. Lett. 2018, 20, 2607; e) R. D. Dolewski, P. J. Fricke, A.
McNally, J. Am. Chem. Soc. 2018, 140, 8020.
[11] M. A. Larsen, J. F. Hartwig, J. Am. Chem. Soc. 2014, 136, 4287.
[12] a) M. Grayson, P. T. Keough, J. Am. Chem. Soc. 1960, 82, 3919; b) G.
A. Razuvaev, N. A. Osanova, T. G. Brilkina, T. I. Zinovjeva, J. Organomet.
Chem. 1975, 99, 93; c) G. A. Razuvaev, N. A. Osanova, J. Organomet.
Chem. 1972, 38, 77; d) C. T. Eyles, S. Trippett, J. Chem. Soc. C. 1966,
67; e) P. A. Byrne, Y. Ortin, D. G. Gilheany, Chem. Commun. 2015, 51,
1147.
[13] See the Supporting Information for a mechanistic scheme.
[14] a) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57,
10257; b) M. Baumann, I. R. Baxendale, Beilstein J. Org. Chem. 2013,
9, 2265.
[15] Trialkylphosphines often result in regioisomeric mixtures during salt-
formation and are more challenging to purify. The resulting salts are also
less effective as coupling partners and result in
decomposition products.
a number of
[16] T. Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal, S. W. Krska, Chem.
Soc. Rev. 2016, 45, 546.
[17] P. T. C. Wan, M. J. Garnett, S. M. Roe, S. Lee, D. Niculescu-Duvas, V.
M. Good, C. M. Jones, C. J. Marshall, C. J. Springer, D. Barford, R.
Marais, Cell, 2004, 116, 855.
[18] K. J. Gotnik, H. M. V. Verheul, Angiogenesis 2010, 13, 1.
This article is protected by copyright. All rights reserved.

10.1002/anie.201807322
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Ryan G. Anderson, Brianna M. Jett and
Prof. Andrew McNally*
Page No. – Page No.
A Unified Strategy to Couple
Aromatic Heteronucleophiles to
Azines and Pharmaceuticals.
Text for Table of Contents
Aromatic heteronucleophiles, such as phenols, thiophenols, anilines, imidazoles and pyrazoles, are frequently coupled to pyridine
and diazine heterocycles to make drug-like molecules. Metal catalysts are most commonly used to facilitate this transformation, but
the wide variety of reaction protocols and complex catalytic cycles can limit their use for complex heterocycles. We present an
alternative approach where seven distinct classes of nucleophiles are coupled to azine phosphonium salts via a nucleophile addition-
P-ligand coupling mechanism. A narrow range of reaction conditions and applicability to drug-like fragments as well as complex
bioactive molecules are advantages of this approach.
.
This article is protected by copyright. All rights reserved.