Nonsymmetrical Bis-Azine Biaryls from Chloroazines: A Strategy Using Phosphorus Ligand-Coupling

Article abstract of DOI:10.1021/jacs.9b08504

Distinct approaches to synthesize bis-azine biaryls are in demand as these compounds have multiple applications in the chemical sciences and are challenging targets for metal-catalyzed cross-coupling reactions. Most approaches focus on developing new reagents as the formal nucleophilic coupling partner that can function in metal-catalyzed processes. We present an alternative approach using pyridine and diazine phosphines as nucleophilic partners and chloroazines where the heterobiaryl bond is formed via a tandem S_NAr-phosphorus ligand-coupling sequence. The heteroaryl phosphines are prepared from chloroazines and are bench-stable solids. A range of bis-azine biaryls can be formed from abundant chloroazines using this strategy that would be challenging using traditional approaches. A one-pot cross-electrophile coupling of two chloroazines is feasible, and we also compared the phosphorus-mediated strategy with metal-catalyzed coupling reactions to show advantages and compatibility.

Full text of DOI:10.1021/jacs.9b08504

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Article
Non-Symmetrical Bis-Azine Biaryls from Chloroazines:
A Strategy Using Phosphorus Ligand-Coupling
Benjamin T Boyle, Michael C Hilton, and Andrew McNally
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08504 • Publication Date (Web): 04 Sep 2019
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Non-Symmetrical Bis-Azine Biaryls from Chloroazines: A
Strategy Using Phosphorus Ligand-Coupling
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Benjamin T. Boyle , Michael C. Hilton and Andrew McNally*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
KEYWORDS Bipyridines, bis-azine biaryls, phosphorus, ligand-coupling, cross-coupling, chloropyridines.
ABSTRACT: Distinct approaches to synthesize bis-azine biaryls are in demand as these compounds have multiple applications in
the chemical sciences and are challenging targets for metal-catalyzed cross-coupling reactions. Most approaches focus on
developing new reagents as the formal nucleophilic coupling partner that can function in metal-catalyzed processes. We present an
alternative approach using pyridine and diazine phosphines as nucleophilic partners and chloroazines where the heterobiaryl bond is
N
formed via a tandem S Ar-phosphorus ligand-coupling sequence. The heteroaryl phosphines are prepared from chloroazines and
are bench-stable solids. A range of bis-azine biaryls can be formed from abundant chloroazines using this strategy that would be
challenging using traditional approaches. A one-pot cross-electrophile coupling of two chloroazines is feasible, and we also
compared the phosphorus-mediated strategy with metal-catalyzed coupling reactions to show advantages and compatibility.
INTRODUCTION
Bis-azine biaryls are widely applied in the chemical
sciences with applications in drug development, as ligands for
1
metal complexes and as components of materials (eq 1).
Transition metal-catalyzed cross-coupling reactions are most
commonly used to synthesize non-symmetrical variants,
however, pyridine and diazine couplings represent some of the
2
most challenging cases for this class of reactions. Readily
available and stable cross-coupling precursors are often
limiting factors; haloazines are relatively abundant from
commercial sources compared to nucleophilic partners such as
pyridyl zincs, stannanes, silanes and Grignards that often have
3
to be prepared and carefully handled. Suzuki-Miyaura
reactions are the most widely applied in medicinal chemistry
4
as azine boronic acids are typically bench-stable powders.
Despite this advantage, halopyridines remain dramatically
more commercially available than pyridine boronic acids, and
2-pyridyl boronic acids have a proclivity to decompose during
5
,6
cross-coupling reactions.
Herein we show that
heteroarylphosphines can serve as nucleophilic partners and
couple with haloazines where the biaryl bond is formed via a
7
phosphorus ligand-coupling reaction. These phosphines are
straightforward to prepare from haloazines and are bench-
stable. Preliminary examples of a net cross-electrophile
coupling are shown via a one-pot coupling of two haloazines.
Several groups have developed alternatives to azine boronic
acids for metal-catalyzed cross-coupling reactions. Potassium
trifluoroborate salts and MIDA boronates display enhanced
stability compared to boronic acids, but a general platform for
azine-azine coupling has yet to be established using these
phosphorus ligand-coupling reactions to form the biaryl
1
0
bond. However, the inherent selectivity of the two C–P
bond-forming steps restrict access to bis-azine biaryls within
some isomeric patterns such as 2,2’-bipyridines (vide infra).
Furthermore, certain functional groups and azine substitution
patterns are not tolerated. We envisioned a strategy analogous
to metal-catalyzed cross-coupling using chloroazines and het
8
reagents. Willis advanced this area by demonstrating that
pyridyl sulfinate salts and allyl sulfones are viable alternatives
9
for Suzuki couplings. Recently, we reported an alternative
strategy to form bis-azine biaryls by constructing bis-azine
phosphonium salts from C–H precursors and then exploiting
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Scheme 1. Key Developments in Phosphorus Ligand-Coupling Reactions to Synthesize Bipyridines
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eroaryl phosphines as precursors (eq 2). This approach could
overcome limitations of current metal-catalyzed processes as
well as result in a suite of bis-azine biaryls that are beyond the
scope of our original report. Pyridyl and diazinyl phosphines,
prepared in one step from chloroazines, can function as
nucleophiles and couple with a second chloroazine via a
report, Uchida and Oae showed that treating a tripyridyl
phosphonium salt with acidic water could result in
symmetrical bipyridines (Scheme 1C).
11c
In a different
approach, they also demonstrated that organometallic reagents
could be added to phosphine oxides to trigger ligand-coupling
1
1d
(Scheme 1D).
tandem
N
S Ar-ligand-coupling sequence. The mechanism
Despite these seminal contributions, bipyridine synthesis via
phosphorus ligand-coupling strategies received little further
attention and, consequently, never found widespread use. Two
principal factors can account for the absence of subsequent
developments. First, the ligand-coupling precursors lack
generality towards a range of pyridine substrates via the
methods laid out in the reports described above. Specifically,
the methods to form these precursors can require multiple
steps and are not practical for cross-coupling reactions of two
pyridine coupling partners. Second, and as a result, the reports
showed only dimerizations and macrocyclizations that did not
highlight the potential of these reactions for pyridine-pyridine
cross-coupling. Our laboratory was interested in exploiting
these phosphorus ligand-coupling reactions, but, in contrast to
the previous reports, we sought to devise a practical system
where widely available halopyridines (and other haloazines)
partners are coupled to form non-symmetrical bipyridines. In
this way, the disconnection logic would replicate metal-
catalyzed cross coupling; the nucleophilic partner is a pyridyl
phosphine, derived from the corresponding halide in one step.
The electrophilic partner is a halopyridine, and phosphorus
ligand-coupling replaces the action of a transition metal
catalyst in the biaryl bond-forming step.
involves forming a bis-heteroarylphosphonium salt (I) that is
intercepted in acidic alcohol or aqueous solutions to form a
P(V) alkoxyphosphorane intermediate (II). In line with our
previous studies, we anticipated that subsequent ligand-
coupling would proceed via an asynchronous process,
involving
intermediate.
a
dearomatized species III as
a
discrete
HISTORICAL CONTEXT AND BACKGROUND
Reports of forming bipyridines via phosphorus ligand-
coupling reactions date back to the 1940s with seminal works
by Mann, Newkome, Uchida, and Oae showing the feasibility
1
1
of the process using several distinct precursors (Scheme 1).
In all cases, the ligand-coupling step occurs after forming a
P(V) alkoxyphosphorane intermediate, although the reagent-
trigger can differ markedly. The earliest report of using
halopyridines as precursors for phosphorus ligand-coupling
comes from Mann in 1948 (Scheme 1A) where di- and
tripyridyl phosphines were treated with methyl iodide in
methanol and resulted in the formation of 2,2'-bipyridinium
11a
dimers. The authors propose a free radical mechanism, but
subsequent developments suggest this process occurs via a
phosphorus ligand-coupling process. Despite this early report,
the next use of this strategy came 30 years later from
Newkome (Scheme 1B). By reacting a phosphine oxide
containing two 2-pyridyl groups with a sodium alkoxide at
Scheme 2 shows specific limitations of our previous
approach using azine C–H bonds as precursors and potential
10
solutions using chloroazines. In the former case, two C–P
bond-forming reactions are required to form bis-heterocyclic
phosphonium salt I (Scheme 2A). Fragmentable phosphine IV
o
11b
1
40 C, a 2,2'-bipyridine product formed. Following this
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is used with Tf
azinylphosphine (not shown); the process is then repeated with
Scheme 2. Limitations of Heterobiaryl Synthesis Using C–H Precursors and an Alternative Strategy via Chloroazines
2
O and DBU as a base to form an
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the second azine coupling partner to form salt I. Under these
Isolated yields from 2.0 mmol scale reactions. Run on 10
conditions, common functional groups such as alcohols,
mmol scale.
12,13
phenols and alkyl-substituted amides,
to their propensity to react with Tf O (Scheme 2B). Pyridines
with certain substitution patterns are also not amenable; 2,6-
disubstituted pyridines and 2-CF pyridines are unsuccessful
are not tolerated due
2
as the sp nitrogen atom is either too sterically crowded or
reduced in nucleophilicity such that reaction with Tf O is
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ineffective. For pyridines and quinolines, both C–P bond-
forming reactions are inherently 4-selective, whereas 2-
position selectivity can only be achieved when the 4-position
2
3
Ar Reactions to Form Heteroarylphosphinesa,b
Table 1. S
N
14
is blocked. Using this sequence to prepare 2,2’-bipyridines
for example, requires 4-position substituents to be present to
ensure the correct positional selectivity. Similarly, C–P bond-
formation in diazines is also inherently selective; pyrimidines
react at the 4-position in this manifold, and this selectivity
restricts the possible isomeric patterns in the resulting bis-
azine biaryl. The strategy in Scheme 2C can potentially
overcome these issues by using
N
S Ar reactions with
chloroazines for each C–P bond-forming event. Scheme 2B
shows classes of readily available chloroazines where the
previous functional group incompatibilities and regiomeric
constraints can be addressed.
RESULTS AND DISCUSSION
Synthesis of Heteroarylphosphines. We first developed
conditions for S
HPPh and intentionally prepared heteroarylphosphines that
were precluded from our previous study by steric, electronic or
N
Ar couplings between chloroazines and
2
1
0,15
isomeric constraints (Table 1).
For 2- and 4-
chloropyridines, heating in chlorobenzene at 130 ºC with one
equivalent of TfOH was effective, and pyridylphosphines 2a-
2
g were formed in high yields (condition set A). addressing
the restrictions mentioned above in C–P bond formation (vide
supra). For more Ar active substrates, such as
S
N
16
chloroquinolines, chloroisoquinolines and chlorodiazines,
trifluoroethanol (TFE) at 80 ºC was sufficient and acid
activation was not required (condition set B). Notably, these
conditions allow access to phosphines at the 2-position of
quinolines and pyrimidines. We found that these
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heteroarylphosphines arebench-stable but, as a precaution,
they were kept in a –20 ºC refrigerator for long-term storage.
Tandem S Ar-Ligand-Coupling Sequences. With a set of
heteroaryl phosphines in hand, we next developed one-pot
procedures to form bis-azine biaryls via the tandem S Ar-
ligand-coupling sequence (Table 2). We found that coupling
reactions could be separated into three categories depending
N
on the ease of the S Ar process. First, 2,4-and 4,4’-bipyridines
TFE are added, and heating at 80 ºC is optimal for the ligand-
coupling process (condition set A’). Without NaOTf, the S Ar
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reaction does not reach full conversion, and we presume that
bis-azine phosphonium salt formation is promoted by anion
exchange and precipitation of NaCl. By employing these
conditions, a set of 2,4- and 4,4’- bipyridines are formed in
reasonable yields (3a-3e). Bipyridine 3b is notable as the alkyl
amide group was incompatible with our previous protocol.
Second, chloroquinolines and chlorodiazines couple
heteroarylphosphines using a single-stage protocol. In line
with the observations in Table 1, these heterocycles undergo
N
N
were synthesized in a two-stage process; heating the
phosphine and chloropyridine in dioxane at 120 ºC with one
equivalent each of HCl and NaOTf drives the S
completion and forms the bis-heterocyclic phosphonium salt.
Then, a further equivalent of HCl, ten equivalents of H O, and
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Ar reaction to
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more facile S
coupling
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Ar processes and the tandem S Ar-ligand-
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a
Table 2. Tandem S
N
Ar-Ligand-Coupling Reactions to Form Non-Symmetrical Bis-Azine Biaryls
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a
b
Isolated yields are reported. 3f was formed using a two-stage protocol: 1.2 equiv chloroazine, 2.2 equiv NaOTf, TFE, 80 ºC then 1.2
c
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equiv
HCl
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water
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added.
TfOH
used
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b
sequence is performed in TFE at 80 ºC with H
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O, HCl and
Isolated yields are reported. TFE/Toluene 1:1 used in the
NaOTf as additives (condition set B’). By employing these
conditions, a set of 2,4- and 4,4- pyridine-quinolines are
formed (3f-3l) and include examples of pyridines with 2,6-
disubstitution, 4-position C–H bonds, as well as products
containing phenols and alcohols. Furthermore, 2,2-pyridine-
quinoline systems 3m-3o can also be synthesized that are
challenging to prepare via Suzuki-Miyaura couplings (vide
infra). Similarly, 3p is a 2,2’-biquinoline that includes a C–Br
bond that would typically be active in transition metal-
catalyzed processes. However, an attempt to form 4,4’-
biquinoline 3q failed; we presume unfavorable steric
interactions occur in the ligand-coupling transition state in this
case. Diazines can be used as both formal nucleophilic
final stage.
increasing the efficiency of these process, as well as
expanding the scope to other azine-azine couplings.
In Scheme 3, we examined other important attributes of the
ligand-coupling protocol for bis-azine biary synthesis. First,
running the reaction on a gram scale showed minor yield loss
when forming 3a (Scheme 3A). Second, there was no change
in efficiency when conducting the reaction under an air or
nitrogen atmosphere (Scheme 3B). Third, we combined the
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S Ar method to form heteroarylphosphines with our
previously reported protocol to form phosphonium salts from
C–H precursors (Scheme 3C). By combining the two
approaches, bipyridines can potentially be formed that are
outside of the scope of either method alone. As an example,
we used phosphine 2f formed from the S
(and not amenable to synthesis via the C–H protocol as 2,6-
phosphines
and
electrophilic
chlorides;
a
2-
pyrimidylphosphine was coupled with a chloroisoquinoline in
moderate yield (3r), and diazine-diazine coupling is possible
using this approach (3s-3t). At this point pyrazines perform
poorly as coupling partners; a short survey of pyridine,
quinoline and diazine partners resulted in no coupled products
or poor yields (see the Supporting Information). Third, we
targeted 2,2’-bipyridines using this strategy due to the
challenges in synthesizing these systems using Suzuki-
Miyaura cross-coupling reactions (vide supra). Condition set
A’ was modified to C’, where changes in solvent, acid and
additive resulted in higher yields of bipyridine products (see
Supporting Information). Examples 3u-3z show a variety of
isomeric patterns, as well as substituents such as aliphatic
N
Ar protocol in Table
1
2
disubstitution prevents reaction with Tf O), and Loratadine to
form bis-pyridyl phosphonium salt 4; subsequent ligand-
coupling using acidic ethanol resulted in novel 4,4'-bipyridine
3ab. Interchanging both methods to either make heteroaryl
phosphines or for phosphonium salt formation-coupling
sequences can, therefore, result in distinct structural and
functional group diversity in the bis-azine biaryl products.
Scheme 3. Other Attributes of the Ligand-Coupling
Process
a
5
amines, SF groups, thiophenes, amides and chlorides. As with
all other examples in Table 2, these bipyridine products could
not be formed using our previous approach from C–H
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precursors. The moderate yields approximate those in our
previous report involving 2,2’-bipyridine couplings, and
further investigations into the mechanism of this process are
ongoing.
We developed a one-pot, net cross-electrophile coupling of
two chloroazines in a stage-wise protocol involving sequential
18
addition of reagents (Table 3). We hypothesized that the
heteroarylphosphine could be formed in situ and reacted with
the second chloroazine via a tandem S Ar-ligand-coupling
N
sequence from Table 2. The four examples, 3e, 3f, 3i and 3y,
in Table 3 show that pyridine-pyridine and pyridine-quinoline
couplings are viable using this process forming products in
reasonable yields, with 2,2’-, 2,4’- and 4,4’-conectivity
between the two heterocycles. Current efforts are focused on
Table 3. One-Pot Cross-Coupling of Chloroazinesa
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a
b
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Isolated yields are reported. Yields calculated by H NMR
salt formation requires 130 ºC in chlorobenzene. Under these
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using 1,3,5-trimethoxybenzene as an internal standard.
conditions, we have observed side reactions that can reduce
yields, including dehalogenation of the chloroazine partner
and a chloride-phosphorus metathesis process shown in Figure
1
B. We also observed the same metathesis in condition set A'
GUIDELINES AND LIMITATIONS
if we did not store NaOTf in a glove box or desiccator,
presumably because of the influence of water during salt
formation. Figure 1C shows problematic substrates for the
ligand-coupling process. We have observed that alkoxy
substituents are prone to dealkylation during the reaction,
although this pathway is mitigated by using TfOH rather than
HCl in the ligand coupling step. Bromides and iodides at the
3-position of pyridines undergo dehalogenation during
heteroaryl phosphine and phosphonium salt formation. Pyridyl
fluorides result in reduced yields when employed in place of
It is important to consider which of the chloroazine partners
to convert into the heteroaryl phosphine in the first stage of the
coupling sequence. In general, it is advisable to transform the
N
least S Ar active chloroazines into the phosphine (Figure 1A).
In that way, lower temperatures are applicable for the salt-
formation-ligand-coupling step. For example, to make a 2,2'-
pyridine-quinoline, the optimal order is to first form a pyridyl
phosphine and then employ this phosphine as a nucleophile
with the cholorquinoline (condition set B' from Table 2).
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chlorides or bromides in the tandem S Ar-ligand-coupling
step; we believe that the liberated fluoride anion reacts with
the phosphonium salt and C–H products are observed in the
LCMS of the crude reaction mixture. Certain functional
groups and substitution patterns result in slower ligand-
coupling or lower yields of bipyridine products. When one of
the pyridine coupling partners contains an electron-donating
group, such as hydroxy, alkoxy and amino groups, reaction
rates are reduced. We also found that 2-chloro-6-aryl pyridines
and 2-chloro-3-substituted pyridines are sluggish in the
coupling step and yields suffer as a consequence. For each
additional basic nitrogen atom in the substrate, an extra
1
9
equivalent of acid is required. Finally, the mechanistic
principles of this approach dictate that Ar-inactive
substrates, such as 3-halopyridines and 5-halopyrimidines, are
not viable.
S
N
COMPARISON
PALLADIUM-CATALYZED
REACTIONS
We chose three cases where the phosphorus ligand-coupling
approach for bis-azine biaryl synthesis could have advantages
over, or be complementary to, metal-catalyzed cross-coupling
reactions. Scheme 4B compares 2,2'-bipyridine synthesis to
Suzuki couplings using boronic acid surrogates that are
typically more stable under cross-coupling conditions. Using
2-pyridyl BF
moderate yields of 3aa, whereas the reaction was more
efficient using diphenyl-2-pyridylphosphine.
results reinforce that 2,2-bipyridine synthesis via Pd-Suzuki
reactions are challenging, although we acknowledge that
further reaction development could address these problems.
2
Next, we examined whether the PPh group could proceed
through a Pd cross-coupling reaction in the presence of
another nucleophilic partner. Using Fu's conditions for Suzuki
coupling, where PCy
formed in a reasonable yield with the phosphine group
available for coupling in a subsequent step (Scheme 4B).
TO
CROSS-COUPLING
8
3
K salts or MIDA boronates, we obtained low to
8
b,20,21
These
3
is a ligand for palladium, biaryl 2n
2
2,23
Selectively transforming polyhalogenated azines is an
advantage that the phosphorus-mediated approach could hold
over metal-catalyzed reactions. We selected quinoline
dihalides 5 and 6 to test this hypothesis and used reported Pd-
catalyzed methods that specifically target haloazines. A
Negishi coupling reaction, using conditions reported by
Luzung and Yin, resulted in a mixture of products in favor of
bis-bipyridine 3af, even though a 1.0:1.2 ratio of halide to
Figure 1. Guidelines and Limitations for Heteroaryl Phosphine
Formation and S Ar-Ligand-Coupling Sequences.
N
In the opposite order, using a quinolyl phosphine as a
nucleophile, condition set C' is required where phosphonium
24
heteroaryl zinc was employed. A Stille reaction was selective
for 4-isomer 3ac, although products 3ae and 3af were present
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in the reaction mixture.25 The phosphorus-mediated approach,
on the other hand, due to its propensity to select the most S Ar
active position on the scaffold resulted in a single regioisomer
3ac.
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Scheme 4. Compatibility and Comparison to Metal-Catalyzed Cross-Coupling Reactionsa
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Yields and product ratios calculated by H NMR using 1,3,5-trimethoxybenzene as an internal standard. Isolated yield shown.
CONCLUSIONS
In summary, we have developed an alternative strategy to
form bis-azine biaryls by coupling azinylphosphines with
AUTHOR INFORMATION
Corresponding Author
chloroazines. The reaction proceeds via a tandem S
N
Ar-ligand-
* andy.mcnally@colostate.edu
coupling sequence, and the heteroaryl phosphines are bench-
stable solids that are prepared from chloroazines in a separate
step. A diverse set of bis-azine biaryl products can be formed,
including substitution patterns such as 2,2’-bipyridines, that
are challenging for traditional metal-catalyzed approaches.
Abundant chloroazines, simple protocols and valuable bis-
azine biaryl products make this approach useful for medicinal
chemists.
ORCID
Benjamin T. Boyle: 0000-0002-9360-2179
Michael C. Hilton: 0000-0001-5734-3547
Andrew McNally: 0000-0002-8651-1631
ACKNOWLEDGMENT
This work was supported by The National Institutes of Health
(NIGMS) under award number R01 GM124094.
ASSOCIATED CONTENT
Supporting Information
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