Deaminative Reductive Cross-Electrophile Couplings of Alkylpyridinium Salts and Aryl Bromides

Article abstract of DOI:10.1021/acs.orglett.9b01014

A nickel-catalyzed reductive cross-coupling of alkylpyridinium salts and aryl bromides has been developed using Mn as the reductant. Both primary and secondary alkylpyridinium salts can be used, and high functional group and heterocycle tolerance is observed, including for protic groups. Mechanistic studies indicate the formation of an alkyl radical, and controlling its fate was key to the success of this reaction.

Full text of DOI:10.1021/acs.orglett.9b01014

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Deaminative Reductive Cross-Electrophile Couplings of
Alkylpyridinium Salts and Aryl Bromides
Jennie Liao,† Corey H. Basch,†,§ Megan E. Hoerrner,†,§ Michael R. Talley,† Brian P. Boscoe,‡
Joseph W. Tucker,‡ Michelle R. Garnsey,*,‡ and Mary P. Watson*,†
†Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, United States
‡Medicine Design, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: A nickel-catalyzed reductive cross-coupling of
alkylpyridinium salts and aryl bromides has been developed
using Mn as the reductant. Both primary and secondary
alkylpyridinium salts can be used, and high functional group
and heterocycle tolerance is observed, including for protic
groups. Mechanistic studies indicate the formation of an alkyl
radical, and controlling its fate was key to the success of this
reaction.
he increasing prevalence of sp3-hybridized carbons in
Although the use of aryl boronic acids presents control over
the arylation regioselectivity, it also presents limitations. Due
Tpharmaceuticals, along with their presence in natural
to the basic conditions required for boronic acid activation,
pyridinium salts with β-electron-withdrawing groups undergo
elimination, and other protic groups are also problematic. An
excess (3.0 equiv) of the aryl boronic acid is required.5a Third,
aryl boronic acids must be prepared from aryl halides, adding
steps and limiting opportunities for efficient parallel synthesis.
Finally, the availability of aryl boronic acids is much more
limited than aryl bromides. In contrast to only 6200 (het)aryl
boronic acids and esters, there are >56 000 (het)aryl bromides
in Pfizer’s inventory. Similar constraints limit the potential of
any organometallic coupling partner. Thus, a method for direct
use of aryl bromides would be of high value.
Despite the exquisite methods developed for reductive
couplings of other alkyl electrophiles,3d,g,11 it was unclear if the
reduction of the pyridinium cation and potential side reactions
of the alkyl radical intermediate could be controlled in the
presence of a stoichiometric reductant. Overcoming these
challenges, we report conditions for the efficient coupling of
alkyl pyridinium salts with aryl bromides (Scheme 1). This
method uses abundant and diverse aryl bromides and
approximately equimolar amounts of alkyl pyridinium salt
and aryl bromide, and the neutral conditions allow exceptional
scope of pyridinium salts, particularly those with base-sensitive
functional groups. During the preparation of this manuscript,
Han and Rueping reported couplings of alkylpyridinium salts
and aryl iodides.12 These reports demonstrate feasibility of a
reductive coupling. However, it is important to note that aryl
iodides are less available than aryl boronic acids and esters; for
products and other targets, has spurred exciting innovations in
the development of reagents and methods for the incorpo-
ration of alkyl groups.1,2 Methods that harness ubiquitous
functional groups in cross-couplings provide opportunities to
exploit previously untapped feedstocks and for late-stage
functionalization.3 Our efforts focus on methods that enable
alkyl primary amines to be transformed into alkyl electrophiles.
Alkyl amines are prevalent in molecules ranging from simple
starting materials to complex natural products and drug
candidates.1b,4 They are easy to prepare, stable, and broadly
compatible with many functional groups, allowing them to be
carried deep into a synthetic sequence particularly when
protected.4c,d From the perspective of medicinal discovery,
alkyl amines are present in pharmaceutical libraries in vast
numbers and offer considerable diversity. For example, Pfizer’s
internal chemical inventory has >47 000 alkyl primary amines
(vs <30 000 primary and secondary alkyl halides).
We identified that alkyl amines, including those with
unactivated alkyl groups, can become effective reagents for
cross-couplings via conversion to Katritzky pyridinium
salts.5−7,5c,d,8,9 These Katritzky pyridinium salts are easily
prepared in a single step from the primary amine, are air- and
moisture-stable, and are convenient to purify. Their formation
is selective for primary amines, allowing other Lewis basic
groups to be tolerated in the substrate. We demonstrated a
nickel-catalyzed Suzuki−Miyaura arylation of alkylpyridinium
salts to form C(sp3)−C(sp2) bonds, the first example of using
an unactivated alkyl amine derivative in a cross-coupling.5a
Since our discovery, we and others have continued to develop
this underappreciated class of reagents.5,10
Received: March 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01014
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of the alkyl radical intermediate to another equivalent of 3a.
Changing the reductant to Mn0 gave increased yield (entry 2).
Further improvement was observed with the addition of LiCl
or MgCl2, by changing the solvent to NMP and by reducing
concentration (entries 3−5). These additives may accelerate
reduction of the NiII intermediates or assist in activating the
surface of the Mn0.13 Under these conditions, the equivalents
of Mn0 could be reduced (entry 6). Hypothesizing that an
electron-rich ligand was necessary to promote single-electron
transfer (SET) to the pyridinium cation, we found that 4,4′-
diOMeBipy provided an even higher yield of 74% (entry 7).
Because the aryl halide is often the precious component, we
investigated conditions with aryl bromide as the limiting
reagent and observed 85% isolated yield (1.2 equiv of
pyridinium 3a, entry 8). Control experiments confirmed that
NiCl2·DME, ligand, and Mn0 are required (entries 9−11 and
13) and that MgCl2 still provides a beneficial effect (entry 12).
With minimal precaution taken to exclude air and moisture
(set up under air, no drying of glassware or solvents), 53%
yield is observed (entry 14).
Scheme 1. Reductive Coupling of Alkyl Pyridinium Salts
and Aryl Bromides
example, less than 300 (het)aryl iodides are in Pfizer’s internal
inventory, making these methods of limited utility for the
incorporation of diverse and readily available aryl groups.
In an effort to optimize conditions for the incorporation of
heteroaryls, we selected the reductive coupling of pyridinium
salt 3a and 3-bromoquinoline for optimization. To maximize
the utility of this reaction for the use of precious alkyl amines
and/or precious aryl bromides, we prioritized conditions that
would allow approximately equimolar amounts of alkyl
pyridinium salt and aryl halide to be used. Using NiBr2·DME
and 4,4′-ditBuBipy, a promising 9% yield was observed with Zn
as the reductant (Table 1, entry 1). However, dihydropyridine
5 was a major competing product, likely arising from addition
With these conditions in hand, we turned to the reductive
coupling of secondary alkylpyridinium salts. Disappointingly,
only 19% yield of product 6 was observed, and dihydropyridine
7 was formed in 32% yield (Scheme 2). In the absence of Ni
Scheme 2. Optimization of Secondary Alkyl Pyridinium
a
Salt
a
Table 1. Optimization of Primary Alkyl Pyridinium Salt
a
Conditions: pyridinium salt 3b (0.50 mmol), 3-bromoquinoline (1.1
equiv), NiCl2·DME (10 mol %), 4,4′-diOMeBipy (12 mol %), Mn0
(2.0 equiv), MgCl2 (1.0 equiv), NMP (0.17 M), 80 °C, 24 h, unless
noted otherwise. Yields determined by 1H NMR using 1,3,5-
trimethoxybenzene as internal standard.
b
yield (%)
entry
ligand
additive
4
5
Ar−Ar
cd
,
1
2
3
4,4′-ditBuBipy
4,4′-ditBuBipy
4,4′-ditBuBipy
4,4′-ditBuBipy
4,4′-ditBuBipy
4,4′-ditBuBipy
4,4′-diOMeBipy
4,4′-diOMeBipy
4,4′-diOMeBipy
none
−
−
LiCl
LiCl
MgCl2
MgCl2
MgCl2
MgCl2
MgCl2
MgCl2
MgCl2
−
9
24
25
14
12
8
5
4
4
d
d
26
54
60
65
67
74
85
0
0
0
50
0
53
catalyst, product 7 is formed in 39% yield, indicating a
noncatalyzed competitive pathway for the production of the
isopropyl radical via direct reduction by Mn0. Hypothesizing
that 7 forms from addition of the isopropyl radical to
pyridinium cation 3b instead of combination with a Ni(II)
intermediate (see mechanism discussion below), we proposed
that maintaining a low concentration of pyridinium cation vs
Ni catalyst would prevent formation of 7 and give higher yield
of 6. Indeed, slow addition of a solution of 3b and aryl bromide
resulted in a much improved 84% yield.14
4
10
15
17
15
n.d.
0
14
0
12
0
5
6
7
8
e
e
6
7
ef
,
g
n.d.
36
16
30
24
0
efh
, ,
9
ef
,
10
11
12
13 ,
14
ef h
, ,
none
ef
,
4,4′-diOMeBipy
4,4′-diOMeBipy
4,4′-diOMeBipy
fi
MgCl2
MgCl2
These optimized conditions proved general for a wide range
of alkyl pyridinium salts and aryl bromides (Scheme 3).
Primary and secondary alkyl pyridinium salts underwent
coupling in good yield, as did a benzylic pyridinium salt
(15). Even a quaternary carbon can be formed via cross-
coupling of a tertiary alkyl pyridinium salt, albeit in 35% yield
(20). Pyridinium salts with more bulky tertiary alkyls cannot
be prepared due to hindrance of the 2,6-diphenyls. In addition
to general exploration of functional group tolerance, we were
particularly interested in substrates that failed under the basic
conditions of our Suzuki−Miyaura arylation.5a Excitingly,
ef j
, ,
g
n.d.
n.d.
a
Conditions: pyridinium salt 3a (0.10 mmol), 3-bromoquinoline (1.1
equiv), NiCl2·DME (10 mol %), ligand (12 mol %), Mn0 (3.0 equiv),
additive (0 or 1.0 equiv), NMP (0.17 M), 80 °C, 24 h, unless noted
b
1
otherwise. Determined by H NMR using 1,3,5-trimethoxybenzene
c
d
as internal standard. Zn0 instead of Mn0. NiBr2·DME (10 mol %),
e
f
DMA (0.33 M). Mn0 (2.0 equiv). 3a (1.2 equiv), 3-bromoquinoline
g
h
i
(1.0 equiv). 1.0 mmol scale. Isolated yield. No NiCl2·DME. No
j
Mn0. Minimal precautions to protect from air and moisture. n.d. =
not determined.
B
DOI: 10.1021/acs.orglett.9b01014
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Amine intermediates used in the synthesis of the pharmaceut-
icals mosapride and Lipitor can also be arylated (24−26).15
Notably, the arylation to form 25 was successful on the gram
scale, demonstrating the scalability of this chemistry. Finally,
arylation of the pharmaceutical amlodipine provides a dramatic
example of the functional groups tolerated under these mild
reaction conditions (27).16
Scheme 3. Substrate Scope
We also observed excellent scope with respect to the aryl
bromide. Aryl boronate esters (13) can be incorporated into
the products. The use of 2-pyridyl bromide enabled the
challenging 2-pyridyl group to be installed (14), highlighting
another advantage over using an aryl boronic acid.17 A range of
other heteroaryl bromides were also effective, including
quinolyl (4, 6, 12, 20, 22), 3-pyridyl (8), dibenzothiophenyl
(11), benzofuranyl (19), and pyrimidyl (21). 3-Pyridyl iodide
and chloride provided <10% yield.18 Aryl bromides with ortho
substitution, electron-donating groups, and some complex
heteroaryls provided low yields.19 Saturated heterocycles,
including morpholines 9, 24, and 25, piperazine 10, piperidine
19, pyrrolidine 22, ketal 26, and dihydropyridine 27, were also
tolerated. Additional functional groups compatible with this
method include dioxalane (9, 14), Boc-protected amines (10,
19, 22), esters (11, 16, 21, 26, 27), trifluoromethyls (12, 23,
27), nitriles (15, 26), ethers (15, 27), thioethers (21),
isoxazoles (25), and aryl chlorides (27). However, these
conditions fail for alkyl or alkynyl bromides.
We also investigated one-pot transformations of amine to
arylalkane. Although simultaneous addition of pyrilium salt,
aryl bromide, catalyst, and other reagents failed, telescoping
pyridinium formation and cross-coupling provided 50% yield
(Scheme 4). This yield is lower than when pyridinium salt 3a is
isolated (75%), but this protocol may be advantageous in
certain cases, such as parallel synthesis.
Scheme 4. Telescoped Pyridinium Formation and Cross-
Coupling
This reaction likely proceeds via a mechanism analogous to
reductive cross-couplings of alkyl halides with aryl halides
(Scheme 5A).20 Oxidative addition of aryl bromide to a Ni0
intermediate generates an arylnickel(II) bromide. Single-
electron transfer (SET) from a NiI intermediate to the
pyridinium salt generates a neutral pyridyl radical, which then
fragments to give alkyl radical 28. Alkyl radical 28 may also
form via reduction by Mn0, particularly for secondary
alkylpyridinium salts. Combination of radical 28 with an
arylnickel(II) intermediate delivers NiIII species 29. Reductive
elimination then releases product 30 and regenerates a NiI
intermediate. In support of the oxidative addition of the aryl
bromide, 24% yield of product 4 is observed when tetrakis-
(dimethylamino)ethylene (TDAE) is used in place of Mn0,
suggesting an arylmanganese intermediate is not required
(Scheme 5B). The intermediacy of alkyl radical 28 is
consistent with the observed opening of cyclopropylmethylpyr-
idinium 3s and the formation of TEMPO-trapped adduct 32
a
Conditions: pyridinium salt 3 (1.2 mmol), aryl bromide (1.0 mmol),
NiCl2·DME (10 mol %), 4,4′-dimethoxy-2,2′-bipyridine (12 mol %),
Mn0 (2.0 equiv), MgCl2 (1.0 equiv), NMP (0.17 M), 80 °C, 24 h.
b
Average isolated yields ( 5%) from duplicate experiments. Slow
addition of pyridinium salt 3 (1.0 mmol) and aryl bromide (1.1
mmol). 4.0 mmol scale, single experiment.
c
pyridinium salts with β-electron-withdrawing groups are
effective substrates (11 and 12); elimination is not observed
under these mild, neutral conditions. Protic functional groups
(primary amide, indole, alcohol, and dihydropyridine) were
also well tolerated (16−18, 23, and 27). Successful pyridinium
formation and arylation of a number of natural product and
pharmaceutically relevant alkyl amines highlight another
advantage of using alkyl amines as precursors for late-stage
functionalization. For example, pyridinium salts derived from
amino acids (21, 22) and amino alcohols (23) can be utilized.
C
DOI: 10.1021/acs.orglett.9b01014
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Fellowships (J. L., C.H.B.). We thank the Martin and
Molander groups for helpful discussions. Data were acquired
at UD on instruments obtained with the assistance of NSF and
NIH funding (NSF CHE0421224, CHE1229234,
CHE0840401, and CHE1048367; NIH P20 GM104316, P20
GM103541, and S10 OD016267). We thank Lotus Separa-
tions, LLC, for assistance with SFC.
Scheme 5. Mechanism and Supporting Experiments
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01014.
Experimental details and data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*M. G.: michelle.garnsey@pfizer.com.
*M.P.W.: mpwatson@udel.edu.
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ORCID
Jennie Liao: 0000-0002-8351-8731
Mary P. Watson: 0000-0002-1879-5257
Author Contributions
§C.H.B. and M.E.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the NIH (R01 GM111820), Pfizer, Inc., and
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F
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