Cobalt-Catalyzed Alkylation of Drug-Like Molecules and Pharmaceuticals Using Heterocyclic Phosphonium Salts

Article abstract of DOI:10.1021/acscatal.9b00851

Alkylated pyridines are common in pharmaceuticals, and metal catalysis is frequently used to prepare this motif via Csp²-Csp³ coupling processes. We present a cobalt-catalyzed coupling reaction between pyridine phosphonium salts and alkylzinc reagents that can be applied to complex drug-like fragments and for late-stage functionalization of pharmaceuticals. The reaction generally proceeds at room temperature, and 4-position pyridine C-H bonds are the precursors in this strategy. Given the challenges in selectively installing (pseudo)halides in complex pyridines, this two-step process enables sets of molecules to be alkylated that would be challenging using traditional cross-coupling methods.

Full text of DOI:10.1021/acscatal.9b00851

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Letter
Cobalt-Catalyzed Alkylation of Drug-Like Molecules and
Pharmaceuticals Using Heterocyclic Phosphonium Salts
xuan zhang, and Andrew McNally
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00851 • Publication Date (Web): 22 Apr 2019
Downloaded from http://pubs.acs.org on April 22, 2019
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Cobalt-Catalyzed Alkylation of Drug-Like Molecules and
Pharmaceuticals Using Heterocyclic Phosphonium Salts
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Xuan Zhang and Andrew McNally*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States.
Supporting Information Placeholder
methods exist to install alkyl groups via C–H
ABSTRACT: Alkylated pyridines are common in
pharmaceuticals, and metal catalysis is frequently
used to prepare this motif via Csp2-Csp3 coupling
processes. We present a cobalt-catalyzed coupling
reaction between pyridine phosphonium salts and
alkylzinc reagents that can be applied to complex
functionalization reactions including Minisci-type
reactions and metal-catalyzed coupling reactions with
alkenes.5,6 Despite significant progress, controlling
regioselectivity and tolerating a broad range of
pyridines can be problematic in these respective
reaction types. Adding organometallics to pyridinium
salts is another approach and Fier recently showed an
example where an alkyl group was added via this
drug-like
fragments
and
for
late-stage
functionalization of pharmaceuticals. The reaction
generally proceeds at room temperature, and 4-
position pyridine C–H bonds are the precursors in this
strategy. Given the challenges in selectively installing
(pseudo)halides in complex pyridines, this two-step
process enables sets of molecules to be alkylated that
would be challenging using traditional cross-coupling
methods.
Pyridines, alkylation, late-stage, phosphonium salts,
cross-coupling, cobalt-catalysis, alkyl Negishi.
Pyridines are important pharmacophores in
therapeutic compounds, but their precise function is a
combined effect of the heterocycle and its adorning
substituents.1 Alkylated pyridines are particularly
common, and examples of their occurrence in
marketed drugs are shown in eq 1. The alkyl groups
serve various roles in drug development, such as
occupying hydrophobic pockets, changing binding
properties of the Lewis basic nitrogen atom,
protecting against oxidative metabolism as well as
serving as linkers to other portions of the molecule.2
The effect of alkyl groups on pyridines is also relevant
for other applications such as ligands, materials and
redox active molecules in batteries.3,4 As such,
methods to add alkyl groups to pyridines are broadly
useful in several disciplines of applied chemistry.
reaction pathway.7 The most common methods to
make alkylated pyridines are transition metal-
catalyzed
cross-coupling
reactions
between
pyridyl(pseudo)halides and alkyl organometallic
reagents.8 These reactions are broadly effective to
alkylate pyridine building blocks where halide or
psuedohalides are commercially available, or can be
Coupling reactions are modular and efficient ways
of forming Csp2-Csp3 bonds between pyridines and
functionalized carbon-bearing groups. Several
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prepared. In drug development however, pyridine-
Page 2 of 9
be directly and selectively installed on a broad range
of substrates, and subsequent transformations are
compatible with polar functional groups that are often
found in drug like-molecules.10 Furthermore, the
reaction is 4-selective for pyridines, a position that is
difficult to access using most methods. We have
previously shown that phosphonium ions can serve as
pseudohalides in a nickel-catalyzed coupling process
with (hetero)aryl boronic acids. Combining a Ni(0)
catalyst with an NHC ligand was crucial for selective
heterocycle vs. phenyl coupling using PPh3-derived
azine salts.9d Our attempts at developing an alkylation
reaction began with pyridine phosphonium salt 1a
and butylzinc as a coupling partner in THF at 50 ºC
(Table 1). Entry 1 shows that our previous nickel-
system results in an unselective mixture of
butylpyridine 2a and phenyl-coupling product 3.
Using phosphine or bipyridine ligands were similarly
unselective, as were ligated palladium catalysts
(entries 2–5). We instead turned our attention to
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containing molecules are often complex and devoid of
cross-coupling handles. Furthermore, these molecules
have multiple reactive sites, substitutional variability
and an excess of polar function groups making
selective (pseudo)halogenation of C–H bonds
challenging, or impossible, using existing methods (eq
2). Our goal was therefore to address this challenge
using an alternative cross-coupling precursor, and
9
herein we present
a cobalt-catalyzed coupling
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reaction between alkylzinc reagents and pyridine
phosphonium salts (eq 3). The reaction
Table 1. Development of a Phosphonium Salt Alkylation
Reaction
cobalt-catalysis and tested
a Co(III) salt with
bipyridine (L1) as a ligand.11,12 Gratifyingly, the
reaction was selective for pyridine 2a with only traces
of butylbenzene 3 observed in the reaction mixture
(entry 6), although the reaction efficiency was low.
Conducting the reaction at room temperature
resulted in a similar yield of 2a (entry 7). Methoxy
substituted bipyridine L2 was significantly more
effective as a ligand indicating that increased electron
density at the metal center improves reactivity. A
screen of Lewis basic additives revealed that N-Me
imidazole further increase the efficiency of the
reaction (entries 8 & 9).13 We hypothesized that the
additive
aYields
calculated
by
GC
using
1,3,5-
trimethoxybenzene as a standard. THF concentration
0.1 M. bTHF concentration 0.033 M.cIsolated yield.
operates at room temperature and forms a diverse set
of alkylated pyridines from C–H precursors.
Our laboratory is developing a program where
phosphonium groups can serve as generic functional
handles to functionalize pyridines and diazines.9 This
strategy overcomes significant deficiencies of using
heteroaryl (pseudo)halides as the C–+PPh3 group can
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Table 2. Scope of Alkyl Zinc Reagentsa
b
aIsolated yields of products are shown. The reaction
c
1
was run at 50 ºC. 10 mol% Co(acac)3 and 10 mol% L3
2
3
used.
sequesters the ZnClOTf byproduct; entry 10 shows
that adding a Zn(II) salt at the outset of the reaction is
deleterious to the yield of the process and supports
our hypothesis. The reaction was further improved by
decreasing the concentration to 0.033 M (entry 11)
and employing cyclohexyloxy-substituted bipyridine
L3 is the most effective protocol (entry 12). We
assume a low valent ligated cobalt species (Co(0) or
Co(I)) is the active catalyst and a typical oxidative
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addition-transmetalation-reductive
elimination
sequence constitutes the catalytic cycle.
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Table 3. Scope of Pyridine Building Blocks, Drug-Like Fragments and Complex Bioactive Moleculesa,b
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aTypical salt-forming conditions: azine (1.0 equiv), Tf2O (1.0 equiv), PPh3 (1.1 equiv), DBU (1.1 equiv) CH2Cl2 or
b
EtOAc, –78 ºC to rt. Isolated yields of products as single regioisomers (unless stated) are shown with yields of
phosphonium salts in parentheses. cThe reaction was conducted at 50 ºC. dA 3.5:1 mixture of 2u and 2,4-
dicyclobutylpyridine was observed in the crude 1H NMR spectrum.
The scope of alkylzinc reagents was examined using
phosphonium salt 1b as a representative substrate
(Table 2).9f Linear zinc reagents, containing phenyl,
chloro, cyano and ester groups, provide products 2b-
2e in moderate to good yields (2b-2e); conducting the
reaction at 50 ºC is optimal in the latter two cases. Silyl
ethers and carbazole fragments are also tolerated (2f
& 2g). Benzylzinc is a reasonable coupling partner
(2h), and cyclopropyl- and cyclobutylzincs result in
high yields of alkylated products (2i
& 2j).
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Cyclopentylzincs are less effective in this process but
usable quantities of 2k were obtained; we are
uncertain of the exact reasons for the decreased
yields, but we presume that an unfavorable steric
interaction is operative. This point was exemplified
when iso-propylzinc was examined; an isomeric
mixture of products 2l and 2m were obtained with the
linear product significantly favored. Our hypothesis is
that branched to linear isomerism occurs at a Co(II)-
forming phosphonium salts on 3-substituted
pyridines over 2-substituted isomers. Pyridine-
containing structures possessing a benzhydril center,
a protected pyrrolidine (2aa & 2ab) as well as a
precursor to the antihistamine bepotastine (2ac) can
also be alkylated. Quinolines are alkylated at the 2-
position when the 4-position is substituted (2ad &
2ae). A pyrimidine was also alkylated in this protocol,
and although the yield of 2af was low, a single
regioisomer was formed; C–P bond cleavage and
return of the C–H precursors was the main side
product in this reaction. Methylation of azines is a
common strategy in drug development and we tested
MeZnCl in this coupling process.15,16 While less
efficient than n-BuZnCl as a coupling reagent, four
examples of pyridines and quinolines were alkylated
in reasonable yields (2ag-2aj).17
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species via
a reversible -hydride elimination-
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hydrometallation sequence, and that the less hindered
linear alkylcobalt isomer undergoes reductive
elimination more rapidly.14 Examples of unsuccessful
coupling reactions include allyl zinc reagents, where a
complex mixture of products was observed, -zinc
carbonyls and a iodozinc amino acid derivative.
In Table 3, we applied the phosphonium-mediated
Late-stage
functionalization
of
therapeutic
coupling process to
a range azine-containing
compounds is an area of current importance in
medicinal chemistry and we examined five drug
compounds in the phosphonium-mediated strategy.18
The antihistamine, chlorphenamine is effective in this
protocol with butylated and cyclobutylated
structures. Pyridine building blocks containing
functional groups such as cyano, trifluoromethyl,
esters, methoxy, and boronic esters are tolerated (2n-
2r). Quinoline salts are amenable to the strategy and
2s was obtained as a single regioisomer. A 3-
fluoropyridine salt performed well in the Co-coupling
reaction (2t), however, a 2-substituted isomer was
formed along with the corresponding bis-alkylated
product in a 3.5:1 ratio (2u). Substrates that result in
low salt yields or give no C–P bond-formation include
2,6-disubstituted pyridines, acridines, 2-CF3-
pyridines and pyridines with more than two electron-
withdrawing groups or electron-donating groups.
Limitation of pyridyl phosphonium salts in the zinc
coupling process include chloro-, bromo-, and
iodopyridines that result in mixtures of alkylated
products via the C–Hal and C–P bonds as well as bis-
alkylation (vide infra). At this point, 2-
pyridylphosphonium salts are unsuccessful as
coupling partners as well as salts derived from 2,2-
bipyridines. Amino substituents at the 2-position of
lead to trace amounts of products and attempted
alkylation of a 3,5-dimethylphonium salt resulted in
return of the C–H precursor.
Next, a set of complex azines that approximate
structures encountered in medicinal chemistry
programs was tested.10 Starting with 3-substituted
pyridines, nicotine could be taken through the two-
step process and alkylated in moderate yield (2w).
Alkylated pyridines 2x and 2y are notable due to the
presence of other heterocycles and basic amines. Site-
selective alkylation reactions are desirable, and a
butyl group could be selectively installed on the 3-
substituted pyridine in 2z due to the preference of
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derivatives 2ak and 2al obtained in good yields.
Loratadine was cyclopropanated at the 4-position
Scheme 1. Chemoselective Co-Catalyzed
Alkylationsa
halogenated heterocycles as partners will provide
new opportunities in drug-development programs.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org
aIsolatedyields shown are of a mixture of 2aqand 2ar.
Standard C–P bond formation: 1as (1.0 equiv), Tf2O (1.0
equiv), PPh3 (1.1 equiv), DBU (1.0 equiv) CH2Cl2, –78 ºC
to rt. Switch C–P bond formation: 1as (1.0 equiv), Tf2O
(2.0 equiv), PPh3 (2.0 equiv), NEt3 (2.0 equiv) CH2Cl2, –78
ºC to rt. Co-catalysis: 10 mol% Co(acac)3, 10 mol% L3, N-
Methylimidazole (1.5 equiv), THF, 50 ºC.
AUTHOR INFORMATION
9
Corresponding Author
*andy.mcnally@colostate.edu
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ORCID
of the pyridine moiety in excellent yield (2am).
Pyriproxyfen, a pesticide, is also alkylated efficiently
(2an). A steroidal treatment for prostate cancer,
abiraterone acetate, can be conveniently converted
into alkylated derivative 2ao, and a protected version
of varenicline, possessing a quinoxaline core, is
alkylated adjacent to the heterocyclic nitrogen atom
(2ap).
Andrew McNally: 0000-0002-8651-1631
ACKNOWLEDGMENT
This work was supported by The National Institutes of Health
(NIGMS) under award number R01 GM124094 and partial
support from the Donors of the American Chemical Society
Petroleum Research Fund (ACS PRF56878-DNI1).
We next explored chemoselective Co-catalyzed
couplings and site-selective switching reactions in
polyazine substrates (Scheme 1). In our Ni-catalyzed
Suzuki-reaction, aryl bromides preferentially react
over pyri dylphosphonium salts.8d In this Co-catalyzed
process, we found the opposite order of
chemoselectivity. Salt 1aq,
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(17) In these cases, we found that adding a catalytic amount
of i-PrMgCl to the reaction mixture improved the yields of
methylated products. See Supporting Information for
details.
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(12) Cobalt halides can be used as catalysts but are marginally
less efficient than Co(acac)3. See Supporting Informtion
for more details.
(13) See the Supporting Information for an additive screen and
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(14) O’Neil, M.; Cornella, J. Retaining Alkyl Nucleophile
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(16) Ritter recently reported a Ni-catalyzed methylation of
pharmaceutically-relevant molecules via ammonium salts
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