Visible Light-Mediated Decarboxylative Alkylation of Pharmaceutically Relevant Heterocycles

Article abstract of DOI:10.1021/acs.orglett.8b01250

A net redox-neutral method for the decarboxylative alkylation of heteroarenes using photoredox catalysis is reported. Additionally, this method features the use of simple, commercially available carboxylic acid derivatives as alkylating agents, enabling the facile alkylation of a variety of biologically relevant heterocyclic scaffolds under mild conditions.

Full text of DOI:10.1021/acs.orglett.8b01250

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible Light-Mediated Decarboxylative Alkylation of
Pharmaceutically Relevant Heterocycles
Alexandra C. Sun,‡ Edward J. McClain,‡ Joel W. Beatty, and Corey R. J. Stephenson*
Willard Henry Dow Laboratory, Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor,
Michigan 48109, United States
S
* Supporting Information
ABSTRACT: A net redox-neutral method for the decarboxylative alkylation of heteroarenes using photoredox catalysis is
reported. Additionally, this method features the use of simple, commercially available carboxylic acid derivatives as alkylating
agents, enabling the facile alkylation of a variety of biologically relevant heterocyclic scaffolds under mild conditions.
he direct C−H functionalization of N-heteroarenes
Tprovides expedient access to an array of heterocyclic
motifs prevalent throughout many natural products, advanced
materials, and pharmaceuticals.1 In the context of drug
discovery, C−H (perfluoro)alkylation strategies can facilitate
both the diversification of structural libraries as well as the late-
stage modification of clinical candidates.2 To this end, our
group has reported a radical trifluoromethylation strategy that
enables the direct trifluoromethylation of a range of vinyl, aryl,
and heteroaryl substrates using photoredox catalysis.3 The
employment of pyridine N-oxide as a redox auxiliary provides a
novel mode of activating carboxylic acid derivatives, such as
trifluoroacetic anhydride, by inducing reductive decarboxylation
to generate the trifluoromethyl radical. This reaction paradigm
of coupling electron-deficient radicals with electron-rich
heterocycles (Figure 1A) has been further elaborated upon in
accessing the chlorodifluoromethyl radical for the synthesis and
diversification of difluoromethylheteroarenes, as detailed in the
preceding manuscript. A separate, orthogonal mode of
reactivity achievable by altering the electronics of this system
involves the direct coupling of electron-deficient heterocyclic
N-oxides with electron-rich alkyl radicals. This fragment
coupling approach invokes the use of a heterocyclic N-oxide
reagent as both a transient redox auxiliary as well as a coupling
partner for electron-rich alkyl radicals. Specifically, the
decarboxylation of electron-rich carboxylic acid derivatives
through reduction of electron-poor heterocyclic N-oxides
generates an electronically matched pair of reactants, which
can combine and provide coupled products in a selective
fashion. We envisioned the immediate applicability of this
reaction paradigm toward the design of a facile Minisci
alkylation reaction. The Minisci reaction (Figure 1B), which
Figure 1. (A) Reaction design principles. (B) Oxidative alkyl radical
generation. (C) Reductive alkyl radical generation.
involves the direct C−H alkylation of heteroarenes by a carbon-
centered radical, has garnered much attention and has
undergone significant development in recent years.4−6 Minisci’s
Received: April 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01250
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Organic Letters
Letter
Scheme 1. Alkyl Carboxylic Acid Derivative Scope
a
b
Isolated yields of reactions run on a 0.8 mmol scale with 1.6 mL of acetonitrile (0.5 M) and 1.1 equiv of acid chloride reagent. Isolated as a mixture
c
d
e
with 4-phenylpyridine. Run using difluoroacetic anhydride (1.1 equiv). Endo isomer obtained. See the SI Experimental Procedures for overall
mass balance details.
original protocol for the decarboxylative alkylation of hetero-
cycles relied on the use of stoichiometric silver salts, persulfate
oxidants, and elevated temperatures.4a Since this initial
publication, methods for achieving the Minisci alkylation have
evolved to incorporate a diverse range of alkylating agents,
including trifluoroborate salts,5a,b sulfinates,5c,d and alcohols.6a
In particular, the application of photoredox catalysis for Minisci
alkylations has led to significant improvements in the
sustainability of this transformation, with the development of
conditions that require lower reagent loadings and nonoxidative
routes for alkyl radical generation.6
While a multitude of protocols have been developed for the
oxidative generation of alkyl/fluoroalkyl radicals for Minisci-
type transformations, methods that promote the reductive
radical alkylation of N-heteroarenes are comparatively less
established (Figure 1C).6b,g,h In the context of photoredox
catalysis, the formation of alkyl radicals through a reductive
pathway would enable a net redox−neutral catalytic cycle,
thereby eliminating the need for a stoichiometric terminal
oxidant. Notably, in 2014, DiRocco and co-workers reported
the photocatalytic alkylation of N-heterocycles through the
reductive generation of alkyl radicals using perester reagents.6b
Recently, the groups of Sherwood and Proctor have
independently demonstrated the usage of N-(acyloxy)-
phthalimides for the reductive decarboxylation of alkyl
carboxylic acids in Minisci-type transformations.6g,h In compar-
ison with previously reported Minisci alkylation methods, the
decarboxylative alkylation strategy disclosed herein precludes
the use of strongly acidic conditions and a sacrificial redox
auxiliary. In using a fragment-coupling approach, waste
production can be inevitably decreased, as the mutual substrate
activation through acylation avoids the use of stoichiometric
additives for inherent reactivity. Reduced heterocyclic N-oxides
can additionally act as endogenous bases, and reactive radical
intermediates can be controlled based upon the electronics of
reagents in the system.
Pivaloyl chloride and 4-phenylpyridine N-oxide were chosen
as model substrates for initial pyridine alkylation evaluation.
Upon screening several solvents and photocatalysts,7 we
discovered that a combination of acetonitrile and 1 mol % of
[Ir(ppy)2(dtbbpy)]PF6 furnished the desired 2-tert-butyl-4-
phenylpyridine product in 75% yield as well as the 2,4-di-tert-
butylated product in 5% yield (Scheme 1, 1). Under the
optimized conditions, the scope of decarboxylative alkylations
was examined with a number of alkyl carboxylic acid derivatives.
Successful methylation (2) of 4-phenylpyridine N-oxide was
achieved, albeit at a lower yield (20%), due to decreased radical
stability and nucleophilicity.8 Difluoromethylation (3) was also
achieved with the use of difluoromethylacetic anhydride as a
source of the CF2H radical. Moreover, propionic acid could be
used for the ethylation (4) of 4-phenylpyridine in modest yield
(50%). This protocol proved amenable to the coupling of 4-
phenylpyridine with a wide range of secondary and tertiary
cyclic alkanes (5−13), including the cyclohexyl (9) motif,
which has been demonstrated to be a bioisostere of the phenyl
functionality.9 Linear alkyl chains (14) could also be
successfully accessed in modest yields, along with bridged
cyclic alkane motifs such as the medicinally relevant
norbornene bicycle (12).10 In contrast, the benzylation (15)
of 4-phenylpyridine N-oxide proceeded with significantly
diminished yields. A predominant side reaction that was
observed involved the formal decarbonylation of phenylacetyl
chloride, yielding 73% formation of benzyl chloride. Fur-
thermore, these conditions enabled the successful appendage of
medicinally relevant fluorinated isosteres11 onto heteroarenes,
including the first example of incorporating the 1-fluorocyclo-
propane motif (17) onto a heterocyclic scaffold in one step
from its carboxylic acid precursor. A variety of heterocyclic
motifs (19−24) successfully underwent cross coupling with 4-
phenylpyridine N-oxide, including the tetrahydropyranyl (16)
and piperidinyl (22−24) ring systems, which have been used as
H-bond donor/acceptor probes in SAR studies.12 Most notably,
we have demonstrated the unique coupling of a tertiary
B
DOI: 10.1021/acs.orglett.8b01250
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Scheme 2. Heterocyclic N-Oxide Scope
a
Isolated yields of reactions run on a 0.8 mmol scale with 1.6 mL of acetonitrile (0.5 M) and 1.1 equiv of acid chloride or anhydride reagent.
Asterisks denote additional sites of functionalization. See the SI Experimental Procedures for overall mass balance details.
b
c
azetidine-derived radical (20) with an unactivated heteroarene,
fragment coupling approach. As is evidenced by the significant
recovery of N-oxide starting material, the observed lack of
reactivity is suspected to be due to the diminished
nucleophilicity of the N-oxide motif rather than inefficient
radical addition.14 tert-Butylation of quinoxaline did proceed
successfully, however, in the presence of pyridine N-oxide as a
redox auxiliary (Scheme 3, 38). Furthermore, transitioning
a transformation otherwise inaccessible to traditional transition
metal-mediated cross-coupling methods. Overall, a variety of
alkyl substrates, differing in size and electronic properties, have
been demonstrated to be successful coupling partners in this
transformation. An added benefit to this methodology entails
the direct in situ formation of noncommercially available acid
chloride reagents from the corresponding carboxylic acid (via
oxalyl chloride and catalytic DMF), followed by addition of the
heterocyclic N-oxide, without the need for any additional
purification or isolation steps.
Scheme 3. Alkylation of Heterocycles with Pyridine N-Oxide
In the next phase of this study, we evaluated a variety of
diverse and pharmaceutically relevant heterocyclic motifs
(Scheme 2). The tert-butylation of mildly electron-deficient
pyridine N-oxide derivatives, such as ethyl isonicotinate N-
oxide (25) as well as 4-acetylpyridine N-oxide (26), proceeded
in good yields (75% and 52% respectively). Additionally, our
studies showed that electron-rich pyridine N-oxides, such as
alkylated N-oxides and protected alcohols (27−29), could
undergo tert-butylation in good to modest yields. 7-Azaindole,
which can be considered as a bioisostere of the indole and
purine motifs and constitutes an essential subunit of many
pharmacophores,2b,13 could also be functionalized regioselec-
tivity (30) using this protocol. Quinoline N-oxide was
successully tert-butylated in 76% yield, leading to a 4:3 mixture
of regioisomers (33). Several quinoline N-oxide derivatives
containing methyl, methoxy, bromo, and chloro substituents, in
addition to benzoquinoline, were alkylated in modest yields
(31−36). The lower yields observed in the tert-butylation of
lepidine N-oxide (34) can be attributed to competing
deprotonation of the methyl substituent upon generation of
the acylated species, which results in displacement of pivalic
acid and precludes reductive alkyl radical generation.
Furthermore, difluoromethylation of 6-methoxyquinoline (37)
exclusively resulted in functionalization at the 4-position.
While a variety of pyridine- and quinoline-based heterocyclic
scaffolds could be accessed as coupling partners, functionaliza-
tion of other five- and six-membered heterocyclic N-oxides,
including benzylimidazole, quinoxaline, pyrimidine, and pyr-
idazine N-oxide derivatives could not be achieved using this
a
Isolated yields of reactions run on a 0.8 mmol scale with 5 equiv of
pyridine N-oxide, 5.5 equiv of acid chloride or anhydride reagent, and
1.6 mL of acetonitrile (0.5 M).
from simple heterocyclic substrates to more complicated,
biologically relevant molecular scaffolds presents further
challenges, as both the selective formation of the N-oxide
functionality and the ability to predict the nucleophilicity of the
N-oxide increase in complexity. We envisioned that the use of
pyridine N-oxide as a sacrificial redox auxiliary would be an
ideal platform for the alkylation of complex pharmacophore
molecules. This concept came to fruition as subjection of
brimonidine, a drug molecule used for the treatment of rosacea
and open-angle glaucoma, to decarboxylative alkylation
conditions furnished the tert-butylated derivative in 11% yield
(39). Additionally, we were able to tert-butylate (44% yield) the
imidazopyridazine core structure (41).15 Further diversification
of the scaffold gave rise to the methylated (42) (16% yield) and
difluoromethylated (43) (13% yield) analogues.
C
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Quantum yield studies indicate that radical-chain processes
are operative in our system, as evidenced by a ϕ of 1.7.7
Crossover experiments demonstrate the viability of both
intramolecular fragment coupling, as well as intermolecular
radical propagation pathways, as the decarboxylative alkylation
of two differentially functionalized acylated species gave rise to
an approximately 1:1 distribution of self-functionalized and
cross-functionalized products.7 Finally, we have demonstrated
the capability to run this decarboxylative alkylation reaction on
gram scale both in batch and in flow, suggesting that this
methodology may translate beyond discovery scale. Using a 900
μL flow reactor, 1 g of quinoline N-oxide was tert-butylated in
an overall 71% yield (relative to 68% yield on a 1 g scale in
batch), with a residence time of 2.25 min.7
In conclusion, we have reported an operationally simple and
visible light-mediated method for the decarboxylative alkylation
of heterocyclic N-oxides. Most significantly, this protocol offers
a platform for the reductive generation of alkyl radicals without
the reliance on stoichiometric additives, harsh reagents, and
sacrificial redox auxiliaries. We envision this methodology to be
of significant utility and practicality for the diversification of
heterocyclic scaffolds in a multitude of medicinal applications.
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.8b01250.
Descriptions of batch and flow photochemical setups,
additional data, procedures, and characterization data for
all compounds (PDF)
(7) See the Supporting Information for experimental details.
(8) De Vleeschouwer, F.; Van Speybroeck, V.; Waroquier, M.;
Geerlings, P.; De Proft, F. Org. Lett. 2007, 9, 2721.
(9) Gunaydin, H.; Bartberger, M. D. ACS Med. Chem. Lett. 2016, 7,
341.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: crjsteph@umich.edu.
ORCID
(10) Stockdale, T. P.; Williams, C. M. Chem. Soc. Rev. 2015, 44, 7737.
(11) (a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.;
Meanwell, N. A. J. Med. Chem. 2015, 58, 8315. (b) Purser, S.; Moore,
P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(c) Ritchie, T. J.; Macdonald, S. J. F. Eur. J. Med. Chem. 2016, 124,
1057.
Corey R. J. Stephenson: 0000-0002-2443-5514
Author Contributions
‡A.C.S. and E.J.M. contributed equally.
Notes
(12) Murphy-Benenato, K. E.; Olivier, N.; Choy, A.; Ross, P. L.;
Miller, M. D.; Thresher, J.; Gao, N.; Hale, M. R. ACS Med. Chem. Lett.
2014, 5, 1213.
(13) Popowycz, F.; Routier, S.; Joseph, B.; Merour, J.-Y. Tetrahedron
2007, 63, 1031.
The authors declare no competing financial interest.
(14) Baidya, M.; Brotzel, F.; Mayr, H. Org. Biomol. Chem. 2010, 8,
1929.
(15) Douglas, J. J.; Cole, K. P.; Stephenson, C. R. J. J. Org. Chem.
ACKNOWLEDGMENTS
■
The authors acknowledge the financial support of this research
from the NIH NIGMS (R01-GM096129), the Camille Dreyfus
Teacher−Scholar Award Program, and the University of
Michigan. This material is based upon work supported by the
National Science Foundation Graduate Research Fellowship for
A.C.S. (supported under Grant No. DGE 1256260). The
authors thank Eli Lilly for providing compound 40.
2014, 79, 11631.
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DOI: 10.1021/acs.orglett.8b01250
Org. Lett. XXXX, XXX, XXX−XXX