Decarboxylative N-Alkylation of Azoles through Visible-Light-Mediated Organophotoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.1c01745

An organophotoredox-catalyzed decarboxylative cross-coupling between azole nucleophiles and aliphatic carboxylic acid-derived redox-active esters is demonstrated. This protocol efficiently installs various tertiary or secondary alkyl fragments onto the nitrogen atom of azole nucleophiles under mild and transition-metal-free conditions. The pyridinium additive successfully inhibits the formation of elimination byproducts from the carbocation intermediate. This reaction is applicable to the synthesis of a protein-degrader-like molecule containing an azole and a thalidomide.

Full text of DOI:10.1021/acs.orglett.1c01745

pubs.acs.org/OrgLett
Letter
Decarboxylative N‑Alkylation of Azoles through Visible-Light-
Mediated Organophotoredox Catalysis
̃
Rino Kobayashi, Shotaro Shibutani, Kazunori Nagao,* Zenichi Ikeda, Junsi Wang, Ignacio Ibánez,
Matthew Reynolds, Yusuke Sasaki, and Hirohisa Ohmiya*
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ABSTRACT: An organophotoredox-catalyzed decarboxylative
cross-coupling between azole nucleophiles and aliphatic carboxylic
acid-derived redox-active esters is demonstrated. This protocol
efficiently installs various tertiary or secondary alkyl fragments onto
the nitrogen atom of azole nucleophiles under mild and transition-
metal-free conditions. The pyridinium additive successfully inhibits
the formation of elimination byproducts from the carbocation
intermediate. This reaction is applicable to the synthesis of a protein-degrader-like molecule containing an azole and a thalidomide.
zoles are an important class of scaffolds found in many
pharmaceutical compounds and drug candidates, includ-
Scheme 1. N-Alkylation of Azoles
A
ing antifungal drugs.1 Among them, N-alkylated azoles have
gained much attention in recent medicinal chemistry.2 To this
end, a variety of synthetic methods for N-alkylation of azoles
have been developed. For the introduction of primary or
secondary alkyl groups to azoles, nucleophilic substitution with
alkyl electrophiles, including the Mitsunobu reaction, are
commonly employed.3 An alternative approach is the oxidative
N-alkylation of azoles using hydrocarbons bearing weak C−H
bonds and reactive oxidants.4 On the other hand, the
introduction of tertiary alkyl groups onto azoles depends on
conventional SN1-type reactions using tertiary alkyl halides or
tertiary alcohols with strong acids.5 Because of the difficulty of
substrate preparation and the poor functional group tolerance,
tertiary N-alkylation of azoles remains a key challenge for
medicinal chemists.
Recently, alkyl-radical-mediated N-alkylation of azoles under
mild reaction conditions has been intensively studied.
MacMillan and co-workers demonstrated that a copper catalyst
enabled the connection of nitrogen nucleophiles and alkyl
radicals generated from aliphatic carboxylic acid-derived
hypervalent iodine reagents with metallaphotoredox catalysis
(Scheme 1A).6 This approach enables the installation of
various primary, secondary, and tertiary alkyl groups onto the
nitrogen atom of nitrogen-based nucleophiles, including azoles.
Although a few examples of tertiary alkylation were
demonstrated, the scope of alkyl fragments was restricted.7
Against this background, Baran and co-workers expanded the
synthetic toolbox by employing electrochemical generation of
carbocations from aliphatic carboxylic acids to achieve N-
alkylation of azoles (Scheme 1B).8
alkylation source.9 The reaction proceeds through a redox-
neutral radical−polar crossover mechanism.10 Therein a
photoinduced single electron transfer (SET) from the catalyst
N-phenylbenzo[b]phenothiazine (PTH1)11 to a redox-active
ester12 produces a PTH1 radical cation and a radical anion
form of the redox-active ester, which releases an alkyl radical
with carbon dioxide and phthalimide anion. The resultant alkyl
radical is oxidized by the PTH1 radical cation to give the
Received: May 25, 2021
Published: June 17, 2021
We previously reported visible-light-mediated organopho-
toredox catalysis for alkylation of heteroatom nucleophiles
using aliphatic carboxylic acid-derived redox-active esters as an
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.orglett.1c01745
Org. Lett. 2021, 23, 5415−5419
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corresponding alkylsulfonium intermediate, which engages
with various heteroatom nucleophiles.
examined, the reaction efficiency was not improved (entries
4 and 5).
Other phenothiazine catalysts were examined (Table 1,
entries 6−9). Incorporation of an electron-deficient group on
the N-substituent of the benzo[b]phenothiazine catalyst did
not improve the yield of N-alkylated product (entries 6 and 7).
The reactions employing isomers of the benzophenothiazine
core as the organophotoredox catalyst did not proceed well
(entries 8 and 9).
In this work, we extended this visible-light-mediated
organophotoredox protocol to N-alkylation of azoles (Scheme
1C). Various tertiary and secondary benzyl fragments were
efficiently transferred from carboxylic acid-derived redox-active
esters to azoles under mild and transition-metal-free
conditions. This protocol provides an alternative synthetic
tool for N-alkylation of azoles.
The identity of the additive had an immense effect on the
formation of the desired product (Table 1, entries 10−14). We
assumed that the phthalimide anion generated from single-
electron reduction of a redox-active ester would act as a base to
promote the unproductive elimination (E1/E2) reaction. To
suppress this side reaction, a series of pyridinium salts (pKa =
3.4 for pyridinium in DMSO13) bearing a lower pKa than
phthalimide (pKa = 8.314) were examined. Unfortunately,
pyridinium tetrafluoroborate did not improve the product yield
(entry 10). A 2,6-di-tert-butylpyridine-derived HBF4 salt
showed comparable reactivity to LiBF4 (entry 11). Further
screening of pyridinium salts revealed that pyridinium salts
derived from 2,6-lutidine or 2,4,6-collidine increased the
product yield (entries 12 and 13). Finally, increasing the
amount of A4 and 2a drastically improved the yield of 3aa
(entry 14). This protocol was equally applicable on a 1 mmol
scale with a limited impact on the yield (entry 15).
The optimization of the reaction conditions for N-alkylation
of azoles was explored with 6-bromoindazole (1a) and pivalic
acid-derived redox-active ester 2a. After a quick screening, the
reaction of 1a and 2a was found to proceed in the presence of
PTH1 and lithium tetrafluoroborate salt as cocatalysts in 1,2-
dichloroethane under blue LED irradiation for 24 h to produce
the N-alkylated product 3aa in 20% yield (Table 1, entry 1).
MeCN, which was found to be the best reaction medium in
our previous report on etherification reactions, did not give the
desired product at all (entry 2). THF afforded the coupling
product 3aa in low yield (entry 3). Although other halogenated
solvents such as 1,2-dichlorobenzene and DCM were
a
Table 1. Screening of the Reaction Conditions
With the optimal reaction conditions established, the scope
of azoles was investigated with tert-butyl redox-active ester 2a
(Figure 1, top). A simple indazole also participated in the
reaction as an azole donor (3ba). Ester- or amide-substituted
indazoles were found to be suitable substrates (3ca−3ea). The
reaction with 4-methylindazole afforded the N-tert-butylated
product, although the yield was low (3fa). The reaction with
benzotriazole gave a mixture of regioisomers (3ga). A pyrazole
substrate efficiently coupled with 2a to give the desired
product (3ha). The scope of azoles was also evaluated with
tertiary benzylic redox-active ester 2b. In comparison with 2a,
the reactions with 2b gave the coupling products in relatively
high yields (3ab, 3ib, and 3db). A highly functionalized
pyrazole was also identified as a suitable substrate (3jb). When
a purine derivative and 5-azaindole were used as reaction
substrates, the corresponding coupling products 3kb and 3lb,
respectively, were obtained in moderate yields. These
substrates did not give any coupling product with 2a (data
not shown). As with 3ga, the reactions with benzotriazole 1g
gave a mixture of regioisomers (3gb). This protocol was not
applicable to other heteroatomatics containing carbazoles and
indoles (data not shown).
Our attention turned to the scope of aliphatic redox-active
esters (Figure 1, bottom). An acyclic aliphatic substituent
could be readily introduced (3dc and 3bd). The low yield of
3bd was thought to be due to the competitive elimination
reaction. Our protocol facilitated the installation of various 1-
methylcycloalkyl groups on the nitrogen atom of an indazole
fragment (3be−bg). The carboxylic acid moiety of gemfibrozil
was transformed into an azole group using this organo-
photoredox catalytic method (3bh). Both acyclic and cyclic
tertiary benzylic redox-active esters worked as N-alkylating
reagents (3bb, 3di, 3dj, 3bk, and 3bl). Secondary benzylic
azoles could be prepared using the corresponding carboxylic
acids, including ketoprofen (3gm, 3bn, and 3bo). Although we
tested the reactions with unactivated secondary or primary
redox-active esters, the desired product were not obtained
a
The reaction was carried out with 1a (0.2 mmol), 2a (0.3 mmol),
PTH1 (0.01 mmol), and LiBF4 (0.02 mmol) in solvent (0.5 mL)
b
under blue LED irradiation for 24 h. 1H NMR yields.
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Scheme 2. Mechanistic Studies and Application to the
Synthesis of a Protein-Degrader-like Molecule
was checked (Figure S4). As a result, the formation of the
alkene was suppressed, albeit slightly. Next, cyclic voltammetry
experiments on A4 and 2a were carried out (see Figures S5
and S6). The CVs of A4 and 2a showed irreversible waves (Epc
= −1.62 and −1.33 V vs SCE, respectively). Upon the addition
a
Figure 1. Substrate scope. Notes: The reaction was carried out with
1 (0.2 mmol), 2 (0.4 mmol), PTH1 (0.01 mmol), and A4 (0.4 mmol)
in DCE (0.5 mL) under blue LED irradiation for 24 h. bThe reaction
was carried out with 1 (0.2 mmol), 2 (0.3 mmol), PTH1 (0.01
mmol), and LiBF4 (0.02 mmol) in AcOEt (0.5 mL) under blue LED
of A4 to 2a, the reduction wave of 2a slightly moved to Epc
=
−1.12 and −1.22 V vs SCE (Figure S7). Following our
previous report, we investigated whether A4 is involved in the
formation of a charge-transfer complex between PTH1 and the
redox-active ester. The UV−vis absorption spectra for various
combinations of PTH1, 2a, and A4 were measured under the
optimal reaction conditions (Figure S8). No significant shift of
the absorption band was observed when A4 was added to the
mixture of PTH1 and 2a. These observations above suggested
that A4 possibly acts as a Brønsted acid that facilitates the
electron transfer from PTH1 to the redox-active ester and
traps the catalytically generated phthalimide anion.
On the basis of the mechanistic studies shown above, the
proposed mechanism for the organophotoredox-mediated
radical−polar crossover is summarized in Scheme 2B. First,
PTH1 and redox-active ester 2 assemble to form charge-
transfer complex B. Blue LED irradiation induces SET from
PTH1 to 2 to afford the radical cation form of PTH1 (C) and
c
irradiation for 24 h. See the Supporting Information for the details.
(data not shown), possibly because of the slow formation of
the corresponding alkyl radicals.
To shed light on the reaction mechanism, various studies
were conducted. First, the reaction of 1b and redox-active ester
2p bearing a β-alkoxy substituent was conducted (Scheme 2A).
The alkylation occurred at the α-alkoxy position and not at the
original α-carbonyl position. This 1,2-carbocation rearrange-
ment supported the hypothesis that a carbocation intermediate
or an equivalent species plays a role in this catalytic cycle.
The role of additive A4 was also investigated. First, to see
whether A4 inhibits the elimination (E1/E2) reaction, the
product ratio of the reactions of 1b and 2h with or without A4
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the radical anion form of 2 (D). In the presence of collidine
HBF4 (A4), D generates alkyl radical E with the release of
carbon dioxide, phthalimide, and collidine. Recombination of
C and E through SET followed by complexation affords
alkylsulfonium intermediate F, which then reacts with azole
nucleophile 1 in the presence of collidine to give the N-
alkylated product 3 and regenerate A4 and PTH1.
Matthew Reynolds − Research, Takeda Pharmaceutical
Company Limited, Fujisawa, Kanagawa 251-8555, Japan
Yusuke Sasaki − Research, Takeda Pharmaceutical Company
Limited, Fujisawa, Kanagawa 251-8555, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01745
To demonstrate the synthetic utility of this decarboxylative
alkylation, this protocol was applied to synthesis of a protein-
degrader-like molecule15 (Scheme 2C). For this purpose, a
partial protein-degrader-like precursor 2q bearing a thalido-
mide as an E3 ligase ligand moiety and a tertiary redox-active
ester as a cross-linker moiety was prepared. The reaction of 1a
and 2q under the standard reaction conditions proceeded to
afford the coupling product 3aq.
In conclusion, we have developed a synthetic tool for N-
alkylation of azole compounds using visible-light-mediated
organophotoredox catalysis. The collidine HBF4 additive acts
as a Brønsted acid that efficiently inhibits the elimination
reaction of the carbocation intermediate caused by the
phthalimide anion. Notably, this reaction does not require
transition metals, external oxidants/reductants, and strong
acids, which have been utilized in previously reported methods.
The high functional group tolerance of this protocol was
demonstrated through the application of this reaction to the
synthesis of a protein-degrader-like molecule. On the basis of
this achievement, our group is aiming to expand the scope of
amine nucleophiles that can be employed in this reaction.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI (Grants
JP21H04681, JP17H06449, and JP21K15223), Kanazawa
University (SAKIGAKE Project 2020), Takeda Pharmaceutical
Company Limited, and JST PRESTO (Grant JPMJPR19T2).
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Experimental details and characterization data for all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Kazunori Nagao − Division of Pharmaceutical Sciences,
Graduate School of Medical Sciences, Kanazawa University,
Kanazawa 920-1192, Japan; orcid.org/0000-0003-
3141-5279; Email: nkazunori@p.kanazawa-u.ac.jp
Hirohisa Ohmiya − Division of Pharmaceutical Sciences,
Graduate School of Medical Sciences, Kanazawa University,
Kanazawa 920-1192, Japan; JST, PRESTO, Kawaguchi,
Saitama 332-0012, Japan; orcid.org/0000-0002-1374-
1137; Email: ohmiya@p.kanazawa-u.ac.jp
Authors
Rino Kobayashi − Division of Pharmaceutical Sciences,
Graduate School of Medical Sciences, Kanazawa University,
Kanazawa 920-1192, Japan
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Zenichi Ikeda − Research, Takeda Pharmaceutical Company
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Junsi Wang − Research, Takeda Pharmaceutical Company
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̃
Ignacio Ibánez − Research, Takeda Pharmaceutical Company
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