Ligand-Accelerated Iron Photocatalysis Enabling Decarboxylative Alkylation of Heteroarenes

Article abstract of DOI:10.1021/acs.orglett.9b01439

A mild, practical protocol for the decarboxylative alkylation of heteroarenes has been accomplished via iron photocatalysis. A diverse range of carboxylic acids readily undergo oxidative decarboxylation and then couple with a broad array of heteroarenes in this transformation. The photoexcited state lifetimes of iron complexes are typically much shorter than those of iridium and ruthenium complexes. Here we describe our effort on iron photocatalysis by utilizing the intramolecular charge transfer pathway of iron-carboxylate complexes.

Full text of DOI:10.1021/acs.orglett.9b01439

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ligand-Accelerated Iron Photocatalysis Enabling Decarboxylative
Alkylation of Heteroarenes
Zhenlong Li, Xiaofei Wang, Siqi Xia, and Jian Jin*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai
200032, China
S
* Supporting Information
ABSTRACT: A mild, practical protocol for the decarboxylative alkylation of heteroarenes has been accomplished via iron
photocatalysis. A diverse range of carboxylic acids readily undergo oxidative decarboxylation and then couple with a broad array
of heteroarenes in this transformation. The photoexcited state lifetimes of iron complexes are typically much shorter than those
of iridium and ruthenium complexes. Here we describe our effort on iron photocatalysis by utilizing the intramolecular charge
transfer pathway of iron−carboxylate complexes.
ron is the second most abundant metal on Earth only after
aluminum. Iron complexes were the most frequently
I
investigated compounds in the area of photochemistry and
photophysics of inorganic compounds prior to the 1970s.1
However, the attention of photochemists was shifted to the
redox-active, luminescent Ru(II) and Ir(III) polypyridyl
complexes with long-lived excited states,2 which provided
ample opportunity for photoredox catalysis to activate organic
substrates via an intermolecular single-electron transfer path-
way.3 From the green chemistry points of view, there is a long-
standing interest in replacing the precious metals in photo-
active coordination complexes by more earth-abundant
elements.4 However, the photoexcitable charge-transfer states
of most iron complexes are limited by picosecond or
subpicosecond deactivation through low-lying metal-centered
states, resulting in inefficient electron-transfer reactivity and
complete lack of photoluminescence. Recent efforts to increase
the excited state lifetimes of iron complexes have focused on
increasing the ligand field strength and hence raising the
energies of the metal-centered states by the use of strong
donor ligands such as N-heterocyclic carbenes. Very recently,
Figure 1. Photochemistry of iron complexes.
̈
Warnmark and co-workers reported an Fe(III) complex with a
relatively long-lived (2 ns) doublet ligand-to-metal charge-
transfer (2LMCT) state.5 Together with advances from other
groups,6 it makes iron photoredox catalysis promising. On the
other hand, increasing the excited state lifetimes is not the only
approach to achieving useful photoreactivity of iron complexes.
Chemists are exploring the potential of intramolecular charge-
transfer mode by coordination of organic substrates directly to
iron, wherein long-lived excited states of iron complexes are
not necessarily essential (Figure 1A). The photoinduced
reduction of ferrioxalate was first reported by Parker in
1953.7 The ferrioxalate complex is used widely as an
actinometer in quantum yield determinations as a result of
its high absorbance and reaction quantum yield. However, the
photoreactivity of the Fe(III) carboxylate complexes finds rare
application in synthetic organic chemistry so far. We sought to
take advantage of this reactivity and use the resulting alkyl
Received: April 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01439
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
radicals from the oxidative decarboxylation to fulfill alkylation
reactions.
1 followed by deprotonation would readily form the Fe(III)−
carboxylate complex 3. Photoexcitation of the iron complex 3
should render an intramolecular ligand-to-metal charge-trans-
fer event to generate the reduced Fe(II) 4 and a carboxyl
radical 5, which after CO2 extrusion would produce the desired
alkyl radical 6. The nucleophilic alkyl radical 6 would then add
to the protonated electron-deficient heteroarenes 7 in a
Minisci-type pathway to afford the aminyl radical cation 8. The
resulting α-C−H bond of 8 is sufficiently acidic to undergo
deprotonation to form the α-amino radical 9, which could be
oxidized by Fe(III) to furnish the desired alkylation product
10. The terminal oxidant would serve to bring Fe(II) back to
Fe(III) to close the catalytic cycles.
We began our investigation into this decarboxylative
alkylation of heteroarenes by exposing the water−DMSO
solution of lepidine and isobutyric acid to visible light (Kessil
40 W 456 nm LED) in the presence of iron salt for 8 h (Table
1). With 1 equiv of Fe2(SO4)3, it afforded the desired aryl-alkyl
product 11 in 40% yield (entry 1), while the combination of 5
mol % Fe(III) or Fe(II) with 2 equiv of NaBrO3 gave no
desired product (entries 2 and 3). To our delight, a dramatic
In the medicinal chemistry community, there is a growing
demand for the direct introduction of alkyl groups to
heteroarenes, given their influence on drug metabolism and
pharmacokinetic profiles.8 The open-shell addition of alkyl
radical intermediates to heteroarenes, known as the Minisci
reaction, has become a mainstay transformation with broad
application within modern drug discovery.9 In few cases, the
alkyl radicals are derived from alkanes by a hydrogen atom
transfer mechanism,10 while most of the current methods
depend on the use of prefunctionalized reagents as alkyl radical
precursors, such as carboxylic acids and derivatives,11 boronic
acids and derivatives,12 sulfinates,13 peroxides,14 alcohols,15
halides,16 olefins,17 1,4-dihydropyridines,18 pyridiniums,19 and
sulfones.20 Radical decarboxylative strategy is appealing since
carboxylic acids are inexpensive, stable, and the second largest
group of commercially available organic building blocks only
after amines (Figure 1B).21 Minisci and co-workers reported a
silver-catalyzed decarboxylative alkylation protocol with the
oxidant persulfate under heat conditions,11a followed by a
modification with Selectfluor as the oxidant recently.11e An
iridium photoredox catalyst−persulfate system at room
temperature was successfully developed more recently.11h
Hypervalent iodine compounds also witnessed intensive
research studies in decarboxylative alkylation since the early
report using bis(trifluoroacetoxy)iodobenzene (PIFA) under
UV or heat conditions.11b Photoredox catalytic methods with
acetoxybenziodoxole (BI-OAc) and PIFA made the decarbox-
ylation events happen smoothly by irradiation of visible
light.11i,j Compared to precious silver and iridium (photo)-
catalysts, iron is earth-abundant and nontoxic. Early in 1986,
Sugimori reported a light-induced decarboxylative alkylation of
heteroarenes using stoichiometric Fe2(SO4)3.22 As our first
step toward photochemistry of iron complexes, we developed a
catalytic protocol for decarboxylative alkylation of heteroarenes
via iron photocatalysis. Notably, the iron catalytic cycle was
achieved by the identification of picolinic acid as the ligand,
which would lead to further development for iron photo-
catalysis through ligand modulation. Moreover, in previous
methods the expensive organic oxidants (Selectfluor and
hypervalent iodine reagents) were typically used, so we sought
to find alternative inorganic oxidants with low prices.
a
Table 1. Optimization of the Reaction Conditions
picolinic
acid
yield
[%]
entry
iron(II)
oxidant
wavelength
b
1
2
-
-
-
-
-
456 nm
456 nm
40
0
c
2 equiv
NaBrO3
3
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
10 mol %
-
2 equiv
NaBrO3
2 equiv
NaBrO3
456 nm
456 nm
456 nm
456 nm
440 nm
427 nm
390 nm
456 nm
440 nm
0
4
5 mol %
60
94
85
85
83
49
39
90
5
10 mol % 2 equiv
NaBrO3
15 mol % 2 equiv
NaBrO3
10 mol % 2 equiv
NaBrO3
10 mol % 2 equiv
NaBrO3
10 mol % 2 equiv
NaBrO3
10 mol % 2 equiv
NaClO3
20 mol % 3 equiv
NaClO3
6
7
8
A detailed description of our proposed mechanism for the
decarboxylative alkylation is illustrated in Scheme 1. We
postulated that coordination of the carboxylic acid 2 to Fe(III)
9
10
11
Scheme 1. Proposed Mechanism for the Decarboxylative
Alkylation of Heteroarenes
12
13
14
10 mol %
10 mol %
-
20 mol % 3 equiv NaIO4 440 nm
80
86
0
20 mol % 3 equiv KIO3
440 nm
456 nm
10 mol % 2 equiv
NaBrO3
15
16
-
-
-
dark
dark
0
0
5 mol %
10 mol % 2 equiv
NaBrO3
17
5 mol %
10 mol % 2 equiv
NaBrO3
dark, 80 °C
0
a
Yields determined by 1H NMR using 1,3-benzodioxole as the
internal standard after workup following the general procedure in
b
c
Supporting Information. 1 equiv of Fe2(SO4)3 used. 2.5 mol % of
Fe2(SO4)3 used. LED = light-emitting diode.
B
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Organic Letters
Letter
a
Scheme 2. Scope of the Carboxylic Acids
a
b
c
d
Isolated yields. See Supporting Information for experimental details. 440 nm LED used. 427 nm LED used. 390 nm LED used.
ligand acceleration effect was observed. The alkylation product
11 could be obtained in 60% yield when picolinic acid was
added into the reaction at 1:1 ratio of iron to ligand (entry 4).
The yield could reach up to 94% with 2 folds of the ligand
(entry 5). Further increase of the amount of picolinic acid led
to a slight yield drop (entry 6). A downward trend of the yield
C
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Letter
a
Scheme 3. Scope of the Heteroarenes
a
b
Isolated yields. See Supporting Information for experimental details. 440 nm LED used.
was noticed as the wavelength of light was changed from 456
to 440, 427, and 390 nm, mainly due to the product
decomposition under higher-energy conditions (entries 7−9).
Then we tried out most of the common inorganic oxidants
which are metal-free, including but not limited to halogen-
containing oxidants, persulfate, hydrogen peroxide, and
D
DOI: 10.1021/acs.orglett.9b01439
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Organic Letters
Letter
oxygen. It turned out that sodium chlorate was a compatible
oxidant for the reaction, which provided the product 11 up to
90% yield with the irradiation of 440 nm light (entries 10 and
11). Furthermore, periodate and iodate also performed well as
the terminal oxidant in the transformation (entries 12 and 13).
We speculate that these oxidants have suitable oxidizing ability
to turn over the iron catalyst while not being detrimental to the
radical process. Indeed, the critical roles of the iron salt and
light in the protocol were demonstrated through control
experiments. There was no desired product 11 formed in the
absence of either iron salt or light, even heated to 80 °C
(entries 14−17).
With the optimal conditions in hand, we sought to evaluate
the generality of this decarboxylative alkylation protocol. As
highlighted in Scheme 2, a wide range of carboxylic acids can
serve as alkylating agents in this reaction under the identified
conditions A (with NaBrO3 and 456 nm LED) and B (with
NaClO3 and 440 nm LED). It is of note that primary,
secondary, and tertiary alkyl carboxylic acids are all amenable
substrates for the alkylation reaction, with no obvious bias. A
variety of functional groups attached to the alkyl radical
precursors were well tolerated, including alkenes (14, 21, 22,
and 36), halides (23, 38, 42, 43, and 47), ketones (24, 39, and
40), esters (41), ethers (25−31, 44, 46, and 47), and alcohols
(45 and 52). Cyclic alkyl radicals with different sizes
underwent the addition to the heteroarene smoothly (16−
31, 49−31). Moreover, acetic acid was successfully used to
deliver the magic methyl group into the product 32, as well as
a number of α-oxy acids for the incorporation of oxyalkyl
groups (27, 30, and 45−47).
Next, we explored the scope of the alkylation reaction with
respect to the heteroarene component (Scheme 3). A broad
array of heteroarenes were coupled oxidatively with isobutyric
acid in good to excellent yield under the identified conditions
A (with NaBrO3 and 456 nm LED) and B (with NaClO3 and
427 nm LED). Quinolines with electron-withdrawing or
-donating substituents (such as ester, cyanide, halides, phenyl,
methoxy, hydroxyl groups) were alkylated effectively (53−62,
50−97% yield). Isoquinolines performed well, including those
with nonparticipating functionality (such as ester, cyanide, and
halides) (8% yield). Isoquinolines performed well, including
those with nonparticipating functionality (such as ester,
cyanide, and halides) (63−68, 57−67% yield), in addition to
phenanthridines, quinazolines, phthalazines, and quinoxalines
(69−74, 57−96% yield). Moreover, various pyridine deriva-
tives containing diverse functionality could be converted into
the desired aryl-alkyl products in good yield (75−79, 60−71%
yield). It is important to note that pyrimidines are competent
substrates for the alkylation protocol, including those with
halide substituents (80−85, 45−83% yield). Substituted
pyridazines and pyrazines afforded the alkylated products in
useful yield (86−91, 49−82% yield). We were pleased to find
that a variety of 5-membered heteroarenes could participate in
the protocol. Benzothiophenes with electron-withdrawing
groups at the C2 position reacted at the C3 position
regioselectively (92 and 93, 70 and 69% yield). Gratifying,
benzothiazoles underwent the alkylation predominantly at the
C2 position (94−98, 33−66% yield), as did benzoimidazoles
(99 and 100, 50 and 90% yield). It is worth mentioning that
the decarboxylative alkylation could be extended to the purine
derivative (101, 80% yield).
outlined in Scheme 1. The decarboxylative alkylation is
completely shut down by the addition of free radical scavenger,
TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl), indicating a
radical mechanism (Figure S1A). The light/dark experiments
using alternating intervals of light and dark demonstrate that
the constant irradiation of visible light is necessary to drive the
alkylation to completion (Figure S1B). The UV−vis spectra
show that the iron salt or ligand separately has minimal optical
absorption in the visible range. However, the 1:1 solution of
iron and ligand exhibits a significantly enhanced absorption of
visible light, which is even stronger for the 1:2 solution (Figure
S1C). Based on the results, we speculate that the ligand
coordination makes Fe(II) more prone to be oxidized after
light absorption. Further exploration into the mechanism is
being conducted in our lab.
In summary, we have developed a mild and practical
protocol for the decarboxylative alkylation of heteroarenes via
iron photocatalysis. This new method shows broad scopes with
regard to both the carboxylic acids and heteroarene substrates
bearing a variety of functional groups. Remarkably, the reaction
represents a successful extension of iron photochemistry into
synthetic organic chemistry. Although the photoexcited state
lifetimes of iron complexes are typically much shorter than
those of iridium and ruthenium complexes, they have a huge
potential to design diverse transformations via the intra-
molecular charge transfer pathway of iron−substrate com-
plexes. As such, we anticipate this iron photocatalytic
decarboxylation strategy will find more application in both
academic and pharmaceutical sciences.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01439.
General experimental procedures, mechanistic studies,
reaction setup, characterization data, and spectra for all
key compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jjin@sioc.ac.cn.
ORCID
Siqi Xia: 0000-0002-2898-6540
Jian Jin: 0000-0001-9685-3355
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the “Thousand Plan” Youth
program, Chinese Academy of Sciences, Shanghai Institute of
Organic Chemistry, and CAS Key Laboratory of Synthetic
Chemistry of Natural Substances.
Preliminary mechanistic studies have been conducted (see
Supporting Information) to support the proposed pathway
E
DOI: 10.1021/acs.orglett.9b01439
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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