Visible-Light-Photocatalyzed Reductions of N-Heterocyclic Nitroaryls to Anilines Utilizing Ascorbic Acid Reductant

Article abstract of DOI:10.1021/acs.orglett.9b01205

A photoreductive protocol utilizing [Ru(bpy)₃]²⁺ photocatalyst, blue light LEDs, and ascorbic acid (AscH₂) has been developed to reduce nitro N-heteroaryls to the corresponding anilines. Based on experimental and computational results and previous studies, we propose that the reaction proceeds via proton-coupled electron transfer between AscH₂, photocatalyst, and the nitro N-heteroaryl. The method offers a green catalytic procedure to reduce, e.g., 4-/8-nitroquinolines to the corresponding aminoquinolines, substructures present in important antimalarial drugs.

Full text of DOI:10.1021/acs.orglett.9b01205

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Photocatalyzed Reductions of N‑Heterocyclic
Nitroaryls to Anilines Utilizing Ascorbic Acid Reductant
Aleksandar R. Todorov, Santeri Aikonen, Mikko Muuronen,† and Juho Helaja*
Department of Chemistry, University of Helsinki, A.I. Virtasen aukio 1, 00014 Helsinki, Finland
S
* Supporting Information
ABSTRACT: A photoreductive protocol utilizing [Ru-
(bpy)3]2+ photocatalyst, blue light LEDs, and ascorbic acid
(AscH2) has been developed to reduce nitro N-heteroaryls to
the corresponding anilines. Based on experimental and
computational results and previous studies, we propose that
the reaction proceeds via proton-coupled electron transfer
between AscH2, photocatalyst, and the nitro N-heteroaryl.
The method offers a green catalytic procedure to reduce, e.g., 4-/8-nitroquinolines to the corresponding aminoquinolines,
substructures present in important antimalarial drugs.
eduction of an aromatic nitro compound is a prototypical
way to prepare arylamines that are common substructures
Scheme 1. Visible Light Nitroaryl Photoreduction
Reduction Protocols
R
in pharmaceuticals, agrochemicals, dyes, and pigments and in a
variety of other fine and specialty chemicals.1 This fundamental
transformation can be performed using a plethora of synthetic
and catalytic protocols: conventional stoichiometric reagents,
e.g., SnCl2, TiCl3, Raney Ni, Zn, Sn, Fe, and Na2S, are
appropriate for specific lab-scale conversion,2 while transition-
metal-catalyzed hydrogenations (e.g., Pd, Au, and Pt on various
supports: C, TiO2, etc.) dominate industrial applications.3
Lately, heterogeneous photocatalytic nitroarene reductions on
various materials, e.g., semiconductors, nanoparticles, and
nanocomposites, have also been under intensive development.4
Recent advances in photoredox catalysis (e.g., metal
complexes and organic dyes) have enabled new strategies for
reductive organic conversions.5 The early photoreductions of
nitrobenzenes to anilines were carried out under intense xenon
lamp irradiation including UV wavelengths. In a pioneering
example, Fukuzumi and co-workers used an excess of
dihydroacridine as a reductant for triplet excited PhNO2 in
the presence of HClO4/H2O additives in MeCN.6 Later on,
Hirao and co-workers developed a more convenient method,
exploiting a Ru(bpy)2(MeCN)2(PF6)2 photosensitizer and
hydrazine as reductant, while the most intense UV light was
filtered out (<300 nm).7 Ananthakrishnan and co-workers
employed visible light in 4-nitrophenol photoreduction using
resin-supported eosin Y with a large excess of NaBH4 (Scheme
1a).8 Tung and co-workers developed the method further to
extend the substrate scope by utilizing green light-emitting
diodes (LEDs) as a light source, eosin Y as a photosensitizer,
and triethanolamine (TEOA) as a reductant (Scheme 1b).9
Our interest has been in the development of catalytic
methods for quinoline modifications. Previously, we developed
a protocol for photoreductive removal of O-benzyl groups from
oxyarene N-heterocycles.10 At the beginning of the current
study, we observed that even the eosin Y/TEOA photo-
reduction protocol (Scheme 1b) was widely tolerant for
nitrophenyl functional groups, the method was incompatible
with nitroquinolines (Table S7). Therefore, we developed here
a photocatalytic protocol for reducing nitro groups in N-
(oxo)heterocyclic nitroaryls (Scheme 1c) leading to amino-
quinoline structures present in many important antimalarial
pharmaceuticals, e.g., in traditional chloroquine11 and
primaquine12 as well as recently FDA-approved tafenoquine13
(Figure 1).
First, we studied the photoreduction of 2-methoxy-6-
nitroquinoline 1a in the presence of ascorbic acid (AscH2)
Received: April 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01205
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Scheme 2. Reaction Scope Study
Figure 1. Examples of 4-/8-aminoquinoline-containing antimalarial
drugs.
Table 1. Effect of Deviation from Standard Reaction
a
Conditions
b
entry
variation from standard conditions
none
yield (%)
c
1
83 (82)
2
no light
0
3
4
air atmosphere
no photocatalyst
28
0
5
6
7
8
0.5% [Ru] loading
(Ir[dF(CF3)ppy]2(dtbbpy))PF6 (1 mol %)
[Ir(dtbbpy)(ppy)2]PF6 (1 mol %)
no AscH2
52
28
16
0
9
AscH2 (2 equiv)
AscH2 (3 equiv)
18
79
0
10
11
12
13
14
15
16
17
18
19
20
Na-ascorbate instead of AscH2
30 min reaction time
MeOH
MeOH/H2O (10:1)
MeOH/H2O (6:1)
MeOH/H2O (2:1)
EtOH/H2O (1:1)
AcOH additive (10 vol %)
DMF
36
29
41
62
71
81
58
11
0
MeCN
a
b
Full reaction optimization in Tables S1−S7. GC yield: average of
c
two runs. Isolated yield by SiO2 column chromatography
as the reductant and Ru(bpy)3Cl2 as the photosensitizer
according to earlier successful protocols for reductions by us
and others.14 Optimization of the reaction conditions, i.e.,
photocatalyst, reductant amount, solvent, concentration, and
reaction time, provided aniline 2a with 83% yield after 1 h
irradiation with blue LEDs light (455 nm) in the presence of 4
equiv of AscH2 and 1 mol % of the [Ru] catalyst in MeOH/
H2O (0.02 M) at rt (Tables S1−S7). Varying the reaction
conditions from the optimal shows that reaction does not take
place without light, AscH2, or photocatalyst and the reaction is
sensitive to air atmosphere (entries 2, 8, 4, and 3 Table 1). The
reaction was also sensitive to the amount of reactants (entries
5, 9, and 10), and interestingly, the optimal solvent
compositions proved to be 4:1 MeOH/H2O and 1:1 EtOH/
H2O. The reaction proceeds poorly or not at all in polar
aprotic solvents, e.g., DMF and MeCN, even though MeCN
was employed as solvent in the previous AscH2 and [Ru]-
photocatalyst studies.14
a
b
Average isolated yields of two runs after SiO2 chromatography. Up-
scaled (4 mmol) reaction under the same light source, 0.5 mol % of
[Ru] catalyst.
ing amines 2b−2f required slightly longer reactions times,
1.5−5 h, depending on the substituent positions. The obtained
yields were, however, still high (86−97%) with 2d being an
exception by producing unidentified polymeric side products.
Next, we studied the scope of the reaction (Scheme 2);
reduction of nitromethoxyquinolines 1b−1f to the correspond-
B
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Scheme 3. Synthesis of Hydroxylamine and Nitrone
The excellent yield of 2f demonstrates that halogen
substituents in the nitro/amino aryl ring are also well tolerated.
In addition, the monosubstituted 5-, 6-, 7-, or 8-nitroquinolines
are converted into amines 2g−2j with up to quantitative yields,
and the 2-methyl substituent improved the 8-aminoquinoline
yield from 75 to 90% (2g vs 2k). Importantly, the protocol
proved to be scalable: reduction of 1e on a larger 4 mmol (vs
0.2 mmol) scale with reduced catalyst loading ([Ru] 0.5 mol
%) yielded 73% of 2e after 24 h reaction time.
A poor yield of 16% received for 2l indicates that the
combination of 6-nitro-8-ether substitution is unfavorable for
the reaction. On the other hand, 2-methyl-8-nitroquinolines
with allyl ether, acyl, or triflyl at the 6-position gave high yields
of 83%, 91%, and 96% for 2m, 2n, and 2o, respectively,
although the TfO compound (2o) required longer reaction
time (7.5 h). The chemoselectivity of the method was further
Figure 3. Conversion of 1c to 2c via observed hydroxylamine
1
intermediate 1c′ followed by H NMR monitoring (SI). Structures
are presented in Figure 2a.
highlighted with a 79% yield of 6-alkyne-substituted 8-amino-
4-methoxyquinone 2p after 23 h reaction time.
Another attractive class of target molecules is 4-nitroquino-
lines (Scheme 2), which are commonly prepared by nitration
of N-oxoquinolines and require the use of trivalent phosphorus
compounds for removal of the N-oxo groups.15 Our received
yields of 57%, 35%, and 25% for 2q, 2i, and 2j, respectively,
using N-oxo compounds as starting materials are therefore
highly encouraging.
Figure 2. (a) Schematic representation of the nitro reduction to amine. (b) Condensation intermediates.
C
DOI: 10.1021/acs.orglett.9b01205
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and nitrobenzene (4), in which concentrations of these
substrates were fixed and the amount of AscH2 was varied
(Figure 4). The nonlinear behavior in both cases indicates an
MS-PCET-type reaction as suggested by Qiu and Knowles.18b
Next, (B) the protonated nitro substrate is reduced by [Ru+]:
reduction of protonated nitro compound with [Ru+] is a more
exergonic process (ΔG ≤ −15.9 kcal/mol) than with [*Ru2+]
(−12.7 [1g] ≤ ΔG ≤ −0.9 [3d] kcal/mol), and reduction of
[*Ru2+] to [Ru+] by AscH− is an exergonic process (−8.3
kcal/mol). The protonation energies of reactive nitro
substrates by AscH2 were calculated to vary between
thermoneutral (0.7 kcal/mol for 1c) and endergonic (15.4
kcal/mol for 3d), where the endergonicity of protonation does
not exclude hydrogen-bonding interactions between acid and
base, which in turn can facilitate MS-PCET reactions.18
The protonation of hydroxylamine (C) and the subsequent
reduction of [*Ru2+] to [Ru+] by AscH− (D) are required for
the reduction of the substrate by [Ru+] (E, Figure 2a), as the
reduction of electron-rich hydroxylamine quinolines would be
Figure 4. Modified Stern−Volmer titration, where [Ru] and quencher
1k or 4 were kept constant and AscH2 quencher was varied.
2+
endergonic with *Ru(bpy)3 (ΔG ≥ 27.9 kcal/mol, SI). The
pKaH values for unreactive hydroxylamine intermediates of 3d
and 4 indicates that the protonation is endergonic: 10.1 kcal/
mol for 3d′ and 8.9 kcal/mol for 4′. In turn, the reactive
hydroxylamine intermediates are easily protonated (C, Figure
2a) with free energies of −0.8, 2.4, and 2.0 kcal/mol for 1c, 1d,
and 1g, respectively. The reduction of protonated hydroxyl-
amine quinolines would be endergonic with [*Ru2+] (4.8 ≤
ΔG ≤ 12.5 kcal/mol, SI), while the process is exergonic with
the obtained ground state [Ru+] (ΔG ≤ −2.5 kcal/mol, SI).
In summary, we have developed a chemoselective and green
photoreductive protocol for reduction of nitro N-heteroaryls
that exploits AscH2 as hydrogen source. The method
complements the existing photoredox catalysis protocols,
extending their applicability for the N-heteroaryls.
Last, we also tested the substrate scope for producing 6-
aminoisoquinoline 2r and 5-aminobenzothiazole 2s, which
worked with decent to good yields (Scheme 2). Other tested
N-heterocycles fell into the category of unsuitable substrates
(3a−3h, SI), being either unreactive, stopping at hydroxyl-
amine intermediate stage (3d, Scheme 3), or leading to side
products and oligomerization, which limit the scope of the
method.
Interestingly, for 1-acyl-4-nitroindazole 3d and nitrobenzene
4,very good yields (79%) of hydroxylamine 3d′ and (54%)
nitrone 5, respectively, were obtained instead of their amine
products (Scheme 3). Therefore, we decided to study the
reaction mechanism to understand why the reaction is not
driven to amine formation in these cases.
First, the mechanism of the photoreduction was studied by
monitoring the conversion of 1c to 2c with NMR. Hydroxyl-
amine intermediate (1c′) was increasingly formed and
consumed in the course of the reaction (Figures 2a and 3
and SI) in accordance with the previously proposed
mechanism for the nitrobenzene reduction.16,17 The acquired
NMR data showed no traces of other species, indicating that
the reduction proceeds via the direct route (Figure 2a and SI)
rather than through the condensation of hydroxylamine and
nitroso intermediates (Figure 2b).
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.9b01205.
Experimental procedures, full reaction optimization
tables, 1H NMR reaction monitoring, computational
procedures and details, and 1H and 13C NMR spectra for
all compounds (PDF)
Initially, we considered the first step of the mechanism to be
reduction of substrate, or protonation of the substrate followed
by its reduction. However, Stern−Volmer measurements
pointed out that a 1:1 mixture of 1k/AscH2 was a superior
quencher of [*Ru2+] compared to either of the components
alone, indicating their cooperative role (SI). Furthermore, the
computed oxidation potentials indicate oxidation of ascorbic
acid with [*Ru2+] to be an endergonic process (17.5 kcal/mol,
SI), and neither do the experimentally observed yields
correlate with the computed reduction potentials of the
protonated or nonprotonated substrates (see SI for E°red and
E°red,H+ values). Therefore, we propose the mechanism
depicted in Figure 2a: (A) the reaction is initiated by a
multisite proton-coupled electron transfer (MS-PCET)18
between the nitro quinoline, AscH2, and [*Ru2+], i.e., proton
and electron are transferred from one donor to two separate
acceptors. This is supported by Stern−Volmer titrations for 1k
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: juho.helaja@helsinki.fi.
ORCID
Santeri Aikonen: 0000-0003-2675-7290
Mikko Muuronen: 0000-0001-9647-7070
Juho Helaja: 0000-0001-8645-617X
Present Address
†(M.M.) BASF SE, Carl-Bosch-Str. 38, 67056 Ludwigshafen,
Germany.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b01205
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
some 4-substituted nicotinic acids and nicotinamides. J. Chem. Soc. C
1966, 0, 1816−1821.
ACKNOWLEDGMENTS
■
Financial support from the Academy of Finland (Project No.
129062) is acknowledged. The Finnish National Centre for
Scientific Computing (CSC) is recognized for computational
resources.
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(17) Haber, F. Uber stufenweise reduktion des nitrobenzol mit
begrenztem kathodpotential. Z. Elektrochem. Angew. Phys. Chem. 1898,
4, 506−514.
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Org. Lett. XXXX, XXX, XXX−XXX