Photocatalytic redox-neutral hydroxyalkylation of: N -heteroaromatics with aldehydes

Article abstract of DOI:10.1039/d0sc04114a

Hydroxyalkylation of N-heteroaromatics with aldehydes was achieved using a binary hybrid catalyst system comprising an acridinium photoredox catalyst and a thiophosphoric acid organocatalyst. The reaction proceeded through the following sequence: (1) photoredox-catalyzed single-electron oxidation of a thiophosphoric acid catalyst to generate a thiyl radical, (2) cleavage of the formyl C-H bond of the aldehyde substrates by a thiyl radical acting as a hydrogen atom transfer catalyst to generate acyl radicals, (3) Minisci-type addition of the resulting acyl radicals to N-heteroaromatics, and (4) a spin-center shift, photoredox-catalyzed single-electron reduction, and protonation to produce secondary alcohol products. This metal-free hybrid catalysis proceeded under mild conditions for a wide range of substrates, including isoquinolines, quinolines, and pyridines as N-heteroaromatics, as well as both aromatic and aliphatic aldehydes, and tolerated various functional groups. The reaction was applicable to late-stage derivatization of drugs and their leads. This journal is

Full text of DOI:10.1039/d0sc04114a

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Photocatalytic Redox-Neutral Hydoxyalkylation of N-
Heteroaromatics with Aldehydes
Hiromu Fuse, a Hiroyasu Nakao, a Yutaka Saga, b Arisa Fukatsu, c Mio Kondo, b Shigeyuki Masaoka, b
Received 00th January 20xx,
Accepted 00th January 20xx
Harunobu Mitsunuma,*a and Motomu Kanai*a
DOI: 10.1039/x0xx00000x
A hydroxyalkylation of N-heteroaromatics with aldehydes was achieved using a binary hybrid catalyst system comprising an
acridinium photoredox catalyst and a thiophosphoric acid organocatalyst. The reaction proceeded through the following
sequence: 1) photoredox-catalyzed single-electron oxidation of a thiophosphoric acid catalyst to generate a thiyl radical, 2)
cleavage of the formyl C‒H bond of the aldehyde substrates by a thiyl radical acting as a hydrogen atom transfer catalyst to
generate acyl radicals, 3) Minisci-type addition of the resulting acyl radicals to N-heteroaromatics, and 4) a spin-center shift,
photoredox-catalyzed single-electron reduction, and protonation to produce secondary alcohol products. This metal-free
hybrid catalysis proceeded under mild conditions for a wide range of substrates, including isoquinolines, quinolines, and
pyridines as N-heteroaromatics, as well as both aromatic and aliphatic aldehydes, and tolerated various functional groups.
The reaction was applicable to late-stage derivatization of drugs and their leads.
www.rsc.org/
An alternative pathway to hydroxyalkylated N-
heteroaromatics is an oxidative Minisci reaction (Figure 1A
(b)).6-8 Due to the inertness of an α-oxy C‒H bond of alcohols,
however, this process requires the strong oxidant and large
excess of alcohols resulting low generality. On the other hand,
Introduction
The hydroxyalkylated N-heteroaromatics are ubiquitously
present in bioactive compounds and are versatile intermediates
in the synthesis of pharmaceuticals/agrochemicals. Although
transition metal-catalyzed addition reactions of aromatic
compounds to various electrophiles through C(sp2)‒H bond
activation are reported,1 the use of carbonyl groups as
electrophiles has remained difficult due to the reversibility of
the C‒C bond-forming step.1,2 Specifically, the catalyzed direct
N-heteroarylation of aldehydes has been limited to a C3-
selective dehydrogenative reaction in the presence of silanes,
Melchiorre
recently
reported
the
photochemical
hydroxyalkylation of quinolines and isoquinolines by novel spin-
center shift (SCS) process (Figure 1A (c)).9,10 Although the
reaction proceeded under mild conditions, the acyl radical
sources, 4-acyl-1,4-dihydropyridines, were prepared from the
corresponding ketoaldehydes by harsh conditions (i.e. heating
neat at 120‒130
C). This limited substrate generality of
hydroxyalkyl groups and made the overall process less atom
economic. Herein, we report a new catalytic method for
synthesizing hydroxyalkylated N-heteroaromatics through
Minisci-type reaction between N-heteroaromatics and
aldehydes, mediated by a hybrid catalyst system comprising an
acridinium photoredox catalyst and a thiophosphoric acid (TPA)
organo-hydrogen atom transfer (HAT) catalyst (Figure 1B).11
Notably, this reaction proceeded under redox-neutral
conditions with high atom economy. This is in contrast to
which proceeded at a high temperature (135 C) and has a
limited substrate scope.3 Consequently, N-heteroarylation of
aldehydes mainly relies on stoichiometric carbanion chemistry
through the deprotonation of a C(sp2)‒H bond with pKa greater
than 40 using strong bases (Figure 1A (a)).4 Regio- and
chemoselective C‒H metalation and functionalization reactions
of N-heteroaromatics using less nucleophilic Brφnsted bases
are reported.5 Several types of functional groups, however, are
not compatible with those reaction conditions.
previously-reported
Minisci
reactions
between
N-
heteroaromatics and aldehydes, which required stoichiometric
strong oxidants and produced acylated products.12
a. Graduate School of Pharmaceutical Sciences, The University of Tokyo 7-3-1
Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: h-mitsunuma@mol.f.u-tokyo.ac.jp;
kanai@mol.f.u-tokyo.ac.jp
b. Department of Applied Chemistry, Graduate School of Engineering, Osaka
University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
c. Department of Life and Coordination-Complex Molecular Science, Institute for
Molecular Science (IMS), 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787,
Japan
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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implied hydroxyalkylated N-heteroaromatics were unstable in
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their reaction conditions.14a,d
DOI: 10.1039/D0SC04114A
Our working hypothesis for the catalytic cycle is shown in
Figure 2. A photoredox catalyst Mes-Acr+ in the excited state
(*Mes-Acr+) oxidizes an organocatalyst (RSH) to produce a
radical (RS•) acting as a HAT catalyst. This radical cleaves the
formyl C‒H bond of aldehyde
reacts with protonated N-heteroaromatics
reaction, giving radical cation . Deprotonation of
benzylic carbon-centered radical , which is converted to the α-
oxy radical via SCS. Finally, is reduced by the reduced
photoredox catalyst (Mes-Acr), and the subsequent
protonation affords target compound . On the basis of our
2
. The resulting acyl radical
through a Minisci
affords
4
5
6
6
7
8
8
3
previous findings, we envisioned that the combination of an
acridinium photoredox catalyst (Mes-Acr+) and TPA
organocatalyst would realize the designed hybrid catalysis.15,16
Figure 1. Overview of C–H hydroxyalkylation of N-
heteroaromatics. (A) Previous works: (a) using a stoichiometric
strong base or a transition metal catalyst. (b) oxidative Minisci
reaction. (c) Melchiorre’s work using 4-acyl-1,4-
dihydropyridines. (B) Present work: (d) binary hybrid catalysis
comprising a photoredox catalyst and an organo-HAT catalyst.
Figure 2. Proposed catalytic cycle.
Results and discussion
Optimization of reaction conditions
Because the bond dissociation energy of a formyl C‒H bond of
aldehydes (88.7 kcal/mol)13a is much smaller than that of a
C(sp2)‒H bond of N-heteroaromatics (105 kcal/mol),13b we
planned to incorporate a SCS process in the overall catalytic
cycle to produce alcohol products (see below). There are
preceding examples in which the SCS process was combined
with the photoredox-catalyzed Minisci-type reaction of N-
heteroaromatics.14 In those examples, formal alkylations of N-
heteroaromatics were achieved using alcohols, ethers, or
carbonyl compounds as an alkyl source. Especially, MacMillan14a
and Huang14c,d achieved the incorporation of HAT and SCS
processes. Despite the versatile roles of hydroxy groups in
organic synthesis, however, they were eliminated in their
reaction conditions. Moreover, their mechanistic studies
2 | J. Name., 2012, 00, 1-3
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Table 1. Optimization of the Reaction Conditions.a
aromatic ring did not significantly affect the results. Moreover,
steric hinderance at the ortho-position of the phenyl ring of
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DOI: 10.1039/D0SC04114A
aldehydes did not interfere with the reaction (3g). Aliphatic
aldehydes, which are challenging substrates due to the
presence of acidic α-C‒H bonds and low electrophilicity,3a were
a competent class of substrates in this reaction (3h
result, several hydroxy-alkylated isoquinolines containing ester
3i), phthalimide (3j), ketone (3k), and halogen (3l) were
‒l). As a
(
obtained in high yield. We then examined the scope of N-
heteroaromatics. Various brominated isoquinolines exhibited
good reactivity
(3m‒p). The reactions of isoquinolines
containing amide (3q) and ester (3r) proceeded in good yield.
This catalyst system was also applicable to the
hydroxyalkylation of quinolines (3s
‒z). Quniolines containing
ester (3u), halogen (3v ), ether (3y), and phenyl (3z) groups
‒
x
were competent substrates. Moreover, pyridine derivatives
were successfully converted to the corresponding products
(
3aa
Steric hinderance did not interrupt reaction progress and
substituted pyridines were synthesized (3ab ac).
‒ad). Ketone and ester functionalities were tolerated.
‒
a General reaction conditions: 1a (0.10 mmol), 2a (0.20 mmol),
Mes-Acr+ (0.005 mmol), TPA (0.010 mmol), and TFA (0.20 mmol)
were reacted in dichloromethane (DCM; 2.0 mL) at room
b
temperature under blue LED irradiation for 7 h. Yield was
determined by 1H NMR analysis of the crude mixture using
c
1,1,2,2-tetrachloroethane as an internal standard. Isolated
d
e
f
yield in parenthesis. Without Mes-Acr+. Without TFA.
Without photoirradiation. g 1 equiv TEMPO was added.
We conducted optimization studies using isoquinoline (1a) and
benzaldehyde (2a) (Table 1). Despite several possible side
reactions such as reductive deoxygenation of 3a and reduction
of 2a 14
we identified the optimized reaction conditions
,
comprising 5 mol % Mes-Acr+ photoredox catalyst and 10 mol %
TPA organocatalyst in the presence of 2 equiv TFA, affording 3a
in 94% yield (entry 1). Other organocatalysts for HAT, such as
thiols,14a,17a quinuclidine,17b and benzoic acid17c did not afford
the product (entries 2‒5). Control experiments revealed that
Mes-Acr+, TPA, TFA, and visible light irradiation were
indispensable for efficient reaction progress (entries 6‒9). The
addition of 1 equiv TEMPO inhibited the reaction (entry 10),
indicating the presence of radical intermediates.
Substrate scope
Under the optimized conditions, we investigated the substrate
scope (Figure 3). We first studied the aldehyde side (3a‒l) using
isoquinoline (1a) as an N-heteroaromatic substrate. Aromatic
aldehydes containing various functional groups such as halogen
(
3b‒d), ether (3e), trifluoromethyl (3f), and alkyl (3g) groups
tolerated the reaction conditions. The electron density of the
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were reacted in dichloromethane (DCM; 2.0 mL) at room
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DOI: 10.1039/D0SC04114A
temperature under blue LED irradiation for 7 h. Yield is isolated
yield unless otherwise noted. b 5 equiv of the aldehyde was used
with the reaction time 13 h. c Reaction time was 3 h. d Reaction
time was 5 h.
Furthermore, this reaction was applicable to late-stage
modifications of complex molecules because of the mild con-
ditions (Figure 4). Thus, camptothecin, which has anti-cancer
activity, was transformed to the corresponding C7-
hydroxyalkylated derivative (3ae). Introduction of functional
groups to the C7-position of camptothecin could improve its
pharmacologic properties.18 A fasudil (ROCK2 inhibitor) de-
rivative also reacted with propionaldehyde with excellent yield
(
3af). Functionalized hydroxyalkyl groups, which were difficult
to use in the previous radical-mediated reactions, were also
introduced to N-heterocycles under the present conditions
(
3ag‒3ak). Thus, aldehydes derived from oxaprozin, loxoprofen,
dehydrocholic acid, an amino acid derivative, and a sugar
derivative afforded the corresponding N-heteroarylated
products in good yields. It is noteworthy that substrates
containing an oxazole ring which is susceptible to oxidative
conditions (3ag
tolerated our reaction conditions.
) )
19 or a relatively weak benzylic C-H bond (3ah
Figure 3. Substrate scope.a
a General reaction conditions: 1a (0.10 mmol), 2a (0.20 mmol),
Mes-Acr+ (0.005 mmol), TPA (0.010 mmol), and TFA (0.20 mmol)
4 | J. Name., 2012, 00, 1-3
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benzaldehyde-d (2a
-
d
) was exposed to the reaction conditions,
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target compound 3a contained 85%-H atDtOhIe: 1α0.-1p0o39s/iDti0oSnC0o4f1t1h4eA
hydroxy group (Figure 5a). Thus, the formyl C‒H bond of the
aldehyde was cleaved in the overall catalytic cycle. When TFA-d
was utilized as an acid additive, however, 62%-H was still
incorporated at the α-position (Figure 5b). This result was
contradictory to our hypothesis (Figure 2), and could be due to
contamination by H2O. Therefore, we assessed the H/D ratio
incorporated in 3a in mixed solvents containing variable
amounts of D2O. As a result, incorporation of D increased up to
95% according to the D2O concentration (Figure 5b). This result
indicates that the hydrogen atom at the α-position of the
hydroxy group is introduced via protonation. These deuteration
experiments support the feasibility of our mechanistic
hypothesis shown in Figure 2. The quantum yield was
determined to be 0.046, which supports that the reaction
proceeded through a closed catalytic cycle, not a radical chain
pathway (see SI for details).
Figure 5. Mechanistic information for deuterium
incorporation.a
a Yield was determined by 1H NMR analysis of the crude mixture
using 1,1,2,2-tetrachloroethane as an internal standard.
Conclusions
In conclusion, we developed a binary hybrid catalyst system to
achieve a one-step, redox-neutral hydroxyalkylation of N-
heteroaromatic compounds with aldehydes without using a
metal species. The reaction proceeded under mild conditions
and high atom economy, enabling a broad substrate scope and
application to late-stage modifications of drug-related
molecules. Keys to the success were the sequential HAT, Minisci,
and SCS processes. Further mechanistic studies are ongoing in
our laboratory.
Figure 4. Late-stage modification of multifunctional substrates.a
a
General reaction conditions:
1 (0.10 mmol), 2 (0.20 mmol),
Mes-Acr+ (0.005 mmol), TPA (0.010 mmol), and TFA (0.20 mmol)
were reacted in dichloromethane (DCM; 2.0 mL) at room
temperature under blue LED irradiation for 3 h. Yield is isolated
b
yield unless otherwise noted. 1.2 equiv of the aldehyde was
c
used. The target compound was isolated as the lactone.
Reaction was conducted at 0.035 mmol scale.
Acknowledgements
To gain preliminary insight into the mechanism, reactions
were conducted using deuterated compounds (Figure 5). When
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1, 1659; (d) J. A. Weitgenant, J. D.
Helquist, Org. Lett., 1999,
This work was supported in part by JSPS KAKENHI Grant
Numbers JP17H06442 (M.Ka.) (Hybrid Catalysis), 18H05969
(H.M.), 19J23073 (H.F.), 17H06444 (S.M.) (Hybrid Catalysis),
20H02754 (M.Ko.), and 20K15955 (Y.S.). We thank Professor
Masahiro Terada and Dr. Jun Kikuchi in Tohoku University for
sending us an enantiomerically-pure TPA derivative. We also
thank Professor Yasuteru Urano, Dr. Tasuku Ueno, and Dr. Toru
Komatsu in the University of Tokyo for helpful discussion on
mechanistic studies.
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Mortison, D. J. O'Neill, B. Mowery, A. Puranen and P. Helquist,
DOI: 10.1039/D0SC04114A
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11 After a preliminary version of this manuscript was posted in
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Huang reported a similar photocatalytic transformation
promoted by 4CzlPN-LiBr. The scope of their method,
however, is limited to reactions of simple aromatic aldehydes
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Previously-reported transition metal-catalyzed C(sp2)-H
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and required electron-deficient aldehydes or stoichiometric
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16 Electron transfer between *Mes-Acr+ and TPA is feasible on
the basis of the following experimental results and data: (a)
Stern-Volmer quenching was observed between Mes-Acr+
and TPA, but not between Mes-Acr+ and aldehyde 2a. See
Supplementary information (SI). (b) The transient absorption
spectra supported electron transfer from TPA to *Mes-Acr+.
See ref. 15a. (c) The oxidation potential of TPA (+1.18 V vs. SCE,
see ref. 15a) is smaller than the reduction potential of *Mes-
Acr+ (1.88 V vs. SCE, see S. Fukuzumi, K. Ohkubo and T.
Suenobu, Acc. Chem. Res., 2014, 47, 1455).
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Early examples by radical reaction were known as Emmert
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