Photochemical C?H Hydroxyalkylation of Quinolines and Isoquinolines

Article abstract of DOI:10.1002/anie.201910641

We report herein a visible light-mediated C?H hydroxyalkylation of quinolines and isoquinolines that proceeds via a radical path. The process exploits the excited-state reactivity of 4-acyl-1,4-dihydropyridines, which can readily generate acyl radicals upon blue light absorption. By avoiding the need for external oxidants, this radical-generating strategy enables a departure from the classical, oxidative Minisci-type pattern and unlocks a unique reactivity, leading to hydroxyalkylated heteroarenes. Mechanistic investigations provide evidence that a radical-mediated spin-center shift is the key step of the process. The method's mild reaction conditions and high functional group tolerance accounted for the late-stage functionalization of active pharmaceutical ingredients and natural products.

Full text of DOI:10.1002/anie.201910641

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201910641
German Edition: DOI: 10.1002/ange.201910641
Synthetic Photochemistry
Hot Paper
À
Photochemical C H Hydroxyalkylation of Quinolines and
Isoquinolines
Bartosz Bieszczad, Luca Alessandro Perego, and Paolo Melchiorre*
À
Abstract: We report herein a visible light-mediated C H
hydroxyalkylation of quinolines and isoquinolines that pro-
ceeds via a radical path. The process exploits the excited-state
reactivity of 4-acyl-1,4-dihydropyridines, which can readily
generate acyl radicals upon blue light absorption. By avoiding
the need for external oxidants, this radical-generating strategy
enables a departure from the classical, oxidative Minisci-type
pattern and unlocks a unique reactivity, leading to hydroxy-
alkylated heteroarenes. Mechanistic investigations provide
evidence that a radical-mediated spin-center shift is the key
step of the process. The methodꢀs mild reaction conditions and
high functional group tolerance accounted for the late-stage
functionalization of active pharmaceutical ingredients and
natural products.
N
-Heteroarenes are ubiquitous motifs in natural products
Figure 1. a) Classical Minisci reaction of acyl radicals with N-hetero-
and active pharmaceutical ingredients.[1] The venerable
Minisci reaction[2] (i.e. the addition of a carbon-centered
radical to a heteroarene followed by formal hydrogen atom
arenes where intermediate I is oxidized by an external oxidant to form
the acylated product II. b) Diverting from the classical Minisci-type
chemistry: the photochemistry of 4-acyl-1,4-dihydropyridines 1 secures
the generation of acyl radicals in the absence of an external oxidant,
thus triggering an unusual hydroxyalkylation of N-heteroarenes; SET;
single-electron transfer.
À
loss) provides a rapid and direct method for heterocycle C H
alkylation.[3] This direct functionalization of N-heteroarenes
avoids the need for de novo heterocycle synthesis, thus
explaining the recent renewed interest in Minisci-type
chemistry.[4]
Recent advances in radical generation strategies, which
include photoredox catalysis[6] and electrochemistry,[7] have
enabled the use of a wider variety of radical precursors that
often operate under much milder conditions. These methods[8]
have facilitated the introduction of structurally different
radicals into complex heteroarenes, and they have been
quickly adopted by medicinal chemists for the late-stage
diversification of pharmaceutically relevant compounds.[9]
Despite this progress, both classical and modern Minisci
protocols have limitations. In particular, there is an intrinsic
mechanistic tie in the need for an oxidant to promote the re-
aromatization of intermediates I and drive the overall
reaction forward (Figure 1a). The highly oxidative conditions
of typical Minisci protocols may therefore limit the functional
group tolerance and the application to more complex targets.
In their pioneering works, Minisci and co-workers used
silver oxidants at elevated temperatures to generate alkyl and
acyl radicals from the corresponding carboxylic acids (Fig-
ure 1a).[2] Upon radical addition to the heteroarene, a stoi-
chiometric amount of persulfate secured the aromaticity-
driven oxidation of the radical intermediate I, leading to the
final product (the acylation[5] adduct II is shown in Figure 1a).
[*] Prof. Dr. P. Melchiorre
ICREA
Passeig Lluꢀs Companys 23, 08010 Barcelona (Spain)
Dr. B. Bieszczad, Dr. L. A. Perego, Prof. Dr. P. Melchiorre
ICIQ – Institute of Chemical Research of Catalonia, the Barcelona
Institute of Science and Technology
Avenida Paꢁsos Catalans 16 – 43007, Tarragona (Spain)
E-mail: pmelchiorre@iciq.es
À
Herein, we report a rare example of radical C H
functionalization of quinolines and isoquinolines operating
under reducing conditions, where the ability to generate acyl
radicals without using external oxidants allowed a departure
from the typical mechanistic pattern of the Minisci-type
chemistry (Figure 1b). This study was motivated by our
recent finding that 4-acyl-1,4-dihydropyridines (acyl-DHPs,
1) can unveil a rich photochemistry upon absorption of visible
light.[10] The excited acyl-DHPs 1* can then act as strong
single-electron transfer (SET) reductants, thus securing
reducing conditions, while generating nucleophilic acyl rad-
icals.[10,11] Wondering if it was possible to harness the photo-
Homepage: http://www.iciq.org/research/research_group/prof-
paolo-melchiorre/
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.201910641.
ꢂ 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs License, which
permits use and distribution in any medium, provided the original
work is properly cited, the use is non-commercial and no modifica-
tions or adaptations are made.
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chemistry of 1 in acyl radical additions to activated N-
heteroarenes, we found that the reaction yielded the hydrox-
yalkylated products III and not the typical Minisci-type
acylated adducts II. This is because the absence of an external
oxidant disables the classical pattern, and the rearomatization
of intermediate I takes place concomitantly to the formal
reduction of the carbonyl moiety. In this communication, we
detail the synthetic scope of this photochemical process,
which allows the preparation of adducts that are difficult to
access by traditional polar and Minisci-type chemistry. We
also discuss preliminary mechanistic studies that rationalize
the observed reactivity.
pathways generally require multi-step redox-inefficient
sequences and the use of pre-functionalized heteroarenes,[13]
while only a few direct Minisci-type strategies are available.[14]
Our method uses easily available substrates (acyl-DHPs 1 are
synthesized in a one-step procedure, see section B in the
Supporting Information) and works well with a variety of
benzo-fused azines, allowing the hydroxyalkylation of both
isoquinoline and quinoline substrates (Figure 2a). For the
latter, the presence of a substituent directed the selective
functionalization at either the C2 or C4 position, while
unsubstituted quinoline substrates afforded a 1:1 regioiso-
meric mixture (details in Figure S2 of the Supporting
Information).[15] A remarkable functional group tolerance
was observed, particularly for moieties prone to oxidation.
For example, the reaction conditions tolerate both primary
amines (-NH2, product 3c) and alcohols (-OH, adduct 3 f),
a phenol group (3d), and a diarylamine moiety (3k).
Table 1: Optimization studies and control experiments.[a]
To demonstrate the potential utility for medicinal chemis-
try, we used our protocol on complex and bioactive molecules.
We prepared advanced intermediates of a potent PKA
inhibitor H-89 and an antimalarial agent, which smoothly
underwent hydroxyalkylation to form 3c and the 4-hydrox-
yquinoline-b-glucoside derivative 3j, respectively. We also
functionalized quinine (3i), and the anticancer agents bosu-
tinib (3k) and camptothecin (3o). The protocol also allowed
the single-step access to 4-quinolinemethanol derivative (3l),
a purine receptor antagonist. One limitation is that pyridine
substrates were poorly reactive (e.g. 2-chloro-4-(trifluorome-
thyl)pyridine provided a complex mixture of products with
80% of recovered starting material). A complete list of
moderately successful and unsuccessful substrates for this
strategy is reported in Figure S2 of the Supporting Informa-
tion.
To evaluate the scope of the acyl-DHP 1 radical pre-
cursors, we selected a functionalized intermediate used in the
synthesis of HIF protyl-hydroxylase inhibitor roxadustat
(Figure 2b). For aromatic moieties in 1, different substitution
patterns were tolerated well, regardless of their electronic and
steric properties, affording the corresponding hydroxyalky-
lated products 3p–x in good yields. We also installed
a naphthyl (3q) and an amide functionality (3u). Finally,
alkyl substituents could be readily introduced (3v), including
a cyclopropyl moiety (3w).
We then studied the reaction mechanism with experimen-
tal and theoretical tools. First, we checked if the Minisci-type
acylation product, the ketone 4a, could be an intermediate of
the process (Figure 3a). When an independently prepared
and authentic sample of 4a was subjected to the reaction
conditions, the reduced product 3a was not formed at all in
the absence of light, while traces of 3a were observed (14%
yield) under irradiation. These experiments exclude the
possibility that acyl-DHP 1a could serve as a reducing
agent, and they suggest that Minisci-type acylation product
4a is not formed under our photochemical conditions.
A plausible mechanism of the overall process is depicted
in Figure 3c. Visible-light excitation turns 1a into a strong
reducing agent (Ered (1a+C/1a*) = À1.1 V vs. SCE in CH3CN,
as estimated from electrochemical and spectroscopic meas-
urements).[10] The significantly lower redox potential of the
Entry
Variation from standard conditions
Yield (3a) [%][b]
1
2
3
4
5
6
none
no light
no acid
2.0 equiv of water
no solvent degassing
1.5 mmol scale[e]
72
[c]
–
12[d]
71
68
70
[a] Reactions performed on a 0.2 mmol scale at 258C for 12 h using
0.6 mL of CH3CN under illumination by a single high-power (HP) LED
(lmax =465 nm, 30 mWcmÀ2) and using 1.2 equiv of 1a and 2 equiv of
TFA. [b] Yield of 3a determined by 1H NMR analysis of the crude mixture
using trichloroethylene as the internal standard. [c] Starting material
only. [d] Complex mixture. [e] Reaction performed in EvoluChemꢃ 18W
photoreactor (emission at 455 nm). The yield of the isolated 3a is given.
TFA: trifluoroacetic acid.
For our initial explorations (Table 1), we selected the
benzoyl derivative 1a and isoquinoline 2a as the model
substrates. 1a can absorb light in the visible region (see
Figure S4 in the Supporting Information). The experiments
were conducted in CH3CN using a blue (HP) LED (lmax
=
460 nm) with an irradiance of 30 mWcmÀ2, as controlled by
an external power supply (details of the illumination set-up
are reported in Figure S1). When using TFA (2 equiv) to
activate 2a, the reaction exclusively afforded the hydroxyal-
kylated product 3a in 72% yield (entry 1). The reaction did
not proceed without irradiation, confirming its photochemical
character (entry 2). When the reaction was carried out
without acid, a complex mixture of products was formed
along with 3a in 12% yield (entry 3). As a testament to the
methodꢀs robustness, the system tolerates traces of water
(entry 4) and the reaction could be efficiently performed
without degassing the solvent (entry 5). The process could
also be scaled up without compromising the efficiency
(entry 6).
We then evaluated the synthetic potential of this photo-
chemical strategy (Figure 2). The resulting hydroxyalkylated
N-heteroarene products 3 are important scaffolds,[12] which
are difficult to access by other synthetic methods. Polar
2
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À
Figure 2. Substrate scope for the photochemical C H hydroxyalkylation of N-heteroarenes. Survey of the a) quinolines and isoquinolines, and
b) radical precursors 1 that can participate in the reaction. Reactions performed on 0.2 mmol scale using 1.2 equiv of 1 and 0.6 mL of CH3CN.
Yields refer to isolated products (average of two runs per substrate).[a] Performed in chloroform.[b] Reaction time: 48 h.[c] Performed at À108C for
64 h.[d] Performed in a CH3CN/DMSO mixture (1:1) for 48 h.
protonated 6,7-dimethoxyisoquinoline 2b (Ered(2b-H+/2b-
HC) = À1.32 V vs. SCE in CH3CN, see Figure 3b), which is
a particularly effective substrate of this protocol, indicates
that the SET from 1a* to 2b-H+ is thermodynamically
unfeasible.[16] Electrochemical measurements also highlight
that the pyridinium ion (Pyr-H+), which arises from the
photolysis of 1a, has the right redox properties to accept an
electron from 1a* (Ered (Pyr-H+/PyrHC) = À1.01 V vs. SCE in
CH3CN). This SET event triggers the formation of the
unstable acyl-DHP radical cation IV, which decomposes to
deliver the acyl radical V. V then adds to the protonated
heteroarene 2a-H+ to afford the radical intermediate VI.
Deprotonation leads to the a-amino radical of type I. Acid
activation of the carbonyl moiety in I triggers the rear-
omatization of the azine ring, while the spin density is shifted
by one atom and is localized at the benzylic position of the
ensuing radical VII. This step formally corresponds to a spin-
center shift (SCS)-type process (vide infra).[17] SET reduction
of VII (Ered (VII/VIII) =+ 0.06 V vs. SCE, as estimated by
DFT calculations (see section G for details) from PyrHC leads
to the carbanion VIII, which is eventually protonated to form
product 3a. This step is supported by the deuterium
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Figure 3. a) Control experiments. b) Redox properties of Pyr-H+ (left) and 2b-H+ (right). c) Proposed mechanism. d) Deuteration experiment
performed in CH3OD using TFA-d. e) Computed free energy profile for the addition of the benzoyl radical V to isoquinolinium (2a-H+) and
subsequent prototropy from VI to VII. Relative free energies are reported in kcalmolÀ1 at 298 K and 1 atm. Inset: spin density isosurfaces
(value=0.009 ea0À3) for I and VII, supporting the SCS process.
incorporation experiment depicted in Figure 3d (85% D
incorporation at a-OH position of 3a).
favorable (DG = À13.1 kcalmolÀ1) and (ii) protonation of
the carbonyl group in I induces a shift of the spin density to
the adjacent benzylic carbon (Figure 3e). Radical-mediated
SCS plays an important role in both a biochemical[17b] and
synthetic context[17c] (Figure 4a and b, respectively). Mecha-
nistically, it is generally associated with the elimination of
a leaving group (typically water) located at the atom adjacent
to the radical center. Here, we propose extending the narrow
definition of SCS[17a] to include a carbonyl group (and p-
electrons in general), which serves a similar purpose as the
leaving group (Figure 4c).
Two aspects of the proposed mechanism require further
comment. Firstly, we propose that the Pyr-H+/PyrHC couple
acts as an electron mediator, effectively shuttling an electron
from the highly reducing 1a* to the fleeting intermediate
VII.[18] This scenario is consonant with the observation that
the addition of Pyr-H+ (50 mol%) to a CH3CN solution of 1a
increased the initial rate of radical generation via photolysis,
as corroborated by EPR investigations (see section H in the
Supporting Information). Secondly, the proposed SCS step,
which converts I into VII (Figure 3c), is supported by
theoretical studies at the DFT level,[19] which show that (i)
prototropy converting VI to VII is thermodynamically
In summary, we have developed a photochemical method
for the direct hydroxyalkylation of quinolines and isoquino-
lines. This transformation, which would be difficult to achieve
4
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[4] For recent developments, see: R. S. J. Proctor, R. J. Phipps,
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201900977; Angew. Chem. 2019, https://doi.org/10.1002/ange.
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[5] For classical acylation strategies: a) T. Caronna, G. Fronza, F.
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Figure 4. Spin-center shift (SCS) pathways: water acting as a leaving
group in the SCS-based a) DNA biosynthesis and b) Minisci-type
alkylation of N-heteroarenes. c) Proposed SCS where the carbonyl
group facilitates the shift of spin density.
by other direct methods, shows a mechanistic departure from
the classical Minisci chemistry. This divergence is enabled by
the acyl radical generation strategy, which avoids the need for
external oxidants. The key step is a SCS process, where
carbonyl p-electrons act similarly to a leaving group.
[9] M. A. J. Duncton, MedChemComm 2011, 2, 1135 – 1161.
[10] G. Goti, B. Bieszczad, A. Vega-PeÇaloza, P. Melchiorre, Angew.
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Acknowledgements
[11] For the ability of 1,4-dihydropyridines to generate radicals upon
visible-light absorption, see: a) L. Buzzetti, A. Prieto, S. R. Roy,
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Financial support was provided by MICIU (CTQ2016-75520-
P), the AGAUR (Grant 2017 SGR 981), and the European
Research Council (ERC-2015-CoG 681840 – CATA-LUX).
Conflict of interest
The authors declare no conflict of interest.
Keywords: dihydropyridines · Minisci reaction ·
photochemistry · radical chemistry · synthetic methods
[1] a) A. F. Pozharskii, A. T. Soldatenkov, A. R. Katritzky, Hetero-
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[16] SET reduction from 1a* to other protonated azines, including
isoquinoline 2a (E (2a-H+/2aC) = À1.16 V vs. SCE) cannot be
excluded as an alternate minor path.
[17] For a review: a) P. Wessig, O. Muehling, Eur. J. Org. Chem. 2007,
2219 – 2232. For selected examples, see: b) H. Eklund, U. Uhlin,
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complex facilitated the formation of the alkyl radical acting as
electron mediator, see Ref. [11b].
[19] Model chemistry: M06-2X/6–311 + G(3df,2p)//M06-2X/6–31 +
G(d), IEF-PCM (CH3CN), see sections G and K in the
Supporting Information for full computational details.
Manuscript received: August 20, 2019
[18] This hypothesis is reminiscent of our previous study on the direct
excitation of 4-alkyl 1,4-dihydropyridines, in which a nickel
Accepted manuscript online: September 17, 2019
Version of record online: && &&, &&&&
6
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Communications
Synthetic Photochemistry
In a different light. A visible light-medi-
À
ated C H hydroxyalkylation of quinolines
B. Bieszczad, L. A. Perego,
P. Melchiorre*
and isoquinolines that proceeds via
a radical path exploits the excited-state
reactivity of 4-acyl-1,4-dihydropyridines 1,
which can readily generate acyl radicals
upon blue light absorption. By avoiding
the need for external oxidants, this strat-
egy enables a departure from the classi-
cal, oxidative Minisci-type pattern and
unlocks a unique reactivity, leading to
hydroxyalkylated heteroarenes.
&&&& — &&&&
À
Photochemical C H Hydroxyalkylation of
Quinolines and Isoquinolines
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