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Synthetic Photochemistry Hot Paper

Chemie

International Edition: DOI: 10.1002/anie.201910641
German Edition:
DOI: 10.1002/ange.201910641

Photochemical CÀH Hydroxyalkylation of Quinolines and
Isoquinolines
Bartosz Bieszczad, Luca Alessandro Perego, and Paolo Melchiorre*
Abstract: We report herein a visible light-mediated CÀH
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 methods 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
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
loss) provides a rapid and direct method for heterocycle CÀH
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]
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 (Figure 1 a).[2] Upon radical addition to the heteroarene, a stoichiometric amount of persulfate secured the aromaticitydriven oxidation of the radical intermediate I, leading to the
final product (the acylation[5] adduct II is shown in Figure 1 a).
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
[*] Prof. Dr. P. Melchiorre
ICREA
Passeig Lluís 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 Països Catalans 16 – 43007, Tarragona (Spain)
E-mail: pmelchiorre@iciq.es
Homepage: http://www.iciq.org/research/research_group/profpaolo-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.

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 rearomatization of intermediates I and drive the overall
reaction forward (Figure 1 a). The highly oxidative conditions
of typical Minisci protocols may therefore limit the functional
group tolerance and the application to more complex targets.
Herein, we report a rare example of radical CÀH
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 1 b). 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 radicals.[10, 11] Wondering if it was possible to harness the photochemistry of 1 in acyl radical additions to activated Nheteroarenes, we found that the reaction yielded the hydroxyalkylated 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

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Figure 1. a) Classical Minisci reaction of acyl radicals with N-heteroarenes 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.

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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.
Table 1: Optimization studies and control experiments.[a]

Entry

Variation from standard conditions

Yield (3 a) [%][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 25 8C 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 1 a and 2 equiv of
TFA. [b] Yield of 3 a 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 EvoluChem 18W
photoreactor (emission at 455 nm). The yield of the isolated 3 a is given.
TFA: trifluoroacetic acid.

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For our initial explorations (Table 1), we selected the
benzoyl derivative 1 a and isoquinoline 2 a as the model
substrates. 1 a 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 mW cmÀ2, 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 2 a, the reaction exclusively afforded the hydroxyalkylated product 3 a 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 3 a in 12 % yield (entry 3). As a testament to the
methods 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 photochemical strategy (Figure 2). The resulting hydroxyalkylated
N-heteroarene products 3 are important scaffolds,[12] which
are difficult to access by other synthetic methods. Polar
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
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benzo-fused azines, allowing the hydroxyalkylation of both
isoquinoline and quinoline substrates (Figure 2 a). 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 regioisomeric 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 3 c) and alcohols (-OH, adduct 3 f),
a phenol group (3 d), and a diarylamine moiety (3 k).
To demonstrate the potential utility for medicinal chemistry, 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 3 c and the 4-hydroxyquinoline-b-glucoside derivative 3 j, respectively. We also
functionalized quinine (3 i), and the anticancer agents bosutinib (3 k) and camptothecin (3 o). The protocol also allowed
the single-step access to 4-quinolinemethanol derivative (3 l),
a purine receptor antagonist. One limitation is that pyridine
substrates were poorly reactive (e.g. 2-chloro-4-(trifluoromethyl)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 Information.
To evaluate the scope of the acyl-DHP 1 radical precursors, we selected a functionalized intermediate used in the
synthesis of HIF protyl-hydroxylase inhibitor roxadustat
(Figure 2 b). For aromatic moieties in 1, different substitution
patterns were tolerated well, regardless of their electronic and
steric properties, affording the corresponding hydroxyalkylated products 3 p–x in good yields. We also installed
a naphthyl (3 q) and an amide functionality (3 u). Finally,
alkyl substituents could be readily introduced (3 v), including
a cyclopropyl moiety (3 w).
We then studied the reaction mechanism with experimental and theoretical tools. First, we checked if the Minisci-type
acylation product, the ketone 4 a, could be an intermediate of
the process (Figure 3 a). When an independently prepared
and authentic sample of 4 a was subjected to the reaction
conditions, the reduced product 3 a was not formed at all in
the absence of light, while traces of 3 a were observed (14 %
yield) under irradiation. These experiments exclude the
possibility that acyl-DHP 1 a could serve as a reducing
agent, and they suggest that Minisci-type acylation product
4 a is not formed under our photochemical conditions.
A plausible mechanism of the overall process is depicted
in Figure 3 c. Visible-light excitation turns 1 a into a strong
reducing agent (Ered (1 a+C/1 a*) = À1.1 V vs. SCE in CH3CN,
as estimated from electrochemical and spectroscopic measurements).[10] The significantly lower redox potential of the
protonated 6,7-dimethoxyisoquinoline 2 b (Ered(2 b-H+/2 bHC) = À1.32 V vs. SCE in CH3CN, see Figure 3 b), which is
a particularly effective substrate of this protocol, indicates
that the SET from 1 a* to 2 b-H+ is thermodynamically
unfeasible.[16] Electrochemical measurements also highlight
that the pyridinium ion (Pyr-H+), which arises from the

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Figure 2. Substrate scope for the photochemical CÀH 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 À10 8C for
64 h.[d] Performed in a CH3CN/DMSO mixture (1:1) for 48 h.

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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 3 a. This step is supported by the deuterium
incorporation experiment depicted in Figure 3 d (85 % D
incorporation at a-OH position of 3 a).
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 1 a* to the fleeting intermediate

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photolysis of 1 a, has the right redox properties to accept an
electron from 1 a* (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 2 a-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 rearomatization 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-

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Figure 3. a) Control experiments. b) Redox properties of Pyr-H+ (left) and 2 b-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 (2 a-H+) and
subsequent prototropy from VI to VII. Relative free energies are reported in kcal molÀ1 at 298 K and 1 atm. Inset: spin density isosurfaces
(value = 0.009 e a0À3) for I and VII, supporting the SCS process.

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VII.[18] This scenario is consonant with the observation that
the addition of Pyr-H+ (50 mol %) to a CH3CN solution of 1 a
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 3 c), is supported by
theoretical studies at the DFT level,[19] which show that (i)
prototropy converting VI to VII is thermodynamically
favorable (DG = À13.1 kcal molÀ1) and (ii) protonation of
the carbonyl group in I induces a shift of the spin density to
the adjacent benzylic carbon (Figure 3 e). Radical-mediated
SCS plays an important role in both a biochemical[17b] and
synthetic context[17c] (Figure 4 a and b, respectively). Mechanistically, it is generally associated with the elimination of
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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 pelectrons in general), which serves a similar purpose as the
leaving group (Figure 4 c).
In summary, we have developed a photochemical method
for the direct hydroxyalkylation of quinolines and isoquinolines. This transformation, which would be difficult to achieve
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.

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[7]
[8]

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.

[9]
[10]

Acknowledgements
[11]

Financial support was provided by MICIU (CTQ2016-75520P), the AGAUR (Grant 2017 SGR 981), and the European
Research Council (ERC-2015-CoG 681840 – CATA-LUX).
[12]

Conflict of interest
The authors declare no conflict of interest.
Keywords: dihydropyridines · Minisci reaction ·
photochemistry · radical chemistry · synthetic methods

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[18] This hypothesis is reminiscent of our previous study on the direct
excitation of 4-alkyl 1,4-dihydropyridines, in which a nickel
complex facilitated the formation of the alkyl radical acting as
electron mediator, see Ref. [11b].

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[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.

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Manuscript received: August 20, 2019
Accepted manuscript online: September 17, 2019
Version of record online: && &&, &&&&

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Communications
B. Bieszczad, L. A. Perego,
P. Melchiorre*

&&&&—&&&&

Photochemical CÀH Hydroxyalkylation of
Quinolines and Isoquinolines

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In a different light. A visible light-mediated CÀH hydroxyalkylation of quinolines
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 strategy enables a departure from the classical, oxidative Minisci-type pattern and
unlocks a unique reactivity, leading to
hydroxyalkylated heteroarenes.

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Synthetic Photochemistry

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