Aldehydes as Photoremovable Directing Groups: Synthesis of Pyrazoles by a Photocatalyzed [3+2] Cycloaddition/Norrish Type Fragmentation Sequence

Article abstract of DOI:10.1021/acs.orglett.1c01665

A straightforward methodology for the regioselective synthesis of pyrazoles has been developed by a domino sequence based on a photoclick cycloaddition followed by a photocatalyzed oxidative deformylation reaction. Distinguishing features of this protocol include an unprecedented photoredox-catalyzed Norrish type fragmentation under green-light irradiation and the use of α,β-unsaturated aldehydes as synthetic equivalents of alkynes, where the aldehyde is acting as a novel photoremovable directing group.

Full text of DOI:10.1021/acs.orglett.1c01665

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Letter
Aldehydes as Photoremovable Directing Groups: Synthesis of
Pyrazoles by a Photocatalyzed [3+2] Cycloaddition/Norrish Type
Fragmentation Sequence
Ana Pascual-Escudero, Laura Ortiz-Rojano, Silvia Simón-Fuente, Javier Adrio,* and María Ribagorda*
Cite This: Org. Lett. 2021, 23, 4903−4908
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ABSTRACT: A straightforward methodology for the regioselective
synthesis of pyrazoles has been developed by a domino sequence based
on a photoclick cycloaddition followed by a photocatalyzed oxidative
deformylation reaction. Distinguishing features of this protocol include an
unprecedented photoredox-catalyzed Norrish type fragmentation under
green-light irradiation and the use of α,β-unsaturated aldehydes as
synthetic equivalents of alkynes, where the aldehyde is acting as a novel
photoremovable directing group.
Scheme 1. Synthesis of Pyrazoles and Pyrazolines from
Tetrazoles
yrazoles are privileged structures in organic and medicinal
Pchemistry, because they are present in numerous natural
products and therapeutic agents based on small molecules,
such as Celecobix, Rimonabant, or Lersivirine, among others.1
Furthermore, pyrazoles have been extensively used as ligands
in transition metal-catalyzed processes.2 Accordingly, the
development of new methods to facilitate the concise
preparation of structurally diverse pyrazoles is a very appealing
synthetic goal. Among the plethora of reported methodologies
for pyrazole synthesis, the traditional condensation of
hydrazine derivatives with diverse substituted carbonyl
compounds has been the most commonly employed.3
Alternatively, 1,3-dipolar cycloaddition has also played a
prevalent role due to its great versatility.4 The use of
diazoalkanes5 or nitrile imines6 as dipoles and activated
alkynes as dipolarophiles is a straightforward procedure for
the preparation of pyrazoles. With activated alkenes as
dipolarophiles, the resulting pyrazolines required an extra
elimination7 or oxidation step8 for aromatization to synthesize
pyrazoles. However, non-activated alkyl-substituted alkynes or
alkenes have been scarcely studied because they usually lead to
regioisomeric mixtures in low conversions.
Traditionally, the nitrile imine dipoles can be generated in
situ either from α-halohydrazones in the presence of a base9 or
from tetrazole precursors. Of special relevance is the light-
induced 1,3-dipolar cycloadditions of 1,3-diaryltetrazoles that
have been widely applied in biological and material chemistry
(Scheme 1).10 Huisgen and co-workers11 reported the first
example of this photoactivated cycloaddition for the synthesis
of pyrazolines. More recently, Lin and co-workers12 have
proven the usefulness of this clean and atom-economical
transformation with a wide range of alkenes as dipolarophiles
(Scheme 1, pyrazolines).
α,β-Unsaturated aldehydes have been extensively used as
dipolarophiles in 1,3-dipolar cycloadditions13 with a great
variety of dipoles.14,15 The synthetic versatility of the formyl
group is beyond any doubt because it can be straightforwardly
converted into many other functional groups. However,
examples of reactions involving C−C bond cleavage by formyl
Received: May 17, 2021
Published: June 7, 2021
https://doi.org/10.1021/acs.orglett.1c01665
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4903−4908
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group elimination are scarce. Conversely, the photochemical
UV-induced cleavage of aldehydes or ketones into two radical
intermediates, known as the Norrish reaction, has been widely
studied, including several applications in natural product
synthesis.16 Because there are not reported procedures for
the efficient utilization of non-activated alkynes as dipolar-
ophiles in this kind of cycloaddition, we envisaged that an α,β-
unsaturated aldehyde could act as an alkyne surrogate,
increasing the reactivity and temporally controlling the
regioselectivity of the cycloaddition. Herein, we report a
sequential dipolar photoclick reaction followed by a Norrish
type deformylation step under green-light irradiation using
eosin Y as a photoredox catalyst. To the best of our knowledge,
there are no photocatalytic examples for this fragmentation
besides the important advantages of this approximation.17,18
In connection with our previous work on tetrazole
photoclick 1,3-dipolar cycloadditions,19 we set out to explore
the application of this methodology to the synthesis of
pyrazoles using unsaturated aldehydes as synthetic equivalents
of alkynes.
For this purpose, we initially studied the Norrish type
deformylation reaction of formyl pyrazoline 1a, previously
prepared by a UV-light-induced dipolar cycloaddition reaction
between the corresponding diaryltetrazole and methacrolein.20
UV-light irradiation of 1a gave the desired pyrazole 2a in 44%
yield after 24 h (Table 1, entry 1). This result evidenced the
potential use of methacrolein as a synthetic equivalent of
propyne gas leading to a regioselective synthesis of pyrazole 2a.
Our next purpose was to evaluate the C−C fragmentation
process using a photocatalyst under irradiation with a less
energetic light. We were pleased to find that iridium PC-1 (5
mol %) was able to catalyze the oxidative deformylation
reaction under blue light (420 nm), affording 2a in 66% yield
after 6 h (Table 1, entry 2). The addition of Et3N significantly
increased the reaction rate, allowing the isolation of 2a in 72%
yield after 30 min (entry 3). Control experiments showed that
light irradiation and a photocatalyst were indispensable for the
reaction to proceed (entries 4−6). The use of other bases such
as 2,6-lutidine or K2CO3 gave similar results, although cleaner
reaction mixtures were obtained in the latter case (entries 7
and 8). Other iridium sources such as PC-2 or PC-3
successfully worked (entries 9 and 10). Finally, the reaction
using inexpensive eosin Y (5 mol %), as an organic
photocatalyst, under green LED irradiation provided 2a in
78% yield (entry 11). The reaction without the base displayed
a similar efficiency (entry 12). A control experiment proved
that green-light irradiation was necessary for the reaction to
take place (entry 13). The organic catalyst loading could be
decreased to 1 mol % without impairing the reaction yield
(entry 14). The transformation was also successfully performed
on a gram scale (entry 15).
With the optimized reaction conditions in hand, we
wondered if this pyrazole scaffold could be accessed from
1,3-diaryltetrazoles in a domino process that would embrace a
photoclick dipolar cycloaddition followed by an oxidative
deformylation. For this purpose, an Ultra-Vitalux (OSRAM)
lamp20 was used as the irradiation source. This lamp has
emission signals at λ values of 315 nm (UV), 440 nm (blue),
and 540 nm (green), which would allow both UV-light-
promoted cycloaddition and the blue- or green-light-photo-
catalyzed deformylation process, providing an easier reaction
setup.21 Gratifyingly, the reaction between tetrazole 3a and
methacrolein gave 2a as a single regioisomer in 72% yield, after
5 h at rt (Scheme 2).
Table 1. Optimization of the Reaction Conditions
Scheme 2. Domino Photoinduced Cycloaddition/Oxidative
Deformylation Sequence
a
entry
[PC]
hν
base
none
time (h)
yield (%)
b
1
2
3
4
5
6
7
8
none
PC-1
PC-1
−
UV
24
6
0.5
6
6
6
0.5
0.5
0.5
0.5
0.5
0.5
18
0.5
8
44
66
72
0
0
0
71
75
76
78
78
73
0
blue
blue
blue
blue
−
blue
blue
blue
blue
green
green
−
none
Et3N
−
Et3N
Et3N
c
The process using Ir-PC-1 and Et3N also gave 2a in a 70%
yield. The use of blue or green LEDs as the single irradiation
source resulted in the full recovery of tetrazole 3a, underlining
that the photoredox catalyst was exclusively catalyzing the
second step. The reaction without any photocatalyst under the
Ultra-Vitalux lamp gave pyrazole 2a in significantly lower yield
and longer reaction times (irradiation for 24 h) (Scheme 2).
The global process using the photoredox catalyst opens the
possibility of using the formyl group as novel photoremovable
directing groups under mild reaction conditions.22
c
c
−
PC-1
PC-1
PC-1
PC-2
PC-3
PC-4
PC-4
PC-4
c
2,6-lutidine
c
K2CO3
c
9
K2CO3
c
10
11
12
13
14
15
K2CO3
c
K2CO3
−
−
−
−
d
PC-4
PC-4
green
green
76
d
e
The simple one-step preparation of pyrazoles led us to study
the scope of the process with regard to the substitution at the
nitrile imine precursor. As shown in Scheme 3, different
electron-donating and electron-withdrawing groups underwent
the dipolar/oxidative deformylation process successfully. o-,
72
a
b
c
Isolated yield after purification. UV λ 315 nm. With 1.5 equiv.
d
e
With 1 mol % eosin Y. On a 3.5 mmol scale (gram-scale). Blue
LEDs at a λ of 420 nm and green LEDs at a λ of 535 nm.
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alized alkyl groups at the α-position of the aldehyde (pyrazoles
6d and 6e).
Scheme 3. Scope of the Domino Sequence
To evaluate the scope of this reaction with more sterically
challenging substrates, α,β-disubstituted aldehydes were next
evaluated (Scheme 3B). Despite a decrease in the reactivity
observed in the first dipolar cycloaddition step, pyrazoles 6f−j
could be obtained as single regioisomers. All of these results
pointed out that this protocol opens a regioselective access to
5-alkyl tri- and tetrasubtituted pyrazoles, which was elusive
with other cycloaddition methodologies.5−8
It is known that ketones are also suitable substrates for
Norrish fragmentation reactions. Therefore, we next studied
the possibility of expanding the scope of this methodology to
the use of α,β-unsaturated methyl ketones as dipolarophiles.
For this purpose, we prepared pyrazoline 1b, with a pendant
methyl ketone, through the corresponding 1,3-dipolar cyclo-
addition between 3a and 3-methyl-3-buten-2-one. The reaction
of 1b under optimized reaction conditions was completed after
1 h, affording pyrazole 2a together with compound 7, in a
54:46 ratio (Scheme 4A). Although in this case pyrazole 2a
Scheme 4. Photocatalyzed Fragmentation of 1b, 9, and 1a
was obtained in moderate yield, this result highlights the
significant potential of this green-light-catalyzed C−C
fragmentation. The reaction with other 2-methyl α,β-
unsaturated carbonyl derivatives, such as the carboxylic acid,
the ethyl ester, or the N-methyl amide, gave the corresponding
pyrazolines from the dipolar reaction; however, no carbonyl
fragmentation was observed in any case.24
To improve our understanding of the reaction pathway, we
conducted a series of experiments. The addition of radical
scavenger TEMPO [(2,2,6,6-tetramethylpiperidin-1-yl)oxyl] to
the photoreaction of 1b slowed the fragmentation process. As a
result, a mixture of starting pyrazoline 1b, pyrazole 2a, and
compound 7 was observed in a 47:41:12 ratio after irradiation
for 1 h (detected by 1H NMR). This reaction was also
monitored by ESI-MS detecting the [M + H+] ion (m/z
200.1643) that corresponds to TEMPO adduct 8, which
indicates the involvement of the acyl radical (Scheme 4B).20,25
Moreover, the reaction did not proceed with formyl
dihydroisoxazole 9, recovering the starting material unaltered.
This is suggestive of the involvement of N-1 of the pyrazoline
under the photoredox process. We also observed that the
reaction was completely inhibited in the absence of O2
(reaction under N2 through a “freeze−pump−thaw” cycle)
(Scheme 4C).
a
b
c
Isolated yield. Eosin Y (5 mol %). Eosin Y (2 mol %).
m-, and p-methoxy-substituted phenyl tetrazoles furnished the
corresponding pyrazoles in good yields (2b−d, respectively).
Different functional groups such as fluoro, cyano, or carboxylic
acids were perfectly compatible (2e−g, respectively). Interest-
ingly, because no external oxidant was required in this
protocol, groups sensitive to oxidant conditions such as formyl
or benzylic alcohol were well tolerated (2h and 2i). Similarly,
3-heteroaromatic substituted pyrazoles, such as pyridyl or
thienyl derivative 2j or 2k, respectively, were also obtained in
good yields. The cycloaddition of tetrazole 3l bearing an
alkenyl substituent proceeded similarly, giving rise to 2l as the
only detectable isomer (no isomerization of the remaining
double bond was observed).23 Alkyl-substituted pyrazole 2m
was also obtained in good yield.
Next, we studied the compatibility of this photocatalyzed
cycloaddition/fragmentation sequence with other α,β-unsatu-
rated aldehydes as dipolarophiles (Scheme 3B). The reaction
of 2-ethyl and 2-propyl acrolein under the optimized reaction
conditions afforded pyrazoles 6a and 6b in 55% and 54%
yields, respectively. A benzyl substituent in the aldehyde was
also well tolerated, leading to pyrazole 6c in 56% yield. The
reaction sequence proceeded in similar yields with function-
On the basis of all of these results, a plausible mechanism is
proposed in Scheme 5. First, photolysis of tetrazole 3 generates
nitrile imine dipole that, upon 1,3-dipolar cycloaddition with
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28049 Madrid, Spain; Institute for Advanced Research in
Chemical Sciences (IAdChem), Universidad Autónoma de
Madrid, 28049 Madrid, Spain; orcid.org/0000-0001-
7185-4095; Email: maria.ribagorda@uam.es
Scheme 5. Mechanistic Proposal for the Domino
Photoinduced Cycloaddition/Oxidative Deformylation
Javier Adrio − Departamento de Química Orgánica, Facultad
de Ciencias, Universidad Autónoma de Madrid, 28049
Madrid, Spain; Institute for Advanced Research in Chemical
Sciences (IAdChem), Universidad Autónoma de Madrid,
28049 Madrid, Spain; orcid.org/0000-0001-6238-6533;
Email: javier.adrio@uam.es
Authors
Ana Pascual-Escudero − Departamento de Química
Orgánica, Facultad de Ciencias, Universidad Autónoma de
Madrid, 28049 Madrid, Spain; orcid.org/0000-0001-
5780-1739
Laura Ortiz-Rojano − Departamento de Química Orgánica,
Facultad de Ciencias, Universidad Autónoma de Madrid,
28049 Madrid, Spain
Silvia Simón-Fuente − Departamento de Química Orgánica,
Facultad de Ciencias, Universidad Autónoma de Madrid,
28049 Madrid, Spain
the α,β-unsaturated compound, leads to pyrazoline 1. Visible-
light irradiation of eosin Y generates an excited-state oxidant
(E1/2 = 0.86 V vs SCE) that can accept a single electron
transfer from N-1 of pyrazoline (for 1a, E1/2 = 0.68 V vs
SCE),20 thus forming aminyl radical cation II and the reduced
state of the photocatalyst.26 Radical cation II evolves via a C−
C bond fragmentation of the carbonyl group, generating a
formyl (R = H) or an acyl radical (R = Me) favored by the
formation of pyrazolinium cation III that aromatizes to the
corresponding pyrazole IV after losing a proton. Oxidation of
the photocatalyst by oxygen completes the catalytic cycle. The
lack of reactivity under a nitrogen atmosphere supports the
proposed reductive quenching cycle. Moreover, the formation
of byproduct 7 (Scheme 4A) in the reaction with 3-methyl-3-
buten-2-one supported the formation of radical cation II (R =
Me), which can evolve via β-hydrogen abstraction of the
methyl group, followed by a ring opening of the heterocycle.
The formation of 2a without a photocatalyst (Table 1, entry 1)
and under UV light could be rationalized on the basis of a
similar photoclick reaction followed in this case by a UV-light
Norrish type I formyl fragmentation16 and oxidation sequence.
In conclusion, an innovative procedure for the preparation
of pyrazoles has been developed using a domino photoinduced
1,3-dipolar cycloaddition/photoredox-catalyzed formyl frag-
mentation sequence. To the best of our knowledge, this is the
first report describing an oxidative deformylation reaction
using a photoredox catalyst under visible-light irradiation. An
important advantage is that the domino sequence took place in
the presence of an inexpensive organic photocatalyst such as
eosin Y. The regiocontrol exerted by the formyl group allowed
better access to tri- and tetrasubstituted 5-alkyl pyrazoles.
Moreover, this protocol is compatible with the presence of
groups sensitive to oxidizing conditions. These results
demonstrate the possibility of using aldehydes as a clean
photoremovable directing group and open the door for further
investigations of other different systems.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01665
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the MINECO (CTQ2014-53894-
R and CTQ2017-85454-C2-2-P) and FEDER/MICIU
(PGC2018-098660-B-I00) of Spain. L.O.-R. thanks MINECO
for a FPI fellowship, and A.P.-E. thanks CAM for a
postdoctoral fellowship.
DEDICATION
This paper is dedicated to Professor Carmen Carren
occasion of her retirement from Universidad Autonoma de
Madrid.
■
̃
o on the
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01665.
General experimental procedures, characterization data,
and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
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Organic Letters
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(20) For details, see the Supporting Information.
(21) Alternatively, a UV lamp combined with green or blue LEDs
can be use as the light irradiation source.
(22) For the synthesis of 5-alkyl-1H-pyrazolines by a formal
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(23) The reaction between 3l and methacrolein in the absence of
eosin gave a 1:1 mixture of E-2l and Z-2l isomers, probably as a
consequence of the long irradiation times required to complete the
reaction (1 day).
(24) For other α,β-unsaturated aldehydes and ketones that were not
suitable for this study as dipolarophiles, see the Supporting
Information.
(25) All of the attempts to detect the formyl radical formed in the
reaction among 3a, methacrolein, and TEMPO were unsuccessful.
(26) Stern−Volmer quenching studies between a photocatalyst (PC-
1 or eosin Y) and pyrazoline 1a were inconclusive due to the
fluorescent properties of 1a (λem = 476 nm, and λex = 420 nm).
4908
https://doi.org/10.1021/acs.orglett.1c01665
Org. Lett. 2021, 23, 4903−4908