Exploiting Synergistic Catalysis for an Ambient Temperature Photocycloaddition to Pyrazoles

Article abstract of DOI:10.1002/chem.201904210

Sydnone-based cycloaddition reactions are a versatile platform for pyrazole synthesis, however they operate under harsh conditions (high temperature and long reaction times). Herein we report a strategy that addresses this limitation utilizing the synergistic combination of organocatalysis and visible-light photocatalysis. This new approach proceeds under ambient conditions and with excellent levels of regiocontrol. Mechanistic studies suggest that photoactivation of sydnones, rather than enamines, is key to the successful implementation of this process.

Full text of DOI:10.1002/chem.201904210

A Journal of
Accepted Article
Title: Exploiting Synergistic Catalysis for an Ambient Temperature
Photocycloaddition to Pyrazoles
Authors: Joseph P.A. Harrity, Christopher P. Lakeland, and David W.
Watson
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To be cited as: Chem. Eur. J. 10.1002/chem.201904210
Link to VoR: http://dx.doi.org/10.1002/chem.201904210
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Exploiting Synergistic Catalysis for an Ambient Temperature
Photocycloaddition to Pyrazoles**
Christopher P. Lakeland,[a] David W. Watson,[b] and Joseph P. A. Harrity*[a]
Abstract: Sydnone based cycloaddition reactions are a versatile
platform for pyrazole synthesis, however they operate under harsh
conditions (high temperature and long reaction times). Herein we
report a strategy that addresses this limitation utilizing the synergistic
combination of organocatalysis and visible light photocatalysis. This
new approach proceeds under ambient conditions and with excellent
levels of regiocontrol. Mechanistic studies suggest that
photoactivation of sydnones, rather than enamines, is key to the
successful implementation of this process.
Scheme 1. Hypothesis for a photocatalytically promoted sydnone cycloaddition
reaction.
Pyrazole containing molecules are prevalent within the medicinal
and agrochemical industries,1-3 and have been traditionally
(Scheme 1). Herein we report that sydnones participate in
accessed by cycloaddition or condensation strategies.4-5 Work
catalytic, visible-light promoted cycloaddition reactions with
within our laboratory has sought to establish sydnone
enamines to produce pyrazole products with excellent levels of
cycloadditions6 with alkynes as a versatile platform for the
regiocontrol.
7-14
synthesis of pyrazole containing molecules.
While this
We began our investigation of a potential photocatalytic sydnone-
enamine cycloaddition (PSEC) reaction using N-phenylsydnone
(1a) and n-butyl substituted enamine (2a) in acetonitrile at room
temperature with Ru(bpy)3(PF6)2 as the photocatalyst. Gratifyingly
the reaction afforded 1,4-disubstituted pyrazole 3aa in 33% yield
as a single regioisomer. However, despite the low yield, analysis
of the crude 1H NMR spectrum showed complete consumption of
sydnone 1a. Speculating that sydnone decomposition was due to
competing reduction by the photo-activated Ru-catalyst, we
decided to add a competing ‘electron sink’. Indeed, while the
addition of methyl viologen dichloride (MVCl2) resulted in only a
slight improvement to the yield, it was accompanied by
significantly less sydnone decomposition (43% yield at ~50%
conversion of sydnone). Finally, a solvent screen identified NMP
as the optimal co-solvent, and ethyl viologen diiodide (EVI2) as a
less expensive electron sink, allowing the product pyrazole to be
generated in high yield (Scheme 2, see SI for full optimization).
The unique reactivity offered by the combination of visible light
photocatalysis and enamine dienophiles is highlighted in
equations (1) and (2). Classical thermally promoted reactions of
transformation demonstrates a broad scope and is tolerant of a
range of functionalities, there remain a number of associated
challenges relating to reaction regiocontrol, as well as the
requirement for elevated temperatures and prolonged reaction
times. Recently, these problems have been addressed through
the use of substrate directed cycloadditions,14 strained
alkynes15,16 and copper promoter systems.11,17,18 However, these
methods still usually require specifically tailored substrates to
proceed efficiently.
In an effort to conceive of new and alternative methods for the
promotion of sydnone cycloaddition reactions, we became
interested in the use of dienophiles that could be activated
towards cycloaddition using visible light photocatalysis. Indeed,
previous reports from Yoon and co-workers highlight the Diels-
Alder reactions of electron rich dienes and dienophiles via the
intermediacy of
a
radical cation.19,20 An additional key
consideration in the case of sydnones however, is that the initial
cycloadduct undergoes rapid loss of carbon dioxide to produce a
cyclic azomethine imine that can undergo several decomposition
pathways. Enamines were thus identified as ideal reaction
partners as: (1) they are known to undergo one electron oxidation
in the presence of Ru-complexes and visible light;21,22 (2) the
amine unit could function as a leaving group that would allow the
dipolar intermediate to convert to a stable pyrazole product
[a]
C. P. Lakeland, Prof. J. P. A. Harrity
Department of Chemistry, University of Sheffield
Sheffield, S3 7HF (U.K.)
E-mail: j.harrity@sheffield.ac.uk
[b]
Dr. D. W. Watson
Chemistry, Oncology R&D
AstraZeneca, Cambridge (U.K.)
[**]
We are grateful to the EPSRC and AstraZeneca for financial support.
We also thank Dr. Tim. Craggs and Prof. Jim Thomas for help with
Stern-Volmer and cyclic voltammetry experiments.
Supporting information for this article is given via a link at the end of
the document.
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Scheme 2. PSEC reaction optimization and comparison to other methods.
Scheme 4. Intramolecular PSEC reaction. [a] Reaction conditions: sydnone (0.5
mmol), Me2NH (0.1 mmol, 20 mol%), Ru(bpy)3(PF6)2 (25 μmol, 5 mol%), EVI2
(0.5 mmol), NMP (5 mL, 0.1 M), 48 h at room temperature under blue LED
irradiation. [b] Reaction run at 0.025 M.
Scheme 3. Amine catalyzed PSEC reaction.
alkynes and sydnones requires long reaction times, high
temperatures and provides the regioisomeric pyrazole 3aa’ as the
major product. Moreover, enamines are not converted to
pyrazoles under thermal conditions, even after heating over
extended periods.
high yield. The use of phenylacetaldehyde as a substrate allowed
access to 1,4-diphenylpyrazole in moderate yield. Protected
amines (3aj) and alcohols (3ai) were also tolerated and carbonyl
derivatives including ester (3ag) and amide (3ah) had no adverse
impact on the reaction.
Limitations to the method were also uncovered; while meta-
substituted N-aryl sydnones were found to react smoothly (3hb),
ortho-substituted analogues failed to react under the optimized
conditions. Moreover, N-alkyl sydnones and 4-substituted
sydnones were also found to be inert to intermolecular
cycloaddition under PSEC conditions. However, we were able to
apply the PSEC reaction to the synthesis of bicyclic pyrazole
scaffolds by employing sydnone substrates bearing a tethered
aldehyde moiety (Scheme 4). As such, pyrazoles 5a and 5b were
synthesized in 78% and 52% yield, respectively.
During our optimization studies, we noted that the pyrazole was
generated alongside an aliphatic by-product that we assigned to
the product of aldol condensation of enamine 2a. Indeed, this by-
product became significant when we undertook our PSEC
reactions on larger scale, leading to lower isolated yields of
pyrazole of around 50-60%. Working under the assumption that
decreasing the concentration of enamine could limit this
unproductive side reaction, we decided to perform the PSEC
reaction on in situ generated enamine using sub-stoichiometric
quantities of piperidine as an organocatalyst. To our delight, we
were able to react sydnone 1a directly with hexanal in the
presence of 20 mol % piperidine to generate the desired sydnone
in 86% yield (Scheme 3).
Having established successful conditions for an organocatalytic
PSEC reaction, we next turned our attention to the reaction scope.
Electronically rich and neutral N-aryl sydnones reacted smoothly
to afford pyrazoles 3ab/3bb in high yield and with complete
regioselectivity. Furthermore, sydnones bearing electron
withdrawing groups such as nitrile (3cb) and halides (3db-3gb)
are tolerated, opening up the possibility for further
functionalization of the pyrazole products. In addition to butyl and
isopropyl moieties, various other alkyl groups including methyl
We next investigated the mechanism of the PSEC reaction using
various methods. Firstly, control and on/off experiments
demonstrated the light promoted nature of the PSEC reaction
(see supporting information).
The existence of radical
intermediates was then probed using several radical traps
(Scheme 5). Interestingly, the yield of the PSEC reaction
remained essentially unchanged in all cases and none of the
expected radical combination adducts were observed.
(3ad), cyclohexyl (3ac-3ec) and benzyl (3ae) could be installed in
Table 1. Scope of the organocatalytic PSEC reaction.[a]
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[a] Reaction conditions: sydnone (0.5 mmol), aldehyde (1.5 mmol), Me2NH (0.1 mmol, 20 mol%), Ru(bpy)3(PF6)2 (25 μmol, 5 mol%), EVI2 (0.5 mmol), NMP (5 mL,
0.1 M), 48 h at room temperature under blue LED irradiation. [b] Piperidine (0.1 mmol, 20 mol%).
photocatalyst quenching species under the PSEC reaction
conditions.25
6
5
4
A
3
B
C
2
1
D
0
0
10
20
[quencher]/ mM
Figure 1. Luminescence quenching of Ru(bpy)2(PF6)2.
Scheme 5. Investigations into radical intermediate formation. [a] Radical trap
experiments: 1a (0.5 mmol), 4b (1.5 mmol), Me2NH (0.1 mmol), Ru(bpy)3(PF6)2
(25 µmol), EVI2 (0.5 mmol), additive (1.5 mmol) NMP (5 mL) under blue LED
irradiation for 48 h. [b] Radical clock experiments: 1a (0.5 mmol), aldehyde (1.5
mmol), Me2NH (0.1 mmol), Ru(bpy)3(PF6)2 (25 µmol), EVI2 (0.5 mmol), NMP (5
mL) under blue LED irradiation for 48 h.
In addition, cyclic voltammetry was used to determine the mode
of sydnone based luminescence quenching. Voltammetric
measurements of N-phenylsydnone discovered an irreversible
oxidation peak (Ep/2 = + 1.48 vs Fc/Fc+) and irreversible reduction
peak (Ep/2 = - 1.87 vs Fc/Fc+), indicating that an electron transfer
Additionally, radical clock experiments using cyclopropyl
substituted aldehyde 4k and tethered alkene containing aldehyde
4l afforded the corresponding pyrazoles 3ak and 3al in good yield
without any evidence of rearrangement. Overall these results
suggest that formation of any radical species on the enamine is
unlikely.23
2+
event between N-phenylsydnone and Ru(bpy)3
would be
significantly endergonic (see supporting information). Therefore,
2+
it seems likely that the fluorescence quenching of Ru(bpy)3 by
N-phenylsydnone operates via a photosensitisation mechanism.26
Finally, we sought to determine the fate of the photoexcited
sydnone species generated during the course of the reaction.
Previous reports on UV promoted sydnone cycloadditions
indicate that product formation occurs via the reaction of an in-situ
Stern-Volmer luminescence quenching was then employed to
determine the catalyst quenching species within the PSEC
reaction. As expected, enamine A exhibited strong quenching of
the photoexcited catalyst (KSV = 9.08 x 101 M-1) while the
corresponding aldehyde B provided no observable decrease in
luminescence. Surprisingly, N-phenylsydnone C also gave a
prominent quenching of the photocatalyst (KSV = 2.01 x 102 M-1)
while N-benzylsydnone D (unreactive under PSEC conditions)
gave, by comparison, negligible quenching (Figure 1). In an
attempt to understand the role of sydnone based luminescence
quenching we performed photocatalytic cycloaddition reactions
with other dipolarophiles; specifically, those which cannot quench
the excited state photocatalyst. The reaction of N-phenylsydnone
and 1-hexyne24 under photocatalytic conditions failed to afford
any of the desired pyrazole 3aa, but 2,3-dihydrofuran (Ered ~ +1.5
V vs SCE)22 reacted with N-phenylsydnone to afford pyrazole
3am in 38% yield (Scheme 6). This result demonstrates that
photocatalytic activation of the sydnone partner alone is sufficient
for a successful cycloaddition reaction. Taken together with the
improved yield under organocatalytic conditions and superior rate
of quenching for N-phenylsydnone over enamine A, these results
indicate that the sydnone substrate is likely the major
formed nitrilimine dipole following
a
decarboxylative
rearrangement of the sydnone.27 In the case of C4-unsubstituted
sydnone this would lead to the sydnone hydrogen atom ending up
on either the C3 or C5 position of the pyrazole product, depending
on whether the photoexcited sydnone undergoes decarboxylative
rearrangement or a direct cycloaddition reaction, respectively
(Scheme 7[a]). In the event, deuterated sydnone 3k underwent a
successful PSEC reaction to produce pyrazole 3kb in 87% yield
with no evidence of a decarboxylative rearrangement (Scheme
7[b]).
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energy transfer between the excited state photocatalyst and
sydnone substrate is crucial for the observed reactivity.
Scheme 6. Photocatalytic cycloaddition with other dipolarophiles. Reaction
conditions: 1a (0.5 mmol), dipolarophile (1.5 mmol), Ru(bpy)3(PF6)2 (25 µmol),
EVI2 (0.5 mmol), NMP (5 mL, 0.1 M) at room temperature under blue LED
irradiation.
Scheme 8. Proposed mechanism of the PSEC reaction.
Experimental Section
Typical
photocatalytic cycloaddition
procedure as
exemplified by the formation of 3aa: A flame-dried screw cap
vial was charged with N-phenylsydnone (81 mg, 0.5 mmol),
Ru(bpy)3(PF6)2 (21 mg, 25 µM) and EVI2 (230 mg, 0.5 mmol)
under nitrogen. Anhydrous, degassed NMP (5.0 mL) was then
added via syringe followed by hexenal (150 mg, 1.5 mmol) and
dimethylamine (0.05 mL, 2.0 M in THF). The vial was then
subjected to three vacuum/nitrogen cycles, sealed and irradiated
using a kessil A160WE tuna blue aquarium light for 48 hours. The
reaction was then diluted with water (40 mL) and extracted with
diethyl ether (4 x 25 mL). The combined organic layers were then
washed with brine (25 mL), dried over anhydrous magnesium
sulfate and concentrated under vacuum. Purification by flash
silica column chromatography (gradient from 0-5% Et2O in 40-60
Scheme 7. Investigating the fate of photoexcited sydnone.
Based on the combination of these results we propose the
mechanism shown in Scheme 8. The cycle begins with an energy
transfer from the excited state photocatalyst to sydnone I.28
Excited sydnone II can then undergo a [4+2] cycloaddition
reaction with enamine III to generate the bridged intermediate IV.
Rapid loss of CO2 from IV leads to the dipolar intermediate V
which can then undergo an elimination event to deliver the
pyrazole product VI and regenerate the amine organocatalyst.
1
petroleum ether) afforded 3aa as a yellow oil (86 mg, 86%). H
NMR (400 MHz, CDCl3) δ 7.70 (d, J = 0.5 Hz, 1H), 7.69 – 7.64 (m,
2H), 7.55 (s, 1H), 7.46 – 7.39 (m, 2H), 7.28 – 7.21 (m, 1H), 2.53
(t, J = 7.5 Hz, 2H), 1.65 – 1.56 (m, 2H), 1.45 – 1.35 (m, 2H), 0.95
(t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 141.3, 140.6,
129.6, 126.2, 125.0, 124.3, 119.0, 33.2, 24.2, 22.6, 14.2; FTIR
νmax 2927, 2855, 1599, 1502, 1464, 1395, 1041, 1015, 952, 753
cm-1.
In conclusion, a visible light promoted synthesis of pyrazoles has
been developed. The reaction takes advantage of a synergistic
combination of photo- and organocatalysis to promote
a
cycloaddition between sydnones and enamines under mild
conditions and with excellent regioselectivity. This process
represents the first photocatalytic cycloaddition reaction involving
sydnones. Preliminary mechanistic investigations indicate that an
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Keywords: enamines · pyrazoles · sydnones ·
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quenching step. Furthermore, if photoredox mediated oxidation of the
enamine is responsible for formation of the aldol dimerization product,
then decreasing enamine concentration under organocatalytic conditions
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Christopher P. Lakeland, David W.
Watson, Joseph P. A. Harrity*
Page No. – Page No.
Exploiting Synergistic Catalysis for
an Ambient Temperature
Photocycloaddition of Sydnones
A photo finish! The synergistic combination of organocatalysis and visible light
photocatalysis offers a mild route to pyrazoles that proceeds under ambient
conditions and with excellent levels of regiocontrol.
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