Aryl Pyrazoles from Photocatalytic Cycloadditions of Arenediazonium

Article abstract of DOI:10.1021/acs.orglett.0c02514

A photocatalytic synthesis of 1,5-diaryl pyrazoles from arenediazoniums and arylcyclopropanols is reported. The reaction proceeded under mild conditions (rt, 20 min) with catalytic [Ru(bpy)3]2+ under blue-light irradiation and exhibited compatibility with several functional groups (e.g., I, SF5, SO2NH2, N3, CN) and perfect levels of regiocontrol. Mechanistic studies (luminescence spectroscopy, CV, DFT, radical trapping, quantum yield determination) documented an initial oxidative quenching of the excited photocatalyst and the operation of a radical-chain mechanism.

Full text of DOI:10.1021/acs.orglett.0c02514

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Letter
Aryl Pyrazoles from Photocatalytic Cycloadditions of
Arenediazonium
Luana Cardinale, Michael Neumeier, Michal Majek,* and Axel Jacobi von Wangelin*
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ABSTRACT: A photocatalytic synthesis of 1,5-diaryl pyrazoles from
arenediazoniums and arylcyclopropanols is reported. The reaction
proceeded under mild conditions (rt, 20 min) with catalytic
[Ru(bpy)3]2+ under blue-light irradiation and exhibited compatibility
with several functional groups (e.g., I, SF5, SO2NH2, N3, CN) and
perfect levels of regiocontrol. Mechanistic studies (luminescence
spectroscopy, CV, DFT, radical trapping, quantum yield determi-
nation) documented an initial oxidative quenching of the excited photocatalyst and the operation of a radical-chain mechanism.
Scheme 1. Dark and Photocatalytic Reactions of
Arenediazonium Salts
renediazonium salts constitute synthetically versatile
Abuilding blocks for aromatic substitutions by virtue of
their easy availability as stable crystalline solids, the high
thermodynamic driving force to form reactive aryl radical, aryl
cation, or arylmetal species by loss of N2 (Scheme 1, middle),
and the wide variety of onward reactions with many reagents.1
Numerous protocols involving thermal, metal-catalyzed,
electrochemical, and photoredox conditions were reported
that enable facile formations of C−C and C−Het bonds (X =
Hal, S, O, N, P, Si, B, and many more, see Scheme 1, top).2 On
the other hand, the arsenal of addition reaction mechanisms
that conserve the N2 function into the product structure is
much less diverse. Examples include azo-couplings with
electron-rich benzenes,3 cycloadditions,4 radical trappings,5
and Japp−Klingemann-type reactions.6 These protocols
proceed through thermal, oxidative, or metal-catalyzed reaction
mechanisms (Scheme 1, b). Photocatalytic reaction pathways
of arenediazonium salts that operate with retention of N2 are
very rare due to the facile reductive mesolysis of
arenediazonium salts at very low redox potentials of ∼0 V
(vs SCE).7 There are only three literature reports of
photocatalytic arenediazonium reactions which all include the
trapping of alkyl radicals to give acyclic azo-compounds.8
Minimal mechanistic insight has been provided, especially with
regard to the inertness of arenediazonium to 1e-reduction in
the presence of sufficiently strong photoreductants. This work
reports an unprecedented photocatalytic cycloaddition of
arenediazonium with cyclopropanol to form 1,5-diaryl
pyrazoles with perfect regiocontrol. A detailed analysis of the
underlying mechanism by preparative, spectroscopic, and
theoretical methods is given. This method provides a
straightforward access to N-aryl pyrazoles,9 which constitute
key motifs of pharmaceutical blockbusters such as celecoxib,
lonazolac, and rimonabant (Scheme 1, c), agrochemicals, and
ligands of metal-catalyzed cross-coupling reactions.10
Received: July 31, 2020
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We envisioned utilizing 1-aryl-1-cyclopropanols as C3-
building blocks that can easily be prepared by organometallic
addition to benzoyl derivatives in a Simmons−Smith11 or
Kulinkovich reaction.12 1-Aryl-1-cyclopropanols could engage
in photocatalytic ring-opening to provide a benzoylethyl motif
exhibiting 1,3-dipolarophilic reactivity.13 In the presence of
arenediazonium, radical trapping would result in the formation
of β-aryl propiophenones via N2-elimination14 or diaryl
pyrazoles via N2-retentive formal cycloaddition (Scheme 2).
dark proton-coupled electron transfer mechanism in the
presence of stoichiometric Cu(II) salt was postulated.9i
The substrate scope was explored upon variation of both
starting materials. Arenediazonium salts bearing electron-
withdrawing and electron-donating substituents in the ortho-,
meta-, and para-positions were equally reactive (Scheme 3).
a
Scheme 3. Substrate Scope of Arenediazonium Salts
Scheme 2. (Top) Postulated Reactions of Arylcyclopropanol
with Arenediazonium to Give β-Aryl Phenones (via N2-
Elimination) or 1,5-Diaryl Pyrazoles (via N2-Conservation).
(Bottom) Key Discoveries of Photocatalytic Aryl Pyrazole
Synthesis
a
An = 4-anisyl; isolated yields are given.
Generally, no significant electronic effect on the reactivity of
the diazonium salts was observed (3aa−3ao). However,
naphthalenediazonium tetrafluoroborate and 4-(methylthio)-
benzenediazonium tetrafluoroborate gave complex product
mixtures and only low yields of the corresponding pyrazoles
(<25%), possibly by unwanted radical attack on the
naphthalene and thioether moieties.19 Variations of the
cyclopropanol derivative revealed a significant influence of
their individual electronic properties (Scheme 4): electron-
donating substituents enabled high yields of the diaryl
pyrazoles (3aa−3ca, 3ha−3ja); electron-withdrawing substitu-
ents showed poor conversions under the reaction conditions
Our initial investigations of the model reaction between 1-
anisyl-1-cyclopropanol (1a) and 4-methoxybenzenediazonium
tetrafluoroborate (2a) with the organic photocatalyst eosin Y
indeed afforded the pyrazole 3aa in 42% yield as the sole
product (Table S1). The product yield could be increased to
87% after 20 min reaction time when using [Ru(bpy)3]Cl2·
6H2O as photocatalyst and the appropriate irradiation
wavelength. Further decrease of the catalyst loading (<5 mol
%) or reaction time gave inferior yields. The observed
reactivity is noteworthy as the photocatalytic conditions with
virtually all common molecular photocatalysts (including eosin
Y, Ru(bpy)3Cl2·6H2O, Ir(ppy)3) provide sufficient reduction
ability to mesolyze arenediazonium salts irreversibly via an
SET.15 Control experiments in the absence of photocatalyst
and light, respectively, did not afford any products.17,18 The
optimal conditions involved reaction of the arene-diazonium
salt 1a (1.5 equiv) with the arylcyclopropanol 2a in acetonitrile
at room temperature for 20 min under blue light irradiation
(455 nm) in the presence of catalytic Ru(bpy)3Cl2·6H2O. The
resultant 1,5-diaryl pyrazole is a common structural motif of
fine chemicals and pharmaceuticals that is conventionally
assembled from aryl 1,3-dicarbonyl derivatives and aryl
hydrazines, with the latter substrates being prepared by Cu-
catalyzed aminations of aryl halides.16 A related Cu-mediated
oxidative cyclization to N-aryl pyrazoles was reported, and a
a
Scheme 4. Substrate Scope of Cyclopropanols
a
An = 4-anisyl; isolated yields are given; 24 h.
B
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Figure 1. (a) Luminescence quenching of [Ru(bpy)3]Cl2 with the substrates 1a and 2a. c(q) = quencher concentration (mol/L). (b) Cyclic
voltammetry spectra of 1a, 2e, and an equimolar mixture. (c) Reduction potentials Ered of substrates and photocatalyst (vs SCE). (d) Postulated
trapping of intermediate 1•+ and the feasibility of radical chain propagation. (e) Proposed mechanism based on preparative, spectroscopic, and
theoretical studies.
(3da−3ga). Increased steric hindrance on the cyclopropane
did not lead to decreased yields (3la). Alkyl- and benzyl-
substituted cyclopropanols gave low yields (3ka, 3ma, and
3na). The higher homologue 1-phenyl-1-cyclobutanol (1q)
gave no ring-opening or heterocycle formation.
In an effort to elucidate the mechanism of this photocatalytic
pyrazole synthesis, we conducted a series of preparative,
spectroscopic, and theoretical studies. The preservation of the
N2 moiety within the product structure is a very rare feature of
reactions with arenediazonium salts.5a,8,9d Under photo-
catalytic conditions, this is even less likely due to the very
facile 1e-reduction of arenediazonium salts (at ∼0 V vs SCE)
followed by irreversible mesolysis and N2 evolution.5
Consequently, we probed whether the photocatalytic mecha-
nism involved any reduction event of the arenediazonium at all
or rather oxidation of the cyclopropanol by the photocatalyst.
A Stern−Volmer study, however, documented that efficient
luminescence quenching of excited-state [Ru(bpy)3]Cl2
([Ru2+]*) was indeed operative with the diazonium salt 2a
(see the Supporting Information for details). Consistently, no
quenching was observed with the electron-poor and electron-
rich cyclopropanols 1g and 1a, respectively (Figure 1a).
The nonlinearity of the plot for 2a is a direct consequence of
the kinetic salt effect20 of increased ionic strength of the
solution by addition of the diazonium salt. Quencher and
catalyst are charged species, so the ionic strength affects the
rate of their reaction with each other. According to the
Debye−Huckel theory, the Stern−Volmer quenching con-
̈
stants K3, extrapolated to zero ionic strength, were calculated.
KSV0 increased with lower electronic density of the
C
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arenediazonium: KSV0(2a) = 88 dm3/L; KSV0(2e) = 490 dm3/
L; KSV0(2i) = 1500 dm3/L. These data are indicative of an
oxidative quenching of the excited photocatalyst [Ru2+]* by
the diazonium salt. This is further supported by the observed
gas evolution during the reaction. The reductive mesolysis of
the arenediazonium salt is also in full accord with the detection
of an aryl-TEMPO adduct and the inhibition of product
formation by addition of 2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO, Figure S2). Further insight into the operating redox
events was provided by the analysis of the redox potentials
(Figure 1c). Cyclic voltammetry (CV) confirmed that facile
reduction of arenediazonium salts is thermodynamically
feasible with the excited-state photocatalyst: Ered(2a) =
−0.18 V; Ered(2e) = 0.00 V; Ered(2i) = +0.03 V;
Ered([Ru2+]*)= −0.81 V (vs SCE).21 The difference in redox
potentials of this series explains the observed trend in the
quenching constants KSV0 above where easily reduced
compounds quench [Ru2+]* faster. On the other hand,
[Ru2+]* (Ered = +0.77 V) is not a sufficiently strong oxidant
for the 1e-oxidation of any of the cyclopropanols (Ered > + 1
V). These data support the notion of an initiating oxidative
quenching of [Ru2+]*. The resultant ground-state [Ru3+] is
sufficiently oxidizing (Ered = +1.29 V) to convert electron-rich
cyclopropanols (Ered(1a) = +1.08 V), while 1e-oxidations of
electron-poor cyclopropanols are thermodynamically unfa-
vored and only feasible when coupled with efficient follow-
up reactions (Ered(1g) = +1.40 V; Ered(1k) = +1.54 V; i.e.,
<250 mV uphill).22 Unstrained cycloalkanols have reduction
potentials (Ered (1q) = +1.72 V) that are prohibitive for
oxidations with [Ru3+] (Figure 1c). A proton-coupled electron
transfer mechanism in combination with a more strongly
oxidizing photosensitizers such as acridinium salts could
overcome this limitation.23 The operation of an H atom-
abstraction mechanism9i was excluded based on the perfect
correlation of cycloalkanol reactivities and oxidation potentials.
The fate of the oxidized cyclopropanols was another puzzle
piece of the operating reaction mechanism. One-electron
oxidations of cyclopropanols have been known to result in
labile radical cations that undergo rapid ring-opening to β-keto
radicals.14a The feasibility of trapping of the intermediate
benzoylethyl radicals 1•+ with arenediazonium 2 was probed
by a CV experiment (Figure 1b): The cyclopropanol 1a (blue
line) displayed an irreversible oxidation wave (Ered = +1.08 V),
the diazonium salt 2f (red line) an irreversible reduction wave
(Ered = +0.00 V). However, subjection of an equimolar mixture
of both substrates to such CV electrolysis (black line;
increasing potentials from 0.5 V), an unchanged oxidation
peak of 1a was observed while the reduction peak of 2e
disappeared. This is indicating that the oxidized alcohol 1a•+
underwent chemical reaction with the diazonium salt prior to
reduction of the latter. The resultant adduct of 1•+ and 2 (i.e.,
4•+) engages in 1e-reduction to a neutral compound that
cyclizes to a pyrazole. Further insight was derived from the
quantum yield of Φ = 4.2 for the formation of 3aa. This value
indicates the presence of an efficient radical chain propagation,
which most likely is the oxidation of cyclopropanol 1 with the
radical adduct 4•+ (Figure 1d). To probe its feasibility, we
utilized the model compound 2-ethyl-1-phenyldiazene (5),
which should exhibit similar redox properties as 4 but undergo
no onward cyclization reaction. CV spectra showed irreversible
oxidation of 5 at +1.55 V. This value is likely to include
overpotential, so we also obtained a DFT-derived theoretical
reduction potential of 5 (+1.40 V, see Supporting Informa-
tion). In comparison with the reduction potentials of the
cyclopropanols (1.08−1.54 V), these support the operation of
radical chain propagation by reactions of the cyclopropanols 1
with the radical adduct intermediates 4•+ (Figure 1d). Based
on the collected mechanistic data, we propose the reaction
mechanism shown in Figure 1e. The reaction is initiated by
oxidative quenching of [Ru2+]* with the arenediazonium salt 2.
The resultant [Ru3+] oxidizes the strained alcohol 1 to give 1•+
which undergoes rapid ring-opening and radical trapping with
the arenediazonium salt. The radical cation adduct 4•+ can
engage in a radical chain process by oxidizing another molecule
of 1 or quench the excited catalyst to close the photocatalytic
cycle. As the radical chain process is dominant (Φ = 4.2),
cocatalytic amounts of the arenediazonium 2 are required to
produce the key oxidant [Ru(bpy)33+] salt must be used to
activate the catalyst, which is also evident from the optimal
reaction conditions involving a slight excess of 2. The adduct 4
undergoes cyclization and dehydration to give the pyrazole 3.
In conclusion, this protocol enables a rare photocatalytic
reaction of arenediazonium that proceeds with conservation of
the diazo function. In the presence of arylcyclopropanols, N-
arylpyrazoles are obtained within 20 min under blue light
irradiation in good yields. The reaction displayed high
regiocontrol (only 1,5-diaryl pyrazoles formed) and high
functional group tolerance (F, Cl, N3, CO2Me, CN, CF3, SF5,
thiophene, alkyne). Combined synthetic, spectroscopic, and
theoretical studies supported the notion of a radical chain
mechanism, which involves photocatalytic initiation by
oxidative photocatalyst quenching with the arenediazonium,
oxidation of the arylcyclopropanol with ground-state [Ru3+]*,
and radical chain propagation between the arylcyclopropanol
and the radical cationic adduct of both starting materials.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02514.
Experimental procedures, analytical data, and spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Michal Majek − Department of Organic Chemistry, Comenius
University, 84215 Bratislava, Slovakia; Email: michal.majek@
uniba.sk
Axel Jacobi von Wangelin − Department of Chemistry,
University of Hamburg, 20146 Hamburg, Germany;
orcid.org/0000-0001-7462-0745; Email: axel.jacobi@uni-
hamburg.de
Authors
Luana Cardinale − Department of Chemistry, University of
Hamburg, 20146 Hamburg, Germany
Michael Neumeier − Department of Chemistry, University of
Hamburg, 20146 Hamburg, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02514
Notes
The authors declare no competing financial interest.
D
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ACKNOWLEDGMENTS
■
We thank Maximilian T. P. Ruffer (UHH) for technical
assistance.
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