Visible-light-driven copper-catalyzed aerobic oxidative cascade cyclization of N-tosylhydrazones and terminal alkynes: Regioselective synthesis of 3-arylcoumarins

Article abstract of DOI:10.1039/c9cc01801h

We present the first example of sustainable, intuitive, highly regioselective, visible-light-driven copper catalyzed aerobic oxidative cascade cyclization of N-tosylhydrazones with terminal alkynes for the preparation of 3-arylcoumarins at room temperature. This operationally simple methodology has been successfully applied to a wide range of N-tosylhydrazones and alkynes (49 examples), and proceeds well to afford biologically active compounds, such as monoamine oxidase B (MAO-B) inhibitor and horseradish peroxidase (HRP) inhibitor, in satisfactory yields under mild conditions. Furthermore, mechanistic studies suggest that the reaction proceeds via a copper(ii)-superoxo or -peroxo complex mediated oxidative annulation of terminal alkynes, as evidenced by ¹⁸O₂ isotopic-labelling experiments.

Full text of DOI:10.1039/c9cc01801h

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10.1039/C9CC01801H.
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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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DOI: 10.1039/C9CC01801H
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Visible-Light-Driven Copper-Catalyzed Aerobic Oxidative Cascade
Cyclization of N-Tosylhydrazones and Terminal Alkynes:
Regioselective Synthesis of 3-Arylcoumarins
Received 00th January 20xx,
Received 00th January 20xx,
Accepted 00th January 20xx
Ayyakkannu Ragupathi, Arunachalam Sagadevan, Vaibhav Pramod Charpe, Chun-Cheng
Lin, Jih Ru Hwu, and Kuo Chu Hwang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We present the first example of sustainable, intuitive, highly
regioselective, visible-light-driven copper catalyzed aerobic
oxidative cascade cyclization of N-tosylhydrazones with terminal
alkynes for the preparation of 3-arylcoumarins at room
temperature. This operationally simple methodology has been
successfully applied to a wide range of N-tosylhydrazones, alkynes
(49 examples), and proceeds well to afford biologically active
compounds, such as monoamine oxidase B (MAO-B) inhibitor,
horseradish peroxidase (HRP) inhibitor in satisfactory yields under
mild conditions. Furthermore, mechanistic studies suggest that
the reaction proceeds via copper(II)-superoxo or -peroxo complex
mediated oxidative annulation of terminal alkynes, as evidenced
by 18O2 isotopic-labelling experiments.
Scheme 1. Biologically active compounds with 3-arylcoumarin
motif.
common drawbacks include: a) requirement of preparation of pre-
functionalized starting materials with low stability, b) overall multi-
steps process, thus being less eco-friendly, c) harsh
reactionconditions, d) requires an precious metal catalyst, and e) a
stoichiometric amount of strong oxidants/ ligands.
Direct utilization of readily accessible starting materials on the
development of a new and highly efficient synthetic approach for
the construction of heterocyclic molecules has become
a
challenging goal in modern synthetic organic chemistry. Among
heterocycles, coumarins are important and ubiquitous structural
motifs
found
in
natural
products,
pharmaceuticals,
photochemotherapy, photosensitizers, flavours, and organic
luminescent materials.1 In particular, 3-arylcoumarin skeletons are
used as pharmaceutical drugs, such as; anticancer, anti-HIV,
antimalarial, antibacterial, antioxidant, anti-inflammatory, anti-
2
depressant, anti-tumour drugs (Scheme 1) and could be used in a
diverse array of powerful bond-forming reactions for the
construction of complex natural products and macromolecules.3
Due to their great potentials of biological activities,2,3 considerable
powerful approaches have been developed for the synthesis of the
coumarin moiety, including the classical name reactions such as; (a)
Pechmann condensation;4 (b) Perkin reaction;5 (c) Wittig reaction;6
(d) Knoevengal condensation.7 Apart from these classical reactions,
recently transition metal complexes have emerged as promising
catalysts in various methods for the preparation of 3-arylcoumarins
(Scheme 2a).8,9 Despite significant developments has been made,
Scheme 2. Transition-metal-catalyzed cascade cyclization reactions.
In 2014, Li et al. reported an efficient method for regioselective
synthesis of 3-arylcoumarins through rhodium-catalysed oxidative
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coupling of salicylaldehydes and terminal alkynes at high internal alkynes are also well tolerated to generate the
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temperature (Scheme 2b).10 This approach, however, suffers from corresponding 3-aryl coumarins in good yieldDsO(I:31x0-.31y0)3.9/C9CC01801H
limited substrates scope, as well as employing stoichiometric
pyridine-N-oxides as an oxidant, thus leading to generation of Table 1. The scope of N-tosylhydrazones (1).a
undesired waste, and is less eco-friendly. Thus, further
development and discovery of new types of cheap metal- catalyzed
cascade cyclization reactions using molecular oxygen as an oxidant,
especially under low-energy visible-light irradiation, would be of
great importance, which remains unexplored neither by thermal
nor by the photochemically initiated process.
Recently, visible light initiated, copper catalysed reactions have
enabled the invention of a wide variety of non-traditional bond
constructions in modern synthetic organic chemistry,11,12 such as; C-
C cross-couplings, and various C-N, C-S, and C-O cross-coupling
reactions. In this communication, we report the first example of
visible-light-driven oxidative annulation of N-tosylhydrazones with
terminal alkynes for the preparation of regioselective 3-
arylcoumarins through a SET process with molecular O2 as a green
oxidant, simple and inexpensive catalyst (5 mol% CuCl, KOtBu (1.2
eq.) as a catalyst under mild conditions without any external
organic oxidants/ligands at room temperature (Scheme 2d).
Moreover, the use of molecular O2 as an oxidant for oxidative
functionalization of organic molecules has attracted considerable
attention owing to its low-cost, abundant, and environmentally
benign nature.13 In this regards, copper-catalyzed activation of
molecular O2 for the construction of oxygen-containing
heterocycles (i.e. coumarins) via in-situ forming copper(II)-superoxo
or -peroxo complex has been of long-standing interest to synthetic
organic chemistry. Furthermore, due to the stability and versatile
reactivity, N-tosylhydrazones have recently been employed as a
powerful coupling partner with terminal alkynes for the synthesis of
allenes or heterocyclic molecules catalysed by transition-metal-
catalysts (Cu or Pd or Co-complexes) (Scheme 2c).14 Importantly, as
compared to previous work of copper-catalyzed coupling of N-
tosylhydrazones and terminal alkynes (at harsh thermal
condition),14a the current photoredox process is an unprecedented
and powerful method for regioselective synthesis of 3-arylcoumarin
via copper-catalyzed oxidative cascade cyclization (6-endo-dig ring
closure) of N-tosylhydrazones and terminal alkynes with O2 under
a
Standard condition. Isolated yield after purification by column
chromatography on silica gel.
low energy visible-light irradiation (Scheme 2d), which was not
achievable by existing literature thermal processes.
Impressively, hydroxyl salicyl hydrazones can also react well with
hydroxyl aryl alkyne to produce the corresponding desired products
(3z-3z1) in 86-89% yields under very mild conditions without the
need of pre-protection at the hydroxy functional group.14b Products
containing phenol functional group on the coumarin ring are very
useful for a broad range of further synthetic transformations, or to
act as radical scavengers in the field of pharmaceuticals.16 Finally,
we further explore the diversity of substituted 2-
With the optimized reaction condition in hand (Table S1, entry 4
in SI), we next moved on to examine the substrate scope of this
cascade oxidative annulation reaction. As shown in Table 1, a great
variety of electron rich and deficient salicyl N-tosylhydrazones (1b,
1f & 1j) were subjected to react with phenylacetylenes and
derivatives of aryl alkynes (R2 = H, 4-Me, 3-OMe, & 4-F) (2b-2m),
leading to the formation of the corresponding 3-arylcoumarins (3b-
3m) smoothly in good yields of 74-86% yields with good
regioselectivity. Remarkably, the naphthalene based N-
tosylhydrazones (1n) also proceeded well in this cascade oxidative
annulation and produced 3n in 81% yield. To improve this context,
we further evaluated distinct phenylacetylene derivatives (4-nBu, 4-
F, 2-CF3), which furnished the desired 3-arylcoumarins derivatives in
better yields (79~81%, 3o-3q). It is noteworthy that various
substituents on hetero arylalkynes, such as 2- and 3-thienylalkynes,
2-, -3,and 4-ethynyl pyridine and 5-ethynylpyrimidine were also well
tolerated, providing the corresponding 3-arylcoumarin products in
62-87% yield (3r-3w). Note that the hetero atom-substituted
coumarins and naphthalene-fused 3-arylcoumarin derivatives are
useful in the field of pharmaceuticals drugs, material science, and
photo luminescence.15 Moreover, 1,4-diynes and substituted
hydroxyacetophenone-N-tosyl-hydrazone
and
2-
hydroxybenzophenone-N-tosylhydrazone to couple with arylalkynes.
It was found that these coupling reactions proceeded very
successfully to afford the corresponding substituted 3-arylcoumarin
products in moderate yields (27-56%, 3aa-3ac).
To further explore the substrates scope, a variety of terminal
alkynes were examined. As shown in Table 2, the current reaction
is not limited to electron rich and electron deficient alkynes, but it
also works well with other electron-rich and deficent bearing
substituents on the phenyl ring at all ortho, meta, and para
positions, and substituted internal alkynes, leading to the formation
of corresponding functionalized 3-arylcoumarins(77-86%, 4b-4o)
(Table 2). Notably, aliphatic terminal alkynes, such as cyclohexyl,
cyclohexenyl, and liner terminal alkynes (hexyl, heptyl, and 1,9-
2 | J. Name., 2012, 00, 1-3
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dialkyne) were also compatible in the current reaction, and afford indicating that the oxygen atom in the 3-arylcoumarin products
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the corresponding desired products, albeit in low yields (26-42%, mainly originates from molecular O2.
DOI: 10.1039/C9CC01801H
4p-4t).
Table 2. The scope of terminal alkynes (2).a
Scheme 3. Mechanistic control experiments.
Based on the above mechanistic results, a reaction mechanism is
depicted and shown in (Scheme 4). Photoirradiation of in-situ
generated Cu(I)-phenylacetylide (2a') generates a long-lived triplet
excited state of Cu(I)-phenylacetylide 5 (Ƭ= 15.95 μs).12 The excited
state of Cu(I)-phenylacetylide 5 (Eredox= -2.048 VSCE in CH3CN)12a,b
then undergoes a SET process to donate an electron to O2 and
generates the intermediates Cu(II)-phenylacetylide 6 as well as
superoxide radical anion, as evidenced by EPR measurements (see
S.I.).12a,b The bond dissociation energy of the phenoxyl O-H bond is
~90 kcal mol-1,18 which is smaller than the O-H bond formation
energy (105~110 kcal/mol)18 of H2O2. Hydrogen atom abstraction
from the phenoxyl O-H group of 1a by superoxide anion radical is
thus exothermic and thermadynamically allowed, which leads to
the generation of phenoxyl radical 7. In the next stage, the
phenoxyl radical 7 attacks the CuII-phenylacetylide 6 to regenerate
the copper(I) catalyst and furnishes the copper(I)-coordinated
alkyne complex 8. It is known that free CuCl could coordinate to the
disubstituted alkyne moiety through a π-alkyne complex, thereby
enhancing its electrophilicity.19,12c The resulting electron-deficient
CuI-coordinated complex 8 then undergoes base (KOtBu)-promoted
6-endo-dig ring closure, which selectively occurred over 5-endo-dig
ring closure pathway,20 leading to the formation of the complex 9.
Indeed, Cu(I) containing complex 9 readily reacts with molecular O2
to form copper(II) peroxo complex 10.21,12c Isomerization of the
resulting copper(II) peroxo complex 10 to copper(I) species 11
occurs with concurrent formation of a carbon-oxygen bond.22,12c
Finally, complex 11 would generate oxy-radical 12 (via homolytic
a
Standard condition. Isolated yield after purification by column
chromatography on silica gel.
Notably, aliphatic terminal alkynes are unsuccessful coupling
partners in the previous thermal processes, 10,14d on the contrast,
the current photoredox method proved to be amenable with
aliphatic terminal alkynes. Finally, the product of 3a, 4f, and 4k was
confirmed by single-crystal X-ray diffraction.17 It is worth noting that
in all cases, a trace amount of homocoupling 1,3-diyne product was
observed under aerobic conditions.12 Finally, to demonstrate the
applicability of the current protocol, bioactive molecules, such as
MAO-B inhibitor (3d) and HRP-inhibitor (3z1) were prepared in a
gram scale under the standard reaction condition. Compared with
traditional literature thermal routes,3 the current photoredox
method circumvents the need of any protecting reagents for acid
sensitive functional groups (such as OH, COOH, etc.) and high
temperature, providing a greener and more economical route for
the synthesis of hydroxyl
functionality-bearing coumarin
derivatives under very mild conditions in two steps (75-79% total
yields) (See details in SI). In addition, we have also evaluated the
green metrics for the compounds 3d and 3z1 (see details in the SI).
To gain mechanistic insights, a series of control experiments were
carried out (Scheme 3). First, in the absence of phenyl acetylene
and CuCl, pre-synthesized Cu(I)-phenylacetylide( 2a’) was used to
react with salicylhydrazones (1a), which leads to the generation of
the desired 3-arylcoumarins (3a) in 67% yield after 15h blue LED
irradiation (eq 1). This result suggests that in situ generated Cu(I)-
phenylacetylide might be the key light-absorbing photocatalyst
responsible for the cascade oxidative cyclization reaction.12
Furthermore, when the reaction was performed under an N2
atmosphere (see eq. 2), the corresponding 3-arylcoumarin was not
formed, indicating the necessity of molecular O2 for the formation
of coumarins. Moreover, under the standard reaction condition, the
presence of a radical scavenger, TEMPO (10~50 mol%), totally
quenches the formation of 3-arylcoumarin (3a) (see eq 3),
suggesting that a radical intermediate might be involved in the
reaction. Finally, isotopic-labelling experiments using 18O2 (98%)
instead of 16O2 (see eq 4), were performed. The 18O atoms were
found to incorporate into the product (at the carbonyl oxygen
position, 82% enrichment) (see mass spectra in SI), unambiguously
Scheme 4. A proposed reaction mechanism.
cleavage)13,23 and a subsequent radical elimination of N2, TsOH to
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provide the desired product 3a and regenerate the CuCl catalyst.
In summary, we have demonstrated the first example of visible-
light-driven copper-catalyzed oxidative annulation of salicyl
hydrazones with wide range of commercially available terminal
alkynes, including aliphatic terminal alkynes, as starting substrates
without any need of external oxidants (organic oxidants) at room
temperature with complete regioselectivity. The reaction occurs
most probably via a unique base-promoted 6-endo-dig ring closure
process, photoredox initiated C=N double bond cleavage and N2
evolution. Also, we have observed that the desired products are
totally different from those obtained by thermal heating methods.
It is mainly due to the different reaction mechanisms, i.e.,
photoinduced electronic excitation-single electron transfer vs.
thermal heating induced nuclear vibrational excitation-bond
stretching/breaking/re-formation. As an additional benefit, this
efficient method gives the best synthetic route to prepare bioactive
molecules, such as MAO-B inhibitor and HRP-inhibitor at very mild
conditions without the need of hydroxy group pre-protection. The
current method can be readily scaled up to a preparative gram (1–2
g) scale. From a synthetic point of view, the current photoredox
method involving utilization of O2 as oxidant, inexpensive copper as
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a
catalyst and low energy visible light for photo-excitation,
represents an extremely simple and an eco-friendly process for the
regioseletive synthesis of 3-arylcoumarins under very mild
conditions.
This work was supported by the Ministry of Science and
Technology, Taiwan.
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Graphical Abstract
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DOI: 10.1039/C9CC01801H
Visible-Light-Driven Copper-Catalyzed Aerobic Oxidative Cascade Cyclization of N-
Tosylhydrazones and Terminal Alkynes: Regioselective Synthesis of 3-Arylcoumarins
Ayyakkannu Ragupathi, Arunachalam Sagadevan, Vaibhav Pramod Charpe, Chun-Cheng Lin, Jih Ru Hwu, and Kuo
Chu Hwang*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan.
E-mail:
kchwang@mx.nthu.edu.tw; Fax: (+886) 35711082.
An intuitive visible-light-driven copper-catalyzed process can accomplish regioselective functionalized 3-
arylcoumarins via oxidative annulation of simple N-tosylhydrazones with terminal alkynes under O2 (1 atm.) at
room temperature. This transformation represents a green and atom economical approach to preparation of
substituted 3-arylcoumarins with single regio-isomer from readily available feedstocks.
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