Metal-free C(3)-H arylation of coumarins promoted by catalytic amounts of 5,10,15,20-tetrakis(4-diethylaminophenyl)porphyrin

Article abstract of DOI:10.1039/c5cc02349a

The metal-free C-H arylation of coumarins was achieved in the presence of catalytic amounts of 5,10,15,20-tetrakis(4-diethylaminophenyl)porphyrin. This mild and environmentally friendly Meerwein arylation provided facile access to a broad variety of 3-arylcoumarins in synthetically useful yields.

Full text of DOI:10.1039/c5cc02349a

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Metal-free C(3)-H arylation of coumarins promoted by
catalytic amounts of 5,10,15,20-tetrakis(4-
diethylaminophenyl)porphyrin
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Masahiro Kojima,a Kounosuke Oisaki*a and Motomu Kanai*a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
The metal-free C-H arylation of coumarins was achieved in the
presence of catalytic amounts of 5,10,15,20-tetrakis(4-
diethylaminophenyl)porphyrin.
This
mild
and
environmentally friendly Meerwein arylation provided facile
access to a broad variety of 3-arylcoumarins in synthetically
useful yields.
Coumarins represent a highly desirable structural motif in
medicinal chemistry, chemical biology, and materials chemistry.1-
3 For example, 3-arylcoumarins have recently been reported to act
as monoamine oxidase B (MAO-B) inhibitors,1 which has
important implications for the design of new drugs against
Parkinson’s and Alzheimer’s disease. Coumarin derivatives also
play a crucial role in chemical biology, as their fluorescent
properties under physiological conditions can be controlled.2
Coumarin-based dyes on the other hand are employed in artificial
light-harvesting materials and act as dopants in organic light-
emitting diodes.3 Therefore, a new synthetic method allowing for
effective diversification of the coumarin motif would potentially
contribute to various fields of chemical science. The direct
catalytic C-H bond functionalization of coumarins presents a facile,
mild, atom efficient, and environmentally friendly option to extend
existing coumarin libraries. And indeed, palladium-catalyzed
C(3)-H and C(4)-H arylations have been reported to afford a
variety of 3- and 4-arylcoumarins, respectively.4 However, this
synthetic approach is severely constrained by high temperatures,
the need of stoichiometric amounts of metal oxidants, and its
limited functional group tolerance. Another classical method for
the direct C(3)-H arylation of coumarins is the Meerwein
arylation,5 but especially the copper-mediated Meerwein arylation
of coumarins suffers from low to moderate yields.6 Herein, we
would like to report a porphyrin-mediated Meerwein C(3)-H
arylation of coumarins in the absence of any metals.
In 2012, König disclosed an Eosin Y-mediated Meerwein
arylation under exposure to photoirradiation (visible light),7a and
the observed mild reaction conditions, as well as the absence of
potentially environmentally harmful metal catalysts, renders this
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metal-free reaction protocols particularly attractive. König’s yield (entry 10; Table 1). The reaction did not proceed in the absence
seminal work was soon followed by several reports on metal-free of 4e (entry 11; Table 1), and previously-reported promoters provided
Meerwein arylations of (hetero)arenes,7a alkenes,7f alkynes,7b,7c 3a in lower yield (0-15%, entries 12-15; Table 1). These observations
and isonitriles.7h On the other hand, several catalytic and/or suggest that 4e is the most effective organic promoter for the
stoichiometric transition metal-free promoters, such as organic Meerwein-type C-H arylation of coumarins,18,19 whereby the N,N-
dyes,7 TEMPONa,8 iodide,9 ascorbic acid,10 benzoyl peroxide,11 diethylaniline moiety alone is unable to afford 3a (entry 16; Table 1),
bases,12 or methanol13 were identified to mediate Meerwein-type implying that the presence of the porphyrin skeleton is indispensable.
arylations. However, to the best of our knowledge, none of these
Subsequently, the optimized reaction conditions were used to
metal-free arylation methods has so far been applied to the C-H evaluate the scope with respect to the coumarin derivatives (Table 2).
arylation of coumarins.14
Coumarins with electron-donating groups (e.g. Me, OMe, OEt, OH,
or NEt2) afforded 3b-f in good yield (61-78%, entries 2-6; Table 2).
Electron-deficient 6-nitrocoumarin (1g), as well as amide substituted
coumarin 1h furnished the corresponding target compounds in 36 and
60% yield, respectively (entries 7, 8; Table 2), and it should be noted
that the functional groups of 1g and 1h were not compatible with
oxidative Heck-type C(3)-H arylation conditions.4 C(4)-substituted
coumarins 1i and 1j are also good substrates (63-71%, entries 9, 10;
Table 2), despite their intrinsically high steric demand.
The scope of this reaction with respect to the aryldiazonium
tetrafluoroborates is summarized in Table 3. Unsubstituted
phenyldiazonium tetrafluoroborate 2b, as well as diazonium
tetrafluoroborate 2c with an electron-donating methyl substituent,
afforded the corresponding coupling products in good yield (70-72%,
entry 1, 2; Table 3). Diazonium tetrafluoroborates with electron-
withdrawing halogen, ester, trifluoromethyl, or nitro substituents
afforded comparable yields (45-71%, entries 4-9; Table 3). Especially
the high tolerance towards bromo- and iodo-substituents should be
highlighted here, as they were not tolerant in Heck-type reactions and
they may be beneficial for further derivatizations. Marginally lower
yields were obtained from aryl diazonium tetrafluoroborates with
substituents at ortho- or meta-position (53-59%, entries 10, 11; Table
3). These results corroborate the high versatility of the present C-C
bond formation reactions, especially compared to the previously
reported Heck-4 or Meerwein-type C-H arylations of coumarins.5
Preliminary mechanistic investigations for this porphyrin-
mediated transformation supported the presence of the aryl
diazonium-derived aryl radical intermediates and the coumarin-
derived benzyl radical intermediates.20 Based on these
observations, a working hypothesis for the reaction mechanism
is postulated in Scheme 1. One electron reduction of aryl
diazonium tetrafluoroborate with 4e affords aryl radical
and nitrogen gas. Addition of the aryl radical to coumarin (1a
furnishes a benzyl radical intermediate , which is oxidized
5
(Ar●)
Our initial hypothesis was based on the idea that organic
electron mediators that are chemically more stable than Eosin Y
should enable the metal-free C-H arylation of coumarins. A good
example for such stable mediators is porphyrins, which have an
established track record as robust electron mediators in artificial
photosynthetic systems.15 The beneficial electron-donating ability
of metal-free porphyrins in combination with the advantageous
electron-accepting ability of their radical cations, formed by one-
electron oxidation, should render these compounds ideal catalyst
candidates for synthetic transformations involving redox
processes.16
)
6
either by 4e radical cation or by another aryl diazonium
tetrafluoroborate. The moderate yield produced for nitro-
substituted substrates (36%, entry 7; Table 2 and 45%, entry 9;
Table 3) could be rationalized by considering that the electron-
withdrawing functionality retards oxidation of
6 .
by 4e●+
Regeneration of 4e or the alternative radical chain process
promotes the reactions until aryl diazonium tetrafluoroborates
are consumed.
In conclusion, we established a metal-free Meerwein-type
C(3)-H arylation of coumarins by using catalytic amounts of
5,10,15,20-tetrakis(4-diethylaminophenyl)porphyrin (4e). This
method is characterized by a high functional group tolerance and
mild reaction conditions, while providing versatile access to a
wide variety of 3-arylcoumarins in synthetically useful yields,
thus rendering this method superior to previously reported
Meerwein-type arylations. Further studies on the exact reaction
mechanism as well as on applications involving other types of
Meerwein arylations are currently in progress in our laboratory
and will be reported in due course.
Initially, we investigated catalytic amounts of 5,10,15,20-
tetrakisphenylporphyrins 4a-f, in order to assess their potential to
promote the C(3)-H arylation of coumarins with 4-
methoxybenzenediazonium tetrafluoroborate (2a; entries 1-6; Table
1). Using 5,10,15,20-tetrakis(4-aminophenyl)porphyrin (4c) afforded
the targeted coumarin 3a in 17% yield (entry 3; Table 1). Although
4d did not promote the reaction presumably due to its very low
solubility,17 the highest yield for 3a was obtained from 4e (24%, entry
5; Table 1), whereby the presence or absence of light did not affect
the yield significantly, suggesting a thermal reaction pathway (entry
7; Table 1). Optimal reaction conditions were established for 10 mol%
of 4e (entries 5, 8, 9; Table 1) and 40 °C, which furnished 3a in 63%
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aGraduate School of Pharmaceutical Sciences, The University of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. bJST-ERATO Kanai Life
Science Catalysis Project, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-
mail: oisaki@mol.f.u-tokyo.ac.jp; kanai@mol.f.u-tokyo.ac.jp
† Electronic Supplementary Information (ESI) available: Experimental
details including procedures, syntheses, and the characterization of new
products, as well as preliminary mechanistic studies. See
DOI: 10.1039/c000000x/
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We would like to thank Prof. Shu Kobayashi and Dr. Masaharu
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and a Grant-in-Aid for Scientific Research on Innovative Areas
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MEXT, Japan (M. Kanai). M. Kojima is grateful for a fellowship from
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Notes and references
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19 An ICP analysis showed unambiguously that the amount of metal
contamination (Ti, Fe, Cu, Pd) in 4e was below the detection limit: Ti <
2.6 ppb, Fe < 3.5 ppb, Cu < 1.2 ppb, Pd < 4.5 ppb.
20 An aryl radical-trap experiment (SI, section 3a) and a radical clock
experiment (SI, section 3b) suggested the involvement of aryl and benzyl
radical intermediates, respectively.
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