Smooth Metal-Free Photoinduced Preparation of Valuable 8-Arylxanthines

Article abstract of DOI:10.1002/ejoc.201900638

A set of 8-arylxanthines was prepared under metal-free conditions and in aqueous solvents from arylazo sulfones and caffeine or theophylline. Notably, the process took place by simply exposing the reaction vessel to visible or solar light, and unreacted xanthine could be easily recovered during the purification step.

Full text of DOI:10.1002/ejoc.201900638

A Journal of
Accepted Article
Title: Smooth Metal-free Photoinduced Preparation of Valuable 8-
Arylxanthines
Authors: Havall Othman Abdulla, Ahmed A. Amin, Carlotta Raviola, Till
Opatz, Stefano Protti, and Maurizio Fagnoni
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900638
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900638
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10.1002/ejoc.201900638
European Journal of Organic Chemistry
COMMUNICATION
Smooth Metal-free Photoinduced Preparation of Valuable 8-
Arylxanthines.
Havall Othman Abdulla,[a,b] Ahmed A. Amin,[c] Carlotta Raviola,[a] Till Opatz,[d] Stefano Protti,*[a] and
Maurizio Fagnoni*[a]
A set of 8-arylxanthines was prepared under metal-free conditions
and in aqueous solvents from arylazo sulfones and caffeine or
theophylline. Notably, the process took place by simply exposing the
reaction vessel to visible or solar light, and unreacted xanthine could
be easily recovered during the purification step.
Introduction
Xanthines are a class of compounds widely investigated for their
biological properties. Such derivatives have been studied in
terms of selectivity and affinity as adenosine receptor
antagonists (ARs),[1] that are crucial targets in the treatment of
several diseases including asthma, diabetes, cardiac infarction
and Parkinson’s disease.[2] Moreover, xanthines were
investigated
as
progesterone
receptor
antagonists,[3]
monoamine oxidase B inhibitors[4] for the treatment of asthma[5]
and acute renal failure[6] as well as in combination with
nonsteroidal anti-inflammatory drugs to augment their
antinociceptive effects.[7] It is widely recognized in literature that
the presence of an aryl substituent in position 8 of the xanthine
scaffold can improve their biological performances depending on
the substitution pattern on the aromatic ring.[8]
Scheme 1. Approaches for the preparation of 8-arylxanthines.
Such premises led to the development of a facile protocol for the
direct C-H arylation of xanthines to 8-arylxanthines. The
versatility of this approach lies in the combinatorial variation of
both reactants, i.e. of xanthines (mainly caffeine and
theophylline) and the aryl donors. Suitable aryl donors are
activated by cleavage of an Ar-X bond (in aryl iodides,[9a-d]
bromides,[9e-i] and chlorides[9j,k]), of an Ar-O bond,[10] an Ar-S
bond,[11] or by the reaction with trialkoxy(aryl)silanes,[12] tin
reagents[12] as well as with arylboronic acids[13] benzoic acids,[14]
aryl iodonium salts,[15] or arylmagnesium halides.[16] Rarely, the
arylated xanthine has been formed by a cross-dehydrogenative
coupling reaction.[17] However, it should be noticed that all the
available protocols usually require the presence of transition
metal catalysts (mainly in platinum-group metals) under harsh
conditions (e.g. high temperature, Scheme 1a).
In search for milder reaction conditions, a protocol has been
developed which utilizes photoredox catalysis (Scheme 1b), but
also in this case a metal-based photocatalyst (a Ru(II) complex)
was required to promote the reaction of some aryl diazonium
salts with caffeine. The corresponding arylated derivatives were
obtained in variable yields through the intermediacy of aryl
radicals.[18]
In view of the above, it is apparent that an efficient and metal-
free synthesis of 8-arylxanthines is still lacking. The avoidance
of toxicologically relevant metal contaminants is particularly
important in this case since the arylation reaction is performed at
a very late or even the final synthetic stage and the products
permit e.g. cyclometalations (where the risk of sticking Ru and
Pd covalently to the products is present) to take place.[19]
Recently, we investigated the generation of aryl radicals by
visible-light irradiation of arylazo sulfones,[20,21] a class of
compounds exhibiting a wavelength selective behavior.[22] We
surmised that the photogenerated aryl radicals may permit the
smooth metal-free arylation of xanthines under visible or solar
light irradiation as described in Scheme 1c.
[a]
Mr. H. Othman Abdullah, Dr. C. Raviola, Prof S. Protti, Prof. M.
Fagnoni
PhotoGreen Lab, Department of Chemistry, University of Pavia
Viale Taramelli 12, 27100 Pavia, Italy. E-mail: fagnoni@unipv.it
stefano.protti@unipv.it
Homepage: http://www-2.unipv.it/photogreenlab/
Chemistry Department, College of Science, Salahaddin University-
Erbil, Iraq
[b]
[c]
Results and Discussion
Prof. A. A. Amin
Chemistry Department, College of Education, Salahaddin
University-Erbil, Iraq
Prof. Dr. T. Opatz
Institute of Organic Chemistry, Johannes Gutenberg University of
Mainz, 55128 Mainz, Germany
With the aim of designing a method for the metal-free arylation
of xanthines, we focused on a model reaction, the coupling of 1-
(methylsulfonyl)-2-(4-cyanophenyl)diazene (1a) with caffeine (2).
The reaction was performed under different conditions, and the
obtained results are summarized in Table 1.
[d]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900638
European Journal of Organic Chemistry
COMMUNICATION
3a.[a]
Table 1. Optimization of the conditions for the synthesis of 8-arylated caffeine
on a 1 mmol scale to give 3c in a higher yield (61%). Better
results were obtained for the 4-nitro and 4-carboxymethyl
substituted arylazo sulfones 1f,g, and the desired heterocycles
(3f,g) were isolated in 72% and 81% yield, respectively. The
process was found suitable for the preparation of 3-cyano
derivative 3h (52% yield), for dihalo substituted 3i,j and was also
applied successfully to substrates bearing electron-donating
substituents such as -CH3, -tBu and -OCH3 (3k-m). Importantly,
excess caffeine was almost completely recovered (>90%) in
each case during the purification step and could be reused
without further purification.
Table 2. Synthesis of 8-arylxanthines 3 and 5.
Early experiments were carried out in a Pyrex vessel[23] upon
visible light exposition, by using a 32W Kessil lamp (456 nm) as
the light source (tirr = 16 h). In chloroform, irradiation of 1a in the
presence of 10 equiv of 2 afforded only traces (< 5%) of 8-
arylated derivative 3a (entry 1). Similar results were obtained in
aqueous acetone and methanol (entries 2,3). Notably, when
shifting to a MeCN-water 9:1 mixture (entry 4), 3a was isolated
in 22% yield. The amount of caffeine strongly influenced the
outcome of the process (entry 5) and an acceptable yield (42%)
was observed when increasing the excess of 2 to 20 equiv
(entry 6). In view of these results we decided to adopt the
“Sunflow” reactor, (See Figure S1, in the Supplementary
Information) a simple microcapillary (OD: 1.6 mm, ID: 1.0 mm,
10 m length) stopped flow system able to exploit sunlight as an
eco-friendly energy source previously developed to accelerate
different photocatalyzed and photoinduced reactions.[24] The use
of the “Sunflow” reactor led to a significant increase in the
efficiency of the process, and 3a was isolated in 54% yield after
only 4 h of exposition to natural sunlight at the department of
chemistry of Pavia (latitude 45°11’ N, 9°09’ E, 77 m above sea
level) during the July-September period (entry 7). However, in
this case we observed the partial precipitation of 2 during the
irradiation. In order to avoid this, and on the basis of previously
reported literature,[18] we added formic acid to the reaction
mixture (final concentration: 1.8 M). This allowed to improve the
arylation process under both Kessil lamp and sunlight irradiation,
with 3a isolated in 53% and 56% yield respectively (entries, 8,9).
Finally, as pointed out in entry 10, no reaction took place in the
absence of light.
We thus adopted the conditions described in entry 9 to
investigate the scope of the reaction. In selected cases, the 32W
Kessil lamp was a convenient alternative as the light source (see
conditions in entry 8). A set of arylazo sulfones was then
synthesized and exploited in the photoinduced coupling with
caffeine. As depicted in Table 2 (upper part), a library of 8-
arylated caffeines 3a-m was prepared. 4-Halophenyl (3b-d) and
4-acetylphenyl (3e) substituted derivatives were all obtained in
acceptable yields (40-50%) by using both a sunflow reactor and
batch conditions. In the case of 1c, the reaction was performed
Then, we extended the scope of the reaction by arylating
theophylline (4). However, in this case, because of the low
solubility of 4, MeCN:aqueous HCl 2:1 was adopted (final HCl
concentration = 1.1 M) as the reaction medium although this
prevent the use of the microcapillary tube of the Sunflow reactor.
For these reasons, we moved to batch conditions, by using a
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10.1002/ejoc.201900638
European Journal of Organic Chemistry
COMMUNICATION
SolarBox (equipped with a 1.5 kW Xe lamp able to mimic the
solar emission spectrum) as the photochemical reactor (See the
ESI file for further details).
well tolerated the presence of various groups (whether electron-
donating or electron-withdrawing) on the aromatic ring. The
arylated xanthines were formed in a yield comparable with that
obtained in related reactions but starting from the aryl diazonium
salts[18] and in a shorter time (4-16 h in place of 24-60 h). The
excess of the heterocycles used in the reaction could be almost
completely recovered (> 90 %) and reused without further
purification, thus minimizing the ecological footprint as well as
raw material costs of the process.
As depicted in Table 2 (lower part), arylation took again place in
acceptable yields (41-50%) with arylazo sulfones containing
electron-withdrawing (EWG) substituents (5a, 5c, 5d, 5f,g), and
a comparable result was obtained for 5a when using a 32W
Kessil lamp as the light source. However, in the case of 4-tert-
butyl derivative 1l only a small amount of product (25% yield)
was isolated.
The photoreactivity of arylazo sulfones has been investigated in
some detail by our group.[20,21] We can thus assume that visible
light irradiation of 1 (Scheme 2, path a) led to the homolytic
cleavage of the N-S bond from the singlet excited state 1n*,
affording, after loss of gaseous N2, the corresponding aryl
Experimental section
General procedure for the synthesis of 8-arylcaffeines 3. A
nitrogen equilibrated solution of the chosen arylazo sulfone 1
(0.25 mmol, 1.0 equiv, 0.05 M) 2 (5 mmol, 20 equiv, 1M), formic
acid (350 L, 1.8 M) in MeCN:H2O 4:1 mixture (5 mL) was
injected in the stopped “sunflow” reactor via a Luer‐Lock syringe,
then the reactor was positioned outside and exposed to sunlight
for 4 h. Then, the reaction mixture was withdrawn from reactor,
collected and the solvent removed under reduced pressure. The
crude product was purified via column chromatography (eluant:
cyclohexane:ethyl acetate mixture) to afford the desired product
3. The same reaction was performed also by irradiating a pyrex
vessel containing the reaction mixture at 456 nm with a 32W
Kessil Lamp. In all cases, > 90% of the unreacted 2 was
recovered and reused as it is.
•
(Ar•)/methanesulfonyl (CH3SO2 ) radical pair (path b). The
xanthine core underwent a regioselective addition of Ar• at the 8-
position in accordance with related works (path c).[18] Oxidation
of the generated radical adduct 6• by methanesulfonyl radical
followed by deprotonation[21a] or direct hydrogen abstraction[21b]
•
from 6• by CH3SO2 (path d) resulted in the formation of the
functionalized heterocycle. Irradiation under natural or simulated
solar light may likewise cause the generation of a triplet phenyl
cation upon absorption of arylazo sulfones 1 in the UV
region.[20,22] Arylation of xanthines by this intermediate cannot be
excluded as a minor path.
General procedure for the synthesis of 8-aryltheophyllines 5.
A nitrogen purged solution of the chosen arylazo sulfone 1 (0.25
mmol, 1.0 equiv, 0.05 M), 4 (5 mmol, 20 equiv, 1M), in
MeCN:aqueous HCl mixture (HCl concentration: 1.1 M, 5 mL)
was irradiated by means of a SolarBox simulator equipped with
a 1.5 kW Xe lamp (500 W·m–2 light intensity) for 24 h. The
photolyzed solution was concentrated under reduced pressure
and the desired product was isolated by washing the resulting
residue with hot water.
Conflicts of interest
There are no conflicts to declare.
Scheme 2. Proposed mechanism of the arylation of xanthines via
arylazo sulfones.
Acknowledgements
Havall Othman Abdulla is grateful to the Chemistry Department,
College of Science, Salahaddin University-Erbil (Iraq) for
financial support.
Conclusions
As mentioned in the introduction, the development of
a
procedure for the selective arylation in position 8 of the xanthine
core is a significant goal in medicinal chemistry.[8] Due to the
restrictive legislation on the presence of toxicologically relevant
trace metals in pharmaceutics,[25] the recent dramatic price
increase of transition metals such as Pd and Ru[26] as well as the
environmental burden of their extraction[27] calls for
advantageous metal-free routes. To the best of our knowledge,
the protocol described herein represents the first metal-free
procedure for the preparation of arylated compounds 3 and 5,
that have been obtained in discrete to good yields upon either
visible or solar light irradiation. The reaction may be smoothly
carried out under batch or flow conditions and the conditions
Keywords: Arylation • Aryl radicals • Azosulfones • Visible light •
Xanthines
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COMMUNICATION
COMMUNICATION
Photochemical Synthesis
H. O. Abdulla, A. A. Amin, C. Raviola, T.
Opatz, S. Protti* and M. Fagnoni.*
Page No. – Page No.
A set of 8-arylxanthines was prepared under metal-free conditions and in aqueous
solvents from arylazo sulfones and caffeine or theophylline. Notably, the process took
place by simply exposing the reaction vessel to visible or solar light, and unreacted
xanthine could be easily recovered during the purification step.
Smooth Metal-free Photoinduced
Preparation
of
Valuable
8-
Arylxanthines.
This article is protected by copyright. All rights reserved.