Concise Xanthine Synthesis through a Double-Amidination Reaction of a 6-Chlorouracil with Amidines using Base-Metal Catalysis

Article abstract of DOI:10.1002/cssc.201601483

A new and concise route towards xanthines through a double-amidination reaction is described; consecutive intermolecular C?Cl and intramolecular oxidative C?H amidination. N-uracil amidines are obtained through S_NAE on a 6-chlorouracil with amidines. Direct Cu-catalyzed oxidative C?H amidination on these N-uracil amidines yields polysubstituted xanthines. Sustainable oxidants, tBu₂O₂or O₂, can be used in this oxidase-type reaction. The protocol allows for the introduction of N1, N3, N7, and C8 substituents during the xanthine-scaffold construction, thus avoiding post-functionalization steps. Both 6-chlorouracils and amidines are readily available commercially or through synthesis.

Full text of DOI:10.1002/cssc.201601483

Accepted Article
Title: Concise Xanthine Synthesis via a Double Amidination Reaction
of a 6-Chlorouracil with Amidines using Base Metal Catalysis
Authors: Bénédicte Morel, Philippe Franck, Johan Bidange, Sergey
Sergeyev, Dan Smith, Jonathan Moseley, and Bert UW Maes
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To be cited as: ChemSusChem 10.1002/cssc.201601483
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Concise Xanthine Synthesis via a Double Amidination Reaction of
a 6-Chlorouracil with Amidines using Base Metal Catalysis
Bénédicte Morel,[a] Philippe Franck,[a] Johan Bidange,[a] Sergey Sergeyev,[a] Dan Smith,[b] Jonathan
Moseley,[b] Bert U. W. Maes*[a]
Abstract: A novel and concise route towards xanthines via a double
amidination reaction is described; consecutive intermolecular C-Cl
and intramolecular oxidative C-H amidination. N-uracil amidines are
obtained via SNAE on a 6-chlorouracil with amidines. Direct Cu-
catalyzed oxidative C-H amidination on these N-uracil amidines
yields polysubstituted xanthines. Sustainable oxidants, di-tert-butyl
peroxide or oxygen, can be used in this oxidase type reaction. The
protocol allows for the introduction of N1, N3, N7 and C8
substituents during the xanthine scaffold construction, thus avoiding
post-functionalization steps. Both 6-chlorouracils and amidines are
readily available commercially or through synthesis.
prepared using
a
Pinner approach, starting from the
corresponding nitriles and amines, and allow installation of R7 at
N7 regioselectively.[8,9] In comparison to the Traube synthesis
our approach is shorter, prevents a post-functionalization step
on N7 of the xanthine, and avoids a two-step pre-activation,
involving nitrosation with unstable nitrous acid and subsequent
reduction, at C5 of the uracil precursor.[10] These aspects make
our approach attractive from a sustainable chemistry point of
view.
Results and Discussion
Two protocols were developed towards the synthesis of N-uracil
amidines 3 via SNAE on 6-chlorouracils (Table S3). The first one
requires 2.3 equivalents of amidine, acting both as nucleophile
and base, in 3-ethyl-3-pentanol at 100°C. The second one uses
1.5 equivalents of amidine in combination with 0.7 equivalents of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in tert-butanol at 80°C.
Alcohols as solvent and DBU as a base are preferred from a
sustainability point of view.[11] The latter approach is especially
interesting for expensive amidines. Interestingly, with N-
substituted amidines generally only the unsubstituted nitrogen
participates in the SNAE reaction allowing to obtain one
regiosiomer. The target N-uracil amidines could often be purified
Introduction
The purine scaffold is one of the most important heterocyclic
motifs and can be considered as a privileged scaffold in
medicinal chemistry.[1] Purine derivatives, such as xanthines,
display a wide variety of biological activities and this core can be
found in natural products (e.g. caffeine, theobromine) and APIs
(e.g. Linagliptin, Dasantafil, Bamifylline and Istradefylline).[2] The
most common way to synthesize xanthines is known as the
Traube synthesis (Scheme 1),[3] involving imidazole ring
formation via condensation of a one-carbon fragment (an
activated carboxylic acid[4] or an aldehyde[5]) with a 5,6-
diaminouracil. The latter is made via nitrosation of a 6-
aminouracil followed by reduction. A second general but less
frequently applied synthetic approach to xanthines builds up the
uracil ring via addition of an alkyl 4-aminoimidazole-5-
carboxylate to an isocyanate, which then cyclizes under basic
conditions.[6] This route is less attractive as the pre-
by
simple
precipitation,
avoiding
solvent-consuming
chromatography on silica gel.
Then, the direct oxidative amidination was investigated. Cross
dehydrogenative C-N bond formation using base metal catalysis
has received considerable attention in the last 5 years.[12,13] Only
one direct oxidative amination reaction on uracils is hitherto
described and reported by our group.[14] In this oxidase type
functionalized imidazole substrate requires
a
multi-step
reaction
a
stoichiometric oxidant is required. From
a
synthesis. Herein we report a new and general approach
towards N1, N3, N7 and C8 substituted xanthines, involving two
consecutive C-N bond forming steps starting from readily
available N1, N3 substituted 6-chlorouracils (A) (Scheme 1).
SNAE of the C6 halogen by an amidine leads to an N-uracil
amidine (B), which can be further converted to the
corresponding xanthine (C) via a direct oxidative amidination
reaction.[7] The required amidine reagents can be easily
sustainability point of view, oxygen and peroxides (H2O2 or
RO2R) are the most desirable candidates as the waste
compounds are respectively water and alcohols.[15] Therefore,
these were considered for the optimization of our cyclization
reaction. In a preliminary set of experiments with N-(1,3-
dibenzyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)benzimid-
amide (1) as model substrate, aerobic conditions highlighted CuI
as the catalyst of choice (Figure S1). A few other copper
sources (Cu(OAc)2·H2O, CuBr2, Cu0 nanoparticles) gave similar
yields of the desired xanthine, but converted slower than CuI.
Ligands and acids had no or negative effect on the reaction
(Table S9, Figure S2). The choice of solvent was critical for the
reaction efficiency. Apart from dimethylsulfoxide (DMSO) and
tetramethylene sulfoxide, the other solvents tested afforded
maximum 15% of reaction product. This solvent scores well from
the point of view of health and safety and intermediate with
respect to environmental aspects.[16] Using DMSO, full
conversion was achieved within 3 hours using 15 mol% of CuI at
120°C under O2 atmosphere. This afforded 1,3-dibenzyl-8-
phenylxanthine (2) in 78% yield (Scheme 2).[17]
[a]
B. Morel, P. Franck,Dr. J. Bidange, Dr. S. Sergeyev, Prof. Dr.
B.U.W. Maes
Organic Synthesis, Department of Chemistry
University of Antwerp
Groenenborgerlaan 171, 2020 Antwerp (Belgium)
E-mail: bert.maes@uantwerpen.be
Dr. D. Smith, Dr. J. Moseley
[b]
CatSci Ltd
CBTC2, Capital Business Park, Wentloog, Cardiff CF3 2PX (United
Kingdom)
Supporting information for this article is given via a link at the end of
the document.
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Scheme 1. Classical and new approach for the synthesis of polysubstituted xanthines.
oxidant, but the CuI and CuII salts tested performed worse than
CuI (Table S14). Other cheap and abundant base-metal
catalysts (iron, cobalt and nickel) were also tried, but they did
not give any reaction (Table S15). Control experiments showed
that both catalyst and peroxide were essential as no reaction
product was obtained when one of them was omitted (Table
S13). Other solvents than DMSO were also explored such as
cyclopentylmethyl ether, 2-methyl THF or propylene
carbonate.[11b,11c] Although the latter showed a good mass
balance, the yield was low in all cases (Table S16). Therefore
DMSO was retained as the solvent of choice for the
transformation.[16] Lowering the reaction temperature to 90°C
gave a slower reaction and full conversion of the substrate
required 3 hours (Figure S5); the use of O2 at this temperature
required 16 hours. Although the use of a lower temperature is
feasible for the direct oxidative amidination reaction, we decided
to stick to 120°C and tBu2O2 as oxidant for the scope study as
this combination gave the fastest reactions. Interestingly, a
gradual addition of the peroxide can also be applied, allowing
the peroxide concentration to be kept low in the reaction medium
(Scheme S3, Figure S3). However, from a practical point of view
on a small scale (discovery), we decided not to apply this
procedure during the scope study.
Scheme 2. Direct Cu-catalyzed oxidative C-H amidination of 1 using O2 or
tBu2O2 as oxidant. [a] Isolated yield. [b] NMR yield (1,3,5-trimethoxybenzene as
internal standard).
We then applied the optimized conditions with tBu2O2 (15 mol%
of CuI and 2 eq. of tBu2O2, in DMSO at 120°C) to a set of
synthesized N-uracil amidines 3 (Table S3). To our delight, the
majority of these substrates were converted into the
corresponding xanthines in good to excellent yields (Scheme 3).
The N-uracil benzenecarboximidamide could bear both primary
and secondary N-alkyl substituents (3a-d). The structure of 4b
was confirmed by X-ray crystallography (Figure S8). Only a tert-
butyl group (3e) proved to be incompatible, presumably due to
Figure 1. Comparison of reaction rates on the direct oxidative amidination of
N-(1,3-dibenzyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)benzimidamide (1)
using oxygen and tBu2O2 as oxidant. Measured initial rates of the reactions:
vin(O2) = 2.3086.10-5 M.s-1; vin((tBuO)2) = 28.051.10-5 M.s-1.
its steric character. The protocol tolerated
substituents on the aryl ring of
a
the
variety of
Interestingly, when using tBu2O2 as the oxidant, 1 fully converted
N-uracil
within 30 minutes and 2 was isolated in 71% yield (Scheme 2).
Comparison of the initial rates revealed that the reaction with
peroxide is more than 10 times faster than with O2 as oxidant
(Figure 1). The specific dialkyl peroxide used is one of the most
stable ones, widely used in polymer industry and only produces
tert-butanol as waste. Other peroxides gave a lower yield and
sometimes a low mass balance was obtained (Table S12).
Different copper sources were probed using tBu2O2 as the
benzenecarboximidamide, with both electron-donating and
electron-withdrawing groups (3g-l). Notably, the para-iodo
substituted xanthine 4k, which can be used for further cross-
coupling reactions, was obtained in a good yield. As fluorine can
have a major influence on the pharmacological properties of a
drug[18], we were pleased to see that this method is also
compatible with this halogen (3l). N-uracil heteroarene-
carboximidamide derivatives could also be used as exemplified
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by 3m. Even N-uracil alkanimidamides were generally well
tolerated (3n-t), although some of these substrates gave a lower
yield.
product could be obtained for 3e. Remarkably, 1,3-dimethyl-8-
ethyl-3,7-dihydro-1H-purine-2,6-dione (4r) was afforded in 97%
yield using peroxide as oxidant while under aerobic conditions
no xanthine was formed. No 3r was recovered in the latter case
and its decomposition mechanism is unclear. It is interesting to
note that 4q is an intermediate in the synthesis of the API
Bamyfilline.[19] Importantly, irrespective of the oxidant used
several xanthines could be isolated by simple precipitation (2,4a-
b,g,j,k,q).
Scheme 3. Scope of the direct Cu-catalyzed oxidative C-H amidination of N-
uracil amidines (3) using O2 or tBu2O2 as oxidant [a,b]
.
Subsequently, we investigated whether the copper catalyst
could be reused with model substrate 1. When adding new
substrate and tBu2O2 oxidant at the end of the first amidination
reaction, full conversion to 2 could be again achieved within 20
minutes in a second reaction (Figure 2). Even a successive four
times loading of substrate 1 and tBu2O2 resulted in a similar
yield (69% versus 71%) of the desired xanthine 2, demonstrating
that the copper does not degrade at the end of the reaction
(Scheme 4). A similar result was obtained when O2 was used as
the oxidant giving 65% yield (Scheme 4).
Figure 2. Graphical representation of the reuse of the copper catalyst
exemplified for substrate 1 and tBu2O2. After the first reaction was completed,
a second batch of 1 and tBu2O2 were added. Conversion was determined by
Online IR reaction monitoring.
[a] Cond. 1: 3 (0.5 mmol), CuI (15 mol%), tBu2O2 (2 eq.), DMSO (0.5M), 120°C
(oil bath), 2 h, closed vial, N2 atmosphere (balloon). Inert atmosphere is not
essential for this reaction but was applied to exclude contribution of O2 oxidant
present in air. Cond. 2: 3 (0.5 mmol), CuI (15 mol%), DMSO (0.5M), 120°C, 18
[b]
h, O2 atmosphere (balloon). Reaction times were not minimized.
yield.
Isolated
6 h.
[c]
[d]
[e]
NMR yield (1,3,5-trimethoxybenzene as internal standard).
Only 3e was detected in the crude reaction mixture via NMR analysis. [f] No 3r
or 4r were isolated.
Scheme 4. Catalyst reuse: experiments with four successive loadings of
substrate 1 and oxidant, using tBu2O2 or O2.
O2 was then tested as alternative oxidant for the substrate scope.
Generally, under the optimized conditions (15 mol% of CuI, with
an O2 balloon, in DMSO at 120°C) higher and in some cases
similar yields were obtained under the aerobic conditions though
a much longer reaction time was required (Scheme 3). Again no
Finally, although our method is designed to install the target
substituents at N1 and N3 when building up the xanthine
scaffold, it is also possible to work with N-protective groups. 1,3-
Dibenzyl-8-phenyl-7-propylxanthine (3u) for instance could be
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[4]
[5]
a) C. E. Muller, J. Sandoval-Ramirez, Synthesis 1995, 1295-1299; b) S.
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deprotected with BBr3 in 58% yield using a literature procedure
(Scheme S5).[20] This allows post-decoration of the uracil moiety,
via N-alkylation/arylation or dehydroxychlorination and
subsequent consecutive SNAr which is especially interesting for
medchem purposes.
a) A. D. De Araujo, E. Bacher, F. W. J. Demnitz, D. A. Santos,
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In summary, we have developed a short two-step procedure
for the synthesis of polyfunctionalized xanthines starting from
readily available 1,3-disubstituted 6-chlorouracils and amidines.
SNAE with amidines afforded the substrates for direct oxidative
amidination in moderate to good yields. Cu-catalyzed cross
dehydrogenative coupling on these substrates provided N1, N3,
N7 and C8 substituted xanthines in good yields. Although O2
gives a significantly slower reaction versus tBu2O2 as oxidant for
the cross dehydrogenative C-N bond formation, the former is
generally preferred from a yield point of view. Both the use of a
readily available and cheap base metal (Cu) and a sustainable
oxidant (O2 or tBu2O2) make this protocol valuable for application
in both discovery and chemical development projects.
Interestingly, in both steps of the new approach, precipitation of
the target compound can often be used for purification, avoiding
wasteful column chromatography. The copper catalyst was
proven to be reusable hereby further contributing to the
sustainability of the new approach.
[7]
[8]
For a feature article dealing with C-C bond formation via direct catalytic
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a more
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[10] For pre-activation with bromo, see: B. G. Szczepankiewicz, J. J. Rohde,
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Acknowledgements
We would like to thank Dr. R. Harris, Dr. L. Naya-Salgado and
Dr. J. Hayler of GSK, Dr. J. De Houwer and Dr. C. M. L. Vande
Velde of UA, Dr. M. Zeller of YSU (X-ray crystallography) for
their contribution to this work. The research leading to these
results has received funding from the Innovative Medicines
Initiative (www.imi.europa.eu) Joint Undertaking under grant
agreement n°115360, resources of which are composed of
financial contribution from the European Union’s Seventh
Framework Programme (FP7/2007-2013) and EFPIA companies’
in kind contribution, COST Action CHAOS, Fund for Scientific
Research (FWO-Flanders) and the Hercules foundation. X-ray
diffractometers were funded by NSF Grants 1337296 and
0087210, Ohio Board of Regents Grant CAP-491, and by
Youngstown State University.
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[14] Our group reported C8-N9 (di)azino annulated xanthine synthesis from
C5-[(di)azinylamino]uracils via iron catalyzed C6 direct oxidative
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Royal Society of Chemistry, 2016.
Keywords: Xanthine • oxidative C-H amination • cross
dehydrogenative reaction
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[17] The synthesis of 2-aryl-1H-benzimidazoles via Cu-catalyzed aerobic
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a
very low conversion to 2-aryl-1H-
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Entry for the Table of Contents
FULL PAPER
Bénédicte Morel, Philippe Franck, Johan
Bidange, Sergey Sergeyev, Dan Smith,
Jonathan Moseley, Bert U. W. Maes*
Page No. – Page No.
Concise Xanthine Synthesis via a
Double Amidination Reaction of a 6-
Chlorouracil with Amidines using
Base Metal Catalysis
A novel two-step approach for the synthesis of polysubstituted xanthines is
described. Starting from simple building blocks, 6-chlorouracil and amidines, a
SNAE amidination reaction was developed, followed by a base-metal catalyzed
intramolecular direct oxidative amidination. Molecular oxygen or di-tert-butyl
peroxide can be used as oxidant for the latter transformation.
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