Xanthate-based microwave-assisted C–H radical functionalization of caffeine, 1,3-dimethyluracil, and imidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2017.02.050

Xanthate-based radical chemistry was used for the regioselective direct alkylation of caffeine, uracil, and imidazo[1,2-a]pyridine systems, using dilauroyl peroxide as initiator and oxidant, under microwave irradiation. Under these conditions, several electrophilic radicals (located alpha to a carbonyl function such as esters, amides, ketones, malonates and cyano groups) were added to the title heterocyclic systems. The methodology allows the intermolecular regioselective construction of a sp²-sp³C–C bond via a C–H functionalization in an aromatic substitution, from readily available starting materials.

Full text of DOI:10.1016/j.tetlet.2017.02.050

Accepted Manuscript
Xanthate-based microwave-assisted C-H radical functionalization of caffeine,
1,3-dimethyluracil, and imidazo[1,2-a]pyridines
Víctor M. Pérez, Daniela Fregoso-López, Luis D. Miranda
PII:
S0040-4039(17)30230-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.050
TETL 48661
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 January 2017
13 February 2017
15 February 2017
Please cite this article as: Pérez, V.M., Fregoso-López, D., Miranda, L.D., Xanthate-based microwave-assisted C-
H radical functionalization of caffeine, 1,3-dimethyluracil, and imidazo[1,2-a]pyridines, Tetrahedron Letters
(2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.050
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Víctor M. Pérez, Daniela Fregoso-López and Luis D. Miranda

1
Tetrahedron Letters
Xanthate-based microwave-assisted C-H radical functionalization of caffeine, 1,3-
dimethyluracil, and imidazo[1,2-a]pyridines.
Víctor M. Pérez, Daniela Fregoso-Lópeza, and Luis D. Mirandaa
aInstituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior S. N., Ciudad Universitaria, Coyoacán, Ciudad de México. 04510,
México.ꢀ
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Xanthate-based radical chemistry was used for the regioselective direct alkylation of caffeine,
uracil, and imidazo[1,2-a]pyridine systems, using dilauroyl peroxide as initiator and oxidant,
under microwave irradiation. Under these conditions, several electrophilic radicals (located
alpha to a carbonyl function such as esters, amides, ketones, malonates and cyano groups) were
added to the title heterocyclic systems. The methodology allows the intermolecular
regioselective construction of a sp2-sp3 C-C bond via a C-H functionalization in an aromatic
substitution, from readily available starting materials.
Available online
Keywords:
Xanthate
Free radicals
Caffeine
2009 Elsevier Ltd. All rights reserved.
Uracil
imidazo[1,2-a]pyridines
———
 Corresponding author. Tel.: +52 55 5622-4440; e-mail: lmiranda@unam.mx

2
Tetrahedron
Direct intermolecular alkylation of heteroaromatic systems is a
caffeine has also been reported to undergo oxidative substitution
at C-8 under the presence of CF34a,e and methyl sulfonyl
radicals.4b Thus, to investigate if the caffeine system could be
alkylated under xanthate-based conditions, a brief optimization
screening was conducted. Toward this goal, caffeine (1) and the
xanthate of ethyl acetate (4) were utilized as the model substrates
(Table 1).
process of great significance (Figure 1).1 In principle, through a
C-H bond functionalization, the process allows the regioselective
installation of an alkyl group onto an heteroaromatic system. The
process may be used for preparation of synthetically useful
intermediates or for attractive late stage functionalization in a
long synthetic sequence. Although Friedel-Crafts reactions might
be thought to be the method of choice to carry out this procedure,
this methodology generally suffers from the well-known 1,2-
hydride and/or alkyl rearrangement of the cationic intermediate
(Wagner–Meerwein rearrangement), along with the requirement
for electron-rich aromatic systems.2 Indeed, due to these
drawbacks, the intermolecular version of the Friedel-Crafts
process has found limited synthetic applications. In contrast, its
neutral nature and the lack of 1,2 shifts of free radicals have
encouraged the use of this intermediates for the intermolecular
creation of a sp2-sp3 C-C bond by a C-H functionalization in an
aromatic substitution (Minisci reaction).3 Indeed, the last decade
has witnessed tremendous efforts to develop practical methods to
accomplish such processes and several conditions have been
established, most of them under metal-catalyzed conditions.4 In
this context, the xanthate-based radical chemistry embraces
special importance because not only permits the efficient
generation of alkyl radicals, but it also frequently uses lauroyl
peroxide in the initiation step, which, in principle, facilitates the
oxidative process for the rearomatization pathway under matal-
free conditions.5 Furthermore, the degenerated radical addition-
fragmentation pathway involved in the mechanism allows the
intermediate free radical to persist longer in the reaction medium,
enabling it to be trapped by poor radical acceptors, such as
aromatic systems.5,6 Accordingly, in 2003 we first reported an
oxidative direct intermolecular alkylation of several
heteroaromatic systems (indoles, pyrroles, furans, and
thiophenes) with several electrophilic radicals (located alpha to a
carbonyl function), using xanthate chemistry.7 Later, we further
demonstrated that the process could be applicable to the
alkylation of flavones6d and coumarines.6e In addition, Zard and
coworkers observed that electrophilic radicals were also useful
partners to the C-2 alkylation of indoles.7 With the objective to
extend the scope of this tool, we then became interested in the
alkylation of caffeine, 1,3-dimethyluracil, and imidazo[1,2-
a]pyridines using the same xanthate-based radical chemistry. Our
preliminary observations within this endeavor are summarized
herein.
Table 1. Optimization of the radical alkylation.
experimenta
solvent
temp. (°C)
yield [%]
1b
2b
3b
4c
5c
6c
ClCH2CH2Cl
AcOEt
Tolueno
ClCH2CH2Cl
AcOEt
Tolueno
85
77
100
85
77
34
24
----
39
29
18
100
[a] Reaction at [0.1M]: caffeine (1 equiv), xanthate (2 equiv)
and lauroyl peroxide (DLP) (2 equiv), [b] under convectional
heating, [c] under microwave heating.
Table 2. Radical alkylation of caffeine
Thus, portionwise additions of lauroyl peroxide (DLP) (2
equiv.; 0.28 equiv. every 1 h) to a 0.1 M solution of 1 (1 equiv.)
and xanthate 4 (2 equiv.) in 1,2-dichloroethane at 85 °C under
conventional heating afforded the desired C-8 alkylated caffeine
5 in 34% yield, after 8 h of reaction (entry 1, Table 1).6 When the
solvent was changed to ethyl acetate at lower temperature (entry
2), the yield was reduced. Similarly, the use of toluene at 100 ºC
lead only to decomposition of the xanthate (entry 3). In contrast,
when the reaction was carried out using microwave irradiation in
dichloroethane (DCE), adding 2 equiv. of lauroyl peroxide (DLP)
(0.28 equiv/15 min) not only reduced the time considerably (2 h),
but also slightly increased the yield (entry 4). Similar increments
in the yields were observed using AcOEt and toluene under
microwave irradiation (entries 5 end 6), although the best yield
was observed with DCE. Consequently, conditions used in entry
4 were further utilized to explore the scope of the process. To this
end, various xanthates 4a-k (Table 2) were prepared by
substitution of the corresponding halo derivative with
commercially available potassium ethyl xanthogenate.6,10
Figure 1. Oxidative radical substitution.
Figure 2. Caffeine, 1,3-dimethyluracil and imidazo[1,2-a]pyridines.
Caffeine is a methylxanthine alkaloid and one of the most
consumed psychoactive substances in the world with several
important pharmaceutical activities.8 It has been reported that
caffeine and its derivatives affect the neural and cardiovascular
systems and display remarkable effects on apoptosis and DNA
repair, along with cell cycle function and regulation, among other
important biological activities.9 The conjugated system of

3
As observed in Table 2, radicals from xanthates derived not
only from esters, but also from acetonitrile gave good yields in
the alkylation process. Xanthates derived from amides of
morpholine (10), diethylamine (11), and pyrrolidine (12)
afforded moderate yields in the process. With the same reaction,
it was also possible to introduce both the ethyl and methyl
malonate moieties (13 and 14) in moderate yields. The acetone-
derived product 8, was only detected in trace amount in an
inseparable mixture and the secondary butanone-derived radical
(15) failed to add to the caffeine system. Along the same lines,
the caffeine-demethylated congeners theobromine and
theophylline were tested in the same reaction system. However,
we were unable to carry out these experiments owing to the
insolubility of these substances in most of the organic solvents.
Table 4. Oxidative radical alkylation of imidazo[1,2-a]pyridines..
After the study of the behavior of the caffeine aromatic system,
we then focused our attention on the application the same
methodology to directly install the same alkyl groups onto the
1,3-dimethyluracil system 2. Uracil, one of the four nucleobases
in RNA, is a pyrimidine with remarkable pharmacological
activities.11 As expected, under the optimized conditions 1,3-
dimethyluracil 2 was selectively alkylated at C-54b,e,f with the
corresponding xanthates. Results of the radical alkylation of this
conjugated system are summarized in Table 3.
Table 3. Oxidative radical alkylation of 1,3-dimethyluracil.
Thus far, we had demonstrated for the first time that the
xanthate-based radical chemistry could be utilized for the
intermolecular alkylation of caffeine and uracil with several
electrophilic radicals. Similarly, imidazo[1,2-a]pyridines (IPs)
had been reported to exhibit remarkable biological activities.12 In
fact, some commercial drugs contain IPs e.g., zolimidine
(treatment of peptic ulcers), alpidem and saripidem (treatment of
The yields of the alkylation of uracil were considerably higher
than those observed in the caffeine system. Indeed, the reaction
provided the efficient direct installation of ethyl (16a) and methyl
(16b) acetates, acetonitrile (16c), and even acetone and
acetophenone moieties (16d-e). Amides (16g-i) were also
installed onto the uracil system in good yields. Again, secondary
2-butanoyl moiety was unable to be added under the same
conditions. Methyl malonate was also added, but in low yields
(16j).
anxiety
disorders),
zolpidem
(insomnia
treatment).13
Accordingly, at the outset, this heterocyclic system was selected
to extend the scope of the xanthate chemistry. While we were
working on this study, a similar paper regarding the alkylation of
the IPs using the same xanthate-based radical chemistry was
published.14 Since we were using microwave irradiation in

4
Tetrahedron
2.
Naredla, R. R.; Klumpp, D. A. Chem. Rev. 2013, 113, 6905.
(a) Minisci, F.; Bernardi, R.; Bertini, F.; Galli, R.; Perchinummo,
M. Tetrahedron 1971, 27, 3575. For examples of Minisci reaction:
(b) Minisci, F.; Vismara, E.; Fontana, F.; Morini, G.; Serravalle,
M.; Giordano, C. J. Org. Chem. 1986, 51, 4411. (c) Citterio, A.;
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7960. For a recent perpective see: Yan, M.; Lo, J. C.; Edwards, J.
T.; Baran, P. S. J. Am. Chem. Soc. 2016, 138 (39), 12692.
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(35), 12994. (d) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E.
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For reviews on xanthate-based radical chemistry, see: (a) Quiclet-
Sire, B.; Zard, S. Z. Beilstein J. Org. Chem. 2013, 9, 557– 576. (b)
Zard, S. Z. “Xanthates and RelatedDerivatives as Radical
Precursors”, In Encyclopedia of Radicals in Chemistry, Biology
and Materials, John Wiley & Sons, Ltd, Chichester, UK, 2012. (c)
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shorter reactions times compared with the reported conditions,
3.
we decided to disclose our own results. Thus, as depicted in
Table 4, the yields obtained in our study using microwave
irradiation, were similar to those obtained under reported
conventional heating with xanthates derived from esters (18a,g,l)
amides (18b,m,n), nitriles (18c,h,o,p), and ketones
(18d,e,i,j,q,r,s,t). Novel examples (different from those reported
previously) using amides derived from morpholine (18b) and
malonates (18g,k,u,v) also worked well in the alkylation process.
4.
The proposed mechanism for the radical alkylation is based on
the reported similar processes6 and is illustrated in Scheme 1 with
the caffeine system. First, the radical 20 is generated from the
corresponding xanthate upon the action of the radical 19 which
comes from the thermal fragmentation/decarboxylation process
of the DLP. Then, this radical is added to the heterocyclic system
producing a new radical 21 which, is promptly oxidized to the
cation 22,6 in the presence of a stoichiometric amount of the
peroxide, facilitating the regeneration of the original conjugated
system.
5.
Scheme 1. Proposed mechanism.
6.
(a) Osornio, Y. M.; Cruz-Almanza, R.; Jimenez-Montano, V.;
Miranda, L. D. Chem. Commun. 2003, 2316. (b) Reyes-Gutiérrez,
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Biomol. Chem. 2009, 7, 1388. (c) López, E. F.; Gómez-Pérez, L.
B.; Miranda, L. D. Tetrahedron Lett. 2010, 51, 6000. (d)
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Luján-Montelongo, A.; Olivera-Díaz, D.; Bautista, E.; Ortega, A.;
Campos-González, M. L.; Gámez-Montaño, R. Org. Biomol.
Chem. 2012, 10, 2946. (e) Miranda, L. D.; Icelo-Ávila, E.;
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In closing, we have demonstrated that the xanthate-based radical
chemistry is a practical methodology to regioselectively directly
install several electrophilic radicals (positioned alpha to a
carbonyl function, such as esters, amides, ketones, malonates and
cyano groups) onto caffeine, uracil, and imidazo[1,2-a]pyridine
systems, using dilauroyl peroxide as both initiator end oxidant,
under microwave irradiation. This study not only streamlines the
scope of the xanthate radical chemistry but also contributes to
synthetizing novel derivatives of title heterocyclics towards drug
candidates. The methodology allows the intermolecular
regioselective construction of a sp2-sp3 C-C bond via a C-H
functionalization in an aromatic substitution, from readily
available starting materials and without substrate preactivation.
We believe that this protocol might provide rapid access to more
complex scaffolds by using also more complex xanthates
derivatives.
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Financial support from “Marcos Moshinsky Foundation”, and
PAPIIT-UNAM (IN210516), is gratefully acknowledged. We
also thank R. Patiño, A. Peña, E. Huerta, I. Chavez, R. Gabiño,
Ma. C. García-González, L. Velasco and J. Pérez for technical
support.
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5
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Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
14. Wang, S.; Huang, X.; Ge, Z.; Wang, X.; Li, R. RSC Adv. 2016, 6,
63532.

6
Tetrahedron
Caffeine and uracil was regioselectively alkylated
using xanthate radical chemistry
The study contributes to give access to novel
derivatives of title heterocyclics
In the process a sp2-sp3 C-C bond is formed via a
C-H functionalization.
The protocol may be used to attach caffeine and
uracil with complex structures.