Microwave-Assisted Suzuki–Miyaura and Sonogashira Coupling of 4-Chloro-2-(trifluoromethyl)pyrido[1,2-e]purine Derivatives

Article abstract of DOI:10.1002/ejoc.201900921

The convenient preparation of three imidazo[1,2-a]pyridine-2-carboxamide intermediates is reported through known Strecker–Ugi type multicomponent reactions, Tschitschibabin type condensations, and further synthetic sequences. The derivatives were then efficiently converted to novel 4-chloro-2-(trifluoromethyl)pyrido[1,2-e]purines by their original reactions with 2,2,2-trifluoroacetamide, followed by subsequent dehydroxychlorination reactions. These compounds were cross-coupled under microwave irradiation through SuzukiMiyaura and Sonogashira palladium(0) catalysis to various aromatic and alkynyl reagents, thus providing the related C-4 substituted pyrido[1,2-e]purines of biological interest in good yields.

Full text of DOI:10.1002/ejoc.201900921

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A Journal of
Accepted Article
Title: Microwave-Assisted Suzuki‒Miyaura and Sonogashira Coupling
of 4-Chloro-2-(trifluoromethyl)pyrido[1,2-e]purine Derivatives
Authors: Zahira Tber, Nicolas G. Biteau, Luigi Agrofoglio, Julien
Cros, Stéphane Goffinont, Bertrand Castaing, Cyril Michel
NICOLAS, and Vincent Roy
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900921
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900921
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Microwave-Assisted Suzuki‒Miyaura and Sonogashira Coupling
of 4-Chloro-2-(trifluoromethyl)pyrido[1,2-e]purine Derivatives
Zahira Tber,[a] Nicolas G. Biteau,[a] Luigi Agrofoglio,*[a] Julien Cros,[b] Stéphane Goffinont,[b] Bertrand
Castaing,[b] Cyril Nicolas,[a] and Vincent Roy*[a]
Abstract: The convenient preparation of three imidazo[1,2-
a]pyridine-2-carboxamide intermediates is reported through known
Strecker‒Ugi type multicomponent reactions, Tschitschibabin type
condensations and further synthetic sequences. The derivatives were
chemical biology, as many polycyclic nucleosides are
fluorescent.[6] Moreover, important activities have been
emphasized, such as antihypertension,[7] anti-inflammatory,[5a]
human A3 adenosine receptor antagonism,[5b‒e,8] and inhibition of
PDE1/5 and tyrosine kinase EphB4.[9,5f]
Pyrido[1,2-e]purines of type 1 have hence recently gained
attention in this direction. The new chemical entities have been
shown to behave as powerful PDE5 inhibitors,[9b-d] of which some
had a better selectivity over PDE6 and PDE1 than sildenafil,[9b]
anticancer agents able to induce apoptosis of certain cancer cell
lines or intercalating drugs to fit between base pairs of
oligodeoxynucleotides.[5g,10]
then
(trifluoromethyl)pyrido[1,2-e]purines by way of their original reactions
with 2,2,2-trifluoroacetamide, followed by subsequent
efficiently
converted
to
novel
4-chloro-2-
dehydroxychlorination reactions. These compounds were cross-
coupled under microwave irradiation through Suzuki‒Miyaura and
Sonogashira palladium(0) catalysis to various aromatic and alkynyl
reagents, thus providing the related C-4 substituted pyrido[1,2-
e]purines of biological interest in good yields.
Introduction
Purines are essential ubiquitous heterocyclic aromatic
compounds that consist of a pyrimidine molecule fused to an
imidazole ring. They are the most abundant nitrogen-containing
heterocycles in nature,[1] and accordingly exhibit crucial roles.
They display wide range of biological activities in various cellular
processes involving DNA and RNA, ATP, GTP, cyclic AMP,
NADH, and coenzyme A.[1-2]
Since the early 1900’s,[3] the purine class of compounds have
therefore spurred curiosity from the medicinal and organic
synthetic chemistry community in generating analogs of variously
substituted (heterocyclic) purines of biological interest.[4]
Noteworthy, for some specific pharmacological activities,
purine derivatives have been found to be less potent, while their
surrogates with an additional fused ring motif have been shown to
possess
better
pharmacokinetic
profiles,
enhanced
pharmacological activities and significant physicochemical
properties.[5] The fused and extended imidazopyridines and their
related compounds may indeed serve as valuable tools in
Figure 1. Synthetic routes to pyrido[1,2-e]purines.
As illustrated in Figure 1, the classical methods for the
preparation of pyrido[1,2-e]purines commonly involve the
formation of a suitably functionalized imidazo[1,2-a]pyridine
system 2 (R2 = NO, NO2, NH2; R3 = C≡N, CO2R, CONH2),[11]
followed by construction of the C2‒C3 annulated pyrimidine ring
(path a).[5g,9b,10b,12] Various chemical approaches have been used
in this respect, to give 2 in moderate to good yields, from
[a]
[b]
Zahira Tber, Nicolas G. Biteau, Dr. Cyril Nicolas, Dr. Vincent Roy,
Prof. Dr. Luigi Agrofoglio,
Institut de Chimie Organique et Analytique,
UMR CNRS 7311, Université d’Orléans,
Rue de Chartres - BP 6759, 45067 Orléans cedex 2, France.
vincent.roy@univ-orleans.fr and luigi.agrofoglio@univ-orleans.fr
http://www.icoa.fr/fr/agrofoglio
Julien Cros, Stéphane Goffinont, Dr. Bertrand Castaing,
Centre de Biophysique Moléculaire,
UPR CNRS 4301,
substituted
2-aminopyridines
and
Tschitschibabin
type cascade
condensations,[9b,13]
or
Strecker‒Ugi
reactions.[5g,12a] Ehrlich-Sachs type cyclizations of 2-
nitrosopyridines were also used, albeit with much lower
efficiencies.[10b,12b,14] The imidazo[1,2-a]pyridine derivatives 2
could then be reacted with guanidine, formamide, acetamidine
Rue Charles Sadron, 45072 Orléans, France.
Supporting information for this article is given via a link at the end of
the document.
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acetate, triethyl orthoformate, ammonium formate, or acyl
chloride reagents to give, after few other reactions, the expected
pyrido[1,2-e]purines of type 1.
Herein, we thus report our studies concerning the
straightforward and efficient preparation of such compounds (i.e.,
A).
As miscellaneous, compounds 1 may also be readily available
through few synthetic sequences and (i) ring-closing metathesis
of 8,9-diallyl-6-chloro-purine 3 (path b),[10g] (ii) silver-catalyzed
intramolecular hydroamination of terminal alkynes of type 4 (path
c),[15] (iii) double C‒H arylations of 9-phenylpurines 5, or (iv)
consecutive Suzuki-Miyaura and direct C‒H arylation of 9-(2-
bromophenyl)purines 6 (path b).[16] Intramolecular cyclization
Results and Discussion
Synthesis
reactions
of
1,3-bis(4-methoxybenzyl)-5-(pyridin-2-
ylamino)pyrimidine-2,4(1H,3H)-diones 7 could be performed
otherwise (path d).[17]
Worth noting, oxidatively damaged DNA, which result from the
attack of sugar and base moieties by reactive oxygen species
(ROS) are formed as byproducts of normal cell metabolism and
during exposure to endogenous or exogenous chemical or
physical agents. Guanine, having the lowest redox potential, is
the DNA base the most susceptible to oxidation, yielding
mutagenic 8-oxo-7,8-dihydroguanine (8-oxoG). In eukaryotic cells,
8-oxoG is primarily repaired by the base excision repair pathway
(BER) initiated by the DNA N-glycosylase hOGG1.[18] Human
molecular and epidemiological studies have shown that hOGG1
can affect significantly cancer proliferation and other diseases
development, such as Neurodegenerative diseases (NDD).[19,20]
hOGG1 is therefore considered as a pertinent pharmalogical
target.[20,21]
Along our ongoing research program directed at generating
small molecule modulators of hOGG1, we were interested in the
synthesis of pyrido[1,2-e]purine scaffolds that would feature a CF3
substituent at C-2 and an aromatic functional group at C-4 that
would possibly be connected via a rigid carbon‒carbon (Csp2‒
Csp) bond. Surprisingly, there is no example of such derivatives
in the literature so far.
Figure 2. Retrosynthetic planning.
As depicted here above (Figure 2), our retrosynthetic planning
for the making of compounds A follows path a (e.g., Fig. 1). It
requires novel 4-chloro-2-(trifluoromethyl)pyrido[1,2-e]purines B
that would be derivatized through Pd-catalyzed cross-coupling
chemistry. The synthesis of B would in turn, be achieved through
dehydroxychlorination
of
hitherto
unknown
2-
(trifluoromethyl)pyrido[1,2-e]purin-4-ol derivatives C, obtained
from the original reactions of imidazo[1,2-a]pyridine-2-
carboxamides D and 2,2,2-trifluoroacetamide (CF3(CO)NH2).
Carboxamides D would be readily prepared, using known reaction
sequences from commercial heterocyclic 2-amidines E.[9,12a]
Scheme 1. Synthesis of 4-chloro-2-(trifluoromethyl)pyrido[1,2-e]purine derivatives 17a‒17c.
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A set of aminoimidazo[1,2-a]pyridine-2-carboxamides 8a‒8c
(R1 = H (a), 4-Me (b), 5-Me (c)) were thus generated as model
substrates (Scheme 1). Following a desilylative Strecker‒Ugi type
multicomponent reaction, the 2-aminopyridine 9a was reacted
with ethylglyoxalate 10 in the presence of TMSCN and 1,4-
diazabicyclo[2.2.2]octane (DABCO) under microwave irradiation
(120 °C) to give 11a in moderate yield (60%).[5g,12a] 8a was
afforded by subsequent reaction with aqueous ammonia at 70 °C
for 48 h (81%). Compounds 8b and 8c were prepared otherwise
according to a Tschitschibabin type condensation protocol.[9b]
Aminopyridines 9b and 9c were therefore converted into
imidazo[1,2-a]pyridine-2-carboxylates 12b (50%) and 12c (60%)
respectively, by refluxing in EtOH (route a) or MeOH (route b) with
ethyl bromopyruvate 13. The regioselective nitrations (e.g.,
H2SO4/HNO3) of 12b‒c were then performed at 0 °C to provide
the mono-nitro products 14b‒c in good yields (81 vs. 70%). Next,
the nitroesters 14b‒c were stirred in a mixture of aqueous
ammonia and THF at room temperature, to provide nitroamides
15b‒c in excellent yields (90 and 91%). Reductions of 15b‒c to
the corresponding aminoamides 8b‒c were achieved by catalytic
hydrogenation (10% Pd‒C, rt, route c), or treatment with Tin(II)
chloride in EtOH at 100 °C under μW irradiation (route d).[9b] From
the pyridine-carboxamide intermediates 8a‒8c, annulation and
chlorination reactions were then carried out by heating at 160 °C
with CF3(CO)NH2 used as solvent (24 h) and treatment with an
excess of SOCl2 under reflux (1.5 h). The 2-
(trifluoromethyl)pyrido[1,2-e]purin-4-ol derivatives 16a‒16c (58-
73%) and 4-chloro-2-(trifluoromethyl)pyrido[1,2-e]purines 17a‒
17c were obtained in moderate to good yields (i.e., 60-77%).
With compounds 17a‒17c in hands, we decided to investigate
further post-modification of the pyrimidine substitution pattern.
Easy post-decoration of 4-chloro-pyrido[1,2-e]purines through
nucleophilic substitutions with (aryl)- amines, alcohols and thiol
reagents has already been described;[5g,12a] but to the best of our
knowledge, there is no mention of their transition-metal catalyzed
cross-coupling reactions with C-Nu.
The Suzuki−Miyaura reaction is a cornerstone of modern
organic synthesis. Unlike many cross-coupling strategies, it is a
routine, versatile and benign reaction that is cost-effective,
scalable and maybe amenable to green chemistry principles and
industrial standards.[22] It was successfully applied to many
different coupling partners, including nitrogen-containing
heterocycles using catalytic amount of palladium(II) acetate (0.1
eq.), Xantphos (0.2 eq.) as ligand and potassium carbonate (2
equiv.) as base in toluene at elevated temperature. In addition,
conventional thermal heating could be replaced by microwave
irradiation in a sealed reactor with major improvement in terms of
yields and reaction times.[23] These conditions were thus tested
with p-tolylboronic acid and chloropurine 17a as model substrate
to give 18a in good yield (85%) after 50 min of reaction at 100 °C
(Table 1, entry 1). Triphenyl phosphine, and BINAP,[24] together
with Xantphos,[25] have become the most often used ligands for
palladium-catalyzed carbon‒carbon and the more challenging
carbon‒nitrogen bond-forming reactions.[26,27] Thus, subsequent
cross-coupling reactions were next conducted with PPh3 and
BINAP, but a disappointing yield decrease was noticed (entries 2-
tetrakis(triphenylphosphine)palladium(0) through insertion of
Pd(OAc)2 and PPh3 (entry 2) vs. direct addition of Pd(PPh3)4
(entry 4) did not produce any variation of the reaction yield (ca.
80%). When the influence of the solvent was assessed (H2O,
H2O/DME, 1,4-dioxane), slight to dramatic decrease of the
catalytic efficiency was noted (entries 5-7). It was also the case
when Cs2CO3 was replaced by K2CO3 as base (entry 8). Finally,
reaction temperature was increased to 120 °C to give a
satisfactory 84% yield after a period of reaction of 30 min (entry
9). Interestingly, there was no cross-coupling reaction without a
catalyst (entry 10), which excludes an addition/elimination
pathway.
Table 1. Optimization of the conditions for the Suzuki‒Miyaura coupling
reaction of p-tolylboronic acid and compound 17a.[a]
Entry
Catalyst
Ligand
Solvent
Yield (%)
of 18a
1
2
3
4
5
6
7
8
9
10
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Xantphos
PPh3
toluene
toluene
toluene
toluene
H2O
85
80
BINAP
‒
60
79
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
‒
50
H2O/DME
1,4-dioxane
toluene
toluene
toluene
40
70
77[b]
84[c]
traces
[a] Typical reaction conditions: Ar atmosphere, compound 17a (1 eq.), p-
tolylboronic acid (1.5 eq.), K2CO3 (2 eq.) as base, catalyst (0.1 eq.),
additional ligand (0.2 eq.), heating at 100 °C under microwave irradiation for
50 min in a sealed reactor. [b] Cs2CO3 (2 eq.) instead of K2CO3 (2 eq.) were
added. [c] Heating was performed at 120 °C for 30 min.
The scope of the reaction was then explored using various
organoboronic acids under the optimized aforementioned
conditions (entry 9). As depicted in Scheme 2, yields obtained
were good for most products (e.g., 65-85%). It is worth noting that
a better reactivity was observed for boronic acids substituted with
a methyl or an electron-withdrawing group. The outcomes were
also indicative of the influence of the substituent position on the
reactivity of the boronic acid. Comparing the same moiety, the p-
3).
Of
note,
in
situ
generation
of
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