Cu-Catalyzed C-H Activation Reaction: One-Pot Direct Synthesis of Xanthine and Uric Acid Derivatives from 5-Bromouracil

Article abstract of DOI:10.1055/a-1542-9683

A one-pot direct synthesis of xanthine and uric acid derivates is reported. This simple yet efficient methodology illustrates concurrent formation of two C-N bonds using CuBr ₂as catalyst and one of those C-N bonds is formed by uracil C6-H bond activation.

Full text of DOI:10.1055/a-1542-9683

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, A–E
letter
A
en
S. Hazra et al.
Letter
Synlett
Cu-Catalyzed C–H Activation Reaction: One-Pot Direct Synthesis
of Xanthine and Uric Acid Derivatives from 5-Bromouracil
Somjit Hazraa
Biplab Mondala
Brindaban Roy*a
Habibur Rahaman*b
R3 NH
O
O
O
O
R1
O
R1
O
R1
O
Br
N
N
i)
i)
N
N
N
NH2·HCl
N
N
H
H
R3
N
O
CuBr2 (20 mol%)
DMEDA (20 mol%)
toluene, 110 °C
36 h
N
H
N
R2
N
R2
CuBr2 (20 mol%)
N
R2
DMEDA (20 mol%)
toluene, 110 °C
36–40 h
xanthine derivatives
uric acid derivatives
2 examples
a Department of Chemistry, University of Kalyani, Kalyani,
Nadia, West Bengal, India
7 examples
broybsku@gmail.com
broybs@rediffmail.com
b Department of Chemistry, Ranaghat College, Ranaghat,
Nadia, West Bengal, 741201, India
hr1977@gmail.com
BHDeMreaipbnaaidiCblraoutbhbmrrraro1Reeny9nasbR7phtso7oao@k@ymnfurdgC@eaimhdnngeigamfmfiAmla.icuisalot.icrhmlyo.oc,mroRUsmannivaegrhsaityCoofllKegaley,aRnain, Kagahlyaatn, Ni, aNdaida,iaW, WesetsBteBnegnagl,aIln, Idnidaia
Received: 25.05.2021
Accepted after revision: 02.07.2021
Published online: 02.07.2021
caffeine, 1,3,7-trimethylxanthine, on the other hand, is the
most frequently used psycho stimulant drug worldwide.14
Caffeine is central nervous system and metabolic stimu-
lant7 and it has huge positive15 effects on human body. It
decreases the risk of cardiovascular disease and type 2 dia-
betes.15c Crude caffeine has potent hydrophilic antioxidant
activity (145 mol Trolox equivalent TE/g) and lipophilic
antioxidant activity (66 mol TE/g). It also inhibits cycloox-
ygenase-2 with a higher potency (IC50, 20 lg/mL) in com-
parison to aspirin (IC50, 190 lg/mL). It also increases glu-
cose uptake 1.45-fold in cultured human skeletal muscle
cells and 2.20-fold in adipocytes.16 So far as the side effect is
concerned, the excess use of it may increase the chance of
bladder cancer.17 Previously, xanthine derivatives were pre-
pared from uracil in mainly three ways. The first method
involves multiple steps, from 5,6-disubstituted uracil and
amidines,18a in the second method 5,6-diaminouracil was
microwave irradiated with triethyl orthoformate (not
shown here),18b and the third way involves treating sodium
azide with 5-halo-6-substituted uracil (Scheme 1).19
DOI: 10.1055/a-1542-9683; Art ID: st-2021-b0203-l
Abstract A one-pot direct synthesis of xanthine and uric acid deri-
vates is reported. This simple yet efficient methodology illustrates con-
current formation of two C–N bonds using CuBr2 as catalyst and one of
those C–N bonds is formed by uracil C6–H bond activation.
Key words C–H activation, C–N bond formation, xanthine, uric acids,
copper, one-pot cyclization
Metal-catalyzed C–N bond formation is a topic of ex-
treme importance to the synthetic chemists1 and much at-
tention has been given in developing newer methods. The
bulk share of focus was deployed for the development of
Ullmann N-arylations2 and the palladium-catalyzed amina-
tion of aryl halides, pioneered by the laboratories of
Buchwald and Hartwig.3 Very recently a surge of interest
has been poured in developing methods for constructing C–
N bonds by direct aromatic C–H functionalization. Most of
these reactions utilize Pd(II) as catalysts.4 In this context we
have also developed a Pd/Cu co-catalytic system for indole
C2–H bond functionalization.5 In 2008, Buchwald and co-
workers reported a novel method in their effort to synthe-
size benzimidazoles from amidines by Cu(II)-catalyzed in-
tramolecular C–H activation reaction.6
O
O
O
N
O
N
N
nBu
O
N
N
N
N
O
Substituted xanthine derivatives are well-known for
their pharmacological activities,7 as adenosine receptor an-
tagonists, inducers of histone deacetylase, phosphodiester-
ase inhibitors, etc. For example, denbufylline and pentoxi-
fylline are potent phosphodiesterase inhibitors (Figure 1).8–
N
nBu
Denbufylline
Pentoxifylline
O
N
OH
O
N
O
N
H
N
N
N
N
N
N
N
N
O
N
O
O
10
Whereas theophylline and 1,3-dimethylxanthine, which
naturally occur, are extensively utilized as an antiasthmatic
drug,11,12 lisofylline, another xanthine derivative, is an ex-
perimental anti-inflammatory drug.13 The plant alkaloid
Lisofylline
Caffeine
Theophylline
Figure 1 Xanthine drugs
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Hazra et al.
Letter
Synlett
At the outset, we treated 5-bromouracil with acetami-
dine under various metal-free conditions (explorations
were done with the amount of amidine, temperature, sol-
vent, and introduction of base, not shown in Table 1), but
failed to obtain the amidinated product.
O
O
O
R1
O
R1
N
Br
R1
NaN3
DMF
N
X
+
O
H2N
HN
N
2 steps
N
R3
R3
HN
N
R2
O
N
R2
N
H
O
N
R2
R3
Scheme 1 Previous synthesis of xanthine derivative
As there are a number of methods available for similar
amination or amidination reactions where copper21,22 or
palladium23 were used as catalysts, so we first attempted
the amidination reaction of 5-bromouracil with Pd2(dba)3
catalysts. We noticed that it resulted in complete debromi-
nation when polar solvents like DMAc or dioxane were used
(Table 1, entries 2, 4) and in nonpolar solvent (o-xylene) 5-
bromouracil (2a) remained intact. Changing the base also
did not alter the course of the reaction (Table 1, entries 1,
3). We then started exploring the amidination reaction
with copper salts. Interestingly, when CuI (10 mol%) was
used in the presence of K2CO3 and DMEDA (10 mol%, ligand)
in toluene at 110 °C, it gave the xanthine derivative 3a along
with some debrominated product and not the amidinated
product. This exciting result prompted us to explore further
We envisioned that if we would manage to activate the
uracil C6–H bond20 to form a C–N bond, a possible discon-
nection could be hypothesized which would bring high de-
gree of variability into the core structure of xanthine deriv-
atives. Our goal was to carry out an amidination reaction on
5-halouracil with amidine and then to explore the amidi-
nated product for a C–H activation study (Scheme 2).
O
O
R1
O
R1
O
N
X
H2N
HN
N
N
R3
+
R3
N
H
N
R2
N
R2
Scheme 2 Our disconnection strategy at the ring fusion
Table 1 Optimization of Amidination and C–H Activation Reactiona
O
O
Br
N
N
HCl·H2N
HN
N
+
N
36 h
O
N
O
N
H
2a
1
3a
Entry
Cat
(mol%)
Additive/base
Temp (°C)
Solvent
Yield (%)b
Conv. (%)
1
2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
CuI
Cs2CO3, Xanthphos
Cs2CO3, Xanthphos
Nat-BuO
110
100
110
110
110
110
110
110
110
110
110
110
110
100
110–130
110
110
140
o-xylene
dioxane
o-xylene
DMAc
N.R.
0
100
0
debromination
3
N.R.
4
Nat-BuO
debromination
100
80
50
60
65
100
72
65
60
15
21
80
70
62
90
5
K2CO3, DMEDA
K2CO3, DMEDA
K2CO3, DMEDA
K2CO3, DMEDA
Cs2CO3, DMEDA
Cs2CO3, DMEDA
KOAc, DMEDA
K3PO4, DMEDA
Cs2CO3, DMEDA
Cs2CO3, DMEDA
Cs2CO3, DMEDA
Cs2CO3, L-proline
Cs2CO3, 1,10-phen
Cs2CO3, DMEDA
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
40
6
CuBr
10
7
CuCl2
20
8
CuBr2
66
9
CuBr2
debromination
10
11
12
13
14
15
16
17
18
CuBr2
82c
20
14
–
CuBr2
CuBr2
CuBr2
CuBr2
dioxane
o-xylene
toluene
toluene
toluene
–
CuBr2
10
25
22
36
CuBr2
CuBr2
CuBr2
a Reaction conditions: 5-bromouracil (1 equiv), acetamidine hydrochloride (2 equiv), Cs2CO3 (3 equiv), CuBr2 (20 mol%), DMEDA (20 mol%).
b Yields were calculated after flash chromatography.
c Reaction performed in sealed tube; N.R. = no reaction.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

C
S. Hazra et al.
Letter
Synlett
for the preparation of xanthine derivatives in one pot. We
noticed that the reaction under inert atmosphere (after de-
gassing the reaction mixture) produced greater amount of
the desired product and suppressed the formation of debro-
minated product to a large extent. However, the reaction
was sluggish in nature. An increase in catalyst and ligand
loading to 20 mol% resulted in a better yield of the product
3a (40%, 36 h, Table 1, entry 5). CuBr did not respond very
well in the desired transformation as it gave mostly the de-
brominated uracil along with the product (10%, Table 1, en-
try 6). Then we tried other Cu(II) salts for the transforma-
tion. The use of Cu(OAc)2 was not fruitful as it resulted in
the debromination of the substrate (Table 1, entry 9). CuCl2
yielded the product (20%) along with some debrominated
product (Table 1, entry 7), but CuBr2 was found to be more
effective as the yield increased to 66% (conversion 65%) and
very small amount of debrominated product was formed
(Table 1, entry 8). Then we explored further with CuBr2
salts under different conditions. The roles of other bases
were screened. Eventually a better yield (82%) was observed
(Table 1, entry 10) with Cs2CO3 (conversion 72%), but the
formation of debrominated product could not be avoided
entirely. Other bases like KOAc and K3PO4 were found to be
less useful (Table 1, entries 11, 12). We then changed the
solvent system and the polar solvents behaved very poorly
in this reaction. In DMF and dioxane, neither the debromi-
nated product nor the xanthine product was formed. Most
of the starting materials remained intact while some of it
got decomposed (Table 1, entries 13, 14). In o-xylene, the
reaction was carried out in 110 °C at first for 24 h and then
the temperature was increased to 130 °C. The yield was dis-
appointing (10%) resulting mainly in the debrominated
product. The optimization of ligands ensured that DMEDA
is by far the most effective compared to L-proline or 1,10-
phenanthroline (Table 1, entries 16, 17). We then carried
out the reaction in sealed tube at 140 °C, but the yield was
moderate and the amount of debrominated product was
also greater, if compared to entry 10 (Table 1, entry 18).
With the optimized reaction conditions24 in hand, we
explored the substrate scope of the reaction. The yield of
the reaction was moderately good with various uracil sub-
strates (66–82%) depicted in Table 2. One major setback was
the debrominated product, as we could not stop its forma-
tion entirely, and another was the moderate conversion of
the substrate in spite of carrying out the reaction for longer
periods of time (36 h). However, when we ran the reaction
with a mixture of 2e and 2e′ (1:1), where the n-Bu and Et
groups were exchanged on uracil N-atoms, we isolated the
corresponding products in a 3:2 ratio (in favor of 2e′), as a
mixture in a combined yield of 66%.
Table 2 Synthesis of Xanthine Derivatives
O
O
Cl
R1
R1
O
X
H3N
HN
N
N
N
R3
R3
+
N
O
N
N
R2
3a–g
H
36 h
R2
2
1
Product 3
R1
R2
Me
R3
Yield (%)
3a
Me
Me
82
81
77
68
66
75
82
3b
Et
Et
Et
Me
Et
Me
Me
Me
Me
Ph
3c
3d
n-Pr
3e/3e′
3f
n-Bu/Et
Me Me
Et Et
3g
Ph
be a good substrate for this reaction, but under the set of
our reaction conditions only the deiodination product was
obtained. 5-Fluorouracil was also employed as a substrate
for the reaction, but it failed to deliver the corresponding
product owing to its poor leaving-group capacity.
We then wanted to explore the same methodology for
the formation of uric acid derivatives, and we successfully
synthesized two uric acid derivatives 4 with N,N-dimethy-
lurea. The reaction was found to be a little bit sluggish com-
pared to acetamidine analogues. The amount of debromi-
nated product was slightly greater (conversion around 70%).
The yields of the products were 65% and 56%, respectively
(Table 3).
Table 3 Synthesis of Uric Acid Derivativesa
O
O
R1
O
X
R1
O
N
N
HN
HN
N
N
O
+
O
N
N
R2
R2
Entry Starting material 2 Product 4
Time (h) Yield (%)b
O
O
Br
N
N
N
N
1
2
36
40
65
56
O
2a
O
N
O
N
4a
O
O
Br
2b
Et
Et
N
N
N
O
N
O
N
O
N
Therefore, we assume a steric effect operates and pro-
duces the 3e′ as the major product (Table 2, 3e/3e′). We also
found that the benzamidine took part in this reaction effi-
ciently (Table 2, 3f and 3g). The 5-iodouracil is believed to
4b
a Reaction conditions: 5-bromouracil (1 equiv), N,N-dimethylurea (2 equiv),
Cs2CO3 (3 equiv), CuBr2 (20 mol%), DMEDA (20 mol%) refluxed in toluene at
110 °C.
b Yields were calculated after flash chromatography.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

D
S. Hazra et al.
Letter
Synlett
O
H
N
R1
O
N
N
N
NH
R2
Br
Br
Ln
Ln
3
II
Cu I
Cu 0
NH2
Cu
1
by N-nucleophile
reductive
elimination
O
H
N
R1
O
NH
NH
N
N
Ln
Ln
N
R2
O
Cu
O
Cu
H
R2
R1
O
Ln
5
R1
O
N
Ln
10
N
N
Br
N
Nh
NH
N
R2
III
Cu
conversion of
CuII into CuI
8
Ln
N
H
– HBr
C–H activation
7
Br
Ln
Br
Br
II
O
oxidative
addition
NH
NH
H
N
Cu
R1
N
Ln
Ln
I
N
by N-nucleophile
Cu
O
O
N
R2 Br
H
6
R1
O
Br
Cu
N
Ln
9
Ln
N
R2
2
Scheme 3 Proposed mechanism of the reaction
Under metal-free conditions 5-bromouracil did not re-
act at all, and in the presence of Pd salts debromination was
observed. The mechanistic pathway of copper-mediated
coupling reaction has been extensively studied by Yu Lan
and his group.25 In a recent study, they have shown that the
CuII species can be generated from CuI by radical-type reac-
tion or single-electron transfer (SET) oxidation and it can
also be oxidized to CuIII species by SET or using a nucleop-
Conflict of Interest
The authors declare no conflict of interest.
Funding Information
We thank the Department of Science and Technology, Ministry of Sci-
ence and Technology, India (DST, New Delhi) for financial assistance
through DST PURSE program and DST fast track scheme. Two of us
(SH & BM) are thankful to CSIR (New Delhi) and University of Kalyani,
hilic radical.25 Based on the literature precedents21,22,25,26
a
hypothesized mechanism of this reaction is depicted in
Scheme 3.
respectively, for research fellowships.
D
epartme
n
t
o
f
S
ciencean
d
T
e
ch
n
o
lo
g
y
, Ministry
o
f
Science
a
n
d
T
e
ch
n
o
lo
g
y
, In
d
ia
C
o
u
nci
l
o
f
Scie
n
tific
a
n
dI
n
d
ustrial
R
esearch, In
d
i
aU
n
iversiyt
o
f
K
al
y
an
i
The acetamidine 1 reacts with CuII to form the adduct 5
which subsequently produces the intermediate 6. The oxi-
dative addition of 6 to the uracil 2 provides intermediate 7.
The reductive elimination of 7 generates compound 8 and
CuI species. The CuI on further oxidation produces CuII spe-
cies in the cycle. In compound 8 where nitrogen acts as a
nucleophile reacted with CuII and produces intermediate 9
in which a suitable C–H bond is present for activation. The
C6–H bond of uracil gets activated and a new Cu–C bond is
formed as shown in the intermediate 10. Further, the reduc-
tive elimination of 10 produces the desired compound 3.
In conclusion, we have developed a very important
method for the synthesis of xanthine and uric acid deriva-
tives by Cu-catalyzed C–H activation reaction. Though the
reaction is sluggish in nature, the one-pot convergence of
two components uracil and amidine or N,N-dimethylurea,
makes it a very unique and interesting reaction. It leads to
the simultaneous formation of two C–N bonds without pre-
activating uracil C6–H bond. Considering the one-pot na-
ture of the reaction, the yield of the reaction is undoubtedly
very good.
Acknowledgment
We thank the DST (New Delhi) for providing FT-IR, NMR spectrometer
(400 MHz) and CHN analyzer.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1542-9683. Su
p
p
orti
n
gInformatio
n
Su
p
p
ortingInformatio
n
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To an oven-dried 25 mL round-bottom flask was added 5-bro-
mouracil (1 mmol), acetamidine or benzamidine hydrochloride
(1.4 mmol), CuBr2 (0.2 mmol), and Cs2CO3 (3 equiv) under nitro-
gen. Dry toluene (2 mL) was added with a syringe, and the
mixture was degassed for 30 min. Then DMEDA (20 mol%) was
added via a syringe under nitrogen. After the resulting reaction
mixture was stirred for 36 h, the product was extracted with
ethyl acetate and washed with water three times. The organic
layer was dried over anhydrous Na2SO4 and filtered. Following
concentration under reduced pressure, the residue was purified
by silica gel chromatography to elute the product.
1,3,8-Trimethyl-1H-purine-2,6(3H,9H)-dione (3a)
Yield 82%; mp >225 °C. IR (neat): 1644, 1709, 2965, 3049, 3105,
3158 cm–1 1H NMR (CDCl3, 400 MHz):  = 2.59 (s, 3 H, CCH3),
.
3.47 (s, 3 H, NCH3), 3.62 (s, 3 H, NCH3), 12.16 (s, 1 H, NH). 13C
NMR (CDCl3, 100 MHz):  = 14.7, 28.3, 30.2, 106.6, 149.6, 151.5,
152.0, 155.8. HRMS (TOF, MS, ES+): m/z calcd for C8H10N4O2H
[M+ + H]: 195.0882; found: 195.0874.
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