Exploration of polystyrene-supported 2-isobutoxy-1-isobutoxycarbonyl-1,2- dihydroquinoline (PS-IIDQ) as new coupling agent for the synthesis of 8-substituted xanthine derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.04.135

Polystyrene-supported 2-isobutoxy-1-isobutoxycarbonyl-1,2-dihydroquinoline (PS-IIDQ), a polymer supported covalent coupling reagent, was successfully employed for the first time in the synthesis of 8-substituted xanthine derivatives. PS-IIDQ was observed

Full text of DOI:10.1016/j.tetlet.2012.04.135

Tetrahedron Letters 53 (2012) 4631–4635
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Exploration of polystyrene-supported
2-isobutoxy-1-isobutoxycarbonyl-1,2-dihydroquinoline (PS-IIDQ) as new
coupling agent for the synthesis of 8-substituted xanthine derivatives
Prabal Bandyopadhyay a, Manisha Sathe a, Pratibha Sharma b, M.P. Kaushik a,
⇑
a Process Technology Development Division, Defence R&D Establishment, Jhansi Road, Gwalior 474 002, MP, India
b School of Chemical Sciences, Devi Ahilya University, Khandwa Road, Indore 452 001, MP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Polystyrene-supported 2-isobutoxy-1-isobutoxycarbonyl-1,2-dihydroquinoline (PS-IIDQ),
a polymer
Received 31 March 2012
Revised 28 April 2012
Accepted 29 April 2012
Available online 3 May 2012
supported covalent coupling reagent, was successfully employed for the first time in the synthesis of
8-substituted xanthine derivatives. PS-IIDQ was observed to be more efficient than IIDQ and polymer-
supported carbodiimide (PS-EDC).
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Purine
PS-IIDQ
Adenosine receptor antagonist
Coupling agent
Polymer support
Poly-substituted xanthine (purine-2,6-dione) derivatives are
one of the most important chemical classes of adenosine receptor
(AdoR) antagonists.1a Potent and selective AdoR antagonists dis-
play therapeutic potential as kidney protective (A1), antifibrotic
(A2A), neuroprotective, antiasthmatic (A2B), and antiglaucoma (A3)
agents.1 To elicit high affinity toward AdoRs, adenosine receptor
carboxylic acid 20, exploiting route 2. Conventionally, the first step
involves the formation of 1,3-dialkyl-6-amino-5-carboxamidoura-
cil (acylated) intermediate 30 in the presence of l-ethyl-3-[3-
(dimethylamino)propyl]carbodiimide hydrochloride (EDACꢀHCl)4
or diisopropylcarbodiimide (DIC)4a,5 as coupling agent at room
temperature for several hours. However, none of the reagents
reported so far can lead to the target compound with good conver-
sion and most of them suffer from several bottlenecks, viz., use of
unstable coupling agents, necessity of pre-activation step i.e. the
carboxylic acid has to be added to the coupling reagent prior to
antagonists should be a flat, aromatic,
p-electron rich, nitrogen-
containing heterocycle.2 Development of new approaches for their
syntheses, employing efficient and economical routes, is thus a
fascinating area of current research.
A number of synthetic routes have been reported for the synthe-
sis of 8-substituted xanthine derivatives. The annulation strategies
explored for the construction of xanthine nucleus 4, involves the
treatment of 5,6-diaminouracil 1 either with aldehyde 2 (route 1)
or with carboxylic acid 20 (route 2) via the intramolecular ring clo-
sure of the 6-amino-5-iminouracil intermediate 33 under oxidative
reaction conditionsor by disconnection ofthe corresponding amino-
acylaminouracil intermediate 30 (Scheme 1), respectively.
Recently we have developed a rapid one-step protocol for the
synthesis of a variety of 8-substituted xanthines considering alde-
hyde route.3 Now we became interested in the prospect of devel-
oping a one-pot route to xanthines through a direct coupling
between the readily available 5,6-diaminouracils 1 and a pertinent
O
O
H
C
R1
O
N
R3
S
R3
H
O
C
N
l
o
2
2
n
r
l
o
i
,
t
F
a
e
s
n
o
C
e
N
NH2
d
3
n
]
1
o
[
O
]
C
e
R2
t
u
O
O
R
H
N
[
3
R1
O
NH2
NH2
R1
O
N
N
R3
R3
OH
N
N
R2
1
O
H
N
2'
n
O
C
R3
A
c
O
y
H
N
R2
l
a
t
i
o
R1
O
[
R
4
o
O
a
N
u
t
N
e
2
.
]
q
a
R
1 = R2 = Alkyl gr.
R3 = Aryl / Alkyl gr.
N
NH2
R2
3'
⇑
Corresponding author. Tel.: +91 751 2343972; fax: +91 751 2340042.
E-mail address: mpkaushik@rediffmail.com (M.P. Kaushik).
Scheme 1. Pathways for synthesis of 8-substituted xanthines through aldehyde
(route 1) or carboxylic acid (route 2) routes.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.135

4632
P. Bandyopadhyay et al. / Tetrahedron Letters 53 (2012) 4631–4635
Table 1
Table 2
Effect of PS-IIDQ concentration for the synthesis of 6-amino-5-benzoxamido-1,3-
Comparison of coupling performance of PS-IIDQ with PS-EDC and IIDQ for the
dimethyluracil (3a)a
synthesis of 6-amino-5-benzoxamido-1,3-dimethyluracil (3a)a
Entry
PS-IIDQ concn (equiv)
Timeb (h)
Yieldc (%)
Sl. No.
Coupling agent
Yieldb (%)
Purityc
a
b
c
d
e
1
1.5
2
2.5
3
1
1
1
2
2
52
67
83
81
78
1.
2.
3.
PS-IIDQ
IIDQ
PS-EDC
83
81
49
100
84
81
a
Reaction condition: the mixture of 5,6-diamino-1,3-dimethyluracil (1 equiv,
1 mmol) and benzoic acid (1 equiv, 1 mmol) with 2 equiv of coupling agent was
stirred in CH3CN/H2O (9:1, v/v) (10 mL) at room temperature for 1 h.
a
Reaction condition: the mixture of 5,6-diamino-1,3-dimethyluracil (1 equiv,
1 mmol) and benzoic acid (1 equiv, 1 mmol) with different concentration (equiv) of
PS-IIDQ was stirred in CH3CN/H2O (9:1, v/v) (10 mL) at room temperature.
b
Isolated yield.
All the reactions monitored by TLC and HPLC.
c
b
All the reactions monitored by TLC.
Isolated yield.
c
uracil with various carboxylic acid derivatives.
A series of
substrates have been coupled and cyclized to afford the target het-
erocycles at moderate temperature with quantitative yields and
high purity.
the addition of the diamine, poor stability of the coupling agent in
the presence of a base, and most importantly, the formation of by-
products, and low yields.
In order to standardize the reaction conditions, the coupling
conditions for PS-IIDQ were first optimized by coupling 5,6-diami-
no-1,3-dimethyluracil with benzoic acid in different solvents. It
was found that 5,6-diamino-1,3-dimethyluracil, benzoic acid and
PS-IIDQ in 1:1:2 equiv ratios in acetonitrile gave better results.
To determine the optimal conditions for effective coupling, conju-
gates were prepared at five different equivalent ratios (1:1, 1:1.5,
1:2, 1:2.5, and 1:3) of starting materials and PS-IIDQ and it has
been found that only 2 equiv (Table 1, entry c) of PS-IIDQ was nec-
essary to ensure the high conversion for the formation of amide
bond (acylation).
The reaction conditions were further optimized to give better
result and it was found that the addition of a few drops of water
with acetonitrile increased the initial homogenity of the reaction
mixture which may cause better reactivity and yield. Further,
replacement of acetonitrile with other water miscible solvents
such as, methanol or ethanol did not succeed in giving good yields.
The best result was obtained from a mixture of acetonitrile and
water (9:1, v/v). The synthesis of 8-substituted xanthine12 deriva-
tives using PS-IIDQ is shown schematically in Scheme 2.
Synthesis of 8-substituted xanthine was carried out with both
PS-IIDQ and IIDQ under the optimized reaction conditions followed
by a quick aqueous work-up. The different amides were in most
cases obtained in acceptable yield and very high purity. It was no-
ticed that the results were better in terms of purity when PS-IIDQ
was used. This illustrates the advantage of PS-IIDQ over the classic
solution-phase reagent IIDQ, where an intensive work-up is neces-
sary to remove all the quinoline generated during the coupling. In
order to assess the coupling performance of PS-IIDQ compared to
existing supported carbodiimide approaches, specifically PS-EDC,
they were used separately as coupling reagents in the optimized
reaction conditions and PS-IIDQ was observed to be more efficient
than polymer-supported carbodiimides (PS-EDC) and gave better
yields and higher purity for amide bond formation (Table 2).
With the optimized reaction conditions in hand, the scope of
the protocol was further explored for the reaction of a variety of
substituted aryl carboxylic acids (Table 3). An excessive coupling
The second step of the reaction proceeds via intramolecular ring
closure reaction of intermediate 30 leading to the formation of xan-
thine nucleus using aqueous NaOH solution4,5 under reflux condi-
tion. Most recently, this step, was also studied by making use of
1,1,1,3,3,3-hexamethyldisilazane (HMDS) under conventional
heating6a as well as microwave6b conditions. However, very low
polarity of HMDS can cause solubility problems when polar com-
pounds are to be reacted. Also, high temperatures (>120 °C) and
long reaction times (from several hours to several days) are gener-
ally required, especially if uracil derivatives containing polar
groups are used as precursors.7,8 Therefore, as a consequence,
search for new methods/reagents to overcome these limitations
are still an important experimental challenge to organic chemists.
Over the past decade, interest in the development of new polymer-
supported reagents has increased,9 predominantly because these
reagents combine the traditional advantages of solution phase
chemistry with the convenience of solid-phase handling. Thus
using polymer-supported materials, unreacted reagents and by-
products remain on the resin and in turn can be easily removed
by filtration.
Recently, Bradley and Valeury reported10 polystyrene-sup-
ported
2-isobutoxy-1-isobutoxycarbonyl-1,2-dihydroquinoline
(PS-IIDQ) as an efficient coupling reagent that couples carboxylic
acids to amines to form amide bond in good yields and high purity.
Therefore, encouraged by its features and associated advantages,
including that it does not require any pre-activation, i.e. the order
of addition of the amine, acid, and IIDQ makes no difference to the
efficiency of coupling. Also the formation of volatile by-products
and high stability of IIDQ under general laboratory conditions
and its stability in the presence of base are the added advantages.
With these issues in mind a polymer-supported equivalent of IIDQ
was targeted. In continuation of our efforts in the field of new syn-
thetic methodologies for the synthesis of nitrogen heterocycles,11
and our recent report on the synthesis of 8-substituted xanthines,3
the objective of the present study is to demonstrate the application
of PS-IIDQ for the first time in the one-pot synthesis of 8-substi-
tuted xanthine derivatives by coupling 5,6-diamino-1,3-dimethyl-
O
O
N
O
C
O
N
O
N
O
N
H
N
O
O
H
N
NH2
NH2
R
O
N
aq. NaOH
N
(PS-IIDQ)
N
R
CH3CN
Reflux
R
OH CH3CN/ H2O (9:1)
r.t.
N
O
O
O
NH2
2'
1
3'
4
R = Aryl/ cycloaryl/ heteroaryl/ alkyl gr.
Scheme 2. PS-IIDQ mediated one-pot synthesis of 8-subtituted xanthines.

P. Bandyopadhyay et al. / Tetrahedron Letters 53 (2012) 4631–4635
4633
Table 3
PS-IIDQ mediated synthesis of 8-substituted xanthinesa
Entry
Acid (20)
OH
Product (4)
Timeb (h)
Yieldc (%)
O
H
N
N
O
a
3
78
71
74
76
64
68
70
67
N
O
O
O
O
O
O
O
O
O
N
O
OH
H
N
O
N
N
N
N
N
N
N
N
b
c
d
e
f
3.5
3
O
N
O
N
O
OH
H
N
O
N
N
O
OH
H
N
O
3
OH
N
N
HO
N
O
OH
H
N
O
4
N
N
N
O
O
Cl
H
N
Cl
OH
3
N
N
O
OH
H
N
O
g
h
3.5
3
Br
N
Br
F
N
O
O
F
H
N
OH
N
N
OH
O
H
N
O
i
j
3.5
3
65
71
Cl
N
N
O
Cl
Cl
OH
Cl
H
N
N
N
O
NO2
N
O
O
N
O
O2N
O
O
H
N
OH
OH
OH
k
l
4
3
3
73
72
79
N
O
N
O
OH
O
H
N
N
N
N
N
O
O
O
N
O
O
O
O
O
H
N
OH
OH
m
N
N
O
O
O
O
H
N
O
n
4
74
N
N
(continued on next page)

4634
P. Bandyopadhyay et al. / Tetrahedron Letters 53 (2012) 4631–4635
Table 3 (continued)
Entry
Acid (20)
Product (4)
Timeb (h)
Yieldc (%)
62
O
O
H
O
N
N
O
N
N
OH
o
p
q
4
O
O
N
O
O
HO
H
N
4.5
73
NH
N
N
O
N
H
O
H
N
N
N
OH
4.5
3
65
71
N
O
O
N
O
O
H
N
OH
r
N
N
a
Reaction conditions: (a) 5,6-diamino-1,3-dimethyluracil (1 equiv), carboxylic acid derivative (1 equiv), and PS-IIDQ (2 equiv) in CH3CN/H2O at rt, (b) 2.5 N aqueous NaOH
solution, CH3CN, reflux.
b
Total reaction time (step I + step II).
Isolated yield.
c
O
H
R
O
O
O
O
RCOO
HO
O
N
O
H
N
O
N
O
O
O
O
O
O
R
O
III
II
I
O
PS-IIDQ
N
O
O
O
R
O
O
IV
OH
O
O
N
O
O
H
N
O
N
N
H
N
OH
H2N
H2N
HO
N
R
R
H2O
N
N
N
OH
R
OH
H2N
CO2
N
O
H2N
O
N
O
H2N
O
V
VI
VII
VIII
O
O
H
N
H
N
H2O
N
R
N
R
HO
N
N
H
N
O
N
O
X
IX
OH
Scheme 3. Proposed mechanism for the PS-IIDQ mediated one-pot synthesis of 8-substituted xanthines.
time of 2 h was used in order to enable difficult substrates to react.
This contrasts with many coupling reagents, which although often
having a very high intrinsic reactivity are unstable in solution, with
most of the reagent (or active HOBt ester) having degraded after an
hour, a characteristic which is unsuitable for hindered substrates
or if the coupling is slow. Considering this problem, PS-IIDQ offers
a good balance between reactivity and stability. The desired cou-
pling followed by intramolecular cyclization was obtained with
mono and di substituted aryl carboxylic acids (Table 3, entries
a–k) with 64–78% yield. Likewise, using this protocol, substituted
cinnamic acid derivatives and 5,6-diamino-1,3-dimethyluracil
underwent coupling followed by intramolecular ring closure to
give the corresponding 8-styryl-7H-xanthine derivatives (Table 3,
entries l, m, and n) with 72–79% yield. Furthermore, heteroaryl car-
boxylic acid such as furan-2-carboxylic acid (Table 3, entry o) also
afforded the desired products with 62% yield. Additionally, the
reaction was also successful with cycloaryl carboxylic acid, such
as indole-3-carboxylic acid, naphthalene-2-carboxylic acid (Table 3,
entries p and q), under the same reaction condition with 65–73%
yield. Our effort to produce 1,3,8-trialkyl xanthine derivative, that
is, 8-propyl-1,3-dimethyl-7H-xanthine (Table 3, entry r) was also
successful with 71% yield. In all these cases, the reactions were
clean and the products were obtained with simple work-up in
quantitative yields and high purity.

P. Bandyopadhyay et al. / Tetrahedron Letters 53 (2012) 4631–4635
4635
The structures of all the synthesized compounds were con-
firmed by FT-IR, 1H NMR, ESI-MS data, and their purity by HPLC
analysis. PS-IIDQ was easily regenerated; intensive washing fol-
lowed by reaction with isobutyl chloroformate yielded a recycled
polymer-supported IIDQ with an efficiency similar to the original
material.
Pratap for recording MS and NMR spectra, respectively. P.B. is
thankful to DRDO, New Delhi, for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
135. These data include MOL files and InChiKeys of the most
important compounds described in this article.
On the basis of the above observations and literature reports,13
a plausible mechanism for the synthesis of 8-substituted xanthine
derivatives using PS-IIDQ is depicted in Scheme 3. The treatment of
a carboxylic acid with PS-IIDQ I in MeCN/H2O rapidly generates
in situ the corresponding isobutoxycarbonyl mixed anhydride14
IV. Attack by nucleophile (amine) V preferentially takes place at
the less hindered and more electrophilic carbonyl of the carboxylic
acid moiety, giving VI by forming amide bond concurrently with
the release of volatile carbon dioxide and isobutanol as by-prod-
ucts. The electronic environment on nitrogen of two free amino
groups of 5,6-diamino-1,3-dimethyluracil V are not identical. The
electrons present on nitrogen of –NH2 group (adjacent to N–CH3
group) take part in resonance with the pyrimidine ring, due to
which the electron availability on that nitrogen is reduced, while
the electron density on nitrogen of the other –NH2 group (adjacent
to C@O group) is much greater due to their non-participation in
resonance. This electron rich nitrogen attacks the electron deficient
carbonyl carbon of carboxylic acid moiety of IV to form selectively
6-amino-5-carboxamido-1,3-dimethyluracil intermediate VI. The
cleavage of the amide bond of VI occurs by the attack of hydroxide
anions to form VII, which on dehydration, gives VIII. In the subse-
quent steps, the intermediate VIII cyclizes to afford xanthine nu-
cleus X. It is noteworthy to mention that, starting from the
formation of VI, the intramolecular ring closure occurs selectively
from one side of the carbon skeleton to afford exclusively a single
product.
In conclusion, we successfully demonstrated the application of
PS-IIDQ for the first time in the synthesis of 8-substituted xanthine
derivatives starting from 5,6-diamino-1,3-dimethyluracil. PS-IIDQ
was observed to be an efficient polymer-supported coupling re-
agent as compared to IIDQ and polymer-supported carbodiimide
(PS-EDC) for amide bond formation with better yields and higher
purity. Additionally, it does not require any pre-activation, stable
in the presence of base and high stability under general laboratory
conditions. A clean and efficient reaction, simple isolation of the
product and wide applicability to a variety of substrate (including
hindered substrates) renders this method to be of high practical
utility.
References and notes
1. (a) Baraldi, P. G.; Tabrizi, M. A.; Gessi, S.; Borea, P. A. Chem. Rev. 2008, 108, 238;
(b) Müller, C. E.; Jacobson, K. A. Biochim. Biophys. Acta 2011, 1808, 1290; (c)
Fredholm, B. N.; Ijzerman, A. P.; Jacobson, K. A.; Klotz, K.-N.; Linden, J.
Pharmacol. Rev. 2001, 53, 527.
2. Jacobson, K. A.; Van Galen, P. J. M.; Williams, M. J. Med. Chem. 1992, 35, 407.
3. Bandyopadhyay, P.; Agrawal, S. K.; Sathe, M.; Sharma, P.; Kaushik, M. P.
Tetrahedron 2012, 68, 3822. and references cited therein.
4. (a) Daly, J. W.; Padgett, W.; Shamim, M. T.; Butts-Lamb, P.; Waters, J. J. Med.
Chem. 1985, 28, 487; (b) Zablocki, J.; Kalla, R.; Perry, T.; Palle, V.; Varkhedkar,
V.; Xiao, D.; Piscopio, A.; Maa, T.; Gimbel, A.; Hao, J.; Chu, N.; Leung, K.; Zeng, D.
Bioorg. Med. Chem. Lett. 2005, 15, 609.
5. (a) Nieto, M. I.; Balo, M. C.; Brea, J.; Caamaño, O.; Cadavid, M. I.; Fernández, F.;
Mera, X. G.; López, C.; Rodríguez-Borges, J. E. Bioorg. Med. Chem. 2009, 17, 3426;
(b) Daly, J. W.; Padgett, W. L.; Shamim, M. T. J. Med. Chem. 1986, 29, 1520.
6. (a) Hockemeyer, J.; Burbiel, J.; Müller, C. E. J. Org. Chem. 2004, 69, 3308; (b)
Burbiel, J. C.; Hockemeyer, J.; Müller, C. E. J. Beilstein Org. Chem. 2006, 2, 20.
7. Sauer, R.; Maurinsh, J.; Reith, U.; Fülle, F.; Klotz, K. N.; Müller, C. E. J. Med. Chem.
2000, 43, 440.
8. Weyler, S.; Hayallah, A.; Müller, C. E. Tetrahedron 2003, 59, 47.
9. (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.;
Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem. Soc.,
Perkin Trans. 1 2000, 3815; (b) Kirschning, A.; Monenschein, H.; Wittenberg, R.
Angew. Chem., Int. Ed. 2001, 40, 650; (c) Bhalay, G.; Dunstan, A.; Glen, A. Synlett
2000, 1846.
10. (a) Valeury, E.; Bradley, M. Tetrahedron 2007, 63, 8855; (b) Valeury, E.; Bradley,
M. Chem. Commun. 2005, 1164.
11. Bandyopadhyay, P.; Sathe, M.; Prasad, G. K.; Sharma, P.; Kaushik, M. P. J. Mol.
Catal. A: Chem. 2011, 341, 77.
12. Typical synthetic procedure for the preparation of the 8-substituted xanthines.
In a round bottom flask, 5,6-diamino-1,3-dimethyluracil (0.170 g, 1 mmol,
1 equiv) and carboxylic acid derivative (1 mmol, 1 equiv) were stirred in
CH3CN/H2O (9:1, v/v) (10 mL) for 10 min. To this, PS-IIDQ (2 equiv) (loading of
the resin 1.6 mmol gꢁ1) was added. The reaction mixture was then stirred at
room temperature for 1–2 h. The unreacted reagents and by-products
(polymer-supported quinolines) remain adsorbed on the resin surface and
thereby removed through filtration at the end of the reaction work-up. The
mother liquor was then concentrated under reduced pressure and mixed with
CH3CN (10 mL) and 2.5 N aqueous NaOH solution (15 mL). The mixture was
heated under reflux for the appropriate time in each case and allowed to cool
down to room temperature. After cooling to 0 °C, the corresponding 1H-purine-
2,6-dione precipitated by adjusting the pH to 5.0 with concentrated HC1. After
filtration and washing with cold 1 N HCl, and H2O, further washed with ethyl
acetate (2 ꢂ 5 mL) and methanol (3 ꢂ 5 mL) to obtain the pure product. The
progress of the reaction was monitored by TLC (dichloromethane:
methanol = 19:1, v/v) as well as by HPLC (HPLC grade methanol (100%) was
used as an isocratic eluent at a flow rate of 1 mL minꢁ1).
Acknowledgments
13. Sathe, M.; Derveni, M.; Allen, M.; Cullen, D. C. Bioorg. Med. Chem. Lett. 2010, 20,
1792.
14. Vaughan, J. R. J. Am. Chem. Soc. 1951, 73, 3547.
We thank Director, DRDE, Gwalior for his keen interest and
encouragement. We also thank Mr. A. K. Srivastava and Mr. Ajay