Synthesis and characterization of 9-methyl-2-morpholin-4-yl-8-substituted phenyl-1H-purine derivatives using polyphosphoric acid (PPA) as an efficient catalyst

Article abstract of DOI:10.1016/j.tetlet.2011.08.076

We demonstrate the synthesis of various purine derivatives through the coupling of N⁴-methyl-2-morpholin-4-yl-pyrimidine-4,5-diamine with various aldehydes by using polyphosphoric acid (PPA) as an efficient catalyst in DMF at reflux temperature

Full text of DOI:10.1016/j.tetlet.2011.08.076

Tetrahedron Letters 52 (2011) 5521–5524
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Synthesis and characterization of 9-methyl-2-morpholin-4-yl-8-substituted
phenyl-1H-purine derivatives using polyphosphoric acid (PPA) as an
efficient catalyst
P. Sadanandam a, V. Jyothi b, M. Adharvana Chari b,c, , Parthasarathi Das d, , K. Mukkanti a,
⇑
⇑
⇑
a Centre for Chemical Sciences and Technology, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 085, A.P., India
b Dr. MACS Bio-Pharma Pvt. Ltd, Plot-32/A, Westren Hills, Kukatpally, Hyderabad 500 085, A.P., India
c Department of Complexity Science and Engineering, School of Frontier Sciences, 5-1-5, Kashiwanoha, Kashiwa, University of Tokyo, Chiba 277-8561, Japan
d Aurigene Discovery Technologies Limited, Bollaram Road, Miyapur, Hyderabad 500049, A.P., India
a r t i c l e i n f o
a b s t r a c t
We demonstrate the synthesis of various purine derivatives through the coupling of N4-methyl-2-mor-
pholin-4-yl-pyrimidine-4,5-diamine with various aldehydes by using polyphosphoric acid (PPA) as an
efficient catalyst in DMF at reflux temperature. The PPA catalyst gave better yields (70–85%) in short reac-
tion times (45–60 min). This commercially available cheap catalyst is more active than many reported
expensive catalysts. Many aldehydes underwent the above conversion to form a series of 9-methyl-2-
morpholin-4-yl-8-phenyl-9H-purines.
Article history:
Received 17 July 2011
Revised 11 August 2011
Accepted 14 August 2011
Available online 22 August 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
N4-Methyl-2-morpholin-4-yl-pyrimidine-
4,5-diamine
Aldehydes
Polyphosphoric acid (PPA)
9-Methyl-2-morpholin-4-yl-8-phenyl-9H-
purines
The purines, including substituted purines and their tautomers
are the most widely distributed as nitrogen-containing heterocycles
in nature. Some, as components of nucleic acids and coenzymes, play
vital roles in the genetic and metabolic processes of all living
organisms. The purine bases, adenine and guanine together with
pyrimidines, are fundamental components of all nucleic acids.
Purine-related compounds have been investigated as potential
chemotherapeutic agents. In particular, 6-mercaptopurine in the
form of its nucleoside phosphate, inhibits several enzymes required
for the synthesis of adenosine and guanosine nucleotides, and thus
proves useful in selectively arresting the growth of tumors. The
pyrazolopyrimidine has been used in gout therapy Emil Fischer,
nobel laureate in chemistry in 1902, attributed the name purine to
the fused imidazo [4,5-d] pyrimidine compound in 1884 and
achieved its synthesis in 1898.1 He further showed through a series
of elegant transformations that the natural substances adenine,
xanthine, caffeine, uric acid, and guanine correspond to different
hydroxyl and amino derivatives of this fundamental system.2 Pur-
ines bearing functionality at one or more of the seven peripheral
atoms which make up its bicyclic structure can be readily synthe-
sized by well-established routes from monocyclic precursors.3 In
order to gain further insight into the structural requirements for
active antimycobacterial purines, we needed easy access to 9-
arylpurines. Polyfunctionalized purines substituted at the 2, 6 and
8 positions are also obtained through the reaction of suitably
activated purine intermediates with heteroatom and carbon
nucleophiles through SNAr-type substitution and transition metal
catalyzed coupling reactions.4–15 N-Alkylation/acylation or
Vorbruggen16–18 and other electrophile based reactions, can also
be used to introduce functionality onto the nitrogen atoms in the
purine ring. An example of this methodology is the highly selective
N-9 alkylation of purines under Mitsunobu conditions.11,15,19,20
Purine derivatives acting as interferon inducers,21–23 inhibitors of
Hsp90,24,25 antimycobacterial purines,27–30 inhibitors of leukotriene
A4 hydrolase,31 sulfotransferase inhibitors,32,33 Src tyrosine kinase
inhibition,34,35 P38 MAP kinase inhibitors,36–38 inhibitors of inosi-
a
tol-1,4,5-trisphosphate-3-kinase39 and cyclin-dependent kinase
inhibitors.40 In addition to the above, purines are also involved in
many metabolic processes as cofactors associated with a great num-
ber of enzymes and receptors, notably ATP, GTP, GDP, cAMP, cGMP,
AcCoA, NAD, NADP, FAD, PAPS and SAM,41,42 which play key roles at
different phases of the cell cycle, in cell signalling and other funda-
mental biological processes.43 Indeed, a great variety of di, tri, or
tetrasubstituted purines described in the literature have been found
to be potent inhibitors. This wide range of biological activities
⇑
Corresponding authors. Fax: +91 40 40206647 (M.A.C.).
E-mail address: drmac_s@yahoo.com (M. Adharvana Chari).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.076

5522
P. Sadanandam et al. / Tetrahedron Letters 52 (2011) 5521–5524
Table 1
displayed by purines is conferred by a judicious choice of the nature
of the substituents that can be combined on the N-1, C-2, N-3, C-6, N-
7, C-8 and N-9 centers. With such an easy access to so much struc-
tural diversity, the purine core has become a privileged structure
in medicinal chemistry,44 and an important scaffold in the prepara-
tion of combinatorial libraries. In general, two strategies are applied
for the preparation of purine libraries. In the first procedure, a pre-
formed purine ring loaded with various reactive functionalities is di-
rectly modified, which allows good regiocontrol at C-2, C-6, C-8, and
N-9. Alternatively, substituted pyrimidine or imidazole precursors
are functionalised, generating the second heterocycle of the purine
core in the process with better region control at N-1, N-3, N-7, and
N-9. Recently the synthesis of several purine derivatives like 6-
aminopurines,45 6-amidopurines,46 9-substituted purines,47 Mi-
chael addition of adenine,48 arylation at N-9 of purines,49xanthine
derivatives from 6-aminouracils,50 and N-1 (or N-3) mono substi-
tuted 5,6-diaminouracil51 pyrimidine precursors of 2,6,8,9-tetra-
Effect of various solvents on the synthesis of purine derivative 6a using PPAa
Entry
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
CH2Cl2
THF
CH3OH
DME
CH3CN
H2O
DMF
2
2
2
1
1
2
1
55
58
65
60
62
30
82
a
Reaction conditions: N4-methyl-2-morpholin-4-yl-pyrimidine-4,5-diamine
(1 equiv), benzaldehyde (1.2 equiv), PPA (1.5 equiv), solvent (5 ml), reflux
temperature.
closing reagent, reaction medium and solvent, spinning solvent. It
has been used mainly as a ring closing reagent but its scope has not
been fully explored. Here it has been applied for oxidative dehy-
drogenation of the cyclic intermediates formed from the condensa-
substituted
purines,52
8,9-disubstituted
adenines,532,8,9-
trisubstituted adenine inhibitors of HSP90,26 6,7,8-trisubstituted
purines54, N-9-substituted 2,8-diaminopurines55 and 2-(N-benzyl-
pyrrolyl)-benzimidazoles using PPA56 are reported. Here in the pres-
ent work we wish to report the synthesis of various purine
derivatives using simple polyphosphoric acid (PPA) as catalyst.
In continuation of the development of useful synthetic method-
ologies, initially, we have attempted the condensation of N4-
tion of N4-methyl-2-morpholin-4-yl-pyrimidine-4,5-diamine
5
and substituted aldehydes. Here, we have studied that purine
derivatives 6(a–l) can be synthesized57 efficiently by treatment
of N4-methyl-2-morpholin-4-yl-pyrimidine-4,5-diamine
5 with
substituted aldehydes using polyphosphoric acid (PPA) and DMF
as the solvent at reflux temperature. Several aromatic, heteroaro-
matic and aliphatic aldehydes underwent the above conversion
to form a series of 9-methyl-2-morpholin-4-yl-8-phenyl-9H-pur-
ines 6(a–l). Aromatic aldehydes containing both electron-donating
and electron-withdrawing groups worked well along with the
heteroaryl substituted aldehydes. Purine derivatives can be
synthesized efficiently by treatment of N4-methyl-2-morpholin-
4-yl-pyrimidine-4,5-diamine with aldehydes using PPA as an effi-
cient ring closing reagent at room temperature. Similarly, different
solvents were tested for the synthesis of 9-methyl-2-morpholin-4-
yl-8-phenyl-9H-purines 6a. The reaction in dichloro methane
(DCM), tetrahydrofuran (THF) gave the corresponding 9-methyl-
2-morpholin-4-yl-8-phenyl-9H-purines in low yield and also
required prolonged reaction times (entries 1 and 2), whereas the
reaction in methanol (MeOH), dimethoxy ethane (DME), acetoni-
trile (ACN) has resulted in slightly improved yields of the products
(entries 3–5). However, the reaction in DMF gave 82% of the corre-
sponding 9-methyl-2-morpholin-4-yl-8-phenyl-9H-purines 6a in
1 h, as can be seen from the Table 1.
methyl-2-morpholin-4-yl-pyrimidine-4,5-diamine
5 (1.0 mmol)
with benzaldehyde (1.2 mmol) at reflux temperature in dimethyl
formamide (DMF) solvent (5 ml) under nitrogen atmosphere, using
polyphosphoric acid (1.5 equiv) as catalyst. The mixture was stir-
red at reflux temperature for about 1 h and afforded 82% yield of
6a.
N4-Methyl-2-morpholin-4-yl-pyrimidine-4,5-diamine 5 is used
as starting material for our scheme, which can be prepared from
the 5-nitro uracil 1 by series of known synthetic reactions. 5-Ni-
tro-1H-pyrimidine-2,4-dione (5-nitro uracil) 1 can be prepared
by using uracil upon treatment with fuming nitric acid and
H2SO4. 5-Nitro-1H-pyrimidine-2,4-dione (5-nitro uracil) on treat-
ment with of phosphorous oxychloride and diisopropyl ethylamine
will give 2,4-dichloro-5-nitropyrimidine 2 which was further used
without purification. As per the Scheme 1, various reagents have
been used to achieve the starting material 5. Polyphosphoric acid
(PPA) is a powerful dehydrating agent. This can also be used as ring
NO2
NO2
NO2
Cl
HN
MeNH2
HN
N
POCl3, Reflux, 3 h
Cl
N
N
H
O
N
H
1
O
Cl
N
Diisopropyl
Ethanamide
THF, -78°C
3
2
(2-Chloro-5-nitro-
1,2-dihydro-pyrimidin
-4-yl)-methyl-amine
5-Nitro-1 H-pyrimidine
2,4-Dichloro-5-nitro-pyrimidine
-2,4-dione
NO2
NH2
N
N
Reduction
Morpholine
N
N
N
H
N
N
N
H
O
SnCl4, Ethanol, Reflux
O
Acetone,
0°C, 1h
5
4
N4-Methyl-2-morpholin-4-yl-
Methyl-(2-morpholin-4-yl-5-nitro-
pyrimidin-4-yl)-amine
pyrimidine-4,5-diamine
R
N
N
OHC
N
N
N
R
O
PPA, DMF,
Reflux, 45-60 m
6 (a-l)
9-Methyl-2-morpholin-4-yl-8-
R = Alkyl, Aryl
phenyl-1 H-purine
Scheme 1. Synthesis of purine derivatives using PPA.

P. Sadanandam et al. / Tetrahedron Letters 52 (2011) 5521–5524
5523
The method is suitable for the preparation of 9-methyl-2-mor-
pholin-4-yl-8-phenyl-9H-purines from an acid sensitive aldehyde
such as furfuraldehyde and the sterically hindered aldehyde,
2,3,4-trimethoxybenzaldehyde. The reaction conditions are mild
and the experimental procedure is simple. The products were
formed (Table 2) in high yields (70–85%) in 45–60 m. The
structures of the products were determined from their spectral
(IR, 1H NMR and MS) data.
The present work reveals that the synthesis of purine deriva-
tives using PPA mediated condensation methodology. In continua-
tion of the development of useful synthetic methodologies, we
have observed that purine derivatives can be synthesized
Table 2
Synthesis of various 9-methyl-2-morpholin-4-yl-8-phenyl-9H-purine derivatives 6(a–l)
S.no.
Aldehyde
Diamine (5)
Product 6(a–l)a
Time (min)
60
Yieldb (%)
82
O
H
NH2
NH
N
N
N
N
a
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
NO2
NH2
NH
NO2
OH
N
N
N
N
N
N
O
H
N
N
N
b
c
45
50
50
85
84
84
O
O
O
H
H
H
NH2
NH
N
N
N
N
N
N
N
N
O
O
O
OH
NH2
NH
O2N
N
N
NO2
d
NH2
NH
O
HO
Br
O
O
O
O
.
N
N
N
N
e
45
71
N
N
N
N
O
O
O
O
H
NH2
NH
N
N
N
OH
N
N
f
45
50
83
70
O
Br
O
Br
H
NH2
NH
N
N
N
N
Br
N
N
N
N
N
N
N
g
N
N
N
N
N
O
O
NH2
NH
O
O
O
O
H
N
N
N
N
h
i
50
45
80
82
NH2
NH
CHO
N
N
N
N
N
N
N
N
N
O
O
S
NH2
NH
N
N
N
CHO
S
j
50
50
72
84
N
N
O
CHO
NH2
NH
N
N
N
N
k
N
N
N
N
N
N
N
O
O
O
O
N
N
CHO
F
NH2
NH
N
F
N
N
l
50
72
a
All products were characterized by IR, NMR, and mass spectroscopy.
Yield refers to pure products after purification by column chromatography.
b

5524
P. Sadanandam et al. / Tetrahedron Letters 52 (2011) 5521–5524
efficiently by treatment of N4-methyl-2-morpholin-4-yl-pyrimi-
dine-4,5-diamine with aldehydes using polyphosphoric acid
(PPA) and DMF as the solvent at reflux temperature. N4-Methyl-
2-morpholin-4-yl-pyrimidine-4,5-diamine is used as starting
material for our scheme, which can be prepared from the uracil
by five known synthetic reactions. The reaction conditions are mild
and the experimental procedure is simple. Further interdisciplin-
ary studies are now under way searching for other novel types of
biologically active compounds. Several types of compounds have
found use in chemical biology and bioanalysis. The methodology
of the condensation reactions on purines and nucleosides is now
widely used in many laboratories and also the new cytostatic
and antiviral compounds are inspiring further design of new com-
pounds with potential biological activity.
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57. Experimental: Synthesis of 9-methyl-2-morpholin-4-yl-8-phenyl-9H-purine
derivatives (6(a–l)): To the mixture of 2-morpholin-4-yl-pyrimidine-4,5-
diamine (1 equiv) and aldehyde (l.2 equiv) in DMF (5 ml) under N2
atmosphere, PPA (1.5 equiv) was added. The mixture was stirred at reflux
temperature for about 45–60 min. The reaction was monitored by TLC. After
completion of the reaction, the reaction mixture was poured in ice cold water.
The precipitate formed was filtered and dried to afford the desired product as
off white or pale yellow solid (yield: ꢀ70–85%). All compounds were confirmed
by I.R, NMR, Mass and representative compound spectral data was given below
and other compounds data was given in Supplementary data. 6l: 8-(4-fluoro-
phenyl)-9-methyl-2-morpholin-4-yl-9H-purine(Table 2): White solid; mp:
134–136 °C; IR (KBr): 3435.27, 2854.94, 1615.73, 1112.48 cmÀ1 1H NMR
;
32. (a) Armstrong, J. I.; Portley, A. R.; Chang, Y. T.; Nierengarten, D. M.; Cook, B. N.;
Bowman, K. G.; Bishop, A.; Gray, N. S.; Shoka, K. M.; Schultz, P. G.; Bertozzi, C. R.
Angew.Chem., Int. Ed. 2000, 39, 1303; (b) Chapman, E.; Ding, S.; Schultz, P. G.;
Wong, C. H. J. Am. Chem. Soc. 2002, 124, 14524.
(400 MHz, DMSO-d6): d 3.65–3.85 (m, 8H), 3.88 (s, 3H), 7.42 (t, J = 7.2 Hz, 2H),
7.98 (t, J = 7.4 Hz, 2H), 8.79 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6): d
164.69, 161.40, 155.44, 154.69, 151.40, 147.99, 131.30, 131.18, 126.86, 126.14,
125.20, 115.96, 115.67, 65.00, 44.66, 29.94 ppm; m/z: 314.17(M+).