Synthesis and molecular docking studies of novel 2-(2-amino-6-phenyl-4-pyrimidinylamino) ethanol derivatives: Using ring-opening reactions of cyclic ketene-N,O-acetal

Article abstract of DOI:10.13005/ojc/330361

A series of six novel 2-(2-amino-6-phenyl-4-pyrimidinylamino) ethanol derivatives have been synthesized starting from commercially available substituted acetophenones via Oxoketene Dithioacetals with high yields. Ketene dithioacetal store act with 2-amino

Full text of DOI:10.13005/ojc/330361

ISSN: 0970-020 X
CODEN: OJCHEG
2017, Vol. 33, No. (3):
Pg.1555-1562
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Synthesis and Molecular Docking Studies of Novel
2-(2-Amino-6-Phenyl-4-Pyrimidinylamino) Ethanol Derivatives:
Using Ring-Opening Reactions of Cyclic Ketene-N,O-Acetal
G.M.V.N.A.R. RAVI KUMAR and ARUMUGAM THANGAMANI*
Department of Chemistry, Karpagam University, Karpagam academy of higher education,
Coimbatore-641021, Tamil Nadu, India.
*Corresponding author E-mail: Thangabell2003@gmail.com
http://dx.doi.org/10.13005/ojc/330361
(Received: May 03, 2017; Accepted: May 31, 2017)
AbSTRACT
A series of six novel 2-(2-amino-6-phenyl-4-pyrimidinylamino) ethanol derivatives have
been synthesized starting from commercially available substituted acetophenones via Oxoketene
Dithioacetals with high yields.Ketene dithioacetal store act with 2-aminoethanol or l-amino-2-propanol
to afford the corresponding substituted 2-methyleneoxazolidines which are utilized in the synthesis
of 6-aryl-2-amino-4-pyrimidinamine Derivatives. The molecular docking studies revealed that all the
synthesized compounds best fit into the active site of HDAC2, anti-cancer protein.
Keywords: 2-amino-pyrimidine Derivatives, Ketene dithioacetals, Cyclic Ketene N,
O-acetal, molecular docking
INTRODUCTION
nucleus which acts as tyrosine kinase inhibitors.
Pyrimidine containing compounds are renowned
for their biological activities due to the existence
of pyrimidine base in genetic material of cells
particularly in thymine, cytosine and uracil, which
form the building blocks of DNA and RNA. 6-aryl-
2,4-Diamino pyrimidine (I) derivatives are known
to exhibit important biological activities such as
Cancer is a primary cause of death globally,
impacting above 14 million people per annum.
Among various types of cancers, Colon cancer is
the most common type. Throughout the world, this
cancer is the most frequently diagnosed (second
in women and third in men) and it consistently lies
within the five most serious types of cancer each
year. This fact clearly emphasizes the need for
detection of novel chemotherapeutic agents with
potent anticancer activities. The core moiety of
several anticancer agents comprised the pyrimidine
antifilarial to poisomerase II inhibitors1 MTH-1
,
inhibitors for treating cancer3, anti-nflammators4and
they are known to show potential anti plasmodial
agents2. But the synthesis and biological activity
of 2-(2-amino-6-phenyl-4-pyrimidinylamino)ethanol

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Scheme 1: Earlier methodology
RESULTS AND DISCUSSION
(I) derivatives are not much investigated. These
pyrimidine derivatives were previously synthesized
from ketene S, Sacetals by treating with guanidine11.
And these pyrimidine derivatives having sulfide group
was oxidized to to sulphone and substituted with
amine1, 2, 6 (scheme-1). But the main disadvantage
involves nucleophilic Substitution on pyrmidine ring
having sulphone group need conditions.
The synthetic strategy started from the
commercially available substituted acetophenones.
The substituted acetophenones were treated with
NaH and CS2 followed by methylation using MeI,
resulted the a-Oxoketene dithioacetals in a one
pot reaction7-9 (Scheme 1). Further these ketene
dithioacetal were treated with 2-ethanolamine
under basic conditions yielded the required Cyclic
N,O-ketenecetals10(3a-3f). From the yield values in
the tabular result (table-1), it is clearly showing that
ketene dithioacetals having electron donating groups
on aromatic ring are much favorable for the reaction.
Whereas ketene dithioacetals having electron
withdrawing groups on aromatic ring has comparably
less reactivity, because of the delocalization of the
electron cloud and stabilsation of the molecule.1H-
and 13C-NMR spectra of the synthesized cyclic N,O-
ketenecetals(3a-3e) shows the presence of only one
set of signals, representing that these compounds
are not a mixture of E and Z isomers. Because of
the presence of intra molecular hydrogen bond (as
shown in figure 1)these compounds (3a-3e) are
purely in the form of E-isomer9.The compound 3fwas
existed as a mixture of E, Z isomers in 10:1 ratio.
The other drawback is more number of
steps are required in this strategy, thereby combined
yield seems to be less (scheme 1).
AIM AND ObJECTIVES
The 2-(2-amino-6-phenyl-4-pyrimidinyl
amino) ethanol derivatives were planned to
synthesize in the aim of exploring their anticancer,
antibacterial and antimicrobial activity. Here by,
we are proposing a versatile novel method to
synthesize these compounds in very high yields
(via a-Oxoketene Dithioacetals) from commercially
available and cheap starting materials such as
acetophenones. Here, we describe the synthesis of
some new heterocyclic ketene N, O-acetals and their
reactions with guanidine hydrochloride.
These Cyclic N,O-ketene acetals were
made to react with guanidine hydrochloride using
potassium tert. Butoxide as base resulted the
required 2-(2-amino-6-aryl-4-pyrimidinamino)
ethanol Derivatives (4a-4f). From the yield values
in tabular result (table-2), it is showing that electron
withdrawing groups on aromatic ring is favorable for
the reaction.The structures of all the six compounds
were fully characterized by1H NMR,13C NMR, Mass
and IR.
Retro synthetic analysis
2-(2-amino-6-aryl-4-pyrimidinamino)
ethanol (I) derivatives could be synthesized
from guanidine and 2-Oxazolidin-2-ylidene-1-
phenylethanone (II), five-membered cyclic ketene-
N,O-acetals. These five-membered cyclic ketene-
N,O-acetals can be achieved from commercially
available substituted acetophenones through ketene-
S,S-acetals (Scheme 2).

KUMAR & THANGAMANI, Orient. J. Chem., Vol. 33(3), 1555-1562 (2017)
1557
R1
R2
O
R1
R2
O
R1
R2
NH2
1) NaH and CS2
NaH
DMF
O
S
2) MeI
(One pot reaction)
OH
R3
HN
R3
S
R3
O
Cyclic N,O-ketene acet
Substituted
Acetophenone
Ketene thioacetals
3a-3f
Table 1: Synthesis of Cyclic Ketone N2O-
acetals
Compound R1
R2
R3
Yield
3a
3b
3c
3d
3e
3f
H
OMe
H
CL
F
OMe
H
H
H
H
OMe
H
H
H
H
99%
98.6%
94.8%
93.5%
93.1%
60%
NO2
H
H
R1
R1
R1
R2
R1
R2
O
R3
N
R2
R3
R2
O
S
S
O
R3
O
R3
H2N
N
NH
HN
Ketene S,S-acetals
Substituted
Acetophenone
I
II
OH
2-(2-amino-6-arylpyrimidin
-4-ylamino)ethanol
cyclic
ketene-N,O-acetal
Scheme 2: Retrosynthesis Analysis
Plausible mechanism
docking studies using protein prep wizard of
Schrödinger 2016 (Maestro 11, Schrödinger, LLC,
New York, NY). Bond orders and formal charges
were added for hetero groups, and hydrogen’s were
added to all atoms in the system. Water molecules
with in 5A0 distance were removed. For each
structure, a brief relaxation was performed using an
all-atom constrained minimization carried out with
the Impact Refinement module using the OPLS-
2005 force field to alleviate steric clashes that may
exist in the original PDB structure.The minimization
was terminated when the energy converged or the
RMSD reached a maximum cut off of 0.30 Å.
A postulated reaction pathway for the
formation of product undergoes Michael addition
with push–pull alkene, which was followed by
intramolecular cyclization by the breakage of C-O
bond to afford required products in good yields.
Docking Studies
Materials and methods
Ligand preparation
Geometry optimized 2D structure of
synthesized molecules was sketched and prepared
for docking by using Ligprep, a versatile program
of Schrödinger suite 2015 and minimized using
OPLS-2005 force field.A total 10 conformation were
generated.
Benzamide with Grid co-ordinates of
X: 66.51, Y: 29.55, Z: 1.38 in anticancer HDAC2
protein.
Protein preparation
Crystal co-ordinates for HDAC2(PDB
ID:3MAX) were taken from protein databank
(http://www.rcsb.org). Protein was prepared for
Glide Docking
All the synthesized compounds (4a-4f) were
docked into active site pockets of corresponding

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KUMAR & THANGAMANI, Orient. J. Chem., Vol. 33(3), 1555-1562 (2017)
R1
R1
KtOBu
H2N
H2N
R3
R2
R3
R2
O
NH2Cl
+
DMSO: Toluene
1:1
100 0C, 5 hrs
N
O
H2N
N
NH
HN
4a-4f
2-(2-amino-6-arylpyrimidin
-4-ylamino)ethanol
cyclic
ketene-N,O-acetal
OH
Table 2: Synthesis of 2-(2-amino-6-aryl-4-
pyrimidinamino) ethanol Derivatives
Compund R1
R2
R3
Yield
4a
4b
4c
4d
4e
4f
H
OMe
H
CL
F
OMe
H
H
H
H
OMe
H
H
H
H
35.8%
40.2%
61.6%
62.1%
62.9%
60%
NO2
H
H
protein by using GLIDE13 module of Schrödinger. of toluene, two equivalents of guanidine. HCl and
Standard precision docking was performed. A total 2 equivalents potassium tert. But oxide was added
of 10 ligand conformations were allowed and finally at RT. it was stirred at 1100C for 5 hours. Quenched
top score conformation was selected as active the reaction mixture with water and extracted with
conformation. Molecules were analysed based on 10% methanol in chloroform to get the product,
docking score, interacting amino acids, and hydrogen which was stirred with diethyl ether and filtered to
bonds (Table 3).N-(2-aminophenyl) Benzamide was get required product.All the synthesized compounds
1
considered as standards for
HDAC2 respectively.
were confirmed by H NMR, 13C-NMR, Mass and
IR.
ExPERIMENTAL SECTION
2-(2-amino-6-(2,6-dimethoxyphenyl)pyrimidin-4-
ylamino)ethanol (4a)
M.P.1900C;Rf value 0.45 (in 10% Methanol
in DCM); H1 NMR (500 MHz, DMSO-d6, 27°C)
General procedure for the synthesis of Cyclic
N,O-kenteneacetal (3a to 3f)
Tothestartingmaterial(ketenediothioacetal) d ppm 3.3(2H, bs), 3.5 (2H, bs), 3.64 (6H, s), 4.72
taken in DMF,2 equivalents of ethanolamine was (1H, s, D2O exchangeable), 5.59 (1H, s), 5.82 (2H, s,
added. Then 5 equivalents of sodium Hydride was NH2, D2O exchangeable), 6.65 (2H, d, J=8.5), 6.74
added at 0 degrees and it was stirred at RT for (1H, bs, D2O exchangeable ) 7.26 (1H, t, J=8.5);13C
2 hours. Quenched the reaction mixture with Ice NMR (400 MHz, DMSO-d6, 250C) d ppm 42.5, 55.4
cold water and extracted with ethyl acetate to get , 60.0 , 96.9, 103.9, 118.3, 129.0, 157.1, 159.7,
the product. All the synthesized compounds were 162.7, 163.1; ESI MS: [M.++H] 291 m/z; IR: 3477
confirmed by 1H and 13C-NMR spectral data.
cm-1, 3415 cm-1, 3332 cm-1, 3198 cm-1, 2960 cm-1,
2929 cm-1, 2853 cm-1
General procedure for the synthesis of 2-(2-
amino-6-phenyl-4-pyrimidinylamino)ethanol (4a 2-(2-amino-6-(4-methoxyphenyl)pyrimidin-4-
to 4f) ylamino)ethanol (4b)
M.P. 1480C; Rf value 0.50 (in 10% Mein
ketene derivatives) taken in 10ml of DMSO and 10ml DCM);1H NMR (300MHz, DMSO) ä ppm 3.3 (2H, t),
To the 500mg of Starting material (N,O-

KUMAR & THANGAMANI, Orient. J. Chem., Vol. 33(3), 1555-1562 (2017)
1559
(2H,d, J=7.5);13C NMR (400 MHz, DMSO-d6, 250C)
d ppm 42.7, 60.0, 90.9, 126.1, 127.2, 128.2, 128.9,
129.2, 138.3, 161.4, 163.4, 164.1; ESI MS: [M.++H]
231 m/z; IR: 3386 cm-1, 3325 cm-1, 3221cm-1, 3110
cm-1, 2992 cm-1, 2938 cm-1, 2879 cm-1
R1
R2
O
O
R3
N
H
Intramolecular
2-(2-amino-6-(4-chlorophenyl)pyrimidin-4-
ylamino)ethanol (4d)
Hydrogen bonding
M.P.1780C;Rf value 0.49 (in 10% Methanol
Fig. 1
in DCM); H1 NMR (500 MHz, DMSO-d6, 27°C)
d ppm 3.3 (2H, t, J=5.4), 3.50-3.53 (2H, m),4.73
(1H, t, J=5, Exchangeable proton), 5.97 (2H,s, -NH2,
exchangeable proton), 6.26 (1H, S), 6.87 (1H,bs,
exchangeable proton), 7.39-7.45 (3H,m), 7.99 (2H,
d, J=6.5); 13C NMR (400 MHz, DMSO-d6, 250C )
d ppm 42.7, 59.9, 67.4, 72.5 , 90.95, 127.9, 128.1,
128.3, 133.9, 137.1, 160.1, 163.3, 164.1. ESI MS:
[M.++H] 265 m/z;IR:3403 cm-1, 3317 cm-1, 3217 cm-1,
3104 cm-1, 2951 cm-1, 2924 cm-1, 2868 cm-1
Table 3: Docking scores
Compound Code HDAC2 docking score
4a
4b
4c
4d
4e
4f
-7.477
-5.686
-7.945
-7.774
-7.725
-7.998
2-(2-amino-6-(4-fluorophenyl)pyrimidin-4-
ylamino)ethanol (4e)
Standard [N-(2-aminophynel) -13.015
Benzamide]
M.P. 158-1590C, Rf value 0.47 (in 10%
Methanol in DCM) H1 NMR (500 MHz, DMSO-d6,
27°C) d ppm 3.3 (2H, t, J=5.4), 3.51 (2H, t, J=5.9),
5.99 (2H, S, -NH2, Exchangeable proton), 6.25
(1H,s), 6.90 (1H,bs, Exchangeable proton), 7.26 (2H,
t, J=8.8), 7.94 (2H,s);13C NMR (400 MHz, DMSO-d6,
250C) d ppm 42.14 , 60.0, 91.0, 115.2, 128.4, 134.8
, 158.3, 160.3, 161.6, 163.3, 164.1, 164.2; ESI MS:
[M.++H] 249 m/z;IR:3398 cm-1, 3221 cm-1, 3152 cm-1,
2994 cm-1, 2953 cm-1, 2937 cm-1, 2879 cm-1
3.4 (2H, t,J=5.4), 3.77 (3H,s),4.71 (1H, t, J=5.1, D2O
exchangeable), 5.90 (2H, s, D2O exchangeable),
6.18 (1H,s),6.76 (1H, S, D2O exchangeable), 6.96
(2H,d, J=8.7), 7.83 (2H,d,J=5.4);13C NMR (400 MHz,
DMSO-d6, 250C) d ppm 42.7, 55.1, 60.1, 89.9, 113.6,
127.5, 130.6, 160.2, 163.2 , 164.1; IR: 3443 cm-1,
3315 cm-1, 3218 cm-1, 2987 cm-1, 2956 cm-1, 2937
cm-1, 2862 cm-1
2-(2-amino-6-phenylpyrimidin-4-ylamino)ethanol
(4c)
2-(2-amino-6-(4-nitrophenyl)pyrimidin-4-ylamino)
ethanol (4f)
M.P.1180C;Rf value 0.65 (in 10% Methanol
in DCM) H1 NMR (500 MHz, DMSO-d6, 27°C) d
ppm 3.3(2H, t), 3.5 (2H, dd, J=6, J=11.5), 4.72 (1H,
t, J=5, Exchangeable proton), 6.02 (2H, s, -NH2,
Exchangeable proton), 6.27 (1H, s), 6.95 (1H, bs,
Exchangeable proton), 7.49 (2H, d, J=8.5), 7.91
M.P.1920C, Rf value 0.38 (in 10% Methanol
in DCM); H1 NMR (300 MHz, DMSO-d6, 27°C)
d ppm 3.5 (2H, t), 3.79 (2H, t, J=3),4.91 (2H, s), 5.83
(1H,bs),6.28 (1H, S), 7.97 (1H,d), 8.08 (2H, d, J=4.5),
8.26 (2H,d,J=4.8); 13C NMR (400 MHz, DMSO-d6,
Fig. 2: Plausible mechanism

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Fig. 3: Ligand diagrams
250C) d ppm 42.1, 59.8, 94.9, 123.6, 123.3, 144.6, (E)-2-(oxazolidin-2-ylidene)-1-phenylethanone
147.8, 163.5, 163.8, 164.2;ESI MS:[M.++H] 275 m/z; (compound 3c)
IR: 3441cm-1, 2954 cm-1, 2918 cm-1
H1 NMR (400 MHz, DMSO-d6, 25°C) d ppm
3.72 (2H, t, J=8.4), 4.46 (2H, t, J=8.4), 5.55 (1H, s),
(E)-1-(4-methoxyphenyl)-2-(oxazolidin-2-ylidene) 7.41 (3H, m), 7.83 (2H, d, J=6.4), 9.81 (1H, bs);C13
ethanone (Compound 3b)
NMR (400MHz, DMSO-d6, 250C) d ppm 46.8, 67.3,
H1 NMR (300 MHz, DMSO-d6, 27°C) d ppm 72.5, 126.4, 128.3, 133.2, 139.9, 169.6, 184.7.
3.70 (2H, t, J=8.4), 3.78 (3H, s), 4.45(2H, t, J=8.4),
5.50 (1H, s), 6.93 (2H, d, J=8.7), 7.79 (2H, d, J=8.7), (E)-1-(4-chlorophenyl)-2-(oxazolidin-2-ylidene)
9.72 (1H, bs); C13 NMR (400MHz, DMSO-d6, 250C) ethanone (compound 3d)
d ppm 43.015, 55.501, 67.0, 67.2, 72.0, 113.2, 128.2,
128.2, 132.5, 161.0, 169.3, 184.2.
H1 NMR (400 MHz, DMSO-d6, 25°C) d ppm
3.72 (2H, t, J=8.4), 4.47 (2H, t, J=8.4), 5.53 (1H, s),
7.42 (2H, d, J=8.4), 7.83 (2H, dd, J=8.8, J=2.0), 9.81

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(1H, bs);C13 NMR (400MHz, DMSO-d6, 250C) d ppm (400MHz, DMSO-d6, 250C) d ppm 43.0, 43.1, 67.6,
43.0, 67.4, 72.5, 128.0, 128.3, 135.0, 138.6, 169.6, 73.6, 123.3, 124.8, 127, 127.7, 145.4, 148.3, 169.8,
183.2.
182.0.
(E)-1-(4-fluorophenyl)-2-(oxazolidin-2-ylidene)
ethanone (compound 3e)
CONCLUSION
H1 NMR (400 MHz, DMSO-d6, 25°C) d
Six novel pyrimidine derivatives (4a to
ppm 3.72 (2H, t, J=8.4), 4.469 (2H, t, J=8.4), 5.53 4f) were prepared and characterized by IR, Mass,
(1H, s), 7.19 (2H, d, t=8.8), 7.87 (2H, m), 9.76 (1H, 1H and 13C-NMR spectral data. In conclusion, we
bs); C13 NMR (400MHz, DMSO-d6, 250C) d ppm have successfully synthesized 2-(2-amino-6-aryl-4-
43.054, 67.3, 72.3, 114.7, 114.9, 128.8, 128.9, 136.4, pyrimidinamino) ethanol Derivatives. The molecular
136.4, 162.2, 164.6, 169.6, 183.4.
docking studies for the synthesized compounds
revealed that all the synthesized compounds best
(E,Z)-1-(4-nitrophenyl)-2-(oxazolidin-2-ylidene) fit into the active site of HDAC2. Compound 4c, 4d,
ethanone (compound 3f as a mixture of E,Z 4f is showing better results.
isomers in10:1 ratio)
H1 NMR (400 MHz, DMSO-d6, 25°C) d
ppm 3.71 (0.2H, t, J=8), 3.75 (2H, t, J=8.8), 4.45
(0.2H, t, J=8.4), 4.51 (2H, t, J=8.8), 5.51 (0.1H,
ACKNOwLEDGEMENTS
The authors expressed their gratitude to
s), 5.61 (1H, s), 7.25 (0.2H, dd, J=2, J=6.8), 7.75 Dr. M. Mallika, Department of Medicinal Chemistry,
(0.2H, dd, J=2, J=6.8), 8.03-8.06 (2H, m), 8.21-8.24 NIPER- Hyderabad, for providing docking facility for
(2H, m), 9.76 (0.1H, bs), 9.92 (1H, bs); C13NMR the present research work.
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