Upload
truongkhue
View
234
Download
7
Embed Size (px)
Citation preview
INTRODUCTION INTRODUCTION
1
CC
C
NC
NC
C
CN
C
N
CC
CN
C
NC
C
CN
C
N
CC
CN
C
NC
C
CN
C
NC
C
CN
C
N
(ii) (i) (iii) (iv)
(v) (vi) (vii)
SYNTHESIS OF PYRIMIDINE DERIVATIVES
A) Synthesis of pyrimidine nucleus:
Pyrimidines (1,3-diazines) and their fused analogues form a large group
of heterocyclic compounds which share in building of nucleic acids, DNA
and RNA. These compounds have given attention in the last period due to
their interesting biological activities and therapeutic applications.
In fact, there are seven types of pyrimidine ring closure (i-vii)
depending upon the nature of fragments that combine together to form the
pyrimidine nucleus (1)
. Also, pyrimidine derivatives can be synthesized by
ring transformation and ring expansion.
INTRODUCTION INTRODUCTION
2
CHO
+
O
Urea
YbCl3 NH
NH
Ph
O
Ph
O
ArCHONaOH
O
Ar
NH
C
NH2H2N
.HCl
N N
Ar
NH22a-f
i) Synthesis of pyrimidine from C-C-C and N-C-N fragments:
This type is the most useful and widely used one for the construction
of a pyrimidine ring from non-heterocyclic precursors. It involves the
condensation of an amidine, urea, thiourea, guanidine or their derivatives
with 1,3-bifunctional three-carbon fragment.
Condensation of benzaldehyde, cyclopentanone and urea in the presence
of YbCl3 (Lewis acid) under free-solvent conditions yielded pyrimidine
derivative (1) (2)
.
α-Ionone was condensed with different aldehydes under phase transfer
conditions and the produced chalcones were refluxed with guanidine
hydrochloride in isopropanol in the presence of silver oxide to afford the
pyrimidine derivatives (2a-f) (3)
.
Ar
a 4-MeO-C6H4
b 3-MeO-C6H4
c 4-Cl-C6H4
d 4-F-C6H4
e 4-BnO-C6H4
f 4-NO2-C6H4
1
INTRODUCTION INTRODUCTION
3
N
O
R
NH
CNH2N
H
.HCl
Sodium isopropoxide,
Isopropanol
N
N
N
NH (CH2)3
R
N
N
N
N
(CH2)3
3a-e
4a-e
CH3COCH2CO2Et
O
NH2H2N
Cu(OTf)2
CH3CN
NH
NH
Ph
H3C O
EtO
OCHO
5
The biologically active pyrimidine derivatives (4a-e) were produced by
the reaction of chalcones (3a-e) with guanidine derivative in isopropanol
and sodium isopropoxide (4)
.
High yield of 3,4-dihydropyrimidin-2(1H)-one derivative (5) was
obtained by the three-component condensation reaction of benzaldehyde,
ethyl acetoacetate and urea in acetonitrile and employing copper (II) triflate as
a reusable catalyst (5)
.
The pharmacologically active 6-methylenesubstituted-4-trichloromethyl-
2-methylsulfanylpyrimidines (7a-d) were achieved by refluxing the
halogenated enone (6) with S-methylisothiourea sulphate in methanol/water
(3:1 v/v) in the presence of hydrochloric acid followed by nucleophilic
substitution reactions (6)
.
R
a H
b 4-SMe
c 4-Me
d 4-Cl
e 4-OMe
INTRODUCTION INTRODUCTION
4
O
Cl3C
OCH3
Br MeS
NH
NH2
.H2SO4
2
MeOH/H2O
HClN
N
CCl3
SMe
Br
HZ
N
N
CCl3
SMeZ
CHO
R
O
OEtNC
NH
C
NH2H2N
.HCl NaOH, EtOHN
N
CN
OHH2N
R
The reaction of aromatic aldehydes, ethyl cyanoacetate and guanidine
hydrochloride in alkaline ethanol under reflux afforded 2-amino-5-cyano-6-
hydroxy-4-arylpyrimidines (8a-g) (7)
.
Z
a SC6H5
b Morpholin-4-yl
c Piperidinyl
d N(CH2CH3)2
R
a H
b 3-NO2
c 2-Cl
d 4-OMe
e 3-Cl
f 4-OH
g 2-NO2
6
7a-d
8a-g
INTRODUCTION INTRODUCTION
5
NH2
NH
HNN Ar
O
F3C CH3
OEt
EtOH
rt
N
N
CF3
H3C NH
N Ar
C C
MeS
MeS CN
C
O
OMe
CH3CONH2
NaH
O
CNH
H3CC
C
SMe
COOMe
CN
MeOH
HN
N
H3C
O
COOMe
SMe
Novel 2-(N'-benzylidenehydrazino)-4-trifluoromethylpyrimidines (11a-f)
were produced by the cyclocondensation reaction of N-guanidino-
benzylimines (9a-f) with enone (10) through stirring in ethanol at room
temperature (8)
.
ii) Synthesis of pyrimidine from C-C-C-N and C-N fragments:
Ketenethioacetal (12) was reacted with acetamide in the presence of
sodium hydride in a mixture of benzene and DMA to give (13), which
cyclized on refluxing in methanol to the pyrimidine derivative (14) (9)
.
Ar
a C6H4
b 2-HO-C6H4
c 4-Me-C6H4
d 4-Cl-C6H4
e 4-MeO-C6H4
f 4-NO2-C6H4
9a-f 10
11a-f
12 13
14
INTRODUCTION INTRODUCTION
6
N
HNH3C O
Ph
O
NH2
H3C OEt
O
PhNCO
15
O
EtO OEt
O
CF3CNNa / ether
OEtO
EtOOCNH2
CF3
OEtO
EtOOCN
CF3
CF3CNCF3
H2N
- EtOH
N
N
CF3
CF3HO
EtOOC
HN
NH
CN
S
S
Ph
S
NCSPh
NC
SH2N
6-Methyl-3-phenyluracil (15) was obtained by the reaction of ethyl
β-aminocrotonate with phenylisocyanate (10)
.
The condensation reaction of diethyl malonate and two molecules of
trifluoroacetonitrile furnished ethyl 2,6-bis(trifluoromethyl)-4-hydroxy-
pyrimidine-5-carboxylate (16) (11)
.
3-Phenylthioacryloylisothiocyanate was reacted with 2-cyanothio-
acetamide and yielded 6-styryl-2,4-dithioxo-1,2,3,4-tetrahydropyrimidine-
5-carbonitrile (17) (12)
.
16
17
INTRODUCTION INTRODUCTION
7
NH2H3C
O
X
Ar C NCS
O
NH2
H3C
S
NHX
O
ArO
- H2O
NH3C
S
NHX
O
Ar
C N
MeS
MeS
CN
NC-CH2CSNH2
NH2X
NC
N NH
NH2
MeS
CN
S
N
N
SMe
X NH2
NC
21
20
iii) Synthesis of pyrimidine from C-C-N and C-N-C fragments:
Addition of enaminoketone or enaminoester to aroylisothiocyanate
provided the intermediate (18), which undergoes cyclodehydration in basic
medium to give the corresponding pyrimidine derivative (19a-d) (13-15)
.
Cycloaddition of chalcogen (20) with 2-cyanothioacetamide in sodium
ethoxide afforded pyrimidine derivative (21) (16)
, while cycloaddition of
the same compound with 3-aminoacrylonitrile derivatives in DMSO and
anhy. K2CO3 at room temperature yielded the derivatives (22a,b) (17)
.
X Ar
a OEt C6H5
b OEt 4-MeO-C6H4
c OEt 4-Cl-C6H4
d CH3 C6H5CH=CH
X
a Pyrrolidinyl
b Morpholin-4-yl
18
19a-d
22a,b
INTRODUCTION INTRODUCTION
8
NH2
NH2
O C(OEt)2 or
CO2 / MeOHNH
NH
O
23
NH2H3C
HNH2
O
N N
CH3HO
R
Base
+ (RCO)2O
24a,b
H3C CH
C
C
O
O
NH2
NH2
MeCH(COOMe)2
N N
HO
Me
OH
MeCHCO2Me
25
iv) Synthesis of pyrimidine from N-C-C-C-N and C fragments:
1,3-Diaminopropane was reacted with diethyl carbonate (18)
or carbon
dioxide in methanol (19)
and yielded perhydropyrimidin-2-one (23).
2-Alkenyl-6-methyl-4-hydroxypyrimidines (24a,b) were produced by
the reaction of β-aminocrotonamide with α,β-unsaturated acid anhydride
followed by cyclization in basic medium (20)
.
The reaction of 2-methylmalonodiamide with an ester such as
2-methylmalonic ester afforded 4,6-dihydroxypyrimidine derivative (25) (21)
.
R
a CH2=CH
b CH3-CH=CH
INTRODUCTION INTRODUCTION
9
H
H3C CH3
CH3
O
HO NH4OAc
MW
H
H3C CH3
CH3
HN
H2N
PhCHO
MW
H
H3C CH3
CH3
N
N
H
Ph
H
H3C CH3
CH3
N
N
Ph
B 27
26 A
(CH2)n
O
+N
H2N SCH3
CN
DBU
N
N SCH3
NH2
(CH2)n
28
Steroidal pyrimidine (27) was prepared through microwave-assisted
three-component reaction of 2-hydroxymethylene-3-ketocholestan (26),
benzaldehyde and ammonium acetate for 6 min. The mechanism involves the
formation of β-aminoketoimine intermediate (A), which condensed with
benzaldehyde led to diimine intermediate (B). Then the latter was cyclized
and auto-oxidized to the product (22)
.
v) Synthesis of pyrimidine from C-N-C-N and C-C fragments:
The reaction of cyclopentanone or cyclohexanone with 3-cyano-2-
methylisothiourea in the presence of DBU as base catalyst afforded
4-aminopyrimidine derivatives (28) (23)
.
n = 1 or 2
INTRODUCTION INTRODUCTION
11
NH
NR1
Y
R2
R3
COR4
- HY
N
N
R1
R3
COR4
R2
30 29 31
NH
O
HOOC
NH2
N
NH
O
Ph
O
32
1,3-Diaza-1,3-butadienes (29) were reacted with electron-deficient
acetylenes (30) under mild conditions to provide pyrimidine derivatives
(31) (24)
.
vi) Synthesis of pyrimidine from C-C-C-N-C and N fragments:
N-phenyluracil (32) was prepared by the addition of aniline to
N-propynoylcarbamic acid (25)
.
1-Chloro-1,1-difluoro-4-phenylaminobut-3-en-2-one was reacted with
n-propylamine and formaldehyde in DMSO under mild conditions and the
corresponding pyrimidine derivative (33) was obtained (26)
.
R1 = Ph, EtO2C, (EtO)2CH, Cl3C
R2 = H, Me, Ph, 4-Me-C6H4
R3 = H, Me, Ph, MeO2C
R4 = H, OMe, OEt
Y = OR, SMe, NMe2
INTRODUCTION INTRODUCTION
11
H
PhHN
H
O
CF2Cl
CH3CH2CH2NH2 2 HCHO
DMSO
N
N
Ph
CH2CH2CH3
CF2Cl
O
33
N
C
CH3H3C
O CH3
S
H2N NH2 2
MeOH
rt
N N
NHHN
S
H3C
H3C
CH3 H3C
CH3
CH3
S
34
4-Isothiocyanato-4-methyl-2-pentanone was reacted with benzidine in
methanol at room temperature with two to one molar ratio and yielded
bis(2-thioxopyrimidin-1-yl) biphenyl derivative (34) (27)
.
INTRODUCTION INTRODUCTION
12
N
C
CH3
O H
S
N NHNH2
MeOH
RefluxN NH N
NH
S
CH3
HO
35
HNR
NH
O
S
Ph
EtONa
NR
NH
O
S
Ph
37 36
HN
Ph
CO2C2H5
ONH2
PCl5 / CHCl3N
NH
Ph
CO2C2H5
OO
38
Pyrimidine-2-thione derivative (35) was obtained by refluxing
2-hydrazinopyridine with 3-isothiocyanatobutanal in methanol (28)
.
vii) Synthesis of pyrimidine from N-C-C-C-N-C fragment:
N-propenoylthiourea derivatives (36) were cyclized in sodium ethoxide
to 2-thioxoperhydropyrimidin-4-ones (37) (29)
.
Oxidative cyclization of ethyl ester of benzoyl asparagine by using
phosphorus pentachloride in chloroform yielded ethyl 2-phenyl-6-
oxotetrahydropyrimidine-5-carboxylate (38) (30)
.
INTRODUCTION INTRODUCTION
13
N
O CH3
O
NH
Ph
O(CH3)2NH
N
N CH3
O
NH
Ph
O
CH3
39
O
N
X
OH
HOH2NAr
MW
K-10 clay OH
N
X
OH
HOArHN
O
N
X
OH
HOArHN
- H2O
N
N
X
OH
HO
Ar
40
41a-f 41a-f
viii) Synthesis of pyrimidine by ring transformation and ring
expansion:
2-Benzoylamino-6-methyl-1,3-oxazin-4-one was transformed into
pyrimidine derivative (39) via the reaction with dimethylamine (31)
.
Solvent-free microwave irradiation of a mixture of 1,3-oxazin-2-ones
(thiones) (40) and aromatic amines in the presence of K-10 clay through
amine-driven dehydrative ring transformation result in formation of
pyrimidine derivatives (41a-f) (32)
.
X Ar
a O C6H5
b O 4-Cl-C6H4
c O 4-MeO-C6H4
d S C6H5
e S 4-Cl-C6H4
f S 4-MeO-C6H4
INTRODUCTION INTRODUCTION
14
NH
R1
H
N
O
N
O
R2
OEt
H2
Pd / C
NH
R1
H
NH
O
NH
O
R2
OEt
- EtOH
NR1
HN
OH
NH
O
R2
42
43
The hydrogenation of 1,2,4-oxadiazole derivatives (42) lead to the
reductive cleavage of N-O bond followed by cyclization to give the
pyrimidine derivatives (43) (33)
.
INTRODUCTION INTRODUCTION
15
HN
N
N
H2N SCH2CO2Et
+ CH3COCH2CH(OMe)2N
a / EtO
H
N
N
N
SCH2CO2Et
rt
NH3C
45
44
HN
N
N
H2N SBn
+ CH2(COOEt)2
CH3ONa
N
N
N
N
OH
HO
SBn
46
B) Synthesis of fused pyrimidines:
1. Synthesis of triazolopyrimidines:
1.1. From triazole derivatives:
The aminotriazole derivative (44) was cyclized with acetylacetaldehyde
dimethylacetal in Na / EtOH at room temperature to give ethyl 2-(5-methyl-
1,2,4-triazolo[1,5-a]pyrimidin-ylthio)acetate (45) (34)
.
2-Benzylthio-5,7-dihydroxy-1,2,4-triazolo[1,5-a]pyrimidine (46) was
prepared by the cyclization reaction of 3-amino-5-benzylthio-2H-1,2,4-
triazole with diethyl malonate in sodium methoxide (35)
.
Cyclization of 3-amino-2-(cyanoethyl)-5-substituted-1,2,4-triazoles
(47a-c) by refluxing in toluene for 48 hours afforded 5-amino-1,2,4-triazolo-
[1,5-a]pyrimidine derivatives (48a-c) (36)
.
INTRODUCTION INTRODUCTION
16
Toluene
refluxN
N NH2N
N
NR
CH2CH2CN
NH2
N
N
R
47a-c 48a-c
N
N
H3C NH
NH2
Ar
NaNO2 / AcOH
CH2Cl2
N
N
H3C
Ar
N
N
N
F3C F3C
Ar = MeO
OMe
Br
49 50
1.2. From pyrimidine derivatives:
Triazolo[4,5-d]pyrimidine derivative (50) was achieved by the
diazotization of the pyrimidine derivative (49) with sodium nitrite and
acetic acid in methylene chloride (37)
.
The reaction of 4-hydrazinopyrimidine derivatives (51a-c) with
trimethylorthoformate in THF afforded the triazolo[4,3-c]pyrimidine
derivatives (52a-c) as novel Syk inhibitors (38)
.
R
a CH3
b C2H5
c Ph
INTRODUCTION INTRODUCTION
17
N
N
HN
NC
NHNH2
NH
Ar
N
N
HN
NC
NH
Ar
NN
Ar'Ar'
CH (OMe)3
51a-c 52a-c
Ar =
MeO
MeO
NMeS
NC
NH2
CH3
CH3
O
CH(OEt)3
Ac2O
NMeS
NC
N
CH3
CH3
O
HC OEt
Ar NH2
CH3CN
NMeS
NC
CH3
NN
CH2
Ar
53
54a-d
2. Synthesis of pyridopyrimidines:
2.1. From pyridine derivatives:
Pyrido[4,3-d]pyrimidine derivative (54a-d) was produced by the reaction
of 4-aminopyrimidine derivative (53) with triethyl orthoformate using
acetic anhydride as catalyst followed by treatment with different amines in
acetonitrile (39)
.
Ar’
a CH2CH2OTBS
b CH2CO2But
c CH2CH2NHBoc
Ar
a C6H5CH2
b 2-F-C6H4CH2
c 4-F-C6H4CH2
d 4-F-C6H4CH2CH2
INTRODUCTION INTRODUCTION
18
O
Ar
CH2
NH
Me
MeCl
+
N
R
EtOH
HCl
N
N
H
Ar
O
R
Cl
NH2
56 55
57a-c
HN
NH
O
S N Ph
C CEtOOC COOEt HN
NH
O
S N
COOEt
COOEt
Ph
58 59
Condensation of 2-aminopyridines (56) with enone Mannich bases (55)
in ethanol and the presence of hydrochloric acid afforded pyrido[1,2-a]-
pyrimidines (57a-c) (40)
.
2.2. From pyrimidine derivatives:
Cycloaddition reaction of azadiene (58) with diethyl acetylene-
dicarboxylate yielded pyrido[2,3-d]pyrimidine derivative (59) (41)
.
5-Aryl-5,11-dihydro-1H-indeno[2’,1’:5,6]pyrido[2,3-d]pyrimidine-2,4,6-
triones (60a-e) were prepared by Hantzsch cyclization of indan-1,3-dione
with aromatic aldehyde and 6-aminouracil in acetic acid (42)
.
R Ar
a H 4-Br-C6H4
b 3-Me C6H5
c 6-Me C6H5CH2O
INTRODUCTION INTRODUCTION
19
O
O
+ Ar CHO +NH
HNH2N
O
O
AcOH
HN
NH
HN
O Ar
O
O
60a-e
N NH
NH2R
+
O
O
CH3
Ph
O
NN
N
R
Ph
CH3
O OH
MW
61a-d
62a-d
3. Synthesis of pyrazolopyrimidines:
3.1. From pyrazole derivatives:
6-(2-Hydroxybenzoyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidines
(62a-d) were achieved by regioselective microwave-assisted reaction of
5-aminopyrazole derivatives (61a-d) with 3-benzoyl-2-methyl-4H-chromen-
4-one (43)
.
Ar
a C6H5
b 3-F3C-C6H4
c 3-Br-C6H4
d 3-CN-C6H4
e 3-F-C6H4
Ar
a CH3
b But
c 4-Br-C6H4
d 4-NO2-C6H4
INTRODUCTION INTRODUCTION
21
N
HN
H2N
EtOOC
O
Me2N
+ AcOH N
N
N
COOEt
NO2
NO2
Fe/ AcOH
N
N
N
COOEt
NH2
Ar COCl
PyridineN
N
N
COOEt
HN
COAr
63
F3C
Ar =
64
N
NH
O
O
H3C
NH
NH2
+N
C
O
Ph
EtOHN
NH
O
O
H3C
NH
N
NHPh
65 66
The B-Raf kinase inhibitor pyrazolo[1,5-a]pyrimidine-3-carboxylate
derivative (64) was synthesized from the reaction of 5-amino-1H-pyrazole-
4-carboxylate with compound (63) in acetic acid followed by reduction and
aroylation (44)
.
3.2. From pyrimidine derivatives:
6-Hydrazinouracil (65) was reacted with phenylisocyanate at room
temperature then refluxed in ethanol to furnish the corresponding
pyrazolo[3,4-d]pyrimidine (66) (45)
.
INTRODUCTION INTRODUCTION
21
O
N
NH2
R +
O
COOEt
Xylene
O
N
RN O
O
N
RN
O
+
67a-c
68a-c 69a-c
N
ONH2
CN
CH (OEt)3
N
ON
CN
CH
OEt
N
ON
N
NH
RN
ON
N
NHR
Base
RNH2
71a-d 72a-d
70
4. Synthesis of oxazolopyrimidines:
4.1. From oxazole derivatives:
2-Amino-5-substituted-2-oxazolines (67a-c) were refluxed with ethyl
2-oxocyclopentane carboxylate in xylene to afford a mixture of isomeric
oxazolo[3,2-a]pyrimidines (68a-c) and (69a-c) (46)
.
Reaction of 5-aminooxazole-4-carbonitrile with triethyl orthoformate
gave an ethoxymethyleneamino derivative (70) which cyclized with the
appropriate amine to the isolable 7-iminooxazolo[5,4-d]pyrimidine
derivatives (71a-d). However, the latter underwent a Dimorth rearrangement
under basic conditions to7-amino derivatives (72a-d) (47)
R
a C6H5O
b Piperidinyl
c 4-Et-C6H4O
R
a Me
b Et
c Prn
d PhCH2
INTRODUCTION INTRODUCTION
22
N
N
O
O
R
N3
R1
+PPA
N
N
O
O
R
R1
N
O
PhPh COOH
74 73
N
N
O
O
R
O
R1
+ N
Cl
Cl
CH3
CH3
Cl
CHCl3N
N
O
O
R
O
R1
Cl
NMe2
N
N
O
O
R
O
R1
N3
NMe2
(CH3)3SiN3
N
N
O
O
R
R1
O
N
NMe2
reflux
rt
75
76 77
4.2. From pyrimidine derivatives:
Oxazolo[5,4-d]pyrimidine-5,7-diones (74) were produced by thermolytic
reaction between 6-azidouracils (73) and benzoic acid in the presence of
PPA (48)
.
Condensation of 1,3-disubstitutedbarbituric acid (75) with dimethyl-
dichloromethyleniminium chloride and subsequent treatment with trimethyl-
silylazide afforded (77) through the rearrangement of the highly unstable
α-azidoenamines (76) (49)
.
INTRODUCTION INTRODUCTION
23
N
SS
N
CO2Et
CPh N Ph
+ R NH2N
SS
N
CO2Et
CPhNHPh
NHR
EtONa
EtOH
N
S
S
Ph
N
N
Ph
O
NHR
78
79a-e
N
SNH2
+OR'
R
acetone N
SN R'
R
80a-d
5. Synthesis of thiazolopyrimidines:
5.1. From thiazole derivatives:
Thiazolo[4,5-d]pyrimidines (79a-e) were obtained by the reaction of
thiazole carbodiimide derivative (78) with different amines followed by
cyclization in sodium ethoxide and ethanol (50)
.
The reaction of 2-aminothiazoline with α,β-unsaturated carbonyl
compounds under mild conditions yielded dihydrothiazolo[2,3-a]pyrimidines
(80a-d) (51)
.
R
a 3-MeBn
b 2-FBn
c 4-FBn
d Bui
e But
R R’
a Me H
b Ph Me
c Ph Et
d Ph Ph
INTRODUCTION INTRODUCTION
24
HN
NH
O
SCN
NH2O
DMFHN
NH
O
O N
S
NH2
81
NH
NH
Ar
MeO2C
H3C S
+ ClCH2COOH +
R
CHO
AcOH / Ac2O
N
N
Ar
MeO2C
H3C S
O
CH
R
NaOAc82
83a-d
F
Ar =
5.2. From pyrimidine derivatives:
Preparation of 2-aminothiazolo[4,5-d]pyrimidine-5,7-dione (81) was
achieved via thermal cyclization of 4-aminouracil-5-thiocyanate in DMF (52)
.
Three-component reaction of pyrimidine derivative (82), chloroacetic
acid and aromatic aldehyde produced thiazolo[3,2-a]pyrimidines (83a-d) (53)
.
R
a H
b 4-Me
c 4-MeO
d 4-Cl
INTRODUCTION INTRODUCTION
25
N
N
OH
OH
HNO3 / AcOH
N
N
OH
OH
NO2
20o c
84
REACTIONS OF PYRIMIDINES
1) Electrophilic substitution:
Formal replacement of a CH unit in pyridine by a nitrogen atom reduces
the capacity of corresponding diazine towards electrophilic substitution.
Electrophilic substitution is difficult in simple inactivated diazine because of
both extensive protonation under strongly acidic conditions and the inherent
lack of reactivity of the free base. For these reasons, one strongly electron-
releasing group, at least, must be present to make the reaction successful.
a) Nitration:
Pyrimidines normally require the presence of at least two electron-
releasing groups for successful nitration. Thus, 4,6-dihydroxypyrimidine was
nitrated using nitric acid in acetic acid at 20c to give the 5-nitroderivative
(84) (54)
.
b) Sulphonation:
Contrary to nitration, sulphonation needs only one electron releasing
group and takes place at position 5. Sulphonation of 2-aminopyrimidine using
fuming sulphuric acid at 180c gave 2-amino-5-sulphopyrimidine (85) (55)
,
while chlorosulphonation of 2,4-dihydroxypyrimidine at 110c gave
5-(chlorosulphonyl)-2,4-dihydroxypyrimidine (86) which reacted with sodium
carbonate to give 2,4-dihydroxy-5-sulphopyrimidine (87) (56)
.
INTRODUCTION INTRODUCTION
26
N
N
NH2
H2SO4
180oc
N
N
NH2
SO3H
85
N
N
OH
OH
ClSO3H
110oc
N
N
OH
OH
SO2Cl
Na2CO3
N
N
OH
OH
SO3H
86 87
N
H
N
NH2
O
Br2 / AcOH
N
H
N
NH2
O
Br
88 89
N
H
NH
O
O
F2 / H2SiF2
N
H
NH
O
O
F
90
c) Halogenation:
Typically, pyrimidines having at least one electron-releasing substituent
may be halogenated at position 5 by chorine or bromine in aqueous solution
or by bromine in acetic acid. N-chlorosuccinimide, N-bromosuccinimide,
phosphoryl chloride, phosphoryl bromide and phosphorous pentachloride
have been used for the 5-halogenation of some pyrimidines.
The reaction of cytosine (88) with bromine in acetic acid provided
5-bromocytosine (89) as a major product (57)
.
5-Fluorouracil (90) was prepared by the interaction of uracil with
fluorine in 40% H2SiF2 at 70c (58)
.
INTRODUCTION INTRODUCTION
27
N
N
CH3
SH CH3
+
+N2
SO2NH2 N
N
CH3
SH CH3
NN
SO2NH2
91 92
N
H
N
O
MeS Ph
CN
PhNH2
N
H
N
O
PhHN Ph
CN
93 94
N
NH
O O
Cl
CH3
RNHNH2
N
NH
O O
NRNH2
CH3
95 96a-c
d) Diazo-Coupling:
Pyrimidines may be coupled with diazotized amines to give 5-arylazo-
derivatives. Thus, treatment of 4,6-dimethyl-2-mercaptopyrimidine (91) with
diazotized p-aminobenzenesulphonamide leads to the formation of 4,6-
dimethyl-5-(sulphamylbenzeneazo)-2-mercaptopyrimidine (92) (59)
.
2) Nucleophilic substitution:
a) Reaction with amines and hydrazines:
5-Cyano-2-methylthio-6-phenylpyrimidine-4-one (93) was reacted with
aniline to give 5-cyano-2-(phenylamino)-6-phenylpyrimidine-4-one (94) (60)
.
6-Chloro-3-methyluracil (95) was reacted with hydrazine, methyl-
hydrazine and benzylhydrazine to give the corresponding hydrazino-
pyrimidines (96a-c) (61)
.
R
a H
b Me
c Bn
INTRODUCTION INTRODUCTION
28
N
N
Cl
ClH3C
NaOH N
N
OH
ClH3C
97
N
NSH3C
O
O KCNN
NNC
98 99
N
NH
Ar
NC
SMe
S
+ BrCH2COOEtK2CO3
N
N
Ar SMe
SEtO2C
H2N
100a-c 101a-c
b) Hydrolysis:
The reaction of 4,6-dichloro-2-methylpyrimidine with sodium hydroxide
provided 4-chloro-6-hydroxy-2-methylpyrimidine (97) (62)
.
c) Cyanation:
Treatment of 2-pyrimidinyl-methylsulfone (98) with potassium cyanide
afforded 2-cyanopyimidine (99) (63)
.
3) Alkylation and acylation:
2-Methylthio-4-thioxopyrimidines (100a-c) were treated with ethyl
bromoacetate and potassium carbonate in ethanol to give thieno[2,3-d]-
pyrimidines (101a-c) (64)
.
Ar
a C6H5
b 4-MeO-C6H4
c 4-Cl-C6H4
INTRODUCTION INTRODUCTION
29
N
N
NH2
OCH3H3C
(ClCH2CO)2O N
N
NHCOCH2Cl
OCH3H3C
102
103
104
105
2-Chloroacetamido-4-methoxy-6-methylpyrimidine (102) was obtained
by acylation of 2-amino-4-methoxy-6-methylpyrimidine with (ClCH2CO)2O
in dioxane (65)
.
4) Reaction with active methylene group containing compounds:
2-Aminopyrimidine was reacted with ethyl 2-chloroacetoacetate
and furnished ethyl imidazo[1,2-a]pyrimidine-5-carboxylate (103) which
was converted into the corresponding carboxylic acid (104) by alkaline
hydrolysis (66)
.
Reaction of 4-amino-5-phenylpyrimidine with diethyl phenylmalonate
gave pyrimido[1,6-a]pyrimidine derivative (105) (67)
.
N
N
NH2
+ CH3COCH(Cl)COOEt
N
N
N
CH3
COOEt
N
N
N
CH3
COOH
-OH
N N
NH2
Ph
+ PhCH(COOEt)2
N N
Ph
N O
Ph
INTRODUCTION INTRODUCTION
31
106
107 108
BIOLOGICAL ACTIVITY OF PYRIMIDINE DERIVATIVES
Condensed and non-condensed pyrimidines are biologically interesting
molecules that have established utility in the pharmaceutical and the
agrochemical industries. Compounds with these ring systems have diverse
pharmacological activity such as anticancer (68)
, anti-inflammatory (69,70)
,
antitumor (17,71)
, antibacterial (72-74)
, antimalarial (75)
and antifungal (76)
.
A number of substituted quinolinyl pyrimidines (106) were synthesized
as a new class of anti-infective agents and showed a good antitubercular and
antimalarial activities (77)
.
A series of novel 2,4,5-trisubstituted pyrimidine derivatives (107and
108) were evaluated for inhibition against the human hepatocellular
carcinoma BEL-7402 cancer cell line and several compounds showed potent
inhibition with an IC50 value less than 0.10 µM (78)
.
NCl
O
N
N
R
NH2
N
N
CH3
R2
OH
N
N
NH2
R2
OH
INTRODUCTION INTRODUCTION
31
109
110
N-Benzyl-2-[2-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-4-yl]-
acetamide (109) can be used as inhibitor of human hydroxysteroid
dehydrogenase (HSD) (79)
.
Pharmacological studies of some substituted 1H-pyrazolylthiazolo[4,5-d]-
pyrimidines (110) showed that they possess anti-inflammatory and
antimicrobial activities (80)
.
2-(2-Aroylaroxy)-4,6-dimethoxypyrimidines (111) were screened for
their anti-inflammatory activity and have shown superior anti-inflammatory
activity in the range 21.5-48.6 % . Compounds with chloro and fluoro groups
at para position in benzoyl and phenoxy moieties of benzophenone elicited
maximum inhibition (48.6 %) (81)
.
MeO
N
H
N
O
O
NH
NH
N
S
N
O
N
N
R
NN CH3
INTRODUCTION INTRODUCTION
32
111
112 113
114 115
A new series of 2,4,6-trisubstituted pyrimidine derivatives (112, 113,
114 and 115) showed an excellent activity against leishmania (82)
.
N
N
OCH3
OCH3OO
R1
R2
OCH3
H3CO
H3CO
NN
NH2
N
OCH3
H3CO
H3CO
NN
NH2
N
O
OCH3
H3CO
H3CO
NN
NH2
N
NEt
OCH3
H3CO
H3CO
NN
NH2
NH
CH3
CH3
CH3