Ugx 11 GJ 5685697

J. Pharm. Appl. Chem., 2, No.
3, 103-127 (2016) 103

Journal of Pharmaceutical and Applied Chemistry
An International Journal
http://dx.doi.org/10.18576/jpac/020301
Chemistry of Thienopyrimidines and Their Biological

Applications
Mohamed Abdel-Megid1,*, Kamlia M.Elmahdy2, Azza M. Elkazak2, Magdy H.Seada2 and Osama F. Mohamed2
1
College of science and humanities studies (hurrymila), Shaqra University, KSA.
2
Chemistry Department, Faculty of Education, Ain-Shams University, Roxy, Cairo, Egypt.
Received: 5 Jan. 2016, Revised: 2 Jun. 2016, Accepted: 6 Jun. 2016.
Published online: 1 Sep. 2016.
Abstract: The recent studies on the synthesis, reactions and biological applications of isomeric thienopyrimidine
derivatives have been reported in this review
Keywords: Thienopyrimidines, synthesis, reactions, biological applications.
1 Introduction 2 Synthesis Of Thienopyrimidines

Thiophene containing compounds are well known to The building of thienopyrimidine moiety has been achieved
exhibit various biological effects. Heterocycles containing either by annulations of pyrimidine nucleus on the parent
the thienopyrimidine moiety are of interest because of their thiophene ring or annulations of thiophene nucleus on the
interesting pharmacological and biological activities [1– parent pyrimidine ring. Also, they obtained from acyclic
3]. They bear structural analogy and isoelectronic relation compounds.
to purine and several substitutedthieno[2,3-d]pyrimidine
derivatives shown to exhibit prominent and versatile 2.1 Annulations of pyrimidine on thiophene ring
biological activities [4,5]. Over the last two decades, many
thienopyrimidines have been found to exhibit a variety of The simple approach to the formation of a new pyrimidine
pronounced activities. Many of their derivatives have been ring involves introducing a one-carbon fragment between
synthesized as potential anticancer [6], analgesic [7], two suitable and vicinal functional groups in thiophene
antimicrobial [8-9] and antiviral agents [10]. ring.
Recently, we reported some reviews on pyrimidinethiones 2.2- Using thiophene having vicinal amino ester
[11] and condensed pyrimidines, namely pyrazolo- groups
pyrimidines [12] and furopyrimidines [13]. The work deals
with the study of the synthesis, reactions and biological Thiophene derivatives having vicinal amino ester groups is
applications of thienopyrimidines in view of their great considered a suitable synthon for the synthesis of
importance. In the last decade, thienopyrimidines were thienopyrimidines via its interaction with various suitable
reviewed [14]. The three fundamental thienopyrimidine reagents.
systems are thieno[2,3-d]pyrimidine (Ι), thieno[3,2-d]
pyrimidine (II) and thieno[3,4-d]pyrimidine (Ш). This 2.2.1- With isocyanate and isothiocyanate
article aimed to show the recent novel precursors to derivatives
synthesize thienopyrimidine derivatives and reported their
application in pharmaceutical and biological evaluations in Reaction of ethyl 2-amino-5-benzoyl-4-methylthiophene-3-
the last decade. carboxylate (1) [15] with phenyl isothiocyanate and/or
N phenyl isocyanate in presence of a catalytic amount of
N triethylamine afforded the corresponding
N
S thioureidothiophene and/or ureidothiophene 2a,b, which
S N
N S
N underwent cyclization in etnanolic sodium ethoxide to yield
(I) (II) (III) thieno[2,3-d]pyrimidinone derivatives 3a,b, respectively.
* Corresponding author E-mail:mabdelmegid@yahoo.com

© 2016 NSP
Natural Sciences Publishing Cor.
104 M. Abdel-Megid et al.: Chemistry of Thienopyrimidines and their …
Moreover, treatment of compound 1 with benzoyl 4-isopropylthiophene-3-carboxylate (8) gave ethyl 4-
isothiocyanate in ethanolic sodium hydroxide gave 6- isopropyl-2(3-methylthiourenyl)thiophene-3-carboxylate
benzoyl-2-thioxothieno[2,3-d]pyrimidine derivative 4 [16]. (9) followed by cyclization in aqueous sodium hydroxide
O O
to yield 5-isopropyl-2-mercapto-3-methylthieno[2,3-d]
Me OEt Me OEt pyrimidin-4-one (10) [19].
PhNCS or PhNCO
Ph Ph Me O
NH2 Et3N, reflux 8h, 60-70% NH Me O Me O
S S OEt
Me
O 1 O OEt Me NMe
2a,b NHPh Me
X MeNCS, reflux 3h aq.NaOH
PhCONCS NH reflux 1h, 67% SH
EtONa, reflux 8h, EtOH, 71% S
NaOH, reflux 6 h, 70% N
NH2 S
70-75% S
NHMe 10
O 9 S
O 8
Me NH Me NPh In the same way, cyclocondensation of ethyl 2-amino-5-
Ph
N
S Ph X carbamoyl-4-methylthiophene-3-carboxylate (11) [20] with
N
O
S H S H benzyl isothiocyanate in presence of anhydrous potassium
4 O
3a,b
a, X = S
carbonate gave sulfanylthieno[2,3-d]pyrimidine derivative
b, X = O 12 [21].
2-Aminothiophene-3-carboxylates 5a,b [14] were used for O O
Bn
synthesis of 3-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)- Me OEt
Me N
diones 6a,b via conversion with N-ethylisocyanate BnNCS/ K2CO3 H2N
H2N SH
followed by the cyclization using ethanolic sodium MeCN, reflux 15h, 78% N
NH2 S
hydroxide [17]. S
O
O
11 12
O O
1 1 Et
R OEt R
N In addition to, thienylthiourea derivatives 14a-e were
i) EtNCO, CH 2Cl2, reflux 5h prepared by addition of 2-amino-3-ethoxycarbonyl-4,5-
2 ii) NaOH, EtOH, reflux 1.5h O disubstitutedthiophenes 13a,b [15,22] to alkyl or aryl
2
R NH2 R N
S S isothiocyanates, either by heating at reflux or under
H
5a,b 1 2 6a,b microwave irradiation [23-25]; the latter method afforded
a, R = Me, R = Ph;
higher yields of the desired products in shorter time.
b, R 1 R 2 = -(CH 2)4-
Compound 14a was also prepared by condensation of
Also, 3-(4-chlorophenyl)-2-hydroxy-5,6,7,8-tetrahydro- amino ester 13a with phenyl thiourea under microwave
benzo[b]thieno[2,3-d]pyrimidin-4-one (7) was synthesized irradiation. Furthermore, cyclization of compound 14a-e
from treatment of compound 5b with p-chlorophenyl- using alcoholic potassium hydroxide gave the mono-
isocyanate at 120˚C and followed by cyclization by potassium salts of the corresponding 3-substituted-2-
aqueous potassium hydroxide solution [18]. thioxo-4,5-disubstitutedthieno[2,3-d]pyrimidin-4-ones 15a-
Cl
e. 2-Thioxo derivatives 16a-d were prepared either from
the appropriate potassium salts 15 by acidification or from
O O the amino ester derivatives 13a,b via cyclocondensation
OEt N
with aryl isothiocyanates [26,27].
i) p-ClC6H4NCO, reflux 3h
OH
ii) KOH, H 2O, reflux 3h N
NH2
S S
5b 7
Further, addition of methyl isothiocyanate to ethyl 2-amino-
© 2016 NSP
J. Pharm. Appl. Chem., 2, No. 3, 103-127 (2016)/ http://www.naturalspublishing.com/Journals.asp 105
O O
R
1
OEt R
1
NR
3
addition reactions. Treatment of compound 24a-f with
p-Cl-C 6H4NCS, reflux 20h
S
aqueous alcoholic potassium hydroxide caused
2
2 N
R
S
NH2 acetonitrile R
S H intramolecular cyclization with formation of the potassium
13a,b
1 2
16a-d 1 2 3
a, R R = (CH 2)2N(CH3)CH2, R = p-Cl-C 6H4;
1 2 3
salts of 4-oxo-2-thioxothieno[2,3-d]pyrimidines 25a-f. 2-
a, R R = (CH 2)2N(CH3)CH2; b, R R = (CH 2)2N(CH3)CH2, R = (CH 2)3CH3;
1 2
b, R R = -(CH 2)5-
1 2 3
c, R 1R 2 = -(CH 2)5-, R 3 = C 6H5; Thioxothienopyrimidines 26a-f were isolated by
d, R R = -(CH 2)5-, R = p-Cl-C 6H4
PhNHCSNH2 R NCS, EtOH, reflux 1-4h
3
acidification of aqueous solutions of 25a-f [31].
EtOH, MW 20 sec or MW 45 sec H2O, HCl, r.t.
Me O O
Me
O Et Et
O OEt OEt
1 1
R OEt R 3 RNCS, reflux 7-12h
KOH, EtOH, reflux 2-6h NR
X X
- +
2 SK NH2
R NH 2
N S NH
S R
S S
NHR
3
15a-e 23a,b
14a-e S 24a,b NHR
1 2 3 S
10,11a, R R = (CH 2)2N(CH3)CH2, R = C 6H5;
1 2 3 a, X = O
b, R1 R2 = (CH 2)2N(CH3)CH2, R3 = p-Cl-C 6H4;
c, R R = (CH 2)2N(CH3)CH2, R = (CH 2)3CH3; KOH, 50% aq. EtOH
1 2 3 b, X = S
d, R R = -(CH 2)5-, R = C 6H5;
1 2 3
e, R R = -(CH 2)5-, R = p-Cl-C 6H4 Me O
Et Me O
NH Et
Reaction of ethyl 2-amino-4-methyl-5-(4-nitro/methoxy- X
HCl NR
S
phenyl)thiophene-3-carboxylate 17a,b with a variety of S
N X - +
SK
H N
isocyanates gave the corresponding ureas, which were S
26a-f 25a-f
cyclized under basic conditions to afford thieno[2,3-d]
24a, X = O, R = COPh; b, X = S, R = COPh
pyrimidine derivatives 18a-l [28]. 26a, X = O, R = H; b, X = S, R = H
24c, 26c, X = O, R = Ph; d, X = S, R = Ph,
O O 2
R e, X = O, R = Me; f, X = S, R = Me
Me Me
OEt N
2
i) R NCO, pyridine
o O
Also, treatment of compound 5b with phenyl isocyanate in
stir at 45 C 2h N
1
S
NH2 ii) MeOH/MeONa or 1
S H dry toluene afforded 3-phenyl-5,6,7,8-tetrahydrobenzo[b]
R EtOH/ EtONa R 18a-l
17a,b thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (27) [32].
1 1 2 1 2
a, R = NO 2; b, R = OMe a, R = NO 2, R = Ph; b, R = NO 2, R = 3-MeOC 6H4; O O
1 2 i 1 2
c, R = OMe, R = Bu; d, R = OMe, R = cyclohexyl;
1 2 1 2
e, R = OMe, R = Bn; f, R = OMe, R = Ph; OEt NPh
1 2 1 2
g, R = OMe, R = 2-MeOC 6H4; h, R = OMe, R = 4-MeOC 6H4; i) toluene, reflux 3h, 67%
1 2
i, R = OMe, R = 4-MeOC 6H4; j, R = OMe, R = 2-ClC 6H4;
1 2
+PhNCO ii) aq. KOH(10%), reflux 3h O
1 2 1 2
k, R = OMe, R = 3-ClC 6H4; l, R = OMe, R = 4-ClC 6H4 NH2 N
S S H
27
On the other hand, thiophene-3,4-dicarboxylates 20a,b 5b
were obtained by refluxing the corresponding β-amino Addition of appropriate isothiocyanate to amino ester
esters of thiophenes 19a,b with benzoyl isothiocyanate in derivatives of thiophenes 28 [33] under reflux conditions
acetone [29]. Refluxing of compound 20a,b in ethanolic yielded thienylthioureas 29, which on refluxing in ethanol
potassium hydroxide solution, it gave the respective and hydrochloric acid gave the corresponding thieno[2,3-d]
monopotassium salts 21a,b, which on acidification with pyrimidine-2(1H)-thione derivatives 30 [34].
concentrated hydrochloric acid afforded the corresponding
O O
thieno[2,3-d]pyrimidine-5-carboxylates 22a,b, respectively R
1
OEt 1
R OEt
[30]. 3
R NCS, reflux 3-24h
O 2 2
O R NH2 EtOH R NH
1 1
S S
R OEt R OEt
28 3
SCNCOPh, reflux 1h 29 NHR
S
2 2
R NH2 acetone R NH EtOH / HCl, reflux 24h
S S
19a,b
20a,b NHCOPh O
S
1
R 3
KOH, EtOH, reflux 3-6h NR
O
1 O S
R 2
NH 1 R N
H2O, HCl, r.t. R S H
NH
S - +
30
2
N stir SK
R 1 2
S H 2
N R R = -CHMe-(CH 2)3-, -CH 2CHMe-(CH2)-,
R
S
22a,b 1 2
-(CH2)2-CHMeCH2-
a, R R = -CH(COOC 2H5)CH2CH2- 21a,b 3
R = Me, Et, Ph
b, R 1R2 = -CH(COOC 2H5)CH2CH2CH2-
Furthermore, treatment of compounds 5b or ethyl 2-amino-
Also, treatment of 2-amino-5-ethyl-5-methyl-3-ethoxy- 4,5-dimethyl-thiophene-3-carboxylate (31) [14] with
carbonyl-4,5-dihydro-7H-thieno[2,3-c]pyran(thiopyran) methyl isothiocyanate in refluxing glacial acetic acid
(23a,b) with various isothiocyanates gave the furnished the corresponding thiourea derivatives 32, which
corresponding 2-N-thioureides of the thiophenes 24a-f. were cyclized to the corresponding thiones 33 by refluxing
This reaction belongs to the general class of nucleophilic in sodium ethoxide then cooled and acidified with 6 N HCl
© 2016 NSP
O
[35]. O
1
O 1 R
R OEt OEt
1
O 3
R OEt 1 SCNC6H4-R
R OEt
glacial AcOH, 84% 2
2
+ MeNCS R
2
S
NH2 R
S
NH
R NH2 2 3
S R NH NHC 6H4R
S 31, 37 38a-i S
5b, 31
32 NHMe 1 2
S 31, R = R = Me
1 2 NH2NH2.H 2O
5b, R R = -(CH 2)4- 1 2
1 2 i) NaOEt, reflux 10 min 37, R = H, R = Ph
31, R = R = Me EtOH, reflux 12h
ii) HCl (6N), 89%
O
O NH2
1
1 R
R N
NMe
3
S NHC 6H4R
2
2
N R N
R S
S H 39a-i
33 1 2 3
a-e, R = H, R = Ph, R = H, Me, OMe, Cl( p), Cl(o)
Moreover, cyclocondensation of compound 31 with aryl 1 2
f-i, R = R = Me, R = H, Me, Cl( p), Cl(o)
3
isocyanates in the presence of potassium t-butaoxide

Also, treatment of amino ester 5b, 40 with the appropriate
yielded 3-aryl-5,6-dimethylthieno[2,3-d]pyrimidin-
isocyanates gave N-(3-carbethoxy-4,5,6,7-tetrahydrobenzo
2,4(1H,3H)-dione 34a-e [36].
[b]thien-2-yl)-N`-substitutedthioureas 41a-h [39,40], which
O
Me
O on hydrazinolysis frunished 3-amino-2-susbstitutedamino-
OEt Me
t-BuOH, t-BuOK
NAr thieno[2,3-d]pyrimidin-4(3H)-ones 42a-h [41,42].
+ ArNCO
reflux 3h, 58-73% O O O O
Me NH2 N 1
NH2
S Me 1 R
S H 1 R OEt N
R OEt
31 NH 2NH 2.H 2O
34a-e RNCS
reflux 8-14h 2
NHR
a, Ar = Ph; b, Ar = 4 -MeC6H4; c, Ar = 3-MeC 6H4; 2 R N
2 R
R NH2 NH S
d, Ar = 3-ClC 6H4; e, Ar = 3,4-Cl 2-C 6H3 S S
42a-h
5b, 40 41a-h NHR
S
While, reaction of compound 11 with phenyl isothiocyanate 1 2
5b, R R = (CH 2)4; 40, R R = (CH 2)3
1 2
1 2
1 2
a, R R = -(CH 2)4-, R = Me;
b, R 1R 2 = -(CH 2)4-, R = Et;
in acetonitrile in the presence of anhydrous potassium c, R R = -(CH 2)4-, R = Ph;
1 2
carbonate yielded 2-mercapto-5-methyl-4-oxo-3-phenyl- d, R1 R2 = -(CH 2)4-, R = 4-MeC 6H4;
e, R1 R2 = -(CH 2)4-, R = Bn;
3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide (35) f, R 1R 2 = -(CH 2)4-, R = 4-ClC 6H4;
g, R 1R 2 = -(CH 2)3-, R = Ph;
[37]. h, R R = -(CH 2)3-, R = 4-ClC 6H4;
O O
2.2.2 With formamide
Me
Me OEt NPh
MeCN, anhy. K 2CO3
H2N + PhNCS reflux 15h, 78%
H2N
N
SH 5-Methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-
S
NH2 S carboxamide (43) was prepared via reaction of compound
O
O
11 35 11 with formamide [37].
On the other hand, treatment of compound 8 with excess of O
O
potassium thiocyanate in dioxane afforded 5-isopropyl-2- Me
NH
Me OEt
mercaptothieno[2,3-d]pyrimidin-4(3H)-one (36) [19]. reflux 3h, 76%
H2N
+ HCONH2 H2N
N
left at rt for 24h S
NH2
S O
43
When thiophene derivatives 31 and/or 37 were allowed to O
11
react with the substituted aryl isothiocyanate, they gave N-
aryl-N`-(3-carboethoxythien-2-yl)-thioureas 38a-i, which
reacted with hydrazine hydrate to give 3-amino-3,4- Also, treatment of ethyl 2-aminothiophene-3-carboxylate
dihydro-2-substitutedphenylaminothieno[2,3-d]pyrimidin- derivatives 44, 5b, 45a-f. 13b and 46 with formamide gave
4(3H)-ones 39a-i [38]. 4-hydroxythieno[2,3-d]pryimidine derivatives 47-51 in
good yield [43-50].
Me O Me O
Me OEt Me NH
KSCN,dioxane, EtOH
SH
reflux 6h, 50% N
NH2 S
S
36
8
© 2016 NSP
O HO O
2 2 O 1
O
R OEt R 1
R OEt
N R NC 1
reflux 2-12h OEt o R
+ HCONH2 7-84%
dioxane, 20 C NH
R
1
NH2 1
N 2
+ R
2
S
NH
S R R NH2 dry HCl, 74-85% 2
N
S S Cl R
NH.HCl S Cl
1 2 5b, 46 Cl 57a,b
1 2 47, R = R = H 1 2
44, R = R = H 1 2 5b, R R = -(CH 2)4- 56 1 2
1 2 48, R R = -(CH 2)4- a, R R = -(CH 2)4-
1 2
5b, R R = -(CH 2)4- 1 2 1 2 46, R = Me, R = COOEt 1
b, R = Me, R = COOEt
2
1 2 1 2 49a, R = Et, R = H; 49b, R = Me, R = H;
45a, R = Et, R = H; 45b, R = Me, R = H; 1 2 1 2
1 2 1 2 49c, R = i-Pr, R = H; 49d, R = t-Bu, R = H;
45c, R = i-Pr, R = H; 45d, R = t-Bu, R = H; 1 2 1 2
1 2 1 2 49e, R = Bn, R = H; 49f, R = Me, R = Et
45e, R = Bn, R = H; 45f, R = Me, R = Et
1 2
13b, R R = -(CH 2)5- 1
1 2
50, R R = -(CH 2)5-
2
Also, treatment of compound 31 or 40 with alkyl/aryl nitrile
51, R = COOEt, R = Me
1 2
46, R = COOEt, R = Me in dioxane using dry hydrochloric acid afforded the
corresponding 2-alkyl/arylthieno[2,3-d]pyrimidin-4(3H)-
Moreover, cyclization of ethyl 2-amino-5-ethylthiophene-3-
ones 58 [56].
carboxylate (45a) with formamide under microwave
irradiation at 350W for 25-28 minute gave thieno[2,3-d] O O
1 1
pyrimidine derivative 49a in good yield [51]. hydrogen R OEt R
NH
chloride gas through a solution of compound 5b or 46 with dioxane, reflux 3h
+ RCN
dry HCl R
3-chloropropanonitrile through intermediate 56 [55]. R
2
NH2 R
2
N
S S
31, 40 58
1 2 R = Me, Ph, Et, n-Pr,
O O 31, R = R = Me
Bn, C 5H4N
1 2
40, R R = -(CH 2)3-
OEt 350 W, NH
25-28 min On the other hand, reaction of compound 5b with
+ HCONH2 87-92% N cyanamide and 1-arylcyanamides gave 2-aminothieno
Et NH2 Et
S S [2,3-d]pyrimidin-4(3H)-ones 59. A similar reaction of
45a 49a cyanoguanidine derivatives with compound 5b afforded 2-
guanidinothieno[2,3-d]pyrimidin-4(3H)-ones 60 [57].
Also, treatment of methyl 4-acylamino-3-aminothiophene-
O
2-carboxylates 52a,b with formamide gave 7-acylamino- CN
OEt
NH O
O
NC
3,4-dihydrothieno[3,2-d]pyrimidin-4-ones 53a,b [52]. HN
R
NH NHR`
NH
NH
NH
O NHR NH2 N
O S S
NH NH2 N NH
NH N S 5b R`HN
60
R reflux 7h, 65-71%
59
OMe R NH R` = H, p-tolyl, m-tolyl, p-ClC6H4, p-MeOC 6H4
S
+ HCONH2 R = H, p-tolyl, o-tolyl, p-ClC6H4, p-MeOC 6H4
S
O
52a,b O
a, R = Ph 53a,b
b, R = 4-MeC 6H4
Also, treatment of compound 46 with acetonitrile or
benzonitrile yielded the corresponding 2-(methyl/phenyl)-
Similarly, ethyl 3-aminobenzothiophene-2-carboxylate (54) thieno[2,3-d]pyrimidines 61a,b [50].
[53] reacted with formamide under reflux conditions to O O
afford benzothieno[3,2-d]pyrimidin-4(3H)-one (55) [54]. Me OEt Me
NH
dry HCl gas
O + MeCN / or PhCN O R
NH2 2-4h, 76%/ 90% N
S S
NH2 N EtO EtO
46 61a,b
OEt reflux 2h, 76% NH a, R = Me;
S
+HCONH2 b, R = Ph
S
O 55 O
54
By the same manner, reaction of compounds 5b and/or 45a

with different nitrile compounds afforded 4-hydroxy-
thieno[2,3-d]pyrimidine derivatives 62a,b [58].
2.2.3 With nitrile compounds
2-(2-Chloroethyl)-thieno[2,3-d]pyrimidin-4(3H)-ones 57a,b
were prepared via passing of a stream of dry hydrogen
chloride gas through a solution of compound 5b or 46 with
3-chloropropanonitrile through intermediate 56 [55].
© 2016 NSP
O O O O
HO NH2
2
R OEt 2 Me OEt Me NHNH 2 Me N
R
o N NH2NH2.H 2O CS2, EtONa
a) reflux 8h/ 50 C O
1
+ RCN
b) AlCl3, 15h, 30% R
O
reflux 8h, 80% NH2 reflux 15h , 68%
O
N
S
R NH2 1
N NH2 S S
S R S H
S EtO EtO EtO
46 68 69
5b, 45a 62a,b
1 2
1 2 a, R R = -(CH 2)4-
5b, R R = -(CH 2)4- 1 2
1
45a, R = Et, R = H
2 b, R = Et, R = H 2.2.5 With triethyl orthoformate
R = Cl 3C, Bn
Reaction of methyl 3-aminothiophenehydrochloride-4- Treatment of amino ester 11 with triethyl orthoformate and
carboxylate (63) [58] with 2-cyanomethylbenzoic acid in benzyl amine furnished 3-benzyl-5-methyl-4-oxo-3,4-
presence of triethylamine gave 2-(4-oxo-3,4-dihydrothieno dihydrothieno[2,3-d]pyrimidine-6-carboxamide (71a) in
[3,4-d]pyrimidin-2-yl)methylbenzoic acid (64) in good 83% yield accordance with the previously reported reaction
yield [60]. conditions [64]. Accordingly, compounds 71b-e were
O
synthesized via the one pot reaction condition by reaction
of amino ester 11 with triethyl orthoformate and
S
NH appropriate amine in 79-85% [37].
COOMe O O
CH2CN N R
S O
PhCl, Et 3N, Boil 2h Me OEt Me N
+ O HC(OEt)3 H3C OEt
R-NH 2, 3h O
NH2.HCl COOH 90%
COOH NH2 reflux 3h O o
stir at 40 C
N
S S
H2N N H2N
S 71a-e
11 H2N
63 OEt a, R = Bn; b, R = -CH 2CH2OH; c, R = Pr;
64 70
d, R = cyclohexyl; e, 2-pyridyl
2.2.4 With carbon disulfide Also, reaction of amino ester 1, 31 with triethyl
orthoformate and sodium azide afforded 2-(1H-tetrazol-1-
Effect of carbon disulfide on vicinal amino ester was yl)thiophenes 72a,b, which cyclized to 2,3-diamino-
observed. Treating of thiophenes 5b, 65 [14] with carbon thieno[2,3-d]pyrimidin-4(3H)-one derivatives 73a,b on
disulfide in aqueous sodium hydroxide followed by refluxing with hyrazine hydrate [65,66].
addition of dimethyl sulphate yielded sulfanylthiocarbonyl- O O
aminothiophene derivatives 66a,b, which on hydrazinolysis Me OEt Me OEt
gave 3-amino-2-mercaptothieno[2,3-d]pyrimidin-4-ones + HC(OEt)3
gl. AcOH, reflux 2h
N
67a,b [61,62]. R
S
NH2 NaN3, 65% R
S
N N
N
O 72a,b
O 1, 31
1
R OEt 1
R 1, R = COPh; 31, R = Me NH 2NH 2.H 2O,
i) NaOH, DMSO stir 30 min OEt
2
+ CS2 o reflux 7h, 75-80%
R NH2 ii) Me 2SO4, stir at 5-10 C, 2h
S 2
R NH
S
O
5b, 65 SMe NH2
1 2 1 2
66a,b S Me N
5b, R R = -(CH 2)4-, 65, R =Me; R = COMe
reflux on water bath 8h NH 2NH 2.H 2O NH2
R N
S
O 73a,b
1
NH2
R a, R = COPh; b, R = Me
N
R
2
N
SH 2.2.6 With acetic anhydride
S
67a,b
1 2 1 2
a, R R = -(CH 2)4-, b, R =Me; R = COMe Acylation of the amino ester 11 and/or 46 with acetic
The acid hydrazide 68 obtained by refluxing of ethyl anhydride gave N-acetylated derivatives 74a,b, which
thiophene-3-carboxylate 46 with hydrazine hydrate cyclized on treatment with hydrazine hydrate in ethanol to
underwent cyclocondensation on treatment with carbon yield 3-aminothieno[2,3-d]pyrimidine derivatives 75a,b in
disulfide to give 3-amino-6-carboxyethyl-5-methyl-2- good yield [37,63].
O
thioxothieno[2,3-d]pyrimidin-4-one (69) [63]. O
O
NH2
Me OEt Me
Me OEt N
(MeCO)2O NH 2NH 2.H 2O, EtOH,
reflux 3h, 77-90% reflux 2-8h, 79-83% Me
R NH2 R N
S R S
NHCOMe
S
11, 46 75a,b
74a,b
11, R = CONH 2; 46, R = COOEt a, R = CONH 2; b, R = COOEt
© 2016 NSP
On the other hand, ethyl 2-amino-4-(2-furanyl)-thiophene- Cl
3-carboxylate (76) [14] was converted into ethyl 2- O

O
O OEt N
acetylamino-4-(2-furanyl)-thiophene-3-carboxylate (77) by O O
OEt 4-ClC6H4CH2NH2
nucleophilic acylation of amino group with acetic EtO Cl
NH fusion 8h,
NH
reflux 3h, 87% o S
anhydride according to modified literature method [33]. NH2 S O 230-240 C
Zinc dust was added in catalytic amount to improve the S EtO

85
5b 84
overall yield of compound 77. Hydrazinolysis of compound
77 afforded 3-amino-5-(2-furanyl)-2-methyl-3H-thieno
[2,3-d]pyrimidin-4-one (78) [67]. 2.2.8 With urea and their derivatives
O O O
NH2
Methyl 3-aminothiophene-2-carboxylate (86) was
O OEt
(MeCO)2O stir, 80%
O OEt
NH2NH2.H2O,
O
N condensed with urea at 190°C to yield thieno[3,2-d]
Zn dust, water bath 10 min.
dry EtOH, reflux 3h
N
Me pyrimidin-2,4(1H,3H)-dione (87) in high yield [70].
NH2 NHCOMe
S S S
76 78 NH2 H
77
NH2 o N O
reflux 190 C
O + O
2.5h,98% NH
S NH2 S
OMe
86 O
87
2.2.7 With chloroformate derivatives
Treatment of thiophene derivative 79 with p-nitro-phenyl Also, 4-substitutedthiophenes 88a,b were condensed with
chloroformate in basic medium gave carbonylamino- 1,3-dicarbmethoxy-2-methyl-2-thiopseudourea (89) [71] to
thiophene 80, which reacted with (E)-3-(4-(tert- give the guanidine adducts 90, which was found to be more
butyldimethylsilyloxy) phenyl)-prop-2-en-1-amine (81a) or convenient to add an excess of sodium methoxide,
(E)-3-(4-methoxyphenyl)-prop-2-en-1-amine (81b) in whereupon cyclization occured with concomitant loss of a
presence of pyridine gave ureidothiophene derivatives carbamate group to give pyrimidinone derivatives 91a,b.
82a,b. Refluxing of compounds 82a,b in sodium methoxide The remaining carbamate group underwent hydrolysis and
yielded thieno[2,3-d]pyrimidines 83a,b[68]. decarboxlation on treatment with aqueous sodium
O Ph
hydroxide to yield thieno[3,2-d]pyrimidin-4-ones 92a,b
Ph
O
Cl O
O [72].
OEt
OEt
NCOOMe
pyridine, r.t. 6-12h O
O + NH NH2 NH
NH2 77% S
S NHCOOMe NHCOOMe
EtO O HgCl2, Et 3N, DMF R
EtO O R O
NO 2
80
O + MeS
79 NCOOMe stir overnight S
S OMe OMe
89
88a,b 90a,b
NH2
NO 2 NaOMe, stir 12h

NHCOOMe
NH2
N
pyridine, THF, r.t. 12-24h N o NH
NH NaOH, 55 C, 2h R
a, R = TBDMS R
b, R =Me
OR 63-78% S O
81a,b S O
Ph 91a,b
Ph 92a,b
O
O a, R = 3-pyridinyl
OR OEt
b, R = phenyl
N
O O
NaOMe, reflux 3h O
S
NH
2.2.9 With other reagents
N
S H 88-90% EtO
EtO O
HN
83a,b Azidothiophene ester 94 was prepared by reacting of
aminothiophene derivative 93 [73] with sodium nitrite and
sodium azide. Refluxing of compound 94 with one
a, R = H equivalent of triphenylphosphine yielded 3-triphenyl-
b, R = Me
RO
82a,b
phosphiniminothiophene 95, which underwent aza-Wittig
type reaction with phenylisocyanate to give highly reactive
Also, condensation of compound 5b with ethyl carbodiimide intermediate 96, which was reacted with
chloroformate gave 2-ethoxycarbonylaminothiophene 84, absolute ethanol under refluxing conditions to give 2-
which was fused with p-chlorobenzylamine to afford 3-(4- ethoxy-thieno[3,2-d]pyrimidine 97 and 2,4-dioxothieno
chlorobenzyl)-5,6,7,8-tetrahydro-1H-benzo[4,5]thieno [3,2-d]pyrimidine 98. Also, compound 96 was reacted with
[2,3-d]pyrimidin-2,4-dione (85) [49,69].
© 2016 NSP
secondary amines in sodium ethoxide to afford the
corresponding thieno[3,2-d]pyrimidines 99a-c[74].
NC N3 NC N
NC NH2 PPh3 O O
O
NaNO2/ NaN 3 PPh3
OEt OEt
OEt OEt OEt 2,4-dichloro- OEt
MeS dry toluene
MeS S MeS i-PrNCO, CH2Cl2
S S 6-methylphenol
O O o
93 O 94 95
N 0-5 C, 8-12h N
S N S
dry benzene PhNCO S
PPh3
105 106 N i-Pr NHi-Pr
O
NPh Me
NC N
H O
OEt Cl
NC N
NC N absolute EtOH
OEt
N
+ N Ph reflux 1h MeS
Ph S 107
MeS
MeS S O Cl
S
O 96
O 97
98 K2CO3
1 2
HNR R , EtONa O
1 2
HNR R N i-Pr
NC N
N O
Ph N
MeS
S
S Cl Me
O
99a-c
1 2
a, R R = morpholino
1 2
b, R 1 R2 = piperidino
c, R R = 4-methylpiperidino 108 Cl
By the same way, treatment of iminophosphorane 100 [75] Diethyl 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-

with aromatic isocyanates gave carbodiimide 101, which 3,6-dicarboxylate (109) [78] was reacted with thiophosgene
were allowed to react with primary amines to provide to afford 2-isothiocyanatothieno[2,3-c]pyridine 110, which
guanidine intermediate 102. Even in refluxing toluene, treated with ethyl glycinate to yield thieno[2,3-c]pyridine
compound 102 did not cyclize, however, in the presence of 111. Moreover, compound 111 underwent intracyclo-
catalytic amount of sodium ethoxide, compound 102 was addition in presence of sodium ethoxide to give thieno
converted easily to 2-alkylaminobenzo[b]thieno[3,2-d] [2,3-d]pyrimidine derivative 112 [79].
pyrimidin-4(3H)-ones 103 and 104 in satisfactory yields at O O
room temperature [76]. OEt OEt

stir 6h at r.t.
NR NHR EtOOC N + CSCl2 EtOOC N
NH2 60% NCS
NHR` S S
Ph3P
N N 110
R`NH 2, CH2Cl2 109
N RNCO, CH2Cl2
OEt 0.5-1h
o
0-5 C, 8-12h OEt H2NCH2COOEt, THF
OEt
S S TEA, stir 1h, 79%
S O
101 O O
O 102
100 O OEt
COOEt
EtOH/CH2Cl2, EtONa EtOH/ CH 2Cl2 0.5h N EtOOC N
NaOEt, 75%
6-10h N NH
EtOOC S stir 10 min S
N
NHR` NHR S NH
N H 111 S
N
112
NR NR` COOEt
S S
103
O
104
O 2.3 Using thiophene having vicinal cyanoamino
R = i-Pr, n-Bu, R` = t-Bu, i-Pr, n-C
Bn, Et, n-Pr, n-C 6H13, H, Me
6H11, groups
Also, condensation of iminophosphorane 105 with Also, thiophene derivatives having vicinal cyanoamino
isopropyl isocyanate in anhydrous dichloromethane yielded groups is considered a suitable reagent for the synthesis of
carbodiimide 106, which was allowed to dissolve in thienopyrimidines via its interaction with various suitable
acetonitrile then reacted with 2,4-dichloro-6-methylphenol reagents.
to give 2-iminothiophene 107, which treated with excess
potassium carbonate to afford thieno[2,3-d]pyrimidine 2.3.1 With formic acid
derivative 108 [77].
Formic acid was reacted with 5-amino-3-(4-chloro-
phenyl)thiophene-2,4-dicarbonitrile (113) to give 5-(4-
chlorophenyl)-3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-
6-carboxamide (114) in good yield [80].
© 2016 NSP
Cl H2N
Cl 1
R CN 1
O R N
i) HC(OEt) 3
NH
CN
2
reflux 12h, 80% H2N R NH2 ii) NH 3 2
+ HCOOH
N S R N
NC NH2 S S
S O
114 121a-f
113 122a-f
1 2
In similar manner, thieno[3,2-d]pyrimidin-4(3H)-ones a, R R = -(CH 2)4-;
1 2
116a,b were synthesized by treatment of 3-amino-2-cyano- b, R R = 7-methoxytetrahydrobenzo;
1 2
5-indol-3-ylthiophenes 115a,b with formic acid in the c, R = Me, R = H;
1 2
presence of catalytic amount of sulfuric acid in 84% and d, R R = 3,4-dihydronaphtho[1,2];
88% yield, respectively [81]. 1 2
e, R R = naphtho[1,2];
N 1 2
f, R R = 4-aminopyrimido[4,5]
NH2 o NH
H2SO4, 40 C
+ HCOOH S
O
2.3.3 With carbon disulfide
CN N
S
N
R
Action of carbon disulfide on 2-amino-4,5,6,7-tetrahydro-
R
115a,b a, R = H
116a,b
benzo- and/or 4,5,6,7,8-pentahydrocyclohepta-thiophene-3-
b, R = Bn carbo-nitrile 121a, 123 [14] in dry pyridine gave the
corresponding susbtitutedthieno[2,3-d]pyrimidine-2,4(1H,
Also, cyclocondensation of 2-amino-4,5-bis(4-chloro- 3H)-dithiones 124a,b [85].
phenyl)-thiophene-3-carbonitrile (117) with formic acid
HN S
and acetic anhydride led to formation of 5,6-bis(4- R
1
CN R
1
Dimorth R
1
NH
S
chlorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one (118) [82]. CS2/ pyridine
S
rearrangement
S
2 2 2
R NH2 R N R N
Cl Cl S S H
S H
121a, 123 124a,b
1 2
1 2 a, R R = -(CH 2)4-
O 121a, R R = -(CH 2)4- 1 2
b, R R = -(CH 2)5-
CN 1 2
123, R R = -(CH 2)5-
Ac2O NH
+ HCOOH
reflux 16h, 86%
NH2 N
S S
Cl Cl
117 118
2.3.4 With nitrile compounds
2.3.2 With triethyl orthoformate
Cyclocondensation of ethyl 5-amino-4-cyano-3- Nitriles reacted with vicinal aminocyanothiophene to yield
methylthiophene-2-carboxylate (119) with the target thienopyrimidines. Thus, interaction of 2-amino-
triethylorthoformate in the presence of few drops of acetic 4,5-dimethylthiophene-3-carbonitrile (125)[14] with
acid as a catalyst and appropriate susbtitutedaniline chloroacetonitrile in the presence of hydrogen chloride gas
afforded ethyl thieno[2,3-d]pyrimidine-6-carboxalyte gave two possible thieno[2,3-d]pyrimidine derivatives 126
derivatives 120a-d [83]. and 127 according to the following scheme [86].
R
H3C CN HN
Me CN halosubstituted Me
aniline N
AcOH, reflux 6h O OEt
N reflux 4h
O HC(OEt)3 S O
NH2 EtO N
S S
EtO EtO 120a-d
119
a, R = 4-Cl; b, R = 4-F;
c, R = 3-Cl,4-F; d, R = 2,4-di-F
Similarly, 4-aminothieno[2,3-d]pyrimidine derivatives

122a-f can be obtained by reaction of 2-amino-3-
cyanothiophene derivatives 121a-f with
triethylorthoformate followed by treatment with ammonia
at 0°C [84].
© 2016 NSP
Me CN CN
Me CN NC (NC)2HC
o
ClCH2CN, 5-10 C CN
NH2 N
HCl, dioxane, 8h N CH2(CN)2
NH2 Me
Me S Ph
S
NHCOPh sodium hydride NHCOPh N
CH2Cl S S S
125 HCl.H 2N 132
131
path (a), 27%

2.3.5 With isothiocyanates
path (b), 73%
-
Addition of aryl isothiocyanate to compounds 121a and 125
+ Cl
Me N H Me N in basic medium afforded 2-(N-arylthioureido)-3-
cyanothiophenes 133a,b which converted into 4-arylamino-
Me
S
N Me N 2-thioxothieno[2,3-d]pyrimidines 134a,b on refluxing with
S
CH2Cl
pyridine [91].
- + CH2Cl
HCl.H 2N Cl H 3N ArHN
1
1 R CN 1
R CN R N
ArNCS pyridine
2 S
2 NaOH R NH reflux 3h 2
N
R NH2 S R
NH2.HCl Cl S S H
Me Me S
ArHN
N 133a,b 134a,b
N 121a, 125
Me Me 1 2 1 2
121a, R R = -(CH 2)4- a, R R = -(CH 2)4-
1 2
S N CH2Cl S N CH2Cl 1 2 b, R = R = Me
125, R = R =Me
Ar = Ph, 4-Me-C 6H4, 3-MeC 6H4,
126 127 4-ClC6H4, 4-MeOC 6H4, 4-EtOC 6H4
Similarly, chloroacetonitrile was reacted with thiophenes Also, addition of benzoyl isothiocyanate to cyanoamino
121a in presence of hydrogen chloride gas to yield 2- thiophene derivatives 135 gave benzoylthioureas 136.
chloromethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d] Thermal ring closure of these intermediates in aqueous
pyrimidin-4-yl amine (128) [87]. sodium hydroxide solution was followed by the reaction
H2N with alkyl halides giving rise to the corresponding 4-
CN
N
aminothieno[2,3-d]pyrimidine derivatives 137 [92].
ClCH2CN/ HCl (g)
H2N
1
dioxane/ r.t. CH2Cl 1 R CN R
1
NH2 N R CN N
S
S PhCONCS i) NaOH-EtOH, reflux SR
3
2
121a 2 acetone, r.t. R
S
NH 3 R
2
N
128 R
S
NH2 ii) R X, r.t. S
S
PhOCHN
Moreover, treatment of 2-aminothiophene-3-carbonitrile 135 136 137
(129) with aryl and heteroaryl nitriles in presence of a R1R2 = -(CH 2)3-, -CH 2O(CH2)2-, 3
R = CH 2COOEt, (CH2)2Ph
-CH2N(Bn)(CH2)2-
catalytic amount of t-BuOK gave the corresponding 4-
aminothieno[2,3-d]pyrimidine derivatives 130 [88]. 2.3.6 With amidine derivatives
H2N
CN Treatment of 2-aminothiophene-3-carbonitrile 138
N
RCN, dioxane
with different cyclizing agents like guanidine carbonate
o R and/or chloroformamidine hydrochloride gave 2,4-
NH2 t-BuOK, 100 C N
S S diaminothieno[2,3-d]pyrimidine derivative 139 [93].
129 130 OBn
OBn
R = 2-methylfuran-5-yl, Ph
NH
On the other hand, addition of the cyano group of 2- H2N
CN
benzamido-4,5-dihydrothiophene-3-carbonitrile (131) [88] X NH2 N
to malononitrile afforded the intermediate β-enaminonitrile, NH2
X = NH 2, Cl NH2
S N
which underwent cyclization to give malnonitrile derivative BnO
S
138 BnO
132 [90]. 139
© 2016 NSP
2.3.7 By Mannich reaction Also, condensation of 3-amino-5-(1-benzyl-1H-indol-3-yl)-

2-thiophene-carboxamide (146) with heptaldehyde, p-
The three components condensation of 2-amino-3-cyano- anisaldehyde, 3,4,5-trimethoxybenzaldehyde and p-chloro-
4,5-dihydrothiophene 140 with p-toluidine and benzaldehyde in methanol containing 6% concentrated
formaldehyde led to the formation of 6-benzoyl-5-(2- hydrochloric acid afforded 6-(1-benzyl-1H-indol-3-yl)-2-
chlorophenyl)-3-(4-methylphenyl-3,4,5,6-tetrahydrothioeno substituted thieno[2,3-d]pyrimidin-4-ol derivatives 147a-d
[2,3-d]pyrimidine-4a(2H)-carbonitrile (141) [94]. [99].
Me R
N
Cl
NH2 NH
Cl NH2 RCHO, MeOH
NC
CN N NH2 6% HCl S
DMF, reflux 1 min N O
Ph
+ + HCHO o
kept at 20 C Ph S
Bn
N N O
NH2 24h, 76% S
S Bn R
Me O N
O 141 146
140
N
2.4 Using thiophene having Vicinal amino N

S
OH
carboxamido groups Bn
147a-d
2.4.1 With aldehydes a, R = n-hexyl; b, R = 4-MeOC 6H4;

c, R = 3,4,5-(MeO) 3C6H2, d, R = 4-ClC 6H4
Cyclocondensation of 2-amino-4,5,6,7,8,9- Moreover, treatment of 2-amino-3-thiophenecarboxamide

hexahydrocycloocta[4,5]thiophene-3-carbox-amide (142) derivative 148 with different aromatic aldehydes in normal
with the appropriate pyridine carboxaldehyde in the butanol and hydrochloric acid gave the corresponding
presence of concentrated hydrochloric acid resulted in dry thieno[2,3-d]pyrimidinone derivatives 149 [100].
DMF in 2-(2-and/or 4-pyridyl)-5,6,7,8,9,10-hexahydro- O O
cycloocta[4,5]thieno[2,3-d]pyrimidin-4(3H)-one 143a,b NH2
NH
[95]. EtO
RCHO, HCl (cat.) EtO
O N N
H o R
N NH2 n-BuOH, 80 C, 10h N
O O S S
O
NH2 R 148
ArCHO 149
N R = 2,3-dihydrobenzo[1,4]dioxin-6-yl,
dry DMF/HCl
NH2 S 4-(methylthio)phenyl, 4-methoxyphenyl,
2-benzo[1,3]dioxol-5-yl, 4-isopropenyl-
S cyclohex-1-enyl, 3,4,5-trimethoxyphenyl
142 143a,b
a, R = 2-pyridinyl
b, R = 4-pyridinyl 2.4.2 With acid halides
In the same manner, treatment of 3-carbxamidothiophene Condensation of compound 146 with chloroacetyl
derivative 144 with 3,4,5-trimethoxybenzaldehyde or chloride in dry tetrahydrofuran and catalytic amount of
cinnamaldehyde afforded the corresponding thieno[2,3-d] triethylamine led to the formation of 3-[(chloroacetyl)-
pyrimidin-4(3H)-ones 145a,b [96,97]. Likewise, compound amino]-2-thiophene 150, which reacted with different
144 was reacted with 2-nitrocinnamaldehyde or 2- amines to afford 3-substitutedamino-2-thiophene 151. The
methylcinnamaldehyde in the presence of catalytic amount later compound reacted with 2N sodium hydroxide to give
of hydrochloric acid to give 2-substitutedthieno[2,3-d] 2-substitutedthieno[2,3-d]pyrimidin-4(3H)-ones 152 [99].
pyrimidin-4(3H)-ones 145c,d [98]. O
NH2 NH
O ClCH2COCl, Et 3N
O NH2 o CH2Cl
THF, 0 C to r.t.
NH2 NH2
S S
NH N O
appropriate aldehyde O N
Bn Bn
R 150
NH2 MeOH, conc. HCl 146
S N 1 2
S R R NH, K 2CO3
144 145a-d
MeCN, reflux
O
1 2 NH
a, R = 3,4,5-trimethoxyphenyl; NR R
N 1 2
b, R = styryl; CH2NR R
2N NaOH NH2
c, R = 2-aminostyryl; NH
DMF, reflux S
d, R = 1-phenylprop-1-en-2-yl S N O
N O Bn 151
Bn 152
1 2
R R = piperdinyl, morpholinyl, N-methylpiperazinyl,
N-benzylpiperazinyl, pyrrolidinyl
© 2016 NSP
Similarly, treatment of compound 144 with ethyloxalyl O O
chloride in dry pyridine gave ethyl N-[3-(aminocarbonyl)- NH2 NH
4,5,6,7-tetrahydrobenzo[b]thien-2-yl]-oxamate (153), HC(OEt)3
Me toluene, 80% Me
which converted into thieno[2,3-d]pyrimidine derivative NH2 N
S S
(154) on pyrolysis at 260°C [101].
159 160
O O
O
NH2
NH2
NH 2.4.6 With 1,3-dicarbonyl compounds
EtOOCCOCl pyrolysis
COOEt
pyridine N
NH2
S
S
NHCOCOOEt S Reactions of ethyl 3-amino-4-cabamoyl-5-methyl-
154
144 153 thiophene-2-carboxylate (161) with carbonyl compounds
(acetylacetone, benzoylacetone, ethyl acetoacetate,
2.4.3 With formamide acetoacetanilide, ethyl benzoylacetate and α-
cyanoacetophenone) 162a-f gave intermediate enamine
Cyclocondensation of dicaroxamide derivative 155 163a-f, which cyclized to afford thieno[3,4-d]pyrimidines
with formamide afforded thieno[2,3-d]pyrimidine 114 164a-f [105].
[102].
O NH2 H
O N
O NH2 R
Cl
Cl Me NH2
RCOCH2R`
R` NH
CH2R`
162a-f Me
Me NH
O S H2O S
R
O COOEt S
COOEt
NH 161 COOEt
NH2 163a-f 164a-f
HCONH2 H2N
a, R = Me, R` = COMe; b, R = Me, R` = COPh;
H2N N
reflux 5h, 76% c, R = Me, R` = CO 2Et; d, R = Me, R` = CONHPh;
NH2 S
S e, R = Ph, R` = CO 2Et; f, R = Ph, R` = CN
O
O 114
155
2.4.7 With halogenated compounds
2.4.4 With formic acid
Cyclization of 2-amino-4-methyl-5-phenyl-
Treatment of formic acid with 3-amino-4- thiophene-3-carboxamide (165) [14] by effect of
carbamoyl-5-methyl-2-(N-phenylcabamoyl)thiophene (156) thiophosgene in dichloromethane afforded 5-methyl-6-
gave mixture of 6-methyl-4-oxo-3-phenyl-3,4- phenyl-2-thioxo-2,3-dihydrothieno[2,3-d]pyrimidin-4(3H)-
dihydrothieno[2,3-d]pyrimidine-7-carboxamide (157) and one (166) in excellent yield [17].
5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-7- O
O
carboxanilide (158) in 81and 7% yields, respectively [103]. Me NH2 Me NH
H SCCl2/ K 2CO3, CH2Cl2
O N
O Ph r.t. 1.5h, 93% S
O NH2 Ph N
N S
H2N N S H
H2N NH2 HCOOH + Me 165 166
N Ph S
NHPh NHPh
Me Me
S
S
O
O
158
O When 2-amino-5-ethylthiophene-3-carboxamide (167) was
157
156 allowed to react with benzoyl chloride it gave the
carboxamido derivative 168. Heating compound 168 with
2.4.5 With triethylorthoformate aqueous sodium hydroxide, 6-ethyl-2-phenylthieno[2,3-d]
pyrimidin-4(1H)-one (169) is produced [47].
Cyclocondensation of 2-amino-6-methyl-4,5,6,7-
O O
tetrahydrobenzo[b]thiophene-3-carboxamide (159) [14] O
NH2 NH2 NH
with triethylorthoformate afforded 7-methyl-5,6,7,8- PhCOCl, Et3N aq. NaOH, reflux
Ph
tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4-one (160) Et
S
NH2
benzene, reflux
Et
S
NHCOPh
25% Et
S
N
[104]. 167 168

169
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3. Annulations of Thiophene on Pyrimidine 2,4(1H,3H)-dione (179). Compound 179 can be also

Ring obtained from cyclocondensation of 6-chloro-5-formyl-1,3-
dimethyluracil (180) with ethyl 2-mercaptoacetate
[111,112].
The starting susbtituted pyrimidines are less readily
O
accessible for the synthesis of thienopyrimidines. The O
Me
location of the ring sulphur in thieno[2,3-d]pyrimidines N
Me
TEA, reflux 1h, 52% N
suggests that pyrimidines bearing a sulphu + HSCH2CO2Et
Cl N O EtO 2CCH2S N O
r at C-6 would serve as good candidates for developing the Me Me
thiophene ring. whereas, pyrimidines with a sulphur 177
178
POCl3-DMF
function at C-5 represent the most efficient precursors for reflux 30 min, 67%
the synthesis of thieno[3,2-d]pyrimidines. O

O
Me
OHC Me N
3.1 From uracil and thiouracil derivatives N EtONa, reflux 2h EtO 2C
+ HSCH2CO2Et
51% S
Cl N O N O
Thiouracils represent important starting materials which Me Me
cooperate in construction of the target thienopyrimidines. 180 179
Thiation of thiouracil derivative 170 [106] using

phosphorus pentasulphide in dry pyridine afforded thiated When 6-mercaptouracil (181) [113] was allowed to react
product 171 [107]. Alkylation of 171 with chloroaceto- with chloroacetaldehyde in the presence of sodium acetate
nitrile furnished 4-(4-chlorophenyl)-6-[(cyanomethyl)thio]- at room temperature, 1,3-dimethylthieno[2,3-d]pyrimidine-
2-(methylthio)pyrimidine-5-carbonitrile (172). Base- 2,4-(1H, 3H)-dione (182) was obtained [112].
induced intramolecular cyclization of 172 afforded 5- O
O
amino-4-(4-chlorophenyl)-2-(methylthio)thieno[2,3-d] Me
Me
pyrimidine-6-carbonitrile (173) [108]. N AcONa, 66% N
O S SCH2CN
+ ClCH2CHO
stir overnight
NC NC HS N O S
NH NH ClCH2CN/ dry acetone
NC
N
N O
P 2S 5
reflux 6h, 72% Me
N SMe N SMe N SMe
Me
171 181 182
Cl 170 Cl 172
Cl
reflux 4h, 83% DMF/ TEA Also, treatment of 1,3-dimethyluracil (183) with
NC chlorosulfonic acid afforded 5-chloro-sulfonyl-1,3-
S
dimethyluracil (184) [114], which was reduced on refluxing
H2N
N with zinc dust and sulfuric acid. Alkylation of the resulting
N SMe 1,3-dimethyl-5-thiouracil derivative 184 with propargyl
Cl 173 bromide afforded 5-(2-propynylthio)uracil 185, which
underwent cyclization in dimethyl sulfoxide to give 1,3,6-
trimethylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (186)
Also, treatment of 5-(2-hydroxyethyl)-6-methyl-2- in good yield [115].
methylthiopyrimidin-4(3H)-one (174) with phosphorus O O
O
oxychloride gave 4-chloro-5-(2-chloroethyl)-6-methyl-2- Me
N chlorosulfonic Me
N
SO2Cl
Me S
acid i) Zn, H 2SO4, reflux 1h N CH
methylthiopyrimidin-4(3H)-one (175), which was reacted
O N O N ii) NaOH,HC CCH2Br
with thiourea in presence of anhydrous sodium carbonate to Me
O N
Me
yield 5,6-dihydro-2-methylthio-4-methylthieno[2,3-d] 183 184
Me
185
pyrimidine (176) [109]. DMSO, 145 C
o
HO
Me Cl
Me Me O
Me S
N POCl3, reflux 2h N N
N H2NCSNH2/ EtOH
77% anhy. Na 2CO3,
O N SMe S N SMe O N
Cl N SMe reflux 2h, 78%
H Me Me
174 176 186
175
Moreover, condensation of 6-chloro-1,3-dimethyluracil 3.2 From thioxopyrimidine derivatives

(177) [110] with ethyl 2-mercaptoacetate gave 6-
ethoxycarbonyl-methylthio-1,3-dimethyluracil (178), which Cyclization of 6-thioxopyrimidine 187 [116,117]
underwent the Vilsmeier-Haack reaction to afford 6- with ethyl chloroacetate in DMF in the presence of excess
ethoxycarbonyl-1,3-dimethylthieno[2,3-d]pyrimidine- of anhydrous potassium carbonate at room temperature
© 2016 NSP
formed the nonisolable S-alkylated intermediate, which via In the same manner, alkylation of 6-mercaptopyrimidine
nucleophilic substitution and intramolecular cyclo- 195 [120] with ethyl bromoacetate in the presence of TEA
condensation gave thieno[2,3-d]pyrimidine derivative 188 produced 6-ethoxycarbonylmethylmercaptopyrimidine 196,
[118]. which was refluxed with sodium ethoxide to yield 3-
Me Me hydroxythieno[2,3-d]pyrimidine 197. However, the latter
CN CN compound was also prepared directly from compound 195
N DMF/ K2CO3 N
+ ClCH2COOEt on refluxing with ethyl bromoacetate in the presence of
stir 4h at r.t., 92%
Ph N S Ph N SCH2COOEt sodium ethoxide [121].
H
Me O
Me O
187
N OEt
EtOH/TEA N OEt
Me NH2
-
Ar + BrCH2COOEt reflux 30min, 60% Ar
-
N SH
N SCH2COOEt
N 195
COOEt 196
Ph N S
NaOEt, reflux 2h
Me OH
188 60%
NaOEt, reflux 30 min
Also, condensation of 4-mercaptopyrimidine derivative N 58%
COOEt
189 with ethyl bromoacetate in the presence of sodium Ar
-
S
N Me
carbonate yielded ethyl (2-(5-acetyl-2-(benzo[d][1,3] 197 N
dioxol-5-yl)vinyl)-6-(methylpyrimidin-4-yl)-sulfanyl) -
Ar =
acetate (190), which cyclized on refluxing in ethanol
containing catalytic amount of triethylamine to afford
thieno[2,3-d]pyrimidinederivative 191. In addition, Reaction of compound 195 with chloro reagents, namely,
compound 191 can be prepared directly from compound chloro-N-phenylacetamide, chloroacetamide and phenacyl
189 with ethyl bromoacetate in the presence of triethyl- chloride in refluxing ethanol containing TEA as a catalyst
amine in refluxing ethanol [119]. afforded 2-substitutedmercaptopyrimidines 198a-c. The
Me O
Me O
latter derivativesunderwent intramolecular cyclization using
sodium ethoxide yielding the corresponding fused thieno-
N Me Na 2CO3, stir 1h, 70% N Me
-
+ BrCH2COOEt pyrimidines 199a-c [121].
Ar N SH -
Ar N SCH2COOEt Me O
Me O
189 190 Me OH
EtOH/TEA N OEt N OEt O
reflux 1h, 65% EtOH/TEA ClCH2COR, TEA - EtONa, reflux 1h N
- Ar
Me Me Ar reflux 30 min, 58-70% -
reflux 2h, 70% N SH N SCH2COR Ar
56-72% N S R
N 195 198a-c
COOEt Me 199a-c
O
- -
Ar N S Ar = N
-
O Ar = a, R = NHPh; b, R = NH 2; c, R = Ph
191
Moreover, treatment of compound 189 with N-phenyl-

chloroacetamide in presence of anhydrous sodium acetate Moreover, 4-methyl-2-phenyl-6-mercaptopyrimidine-5-
gave thieno[2,3-d]pyrimidine 193 viathe non-isolated carbonitrile (200) was reacted with chloroacetonitrile
intermediate192. While, reaction of compound 189 with and/or chloroacetamide in the presence of sodium ethoxide
phenacylbromide in the presence of TEA in refluxing to give S-alkylated derivatives as intermediates 201a,b
ethanol furnished thieno[2,3-d]pyrimidine derivative 194 which upon heating cyclized to the corresponding
[119]. thieno[2,3-d]pyrimidines 202a,b [122,123].
Me O Me O Me Me
Me NH2
CN
N Me N Me N CN EtONa N
AcOH, AcONa EtOH, EtONa
+ ClCH2CONHPh + ClCH2Y N Y
- reflux 20h, 50% - Ph N SH stir 0.5h then heat S
Ar N SH Ar N S o Ph N
0.5h at 70 C, 88% Ph N SCH2Y
189 NHPh 200 202a,b
201a-c
a, Y = CN
BrCH2COPh/ TEA O b, Y = CONH 2
192
EtOH reflux 1h, 65%
In addition to, 2,4-diamino-6-mercaptopyrimidine (203)
Me Me
Me Me [124] was reacted with α-haloketones to afford the desired
NHPh
N
NHPh N 2,4-diaminothieno[2,3-d]pyrimidine derivatives 205
-
Ar N S O Ar
-
N S O through an intermediate pyrimidyl sulfide derivatives 204
194 193 [125].
O
-
Ar =
O
© 2016 NSP
NH2 NH2 NH2 NH2 NH2
O R O R CN
N (CH2OH) 2, MeONa N N K2CO3, EtOH/THF (5:1) N
+ o + HSCH2CO2Et COOEt
heat at 120 C, 30 min reflux 6h, 93%
H2N N SH X R` H2N N S R` Me2N N Cl Me2N N S
203 213 214

204
o
Also, heating of pyrimidine-5-carbaldehydes 215a-c with
Ph2O, Oil bath 210 C
ethyl mercaptoacetate at reflux in the presence of TEA
yielded the corresponding ethyl 2-methylthiothieno[2,3-d]
NH2 R pyrimidine-6-carboxylate derivatives 216a-c [130].
N
R` NR2
NR2
H2N N S CHO
N EtOH, TEA N
205 + HSCH2COOEt CO2Et
R =Ph, 4-Br-C 6H4, 2,4-Me 2-C 6H3, MeS N Cl reflux 5-9h, 67-90%
MeS N S
3,4-(OMe) 2-C 6H3, Me
R` = H, Bn 215a-c
a, R 2 = Me 216a-c
b, R 2 = -(CH 2)4
3.3 From Chloropyrimidine derivatives c, R 2 = -(CH 2)5
Substitution of methyl thioglycolate for the Furthermore, 4-chloro-2-substitutedpyrimidine-5-carbo-

chlorine atom in 4-chloro-6-methylthio-2-phenyl- nitrile 217a-c were allowed to react with one equivalent of
pyrimidine-5-carbonitrile (206) in the presence of TEA mercaptoacetic acid derivatives in refluxing ethanol
afforded thieno[2,3-d]pyrimidine derivative 207 [126]. containing powdered sodium carbonate to afford the
corresponding 5-aminothieno[2,3-d]pyrimidines 218a-f
SMe
SMe NH2
[131].
CN
N NH2
MeOH/TEA N CN
+ HSCH2COOMe reflux 4h COOMe N
2
anhy. Na 2CO3, EtOH N 2
Ph N Cl 63% S 1
+ HSCH2COR
reflux 4h, 29-88%
COR
Ph N R N Cl
R
1
N S
206 217a-c 218a-f
207 1 1 2
a, R 1= MeS; a, R = MeS; R = OEt;
b, R = Ph; 1 2
Also, cyclocondensation of 4-chloro-6-(3-methoxyphenyl)- 1
c, R = Me 2N
b, R 1 = Ph; R 2 = OMe;
c, R = Ph; R = NHPh;
2-methylthiopyrimidine-5-carbonitrile (208) with ethyl 1 2
d, R = Ph; R = NH-2-naphthyl;
1 2
e, R = Me 2N; R = OEt;
thioglycolate yielded 3-amino-2-carbethoxy-6-ethoxy-4-(3- 1 2
f, R = Me 2N; R = NHPh
methoxyphenyl)thieno[2,3-d]pyrimidine (209) [127].
OMe
In addition to, condensation of chloropyrimidine derivative
OMe
219 with ethyl 2-mercaptoacetate under fusion conditions
yielded ethyl 2-(p-chlorophenyl)-4,5-dimethylthieno[2,3-d]
NH2
pyrimidine-6-carboxylate (220) [132].
CN
N N Me
EtONa, reflux 6h COOEt Me
+ HSCH2COOEt
39% S
COMe
o
Me
EtO N N fusion at 120 C, 15 min

MeS N Cl N
+ HSCH2COOEt
85%
CO2Et
208 209 N Cl S
N
219 220
Cl
Similarly, 6-chloropyrimidine-5-carbonitriles 210 were Cl
subjected to react with mercaptoacetic acid derivatives to

give the corresponding 6-substitutedpyrimidine-5-
4. Synthesis of Thienopyrimidines from
carbonitriles 211, which cyclized by the effect of sodium Acyclic Compounds
ethoxide to afford 5-aminothieno[2,3-d]pyrimidines 212
[128]. Treatment of methylethyl ketone 221, N-cyanoacetyl
CO2Et CO2Et
urethane 222 and sulfur in the presence of diethyl amine
CO2Et
CN CN
NH2 yielded 2,4-dioxo-6-methylthieno[2,3-d]pyrimidine 223 in
N EtOH/TEA N
EtONa N one step in an excellent yield [132].
+ HSCH2Z 60-95% 58-90%
Z
R N Cl R N S Z S O
R N
210 211 O O
212 NH
R = -NMe 2, -NEt 2, pyrrolidin-1-yl,
Z = CO 2Et, CONH 2 Me
Me + NC
NHCOOEt
S, Et 2NH Me
piperidin-1-yl
S N O
221 H
Moreover, ethyl thieno[2,3-d]pyrimidine-6-carboxylate 214 222
223
was prepared in good yield by the reaction of 2-
(dimethylamino)pyrimidine 213 with ethyl 2-mercapto- Also, the reaction of α-cyano-β-chlorocinnamonitrile 224
acetate in refluxing EtOH/THF (5:1) [129]. with KSCN , ROH and active bromomethylene derivatives
(BrCH2X) afforded the corresponding thieno[2,3-d]
© 2016 NSP
pyrimidine derivatives 225 [133]. subutitutedthieno[2,3-d]pyrimidines 226 [88].
Ph NH2 H2N H2N
Ph CN 1 N N
i) R OH/ KSCN, reflux 1 h N 2 NBS, DMF
R
2 R R
Cl CN ii) BrCH2R , :B 1 S 50-84%
R O N N Br N
S S
224 225
130 226
1 2
R = alkyl; R = acyl, CONH 2, alkoxycarbonyl, CN R = 2-methylfuran-5-yl, Ph
Also, 6-bromo-1,3-dimethylthieno[2,3-d]pyrimidine-
5. Reactions of Thienopyrimidines 2,4(1H, 3H)-dione (227) was formed by addition of a
Knowledge of the behavior of heterocyclic solution of bromine dissolved in acetic acid to thieno-
systems under conditions of the principal reactions is pyrimidine 182 [112].
required to perform the directed synthesis of practically O O
important, particularly of biologically active, compounds.
Me Me
As earlier, considerable recent attention has been given to N Br2/AcOH, r.t. N
investigations into modifications of susbtituents in the Br
stir 1h,92%
performed thienopyrimidine structure. In addition to, many S N O S N O
studies were devoted to the use of various thienopyrimidine Me Me
derivatives in the synthesis of linearly and angularly 182 227
polyannelated heterocyclic systems. There are some of
these reactions attributed to thiophene ring and other due to 5.1.1.2 Vilsmeier-Haack reaction
pyrimidine ring.
The Vilsmeier-Haack reaction of compound 182 using
5.1 Reactions attributed to thiophene ring phosphorus oxychloride and DMF resulted in the formation
of 6-formyl-1,3-dimethylthieno[2,3-d]pyrimidine-2,4(1H,
5.1.1 Reactions at thiophene carbons 3H)-dione (228) [112].
O O
Electrophilic substitutions like halogenation, Me o Me
Vilsmeier formylation, nitration and alkylation, were N POCl3-DMF/100 C N
demonstrated in thieno[2,3-d]pyrimidines (I) and thieno OHC
stir 1h, 92%
S S
[3,4-d]pyrimidines (III) involved position 6 and equivalent N O N O
position 7, respectively, which is typical of thiophene itself Me Me
and suggested a weak influence of annelation with the 182 228
pyrimidine ring. A different situation is observed for
electrophilic substitution in thieno[3,2-d]pyrimidines (II), 5.1.1.3 Nitration
where the influence of annelation of the pyrimidine ring is
stronger than the effect of orientation of the sulfur atom in Thieno[2,3-d]pyrimidine 182was nitrated using a
the thiophene ring and, concequently, the attack occurred at solution of fuming nitric acid in concentrated sulfuric acid
position 7. to afford 6-nitro-1,3-dimethylthieno[2,3-d]pyrimidine-2,4
(1H,3H)-dione (229) [112].
N O O
N
N Me Me
S o
N N HNO 3/H 2SO4, 0 C N
N S S O 2N
N stir 1h,25%
S N O S
(I) (III) N O
(II)
Me Me
182 229
5.1.1.4 Alkylation
5.1.1.1 Halogenation
2-(2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-
Bromination of compound 130 with mild
6-yl) propan-2-ol (231) was obtained from treatment of 2-
bromonating agent, N-bromosuccinimde (NBS), in
chloro-4-morphlin-4-ylthieno[3,2-d]pyrimidine (230) with
dimethyl formamide afforded 4-amino-6-bromo-2-
n-BuLi followed by addition of dry acetone[70].
© 2016 NSP
Cl
Cl N S O S O
3
N R
N i) n-BuLi/dry THF, stir 1 h 2 dry acetone, K 2CO3 N
NH
N -78oC to r.t. + ClCOOEt and/or ClCH2R
reflux 2h, 64-73%
1 2 S 1
S N CH2R R = CN, COMe N CH2R
ii) dry acetone, stir 2h, 83% Me N
S
236a,b 237a-d
S N HO a, R = Cl; b, R = Ph
1
a, R = Cl, R = COOEt;
3
Me 231 O
1
b, R = Ph, R = COOEt;
3
1 3
230 c, R = Ph, R = CH 2CN;
O 1 3
d, R = Ph, R = CH 2COMe
5.1.2 Ring opening of the thiophene ring Silylation of thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione

(238) with 1,1,1,3,3,3-hexamethyl-disilazane (HMDS) in
Ethyl 3-(2-ethoxy-2-oxoethyl)-2,5-dimethyl-4- the presence of a catalytic amount of ammonium sulfate
oxo-3,4-dihydrothieno[3,4-d]pyrimin-dine-7-carboxylate gave the corresponding silylated compounds, which
(232) was underwent desulfurization under the action of condensed with methyl 3-fluoro-2,3-dideoxy-5-O-(4-
Raney nickel to yield ethyl 4-(ethoxycarbonylmethyl)-5- phenylbenzoyl)-β-D-erythro-pentofuranoside (239) in
ethyl-2-methyl-6-oxo-1,6-dihydropyrimidin-1-yl-acetate acetonitrile using trimethylsilyl trifluoromethanesulfonate
(233) [105]. (TMS triflate) as a catalyst according to the method of
COOEt COOEt Vorbrüggen [136]to yield the corresponding thieno[2,3-d]
COOEt
O N Me O N Me
pyrimidin-2,4(1H,3H)-dione 240 in 56% yield and the
Raney Ni, EtOH
O N Me
H2 acyclic nucleoside 241 in 17% yield [137].
N Me N
Me reflux 4h, 63% Me N O
O
S
COOEt EtOOC O NH
EtOOC NH
232 RO
233 OMe
NH O o S N O S
+
HMDS, (NH 4)2SO4, 140 C RO O + OH
N O
In the same way, hydrogenation of 6-formylthieno[2,3-d] S N O
MeCN, TMS triflate
RO OMe
H
pyrimidine 228 with Raney nickel under 50 atmospheres F
F
238 239 F
induced desulfurization to give 5-(3-hydroxypropyl)-1,3- 240 241
dimethyluracil (234) [112]. Similarly, condensation of the silylated heterocycle

O O thieno[2,3-d]pyrimidin-4-one 242 with 1-O-acetyl-2,3,5-tri-
Me Me O-benzoyl-β-D-ribofuranose (243a) in the presence of
HO N
OHC
N
Raney Ni, EtOH stannic chloride or with 2,3,5-tri-O-acetyl-D-ribofuranosyl
S
reflux 7h, 34% N O
bromide (243b) in the presence of mercuric oxide and
N O
Me
mercuric bromide yielded 3-β-D-ribofuranosylthieno[2,3-d]
Me
234 pyrimidin-4-one (244) [138].
228
OH OH
O
Also, when compound 209 allowed to react with hydrazine RO
O
X
hydrate, it gave unexpectedly a ring opened compound, 2,4- NH O
HMDS, reflux 4h, SnCl 4 N
dihydrazino-6-(3-methoxyphenyl)-pyrimidine-5- + CH2Cl2 or dry benzene
O
OR
S N S
stir 24h N
carbonitrile (235) [134]. OR OR
244
OMe 242 243a,b
OMe a, R = COPh, X = MeCO 2;
b, R = COMe, X = Br
NH2 Also, thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones 18a-l

CN was alkylated with 2,6-difluorobenzyl chloride in the
NH 2NH 2,H 2O, pyridine N
N
COOEt reflux 3h, 56% presence of potassium carbonate to furnish the
H2NHN N NHNH 2
EtO N S corresponding 1-(2,6-difluorobenzyl)thieno[2,3-d]
235 pyrimidin-2,4(1H,3H)-diones 245a-l [28].
209
Cl
Me O O
5.2 Reactions attributed to nitrogen of the N
R
2
F F
K2CO3, KI, DMF
Me
N
R
2
1 1
pyrimidine ring R
S N O
+ reflux 4h, 73-93%
R
S N O
F
H
18a-l 1 2 1 2 245a-l
a, R = NO 2, R = Ph; b, R = NO 2, R = 3-MeOC 6H4;
Treatment of 5-(2-thienyl)thieno[2,3-d]pyrimidin- 1
c, R = OMe, R = Bu;
2 i 1 2
d, R = OMe, R = cyclohexyl;
1 2 1 2 F
e, R = OMe, R = Bn; f, R = OMe, R = Ph;
4(3H)-one 236a,b with ethyl chloroformate and/or 1 2
g, R = OMe, R = 2-MeOC 6H4; h, R = OMe, R = 4-MeOC 6H4;
1 2
1 2 1 2
chloroacetonitrile in the presence of potassium carbonate i, R = OMe, R = 4-MeOC 6H4; j, R = OMe, R = 2-ClC 6H4;
1 2 1 2
k, R = OMe, R = 3-ClC 6H4; l, R = OMe, R = 4-ClC 6H4
gave the corresponding 3-substitutedthieno[2,3-d]
pyrimidine 237a-c [135]. Alkylation of thienopyrimidinone 246 with ethyl 2-
bromopropionate and/or 2-bromopropionic acid gave ethyl
© 2016 NSP
2-(6-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)- R
yl)propanoate (247a) and/or 2-(6-methyl-4-oxothieno
[2,3-d]pyrimidin-3(4H)-yl)propanoic acid (247b),
respectively [139]. HN
O OR Me N
O O
MeCH(Br)CO2R
N Me N
NH N
Me NaH, benzene reflux 48h Me N S
S S N
N O
246 247a,b
a, R = Et; b, R = H 250a-d
Condensation of thieno[2,3-d]pyrimidindionederivatives R`
a, R = 2,4-di-F, R` = 4-Cl; b, R = 2,4-diF, R` = H;
c, R = 4-F, R` = H; d, R = 4-F, R`= 4-Cl
248a-c with alkyl halide in the presence of
benzyltriethylammonium chloride (BTEAC) yielded 1,3- Also, 2,4-dichlorothieno[3,2-d]pyrimidine (251) is one of
dialkylthieno[2,3-d] pyrimidindione 249 [140]. the intermediates for synthesizing anticancer medicines
R
1 O
R
1 O [163].
3
R
2 NH 3
NaOH, BTEAC
N Cl
R + R X R
2
S N O
reflux 4h
S
N
N O
H 3
248a-c 249 R
1
a, R = R =Me;
2
X = Cl, Br, I
3
R = Me, Et, Pr, Bu, allyl
N
1 2
b, R R = -(CH 2)4-;
1
c, R =Ph, R = H
2
S
Cl
6. APPLICATIONS OF THIENOPYRIMIDINES 251
Thienopyrimidines are interesting heterocyclic Moreover, biological assays on endothelial cell tube
compounds and a number of derivatives of these formation proved thieno[2,3-d]pyrimidine derivative 152 as
compounds display therapeutic activity as antimicrobial a new anti-angiogenic lead compound that showed to be
[141-144], antiviral [145,146], anti-inflammatory more efficient in inhibiting endothelial cell tube formation
[147,148], antidiabetic [149], antioxidant [150], antitumor induced by VEGF (vascular endothelial growth factor) and
[151-155] and anticancer agents [155,156]. Despite the compound 152 did not cause any cytotoxic side effect to
breadth of biological activities displayed by these agents, endothelial cells [99].
the antibacterial activity of this class of compounds has
been underexplored. 1 2
NR R
N
Moreover, thieno[2,3-d]pyrimidines have fascinated
importance in medicinal chemistry, exhibiting pharma- NH
cological and therapeutic properties such as antidepressant
[158], antiplatelet [159], antihypertensive [160], herbicidal S
[161] and plant growth regulatory properties [162]. N O
The compounds having thieno[2,3-d]pyrimidines in Bn 152
combination with 1,3,4-oxadiazoles exhibited greater
antioxidant activity. 4-Substitutedaminothieno[2,3-d] 1 2
R R = piperdinyl
pyrimidines 250a-d showed excellent, almost equivalent to
that of standards, where the presence of electron donating The antibacterial activity of thieno[2,3-d]pyrimidine
substituent on both sides of thienopyrimidine ring enhances derivative 252 was comparable with that of ampicillin
the activity and electron withdrawing groups decrease [82]. against B. subtilis. Also, the antifungal activity of
compound 252 was about half that of fluconazole against
C. albicans [164].
© 2016 NSP
thienopyrimidines derivatives. Synth. Commun. 1, 40: 1149
N (2010).
N F
[5] Rashad, A. E.; Shamroukha, A. H.; Sayed, H. H.; Awad, S.
Me N M. and Abdelwahed, . A. M; Some novel thiopyrimidine
nucleoside analogs: Synthesis and in vitro antimicrobial
evaluation; Synth. Commun. 41, 652 (2011).
O
N [6] Amr, A. E.; Mohamed, A. M.; Mohamed, S. F.; Abdel-
S Hafez, N. A. and Hammam, A. G; Synthesis and anticancer
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J. Pharm. Appl. Chem., 2, No.

3, 103-127 (2016) 103

Chemistry of Thienopyrimidines and Their Biological

1 Introduction 2 Synthesis Of Thienopyrimidines

* Corresponding author E-mail:mabdelmegid@yahoo.com

Further, addition of methyl isothiocyanate to ethyl 2-amino-

isocyanates in the presence of potassium t-butaoxide

By the same manner, reaction of compounds 5b and/or 45a

3-carboxylate (76) [14] was converted into ethyl 2- O

Zinc dust was added in catalytic amount to improve the S EtO

2.2.7 With chloroformate derivatives

NO 2 NaOMe, stir 12h

By the same way, treatment of iminophosphorane 100 [75] Diethyl 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-

room temperature [76]. OEt OEt

Similarly, 4-aminothieno[2,3-d]pyrimidine derivatives

path (a), 27%

2.3.7 By Mannich reaction Also, condensation of 3-amino-5-(1-benzyl-1H-indol-3-yl)-

2.4 Using thiophene having Vicinal amino N

2.4.1 With aldehydes a, R = n-hexyl; b, R = 4-MeOC 6H4;

Cyclocondensation of 2-amino-4,5,6,7,8,9- Moreover, treatment of 2-amino-3-thiophenecarboxamide

[104]. 167 168

3. Annulations of Thiophene on Pyrimidine 2,4(1H,3H)-dione (179). Compound 179 can be also

the synthesis of thieno[3,2-d]pyrimidines. O

Thiouracils represent important starting materials which Me Me

cooperate in construction of the target thienopyrimidines. 180 179

Thiation of thiouracil derivative 170 [106] using

Moreover, condensation of 6-chloro-1,3-dimethyluracil 3.2 From thioxopyrimidine derivatives

Moreover, treatment of compound 189 with N-phenyl-

203 213 214

Substitution of methyl thioglycolate for the Furthermore, 4-chloro-2-substitutedpyrimidine-5-carbo-

EtO N N fusion at 120 C, 15 min

subjected to react with mercaptoacetic acid derivatives to

5.1.2 Ring opening of the thiophene ring Silylation of thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione

dimethyluracil (234) [112]. Similarly, condensation of the silylated heterocycle

NH2 Also, thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones 18a-l

[14] Litvinov,V.D.Thienopyrimidines:synehesis,properties and

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