New Convenient Strategy for Annulation of Pyrimidines to Thiophenes or Furans via the One-pot Multistep Cascade Reaction of 1 H -Tetrazoles with Aliphatic Amines

Article abstract of DOI:10.1021/co5001376

A versatile, convenient, efficient and high-yield synthetic method for 2-R³,R⁴-amino-5-R¹-6-R²-thieno[2,3-d]pyrimidin-4(3H)-ones, 2-R³,R⁴-amino-5-R¹-6-R²-thieno[3,2-d]pyrimidin-4(3H)-ones, and benzofuro[3,2-d]pyrimidin-4(3H)-ones preparation has been developed. The reaction proceeded without using solvents and included several steps. A variety of thieno[2,3-d]pyrimidine and thieno[3,2-d]pyrimidine derivatives with substituents of different nature were obtained in high yields from substituted alkyl 2-(1H-tetrazol-1-yl)thiophene-3-carboxylates, 3-(1H-tetrazol-1-yl)thiophene-2-carboxylates, and 3-(1H-tetrazol-1-yl)benzofuran-2-carboxylate after their treatment with aliphatic amines.

Full text of DOI:10.1021/co5001376

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Article
A New Convenient Strategy for Annulation of Pyrimidines
to Thiophenes or Furans via the One-pot Multistep
Cascade Reaction of 1H-Tetrazoles with Aliphatic Amines
Nazariy T. Pokhodylo, Olga Ya. Shyyka, Vasyl S. Matiychuk, and Mykola D. Obushak
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/co5001376 • Publication Date (Web): 19 Jun 2015
Downloaded from http://pubs.acs.org on June 23, 2015
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A New Convenient Strategy for Annulation of Pyrimidines to Thiophenes
or Furans via the One-pot Multistep Cascade Reaction of 1HꢀTetrazoles with
Aliphatic Amines
8
9
Nazariy T. Pokhodylo,* Olga Ya. Shyyka, Vasyl S. Matiychuk, Mykola D. Obushak
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Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i
Mefodiya St. 6, Lviv 79005, Ukraine.
E-mail: pokhodylo@gmail.com
Abstract — A versatile, convenient, efficient and highꢀyield synthetic method for 2ꢀ
R3,R4ꢀaminoꢀ5ꢀR1ꢀ6ꢀR2ꢀthieno[2,3ꢀd]pyrimidinꢀ4(3H)ꢀones, 2ꢀR3,R4ꢀaminoꢀ5ꢀR1ꢀ6ꢀ
R2ꢀthieno[3,2ꢀd]pyrimidinꢀ4(3H)ꢀones and benzofuro[3,2ꢀd]pyrimidinꢀ4(3H)ꢀones
preparation has been developed. The reaction proceeded without using solvents and
included several steps. A variety of thieno[2,3ꢀd]pyrimidine and thieno[3,2ꢀ
d]pyrimidine derivatives with substituents of different nature were obtained in high
yields from substituted alkyl 2ꢀ(1Hꢀtetrazolꢀ1ꢀyl)thiopheneꢀ3ꢀcarboxylates, 3ꢀ(1Hꢀ
tetrazolꢀ1ꢀyl)thiopheneꢀ2ꢀcarboxylates
and
3ꢀ(1Hꢀtetrazolꢀ1ꢀyl)benzofuranꢀ2ꢀ
carboxylate after their treatment with aliphatic amines.
Keywords: tetrazole, thieno[2,3ꢀd]pyrimidinꢀ4(3H)ꢀone, thieno[3,2ꢀd]pyrimidinꢀ
4(3H)ꢀone, benzofuro[3,2ꢀd]pyrimidinꢀ4(3H)ꢀone, heterocyclization.
Introduction
Thienopyrimidine derivatives have attracted considerable interest in
pharmaceutical discovery in cancer and antivirus research.1ꢀ9 Therefore, the
development of new efficient and mild syntheses of the thienopyrimidine framework
is a useful task, particularly when oneꢀstep procedures from readilyꢀavailable reagents
can be employed.11
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The Gewald thiophenes12 are used as starting materials in many routes to
thieno[2,3ꢀd]pyrimidines.13ꢀ20 We have recently reported that alkyl 2ꢀ(1Hꢀtetrazolꢀ1ꢀ
yl)ꢀ4ꢀR1ꢀ5ꢀR2ꢀthiopheneꢀ3ꢀcarboxylates, obtained from alkyl 2ꢀaminoꢀthiopheneꢀ3ꢀ
carboxylates by the reaction with triethyl orthoformate and sodium azide under
conditions of hydrazinolyzation of the ester group, underwent recyclization including
cleavage of the tetrazole ring, elimination of the nitrogen molecule and annulation of
the pyrimidinone core (Scheme 1).21 This simple and convenient synthetic path
opened access to 2,3ꢀdiaminothieno[2,3ꢀd]pyrimidinꢀ4(3H)ꢀones and allowed us to
presume that the tetrazole ring cleavage and loss of nitrogen could proceed under mild
conditions (hydrazine solution). The ready access to the cyanamide moiety makes
alkyl 2ꢀ(1Hꢀtetrazolꢀ1ꢀyl)ꢀ4ꢀR1ꢀ5ꢀR2ꢀthiopheneꢀ3ꢀcarboxylates the potentially useful
precursors to a range of thieno[2,3ꢀd]pyrimidinꢀ4(3H)ꢀones, a transformation
elaborated here.
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Scheme 1. 2,3ꢀDiaminothieno[2,3ꢀd]pyrimidinꢀ4(3H)ꢀones synthesis
O
R1
R1
R2
COOEt
NH2
R1
R2
CH(OEt)3
COOEt
N2H4
NH2
NH2
N
R2
NaN3,
AcOH
N
N
N
S
S
S
N
N
Results and Discussion
As a continuation of our work on the tetrazole ring cleavage via nucleophilic
attack, we examined a number of amines in such a reaction to find its scope and
limitations. Replacement of hydrazine by basic amines led to the same type of
reaction (Scheme 2), which could be performed without solvent by simple heating to
80ꢀ90 °C in a small excess of amine. The reaction time depended on the basicity and
nucleophility of amine. Monitoring of the reaction progress was performed using TLC
on Silufol plates and IR spectroscopy, noting a characteristic shift of the carbonyl
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absorption band from 1710ꢀ1725 cmꢀ1 in the initial tetrazoles to 1660ꢀ1680 cmꢀ1 in the
target thienopyrimidines.
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Scheme 2. Synthesis of novel thieno[2,3ꢀd]pyrimidinꢀ4(3H)ꢀones 3.
O
O
R1
OR3
N
R1
R2
H
R5
R5
N
solvent free
+
HN
R4
2a-o
N
R2
N
N
S
R4
N
S
N
3a-y
1a-c
1a: R1=R2=Me
1b: R1=R2=ꢀ(CH2)2ꢀ
1c: R1=Ph, R2=H
We examined a number of different amines, shown in Figure 1. The results,
summarized in Table 1 and shown in detail in Table 2, revealed three main outcomes.
Interestingly, aqueous ammonia was found to be unreactive, perhaps due to a great
decrease in the solubility of NH3 (11.1 g per 100 g of water) at the temperature of the
reaction (70 °C). In case of other reagents, a good correlation between the basicity of
amines and the ability to form thienopyrimidines was found. The target
thienopyrimidines 3a-y were easily prepared in excellent yield from thienotetrazoles
and a wide range of basic and nucleophilic amine reagents, giving more than 30 new
compounds of this class, was found. In contrast, weakly basic amines 2q-v (pKa < 6)
were unreactive in this protocol. Since good nucleophiles in this category (hydrazines
and an aminoether) were also ineffective, it is rather basicity than nucleophilicity that
is the most important. Diisopropylamine 2p was found to be sufficiently basic to
generate cyanamides 4a-c, but too hindered to add to these electrophiles. Intermediate
cyanamides 4a and 4b were also easily obtained in quantitative yields by the addition
of tetrazole 1 to sodium methoxide in methanol at room temperature.
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Me
N
N
O
Me
Me
NH2
O
OH
5
6
7
8
HN
N
H
N
H
N
N
H
2f
N
H
NH2
2a
NH2
2b
H
2e
2d
2g
2h
2c
9
NH2
10
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NH2
N
H2N
NH2
H2N
S
NH
Me
Me
Me
Me
N
H
2j
2l
2n
2m
2k
2i
COOMe
Me
Me
N
Me Me
Me
O
Me
N
H
HN
Me
2o
H2N
N
N
H
HN
HN
NH2
NH2
Me
2s
NH2
2v
2p
2q
2r
2u
2t
Figure 1. Amines tested in the reaction.
Table 1. General results of reactions with the use of amines shown in Figure 1 with
tetrazoles 1a-c.
Type of amines
Result
Complete formation of the
O
R
R1
R2
R4
N
1) strong base, strong
expected thienopyrimidinꢀ4(3H)ꢀ
N
S
R5
N
nucleophile 2a-o
ones; isolated yields >88%
3a-y
O
R1
R2
OR
NH
2) strong base, weak Isolation of intermediate
S
4a-c
nucleophile 2p
cyanamide in >98% yield
N
No reaction, with recovery of initial reagents, for
reactions up to 20 h at 160°C in case of aniline
3) weak base 2q-v
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Table 2. Detailed results of the reactions of tetrazoles 1a-c with amines 2a-o.
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5
6
7
8
9
Yield, %a (product number)
Tetrazole
involved
in
Reaction
time,
minutes
Product
Baseꢀnucleophile
R1+R2= R1=Ph,
ꢀ(CH2)2ꢀ R2=H
R1=R2=Me
reaction
3a-y
O
2a-q
1a-c
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R1
R2
OH
NH
N/Ab
H2N
OH
S
30
95 (3a)
96 (3b)
1a,1b
N
NH
2a
3a,b
R1
O
R2
NH
NH2
H2N
93
(3d)
45
60
95 (3c)
N/A
NH2
1a,1c
1a,1c
S
N
NH
2b
3c,d
O
H
R1
R2
N
N
2c
96 (3e)
95 (3g)
N/A
N/A
92 (3f)
N
N
H
S
3e,f
O
H
N
R1
R2
N/A
N
N
45
30
1a
S
2d
N
H
3g
O
H
N
R1
R2
O
N
O
2e
93 (3h)
94 (3i)
93 (3j)
1a-c
N
S
N
H
3h-j
O
H
R1
R2
Me
Me
Me
O
N
N
2f
30
30
30
45
94 (3k)
93 (3l)
N/A
N/A
N/A
N/A
O
1a
1a
N
N
H
S
Me
3k
O
H
N
H
R1
R2
N
N
2g
NH
N
S
N
H
3l
O
Me
N
H
N
R1
R2
N
95 (3m)
89 (3p)
95 (3n) 93 (3o)
89 (3q) 88 (3r)
1a-c
1a-c
N
Me
N
2h
S
N
H
3m-o
O
R1
R2
H
N
2i
N
NH
N
S
3p-r
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R1
O
N
Me
NH2
Me
3
4
5
6
7
8
9
R2
NH
NH
Me
Me
2j
30
30
60
90 (3s)
96 (3u)
90 (3v)
91 (3t)
N/A
N/A
N/A
N/A
1a,1b
1a
S
Me
Me
Me
Me
NH
N
H
3s,t
R1
O
NH2
R2
NH
2k
S
N
NH
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3u
R1
O
N
R2
NH
NH
2l
S
N/A
1a
S
S
NH2
3v
R1
O
R2
NH
2m
2n
S
60
60
30
90 (3w)
90 (3x)
91 (3y)
N/A
N/A
N/A
N/A
N/A
N/A
1a
1a
1a
N
NH
NH2
3w
R1
O
R2
NH
NH
N
S
NH2
N
N
3x
R1
O
H
R2
NH
Me N
2o
COOMe
S
N
N
COOMe
Me
3y
a Yields of compounds after isolation and purification in a single experiment are given.
b N/A – reactions are not studied.
Consistent with these observations is the proposed threeꢀstep reaction
mechanism shown in Scheme 3, involving the tetrazole ring cleavage, nucleophilic
addition, and intramolecular cyclization. The action of base is thought to be crucial to
the first step to induce proton elimination from the tetrazole ring to generate the
tetrazolyl anion, which opens being accompanied by elimination of dinitrogen.
Addition of the corresponding amines to the resulting cyanamide provides a guanidine
moiety that undergoes rapid annulation to the pyrimidine ring. The reaction occurs
regioselectively, with 1H NMR confirming the formation of only one
thienopyrimidine product in each case, having the substituent at the exocyclic
nitrogen atom. The purity of all compounds was established by liquid
chromatography with UV and mass detection.
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Scheme 3. Proposed reaction mechanism.
4
5
6
7
8
9
O
O
R1
R2
R1
OR3
N
OR3
Base
ꢀ N2
N
N
N
R2
N
S
S
H
I
N
4a-c
1a-c
10
11
12
13
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60
R5
HN
II
R4
2
O
H
R5=H
R1
R2
N
H
O
O
N
H
B
R1
R2
A
OR3
O
R1
R2
R4
N
R4
N
R1
S
S
OR3
3
NH
N
III
B
III
A
N
NH
S
R5
R4
R2
3
S
NH
R4
O
N
H
S
R5
R1
R2
N
NH
N
R4
NH2
do not form
N
Recently, in the frame to broaden the applicability of the proposed
thienopyrimidine formation approach, we have used alkyl 3ꢀ(1Hꢀtetrazolꢀ1ꢀyl)ꢀ4ꢀR1ꢀ
5ꢀR2ꢀthiopheneꢀ2ꢀcarboxylates 9 in such a protocol, which were prepared via known
procedures24,25 from commercially available starting materials (Scheme 4).
Scheme 4. 2ꢀR3,R4ꢀaminoꢀ5ꢀR1ꢀ6ꢀR2ꢀthieno[3,2ꢀd]pyrimidineꢀ4(3H)ꢀones synthesis.
OR3
HS
R1
R2
NH2
COOR3
O
Cl
POCl3
NH2OH HCl
DMF
O
N
R2
R2
R1
5a,b
S
R1
6a,b
MeONa, MeOH
t°C
NaN3
7a,b
CH(OEt)3
AcOH
R4
N
R4
N
R5
N
N
R5
R1
R2
N
R1
R2
N
H
N
2
NH
O
COOR3
S
t°C
S
8a,b
9a-f
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The reaction of tetrazoles 8 with amines 2 was carried out under the same
conditions by heating to 80ꢀ90°C without a solvent. The target substituted 2ꢀR3,R4ꢀ
aminoꢀ5ꢀR1ꢀ6ꢀR2ꢀthieno[3,2ꢀd]pyrimidineꢀ4(3H)ꢀones 9e-f were isolated in high
yields. The results are summarized and shown in detail in Table 3.
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Table 3. Detailed results of the reactions of tetrazoles 8 with amines 2
Yield, %a (product
Baseꢀ
nucleophile
Tetrazole involved in
reaction
Reaction
time,
minutes
number)
Product
R1+R2= R1=H, R2=
ꢀ(CH2)2ꢀ Ph
9a-f
2e,h,i,m,n
8a,b
O
O
N
N
R1
R2
2e
45
30
45
95 (9a)
90 (9c)
89 (9d)
93 (9b)
N/A
8a,8b
N
H
NH
S
O
9a,b
Me
N
Me
N
N
N
R1
R2
8a
8a
2h
NH
N
H
S
O
9c
N
N
R1
R2
N/A
2i
NH
NH
S
O
9d
H
N
N
R1
R2
2m
30
45
93(9e)
N/A
8a
8b
NH2
NH
S
O
9e
H
N
N
R1
R2
N
2n
N/A
92(9f)
NH2
N
NH
S
O
9f
a Yields of compounds after isolation and purification in a single experiment are given.
b N/A – reactions are not studied.
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As a continuation of our work we examined a number of heterocyclic tetrazoles
to prove the applicability of such a tetrazole ring cleavage method. For this purpose,
at first, 3ꢀaminoꢀbenzofuran derivative 12 was prepared (Scheme 5)22. Amine 12 was
successfully transformed into the corresponding tetrazole 13 in the same way as the
above described thienotetrazoles were obtained (Scheme 4). The treatment of
tetrazoles 13 with moprholine 2e under the tetrazole ring cleavege conditions gave
benzofuro[3,2ꢀd]pyrimidinone 14 in high yields.
10
11
12
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Scheme 5. Benzofuro[3,2ꢀd]pyrimidinone 14 preparation
NaN3
NH2
OH
N
K2CO3
DMF, t
CH(OEt)3
OEt
O
OEt
Br
O
+
O
N
AcOH, t
11
10
12
O
N
N
NaN3
O
N
N
NH
CH(OEt)3
N
OEt
O
NH
O
AcOH, t
t
O
O
13
14
Moreover, a variety of heterocyclic amines 15a-f (Fig. 2) with the neighboring
in ortho position ester/nitrile group were synthesized in our laboratory according to
known procedures.23ꢀ26 Nowadays, two synthetic pathways: a oneꢀstep procedure, as
described for aminothiophenes and twoꢀstep protocol through isolation of the
intermediate ethoxymethylene amino derivatives were tested for tetrazole ring closure
reactions from the corresponding amines 15a-f. It was found out that, these
derivatives were relatively inert in such reactions, so methods for such heterocyclic
tetrazoles construction and applicability of these tetrazoles in 2ꢀNꢀsubstituted
condensed pyrimidines synthesis are currently under investigation.
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NH2
R
OEt
Ph
O
NH2
N
N
NH2
Ph
S
OEt
O
OEt
O
N
OEt
NH2
X
N
O
6
S
S
R= H, X=CꢀSMe
R= Ph, X=CH
R= Ph, X=N
Ph
N
7
8
9
15a
15b
Me
15d
15e
15f
15c
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Figure 2. Heterocyclic amines 15a-f with the neighboring in ortho position
ester/nitrile group.
Conclusion
It was shown that thieno[2,3ꢀd]pyrimidine as well as thieno[3,2ꢀd]pyrimidine
and benzofuro[3,2ꢀd]pyrimidine derivatives could be easily obtained via a new
solventꢀfree reaction of tetrazoles with amines. This simple reaction accommodates
many different basic amines and proceeds in high yields under mild conditions. The
pathway described here via the readily accessible 2ꢀtetrazolylthiophene is more
convenient than the related approach through 2ꢀisothiocyanate derivatives28 and
complementary to the use of 2ꢀaminothiophenes and secondary cyanamides.27
Reactions of other types of tetrazoles and primary/secondary amines are currently
under investigation in our group and will be reported in due course.
Experimental Procedures
General
13
1H NMR spectra and C NMR spectra were recorded on a Bruker instrument
(500 MHz for 1H, 125 MHz for 13C). The 1H and 13C chemical shifts were reported in
parts per million relative to tetramethylsilane or the deuterated solvent as an internal
reference. Mass spectra were run using Agilent 1100 series LC/MSD with an APIꢀ
ES/APCI ionization mode. IR spectra were recorded on a Specord 80 instrument in
KBr tablets and in solution CCl4.
General procedure for the synthesis of alkyl 3-(1H-tetrazol-1-yl)thiophene-
2-carboxylates 8a,b and ethyl 3-(1H-tetrazol-1-yl)benzofuran-2-carboxylate 13
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A suspension of 50 mmol of the required thiophene 7 or benzofurane 12,
triethyl orthoformate (37.9 mL, 0.23 mol), and sodium azide (3.9 g, 0.06 mol) in
glacial acetic acid (40 mL) was stirred and heated at reflux for 2 h. The reaction
mixture was cooled to room temperature and 7 mL of concd HCl was added. The
solid was filtered off and the filtrate evaporated and the residue was recrystallized
from ethanol.
General procedure for the synthesis of 2-R3,R4-amino-5-R1-6-R2-
thieno[2,3-d]pyrimidine-4(3H)-ones 4,5, 2-R3,R4-amino-5-R1-6-R2-thieno[3,2-
d]pyrimidine-4(3H)-ones 9, benzofuro[3,2-d]pyrimidin-4(3H)-one 14
A suspension of an appropriate tetrazole 1a-c, 8a,b, 13 (1 mmol) in 0,7ꢀ1 mL
of the corresponding amine 2a-p was heated at 80ꢀ90 °C for 0,5ꢀ1 hour (mentioned in
Tables 2, 3), then cooled and diluted with water. The solid was filtered and
recrystallized from ethanol.
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Supporting Information
1
13
Compound characterization data, H NMR and C NMR spectra for new
compounds are reported. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: pokhodylo@gmail.com
Notes
The authors declare no competing financial interest.
References
(1)
(2)
Jordan, A.; Bedford, S.; Burkhard, K.; Yule, I.; Poullennec, K.
Thienopyrimidine compounds and compositions. US 2010/0298349 A1.
Babu, Y.; Chand, P.; Wu, M.; Kotian, P. L.; Kumar, V. S.; Lin, T.ꢀH.; Elꢀ
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Page 12 of 16
1
2
3
Kattan, Y.;Ghosh, A. K. Therapeutic furopyrimidines and thienopyrimidines
.
4
5
WO 2006/050161.
6
7
8
9
(3)
McClellan, W. J.; Dai, Y.; AbadꢀZapatero, C.; Albert, D. H.; Bouska, J. J.;
Glaser, K. B.; Magoc, T. J.; Marcotte, P. A.; Osterling, D. J.; Stewart, K. D.;
Davidsen, S. K.; Michaelides, M. R. Discovery of potent and selective
thienopyrimidine inhibitors of Aurora kinases. Bioorg. Med. Chem. Lett. 2011,
21, 5620ꢀ5624.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4)
(5)
Gangjee, A; Matherly, L. H. Methods of using substituted pyrrolo[2,3ꢀ
d]pyrimidines for targeting tumor cells and treating cancer. 2006 / US8258143
B2.
Edgar, K. A.; Wallin, J. J.; Berry, M.; Lee, L. B.; Prior, W. W.; Sampath, D.;
Friedman, L. S.; Belvin, M. IsoformꢀSpecific Phosphoinositide 3ꢀKinase
Inhibitors Exert Distinct Effects in Solid Tumors. Cancer Res. 2010, 70, 1164ꢀ
1172.
(6)
Heffron, T. P.; Wei, B. Q.; Olivero, A.; Staben, S. T.; Tsui, V.; Do, S.;
Dotson, J.; Folkes, A. J.; Goldsmith, P.; Goldsmith, R.; Gunzner, J.; Lesnick,
J.; Lewis, C.; Mathieu, S.; Nonomiya, J.; Shuttleworth, S.; Sutherlin, D. P.;
Wan, N. C.; Wang, S.; Wiesmann, C.; Zhu, B.ꢀY. Rational Design of
Phosphoinositide 3ꢀKinase α Inhibitors That Exhibit Selectivity over the
Phosphoinositide 3ꢀKinase β Isoform. J. Med. Chem. 2011, 54, 7815ꢀ7833.
Rheault, T. R.; Ceferro, T. R.; Dickerson, S. H.; Donaldson, K. H.; Gaul, M.
D.; Goetz, A. S.; Mullin, R. J.; McDonald, O. B.; Petrov, K. G.; Rusnak, D.
W.; Shewchuk, L. M.; Spehar, G. M.; Truesdale, A. T.; Vanderwall, D. E.;
Wood, E. R.; Uehling, D. E. Thienopyrimidineꢀbased dual EGFR/ErbBꢀ2
inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 817ꢀ820.
(7)
(8)
Sham, H. L.; Konradi, A. W.; Hom, R. K.; Probst, G. D.; Bowers, S.; Truong,
A.; Neitz, R. J.; Sealy, J.; Toth, G. Inhibitors of JUN Nꢀterminal kinase. WO
2010/091310.
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2
3
4
5
6
7
8
9
(9)
Bowers, S.; Truong, A. P.; Neitz, R. J.; Hom, R. K.; Sealy, J. M.; Probst, G.
D., et al. Design and synthesis of brain penetrant selective JNK inhibitors with
improved pharmacokinetic properties for the prevention of neurodegeneration.
Bioorg. Med. Chem. Lett. 2011, 21, 5521ꢀ5527.
10
11
12
13
14
15
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21
22
23
24
25
26
27
28
29
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31
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43
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(10) Dömling, A.; Wang, W.; Wang, K. Chemistry and biology of multicomponent
reactions. Chem. Rev. 2012, 112, 3083ꢀ3135.
(11) Dömling, A. Multicomponent Reactions ꢀ Superior Chemistry Technology For
The New Millennium. Org. Chem. Highlights 2005, April 5.
(12) Gewald, K.; Schinke, E.; Bottcher, H. 2ꢀAminoꢀThiophene aus
methylenaktiven nitrilen carbonylverbindungen und schwefel. Chem. Ber.
1966, 99, 94–100.
(13) Litvinov V. P. The Chemistry of Thienopyrimidines. Adv. Het. Chem. 2006,
92, 83ꢀ143.
(14) Huang, Y.; Doemling, A. The Gewald Multicomponent Reaction. Molecular
diversity. 2011, 15, 3ꢀ33.
(15) Litvinov V. P. Thienopyrimidines: synthesis, properties, and biological
activity. Russ. Chem. Bull. 2004, 53, 487ꢀ516.
(16) Puterová, Z.; Krutošíková, A.; Véghc, D. Gewald reaction: synthesis,
properties and applications of substituted 2ꢀaminothiophenes. Arkivoc. (i)
2010, 209ꢀ246.
(17) Wang, K.; Kim, D.; Doemling, A. Cyanoacetamide MCR (III): Threeꢀ
Component Gewald Reactions Revisited. J. Comb. Chem. 2010, 12, 111ꢀ118.
(18) Vovk, M. V.; Bolbut, A. V.; Boiko, V. I.; Pirozhenko, V. V; Chemega, A. N.;
Tolmachev, A. A. Synthesis of 2ꢀTrihalomethylꢀ3,4ꢀdihydrothieno[2,3ꢀ
d]pyrimidinꢀ4ꢀones. Chem. Heterocycl. Compd. 2004, 40, 370ꢀ376.
(19) Gangjee, A.; Qiu, Y.; Kisliuk, R. L. Synthesis of classical and nonclassical 2ꢀ
aminoꢀ4ꢀoxoꢀ6ꢀbenzylthienoꢀ[2,3ꢀd]pyrimidines as potential thymidylate
synthase inhibitors. J. Heterocycl. Chem. 2004, 41, 941–946.
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4
5
6
7
(20) FernandezꢀMato, A.; Peinador, C.; Quintela, J. M. Synthesis and
Characterization of Substituted Pyrazino[2',3':4,5]thieno[3,2ꢀd]pyrimidines
and Related Molecules Synthesis 2011, 3323ꢀ3331.
8
9
(21) Pokhodylo, N.T.; Matiychuk, V.S.; Obushak M.D. New convenient synthesis
of 2,3ꢀdiaminothieno[2,3ꢀd]pyrimidinꢀ4(3H)ꢀone derivates from substituted
alkyl 2ꢀ(1Hꢀtetrazolꢀ1ꢀyl)thiopheneꢀ3ꢀcarboxylates. Tetrahedron. 2008, 64,
7, 1430ꢀ1434.
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26
27
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46
47
48
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53
54
55
56
57
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59
60
(22) Gewald, K.; Jaensch, H.ꢀJ. 3ꢀAminoꢀbenzo[b]furane. Journal für Praktische
Chemie. 1973, 315, 779 – 785.
(23) Liu, H.; He, X.; Choi, H.ꢀS.; Yang, K.; Woodmansee, D.; Wang, Z.; Ellis, D.
A.; Wu, B.; He, Y.; Nguyen, T. N. Preparation of pyrazolopyrimidinones and
analogs, and their compositions as cannabinoid CB1 receptor inhibitors, WO
2006047516, 2006, 259 pp.
(24) Gewald, K. Reaktion von methylenaktiven Nitrilen mit Senfolen und
Schwefel. Journal für Praktische Chemie. 1966, 32, 26 – 30.
(25) Peet, N.P.; Lentz, N.L.; Sunder, S.; Dudley, M.W.; Ogden, A.M.L.
Conformationally Restrained, Chiral (Phenylisopropyl)aminoꢀSubstituted
Pyrazolo[3,4ꢀd]pyrimidines and Purines with Selectivity for Adenosine A1
and A2 Receptors. Journal of Medicinal Chemistry, 1992, 35, 17, 3263 –
3269.
(26) Sakurai, A.; Midorikawa, H. The Cyclization of Ethyl Cyanoacetate and
Ketones by Ammonium Acetate. Bull. of the Chem. Soc. of Japan, 1967, 40,
1680 – 1684.
(27) Shishoo, C. J.; Devani, M. B.; Pathak, U. S.; Ananthan, S.; Bhadti, V. S.; et al.
Reaction of nitriles under acidic conditions. Part III. A facile synthesis of
thienopyrimidinꢀ4(3H)ꢀones. J. Het. Chem. 1984, 21, 375ꢀ380.
(28) Modica, M., Santagati, M., Guccione, S., Russo, F., Cagnotto, A., Goegan,
M., Mennini, T. Design, synthesis and binding properties of novel and
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selective 5ꢀHT3 and 5ꢀHT4 receptor ligands. Eur. J. Med. Chem. 2000, 35,
4
5
1065ꢀ1079.
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A New Convenient Strategy for Annulation of Pyrimidines to Thiophenes or Furans via the One-pot
Multistep Cascade Reaction of 1H-Tetrazoles with Aliphatic Amines
Nazariy T. Pokhodylo,* Olga Ya. Shyyka, Vasyl S. Matiychuk, Mykola D. Obushak
Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya St. 6, Lviv
79005, Ukraine
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One-step solvent-free reaction
N
N
O
N
N
N
N
R1
R2
OR3
N
R1
R2
N
N
OR3
OR3
N
N
S
O
S
N
O
O
R5
R5
R5
HN
R4
HN
t
t
HN
R4
R4
t
R4
N
R4
N
R5
O
R5
R1
R2
H
N
R1
R2
N
R5
N
NH
N
NH
R4
N
O
S
S
O
O
Keywords: tetrazole, thieno[2,3ꢀd]pyrimidinꢀ4(3H)ꢀone, thieno[3,2ꢀd]pyrimidinꢀ
4(3H)ꢀone, benzofuro[3,2ꢀd]pyrimidinꢀ4(3H)ꢀone, heterocyclization.
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