Study on the cyclization of 6-arylethynylpyrimidine-5-carbaldehydes with tert-butylamine: microwave versus thermal preparation of pyrido[4,3-d]pyrimidines

Article abstract of DOI:10.1016/j.tet.2009.05.015

Thermal and microwave initiated cyclization of 2,4-disubstituted 6-arylethynylpyrimidine-5-carbaldehydes with tert-butylamine has been studied. A novel high-yielding preparation of 2,4-disubstituted 7-arylpyrido[4,3-d]pyrimidines has been developed. The i

Full text of DOI:10.1016/j.tet.2009.05.015

Tetrahedron 65 (2009) 5752–5759
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Study on the cyclization of 6-arylethynylpyrimidine-5-carbaldehydes with tert-
butylamine: microwave versus thermal preparation of pyrido[4,3-d]pyrimidines
,
b
a
a
a
Inga Cikotiene a , Visvaldas Kairys , Rita Buksnaitiene , Marius Morkunas , Simonas Rudys ,
*
Algirdas Brukstus a, Miguel X. Fernandes b
a Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, LT 03225, Vilnius, Lithuania
b Centro de Qu´ımica da Madeira, Departamento de Qu´ımica, Universidade da Madeira, Campus da Penteada, 9000-360, Funchal, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Thermal and microwave initiated cyclization of 2,4-disubstituted 6-arylethynylpyrimidine-5-carbalde-
hydes with tert-butylamine has been studied. A novel high-yielding preparation of 2,4-disubstituted 7-
arylpyrido[4,3-d]pyrimidines has been developed. The intermediate compounds were isolated and
possible mechanism of the reactions is discussed.
Received 26 February 2009
Received in revised form 22 April 2009
Accepted 7 May 2009
Available online 13 May 2009
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
Keywords:
Cyclization
Microwave
6-Arylethynylpyrimidine-5-carbaldehydes
Pyrido[4,3-d]pyrimidines
1,6-Electrocyclic reaction
1. Introduction
In our research, which was aimed at the use of 6-arylethy-
nylpyrimidines for the synthesis of fused pyrimidine derivatives,5
we have successfully applied Larock’s method for the synthesis of
the pyrido[4,3-d]pyrimidine heterosystem by the intramolecular
cyclization of 4-amino-5-N-tert-butyliminomethyl-2-methylthio-
6-phenylethynylpyrimidine catalyzed by AgNO3.6 However, on the
way to explore the scope of the formation of the pyrido[4,3-d]py-
rimidine system and to synthesize more derivatives with potential
biological activity,7 we have found recently that some 2,4-di-
substituted 6-arylethynylpyrimidine-5-carbaldehydes, bearing N-
alkylamino- or N,N-dialkylamino groups in position 4 of the
pyrimidine ring, underwent unexpected thermal cyclization with
tert-butylamine to produce 2,4-disubstituted 7-arylpyrido[4,3-
d]pyrimidines in good yields in the absence of any catalysts. The
intermediate compounds were isolated and possible mechanisms
of the reactions were discussed.8 In this paper we wish to report
results of our more extensive investigations.
Functionally substituted alkynes are versatile intermediates in
the synthesis of heterocyclic or carbocyclic compounds.1 A literature
survey revealed that intramolecular cyclization of alkynes, which
contain a nucleophile in close proximity to the carbon–carbon
triple bond is extremely effective for the synthesis of a wide variety
of heterocycles.2 Several years ago, Larock’s group reported about
interesting transition metal-mediated3 or electrophile-induced4
cyclization of N-tert-butyl-o-(1-alkynyl)benzaldimines and their
analogs. These methods are very effective for the synthesis of
a wide variety of isoquinolines, pyridines, and naphthyridines
(Scheme 1).
R
R
R
R
R
R
O
N
NH2
N
[M] or EX
R
R
H(E)
R
2. Results and discussion
Scheme 1. Literature results overview.
The starting compounds 2a–t were synthesized by the
palladium-catalyzed Sonagashira coupling of the corresponding
2,4-disubstituted 6-chloropyrimidine-5-carbaldehydes9 1a–t with
1-arylacetylenes according to procedure described earlier (Scheme
2, Table 1).5c,d
* Corresponding author. Tel.: þ370 5 219 31 95; fax: þ370 5 233 09 87.
E-mail address: inga.cikotiene@chf.vu.lt (I. Cikotiene).
0040-4020/$ – see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.015

I. Cikotiene et al. / Tetrahedron 65 (2009) 5752–5759
5753
R1
N
Table 2
R2
R1
N
R2
Optimization of the synthesis of 2,4-disubstituted 7-arylpyrido[4,3-d]pyrimidines
N
N
N
N
Entry
Starting
comp.
Conditions 1
Conditions 2
Conditions 3
i
O
O
tert-BuNH2,
tert-BuNH2,
tert-BuNH2,
DMF, microwave
oven, 500 W
R
R
Cl
sealed tube,
sealed tube,
80–90 ꢀ
C
120–130 ꢀ
C
R3
1a-t
2a-t
Product
Yield, %
Product
Yield, %
Product
Yield, %
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
3a
3b
4c
4d
4e
4f
93a
93a
60a
58a
62a
58a
24a
20a
5a
5b
5c
5d
5e
5f
25b
18b
80b
80a
95a
85a
75a
72a
5a
5b
5c
5d
5e
5f
95c
90c
91c
92c
98d
97d
97e
96e
Scheme 2. Reagents: (i) 1-arylacetylene (1.2 equiv), PdCl2(PPh3)2 (2 mol %), CuI
(1 mol %), Et3N, DMF, Ar, 40 ꢀC, 2–4 h.
Table 1
Data of the synthesis of 2,4-disubstituted 6-arylethynylpyrimidine-5-carbaldehydes
2a–t
2g
2h
4g
4h
4g
4h
5g
5h
Entry
Starting comp.
R
NR1R2
Product
R3
Yield, %
a
Reaction time: 24 h.
Reaction time: 48 h.
Reaction time: 20 min.
Reaction time: 10 min.
Reaction time: 1 h.
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
H
NH2
NH2
NHCH3
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
C2H5
H
H
H
H
H
C2H5
H
H
H
C2H5
F
C2H5
F
C2H5
H
C2H5
H
H
42
45
85
59
80
85
82
75
82
66
90
89
82
88
85
56
74
63
45
65
b
c
d
e
NHC2H5
N(CH2)4O
N(CH2)5
NHC6H5
NHC6H5
NHCH2C6H5
N(CH3)2
N(CH2)4
N(CH2)4
N(CH2)4
N(CH2)4O
N(CH2)4O
N(CH2)5
NHCH2C6H5
NHCH2C6H5
N(CH2)4
N(CH2)4O
moiety, but also a 1,2-addition of the second tert-butylamine mol-
ecule to the C^C bond took place, leading to a formation of yellow
colored products 4c–h (conditions 1, entries 3–8). The stereo-
chemistry of addition of nucleophiles to the C^C bond of 6-aryl-
ethynylpyrimidines has been studied and reported in our previous
paper.10 When the same reactions proceeded under higher (120–
130 ꢀC) temperatures, compounds 1a–f converted to the corre-
sponding 7-arylpyrido[4,3-d]pyrimidines 5a–f (conditions 2,
entries 1–6). It is noteworthy that formation of 4-amino-2-methyl-
thiopyrido[4,3-d]pyrimidines 5a,b was slower and the yields of the
obtained products were low (conditions 2, entries 1 and 2). On the
otherhand, heatingof the corresponding 4-anilino-6-arylethynyl-2-
methylthiopyrimido-5-carbaldehydes 1g,h with an excess of tert-
butylamine in sealed tubes at 120–130 ꢀC did not lead to the
formation of 4-anilino-7-aryl-2-methylthiopyrido[4,3-d]pyrimi-
dines (5g,h), but formation of the intermediates 4g,h was observed
(conditions 2, entries 7 and 8). To our pleasant surprise, when
solutions of compounds 1a–h and tert-butylamine in dimethyl-
formamide were irradiated in a microwave oven, after 10–60 min
a high-yielding formation of 2,4-disubstituted 7-arylpyrido[4,3-d]-
pyrimidines (5a–h) was observed (conditions 3, entries 1–8). Thus,
we have optimized an efficient, concise, and high-yielding method
of synthesis of 2,4-disubstituted 7-arylpyrido[4,3-d]pyrimidines from
2,4-disubstituted 6-arylethynylpyridopyrimidines and tert-butyl-
amine. According to the present methodology, we have prepared
various 2,4-disubstituted 7-arylpyrido[4,3-d]pyrimidines 5a–t via
the thermal reaction of 2,4-disubstituted 6-arylethynylpyrimidine-
5-carbaldehydes 1a–t with tert-butylamine. The results are sum-
marized in Scheme 3 and Table 3.
9
10
11
12
13
14
15
16
17
18
19
20
1j
1k
1l
2j
2k
2l
1m
1n
1o
1p
1q
1r
1s
1t
2m
2n
2o
2p
2q
2r
2s
2t
H
H
H
In order to study the generality of the preparation of the pyr-
ido[4,3-d]pyrimidine framework via a one-pot synthetic method
from 2,4-disubstituted 6-arylethynylpyridopyrimidines and tert-
butylamine, several starting compounds bearing substituents pos-
sessing different steric and electronical properties in position 4 of
the pyrimidine ring were chosen and their reactions with tert-
butylamine under different conditions were studied. The reaction
of title compounds with tert-butylamine revealed a variety of be-
haviors depending on reaction conditions. The results are sum-
marized in Figure 1 and Table 2.
Thus, compounds 2a,b bearing a primary amino group in position
4 of the pyrimidine ring, treated with tert-butylamine in sealed tube
at 80–90 ꢀC temperature, gave the corresponding 4-amino-6-aryl-
ethynyl-5-N-tert-butyliminomethyl-2-methylthiopyrimidines 3a,b
(conditions 1, entries 1 and 2). These were the only two examples of
the selective formation of logically expected3,4 tert-butylimines 3.
When the reaction of the other 2,4-disubstituted 6-arylethy-
nylpyrimidine-5-carbaldehydes (1c–h) with an excess of tert-
butylamine in sealed tubes at 80–90 ꢀC was performed, we have
found thatnotonlythereaction of tert-butylaminewith the carbonyl
In our previous report8 we have shown that the cyclization
of 2,4-disubstituted 6-arylethynylpyrimidine-5-carbaldehydes 2
with tert-butylamine proceeded via N-(tert-butyl)-N-{4-[(Z)-2-
aryl-2-(tert-butylamino)vinyl]pyrimidin-5-yl}methyleneamines 4.
1
R2
1
R2
R
1
R2
R
N
N
R
N
N
N
N
N
N
N
N
N
N
R
R
R
HN
R3
R3
R3
3
4
5
Figure 1. Products of the reactions of 2,4-disubstituted-6-arylethynylpyrimidine-5-carbaldehydes (2) with tert-butylamine.

5754
I. Cikotiene et al. / Tetrahedron 65 (2009) 5752–5759
Table 4
R2
R1 R2
N
R1
N
Rates of the intramolecular cyclizations of N-(tert-butyl)-N-{4-[(Z)-2-aryl-2-(tert-
butylamino)vinyl]pyrimidin-5-yl}methyleneamines 4 under various conditionsa
N
N
tert-BuNH2
N
N
N
O
Entry
Comp.
tert-BuNH2,
120 ꢀC
DMF,
120 ꢀ
2-PrOH,
reflux
Xylene,
reflux
DMF,
MW, 500 W
R
R
C
R3
1
2
3
4d
4e
4g
10 h
3 h
n/a
30 min
10 min
n/a
6 h
3 h
n/a
3 h
1.5 h
n/a
20 min
5 min
40 min
R3
2a-t
5a-t
a
Scheme 3.
Reactions were analyzed by TLC.
It is noteworthy that the reaction rates depend on the nature of
the substituent in position 4 of the pyrimidine ring. Thus, the
shortest reaction times were for the 4-N,N-dialkylamino de-
rivatives, and the longestdfor the 4-anilino derivatives. We have
studied the influence of solvent on cyclization rates of in-
termediates 4d,e,g. The results are summarized in Table 4. The most
suitable solvent for the cyclization of the intermediates 4 under
either convectional or microwave-induced heating was dimethyl-
formamide, followed by p-xylene. On the other hand, 2-propanol
and tert-butylamine seemed to be less effective. It should be noted
that the cyclization of the intermediate adduct 4g bearing an
anilino substituent in position 4 of the pyrimidine ring did not
undergo cyclization into 4-anilino-2-methylthio-7-phenylpyrido[4,3-
d]pyrimidine 5g under conventional heating conditions. The satis-
factory result was obtained only when compound 4g was dissolved in
dimethylformamide and heated using microwave irradiation (last
column in Table 4).
We assumed that different cyclization rates could depend
mainly on the different conformations of the intermediates 4. So
intermediates 4c (NR1R2¼NHCH3), 4g (NR1R2¼NHC6H5), and 4j
(NR1R2¼N(CH3)2) were chosen and explored computationally.
Compounds 4c and 4j were selected to model the compounds 4d
and 4e, respectively, to reduce the size of calculations and for the
sake of simplicity. Because of their flexibility, compounds 4 exhibit
especial richness of conformations. Several important rotamers are
shown in Figure 2. We did not attempt to explore all conforma-
tional space exhaustively. Instead, only what we deemed to be
important rotamers were optimized, based on the rotation (flip-
ping) of the tert-butylimino and vinyl substituents with respect to
the plane of the pyrimidine ring. For example, we did not look for
conformers, which involve flipping of R and NR1R2 substituents in
Figure 2. However, the latter substituent was normally selected in
a conformation, which maximized the number of formed hydrogen
bonds (where applicable).
Table 3
Data of the synthesis of 2,4-disubstituted 7-arylpyrido[4,3-d]pyrimidines 5a–t
Entry Starting comp.
R
NR1R2
R3
Product Method Aa Method Bb
Yield, %
Yield, %
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
SCH3 NH2
SCH3 NH2
H
5a
25
18
80
80
95
85
0c
95
90
91
92
98
97
C2H5 5b
SCH3 NHCH3
SCH3 NHC2H5
SCH3 N(CH2)4O
SCH3 N(CH2)5
SCH3 NHC6H5
SCH3 NHC6H5
SCH3 NHCH2C6H5
SCH3 N(CH3)2
SCH3 N(CH2)4
SCH3 N(CH2)4
SCH3 N(CH2)4
SCH3 N(CH2)4O
SCH3 N(CH2)4O
SCH3 N(CH2)5
H
H
H
H
H
5c
5d
5e
5f
5g
97
C2H5 5h
0c
96
98
100
100
94
95
95
97
93
95
96
100
99
9
H
H
H
5i
5j
5k
81
92
89
91
92
90
92
87
80
91
95
89
10
11
12
13
14
15
16
17
18
19
20
2j
2k
2l
C2H5 5l
F
C2H5 5n
F
2m
2n
2o
2p
2q
2r
2s
2t
5m
5o
C2H5 5p
5q
NHCH2C6H5 C2H5 5r
N(CH2)4
N(CH2)4O
H
H
H
H
NHCH2C6H5 H
H
H
5s
5t
a
b
c
Method A: tert-butylamine, sealed tube, 120–130 ꢀC, 24–48 h.
Method B: tert-butylamine (10 equiv), DMF, microwave oven, 500 W,10–60 min.
Intermediates 4g,h were formed, instead.
The possible mechanism is presented in Scheme 4. We assume that
intermediate adducts 4 underwent a 1,6-electrocyclic reaction to
form a six-membered ring. The aromatization of cyclic adduct leads
to elimination of tert-butylamine and 2-methylpropene molecules.
4-Amino-6-arylethynyl-5-N-tert-butyliminomethyl-2-methyl-
thiopyrimidines 3a,b during heating in DMF either at 120–130 ꢀC or
in the microwave oven at 500–700 W did not undergo intra-
molecular catalyst-free cyclization into compounds 5a,b. Cycliza-
tion of 3a,b was successful only in the presence of an equivalent of
tert-butylamine in DMF. So we believe that in latter case the
formation of the intermediate N-(tert-butyl)-N-{4-[(Z)-2-aryl-
2-(tert-butylamino)vinyl]pyrimidin-5-yl}methyleneamines 4a,b
proceeded followed by 1,6-electrocyclic reaction and aromati-
zation to 4-amino-7-aryl-2-methylthiopyrido[4,3-d]pyrimidines
5a,b (Scheme 4).
Table 5 contains the data of calculated relative energies of
rotamers of compounds 4c, 4g, and 4j. Analysis of the geometries of
the rotamers shows that the energy levels appear to be influenced
by the number and strength of the intramolecular hydrogen bonds
formed. The lowest energy rotamer 4_2 for 4c and 4g has two
intramolecular hydrogen bonds while lowest conformer of 4j–4_1j
has only one hydrogen bond and the tert-butylimino moiety is
R1
N
R2
NH2
1
R2
1
R
R2
R
N
N
1
N
N
R
R2
N
NH2
N
N
N
N
O
N
N
N
N
R
R
R
N
R
NH
HN
R3
3
R3
R3
R
NH2
2
4
6
5
Scheme 4.

I. Cikotiene et al. / Tetrahedron 65 (2009) 5752–5759
5755
R1
N
1
R 2
R2
R
N
N
R2
R2
1
R
R1
N
N
N
N
N
N
N
N
N
N
N
N
N
R
NH
R
NH
R
R
HN
HN
R3
R3
R3
R3
4_1
4_2
4_3
4_4
Figure 2. Possible conformers of compounds 4.
synthesized compounds were monitored by TLC using Silica gel 60
F254 aluminum plates (Merck). Visualization was accomplished by
UV light.
Table 5
Energies of important rotamers of 4c, 4g, and 4ja
Entry
Comp.
NR1R2
4_1
4_2
4_3
4_4
The structures of the molecules were initially optimized using
restricted closed shell Hartree–Fock (RHF) wave function, with
subsequently re-optimizing using Density Functional Theory (DFT)
with Becke’s11 three-parameter (B3) exchange functional correc-
tion and the gradient corrected correlation functional due to Lee,
Yang, and Parr12 (LYP). The optimization was generally performed
within C1 symmetry, except for few instances where symmetry of
the molecule allowed to use higher symmetry. The 6-31G(d,p) basis
function was used throughout the calculations: the 6-31G basis
set13 augmented with a d polarization functions on all heavy atoms,
and p polarization functions on all hydrogen atoms. To describe
levels of theory used to obtain results, we use notation A//B, which
denotes level of theory A applied using a geometry optimized at
level of theory B, for instance DFT//HF.
1
2
3
4c
4g
4j
NHCH3
NHC6H5
N(CH3)2
7.7 (8.6)
8.6 (9.4)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
1.8 (1.7)
6.0 (6.2)
5.7 (5.8)
8.3 (8.5)
15.6 (16.8)
16.4 (17.3)
6.0 (6.2)
a
The lowest energy conformer is attributed zero energy. The numbers refer to
relative energies in kcal/mol at DFT-PCM//DFT level, with DFT//DFT result shown in
parentheses.
turned away from bulky N,N-dimethylamino group. Comparison of
4_1 and 4_2 rotamers for 4c and 4g in Table 5 seems to suggest that
the hydrogen bond between NHR and the imino nitrogen is
stronger by about 1 kcal/mol for 4g compared to 4c. This is con-
sistent with observation that the phenyl amine hydrogen is more
acidic compared to the aliphatic. It is of interest to note that only
conformation 4_4 directly leads to cyclization since for the new
bond to be formed both tert-butylimino and vinyl moieties have to
face each other. For 4c and 4g, this rotamer has a relatively high
energy. The rotamer 4_4j has a similar geometry to analogous
rotamers of 4_4c and 4_4g. However, the former rotamer’s energy
is relatively closer to the lowest energy rotamer compared to 4_4c
and 4_4g (6.2 vs 16.8 and 17.3 kcal/mol) because of lower number
of hydrogen bonds formed in the lowest energy conformation, as
discussed above.
The solvent effects in tert-butylamine were estimated using the
Polarizable Continuum Model14 (PCM) representing solvent as
a continuum surrounding the solute. We used the integral equation
formalism14c approach (IEF-PCM) as implemented in the GAMESS15
package (IEF¼–3 keyword). For the PCM calculations, dielectric
constant
3
¼4.3116 and tert-butylamine solvent radius r¼3.4 Å, es-
timated from atomic van der Waals radii, were used.
The calculations were performed using GAMESS quantum
chemistry package15 running under Linux operating system.
More detailed DFT calculations of these reactions will be pub-
lished in due course.
4.2. Compounds 2a–t
3. Conclusions
Compounds 2a–t were prepared according to the method
published earlier.5c,d Data for compounds 2a6 and 2e–g,k5c,d have
been published in the previous papers.
In summary, we have developed a novel, concise, and high-
yielding synthetic method of pyrido[4,3-d]pyrimidine framework
via thermal or microwave-induced cyclization of 2,4-disubstituted
6-arylethynylpyrimidine-5-carbaldehydes with tert-butylamine.
The possible mechanism of the cyclization is proposed and the
evidence has been established by isolation of intermediate com-
pounds. We believe that the present methodology extends promise
for the convenient synthetic protocol for the preparation of pyr-
ido[4,3-d]pyrimidine derivatives of biological interest.
4.2.1. 4-Amino-2-methylthio-6-(4-ethylphenyl)ethynylpyrimidine-
5-carbaldehyde 2b
Yield 45%, mp 163–164 ꢀC (from octane). IR (KBr): nmax¼3384,
3274 (NH2), 2213 (C^C), 1660 (C]O) cmꢂ1 1H NMR (300 MHz,
.
CD2Cl2):
d
¼1.29 (3H, t, J¼7.5 Hz, CH3), 2.59 (3H, s, SCH3), 2.75 (2H, q,
J¼7.5 Hz, CH2), 5.86 (1H, br s, NH), 7.32 (2H, d, J¼8.4 Hz, ArH), 7.61
(2H, d, J¼8.4 Hz, ArH), 8.56 (1H, br s, NH), 10.50 (1H, s, CHO) ppm.
13C NMR (75 Hz, CD2Cl2):
d
¼14.3, 15.2, 29.2, 83.6, 98.4, 108.8, 117.9,
4. Experimental
4.1. General
128.5, 132.7, 147.7, 155.1, 160.9, 177.1, 191.6 ppm. Anal. Calcd for
C16H15N3OS: C 71.36, H 5.42, N 11.89; found: C 71.27, H 5.45, N 11.91.
4.2.2. 4-N-Methylamino-2-methylthio-6-phenylethynylpyrimidine-
5-carbaldehyde 2c
Melting points were determined in open capillaries and are
uncorrected. IR spectra were run in Nujol mulls or in KBr discs on
a Perkin–Elmer FT spectrophotometer Spectrum BX II. 1H NMR
spectra were recorded with a Varian Unity INOVA spectrometer
(300 MHz) using tetramethylsilane as internal standard. Elemental
analysis (C, N, H) results were found to be in good agreement
(ꢁ0.4%) with the calculated values. All reactions and purity of the
Yield 85%, mp 121–123 ꢀC (from octane). IR (KBr): nmax¼3303
(NH), 2213 (C^C), 1653 (C]O) cmꢂ1 1H NMR (300 MHz, CDCl3):
.
d
¼2.61 (3H, s, SCH3), 3.15 (3H, d, J¼4.8 Hz, NCH3), 7.42–7.46 (3H, m,
ArH), 7.63–7.67 (2H, m, ArH), 9.00 (1H, br s, NH), 10.46 (1H, s,
CHO) ppm. 13C NMR (75 Hz, CDCl3):
¼14.6, 41.3, 84.8, 97.7, 111.3,
121.3, 128.8, 130.4, 132.6, 156.1, 159.9, 174.1, 188.2 ppm. Anal. Calcd
d

5756
I. Cikotiene et al. / Tetrahedron 65 (2009) 5752–5759
for C15H13N3OS: C 63.58, H 4.62, N 14.83; found: C 63.70, H 4.56, N
14.95.
NMR (75 Hz, CDCl3):
d
¼14.3, 25.3, 50.6, 84.4, 95.9, 111.4, 115.8, 116.1,
117.1, 134.4, 134.5, 154.7, 156.7, 161.8, 165.1, 173.8, 188.0 ppm. Anal.
Calcd for C18H16FN3OS: C 63.32, H 4.72, N 12.31; found: C 63.60, H
5.00, N 12.12.
4.2.3. 4-N-Ethylamino-2-methylthio-6-phenylethynylpyrimidine-
5-carbaldehyde 2d
Yield 59%, mp 105–107 ꢀC (from 2-PrOH). IR (KBr): nmax¼3424
4.2.9. 6-(4-Ethylphenyl)ethynyl-2-methylthio-4-morpholin-4-
ylpyrimidine-5-carbaldehyde 2n
(NH), 2216 (C^C), 1654 (C]O) cmꢂ1 1H NMR (300 MHz, CDCl3):
.
d
¼1.33 (3H, t, J¼3.0 Hz, CH3), 2.59 (3H, s, SCH3), 3.61–3.70 (2H, m,
CH2), 7.42–7.45 (5H, m, ArH), 7.63–7.66 (2H, m, ArH), 9.03 (1H, br s,
NH), 10.45 (1H, s, CHO) ppm. 13C NMR (75 Hz, CDCl3):
Yield 88%, mp 139–140 ꢀC (from 2-PrOH). IR (KBr): nmax¼2213
(C^C), 1664 (C]O) cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
¼1.29 (3H, t,
d¼13.6, 14.4,
J¼7.2 Hz, CH3), 2.57 (3H, s, SCH3), 2.72 (2H, q, J¼7.2 Hz, CH2), 3.73
(4H, t, J¼4.5 Hz, N(CH2)2), 3.87 (4H, t, J¼4.5 Hz, O(CH2)2), 7.26 (2H,
d, J¼8.1 Hz, ArH), 7.58 (2H, d, J¼8.1 Hz, ArH), 10.48 (1H, s,
41.2, 84.9, 97.2, 111.5, 121.2, 128.9, 130.0, 132.8, 156.2, 159.9, 174.1,
188.8 ppm. Anal. Calcd for C16H15N3OS: C 64.62, H 5.08, N 14.13;
found: C 64.71, H 4.98, N 14.08.
CHO) ppm. 13C NMR (75 Hz, CDCl3):
d
¼14.4, 15.1, 28.9, 49.1, 66.8,
84.1, 98.8, 111.0, 117.9, 128.2, 128.3, 132.5, 147.0, 157.2, 159.2, 174.9,
187.9 ppm. Anal. Calcd for C20H21N3O2S: C 65.37, H 5.76, N 11.44;
found: C 65.46, H 5.79, N 11.41.
4.2.4. 4-Anilino-2-methylthio-6-(4-ethylphenyl)ethynylpyrimidine-
5-carbaldehyde 2h
Yield 75%, mp 150–152 ꢀC (from 2-PrOH). IR (KBr): nmax¼3281
(NH), 2214 (C^C), 1638 (C]O) cmꢂ1
.
1H NMR (300 MHz, CDCl3):
4.2.10. 6-(4-Fluorophenyl)ethynyl-2-methylthio-4-morpholin-4-
ylpyrimidine-5-carbaldehyde 2o
d
¼1.25 (3H, t, J¼7.5 Hz, CH3), 2.57 (3H, s, SCH3), 2.71 (2H, q,
J¼7.5 Hz, CH2), 7.17 (1H, t, J¼7.5 Hz, ArH), 7.21 (2H, t, J¼7.5 Hz, ArH),
7.37 (2H, t, J¼7.5 Hz, ArH), 7.55 (2H, d, J¼7.8 Hz, ArH), 7.70 (2H, d,
J¼7.8 Hz, ArH),10.49 (1H, s, CHO),11.05 (1H, br s, NH) ppm. 13C NMR
Yield 85%, mp 212–213 ꢀC (from 2-PrOH). IR (KBr): nmax¼2216
(C^C), 1667 (C]O) cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
¼2.57 (3H, s,
SCH3), 3.72 (4H, t, J¼5.2 Hz, N(CH2)2), 3.87 (4H, t, J¼5.2 Hz,
(75 Hz, CDCl3):
d¼14.6, 15.1, 28.9, 83.3, 98.9, 108.3, 117.7, 122.2,
O(CH2)2), 7.07–7.13 (2H, m, ArH), 7.62–7.67 (2H, m, ArH), 10.52 (1H,
124.8, 128.2, 128.8, 132.6, 137.3, 147.2, 155.4, 157.1, 177.7, 191.9 ppm.
Anal. Calcd for C22H19N3OS: C 70.75, H 5.13, N 11.25; found: C 70.49,
H 5.21, N 11.29.
s, CHO) ppm. 13C NMR (75 Hz, CDCl3):
d
¼14.0, 49.6, 66.8, 84.5, 95.7,
111.2, 115.9, 116.1, 117.3, 134.6, 134.7, 154.5, 156.5, 161.9, 165.1, 173.8,
188.3 ppm. Anal. Calcd for C18H16FN3O2S: C 60.49, H 4.51, N 11.76;
found: C 60.62, H 4.33, N 11.88.
4.2.5. 4-N-Benzylamino-2-methylthio-6-phenylethynylpyrimidine-
5-carbaldehyde 2i
4.2.11. 6-(4-Ethylphenyl)ethynyl-2-methylthio-4-piperidin-1-
ylpyrimidine-5-carbaldehyde 2p
Yield 82%, mp 138–139 ꢀC (from 2-PrOH). IR (KBr): nmax¼3284
(NH), 2211 (C^C), 1652 (C]O) cmꢂ1
.
1H NMR (300 MHz, CDCl3):
Yield 56%, mp 102–103 ꢀC (from 2-PrOH). IR (KBr): nmax¼2211
d
¼2.56 (3H, s, SCH3), 4.84 (2H, d, J¼5.7 Hz, CH2), 7.35–7.46 (8H, m,
ArH), 7.64–7.67 (2H, m, ArH), 9.41 (1H, br s, NH), 10.48 (1H, s,
CHO) ppm. 13C NMR (75 Hz, CDCl3):
(C^C), 1671 (C]O) cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
¼1.28 (3H, t,
J¼7.5 Hz, CH3), 1.73 (6H, br s, (CH2)3), 2.56 (3H, s, SCH3), 2.70 (2H, q,
J¼7.5 Hz, CH2), 3.64 (4H, br s, N(CH2)2), 7.24 (2H, d, J¼8.4 Hz, ArH),
7.57 (2H, d, J¼8.4 Hz, ArH), 10.44 (1H, s, CHO) ppm. 13C NMR (75 Hz,
d
¼14.4, 44.4, 83.7, 97.7, 108.5,
120.7, 127.6, 128.6, 128.7, 130.3, 132.5, 137.6, 154.8, 159.0, 177.2,
191.6 ppm. Anal. Calcd for C21H17N3OS: C 70.17, H 4.77, N 11.69;
found: C 70.42, H 5.00, N 11.53.
CDCl3):
d
¼14.4, 15.2, 24.1, 26.0, 28.9, 49.8, 84.8, 98.2, 111.0, 118.1,
128.1, 132.4, 146.8, 156.9, 158.9, 174.2, 187.9 ppm. Anal. Calcd for
C21H23N3OS: C 69.01, H 6.34, N 11.50; found: C 69.10, H 5.99, N 11.29.
4.2.6. 4-N,N-Dimethylamino-2-methylthio-6-phenylethynyl-
pyrimidine-5-carbaldehyde 2j
4.2.12. 4-N-Benzylamino-6-phenylethynylpyrimidine-5-
carbaldehyde 2q
Yield 86%, mp 181–183 ꢀC (from 2-PrOH). IR (KBr): nmax¼2217
(C^C), 1666 (C]O) cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
¼2.58 (3H, s,
Yield 74%, mp 119–121 ꢀC (from 2-PrOH). IR (KBr): nmax¼3281
SCH3), 3.19 (6H, s, N(CH3)2), 7.42–7.45 (3H, m, ArH), 7.64–7.67 (2H,
(NH), 2213 (C^C), 1671 (C]O) cmꢂ1 1H NMR (300 MHz, CDCl3):
.
m, ArH), 10.51 (1H, s, CHO) ppm. 13C NMR (75 Hz, CDCl3):
d¼14.4,
d
¼4.85 (2H, d, J¼5.4 Hz, CH2), 7.38–7.49 (8H, m, ArH), 7.65–7.69
(2H, m, ArH), 8.74 (1H, br s, NH), 9.31 (1H, s, CH), 10.61 (1H, s,
CHO) ppm. 13C NMR (75 Hz, CDCl3):
41.0, 84.5, 97.4, 111.0, 120.9, 128.5, 130.1, 132.4, 155.8, 159.7, 173.8,
187.9 ppm. Anal. Calcd for C16H15N3OS: C 64.62, H 5.08, N 14.13;
found: C 64.72, H 5.17, N 14.20.
d
¼44.4, 84.3, 98.5, 120.6, 127.6,
128.6, 128.8, 130.4, 132.4, 137.3, 155.2, 159.8, 161.5, 192.7 ppm. Anal.
Calcd for C20H15N3O: C 76.66, H 4.82, N 13.41; found: C 76.82, H
5.00, N 13.51.
4.2.7. 2-Methylthio-6-(4-ethylphenyl)ethynyl-4-pyrrolidin-1-
ylpyrimidine-5-carbaldehyde 2l
Yield 89%, mp 187–189 ꢀC (from 2-PrOH). IR (KBr): nmax¼2216
4.2.13. 4-N-Benzylamino-6-(4-ethylphenyl)ethynylpyrimidine-5-
carbaldehyde 2r
(C^C), 1669 (C]O) cmꢂ1. 1H NMR (300 MHz, CDCl3):
d¼1.27 (3H, t,
J¼7.5 Hz, CH3), 2.00 (4H, br s, (CH2)2), 2.56 (3H, s, SCH3), 2.72 (2H, q,
J¼7.5 Hz, CH2), 3.55 (4H, br s, N(CH2)2), 7.24 (2H, d, J¼8.4 Hz, ArH),
7.58 (2H, d, J¼8.4 Hz, ArH), 10.53 (1H, s, CHO) ppm. 13C NMR (75 Hz,
Yield 63%, mp 115–117 ꢀC (from 2-PrOH). IR (KBr): nmax¼3280
(NH), 2213 (C^C), 1668 (C]O) cmꢂ1 1H NMR (300 MHz, CDCl3):
.
d
¼1.28 (3H, t, J¼7.5 Hz, CH2CH3), 2.72 (2H, q, J¼7.5 Hz, CH2CH3),
CDCl3):
d
¼14.2, 15.1, 25.3, 28.9, 50.9, 84.2, 97.7, 111.4, 118.2, 128.1,
4.83 (2H, d, J¼5.4 Hz, CH2), 7.26 (2H, d, J¼6.9 Hz, ArH), 7.37 (5H, s,
ArH), 7.59 (2H, d, J¼6.9 Hz, ArH), 8.77 (1H, br s, NH), 9.31 (1H, s, CH),
132.4, 146.7, 155.0, 156.7, 173.7, 188.3 ppm. Anal. Calcd for
C20H21N3OS: C 68.35, H 6.02, N 11.96; found: C 68.62, H 5.98, N
12.15.
10.59 (1H, s, CHO) ppm. 13C NMR (75 Hz, CDCl3):
d
¼15.5, 29.3, 44.7,
84.9, 99.5, 111.7, 118.1, 127.8, 127.9, 128.6, 129.1, 132.8, 137.7, 147.5,
156.3, 160.2, 161.9, 193.2 ppm. Anal. Calcd for C22H19N3O: C 77.40, H
5.61, N 12.31; found: C 77.62, H 5.44, N 12.55.
4.2.8. 6-(4-Fluorophenyl)ethynyl-2-methylthio-4-pyrrolidin-1-
ylpyrimidine-5-carbaldehyde 2m
Yield 82%, mp 210–212 ꢀC (from 2-PrOH). IR (KBr): nmax¼2217
4.2.14. 6-Phenylethynyl-4-pyrrolidin-1-ylpyrimidine-5-
carbaldehyde 2s
(C^C), 1665 (C]O) cmꢂ1. 1H NMR (300 MHz, CDCl3):
br s, (CH2)2), 2.56 (3H, s, SCH3), 3.55 (4H, br s, N(CH2)2), 7.08–7.13
(2H, m, ArH), 7.61–7.66 (2H, m, ArH), 10.50 (1H, s, CHO) ppm. 13C
d
¼2.00 (4H,
Yield 45%, mp 84–86 ꢀC (from 2-PrOH). IR (KBr): nmax¼2212
(C^C), 1669 (C]O) cmꢂ1. 1H NMR (300 MHz, CDCl3):
d¼2.05 (4H,

I. Cikotiene et al. / Tetrahedron 65 (2009) 5752–5759
5757
br s, CH2CH2), 3.50 (4H, br s, N(CH2)2), 7.45–7.46 (3H, m, ArH), 7.65–
7.68 (2H, m, ArH), 8.61 (1H, s, CH), 10.66 (1H, s, CHO) ppm. 13C NMR
(75 Hz, CDCl3):
132.5, 154.8, 156.6, 163.7, 188.2 ppm. Anal. Calcd for C17H15N3O: C
77.40, H 5.45, N 15.15; found: C 77.57, H 5.39, N 15.35.
IR (KBr): nmax¼3442, 3438 (NH) cmꢂ1
.
1H NMR (300 MHz,
CDCl3):
d
¼1.21 (9H, s, t-Bu),1.30 (9H, s, t-Bu), 2.64 (3H, s, SCH3), 5.21
d¼25.3, 49.8, 84.5, 97.1, 111.5, 121.1, 128.4, 129.9,
(1H, s, CH), 7.07 (1H, t, J¼7.8 Hz, ArH), 7.29–7.52 (7H, m, ArH), 7.78–
7.81 (2H, m, ArH), 8.67 (1H, s, CH), 10.55 (1H, br s, NH), 13.61 (1H, br
s, NH) ppm. 13C NMR (75 Hz, CDCl3):
92.5, 98.8, 121.4, 122.8, 127.9, 128.7, 128.9, 129.3, 140.4, 140.8, 152.9,
157.9, 160.5, 163.4, 169.9 ppm. Anal. Calcd for C28H35N5S: C 71.00, H
7.45, N 14.79; found: C 71.21, H 7.19, N 15.00.
d
¼14.4, 30.3, 32.3, 54.1, 57.7,
4.2.15. 4-Morpholin-4-yl-6-phenylethynylpyrimidine-5-
carbaldehyde 2t
Yield 65%, mp 96–98 ꢀC (from 2-PrOH). IR (KBr): nmax¼2213
(C^C), 1680 (C]O) cmꢂ1. 1H NMR (300 MHz, CDCl3):
d¼3.71 (4H, t,
4.3.5. N-{6-Anilino-4-(Z)-2-[(tert-butylamino)-2-(4-ethylphenyl)-
vinyl]-2-methylthiopyrimidin-5-ylmethylene}-2-methylpropan-
2-amine 4h
J¼4.2 Hz, N(CH2)2), 3.84 (4H, t, J¼4.2 Hz, O(CH2)2), 7.43–7.47 (3H, m,
ArH), 7.64–7.67 (2H, m, ArH), 8.62 (1H, s, CH),10.59 (1H, s, CHO) ppm.
13C NMR (75 Hz, CDCl3):
130.2, 132.4, 157.2, 159.2, 164.9, 187.9 ppm. Anal. Calcd for
C17H15N3O2: C 69.61, H 5.15, N 14.33; found: C 69.50, H 5.25, N 14.39.
d
¼49.2, 66.8, 84.4, 98.2, 111.1, 120.8, 128.6,
Yield 72%, mp 133–134 ꢀC (from 2-PrOH). IR (KBr): nmax¼3439,
3428 (NH) cmꢂ1
.
1H NMR (300 MHz, CDCl3):
d
¼1.28 (9H, s, t-Bu),
1.32 (3H, t, J¼7.5 Hz, CH2CH3), 1.34 (9H, s, t-Bu), 2.64 (3H, s, SCH3),
2.74 (2H, q, J¼7.5 Hz, CH2CH3), 5.23 (1H, s, CH), 7.04–7.42 (8H, m,
ArH), 7.78–7.82 (2H, m, ArH), 8.68 (1H, s, CH), 10.54 (1H, br s, NH),
4.3. 4-Amino-5-(tert-butyliminomethyl)-6-(arylethynyl)-2-
methylthiopirimidines 3a,b and N-{4-[(Z)-2-(tert-
butylamino)-2-arylvinyl]-2-(methylthio)pyrimidin-5-
ylmethylene}2-methylpropan-2-amines 4c–h
13.62 (1H, br s, NH) ppm. 13C NMR (75 Hz, CDCl3):
d¼14.2, 15.4,
28.6, 30.1, 32.0, 53.8, 57.4, 92.1, 98.4, 121.1, 122.1, 127.1, 128.6, 128.9,
137.8, 140.1, 144.6, 152.7, 157.6, 160.5, 163.2, 169.6 ppm. Anal. Calcd
for C30H39N5S: C 71.82, H 7.83, N 13.96; found: C 72.01, H 7.96, N
14.00.
Compounds 3a,b and 4c–h were prepared according to the
method published earlier.6,8 Data for compounds 3a6 and 4e,f8 have
been published in the previous papers.
4.4. Typical procedure for the preparation of 2,4-
disubstituted 7-arylpyrido[4,3-d]pyrimidines 5a–t
4.3.1. 4-Amino-5-(tert-butyliminomethyl)-6-[(4-ethylphenyl)-
ethynyl]-2-methylthiopyrimidine 3b
Data for compounds 5a6 and 5e,f,j,n8 have been published in the
previous papers.
Yield 93%, mp 119–120 ꢀC (from 2-PrOH–H2O). IR (KBr):
nmax¼3451, 3429 (NH2), 2211 (C^C) cmꢂ1
.
1H NMR (300 MHz,
Method A. A mixture of the corresponding 2,4-disubstituted 6-
arylethynylpyrimidine-5-carbaldehydes 2a–t (0.2 mmol) and tert-
butylamine (3 mL) in a reaction tube was flushed with argon and
the tube was carefully sealed. The mixture was heated at 120 ꢀC for
24 h (for compounds 5c–t) or 48 h (for compounds 2a,b). The sol-
vent was evaporated under reduced pressure, and the residue was
recrystallized to give compounds 5a–t.
Method B. A solution of the corresponding 2,4-disubstituted 6-
arylethynylpyrimidine-5-carbaldehydes 2a–t (0.2 mmol) and tert-
butylamine (0.15 g, 2 mmol) in DMF (3 mL) was irradiated in
a microwave oven at 500 W for 10 min (for compounds 2e,f,j–p,s,t),
20 min (for compounds 2a–d,i,q,r) or 1 h (for compounds 2g,h).
After heating, the solution was cooled to room temperature, then
cold water (10 mL) was added. The precipitate was filtered, dried,
and recrystallized to give 5a–t.
CDCl3):
d
¼1.28 (3H, t, J¼7.7 Hz, CH3), 1.36 (9H, s, t-Bu), 2.53 (3H, s,
SCH3), 2.75 (2H, q, J¼7.7 Hz, CH2), 5.83 (1H, br s, NH), 7.41 (2H, d,
J¼8.6 Hz, ArH), 7.63 (2H, d, J¼8.6 Hz, ArH), 8.89 (1H, s, CH), 9.93
(1H, br s, NH) ppm. 13C NMR (75 Hz, CDCl3):
d
¼13.9, 14.3, 28.6, 29.7,
57.4, 83.8, 98.4, 108.9, 117.9, 128.5, 132.7, 147.7, 155.1, 160.9, 161.6,
174.1 ppm. Anal. Calcd for C10H24N4S: C 68.15, H 6.86, N 15.89;
found: C 68.31, H 6.88, N 15.83.
4.3.2. N-{4-(Z)-2-[(tert-Butylamino)-2-phenylvinyl]-6-N-
methylamino-2-methylthiopyrimidin-5-ylmethylene}-2-
methylpropan-2-amine 4c
Yield 60%, mp 112–113 ꢀC (from 2-PrOH), Rf¼0.77 (toluene–
ethylacetate, 1:1). IR (KBr): nmax¼3449, 3444 (NH) cmꢂ1
.
1H NMR
(300 MHz, DMSO-d6):
d
¼1.08 (9H, s, t-Bu), 1.15 (9H, s, t-Bu), 2.55
(3H, s, SCH3), 3.07 (3H, d, J¼6.0 Hz, NCH3), 6.48 (1H, s, CH), 7.41 (5H,
s, ArH), 7.98 (1H, s, CH), 9.78 (1H, br s, NH), 9.88 (1H, br s, NH) ppm.
4.4.1. 4-Amino-7-(4-ethylphenyl)-2-methylthiopyrido[4,3-
d]pyrimidine 5b
13C NMR (75 Hz, CDCl3):
116.4, 128.2, 128.4, 128.9, 137.0, 144.9, 153.2, 164.0, 169.0, 176.4 ppm.
Anal. Calcd for C23H33N5S: C 67.11, H 8.08, N 17.01; found: C 67.40, H
8.09, N 17.19.
d
¼13.9, 27.6, 27.9, 28.4, 52.9, 56.7, 106.2,
Yield 18% (method A), 90% (method B), mp 147–149 ꢀC (from
octane). IR (KBr): nmax¼3392, 3372 (NH2) cmꢂ1
.
1H NMR
¼1.27 (3H, t, J¼7.8 Hz, CH3), 2.51 (3H, s,
(300 MHz, (CD3)2CO):
d
SCH3), 2.74 (2H, q, J¼7.8 Hz, CH2), 7.05 (2H, br s, NH2), 7.25 (1H, s,
CH), 7.38 (2H, d, J¼8.7 Hz, ArH), 7.61 (2H, d, J¼8.7 Hz, ArH), 8.74
4.3.3. N-{4-(Z)-2-[(tert-Butylamino)-2-phenylvinyl]-6-N-
ethylamino-2-methylthiopyrimidin-5-ylmethylene}-2-
methylpropan-2-amine 4d
(1H, s, CH) ppm. 13C NMR (75 Hz, CDCl3):
115.3, 127.1, 128.8, 129.5, 138.4, 149.6, 157.2, 157.5, 160.8, 171.8 ppm.
Anal. Calcd for C16H16N4S: C 64.84, H 5.44, N 18.90; found: C
64.79, H 5.51, N 18.84.
d
¼13.8, 14.2, 27.9, 109.3,
Yield 58%, mp 107–109 ꢀC (from 2-PrOH), Rf¼0.79 (toluene–
ethylacetate, 1:1). IR (KBr): nmax¼3445, 3440 (NH) cmꢂ1
.
1H NMR
(300 MHz, DMSO-d6):
d
¼1.09 (9H, s, t-Bu), 1.22 (9H, s, t-Bu), 1.21
(3H, t, J¼6.0 Hz, CH3), 2.52 (3H, s, SCH3), 3.52 (2H, q, J¼6 Hz, CH2),
4.4.2. 4-N-Methylamino-2-methylthio-7-phenylpyrido[4,3-
d]pyrimidine 5c
5.22 (1H, s, CH), 7.45 (5H, s, ArH), 8.59 (1H, s, CH), 10.25 (1H, s, NH),
10.96 (1H, t, J¼6.0 Hz, NH) ppm. 13C NMR (75 Hz, CDCl3):
d
¼13.9,
Yield 80% (method A), 91% (method B), mp 205–207 ꢀC (from 2-
PrOH). IR (KBr): nmax¼3262 (NH) cmꢂ1. 1H NMR (300 MHz, CDCl3):
14.4, 27.7, 27.9, 28.6, 52.9, 56.9, 106.5, 116.3, 128.2, 128.4, 128.6,
137.2, 144.1, 153.2, 164.0, 169.0, 176.5 ppm. Anal. Calcd for
C24H35N5S: C 67.72, H 8.29, N 16.45; found: C 67.50, H 8.19, N 16.55.
d
¼2.68 (3H, s, SCH3), 3.23 (3H, d, J¼3.6 Hz, NHCH3), 6.24 (1H, br s,
NH), 7.51–7.53 (3H, m, ArH), 7.89 (1H, s, CH), 8.09–8.12 (2H, m, ArH),
9.11 (1H, s, CH) ppm. 13C NMR (75 Hz, CDCl3):
d
¼14.4, 42.1, 109.5,
4.3.4. N-{6-Anilino-4-(Z)-2-[(tert-butylamino)-2-phenylvinyl]-2-
methylthiopyrimidin-5-ylmethylene}-2-methylpropan-2-amine 4g
Yield 75%, mp 137–139 ꢀC (from 2-PrOH).
115.6, 127.4, 129.1, 129.8, 138.6, 149.9, 157.5, 157.7, 161.1, 172.0 ppm.
Anal. Calcd for C15H14N4S: C 63.80, H 5.00, N 19.84; found: C 64.00,
H 5.12, N 19.97.

5758
I. Cikotiene et al. / Tetrahedron 65 (2009) 5752–5759
4.4.3. 4-N-Ethylamino-2-methylthio-7-phenylpyrido[4,3-
d]pyrimidine 5d
4.4.9. 7-(4-Fluorophenyl)-2-methylthio-4-pyrrolidin-1-
ylpyrido[4,3-d]pyrimidine 5m
Yield 80% (method A), 92% (method B), mp 190–192 ꢀC (from
octane). IR (KBr): nmax¼3441 (NH) cmꢂ1. 1H NMR (300 MHz, CDCl3):
Yield 92% (method A), 95% (method B), mp 195–197 ꢀC (from 2-
PrOH). 1H NMR (300 MHz, CDCl3):
d
¼2.12 (4H, br s, (CH2)2), 2.63
d
¼1.41 (3H, t, J¼6.0 Hz, CH3), 2.67 (3H, s, SCH3), 3.75–3.81 (2H, m,
(3H, s, SCH3), 3.98 (4H, br s, N(CH2)2), 7.17–7.23 (2H, m, ArH), 7.81
CH2), 6.19 (1H, br s, NH), 7.51–7.53 (3H, m, ArH), 7.89 (1H, s, CH),
(1H, s, CH), 8.08–8.13 (2H, m, ArH), 9.42 (1H, s, CH) ppm. 13C NMR
8.10 (2H, d, J¼6.0 Hz, ArH), 9.18 (1H, br s, CH) ppm. 13C NMR (75 Hz,
(75 Hz, CDCl3):
d
¼14.1, 25.3, 51.0, 114.9, 115.6, 115.9, 128.8, 128.9,
CDCl3):
d¼14.1, 14.3, 36.3, 115.7, 126.8, 127.1, 128.8, 129.5, 138.4,
134.6, 149.3, 156.3, 156.7, 157.5, 162.1, 165.4, 172.1 ppm. Anal. Calcd
for C18H17FN4S: C 63.51, H 5.03, N 16.46; found: C 63.70, H 5.14, N
16.25.
145.7, 154.8, 158.2, 158.6, 173.7 ppm. Anal. Calcd for C16H16N4S: C
64.84, H 5.44, N 18.90; found: C 64.71, H 5.78, N 18.99.
4.4.4. 4-Anilino-2-methylthio-7-phenylpyrido[4,3-d]pyrimidine 5g
Yield 0% (method A), 97% (method B), mp 104–105 ꢀC (from 2-
PrOH). IR (KBr): nmax¼3442 (NH) cmꢂ1. 1H NMR (300 MHz, CDCl3):
4.4.10. 7-(4-Fluorophenyl)-2-methylthio-4-morfolin-4-
ylpyrido[4,3-d]pyrimidine 5o
Yield 92% (method A), 97% (method B), mp 196–197 ꢀC (from 2-
d
¼2.52 (3H, s, SCH3), 7.13 (1H, t, J¼7.8 Hz, ArH), 7.33–7.48 (5H, m,
PrOH). 1H NMR (300 MHz, CDCl3):
J¼3.9 Hz, N(CH2)2), 4.02 (4H, t, J¼3.9 Hz, O(CH2)2), 7.16–7.21 (2H, m,
d
¼2.64 (3H, s, SCH3), 3.93 (4H, t,
ArH), 7.79–7.82 (2H, m, ArH), 7.94 (1H, s, CH), 8.11–8.14 (2H, m,
ArH), 9.75 (1H, s, CH), 10.16 (1H, br s, NH) ppm. 13C NMR (75 Hz,
ArH), 7.82 (1H, s, CH), 8.09–8.13 (2H, m, ArH), 9.41(1H, s, CH) ppm.13C
CDCl3):
d
¼14.3, 111.8, 115.7, 122.0, 125.1, 127.2, 128.9, 129.0, 127.7,
NMR (75 Hz, CDCl3):
129.8, 138.4, 149.0, 157.1, 157.9, 162.9, 172.4 ppm. Anal. Calcd for
C18H17FN4OS: C 60.66, H 4.81, N 15.72; found: C 60.70, H 5.04, N 16.00.
d
¼14.5, 49.9, 66.8, 107.9, 115.4, 127.1, 128.9,
137.4, 138.3, 145.4, 147.5, 155.2, 156.3, 159.0, 173.6 ppm. Anal. Calcd
for C20H16N4S: C 69.74, H 4.68, N 16.17; found: C 69.71, H 5.00, N
16.41.
4.4.11. 7-(4-Ethylphenyl)-2-methylthio-4-piperidin-1-ylpyrido[4,3-
d]pyrimidine 5p
4.4.5. 4-Anilino-7-(4-ethylphenyl)-2-methylthiopyrido[4,3-
d]pyrimidine 5h
Yield 87% (method A), 93% (method B), mp 126–127 ꢀC (from
Yield 0% (method A), 96% (method B), mp 117–119 ꢀC (from 2-
PrOH). IR (KBr): nmax¼3440 (NH) cmꢂ1. 1H NMR (300 MHz, CDCl3):
hexane). 1H NMR (300 MHz, CDCl3):
d
¼1.33 (3H, t, J¼7.5 Hz, CH3),
1.66 (6H, br s, (CH2)3), 2.64 (3H, s, SCH3), 2.76 (2H, q, J¼7.5 Hz, CH2),
3.98 (4H, br s, N(CH2)2), 7.38 (2H, d, J¼8.0 Hz, ArH), 7.87 (1H, s, CH),
8.07 (2H, d, J¼8.0 Hz, ArH), 9.46 (1H, s, CH) ppm. 13C NMR (75 Hz,
d
¼1.32 (3H, t, J¼7.5 Hz, CH2CH3), 2.51 (3H, s, SCH3), 2.71 (2H, q,
J¼7.5 Hz, CH2CH3), 7.14 (1H, t, J¼7.6 Hz, ArH), 7.33–7.48 (4H, m,
ArH), 7.82 (2H, d, J¼7.5 Hz, ArH), 7.95 (1H, s, CH), 8.12 (2H, d,
J¼7.5 Hz, ArH), 9.77 (1H, s, CH), 10.15 (1H, br s, NH) ppm. 13C NMR
CDCl3):
d
¼14.0, 14.2, 24.6, 25.5, 26.4, 50.5, 115.3, 127.1, 128.8, 129.5,
138.4, 149.3, 157.2, 157.6, 161.7, 172.4 ppm. Anal. Calcd for
C21H24N4S: C 69.20, H 6.64, N 15.37; found: C 68.98, H 6.74, N 15.45.
(75 Hz, CDCl3):
d
¼13.7, 14.3, 26.0, 111.9, 115.5, 122.1, 125.5, 127.2,
128.6, 129.2, 127.8, 137.4, 138.3, 145.5, 147.8, 155.2, 156.3, 159.0,
173.6 ppm. Anal. Calcd for C22H20N4S: C 70.94, H 5.41, N 15.04;
found: C 70.79, H 5.33, N 14.94.
4.4.12. 4-N-Benzylamino-7-phenylpyrido[4,3-d]pyrimidine 5q
Yield 80% (method A), 95% (method B), mp 249–250 ꢀC (from 2-
PrOH). IR (KBr): nmax¼3442 (NH) cmꢂ1. 1H NMR (300 MHz, CDCl3):
4.4.6. 4-N-Benzylamino-2-methylthio-7-phenylpyrido[4,3-
d]pyrimidine 5i
d
¼4.97 (2H, d, J¼5.4 Hz, CH2), 6.34 (1H, br s, NH), 7.40–7.56 (8H, m,
ArH), 8.09 (1H, s, CH), 8.14–8.16 (2H, m, ArH), 8.83 (1H, s, CH), 9.26
Yield 81% (method A), 98% (method B), mp 199–200 ꢀC (from 2-
PrOH). IR (KBr): nmax¼3440 (NH) cmꢂ1. 1H NMR (300 MHz, CDCl3):
(1H, s, CH) ppm. 13C NMR (75 Hz, CDCl3):
d¼44.6, 114.3, 127.0, 127.2,
127.6, 128.3, 128.6, 129.4, 137.6, 137.9, 147.7, 151.7, 157.8, 158.7,
159.7 ppm. Anal. Calcd for C20H16N4: C 76.90, H 5.16, N 17.94; found:
C 77.01, H 5.11, N 18.03.
d
¼2.58 (3H, s, SCH3), 4.97 (2H, d, J¼5.4 Hz, CH2), 6.39 (1H, br s, NH)
7.41–7.56 (8H, m, ArH) 8.05 (1H, s, CH), 8.14–8.17 (2H, m, ArH), 9.23
(1H, s, CH) ppm. 13C NMR (75 Hz, CDCl3):
d¼14.5, 44.6, 114.3, 127.0,
127.2, 127.6, 128.3, 128.6, 129.4, 137.6, 137.9, 147.7, 151.7, 157.8, 158.7,
159.7 ppm. Anal. Calcd for C21H18N4S: C 70.36, H 5.06, N 15.63;
found: C 70.08, H 5.13, N 15.88.
4.4.13. 4-N-Benzylamino-7-(4-ethylphenyl)pyrido[4,3-
d]pyrimidine 5r
Yield 91% (method A), 96% (method B), mp 220–222 ꢀC (from 2-
PrOH). IR (KBr): nmax¼3440 (NH) cmꢂ1. 1H NMR (300 MHz, CDCl3):
4.4.7. 2-Methylthio-7-phenyl-4-pyrrolidin-1-ylpyrido[4,3-
d]pyrimidine 5k
d
¼1.32 (3H, t, J¼7.5 Hz, CH2CH3), 2.76 (2H, q, J¼7.5 Hz, CH2CH3),
4.95–5.00 (2H, m, CH2), 6.35 (1H, br s, NH), 7.29–7.48 (7H, m, ArH),
Yield 89% (method A), 100% (method B), mp 155–157 ꢀC (from 2-
8.01 (1H, s, CH), 8.06–8.09 (2H, d, J¼7.8 Hz, ArH), 8.81 (1H, s, CH),
PrOH). 1H NMR (300 MHz, CDCl3):
d
¼2.11 (4H, br s, (CH2)2), 2.64
9.24 (1H, s, CH) ppm. 13C NMR (75 Hz, CDCl3):
114.5, 127.1, 127.3, 127.6, 128.2, 128.7, 129.5, 137.6, 137.9, 147.8, 151.8,
157.9, 158.5, 159.6 ppm. Anal. Calcd for C22H20N4: C 77.62, H 5.92, N
16.46; found: C 78.00, H 5.81, N 16.44.
d
¼13.9, 25.3, 44.7,
(3H, s, SCH3), 3.99 (4H, br s, N(CH2)2), 7.46–7.55 (3H, m, ArH), 7.88
(1H, s, CH), 8.12 (2H, d, J¼7.5 Hz, ArH), 9.46 (1H, s, CH) ppm. 13C
NMR (75 Hz, CDCl3):
129.4, 138.4, 149.3, 156.8, 157.3, 157.6, 172.0 ppm. Anal. Calcd for
C18H18N4S: C 67.05, H 5.63, N 17.38; found: C 66.97, H 5.72, N 17.25.
d
¼14.1, 35.3, 50.9, 109.9, 115.3, 127.0, 128.8,
4.4.14. 7-Phenyl-4-pyrrolidin-1-ylpyrido[4,3-d]pyrimidine 5s
Yield 95% (method A), 100% (method B), mp 170–172 ꢀC (from 2-
4.4.8. 7-(4-Ethylphenyl)-2-methylthio-4-pyrrolidin-1-ylpyrido[4,3-
d]pyrimidine 5l
PrOH). 1H NMR (300 MHz, CDCl3):
d
¼2.15 (4H, br s, CH2CH2), 4.01
(4H, br s, N(CH2)2), 7.49–7.59 (3H, m, ArH), 8.05 (1H, s, CH), 8.15–
Yield 91% (method A), 94% (method B), mp 190–191 ꢀC (from 2-
8.18 (2H, m, ArH), 8.70 (1H, s, CH), 9.60 (1H, s, CH) ppm. 13C NMR
PrOH). 1H NMR (300 MHz, CDCl3):
d
¼1.32 (3H, t, J¼7.5 Hz, CH3), 2.12
(75 Hz, CDCl3):
d
¼35.3, 50.9, 109.9, 115.3, 127.2, 128.8, 129.2, 138.5,
(4H, br s, (CH2)2), 2.64 (3H, s, SCH3), 2.75 (2H, q, J¼7.5 Hz, CH2), 4.00
(4H, br s, N(CH2)2), 7.36 (2H, d, J¼8.1 Hz, ArH), 7.87 (1H, s, CH), 8.06
(2H, d, J¼8.1 Hz, ArH), 9.46 (1H, s, CH) ppm. 13C NMR (75 Hz,
149.3, 156.9, 157.3, 157.6, 162.8 ppm. Anal. Calcd for C17H16N4: C
73.89, H 5.84, N 20.27; found: C 73.65, H 5.69, N 20.21.
CDCl3):
d
¼14.1, 15.4, 28.7, 35.4, 50.9, 109.8, 110.6, 114.8, 127.0, 128.4,
4.4.15. 7-Phenyl-4-morpholin-4-ylpyrido[4,3-d]pyrimidine 5t
135.9, 145.9, 149.3, 156.8, 157.4, 157.7, 171.9 ppm. Anal. Calcd for
C20H22N4S: C 68.54, H 6.33, N 15.99; found: C 68.77, H 6.44, N 16.25.
Yield 89% (method A), 99% (method B), mp 160–161 ꢀC (from
2-PrOH). 1H NMR (300 MHz, CDCl3):
d
¼3.91 (4H, t, J¼3.9 Hz,

I. Cikotiene et al. / Tetrahedron 65 (2009) 5752–5759
5759
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N(CH2)2), 4.01 (4H, t, J¼3.9 Hz, O(CH2)2), 7.46–7.56 (3H, m, ArH),
8.07 (1H, s, CH), 8.15–8.19 (2H, m, ArH), 8.71 (1H, s, CH), 9.62 (1H,
s, CH) ppm. 13C NMR (75 Hz, CDCl3):
127.2, 128.9, 129.6, 138.2, 149.5, 157.1, 157.7, 161.9, 165.2 ppm.
Anal. Calcd for C17H16N4O: C 69.85, H 5.52, N 19.17; found: C
70.01, H 5.60, N 19.29.
d
¼49.8, 66.6, 108.9, 115.4,
Acknowledgements
We express our gratitude to M. Kreneviciene and A. Karosiene for
the recording of NMR and IR spectra, to M. Gavrilova for the ele-
mental analyses data, and to G. Urbelis (Vilnius University) for
helpful discussions. We are indebted to Dr. J. H. Jensen (University of
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Copenhagen) for
comments.
a careful reading of the manuscript and
Visvaldas Kairys is grateful for the support from Portuguese
ˆ
´
Fundaça˜o para a Ciencia e a Tecnologıa, grant SFRH/BPD/41787/
2007.
The work was supported by Lithuanian State Science and Studies
Foundation, Reg. No. T-08032, T-09027; Grants No. T-18/08; T-67/09.
11. Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
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