Study on the reactions of 4-amino-5-nitro-6-phenylethynylpyrimidines with amines and thiols

Article abstract of DOI:10.1016/j.tet.2007.05.125

Reactions of 4-amino-5-nitro-6-phenylethynylpyrimidines with amines and thiols have been investigated. Pyridine catalyzes rearrangement of the title compounds into 6-phenyl-7-oxo-7H-pyrrolo[3,2-d]pyrimidine-5-oxides. Primary and secondary amines and thiol

Full text of DOI:10.1016/j.tet.2007.05.125

Tetrahedron 63 (2007) 8145–8150
Study on the reactions of 4-amino-5-nitro-6-phenylethynyl-
pyrimidines with amines and thiols
*
Inga Cikotiene, Erika Pudziuvelyte, Algirdas Brukstus and Sigitas Tumkevicius
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, LT-03225, Vilnius, Lithuania
Received 2 April 2007; revised 16 May 2007; accepted 31 May 2007
Available online 6 June 2007
Abstract—Reactions of 4-amino-5-nitro-6-phenylethynylpyrimidines with amines and thiols have been investigated. Pyridine catalyzes re-
arrangement of the title compounds into 6-phenyl-7-oxo-7H-pyrrolo[3,2-d]pyrimidine-5-oxides. Primary and secondary amines and thiols
take part in a regio- and stereoselective addition reaction to the triple bond of 5-nitro-6-phenylethynylpyrimidines to form the corresponding
syn-addition (in the case of secondary amines) or anti-addition (in the case of primary amines or thiols) products.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
4-amino-5-nitro-6-phenylethynylpyrimidines 2a and b were
treated with another tertiary amine—triethylamine no
reaction was observed. In the presence of catalytic amount
of secondary amines conversion of 5-nitro-6-phenylethynyl-
pyrimidines 2a and b was incomplete and formation of traces
of intense red or orange products was observed by TLC. Per-
forming reaction of 2a and b with an equivalent amount of se-
lected secondary amines in dichloromethane at room
temperature furnished compounds 4a–f in 90–95% yields
(Scheme 1). The same products were obtained and no cycli-
zation reaction was observed when the starting compounds
were heated to reflux with secondary amines in dimethylfor-
mamide (the latter procedure was used for cyclization of 5-
nitro-6-arylvinylpyrimidines into pyrrolo[3,2-d]pyrimidine
derivatives).6 Neither 13C NMR nor IR spectra of 4a–f
showed the presence of C^C or CO group in the molecules.
In the 1H NMR spectra new singlet at 6.45–6.54 ppm due to
vinylic CH along with signals of the corresponding amine
was observed. These data indicated that addition reaction
of amines to the triple bond took place. It is noteworthy
In our previous publications1,2 it was shown that 4-amino-
6-arylethynyl-5-nitropyrimidines in dry pyridine undergo
smooth intramolecular cyclization to give pyrrolo[3,2-d]-
pyrimidine-5-oxides. The latter compounds, being aza-ana-
logues of isatogens, attract our attention as potential traps
for free radicals in biological milieu.3–5 Therefore, as con-
tinuation of our research aimed on the synthesis of pyrrolo-
[3,2-d]pyrimidine-5-oxides via cyclization of the title
compounds, in this paper we report the results of more exten-
sive investigation, including reactions of 4-amino-5-nitro-6-
phenylethynylpyrimidines with primary and secondary
amines and thiols.
2. Results and discussion
Compounds 2a and b were synthesized by the palladium-
catalyzed Sonogashira coupling of the corresponding
4-amino-6-chloro-5-nitropyrimidines 1a and b with phenyl-
acetylene according to procedure described earlier.1 Com-
pounds 2a and b in dry boiling pyridine underwent smooth
ring closure, to give dark violet pyrrolo[3,2-d]pyrimidine-
5-oxides 3a and b. Moreover, it was established that cycliza-
tion of 2a and b also proceeds using a catalytic amount of
pyridine in boiling 2-propanol (Scheme 1). Encouraged by
this result we decided to investigate the behaviour of the title
compounds in the presence of different amines. When
1
that, in the H NMR spectra of 4a–f, singlets of C–H and
SCH3 in position 2 of the pyrimidine ring were observed in
an upfield region than usual (7.47–7.85 ppm for C2–H and
1.55–1.67 ppm for C2–SCH3) (Table 1). Slow crystallization
of 4a from dichloromethane provided single crystals suitable
for the X-ray crystallographic analysis, which enabled the
outcome of the reaction to be elucidated7 unambiguously
(Fig. 1). Moreover, the crystallographic data of 4a showed
that in the solid state the molecule adopted a conformation
in which the benzene ring is turned out of plane of the pyrim-
idine ring and C(11)H]C(12)–N(13) moiety. The torsion
angle of C(11)–C(12)–C(18)–C(23) was found to be
84.85ꢀ. Thus, the hydrogen at C2 of the pyrimidine ring is
constrained above the benzene ring. As a consequence an
Keywords: 5-Nitro-6-phenylethynylpyrimidines; Addition; Nucleophiles;
Triple bond.
* Corresponding author. Tel.: +370 5 2336508; fax: +370 5 2330987;
e-mail: inga.cikotiene@chf.vu.lt
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.125

8146
I. Cikotiene et al. / Tetrahedron 63 (2007) 8145–8150
O
NH2
N
NH2
NO2
NH2
N
NO2
Cl
i
ii or iii
N
N
N
R
R
N
R
N
O
2a,b
1a,b
3a,b, 90 - 95%
1-3a (R = H);
1-3b (R = SCH3 )
vi or vii
v
iv
NH2
NH2
NO2
NH2
N
NO2
NO2
N
H
N
R
N
H
H
R
N
R
N
S
HN
NR'R''
R'
R'
6a-d, 80 - 90%
5a-c, 80 - 90%
4a-f, 90 - 95%
Scheme 1. Reagents and conditions: (i) 1-phenylacetylene (1.2 quiv), PdCl2(PPh3)2 (2 mol %), CuI (1 mol %), Et3N, Ar, 40 ꢀC, 2 h; (ii) pyridine, reflux, 10 min;
(iii) pyridine (1 drop), 2-propanol, reflux, 30 min; (iv) secondary amine (1 equiv), dichloromethane, 20 min, rt; (v) primary amine (1 equiv), dichloromethane,
48 h, rt; (vi) thiol (1 equiv), dichloromethane, 24 h, rt and (vii) sodium thiolate (1 equiv), methanol, 30 min, rt.
upfield shift of C2–H and C2–SCH3 signals in the 1H NMR
spectra results from shielding effect of benzene ring on these
protons. Thus, these data indicate that compounds formed
in the reaction of 2a and b with secondary amines were
the corresponding 4-amino-5-nitro-6-[(E)-2-phenyl-2-(1-
dialkylamino)ethenyl]pyrimidines 4a–f (Scheme 1).
6a–d were observed in ordinary positions for these groups—
8.20–8.71 ppm and 2.57 and 2.61 ppm, respectively. Proba-
bly, in compounds 5a–c benzene ring is directed away from
the pyrimidine ring and shielding effect of benzene ring in
1
the H NMR spectra for protons at C2 of the pyrimidine
ring is absent. This can be realized if addition reaction of
primary amines and thiols to the triple bond of 2a and b pro-
ceeds with the formation of anti-addition products 5a–c and
6a–d (Scheme 1, Table 1).
Compounds 2a and b appeared to be less reactive towards
primary amines and thiols. Full conversion of 2a and b at
room temperature was achieved after 48 and 72 h, respec-
tively. When sodium thiolates in methanol were used instead
Results obtained for the reactions of 4-amino-5-nitro-6-phe-
nylethynylpyrimidines with amines and thiols could be
of thiols, reaction was completed after 30 min. 1H NMR, 13
C
NMR and IR spectra of the obtained products showed that in
the case of primary amines and thiols addition reaction to
C^C bond took place again. Singlets for C2–H and C2–
1
SCH3 of the pyrimidine ring in the H NMR spectra of
Table 1. Data of reactions of 4-amino-5-nitro-6-phenylethynylpyrimidines
2a and b with amines and thiols
Starting
compound
Amine or thiol
Product
1H NMR dataa(ppm)
C(2)–H
C(2)–SCH3
2a
2b
2a
2b
2a
2a
2a
2b
2a
2a
2b
2a
2a
(CH2)4NH
(CH2)4NH
(CH2)5NH
(CH2)5NH
O(CH2)4NH
C6H5CH2NHCH3 4f
CH3CH2CH2NH2 5a
CH3CH2CH2NH2 5b
C6H5CH2NH2
C6H5SH
C6H5SH
C6H5CH2SH
CH3O2CCH2SH
4a
4b
4c
4d
4e
7.59
—
7.77
—
7.85
7.52
8.21
—
8.20
8.71
—
—
1.55
—
1.67
—
—
—
2.57
—
—
2.61
—
—
5c
6a
6b
6c
6d
8.47
8.54
1H NMR spectra of 4a–e, 5a–c and 6a were recorded in CDCl3, spectra of
4f and 6b–d, in DMSO-d6.
a
Figure 1. ORTEP drawing of compound 4a.

I. Cikotiene et al. / Tetrahedron 63 (2007) 8145–8150
8147
O
NH2
N
O-
N+
NH2
N
O
NH2
N
O
NH2
N
N
N
N
O
N
N
O
N
O
O
R
C6H5
R
C
R
R
N
N
C6H5
N
C6H5
N
C6H5
2a,b
N
II
I
O
N
O
O
NH2
NH2
NH2
N
N
N
C6H5
N
C6H5
N
N
N
N
C6H5
- C5H5N
R
N
R
N
R
O
O
O
3a,b
IV
III
Scheme 2.
NH2
NH2
N
NH2
N
NO2
NO2
NO2
N
N
R'R''NH
N
R
R
N
R
C
N
C6H5
R'
C6H5
H
N
C6H5
2a,b
H
R''
R'
R''
I
NH2
N
NH2
N
NO2
N
NO2
H
N
R
R''=H
R''=H
H
R
H
N
NR'R''
R'
4a-f
5a-c
Scheme 3.
explained as following. Pyridine catalyzes the cyclization of
starting compounds by a mechanism depicted in Scheme 2.
internal or external proton delivery.14 Reaction of the title
compounds with secondary amines led to formation of ther-
modynamically stable 6-[(E)-2-(1-dialkylamino)-2-phenyl-
ethenyl]-5-nitropyrimidines 4a–f. In the case of primary
amines, probably an important factor could be an extra
stability of Z-isomer because of possible intramolecular
H-bonding in compounds 5a–c (Scheme 3).
Another tertiary amine—triethylamine, probably, due to its
hindered nitrogen could not attack the triple bond in C^C
and cyclization of 5-nitro-6-phenylethynylpyrimidines did
not occur. Intramolecular cyclization failed when the title
compounds were treated with primary and secondary
amines, in these cases stable addition products were formed.
Literature survey showed that addition reactions of nucleo-
philes to alkynes have been investigated by several research
groups.8,9 Nucleophilic addition with alkynes bearing elec-
tron withdrawing groups occurs rapidly and no catalyst is
required.10–13 The triple bond of the investigated compounds
2a and b is electron deficient due to the electron deficient
pyrimidine moiety and its nitro group, so it is easily attacked
by different nucleophiles. It is likely that amines attack the
triple bond of compounds 2a and b in the way like pyridine
to form the same zwitterionic intermediate I, which turns
to either syn- or anti-addition products, resulting from an
When thiols or sodium thiolates were used addition reaction
to the triple bond in C^C would be expected to proceed by
‘trans-addition rule’,15,16 so products of anti-addition 6a–d
were formed.
3. Conclusions
In conclusion, the study of the reactions of 4-amino-5-nitro-
6-phenylethynylpyrimidines with amines and thiols showed
that the triple bond of investigated compounds is easily
attacked by different amines and thiols. Pyridine initiates

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I. Cikotiene et al. / Tetrahedron 63 (2007) 8145–8150
intramolecular cyclization of starting compounds to form
pyrrolo[3,2-d]pyrimidine-5-oxides. Reactions of 4-amino-
5-nitro-6-phenylethynylpyrimidines with secondary and
primary amines as well as with thiols are regio- and stereo-
selective and lead to the formation of syn-addition (in the
case of secondary amines) or anti-addition (in the case of
primary amines or thiols) products.
corresponding amine (1 mmol) was added. The reaction
mixture was kept at room temperature for 20 min (in the
case of secondary amine) or for 48 h (in the case of primary
amine). The solvent was evaporated under reduced pressure,
the residue was recrystallized to give compounds 4a–f
or 5a–c.
4.1.3.1. 4-Amino-5-nitro-6-[(E)-2-phenyl-2-(1-pyrrol-
idinyl)ethenyl]pyrimidine (4a). Yield 95%; orange needles;
1
4. Experimental
4.1. General
mp 189–190 ꢀC; IR (KBr) cmꢂ1: 3369, 3246. H NMR
(300 MHz, CDCl3): d 1.99–2.02 (4H, m, (CH2)2), 3.29–
3.33 (4H, m, N(CH2)2), 6.46 (1H, s, CH), 7.26 (2H, br s,
NH2), 7.27–7.40 (5H, m, ArH), 7.59 (1H, s, C(2)H). 13C
NMR (75 MHz, CDCl3): d 25.6; 50.6; 95.6; 122.6; 128.1;
128.5; 128.6; 138.5; 156.6; 158.4; 160.7; 162.5. Anal. Calcd
for C16H17N5O2 (311.34) C, 61.72; H, 5.50; N, 22.49; found
C, 61.72; H, 5.72; N, 22.45.
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
1
BX II. H NMR and 13C NMR spectra were recorded with
a Varian Unity INOVA spectrometer (300 MHz) using tetra-
methylsilane as an internal standard. Elemental analyses (C,
N, H) results were found to be in good agreement (ꢁ0.4%)
with the calculated values. All reactions and purity of
the synthesized compounds were monitored by TLC using
Silica gel 60 F254 aluminium plates (Merck). Visualization
was accomplished by UV light.
4.1.3.2. 4-Amino-2-methylthio-5-nitro-6-[(E)-2-phen-
yl-2-(1-pyrrolidinyl)ethenyl]pyrimidine (4b). Yield 92%;
orange needles; mp 226–228 ꢀC; IR (KBr) cmꢂ1: 3436,
1
3258. H NMR (300 MHz, CDCl3): d 1.55 (3H, s, SCH3),
1.87 (2H, br s, CH2), 1.92 (2H, br s, CH2), 3.10–3.15 (2H,
m, NCH2), 3.51–3.55 (2H, m, NCH2), 6.56 (1H, s, CH),
7.26—7.39 (5H, m, ArH), 7.52 (2H, br s, NH2). 13C NMR
(75 MHz, CDCl3): d 11.9; 24.7; 49.0; 93.4; 119.2; 127.9;
128.2; 128.5; 138.1; 156.8; 158.5; 161.1; 169.4. Anal. Calcd
for C17H19N5O2S (357.44) C, 57.13; H, 5.36; N, 19.59;
found C, 57.18; H, 5.30; N, 19.76.
Compounds 2a and b were prepared according to method
published earlier.1
4.1.1. 4-Amino-2-methylthio-5-nitro-6-phenylethynyl-
pyrimidine (2b). Yield 70%; yellow needles; mp 169–
170 ꢀC; IR (KBr) cmꢂ1: 3445, 3264, 2205. 1H NMR
(300 MHz, (CD3)2CO): d 2.56 (3H, s, SCH3), 7.55–7.78
(5H, m, ArH), 7.81 (2H, br s, NH2). 13C NMR (75 MHz,
(CD3)2CO): d 15.4; 87.8; 99.5; 119.8; 123.0; 130.6; 132.3;
134.4; 147.7; 158.5; 176.3. Anal. Calcd for C13H10N4O2S
(286.31) C, 54.54; H, 3.52; N, 19.57; found C, 54.62; H,
3.62; N, 19.36.
4.1.3.3. 4-Amino-5-nitro-6-[(E)-2-phenyl-2-(1-piper-
idinyl)ethenyl]pyrimidine (4c). Yield 95%; red needles;
1
mp 139–140 ꢀC; IR (KBr) cmꢂ1: 3361, 3305. H NMR
(300 MHz, CDCl3): d 1.67–1.73 (6H, m, (CH2)3), 3.28–
3.32 (4H, m, N(CH2)2), 6.34 (1H, s, CH), 7.15 (2H, br s,
NH2), 7.29–7.38 (5H, m, ArH), 7.77 (1H, s, C(2)H). 13C
NMR (75 MHz, CDCl3): d 24.2; 26.0; 50.6; 98.3; 123.5;
128.4; 129.1; 129.3; 137.1; 156.6; 157.7; 161.5; 164.4.
Anal. Calcd for C17H19N5O2 (325.36) C, 62.65; H, 5.89;
N, 21.52; found C, 62.82; H, 6.02; N, 21.66.
4.1.2. Synthesis of 4-amino-7-oxo-6-phenyl-7H-pyr-
rolo[3,2-d]pyrimidine-5-oxides (3a and b). To a solution
of the corresponding alkynes 2a or b (1 mmol) in 2-propanol
(3 mL) one drop of pyridine was added and the reaction
mixture was heated to reflux for 30 min. After cooling to
room temperature, the precipitate was filtered off and recrys-
tallized to give compounds 3a and b as dark violet solids.
Data for compound 3a have been published in the previous
paper.1
4.1.3.4. 4-Amino-2-methylthio-5-nitro-6-[(E)-2-phen-
yl-2-(1-piperidinyl)ethenyl]pyrimidine (4d). Yield 92%;
orange needles; mp 203–205 ꢀC; IR (KBr) cmꢂ1: 3439,
1
3247. H NMR (300 MHz, CDCl3): d 1.65–1.70 (6H, m,
(CH2)3), 1.67 (3H, s, SCH3), 3.27–3.31 (4H, m, N(CH2)2),
6.52 (1H, s, CH), 7.20 (2H, br s, NH2), 7.29–7.40 (5H, m,
ArH). 13C NMR (75 MHz, CDCl3): d 13.0; 24.3; 26.0;
50.6; 98.8; 120.8; 128.6; 129.1; 129.6; 137.3; 143.2;
157.4; 161.1; 164.8; 171.1. Anal. Calcd for C18H21N5O2S
(371.46) C, 58.20; H, 5.70; N, 18.85; found C, 58.18; H,
5.55; N, 18.95.
4.1.2.1. 4-Amino-2-methylthio-7-oxo-6-phenyl-7H-
pyrrolo[3,2-d]pyrimidine-5-oxide (3b). Yield 85%; dark
violet crystals; mp 210–212 ꢀC; IR (KBr) cmꢂ1: 3429,
3226, 1725. H NMR (300 MHz, DMSO-d6): d 2.60 (3H,
1
s, SCH3), 7.20 (1H, s, NH), 7.47–7.50 (3H, m, ArH), 8.19
(1H, s, NH), 8.39–8.43 (2H, m, ArH). 13C NMR (75 MHz,
DMSO-d6): d 13.9; 119.1; 125.3; 126.5; 127.9; 129.4;
148.9; 150.6; 151.1; 174.2; 185.7. Anal. Calcd for
C13H10N4O2S (286.31) C, 54.54; H, 3.52; N, 19.57; found
C, 54.42; H, 3.36; N, 19.79.
4.1.3.5. 4-Amino-5-nitro-6-[(E)-2-(4-morpholinyl)-2-
phenylethenyl]pyrimidine (4e). Yield 90%; red needles;
1
mp 168–170 ꢀC; IR (KBr) cmꢂ1: 3416, 3358. H NMR
(300 MHz, CDCl3): d 3.25 (4H, t, J¼4.5 Hz, N(CH2)2),
3.79 (4H, t, J¼4.5 Hz, O(CH2)2), 6.24 (1H, s, CH), 6.86
(2H, br s, NH2), 7.30–7.38 (5H, m, ArH), 7.85 (1H, s,
C(2)H). 13C NMR (75 MHz, CDCl3): d 49.1; 66.6; 99.5;
124.9; 128.5; 129.3; 129.5; 135.9; 156.9; 157.9; 161.4;
162.7. Anal. Calcd for C16H17N5O3 (327.34) C, 58.71; H,
5.23; N, 21.39; found C, 59.01; H, 5.31; N, 21.22.
4.1.3. Reaction of 4-amino-2-methylthio-5-nitro-6-phe-
nylethynylpyrimidines (2a and b) with amines. General
procedure. To a solution of the corresponding alkynes
2a or b (1 mmol) in dichloromethane (5 mL), the

I. Cikotiene et al. / Tetrahedron 63 (2007) 8145–8150
8149
4.1.3.6. 4-Amino-5-nitro-6-{(E)-2-[benzyl(methyl)-
amino]-2-phenylethenyl}pyrimidine (4f). Yield 90%; red
for 30 min at room temperature. The precipitate was filtered
off and recrystallized to give compounds 6a–d.
1
needles; mp 144–146 ꢀC; IR (KBr) cmꢂ1: 3423, 3276. H
NMR (300 MHz, DMSO-d6): d 2.93 (3H, s, NCH3), 4.32
(2H, s, NCH2), 6.07 (1H, s, CH), 7.23–7.32 (10H, m,
2ArH), 7.52 (1H, s, C(2)H), 7.54 (2H, br s, NH2). 13C
NMR (75 MHz, DMSO-d6): d 26.1; 56.5; 96.9; 125.8;
127.6; 127.7; 128.5; 128.9; 129.0; 129.6; 137.6; 137.7;
156.6; 157.6; 160.1; 162.5. Anal. Calcd for C20H19N5O2
(361.40) C, 66.47; H, 5.30; N, 19.38; found C, 66.53; H,
5.38; N, 19.26.
4.1.4.2.1. 4-Amino-5-nitro-6-[(Z)-2-phenyl-2-(phenyl-
thio)ethenyl]pyrimidine (6a). Yield 69% (method A), 82%
(method B); yellow needles; mp 167–169 ꢀC; IR (KBr)
1
cmꢂ1: 3435, 3268. H NMR (300 MHz, CDCl3): d 7.02
(2H, br s, NH2), 7.07–7.09 (3H, m, ArH), 7.19–7.23 (5H,
m, ArH), 7.36 (1H, s, CH), 7.45–7.49 (2H, m, ArH), 8.71
(1H, s, C(2)H). 13C NMR (75 MHz, CDCl3): d 124.0;
127.6; 128.2; 128.7; 128.8; 129.2; 133.1; 134.1; 138.8;
152.8; 157.5; 158.6; 159.2. Anal. Calcd for C18H14N4O2S
(350.40) C, 61.70; H, 4.03; N, 15.99; found C, 61.78; H,
3.99; N, 16.23.
4.1.3.7. 4-Amino-5-nitro-6-[(Z)-2-phenyl-2-(propyl-
amino)ethenyl]pyrimidine (5a). Yield 92%; red needles;
1
mp 174–176 ꢀC; IR (KBr) cmꢂ1: 3380, 3359, 3298. H
NMR (300 MHz, CDCl3): d 0.99 (3H, t, J¼7.2 Hz, CH3),
1.60–1.65 (2H, m, CH2), 3.22 (2H, q, J¼7.2 Hz, NHCH2),
6.40 (1H, s, CH), 7.29 (2H, br s, NH2), 7.43–7.49 (5H, m,
ArH), 8.21 (1H, s, C(2)H), 11.67 (1H, t, J¼7.2 Hz, NH).
13C NMR (75 MHz, CDCl3): d 11.4; 24.0; 47.2; 92.3;
119.4; 127.7; 128.5; 129.4; 136.7; 156.8; 158.4; 159.1;
166.7. Anal. Calcd for C15H17N5O2 (299.33) C, 60.19; H,
5.72; N, 23.40; found C, 60.36; H, 5.86; N, 23.61.
4.1.4.2.2. 4-Amino-2-methylthio-5-nitro-6-[(Z)-2-phen-
yl-2-(phenylthio)ethenyl]pyrimidine (6b). Yield 57%
(method A), 85% (method B); yellow needles; mp 173–
1
175 ꢀC; IR (KBr) cmꢂ1: 3461, 3263. H NMR (300 MHz,
DMSO-d6): d 2.61 (3H, s, SCH3), 7.10–7.48 (10H, m,
2ArH), 7.31 (1H, s, CH), 8.50 (2H, br s, NH2). Anal. Calcd
for C19H16N4O2S2 (396.49) C, 57.56; H, 4.07; N, 14.13;
found C, 57.73; H, 4.38; N, 14.02.
4.1.3.8. 4-Amino-2-methylthio-5-nitro-6-[(Z)-2-phen-
yl-2-(propylamino)ethenyl]pyrimidine (5b). Yield 80%;
red needles; mp 168–170 ꢀC; IR (KBr) cmꢂ1: 3414, 3258,
3220. 1H NMR (300 MHz, CDCl3): d 1.00 (3H, t,
J¼7.2 Hz, CH3), 1.60–1.64 (2H, m, CH2), 2.57 (3H, s,
SCH3), 3.23 (2H, q, J¼7.2 Hz, NHCH2), 6.46 (1H, s, CH),
7.20 (2H, br s, NH2), 7.44–7.48 (5H, m, ArH), 11.39 (1H,
t, J¼7.2 Hz, NH). 13C NMR (75 MHz, CDCl3): d 11.5;
14.3; 24.0; 47.3; 92.3; 117.4; 127.7; 128.5; 129.4; 136.8;
157.7; 158.9; 166.4; 171.7. Anal. Calcd for C16H19N5O2S
(345.43) C, 55.64; H, 5.54; N, 20.27; found C, 55.54; H,
5.57; N, 20.14.
4.1.4.2.3. 4-Amino-5-nitro-6-[(Z)-2-(benzylthio)ethenyl-
2-phenyl]pyrimidine (6c). Yield 57% (method A), 80%
(method B); yellow needles; mp 185–187 ꢀC; IR (KBr)
1
cmꢂ1: 3438, 3279. H NMR (300 MHz, DMSO-d6): d 3.54
(2H, s, SCH2), 6.91 (1H, s, CH), 7.01–7.04 (2H, m, ArH),
7.17–7.20 (3H, m, ArH), 7.43–7.48 (5H, m, ArH), 7.96
(2H, br s, NH2), 8.47 (1H, s, C(2)H). 13C NMR (75 MHz,
DMSO-d6): d 37.5; 122.1; 126.4; 127.7; 127.8; 127.9;
128.1; 128.3; 128.4; 136.6; 139.3; 151.6; 156.4; 157.1;
163.3. Anal. Calcd for C19H16N4O2S (364.42) C, 62.62; H,
4.43; N, 15.37; found C, 62.82; H, 4.56; N, 15.56.
4.1.4.2.4. Methyl {[(Z)-2-(6-amino-5-nitro-4-pyrim-
idinyl)-1-phenylethenyl]thio}acetate (6d). Yield 60%
(method A), 90% (method B); yellow needles; mp 153–
155 ꢀC; IR (KBr) cmꢂ1: 3432, 3260, 1738. 1H NMR
(300 MHz, DMSO-d6): d 3.16 (2H, s, SCH2), 3.51 (3H, s,
OCH3), 6.98 (1H, s, CH), 7.40–7.45 (5H, m, ArH), 8.03
(2H, br s, NH2), 8.54 (1H, s, C(2)H). 13C NMR (75 MHz,
DMSO-d6): d 34.4; 51.4; 122.9; 125.7; 127.7; 128.1;
128.3; 138.6; 150.4; 156.3; 156.4; 157.1; 168.4. Anal. Calcd
for C15H14N4O4S (346.36) C, 52.02; H, 4.07; N, 16.18;
found C, 52.02; H, 3.99; N, 16.08.
4.1.3.9. 4-Amino-5-nitro-6-[(Z)-2-phenyl-2-(benzyl-
amino)ethenyl]pyrimidine (5c). Yield 83 %; red needles;
1
mp 133–135 ꢀC; IR (KBr) cmꢂ1: 3424, 3262, 3220. H
NMR (300 MHz, CDCl3): d 4.50 (2H, d, J¼6.6 Hz,
NHCH2), 6.46 (1H, s, CH), 7.15 (2H, br s, NH2), 7.24–7.45
(10H, m, 2ArH), 8.20 (1H, s, C(2)H), 11.93 (1H, br s, NH).
13C NMR (75 MHz, CDCl3): d 49.1; 92.8; 126.6; 127.4;
127.8; 128.5; 128.8; 129.5; 136.4; 138.5; 156.9; 158.2;
159.4; 166.3. Anal. Calcd for C19H17N5O2 (347.37) C,
65.69; H, 4.93; N, 20.16; found C, 65.88; H, 5.14; N, 19.90.
4.1.4. Reaction of 4-amino-2-methylthio-5-nitro-6-
phenylethynylpyrimidines 2a and b with thiols. General
procedures.
Acknowledgements
4.1.4.1. Method A. To a solution of the corresponding
alkynes 2a or b (1 mmol) in dichloromethane (5 mL), the
corresponding thiol (1 mmol) was added. The reaction mix-
ture was kept at room temperature for 72 h. The solvent was
evaporated under reduced pressure, the residue was recrys-
tallized to give compounds 6a–d.
We express our gratitude to M. Kreneviciene and A. Karo-
siene for recording the NMR and IR spectra, to E. Kersuliene
and M. Gavrilova for performing the elemental analyses and
to Dr. S. Belyakov (Institute of Organic Synthesis, Ryga,
Latvia) for the X-ray measurements.
References and notes
4.1.4.2. Method B. To a solution of the corresponding
alkynes 2a or b (1 mmol) in methanol (5 mL), the corre-
sponding sodium thiolate, prepared from sodium (0.023 g,
1 mmol), anhydrous methanol (3 mL) and corresponding
thiol (1 mmol) were added. The reaction mixture was stirred
1. Susvilo, I.; Brukstus, A.; Tumkevicius, S. Synlett 2003, 1151.
2. Tumkevicius, S.; Susvilo, I.; Brukstus, A. Chem. Heterocycl.
Compd. 2004, 40, 1335.

8150
I. Cikotiene et al. / Tetrahedron 63 (2007) 8145–8150
3. Nepweu, R.; Souchard, J. P.; Rolland, Y.; Dorrey, G.; Spedding,
M. Biochem. Biophys. Res. Commun. 1998, 242.
4. Rosen, G. M.; Tsai, P.; Barth, E. D.; Dorey, G.; Casara,
P.; Spedding, M.; Halpern, H. J. J. Org. Chem. 2000, 65,
4460.
8. Balme, G.; Bouyssi, D.; Lomberget, T.; Monteiro, N. Synthesis
2003, 2015.
9. Houpis, I. N.; Lee, J. Tetrahedron 2000, 56, 817.
10. Zhang, M.-X.; Eaton, P. E.; Steele, I.; Gilardi, R. Synthesis
2002, 2013.
5. Genisson, V. B.; Bouniol, A.-V.; Nepveu, F. Synlett 2001, 700.
6. Senda, S.; Hirota, K.; Sudzuki, M.; Takahashi, M. Chem.
Pharm. Bull. 1977, 25, 563.
11. Dolfini, J. E. J. Org. Chem. 1965, 30, 1298.
12. Huisgen, R.; Giesse, B.; Huber, H. Tetrahedron Lett. 1967, 8,
1883.
7. Crystal
structure
analysis
for
4a:
C16H17N5O2,
13. Trofimov, B.; Sobenina, L. N.; Mikhaleva, A. I.; Ushakov, I. A.;
Vakulskaya, T. I.; Stepanova, Z. V.; Toryashinova, D. D.;
Mal’kina, A. G.; Elokhina, V. N. Synthesis 2003, 1272.
14. Lahiri, S.; Mahajan, M. P.; Prasad, R.; George, M. V.
Tetrahedron 1977, 33, 3159.
Mr¼311.34 g molꢂ1, orthorhombic, space group Pbca, a¼
ꢀ
˚
7.2102(2), b¼15.5331(5), c¼27.4642(12) A, a¼b¼g¼90 ,
V¼3075.9 A , Z¼8, r¼1.345 g cm , m¼0.09 mmꢂ1, F(000)¼
1312. X-ray diffraction data were collected on a Nonius
Kappa CCD diffractometer at the temperature 293 K using
3
3
˚
15. Truce, W. A.; Simms, J. A.; Boudakian, M. M. J. Am. Chem.
Soc. 1956, 78, 695.
˚
graphite-monochromated Mo Ka radiation (l¼0.71073 A).
Structure 4a was solved by direct methods with SIR97
program17 and refined by full-matrix least squares techniques
with anisotropic non-hydrogen atoms. Hydrogen atoms were
refined in the riding model. The refinement calculations
were carried out with the help of SHELX97 program.18
ORTEP19 view of the molecule is shown in Figure 1.
Crystallographic data for structure 4a have been deposited at
the Cambridge Crystallographic Data Centre (CCDC number
634831).
16. Truce, W. A.; Simms, J. A. J. Am. Chem. Soc. 1956, 78, 2756.
17. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G.; Polidori,
G.; Spagna, R. J. Appl. Crystallogr. 1999, 32, 115.
18. Sheldrick, G. M. SHELXL97, Program for the Refinement of
€
Crystal Structures; University of Gottingen: Gottingen,
€
Germany, 1997.
19. Johnson, C. K. ORTEP-II, Report ORNL-5138; Oak Ridge
National Laboratory: Oak Ridge, TN, 1976.