Tandem reactions of 6-phenylethynylpyrimidine-5-carbaldehydes with alcohols: regioselective synthesis of 5-alkoxy-(7Z)-7-benzylidene-5,7-dihydrofuro[3,4-d]pyrimidines and 5-alkoxy-7-phenyl-5H-pyrano[4,3-d]pyrimidines

Article abstract of DOI:10.1016/j.tet.2009.10.108

An efficient and versatile tandem processes of acetalisation and cycloisomerization reactions have been developed for the reactions of 6-phenylethynylpyrimidine-5-carbaldehydes. The influence of the catalyst and role of the substituent in the position 4 o

Full text of DOI:10.1016/j.tet.2009.10.108

Tetrahedron 66 (2010) 251–258
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem reactions of 6-phenylethynylpyrimidine-5-carbaldehydes with alcohols:
regioselective synthesis of 5-alkoxy-(7Z)-7-benzylidene-5,7-dihydrofuro[3,4-d]-
pyrimidines and 5-alkoxy-7-phenyl-5H-pyrano[4,3-d]pyrimidines
*
Inga Cikotiene , Rita Buksnaitiene, Simonas Rudys, Marius Morkunas, Dainius Motiejaitis
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, LT-03225, Vilnius, Lithuania
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and versatile tandem processes of acetalisation and cycloisomerization reactions have been
developed for the reactions of 6-phenylethynylpyrimidine-5-carbaldehydes. The influence of the catalyst
and role of the substituent in the position 4 of the pyrimidine ring have been studied. Regioselective
synthesis of 5,7-dihydrofuro[3,4-d]pyrimidine and pyrano[4,3-d]pyrimidine cores is described.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 28 August 2009
Received in revised form
14 October 2009
Accepted 29 October 2009
Available online 1 November 2009
Keywords:
Acetalisation
5-exo-Dig or 6-endo-dig cyclization
Tandem reactions
Furo[3,4-d]pyrimidines
Pyrano[4,3-d]pyrimidines
1. Introduction
Base-catalyzed transformations of aromatic or heteroaromatic
aldehydes having an o-alkynyl substituent leading mainly to the
Functionally substituted alkynes are versatile intermediates in
the synthesis of heterocyclic or carbocyclic compounds.1 A litera-
ture survey revealed that cyclization of the carbonyl group on
alkynes could undergo transition metal-catalyzed or electrophile-
induced 5-exo-dig and/or 6-endo-dig cyclization reactions
(Scheme 1). Thus, Yamamoto et al. reported reactions of acetylenic
aldehydes with alcohols catalyzed by palladium.2 The Pd(II)
salt employed was claimed to exhibit a dual role both as a Lewis
acid and a transition metal catalyst. In a more recent study, the
analogous cyclization of the same acetylenic carbonyl precursors
with nucleophiles was achieved in the presence of Cu(I),3 Cu(II),3
Ag(I),4 Au(I),4 Au(III)4 salts, bis(pyridine) iodonium tetra-
fluoroborate (IPy2BF4)5 and HBF4.5 Recently, the Larock group found
that o-(1-alkynyl)-substituted arene carbonyl compounds treated
with electrophiles, such as NBS, I2, ICl, PhSeBr, 4-NO2C6H4SCl and
various alcohols or carbon-based nucleophiles underwent smooth
three-component reaction to form high-substituted oxygen
heterocycles.6 It was shown that electrophiles attacked the triple
bond of the starting compounds, therefore nucleophilic attack of
neighbouring carbonyl oxygen became more favourable.
5-exo-dig cyclization reactions were also reported.7
R''
R''
O
O
R
R
R
R
R
R
R''OH
O
O
R'
H(E)
and/or
O
[M], EX
or base
R'
R'
H(E)
Scheme 1. Literature results overview.
Recently we have studied novel, transition metal catalyst- and
initiator-free tandem acetalisation/5-exo-dig cyclization reactions of
2,4-disubstituted 6-phenylethynylpyrimidine-5-carbaldehydes to 5-
alkoxy-(7Z)-7-benzylidene-5,7-dihydrofuro[3,4-d]pyrimidines.8 We
showed that transformations of 4-dialkylamino-6-phenylethynyl-
pyrimidine-5-carbaldehydes proceeded smoothly and provided high
yields of the 5,7-dihydrofuro[3,4-d]pyrimidine derivatives when
1 equiv of sodium or potassium alkoxides in the appropriate primary
alcohol at reflux were used. Moreover, we observed that 6-phenyl-
ethynylpyrimidine-5-carbaldehydes bearing an alkylamino or aryla-
mino substituent in the position 4 of the pyrimidine ring did not
undergo acetalisation/cyclization reactions. Due to limitations of
this methodology we searched for methods with an extended
scope including the investigation of substituent effects on the
regioselectivity of the reactions.
* 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 Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.108

252
I. Cikotiene et al. / Tetrahedron 66 (2010) 251–258
2. Results and discussion
methoxy-4-morpholino-5,7-dihydrofuro[3,4-d]pyrimidine (2a)
took place.8 Reaction proceeded smoothly and provided high
yields of 2a when 1 equiv of sodium or potassium methoxide
were used (entries 2, 3). Then we tried to change the regiose-
lectivity of ring-closure and for this purpose we used catalytic
The starting compounds 1a-h were synthesized by the
palladium-catalyzed Sonagashira coupling of the corresponding
2,4-disubstituted 6-chloropyrimidine-5-carbaldehydes with phe-
nylacetylene according to procedure described earlier.8,9
amounts of different transition metals salts in order to form
p-
As we have found recently,8 4-dialkylamino-6-phenylethynyl
pyrimidine-5-carbaldehydes undergo smooth base-catalyzed ace-
talisation/5-exo-dig cyclization reactions with primary alcohols,
leading to the high-yielding formation of 5-alkoxy-(7Z)-7-benzyl-
idene-5,7-dihydrofuro[3,4-d]pyrimidines. On the other hand,
6-phenylethynylpyrimidine-5-carbaldehydes bearing amino-,
alkylamino- or arylamino groups in position 4 of the pyrimidine
ring did not undergo the same process. In order to study the gen-
erality and regioselectivity of the acetalisation/cyclization reaction
two starting compounds bearing morpholino (as N,N-dialkylamino
group, compound 1a) and anilino (as arylamino group, compound
1b) in position 4 of the pyrimidine ring were chosen and their
reactions with methanol under the different conditions were
studied. The results are summarized in Scheme 2 and Table 1.
complexes between triple bond and metal ion.10 As shown in
Table 1, CuI and AuCl3 (entries 4, 8) were ineffective. After the
long heating and work up of the reaction mixtures, the initial
compound was recovered. Using 5 mol % of palladium (II) chlo-
ride or silver (I) oxide led to the formation of only 5-exo-dig
cyclization product 2a (entries 6, 9). However, the reaction of 1a
with methanol in the presence of Cu(OTf)2, PdCl2(PPh3)2, AgNO3
or CF3CO2Ag proceeded with poor regioselectivity and the for-
mation of mixtures of 2a and 3a was observed in these cases
(entries 5, 7, 10, 11). We were pleasantly surprised when during
heating of solution of 1a in 1,2-dichloroethane in the presence of
3 equiv of methanol and 5 mol % of AgNO3 in microwave oven
after 5 min a high-yielding regioselective formation of 6-endo-
dig cyclization product 3a was observed (entry 12). Using
CF3CO2Ag at the same conditions provided slightly lower regio-
selectivity (entry 13). However, irradiation of the reaction mix-
ture in the presence of a catalytic amount of silver (I) nitrate
together with an equivalent of potassium methoxide completely
reversed the regioselectivityda high-yielding formation of 2a
was observed (entry 14).
R
N
R
N
O
R
N
O
CH3OH
N
O
N
O
N
+
O
S
S
S
H
The next compound that we chose was 4-anilino-2-methylthio-
6-phenylethynylpyrimidine-5-carbaldehyde (1b). As we have
found recently, compound 1b treated by sodium methoxide in
methanol did not undergo acetalisation/cyclization reactions
(entries 15, 16). Moreover silver (I) oxide also did not catalyzed the
formation of furo[3,4-d]pyrimidine 2b or pyrano[4,3-d]pyrimidine
1a,b
2a,b
3a,b
1-3a: R = N(CH2)4O;
1-3b: R = NHC6H5
Scheme 2.
Table 1
Optimization of the acetalisation/5-exo-dig or 6-endo-dig cyclization reactions of 4-substituted 2-methylthio-6-phenylethynylpyrimidine-5-carbaldehydes (1a,b) with
methanol (Scheme 2)
Entry
Start. comp.
Base
Catalyst
Conditions
5-exo-dig product (2)
6-endo-dig product (3)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
K2CO3
NaOCH3
KOCH3
d
d
CH3OH, reflux, 2 h
CH3OH, reflux, 1 h
CH3OH, reflux, 0.5 h
CH3OH, reflux, 20 h
CH3OH, reflux, 5 h
CH3OH, reflux, 5 h
CH3OH, reflux, 5 h
CH3OH, reflux, 5 h
72%a
d
d
d
d
92%a
d
93%a
CuI
Cu(OTf)2
PdCl2
PdCl2(PPh3)2
AuCl3
Ag2O
AgNO3
CF3CO2Ag
AgNO3
CF3CO2Ag
AgNO3
d
No reactionb
0.73c
d
0.27c
d
0.74c
d
60%a
d
0.26c
d
No reactionb
39%a
9
d
CH3OH, reflux, 40 h
CH3OH, reflux, 4 h
CH3OH, reflux, 4 h
d
10
11
12
13
14
15
16
17
18
19
20
21
23
24
d
0.41c
0.59c
0.51c
96%a
0.96c
d
d
0.49c
d
d
CH3OH/DCE, MW, 610 W, 5 min
CH3OH/DCE, MW, 610 W, 5 min
CH3OH/DCE, MW, 610 W, 5 min
CH3OH, reflux, 20 h
CH3OH, MW, 610 W, 30 min
CH3OH, reflux, 24 h
CH3OH/DCM, rt, 48 h
CH3OH/DCM, rt, 48 h
CH3OH, reflux, 4 h
d
0.4c
KOCH3
KOCH3
KOCH3
d
98%a
No reactionb
No reactionb
No reactionb
79%a
d
Ag2O
KOCH3
KOCH3
d
AgNO3
CF3CO2Ag
AgNO3
CF3CO2Ag
AgNO3
CF3CO2Ag
d
82%a
d
d
85%a
87%a
96%a
98%a
d
CH3OH, reflux, 4 h
CH3OH/DCE, MW, 610 W, 10 min
CH3OH/DCE, MW, 610 W, 10 min
d
d
d
d
d
a
Isolated yield.
b
c
Starting material recovered.
Ratio estimated by 1H NMR analysis.
First of all, we studied the reactivity of 2-methylthio-4-mor-
3b (entry 17). In all these cases after the work up of the reaction
mixtures the initial compound 1b was recovered. On the other
hand, using a catalytic amount of silver (I) salts together with
potassium methoxide gave slow but regioselective acetalisation/5-
exo-dig cyclization (entries 18, 19). Interestingly, when we used
pholino-6-phenylethynylpyrimidine-5-carbaldehyde (1a) with
methanol under the different conditions. During heating a solu-
tion of the starting compound in methanol in the presence of
bases, the regioselective formation of (7Z)-7-benzylidene-5-

I. Cikotiene et al. / Tetrahedron 66 (2010) 251–258
253
Table 2
only silver catalysts without addition of bases, we observed regio-
selective formation of 6-endo-dig cyclization product 3b. The same
result was obtained even during convectional or microwave heat-
ing (entries 20–24).
Data of the synthesis of 2,4-disubstituted 5-alkoxy-(7Z)-7-benzylidene-5,7-dihy-
drofuro[3,4-d]pyrimidines 2a–r (Scheme 3)
Entry Starting
comp.
R
R0
R00
Product Method Yield, %
So, we have found that the optimal acetalisation/5-exo-dig cy-
clization of 4-N,N-dialkylamino-6-phenylethynylpyrimidine-5-
carbaldehydes conditions are: an equivalent of potassium alkoxides
in alcohols, convectional or microwave heating. The best conditions
for the acetalisation/5-exo-dig cyclization of 6-phenyl-
ethynylpyrimidine-5-carbaldehydes bearing amino, alkylamino or
arylamino groups in position 4 of the pyrimidine ring are: an
equivalent of potassium alkoxide, alcohol (3 equiv), 5 mol % of sil-
ver (I) nitrate or silver (I) trifluoroacetate in dichloromethane at
room temperature. The optimal acetalisation/6-endo-dig cycliza-
tion of 4-N,N-dialkylamino-6-phenylethynylpyrimidine-5-carbal-
dehydes conditions are: alcohol (3 equiv), 1,2-dichloroethane,
5 mol % of silver (I) nitrate, irradiation of the reaction mixture in
microwave oven (610 W) for 5 min. The best conditions for the
acetalisation/6-endo-dig cyclization of 6-phenylethynylpyrimidine-
5-carbaldehydes bearing amino, alkylamino or arylamino groups in
position 4 of the pyrimidine ring are: alcohol (3 equiv), 1,2-di-
chloroethane, 5 mol % of silver (I) nitrate or silver (I) tri-
fluoroacetate convectional heating for 4 h or irradiation of the
reaction mixture in microwave oven (610 W) for 10 min. We have
also found, that in the presence of silver (I) salts, addition of water
to the triple bond of 6-phenylethynylpyrimidine-5-carbaldehydes
takes place,11 so use of anhydrous solvents is strongly
recommended.
1
2
3
4
5
6
7
8
1a
1a
1b
1a
1a
1a
1a
1a
1a
1b
1c
1d
1d
1d
1d
1e
1e
1e
1f
SCH3 N(CH2)4O CH3
SCH3 N(CH2)4O CH3
2a
2a
2b
2c
2c
2d
Aa
Bb
Cc
A
B
B
B
A
B
C
93
100
82
90
97
SCH3 NHC6H5
CH3
SCH3 N(CH2)4O C2H5
SCH3 N(CH2)4O C2H5
SCH3 N(CH2)4O C4H9
SCH3 N(CH2)4O CH(CH3)2 2e
SCH3 N(CH2)4O C(CH3)3
SCH3 N(CH2)4O C(CH3)3
78
89
2f
2f
2g
2h
2i
5d
9
90
76
82
95
93
79
71
90
85
89
92
94
89
10
11
12
13
14
15
16
17
18
19
20
21
SCH3 NHC6H5
SCH3 NH2
C2H5
CH3
C
SCH3 N(CH2)4
SCH3 N(CH2)4
SCH3 N(CH2)4
SCH3 N(CH2)4
SCH3 N(CH2)5
SCH3 N(CH2)5
SCH3 N(CH2)5
CH3
C2H5
C4H9
CH(CH3)2 2l
CH3
C2H5
C4H9
CH3
A
A
A
B
A
B
2j
2k
2m
2n
2o
2p
2q
2r
B
H
H
H
N(CH2)4
N(CH2)4
N(CH2)4O C2H5
A
A
A
1f
1g
C2H5
a
Method A: potassium alkoxide (1 equiv), alcohol, reflux, 0.5–3 h.
Method B: potassium alkoxide (1 equiv), alcohol (3 equiv), 1,2-dichloroethane,
b
microwave oven, 610 W, 5 min.
c
Method C: potassium alkoxide (1 equiv), alcohol (3 equiv), CF3CO2Ag (5 mol %),
dichloromethane, rt 24–48 h.
d
Starting material was recovered.
According to the presented methodologies, we have prepared
various 5,7-dihydrofuro[3,4-d]pyrimidines (2) (Scheme 3) and 5H-
pyrano[4,3-d]pyrimidines (3) (Scheme 4). The results are summa-
rized in Tables 2 and 3. It is noteworthy that use of sterically hin-
dered 2-propanol or tert-butanol resulted in an incomplete reaction
even after prolonged reflux.8 (Table 2, entry 7). However, using
a microwave induced methodology, secondary and tertiary alcohols
promote the nucleophilic cyclization effectively (Table 2, entries 7,
9, 15).
From these results we can propose three possible mechanistic
pathways for the acetalisation/cyclization reactions. We believe
that base-induced acetalisation/5-exo-dig cyclization proceeds by
a tandem type reactiondformation of an intermediate hemiacetal
and immediate nucleophilic cyclization to form the 5,7-dihy-
drofuran ring. We speculate, that 6-phenylethynylpyrimidine-5-
carbaldehydes bearing an NHR0 moiety in the position 4 of the
pyrimidine ring, exist in an unfavourable conformation where the
carbonyl group is turned towards the NHR0 moiety to form an
intramolecular hydrogen bond and directed away from the C^C
bond,12 therefore tandem reactions become impossible. Using
a catalytic amount of silver nitrate or silver trifluoroacetate resulted
the complexation of Agþ with C^C bond (intermediate 4), thus
making rotation of C]O to the activated triple bond more favour-
able (Scheme 5).
after catalyst recycling, yields the 5-exo-dig product 2. Moreover,
it is important to note again, that 6-phenylethynylpyrimidine-5-
carbaldehydes bearing an NHR0 moiety in the position 4 of the
pyrimidine ring adopt an unfavourable conformation12 and do
R''
O
R'
R'
N
O
R''OH
N
O
N
R
N
R
3
1
Scheme 4.
Table 3
Data of the synthesis of 2,4-disubstituted 5-alkoxy-7-phenyl-5H-pyrano[4,3-d]py-
rimidines 3a–k (Scheme 4)
Entry Starting
comp.
R
R0
R00
Product Method Yield, %
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1a
1a
1a
1b
1b
1c
1d
1d
1f
SCH3 N(CH2)4O
SCH3 N(CH2)4O
SCH3 NHC6H5
SCH3 NHC6H5
SCH3 N(CH2)4O
SCH3 N(CH2)4O
SCH3 N(CH2)4O
SCH3 NHC6H5
SCH3 NHC6H5
SCH3 NH2
CH3
CH3
CH3
CH3
C2H5
C4H9
3a
3a
3b
3b
3c
3d
Da
Eb
D
E
E
E
E
D
E
E
D
E
49c
96
85
96
88
85
98
78
84
79
Two of our investigated catalystsdsilver (I) oxide and palla-
dium (II) chloride also led to the acetalisation/5-exo-dig cycliza-
tions, so we suppose that these species coordinate with the
oxygen of the carbonyl moiety of the starting compounds. Thus,
intermediate acetal derivative 5 cyclizes to give complex 6 and,
CH2ChCH 3e
C2H5
C4H9
CH3
CH3
CH3
CH3
CH3
3f
3g
3h
3i
3i
3j
9
10
11
12
13
14
15
SCH3 N(CH2)4
SCH3 N(CH2)4
39c
89
44c
82
87
R'
N
R'
N
R''
O
R''OH
H
H
H
N(CH2)4
N(CH2)4
NHCH2C6H5 CH3
D
E
D
N
O
N
1f
1h
3j
3k
O
R
R
H
a
Method D: alcohol, AgNO3 (5 mol %), reflux, 4–6 h.
Method E: alcohol (3 equiv), AgNO3 (5 mol %), 1,2-dichloroethane, microwave
b
2
1
oven, 610 W, 5–10 min.
c
Mixture of 2 and 3 was formed.
Scheme 3.

254
I. Cikotiene et al. / Tetrahedron 66 (2010) 251–258
B:
of the triple bond of 1, the enhancement of electrophilicity of the
alkyne gives rise to subsequent nucleophilic attack of the car-
bonyl oxygen atom on the electron deficient alkyne to yield the
intermediate complexes 7 and/or 8. The solvent/nucleophile al-
cohol can then attack intermediates 7 and 8 and lead to catalyst
H
R''
O
O
R' R'
N
N
R''
R'
R'
O
N
N
1
O
N
R
N
R
H
recycling and liberation of the products
2 and/or 3. It is
noteworthy that 4-dialkylamino-6-phenylethynylpyrimidine-
5-carbaldehydes during refluxing in alcohols in the presence of
catalysts gave mixture of 5-exo-dig and 6-endo-dig cyclization
products 2 and 3. This could be explained by the conformation of
starting compounds, we believe that carbonyl group is turned
away from N,N-dialkylamino moiety and it is close to the C^C
bond.12 So, after the complexation the nucleophilic attack by the
carbonyl oxygen occurs very quickly and control of regiose-
lectivity is lost. Fortunately, microwave heating of the reaction
mixture led to better 6-endo-dig regiochemistry. On the other
hand, 6-phenylethynylpyrimidine-5-carbaldehydes bearing NHR0
moiety in the position 4 of the pyrimidine ring exist in a different
conformation where the carbonyl group is turned towards the
NHR0 moiety to form an intramolecular hydrogen bond and di-
rected away from the C^C bond.12 Thus, after the complexation
2
H
R''
O
B:
R'
H
R''
H
R'
H
N
N
R''
H
R'
O
O
N
N
O
N
N
N
N
O
O
N
R
R
R
H
Ag+
Ag+
2
1
4
Scheme 5. Mechanistic path A.
not undergo acetalisation/5-exo-dig cyclizations without forma-
tion of -complexes between the triple bond and catalysts
(Scheme 6).
p
R''
R' R'
N
N
R' R'
N
N
R'
R' R'
N
N
R'
R''
N
N
1
O
R''
O
[M]
O
R''OH
O[M]
N
O
O
O
R
N
R
N
R
R
N
H
[M]
6
2
5
[M]
H
R'
O
N
N
no reaction
N
R
1
Scheme 6. Mechanistic path B.
The path
C
(Scheme 7) accounts for the Cu(OTf)2,
the carbonyl group rotates to the triple bond slowly and only
after the rotation the cyclization process can take place. During
this slower process we obtain high regioselectivity.
PdCl2(PPh3)2, AgNO3 and CF3CO2Ag catalysts without using bases
(Table 1, entries 5, 7, 10–13, 20–24), for which upon coordination
R'
R'
R' R'
R'
R'
N
N
N
R''
O
N
N
R''OH
i
N
N
N
O
O
O
fast
R
N
R
R
H
[M]
[M]
fast
R'
1
7
2
ii
R'
R'
R'
R''
O
N
N
O
R''OH
slow
N
O
N
R
N
R
N
[M]
H
3
8
H
H
R'
R'
O
H
H
R'
R'
R''
O
N
N
N
N
N
O
N
N
R''OH
N
N
O
N
O
N
R
R
N
R
R
[M]
H
[M]
[M]
3
1
8
Scheme 7. Mechanistic path C.

I. Cikotiene et al. / Tetrahedron 66 (2010) 251–258
255
3. Conclusions
NMR (300 MHz, CDCl3):
d
¼2.64 (3H, s, SCH3), 3.48 (3H, s, OCH3),
6.51 (1H, s, CH), 6.53 (1H, s, CH), 6.84 (1H, br s, NH), 7.20 (1H, t,
J¼7.2 Hz, ArH), 7.28–7.31 (1H, m, ArH), 7.38–7.44 (4H, m, ArH), 7.66
(2H, d, J¼7.2 Hz, ArH), 7.82 (2H, d, J¼7.2 Hz, ArH) ppm. 13C NMR
In summary, we have developed a novel, concise and regiose-
lective synthetic methods of 5,7-dihydrofuro[3,4-d]pyrimidine and
5H-pyrano[4,3-d]pyrimidine frameworks via acetalisation/cycliza-
tion reactions of 2,4-disubstituted 6-phenylethynylpyrimidine-5-
carbaldehydes. We have demonstrated the influence of the
substituent of the 4dposition of the pyrimidine ring on the com-
pound0s reactivity and regioselectivity of the reaction. The micro-
wave-induced cycloizomerisation allows use of sterically hindered
alcohols. Silver nitrate or silver trifluoroacetate were found to be
effective catalysts for the cyclization processes and it was shown
that we can control the regiochemistry depending on microwave or
convectionl heating, on the presence or absence of base, as well as
on the type of catalyst. Three possible mechanisms of the cycliza-
tions were proposed. We believe that the present methodologies
enables efficient synthetic protocols for the preparation of furo[3,4-
d]pyrimidines and pyrano[4,3-d]pyrimidines.
(75 Hz, CDCl3):
d
¼14.5, 53.6, 102.5, 104.8, 106.8, 121.5, 124.5, 127.1,
128.5, 128.9, 129.3, 134.5, 137.7, 150.0, 155.3, 161.5, 175.0 ppm. Anal.
Calcd for C21H19N3O2S: C, 66.82; H, 5.07; N, 11.13. Found: C, 66.95;
H, 5.16; N, 11.07.
4.2.2. (7Z)-7-Benzylidene-5-ethoxy-2-methylthio-4-morpholin-4-yl-
5,7-dihydrofuro[3,4-d]pyrimidine 2c. White solid, yield 90%
(method A), 97% (method B), mp 173–174 ꢁC (from EtOH). 1H NMR
(300 MHz, CDCl3):
d
¼1.29 (3H, t, J¼7.2 Hz, CH3), 2.60 (3H, s, SCH3),
3.75–3.87 (8H, m, N(CH2)4O), 3.80 (2H, q, J¼7.2 Hz, CH2), 6.51 (1H, s,
CH), 6.66 (1H, s, CH), 7.26 (1H, t, J¼7.5 Hz, ArH), 7.40 (2H, t, J¼7.5 Hz,
ArH), 7.82 (2H, d, J¼7.5 Hz, ArH) ppm. 13C NMR (75 Hz, CDCl3):
d
¼14.1, 20.6, 45.4, 66.3, 68.6, 100.9, 105.5, 106.4, 126.8, 128.4, 129.1,
132.9, 156.5, 157.7, 162.5, 172.6 ppm. Anal. Calcd for C20H23N3O3S: C,
62.32; H, 6.01; N, 10.90. Found: C, 62.55; H, 5.99; N, 11.09.
4. Experimental
4.1. General
4.2.3. (7Z)-7-Benzylidene-5-butoxy-2-methylthio-4-morpholin-4-yl-
5,7-dihydrofuro[3,4-d]pyrimidine 2d. White solid, yield 78%
(method B), mp 163–164 ꢁC (from 2-PrOH). 1H NMR (300 MHz,
Melting points were determined in open capillaries and are un-
corrected. 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 synthesized
compoundswere monitoredbyTLC usingSilicagel60F254 aluminium
plates (Merck). Visualization was accomplished by UV light.
Data for compounds 2a,i,m have been published in the previous
paper.8
CDCl3):
d
¼0.94 (3H, t, J¼7.2 Hz, CH3), 1.39–1.43 (2H, m, CH2), 1.52–
1.54 (2H, m, CH2), 2.60 (3H, s, SCH3), 3.76–3.87 (8H, m, N(CH2)4O),
3.80–3.84 (2H, m, CH2), 6.52 (1H, s, CH), 6.64 (1H, s, CH), 7.26 (1H, t,
J¼7.5 Hz, ArH), 7.41 (2H, t, J¼7.5 Hz, ArH), 7.82 (2H, d, J¼7.5 Hz, ArH)
ppm. 13C NMR (75 Hz, CDCl3):
d¼13.9, 14.1, 22.6, 29.3, 45.4, 66.3,
67.6, 99.9, 105.4, 106.2, 126.5, 128.4, 129.2, 130.9, 155.5, 157.3, 162.0,
174.6 ppm. Anal. Calcd for C22H27N3O3S: C, 63.90; H, 6.58; N, 10.16.
Found: C, 64.05; H, 6.59; N, 10.07.
4.2.4. (7Z)-7-Benzylidene-5-isopropoxy-2-methylthio-4-morpholin-
4-yl-5,7-dihydrofuro[3,4-d]pyrimidine 2e. White solid, 89% (method
B), mp 155–156 ꢁC (from 2-PrOH). 1H NMR (300 MHz, CDCl3):
4.2. Typical procedures for the preparation of 2,4-
disubstituted 5-alkoxy-(7Z)-7-benzylidene-5,7-
dihydrofuro[3,4-d]pyrimidines 2a–r
d
¼1.27 (3H, d, J¼6.0 Hz, CH3), 1.31 (3H, d, J¼6.0 Hz, CH3), 2.59 (3H, s,
SCH3), 3.77–3.85 (8H, m, N(CH2)4O), 4.15 (1H, sept, J¼6.0 Hz, CH2),
6.51 (1H, s, CH), 6.71 (1H, s, CH), 7.23 (1H, t, J¼7.5 Hz, ArH), 7.39 (2H,
t, J¼7.5 Hz, ArH), 7.81 (2H, d, J¼7.5 Hz, ArH) ppm. 13C NMR (75 Hz,
Method A: To
a
solution of the corresponding 6-phenyl-
CDCl3):
d¼14.2, 22.5, 22.7, 45.4, 66.6, 70.5, 101.7, 104.6, 106.7, 126.8,
ethynylpyrimidine-5-carbaldehyde 1a,d–g (0.3 mmol) in an alco-
hol (5 mL) a solution of potassium alkoxide (0.3 mmol) in the
appropriate alcohol (2 mL) was added. The resulting reaction
mixture was refluxed for 0.5–2 h. The solvent was evaporated un-
der reduced pressure, the residue washed with water, filtered and
recrystallized to give compounds 2a,c–f,i–r.
128.4, 129.1, 134.9, 150.0, 157.3, 162.2, 173.1 ppm. Anal. Calcd for
C21H25N3O3S: C, 63.13; H, 6.31; N, 10.52. Found: C, 63.35; H, 6.29; N,
10.49.
4.2.5. (7Z)-7-Benzylidene-5-tert-butoxy-2-methylthio-4-morpholin-
4-yl-5,7-dihydrofuro[3,4-d]pyrimidine 2f. White solid, yield 5%
(method A), yield 90% (method B), mp 189–190 ꢁC dec (from
Method B: A solution of the corresponding 2,4-disubstituted
6-phenylethynylpyrimidine-5-carbaldehyde 1a,d–g (0.3 mmol),
alcohol (0.9 mmol) and potassium alkoxide (0.3 mmol) in 1,2-di-
chloroethane (3 mL) was placed in closed 15 mL vessel and irradi-
ated in a microwave oven at 610 W for 5 min. After the heating, the
solution was cooled to room temperature, filtered through a silica
gel layer, concentrated and the solid residue was recrystallized or
purified by flash column chromatography to give 2a,c–f,i–r.
Method C: A solution of the corresponding 2,4-disubstituted
6-phenylethynylpyrimidine-5-carbaldehyde 1b,c (0.3 mmol), alco-
hol (0.9 mmol), silver trifluoroacetate (5 mol %) and potassium
alkoxide (0.3 mmol) in dichloromethane (3 mL) was stirred at room
temperature for 24–48 h. After the reaction was complete, the
solution filtrated through a silica gel layer, concentrated and the
solid residue was recrystallized or purified by flash column chro-
matography to give 2b,g,h.
butanol). 1H NMR (300 MHz, DMSO-d6):
d
¼1.91 (9H, s, (CH3)3),
2.29 (3H, s, SCH3), 3.48–3.58 (8H, m, N(CH2)4O), 6.14 (1H, s, CH),
6.62 (1H, s, CH), 6.97 (1H, t, J¼7.5 Hz, ArH), 7.05 (2H, t, J¼7.5 Hz,
ArH), 7.50 (2H, d, J¼7.5 Hz, ArH) ppm. 13C NMR (75 Hz, DMSO-
d6):
d
¼13.5, 28.4, 44.8, 65.7, 72.0, 100.3, 100.8, 107.1, 126.0, 127.7,
128.1, 134.2, 149.5, 156.5, 161.2, 171.8 ppm. Anal. Calcd for
C22H27N3O3S: C, 63.90; H, 6.58; N, 10.16. Found: C, 63.98; H, 6.57;
N, 10.27.
4.2.6. 4-Anilino-(7Z)-7-benzylidene-5-ethoxy-2-methylthio-5,7-di-
hydrofuro[3,4-d]pyrimidine 2g. White solid, 76% (method C), mp
148–149 ꢁC (from 2-PrOH). IR (KBr): nmax¼3438 (NH) cmꢂ1. 1H NMR
(300 MHz, DMSO-d6):
d¼1.19 (3H, t, J¼6.9 Hz, CH3), 2.56 (3H, s,
SCH3), 3.71–3.73 (1H, m, OCH2), 3.83–3.87 (1H, m, OCH2), 6.35 (1H,
s, CH), 6.68 (1H, s, CH), 7.16 (1H, t, J¼7.2 Hz, ArH), 7.27 (1H, t,
J¼7.5 Hz, ArH), 7.38–7.44 (4H, m, ArH), 7.67 (2H, d, J¼7.2 Hz, ArH),
4.2.1. 4-Anilino-(7Z)-7-benzylidene-5-methoxy-2-methylthio-5,7-di-
7.82 (2H, d, J¼7.5 Hz, ArH) ppm. 13C NMR (75 Hz, DMSO-d6):
¼13.6,
d
hydrofuro[3,4-d]pyrimidine 2b. White solid, yield: 82% (method C),
15.1, 63.6, 100.5, 105.3, 108.5, 121.8, 123.8, 126.9, 128.5, 128.7, 128.9,
134.4, 138.3, 150.2, 154.8, 160.0, 173.0 ppm. Anal. Calcd for
mp 174–176 ꢁC (from MeOH). IR (KBr): nmax¼3437 (NH) cmꢂ1
.
1H

256
I. Cikotiene et al. / Tetrahedron 66 (2010) 251–258
C22H21N3O2S: C, 67.50; H, 5.41; N, 10.73. Found: C, 67.45; H, 5.36; N,
10.66.
1.67–1.61 (6H, m, (CH2)3), 2.60 (3H, s, SCH3), 3.62–3.65 (2H, m,
OCH2), 3.78–3.79 (4H, m, N(CH2)2), 6.48 (1H, s, CH), 6.65 (1H, s, CH),
7.25 (1H, t, J¼7.8 Hz, ArH), 7.38 (2H, t, J¼7.8 Hz, ArH), 7.81 (2H, d,
4.2.7. 4-Amino-(7Z)-7-benzylidene-5-methoxy-2-methylthio-5,7-di-
hydrofuro[3,4-d]pyrimidine 2h. White solid, 82% (method C), mp
J¼7.8 Hz, ArH) ppm. 13C NMR (75 Hz, CDCl3):
¼14.2, 19.5, 27.0,
d
30.2, 31.9, 48.2, 49.3, 67.7, 100.3, 105.4, 106.6, 126.8, 128.4, 129.4,
134.7, 150.4, 156.8, 161.9, 172.1 ppm. Anal. Calcd for C23H29N3O2S: C,
67.12; H, 7.10; N, 10.21. Found: C, 67.15; H, 6.99; N, 10.28.
175–176 ꢁC. IR (KBr): nmax¼3443, 3440 (NH2) cmꢂ1
.
1H NMR
(300 MHz, CDCl3):
d
¼2.47 (3H, s, SCH3), 3.48 (3H, s, OCH3), 6.26 (1H,
s, CH), 6.52 (1H, s, CH), 6.88 (2H, br s, NH2), 7.24 (1H, t, J¼7.2 Hz,
ArH), 7.38–7.44 (2H, m, ArH), 7.80 (2H, d, J¼7.2 Hz, ArH) ppm. 13C
4.2.13. (7Z)-7-Benzylidene-5-methoxy-4-pyrrolidin-1-yl-5,7-dihy-
drofuro[3,4-d]pyrimidine 2p. White solid, yield 92% (method A), mp
NMR (75 Hz, CDCl3):
d
¼14.2, 54.6, 101.5, 103.8, 104.8, 121.5, 124.6,
128.1, 132.5, 151.0, 155.2, 162.5, 173.2 ppm. Anal. Calcd for
C15H15N3O2S: C, 59.78; H, 5.02; N, 13.94. Found: C, 59.90; H, 4.98; N,
13.90.
145–147 ꢁC (from MeOH). 1H NMR (300 MHz, CDCl3):
d¼2.05 (4H, br
s, CH2CH2), 3.56(3H, s, OCH3), 3.80(4H, brs, N(CH2)2), 6.50(1H, s, CH),
6.70 (1H, s, CH), 7.25 (1H, t, J¼7.8 Hz, ArH), 7.39 (2H, t, J¼7.8 Hz, ArH),
7.80 (2H, d, J¼7.8 Hz, ArH), 8.61 (1H, s, CH) ppm. 13C NMR (75 Hz,
4.2.8. (7Z)-7-Benzylidene-5-ethoxy-2-methylthio-4-pyrrolidin-1-yl-
5,7-dihydrofuro[3,4-d]pyrimidine 2j. White solid, yield 93%
(method A), mp 152–154 ꢁC (from 2-PrOH). 1H NMR (300 MHz,
CDCl3):
d
¼24.1, 46.9, 53.9,101.7,106.4,109.7,126.9,128.4,129.2,134.8,
150.7, 156.3, 159.6, 160.3 ppm. Anal. Calcd for C18H19N3O2: C, 69.88; H,
6.19; N, 13.58. Found: C, 69.80; H, 6.01; N, 13.44.
CDCl3):
d
¼1.30 (3H, t, J¼6.9 Hz, CH3),1.96–2.05 (4H, m, (CH2)2), 2.60
(3H, s, SCH3), 3.48–3.59 (2H, m, OCH2), 3.71–3.93 (4H, m, N(CH2)2),
6.46 (1H, s, CH), 6.67 (1H, s, CH), 7.28 (1H, t, J¼7.8 Hz, ArH), 7.39 (2H,
t, J¼7.8 Hz, ArH), 7.81 (2H, d, J¼7.8 Hz, ArH) ppm. 13C NMR (75 Hz,
4.2.14. (7Z)-7-Benzylidene-5-ethoxy-4-pyrrolidin-1-yl-5,7-dihydro-
furo[3,4-d]pyrimidine 2q. White solid, yield 94% (method A), mp
134–136 ꢁC (from EtOH). 1H NMR (300 MHz, CDCl3):
d¼1.33 (3H, t,
CDCl3):
d
¼13.5, 15.2, 22.9, 25.6, 47.8, 48.9, 63.2, 100.1, 105.8, 107.1,
J¼6.9 Hz, CH3), 2.05 (4H, br s, CH2CH2), 3.75 (4H, br s, N(CH2)2), 3.77–
3.82 (1H, m, OCH2), 3.92–4.02 (1H, m, OCH2), 6.49 (1H, s, CH), 6.70
(1H, s, CH), 7.25 (1H, t, J¼7.8 Hz, ArH), 7.39 (2H, t, J¼7.8 Hz, ArH), 7.80
(2H, d, J¼7.8 Hz, ArH), 8.60 (1H, s, CH) ppm. 13C NMR (75 Hz, CDCl3):
126.8, 128.6, 128.7, 134.6, 150.5, 155.0, 160.0, 171.9 ppm. Anal. Calcd
for C20H23N3O2S: C, 65.01; H, 6.27; N,11.37. Found: C, 65.05; H, 6.39;
N, 11.26.
d
¼15.3, 25.8, 46.9, 63.2, 101.5, 105.7, 110.1, 126.8, 128.4, 129.1, 134.9,
4.2.9. (7Z)-7-Benzylidene-5-butoxy-2-methylthio-4-pyrrolidin-1-yl-
5,7-dihydrofuro[3,4-d]pyrimidine 2k. White solid, yield 79%
(method A), mp 138–140 ꢁC (from 2-PrOH). 1H NMR (300 MHz,
150.8, 156.3, 159.5, 160.2 ppm. Anal. Calcd for C19H21N3O2: C, 70.57;
H, 6.55; N, 12.99. Found: C, 70.70; H, 6.49; N, 13.03.
CDCl3):
d
¼0.93 (3H, t, J¼7.2 Hz, CH3), 1.37–1.45 (4H, m, (CH2)2),
4.2.15. (7Z)-7-Benzylidene-5-ethoxy-4-morpholin-1-yl-5,7-dihydro-
furo[3,4-d]pyrimidine 2r. White solid, yield 89% (method A), mp
2.00–2.05 (4H, m, (CH2)2), 2.61 (3H, s, SCH3), 3.61–3.85 (6H, m,
N(CH2)2, OCH2), 6.47 (1H, s, CH), 6.71 (1H, s, CH), 7.25 (1H, t,
J¼7.5 Hz, ArH), 7.39 (2H, t, J¼7.5 Hz, ArH), 7.80 (2H, d, J¼7.5 Hz, ArH)
141–142 ꢁC (from EtOH). 1H NMR (300 MHz, CDCl3):
d
¼1.32 (3H, t,
J¼6.9 Hz, CH3), 3.74–3.78 (2H, m, OCH2), 3.75 (8H, br s, N(CH2)2O),
6.54 (1H, s, CH), 6.70 (1H, s, CH), 7.27 (1H, t, J¼7.5 Hz, ArH), 7.41 (2H,
t, J¼7.5 Hz, ArH), 7.81 (2H, d, J¼7.8 Hz, ArH), 8.63 (1H, s, CH) ppm.
ppm. 13C NMR (75 Hz, CDCl3):
d¼14.2, 19.5, 27.0, 31.9, 48.2, 49.3,
67.7, 100.9, 106.7, 107.7, 127.5, 129.3, 129.4, 135.3, 151.2, 155.8, 160.4,
172.6 ppm. Anal. Calcd for C22H27N3O2S: C, 66.47; H, 6.85; N, 10.57.
Found: C, 66.35; H, 6.79; N, 10.48.
13C NMR (75 Hz, CDCl3):
126.1, 128.4, 129.5, 134.9, 151.8, 156.3, 159.5, 161.2 ppm. Anal. Calcd
for C19H21N3O3: C, 67.24; H, 6.24; N, 12.38. Found: C, 67.33; H, 6.40;
N, 12.13.
d
¼15.3, 46.9, 58.9, 63.3, 101.0, 105.2, 110.5,
4.2.10. (7Z)-7-Benzylidene-5-isopropoxy-2-methylthio-4-pyrrolidin-
1-yl-5,7-dihydrofuro[3,4-d]pyrimidine 2l. White solid, yield 71%
(method B), mp 144–145 ꢁC (from 2-PrOH). 1H NMR (300 MHz,
4.3. Typical procedures for the preparation of 2,4-
disubstituted 5-alkoxy-7-phenyl-5H-pyrano[4,3-
d]pyrimidines 3a–k
CDCl3):
d
¼1.24 (3H, d, J¼6.0 Hz, CH3), 1.27 (3H, d, J¼6.0 Hz, CH3),
1.99–2.05 (4H, m, (CH2)2), 2.55 (3H, s, SCH3), 3.62–3.70 (6H, m,
N(CH2)2,), 4.16 (1H, sept, J¼6.0 Hz, CH2), 6.29 (1H, s, CH), 7.02 (1H, s,
CH), 7.22 (1H, t, J¼7.5 Hz, ArH), 7.39 (2H, t, J¼7.5 Hz, ArH), 7.77 (2H,
Method D: To a solution of the corresponding 6-phenyl-
ethynylpyrimidine-5-carbaldehyde 1a–d, f–g (0.3 mmol) in an
alcohol (5 mL) silver nitrate (2.54 mg, 0.015 mmol) was added. The
resulting reaction mixture was refluxed for 4–6 h. The solvent was
evaporated under reduced pressure, the residue was dissolved in
chloroform, filtered through a silica gel layer, concentrated and the
solid residue was recrystallized or purified by flash column chro-
matography to give 3a–k.
Method E: A solution of the corresponding 2,4-disubstituted
6-phenylethynylpyrimidine-5-carbaldehyde 1a–d, f–g (0.3 mmol),
alcohol (0.9 mmol) and silver nitrate (2.54 mg, 0.015 mmol) in 1,2-
dichloroethane (3 mL) was placed in closed 15 mL vessel and irra-
diated in a microwave oven at 610 W for 5–10 min. After the
heating, the solution was cooled to room temperature, filtered
through a silica gel layer, concentrated and the solid residue was
recrystallized or purified by flash column chromatography to give
3a–k.
d, J¼7.5 Hz, ArH) ppm. 13C NMR (75 Hz, CDCl3):
¼14.2, 22.5, 22.7,
d
24.6, 49.3, 69.7, 101.9, 104.7, 105.7, 127.6, 129.4, 129.4, 135.3, 151.3,
155.8, 161.4, 173.8 ppm. Anal. Calcd for C21H25N3O2S: C, 65.77; H,
6.57; N, 10.96. Found: C, 65.85; H, 6.51; N, 10.99.
4.2.11. (7Z)-7-Benzylidene-5-ethoxy-2-methylthio-4-piperidin-1-yl-
5,7-dihydrofuro[3,4-d]pyrimidine 2n. White solid, yield 85%
(method B), mp 122–124 ꢁC (from 2-PrOH). 1H NMR (300 MHz,
CDCl3):
d
¼1.30 (3H, t, J¼6.9 Hz, CH3), 1.67–1.70 (6H, m, (CH2)3), 2.60
(3H, s, SCH3), 3.70–3.78 (4H, m, N(CH2)2), 3.80–3.85 (2H, m, OCH2),
6.48 (1H, s, CH), 6.66 (1H, s, CH), 7.25 (1H, t, J¼7.8 Hz, ArH), 7.39 (2H,
t, J¼7.8 Hz, ArH), 7.81 (2H, d, J¼7.8 Hz, ArH) ppm. 13C NMR (75 Hz,
CDCl3):
d¼14.2, 15.2, 24.6, 25.9, 46.5, 43.1, 101.3, 105.4, 106.3, 126.7,
128.4, 129.2, 134.9, 150.4, 156.8, 161.9, 173.1 ppm. Anal. Calcd for
C21H25N3O2S: C, 65.77; H, 6.57; N, 10.96. Found: C, 65.55; H, 6.44; N,
11.02.
4.2.12. (7Z)-7-Benzylidene-5-butoxy-2-methylthio-4-piperidin-1-yl-
5,7-dihydrofuro[3,4-d]pyrimidine 2o. White solid, yield 89%
(method B), mp 124–126 ꢁC (from 2-PrOH). 1H NMR (300 MHz,
4.3.1. 5-Methoxy-2-methylthio-4-morpholin-4-yl-7-phenyl-
5H-pyrano[4,3-d]pyrimidine 3a. Yellowish solid, yield 49% (method
D), 96% (method E), mp 175–177 ꢁC (from MeOH). 1H NMR
CDCl3):
d
¼0.94 (3H, t, J¼7.2 Hz, CH3), 1.30–1.28 (4H, m, (CH2)2),
(300 MHz, CDCl3):
d¼2.61 (3H, s, SCH3), 3.57 (3H, s, OCH3), 3.79–3.82

I. Cikotiene et al. / Tetrahedron 66 (2010) 251–258
257
(8H, m, N(CH2)4O), 6.13 (1H, s, CH), 6.99 (1H, s, CH), 7.43–7.46 (3H, m,
ArH), 7.89–7.93 (2H, m, ArH) ppm. 13C NMR (75 Hz, CDCl3):
48.4, 54.9, 66.6, 96.7, 100.5, 101.3, 125.8, 128.8, 130.7, 132.1, 156.6,
157.7, 160.0, 168.9 ppm. Anal. Calcd for C19H21N3O3S: C, 61.44; H,
5.70; N, 11.31. Found: C, 61.56; H, 5.91; N, 11.19.
d
¼0.97 (3H, t, J¼6.8 Hz, CH3), 1.27–1.30 (2H, m, CH2), 1.50–1.54 (2H,
d¼16.2,
m, CH2), 2.60 (3H, s, SCH3), 3.68 (2H, t, J¼6.8 Hz, OCH2), 6.55 (1H, s,
CH), 6.58 (1H, br s, NH), 6.59 (1H, s, CH), 7.19 (1H, t, J¼7.5 Hz, ArH),
7.39–7.47 (5H, m, ArH), 7.60 (2H, d, J¼7.5 Hz, ArH), 7.66–7.69 (2H, m,
ArH), ppm. 13C NMR (75 Hz, CDCl3):
d¼13.6, 14.4, 19.2, 31.6, 64.1,
85.9, 99.7, 103.2, 122.5, 125.8, 126.9, 128.9, 129.2, 129.9, 131.7, 132.1,
156.7, 156.7, 162.0, 173.9 ppm. Anal. Calcd for C24H25N3O2S: C,
68.71; H, 6.01; N, 10.02. Found: C, 68.77; H, 6.09; N, 10.11.
4.3.2. 4-Anilino-5-methoxy-2-methylthio-7-phenyl-5H-pyrano[4,3-
d]pyrimidine 3b. Yellowish solid, yield 85% (method D), 96%
(method E), mp 115–117 ꢁC. IR (KBr): nmax¼3441 (NH) cmꢂ1
.
1H
NMR (300 MHz, CDCl3):
d
¼2.56 (3H, s, SCH3), 3.61 (3H, s, OCH3),
4.3.8. 4-Amino-5-methoxy-2-methylthio-7-phenyl-5H-pyrano[4,3-
6.48 (1H, s, CH), 6.54 (1H, s, CH), 7.00 (1H, br s, NH), 7.15 (1H, t,
d]pyrimidine 3h. Yellowish solid, yield 79% (method E), mp 178–
J¼7.5 Hz, ArH), 7.39–7.49 (5H, m, ArH), 7.60 (2H, d, J¼7.5 Hz, ArH),
180 ꢁC (from MeOH). IR (KBr): nmax¼3442, 3439 (NH2) cmꢂ1
.
1H
7.82–7.83 (2H, m, ArH) ppm. 13C NMR (75 Hz, CDCl3):
99.7, 100.4, 101.3, 122.5, 125.8, 126.7, 128.8, 129.2, 129.8, 130.7, 132.1,
156.6, 157.7, 160.0, 169.9 ppm. Anal. Calcd for C21H19N3O2S: C,
66.82; H, 5.07; N, 11.13. Found: C, 66.85; H, 5.06; N, 11.27.
d
¼14.2, 56.9,
NMR (300 MHz, DMSO-d6):
d¼2.49 (3H, s, SCH3), 3.54 (3H, s, OCH3),
6.44 (1H, s, CH), 6.66 (1H, s, CH), 7.18 (2H, br s, NH2), 7.48–7.50 (3H,
m, ArH), 7.88–7.91 (2H, m, ArH) ppm. 13C NMR (75 Hz, DMSO-d6):
d
¼14.4, 55.2, 96.7, 98.1, 100.3, 126.2, 129.5, 131.1, 133.6, 154.7, 157.1,
159.9, 171.2 ppm. Anal. Calcd for C15H15N3O2S: C, 59.78; H, 5.02; N,
13.94. Found: C, 60.00; H, 5.09; N, 14.02.
4.3.3. 5-Ethoxy-2-methylthio-4-morpholin-4-yl-7-phenyl-5H-pyr-
ano[4,3-d]pyrimidine 3c. Yellowish solid, yield 88% (method E), mp
157–158 ꢁC (from 2-PrOH-octane). 1H NMR (300 MHz, CDCl3):
4.3.9. 5-Methoxy-2-methylthio-4-pyrrolidin-4-yl-7-phenyl-5H-pyr-
ano[4,3-d]pyrimidine 3i. Yellowish solid, yield 39% (method D), 89%
(method E), mp 117–118 ꢁC (from MeOH). 1H NMR (300 MHz,
d
¼1.22 (3H, t, J¼7.2 Hz, CH3), 2.56 (3H, s, SCH3), 3.53–3.60 (2H, m,
OCH2), 3.69–3.82 (8H, m, N(CH2)4O), 6.29 (1H, s, CH), 6.68 (1H, s,
CH), 7.44–7.46 (3H, m, ArH), 7.82–7.85 (2H, m, ArH) ppm. 13C NMR
CDCl3):
d
¼1.95–1.98 (4H, br s, (CH2)2), 2.51 (3H, s, SCH3), 3.55 (3H, s,
(75 Hz, CDCl3):
d
¼14.0,14.9, 48.9, 63.4, 66.7, 96.0,101.2,102.3,125.4,
OCH3), 3.60–3.67 (4H, m, N(CH2)2), 6.50 (1H, s, CH), 6.58 (1H, s, CH),
128.6, 130.1, 133.1, 156.4, 157.0, 161.4, 171.0 ppm. Anal. Calcd for
C20H23N3O3S: C, 62.32; H, 6.01; N, 10.90. Found: C, 62.51; H, 5.89; N,
11.01.
7.40–7.44 (3H, m, ArH), 7.79–7.83 (2H, m, ArH) ppm. 13C NMR
(75 Hz, CDCl3):
d
¼13.2, 25.4, 48.6, 54.1, 97.5, 98.2,101.3,125.3,128.6,
129.8, 133.2, 155.2, 155.7, 156.7, 170.4 ppm. Anal. Calcd for
C19H21N3O2S: C, 64.20; H, 5.95; N, 11.82. Found: C, 64.36; H, 5.90; N,
11.69.
4.3.4. 5-Butoxy-2-methylthio-4-morpholin-4-yl-7-phenyl-5H-pyr-
ano[4,3-d]pyrimidine 3d. Yellowish solid, yield 85% (method E), mp
134–135 ꢁC (from octane). 1H NMR (300 MHz, CDCl3):
d¼0.86 (3H, t,
4.3.10. 5-Methoxy-4-pyrrolidin-4-yl-7-phenyl-5H-pyrano[4,3-d]py-
rimidine 3j. Yellowish solid, yield 44% (method D), 82% (method E),
J¼7.2 Hz, CH3), 1.27–1.30 (2H, m, CH2), 1.50–1.54 (2H, m, CH2), 2.56
(3H, s, SCH3), 3.56–3.60 (1H, m, OCH), 3.78–3.83 (8H, m, N(CH2)4O),
4.00–4.07 (1H, m, OCH), 6.23 (1H, s, CH), 6.89 (1H, s, CH), 7.42–7.45
(3H, m, ArH), 7.86–7.89 (2H, m, ArH) ppm. 13C NMR (75 Hz, CDCl3):
mp 112–113 ꢁC (from MeOH). 1H NMR (300 MHz, CDCl3):
d¼2.02
(4H, br s, CH2CH2), 3.59 (3H, s, OCH3), 3.80 (4H, br s, N(CH2)2), 6.56
(1H, s, CH), 6.79 (1H, s, CH), 7.40–7.44 (3H, m, ArH), 7.79–7.83 (2H,
d
¼13.6, 14.9, 19.2, 31.4, 48.6, 66.7, 67.6, 95.9, 101.0, 101.9, 125.6,
m, ArH), 8.54 (1H, s, CH) ppm. 13C NMR (75 Hz, CDCl3):
53.9, 101.7, 106.4, 109.9, 126.5, 128.4, 129.6, 134.8, 150.7, 157.3, 159.6,
162.3 ppm. Anal. Calcd for C18H19N3O2: C, 69.88; H, 6.19; N, 13.58.
Found: C, 69.82; H, 6.09; N, 13.45.
d
¼25.1, 46.9,
128.6, 130.3, 132.7, 156.9, 157.1, 160.7, 170.2 ppm. Anal. Calcd for
C22H27N3O3S: C, 63.90; H, 6.58; N, 10.16. Found: C, 63.95; H, 6.44; N,
10.25.
4.3.5. 2-Methylthio-4-morpholin-4-yl-7-phenyl-5-(prop-2-ynyloxy)-
5H-pyrano[4,3-d]pyrimidine 3e. Yellow solid, yield 98% (method E),
4.3.11. 4-Benzylamino-5-methoxy-7-phenyl-5H-pyrano[4,3-d]py-
rimidine 3k. Yellowish solid, yield 87% (method D), mp 129–130 ꢁC.
mp 115–117 ꢁC. IR (KBr): nmax¼2118 (ChC) cmꢂ1
.
1H NMR
IR (KBr): nmax¼3440 (NH) cmꢂ1. 1H NMR (300 MHz, CDCl3):
¼3.55
d
(300 MHz, CDCl3):
d
¼2.56 (3H, s, SCH3), 2.60 (1H, t, J4¼2.4 Hz,
(3H, s, OCH3), 4.78 (2H, t, J¼4.5 Hz, CH2), 5.55 (1H, br s, NH), 6.42
hCH), 3.78–3.83 (8H, m, N(CH2)4O), 4.30 (1H, dd, J2¼16.2 Hz,
J4¼2.4 Hz, OCH), 4.60 (1H, dd, J2¼16.2 Hz, J4¼2.4 Hz, OCH), 6.62
(1H, s, CH), 6.72 (1H, s, CH), 7.44–7.47 (3H, m, ArH), 7.82–7.85 (2H,
(1H, s, CH), 6.57 (1H, s, CH), 7.32–7.42 (8H, m, ArH), 7.82–7.84 (2H,
m, ArH), 8.59 (1H, s, CH) ppm. 13C NMR (75 Hz, CDCl3):
96.6, 98.4, 125.5, 127.5, 128.2, 128.7, 129.3, 130.4, 138.6, 146.8, 157.3,
158.3 ppm. Anal. Calcd for C21H19N3O2: C, 73.03; H, 5.54; N, 12.17.
Found: C, 72.98; H, 5.43; N, 12.16.
d
¼44.7, 53.6,
m, ArH) ppm. 13C NMR (75 Hz, CDCl3):
77.7, 92.9, 101.5, 101.6, 125.2, 128.7, 130.2, 132.5, 155.7, 157.0, 161.4,
171.3 ppm. Anal. Calcd for C21H21N3O3S: C, 63.78; H, 5.35; N, 10.63.
Found: C, 63.87; H, 5.42; N, 10.75.
d
¼14.0, 48.8, 53.1, 66.8, 76.1,
Acknowledgements
4.3.6. 4-Anilino-5-ethoxy-2-methylthio-7-phenyl-5H-pyrano[4,3-
d]pyrimidine 3f. Yellowish solid, yield 78% (method D), mp
We thank Lithuanian State Science and Studies Foundation for
the financial support (Reg. No. T-09027; Grant No. T-67/09).
We express our gratitude to Dr. Visvaldas Kairys (University of
Madeira, Portugal) for the performing of some theoretical
calculations.
122–123 ꢁC. IR (KBr): nmax¼3442 (NH) cmꢂ1
.
1H NMR (300 MHz,
¼1.22 (3H, t, J¼7.2 Hz, CH3), 2.49 (3H, s, SCH3), 3.59–3.64
DMSO-d6):
d
(2H, m, OCH2), 6.79 (1H, s, CH), 6.91 (1H, s, CH), 7.18 (1H, t, J¼7.5 Hz,
ArH),7.39–7.47(5H, m, ArH),7.60(2H, d,J¼7.5 Hz,ArH), 7.82–7.84(2H,
m, ArH), 8.99 (1H, br s, NH) ppm. 13C NMR (75 Hz, DMSO-d6):
d¼14.2,
15.2, 58.9, 99.7, 100.2, 101.5, 122.5, 125.8, 126.7, 128.8, 129.2, 129.9,
130.7,132.1,156.7,157.7,162.0,170.9 ppm. Anal.CalcdforC22H21N3O2S:
C, 67.50; H, 5.41; N, 10.73. Found: C, 67.47; H, 5.40; N, 10.66.
References and notes
1. (a) Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH: Weinheim,
Germany, 1995; (b) Chemistry of Triple-Bonded Functional Groups; Patai, S., Ed.;
Wiley: New York, NY, 1994.
2. (a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124,
764; (b) Nakamura, H.; Ohtaka, M.; Yamamoto, Y. Tetrahedron Lett. 2002, 7631.
3. Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004, 69, 5193.
4.3.7. 4-Anilino-5-butoxy-2-methylthio-7-phenyl-5H-pyrano[4,3-
d]pyrimidine 3g. Yellowish solid, yield 84% (method E), mp 108–
109 ꢁC. IR (KBr): nmax¼3445 (NH) cmꢂ1. 1H NMR (300 MHz, CDCl3):

258
I. Cikotiene et al. / Tetrahedron 66 (2010) 251–258
4. Godet, T.; Vaxelaire, C.; Michel, C.; Milet, A.; Belmont, P. Chem.d Eur. J. 2007, 13,
5632.
5. Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. J. Am. Chem. Soc.
2003, 125, 9028.
6. (a) Yue, D.; Della Ca, N.; Larock, R. C. Org. Lett. 2004, 6, 1581; (b) Yue, D.; Della
Ca, N.; Larock, R. C. J. Org. Chem. 2005, 70, 3381.
7. (a) Godet, T.; Bosson, J.; Belmont, P. Synlett 2005, 2786; (b) Kanazawa, C.; Ito, A.;
Terada, M. Synlett 2009, 638.
8. Cikotiene, I.; Morkunas, M.; Motiejaitis, D.; Rudys, S.; Brukstus, A. Synlett 2008,
1693.
9. Cikotiene, I.; Kairys, V.; Buksnaitiene, R.; Morkunas, M.; Motiejaitis, D.; Rudys,
S.; Brukstus, A.; Fernandes, M. X. Tetrahedron 2009, 65, 5752.
10. (a) Lewandos, G. S.; Gregston, D. K.; Nelson, F. R. J. Organomet. Chem.1976,118, 363;
(b)Jong, T.-T.;Leu,S.-J.J. Chem. Soc.,PerkinTrans.11990, 423;(c)Sun,J.;Kozmin,S. A.
Angew. Chem. 2006, 118, 5113; (d) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem.
2006, 118, 8064; (e) Hashmi, A. S. K. Angew. Chem. 2005, 117, 7150; (f) Chen, L.;
Li, C.-J. Adv. Synth. Catal. 2006, 348,1459; (g) Zeni, G.; Larock, R. C. Chem. Rev. 2004,
104, 2285; (h) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079.
11. Representative procedure of addition of water to the triple bond of 6-phenyl-
ethynylpyrimidine-5-carbaldehydes. Synthesis of 4-anilino-6-[(Z)-2-hydroxy-
4-anilino-2-methylthio-6-phenylethynylpyrimidine-5-carbaldehyde (1b) (0.1 g,
0.29 mmol) and silver (I) nitrate (2.45 mg, 0.0145 mmol) in 95% ethanol (3 mL)
was irradiated in a microwave oven at 610 W for 10 min. After heating, the
solution was cooled to room temperature, the solvent was evaporated under
reduced pressure, and the residue was purified by flash column chromatogra-
phy. Yellow solid, yield 79%, mp 162–163 ꢁC (from ethanol). IR (KBr): nmax¼3468
(broad) (OH, NH), 1624 (C]O) cmꢂ1
.
1H NMR (300 MHz, CDCl3):
d
¼2.51 (3H, s,
SCH3), 6.63 (1H, s, CH), 7.08 (1H, t, J¼8.7 Hz, ArH), 7.26–7.32 (2H, m, ArH), 7.36–
7.39 (3H, m, ArH), 7.56–7.59 (2H, m, ArH), 7.82–7.85 (2H, m, ArH), 10.30 (1H, s,
CH), 11.61 (1H, br s, NH), 16.09 (1H, s, OH) ppm 13C NMR (75 Hz, CDCl3):
d
¼13.4,
85.6, 98.9, 121.6, 121.9, 124.3, 125.8, 127.9, 128.1, 130.4, 134.9, 136.7, 156.7, 164.8,
171.9, 187.6 ppm. Anal. Calcd for C20H17N3O2S: C 66.10, H 4.71, N 11.56. Found: C
66.29, H 4.89, N 11.65. This compound in chloroform solution exists as a tau-
tomeric mixture of enol (79%) and keto form (21%).
12. The structures of several starting compounds were optimized using Density
Functional Theory (DFT) methods. It was observed, that the carbonyl group is
turned towards to the NHR0 moiety (in 6-phenylethynylpyrimidine-5-carbal-
dehydes bearing primary amino, alkylamino or aniline group in the position 4
of the pyrimidine ring) or turned towards to the triple bond (in 6-phenyl-
ethynylpyrimidine-5-carbaldehydes bearing N,N-dialkylamino group in the
position 4 of the pyrimidine ring).
2-phenylvinyl]-2-methylthiopyrimidine-5-carbaldehyde (9).
A solution of