Single-step synthesis of substituted 7-aminopyrano[2,3-d]pyrimidines

Article abstract of DOI:10.1007/s11172-005-0128-4

A single-step method for the synthesis of substituted 7-aminopyrano[2,3-d] pyrimidines was developed. The method involves a three-component reaction of barbituric acid or 4,6-dihydroxypyrimidine with aromatic aldehydes and malononitrile in DMF in the pres

Full text of DOI:10.1007/s11172-005-0128-4

2342
Russian Chemical Bulletin, International Edition, Vol. 53, No. 10, pp. 2342—2344, October, 2004
Singleꢀstep synthesis of substituted 7ꢀaminopyrano[2,3ꢀd]pyrimidines
ꢀ
A. A. Shestopalov, L. A. Rodinovskaya, A. M. Shestopalov, and V. P. Litvinov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
Eꢀmail: vpl@ioc.ac.ru
A singleꢀstep method for the synthesis of substituted 7ꢀaminopyrano[2,3ꢀd]pyrimidines
was developed. The method involves a threeꢀcomponent reaction of barbituric acid or
4
,6ꢀdihydroxypyrimidine with aromatic aldehydes and malononitrile in DMF in the presence
of Nꢀmethylmorpholine as a catalyst.
Key words: malononitrile, barbituric acid, 4,6ꢀdihydroxypyrimidine, pyrano[2,3ꢀd]pyriꢀ
midines.
Substituted 2ꢀaminoꢀ4Hꢀpyrans are of great practical
of aldehydes 1, malononitrile (2), and barbituric acid (3)
(Scheme 1). It was found that these reactions in DMF in
the presence of Nꢀmethylmorpholine at 90—95 °C give
interest. Some of them have been found to exhibit antiꢀ
bacterial and anticancer activities, while others can poꢀ
tentially be used to cure people of Alzheimer's and
3
earlier reported 7ꢀaminoꢀ5ꢀarylꢀ6ꢀcyanoꢀ2,4ꢀdioxoꢀ
1
,2
Parkinson's diseases and various types of sclerosis. Earꢀ
lier, these compounds were synthesized in two steps:
2,3,4,5ꢀtetrahydroꢀ1Hꢀpyrano[2,3ꢀd]pyrimidines 8. Unꢀ
der these conditions, the yields of compounds 8a,b were
85 and 89%, respectively, which is comparable with the
yields of pyrano[2,3ꢀd]pyrimidines obtained at the secꢀ
ond step of the previously reported reactions from the
corresponding arylidenemalononitriles and barbituric
(
1) first, arylidenemalononitrile was synthesized from an
aldehyde and malononitrile and then its reaction with
,3ꢀdicarbonyl compound was carried out or (2) first, an
α,βꢀunsaturated carbonyl compound was synthesized from
an aldehyde and 1,3ꢀdicarbonyl compound (ethyl acetoacꢀ
etate or barbituric acid) and then the reaction with
malononitrile was carried out.1,2
With the aim of developing a singleꢀstep method for
the synthesis of 2ꢀaminoꢀ4Hꢀpyrans annelated with the
pyrimidine ring, we studied threeꢀcomponent reactions
1
3
acid (87 and 92%) and even exceed them by 12—15%
with respect to the total yield after the two steps.
The high regioselectivity of this reaction is probꢀ
ably due to a strict sequence of transformations (see
Scheme 1). Apparently, electrophilic olefin 4 (through
the Knoevenagel reaction) and nucleophilic barbiturate
Scheme 1
1
, 8: Ar = Ph (a), 4ꢀClC H (b)
6 4
Reagents and conditions: i. DMF, Nꢀmethylmorpholine, 15 min, 90—95 °C.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2242—2244, October, 2004.
1
066ꢀ5285/04/5310ꢀ2342 © 2004 Springer Science+Business Media, Inc.

Synthesis of 7ꢀaminopyrano[2,3ꢀd]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
2343
anion 5 are initially generated simultaneously from the
starting compounds in the presence of a base. A subseꢀ
quent Michael reaction of intermediates 4 and 5 yields
adduct 6 which undergoes Thorpe—Ziegler intramolecuꢀ
lar cyclization into iminopyran 7. The 1,3ꢀsigmatropic
shift results in aminopyrans 8. The structures of products
Scheme 2
8
a,b were confirmed by a comparison of their IR and
1
H NMR spectra and melting points with the literature
data for these compounds.
3
We discovered that 4,6ꢀdihydroxypyrimidine (9) also
enters into this reaction under analogous conditions to
give substituted 7ꢀaminopyrano[2,3ꢀd]pyrimidines 10a—d
in 88—92% yields (Scheme 2).
Apparently, the reaction between compounds 1, 2,
and 9 follows Scheme 1, occurring as a sequence of transꢀ
formations: Knoevenagel reaction → Michael reacꢀ
tion → Thorpe—Ziegler reaction.
Ar = 4ꢀМеOOCC6H4 (1c, 10a), 4ꢀEtOC6H4 (1d, 10b),
2
ꢀCF C H (1e, 10c), 3,4ꢀ(MeO) C H (1f, 10d)
3 6 4 2 6 3
Products 10a—d are highꢀmelting colorless powders.
They are insoluble in most organic solvents, which makes
it difficult to study their tautomerism. However, by comꢀ
Reagents and conditions: i. DMF, Nꢀmethylmorpholine,
5 min, 90—95 °C.
1
1
paring their IR and H NMR spectra with relevant data
can assume that the compounds obtained exist in one
tautomeric form, namely, as 7ꢀaminoꢀ5ꢀarylꢀ6ꢀcyanoꢀ4ꢀ
oxoꢀ4,5ꢀdihydroꢀ3Hꢀpyrano[2,3ꢀd]pyrimidines 10. The
3
for compounds 8 and 2Hꢀpyrano[3,2ꢀc]pyridineꢀ2,5ꢀ
4
4,5
diones or 2Hꢀpyrano[2,3ꢀd]pyridazineꢀ2,5ꢀdiones, one
Table 1. Physicochemical and spectral properties of 7ꢀaminoꢀ5ꢀarylꢀ6ꢀcyanoꢀ4ꢀoxoꢀ4,5ꢀdihydroꢀ3Hꢀpyrano[2,3ꢀd]pyrimidines 10a—d
Comꢀ M.p. Yield Found
Molecular
formula
IR, ν/cm–1
1H NMR, δ (J/Hz)
H(2) NH2 NH
(
%)
N
poꢀ
/°С
(%) Calculated
δ(NH ), NH2 C≡N H(5)
R
2
und
C
H
CONH
(s, 1 H) (s, 1 H) (s, 2 H) (s, 1 H)
1
1
0a 293—295 87 59.48 3.97 16.95 C H N O 1638, 3198, 2196 4.51
8.12
7.14
12.68 3.82 (s, 3 H, Me);
7.34, 7.90 (both d,
16
12
4
4
5
9.26 3.73 17.28
1672, 3264,
1
1
695, 3388,
710 3404
2 H each, C H ,
6
4
J = 7.9)
0b 274—276 92 61.72 4.37 17.83 C H N O 1637, 3190, 2195 4.34
8.11
7.08
12.68 1.29 (t, 3 H, Me,
J = 7.9); 3.98
16
14
4
3
6
1.93 4.55 18.05
1675, 3244,
689 3375,
402
1
(q, 2 H, CH2,
J = 7.9); 6.84,
3
7
.11 (both d, 2 H
each, C H ,
6
4
J = 7.8)
1
0c 289—291 90 53.72 2.85 16.54 C H F N O 1634, 3175, 2198 4.79
8.12
7.11
12.61 7.28 (d, 1 H,
1
5
9
3
4
2
5
3.90 2.71 16.76
1675, 3250,
687 3386,
400
C H , J = 7.3);
7.41 (dd, 1 H,
6
4
1
3
C H , J = 7.3,
6
4
J = 7.1); 7.58
dd, 1 H, C H ,
(
6
4
J = 7.1, J = 6.9);
.65 (d, 1 H,
C H , J = 6.9)
7
6
4
1
0d 284—286 91 58.53 4.12 17.45 C H N O 1632, 3178, 2195 4.36
8.12
7.10
12.69 3.82 (s, 6 H,
2 Me); 6.65 (d,
1 H, C H ,
16
14
4
4
5
8.89 4.32 17.17
1679, 3262,
689 3374,
408
1
6
3
3
J = 6.7); 6.80
(
s, 1 H, C H );
6
3
6
.87 (d, 1 H,
C H , J = 6.7)
6
3

2344
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
Shestopalov et al.
1H NMR spectra of these compounds contain, apart from
1
and hexane to give spectrally pure compounds 8a,b ( H NMR
1
data). The IR and H NMR spectra of compounds 8a,b agree
signals for the aryl, NH , and H(5) protons, signals for
2
with the literature data.3
the H(2) proton as a singlet at δ 8.11—8.12 and the NH
proton at δ 12.61—12.69. In the presence of other tauꢀ
tomers, the signals for the OH or N(1)H protons should
be shifted upfield to δ 6.5—6.8 because they become
shielded with the aryl substituent or the O atom of the
Compound 8a. Yield 85%, m.p. 209—211 °C (cf. Ref. 3: m.p.
2
2
10—211 °C).
Compound 8b. Yield 89%, m.p. 241—242 °C (cf. Ref. 3: m.p.
40—241 °C).
7
ꢀAminoꢀ5ꢀarylꢀ6ꢀcyanoꢀ4ꢀoxoꢀ4,5ꢀdihydroꢀ3Hꢀpyraꢀ
2
—5
pyran ring. This correlates with the literature data
and
no[2,3ꢀd]pyrimidines 10a—d were obtained as described for comꢀ
pounds 8 from equimolar amounts of the corresponding aldeꢀ
hydes 1c—f, malononitrile (2), and 4,6ꢀdihydroxypyrimidine (9).
Physicochemical and spectral data for compounds 10 are given
in Table 1.
1
the H NMR spectra calculated for all possible tautomers
of pyranopyrimidines 10. The IR spectra of compounds 10
show characteristic absorption bands of the conjugated
CN group and bands due to the stretching and bending
vibrations of the CONH and NH groups (Table 1), which
agree with the literature data.
2
—5
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 02ꢀ03ꢀ
3
3
2063).
Experimental
References
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1
2
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1
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6
(
Engl. Transl.)].
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hexane—acetone (5 : 3) as the eluent; spots were visualized with
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3
4
5
2
7
ꢀAminoꢀ5ꢀarylꢀ6ꢀcyanoꢀ2,4ꢀdioxoꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀ
pyrano[2,3ꢀd]pyrimidines 8a,b. A mixture of aldehyde 1a,b
(
(
0.01 mol), malononitrile (2) (0.01 mol), barbituric acid (3)
0.01 mol), and Nꢀmethylmorpholine (0.2 mL, 0.002 mol) in
4
1
0 mL of freshly distilled DMF was stirred at 90—95 °C for
5 min. The hot solution was filtered through a folded filter,
kept at 4 °C for a day, diluted with water (5—6 mL), and acidiꢀ
fied with 10% HCl (1 mL). The precipitate that formed was
filtered off and washed in succession with hot water, ethanol,
Received March 11, 2004;
in revised form June 9, 2004