Synthesis of substituted pyrido[1,2-a]pyrimidines from 2-arylmethylidene-3- fluoroalkyl-3-oxopropionates

Article abstract of DOI:10.1007/s11172-006-0198-y

Cyclocondensation of 2-arylmethylidene-3-fluoroalkyl-oxopropionates with 2-amino-pyridine occurs at both the polyfluoroacylvinyl and alkoxycarbonylvinyl fragments to give alkyl 4-aryl-2-polyfluoroalkyl-4H-pyrido[1,2-a]pyrimidine-3- carboxylates and 4-aryl

Full text of DOI:10.1007/s11172-006-0198-y

Russian Chemical Bulletin, International Edition, Vol. 54, No. 12, pp. 2841—2845, December, 2005
2841
Synthesis of substituted pyrido[1,2ꢀa]pyrimidines from
2ꢀarylmethylideneꢀ3ꢀf luoroalkylꢀ3ꢀoxopropionates
M. V. Pryadeina, Ya. V. Burgart, M. I. Kodess, and V. I. Saloutinꢀ
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 ul. S. Kovalevskoi/Akademicheskaya, 620219 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 5954. Eꢀmail: saloutin@ios.uran.ru
Cyclocondensation of 2ꢀarylmethylideneꢀ3ꢀfluoroalkylꢀ3ꢀoxopropionates with 2ꢀaminoꢀ
pyridine occurs at both the polyfluoroacylvinyl and alkoxycarbonylvinyl fragments to give alkyl
4ꢀarylꢀ2ꢀpolyfluoroalkylꢀ4Hꢀpyrido[1,2ꢀa]pyrimidineꢀ3ꢀcarboxylates and 4ꢀarylꢀ2ꢀhydroxyꢀ3ꢀ
polyfluoroacylꢀ4Hꢀpyrido[1,2ꢀa]pyrimidines, respectively. When treated with copper(II) acetate,
the pyrido[1,2ꢀa]pyrimidines yield metal complexes.
Key words: cyclocondensation, regioisomerism, 2ꢀarylmethylideneꢀ3ꢀfluoroalkylꢀ3ꢀ
oxopropionate, 2ꢀaminopyridine, pyrido[1,2ꢀa]pyrimidine, complex formation.
Scheme 1
Pyrimidines are essential structural units found in natuꢀ
ral compounds (nucleic acids, vitamin B1), synthetic
drugs (barbiturates), and chemotherapeutic preparations
(fluorouracil).1a,2 Interest in the synthesis of pyrimidine
derivatives is due to their biological activities. 1,3ꢀDiꢀ
carbonyl compounds and their derivatives are widely used
as starting reagents for the synthesis of pyrimidines. Earꢀ
lier,3 we have found that 2ꢀarylmethylideneꢀ3ꢀfluoroalkylꢀ
3ꢀoxopropionates react with 3ꢀaminoꢀ1,2,4ꢀtriazole and
5ꢀaminotetrazole to give 6ꢀalkoxycarbonylꢀ7ꢀalkyl(aryl)ꢀ
5ꢀfluoroalkylꢀ1,2,4ꢀtri(tetr)azolo[1,5ꢀa]pyrimidines.
In the present work, we studied reactions of 2ꢀarylꢀ
methylideneꢀ3ꢀoxoꢀ3ꢀpolyfluoroalkylpropionates 1 with
2ꢀaminopyridine with the aim of obtaining heteroanneꢀ
lated pyrimidines.
We found that in contrast to the previous3 transformaꢀ
tions with aminoazoles, the cyclocondensation of esters
1a—d with 2ꢀaminopyridine is not regioselective since
products of two types 2a—c and 3a—e were obtained
(Scheme 1). The reactions between equimolar amounts
of esters 1 and 2ꢀaminopyridine were carried out in boilꢀ
ing anhydrous benzene. Monitoring of the process by TLC
revealed the immediate formation of two products. In
other solvents (ethanol, diethyl ether, and DMF), the
reactions were less selective and yielded difficultꢀtoꢀsepaꢀ
rate mixtures of products, the conversions of the starting
esters 1 being incomplete. Note that heterocycles 2 and 3
were not obtained by threeꢀcomponent condensation of a
3ꢀoxo ester, an aldehyde, and 2ꢀaminopyridine (in conꢀ
trast to analogous reactions with aminoazoles).3
R = Et, Ar = Ph, RF = HCF2 (1a, 2a, 3a), CF3 (1b, 2b, 3b);
R = Et, Ar = MeOC6H4, RF = CF3 (1c, 3c);
R = Me, Ar = Ph, RF = H(CF2)2 (1d, 2c, 3d);
R = Me, Ar = MeOC6H4, RF = H(CF2)2 (1e, 3e);
Ar = Ph (4a), 4ꢀMeOC6H4 (4b)
tacked by a nucleophile. At the same time, 2ꢀaminoꢀ
pyridines in cyclocondensation with 1,3ꢀdicarbonyl comꢀ
pounds and their derivatives can act as N,Nꢀ or N,Cꢀdiꢀ
nucleophiles.4—6 Thus, the reactions under study can theoꢀ
retically yield eight heterocyclic structures, depending on
2ꢀArylmethylideneꢀ3ꢀoxopropionates 1 contain three
nonequivalent electrophilic reactive sites (fluoroacyl
group, ester fragment, and C=C bond) that can be atꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2745—2749, December, 2005.
1066ꢀ5285/05/5412ꢀ2841 © 2005 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005
Pryadeina et al.
the electrophilic site in ester 1 under an initial attack by
the amine and on the nucleophilic site (N or C) in
2ꢀaminopyridine involved in subsequent cyclization.
The structures of heterocycles 3 were determined
chemically. It was found that compounds 3a—e are unꢀ
stable and partially decompose in boiling ethanol to give
(E)ꢀNꢀ(pyridinꢀ2ꢀyl)ꢀ3ꢀarylpropꢀ2ꢀenamides 4a,b (see
Scheme 1). Their structures were proven by IR and 1H and
13C NMR spectroscopy. For more exact signal assignꢀ
1
Elemental analysis data and IR and H NMR spectra
suggest that products 2a—c are alkoxycarbonylpyriꢀ
do[1,2ꢀa]pyrimidines formed by cyclocondensation of esꢀ
ters 1 through the polyfluoroacylvinyl fragment with the
N,Nꢀsites of 2ꢀaminopyridine. However, the aforemenꢀ
tioned data was insufficient for making our choice beꢀ
tween two equiprobable structures 2A and 2B.
1
ments in the H and 13C NMR spectra of compounds 4,
1
1
the 2D H—13C HSQC and 2D H—13C HMBC NMR
spectra of compound 4b were recorded. The 2D HSQC
data allowed the assignment of the protonated C atoms,
which were exactly located in the molecule from the
2D HMBC data (see Experimental and Table 1). Amides
4a,b can be obtained only from pyrido[1,2ꢀa]pyrimidines
3A via their deacylation followed by cleavage of the
C(4)—N(5) bond of the heterocycle, because aromatic
azaheterocycles, especially with the N atom as a bridgeꢀ
head, undergoes relatively easy opening.1b
Therefore, heterocycles 3a—e are 4ꢀarylꢀ2ꢀhydroxyꢀ
3ꢀpolyfluoroacylꢀ4Hꢀpyrido[1,2ꢀa]pyrimidines 3A. Their
formation involves initial addition of the amino group of
2ꢀaminopyridine to the alkoxycarbonyl residue of ester 1
followed by cyclization through the C=C bond and the
pyridine N atom (see Scheme 1).
It should be noted that the yields of the products varꢀ
ied with the size of the fluoroalkyl substituent. For inꢀ
stance, with an increase in its size, the yield of 3ꢀpolyꢀ
fluoroacylpyrido[1,2ꢀa]pyrimidine 3 increased, while the
yield of 3ꢀalkoxycarbonylpyrido[1,2ꢀa]pyrimidine 2 deꢀ
creased. Apparently, this is due to steric hindrances preꢀ
sented by a bulky polyfluoroalkyl substituent to 2ꢀaminoꢀ
pyridine attacking the acyl C atom.
In addition, the yields of the products depend on the
structure of the arylmethylidene substituent. For instance,
we failed to isolate pyrido[1,2ꢀa]pyrimidines 2d,e (Ar =
4ꢀMeOC6H4; RF = CF3 and R = Et (d) and RF = H(CF2)2
and R = Me (e)) from the reaction products of 4ꢀmethoxyꢀ
phenyl esters 1c,e, although they were detected by TLC
(products 2 and 3 have distinctive features). Apparently,
heterocycles 2d,e cannot be isolated from the reaction
mixture in the individual state because of their high soluꢀ
bilities in virtually all the solvents used.
In contrast to 2ꢀarylmethylideneꢀ3ꢀoxoꢀ3ꢀpolyfluoroꢀ
alkylpropionates 1, the reaction of 2ꢀphenylmethylideneꢀ
acetoacetate yielded a difficultꢀtoꢀseparate mixture from
which no individual products were isolated. Obviously,
this is due to the lowered selectivities of these processes.
Pyrido[1,2ꢀa]pyrimidines 2 and 3 can exhibit not only
potential biological activity but also complexing properꢀ
ties. Indeed, when treated with copper(II) acetate, 2ꢀhyꢀ
droxyꢀ3ꢀpolyfluoroacylpyrido[1,2ꢀa]pyrimidines 3d,e
formed copper chelate complexes 5a,b (Scheme 2) due to
the presence of the enolized 1,3ꢀdicarbonyl fragment.
The structures of compounds 2 were determined from
1
the 2D H—13C HMBC NMR spectrum of product 2c.
An analysis of the 2D HMBC spectrum revealed that the
signal at δ 138.03 (C(6)) shows a cross peak with the
signal at δ 6.51 (s, H(4)) and the signal at δ 61.85 (C(4))
shows a cross peak with the signal at δ 8.18 (dd, H(6),
4
3JH(6),H(7) = 6.8 Hz, JH(6),H(8) = 1.7 Hz); this is unamꢀ
biguous evidence for structure 2A.
A comparison of the 1H and 19F NMR spectra of
compound 2c with those of products 2a,b allowed us to
assign to the latter the structures of alkyl 4ꢀarylꢀ2ꢀ
polyfluoroalkylꢀ4Hꢀpyrido[1,2ꢀa]pyrimidineꢀ3ꢀcarboxyꢀ
lates, which form as the result of the initial addition of the
amino group of 2ꢀaminopyridine to the fluoroacyl fragꢀ
ment of ester 1 followed by cyclization via addition of the
pyridine N atom to the C=C bond (see Scheme 1).
Such a reaction pathway is typical of 2ꢀarylmethylꢀ
ideneꢀ3ꢀfluoroalkylꢀ3ꢀoxopropionates 1, which react with
phenylhydrazine,7 3ꢀaminoꢀ1,2,4ꢀtriazole, and 5ꢀaminoꢀ
tetrazole3 to form heterocycles. However, this is not the
only reaction pathway for 2ꢀaminopyridine since comꢀ
pounds 3 were also isolated from the reaction products,
along with the expected pyrido[1,2ꢀa]pyrimidines 2.
According to elemental analysis data and IR and
1H NMR spectra, products 3 are polyfluoroacylpyriꢀ
do[1,2ꢀa]pyrimidines, whose formation involves the
alkoxycarbonylvinyl fragment of ester 1 and the N,Nꢀsites
of 2ꢀaminopyrimidine. However, the spectral data were
poorly informative, which made it difficult to choose beꢀ
tween two alternative regioisomeric structures 3A and 3B.
Ethyl
4ꢀphenylꢀ2ꢀtrifluoromethylꢀ4Hꢀpyriꢀ
do[1,2ꢀa]pyrimidineꢀ3ꢀcarboxylate 2b reacted with
copper(II) acetate to give complex 6. Apparently, the pyꢀ

Synthesis of pyrido[1,2ꢀa]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005 2843
Scheme 2
Table 1. 13C NMR spectra of compounds 2c, 3d, and 4b in
DMSOꢀd6
Atom
δ (JC,F/Hz)
2c
3d
4b
Ar = Ph (3d, 5a), 4ꢀMeOC6H4 (3e, 5b)
C(1)
C(2)
—
—
160.22
164.39
119.33
147.13 (t,
2JC,F = 25.4)
96.66
61.85
138.03
115.27
139.58
122.49
150.81 (dd,
4JC,F = 3.0,
4JC,F = 1.4)
164.13
ridine N atom is involved in the coordination with the
metal.
C(3)
C(4)
C(6)
С(7)
C(8)
C(9)
C(9a)
86.44
64.84
140.69
55.30
—
Thus, we demonstrated that the cyclization of
2ꢀarylmethylideneꢀ3ꢀfluoroalkylꢀ3ꢀoxopropionates 1 with
2ꢀaminopyridine occurs at both the fluoroacylvinyl and
alkoxycarbonylvinyl fragments to give alkyl 4ꢀarylꢀ2ꢀ
polyfluoroalkylꢀ4Hꢀpyrido[1,2ꢀa]pyrimidineꢀ3ꢀcarboxyꢀ
lates 2 and 4ꢀarylꢀ2ꢀhydroxyꢀ3ꢀpolyfluoroacetylꢀ4Hꢀ
pyrido[1,2ꢀa]pyrimidines 3, respectively. Compounds 2
and 3 form complexes with transition metal ions.
140.00
114.61
144.37
117.68
148.48
—
—
—
—
C(10)
C(11)
170.98 (t,
—
—
2J = 24.8)
110.9 (tt,
1J = 248.2,
2J = 29.5)
112.9 (tt,
1J = 251.4,
2J = 29.4)
51.44
Experimental
IR spectra were recorded on a Perkin—Elmer Spectrum
One spectrometer (Nujol, 400—4000 cm–1). NMR spectra were
recorded on Bruker DRXꢀ400 (400 (1H) and 100 MHz (13C),
SiMe4 as the standard; 376 MHz (19F), C6F6 as the standard)
and Tesla BSꢀ587A spectrometers (75.3 MHz (19F), C6F6 as the
standard). Elemental analysis was carried out on a Perkin—Elmer
PE 2400 II CHNSꢀO analyzer. Mass spectra were recorded on a
Varian MATꢀ311A instrument.
C(12)
C(13)
113.25 (dddd,
1JC,F = 253.5,
1JC,F = 250.8,
2JC,F = 26.8,
2JC,F = 22.8)
110.20 (dddd,
1J = 249.8, 1J = 247.8,
2J = 34.1, J = 27.2)
—
—
—
2
The starting 2ꢀarylmethylideneꢀ3ꢀfluoroalkylꢀ3ꢀoxopropioꢀ
nates 1a—e were prepared according to known procedures.8,9
Reactions of 2ꢀarylmethylideneꢀ3ꢀfluoroalkylꢀ3ꢀoxoproꢀ
pionates 1 with 2ꢀaminopyridine (general procedure). A mixture
of ester 1 (0.01 mol) and 2ꢀaminopyridine (0.01 mol, 0.94 g) in
dry benzene (20 mL) was refluxed for 4—6 days. The precipitate
that formed was filtered off and washed with boiling chloroform
(for compounds b,c, with diethyl ether) to give compounds 3a—e.
The filtrate was concentrated and chromatographed on silica gel
with chloroform as an eluent to give compounds 2a—c.
Ci
Со
Cm
Сp
C(2´)
C(3´)
C(4´)
C(5´)
C(6´)
140.79
125.98
128.87
128.70
—
—
—
—
—
140.66
125.41
128.72
128.02
—
—
—
—
—
127.19
129.43
114.45
160.70
152.27
113.57
138.07
119.25
148.00

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Pryadeina et al.
Ethyl 2ꢀdifluoromethylꢀ4ꢀphenylꢀ4Hꢀpyrido[1,2ꢀa]pyrimiꢀ
dineꢀ3ꢀcarboxylate (2a). The yield was 42%, m.p. 236—238 °C.
Found (%): C, 65.54; H, 4.93; F, 11.36; N, 8.29. C18H16F2N2O2.
2ꢀHydroxyꢀ4ꢀphenylꢀ3ꢀtrifluoroacetylꢀ4Hꢀpyriꢀ
do[1,2ꢀa]pyrimidine (3b). The yield was 25%, m.p. 235—238 °C.
Found (%): C, 60.09; H, 3.48; F, 17.96; N, 8.68. C16H11F3N2O2.
Calculated (%): C, 60.00; H, 3.46; F, 17.80; N, 8.75. IR, ν/cm–1
:
Calculated (%): C, 65.45; H, 4.88; F, 11.50; N, 8.48. IR, ν/cm–1
:
3067, 3030 (C—H); 1684 (C=O); 1637, 1591 (C=C, C=N);
3448, 3340, 2700 (OH); 3098 (C—H); 1677 (C=O); 1645, 1595,
1550 (C=C, C=N); 1202—1098 (C—F). 1H NMR (DMSOꢀd6),
δ: 6.93 (s, 1 H, H(4)); 7.11 (m, 2 H, Ph); 7.27—7.37 (m, 5 H,
1131—1022 (C—F). 1H NMR (DMSOꢀd6), δ: 1.16 (t, 3 H,
3
CH2CH3, JH,H = 7.1 Hz); 4.08, 4.07 (both dq, 1 H each,
CH2CH3, 2JH,H = 10.8 Hz, 3JH,H = 7.1 Hz); 6.47 (d, 1 H, H(4),
H(7), H(9), Ph); 8.18 (ddd, 1 H, H(8), JH(8),H(9) = 8.7 Hz,
3
3
JH,H = 1.4 Hz); 6.77 (td, 1 H, H(7), JH(7),H(6)
=
3JH(7),H(8)
3
=
=
3JH(8),H(7) = 7.3 Hz, 4JH(8),H(6) = 1.4 Hz); 8.80 (br.d, 1 H, H(6),
3JH(6),H(7) = 6.5 Hz); 10.93 (s, 1 H, OH). 19F NMR (DMSOꢀd6),
δ: 92.45 (s, CF3).
4
6.7 Hz, JH(7),H(9) = 1.0 Hz); 7.0 (dd, 1 H, H(9), JH(9),H(8)
4
8.8 Hz, JH(9),H(7) = 1.0 Hz); 7.28—7.37 (m, 5 H, Ph); 7.38 (t,
1 H, HCF2, 2JH,F = 54.5 Hz); 7.57 (ddd, 1 H, H(8), 3JH(8),H(7)
6.7 Hz, 3JH(8),H(9) = 8.8 Hz, 4JH(8),H(6) = 1.4 Hz); 8.06 (dd, 1 H,
=
2ꢀHydroxyꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀtrifluoroacetylꢀ4Hꢀpyriꢀ
do[1,2ꢀa]pyrimidine (3c). The yield was 48%, m.p. 210—211 °C.
Found (%): C, 58.17; H, 3.56; F, 16.48; N, 7.94. C17H13F3N2O3.
H(6), JH(6),H(7) = 6.7 Hz, JH(6),H(8) = 1.4 Hz). 19F NMR
(DMSOꢀd6), δ: 41.83 (m, HCF2, midpoint of the AB system).
Ethyl 4ꢀphenylꢀ2ꢀtrifluoromethylꢀ4Hꢀpyrido[1,2ꢀa]pyrimiꢀ
dineꢀ3ꢀcarboxylate (2b). The yield was 38%, m.p. 145—146 °C.
Found (%): C, 62.33; H, 4.46; F, 16.14; N, 8.17. C18H15F3N2O2.
3
4
Calculated (%): C, 58.29; H, 3.74; F, 16.27; N, 8.00. IR, ν/cm–1
:
3087 (C—H); 3443, 2685 (OH); 1675 (C=O); 1645, 1596, 1552
(C=C, C=N); 1138—1200 (C—F). 1H NMR (DMSOꢀd6), δ:
3.70 (s, 3 H, OMe); 6.83 (s, 1 H, H(4)); 6.88, 7.10 (both d,
Calculated (%): C, 62.07; H, 4.34; F, 16.36; N, 8.04. IR, ν/cm–1
:
2 H each, C6H4, JH,H = 8.7 Hz); 7.29 (dd, 1 H, H(9),
3
3031 (C—H); 1714 (C=O); 1636, 1583, 1530 (C=C, C=N);
1171—1085 (C—F). 1H NMR (DMSOꢀd6), δ: 1.17 (t, 3 H,
3JH(9),H(8) = 8.8 Hz, 4JH(9),H(7) = 1.0 Hz); 7.33 (ddd, 1 H, H(7),
3
4
3JH(7),H(6) = 6.0 Hz, JH(7),H(8) = 7.0 Hz, JH(7),H(9) = 1.0 Hz);
3
3
3
CH2CH3, JH,H = 7.1 Hz); 4.09 (q, 2 H, CH2CH3, JH,H
=
=
8.14 (ddd, 1 H, H(8), 3JH(8),H(9) = 8.8 Hz, JH(8),H(7) = 7.0 Hz,
3
3
7.1 Hz); 6.53 (s, 1 H, H(4)); 6.89 (td, 1 H, H(7), JH(7),H(6)
4JH(8),H(6) = 1.1 Hz); 8.82 (dd, 1 H, H(6), JH(6),H(7) = 6.0 Hz,
3JH(7),H(8) = 6.8 Hz, JH(7),H(9) = 1.1 Hz); 7.07 (dd, 1 H, H(9),
4JH(6),H(8) = 1.1 Hz); 10.90 (s, 1 H, OH). 19F NMR (DMSOꢀd6),
δ: 92.42 (s, CF3).
4
3JH(9),H(8) = 8.2 Hz, JH(9),H(7) = 1.1 Hz); 7.24—7.37 (m, 5 H,
4
3
2
Ph); 7.65 (ddd, 1 H, H(8), JH(8),H(9) = 8.2 Hz, JH(8),H(7)
6.8 Hz, JH(8),H(6) = 1.6 Hz); 8.16 (dd, 1 H, H(6), JH(6),H(7)
6.8 Hz, JH(6),H(8) = 1.6 Hz). 19F NMR (DMSOꢀd6), δ: 105.49
=
=
2ꢀHydroxyꢀ4ꢀphenylꢀ3ꢀ(2,2,3,3ꢀtetrafluoropropionyl)ꢀ
4Hꢀpyrido[1,2ꢀa]pyrimidine (3d). The yield was 56%, m.p.
245—247 °C. Found (%): C, 57.79; H, 3.49; F, 21.35; N, 7.96.
C17H12F4N2O2. Calculated (%): C, 57.96; H, 3.43; F, 21.57;
N, 7.95. IR, ν/cm–1: 3340, 2712 (OH); 3080 (C—H); 1655
(C=O); 1593, 1565, 1519 (C=C, C=N); 1129—1100 (C—F).
1H NMR (DMSOꢀd6), δ: 6.97 (s, 1 H, H(4)); 7.08 (dddd, 1 H,
4
3
4
(s, CF3).
Methyl 4ꢀphenylꢀ2ꢀ(2,2,3,3ꢀtetrafluoroethyl)ꢀ4Hꢀpyriꢀ
do[1,2ꢀa]pyrimidineꢀ3ꢀcarboxylate (2c). The yield was 30%, m.p.
126—128 °C. Found (%): C, 58.89; H, 3.71; F, 20.55; N, 7.78.
C18H14F4N2O2. Calculated (%): C, 59.03; H, 3.85; F, 20.74;
N, 7.65. IR, ν/cm–1: 3037 (C—H); 1696 (C=O); 1635, 1569
(C=C, C=N); 1120—1077 (C—F). 1H NMR (DMSOꢀd6), δ:
2
2
3
(CF2)2H, JH,F(2A) = 53.5 Hz, JH,F(2B) = 55.3 Hz, JH,F(1B)
=
10.0 Hz, 3JH,F(1A) = 4.3 Hz); 7.09 (m, 2 H, Ph); 7.25—7.39 (m,
5 H, H(7), H(9), Ph); 8.19 (ddd, 1 H, H(8), 3JH(8),H(9) = 8.7 Hz,
4
3.63 (s, 3 H, OMe); 6.51 (s, 1 H, H(4)); 6.89 (ddd, 1 H, H(7),
3JH(8),H(7) = 7.3 Hz, JH(8),H(6) = 1.4 Hz); 8.83 (dd, 1 H, H(6),
4
4
3JH(7),H(8)
=
3JH(7),H(6) = 6.8 Hz, JH(7),H(9) = 1.3 Hz); 6.92
3JH(6),H(7) = 6.8 Hz, JH(6),H(8) = 1.4 Hz); 10.92 (s, 1 H, OH).
2
2
(dddd, 1 H, H(CF2)2, JH,F(2)B = 54.3 Hz, JH,F(2)A = 52.1 Hz,
19F NMR (DMSOꢀd6), δ: 24.78 (m, 2 F, HCF2CF2, AB system,
3JH,F(1)A = 8.8 Hz, JH,F(1)B = 2.3 Hz); 7.01 (dd, 1 H, H(9),
∆
= 2.46, J2AB = 297.3 Hz, JF(2A),H = 53.5 Hz, JF(2B),H =
3
2
2
2AB
3JH(9),H(8) = 9.0 Hz, JH(9),H(7) = 1.3 Hz); 7.26—7.37 (m, 5 H,
55.3 Hz, JF(2A),F(1B) = 11.5 Hz, JF(2B),F(1A) = 10 Hz); 40.97
4
3
3
3
3
Ph); 7.64 (ddd, 1 H, H(8), JH(8),H(9) = 9.0 Hz, JH(8),H(7)
6.8 Hz, JH(8),H(6) = 1.7 Hz); 8.18 (dd, 1 H, H(6), JH(6),H(7)
6.8 Hz, JH(6),H(8) = 1.7 Hz). 19F NMR (DMSOꢀd6), δ: 26.53
=
=
(m, 2 F, HCF2CF2, AB system, ∆ = 5.89, J1AB = 258.5 Hz,
1AB
4
3
3
3JF(1A),F(2B) 3JF(1B),F(2B) 3JF(1B),H = 10 Hz, JF(1A),F(2A)
= = =
4
3JF(1A),H = 4.3 Hz). MS (EI, 70 eV), m/z (Irel (%)): 352 [M]+
(3); 275 [M – Ph]+ (4); 259 [M – C5H4N – NH]+ (100);
223 [M – CO(CF2)2H]+ (100); 102 [CH – Ph]+ (10); 78
[C5H4N]+ (9). The 13C NMR spectrum is given in Table 1.
2ꢀHydroxyꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ(2,2,3,3ꢀtetrafluoroꢀ
propionyl)ꢀ4Hꢀpyrido[1,2ꢀa]pyrimidine (3e). The yield was 52%,
m.p. 224—225 °C. Found (%): C, 56.51; H, 3.87; F, 19.72;
N, 7.26. C18H14F4N2O3. Calculated (%): C, 56.55; H, 3.69;
F, 19.88; N, 7.33. IR, ν/cm–1: 3474, 3310, 2689 (OH); 3151,
3096 (C—H); 1660 (C=O); 1593, 1547, 1510 (C=C, C=N);
1121—1100 (C—F). 1H NMR (DMSOꢀd6), δ: 3.69 (s, 3 H,
OMe); 6.87* (s, 1 H, H(4)); 6.87*, 7.09 (both d, 2 H each,
(m, 2 F, HCF2CF2, AB system, ∆
= 3.78, J2AB = 291.3 Hz,
2AB
2JF(2B),H = 54.3 Hz, 2JF(2A),H = 52.1 Hz, 3JF(2A),F(1B) = 15.3 Hz,
3JF(2B),F(1A) = 14.5 Hz, 2JF(2B),F(1B) = 8.2 Hz); 41.46 (dddd, 1 F,
HCF2CF2, J1AB = 268.2 Hz, 3JF(1B),F(2A) = 15.3 Hz, 3JF(1A),H
8.8 Hz, 3JF3(1B),F(2B) = 8.2 Hz); 50.46 (dd, 1 F, HCF2CF2, J1AB
=
=
268.2 Hz, JF(2A),F(1B) = 15.3 Hz). The 13C NMR spectrum is
given in Table 1.
3ꢀDifluoroacetylꢀ2ꢀhydroxyꢀ4ꢀphenylꢀ4Hꢀpyrido[1,2ꢀa]pyriꢀ
midine (3a). The yield was 47%, m.p. 246—248 °C. Found (%):
C, 63.42; H, 3.84; F, 12.43; N, 9.13. C16H12F2N2O2. Calcuꢀ
lated (%): C, 63.58; H, 4.00; F, 12.56; N, 9.25. IR, ν/cm–1
:
3
2
3090 (C—H); 2690 (OH); 1660 (C=O); 1580, 1540, 1500 (C=C,
C6H4, JH,H = 8.7 Hz); 7.12 (dddd, 1 H, (CF2)2H, JH,F(2A)
=
=
C=N); 1100—1090 (C—F). 1H NMR (DMSOꢀd6), δ: 6.90 (s,
53.4 Hz, JH,F(2B) = 54.6 Hz, JH,F(1B) = 9.4 Hz, JH,F(1A)
2.5 Hz); 7.32 (br.d, 1 H, H(9), JH(9),H(8) = 8.6 Hz); 7.33 (br.t,
1 H, H(7), JH(7),H(6) = 6.9 Hz); 8.14 (br.t, 1 H, H(8),
3JH(8),H(9) = 8.6 Hz); 8.84 (br.d, 1 H, H(6), 3JH(6),H(7) = 6.9 Hz);
2
3
3
2
3
1 H, H(4)); 7.04 (t, 1 H, HCF2, JH,F = 55.6 Hz); 7.09—7.37
3
3
(m, 7 H, H(7), H(9), Ph); 8.12 (t, 1 H, H(8), JH(8),H(9)
=
3JH(8),H(7) = 7.3 Hz); 8.71 (dd, 1 H, H(6), JH(6),H(7) = 5.6 Hz,
4JH(6),H(8) = 1.5 Hz); 10.92 (br.s, 1 H, OH). 19F NMR
(DMSOꢀd6), δ: 37.79 (d, HCF2, 2JF,H = 55.6 Hz).
3
* The signals overlap.

Synthesis of pyrido[1,2ꢀa]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005 2845
F, 19.84; N, 7.31. IR, ν/cm–1: 1660 (C=O); 1594, 1563 (C=C,
10.89 (br.s, 1 H, OH). 19F NMR (DMSOꢀd6), δ: 23.50 (m, 2 F,
2
HCF2CF2, AB system, ∆ = 2.26, JAB = 297.8 Hz, JF(2A),H
=
C=N); 1097—1166 (C—F).
B
2
3
53.4 Hz, JF(2B),H = 54.6 Hz, JF(2A),F(1B) = 14.2 Hz,
Bis{4ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ(2,2,3,3ꢀtetrafluoropropionyl)ꢀ
4Hꢀpyrido[1,2ꢀa]pyrimidinꢀ2ꢀolato}copper(II) (5b). The yield was
85%, m.p. 210—212 °C. Found (%): C, 52.45; H, 3.30; F, 18.20;
N, 6.75. C36H28CuF8N4O6. Calculated (%): C, 52.21; H, 3.41;
F, 18.34; N, 6.77. IR, ν/cm–1: 1636 (C=O); 1593, 1563 (C=C,
C=N); 1180—1109 (C—F).
2
JF(2B),F(1A) = 12.8 Hz); 38.03 (ddd, 1 F, HCF2CF2, JF,F
=
258.7 Hz, JF(1B),F(2A) = 14.2 Hz, 3JF(1B),H = 9.4 Hz); 43.88 (dd,
1 F, HCF2CF2, JF,F = 258.7 Hz, JF(1A),F(2B) = 12.8 Hz). MS
(EI, 70 eV), m/z (Irel (%)): 382 [M]+ (1); 354 [M – H2CN]+ (2);
253 [M – CO(CF2)2H]+ (100); 289 [M – C5H4N – NH]+
(100); 132 [CH – C6H4 – OMe]+ (15); 89 [H(CF2)2]+ (7); 78
[C5H4N]+ (39).
Bis(3ꢀethoxycarbonylꢀ4ꢀphenylꢀ2ꢀtrifluoromethylꢀ4Hꢀpyriꢀ
do[1,2ꢀa]pyrimidine)diacetatocopper(II) (6). The yield was 93%,
m.p. 146—148 °C. Found (%): C, 54.25; H, 4.25; F, 13.21;
N, 6.09. C40H36CuF6N4O8. Calculated (%): C, 54.70; H, 4.13;
F, 12.98; N, 6.38. IR, ν/cm–1: 1714 (C=O); 1583, 1530 (C=C,
C=N); 1179—1058 (C—F).
(E)ꢀNꢀ(Pyridinꢀ2ꢀyl)cinnamamide (4a). Compound 3d
(0.01 mol) was refluxed in ethanol (10 mL) for 2 h. The reaction
mixture was concentrated and diethyl ether (10 mL) was added.
The precipitate that formed was filtered off and recrystalꢀ
lized from hexane to give compound 4a (1.86 g, 83%), m.p.
127—128 °C. Found (%): C, 74.62; H, 5.25; N, 12.30.
C14H12N2O. Calculated (%): C, 74.99; H, 5.39; N, 12.49. IR,
ν/cm–1: 3324, 1578 (NH); 3102 (C—H); 1694 (C=O, amide);
1647, 1634 (C=C, C=N). 1H NMR (DMSOꢀd6), δ: 7.07 (d,
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos. 03ꢀ03ꢀ33118
and 05ꢀ03ꢀ32384), the Council on Grants of the Presiꢀ
dent of the Russian Federation (Program for State Supꢀ
port of Leading Scientific Schools of the Russian Federaꢀ
tion (Grant NShꢀ1766.2003.3), and the Russian Foundaꢀ
tion for Promotion of Home Science.
3
1 H, H(2), JH(2),H(3) = 15.8 Hz); 7.13 (ddd, 1 H, H(5´),
3
4
3JH(5´),H(4´) = 7.3 Hz, JH(5´),H(6´) = 4.9 Hz, JH(5´),H(3´)
=
1.0 Hz); 7.44 (m, 3 H, Ph); 7.62 (m, 2 H, Ph); 7.65 (d, 1 H,
H(3), 3JH(3),H(2) = 15.8 Hz); 7.82 (ddd, 1 H, H(4´), 3JH(4´),H(3´)
=
8.4 Hz, 3JH(4´),H(5´) = 7.3 Hz, 4JH(4´),H(6´) = 1.9 Hz); 8.25 (br.d,
3
1 H, H(3´), JH(3´),H(4´) = 8.4 Hz); 8.35 (ddd, 1 H, H(6´),
References
4
5
3JH(6´),H(5´) = 4.9 Hz, JH(6´),H(4´) = 1.9 Hz, JH(6´),H(3´)
=
1.0 Hz); 10.70 (s, 1 H, NH).
1. Comprehensive Organic Chemistry, Eds S. D. Barton and W. D.
Ollis, Pergamon Press, New York, 1979.
2. Heterocyclic Compounds, Ed. R. C. Elderfield, J. Wiley and
Sons, New York, 1957.
3. M. V. Pryadeina, Ya. V. Burgart, V. I. Saloutin, M. I. Kodess,
E. N. Ulomskii, and V. L. Rusinov, Zh. Org. Khim., 2004, 40,
938 [Russ. J. Org. Chem., 2004, 40 (Engl. Transl.)].
4. K. V. Vatsuro and G. L. Mishchenko, Imennye reaktsii v
organicheskoi khimii [Named Organic Reactions], Khimiya,
Moscow, 1976, p. 217 (in Russian).
5. J. C. Sloop, C. L. Bumgardner, and W. D. Loehle, J. Fluor.
Chem., 2002, 118, 135.
6. F. A. Selimov, U. M. Dzhemilev, and O. A. Ptashko,
Metallokompleksnyi kataliz v sinteze piridinovykh osnovanii [Caꢀ
talysis by Metal Complexes in the Synthesis of Pyridine Bases],
Khimiya, Moscow, 2003, p. 239 (in Russian).
7. M. V. Pryadeina, Ya. V. Burgart, M. I. Kodess, V. I. Saloutin,
and O. N. Chupakhin, Izv. Akad. Nauk, Ser. Khim., 2004,
1210 [Russ. Chem. Bull., Int. Ed., 2004, 53, 1261].
8. M. V. Pryadeina, O. G. Kuzueva, Ya. V. Burgart, and V. I.
Saloutin, Zh. Org. Khim., 2002, 38, 244 [Russ. J. Org. Chem.,
2002, 38, 224 (Engl. Transl.)].
9. M. V. Pryadeina, O. G. Kuzueva, Ya. V. Burgart, V. I.
Saloutin, K. A. Lyssenko, and M. Yu. Antipin, J. Fluor. Chem.,
2002, 110, 1.
(E)ꢀNꢀ(Pyridinꢀ2ꢀyl)ꢀ3ꢀ(4ꢀmethoxyphenyl)propꢀ2ꢀenamide
(4b) was obtained analogously from compound 3e (0.01 mol).
The yield of compound 4b was 1.74 g (80%), m.p. 120—122 °C.
Found (%): C, 70.79; H, 5.66; N, 10.99. C12H13N2O2. Calcuꢀ
lated (%): C, 70.85; H, 5.55; N, 11.02. IR, ν/cm–1: 3244 (NH);
3042 (C—H); 1693 (C=O, amide); 1629, 1605 (C=C, C=N).
1H NMR (DMSOꢀd6), δ: 3.81 (s, 3 H, OMe); 6.91 (d, 1 H,
H(2), 3JH(2),H(3) = 15.6 Hz); 7.02 (d, 2 H, C6H4, 3JH,H = 8.9 Hz);
7.11 (ddd, 1 H, H(5´), JH(5´),H(4´) = 7.2 Hz, JH(5´),H(6´) = 4.9 Hz,
JH(5´),H(3´) = 1.1 Hz); 7.57 (d, 2 H, C6H4, 3JH,H = 8.9 Hz); 7.59
3
(d, 1 H, H(3), JH(3),H(2) = 15.6 Hz); 7.80 (ddd, 1 H, H(4´),
3
4
3JH(4´),H(3´) = 8.5 Hz, JH(4´),H(5´) = 7.2 Hz, JH(4´),H(6´)
=
3
1.9 Hz); 8.24 (ddd, 1 H, H(3´), JH(3´),H(4´) = 8.5 Hz,
JH(3´),H(5´) = 1.1 Hz, JH(3´),H(6´) = 0.9 Hz); 8.34 (ddd, 1 H,
H(6´), JH(6´),H(5´) = 4.9 Hz, JH(6´),H(4´) = 1.9 Hz, JH(6´),H(3´)
0.9 Hz); 10.59 (s, 1 H, NH). MS (EI, 70 eV), m/z (Irel (%)): 254
[M]+ (29); 226 [M – H2CN]+ (14); 161 [M – C5H4NNH]+
(100); 133 [C6H4 – OMe – CH=CH]+ (28); 77 [Ph]+ (9). The
13C NMR spectrum is given in Table 1.
Synthesis of copper(II) complexes 5a,b and 6 (general proceꢀ
dure). A solution of compound 2 or 3 (0.01 mol) in acetone
(5 mL) was mixed with copper(II) acetate dihydrate (0.005 mol)
in water (5 mL). The resulting oil was subjected to extraction
with chloroform. The solvent was removed and the solid residue
was reprecipitated from acetone with water and dried in vacuo.
Bis{4ꢀphenylꢀ3ꢀ(2,2,3,3ꢀtetrafluoropropionyl)ꢀ4Hꢀpyriꢀ
do[1,2ꢀa]pyrimidinꢀ2ꢀolato}copper(II) (5a). The yield was 90%,
m.p. 224—226 °C. Found (%): C, 53.19; H, 3.05; F, 19.75;
N, 7.17. C34H22CuF8N4O4. Calculated (%): C, 53.30; H, 2.98;
=
Received June 24, 2005;
in revised form September 21, 2005