Reaction of aromatic aldehydes with β-dicarbonyl compounds in a catalytic system: Piperidinium acetate - 1-butyl-3-methylimidazolium tetrafluoroborate ionic liquid

Article abstract of DOI:10.1007/s11172-005-0386-1

Condensation of aromatic (heteroaromatic) aldehydes with 1,3-dicarbonyl compounds under the 1-butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF₄]) ionic liquid - piperidinium acetate catalytic system (0.2 equiv. of each component) in the absence of a solvent affords, depending on the structures of the reagents, 2-arylidene derivatives of methyl acetoacetate and acetylacetone, diethyl 2,4-bis(trifluoroacetyl)-3-phenylpentanedioate, or dimethyl 2-aryl-4-hydroxy-6-oxocyclohexane-1,3-dicarboxylates. The reactions of the resulting 2-arylidene derivatives with O-methylisourea in the [Bmim][BF ₄] ionic liquid produced methyl 2-methoxy-4-methyl-6- aryldihydropyrimidine-5-carboxylates and 1-(2-methoxy-4-methyl-6- phenyldihydropyrimidin-5-yl)ethanone (mixtures of 3,6- and 1,6-dihydro isomers), which were transformed into the corresponding 3,4-dihydropyrimidin-2(1H)-one derivatives.

Full text of DOI:10.1007/s11172-005-0386-1

Russian Chemical Bulletin, International Edition, Vol. 54, No. 5, pp. 1233—1238, May, 2005
1233
Reaction of aromatic aldehydes with βꢀdicarbonyl compounds
in a catalytic system: piperidinium acetate—1ꢀbutylꢀ3ꢀmethylimidazolium
tetrafluoroborate ionic liquid*
E. S. Putilova, N. A. Troitskii, and S. G. Zlotinꢀ
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: zlotin@ioc.ac.ru
Condensation of aromatic (heteroaromatic) aldehydes with 1,3ꢀdicarbonyl comꢀ
pounds under the 1ꢀbutylꢀ3ꢀmethylimidazolium tetrafluoroborate ([Bmim][BF4]) ionic liqꢀ
uid—piperidinium acetate catalytic system (0.2 equiv. of each component) in the absence of a
solvent affords, depending on the structures of the reagents, 2ꢀarylidene derivatives of methyl
acetoacetate and acetylacetone, diethyl 2,4ꢀbis(trifluoroacetyl)ꢀ3ꢀphenylpentanedioate, or diꢀ
methyl 2ꢀarylꢀ4ꢀhydroxyꢀ6ꢀoxocyclohexaneꢀ1,3ꢀdicarboxylates. The reactions of the resulting
2ꢀarylidene derivatives with Oꢀmethylisourea in the [Bmim][BF4] ionic liquid produced meꢀ
thyl 2ꢀmethoxyꢀ4ꢀmethylꢀ6ꢀaryldihydropyrimidineꢀ5ꢀcarboxylates and 1ꢀ(2ꢀmethoxyꢀ4ꢀmeꢀ
thylꢀ6ꢀphenyldihydropyrimidinꢀ5ꢀyl)ethanone (mixtures of 3,6ꢀ and 1,6ꢀdihydro isomers),
which were transformed into the corresponding 3,4ꢀdihydropyrimidinꢀ2(1H )ꢀone derivatives.
Key words: Knoevenagel condensation, ionic liquids, catalysis, cyclohexanoneꢀ2,4ꢀdiꢀ
carboxylic acids, dihydropyrimidines, 3,4ꢀdihydropyrimidinꢀ2(1H )ꢀones.
Baseꢀcatalyzed condensation of aldehydes with methꢀ
yleneꢀactive compounds (Knoevenagel reaction) is widely
used for the synthesis of polyfunctional organic comꢀ
pounds with different structures.1,2 This reaction is generꢀ
ally performed in polar organic solvents (for example, in
EtOH or THF), which provide good solvation of CHꢀacid
anions and promote dehydration of aldols.3—11 Recently,
the results of investigation of Knoevenagel condensation
in solutions of imidazolium salts with fluorineꢀcontaining
anions have been reported.12—19 The latter belong to moisꢀ
tureꢀresistant ionic liquids (IL) of the second generaꢀ
tion.20—23 The use of this class of solvents made it possible
to decrease the reaction time and increase the yields of
the products.13,16—19 In some cases, the reaction occurs
in the absence of a base catalyst, because IL acts as a
catalyst by itself.18,19 However, IL are of limited usefulꢀ
ness as solvents because of their relatively high cost.24
The published data suggest that catalytic amounts of
IL are sufficient for the Knoevenagel reaction to occur.
The reactions performed directly in a binary mixture of
the starting compounds without a solvent are most promꢀ
ising from the viewpoint of green chemistry.25,26
as a solvent,13,18 on the reaction of aromatic aldehydes
with βꢀdicarbonyl compounds. The reaction was carried
out in the absence of a solvent and a catalyst or in the
presence of piperidinium acetate ([Pip][OAc]) as a base
catalyst for Knoevenagel condensation.5,10 The influence
of IL on the Knoevenagel reaction in the absence of a
solvent has been earlier unknown.
We studied condensation of benzaldehyde (1a) with
methyl acetoacetate (2a) as the model reaction (Scheme 1,
Table 1).
Scheme 1
Cat is a catalyst
We found that compounds 1a and 2a, which do not
react with each other in the absence of a catalyst, give
condensation product 3a (a mixture of Z and E isomers)
upon the addition of 0.2 equiv. of [Bmim][BF4] and/or
[Pip][OAc] to the reaction mixture. The [Bmim][BF4]
salt exhibits low catalytic activity. At 120 °C, the yield
of product 3a is at most 18%. As expected, acetate
[Pip][OAc] proved to be a more active catalyst. In the
To verify this hypothesis, we studied the effect of cataꢀ
lytic amounts of 1ꢀbutylꢀ3ꢀmethylimidazolium tetraꢀ
fluoroborate ([Bmim][BF4]), which has been used earlier
* Dedicated to Academician N. K. Kochetkov on the occasion
of his 90th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1199—1204, May, 2005.
1066ꢀ5285/05/5405ꢀ1233 © 2005 Springer Science+Business Media, Inc.

1234
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 5, May, 2005
Putilova et al.
Table 1. Influence of the additives of [Bmim][BF4] (0.2 equiv.)
and [Pip][OAc] (0.2 equiv.) and the reaction conditions on the
yield of methyl 2ꢀacetylꢀ3ꢀphenylacrylate (3a) produced by conꢀ
densation of benzaldehyde (1a) with methyl acetoacetate (2a) in
a binary solution of the starting compounds
Scheme 2
Additive
τ/h
T/°C Yield of 3a (%)
—
6
4
20
4
120
120
20
0
18
70
85
[Bmim][BF4]
[Pip][OAc]
[Bmim][BF4]—[Pip][OAc]
1: Ar = Ph (a), 4ꢀMeOC6H4 (b), 2ꢀClC6H4 (c)
2: R = OMe (a), Me (b)
20
3
a
b
c
d
e
Ar
Ph
Ph
R
OMe
Me
OMe
Me
OMe
presence of the latter, product 3a was prepared in
70% yield already at 20 °C. The best results were obtained
with the use of the combined [Bmim][BF4]—[Pip][OAc]
salt system (0.2 equiv. of each component). In this case,
the yield of ketoester 3a was as high as 85%, the reacꢀ
tion time being substantially shorter. Apparently, the
[Bmim][BF4] and [Pip][OAc] salts complement each
other under the reaction conditions: [Pip][OAc] acts as a
base, whereas [Bmim][BF4] stabilizes the carbanion of
the CHꢀacid (presumably, through hydrogen bonding with
the involvement of the proton at position 2 of the imidꢀ
azole ring27).
4ꢀMeOC6H4
4ꢀMeOC6H4
2ꢀClC6H4
The use of the [Bmim][BF4]—[Pip][OAc] catalytic
system in condensation of various aldehydes and CHꢀacids
demonstrated that, depending on the structures of the
reagents, the reaction can afford different products
(Table 2). For example, benzaldehyde (1a), 4ꢀmethoxyꢀ
benzaldehyde (1b), and 2ꢀchlorobenzaldehyde (1c) conꢀ
taining either an inactivated or sterically hindered alꢀ
dehyde group react with methyl acetoacetate (2a)
Table 2. Comparative estimates of the yields of the condensation products of aldehydes 1a—i with methyl
acetoacetate (2a), acetylacetone (2b) and ethyl trifluoroacetylacetate (2c) under different conditions
Reagents
Catalytic system*
Condensation
product
Yield (%)
B.p./°C (p/Torr)
[m.p./°C]
1а + 2а
1a + 2b
[Bmim][BF4]—[Pip][OAc]
EtOH (30)—[Pip][OAc] (1)
[Bmim][BF4]—[Pip][OAc]
THF (25)—СuCl2 (cat.)
[Bmim][BF4]—[Pip][OAc]
[Bmim][BF4]—[Pip][OAc]
C6H6 (25)—Piperidine (1)
[Bmim][BF4]—[Pip][OAc]
3a
3b
73
122—123.5 (3)
140—142 (3)
855
75
98 7
82
90
53 8
85
1a + 2c
1b + 2a
4
3c
[183—186]
135.5—137 (3)
1b + 2b
3d
156—157 (3)
[62—64]
[49—51]8
C6H6 (25)—Piperidine (1)
[Bmim][BF4]—[Pip][OAc]
C6H6 (25)—[Pip][OAc] (1)
[Bmim][BF4]—[Pip][OAc]
MeOH (25)—Piperidine (1)
[Bmim][BF4]—[Pip][OAc]
MeOH (25)—Piperidine (1)
[Bmim][BF4]—[Pip][OAc]
[Bmim][BF4]—[Pip][OAc]
EtOH (30)—Piperidine (1)
[Bmim][BF4]—[Pip][OAc]
EtOH (30)—Piperidine (1)
[Bmim][BF4]—[Pip][OAc]
64 8
80
1c + 2a
1d + 2a
1e + 2a
3e
5a
5b
153—155 (3)
195—196 (10)
[174—176]
[183—185]
[168—169]
[175—177]
[162—164]
[193—195]
[193.5—194.5]
[191—192]
[191—192]
[167—168]
84 10
87
78 11
85
80 11
89
1f + 2a
1g + 2a
5c
5d
84
75 5
80
1h + 2a
1i + 2a
5e
5f
73 5
92
* The composition of the catalytic system is given in parentheses in molar equivalents with respect to the starting
aldehyde or CHꢀacid; in all cases, 0.2 equiv. of each reagent was used in the reactions involving the
[bmim][BF4]—[Pip][OAc] system.

C5H10NH•HOAc—[Bmim][BF4]
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 5, May, 2005
1235
Scheme 3
and acetylacetone (2b) in the presence of the
[Bmim][BF4]—[Pip][OAc] catalytic system to form arylꢀ
idene derivatives 3a—e (Scheme 2). The 1H NMR spectra
(signals for the protons of C(O)CH3 and ArCH=) demꢀ
onstrate that products 3a,c,e exist as 3 : 2 mixtures of the
Е and Z isomers.
rangement of the protons at positions 1—3 of the cycloꢀ
hexane ring.28 The axial arrangement was assigned to the
hydroxy group in products 5a—f by analogy with comꢀ
pound 5 (Ar = Ph) synthesized earlier.28
It should be emphasized that, although 3ꢀhydroxyꢀ
cyclohexanꢀ1ꢀone derivatives (5) have been prepared earꢀ
lier in the reactions of aldehydes with βꢀdicarbonyl comꢀ
pounds in organic solvents,5,11,28 the reactions in soluꢀ
tions of IL always produced exclusively compounds 3.13—18
Only one example of the addition of two CHꢀacid molꢀ
ecules to one aldehyde molecule (to give an analog of
compound 4) in the presence of IL as a solvent has been
documented (the reaction of salicylaldehyde with cyanoꢀ
acetic ester)12.
Therefore, the [Bmim][BF4]—[Pip][OAc] system is
an efficient catalyst for condensation of aromatic aldeꢀ
hydes with βꢀdicarbonyl compounds, which allows one to
synthesize linear and cyclic products with different strucꢀ
tures in the absence of an organic solvent using a catalytic
amount of an ionic liquid.
The [Bmim][BF4]—[Pip][OAc] catalytic system enꢀ
ables one to perform oneꢀpot multistep syntheses of hetꢀ
erocycles involving Knoevenagel condensation as the first
step. For example, the reactions of compounds 3a,b,e,
which were prepared (without additional purification)
under the aboveꢀdescribed conditions, with Oꢀmethylꢀ
isourea in the [Bmim][BF4] ionic liquid (4 equiv.) proꢀ
duced dihydropyrimidine derivatives 6a—c (Scheme 5) in
high yields as mixtures of isomeric 3,6ꢀ (6) and 1,6ꢀdiꢀ
hydropyrimidines (6´) (1H NMR data). The 6 : 6´ isomer
ratio is 2 : 1 in products 6a,b and 3 : 1 in product 6c.
The results of our study demonstrated that the conꢀ
densation process is substantially affected by IL. The reꢀ
actions of benzaldehyde and 2ꢀchlorobenzaldehyde with
ethyl acetoacetate in DMF afforded exclusively 3,6ꢀdiꢀ
hydropyrimidines.29 Apparently, under the reaction conꢀ
ditions (in the presence of NaHCO3), compounds 6 in an
IL medium, which is more polar than DMF,27 undergo
partial isomerization to give 6´.
The reaction of benzaldehyde 1a with the stronger
CHꢀacid, viz., ethyl trifluoroacetylacetate (2c), proceeds
with the involvement of two molecules of the CHꢀacid to
give diethyl 2,4ꢀbis(trifluoroacetyl)ꢀ3ꢀphenylpentaneꢀ
dioate (4) (Scheme 3) regardless of the component ratio.
Under the conditions used, condensation of aromatic
aldehydes containing electronꢀwithdrawing substituents
in the meta and para positions of the aromatic ring (1d—h)
and 2ꢀthiophene aldehyde (2i) with methyl acetoacꢀ
etate (2a) affords exclusively 2ꢀarylꢀ4ꢀhydroxyꢀ6ꢀoxoꢀ
cyclohexaneꢀ1,3ꢀdicarboxylic acid derivatives (5a—f)
(Scheme 4). Apparently, the formation of compounds
5a—f occurs through intramolecular aldol cyclization of
analogs of compound 4, which are generated in situ under
the reaction conditions. The yields of products 3 and 5
are, as a rule, close to (and, in some cases, are higher
than) the yields of the same products prepared under
standard conditions (see Table 2).
Scheme 4
1
d
e
f
g
h
i
5
a
b
c
d
e
f
Ar
4ꢀClC6H4
4ꢀFC6H4
4ꢀMeO2CC6H4
4ꢀNO2C6H4
3ꢀNO2C6H4
2ꢀThienyl
We failed to isolate condensation products 6a—c,
which are oils, in analytically pure form. These comꢀ
pounds were identified by 1H NMR spectroscopy and
their structures were confirmed by the transformations
into the corresponding 3,4ꢀdihydropyrimidinꢀ2(1H )ꢀone
derivatives (7a—c) by Nꢀalkoxycarbonylation and Oꢀdeꢀ
methylation (cf. lit. data11) (see Scheme 5).
The reaction is stereoselective. In spite of the presence
of four asymmetric centers, compounds 5a—f (1H NMR
spectroscopic data) were synthesized as individual diaꢀ
3
stereoisomers. The spinꢀspin coupling constants J1,2
3
and J2,3 (8.7—12.3 Hz) correspond to the diaxial arꢀ

1236
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 5, May, 2005
Putilova et al.
Scheme 5
cording to a procedure described earlier.30 The solvents were
dried according to standard procedures.31
Condensation of aldehydes 1a—i with βꢀdicarbonyl compounds
2a—c (general procedure). A mixture of aldehyde (3 mmol), a
βꢀdicarbonyl compound (3 mmol), freshly prepared [Pip][OAc]
(0.05 g, 0.6 mmol), and [Bmim][BF4] (0.14 g, 0.6 mmol) was
stirred at 20 °C for 5 h. Then the reaction mixture was diluted
with benzene (10 mL), successively washed with water (2×5 mL),
concentrated NaHCO3 (2×5 mL) and NaCl (2×5 mL) soluꢀ
tions, 2 N H2SO4 (5 mL), and water (2×5 mL), and dried over
MgSO4. The solvent was removed and the residue was distilled
in vacuo or crystallized from 75% PriOH. The boiling (melting)
points of products 3a—e, 4a, and 5a—f are given in Table 2.
1
Methyl Eꢀ and Zꢀ2ꢀacetylꢀ3ꢀphenylacrylates (3a). H NMR
(DMSOꢀd6), δ: 2.32 (s, 1.2 H, CMe, Zꢀ3a); 2.43 (s, 1.8 H,
CMe, Eꢀ3a); 3.78 (s, 3 H, OMe); 7.38—7.50 (m, 5 H, Ph); 7.61
(s, 0.4 H, CH, Zꢀ3a); 7.71 (s, 0.6 H, CH, Eꢀ3a).
3ꢀ(Benzylidene)pentaneꢀ2,4ꢀdione (3b). 1H NMR
(DMSOꢀd6), δ: 2.26 and 2.30 (both s, 3 H each, Me); 7.14—7.30
(m, 5 H, Ph); 7.68 (s, 1 H, CH).
Methyl Eꢀ and Zꢀ2ꢀacetylꢀ3ꢀ(4ꢀmethoxyphenyl)acrylates
(3c). 1H NMR (CDCl3), δ: 2.32 (s, 1.2 H, CMe, Zꢀ3c); 2.34 (s,
1.8 H, CMe, Eꢀ3c); 3.73—3.82 (m, 6 H, OMe); 6.80—6.88 and
7.25—7.38 (both m, 2 H each, HAr); 7.46 (s, 0.6 H, CH, Eꢀ3c);
7.56 (s, 0.4 H, CH, Zꢀ3c).
3ꢀ(4ꢀMethoxybenzylidene)pentaneꢀ2,4ꢀdione (3d). 1H NMR
(CDCl3), δ: 2.31 and 2.39 (both s, 3 H each, CMe); 3.83 (s, 3 H,
OMe); 6.89 and 7.34 (both d, 2 H each, HAr, J = 8.0 Hz); 7.41
(s, 1 H, CH).
Methyl Eꢀ and Zꢀ2ꢀacetylꢀ3ꢀ(2ꢀchlorophenyl)acrylates (3e).
1H NMR (CDCl3), δ: 2.26 (s, 1.8 H, CMe, Eꢀ3e); 2.45 (s,
1.2 H, CMe, Zꢀ3e); 3.70 (s, 1.8 H, OMe, Eꢀ3e); 3.83 (s, 1.2 H,
OMe, Zꢀ3e); 7.28—7.56 (m, 4 H, C6H4); 7.81 (s, 0.4 H, CH,
Zꢀ3e); 7.86 (s, 0.6 H, CH, Eꢀ3e).
6, 6´, 7
Ar
R
6 : 6´
a
b
c
Ph
Ph
2ꢀClC6H4
OMe
Me
OMe
2 : 1
2 : 1
3 : 1
Diethyl 2,4ꢀbis(trifluoroacetyl)ꢀ3ꢀphenylpentanedioate (4).
Found (%): C, 47.55; H, 3.40. C14H14F6O6. Calculated (%):
C, 47.67; H, 3.29. 1H NMR (DMSOꢀd6), δ: 0.81 (t, 6 H, Me,
J = 7.1 Hz); 2.82 (t, 1 H, CH, J = 11.9 Hz); 3.30 (d, 2 H, CH,
J = 11.9 Hz); 3.74 (m, 4 H, CH2, JH,H = 7.1 Hz, JH,F = 3.7 Hz);
4.07 (t, 1 H, CH, J = 11.9 Hz); 7.20—7.35 (m, 5 H, Ph).
Dimethyl 2ꢀ(4ꢀchlorophenyl)ꢀ4ꢀhydroxyꢀ4ꢀmethylꢀ6ꢀoxoꢀ
Reagents and conditions: i. H2N+=C(OMe)NH2•[0.5 SO4]–
(1 equiv.), NaHCO3 (4 equiv.), [Bmim][BF4] (4 equiv.), 50 °C,
24 h; ii. ClCO2Et, Py, CH2Cl2, 20 °C, 30 min; iii. HCl
(0.1 equiv.), MeOH, 20 °C, 40 min.
1
cyclohexaneꢀ1,3ꢀdicarboxylate (5a). H NMR (CDCl3), δ: 1.27
Alkoxycarbonylation occurs regioselectively. The
1N position of the ester group in products 7a—c was conꢀ
firmed by the presence of a crossꢀpeak (Overhauser efꢀ
fect) of the closelyꢀspaced protons of the 3ꢀNH and 4ꢀMe
groups in compound 7a. The identity of alkoxycarboꢀ
nylation products of both isomers 6 and 6´ is, apparently,
attributed to the identity of the anions formed by deprotoꢀ
nation of these NHꢀacids under the action of a base.
(s, 3 H, Me); 2.40 and 2.88 (both d, 1 H each, H(5), J =
13.7 Hz); 3.30 (d, 1 H, H(3), J = 9.9 Hz); 3.40 and 3.49 (both s,
3 H each, OMe); 3.85—3.96 (m, 2 H, H(1), H(2)); 4.66 (s, 1 H,
OH); 7.24—7.33 (m, 4 H, C6H4, J = 8.3 Hz).
Dimethyl 2ꢀ(4ꢀfluorophenyl)ꢀ4ꢀhydroxyꢀ4ꢀmethylꢀ6ꢀoxoꢀ
cyclohexaneꢀ1,3ꢀdicarboxylate (5b). 1H NMR (DMSOꢀd6), δ:
1.27 (s, 3 H, CMe); 2.38 and 2.90 (both d, 1 H each, H(5), J =
13.4 Hz); 3.28 (d, 1 H, H(3), J = 8.9 Hz); 3.38 and 3.49 (both s,
3 H each, OMe); 3.83—3.97 (m, 2 H, H(1), H(2)); 4.70 (s,
1 H, OH); 6.98 and 7.32 (both dd, 2 H each, HAr, JH,H
JH,F = 8.5 Hz).
=
Experimental
Dimethyl 4ꢀhydroxyꢀ4ꢀmethylꢀ2ꢀ[(4ꢀmethoxycarbonyl)pheꢀ
nyl]ꢀ6ꢀoxocyclohexaneꢀ1,3ꢀdicarboxylate (5c). Found (%):
C, 60.34; H, 5.88. C19H22O8. Calculated (%): C, 60.31; H, 5.86.
1H NMR (DMSOꢀd6), δ: 1.28 (s, 3 H, CMe); 2.38 and 2.92
(both d, 1 H each, H(5), J = 13.7 Hz); 3.36 (d, 1 H, H(3), J =
8.7 Hz); 3.37, 3.47, and 3.85 (all s, 3 H each, OMe); 3.90—4.02
(m, 2 H, H(1), H(2)); 4.77 (s, 1 H, OH); 7.43 and 7.88 (both d,
2 H each, HAr, J = 8.3 Hz).
The NMR spectra were recorded on a Bruker AMꢀ300 inꢀ
strument (300.13 MHz). Elemental analysis was carried out on a
Perkin—Elmer 2400 instrument. Commercial (Acros) aldehydes
1a—i and βꢀdicarbonyl compounds 2a—c were used without
additional purification. Acetate [Pip][OAc] was prepared imꢀ
mediately before the reactions by mixing equimolar amounts of
piperidine and AcOH, and [Bmim][BF4] was synthesized acꢀ

C5H10NH•HOAc—[Bmim][BF4]
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 5, May, 2005
1237
Dimethyl 4ꢀhydroxyꢀ4ꢀmethylꢀ2ꢀ(4ꢀnitrophenyl)ꢀ6ꢀoxocycloꢀ
hexaneꢀ1,3ꢀdicarboxylate (5d). 1H NMR (CDCl3), δ: 1.37 (s,
3 H, CMe); 2.57 and 2.78 (both d, 1 H each, H(5), J = 14.2 Hz);
3.11 (d, 1 H, H(3), J = 11.9 Hz); 3.43 (s, 3 H, OMe); 3.45 (s,
1 H, OH); 3.60 (s, 3 H, OMe); 3.70 (d, 1 H, H(1), J = 10.1 Hz);
4.19 (dd, 1 H, H(2), J1 = 11.9 Hz, J2 = 10.1 Hz); 7.46 and 8.21
(both d, 2 H each, HAr, J = 8.7 Hz).
Dimethyl 4ꢀhydroxyꢀ4ꢀmethylꢀ2ꢀ(3ꢀnitrophenyl)ꢀ6ꢀoxocycloꢀ
hexaneꢀ1,3ꢀdicarboxylate (5e). 1H NMR (DMSOꢀd6), δ: 1.31
(s, 3 H, CMe); 2.42 and 2.97 (both d, 1 H each, H(5), J =
13.7 Hz); 3.40 (s, 3 H, OMe); 3.48 (d, 1 H, H(3), J = 8.8 Hz);
3.51 (s, 3 H, OMe); 4.00—4.17 (m, 2 H, H(1), H(2)); 4.78 (br.s,
6c and 6´c); 8.27 (d, 0.25 H, NH, 6´c, J = 4.5 Hz); 9.22 (s,
0.75 H, NH, 6c).
Synthesis of 3,4ꢀdihydropyrimidinꢀ2(1H )ꢀone derivatives
7a—c (general procedure). Ethyl chloroformate (0.32 g, 3 mmol)
and pyridine (0.23 g, 3 mmol) were successively added to a
solution of a mixture of isomers 6a—c (3 mmol) in CH2Cl2
(5 mL). The reaction mixture was kept at 20 °C for 30 min. The
solvent was removed in vacuo, the residue was dissolved in methaꢀ
nol (5 mL), and 3—5 drops of 2 M HCl were added to the
resulting solution until the mixture became turbid. Then the
reaction mixture was kept at 20 °C for 40 min. The solvent was
removed and the residue was crystallized from diethyl ether and
dried in air.
1 H, OH); 7.54 (t, 1 H, mꢀHAr, J = 7.9 Hz); 7.73 (d, 1 H, oꢀHAr
,
J = 7.9 Hz); 8.08 (d, 1 H, pꢀHAr, J = 7.9 Hz); 8.33 (s, 1 H, oꢀHAr).
Dimethyl 4ꢀhydroxyꢀ4ꢀmethylꢀ6ꢀoxoꢀ2ꢀthiophenꢀ2ꢀylcycloꢀ
hexaneꢀ1,3ꢀdicarboxylate (5f). Found (%): C, 55.47; H, 5.45;
S, 9.68. C15H18O6S. Calculated (%): C, 55.20; H, 5.56; S, 9.83.
1H NMR (DMSOꢀd6), δ: 1.26 (s, 3 H, CMe); 2.35 and 2.88
(both d, 1 H each, H(5), J = 13.3 Hz); 3.25 (d, 1 H, H(3), J =
12.0 Hz); 3.47 and 3.55 (both s, 3 H each, OMe); 3.85 (d, 1 H,
H(1), J = 12.3 Hz); 4.20 (t, 1 H, H(2), J = 12.3 Hz); 4.78 (s,
Methyl 3ꢀethoxycarbonylꢀ6ꢀmethylꢀ2ꢀoxoꢀ4ꢀphenylꢀ3,4ꢀ
dihydropyrimidineꢀ(1H)ꢀ5ꢀcarboxylate (7a). Found (%):
C, 64.71; H, 6.49; N, 8.62. C17H20N2O4. Calculated (%):
C, 64.54; H, 6.37; N, 8.86. 1H NMR (DMSOꢀd6), δ: 1.31 (t,
3 H, CH2CH3, J = 7.0 Hz); 2.30 (s, 3 H, CMe); 3.68 (s, 3 H,
OMe); 4.25 (q, 2 H, CH2, J = 7.0 Hz); 6.16 (s, 1 H, CH);
7.18—7.35 (m, 5 H, Ph); 10.05 (s, 1 H, NH).
5ꢀAcetylꢀ3ꢀethoxycarbonylꢀ6ꢀmethylꢀ4ꢀphenylꢀ3,4ꢀdihydroꢀ
pyrimidinꢀ(1H)ꢀ2ꢀone (7b). Found (%): C, 68.21; H, 6.80;
N, 9.17. C17H20N2O3. Calculated (%): C, 67.98; H, 6.71;
1 H, OH); 6.86—6.95 (m, 2 H, HHet); 7.19 (d, 1 H, HHet
,
J = 4.7 Hz).
1
Synthesis of 3,6ꢀ and 1,6ꢀdihydropyrimidine derivatives
(6a—c) (general procedure). A mixture of compounds 3a, 3b, or
3e (3 mmol), Oꢀmethylisourea sulfate (0.37 g, 3 mmol), NaHCO3
(1.0 g, 12 mmol), and [Bmim][BF4] (2.72 g, 12 mmol) was
vigorously stirred at 55—65 °C for 24 h, cooled to room temꢀ
perature, and extracted with a 3 : 1 benzene—diethyl ether mixꢀ
ture (2×5 mL). The organic solution was successively washed
with water (2×5 mL), concentrated aqueous NaHCO3 (2×5 mL)
and NaCl (2×5 mL) solutions, and water (2×5 mL) and dried
over MgSO4. The solvent was removed in vacuo and compounds
6a—c were obtained as a mixture of isomers, which were used in
reactions without additional purification.
N, 9.33. H NMR (DMSOꢀd6), δ: 1.32 (t, 3 H, CH2CH3, J =
7.1 Hz); 2.27 (s, 3 H, CMe); 2.33 (s, 3 H, C(O)Me); 4.26 (q,
2 H, CH2, J = 7.0 Hz); 6.25 (s, 1 H, CH); 7.20—7.61 (m,
6 H, NH, Ph).
Methyl 4ꢀ(4ꢀchlorophenyl)ꢀ3ꢀethoxycarbonylꢀ6ꢀmethylꢀ2ꢀ
oxoꢀ3,4ꢀdihydropyrimidineꢀ(1H)ꢀ5ꢀcarboxylate (7c). Found (%):
C, 58.45; H, 5.30; Cl, 9.97; N, 8.11. C17H20ClN2O4. Calcuꢀ
lated (%): C, 58.21; H, 5.46; Cl, 10.11; N, 7.99. 1H NMR
(DMSOꢀd6), δ: 1.28 (t, 3 H, CH2CH3, J = 7.1 Hz); 2.31 (s, 3 H,
CMe); 3.60 (s, 3 H, OMe); 4.20 (q, 2 H, CH2, J = 7.1 Hz); 6.40
(s, 1 H, CH); 7.21—7.35 (m, 4 H, C6H4Cl); 10.20 (s, 1 H, NH).
A mixture of methyl 2ꢀmethoxyꢀ4ꢀmethylꢀ6ꢀphenylꢀ3,6ꢀ
dihydropyrimidineꢀ5ꢀcarboxylate (6a) and methyl 2ꢀmethoxyꢀ4ꢀ
methylꢀ6ꢀphenylꢀ1,6ꢀdihydropyrimidineꢀ5ꢀcarboxylate (6´a). The
yield was 73%, oil. 1H NMR (DMSOꢀd6), δ: 2.26 (s, 2 H, CMe,
6a); 2.30 (s, 1 H, CMe, 6´a); 3.55 (s, 3 H, OMe, 6a and 6´a);
3.64 (s, 2 H, OMe, 6a); 3.75 (s, 1 H, OMe, 6´a); 5.30 (d, 0.33 H,
CH, 6´a, J = 4.5 Hz); 5.45 (s, 0.66 H, CH, 6a); 7.10—7.31 (m,
5 H, Ph, 6a and 6´a); 8.33 (d, 0.33 H, NH, 6´a, J = 4.5 Hz);
9.18 (s, 0.66 H, NH, 6a).
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 03ꢀ03ꢀ32659)
and the Russian Academy of Sciences (Program of Basic
Research of the Presidium of the Russian Academy of
Sciences).
References
A mixture of 1ꢀ(2ꢀmethoxyꢀ4ꢀmethylꢀ6ꢀphenylꢀ3,6ꢀdihydroꢀ
pyrimidinꢀ5ꢀyl)ꢀ (6b) and 1ꢀ(2ꢀmethoxyꢀ4ꢀmethylꢀ6ꢀphenylꢀ1,6ꢀ
dihydropyrimidinꢀ5ꢀyl)ethanones (6´b). The yield was 72%, oil.
1H NMR (DMSOꢀd6), δ: 1.95 (s, 1 H, CMe, 6´b); 2.10 (s, 2 H,
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(DMSOꢀd6), δ: 2.30 (s, 2.25 H, CMe, 6c); 2.33 (s, 0.75 H,
CMe, 6´c); 3.46 (s, 3 H, OMe, 6c and 6´c); 3,58 (s, 2.25 H,
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J = 4.5 Hz); 5.82 (s, 0.75 H, CH, 6c); 7.12—7.36 (m, 4 H, C6H4
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