New aspects of the aldol condensation of acetylpyridines with aromatic aldehydes

Article abstract of DOI:10.1023/B:RUCB.0000037863.85554.35

Aldol condensation of acetylpyridines with aromatic aldehydes was studied. A series of new products of cascade reactions were isolated and characterized.

Full text of DOI:10.1023/B:RUCB.0000037863.85554.35

Russian Chemical Bulletin, International Edition, Vol. 53, No. 4, pp. 911—915, April, 2004
911
New aspects of the aldol condensation of
acetylpyridines with aromatic aldehydes
S. Z. Vatsadze, V. N. Nuriev,ꢀ I. F. Leshcheva, and N. V. Zyk
Department of Chemistry, M. V. Lomonosov Moscow State University,
Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (095) 939 0290. Eꢀmail: nvn@org.chem.msu.ru
Aldol condensation of acetylpyridines with aromatic aldehydes was studied. A series of new
products of cascade reactions were isolated and characterized.
Key words: aldol condensation, pyridinecarbaldehydes, acetylpyridines, diastereospecificity,
chalcones, organic ligands.
Scheme 1
1,3ꢀDiarylpropenones, or chalcones, are key intermeꢀ
diates in organic synthesis and are widely used in heteroꢀ
cyclization reactions.1,2 With the aim of preparing new
heterocyclic compounds containing one or several pyriꢀ
dine fragments, which are promising ligands for supramoꢀ
lecular chemistry and crystal engineering,3,4 we develꢀ
oped procedures for the synthesis of 1,3ꢀdipyridylproꢀ
penones. The main approach to the synthesis of α,βꢀunꢀ
saturated ketones was based on aldol condensation.5,6 It
is known7—10 that the reactions of acetylpyridines with
pyridinecarbaldehydes as well as with analogous comꢀ
pounds often afford byꢀproducts of the aldol synthesis,
because the chalcone analog that formed can be involved
in the Michael reaction. In addition to the nature of subꢀ
strates, the reaction pathway and the character of the
reaction products depend substantially on the polarity of
the solvent, the base strength, the reaction temperature,
and the order of addition of the reagents.9
Study of condensation of 3ꢀacetylpyridine with
nicotinaldehyde demonstrated that an increase in the base
strength (the use of K2CO3 instead of Na2CO3) and a
decrease in the polarity of the medium (the use of 60%
aqueous EtOH instead of water) lead to a decrease in the
ratio of enone 1a to diketone 2a (Scheme 1, Table 1).
When reproducing known procedures for the synthesis
of 1,3ꢀbis(4ꢀpyridyl)propenone (1b) or isomeric enones
1c,d,5,6,8,9,11—14 we found that the reaction gave hydroxy
diketone 3b as the major product under virtually all conꢀ
ditions. Propenone 1b was prepared by the Wittig reaction
of 4ꢀpyridinecarbaldehyde with (4ꢀpyridyl)carbonylꢀ
methylidenetriphenylphosphorane (5).15 The formation
of 1b was detected by TLC based on comparison with
isomeric compound 1a. Product 1b was also identified in
the mixture with the starting compounds (Scheme 2) by
1H NMR spectroscopy. The assignment of the signals in
the spectrum was made based on the data for anaꢀ
logs.14,16,17
R1
R2
R1
R2
a
b
c
d
3ꢀPy
4ꢀPy
3ꢀPy
4ꢀPy
3ꢀPy
4ꢀPy
4ꢀPy
3ꢀPy
e
f
g
Ph
4ꢀPy
4ꢀPy 2ꢀThienyl
4ꢀPy
Ph
The structure of diketone 3b was established by IR and
1H NMR spectroscopy (the assignment of the signals was
made by the 1H—1H double resonance method), mass
spectrometry, and elemental analysis (Tables 2 and 3).
For isomers 1c,d, it was also demonstrated that enones
were prepared as minor reaction products, whereas
diketones 3c,d were isolated in higher yields. In addition,
the reactions afforded isomeric products 4c,d. According
to the massꢀspectrometric data, these possess the same
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 874—878, April, 2004.
1066ꢀ5285/04/5304ꢀ0911 © 2004 Plenum Publishing Corporation

912
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
Vatsadze et al.
Table 1. Yields of aldol condensation products (water, Na2CO3)a
Scheme 2
Major
(side)
product
R1
R2
Yieldb (%) of
major (side)
product
1a (2a)
1b
1e
2a (1a)d
3ꢀPy
4ꢀPy
Ph
3ꢀPy
4ꢀPy
3ꢀPy
3ꢀPy
4ꢀPy
4ꢀPy
4ꢀPy
3ꢀPy
4ꢀPy
4ꢀPy
3ꢀPy
4ꢀPy
4ꢀPy
3ꢀPy
3ꢀPy
Ph
68 (<10)
<10 c
81
43 (21)
3b
95
3c (1c, 4c)
4a f
4d (1d, 3d)
4f
55 (<5,e 28)
62
46 (<5,e 12)
constant (∼2.4 Hz) between the hydroxy H(7) proton and
the H(5) proton.18,19 It should be emphasized that all
reaction products belong to the same type of diastereꢀ
omers, i.e., the reaction proceeds diastereospecifically.
78
74
4g
2ꢀThienyl
a Except for 1b, which was synthesized by the Wittig reaction.
b The yields are given for individual compounds prepared under
optimum conditions, unless otherwise indicated.
1
Analysis of the reaction mixtures by H NMR spectrosꢀ
copy demonstrated that before isolation the percentage of
the minor diastereomer is no higher than 5% with respect
to the major diastereomer. Since the ratio between the
reaction products 3c and 4c differs substantially from the
3d : 4d ratio, we studied the influence of the nature of the
aryl substituent in the carbonyl and methylene compoꢀ
nents on the character of the compounds formed. In the
case of the less reactive methylene component of acetoꢀ
phenone and pyridineꢀ4ꢀcarbaldehyde, the reactions afꢀ
forded enone 1e as the only product, whereas the reacꢀ
tions of 4ꢀacetylpyridine with benzaldehyde and thioꢀ
pheneꢀ2ꢀcarbaldehyde gave rise to 4f,g, which are strucꢀ
tural analogs of compound 4c, as the major products. The
results of our study led to the conclusion that the methylꢀ
ene component makes the major contribution to the side
1
c According to the H NMR spectroscopic data.
d EtOH—H2O, K2CO3.
e The product was identified by TLC based on comparison
with 1a.
f KOH.
scheme of molecular ion fragmentation. The cyclic strucꢀ
ture of the saturated core of compound 4c and its analogs
4d—f has a substantial effect on the chemical shifts of the
geminal protons H(5) and H(6) (δ ≈ 2 and 3.2, respecꢀ
tively; Jgem ≈ 12—13 Hz; Table 4). This difference is apꢀ
parently associated with the influence of the O atom of
the hydroxy group and the rigid geometry of the structure.
The model with the given arrangement of the substituents
is also evidenced by the presence of the W spin coupling
Table 2. Physicochemical characteristics and results of elemental analysis for the compounds synthesized
Comꢀ M.p./°C
pound
Found
Calculated
Molecular
formula
IR,
ν/cm–1
MS,
m/z (Irel (%))
(%)
C
H
N
1e
3b
71 (72 8)
158
—
—
—
—
—
—
70.85
71.22
70.90
71.22
70.66
71.22
72.60
73.18
72.82
73.18
72.68
73.18
78.20
77.90
66.98
67.49
5.34
5.06
5.52
5.06
5.12
5.06
5.45
5.02
4.81
5.02
4.90
5.02
5.66
5.42
5.22
4.57
11.78
12.78
12.22
12.78
11.84
12.78
13.12
12.93
12.42
12.93
12.58
12.93
8.12
C26H22N4O3
C26H22N4O3
C26H22N4O3
C33H27N5O3
C33H27N5O3
C33H27N5O3
C35H29N3O3
3400, 1690
438 [M]+• (2), 106 [PyCO]+• (100)
438 [M]+• (6), 106 [PyCO]+• (100)
438 [M]+• (5), 106 [PyCO]+• (100)
541 [M]+• (7), 106 [PyCO]+• (100)
541 [M]+• (7), 106 [PyCO]+• (100)
541 [M]+• (7), 106 [PyCO]+• (100)
539 [M]+• (7), 208 [PyCOCH=CHPy]+• (100)
551 [M]+• (7), 137 [COCH=CHTh]+• (100)
3c
3d
4a
4c
4d
4f
151
(decomp.)
153
(decomp.)
186
3380, 1690
3350, 1680
3400, 1705
3350, 1700
3320, 1700
3400, 1680
179
184
167
189
7.79
8.24
7.62
4g
C31H25N3O3S2 3390, 1695

Novel products of aldol condensation
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
913
1
Table 3. H NMR spectra (CDCl3) of 2ꢀhetaryl(hydroxy)methylꢀ1,3,5ꢀtrihetarylpentaneꢀ1,5ꢀdiones 3b—d
Comꢀ
pound
δ (J/Hz)
H(1) (t)
H(2) (td)
H(3) (dd)
H(4) (dd)
H(5) (d)
5.58
H(6) (s)
6.99
H (arom.)
3b
3c
3d
3.75 (J1,5
=
4.08
(J2,3 = J2,1
1.95
2.18
8.56—6.95 (16 H)
8.90—7.08 (16 H)
8.82—7.00 (16 H)
J1,2 = 10.0)
=
(J3,4 = 13.7,
J3,2 = 10.0)
2.05
(J3,4 = 13.6,
J3,2 = 10.3)
1.88
(J4,3 = 13.7,
J4,2 = 3.9)
2.15
(J4,3 = 13.6,
J4,2 = 3.8)
2.24
(J5,1 = 10.0)
10.0, J2,4 = 3.9)
4.02
3.80 (J1,5
=
5.61
(J5,1 = 10.3)
6.95
7.05
J1,2 = 10.3)
(J2,3 = J2,1
=
10.3, J2,4 = 3.8)
4.04
3.73 (J1,5
=
5.65
J1,2 = 11.0)
(J2,3 = J2,1
11.0, J2,4 = 3.7)
=
(J3,4 = 13.3,
J3,2 = 11.0)
(J4,3 = 13.3,
J4,2 = 3.7)
(J5,1 = 11.0)
1
Table 4. H NMR spectra (DMSOꢀd6) of 2,4ꢀdihetaroylꢀ1,3,5ꢀtrihetarylꢀsubstituted cyclohexanols 4a,c,d,f,g
Comꢀ
pound
δ (J/Hz)
H(5)
H(1) (d)
5.10
H(2)
H(3) (t)
H(4)
H(6)
H(7)* (d)
5.40
H (arom.)
9.02—6.99
4a
4c
4d
4.45 (dd,
4.82 (J3,4
=
4.18 (ddd,
J4,3 = 4.8,
J4,5 = 12.2,
J4,6 = 3.6)
3.42 (td, J5,6
J5,4 = 12.2,
J5,7 = 2.4)
=
1.82 (dd,
(J1,2 = 11.9) J2,1 = 11.9,
J2,3 = 4.8)
J3,2 = 4.8)
J6,5 = 12.2,
J6,4 = 3.6)
(J7,5 = 2.4) (20 H)
5.08
4.52 (dd,
4.89 (J3,4
=
4.18 (ddd,
J4,3 = 4.5,
J4,5 = 12.5,
J4,6 = 3.4)
3.32 (t, J5,6
J5,4 = 12.5,
J5,7 = 2.3)
=
1.85 (ddd,
J6,5 = 12.5,
J6,4 = 3.4)
5.12
9.06—7.12
(J1,2 = 12.6) J2,1 = 12.6,
J2,3 = 4.5)
J3,2 = 4.5)
(J7,5 = 2.3) (20 H)
5.18
4.45 (dd,
4.82 (J3,4
=
4.18 (ddd,
J4,3 = 4.6,
J4,5 = 12.5,
J4,6 = 3.4)
3.42 (t, J5,6
J5,4 = 12.5,
J5,7 = 2.4)
=
1.82 (dd,
5.40
8.72—6.95
(J1,2 = 12.0) J2,1 = 12.0,
J2,3 = 4.6)
J3,2 = 4.6)
J6,5 = 12.5,
J6,4 = 3.4)
(J7,5 = 2.4) (20 H)
4f
5.51
(J1,2 = 12.9)
4.15—4.11
(m)
4.30 (J3,4
J3,2 = 4.5)
=
4.15—4.11 (m) 3.20 (t, J5,6
=
2.09 (dd,
J6,5 = 13.0,
J6,4 = 3.4)
5.00
8.60—6.80
J5,4 = 13.0,
J5,7 = 2.3)
(J7,5 = 2.3) (22 H)
4g
5.52
4.42 (dd,
4.48 (J3,4
J3,2 = 4.2)
=
4.35 (ddd,
J4,3 = 4.2,
J4,5 = 12.5,
J4,6 = 3.5)
3.00 (t, J5,6
J5,4 = 12.5,
J5,7 = 2.2)
=
2.14 (dd,
J6,5 = 12.5,
J6,4 = 3.5)
4.98
8.55—6.40
(J1,2 = 12.8) J2,1 = 12.8,
J2,3 = 4.2)
(J7,5 = 2.2) (18 H)
* The chemical shift δ changes upon the addition of D2O.

914
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
Vatsadze et al.
reactions giving rise to acyclic and cyclic products of
types 2—4. This component enhances the reactivity of
ketone and its intermediates as donors and also indirectly
influences the activity of the resulting chalcone analog as
an acceptor in the Michael reaction.
Based on the above results, we proposed a scheme
of formation of the products of the cascade synthesis
(Scheme 3).
was not generated in the reaction of the corresponding
aldehyde with ketone, but it was synthesized in good yield
by the reaction of enone 1a with symꢀ1,5ꢀdiketone 2a.
The compounds synthesized hold promise as synthetic
intermediates as well as for purposes of coordination
chemistry.
Scheme 4
Scheme 3
1
R = 3ꢀPy
Experimental
The 1H NMR spectra were recorded at 30 °C on a Varian
VXRꢀ400 instrument operating at 400 MHz with the use of
CDCl3 and DMSOꢀd6 as the solvents. The 1H—1H spin couꢀ
pling constants are given. The IR spectra were measured on a
URꢀ20 spectrometer in Nujol mulls. The mass spectra were
obtained on an HPꢀ5890 mass spectrometer with direct inlet of
the sample; the temperature of the ion source was 150 °C; the
energy of ionizing electrons was 70 eV; the accelerating voltage
was 3 kV; the range of 1 was 40—550 amu. The melting points
were determined on an ElectroThermalꢀ9100 instrument in open
capillary tubes; the uncorrected melting points are given.
Acetylpyridines, pyridinecarbaldehydes, and thiopheneꢀ2ꢀcarbꢀ
aldehyde (Acros) were used without additional purification. The
course of the reactions and the purity of the reaction products
were monitored by TLC on a fixed layer of silica gel (Silufol
plates). Preparative separation of the reaction mixtures was
carried out by column chromatography on Acros silica gel
(SiO2 35—60 µm).
i. Michael addition; ii. Elimination.
The first step of the reaction involves the reversible
formation of aldol I followed by its transformation into
the E isomer of enone II. In the case of high reactivity of
chalcone as the acceptor as well as high reactivity of aldol
and aryl methyl ketone as donors, the Michael reacꢀ
tion affords nonsymꢀhydroxymethylꢀ1,5ꢀdiketone III or
symꢀ1,5ꢀdiketone IV. Substrate IV also contains the
active methylene component and is involved in the
Michael addition with chalcone to give intermediate V.
symꢀ1,5,7ꢀTriketone V is very labile. It is known18—20 that
such compounds readily undergo the Baylis—Hillman
transformation accompanied by intramolecular aldol conꢀ
densation to form cyclic product VI. The chemical nature
of the methylene and carbonyl components influences
primarily the rate of formation and reactivity of intermeꢀ
diates. It should be noted that product III is formed only
if both reagents are rather reactive and it is not involved in
the competitive Michael addition only due to very poor
solubility.
(2E)ꢀ1,3ꢀBis(4ꢀpyridyl)propenone (1b). A suspension of
(4ꢀpyridyl)carbonylmethylidenetriphenylphosphorane (5) (2 g,
5.2 mmol) and pyridineꢀ4ꢀcarbaldehyde (0.6 g, 5.5 mmol) in
toluene (50 mL) was heated under argon. The reaction mixture
was allowed to cool and then concentrated. The residue was
extracted with CH2Cl2 (3×20 mL). The extract was washed with
water (2×5 mL), CH2Cl2 was removed, and the residue was
washed on a filter with small portions of Et2O. The mixture was
1
analyzed without additional purification. H NMR (CDCl3), δ:
9.05 (d, H(2), H(6), PyC(O), 3J = 6.8 Hz); 8.75 (d, H(2), H(6),
PyCH=CH, 3J = 6.8 Hz); 7.96 (d, PyCH=CHC(O)Py, 3J =
15.3 Hz); 7.72 (d, H(3), H(5), PyC(O), 3J = 6.8 Hz); 7.55 (d,
PyCH=CH, 3J = 15.3 Hz); 7.32 (d, H(3), H(5), PyCH=CH,
3J = 6.8 Hz).
To confirm the above facts, we carried out the indeꢀ
pendent synthesis of compound 4a (Scheme 4). The latter
Condensation of aromatic aldehydes with acetylpyridines (genꢀ
eral procedure). An aqueous solution of a base (a 10% Na2CO3

Novel products of aldol condensation
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
915
solution; in the case of compound 4a, a 1 M KOH solution) was
added to a solution of an aldehyde (50 mmol) and a ketone
(50 mmol) in water (100 mL). The mixture was stirred at ~20 °C
for 4—12 h. Insoluble reaction products were filtered off and
washed with water. The precipitates were dried in vacuo using a
waterꢀaspirator pump. Compounds 1a,e, 3b, and 4c,d,f,g
were isolated. The mother liquor was extracted with CH2Cl2
(3×50 mL), the solvent was evaporated, and the residue was
subjected to chromatographic separation on a column with SiO2
using a 90 : 10 CHCl3—MeOH mixture as the eluent to prepare
compounds 2a, 3c,d, and 4a. The melting points and data from
IR and 1H NMR spectroscopy, mass spectrometry, and elemenꢀ
tal analysis of compounds 3b—d and 4a,c,d,f are given in
Tables 2—4.
(2E)ꢀ1,3ꢀBis(3ꢀpyridyl)propenone (1a) was synthesized acꢀ
cording to the general procedure in 68% yield, m.p. 128 °C
(from ethyl acetate) (cf. lit. data11: m.p. 130 °C). 1H NMR
(CDCl3), δ: 9.23 (d, 1 H, C(O)PyH(2), 4J = 1.8 Hz); 8.86 (d,
1 H, H(2)PyCH=CH, 4J = 1.8 Hz); 8.82 (dd, 1 H, H(6)PyC(O),
3J = 4.9 Hz, 4J = 1.8 Hz); 8.65 (dd, 1 H, H(6)PyCH=CH, 4J =
on Aromatic Unsaturated Ketones], Folio, Kharkov, 1998,
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4
3
4.9 Hz, J = 1.8 Hz); 8.30 (dt, 1 H, H(4)PyC(O), J = 8.0 Hz,
10. U. Kube and U. Holzgrabe, Monatsh. Chem., 2001, 132, 407.
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4J = 1.8 Hz); 7.96 (dt, 1 H, H(4)PyCH=CH, 3J = 8.0 Hz, J =
1.8 Hz); 7.82 (d, 1 H, PyCH=CHC(O)Py, J = 15.5 Hz); 7.55
(d, 1 H, PyCH=CHC(O)Py, 3J = 15.5 Hz); 7.47 (dd, 1 H,
H(5)PyC(O), 3J = 8.0 Hz, 3J = 4.9 Hz); 7.38 (dd, 1 H,
H(5)PyCH=CH, J = 8.0 Hz, J = 4.9 Hz). 1,3,5ꢀTris(3ꢀpyriꢀ
dyl)pentaneꢀ1,5ꢀdione (2a) was obtained from the mother liquor
in 10% yield, m.p. 134 °C (from EtOH) (cf. lit. data11: m.p.
168 °C). Compounds 1a and 2a were isolated using a procedure
published earlier7 (in the presence of potassium carbonate; in a
40 : 60 aqueousꢀethanolic solution) in 21 and 43% yields, reꢀ
spectively.
4
3
3
3
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1967, 16, 14.
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This study was financially supported by the Russian
Foundation for Basic Research (Project No. 03ꢀ03ꢀ
32401).
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45, 6545.
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References
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aromaticheskikh nepredel´nykh ketonov [Azaheterocycles Based
Received September 19, 2003;
in revised form April 7, 2004