ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 10, pp. 1864–1868.

© Pleiades Publishing, Ltd., 2013.

Original Russian Text © O.A. Nurkenov, S.D. Fazylov, A.E. Arinova, K.M. Turdybekov, D.M. Turdybekov, S.A. Talipov, B.T. Ibragimov, 2013, published in
Zhurnal Obshchei Khimii, 2013, Vol. 83, No. 10, pp. 1654–1659.

Synthesis, Structure and Chemical Transformations

of 4-Aminobenzaldehyde
O. A. Nurkenova, S. D. Fazylova, A. E. Arinovaa, K. M. Turdybekovb,
D. M. Turdybekovc, S. A. Talipovd, and B. T. Ibragimovd
a
Institute of Organic Synthesis and Coal Chemistry of the Republic of Kazakhstan,
ul. Alikhanova 1, Karaganda, 100008 Kazakhstan
e-mail: nurkenov_oral@mail.ru
b
International Research and Production Holding “Phytochemistry,” Karaganda, Kazakhstan
c
Multiple-Discipline Humanitarian-Technical University, Karaganda, Kazakhstan
d
Academician Sadykov Institute of Bioorganic Chemistry,
Academy of Sciences of the Republic of Uzbekistan, Tashkent, Uzbekistan

Received October 29, 2012

Abstract—A possibility of nucleophilic substitution of the fluorine atom in 4-fluorobenzaldehyde with amines
(morpholine, piperidine or cytisine) under convection heating and microwave irradiation was shown. Reactions
of 4-morpholinyl- and 4-piperidinylbenzaldehyde with hydrazides of isonicotinic and salicylic acids afford the
corresponding hydrazones. The structure of the synthesized compounds was confirmed by IR, 1H NMR
spectroscopy, mass spectrometry, and X-ray analysis data.
DOI: 10.1134/S1070363213100113

It is known that aldehydes are important synthons aldehydes containing a biologically active amino
for the synthesis of various classes of organic moiety in the para-position of the aromatic ring.
compounds including heterocycles [1–3]. According to By analogy with the method described in [4], we
[4], amino-substituted aromatic aldehydes can be performed the substitution of the fluorine atom in 4-
obtained by reacting the corresponding amines fluorobenzaldehyde by the amino moiety (morpholine,
(morpholine, piperidine) and o-fluorobenzaldehydes piperidine or cytisine). We found that the heterocyclic
under reflux in DMF in the presence of potassium amines react with 4-fluorobenzaldehyde under reflux
carbonate. Synthesized amino-substituted aromatic in DMF in the presence of potassium carbonate within
aldehydes are used further for the synthesis of 20 h to give 4-aminobenzaldehydes I–III. The reaction
important heterocyclic quinolines spiro derivatives. probably occurs by an addition-elimination mechanism.
These reactions with halogenated aldehydes are
interesting because the lone pair of the fluorine atom is Synthesis of 4-aminobenzaldehydes is a long pro-
ρ,π-conjugated with the double bond or with a π- cess (over 20 h). Furthermore, yields of the reaction
electronic system of the ring. It should also be noted depend on the structure of amines.
that in the nucleophilic substitution of alkyl halides the Use of microwave activation is known to signi-
iodide and bromide ions are better leaving groups, and ficantly reduce the reaction time: from several hours or
the fluoride ions are the most difficult leaving groups. days to few minutes. The reaction rate is increased 10–
In the SNAr reactions an opposite sequence is often 100 times. The use of microwave irradiation allows
observed: fluorine-derived substrates react with higher also performing many syntheses, which failed to occur
rate (if the ring contains the electron-acceptor in standard conditions, and also leads to a change in
substituents in the ortho- and para-positions). These the reaction selectivity and direction [1, 3]. In order to
features of the electronic structure of fluorobenzal- intensify the process of the synthesis of aldehydes I–
dehydes are of particular scientific interest. In this III, we studied the preparation of compound I under
regard, we were interested in the synthesis of aromatic the microwave activation.

1864
 SYNTHESIS, STRUCTURE AND CHEMICAL TRANSFORMATIONS 1865

O O
K2CO3, DMF
NH + F C N C
H 140oC
H
I−III

N
N = O N (I), N (II), (III).

A special mode of syntheses under microwave In order to determine the spatial structure of the
irradiation includes the use of a solid support, i. e., a synthesized 4-aminobenzaldehydes I–III we per-
material, which is transparent in the microwave formed X-ray diffraction analysis of 4-(N-cytisine)benz-
radiation region, but possesses catalytic properties. aldehyde III, a general view of whose molecule is
The elementary interaction acts occur on its surface shown in the figure.
[5–9]. For the reaction under study we used a specially
prepared catalyst supported on a Silpearl silica gel, The data obtained show that the bond lengths and
twice activated with potassium carbonate. For uniform angles in the structure of III are close to standard
distribution of potassium carbonate on silica gel, the values, except for the bond angles at the atom N12
latter was suspended into aqueous solution of K2CO3. (Tables 1, 2) [1]. Sum of the bond angles at the
Then water was evaporated, and the resulting dry trigonal planar atom N12 is 351.3°, which is caused by
residue was ground in a mortar and dried at 120°C. the conjugation of the unshared electron pair of the
nitrogen atom with a π-system of the phenyl ring.
Under microwave irradiation the synthesis of 4-(N-
Usually the coordination of this atom is close to
morpholyl)benzaldehyde I can be successfully carried
pyramidal, such as in the molecule of N-methylcytisine
out in 30 min in DMF using the above support.
[2] and N-cyanomethylcytisine [3]. Dihydropyridine
General procedure for the synthesis is given in the
ring in compound III is planar within the accuracy of
experimental part. Aldehyde III was prepared
±0.005 Å, the atom O1 is practically in the plane (the
similarly.
deviation is 0.021 Å). Tetrahydropyridine ring takes
In the 1H NMR spectrum (DMSO-d6, 500 MHz) of the conformation of near ideal sofa (ΔСS8 0.75°), the
compound I the signals of methylene protons of bridging atom C8 is deviated from the mean plane of
morpholine fragment appear as two triplets at 3.36 and the remaining ring atoms by 0.758±0.006 Å. Piperidine
3.72 ppm. Two doublets at 7.73 and 7.08 ppm ring has a distorted chair conformation (ΔСS8 3.9°)
correspond to ortho- and meta-protons of the phenyl (torsion angles are shown in Table 3). Aldehyde group
moiety. Aldehyde proton is observed as a narrow is in the plane of the phenyl ring (±0.01 Å), the torsion
singlet at 9.76 ppm. angle С18С19С20О2 is 0.6(5)°.

General view of the molecule of 4-(N-cytisinyl)benzaldehyde III.

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1866 NURKENOV et al.

Table 1. Bond lengths in the structure of III Table 2. Bond angles in the structure of III

Bond d, Å Bond d, Å Angle ω, deg Angle ω, deg

1 2 9 13 6 1 2 13 9 10
O –C 1.245(4) C –C 1.507(4) CNC 122.7(3) C CC 111.9(3)
2 20 9 10 6 1 10 1 10 9
O –C 1.214(4) C –C 1.526(4) CNC 123.1(2) NC C 114.5(2)
1 6 11 12 2 1 10 12 11 7
N –C 1.379(3) C –N 1.468(3) CNC 114.2(2) N C C 112.2(2)
1 2 12 14 1 2 1 14 12 13
N –C 1.398(4) N –C 1.387(3) OCN 119.3(3) C N C 119.0(2)
1 10 12 13 1 2 3 14 12 11
N –C 1.474(4) N –C 1.467(4) OCC 125.6(3) C N C 118.6(2)
2 3 14 15 1 2 3 13 12 11
C –C 1.425(5) C –C 1.395(4) NCC 115.2(3) C N C 113.7(2)
3 4 14 19 4 3 2 12 13 9
C –C 1.350(5) C –C 1.416(4) CCC 121.8(3) N C C 112.1(2)
C4–C5 1.388(4) C15–C16 1.385(4) C3C4C5 120.1(3) N12C14C15 122.0(3)
5 6 16 17 6 5 4 12 14 19
C –C 1.345(4) C –C 1.373(4) CCC 120.8(3) N C C 120.8(2)
6 7 17 18 5 6 1 15 14 19
C –C 1.501(4) C –C 1.393(4) CCN 119.5(3) C C C 117.1(3)
7 8 17 20 5 6 7 16 15 14
C –C 1.514(4) C –C 1.449(4) CCC 121.7(3) C C C 120.4(3)
7 11 18 19 1 6 7 17 16 15
C –C 1.523(4) C –C 1.362(4) NCC 118.8(2) C C C 122.3(3)
8 9 6 7 8 16 17 18
C –C 1.507(4) CCC 109.9(2) C C C 117.3(3)
6 7 11 16 17 20
CCC 110.2(2) C C C 121.8(3)
8 7 11 18 17 20
The synthesized 4-aminobenzaldehydes I–III are CCC 112.1(2) C C C 120.9(3)
reactive synthons for various chemical transforma- 9
CCC 8 7
106.1(2) C C C19 18 17
121.9(3)
tions, in particular, for condensation with hydrazides. 8 9 13 18 19 14
CCC 110.4(3) C C C 120.9(3)
Thus, reactions of the above aminoaldehydes I, III
with hydrazides of isonicotinic and salicylic acids in C8C9C10 111.5(2) O2C20C17 125.1(3)
alcoholic medium result in the corresponding hyd-
razones IV–VII in 74 and 82% yield, respectively. (CuKα, graphite monochromator, θ/2θ-scanning, 2θ ≤
Physicochemical characteristics and elemental 134°). Crystals of III are rhombic; a 11.2684(6), b 11.511
analysis data of the synthesized aminoaldehydes I–III (4), c 11.815(3) Å, V 1471.5(8) Å3, Z 4, C18H18N2O2;
and hydrazones IV–VII are presented in Table 4. space group P212121, dcalc 1.329 g cm–3. The structure
was solved by the direct method. The positions of the
Thus, we synthesized 4-aminobenzaldehydes and non-hydrogen atoms were refined by a full-matrix
potentially bioactive hydrazones on their basis. A least-square method in an anisotropic approximation.
comparative study of the influence of convection and Hydrogen atoms were placed into the geometrically
microwave heating on the yield of the target product calculated positions and included into the refinement
was performed. in the rider model, except for the aldehyde hydrogen
EXPERIMENTAL atom, which was revealed by the difference synthesis
The IR spectra were recorded on a NICOLET Table 3. Some intracyclic torsion angles in the structure of
Avatar-320 Fourier transform spectrometer from KBr III
pellets. 1H NMR spectra were registered on a Bruker
DRX500 spectrometer (500 MHz, CDCl3, DMSO-d6), Angle τ, deg Angle τ, deg
internal reference TMS. Melting points were measured 10
C NCC 1 6 7
–1.2(4) 11
C CCC 7 8 9
59.4(3)
on a Boetius instrument (measurement error ±0.1°C).
N1C6C7C8 33.7(4) C7C8C9C13 –61.6(3)
TLC analysis was carried out on Silufol UV-254 and
6 7 8 9 8 9 13 12
Sorbfil plates, detecting with iodine vapor. CCCC –63.5(3) CCC N 58.8(4)
7 8 9 10 11 12 13 9
X-Ray diffraction analysis of compound III. Unit CCCC 63.3(3) C N C C –50.9(3)
cell parameters and intensities of 2209 independent 8
CCC N 9 10 1
–32.1(3) 7
CC N C 11 12 13
47.8(3)
reflections were measured on a Xcalibur diffractometer 6
CNC C 1 10 9
0.2(4) 8
CCC N 7 11 12
–53.3(3)

RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 10 2013

 SYNTHESIS, STRUCTURE AND CHEMICAL TRANSFORMATIONS 1867

O O
H H H
C N NH2 C N N C R
H
C R 2 2
+
O 1 1
N I, ΙΙ N IV, V
1
OH OH
2
O O
3
C C
4 H
NHNH2 NHN C R
VI, VII

R= O N (I), N (II).

of the electron density and its coordinates were isotro- reaction mixture was added 100 mL of water, and the
pically refined. In the calculations 1502 reflections product was extracted with ethyl acetate (3×60 mL).
with I ≥ 2σ(I) were used. The final divergence factors The combined solutions were dried over anhydrous
are R1 0.0411, wR2 0.0893. The structure was solved Na2SO4 and evaporated to dryness. The resulting
and refined using the program packages SHELXS- 97 precipitate was recrystallized from 2-propanol.
[ 4] and SHELXL- 97 [ 5]. The coordinates of the
4-(N-Morpholinyl)benzaldehyde (I). Yield 54%,
atoms are deposited at the Cambridge Crystallographic
mp 69–70°C. IR spectrum, ν, cm–1: 1674 (С=О). 1Н NMR
Data Center (CCDC 886090).
spectrum, δ, ppm: 3.36 t [4H, N(CH2)2, JНН 4.0 Hz],
3.72 t [4H, O(CH2)2, JНН 4.3 Hz], 7.08 d (1Н, СНAr,
General procedure for the synthesis of
JНН 7.8 Hz), 7.73 d (1Н, СНAr, JНН 8.9 Hz), 9.76 s [1Н,
aminoaldehydes I–III under standard conditions.
С(О)Н]. Found, %: С 69.39; Н 7.05; N 7.37.
To a solution of 0.02 mol of 4-fluorobenzaldehyde in
С11H13NO2. Calculated, %: С 69.09; Н 6.85; N 7.32.
15 mL of DMF was added 0.022 mol of the appropriate
amine (morpholine, piperidine, or cytisine) and 4-(N-Piperidinyl)benzaldehyde (II). Yield 95%,
0.025 mol of potassium carbonate. The reaction mp 57–58°C. IR spectrum, ν, cm–1: 1674 (С=О). 1Н
mixture was heated on a glycerol bath to reflux at a NMR spectrum, δ, ppm: 1.60 br.m (6Н, СН2СН2СН2),
temperature of 140–150°C for 20 h. Then to the 3.42 t (2Н, NСН2, JНН 5.6 Hz), 7.01 d (1Н, СНAr, JНН

Table 4. Physicochemical characteristics and elemental analysis data of the compounds I–VII

Found, % Calculated, %
Comp.
Yield, %а mp, °C Formula
no. С Н С Н

I 54 (71) 69–70 69.39 7.05 С11H13NO2 69.09 6.85

II 95 57–58 81.16 8.49 С12H15NO 76.16 7.99

III 35 (67) 244–245 78.29 7.03 С19H19NO2 77.79 6.53

IV 80 256–257 70.79 6.35 С17H18N4O2 65.79 5.85

V 87 206–207 70.61 7.04 С18H20N4O 70.11 6.54

VI 83 199–200 66.95 6.39 С18H19N3O3 66.45 5.89

VII 74 227–228 71.07 7.05 С19H21N3O2 70.57 6.55

a
Yields of compounds obtained using microwave activation are given in parentheses.

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1868 NURKENOV et al.

7.2 Hz), 7.69 d (1Н, СНAr, JНН 8.9 Hz), 9.68 s [1Н, СН=N), 11.85 br.s (1Н, NH). Found, %: C 65.84; H
С(О)Н]. Found, %: С 76.32; Н 8.15; N 7.45. 5.97; N 18.10. C17H18N4O2. Calculated, %: C 65.79; H
С12H15NO. Calculated, %: С 76.16; H 7.99; N 7.40. 5.85; N 18.05.
4-(N-Cytisinyl)benzaldehyde (III). Yield 42%, N-[4-(Piperidin-1-yl)benzylidene]isonicotinylhyd-
mp 244–245°C. IR spectrum, ν, cm–1: 1674 (С=О), razide (V). Yield 87%, mp 206–207°C. IR spectrum,
1655 (С=О). 1Н NMR spectrum, δ, ppm: 1.96 br.t (2Н, ν, cm–1: 1682 (С=О). 1Н NMR spectrum, δ, ppm: 1.60
Н8), 2.57 br.s (1Н, Н9), 3.08 br. d (1Н, Н7, J 12.5 Hz), br.s (6Н, СН2СН2СН2), 3.30 t (2Н, NСН2, JНН 5.4 Hz),
3.15 d. d (1H, H11a, J11a,11e 12.3, J11a,9 2.2 Hz), 3.25 br.d 6.99 d (1Н, СНAr, JНН 6.4 Hz), 7.55 d (1Н, СНAr, JНН
(1Н, Н13а, J13a,7 2.3 Hz), 3.72 d. d (1Н, Н10а, J10a,9 5.9, 8.8 Hz), 8.77 d (1Н, СН1, JНН 6.6 Hz), 7.81 d (1Н,
J10a,10e 15.5 Hz), 3.94 d (1Н, Н10е, J10е,10а 15.4 Hz), СН2), 8.35 s (1Н, СН=N), 11.82 br.s (1Н, NH). Found,
3.95 br.s (1Н, Н13е), 4.14 br.d (1Н, Н11е, J11е,11a %: C 70.26; H 6.65; N 18.22. C17H18N4O2. Calculated,
12.5 Hz), 6.15 d.d (1Н, Н3, J3,4 9.0, J3,5 1.3 Hz), 6.22 %: C 70.11; H 6.54; N 18.17.
d.d (1Н, Н5, J5,4 6.9, J5,3 1.3 Hz), 6.91 d (2НAr, J
2-Hydroxy-N-(4-(piperidin-1-yl)benzylidene)-
8.9 Hz), 7.32 d. d (1Н, Н4, J4,5 6.9, J4,3 9.0 Hz), 7.62 d
benzohydrazide (VII). Yield 74%, mp 227–228°C. IR
(2НAr, J 8.9 Hz), 9.66 s [1Н, С(О)Н]. Found, %: C
spectrum, ν, cm–1: 1662 (C=O). 1H NMR spectrum, δ,
73.87; H 6.54; N 4.82. C18H18N2O2. Calculated, %: C
ppm: 1.58 br.s (6Н, СН2СН2СН2), 3.36 s (2Н, NСН2),
73.45; H 6.16; N 4.77.
6.98 d (1Н, СНAr, JНН 6.8 Hz), 7.56 d (1Н, СНAr, JНН
General procedure for the synthesis of amino- 8.8 Hz), 7.43 t (1Н, СН2Ar, JНН 6.9 Hz), 6.95 d (1Н,
aldehydes I, III under microwave irradiation. To a СН3Ar, JНН 7.4 Hz), 7.90 d (1Н, СН4Ar, JНН 7.8 Hz), 8.33
solution of 0.02 mol of 4-fluorobenzaldehyde in 15 mL s (1Н, СН=N), 11.67 br.s (1H, OH), 12.08 br.m (1Н,
of DMF was added 0.022 mol of the appropriate amine NH). Found, %: C 70.59; H 6.61; N 13.22. C19H21N3O2.
(morpholine or cytisine) and 0.025 g of potassium Calculated, %: C 70.54; H 6.55; N 12.99.
carbonate. The reaction mixture was irradiated in a
microwave device LG MS2022G at irradiation power REFERENCES
of 500 W for 30 min with minor interruptions. Then to 1. Villemin, D., Martin, В., and Bar, N., Molecules, 1998,
the reaction mixture was added 100 mL of water, and no. 3, p. 88.
the product was extracted with ethyl acetate (3×60 mL). 2. Lacova, M., Gasparova, R., Loos, D., Liptay, T., and
The combined solutions were dried over anhydrous Pronayova, N., Molecules, 2000, no. 5, p. 167.
Na2SO4 and evaporated to dryness. The resulting 3. Kubrakova, I.V., Myasoedova, G.V., and Eremin, S.A.,
precipitate was recrystallized from 2-propanol. Zh. Analit. Khim., 2006, no. 2, p. 27.
General procedure for the synthesis of hyd- 4. D’yachenko, E.V., Glukhareva, T.V., Nikolaenko, E.F.,
Tkachev, A.V., and Morzherin, Yu.Yu., Russ. Chem.
razones IV–VII. To a solution of 0.003 mol of amino-
Bull., 2004, no. 6, p. 1240.
benzaldehyde I, III in 10 mL of ethanol was added
5. Giguire, R.J., Bray, T.L., Dunkan, S.M., and Majetich, G.,
0.003 mol of the appropriate hydrazide (isonicotinyl-
Tetrahedron Lett., 1986, vol. 27, p. 4945.
hydrazine, salicylic acid hydrazide). The reaction mix-
6. Microwaves in Organic Synthesis, Loupy, A., Ed.,
ture was refluxed at 60–70°C for 2–2.5 h. The pre- Weinheim: Wiley-VCH, 2002, ch. 12, p. 405.
cipitate formed was filtered off, washed with ethanol,
7. Wan, Y., J. Med. Chem., 2004, no. 47, p. 5995.
dried, and recrystallized from 2-propanol.
8. Erdelyi, M. and Gogoll, A., Synthesis, 2002, no. 11,
N-(4-Morpholinobenzylidene)isonicotinylhydra- p. 1592.
zide (IV). Yield 80%, mp 256–257°C. IR spectrum, ν, 9. Murray, J.K., J. Am. Chem. Soc., 2005, no. 127, p. 13271.
cm–1: 1680 (С=О). 1Н NMR spectrum, δ, ppm: 3.23 t 10. Kulakov, I.V., Turdybekov, D.M., Zhambekov, Z.M.,
[4H, N(CH2)2, JНН 4.2 Hz], 3.74 t [4H, O(CH2)2, JНН Nurkenov, O.A., Ibragimov, B.T., Talipov, S.A., and
4.5 Hz], 7.02 d (1Н, СНarom, JНН 6.2 Hz), 7.61 d (1Н, Turdybekov, K.M., Khim. Prirod. Soed., 2009, no. 5,
СНAr), 8.78 d (1Н, СН1), 7.80 d (1Н, СН2), 8.35 s (1Н, p. 572.

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