Single-Pot Synthesis Method of 2-Hydroxybenzylidene-4-[(aza, thio)xanthenyl]anilines and Their Plant Growth Regulator Activity

Article abstract of DOI:10.1134/S1070363219040042

The synthesis of 2-hydroxybenzylidene-4-[(aza, thio)xantenyl]anilines has been carried out via the reaction of 2-hydroxybenzaldehyde, aniline, and (aza, thio)xanthydrol in acetic acid or ethanol medium. Two competing pathways leading the formation of 2-hy

Full text of DOI:10.1134/S1070363219040042

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 4, pp. 663–667. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Authors(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 4, pp. 522–527.
Single-Pot Synthesis Method
of 2-Hydroxybenzylidene-4-[(aza, thio)xanthenyl]anilines
and Their Plant Growth Regulator Activity
V. Yu. Gorokhova*, Ya. V. Bykova, S. A. Batueva, E. A. Lystsovab,
S. M. Gorokhovaa, and N. N. Yaganovaa
a Academician D.N. Pryanishnikov Perm State Agro-Technological University, ul. Petropavlovskaya 23, Perm, 614000 Russia
*e-mail: Gorokhov_V.Yu@mail.ru
b Perm State National Research University, Perm, Russia
Received November 1, 2018; revised November 1, 2018; accepted November 8, 2018
Abstract—The synthesis of 2-hydroxybenzylidene-4-[(aza, thio)xantenyl]anilines has been carried out via the
reaction of 2-hydroxybenzaldehyde, aniline, and (aza, thio)xanthydrol in acetic acid or ethanol medium. Two
competing pathways leading the formation of 2-hydroxybenzylidene-4-[(aza, thio)xantenyl]anilines have been
revealed by means of chromato−mass spectrometry. The growth-regulating activity of 2-hydroxybenzylidene-4-
(5H-benzopyrano[2,3-b]-pyridin-5-yl)aniline towards spring wheat (Gornouralskaya variety) has been studied.
Keywords: 4-heterylacetanilides, 2-hydroxybenzylidene-4-[(aza, thio)xantenyl]anilines, aromatic imines, plant
growth regulators
DOI: 10.1134/S1070363219040042
The interest to N-benzylideneaniline is due to their
diverse biological activity. The species exhibiting
antioxidant [1], antituberculous [2], and antibacterial
activity [3] are known among this class of compounds.
Some aromatic imines are used in agriculture as plant
growth regulators [4–9].
heterocyclic substituent (9Н-xanthene, 9Н-thioxanthene,
or 1-azaxanthene) in acetic acid medium [25] and have
investigated antimicrobial activity of some of them [26].
This study aimed to elucidate the effect of the
solvation factor on the direction of a single-pot syn-
thesis of 2-hydroxybenzylidene-4-[(aza,thio)xanthenyl]-
anilines and investigate their utilitarian properties.
The known methods of synthesis of aromatic
imines include direct interaction between benzal-
dehyde and aniline (or their derivatives) in the medium
of toluene [10–11], ethanol [13–16], methanol [17],
ethanol–acetic acid [18, 19], or in the absence of any
solvent [20]. N-Benzylideneanilines (imines) can be
also obtained via the condensation of benzyl alcohol
with aniline in toluene in the presence of molecular
oxygen and catalysts based on Au, Pd, Ru [21], or via
condensation of aromatic nitroso compounds with the
species containing activated methylene group [22].
The formation of derivatives of N-benzylideneanilines
in the reactions of dehydrogenation of the corresponding
tertiary amines has been demonstrated [23, 24].
Single-pot synthesis of 2-hydroxybenzylidene-4-
[(aza,thio)xanthenyl]anilines 4a–4c was performed via
the interaction of 2-hydroxybenzaldehyde 1, aniline 2,
and the corresponding hydrols (9Н-xanthen-9-ol 3a,
5H-benzopyrano[2,3-b]pyridin-5-ol 3b, or 9Н-thio-
xanthen-9-ol 3c) in 43% acetic acid or 96% ethanol in
the presence of hydrochloric acid(Scheme 1). When
acetic acid was used as solvent, the yield of the target
product was of 47–60%, being of 45–84% in the case
of ethanolic medium.
Several competing pathways of the reaction can
often be operative in multicomponent systems.
Detailed investigation of the influence of the solvent
nature on the course of the considered reaction was
performed by means of chromato–mass spectrometry
(Table 1). The obtained data revealed two directions of
We have earlier elaborated a synthetic method
allowing the preparation of para-substituted N-benzyl-
ideneanilines the aniline part of which contains a
663

664
GOROKHOV et al.
Scheme 1.
H2N
CHO
OH
HtOH
+
+
N
Ht
OH
2
3a−3c
4a−4c
1
(a),
(b),
(c).
Ht =
O
N
O
S
Scheme 2.
CHO
OH
1
−H2O
N
Ht
H2N
H2N
OH
AcOH
−H2O
а
+ HtOH
4a−4c
Ht
H
N
3a−3c
2
A
AcOH
O
−H2O
Ht
5a−5c
the formation of 2-hydroxybenzylidene-4-[(aza,thio)-
xanthenyl]anilines 4a–4c. In detail, the acylation of
intermediate A affording 4-heterylacetanilides 5a–5c
was found competing with the formation of the final
products 4a–4c in the acetic acid medium, hence, the
reaction occurred via pathway a (Scheme 2).
mass. The low content of compound 4b was likely
related to low rate of heterylation (pathway b, Scheme 3).
In the case of xanthydrol 3a, the yield of the target
product 4a was high, but intermediate B was not
detected, probably due to fast heterylation.
Analysis of the reaction mixture during the process
involving thioxanthydrol 3c revealed approximately
equal contents of 4-thioxanthenylacetanilide 5c and
intermediate B, pointing at the formation of compound
The reaction involving azaxanthydrol 3b in
ethanolic medium occurred predominantly through the
formation of intermediate B detected in the reaction
Table 1. The effect of solvent on the composition of reaction mixture during synthesis of 2-hydroxybenzylidene-4-[(aza,thio)-
xanthenyl]anilines 4a–4c
Content, %
Reaction mixture component
3a
3b
3c
AcOH
–
EtOH
5.06
–
AcOH
10.16
57.94
27.23
4.67
EtOH
0.32
26.36
73.32
–
AcOH
0.25
EtOH
Intermediate A
Intermediate B
4a–4c
–
–
–
20.22
63.07
16.46
99.06
0.94
94.94
–
100
–
5a–5c
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019

SINGLE-POT SYNTHESIS METHOD
665
Scheme 3.
b
EtOH
HCl
CHO
OH
H2N
3a−3c
+
−H2O
−H2O
N
Ht
N
OH
OH
B
4a−4c
2
1
4c via the pathway a or b. When the solvent was
changed to ethanol (thus excluding the competing
acylation process), the formation of compounds 4a–4c
occurred via pathway b, the target products yield being
slightly improved.
enhanced the intensity of nutritive materials consump-
tion by the plant.
When applied in concentration of 0.005 and
0.001%, the tested compound increased the number of
grains per raceme by 2–3%, and biological productivity
of the wheat was increased by 0.13–0.15 t/ha with
respect to the control experiment as well as the
reference active compound (Table 4).
We further assessed the growth regulation activity
of the heterylated imines towards spring wheat
(Gornouralskaya) via a known method [27]. We
selected compound 4b for that study, since it contained
two potentially physiologically active fragments (azo-
methine and azaxanthene) capable of growth
regulation [4–9, 28].
In summary, the change of the solvent (acetic acid
to ethanol) in the synthesis of 2-hydroxybenzylidene-4-
[(aza,thio)xanthenyl]anilines led to slight increase in
the yield of the target products and avoided the
formation of the side products (acetanilides). The
agrochemical experiments revealed positive effect of 2-
hydroxybenzylidene-4-(5Н-benzopyrano[2,3-b]pyridin-
5-yl)aniline on the growth and productivity of the
Gornouralskaya spring wheat, the active component
concentration being 0.005 or 0.001%.
According to the data in Table 2, compound 4b
applied in concentration of 0.001% enhanced the
number of productive plants by 5%, and the total
number of stems was increased by 7–13% over the
entire concentration range studied. When applied in
concentrations 0.001 and 0.0005%, it induced the
increase in the average height of the plants by 8 and
6%, respectively, the straw mass was increased by 22–
23% at the compound concentration 0.005 and
0.0001%, and the ear mass was increased by 5–12%
(Table 3).
EXPERIMENTAL
1Н NMR spectra were recorded using a Mercury
300ВВ instrument (Varian, USA) (300 MHz, СDCl3,
HMDS as internal reference). Mass spectra were
obtained using an Agilent Technologies 6890N/5975B
chromato–mass spectrometer (USA); column НР-5ms
(30 × 0.25 mm, 0.25 μm), helium as carrier gas,
A distinct feature of the action of compound 4b was
significant (by 98%) increase in the wheat roots mass
when applied in concentration of 0.001%, which
Table 2. Growth of winter wheat (Gornouralskaya) affected by compound 4b
Number of plants
Number of stems
productive
total
productive
change, +/–
total
Experiment
с, %
pc/m2 change, +/– pc/m2
pc/m2
change, +/–
pc/m2
change, +/–
Control
Reference
4b
290
258
290
304
284
256
–
290
258
282
304
218
256
–
348
356
372
384
392
380
–
338
326
338
326
338
326
–
–16
0
–16
–4
+3
–6
+2
+9
+14
+5
0.0050
0.0010
0.0005
0.0001
+12
+17
+21
+15
+7
–4
–17
+7
–36
–17
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019

666
GOROKHOV et al.
Table 3. Effect of compound 4b on vegetative and generative parts of the wheat
Average height
Straw mass
Ears mass
change, +/–
Roots mass
change, +/–
Experiment
с, %
cm
change, +/–
–
g
change, +/–
–
g
g
Control
Reference
4b
94.50
89.30
88.60
305.56
354.98
371.58
250.84
184.80
240.70
–
121.10
195.04
239.34
–
–5.17
–5.90
+24.71
+23.01
–33.02
–5.07
+36.97
+59.12
0.0050
0.0010
0.0005
101.75
100.75
–+7.25
–+6.25
356.42
314.18
+25.43
+4.31
274.08
262.54
–+11.62
– +5.85
130.36
164.36
+4.63
+21.63
0.0001
101.00
–+6.50
374.92
+34.68
281.60
–+15.38
159.92
+19.41
electron impact ionization at 70 eV, column
temperature 100°С. The compounds purity was deter-
NMR spectrum, δ, ppm: 5.27 s (1Н, С9Н, Ht), 6.85–
7.37 m (16Н, Ar + Ht), 8.54 s (1Н, СН=N), 13.20 br. s
(1Н, ОН). Mass spectrum, m/z (Irel, %): 377 (69) [М]+,
360 (1), 271 (1), 257 (10), 196 (1.1), 181 (100), 120
(0.6), 76 (1.7).
mined
by
means
of
TLC
on
Sorbfil
PTSKh-P-A-UV plates.
Compounds 4a–4c (general procedure). A mixture
of equimolar (1 mmol each) of 2-hydroxybenzal-
dehyde 1, aniline 2, and the corresponding hydrol 3a–
3c in 7 mL of 43% acetic acid (or 7 mL of 96%
ethanol with 1 drop of 36% hydrochloric acid) was
heated during 10 min at 90°С. The reaction mass was
cooled and neutralized with 25% ammonia solution.
The crystalline precipitate was washed with water and
recrystallized from ethanol.
2-Hydroxybenzylidene-4-(5Н-benzopyrano[2,3-
b]pyridin-5-yl)aniline (4b). Yield 0.22 g (60%, AcOH),
0.17 g (45%, EtOH + HCl), yellow crystals, mp 194°С
1
(EtOH). Н NMR spectrum, δ, ppm: 5.34 s (1Н, С5Н,
Ht), 6.89–7.44 m (15Н, Ar + Ht), 8.20–8.21 m (1Н,
СН=N, Ht), 8.56 s (1Н, СH=N), 13.14 br. s (1Н, ОН).
Mass spectrum, m/z (Irel, %): 378 (78) [М]+, 361 (1),
260 (14), 258 (10.5), 196 (1.5), 182 (100), 120 (1), 76
(2.5).
2-Hydroxybenzylidene-4-(9Н-xanthen-9-yl)-aniline
(4a). Yield 0.18 g (49%, AcOH), 0.32 g (84%, EtOH +
HCl), light-yellow crystals, mp 177–178°С (EtOH). 1Н
2-Hydroxybenzylidene-4-(9Н-thioxanthen-9-yl)-
aniline (4c). Yield 0.35 g (47%, AcOH), 0.28 g (74%,
Table 4. Effect of compound 4b on the wheat crop productivity
Number of
productive stems
Number of grains in
raceme
Mass of 1000
grains
Productivity of
raceme
Biological
productivity
Experi-
ment
с, %
pc/m2
pc
g
g
t/ha
Control
Reference
4b
338
326
338
326
338
326
–
–6
14.08
14.33
14.43
14.53
14.28
14.53
–
35.23
–
0.50
0.49
0.48
0.51
0.50
0.50
–
–0.01
–0.02
+0.01
0
1.69
1.60
1.64
1.82
1.84
1.75
–
+0.25
+0.35
+0.45
+0.20
+0.45
34.44
33.33
35.05
35.32
34.66
–0.79
–1.90
–0.18
+0.09
–0.57
–0.09
–0.05
+0.13
+0.15
+0.06
0.0050
0.0010
0.0005
0.0001
+2
+9
+15
+6
0
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019

SINGLE-POT SYNTHESIS METHOD
667
1
10. Hania, M.M., Eur. J. Med. Chem., 2009, vol. 6, no. 3,
EtOH + HCl), yellow crystals, mp 150°С (EtOH). Н
NMR spectrum, δ, ppm: 5.35 s (1Н, С9Н, Ht), 6.84–
7.64 m (16Н, Ar + Ht), 8.51 s (1Н, СН=N), 13.21 br. s
(1Н, ОН). Mass spectrum, m/z (Irel, %): 393 (64) [М]+,
376 (0.7), 288 (0.6), 273 (6.8), 197 (100), 182 (100),
196 (4.2), 120 (0.6), 76 (2).
p. 629.
11. Dutta, S., Pharm. Chem. J., 2014, vol. 48, no. 7, p. 448.
doi 10.1007/S11094-014-1129-0
12. De-Chun, Z., Acta Crystallogr., 2002, vol. 58, p. 351.
doi 10.1107/S0108270102006479
13. Senthilkannan, K. and Gunasekaran, S., Int. J. Chem.
Tech. Res., 2013, vol. 5, no. 6, p. 3051.
N-[4-(9H-Xanthen-9-yl)phenyl]acetamide (5a) could
not be isolated in the individual form. Mass spectrum,
m/z (Irel, %): 315 (41.0) [М]+, 257 (7.0), 181 (100), 152
(8.2).
14. Hankare, A.S. and Barhate, V.D., Int. J. Curr. Pharm.
Res., 2014, vol. 6, no. 1, p. 30.
15. Ibrahim, M.N., Hamad, K.J., and Al-Joroshi, S.H.,
Asian J. Chem., 2006, vol. 18, no. 3, p. 2404. doi
10.1007/s10973-015-4617-x
N-[4-(5H-Chromeno[2,3-b]pyridin-5-yl)phenyl]-
acetamide (5b) could not be isolated in the individual
form. Mass spectrum, m/z (Irel, %): 316 (37.7) [М]+,
273 (16.4), 182 (100), 43 (12.5).
16. Bae, S.J., Ha, Y.M., Park, Y.J., Park, J.Y., Song, Y.M.,
Ha, T.K., Chun, P., Moon, H.R., and Chung, H.Y., Eur.
J. Med. Chem., 2012, vol. 57, p. 383. doi 10.1016/
j.ejmech.2012.09.026
N-[4-(9H-Thioxanthen-9-yl)phenyl]acetamide (5c)
could not be isolated in the individual form. Mass
spectrum, m/z (Irel, %): 331 (31.6) [М]+, 288 (7.9), 197
(100), 165 (10.5).
17. Dikusar, E.A., Potkin, V.I., and Stopin, S.G., Vestn.
Vitebsk. Gos. Tekhnol. Univ., 2012, no. 22, p. 116.
18. Upadhyaya, K., Gude, V., Mohiuddin, G., and
Nandiraju, R.V.S., Beilstein J. Org. Chem., 2013, vol. 9,
p. 26. doi 10.3762/bjoc.9.4.
CONFLICT OF INTERESTS
No conflict of interest was declared by authors.
REFERENCES
19. Yong-S.Y., Jun-Hwan, I., Bong-Hwan, H., Myongsoo, L.,
and Moon-Gun, C., Bull. Korean Chem. Soc., 2001,
vol. 22, no. 12, p. 1350.
20. Schmeyers, J., Toda, F., Bo, J., and Kaupp, G., J. Chem.
Soc. Perkin Trans. 2, 1998, p. 989. doi 10.1039/
A704633B
1. Calil, N.O., de Carvalho, G.S.G., Zimmermann Franco, D.C.,
da Silva, A.D., and Barbosa Rapos, N.R., Lett. Drug
Design Discov., 2012, no. 9, p. 8. doi 10.2174/
157018012798192928
21. Hao, S., Fang-Zheng, S., Ji, N., Yong, C., He-Yong, H.,
and Kang-Nian, F., Angew. Chem. Int. Ed., 2009,
vol. 48, p. 4390. doi 10.1002/anie.200900802
2. Tlegenov, R.T., Khim. Rast. Syr’ya, 2007, no. 4, p. 69.
22. Ehrlich, P. and Sachs, F., Ber., 1899, vol. 32, p. 2341.
23. Yunnikova, L.P., Chem. Heterocycl. Compd., 1995,
vol. 31, no. 7, p. 877. doi 10.1007/BF01170754
24. Yunnikova, L.P., Zh. Org. Khim., 1995, vol. 31, no. 1,
3. Karki, S.S., Butle, S.R., Shaikh, R.M., Zubaidha, P.K.,
Pedgaonkar, G.S., Shendarkar, G.S., and Rajput, C.G.,
Res. J. Pharm. Biol. Chem. Sci., 2010, vol. 1, no. 4,
p. 707.
4. Johnson, W.O., Warner, H.L., and Yih, R.Y., USA
Patent 3862833, 1975.
5. Huneck, S., Schreiber, K., Schulze, C., and Sembdner, G.,
DDR Patent 122915, 1976.
6. Grimmecke H-D., Huneck, S., Schreiber, K., Schulze, C.,
and Sembdner, G., DDR Patent 123053, 1976.
p. 76.
25. Gorokhov, V.Y., and Shchurenko, S.М., Butlerov.
Soobshchen., 2014, vol. 39, no. 8, p. 91.
26. Gorokhov, V.Y. and Makhova, T.V., Pharm. Chem. J.,
2016, vol. 50, no. 8, p. 530. doi 10.1007/s11094-016-
1483-1
7. Mazitova, A.K., Khamaev, V.Kh., Aminova, G.K.,
Suhareva, I.A., and Spars, N.P., FR Patent 2146251,
1999; Buyll. Izobret., 1996, no. 6.
8. Mazitova, A.K., Khamaev, V.Kh., Suhareva, I.A., and
Ulyamaeva, E.Sh., RF Patent 2146252, 1999; Buyll.
Izobret., 1996, no. 6.
27. Dospekhov, B.A., Metodika polevogo opyta (s osnovami
statisticheskoi obrabotki rezul’tatov issledovanii)
[Methods of Field Experience (with the Basics of
Statistical Processing of Research Results)], Moscow:
Kniga po Trebovaniyu, 2012.
28. Peter, P., Costin, R., Norbert, M., Juergen, K., Uwe, K.,
Matthias, G., Helmut, W., Andreas, L., and Karlotto, W.,
EU Patent 1994/000073, 1994.
9. Timofeev, V.P., Selimov, F.A., and Dzhemelev, U.M.,
RF Patent 2101277С1, 1998; Buyll. Izobret., 2006, no. 31.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019