Synthesis of (E)-4-ethoxyphenyliminomethylaryls and their hydrochlorides

Article abstract of DOI:10.1134/S1070363212110175

Condensation of p-phenetidine with the substituted aromatic benzaldehydes in methanol results in (E)-4-methylethoxyphenyliminoaryl derivatives. The latter react with gaseous hydrogen chloride in diethyl ether to form 4-ethoxymethylphenyliminoaryl hydrochl

Full text of DOI:10.1134/S1070363212110175

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 11, pp. 1830–1833. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © E.A. Dikusar, V.I. Potkin, N.G. Kozlov, S.G. Stepin, R.T. Tlegenov, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82,
No. 11, pp. 1840–1843.
Synthesis of (E)-4-Ethoxyphenyliminomethylaryls
and Their Hydrochlorides
E. A. Dikusara, V. I. Potkina, N. G. Kozlova, S. G. Stepinb, and R. T. Tlegenovc
a Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
ul. Surganova 13, Minsk, 220072 Belarus
e-mail: dikusar@ifoch.bas-net.by
b Vitebsk State Technological University, Vitebsk, Belarus
cKara-Kalpak State University, Nukus, Uzbekistan
Received November 1, 2011
Abstract—Condensation of p-phenetidine with the substituted aromatic benzaldehydes in methanol results in
(E)-4-methylethoxyphenyliminoaryl derivatives. The latter react with gaseous hydrogen chloride in diethyl
ether to form 4-ethoxymethylphenyliminoaryl hydrochlorides.
DOI: 10.1134/S1070363212110175
p-Phenetidine (4-ethoxyaniline) I has acquired
special importance as the starting material for the
synthesis of numerous febrifuge, antipyretic, and anti-
neuralgic drugs, beginning with phenacetin (acetyl-p-
phenetidine) obtained in 1887 [1].
In this work we have developed a preparative
method for the synthesis of new (E)-4-ethoxy-
phenyliminomethylaryl derivatives IIIa–IIIv, IVa–
IVj, VIIa–VIId in the yield of 87–93% via the
condensation of p-phenetidine I with aromatic alde-
HCl
OEt
OEt
N
N
NH2
HC
HC
CHO
R2
R2
R2
HCl
+
R
R
R
R1
II
R1
IIIа–IIIv, IVа–IVj
R1
Vа–Vv, VIа–VIj
OEt
I
II, III, V, R = R1 = R2 = H (а); R = R1 = H, R2 = 4-OH (b), 4-OMe (c); R = H, R1 = 2-OH, R2 = 4-OH (d), 3-OMe (e); R =
H, R1 = 3-OH, R2 = 4-OMe (f); R = H, R1 = 3-OMe, R2 = 4-OH (g), R2 = 4-OМе (h); R = 3-OMe, R1 = 4-OMe, R2 = 6-Br
(i); R = H, R1 = 3-OMe, R2 = 4-OOCMe (j), 4-OOCEt (k), 4-OOCPr (l), 4-OOC-i-Pr (m), 4-OOCBu (n), 4-OOC-i-Bu (o),
4-OOC(CH2)8Me (p), 4-OOC(CH2)11Me (q), 4-OOC(CH2)16Me (r), 4-OOCPh (s), 4-OOCPh-2,4-Cl2 (t), 4-OCOOMe (u),
4-COO-Ad-1 (v); IV, VI, R = H, R1 = 3-OEt, R2 = 4-OH (a), 4-OMe (b), 4-OOCMe (c), 4-OOCEt (d), 4-OOCPr (e),
4-OOC-i-Pr (f), 4-OOCBu (g), 4-OOC-i-Bu (h), 4-OOCPh (i), 4-OOCPh-4-Me (j).
Ft
N
Ft
HC
N
Ft
OH
HC
N
HC
HO
HO
R3O
Me
O
C
CH2
Me
Me
2
CH
VIIа
O
2
N
Ft
VIIb, VIIc
VIId
VIIа–VIId, Ft = 4-OEtC6H4, R3 = Me (b), Et (c).
1830

SYNTHESIS OF (E)-4-ETHOXYPHENYLIMINOMETHYLARYLS
1831
Table 1. Yields, melting points, and elemental analysis data of azomethines IIIa–IIIv, IVa–IVj, VIIa–VIId
Found, %
Calculated, %
М
Comp. Yield,
mp, °С
Formula
no.
%
C
H
N
C
H
N
found
calculated
87
89
88
92
90
92
93
91
88
87
87
88
90
90
91
87
89
91
90
92
90
88
90
89
93
92
91
90
89
88
90
75–76
217–218
132–133
167–168
99–100
142–143
106–107
105–106
117–118
97–98
90–91
57–58
85–86
74–75
77–78
65–66
57–58
73–74
146–147
114–115
107–108
156–157
109–110
101–102
88–89
77–78
83–84
93–94
73–74
80.23 6.85
74.90 6.42
75.56 6.80
70.39 6.02
71.13 6.38
71.20 6.44
71.17 6.45
71.84 6.87
56.51 5.14
69.20 6.19
70.03 6.56
70.64 6.95
70.72 6.83
71.38 7.19
71.25 7.10
73.57 8.36
74.90 8.84
76.18 9.65
73.84 5.72
62.41 4.33
65.86 5.92
77.00 6.68
71.86 6.78
72.18 7.21
69.92 6.51
70.56 7.03
71.15 7.16
71.06 7.22
71.87 7.40
71.70 7.51
74.25 6.14
5.89
5.42
5.12
5.05
4.87
4.91
4.80
4.65
3.67
4.21
3.95
3.88
3.75
3.65
3.86
3.20
2.67
2.18
3.28
2.80
3.85
2.64
4.62
4.48
4.03
3.86
3.81
3.60
3.29
3.52
3.28
C15H15NO
C15H15NO2
C16H17NO2
C15H15NO3
C16H17NO3
C16H17NO3
C16H17NO3
C17H19NO3
C17H18BrNO3
C18H19NO4
C19H21NO4
C20H23NO4
C20H23NO4
C21H25NO4
C21H25NO4
C26H35NO4
C29H41NO4
C34H51NO4
C23H21NO4
79.97
74.67
75.27
70.02
70.83
70.83
70.83
71.56
56.06
68.99
69.71
70.36
70.36
70.96
70.96
73.38
74.48
75.94
73.58
6.71
6.27
6.71
5.88
6.32
6.32
6.32
6.71
4.98
6.11
6.47
6.79
6.79
7.09
7.09
8.29
8.84
9.56
5.64
4.31
5.81
6.65
6.71
7.07
6.47
6.79
7.09
7.09
7.37
7.37
5.95
6.22
5.81
5.49
5.44
5.16
5.16
5.16
4.91
3.85
4.47
4.28
4.10
4.10
3.94
3.94
3.29
3.00
2.60
3.73
3.15
4.25
2.98
4.91
4.68
4.28
4.10
3.94
3.94
3.79
3.79
3.60
219
234
246
251
262
264
266
279
357
306
319
333
336
348
346
409
450
527
366
431
322
456
276
284
322
332
348
346
361
363
382
225
241
255
257
271
271
271
285
364
313
327
341
341
355
355
426
468
538
375
444
329
470
285
299
327
341
355
355
369
369
389
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIia
IIIj
IIIk
IIIl
IIIm
IIIn
IIIo
IIIp
IIIq
IIIr
IIIs
IIItb
IIIu
IIIv
IVa
IVb
IVc
IVd
IVe
IVf
C23H19Cl2NO4 62.17
C18H19NO5
C30H31NO4
C17H19NO3
C18H21NO3
C19H21NO4
C20H23NO4
C21H25NO4
C21H25NO4
C22H27NO4
C22H27NO4
C24H23NO4
65.64
76.73
71.56
72.22
69.71
70.36
70.96
70.96
71.52
71.52
74.02
IVg
IVh
IVi
84–85
138–139
90
89
90
91
155–156
205–206
204–205
171–172
74.15 6.38
80.48 6.19
69.47 6.03
70.13 6.28
3.06
5.78
4.40
3.87
C25H25NO4
C30H28N2O2
C36H36N2O8
C38H40N2O8
74.42
80.33
69.22
69.92
6.25
6.29
5.81
6.18
3.47
6.25
4.48
4.29
389
Insoluble
603
403
449
625
653
IVj
VIIa
VIIb
VIIc
640
87
282–283
73.50 6.36
3.38
C46H48N2O8
73.00
6.39
3.70
Insoluble
757
VIId
a Found Br, %: 21.46. Calculated Br, %: 21.94. b Found Cl, %: 15.58. Calculated Cl, %: 15.96.
hydes
II:
benzaldehyde,
anisaldehyde,
and
anhydrous ether results in the corresponding 4-
ethoxyphenyliminomethylaryl hydrochlorides Va–Vv,
VIa–VIj in the yield of 89–95%. Under the reaction
conditions, the hydrolysis of the ester side groups in
compounds Vj–Vv, VIc–VIj did not occur. We failed
to obtain the hydrochlorides of dibasic Schiff bases
VIIa–VIId because of their low solubility in diethyl
ether and benzene.
veratraldehyde, aldehydes of the vanillin series, 4,4'-
diformylbiphenyl and gossypol [2,2'-bis(1,6,7-trioxo-
3-methyl-5-isopropyl-8-naphthaldehyde]. The synthesis
was carried out in anhydrous methanol at reflux.
The reaction of the monobasic azomethines IIIa–
IIIv, IVa–IVj with the gaseous hydrogen chloride in
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 11 2012

1832
DIKUSAR et al.
Table 2. Yields, melting points, and elemental analysis data of hydrochlorides Va–Vv, VIa–VIj
Found, %
Calculated, %
Comp.
no.
mp,
°С
Yield, %
Formula
C
H
Cl
N
C
H
Cl
N
91
92
90
93
94
93
93
89
90
94
94
93
92
95
93
93
94
92
92
90
89
91
90
93
93
92
92
93
92
95
94
90
112–113
229–230
192–193
134–135
177–178
184–185
119–120
237–238
189–190
197–198
176–177
168–169
177–178
163–164
169–170
157–158
151–152
84–85
221–222
203–204
186–187
206–207
117–118
223–224
173–174
183–184
180–181
188–189
161–162
169–170
191–192
205–206
69.24
65.09
66.13
61.50
62.81
62.19
62.60
63.78
51.15
62.12
63.20
63.93
63.84
64.65
64.10
67.88
69.54
71.37
67.39
57.82
59.45
71.53
63.56
64.58
62.95
63.49
64.76
64.25
65.65
65.70
68.11
68.72
6.28
5.73
6.08
5.28
6.10
5.99
6.05
6.41
4.22
5.48
6.18
6.45
6.61
6.40
6.92
8.04
8.57
9.35
5.46
4.18
5.73
6.41
6.38
6.47
6.24
6.61
6.92
6.78
7.09
7.24
5.43
6.13
13.10
12.22
12.04
11.70
11.19
11.40
11.28
10.59
28.60
10.19
9.31
9.02
8.99
8.73
8.87
7.18
6.65
5.80
8.19
21.91
9.58
6.86
10.62
10.23
9.51
9.18
8.46
8.59
8.34
5.14
4.86
4.66
4.45
4.30
4.21
4.62
4.03
3.23
3.68
3.44
3.73
3.36
3.25
3.19
2.76
2.41
2.07
3.20
2.66
3.47
2.53
3.99
3.85
3.54
3.37
3.22
3.15
3.05
3.41
2.92
2.84
C15H16ClNO
C15H16ClNO2
C16H18ClNO2
C15H16ClNO3
C16H18ClNO3
C16H18ClNO3
C16H18ClNO3
C17H20ClNO3
68.83
64.87
65.86
61.33
62.44
62.44
62.44
63.45
6.16
5.81
6.22
5.49
5.89
5.89
5.89
6.26
4.78
5.76
6.09
6.40
6.40
6.69
6.69
7.85
8.40
9.13
5.38
4.19
5.51
6.37
6.26
6.60
6.09
6.40
6.69
6.69
6.95
6.95
5.68
5.96
13.54
12.76
12.15
12.07
11.52
11.52
11.52
11.02
28.79
10.13
9.74
9.38
9.38
9.05
9.05
7.67
7.03
6.17
8.61
22.12
9.69
7.01
11.02
10.56
9.74
9.38
9.05
9.05
8.73
5.35
5.04
4.80
4.77
4.55
4.55
4.55
4.35
3.50
4.00
3.85
3.71
3.71
3.57
3.57
3.03
2.78
2.44
3.40
2.91
3.83
2.77
4.35
4.17
3.85
3.71
3.57
3.57
3.45
3.45
3.29
3.18
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
Vi
Vj
Vk
Vl
Vm
Vn
Vo
Vp
Vq
Vr
C17H19BrClNO3 50.96
C18H20ClNO4
C19H22ClNO4
C20H24ClNO4
C20H24ClNO4
C21H26ClNO4
C21H26ClNO4
C26H36ClNO4
C29H42ClNO4
C34H52ClNO4
C23H22ClNO4
C23H20Cl3NO4
C18H20ClNO5
C30H32ClNO4
C17H20ClNO3
C18H22ClNO3
C19H22ClNO4
C20H24ClNO4
C21H26ClNO4
C21H26ClNO4
C22H28ClNO4
C22H28ClNO4
C24H24ClNO4
C25H26ClNO4
61.80
62.72
63.57
63.57
64.36
64.36
67.59
69.10
71.11
67.07
57.46
59.10
71.21
63.45
64.38
62.72
63.57
64.36
64.36
65.10
65.10
67.68
68.25
Vs
Vt
Vu
Vv
VIa
VIb
VIc
VId
VIe
VIf
VIg
VIh
VIi
VIj
8.19
8.38
7.76
8.73
8.32
8.06
The synthesized compounds IIIa–IIIv, IVa–IVj,
Va–Vv, VIa–VIj, VIIa–VIId are stable yellow or
orange crystalline substances with the clear melting
points (Tables 1, 2). Azomethines IIIa–IIIv, IVa–IVj
are soluble in diethyl ether, benzene, chloroform, and
DMSO, and insoluble in water. The hydrochlorides
Va–Vv, VIa–VIj are insoluble in nonpolar aprotic
solvents, but they are soluble in alcohol, acetone,
DMSO, and moderately soluble in water. This fact
makes convenient and promising the study of their
biological activity [2, 3].
bands (ν, cm–1): 3100–3030, 880–690 (CHarom), 2980–
2850 (CHaliph), 1770–1720 (C=Oester) (IIIj–IIIv, IVc–
IVj, VIIc, VIId), 1610–1460 (C=Carom), 1630–1615
(C=N), 1275–1020 (C–O). There is no absorption band
ν(C=Oaldehyde) at 1700–1680 cm–1, characteristic of the
original benzaldehydes II . In the IR spectra of the
hydrochlorides Va–Vv, VIa–VIj there are additional
absorption bands at 2750–2250 (N+H) and 1670–
1650 cm–1 (C=N+). The IR spectra of the
hydrochlorides Vj–Vv, VIc–VIj contain the absorption
band ν(C= Oester), the position and intensity of which
have not changed in comparison with the starting
azomethines IIIj–IIIv, IVc–IVj.
The IR spectra of the Schiff bases IIIa–IIIv, IVa–
IVj, VIIa–VIId contain the characteristic absorption
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 11 2012

SYNTHESIS OF (E)-4-ETHOXYPHENYLIMINOMETHYLARYLS
1833
1
In the H NMR spectra of the Schiff bases IIIa–
IIIv, IVa–IVj, VIIa–VIId there are the proton signals
of the p-phenetidine fragment (δ, ppm): 1.2–1.7 t (Me),
3.8–4.3 q (CH2), 6.7–7.4 m (С6Н4), 8.4–8.7 s (HC=N),
which indicates their E-configuration [4]. The MeO
proton signals are singlets in the range of 3.8–4.0 ppm
(IIIc, IIIe–IIIv, IVb, VIIb). The EtO proton signals in
IVa–IVj, VIIc are observed in the range of 1.2–1.7
(t, Me) and 3.8–4.3 (q, CH2). In the 1H NMR spectra of
the hydrochlorides Va–Vv, VIa–VIj the singlet signals
in the ranges of 10.0–10.2 and 10.1–11.2 ppm belong
to the HC=N+ and HN+Cl– groups.
methanol, and dried in air for 6–8 h.
Bisazomethines (VIIa–VIId). A solution of 10 mmol
of p-phenetidine I and 5 mmol of the appropriate
dibasic aromatic aldehyde II in 50 ml of anhydrous
methanol was refluxed for 45 min. The target products
were isolated as described above.
4-Ethoxyphenyliminomethylaryles hydrochlorides
(Va–Vv, VIa–VIj). Dry hydrogen chloride [5] was
bubbled through a cooled (0–5°C) solution of 1 mmol
of azomethine IIIa–IIIv or IVa–IVj in 30–50 ml of
anhydrous ether for 10–15 min. The formed precipitate
was filtered off, washed with cold ether, and dried in
air for 3–4 h.
1
The IR and H NMR spectra of compounds IIIa–
IIIv, IVa–IVj, Va–Vv, VIa–VIj, VIIa–VIId contain
the absorption band and the proton signals confirming
the presence of all the corresponding structural
fragments of the ester groups.
REFERENCES
1. Mashkovskii, M.D., Lekarstvennye preparaty (Drugs),
Moscow: Novaya Volna, 2001, vols. 1, 2.
2. Stahl, P.H. and Wermuth, C.G., Handbook of
Pharmaceutical Salts. Properties, Selection, and Use,
Weinhem: Wiley-VCH Verlag GmbH & Co. KgaA,
2002.
3. Dikusar, E.A., Kozlov, N.G., Potkin, V.I., Tlegenov, R.T.,
and Uteniyazov, K.U., Aminovye soli organicheskikh
kislot: sintez, svoistva, biologicheskaya aktivnost’ i
primenenie (Amine Salts of Organic Acids: Synthesis,
Properties, Biological Activity, and Application),
Nukus: Karakalpakstan, 2009.
4. Dyer, J.R., Prolozheniyz absorbtsionnoi spectroskopii
organicheskikh soedinenii (Applications of Absorption
Spectroscopy of Organic Compounds), Moscow:
Khimiya, 1970.
5. Karyakin, Yu.V. and Angelov, I.I., Chistye khimicheskie
veshchestva (Pure Chemicals), Moscow: Khimiya,
1974.
EXPERIMENTAL
The IR spectra were recorded on a spectro-
photometer Protege-460 Nicolet FTIR (thin layer,
KBr). The H NMR spectra were registered on a
spectrometer Tesla BS-587A (100 MHz) relative to
internal TMS using deuterochloroform or DMSO-d6 as
the solvents. The molecular weights of the
azomethines obtained were determined by the cryo-
scopy in benzene.
1
(E)-4-Ethoxyphenyliminomethylaryles (IIIa–IIIv,
IVa–IVj). A solution of 5 mmol of p-phenetidine I
and 5 mmol of the appropriate aromatic aldehyde II in
40 ml of anhydrous methanol was refluxed for 30–
45 min. The solution was cooled to 0–5°C. The
azomethines were filtered off, washed with cold
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 11 2012