Synthesis of azomethines based on 4-formylphenyl m-carboranyl-C-methanoate

Article abstract of DOI:10.1134/S1070363212060059

A preparative method for the synthesis of m-carborane azomethines via the condensation of mcarborane- C-4-formylphenyl methanoate with aliphatic, cycloaliphatic, and aromatic amines was developed. Original Russian Text. V.M. Fomin, A.E. Shirokov, 2012.

Full text of DOI:10.1134/S1070363212060059

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 6, pp. 1069–1072. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © E.A. Dikusar, V.I. Potkin, N.G. Kozlov, D.A. Rudakov, T.D. Zvereva, S.K. Petkevich, M.M. Ogorodnikova, A.P. Yuvchenko,
M.P. Bei, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 6, pp. 910–913.
Synthesis of Azomethines
Based on 4-Formylphenyl m-Carboranyl-C-methanoate
E. A. Dikusara,b, V. I. Potkina, N. G. Kozlova, D. A. Rudakova, T. D. Zverevaa,
S. K. Petkevicha, M. M. Ogorodnikovaa, A. P. Yuvchenkob, and M. P. Beib
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 Institute of Chemistry of New Materials, National Academy of Sciences of Belarus, Minsk, Belarus
Received April 25, 2011
Abstract—A preparative method for the synthesis of m-carborane azomethines via the condensation of m-
carborane-C-4-formylphenyl methanoate with aliphatic, cycloaliphatic, and aromatic amines was developed.
DOI: 10.1134/S1070363212060059
Previously a synthesis has been reported of o(m)-
carborane-containing azomethines starting from o(m)-
carboranyl-C-methylene-4-formyl benzoates [1]. The
nitrogen-containing carborane derivatives are of
interest as the agents in the boron neutron capture
therapy of the neoplastic diseases, radionuclide dia-
gnostics and therapy [2, 3].
amines IV. The yield of compounds V was 85–89%.
The starting 4-formylphenyl m-carboranyl-C-methanoate
III was synthesized by the esterification of 4-
formylmethanol I with m-carboranyl-C-carboxylic acid
chloride II in the presence of pyridine in 91% yield.
The resulting carborane derivatives III, Va–Vz are
crystalline or amorphous glassy substances, soluble in
Et2O, DMF, DMSO, and CHCl3. The composition of
compounds III and V was proved by the elemental
analysis and molecular weight determination (see the
table), the structure, by spectral methods.
In this work we describe a method of the preparative
synthesis of new m-carborane azomethines V via the
condensation of 4-formylphenyl m-carboranyl-C-metha-
noate III with aliphatic, cycloaliphatic, and aromatic
NR
CHO
H
CHO
HC
C
Py
RNH2
+
Py HCl
IV
CCl
O
C
O
O
O
O
OH
I
C
C
II
C
C
HC
Vа−Vz
HC
III
V, R = n-C18H37 (a), СH(1-Ad)Me (b), L-CH(CHMe2)CO2Me (c), L-CH(CHCH2Me2)CO2Me (d), L-CH(CHMeEt)CO2Me
(e), C6H5 (f), 4-MeC6H4 (g), 2-biphenyl (h), 4-biphenyl (i), 1-naphthyl (j), 2-naphthyl (k), 4-FC6H4 (l), 3-BrC6H4 (m),
4-BrC6H4 (n), 4-IC6H4 (o), 1-bromo-2-naphthyl (p), 2-hydroxyphenyl (q), 4-ethoxyphenyl (r), 4-phenoxyphenyl (s),
4-MeC(O)C6H4 (t), 4-EtC(O)C6H4 (u), C6H4-3-COOH (v), C6H4-4-COOH (w), C6H4-4-COOEt (x), C6H4-4-COOBu (y),
(z).
N
O
1069

1070
DIKUSAR et al.
Yields, melting points, and elemental analysis data of compounds III, V, and VII
Found, %
Calculated, %
М
Comp. Yield,
mp, °С
Formula
no.
%
С
H
B
N
–
С
H
B
N
–
found calculated
91
85
87
86
88
89
88
88
85
89
88
88
86
87
89
88
86
87
88
88
87
86
88
89
85
85
89
53
59
103–104 41.25
5.64
9.89
7.80
6.93
7.12
7.10
5.73
6.19
5.78
5.80
5.50
5.74
5.38
4.65
4.46
4.23
4.67
5.68
6.19
5.64
5.73
6.10
5.03
5.25
5.96
6.18
5.24
6.28
6.22
36.62
19.45
23.32
26.24
25.35
25.42
29.10
28.06
23.95
24.01
25.29
25.54
27.68
23.95
24.10
21.62
21.39
27.88
26.09
23.23
26.05
25.18
25.80
25.96
24.23
22.78
24.45
19.65
19.74
C10H16B10O3
41.08 5.52 36.98
284.6
292.3
543.8
453.6
405.5
419.5
419.5
367.5
381.5
443.6
443.6
417.5
417.5
385.4
446.4
446.4
493.4
496.4
383.5
411.5
459.6
409.5
423.5
411.5
411.5
439.5
467.6
434.5
539.7
539.7
III
44–45
60–61
–
61.98
58.62
47.69
49.03
48.86
2.32 C28H53B10NO2
2.75 C22H35B10NO2
3.02 C16H27B10NO4
3.10 C17H29B10NO4
3.05 C17H29B10NO4
3.35 C16H21B10NO2
3.20 C17H23B10NO2
2.87 C22H25B10NO2
2.90 C22H25B10NO2
3.06 C20H23B10NO2
2.99 C20H23B10NO2
3.25 C16H20B10FNO2
61.84 9.82 19.88 2.58 527.4
58.25 7.78 23.83 3.09 444.0
47.39 6.71 26.66 3.45 391.5
48.67 6.97 25.77 3.34 407.6
48.67 6.97 25.77 3.34 412.1
52.30 5.76 29.42 3.81 359.2
53.52 6.08 28.34 3.67 373.2
59.57 5.68 24.37 3.16 428.3
59.57 5.68 24.37 3.16 435.0
57.53 5.55 25.89 3.35 406.7
57.53 5.55 25.89 3.35 411.2
49.86 5.23 28.05 3.63 369.8
IVa
IVb
IVc
IVd
IVe
IVf
–
34–35
143–144 52.74
174–175 53.78
131–132 59.91
206–207 59.88
151–152 57.89
145–146 57.95
115–116 50.04
IVg
IVh
IVi
IVj
IVk
IVla
IVmb
IVnc
IVod
IVpe
IVq
IVr
IVs
52–53
43.44
2.84 C16H20B10BrNO2 43.05 4.52 24.22 3.14 431.9
2.78 C16H20B10BrNO2 43.05 4.52 24.22 3.14 436.1
148–149 43.37
160–161 39.20
207–208 48.52
157–158 50.45
154–155 52.86
122–123 57.91
2.55 C16H20B10INO2
38.95 4.09 21.91 2.84 482.0
2.43 C20H22B10BrNO2 48.39 4.47 21.78 2.82 481.8
3.24 C16H21B10NO3
3.02 C18H25B10NO3
2.87 C22H25B10NO3
3.14 C18H23B10NO3
3.02 C19H25B10NO3
2.98 C17H21B10NO4
3.02 C17H21B10NO4
2.85 C19H25B10NO4
2.57 C21H29B10NO4
6.08 C20H24B10N2O3
2.26 C28H33B10N2O3
2.41 C28H33B10N2O3
50.12 5.52 28.19 3.65 372.4
52.54 6.12 26.27 3.40 403.5
57.50 5.48 23.53 3.05 443.7
52.80 5.66 26.40 3.42 397.6
53.88 5.95 25.53 3.31 415.2
49.62 5.14 26.27 3.40 422.7
49.62 5.14 26.27 3.40 423.0
51.92 5.73 24.60 3.19 429.5
53.94 6.25 23.12 3.00 449.7
52.52 5.10 24.88 6.45 426.1
62.32 6.16 20.03 2.60 520.4
62.32 6.16 20.03 2.60 524.2
45–46
43–44
52.99
54.07
IVt
IVu
IVv
IVw
IVx
IVy
IVz
VIIа
VIIb
219–220 49.86
306–307 49.97
146–147 52.20
63–64
54.21
187–188 52.86
307–308 62.71
336–337 62.63
Found F, %: 4.12. Calculated F, %: 4.93. b Found Br, %: 17.73. Calculated Br, %: 17.90. c Found Br, %: 17.64. Calculated Br, %: 17.90.
a
Found I, %: 25.08. Calculated I, %: 25.72. e Found Br, %: 15.76. Calculated Br, %: 16.10.
d
The IR spectra of carborane aldehyde III and
group is observed at δ 10.0 ppm. The 1H NMR spectra
of azomethines Va–Vz contain the signal of HC=N-
group at δ 8.5 ± 0.2 ppm, which is characteristic of the
Schiff bases of (E)-configuration [4].
azomethines V contain the following characteristic
absorption bands, ν (cm–1): 3063±2 (С–Нcarb), 2605±5
(B–H), 1758±2 (C=Oester), 1595±5, 1500±5, 1415±5
(С=СAr), 1250±10, 1200±10 (С–О), 870±5, 850±5,
830±5, 795±5, 725±5 (С–НAr), 1697 (C = Oald), 1633 ±
Azomethines Vj and Vk were introduced into the
reaction with a CH-acid, 5,5-dimethyl-1,3-cyclo-
hexanedione (dimedone) VI to give 4-(10,10-dimethyl-
8-oxo-7,8,9,10,11,12-hexahydrobenzo[c]acridin-7-yl)
phenyl (VIIа) and 4-(9,9-dimethyl-11-oxo-7,8,9,10,11,12-
hexahydrobenzo[а]acridin-12-yl)phenyl (VIIb) m-
1
14 (C=N). In the H NMR spectra of m-carborane
derivatives III and V there are the characteristic
signals of the protons of carborane fragment at δ 3.2 ±
0.1 ppm and aromatic protons at 7.1–8.0 ppm. In the
spectrum of carborane aldehyde III the signal of CHO-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 6 2012

SYNTHESIS OF AZOMETHINES BASED ON 4-FORMYLPHENYL
1071
Vj, Vk
VI
H
C
Me
Me
10
O
C
8
Me
HN
O
O
11
O
4
9
7
2
Me
12
2
4
O
NH
O
C
C
H
VIIb
VIIа
carboranyl-С-carboxylates in 51 and 57% yields
relative to the initial dimedone VI. The reaction takes
place at reflux over 1–2 h.
densation was preferable in this case. The hexa-
hydrobenzo[a]acridines VII are colorless crystalline
substances with a distinct melting points (see the
table).
Under milder conditions, like mixing warm
alcoholic solutions of the reagents, the cyclization
products precipitate within 24 h. The ease of the
cyclization is probably due to a great propensity of 1,3-
diketones to enolization. However, the cyclic 1,3-
diketones VI in anhydrous benzene are mainly in the
keto-form, so it is expectable that the reaction rate in
benzene would change. Indeed, the formation of
hexahydrobenzo[a]acridine derivatives occurs only
after boiling the reagents in benzene for 3 h. The time
of the start of the products formation can easily be
determined: they are insoluble in alcohol and benzene,
and precipitate in crystalline form from a hot solution.
These data demonstrate the dependence of the
cyclization process on the enolization degree of 1,3-
diketones. In order to increase the yield of the reaction
products VII and to simplify the procedures of their
A possible mechanism of the three-component
cyclocondensation we repeatedly discussed [5, 6]. The
most probable course of the reaction is through a stage
of the Mannich base formation followed by the
rearrangement into 1,5-aminodiketone intermediate,
wich undergoes heterocyclization to give products VII.
The structure of compounds VII was confirmed by the
IR and 1H NMR spectra.
EXPERIMENTAL
The IR spectra were recorded on a Protégé-460
FTIR-spectrophotometer (Nicolet) from a thin layer or
1
KBr pellets. The H NMR spectra were registered on
an Avance-500 Bruker spectrometer (500 MHz) from
the 10% solutions in chloroform-d, the chemical shifts
were measured relative to TMS as an internal
reference. The molecular weight was determined by
the cryoscopy in benzene.
preparation, we carried out
a three-component
heterocyclization of m-carboranyl-C-carboxylate III
with 1- or 2-naphthylamine (IVj, IVk) and dimedone
VI. The reaction was performed by boiling the
components in butyl alcohol. Hexahydrobenzo[a]
acridines VII formed under these conditions within
20–30 min with the yields 53% (VIIa) and 59%
(VIIb). As can be seen from the data, the synthesis of
benzo[a]acridine esters of m-carboranyl-C-carboxylic
acid VII through the three-component cyclocon-
m-Carboranyl-C-carboxylic acid chloride II was
obtained by the reacting of m-carboranyl-C-carboxylic
acid with PCl5 [7].
4-Formylphenyl
m-carboranyl-C-methanoate
(III). To a solution of 0.1 mol of 4-formylphenol I and
0.1 mol of m-carboranyl-C-carboxylic acid chloride II
in 100 ml of anhydrous benzene was added 0.1 mol of
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 6 2012

1072
DIKUSAR et al.
1
anhydrous pyridine in 30 ml of benzene within 30 min
with cooling to 10–15°C and vigorous stirring. The
mixture was stirred for 1 h and diluted with 500 ml of
water. The organic layer was separated, washed with
water (3×200 ml) and saturated aqueous NaHCO3
solution (2×200 ml), dried over MgSO4, and
evaporated. The residue was crystallized from a
benzene–hexane mixture.
848±3, 815±5, 750±5 (С–НAr). Н NMR spectrum, δ,
ppm: 0.83 s (3H, CH3), 1.03 s (3H, CH3), 2.00 d (1Н,
СН, 2Ј 14 Hz), 2.21 d (1Н, СН, 2Ј 14 Hz), 2.38 d (1Н,
СН, 2Ј 14 Hz), 2.41 m (10Н, В10Н10), 2.62 d (1Н, СН,
2Ј 14 Hz), 4.33 s (1Н, СНcarb), 5.82 s (1Н, Н7), 6.92–
7.91 m (10НAr), 9.72 s (1Н, NH) (VIIa); 0.84 s (3H,
2
CH3), 1.02 s (3H, CH3), 2.01 d (1Н, СН, Ј 14 Hz),
2.22 d (1Н, СН, 2Ј 14 Hz), 2.38 d (1Н, СН, 2Ј 14 Hz),
2.42 m (10Н, В10Н10), 2.63 d (1Н, СН, 2Ј 14 Hz), 4.33
s (1Н, СНcarb), 5.83 s (1Н, Н7), 6.90–7.93 m (10НAr),
9.72 s (1Н, NH) (VIIb).
m-Carborane azomethines (Va–Vz). A solution
of 5 mmol of 4-formylphenyl m-carboranyl-C-metha-
noate III and 5 mmol of the corresponding primary
amine IV in 40 ml of anhydrous ethanol was boiled for
30–45 min. The solution was cooled to 0–5°C. The
azomethine crystals were filtered off, washed with cold
methanol, dried in air for 6–8 h. The final purification
was performed by the column chromatography on a
neutral alumina (40–100 mesh) of II degree of activity
by Brockmann. Eluent benzene.
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0.5 mmol of azomethine Vj or Vk and 0.5 mmol of
dimedone VI in 20 ml of butanol was boiled to a
precipitate formation (~ 1–2 h). The precipitate was
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amine IVj or IVk and 0.35 mmol of 4-formylphenyl
m-carboranyl-C-methanoate III in 20 ml of 1-butanol
was boiled for 10 min, the reaction mixture was cooled
and mixed with 0.35 mmol of dimedone VI. The mix-
ture was heated until the precipitate formation ceased
(0.5 h). The precipitate was treated as described above.
IR spectrum, ν, cm–1: 3254±5, 3190±5 (N–H),
3066±2 (С–Нcarb), 2606±2 (B–H), 1762±2 (C=Oester),
1601±2 (С=Оcarbonyl), 1615±2, 1583±2, 1519±2
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