Reaction of aromatic aldehydes with ammonium acetate

Article abstract of DOI:10.1023/A:1020997325550

By reaction of aromatic aldehydes with ammonium acetate a series of 1,2-diaryl-1,2-diamino-ethanes and their derivatives was obtained. The mechanism of reaction was suggested and its principal stages were proved. Reactions with ammonium acetate of aromatic aldehydes containing ortho-substituents resulted in the corresponding 2,4,5-triaryl-4,5-dihydroimidazoles.

Full text of DOI:10.1023/A:1020997325550

Russian Journal of Organic Chemistry, Vol. 38, No. 8, 2002, pp. 1149 1153. From Zhurnal Organicheskoi Khimii, Vol. 38, No. 8, 2002,
pp. 1200 1205.
Original English Text Copyright
2002 by Proskurnina, Lozinskaya, Tkachenko, Zefirov.
*
Reaction of Aromatic Aldehydes with Ammonium Acetate
M. V. Proskurnina, N. A. Lozinskaya, S. E. Tkachenko, and N. S. Zefirov
Moscow State University, Moscow, 119899 Russia
Received July 3, 2001
Abstract By reaction of aromatic aldehydes with ammonium acetate a series of 1,2-diaryl-1,2-diamino-
ethanes and their derivatives was obtained. The mechanism of reaction was suggested and its principal stages
were proved. Reactions with ammonium acetate of aromatic aldehydes containing ortho-substituents resulted
in the corresponding 2,4,5-triaryl-4,5-dihydroimidazoles.
1
,2-Diaryl-1,2-diaminoethanes
building blocks in designing enantioselective catalysts
1 8]. Moreover, these diamines are interesting as
are
important
hydrolysis was converted into meso-1,2-diphenyl-1,2-
diaminoethane (IVa) [2].
[
A possibility to perform the reaction yielding
compound IIa under the action of microwave irradia-
tion was further demonstrated by this single example
models for preparation of twin-drug analogs [9] of
benzylamine derivatives. The synthesis of diamines
from this series is based on intermediate formation of
hydrobenzamide in reaction between benzaldehydes
and ammonia [4 7]. Although the study of this reac-
tion was described in an enormous number of reports,
the structure of all intermediates of the process includ-
ing hydrobenzamide and amarine was unambiguously
proved only in 1997 [6].
[
8]. Although the reaction was obviously attractive for
its synthetic promise and easy performance it was not
further investigated. The target of the present study is
the extension of possibilities of this synthetic
procedure.
We found that benzaldehyde (Ia) proper, and also
p-fluorobenzaldehyde (Ib), p-bromobenzaldehyde(Ic),
We believed that from the synthetic viewpoint the
statement on ready reaction between three aromatic
aldehydes and ammoium acetate [2, 8] was very
interesting. With benzaldehyde (Ia) the reaction
afforded benzylbenzoyl derivative IIa that by acid
3
,4-dichlorobenzaldehyde (Id), and 4-methoxybenz-
aldehyde (Ie) at heating with ammonium acetate fur-
nished the corresponding benzylidenebenzoyl deriva-
tives IIa e. The hydrolysis with sulfuric acid resulted
in the meso-diamines IVa c. In each case the hydro-
lysis can be stopped at the stage of monobenzoyl
derivatives IIIa e; this is very important because
therefore a formation of intermediates is ensured
already having benzoyl protection of one amino group.
It was reported in [2] by the example of anis-
aldehyde that the donor substituents in the aromatic
R = R = H (a); R = 4-F, R = H (b); R = 4-Br,
R = H (c); R = 3-Cl, R = 4-Cl (d); R = 4-MeO,
R = H (e).
*
The study was carried out under financial support of the Rus-
sian Foundation for Basic Research (grant no. 01-03-33085).
1
070-4280/02/3808-1149$27.00 2002 MAIK Nauka/Interperiodica

1
150
PROSKURNINA et al.
ring prevented formation of compound of type II in
reaction with ammonium acetate. It was assumed
from this result that this reaction was impossible with
aldehydes having donor substituents in the aromatic
ring. However we demonstrated that the anisaldehyde
reacted with ammonium acetate to yield compound
IIe but it took more time. A similar reaction sequence
was also performed with 2-thiophenecarbaldehyde (V)
mixture of ammonium acetate with a little benz-
aldehyde** the compounds that may arise in the inter-
mediate stages, namely, hydrobenzamide (VIII) and
amarine IX prepared by independent procedure.
Therewith in both cases we obtained benzylidene-
benzoyl derivative IIa in good yield.
However an attempt to prepare the corresponding
threo-derivative II by reaction of trans-2,4,5-tri-
phenylimidazoline with ammonium acetate and equi-
molar amount of benzaldehyde was unsuccessful.
After three days of maintaining the reaction mixture
the unreacted initial compound and a small amount of
erythro-product II originating from benzaldehyde
used were isolated.
(compounds V
VI
VII).
Thus the reaction of aromatic aldehydes with
ammonium acetate can be used to synthesize sym-
metrical vicinal diamines and simple derivatives
thereof.
It is known that the reaction between aromatic alde-
hydes and ammonia provides hydrobenzamide VIII
that in its turn can transform into amarine IX [6].
We also found that ortho-substituted benz-
aldehydes, namely, 2-nitro- (If) and 2,6-dichloro-
benzaldehyde (Ig) react with ammonium acetate under
the same conditions furnishing the corresponding cis-
2
,4,5-triaryl-4,5-dihydroimidazolines X.
R = NO , R = H (f); R = R = Cl (g).
2
The cis-configuration of the aryl substituents in
The mechanism of reaction we were studying
apparently should also involve intermediate formation
of compounds of VIII and IX types, and thus
ammonium acetate should be a source of ammonia.
To prove this assumption we added to the reaction
compound Xg was proved by X-ray diffraction study
**
(
Fig. 1).*
This result suggests that the reaction between
aldehydes and ammonium acetate initially follows the
*
*
The X-ray diffraction analysis has been carried out by K. A. Potekhin (Vladimir State Pedagogical University) and will be
completely published elsewhere.
To preserve the stoichiometry of the process requiring four benaldehyde molecules.
*
**
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 8 2002

REACTION OF AROMATIC ALDEHYDES WITH AMMONIUM ACETATE
1151
Fig. 1. Structure of compound Xg according to the X-ray
diffraction analysis.
Thus we demonstrated that the reaction with
ammonium acetate of aromatic aldehydes, especially
those containing electron-withdrawing substituents,
was a convenient and simple preparation procedure
for vicinal 1,2-diaryldiamines and their derivatives.
Amine fragments in the reaction product obtained are
differently substituted, providing a possibility to
selective deprotection of one of amino groups in
order to carry out further modification of the other
one. Besides convenient approach to the synthesis of
difficultly accessible 2,4,5-triaryl-substituted imid-
azolines was developed.
Fig. 2. Structure of compound XIII according to the X-ray
diffraction analysis.
scheme similar to that previously assumed [6] for the
reaction of aldehydes with ammonia solutions.
In the first stage formed hydrobenzamide VIII
that under the base action was converted into anion
XI. The latter underwent a stereospecific disrotatory
ring closure resulting in cis-triphenylimidazoline
IX. The compound further reacted with benz-
aldehyde and through a series of intermediates formed
benzylidenebenzoyl derivative IIa.
EXPERIMENTAL
IR spectra of compounds under investigation were
recorded on spectrphotometer Specord UR-20 from
solutions in chloroform in thin film or from mulls in
1
13
mineral oil. H and C NMR spectra were registered
on spectrometers Bruker AC-300 and Bruker AC-200.
The presence of ortho-substituents hampers the
subsequent reaction of 2,4,5-triaryl-4,5-dihydro-
imidazole of IX type with a new aldehyde molecule,
and the reaction stops at this stage (see the above
conversion of 2,6-dichlorobenzaldehyde into cis-
The chemical shifts are listed in
from the signal of the corresponding solvent or from
TMS as internal reference.
scale measured
General procedure for the synthesis of 1,2-di-
aryl-N-arylmethylene-N -aroyl-1, 2-diamino-
ethanes IIa e. The mixture of aldehyde and am-
monium acetate was heated to 120 C and stirred at
this temperature for 3 h. The reaction mixture was
cooled, the precipitate was filtered off, and washed
with water, 5% solution of NaOH, and hot alcohol.
A sample for analysis was recrystallized from 95%
ethanol.
2
,4,5-triaryl-4,5-dihydroimidazoles). An uncommon
result was also obtained in reaction of ammonium
acetate with 4-pyridinecarbaldehyde XII. The main
reaction product was the corresponding 2,4,5-tris(4-
pyridinyl)imidazole XIII crystallized as a hydrate as
was confirmed by X-ray diffraction study (Fig. 2).
In this case the prevailing process was oxidation
of dihydroimidazole XIV into imidazole XIII
1
,2-Diphenyl-N-phenylmethylene-N -benzoyl-
(
apparently with the air oxygen) and not the opening
of the five-membered ring in keeping with the above-
described general scheme of the reaction:
1
,2-diaminoethane IIa. From 41.2 g (0.38 mol) of
benzaldehyde and 83 g (1.08 mol) of ammonium
acetate was prepared 25 g (65%) of compound IIa,
mp 257 C. IR spectrum, cm : 3400 (NH), 2900
100, 1640 (doublet). H NMR spectrum (DMSO-d ):
.8 d (1H, CH N=), 5.65 t (1H, CH NHCO) 7.05
.7 m (20H, C H ), 8.0 s (1H, CH=N), 8.8 d. (1H,
1
1
3
4
7
6
6
5
NH). Found, %: C 83.01; H 5.91; N 6.72.
C H N O. Calculated %: 83.14; H 5.98; N 6.93.
2
8
24
2
1
, 2-Di(4-fluorophenyl)-N-(4-fluorophenyl)-
methylene-N -(4-fluorobenzoyl)-1,2-diaminoethane
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 8 2002

1
152
PROSKURNINA et al.
1
(
IIb). From 5 g (0.04mol) of 4-fluorobenzaldehyde
cm : 3400 (NH), 2900 3100, 1640 (doublet).
1
(Ib) and 10 g (0.13 mol) of ammonium acetate we
H NMR spectrum (DMSO-d ): 5.1 d (1H, CH N=),
6
5.65 t (1H, CH NHCO), 6.9 m (2H, C H S), 7.1 m
4
3
1
(4H, C H S), 7.3 7.45 m (3H, C H S), 7.65 7.8 m
4 3 4 3
CH N=), 5.55 t (1H, CH NHCO), 6.9 7.15 m (8H,
C H F), 7.45 t (2.5H, C H F), 7.55 t (2.5H, C H F),
(3H, C H S), 8.35 s (1H, CH=N), 9.0 d (1H, NH).
4 3
Found, %: C 56.18; H 3.73; N 6.35. C H N OS .
6
4
6
4
6
4
20 16
2
4
7
.7 q (3H, C H F), 8.0 s (1H, CH=N), 8.65 d (1H,
Calculated,%: C 56.05; H 3.76; N 6.54.
6
4
NH). Found, %: C 70.57; H 4.23; N 5.90.
C H F N O. Calculated, %: C 70.58; H 4.23; N
General procedure for hydrolysis of 1,2-diaryl-
N-arylmethylene-N -aroyl-1,2-diaminoethanes
IIa e. Compound II was boiled with 60 75%
sulfuric acid, the reaction mixture was cooled, the
precipitate of monoaroylamine III was filtered off,
washed with water and 5% solution of NaOH, and
recrystallized from ethanol. Initial compound that did
not dissolve in hot alcohol could be repeatedly hydro-
lyzed. Alkalizing the filtrate to strongly alkaline reac-
tion we separated meso-1,2-diaryl-1,2-ethylenedi-
amines IV. The relative yield of aroyl derivative III
and diamine IV is controlled by sulfuric acid con-
centration and by time of boiling. The definite condi-
tions are given separately for each compound. The
prevailing diamine formation is seen from nearly
complete dissolution of the precipitate.
2
8
20
4
2
5
.88.
1
, 2-Di(4-bromophenyl)-N-(4-bromophenyl)-
methylene-N -(4-bromobenzoyl)-1,2-diaminoethane
IIc. From 10 g (0.054 mol) of 4-bromobenzalde-
hyde (Ic) and 13 g (0.168 mol) of ammonium acetate
we obtained 7 g (72%) of compound IIc, mp 265 C.
1
H NMR spectrum (DMSOd )): 4.35 d (1H,
6
CH N=), 5.15 t (1H, CH NHCO), 7.35 7.7 m
(
16H, C H Br), 8.0 s (1H, CH=N), 8.7 d (1H, NH).
6 4
Found, %: C 46.78; H 2.83; N 3.98. C H Br N O.
2
8
20
4
2
Calculated, %: C 46.70; H 2.80; N 3.89.
1
, 2-Di(3, 4-dichlorophenyl)-N-(3,4-dichloro-
phenyl)methylene-N -(3,4-dichlorobenzoyl)-1,2-di-
aminoethane (IId). From 3.2 g (0.018 mol) of 3,4-di-
chlorobenzaldehyde (Id) and 8 g (0.108 mol) of
ammonium acetate we obtained 1.7 g (53%) of com-
N-Benzoyl-meso-1, 2-diphenyl-1, 2-diamino-
ethane (IIIa). From 25 g (0.061 mol) of compound
IIa, 55 ml of concn. H SO , and 200 ml of water
1
pound IId, mp 248 250 C. H NMR spectrum
2
4
(
DMSO-d )): 4.8 d (1H, CH N=), 5.55 t (1H,
6
after boiling for 12 h we obtained 12 g (63%) of
1
CH NHCO), 7.3 7.55 m (4.5H, C H Cl ), 7.56
6
3
2
compound IIIa, mp 204 C. IR spectrum, cm : 3400
1
7
.65 m (4H, C H Cl ), 7.75 s (2H, C H Cl ), 7.85 s
6 3 2 6 3 2
(NH), 2900 3100, 1640. H NMR spectrum
(
2H, C H Cl ), 8,1 s (1H,CH=N), 8.9 d (1H, NH).
6 3 2
(DMSO-d CCl ): 4.55 d (1H, CH NH ), 5.45 t
6
4
2
Found, %: C 49.48; H 2.38; N 4.20. C H Cl N O.
2
8
16
8
2
(1H, CH NHCO), 7.05 7.7 m (15H,C H ), 8.5 d
6 5
Calculated, %: C 49.45; H 2.37; N 4.12.
(
1H, NHCO). Found, %: C 79.68; H 6.21; N 8.79.
C H N O. Calculated, %: C 79.72; H 6.37; N 8.85.
1
,2-Di(4-methoxyphenyl)-N-(4-methoxyphenyl)-
22 20
2
methylene-N -(4-methoxybenzoyl)-1,2-diamino-
ethane IIe. From 7 g (0.013 mol) of 4-methoxy-
benzaldehyde Ie and 13 g (0.168 mol) of ammon-
ium acetate we obtained within 24 h 2.9 g (22%) of
On alkalizing the filtrate to strongly alkaline reac-
tion 1.2 g of meso-1,2-diphenyl-1,2-ethylenediamine
IVa) was separated.
(
1
meso-1,2-Diphenyl-1,2-diaminoethane IVa. From
5 g (0.061 mol) of compound IIa, 65 ml of
compound IIe, mp 218 C. H NMR spectrum
2
(
DMSO-d CCl : 3.69 s (3H, OMe), 3.70 s (3H,
6 4
concn. H SO , and 200 ml of water after boiling for
OMe), 3.8 s (6H, OMe), 4.66 d (1H, CH N=),
2
4
2
4 h we isolated 1.3 g of compound IIIa and on
5
7
7
7
.45 t (1H, CH NHCO), 6.7 6.9 m (8H, C H OMe),
6 4
alkalizing the reaction mixture 7 g (85%) of diamine
,35d (2H, C H OMe), 7.45 d (2H, C H OMe),
6
4
6
4
1
IVa, mp 123 C. H NMR spectrum (DMSO-d6
.55 d (2H, C H OMe), 7.65 d (2H, C H OMe),
6
4
6
4
.9 s (1H, CH=N), 8.19 d ( 1H, NH). Found, %:
CCl4): 3.95 s, (2H, CH), 7.15 7.3 m (10H, C6H5).
Found, %: C 79.12; H 7.85; N 12.92. C H N .
C 73.30; H 5.99; N 5.28. C H N O . Calculated,
3
2
32
2
5
14 16
2
%
: C 73.26; H 6.15; N 5.34.
,2-Di(2-thienyl)-N-(2-thienylmethylene)-N -(2-
thenoyl)-1,2-diaminoethane (VI). From
Calculated,%: C 79.21; H 7.60; N 13.20.
N-(4-Bromobenzoyl)-meso-1, 2-di(4-bromo-
phenyl)-1,2-diaminoethane IIIc. From g
1
5
g
7
(
(
(
0.05 mol) of 2-thiophenecarbaldehyde (V) and 10 g
0.13 mol) of ammonium acetate we obtained 3.1 g
58%) of compound VIc, mp 207 C. IR spectrum,
(0.061 mol) of compound IIc, 33 ml of concn.
H SO , and 100 ml of water after boiling for 24 h we
2
4
obtained 3 g (56%) of compound IIIc, mp 201 C.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 8 2002

REACTION OF AROMATIC ALDEHYDES WITH AMMONIUM ACETATE
1153
1
H NMR spectrum (DMSO-d CCl4): 4.50 d (1H,
reaction mixture was cooled, the precipitate was
filtered off, washed with water, 5% solution of NaOH,
and recrystallized from ethanol. Yield 0.71 g (50%),
mp 244 246 C. H NMR spectrum (DMSO-d6):
5.98d (1H, CH), 6.18 d (1H, CH), 7.25 7.56 m
6
CH NH ), 5.35 t (1H, CH NH), 7.35 7.65 d.d
2
(
12H, C H Br), 8.65 d (1H, NHCO). Found, %:
6 4
1
C 45.58; H 3.08; N 4.95. C H Br N O. Calculated,
2
1
17
3
2
%
: C 45.60; H 3.10; N 5.06.
(
6H, C H NO ), 7.65 d (1H, C H NO ), 7.73 d (1H,
6 4 2 6 4 2
On alkalizing the filtrate to strongly alkaline
reaction 0.2 g of meso-1,2-di(4-bromophenyl)-1,2-
diaminoethane (IVc), mp 123 124 C, was separated.
C H NO ), 7.8 d (1H, C H NO ), 7.88 t (1H,
C H NO ), 8.0 d (1H, C H NO ), 8.5 d (1H,
C H NO ) 8.3 s (1H, NH). Found,%: C 58.26;
H 3.39; N 16.42. C H N O . Calculated,%:
6
4
2
6
4
2
6
4
2
6
4
2
6
4
2
N-(4-Methoxybenzoyl)-meso-1,2-di(4-methoxy-
2
1
15
5
6
phenyl)-1,2-diaminoethane IIIe. From 0.9
g
C 58.20; H 3.49; N 16.16.
(
1.7 mmol) of compound IIe, 3 ml of concn. H SO ,
2
4
2
,4,5-Tris(4-pyridinyl)-imidazole XIII. A mix-
and 12 ml of water after boiling for 24 h we obtained
ture of 2 g (0.018 mol) of 4-pyridinecarbaldehyde
XII and 8 g (0.1 mol) of ammonium acetate was
heated to 120 C with stirring for 3 h. The reaction
mixture was cooled, the precipitate was filtered off,
washed with water, 5% solution of NaOH, and re-
crystallized from ethanol. Yield 1.2 g (67%), mp
0
1
.4 g (0.98 mmol) of diaminoethane IIIe (58%), mp
1
92 C. H NMR spectrum (DMSO-d CCl ): 3.71 s
6
4
(
3H, OMe), 3.76 s (3H, OMe), 3.82 s (3H, OMe),
4
6
7
.23 d (1H, CH NH ), 4.55 t (1H, CH N=), 6.75
2
.9 m (6H, C H OMe), 7.3 d (4H, C H OMe),
6
4
6
4
.55 d (2H, C H OMe), 8.1 d (1H, NH). Found, %:
6
4
3
33 C (the compound crystallized as monohydrate).
C 70.91; H 6.43; N 6.83. C H N O . Calculated,
2
4
26
2
4
1
%
: C 70.92; H 6.45; N 6.89.
N-Thenoyl-meso-1,2-di(2-thienyl)-1,2-diamino-
ethane VII. From 3.1 g (0.0072 mol) of compound
VI, 10 ml of concn. H SO , and 100 ml of water after
H NMR spectrum (DMSO-d6): 7.5 s (4H, C5H4N),
.0 s (2H, C H N), 8.6 d (5,5H, C H N), 13.2 br. s
8
5
4
5
4
13
4
(
1H, NH). C NMR spectrum (DMSO-d ): 120 (C
6
5
of imidazole ring), 122.9 (C of imidazole ring),
1
2
4
2
36.8 (C of imidazole ring), 145.1 (C H N), 149.9
5 4
boiling for 12 h we obtained 1.4 g (58%) of thenoyl-
diaminoethane VII, mp 137 149 C. H NMR spec-
trum (DMSO-d CCl4): 4.75 d (1H, CH NH ),
5
1
(C5H4N), 150 (C5H4N), 163.8 (C5H4N). Found, %:
C 68.28; H 4.83; N 23.12. C H N H O. Calculat-
1
8
13
5
2
6
2
ed,%: C 68.13; H 4.76; N 22.07.
.45 t (1H, CH NHCO), 6.9 7.05 m (2H, C H S),
4 3
7
7
.05 7.2 m (3H, C H S), 7.35 7.5 m (2H, C H S),
4 3 4 3
REFERENCES
.65 7.8 m (2H, C H S), 8.85 d (1H, NH). Found,
4 3
%
: C 53.91; H 4.25; N 8.40. C H N S O. Cal-
15 14 2 3
1
. Williams, O.F. and Bailar, J.C., J. Am. Chem. Soc.,
959, vol. 81, no. 17, p. 4464.
culated,%: C 53.86; H 4.22; N 8.38.
,4,5-Tris(2,6-dichlorophenyl)-4,5-dihydro-1H-
imidazole Xg. A mixture of 4.7 g (0.027 mol) of
,6-dichlorobenzaldehyde and 8 g (0.10 mol) of
1
2
2. Trippett, S,, J. Chem. Soc., 1957, no. 11, pp. 4407 4409.
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2
ammonium acetate was heated to 120 C with stirring
for 3 h. The reaction mixture was cooled, the pre-
cipitate was filtered off, washed with water, 5%
solution of NaOH, and recrystallized from ethanol.
4. Gutsche, C.D. and Mei, G.C., J. Am. Chem. Soc.,
1
985, vol. 107, no. 26, pp. 7964 7968.
5
6
7
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1
Yield 2.72 g (60%), mp 138 143 C. H NMR
spectrum (DMSO-d ): 6.05 br. s (1H, CH), 6.45 br.s
1
997, vol. 38, no. 50, pp. 8631 8634.
6
. Lucet, D., Le Gall, T., and Mioskowski, C., Angew.
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(
1H, CH), 7.05 7.2 m ( 5.5 H, C H Cl ), 7.43
6 3 2
7
.6 m (3.5H, C H Cl ), 8.5 d (1H, NH). Found, %:
6 3 2
2
627.
C 50.06; H 3.60; N 4.64. C H Cl N . Calculated,
%
2
1
12
6
2
8
. Lancashire, R.J. and Reese, P.B., Electron Conf.
Trends. Org. Chem. CD-ROM., 1995 (Pub. 1996),
Paper 57.
: C 49.94; H 2.39; N 5.55.
2
,4,5-Tris(2-nitrophenyl)-4,5-dihydro-1H-imid-
azole Xf. A mixture of 1.5 g (0.01 mol) of 2-nitro-
benzaldehyde and 3 g (0.039 mol) of ammonium
acetate was heated to 120 C with stirring for 3 h. The
9. Bourguignon, J.-J., The Practice of Medicinal
Chemistry, Wermith, C., Ed., Acad. Press: London,
1996, pp. 261 293.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 8 2002