Mechanism of the recyclization of 2-amino-5-benzylidene-1,3-thiazol-4(5H)- one into derivatives of 2-amino-5-benzylidene-1,5-dihydro-4H-imidazol-4-one

Article abstract of DOI:10.1007/s10593-008-0005-9

Mechanisms are given for reactions taking place upon heating 2-amino-5-benzylidene-1,3-thiazol-4(5H)-one in a medium consisting of a secondary amine.

Full text of DOI:10.1007/s10593-008-0005-9

Chemistry of Heterocyclic Compounds, Vol. 44, No. 1, 2008
MECHANISM OF THE RECYCLIZATION
OF 2-AMINO-5-BENZYLIDENE-1,3-THIAZOL-
4(5H)-ONE INTO DERIVATIVES
OF 2-AMINO-5-BENZYLIDENE-
1,5-DIHYDRO-4H-IMIDAZOL-4-ONE
S. M. Ramsh, A. V. Smirnova, S. Yu. Solovyova, and Song Minyan
Mechanisms are given for reactions taking place upon heating 2-amino-5-benzylidene-1,3-thiazol-
4(5H)-one in a medium consisting of a secondary amine.
Keywords: 2-amino-5-benzylidene-1,3-thiazol-4(5H)-one, derivatives of 2-amino-5-benzylidene-
1,5-dihydro-4H-imidazol-4-one, diethylamine, morpholine, piperidine, aminolysis, recyclization.
In previous work [1], we showed that the aminolysis of 2-amino-5-benzylidene-1,3-thiazol-4(5H)-one
(5-benzylidenepseudothiohydantoin, 1) in piperidine or morpholine leads not only to the expected products of
transanimation – 2-morpholino (2a) or 2-piperidino derivative 2b, but also recyclization to give imidazole
derivatives 3a or 3b.
O
O
N
N
HNR2
R2N
CHPh
H2N
S
CHPh
S
H2N
H
1
A
O
O
O
N
N
N
R2N
CHPh
R2N
N
CHPh
R2N
S
CHPh
R2N
H2N
H
4a,b
3a-c
2a,b
a R2 = (CH2)2O(CH2)2, b R2 = (CH2)5, c R = Et
__________________________________________________________________________________________
St. Petersburg State Technological Institute (Technical University), St. Petersburg 198013, Russia;
e-mail: gsramsh@mail.wplus.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 111-114,
January, 2008. Original article submitted November 16, 2007.
92
0009-3122/08/4401-0092©2008 Springer Science+Business Media, Inc.

Although the formation of compounds 2a,b may occur without opening of the heterocycle, i.e., directly
from the compound 1 by means of addition-elimination at the C(2)=N(2) bond [2], the formation of 3a,b is
possible only as the result of ring opening and subsequent recyclization. In previous work [1], we proposed that
the isolation of 2a and 3a or of 2b and 3b from the same reaction mixture is a consequence of a unique Dimroth
rearrangement involving aminolytic ring opening a the C(2)–S(1) bond and subsequent parallel recyclization of
acyclic intermediate A to give the corresponding aminothiazolinone 2 and aminoimidazolinone 3. Aminolysis of
5-benzylidene-pseudothiohydantoin 1 with opening of the C(2)–S(1) bond in the ring is in accord with
experimental findings on the alkaline hydrolysis [2], alcoholysis [3], and aminolysis [4] of derivatives of
2-amino-1,3-thiazol-4(5H)-one (pseudothiohydantoin).
However, our more extensive study of this reaction in the present work showed that the mechanism for
the formation of compounds 3 is different. Indeed, acyclic products 4a (in aminolysis by morpholine) and 4b (in
the aminolysis by piperidine) were isolated from the reaction mixtures. Products 4 proved extremely unstable
and convert to imidazole derivatives 3a,b, respectively, upon attempts to recrystallize these compounds from
toluene or 2-propanol. Analysis of the experimental data showed that the noncrystalline compounds in virtually
all reactions yielding 3a,b are intermediate acrylamides 4a,b, respectively. Thus, we propose that the major
reaction pathway leading to aminoimidazolinones 3 consists of consecutive transformations 1 → A → 4 → 3,
i.e., may be a two-step aminolysis-recyclization process with substitution of the heteroatom. The reaction
pathway 1 → A → 3 is extremely insignificant, if it occurs at all.
We should note that these experimental findings do not permit us to distinguish between the two
possible mechanisms for the formation of 2 involving either direct formation from 1 (1 → 2) or formation
through intermediate A (1 → A → 2).
Only aminoimidazolinone 3c was isolated from the reaction mixture in the aminolysis with diethylamine
as the medium. The corresponding aminothiazole 2 and intermediate 4 were not isolated in this case.
EXPERIMENTAL
1
The H NMR spectra were taken on a Bruker AM-400 spectrometer at 400 MHz and a Bruker AM-200
spectrometer at 200 MHz in DMSO-d6 with DMSO-d6 as the internal standard. The IR spectra were taken on a
Shimadzu FTIR-8400S. The electron impact mass spectra of 3a,b were taken on a Finnigan MAT INCOS 50
spectrometer at 70 eV. Thin-layer chromatography was carried out on Silufol-254 plates with 1:2 acetone–
hexane and 1:10 ethanol–chloroform as the eluents.
2-Amino-5-benzylidene-1,3-thiazol-4(5H)-one (1) was obtained according to Liberman [5].
5-Benzylidene-2-morpholino-1,5-dihydro-4H-imidazol-4-one (3a) and 5-Benzylidene-2-morpho-
lino-1,3-thiazol-4(5H)-one (2a). Compound 1 (2.00 g, 9.79 mmol) in morpholine (9.20 g, 9.20 ml, 106 mmol)
was heated at reflux until the starting reagent fully dissolved (~5 min). The reaction mixture was left at about
20°C for 12 h. The precipitate formed was filtered off, washed with 1:1 petroleum ether–ethanol, and treated
consecutively with boiling acetone and 2-propanol. The precipitate, which formed from the 2-propanol solution
after 48 h, was recrystallized from 2-propanol to give 0.24 g (9%) 3a, mp 220-221°C (mp 232°C for the
Z-isomer [6]).
A precipitate formed from the combined filtrate after 30 min was recrystallized twice from toluene to
give 0.14 g (5%) 2a; mp 202-204°C (mp 202-204°C [7], mp 203-204°C [8]).
N-[Amino(morpholin-4-yl)methylene]-2-morpholin-4-yl-3-phenylacrylamide (4a). Compound 1
(2.00 g, 9.79 mmol) in morpholine (10.0 g, 10.0 ml, 115 mmol) was heated at reflux for 30 min and left stand
for 24 h. The precipitate formed was filtered off, dried, and treated with hot acetone to give 0.674 g (20%) 4a;
mp 208-210°C. IR spectrum (neat), ν, cm-1: 3420, 3182 (N–H), 1677 (C=O), 1592 (C=N). 1H NMR spectrum, δ,
ppm (J, Hz): 8.00 (2H, d, J = 8.3, arom); 7.33 (2H, t, J = 7.4, arom); 7.19 (1H, t, J = 7.0,
93

arom); 6.32 (1H, s, =CHC6H5); 3.70 (4H, m, OCH2 morpholino); 3.61 (4H, m, NCH2 morpholino); 3.49 (4H, t,
J = 4.5, OCH2 morpholino); 2.66 (4H, t, J = 4.5, NCH2 morpholino). Found, %: C 62.20; H 7.60; N 16.32.
C18H24N4O3. Calculated, %: C 62.77; H 7.02; N 16.27.
5-Benzylidene-2-morpholino-1,5-dihydro-4H-imidazol-4-one (3a). A. Compound
1
(1.00 g,
4.90 mmol) in morpholine (4.60 g, 4.60 ml, 52.8 mmol) was heated for ~10 min until the starting reagent
dissolved completely. After 48 h, the precipitate formed was filtered off, washed with acetone, and recrystallized
from 2-propanol to give compound 3a (0.132 g, 10.5%); mp 210°C (for the Z-isomer, mp 232°C [6]). IR
spectrum (neat), ν, cm-1: 3437, 3113 (N–H), 1706 (C=O), 1643 (C=N). 1H NMR spectrum, δ, ppm (J, Hz): 11.24
(1H, s, NH); 7.96 (2H, d, J = 6.8, arom); 7.30 (2H, t, J = 7.3, arom); 7.18 (1H, t, J = 7.9, arom); 6.30 (1H, s,
=CH6H5); 3.70 (4H, m, OCH2 morpholino); 3.62 (4H, m, NCH2 morpholino). Mass spectrum, m/z (Irel, %): 259
[M++2] (1.4), 258 ]M++1] (17), 257 [M+] (100). Found, %: C 65.35; H 5.83; N 16.47. C14H15N3O2. Calculated,
%: C 65.35; H 5.88; N 16.33.
B. Compound 4a (1.18 g, 3.43 mmol) in 2-propanol was heated at reflux until completed dissolved and
then heated at reflux for an additional 10-15 min. The precipitate formed upon cooling was recrystallized from
toluene to give compound 4a (0.449 g, 51.3%); mp 200°C (for the Z-isomer, mp 232°C [6]).
5-Benzylidene-2-piperidino-1,5-dihydro-4H-imidazol-4-one (3b) and 5-Benzylidene-2-piperidino-
1,3-thiazol-4(5H)-one (2b). Compound 1 (1.00 g, 4.90 mmol) in piperidine (9.57 g, 11.1 ml, 112 mmol) was
heated at reflux for ~10 min until dissolved and then left for 24 h at ~20°C. The precipitate formed was filtered
off, washed with 10:1 petroleum ether–ethanol, and recrystallized from toluene to give compound 3b (0.250 g,
20%); mp 208-210°C (for the Z-isomer, mp 198°C [6]).
A precipitate of 2b formed after letting the combined filtrate stand for several days. This precipitate was
recrystallized consecutively from toluene and ethanol to give compound 2b (0.253 g, 19%); mp 202-204°C
(mp 202-204°C [7], mp 209-211°C [8]).
N-[Amino(piperidin-1-yl)methylene]-2-piperidin-1-yl-3-phenylacrylamide (4b). Compound
1
(1.00 g, 4.90 mmol) in piperidine (6.02 g, 7.00 ml, 70.7 mmol) was heated at reflux for ~20 min until the
starting reagent completely dissolved. After 24 h, the precipitate formed was filtered off, washed with petroleum
ether, dried, and treated with hot acetone to give compound 4b (0.337 g, 20%); mp 204-205°C. IR spectrum
1
(neat), ν, cm-1: 3433, 3181 (N–H), 1675 (C=O), 1579 (C=N). H NMR spectrum, δ, ppm (J, Hz): 7.91 (2H, d,
J = 6.7, arom); 7.28 (2H, t, J = 6.7, arom); 7.14 (1H, t, J = 7.3, arom); 6.25 (1H, s, =CHC6H5); 3.58 (4H, m,
NCH2 piperidino); 2.69 (4H, m, NCH2 piperidino); 1.61 (6H, m, (CH2)3 piperidino); 1.45 (6H, m,
(CH2)3 piperidino). Found, %: 71.36; H 8.44; N 16.60. C20H28N4O. Calculated, %: C 70.56; H 8.29; N 16.46.
5-Benzylidene-2-piperidino-1,5-dihydro-4H-imidazol-4-one (3b). A. Compound
1
(2.00 g,
9.79 mmol) in piperidine (6.88 g, 8.0 ml, 80.8 mmol) was heated at reflux for ~15 min until the starting reagent
was completely dissolved. The precipitate formed after several hours was filtered off, washed with acetone, and
recrystallized from toluene to give compound 3b (1.43 g, 57%); mp 200-202°C (for the Z-isomer mp 198°C [6]).
1
IR spectrum (neat), ν, cm-1: 3441, 3117 (N–H), 1702 (C=O), 1651 (C=N). H NMR spectrum, δ, ppm (J, Hz):
11.06 (1H, s, NH); 7.98 (2H, d, J = 7.9, arom); 7.30 (2H, t, J = 7.3, arom); 7.18 (1H, t, J = 7.3, arom); 6.23 (1H,
s, =CHC6H5); 3.61 (4H, m, NCH2); 1.66 (6H, m, (CH2)3 piperidino). Mass spectrum, m/z (Irel, %): 257 [M++2]
(1.0), 256 [M++1] (16), 255 [M+] (89). Found, %: C 70.71; H, 6.60; N 16.38. C15H17N3O. Calculated, %:
C 70.56; H 6.71; N 16.46.
B. Compound 4b (0.633 g, 1.86 mmol) in toluene was heated at reflux until completely dissolved.
Heating at reflux was continued for an additional 10-15 min. After 24 h, the precipitate was filtered off to
give compound 4b (0.109 g, 23%); mp 200°C (for the Z-isomer, mp 198°C [6]).
5-Benzylidene-2-diethylamino-1,5-dihydro-4H-imidazol-4-one (3c). Compound
1
(1.00 g,
4.90 mmol) in diethylamine (10.58 g, 15.0 ml, 144.7 mmol) was heated at reflux for ~5 h until the starting
reagent was completely dissolved. Diethylamine was distilled off in a weak vacuum at ~20°C. The residue,
which solidified after standing for several days, was stirred for 30 min with benzene (30 ml) at ~20°C.
94

The benzene solution was decanted from the oily residue through a paper filter and benzene was distilled off in a
weak vacuum until dryness. The solidified residue in 2-propanol (25 ml) was heated at reflux. The precipitate
was filtered off after 24 h to give compound 3c (0.108 g, 9%); mp 165°C. IR spectrum, ν, cm-1: 3382, 3122 (N–H),
1
1699 (C=O), 1650 (C=N). H NMR spectrum, δ, ppm (J, Hz): 11.17 (1H, s, NH); 8.00 (2H, d, J = 5.9, arom);
7.30 (2H, t, J = 6.9, arom); 7.17 (1H, t, J = 6.4, arom); 6.21 (1H, s, =CHC6H5); 3.51 (4H, m, NCH2CH3); 1.19
(6H, m, NCHCH3). Found, %: C 69.08; H 7.18; N 17.35. C14H17N3O. Calculated, %: C 69.11; H 7.04; N 17.27.
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