Synthesis of spiroheterocyclic systems from barbituric acids and N,N-disubstituted o-aminobenzaldehydes

Article abstract of DOI:10.1007/s11178-005-0263-2

Reactions of barbituric, 1,3-dimethylbarbituric, and 2-thiobarbituric acids with 2-(1-pyrrolidinyl)benzaldehyde, its 6- and 7-membered homologs, and 4-phenylpiperazine and morpholine analogs lead to formation of fused systems with a spirocyclic 2,4,6-trio

Full text of DOI:10.1007/s11178-005-0263-2

Russian Journal of Organic Chemistry, Vol. 41, No. 6, 2005, pp. 901–906. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 6, 2005,
pp. 920–925.
Original Russian Text Copyright © 2005 by Krasnov, Kartsev.
Synthesis of Spiroheterocyclic Systems from Barbituric Acids
and N,N-Disubstituted o-Aminobenzaldehydes
K. A. Krasnov1 and V. G. Kartsev2
1 Mechnikov St. Petersburg State Medical Academy, Piskarevskii pr. 47, St. Petersburg, 195067 Russia
e-mail: veselkoff@mail.ru
2 INTERBIOSKRIN Ltd., Chernogolovka, Moscow oblast, Russia
Received July 5, 2004
Abstract—Reactions of barbituric, 1,3-dimethylbarbituric, and 2-thiobarbituric acids with 2-(1-pyrrolidinyl)-
benzaldehyde, its 6- and 7-membered homologs, and 4-phenylpiperazine and morpholine analogs lead to
formation of fused systems with a spirocyclic 2,4,6-trioxopyrimidine fragment. The process involves
intermediate formation of labile 5-arylmethylidenebarbituric acids which exhibit t-amino effect and undergo
spontaneous isomerization to give the final products. The observed spirocyclizations are characterized by
an anomalously high rate.
It is known [1–3] that reactions of barbituric acids
with aromatic aldehydes give as a rule either the cor-
responding 5-arylmethylidene derivatives or bis(pyri-
midin-5-yl)arylmethanes. Condensations of barbituric
acid (Ia) with aldehydes containing a nucleophilic
group, e.g., NH2 or OH, in the ortho position [1, 4]
may be accompanied by further cyclization of 5-aryl-
methylidenebarbituric acids with formation of fused
systems.
The observed pattern led us to presume that the first
step in the reaction of acid Ia with aldehyde IIa is
a normal Knoevenagel condensation yielding 5-aryl-
methylidene-2,4,6-pyrimidinetrione A. It is known that
compounds possessing an analogous π-system are
characterized by an intense red–orange color. A model
of such chromophore is 5-(4-dimethylaminobenzyli-
dene)barbituric acid (λmax 447 nm, ε = 33500 [5]). The
subsequent rearrangement of intermediate A to spiro-
cyclic system IIIa can be regarded as a sort of an ano-
malous cyclizations which were discussed in [6] under
the generic name “tert-amino effect.” This term almost
was not used in Russian literature. However, we
believe that the t-amino effect implies primarily elec-
tronic factors favoring hydride ion abstraction from the
α-carbon atom of a tertiary amine and that the use of
this term as applied to a reaction is not quite correct.
Therefore, the rearrangement discussed in the present
article is referred to as t-spirocyclization, and reactions
involving tert-amino effect are generically called
t-reactions.
In the reaction of acid Ia with an equimolar amount
of 2-(1-pyrrolidinyl)benzaldehyde (IIa) in aqueous
ethanol, instead of the expected 5-[2-(1-pyrrolidinyl)-
phenylmethylidene]hexahydropyrimidine-2,4,6-trione
like A, we isolated in 96% yield an unusual product,
2,4,6-trioxospiro[perhydropyrimidine-5,5'-1',2',3',3a',-
4',5'-hexahydropyrrolo[1,2-a]quinoline] (IIIa), as
a colorless crystalline substance (Scheme 1). The
structure of IIIa was determined on the basis of its
1H NMR and mass spectra. Further study of this
unexpected reaction allowed us to detect formation of
an intensely red intermediate, assumingly 5-aryl-
methylidenehexahydropyrimidine-2,4,6-trione A. After
mixing colorless solutions of compounds Ia and IIa,
the mixture instantaneously turned red, the color
became more intense during the first 10–20 s and then
lost its intensity, and final product IIIa separated from
the mixture as colorless crystals. The reaction per-
formed in 60% ethanol at 50°C (concentrations of Ia
and IIa 0.2 and 0.22 M, respectively) was complete in
about 2 min.
It is known that t-amino effect is inherent to tertiary
aromatic amines possessing a π-acceptor substituent
(carbonyl, nitro, α- or β-cyanovinyl group, etc.) in the
ortho position. At elevated temperature these com-
pounds undergo cyclization with participation of the
α-carbon atom in the alkylamino group to form a new
heterocyclic system. The activation barrier to t-reac-
tions is fairly high; therefore, they require severe con-
ditions (as a rule, prolonged heating at 100–150°C and,
1070-4280/05/4106-0901 © 2005 Pleiades Publishing, Inc.

KRASNOV, KARTSEV
902
Scheme 1.
R2
R2
Z
O
R1
X
O
R3
O
N
O
N
N
R1
X
R1
X
+
CHO
R3
–H2O
N
N
N
O
N
Z
R3
O
Z
R1
N
N
R1
R2
R1
Ia–Ic
IIa–IIg
A
IIIa–IIIl
I, R1 = H (a, c), Me (b); X = O (a, b), S (c); II, R2 = H (a, e, f), NO2 (b–d, g); R3 = H (a–f), Me (g); Z = bond (a, b), CH2 (c, g),
(CH2)2 (d), NPh (e), O (f); III, R1 = H (a–g, l), Me (h–k); R2 = H (a, e–g, j), NO2 (b–d, h, i, k); R3 = H (a–f, h–l), Me (g); X = O
(a–k), S (l); Z = bond (a, b, h), CH2 (c, g), (CH2)2 (d, i, k), NPh (e, j), O (f).
in some cases, addition of a Lewis acid). The mechan-
ism of activation of the alkylamino group in t-reactions
remains not quite clear.
The reaction of acid Ia with 5-nitro-2-(1-pyrroli-
dinyl)benzaldehyde (IIb) gave spirocyclic derivative
IIIb, and the rate of the process was as high as in
the reaction of Ia with IIa. Theoretically, the presence
of a nitro group should sharply reduce the electron
density on the amino nitrogen atom in the para posi-
tion, and the rate of t-spirocyclization should decrease
due to both hindered hydride ion abstraction and desta-
bilization of intermediate zwitterion B. Nevertheless,
the overall rate of the process was limited by the
formation of the corresponding 5-arylmethylidene-
2,4,6-pyrimidinetrione A, while its subsequent rear-
rangement was faster than the initial condensation
stage.
Other o-aminobenzaldehydes IIc–IIg reacted with
barbituric acid (Ia) according to a similar scheme. As
a result, spirocyclic systems IIIc–IIIg were obtained
directly. In the reaction with 5-nitro-2-(2-methylpiperi-
dino)benzaldehyde (IIg) the cyclization selectively
involved the tertiary carbon atom despite formation of
more sterically strained structure IIIg.
Several types of t-reactions are known. Among
these, the closest analog to the reaction under study is
thermal isomerization of 2-vinyl-1-phenylpyrrolidine
derivatives IV, which involves 1,5-hydride shift to
give intermediate dipolar ion B and subsequent
cyclization to fused pyrroloquinoline system V [7]
(Scheme 2).
t-Reactions with cyclic CH acid derivatives were
studied to a considerably lesser extent; synthesis of
spirocyclic systems from CH acids was reported only
in [8, 9]. Therefore, the reaction of barbituric acid (Ia)
with aldehyde IIa attracts interest not only as a syn-
thetic route to difficultly accessible spirocyclic system
IIIa but also as an example of anomalously fast t-reac-
tion. The isomerization of the corresponding 5-aryl-
methylidene-2,4,6-pyrimidinetrione A was so fast that
we did not succeed in isolating it and even detecting
1
by H NMR spectroscopy when the reaction was per-
1,3-Dimethylbarbituric acid (Ib) is a close analog
of acid Ia. Compound Ib reacted with aldehydes IIa,
IIb, IId, and IIf under similar conditions to afford
compounds IIIh–IIIk. Likewise, the reaction of
2-thiobarbituric acid (Ic) with aldehyde IId gave
formed in an NMR ampule at 20°C in DMSO-d6, the
initial reactant concentration being 0.2 M. Under these
conditions, the t-spirocyclization occurred at a con-
siderably higher rate than the first condensation stage.
Scheme 2.
R
118°C, 2 h
R'
R = R' = CN
N
N
R
N
R
R'
R'
IV
B
V
R, R' = CN, COOEt.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

SYNTHESIS OF SPIROHETEROCYCLIC SYSTEMS FROM BARBITURIC ACIDS
903
Scheme 3.
NO2
O2N
O
O2N
O
N
N
Ic
Ib
CHO
Me
O
O
Me
O
O
–H2O
N
N
H
N
O
N
O
N
O
Me
Me
VI
VII
NO2
O2N
O
N
O
N
Me
O
O
Me
O
N
N
N
O
N
O
O
Me
Me
C
VIII
therein are related to addition of nucleophiles at the
exocyclic C=C bond in 5-arylmethylidenebarbituric
acids; very strong polarization of that bond endows
these compounds with Lewis acid properties [10].
Reactions of amines at the C=C bond leads to forma-
tion of stable zwitterionic systems with a structure
analogous to hypothetical intermediate C. The 1,5-hy-
dride shift in VII with formation of zwitterion C may
be treated as intramolecular capture of a nucleophilic
species, i.e., hydride ion, from the NCH2 group. Most
probably, hydride ion abstraction occurs through
a 6-membered cyclic transition state.
2-thioxo-4,6-dioxopyrimidine derivative IIIl. In all the
above reactions, the t-spirocyclization of intermediate
5-arylmethylidene derivatives A occurred through
a negligible activation barrier, and its rate was so high
that these intermediates could not be isolated.
In the condensation of 1,3-dimethylbarbituric acid
(Ib) with 2-morpholino-5-nitrobenzaldehyde (VI) in
ethanol at 50°C we succeeded in isolating intermediate
1,3-dimethyl-5-(2-morpholino-5-nitrobenzylidene)-
hexahydropyrimidine-2,4,6-trione (VII). This provides
an additional support to the assumption that 5-aryl-
methylidenebarbituric acids are formed as interme-
diates in the reactions under study. Compound VII is
stable under standard conditions, while it undergoes
isomerization into spirocyclic derivative VIII at ele-
vated temperature, e.g., on heating for 1 min at 100°C
in acetic acid (Scheme 3). Presumably, the reason for
the lower rate of t-spirocyclization of compound VII,
as compared to the other analogs like A, is reduction of
the electron density on the α-carbon atom in the alkyl-
amino group due to acceptor effects of the nitro group
and morpholine oxygen atom. Nevertheless, even in
this case the isomerization rate is anomalously high in
comparison with the known [6–9] examples of t-reac-
tions, the fastest of which are slower by three orders of
magnitude under analogous conditions.
To conclude, it should be noted that t-spirocycliza-
tion of barbituric acid derivatives not only provides
a new synthetic approach to difficultly accessible
heterocyclic systems with a spiropyrimidine fragment
but also demonstrates an unusual example of t-amino
effect. Further studies on t-amino effect in derivatives
of cyclic CH acids are expected to considerably extend
the scope of application of t-reactions in organic
chemistry.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Bruker AM-500 spectrometer at 500 and 125 MHz,
respectively. The mass spectra (electron impact, 70 eV)
were obtained on an MKh-1303 instrument with direct
sample admission into the ion source (150°C). The
purity of the products was checked by the analytical
Taking the above into account, of specific interest
are the mechanism of t-spirocyclization and factors
producing anomalous t-amino effect in systems like A
and VIII. We believe that the processes occurring
1
data, H NMR spectra, and TLC [Silufol UV-254
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

KRASNOV, KARTSEV
904
(C6a'), 126.42 (C8'), 127.70 (C6'), 143.29 (C9a'), 150.13
(C2), 168.67 and 172.04 (C4 and C6). Found, %:
C 63.13; H 5.31; N 14.70. C15H15N3O3. Calculated, %:
C 63.15; H 5.30; N 14.73.
plates; solvent systems: chloroform, chloroform–ethyl
acetate (1:1), or 2-propanol–water (4:1)].
Compounds Ia–Ic, IIc, and IIf were commercial
products. Aldehydes IIa and IIe were synthesized
from o-fluorobenzaldehyde and the corresponding
amines according to the procedures described in [7]
and [11].
Compounds IIIb–IIIl were synthesized in a similar
way; they were isolated as yellow (IIIb–IIId, IIIg,
IIIi, IIIj, IIIl) or colorless crystalline substances (IIIe,
IIIf, IIIh, IIIk).
5-Nitro-2-(1-pyrrolidinyl)benzaldehyde (IIb). To
a solution of 0.1 mol of 2-chloro-5-nitrobenzaldehyde
in 40 ml of DMF we added 0.11 mol of anhydrous
K2CO3 and 0.11 mol of pyrrolidine. The mixture was
stirred for 6 h at 75–90°C, cooled, and diluted with
150 ml of water, and the precipitate was filtered off
and washed with water. The crude product was dis-
solved in 20% hydrochloric acid, the undissolved
material was filtered off, and the filtrate was diluted
with water and made alkaline by adding aqueous am-
monia. The precipitate was filtered off, washed with
water, recrystallized from aqueous ethanol, and dried
at 30°C under reduced pressure. Yield 18.5 g (84%),
yellow crystalline substance, mp 131°C.
7'-Nitrospiro[perhydropyrimidine-5,5'-1',2',3',-
3a',4',5'-hexahydropyrrolo[1,2-a]quinoline]-2,4,6-
trione (IIIb). Yield 84%, mp 305°C (decomp.; from
1
aqueous DMF). H NMR spectrum (DMSO-d6), δ,
ppm (J, Hz): 1.65 m and 2.03 m (2H, AB system,
CH2), 2.18 m (2H, CH2CH), 2.96 d and 3.27 d (2H,
AB system, CH2Ar, J = 17.2), 3.30 m and 3.69 m (2H,
AB system, NCH2), 3.88 d.d (1H, NCH, J1 = 10.3,
J2 = 5.8), 6.51 d (1H, Harom, J = 9.2), 7.88 d (1H, Harom
,
J = 2.2), 7.95 d.d (1H, Harom, J1 = 9.2, J2 = 2.2), 11.25 s
(1H, NH), 11.51 s (1H, NH). Found, %: C 54.51;
H 4.30; N 16.92. C15H14N4O5. Calculated, %: C 54.55;
H 4.27; N 16.96.
5-Nitro-2-(1-azepanyl)benzaldehyde (IId) was
synthesized in a similar way. Yield 95%, yellow crys-
talline substance, mp 133°C.
8'-Nitrospiro[perhydropyrimidine-5,5'-1',2',3',-
3a',4',5'-hexahydropyrido[1,2-a]quinoline]-2,4,6-
trione (IIIc). Yield 81%, mp 265°C (decomp.; from
1
aqueous DMF). H NMR spectrum (DMSO-d6), δ,
5-Nitro-2-(2-methylpiperidino)benzaldehyde
(IIg) was synthesized in a similar way from 2-chloro-
5-nitrobenzaldehyde and 2-methylpiperidine. Yield
95%, yellow crystalline substance, mp 69°C.
ppm (J, Hz): 1.30–1.90 m (6H, 3CH2), 3.04 d and
3.35 d (2H, AB system, CH2Ar, J = 17.3), 3.09 d.d and
3.71 d.d (2H, AB system, NCH2, J1 = 12.7, J2 = 10.9),
4.22 d.d (1H, NCH, J1 = 13.8, J2 = 5.6), 6.90 d (1H,
Spiro[perhydropyrimidine-5,5'-1',2',3',3a',4',5'-
hexahydropyrrolo[1,2-a]quinoline]-2,4,6-trione
(IIIa). A hot solution of 0.01 mol of barbituric acid
(Ia) in 40 ml of 60% ethanol was added under stirring
to a solution of 0.01 mol of aldehyde IIa in 20 ml of
ethanol, heated to 50°C. The mixture was stirred for
5 min at 50°C and was kept for 1 h at room tempera-
ture. The precipitate was filtered off, washed with
aqueous ethanol, and dried at 40°C under reduced
pressure. Yield 2.74 g (96%), mp 252°C (from
H
arom, J = 9.2), 7.85 d (1H, Harom, J = 2.3), 7.90 d.d
(1H, Harom, J1 = 9.2, J2 = 2.3), 11.27 s (1H, NH), 11.28 s
(1H, NH). Found, %: C 55.90; H 4.63; N 16.22.
C16H16N4O5. Calculated, %: C 55.81; H 4.68; N 16.27.
3'-Nitrospiro[perhydropyrimidine-5,5'-5',6',6a',-
7',8',9',10',11'-octahydroazepino[1,2-a]quinoline]-
2,4,6-trione (IIId). Yield 90%, mp >320°C (decomp.;
1
from aqueous DMF). H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 1.25–1.99 m (8H, 4CH2), 2.93 d and
3.45 d (2H, AB system, CH2Ar, J = 18.2), 3.28 m and
3.90 m (2H, AB system, NCH2), 3.94 d.d (1H, NCH,
J1 = 11.0, J2 = 3.7), 6.68 d (1H, Harom, J = 9.7),
7.88 d.d (1H, Harom, J1 = 9.7, J2 = 2.4), 7.93 d (1H,
1
aqueous DMF). H NMR spectrum (DMSO-d6), δ,
ppm (J, Hz): 1.64 m and 2.11 m (2H, AB system,
CH2CH), 2.00 m (2H, CH2), 3.01 d and 3.31 d (2H,
AB system, CH2Ar, J = 16.9), 3.21 m and 3.52 m (2H,
1
2
Harom, J = 2.4), 11.06 s (1H, NH), 11.25 s (1H, NH).
AB system, NCH2), 3.70 d.d (1H, NCH, J = 8.5, J =
6.0), 6.46 d (1H, Harom, J = 8.3), 6.52 t (1H, Harom, J =
7.2), 6.93 d (1H, Harom, J = 7.2), 7.98 t (1H, Harom, J =
8.3), 11.10 s (1H, NH), 11.37 s (1H, NH). 13C NMR
spectrum (DMSO-d6), δC, ppm (J, Hz): 22.62 (CH2),
27.30 (CH2CH), 34.44 (CH2Ar), 47.32 (NCH2), 47.93
(C5), 62.72 (NCH), 110.89 (C9'), 115.22 (C7'), 119.45
Found, %: C 56.94; H 5.09; N 15.59. C17H18N4O5. Cal-
culated, %: C 56.98; H 5.06; N 15.63.
3'-Phenylspiro[perhydropyrimidine-5,5'-
1',2',3',3a',4',5'-hexahydro-1H-pyrazino[1,2-a]-
quinoline]-2,4,6-trione (IIIe). Yield 95%, mp 296°C
1
(decomp.; from aqueous DMF). H NMR spectrum
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

SYNTHESIS OF SPIROHETEROCYCLIC SYSTEMS FROM BARBITURIC ACIDS
905
(DMSO-d6), δ, ppm (J, Hz): 2.72 t (1H, NCH2, J =
10.3), 2.95 m (1H, NCH2), 3.14 d and 3.27 d (2H, AB
system, CH2Ar, J = 16.1), 3.15 m (1H, NCH2), 3.46 m
and 4.07 m (2H, AB system, NCH2), 3.63 m (1H,
NCH2), 3.69 d.d (1H, NCH, 1J = 10.4, 2J = 5.1), 6.64 t
(1H, Harom, J = 6.9), 6.77 t (1H, Harom, J = 6.9), 6.84 d
(2H, Harom, J = 9.2), 6.88 d (1H, Harom, J = 8.0), 6.94 d
(1H, Harom, J = 6.9), 7.04 t (1H, Harom, J = 8.1),
7.18 d.d (2H, Harom, J = 8.1), 11.21 s (1H, NH), 11.40 s
(1H, NH). Found, %: C 67.04; H 5.37; N 14.85.
C21H20N4O3. Calculated, %: C 67.01; H 5.36; N 14.88.
1,3-Dimethyl-7'-nitrospiro[perhydropyrimidine-
5,5'-1',2',3',3a',4',5'-hexahydropyrrolo[1,2-a]-
quinoline]-2,4,6-trione (IIIi). Yield 83%, mp 294°C
1
(from EtOH–CHCl3). H NMR spectrum (CDCl3), δ,
ppm (J, Hz): 1.46 m and 2.02 m (2H, AB system,
CH2), 2.09 m (2H, CH2CH), 3.07 d and 3.27 d (2H, AB
system, CH2Ar, J = 16.6), 3.21 s and 3.39 s (3H each,
NMe), 3.36 m and 3.71 m (2H, AB system, NCH2),
3.88 d.d (1H, NCH, J1 = 10.9, J2 = 6.0), 6.52 d (1H,
Harom, J = 8.4), 7.95 d (1H, Harom, J = 2.1), 8.09 d.d
(1H, Harom, J1 = 8.4, J2 = 2.1). Found, %: C 56.98;
H 5.06; N 15.62. C17H18N4O5. Calculated, %: C 56.98;
H 5.06; N 15.63.
Spiro[perhydropyrimidine-5,5'-1',3',4',9',-
10',10a'-hexahydro-2'-oxa-4a'-azaphenanthrene]-
2,4,6-trione (IIIf). Yield 92%, mp 320°C (decomp.;
1,3-Dimethyl-3'-nitrospiro[perhydropyrimidine-
5,5'-5',6',6a',7',8',9',10',11'-octahydroazepino-
[1,2-a]quinoline]-2,4,6-trione (IIIj). Yield 95%,
1
from aqueous DMF). H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 2.93 m and 3.57 m (2H, AB system,
NCH2), 3.08 d and 3.28 d (2H, AB system, CH2Ar, J =
15.0), 3.31 m and 3.40 m (2H, AB system, OCH2CH,
J1 = 11.5, J2 = 8.1), 3.72 d.d (1H, NCH, J1 = 11.5, J2 =
5.2), 3.81 m and 3.89 m (2H, AB system, OCH2CH2),
6.66 t (1H, Harom, J = 6.9), 6.83 d (1H, Harom, J = 9.2),
6.93 d (1H, Harom, J = 8.1), 7.04 t (1H, Harom, J = 8.1),
11.23 s (1H, NH), 11.44 s (1H, NH). Found, %:
C 59.77; H 5.05; N 16.88. C15H15N3O4. Calculated, %:
C 59.80; H 5.02; N 13.95.
1
mp 259°C (from EtOH–CHCl3). H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.40–1.65 m (6H, 3CH2),
1.70 m and 1.99 m (2H, AB system, CH2CH), 3.15 m
and 3.83 m (2H, AB system, NCH2), 3.18 d and 3.45 d
(2H, AB system, CH2Ar, J = 18.5), 3.27 s and 3.32 s
(3H each, NMe), 3.62 d.d (1H, NCH, J1 = 10.0, J2 =
5.1), 6.65 d (1H, Harom, J = 9.9), 8.01 d.d (1H, Harom
,
J1 = 9.9, J2 = 2.5), 8.04 d (1H, Harom, J = 2.5). Found,
%: C 59.06; H 5.74; N 14.49. C19H22N4O5. Calculated,
%: C 59.06; H 5.74; N 14.50.
5'-Methyl-8'-nitrospiro[perhydropyrimidine-
5,5'-1',2',3',3a',4',5'-hexahydropyrido[1,2-a]quino-
line]-2,4,6-trione (IIIg). Yield 79%, mp 203°C
1,3-Dimethyl-3'-phenylspiro[perhydropyrimi-
dine-5,5'-1',2',3',3a',4',5'-hexahydro-1H-pyrazino-
[1,2-a]quinoline]-2,4,6-trione (IIIk). Yield 96%,
1
(decomp.; from aqueous DMF). H NMR spectrum
1
(DMSO-d6), δ, ppm (J, Hz): 1.16 s (3H, Me), 1.47–
1.94 m (5H, CH, 2CH2), 2.94 d.d and 3.79 d.d (2H, AB
system, NCH2, J1 = 12.8, J2 = 4.1), 3.06 d and 3.58 d
mp 188°C (from EtOH–CHCl3). H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 2.72 d.d and 4.08 d.d (2H, AB
system, NCH2CH, J1 = 11.5, J2 = 9.2), 3.06 m and
3.29 m (2H, AB system, NCH2), 3.10 d and 3.56 d (2H,
AB system, CH2Ar, J = 17.3), 3.21 s and 3.40 s (3H
each, NMe), 3.37 m and 3.51 m (2H, AB system,
NCH2), 3.82 d.d (1H, NCH, J1 = 9.2, J2 = 3.6), 6.79 m
(4H, Harom), 6.88 t (1H, Harom, J = 6.9), 6.94 d (2H,
(2H, AB system, CH2Ar, J = 17.9), 6.84 d (1H, Harom
,
J = 9.0), 7.88 d (1H, Harom, J = 2.3), 7.93 d.d (1H,
H
arom, J1 = 9.0, J2 = 2.3), 11.24 s (1H, NH), 11.36 s
(1H, NH). Found, %: C 57.02; H 5.10; N 15.56.
C17H18N4O5. Calculated, %: C 56.98; H 5.06; N 15.63.
H
arom, J = 9.2), 7.02 d (1H, Harom, J = 8.1), 7.17 t (1H,
1,3-Dimethylspiro[perhydropyrimidine-5,5'-
1',2',3',3a',4',5'-hexahydropyrrolo[1,2-a]quinoline]-
2,4,6-trione (IIIh). Yield 96%, mp 162°C (from
Harom, J = 8.1), 7.25 d.d (2H, Harom, J = 8.1). Found, %:
C 68.22; H 6.01 N 13.81. C23H24N4O3. Calculated, %:
C 68.30; H 5.98; N 13.85.
1
EtOH–CHCl3). H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 1.49 m and 2.06 m (2H, AB system, CH2CH),
2.00 m (2H, CH2), 2.98 d and 3.56 d (2H, AB system,
CH2Ar, J = 16.7), 3.21 s and 3.37 s (3H each, NMe),
3.32 m and 3.59 m (2H, AB system, NCH2), 3.70 d.d
(1H, NCH, J1 = 9.5, J2 = 6.0), 6.57 d (1H, Harom, J =
8.4), 6.64 t (1H, Harom, J = 7.1), 6.99 d (1H, Harom, J =
8.4), 7.14 t (1H, Harom, J = 7.1). Found, %: C 65.15;
H 6.11; N 13.39. C17H19N3O3. Calculated, %: C 65.16;
H 6.11; N 13.41.
3'-Nitro-2-thioxospiro[perhydropyrimidine-5,5'-
5',6',6a',7',8',9',10',11'-octahydroazepino[1,2-a]-
quinoline]-4,6-dione (IIIl). Yield 77%, mp 261°C
(from aqueous EtOH). 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 1.35–2.03 m (8H, 4CH2), 3.01 d and
3.48 d (2H, AB system, CH2Ar, J = 18.4), 3.27 m and
3.91 m (2H, AB system, NCH2), 3.75 d.d (1H, NCH,
J1 = 10.4, J2 = 5.8), 6.67 d (1H, Harom, J = 9.2),
7.89 d.d (1H, Harom, J1 = 9.2, J2 = 2.3), 7.95 d (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

KRASNOV, KARTSEV
906
H
arom, J = 2.3), 12.11 s (1H, NH), 12.24 s (1H, NH).
3.09 d and 3.55 d (2H, AB system, CH2Ar, J = 16.1),
3.25 m (2H, NCH2), 3.27 s and 3.38 s (3H each, NMe),
3.64 m and 3.72 m (2H, AB system, OCH2CH2, J1 =
11.0), 3.86 m and 3.92 m (2H, AB system, OCH2CH,
J1 = 10.4), 4.00 d.d (1H, NCH, J1 = 11.0, J2 = 3.6),
6.84 d (1H, Harom, J = 9.5), 7.88 d (1H, Harom, J = 2.4),
6.84 d.d (1H, Harom, J1 = 9.5, J2 = 2.4). Found, %:
C 54.58; H 4.87; N 14.95. C17H18N4O6. Calculated, %:
C 54.54; H 4.85; N 14.97.
Found, %: C 54.42; H 4.81; N 14.92; S 8.49.
C17H18N4O4S. Calculated, %: C 54.53; H 4.85; N 14.96;
S 8.56.
2-Morpholino-5-nitrobenzaldehyde (VI) was
synthesized as described above for compounds IIb,
IId, and IIg. Yield 90%, yellow crystalline substance,
mp 116°C.
1,3-Dimethyl-5-(2-morpholino-5-nitrobenzyli-
dene)hexahydropyrimidine-2,4,6-trione (VII). A hot
solution of 0.01 mol of compound Ib in 20 ml of
ethanol was added under stirring to a solution of
0.01 mol of aldehyde VI in 40 ml of ethanol, heated to
50°C. The mixture was kept at room temperature until
a crystalline product began to separate, cooled to 10°C,
and kept for 1 h at that temperature. The precipitate
was filtered off, washed with aqueous ethanol, and
dried at 20°C under reduced pressure. Yield 3.18 g
(85%), yellow–orange crystalline substance, mp 231°C
REFERENCES
1. Levina, R.Ya. and Velichko, F.K., Usp. Khim., 1960,
vol. 29, p. 929.
2. Bojarski, J.T., Mockrosz, J.L., Barton, H.J., and
Paluchowska, M.H., Adv. Heterocycl. Chem., 1985,
vol. 38, p. 229.
3. Krasnov, K.A., Selected Methods for Synthesis and
Modification of Heterocycles, Kartsev, V.G., Ed.,
Moscow: Iridium, 2002, vol. 1, p. 281.
4. Fiqueroa-Villwe, J.D. and Cruz, E.R., Tetrahedron,
1
(decomp.; from CHCl3–CCl4). H NMR spectrum
1993, vol. 49, p. 2855.
(CDCl3), δ, ppm (J, Hz): 3.16 t (4H, NCH2, J = 4.8),
3.39 s and 3.43 s (3H each, NMe), 3.88 t (4H, OCH2,
J = 4.8), 7.06 d (1H, Harom, J = 8.9), 8.29 d.d (1H,
5. Ivin, B.A., D’yachkov, A.D., Vishnyakov, I.M.,
Smorygo, N.A., and Sochilin, E.G., Zh. Org. Khim.,
1979, vol. 11, p. 1337.
H
H
arom, J1 = 8.9, J2 = 2.4), 8.52 s (1H, =CH), 8.80 d (1H,
arom, J = 2.4). Found, %: C 54.62; H 4.88; N 14.94.
6. Meth-Cohn, O., Adv. Heterocycl. Chem., 1996,
vol. 65, p. 1.
C17H18N4O6. Calculated, %: C 54.54; H 4.85; N 14.97.
7. Nijhuis, W.H.N., Verboom, W., El-Fadl, A.A.,
Harkema, S., and Reinhoudt, D.N., J. Org. Chem., 1989,
vol. 54, p. 199.
8. Schwartz, A., Beke, G., Kovari, Z., Bocskey, Z.,
Farkas, O., and Matyus, P., J. Mol. Struct. (Theochem),
2000, vol. 528, p. 49.
9. Karolyhazy, L., Regdon, G., Elias, O., Beke, G.,
Tabi, T., Hodi, K., Eros, I., and Matyus, P., J. Mol.
Struct. (Theochem), 2003, vols. 666–667, p. 667.
1,3-Dimethyl-7'-nitrospiro[perhydropyrimidine-
5,10'-1',3',4',9',10',10a'-hexahydro-2'-oxa-4a'-aza-
phenanthrene]-2,4,6-trione (VIII). A solution of
5 mmol of compound VII in 15 ml of glacial acetic
acid was heated for 1 min at 100–110°C and was then
kept at room temperature. When a crystalline product
separated, the mixture was cooled to 10°C, and the
precipitate was filtered off, washed with ethanol, and
dried at 40°C under reduced pressure. Yield 3.18 g
(82%), yellow crystalline substance, mp 256°C (from
10. Haslinger, E., Reithmaier, M., Robien, W., and Wol-
schann, P., Monatsh. Chem., 1984, vol. 115, p. 375.
11. Nijhuis, W.H.N., Verboom, W., and Reinhoudt, D.N.,
1
AcOH). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
Synthesis, 1987, no. 7, p. 641.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005