Reactions of 5-dihydrocotarnyl-1,3-dimethylbarbituric acid and other cotarnine derivatives with 1,3-dimethylbarbituric acid. X-ray diffraction analysis of a 5,5-spiro derivative of 1,3-dimethylbarbituric acid

Article abstract of DOI:10.1023/A:1020983527851

6-Methyl-4-methoxy-5,6,7,8-tetrahydro-2H-[1,3]dioxolo[4,5-g] isoquinolin-5-ol (cotarnine) and its derivatives, namely, 5-dihydrocotarnyl-1,3-dimethylbarbituric acid, dihydrocotarnylnitromethane, and dihydrocotarnylphenylacetonitrile, react with an excess

Full text of DOI:10.1023/A:1020983527851

1540
Russian Chemical Bulletin, International Edition, Vol. 51, No. 8, pp. 1540—1544, August, 2002
Reactions of 5ꢀdihydrocotarnylꢀ1,3ꢀdimethylbarbituric acid
and other cotarnine derivatives with 1,3ꢀdimethylbarbituric acid.
Xꢀray diffraction analysis of a 5,5ꢀspiro derivative of
1,3ꢀdimethylbarbituric acid
b
c
K. A. Krasnov,a V. G. Kartsev, and V. N. Khrustalev
ꢀ
aI. I. Mechnikov St.ꢀPetersburg State Medical Academy,
47 Piskarevskii prosp., 195067 St.ꢀPetersburg, Russian Federation.
Fax: +7 (812) 350 4428. Eꢀmail: veselkoff@mail.ru
b"Interbioscreen" Company,
8 Institutskii prosp., 142432 Chernogolovka, Moscow region, Russian Federation.
Fax: +7 (095) 913 2114. Eꢀmail: screen@ibscreen.ru
cA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5085. Eꢀmail: vkh@xrlab.ineos.ac.ru
6ꢀMethylꢀ4ꢀmethoxyꢀ5,6,7,8ꢀtetrahydroꢀ2Hꢀ[1,3]dioxolo[4,5ꢀg]isoquinolinꢀ5ꢀol (cotarꢀ
nine) and its derivatives, namely, 5ꢀdihydrocotarnylꢀ1,3ꢀdimethylbarbituric acid, dihydroꢀ
cotarnylnitromethane, and dihydrocotarnylphenylacetonitrile, react with an excess of
1,3ꢀdimethylbarbituric acid to give its 5,5ꢀspiro derivative. The structure of the latter was
proved by Xꢀray diffraction analysis. A possible reaction mechanism was discussed.
Key words: cotarnine, 1,3ꢀdimethylbarbituric acid, 5ꢀdihydrocotarnylꢀ1,3ꢀdimethylꢀ
barbituric acid, 5,5ꢀspiro derivatives of barbituric acid, Xꢀray diffraction analysis, NMR
spectroscopy.
Earlier,1,2 it has been found that heating of
4ꢀmethoxyꢀ6ꢀmethylꢀ5,6,7,8ꢀtetrahydroꢀ2Hꢀ[1,3]diꢀ
oxolo[4,5ꢀg]isoquinolinꢀ5ꢀol (cotarnine, 1) with 1,3ꢀdiꢀ
methylbarbituric acid (2) in chloroform yields 5ꢀ(8ꢀmethꢀ
oxyꢀ2ꢀmethylꢀ6,7ꢀmethylenedioxyꢀ1,2,3,4ꢀtetrahydroisoꢀ
quinolinꢀ1ꢀyl)ꢀ1,3ꢀdimethylbarbituric (5ꢀdihydrocotarꢀ
nylꢀ1,3ꢀdimethylbarbituric) acid (3). The structure of
the compound obtained was determined using Xꢀray difꢀ
When heating compound 3 and acid 2 under drastic
conditions, we found that methylamine is eliminated
and that the reaction product is a 5,5ꢀspiro derivative of
barbituric acid (4), which can also be obtained directly
from cotarnine and acid 2. In the latter case, the reaction
probably proceeds through intermediate 3 (Scheme 1).
According to the Xꢀray diffraction data (Fig. 1), crystal
4 is a racemate. Two crystallographically independent
molecules (A and B) in its unit cell are linked by a
1
fraction analysis and H NMR spectroscopy.
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1418—1421, August, 2002.
1066ꢀ5285/02/5108ꢀ1540 $27.00 © 2002 Plenum Publishing Corporation

5,5ꢀSpiro derivative of 1,3ꢀdimethylbarbituric acid
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 8, August, 2002
1541
O(2´)
C(7´)
C(2´)
N(1´)
C(8´)
C(6´)
C(10)
O(4)
N(3´)
O(16)
C(17)
O(6´)
C(5)
C(4´)
O(4´)
C(6)
O(3)
C(4)
C(16)
C(4A)
C(3A)
N(11)
C(12)
C(2)
C(7)
C(15)
C(14)
C(8A)
C(9A)
C(8)
O(1)
C(9)
O(12)
N(13)
O(14)
C(18)
Fig. 1. Molecular structure of compound 4 (one of the two crystallographically independent molecules is shown with anisotropic
thermal displacement ellipsoids (50% probability)).
pseudocenter of inversion with the following coordinates:
0.2480, 0.8223, and 0.2651. Both independent molecules
have virtually the same geometry, except for the torsion
angle of the Me fragment in the methoxy group (the
C(3A)—C(4)—O(4)—C(10) angle in A is –83.5(8)°, while
the analogous C(3AA)—C(4AB)—O(4A)—C(10A) angle
in B is 10.6(12)°). For this reason, only structure A will
be considered in the discussion that follows. The bond
lengths and angles in compound 4 have standard values.
The trioxopyrimidine rings exist in a "sofa" conformaꢀ
tion; the C(6) and C(15) atoms deviate from the plane of
the other atoms in the corresponding heterocycle by 0.397
and 0.224 Å, respectively. The cyclohexene fragment
has the same conformation (the C(6) atom extends
0.711 Å from the plane of the other ring atoms). The
conformation of the 1,3ꢀdioxolane ring is an "envelope"
with the C(2) atom deviating from the plane of the hetꢀ
erocycle by 0.205 Å. The dihedral angles between
the C(5)—C(4A)—C(8A)—C(8)—C(7) plane in the
cyclohexene ring and the C(16)—N(11)—C(12)—
N(13)—C(14) and C(6´)—N(1´)—C(2´)—N(3´)—C(4´)
planes in the trioxopyrimidine rings are 89.7° and 63.7°,
respectively. The molecules are stacked along the Y axis;
the molecular stacks are united into layers linked by
axis 21 and running parallel to the XY0 plane.
the solvent nature (Table 1), being higher in more polar
solvents.
Like cotarnine, dihydrocotarnylnitromethane (5) and
dihydrocotarnylphenylacetonitrile (6) react with acid 2
to give spiro derivative 4. Apparently, these reactions
also proceed through intermediate 3.
Apart from spiro derivative 4, the reactions studied afꢀ
ford 4ꢀmethoxyꢀ6ꢀmethylꢀ5,6,7,8ꢀtetrahydroꢀ2Hꢀ[1,3]diꢀ
oxolo[4,5ꢀg]isoquinoline (7) (5—8%), 1,3,5ꢀtrimethylꢀ
barbituric acid (8) (2—5%), and unidentified compounds
with molecular masses >700 (50—70%).
The yield of spiro derivative 4 from the reaction of
compound 1 (or 3) with acid 2 significantly depends on

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Russ.Chem.Bull., Int.Ed., Vol. 51, No. 8, August, 2002
Krasnov et al.
Table 1. Reaction conditions for cotarnine (1) and its derivaꢀ
tives (3, 5, and 6) with 1,3ꢀdimethylbarbituric acid (2) and the
yields of compound 4
rectly confirmed by its yellow color in aprotic solvents
(λ
= 408—412 nm). Such a color is characteristic of
max
5ꢀalkoxybenzylidenebarbituric acids;5 its intensity is enꢀ
hanced with heating and returns to the starting level
upon cooling.
Starting reagents
Solvent
Yield of 4 (%)
(number of moles)
Step 2 (9 → 10). 5ꢀBenzylidenebarbituric acids are
known to show oxidative properties since their active
C=CHAr double bond can easily be reduced, e.g., by
heating with formic acid in the presence of Me3N.6 We
assumed that tautomer 9 disproportionates in situ (its
amino group undergoes intramolecular oxidation, while
the arylidene double bond is reduced) to give intermediꢀ
ate 10. Taking into account that redox reactions of
5ꢀbenzylidenebarbituric acids are catalyzed by bases,6
we carried out the reaction of compound 3 with acid 2 in
the presence of Et3N and, as expected, significantly inꢀ
creased the yield of product 4 (see Table 1).
1 (1) + 2 (2)
1 (1) + 2 (2)
1 (1) + 2 (2)
3 (1) + 2 (1)
1 (1) + 2 (2)
3 (1) + 2 (1)
1 (1) + 2 (3)
1 (1) + 2 (3) + Et3N (1)
3 (1) + 2 (2) + Et3N (1)
5 (1) + 2 (2)
—
6
9
nꢀDecane
PhBr
PhBr
MeCONMe2
MeCONMe2
MeCONMe2
MeCONMe2
MeCONMe2
MeCONMe2
MeCONMe2
16
17
22
24
28
44
48
33
35
6 (1) + 2 (2)
Step 3 (10 → 11). The intramolecular Michael cyꢀ
clization of compound 10 seems to be quite obvious.
Step 4 (11 + 2 → 4). Apparently, the final step of this
process should be regarded as analogous to the known7
alkylation of barbituric acids with alkylamines. In this
case, intermediate amino derivative 11 can be assumed
to be protonated with an excess of acid 2. The resulting
nucleophilic carbanion 2– attacks the secondary C atom
of the CH+NH2Me fragment in substrate 11+ to give,
upon elimination of neutral methylamine, compound 4.
An alternative attack of carbanion 2– on the +NMe group
of the same substrate results in the splitting of the Me
The mechanism of the reaction under discussion reꢀ
mains the most difficult problem. We assumed that the
formation of compound 4 includes four steps (Scheme 2).
Step 1 (3 → 9). It is known that ringꢀchain tautomerꢀ
ism is possible for cotarnine and some of its derivaꢀ
tives.3,4 We thus believe that there is an equilibrium in
solution between compound 3 and a corresponding
5ꢀarylideneꢀ1,3ꢀdimethylbarbituric acid 9, which acꢀ
counts for no higher than 0.1% of the tautomeric mixꢀ
ture. The opening of the tetrahydropyridine ring in comꢀ
pound 3, which is colorless in the solid state, is indiꢀ
Scheme 2

5,5ꢀSpiro derivative of 1,3ꢀdimethylbarbituric acid
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 8, August, 2002
1543
1 H, exoꢀH(5´), J = 15.5 Hz); 3.19 (s, 6 H, N(1a)Me +
N(3a)Me); 3.20 (d, 1 H, endoꢀH(5´), J = 15.5 Hz); 3.27,
3.36 (both s, 3 H each, N(1)Me, N(3)Me); 3.37 (dd, 1 H,
endoꢀH(8´), J = 14.0 Hz, J = 6.0 Hz); 3.45 (m, 1 H, H(7´));
3.78 (d, 1 H, H(5´), J = 7.0 Hz); 3.90 (s, 3 H, OMe); 5.82 (AB
system, 2 H, OCH2O, J = 19.0 Hz); 6.26 (s, 1 H, Ar). 13C NMR
(CDCl3), δ: 28.4, 28.5, 28.6, 29.1 (N(1)Me, N(3)Me, N(1a)Me,
N(3a)Me); 29.7 (C(5´)); 36.7 (C(8)); 41.5 (C(7)); 49.3 (C(5));
50.9 (C(5a)); 59.3 (MeO); 100.7 (OCH2O); 101.9 (C(1´)); 114.2
(C(2´)); 128.6 (C(4´)); 133.9 (C(3´)); 140.1 (C(4″)); 148.4
(C(8″)); 151.3 (C(2), C(2a)); 167.9, 168.2, 169.4, 171.8 (C(4),
C(6), C(4a), C(6a)). MS, m/z (Irel (%)): M+ 500 (3), 344
(100), 327 (11), 259 (2), 229 (5), 189 (1), 157 (2), 143 (1).
4ꢀMethoxyꢀ6ꢀmethylꢀ5,6,7,8ꢀtetrahydroꢀ2Hꢀ[1,3]diꢀ
oxolo[4,5ꢀg]isoquinoline (7). A solution of fraction 1 in chloroꢀ
form (see above) was treated with 5% HCl (20 mL). An aqueꢀ
ous acid extract was separated and washed with pure chloroꢀ
form (10 mL). Then the aqueous solution was alkalified with
aqueous NH3, and the organic material was extracted with
ether (2×20 mL). The combined ethereal solutions were washed
with water, dried with Na2SO4, and saturated with dry HCl at
0 °C. The precipitate that formed was washed with ether, dried,
dissolved in 5 mL of water, and alkalified with KOH. The
resulting oil was extracted with ether, and the extract was washed
with water and concentrated in vacuo to give compound 7
(100—200 mg, 5—8%) as a light yellow oil. Product 7 is identiꢀ
cal with an authentic sample obtained in an independent way
(TLC and 1H NMR data).10 The oil crystallized within one to
two days, m.p. 51—52 °C (cf. Ref. 10: m.p. 55 °C). 1H NMR
(CDCl3), δ: 2.41 (s, 3 H, NMe); 2.57 (t, 2 H, ArCH2, J =
5.5 Hz); 2.77 (t, 2 H, NCH2, J = 5.5 Hz); 3.40 (s, 2 H, CH2);
2.57 (s, 3 H, OMe); 5.83 (s, 2 H, OCH2O); 6.27 (s, 1 H, ArH).
1,3,5ꢀTrimethylbarbituric acid (8). A solution of fraction 2
in chloroform (see above) was evaporated to dryness to give a
mixture of acids 2 and 8 (0.5—1.3 g). The mixture was anaꢀ
lyzed using TLC and 1H NMR spectroscopy as described earꢀ
lier.7 The yield of compound 8 was 30 to 80 mg (5—8%).
Xꢀray diffraction analysis of compound 4. Crystals of comꢀ
pound 4 were grown from CHCl3—heptane, 1 : 5 (C23H24N4O9,
M = 500.46). The crystals are monoclinic, space group P21/c,
at T = 293 K: a = 23.274(4) Å, b = 12.966(3) Å, c = 15.395(3) Å,
group; this can account for the formation of compound
8 by methylating the starting acid 2. Insofar as the molar
ratio of derivative 4 to compound 8 in the final reaction
mixture is ∼7—8 : 1, one can state that substrate 11+
undergoes selective splitting. Intermediate 11 was not
isolated, probably because of its substantially higher reꢀ
activity under these conditions compared to, e.g., Et3N,
which is dealkylated with acid 2 at a noticeable rate only
at T >170 °C.
It should be noted in conclusion that the aforesaid
unusual multistep process yielding the new spiroheteroꢀ
cyclic system 4 calls for further investigation aimed at
extending the discovered reactions to other derivatives
of barbituric acid and cotarnine analogs.
Experimental
1
H and 13C NMR spectra were recorded on a Bruker
AMꢀ500 spectrometer (500 and 125 MHz, respectively). Mass
spectra were recorded on an MXꢀ1303 instrument (direct inlet
of a sample into the ion source at 150 °C, ionizing voltage
70 eV). The purity of the reaction products was checked by
TLC on Silufol UVꢀ254 plates in CHCl3—AcOEt (4 : 1),
CHCl3—AcOEt—AcOH (3 : 2 : 0.1), PriOH—water (4 : 1), or
DMF—NH4OH (25%) (3 : 1).
Cotarnine (1) was isolated from cotarnine hydrochloride
according to the known procedure.8 Dihydrocotarnylnitroꢀ
methane (5) and dihydrocotarnylphenylacetonitrile (6) were
prepared by the reactions of cotarnine (1) with nitromethane or
phenylacetonitrile, respectively.9 5ꢀ(4ꢀMethoxyꢀ6ꢀmethylꢀ
5,6,7,8ꢀtetrahydroꢀ2Hꢀ[1,3]dioxolo[4,5ꢀg]isoquinoline (7) was
synthesized by reducing cotarnine;10 1,3,5ꢀtrimethylbarbituric
acid (8) was obtained by methylation of acid 2.6
4´ꢀMethoxyꢀ1,3ꢀdimethylꢀ7´ꢀ(1,3ꢀdimethylꢀ2,4,6ꢀtrioxoꢀ
perhydropyrimidinꢀ5ꢀyl)ꢀ2,4,6ꢀtrioxospiro[perhydropyrimidineꢀ
5,6´ꢀ(5´,6´,7´,8´ꢀtetrahydro[1,3]dioxolo[4,5ꢀg]naphthalene)]
(4) (general procedure). Cotarnine 1 or its derivatives 3, 5,
and 6 (1 mmol) was mixed with acid 2 (2 or 3 mmol). The
reaction was carried out either in 10 mL of a solvent or without
any solvent (see Table 1). The reaction mixture was refluxed in
an oil bath at 160 °C for 20 min, cooled, and treated with
aqueous 5% NH3 (50 mL). The precipitate that formed was
filtered off, and the organic material was extracted from the
aqueous solution with CHCl3 (3×20 mL). The extracts were
combined (fraction 1). The aqueous solution was acidified with
HCl to pH 1, and the precipitate that formed was filtered off
and washed with water. The organic material was extracted
from the resulting aqueous acid solution with CHCl3 (3×20 mL),
and the extracts were combined (fraction 2). The precipitate
was transferred from the filter to a flask and treated with 3%
AcONa (100 mL) while stirring it for 1 h. The undissolved
portion was separated, the solution was acidified with HCl to
pH 1, and the precipitate that formed was filtered off, washed
with water, and dried to give compound 4 as colorless crystals,
m.p. 234—235 °C (from CCl4). The yield of 4 is given in Table 1.
Found (%): C, 55.13; H, 4.77; N, 11.15. C23H24N4O9. Calcuꢀ
lated (%): C, 55.20; H, 4.83; N, 11.19. 1H NMR (CDCl3), δ:
2.71 (dd, 1 H, exoꢀH(8´), J = 14.0 Hz, J = 6.0 Hz); 2.86 (d,
β = 98.714(15)°, V = 4591.9(17) Å3, Z = 8, dcalc = 1.448 g cm–3
,
F(000) = 2096, µ = 0.113 mm–1. The unit cell parameters and
the intensities of 5963 reflections were measured on a Siemens
P3/PC automated fourꢀcircle diffractometer (T = 293 K,
λꢀMoKα radiation, graphite monochromator, θ/2θ scan mode,
θ
max = 23°). The structure was determined by the direct method
and refined by the fullꢀmatrix leastꢀsquares method in the anisoꢀ
tropic approximation for nonhydrogen atoms. The H atoms
were located geometrically and refined in the isotropic apꢀ
proximation with fixed coordinates (riding model) and therꢀ
mal parameters (Uiso(H) = 1.5Ueq(C) for the Me group and
Uiso(H) = 1.2Ueq(C) for the other groups). The final discrepꢀ
ancy factors are R1 = 0.0696 for 3067 independent reflections
with I > 2σ(I ) and wR2 = 0.1536 for all 5784 independent
reflections. All calculations were performed with the use of the
SHELXTL PLUS program package (Version 5.10).11
Tables of atomic coordinates, bond lengths and angles,
torsion angles, and anisotropic thermal parameters for comꢀ
pound 4 have been deposited with the Cambridge Crystalloꢀ
graphic Database.

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Krasnov et al.
5. B. A. Ivin, A. D. D´yachkov, I. M. Vishnyakov, N. A.
Smorygo, and E. G. Sochilin, Zh. Org. Khim., 1979, 11,
1337 [J. Org. Chem. USSR, 1979, 11 (Engl. Transl.)].
6. S. Minoru and V. Chiruka, Chem. Pharm. Bull., 1969,
17, 738.
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos. 00ꢀ03ꢀ
32840a and 00ꢀ15ꢀ97359).
7. K. A. Krasnov, Zh. Org. Khim., 2000, 36, 302 [Russ. J. Org.
Chem., 2000, 36, 280 (Engl. Transl.)].
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Received January 22, 2002;
in revised form May 14, 2002