intramolecular sandwich conformation and a pseudoframework, determines to a large extent the spectral and physicochemical
properties of these compounds. The principal reason for the appearance of these structures is considered to be the existence of
distant π—π interactions between the cytisine and 2,4,6-trioxopyrimidine parts of the molecule. It is expected that further study
of5-cytisylmethyl derivativesofbarbituric acid and related compounds will shed further light on the nature ofthese interactions.
EXPERIMENTAL
PMRspectra were recorded on a Bruker AM-500 spectrometer at working frequency500 MHz in CDCl . Signals were
3
identified using standard NMR methods of HH-COSY and NOESY. Temperature dependences of proton spectra were
investigated in the range 20 to -60°C in steps of 10°C.
The purity of the starting materials and products was monitored using TLC [on Silufol UV-254 plates using CHCl ,
3
CHCl :EtOAc (3:1), and CHCl :EtOAc:HOAc (3:2:0.1)], PMR (Table 3), and elemental analyses.
3
3
Cytisine (pharmacopoeic) isolated from willow thicket seeds of purity at least 99% was used in the experiments.
The syntheses and properties of compounds 3a-g have been described [2].
X-ray Structure Analysis. Compound 3b (0.1 g) was dissolved in CHCl (1 mL) and treated with CCl (3 mL) and
3
4
heptane (5 mL) to grow crystals. The solution was placed in a cylinder and held at 20°C for 10 days, during which 3/4 of the
initial solvent volume evaporated naturally. The resulting crystals were separated and washed with hexane.
Crystals of 3b (C28H32N4O5, M = 504.58) are monoclinic, space group P2 , a = 8.4590(12), b = 16.674(2), c =
1
-1
3
3
9.0412(13) Å, β = 102.135(4)°, V = 1246.7(3) Å , Z = 2, d = 1.344 mg/cm , F(000) = 536, mk = 0.094 mm .
c
Unit-cell constants and intensities of 8537 reflections were measured on an automated Bruker diffractometer SMART
CCD 1000 (T = 110 K, MoK , -scanning in steps of 0.3° and exposures of 10 sec per frame, Θmax = 27°). The structure was
solved bydirect methods and refined byanisotropic full-matrix least-squares methods for nonhydrogen atoms. Hydrogen atoms
were located in difference Fourier syntheses and refined isotropically. The final agreement factors were R = 0.0498 for 4566
1
independent reflections with I > 2 σ(I) and wR = 0.1338 for all 5362 independent reflections. Calculations were made using
2
theSHELXTLPLUS(Version 5.10) programs [10]. Atomic coordinates, bond lengths, bond and torsion angles, andanisotropic
temperature factors for 3b have been deposited in the Cambridge Structural Database.
Preparation of 1,3-Dimethyl-5-arylmethylbarbituric Acids (1h-j) and Their 2-Thio Analogs (1k-o). General
Method. 1,3-Dimethylbarbituric acid (5a, 0.01 mole) or 1,3-dimethyl-2-thiobarbituric acid (5f, 0.01 mole) was dissolved in
EtOH (30 mL), treated with the appropriate aldehyde (0.011 mole), heated toboiling, and cooled. The precipitate of 5-arylidene
derivative was separated and washed with hot EtOH (70%). The crude precipitate was added to a mixture of isopropanol
(70 mL) and water (20 mL), heated to 40-50°C, stirred, treated in small portions with NaBH (0.02 mole) to produce a
4
homogeneous solution, stirred at room temperature for 10 min, diluted with water (100 mL), and cooled to room temperature.
The precipitate was filtered off. The filtrate was acidified with HCl to pH 1. The resulting precipitate was separated, washed
with EtOH (30%), and recrystallized from aqueous alcohol.
This method produced the compounds:
1h. 1,3-Dimethyl-5-(2-furylmethyl)barbituric acid, 28%, mp 86-87°C;
1i. 1,3-Dimethyl-5-(1-methylindolyl-3-methyl)barbituric acid, 39%, mp 146-148°C;
1j. 1,3-Dimethyl-5-(1-benzylindolyl-3-methyl)barbituric acid, 43%, mp 117-118°C;
1k. 1,3-Dimethyl-2-thio-5-(4-methoxybenzyl)barbituric acid, 30%, mp 98-100°C;
1l. 1,3-Dimethyl-2-thio-5-(3,4-dimethoxybenzyl)barbituric acid, 42%, mp 102-104°C;
1m. 1,3-Dimethyl-2-thio-5-(2,6-dichlorobenzyl)barbituric acid, 27%, mp 96-98°C;
1n. 1,3-Dimethyl-2-thio-5-(α-naphyhylmethyl)barbituric acid, 29%, mp 163-165°C;
1o. 1,3-Dimethyl-2-thio-5-(9-anthrylmethyl)barbituric acid, 40%, mp 181-183°C.
Preparation of 1,3-Dimethyl-5-arylmethyl-5-cytisylmethylbarbituric Acids (3h-j) and 2-Thio Analogs (3k-o).
General Method. A mixture of the appropriate 1,3-dimethyl-5-arylmethylbarbituric acid (1h-o, 0.01 mole) and cytisine base
(2, 0.011 mole) was treated with alcohol (2 mL) and water (30 mL) and stirred with heating to less than 45°C until completely
dissolved. The solution was cooled to room temperature, treated with stirring with formaldehyde (0.014 mole, 20% aqueous
solution), and left for 6 h. The resulting precipitate was filtered off, washed with alcohol (40%), and dried in air.
The following compounds were prepared by this method:
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