Ring opening of cyclobutane in 1,3-dimethyl-5-methylenebarbituric acid dimer by various nucleophiles

2.1 Nitrogen nucleophiles

Zwitterionic derivatives of barbiturates 6–9 (Scheme 1) were prepared based on the nucleophilic character of the N atom present in the secondary and tertiary amines; these products were obtained in good yield by a one-pot reaction of 5 with various amines. NMR data of the target products are in full agreement with the proposed structures. In addition, distortionless enhancement by polarization transfer experiments showed no signal for C5 of the barbiturate moiety of 6–9, which indicates that the barbiturate anion was formed rather than 1,3-dimethyl-5-aminoalkylbarbituric acid (Fig. 3).

Fig. 3:

Non-formed product of 1,3-dimethyl-5-aminoalkylbarbituric acid.

Further, the crystal and molecular structure of 6 (Fig. 4, Tables 1 and 2) was determined by single-crystal X-ray diffraction to confirm the proposed structure. The asymmetric unit of 6 contains two independent heterocycles with one water molecule. The dihedral angle between the two rings (N11/C11/N21/C41/C31/C21) and (N12/C12/N22/C42/C32/C22) is 14.8°. In the crystal there are four strong hydrogen bonds N31–H31···O32, N32–H32···O31, O1W–H1W1···O22, and O11···H1W2–O1W# (symmetry operation #: 1/2–x, 1/2+y, 3/2–z) with donor–acceptor distances of 2.749(3), 2.846(3), 2.803(3), and 2.967(3) Å, respectively, and donor–H···acceptor angles of 167(3)°, 154(3)°, 172(4)°, and 156(3)°, respectively.

Fig. 4:

View of the molecular structure of compound 6 in the crystal (symmetry operation #: 1/2–x, –1/2+y, 3/2–z).

These intermolecular hydrogen bonds connect the two crystallographically independent molecules with each other via water molecules. Bond angles and bond lengths are in the expected range (Table 2). Similar molecular structures have been described by us (1,3-diethyl-5-(diethylaminium)ethylene-2-thiobarbituric acid adduct [13]) and others [14], [15], [16] as were found by WebCSD [17].

2.2 Cyanide nucleophile

An excess amount of cyanide anion was employed to attack the exocyclic carbon in 5 leading to 10 in good yield under mild conditions, as shown in Scheme 1. Due to the low solubility of potassium cyanide in organic solvents, water was used as solvent to increase the concentration of free cyanide anion and avoid usage of 18-crown-6. We have prepared compound 10 by reacting the pyridinium adduct of 1,3-dimethyl-5-methylenebarbituric acid with sodium cyanide [9]. NMR and MS data of 10 are in full agreement with those already published [9]. Currently, our research is concerned with acidification of the present barbiturate anion, and then hydrolysis of the cyano group under an acidic condition to afford new acid of barbituric nucleus.

2.3 Phosphorus, arsenic, and antimony nucleophiles

Products 11–13 were prepared in good yield by reacting 5 with Ph₃E (11, E=P; 12, E=As; 13, E=Sb) under reflux (Scheme 1), in contrast to mild conditions employed during the synthesis of 6–10; this could be attributed to the steric factor of Ph₃E.

It is worth mentioning that compound 11 was prepared via reacting pyridinium adduct of 1,3-dimethyl-5-methylenebarbituric acid with triphenylphosphine [11]. On the other hand, the analogous reactions using arsenic and antimony were unsuccessful. Based on this result one can assume that the ring strain of cyclobutane in 5 increases the reactivity of the exocyclic methylene group towards nucleophilic attack.

Products 6–13 were synthesized using excess amount of the particular nucleophile; employment of stoichiometric amounts afforded a mixture of products (as evidenced from NMR spectra). A plausible mechanism for the formation of the target products is shown in Scheme 2. Nucleophilic attack occurs simultaneously at both carbons of the two exocyclic methylene groups leading to synchronous double ring opening from opposite cites; the whole process takes place in one step whereby the dimer 5 splits into two identical zwitterions.

Scheme 2:

Plausible mechanism of ring-opening.

However, the reaction of thiophenoxide or thiocyanate anions with 5 failed to afford any product; this might be attributed to the weakness of a sulfur atom as nucleophile in both cases.

4.1 General procedure for the synthesis of 6–9

To a solution of 5 [12] (5 mmol) in diethyl ether (30 mL), the appropriate amines (10 mmol) were added at room temperature, and the resulting mixtures were stirred for 24 h. Thereafter, the precipitate was filtered off and washed with diethyl ether (20 mL).

4.2 Synthesis of compound 10

To a solution of 5 (5 mmol) in tetrahydrofuran (30 mL), potassium cyanide (10 mmol in 3 mL water) was added at room temperature and the resulting mixture then stirred for 24 h. The precipitated product was then filtered off and washed with diethyl ether (20 mL).

4.3 General procedure for the synthesis of 11–13

To a solution of 5 (5 mmol) in ethanol (30 mL), Ph₃E (10 mmol) was added at room temperature and the resulting mixture then refluxed for 8 h. After cooling, the solvent was removed in vacuo to dryness. The residue was treated with diethyl ether (15 mL) followed by filtration of the precipitated product which was collected and dried.

4.4 Crystal structure determination

X-ray diffraction data of 6 were collected using an Oxford Agilant diffractometer equipped with Xcalibur, Eos detector [18]. Data collection statistics is presented in Table 1, while selected bond lengths and angles are given in Table 2. The structure was solved and refined with the Shelxtl program package [19] and full-matrix least squares and difference Fourier cycles were performed. Non-hydrogen atoms were refined anisotropically based on F² values. Hydrogen atoms were fixed at calculated positions and refined using a riding model with U_iso(H)=1.5U_eq(C).

CCDC 1523235 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.