were designed to display either an ADA or an AADA array
of hydrogen-bonding sites, depending on the tautomeric form
of the pyrimidinone unit (Figure 1). We were particularly
Figure 2. Pluton representation of single-crystal X-ray structure
of compound 3a. The dimer consists of both independent molecules.
distance between the atoms connected to the amino group
(average distance 2.49 Å). This results in a nonlinear ADA
array, with an N-N-N angle of 165.2° and 167.5° for the
nonequivalent molecules in the unit cell. The molecule is
also not fully planar; the planes of the rings are at an angle
of 1.99(7)° and 4.69(7)° for the two independent molecules.
These deviations from linearity may have a pronounced effect
on the capability of 3a to bind molecules with linear DAD
arrays.
Figure 1. Synthesis of dipyrimidin-2-ylamines 3a (R ) CH3) and
3b (R ) CF3). (i) Ammonium chloride, phenol, 120 °C. (ii) Ethyl
acetoacetate or ethyl 1,1,1-trifluoroacetylacetate, biguanidinium
sulfate, NaOH, EtOH, reflux. (iii) 2,4-Pentanedione, HOAc, reflux.
Two tautomeric forms of 3 are shown: 2-(4,6-dimethylpyrimidin-
2-ylamino)-6-methyl-[1H]-pyrimidin-4-one, featuring an AADA
array, and 6-methyl-[3H]-pyrimidin-4-one, featuring an ADA array.
The observed NOE effect in the [3H] tautomer is indicated with a
double-headed arrow.
In the crystalline state two hydrogen bonds are observed
between two distinct molecules of 3a, indicating that
interaction between molecules via hydrogen bonds is also
likely in solution. Dimerization of 3a and 3b in CDCl3
solution was determined with 1H NMR dilution experiments,
and both compounds were indeed found to self-associate (3a
Kdim ) 12 M-1, 3b Kdim ) 9 M-1 in CDCl3 at 298 K).
Nuclear Overhauser experiments using selective excita-
tion13 were performed to establish the tautomeric form of
3a in CDCl3 solution. No NOE effect was observed on the
intramolecularly hydrogen-bonded proton when the pyrimi-
dinone methyl group was excited, while a significant effect
was observed upon excitation of the pyrimidine methyl
groups. This indicates that the [3H] tautomer of 3a is also
favored in solution.
interested in the possibility of biasing the tautomeric form
of 3 by complexation with complementary DAD or DDAD
arrays.
Compounds 3a and 3b were synthesized by two successive
cyclocondensation reactions of biguanide 1, using ethyl
acetoacetate followed by pentanedione,10 and were obtained
in yields of 69% and 50%, respectively. Pyrimidinones
usually exist in the [3H] form, presumably because this
tautomer has a smaller dipole moment than the [1H]
tautomer.11 We expected to observe the former tautomer in
compound 3a. The relative stability of the [1H] tautomer
was anticipated to be higher in fluorinated derivative 3b,
since the dipole moment of the pyrimidinone moiety of this
tautomer is partly compensated by the CF3 group.
Complexation of 3a and 3b with compounds 4 and 5,
featuring DAD arrays of hydrogen-bonding sites, and with
6, featuring a DDAD array, was investigated using 1H NMR
titration experiments. The results were compared with
association constants of these compounds with N-1-propyl-
thymine 7, featuring a linear14 ADA array (Figure 3).
The association constants are summarized in Table 1.
N-Propylthymine 7 binds to DAD molecules with little
selectivity; Ka values range from 845 M-1 for the complex
A single-crystal X-ray study12 (see Supporting Information)
confirms the presence of the [3H] tautomer of 3a in the solid
state (Figure 2). The asymmetric unit consists of two
molecules, with slightly different conformations. Figure 2
shows the presence of an intramolecular hydrogen bond
between the heterocyclic units. The N - N distance between
the nitrogen atoms involved in the intramolecular hydrogen
bond (average distance 2.67 Å) is larger than the C - C
(10) Curd, F. H. S.; Graham, W.; Rose, F. L. J. Chem. Soc. 1948, 594-
596.
(11) Elguero, J.; Marzin, C.; Katritzky, A. R.; Linda, P. In AdVances in
Heterocyclic Chemistry, the Tautomerism of Heterocycles; Academic
Press: New York, 1976.
(12) R1 ) 0.046, wR2 ) 0.120, S ) 1.04 for 337 parameters and 5297
reflections. The coordinates of the NsH hydrogen atoms have been refined.
(13) Stott, K.; Keeler, J.; Van, Q. N.; Shaka, A. J. J. Magn. Reson. 1997,
125, 302-324.
(14) Crystal structures of N-alkylthymines show a deviation from linearity
of the array of 2-4°. (a) Kvick, A.; Koetzle, T. F.; Thomas, R. J. Chem.
Phys. 1974, 61, 2711-2719. (b) Hamilton, A. D.; Van Engen, D. J. Am.
Chem. Soc. 1987, 109, 5035-5036.
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Org. Lett., Vol. 3, No. 24, 2001