Synthesis, Molecular Structure and Reactivity of 5-methylidene-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolines

– Synthesis of novel


Introduction
The well known aryliminoimidazolidines such as clonidine and moxonidine exhibit antihypertensive activity mediated by α-adrenergic and/or imidazoline receptors [1,2].These compounds possess several rotational degrees of freedom and, therefore, offer opportunities for preparation of restricted analogs.
The structures of the compounds 2, 3 and 4 were confirmed by elemental analyses as well as IR and NMR spectroscopic data.For example, the 1 H NMR spectrum of 2 showed a multiplet in the range of δ 3.59-3.68originating from CH 2 -CH 2 grouping of the imidazoline ring.Two distinct singlets at δ 3.71 and δ 4.51 were assigned to the nonequivalent olefinic Cβ-H protons.(i) 2-Amino-4-R The fusion of the two ring systems was confirmed by the presence in the 13 C-NMR spectrum of two signals at δ 140.17 and δ 154.11, attributable to the C-5 and C=N carbon atoms of the imidazoquinazoline moiety, respectively.On the other hand, a characteristic feature of the 1 H-NMR spectrum of the 1-substituted derivative 3 is the presence of two distinct multiplets in the range of δ 3.66-3.71and δ 4.07-4.09integrating to six and two protons, respectively, attributable to the two CH 2 -CH 2 groupings of the imidazoline rings.In 13 C-NMR spectrum, two broad carbon resonances were observed at δ 45.66 and δ 50.92, attributable to C-4′ and C-5′ of the 2-substituted imidazoline ring, and a signal at δ 148.75, which in the HSQC (heteronuclear single quantum coherence) spectrum did not correlate to any 1 H resonances. Analysis of the long-range 1 H- 13 C coupling pattern obtained from the HMBC (heteronuclear multiple bond coherence) experiment allowed us to assign this signal to the C-2′ carbon atom of the imidazoline ring.The structure of 3 was then confirmed unambiguously by X-ray crystallographic analysis (Figure 2).3) Å is longer than the double bond in a disubstituted vinyl group (1.321 Å) [6] indicating that it is conjugated with the guanidine fragment and the benzene ring.The nitrogen atoms N3 and N11 show sp 2 hybridization, the maximum displacement of the N atom from the plane of its substituents being 0.037 Å.
Next, we examined the reaction of 1,2,3,5-tetrahydroimidazo[2,1-b]quinazolines 2 and 4 with dimethyl acetylenedicarboxylate (DMAD).It is well known, that the reactions of enamines with DMAD, depending on solvent and temperature, afford either the cycloaddition [13,14] or Michael addition [13,15] products.To identify reactive sites both at the alkene and nitrogen atom incorporated into guanidine moiety, the electronic structure of 2 was studied using ab initio 6-31G** calculations [7].Reactive sites will correspond to regions where either the highest-occupied molecular orbital (orbital-controlled reactions) or negative charge (electrostatically-controlled reactions) is large.As shown in Scheme 1, the imidazoquinazoline 2 can exist in two possible tautomeric forms, the N1-H tautomer (2) or the N10-H tautomer (2A).Calculations of the corresponding energies indicate that 2 is more stable than 2A by 5.1 kcal/mol (Figure 3).Compound 2 was then subjected to reaction with electrophilic acetyl chloride and benzoyl chloride in pyridine at ambient temperature to afford the corresponding N1-substituted enaminones 17 and 18, respectively (Scheme 3).It is well known that enaminones can exist in the four possible conformations depicted in Figure 5 due to restricted rotation around the C=C double and the C−C=O single bonds [16][17][18][19][20][21][22].
Analysis of the 1 H-NMR spectra of compound 17 run in CDCl 3 revealed doubled signals indicating the presence of a mixture of ZZ and EZ isomers (Figure 6).The olefinic Cβ-H proton appears at δ 5.22 for 17 (EZ), and at δ 6.13 for 17 (ZZ).Deshielding of the olefinic proton of ZZ isomer results from its relative proximity to the benzene ring.Furthermore, the aromatic proton C6-H of the EZ isomer (δ 9.03) is downfield of that of the ZZ isomer (δ 7.84) by 1.19 ppm, while signals of other protons are not duplicated.
As shown in Figure 6, the ROESY spectrum of 17 displayed intense NOE cross peaks between the resonances of Cβ-H and both CH 3 and C6-H for ZZ isomer, whereas for isomer EZ the corresponding NOE effect was observed between Cβ-H and CH 3 group only.Based on the relative intensities of signals observed in 1 H NMR spectrum we conclude that in CDCl 3 the compound 17 exists in form of a mixture of two isomers ZZ and EZ in ratio 3.3 : 1.
Quantum chemical calculations [7] indicate that the EZ and ZZ isomers of 17 differ in energy by only 1.1 kcal/mol.Based upon their calculated dipole moments, EZ (µ = 7.54 D) would be predicted to predominate over ZZ (µ = 2.89 D) in polar solvents.Indeed, an inspection of the 1 H NMR spectrum of 17 run in DMSO-d 6 revealed a change of the ZZ/EZ isomer ratio to 1 : 1.1 (see Experimental section).
Hence, these data postulate that the isomerism observed is due to a restricted rotation around the C=C double bond and the interconversion between ZZ and EZ isomers is possible via a zwitterionic intermediate of type F (Figure 6).
It should be pointed out that 2-(1-benzoyl-2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-ylidene)-1phenyl-ethen-1-one (18) exists both in solution and solid phase as a single ZZ isomer, which was confirmed by NMR spectroscopy and X-ray crystallographic analysis (Figure 7).The tricyclic system of 18 is less planar than in 3 (cf.Figure 2) due to the steric hindrance caused by introduction of the benzoyl substituent at C14.The release of this strain is accomplished by a twist about the formally double C4-C14 and partially double C14-C15 bonds by 21.6º and 31.3º,respectively.In effect the carbonyl O16 is at a distance of 2.24 Å from one of the imidazolidine C13 hydrogen atoms, i.e. at a distance ca.0.4 Å shorter than the sum of appropriate van der Waals radii [23].The formally double bond C4-C14 which is conjugated not only with the quinazoline moiety like in 3 but also with the benzoyl group is significantly longer and equals to 1.367(3) Å.The tertiary amide group is strongly non-planar with atoms C12 and C2 deviating from the plane of C25, C23, O24 and N11 by -0.224 and 0.539 Å, respectively.Contrary to 3, the nitrogen atoms N3 and N11 show hybridization intermediate between sp 2 and sp 3 with the displacement of the N atoms from the plane of their substituents equal to 0.099 and 0.146 Å, respectively.
Finally, we have also performed the reaction of 2 with methanesulfonyl chloride (MsCl).The reaction proceeded smoothly in pyridine at ambient temperature and furnished 1-mesyl derivative 19 (Scheme 3), which, as evidenced by its 1 H-NMR spectrum run in DMSO-d 6 , exists as a mixture of ZZ and EE isomers in a 1 : 9 ratio, respectively.

General
Melting points (mp) were determined on a Büchi 535 apparatus and are uncorrected.IR spectra (KBr pellets) were measured on a Perkin Elmer 1600 FTIR spectrophotometer. 1 H-NMR and 13 C-NMR were recorded on a Varian Gemini 200 or Varian Unity 500 spectrometer and chemical shifts (δ) are expressed in ppm relative to internal tetramethylsilane.2D NMR experiments were carried out on a Varian Unity Plus 500 spectrometer.Mass spectra were recorded on a Finnigan MAT 95 spectrometer at 70 eV.The starting 2-chloro-4,5-dihydroimidazole (1) and N-oxides N-(3-or 4-R 3benzylidene)aniline (5-9) were prepared according to procedures described previously [24,25].
Procedure A: The precipitate thus obtained was separated by suction, washed successively with anhydrous THF (6 mL) and anhydrous acetone (10 mL) and dried to give the products 10 and 11, respectively.

Procedure B:
The insoluble side products were filtered off and then the solvent was distilled off under reduced pressure.The residue was treated with anhydrous acetone (7 mL), and the precipitate thus obtained was collected by filtration, washed with acetone (5 mL) and dried to give the products 12-14.(12) (15,16).

Figure 2 .
Figure 2. ORTEP drawing showing the asymmetric part of the unit cell of 3 and atom labelling.Hydrogen bonds are shown with dashed lines.Displacement ellipsoids are drawn at 50% probability level.