New efficient synthesis of imidazo[2,1-b]quinazoline-2,5(1 H ,3 H )- diones by a consecutive aza-Wittig/heterocumulene-mediated annulation

The carbodiimide 2 , obtained from aza-Wittig reaction of iminophosphorane 1 with aromatic isocyanate, reacted with α -amino ester in the presence of triethylamine to give imidazo[2,1-b]quinazoline-2,5(1 H ,3 H )-diones 5 (when R 2 is H) or quinazolinones 6 (when R 2 is not H). Imidazo[2,1-b]quinazoline-2,5(1 H ,3 H )-diones 5 were prepared more generally by another route, using a consecutive aza-Wittig / heterocumulene-mediated annulation of iminophosphoranes 9 with isocyanates and catalytic sodium ethoxide.


Introduction
Due to the broad spectrum of biological properties of derivatives of quinazolinone their synthesis has been a focus of significant interest for many years.Some of these activities include antimicrobial, 1 antiinflammatory, 2 antifungal, 3 anticancer, 4 and AMPA receptor antagonist properties. 5The range of chemical structures and their biological activities have made synthetic studies of quinazolinones very attractive.Similarly, heterocycles containing the imidazolone nuclei also exhibit various biological activities, with several exhibiting antibacterial, antifungal activities, leukotriene B 4 receptor antagonist properties, and potassium channel openers. 6Others in the same class appear in a variety of biologically active molecules, particularly in some alkaloids in which a common structural unit is a derivatized 2-amino-4H-imidazol-4-one moiety. 7Thus is likely that the introduction of an imidazolone ring into the quinazolinone system would influence the biological activities significantly.In fact, some imidazo[2,1-b]quinazoline-2,5(1H,3H)-diones have been used as gastric secretion inhibitors. 8However, there are only few reports on the synthesis of imidazo[2,1-b]quinazoline-2,5(1H,3H)-diones.
The previously reported methods for the preparation of some representative derivatives of this ring system involve either reaction of anthranilic acid with 2-methylthioimidazolones 9 or cyclization of 2-methylthioquinazolin-4(3H)-ones with amine. 8However, these methods often require multistep reaction processes or heating at high temperature.Until now, no general and simple approach to the imidazo[2,1-b]quinazoline-2,5(1H,3H)-diones has been reported.
The aza-Wittig reactions of iminophosphoranes have received increased attention in view of their utility in the synthesis of nitrogen heterocyclic compounds. 10Recently we have been interested in the synthesis of quinazolinones, thienopyrimidinones and imidazolones via aza-Wittig reaction, with the aim of evaluating their fungicidal activities. 11Here we report a new approach to the synthesis of imidazo[2,1-b]quinazoline-2,5(1H,3H)-diones via a consecutive aza-Wittig / heterocumulene-mediated annulation.

Results and Discussion
Iminophosphorane 1 reacted with aromatic isocyanates to give carbodiimides 2, which were then reacted with an α-amino ester at room temperature in the presence of triethylamine.Imidazo[2,1b]quinazoline-2,5(1H,3H)-diones 5 were obtained exclusively where the R 2 group is H, but only quinazolinones 6 were produced where R 2 group was not H (Scheme 1).
The literature suggests 12 that the reaction of carbodiimides 2 with an α-amino ester is likely to afford primarily guanidine intermediates of type 3. From 3, the formation of three cyclized products imidazolone 4 (via path b), quinazolinone 6 (via path a), and quinazolinone 7 (via path c) could in principle take place.The formation of 5 (R 2 = H) is expected to come about as a result of a cascade cyclization of 3 to an imidazolone intermediate 4, and further base catalytic cyclization between the imidazolone ring's NH and ethoxylate.The result also illustrated that the imidazolone 4 is more easily produced from intermediate 3 than quinazolinone 6 when the R 2 group is H, but the quinazolinone 6 is preferentially formed when R 2 group is not H.The reaction selectivity is probably due to the steric hindrance of the R 2 group which retards the cyclization of 3 to 4 (via path b) in the cases where the R 2 group is not H.

COOEt
The exclusive formation of 6 (where R 2 group is not H) can be rationalized in terms of a base catalytic cyclization of the guanidine intermediate 3 to give 6 across the arylamino group (R 1 = Ar) (path a) rather than the alkylamino one (path c).This is likely to be due to the preferential cyclization of more acidic -NHR 1 in the basic conditions.The same selectivity is observed in similar cases. 13The structure of 6 is deduced from 1 H NMR data.For example, the 1 H NMR spectrum of 6d (R 2 = i-Pr) shows the signals of NH at 4.53 ppm as a doublet and NCH at 4.72 ppm as two doublets, which strongly suggest the existence of a NHCH(i-Pr)COOEt group in 6d.The structure of 6 was confirmed by X-ray crystallographic analysis.A single crystal of 6b was obtained by slow evaporation from a dichloromethane-petroleum solution.X-ray structure analysis verified again the proposed structure, and showed that the quinazolinone system is approximately planar.The double bond length of C( 14)=N(2) is 1.299(16) Å longer than the typical C=N(1.28Å), while the single bond lengths of C(1)-N(2), C(14)-N(1), C(14)-N(3) and C(7)-N(1) are 1.384(18) Å, 1.385(14) Å, 1.355(2) Å and 1.410(19) Å respectively, are shorter than the typical C-N(1.47Å), showing a degree of delocalization (Figure 1).The imidazo[2,1-b]quinazoline-2,5(1H,3H)-diones 5 were prepared more generally by another synthetic route.The iminophosphoranes 9, which were obtained from Staudinger reaction of azides 8 and triphenyl phosphine, 14 reacted with aromatic isocyanate at room temperature and were then treated with sodium ethoxide to give imidazo[2,1-b]quinazoline-2,5(1H,3H)-diones 5 in good overall yields (65-90%, Table 2, Scheme 2).It is conceivable that the conversion of 9 into 5 involves consecutive processes where an initial aza-Wittig reaction between the iminophosphorane 9 and the isocyanate gives carbodiimide 10 as a highly reactive intermediate, which easily undergoes ring closure across the acylamino group to give the quinazolinone 11.Further cyclization of 11 in the presence of a catalytic amount of sodium ethoxide produces imidazo[2,1-b]quinazoline-2,5(1H,3H)-dione, 5.It is noteworthy that the reaction can be carried out easily at room temperature.Unfortunately, racemization of the product 5 took place under the reaction conditions where chiral starting material 9 was used.This is probably due to the easy racemization of C-3 of the imidazo[2,1-b]quinazoline-2,5(1H,3H)dione ring under the basic condition.

Scheme 2
The structure of imidazo[2,1-b]quinazoline-2,5(1H,3H)-diones, 5, was confirmed by their spectroscopic data.For example, the 1 H NMR spectrum of 5d shows two signals at 4.93 ppm as quartets, and 1.91 ppm as a doublet, due to the CH and CH 3 , respectively.The signals attributable to the 6-H and other Ar-Hs are found at 8.25 and 7.71-7.38ppm as a doublet and multiplet, respectively.The IR spectra of 5d had two C=O absorption bands at 1756 and 1698 cm -1 , due respectively to the imidazolone and quinazolinone carbonyl group.The mass spectrum of 5d shows a strong molecular ion peak at m/z 291 with 100% abundance.Furthermore, a single crystal of 5o was obtained from its dichloromethane solution.X-ray structure analysis verified again the proposed structure, and showed that all ring atoms in the tricyclic moiety are essentially planar, with the maximum deviations -0.041(2) and 0.045(2) Å for C (10) and N(2) respectively from the heterocyclic plane (Figure 2   In conclusion, we have developed an efficient synthesis of imidazo[2,1-b]quinazoline-2,5(1H,3H)-diones via a consecutive aza-Wittig/heterocumulene-mediated annulation.This method utilizes easily accessible starting material and allows mild reaction conditions, straightforward product isolation and good yields.

Experimental Section
General Procedures.Melting points were determined using a X-4 model apparatus (Beijing Taike Company).IR spectra were recorded on a Perkin Elmer PE-983 infrared spectrometer, as KBr pellets with absorption in cm -1 .MS were measured on a Finnigan Trace MS spectrometer, at 70eV.NMR spectra were recorded in CDCl 3 on a Varian Mercury 400 or 600 spectrometer and resonances are given in ppm (δ) relative to TMS.Elementary analyses were taken on a Vario EL III elementary analysis instrument in the Center of Analysis and Testing, College of Chemistry, Central China Normal University.

General procedure for the preparation of imidazo[2,1-b]quinazoline-2,5(1H,3H)-diones 5a-5p from iminophosphorane 9
To a solution of iminophosphorane 9 14 (2 mmol) in dry dichloromethane (15 mL) was added isocyanate (2 mmol) under nitrogen at room temperature.The reaction mixture was stirred for 24 h at room temperature and then several drops of EtONa in ethanol were added.The mixture was stirred for 1-6 h at room temperature.The solution was concentrated under reduced pressure and the residue recrystallized from EtOH or purified by a short silica gel column to give imidazo [

Figure 2 .
Figure 2. ORTEP diagram of the crystal structure of tricyclic compound 5o (drawn at the 50% thermal ellipsoids).Only the major conformer is shown, and the disordered atoms have been omitted for clarity.

Table 2 .
Preparation of compounds 5 from iminophosphorane 9 a Isolated yields based on iminophosphorane 9.