Stereoselective annelation of 3-substituted imidazo[4,5-b ]pyridines with cyanoacetylenic alcohols and domino rearrangement of the adducts

Imidazo[4,5-b ]pyridines are readily annelated (45-50 o C, 24-30 h, MeCN) with cyanoacetylenic tertiary α-alcohols to give stereoselectively functionalized 1,3-oxazolo[3,2-a ]imidazo[4,5-b ]pyridines in 50-88% yields. The adducts undergo a facile stereoselective hydrolytic domino rearrangement to functionalized derivatives of 2,3-diaminopyridines.


Introduction
Derivatives of imidazole and pyridine are of special interest in drug design. 1,2The condensed heterocyclic systems consisting of imidazole and pyridine rings (imidazopyridines) often possess pharmaceutically valuable properties which are not typical for either of the separate moieties.For example, a popular soporific remedy, "Zolpidem" ("Ivadal"), is a functionalized imidazo [1,2a]pyridine. 2Among other derivatives of imidazopyridines, are potent nitric-oxide synthase inhibitors of inflammatory diseases, 3 inhibitors of AKT kinase, 4 preventive and/or therapeutic agents for neutrophilic inflammation disease, 5 compounds with tuberculostatic 6 and hypoglycemic 7 activities, angiotensin II receptor antagonists, 8 and anticoccidial agents. 9A series of imidazo [1,2-a]pyridines bearing sulfonylurea functions exhibit herbicidal activity. 10ost reported syntheses of imidazopyridines are, as a rule, laborious and multi-step (up to 6 steps).Therefore, the search for novel straightforward approaches to the synthesis of functionalized imidazopyridines remains a challenge.
The objective of this present work was to develop a straightforward efficient approach to the synthesis of new condensed functionalized heterocyclic systems combining and imidazo [4,5b]pyridine skeleton and a 1,3-oxazole moiety.For this, we have studied the reaction of substituted imidazo [4,5-b]pyridines with readily available cyanoacetylenic tertiary α-alcohols. 11rom out recent findings related to the annelation of the cyanoacetylenic alcohols with pyridines, 11b,12 quinoline and quinoxaline, 13 phenanthridines, 14 natural alkaloids 15 and substituted benzimidazoles 16 one might expect that either the pyridine or the imidazole (or both) components of an imidazo [4,5-b]pyridine would be involved in the reaction to furnish novel 1,3oxazoloimidazopyridine tricyclic fused scaffolds.Therefore, a fundamental part of the objective is also the issue of competition between the imidazole and pyridine nitrogen atoms as nucleophiles towards the electron-deficient acetylenic bond.
When carried out at room temperature (20-25 o C), completion of the annelation takes a much longer time (up to 147 h), though the yields of the adducts 3a-e increase by approximately 10% (relative to the yields shown in Table 1), obviously due to the milder reaction conditions.
The pyridine nitrogen atom was not involved into the annelation even when adduct 3c was allowed to react with cyanoacetylenic alcohol 2b (20-25 o C, 147 h).Also, no bis-adduct was isolated even when the reactants 1a and 2b were taken in the 1:2 molar ratio.
The structure of adducts 3a-e was established by NMR ( 1 H, 13 C, 2D) and IR spectroscopy.Thus, in the 1 H NMR spectra of 1,3-oxazoloimidazopyridines 3a-e, olefinic protons (H-10, the =CHCN fragment) appear as singlets in the region 4.43-4.55ppm thus indicating to the formation of only one isomer (NOESY).In the IR spectra, the absorption bands of the cyano groups on the double bond are observed at 2202-2213 cm -1 .
Table 1.Formation of 1,3-oxazoloimidazopyridines 3a-e from substituted imidazo [4,5b]pyridines 1a-c and cyanoacetylenic alcohols 2a,b According to the NOESY spectra, the 1,3-oxazoloimidazopyridines 3a-e are Z-isomers: the cross-peaks between olefinic proton H-10 and the immediately adjacent protons of cyclohexyl (for 3c) or Me group (for 3e) are observed (Figure 1).Apparently, the annelation is triggered by the addition of imidazopyridines 1a,b via their imidazole nitrogen atom N(1) as neutral nucleophiles to cyanoacetylenic alcohols 2a,b to generate zwitterions A having a vinyl carbanion moiety which is then converted into the oxygencentered zwitterions B the proton transfer (in either an intra-or intermolecular manner) from the hydroxyl group to the carbanionic center.The secondary zwitterions B undergo the ring closure at the C(2) position of the imidazole ring to form the final annelated adducts 3a-d (Scheme 1).
The Z-configuration of the final adducts 3a-d is the expected result of the nucleophilic addition to acetylenes, which is known to proceed in a concerted trans-fashion. 17Notably, the 1,3-oxazoloimidazopyridines 3a-d retain a contribution of zwitterionic form B (an inner salt).A similar consideration is true also for the formation of adduct 3e.
The regioselectivity of the annelation likely results from the steric constrains between the cyanomethylene group and the substituents R 1 at the imidazole N(3) atom in the possible alternative adducts 4 (cf.Table 1).Indeed, the nucleophilicities of N(1) of the imidazole ring and N(4) of the pyridine ring should not differ significantly since the basicities of pyridine and benzimidazole, an analog of the imidazopyridines 1a,b, are close (pKa = 5.20 and 5.50 for pyridine and benzimidazole, respectively 1 ).This conclusion is in agreement with the low yield (18%) of adduct 3e, in which the cyanomethylene group faces the steric repulsion from the lone electron pair of the N(4) pyridine atom.
Table 2. Rearrangement of 1,3-oxazoloimidazopyridines 3a-e to pyridinyl-N-substituted formamides 5a-e 5a-d (E)-Pyridinyl-N-substituted formamides 5a-e were isolated as crystals.Their structures are based on analogy with that of formamide 5c, which was established by X-ray diffraction analysis, and confirmed using 1 Н and 13 С NMR, UV and IR techniques.18)N( 17)C (19)  atoms is practically planar, maximum deviation of atoms from its average plane being 0.02 Å (C(18) atom).This plane forms with planes of the furan and pyridine moieties the dihedral angles of 117.4 and 130.5 o , respectively.The rearrangement of 3e to 5e would pass through similar steps.
The driving force of this multi-step rearrangement is plausibly the formation of a long-range through-conjugated system of the push-pull type, accomplished in the final products 5a-d.Despite the distorted coplanarity of the pyridine and furan rings in the crystal state (the corresponding dihedral angle is 125.4 o , Figure 2), the conjugation can still be partly realized, particularly in solution, or in excited or transition states (during certain reactions).
Easrlier, a simlar deep rearrangement was observed for the adducts of benzimidazoles with cyanoacetylenic tertiary α-alcohols.16a The rearrangement products 5a-e can be prepared directly from reactants 1 and 2 avoiding the isolation of annelated species 3a-e by passing the reaction mixture through a layer of alumina.
In the 1 H NMR spectra of (E)-pyridinyl-N-substituted formamides 5a-e, the proton of the formamide fragment (H-14) is observed in the region 8.23-8.78ppm.In the 13 C NMR spectra, carbonyl carbon resonates at 163.2-169.8ppm.In the IR spectra, the absorption bands of the C=O group are present at 1659-1684 cm -1 .
The direct synthesis of the rearrangement products 5a-e was monitored as an example of a three-component reaction, between imidazopyridine 1a, cyanoacetylenic tertiary α-alcohol 2a and water (1:1:1 molar ratio) in CD3CN solution (room temperature, NMR tube).The reaction was followed by the methyl and olefin proton signals in the 1 H NMR spectra (Scheme 3).When the reaction mixture was passed through the column packed with alumina (chloroform/benzene/ethanol, 20:4:1, mixture as eluent), the final rearrangement products 5a was isolated (Scheme 2).
Thus, the monitoring confirms Schemes 1 and 2, though under the conditions employed, the combined rearrangement annelation sequence proceeds only slowly and did not reach completion, so that even after 35 days the reaction mixture consisted of intermediates C and D.

Conclusions
In conclusion, a novel one-pot efficient methodology for the stereoselective synthesis of previously unknown imidazo [4,5-b]

Experimental Section
General.NMR spectra were run on a Bruker DPX-400 spectrometer with HMDS as an internal standard.UV-VIS spectra were measured on a Perkin-Elmer Lambda 35 spectrometer at room temperature (EtOH, d = 0.1 cm).IR spectra were recorded on a IFS 25 instrument.Column and thin-layer chromatography was carried out on neutral Al2O3 with chloroform/benzene/ethanol (20:4:1) mixture as eluent (length of column = 35 cm, Ø = 0.8 cm).The reaction was monitored by the disappearance of absorption bands of initial acetylenes 2a,b in the reaction mixture (IR spectroscopy).Alkylation of imidazo [4,5-b]pyridines 1a,b was carried out according to the procedures: 19   X-ray diffraction.The X-ray diffraction study of compound 5c was carried out on an Enraf-Nonius CAD-4 diffractometer at room temperature (/2-scans, Mo-K radiation, graphite monochromator).The crystal structure was solved by direct methods followed by Fouriersyntheses using SHELXS-97 programs. 22The structure refined by a full matrix least-squares anisotropic procedure using SHELXTL-97 programs. 23The parameters of hydrogen atoms were defined experimentally and refined anisotropically, except for parameters of hydrogen of the methyl group which were calculated geometrically.These data are available via www.ccdc.cam.uk/contsretrieving.html (or from CCDC, 12 Union Cambrige CB2 1EZ, UK, fax: +44 (0) 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk).Any request to the CCDC for data should quote the full literature citation and CCDC reference number CCDC 826322 (for 5c).

Scheme 3 .
Scheme 3. Monitoring of the three-component reaction of imidazopyridine 1a with cyanoacetylenic alcohol 2a and water.

Figure 4 .
Figure 4. Labeling of hydrogen and carbon atoms in compounds 3a-e and 5a-e.