Application of ( 2Z )-3-dimethylamino-2-(1 H -indole-3-carbonyl) acrylonitrile in the synthesis of novel 3-heteroarylindoles: condensed meridianine analogs

3-Dimethylamino-2-(1 H -indole-3-carbonyl)acrylonitrile ( 2) was treated with phenylhydrazine, in refluxing basic ethanol, afforded a single product N -1 or N -2 substituted pyrazole. Basic promoted cyclization of enaminonitrile 2 with α -heteroarylamines as N,N -1,3-dinucleophiles, condensed indolylpyrimidines as a new class of meridianine natural product analogs were obtained in moderate to good yields.


Results and Discussion
Enaminones are important synthetic intermediates, particularly as building blocks for the preparation of many heterocyclic systems. 280][31] In fact, the reaction between enaminones and 1,2-bisnucleophiles may led to two possible regioisomers because the cyclization may proceed via two possible mechanisms that differ in their sequential nucleophilic attack/amine exchange reaction.Thus, when the enaminonitrile 2 24,25 , obtained by condensation of 3-cyanoacetyl indole 1 26 with dimethylformamide dimethylacetal (DMFDMA), was treated with phenylhydrazine, in refluxing ethanol, it afforded a single product N-1 or N-2 substituted pyrazoles (3a, 3b or 3c).The structure of the expected pyrazole 3c was excluded from the lack of cyano group in both IR and 13 C NMR spectrums.The regiochemistry of the reaction was determined by NOE experiment on the isolated product.As well, the pyrazole 3b was discarded on the basis of NOE experiment that showed no interaction between pyrazole proton H-5 and the ortho protons of the phenyl group, allowing us to assign the structure of 5-amino-1-phenyl-1Hpyrazol-4-yl)(1H-indol-3-yl)methanone (3a) to this product.Moreover, there is a different in chemical shift of pyrazole proton signal in both other two possible compounds (3a or 3b).Thus, the expected chemical shift of pyrazole proton (H-5) of compound 3b is higher in frequency than pyrazole proton (δ = 8.20, H-3) of the obtained compound 3a, which was confirmed also by 13 C NMR and HSQC experiments at higher frequency (δ = 140.40,C-3), (Scheme 1).Moreover, the absolute structure of 3a was completely solved by X-ray diffraction analysis (Fig. 2).

Figure 2. X-ray single crustal of compound 3a
Recently Stanovnik et al. reported the synthesis of both condensed indolylpyrimidones as meridianine analogs 22 and polycyclic meridianin analogs with uracil structural unit. 23he behavior of enaminonitrile 2 toward some primary heteroarylamines with the amino group attached at the α-position with respect to the ring nitrogen atom (N,N-dinucleophiles) was also investigated.Thus, when compound 2 was treated with substituted 5-aminopyrazole derivatives 4a-d in the presence of a catalytic amount of piperidine, they afforded the corresponding 1H-pyrazolo [1,5-a]pyrimidine derivatives 5a-d, which considered as condensed meridianine analogs (Scheme 2).The structure of pyrazolopyrimidine derivatives 7a-d was excluded as a result of the lack of amino group in IR and also lack of carbonyl group in both IR and 13 C NMR spectrums.The other possible structure of 6a-d was ruled out on the basis of the 1 H NMR spectrum of the isolated products.For example, the 1 H NMR spectrum of compound 5a, taken as a typical example, which revealed a singlet signal at δ 8.77 which was assigned for the pyrimidine H-2 in structure 5 and not H-4 in structure 6.Although spectral data seemed of no help in distinguishing between structures 5 and 6. 32 However, structure 5b, as an example, was definitely established for the reaction products by an alternate synthesis.For example, the reaction of 5-amino-3-methylpyrazole (4b) with DMF-DMA and subsequent condensation of the formed amidine, 5-N-(N,Ndimethylaminomethylene)amino-3-methyl-1H-pyrazole 36  (8), with 3-cyanoacetyl indole (1)  afforded a product identical in all respects (TLC, mp, and spectra) with those of compound 7-

Scheme 2
Treatment of the enaminonitrile 2 with 2-aminobenzimidazole in pyridine under reflux gave only one isolable product.The isolated product was identified as 4-amino-3-(indolo-3carbonyl)pyrimido[1,2-a]benzimidazole (10) (Scheme 3).The IR spectrum of the reaction product revealed two bands due to amino and carbonyl functions.Moreover, the 1 H NMR spectrum of compound 10 revealed new singlet signal at δ 8.10 due to pyrimidine proton and carbonyl signal in 13 C NMR spectrum at δ 182.35.The formation of product 10 is assumed to take place via the addition of the exocyclic amino group in 2-aminobenzimidazole to the activated double bond in the enaminonitrile 2 to give the acyclic non-isolable intermediate 9 which undergo intramolecular cyclization and subsequent aromatization via the loss of dimethylamine under the reaction conditions to afford the final product 10 as depicted in Scheme 3. The structure of the pyrimido[1,2-a]benzimidazole 10 was further confirmed by its alternate synthesis via the reaction of 3-cyanoacetyl indole (1) with N`-(1H-benzimidazol-2-yl)-N,Ndimethylformamidine (11)  37 which afforded product identical in all respects (mp, mixed mp, TLC, IR, and mass spectra) with that obtained from the reaction of the enaminonitrile 2 with 2aminobenzimidazole as shown in Scheme 3.

Scheme 3
The enaminonitrile 2 was also reacted with 2-aminobenzothiazole in pyridine under reflux to give only one isolable product.The isolated product was identified as, the open form, 3-(benzothiazol-2-ylamino)-2-(1H-indole-3-carbonyl)acrylonitrile ( 12) over the possible closed isomer 13 (Scheme 4).Thus, IR spectrum of the reaction product revealed two bands due to cyano and carbonyl functions.Moreover, the 1 H NMR spectrum of compound 12 revealed a characteristic singlet signal at δ 8.02 attribute to the olefinic proton of the open structure.The structures of the reaction products were assigned based on their elemental analyses and spectral data.

Conclusions
In conclusion, we have clearly determined the structures of the reaction products of enaminonitrile 2 with N,N-dinucleophiles such as phenylhydrazine and primary heteroarylamines with the amino group attached at the α-position with respect to the ring nitrogen atom under basic reaction conditions.Thus, from the reaction of enaminonitrile 2 with phenylhydrazine one regioisomer 3a can be obtained.Basic promoted cyclization of enaminonitrile 2 with αheteroarylamines as N,N-1,3-dinucleophiles, condensed indolylpyrimidines as a new class of meridianine natural product analogs were obtained.Thus, (2Z)-3-dimethylamino-2-(1H-indole-3carbonyl)acrylonitrile 2 is a suitable reagent for a one step preparation of indolyl substituted heterocycles.

Experimental Section
General Procedures.Melting points were determined on a Gallenkamp melting point apparatus.IR spectra were recorded on Shimadzu FT-IR 8101 PC infrared spectrophotometer. 1 H NMR spectra were recorded on a Jeol EX-270 MHz spectrometer using DMSO-d6 as solvent and TMS as the internal standard, 13 C NMR spectra were recorded on a varian Mercury VX 300 NMR using DMSO-d6 as solvent and TMS as an internal standard.Mass spectra were recorded on a Finnigan mat.SSQ-7000 GC-MS spectrometer.Microanalyses were performed at the Microanalytical Center of Cairo University.Aminopyrazoles 4a-d, [33][34][35] 8, 36 11 37 and 3cyanoacetyl indole (1) 26 were prepared according to procedures in the literature.