Synthesis of oxindolyl-pyrimidines and oxindolyl-furopyrimidines from isatin-derived propargylic alcohols

A Brønsted acid-catalyzed reaction of 6-amino uracil and isatin-derived propargylic alcohols for the synthesis of a series of oxindole-fused pyrimidine in good-to-high yields was achieved (up to 94%). Furthermore, the reaction of isatin-derived propargylic alcohols and 1,3-dimethylbarbituric acid or ethyl 3-aminocrotonate gave oxindoles containing furopyrimidine or pyrrole, respectively, in moderate-to-good yields under relatively mild reaction conditions. A Brønsted acid-catalyzed reaction of 6-amino uracil, 1,3-dimethylbarbituric acid or ethyl 3-aminocrotonate with isatin-derived propargylic alcohols for the synthesis of oxindole-fused pyrimidine, furopyrimidine or pyrrole.


Introduction
The structures contain pyrimidines belonging to a diverse, interesting and potent drug family [1,2]. They display a wide range of pharmacological and biological activities such as antitumor [3], antibacterial [4], antifungal [5], Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1373 8-020-01893 -3) contains supplementary material, which is available to authorized users. antimalarial [6] and anticonvulsant [7] activities. Moreover, several pyrimidine derivatives are valuable drugs for the treatment of hyperthyroidism, acute leukemia in children and adult granulocytic leukemia [7]. Therefore, the improvement in simple and effective methods for the synthesis of pyrimidine frameworks has attracted much attention in the area of synthetic and medicinal chemistry. Recently, uracils as inexpensive purchasable in the market have been extensively employed as appropriate starting materials for the synthesis of pyrimidine derivatives via many synthetic methodologies [8][9][10][11]. Similarly, the oxindoles containing heterocycles in the 3 position have appeared as attractive synthetic targets because of their presence as a core structure of many natural products and biologically active molecules [12][13][14][15]. Several oxindoles containing pyrimidine skeleton possess biological activity against leukemia, lung, and prostate cancer cell lines [16]. They showed analgesic, antipyretic, and anti-inflammatory activity [17]. Therefore, the introduction and development of synthetic methods for the synthesis of new oxindoles containing pyrimidine skeleton is very important.

Materials and methods
Melting points were measured on an Electrothermal 9100 apparatus and are uncorrected. 1 H and 13 C NMR spectra were recorded on a BRUKER DRX-300 AVANCE spectrometer at 500.13 and 125.77 MHz, respectively. 1 H and 13 C NMR spectra were obtained on solutions in DMSO-d 6 using TMS as internal standard. IR spectra were recorded using an FTIR apparatus. EI-MS (70 eV) was obtained using Agilent Technologies, 5975C VL MSD with Tripe-Axis Detector in m/z. The X-ray diffraction measurements were made on a STOE IPDS-II diffractometer with graphite monochromated Mo-Kα radiation.

General procedure for preparation of oxindole compounds
To the mixture of propargylic alcohol (1) (1 mmol) and 6-Amino-1,3-dimethyluracil (2), ethyl 3-aminocrotonate (4) or 1,3-dimethylbarbituric acid (6) (1 mmol) in dichloromethane, p-TSA (2 mmol) was added. Then, the reaction was heated to reflux for an appropriate time. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to room temperature and diluted with water. The organic phase was extracted, and the product was obtained after purification by preparative TLC.
Due to very low solubility of the products 3a-e, we cannot report the 13 C-NMR data for these products. The structure was solved by using SHELXS. The structure refinement and data reduction were carried out with SHELXL of the X-Step32 suite of programs. The non-hydrogen atoms were refined anisotropically by full matrix least squares on F 2 values to final R 1 = 0.0731, wR 2 = 0.2090 and S = 1.035 with 311 parameters using 4131 independent reflection (θ range = 1.91°-25.00°). Hydrogen atoms were located from expected geometry and were not refined (CCDC No. 1922305). The structure was solved by using SHELXS. The structure refinement and data reduction were carried out with SHELXL of the X-Step32 suite of programs. The non-hydrogen atoms were refined anisotropically by full matrix least squares on F 2 values to final R 1 = 0.0992, wR 2 = 0.2586 and S = 0.847 with 273 parameters using 5160 independent reflection (θ range = 2.46°-27.00°). Hydrogen atoms were located from expected geometry and were not refined (CCDC No. 1900687).    Amino-1,3-dimethyl-5-(1-methyl-2-oxo-3-(phenylethynyl)  indolin-3-yl)dihydro pyrimidine-2,4(1H, 3H) 13 -2,4(1H,3H)

Results and discussion
Initial investigation was started by performing the reaction of 3-hydroxy-3-(phenylethynyl)indolin-2-one 1a and 6-amino-1,3-dimethyluracil 2 in refluxing MeCN in the absence of any catalyst, as a model reaction (Table 1, Entry 1). The progress of reaction was monitored by TLC (EtOAc/n-hexane, 1:1/as eluent). After 4 h, no product was obtained under these conditions. Then, the model reaction was conducted in the presence of different catalysts such as K10, ZnCl 2 , AlCl 3 , FeCl 3 , ZnBr 2 /p-TSA, Sc(OTf) 2 , Cu(OTf) 2 and p-TSA in MeCN at reflux conditions for 4 h (Entries 2-9). The progress of all reactions was monitored by TLC. Eventually, it was found that p-TSA is the catalyst of choice since it gave the product 3a in 50% yield (Entry 9). Subsequently, the model reaction was tested in different solvents such as DCM, MeNO 2 , toluene, and EtOH using p-TSA as catalyst (Entries [10][11][12][13][14]. No desired product was obtained in protic solvent such as EtOH, and only low yields were obtained in MeNO 2 and toluene. To our delight, the model reaction in DCM at reflux conditions afforded the product 3a in 93% yield (Entry 10). When the reaction was performed at room temperature, the product 3a was obtained in only poor yield after 7 h (Entry 11). Based on the previous reports [23][24][25][26][27][28][29], a plausible mechanism is proposed in Scheme 1. Usually, both aryl propargylic derivative (α-adduct) and alkenylated arene (γ-adduct) were produced in variable yields. Then, the nucleophilic reaction of I and 6-amino-1,3-dimethyluracil 2 generates product 3a.
Next, the scope of the reaction was examined using various isatin-derived propargylic alcohols 1a-e, and in all cases the desired 2-oxo-3-(phenylethynyl)indolin-3-yldihydro pyrimidine-diones 3a-e were obtained in good-tohigh isolated yields ( Table 2). The structure of all products was deduced from their IR, 1 H, and 13 C NMR spectra. The Scheme 1 A proposed mechanism for the reaction Table 2 Synthesis of product 3 structure of 3a and 3b was confirmed by single-crystal X-ray analysis (Fig. 3, see SI).
When we performed the reaction of ethyl 3-aminocrotonate 4 with propargylic alcohols 1 under the same reaction conditions, interestingly the oxoindolin-3-yl pyrrole 5 was obtained in 60% isolated yield (Scheme 2).
To further explore the potential of this protocol, we investigated the reaction of propargylic alcohol 1 with 1,3-dimethylbarbituric acid 6. This reaction afforded oxoindolin-3-yl-furopyrimidines 7 in good isolated yields (Scheme 3).
A reasonable mechanism for the synthesis of 5 and 7 is shown in Scheme 4. The nucleophilic reaction of II and 1,3-dimethylbarbituric acid 6 or 3-aminocrotonate 4 could afford the corresponding allene intermediate III. Finally, a 5-exo-dig cyclization affords product 5 and 7. The carbonyl group of oxindole moiety would facilitate the Michael-type cyclization [24].
Finally, selected synthesized compounds were screened for antimicrobial activity. The microorganisms used in this study were Escherichia coli ATCC 25922, Pseudomonas aeruginusa ATCC 85327 (Gram-negative bacteria), Enterococcus faecalis ATCC29737 and Staphylococcus aureus ATCC 25923 (Gram-positive bacteria). The minimum inhibitory concentration (MIC) of the synthesized compounds was determined by microdillution method [42] and compared to Tetracycline as a commercial antibiotic ( Table 3). As can be seen from Table 3, good antibacterial activity was

Conclusions
To conclude, various oxindoles-fused heterocycles were synthesized by the reaction of isatin-derived propargylic alcohol and 6-amino uracil, ethyl 3-aminocrotonate or dimethylbarbituric acid. The method could be a powerful procedure to develop the library of oxindoles with pharmaceutical capabilities under mild reaction conditions.

Supporting information
Supplementary data (experimental procedures, 1 H NMR, 13 C NMR spectra and also mass analysis for compounds) associated with this article can be found, in the online version.