New One-Pot Pathway for the Synthesis of 2H–Pyrrolo[2,3-d]Pyrimidine-2,4-(3H)-Diones and 1H-Benzo[f]Indole-4,9-Dione Derivatives Substituted 3-Hydroxy-1,4-Naphthoquinonyl

Abstract One-pot three components effective methods are reported for the synthesis of two important families of organic compounds, 2H-pyrrolo[2,3-d]pyrimidine-2,4(3H)-diones substituted 5-(3-hydroxy-1,4-naphthoquinonyl) and 1H-benzo[f]indole-4,9-diones substituted 3-(3-hydroxy-1,4-naphthoquinonyl), by employment of new starting materials. The formers were prepared via the one-pot condensation reaction between phenylglyoxal, 2-hydroxynaphtoquinone and 2-amino-1,4-naphthoquinone derivatives and the later through the reaction of phenylglyoxal, 2-hydroxy naphthoquinone and 2-amino-1,4-naphthoquinone derivatives. The reaction medium for the synthesis of both procedures was acetic acid/water (1:1; v/v) at 100 °C, and various derivatives of these compounds were obtained with high-efficiency and identified by their IR, 1H- and 13C-NMR spectra. In spite of their apparent planar structures, the NMR spectra of some products shown asymmetric properties of CH2 protons or existence of two diastereomers due to restriction of Chydroxyquinoline˗Cpyrrol bonds, together with formation of relatively stable nonplanar eight membered ring resulted from hydrogen bond formation between hydroxynapthoquinone’s OH and carbonyl groups of uracil motifs.


Results and discussion
In the first attempt for synthesis of pyrrolo [2,3-d]pyrimidine substituted 3-hydroxy-1,4-naphthoquinonyl derivatives, phenylglyoxal 1 (1 mmol), 2-hydroxy-1,4-naphthaquinone 2 (1 mmol), and 6-aminouracil 3c (1 mmol) were allowed to react in a mixture of acetic acid/water (1:1), at 100 C (Scheme 2). Fortunately, under these conditions, the product 4c was precipitated as a brown powder from the reaction mixture and extracted without the need for additional purification in excellent yield (95%) after 4 hours of the reaction time. This prevented us from making much effort to change the reaction conditions, although it showed a declining efficiency by lowering the temperature to 50 C or directing the reaction in pure water or acetic acid.
The spectral studies of the product 4c proposed that this product has a nonplanar structure because of the restriction of rotation of C hydroxyquinoline -C pyrrolopyrimidine bonds together with the formation of relatively stable nonplanar eight membered ring resulted from hydrogen bonding between hydroxynapthoquinone's OH and carbonyl groups of uracil moiety. Accordingly, product 4c has two enantiomeric stereoisomers 4cI and 4cII which were slowly interconverted via sterically hindered planar stereoisomer 4c-planar. On the other hand, as a result of conformational flexibility of eight membered rings 4cI and 4cII, the nmr spectrum of 4c as well as some the other derivatives of pyrrolo[2,3-d]pyrimidine-2,4(3H)-diones substituted 5-(3-hydroxy-1,4-naphthoquinonyl) 4 showed two major and minor slowly interconverted conformers ( Figure 2).
The structure of pyrrolo[2,3-d]pyrimidine 4c was characterized based on its IR, 1 H-and 13 C-NMR spectra. The most important absorption bands in the IR spectrum were appeared as strong and distinct peaks at 3471, 3388, 1698, 1672, 1654, and 1638 cm À1 , related to the symmetric and asymmetric stretching of OH and NH groups as well as carbonyl groups of the pyrimidine, and quinone rings. 1 H-NMR spectrum of this compound clearly represents two rotamers. Thus, in the 1 H-NMR spectrum, two methyl groups are appeared as two overlapped singlets in the range of 3.16-3.19 and 3.57-3.59 ppm ( Figure 3). Aromatic protons were appeared as four groups of multiple peaks in d ¼ 7.20-7.29, 7.31-40, 7.46-7.56 and 7.67-7.95 ppm. In addition, two doubletdoublet peaks are appeared in the range of 7.99 and 8.03 ppm with coupling constant of J 1 ¼ 2.37, J 2 ¼ 6.57 and J 1 ¼ 2.34, J 2 ¼ 6.42, respectively. In the range d ¼ 10.52-11.51 a broad peak corresponding to OH group is appeared, and NH protons is resonated at d ¼ 11.84 as a singlet. The impossibility of counting the number of aromatic protons is also probably due to the presence of two rotamers that cannot be converted quickly. The 13 C-NMR spectrum shows twentytwo distinct peaks that are fully consistent with the proposed structure. The carbon of the methyl groups resonated in the range d ¼ 27.8 and 31.1 and the pyrrole carbons and other aromatic ring carbon resonated as 15 separate peaks in the range d ¼ 99.9-135.2. The peaks related to the carbons of the carbonyl groups as well as the carbon attached to the hydroxy group are appeared in the range d ¼ 140.1-180.5 ppm. The carbon attached to OH group and the carbonyl between the two N-Me groups are resonated at the lower frequencies of this range and the peaks of the hydroxyquinone ring ketones are also located at d ¼ 181.5 and 183.8 ppm.
In order to evaluate the feasibility of this new strategy for the synthesis of pyrrolo[2,3-d]pyrimidine substituted 3-hydroxy-1,4-naphthoquinonyl derivatives 4, various amiouracil derivatives 3  were subjected to the one-pot reaction with phenylglyoxal 1 and 2-hydroxy1,4-naphthoquinone 2 under the reaction conditions. The structure of the synthesized compounds is shown in Table 1. All reactions were completed in less than 5 hours and due to the insolubility of products in reaction medium, their separation was easily done by filtration, and after washing with a small amount of cold acetic acid and water, they purely were separated in good to high efficiency. They were shown physical and spectral patterns as structurally well stablished product 4, thus their structures were proposed to be as pyrrolo [2,3-d]pyrimidine-2,4-(3H)-diones bearing 3-hydroxy-1,4-naphthoquinonyl derivatives. We found in our studies that if aminouracil derivatives 3 replaced by 2-amino-1,4-naphthoquinones 5, a new family of organic compounds, 1H-benzo [f]indole-4,9-diones substituted 3hydroxy-1,4-naphthoquinonyl 6, would be synthesized under the same reaction conditions (Scheme 3).
Initially, according to the previously reported procedure, 35 by addition of the amines to 1,4naphthoquinone at room temperature in ethanol as solvent, 3-amino-1,4-naphthoquinone derivatives 5 were prepared with excellent efficiency. Due to the reaction of 2-amino-1,4-naphthoquinone 5a with 2-hydroxy-1,4-naphthoquinone and phenylglyoxal in acetic acid/water (1: ]indole-4,9-dione 6a was synthesized with good efficiency. The structure of this compound was identified based on its IR, 1 H-and 13 C-NMR spectra. The most important absorption bands in the IR spectrum of this compound are observed at the frequencies 1660, 1714, 1731, and 1789 cm À1 for the carbonyl groups and one peak at 3355 cm À1 for the OH vibrations. In the 1 H-NMR spectrum of this compound, eighteen hydrogens were resonated in the aromatic region, corresponding to the phenyl rings. The peaks are all multiplet and appeared in the ranges d ¼ 7.06-7.10, 7.17-7.20, 7.40-7.43, 7.79-7.89, 7.90-7.99, and 8.00-8.09 ppm. The OH proton was appeared as a broad peak in the d ¼ 11.33. The 1 H-NMR spectrum of compound 6 h showed two doublets at d ¼ 5.67-5.83 for diastereotopic benzylic methylene protons which stablished a nonplanar structure for products 6. On the other hand, existence of two distinctly separate peaks for methyl protons of compound 6e at 2.23 and 2.25 ppm, clearly stablished that rotation of N-Ar bond is restricted at room temperature. This bond rotation restriction is also observed for products 6b, 6d and 6f which introduced additional evidence about nonplanarity of the structure of products 1H-benzo [f]indole-4,9-diones substituted 3-hydroxy-1,4-naphthoquinonyl (6). Based on these results, it can be concluded that products 6, like products 2, has two enantiomeric stereoisomers 6-I and 6-II which were slowly interconverted via sterically hindered planar stereoisomer 6-planar ( Figure 4).
The scope of this reaction for synthesis of various derivatives of 3-hydroxy-1,4-dihydronaphthalen-2-yl-1H-benzo [f] indole-4,9-diones 6 was studied by employment of some 2-amino-1,4naphthoquinones 5 ( Table 2). Aniline and its derivatives that have electron donating groups were well worked in this reaction and the corresponding products obtained with good to high yields (products 6a-g). Moreover, 2-amino-1,4-naphthoquinones including benzylic, 5h, and aliphaticamines, 5i-j, were also subjected to the reaction conditions and the related products 6h-j were synthesized with high efficiency.
water as a solvent under reflux conditions in less than 5 hours, and new derivatives of these organic compounds were synthesized with high efficiencies. The reactions were clean and the products were easy to separate, as they did not dissolve in the reaction solvent and precipitated in the reaction vessel, and pure products were obtained without the need for additional operations.

Chemicals, instrumentation and analysis
All starting materials and correlated apparatuses were purchased from credible commercial suppliers, and used without further purification. The reaction monitoring was accomplished by TLC on silica gel PolyGram SILG/UV254 plates. Melting points deter-mined in open capillary tubes in a Barnstead Electrothermal 9100 BZ circulating oil melting point apparatus. The structure of the synthesized products was characterized using FT-IR, 1 H-and 13 C-NMR spectra. The FT-IR spectra reached an acquisition step of the basic spectra over the region 400-4000 cm À1 with NICOLET IR100 FT-IR. Here, spectroscopic-grade KBr was harnessed. 1 H-NMR (400 MHz) and 13 C-NMR (100 MHz) spectra were recorded on a Bruker Avance (DRX 400 MHz) in DMSO-d 6 solvent with a commercially introduced internal standard, namely tetramethylsilane (TMS).