Cascade process for direct synthesis of indeno[1,2-b]furans and indeno[1,2-b]pyrroles from diketene and ninhydrin

Novel and efficient multicomponent reactions (MCRs) involving diketene, ninhydrin (indane-1,2,3-trione) and one primary amine (3CR) or two different primary amines (4CR) were achieved for the successful synthesis of dihydro-4H-indeno[1,2-b]furan-3-carboxamides or tetrahydroindeno[1,2-b]pyrrole-3-carboxamides, respectively. The merits of this method are highlighted by using either commercially available or easily accessible starting materials, operational simplicity, facile workup procedure, efficient usage of all the reactants, tolerance of a variety of functional groups and ability to conduct under un-catalyzed reaction condition. The products were also isolated by just decantation of the solvent, and for the purification column chromatography was non-required.


Introduction
Furans, five-membered aromatic heterocycles, contain one oxygen atom which is usually found in diverse important compounds clouding naturally occurring compounds, Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1103 0-019-09996 -7) contains supplementary material, which is available to authorized users. medicines and polymers [1]. Besides, furans were used as synthetic intermediates to attain other valuable compounds [2][3][4][5]. Remarkably, the formation of this important structural framework has obtained considerable attention and an extensive range of methods were reported for the synthesis of furans and derivatives [6][7][8].
Indeno heterocycles frameworks are broadly found in various naturally occurring compounds and synthetic compounds having biological activities [9]. Particularly, furan and indeno-fused furan are valuable building blocks of intense biological potent molecules. For instance, the tricyclic indenofuran vocalizes the key substructures of GR-24 [10], (+)-strigol [11] and desmethylsorgolactone [12] (Fig. 1). These biological active compounds were used for the treatment of metabolic disorders. Also, due to the significance role of them in drug discovery, they were followed intensively in recent years [13].
Moreover, simple N-heterocycles have obtained significant attention due to their significant biological activities and their role as pharmacophores [17]. Remarkably, pyrrole, one of the most important simple heterocycles, is found in a wide range of synthetic and natural product having significant activities, both in materials science and in pharmacology. Biologically active pyrroles could make the structure of porphyrin rings that serve as a key scaffold in vitamin B 12, heme, chlorophyll or bile pigments [18]. Pyrrole subunit has various usages in therapeutically potent compounds such as antibiotics, fungicides, anti-inflammatory drugs [19] and antitumor agents [20]. They were used to inhibit cellular DNA polymerases protein kinases and reverse transcriptase [human immunodeficiency virus type 1 (HIV-1)]. Besides, in catalytic reactions, pyrroles are used as catalyst for corrosion inhibitor [21], polymerization process [22] and preservative [23]. Besides, some of these compounds are valuable intermediates in the formation of biologically active naturally occurring alkaloids [24] and heterocyclic compounds [25].
Moreover, a base-promoted cascade reaction of (E)-2-alkynylphenylchalcone and 2-isocyanoacetate was achieved to produce a unique and significant method for the formation of tetrahydroindeno [2,1-b]pyrrole derivatives in high yields [27].
These approaches have their own advantages and disadvantages. For some of them, the usage of expensive reagents is needed, some other only can be accomplished under severe conditions, and the products isolation is cumbersome afford in low yields in comparatively long reaction time.
Diketene (4-methyleneoxetan-2-one) that is a reactive and valuable compound is used for the introduction of substituted C2, C3 and C4 parts into organic compounds; however, it is best known as being agent for the construction of acetoacetic acids. Noticeably, diketene is an ideal compound for chemical investigation, since it is easily available, cheap, reactive and highly substituted [33]. Because of the significance and unique reactivities of ketenes and diketene, we have demonstrated the usages of ketenes and diketene as the privileged synthons in the formation of heterocyclic derivatives [34][35][36][37][38][39][40][41][42][43]. Our group has been pursuing different methods for divers organic compounds and pharmacologically fused polyheterocyclic syntheses using enamines, aminals and other intermediates for the past few years [44][45][46][47][48][49][50][51][52][53][54][55]. On the other hand, we have also recently published three 5-component reactions on the applications of DK as an outstanding synthon in the synthesis of heterocyclic compounds [56][57][58]. Fortified by these successful efforts, herein, we wish to report efficient and simple methods for the synthesis of indeno[1,2-b]furan-3-carboxamides and indeno [1,2-b]pyrrole-3-carboxamides through one-pot, three and four-component reactions in the absence of any catalysts at room temperature.
In the present work, application of synthetic ligand was studied due to photophysical property and its sensitivity to pH variation. The π-conjugated system with color property of organic ligands offers researchers to focus on ability of them in sensing at different organic, inorganic and biological systems. We focused on the pH sensing of the synthetic ligand which can be employed as a pH sensor specially in alkaline media.

Results and discussion
Initially, we tried to the synthesis of dihydro-4H-indeno[1,2b]furan-3-carboxamides. One-pot, three component reaction of diketene, isobutylamine and ninhydrin were selected as model reaction. In a pilot reaction, diketene and butylamine were combined at room temperature under solvent-free condition. The ring opening of diketene was observed using monitoring by thin-layer chromatography. After the formations of oxobutanamide for 15 min, ninhydrin and dichloromethane were introduced. The resulting reaction mixture was stirred until the completion of the reaction. During the progress of reaction, an aliquot was taken by syringe and detected by TLC. After the formation of the product, the obtained product was isolated, filtered and washed with cold ethanol to afford the indeno[1,2-b]furan-3-carboxamide 2a in excellent yield. This reaction was tested in different solvents such as EtOH, MeCN and THF in order to obtain suitable reaction medium to give the target compound 2a.
The results are summarized in Table 1. The best result was obtained in CH 2 Cl 2 at room temperature.
Subsequently, to validate the broad view of this efficient synthetic protocol, different types of primary amine (propylamine, butylamine, isobutylamine, benzylamine and cyclopentylamine) were examined under the standard conditions that could react and smoothly generate the desired products 2a-e in good to excellent yields; and the reaction was completely finished within one hour in all cases at room temperature.
Encouraged by this finding, in the following, we tried to the synthesis of tetrahydroindeno [1,2-b] pyrrole-3-carboxamides and the reaction was evaluated in a four-component manner. The reaction was carried out by the sequential addition of reagents: first primary amine 1, diketene and second primary amine 3 in one flask under solvent-free conditions at room temperature (Scheme 2). The resulting reaction mixture was stirred to complete the reaction as monitored by thin-layer chromatography (TLC). After the formation of enaminone (20 min), ninhydrin with dichloromethane was introduced and the reaction was steered for 40 min. After workup, the precipitated solid was filtered off under reduced pressure, washed with ethanol and crystallized from ethanol in excellent yield. Despite having a good result at hand, just for being prudent, we examined other solvents such as EtOH, MeCN and THF which did not give any better result in comparison with CH 2 Cl 2 application (Table 1). Although pleased with these results, we tried to optimize the reaction conditions at raised temperature and no growth in yield was observed by increasing the temperature from room temperature to boiling points of ethanol (76 °C) ( Table 1, entries 5). Therefore, it could be determined that the best reaction conditions for the construction of 3a were using CH 2 Cl 2 at room temperature ( Table 1).
The scope and efficiency of this method was investigated under the optimal reaction conditions. For this purpose, diketene, various primary amines (propylamine, butylamine, isobutylamine and benzylamine) and ninhydrin were reacted together in CH 2 Cl 2 at room temperature to provide the desired product 4a-h in excellent yields. The results are summarized in Table 2.
The molecular structure of all synthetic compounds 2a-e and 4a-h was elucidated from their mass spectrometric analyses, IR, and high-field 1 H-NMR and 13 C-NMR. (Full spectra and spectral data of all target compounds can be found in Supporting information.). In the first reaction series, the IR spectrum of compound 2a showed a broad absorption band in 3446 due to the OH and NH stretching frequencies. Also, absorption bands at 1714, 1644 and 1561 are due to C=O, NCO and NC=C groups stretching frequencies. The 1 H-NMR spectrum of 2a showed multiple picks in δ = 0.94-0.96 ppm for CH 3 in isobutyl and multiple picks in δ = 1.74-1.8 ppm for CH of alkyl. Also Because of the existence of two stereogenic centers in the products 2a-e and 4a-h, mixture of two diastereomers was expected. For 2a and 2b products, two diastereomers were formed. But, the 1 H and 13 C-NMR spectral data of 2c-e and 4a-h clearly indicated that only one of the two possible diastereomers was obtained for these products.
A probable mechanism for the synthesis of indeno[1,2b]furans 2 and indeno[1,2-b]pyrrole 4 is illustrated in Scheme 3. The first step begins with a nucleophilic addition of the amine group to diketene followed by ring opening and H-transfer to produce oxobutanamide 5. Then, this oxobutanamide 5 undergoes by equilibrium between enol and ketone to give 6. Then, enol attacks to the carbonyl group in ninhydrin to give the intermediate 7, which undergoes successive enol-ketone tautomerization, followed by nucleophilic addition of the oxygen to the carbonyl group, resulting in the formation of product 2 (Scheme 3). On the other hand, for the synthesis of indeno[1,2-b]pyrrole-3-carboxamides 4, the first step begins with a nucleophilic addition of amine group to diketene followed by ring opening and proton transfer to produce oxobutanamide 5. Then, the other primary amine condenses with a ketone moiety to form β-enaminone 9. Next, the reaction enaminone 9 and the ninhydrin undergo a nucleophilic attack to give the intermediate 10 followed  by nucleophilic addition of the amino group to the carbonyl group, resulting in the formation of product 4. The absorbance measurement was carried out by doublebeam UV-Vis spectrophotometer using a 1 cm quartz cell (Perkin-Elmer, Lambda 35, USA).
The photophysical property of the synthetic ligand dihydro-4H-indeno[1,2-b]furan-3-carboxamide 3a was studied for investigation of its application. The appropriate amount of ligand was dissolved in EtOH:H 2 O (50:50) and its absorption spectra recorded at room temperature. Three absorption bonds observed at 200, 240 and 350 nm increase by concentration (Fig. 2).
In order to study of the effect of pH, the UV-Vis absorption spectra were measured at pH range from 2 to 12. The UV-Vis spectra are shown in Fig. 3. When the pH value increased from 2 to 7, the slight decrease in all absorption bonds was observed. The best sensitivity of synthetic ligand to pH was obtained in the basic value of pH where the new absorption bond was appeared at 400 nm and increased strongly by changing pH from 7 to 13. The effect of pH on absorption spectra is shown in Fig. 3, and the yellow color of the solution was observed by this effect. This result demonstrates that the solution pH can change the absorption spectra of synthetic ligand related to its structure. In this pH, when hydrogen (NH) is separated, conjugated π-system is extended and the extended system of conjugated π-bonds causes rise to a strong UV absorbance.
The pH sensor could be applied in the pH detection of real samples such as water samples based on ligand name in order to check their safety and presence of pollutions.

Experimental
The diketene, various amines and ninhydrin were obtained from Merck (Germany) and Fluka (Switzerland) and were used without further purification. Elemental analyses for C, H and N have been accomplished using a Heraeus CHN-O-Rapid analyzer. Mass spectra have been recorded on a FINNIGAN-MATT 8430 mass spectrometer operating at an ionization potential of 70 eV. 1 H NMR (400 and 500 MHz) and 13 C NMR (100 and 125 MHz) spectra have been provided using Bruker DRX-400 AVANCE and Bruker DRX-500 AVANCE spectrometers. IR spectra have been recorded as KBr pellets on a NICOLET FT-IR 100 spectrometer, and melting points were measured on an Electrothermal 9100 apparatus.

General procedure for the synthesis of 2a-e
Primary amine (1 mmol) and diketene (1 mmol) were mixed and maintained at room temperature for 15 min in solventfree condition. Next, ninhydrin (1 mmol) and CH 2 Cl 2 (2 ml) were added to the mixture of reaction. The mixture was reacted for the appropriate time. The progress of the reaction was monitored using TLC. After the completion of the reaction (45 min), the mixture was filtered off and purified through recrystallization from ethanol to give the corresponding products 2 in high purity.