An efficient synthesis of furan-3(2H)-imine scaffold from alkynones

A novel efficient method to generate spiro furan-3(2H)-imine derivatives is established by the reaction between the α,β-unsaturated ketones and aniline derivatives. The reaction involves 1,4- addition of aniline followed by the subsequent intramolecular cyclization mediated by tertiary alcohol to produce the furan-3(2H)-imine. All the synthesized compounds are characterized using nuclear magnetic resonance and high-resolution mass spectrometry (HRMS).


Introduction
Furanone occupies an important area in heterocyclic chemistry because it has a large spectrum of biological activities such as anti-cancer [1,2], anti-inflammatory [3] and antibiotic [4]. In addition, furanone is highly appreciated by the food industry as it is considered a key flavour compound in many fruits [5].
Over many decades, imine moiety has been receiving increasing attention due to a wide range of biological activities as well like anticancer [6], antioxidant [7], antimalarial [8], antibacterial [9,10] and anti-HIV [11]. Recently, imine-nanocapsules show a highly effective delivery of an insufficiency soluble cancer drug into tumour cells [12]. Organic imine cages also show significant applications in the detection of toxic organic pollutants [13].

Results and discussion
The treatment of propargylic alcohol derivatives 2(a-b) with n-BuLi at −78°C generates the deprotonated anion intermediate, where the resulting anion in situ reacts with benzaldehyde derivatives 1(a-c) to offer but-2-yne-1,4-diol derivatives 3(a-d) in 73-85% yield (scheme 2) [26]. The precursor α, β-unsaturated ketone derivatives 4(a-d) are achieved in 64-84% yield by the oxidation of diols 3(a-d) under mild condition using MnO 2 (scheme 2) [27]. By having compounds 4(a-d) in hand, the synthesis of the target compounds 6(a-t) has been achieved in a one-step reaction through heating of aniline derivatives and 4-hydroxybut-2-ynone 4(a-d) in MeCN:H 2 O (1 : 1) for 0.5-3 h. The desired products 6(a-t) are obtained in good to excellent yield as are shown in table 1. The geometry of the C=N double bonds in the products has been concluded based on the associated steric effects.
royalsocietypublishing.org/journal/rsos R. Soc. Open Sci. 8: 211145 It is clear from the obtained results that the reaction of 4-aminophenol with cyclohexyl moiety gives the best percentage yields, indeed, 6e, 6j and 6o with 91%, 94% and 91%, respectively, and are produced in just 0.5 h for 6e and 6j (table 1).
Scheme 3 shows another approach where furan-3(2H )-one 5 is chosen as the building block for the synthesis of furan-3(2H )-imine through the condensation reaction with aniline derivatives. However, Table 1. Synthesis of furan-3(2H )-imine 6(a-t). there is not any significant amount of the target product being observed in such reaction, hence, the suggested reaction pathway is not favoured. The lack of reactivity of compound 5 can be associated with the electron-donating effects of oxygen atom in the β-position which can significantly reduce the electrophilicity of carbonyl group (scheme 3). Scheme 4 shows a plausible mechanism for the final product formation, exemplified by compound 6a. Herein, an initial 1,4-addition produces the intermediate zwitterions A that is followed by a hydrogen transfer to produce the enamine B. Prevalent isomerization of B produces the imine C, in which intramolecular nucleophilic attack of the tertiary alcohol to the carbonyl moiety produces the cyclic hydroxylfurane skeleton D. The intermediate D releases water to produce furan-3(2H ) imine derivative 6a.
Aniline derivatives with hydroxy group show excellent yields, while aniline with electronwithdrawing group such as 4-chloroaniline and 4-nitroaniline is observed in trace amounts. The purity of all products is identified by thin-layer chromatography (TLC) using different mobile phases with different polarities. All the synthesized analogues are characterized by 1 H, 13 C nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). The 1 H NMR spectra of each 6(a-t) show a significant peak at δ = 5.91-6.50 ppm that can be associated with the CH at α-imine moiety. Each 13 C NMR spectrum shows a signal at δ = 89.1-92.6 ppm which is related to the spiro quaternary carbon and a peak at δ = 92.4-93.9 ppm for the CH at α-imine moiety, while the peak at δ = 170.8-174.3 ppm belongs to imine carbon. Compound 6o is further characterized by DEPT 135, COSY, HMQC and HMBC as an example, the spectral data are fitted to the suggested structure. Figure 1 shows the significant correlations which are derived from these techniques for compound 6o.
When the same reaction is performed with the 4-aminopyridine or hydroxyl amine, the only obtained product is furan-3(2H )-one 5 (scheme 5), which reflects the low stability of the imine product in both cases. The stability compound 6a is examined in a basic medium by refluxing in 10% NaOH for 5 h, and in acidic medium by heating at 80°C in 5% H 2 SO 4 for 24 h. These reactions show no changes on 6a under these conditions indicating the high stability of these analogues. royalsocietypublishing.org/journal/rsos R. Soc. Open Sci. 8: 211145

Conclusion
Furan-3(2H )-imine analogues have been synthesized in one step by 1,4-addition of aniline derivatives to α,β-unsaturated carbonyl moieties, which undergo intramolecular cyclization via tertiary spiro alcohol to produce the desired products. The structures of all newly synthesized compounds have been confirmed by NMR spectra and HRMS of representative analogues.

General procedure for the preparation of compound 4
To a suspension of diol 3 (20.96 mmol, 1 eq) in CH 2 Cl 2 (150 ml), an excess of MnO 2 (209.60 mmol, 10 eq) is added, the mixture is then stirred for 20 h at r.t. The suspension is then filtered through a pad of Celite, evaporated to dryness and the product is purified by column chromatography (SiO 2 , hexanes-EtOAc, 6 : 1) to give ketone 4. Note: compound 4d is synthesized from compound 3d and used in the next step without further purification.
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