Ring-closing metathesis as a key step to construct the 2,6-dihydropyrano[2,3-c ]pyrazole ring system

A simple and efficient synthetic route to the 2,6-dihydropyrano[2,3-c ]pyrazole ring system was developed by employing ring-closing metathesis (RCM) as a key step. The required diene substrate for the RCM reaction was prepared by a three-step procedure starting form 1-phenyl-1 H -pyrazol-3-ol. Treatment of the obtained 4- ethenyl-1-phenyl-3-[(prop-2-en-1-yl)oxy]-1 H -pyrazole with Grubbs‘ first-generation catalyst afforded the target 2-phenyl-2,6-dihydropyrano[2,3-c ]pyrazole. 2-(4-Fluorophenyl)- and 2-(4-bromophenyl)-2,6-dihydropyrano[2,3-c ]pyrazole were synthesized by an analogous way. The structures of the obtained heterocyclic products were unequivocally confirmed by detailed 1 H, 13 C, 15 N and 19 F NMR spectroscopic experiments and HRMS measurements . The optical properties of 2-phenyl-2,6-dihydropyrano[2,3-c ]pyrazole were studied by UV–Vis and fluorescence spectroscopy.


Results and Discussion
The synthetic strategy designed to construct the 2,6-dihydropyrano [2,3-c]pyrazole ring system employs a diene substrate that contains an ethene unit attached to an allyloxy unit onto the pyrazole core, which can participate in the RCM reaction (Scheme 1).][29][30] The O-allylation of 1a with allyl bromide in the presence of NaH gave O-allylated pyrazole 2a. 31 To introduce a formyl group at the 4-position of the pyrazole ring, we employed a previously reported procedure based on the Vilsmeier-Haack reaction. 32Heating compound 2a with POCl 3 in N,N-dimethylformamide (DMF) at 60 °C resulted in the formation of the desired pyrazole-4-carbaldehyde 3a in 91% yield (Scheme 1).The characteristic signals of aldehyde 3a in the 1 H NMR spectrum were the singlets at 8.25 (5-H) and 9.88 ppm (CHO).The 13 C NMR spectrum contained the signal of a formyl carbon at 183.4 ppm.
Next, we investigated the conversion of aldehyde 3a into 4-ethenylpyrazole 4a.One of the most popular methods for the synthesis of alkenes from aldehydes and ketones is the Wittig reaction, which is based on the coupling of carbonyl compounds with single-substituted phosphonium ylides. 33To introduce a methylene group, methylenetriphenylphosphorane (Ph 3 P=CH 2 Ph 3 P + -CH 2 -) generated by the addition of a base to a solution of methyltriphenylphosphonium bromide or iodide is typically used as an ylide source. 34,35For example, the Wittig reaction of benzaldehyde with methyltriphenylphosphonium iodide in the presence of K 2 CO 3 in DME provided styrene in 90% yield. 35In our case, the reaction of aldehyde 3a with methyltriphenylphosphonium iodide in the presence of KOtBu in toluene resulted in the formation of 4ethenylpyrazole 4a in 89% yield.Having prepared the required diene 4a, we further investigated its RCM reaction in order to convert the latter into the target compound 5a.When 4a was heated with Grubbs' first-generation catalyst in dichloromethane, no RCM reaction occurred.However, the replacement of the solvent with THF gave the desired 2-phenyl-2,6-dihydropyrano[2,3-c]pyrazole 5a in 42% yield.The application of microwave heating allowed to shorten the RCM reaction time from 48 h to 3 h, but the isolated yield of 5a was only 34%.
The heterocyclic compounds of type 5 represent dihydropyrano [2,3-c]pyrazole substructures related to important functional organic molecules with wide biomedical applications.Because popular NMR prediction programs, such as ACD C+H predictor, 36 depend on high-quality data with unambiguously assigned resonances, we carried out NMR studies with compound 5a in an attempt to fully map all the NMR signals for 1 H, 13 C and 15 N as accurately as possible (Figure 1).The desired results were achieved through a combination of standard NMR techniques, such as DEPT, gs-HSQC, gs-HMBC, COSY, TOCSY, NOESY 37 , H2BC 38 and 1,1-ADEQUATE 39 experiments.The broad-band decoupled 13 C NMR spectrum of compound 5a showed resonances for 10 carbon atoms.The DEPT-90 and 135 spectra indicated the presence of 1 methylene and 6 methine carbon atoms.Comparison of the DEPT spectrum with the broad-band decoupled 13 C NMR spectrum revealed the presence of 3 quaternary carbons.The multiplicity-edited 1 H- 13 C HSQC spectrum indicated that the methylene protons H-6 have one-bond connectivity with the C-6 carbon at 68.8 ppm.Moreover, this also revealed heteronuclear interactions between the protons of two pairs of chemically equivalent methine groups (7.36-7.40 and 7.54-7.58ppm), with their respective carbons, which resonated at 129.4 and 117.6, respectively.The data from the 1 H- 13 C HMBC spectrum revealed long-range correlations of the methylene protons with the quaternary carbon C-7a (at 161.9 ppm) and protonated carbons C-5 (at 119.0 ppm) and C-4 (118.1 ppm).The aforementioned protonated carbon C-4 showed correlation with quaternary carbon C-3a in the 1,1-ADEQUATE spectrum, which was also supported by the correlation of C-3 with C-3a.The 15 N NMR data were obtained via a 1 H-15 N HMBC experiment.Both nitrogen atoms showed appropriate couplings to H-3, and in the case of N-2, it had strong coupling with the aromatic protons 2-H and 6-H.The TOCSY spectrum showed that there were two distinct spin systems in the molecule.The 1 H-1 H connectivities within each spin system were confirmed using the data from the COSY, TOCSY and NOESY spectra.Compounds 5b,c were obtained analogously to compound 5a.Although the preparation of the starting compound 1b was reported in a patent applications, 40,41 neither a detailed synthesis description nor spectroscopic data of the product were provided.The O-allylation of 1b and 1c 42 and the subsequent formylation of 2b,c produced aldehydes 3b,c which after conversion to the corresponding ethenyl derivatives afforded the diene substrates 4b and 4c.Treatment of 4b,c with Grubbs' first-generation catalyst resulted in the formation of the target compounds 5b and 5c in 56% and 39% yield, respectively.
The optical properties of compound 5a were investigated by UV-Vis spectroscopy and fluorometric measurements.The electronic absorption spectra of compound 5a in THF did not show absorption bands in the visible region of the electronic spectra, and it showed an absorption maximum at 310 nm (Figure 3, a).Upon excitation of compound 5a at 320 nm (in THF solution), the fluorescence spectrum exhibited three peaks at 360, 381 and 395 nm (Figure 3, b).The fluorescence quantum yield (Φ f ) of the solution was estimated by the integrating sphere method and gave a Φ f value of ca.1%.

Experimental Section
General.Microwave reactions were conducted using a CEM Discovery Synthesis Unit (CEM Corp., Matthews, NC).The machine consists of a continuous focused microwave power delivery system with operator-selectable power output from 0 to 300 W. The reactions were performed in glass vessels (capacity 10 mL) sealed with septum.In the case of an open vessel conditions the reactions were performed in a round bottom flask (capacity 25 mL) connected to a reflux condenser.All experiments were performed using a stirring option.For thin layer chromatography (TLC), Merck pre-coated TLC plates (Silica gel 60 F 254 ) were employed.The purification of the products was performed using flash chromatography on a glass column with silica gel (high purity grade 9385, pore size 60 A, 230-400 mesh particle size).The melting points were determined in capillary tubes, on a capillary melting point apparatus Büchi Melting Point M-565 and are uncorrected.The 1 H, 13 C and 15 N NMR spectra were recorded in CDCl 3 solutions at 25 °C on a Bruker Avance III 700 (700 MHz for 1 H, 176 MHz for 13 C, 71 MHz for 15 N) spectrometer equipped with a 5 mm TCI 1 H-13 C/ 15 N/D z-gradient cryoprobe.The chemical shifts, expressed in ppm, were relative to tetramethylsilane (TMS).The 15 N NMR spectra were referenced to neat, external nitromethane (coaxial capillary). 19F NMR spectra (376.46MHz, absolute referencing via δ ratio) were obtained on a Bruker Avance III 400 instrument with a 'directly' detecting broadband observe probe (BBO).The full and unambiguous assignments of the 1 H, 13 C, 15 N and 19 F NMR resonances were achieved using standard Bruker software and a combination of standard NMR spectroscopic Wavelength, nm techniques, such as DEPT, COSY, TOCSY, NOESY, gs-HSQC, gs-HMBC, H2BC and 1,1-ADEQUATE.The infrared spectra were recorded on a Bruker Vertex v70 FTIR spectrometer equipped with a diamond ATR accessory.
The UV-vis spectra were recorded using 0.1 mM solutions of the compounds in THF on a Shimadzu 2600 UV/Vis spectrometer.The fluorescence spectra were recorded on a FL920 fluorescence spectrometer from Edinburgh Instruments.The PL quantum yields were measured from dilute solutions by an absolute method using Edinburgh Instruments integrating sphere excited with a Xe lamp.Optical densities of the sample solutions were ensured to be below 0.1 to avoid reabsorption effects.All optical measurements were performed at rt under ambient conditions.HRMS spectra were recorded with a Bruker maXis or Bruker micrOTOF-QIII spectrometers.

General procedure for the allylation of 1H-pyrazol-3-oles giving 3-[(prop-2-en-1-yl)oxy]-1H-pyrazoles (compounds 2a-c).
The solution of 1a-c (10 mmol) in dry DMF (15 mL) was cooled to 0 °C under inert atmosphere and NaH (60% dispersion in mineral oil, 400 mg, 10 mmol) was added portionwise.After mixing for 15 min at 0 °C, the mixture was gradually warmed up to 40°C temperature and stirred for additional 15 min.Then it was subsequently raised to 60°C and an allyl bromide (12 mmol, 1.0 mL) was added dropwise over the 10 min.The mixture was stirred at 60°C for 8 h, diluted with 60 ml of water and extracted with ethyl acetate.The organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtrated, and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel with hexane/ethylacetate 15:1, v/v.To yield compounds 2a-c.

General procedure for the Wittig olefination of 3-[(prop-2-en-1-yl)oxy]-1H-pyrazole-4-carbaldehydes giving 4-ethenyl-3-[(prop-2-en-1-yl)oxy]-1H-pyrazoles (compounds 4a-c).
To a suspension of methyltriphenylphosphonium iodide (1.83 g, 4.5 mmol) in dry toluene (60 mL) under inert atmosphere, the potassium tertbutoxide (1.01 g, 9 mmol) was added in one portion.The reaction mixture was stirred at room temperature for 30 min and subsequently refluxed for another 30 min.Formation of the ylide can be visibly observed by its persistent yellow color.After refluxing, the reaction mixture was allowed to come to room temperature and kept in an ice bath, followed by dropwise addition of an appropriate aldehyde 3a-c (3 mmol) dissolved in dry toluene (30 mL).Then the reaction was carried out in room temperature for 3-5 hours, and the progress was monitored by TLC.Upon completion, the reaction was quenched by saturated solution of ammonium chloride and the organic layer was extracted with ethyl acetate several times.The organic layers were combined, dried over Na 2 SO 4 , filtrated, and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel with hexane/ethylacetate 15:1, v/v to yield compounds 4a-c.