5-Dimethylamino-1-phenylchromeno[2,3-c]pyrazol-4(1H)-one

Abstract

The title compound was prepared by treatment of 5-fluoro-1-phenylchromeno[2,3-c]pyrazol-4(1H)-one with aqueous dimethylamine. Detailed spectroscopic data (¹H NMR, ¹³C NMR, ¹⁵N NMR, IR, MS) are presented.

In the course of a program devoted to the synthesis of new heterocyclic scaffolds we recently presented the synthesis of various heterocyclic xanthone analogues of type A containing a [5,6]pyrano[2,3-c]pyrazol-4(1H)-one substructure (Figure 1) [1,2,3,4,5,6,7]. In these compounds, one benzene ring of the parent xanthone is replaced by a pyrazole system and the other one by a variable heteroaromatic moiety or by a (substituted) benzene ring.

Due to the importance of fluorinated compounds in medicinal chemistry [8,9,10,11,12] we also synthesized appropriate congeners B carrying fluoro substituents at different positions of a chromeno[2,3-c]pyrazol-4(1H)-one scaffold, for instance at positions 5, 6, 7 and 8 (Figure 1) [13]. During the synthesis of 5-fluoro-1-phenylchromeno[2,3-c]pyrazol-4(1H)-one (3, Scheme 1) we observed an interesting phenomenon. The preparation of 3 was accomplished by cyclization of intermediate 2, which was obtained upon reaction of 1-phenyl-2-pyrazolin-5-one (1) with 2,6-difluorobenzoyl chloride under the conditions described by Jensen for the C-4 acylation of pyrazolones (calcium hydroxide, dioxane, reflux) [14]. When the cyclization of 2 (NaH/DMF) was carried out under forced conditions and prolonged heating, besides the desired fluoro compound 3 also the corresponding dimethylamino congener 4 was obtained in increasing extent (Scheme 1). This finding can be accounted to the known decomposition of DMF (N,N-dimethylformamide) at its boiling temperature, leading to the liberation of dimethylamine [15]. This process can also occur at lower temperatures when catalyzed by basic or acidic materials [15]. This special property of DMF has been actually utilized for N,N-dimethylaminations of reactive aryl or benzyl halides with DMF, either in the presence or absence of catalysts [16]. Also the conversion of active haloheteroarenes into the corresponding N,N-dimethylamino compounds has been described in this way, as an example the synthesis of 6-chloro-3-(dimethylamino)pyridazine from 3,6-dichloropyridazine (95% yield) via 48 hours reflux in DMF solution may serve [16].

For comparison purposes, we prepared amine 4 in an alternative way, i.e. by reaction of 3 with excess aqueous dimethylamine. The latter procedure is definitely advantageous compared to the above mentioned one, as here the title compound is smoothly obtained under mild conditions without any by-products, thus superseding a chromatographic separation (Scheme 1).

A detailed characterization of compound 4 including IR, MS and NMR (¹H, ¹³C, ¹⁵N) spectral data as well as microanalytical data is given in the Experimental. Full and unambiguous assignment of all ¹H, ¹³C and ¹⁵N NMR resonances was achieved by combined application of standard NMR spectroscopic techniques such as ¹H-coupled ¹³C-NMR (gated decoupling), APT, COSY, NOESY, gs-HSQC and gs-HMBC [17].

Experimental

The melting point was determined on a Kofler hot-stage microscope and is uncorrected. The mass spectrum was obtained on a Shimadzu QP 1000 instrument (EI, 70 eV), the IR spectrum on a Perkin-Elmer FTIR 1605 spectrophotometer (KBr-disc). The elemental analysis was performed at the Microanalytical Laboratory, University of Vienna. All NMR spectra were recorded from CDCl₃ solutions on a Bruker Avance 500 instrument with a ‘directly’ detecting broadband observe probe (BBFO) at 298 K (500.13 MHz for ¹H, 125.76 MHz for ¹³C, 50.68 MHz for ¹⁵N). The centre of the solvent signal was used as an internal standard which was related to TMS with δ = 7.26 ppm (¹H in CDCl₃) and δ = 77.0 ppm (¹³C in CDCl₃). The digital resolutions were 0.2 Hz/data point in the ¹H and 0.4 Hz/data point in the ¹H-coupled ¹³C-NMR spectra (gated decoupling). The ¹⁵N NMR spectrum (gradient-selected ¹⁵N,¹H-HMBC) was referenced against external nitromethane.

5-Dimethylamino-1-phenylchromeno[2,3-c]pyrazol-4(1H)-one (4)

In a reaction flask closed with a balloon, to a solution of 5-fluoro-1-phenylchromeno[2,3-c]pyrazol-4(1H)-one (3) (28 mg, 0.1 mmol) in 1,4-dioxane (4 mL) was portionwise added an aqueous solution (40%) of dimethylamine (400 μL) via syringe. Then the mixture was stirred at room temperature for 3 hours. Evaporation of the solvents under reduced pressure produced a light-colored residue which was washed with water and dried to afford 23 mg (75%) of chromatographically pure 4. For analytical purposes the material was recrystallized from EtOH to give 19 mg (62%) of 4 as yellowish crystals with mp 184–186 °C.

IR (KBr) ν (cm⁻¹): 1651 (C=O).

MS (EI, 70 eV): (m/z, %) 305 (M⁺, 32), 291 (20), 290 (100), 276 (52), 121 (15), 77 (31) 51 (28).

¹H NMR (CDCl₃): δ (ppm) 2.98 (s, 6H, NMe₂), 6.90 (dd, 1H, H-6, ³J(H6,H7) = 8.3 Hz, ⁴J(H6,H8) = 1.0 Hz), 6.96 (dd, 1H, H-8, ³J(H8,H7) = 8.2 Hz, ⁴J(H8,H6) = 1.0 Hz), 7.40 (m, 1H, Ph H-4), 7.47 (dd, 1H, H-7, ³J(H7,H6) = 8.3 Hz, ³J(H7,H8) = 8.2 Hz), 7.55 (m, 2H, Ph H-3,5), 7.90 (m, 2H, Ph H-2,6), 8.18 (s, 1H, H-3).

¹³C NMR (CDCl₃): δ (ppm) 44.8 (NMe₂, ¹J = 136.3 Hz, ³J = 4.1 Hz), 107.7 (C-3a, ³J(C3a,H3) = 9.8 Hz), 108.1 (C-8), 112.9 (C-6), 113.4 (C-4a), 121.0 (Ph C-2,6), 127.4 (Ph C-4), 129.4 (Ph C-3,5), 133.0 (C-7, ¹J = 160.9 Hz), 136.8 (C-3, ¹J = 193.6 Hz), 137.3 (Ph C-1), 151.6 (C-9a, ³J(C9a,H3) = 4.8 Hz), 154.4 (C-5), 157.9 (C-8a), 172.6 (C-4).

¹⁵N NMR (CDCl₃): δ (ppm) –325.5 (NMe), –188.8 (N-1), –91.7 (N-2).

Anal. Calcd for C₁₈H₁₅N₃O₂: C, 70.81%; H, 4.95%; N, 13.76%. Found: C, 70.47%; H, 4.73%; N 13.54%.