Non-Classical Transformation of Benzendiazonium Hydrogen Sulfates. Access to 1,3-Dimethylisochromeno[4,3-c]pyrazol-5(1H)-one, a Potential Benzodiazepine Receptor Ligand

The compound 2-((1,3-dimethyl-1H-pyrazol-5-yl)(methyl)carbamoyl)benzene-diazonium hydrogen sulfate (10) was reacted with copper sulfate and sodium chloride, in the presence of ascorbic acid as reducing agent, to afford a mixture of the chlorinated epimers 4′-chloro-2,2′,5′-trimethyl-2′,4′-dihydrospiro[isoindoline-1,3′-pyrazol]-3-one (18) and (19), the epimers 4′-hydroxy-2,2′,5′-trimethyl-2′,4′-dihydrospiro[isoindoline-1,3′-pyrazol]-3-one (20) and (21), and N-(1,3-dimethyl-1H-pyrazol-5-yl)benzamide (22). Under the foregoing conditions, diazonium salt 10 affords neither the 2-chloro-N-(1,3-dimethyl-1H-pyrazol-5-yl)-N-methylbenzamide (23) nor the tricyclic derivative 24, the classical products of the Sandmeyer and Pschorr reactions, respectively. Finally, by heating 20 at 210 °C the compound 1,3-dimethylisochromeno[4,3-c]pyrazol-5(1H)-one (24) was obtained. The transformation under the above conditions of 2-((4-chloro-3-methyl-1-phenyl-1H-pyrazol-5-yl)(methyl)carbamoyl)benzendiazonium hydrogen sulphate (11) afforded 4′,4′-dichloro-2,5′-dimethyl-2′-phenyl-2′,4′-dihydrospiro[isoindoline-1,3′-pyrazol]-3-one (29) as the sole reaction product.


Introduction
Previously we reported the transformation of diazonium hydrogen sulphate 2 derived from 2-amino-N-methyl-N-(3-methyl-1-phenyl-1H-pyrazol-5-yl)benzamide (1).This reaction was carried out with CuSO 4 and NaCl, in the presence of ascorbic acid as a reducing agent [1] (Scheme 1).The above mixture was used earlier by Hanson and co-workers [2] to perform the Sandmeyer reaction on 4-chlorobenzendiazonium chloride in a homogeneous aqueous phase.Ascorbic acid reduces Cu(II) to Cu(I) which, in turn, reduces the diazonium ion to a diazenyl radical.The latter intermediate decomposes to dinitrogen and the phenyl radical.Copper(II) ions form complexes with chloride ions which are able to transfer a chloro radical to the 4-chlorophenyl by a ligand transfer process to afford 1,4-dichlorobenzene [2].The diazonium hydrogen sulfate 2 afforded neither the chloro derivative 3, the product of the classical Sandmeyer reaction, nor the tricyclic derivative 9, the expected product of the competitive Pschorr ring closure, and instead we obtained epimers 7 and 8 [1].Scheme 1. Transformation of the diazonium salt 2 by reaction with CuSO 4 /NaCl/ascorbic acid.Recently a re-investigation of the transformation reaction of diazonium salt 2 in the presence of CuSO 4 /NaCl/ascorbic acid has allowed to establish that a demethylation process also takes place to give N-(3-methyl-1-phenyl-1H-pyrazol-5-yl)benzamide 4 (for the mechanism see Scheme 5, below).Moreover, trace amounts of the hydroxy spiro derivatives 5 and 6 [1] were detected by TLC analysis.In our continuing research on this reaction [1,[3][4][5], we became interested in investigating the behaviour of substrates possessing an alkyl group, such as methyl, in lieu of the pyrazole N-phenyl, as well as a substituent at the 4-position of the pyrazole nucleus, in order to verify whether such modifications are able to influence the course of the reaction.In fact, phenyl and methyl groups exert different electronic as well as steric effects on the pyrazole ring.Moreover, electronic and steric effects engendered by the substituent at the 4-position of the pyrazole nucleus could also affect the reaction outcome.Here, we describe the CuSO 4 /ascorbic acid-catalyzed decomposition in the presence of NaCl of the diazonium hydrogen sulfates 10 and 11 (Figure 1).These intermediates bear a methyl group or a chloro atom on the pyrazole nucleus, at positions 1 or 4, respectively.

Results and Discussion
Benzendiazonium hydrogen sulfates derivatives 10 and 11 were prepared following Schemes 2 and 3. Scheme 2. Preparation of the amino derivative 17 and its transformation.The amine 12 was reacted with acetic anhydride to give the acetamide derivative 13 which, in turn, was methylated with methyl iodide (Scheme 2).The obtained di-substituted acetamide derivative 14 was hydrolyzed with a potassium hydroxide ethanol-water solution to give the pyrazol-5-amine 15.
The preparation of substrate 11 started with the reaction of the 2-nitrobenzamide derivative 25 with a seven-fold excess of nitrous acid in acetic acid, resulting in the direct introduction of a diazo group at the 4-position of the pyrazole nucleus [6,7] (Scheme 3).The transformation in situ of the diazonium salt 26 into the chloro derivative 27 was performed with CuSO 4 , NaCl and ascorbic acid [1,2].Compound 27 was then reduced with iron in acetic acid, and the aniline derivative 28 thus obtained was diazotized to furnish 11.
The reaction of this diazonium salt under the same conditions employed earlier for 2 and 10 afforded the dichloro spiro derivative 29, as the sole product of reaction (Scheme 3).Compound 29 was then converted into dione derivative 31, possibly via intermediate 30, upon refluxing in water.The new compounds were characterized by means of analytical and spectral data.The relative configuration of the pyrazoline C(4′)-atom of the spiro-compounds 18-21 were not determined.The work up of the reaction mixture obtained by transformation of 10 did not allow us to isolate the epimers 18 and 19.The 1 H-NMR spectrum of the obtained mixture showed singlets at 2.05, 2.07, 2.37, 2.44, 2.79 and 2.81 ppm, as well as at 5.54 and 5.83 ppm (ratio 1:2.25), consistent with the methyls and the pyrazoline H-4 of both epimers.On the contrary, epimers 20 and 21 were obtained as single compounds.The 1 H-NMR spectrum of 20 showed three singlets at 1.94, 2.34 and 2.78 ppm, attributable to three methyls, and two doublets centered at 5.11 and 6.12 ppm for the pyrazoline H-4 and OH-4, respectively.Upon D 2 O exchange the OH signal in the the spectrum disappeared, and the H-4 doublet collapsed to a singlet.The IR spectrum confirmed the presence of the pyrazoline hydroxyl by the absorption band at 3,263 cm −1 .The epimer 21 produced very similar IR and 1 H-NMR spectra.The analogous compounds 22 and 4 were identified by comparison of their physical and spectroscopic data with authentic specimens (see the Experimental Section).
As regards 29, the 1 H-NMR spectrum showed signals at 2.38 and 2.66 ppm for two methyls, as well as those in the range 6.70-7.96ppm for nine aromatic protons.The assigned structure of compound 29 was confirmed by its 13 C-NMR spectrum and by its chemical modification.In fact, the action of water on compound 29 afforded a product which was identical in all respects (mixed melting point, TLC, MS, IR) to dione derivative 31 [1].
Rationalization of the formation of 18, 19, 20, 21 and 4, 22 is outlined in the Schemes 4 and 5. Formation of the chloro epimers 18 and 19 from 10 takes place via the intermediates 33 and 34 (Scheme 4).The latter transforms to 18 and 19 by a chloro transfer process from copper(II)-chloro complexes [1,2].As regards the hydroxy spiro epimers 20 and 21, they might be afforded by two different mechanisms: by transfer of H 2 O + from the hydratation shell of the aqueous copper(II)-complex [8] to radical spiro intermediate 34, or by nucleophilic replacement of the chloro atom in 18 and 19 by attack of a molecule of water.We noted that the chloro epimers 7, 8 (Scheme 1) and 18, 19 (Scheme 2) were obtained as precipitates from the solutions of diazonium salts 2 and 10 respectively, being the yield for 7, 8 [1] quite higher than that of 18, 19 (45% versus 8%).Moreover, extraction of the mother liquors of the above reaction mixtures of 2 and 10 allowed us to obtain hydroxy spiro epimers only in the case of 10 (that is 20 and 21, yield 7%). Instead, only trace amounts of the hydroxy spiro epimers 5, 6 could be detected by TLC in the crude mixture of 7, 8.We also observed that the mixture of 18 and 19 could be transformed in 20 and 21 when it was reacted with cold (5 °C) 0.09 M sulfuric acid solution, where 18, 19 slowly dissolved, allowing the mixture to stand at r.t. for 1 h, mimicking thus the pH conditions of the reaction medium in which 10 transformed.When the same experiment was performed with the mixture of 7 and 8 no dissolution of the epimers in the acidic medium was observed.The suspension was extracted with ethyl acetate, and TLC of the extract did not reveal any transformation to give 5 and 6.At this point we realized that the low yield for 18, 19 is due to their solubility in the reaction medium, where they undergo a nucleophilic substitution by attack of a molecule of water to afford the hydroxy spiro epimers 20 and 21.Nevertheless, a radical transfer process of H 2 O + to the spiro intermediate 34 to give 20, 21 can't be ruled out (Scheme 4).Considering all the above data we concluded that the apparent different chemical behaviour between diazonium salts 2 and 10 is due to different solubilities of phenyl-and methyl-substituted chloro epimers, rather than to any electronic and steric effects of the N-phenyl-or N-methyl-pyrazole substituents.
As regards the transformation of the diazonium salt 11, performed under the identical conditions followed for the chemical analogues 10 and 2, the production of the dichloro spiro compound 29 was observed, which demonstrates that substitution at the 4-position of the pyrazoline nucleus does not hinder the ligand radical transfer process from the copper(II)-chloro complex to radical species 38 (Scheme 6).The spiro compound 20 proved to be a useful intermediate since it was transformed by heating at 210 °C into 1,3-dimethylisochromeno[4,3-c]pyrazol-5(1H)-one (39) (Scheme 7).The latter compound has the potential as a benzodiazepine receptor ligand.In fact, this compound shows two hydrogen bond acceptor atoms at the distance of about 3.5 Å, that is the isochromene oxygen and the nitrogen at position 2 of the pyrazole nucleus, which are mandatory in the molecule for a good affinity at the benzodiazepine binding site [10].

General
Reaction progress was monitored by TLC on silica gel plates (Merck 60, F 254 , 0.2 mm).Organic solutions were dried over Na 2 SO 4 .Evaporation refers to the removal of solvent on a rotary evaporator under reduced pressure.All melting points were determined on a Büchi 530 capillary melting point apparatus and are uncorrected.IR spectra were recorded with a Perkin Elmer Spectrum RXI FT-IR System spectrophotometer as solid in KBr disc. 1 H-NMR and 13 C-NMR spectra were obtained in CDCl 3 or DMSO-d6 at 300.13 and 75.47 MHz respectively, using a Bruker AC series 300 MHz spectrometer (tetramethylsilane as an internal standard): chemical shifts are expressed in ppm values.Mass spectra at 70 eV were obtained using an Autospec Ultima Ortogonal T.O.F.T. (Micromass) spectrometer.Merck silica gel (Kiesegel 60/230-400 mesh) was used for flash chromatography columns.Microanalyses data (C, H, N) were obtained by an Elemental Vario EL.III apparatus and are within ±0.4% of the theoretical values.Yields refer to products after one crystallization.The names of the compounds were obtained using the Chem Draw 9.0.1 software of Cambridge Soft (Cambridge MA, USA).(13) This compound was prepared following a literature method [11] modified by us: 1,3-dimethyl-1Hpyrazol-5-amine (12, 11.4 g, 0.102 mol) was reacted under stirring at r.t. with acetic anhydride (45 mL) for 24 h.After this time the solution was evaporated to give an oily residue which solidified when treated with triturated ice (20 g) and scraped.After filtration the material was air dried and crystallized from ethyl acetate/petroleum ether (b.p. 40-70 °C) to give 13 in 70% yield; mp: 43-45 °C; IR (KBr, cm −1 ): 3,123 (broad, NH), 1,667 (CO); 1

Preparation of N-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)benzamide (4)
From the transformation of the diazonium salt 2 by the CuSO 4 /NaCl/ascorbic acid reagent combination: the diazonium hydrogen sulfate 2 derived from compound 1 [1] (5.9 mmol) was decomposed following the procedure used for 10.The suspension obtained was filtered, and the solid was crystallized from ethanol (95% V/V) to give epimers 7, 8.The mother liquors when evaporated leave a residue (350 mg) which was processed by preparative TLC (two plates, 20 × 20 cm, thickness 2 mm, ethyl acetate/petroleum ether 3:7 as eluent).Work up allowed us to obtain a product (140 mg) which was identical in all respects (mp, mixed mp, IR, 1 H-NMR) to an authentic specimen of compound 4 [7].The aqueous mother liquors were saturated with sodium chloride and extracted with ethyl acetate (4 × 150 mL).The combined extracts were evaporated to give a residue (70 mg) which was processed by preparative TLC.More of compound 4 (20 mg) was obtained following the above procedure, overall yield 10%.

Preparation of N-(4-Chloro-3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-methyl-2-nitrobenzamide (27)
This compound was prepared by modifying the procedure reported in reference [14].Compound 25 [15] (2 g, 5.95 mmol) was dissolved in acetic acid (57 mL) and then concentrated hydrochloric acid (36.5% w/w, 4.3 mL) was added.To the stirred solution a potassium nitrite aqueous solution (3.5 g of KNO 2 in 1.8 mL of H 2 O) was added dropwise and stirring was continued for a further 24 h.The obtained suspension was filtered and the filtrate was treated first with an aqueous solution (300 mL) of hydrochloric acid (0.24 M), copper sulphate pentahydrate (0.3 M) and sodium chloride (0.75 M) and then with ascorbic acid (260 mg, 1.48 mmol).The mixture was stirred for 1 h at r.t. and then filtered.The solid product obtained was crystallized from ethanol (95% V/V) to give 27 (yield 60%) identical in all respects (mixed melting point, TLC, MS, IR) to an authentic specimen of compound 27 [14].

Conclusions
The diazonium salts 2 and 10 show as unique structural diversity the different substituent at the 1-position of the pyrazole nucleus, that is phenyl or methyl.The above diversity does not lead to a different chemical reactivity of these diazonium salts when they are reacted with the reagents copper sulphate/ascorbic acid/sodium chloride.In fact, the observed difference in the composition of the reaction mixtures of 10 and 2 is not due to different electronic and/or steric effects of the pyrazole substituents at 1-position, but rather to a remarkable differential solubility between the pairs of epimers 18, 19 and 7, 8. Epimers 18, 19 partially dissolve in the reaction mixture and undergo nucleophilic replacement of the chloro atom to give the hydroxy spiro derivatives 20, 21, whereas epimers 7, 8 do not follow this pathway.As regards diazonium salt 11, the presence of a substituent at the 4-position of the pyrazole moiety does not hinder this position, and a dichloro spiro derivative 29 is obtained.

Scheme 3 .X
Scheme 3. Preparation of the amino derivative 28 and its transformation.