Reactions with Hydrazonoyl Halides. 31. Synthesis of Some New Pyrrolidino[3,4-c]pyrazolines, Pyrazoles, and Pyrazolo[3,4-d]pyridazines

Abstract

Pyrrolidino[3,4-c]pyrazoline and pyrazole derivatives were synthesized via reactions of a substituted hydrazonoyl bromide with N-arylmaleimides and active methylene reagents, respectively. Synthesized pyrazoles were reacted with hydrazine hydrate to give the corresponding pyrazolo[3,4-d]pyridazines.

Introduction

Hydrazonoyl halides have been widely employed in the synthesis of heterocyclic derivatives [2,3,4,5]. In continuation of our interest in the synthesis of heterocyclic systems containing a pyrazole moiety [6,7,8,9,10], we report herein a facile synthesis of pyrrolidino[3,4-c]pyrazoline, pyrazole, and pyrazolo[3,4-d]pyridazine derivatives.

Results and Discussion

Treatment of the hydrazonoyl bromide 1 [10] with the appropriate N-arylmaleimides 2a-c in benzene containing triethylamine afforded pyrrolidino[3,4-d]pyrazolines 3a-c (cf. Scheme 1). The structures of compounds 3a-c were confirmed by their spectroscopic data. For example, the ¹H NMR spectrum of 3a showed signals at δ = 1.11 (t, 3H, CH₃CH₂); 2.33 (s, 3H, CH₃); 2.41 (s, 3H, CH₃); 4.12 (q, 2H, CH₂CH₃); 5.20 (d, J=7Hz, 1H, pyrazoline H-4); 5.49 (d, J=7Hz, 1H, pyrazoline H-5) and 7.16-7.46 (m, 13H, ArH). The IR spectra of 3a-c were characterized by two widely separated bands in the region 1790-1690 cm^-1 assigned the CO-NAr-CO grouping [11].

Also, the hydrazonoyl bromide 1 was reacted with each of malononitrile, ethyl cyanoacetate, dibenzoylmethane, benzoylacetonitrile, acetoacetanilide, and ω-benzenesulfonylacetophenone in ethanolic sodium ethoxide to give substituted pyrazoles 4a-g (Scheme 1). Structures 4a-g were confirmed on the basis of spectral data. For example, the IR spectrum of compound 4c revealed bands at 1720, 1685, 1660 cm^-1 (CO groups) and its ¹H NMR spectrum showed signals at δ = 1.23 (t, 3H, CH₃CH₂); 2.32 (s, 3H, CH₃); 2.39 (s, 3H, CH₃); 4.24 (q, 2H, CH₂CH₃); 7.19-8.09 (m, 18H, ArH).

Pyrazoles 4a,b and 4d-g were converted to the corresponding pyrazolo[3,4-d]pyridazines 6a,b and 6d-g, respectively, on boiling under reflux with hydrazine hydrate in ethanol. The structure of the prod- ucts could conceivably be formulated as either 5 or 6. Based on analytical analyses and spectral data, structures 5 were ruled out. The formation of the products of type 6 can be explained via elimination of water, to give the hydrazone intermediate 7, which then readily cyclized to product 6 (cf. Scheme 2). Alternatively, the formation of the product can be explained by formation of the hydrazide 8, followed by elimination of water to give pyrazolo[3,4-d]pyridazines 6. All attempts to isolate intermediates 7 and 8 were unsuccessful.

Experimental

General

All melting points were determined on an Electrothermal apparatus and are uncorrected. IR spectra were recorded (KBr discs) on a Shimadzu FT-IR 8201 PC spectrophotometer. ¹H NMR spectra were recorded in CDCl₃ on a Varian Gemini 200 MHz spectrometer and chemical shifts are expressed in δ units using TMS as an internal reference. Elemental analyses were carried out at the Microanalytical Center of the University of Cairo, Giza, Egypt. Hydrazonoyl bromides 1 [10] and N-arylmaleimides 2a-c [12] were prepared as previously reported.

General procedure for the synthesis of 5-aryl-1-(4-chlorophenyl)-3-[3'-ethoxycarbonyl-5'-methyl-1'- (4-tolyl)-4'-pyrazoloyl]pyrrolidino[3,4-c]pyrazoline-4,6-diones (3a-c)

A solution of the substituted hydrazonoyl bromide 1 (2.5 g, 0.005 mmol), the appropriate N-arylmaleimides 2a-c (0.005 mol) and triethylamine (0.7 mL, 0.005 mol) in dry benzene (20 mL) was refluxed for 3 h. The solvent was removed under vacuum and the residue triturated with petroleum ether (b.p. 40/60°C, 10 mL). The resulting solid was collected, washed and crystallized from acetic acid or ethanol to give 3a-c (cf.

Table 1. Analytical data of the newly synthesized compounds.

Compd no.	Color	Yield %	M.P., °C Solvent	Mol.Formula Mol.Wt.	% Analyses, Calcd. /Found
					C	H	N	S
3a	Yellowish	77	250-253	C32H26ClN5O5	64.48	4.40	11.75
	green		EtOH	596.05	64.70	4.30	11.60
3b	Yellowish	78	228-230	C33H28ClN5O5	64.97	4.63	11.48
	green		EtOH	610.07	65.10	4.50	11.30
3c	Yellowish	82	285-287	C33H28ClN5O6	63.31	4.51	11.19
	green		AcOH	626.07	63.10	4.50	11.00
4a	Yellow	85	208-10	C25H21ClN6O3	61.41	4.33	17.19
			EtOH	488.94	61.22	4.20	17.30
4b	Colorless	80	243-245	C27H26ClN5O5	60.50	4.89	13.07
			EtOH	535.99	60.60	4.90	12.90
4c	Yellow	92	197-200	C37H29ClN4O4	70.64	4.65	8.91
			EtOH	629.12	70.60	4.40	8.80
4d	Yellow	76	185-187	C31H24ClN5O3	67.70	4.40	12.73
			EtOH	550.02	67.90	4.30	12.80
4e	Yellow	69	175-178	C32H28ClN5O4	66.03	4.85	12.03
			EtOH	582.06	66.10	5.00	11.90
4f	Yellow	82	127-130	C36H29ClN4O5S	65.01	4.39	8.42	4.82
			EtOH	665.17	65.20	4.10	8.20	4.90
4g	Brown	78	140-143	C44H39ClN6O7S	63.57	4.73	10.11	3.86
			EtOH	831.35	63.40	4.73	10.20	3.70
6a	Orange	72	200-203	C23H17ClN8O	60.46	3.75	24.52
			EtOH	456.90	60.20	3.90	24.70
6b	Yellow	62	227-230	C22H22ClN7O3	59.58	4.40	19.46
			EtOH	503.95	59.50	4.40	19.60
6d	Colourless	70	310-12	C29H20ClN7O	67.25	3.89	18.93
			EtOH	517.98	67.30	4.10	18.80
6e	Colourless	66	307-10	C30H24ClN7O2	65.51	4.40	17.83
			EtOH	550.02	65.50	4.50	17.90
6f	Yellow	73	197-200	C34H25ClN6O3S	64.50	3.98	13.27	5.60
			EtOH	633.13	64.40	4.20	13.40	5.40
6g	Yellow	78	320-22	C42H35ClN8O5S	63.11	4.41	14.02	4.44
			EtOH	799.31	63.30	4.20	14.20	4.30

).

General procedure for the synthesis of 4,5-disubstituted 1-(4-chlorophenyl)- 3-[3'-ethoxy-carbonyl-5'- methyl-1'-(4-tolyl)-4'-pyrazoloyl]pyrazoles (4a-g)

The appropriate active methylene compound (malononitrile, ethyl cyanoacetate dibenzoylmethane, benzoylacetonitrile, acetoacetanilide, ω-benzenesulfonylacetophenone, or ketosulfone. (0.005 mol) was added to an ethanolic sodium ethoxide solution [prepared from sodium metal (0.11 g-atom) in absolute ethanol (20 mL)]. After stirring for 10 minutes, the hydrazonoyl bromide 1 (2.5 g, 0.005 mol) was added and stirring was continued for an additional 30 minutes. The reaction mixture was left overnight at room temperature and the precipitated product was collected by filtration. The solid was washed with water and recrystallized from ethanol to give the corresponding pyrazoles 4a-g, respectively (cf. Table 1).

General procedure for the synthesis of 4,5-disubstituted 4-[1-(4-chlorophenyl)-3-pyrazolyl]-2,6- dihydro-3-methyl-2-(4-tolyl)-pyrazolo[3,4-d]pyridazin-7-ones (6a,b,d-g)

The appropriate pyrazoles (4a,b and 4d-g) (0.005 mol) in a mixture of ethanol (20 mL) and hydrazine hydrate (0.75 mL, 0.015 mol) were refluxed for 4h, during which time the pyrazole dissolved and the corresponding pyrazolo[3,4-d]pyridazine precipitated. The latter was collected, washed with water and recrystallized from ethanol or dimethylformamide to give 6a,b,d-g (cf. Table 1).