Acid-Catalyzed [3+2] Cycloaddition of Enones with Azomethine Imines for Easy Access to Tetrahydropyrazolopyrazolones

Abstract

Aluminum chloride (AlCl₃) or zirconium chloride (ZrCl₄) catalyzes efficiently the [3+2] cycloaddition of N,N′-cyclic azomethine imines with enones which contain the vinyl group. The scope of the reaction towards various azomethine imines and enones has been explored. Access to diastereomerically pure 6-acyl-5-aryltetrahydropyrazolo[1,2-a]pyrazol-1(5H)-ones is provided by easy chromatographic separations.

Key words

dipolar cycloaddition - N,N′-cyclic azomethine imine - enone - N,N′-bicyclic heterocycles - Lewis acid

Dinitrogenated fused heterocycles are valuable bioactive molecules. For example, tetrahydropyrazolo-pyrazo­lones[1] have been investigated as antibacterials and potential anti-Alzheimer’s agents while some pyrazolo-cinnolines such as the cinnopentazone[2] exhibit anti-inflammatory and antipyretic activity. Furthermore, the considerable attention has been paid to the observation of the analogues of LY186826 which belongs to the group of non-β-lactam antibacterials.[3] One of the simplest routes to these heterocycles is the cycloadditions of the N,N′-cyclic azomethine imines. Although these stable 1,3-dipoles of allylic type were discovered in 1968,[4] their use in the dipolar cycloadditions became more attractive 35 years later when Fu et al. achieved the asymmetric catalysis of the reaction with alkynes.[5] Over the last two decades, the cycloadditions of N,N′-cyclic azomethine imines have been established as a powerful method for the construction of the structurally diverse N,N′-bicyclic heterocycles with the potential biological activities. The current reports distinguish different [3+2] cycloadditions of the 1,3-dipoles with compounds which contain C=C,[6] C≡C,[5] [7] or C=C=C,[8] bonds providing an easy access to the different tetrahydropyrazolo-pyrazo­lones. Moreover, [3+3],[9] [4+3],[8c] [3+2+1],[10] and [3+2+3][8b] cycloadditions of N,N′-cyclic azomethine imines draw increasing attention, since they are proved as the suitable methods for the synthesis of diverse tetrahydropyrazolo-pyridazinones, -diazepinones, and -diazocinones. However, to the best of our knowledge, there has not been reported any example so far where N,N′-cyclic azomethine imines have been treated by enones which contain the vinyl group. Herein, we report the simple route to the 6-acyl-5-aryltetrahydropyrazolo[1,2-a]pyrazol-1(5H)-ones which are prepared using the reaction between N,N′-cyclic azomethine imines and enones.

[3+2] Cycloadditions of azomethine imines are generally catalyzed processes promoted by acid catalysts or organocatalysts,[11] although some reactions are performed without their presence.[12] Therefore, we initially examined the direct reaction between 3-buten-2-one (2a) and benzylidene-5-oxopyrazolidin-2-ium-1-ide (1a) in a dichloromethane at the ambient temperature which gives 32% of 6-acetyl-5-phenyltetrahydropyrazolo[1,2-a]pyrazol-1(5H)-one (3a, Table [1], entry 1). Due to the fact that the preliminary result has not been satisfactory, we decided to involve the catalysis by acids. In doing so, the initial investigations were continued in the presence of AlCl₃.

Table 1 Optimization for the [3+2] Cycloaddition of Azomethine Imine 1a with 3-Buten-2-one (2a)^a

Entry	Solvent	Catalyst	Catalyst loading (mol%)	Yield (%)c	Ratio cis/trans d
1	CH2Cl2	–	–	32	20:80
2	CH2Cl2	AlCl3	5	57	42: 58
3	CH2Cl2	AlCl3	10	85	51:49
4	CH2Cl2	AlCl3	20	94	58:42
5b	CH2Cl2	AlCl3	20	93	57:43
6	CH2Cl2	AlCl3	50	68	77:23
7	CH2Cl2	AlCl3	100	52	85:15
8	CH2Cl2	ZrCl4	20	89	61:39
9	CH2Cl2	FeCl3	20	46	60:40
10	CH2Cl2	HBF4	20	33	57:43
11	CH2Cl2	AcOH	20	94	24:76
12	CH2Cl2	l-tartaric acid	20	68	20:80
13	CH2Cl2	(S)-lactic acid	20	85	54:46
14	CH2Cl2	PTSA	20	49	52:48
15	CHCl3	AlCl3	20	65	77: 23
16	C2H4Cl2	AlCl3	20	88	70:30
17	THF	AlCl3	20	75	67:33
18	1,4-dioxane	AlCl3	20	77	45:55
19	MeCN	AlCl3	20	69	77:23
20	Tol	AlCl3	20	40	61:39
21	MeOH	AlCl3	20	trace	–

^a Unless otherwise indicated, reactions were carried out with 1a (0.6 mmol, 1.2 equiv), 2a (0.5 mmol, 1 equiv), catalyst in solvent (5 mL) for 48 h at r.t.

^b Reaction was carried out in refluxing CH₂Cl₂.

^c Isolated yields.

^d Calculated on the basis of isolated yields.

The utilization of AlCl₃ significantly increased the yield of the cycloaddition product 3a, whereby the catalyst loadings remarkably affected the results. It was found that the optimal loading of AlCl₃ was 20 mol% (Table [1], entry 4), whereas either higher or lower amounts of the catalyst decreased the yield (Table [1], entries 2, 3, 6, and 7). Besides, the catalyst loadings prominently influenced the cis/trans ratio of the product. So, higher loadings of AlCl₃ afforded the mixtures enriched by cis isomer (Table [1], entries 6 and 7), whereas a lower amount of this catalyst favored the formation of the trans isomer (Table [1], entry 2). Interestingly, the increase of the reaction temperature had no significant effect on the yield and cis/trans ratio (Table [1], entry 5). However, it was observed that the cis/trans ratio of the products depended on the used catalyst.

Seven more acidic catalysts were screened (Table [1], entries 8–14). The results show that Lewis acids favored a formation of the cis isomer (Table [1], entries 4, 8, 9). On the other hand, the influence of the applied Brønsted acids depended on a case-by-case basis (Table [1], entries 10–14). Evidently, the best results were achieved with AlCl₃ and ZrCl₄ (20 mol%, Table [1], entries 4 and 8), thus these two catalysts were the indispensable elements of the later investigations.

Furthermore, the effects of the seven solvents were studied in the presence of 20 mol% of AlCl₃ (Table [1], entries 15–21). After 48 hours, the use of the protic solvent such as methanol resulted in the formation of 3a in trace amounts (Table [1], entry 21). Moreover, the other examined solvents (Table [1], entries 15–19) except the toluene (Table [1], entry 20) were equally efficient for this reaction and produced 3a in good yields (65–88%).

The scope of the reaction was explored using the set of enones with the vinyl group (2a–g) and azomethine imines (1a–c) under optimized reaction conditions: AlCl₃ or ZrCl₄ as the catalyst with a loading of 20 mol%, dichloromethane as the solvent, and 20% excess of N,N′-cyclic azomethine imines 1a–c.[13] [14] Although the acetic acid caused highly efficient results in the preliminary investigations (reaction between 1a and 2a), its catalytic effect in the next few examples was rather poor. Since the goal of the study was to develop a widely useful methodology under mild conditions, further examinations with this catalyst were not performed.

However, the seven enones 2a–g and the three different azomethine imines 1a–c were examined in 1,3-dipolar cy­cloadditions catalyzed by AlCl₃ or ZrCl₄ (Scheme [1]). Products, 3a–u, were obtained in moderate to very high yields of 50–98%, and the results evidently showed that the catalysis by ZrCl₄ had a minor advantage in comparison to the AlCl₃-catalyzed procedure. Although both catalytic reactions (with ZrCl₄ or AlCl₃) proceeded smoothly under the mild conditions, we observed that the AlCl₃-catalyzed processes always afforded 5% or more of the aryl-aldehyde formed by the degradation of the appropriate azomethine imine 1a–c. To determine which catalyst had the weaker influence on this degradation, we were stirring the mixtures of azomethine imine 1a/AlCl₃ and 1a/ZrCl₄ in dichloromethane for two days. The analyses of the NMR spectra of the mixture that was stirred for two days showed that the first one (1a/AlCl₃) contained 20% of the benzaldehyde, while the traces of it were detected in the mixture 1a/ZrCl₄.

Scheme 1 Substrate scope of Lewis acid catalyzed [3+2] cycloaddition of azomethine imines 1 with enones 2. Reactions were carried out with 1 (0.6 mmol, 1.2 equiv), 2 (0.5 mmol, 1 equiv), catalyst (0.1 mmol, 0.2 equiv) in CH₂Cl₂ (5 mL) for 48 h. ^a Isolated yields, catalyzed by AlCl₃. ^b Isolated yields, catalyzed by ZrCl₄. ^c cis/trans ratio calculated on the basis of isolated yields. * Isolated yield of trans diastereoisomer (cis diastereoisomer was not isolated pure).

In general, the catalysis of the cycloaddition with 20 mol% of a Lewis acid (ZrCl₄ or AlCl₃) provided the products 3a–u as mixtures of the corresponding diastereoisomers in which the trans isomers in most cases were major products. Yet, to our delight, these mixtures were easily separable by the column chromatography which enabled an easy access to the stable, diastereomerically pure 6-acyl-5-aryltetrahydropyrazolo[1,2-α]pyrazol-1(5H)-ones (cis- and trans- 3a–u).

One of them (cis-3a) was quite suitable for the crystallographic examinations, and the results helped us to determine the relative configurations of all cycloadducts by the analysis of the ¹H NMR spectra of diastereoisomers. The molecular structure of the compound cis-3a (Figure [1]) was determined by a single-crystal X-ray analysis.[15] The results clearly confirmed that both nitrogen atoms are sp³-hybridized with the tetrahedral geometry of corresponding bonds (the sum of bond angles around the N1 and N2 atoms is 341° and 319°, respectively).[16] Both five-membered rings adopt an envelope conformation since that the N1–C1–C2–C3 and N1–C7–C6–C5 fragments are practically planar (the N1–C1–C2–C3 and N1–C7–C6–C5 torsion angles are –1.6(2)° and 4.3(2)°, respectively) while the N2 atom is significantly displaced from these planes [0.394(3) Å and –0.613(3) Å]. From observing bond lengths it is obvious that all bonds within two rings are single bonds whilst the C5–C6 bond [1.564(3) Å] represents the longest bond in the whole molecule.

Figure 1 Molecular structure of the compound cis-3a with 40% probability displacement ellipsoids and the atom-numbering scheme

We also noticed that the pyrazolidinone ring has moved away from the magnetic influence of the aromatic ring. The signal in the ¹H NMR spectrum which originated from the protons at C-2 is relatively simple (pseudo triplet) and appears at δ = 2.71 ppm (Figure [2]). On the other hand, the shape of ¹H NMR signal for the analogous methylene group in the spectrum of trans-3a is a complex multiplet at δ = 2.68 ppm, which indicates substantially shielding of protons at C-2 by the electron-rich aromatic ring (Figure [2], dashed line). This significant difference between the NMR data for the two diastereoisomers occurs in spectra of each cis/trans pair of products 3a–u and it was used for the structural identification of all diastereoisomers.

In respect of the stereochemical outcome of the reactions, we do not have firm explanations for it. Generally speaking, the use of Lewis acid vs. protic acid can affect the stereoselectivity changes, but in all cases we obtained both diastereoisomers.

Figure 2 Models of cis-3a and trans-3a (drawn on the basis of the X-ray crystal structure analysis of cis-3a) with corresponding ¹H NMR signals for protons at C-2

Taking this into consideration, the four possible models for the intermediates were proposed (Figure [3]). This can be illustrated by the synthesis of 3a. Thus, N,N′-cyclic azomethine imine 1a can adopt the Z- or E-planar conformation whereupon the 2a approached it forming corresponding exo- (II and III) and endo-transition-state assemblies (I and IV). The transition states II and IV afforded the cis diastereoisomer while the trans-3a was obtained via the transition states I and III. Still, the real mechanism of these reactions will be investigated in the future.

Figure 3 Possible reaction models in the synthesis of 3a

In conclusion, enones with the vinyl group have been for the first time employed in the reaction with azomethine imines providing simple access to 6-acyl-5-aryltetrahydropyrazolo[1,2-a]pyrazol-1(5H)-ones in a moderate to excellent chemical yield (up to 98%). Products were easily separable which simplified isolation of the pure diastereoisomers. Eventually, they could be of interest for the bioactivity studies. Experimentally the procedure was quite a simple one carried with the inexpensive, commercially available catalysts.

Acknowledgment

We thank the Ministry of Education, Science and Technological Development of the Republic of Serbia for financial support (Grant 172034).

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• 13 General Procedure for [3+2] Cycloaddition of N,N′-Cyclic Azomethine Imines 1 and Enones 2 In a 25 mL flask, enone 2 (0.5 mmol) was added to a stirred mixture of N,N′-cyclic azomethine imine 1 (0.6 mmol) and catalyst (AlCl₃ or ZrCl₄, 0.1 mmol) in CH₂Cl₂ (5.0 mL) at r.t. The mixture was stirred for 48 h. The solvent was then removed by distillation, and the crude mixture was separated by silica gel chromatography (hexane–EtOAc = 5:5 to 4:6). Fractions were collected and concentrated in vacuo to provide the pure products 3.
• 14 Selected Data for Products trans-3a 39% yield for AlCl₃-catalyzed reaction (35%yield for ZrCl₄-catalyzed reaction), pale yellow solid; mp 90 °C. ¹H NMR (200 MHz, CDCl₃): δ = 7.50–7.27 (m, 5 H, Ph), 4.13–3.92 (m, 1 H, H-6), 3.74–3.51 (m, 3 H, H-5, H-7a, and H-7b), 3.41 (ddd, J = 11.5, 9.4, 7.6 Hz, 1 H, H-3b), 2.99 (ddd, J = 11.5, 9.0, 6.6 Hz, 1 H, H-3a), 2.84–2.48 (m, 2 H, H-2a, and H-2b), 1.99 (s, 3 H, Me). ¹³C NMR (50 MHz, CDCl₃): δ = 204.1 (CO), 172.9 (C-1), 136.5 (Ph), 128.5 (Ph), 128.2 (Ph), 127.5 (Ph), 70.5 (C-5), 61.7 (C-6), 45.3 (C-3), 42.7 (C-7), 30.7 (C-2), 29.8 (Me). IR (KBr): 3030, 2952, 1713, 1455, 1361, 1169, 750, 703 cm^–1. Anal. Calcd for C₁₄H₁₆N₂O₂ (244.29): C, 68.83; H, 6.60. Found: C, 68.79; H, 6.62. cis-3a 55% yield for AlCl₃-catalyzed reaction (54% yield for ZrCl₄-catalyzed reaction), white solid; mp 160 °C. ¹H NMR (200 MHz, CDCl₃): δ = 7.53–7.26 (m, 5 H, Ph), 4.04–3.71 (m, 4 H, H-5, H-6, H-7a, and H-7b), 3.54 (pseudo dt, J = 11.1, 8.2 Hz, 1 H, H-3b), 2.91 (ddd, J = 11.1, 9.5, 6.9 Hz, H-3a), 2.71 (pseudo t, J = 8.2 Hz, 2 H, H-2a, and H-2b), 1.52 (s, 3 H, Me). ¹³C NMR (50 MHz, CDCl₃): δ = 205.4 (CO), 172.3 (C-1), 134.0 (Ph), 128.8 (Ph), 128.6 (Ph), 127.8 (Ph), 71.1 (C-5), 58.0 (C-6), 46.0 (C-3), 42.0 (C-7), 31.6 (C-2), 30.6 (Me). IR (KBr): 3062, 2966, 1709, 1699, 1458, 1357, 1175, 1090, 776, 712 cm^–1. Anal. Calcd for C₁₄H₁₆N₂O₂ (244.29): C, 68.83; H, 6.60. Found: C, 68.80; H, 6.63.
• 15 CCDC 1497416 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge via www.ccdc.cam.ac.uk/getstructures.
• 16 In the case of sp² hybridization, this sum would be equal or close to 360°.