Multi-component synthesis of piperidines and dihydropyrrol-2-one derivatives catalyzed by a dual-functional ionic liquid

Abstract

N,N,N’,N’-tetramethyl-N,N’-bis(sulfo)ethane-1,2-diaminium mesylate ([TMBSED][OMs]₂) was employed for the synthesis of piperidines and dihydropyrrol-2-ones via one-pot multi-component reactions in simple and green processes. This pseudo five-component reaction of aromatic aldehydes, anilines and alkyl acetoacetates was carried out under reflux conditions in ethanol to afford substituted piperidines. Also, dihydropyrrol-2-one derivatives were synthesized by means of four-component reactions of various amines, dialkyl acetylenedicarboxylates and formaldehyde in ethanol at room temperature. The present approaches have several advantages such as good yields, easy work-ups, short reaction times, and utilize mild and clean reaction conditions.

Introduction

In recent years, ionic liquids (ILs) have been extensively used and have attracted remarkable research interest as catalysts for the green synthesis of the organic compounds due to their tunable physical and chemical properties. ¹ ILs have also been employed because of their advantages, including high thermal and chemical stability, low vapor pressure, non-flammability, and good ionic conductivity, as well as ability to catalyze numerous types of organic reactions, their ability to be used in solvent-free or solution conditions, the ease of changing the cation or anion in their structures to modify their physical and chemical properties, and their ability to dissolve in many organic and inorganic materials.^2–5

Piperidine derivatives, as a valuable class of nitrogen-containing heterocycles, have received much attention owing to their properties such as anti-hypertensive, ⁶ neurotoxic activity, ⁷ anti-bacterial, ⁸ treatment of Alzheimer’s diseases, ⁹ anticonvulsant, anti-inflammatory, ¹⁰ anticancer, ¹¹ and antimalarial. ¹² Recently, multicomponent reactions (MCRs) have been employed for the synthesis of substituted piperidines.^13–22

In addition, dihydropyrrol-2-ones are important in organic synthesis due to their wide spectrum of activity which includes anti-microbiological,^23,24 antitumor,^25,26 anti-inflammatory, ²⁷ antimalarial, ²⁸ antifungal, ²⁹ antidiabetics, ³⁰ and antibiotic properties. ³¹ Therefore, many methodologies have been developed to synthesize these practical heterocycles.^32–38 However, some of the above-mentioned methods for the synthesis of both those types heterocycles have disadvantages such as long reaction times, low or moderate yields, and environmental pollution. Hence, the development of beneficial and environmentally friendly methods for the preparation of these compounds is still in demand.

In this work, N,N,N’,N’-tetramethyl-N, N’-bis(sulfo)ethane-1,2-diaminium mesylate ([TMBSED][OMs]₂) was used as an effective dual-functional IL for the synthesis of substituted piperidines and dihydropyrrol-2-one derivatives via one-pot MCRs in ethanol as a green solvent (Scheme 1).

Scheme 1.

Synthesis of piperidines 4 and dihydropyrrol-2-ones 9 in the presence of ([TMBSED][OMs]₂).

Results and discussions

[TMBSED][OMs]₂ was synthesized according to the our previously reported work. ³⁹ To optimize the amount of the catalyst for the synthesis of substituted piperidines, the reaction of aniline (2 mmol), methyl acetoacetate (1 mmol), and benzaldehyde (2 mmol) was selected as a model system. Next, 5, 10, and 15 mol% of [TMBSED][OMs]₂ were examined at ambient temperature, 50°C, and reflux conditions in EtOH. According to the results in Table 1, 10 mol% of the IL catalyst afforded methyl 1,2,5,6-tetrahydro-1,2,6-triphenyl-4-(phenylamino)pyridine-3-carboxylate (4a) in 93% yield under reflux conditions in 55 min as the best result (Table 1, entry 8).

Table 1.

Optimization of the reaction conditions for the synthesis of 4a.

Entry	Catalyst (mol%)	Temp (oC)	Time (min)	Yield (%) a
1	5	rt	100	―
2	10	rt	100	25
3	15	rt	100	32
4	5	50	80	59
5	10	50	75	62
6	15	50	65	62
7	5	reflux	60	80
8	10	reflux	55	93
9	15	reflux	55	94

a

Isolated yield.

Next, the pseudo five-component reaction of anilines 1 (2 mmol), methyl/ethyl acetoacetate 2 (1 mmol) and aromatic aldehydes 3 (2 mmol) was investigated under the optimized conditions for the preparation of functionalized piperidines 4a-j (Table 2). A wide range of substituted and structurally diverse aldehydes and anilines was utilized to give the corresponding products in high to excellent yields using the acidic IL. Next, we examined n-heptanal and n-heptylamine as examples of aliphatic aldehydes and amines instead of benzaldehyde and aniline, respectively. However, the desired products were not obtained (Table 2, entries 11 and 12). This may be due to the tendency of aliphatic aldehydes to produce enamines rather than imines and that these condense with any remaining aldehyde. In addition, in the presence of n-heptylamine, the higher basicity of the aliphatic amine compared to aniline can lead to salt formation with the catalyst. ⁴⁰

Table 2.

Preparation of functionalized piperidines 4a-j in the presence of [TMBSED][OMs]_2..

Entry	Ar	Ar’	R1	Product	Time (min)	Yield (%) a	M.p. (°C)
							Found	Reported
1	Ph	Ph	Me	4a	55	93	180–182	185–186 15
2	Ph	4-MeO-C6H4	Me	4b	60	94	188–189	186–188 15
3	Ph	4-Me-C6H4	Et	4c	60	87	224–226	228–231 15
4	4-MeO-C6H4	4-Me-C6H4	Et	4d	60	81	219–221	221–224 16
5	4-Me-C6H4	4-Me-C6H4	Et	4e	70	95	169–171	169–171 22
6	4-Me-C6H4	Ph	Me	4f	55	88	194–196	190–192 20
7	4-Cl-C6H4	4-Br-C6H4	Me	4g	60	88	161–162	160–163 12
8	4-Br-C6H4	Ph	Et	4h	60	90	196–198	196–198 22
9	4-Cl-C6H4	Ph	Me	4i	55	89	205–207	202–203 12
10	Ph	4-O2N-C6H4	Me	4j	120	52	234–236	239–242 12
11	n-heptylamine	Ph	Et	―	24 h	―	―	―
12	Ph	n-heptanal	Et	―	24 h	―	―	―

a

Isolated yield.

Based on the literature,^14–16 the proposed mechanism for this pseudo five-component reaction is displayed in Scheme 2. It was assumed that the aniline 1 reacts with the β-ketoester 2 to give enamine A in the presence of [TMBSED][OMs]₂ and that it also reacts with aldehyde 3 to give imine B with elimination of water. Afterwards, the reaction of enamine A and activated imine B via an intermolecular Mannich-type reaction led to intermediate C. The reaction of intermediate C with a second molecule of the aldehyde produces intermediate D, which undergoes tautomerization to afford intermediate D. Following an intramolecular Mannich-type reaction to form intermediate E, deprotonation and tautomerization provided the corresponding functionalized piperidine 4.

Scheme 2.

The proposed mechanism for the preparation of piperidine derivatives.

To demonstrate the applicability of the presented work, it can be compared with several reported results in the literature. The results show that the reactions were performed in short times and gave excellent yields in the presence of [TMBSED][OMs]₂ when compared to other catalysts (Table 3).

Table 3.

Comparison the results of [TMBSED][OMs]₂ with other catalysts in the synthesis of compound 4a.

Entry	Catalyst (mol%)	Conditions	Time	Yield (%) a [Ref]
1	Iodine (10 mol%)	MeOH, rt	8 h	81 15
2	ZrOCl2.8H2O (20 mol%)	EtOH, reflux	3.5 h	80 13
3	TBATB (10 mol%)	EtOH, rt	24 h	74 14
4	[Hpyro][HSO4] (15 mol%)	EtOH, reflux	8 h	77 21
5	Al(H2PO4)3 (0.1 g)	EtOH, rt	12 h	80 20
6	CAN (15 mol%)	MeCN, rt	20 h	82 16
7	[TMBSED][OMs]2 (10 mol%)	EtOH, reflux	55 min	93 (present work)

a

Yields refer to isolated pure products based on the reaction of aniline (2 mmol), methyl acetoacetate (1 mmol) and benzaldehyde (2 mmol).

We next synthesized dihydropyrrol-2-ones 9 using the [TMBSED][OMs]₂ catalyst. First, optimization studies were performed using aniline (2 mmol), dimethyl acetylenedicarboxylate (1 mmol) and formaldehyde (1.5 mmol) in EtOH as a model reaction. The reaction was carried out with 10, 20, and 30 mol% of the catalyst at room temperature over 2.5–3 h and the corresponding product 9a was obtained in yields of 80%, 95%, and 96%. Increasing the amount of catalyst to 30 mol% did not increase the reaction yield further. Therefore, the substrate scope of the reaction was investigated utilizing a range of structurally diverse aliphatic and aromatic amines and dimethyl/ethyl acetylenedicarboxylates in the presence of 20 mol% of [TMBSED][OMs]₂. The corresponding dihydropyrrol-2-ones 9a-j were synthesized in good to high yields in short reactions times (Table 4).

Table 4.

Preparation of dihydropyrrol-2-one derivatives in the presence of [TMBSED][OMs]_2..

Entry	R2	R3	Ar″	Product	Time (h)	Yield (%) a	M.p. (°C)
							Found	Reported
1	Ph	Me	Ph	9a	2.5	95	152–154	155–156 34
2	4-Cl-C6H4	Me	4-Cl-C6H4	9b	2	93	171–173	173–174 34
3	4-Me-C6H4	Me	4-Me-C6H4	9c	2.5	91	175–177	177–178 34
4	Ph	Et	Ph	9d	3	90	134–136	138–140 33
5	4-MeO-C6H4	Et	4-MeO-C6H4	9e	3	85	152–154	152–154 20
6	n-C3H7	Et	Ph	9f	2.5	89	76–77	78–79 33
7	n-C4H9	Me	4-Cl-C6H4	9g	2.5	90	92–94	92–94 38
8	n-C4H9	Et	4-Br-C6H4	9h	2.5	92	94–96	94–96 35
9	Ph-CH2	Me	4-Me-C6H4	9i	2	94	143–145	144–146 38
10	Ph-CH2	Me	Ph	9j	2	90	137–138	139–140 34

a

Isolated yield.

A possible reaction mechanism for the preparation of dihydropyrrol-2-ones 9 is presented in Scheme 3. ³⁴ First, the reaction of amine 5 with dialkyl acetylenedicarboxylate 6 leads to intermediate G. Second, condensation between amine 7 and formaldehyde 8 in the presence of [TMBSED][OMs]₂ produces imine H. Reaction between intermediate G and imine H then generates intermediate I. Cyclization of intermediate I leads to intermediate J, which in the final step tautomerizes to give the corresponding dihydropyrrol-2-one 9.

Scheme 3.

The proposed mechanism for the synthesis of dihydropyrrol-2-ones 9.

A comparison the results obtained with [TMBSED][OMs]₂ and some reported catalysts for the synthesis of product 9c shows that [TMBSED][OMs]₂ can act as effective and efficient catalyst with respect to the reaction time and yield (Table 5).

Table 5.

Comparison the results of [TMBSED][OMs]₂ with other catalysts in the synthesis of compound 9c.

Entry	Catalyst	Conditions	Time (h)	Yield (%) a [Ref]
1	Iodine (10 mol%)	MeOH, rt	1	78 34
2	Nano-TiCl4/SiO2(0.08 g)	EtOH, 70°C	2.5	80 32
3	p-TsOH·H2O (15 mol%)	MeOH, rt	3	83 38
4	Cu(OAc)2·H2O (80 mg)	MeOH, rt	6	91 37
5	[TMBSED][OMs]2 (20 mol%)	EtOH, rt	2.5	91 (present work)

a

Yields refer to isolated pure products.

Conclusion

In summary, we have developed efficient one-pot procedures for the synthesis of functionalized piperidines and dihydropyrrol-2-one derivatives using [TMBSED][OMs]₂ as a catalyst. These methods offered several advantages such as short reaction times, good to high yields, simplicity in operation, no need for column chromatography, and a green aspect by using ethanol as the solvent.

Experimental

Materials

All chemicals were obtained from Merck, Fluka and Sigma-Aldrich and were used without subsequent purification. The nuclear magnetic resonance (NMR) spectra were recorded with a Bruker DRX-400 AVANCE instrument (400 MHz for ¹H, 100 MHz for ¹³C) in dimethyl sulfoxide (DMSO)-d₆ as solvent. Melting points were measured on an Electro thermal 9100 apparatus. Please see the supplemental material for the spectral data of some selected compounds.

General procedure for the synthesis of piperidines 4

A solution of aromatic amine 1 (2 mmol) and alkyl acetoacetate 2 (1 mmol) in ethanol (10 mL) was stirred for 30 min in the presence of [TMBSED][OMs]₂ (10 mol%) at room temperature. Next, the aromatic aldehyde 3 (2 mmol) was added and the reaction mixture was allowed to stir for the appropriate amount of time under reflux. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the mixture was cooled to room temperature. The resulting precipitate was collected by filtration and washed with EtOH (3 × 2 mL) to give the pure product.

General procedure for the preparation of dihydropyrrol-2-ones 9

A mixture of amine 5 (1 mmol) and dialkyl acetylenedicarboxylate 6 (1 mmol) in EtOH (10 mL) was stirred for 30 min. Next, amine 7 (1 mmol), formaldehyde 8 (1.5 mmol) and [TMBSED][OMs]₂ (20 mol%) were added successively. The reaction mixture was allowed to stir at room temperature for the appropriate amount of time. After completion of the reaction (monitored by TLC), the solid precipitate was filtered off and washed with EtOH (3 × 2 mL) to give the pure product 9.

Supplemental Material

Supplemental_Material – Supplemental material for Multi-component synthesis of piperidines and dihydropyrrol-2-one derivatives catalyzed by a dual-functional ionic liquid

Supplemental material, Supplemental_Material for Multi-component synthesis of piperidines and dihydropyrrol-2-one derivatives catalyzed by a dual-functional ionic liquid by Narjes Basirat, Seyed Sajad Sajadikhah and Abdolkarim Zare in Journal of Chemical Research