Convenient and efficient synthesis of disubstituted piperazine derivatives by catalyst-free, atom-economical and tricomponent domino reactions

Abstract

One-pot, atom-economical, catalyst-free and tri-component domino reactions are applied to the diversity-oriented synthesis (DOS) of disubstituted piperazine derivatives under mild conditions with moderate to high yields. This protocol exhibits potential applicability in the synthesis of pharmaceuticals, liquid crystals, complexes, etc. Because of its operational simplicity and convenience, it may be suitable for application in large-scale synthesis.

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Some reactions and synthetic methodologies, for example cascade, tandem, one-pot, multicomponent domino reactions, atom-economical, catalyst-free, ring opening, supramolecular self-assembly, diversity-oriented synthesis (DOS) and functional-oriented synthesis (FOS), are increasingly applied to the construction of natural and designed molecules. Such processes, in which ideally a single event triggers the conversion of a starting material to a product which then becomes a substrate for the next reaction until termination leads to a stable final product, are highly desirable not only due to their elegance, but also because of their efficiency and economy in terms of reagent consumption and purification. Often, these one-pot multistep procedures are accompanied by dramatic increases in molecular complexity and impressive selectivity. The discovery of new molecular diversity from nature and the demand for more efficient and environmentally benign chemical processes dictates and invites the further development of such synthetic strategies and tactics as we move into a new age of chemical synthesis.¹

Piperazine ring and its derivatives present in many nature products, such as anticancer Aspernigerin (Scheme 1), etc.²

Scheme 1 Aspernigerin.

The new classes of hybrid anticancer drugs were obtained by selective functionalization of the piperazine scaffold following fragment-based drug design. The piperazine nucleus and its substituted products play an important role in anticancer (the invention compounds are useful for the treatment of cancers including glioblastomas, lung cancers, colon cancers, gastric (stomach) cancer, breast cancer, esophageal cancer, and prostate cancer, liver cancer, breast cancer, leukemia, lymphoma, kidney cancer, skin cancer, pancreatic cancer…) activity³ and pharmacological properties. The arylpiperazine framework is observed in agreat deal of compounds of pharmaceutical interest. In 2001, the MDDR (MDL Drug Data Report) listed 2271 phenylpiperazines which totaled 65 structures in clinical trials or higher across 23 therapeutic areas.⁴ The piperazine or piperazinone core also presents in the compounds that are possessing anti-fungal, anti-depressant, anti-malarial, anti-migraine, anti-diabetic, anti-thrombotic, anti-aggregating, etc.⁵ Piperazine derivatives are important intermediates in organic synthesis and can be used as the building blocks in pharmaceutical and fine chemical industries. Some disubstituted piperazine derivatives are applications in liquid crystals,⁶ complexe,⁷ coatings, sealing materials, adhesives and hot-melt adhesive,⁸ self-assembled monolayer in an electronic device,⁹ novel charge-transfer polymers in solar cells et al.,¹⁰ non-aqueous gel ion conductor compositions used in batteries,¹¹ self-assembly of supra-molecular polymer materials,¹² antistatic agents and vulcanization accelerators,¹³ etc.

Aromatic ring, aromatic heterocyclic ring and its derivatives are the parent structure of many nature products. Most of the heterocyclic nucleuses use exhibit remarkable pharmacological activities. The new classes of hybrid derivatives were obtained by selective of the heterocyclic ring scaffold. The 1H-1,2,3-triazole derivative is a heterocyclic compounds with wide biological activity and applications in many fields.¹⁴ The triazole ring nucleus also exhibits remarkable pharmacological activities and selective functionalization of the heterocyclic ring scaffold.¹⁵ Amino acid is the smallest unit formation of protein and polypeptide, and the most of amino acids was chiral. Some amino acids are used for important chiral tool sources in chiral synthesis or asymmetric synthesis. Proteins and peptides are chiral, enzyme and cell is also composed of chiral proteins. The cancer or some diseases is caused by some enzymes or cells. Hence, to inhibit these enzymes or cells, the chiral drugs was required.

In the one-pot, atom-economical, catalyst-free, supra-molecular homo- and hetero-synthon, ring opening and tri-component domino reactions are being applied to the diversity-oriented synthesis and construction progress of designed molecules. In the processes, the conversion of a starting material to a product is highly desirable, efficient and economic in terms of reagent consumption and purification. These multistep, one-pot procedures are accompanied by dramatic increases in molecular complexity and impressive selectivity, and are suitable for application in scale the synthesis. To examine the yield of diversity-oriented synthesis (DOS), atom-economical, one-pot and tri-component domino reactions, we chose the 1-naphthoic acid (4), dimethyl acetylene dicarboxylate (DMAD) as a model substrate. The yield of 4a and 4b is examined by the change of 1,4-diazabicyclo[2.2.2]octane (DABCO) mol%. Finally result shows, when the amount of DABCO is less, it is a catalyst and main product 4b is obtained. When the amount of DABCO is more than 0.6 equivalent, it acts as a reactant and gives major product 4a. The reaction is shown in Scheme 2. The results of the reaction using different amount of DABCO are shown in Fig. 1.

Scheme 2 Synthesis conditions of title compound 4a.

Fig. 1 The yield of title compound 4a is changed by quantity of DABCO added.

The new class derivatives for selective functionalization of the aromatic ring scaffold. Some novel disubstituted piperazine derivatives were synthesized by substituted aromatic acids (Table 1).

Table 1 Synthesis of some novel aryl piperazine derivatives

Entry	Ar-COOH	Yields (%)
1	4-Br-C6H4-COOH	1a (86%)
		1b (11%)
2	2-Cl-C6H4-COOH	2a (86%)
		2b (9%)
3	β-C10H7-OCH2COOH	3a (72%)
		3b (16%)
4	α-C10H7-COOH	4a (82%)
		4b (12%)
5	α-C10H7-CH2COOH	5a (62%)
6	2-CH3COO-C6H4-COOH	6a (43%)
7	4-F-C6H4-COOH	7a (89%)
8	Ph-CH=CH-COOH	8a (59%)
9	4-NC-C6H4-COOH	9a (57%)
10	4-CH3O-C6H4-COOH	10a (75%)
11	Ph-CH(OH)-COOH	11a (79%)
12	2-Br-C6H4-COOH	12a (84%)
13	2-CH3O-C6H4-COOH	13a (64%)
14	3-CH3O-C6H4-COOH	14a (74%)
15	3-Cl-C6H4-COOH	15a (85%)
16	2-F-C6H4-COOH	16a (81%)
17	3-CH3-C6H4-COOH	17a (75%)
18	Ph-COOH	18a (89%)
19	Ph-CH2COOH	19a (74%)
20	3-CH3-C6H4-COOH	20a (66%)
21	2,4-DiCl-C6H3-OCH2COOH	21a (69%)
22	C6H3-OCH2COOH	22a (72%)
23	α-C10H7-OCH2COOH	23a (75%)
24	4-I-C6H4-COOH	24a (74%)
25	2-I-C6H4-COOH	25a (65%)
26	2-CH3COO-C6H4-COOH	26a (31%)
27	Nicotinic acid	27a (68%)
28	5-Bromopyridine-3-COOH	28a (89%)
29	Quinoline-2-COOH	29a (71%)
30	Pyrazine-2-COOH	30a (66%)
31	(Tetrazol-1-yl)acetic acid	31a (55%)
32	Furan-2-COOH	32a (79%)
33	Picolinic acid	33a (77%)
34	4-Br-C6H4-COOH, R = –CH3	34a (45%)
35	4-Br-C6H4-COOH, R = –Et	35a (39%)
		35b (25%)

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Some novel disubstituted piperazine derivatives were synthesized by substituted 1,2,3-triazolyl acids (Table 2).

Table 2 Synthesis of some novel 1H-1,2,3-triazolyl piperazine derivatives

Entry	Ar-COOH	Yields (%)
36	1-(4-Chlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid	36a (68%)
		36b (25%)
37	5-Methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid	37a (71%)
38	1-(4-Ethoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid	38a (64%)
39	5-Methyl-1-(naphthalen-2-yl)-1H-1,2,3-triazole-4-carboxylic acid	39a (82%)
40	1-(4-Methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid	40a (60%)
41	1-(4-Chlorophenyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylic acid	36a (63%)
42	1-(2-Bromophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid	42a (35%)
43	1-(2-Bromophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid	43a (49%)
44	1-(3-Chlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid	44a (67%)

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When 1-[1-(1-aryl-5-methyl-1H-1,2,3-triazole-4-carboyloxyl) ethan-2-yl]-4-[(E)-1,2-(dimethoxycarbonyl)ethen-1-yl]piperazine derivatives were synthesized, novel compounds 42a and 43a were obtained by the reaction of 1-(2-bromophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid, DABCO, dimethyl but-2-ynedioate. Compound 43a is a normal product, but 1-{2-[2-diazo-3-(E)-(2-bromophenylimino)butyroyloxyl]ethan-1-yl}-4-[(dimethoxycarbonyl)-ethen-1-yl]piperaine 42a is a compound involving diazo compound by showing strong IR absorption at 2125 cm⁻¹.¹⁶ The structures are shown in Scheme 3.

Scheme 3 The target compound 42a and 43a.

Some target compounds were synthesized by amino acid or substituted amino acid. The reaction is shown in Table 3.

Table 3 Synthesis of some novel (un)substituted amino carboxylic acid piperazine derivatives

Entry	Ar-COOH	Yields (%)
45	2-(Phenylamino)benzoic acid	45a (89%)
46	(±)-5-Oxopyrrolidine-2-carboxylic acid	46a (68%)
47	2-(Benzamido)acetic acid	47a (90%)
48	2-(1H-Indol-3-yl)acetic acid	48a (61%)
49	1H-Indole-2-carboxylic acid	49a (77%)
50		50a (69%)
51		51a (55%)
52		52a (78%)

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When the target compounds were synthesized by some amino carboxylic acid, the products with bis(E)-1,2-(dimethoxycarbonyl)ethen-1-yl compounds 50a, 51a and 52a were obtained (Scheme 4).

Scheme 4 The target compound 50a, 51a and 52a.

A proposed mechanism of this reaction is shown (in Scheme 5) based on the previous investigation.¹⁷ Initially, reaction of Ar-COOH (dimeric supra-mol. homo-synthon) 1 and DABCO form a DABCO aromatic acid salt (supra-mol. hetero-synthon) a. Then, an intermolecular nucleophilic addition reaction of hetero-synthon a attacks DMAD was happened and the corresponding zwitterionic intermediate b and c were given. When the aromatic acid anion b attacks DABCO cationic intermediate c, a reaction of nucleophilic substitution was reacted and the final products 1a–52a is obtained. If reaction was Michael addition of anion b to intermediate c, zwitterionic intermediate d was given, then DABCO was eliminated from intermediate d to afford the final product 1b–4b (Scheme 5).

Scheme 5 Plausible mechanism for the reaction.

In order to prove the configuration of DMAD adduct, the compound 34a, 35a and 35b are synthesized. It was good known that the C=C configuration can be proved by the adjacent hydrogen coupling constant of olefinic bond. The compound 34a, 35a and 35b was trans configuration by the coupling constant of olefinic hydrogen, hence, the addition reaction of acetylene, DMAD and DABCO, which was proved for cis adducted. In the meantime, the C=C configuration for cis adducts and piperazine ring conformation is also confirmed by crystalline structure of the target compounds 40a. The crystal structure of compound 40a is shown in Fig. 2. The supra-molecular structure of compound 40a is shown in Fig. 3.

Fig. 2 A mercury (CCDC, 2005†) view of the molecular structure of 40a (CCDC no: 1019130†).

Fig. 3 The π–π accumulation structure of 40a supra-molecular.

In summary, catalyst-free, one-pot, atom-economical, supra-molecular homo- and hetero-synthon, ring opening and tri-component domino reactions are applied to diversity-oriented synthesis (DOS) of disubstituted piperazine derivatives under mild conditions with moderate to high yields. This protocol exhibits potential applicability in the synthesis of pharmaceuticals and natural products, because of the operational simplicity, the convenient and available reactants. The target compounds are synthesized for an organic whole structure of procaine part and anticancer drugs heterocyclic compounds. We should point out that the target compounds is of low expenditure and novel in biological and pharmacological fields, and suitable for application in the industrial scale synthesis.

Acknowledgements

We are grateful to acknowledge financial support from Lanzhou University SKLAOC.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, characterization data, ¹H and ¹³C NMR spectra, X-ray crystal data of products. CCDC 1019130. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra14811h

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