Five- and six-membered nitrogen heterocycles are common structural units that have been studied due to their importance in natural compounds, synthetic drugs and medicines. In this study, the development of new synthetic methods towards the formation of fused nitrogen heterocyclic (γ-lactam) rings system were successfully established. The key intermediate γ-lactam ring unit which exists in the more stable enol form and also appears as racemic mixture, was successfully prepared
Keywords: Bicyclic fusedenamine hydrogenationlactam
The five-membered nitrogen-heterocycles are key elements that typically found in naturally occurring substances. The wide-ranging spectrum of pharmacological effects of this type of compound has attracted significant interests especially in synthetic drugs researches ( Hameed & Akhtar, 2011), in agricultural industry and in organic synthesis. The pyrrolidine (also known as tetrahydropyrrole) ring structure especially γ-lactam (α-carbonyl pyrrolidine) possess significant Structure-Activity Relationship (SAR) and versatile reaction intermediates for pharmaceutical drug’s productions for example doxapram, aniracetam, lactacystin and cotinine. Likely, the alkaloid cotinine that found in tobacco is verified for antipsychotic-like effects ( Buccafusco & Terry, 2009), thus it was widely used biomarker to cure Alzheimer’s diseases ( Grizzell \7 Echeverria, 2014), schizophrenia and depression.
The synthetic approaches of α-carbonyl pyrrolidine include 1,3-dipolar cycloaddition ( Li, Tong, Li, Tao, & Wang, 2011), ring-closing metathesis ( Majumdar, Muhuri, Islam, & Chattopadhyay, 2009), solid-phase synthesis ( Vergnon, Pottorf, Winters, & Player, 2004) and multicomponent reaction ( Wei & Shaw, 2007). Moreover, Friedel- Crafts alkenylation of ionic liquids ( Song, Jung, Choung, Roh, & Lee, 2004), Rhodium-catalyzed arylation-cyclisation of N-tosylarylimines ( Wang, Feng, Xu, & Lin, 2007) and an intramolecular Wurtz-Fittig coupling reaction ( Campbell, Dedinas, & Trumbower-Walsh, 2010) similarly have been conveyed on the formation of the respective cyclic ring system. Whereas, a classic approach to synthesize six-membered (δ)-lactam ring are involved the formation of heterocyclic ketene aminal ( Huang & Liu, 1989), (3,3) sigmatropic rearrangement ( Cheung & Yudin, 2006) and Huisgen (3+2) dipolar cycloaddition ( Kumar & Rode, 2007).
A review of the literature discloses that no inclusive syntheses of fused 5,5- and 6,5-bicyclic
What are the simplest and approachable synthetic methodologies to transform the 2,3-pyrrolidinedione into fused bicyclic 6,5-lactam and 5,5-lactam ring systems?
Purpose of the Study
To design and construct the chemical conversions of highly substituted 2,3-pyrrolidinedione that serve as a core to synthesize a new fused bicyclic 5/6-nitrogen-heterocyclic-lactam ring moieties employing an amine (either enamine or imine) initial product.
All chemicals and reagents were purchased from Merck and Aldrich. Column chromatography (CC) was carried out using Merck Kieselgel 60 with 70-230 mesh ASTM. Thin layer chromatography (TLC) was performed using 20x20 (cm) aluminium sheets coated with Merck Kieselgel 60 F 254. The TLC plates were visualized at λ = 254nm under ultraviolet light and was exposing to I 2 vapour or staining with KMnO 4 solution. The qualitative MS was analysed on LCMS/MS Q-TOF Agilent Technologies 6520 (for liquid sample) or MSI-High Resolution Mass Spectrometer (HRMS) Model CO-1600 Autoconcept (for solid sample). Melting points (m.p.) were determined
Preparation of Compound (4)
A NH 4CO 2H (5.0x10 -3 mol) was poured into
Preparation of Compound (5)
In a flask, a reaction mixture of
Preparation of Compound (6)
The 10% Pd-C (1.3x10 -3 mol) was added into the solution of
Preparation of Compound (2)
Preparation of Compound (7)
Preparation of Compound (8)
Preparation of Compound (9)
Benzylamine (2.0x10 -3 mol) was added into a solution of
Preparation of Compound (10)
To a solution of
Preparation of Compound (3)
A catalytic amount of 10% Pd-C (1.0x10 -3 mol) was added into a solution of
Among a list of the produced reaction products of our prior work ( Mohammat et al., 2012), compound
The coupling reaction between
In short, the five-steps pathway successfully synthesize the targeted fused lactam 2 from 1a with an overall yield of 21% (Figure
Compared to 6,5-lactam ring system that need the CO functionality at C 4 position, the synthesis of 5,5-lactam ring system is likely contrariwise. The elimination of ethyl ester group at C 4 position and the replacement by ethyl acetyl group are essential prior to intramolecular cyclisation step. A
The nucleophilic addition reaction was designed for a next step by treating 8 with NH 2OH·HCl and BnNH 2 to give hydroxyl-imine 10 and
In brief, fused lactam 3 was well synthesized with an overall yield of 4% in the six-steps pathway (Figure
Both bicyclic fused 6,5- and 5,5-lactams were successfully produced and reported for the first time from highly substituted and accessible 2,3-dioxo-5-(substituted)arylpyrroles. Both synthetic methodologies require
Authors thanks the Institute of Science (IoS), Integrative Pharmacogenomics Institute (iPROMISE) and Faculty of Applied Sciences (FSG) Universiti Teknologi MARA (UiTM) for providing research facilities. This research was funded by Malaysian Ministry of Education through 600-RMI/FRGS TD 5/3 (1/2014) of Fundamental Research Grant Scheme (FRGS) Top Down Grant.
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30 March 2020
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Nurul Syafiqah, R., Ahmad Sazali, H., Zurina, S., & Mohd Fazli, M. (2020). The Syntheses Of Fused Cyclic 5/6-Membered Ring Lactams Via Enamine Hydrogenation. In & N. Baba Rahim (Ed.), Multidisciplinary Research as Agent of Change for Industrial Revolution 4.0, vol 81. (pp. 749-758). European Publisher. https://doi.org/10.15405/epsbs.2020.03.03.87