Synthesis of 7-Membered Heterocyclic Compounds and Their Biological Activity

Heterocyclic compounds are an important class of organic compound. Owing to their usefulness in synthetic processes, numerous heterocyclic compounds are currently known, and this number is growing quickly. The uses of heterocyclic compounds are numerous. They are mostly used as veterinary goods, agricultural chemicals, and medications. Additionally, they are used as sanitizers, cleansers, antioxidants, corrosion inhibitors, co-polymers, and dye ingredients. The ring of a heterocyclic compound contains at least two unique components as members. On such a cyclic ring, the frequent heteroatoms are oxygen, nitrogen as well as sulphur. The most stable heterocyclic compound is a 7-membered ring over other heterocyclic compounds. Hence this article specifically reviews the synthesization of 7-membered heterocyclic compounds and their biological activity. The set of reviewed articles chosen in the current attempt is selected after the rigorous process of evaluating each aspect related to the 7-membered heterocyclic compound. This review paper will be of great interest to scientific groups working in the field of organic molecule synthesis and development.


Introduction
The broadest and most diverse families of organic compounds are heterocyclic compounds (1).However, by substituting a part of carbon ring with heteroatoms, any carbocyclic compound, irrespective to the structure and function, may theoretically be transformed into a collection of heterocyclic analogues (2).The permutations and combinations of such a substitution are extensive.The study has been not limited to oxygen, nitrogen, and sulphur which are the commonly heterocyclic elements but to phosphorus and other elements also.Heterocyclic compounds are typically present in high concentrations in both plant and animal products, and they represent a significant component of about half of all known natural organic molecules.Some significant classes of natural heterocyclic compounds include alkaloids, natural colors, medicines, proteins, and enzymes.Based on their electronic composition, heterocyclic compounds can be classified into saturated and unsaturated compounds (3).With altered steric properties, saturated heterocyclic molecules act as their acyclic derivatives.The typical amines and ethers are piperidine and tetrahydrofuran.However, due to their lack of constraints, unsaturated heterocyclic compounds with rings of 5 and 6 members have undergone substantial research.These unstrained, unsaturated heterocyclic compounds include benzo-fused analogues of pyridine, thiophene, pyrrole, and furan.The benzo-fused heterocycles quinoline, isoquinoline, indole, benzothiophene, and benzofuran are some notable examples (4).The use of

Different types of heterocyclic compounds
The classification of the heterocyclic compounds can be done based on their structural and electronic configurations.The names of the groups are aliphatic heterocyclic compounds and aromatic heterocyclic compounds (9).The cyclic ethers, thioethers, amides and amines are among the aliphatic heterocyclic compounds.Saturated heterocycles are aliphatic heterocycles devoid of double bonds.On the other hand, aromatic heterocyclic molecules resemble benzene (10).Additionally, aromatic heterocyclic compounds adhere to Huckel's criterion.Three or more atoms, either saturated or unsaturated, can make up a heterocyclic ring.Additionally, heterocyclic rings may have many heteroatoms, which may be same or different.Further the heterocyclic compounds can also be classified into various groups based on the different structural variations (11).Based on the structural variation, heterocyclic compound can vary from 3-membered to 7-membered heterocyclic compound.The 3-atom heterocyclic compounds can either be saturated or unsaturated.They can also be divided into two groups based on the number of heteroatoms present: compounds with one heteroatom that are heterocyclic and compounds with two heteroatoms.If the ring contains one heteroatom, as the name would imply -Aziridine, Oxirane, Thirane, Azirine, Oxirene, and Thirene are a few examples of the heterocycles with two heteroatoms in three membered rings.Compounds with a four-membered heterocycle have four-atom heterocyclic molecules that can either be saturated or unsaturated.They can also be divided into two groups based on the number of heteroatoms present: compounds with one heteroatom that are heterocyclic and compounds with two heteroatoms that are heterocyclic.If ring contains one heteroatom, they include azetidine, oxytidine, thietidine, azete, oxytidine, and thiete.Heterocyclic Compounds with five members swapping out a C=C bond for a hetero atom containing a lone pair of electrons, these heterocyclic compounds are created from benzene.They can also divide them into two groups based on the number of heteroatoms present.Thiophene, pyrrole, and furan are some examples with one heteroatom.Similarly, we have a range of heterocyclic compounds.Research on these compounds have led to generation of a library of compounds with millions of molecules just by varying the substituent on the ring.The side chain which can range from any functional group ranging from halogens, nitro, alkyl to alcohol and carbonyl.Unsaturated side chains provide opportunity for further derivatization of the molecules resulting in another library of compounds.It is not possible to mention all the compounds with in single effort and thereby the present review focus on 7-membered heterocyclic compounds forms its synthesis to biological application which provide the significance of these molecules in medicinal chemistry.

Synthesis of Azepine
Aside from these, 7-membered heterocyclic compounds contain heteroatoms such as nitrogen and nitrogen/sulfur, with saturated and unsaturated skeletons being diazepanem, diazepine, and thiazepine, respectively.These are more stable heterocyclic compounds as compared to the other heterocyclic compounds.Here in the reported work the synthesis of some heterocyclic compounds have been discussed with their biological activities.
In the next sub section, the synthesis of its various types of heterocyclic compounds has been mentioned for a clear understanding such as Azepine, Oxepin, Thiepin and Diazepine.

Synthesis of Azepine
Azepines are heterocycles with seven members and one nitrogen atom.Han et al. reported that azepines can be made synthetically using a variety of transition metal-catalyzed processes.The tandem hydroamination/alkynylation process of tethered alkynylamines 1, catalyzed by copper(I) afforded azepine derivatives 2 with substitution at 2 positions.This process proceeds quickly and delivers great results under microwave conditions and furnished yield up to 90% (12).Xu et al. reported that iron (III)-catalyzed Prins cyclization or halogenation of an acetal 3, which results in the formation of 4, under conventional heating method provide 51% yield (13).A wide range of synthetic protocol have been proposed and thoroughly studied for the preparation of azepine derivatives.Reporting each and every synthesis is out of scope of this present review and therefore we have selected some of very efficient and simple protocols so as to sum up the advancement in the synthetic strategy of the mentioned compounds.We hope that the given methodologies are enough to shed light on the significance and diversity of the azepine molecules in chemistry as well as biology.Cui et al. reported that in the [5+2] two steps annulation of secondary amine, alkylation of dibenzylamine with pent-4-yn-1-yl tosylate afforded alkyne 5, which upon subjection to N-oxidation and gold(I)-catalyzed cyclization afforded azepan-4-one 6 (14).This reaction uses important gold catalyst, provided approximately 87 % yield, and typically exhibits strong regioselectivity in conjunction with appreciable diastereoselectivities.Lovick et al. reported that intramolecular amino hydroxylation of N-hexenyl sulfonamide 7 without the use of metals produced 3hydroxyhexahydroazepine 8, with 7-endo selectivity (15).This suggested that these simple and facile techniques to develop nitrogen-containing heterocycles provided by the development of the accompanying intramolecular alkene aminohydroxylations, which may also allow for improved regioselectivity and stereo-control during ring formation.Vervisch et al. reported synthesis of piperidine with chiral center from aziridine.The ring-expanded hexahydroazepine 10 and a straight substitution product 11 was produced by the reaction of nucleophiles with 2-chloromethylpiperidine 9 (16).Compound 9 was obtained by a simple reaction of diastereomeric aziridines.This results in the formation of diastereomeric azepine 10.The aryl group on the nitrogen serves the possibility of further derivatization of the product which will lead to the development of a library of compound with azepine nucleus.Therefore, this synthetic protocol can be further subjected to studies for drug-discovery and other possible applications.Winter et al. reported that the carbamates can be produced by the photochemically induced ring contraction of N-chlorolactams.Because the trans isomeric piperidine 13 was formed from the matching trans hexahydroazepinone 12 and the cis dimethylpiperidine at yield 43% from the cis dimethylazepinone, the rearrangement was demonstrated to be stereospecific.This fact, while not particularly surprising, is crucial for both the synthesis of natural products and from a mechanistic perspective as well (17).(20).Conioxepinols A-D, four new polyketide-derived oxepinochromenones that were found in the endolichenic fungus Coniochaeta sp., were also reported by wang et al. (21).In the context of a research of p38 MAP kinase inhibitors, Dorn et al. reported the synthesis of dibenzoxepinones 18 by intramolecular Friedel-Crafts acylation of the appropriate acid chloride generated in situ (22).Due to its role in the production of proinflammatory cytokines including TNF-a and IL-1b, the p38 MAP kinase is a crucial enzyme in inflammatory disorders.Since these cytokines are suppressed by small molecule p38 inhibitors, p38 is a prospective pharmacological target for cutting-edge anti-inflammatory treatments.Rupcic et al. reported Dibenzoxepinones 18 are oxidised by selenium dioxide to produce diketones, which can then be converted into imidazolodibenzoxepines 19 by reacting with ammonium acetate (23).Many reactions schemes have been reported by different authors few of which are shown ahead.

Scheme 10: Synthesis of Thiepin Method 1
Another synthetic method has been brought to light by Boutillier et al. by using radical addition method in which there is a transfer of xanthates 33 with alkenes.This results in the formation of another xanthate derivative 34.A subsequent aminolysis reaction provides a thiol derivative in the presence of base.The final step constitutes of an intramolecular nucleophilic aromatic substitution of ortho-fluorine to give benzothiepines 35 (32).

Synthesis of Diazepine
Dutta et al. reported that the ring enlarged tetrahydro-1,3-diazepine carboxylic acid 40 was created by the cyanamide-induced rearrangement of epoxy-lactam 38, which was intended to create RNA-guided ligand libraries.It was suggested that the cyanamide ring-opening of the epoxide, silyl migration, and proton transfer are the steps in the rearrangement that provide lactam 39.Under the reaction conditions, a complex procedure involving the lactam nitrogen ring-closing onto the pendant nitrile moiety of 39 and resulting 40 in poor yield occurs (34).Examples of few reaction schemes are as following: N, N Dibenzyl-1,4-diaminobutane 43, PhTMG (1,1,3,3), and diphenyl phosphoryl azide (DPPA) reacts to give anactivating carbamoyl species 44, which undergoes subsequent ring-closing to form 1,3diazepan-2-one 45 (36).
Reagents: CO Various methods for synthesizing different 7-membered Heterocyclic Compounds have been studied in this section.In the next section, various biological uses of 7-membered heterocyclic compounds have been given.

Biological activity of 7-membered heterocyclic compound
The commonly prevalent atoms present in heterocyclic compounds are N, O, S however heterocyclic rings including additional heteroatoms are also well known.Heterocyclic compounds are cyclic organic molecules containing at least one heteroatom.A carbocyclic compound is an organic cyclic compound having all its carbon atoms arranged in rings.Due to their involvement in numerous diseases, heterocyclic compounds are irrespective of the essential types of organic chemicals that are used in various biological disciplines.The major skeleton of many biological compounds, including hemoglobin, chlorophyll, vitamins, DNA and RNA and many more, is a heterocyclic ring.Numerous heterocyclic substances have been utilized for treating variety of common ailments, e.g., use of triazine derivatives as antibacterial herbicide, urinary antiseptic, and anti-inflammatory drug.Furthermore, these organic molecules are crucial structural element in healthcare chemistry.those that are also frequently present in high concentrations in biomolecules, including enzymes, vitamins, organic ingredients, and biologically active compounds, such as those with antiallergic, anticonvulsant, antibacterial, antifungal, enzyme inhibitory, herbicidal, anti-HIV, antidiabetic, and insecticidal properties.The following section discussed about these biological activities of Heterocycles compound.

Antimicrobial activity of Oxazepine
At this time, oxazepine-derived medications were introduced for use in reducing anxiety and stressrelated mental discomfort.In addition to five carbon atoms, oxazepine is an unsaturated, seven-membered compound that also contains heteroatoms, oxygen in position 1, and nitrogen in position 3.
It is created through the pericyclic cycloaddition of Schiff bases with anhydrides (37).Oxazepine and its derivatives are important in medicine and biology, and they are used in pharmaceuticals.7 Imidazole 1, a five-membered heterocyclic molecule with nitrogen atoms in the 1st and 3rd positions, is a component of histidine 2. It possesses remarkable biological properties like antibacterial, antiviral, anticancer, and antidepressant effects (38).In 2012 Juburi et al proved that the antibacterial activity of the produced imides can examined using the cup plate method on a mulorhenton agar medium using four bacterial strains and the Candida albicans fungus.All chemicals tested should be at a concentration of 100g/mL in DMSO, the solvent employed (39).
Using the below method antimicrobial activity of newly prepared oxazepine (Table 1) and (

Potential agents against inflammation
In 2012, Nakamura et al synthesized the 7-membered N/O-heterocyclic compounds with an aim to further produce potential agents against inflammation.Through the 7-endo-dig cyclization and subsequent C-C bond creation of 2-(1-alkynyl) phenylacetamide, a Pd-catalyzed regioselective synthesis of 4,5-disubstituted 7-membered N/O-heterocycles was accomplished.When PdCl2 was induced in aqueous CH3CN, the ligand/additive free cascade reaction occurred even though distinct and independent uses of allyl bromine and methyl vinyl ketone produced an O-and N-heterocycle, respectively.The goal of the pharmacological assay was to find the first instance of a novel PDE4B inhibitor based on 1H-benzo[d]azepin-2(3H)-one.Similarly, the 7-membered heterocyclic compounds can be synthesized to act like as antioxidant, anticonvulsant, antiallergic, herbicidal and Antibacterial etc (40).

Conclusion
Heterocyclic chemistry serves as an illustration for the lack of clear boundaries because it permeates many of the other chemical fields.The activities of life are intricately linked with heterocycles.The crucial importance of heterocycles to the pharmaceutical and agrochemical industries is frequently linked to their existence in nature.Countless heterocyclic systems are available thanks to organic chemistry.In 21 st century most of the researchers paid attention to heterocyclic molecules because of their application in biology and chemistry and 90% of novel medications include heterocyclic molecules.
In this paper, a review of the synthesis of 7-membered heterocyclic compounds and their biological activities has been covered.Various methodologies to develop various types of 7-membered heterocyclic compounds have been covered in this article.Along with this, the applications of 7membered heterocyclic compounds in terms of potential agents such as anticancer, anti-HIV, antimicrobial, antifungal, etc. have been examined in this review.

12 13 Reagents and conditions : hv, 254 nm, CH 2 Cl 2 , -78 o C, Methanol, Pot. carbonate, room temp., 18h, 51%
(19)to the combined effects of an electron-withdrawing carboxylate group and a highly strained carbon-nitrogen double bond, these reactions can be carried out under quite mild conditions.Synthesis of Azepine Method 52.2.Synthesis of OxepinHuang et al. and Pan et al. reported that Dibenzoxepinediones from Mangrove Endophytic Fungus are two novel natural compounds discovered in 2010 that contain benzoxepine.They were derived from a mangrove endophytic fungal culture broth extract harvested from Bruguiera gymnoihiza (L.) Savigny, cultivated in a coastal salt marsh in Guangxi province, China(19) Scheme 4: Synthesis of Azepine Method 4 Dubinina et al. reported that the silica gel-promoted ring expansion of the bicyclic molecule 16, produced by the Diels-Alder reaction of diene 14 and azirine 15, results in the dihydroazepin-4-one 17 (18).
(28)tt et al. reported that 2-bromooxepine 23, which is a new member of the septanoside family of carbohydrate mimics, is synthesized by the ring extension of the gem dihalocyclopropane 22, produced itself from D-glucose(25).Hashimoto et al. reported the reaction of dihydro-2H-pyran-4(3H)-one 24 and N-diazoacetyl camphorsultam 25 generated Oxepin-4-one-5-carboxylate 26 with high diastereoselectivity.(26).Synthesis of Oxepin Method 3 A plethora of review articles have been dedicated on the subject highlighting the synthesis of oxepine and its derivatives using a variety of intriguing novel transition metal-catalyzed processes.Bruder et al. reported that the ring-closing metathesis was an important step in the synthesis of the oxepinochromone ptaeroxylin, as well as related, naturally derived ptaeroxylinol and eranthin(27).Alcaide et al.Tetrahydrooxepine 28 was produced by an intriguing palladium-catalyzed cyclization of an allene 27 generated from glyceraldehyde.It was proposed that in order to renew the catalyst(28).

Table 2 )
(38) evaluated by Hame et.al and Hassan et.al on various microbial strains including several grampositive and gram-negative bacteria.Hame et.al and Hassan et.al reported that the compound 46-49 are highly active for the inhibition of gram-positive bacteria.As per the results, compound 46 was found to be slightly active from gram positive bacteria (staphylococcus aureus and streptococcus pyogenes) whereas compounds 46-49 were found to be highly active for gram-positive bacteria (Staphylococcus aureus).Compound 46,51 exhibited high activity for gram positive bacteria (Staphylococcus pyogenes).Compound 49-51 showed high activity for gram negative bacteria (Klebsiella pneumoniae) and compound 49,51 were found to exhibit high activity for E coli.Compound 51 showed high activity for Fungi (candida albicans) where as other compound were found moderately or slightly active for (candida albicans)(38).

Table 2 :
Physical characteristics and structure of compound (49-51)3.2.Anticancer and Anti-HIV AgentsIn 2003 Eicher et al has synthesized seven-membered heterocycles for preparing the anticancer as well as anti-HIV agents.Many reports suggest that several anti-cancer and anti-HIV drugs have thiepine ring fused with other heterocyclic moiety such as pyridine, pyridones and pyrans.Upon combining 7membered ring ketones 1, 2, and 3 with an arylidene-m alononitrile, fused-ring pyridines 6, 7, and 17-19 were produced, as well as the ylidenem alononitriles 14, 15, and 16, which were then treated using aromatic aldehydes, respectively.Reaction of arylmethylenecyanoacetamide with the ketones 1, 2, and 3, afforded related pyridones 11, 12, and 13.The condensation of the ketones 4 and 5 with methylononitrile under basic conditions was necessary for synthesizing the fused-ring pyranes 8 and 9.The rearrangment of 8 in acidic conditions afforded tetrahydropyridine 10.Combining 15 with benzaldehyde afforded pyran 20.As per the test results, several of the produced molecules showed good anticancer activity in contrast to the reference compound 5-fluorodeoxyuridine, and moderate anti-H IV activity in comparison to AZT.