Organic Heterocyclic Chemistry

Heterocyclic compounds are highly important class of organic compounds due to large number of applications such as pharmaceutical, biological, agrochemical, industrial, biotechnology, and material chemistry. In fact, the major pharmaceuticals, biologically active and agrochemicals are heterocyclic compounds. Large and variety of heterocyclic compounds are reported in the literature so far. The importance due to the design and the synthesis of heterocyclic chemistry is increasing rapidly day by day in synthetic and medicinal organic chemistry. The heterocyclic chemistry is recognized as an important discipline of general significance that hit the major aspects of recent chemical science, medicine, and organic chemistry. In the heterocyclic chemistry various structural motifs of the molecules provided pharmacological and biological activities to compounds. The Oxadiazoles motif is one of such significant heterocyclic motif, which play an important role in bio-isosteric and metabolically stable molecules, a replacement for the associate organic molecular unit.
Indeed, 1,2,4-oxadiazoles have received tidy attention in the pharmaceutical industry as heterocyclic drug moieties. They have been utilized within the style of diverse biologically active templates like muscarinic agonists, trypsin enzyme inhibitors, opposed inflammatory agents, aminoalkane H3 antagonists, anticancer agents, and MAO inhibitors. Moreover, the derivative of chromene moiety leads to a wide range of biological activities due to their interactive nature with various protein moieties. Benzopyran derivatives are also exhibit important biological activities such as anticancer, antioxidant and antimicrobial activity etc. Furan and its derivatives exhibit biological activity such as in the defense system.  They find applications as oxidants, antioxidants, as brightening agents, for drugs and in other fields of medicinal and agrochemistry. Benzofuran derivatives are also present in many natural products exhibits properties like physiological, pharmacological and toxic etc. They also display many applications like sedatives, anti-oxidants, pharmaceuticals, cosmetics etc. Moreover, benzofuran derivatives are also possess various pharmacological and biological activities such as antimicrobial, antibacterial, antifungal, antitubercular, antidiabetic, antidepressant, antioxidant, anticonvulsant and analgesic activities. In this context, in the first study, we focused on the design and synthesis of a series twelve 1,2,4-oxadiazole contained 8,9-dihydropyrano chromene moieties derivatives. All the twelve new derivatives were synthesized successfully and characterized by spectroscopic data and CHN analysis. Moreover, they were screened for antimicrobial study and they exhibited better microbial inhibition against selected microorganisms compared with the standard drug chloramphenicol.  Among the many substitutes on the benzene ring, electronegative substituents such as chlorine, bromine etc. showed excellent biological activity. 
In the second part, we synthesized nine substituted-styryl furo-chromen-methanones, by reacting aryl-hydroxy-2H-chromenones with 2-bromo-1-(4-bromophenyl)ethanones under microwave strategy with high yields. All these newly synthesized compounds were characterized by spectral and CHN analysis. Additionally, they have been screened for antimicrobial study and these are exhibited better microbial inhibition against selected microorganisms. Among the many substitutes on the benzene ring, electronegative substituents like chlorine and bromine etc. showed excellent biological activity. Moreover, these biological evolution results were the good correlation with molecular docking studies too.
In third part of work, we have developed a prototype facile and efficient, mild and straightforward method for the synthesis of 7’,9’-dihydrospiro [indoline-2,11’-pyrazolo [3,4-f] pyrimido [4,5-b] quinoline] -3,8’, 10’(1’H,6’H)-triones,  by using acetic as a catalyst in ethanol solvent by this new MCR (a multicomponent reaction should be by definition performed one-pot) a three-component synthetic method, we achieved sixteen new trione derivatives with more operational simplicity, short reaction time and good yields (up to 93 %).  We are confident that, this study provides a roadmap for the design and synthesis of new heterocyclic compounds for desired applications as drugs.

The morpholine (1,4-oxazinane) motif attracted significant attention due to its widespread availability in natural products and biologically relevant compounds. This review describes recent advances in the synthesis of morpholines and their carbonyl-containing analogs from 1,2-amino alcohols, aziridines, epoxides, and related compounds. Special attention is paid to the syntheses performed in a stereoselective manner and using transition metal catalysis. Selected works published since 2013 are covered.

A new series of N-acylhydrazone derivatives of 2-mercaptobenzimidazole (2-MBI) has been synthesized through S-alkylation with 1-bromotetradecane and N-alkylation with ethyl-2-chloroacetate. The resulting ester was synthetically modified through hydrazine hydrate to acyl hydrazide which was condensed with aromatic al-dehydes to afford the title N-acylhydrazones (4-17). Chemical structures of the newly synthesized compounds have been confirmed through mass, FT-IR and 1 HNMR techniques. In vitro free radical scavenging and α-glu-cosidase inhibition activities of the compounds were investigated with reference to the standard ascorbic acid and acarbose, respectively. Amongst the target compounds, 13 showed the highest inhibition in DPPH scavenging assay (IC 50 = 131.50 µM) and α-glucosidase inhibition potential (IC 50 = 352 µg/ml). We extended our investigations to explore the mechanism of enzyme inhibition and conducted docking analysis by using Molecular Operating Environment (MOE 2016.08). A homology model for α-glucosidase was constructed and validated using Ramachandran plot. Docking studies were also carried out on human intestinal α-glucosidases. In view of the importance of the nucleus involved, the synthesized compounds might find extensive medicinal applications as reported in the literature.

Three-component reaction of 3-amino-1H-1,2,4-triazole or 5-amino-2H-1,2,3-triazole derivatives, acetaldehyde, and 1,3-dicarbonyl compounds (acetylacetone or β-keto esters) in water under microwave irradiation leads to regioselective formation of 4,7-dihydro[1,2,4]- triazolo- and 4,7-dihydro[1,2,3]triazolo[1,5-a]pyrimidines. Using ethyl 4,4,4-trifluoro-3-oxobutanoate as 1,3-dicarbonyl compound under the same conditions allows to obtain the corresponding 5-hydroxy-4,5,6,7-tetrahydro derivatives, which fail to dehydrate in the reaction medium.

Three-component heterocyclizations of pyruvic acids and their esters with 5-aminopyrazoles and aromatic aldehydes, in addition to the sequential versions of these reactions, under different activating conditions were studied. Under conventional heating, pyrazolopyrimidine derivatives containing a hy-droxyl group in the 6-position were formed in both two-and three-component treatments. Whereas the application of an inert atmosphere did not influence the outcome of these reactions, the use of ultrasonic irradiation led to the formation of 7-hydroxy-tetrahydropyrazolopyrimidines in multi-component reactions and 6-hydroxy-dihydropyrazolopyrimidines in the case of a step-by-step approach. The products of the latter treatment were further transformed into heteroaromatized 6-hydroxy-pyrazolopyrimidines by conventional heating.

A library of 19 novel 4-(4-phenylpiperazine-1-yl)benzamidines has been synthesized and evaluated in vitro against Pneumocystis carinii. Among these compounds, N-ethyl- and N-hexyl-4-(4-phenylpiperazine-1-yl)benzamidines emerged as the most promising compounds, with inhibition percentages at 10.0 microg/mL of 87% and 96%, respectively. Those compounds remained active at 0.1 microg/mL.

Thiazole, a five-membered heterocyclic compound constitutes the skeleton of various commercially marketed drug candidates and the heart-core in a diverse range of entities of biological and medicinal interest. It is a versatile and essential component of natural products and medicinally significant heterocyclic compounds. The chemistry of thiazoles was widely developed in terms of anti-microbial, anti-cancer, anti-tubercular, anti-oxidant, anti-inflammatory, and other therapeutically active agents after the pioneering work of Hofmann and Hantzsch, Bogert and coworkers in 1887. Besides these, thiazole heterocycles are also useful as the constituents of several dyes and photographic materials. The present review encompasses and highlights the recent progress in the development of thiazole based heterocyclic compounds for various applications focusing it a scaffold of biological and medicinal interest.

Substituted 1H-pyrazolo[3,4-b]pyridine-4-and 1H-pyrazolo[3,4-b]pyridine-6-carboxamides have been synthetized through a Doebner-Ugi multicomponent reaction sequence in a convergent and versatile manner using diversity generation strategies: combination of two multicomponent reactions and conditions-based divergence strategy. The target products contain as pharmacophores pyrazolopyridine and peptidomimetic moieties with four points of diversity introduced from readily available starting materials including scaffold diversity. A small focused compound library of 23 Ugi products was created and screened for antibacterial activity.

Condensation of 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine with a range of anilines gave 22 N-aryl-3,5-dichloro-4H-1,2,6-thiadiazin-4-imines in 43-96% yields. The scope and limitations of this condensation are briefly investigated. Furthermore, mono- and bis-substitution of the C-3 and C-5 chlorines of 3,5-dichloro-N-phenyl-4H-1,2,6-thiadiazin-4-imine by amine and alkoxide nucleophiles is explored. Finally, Stille coupling chemistry is used to prepare several N-phenyl-3,5-diaryl-4H-1,2,6-thiadiazin-4-imines.

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In a search for antiprotozoan compounds, 34 new 3,5-disubstituted-tetrahydro-2H-1,3,5-thiadiazine-
2-thione derivatives were synthesized and tested in vitro against Trypanosoma cruzi
and Trichomonas vaginalis. Some of them showed important antiprotozoan activity. In vivo
assays of compounds which showed remarkable in vitro activity against T. vaginalis were
carried out.

A new series of N-acylhydrazone derivatives of 2-mercaptobenzimidazole (2-MBI) has been synthesized through S-alkylation with 1-bromotetradecane and N-alkylation with ethyl-2-chloroacetate. The resulting ester was synthetically modified through hydrazine hydrate to acyl hydrazide which was condensed with aromatic aldehydes to afford the title N-acylhydrazones (4-17). Chemical structures of the newly synthesized compounds have been confirmed through mass, FT-IR and HNMR techniques. In vitro free radical scavenging and α-glucosidase inhibition activities of the compounds were investigated with reference to the standard ascorbic acid and acarbose, respectively. Amongst the target compounds, 13 showed the highest inhibition in DPPH scavenging assay (IC = 131.50 µM) and α-glucosidase inhibition potential (IC = 352 µg/ml). We extended our investigations to explore the mechanism of enzyme inhibition and conducted docking analysis by using Molecular Operating Environment (MOE 2016.08). A ho...

The existence of large aromatic monocycles has been proved impossible based on interaction of three-electron bonds through the cycle at distances between the bonds (through the cycle) greater than 3.5 Å due to the lack of energy interaction (the length of chemical bonds is in the range of distances 0.74 Å – 3.5 Å). The chemical bond (two-electron and three-electron) is considered on the assumption that the electrons in a chemical bond can be regarded as being in an entangled quantum state, that is, the chemical bond is seen as a new "indivisible" particle. There has been provided an algorithm for calculating the two-electron chemical bond "on the tip of the pen". An attempt was made to explain the mechanism of interaction of particles in an entangled quantum state on the basis of a new model of the interfering Universe. The interaction of two three-electron bonds in a molecule of benzene at a distance of 2.42 Å (on opposite sides) can be explained if we consider these two three-electron bonds as two particles (two fermions) in an entangled quantum state [1, p. 4-11]. That is, these two fermions are in an entangled quantum state. Quantum entanglement is a quantum mechanical phenomenon, in which the quantum states of two or more fermions or bosons prove to be interconnected [2-6]. And surprisingly, this interconnection remains at virtually any distance between the particles (when there are no other known interactions). It should be realized that the entangled quantum system is in fact an "indivisible" object, a new particle with certain properties (and the particles of which it is composed should meet certain criteria). And most importantly, when measuring the spin (or other property) of the first particle we will automatically unambiguously know the spin (property) of the second particle (let's say we get a positive spin of the first particle, then the spin of the second particle will always be negative, and vice versa). Two particles in an entangled state prove to be bound by an "invisible thread", that is, in fact, they form a new "indivisible" object, a new particle. And this is an experimental fact.

Using the concept of three-electron bond one can represent the actual electron structure of benzene, explain specificity of the aromatic bond and calculate the delocalization energy. It was shown, that functional relation y = a + b/x + c/x^2 fully describes dependence of energy and multiplicity of chemical bond on bond distance. In this article carbon-to-carbon bonds are reviewed. Using these dependences it is possible to calculate chemical bound energy by different bond distance or different multiplicity of chemical bond, that makes possible to calculate delocalization energy of benzene molecule.

CONSPECTUS: Selective syntheses are now available for compounds of many classes, based on C-centered radicals, exploiting a diverse range of mechanisms. The prospect for chemistry based around N-and O-centered radicals is probably more favorable because of the importance of heterocycles as biologically active materials. Heteroradical chemistry is still comparatively underdeveloped due to the need for safe and easy ways of generating them. Oxime esters appeared promising candidates to meet this need because literature reports and our EPR spectroscopic examinations showed they readily dissociated on photolysis with production of a pair of N-and O-centered radicals. It soon became apparent that a whole suite of benign oxime-containing molecules could be pressed into service. The bimodality of the oxime motif meant that by suitable choice of functionality the reactions could be directed to yield selectively products from either the N-centered radicals or from the O-centered radicals. We found that on one hand photolyses of acetophenone oxime esters of carboxylic acids yielded alicyclics. On the other hand, aromatic and heteroaromatic acyl oximes (as well as dioxime oxalates) afforded good yields of phenanthridines and related heterocycles. Easily prepared oxime oxalate amides released carbamoyl radicals, and pleasingly, β-lactams were thereby obtained. Oxime carbonates and oxime carbamates, available via our novel 1,1'-carbonyldiimidazole (CDI)-based preparations, were accessible alternatives for iminyl radicals and hence for phenanthridine preparations. In their second modes, these compounds proved their value as precursors for exotic alkoxycarbonyloxyl and carbamoyloxyl radicals. Microwave-assistance was shown to be a particularly convenient procedure with O-phenyl oxime ethers. The iminyl radicals generated from such precursors with alkene, alkyne, and aromatic acceptor substituents furnished pyrrole, quinoline, phenanthridine, benzonaphthiridine, indolopyridine, and other systems. Microwave irradiations with 2-(aminoaryl)alkanone O-phenyl oximes enabled either dihydroquinazolines or quinazolines to be obtained in very good yields. The fine quality of the EPR spectra, acquired during photolyses of all the O-carbonyl oxime types, marked this as an important complement to existing ways of obtaining such spectra in solution. Quantifications enabled SARs to be obtained for key reaction types of N-and O-centered radicals, thus putting mechanistic chemistry in this area on a much firmer footing. Surprises included the inverse gem-dimethyl effect in 5-exo-cyclizations of iminyls and the interplay of spiro-with ortho-cyclization onto aromatics. Insights into unusual 4-exo-cyclizations of carbamoyl radicals showed the process to be more viable than pent-4-enyl 4-exo-ring closure. Another surprise was the magnitude of the difference in CO 2 loss rate from alkoxycarbonyloxyl radicals as compared with acyloxyl radicals. Their rapid 5-exo-cyclization was charted, as was their preferred spiro-cyclization onto aromatics. The first evidence that N-monosubstituted carbamoyloxyls had finite lifetimes was also forthcoming. It is evident that oxime derivatives have excellent credentials as reagents for radical generation and that there is ample room to extend their applications to additional radical types and for further heterocycle syntheses. There is also clear scope for the development of preparative procedures based around the alkoxyl and aminyl radicals that emerge downstream from oxime carbonate and oxime carbamate dissociations.

The chlorine atoms in 3,5-dichloro-4-dicyanomethylene-1,2,6-thiadiazine 1 are readily displaced by thiophenols in
the presence of Hünig’s base, the first at
78 C and the second at 20 C to give the orange mono- and bis-arylthio
derivatives in high yield (Table 1). Similarly secondary amines give the red mono- and blue bis-amino compounds
in high yield (Table 2); piperidine, for example, gives the former at
78 C and the latter at
30 C. A low limit of
reactivity is reached with diisopropylamine which gives the mono derivative only, in low yield (30%). Reactions with
ammonia and with primary amines are complex since the amines formed can cyclise onto the adjacent cyano group,
aniline giving only a low yield of the pyrrolo[2,3-c][1,2,6]thiadiazine 8. The 4-dicyanomethylene compound 1 is more
reactive than the known 4-oxo analogue 2, but can suffer the added complications of cyano group cyclisation and
hydrolysis of dicyanomethylene to the keto group. 3,5-Dimorpholino-4-dicyanomethylene-1,2,6-thiadiazine 7c is
oxidized to the sulfoxide 9 with MCPBA or N2O4, and 9 reverts to 7c with triphenylphosphine–tetrachloromethane,
all in high yield. Thiadiazine 1 undergoes a complex reaction with DMSO at 20 C to give the three furo[2,3-c]-
[1,2,6]thiadiazines 10, 11 and (tentatively) 12 which could all arise from the initial product 13 of displacement of
chlorine by DMSO, by cyclisation and sulfoxide type rearrangements. Mechanisms are proposed for all new
reactions.

The chloride ion catalysed addition of SCl2 to TCNE gives the 4-dicyanomethylene-1,2,6-thiadiazine 2 (60%) with two minor  products (5%) of extensive molecular rearrangement, the pyrimidine 4 and the pyrroloimidazothiadiazine 5. Mechanisms proposed for the formation of all three products involve the interaction of SCl2 with one cyano group and neighbouring group participation by geminal and vicinal cyano groups. The dicyanomethylene thiadiazine 2 reacts further with SCl2 to give the pyrrolo-1,2,6-thiadiazine 19. The two chlorine atoms of the pyrroloimidazothiadiazine 5 are successively replaced by pyrrolidine to give the substitution products 20 and 21 in high yield. 1H and 13C NMR spectra show that rotation of the pyrrolidine ring on the thiadiazine is considerably slower than for that on the pyrrole ring, and there is electron delocalisation across the new 14π tricyclic heteroaromatic system.

4,5-Dichloro-1,2,3-dithiazolium chloride 1 condenses with active methylene compounds, such as malononitrile, barbituric acid and Meldrum’s acid, to give the dithiazol-5-ylidene derivatives, such as 3, 4 and 5, in modest yields. Better yields are obtained from 4-chloro-1,2,3-dithiazole-5-thione 6. Thus the thione 6 condenses with diphenyldiazomethane in a very mild version of the Barton double extrusion synthesis of hindered alkenes; this requires neither heat to extrude nitrogen nor a phosphine to abstract sulfur, to give the alkene 7 (83%) (Scheme 1). This alkene rearranges at room temperature, with loss of hydrogen chloride and sulfur, to give the benzothiophene 13 (89%) in a new thiophene ring-forming reaction (Scheme 2). The thione 6 also condenses with tetracyanoethylene oxide to give a better yield of the dicyanomethylene compound 3 (70%) (Scheme 4). Compound 3, in turn, reacts with morpholine and with chloride ions (Scheme 5) to give 3-morpholino- 19 (60%) and 3-chloro- 20 (100%) isothiazole-4,5-dicarbonitrile, in a new isothiazole ring synthesis. Mechanisms are proposed for all of these reactions.

Reactions of 2-amino-N'-arylbenzamidines with butanedione resulted in the formation of 2-acetyl-3-aryl-2-methyl-2,3-dihydroquinazolin-4(1H)-ones instead of the expected 2-acetyl-4-arylamino-2-methyl-1,2-dihydroquinazolines. The intermediate 1-(3-aryl-4-imino-2-methyl-1,2,3,4-tetrahydroquinazolin-2-yl)-ethanones were hydrolyzed to the final products by water molecules present in the reaction medium.

Abstract: Organomercurials of 1, 3, 4-oxadiazoles, 1, 3, 4-thiadiazoles, 1, 2, 4-triazolo [3, 4-b]-1, 3, 4-thiadiazoles containing mercapto group in the 2-position have been synthesised under microwave irradiation in open vessels using a domestic microwave oven as compared to the conventional method. The reaction time has been brought down from hours to minutes with improved yields. The organomercurials have also been shown to exihibit promising antifungal activity.