These reactions are used for the synthesis of heterocycles using the MCR approach, which is also highlighted in the first chapter of the thesis. A key feature of this protocol is the intermolecular hydrogen bond-driven γ-selective C–C bond formation of the β-ketoester rather than the α-selective C–C bond formation for the regioselective synthesis of 1,5-benzodiazapine derivatives.
Synthesis of pyran annulated heterocyclic compounds using DMAP as a catalyst through One-pot three-component reaction
Pyridinium ylide mediated one-pot three-component regio- and diastereoselective synthesis of trans -2,3-dihydrofuran derivatives
GENERAL REMARKS
Brief review on importance of 1,3-dicarbonyl compounds for the syntheses of heterocycles
Multicomponent reactions (MCRs)
In 1850, Strecker first reported12 the synthesis of α-aminonitrile derivatives by the condensation of aldehyde/ketone, hydrogen cyanide and amine or its equivalent, which is a major breakthrough for the modern contribution to the development of multicomponent reaction. In the year 1921, Passerini 14 demonstrated isocyanide-based three-component reaction (3-CR) for the synthesis of depsipeptide-like elements starting from carboxylic acid, carbonyl compound and isocyanide.
Use of 1, 3-Dicarbonyl Compounds in Multicomponent Reactions
Later, Ugi15a and his co-worker have shown a remarkable contribution to the construction of dipeptide elements using isocinide-based MCR by adding the amine to the starting material of Passerini. Using isocyanides as one of the main starting materials, Ugi and co-workers have shown the versatility of the multicomponent reaction for synthesizing a large number of new molecules.15b Likewise, 1,3-dicarbonyls have been widely used in multicomponent reactions ( MCRs ) from different research groups for the synthesis of numerous compounds.16 Therefore, the synthetic application of 1,3-dicarbonyl compounds are addressed below towards the synthesis of heterocyclic compounds as the aim of my research work to synthesize heterocyclic compounds using types of similar starting materials.
Synthesis of heterocycles involving MCRs based on the Hantzsch reaction The Hantzsch Reaction
Later, Moseley demonstrated19 the synthesis of fused 1,4-dihydropyridine 14 as ZD0947 (15), a potassium channel opener, involving the Hantzsch reaction as shown in Scheme 5. More recently Kappe et al.24 devised the modified Hantzsch reaction. for the synthes of the stereoselective synthesis of pyrazolo[4,3-c]quinolizin-9-ones using microwave irradiation of a mixture of dimedone (10), aminopyrazoles 20, and aromatic aldehydes in the presence of a base.
Synthesis of heterocycles involving MCRs based on the Michael reactions .1 The Michael Addition
- Five-Membered Heterocycles .1 Synthesis of Pyrrole Derivatives
- Seven membered heterocycles Diazepines Synthesis
Shi et al.35 described the synthesis of substituted dihydrofuran derivatives 41 by a Lewis base-catalyzed cascade condensation reaction of nitroalkenes 38, aldehydes 39 and 1,3-dicarbonyl compounds 40 as shown in Scheme 13. The same group further demonstrated38b the synthesis of polyfunctionalized pyridines using β,γ-unsaturated α-ketocarbonyls instead of α,β-unsaturated aldehydes or ketones.
Synthesis of heterocycles through MCRs based Knoevenagel reaction
- Five-Membered Heterocycles
- Six-Membered Heterocycles .1 Synthesis of Pyran Derivatives
Furthermore, this approach has been further extended to cyclic 1,3-dicarbonyls 79 for the synthesis of tetrahydrobenzopyran derivatives, also known as tetrahydrochromenes, due to their wide range of biological activities. Indeed, a four-component Knoevenagel–Michael addition cyclization sequence has been used for the synthesis of dihydropyranopyrazole derivatives 91 from hydrazine hydrate 89, malononitrile, β-ketoester, and aldehyde/ketone 90 (Scheme 31).65.
Synthesis of heterocycles through MCRs based Mannich reaction
- Seven-Membered Heterocycles 1,5-Benzodiazepine Derivatives
In this transformation, the chiral phosphoric acid derivative 103 was used for the synthesis of a wide range of 2,5-dihydropyrrole derivatives. The utility of 1,3-dicarbonyl compounds for the synthesis of various heterocyclic compounds by MCRs has been elaborated in the above section.
MCRs based Tietze reaction and total synthesis of natural products .1 Warfarin synthesis
From the literature, it is worth noting that 1,3-dicarbonyl compounds have great potential for the synthesis of multiple heterocycles as well as the synthesis of natural products. With this theme in mind, we perceived that 1,3-dicarbonyl compounds can be further exploited for its application in organic synthesis.
Results and DiscussionSynthesis of highly functionalized
Results and Discussion
Synthesis of functionalized piperidines
The reactions of various aromatic aldehydes containing aromatic ring substituents such as OMe, Cl, Br and NO2 with aniline and methyl acetoacetate were carried out under the same reaction conditions. Some aldehydes, such as β-naphthaldehyde and n-butanal, did not give the corresponding functionalized piperidines.
Criteria for the formation of piperidine derivatives
It was projected that β-ketoester reacts with amine to give enamine 123, which further reacts with aldehyde to give a Knoevenagel-type product. This acts as a reactive diene and it undergoes an aza-Diels-Alder reaction with imine 124 to give substituted piperidines.
A plausible mechanism for the formation of highly substituted piperidine
In addition, mechanistic studies revealed that the possibility of formation of piperidines through double Mannich-type reactions should not be discarded instead of Knoevenagel-type intermediate. C H A P T E R I I: Experimental section D is cus ions Synthesis of highly functionalized piperidines.
Experimental Section DiscussionsSynthesis of highly functionalized piperidines
TBATB) as pre-catalyst
The reaction mixture was stirred at 0 – 5 °C temperature in an ice-water bath until all the V2O5 was dissolved and the solution turned reddish brown. Complete crystallographic data for compound 1221 for the structural analysis have been deposited with the Cambridge Crystallographic Data Centre, CCDC No.
Hydrogen-bond-mediated regioselective synthesis of 1,5-benzodiazepines by employing
In the second chapter we demonstrated the usefulness of β-diketoesters for the synthesis of highly substituted tetrahydropiperidines via MCR using organic ammounimtribromide, namely TBATB as a catalyst. They also observed that the same reaction did not give a good yield in the presence of p-TSA for the synthesis of 1,5-benzodiazapines when o-phenylenediamine was used instead of ethylenediamine.101 Interestingly, the synthesis of 1,5-benzodiazapines was achieved using pentafluorobenzoic acid with the same combination. We observed that 2,6-pyridinedicarboxylic acid (2,6-PDCA) could be a useful organocatalyst for the synthesis of 1,5-benzodiazepines.
In summary, we have successfully demonstrated a simple synthetic protocol for the synthesis of 1,5-benzodiazepine derivatives using o-phenylenediamine, β-ketoesters, and aromatic aldehydes via one-pot reactions.
Experimental Section Hydrogen-bond-mediated regioselective
To a stirred mixture of o-phenylenediamine (1.0 mmol) and β-ketoesters (1.0 mmol) in 3 mL of dichloroethane in a 25 mL round-bottom flask was added 2,6-pyridinedicarboxylic acid (34 mg, 0.2 mmol) and held. to stir for 2 hours at room temperature. Then aromatic aldehyde (1 mmol) was added to it and the reaction flask was transferred to a hot oil bath for reflux. The complete crystallographic data of compound 134n for structural analysis have been deposited at the Cambridge Crystallographic Data Centre, CCDC No.
Results and DiscussionSynthesis of pyran annulated heterocyclic
Plausible mechanism for the formation of pyran-annulated heterocyclic compounds
Furthermore, the role of the catalyst was confirmed by carrying out two consecutive reactions involving 4-chlorobenzaldehyde, malononitrile and 4-hydroxycoumarin in the presence of the DMAP catalyst and without the catalyst, respectively. The desired product 142j was obtained in 5 min in 94% yield in the presence of catalyst, while the same reaction gave only 63% yield after 1 h without catalyst. The filtrate containing the catalyst was reused for a similar reaction scale for the same substrates.
Run 1 Run 2 Run 3 Run 4 Run 5
Experimental Section Synthesis of pyran annulated heterocyclic
The solid precipitate was formed immediately in case of malononitrile or it took 20-30 min for ethyl cyanoacetate. Then, C-H activated acid compound (1 mmol) was added to the reaction mixture and it was stirred under reflux conditions for stirring. After completion of the reaction, the solid precipitate came out under hot conditions at the set time mentioned in the Table 9 and Table 10.
The reaction mixture was brought to room temperature and the solid precipitate was filtered off to obtain the desired product.
Results and DiscussionPyridinium ylide mediated one-pot three-
Three-component reaction for the synthesis of fused trans-2,3-dihydrofuran derivatives
In order to optimize the reaction conditions, various experimental reactions were carried out with a combination of α-phenacyl bromide, pyridine, 4-chlorobenzaldehyde and 4-hydroxycoumarin, in the presence of catalytic amount of sodium hydroxide in water under reflux conditions. After optimization, the reaction of 4-hydroxycoumarin, benzaldehyde and α-phenacyl bromide gave the desired product 151b in 82% yield in the presence of 10 mol% NaOH under identical reaction conditions. Interestingly, the lactone ring of 4-hydroxycoumarin did not open in the presence of 10 mol% NaOH solution under the experimental conditions.
To evaluate the extent of this three-component reaction, the reactions of dimedone with aromatic aldehydes and α-phenacyl bromide in the presence of 10 mol% were studied.
Plausible Mechanism for the formation of trans-2,3-dihydrofuran derivatives
The intermediate 156 undergoes simultaneous cyclization with the elimination of pyridine to give the desired product trans -2,3-dihydrofuran derivatives 151 or 152 in a regio- and diastereoselective manner, similar to the Michael Initiated Ring Closure (MIRC) reaction. It was previously reported that the coupling constant of the cis-2,3-dihydrofuran derivative would have been 10 Hz, which is higher than the trans isomer, as shown in Figure 30. Furthermore, the structures and relative stereochemistry of fused trans-2, 3-dihydrofuran derivatives 152e were further confirmed by some XRD crystallographic data where the dihedral angle between C2 and C3 is respectively.
In summary, we have designed a simple and efficient protocol for the synthesis of trans-2,3-dihydrofuran derivatives in good yields via one-pot three-component condensation reaction of aromatic aldehydes, dimedone or 4-hydroxycoumarin, α-phenacyl bromide/4. -nitrobenzyl bromide and pyridine in presence of 10% aqueous NaOH solution.
Experimental Section Pyridinium ylide mediated one-pot three-
Subsequently, 4 ml of 10% aqueous solution of NaOH and the reaction mixture were transferred to a heated oil bath under reflux conditions. Complete crystallographic data for compound 152e for the structural analysis have been deposited with the Cambridge Crystallographic Data Centre, CCDC No. Copies of this information can be obtained free of charge from the Director, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, United Kingdom, (Fax: +44 -.
Results and DiscussionSynthesis of tetra-substituted pyrroles by four-
Plausible mechanism for the formation of substituted pyrrole derivatives Subsequently, the enamine 159 reacts with nitrostyrene 161 to provide Michael adduct
From this observation, we can believe that generated NiO coming out of the reaction further participates in the catalytic cycle for the formation of the product. However, the detailed mechanism is under investigation, which will be revealed throughout the article. It is noted that larger XRD peaks for NiO lie in the diffraction angle (θ range of 20°-50°) in the X-ray diffractogram. These peaks may be related to Ni- and or NiO-based complex(es) present in traces in the compounds.
The presence of NiCl2 in the compounds could not be noticed because the fingerprint XRD peaks of NiCl2 (expected at 2θ ~15°) are absent in XRD.156b. "by-product" of the reaction under study.
Experimental Section Synthesis of tetra-substituted pyrroles by four-
The reaction mixture was then refluxed in a heated oil bath with constant stirring. After completion of the reaction, monitored by TLC, the reaction mixture was warmed to room temperature and excess nitromethane was removed in a rotary evaporator. Then the crude residue was dissolved in 25 mL of dichloromethane and the solid particles were removed by filtration.
The organic extract was concentrated and the crude residue was finally purified through a silica gel column chromatography.
Conclusion and Future Perspective
One-pot three-component reaction for the synthesis of pyran annulated heterocyclic compounds using DMAP as catalyst' Abu T. Novel three-component reaction: Synthesis of 1-[(alkylthio)(phenyl)methyl]-naphthalen-2-ol catalyzed of bromodimethylsulfonium bromide (BDMS)' Abu T. Synthesis of highly functionalized piperidines by one-pot multicomponent reaction using tetrabutylammonium tribromide (TBATB)' Abu T.
Pyridinium ylide-mediated one-pot, three-component regio- and diastereoselective synthesis of trans-2,3-dihydrofuran derivatives 'Abu T.
Author's personal copy
A wide range of frequently tetra-substituted pyrrole derivatives were synthesized through the one-pot four-component condensation reaction of aromatic aldehydes, benzylamines, b-ketoesters and nitroalkanes in the presence of 10 mol% NiCl26H2O in good yields. Furthermore, the extent of the reaction was also verified with chiral benzylamines such as (R)-1-phenylethanamine or (S)-1-phenylethanamine under similar conditions, and the preferred products 5 and 5 were isolated in 76% and 72% yields (Table 2, entry 19, respectively and 20). From this observation, we believe that the NiO formed in the reaction further participates in the catalytic cycle for the formation of the product.
The contact residues of the synthesized derivatives from the docking studies are analyzed for their conservation within the PDE family used in the current study.
