Syntheses of N-heterocycles via arene functionalization of nitrosoarenes

I greatly appreciate and acknowledge the support received from other laboratories of Department of Chemistry, IIT Guwahati. I would like to thank all the operators and staff members of Department of Chemistry, IIT Guwahati.

Members of Doctoral committee

Reactivity of nitrosoarenes

N-Aminations of Benzylamines and Alicyclic Amines with Nitrosoarenes to Hydrazones and Hydrazides

Lewis Acid Catalyzed Pseudo Three-Component Annulation of Nitrosoarenes and (Epoxy)styrenes to provide

Nitroso-azomethine ene reaction enabled three component annulations of nitrosoarene, azomethine and alkene to

Abstract

Reactivity of nitrosoarene

Diverse reactivity of nitrosoarene

From previous reports on various reactions of nitrosoarenes, it is well anticipated that important heterocyclic cores can be synthesized, viz. indoles, acridine, phenazine, carbazole, etc., using C-H functionalization of nitrosoarenes. Most of these strategies for the C–H functionalization of nitrosoarenes are based on a metal-mediated route, including external oxidants, along with a multistep synthesis with an undesired side product.

Metal-Free Sequential C(sp 2 )−H and C(sp 3 )−H Aminations of Nitrosoarenes and N-Heterocycles to Ring-Fused Imidazoles

Proposed mechanism for metal free annulation of nitrosoarene and N-heterocycles

N-Aminations of Benzylamines and Alicyclic Amines with Nitrosoarenes to Hydrazones and Hydrazides

Substrate scope of hydrazones
Substrate scope of hydrazides
Proposed mechanism for hydrazone and hydrazides
Scope of 2,4-di-substituted and 4-substituted quinoline derivatives
Proposed mechanism for annulation of nitrosoarene and styrene
Scope of 3-aryl quinoline derivatives
Proposed mechanism for annulation of nitrosoarene and epoxystyrene

Lewis acid-catalyzed annulation reaction via arene functionalization of nitrosoarenes was developed and C-C cleavage of (epoxy)styrene to provide arylquinolines was developed. Subsequently, the Cu(OTf)2-catalyzed annulation reaction of nitrosobenzene with epoxy-styrene is developed to provide 3-arylquinolines.

CHAPTER V: Nitroso-azomethine ene reaction enabled three component annulations of Nitrosoarene, azomethine and alkene to Arylquinolines

Substrates of differently substituted quinolines

Scope of 2-phenylquinolines

Proposed mechanism for nitrones and its annulation with styrene and vinylether

CHAPTER - 1

Introduction
Monomer-dimer equilibrium of nitroso compounds
Diverse reactivities of nitrosoarenes

Nitroso-Aldol Reaction

General scheme for N-nitroso aldol reaction
N-nitroso-aldol reaction by Lewis et al

Nitroso-ene Reaction

Nitroso-ene reaction
Selected examples of Nitroso-ene reaction

Reaction with Donor-Acceptor cyclopropane

Reaction of nitrosoarene with donor-acceptor cyclopropanes
Cycloaddition reaction of nitrosoarene
Selected examples of [2+2]-cycloaddition reaction of nitrosoarene

C-H amination using nitrosoarenes

C(sp 2 )-H functionalization of nitrosoarene
Conclusion
References

Experiments showed that the reaction of various aromatic and aliphatic nitroso compounds with some enolate anions generate α-hydroxyamino ketones (Scheme 3, eq. 2)12 via the N-nitroso aldol pathway. The reaction was carried out in benzene at 0 oC at room temperature with 1-morpholino-1-cyclohexene 1.6 (Scheme 4, eq. 3), the corresponding aniline derivative 1.9 was isolated from the reaction together with α-hydroxyaminoketone.13 .

CHAPTER - 2

Introduction

Known methods for the synthesis of ring-fused imidazoles

Synthesis of ring fused imidazole via condensation reaction

Multistep synthesis of benzimidazoles

Synthesis of fused imidazoles by Skibo et al

Imidazole synthesis via metal free annulation reaction of substituted amines

Synthesis of imidazole through annulation reaction

Metal-free sequential C(sp2)−H and C(sp3)−H aminations of nitrosoarenes and N-heterocycles to ring-fused imidazoles.

Synthesis of ring fused imidazoles using substituted nitrobenzene

Drawback of the known methods
Hypothesis

The significant disadvantage of the known methods stems from the use of dangerous organic or metallic oxidants, reductants and the involvement of a multi-step reaction sequence. In the context of the applicability, the synthesis of these important pharmacophores via direct annulation of nitrosoarenes with N-heterocycles under conditions free of metal and hazardous reagents would be advantageous compared to the known protocols.

Electrophilicity comparison between nitro and nitroso compounds

Preliminary Result

In addition, the reactivity of nitrosoarene towards nucleophiles varies with the variation of reaction conditions.22 In accordance with the ongoing research for the development of new C−H functionalization strategy, is the possibility of direct C(sp2)−H functionalization. of a nitrosoarene was examd. Population of the same atom A (PA (N+1)) of the same molecule with (N+1) electrons is determined in a similar way (without further optimization).

Preliminary result

Optimization of reaction conditions
Scope of nitrosoarenes

The yield of benzimidazole 2.9a was increased by increasing the reaction time and temperature (Table 1, entries 4, 5). Further variation of the reaction time did not affect the yield of the desired product (Table 1, entries 8-10).

Table 1: Optimization of the reaction conditions

Preparation of aromatic nitroso compounds

Scope of successive C(sp 2 )-H / C(sp 3 )-H amination with various nitroso compounds and cyclic secondary amines
Crystal structures of ring fused imidazoles
Plausible mechanism
Gram scale synthesis

Carrying out the reaction with less equivalence of pyrrolidine provided a lower yield of the desired product (Table 1, entry 7). Decrease in yield of the desired imidazole was observed in various other solvents viz. xylene (Table 1, entry 18), dioxane (Table 1, entry 19).

Table 2: X-ray crystal structure of ring fused imidazole.

Gram-scale synthesis

Synthetic application

However, the desired imidazole 2.9a was not formed in the reaction, which eliminated the possibility of imidazole formation involving pyrroline. The desired benzimidazole 2.9a can also be synthesized on a gram scale, following the standard procedure using nitrosobenzene 2.35 , pyrrolidine 2.38 , and 2,4-DCBA under refluxing toluene conditions.

Synthetic application of imidazole derivatives

Conclusion
Experimental Section
References

Then the solvent was evaporated under reduced pressure and the crude mixture was subjected to column chromatography (neutral alumina) to yield analytically pure products. The mixture was then extracted with ethyl acetate (3x20 mL) and combined organic layers were dried over.

CHAPTER - 3

Aminations of Benzylamines and Alicyclic Amines with Nitrosoarenes to Hydrazones and Hydrazides

Introduction
Known methods for the synthesis of hydrazones

Several methods have been established for the synthesis of frameworks from different starting materials. In 2014, Shangkarling et al presented an efficient synthesis of hydrazones 3.8 from carbonyl partners 3.7 and phenylhydrazine 3.2.

Figure 1: Biologically active hydrazone molecules.

Syntheses of hydrazones via condensation reaction

Syntheses of hydrazones from alcohols

Using this method, a wide range of hydrazones 3.10 was obtained (Scheme 2, eq 4). 11 In the same year, Satyanarayana et al. The method provides complete selectivity for arylhydrazones without N-alkylated side products, which showed new possibilities for the development of dehydrogenative coupling reactions without catalytic acceptors.15.

Selected examples of syntheses of hydrazones from alcohols

Syntheses of hydrazones from alkenes and alkynes

This protocol leads to a wide variety of substituted keto-N-acylhydrazones 3.26 in good yields (Scheme 4, eq 11).18.

Syntheses of hydrazones from olefins and alkynes

Various other methods for the syntheses of hydrazones

Syntheses of hydrazones from azide, oxime and halo compounds

Syntheses of hydrazones from halide, toluene compounds

Drawback of the known methods
Hypothesis

Although, classical condensation of arylhydrazine with an aldehyde and coupling of hydrazines with an alcohol are mainly used for the synthesis of hydrazone derivatives.15,24a,b However, the synthetic utility of these methods is very limited due to the limited availability of arylhydrazine. due to their inherent instability issues and difficulties in their synthesis.24c Therefore, the development of an alternative method for the synthesis of arylhydrazones from readily available starting material is essential.16,25.

Expected imidazole from reaction with primary amine

Preliminary Result

Preliminary result

Known reaction of primary amines with nitroso

The previous literature regarding the reactivity of nitrosoarenes with primary amines revealed that nitrosoarenes 3.49 react with alkyl and arylamines 3.48 to provide the corresponding azo derivatives 3.51 which form an N=N bond (Scheme 9, cf Interestingly, a similar reaction of 3laminesoarenes with nitrosoarenes) 3.52 does not provide the desired azo derivative;27b the reaction produces azoxy derivatives 3.54 and the corresponding aldehyde. A careful analysis of the mechanistic rationalization revealed that the elimination of water involving N–H cleavage of initial N -hydroxyhydrazine derivative 3.50 provides the azo compound for alkyl or aryl amines (Scheme 9 , eq 20) .

Reaction known for primary amines and nitrosoarenes

Substrate scopes of hydrazones and hydrazides

With this initial result in hand, further experiments were performed to optimize the reaction conditions for better yields of the hydrazone. The yield of the reaction improved slightly when the reaction was performed in the presence of acetic acid (Table 1, entry 2).

Substrate scope of the N-amination reaction

Nitrosoarenes and benzylamine containing both electron-donating and electron-withdrawing groups participated in the N-amination reaction to give the corresponding hydrazones 3.45a-aa in moderate to good yields. Therefore, benzylamines with electron-donating groups (-Me, -OMe) efficiently reacted with nitrosoarene having electron-withdrawing groups (-Cl, -F, -Br, etc.) to provide the desired hydrazones 3.45h -aa in good yields.

Substrate scope of hydrazides

Crystal structures of hydrazide
Synthetic application

The iminium intermediate 3.64 is trapped by H2O to provide the corresponding hemiaminal 3.65 which on subsequent oxidation gives the hydrazide 3.59.30. Accordingly, benzylamines 3.52 were N-geminated under standard conditions to give the corresponding hydrazones which were further reacted with primary alkylamines in the presence of iodine and aq.TBHP in the same pot to provide the corresponding triazoles 3.66a-d in acceptable yields (Scheme 13). . .

One-pot triazole synthesis

Conclusion
References

TBHP (3 eq.) was added successively to the reaction mixture and the mixture was refluxed at 90 oC for another 4 h. The reaction mixture was then cooled to room temperature, 15 mL of water was added to the mixture, and the mixture was extracted with DCM (3 × 30 mL).

CHAPTER - 4

Introduction

Quinoline derivatives are ubiquitous substructures of natural products and unnatural compounds that possess valuable biological activities.1 Functionalized quinolines, especially aryl-quinolines, are widely found as the key scaffold of many natural products and bioactive molecules (Figure 1).2 Therefore, efforts are being made. devoted to the development of new and more efficient synthetic methods for the synthesis of functionalized quinoline derivatives.3,13,21 The development of new synthetic methods to obtain quinoline derivatives with a wide structural diversity, starting from readily available starting materials under simple reaction conditions remains still challenging and desirable.

Name reaction for the synthesis of quinolines

Skrup and Combes quinolines synthesis

Use of Povarov reaction for quinoline synthesis

Quinoline synthesis by Fernandes et al

Known methods of quinoline synthesis

The reaction was based on the simultaneous formation of the C-C and C-N bond under metal-free conditions (Scheme 4, eq. 7).13 In 2018, Anbarasan et al. Various substituted quinoline derivatives of biological importance 4.23 were obtained in good to excellent yields (Scheme 4, eq. 8).14.

Quinoline synthesis from different olefins

Due to the important bioactivity of quinoline scaffolds, considerable research has been devoted to developing new methods for the construction of substituted quinoline compounds, not only via Povarov reaction, but by exploiting other synthetic strategies. Highly substituted quinolines 4.30 were obtained from the reaction of glycine esters 4.28 with unactivated alkenes 4.29 at room temperature under air (Scheme 5, eq. 10).16 In 2018, Michelet et al.

Quinoline synthesis from aromatic amines

Quinoline synthesis from alcohols and alkenes

Known methods for 3-substituted quinoline synthesis

Known methods for 3-arylquinolines synthesis

Nitrone, which is known for their 1,3-dipolar cycloaddition reaction with styrene/olefin.28 Connell et al.

Known reaction of nitrone with styrene

Reactivity-switch in presence of Lewis acid

Preliminary Results

To explore the proposed hypothesis, the study was started by performing a reaction of nitrone 4.47 with styrene 4.58 in the presence of a catalytic amount of Sc(OTf)3. For this, nitrone 4.47 was prepared from benzaldehyde 4.16 and nitrobenzene 4.57 using Zn and NH4Cl following the literature procedure (Scheme 11, Eq.

Preliminary result with nitrone

Preliminary result with nitrosobenzene

Scope of successive cycloaddition with various nitroso compounds and styrene derivatives

The increase in yields of the desired products was obtained with an increase in the relative stoichiometry of 4-methylstyrene (Table 1, entry 2.3). Running the reaction with a lower catalyst loading yielded an inferior yield of the desired product (Table 1,.

Scope of the annulation reaction of nitrosoarenes and styrenes

After the successful annulation reaction of styrene derivatives with nitrosoarene, standard reaction conditions for the bis-vinyl system were used.

Reaction of nitrosobenzene with bis-vinyl system

Lewis acid-catalyzed reactivity switch: pseudo three-component annulation of nitrosoarenes and (epoxy)styrenes 4.52 nitrosoarenes and styrene following a radical pathway. to provide the tetrahydroquinoline derivatives 4.56 and 4.55, respectively. Aromatization and dehydration of 4.56 and 4.55 produced the corresponding dihydroquinoline 4.74 and 4.73 which upon surface oxidation afforded the observed aryl quinolines 4.60 and 4.60'.

Proposed mechanism for annulation of nitrosoarene and styrene

Controlled experiment for quinoline synthesis

Additional Reactions

After the successful annulation reaction of nitrosoarene with styrene derivatives, the reaction of nitrosobenzene with various olefins was tested.

Proposed mechanism for annulation of nitrosoarene and trans-β methyl styrene

Reaction of nitrosobenzene with other olefin system

Initial Result of 3-phenyl quinoline

Reaction of nitrosobenzene with epoxy-styrene

Optimization Table

The lower yield of the desired quinoline 4.40a was observed with the equal ratio of both the reactants (Table 2, entry 1). Increase in the relative stoichiometry of styrene epoxide increases the yield of the product (Table 2, entry 2).

Scope of the reaction of nitrosoarenes with styrene oxide derivatives

Plausible Mechanism

Optimized conditions using a cost-effective Cu(OTf)2 catalyst were used to study the substrate size of the reaction. The metal-coordinated nitrone 4.53 reacted with the enolate 4.88, which was generated in situ from styrene oxide 4.85 via Meinwald rearrangement,37 either by a coordinated or stepwise pathway to provide the N-oxide 4.87.

Proposed mechanism for annulation of nitrosoarene and epoxystyrene

Nucleophilic nitrosobenzene 4.52 added to the least hindered site of styrene oxide 4.85 is activated by coordination to Cu(II).

Controlled experiments for the synthesis of 3-arylquinoline

Conclusion
References

The reaction mixture was diluted with water (1X20 mL) and the reaction mixture was extracted with DCM (3X20 mL). The reaction mixture was diluted with water (1x20 mL) and the reaction mixture was extracted with DCM (3X20 mL).

CHAPTER - 5

Introduction

The ene reaction, an important transformation in organic synthesis, was discovered by Alder in 1943.1 The reaction takes place between an alkene with an allylic hydrogen (ene) and an enophile, to form a new σ-bond ( Scheme 1, eq. 1).1 Ene reaction, where a Schiff base is chosen as an enophile, is often known as an imino-ene reaction (Scheme 1, eq.

Variety of ene reactions

Literature Reports on Nitrone formation from nitrosobenzene
Hypothesis

According to the literature, [3+2]-cycloaddition reaction of the imine 5.17 with nitroso is documented to form nitrones. Therefore, the study of the reactivity of imine with nitrosoarene will be important in the context of nitrone synthesis (Scheme 4, eq. 10).

Hypothesis of the nitrone formation

Literature known imine reaction with nitroso

The reaction results in the formation of tetrahydro-1,2-oxazine 5.16 instead of the normal cycloadduct isoxazolidine via in situ nitrone 5.11 formation (Scheme 3, cf. 8).9. Due to the presence of acidic proton, the deprotonation step will be easy for imine 5.17 to yield 5.18 or 5.19 which very easily underwent [3 + 2] cycloaddition with nitrosoarene to form nitrone (Scheme 4, eq. 9).

Known reaction of imine with nitroso compounds

Literature Report on 2,4-disubstituted quinolines

General protocol for quinoline syntheses

Selected known methods for 2-phenylquinolins

The reaction proceeded via blue light-mediated carbon–carbon double bond isomerization of 5,32 in the absence of any photo-redox catalyst (Scheme 7, eq. 13).13 The following year, Cheon et al.

Syntheses of 2-aryl quinoline from aminostyryl ketone

Selected examples of 2-phenylquinoline from amino benzyl alcohol

Preliminary Result for nitrone

Preliminary result for nitrone synthesis

Optimization of the reaction
Scope of nitrone formation from symmetric and unsymmetric imines

Initially, the reaction of nitrosobenzene with an imine was investigated in various solvents without changing the relative stoichiometry of the two reactants (Table 1, entries 1–8). A moderate yield was observed with toluene (Table 1, entry 2), but was not improved using DCM (Table 1, entry 3).

Synthesis of nitrones from imines containing different substituents at aldehyde and amine component

Preliminary result for the synthesis of quinoline

Preliminary result for quinoline synthesis

One-pot optimization
Substrate scope of quinolines

Based on the preliminary result, different reaction conditions were screened to obtain a better yield of the quinolines. The tolerance of the imine and styrene derivatives was also checked under the optimized condition.

Substrate scopes with differently substituted quinolines

Substrate scope of 2-phenylquinoline

Decreasing yield of the desired product was observed with decreasing reaction time (Table 3, entry 5). The substrate scope of 2-arylquinoline 5.35a-l was also investigated by reacting various nitrosoarenes and imines in the presence of ethylvinyl ether.

Table 3: Optimization Table Entry Eq. of

Substrate scope of 2-arylquinolines

Plausible Mechanism

The nitroso-azomethine reaction enabled three-component annulations of nitrosoarene, azomethine, and alkene to arylquinoline intermediates 5.50 and 5.50', respectively.

Plausible mechanism for the annulation

Controlled Experiments

Asymmetric imine 5.58 and 5.58' were reacted separately with nitrosobenzene 5.2 to control the relative ratio of the two nitrones 5.42j and 5.11.

Controlled reaction with unsymmetric imines

Controlled reactions with N-phenyl maleimide

Deuterium exchanged reactions
Controlled experiment with other imine

Deuterium experiment with other imine

Syntheses of oxazolidine

Substrate scope of oxazolidines

Identification of imine as an intermediate

Identification of imine in the reaction mixture

Conclusion

The crude mixture was subjected to flash chromatography (silica gel) to obtain analytically pure products. The crude mixture was subjected to column chromatography (neutral aluminum oxide) to obtain analytically pure products.