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Expeditious strategies towards the construction of C-C and C-heteroatom bonds


Academic year: 2023

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Babulal Das for the help he has provided me with the Single Crystal XRD studies during my Ph.D. My heartfelt thanks to him for being there by my side during the highs and lows of my life.


Coupling chemistry is an important synthetic approach to the construction of CC and Cheteroatom bonds that has been widely explored in industry and academia. The third section of this chapter provides a brief account of exploration of oxirane chemistry towards the formation of CC and Cheteroatom bonds.

To check the efficiency of the catalyst for the next catalytic cycle, the catalyst was detd. In conclusion, we have developed a simple and efficient CuO nanoparticle-catalyzed method for the synthesis of 2,3-substituted quinazolinones by the coupling of 2-halobenzamides and (aryl)methanamines.

CHAPTER III: Base-Promoted Synthesis of Quinoline-4(1H)- thiones from o-Alkynylanilines and Aroyl Isothiocyanates

The presence of different substituents on the phenyl rings of o-alkynylanilines also enabled excellent product yields in the reaction with different aroyl isothiocyanates. A probable mechanism for the synthesis of quinolin-4(1H)-thiones. In conclusion, we have demonstrated a metal-free approach for the synthesis of quinoline-4(1H)-thione derivatives.

The analysis of the product confirms a [4 + 2] annulation of alkyne via oxidative CH/SH bond cleavage versus other competing annulations (CH/NH or CH/OH). Plausible Mechanism for Cancellation of Quinoline-4(1H)-Thions In summary, we have demonstrated the first thiocarbonyl-directed regiospecific cancellation of alkynes with quinoline-4(1H)-thions.

N,N-Dimethylacetamide (DMA) as a Methylene Synthon for Regioselective Linkage of Imidazo[1,2-a]pyridine

To determine the source of the methylene carbon in the product, a similar reaction was performed separately with N,N-dimethylformamide (DMF) and N,N-diethylacetamide (DEA) instead of DMA under otherwise identical conditions. When the reaction was carried out with DMF-d7, the insertion of a deuterated methylene group was observed, which was confirmed by HR-MS analysis of the reaction mixture.

CHAPTER VI: Organocatalytic Regioselective Concomitant Thiocyanation and Acylation of Oxiranes Using Aroyl

Another peak at 1705 cm-1 may be due to the presence of a carbonyl group in the resulting product. In conclusion, we have demonstrated a biomimetic organocatalytic bisfunctionalization of oxiranes from aroyl/acylisothiocyanates in the presence of NMI.


Chapter II CuO Nanoparticle Catalyzed Synthesis of 2,3-Disubstituted Quinazolinones via Sequential N-Arylation and Oxidative CH Amidation 83. An Overview of Cascade Reactions, Metal-Catalyzed C  H Functionalization and Oxirane Construction Chemistry for.


IA. An Overview of Cascade Reactions

IA.1. Introduction

Other important issues that organic chemists must deal with are summarized in the ideal synthesis proposed by Wender et al. Until now, the normal procedure for organic compound synthesis has been a stepwise formation of individual bonds in the target molecules, with a workup and isolation step after each transformation.

IA.2. Historical Background

These reactions involve the transformation of two or more bond-forming reactions under identical conditions, in which the latter transformations occur in the functionalities obtained in the first bond-forming reactions. Robinson15 described a domino process for the synthesis of tropinon which was later improved by Schöpf16 using succinaldehyde, methylamine and acetonedicarboxylic acid without isolating any intermediate.

IA.3. Classification of Cascade Reactions

Copper-catalyzed synthesis of benzofuran[3,2-c] quinoline-6[5-H]one Lv group reported a new and efficient Cu(I)-catalyzed CS coupling/double cyclization leading to the synthesis of pyrrolo[ 3, led, 2,1-cl]phenothiazines. Copper-Catalyzed Synthesis of Pyrrolo[3,2,1-kl]phenothiazines Du and co-workers reported an unusual Cu(II)-promoted cascade reaction involving the annulation of diarylalkyne sulfonamides to form 5,10-dihydroindolo[3,2-b]. indoles (Scheme IA.5.3).62 This unprecedented process incorporates two consecutive CN bond formation, leading to an efficient synthesis of biologically important indoloindole derivatives.

IA.6. Cascade Reaction in Natural Product Synthesis

Metal-free synthesis of 3-sulfenylindoles. such as CH activation, organocatalysis, and photoredox chemistry) together with the evergreen creativity of the synthetic organic chemist, concise and efficient routes to complex bioactive natural products can be designed. Carbopalladation cascades in the synthesis of rubriflordilactone A The transformation involves the cascade cyclization of a complex bromoendiyne (1).

IA.7. References


IB.1. Introduction

IB.2. Traditional Vs Modern Approach

Scheme IB.2.2 shows how transition metal-catalyzed cross-coupling reactions have evolved from traditional coupling to the modern approach of CH bond functionalization. During oxidative addition, the transition metal coordinates to the CH σ-bond and donates electron density to the σ* orbital of the CH bond (Scheme IB.4.1, complex A). This reduces the bond order and weakens the CH bond, resulting in the formation of a new metal–carbon bond (Scheme IB.4.1, complex B).

Mild reaction conditions, broad substrate scope, and good functional group tolerance are the notable features of the reaction (Scheme IB.5.1.14).70. The Fu group developed a cross-dehydrogenative coupling reaction for the synthesis of imides from aldehydes and secondary or tertiary amides (Scheme IB.5.2.9).81 The reaction takes place in the presence of catalyst CuBr2 and NBS as oxidant. The Li group developed a new CC bond formation based on the direct oxidative Csp2H/Csp3H coupling of directing arenes and cycloalkanes in the presence of Ru(II) catalyst and di-tert-butyl peroxide (DTBP) as oxidant (form IB.5.3.4).90.

IB.7. References


IC. A Brief Account on Oxirane Chemistry

IC.1. Introduction

IC.2. Synthesis of Oxiranes

The use of sulfur ylides is another method adopted by many organic chemists for oxirane synthesis (Scheme IC.2.2.2).9 Sulfur ylides can be produced by various methods such as (i) desilylation of (trimethylsilyl)methylsulfonium salts using CsF in DMSO10a (ii) in situ generation by decarboxylation of carboxymethylsulfonium betaine10b (iii) from trimethylsulfonium iodide and sodium hydride10c (iv) using the Simmons-Smith reagent to generate sulfur ylides from sulfides.10d. A widely used method for oxirane preparation is the Priležaev reaction, which involves the epoxidation of alkenes with peracids via a cyclic transition state, as shown in Scheme IC. These reactions are highly exothermic. The combination of formamide and hydrogen peroxide effectively oxidizes tri- and cis-disubstituted alkenes (Scheme IC.2.3.2).16 Water-soluble alkenes can be epoxidized directly using bicarbonate-activated H2O2 in a mixed solvent system.17.

In substrates with multiple double bonds, the most electron-rich double bond is selectively epoxidized (Scheme IC.2.3.4).21. Terminal alkenes have been oxidized to epoxides using 2-ethylhexanal and oxygen in the absence of any catalyst or solvent.22a A metal-free approach has been reported for the epoxidation of olefins via in situ formation of H2O2 from alcohols and O2 under the influence of N-hydroxyphthalimide (NHPI) and hexafluoroacetone (HFA) (Scheme IC.2.3.5).22b However, the epoxidation of olefins by O2 in the presence of aldehyde proceeds via the formation of an acyl peroxy radical.22c. For example, Oxone, pyridine, 2-pyrrolidine derivative in the presence of CH3CN selectively converts triene into a single epoxide (Scheme IC.2.3.6).24 The mechanism is assumed to proceed via a process of single-electron transfer (SET) in which radical cation intermediate.

IC.3. Reactivity of Oxiranes

Regio- and Stereoselective Ring Opening of 2,3-Diaryloxiranes The Doyle group reported the enantioselective ring opening of epoxides with a fluoride anion promoted by a cooperative dual catalytic system (Scheme IC.3.1.2).37. Venkateswarlu and co-workers demonstrated protective ring opening of epoxide with pivaloyl halides in the absence of any catalyst and under solvent-free conditions (Scheme IC.3.1.3).38 The protocol gives high yields and involves simple experimental procedures. The same group reported the first reductive coupling of epoxides with aldehydes in the presence of a Wilkinson catalyst (Scheme IC.3.2.6).49 Experimental studies show that epoxide ring opening occurs before aldehyde reduction.

Ring opening of oxirane with amines catalyzed by various metal salts The Chakraborti group reported the reaction of epoxide with amines catalyzed by Zn(II) salt, giving 2-aminoalcohols in high yields (Scheme IC.3.3.2).52 The transformation takes place in the solvent-free state with excellent chemo-, regio- and stereoselectivities. Regioselective alkyl and alkynyl substitution of epoxy alcohols Alam, Wise and co-workers described a Cu-catalyzed regioselective ring opening of epoxides with Grignard reagents (Scheme IC.3.4.4).62 The reaction afforded the desired products in >90% yield with excellent regioselectivity and purity . Bégué and co-workers demonstrated a one-pot synthesis of -hydroxysulfoxides by ring opening of oxiranes with thiols in hexafluoroisopropanol (HFIP) solvent followed by selective oxidation (Scheme IC.3.5.1).69 The reaction takes place in the absence of any catalyst.

Figure IC.3.1. Ring-opening in 1,2-disubstituted oxiranes
Figure IC.3.1. Ring-opening in 1,2-disubstituted oxiranes

IC.4. References

ABSTRACT: A CuO nanoparticle-catalyzed synthesis of 2,3-disubstituted quinazolinones has been achieved from 2-halobenzamides and (aryl)methanamines under an air atmosphere. This synthesis of N-heterocycle involves a sequential Ullmann coupling [between 2-halobenzamide and (aryl)methanamine], oxidation of the in situ generated secondary amine to imine. This is then followed by an intramolecular nucleophilic attack of the amidic N–H on the imine carbon (C–N bond formation), resulting in the synthesis of 2,3-disubstituted quinazolinones.

The recyclability of the catalyst and the tolerance of a wide range of functional groups make this method efficient and cost-effective.


  • Introduction
  • Strategies for the Synthesis of Quinazolinones
  • Present Work
  • Experimental Section
    • General Information: All the compounds were commercial grade and used without further purification. Organic extract was dried over anhydrous sodium sulfate
    • Crystallographic Description
  • References
  • Spectral Data
  • Spectra
  • Introduction
  • Idea Towards the Synthesis of Quinoline-4(1H)-thiones
  • Present Work
  • Experimental Section
    • General Information: All the compounds were commercial grade and used without further purification. Organic extract was dried over anhydrous sodium sulfate
    • Crystallographic Description
  • References
  • Spectral Data
  • Spectra

As shown in Scheme II.3.1, most of the substrate studied give good to moderate yields of products regardless of their electronic environment. An intramolecular nucleophilic attack of the amidic NH on the imine carbon generates (E) which is finally oxidized to give product (1a) (Scheme II.3.3). After completion of the reaction (as indicated by the TLC), the reaction mixture was cooled to room temperature and mixed with water (10 mL) and the product was extracted with ethyl acetate (2 x 20 mL).

Motivated by the synthesis of quinolin-4(1H)-thiones, further optimization of the reaction parameters was tailored to increase the productivity of the reaction. Surprisingly, when the reaction was carried out in the absence of catalyst under otherwise identical conditions, the yield of product was significantly improved (77%), while only a trace (13%) of product was observed in the absence of base (Table III. 3.1, entries 13 and 14 ). Lower yield at higher temperature may be due to degradation or dimerization of the product.

The scope and generality of the base-promoted reaction was extended to a variety of o-alkynylaninines and aroylisothiocyanates under the optimized reaction conditions (Table III.3.1, entry 20). After completion of the reaction (as indicated by TLC), the crude mixture was evaporated in vacuo to remove CH3CN solvent and the reaction mixture was mixed with ethyl acetate (20 mL).

Table II.3.1. Screening of the reaction conditions a
Table II.3.1. Screening of the reaction conditions a


Figure IA.1.1. The ideal chemical synthesis proposed by Wender et al.
Figure IC.3.1. Ring-opening in 1,2-disubstituted oxiranes
Figure II.1.1. Natural products and drug compounds containing quinazolinone  skeleton
Table II.3.1. Screening of the reaction conditions a


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