Thanks to my foster friends Athar Bhai and Kamal Bhai for all the support and motivation at the beginning of my study away from home. My deepest gratitude to my parents, whose great sacrifices, unconditional love at every stage of my life motivated me to overcome all challenges.
S YNOPSIS
During cascade reactions, preservation of the functional group in a molecule is one of the challenging tasks for synthetic organic chemists. Therefore, there are numerous reports of palladium-, silver-, and copper-catalyzed cascade reactions in recent times.
CHAPTER II: Copper(II)-Catalyzed Cross-Dehydrogenative Coupling of N,N-Disubstituted Formamides and Phenols: A
The first method for the synthesis of carbamates by sp2 CH bond activation of dialkylformamides was reported by Reddy and co-workers in 2011. In the CO bond formation segment, the use of dialkylformamides as an aminocarbonyl substituent was used to synthesize carbamates by reacting them with phenols and enols that have ortho carbonyl directing groups.
SECTION IIIA: Thioesterification of Alkylbenzenes with Thiols via Copper-Catalyzed Cross Dehydrogenative Coupling
Various reaction parameters such as catalysts, oxidants and temperature were analyzed to obtain the optimum conditions for this reaction and it was found that the use of Cu(OAc)2.2H2O (20 mol %), TBHP oxidant 56 M in decane (4 equiv ) at a reaction temperature of 95 oC under air atmosphere is the most suitable conditions for our further exploration to expand the scope of this transformation. In conclusion, a CDC protocol has been developed for the S-aroylation of thiols using alkylbenzenes as aroyl substituents in the presence of Cu/TBHP.
SECTION IIIB: Regiospecific Benzoylation of Electron- Deficient N-Heterocycles with Methylbenzenes via a Minisci-
Until now, a number of methods have been developed for the synthesis of electron-deficient heterocycles, but their functionalization using cross-dehydrogenative coupling is far less visited. It was found that the use of AlCl3 (25 mol%) and TBHP (5-6 M in decane) (3 equiv) at 95 oC under N2 atmosphere is the best optimized condition to explore the substrate scope of the present protocol .
Cascade Synthesis of Dihydrobenzofurans and Aurones via Palladium-Catalyzed Isocyanides Insertion into 2-
In summary, we have developed a palladium-catalyzed cascade process involving isocyanide insertion and Csp2H cross-coupling for the synthesis of 2,3-disubstituted benzofurans. SECTION VA: Cs2CO3 as a source of carbonyl and ether oxygen in a Cu-catalyzed cascade synthesis of.
It has been reported that Cs2CO3 serves as a CO2 source for the synthesis of cyclic or acyclic carbonates. In conclusion, we have developed a new protocol for the synthesis of benzofuro[3,2-c]quinoline-6(5H)-one derivatives catalyzed by Cu(II).
SECTION VB: Microwave-Assisted Cascade Strategy for the Synthesis of Indolo[2,3-b]quinolines from 2-
Most available synthetic strategies for the synthesis of indolo[2,3-b]quinolines are based on the use of indole and its derivative as one of the coupling partners. Thus, in an effort to overcome the limitations of the previous methods, we have developed a simple and versatile protocol for the synthesis of indolo[2,3-b]quinolines from 2-(phenylethynyl)anilines and arylisothiocyanates.
C ONTENTS
An Overview of Metal-Catalyzed CH Functionalization and Cascade
Copper(II)-Catalyzed Cross-Dehydrogenative Coupling of N,N- Disubstituted Formamides and Phenols: A Direct Access to Carbamates 51
Cascade Synthesis of Dihydrobenzofurans and Aurones via Palladium- Catalyzed Isocyanides Insertion into 2-Halophenoxy Acrylates
A microwave-assisted cascade strategy for the synthesis of indolo[2,3-b]quinolines from 2-(phenylethynyl)anilines and aryl isothiocyanates 221 .
C HAPTER IA
IA.1. Introduction
IA.2. Traditional Vs Modern Approach
Due to the ubiquitous nature of CH bonds in organic molecule, selective functionalization of each CH bond is quite challenging. This in turn weakens the CH bond and can lead to the formation of a new metal-carbon bond (Scheme IA.4.1, complex B).
IA.7. References
C HAPTER IB
IB. An Outline of Metal-Catalyzed Cascade Reactions
IB.1. Introduction
In this respect the economy of steps is an important factor, since accessibility is highly dependent on the number of steps needed to reach the desired compound.2 Other important issues currently challenging organic chemists are nicely summarized in the ideal synthesis proposed by Wender et al. These types of reactions involve two or more bond formations in the same reaction state, where the subsequent transformation occurs in the functionalities created in the previous bond formation step.
IB.2. Historical Background
Therefore, the reaction would allow the synthesis of organic compounds in an ecologically and economically favorable way. Schöpf and Robinson10 performed the first cascade reaction for the synthesis of natural product tropinone and cocaine alkaloid structural component by assembling a mixture of succinaldehyde, methylamine and acetone dicarboxylic acid.
IB.3. Classification of Cascade Reactions
This strategy was extended for the synthesis of tetracyclic indole skeleton by introducing an internal nucleophile. Together with the Pd(OAc)2 as catalyst, a ligand P(n-Bu)3 and a base Cs2CO3 are required for the synthesis of 3-iminoindol-2-amines. A new and efficient strategy for the synthesis of isocoumarins and phthalides was developed by Ji et al.
IB.5. Cascade Reactions in Natural Product Synthesis
IB.6. References
Copper(II)-catalyzed cross-dehydrogenative coupling of N,N-disubstituted formamides and phenols: a direct access to carbamates. Abstract: An efficient copper-catalyzed protocol has been developed for the synthesis of carbamates from dialkylformamides and phenols that have directing groups such as benzothiazole, quinoline and formyl in their ortho-position. In this chelation-assisted approach, CO bond formation takes place via a cross-dehydrogenative coupling (CDC) between formyl CH of dialkylformamides and phenolic OH in the presence of copper(II) acetate/aqueous tert-butyl hydroperoxide.
C HAPTER II
Copper(II)-Catalyzed Cross-Dehydrogenative Coupling of N,N-Disubstituted Formamides and
- Introduction
- Strategies for the Synthesis of Carbamates
- Present Work
- Experimental Section
- Crystallographic Description
- General Procedure for the Synthesis of 2-Formylphenyl dimethylcarbamate (12a): An oven-dried round-bottom flask was charged with salicylaldehyde (122 mg, 1
- Intermolecular Competing Kinetic Isotope Effect (KIE) Experiment with Deuterated Formamide: To a solution of 4-methoxy-2(5-
- References
- Spectral Data
- Spectra
The first method for the synthesis of carbamates via sp2 CH bond activation of dialkylformamides was reported by Reddy and co-workers in 2011 (Scheme II.2.4).12a They achieved this by using orthoacetyl as the directing group using Cu(II) salt as catalyst and tert-butyl hydroperoxide (TBHP) as terminal oxidant. No further improvement in yield was observed even when the amount of oxidant was increased beyond 3 equiv. (table II.3.1, entry 10). The reaction of 2-(benzo[d]thiazol-2-yl)phenol (1) and DMF (a) in the presence of a radical scavenger such as TEMPO [2,2,6,6-tetramethylpiperidin-1-oxyl] resulted in the formation of carbamate (1a) in < 5% yield, indicating a radical pathway for the reaction (Scheme II.3.5).22a Surprisingly, when the reaction was carried out in the presence of another radical scavenger such as 1,4-cyclohexadine there was no retardation of the reaction rate and the yield remained unchanged.
Chapter IIIA
C HAPTER IIIA IIIA. Thioesterification of Alkylbenzenes with Thiols via
IIIA.1. Introduction
IIIA.2. Strategies for the Thioesters Synthesis
Thiocarbonylation of the haloarene with thiols and carbon monoxide. iii) N-heterocyclic carbene-catalyzed redox coupling of aldehydes with thiols Murata et al. The first reports for the thioester synthesis via radical coupling of aldehyde with disulfide in water were reported by Kita et al. The decarboxylative coupling of -oxo acids with thiols or disulfide for the thioester synthesis has also been developed by Mao et al.
IIIA.3. Present Work
Additionally, thioester formation via the thioether intermediate obtained from the coupling of the thiol with the benzyl radical/cation was ruled out due to the results obtained from the control experiments in Scheme IIIA.3.2.ii and iii. A presynthesized benzyl(4-chlorobenzyl)sufflan (h) with two benzylic carbons failed to undergo benzylic oxidation under the reaction conditions at either benzylic position, instead giving the sulfur oxidation product 1-(benzylsulfinyl)methyl)- 4-chlorobenzene (k ) (Scheme IIIA.3.2.ii). The coupling reaction between thiol (1) and toluene (a) was significantly inhibited in the presence of the radical scavenger (TEMPO) giving <7% product yield indicating a radical nature of the reaction (Scheme IIIA.3.2.iv ).
IIIA.4. Experimental Section
The crude product was purified on a silica gel column and eluted with 9:1 (hexane/ethyl acetate) to give S-4-methoxyphenyl benzothioate (1a) (170 mg, 70%). The crude product was purified over a silica gel column and eluted with hexane to give the expected product in 38% yield (5a and 5a'). The ratio of deuterated (5a') to non-deuterated (5a) S-aroylated product was calculated based on the integration ratio of the aromatic proton peak at δ 8.02 (originating from toluene) and the –CH3 proton at δ 2.41 (originating from thiol ).
IIIA.5. References
IIIA.6. Spectral Data
IIIA.7. Spectra
Chapter IIIB
C HAPTER IIIB IIIB. Regiospecific Benzoylation of Electron-Deficient
IIIB.1. Introduction
Metal-free approach to acylation of N-heterocycles A trifluoroacetic acid (TFA) and TBHP-mediated cross-dehydrogenative coupling between N-heterocycles and aldehydes was developed by Liu et al.11c Apart from this later, the same group also described a MnO2-catalyzed acylation of N- heterocycles using methylarenes as an aroyl source in the presence of TBHP as an oxidant and TFA as an additive (Scheme IIIB.2.3). Pd(II)-Catalyzed Aroylation of N-Heterocycles with the -Nitro Acid Very recently, Singh and co-workers developed a facile and efficient decarboxylative protocol for the acylation of isoquinoline in aqueous medium using -keto acid as the aroyl source and K2S2O8 as the oxidant. metal or additives (schedule IIIB.2.5).11f. Decarboxylative aroylation of N-heterocycles with -keto acids Therefore, the development of new and efficient CDC reactions in which such challenges can be overcome is of great importance in synthetic organic chemistry (Scheme IIIB.2.6).
IIIB.3. Present Work
Maintaining the temperature at 95 oC and carrying out the reaction under N2 atmosphere led to a 6% further improvement in the yield (Table IIIB.3.1, entry 15). As can be seen from Scheme IIIB.3.1, all these isoquinolines underwent efficient coupling with alkylbenzenes (a and d) under the present reaction conditions to provide products (2a), (3a), (4a) and (4d) which are well for moderate yields (Scheme IIIB.3.1). Significant quenching of product formation in the presence of radical inhibitor (TEMPO) was observed (Scheme IIIB.3.4). 5%) of coupled product, a TEMPO ester (58%) was also isolated.
IIIB.4. Experimental Section
After completion of the reaction, as shown by TLC, the reaction mixture was cooled to room temperature and ethyl acetate (30 mL) was added. The ratio of deuterated (1a') to non-deuterated (1a) aroylated product was calculated from the integration ratio of the peak of the aromatic proton at δ 7.48 (originating from toluene) and the aromatic proton at δ 8.60 (originating from N-heterocycles). . By correlation with the original spectra (1a), the number of protons at δ 7.48 should be 2, and the integration found for the same should be 2.00.
IIIB.5. References
IIIB.6. Spectral Data
IIIB.7. Spectra
Abstract: A palladium-catalyzed isocyanide insertion into 2-halophenoxyacrylates leading to an unprecedented synthesis of dihydrobenzofurans (DHBs) with two exocyclic double bonds has been achieved. The iodo analog gives dihydrobenzofurans (DHBs) with an exocyclic imine, while the broma analog gives a product in which the imine bond is in the reduced state.
C HAPTER IV
Cascade Synthesis of Dihydrobenzofurans and Aurones via Palladium-Catalyzed Isocyanides Insertion
- Introduction
- Strategies for the Synthesis of Dihydrobenzofurans and Aurones
- Present Work
- Experimental Section
An intramolecular Chan-Lam coupling has been reported for the synthesis of 2,3-disubstituted DHBs in two-step reaction catalyzed by gold and copper (Scheme IV.2.3).12j. A number of carbene insertions in CH bond have been developed by various groups using Rh catalyst (Scheme IV.2.7).11. To establish this, a reaction was carried out in the presence of 10 equiv. D2O under otherwise identical conditions (scheme IV.3.5b).
