I hereby declare that the matter included in this thesis is the result of research carried out by me at the Department of Chemistry, Indian Institute of Technology, Guwahati, India, under the guidance of Prof. Her thesis entitled “Investigation of Newer Strategies for the Construction of CC and Cheteroatomic Bonds under Metallic and Nonmetallic Conditions” is an authentic record of the results obtained through research work at the Department of Chemistry, Indian Institute of Technology Guwahati, Assam, India.
A CKNOWLEDGEMENT
I would like to express my sincere thanks to my best friends Sonu, Bebina, Rosy, Rasmi, Chandini, Soumita, Nibi and Amiya for their constant support, encouragement and all the help they provided whenever was required. I would like to express my best regards to my teachers Chitta Sir, Rajesh Sir, Purusottam sir, Rasmi Sir, Sarat Sir, Sabita Mam, Seetaram Sir, Varadwaj Sir and Purnendu Sir for their outstanding teaching, ideas deep and blessings.
S YNOPSIS
An Overview of CH Functionalisation, Cross Dehydrogenative Coupling and Other Newer Aspects of CC
This chapter describes a copper(II)-catalyzed o-benzoxylation of 2-arylpyridines using arylmethylamines as arylcarboxy-surrogates in the presence of oxidant. From the experimental observations, a tentative mechanism for the copper-catalyzed o-benzoxylation of 2-arylpyridines is proposed as depicted in Scheme II.2.
CHAPTER III: Benzyl Bromides as Aroyl Surrogates in Substrate Directed Pd Catalysed o-Aroylation
The optimized condition was then applied to the o -arolation of 2-phenylpyridines using various substituted benzyl bromides. A moderate to good yield of the aroylated product was obtained from the oxidative coupling of benzo[h]quinoline and substituted benzyl bromides.
One-Pot Sequential Synthesis of N-(2-(Phenylsulfinyl)phenyl)acetamides: A Ring Opening (Phenylsulfinyl)phenyl)acetamides: A Ring Opening Rearrangement Functionalization (RORF). Finally, a two-step optimized process was developed for the synthesis of N-(2-(p-tolylthio)phenyl)acetamide (1da!).
C ONTENTS
Chapter II- Benzylamine as Arylcarboxy Surrogate: A Copper Catalysed o- Benzoxylation of 2-Phenylpyridines Using Benzylamines
Chapter III- Benzyl Bromides as Aroyl Surrogates in Substrate Directed Pd Catalysed o-Aroylation
Chapter IV-Transition Metal-free Synthesis of α-Ketoamides From Arylmethyl Ketones and Alkylphosphoramides
Spectra 151 Chapter V - One-pot sequential synthesis of N-(2-(phenylsulfinyl)phenyl)acetamides: a ring-opening rearrangement functionalization (RORF).
Chapter VI-Cyano-Sacrificial (Arylthio)arylamination of Quinoline and Isoquinoline N-Oxides Using N-(2-(Arylthio)aryl)cyanamides
An Overview of CH Functionalisation, Cross Dehydrogenative Coupling and Other Newer
Aspects of CC and CHeteroatom Bond Formations
- Introduction
- Traditional vs modern approach
- Challenges to achieve CH functionalisation
- Mechanism of CH functionalisation
An outline of the various types of transition metal-catalyzed cross-coupling and CH bond functionalization reactions are listed in Scheme I.2.2. The CH bonds involved in CH bond functionalization strategies are mostly sp2 or sp3 hybridized and have pKa values greater than 3035.
Then the in situ generated CM bond-bearing species can be converted to a new functional group with the reaction of either an external reagent or an organic ligand attached to the metal center. On the other hand, in an outer-sphere mechanism, the CH bond within the substrate reacts with an actively chelated ligand of the metal.
Finally, the separation of CH proceeds with increasing the oxidation state of the metal.
Modern era of CH functionalisation
- Directing group (DG) assisted C H bond functionalisation
- Representative examples of directing group assisted CC bond formation
- Representative examples of CO bond formations
- Representative examples of CN bond formation
- Representative examples of CS bond formation
- Representative examples of CB, CSi and CP bond formation
- Representative examples of CX (X = F, Cl, Br, I) bond formation
- Cross-dehydrogenative coupling
- Representative examples of CO, CN, CS and CP bond formations
Therefore, CN bond building via transition metal-catalyzed CH bond activation is also an important strategy in organic synthesis. Some examples of transition metal catalyzed CS bond formation reactions via CH bond functionalization are shown below.
Directing group assisted cross dehydrogenative coupling
- Representative examples of CC bond formation
- Represented examples of directed CO bond formation
- Representative examples of directed CN bond formation (a) Amination
A Pd-catalyzed amide-directed Csp2–H arylation using simple arenes as arylating agents was reported by the Yu group (Scheme I. The reaction showed remarkably high paraselectivity for Csp2–H / Csp2–H coupling reactions. Pyridine-enabled cross-dehydrogenative Csp2–H bond coupling of polyfluoroarenes and Csp3–H bond activation of amides were revealed by Ge et al. In 2014, Yu and co-workers developed Cu(II)-promoted ortho-alkynylation of arenes and heteroarenes with terminal alkynes to prepare aryl alkynes via Csp2 –H / Csp–.
A highly regioselective o-benzoxylation of N-alkylbenzamide with aromatic acid was developed in the presence of [RuCl2(p-cymene)]2, AgSbF6 and (NH4)2S2O8 through Csp2–H activation (Scheme I.
- Representative examples of directed CS, C P, C Si bond formation
- An array of exceptions
- Directed CH bond functionalisation via redox neutral process
- Directing group assisted site selectivity beyond ortho CH functionalisation
- Asymmetric CH activation
- CH activation: A new paradigm for total synthesis
- Total synthesis of (+)-Lithospermic Acid
- Other newer aspects of transition metal catalysed reactions leading to CC and Cheteroatom bond formations beyond C-
- One pot sequential reaction
- Rearrangement reaction
- References
In 2006, Yu and co-workers have demonstrated the coupling reaction of 2-phenylpyridine with thiophenol to produce thiolated arenes via Cu-catalyzed C–H functionalization (Scheme I. Remote control of site selectivity, especially meta-selective CH functionalization of electron-rich arenes is one of the most challenging tasks in organic synthesis. In 2012, the first report on template-based meta-CH functionalization was discovered by Yu and co-workers (Scheme I.5.4.2.2).
Nitrile-based templates used for metaselective CH functionalization Most template-based metaselective CH functionalizations involve a weakly coordinating nitrile group.
Benzylamine as Arylcarboxy Surrogate: A Copper Catalysed o -Benzoxylation of 2-
Phenylpyridines Using Benzylamines
Benzylamine as Arylcarboxy Surrogate: A Copper Catalysed o-Benzoxylation of 2-
Introduction
The reaction led to an exclusive formation of the o-benzoxylated product (OCOAr) (path-b, Scheme II.1.1) instead of an o-aroylated product (COAr) which was observed using the catalyst Pd.5a This observation highlights divergence in selectivity achieved by varying the transition metal catalyst. Additionally, the present protocol for the formation of a CO ester bond using benzylamine as the new arylcarboxy (ArCOOsubstituent is unparalleled in previous literature reports. Furthermore, the guiding group assisted the formation of the C bond O generally focused on acetoxylation7. and hydroxylation7df,8 via CH bond activation.
Strategies for ortho-benzoxylation
Present work
Among all the catalysts screened, Cu(OAc)2 (Table II.3.1, entry 1) was found to be the best. Increasing the amount of TBHP (5-6 M in decane) from 5 to 6 equivalents increased the product yield from 66% to 72% (Table II.3.1, point 8), whereas no significant change in yield was observed when using of 7 equivalents of the same (table II.3.1, point 9). Control experiments suggest that both catalyst and oxidant combination are indispensable for this transformation (Table II.3.1, entries 14 and 15).
The coupling partner is most likely the tert -butyl benzoperoxate generated in situ from the reaction of the aldehyde and TBHP; similar to the final o-benzoxylation of (1) using alkenes and terminal alkynes.3 The aldehyde is obtained by hydrolysis of the imine which in turn is formed by the oxidation of benzylamine.4b.
Experimental section
- Mechanistic investigation in the presence of radical scavenger TEMPO: An oven-dried round bottom flask fitted with a reflux condenser was charged with 2-
Radical species on subsequent binding with Cu(II) complex (D) give Cu(III) intermediate (E). This protocol shows the different selectivities and reactivities of Cu and Pd catalysts for the same reaction. The reaction mixture is cooled to room temperature and ethyl acetate (15 mL) is added to it, and the remaining particles are filtered through filter paper, which is washed with ethyl acetate (2 x 2.5 mL).
The ethyl acetate layer was washed with 5% sodium bicarbonate solution (2 x 5 mL) and water (2 x 5 mL) and the organic layer was dried over anhydrous Na 2 SO 4 and the solvent was evaporated under reduced pressure.
Mechanistic investigation in the presence of the radical scavenger TEMPO: An oven-dried round-bottom flask equipped with a reflux condenser was charged with 2- oven-dried round-bottom flask equipped with a reflux condenser was charged with 2- phenylpyridine (1) (77.5 mg, 0.5 mmol), benzylamine (a) (54 mg, 0.5 mmol), Cu(OAc)2.
Spectral data
Spectra
Benzyl Bromides as Aroyl Surrogates in Substrate Directed Pd-Catalysed o -
Aroylation
Benzyl Bromides as Aroyl Surrogates in Substrate Directed Pd-Catalysed o-Aroylation
Introduction
Strategies for ortho-aroylation
Here, benzyl ether undergoes an oxidative CO bond cleavage leading to the formation of new CC bond with various directing arenes such as ketoximes, 2-arylpyridines and phenoxypyridines.14f. o-Aroylation with benzyl alcohol and ethers as ArCO source. Our group has reported a Pd-catalyzed cross-dehydrogenative coupling strategy for the o-aroylation of directing arenes using alkylbenzenes as the synthetic equivalent of an aroyl moiety (Scheme III.2.5). Wu and co-workers have demonstrated a palladium-catalyzed ortho-acylation of 2-arylpyridines, serving arylmethylamines as the new, inexpensive and readily available acylation reagents (Scheme III.2.6).
In this protocol, benzylamine is oxidized to an imine, which is hydrolyzed to benzaldehyde and finally acts as an alternative aroyl source for this o-aroylation process.16. o-Aroylation using arylmethylamines as ArCO source. e).
Present work
Optimization of reaction conditions: As already mentioned, an initial experimental reaction was carried out between 2-phenylpyridine (1) (0.5 mmol) and benzyl bromide (a) (1 mmol) in the presence of Pd(OAc)2 (5 mol) . %) and the oxidant TBHP (56 M in decane) (4 eq.) in chlorobenzene (2 mL) at 120 oC. Since the second oxidant NMO (2 equiv) is used along with the primary oxidant TBHP (4 equiv), the reaction is expected to proceed with a smaller amount of TBHP. With this in mind and keeping all other parameters as such, the reaction was carried out with a combination of TBHP (2 equiv) and NMO (2 equiv).
A twofold increase in the catalyst loading had no significant effect on the product yield (Table III.3.1, entry 11).
Mechanisic investigation
Experimental section
- Mechanistic investigation in the presence of radical scavenger TEMPO: An oven-dried reaction flask was charged with 2-phenylpyridine (1) (77.5 mg, 0.5 mmol)
NMR spectra were recorded in CDCl3 with tetramethylsilane as the internal standard for 1H NMR (400 MHz and 600 MHz) CDCl3 solvent as the internal standard for 13C NMR (100 MHz and 150 MHz). After completion of the reaction, it was cooled to room temperature and mixed with ethyl acetate (30 mL) and filtered. The crude product was purified over a column of silica gel and eluted with a mixture of hexane/ethyl acetate (9.3:0.7) to give phenyl(2-pyridin-2-yl)phenylmethanone (1a) (102 mg, 79% yield) .
The flask was placed on a condenser and the resulting reaction mixture was stirred in a preheated oil bath maintained at 120°C.
Spectral Data
Spectra
Transition Metal-free Synthesis of α- Ketoamides from Arylmethyl Ketones and
Alkylphosphoramides
Transition Metal-free Synthesis of α-Ketoamides from Arylmethyl Ketones and
Introduction
Strategies for α-ketoamides synthesis
Present work
Furthermore, increasing the oxidant loading to 8 equivalents did not show a significant improvement in product yield (Table IV.3.1, entry 12). This finding confirms the formation of a small amount of phenylglyoxal from acetophenone, resulting in the formation of amide (1a') in the reaction. A further decrease in product yield (1 g) (48%) was observed with a strongly electron-withdrawing group such as –CF3. g) is present at the para position of arylmethylketone (g).
A good yield of α-ketoamide formation (1l) was also observed when 2-acetylthiophene (l) was used in the reaction process.
Mechanistic investigation
Experimental section
- Experiments performed for mechanistic investigation
- Experimental procedure for the detection of hypervalent iodine species
The flask was fitted with a condenser and the resulting reaction mixture was stirred in a preheated oil bath maintained at 130 oC. Then the reaction mixture was quenched with saturated Na2S2O3 solution and extracted with ethyl acetate. The solvent was then evaporated under reduced pressure and the residue was purified by column chromatography with an eluent hexane/ethyl acetate (65/35) to give the N,N-dimethylbenzamide (1a´) in an isolated yield of 77%.
It was then fitted with a condenser and the resulting reaction mixture was stirred in a preheated oil bath maintained at 130 oC.
Spectral data
Spectra
Ring Opening Rearrangement Functionalisation (RORF)
One Pot Sequential Synthesis of N-(2- (Phenylsulfinyl)phenyl)acetamides: A Ring
RORF)
Introduction
2-(Arylthio)arylcyanamides and guanidines, lose their cyano group in the presence of the corresponding nucleophiles viz. 2-(Phenylthio)phenylcyanamide can be obtained from 2-aminobenzothiazole and iodobenzene in the presence of CuSO4.5H2O via an intermolecular CS ring-opening reaction. a fragile NCN bond which can undergo a sacrificial cyano acetolysis similar to that of 1,3-diarylguanidine to generate an acetamide [Scheme V.1.1, (iii)]. N-(2-(phenylthio)phenyl)acetamide bearing a diarylsulfide moiety can be further oxidized to its sulfoxide analog in the presence of a suitable oxidant [Scheme V.1.1, (iii)].
An initial experiment was performed using 2-aminobenzothiazole and iodobenzene in the presence of CuSO4.5H2O and Cs2CO3.
Strategies for the synthesis of arylthio-arylcyanamide
Due to their enormous utility, many synthetic routes have been developed for the synthesis of arylthio-arylcyanamides. i) Synthesis of 2-(arylthio)arylcyanamides from 2-(haloaryl)thioureas. In the same year, our group also developed a similar protocol for the synthesis of 2-(arylthio)arylcyanamides from the coupling of various 2-(haloaryl)thioureas and iodobenzene in the presence of CuI, DMEDA, and NaOH.9c. Synthesis of 2-(arylthio)arylcyanamides from 2-(haloaryl)thioureas. ii) Synthesis of 2-(arylthio)arylcyanamides from 1-iodo-2-isothiocyanatobenzene Single arc three-component reaction of 1-iodo-2-isothiocyanatobenzene, aq.
Here, Fe2(SO4)3.H2O and 1,10-phenanthroline were used to perform the intermolecular CS coupling reaction of the in situ generated 2-(haloaryl)thiourea and iodobenzene.9d.
Present work
Input Catalyst (mol %) Base (equiv.) Solvent AcOH Temp. ii) acetic acid (aʹ), time (5 hours).bYields of pure isolated product. In addition to these mono-substituted aryl iodides, di-substituted aryl iodides, such as 2-CH3-4-Cl (j) and 3-F-4-OCH3 (k) all underwent efficient transformations with benzo[d ]thiazole -2- amine (1) and acetic acid (aʹ) giving the desired N-acetylated products (1jaʹ, 50%) and (1kaʹ, 67%), respectively. Further, the presence of a less deactivating substituent 6-F (3) on the benzothiazole ring underwent N-acetylation with a variety of substituted iodoarenes and AcOH (a').
From the trend in yields obtained in scheme V.3.1, no proper correlation could be rationalized between the nature of the substituents and their bond position with the actual yield obtained.
