C- H, C-C, C-O, C-N, activations and functionalizations
C-H activation & functionalization
C-H activation & functionalization
Functionalization of inert C-H bonds has drawn much attention in the organic synthesis attributable to the non requirement of pre-functionalization of the substrate, thereby improving the atom economy and step economy, and minimizing the impact on the environment chemical pollution.
Functionalization of inert C-H bonds has drawn much attention in the organic synthesis attributable to the non requirement of pre-functionalization of the substrate, thereby improving the atom economy and step economy, and minimizing the impact on the environment chemical pollution.
BondBond Dissociation Energies (KJ/mol)
BondBond Dissociation Energies (KJ/mol)
Phenyl C−H 476
Phenyl C−H 476
H-C 413
H-C 413
C−H bond α to ketone 402
C−H bond α to ketone 402
Acetylenic C−H 556
Acetylenic C−H 556
Benzylic C−H 377
Benzylic C−H 377
Vinyl C−H 464
Vinyl C−H 464
Allylic C−H 372
Allylic C−H 372
C-C 347–377
C-C 347–377
N-C 305
N-C 305
O-C 360
O-C 360
Alkene C=C ~710
Alkene C=C ~710
Alkyne C≡C ~960
Alkyne C≡C ~960
However, due to the high bond energy, low polarity and low reactivity of C-H bonds, it is very difficult to achieve effective conversion. Non-precious-metal catalyzed and metal-free reactions are of increasing importance in chemistry due to the outstanding ecological and economic properties of these metals.
However, due to the high bond energy, low polarity and low reactivity of C-H bonds, it is very difficult to achieve effective conversion. Non-precious-metal catalyzed and metal-free reactions are of increasing importance in chemistry due to the outstanding ecological and economic properties of these metals.
Building a carbon–carbon linkage directly from two simple carbon–hydrogen (C–H) bonds has emerged as an attractive and challenging goal in catalysis. This reaction is more atom economical and environmentally friendly than other cross-coupling reactions, and can be considered as a complementary strategy to the existing direct C–H bonds activations.
Building a carbon–carbon linkage directly from two simple carbon–hydrogen (C–H) bonds has emerged as an attractive and challenging goal in catalysis. This reaction is more atom economical and environmentally friendly than other cross-coupling reactions, and can be considered as a complementary strategy to the existing direct C–H bonds activations.
Activation of C(sp3)-H bonds
Activation of C(sp3)-H bonds
In particular, the functionalization reaction of C (sp3) -H bonds is more challenging. Generally, a C(sp3 )–H bond is not considered as a functional group due to its low reactivity and high thermodynamic stability. The development of mild and efficient methodologies to directly convert C(sp3 )–H bonds into other important functionalities would be of meaningful importance in fundamental research and industrial production.
In particular, the functionalization reaction of C (sp3) -H bonds is more challenging. Generally, a C(sp3 )–H bond is not considered as a functional group due to its low reactivity and high thermodynamic stability. The development of mild and efficient methodologies to directly convert C(sp3 )–H bonds into other important functionalities would be of meaningful importance in fundamental research and industrial production.
Our group mainly focuses on the related reactions of unactivated C (sp3) -H bond to form C -C bonds efficiently.
Our group mainly focuses on the related reactions of unactivated C (sp3) -H bond to form C -C bonds efficiently.
Direct C(sp3)–H bond functionalization of 2-alkyl azaarenes is an efficient and atom economical synthetic strategy to access various substituted azaarene derivatives. Likewise, the construction of C(sp3)-C(sp3) bond is an essential chemical transformation in synthetic chemistry due to its abundance in organic scaffolds. In the current research, C(sp3)-C(sp3) bond formation using a range of alkyl building blocks has been developed.
Direct C(sp3)–H bond functionalization of 2-alkyl azaarenes is an efficient and atom economical synthetic strategy to access various substituted azaarene derivatives. Likewise, the construction of C(sp3)-C(sp3) bond is an essential chemical transformation in synthetic chemistry due to its abundance in organic scaffolds. In the current research, C(sp3)-C(sp3) bond formation using a range of alkyl building blocks has been developed.
C-H activation can also lead to the following C-C bond formation
C-H activation can also lead to the following C-C bond formation
sp3C-sp3C
sp3C-sp3C
sp3C–H bond alkylation of ketones with alkenes,
sp3C–H bond alkylation of ketones with alkenes,
alkylation of C(sp3)–H bonds of methyl ketones, methyl azaarenes with alcohols
alkylation of C(sp3)–H bonds of methyl ketones, methyl azaarenes with alcohols
sp3C-sp2C
sp3C-sp2C
Arylation, heteroarylation of ketones, Alkenylation of ketones ,
Arylation, heteroarylation of ketones, Alkenylation of ketones ,
Direct α-olefination of N-heteroarenes (methyl azaarenes)
Direct α-olefination of N-heteroarenes (methyl azaarenes)
Intramolecular oxidative cross coupling reaction of C(sp2)–H/C(sp3)–H bonds
Intramolecular oxidative cross coupling reaction of C(sp2)–H/C(sp3)–H bonds
Benzylic C(sp3)–H/C(sp2)–H cross-dehydrogenative coupling
Benzylic C(sp3)–H/C(sp2)–H cross-dehydrogenative coupling
Hydroacylation of alkenes, hydroamination, hydroalkylation, hydroalkoxylation, hydrocarboxylation
Hydroacylation of alkenes, hydroamination, hydroalkylation, hydroalkoxylation, hydrocarboxylation
sp3C-spC , sp2C-spC , spC-spC
sp3C-spC , sp2C-spC , spC-spC
C-H functionalization leading to Csp3-Csp coupling is less common
C-H functionalization leading to Csp3-Csp coupling is less common
Alkynylation with alkynes, Hydroacylation of alkynes, direct Alkynylation of Arenes and Heterocycles with Alkynyl Halides,
Alkynylation with alkynes, Hydroacylation of alkynes, direct Alkynylation of Arenes and Heterocycles with Alkynyl Halides,
sp2C-sp2C
sp2C-sp2C
Arylation, heteroarylation Alkenylation
Arylation, heteroarylation Alkenylation
Functionalization reaction of C (sp2) -H bonds
Functionalization reaction of C (sp2) -H bonds
Selective functionalization of one specific C(sp2 )–H bond in a complex molecule without the assistance of a directing group represents the state of the art in organic synthesis and will be a dynamic topic in future. In the past decade, many excellent methods have been developed to accomplish this goal with transition metal catalysts and even under metal-free conditions. Aldehydes with electron-withdrawing groups gave good yields of the corresponding products. Aldehydes with electron-donating groups gave a slightly lower yield of the product presumably due to the difficult C–H bond cleavage of aldehyde.
Selective functionalization of one specific C(sp2 )–H bond in a complex molecule without the assistance of a directing group represents the state of the art in organic synthesis and will be a dynamic topic in future. In the past decade, many excellent methods have been developed to accomplish this goal with transition metal catalysts and even under metal-free conditions. Aldehydes with electron-withdrawing groups gave good yields of the corresponding products. Aldehydes with electron-donating groups gave a slightly lower yield of the product presumably due to the difficult C–H bond cleavage of aldehyde.
Proximity-driven metalation has been extensively exploited to achieve reactivity and selectivity in carbon-hydrogen (C-H) bond activation. Despite the substantial improvement in developing more efficient and practical directing groups, their stoichiometric installation and removal limit efficiency and, often, applicability as well
Proximity-driven metalation has been extensively exploited to achieve reactivity and selectivity in carbon-hydrogen (C-H) bond activation. Despite the substantial improvement in developing more efficient and practical directing groups, their stoichiometric installation and removal limit efficiency and, often, applicability as well
Transition-metal-catalyzed C–H bond functionalization directed by heteroatom directing groups is one of the most powerful tools in recent organic synthesis for the regioselective formation of carbon–carbon and carbon–heteroatom bond
Transition-metal-catalyzed C–H bond functionalization directed by heteroatom directing groups is one of the most powerful tools in recent organic synthesis for the regioselective formation of carbon–carbon and carbon–heteroatom bond
sp2(C)– sp(C)coupling
sp2(C)– sp(C)coupling
Non directed sp2(C)– sp2(C)coupling
Non directed sp2(C)– sp2(C)coupling
Directed sp2(C)– sp2(C)coupling
Directed sp2(C)– sp2(C)coupling
(Arene and olefin or olefin and olefin or aldehyde and olefin)
(Arene and olefin or olefin and olefin or aldehyde and olefin)
The olefination of unreactive aryl C–H bonds catalyzed by transition metals is among the most significant chemical transformations in organic syntheses The olefination of arene via the C–H activation have been accomplished by noble metal catalyst such as ruthenium,rhodium,palladium,cobalt,and iridium,with high temperature and organic solvents. These catalysts generally show high reactivity and broad substrate scope. Selective olefination, for instance Mono- and di-olefination via C–H activation has been of great interest and could be controlled by changing the solvent, catalyst or substrate. Selective synthesis of mono- and di-olefinated products at room temperature is yet to be developed. Many volatile and environmentally toxic organic solvents are commonly applied in the C–H olefination. In recent years, many researchers have paid attention to the replacement of these harmful solvents with an eco-friendly medium to meet the requirement of green chemistry. Though water and polyethylene glycol are extensively studied in some chemical transformations, their applications are significantly restricted by the low solubility of starting compounds and metal catalysts. Considering this, it is preferable to find an excellent medium to allow the C–H olefination to perform smoothly under mild conditions and reuse the metal catalyst.
The olefination of unreactive aryl C–H bonds catalyzed by transition metals is among the most significant chemical transformations in organic syntheses The olefination of arene via the C–H activation have been accomplished by noble metal catalyst such as ruthenium,rhodium,palladium,cobalt,and iridium,with high temperature and organic solvents. These catalysts generally show high reactivity and broad substrate scope. Selective olefination, for instance Mono- and di-olefination via C–H activation has been of great interest and could be controlled by changing the solvent, catalyst or substrate. Selective synthesis of mono- and di-olefinated products at room temperature is yet to be developed. Many volatile and environmentally toxic organic solvents are commonly applied in the C–H olefination. In recent years, many researchers have paid attention to the replacement of these harmful solvents with an eco-friendly medium to meet the requirement of green chemistry. Though water and polyethylene glycol are extensively studied in some chemical transformations, their applications are significantly restricted by the low solubility of starting compounds and metal catalysts. Considering this, it is preferable to find an excellent medium to allow the C–H olefination to perform smoothly under mild conditions and reuse the metal catalyst.
For eg selective mono and di-olefination of 2-phenylpyridines and related arenes using styrenes utilising ([Cp*RhCl2]2); (Cp*Rh(OAc)2); ([Cp*CoCl2]2); ([Ru(p-cymene)Cl2]2) catalysts
For eg selective mono and di-olefination of 2-phenylpyridines and related arenes using styrenes utilising ([Cp*RhCl2]2); (Cp*Rh(OAc)2); ([Cp*CoCl2]2); ([Ru(p-cymene)Cl2]2) catalysts
Functionalization reaction of C (sp) -H bonds
Functionalization reaction of C (sp) -H bonds
Hydroacylation reactions
Hydroacylation reactions
(alkene or alkyne and carbonyl group- sp2 C-H aor sp C-H and sp2 C activations)
(alkene or alkyne and carbonyl group- sp2 C-H aor sp C-H and sp2 C activations)
Hydroacylation is a reaction in which alkene or alkyne or a carbonyl group is inserted into a formyl C-H bond. (the formal addition of an aldehyde CH bond across an unsaturated C-C bond), The product may be a ketone or chalcones. The hydroacylation begins with oxidative addition of the aldehydic carbon-hydrogen bond. The resulting acyl metal hydride complex next binds the alkene, the alkene inserts into either the metal-acyl or the metal-hydride bonds. In the final step, the resulting alkyl-acyl or beta-ketoalkyl-hydride complex undergoes reductive elimination .
Hydroacylation is a reaction in which alkene or alkyne or a carbonyl group is inserted into a formyl C-H bond. (the formal addition of an aldehyde CH bond across an unsaturated C-C bond), The product may be a ketone or chalcones. The hydroacylation begins with oxidative addition of the aldehydic carbon-hydrogen bond. The resulting acyl metal hydride complex next binds the alkene, the alkene inserts into either the metal-acyl or the metal-hydride bonds. In the final step, the resulting alkyl-acyl or beta-ketoalkyl-hydride complex undergoes reductive elimination .
Transition metal-catalyzed alkene hydroacylation, has emerged as a powerful, catalytic process to synthesize ketones, greatly expanded the scope and synthetic utility of these hydroacylation reactions in recent years. Intramolecular alkene hydroacylation reactions are now well-established methods to synthesize carbocyclic and heterocyclic ketones, often with high enantioselectivities.
Transition metal-catalyzed alkene hydroacylation, has emerged as a powerful, catalytic process to synthesize ketones, greatly expanded the scope and synthetic utility of these hydroacylation reactions in recent years. Intramolecular alkene hydroacylation reactions are now well-established methods to synthesize carbocyclic and heterocyclic ketones, often with high enantioselectivities.
These transformations generally occur in the presence of transition-metal or NHC catalysts, and the selection of the specific catalyst type determines the regiochemical outcome of the reaction. NHC-catalyzed intramolecular hydroacylations occur with exoselectivity (formal Markovnikov selectivity), while transition metal-catalyzed hydroacylations can occur with either endo-selectivity (formal anti-Markovnikov selectivity) or exo-selectivity. In addition, the development of intermolecular hydroacylations of new combinations of alkenes and alkynes with aldehydes continues to rapidly expand and provide direct routes to new ketones from simple starting materials.
These transformations generally occur in the presence of transition-metal or NHC catalysts, and the selection of the specific catalyst type determines the regiochemical outcome of the reaction. NHC-catalyzed intramolecular hydroacylations occur with exoselectivity (formal Markovnikov selectivity), while transition metal-catalyzed hydroacylations can occur with either endo-selectivity (formal anti-Markovnikov selectivity) or exo-selectivity. In addition, the development of intermolecular hydroacylations of new combinations of alkenes and alkynes with aldehydes continues to rapidly expand and provide direct routes to new ketones from simple starting materials.
Aldehyde- alkyne metathesis (sp2 C- and sp C-H activation)
Aldehyde- alkyne metathesis (sp2 C- and sp C-H activation)
An intramolecular ring-closing alkyne–carbonyl metathesis reaction has received much attention, since valuable functionalized hetero- and carbocycles can be readily formed under mild conditions. Moreover, such reactions are highly efficient and atom-economical by nature, unfortunately, and have been less explored. Notably, this reaction has been mostly employed for the synthesis of five- or six- membered heterocycles or carbocycles and seven-membered heterocycles
An intramolecular ring-closing alkyne–carbonyl metathesis reaction has received much attention, since valuable functionalized hetero- and carbocycles can be readily formed under mild conditions. Moreover, such reactions are highly efficient and atom-economical by nature, unfortunately, and have been less explored. Notably, this reaction has been mostly employed for the synthesis of five- or six- membered heterocycles or carbocycles and seven-membered heterocycles
This reaction normally proceeds through a [2 + 2] cycloaddition and cycloreversion processes by the activation of the carbonyl group by formation of σ-complex or activation of alkyne by formation of π-complex or activation of both simultaneously depending on the catalyst.
This reaction normally proceeds through a [2 + 2] cycloaddition and cycloreversion processes by the activation of the carbonyl group by formation of σ-complex or activation of alkyne by formation of π-complex or activation of both simultaneously depending on the catalyst.
Generally, this reaction is initiated either by Brønsted acids or Lewis acids such as TfOH, HBF4, BF3·OEt2, , In(OTf)3, AgSbF6, AuCl3, and a combination of AuCl3/AgSbF6 acting as a catalyst for this process. During our ongoing interest in the area of development of Deep eutectic system catalyzed reactions, has employed an intramolecular alkyne–carbonyl metathesis strategy in developing an alternative process for the efficient construction of carbo- and heterocycles
Generally, this reaction is initiated either by Brønsted acids or Lewis acids such as TfOH, HBF4, BF3·OEt2, , In(OTf)3, AgSbF6, AuCl3, and a combination of AuCl3/AgSbF6 acting as a catalyst for this process. During our ongoing interest in the area of development of Deep eutectic system catalyzed reactions, has employed an intramolecular alkyne–carbonyl metathesis strategy in developing an alternative process for the efficient construction of carbo- and heterocycles
Furthermore, DES is inexpensive and environmentally friendly so it is highly desirable in organic synthesis. Keeping in mind these facts, we envisioned that the alkyne–carbonyl metathesis strategy could also be applied to the synthesis of functionalised seven-membered oxygen heterocycles such as ------ from easily available starting materials
Furthermore, DES is inexpensive and environmentally friendly so it is highly desirable in organic synthesis. Keeping in mind these facts, we envisioned that the alkyne–carbonyl metathesis strategy could also be applied to the synthesis of functionalised seven-membered oxygen heterocycles such as ------ from easily available starting materials
Late stage-diversification through direct C-H activation and functionalization strategy
Late stage-diversification through direct C-H activation and functionalization strategy
late stage C–H Direct arylation, late stage C–H heteroarylation, late stage C–H alkynylation, late stage C-H amination late-stage aroylation,
late stage C–H Direct arylation, late stage C–H heteroarylation, late stage C–H alkynylation, late stage C-H amination late-stage aroylation,
C–C/C–N/C-O/C-S bond formation via C–H C-C, C-N activation & functionalization
C–C/C–N/C-O/C-S bond formation via C–H C-C, C-N activation & functionalization
Activation of abundant C-O, C-N and C-C bonds via oxidative addition of a low-valent, electron-rich transition metal. nickel(0), rhodium(I), ruthenium(0) and iron catalysts for electronically activated substrates, sometimes assisted by chelating functional groups
Activation of abundant C-O, C-N and C-C bonds via oxidative addition of a low-valent, electron-rich transition metal. nickel(0), rhodium(I), ruthenium(0) and iron catalysts for electronically activated substrates, sometimes assisted by chelating functional groups
allylic alkylation with alkynes, hydroallylation, hydroamination, hydroalkylation, hydroalkoxylation, hydrocarboxylation of alkynes as redox-neutral allyl precursors, allylation of tautomerizable heterocycles with alkynes
allylic alkylation with alkynes, hydroallylation, hydroamination, hydroalkylation, hydroalkoxylation, hydrocarboxylation of alkynes as redox-neutral allyl precursors, allylation of tautomerizable heterocycles with alkynes
Transesterification, transamidation, decarboxylative chemoselective Amination of Aryl Acetic Acids, deaminative alkynylation of amines,
Transesterification, transamidation, decarboxylative chemoselective Amination of Aryl Acetic Acids, deaminative alkynylation of amines,
decarboxylative Csp3-Csp3 (utilizing nitromethane), Csp3-Csp2 (utilizing indole) , and Csp3-Csp utilizing(alkynes) coupling of amines (pyrrolidine carboxylic acid)
decarboxylative Csp3-Csp3 (utilizing nitromethane), Csp3-Csp2 (utilizing indole) , and Csp3-Csp utilizing(alkynes) coupling of amines (pyrrolidine carboxylic acid)
