Designing of templates to reach the distal C-H bond
​
A practical protocol to simplify natural product synthesis by site selective C–H functionalization had always been a coveted target for chemists. Most often, directing group assisted metallacycle formation has served as an efficient strategy in ensuring promising regioselectivity. In this regard wide variety of ortho- functionalization stands as an archetype. Despite significant progress, directing group- assisted selective distal C–H functionalization in arenes (at meta- and para- positions) had remained an unexplored venture mainly due to the formation of a geometrically constrained metallacyclic transition state.
To address these issues, a novel class of cleavable linker with nitrile based templates that direct efficient functionalization of distal para- and meta-C–H bonds are introduced. Recently, more robust heterocycle-based directing template has been designed to deliver the various and most useful functionalizations at remote meta-position. Applicability of these template based strategies have been demonstrated by synthesizing various natural products and complex molecules through post synthetic modifications.
Representative Publications:
​
​1. Palladium Catalyzed Aryl C-H Olefination with Unactivated, Aliphatic Alkenes
Deb, A.; Bag, S.; Kancherla, R.; Maiti, D. J. Am. Chem. Soc. 2014, 136, 13602.
​
2. Remote para-C-H Functionalization of Arenes by a D-Shaped Biphenyl Template-Based Assembly
Bag, S.; Patra, T.; Modak,A.; Deb, A.; Maity, S.; Dutta, U.; Dey, A.; Kancherla, R.; Maji, A.; Hazra, A.; Bera, M.; Maiti, D.
J. Am. Chem. Soc. 2015, 137, 11888.
​
3. Palladium-Catalyzed Directed para C-H Functionalization of Phenols
Patra, T.; Bag, S.; Kancherla, R.; Mondal, A.; Dey, A.; Pimparkar, S.; Agasti, S.; Modak, A.; Maiti, D.
Angew. Chem. Int. Ed. 2016, 55, 7751.
​
4. Detailed Mechanistic Studies on Palladium Catalyzed Selective C-H Olefination with Aliphatic Alkenes: A Significant Influence of Proton Shuttling
​Deb, A.; Hazra, A.; Peng, Q.; Paton, R. S.; Maiti, D. J. Am. Chem. Soc. 2017, 39, 763.
​
5. Template-assisted meta-C–H alkylation and alkenylation of arenes
Bag, S.; Jayarajan, R.; Mondal, R.; Maiti, D. Angew. Chem. Int. Ed. 2017, 56, 3182.
6. XPhos Ligated Rhodium Catalyzed meta-C-H Functionalization of Arenes
Bera, M.; Agasti, S.; Chowdhury, R.; Mondal, R.; Pal, D.; Maiti, D. Angew. Chem. Int. Ed. 2017, 56, 5272.
​
7. Palladium-catalyzed meta-C–H allylation of arenes: A unique combination of pyrimidine-based template and hexafluoroisopropanol
Bag, S.; K, S.; Mondal, A.; Jayarajan, R.; Dutta, U.; Porey, S.; Sunoj, R. B.; Maiti. D. J. Am. Chem. Soc., 2020, 142, 12453.
​
8. Para-Selective Arylation of Arenes: A Direct Route to Biaryls by Norbornene Relay Palladation
Dutta, U†.; Porey, S†.; Pimparkar, S.; Mandal, A; Grover, J; Koodan, A; Maiti, D. Angew. Chem. Int. Ed., 2020, 59, 20831.
9. An Alkyne Linchpin Strategy for Drug:Pharmacophore Conjugation: Experimental and Computational Realization of a meta-selective Inverse Sonogashira Coupling
Porey, S.; Zhang, X.; Bhowmick, S.; Singh, V. K.; Guin, S.; Paton, R. S.; Maiti. D. J. Am. Chem. Soc., 2020, 142, 3762.
Directing group assisted aliphatic C-H functionalization
​
The evolution of C–H activation/functionalization strategy has been potentially expediting the synthesis of target molecules through new disconnections in retrosynthetic analysis. By far the toughest challenge in this area is to regioselectively functionalize a particular sp3 C-H bond in alkanes. The minute reactivity differences of multitude of inert C‒H bonds and the fluxionality in aliphatic chains restricts the selective transformation at a core site within a complex molecule. Hence to incorporate functionality at a-sp3 carbon to a functional group relies on the traditional electrophilic addition or radical based reactions.
While the same at beta-carbon of carboxylic acid or gamma-carbon of amine can be performed by the assistance of directing group and transition metal. The feasibility of these reactions depends on the favored thermodynamics of the stable five membered metallacycle. However, striving for a distal sp3 C–H bond activation, other than these accessible positions, leads to more complex issues owing to thermodynamic constraints of larger metallacycle. Hence a paradigm for C-H activation reactions to functionalize more distal carbon centers is required that may impart the molecule with specific structural and functional features which would be acceptable as a lucrative molecule.
The group is currently involved in designing of more efficient of directing groups that can address the existing shortcomings and go out of stretch to offer more efficient and reliable method for distal aliphatic C–H activation at delta, epsinol and further in a selective way alongside overcoming the constitutional and conformational barriers inherent in a linear molecule. The developed protocols will open up the gates to exploit C-H activations in industries for step-economic synthesis of drugs, natural products and agrochemicals by ornamenting different molecules regioselectively, making it a versatile tool in chemist’s pocket.
Representative Publications:
​​
​1. Experimental and Computational Studies on Remote γ‑C(sp3)−H Silylation and Germanylation of Aliphatic Carboxamides
Deb, A.; Singh, S.; Seth, A.; Pimparkar, S.; Bhaskararao, B.; Guin, S.; Sunoj, R. B.; Maiti, D. ACS Catal. 2017, 7, 8171.
​
2. Promoting Highly Diastereoselective γ‑C−H Chalcogenation of α‑Amino Acids and Aliphatic Carboxylic AcidsGuin, S.; Deb, A.; Dolui, P.; Chakraborty, S.; Singh, V. K.; Maiti, D. ACS Catal. 2018, 8, 2664.
3. Iterative Arylation of Amino Acids and Aliphatic Amines via-C(sp3)-H Activation: Experimental and Computational Exploration
Guin, S†.; Dolui, P†.; Zhang, X.; Paul, S.; Singh, V. K; Pradhan, S.; Chandrashekar, H. B.; S. S. Anjana.; Paton, R. S.; Maiti, D. Angew. Chem. Int. Ed. 2019, 58, 5633.
4. Ligand Enabled delta-C(sp3)-H Borylation of Aliphatic Amines
H. B. Chandrashekar, Dolui. P.; Li, B.; Mandal, A.; Liu, H; Guin, S; Ge, H; Maiti, D. Angew. Chem. Int. Ed. 2021, 60, 18194.
5. Simplifying the Synthesis of Non-proteinogenic Amino Acids via Palladium Catalysed (delta)-Methyl C-H Olefination of Aliphatic Amines and Amino Acids
​Bhattacharya, T.; Baroliya, P. K.; Al-Thabaiti, S. A.; Maiti, D. JACS Au, 2023, 3, 1975.
​​
6. Ligand controlled orthogonal selectivity between δ and γ positions of long chain picolinamides
Sinha, S. K.;† Goswami, N.;† Li, Y.;† Maji, S.; Raja, D.; Sarala, A. S.; Guin, S.; Paton. R. S.; Maiti, D. ACS Catal. 2024, 14, 12681.
​
7. Generating Pd-catalyzed δ C‒H chalcogenation of aliphatic picolinamides: systematically decreasing the bias
Sinha, S. K.; Gholap, A.; Yazhinimuthu, C. M.; Pal, A.; Kapdi, A. R.; Maiti, D. Chem. Sci., 2025, 16, 7936.
Non-directed C-H functionalization of Arenes
​
Non-directed C–H activation represents a pioneering approach in organic synthesis, wherein specific C–H bonds within molecules are selectively activated without relying on directing groups. Non-directed C–H activation is a novel and highly advantageous method for regioselective functionalization in the current context of organic synthesis. Previously, the functionalization of C–H bonds was hindered by the necessity of directing groups to channel reactions towards desired sites. In contrast, non-directed C–H activation enables the direct transformation of inert C–H bonds into valuable functional groups, offering significant advantages in terms of step and atom economy, as well as environmental sustainability. The emergence of non-directed C–H activation has led to extensive research efforts focused on developing catalysts and methodologies. These endeavors aim to exploit the synthetic capabilities of inert C–H bonds, thereby revolutionizing organic chemistry and simplifying synthetic routes.
Representative Publications:
​
​1. Dual Ligand Enabled Non-Directed C−H Chalcogenation of Arenes and Heteroarenes
Sinha, S. K.;† Panja, S.;† Grover, J.;† Hazra, P. S.; Pandit, S.; Bairagi, Y.; Zhang, X.; Maiti, D. J. Am. Chem. Soc., 2022, 144, 12032.
​
2. Non-Directed C-H/C-F Coupling for the Synthesis of α-Fluoro Olefinated Arenes
Porey, S.; Bairagi, Y.; Guin, S.; Zhang, X.; Maiti, D. ACS Catal. 2023, 13, 14000.
​
3. Deuteration and Tritiation of Pharmaceuticals by Non-Directed Palladium Catalyzed C–H Activation in Heavy and Super-Heavy Water
Teja, C.; Kolb, S.; Colonna, P.; Grover, J.; Garcia-Argote, S.; Lahiri, G. K.; Pieters, G.; Werz. D. B.; Maiti, D. Angew. Chem. Int. Ed., 2024, e202410162
​
4. Synthesis of β-(Hetero)aryl Ketones via Ligand-Enabled Nondirected C-H Alkylation
Bairagi, Y.;† Porey, S.;† Vummaleti, S. V. C.; Zhang, X.; Lahiri. G. K.; Maiti, D. ACS Catal., 2024, 14, 15654.​​
Transforming Inert Bonds: DG-Free C(sp³)–H Functionalization Strategies for Selective Molecular Editing
​​
DM Lab has extensively advanced the field of directing-group-free (DG-free) aliphatic C(sp³)–H functionalization, addressing a key challenge in modern catalysis: the reliance on covalently installed directing groups, which often require additional synthetic steps and limit substrate generality. In contrast, DG-free strategies streamline synthesis and enable late-stage modifications, especially when applied to native functionalities like carboxylic acids and amides, which are abundant in bioactive molecules, pharmaceuticals, and natural products. To this end, the lab has developed versatile and selective catalytic methods for β- and γ-C–H activation in such substrates.
By innovating with ligand-enabled Pd(II) catalysis, often in conjunction with cooperative ligand systems (e.g., pyridone, MPAA, phosphines), the group has successfully addressed challenges associated with weak substrate coordination and remote site selectivity. Their strategies enable β- and γ-C(sp³)–H arylation, alkenylation are fundamentally driven by dehydrogenative C–H activation mechanisms. Notably, they have realized the construction of lactones—including six-, seven-membered, and unsaturated bicyclic frameworks—through tandem processes involving C–H activation, olefination, and lactonization. In parallel, the lab has developed decarboxylative functionalization strategies that employ carboxylic acids as transient activating groups to unlock remote multicomponent functionalizations, and has also harnessed skeletal rearrangements via C(sp³)–C(sp³) bond activation to enable C–C bond formation and structural reorganization of strained carbocyclic frameworks. These protocols also allow iterative functionalization, distal methylene selectivity, and C–H functionalization of free N–H amides, thereby expanding the accessible chemical space from simple aliphatic feedstocks. Collectively, the lab's contributions establish robust and modular platforms for the complexity-generating transformation of otherwise inert aliphatic C–H bonds in a DG-free manner.
Representative Publications:
​
​1. Ligand-Enabled Pd(II)-Catalyzed Iterative γ-C(sp3)-H Arylation of Free Aliphatic Acid
Dolui, P†.; Das, J†.; Chandrashekar, H. B.; Anjana, S. S.; Maiti, D. Angew. Chem. Int. Ed. 2019, 58, 13773.
​
2. A Direct Route to Six and Seven Membered Lactones via γ-C(sp3)-H Activation: A Simple Protocol to Build Molecular Complexity
Das, J†.; Dolui, P†.; Ali, W.; Biswas, J. P.; Chandrashekar, H. B.; Prakash, G; Maiti, D. Chem. Sci. 2020, 11, 9697.
​
3. Pd Catalyzed Dual-γ-1,1-C(sp3)-H Activation of Free Aliphatic Acids With Allyl-O Moieties
Das, J.; Pal, T.; Ali, W.; Sahoo, S. R.; Maiti, D. ACS Catal., 2022, 12, 11169.
​
4. Access to Unsaturated Bicyclic Lactones by Overriding Conventional C(sp3)-H Site Selectivity
Das, J.; Ali, W.; Ghosh, A.;† Pal, T.;† Mandal, A.;† Teja, C.; Dutta, S.; Pothikumar, R.; Ge, H.; Zhang, X.; Maiti, D. Nat. Chem., 2023, 15, 1626.
​
5. Tandem Dehydrogenation-Olefination-Decarboxylation of Cycloalkyl Carboxylic Acids via Multifold C-H Activation
Pal, T.; Ghosh, P.; Islam, M., Guin, S.; Maji, S.; Dutta, S.; Das, J.; Ge, H.; Maiti, D. Nat. Commun., 2024, 15, 5370.
​
6. Surpassing the Limited Coordination Affinity of Native Amides by Introducing Pyridone-Pd-AgOAc Cluster to Promote Distal γ-C(sp3)-H Arylation
Goswami, N.; Kumar, N.; Gupta, P.; Maiti, D. ACS Catal. 2024, 14, 3798.
​
7. Cooperative Ligand Enabled Facile Synthesis of γ-C(sp3)−H Alkenylated Aliphatic Amides: A Comprehensive Protocol to Free N−H Tolerance
Dutta, S.; Kumar, N.; Islam, M.; Ali, W.; Gupta, P.; Maiti, D. ACS Catal., 2025, 15, 5295.
​
8. Pd-Catalyzed Skeletal Rearrangement via C(sp³)-C(sp³) Activation to Access α,β-Unsaturated δ/γ-Lactone
Manna, K.;† Maji, S.;† Sharma, A.; Kumar, N.; Gupta, P.; Maiti, D. Angew. Chem. Int. Ed., 2025, 64, e202423175.
Enantioselective C–H Activation: Streamlining Synthesis of Chiral Architectures
​
Asymmetric C–H activation catalyzed by transition metals represents a transformative tool in modern organic synthesis, enabling the direct functionalization of otherwise inert C–H bonds with high levels of regio-, chemo-, and enantioselectivity. This strategy bypasses the need for pre-functionalized substrates, making it atom- and step-economical, and highly attractive for synthesizing chiral molecules, including pharmaceuticals and natural products
Representative Publications:
​
​1. Photoinduced Regioselective Olefination of Arenes at Proximal and Distal Sites
Saha, A.;† Guin, S.;† Ali, W.; Bhattacharya, T.; Sasmal, S.; Goswami, N.; Prakash, G.; Sinha, S. K.; Chandrashekar, H. B.; Panda, S.; Anjana, S. S.; Maiti, D. J. Am. Chem. Soc., 2022, 144, 1929.
​
2. Combinatorial Ligand Assisted Simultaneous Control of Axial and Central Chirality in Highly Stereoselective C-H Allylation
Bhattacharya, T.; Ghosh, S.; Dutta, S.; Guin, S.; Ghosh, A.; Ge, H.; Sunoj, R. B.; Maiti, D. Angew. Chem. Int. Ed., 2023, 63, e20231011.
​
3. Pallada-Electrocatalysis Enables Distal Regioselective and Atroposelective Olefination Reactions
Panja, S.; Pan, A.; Biswas, S.; Das, C.; Guha, A.; Nimje, R. Y.; Dhar, T. G. M.; Gupta, A.; Mathur, A.; Dutta, A.; Roy, L.; Maiti, D.
Non-Covalent Interaction-Guided Palladium Catalysis for Distal C–H Functionalization of Arenes
​
Palladium-catalyzed non-covalent interaction-guided distal functionalization of arenes represents a cutting-edge strategy in site-selective C–H activation, enabling transformations at positions far from traditional directing groups. Unlike classical approaches that rely on strong covalent coordination to guide metal insertion, this method utilizes weak, reversible interactions—such as silicon-fluorine Lewis' acid-base interaction, hydrogen bonding, ion-pairing, π–π stacking, or electrostatic interactions—to orient the palladium catalyst in proximity to remote C–H bonds. These interactions, often facilitated by specially designed ligands or templates, allow precise control over regioselectivity without the need for covalently attached directing groups. This approach is particularly advantageous for late-stage functionalization of complex molecules, including pharmaceuticals and bioactive compounds, as it enables selective modification of inert arene positions with minimal structural perturbation. Overall, non-covalent interaction-guided palladium catalysis is expanding the synthetic toolbox for programmable and predictable arene functionalization.
Representative Publications:
​
​1. Silicon-fluorine non-covalent interaction guided distal functionalization of di- and tri- fluoro alkyl benzene
Maji, S.; Sebastian, A.; Mondal, P.; Manna, K.; Pal, A.; Datta, A.; Maiti, D. https://www.researchsquare.com/article/rs-6523406/v1.​