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1.
Chem Rev ; 122(6): 5682-5841, 2022 03 23.
Article in English | MEDLINE | ID: mdl-34662117

ABSTRACT

Transition-metal-catalyzed C-H activation has developed a contemporary approach to the omnipresent area of retrosynthetic disconnection. Scientific researchers have been tempted to take the help of this methodology to plan their synthetic discourses. This paradigm shift has helped in the development of industrial units as well, making the synthesis of natural products and pharmaceutical drugs step-economical. In the vast zone of C-H bond activation, the functionalization of proximal C-H bonds has gained utmost popularity. Unlike the activation of proximal C-H bonds, the distal C-H functionalization is more strenuous and requires distinctly specialized techniques. In this review, we have compiled various methods adopted to functionalize distal C-H bonds, mechanistic insights within each of these procedures, and the scope of the methodology. With this review, we give a complete overview of the expeditious progress the distal C-H activation has made in the field of synthetic organic chemistry while also highlighting its pitfalls, thus leaving the field open for further synthetic modifications.


Subject(s)
Biological Products , Transition Elements , Biological Products/chemistry , Catalysis , Transition Elements/chemistry
2.
Angew Chem Int Ed Engl ; 59(47): 20831-20836, 2020 11 16.
Article in English | MEDLINE | ID: mdl-32754958

ABSTRACT

Biaryl compounds are extremely important structural motifs in natural products, biologically active components and pharmaceuticals. Selective synthesis of biaryls by distinguishing the subtle reactivity difference of distal arene C-H bonds are significantly challenging. Herein, we describe para-selective C-H arylation, which is acheived by a unique combination of a meta-directing group and norbornene as a transient mediator. Upon direct meta-C-H palladation, one-bond relay palladation occurs in presence of norbornene and subsequently para-C-H arylation is achieved for sulfonates, phosphonates and phenols bearing 2,6-disubstitution patterns. The protocol is amenable to electron-deficient aryl iodides. Multisubstituted arenes and phenols are obtained by postsynthetic modification of the products. The protocol allows the synthesis of hexa-substituted benzene by sequential selective distal C-H functionalization.

3.
J Am Chem Soc ; 142(28): 12453-12466, 2020 07 15.
Article in English | MEDLINE | ID: mdl-32496791

ABSTRACT

Controlling remote selectivity and delivering novel functionalities at distal positions in arenes are an important endeavor in contemporary organic synthesis. In this vein, template engineering and mechanistic understanding of new functionalization strategies are essential for enhancing the scope of such methods. Herein, meta-C-H allylation of arenes has been achieved with the aid of a palladium catalyst, pyrimidine-based auxiliary, and allyl phosphate. 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) was found as a critical solvent in this transformation. The role of HFIP throughout the catalytic cycle has been systematically studied. A broad substrate scope with phenethyl ether, phenol, benzylsulfonyl ester, phenethylsulfonyl ester, phenylacetic acid, hydrocinnamic acid, and 2-phenylbenzoic acid derivatives has been demonstrated. Interestingly, conformationally flexible arenes have also been selectively allylated at the meta-position using allyl phosphate. A combination of 1H NMR, 31P NMR, ESI-MS, kinetic experiments, and density functional theory (DFT) computations suggested that reaction proceeds through a ligand-assisted meta-C-H activation, allyl addition forming a Pd-π-allyl complex which is then followed by a turnover determining the C-C bond formation step leading to the meta-allylated product.

4.
J Am Chem Soc ; 142(8): 3762-3774, 2020 02 26.
Article in English | MEDLINE | ID: mdl-31910623

ABSTRACT

The late-stage functionalization (LSF) of pharmaceutical and agrochemical compounds by the site-selective activation of C-H bonds provides access to diverse structural analogs and expands synthetically-accessible chemical space. We report a C-H functionalization LSF strategy that hinges on the use of an alkyne linchpin to assemble conjugates of sp2-rich marketed pharmaceuticals and agrochemicals with sp3-rich 3D fragments and natural products. This is accomplished through a template-assisted inverse Sonogashira reaction that displays high levels of selectivity for the meta position. This protocol is also amenable to distal structural modifications of α-amino acids. The transformation of alkyne functionality to other functional groups further highlights the applicative potential. Computational and experimental mechanistic studies shed light on the detailed mechanism. Turnover-limiting 1,2-migratory insertion of the bromoalkyne coupling partner occurs after relatively fast C-H activation. While this insertion occurs unselectively, regioconvergence results from one of the adducts undergoing a 1,2-trialkylsilyl migration to form the alkynylated product. A heterobimetallic Pd-Ag transition structure is essential for product formation in the ß-bromide elimination step.


Subject(s)
Alkynes/chemistry , Pharmaceutical Preparations/chemistry , Biological Products/chemistry , Molecular Structure
5.
Angew Chem Int Ed Engl ; 58(39): 13808-13812, 2019 09 23.
Article in English | MEDLINE | ID: mdl-31336005

ABSTRACT

Distal C-H bond functionalization of heterocycles remained extremely challenging with covalently attached directing groups (DG). Lack of proper site for DG attachment and inherent catalyst poisoning by heterocycles demand alternate routes for site selective functionalization of their distal C-H bonds. Utilizing non-productive coordinating property to hold the heterocycle into the cavity of a template system in a host-guest manner, we report distal C-H alkylation (C-5 of quinoline and thiazole, C-7 of benzothiazole and benzoxazole) of heterocycles. Upon complexation with heterocyclic substrate, nitrile DG in template directs the metal catalyst towards close vicinity of the specific distal C-H bond of the heterocycles. Our hypothesized pathway has been supported by various X-ray crystallographically characterized intermediates.

6.
J Org Chem ; 84(12): 8315-8321, 2019 06 21.
Article in English | MEDLINE | ID: mdl-31120754

ABSTRACT

An efficient method has been developed to afford highly C-5 selective olefination of thiazole derivatives utilizing a bifunctional template in an intermolecular fashion. Coordinative interaction between the substrates and the metal chelated template backbone plays a crucial role in high C-5 selectivity. Excellent selectivity for the C-5 position was observed while mono substituted (2- or 4-) or even more challenging unsubstituted thiazoles were employed.

7.
Chemistry ; 25(3): 750-753, 2019 Jan 14.
Article in English | MEDLINE | ID: mdl-30414281

ABSTRACT

A silver(I) catalyzed regioselective trifluoromethylation of allenes using Langlois's salt (NaOSOCF3 ) is demonstrated. This transformation enables direct expedient access to α-trifluoromethylated acroleins, which are valuable synthons for a number of pharmaceuticals and agrochemicals containing vinyl-CF3 moieties. Versatility of this trifluoromethylation method has been established with good yield and excellent regioselectivity. Preliminary experiments and computational studies were carried out to elucidate the mechanistic insight of this protocol.

8.
Chemistry ; 24(68): 17906-17910, 2018 Dec 05.
Article in English | MEDLINE | ID: mdl-30184288

ABSTRACT

Achieving site-selective C-H functionalization of arene is a fundamental challenge, as it is mainly controlled by the electronic nature of the molecules. A chelation-assisted C-H functionalization strategy overcomes the selectivity issues by utilizing distance and geometry of covalently attached directing groups (DGs). This strategy requires stoichiometric DG installation/removal and a suitable functional group on which to tether the DG. Such strategies are ineffective for small heterocycles unless suitable functional groups are added. Moreover, heterocycles are not the judicious choice as substrates owing to the possibilities of catalyst deactivation. Inspired by recent developments, this work demonstrates the utilization of a chelating template backbone bearing covalently attached directing groups, which enables site-selective remote C-H functionalization of heterocycles. The observed selectivity is the outcome of non-covalent interactions between the heterocycles and bifunctional template backbone.

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