The α,α‐Dihalocarbonyl Building Blocks: An Avenue for New Reaction Development in Organic Synthesis

Abstract

The α,α‐dihalocarbonyl moiety is a bifunctional system with a gem‐dihalocarbon and a carbonyl carbon in 1,2‐fashion. This is one of the privileged scaffolds in medicinal chemistry due to its chemical and metabolic stability and lipophilicity. They have also been found in numerous structurally divergent natural products and most of their fabricated structures have already been in medicinal use. Apart from their important use in medicinal chemistry, the α,α‐dihalocarbonyl groups have been employed as key building blocks for the development of novel synthetic strategies and utilized as intermediates in total synthesis. In addition to the traditional transformations such as oxidations, reductions, and C−C bond formations, recently several new and non‐classical reactions have also been developed. This review provides short description of existing methods for their synthesis and detailed discussion on the efforts for the discovery and development of new reactions by employing α,α‐dihaloketones as synthetic building blocks. We have presented their use as key functional groups for the synthesis of polycyclic systems of medicinal and material importance and natural products.

Applications of Oxone® in Organic Synthesis: An Emerging Green Reagent of Modern Era

“…Therefore, the development of more appropriate methods for oxyhalogenation of alkynes into the α,α-dihaloketones is highly desirable. [180][181][182] In this line, Madabhushi et al developed a new approach for the synthesis of α,α-dihaloketones 210 a-l from oxyhalogenation of alkynes 209 using oxone as an oxidant and KX (X=Cl, Br, or I) as suitable halogen sources under mild condition (Scheme 67). [183] As can be inspected from the Scheme 68, herein, oxone and halides generate the dihalomonoxide (X 2 O) which participate in oxyhalogenation of alkynes 209 by converting it into the α,αdihaloketones 210 a-l through the intermediates 213-215.…”

Hypervalent Iodine-Mediated Chemoselective Bromination of Terminal Alkynes

“…Halogenated organic compounds play an important role in organic synthesis as synthetic intermediates or key synthetic precursors due to their feasible transformation into a variety of functional compounds for material science, bioactive compounds, or industrial chemicals ( Chen et al, 2010 ; Adimurthym et al, 2013 ; Wu et al, 2017 ). For example, monohaloalkynes and α,β-dihaloalkenes have found a variety of application as dual functionalized molecules ( Brand and Waser, 2012 ; Shi and Lei, 2014 ; Wu and Jang, 2014 ; Shi, 2015 ), and α,α-dihaloketones are important building blocks in the synthesis of heterocyclic compounds, unsaturated acids and acetylenic alcohols, and cyclopropanation ( Furukawa et al, 1976 ; Kawabata et al, 1977 ; Kowalski and Fields, 1982 ; Zhdankin and Stang, 1993 ; SooáKim et al, 1995 ; Madabhushi et al, 2013 ; Sadhukhan et al, 2020 ). In addition, α,α-dihaloketones and tetrahalides have been reported to be potent antitumor, antibacterial, antifungal, antineoplastic, antiviral, and antioxidizing agents ( Butler and Walker, 1993 ; Bora et al, 2000 ; Khazaei et al, 2010 ).…”

Dichlorination of β-Keto Esters and 1,3-Diketones Mediated by Oxone/Aluminum Trichloride Mixture in Aqueous Medium

“…[1][2][3] Specifically, compounds containing the ,-dihalocarbonyl moiety have been extensively utilized in medicinal chemistry as a result of chemical and metabolic stability as well as their significant lipophilicity. [4][5][6] In addition to their use and importance in medicinal chemistry, these compounds are utilized as building blocks in organic synthesis. [6][7][8][9] In general, the formation of carbon-chlorine bond is a useful and important transformation in organic chemistry.…”

“…[4][5][6] In addition to their use and importance in medicinal chemistry, these compounds are utilized as building blocks in organic synthesis. [6][7][8][9] In general, the formation of carbon-chlorine bond is a useful and important transformation in organic chemistry. [10][11][12] Furthermore, the stereoselective reduction of ,-dichloro dicarbonyl compounds, which are useful precursors in organic synthesis leads to the formation of optically pure ,-dichlorο -hydroxy esters, molecules with high biological activity.…”