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CC BY-NC-ND 4.0 · SynOpen 2022; 06(02): 110-131
DOI: 10.1055/a-1826-2852
Graphical Review

Aryl Methyl Ketones: Versatile Synthons in the Synthesis of Heterocyclic Compounds

Shabber Mohammed  ∗
,
Jason S. West 
,
Mark J. Mitton-Fry∗
The Dr. Ralph and Marian Falk Medical Research Trust (Transformational Award) and the National Institutes of Health (NIH) (R21 AI148986) provided financial support.
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Abstract

The synthesis of aromatic heterocycles has attracted substantial attention due to the abundance of these heterocycles in drug molecules, natural products, and other compounds of biological interest. Accordingly, there is a demand for straightforward synthetic protocols toward such compounds using readily available starting materials. In the past decade, there have been substantial developments in heterocycle synthesis, especially in metal-catalyzed and iodine-assisted approaches. This graphical review focuses on notable reactions from the past decade using aryl and heteroaryl methyl ketones as starting materials, including representative reaction mechanisms.


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Key words

aromatic heterocycles - iodine - ketones - metal-free - fused bicycles - fused tricycles - fused polyheterocycles

Aromatic heterocycles are highly privileged structures in drug discovery and development. Such fragments are found very frequently in biologically active compounds and thus are common building blocks for drugs and natural product derivatives. Beyond their utility in eliciting biological activity, these heterocycles are also useful in modifying ADME (absorption, distribution, metabolism and excretion)/pharmacokinetic properties (introducing lipophilicity or hydrophilicity, improving solubility, fine-tuning hydrogen bonding, etc.) and reducing possible toxicity concerns. The increasing presence of various aromatic heterocycles in drugs is no doubt related to advances in synthetic methodology such as metal-catalyzed cross-couplings,[1a] hetero-couplings,[1b] and metal-free conditions,[1c] [d] enabling rapid access to a wide variety of functionalized heterocyclic scaffolds.

Aryl methyl ketones (AMKs) (also including heteroaryl compounds) are attractive precursors that allow for the facile synthesis of aromatic heterocycles. Iodine, in combination with AMKs, can substitute for several transition metals used in previously reported transformations while also maintaining an excellent atom economy.[1e] [f] [j] This aspect, along with the commercial abundance and cost-effective nature of AMKs, provides an incentive to the research community to discover and further develop such processes for use in drug discovery. Despite the vast literature that has evolved on this topic, there has yet to be a succinct review of the important developments in this area. The present graphical review provides a comprehensive compilation (focused on 2012–2021) of synthetic approaches for 5- and 6-membered, as well as fused and poly-fused heterocycles. Herein, we detail the role of AMKs in the synthesis of such heterocycles. Brief examples of practical syntheses of AMKs are presented in Scheme 1. The application of AMKs to the synthesis of heterocycles follows in Schemes 2 through 111, with an overall organization focused on heterocycle type. Brief reaction mechanisms are highlighted in instructive examples, with colors to aid understanding. Yields and structural diversity are reported in numerous examples to reflect the substrate scope for these reactions, including the use of electron-donating and -withdrawing groups as well as heterocyclic starting materials.

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from left to right Shabber Mohammed was born and raised in Telangana, India. He obtained B.Sc. and M.Sc. degrees from Osmania University (India). He completed his Ph.D. in chemical sciences under the joint supervision of Dr. Ram A. Vishwakarma and Dr. Sandip B. Bharate at the IIIM-Academy of Scientific and Innovative Research, India. After working as a research scientist for 1.3 years at GVK BIO and Piramal Life Sciences, he joined the group of Dr. Thota Ganesh at Emory University as a postdoctoral research scholar. He subsequently worked in the lab of Dr. Lee McDermott at the University of Pittsburgh for two years. His research has mainly focused on the medicinal chemistry of CNS drugs (EP2 receptors and 20-HETE inhibitors) and anticancer drugs (PI3K-mTOR inhibitors). At present, he is a postdoctoral researcher at The Ohio State University in the laboratories of Dr. Mark Mitton-Fry and Dr. Pui-Kai Li. Jason S. West obtained his B.Sc. in pharmaceutical sciences from The Ohio State University in the spring of 2020. During his undergraduate studies, he conducted research in biomedical informatics, microbial engineering, and synthetic medicinal chemistry. He is presently a second-year graduate student at The Ohio State University, pursuing a Ph.D. in synthetic medicinal chemistry. He is currently researching novel bacterial topoisomerase inhibitors as a new therapeutic option for multidrug-resistant bacterial infections in the lab of Dr. Mark Mitton-Fry. Mark J. Mitton-Fry graduated summa cum laude from Carleton College with a B.A. in chemistry, which was followed by a year as a fellow of the Deutscher Akademischer Austauschdienst (DAAD) in Würzburg, Germany. He completed his Ph.D. with Professor Tarek Sammakia at the University of Colorado Boulder before spending nine years in the pharmaceutical industry. He is currently an assistant professor in the Division of Medicinal Chemistry and Pharmacognosy at The Ohio State University. His research team is primarily focused on the discovery of bacterial topoisomerase inhibitors, with additional interests in novel anticancer approaches.
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Figure 1 Synthesis of aryl methyl ketones[1`] [h] [i] [j] and five-membered heterocycles, part I[2a–f]
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Figure 2 Synthesis of five-membered heterocycles, part II[2`] [h] [i] [j] [k] [l]
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Figure 3 Synthesis of five-membered heterocycles, part III[2`] [n] [o] [p] [q] [r]
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Figure 4 Synthesis of five-membered heterocycles, part IV[2`] [t] [u] [v] [w] [x]
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Figure 5 Synthesis of five-membered heterocycles, part V,[2y] [z] and six-membered heterocycles part I[3a–e]
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Figure 6 Synthesis of six-membered heterocycles, part II[3`] [g] [h] [i] [j] [k]
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Figure 7 Synthesis of fused bi-heterocycles, part I[3`] [m] [n] , [4`] [b] [c]
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Figure 8 Synthesis of fused bi-heterocycles, part II[3i] , [4`] [e] [f] [g] [h] [i] [j]
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Figure 9 Synthesis of fused bi-heterocycles, part III[4`] [l] [m] [n] [o] [p] [q] , [5`] [b] [c] [d] [e] [f] [g] [h] [i] [j] [k] [l] [m] [n] [o]
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Figure 10 Synthesis of fused bi-heterocycles, part IV[5p] [q] , [6`] [b] [c] [d] [e]
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Figure 11 Synthesis of fused bi-heterocycles, part V[6`] [g] [h] [i] [j] [k] [l] [m] [n] [o]
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Figure 12 Synthesis of fused bi-heterocycles, part VI[6o] , [7`] [b] [c] [d] [e] [f] [g]
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Figure 13 Synthesis of fused bi-heterocycles, part VII[7`] [i] [j] [k] [l] [m] [n]
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Figure 14 Synthesis of fused bi-heterocycles, part VII,[7`] [p] [q] and fused tri-heterocycles, part I[8`] [b] [c] [d]
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Figure 15 Synthesis of fused tri-heterocycles, part II[7f] , [8`] [f] [g] [h] [i]
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Figure 16 Synthesis of fused tri-heterocycles, part III[8`] [k] [l] [m] [n] [o]
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Figure 17 Synthesis of fused tri-heterocycles, part IV,[8`] [q] [r] [s] [t] and fused polyheterocycles, part I[9a]
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Figure 18 Synthesis of fused polyheterocycles, part II[9`] [c] [d] [e] [f] [g] [h] [i]

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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We are grateful to Dr. Lee McDermott, University of Pittsburgh, and current members of Dr. Mark Mitton-Fry’s research group who have contributed to the development of this field.


Corresponding Authors

Shabber Mohammed
The Ohio State University, College of Pharmacy, Division of Medicinal Chemistry and Pharmacognosy
Columbus, Ohio, 43210
USA   
Mark J. Mitton-Fry
The Ohio State University, College of Pharmacy, Division of Medicinal Chemistry and Pharmacognosy
Columbus, Ohio, 43210
USA   

Publication History

Received: 12 January 2022

Accepted after revision: 06 April 2022

Accepted Manuscript online:
14 April 2022

Article published online:
08 June 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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from left to right Shabber Mohammed was born and raised in Telangana, India. He obtained B.Sc. and M.Sc. degrees from Osmania University (India). He completed his Ph.D. in chemical sciences under the joint supervision of Dr. Ram A. Vishwakarma and Dr. Sandip B. Bharate at the IIIM-Academy of Scientific and Innovative Research, India. After working as a research scientist for 1.3 years at GVK BIO and Piramal Life Sciences, he joined the group of Dr. Thota Ganesh at Emory University as a postdoctoral research scholar. He subsequently worked in the lab of Dr. Lee McDermott at the University of Pittsburgh for two years. His research has mainly focused on the medicinal chemistry of CNS drugs (EP2 receptors and 20-HETE inhibitors) and anticancer drugs (PI3K-mTOR inhibitors). At present, he is a postdoctoral researcher at The Ohio State University in the laboratories of Dr. Mark Mitton-Fry and Dr. Pui-Kai Li. Jason S. West obtained his B.Sc. in pharmaceutical sciences from The Ohio State University in the spring of 2020. During his undergraduate studies, he conducted research in biomedical informatics, microbial engineering, and synthetic medicinal chemistry. He is presently a second-year graduate student at The Ohio State University, pursuing a Ph.D. in synthetic medicinal chemistry. He is currently researching novel bacterial topoisomerase inhibitors as a new therapeutic option for multidrug-resistant bacterial infections in the lab of Dr. Mark Mitton-Fry. Mark J. Mitton-Fry graduated summa cum laude from Carleton College with a B.A. in chemistry, which was followed by a year as a fellow of the Deutscher Akademischer Austauschdienst (DAAD) in Würzburg, Germany. He completed his Ph.D. with Professor Tarek Sammakia at the University of Colorado Boulder before spending nine years in the pharmaceutical industry. He is currently an assistant professor in the Division of Medicinal Chemistry and Pharmacognosy at The Ohio State University. His research team is primarily focused on the discovery of bacterial topoisomerase inhibitors, with additional interests in novel anticancer approaches.
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Figure 1 Synthesis of aryl methyl ketones[1`] [h] [i] [j] and five-membered heterocycles, part I[2a–f]
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Figure 2 Synthesis of five-membered heterocycles, part II[2`] [h] [i] [j] [k] [l]
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Figure 3 Synthesis of five-membered heterocycles, part III[2`] [n] [o] [p] [q] [r]
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Figure 4 Synthesis of five-membered heterocycles, part IV[2`] [t] [u] [v] [w] [x]
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Figure 5 Synthesis of five-membered heterocycles, part V,[2y] [z] and six-membered heterocycles part I[3a–e]
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Figure 6 Synthesis of six-membered heterocycles, part II[3`] [g] [h] [i] [j] [k]
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Figure 7 Synthesis of fused bi-heterocycles, part I[3`] [m] [n] , [4`] [b] [c]
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Figure 8 Synthesis of fused bi-heterocycles, part II[3i] , [4`] [e] [f] [g] [h] [i] [j]
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Figure 9 Synthesis of fused bi-heterocycles, part III[4`] [l] [m] [n] [o] [p] [q] , [5`] [b] [c] [d] [e] [f] [g] [h] [i] [j] [k] [l] [m] [n] [o]
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Figure 10 Synthesis of fused bi-heterocycles, part IV[5p] [q] , [6`] [b] [c] [d] [e]
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Figure 11 Synthesis of fused bi-heterocycles, part V[6`] [g] [h] [i] [j] [k] [l] [m] [n] [o]
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Figure 12 Synthesis of fused bi-heterocycles, part VI[6o] , [7`] [b] [c] [d] [e] [f] [g]
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Figure 13 Synthesis of fused bi-heterocycles, part VII[7`] [i] [j] [k] [l] [m] [n]
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Figure 14 Synthesis of fused bi-heterocycles, part VII,[7`] [p] [q] and fused tri-heterocycles, part I[8`] [b] [c] [d]
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Figure 15 Synthesis of fused tri-heterocycles, part II[7f] , [8`] [f] [g] [h] [i]
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Figure 16 Synthesis of fused tri-heterocycles, part III[8`] [k] [l] [m] [n] [o]
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Figure 17 Synthesis of fused tri-heterocycles, part IV,[8`] [q] [r] [s] [t] and fused polyheterocycles, part I[9a]
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Figure 18 Synthesis of fused polyheterocycles, part II[9`] [c] [d] [e] [f] [g] [h] [i]