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.
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.
Figure 1 Synthesis of aryl methyl ketones[1`]
[h]
[i]
[j] and five-membered heterocycles, part I[2a–f]
Figure 2 Synthesis of five-membered heterocycles, part II[2`]
[h]
[i]
[j]
[k]
[l]
Figure 3 Synthesis of five-membered heterocycles, part III[2`]
[n]
[o]
[p]
[q]
[r]
Figure 4 Synthesis of five-membered heterocycles, part IV[2`]
[t]
[u]
[v]
[w]
[x]
Figure 5 Synthesis of five-membered heterocycles, part V,[2y]
[z] and six-membered heterocycles part I[3a–e]
Figure 6 Synthesis of six-membered heterocycles, part II[3`]
[g]
[h]
[i]
[j]
[k]
Figure 7 Synthesis of fused bi-heterocycles, part I[3`]
[m]
[n]
,
[4`]
[b]
[c]
Figure 8 Synthesis of fused bi-heterocycles, part II[3i]
,
[4`]
[e]
[f]
[g]
[h]
[i]
[j]
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]
Figure 10 Synthesis of fused bi-heterocycles, part IV[5p]
[q]
,
[6`]
[b]
[c]
[d]
[e]
Figure 11 Synthesis of fused bi-heterocycles, part V[6`]
[g]
[h]
[i]
[j]
[k]
[l]
[m]
[n]
[o]
Figure 12 Synthesis of fused bi-heterocycles, part VI[6o]
,
[7`]
[b]
[c]
[d]
[e]
[f]
[g]
Figure 13 Synthesis of fused bi-heterocycles, part VII[7`]
[i]
[j]
[k]
[l]
[m]
[n]
Figure 14 Synthesis of fused bi-heterocycles, part VII,[7`]
[p]
[q] and fused tri-heterocycles, part I[8`]
[b]
[c]
[d]
Figure 15 Synthesis of fused tri-heterocycles, part II[7f]
,
[8`]
[f]
[g]
[h]
[i]
Figure 16 Synthesis of fused tri-heterocycles, part III[8`]
[k]
[l]
[m]
[n]
[o]
Figure 17 Synthesis of fused tri-heterocycles, part IV,[8`]
[q]
[r]
[s]
[t] and fused polyheterocycles, part I[9a]
Figure 18 Synthesis of fused polyheterocycles, part II[9`]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
