Photochemically Mediated Ring Expansion of Indoles and Pyrroles with Chlorodiazirines: Synthetic Methodology and Thermal Hazard Assessment

Abstract

We demonstrate that arylchlorodiazirines serve as photo‐activated halocarbene precursors for the selective one‐carbon ring expansion of N‐substituted pyrroles and indoles to the corresponding pyridinium and quinolinium salts. Preliminary investigations indicate that the same strategy also enables the conversion of N‐substituted pyrazoles to pyrimidinium salts. The N‐substituent of the substrate plays an essential role in: (1) increasing substrate scope by preventing product degradation, (2) enhancing yields by suppressing co‐product inhibition, and (3) activating the azinium products towards subsequent synthetic manipulations. This latter point is illustrated by subjecting the quinolinium salts to four complementary partial reductions, which provide concise access to ring‐expanded products with different degrees of increased C(sp3) character. Thermal analysis of the diazirines by differential scanning calorimetry (DSC) provides detailed insight into their energetic properties, and highlights the safety benefits of photolyzing—rather than thermolyzing—these reagents.

Dearomatization of Pyridines: Photochemical Skeletal Enlargement for the Synthesis of 1,2-Diazepines

“…The scope and limitations of our protocol were explored (Figure 4). First, we found that several N-activators were compatible with our one-pot procedure, including PhCOCl (1), Boc 2 O (13), CbzCl (24), base-sensitive FmocCl (25), AllocCl (26), and even TrocCl (27), with a modest yield. Alkylpyridines gave satisfactory results affording the desired diazepines, although the yield drops when the pyridine is substituted with a benzyl group in the 4-position (28−33).…”

“…Over the past years, many elegant strategies have emerged aiming at editing aromatic skeletons − by inserting, − deleting, , or swapping atoms − in a short amount of time and steps (Figure B). Thus, one could rapidly evaluate the potential interest of drug analogues by interchanging the nature of one (or more) aromatic ring(s).…”

One‐Carbon Ring Expansion of Indoles and Pyrroles: A Straightforward Access to 3‐Fluorinated Quinolines and Pyridines

“…Specifically, one‐carbon ring expansion of indoles and pyrroles, achieved via a [2+1] cycloaddition‐fragmentation‐aromatization sequence, represents a straightforward approach to valuable quinolines and pyridines (Figure 1C). [8a–o] One key design of this transformation lies in the in situ generation of an electrophilic carbene intermediate that bears a suitable leaving group. As pioneers in this field, Ciamician and Dennstedt first realized the transformation of pyrroles into 3‐chloropyridines with chloroform‐derived chlorocarbene, yet low reaction yield and poor functional group tolerance limit its practical implementation [8e,f] .…”

“…As pioneers in this field, Ciamician and Dennstedt first realized the transformation of pyrroles into 3‐chloropyridines with chloroform‐derived chlorocarbene, yet low reaction yield and poor functional group tolerance limit its practical implementation [8e,f] . Aimed to enhance the reaction compatibility and diversify the azine skeletons, continuous efforts have been devoted to the development of new carbene sources [8g–o] . Especially, recent works have made significant progress by employing halodiazoesters or chlorodiazirines as carbene precursors [8l–o] .…”

Direct Access to Quinazolines and Pyrimidines from Unprotected Indoles and Pyrroles through Nitrogen Atom Insertion

“…Transforming parent molecular frameworks into structurally related compounds through the insertion of single atoms has gained increased attention over the last decades, further expanding the synthetically accessible chemical space. − Through the insertion of heteroatoms such as oxygen − or nitrogen − into abundant frameworks, rapid access to a diverse array of shape-similar targets with modulated pharmacokinetic properties is possible. Additionally, applying these strategies to diversify target structures at a late stage obviates time-consuming de novo syntheses and directly affords biologically interesting heterocycles expanding available medicinal chemistry libraries. , Recently, various methods were developed to interconvert widely encountered scaffolds such as indoles and pyrroles into the corresponding carbon-atom extended frameworks, including quinolines and pyridines. − Strategies to afford the corresponding N , N -heterocycles were also disclosed, however, these either depend on harsh reaction conditions and present a limited scope or rely on the use of protecting group strategies that require a separate prefunctionalization step (Figure a). , In addition, the strategically related development of a nitrogen atom insertion into pyrroles to access the corresponding pyrimidine motifs is underdeveloped and was showcased for only two selected examples, 2,3,4,5-tetraphenyl-1 H -pyrrole (Figure b) , and ethyl 4-(4-methoxyphenyl)-2,5-dimethyl-1 H -pyrrole-3-carboxylate …”