Synthesis and Late-Stage Functionalization of Complex Molecules through C–H Fluorination and Nucleophilic Aromatic Substitution

Abstract

We report the late-stage functionalization of multisubstituted pyridines and diazines at the position α to nitrogen. By this process, a series of functional groups and substituents bound to the ring through nitrogen, oxygen, sulfur, or carbon are installed. This functionalization is accomplished by a combination of fluorination and nucleophilic aromatic substitution of the installed fluoride. A diverse array of functionalities can be installed because of the mild reaction conditions revealed for nucleophilic aromatic substitutions (SNAr) of the 2-fluoroheteroarenes. An evaluation of the rates for substitution versus the rates for competitive processes provides a framework for planning this functionalization sequence. This process is illustrated by the modification of a series of medicinally important compounds, as well as the increase in efficiency of synthesis of several existing pharmaceuticals.

Quinuclidine and DABCO Enhance the Radiofluorination of 5‐Substituted 2‐Halopyridines

“…These observations lead us to suggest that the tertiary amines, DABCO or quinuclidine, form a more reactive quaternary ammonium intermediate with a 2‐halopyridine. A 2‐fluoro substituent has been shown to be an effective leaving group in S N Ar reactions on pyridines . Therefore, we also speculate that the radiofluorinated product may form the same quaternary ammonium intermediate reversibly.…”

“…A 2-fluoro substituent has been shown to be an effective leaving group in S N Ar reactions on pyridines. [38] Therefore, we also speculate that the radiofluorinated product may form the same quaternary ammonium intermediate reversibly. Such an intermediate must be formed in relatively low concentration, as we were unable to observe formation in situ by either NMR or HPLC, when precursor and DABCO were heated together in DMSO at temperatures up to 150°C.…”

Diastereoselective Synthesis of Dialkylated Bis(phosphino)ferrocenes: Their Use in Promoting Silver‐Mediated Nucleophilic Fluorination of Chloroquinolines

“…Changes in the amount of AgF added indicated that a quantity lower than 3.0 equivalents was less efficient for fluorination (Table , entries 6 and 7). Concerning the nucleophilic source, AgF 2 , a rather marginally used reagent, was recently identified by Fier and Hartwig as a highly efficient fluorination reagent for direct nucleophilic S N Ar of pyridine derivatives . Under our conditions, AgF 2 was inefficient as a transhalogenation agent (Table , entry 8).…”

“…Additionally, metal‐catalyzed selective nucleophilic fluorination of heteroarenes, which is complementary to electrophilic fluorination, is very topical, as such fluorinated compounds are present in pharmaceuticals, agrochemicals, molecular materials, and medical imaging radiotracers . Consequently, relevant approaches from copper chemistry or by using direct SN Ar ,, albeit under strictly anhydrous conditions, have been reported. Thus, examination of performances from air‐stable robust system under less sensitive conditions remains pertinent.…”

Transition metal complex assisted Csp3–F bond formation

“…23 Additional methods include Cu-mediated fluorination of aryl halides, 24,25 -boronate esters, 26 -trifluoroborates, 27 and -stannanes, 27 Cu-catalyzed fluorination of 2-pyridyl aryl bromides, 28 and C-H bonds, 29 and Ag-mediated and -catalyzed electrophilic fluorination of aryl stannanes, 30,31 and C-H fluorination of pyridines and diazines. 32,33 Finally, a variety of transition metal complexes have been utilized for catalytic allylic fluorination including Pd, [34][35][36][37][38][39] Cu, 40 Rh, 41 and Ir. 42,43 Despite these outstanding approaches, the methods for general and site-specific formation of aliphatic fluorides are rare and relatively underdeveloped.…”