Advances in the Preparation of Fluorinated Isoquinolines : A Decade of Progress

Heterocyclic molecules incorporating fluorinated isoquinoline components are found in many medicinally and agriculturally important bioactive products as well as industrially impactful materials. Within the past decade, a variety of isoquinolinic ring assembly techniques has enabled the introduction of diverse fluorine-containing functionalities which can enhance potential bioactivity and industrial utility. This review examines recent noncatalyzed and transition metal catalyzed synthetic approaches to the assembly of isoquinoline derivatives that are ring-fluorinated and/or result in the incorporation of fluorine-containing functional groups. Specifically, efficient synthetic methods and regioselectivity in the incorporation of functional groups into isoquinoline ring systems are examined.


Discovery of Isoquinoline and Early Synthesis Efforts.
Isoquinoline, the bicyclic aromatic heterocycle shown in Figure 1, was first isolated as the sulfate salt from coal tar in 1885 by Hoogewerf and van Dorp [1].By 1893, several syntheses of isoquinolinoid compounds were published by Pomeranz, Fritsch, Bischler, and Napieralski, reactions which bear their names [2][3][4].Early in the 20th century, Pictet, Gams, and Spengler developed slightly different approaches to prepare isoquinoline derivatives [5,6].
While the synthetic methods shown in Figure 1 enabled construction of different parts of the "A" ring component of the isoquinoline heterocycle, most early preparations required strong acids and refluxing conditions or dehydrating agents and dehydrogenation catalysts which limited functional group survival during the reactions.

Medicinal and Industrial Uses of Isoquinolines.
Since its discovery, isoquinoline has remained an aromatic heterocycle of broad appeal to the synthetic organic, materials science, pharmaceutical, and agrochemical communities.Isoquinoline derivatives have important industrial applications, where they serve as solvents for aromatic molecules, fluorosensors, as components in paints, dyes, and electronic devices [7][8][9].Isoquinoline derivatives such as papaverine have been isolated from natural sources and the isoquinolinoid pharmacore can be found in numerous drugs that possess antitumor, anesthetic, and antibiotic properties [10][11][12].Figure 2 shows some representative examples of important isoquinolinebased molecules.

Effects of Fluorine Incorporation on Molecular Properties.
When fluorine and fluorine-containing groups are incorporated into molecules, dramatic shifts of molecular properties occur in many instances.The inductive effect brought about by fluorine's high electronegativity and its small van der Waals radius of 1.47 Å changes molecular structural and stereoelectronic properties such as conformation, p a , polarity, solubility, and hydrogen-bonding capacity [13][14][15][16][17][18].An example of how these alterations bear directly on materials science applications is found in the fluorinated isoquinolinebased electrophosphorescent iridium complexes used in color displays [9].See Figure 3.
For a number of years, the pharmaceutical industry has leveraged these fluorine-induced molecular property modulations in drug discovery strategies when constructing heteroaromatic pharmacores.Today, nearly 20% of FDAapproved drugs contain fluorine [19].The very strong  sp3 C-F bond (110 kcal/mol) increases the metabolic stability of drugs, enabling better bioavailability and binding affinity [19][20][21][22].Isoquinolines functionalized with fluorine and fluorinecontaining groups, the focus of this review, are key pharmacores with many applications.For example, isoquinoline carboxamides labeled with 18 F have found use as radiolabeling ligands for positron emission tomography [22].Additionally, the preparation of fluorinated, fluoroalkylated, and fluoroarylated isoquinoline variants with antibacterial and antiparasitic properties continues to be an area of significant interest to the medicinal chemistry community.Figure 3 contains several examples of medicinally important isoquinoline derivatives which bear fluorine in their structure.

Recent Synthesis Efforts in the Preparation of Fluorinated
Isoquinolines.This review examines a number of fluorinated isoquinoline preparations which capitalize on noncatalyzed reactions and cyclizations as well as those which employ transition metal catalysis to achieve the isoquinoline architecture.As Figure 4 shows, multiple methods that permit construction of the isoquinoline ring A and ring B components have been advanced and will be examined.More specifically, we will consider those processes shown in Figure 4 which result in isoquinoline ring fluorinations, di-and trifluoromethylations, fluoroarylations, and trifluoromethylarylations. As Figure 5 indicates, fluorine functionality may be introduced at every carbon center of the isoquinoline core, and more than fifty-five examples will be explored in this review.
We will first examine nontransition metal mediated processes and then discuss the scope of transition metal catalysis in the preparation of fluorine-containing isoquinolines.

Ring-Fluorinated, Di-and Trifluoromethylated, Perfluoroalkylated, and Fluoroarylated Isoquinoline Synthesis via Nontransition Metal Mediated Processes
This portion of the review catalogues a broad cross section of isoquinoline preparations reported in the last decade which are not catalyzed by transition metal complexes.Methods examined include both intramolecular and intermolecular cycloadditions, tandem reactions, and multicomponent and single-pot processes which produce a wide array of A and B ring-fluorinated, di-and trifluoromethylated, perfluoroalkylated, and fluoroarylated polyfunctional isoquinolines.In addition, several trifluoromethylation and perfluoroalkylation reactions are shown that produce polyfunctional isoquinolines with a high degree of R f substitution site regioselectivity.

3-and 4-Fluoroisoquinolines via Intramolecular
Ring A Cyclization at N 2 -C 3 and C 3 -C 4 .Ichikawa and coworkers cyclized the difluoroalkene aminotosylate 1 (Scheme 1) under basic conditions in a 6-endo-trig fashion at N 2 -C 3 to obtain the 4-butylated 3-fluoroisoquinoline series 2 in excellent yield [23]. Kiselyov reported a base-promoted intramolecular ring closure of ortho-trifluoromethyl benzyl heterocycles 3 en route to nine tricyclic 4-fluoroisoquinoline derivatives 4. See Scheme 2. The reaction likely proceeds through a C 3 -C 4 cyclization of a quinone methide intermediate arising from elimination of fluoride anion [24].cycloaddition of benzonitriles 8 and 9 to prepare the 1-aminoisoquinolines 10a-b which are fluorinated at the 6-and 7positions in moderate yields [26].Ring B assembly at C 4f -C 5 and C 8f -C 8 :

6-and 7-Fluoroisoquinolines via Intermolecular Ring
Ring A assembly at C 4f -C 4 and C 8f -C 1 : Ring A assembly at C 4 -C 4f : Ring A assembly at C 8f -C 1 :  Wolff rearrangement.An aza-Wittig reaction between the phosphazene and ketene yields the isomeric N-vinylic ketene imines in brackets.Finally, electrocyclic ring closure and a subsequent [1,3]-H migration leads to the formation of isoquinoline isomers.

Fluorinated, Trifluoromethylated, Fluoroarylated, and Trifluoromethylarylated Isoquinoline Synthesis via Transition Metal Mediated Processes
This section catalogues a representative sample of isoquinoline preparations catalyzed by periods 4, 5, and 6 transition metal complexes.Methods examined include those which produce a wide array of A and B ring-fluorinated, trifluoromethylated, and fluoroarylated polyfunctional isoquinolines.In addition, several selective fluorination and trifluoromethylation reactions, done in concert with transition metal catalysts, are shown that produce polyfunctional isoquinolines with a high degree of fluorination and trifluoromethylation site regiocontrol.of eleven fluorine-containing isoquinolines 38 [36].Li's team used the same catalyst system with a slightly different base to couple aryl amidines 39 and diazo compounds 40 to deliver five examples of monofluorinated and trifluoromethylated 1aminoisoquinolines 41 in fair to excellent yields [37].Pawar et al. just released a study of Co(III)-catalyzed C-H/N-N bond functionalization of arylhydrazones 42 with internal alkynes 43 for the synthesis of three ring-fluorinated and fluoroarylated isoquinoline derivatives 44 in very good yields [38], while a 2016 report by Yu et al. catalogued the cycloaddition of oxadiazolones 45 with alkynes 46 to prepare eight ring-fluorinated, trifluoromethylated, and fluoroarylated isoquinolines 47 in yields ranging from 45 to 85% [39].The relatively mild reaction conditions used in these processes permit toleration of a wide scope of substrates.aromatic ketoximes 48 with 4-octyne 49 to prepare fluorinecontaining isoquinolines 50a and 50b in good overall yield [40]. See Scheme 13.

Conclusion
The past decade has been a period of intense exploration of new approaches to the preparation of industrially and medicinally important isoquinolines which incorporate fluorine and fluorine-containing functional groups.This review has examined both nonmetal catalyzed and transition metal catalyzed processes that lead to a wide array of isoquinolines that have fluorine and fluorine-containing groups installed at nearly every position on the fused-ring isoquinoline heterocycle.The reactions reviewed span processes which construct the   isoquinoline core via both A ring and B ring cyclizations.Additionally, these investigations have led to the discovery of milder reaction conditions, improved yields, enhanced regioselectivity, and site-specific ring monofluorination as well as difluoromethylation, trifluoromethylation, perfluoroalkylation, fluoroarylation, and trifluoromethylarylation examples.In all, more than 30 processes producing over 160 new isoquinoline examples have been highlighted.