Abstract
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.
1. Introduction
1.1. 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 [2–4]. 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.
1.2. 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 [7–9]. 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 [10–12]. Figure 2 shows some representative examples of important isoquinoline-based molecules.
1.3. 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, , polarity, solubility, and hydrogen-bonding capacity [13–18]. An example of how these alterations bear directly on materials science applications is found in the fluorinated isoquinoline-based 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 FDA-approved drugs contain fluorine [19]. The very strong C-F bond (110 kcal/mol) increases the metabolic stability of drugs, enabling better bioavailability and binding affinity [19–22]. Isoquinolines functionalized with fluorine and fluorine-containing groups, the focus of this review, are key pharmacores with many applications. For example, isoquinoline carboxamides labeled with 18F 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.
1.4. 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.
2. 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 substitution site regioselectivity.
2.1. 3- and 4-Fluoroisoquinolines via Intramolecular Ring A Cyclization at N2-C3 and C3-C4
Ichikawa and coworkers cyclized the difluoroalkene aminotosylate 1 (Scheme 1) under basic conditions in a 6-endo-trig fashion at N2-C3 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 C3-C4 cyclization of a quinone methide intermediate arising from elimination of fluoride anion [24].
2.2. 6- and 7-Fluoroisoquinolines via Intermolecular Ring A Cyclization at C8f-C1, N2-C3, C1-N2, and C3-C4
In a recent Nature communication, Xie et al. noted that assembly of isoquinoline ring systems at and N2-C3 by metal-free [4 + 2] cycloadditions was rare [25]. An example of their efforts is shown in Scheme 3, where a microwave-mediated, Brønsted acid-catalyzed [4 + 2] cycloaddition of the p-fluorophenyl ynamide 5 and nitriles 6a-b produces 7-fluoroisoquinolines 7a-b in good yield. Conversely, Feng and Wu reported in 2016 the base-promoted C1-N2 and C3-C4 cycloaddition of benzonitriles 8 and 9 to prepare the 1-amino-isoquinolines 10a-b which are fluorinated at the 6- and 7- positions in moderate yields [26].
Yang et al. employed a tandem and C1-N2 bond-forming process with azidoacrylate 11 and asymmetric diazo diketone 12 (Scheme 4) to obtain a 1 : 1 ratio of 7-fluoroisoquinoline isomers 13a and 13b in good yield [27]. This interesting reaction cascade begins with the in situ phosphazene formation of 11 via the Staudinger-Meyer reaction with concomitant ketene formation from 12 via a 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 [,]-H migration leads to the formation of isoquinoline isomers.
2.3. Trifluoromethylated, Ring-Fluorinated, and Perfluorinated Isoquinolines via Inter- and Intramolecular Ring A Cyclizations at C8f-C1 and C4f-C4
Stoltz’s team leveraged their success in C-C bond insertion reactions to develop a Bu4NPh3SiF2 (TBAT) promoted N-acyl dehydroamino ester- (14) aryne (15) annulation that resulted in the successful synthesis of a series of polysubstituted isoquinolines and indoles [28]. TBAT serves as the fluoride anion source that desilylates 15 to generate the aryne upon loss of the triflate. Scheme 5 depicts the preparation of methyl-3-carboxy-1-trifluoromethylisoquinoline (16a) and methyl-3-carboxy-6,7-difluoro-1-methylisoquinoline (16b) in good overall yield.
Zhang and Studer [29] recently reported the intramolecular cyclization of β-aryl-α-isocyano-acrylates 17 and radical perfluoroalkylation using Togni reagents 18 as the source to produce eighteen examples of highly functionalized 1-trifluoromethyl-, 1-pentafluoroethyl-, and 1-heptafluoropropylisoquinolines 19 in good overall yields. See Scheme 6.
2.4. Preparation of Selectively Trifluoromethylated and Difluoromethylated Isoquinolines at C1 and C4
Kuninobu et al. successfully conducted a benzylic trifluoromethylation of the isoquinolinium N-oxide 20 using KBF3CF3 in BF3OEt2 to produce the 1-(2,2,2-trifluoroethyl)isoquinoline 21 in 71% yield [30]. See Scheme 7. As shown in Scheme 8, Ichikawa employed a dehydrogenation treatment of dihydroisoquinoline 22 to achieve the 4-trifluoromethylisoquinoline 23 in high yield. The same substrate was subjected to dehydrofluorination (with subsequent alkene isomerization) to obtain 4-difluoromethylisoquinoline 24 in good yield [31].
2.5. Preparation of 4-Fluoroarylated Isoquinolines
During an examination of tipifarnib analogs for bioactivity, Chennamaneni and coworkers coupled the trityl-protected, tetrahydroisoquinoline 25 with the heterocyclic ketone 26 (Scheme 9) en route to the 4-(2,6-difluorophenyl) isoquinoline 27 in 60% yield [32].
Using amine 28 and 4-fluorobenzaldehyde shown in Scheme 10, Awuah and Capretta combined microwave conditions and acid-catalysis to condense and cyclize the imine adduct at followed by dehydrogenation to produce the 2-(4-fluorophenyl) isoquinoline 29a in excellent overall yield. In a second reaction, 28 was reacted with 4-fluorophenylacetic acid under microwave conditions in the presence of phosphoryl chloride to prepare the 1-(4-fluorobenzoyl)isoqionoline 29b in good yield [33].
3. 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.
3.1. Period 4 Transition Metal Catalysis: Ring-Fluorinated, Trifluoromethylated, Fluoroarylated, and Trifluoromethylarylated Isoquinolines via Inter- and Intramolecular Ring A Cyclization at N2-C3, C4f-C4, and C1-C4
3.1.1. Manganese Catalysis
He et al. researchers utilized the manganese catalyst MnBn(CO)5 in a [4 + 2] annulation at N2-C3 and of imines 30 and alkynes 31 to prepare six fluorinated isoquinolines 32 in good to excellent yields shown in Scheme 11 [34]. Their strategy affords three ring B fluoroisoquinoline regioisomers (32a–c) and a trifluoromethylisoquinoline (32d) as well as a ring A fluorophenylisoquinoline (32e) and a ring A trifluoromethylphenylisoquinoline (32f). Mao’s group recently reported the manganese catalyzed coupling and cyclization of vinyl isocyanides 33 and assorted arylhydrazines 34 en route to three new examples of 7-fluoroisoqinoline 35a, the 1-(4-fluorophenyl)-isoquinoline 35b, and the 1-(4-trifluoromethylphenyl)-isoquinoline 35c in good overall yields [35].
3.1.2. Cobalt Catalysis
Cobalt (III) catalysis has been effectively utilized in N2-C3 and bond formation/cyclizations of oximes, amidines, and hydrazones to prepare a broad array of isoquinolines bearing fluorine and fluorine-containing groups. Examples are depicted in Scheme 12. Sun and coworkers used CpCoI2(CO) to catalyze the regioselective cyclization of the acyl oxime series 36 with both internal and terminal alkynes 37 en route to a diverse set 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 1-aminoisoquinolines 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.
3.1.3. Nickel Catalysis
Yoshida’s group conducted a nickel catalyzed, bond formation/cycloaddition of aromatic ketoximes 48 with 4-octyne 49 to prepare fluorine-containing isoquinolines 50a and 50b in good overall yield [40]. See Scheme 13.
3.1.4. Copper Catalysis
Ohto et al. developed a copper(I)-catalyzed four-component coupling reaction whereby 2-ethynylbenzaldehydes 51, paraformaldehyde, diisopropylamine, and -BuNH2 were cyclized at N2-C3 to give 6-fluoro- and 7-fluoroisoquinolines 52 [41]. See Scheme 14. Fan et al. used isoquinoline-N-oxides 53 and the Togni reagent 54 catalyzed by copper(II) triflate, to prepare sixteen 1-(trifluoromethyl)isoquinolines 55 [42]. Mormino et al. subjected 3-bromoisoquinoline 56 to the phenanthroline-ligated copper trifluoromethylating reagent (phen)CuCF3 57, preparing the 4-trifluoromethylisoquinoline 58 via a radical substitution [43]. These processes provide the target isoquinolines in good overall yields.
3.2. Period 5 Transition Metal Catalysis: Ring-Fluorinated, Trifluoromethylated, Fluoroarylated, and Trifluoromethylarylated Isoquinolines via Inter- and Intramolecular Ring A Cyclization at N2-C3, C4f-C4, C8f-C8, and C1-C4
3.2.1. Ruthenium Catalysis
Scheme 15 depicts two ruthenium catalyzed cyclizations to produce fluorine-containing isoquinolines via N2-C3 and bond formation. He et al. cyclized several diaryl imines 59 with diarylacetylenes 60 with a ruthenium catalyst to prepare six tetrasubstituted, ring-fluorinated, trifluoromethylated, fluoroarylated, and trifluoromethylarylated isoquinolines 61 in yield ranging from 40 to 86% [44]. Chinnagolla and coworkers used a similar methodology and cyclized several diaryl imine chlorides 62 with diarylacetylenes 63 with a ruthenium catalyst to prepare a series of six tetrasubstituted trifluoroethoxyisoquinolines 64 in yield ranging from 61 to 81% [45].
3.2.2. Rhodium Catalysis
Two rhodium-catalyzed preparations of isoquinolines that incorporate fluorine and trifluoromethyl groups are shown in Scheme 16. Qian’s group conducted a rhodium-catalyzed / annulation of fluoropicolinamide 65 with diphenylacetylene 66 to produce the tetraphenyl 4-fluoroisoquinoline 67 in excellent yield [46]. Guimond and Fagnou performed a highly efficient rhodium-catalyzed oxidative cross-coupling and /N2-C3 cycloaddition of aldimines 68 and 4-octyne 69 en route to 6-fluoro- and 6-trifluoromethylisoquinolines 70a and 70b [47]. These catalyzed processes are believed to occur via a sequence involving Rh (III) insertion followed by reductive elimination/electrocyclization to produce the isoquinolines.
3.2.3. Palladium Catalysis
Scheme 17 depicts work conducted by Pilgrim and coworkers in which the protected aryl bromide series 71, acetophenone 72, an electrophile, and ammonium chloride were combined in a palladium catalyzed, three-step, one-pot cycloaddition process to furnish ring-fluorinated isoquinoline 73a, a trifluoromethylated isoquinoline 73b, and trifluoromethylarylated isoquinolines 73c–d in overall yields ranging from 46 to 73% [48]. This procedure begins with the arylation reaction of an enolate, followed by reaction with Selectfluor II, allyl bromide, or 4-bromobenzotrifluoride, respectively, and aromatization with ammonium chloride.
Scheme 18 shows two Pd(OAc)2 catalyzed isoquinoline producing cyclizations. Tian et al. developed an efficient, Pd-catalyzed Heck reaction in which the 2-triflate substituted aryl ketone series 74 was coupled and intramolecularly cyclized with enamine 75 at /N2-C3 and isomerized to produce four examples of ring-fluorinated and fluoroarylated isoquinolines 76 [49]. Yang’s group conducted a palladium catalyzed, microwave-assisted, one-pot reaction via a /N2-C3 cyclization for the synthesis of isoquinolines [50]. The coupling-imination-annulation sequence of reactions using -bromoarylaldehydes 77 and terminal alkynes 78 with ammonium acetate produced three disubstituted 6-fluoroisoquinolines 79. These reactions feature a wide range of substrates with various functional groups, and the corresponding products were obtained in good yields.
3.2.4. Silver Catalysis
Several silver (I) catalyzed N2-C3 cyclizations of o-iminylaryl alkynes have been employed successfully to prepare a broad selection of fluorinated, trifluoromethylthiolated, fluoroarylated, and trifluoromethylarylated isoquinolines. See Scheme 19. Xiao et al. used a silver(I)-catalyzed reaction of 2-alkynylbenzaldoximes 80 with silver (trifluoromethyl)thiolate 81 in the presence of -methoxybenzenesulfonyl chloride to synthesize eleven new 1-[(trifluoromethyl)thio]isoquinolines 82 in yields ranging from 36 to 85% [51]. Xu and Lui utilized an Ag(I)-catalyzed, NFSI aminofluorination of aryliminoalkynes 83 in the development of an efficient synthesis of thirteen examples of 4-fluoroisoquinolines 84 [52]. Jeganathan and Pitchumani used a Ag(I)-exchanged K10-montmorillonite clay catalyzed ring closure of iminoalkynes 85 to prepare three fluoroarylated isoquinolines 86 in good overall yield [53]. This effective cyclization accommodates a variety of iminoalkynes and is noteworthy for its catalyst reusability, simplicity, and environmentally responsible process.
3.3. Period 6 Transition Metal Catalyzed Ring-Fluorinated, Trifluoromethylated, and Fluoroarylated Isoquinolines via Intermolecular Ring A Cyclization at C8f-C1
3.3.1. Iridium Catalysis
Our final entry highlighted in Scheme 20 is the iridium catalyzed fluoroisoquinoline synthesis via a bond-forming/cyclization reaction, conducted by Jiang et al. [54]. This synthesis uses a visible light-promoted insertion of vinyl isocyanides 87 with diphenyliodonium tetrafluoroborate 88 at room temperature to prepare six multisubstituted ring-fluorinated, trifluoromethylated, and fluoroarylated isoquinoline derivatives 89.
4. 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.
Competing Interests
The author declares that there are no competing interests regarding the publication of this paper.