Isoquinolone Syntheses by Annulation Protocols

: Isoquinolones (isoquinolin-1(2 H )-ones) are one of the important nitrogen-heterocyclic compounds having versatile biological and physiological activities, and their synthetic methods have been recently developed greatly. This short review illustrates the significant advances in the construction of isoquinolone ring with atom- and step-economy, focusing on the intermolecular annulation protocols and intramolecular cyclization in the presence of a variety of catalyst systems. The syntheses of isoquinolone-fused rings are also included.

Over the past decades, isoquinolone ring construction through inter-/intramolecular annulation protocols of unsaturated hydrocarbons with nitrogen-containing reaction partners have been rapidly developed by the activation of aryl C-H and aryl C-X (X = halogen) bonds, as well as N-H or N-O bonds. This short review provides an overview of the recent advances on this theme.

Isoquinolone Formation via [4 + 2] Intermolecular Annulations and Analogous Reactions
The cyclocondensation of benzamide derivatives and functionalized arenes with alkynes or C2 synthons have been recently made great progress for the efficient access to isoquinolones via a [4 + 2] annulation manner. The computational studies on the transition-metal-catalyzed aryl C-H oxidative cyclocondensation of benzamides with alkynes affording isoquinolones have also been reported [19].

[4+2]. Intermolecular Annulations via Aryl C-X/N-H Activation
The [4 + 2] intermolecular annulations of ortho-halobenzamides with alkynes via activation of aryl C-X (X = halogen)/N-H bond affording N-substituted isoquinolones have been extensively studied in the presence of nickel complexes under different conditions (Scheme 1). The general proposed mechanism includes the oxidative addition of orhtohalobenzamide to nickel (0) generated in situ in the presence of base leading to the for-mation of nickelacycle, coordinative insertion of alkyne into the nickelacycle giving possible two seven-membered ring nickelacycle intermediates, followed by reductive elimination affording isoquinolinone [20]. With the use of air-stable [Ni(dppe)Br2] as catalyst, in the presence of Zn and Et3N, the reactions of ortho-halobenzamide with internal alkynes afford N-substituted isoquinolone derivatives (R' = alkyl, allyl, benzyl, aryl) in good to high yields [20]. In the cases of unsymmetric internal alkynes and terminal alkynes used, the cyclocondensation shows regioselective manner, and the catalytic procedure can be used for the synthesis of isoquinolinone alkaloid natural products.
Ni(dppp)Cl2 can also catalyze the annulation of ortho-iodobenzamides with alkynes in the presence of Et3N in MeCN by selective cleavage of C-I/N-H bond [21]. Very recently, Ni(cod)2/KO t Bu-catalyzed formation of highly substituted isoquinolones through cyclocondensation of ortho-fluorobenzamides with internal alkynes via C-F/N-H activation has also been reported [22].
With the use of ortho-haloarylamidines as substrates, in the presence of H2O and zinc, Ni(dppp)Cl2-catalyzed annulations with terminal and internal alkynes affords N-aryl isoquinolones in good to high yields (Scheme 2) [23].

[4+2]. Intermolecular Annulations via Aryl C-H/N-O Activation access to N-H Isoquinolones
Transition-metal-catalyzed annulations of alkynes with N-alkoxybenzamides by C-H/N-O bond cleavages with dealkoxylation reaction have been extensively investigated for the formation of N-H isoquinolones (Scheme 6). Guimond and coworkers first studied the cyclocondensation of N-alkoxybenzamides with internal alkynes catalyzed by [Cp*RhCl2]2/CsOAc in methanol to synthesize N-H isoquinolones via C-H/N-O bond activation in 2010, and the mechanism was also investigated in detail [29,30]. The group CONH(OMe) is used as an oxidizing directing group, and the transformation occurs under external oxidant-free conditions. The same catalyst system was then applied in the intramolecular reaction of alkynetethered N-alkoxybenzamides leading to a general and facile synthesis of 3-hydroxyalkylsubstituted N-H isoquinolones as the major products, and one of them can be used in the synthesis of natural product of Rosettacin, which is a polycyclic-fused isoquinolone derivative (Scheme 7) [31].    In the presence of KOAc, [Cp*Co(CO)I2]/AgOAc-catalyzed [4 + 2] annulation of Nchlorobenzamides with alkynes in TFE occurs at room temperature with selective cleavage of C-H/N-Cl bonds (Scheme 11) [49]. In the case of the use of terminal alkyne, the reactions occur with high regioselectivity to give 3-substituted N-H isoquinolones. Scheme 11. N-H isoquinolone formation by cobalt-catalyzed cyclocondensation of N-chloroamides with alkynes.

2.3.[4+2]. Intermolecular Annulations via Aryl C-H/N-H Activation
More atom-economical procedures for the formation of isoquinolones is the oxidative [4 + 2] cyclocondensation of primary and secondary benzamides with internal alkynes with selective cleavages of C-H and N-H bonds (Scheme 12).

Scheme 12. Isoquinolone formation by [4 + 2] intermolecular annulation of benzamides with alkynes via C-H/N-H activation.
Miura and Satoh's group reported the oxidative coupling of primary, secondary, and tertiary benzamides with internal alkynes catalyzed by rhodium complexes and with the use of Cu(OAc)2 . 2H2O as oxidant in 2010 [50]. As shown in Scheme 13, the reaction between primary benzamides with internal alkynes affords isoquinoline-fused polycyclic aromatics resulting from two incorporated molecules of alkynes. In the case of secondary benzamides, N-substituted isoquinolones are formed. Interestingly, the reaction of tertiary benzamides with internal alkynes under similar conditions produces 1-naphthalenecarboxamides through double aryl C-H bond activation (Scheme 14). Scheme 13. Rhodium-catalyzed cyclocondensation of primary/secondary benzamides with internal alkynes affording isoquinolones and fused isoquinolone. In addition, when Pd(OAc)2 was used as a catalyst, in the presence of NaI . 2H2O as additive, the methoxy substituent on nitrogen (R' = alkoxy) was not cleaved during the catalysis under air, and the formation of N-methoxy isoquinolones had high chemoselectivity (Scheme 15) [56,57]. Under similar reaction conditions, using Cu(II) salts as the cooxidants, a broad range of N-alkyl and N-aryl-substituted isoquinolones can also be obtained starting from N-alkyl/aryl benzamides, and N-C bonds are not cleaved either [58]. The mechanistic studies propose that the use of stoichiometric amount of Cu(II) salts as the key oxidant and air as the terminal oxidant are key for the regeneration of active Pd(II) species.

Scheme 15. N-Methoxy isoquinolone formation via highly chemoselective N-H activation.
A similar catalyst system was then applied in the oxidative annulation of N-methoxybenzamides with arynes and cyclooctynes via C−H/N−H activation for the synthesis of fused isoquinolones [59]. Very recently, the annulation of benzamides with arynes using palladium with photoredox dual catalysis has also been developed for the synthesis of benzo-fused isoquinolones [60].
In addition, the first metal-free annulation of N-methoxybenzamides with internal alkynes was reported by Antonchick's group with the use of PhI as catalyst and AcOOH as oxidant in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at room temperature [69]. A mechanism involving the formation of hypervalent iodine reagent of (diacetoxyiodo)benzene (PIDA) is proposed. At the same time, this type of oxidative cycloaddition reaction can also occur using bis(trifluoracetoxy)iodobenzene as oxidant in the presence of trifluoroacetic acid [70].
Rh(III)-catalyzed annulation of benzoyl hydrazines and alkynes affords isoquinolones with deammoniation by cleavage of N-N bond (Scheme 10 a). However, [Ru(pcymene)Cl2]2/AgSbF6-catalyzed reactions of N-(1H-pyrrolo [2,3-b]pyridin-1-yl)-benzamides with internal alkynes afford isoquinolone derivatives with remaining N-N bond untouched (Scheme 16) [71]. In this procedure, N-amino-7-azaindole is used as an efficient bidentate-directing group to promote the selective C-H bond activation. Moreover, 3-Cyclohexylmethyl N-methoxyisoquinolone, which was published as only one example in literature [75], can be synthesized by the cyclocondensation of Nmethoxyisoquinolone with the corresponding -carbonyl sulfoxonium ylide catalyzed by rhodium in HFIP (Scheme 19). The detailed studies for the formation of 3-substituted isoquinolones through the reactions of N-methoxybenzamides and -carbonyl sulfoxonium ylides catalyzed by Cp*Rh(MeCN)3(SbF6)2/Zn(OTf)2 in DCE were then reported by Li and coworkers [76]. Very recently, epoxides as alkylating reagents and C2 synthon have been applied in Pd(OAc)2-catalyzed oxidative annulation of N-alkoxybenzamides to regioselectively synthesize 3-substituted isoquinolones in HFIP solvent (Scheme 20) [77]. The present methodology has been successfully employed in the total syntheses of rupreschstyril, siamine, and cassiarin A (Figure 1).  In addition, as depicted in Scheme 3, -keto esters can be used as a C2 synthon in the formation of isoquinolones via cyclocondensation with ortho-halobenzamides catalyzed by CuI. However, in the presence of Pd(OOCCF3)2 and K2S2O8, the reactions of Nalkoxybenzamides with β-keto esters have also been developed for the synthesis of isoquinolones via selective C-H/N-H activation [78].
Moreover, as shown in Scheme 21, in the presence of [Cp*RhCl2]2, the regioselective formation of substituted isoquinolones through cyclocondensation of N-methoxybenzamide [79] or primary benzamides [80] with diazo compounds has also been developed. In the case of N-methoxybenzamide used, C-H/N-H activation occurs selectively.  The construction of isoquinolone ring can also be realized by the annulation of carbon-carbon double bonds with benzamides with selective C-H/N-H activation.

Isoquinolone Syntheses via Other Intermolecular Annulations
A Ni(cod)2/phosphine-catalyzed denitrogenative alkyne insertion reaction of 1,2,3benzotriazin-4(3H)-ones provides an alternatively efficient approach to substituted isoquinolones (Scheme 24) [101]. A wide-range isoquinolones can be obtained in high yields with the use of internal/terminal alkynes, including borylalkynes. This transformation can also be realized under visible-light irradiation with the assistance of a photocatalyst at room temperature [102].
When ortho-(2-substituted ethynyl)benzonitriles and NaOMe were refluxed in methanol for 16 h, both isoindolones and isoquinolones formed in different ratios, depending on the nature of substituents. Substrates bearing the phenyl and thienyl group and stabilizing the -anion favor the 5-exo-pathway to give isoindolones, whereas pyridinyl and pyrazinyl groups can also stabilize the -anion, but the formation of a more stable intermediate by coordination of sodium with nitrogen atom leads to the formation of isoquinolones via 6-endo cyclization (Scheme 28) [112].

Scheme 28. Formation of isoindolones and isoquinolones.
In addition, in the presence of platinum complexes, the intramolecular cyclization of ortho-alkynylbenzonitriles in alcohols produces 3-substituted isoquinolones [113].
Treatment of ortho-iodobenzoyl azides with terminal alkynes in the presence of Pd/C, PPh3, and CuI in EtOH at 80 °C under N2 afforded 3-substituted isoquinolones as the major products [114]. The formation of isoquinolones is proposed involving in situ generation of ortho-alkynyl benzoyl azides via Pd/C-mediated Sonogashira coupling followed by intramolecular acetylenic Schmidt reaction with denitrogenation (Scheme 29). Aliphatic terminal alkynes show high chemoselectivity to give the corresponding isoquinolones in good to high yields, whereas the use of aryl alkynes affords the desired products in low yield along with other side products.
As shown in Scheme 8, the [4 + 2] cyclocondensation of N-alkoxybenzamides with vinyl acetate gives 3,4-unsubstituted N-H isoquinolones, and vinyl acetate is a good acetylene equivalent. The other approach to 3,4-unsubstituted N-H isoquinolones is designed from the acid-promoted intramolecular cyclization of ortho-vinyl ether benzamides, which are pre-prepared by Suzuki cross-coupling reactions of the corresponding pinacol borate esters with ortho-bromobenzamides (Scheme 32 a) [116]. Using trifluoroacetic acid (TFA) as a solvent, the intramolecular cyclization occurs to form isoquinolone ring with t-butyl group removed under the strong acidic conditions and microwave irradiation. A similar procedure was reported under mild conditions promoted by HCl in dioxane to give Nsubstituted 3,4-unsubstituted isoquinolones (Scheme 32 b) [117].
In 2010, Li and coworker reported a [Cp*RhCl2]2-catalyzed double oxidative cyclocoupling of primary benzamides with two molecules of alkynes affording tetracyclic isoquinolones resulting from the formation of two C-N bonds and two C-C bonds simultaneously with the use of Ag2CO3 as an oxidant (Scheme 33) [52], which is similar to the use of Cu(OAc)2 . 2H2O as the oxidant as shown in Scheme 13. In the presence of CsOAc, the same catalyst also catalyzes the cyclization of N-(pivaloyloxy)benzamide with cyclohexadienone-containing 1,6-enynes, providing one-pot synthesis of tetracyclic isoquinolones under mild conditions (Scheme 34) [122].
[Ru(p-cymene)Cl2]2 not only shows the catalytic activity for the construction of isoquinolone ring as described-above but also has been employed as catalyst in the formation of polycyclic-fused isoquinolones, such as tetracyclic isoquinolones [131] and spiro-fusedisoquinolones [132] (Figure 3).

Conclusions
This mini-review summaries the representative reports on the syntheses of isoquinolones and polycyclic-fused isoquinolones by annulation protocols in one-pot manner, which show atom-and step-economy. The new trend of developing annulation reactions in the synthesis of cyclic compounds has recently been diversified; in addition to transition-metal catalysis, the electrocatalysis [133][134][135][136][137] and photocatalysis [138][139][140][141] with or without combination of metal-catalyzed catalysis have also become the novel and elegant methods in annulation synthesis. The construction of isoquinolone ring under these conditions has also been developed via [4 + 2] annulation of benzamides with terminal/internal alkynes [142][143][144][145][146][147].