1 H -isochromene-1-ones and isoquinoline-1(2 H )-ones with carbonyl group in position 3: Features of synthetic approaches and transformation

Oxygen-containing heterocyclic 1 H -isochromen-1-ones are core structural components of various natural products and biologically active compounds. They are used as functional substrates in the synthesis of biologically active 1 H -isochromen-1-ones and isoquinolin-1(2 H )-ones exhibiting different biological properties and diverse applications. Synthetic approaches to these classes of heterocyclic compounds developed in parallel from the very beginning because one of the strategies for the synthesis of isoquinolin-1-one is the recyclization of the isochromen-1-one system by the action of primary amines. In this review, we comprehensively describe the synthesis of 1 H -isochromen-1-ones and isoquinolin-1(2 H )-ones with a carbonyl function in position 3, summarize their use as synthons in organic chemistry and highlight their biological activities.


Introduction
Oxygen-containing heterocyclic scaffolds are common fragments among natural compounds with many applications in the drug design of pharmacologically relevant derivatives. The 1H-isochromen-1-ones (isocoumarins) are an essential oxygen-containing motif consisting of a α-pyranone ring fused to the benzene ring at 5,6-positions. Due to their attractive properties, substituted isocoumarins are becoming a prominent synthetic intermediate with various synthesis methodologies reported in recent reviews. 1,2 Due to their biosynthetic origin, most natural isocoumarins contain a 3-alkyl (C1-C17) or a (un)substituted 3-phenyl ring on the α-pyranone and 8 oxygenation on the benzene ring. Among isocoumarins functionalized in the 3 rd position, many biologically active compounds of both natural and synthetic origin exist. Some examples are a natural anticancer agent Cytogenin (1) 3 and a metabolite with antimicrobial activity Cephalosol (2). 4 Compound 3 was synthesized along with other derivatives as an analog of the natural antimalarial agent Cladosporin, 5 and bromoketone 4 6,7 was used for the synthesis of 3-hetarylisocoumarins with a possible ability to treat spinal muscular atrophy ( Figure 1). Recently we reviewed publications on amino acid derivatives of isocoumarins and 3,4dihydroisocoumarins. 8 Scheme 1. Recyclization of 1H-isochromen-1-one system into isoquinolin-1(2H)-one.
Despite the significant synthetic potential of such transformations, this topic is represented by a relatively small number of works in the literature. The review covers this subject's entire period of development: from the first experiments with 3-acylisocoumarins in the 1930s to attempts to create new drugs based on 3acylisocoumarins and isoquinolones in the 2000-2020s. Of the so far small number of patented developments in this field (the review includes 10 patents), the most significant is the Duvelisib synthesis method, which is based on the reductive amination of the acetyl group in the substituted isoquinolone.
We describe the application of various methods for implementing the transformation shown in Scheme 1. Thus, the reaction was carried out by heating with primary amines in ethanol at elevated pressure; boiling in ethanol under normal pressure but with an excess of amine; boiling in pyridine; boiling in toluene in an inert atmosphere; and when heated without solvent (for example, heat at 100-120 °С in a sealed tube or an autoclave; you can read more about variations of this technique in reviews 9,10 ). Synthetic equivalents of ammonia were also used: AcONH4, (NH4)2CO3, HCONH2, etc. Such diversity in the reaction procedure allows for choosing the optimal method for individual substrates, which determines the importance of this transformation in the series of isocoumarins and isoquinolones.
This approach has retained its relevance and is used, in particular, for the synthesis of natural alkaloids of the isoquinolin-1(2H)-one series, such as Ruprechstyril 9 11,12 from Ruprechtia tangarana 13 and compound 12 from Isatis Tinctoria 14 (Scheme 2).
Functionalized isoquinolin-1-one appear to be as synthetically attractive as corresponding isocoumarins. Even without considering the reactivity of side functional groups, the isoquinolinone system, in contrast to the isocoumarin system, can undergo modifications in positions 1 or 2 and is therefore a promising source of various isoquinoline derivatives.

Synthesis of 3-Acyl-and 3-Formyl-1H-isochromen-1-ones
One of the widely used approaches to the synthesis of 1H-isochromen-1-ones -the cyclization of ortho-alkenyl benzoates 15 -can also be used to obtain isocoumarins with a carbonyl group in position 3, although the yields of such derivatives are not always sufficiently high. Usually, the ortho-alkenyl benzoates are obtained by metalcatalyzed coupling of ortho-iodobenzoic acids with terminal alkynes. Various acidic reagents are used for their cyclization; in some cases, the formation of ortho-alkenyl benzoates and their cyclization into isocoumarins takes place in one step. 3-Formylisocoumarin (13), the simplest isocoumarin with a carbonyl function in position 3, was synthesized with this approach. It is worth noting that this is a natural compound known under the name Artemidinal and found in the composition of Artemisia dracunculus. 16 3-Formylisocoumarin (13) was successfully obtained with a 44% yield from methyl 2-(3-oxoprop-1-yn-1yl)benzoate (14) in the study of catalytic properties of the AgOTf/p-TSA system (Scheme 3). It should be noted that using the same approach and under similar conditions, a considerable amount of 3-arylisocoumarins was obtained with two times higher yields. 17 Scheme 3. Synthesis of 3-formylisocoumarin (13) from methyl 2-(3-oxoprop-1-yn-1-yl)benzoate (14).
ortho-Formylbenzoic acids are convenient substrates for the construction of 3-acylisocoumarins. These compounds form esters in reaction with halogen ketones, which are then cyclized into ketoisocoumarins by condensation of the aldehyde group and the active methylene group of the ketone. The use of this approach was first reported in the early 20th century; thus, the corresponding isocoumarin 15 was obtained from opianic acid (16) (Scheme 4). 18  In the initial works, during the preparation of 3-acylisocoumarins from ortho-formylbenzoic acids, esters of type 18, 21, and 23 were extracted separately, but later the formation of 3-acylisocoumarins from formylbenzoic acid and haloketones was carried out in one stage, by prolonged boiling in a polar aprotic solvent with base, most often triethylamine; 20-22 the use of DBU was also successful. 23 Ali Ertürk and coworkers conducted a thorough study of the formation process of 3-acetylisocoumarin 13 by the condensation of ortho-formylbenzoic acid and chloroacetone. 27 The authors compared the effectiveness of previously published methods with synthetic procedures in which microwave irradiation was applied in different ways -an open and closed reactor and a completely closed system. However, triethylamine was recognized as the most successful base (superior to potassium carbonate, hydroxide, and phosphate), while the temperature, reaction time, and solvents varied. Some experiments, both by classical methods and with irradiation, were carried out without a solvent. It turned out that almost all methods make it possible to achieve target product yields of more than 80%, but only the use of irradiation in a completely closed system allows the synthesis of the same amount of 3-acetylisocoumarin without a solvent and in the shortest reaction time.
Derivatives 31 under mild conditions and in the presence of chiral catalysts can form 4-hydroxy-3-acyl-3,4dihydroisocoumarins 32 with high diastereo-and enantioselectivity (Scheme 9). 28 When a similar transformation was carried out in the presence of aromatic amines, an intramolecular Mannich reaction occurred (through the intermediate imine formation stage), resulting in 4-amino-3-acyl-3,4dihydroisocoumarins 34 (Scheme 10). 29 Additionally, various chiral proline derivatives were tested as catalysts, but all were inferior to tetrazole 33, resulting in either reduced yields or no conversion. The use of amine 35 resulted exclusively in the formation of 3-acetylisocoumarin 22 from the Schiff base 36 (Scheme 10).
A general method of cyclization of 2-(3-oxobutyl)benzoic acids 37 into 3-acylisocoumarins 38 under the action of copper (II) trifluoromethanesulfonate in combination with copper (II) chloride as an oxidant is patented. The isocoumarin cycle is formed from successive copper-catalyzed C-O coupling and oxidative dehydrogenation, using copper triflate as an oxidant and copper chloride dihydrate as a salt (Scheme 11). 30 This transformation is unique to isocoumarin chemistry, and the mechanism undoubtedly deserves more detailed study in the future.

Scheme 11. Synthesis of 3-acylisocoumarins 38 from 2-(3-oxobutyl)benzoic acids 37.
Another general strategy for the synthesis of 3-acyl(formyl)isocoumarins is based on converting the functional group in position 3 to a carbonyl.
This possibility, in particular, was illustrated by the example of product 39 methyl group conversion into a formyl group under the action of SeO2 (Scheme 12). 31

Scheme 12. Synthesis of 3-formylisocoumarin 13.
Mallabaev and coworkers reported the oxidation of the C=C bond of natural Artemidin with KMnO4 to form Artemidinal 13, 16 which made it possible to prove the structure and relationship of these two isocoumarins of natural origin. This reaction was carried out as the last of the seven stages of the synthesis of Artemidinal (Scheme 13). 32 Interestingly, the construction of the isocoumarin system employed an uncommon approach in the chemistry of isocoumarins -the recyclization of N-methylisoquinolin-1(2H)-one 40 under the action of oxidants. Oxidation of the hydroxyl group with MnO2 was also carried out for natural isocoumarin 47 extracted from Anthemis punctata in order to confirm its structure (an analytical sample was used) (Scheme 15). 33 Scheme 15. Oxidation of (Z)-3-(1-hydroxybut-2-en-1-yl)isocoumarin (47) into (Z)-3-(but-2-enoyl)isocoumarin (48).
Together with a wide range of aromatic and heteroaromatic compounds with a halogenomethyl group, isocoumarin 49 took part in a large-scale study of dimethylselenoxide and potassium benzeneselenite use as oxidizing agents of the halogenomethyl group to an aldehyde group. 34 The optimal conditions for isocoumarin 49 conversion to the corresponding aldehyde 13 are given in Scheme 16.
Several publications 35,36 on establishing the configuration of some natural polycyclic derivatives of a series of dihydroisocoumarins mentioned the removal of aldehyde 51a as a result of the oxidation of Bergenine 50a by NaIO4. In this case, the alkyl fragment elimination occured in addition to the oxidative cleavage of glycol (Scheme 17). A similar transformation leading to the formation of aldehyde 51b was described for dimethylbergenine 50b (Scheme 17). 37,38 Scheme 17. Oxidation of Bergenine and dimethylbergenine into 3-formylisocoumarins 51a,b.
Reduction as an alternative to oxidation was implemented for isocoumarin-3-carboxylic acid ester 52, synthesized by the condensation of homophthalic acid with ethoxalyl chloride. The ester group was converted to an aldehyde via a cleavage step of the corresponding hydrazide 53 (Scheme 18). 39 Note that under these conditions -in the presence of an excess of hydrazine -the authors did not record the recyclization of the isocoumarin cycle, which is generally quite susceptible to the action of hydrazine (see review 10 ). Unfortunately, the interaction of functionalized isocoumarins with hydrazine has not been studied enough to say whether this transformation is general for isocoumarin-3-carboxylic acids.
Conversion of the carboxyl group in position 3 of isocoumarin to the carbonyl group was also successfully carried out with the help of diazomethane. Thus, diazoketone 54 was obtained from anhydride 55, and diazomethane 40

Transformation of 3-Acyl-and 3-Formyl-1H-isochromen-1-ones
Firstly, it should be noted that the reactions that lead to the transformation of 3-acylisocoumarins into the corresponding 3-acylisoquinolones will be considered in the next section as methods for the synthesis of the latter. Several transformations of 3-acyl-and 3-formylisocoumarins that do not affect the heterocyclic system but occur exclusively at the side keto group are known. Thus, the condensation of the above-mentioned aldehyde 13 with an active methylene compound led to acrylic acid 62 (Scheme 21). 31 It is worth noting that the synthesis of pyrazoles 66 was carried out to search for new antibiotics and antifungal drugs. Most substances of this group displayed sufficiently high bioactivity, and the derivative 66 with R = 4-NO2 (Scheme 22) was the most effective: its antimicrobial and antifungal activity was similar to comparison drugs Chloramphenicol and Ketoconazole, respectively. 22 Pyrazoles 67 (Scheme 23) were recently obtained from ketone 63 using a similar approach and tested for antimicrobial activity with other heterocyclic derivatives. 43 Scheme 23. Application of chalcone 63 for the synthesis of 3-(1H-pyrazol-3-yl)isocoumarin 67 with antimicrobial activity.
The synthesis of similar pyrazolylisocoumarins was recently reported via a slightly different sequencethe initial formation of arylhydrazones 71 from the keto group of 3-acetylisocoumarins 70 44 (also for the synthesis of the latter see 27 ) and their subsequent formylation (Scheme 24). The excess of the formylating agent leads to both the pyrazole cycle closure and its formylation. Aldehydes 68 were condensed with barbituric acid, and the resulting derivatives 69 were investigated for their interaction with four human (h) CA isoforms, hCA I, II, IX and XII, known to be important drug targets. The inhibition constants ranged between 2.7-78.9 µM against hCA IX and 1.2-66.5 µM against hCA XII. Therefore, such isocoumarins represent a new class of CA inhibitors. In addition to the target monobromo derivative 74, the dibromo derivative 75 was discovered in the reaction mixture during the bromination of 3-acetylisocoumarin 22 in acetic acid, 46 (Scheme 26). The product 75 was also synthesized using 2.5 equiv. of bromine. Based on bromoketone 74, the authors successfully obtained isocoumarins with thiazol-2-yl, 6-R-imidazo[1,2-a]pyridin-2-yl, imidazo[2,1-b]thiazole and quinoxaline substituents. The monobromo derivative 74 and the dibromo derivative 75 were used to construct the quinoxaline system. 21,47 It is noteworthy that the obtained 3-hetarylisocoumarins were subsequently used to synthesize new 1-amino-3-hetarylisoquinolines -potential anticancer agents. 47,48 Bromination of 3acetylisocoumarin 22 in acetic acid at 5 °С resulted in the formation of 3-(α-bromo)acetylisocoumarin (74). 49 Its subsequent interaction with a methacrylic acid salt resulted in the formation of an ester; the authors studied the temperature decomposition parameters of the specified methacrylate polymer in detail.
3-Hetarylisocoumarin 78's potential to treat spinal muscular atrophy was also investigated; the product showed high activity in vitro but, unfortunately, revealed a weak negative effect on the brain and/or blood plasma when administered orally to rats. 6,50 In order to diversify the list of potential agents for the treatment of spinal muscular atrophy, other isocoumarins with an N-methylpiperazine substituent in position 7 and a heterocyclic substituent (imidazo[2,1-b]thiazole-6-yl, 8-chloroimidazo[1,2-a]pyridin-2-yl, 1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl) in position 3 were successfully obtained through a similar synthetic sequence starting from the α-bromoacetyl derivative 74. 7 Although the isocoumarin system has been reduced by relatively mild reducing agents such as sodium borohydride, there are several examples in the literature where the side C=O-group in 3-acyl-or 3-formylisocoumarins reduces faster.
Thus, sequential reduction of the carbonyl group of isocoumarin 79 to the hydroxy group followed by elimination of the mesylate 81 (Scheme 28) was used for the synthesis of cis-and trans-isomers of Artemidin 43. 51 Scheme 28. Conversion of 3-butyrylisocoumarin 79 for the synthesis of Artemidin.
The 3-acylisocoumarin-based transformation where the lactone fragment and the keto group were preserved was of particular interest. Thus, the interaction of the 4-bromobenzoyl derivative 82 with 1 equiv. of amine completed with the substitution of just the bromine atom by the amine residue, despite the relatively harsh conditions of the transformation (prolonged boiling in DMF) (Scheme 29). 24 Certain amines 83 showed significant antibacterial and fungicidal activity during the initial screening.

Scheme 29. Amination of 4-bromobenzoylisocoumarin 82.
To summarize, we would like to note that a comprehensive study 52 of various chemical transformations of probably the best-known natural representatives of 3-acylisocoumarins -tricyclic derivatives of Brevifolin 84 and Brevifolincarboxylic acid 85 (Figure 2) -was also conducted. The study included the extraction of target compounds from natural raw materials, alkylation, acylation and esterification of functional groups, cleavage of rings, and reactions with N-nucleophiles.

Synthesis of 3-Acyl-and 3-Formyl-isoquinolin-1(2H)-ones
We start this subsection with the review of methods for the construction of 3-acylisoquinolin-1(2H)-ones through the direct addition of a keto group to the isoquinolin-1(2H)-one cycle.
Thus, the catalytic coupling of isoquinolones 86 with cyclobutenones 87 (Scheme 30) was described. 53 The isoquinolone derivatives involved in the reaction contained an -pyridyl substituent at the nitrogen atom (a directing residue capable of chelation with the catalyst metal), and the corresponding chalcones 88 were isolated as reaction products.

Scheme 30. Synthesis of chalcone-type products by coupling of 2-(pyridin-2-yl)isoquinolin-1(2H)-ones with cyclobutenones.
The keto group was successfully introduced into the isoquinolin-1-one system by the transformation of the side group in position 3. Thus, the oxidation of the acetyl group in the 3 rd position of methylisoquinolin-1(2H)-one by SeO2 resulted in 3-formylisoquinolin-1(2H)-one with 80% product yield. 31 The following methods are based on the formation of the isoquinolone cycle during a recyclization reaction.
The first and early publications devoted to the synthesis of 3-acylisocoumarins noted the possibility of their transformation into the corresponding isoquinolones. Thus, isocoumarin 15, obtained from opianic acid 16, gave product 89 (Scheme 31) 54,19 when heated in aqueous ammonia (a similar transformation is described for 3-acetylisocoumarin 19 ). Interestingly, the carboxyl group was not involved in the transformation of the isocoumarin cycle of acrylic acid 62 (see scheme 21) to isoquinolone under the action of ammonia. 31 The main idea for the design and synthesis of a series of 2-benzoyl-3-acyl-4-arylisoquinolones 55,56 was the high ability to inhibit JNK (c-Jun N-terminal protein kinase), inherent in the derivatives 94a-c shown in Figure 3. The isoquinolone system of such potential inhibitors (Scheme 34; structure 94 as an example) was obtained from ortho-carboxybenzophenone 95 in a manner similar to the synthesis of isocoumarins from orthoformylbenzoic acid. Although considerable efforts were directed to the synthesis of the starting substratesamino alcohols 96, it was successfully possible to synthesize the key products 94 in three stages in one-pot manner. 55

Scheme 35. Recyclization of N-(2-oxoalkyl)phthalimides 97 to 3-acetyl-4-hydroxyisoquinolin-1(2H)-ones 98.
Cyclization of ketone 100 formed from benzamide 101 (scheme 36) resulted in the formation of 3acetylisoquinolone 102. 60,61 Moreover, two methods are described for the transformation of product 100 into product 101 -through rearrangement of epoxide 103 (scheme 36a) 60  However, the most effective approach to the synthesis of 3-acylisoquinolones is the coupling of benzamides and similar compounds with alkynes containing either a keto group or another group capable of converting to a carbonyl fragment.
Thus, Ruthenium-catalyzed coupling with C-H activation made it possible to complete the isoquinolin-1(2H)-one cycle to the benzoylated N-terminal of oligopeptide 107 (Scheme 37). 62 Most of the isoquinolin-1(2H)ones obtained in this work contained phenyl substituents in position 3, and only a few contained functional groups such as Ac, COOMe, and CH2CH2OH in this position.
Apparent problems of using asymmetrical alkynes, such as the ketone 108 mentioned above, in similar transformations are probably related to regioselectivity. Indeed, two possible isomers 110a,b were formed during the construction of isoquinolin-1(2H)-one from ketone 108 and N-iminopyridinium ylide 111 with a cobalt catalyst (Scheme 38). 63 It also turned out that it is unnecessary to use compounds with an already existing acyl group to synthesize 3-acylisoquinolones from benzamides and unsaturated compounds as the group can be formed during the reaction.
Thus, N-aminoisoquinolones 112 with a carbonyl group were obtained via cobalt-catalyzed annulation of hydrazides 113 with allenes 114 and simultaneous oxidation with air oxygen (Scheme 39). 64 In general, the synthetic procedure successfully gave more than 30 representatives of N-aminoisoquinolone; the furan analog 112a was also obtained under these conditions, albeit with a low yield (28%).
An alternative method for obtaining 3-acylisoquinolin-1(2H)-ones is also described. 65 Thus, using Rhodium results not only in the C-H activation of the ortho position of N-ethoxybenzamide 116 and its coupling with alkyne 117, but also in the opening of the strained cycle of cyclobutanol (rarely cyclopropanol) with the formation of a product 118; isoquinolone 118a was obtained with a yield of 92% (Scheme 40). According to the reaction mechanism given in the publication, Rhodium (III) was reduced to Rhodium (I) as a result of the coupling process, and the reverse oxidation stage in the catalytic cycle was carried out by the N-OEt fragment of the substrate, which in turn was reduced to the N-H group.
N-methoxybenzamides 120 were successfully employed in a similar transformation, but the reaction conditions were slightly changed -sodium acetate (1 equiv.) was used as the base, and the reaction was carried out in toluene at 80 °C. 66 In general, it is worth noting that the considered set of metal-catalyzed cyclizations allows for a wide variation of substituents, although in some cases, the structure of the starting substrates can make the reaction impossible. As for the key stage of the metal-catalyzed coupling of benzamides with alkynes, the following general scheme is relevant for the above reactions (Scheme 42; M is metal, L is ligands). Moreover, R' can contain a functional group capable of coordination with a metal (as in Schemes 37,39,40,and 41). It is believed that additional chelation of R'-M at the intermediate complex formation stage is one of this transformation's success factors.

Scheme 42.
General mechanism of metal-catalyzed coupling of benzamides with alkynes.
In particular, the coupling of alkynes 124 with a difluoromethylene group with benzamides 125 under the conditions of a Ruthenium-catalyzed reaction resulted not in the isoquinolones but the products of the Lossen rearrangement 126 (Scheme 43). 68

Scheme 43. An unexpected Lossen rearrangement of benzamide derivatives.
Several examples of reactions leading to the formation of 3-acylisoquinolones and their analogs are also known but have not yet found widespread use. An approach to the synthesis of ,-unsaturated ketones during the dehydrohalogenation of -amino-'-halogenoketones was described. 69 Thus, the corresponding isoquinolone 128 was obtained in the 40% yield from the cyclic aminohalogenoketone 129 in this reaction (Scheme 44).
The possibility of the 3-methylisoquinolin-1(2H)-one methyl group oxidation to the formyl group by SeO2 was also mentioned: the reaction is similar to the one given above for 3-methylisocoumarin (Scheme 12). 31 An approach to the synthesis of vinyl derivatives 130 was developed. 70 The oxidation of compound 130a to 1-ethoxy-3-acetylisoquinoline 131 was successfully carried out to demonstrate the synthetic capabilities of the obtained products (Scheme 45). For 3-formylisoquinolin-1(2H)-one 138, reduction with sodium borohydride to the corresponding alcohol, Perkin or Debner condensation with the formation of acrylic acid 139 with an isoquinolone substituent, as well as the Cannizzaro reaction were described (Scheme 48). 31 O-Acylation or O-alkylation occurs through the formation of the enol form of the isoquinolone, which provides prospects for additional modification at position 1 of the heterocycle. Scheme 49 depicts an example of using this strategy to synthesize the isoquinoline 143 as a potential modulator of calcium-sensitive receptors. 72 A Palladium-catalyzed coupling with appropriate boronic acids was used for arylation, and sodium borohydride was used at the reductive amination stage.
The synthetic potential of functionalized isoquinolones (in particular, compounds with a keto group) and their analogues is also indicated by the patented development devoted to the search for new phosphoinositide 3-kinase (PI3K) inhibitors, which mentions the possibility of introducing new substituents into the isoquinoline fragment by coupling at positions 1 and 4 and reductive amination of the carbonyl group. 74

Conclusions
The importance of the 1H-isochromen-1-one and isoquinolin-1(2H)-one derivatives arises from their widespread occurrence in nature, versatility as suitable substrates for functionalization, and remarkable bioactivity. Developing various synthetic methodologies to obtain these heterocycles has continually attracted the attention of synthetic organic chemists. The synthetic approaches to these two classes of heterocyclic compounds have developed in parallel from the beginning since one of the strategies for synthesizing isoquinolin-1(2H)-one is the recyclization of the 1H-isochromen-1-one system by the action of primary amines. Furthermore, the isochromenone and isoquinolinone scaffolds are essential intermediates in organic chemistry. Further, various significant bioactivities have been associated with these scaffolds and reported in the literature. The present review focuses on the studies of new pharmacologically important 1H-isochromen-1-ones and isoquinolin-1(2H)-ones with a carbonyl function in position 3 and their structural analogs. The review also highlights developments towards alternative approaches, and efficient strategies. It also summarizes their use as privileged scaffolds in drug design and discovery.