Remarks on Past, Present, and Future

Chapter 6

Remarks on Past, Present, and Future 6.1 ISOCOUMARIN: A FRAMEWORK OF RENEWED INTEREST Because of natural occurrence1e6 and a vast range of pharmacological activities7e10 (Table 6.1), it was expected that isocoumarin framework would continue to attract interest of organic, medicinal, and natural product chemists. However, this oxygen containing-heterocycles also created enormous interest among the organometallic chemists during the last decade. As a result an impressive number of methodologies (including transition metalecatalyzed domino or cascade reactions, Table 6.2) have emerged11e13 that allowed access not only to isocoumarins with diverse substitution pattern but also to the densely substituted derivatives, the synthesis of which are probably difficult using the traditional or metal-free methods. For transition metalecatalyzed reactions, a large number of catalysts based on 12 or more transition metals including Pd, Pt, Ru, Rh, Au, Ag, Ni, and Cu have been explored and investigated successfully (Table 6.3). Many of these catalysts showed remarkable functional group tolerance, mild conditions (time, temperature, solvents, etc.), efficiency (atom economy and environmental friendliness in some cases), and high yields of products.

6.2 EMERGENCE OF NEW METHODOLOGIES Although some of the methodologies highlighted above are still in the developmental stage (as challenges still remain in the control of chemoselectivity [5-, 6-, exo, endo, cyclization]14 in these cases [Scheme 6.1]), the use of CeH activationebased methods are latest addition to these efforts (Table 6.4). Notably, the metal-catalyzed CeH bond activation strategies15 have emerged as increasingly viable tools for atom- and step-economical CeC and C-heteroatom bondeforming processes. Moreover, it avoids the use of o-halogenated aromatic carboxylic acid derivatives (a requirement for the conventional coupling reactions) as substrates for the synthesis of isocoumarins. However, effectiveness of these approaches depends on devising the useful directing group Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin. https://doi.org/10.1016/B978-0-12-815411-3.00006-0 Copyright © 2019 Elsevier Inc. All rights reserved.

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178 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin

TABLE 6.1 Summary of Natural Occurrences and Pharmacological Activities of Isocoumarins Natural Sources

Pharmacological Activities

Fungi, lichens, liverworts, mold, marine sponges, insect pheromones, insect venoms, higher plants

Antifungal, antibacterial and antialgal activities; serine proteases; inhibitory properties; mutagenic activities; cytotoxic activities; antitumor activities; histamine release inhibitory properties; antidiabetic activities; etc.

TABLE 6.2 Summary of Key Strategies Used for Transition MetaleCatalyzed Synthesis of Isocoumarins Strategy

Method/Synthesis via

Coupling-cyclization

2-(1-Alkynyl)benzoic acids 2-(1-Allenyl)benzoic acids 2-(1-Alkynyl)arene derivatives Use/generation of allenes Generation of isobenzopyrylium salts

Tandem reactions

Arylation/alkenylation/vinylation of 2-(1-alkynyl)benzoic acids

Cyclization

2-Cyanophenyl alkynes, 2-allyl benzaldehydes/benzoic acids

Annulation

Use of internal alkynes, 1,3-diketones, 2-iodo enol esters

Carbonylation

a-(O-haloaryl)-substituted ketones

Decarbonylation

Addition of phthalic anhydride to alkynes

CeH activation-annulation

Benzoic acid derivatives

strategies to ensure site selectivity in intermolecular CeH bond activations and functionalization. Moreover, synthesis of 3,4-unsubstituted isocoumarins is difficult by using these methodologies. Nevertheless, several types of isocoumarins have been synthesized successfully using these CeH functionalization/cyclization strategies with the increasing use of rhodium-based

Remarks on Past, Present, and Future Chapter | 6

179

TABLE 6.3 Summary of Metal Catalysts Used in the Synthesis of Isocoumarins Metal/Transition Metal

Catalysts

Pd

PdCl2 (with or without CuCl2), (PPh3)2PdCl2 (with CuI), PdCl2(MeCN)2, Pd(PPh3)4, Pd(OAc)2, [(dppp) Pd(H2O)2](OTf)2, Pd(dba)2 (with dppf), Pd2(dba)3, Pd(dppf) Cl2lCH2Cl2, 10%Pd/C (with CuI)

Cu

CuI (with or without PPh3), (IPr)CuCl, CuCl2, CuBr2, Cu(OTf)2, Cu(OAc)2lH2O

Au

AuCl3, Tf2NAuL2, PPh3AuCl (with AgOTf or AgSbF6), Ph3PAuNTf2

Hg

HgSO4, Hg(OAc)2

Fe

FeCl3

Cs

CsF

Ru

Ru3(CO)12, [RuCl2(p-cymene)]2 {with or without Cu(OAc)2lH2O}, [Ru(bpy)3]Cl2

Bi

BiCl3 (with BF3lOEt2)

Rh

[Cp*RhCl2]2 {with Cu(OAc)2lH2O or AgOAc or AgBF4 or AgSbF4 or CuO or NaOAc}, [tris(imidazolyl)methanol] Rh(CO)2, Rh6(CO)16, Rh2(OAc)4, [Cp*Rh(MeCN)3][SbF6]2

Ir

(Cp*IrCl2)2 (with AgOAc), Ph Ph

H N O

Ni

Ni(cod)2 (with PMe3)

Ag

AgOAc

Ir

catalysts in the presence or absence of a cocatalyst (Table 6.4). This is not surprising as these catalysts are more tolerant to substituents such as labile (e.g., carboxy, ester, ether, etc.) and deactivated groups (e.g., amino and related nitrogen-containing groups) under acidic conditions. Initially, isocoumarins with a C-3 substituent was the main focus for developing the practical and convenient synthetic methodologies as the majority of the naturally occurring isocoumarins that are of polyketide origin possess a C-3 substituent. However, emergence of newer methodologies including the CeH activation methods has allowed synthetic chemists to introduce substituents at other positions. For example, all these methodologies are capable of affording isocoumarins

180 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin

Het Ar

O

6-endo-dig

O isocoumarin

cyclization

Het Ar

OH O

2-(1-alkynyl)benzoic acid derivatives

5-exo-dig

Het Ar

O

O phthalide

SCHEME 6.1 Cyclization of 2-(1-alkynyl)benzoic acid derivatives.

possessing 3,4-alkyl-, aryl-, alkoxy-, acyl-, and ester substituents in addition to those on their benzene ring. Generally, as evident from Table 6.3, the alkynebased approaches played a central role where the transition metal catalysts or complexes not only activate the carbonehydrogen and carboneheteroatom bonds but also simultaneously coordinate the substrate at the triple bond, thus facilitating the required transformations involving this bond. Notably, the electrophilic activation of alkynes by coordination with nonmetal agents (e.g., halogen, hydrohalic acid, TFA, PTSA, etc.) other than transition metals in the synthesis of isocoumarins has also been studied and documented well.16 Although some of these strategies can be adopted for the synthesis of other isocoumarin analogs such as thiaisocoumarins, phosphaisocoumarins, and seleno and telluro isocoumarins (Table 6.5), different approaches are necessary to introduce O, N, S, I, Br, Cl, Se, or Si substituents on the lactone ring of isocoumarin core. Thus efforts have been devoted to develop appropriate synthetic methodologies with the aim of introducing these substituents. It is worthy to mention that the application of microwave or ultrasound has also been explored in the synthesis of isocoumarins. Nevertheless, all these strategies and methodologies helped synthetic organic chemists to achieve synthesis of many isocoumarin-based natural products (Fig 6.1) such as Thunberginol A and B, g-and d-Rubromycin, legioliulin, achlisocoumarin I, and several other miscellaneous natural product analogs.

6.3 FUTURE DIRECTIONS Overall, as discussed above, the key approaches toward the synthesis of isocoumarins can be summarized as follows: (1) cyclization of 2-alkynyl/ alkenyl benzoic acids, (2) coupling of (2-halo)benzoic acids with alkenes or alkynes, (3) Pd-catalyzed carbonylative cyclization via trapping of acyl-Pd species with internal enolates, (4) NHC-catalyzed oxidative cyclization of 2-alkynyl benzaldehyde, (5) CO insertion processes using either CO gas or its surrogates, (6) Cu-catalyzed coupling of 2-halobenzoates with 1,3-diketones, etc. It is worthy to mention that most of these methodologies involve the use of homogeneous catalytic system that is challenging in

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181

TABLE 6.4 Summary of Key CeH Activation Strategies Used for the Synthesis of Isocoumarins Catalysis

Reactions

Rh(III)/Cu

Coupling of benzoic acids with alkynes

Rh(III)/Ag

Redox neutral CeH bond activationeannulation of O-benzoyl hydroxylamines with alkynes

Rh(III)

Annulation of benzoic acids with alkynes under oxygen atmosphere

N-heterocyclic carbene/Rh(III)

Sequential reaction of benzaldehydes with alkynes in the same pot

Rh(III)

CeH a-acylalkylation/deaminative cyclization of benzamide derivatives with cyclic alkenyl carbonates

Rh(III)

CeH activation/cyclization of benzamides with diazo compounds

Rh(III)

Coupling of benzoic acids with cyclic 2-diazo-1,3-diketones

Rh(III)

Coupling of benzoic acids with geminal substituted vinyl acetates

Ir(III)

Coupling of benzoic acids with alkynes

Ru(II)

Annulations of benzoic acids with alkynes

Pd(II)

Coupling of benzoic acids with olefines

Cu(I)

Domino reaction of o-halobenzoic ester/amide with 1,3-diketones

industrial scale because of their cost, cumbersome separation from the reaction mixture, one time use, and waste generation. Although efforts have been devoted to develop the heterogeneous recyclable catalytic system, they have limited scope and do not address the problem of leaching of metal catalyst into the reaction mixture. Thus more facile and efficient approaches are necessary to address the recyclability and environmental concerns. The immobilization of the catalyst in a liquid phase by dissolving it into a nonvolatile and nonmixing liquid, such as ionic liquids and polyethylene glycols (PEGs), could be the way forward (although complicated synthesis and environmental safety issues of ionic liquids are debatable). From the view point of medicinal/pharmaceutical chemistry,17 research on exploring isocoumarin framework (Table 6.6) has also increased by several folds as evident from the increasing number of reports and publications. It is known that a large portion of small molecules introduced as drugs worldwide can be traced to or are inspired by natural products. These include natural products as it is, natural products derivatives, synthetic compounds with natural productederived pharmacophores and synthetic compounds designed on the basis of knowledge gained from a natural product (natural product mimic).

182 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin

TABLE 6.5 Summary of Strategies Used for the Synthesis of Isocoumarin Derivatives/Analogs Isocoumarin Derivatives/Analogs

Strategies Used

Benzo-fused isocoumarins

(1) Coupling with terminal alkynes followed by condensation with 1,3-dicarbonyl derivatives, (2) tandem cyclization of enediynes

Thienopyranones

(1) Construction of thiophene ring, (2) construction of pyranone ring

Thiaisocoumarins and 2thiaisocoumarins

(1) Coupling-cyclization, (2) o-lithiation, and (3) other methods

Seleno and telluro isocoumarins

Treatment of o-ethynylbenzene ester with dimethyl diselenide or ditelluride followed by other steps

Phosphaisocoumarins

(1) Halocyclization/Cu-mediated cyclization, (2) CeH activation

a-Pyranone-fused N-heterocycles

(1) Coupling-cyclization, oxidative cyclization, (2) domino reaction of o-haloheteroaryl ester/ amide with 1,3-diketones, (3) ninhydrin-based reactions, (4) 3-component reactions, etc.

O OH

OH HO

OH

OH

HO

OH

MeO

O CO2Me

O O

O

O OH

O

OH

O

Thunberginol A

O

O

OH y-Rubromycin

Thunberginol B O MeO

O MeO

O O

O

OH CO2Me

O O Ph

O

Legioliulin

OH δ-Rubromycin

OH HO O OH

O

Achlisocoumarin I

FIGURE 6.1 Examples of some isocoumarin-based natural products, chemical synthesis of which has been reported.

Remarks on Past, Present, and Future Chapter | 6

183

TABLE 6.6 Isocoumarins Explored in Medicinal/Pharmaceutical Chemistry Isocoumarins

Biological Activities/Medicinal Properties

4-Chloro-3-alkoxyisocoumarins

Inhibition of pancreatic cholesterol esterase

2,8-Disubstituted-benzo[c]chromen-6-ones

Inhibition of serine proteases, HIV aspartyl protease, nitric oxide synthase, and protein kinases

Pyranone-fused pyrazolopyrimidine derivatives

Inhibition of phosphodiesterase 4 (PDE4)

Thieno[3,2-c]pyran-4-one derivatives

Inhibition of growth of cancer cells

6H-1-Benzopyrano[4,3-b]quinolin-6-ones

Inhibition of sirtuins

4-Alkyl-3-aroyl and 4-alkyl-3-aminocarbonyl isocoumarin derivatives

Antibacterial/antifungal activities

3-Azole substituted isocoumarins

Antifungal activities

3-Arylisocoumarin derivatives

Inhibitors of 5-LOX (5-lipoxygenase)

3-Glycosylated isocoumarins

Potential inhibition of sodiumdependent glucose cotransporter 2 (SGLT2)

Isocoumarin represents one of such classes that inspired medical researchers over the years and has played key roles in many areas of drug discovery and pharmaceutical research. It is evident that researchers have undertaken a long journey to discover an array of excellent and efficient methodologies for the construction of isocoumarin ring where transition metalecatalyzed reactions occupied the center stage. These efforts are expected to help both medicinal and natural product chemists in synthesizing their target molecules that eventually would strengthen the research on isocoumarins in vast areas of synthetic, medicinal, and pharmaceutical chemistry. No doubt that the newly developed cutting-edge technologies would continue to provide better solutions to the researchers aiming access to the novel or new isocoumarin-based molecules/agents or drugs.

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184 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin 3. Azumi, M.; Ogawa, K-i.; Fujita, T.; Takeshita, M.; Yoshida, R.; Furumai, T.; Igarashi, Y. Bacilosarcins A and B, Novel Bioactive Isocoumarins with Unusual Heterocyclic Cores from the Marine-derived Bacterium Bacillus subtilis. Tetrahedron 2008, 64, 6420e6425. 4. Patel, D. K.; Patel, K.; Kumar, R.; Gadewar, M.; Tahilyani, V. Pharmacological and Analytical Aspects of Bergenin: A Concise Report. Asian Pac. J. Trop. Dis 2012, 2, 163e167. 5. Kim, H. W.; Park, J.; Kang, K. B.; Kim, T. B.; Oh, W. K.; Kim, J.; Sung, S. H. Acylphloroglucinolated Catechin and Phenylethyl Isocoumarin Derivatives from Agrimonia pilosa. J. Nat. Prod. 2016, 79, 2376e2383. 6. Saddiqa, A.; Usman, M.; Cakmak, O. Isocoumarins and 3,4-dihydroisocoumarins, Amazing Natural Products: A Review. Turk. J. Chem. 2017, 41, 153e178. https://doi.org/10.3906/kim1604-66. 7. Zhang, H.; Matsuda, H.; Kumahara, A.; Ito, Y.; Nakamura, S.; Yoshikawa, M. New Type of Anti-diabetic Compounds from the Processed Leaves of Hydrangea Macrophylla var. Thunbergii (Hydrangeae Dulcis Folium). Bioorg. Med. Chem. Lett. 2007, 17, 4972e4976. 8. Qadeer, G.; Rama, N. H.; Shah, J. H. A New Synthesis of Natural Isocoumarin, Thunberginol B. ARKIVOC 2007, (xiv), 12e19. 9. Whyte, A. C.; Gloer, J. B.; Scott, J. A.; Malloch, D. Cercophorins A-C: Novel Antifungal and Cytotoxic Metabolites from the Coprophilous Fungus Cercophora Areolata. J. Nat. Products 1996, 59, 765e769. 10. Varanda, E. A.; Varella, S. D.; Rampazo, R. A.; Kitagawa, R. R.; Raddi, M. S. G.; Vilegas, W.; dos Santos, L. C. Mutagenic and Cytotoxic Effect of Planifolin: A Naphthopyranone Dimer Isolated from Paepalanthus planifolius. Toxicol. Vitro 2006, 20, 664e668. 11. Pal, S.; Chatare, V.; Pal, M. Isocoumarin and its Derivatives: An Overview on Their Synthesis and Applications. Curr. Org. Chem. 2011, 15, 782e800. 12. Ashraf, Z. Metal-catalyzed Synthesis of Isocoumarin Derivatives (Microreview). Chem Heterocycl. Compd. 2016, 52, 149e151. 13. Saeed, A.; Haroon, M.; Muhammad, F.; Larik, F. A.; Hesham, E.-S.; Channar, P. A. Advances in Transition Metal Catalyzed Synthesis of 3-substituted Isocoumarins. J. Organomet. Chem. 2017, 834, 88e103. 14. Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto, Y.; Yonehara, M.; Hiroya, K.; Sakamoto, T. Regiocontrolled Intramolecular Cyclizations of Carboxylic Acids to CarbonCarbon Triple Bonds Promoted by Acid or Base Catalyst. Org. Lett. 2006, 8, 5517e5520. 15. Crabtree, R. H.; Lei, A. Introduction: CH Activation. Chem. Rev. 2017, 117, 8481e8482. 16. Yao, T.; Larock, R. C. Synthesis of Isocoumarins and a-Pyrones via Electrophilic Cyclization. J. Org. Chem. 2003, 68, 5936e5942. 17. Hussain, H.; Green, I. R. A Patent Review of Two Fruitful Decades (1997e2016) of Isocoumarin Research. Expert Opin. Ther. Pat. 2017, 27, 1267e1275. https://doi.org/ 10.1080/13543776.2017.1344220.