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Review

Medicinal Chemistry

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Microwave-assisted synthesis of chromenes: biological and chemical importance

Chromenes constitute chemically important class of heterocyclic compounds having diverse biological and chemical importance. Development of environmentally benign, efficient and economical methods for the synthesis of chromenes remains a significant challenge in synthetic chemistry. The synthesis of chromenes, therefore, has attracted enormous attention from medicinal and organic chemists. Researchers have embraced the concepts of microwave (high speed) synthesis to produce biologically and chemically important chromenes in a time sensitive manner. This review will summarize the recent biological applications such as anticancer, antimicrobial, neurodegenerative and insecticidal activity of new chromenes prepared via microwave irradiation. The development of new methodologies for the synthesis of chromenes including green chemistry processes has also been discussed.

Chromenes probably represent an important structural class of oxygen heterocycles. The chromene ring (benzopyran) system consisting of a benzene ring fused to a pyran ring. The pyran ring is one of the most widely investigated heterocycles. Two important structural classes of chromenes are 4H-chromene (1) and 2H-chromene (2) (Figure 1) . The chromene skeleton is found in a myriad of biologically and chemically important natural and unnatural analogs [1–4]. Chromenes have been known for more than five decades and are generally isolated mainly from the leaves and stems of plants. The chromene nucleus containing important natural products (3–6) (Figure 1) have been isolated and synthesized efficiently [5–7] . Recently, synthetic chromene analogs have emerged as potent anticancer agents. A chromene analog, crolibulin is in Phase II clinical screening for anaplastic thyroid cancer with the National Cancer Institute (NCI; Figure 2)  [8,9] . Several examples of the bicyclic 4H- chromene analogs (8–12) have shown promising anticancer activity for various cancer cell lines (Figure 2)  [9–17] . These new chromenes have shown strong

10.4155/FMC.15.38 © 2015 Future Science Ltd

Shivaputra A Patil*,1, Siddappa A Patil2 & Renukadevi Patil1 Pharmaceutical Sciences Department, College of Pharmacy, Rosalind Franklin University of Medicine & Science, 3333 Green Bay Road, North Chicago, IL 60064, USA 2 Centre for Nano & Material Sciences, Jain University, Jain Global Campus, Bangalore 562112, Karnataka, India *Author for correspondence: Tel.: +1 901 246 4515 [email protected] 1

cytotoxicity against human cancer cell lines through various pathways, including microtubule depolymerization. Some chromenes have been recognized for their biological activities such as antimicrobial [18,19] , anti-HIV [20,21] , antitubercular [22] and antioxidant activities [23] . Due to the wide range of biological activities that have been displayed by chromenes, the scope of chromene research is multifarious extending from rather simple to highly complex molecules. Therefore, considerable interest has been directed toward the synthesis of chromene analogs by several research groups using new synthetic approaches. Development of environmentally benign, efficient and economical methods for the synthesis of biologically important chromenes remains a significant challenge in synthetic chemistry. Among several approaches, multicomponent reactions are considered as one of the most important tools for producing complex chromenes. Recently, researchers have embraced the concepts of microwave (high speed) synthesis to produce biologically and chemically important chromenes in a time sensitive manner.

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Review  Patil, Patil & Patil synthesis is based on the efficient heating of materials by microwave dielectric heating. This heating is dependent on the ability of a specific material such as solvent and/or reagent to absorb microwave energy and convert it into heat. The first reports from Gedye and Giguere revealed the utilization and advantages of microwave irradiation for organic synthesis [24,25] . Since then organic synthesis by microwave energy has gained wide spread importance by synthetic chemists because of the ease and speed of the synthesis of small molecules [26,27] . In recent years, microwave irradiation has brought organic transformations to new dimensions. Microwave energy is usually safe and efficient to conduct reactions and its acceptance is growing in academic laboratories including industrial research. Using microwave energy chemists can successfully achieve most difficult reactions which are not possible by conventional heating. Microwave-assisted organic synthesis is an invaluable technique for drug design and discovery. This technology is environmentally friendly synthetic method in modern synthetic organic chemistry. Microwave heating especially under solventfree conditions is extremely useful in offering reduced pollution. This technology will be the alternative greener method for the organic synthesis. Microwave-assisted synthesis of several heterocyclic scaffolds is reasonably covered in the literature  [28–31] . Now the microwave method is widely used to prepare pharmacologically and chemically

O

O

1

2 OCH3

H3CO R1O

H3CO

O

O

CH3

R1

3: R1 = H 4: R1 = OCH3

5: R1 = H 6: R1 = OCH3

Figure 1. Chromene skeleton(s) (1 and 2) and important natural products (3–6).

Microwave-assisted organic synthesis One of the biggest challenges of synthetic chemists is to accelerate the production of small molecules to satisfy the growing needs of biologists to screen large number of compounds in a quest to identify the lead molecules. Traditional heating required a long time (hours/days) to complete the reactions. Therefore, scientists were alternatively looking for the new technology to speed up the reaction time. Microwave heating compared with traditional heating is much more efficient and allows faster heating to complete the reactions very fast (minutes/seconds). Microwave-assisted OCH3

OCH3

N H3CO

Br

H3CO

O

CN

CN

CN H2N

Br

N

NH2

O

N

NH2

O

NH2

NH2

7

8

Crolibulin/EPC2407

O

9

SP-6-27

MX58151

O O

EtO *

O

O

O OEt

O

O

O

N

O

N

NH2 O

10 CXL017

11 LY294002

O

12 NU7427

Figure 2. Chromene-based anticaner agents.

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Microwave-assisted synthesis of chromenes: biological & chemical importance 

important chromenes. Building of a chromene scaffold is benefiting specially by the privileged use of multicomponent reactions. The multicomponent reaction is one of the major chemical methods to produce substituted chromenes. This short review summarizes the microwave methods for the construction of the chromene ring system and does not include methods for modification or derivatization of chromene ring. Chromenes of biological importance Anticancer agents

Cancer is a disease that has been known to humans for centuries. Cancer is commonly characterized by abnormal cellular growth and it is one of the second leading causes of death worldwide [32] . At present, one quarter of all deaths in the USA are caused by cancer [33] . Past few years, well-planned drug design, discovery and development have established a respectable armamentarium of useful drugs. Cancer treatment and management has been improved tremendously in recent years because of the discovery of targeted therapeutic agents such as imitanib , gefitinib and erlotinib. These drugs improved the patient’s life but complete cure has been a challenging mission for scientists and doctors. One of the primary reasons for the failure in treatment is emergence of resistance in cancer. Cancer cells utilize multiple mechanisms for the development of drug resistance. One important mechanism of drug resistance involves the multidrug transporter, P-glycoprotein (Pgp). Overexpression of Pgp results in decreased drug accumulation within the cancer cell because of the ability to efficiently pump out anticancer drugs. Other important issue of chemotherapeutic drugs is the toxicity to normal cells. Therefore, design, discovery and development of novel anticancer agents to overcome these problems is the focus of several research groups working in academia and pharmaceutical companies. Chromenes are an attractive template for the identification of potential chemotherapeutic anticancer agents. Initially, chromenes have been discovered and developed as apoptosis inducers in cell-based anticancer screening. To date a large number of cytotoxic chromenes have been prepared by domino reaction or microwave energy. Majority of chromenes have been identified as tubulin inhibitors. Few lead chromenes have been produced by conventional methods including the clinical candidate crolibulin are tubulin inhibitors. In addition, they have shown promising vascular disrupting activity. Some chromenes have been identified as Bcl2 antagonists, DNA-PK inhibitors, topoisomerase inhibitors and MDM2-p53 inhibitors [8–17] . Recently, our group reported the microwave-assisted synthesis of compound 8 (SP-6–27) as one of the potent

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Review

Key terms Tubulin inhibitors: Chemotherapeutic agents that interfere directly with the tubulin system. NCI 60 cell line screen: The National Cancer Institute’s (NCI’s) 60 human tumor cell line screens were developed as an in vitro drug discovery tool for identifying anticancer drugs. Aromatase inhibitors: Work by blocking the enzyme aromatase in cancer treatment.

anticancer agent in vitro. We designed and synthesized a focused set of novel chromenes (8, 16a-d) by reacting appropriate phenols (13), aldehydes (14) with melanonitrile (15) in a single step using microwave method (Figure 3) . Purified yields of the newly synthesized chromenes were in the range of 7–14%. Authors are planning to develop new microwave methods to improve the yields of the final chromenes. All chromenes showed activity in the nanomolar range (IC50 : 7.4–640 nM) in two melanoma, three prostate and four glioma cancer cell lines. Preliminary mechanism of action studies suggests that these novel chromenes interact with the colchicine binding site in tubulin. The highly potent chromene 8 (SP-6–27) was sent to the National Cancer Institute Developmental Therapeutic preclinical 60 cancer cell line screen program. Results from the NCI 60 cell line screen indicated that 8 (SP-6–27) has consistent antiproliferative activity against nine major cancer (leukemia, non-small-cell lung, CNS, colon, melanoma, ovarian, renal, prostate and breast) cell lines. 8 (SP-6–27) has been selected for further in vivo testing at NCI. Initial studies from our laboratory results suggest that these new chromenes have broad anticancer activity and were also confirmed by the NCI 60 cell line in vitro assay results. Taken together, these results strongly suggest that the novel chromenes could be further developed as potential therapeutic agents for a variety of aggressive cancers [9,10,34–36] . Bonfield et al. [37] used the microwave energy to synthesize new class of 3-phenylchroman-4-one derivatives (19) as aromatase inhibitors. They developed efficient one step microwave method to obtain final chromanones (19) from the reaction of salicylaldehyde (17) and phenylacetylene (18) in toluene at 200°C using AuCN (5%)/nBu3P (25%) catalytic system. The classical AuCN/nBu3P catalyzed annulation involved heating with high boiling solvent toluene at 150°C for 36 h. Long reaction time and high catalyst usage were the reason to find very high yielding microwave procedure. Purity of all compounds was greater than 95% and yields were in the range of 14.4–51.4%. Aromatase inhibitors have advantages over the traditional hormonal breast cancer therapy in terms of total blockage and possibly reduced side effects. Therefore,

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R1

+ N

+

CN

MW, ET 3N CN

CN

OH

CH3

R1

13

H3C

R2

14

15

NH2

O

N

O R2

H

5% AuCN, 25% nBu3P

R2

MW, toluene, 200°C, 10 min

OH

R1

17

N(CH3)2 H F 16a H Br 16b H 16c OCH3 H 16d F H

8, 16A–D

CH3

O

R1

R2

8

CHO

H3C

R1

R2

18

O

19

R1 = H, F, CI, Br, CH3, tBu, OCH3, OPh, Pyridyl, thiophene, phenanthryl R2 = H, CH3, OCH3, OPh

Figure 3. 4H-chromene and 3-phenylchroman-4-one analogs. MW: Microwave.

aromatase inhibition approach is one of the best strategies to treat hormone-dependent breast cancer. In order to establish structure–activity relationships (SARs), they prepared 23 new chromanones by varying substitutions on the A and B rings. Their SAR revealed that the nonplanarity configuration of the chromanone scaffold might play an important role in enzyme–ligand binding. Among all new chromanones tested for aromatase inhibition the 6-methoxy-3-phenylchroman-4-one (19A: R1 = OMe and R 2 = H) displayed best inhibition (IC50 = 0.26 μM). According to authors, these chromanones could be further optimized for the development of new chemotherapeutic agents for breast cancer. Antimicrobial agents

When we look back on the history of human diseases, infectious diseases account for considerable amount of deaths globally. To treat infectious diseases, more potent antimicrobial agents are very much essential. The modern era of antimicrobial chemotherapy began with Fleming’s discovery of penicillin [38] . Antimicrobial drugs have always been considered one of the wonder discoveries of the 20th century. Use of the antimicrobial agents is further magnified in developing countries, where infective diseases predominate. Mainly two types of agents are used in the treatment of infectious diseases; natural substances produced by microorganisms and synthetic chemotherapeutic agents. Antibacterial & antifungal agents

Kidwai  et al.  [39] developed an easier and ecofriendly greener method for the preparation of

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2-aminochromenes. They synthesized several substituted 2-amino-chromenes (22 and 24) by reacting resorcinol (20) and naphthalen-2-ol (23) with substitute aldehydes (21) using K 2CO3 as green catalyst in water under microwave irradiation (Figure 4) . All these new 2-aminochromenes were obtained in the range of 87–92% yields and the reaction time for the microwave reaction was only 1.9–3.5 min. The main advantage of microwave method was simple workup, higher yields and enhancement of the reaction rates. They tested all new compounds for antibacterial activity using broth microdilution minimum inhibitory concentration method. Most of them have displayed good antibacterial activity toward Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), and Staphylococcus aureus (ATCC 25923). Shah and co-workers [40] produced novel pyrazole substituted 4H-chromenes (26A) as antimicrobial agents. They developed one pot; three component reactions using microwave reaction in the presence of catalytic amount of ammonium acetate to produce pyrazole substituted 4H-chromenes (26A). They used several base catalysts (NaOH, K 2CO3, DMAP, Et3N, piperidine, ammonium acetate) under microwave irradiation conditions to optimize the yield of the products. Among them ammonium acetate turned out to be the good catalyst for the multicomponent reaction. Their microwave procedure provided compounds 26A in excellent yields (85% or more). They reacted various substituted 5-chloro-3-methyl1-aryl-4,5-dihydro-1H-pyrazole-4-carbaldehydes, 2-naphtholas and malononitrile to generate a library

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Microwave-assisted synthesis of chromenes: biological & chemical importance 

Review

R + HO

R-CHO

OH

20

21

OH

+ R-CHO

CN

CH2(CN)2 MW, aq. K2CO3

CH2(CN)2

HO

O

NH2

22

R CN

MW, aq. K2CO3 23

21

R = Phenyl, piperonyl, indolyl, 2-chloro-3-quinolyl

O

NH2

R = Phenyl, piperonyl, indolyl, 2-chloro-3-quinolyl

24

Figure 4. 2-amino-chromene analogs. Aq: Aqueous; MW: Microwave.

of 2-amino-4H-chromenes (26A). Three compounds (26A: R1 = 4-CH3, 3-Cl, 3-Cl; R 2 = Cl, H, CH3 ; R 3 = H, H, Cl) have shown good antibacterial activity against E. coli (zone of inhibition 25) compared with standard drug ampicillin (zone of inhibition 28). In case of antifungal activity, compound (26A: R1 = 4-CH3, 3-OCH3, H) showed good inhibition toward F. oxysporum. All new analogs demonstrated varying degree of antimicrobial activity and their detailed SAR demonstrated that antimicrobial activity influences the minor changes in the substituents on pyrazole and/or naphthol moieties. Sangani  et al.  [41] continued to work on the development of new pyrazole substituted 4H-chromenes (26B) to develop possible structure-activity relationship (SAR). Substituted 5-phenoxypyrazole4-carbaldehydes were reacted with 1,3-cyclohexanedione/dimidone (25B) and malononitrile in the presence of NaOH under microwave irradiation conditions to obtain the desired 4H-chromene derivatives (26B) in good yields (68–90%) (Figure 5) . The newly prepared compounds were screened against three Gram-positive bacteria (Streptococcus pneumoniae, Clostridium ani and Bacillus subtilis), three Gram-negative bacteria (Salmonella typhi, Vibrio cholerae and E. coli) and two fungi (Aspergillus fumigatus and Candida albicans) using the broth microdilution minimum inhibitory concentration method. They established SARs among the 4H-chromenes (26B). Their detailed SAR revealed that a methyl group on the N-phenyl ring of the pyrazole moiety as well as a gem dimethyl group on the benzopyrane ring with either chloro or methyl substituent on the O-phenyl ring of the pyrazole moiety are essential to obtain good antibacterial activity. In case of antifungal activity most of the compounds were potent against C. albicans than against A. fumigatus. The same research group [42] developed an efficient microwave method to prepare 4H-chromene deriva-

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tives 27 as new structural class of antimicrobials. The 2-aryloxyquinoline-3-carbaldehydes were reacted with 1,3-cyclohexanedione/dimidone (25B) and malononitrile in the presence of NaOH using microwave energy to obtain the desired 4H-chromene derivatives (27) in moderate to good yields (64–89%). SAR study among the 4H-chromenes (27) revealed that some of the analogs have shown comparable antibacterial activity against all three Gram-positive bacteria to the standard ampicillin. Antifungal activity of compounds (27) revealed that most of them have shown potent activity against C. albicans and poor activity against A. fumigatus. Similarly, Kathrotiya and Patel [43] have been reported the microwaveassisted synthesis of 3-indolyl-chromenes (28) as antimicrobial agents in good yields (69–86%). They tested all new indolyl-chromenes for similar set of antibacterial and antifungal strains and showed several compounds were more active compared with the standards. Jardosh and Patel [44] have developed one-pot, three component microwave-assisted ceric ammonium nitrate (5 mol%) catalyzed solvent-free method. Using this method, they prepared new 1H-benzo[b] xanthenes (30) and 4H-benzo[g]chromenes (31) in good yields (81–88%) (Figure 6) . They initially optimized the microwave reaction by varying mole ratio of ceric ammonium nitrate and found that 5 mol% was optimum for the higher yields of the products. All newly prepared compounds (30 and 31) were screened for their antibacterial activity against Gram-positive bacteria (S. aureus [MTCC 96], Streptococcus pyogenes [MTCC 442]) and Gram-negative bacteria (E. coli [MTCC 443], P. aeruginosa [MTCC 1688]), and antifungal activity against Fungi (C. albicans [MTCC 227], Aspergillus niger [MTCC 282], and Aspergillus clavatus [MTCC 1323]). The detailed SARs revealed that the 4H-benzo[g]chromenes (31) have shown more promising antimicrobial activity compared with 1H-benzo[b]xanthens (30).

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R1 CHO

H3C N OH

CH3

Cl N

CN R1

O

NC

O

+

NH

NC

HN

NH4OAc, ethanol MW, 4–5 min

R2

R3

N N Cl

NH2

O

R1 = H, 4-CH3, 3-CI R2 = H, CH3, OCH3, OC2H5 R3 = CI

R2

25A

26A R3 R1 CHO

H3C N

R2

O N

N N

H3C O

O

CN

R2 R

R1

R

26B

O +

R R

O

R1

NC NC

25B

NH2

O

NaOH, ethanol MW, 350 W,

R = H, CH3 R1 = H, CH3 R2 = H, CH3, OCH3, CI

R2

N CHO

R1 N

O

O

O CN

R2

R R

O

NaOH, ethanol MW, 350 W,

NH2

27

R = H, CH3 R1 = H, CH3, OCH3 R2 = H, CH3, OCH3, F

H N R1

H N OHC

DMAP, ethanol MW, 350 W,

R1 O CN R R

O

28

NH2

R1 = H, CH3, OCH3, F, CI, SO2CH3, NO2

Figure 5. 4-heteroarly-chromene derivatives. DMAP: 4-Dimethylaminopyridine; MW: Microwave.

In continuation of their work on chromenes, Jardosh and Patel [45] prepared quinolone-based pyrano[4,3-b] chromenes (34) and benzopyrano[3,2-c]chromenes (35) using the similar experimental conditions (Figure 7).

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The yields of the products were in the range 81–88%. They screened newly synthesized chromenes for similar penal bacterial and fungal strains. All new chromenes have showed good antibacterial and antifungal activity.

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Microwave-assisted synthesis of chromenes: biological & chemical importance 

Review

R1 O

O O

O

R R

R1

N

O

R

O N

5 mol% CAN MW 420 W/6 min

+ O

O

H

29

OH O

R2

O O

R

30

R = H, CH3 R1 = H, CH3, OCH3, CI R2 = CN, COO-i-propyl

R1

CN

5 mol% CAN MW 420 W/6 min

N O

O

R2 O O

NH2

31

Figure 6. 1H-benzo[b]xanthenes and 4H-benzo[g]chromenes. CAN: Ceric ammonium nitrate; MW: Microwave.

Inspired by their earlier work on chromane-related heterocycles  [46] , Parmar research group [47] designed and synthesized 12 novel aryldiazenyl chromeno-fused pyrrolidines (37) via intramolecular 1,3-dipolar cycloaddition of azamethine ylide from O-allyl-5-aryldiazenyl salicylaldehyde (36) (Figure 8) . They employed one pot microwave, conventional and solvent-free thermal methods. Among all three methods, the microwave method gave satisfactory yields (79–90%) in reasonably short time (10 min). All 12 compounds were screened for their in vitro antibacterial activity against three Gram-positive (S. pneumoniae, Clostridium ani, B. subtilis) and three Gram-negative (Salmonella typhi, Vibrio cholerae, E. coli) bacteria, and for antifungal activity against two fungi: A. fumigatus and C. albicans by the macro-broth dilution assay. Two compounds (37e: R = Me; R1 = Et and 37l: R = Et; R1 = n-Bu) have shown nearly equal to a standard drug chloramphenicol against all three Gram-negative bacteria whereas one compound (37c: R = Bn; R1 = nPr) has shown better activity than reference drug against Grampositive S. pneumonia bacteria. They also screened all compounds for their antitubercular activity against M. Tuberculosis H37RV bacteria. The compound (37i: R = Et; R1 = Me) was very active against M. Tuberculosis H37RV bacteria and showed the growth inhibition 98% which was comparable to standard.

target mainly reverse transcriptase (RT) [48] and protease  [49] and are widely used in combination as highly active antiretroviral therapy (HAART). Though HAART has been effective in reducing morbidity and mortality, it does not eliminate the virus from patients  [50] . The emergence of multidrug resistance and side effect of existing drugs [51,52] demands the discovery and development of novel anti-HIV drugs. Daurichromenic acid (40), a chromene analog, has shown potent anti-HIV activity in acutely infected H9 cells with an EC50 5.67 ng/ml and a therapeutic index (TI) of 3710. Owing to its importance, Kang et al. [53] have established an efficient microwave-assisted method to obtain daurichromenic acid (40) in the key step in overall yield of 49%. Neurodegenerative agents

As we age our brains age, but only some of us develop neurodegenerative diseases. Much of the individual variation in aging is accounted by lifestyle and the effects of the environment. Detailed understanding of biology of aging may represent important targets to develop novel and effective drugs to treat age-related neurodegenerative diseases [54] . Sirtuins (SIRTs) are NAD-dependent protein deacetylases that have shown beneficiary effects against age-related diseases. The detailed understanding of the role of different SIRTs in aging brain and neurodegeneration will allow research-

Anti-HIV agents

AIDS, a disease resulting from infection with HIV, which is one of the world’s most serious health problems. Currently, US FDA approved antiretroviral drugs

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Key term HIV: HIV is a lentivirus that causes AIDS.

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R1 O

N O

R1

HO

O N

+

O

32

R3

O

34

R1 = H, CH3, CI R = H, CH3

O OH

O

H

O

R3

5 mol% CAN MW 420 W/6 min

R R

O O

O

R1

29 33 O

N

O

O O

O

5 mol% CAN MW 420 W/6 min

O

R3 R3

O

35 Figure 7. Pyrano[4,3-b]chromenes and benzopyrano[3,2-c]chromenes. CAN: Ceric ammonium nitrate; MW: Microwave.

ers in the field to develop new therapeutic agents to overcome neurodegenerative diseases [55–59] . Fridén-Saxin  et al.  [60] have efficiently synthesized several chroman-4-one derivatives (43) (17–88% yields) by reacting compounds (41) with appropriate aldehydes (42) in a single step using microwave energy to establish possible SARs (Figure 9). They evaluated all novel chromenones as inhibitors of SIRT2 enzyme. In their initial SAR, they identified the chiral lead compound 43A (8-bromo-6-chloro-2-pentylchroman-4-one) as potent inhibitor of SIRT2 enzyme. It is well known

COOR1

R

O Ph-N2

that the enantiomers of chiral drugs generally show significant differences in their pharmacokinetics (PK) and pharmacodynamics (PD) and adverse reactions. Therefore, with the aim of elucidating enantiopharmacological profile of the lead 43a, they separated the enantiomers and found that the enantiomers had only slightly different inhibitory activities. Biological activity revealed that enantiomer (−) 43a (IC50 : 1.5 μM) was more active than its other enantiomer (+) 43a (IC50 : 4.5 μM). The detailed SAR revealed that alkyl chain with three to five carbons in C2 position, larger, electron withdrawing

RHN

H

COOR1

H Ph-N2

H

MW

O

N

O

36

37A–L

37a–d; R = Bn, R1 = Me, Et, n-Pr, n-Bu 37e–h; R = Me, R1 = Me, Et, n-Pr, n-Bu 37i–l; R = Et, R1 = Me, Et, n-Pr, n-Bu

O O TMS

OH

O

H

O

O

TMS

OH

38

MW CaCl2.. 2H2O, Et3N. EtOH

OH

OH

HO TBAF

O O

39

THF

O

40

Figure 8. Aryldiazenyl chromeno fused pyrrolidines and daurichromenic acid. EtOH: Ethanol; MW: Microwave; TBAF: Tetra-n-butylammonium fluoride; THF: Tetrahydrofuran.

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Microwave-assisted synthesis of chromenes: biological & chemical importance 

O R

+ OH

41

170°C, 1H. MW

H

R1

O

DIPA, EtOH

O

Review

R = Me, Br, CI, F, NO2, OMe R1 = alkyl, phenyl

R R1

O

42

43

O O

K10-K+

+ H

O

MW

OH

OH

-H2O

O

44

45

O

O

O

46

O

O

O

47

O

O

48

Figure 9. Chroman-4-ones and methylenedioxyprecocene. DIPA: N,N-diisopropylamine; EtOH: Ethanol; MW: Microwave.

groups in the C6- and C8-positions, and an intact carbonyl group were crucial for high potency. Insecticides

Insecticides are agents of chemical or biological origin that control insects by killing or repelling them or otherwise lowering pest infestations to protect crops from damage. The dichlorodiphenyl trichloroethane (DDT) is one of the first synthetic organic insecticides used to manage insects. Since then several classes of insecticides and insecticide synergists have been developed and continued to develop for the better management of crops [61] . Dintzner  et al.  [62] have reported a simple, onepot, solvent-free synthesis of a natural insecticide methylenedioxyprecocene (MDP, 48). The MDP has antijuvenile hormone activity in some insects. They performed perfect green chemistry reaction in which the sesamol (44) was reacted with 3-methyl2-butenal (45) using montmorillonite K10–K+ (prepared by washing K10 with K 2CO3 solution) as catalyst under solvent-free condition with microwave energy. The mechanism involves initial electrophilic addition of 3-methyl-2-butenal (45) to sesamol (44) to provide intermediate (46) followed by dehydration to obtain (47), and subsequent intramolecular hetero-Diels–Alder cyclization. Chromenes of chemical importance

The development of a new methodology for the synthesis chromenes is a great challenge in modern synthetic chemistry. The new synthetic methodologies should aim at minimizing environment pollution by reducing the use of hazardous chemicals such as flammable, volatile and toxic organic solvents. One way to develop such methodologies is the adaptation of green chemistry process to run majority of organic reactions. Green chemistry mainly emphasizes elimination of hazardous reagents or solvents in a chemical reaction.

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It mainly involves the development of reusable catalysts (catalysts are substances that help to speed up the process of chemical reactions without taking part in the reaction) and green solvents (ionic liquids, polyethylene glycol and water). Catalyst plays very vital role in the chemical industrial research. In some cases it is possible to replace polluting chemicals in the reaction to more environmentally friendly catalysts. Developing new catalytic system is very vital to increase speed and yields of the product. Now chemists are trying to carry out many reactions under solvent-free conditions in combination with microwave heating to avoid the use of large amounts of flammable, volatile and toxic organic solvents. The solvent-free reaction conditions have got several advantages such as shorter reaction time; require simple and efficient workup along with easy purification. The development of greener procedure to prepare polycyclic chromenes is always of interest to organic/medicinal chemists. The development of new methodologies of environmentally benign multicomponent procedures under solvent- and catalyst-free using microwave energy is of particular significance. Therefore, the synthesis of chromenes using new catalyst (no catalyst in some cases) and/or solvent less (neat) method using microwave energy has been explored in the following section. Pyranopyridines have shown wide range of biological activities. Due to their biological importance, considerable attention has been directed toward the synthesis of pyranopyridine analogs by microwave energy. In this regard, Raghuvanshi and Singh [63] Key term Green chemistry: Philosophy of chemical research and engineering that encourages the design of products and processes that minimize the use and generation of hazardous substances.

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Review  Patil, Patil & Patil arylcarboxylates (53) with ten different o-hydroxyarylboronic acids (54). The yields of the final products were in the range of 68–98%. Iniyavan et al.  [65] proposed one pot green synthesis of xanthenes (56) and chromenes (57) via a three-component reaction (Figure 11) . They obtained xanthenes (56) and chromenes (57) in excellent yields (82–92%). They reacted 1,3-cyclohexanediones (25), aldehydes and 2-naphthol/4-hydroxycoumarin in ionic liquid under microwave irradiation. Use of ionic liquid [bmim][PF6] makes this new method as perfect green chemistry process. All new compounds were subjected to antioxidant activities using DPPH (2,2-diphenyl1-picrylhydrazyl) free radical scavenging assay. Majority of compounds displayed better antioxidant activity at their higher concentrations. The natural and synthetic indoles possess interesting arrays of pharmacological activities [66–72] . To combine the interesting and remarkable biological activities of both indole and chromene, Jha et al. [73] suggested the synthesis of indole annulated dihydropyrano[3,4-c] chromenes (61). They described a microwave-assisted two step synthesis of compounds (61) (Figure 12) . First step involves the Knoevenagel condensation of O-propargylated salicylaldehyde derivatives (59) with indolin-2-ones (58) to obtain intermediate compounds (60). In second step, compounds 60 were then subjected to microwave-assisted cuprous iodide catalyzed intramolecular hetero-Diels–Alder reaction to get indole-annulated dihydropyrano[3,4-c]chromene derivatives (61) in moderate yields (60–71%). In continuation of their interest in developing new 2-amniochromenes (63 and 64), El-Agrody et al.  [74] developed an efficient microwave method. The

Key term Suzuki–Miyaura coupling reaction: Commonly known as Suzuki coupling which involves the coupling of boronic acids with arylhalides in the presence of palladium catalyst.

have developed a facile 1,8-diazabicyclo[5.4.0]undec7-ene (DBU)-catalyzed multicomponent reaction. The reaction of resorcinol (49), aromatic aldehydes (50) and malononitrile in the presence of 5% DBU gave the desired 2-amino-4H-3-cyano-chromenes (51) (Figure 10) . They tried various catalysts for the multicomponent reaction to identify the best catalytic system for the formation of chromenes (51). Among them 5% DBU in ethanol has produced chromenes in good yields (60–76%). Compounds 51 were further reacted with cyclohexanone in the presence of aluminium chloride under controlled microwave irradiation to obtain the final new pyranopyridine derivatives (52) in excellent yields (85–91%). To obtain higher yield of the final products (52), they optimized the reaction using various Lewis acid catalysts (FeCl3, ZnCl2, Yb(OTf)3, Sc(OTf)3, InCl3, I2) in different solvents (methanol, ethanol, acetonitrile and dichloromethane). In an effort to develop effective synthetic method to the privileged scaffold of dibenzopyranone, Vishnumurthy and Makriyannis [64] have proposed palladium-catalyzed Suzuki–Miyaura coupling reaction. They optimized Suzuki–Miyaura coupling conditions using various catalysts, ligands, bases and solvents. Their optimized conditions for Suzuki coupling requires Pd(PPh3)4 as a catalyst in the presence of Cs2CO3 in DME at 125°C under microwave irradiation for 15 min. They developed a library of dibenzopyranone analogs (55) by coupling 24 different bromo

O R

R–CHO

+ HO

OH

49

50

CH2(CN2)

HO

Ar Br

R2

+

COOCH3

53

HO

O

HO MW AICI3, DCM

NH2

51

10 mol% Pd(PPh3)4

O

N

52 R = Ph, 4-FC6H4, 4-BrC6H4, 4-MeOC6H4, 4-MeC6H4, 2-furly, 3,4,5-(OMe)3C6H2, 4-N(Me)2C6H4

R1 Ar

DMF, H2O MW

54

NH2

CN

MW DBU (5%) EtOH

B(OH)2

R1

R

R2 Ar = aryl, R1 and R2 = EDG/EWG O

O

55

Figure 10. Pyranopyridine and dibenzopyranone analogs. DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene; DMF: Dimethylformamide; EDG: Electron donating group; EWG: Electron withdrawing group; MW: Microwave.

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Review

OH R1

R

56 H OH

O

R

O

O

+ R 1

R

R = H, CH3 R1 = C6H5, 4-CIC6H6, 3,4-(OCH3)2C6H3, 2-FC6H4, 3-NO2C6H4, 3-OHC6H4 3,5-OCH3-4-OHC6H2

R

[bmim][PF6] MW O

O

O

25

R1

O

O

R = H, CH3 R1 = 4-FC6H4, 4-OHC6H4, 3-OHC6H4, 3,4, 5-(OCH3)3C6H2, 3,5-OCH3-4-OHC6H2

R

O

O

O

[bmim][PF6] MW

R

57

Figure 11. Xanthene and chromene derivatives. Bmim: 1-Butyl-3-methylimidazolium; Bmim[PF6] - 1-butyl-3-methylimidazolium hexafluorophosphate; MW: Microwave.

4-methoxy-1-naphthol (62) was reacted with a mixture of aromatic aldehydes and malononitrile or ethyl cyanoacetate in ethanolic piperidine solution gave the desired 2-aminochromenes (63 and 64) in good yields (69–91%). Mekheimer and Sadek [75] have also reported the synthesis of 2-amino-2-chromenes using three-component processes under microwave irradiation. Inspired by the methods of microwave-assisted syn-

thesis of solid phase or solvent-free conditions [76–78] , Subburaj and Trivedi [79] developed base catalyzed reactions under microwave irradiation. They reported the synthesis of 2,2-dimethyl-2H-chromenes (66, 67, 68, 69, 70,71, 72 and 73) by the reaction of various phenolic compounds with 3-methyl-2-butanal (65) under microwave heating (Figure 13) . They obtained the final products in low to moderate yields (12–68%). R2

R2

OHC O +

R1

N R

58

R2

O

O

Et3N

Acetonitrile

DCM O

R1

N 60 R

59

OH

62

NH2

O H3CO

CN Ar

CN ArCHO CNCH2CO2Et or ArHC C

O

CO2Et

EtOH, piperidine MW

O N R

R = Ac, Me R1 = H, CI R2 = OCH3, OC2H5, Br, CI

63

OCH3

R1

61

ArCHO CH2(CN)2 or ArCH=C(CN) 2 EtOH, piperidine MW

O

MW 20 mol% Cul

H3CO

NH2

Ar = 4-F-C 6H4, 4-CI-C6H4, 4-Br-C 6H4, 4-CH3O-C6H4, 2, 4-(OCH3)2-C6H3, 2, 3-(OCH3)2-C6H3

Ar = 4-F-C 6H4, 4-CI-C6H4, 4-Br-C 6H4, 4-CH3O-C6H4, 3, 4-(OCH3)2-C6H3,

COEt

64

Ar

Figure 12. Indole-annulated dihydropyrano[3,4-c]chromene and 2-aminochromene derivatives. EtOH: Ethanol; MW: Microwave.

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Review  Patil, Patil & Patil

Key term Phase-transfer catalyst: Catalyst that facilitates the migration of a reactant from one phase into another phase where reaction occurs.

In continuation of their work on microwave-promoted multicomponent coupling reactions to produce various heterocyclic compounds, Santra et al. [80] developed catalyst- and solvent-free green reactions for the synthesis of rahydrobenzo[b]pyrans (74). 1,3-Cyclic diketones (25) were treated with various aldehydes in the presence of melanonitrile under microwave irradiation gave the final compounds (74) in good yields (74–88%) (Figure 14) . Authors claim that the operational simplicity, solvent- and catalyst-free conditions and non-chromatographic purification technique are the main advantages of this methodology. Abd El-Rahman and Borik [81] also reported the synthesis of rahydrobenzo[b]pyrans (75) by using sand as a green, efficient, safe and inexpensive catalyst. They obtained the final products (75) in excellent yields (81–96%).

In continuation of their work on synthesis of rahydrochromen-5-ones, Sarda et al. [82] prepared 2,4-diphenyl4H-chromen-5-one derivatives (77) by reacting α, β- unsaturated carbonyl compounds (76) with 1, 3-cyclohexanedione (25) in the presence of ZnCl2/ montmorillonite K-10 as solid catalyst. Yields of final products were excellent (84–88%). Important aspect of this process is the recovery of the catalyst and could be reused for several times. Afsaneh and his co-workers [83] reported the synthesis of chromeno[2,3-d]pyrimidine derivatives (79) without using any solvents under microwave irradiation. The reaction of substituted aldehydes (78) with piperidine/morpholine in the presence of malanonitrile gave the final products (79) in brilliant yields (86–96%) under neat reaction conditions (Figure 15). Koussini and Al-Shihria [84] have presented the new one-pot solvent-free method to obtain the substituted 3-nitro-2H-chromenes (81). The compounds 81 were easily prepared by reacting substituted 2-hydroxy benzaldehydes (80) with 2-nitro ethanol supported on anhydrous potassium carbonate using

OH

OHC

Piperidine, MW

O OHC

66

HO

CHO

CHO OHC

OH

OH

OH

Piperidine, MW

+

O

O OH

O

68

67

H O

O

O

OCH3

65

Piperidine, MW 69 OCH3 OH

O

O

O + O

O

71

Piperidine, MW 70 O O

O

+ O

OH OH

O

Piperidine, MW

O

O

OH

O

OH

73

72

Figure 13. 2,2-dimethyl-2H-chromenes. MW: Microwave.

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O

R1-CHO CH2(CN)2

R1 CN

R

Ar CN

O

R R

ArCHO CH2(CN)2

25

O

NH2

R2

O +

R2 O

K-10/ZnCI2 R1

76

R = H, CH3 R1 = R2 = CH3, OH, CI, NO2

R R

MW

O

25

Ar = C6H5, 4-FC6H4, 4-CIC6H4, 4-BrC6H4, 4-OHC6H4, 4-OCH3C6H4, 2,4,6-(OCH3)3C6H2, C4H3O, C4H3S

75

MW Sand

R R

NH2

O

74 O

R R

R = H, CH3 R1 = aryl. alkyl, heteroaryl, cinnamyl

R

MW Neat

O

Review

O

O

R1

77

Figure 14. Rahydrobenzo[b]pyran derivatives. MW: Microwave.

rabutylammmonium bromide as phase-transfer catalyst under microwave irradiation in moderate yields (52–65%). Similar to Sarda et al., Xu and coworkers [85] reported the easily operating synthetic method to obtain 2-hydroxy-2- (trifluoromethyl)2H-chromenes (82) in excellent yields (66–92%). The importance of the method is recovery and reuse of the catalyst without loss of activity. The Knoeve-

nagel condensation of salicylaldehydes (80) with ethyl trifluoroacetoacetate followed by intramolecular cyclization in the presence of silica-immobilized l-proline catalyst gave the desired 2-hydroxy-2(trifluoromethyl)-2H-chromenes (82) and other research groups have also developed green reactions to prepare 2-aminochromenes [86,87] . Sadeghzadeh and Nasseri [88] developed ecofriendly novel Y

Y

CN OH

0.5 eq

OHC

R

CN

N

1 eq

R

N H

N O

MW, neat, 100°C 3–6 min.

78 NO2 R

K2CO3/TBAB

O

MW

O

CHO F3C

80

R

Y: -CH2 Y: -OY: -CH2Y: -OY: -CH2Y: -OY: -CH2Y: -O-

90% 92% 86% 88% 91% 89% 96% 95%

R = H, OMe, 4-C4H4-5, 5-C4H4-6

81

OH R

N

79 HOCH2CH2NO2

OH

R: H; R: H; R: CI; R: CI; R: Br; R: Br; R: OMe; R: OMe;

O

O O

L-proline/SiO2

O

R

O

82

OH CF3

R = H, OMe, OEt, CI, Br, NO2,

Figure 15. Chromeno[2,3-d]pyrimidine and 3-sustituted derivatives. MW: Microwave; TBAB: Tetrabutylammonium bromide.

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Review  Patil, Patil & Patil multifunctional FeNi 3 \SiO2 \HPG\PbS magnetic nanoparticles (MNPs) catalyst in a cost-effective manner. Most importantly, these catalysts can be easily separated with the help of external magnet because of FeNi 3 core. These catalysts can be reused several times without significant losses in performance. Authors successfully prepared 2-amino4H-chromenes utilizing newly generated magnetic nanoparticle catalysts under solvent-free conditions using microwave energy. Authors have discussed several limiting factors such as selection of proper solvents, additives, catalysts and so on, in developing a microwave method to obtain pure and better yielding products. They have highlighted the advantages of the microwave methods they developed to get the final products. However, scale-up is the most significant disadvantage of the microwave reactions of the chromenes developed using solvent or solvent-free reaction conditions even though microwave technology is improving to accommodate process-related problems. The progress of reliable methods for process development and manufacturing of new chemical is of great challenge in microwave-assisted organic synthesis. Future perspective Chromenes have shown potential application as anticancer, antimicrobial, anti-HIV, antitubercular and antioxidant agents. Recent advancement of crolibulin as antitumor agent has stimulated the significant interest in identification of novel chromenes as anticancer agents. Medicinal chemistry focused SAR yielded the dual acting (tubulin inhibition and vascular disruption) crolibulin as clinical candidate. Dual action makes the chromene pharmacophore very exciting. Crolibulin is in Phase II clinical screening for anaplastic thyroid cancer with the NCI. The future research on chromenes holds stimulating results espe-

cially in cancer because of the initial success with crolibulin. Based on crolibulin, compound 8 (SP-6–27), a tubulin inhibitor has been identified as a potent lead anticancer agent from screening. This lead agent showed potent growth inhibition against 60 cell lines in the NCI panel. This promising compound will be developed as possible anticancer agent in near future. The efficient microwave method has been developed to synthesize several biologically important chromene analogs. Thus, the use of microwave irradiation as a greener method for the production of large number of chromene analogs and this technology will help in the initial phases of drug discovery process to identify lead candidates. Future research in chromene area will be the development of environmentally benign, efficient and economical synthetic methods. Among several approaches multicomponent reactions are considered as one of the quickest and most important tool for producing complex chromenes. Researchers have embraced the concepts of microwave (high speed) synthesis to produce a biologically and chemically important chromenes in a time sensitive manner. In conclusion, the future research will be able to produce very efficient new greener methodologies such as catalyst- and solvent-free processes along with microwave heating to produce novel chromene analogs of biological and chemical importance. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Executive summary • Among several chromnene-based anticancer agents, compound 8 (SP-6–27) showed broad anticancer activity in vitro with IC50 range 7.4–640 nM. NCI 60 cell line screening results revealed that it has consistent antiproliferative activity against nine major cancer cell lines. • Two pyrrolidines (37e and 37l) have shown potency as close as a standard drug chloramphenicol against all three Gram-negative bacteria whereas pyrrolidine (37c) has shown better activity than reference drugs against Gram-positive Streptococcus pneumoniae bacteria. Pyrrolidine (37i) is very active against M. Tuberculosis H37RV bacteria and showed the growth inhibition of 98% which is comparable to standard. • The chiral chroman-4-one derivative (43a: 8-bromo-6-chloro-2-pentylchroman-4-one) is identified as potent inhibitor of SIRT2 enzyme. Biological activity revealed that enantiomer (−) 43a (IC50 : 1.5 μM) was more active than its other enantiomer (+) 43a (IC50 : 4.5 μM). • A natural insecticide methylenedioxyprecocene (48) was prepared by green chemistry method. Methylenedioxyprecocene has demonstrated antijuvenile hormone activity in some insects. • Several new greener methodologies such as catalyst- and solvent-free processes along with microwave heating to produce novel chromene analogs of biological and chemical importance have been reported.

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dimethoxyphenyl)-3-cyano-4H-chromenes, a novel series of anticancer agents. Mol. Cancer Ther. 3, 1375–1383 (2004).

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