Benzopyranone

Many 1,2,3,5-benzenetetrol derivatives are used mediciaaHy. For example, khellin [82-02-0] (65), which is a naturally occurring benzopyranone, is used as a coronary vasodilator and bronchodilator (233). Derivatives of khellin are effective local anesthetics and antiarrythmics (234). Similarly, amine derivatives (68) that are prepared from khellinone oxime (66) exhibit hypnotic, sedative, anticonvulsant, antiinflammatory, cardiac analeptic, diuretic, and antiulcerous activity (235) (see Analgesics, antipyretics, and antiinflammatory agents). 

Benzo[g]pteridine, 2,4-diaminotetrahydro-synthesis, 3, 317 Benzopurines, 5, 567 Benzopyranones... 

In the realm of natural product synthesis, Kepler and Rehder utilized the K-R reaction to synthesize ( )-calanolide A (56), a potent non-nucleosidal human irmnunodeficiency virus (HIV-1) specific reverse transcriptase inhibitor. Propiophenone 57 was allowed to react with acetic anhydride in the presence of sodium acetate to afford benzopyranone 58 in 56% yield subsequent deacetylation of 58 gave 59. Flavone 59 was then transformed to ( ) calanolide A (56) over several steps. 

A new series of unfunctionalized (17) and functionalized (18) 3,4-dihydrocoumarins (Fig. 11.11) was synthesized. These new benzopyranones differ from the previous neutral dihydrocoumarins, which are suicide substrates of proteinases (Section 11.4, in that they have a carboxy substituent on their aromatic ring and a side chain phenylacetamido group at the 3-position of the heterocycle instead of a benzyl one in compound 3. 

In an alternative strategy functionalized phenols, such as iodophenol, were involved in palladium-catalyzed carbonylation of alkynes or allenes, producing coumarin or chromone derivatives (Scheme 23) [130-133]. After oxidative addition of the iodoarene to the Pd(0) catalyst the order of insertion of either CO or the unsaturated substrate mainly depends on the nature of the substrate. In fact, Alper et al. reported that CO insertion occurs prior to allene insertion leading to methylene- or vinyl-benzopyranone derivatives [130]. On the contrary, insertion of alkynes precedes insertion of CO, affording couma-rine derivatives, as reported by Larock et al. According to the authors, this unusual selectivity can be explained by the inability of the acyl palladium species to further react with the alkyne, hence the decarbonylation step occurs preferentially [131-133]. 

G. C. Selective benzopyranone and pyrimido[2,l-a]isoquinolin-4-one inhibitors of DNA-dependent protein kinase synthesis, structure-activity studies, and radiosensitization of a... 

The lack of information conveyed by total brain concentration is indicated by studies on KA-672 [6], a lipophilic benzopyranone acetylcholinestrase inhibitor. The compound achieved total brain concentrations of 0.39 iM at a dose of 1 mg kg" equivalent to the IC50 determined in vitro (0.36 juM). Doses up to 10 mg kg were without pharmacological effect. Analysis of CSF indicated concentrations of the compound were below 0.01 juM readily explaining the lack of activity. These low concentrations are presumably due to high (unbound) free drug clearance and resultant low concentrations of free drug in the plasma (and CSF). 

She and co-workers took advantage of the acyl anion equivalent formed from the addition of an NHC to an aldehyde to catalyze the formation of benzopyranones via an intramolecular S 2 displacement (Scheme 50) [167], Various aromatic aldehydes provide alkylation products in moderate yields when the leaving group is either tosylate or iodide. No reaction was observed when phenyl or methyl was placed alpha to the leaving group. 

In addition to the preceding chemotypes, thiazoles, quinolin-2-ones and cycloalkanothieno-pyrimido-thiazoles [79], azolepyrimidines derivatives, trisubstituted pyrimidines, benzo[fc]thiophenecarboxamides and benzofu-rancarboxamides [80-83], and substituted benzopyranones have also been claimed in different patents as PI3K inhibitors [1]. 

There are numerous examples of benzopyrylium salts, benzopyransand benzopyranones, and frequently they have trivial names that reflect their long history (see Box 5.1). Many are natural products, and frequently these compounds contain hydroxy or alkoxy groups (sometimes in the form of a sugar residue). Polyhydroxylated natural products based upon 2-phenylbenzopyrylium (flavylium) salts and with ether linkages to sugars are called anthocyanins, whereas without their sugars they are known as anthocyanidins. 

The unstable dibenz[c,/][l,2]oxazepines (312 R = CN, Cl) have been isolated as the major products of the UV irradiation of 9-cyano- and 9-chloro-acridine 10-oxides (310) in benzene (c/. the analogous Af-imide to 1,2-diazepine conversion on p. 598). Although none of the oxaziridine tautomer (311) was detectable by UV spectroscopy, the subsequent deoxygenation of (312) to acridine suggests the existence of a thermal equilibrium between (311) and (312) (79T1273). These dibenzo compounds (312) are the only fully unsaturated oxazepines yet isolated but the 2,3-benzoxazepin-l-one system (314) has recently been prepared by the reaction of benzonitrile oxide with the benzopyranone (313) (80JCS(Pl)846). 

Bromobenzyl alcohol and its derivatives were converted to phthalides by the palladium catalysed insertion of carbon monoxide and intramolecular quenching of the formed acylpalladium complex. 2-Hydroxymethyl-1-bromonaphthaline, for example, gave the tricyclic product in excellent yield (3.34.). An interesting feature of the process is the use of molybdenum hexacarbonyl as carbon monoxide source. The reaction was also extended to isoindolones, phthalimides and dihydro-benzopyranones 42... 

Regioselective alcoholysis of polyacylated steroids catalyzed by Candida rugosa lipase suspended in acetonitrile or di-isopropyl ether in the presence of octanol has also been reported [88]. Similarly, the alcoholysis of peracetylated chalcones, acetophenones, and benzopyranones has been reported [89]. 

The 2,3-benzoxazepin-l-one system (436) is prepared by the reaction of benzonitrile oxide with the benzopyranone (435) (80JCS(P1)846). The tetrahydro-3,2-benzothiazepine 3,3-dioxide (438) was prepared from (437) by intramolecular sulfonamidomethylation (76CC470). 

The benzofuro[2,3-h][l]benzopyranone system has been found in natural sources as lisetin (244) (66T(S7)333,79H(12)1539,79BCJ529). Benzofuro[2,3-c][l]benzopyran-6-ones (e.g. 245) have also been prepared (80IJC(B)129). 

Table 14 Topological Resonance Energies (TRE) for some Benzopyranones (82JHC625)...

Two disadvantages are associated with this synthesis. Yields range from low to moderate and, of more significance, cyclization of the initially formed ester can give rise to chromones or coumarins or to mixtures of the two heterocycles. With the wide range of analytical techniques now available, it is not difficult to distinguish the isomeric benzopyranones. However, some of the structural assignments in early work have been shown to be erroneous and care is therefore advised in the interpretation of results. 

Tautomerism in the benzopyranone 72 has been studied computationally, and tautomer 72 is calculated to be 1.4kcalmol 1 more stable than 73 <1994JCS(P2)2587>. 3-Acetyl-4-hydroxycoumarin has been studied using UV spectroscopy and by computational methods < 1997CJC365, 2000JR0793>. Tautomer 74 is favored in nonpolar solvents such as CCI4 or hexane. In polar solvents, 75 is favored. Computational studies at both semi-empirical and ab initio levels predict 74 and 75 to be of comparable stability, and significantly more stable than all other possible tautomers. 

Benzopyranone phthalide 821 reacts with enones to afford xanthones in excellent yield (Equation 338, Table 33) <2003OL3753>. 

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