Chromanones reactions

The isoflavone 406 is prepared by the indirect a-phenylation of a ketone by reaction of phenylmercury(II) chloride with the enol acetate 405, prepared from 4-chromanone[371]. A simple synthesis of pterocarpin (409) has been achieved based on the oxypalladation of the oriho-mercurated phenol derivative 408 with the cyclic alkene 407[372,373]. 

R] (a) Hauser, C. R. Swamer, F. W. Adams, J. T. Org. React. 1954, 8, 59. [R] (b) Ellis, G. P., Chromenes, Chromanones, and Chromones from The Chemistry of Hetereocylic Compounds, Weissberger, A. and Taylor, E. C., eds John Wiley Sons, 1977, vol. 31, New York, p.495. Note The author in the former reference refers to the formation of chromones, coumarins, and flavones as the Kostanecki acylation while the latter author calls the formation of chromones and coumarins the Kostanecki-Robinson reaction. 

The 2,2-dialkylchromenes can easily be obtained from the reaction of coumarin 27 with a Grignard reagent.48 This method has been known for a long time and has not been modified much. The parent chromene 28 has been prepared by reduction and dehydration of 4-chromanone.63 Elimin-... 

A typical second step after the insertion of CO into aryl or alkenyl-Pd(II) compounds is the addition to alkenes [148]. However, allenes can also be used (as shown in the following examples) where a it-allyl-r 3-Pd-complex is formed as an intermediate which undergoes a nucleophilic substitution. Thus, Alper and coworkers [148], as well as Grigg and coworkers [149], described a Pd-catalyzed transformation of o-iodophenols and o-iodoanilines with allenes in the presence of CO. Reaction of 6/1-310 or 6/1-311 with 6/1-312 in the presence of Pd° under a CO atmosphere (1 atm) led to the chromanones 6/1-314 and quinolones 6/1-315, respectively, via the Jt-allyl-r 3-Pd-complex 6/1-313 (Scheme 6/1.82). The enones obtained can be transformed by a Michael addition with amines, followed by reduction to give y-amino alcohols. Quinolones and chromanones are of interest due to their pronounced biological activity as antibacterials [150], antifungals [151] and neurotrophic factors [152]. 

Palladium-catalyzed cyclization reactions with aryl halides have been used to synthesize pyrazole derivatives. V-Aryl-lV-(c>-bromobenzyl)hydrazines 26 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2W-indazoles 27 . Palladium-catalyzed cascade intermolecular queuing-cyclocondensation reaction of o-iodophenol (28) with dimethylallene and aryl hydrazines provided pyrazolyl chromanones 29 <00TL7129>. A novel one-pot synthesis of 3,5-disubstituted-2-pyrazolines 32 has been achieved with an unexpected coupling-isomerization sequence of haloarene 30, propargyl alcohol 31, and methylhydrazine <00ACIE1253>. 

The methanochromanone 71 is converted with high trans-selectivity into the furo[2,3-fc]chromanone 72 by reaction with symmetric ketones (Scheme 50) <00H(53)657>. 

Typical procedure for rearrangement with aryl tellurium group transfer (formation of 3-[(aryltelluro)methyl]chromanones)f In a 5 mL flask fitted with a reflux condenser the telluroester (0.1 mmol) was photolysed under argon in benzene (3 mL) with a 250 W GE sunlamp from a distance of 15 cm. Either no cooling bath was used and the heat from the lamp caused the solution to reflux or the reaction was maintained at 8°C by means of a circulating cold water bath. After completion (TEC control) the solvent was removed in vacuo and the residue analysed by NMR spectroscopy. 

Another problem for the synthetic use of PFR is that the ortho-rearranged products may act as internal light filters, stopping the reaction. In synthetic routes leading to chromanones, chromones, and related compounds, this is of vital importance because the overall yield is limited by the photochemical step. Improved yields can be obtained if the a, 3-unsamrated orr/io-hydroxyphenones resulting from PFR are removed and cyclized to chromanones. This can be acomplished in one pot by irradiation in a two-phase system benzene/10% aqueous NaOH, whereby chromanones are directly obtained from phenyl crotonates in 80-90% yields [210]. 

Almost 20 years after the initial report of the Stetter reaction, Ciganek reported an intramolecular variant of the Stetter reaction in 1995 with thiazolium precatalyst 74 providing chromanone 73 in 86% yield (Scheme 10) [64]. This intramolecular substrate 72 has become the benchmark for testing the efficiency of new catalysts. Enders and co-workers illnstrated the first asymmetric variant of the intramolecnlar Stetter reaction in 1996 utilizing chiral triazolinylidene pre-catalyst 14 [65]. Despite moderate selectivity, the implementation of a chiral triazolinylidene carbene in the Stetter reaction laid the fonndation for future work. 

These catalysts induce enantioselectivities in the resulting chromanones and derivatives 78 in up to 97% ee (Table 6). A variety of heteroatom linkers on the aldehyde tether are compatible under the reaction conditions allowing for the synthesis of a variety of desired products in high yields and enantioselectivities. 

In 2004 and 2005, respectively, Bach and Miller independently described the use of chiral thiazolium salts as pre-catalysts for the enantioselective intramolecular Stetter reaction. Bach and co-workers employed an axially chiral A-arylthiazolium salt 109 to obtain chromanone 73 in 75% yield and 50% ee (Scheme 16) [77]. Miller and co-workers found that thiazolium salts embedded in a peptide backbone 65 could impart modest enantioselectivity on the intramolecular Stetter reaction [78]. In 2006, Tomioka reported a C -symmetric imidazolinylidene 112 that is also effective in the aliphatic Stetter reaction, providing three examples in moderate enantioselectivities (Scheme 17) [79]. 

Chromanones,4 In the presence of this amine 4-mcthyl-6-hydroxy-2-pyrone (1) undergoes decarboxylative dimerization to form a coumarochromanone (2) in 42 yield. The pyrone group in 2 undergoes decarboxylative Diels Alder reactions (8, 32G 9, 175 176) with acetylenes to form 4-chromanoncs (3). 

Several authors cited previously (Section II,B,1) have found that, besides the direct cyclization of o-acyl-arylacetic acid derivatives, a suitable method of synthesizing the title compounds involves the reaction of iso-chromanones with amines. This reaction has been investigated in detail (73JHC317). 

A nitrochromone has three easily reducible functions and, for its reduction, conditions and reagents which have little or no effect on the carbonyl or the 2,3-double bond should be chosen. Nitrochromones are reduced by tin-hydrochloric acid, zinc-ammonium chloride, iron-acetic acid, iron-hydrochloric acid or sodium dithionite. It may be easier to control the severity of the conditions in catalytic hydrogenation. Scheme 29 shows that with proper choice of conditions (temperature, pressure, solvent, catalyst), it is often possible to optimize the yield of the desired product (527). Extending the reaction time from about 30 min to 2.5 h increased the yield of the chromanone (528) and none of the hydroxylamine (529) was then detected (70JCS(C)2230). 

A reaction which involves both ring atoms and substituent is of considerable interest because the substrate is of a naturally occurring class of compounds. 3-Arylidene-chromanones (585) or homoisoflavanones, when heated with nickel in xylene isomerize to the 3-benzylchromone (586) (74IJC281) a number of homoisoflavanones occur in the bulbs of Eucomis bicolor, for example, eucomin (585 R = OH, Ar = 4-MeOC6H4). The stereochemistry about the double bond of compound (585 R = MeO) is altered from (E) to (Z) by irradiation at 300-400 nm (8lFOR(40)l05>. 

The photochromic behaviour of the reduced xanthone (587) when irradiated has been studied. The yellow or orange colour thus produced is due to ring opening to the chromanone (588). This colour fades gradually as the reverse reaction proceeds (69JOC2407). 

The carbanion formed when chromanone is treated with a base such as sodium methoxide reacts with ethyl formate to give the 3-hydroxymethylene derivative (S95) and such compounds have been used as intermediates (72JHC1341,70IJC203). When treated with isopentyl nitrite, chromanones usually give the 3-isonitroso derivative but this reaction occasionally behaves anomalously without obvious reason. For example, 7-methoxychromanone is readily converted into its 3-isonitroso derivative (596), but with 7-hydroxychromanone the reaction fails <77HC(31)207). 

Tetrahydropyran-4-ones, for example diethyl 6-methyl-4-oxotetrahydropyran-3,3-dicar-boxylate (600), are brominated at C-3 (77JCS(Pl)l647). Chromanones are readily halogenated at C-3 (see above) when they are treated with phosphorus pentachloride, the reaction does not stop at monochlorination the carbonyl group is attacked and 3,4-dichloro-2//-chromene (601) is formed, an uncommon conversion of a chromanone into a chromene (79TL3901). Chroman yields 4- and 6-bromides when treated with NBS-benzoyl peroxide. 

The Schmidt reaction is conducted+in strong acid and the essential step is the attack by the nucleophilic hydrazoic acid, HN —N=N on the carbonyl group. Chromanone is converted into l,4-benzoxazepin-5-one (644) but a few chromanones give the l,5-benzoxazepin-4-one (645) while others produce both types of oxazepines <77HC(31)207). 

In essence, hydride ion reagents reduce chromanones to chromanols (81T2613), the reaction often being stereospecific (70JCS(C)1006). 

The reaction of chromanones with Grignard reagents also yields chromanols, though dehydration to the chromene may also occur (68T949). In contrast, the Clemmensen reduction of chromanones invariably yields chromans there are many examples (65JCS3882,71JMC758). 

The usual range of solvents associated with Friedel-Crafts reactions is available carbon disulfide and nitrobenzene have found frequent use. The choice of solvent may influence the extent of cyclization. Thus, in ether, 1,2,3,5-tetramethoxybenzene yielded the uncyclized product with 3,3-dimethylacryloyl chloride, whereas in a mixture of ether and tetrachloroethane the major product was the chromanone. This example is also of interest since ring closure could involve either the 2- or 6-methoxy group. In fact, the formation of the 5,6,7-trimethoxy isomer was not observed. The identity of the product was established by conventional 14C labelling (60BSB593). 

A closely related reaction involves that between a saturated acyl halide and a phenol or phenolic ether. A necessary feature of the acid chloride is that it contains a bromine atom at C-2 which allows formation of a double bond during the reaction by loss of bromide. Normal Friedel-Crafts conditions are employed in the first step which leads to an o-hydroxyphenyl 2-bromoalkyl ketone (589). In boiling diethylaniline, hydrogen bromide is lost and the resulting acrylophenone spontaneously cyclizes to the chromanone <24LA(439)132). 

A minor variant of this, method makes use of the reaction between an anisole and a 3-halogenopropanoyl chloride (14CB2585). These same 3-substituted acid chlorides react with phenols to give esters and a Fries rearrangement is now a prerequisite of chromanone formation (58JCS1190). 

If hydrogen fluoride is used as the catalyst, it is possible to use 3-halogenopropanoic acids in this route (68CB2494), whilst with boron trifluoride even 3-hydroxyalkanoic acids afford chromanones in a very fast reaction (63T77). 

The synthesis of some 2,2-spiroannelated chroman-4-ones from o-hydroxyacetophenone and a cycloalkanone in the presence of a secondary amine has been described (78S886). The reaction has also been used to prepare a range of chromanones bearing non-identical or... 

The reaction proceeds via an enamine, since the same product results when the preformed enamine is allowed to react with the acetophenone. An initial addition product (598) can be pictured which may eliminate pyrrolidine to give the enone (599) and hence the chromanone or which may undergo nucleophilic displacement of pyrrolidine by the phenolic moiety (Scheme 226). 

An unusual example involves the addition of a methylene group by the reaction with dimethylsulfoxonium methylide to give the fused cyclopropane (614) (68JCS(C)2302), whilst 2-styrylchromones behave as dienes and undergo cycloaddition to give fused chromanones <75ACH(84)319>. 

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