1-Benzopyrans, 2.3-fused

A neat stereoselective synthesis of trans-fused tetrahydropyrano[3,2-c][l]benzopyrans involves treating salicylaldehydes with alk-4-en-l-ols and triethyl orthoformate. The selectivity is attributed to steric repulsion in the endo transition state, the precursor of the cw-fused compound <96CL889>. 

Both inter- and intra- molecular Diels-Alder reactions of 2-benzopyran-3-ones occur with high endo-selectivity and have been used to synthesise (-)-podophyllotoxin (14) and 4a-substituted cis-BC fused hexahydrophenenthrenes (15), respectively <96JCS(P1)151, 96JCS(P1)705>. 

The ancient Egyptians used the plantAmmi majus, which contains methoxsalen (sometimes called 8-methoxypsoralen, based on a now obsolete method of naming fused heterocycles indexed in Chemical Abstracts under furo[3,2-g][l]benzopyran-7-one, 9-methoxy-, 249), in combination with sunbathing to... 

Flavonoids are natural phenolic systems containing pyrylium and pyrone rings, and provide the most prominent examples. We have met some of these systems under antioxidants (see Box 9.2). Coumarins contain a 2-pyrone system. Note that all of these compounds are fused to a benzene ring and are strictly benzopyran or benzopyrylium systems. 

There are a number of examples of the synthesis of chromans using o-quinone methides as the heterodiene in a hDA reaction. Both pyrano[3 -c]-benzopyrans and cyclopenta[c][l]benzopyrans result from an intramolecular cycloaddition of a substituted o-quinonemethide generated under mild conditions. In the former case, salicylaldehyde and an unsaturated alcohol yield the rra/is-fused tetrahydropyranobenzopyran (Scheme 10) <99JOC9507>. However, the latter synthesis (Scheme 11) is less selective <99BCJ73>. 

Pyrano-fused heterocycles, namely pyrano[3,2-f]quinoline-2,5(6//)-diones, pyrano[3,2-f]benzopyran-2,5(6//)-dione, and pyrano[3,2-f]pyridine-2,5(67T)-diones, have been efficiently prepared by the condensation of 4-hydroxy-2-(l//)-quinolines, 4-hydroxycoumarin, or 4-hydroxy-(17/)-pyridone with a-acetyl-y-butyrolactone or the sodium salt of a-formyl-y-butyro-lactone in the presence of ammonium acetate <1999JHC467>. 

Amino acid-modified furocoumarins were prepared by condensation of the T-hydroxysuccinimide ester of 3-(2,3,5-trimethyl-7-oxofuro[3,2-g]chromen-6-yl)propanoic acid 51 with amino acids <2003JPH177>. Ethyl 3-(7-hydroxy-4-methyl-2-oxo-2/7-3-chromenyl)propanoate 49, prepared in 56% yield by Pechmann condensation of resorcinol and diethyl 2-acetylglutarate in the presence of HCl, was condensed with 3-chlorobutan-2-one in the presence of base to give propanoate 50 (Scheme 4). The MacLeod method was then used to fuse a furan ring to the benzopyran-2-one system. Heating 50 with NaOH solution (1 M) readily cyclized it into the corresponding psoralen furocoumarin 51 with simultaneous hydrolysis of the ester. 

We also discovered the ability of 2-azadienes of this sort to cycloadd to unactivated carbon—carbon double and triple bonds in an intramolecular fashion (89CC267) (Scheme 50) such a process appears to be one of the first examples of intramolecular [4 + 2] cycloadditions of simple 2-azadienes. Azadiene 216 was made from O-allyl salicylaldehyde 215 (R = allyl) and heated at 120°C in toluene to furnish the trans-fused tricyclic adduct 217 in excellent yield further dehydrogenation of 217 with DDQ afforded 5H-[ 1 ]-benzopyran[4,3-6]pyridine 218. On the other hand, when 0-(2-butynyl) salicylaldehyde 215 (R = 2-butynyl) was transformed into azadiene 219 and subjected to heating in a sealed tube at 150°C, pyridine 222 was isolated in very high yield. Its formation can be rationalized to occur via the expected Diels-Alder intermediate 220 thus, [1,5]-H shift in 220 would give rise to tautomer 221, which would suffer electro-cyclic ring-opening and aromatization to pyridine derivative 222. 

The Reformatsky reaction has been applied to the synthesis of fused pyranones and provides an example of selective isomer formation by careful choice of substrate. Hydroxy-methylenecyclohexanone (315) and methyl bromoacetate give 5,6,7,8-tetrahydro-l-benzopyran-2-one (316) through alkylation at the hydroxymethylene carbon atom (54JA6388). However, the benzoyl derivative (317) is unable to form an enolate salt and alkylation occurs at the carbonyl carbon atom, leading to 5,6,7,8-tetrahydro-2-benzopyran-3-one (318) (45HCA771). 

Table 2 does the same for the benzo fused thiins, and again 1H-1- and 2H-2-benzothiopyrans and 10H-thioxanthenes have no counterpart in the benzopyran field. As has been remarked, the picture is further complicated by the variable valency of sulfur which permits the functionalization of the heteroatom of most of the ring systems. Thus,... 

The use of isopropylidine acetals (112) as tethers in the intramolecular Diels-Alder reactions of dienes with alkenes facilitates the formation of civ-fused cycloadducts (113) from an endo transition state (Scheme 41).218 The intramolecular Diels-Alder reaction of 4-[tris-(2-mcthylcthyl)silyl]oxy-2//-thiopyran derivatives with potential dienophiles tethered at C(2), C(3), C(5), and C(6) positions yielded cycloadducts when the dienophiles were activated with a carbomethoxy group.219 By the substitution of a phenylsulfonyl group on the dienophile of 2-benzopyran-3-ones, it is possible to enhance exo addition during intramolecular Diels-Alder cyclizations to yield a predominance of trans-fused hexaphenanthrenes related to natural products.220 The intramolecular Diels-Alder reaction of 2-furfuryl fumarates has been investigated by molecular mechanics (SIBFA)/continuum reaction field computations.221 The intramolecular 4 + 2-photo-cycloaddition of A-benzylcinnamamides (114) in the presence of C(,H6 gives 3-azatricyclo[5.2.2.01,5]undeca-8,10-dien-4-ones (115) with high stereoselectivity (Scheme 42).222... 

Dihydropyridines fused with benzopyrane (415) or with quiniline (416) moieties are obtained from the corresponding 4-(or 6>-hyroxyaryl)-substituted... 

Triazolopyrimidines fused with the benzopyrane ring 419 (usually as mixtures of diastereomers) can be obtained by cyclization of 5-(2-hydroxyaryl)-substituted dihydroazolopyrimidines 417, with aldehydes 418, or by direct condensation of 3-amino-1,2,4-triazole 147 with ort/zo-hydroxyacetophenone 421 and 2 mole of the corresponding aldehyde [409, 410] (Scheme 3.133). In the latter case, the... 

Triflates of transition metals catalyse the reaction between alkenes, salicylaldehydes and trimethyl orthoformate (TMOF) that is particularly useful for the synthesis of fused chromans. Generation of an o-quinone methide and its capture by the alkene is the key feature. The examples in Scheme 4 are illustrative. Tran.v-fused pyrano[3,2-c]benzopyrans... 

When the annellated heteroaromatic group is a five-member ring (43, 44), the properties are best described as intermediate between a naphtho and benzopyran. The standard method of synthesis for diaryl naphthopyrans (acid-catalyzed condensation between a diaryl propargyl alcohol and a naphthol, Scheme 8) is reported not to work for heteroaromatic fused phenols. This is true especially in cases where the heteroaromatic phenol contains a (basic) nitrogen. Alternatively, these pyrans can be prepared by the method of Casiraghi69 outlined in Scheme 16. 

Benzopyrans annelated with 2,3-fused heterocycle 87H(26)1623. Flavonoids, advances since 1980 88MI51. 

The aim of this review is to survey the advances in the chemistry of chrom-3-enes (2//-l-benzopyrans, chrom-/l -enes, a-chromenes) in the last decade. This subject was previously summarized by Wawzonek in 1951. A brief but clear treatment of chrom-3-ene chemistry can be found in Dean s book (1963), where a detailed account is given of all the natural products known at that time. A section of a recent book on the synthesis of natural compounds has been dedicated to chromenes. The present review will not deal with chrom-2-enes, nor with benzo-pyrylium salts, nor with ring-fused pyrano-heterocycles. The reader... 

The Heck reaction is applicable to the synthesis of benzo-fused heterocycles including indolines, 1,2-dihydroquinolines, and benzopyrans. Influence of reaction conditions on diastereoselectivity is witnessed in the cyclization leading to geissoschizol and its isomer. Reaction of 2-cyanothiophene with aryl halides introduces the aryl group to the 5-position."... 

An unexpected product is formed when a chromone-3-nitrile is heated with malonamide and piperidine. 1-Benzopyrans to which a heterocycle is fused at the 2,3-positions have been reviewed [3343, 3346]. 

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