Dihydropyran, reaction with

H-pyran synthesis from, 3, 759 bis(trimethylsiloxy) in pyrrole synthesis, 4, 333 chromene synthesis from, 3, 750 cycloaddition reactions with isocyanates, azetidin-2-ones from, 7, 261 dihydropyran synthesis from, 3, 771 fuiyl... 

As chemists proceeded to synthesize more complicated stmctures, they developed more satisfactory protective groups and more effective methods for the formation and cleavage of protected compounds. At first a tetrahydropyranyl acetal was prepared, by an acid-catalyzed reaction with dihydropyran, to protect a hydroxyl group. The acetal is readily cleaved by mild acid hydrolysis, but formation of this acetal introduces a new stereogenic center. Formation of the 4-methoxytetrahy-dropyranyl ketal eliminates this problem. 

Tetrahydropyranyl ethers are prepared by reaction with 2,3-dihydropyran, and a catalyst such as hydrochloric acid, " phosphorous oxychloride or p-toluenesulfonic acid at room temperature. 3iS-Hydroxy-5-enes " also form pyranyl ethers by distillation of a solution of the steroid and dihy-dropyran in ether without a catalyst. 

Similar cycloaddition reactions were observed with methyl vinyl sulfone (48) and )3-nitrostyrene (48,51). Methyl vinyl ketone, on the other hand, is reported to give dihydropyrans as the initial products (50,52,53). Thus (16) on reaction with methyl vinyl ketone at room temperature for 12 hr gave a 60% yield of 2-dimethylamino-3,3,6-trimethyl-3,4-dihydro-2H-pyran (59). 

The [ 2 + 4]-cycloaddition reaction of aldehydes and ketones with 1,3-dienes is a well-established synthetic procedure for the preparation of dihydropyrans which are attractive substrates for the synthesis of carbohydrates and other natural products [2]. Carbonyl compounds are usually of limited reactivity in cycloaddition reactions with dienes, because only electron-deficient carbonyl groups, as in glyoxy-lates, chloral, ketomalonate, 1,2,3-triketones, and related compounds, react with dienes which have electron-donating groups. The use of Lewis acids as catalysts for cycloaddition reactions of carbonyl compounds has, however, led to a new era for this class of reactions in synthetic organic chemistry. In particular, the application of chiral Lewis acid catalysts has provided new opportunities for enantioselec-tive cycloadditions of carbonyl compounds. 

In contrast to alkoxycarbene complexes, most aminocarbene complexes appear too electron-rich to undergo photodriven reaction with olefins. By replacing aliphatic amino groups with the substantially less basic aryl amino groups, modest yields of cyclobutanones were achieved (Table 10) [63], (Table 11) [64]. Both reacted with dihydropyran to give modest yields of cyclobutanone. Thio-carbene complexes appeared to enjoy reactivity similar to that of alkoxycar-benes (Eq. 15) [59]. 

For those substrates more susceptible to nucleophilic attack (e.g., polyhalo alkenes and alkenes of the type C=C—Z), it is better to carry out the reaction in basic solution, where the attacking species is RO . The reactions with C=C—Z are of the Michael type, and OR goes to the side away from the Z. Since triple bonds are more susceptible to nucleophilic attack than double bonds, it might be expected that bases would catalyze addition to triple bonds particularly well. This is the case, and enol ethers and acetals can be produced by this reaction. Because enol ethers are more susceptible than triple bonds to electrophilic attack, the addition of alcohols to enol ethers can also be catalyzed by acids. " One utilization of this reaction involves the compound dihydropyran... 

Conjugate addition of azide ion to dihydropyran-2,5-diones affords the 3-amino derivative <96SL341>, whilst reaction with bisnucleophiles provides a route to piperazines, thiazines and diazepines <96JHC703>. 

Heterocycles Both non-aromatic unsaturated heterocycles and heteroaromatic compounds are able to play the role of ethene dipolarophiles in reactions with nitrile oxides. 1,3-Dipolar cycloadditions of various unsaturated oxygen heterocycles are well documented. Thus, 2-furonitrile oxide and its 5-substituted derivatives give isoxazoline adducts, for example, 90, with 2,3- and 2,5-dihydro-furan, 2,3-dihydropyran, l,3-dioxep-5-ene, its 2-methyl- and 2-phenyl-substituted derivatives, 5,6-bis(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-2-ene, and 1,4-epoxy-l,4-dihydronaphthalene. Regio- and endo-exo stereoselectivities have also been determined (259). 

Aside from alcohols, other oxygen nucleophiles have also participated in hydroalkoxylation reactions with alkynes. The most common of these are 1,3-dicarbonyl compounds, whose enol oxygens are readily available to add to alkynes. Cyclization reactions of this type have been carried out under Pd(0) catalysis with various aryl or vinyl iodides or triflates, often in the presence of CO, affording the corresponding furan derivatives (Equation (95)).337-340 A similar approach employing cyclic 1,3-diketones has also been reported to prepare THFs and dihydropyrans under Pd, Pt, or W catalysis.341 Simple l-alkyn-5-ones have also been isomerized to furans under the influence of Hg(OTf)2.342... 

A2EPIN-2 -ONE, 44, 41 Dihydropyran, purification of, 41, 77 reaction with dichlorocarbene, 41, 76 Dihydroresorcinol, 41,56 methylation of, 41, 56 reaction with ethanol to yield 3-ethoxy-2-cyclohexenone, 40, 41 Dihydroresorcinoi. monoethyl ether, 40,41... 

An outstandingly reactive diene is l-methoxy-3-(trimethylsilyloxy)-l,3-butadiene ( Danishefsky s diene ) 4, prepared by the action of trimethylsilyl chloride on the ketone 3 in the presence of zinc chloride/triethylamine (equation 7)6. The reaction of diethyl mesoxalate with Danishefsky s diene gives the dihydropyran 5 with the (trimethylsily-loxy)dienes 6 and 7, mixtures of dihydropyrans are obtained, in which the meta-isomers predominate (equations 8 and 9)7. 

The preparation of dibenzo-18-crown-6 polyether directly from catechol and bis(2-chloroethyl) ether has been reported previously. The present procedure is an improvement of this method. Although dibenzo-18-crown-6 polyether can be obtained in 80% yield from bis-[2-(o-hydroxyphenoxy)-ethyl] ether and bis(2-chloroethyl) ether, the former intermediate has to be synthesized by a method involving several steps. One of the hydroxyl groups of catechol must be protected against alkali by reaction with a molecule of dihydropyran or chloromethylm ethyl ether. Then the intermediate is treated with bis(2-chloroethyl) ether in the presence of alkali and, finally, converted into the desired intermediate by acid hydrolysis. The yield of bis[2-(o-hydroxyphenoxy)-ethyl] ether was less than 40% so that the overall yield of dibenzo-18-crown-6 polyether never approached 39-48%, the yield of the present direct method. 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

Tetraacetylethene yields dihydropyrans in hDA reactions with ethyl vinyl ether and cyclopentadiene, but 1,2-dimethylenecyclohexane affords both the hDA and normal Diels-Alder adducts, the latter presumably arising via ring opening of the former adduct to a zwitterionic intermediate (Scheme 2) <99EJ03343>. 

At low temperatures, the Zn enolate derived from dimethyl 3-methylpent-2-endioate 39 reacts with aldehydes in a one-pot aldolisation and cyclisation to yield the syn-dihydropyran-2-one 40. At the higher temperatures necessary to achieve reaction with a-aminoaldehydes, the anri-products predominate indicating thermodynamic control (Scheme 22) <99T7847>. An aldol condensation features in the asymmetric synthesis of phomalactone. The key step is the reaction of the enolate of the vinylogous urethane 41 with crotonaldehyde which occurs with 99% syn-diastereoselectivity and in 99% ee (Scheme 23) <99TL1257>. 

Pyranone 127 reacts with alkenes in the presence of cerium ammonium nitrate via a cyclization reaction that leads to the formation of furo[2,3-3]- and furo[3,2-f]-pyranones in moderate yields (Equation 60). This reaction can be extended to the synthesis of furoquinolinones <1999H(51)2881>. Dihydropyran 128, with either / -diketones or /3-keto esters, undergoes cycloaddition reactions promoted by ceric ammonium nitrate to generate furo[2,3-3]pyrans in good yields (Equation 61) <1996T12495>. 

Acetalation with Enol Ethers Under Kinetically Controlled Conditions. The first mention of the use of an enol ether to protect the hydroxyl group of an alcohol was developed by Paul [46], who introduced the reaction with dihydropyran to give tetrahydro-pyranyl ethers, which is still used 60 years later. In spite of some noticeable developments, such as the preparation of 2 3 -0-aIkylidene derivatives of nucleosides [33] the synthesis of 4,6-O-ethylidene-a-D-glucopyranoside with use of methylvinylether [47] the intra-... 

Recently, substantial progress in stereochemistry of the cycloaddition reaction has been reported [34], Cycloaddition between optically active oxadiene 13 and l-acetoxy-2-ethoxy-ethylene, promoted by dimethylaluminum chloride, leads to dihydropyran 14, with a very high endo-exo stereoselectivity (54 1) and in an almost quantitative yield (see Scheme 6). When trimethylsilyl triflate was used as the promoter in this reaction, the reverse endo-exo selectivity (1 5) has been noted. The dihydropyrans obtained served as substrates for the synthesis of (3-d- and 3-L-mannopyranosides [34]. 

In the presence of aluminum chloride, which presumably lowers the energy of the LUMO of the heterodiene by Lewis acid complexation, electron-rich alkenes give dihydropyrans on reaction with acyl cyanides at room temperature (82AG(E)859). Unsaturated esters further extend the range of diene components of value in these Diels-Alder reactions with inverse electron demand (82TL603). 

The high regiospecificity observed in these reactions corresponds to polarization of the methide as shown (281). This is particularly apparent in the reaction with vinyl ethers ethyl vinyl ether affords the 2-ethoxychroman in quantitative yield and dihydropyran gives the pyranopyran (282 Scheme 74) (70JOC3666). 

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