Dihydropyrans cycloaddition

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... 

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 initial product formed when methyl vinyl ketone is mixed with an enamine [such as N,N-dimethylisobutenylamine (10)] is the dihydropyran (11) from a 1,4 cycloaddition (ll,20a,20b). The chemical reactions that the dihydropyran undergoes indicate that it is readily equilibrated with the cyclobutane isomer 12a and zwitterion 12 (11). Treatment of adduct 11 with phenyllithium gives cyclobutane 13, possibly via intermediate 12a (11). 

Dihydropyrans have been produced by the 1,3 cycloaddition of methyl vinyl ketone (77) or acrolein (29-J7) with enamines (see Section II.A.2). S-Lactones have been formed as a side product in the reaction of dimethyl ketene with enamines (77), and as the primary products in the reaction of excess ketene with enamines derived from ketones (75) (see Section II.A.4). 

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. 

This methodology has been used for the synthesis of the C3-C14 segment 24 of the antitumor agent laulimalide 23 (Scheme 4.22) [35]. The constrained chiral BOX ligand 21c in combination with Cu(OTf)2 afforded dihydropyrane 6f by a cycloaddition reaction in good yield and ee this was converted to the C3-C14 segment 24 via a Ferrier-type rearrangement in several steps. 

A chiral titanium(IV) complex has also been used by Wada et al. for the intermole-cular cycloaddition of ( )-2-oxo-l-phenylsulfonyl-3-alkenes 45 with enol ethers 46 using the TADDOL-TiX2 (X=C1, Br) complexes 48 as catalysts in an enantioselective reaction giving the dihydropyrans 47 as shown in Scheme 4.32 [47]. The reaction depends on the anion of the catalyst and the best yield and enantioselectivity were found for the TADDOL-TiBr2 up to 97% ee of the dihydropyrans 47 was obtained. 

Lewis-acid catalyzed inverse electron-demand Diels-Alder reactions between conjugated carbonyl compounds and simple alkenes and enolethers also allow dihydropyranes to be prepared. SnCU-Catalyzed cycloaddition of... 

As expected, other enol ethers work well in these procedures. For example, Jones and Selenski find that implementation of method F, which occurs by addition of MeMgBr to benzaldehyde 5 in the presence of dihydropyran (DHP) at 78 °C affords a 66% yield of the corresponding tricyclic ketal 59 with better than 50 1 endo diastereoselectivity (Fig. 4.31).27 On the contrary, Lindsey reports use of method H with the benzyl alcohol 35 and diethylketene acetal. The cycloaddition reaction occurs almost instantaneously upon deprotonation of the benzyl alcohol 35 by f-butyl-magnesium bromide in the presence of the ketene acetal and yields the corresponding benzopyran ortho ester 60 in a 67% yield.29... 

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). 

Cycloaddition of 5,6-dihydropyran-2-one with aromatic nitrile oxides leads to 3-aryl-3a,6,7,7a-tetrahydropyrano[3,4-d]isoxazol-4(47/)-ones 98. The latter react with nickel peroxide to give the corresponding dihydropyranoisoxazolones 99. Similar to 2-bromocyclohex-2-enone, 3-bromo-5,6-dihydropyran-2-one undergoes nitrile oxide cycloaddition, followed by dehydrobromination, to form regioi-someric 3-aryl-5,7-dihydropyrano 4,3-c/ isoxazol-7(4//)-ones 100 (Scheme 1.24) (242). 

Intramolecular [4 + 2]cycloaddition of an enaminelenal(enone). Generation in situ of an aldehyde enamine of a substrate also containing an enal or enone group can result in a facile intramolecular [4 + 2]cycloaddition resulting in bicyclic dihydropyrans. Although several sec-amines can be used, N-methylaniline is particularly suitable because of the stability of the adducts. 

In an attempt to further elucidate the mechanism of this process, these workers monitored the reaction between propiophenone enolsilane and fumaroylimide by in situ infrared (IR) spectroscopy, Scheme 25 (240). In the absence of alcoholic additives, the accumulation of an intermediate is observed prior to appearance of product. When i-PrOH is introduced, immediate decomposition of the intermediate occurs with concomitant formation of product. Evans suggests that the intermediate observed in this reaction is dihydropyran (374). Indeed, this reaction may be viewed as a hetero-Diels-Alder cycloaddition followed by alcohol induced decomposition to the desired Michael adduct. That 374 may be acting as a competent inhibitor was suggested by an observed rate reduction when this reaction was conducted in the presence of IV-methyloxazolidinone. 

Tricyclic lactone systems were synthesized by the analogous intramolecular [4+ 2]-reaction followed by hydration and oxidation of the resulting dihydropyran ring. This isomerization-cycloaddition sequence was successfully applied to the synthesis of (+)-platyphyllide [134]. 

Also propiogeninic type macrolide moieties should be accessible via this inverse type hetero-Diels-Alder methodology. This was recently exhibited starting from cis-propenylether as heterodienophile (Schmidt, R.R. Haag-Zeino, B. Hoch, M. Liebigs Ann. Chem., in press). In a highly endo-selective cycloaddition reaction and in subsequent diastereoselective transformations of the methyl substituted dihydropyran obtained a 2,4-dimethyl-... 

An interesting entry to functionalized dihydropyrans has been intensively studied by Tietze in the 1990s using a three-component domino-Knoevenagel Hetero-Diels-Alder sequence. The overall transformation involves the transient formation of an activated heterodienophile by condensation of simple aldehydes with 1,3-dicarbonyls such as barbituric acids [127], Meldrum s acid [128], or activated carbonyls. In situ cycloaddition with electron-rich alkenes furnished the expected functionalized dihydropyrans. Two recent examples concern the reactivity of 1,4-benzoquinones and pyrazolones as 1,3-dicarbonyl equivalents under microwave irradiation. In the first case, a new three-component catalyst-free efficient one-pot transformation was proposed for the synthesis of pyrano-1,4-benzoquinone scaffolds [129]. In this synthetic method, 2,5-dihydroxy-3-undecyl-1,4-benzoquinone, paraformaldehyde, and alkenes were suspended in ethanol and placed under microwave irradiations to lead regioselectively the corresponding pyrano-l,4-benzoquinone derivatives (Scheme 38). The total regioselectivity was... 

A third type of cycloaddition reaction has recently been reported.74 When 5,5,6-trimethyl-3,6-heptadien-2-one 58 was irradiated, two intramolecular cycloaddition products 59 and 60 were obtained, affording the first example of dihydropyran formation from this reaction. Although a reasonable mechanism, analogous to that leading to oxetane formation, has been proposed, it was recognized that 58 is a special type... 

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>. 

A dihydropyran may be an unstable intermediate and may be rapidly transformed to a pyran. Thus when 1-methoxy-1,3-butadiene underwent cycloaddition to ethyl pyruvate, a 45% yield of 2//-pyran 258b was isolated dihydro 257b195 was an intermediate. 

An attractive entry to the carbohydrate synthesis is provided by the cycloaddition reaction. Hetero-Diels-Alder reaction, either between an oxa-diene (a,[3-unsaturated aldehyde) and an nucleophilic dienophile, or between activated diene and carbonyl compound (usually an aldehyde), leads to dihydropyrans, which can be subsequently functionalized to sugars in the desired manner (Scheme 3). 

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]. 

By analogy with the formation of dihydropyrans from unsaturated carbonyl compounds and alkenes (see Section 2.24.2.7.l(i)), the synthesis of 4//-pyrans from the [4 + 23-cycloaddition of unsaturated carbonyl compounds and alkynes would seem to offer some potential. Such a reaction has indeed proved of value, but examples are largely restricted to the use of ynamines as the dienophile (76BSF987). 

Largely because of the widespread interest in cycloadditions, a number of syntheses of dihydropyrans have been developed involving the interaction of four and two atom fragments. Both variations on the [4 + 2] cycloaddition are successful either the diene or the dienophile may be the source of the heteroatom (Scheme 43). A review of heterodiene syntheses with unsaturated carbonyl compounds contains comprehensive lists of dihydropyrans (75CRV651). 

Cycloadditions involving the more nucleophilic vinyl ethers are easier than those above and the reaction has considerable synthetic potential. The reactants are heated at 180-190 °C in a sealed vessel and the adduct is rapidly formed in high yield (50JA3079, 51JA5267). Full experimental details have been published for the synthesis of 3,4-dihydro-2-methoxy-4-methyl-2/f-pyran from methyl vinyl ether, and the same technique was used to prepare a further 13 dihydropyrans (630SC(4)3il>. 

Dialkoxy-3,4-dihydropyrans are produced under mild conditions from the zinc chloride-catalyzed cycloaddition of a,/8-unsaturated carbonyl compounds with ketene acetals (Scheme 47) (81RTC13). At lower temperatures a [2 + 2]-cycloaddition leads to oxetanes, but on warming these compounds revert to starting materials and thence to the thermodynamically favoured dihydropyrans. 

The major features of the [4 + 2]-cycloaddition process have been discussed earlier under dihydropyrans (p. 770) and in this section examples of its application to chroman synthesis will be covered, together with relevant ancillary material. 

The reaction between vinyl ethers and unsaturated carbonyl compounds, which provides a powerful synthetic route to dihydropyrans, has been adapted to the synthesis of pyran-2-ones (72CC863). 2-Chloro-1,1 -dimethoxyethylene, which is a protected form of chloroketene, undergoes cycloaddition with a number of enones to give the cis or trans isomers of 3-chloro-3,4-dihydro-2,2-dimethoxypyrans (338) and (339) or a mixture of both. Although... 

Intramolecular photoaddition in cis-5,5,6-trimethylhepta-3,6-dien-2-one (284) takes a different course,296 yielding not the oxetane but the two dihydropyrans (285 and 286). This is in contrast to the inter-molecular cycloaddition of a, jS-unsaturated aldehydes to alkenes which affords only oxetanes, and has been accounted for in terms of diradical intermediates (287 and 288) formed from the s-cis conformation (284) of the dienone. The intermolecular equivalent is thought to occur by addition to the s-trans conformation. 

The [4 + 2] cycloaddition of a-phenylselenopropenoyl trimethylsilane (75) with 2,3-dimethylbuta-1,3-diene is unusual in that a significant portion of product mixture consists of the hetero-Diels-Alder dihydropyran adduct 76. The phenylselenenyl substituent appears to be responsible for this unusual pattern of reactivity, since propenoyl trimethylsilane gives only the expected regioisomer (77, X = H) (Scheme 116)14. a-Selenenyl substituted a,/l-unsaturated acyl silanes such as 75 were used to prepare a series of substituted dienes in excellent yields through the addition of a-sulphinyl carbanions, Brook rearrangement and expulsion of sulphinate, in a reaction pathway recognisably more typical of acyl silanes (Scheme 117). 

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