Dihydropyrans, formation

McDonald et al. applied their dihydropyran formation to the oligosaccharide synthesis featuring reiterative alkynol cycloisomerization [19c-f]. Dihydropyran 49 was prepared by the method described above and then NIS-promoted glycosyla-tion with the acyclic alkynol 50 followed by Ph3SnH-promoted dehalogenation and... 

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... 

A different competitive reaction on the singlet 1,4-biradical level is observed for 2-acylcyclohex-2-enones 25, which on irradiation in the presence of 2,3-dimethylbut-2-ene afford both l-acylbicyclo[4.2.0]octan-2-ones 26 as well as 3,4,4a,5,6,7-hexahydro-8i7-isochromen-8-ones 27 (Sch. 9). These concurrent photochemical [4 + 2]-cycloadditions represent the first examples of dihydropyran formation from enones and alkenes to be reported in the literature [48]. 

Evidence for the two-step nature of the dihydropyran formation follows from the observation that both cis- and fraws-dibenzoylethene gave the same dihydropyran96, under conditions where cis-trans isomerism of the electrophilic alkene did not occur. On heating, the dihydropyrans rearrange into a mixture of the corresponding alkylated enamines (44 and 45) (Scheme 29). This is kinetically rather than thermodynamically controlled, since the equilibrium composition was obtained only after treatment with acid96, and can therefore be regarded as irreversible in an aprotic solvent (benzene) at 80°C. 

Scheme 11.59 Dihydropyran formation by intramolecular reaction of propargylic carbonate with alcohol.

Dihydropyrans, formation of 1039 Dihydroquercetin 872, 873 2,6-Dihydroxyacetophenones, isotopic perturbation in 339... 

Dihydropyran formation by a 6-endo-dig cyclization from 4-alkynols is achieved with (MeCN)2PdCl2 as catalyst, Pd(OAc)2 is much inferior for structurally complex substrates as that shown below. ... 

The 1.3-allylic diacetate 135 can be used for the formation of the methy-lenecyclopentane 137 with the dianionic compound 136(86]. The cyclohexa-none-2-carboxylate 138 itself undergoes a similar annulation with the 1,3-allylic diacetate 135 to form the methylenecyclohexane derivative 139(90]. The reaction was applied as a key step in the synthesis of huperzin A[91]. On the other hand. C- and 0-allylations of simple J-dikctones or. 1-keto esters take place, yielding a dihydropyran 140(92]. 

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. 

The hindered 11 )5-hydroxyl group fails to react with dihydropyran. However, mixed acetals [e.g., methoxymethyl ether (97)] and hemiacetals e.g., hydroxymethyl ether (98)] are obtained as by-products in the formation of the BMD group. ... 

Fig. 6 RCM-based formation and synthetic potential of dihydropyrans VIII and a-pyrones II...

Scheme 13 RCM-based formation of the advanced dihydropyran fragment 72 in the first total synthesis of cacospongionolide B (74) [60]...

Lewis acids can be used to initiate this cyclization. Cyclization to a tricyclic systems that included formation of a dihydropyran ring was reported using mercuric... 

In the case of terminal alkynes having oxygenated functions in the linear chain (Scheme 10, route D), Martin, Padron, and coworkers found that homopropargylic alcohols reacted properly, yielding 2-substituted dihydropyrans as sole products, probably via a Prins-type cyclization. This cyclization provides a new approach toward 2-alkyM-halo-5,6-dihydro-2//-pyrans through a concomitant C-C and C-O bond formation (Scheme 21) [35]. 

Further examples of the use of the hDA reaction in dihydropyran synthesis include the formation of the fused pyrans 18 from vinylallenes 17 and aldehydes (Scheme 8) <00TL6781> and a trans-fused dihydropyran containing a phosphonate group 19 . A total synthesis of the 11-oxa steroid system is based on an intramolecular Diels-Alder reaction involving an orthoquinodimethane derived from a benzocyclobutene (Scheme 9) <00TL1767>. 

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. 

Other carbohydrate syntheses include the formation of dihydropyrans from diethyl mesoxalate and 1-methoxybutadienes (e.g. equation ll)9. The butadiene 8, which is activated by the presence of two alkoxycarbonylamino groups, adds to diethyl mesoxalate in DMF during 44 h at 180 °C in an autoclave to give the cycloadduct 9 in 34% yield (equation 12)10. 

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... 

More recently, a catalyst-free aqueous version of this strategy was proposed with simple acyclic 1,3-dicarbonyls, formaldehyde, and styrene or anilines derivatives (Scheme 40) [131], In the first case (Scheme 40), the very reactive 2-methylene-1,3-dicarbonyl intermediate reacts smoothly at 80°C with a variety of substituted styrenes to give the corresponding dihydropyrans in moderate to good yields. Remarkably, when styrenes were replaced by A-ethylaniline, a novel five-component reaction involving twofold excess of both formaldehyde and 1,3-dicarbonyl selectively occurred (Scheme 41). The result is the formation of complex fused pyranoquinolines following a Friedel-Craft alkylation - dehydration sequence to furnish the quinoline nucleus, which suffers the Hetero-Diels-Alder cyclization in synthetically useful yields. 

This protective group is introduced by an acid-catalyzed addition of the alcohol to the vinyl ether moiety in dihydropyran. />-Toluenesulfonic acid or its pyridinium salt is used most frequently as the catalyst,3 although other catalysts are advantageous in special cases. The THP group can be removed by dilute aqueous acid. The chemistry involved in both the introduction and deprotection stages is the reversible acid-catalyzed formation and hydrolysis of an acetal (see Part A, Section 8.1). 

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