Tetrahydropyrans reactions

Solvent key THF, tetrahydrofuran THP, tetrahydropyran. Reactions at RT unless specified otherwise. 

Trifluoracetyl-3,4-dihydro-2//-pyran (109) reacts with nucleophiles at C(6) to give ring-opened products, NuCH=C(C0CF3)(CH2)30H. Some of the amino products (e.g. Nu = NEta) are unstable, and undergo intramolecular nucleophilic additions to give tetrahydropyrans. Reactions with Grignards, hydrazine, hydroxylamine, and triethyl phosphite are also reported. 

Alkoxyall l All l Peroxides. / /f-Butyl tetrahydropyran-2-yl peroxide [28627 6-5] (1), where R = tert — butyl, X = OR", R = H, R and R" = 1, 4 butanediyl, has been isolated. This is one of many examples of alkoxyalkyl alkyl peroxides which may be prepared by reaction of hydroperoxides with vinyl ethers (139) ... 

This synthesis came shortly after one by Prelog, Kohlberg, Cerkovnikov, Rezek and Piantanida (1937) based on a series of reactions which, with modifications and extensions. Prelog and his colleagues have applied to the syntheses of bridged heterocyclic nuclei, of which this is an example. 4-Hydroxymethyltetrahydropyran (VI R =. OH) is converted via the bromo-compound (VI R = Br) and the nitrile (VI R = CN) into tetrahydropyran-4-acetic acid of which the ethyl ester (VII) is reduced to 4-()3-hydroxyethyl)-tetrahydropyTan (VIII). This is converted by fuming hydrobromic acid into 3-(2-bromoethyl)-l 5-dibromopentane (IX) which with ammonia in methyl alcohol yields quinuclidine (V). 

The reactions of diazomethane with heterocycles containing a ketonic grouping in the ring do not differ, in principle, from those of alicyclic ketones (see footnotes 3 and 177) ring expansion and the formation of epoxides compete. In general, ring expansion is the more important reaction for example, tetrahydropyran-4-one (99) is converted to l-oxacycloheptan-4-one (100) (60%) and 4,4 -epoxy-4-methyltetrahydropyran (101) (23%). ... 

In order to overcome the special problems posed by brevetoxin B s tetrahydropyran systems, the decision was made to develop and test regio- and stereoselective ring closures employing two types of substrates hydroxy epoxides and hydroxy a,/ -unsaturated esters. The basic concepts of these reactions are shown in Schemes 1 and 2, respectively. 

The cyclization of the homologous epoxide 36 under acidic conditions was also investigated (Table 9.5) [110]. As would be expected, compound 36a reacted by a 6-exo cyclization to give tetrahydropyran 38a (Entry 1). The a, 3-unsaturated hydroxy epoxide 36b gave a 1 3.5 mixture of oxepane 37b and tetrahydropyran 38b (Entry 2). Subjection of 36c and 36d, which both contain more electron-rich 71-systems, to the reaction conditions resulted in preferential 7-endo cyclization to give 37c and 37d, thus confirming the powerful regiodirecting effect of the vinyl moiety (Entries 3 and 4). 

In order to improve the selectivities in these reactions, styrylepoxides 39 and 40 were prepared and subjected to acid-catalyzed cyclizations (Scheme 9.23) [113]. Both compounds, however, afforded almost identical mixtures of diastereomeric oxepanes 41 and 42 (83%, dr 21 79 and 66%, dr 20 80, respectively), while no tetrahydropyran 43 was formed. Clearly, the additional stabilization provided by... 

The outcomes of intramolecular cyclizations of hydroxy vinylepoxides in more complicated systems can be difficult to predict. In a study of the synthesis of the JKLM ring fragment of dguatoxin, epoxide 44 was prepared and subjected to acid-mediated cydization conditions (Scheme 9.24) [114]. Somewhat surprisingly, the expected oxepane 45 was not formed, but instead a mixture of tetrahydropyran 46 and tetrahydrofuran 47 was obtained, both compounds products of attack of the C6 and C5 benzyl ether oxygens, respectively, on the allylic oxirane position (C3). Repetition of the reaction with dimsylpotassium gave a low yield of the desired 45 along with considerable amounts of tetrahydropyran 48. 

As a strategy for the construction of cyclic ethers, the radical cyclization of jS-alkoxyacrylates was used for the preparation of czs-2,5-disubstituted tetrahy-drofurans and cis-2,6-disubstituted tetrahydropyrans. An example is given with S-alkoxymethacrylate 38 as precursor of the optically active benzyl ether of (+)-methyl nonactate, exclusively formed as the threo product (Reaction 44). ° ... 

Although the unsaturated nitrile oxides 124 can be prepared via the aldoxime route (see Scheme 8), the older procedure suffers from the disadvantage that a tenfold excess of allyl alcohol and two additional steps are required when compared to Scheme 15. Therefore, unsaturated nitro ether 123 that can be prepared by condensation of an aldehyde 120 and a nitro alkane followed by Michael addition of alcohol 122, was a useful precursor to nitrile oxide 124 [381. The nitrile oxide 124 spontaneously cyclized to ether 125. This procedure is particularly suitable for the synthesis of tetrahydrofurans (125a-h) and tetrahydropyrans (125i-k) possessing Ar substituents in 72-95% yield (Table 12). The seven-membered ether 1251 was obtained only in 30% yield on high dilution. The acetylenic nitro ether 126 underwent INOC reaction to provide the isoxazole 127. 

A disadvantage of the THP group is the fact that a new stereogenic center is produced at C(2) of the tetrahydropyran ring. This presents no difficulties if the alcohol is achiral, since a racemic mixture results. However, if the alcohol is chiral, the reaction gives a mixture of diastereomers, which may complicate purification and/or characterization. One way of avoiding this problem is to use methyl 2-propenyl ether in place of dihydropyran (abbreviated MOP, for methoxypropyl). No new chiral center... 

Positive halogen reagents can cyclize y- and 8-hydroxyalkenes to tetrahydro-furan and tetrahydropyran derivatives, respectively.85 Iodocyclization of homoal-lylic alcohols generates 3-iodotetrahydrofiirans when conducted in anhydrous acetonitrile.86 The reactions are stereospecific, with the /(-alcohols generating the irons and the Z-isomer the cis product. These are endo-5 cyclizations, which are preferred to exo-4 reactions. 

A tandem combination initiated by a Mukaiyama reaction generates an oxonium ion that cyclizes to give a tetrahydropyran rings.48... 

Recently, a new multicomponent condensation strategy for the stereocontrolled synthesis of polysubstituted tetrahydropyran derivatives was re-published by the Marko group, employing an ene reaction combined with an intramolecular Sakurai cyclization (IMSC) (Scheme 1.14) [14]. The initial step is an Et2AlCl-promoted ene reaction between allylsilane 1-50 and an aldehyde to afford the (Z)-homoallylic alcohol 1-51, with good control of the geometry of the double bond. Subsequent Lewis acid-media ted condensation of 1-51 with another equivalent of an aldehyde provided the polysubstituted exo-methylene tetrahydropyran 1-53 stereoselectively and... 

Scheme 1.14. Domino ene/Sakurai reaction for the synthesis of polysubstituted tetrahydropyrans.

Loh and coworkers used a combination of a carbonyl-ene and an oxenium-ene reaction for the synthesis of annulated tetrahydropyrans 1-61, using methylenecyclo-hexane 1-60 as substrates (Scheme 1.16) [15]. The most appropriate catalyst for this reaction with the aldehydes 1-59 turned out to be In(OTf)3, which furnished the desired products in good to excellent yields and high stereoselectivity [16]. 

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