Dihydropyrane

Submitted by R. L. Sawyer and D. W. Andrds. Checked by Nathan L. Drake and Charles M. Eaker. 

The reaction is carried out in a heated tube similar to that described by Herbst and Manske (Org. Syn. 16, 47 Coll. Vol. 2, 1943, 389) except that the receiving chamber B (loc. cit., Fig. 2) does not have a side arm, and that a 10-cm. water-cooled condenser is attached to the exit end of the tube leading directly to the receiver. The tube is packed with activated alumina (Note 1) held in place at the ends by plugs of glass wool. 

The furnace is heated to 300-340° (Note 2), and 204 g. (195 cc., 2 moles) of tetrahydrofurfuryl alcohol (Note 3) is introduced from the dropping funnel at the rate of 50 cc. per hour. The product, collected in an Erlenmeyer flask which contains 30 g. of anhydrous potassium carbonate, consists of a light brown oil and a lower aqueous layer. When the reaction tube has drained, the lower aqueous layer is separated and discarded. The upper layer is fractionated through a short column, and a fraction boiling at 70-86° is collected. This consists of a mixture of water and dihydropyrane, most of which distils at 83-86°. The residue (25-35 g.) is mainly unchanged tetrahydrofurfuryl alcohol (Note 4). 

The water-dihydropyrane fraction separates into two layers. The lower aqueous layer is separated and discarded. -The upper layer, consisting of fairly pure dihydropyrane, is dried over 5-6 g. 

Several varieties of technical activated alumina were used. After three or four runs the catalyst becomes covered with a brown tar and the yield of dihydropyrane decreases. The catalyst may be regenerated by igniting it at red heat until the tar is burned off. The checkers used 8-14 mesh activated alumina from the Aluminum Ore Company of America. The catalyst was reactivated at 450° by drawing a slow stream of air through it until the tar was burned off. 

---

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. 

Cyano-17-(2 -tetrahydropyranyloxy)-androst-5-en-3j5-ol Acetate A solution of 10 g of 17-cyanoandrost-5-en-3j5,17-diol 3-acetate in 40 ml of 2,3-dihydropyran is treated at the boiling point with 0.2 ml of phosphorus oxychloride for 1.5 hr. The solution is then diluted with ether, washed with aqueous sodium carbonate, and then water, dried over sodium sulfate and distilled under reduced pressure. The oily residue is crystalhzed from petroleum ether to give 6.7 g of 17a-cyano-17j5-(2 -tetrahydropyranyloxy)-androst-5-en-3) -ol acetate mp 127-130° [a]o —92° (diox). The mother liquor when evaporated to dryness yields an oily residue of 7.1 g which resists crystallization attempts. Subsequent reactions (see below) indicate it to be 17jS-cyano-17a-(2 -tetrahydropyranyloxy)-androst-5-en-3jS-ol acetate. 

The 6-substituted 1,4-dioxocins can be used to prepare other 6-substituted derivatives by simple functional group transformations.4,8,9 Especially interesting is the synthesis of the 4/7-4-oxo-2,3-dihydropyran-2-yl-substituted derivative 16 from l,4-dioxocin-6-carbaldehyde (15) by a cyclocondcnsation with Danishefsky s diene.9 Dehydrogenation of 16 yields 2 which can be isomerized to the corresponding isomeric. sr/i-benzene dioxide 3 (X = 4/f-4-oxopyran-2-yl), which is identical with and proved the structure of the naturally occurring antibiotic LL-Z 1220.10... 

Thiopyrans 50a-c were also obtained from the corresponding 2-methoxy-2,3-dihydropyrans by treatment with a H2S-HC1-Ac20-Ac0H mixture (86KGS28). 

Kunitake, Yamaguchi and Aso149 studied the copolymerization of 2-furaldehyde with olefins and vinyl ethers using BF3 Et20 in methylene chloride or toluene at —78 °C. No copolymers were obtained with olefins, but p-tolyl vinyl ether or 2,3-dihydropyran gave polyethers. With the former co-monomer the values of the reactivity ratios were rx = 0.15 0.15 and r2 = 0.25 0.05 (Mj = 2-furaldehyde). 

Reactions of cyclopentyne with alkenes gives [2+2] cycloadduct with complete retention of stereochemistry (Scheme 24) [120], Laird and Gilbert observed the expected [2+2] cycloadduct along with the polycyclic adduct in the reaction of norbomyne with 2,3-dihydropyran (Scheme 24) [121], and located a cyclopropyl-carbene intermediate [122],... 

Complete diastereoselection is observed in the HDA reaction of Danishefsky s diene with o-substituted benzaldehyde chromium tricarbonyl complexes. Decomplexation is facile and good yields of 2-aryl-2,3-dihydropyran-4-ones result <96SL258>. Cis-2,3-disubstituted pyranones are accessible from the Lewis-acid catalysed HDA reaction between (triisopropylsilyloxy) dienes and aldehydes and dehydrogenation of the resulting dihydropyrans <96JOC7600>. 

Cis- and fro/w-stilbenes have been reported to add to 2,3-dihydropyran upon photolysis to yield adducts (44) and (45) as well as two stilbene dimers(88> ... 

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). 

A more useful way of reducing esters to ethers is a two-step procedure applied to the reduction of lactones to cyclic ethers. First the lactone is treated with diisobutylaluminum hydride in toluene at —78°, and the product - a lactol - is subjected to the action of triethylsilane and boron trifluoride etherate at —20° to —70°. y-Phenyl-y-butyrolactone was thus transformed to 2-phenyltetrahydrofuran in 75% yield, and 5-lactone of 3-methyl-5-phenyl-5-hydroxy-2-pentenoic acid to 4-methyl-2-phenyl-2,3-dihydropyran in 72% yield [1034]. 

Scheme 63 Three-component synthesis of 2,3-dihydropyran[2,3-c]pyrazoles...

Alternatively to the direct use of 1,3-dicarbonyls, pyrazol-2-ones, which constitute masked 1,3-dicarbonyls, have been involved in a microwave-assisted organocatalytic MCR with aromatic aldehydes and ethyl vinyl ether leading to 2,3-dihydropyran[2,3-c]pyrazoles (Scheme 63) [167]. 

Radi M, Bernardo V, Bechi B, Castagnolo D, Pagano M, Botta M (2009) Microwave-assisted organocatalytic multicomponent Knoevenagel/hetero Diels-Alder reaction for the synthesis of 2,3-dihydropyran 2,3-c pyrazoles. Tetrahedron Lett 50 6572-6575... 

Hydroxyphenyl)-5-methoxy-6-(3,3-dimethylallyl)-2",2"-dimethylchromene-(5",6" 8,7)-3-(propyl-2-one)-47T-l-benzo-2,3-dihydropyran-2,4-dione. 

Af,N -Dichlorodiiminosuccinonitrile (12) (Section III) reacts with styrene, -methylstyrene, and 2,3-dihydropyran to give the pyrazines 126 directly with loss of 2 mol hydrogen chloride (74JOC3373) (Scheme 43). 

Unsaturated tetrahydropyran derivatives have received only cursory attention in the literature as heterocyclic monomers. 2,3-Dihydropyran and several of its substituted derivatives apparently undergo cationic polymerization in a manner typical of vinyl ethers (72MI11103), while tetrahydropyranyl esters of methacrylic acid (123) are fairly typical free radically polymerizable monomers (Scheme 35) (74MI11105). The THP group was used in this study as a protecting group for the acid functionality, and it was found that deprotection of polymers (124) could be accomplished under extremely mild conditions. 

Additional evidence for a ring current in pyran-4-one is provided by the observation that the ring protons are deshielded by 1 p.p.m. compared to those in 2,3-dihydropyran-4-one. 

Dihydropyran reacts with hydroxyl (including phenolic) groups to form the 2-tetrahy-dropyranyl ether, which is alkali-stable but acid-labile and useful as a protecting group (B-81MI22300). 

Irradiation of reduced pyran-4-ones frequently gives dimeric products which sometimes revert to the monomer. 2,6-Dimethyl-2,3-dihydropyran-4-one (559) in water gives a 96% yield of a mixture of three dimers (560) in a reaction which is reversible (73CJC1267). 

Unsaturated esters containing an electron-withdrawing group in the 2-position react with electron-rich alkenes under mild conditions to give 6-alkoxy-2,3-dihydropyrans which are thermally unstable. 

Although Paul and Tohelitoheff1808 demonstrated in 1947 that 2,3-dihydropyran did not yield the desired epoxy ether with perbenzoic acid, Hurd and Edwards843 claimed in 1949 to have obtained Hus elusive subatanoe. More recently, however, Barker and oo-workers78 reported once again the failure of perbenzoic aoid to produce an epoxy ether from. 2,3-dihydropyran, and Wood and Fletcher confirmed this observation in the sugar Beries.lfi7s... 

The photochemical reaction of t-1 with the cyclic vinyl ether 2,3-dihydropyran was initially reported by Rosenberg and co-workers (103) to yield two isomeric cycloadducts 42 and 43. 

---