Pyrans, dihydro cycloaddition reactions

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). 

A simple approach for the formation of 2-substituted 3,4-dihydro-2H-pyrans, which are useful precursors for natural products such as optically active carbohydrates, is the catalytic enantioselective cycloaddition reaction of a,/ -unsaturated carbonyl compounds with electron-rich alkenes. This is an inverse electron-demand cycloaddition reaction which is controlled by a dominant interaction between the LUMO of the 1-oxa-1,3-butadiene and the HOMO of the alkene (Scheme 4.2, right). This is usually a concerted non-synchronous reaction with retention of the configuration of the die-nophile and results in normally high regioselectivity, which in the presence of Lewis acids is improved and, furthermore, also increases the reaction rate. 

More recently, further developments have shown that the reaction outlined in Scheme 4.33 can also proceed for other alkenes, such as silyl-enol ethers of acetophenone [48 b], which gives the endo diastereomer in up to 99% ee. It was also shown that / -ethyl-/ -methyl-substituted acyl phosphonate also can undergo a dia-stereo- and enantioselective cycloaddition reaction with ethyl vinyl ether catalyzed by the chiral Ph-BOX-copper(ll) catalyst. The preparative use of the cycloaddition reaction was demonstrated by performing reactions on the gram scale and showing that no special measures are required for the reaction and that the dihydro-pyrans can be obtained in high yield and with very high diastereo- and enantioselective excess. 

Inverse electron-demand Diels-Alder reaction of (E)-2-oxo-l-phenylsulfo-nyl-3-alkenes 81 with enolethers, catalyzed by a chiral titanium-based catalyst, afforded substituted dihydro pyranes (Equation 3.27) in excellent yields and with moderate to high levels of enantioselection [81]. The enantioselectivity is dependent on the bulkiness of the Ri group of the dienophile, and the best result was obtained when Ri was an isopropyl group. Better reaction yields and enantioselectivity [82, 83] were attained in the synthesis of substituted chiral pyranes by cycloaddition of heterodienes 82 with cyclic and acyclic enolethers, catalyzed by C2-symmetric chiral Cu(II) complexes 83 (Scheme 3.16). 

Cycloaddition reactions of electron-rich allenes with some heterodienes take place at the C1-C2 bond of the allene to yield heterocycles, a,Unsaturated carbonyl compounds 185 react with the internal C=C bond of ethoxyallene to afford dihydro-pyrans in moderate yields [150]. 

A peroxy acid mediated oxidative rearrangement of 2-alkoxy-3,4-dihydro-2//- pyrans affords 5-alkoxytetrahydrofuran-2-carbaldehydes (79JCS(Pi)847>. This reaction pathway was used in developing a method for the synthesis of optically active monoalkylfurans. (S)-2-Ethoxy-5-s-butyl-3,4-dihydro-2//-pyran (319), obtained through a cycloaddition reaction of (S)-2-s-butylacrolein to ethyl vinyl ether, was converted to (S)-2-s-butyl-5-ethoxytetrahydrofuran-2-carbaldehyde (320) (Scheme 85). 

Z)-(3-Silyloxyacrylonitriles 95 undergo cycloaddition reactions with a,P-unsaturated ketones to form a dihydro-pyran intermediate, which eliminates trimethylsilanol to furnish 3-cyano-4//-pyrans (Scheme 31) <1997S628>. 

Since the disclosures that the thermal dimerizations of acrolein and methyl vinyl ketone provide the 3,4-dihydro-2//-pyrans (1, 2) derived from 4ir and 2Tt participation of the a,3-unsaturated carbonyl compound in a Diels-Alder reaction, an extensive series of related observations have been detailed. This work has been the subject of several comprehensive reviews - - including the Desimoni and Tacco-ni extensive tabular compilation of work through 1974. Consequently, the prior reviews should be consulted for thorough treatments of the mechanism, scope, and applications of the [4 + 2] cycloaddition reactions of a,3-unsaturated carbonyl compounds. The [4 + 2] cycloaddition reactions of 1-oxa-1,3-butadienes with their 4-it participation in the Diels-Alder reaction exhibit predictable regioselectivity with the preferential or exclusive formation of 2-substituted 3,4-dihydro-2W-pyrans (equation 1). The exceptions to the predicted regioselectivity that have been observed involve the poorly matched [4 + 2] cycloaddition reaction of an electron-deficient l-oxa-l,3-butadiene with an electron-deficient dienophile, e.g. methyl crotonate or methacrolein. - Rigorous or simplified theoretical treatments of the [4 + 2] cycloaddition reaction of 1-oxa-1,3-butadienes predict the preferential formation of 2-substituted 3,4-dihy-dro-2f/-pyrans and accommodate the preferred endo approach of the reactants in which the carbon-carbon bond formation is more advanced than carbon-oxygen bond formation, i.e. a concerted but nonsynchronous [4 + 2] cycloaddition reaction. ... 

Diethyl 2-oxo-3-alkenylphosphonates, which are readily accessible from diethyl 2-oxopropylphos-phonate, are useful heterodienes in Diels-Alder reactions. Cycloaddition reactions with vinyl ethers in ( I I in a sealed tube at 85-130°C give satisfactory yields (57-88%) of dihydro-27/-pyrans. The products are isolated as a mixture of 2,4-tra .v and 2,4-czT isomers. When treated with 4 M HCl in THF, the dehydropyran hemiacetal moiety is readily hydrolyzed to provide diethyl 5-formyl-2-oxopentylphosphonates in excellent yields (72-92%, Scheme 5.59). When R> = R =H, the aldehyde undergoes smooth cyclization leading to diethyl 2-oxocyclohexenephosphonate. ... 

Since the thermal dimerizations of acrolein and methyl vinyl ketone were shown to provide the 3,4-dihydro-2//-pyrans l,12 an extensive range of related observations have been disclosed. This work has been the subject of several reviews.3 14 Only the work reported since the extensive Desimoni and Tacconi account5 of the Diels-Alder reaction of a,/3-unsatu-rated carbonyl compounds, 1-oxabutadienes bearing an oxygen atom at the diene terminus, has been detailed herein. The prior reviews should be consulted for an excellent discussion of the mechanism, scope, and application of the [4 + 2] cycloaddition reactions of a,/3-unsaturated carbonyl compounds as well as for extensive tabular compilations of the work through 1974.3-6... 

Annulation of heterocycles with a cyclobutene ring has been achieved by photochemical (2 + 2)-cycloaddition with acetylenes. Both maleic anhydride and N-substituted maleimides yielded 3-oxa- or 3-aza-bicyclo[3.2.0l-hept-6-ene-2,4-diones (167).,89,9° Vinylene carbonates also entered into a cycloaddition reaction with acetylenes to afford 168, which has been employed as starting material for the synthesis of cyclo-butadiene(tricarbonyl)iron or cyclobutenedione.19,-193 3,4-Dihydro-2/f-pyran and 5-methyl-2,3-dihydrofuran reacted with diphenylacetylene to... 

ExceUent yields, diastereo- and enantioselectivities are achieved in the synthesis of 3,4-dihydro-2J/-pyran-2-ones through asymmetric cycloaddition reactions of disubstituted ketenes with p,y-unsaturated a-keto esters carried out in the presence of a chiral Lewis acid (Scheme 44) (140L134). 

It is also worthwhile comparing the intramolecular photochemical cycloaddition reactions of ethylenic aldehydes and ketones with free radical intramolecular additions. For instance, irradiation of 5-hexen-2-one (470) (Scheme 161) in the gas phase gives the oxetane 471 as only cyclized product, as expected from the known photochemical intermolecular reaction between olefins and ketones. If the irradiation is conducted in solution 470 gives 471 (26%) and 472 (18%). With other y,< -unsaturated ketones, the bicyclic compound analogous to 472 may become the major product. With 2-allylcyclanones such as 473 (Scheme 161) bicyclic compounds are obtained (80% yield) as a mixture of 474 and 475, with 475 being the major product, but such compounds are difficult to isolate. " In the same manner, selective irradiation of the carbonyl group of 2-acyl-2,3-dihydro-4/f-pyrans (476) leads exclusively (23% yield) to exo-brevicomin (477) (a sex attractant), neither oxetane formation nor Norrish type II reaction being observed. The formation of the compounds 472, 475, and 477 which was considered as unexpected... 

Similarly, 3-nitrocoumarin (9) behaves as An component in the cycloaddition reactions with electron-rich dienophiles such as ethyl vinyl ether (61), 2,3-dihydrofuran, and 3,4-dihydro-2H-pyran. Under solvent-free conditions and in organic solvent (DCM, CH3COCH3, PhH), the reactions are totally regio- and endo-stereoselective. For example, the cycloaddition of 9 with 61 gives only the adduct 67 with 90% yield (Scheme 5.18). 

The preparation of 5-ACETYL-l,2,3,4,5-PENTAMETHYLCYCLO-PENTADIENE is of value in the synthesis of pentamethyleyclo-pentadiene and many pentamethylcyclopentadienyl metal carbonyl derivatives that are more soluble in organic solvents than those derived from cyclopentadiene. Simple preparations of 5,6-DIHYDRO-2-PYRAN-2-0NE and 2-//-PYRAN-2-ONE make these hitherto rather inaccessible intermediates available for cycloaddition and other reactions. The already broad scope of the Michael reaction has been widened further by including an efficient preparation of ETHYL (E)-3-NITROACRYLATE. Workers in the field of heterocyclic chemistry will find a simplified method for the preparation of 2,3,4,5-TETRA-HYDROPYRIDINE of help. 

More functionalized 5,6-dihydro-2H-pyran-derivatives 71 and 72 have been prepared [26] by cycloaddition of 1 -methoxy-3-trialkylsilyloxy-1,3-butadienes 69 with t-butylglyoxylate (70) (Scheme 5.6). Whereas thermal reactions did not occur in good yields because of the decomposition of the cycloadducts, application of pressure (10 kbar) allowed milder conditions to be used, which markedly improved the reaction yields. The use of high pressure also gives preferentially en Jo-adduct allowing a stereocontrolled synthesis of a variety of substituted 5,6-dihydro-2H-pyran-derivatives, which are difficult to prepare by other procedures. 

Dihydro-2H-pyran-2-ones (e. g., 4-195) are valuable intermediates in the synthesis of several natural products [67]. Hattori, Miyano and coworkers [68] have recently shown that these compounds can be easily obtained in high yield by a Pd2+-catalyzed [2+2] cycloaddition of ct, 3-unsaturated aldehydes 4-192 with ketene 4-193, followed by an allylic rearrangement of the intermediate 4-194 (Scheme 4.42). In this reaction the Pd2+-compound acts as a mild Lewis acid. a,(3-unsaturated ketones can also be used, but the yields are below 20%. 

Examples of the use of heterodienophiles under the action of microwave irradiation are not common. Soufiaoui [84] and Garrigues [37] used carbonyl compounds as die-nophiles. The first example employed solvent-free conditions the second is an example of the use of graphite as a susceptor. Cycloaddition of a carbonyl compound provided a 5,6-dihydro-2H-pyran derivative. These types of reaction proceed poorly with aliphatic and aromatic aldehydes and ketones unless highly reactive dienes and/or Lewis acid catalysts are used. Reaction of 2,3-dimethyl-l,3-butadiene (31) with ethyl glyoxylate (112) occurred in 75% yield in 20 min under the action of microwave irradiation. When conventional heating is used it is necessary to heat the mixture at 150 °C for 4 h in a sealed tube to obtain a satisfactory yield (Scheme 9.33). 

Saalfrank, Hoffmann and co-workers performed a number of reactions with tetra-alkoxyallenes such as 196 (Scheme 8.47) [1, 41, 105, 114—116] and demonstrated that this class of donor-substituted allenes can serve as a 1,3-dianion equivalent of malonic acid. Treatment of 196 with cyclopropyldicarboxylic acid dichloride 197 produces 2,4-dioxo-3,4-dihydro-2H-pyran 198 through release of two molecules of ethyl chloride [115]. Similarily, the reaction of this allene 196 with oxalyl chloride gives 3-chloromalonic acid anhydride derivative 199. This intermediate is a reactive dieno-phile which accepts 2,3-dimethyl-l,3-butadiene in a subsequent [4+2] cycloaddition to afford cycloadduct 200 in good yield [116]. 

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>. 

It has since been shown that the cycloaddition is catalyzed by transition metal salts (78JOC667). Although the yields are generally lower than irr the uncatalyzed reaction, this is outweighed by the advantages of shorter reaction times and a lower cyclization temperature. Illustrative examples of the formation of 2-alkoxy-3,4-dihydro-2//-pyrans are presented in Table 3, which includes a comparison of the two methods of synthesis. 

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... 

Diels-Alder reactions with aldehydes.2 This catalyst is superior to zinc chloride3 for promoting [4 + 2]cycloaddition of aldehydes with l-alkoxy-3-trimethylsilyloxy-1,3-butadienes to form 2,3-dihydro-4//-pyrane-4-ones. The catalyst prepared from bornyl alcohol is somewhat more effective than similar catalysts from simple alcohols, and may be of value for asymmetric induction. 

In a manifestation of the reaction shown above, quinoline rings have also been formed by the cycloaddition of /V-arylketenimines 543 with 3,4-dihydro-2//-pyran 455 under high-pressure conditions (Scheme 100) <2001H(55)1971>. The reaction is proposed to proceed via the initial formation of 544 by attack of the enol ether on the protonated ketenimine subsequent electrophilic aromatic substitution gives 545. Protonation of the enamine to give 546 is followed by elimination to produce 547. Protection of the alcohol with 455 gives 548. 

The use of pyran intermediates for the synthesis of these ring systems has presented few examples. The [4 + 2] cycloaddition of 5-ethenyl-3,4-dihydro-2//-pyrans with DEAD yields compounds (500) <86CB3204>. Reaction of the esters (501) with hydrazine hydrate gave the pyranodiazines (502) <86MI 716-01). 

Phosphonoacrolein, (Et0)2P(0)C(CH0)=CH2, takes part in hDA reactions with alkenes and cyclic conjugated dienes, to give phosphono-substituted 3,4-dihydro-2W-pyrans and their annulated derivatives. The reaction with alkynes gives the 1 1 adduct, a 4//-pyran, initially but this undergoes a second cycloaddition leading to a tetrahydropyrano[3,2-6]pyran 3... 

The [4 + 2 ]cycloaddition of the carbonyl group of aldehydes as well as of ketones and 1,3-butadienes is a well established method for the synthesis of 5,6-dihydropyrans which are useful substrates for the preparation of carbohydrates and many other natural products. Several excellent reviews on this topic have appeared [10-12,14,22]. The first example of this type of reaction using 2,4-dimethyl-1,3-butadiene and formaldehyde to give the 2,4-dimethyl-5,6-dihydro-2/f-pyran in 60% yield was published by Gresham and Steadmen in 1949 (Scheme 2-1, Eq. 1) [57]. 

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