Ene reaction of formaldehyde

Scheme 8C.7. Asymmetric carbonyl-ene reaction of formaldehyde or vinyl and alkynyl analogues of glyoxylale.

Dihydropyrane synthesis." A novel synthesis of a dihydropyrane intermediate (2) for a synthesis of pseudomonic acid (3) involves an ene reaction of formaldehyde with a 1,4-diene, followed by a quasi intramolecular Diels-Alder reaction with formaldehyde as dienophile, both reactions being catalyzed by ethylaluininum dichloride. Thus, reaction of 1 with CH20 (3 equiv.) and C2H5A1C12 (4.5 equiv.) gives 2 in 35-40% yield via a number of intermediates. 

Excellent yields of ene adducts can be obtained from BF3-Et20- or SnCU- catalyzed addition of formaldehyde to alkenes that can give a tertiary carbocation. Limonene reacts selectively at the 1,1-disub-stituted double bond to give ene adduct (9) in 80% yield (equation 6). SnCU- catalyzed addition of formaldehyde to 2,6-dimethyl-2,3-heptadiene gives lavandulol (10) in 35% yield (equation 7). BF3-Et20-catalyzed ene reaction of formaldehyde with (11) occurs exclusively from the less-hindered a-face to give ene adduct (12) with the correct stereochemistry at C-20 and functionality suitable for construction of the vitamin D side chain (equation 8). ... 

Lewis Acid Catalyzed Ene Reactions. Johnson and coworkers have used the BF3-Et20 catalyzed ene reaction of formaldehyde shown in equation (8) to prepare the Inhoffen-Lythgoe diol. ... 

We have used inter- and intramolecular kinetic isotope effects to examine the mechanism of these Lewis acid catalyzed ene reactions. The Lewis acid catalyzed ene reaction has traditionally been though to proceed through either a concerted pericyclic mechanism or a stepwise reaction with a zwitterionic intermediate. We found that the intermolecular isotope effect in the Me2AlQ catalyzed ene reaction of formaldehyde is 1.3 with methylenecyclohexane and methylenecyclohex-ane-2,2,6,6- 4 and 1.4 with 2,3-dimethyl-2-butene and 2,3-dimethyl-2-butene- /i2. Since secondary iotope effects could be responsible for these results, these values are consistent with either a stepwise or concerted mechanism. Intramolecular isotope effects were determined to be 2.9 and 2.7 with 2 and 3, respectively. These substantial intramolecular isotope effects coupled with the small intermolecular isotope effects indicate that the reaction is stepwise with proton transfer following the rate determining step. In an intramolecular competition such as the ene reactions of formaldehyde with 2 and 3 an isotope effect will still be observed if the hydrogen transfer occurs... 

The side products obtained in Lewis acid catalyzed ene reactions of formaldehyde with mono-and 1,2-disubstituted alkenes are consistent with the mechanistic scheme shown in Figure 2. When only 1 equivalent of Me2AlQ is used chloro alcohols are formed as by products. When excess Lewis acid is used chloroalcohols are fonned as transient intermediates which are converted to ene adducts and other products. The chloroalcohols formed from 1,2-disubstituted alkenes result from the stereospecifically cis addition of the hydroxymethyl and chloride groups to the double bond. This result was unexpected since all previous Prins additions have been shown to proceed predominantly by trans addition. 4 Cis addition of chloride and hydroxymethyl groups would be expected from intermediates such as 4 or 5 and 6. 

BINOL-Ti-catalyzed carbonyl-ene reaction of glyoxylate has also been applied to the asymmetric desymmetrization of prochiral ene substrates with planar symmetry and kinetic optical resolution of racemic ether. As shown in Scheme 14.55, optically active products can be obtained with extremely high enantiomeric excesses [140]. The asymmetric desymmetrization of meso olefin derivative via BINOL-Ti-catalyzed carbonyl-ene reaction of formaldehyde, vinyl and alkynyl analogs of glyoxylates has been applied to the synthesis of isocarbocycline analogs [141]. 

BINOL-Ti catalysis is also applicable to carbonyl-ene reaction with formaldehyde or vinylogous and alkynylogous analogs of glyoxylates in the catalytic desymmetrization (vide infra) approach to the asymmetric synthesis of isocarbacycline analogs (Scheme 8C.7) [24],... 

Prins reaction (cf 10, 186-187). Dimethylaluminum chloride is an effective catalyst for the ene addition of formaldehyde (as trioxane or paraformaldehyde) to mono- and 1,2-disubstituted alkenes.5 When 1.5-2.0 equiv. of the Lewis acid is used, homoallylic alcohols are obtained, usually in high yield. y-Chloro alcohols, formed by cis-addition of -Cl and -CH2OH to the double bond, are sometimes also observed when only 1 equiv. of the Lewis acid is present. The advantage of this reaction over the Prins reaction (using HC1) is that m-dioxanes are not formed as by-products, because formaldehyde no longer functions as a nucleophile when complexed to the Lewis acid. 

Formaldehyde-MAPH complexesFormaldehyde (gas) readily undergoes self-polymerization and is usually generated by thermal depolymerizaton of paraformaldehyde, a linear trimer. Treatment of trioxane in CH2C12 at 0° with MAPH generates a complex, CH2=O MAPH, which is stable at 0° for 5 hours, but which decomposes slowly at 25°. The complex can be used for aldol and ene reactions of the aldehyde itself. 

In a clever piece of work, Snider et al. have used a quasi intramolecular carbonyl Diels-Alder cycloaddition to produce a key intermediate for syntheses of pseudomonic acid A (175) (Scheme 20). Thus a Lewis acid catalyzed ene reaction of alkene (170) and formaldehyde afforded (171), which com-plexed with additional formaldehyde to give (172). Intramolecular [4 + 2] cycloaddition of (172) gave adduct (173) which produced dihydropyran (174) upon hydrolysis. 

They also applied this method to the intermolecular ene reactions of aliphatic and aromatic aldehydes with alkenes containing a disubstituted vinylic carbon, a potentially valuable route to homoallylic alcohols [50]. Proton-initiated rearrangements do not take place, because the alcohol-Lewis acid complex formed in the ene reaction reacts readily to give methane and a non-acidic aluminum alkoxide. Formaldehyde and excess Me2AlCl gave good yield of ene adducts with all types of alkene, as exemplified in Sch. 26. 

The kinetic hydrogen isotope effects which have been observed in the hydrogen-ene reactions of deuterium-labelled alkenes with singlet oxygen, tV-pheny I triazolincdione, nitrosopentafluorobenzene, formaldehyde, methyl chloroacrylate, and ethyl propiolate as the enophiles, and the stereoselectivity of the reactions, imply the initial formation of a complex between the alkene group and the enophile. The various products which have been identified in the metalloene reactions can be rationalised on die basis of a similar mechanism (Scheme 9-2).67... 

As described in the sections above, it is well established that reactions of Lewis acid-activated aldehydes and ketones with silyl enolates afford -hydroxy or /7-sil-oxy carbonyl compounds (Mukaiyama aldol reactions). Occasionally, however, ene-type adducts, that is /-siloxy homoallyl alcohols, are the main products. The first example of the carbonyl-ene reaction of silyl enolates was reported by Snider et al. in 1983 [176]. They found that the formaldehyde-MesAl complex reacted smoothly with ketone TMS enolates to give y-trimethylsiloxy homoallyl alcohols in good yield. Yamamoto et al. reported a similar reaction of formaldehyde complexed with methylaluminum bis(2,6-diphenylphenoxide) [177]. After these early reports, Kuwajima et al. have demonstrated that the aluminum Lewis acid-promoted system is valuable for the ene reactions of several aldehydes [178] and for-maldimine [179] with silyl enolates bearing a bulky silyl group. A stepwise mechanism including nucleophihc addition via an acyclic transition structure has been proposed for the Lewis acid-promoted ene reactions. 

Normal aliphatic and aromatic aldehydes, e.g. acetaldehyde and benzaldehyde, are much less reactive than formaldehyde and electron-deficient aldehydes in ene and Prins reactions. Prins reactions of these aldehydes lead to even more complex mixtures of products than Prins reactions of formaldehyde, due to the additional stereocenter introduced in the reaction. Thermal ene reactions of these aldehydes cannot be carried out successfully. Snider and coworkers have found that moderate to good yields of adducts can be obtained from Me2AlCl-catalyzed ene reactions of these aldehydes and 1,1-di-, tri- and tetra-sub-stituted alkenes (equation 14). Use of a stoichiometric amount of Me2AlCl is necessary since the... 

Snider, Phillips, and Cordova very cleverly combined two consecutive ene reactions with a formaldehyde Diels-Alder cycloaddition to produce a dihydropyran that has previously been used in a total synthesis of pseudomonic acid (39).54 Thus, 1,5-diene 32 underwent dimethyla-luminum chloride-catalyzed ene reaction with formaldehyde to afford 33 (Scheme 4-XV) as a 8 1 mixture of trans cis isomers (80%). Isomers were not separated since the cis compound did not undergo the subsequent Diels-Alder reaction. Treatment of acetate 34 with ethylaluminum dichloride and formaldehyde in CH2CI2-CH3NO2 (25°C, 12 hr) gave a 37% yield of adduct 38. This transformation presumably involves initial ene reaction of 34 to give 35, which reacted with formaldehyde to produce complex 36. A quasi-intramolecular Diels-Alder cycloaddition then ensued that led to 37. Hydrolysis of aluminum complex 37 gave the desired pyran 38. 

Table 11.24. Dependence of the Ene Reaction of 704 and Formaldehyde on the Lewis Acid Catalyst...

The ene reaction of olefins was employed to hydroxymethylate jojoba wax using Lewis acids as catalyst (15). Ethylaluminum dichloride and formaldehyde gave both... 

Zeolites have been reported to alter selectivity of O2 reactions and oftentimes alter the selectivity of the Alder-Ene reaction. The use of a zeolite to catalyze the Alder-Ene reaction with formaldehyde was recently reported. The formaldehyde was activated by the zeolite and the products 181 formed proved to be very selective for the least hindered site of the... 

The ene reaction of carbonyl compounds with alkenes is a potentially valuable route to homoallylic alcohols. With reactive, i.e., electron deficient aldehydes such as chloral or methyl glyoxylate, these reactions can be carried out thermally at 100-200 °C or with Lewis acid catalysis at ambient temperature. 1 Formaldehyde undergoes ene reactions with alkenes at 180 C and undergoes Lewis acid catalyzed ene reactions at ambient temperatures with alkenes which can give a tertiary carbocation.3 In the presence of Br0nsted acids, aldehydes and alkenes undergo the Prins... 

The ene reaction of isovaleraldehyde with isoprene provides a 16% yield of ipsenol (7), a pheromone of the bark beetle ips confusus (see Figure 3). lo The major product formed in 60% yield is the Diels-Alder adduct 8 which is related to nerol oxide and rose oxide. Use of Me 2A1Q allows the isolation of acid-sensitive ipsenol, since protic acids are not present in the reaction mixture. The reaction of aldehydes with limonene occurs exclusively at the less substituted double bond as reported by Blomquist for the reaction with formaldehyde. 3a Isovaleraldehyde and limonene give a 70% yield of 9, an intermediate in Crawford s dihydro-ar-turmerone synthesis, n... 

Formaldehyde undergoes Me2AlCl induced reactions with terminal alkynes to give a 2 3 mixture of the ene adduct 10 and the (Z)-chloroalcohol 11 in 50-75% yield (See Figure 4).i3 These products can both be derived from an intermediate such as 4 or 5 and 6. Reaction of formaldehyde, methyl 6-heptynoate and the stronger Lewis acid methylaluminum sesquichloride gives... 

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