Type-II intramolecular ene reactions

Type II intramolecular ene reactions of unsaturated aldehydes and ketones have been extensively investigated. Ene reactions occur thermally or with Lewis acid catalysis to give 3-methylenecyclohexan-ols52-96-109 or 3-methylenecycloheptanols.110-114 3-Methylenecyclopentanols cannot be formed in type II reactions. However, Lewis or Brpnsted acid induced cyclization of y,8-unsaturated aldehydes and ketones gives zwitterionic intermediates that lose a proton to give unsaturated cyclopentanols85122 or rearrange to cyclopentanones.115-121... 

Alkylaluminum halide catalyzed intramolecular ene reactions of p-ketoesters proceed in high yield to give cyclohexanols via either a type I or type II process (See Figure 14). 22 Treatment of 58a with 1.0-1.2 equivalents of Me2AlCl in nitromethane for 60 h at 25 C gives a 67% yield of the cw-fused ene adduct 59a by a type II intramolecular ene reaction. Similar cyclization of 58b gives a 90% yield of 59b. Treatment of 60 with the milder Lewis acid MesAl in nitromethane... 

Type-II intramolecular ene reactions of aldehydes and ketones proceed readily with Me2AICl as the Lewis acid. " Unsaturated aldehydes and ketones can be generated in situ by Mc2 AlCl-catalyzed reaction of Acrolein and Methyl Vinyl Ketone with alkylidenecycloalkanes at low temperatures (eq 12). The mono-cyclic aldehyde reacts further under these conditions. The mono-cyclic ketone can be isolated at low temperature but undergoes a second ene reaction at rt to give the bicyclic alcohol. p-Keto esters form tertiary alcohols in intramolecular ene reactions. The products are stable because they are converted to the aluminum alkoxide (eq 13). Intramolecular Me2AlCl-catalyzed ene reactions have been used for the preparation of the bicyclic mevinolin ring system (eq 14). ... 

Type II intermolecular ene reaction of thioaldehydes was reported by Vedejs and coworkers492 and already mentioned by Schaumann1. Type in has recently appeared and involves the formation of a C—S bond instead of a C—C bond, as in the case of type I. Type III intramolecular ene reaction has been reported for thioketones and for thioaldehydes. The group of Motoki489 examined the thermal cyclization of o-(2-substituted allyloxy) thiobenzophenones 137 leading to 1,5-oxathiocine derivatives 138 (equation 148). 

Table 9 Intramolecular Type II Zinc-ene Reactions Followed by Trapping (171) - (172) - (173) or (174) in THF...

Some examples of lype-II and Type-Ill intramolecular ene reactions are given in Scheme 6.16. 

Intramolecular ene reactions of allenic aldehydes have been extensively explored by Bertrand and CO workers. 29 We have examined some new classes of these cyclizations.30.3i Hash vacuum pyrolysis of 74 or treatment with Me 2A1Q gives mixtures of 75 and 76 in good yield. Diene 75 is the expected product of a type II intramolecular ene reactioa The formation of diene 76... 

Oppolzer has classified intramolecular ene reactions into type I, II and III depending on whether the tether is attached to carbon 1,2 or 3 of the ene component (see equations 4, S and 6). Type IV reactions, which are a variation of type I in which the tether is attached to the terminal rather thim internal end of the enophile, are occasionally observed (see equation 7). Type I reactions with alkenes or alkynes as enophiles have been extensively studied. Only a few examples of type II, III and IV reactions with alkenes or alkynes as enophiles are known. Numerous examples of intramolecular type I, II and III reactions with carbonyl compounds as enophiles are discussed in Volume 2, Chapter 2.1. 

As with other intramolecular ene reactions, this reaction is best suited to the preparation of cyclopentanes, but can also be used for the preparation of cyclohexanes. The reaction cannot be used for the formation of cyclopropanes or cyclobutanes since the unsaturated carbonyl compound is more stable than the ene adduct. 8,e-Unsaturated ketones (167) do not give cyclobutanes (171) by enolization to give (170) followed by a type I reaction but instead give cyclohexanones (169) by enolization to give (168) followed by a type II reaction. Alkynes can replace alkenes as the enophile. Enols can be prepared from pyrolysis of enol esters, enol ethers and acetals and from -keto esters and 1,3-dicaibonyl compounds. Tlie reaction is well suited to the preparation of fused or bridged bicyclic and spirocyclic compounds. Tandem ene reactions in which two rings are formed in one pot from dienones have also been described. The examples discussed below 2-i63 restricted to those published since Conia and Le Perchec s 1975... 

In contrast, intramolecular versions of the metallo-ene process may be regio- and stereo-selective as well as entropically favored and are thus more efficient, similar to intramolecular ene reactions (Volume 5, Chapter 1.1) and [4 + 2] cycloadditions (Volume 5, Chapter 4.4). This holds for two different modes of cyclization in which the enophile is linked by a suitable bridge, either to the terminal carbon atom C-3 (type I) or to the central carbon aton C-2 (type II) of the metallo-ene unit (Scheme 18). The prc nsity of the cyclized alkylmetal intermediates (F) and (H) for further functionalizations and cycli-zations, involving the metallated and two alkenic sites, offers a considerable potential in organic synthesis. 

SCHEME 6.16 Examples of Type-II and lype-III intramolecular ene reactions. 

Depending on the positioning of the bridge linking the ene donor and acceptor, three orientations are possible for the intramolecular ene reaction. These have been described by Oppolzer (1) as Types I, II, and III. Snider (5) has observed, in addition. Type IV [3]. Type I reactions are by far the most studied, especially for five- and six-membered ring forming reactions. It is conceivable, especially as activated ene systems are developed, that Types II-IV will become more important. 

Type I cyclizations are generally restricted to the formation of five-membered rings, whereas formation of six-membered rings occurred more readily than that of five- or seven-membered rings in type II cyclizations. Examples of intramolecular zinc-ene reactions of both types have been reported. 

A seven-membered ring oxygen heterocycle 176 could also be generated by type intramolecular metallo-ene reactions and the zinc-ene process appeared by far more efficient than the magnesium-ene. However, in the nitrogen series, type II zinc-and magne-sium-ene reactions exhibited similar efficiencies and afforded the substituted 3-methylene piperidine 177 in comparable yields (equation 86)121. 

On the other hand, Intramolecular versions of the magnesium-ene reaction commonly proceed in high yield, with good regio- and stereoselectivity, and have furnished elegant syntheses of the carbon skeleton of natural products. Oppolzer [32] has classified intramolecular magnesium-ene reactions as type I, in which the enophile becomes linked to the terminal carbon atom of the magnesium-ene unit, or type II, in... 

ZnCh catalyzed ene reaction of methyl vinyl ketone and acrolein with p-pinene in ether at 25 C gives the expected ene adducts in 62% and 32% yields, respectively. Methyl vinyl ketone is reported to undergo AICI3 catalyzed ene reactions with limonene, carvone and perillaldehyde. Although Lewis acid catalyzed ene reactions of acrolein and methyl vinyl ketone with alkenes are probably general, the initial products often cannot be isolated since the unsaturated carbonyl compound undergoes an intramolecular Lewis acid catalyzed type II ene reaction. ... 

Intramolecular type II ene reaction of prochiral aldehyde (184) can give four adducts both enantiomers of (185) and (186). ° Cyclization on silica gel gives a 1 1 mixture. Cyclization with purified Eu(fod)a as Lewis acid catalyst for one week in CH2CI2 gives an 8 1 mixture of (185), a potential intermediate for the synthesis of anguidine and (186). Use of Eu(hfc)a, (+)-Eu(DPPM)3 or (5)-l,r-bi-2-naph-thol/TiCh as Lewis acid catalyst affords (185), with 20-38% enantiomeric excess. 

Treatment of (165) with SnCU gives exclusively (166).96 The selective formation of an axial alcohol and exocyclic double bond, a general characteristic of type II ene reactions, is required by either a concerted reaction or a stepwise reaction with an intramolecular proton transfer. Similar treatment of (167), as a mixture of isomers, gives the less stable isomer (168) with an axial alcohol and an equatorial methyl group, since the alcohol must be formed axial and the methyl group prefers to be equatorial in the transition state (Scheme 26).97... 

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