Cyclization, radicals alkenes with aldehydes

Another way to construct alkenes is by the addition of carbon radicals to nitrostyrenes such as 5. Ching-Fa Yao of National Taiwan Normal University in Taipei has reported (J. Org. Chem. 2004,69, 3961) an extension of this work, generating the acyl radical from the aldehyde 6, cyclizing it to generate a new radical, then trapping that radical with 5 to give 7. This article includes an overview of the several ways of adding radicals to 5. 

Both disubstituted alkynes (Chapter 3.3, this volume) and isolated terminal double bonds may be reduced by alkali metals in NH3, but isolated double bonds are usually stable to these conditions. However, 16,17-secopregnanes (10 equation 8) afford mixtures of cyclization products (11) and (12) in 61% to 80% yield with Na naphthalenide-THF, Na-NHs-THF, Na-THF or Li-NHs-THF. With Na-NHa-THF-r-butyl alcohol, a 91% yield of a 72 28 mixture of (11) (12) (R = Me) is obtained. This type of radical cyclization of alkenes and alkynes under dissolving metal reduction conditions to form cyclopentanols in the absence of added proton donors is a general reaction, and in other cases it competes with reduction of the carbonyl group. Under the conditions of these reactions which involve brief reaction times, neither competitive reduction of a terminal double bond nor an alkyne was observed. However, al-lenic aldehydes and ketones (13) with Li-NHs-r-butyl alcohol afford no reduction products in which the diene system survives. ... 

As already indicated, carbonyl compounds such as ketones, aldehydes, enones, and quinones possess the property to act as effective electron acceptors in the excited state for generating radical anions in the presence of electron-donating partners such as alkenes, aromatics, ruthenium complexes, amines, and alcohols. We will not consider the reactivity of enones and quinones, but we will focus our attention on the behavior of the radical anions formed from ketones and aldehydes. Four different processes can occur from these radical anions including coupling of two radical anions and/or coupling of the radical anion with the radical cation formed from the donor, abstraction of hydrogen from the reaction media to produce alcohols, cyclization, in the case of ce-unsaturated radical anions, and fragmentation when a C -X bond (X=0, C) is present (Scheme 18). 

Osmium tetroxide used in combination with sodium periodate can also effect alkene cleavage.191 Successful oxidative cleavage of double bonds using ruthenium tetroxide and sodium periodate has also been reported.192 In these procedures the osmium or ruthenium can be used in substoichiometric amounts because the periodate reoxidizes the metal to the tetroxide state. Entries 1 to 4 in Scheme 12.18 are examples of these procedures. Entries 5 and 6 show reactions carried out in the course of multistep syntheses. The reaction in Entry 5 followed a 5-exo radical cyclization and served to excise an extraneous carbon. The reaction in Entry 6 followed introduction of the allyl group by enolate alkylation. The aldehyde group in the product was used to introduce an amino group by reductive alkylation (see Section 5.3.1.2). 

The alcohol is oxidized to the corresponding aldehyde with 1 equivalent of IBX at room temperature. The use of 2.2 equivalents of IBX at a higher temperature causes the additional interaction with the amide moiety, leading to a radical cation that cyclizes on the alkene. Employing excess of IBX in the presence of /j-TsOH produces the introduction of an alkene conjugated with the initially formed aldehyde. 

Intermolecular addition and addition-cyclization reactions of aminium cation radicals with electron-rich alkenes such as ethyl vinyl ether (EVE) allow an entry into products containing the N—C—C—O moiety of 13-amino ethers 70 or the equivalent of /3-amino aldehydes 71. The mild conditions under which aminium cation radicals are generated from PTOC carbamates makes the reactions described in Scheme 22 possible. In the absence of hydrogen atom donors, the /3-amino ethoxy(2-pyridylthio) acetal 71 was the major product. The mixed acetal can easily be converted... 

These cyclizations both involve the reductive intramolecular addition of an electron deficient alkene function to an aldehyde carbonyl function, and both are effected in ca 90 % yields. The mechanism of this latter type of electrochemically induced cyclizations of carbon-carbon double bonds to carbonyl double bonds have been studied rather extensively, with especial attention to the fundamental mechanistic question of whether the cyclization step involves an anion radical, radical, or anionic mechanism [122]. The latter two mechanisms would involve the protonation of the initially formed anion radical intermediate to form a radical, which could then cyclize or, alternatively, be further reduced to an anion, which could then cyclize. Extensive and elegant electrochemical and chemical studies have led to the formulation of these reactions as involving anionic cyclization (Scheme 74). 

Carbonyl couplings. Many variations of cross couplings are possible these include aldehydes with a-dicarbonyl compounds. Ketyl radicals derived from carbonyl compounds also add to alkenes such as acrylonitrile " or N-allyl moieties. Intramolecular cyclizations on terminal alkenes or allene species have also been exploited for synthetic purposes. 

Ketone-Alkene Coupling Reactions. Ketyl radicals derived fromreduction of ketones or aldehydes with Sml2 may be coupled both inter- and intramolecularly to a variety of alkenic species. Excellent diastereoselectivities are achieved with intramolecular coupling of the ketyl radical with Q ,/3-unsaturated esters. In the following example, ketone-alkene cyclization took place in a stereocontrolled manner established by chelation of the resulting Sm(III) species with the hydroxyl group incorporated in the substrate (eq 22). ... 

Substituted v-butyrolactones can be prepared by reaction of aldehydes or ketones with tbe dianion (28), and direct condensation of symmetrical ketones with diethyl 2-oxomalonate provides a useful synthetic route to the butenolides (29). A number of initiators have been used previously to promote the free-radical addition of ketones to alkenes now transition-metal oxides have been shown to be effective. Pent-4-enal is cyclized to cyclopentanone by chlorotris(triphenylphos-phine)rhodium(i) through a non-radical pathway. ... 

RCM was used as a key step in the total synthesis of (+)-puraquinonic acid (86), a fungal metaboHte that induces differentiation in HL-60 cells [16]. Starting from aromatic aldehyde 87, the RCM precursor 88 was prepared in a few steps. Following RCM leading to 89 (88%), the newly formed trisubstituted alkene was involved in a radical cyclization. Bromo acetal 90 was treated with BusSnH and AIBN thus triggering a stereoselective 5-exo trig cyclization reaction. Further steps led to the natural product 86 (Scheme 1.13). 

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