Two-component Reactions with an Intramolecular Cycloaddition

A wide range of solvents can be used. Most appropriate are acetonitrile, dichloro-methane and toluene, but alcohols and water may also be employed. In those cases, depending on the substrates, an additional reaction such as cleavage of formed lactones or acetals might occur. 

Several reviews have already been written about this topic, therefore here only a general overview and the newest developments are presented [la,b,d,g,3]. 

Using aliphatic aldehydes such as 26 the trans-annulated products are formed almost exclusively [15]. Moreover, a stereogenic center at the aldehyde has a strong influence on the facial selectivity. Thus, reaction of 27 led to 28 nearly exclusively. 

A nice extension of this protocol is the use of 5, -unsaturated aldehydes derived from sugars such as D-glucose and D-ribose to yield polyhydroxylated condensed dihydropyrans [18]. Good results were obtained using N,N-dimethylbarbituric acid 

2 as the 1,3-dicarbonyl component whereas Meldrum s acid 35 and dimedone 36 gave less satisfying results. 

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So far, only those domino Knoevenagel/hetero-Diels-Alder reactions have been discussed where the cycloaddition takes place at an intramolecular mode however, the reaction can also be performed as a three-component transformation by applying an intermolecular Diels-Alder reaction. In this process again as the first step a Knoevenagel reaction of an aldehyde or a ketone with a 1,3-dicarbonyl compound occurs. However, the second step is now an intermolecular hetero-Diels-Alder reaction of the formed 1 -oxa-1,3 -butadiene with a dienophile in the reaction mixture. The scope of this type of reaction, and especially the possibility of obtaining highly diversified molecules, is even higher than in the case of the two-component transformation. The stereoselectivity of the cycloaddition step is found to be less pronounced, however. 

One of the most effective approaches to implementing the Diels-Alder participation of 1-oxa-1,3-butadienes is through the use of an intramolecular [4 + 2] cycloaddition reaction.A select set of thermal and Lewis acid-catalyzed intramolecular cycloaddition reactions of unactivated and electron-rich alkenes with a,P-unsaturated aldehydes and ketones has been detailed. Two examples of the poorly matched intramolecular Diels-Alder reaction of an a,P-unsaturated aldehyde (4 ir component) with an a, 3-unsaturated amide (2ir component) have proven successful (190-160 °C) and may be attributed to the entropic assistance provided by the intramolecular reaction. These observations have been applied in... 

The additional ring which arises from an intramolecular HDA reaction may enable us to synthesize various kinds of triquinanes or other polycyclic compounds based on our proposed cycloaddition-fragmentation strategy (Scheme 3). The decrease in entropy associated with tethering the two reactive components suggests that the reaction would be significantly more facile than the intermolecular reaction. This potential rate enhancement, however, is compromised by the dramatic decrease in rate associated with intermolecular cycloadditions with substituted norbor-nadienes (Section IID, Table 7). In fact, before our studies, only one example of an attempted intramolecular HDA reaction was reported in the literature (Eq. 15). Instead of undergoing a [2 + 2 + 2] cycloaddition, an alternative intramolecular ene reaction occurs. ... 

By definition, a diene contains two carbon-carbon double bonds each potentially can be a 2ti-component in a cycloaddition reaction. A [4 + 2] cycloaddition of a 1,3,4-oxadia-zole with a diene can proceed via one or both of two routes. In the first case, only one of the carbon-carbon double bonds from separate molecules reacts in each step, leading to a tandem, double intermolecular cycloaddition. This reaction is not much different from similar reactions with two molecules of an alkene described previously. However, in the second case, the carbon-carbon double bond remaining from the diene after the [4 + 2] cycloaddition step reacts in the [3 + 2] cycloaddition intramolecularly, which leads to a tandem, intermolecular-[4 + 2]/intramolecular-[3 + 2] cycloaddition. 

Benzoindole 114 has been synthesized by a remarkable sequence, in which the benzannulation precursor 113 is pre-assembled starting from two different chromium carbenes. It is formed in a [3+2] cycloaddition, in which the acylamino carbene complex 111 acts as the dipolar component and the alkynylcarbene complex 112 serves as the dipolarophile. The resulting 3-pyrrolylcarbene complex 113 undergoes a photoinduced intramolecular benzannu-lation to give the benzoindole 114 [84a]. This strategy complements an approach towards carbazoles [84b], Isoindolines and 1,2,3,4-tetrahydroisoquinolines are accessible from the reaction of pentacarbonyl (a-methoxyethylidene) chromium with 7r,co-dialkynes bearing a nitrogen atom in the carbon ether [84c]. 

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