Cycloaddition 4 + 2/3 + 2-domino

The forerunner in the Co-catalyzed [2+2+2] cycloaddition domino processes was that identified by Vollhardt and colleagues [273], with their excellent synthesis of steroids. Reaction of 6/4-1 with [CpCo(CO)2] gave compound 6/4-3 with an aromatic ring B via the intermediate 6/4-2. In this process, trimerization of the three alkyne moieties first takes place, and this is followed by an electrocyclic ring opening of the formed cyclobutene to give o-quinodimethane. This then undergoes a Diels-Alder reaction to provide the steroid 6/4-3 (Scheme 6/4.1). 

Supported dipolarophiles were also used to mask nitrones and tether them to a solid phase. After suitable elaboration, the product was released from the resin through a 1,3-dipolar cycloreversion/intramolecular cycloaddition domino process <2003SL1889>. 

N-Allyl difluoro enamines 77 suffered from a rearrangement 2-t2 cycloaddition domino process upon heating to about 140 °C. The effectiveness of final cycloaddition (79) strongly depended on the buUdness of R Sterically encumbered substituents R (CPh20SiMe3) supported the rearrangement (78). In contrast, a small R (SiMcj, Ph) led to substantial amounts of the cycloadduct 79 (Scheme 10.19) [15f]. 

Recently, Iwasawa established a set of transition metal-catalyzed protocols for an efficient construction of N l-C2-fused polycydic indole skeletons via a cycloisomerization-cycloaddition domino reaction of alkynyl imines 172 [222-224]. It was shown that the latter substrates, upon activation with transition metal catalysts, such as W(0), Pt(II), and Au(III), generate reactive azomethine ylide intermediates 174 similar to 166 (Scheme 9.64). Interception of such yUdes with a variety of suitably substituted alkenes 17S via a [3 - - 2]-cydoaddition affords fused indole products 177 through a transient formation of the corresponding metallocarbenoids 176. Transformation of terminal alkynyl imines proceeds with a 1,2-H shift in the 176, whereas... 

SCHEME 20.14 Allylic aIkylation/[5+2] cycloaddition domino reactions. 

SCHEME 5.6. Microwave-assisted diastereoselective synthesis of a 4-spiro-pyrazolidin-3-one via a hydrazone formation/Wolff rearrangement/l,2-hydrogen shift/l,3-dipolar cycloaddition domino sequence. 

Keywords Fischer carbenes Template synthesis Cocyclization Cycloaddition Cyclopentadienes Cyclopentenones Domino reactions... 

To rapidly construct complex structures, a recent synthetic strategy uses the Diels-Alder cycloaddition in sequence with another Diels-Alder reaction or with other reactions without isolating the intermediates (domino, tandem, cascade, consecutive, etc., reactions) [4-6]. Scheme 1.2 illustrates some examples. 

A domino Diels-Alder reaction (the term was chosen from the well-known game) is a one-pot process involving two or more Diels-Alder reactions carried out under the same reaction conditions without adding additional reagents or catalyst such that the second, third, etc., cycloaddition is the consequence of the functionality generated in the previous reaction. A historical example is illustrated in Equation 1.28 [60]. This type of transformation is sometimes named tandem or cascade, but these terms seem less appropriate for describing a time-resolved transformation. 

Figure 6.54 A domino DKR-intramolecular 1,3-dipolar cycloaddition reaction.

A highly diasteieoselective synthesis of substituted 1,2,3,4,4a,9,9a, 10-octahydroacridines 95 with five stereogenic centers has been achieved by domino imine condensation/intramolecular polar [4ti + 2k] cycloaddition of anilines and oo-unsaturated aldehydes 94 <96JPR(338)468>. 

Peer-reviewed journals [18] sections in review [89]. A Knoevenagel condensation is described imder 4.8.2 Cycloadditions - The Diels-Alder Reaction, since both reactions were performed combined in a domino-type process. 

An intermolecular 1,3-dipolar cycloaddition of diazocarbonyl compounds with alkynes was developed by using an InCl3-catalyzed cycloaddition in water. The reaction was found to proceed by a domino 1,3-dipolar cycloaddition-hydrogen (alkyl or aryl) migration (Eq. 12.68).146 The reaction is applicable to various a-diazocarbonyl compounds and alkynes with a carbonyl group at the neighboring position, and the success of the reaction was rationalized by decreasing the HOMO-LUMO of the reaction. 

Another beautiful example of an early domino process is the formation of daphnilactone A (0-19), as described by Heathcock and coworkers [17]. In this process the precursor 0-17 containing two hydroxymethyl groups is oxidized to give the corresponding dialdehyde, which is condensed with methylamine leading to a 2-azabutadiene. There follow a cycloaddition and an ene reaction to give the hexacycle 0-18, which is transformed into daphnilactone A (0-19) (Scheme 0.6). 

Scheme 1.25. Cationic [4+3]-cycloaddition/nucleophilic trapping domino reaction in the synthesis of halocycloheptynes.

The domino process can be catalyzed by a Cu-complex with (S.S)-tBu-bis(oxazo-line) to give 2-616 with excellent enantioselectivity (97-98% ee) [320b,c]. The use of 5 A molecular sieves turned out to be obligatory. Wada and coworkers also reported on a related transetherification/l,3-dipolar cycloaddition procedure to give access to trans-fused bicyclic y-lactones [321]. 

Scheme 2.143. Syntheses of 2-fluoropyrroles via domino carbene addition/1,3-dipolar cycloaddition.

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. 

Scheme 2.183. Examples of the domino nitrone formation/1,3-dipolar cycloaddition.

Scheme 2.184. Synthesis of diverse five-membered heterocycles via domino 1,3-dipole formation/cycloaddition.

Scheme 2.191. Domino condensation/cycloaddition reaction leading to octahydroacridine 2-860.

The combination of pericyclic transformations as cycloadditions, sigmatropic rearrangements, electrocydic reactions and ene reactions with each other, and also with non-pericyclic transformations, allows a very rapid increase in the complexity of products. As most of the pericyclic reactions run quite well under neutral or mild Lewis acid acidic conditions, many different set-ups are possible. The majority of the published pericyclic domino reactions deals with two successive cycloadditions, mostly as [4+2]/[4+2] combinations, but there are also [2+2], [2+5], [4+3] (Nazarov), [5+2], and [6+2] cycloadditions. Although there are many examples of the combination of hetero-Diels-Alder reactions with 1,3-dipolar cycloadditions (see Section 4.1), no examples could be found of a domino all-carbon-[4+2]/[3+2] cycloaddition. Co-catalyzed [2+2+2] cycloadditions will be discussed in Chapter 6. 

An impressive combination of two Diels-Alder reactions is also described by Winkler [4] for the synthesis of the taxane skeleton, though two different Lewis acids must be used for the two cycloadditions. Thus, it does not strictly match the definition of a domino reaction. 

Since the number of domino processes which start with a Diels-Alder reaction is rather large, we have subdivided this section of the chapter according to the second step, which might be a second Diels-Alder reaction, a 1,3-dipolar cycloaddition, or a sigmatropic rearrangement. However, there are also several examples where the following reaction is not a pericyclic but rather is an aldol reaction these examples will be discussed under the term Mixed Transformations . 

Dailey and coworkers [6] extended the studies of Prinzbach using 4-1 as substrate. These authors found that, by employing dicyanoacetylene 4-15 in the reaction with 4-1 the domino adduct 4-16 but not 4-17, as expected, is the main product (Scheme 4.4). In the formation of 4-16 one of the two 1,3-butadiene moieties in 4-1 has reacted with the dienophile 4-14 from the inside, followed by a second [4+2] cycloaddition of the formed dicyanoethene moiety. 4-17 is observed as a side product here, in the first step, the dienophile reacts from the outside, while in the second step the other formed dienophile moiety undergoes a cycloaddition with the second 1,3-bu-tadiene moiety. This mode of action is actually favored in the reaction of all other dienophiles employed, due to their larger size when compared to 4-15. 

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