Domino reactions cycloaddition

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. 

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

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

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. 

In 1987, Vaultier and coworkers [27] developed a combination of a [4+2] cycloaddition of a bora-1,3-diene to provide an allylborane, which then reacts with an aldehyde to give a highly functionalized alcohol. The Lallemand group, as well as Hall and colleagues, has recently used this procedure. In an approach for the synthesis of the antifeedant natural product clerodin (4-83), Lallemand and coworkers performed a three-component domino reaction of 4-80, 4-81 and methyl acrylate to give 4-82 (Scheme 4.18) [28]. 

Padwa s group has not only developed highly efficient domino reactions using transition metal catalysis, but they are also well known for their unique combinations of a cycloaddition and a N-acyliminium ion cyclization. An example of this strategy, which is very suitable for the synthesis of heterocycles and alkaloids, is the reaction of 4-98 to give 4-101 via the intermediates 4-99 and 4-100 (Scheme 4.22). Furthermore, 4-101 was transformed into the alkaloid (+)-y-lycorane 4-102 [32]. 

As with all-carbon Diels-Alder reactions, the hetero-Diels-Alder reaction [41] can also be used as the first step in many combinations with other transformations. In contrast to the normal Diels-Alder reaction, several examples are known where the first step is followed by a 1,3-dipolar cycloaddition. This type of domino reaction has been especially investigated by Denmark and coworkers, and used for the synthesis of several complex natural products. Since Denmark has reviewed his studies in... 

In this section, those domino reactions are described which start with a cycloaddition not of the [4+2] and [3+2] types. The variety referred to is quite high consequently, in addition to the well known [2+2] scheme, [4+3] cycloaddition and the more exotic [5+2] cycloaddition are also outlined. 

Kanematsu s group used a combination of an intramolecular [2+2] cycloaddition of an allenyl ether 4-202 followed by a [3+3] sigmatropic rearrangement (Scheme 4.44) [70]. The substrate for the domino reaction can be obtained in situ by treat-... 

Engler and coworkers [76] developed a new domino process which consists of a [5+3] cycloaddition of a p-quinone monoimide with a styrene derivative followed by a [3+2] or [3+3] cycloaddition. The reaction allows the formation of two additional rings and up to eight stereogenic centers, with high selectivity. The best results, with 58% yield of4-230, were obtained in the transformation of 4-227 and 4-228 in the presence of BF3 Et20 at -20 °C (Scheme 4.49). In addition, the diastereomer 4-231 was obtained in 16 % yield. It can be assumed that the cation 4-229 functions as an intermediate. The process also functions with quinones, though much less efficiently. 

To date, only a few examples are known where a domino reaction starts with an electrocydic reaction, although the value of this approach is clearly demonstrated by the beautiful synthesis of estradiol methyl ether 4-319 through a domino elec-trocyclic/cycloaddition process. There is also an impressive example of a double thermal electrocyclization being used however, the starting material for this domino reaction was prepared in situ by a transition metal-catalyzed transformation, and is therefore discussed in Chapter 6. 

In this section are described those domino reactions which start with a retro-pericy-clic reaction. This may be a retro-Diels-Alder reaction, a retro-l,3-dipolar cycloaddition, or a retro-ene reaction, which is then usually followed by a pericyclic reaction as the second step. However, a combination is also possible with another type of transformation as, for example, an aldol reaction. 

Within this chapter, two sections are devoted to rhodium and ruthenium. The two main procedures using rhodium are first, the formation of 1,3-dipoles from diazocompounds followed by a 1,3-dipolar cycloaddition [10] and second, hy-droformylation [11], The ruthenium-catalyzed domino reactions are mostly based on metathesis [12], with the overwhelming use of Grubbs I and Grubbs 11 catalysts. 

Grigg and coworkers developed bimetallic domino reactions such as the electro-chemically driven Pd/Cr Nozaki-Hiyama-Kishi reaction [69], the Pd/In Barbier-type allylation [70], Heck/Tsuji-Trost reaction/1,3 dipolar cycloaddition [71], the Heck reaction/metathesis [72], and several other processes [73-75]. A first example for an anion capture approach, which was performed on solid phase, is the reaction of 6/1-134 and 6/1-135 in the presence of CO and piperidine to give 6/1-136. Liberation from solid phase was achieved with HF, leading to 6/1-137 (Scheme 6/1.30) [76]. 

The domino reaction of a carbonylylide from a diazoketone followed by a 1,3-dipolar cycloaddition has also been investigated using rutbenium(II)porphyrins 6/2-39 as catalyst [196]. Moreover, Che and coworkers [197] have used the Ru-cata-... 

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). 

It is not quite clear which step takes place first - the Co-catalyzed [2+2+1] cycloaddition of the outer alkyne moiety, or the Diels-Alder reaction of the diene with the inner alkyne to form a 1,4-cyclohexadiene, which then undergoes a Pauson-Khand reaction with the remaining alkyne. Recently, it has been shown that a domino reaction can also be performed using 1 mol of a 1,7-diphenyl-1,6-diyne 6/4-20 and a 1,3-diene 6/4-21 in the presence of Co/C at 150 °C under 30 atm CO, to give the polycyclic compounds 6/4-22 as sole product (Scheme 6/4.7) [282]. 

When the o-ethynylphenyl isopropyl ketone 6/4-113 was treated with 1 equiv. of W(CO)5-THF for 2 h in the presence of 4equiv. of 1,1-diethoxyethylene, the bridged compound 6/4-118 was obtained in 73% yield, and not the expected 3-ethoxy-l-isopropylnaphthalene (Scheme 6/4.28). Iwasawa and coworkers [309] proposed a mechanism for their new domino reaction, which includes a [3+2] cycloaddition followed by insertion of the resulting tungsten carbene moiety into the neighboring C-H bond, with 6/4-114-6/4-117 as possible intermediates. These authors have further shown that 10-20 mol% of W(CO) THF is sufficient, and... 

Aniinophenyl)-a,(J>-ynones react with nitrile oxides by domino [3 + 2] cycloaddition/annulation reactions, giving rise to isoxazolo[4,5-c]quinolines in satisfactory yields (434). Nitrile oxides undergo addition to allylzinc bromide to generate 5-butenylisoxazolines in good yields. The domino reaction combines 1,3-cycloaddition with Wurtz coupling (435). 

Keyword Carbocycles a Cascade Reactions a Cycloadditions a Combinatorial Chemistry a Domino Reactions a Enantioselective Transformations a Ene Reactions a Eieterocydes a Natural products a Preservation of Resources and Environment a Sigmatropic Rearrangements a Tandem Reactions a Transition Metal-Catalyzed Transformations... 

An interesting pericyclic-anionic-pericyclic domino reaction showing a high stereoselectivity is the cycloaddition-aldol-retro-ene process depicted in scheme 20.1581 The procedure presumably starts with a [4+2]-cycloaddition of diene 98 and S02 in presence of a Lewis acid. After opening of the formed adduct reaction with (Z)-silyl vinyl ether 99 leads to a mixture of alk-2-enesulfinic acids 101. It follows a retro-ene reaction which affords a 7 3 mixture of the products 102 and 103. The reaction described by Vogel et al is a nice example for the efficient generation of polypropionate chains with the stereoselective formation of three stereogenic centers and one (0-double bond in a three-component domino reaction in its strict definition. 

A combination of an intramolecular [5+21-cycloaddition of the pyrone 110 followed by an intermolecular [4 + 2]-cycloaddition with dimethyl-butadiene leads to the fused 6,7,5-tricyclocarboxylic system 112 via 111 as described by Rodriguez et al (scheme 22).1621 The prepared skeleton is found in nature in several terpenes. The starting material for this domino reaction is obtained from maltol 109... 

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