Seven-membered cycloadditions

Dipolarophiles utilized in these cycloadditions leading to five-membered heterocycles contain either double or triple bonds between two carbon atoms, a carbon atom and a heteroatom, or two heteroatoms. These are shown in Scheme 9 listed in approximate order of decreasing activity from left to right. Small rings containing a double bond (either C=C or C=N) are also effective dipolarophiles, but these result in six- and seven-membered ring systems. 

Another interesting example is provided by the phenylethynylcarbene complex 173 and its reactions with five-, six-, and seven-membered cyclic enamines 174 to form bridgehead-substituted five-, six-, and seven-membered cycloalkane-annelated ethoxycyclopentadienes with high regioselectivity under mild reaction conditions (Scheme 38) [119,120]. In these transformations the phenylethynylcarbene complex 173 acts as a C3 building block in a formal [3+2] cycloaddition. Like in the Michael additions (reaction route F in Scheme 4), the cyclic electron-rich enamines 174 as nucleophiles attack the... 

Electronically rich 1,3-butadienes such as Danishefsky s diene react with chromium alkenylcarbene complexes affording seven-membered rings in a formal [4S+3C] cycloaddition process [73a, 95a]. It is important to remark on the role played by the metal in this reaction as the analogous tungsten carbene complexes lead to [4S+2C] cycloadducts (see Sect. 2.9.1.1). Formation of the seven-membered ring is explained by an initial cyclopropanation of the most electron-rich double bond of the diene followed by a Cope rearrangement of the formed divinylcyclopropane (Scheme 65). Amino-substituted 1,3-butadienes also react with chromium alkenylcarbene complexes to produce the corre-... 

The use of cycloadditions for synthesizing medium-sized ring lactams is more or less restricted to the generation of seven-membered rings. The simplest method to generate azepinones seems to be the [6-1-1] reaction of a 1,6-dicar-boxylic acid chloride 148/152 and a phosphinimine 149, the in situ formed chloro enamine 150 underwent a Chapman rearrangement to give a cyclic imide 151/153 (Scheme 28)] [36]. 

A plausible mechanism for the [2+2+2] cycloaddition reactions between diynes and heterocumnlenes (or nitriles) is shown in Scheme 5.16. Initially [2+2] oxidative addition of one alkyne and the heterocnmnlene (or nitrile) forms the five-mem-bered intermediate 54 compound 55 is formed after the insertion of the second alkyne and finally the seven-membered compound 55 undergoes reductive elimination to afford the prodnct 56 and regenerate the Ni(0) catalyst. 

The two articles in this current volume describe recent developments with small ring compounds which have not teen compiled in such a context before. T. Hirao discusses selective transformations initiated by transition derivatives in the construction of functionally substituted five-, six- and seven-membered rings as well as open-chair compounds. Cycloadditions onto methylene- and alkylidene-cyclopropane derivatives, described by A. Goti, F. M. Cordero and A. Brandi, not only yield products with spirocyclopropane moieties which can be desirable as such or as potential mimics of gem-dimethyl groupings, but also intermediates which can undergo further transformations with ring-opening of the cyclopropane units. 

The bicyclo[6.1.0]nonatriene 46 is transformed to the 8,8-dihydroindene on treatment with a catalytic amount of [Rh(CO)2Cl]2 [24], The stereoselectivity depends on the reaction temperature. [5 + 2]cycloaddition of vinylcyclo-propanes 47 with alkynes is catalyzed by RhCl(PPh3)3 in the presence of silver triflate to give seven-membered rings 48 [25]. (Scheme 17 and 18)... 

As shown in Scheme 2.21 Id, starting with N-allyl carbohydrate-nitrones (469), a series of chiral six- (470) and seven-membered(471) TV-heterocycles were synthesized (Scheme 2.227). A very interesting and useful aspect of this cycloaddition is the control of regioselectivity by the substitution at the nitrogen atom. Therefore, it is possible to direct reactions towards the syntheses of preferred six- or seven-membered heterocycles from carbohydrate derivatives (722). 

In order to gain more insight into this proposed mechanism, Montgomery and co-workers tried to isolate the intermediate metallacycle. This effort has also led to the development of a new [2 + 2 + 2]-reaction.226 It has been found that the presence of bipyridine (bpy) or tetramethylethylenediamine (TMEDA) makes the isolation of the desired metallacycles possible, and these metallacycles are characterized by X-ray analysis (Scheme 56).227 Besides important mechanistic implications for enyne isomerizations or intramolecular [4 + 2]-cycloadditions,228 the TMEDA-stabilized seven-membered nickel enolates 224 have been further trapped in aldol reactions, opening an access to complex polycyclic compounds and notably triquinanes. Thus, up to three rings can be generated in the intramolecular version of the reaction, for example, spirocycle 223 was obtained in 49% yield as a single diastereomer from dialdehyde 222 (Scheme 56).229... 

Given the commercial availability of alkynes as two-carbon components, the intermolecular [5 + 2]-cycloaddition of alkynes and VCPs represents a potentially practical route to seven-membered rings. However, initial attempts at an intermolecular [5 + 2]-reaction of alkynes and VCPs with modified Wilkinson s catalysts led to cyclotrimerization of the alkynes and/or isomerization of the VCPs. The first intermolecular [5 + 2]-cycloaddition of alkynes was realized... 

The metal-catalyzed [5 + 2]-cycloaddition reaction of VCPs and 7t-systems provides a new concept for seven-membered ring construction that has been significantly advanced over the last decade in the areas of catalyst development, chemo-, diastereo-, and enantioselectivity, substrate scope, and applications to total synthesis. 

The [4 + 3]-cycloaddition is a commonly used method for the synthesis of seven-membered rings.9 Many of these reactions involve metals, principally in the role of a Lewis acid as exemplified in Equation (10). These Lewis acid-catalyzed [4 + 3]-cycloadditions have been reviewed by Rigby,62 Sarhan,63 Harmata,64,65 and Hoffmann,66 and will not be reviewed here due to the role of the metal as a Lewis acid. Several computational papers on this subject have also been published.67-71... 

The palladium-catalyzed hetero-[4 + 3]-cycloadditions reported by Trost and Marrs utilize a metal-complexed trimethylenemethane as the three-carbon component. These complexes react with a,/3-unsaturated imines to produce seven-membered heterocycles in moderate to good yields.84 Two examples of this reaction were reported and are shown in Equations (13) and (14). Only the [4 + 3]-reaction was observed with a,/3-unsaturated imine 76 however, both the [4 + 3]- and the [3 + 2]-modes of reactivity are observed with a,/3-unsaturated imine 79. 

The first metal-catalyzed [4 +2]-reaction of tethered dienes with 7r-systems was reported by Wender and Jenkins using alkynes initially as the two-carbon component.21 This study was based on the earlier observation by Wender and Ihle that in the [4 + 4]-cycloaddition of bis-dienes a competing side-reaction is the [4 + 2]-cycloaddition of the diene with a mono-ene portion of a second diene. The extension of this reaction to the synthesis of seven-membered rings by trapping the metallacycloheptadiene with CO, a formal [4 + 2 + l]-cycloaddition, has been shown in preliminary studies to be feasible. For example, tethered diene-yne 160 can be converted to cycloheptadienone 163 in an Rh(l)-catalyzed [4 + 2 + l]-reaction with CO, albeit the [4 + 2]- and [2 + 2 + l]-reaction products dominate (Equation (29)). The mechanistic scheme (Scheme 44) illustrates the possible metallacyclic intermediates leading to the observed products and provided the conceptual basis for the realization of three novel reaction types ([4 + 2], [2 + 2 + 1], and [4 + 2 + 1 ]).1... 

Metal-mediated and -catalyzed [3 + 2 + 2]-higher-order cycloaddition reactions have also proved to be viable and mechanistically novel methods for the synthesis of seven-membered rings. The reported [3 + 2 + 2]-cycloadditions of allyliridium (Equation (30)),139 -allylcobalt (Scheme 47),140 and allylmanganese (Equation (31 ))141 complexes with alkynes involve the reaction of preformed allylmetal complexes with two separate alkynes, leading to a cycloheptadiene-metal complex. 

Cyclopropanation of l,3-dienes. a,0-Unsaturated carbenes can undergo [4 + 2]cycloaddition with 1,3-dienes (12, 134), but they can also transfer the carbene ligand to an isolated double bond to form cyclopropanes. Exclusive cyclopropanation of a 1,3-diene is observed in the reaction of the a,(3-unsaturated chromium carbene 1 with the diene 2, which results in a frans-divinylcyclopropane (3) and a seven-membered silyl enol ether (4), which can be formed from 3 by a Cope rearrangement. However, the tungsten carbene corresponding to 1 undergoes exclusive [4 + 2]cycIoaddition with the diene 2. 

Monocyclic carbasugars. The 1,3-dipolar cycloaddition was used in the synthesis of polyhydroxylated compound with the seven-membered ring (Fig. 16).29... 

Transition metal-catalyzed [4+ 2]-cycloadditions ofdiene-allenes 247 can lead to different results. With a nickel catalyst Wender et al. isolated the anellated system of two six-membered rings 248 with a rhodium catalyst the anellation of a five- and a six-membered ring 249 was possible (Scheme 15.78) [149]. Both transformations proceed readily at low temperatures whereas the uncatalyzed thermal reaction requires 185 °C. Even an anellation of a six- and a seven-membered ring was achieved. 

Intermolecular [4+2]-cycloaddition of vinylallenes with alkynes is efficiently mediated by means of an electronically tuned rhodium catalyst (Scheme 16.81) [91]. A five-membered rhodacycle is formed from the vinylallene. Coordination followed by insertion of an alkyne to the rhodacycle generates a seven-membered rhodacycle, from which rhodium(I) is eliminated reductively to produce a cyclohexatriene, leading to the aromatic compound. 

The first steps involve coordination and cycloaddition to the metal. Insertion of a third molecule of ethene leads to a more instable intermediate, a seven-membered ring, that eliminates the product, 1-hexene. This last reaction can be a (3-hydrogen elimination giving chromium hydride and alkene, followed by a reductive elimination. Alternatively, one alkyl anion can abstract a (3-hydrogen from the other alkyl-chromium bond, giving 1-hexene in one step. We prefer the latter pathway as this offers no possibilities to initiate a classic chain growth mechanism, as was also proposed for titanium [8]. The byproduct observed is a mixture of decenes ( ) and not octenes. The latter would be expected if one more molecule of ethene would insert into the metallocycloheptane intermediate. Decene is formed via insertion of the product hexene into the metallo-cyclopentane intermediate followed by elimination. 

In this section I refer to a number of cycloadditions which cannot be categorized into the above-described types. For example, Murai and colleagues reported the four-component coupling of alkyne, hydrazone, hydrosilane and CO. Here, the [Ir4(CO)i2]-catalyzed reaction proceeded under pressurized CO conditions at high temperature, whereby a seven-membered nitrogen heterocycle was obtained (Scheme 11.37) [48]. 

Scheme 13.5 Representative thermal cycloadditions for seven-membered ring synthesis.

Under optimized conditions, cycloisomerizations of a number of functionalized hept-l-en-6-ynes took place in good-to-excellent yields (Table 9.3). Heteroatom substitution was tolerated both within the tether and on its periphery. Alkynyl silanes and selenides underwent rearrangement to provide cyclized products in moderate yield (entries 6 and 7). One example of seven-membered ring formation was reported (entry 5). Surprisingly, though, substitution was not tolerated on the alkene moiety of the reacting enyne. The authors surmize that steric congestion retards the desired [2 + 2]-cycloaddition reaction to the point that side reactions, such as alkyne dimerization, become dominant. 

Thiete sulfones show an irregular behavior pattern when involved in cycloaddition reactions. With 1,3-dienes, dienamines, enamines, ynamines, diazoalkenes, cyclopropadiene, and its substitution products, furan, and anthracene, the addition proceeds in the normal fashion. With certain Diels-Alder reagents such as tetraphenylcyclopentadienone (tetracycloneX however, the cyclic sulfones react anomalously. The Diels-Alder adducts undergo decomposition with SO 2 and CO extrusion to a seven-membered ring, the tetraphenylcycloheptatriene 223. Bicyclic octadienone is produced as well (Eq. 62). The mechanism of this unusual reaction is proposed by... 

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