Cycloadditions of VCPs and Alkynes

RhCl(CO)2]2 was discovered early in our work as a new catalyst for the [5+2] cycloaddition of VCPs and alkynes. This catalyst proved to be impressively effective for many of the previously problematic cases and, more generally, allowed the reactions to proceed under mild conditions. Initial interest in [RhCl(CO)2]2 was prompted, in part, by the expectation that it would be less stericaUy encumbered than Wilkinson s catalyst. 

Intermolecular Rhodium-Caialyzed [5+2] Cycloadditions In 1998, Wender et al. reported the first examples of intermolecular metal-catalyzed [5+2] cycloadditions of VCPs with alkynes [32]. While several catalysts have been proved to be efficient in promoting intramolecular [5+2] cycloadditions of VCPs and alkynes, the intermolecular [5+2] process has been Umited until recently to the use of [RhCl(CO)2]2 [33]. The initial study revealed that internal, terminal, electron-rich, and electron-poor alkynes all participated in the [5+2] cycloaddition with VCPs, giving... 

SCHEME 20.18 [5+2] Cycloadditions of VCPs and alkynes catalyzed with [Rh(CioH8) (cod)]+SbF6. ... 

Thus far, the [5 + 2 + 1]-reaction works efficiently with alkynyl esters, amides, aldehydes, and ketones or an alkynyl-substituted allene44 as the two-carbon component (Scheme 58). Just as in the case of the [5 + 21-cycloaddition of VCPs and allenynes, the [5 + 2 + l]-reaction is selective for the allene over the alkyne subunit (Equation (35)). 

Scheme 20.11) [27], as expected by the calculations. Therefore, a comparison of the [RhCl(CO)2l2-catalyzed [5+2] cycloadditions between VCP and acetylene, ethylene, and allene revealed that the reductive elimination involving alkenes was substantially more difficult than those involving alkynes or allenes. However, it is important to indicate that [5+2] cycloadditions of VCPs and alkenes can be efficiently achieved by using [Rh(arene)(cod)] SbFg catalyst [14]. 

Recognizing that intermediates in the [5 + 2]-reaction of VCPs and 7r-systems could be trapped with other components, Wender and co-workers reported a three-component [5 + 2 + l]-cycloaddition involving VCPs, alkynes, and CO that provide efficient access to densely functionalized bicyclo[3.3.0]octenones via a cyclooctadienone intermediate (Scheme 55).129 This reaction converts three commercially available materials to bicyclic products and creates two stereocenters and four C-C bonds. 

The first examples of metal-mediated [5-1-2] cycloadditions between VCPs and tethered alkynes were reported in 1995 (Tab. 13.1) [21]. Initial success was obtained by treating alkyne-VCP 54 with Wilkinsoris catalyst ([RhCl(PPh3)3]) in refluxing toluene for 48 h to produce cycloadduct 55 in 84% yield. Further investigations led to the development... 

Design and Development of Multi-component [5+2+1] Cycloadditions of VCPs, Alkynes, and CO... 

Wender s group has also developed rhodium-catalyzed intermolecular [5-1-2] cycloadditions. At first, they found the catalysis system of Rh(PPh3)3Cl for the intramolecular reactions was not effective at all for the intermolecular reactions. To effect the intermolecular [5-1-2] cycloadditions, [Rh(CO)2Cl]2 must be used and oxygen substitution of the cyclopropane was necessary (see (17)) [37-39]. Then they successfully expanded the substrate to unactivated vinylcyclopropanes by adjusting the substituents. For monosubstituted alkynes, the substitution on the olefin terminus directs the formation of single isomer that minimized steric hindrance (see (18)) [40]. The [5-1-2] cycloadditions can also be applied to VCPs with allenes (see (19)) [41]. It should be noted that the alkyne substituent did not interfere with the reaction, indicating that allenes as reaction partners were superior to alkyne in the [5-1-2] cycloadditions. Curiously, the authors didn t report the corresponding intermolecular [5-1-2] cycloadditions of VCPs with alkenes. 

VCPs have served as valuable five-carbon components in various cycloaddition reactions. Usually, they form six-membered metallacycles upon oxidative cycliza-tion with transition metals. Then, migratory insertion of unsaturated molecules, followed by reductive elimination, furnishes the carbocycles. In particular, intermolecular [5-1-2] annulation of VCPs with alkynes, alkenes, and allenes has been studied extensively (Scheme 2.39) [57]. In addition, VCP-cyclopentene rearrangement has been well documented [56 ]. 

Cycloadditions It must be noted that most of intramolecular rhodium-catalyzed [5+2] cycloadditions of VCPs have involved tethered alkynes. The first examples of metal-catalyzed [5+2] cycloadditions between VCPs and tethered alkynes were reported by Wender et al. in 1995, employing Wilkinson s catalyst ([RhCl(PPh3)3] [8]. Excellent yields were obtained with a variety of tethered alkynes irrespective of the steric and electronic nature of the group... 

Thus far, rhodium(i) complexes are the most general, efficient, and selective catalysts, uniquely enabling [5 + 21-cycloadditions of tethered alkyne-VCPs, alkene-VCPs, and allene-VCPs. For example, when tethered alkene-VCP 7a (Equation (2)) is treated with [(cod)Rh(CioH8)]SbF6, the bicyclo[5.3.0]decene is produced in 96% yield. 

The [5 + 2]-cycloadditions of tethered alkyne-VCPs that are 1,2-disubstituted on the cyclopropane ring 5j—1 have been studied and a mechanism has been advanced to explain the regio- and stereoselectivities of the reactions.37 In most cases, the product resulting from cleavage of the less-substituted (sterically less encumbered) carbon-carbon bond is obtained. The [5 + 2]-reaction is stereospecific in that a /ram-rclationship of the substituents on the cyclopropane leads to a m-relationship of the substituents in the product and vice versa (Equations (4) and (5)). For some tethered alkyne-VCPs which contain a functional group that weakens the carbon-carbon bond of the cyclopropane system, the more substituted (weaker) carbon-carbon bond can be cleaved selectively depending on the choice of catalyst. Thus far, the rhodium(l)-catalysts are more selective catalysts than the mthenium(0)-catalysts in the [5 + 2]-reaction of these substituted alkyne-VCPs (Scheme 7).38... 

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... 

Following their studies on the trapping of intermediates in the [5 + 2]-cycloaddition with CO, which led to the [5 + 2 + l]-process, the Wender group found that when related reactions were conducted with aryl alkynes under an atmosphere of CO, a novel four-component [5 + 2 + 1 + l]-product was observed.172 A VCP, an alkyne, and 2 equiv. of CO react to give the biaryl compounds shown (Scheme 78) via the formation of a nine-membered ring intermediate. 

In our initial studies on the [5+2] cycloaddition, several metal catalysts were screened. Rhodium(I) systems were found to provide the optimum yields and generality [26]. Since the introduction of this new reaction in 1995, our group and others have reported other catalyst systems that can effect the cycloaddition of tethered VCPs and systems. These new catalysts thus far include chlororhodium dicarbonyl dimer ( [RhCl(CO)2]2 ) [27], bidentate phosphine chlororhodium dimers such as [RhCl(dppb)]2 [28] and [RhCl(dppe)]2 [29], and arene-rhodium complexes [(arene)Rh(cod)] SbFs [30]. [Cp Ru(NCCH3)3] PFg has also been demonstrated to be effective in the case of tethered alkyne-VCPs [31], but has not yet been extended to intermolecular systems or other 2n -components. 

The first example of the transition-metal-catalyzed [5+2] cycloaddition of vinylcyclopropane (VCP) with alkyne was reported in 1995 by Wender et al. (Scheme 2-73). Various tethered alkyne-VCPs underwent Rh-catalyzed [5+2] cycloaddition to give bicyclo[5.3.0] products 512 in excellent yields, irrespective of the steric and electronic properties of the R group. 

In addition to the [5+2] cycloaddition of tethered alkyne-VCPs 511, the reactions of tethered alkene-VCPs 513, yielding 514 and tethered allene-VCPs 515, affording 516 have also been developed (Scheme 2-74). 

The first example of the asymmetric [5+2] cycloaddition of alkene-VCP 517 was reported using a Chiraphos-Rh catalyst, which gave c/s-fused bicyclo[5.3.0]decene 518 in 80% yield and 63% ee (Scheme 2-75, eq. 1). The reaction of alkyne-VCP 519 catalyzed by [ RhCl(C2H4)2 2] complex in the presence of NaBAr 4 gave 520 with 99% ee (Scheme 2-75, eq. 2). ... 

Cycloaddition. In 2002, a three-component [5+2+1] cycloaddition of vinyl-cyclopropane 199 (VCP), alkynes 200, and carbon monoxide using [Rh(CO)2Cl]2 as catalyst was reported by Wender and co-workers (162). The process initially leads to an eight-membered ring 201, which upon hydrolytic workup yields bicyclo[3.3.0] octenone products 202 in good to excellent yields (Scheme 90). The process was found to be more efficient with the use of carbonyl-activated alkynes. NMR and x-ray studies of products indicated that CO insertion occurred... 

Two ferrate complexes A and B were used by Fiirstner and co-workers to catalyze the intramolecular [5+2] cycloadditions of alkyne-VCPs to give the corresponding seven-membered products in good to excellent yields with a good substrate scope and diastereoselectivity (see (26)) [59],... 

In sharp contrast to the extensive investigation of VCPs, very few examples of the cycloaddition of allenylcyclopro-panes have been reported. In this area, Mukai and co workers have recently investigated the intramolecular [5+2] cycloaddition of allenylcyclopropanes 21 and alkynes [24]. These reactions were induced by catalysts, such as [RhCl/COlJi or... 

Hayashi and coworkers have developed the highly efficient enantioselective intramolecular [5+2] cycloaddition of heteroatom (O and NTs) alkyne-VCPs 31 under rhodium catalysis [29]. High enantioselectivities of up to >99% ee were achieved for the corresponding cycloadducts 32 by the use of the chiral phosphoramidite ligand 33 in combination with a catalyst such as [RhCKCaH lJi- The reactions were performed at 30 °C in dichloromethane as the solvent and in the presence of sodium tetrakis(3,5-bis(tiilluoromethyl)phe-nyl)borate (Barp) as source of anionic counterion, which produced a series of chiral heteroatom (O and NTs)-tethered cycloadducts in high yields, as shown in Scheme 20.13. 

SCHEME 20.13 Enantioselective [5+2] cycloaddition of heteroatom (O and NTs)-tetheied alkyne-VCPs. 

The use of [RhCl(CO)2]2 in intermolecular [5+2] cycloadditions often require heating, which in turn promotes competing cyclotrimerization of alkyne starting materials, decomposition of the VCP, or formation of undesired secondary isomerization products. Such transition metal-catalyzed intermolecular cycloadditions pose particular chemo-and regioselectivity challenges as well as entropic penalties not encountered in intramolecular processes, as the latter benefit from tether-derived alignment and proximity of reactive functionalities not possible in the former. In this context, Wender et al. have recently demonstrated that the cationic rhodium(I) complex, [RhCCioHsKcod)]" SbFe, promoted the remarkably efficient intermolecular [5+2] cycloaddition of 1-alkoxy-VCP 37, and 1-alkyi-VCP 42... 

Representing an impressively straightforward route to bicyclo[5.3.0]decadiene derivatives, Martin and co-workers have designed a one-step route to the [5 + 2]-cycloadducts from alkynes and VCP building blocks through the use of a sequential [RhCKCO k-catalyzed allylic alkylation/[5 + 2]-cycloaddition (Equation (9)). 

Complex 93 was tested in a variety of [5+2] cycloaddition reactions and compared, where relevant, with some other effective catalysts (Tab. 13.6). Excellent results were obtained with VCPs tethered to terminal and internal alkynes, alkynoates, and aUcenes. 

In the course of our studies on the [6+2] cycloaddition, the formation of products arising from a [6+2-1] path was observed (Scheme 13.20). Conceptually, 249 produces the [6+2] cycloadduct 251, but under certain conditions 49, the [6+2-1] product, is observed, presumably arising through the conversion of 250 to 48. Reflection on this observation suggests that one might start with VCP 41 and an alkyne and trap 48 with CO in the microscopic reverse of the 250-to-48 path to produce 251 by an overall three-component [5+2+1] cycloaddition. This idea worked. 

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