Carbocyclizations intermolecular

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

While intermolecular Heck reaction of a carbocyclic arene as the recipient is reluctant to occur, intramolecular Heck reaction of carbocyclic arenes has been well-precedented as illustrated by the following two examples [13]. 

One active field of research involving the Heck reaction is asymmetric Heck reactions (AHR). The objective is to achieve enantiomerically-enriched Heck products from racemic substrates using a catalytic amount of chiral ligands, making the process more practical and economical Although intermolecular Heck reactions that occurred onto carbocyclic arenes are rare, they readily take place onto many heterocycles including thiophenes, furans, thiazoles, oxazoles,... 

Palladium chemistry of heterocycles has its idiosyncrasies stemming from their different structural properties from the corresponding carbocyclic aryl compounds. Even activated chloroheterocycles are sufficiently reactive to undergo Pd-catalyzed reactions. As a consequence of a and y activation of heteroaryl halides, Pd-catalyzed chemistry may take place regioselectively at the activated positions, a phenomenon rarely seen in carbocyclic aryl halides. In addition, another salient peculiarity in palladium chemistry of heterocycles is the so-called heteroaryl Heck reaction . For instance, while intermolecular palladium-catalyzed arylations of carbocyclic arenes are rare, palladium-catalyzed arylations of azoles and many other heterocycles readily take place. Therefore, the principal aim of this book is to highlight important palladium-mediated reactions of heterocycles with emphasis on the unique characteristics of individual heterocycles. 

Bicyclic derivatives. Polyhydroxylated carbo-bicyclic derivatives may be regarded as carbasugars with the rigid structure resulting from the presence of the additional carbocyclic ring. The most convenient way for construction of the bicyclic skeleton consists of the Diels-Alder reaction of properly functionalized trienes (intramolecular version) or dienes and olefins (intermolecular). 

A similar but different mechanism has also been proposed for the intermolecular CO-SiCaC reaction of phenylacetylene catalyzed by Rh4(CO)i2, which gives silylcyclo-pentenone 9a and 9b (Scheme 7.5) [14]. In this mechanism /9-silylethenyl-[Rh] intermediate Il.lg, arising from insertion of the alkyne moiety into the Si-[Rh] bond, reacts sequentially with a second molecule of phenylacetylene and CO, to afford <5-silylpenta-dienoyl-[Rh] complex II. Ih- Finally, carbocyclization followed by double-bond migration gives 9 a and 9 b. 

Rhodium catalysis has played a critical role in the development of this type of reaction. The rhodium-mediated [4 + 2] carbocyclization between dienes and unactivated olefins or alkynes is a notable early example of this concept [2]. Further investigations demonstrated the extension of this methodology to the reaction between a diene and an allene [3]. Expansion of the scope of this strategy, to both the intra- and intermolecular [5-1-2] homologs of the Diels-Alder reaction, was accomplished with a vinylcyclopropane and either an alkyne or an olefin to afford the carbocyclization adducts (Scheme 11.1) [4, 5]. 

The intermolecular carbocyclization with a strained olefin, such as norbornene 35, has been frequently used for proof-of-prindple in challenging metal-catalyzed transformations. The use of rhodium catalysts fadhtates the intermolecular reaction, albeit in modest yield and with poor regioselectivity (Scheme 11.10). Ethylene 39 can also be utilized to this end, but generally affords the carbocydization products in low yield, as... 

Tab. 12.9 Scope of the intermolecular rhodium-catalyzed [4-I-2-I-2] carbocyclization reaction.

Recent advances in the rhodium-catalyzed [4-1-2] reactions have led to the development of the first highly regioselective intermolecular cyclization, providing access to new classes of carbocycles with both activated and unactivated substrates. The chemo- and stereoselective carbocyclizations of tethered diene-allene derivatives afford new classes of 5,6- and 6,6-bicyclic systems. Additionally, examination of a wide range of factors that influence both diastereo- and enantioselectivity has provided a significant advance in the understanding of catalyst requirements across these systems. 

Intermolecular Allylboration. A tandem aza[4+2] cycloaddition/allyl-boration three-component reaction has been designed based on the prece-dented carbocyclic [4- -2] cycloaddition/allylboration and a snbsequent one-pot variant. Thns, the thermal reaction between hydrazonobutadienes 138, A-substitnted maleimides, and aldehydes provides polysnbstituted a-hydroxy-alkylpiperidines 141 via the cyclic allylboronate intermediate 139 and the proposed chairlike transition stmctnre 140 (Eq. 103). Monoactivated dienophiles like acrylates fail to react with heterodienes 138 bnt the scope of aldehydes is very broad both ahphatic and aromatic aldehydes are snitable, inclnding electron-rich ones. An inverse electron-demand variant to access the corresponding dihy-dropyran derivatives via the intermediacy of enantiomerically enriched pyranyl allylic boronate 76 has been snbsequently developed (see Eq. 64). ° ... 

Cyclopentyl isoxazolidine cycloadduct 324 was prepared by intramolecular nitrone cycloaddition by Baldwin et al. (280,281,352,353) as part of studies toward a total synthesis of pretazettine (Scheme 1.69). Related adducts have been prepared elsewhere (354—356) including fluorine-substituted carbocycles (357) and the adducts prepared by lOAC by Shipman and co-workers (333,334) who demonstrated their potential as a route to aminocyclopentitols (Scheme 1.66, Section 1.11.2). Such bicyclic structures have been prepared in rather unique intermolecular fashion by Chandrasekhar and co-workers (357a) from the cycloaddition of C,N-diphenyl nitrone to fulvene (325). 

The preparation of compound 175, a structurally diverse analogue of the carbocyclic nucleoside ribavarine 176, was reported using an intermolecular 1,3-dipolar cycloaddition of the cyclopentyl azide 174 with methyl propiolate (37) (Scheme 9.37). 

Deprotonation of methylene groups containing two electron-withdrawing alkoxycarbonyl groups with an appropriate base easily converts them into their corresponding enolate anions. These enolate anions are able to attack carbon electrophiles to form new C —C bonds. One of the important applications of this reaction is to construct small carbocyclic rings, in particular cyclobutanes. For example, intermolecular condensation of l,3-dibromo-2,2-dimethylpropane (1) and the dipotassium salt of diethyl malonate (2) gives diethyl 3,3-dimethylcyclobutane-l,l-dicarboxylate (3).18... 

Macro carbocyclic rings can be constructed by cyclization of nitrile oxides derived from oj-nitro-l-al-kenes (Scheme 22). If the intervening bridge is not longer than seven atoms, only fused bicyclic products are obtained. Thus, the nitrile oxide derived from nitro compound (75a) is cyclized in 44% yield to the 5,9-fused bicyclic isoxazoline (76a).38 10-Nitro-l-decene (75b) also cyclized to (76b) in unspecified yield.39 It should be noted that these results go counter to the usual regiochemistry of an intermolecular nitrile oxide cycloaddition where the five-substituted isoxazoline is usually,27 although not always,40 heavily preferred from reaction of a terminal alkene. Thus, geometric constraints have won out over the normal electronic control. 

Lewis acid catalyzed intramolecular coupling of allylsilanes with aziridines serves as a useful route for the synthesis of carbocycles having the y-amino olefin unit 104 (equation 80)149. However, this reaction does not occur in an intermolecular manner. 

The domino carbonylation and Diels-Alder reaction proceed only as an intramolecular version. Attempted carbonylation and intermolecular Diels-Alder reaction of conjugated 2-yne-4-enyl carbonates 101 in the presence of various alkenes as dienophiles give entirely different carbocyclization products without undergoing the intermolecular Diels-Alder reaction. The 5-alkylidene-2-cyclopenten-4-onecarboxy-lates 102 were obtained unexpectedly by the incorporation of two molecules of CO in 82% yield from 101 at 50 °C under 1 atm [25], The use of bidentate ligands such as DPPP or DPPE is important. The following mechanism of the carbocyclization of 103 has been proposed. The formation of palladacyclopentene 105 from 104 (oxidative cyclization) is proposed as an intermediate of 108. Then CO insertion to the palladacycle 105 generates acylpalladium 106. Subsequent reductive elimination affords the cyclopentenone 107, which isomerizes to the cyclopentenone 108 as the final product. 

Chapter 9 describes various methods for the synthesis of carbocyclic systems. The preparation of such systems can be achieved either by connecting two atoms within a single molecule (intramolecular reaction) or joining together two separate molecules (intermolecular reaction). 

The rhodium A-heterocyclic carbine complex [Rh(IMes)(COD)] [IMes = A,A -bis(2,4,6-trimethylphenyl)imidazol-2-ylidine COD = cycloocta-1,5-diene] catalyses the 4 + 2 + 2-carbocyclization of 1,6-enynes (191) to carbocycles [(192) and (193)] (Scheme 54).226 Computational and experimental evidence of a new reaction pathway for the diastereospecific intermolecular rhodium-catalysed 4 + 2 + 2-carbocyclization (g) reactions of 1,6-enynes with r-components has been reported.227... 

The ability of Sml2 to reduce alkyl halides has been exploited in a number of carbon carbon bond-forming reactions. Radicals generated from the reduction of alkyl halides can be trapped by alkenes in cyclisation reactions to form carbocyclic and heterocyclic rings (see Chapter 5, Section 5.3), and the alkyl-samarium intermediates can be used in intermolecular and intramolecular Barbier and Grignard reactions (see Chapter 5, Section 5.4). The reduction of ot-halocarbonyl compounds with Sml2 gives rise to Sm(III) enolates that can be exploited in Reformatsky reactions (Chapter 5, Section 5.5) and are discussed in Section 4.5. 

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