Intramolecular Cascade Cyclizations

The ongoing development of such photochemical/thermal isomerization methods should be of considerable interest as pathways to new ladder-type -PAHs. 

Oxidative and Radical Cyclizatlons - Toward Two-Dimensional n-Systems 

Modest persistence ( 30 min) of the emissive properties was noted for the freeze-dried material under ambient conditions however, rapid loss of emission occurred in solution due to hydrolytic cleavage of B-C bonds. 

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Intramolecular cascade cyclization of compounds 481 in the presence of catalytic amount of HgCl2 gave l,2,3,4-tetrahydro-6H-pyrido[l,2-a]pyr-azin-6-ones 483 (09TL4050). NMR investigations indicated that the reaction goes through intermediate 482, which then cyclized to 483. In the absence of catalyst, the cyclization was found to be sluggish. When instead of (2-N02-Ph)S02 derivative N-benzyloxycarbonyl derivative was used, no cyclized product was obtained. Similar reaction of compound 484 provided a mixture of tricyclic compounds 485 and 486. 

Scheme 10.5 Synthesis of a ladder-type zwitterionic phosphonium-borate bridged polycycle via intramolecular cascade cyclization.

Fukazawa A, Hara M, Okamoto T, Son EC, Xu C, Tamao K, Yamaguchi S (2008) Bis-phosphoryl-bridged stilbenes synthesized by an intramolecular cascade cyclization. Org... 

Tricyclic skeletons such as 85, 87, 89 with a central benzene ring are formed in the fully intramolecular Pd-catalyzed cascade cyclization of 2-bromo-l-ene-//,w-diynes 84, 86, 88 and analogs (Scheme 24). This process involves two alkyne relays in a row and a final 67r-electrocyclization or 6-endo-trig carbopalladation with ensuing / -dehydropalladation. 

Scheme 37 Two cascade cyclizations involving inter- or intramolecular carbopalladations of allenes.

Yttrium-catalyzed cascade cyclization/hydrosilylation of 3-(3-butynyl)-l,5-hexadienes was stereospecific, and syn-19 (R =Gy, R = OGPh3) underwent cascade cyclization/hydrosilylation to form 80b (R = Gy, R = OGPh3) in 97% yield as a single diastereomer (Scheme 20). The regio- and stereoselective conversion of syn-19 to 80b was proposed to occur through an initial 5- x -intramolecular carbometallation via a chairlike transition state that resembles alkenyl olefin eomplex syn- m. followed by S-exo intramolecular carbometallation via a boatlike transition state that resembles alkyl olefin complex boat-llm. The second intramolecular carbometallation presumably occurs via a boatlike transition state to avoid the unfavorable 1,3-interaction present in the corresponding chairlike transition state (Scheme 20). 

Rhodium carbonyl complexes also catalyze the cascade cyclization/hydrosilylation of 6-dodecene-l,l 1-diynes to form silylated tethered 2,2 -dimethylenebicyclopentanes. For example, reaction of ( )-85 with dimethylphenylsilane catalyzed by Rh(acac)(CO)2 in toluene at 50 °G under GO (1 atm) gave 86a in 55% yield as a single diastereomer (Equation (56)). Rhodium-catalyzed caseade cyclization/hydrosilylation of enediynes was stereospecific, and reaction of (Z)-85 under the conditions noted above gave 86b in 50% yield as a single diastereomer (Equation (57)). Rhodium(i)-catalyzed cascade cyclization/hydrosilylation of 6-dodecene-1,11-diynes was proposed to occur via silyl-metallation of one of the terminal G=G bonds of the enediyne with a silyl-Rh(iii) hydride complex, followed by two sequential intramolecular carbometallations and G-H reductive elimination. ... 

Reaction of cyclic sulfates with intramolecular O-nucleophiles leads to cyclic ethers and other heterocycles (Table 1). For example, a hydrolysis of compound 39 has produced predominantly the cyclic alcohols 41 (Scheme 4) < 1995JA12873 >. When the reaction was buffered with pyridine, the sulfate ester 40 was isolated rather than the free alcohol. An alcohol function in an intermediate product may give a route to a polysulfate cascade cyclization, which has been successfully realized in the synthesis of poly(tetrahydrofurans) (Table 1) <1995JA12873>. 

Selective synthesis of benzene derivatives via partially intramolecular cyclic carbopalladation is considerably more complex than the corresponding all-intramolecular processes. As it is generally difficult to specify the cascade-initiation point in the Type Ha cyclization process, it would generally be the least selective path. A priori, the most favorable might be the intra-inter cascade cyclization process (Type lib), since both the point of initiation and the queuing order between the two alkynes is sharply differentiated by the fact that one is intramolecular, while the other is intermolecular. Still, in-... 

The synthesis of complex polycyclic molecules has been achieved by Montgomery et al. by cascade cyclization processes involving nickel enolates [40]. Up to three cycles could be generated in the intramolecular version of the reaction. Alkynyl enal or enone were first converted into their corresponding seven-membered cyclic enolates in the presence of Ni(cod)2/TMEDA [41 ]. These species could be trapped by electrophiles such as aldehydes. For example, upon treatment with the nickel catalyst, dialdehyde 32 afforded spiro-cycle 35 in 49% yield as a single diastereomer (Scheme 17). 

The use of alkenes as sources of electrophiles in Friedel-Crafts alkylations has also been studied. The intramolecular alkylation of l-(2-tolyl)-( )-pent-3-ene gives 1,5-dimethyl-l,2,3,4-tetrahydronaphthalene in 95 % yield [55]. BF3 has been shown to form a complex with nitromethane which is particularly effective in catalyzing proton-initiated cascade cyclization like that shown in Eq. (29) [56]. 

The propagation steps of the zipper -mode cascade cyclization are by definition all-intramolecular processes. Some prototypical examples of the zip-per -mode cascade cyclic carbopalladation producing two to five fused rings in one step are summarized in Scheme 40 [11,113-116,122]. One of the major attractive features of this synthetic methodology is the ease of retrosynthetic analysis, which involves finding a linear line of dissection indicated in bro-... 

We will encounter more of these fantastic tandem cascade Pd-induced cyclizations in Chapter 3. Using microwave heating, Beccalli and co-workers performed an intramolecular Heck cyclization with pyrrole 211 leading to tricycle 212 in excellent yield [127]. 

The fully iniramolecular Pd-catalyzed cascade cyclization of 2-bromo-l-ene-n,m-diynes is a reliable access to tricyclic system in which the central benzene moiety is formed by a formal [2 + 2 + 2] assembly as long as both rings initially formed by intramolecular carbopalla-dation are flve-membered or at most six-membered (Scheme The yields range from... 

Intramolecular six-membered ring formation is also efficient. Treatment of bisdiene 62a with 0.05 equiv of a [Pd(OAc)2/3 PhjP] mixture in THF (65 °C, 24 h) affords the cyclized and intramolecularly trapped diene 63a in good chemical yield (82%) and with good diastereoselectivity (9 1 mixture of two diastereomers) (Scheme 20). The conversion of 62a to 63a is a unique cascade cyclization in that it constructs two new six-membered rings via the net 1,4-addition of the elements carbon and oxygen across a diene subunit. Three stereochemical elements are controlled in the cyclization of 62a to 63a. Two of these elements, the ( )-configuration of the double bond and the trans... 

An intramolecular diastereoselective cascade cyclization reaction of salen with POCI3, gave rise to a new compound 212 that contains two new stereogenic phosphorus atoms and two new stereogenic carbon atoms in the oxadiazepine ring (14PS226). The polycycHc compound, bis(chlorophosphorylated) decahydro-2,4-di(2-hydroxyphenyl)benzo[chiral carbon atoms in the -position to phosphorus. 

Cyclohydrocarbonylation (CHC) is the hydroformylation of a functionalized olefin followed by concomitant intramolecular nucleophillic attack to the newly formed aldehyde moiety leading to a cyclized product. As a variant, the CHC reaction also includes an intramolecular cascade process involving the hydrocarbonylation of a functional alkene, generating an acyl-metal intermediate, which undergoes an intramolecular nucleophilic attack to give the corresponding cyclic compound. CHC reactions have been developed into sophisticated cascade reactions forming bicylic and polycyclic compounds. ... 

The first example of an enantioselective intramolecular cascade Mizoroki-Heck-cyanation sequence was recently reported which included the reaction of amide 104 (Scheme 12.24) [33], The cyanide source employed was potassium ferro(II)cyanide, which has been utilized for the palladium-catalysed cyanation of aryl halides. The proposed reaction pathway for the Mizoroki-Heck-cyanation involves capture of a a-alkylpalladium intermediate. Previous examples of enantioselective Mizoroki-Heck cyclization-anion capture most often involve trapping of the 7r-allylpalladium complexes in group-selective reactions. Reaction conditions were surveyed for the Mizoroki-Heck cyanation sequence. It was found that Pd(dba)2 afforded better enantioselectivities than Pd(OAc)2 with Ag3P04 as the additive. Using PMP under neutral conditions led to racemic product. To improve the enantioselectivity, several bidentate ligands were screened, and the ligand DIFLUORPHOS 54a was found to give the best enantioselectivity. 

The identification of novel ways to incorporate an asymmetric intramolecular Mizoroki-Heck reaction as part of a cascade cyclization sequence has led to attractive approaches for assembling complex polycyclic molecules. Keay and coworkers [54] reported the use of a double Mizoroki-Heck cyclization as the pivotal step in the asymmetric total synthesis of xestoquinone (93), a reduced congener of halenaquinone (Scheme 16.20). In this step, naphthyl triflate 90 was cyclized with Pd2(dba)3 (dba = dibenzylideneace-tone), (5 )-BINAP and 1,2,2,6,6-pentamethylpiperidine (PMP) in toluene at 110°C to give pentacyclic product 92 with impressive efficiency and moderate enantioselectivity. This conversion proceeds by initial asymmetric 6-exo Mizoroki-Heck cyclization to form the central six-membered carbocycle and install the benzylic quaternary stereocentre. The first cyclization event is followed by a second Mizoroki-Heck reaction in which neopentyl... 

Moreover, several resveratrol-derived natural products can be synthesized by a palladium-catalyzed cascade reaction of bromostilbene derivative 121 and tolane 122 (Scheme 60) (110). In this cascade reaction, intermolecular Heck reaction proceeds first, followed by intramolecular Heck cyclization to give the desired carbon framework of dimeric resveratrol natural products. 

Scheme 3.44b).Another efficient palladium-catalyzed intramolecular carbopalladation-cyclization cascade toward tetra- and pentacyclic N-fused heterocycles was developed in 2010. This transformation proceeds via the palladium-catalyzed coupling of aryl halides with internal propargylic esters or ethers followed by a 5-endo-dig cyclization leading to polycyclic pyrrolo-heterocycles in moderate to excellent yields (Scheme 3.44c). 

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