Cyclization cyclocarbonylation

Unusual cyclocarbonylation of allylic acetates proceeds in the presence of acetic anhydride and an amine to afford acetates of phenol derivatives. The cinnamyl acetate derivative 408 undergoes carbonylation and Friedel-Crafts-type cyclization to form the a-naphthyl acetate 410 under severe condi-tions[263,264]. The reaction proceeds at 140-170 under 50-70 atm of CO in the presence of acetic anhydride and Et N. Addition of acetic anhydride is essential for the cyclization. The key step seems to be the Friedel-Crafts-type cyclization of an acylpalladium complex as shown by 409. When MeOH is added instead of acetic anhydride, /3,7-unsaturated esters such as 388 are... 

Ring closure with formation of heterocyclic derivatives may occur when a nucleophilic function is present in the starting alkene and it is suitably placed for cyclization [30-43]. Both kind of the mechanistic pathways shown in path a of Scheme 3 and in Scheme 4 may operate, as exemplified by Schemes 5-6 (Y = O, NR). Clearly, only in the first case carbon monoxide is incorporated into the heterocyclic ring (cyclocarbonylation). 

All these reactions are examples of oxidative cyclocarbonylation-alkoxy-carbonylation. However, the Pdh/KI catalytic system turned out to be a very efficient catalyst also for promoting cyclization-alkoxycarbonylation processes. In fact, optimal conditions were found for selectively converting 4-yn-l-ols into tetrahydrofuran derivatives (Eq. 41) [107] through 5-exo-dig cyclization followed by alkoxycarbonylation (Scheme 19, path a). This kind of process was not possible for the propynyl, 3-yn-l-ol, and 2-ethynylaniline substrates, seen before, for stereoelectronic reasons [302], With the latter substrates, the endo cyclization mode (Scheme 19, path b), although in principle stereo electronically allowed, was not observed. 

Carbonylation of the 3-phenylallyl acetate 258 under somewhat severe conditions in the presence of tertiary amine and acetic anhydride affords the naphthyl acetate derivative 260. This interesting cyclocarbonylation is explained by the Friedel-Crafts-type cyclization of the acylpalladium 259 as an intermediate [118,119]. Even 5-phenyl-2,4-pentadienyl acetate (261) is cyclocarbonylated to afford 2-phenylphenyl acetate (262) [120],... 

Because unsaturated lactones and lactams are of importance as biologically active compounds, the carbonylative cyclization of alkynyl alcohols, alkynyl amines, and their allenyl derivatives has been extensively studied using various transition-metal complexes. Takahashi et al. [35] reported that Ru3(CO)12 also catalyzes the cyclocarbonylation of allenyl alcohols to five- to eight-membered unsaturated lactones (Eq. 20). 

Another important development in the area of catalytic Pauson-Khand type cy-clizations has been the discovery of other transition metal carbonyl complexes which are capable of effecting the catalytic synthesis of cyclopentenones. Two recent reports from Murai and Mitsudo detailed a Ru3(CO)i2-catalyzed enyne cyclocarbonylation, Eqs. (10) and (11) [34,35]. While this protocol allowed for the cyclization of a variety of l,6-enynes,the cyclizations of terminal alkynes as well as 1,7-enynes were problematic. The feasibility of using Cp2Ti(CO)2 as a catalyst for the intramolecular Pauson-Khand type cyclization of a variety of 1,6-and 1,7-enynes (vide infra) has also been demonstrated [36]. Based on the wide array of transition metals that are capable of effecting stoichiometric Pauson-Khand type cyclizations (vide supra), the development of more catalytic systems is to be expected this should greatly facilitate the search for catalytic asymmetric variants. 

In the course of studying the stoichiometric, carbonylative synthesis of y-buty-rolactones from enones and a titanocene complex [37], it was observed that certain aryl enones could be cyclocarbonylated in a catalytic manner, Eq. (12) [38]. This success in effecting a titanocene-catalyzed cyclocarbonylation led to an examination of the analogous reaction with enyne substrates. Indeed, it was found that under similar conditions, a titanocene-catalyzed Pauson-Khand type cyclization was possible, Eq. (13) [36]. 

Scheme 57. Heterocyclization of Alkenylamines and Alcohols via (a) Cyclization—/ -Hydride Elimination, (b) Cyclization—/ -Hydroxy Elimination, (c) Cyclization—Acetalization, (d) Cyclocarbonylation, and (e) Cyclization—Carbonylative Esterification...

Scheme 82. Heterocyclization of Alkynylamines, Amides, Alcohols, and Carboxylic Acids via (a) Cyclization-Protonolysis, (b) Cyclocarbonylation, (c) Cyclization-Esterification, and (d) Cyclization—Reductive Elimination3...

Reactions of acylpalladium complexes involving acylpalladation with arenes or formally equivalent processes have been much less exploited compared with those involving acylpalladation with alkenes or alkynes discussed in the previous section, and to the best of our knowledge, their examples are limited to intramolecular reactions. A few reactions that may include the intramolecular acylmetallation with arenes are known in the case of a rhodium catalyst, but the products are limited to a narrow range of compounds such as indenones.t In contrast, the Pd-catalyzed carbonylation of 3-arylaUyl acetates or hahdes, most typically cinnamyl acetate, involving intramolecular acylpalladation with arenes results in the construction of 1-naphthol, which is a hiding member of cyclic aromatic ketones. The outline of the conversion is sketched in Scheme 1. In fact, this type of carbonylation-cyclization reaction (cyclocarbonylation) can be applied to the synthesis of a variety of fused aromatics, which is summarized in the following subsection. 

Oxidative cyclocarbonylation-alkoxycarbonylation is usually observed when the reaction of alkenols and alkynols is carried out in the presence of external nucleophiles such as alcohols. /3-Lactones and /3-lactams bearing an exocyclic (Z)-(alkoxycar-bonyl)methylene moiety can be prepared according to a very simple oxidative technique starting from propynyl alcohols or amines. Geminal groups have been found to exert a powerful effect on cyclization. 

Quinazolinones are an important class of fused heterocycles that have been reported with remarkable activities in biology and pharmacology such as anticancer, antiinflammatory, anticonvulsant, antibacterial, antidiabetic, hypolipidemic, and protein tyrosine kinase inhibitors. Alper and Zheng reported a palladium-catalyzed cyclocarbonylation of o-iodoanilines with imidoyl chlorides to produce quinazolin-4(3H)-ones in 2008. A wide variety of substituted quinazolin-4(3H)-ones were prepared in 63-91% yields (Scheme 3.27a). The reaction is believed to proceed via in situ formation of an amidine, followed by oxidative addition, CO insertion, and intramolecular cyclization to give the substituted quinazolin-4(3H)-ones. Later on, a procedure was established based on generating the amidine in situ by a copper-catalyzed reaction of terminal allq nes, sulfonyl azide and o-iodo-anilines. The desired quinazolinones can be produced by carbonylation with Pd(OAc)2-DPPB-NEt3-THF as the reaction system. In the same year, Alper s group developed a procedure for 2,3-dihydro-4(lH)-quinazolinone preparation. The reaction started with the reaction of 2-iodoanilines and N-toluenesulfonyl aldimines followed by palladium-catalyzed intramolecular... 

The proposed mechanism for this cyclocarbonylation was shown to involve the insertion of Pd(0) species into the C—O bond of the substrate followed by rearrangement to the allenylpalladium intermediate 29 (as proposed for alkyl systems). Insertion of CO and subsequent reductive elimination may lead to the 2,3-dienoic acid 30, which undergoes cyclization, catalyzed by trace quantities of an acid present in the solvent, to the 2(5//)-furanone 28 (Scheme 10) (93JOC1538). 

The reaction of heterocumulenes or alkynes with ortho-iodoanilines under a carbon monoxide atmosphere has been shown to give4(3ff)-quinazolinones or 2-quinolones, respectively. A related cyclocarbonylation reaction has been used to synthesize new cardanol and cardol derivatives in a regioselective manner. Versatile and efficient routes to various spirocyclic compounds, including [5,5]-, [5,6]- and [5,7]-spiroindolines, have been established by exploiting a sequence of palladium-catalyzed cyclization processes (eq 105). ... 

Substituted-3-acylindoles have been prepared through the palladium-catalyzed carbonylative cyclization of 2 -alkynyltrifluoroacetanylides with vinyl triflates [102,106]. Analogously, the palladium-catalyzed cyclocarbonylation of bis(o-trifluoroacetamido-phenyl)acetylene 59 with vinyl halides and triflates afforded 12-acyUndolo[l,2-c] quinazoline derivatives in high yields. The palladium-catalyzed reaction of 59 with the vinyl triflates 60 at 50 ° C under 5 bar of carbon monoxide allowed the synthesis of the corresponding quinazoline derivative 61 in 98% yield (Scheme 9.29) [107]. 

Under oxidative conditions, acyclic [75a,b] and cyclic [75c] 4-yn-l-ols react via a cyclization-methoxycarbonylation pathway to afford ( )-cyclic-P-alkoxyacrylates 2E-[(methoxycarbonyl)methylene]tetrahydrofurans in good yields under mild conditions (Equations 10.37 and 10.38). The stereochemical outcome is entirely consistent with a reaction initiated by intramolecular nucleophilic attack of the hydroxy group on the palladium-coordinated triple bond to generate a vinylpalladiumiodide intermediate that undergoes methoxycarbonylation to afford the P-alkoxyacrylate. The ketopyranose subunit can also be constructed via a palladium-catalyzed oxidative cyclocarbonylation of substituted 5-yn-l-ols, which occurs with excellent stereose-... 

The common methods for the S5mthesis of p-lactams are cycloaddition reactions such as the Staudinger s ketene-imine cycloadditions, ester enolate-imine cycloadditions, alkyne-nitrone cycloadditions (Kinugasa reaction), alkene-isocyanate cycloadditions, and Torii s cyclocarbonylation of allyl halides with imines. Several cyclizahon reactions of p-amino esters, p-amino acids, p-hydroxamate esters, and a-diazocarbonyls have been developed for the formation of p-lactam ring. N,N-Disubstituted a-haloamides cyclize by C3-C4 bond formation leading to the formation of P-lactam ring. 

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