Activation cyclization

Thus, intramolecular activation (cyclization-elimination) in this series is modulated by steric factors. In addition, hydrolysis may be enzyme-catalyzed, depending on substrates and biological conditions. 

While in most reported cases the nucleophiles were amines, there were few examples involving heterocyclic nitrogens [40], alcoholic oxygens [27] or carbon nucleophiles [42, 43] too. Figure 4 shows a recent example of tandem Ugi-Dieckmann protocol [42]. Ugi convertible isocyanide 2, which requires a basic activation, was used, allowing a domino activation-cyclization of the intermediate 20 to give pyrrolidinediones (tetramic acids) 22. 

Rhoden CRB, Rivera DG, Kreye O, Bauer AK, Westermann B, Wessjohann LA (2009) Rapid Access to N-substituted diketopiperazines by one-pot Ugi-4CR/deprotection -I- activation/ cyclization (UDAC). J Comb Chem 11(6) 1078-1082... 

The combination of pept(o)id-introducing MCRs with subsequent and efficient post-condensation transformations, especially ring-closing protocols, is an efficient concept to produce (cyclic) pseudopeptides. The most important versions make use of protected or convertible functional building blocks to allow later condensation, specially cycfization. Most relevant are Ugi-deprotection-cyclization (UDC), Ugi-activation-cyclization (UAC), and the Ugi-deprotection-activation-cycfization (UDAC), which take advantage of the diverse functionalities incorporated into the previously synthesized MCR-adduct as bi- or polyfunctional building block (Fig. 3) [15, 16]. 

Shifting the side chain to the 4 position (with the necessary tautomeric change) affords an agent with local anesthetic and coronary vasodilator activity. Cyclization of compound 147 by means of phosphorus oxychloride gives the amino-l,2,4-oxodiazole (148) Alkylation of that compound with 2-chlorotriethylamine in the presence of sodium hydroxide proceeds via the tautomer,... 

Inamoto and Doi used C-H activation/cyclization of (V-tosylenamines to prepare 3-arylindoles (equation 3) [35]. The substrates were prepared from symmetrically substituted benzophenones. Chiba s team employed 0-acyloximes to effect a synthesis of indole-3-carboxam-ides (equation 4) [36]. The groups of Queiroz [37] and Thasana [38] employed C-H activation/C-C bond formation to prepare complex indoles (equations 5 and 6). 

The same group [50] developed a remarkable enantioselective synthesis of chiral indenylamines 179 via domino Rh(I)-catalyzed C-H activation/cyclization of aryl ketimines 177 and internal alkynes 170 (a formal [3+2] cycloaddition) (Scheme 3.46). A major challenge of this transformation was the requirement of a catalyst that could accommodate the many different steps in the reaction sequence and show selectivity for instance, imine-directed ortho C-H activation/... 

An active cyclization catalyst will have the function of reducing the exothermicity of the reaction, enabling higher temperatures to be used, thus increasing the rate of O2 diffusion. 

The formation of 2-alkenyl-substituted furans was observed in the palladium-catalyzed cross-coupling reactions between benzyl, aryl, or allyl bromides and conjugated ene-yne-ketones. This reaction involved oxidative addition, alkyne activation-cyclization, palladium carbene migratory insertion, P-hydride elimination, and catalyst regeneration (13JA13502). 

Pinto etal. [52] have reported a consecutive three-component synthesis of oxin-doles that proceeds in the sense of a Sonogashira alkynylation-carbopalladation-CH activation-cyclization sequence, furnishing 3-(diarylmethylene)oxindoles 31 in moderate to good yields (Scheme 12.20). 

Scheme 12.20 Sequentially Pd/Cu-catalyzed Sonogashira carbopalladation-CH activation-cyclization synthesis of 3-(diarylmethylene)indolin-2-ones 31.

The same authors disclosed a convergent three-component access to the indolone scaffold by a sequentially Pd-catalyzed N-arylation-carbopalladation-CH activation-cyclization process [53]. Without further addition of catalyst or ligands after the AT-arylation of the secondary propiolamide, a second aryliodide concludes the synthesis of 3-(diarylmethylene)indolin-2-ones 32 in moderate to good yields via an intermolecular carbopalladation-CH activation - arylation (Scheme 12.21). 

The synthesis of a group of benzofuranones has been accomplished through an intramolecular C—H activation/cyclization sequence catalyzed by palladium(II) acetate (Scheme 2.66) [94]. An iodonium salt was used as the oxidant, and a protected amino acid derivative was used as an additive in the reaction. The authors proposed that the mechanism of the reaction included a Pd(ll)/Pd(IV) cycle and that the oxidant was needed to oxidize the palladium during the catalysis. 

You et al. developed a simple and convenient method for the synthesis of cinno-lines 87 by Rh-catalyzed oxidative C-H activation/cyclization of azo compounds with alkynes [45]. In this reaction, -Bu acts as a leaving group and also promotes the C-N reductive elimination however, the reaction works only for aliphatic internal alkynes with moderate yield (Eq. (5.84)). 

Cui and coworkers reported a Rh(III)-catalyzed C-H activation/cyclization of indoles and pyrroles at the C2 position with various alkyne and alkene substrates to give pyrimidin-2(l//)-ones and 3,4-dihydropyrimidin-2(l//)-ones 101 (Eq. (5.98)) [51]. The reaction tolerates a wide range of substituents on the aromatic rings. Moreover, both symmetrical and unsymmetrical alkynes/alkenes with various functional groups, such as hydroxyl, nitrile, and ester, also react efficiently to provide the expected JV-heterocycles in good to excellent yields. 

A new Rh(III)-catalyzed intermolecular annulation of Af-methoxybenzamides with a, -unsaturated aldehydes or ketones to afford azepinones 118 was reported by Glorias eta/. (Eq. (5.109)) [56a]. The reaction involves a tandem C-H activation, cyclization, and condensation sequence. The substrates with other A/-substituents, such as H, phenyl, and OPiv, did not afford the corresponding products. Vinylcarbenoids were also used as the three-carbon component in the Rh(III)-catalyzed C-H activation and [4-1-3] cycloaddition with benzamides to access azepinones (Eq. (5.110)) [56b]. 

More recently, Fei and coworkers have employed the Ugi/deprotection/activation/ cyclization strategy for their synthesis of DKPs 191 using CIC IW3 (Scheme 7.66) [74] Anhydrous HCl, which forms in situ, helps deprotect the Boc group and activates the amide carbonyl group derived from IW3. 

Similar conditions have promoted five-, six-, and seven-membered ring formations by intramolecular cyclization of arylboron compounds onto ketones (Scheme 31). " Biaryl methanols can be obtained from aryl aldehydes by Rh-catalysed addition of an aryl ring bearing an Al-direcfing group ortho to the activated Cyclization... 

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