Double annulation route

A convenient synthesis of highly functionalized dihydropyrido[2,3-tfjpyrimidines via a double [5 + l]-annulations stoategy was developed. The double annulation route starts from easily available a-alkenoyl-a-carbamoyl ketene-(5,S)-acetals. 2-Amino-3-carbamoyl-5,6-dihydro-4-pyridones was firstly created in excellent yield by a formal [5C + IN] annulation reaction of ketene-(iS. 5)-acetals with ammonia. In the second step, 7,8-dihydropyrido[2,3-d]pyrimidin-4(3/f)-ones (when R = aryl) and 7,8-dihydropyrido[2,3-d]pyrimidines (when R = H), were prepared in good yields by reacting 2-amino-3-carbamoyl-5,6-dihydro-4-pyridones with excessive Vilsmeier reagent (DMF/POCI3) via a second [5 + 1] annulation step. 

Carbopalladation of Arynes by Arylpalladium Complexes Pd-Catalyzed Annulation Reactions of Arynes. Whereas the Pd-catalyzed annulation of alkynes by aiyl halides has proven to be an effective method for the construction of a wide variety of hetero- and carbocycles similar carbopalladation of arynes were unprecedented until Larock and Zhang reported the synthesis of flu-oren-9-ones 115 through the annulation of arynes by o-haloarenecarboxaldehydes (Scheme 12.57) [100]. Larock s group has also developed a Pd-catalyzed annulation of arynes by 2-halobiaryls, affording polycyclic aromatic and hetCToaromatic compounds such as 116 from simple starting materials. Larock and Cheng have independently reported the related double annulation of arynes by simple aryl halides as an efficient route to functionalized triphenylenes (Scheme 12.57) [101]. 

Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 91 resulted in benzofuran 92 [80], Such an approach has become a popular means of synthesizing fused furans. Muratake et al. exploited the intramolecular Heck cyclization to establish the tricyclic core structure en route to the synthesis of a furan analog of duocarmycin SA, a potent cytotoxic antibiotic [81]. Under Jeffery s phase-transfer catalysis conditions, substrate 93 was converted to tricyclic derivatives 94 and 95 as an inseparable mixture (ca. 4 1) of two double bond isomers. 

The double iron-mediated arylamine cyclization provides a highly convergent route to indolo[2,3-fc]carbazole (Scheme 16). Double electrophilic substitution of m-phenylenediamine 34 by reaction with the complex salt 6a affords the diiron complex 35, which on oxidative cyclization using iodine in pyridine leads to indolo[2,3-b]carbazole 36 [98].Thus,ithasbeen demonstrated that the bidirectional annulation of two indole rings can be applied to the synthesis of indolocarbazoles. 

The diacetate of 711 has also been produced in stereoselective fashion via a route beginning with dicyclopentadiene (Scheme LXXVI) Ketone 712 was transformed into dimethylated alcohol 713 whose ozonolysis provided 714. Following Jones oxidation, decarboxylation with concomitant introduction of a double bond was realized by application of Kochi s prowdure. A lengthy quence of steps to adjust functionality led up to annulation by a modified Wichterle sequence. The conversion of 715 to 716 was accomplish by standard reactions. 

In a practical and efficient route to a 5-HT2c receptor agonist precursor, the aniline 106 was subjected to double metalation, followed by treatment with the morpholide 107, affording the intermediate 108, which via annulation eventually gave the indole 109 (Scheme 14) <20050PD508>. 

Since both oxidative splitting of the double bond and aldol condensation represent reliable and general reactions, their sequence serves as an efficient route for the transformation of readily available cyclohexene systems e.g. formed via the Diels-Alder reaction or Robinson annulation) into functionalized cyclopentene derivatives. This standard operational mode is extensively used in total syntheses. One of the numerous examples, the synthesis of helminthosporal 463, the sesquiterpenoid toxin of fungi, is shown in Scheme 2.150. In the initial phases of the synthesis, commercially available (—)-carvomenthone 464 was transformed into 465 via Michael reaction with methyl vinyl ketone to give 466 and subsequent intramolecular aldol condensation. 

A useful reaction for the synthesis of unsaturated seven-membered heterocycles is the (2 + 2)-cycloaddition of heteroaromatic compounds, e.g., 1 //-pyrrole, furan, or thiophene derivatives, with acetylenes. In combination with a subsequent intramolecular (2 + 2)-cycloreversion (Section IV,B,2) of the annulated cyclobutene moiety, ring enlargement with two carbon atoms can be achieved. 1-Heterocycloheptatrienes, such as benzol6]azepines,26,27,65,66 benzo[fc]oxepins,67,68 benzo[6]-thiepins,69,70 and thiepins,18,71 have been successfully prepared in this way other routes are either nonexistent or laborious.72 In these compounds the reacting carbon-carbon double bond constitutes part of a (4n + 2)7r-electron system and in the (2 + 2)-cycloaddition the resonance energy of the aromatic nucleus is lost. Just like the nonaromatic heterocycles, heteroaromatic compounds have been reported to undergo (2 + 2)-cycloaddition reactions both with electron-deficient and with electron-rich acetylenes. 

Among a host of other phosphine-catalysed reactions in which the initial step is the formation of a reactive phosphoniobetaine intermediate by addition to a carbon-carbon double or triple bond are intramolecular cyclisations leading to benzobicyclo[4,3,0]-compounds, " cyclic ethers " and lactones,and a great many intermolecular reactions, e.g., a [3 -b 3]-annulation of modified t-butyl allylic carbonates and alkylidenemalonitriles to give cyclohexenes,phosphine- (and fluoride)- catalysed routes to 1,4-benzothiazepines from cyclic sulfenamides and alkynes, a [4- -3]-annu-lation of allylic carbonates with methyl coumalate to give functionalised bicyclo[3.2.2]nonadienes, the a-carbon addition of cyanide ion, generated in situ from cyanohydrins, to activated alkynes, and a stereoselective... 

Csscade Heck Reaction. Besides cycloisomerization and related reactions, Pd(0) species also catalyzes cascade Heck reactions, which offer attractive routes to a wide variety of polycyclic compounds (99-101). For example, pyra-nosides 107 has been synthesized through 5-exo trig double Heck annulation of bromo-diene 106 in the presence of a catalytic amovmt of Pd(OAc)2 and PPha (Scheme 54) (102). 

In most of the prior syntheses, optically active starting materials were used to synthesize isocarbacyclin (4) and different analogs. Many of these synthetic routes involve either annulation of a five-membered ring onto an optically active cyclopentane derivative (8-11 Fig. 4) that is commercially available or using a starting material that already has a bicyclo[3.3.0]octane skeleton (12 and 13 Fig. 4). An issue that Umited these approaches is how to selectively introduce the endocyclic double bond. 

Oxidative annulations reaction of alkynes is one of the important methods to synthesize fused polycyclic heteroarenes [169-173]. Whereas the above examples show easy ruthenium catalysed insertions of alkynes into aromatic sp C-H bonds efforts have been made with related catalysts to perform the double insertion of alkynes into C-H and heteroatom-hydrogen bonds as a route to a variety of heterocycles. Chae S. Yi, has first shown, using ruthenium(ll) catalyst precursors [RuH(CO)(PCy3)2(NCMe)2]BF4 and preferably Ru3(CO)i2/NH4PF6, the alkenylation and double insertions of alkynes into C-H and N-H bonds for the transformation of indolines with terminal alkynes into quinoline derivatives [(Eq. 86)] [174, 175]. 

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