Transformation of a Six-membered Ring

There has only been one report of a transformation of a six-membered ring into a 1,2,3-triazine. Oxidation of 1-amino- 1 and 3-aminoquinazolin-2(1//Tones 2 with lead(IV) acetate afforded the 1,2,3-benzotriazines 3 in low yields.82... 

Transformations of a six-membered ring into a 1,2,3-triazine connectivity are rare. Two isomeric A -amino-4-methyl- (phenyl-) quinazolin-2-ones have been transformed with LTA into 4-methyl- (phenyl-) 1,2,3-benzotriazine in 23-24% yield <1975J(P1)31> see also CHEC(1984). A recent example is the rearrangement of the cyclic nitrosourea 289 under the influence of strong alkali into the unstable tetrahydro-l,2,3-triazine 11 (Equation 129) <1997SC1569> see also <2006BML427>. 

One of the rare examples, where the palladium catalyzed closure of a six membered ring leads to an aromatic heterocycle is presented in 4.18. Intramolecular transformation of the 2-bromoindole derivative in the presence of a palladium-BINAP catalyst led to the formation of the a-carboline (pyrido[2,3- ]indole) skeleton. The ring closure was accompanied by the oxidation of the intermediate dihydrocarboline derivative.21... 

Although most of the work with Rh-mediated intramolecular C-H insertion has focussed on five-membered ring construction, the first application to natural product synthesis, by Cane, involved establishment of a six-membered ring. Thus, on exposure to Rh2(OAc>4, diazoketone 2 was cyclized to the tricyclic lactone 3 [2. This product had previously been transformed by Paquette into pentalenolactone E (4) [3]. 

On the other hand, the other direction of addition (yd-addition) produces a monosubstituted alkylidene that is sterically comparable to the initiating alkylidene, making this the desired direction of addition. Formation of a six-membered ring in a reaction involving a more reactive terminal alkylidene would transform 43b into 44b. The NMR spectrum of poly-6 reveals two carbonyl carbon resonances. Therefore it was speculated that poly-6 consist of a random distribution of five- and six-membered rings formed through what is nominally tail-to-tail and head-to-head cyclopolymerization of the two acetylenic bonds in the same monomer (Scheme 1). Other uncertainties in catalyst systems of the type are the rate at which alkylidene rotamers interconvert, the extent to which the reactivities of the two alkylidene rotamers differ, and the degree of selective formation of one rotamer when a triple bond reacts with a Mo=C bond. ... 

Other interesting transformations in the heteroyohimbine series include a partial synthesis of dihydromancunine from hirsutine and the formation of eburnamonine analogues by the addition of a six-membered ring between C-14 and Na. 

A triple scission of a six-membered ring on the surface of C60 leading to one of the most remarkable transformations in metal-fullerene chemistry has been observed in 219. This reaction occurred via addition of CpCo(CO)2 on the bis-methano annulene 218 (Equation (36)). 

The second stage of the synthesis, the conversion of the tetracyclic intermediate (282) into steroids, requires the development of methods for introducing an angular substituent at C13 and transformation of the six-membered ring D into a five-membered ring (Scheme 107). 

As diazocarbonyl compounds bearing a substituent other than H on the diazobearing carbon, some cyclic diazoketones were applied to the Pd-mediated polymerization. The a,j3-unsaturated cyclic diazoketone 6 derived from cyclohexenone can be transformed into polymers with a unique structure, where the main chain carbon is one of carbon atoms of a six-membered ring [45] (Scheme 23). In addition, the C=C bond conjugated with C=0 would be directed outward from the main chain, which may render an attack of nucleophiles (1,4-conjugate addition) feasible. As expected, the addition of nucleophiles such as organolithium and sodium salt of diethyl malonate occurred by the reaction with the polymer. 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

The formation of a second ring, based on the generation of a six-membered carbanion followed by alkylation with a difunctional electrophile and further cyclization, was also exploited in the synthesis of hexahydropyrrolo[l,2-tf]pyr-azine-l,4-dione 235 starting from alkoxycarbonyl piperazine-2,5-dione 233. When the key precursor was treated with 2equiv of NaH and 1,3-dibromopropane, the bicyclic compound 234 was obtained in acceptable yield and further transformed into compound 235 by deprotection and decarboxylation (Scheme 30) <2005T8722>. 

Transition metal-catalyzed [4+ 2]-cycloadditions ofdiene-allenes 247 can lead to different results. With a nickel catalyst Wender et al. isolated the anellated system of two six-membered rings 248 with a rhodium catalyst the anellation of a five- and a six-membered ring 249 was possible (Scheme 15.78) [149]. Both transformations proceed readily at low temperatures whereas the uncatalyzed thermal reaction requires 185 °C. Even an anellation of a six- and a seven-membered ring was achieved. 

This type of transformation usually involves contraction of a seven-membered ring into a thermodynamically more stable five- or six-membered ring. 

It is not surprising, that the transition metal catalyzed carbon-heteroatom bond forming reactions constitute a major part of the transformations used for the preparation of heterocyclic systems. This chapter summarises all those catalytic transformations, where the six membered ring is formed in the intramolecular connection of a carbon atom and a heteroatom. Annulation reactions, involving the formation of a carbon-heteroatom bond are discussed in Chapter 4.4. 

The intramolecular nucleophilic attack of a nitrogen atom on an allylpalladium complex was also used to construct a five and a six membered heterocycle in the same step. TV-substituted 2-iodobenzamides bearing an allene function in the appropriate distance from the iodine underwent cyclization through the carbopalladation of the allene moiety by the arylpalladium complex, formed in the first step of the catalytic cycle. The intermediate allylpalladium complex, part of a nine membered ring, cyclized readily to give the pyrroloisoquinolone derivative in excellent yield (4.23.). The nature of the added ligand and the solvent both had a marked influence on the efficiency of the transformation.26... 

---