Other Five-Membered Ring Formations

As with five-membered ring formation, the reactions of ADC compounds which lead to six-membered ring heterocycles can be classified according to how the ADC compound reacts in the initial step. Most common is the Diels-Alder reaction, with the ADC compound acting as dienophile. Six-membered rings also result from the reaction of monoenes with ADC compounds acting as the 4n component, and by cyclization or other transformation of an initial adduct. 

Regiocontrol in intramolecular cyclopropanation is mainly dependent on the site of the unsaturated centre related to the carbenoid centre. In other words, ring size of the bicyclic or polycyclic systems which derive from the cyclopropanation is the key to regiocontrol of this type of reaction. The regioselectivity is independent of the catalyst employed, Five-membered ring formation is favoured over the production of six- or seven-membered rings... 

Five-membered ring formation is very favourable as the conformation needed 4 is reasonable and transition state and product are unstrained. If you make a molecular model of a long chain and fold it round you will find that the atoms that approach each other have a 1,5-relationship. Folding a chain 12 to form a six-membered ring takes the nucleophile past the electrophile 12a and only when the chain folds up in a chair-like fashion can cyclisation 13 occur. 

Acetylation of pyrrole is difficult because if forms a 2 1 complex with stannic chloride (29CB226). Hence, under the conditions used for the other five-membered rings (i.e., acetic anhydride in the presence of one hundredth molar equivalent of stannic chloride or iodine), no reaction occurs, and only 20% acetylation is obtained if the molar proportion of the catalyst is reduced 10-fold. The effect of complex formation also shows up in the inhibition of stannic chloride-catalyzed acetylation of fu-ran or thiophene, on addition of pyrrole (67MI4). Catalyzed acetylation of 2-cyano-, 2-formyl-, or 2-methoxycarbonylpyrrole gives mainly 4-substitution (67CJC897) indicating that the catalyst must also be coordinated with the substrate l-methyl-3-nitropyrrole acetylates only in the 5-posi-tion (57CJC21). 

On the other hand, when the opposite Markovnikov bias occurs, due to tertiary carbocation formation, five-membered ring formation is favored and both the 6,5- and 6,6-fused bicyclic compounds are obtained, in an 82 18 ratio, in 70% overall yield13. 

Two routes are currently known to construct the pyrroloiminoquinone skeleton (Scheme 2). One is route a, in which the indole ring is first synthesized followed by imine formation. The other is route b, in which the dihydroquinoline ring is first formed followed by the five-membered ring formation. 

At 600 and 1200K, Ph + O2 is the overall dominant channel, followed by the phenoxy + O atom channel, both reactions have a noticeably dominance over the other channels. The third important channel is the contribution to Ph OOH, which is of significant importance at both 600 K and 1200 K. The calculations indicate that the five member ring formation, cyclopentene-yl radical, which dissociates to ODY(C5) + HC =0, is a more important path than the formation of the linear C C4DO and CO channel. A competition between two paths, Y(C5 0) + CO, and o-quinone + H, is observable at 1200 K, but at 600 K, the o-quinone + H... 

Several other synthetic methods are also in principle feasible. For example, for the preparation of H-H poly(methyl methacrylate) the cyclopolymerization of meth-acrylic acid derivatives if directed exclusively to the five-membered ring formation (42), and for the preparation of H-H polymers of olefins disubstituted on one carbon atom, the Wurtz synthesis has become feasible. (Eqn. 6,7.)... 

As shown in eq. (3.11), if a hetero atom such as nitrogen, sulfur or oxygen is located at the / -position of the aromatic ring, the lithium metal at first is coordinated by the hetero atom and activated, and then it forms a stable five-membered ring by electrophilic attack at the ortho carbon. The five-membered ring formation reaction as shown in eq. (3.11), proceeds easily not only with lithium but also with the many other metals. This reaction is called orthometalation or cyclometalation [30]. For example, the five-membered ring compounds are produced by reaction of dimethylaminomethybenzene with alkyllithium as shown in eq. (3.12) [31-33]. Similar reactions are known on the compounds of metals such as Si, Sn, Hg, Mn, Cu, Ni, Cr, Co, Pt, Pd, Rh, Ti, V, Sc, Y, La, Nd and Er. [30]. 

In the alkylative cyclization of the 1,6-enyne 372 with vinyl bromide, formation of both the five-membered ring 373 by exn mode carbopalladation and isomerization of the double bonds and the six-membered ring 374 by endo mode carbopalladation are observed[269]. Their ratio depends on the catalytic species. Also, the cyclization of the 1,6-enyne 375 with /i-bromostyrene (376) affords the endo product 377. The exo mode cyclization is commonly observed in many cases, and there are two possible mechanistic explanations for that observed in these examples. One is direct endo mode carbopalladation. The other is the exo mode carbopalladation to give 378 followed by cyclopropana-tion to form 379, and the subsequent cyclopropylcarbinyl-homoallyl rearrangement affords the six-membered ring 380. Careful determination of the E or Z structure of the double bond in the cyclized product 380 is crucial for the mechanistic discussion. 

When formation of either the five- or six-membered ring was possible for N-chloroamine 37, only the five-membered ring was conducive under the Hofmann-Ldffler-Freytag reaction conditions, forming exclusively 6-ethyl-6-aza-bicyclo[3.2.1]-octane (38). No 2-ethyl-2-aza-bicyclo[2.2.2]-octane (39) was observed. On the other hand, 2-methyl-2-aza-bicyclo[2,2.2]octan-6-one (41) was installed by UV irradiation of a solution of A -chloroamine 40 in TFA. Ironically, when the ketone functionality on 40 was protected as its ethylene ketal group, the resultant steric interactions completely prohibited the classic Hofmann-Loffler-Freytag reaction. 

Cyclopolymerizations of other 1,6-dienes afford varying ratios of five- and six-membered ring products depending on the substitution pattern of the starting diene. Substitution of the olefinic methine hydrogen (e.g. 11, R- CH3) causes a shift from five- to six-membered ring formation. More bulky R substituents can prevent efficient cvclization and cross-linked polymers may result. 

Similar cis stereoselectivity was observed in formation of four- and five-membered rings.86 The origin of this stereoselectivity was probed systematically by a study in which a methyl substituent was placed at the C(3), C(4), C(5), and C(6) positions of ethyl 7-bromoheptanoate. Good (>93%) stereoselectivity was noted for all but the C(5) derivative.87 These results are consistent with a chairlike TS with the enolate in an equatorial-like position. In each case the additional methyl group can occupy an equatorial position. The reduced selectivity of the 5-methyl isomer may be due to the fact that the methyl group is farther from the reaction site than in the other cases. 

As mentioned in CHEC-II(1996), three main routes have been reported for the formation of furazan rings (1) the dehydrative cyclisation of 1,2-dioxims (2) the deoxygenation of furoxans and (3) the Boulton-Katritzky rearrangement of other five-membered heterocyclic systems <1996CHEC-II(4)229>. In this section the recent publications on the synthesis of furazans published after 1996 are discussed. 

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