Aromaticity 2+2+2 cycloadditions

In contrast to considerations of 50 years ago, today carbene and nitrene chemistries are integral to synthetic design and applications. Always a unique methodology for the synthesis of cyclopropane and cyclopropene compounds, applications of carbene chemistry have been extended with notable success to insertion reactions, aromatic cycloaddition and substitution, and ylide generation and reactions. And metathesis is in the lexicon of everyone planning the synthesis of an organic compound. Intramolecular reactions now extend to ring sizes well beyond 20, and insertion reactions can be effectively and selectively implemented even for intermolecular processes. 

The photochemical dimerization of unsaturated hydrocarbons such as olefins and aromatics, cycloaddition reactions including the addition of 02 ( A ) to form endoperoxides and photochemical Diels-Alders reaction can be rationalized by the Woodward-Hoffman Rule. The rule is based on the principle that the symmetry of the reactants must be conserved in the products. From the analysis of the orbital and state symmetries of the initial and final state, a state correlation diagram can be set up which immediately helps to make predictions regarding the feasibility of the reaction. If a reaction is not allowed by the rule for the conservation of symmetry, it may not occur even if thermodynamically allowed. 

Thus changing the ligands on dirhodium(II) can provide a switch which, in some cases, can turn competitive transformations on or ofT146. Other examples include the use of dirhodium(II) carboxamides to promote cyclopropanation and suppress aromatic cycloaddition146. For example, catalytic decomposition of diazoketone 105 with dirhodium(II) caprolactamate [Rh2(cap)4] provides only cyclopropanation product 106. In contrast, dirhodium(II) perfluorobutyrate [Rh2(pfb)4] or dirhodium(II)triphenylacetate [Rh2(tpa)4] gave the aromatic cycloaddition product 107 exclusively (equation 100)l46 148. Although we have already seen that rhodium(II) acetate catalysed decomposition of diazoketone 59, which bears both aromatic and olefinic functionalities, afforded stable norcaradiene 60 (equation 70)105, the rhodium(II) acetate catalysed carbenoid transformation within an acyclic system (108) showed no chemoselectivity (equation 101). However, when dirhodi-um(II) carboxamides were employed as catalysts for this type of transformation, only cyclopropanation product 109 was obtained (equation 101). ... 

Cyclopropanation reactions are one set in an array of C-C bond-forming transformations attributable to metal carbenes (Scheme 5.1) and are often mistakenly referred to by the nonspecific term carbenoid. Both cyclopropanation and cyclopropenation reactions, as well as the related aromatic cycloaddition process, occur by addition. Ylide formation is an association transformation, and insertion requires no further definition. All of these reactions occur with diazo compounds, preferably those with at least one attached carbonyl group. Several general reviews of diazo compounds and their reactions have been published recently and serve as valuable references to this rapidly expanding field [7-10]. The book by Doyle, McKervey, and Ye [7] provides an intensive and thorough overview of the field through 19% and part of 1997. 

N — H insertion generally proceeds unidirectionally, C—H insertion leading to a four-membered ring is not infrequently accompanied by C—H insertion, yielding a five-membered ring, and also by aromatic cycloaddition, ylide formation, etc. Few other carbene reactions are employed in the synthesis of azetidines, and their mechanisms are not always clear. 

Intramolecular C—H insertion of carbenoids derived from diazoacetamides provides one of the most convenient routes to y-lactams. However, synthetic application of this reaction may be restricted by the competitive formation of either )8-lactams through aliphatic C—H insertion of 5-lactams through aromatic cycloaddition, etc. The competition between aromatic cydoaddition and C—H insertion is profoundly influenced by the choice of the dirhodium(II) ligand. With diazoacetamide 116 (R = H), Rh2(cap)4 provides y-lactam 117 (R = H) and virtually no 118 (R = H) but Rh2 (acam)4, like Rh2(OAc)4, gives a mixture of the two products 117 and 118 (R = H). With the nitro derivative 116 (R = NO2), use of Rh2(acam)4 results in y-lactam 117 (R = NO2) in 90% yield (92JA1874 93JA8669). 

Comparable levels of stereocontrol were observed in the Rh2(MEPY)4-catalyzed lactonization in Eq. (41) (76% ee) competition from intramolecular aromatic cycloaddition reduced somewhat the chemoselectivity of the reaction [58]. 

In cyclopropanation of styrene with ethyl diazoacetate, Brunner et al. obtained products for which the ee was less than 12<7o, and in an intramolecular cyclopropanation McKervey s group also reached only 12%. In applications to aromatic cycloaddition and CH insertion reactions, ee was higher, but still less than 40%. 

There are several examples of catalyzed aromatic cycloadditions leading to heterocyclic systems. The rhodium(II) acetate-catalyzed intramolecular Buchner reactions of iV-benzyldiazoacetamides 64a/b afford azabicyclo[5.3.0]decatrienes 66a/b in excellent yields. In contrast, the N-methyl derivative 64c gives 66c in moderate yield. Use of rhodium(II) perfluorobutyrate (Rh2(pfb)4) in place of rhodium(II) acetate increases the yield to 54%. Unlike its carbon counterpart, dihydroazulenone 29a (vide supra), 66a is insensitive to either trifluoroacetic acid or boron trifluoride etherate, even in excess, and the unrearranged reactant is recovered intact even after prolonged treatment at room temperature. 

Diazoketones also undergo macrocyclic aromatic cycloaddition reactions. Decomposition of 108 with rhodium(II) prefluorobutyrate yields aromatic cycloaddition products 109 and 110 in 30% and 9% yield, respectively. When cycloheptatriene 109 is exposed to neutral alumina, isomerization to 111 occurs. It is interesting that the 1,4-isomer 110 is inert to rearrangement on both silica and alumina. The ability to formally connect a carbene to a remote aromatic ring provides new opportunities for the construction of macrocyclic compounds. 

The competition between ylide formation and aromatic cycloaddition has also evaluated. Decomposition of diazo acetate 120 in the presence of Rh2(45 -MEOX)4 leads to the sole production of the aromatic cycloaddition product 121 in 55% yield and 84% ee. 

A number of catalysts have been investigated for aromatic cycloaddition on the basic naphthalene system 122. In this case, Rh2(45-1BAZ)4 is superior even to Rh2(4i -MEOX)4 catalyst for highly enantioselective aromatic cycloaddition. 

Bisisomaleimide, hexamethylene, rearrangement to bisimide, 89 Bismaleimides aliphatic, crosslinked, 511 alkenylphenols condensation, 514 aromatic cycloaddition reactions, 266 azomethine condensations, 515 condensation polymer modifiers, 511 crosslinking monomers, 91 crotonitrile condensations, 515 dialdoximes condensation, 514... 

Kohmoto, S., Kobayashi, T., Minami, J., Ying, X., Yamaguchi, K., Karatsu, T., Kitamura, A., Kish-ikawa, K., and Yamamoto, M., Trapping of 1,8-biradical intermediates by molecular oxygen in photocycloaddition of naphthyl-N-(naphthylcarbonyl) carboxamides formation of novel 1,8-epid-ioxides and evidence of stepwise aromatic cycloaddition, /. Org. Chem., 66, 66, 2001. 

Diels-Alder [4 + 2] Cycloadditions. Except as noted below, diethyl azodicarboxylate reacts with conjugated dienes to yield [4 + 2] cycloadducts. When the diene moiety is a vinyl aromatic, cycloaddition with DAD is a powerful route for the preparation of annulated tetrahydropyridazine derivatives. Thus the indole derivative (4) reacts with DAD at rt to afford cycloadduct (5) (eq 8). ... 

The benzene derivative 401 by the intermolecular insertion of acrylate[278], A formal [2 + 2+2] cycloaddition takes place by the reaction of 2-iodonitroben-zene with the 1,6-enyne 402. The neopentylpalladium intermediate 403 undergoes 6-endo-lrig cyclization on to the aromatic ring to give 404[279],... 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

The distinction between these two classes of reactions is semantic for the five-membered rings Diels-Alder reaction at the F/B positions in (269) (four atom fragment) is equivalent to 1,3-dipolar cycloaddition in (270) across the three-atom fragment, both providing the 47t-electron component of the cycloaddition. Oxazoles and isoxazoles and their polyaza analogues show reduced aromatic character and will undergo many cycloadditions, whereas fully nitrogenous azoles such as pyrazoles and imidazoles do not, except in certain isolated cases. 

In this section, reactivity studies will be emphasized while in those devoted to synthesis (Section 4.04.3) theoretical calculations on reactions leading to the formation of pyrazoles (mainly 1,3-dipolar cycloadditions) will be discussed. It should be emphasized that the theoretical treatment of reactivity is a very complicated problem and for this reason, most of the calculations have been carried out on aromatic compounds, as they are the easiest to handle. In general, solvents are not taken into account thus, at the best, the situation described theoretically corresponds to reactions taking place in the gas phase. 

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