Cycloadditions 6+2-1 path

The reaction mechanism proposed for the LiBr/NEta induced azomethine ylide cycloadditions to a,p-unsaturated carbonyl acceptors is illustrated in Scheme 11.10. The ( , )-ylides, reversibly generated from the imine esters, interact with acceptors under frontier orbital control, and the lithium atom of ylides coordinates with the carbonyl oxygen of the acceptors. Either through a direct cycloaddition (path a) or a sequence of Michael addition-intramolecular cyclization (path b), the cycloadducts are produced with endo- and regioselectivity. Path b is more likely, since in some cases Michael adducts are isolated. 

The above dramatic dependence of regio- and stereoselectivity on the nature of the metal can be explained by the reaction mechanism shown in Scheme 11.49 (167). The nitrone cycloadditions of allylic alcohols are again magnesium-specific just like the nitrile oxide reactions described in Section 11.2.2. Magnesium ions accelerate the reaction through a metal ion-bound intramolecular cycloaddition path. On the other hand, zinc ions afford no such rate acceleration, but these ions catalyze the acetalization at the benzoyl carbonyl moiety of the nitrone to provide a hemiacetal intermediate. The subsequent intramolecular regio- and stereoselective cycloaddition reaction gives the observed products. 

Anthracene undergoes a photochemical 9,10,9, 10 -cycloaddition which goes through the excimer as intermediate. Many aromatic molecules follow similar cycloaddition paths. The close approach of the molecules in the excimer is essential for bond formation, and steric hindrance can prevent the reaction unsubstituted anthracene dimerizes so fast that no excimer fluorescence can be detected, 9,10-dimethylanthracene shows both excimer fluorescence and photodimerization, but 9,10-diphenylanthracene shows neither excimer emission nor photodimerization (Figure 4.52). 

In the case of benzophenone, the cycloaddition competes with the isomerization of 103 to cycloheptatriene. Exclusive isomerization was observed with acetophenone and acetone. Carbonyl compounds with triplet energies lower than 69kcal/mol prefer the cycloaddition path. Cyclopent-2-en-l-one is an exception to this rule in spite of its triplet energy of 74 kcal/mol, 2 + 2 cycloadducts were formed rather efficiently. 

Recent reports detail a computational analysis of the photodimerization of 1,3-butadiene that located conical intersections for concerted [4+4] and [2+2] cycloaddition paths [19,20] and have correlated these results with the products observed experimentally [21]. 

It is clear from Fig. 9.10 that in the presence of L, enantioselection occurs during the conversion of 0s04 to 9.41. Two possible paths, one involving (3+2) cycloaddition (Path A) and the other (2+2) cycloaddition (Path B) have been proposed. These are shown in Fig. 9.11. In the former, two new C-O bonds are formed simultaneously. In the latter first a C-O and an Os-C bond... 

The process of ozone cycloaddition (path 1) implies postulates similar to those discussed by Huisgen (12) in terms of a 1,3-dipolar cycloaddition. Although the extent of simultaneity in the formation of the two C—O bonds is an open question, it is assumed that the transition state closely resembles the final state—the primary ozonide—and that its final conversion to give the primary ozonide occurs rapidly. The ratedetermining step is thus the addition of ozone on the olefin. The electrophilic tendency of ozone, which is shown in several cases to play a domi-... 

Section 2.2.5 and Figure 2.33), with the ethylene jt and n MOs (Houk, 1982). In the ortho approach, the benzene MOs and . can interact with the ethylene MOs jt and m, while in the meta approach, and 0,. can interact with Jt and Jt. Therefore, the configuration is predicted to be energetically favored along the ortho cycloaddition path, while the configuration d>s a is stabilized for the ortho and particularly the meta cycloaddition path. The magnitude of the stabilization depends on orbital overlap and relative orbital energies. The former factor favors the ortho approach and the latter the meta approach of the reactants. 

DBN (2) is prepared in 92% yield by treatment of A-(3-azidopropyl)-y-lactam with oxalyl bromide after quenching with anisole (run 3). A trace of the reaction by IR spectrum suggests the formation of a bromoiminium intermediate, which spontaneously cyclizes to the bicyclic system through either 1,2-addition (path A) or [3 + 2]cycloaddition (path B) (Scheme 3.12). 

This biogenetic proposal has spurred interest in the synthesis of structures such as (70). An especially efficient example of the use of intramolecular Diels-Alder reactions to synthesize aspidosperma alkaloids has been developed by Kuehne and co-workers <8373715, 85JOC924, 85JOC4790, 87JOC347). The azepino[4,S-6]indole structure (72) is condensed with a d-haloaldehyde generating (74), which undergoes fragmentation to (75) which contains the secodine synthon. With the secodine type structure only cycloaddition path b is available and aspidosperma structures are formed (76) (Scheme 148). 

Dimerization of o-fuchsones, generated from o-hydroxybenzyl halides by treatment with either triethylamine or a diethylamino-derivatized polymer, affords dibenzo[i>/][l,5]dioxocin (115) and dinaphtho analogues (116 Ar = Ph, 4-FQH4, 4-MeOC6H4) in unspecified yield (Scheme 34). These reactions are reported to follow a stepwise, ionic pathway rather than radical or concerted [ttSs + r8a] thermal cycloaddition paths <82CCC838>. Curiously, no [4 + 2] dimers are formed in these reactions, although such products are favored for simpler o-quinone methides. 

This method is an extension of the known ketene—imine procedure, which has been in use for -lactam formation since the beginning of the century [51]. Examples of this acid chloride - ketene route up to the end of 1971 have been reviewed by Mukerjee and Srivastava [52]. It is interesting to note that, depending upon the experimental conditions, both the concerted 1,2-cycloaddition path and another involving an acylation step and salt formation can be operative [53,54], The former is supported by the formation of by-products of dioxo-piperidine type [55,56]. Use of this procedure has provided a number of azaoctams of type (92) [46]. 

The intramolecular cycloaddition path can afford phanes with different aromatic nuclei. In fact, [2.3]paracyclo(l,4)naphthalenophane was prepared in 8% yield." The method has been applied to prepare [2.n](l,4)- 38, -(1,5)- 39, and -(2,7)naphthalenophanes (n > 3) in reasonable yields. [2.2] (l,4)Naphthalenophane cannot be synthesized by this route. 

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. 

Pasinszki and Westwood investigated the dimerization of chloronitrile oxide CICNO to 3,4-dichloro-l,2,5-oxadiazole-2-oxide 78 (Scheme 48) [98JPC(A) 4939]. From B3-LYP/6-31G calculations, they conclude that the reaction path can be characterized as a typical Firestone-type cycloaddition, a two-step mechanism with a C—C bond forming characterizing the first reaction step. The activation... 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

In an investigation by Yamabe et al. [9] of the fine tuning of the [4-1-2] and [2-1-4] cycloaddition reaction of acrolein with butadiene catalyzed by BF3 and AICI3 using a larger basis set and more sophisticated calculations, the different reaction paths were also studied. The activation energy for the uncatalyzed reaction were calculated to be 17.52 and 16.80 kcal mol for the exo and endo transition states, respectively, and is close to the experimental values for s-trans-acrolein. For the BF3-catalyzed reaction the transition-state energies were calculated to be 10.87 and 6.09 kcal mol , for the exo- and endo-reaction paths, respectively [9]. The calculated transition-state structures for this reaction are very asynchronous and similar to those obtained by Houk et al. The endo-reaction path for the BF3-catalyzed reaction indicates that an inverse electron-demand C3-0 bond formation (2.635 A... 

Benzyne shares a feature with A in the [2+2] cycloaddition reactions. The HOMO-LUMO interaction prefers the three-centered interaction (Scheme 4) [115]. This is in agreement with the calculated reaction path [116]. 

Cycloadditions with the Si(lOO) surface were theoretically [133] concluded to be reactions in the pseudoexcitation band. The conclusion is applicable to thermal [2+2] cycloaddition reactions of unsaturated bonds between heavy atoms. In fact, Sekiguchi, Nagase et al. confirmed that a Si triple bond underwent the stereospecific reactions with alkenes [137] along the path typical of [2+2] cycloaddition in the pseudoexcitation band. The stereospecific [2+2] cycloadditions of were designed by Inagaki et al. (Scheme 28) [138]. 

Oxazole formation can be envisaged as proceeding by three possible pathways 1,3-dipolar cycloaddition of a free ketocarbene to the nitiile (Path A), the formation and subsequent 1,5-cyclisation of a nitrile ylide (Path B) or the formation and subsequent rearrangement of a 2-acyl-2//-azirine (Path C) (Scheme 9). 

Cycloaddition reactions result in the formation of a new ring from two reactants. A concerted mechanism requires that a single transition state, and therefore no intermediate, lie on the reaction path between reactants and adduct. The most important example of cycloaddition is the Diels-Alder (D-A) reaction. The cycloaddition of alkenes and dienes is a very useful method for forming substituted cyclohexenes.1... 

Figure 13-2. Reaction path for the cycloaddition of ethylene to butadiene.

The homoallylation product 16a presumably stems from oxidative cycloaddition of a Ni(0) species across the diene and aldehyde moieties of 15, leading to an oxanickellacycle intermediate 17 (path A, Scheme 5), which undergoes 0-bond metathesis with triethylsilane giving rise to a o-allylnickel 19. On the other hand, formation of 16b may start with addition of a Ni - H species upon the diene followed by intramolecular nucleophilic allylation as described in Eqs. 4-6 (path B). Alternatively, allylic transposition of the NiH group providing 20 from 19 may be related to the formation of 16b. The different reactivity between cyclohexadiene and many other acyclic dienes is also observed for the reaction undertaken under typical homoallylation conditions (see Scheme 14). 

Two possible intramolecular disconnections are available for the [2.2.2] bicyclo-octane ring system (path A and path B, Scheme 1.4). The choice between the initial [4+2] disconnections A and B at first appears inconsequential leading to idealized intermediates of comparable complexity (54 and 57). However, when the [4+2] and [3+2] disconnections are considered in sequence, the difference becomes clear. For path A, retrosynthetic [3+2] disconnection of intermediate 54 leads to the conceptual precursor 56, which embodies a considerable simplification. In contrast, path B reveals a retrosynthetic [3+2] disconnection of intermediate 57 to provide the precursor 59, a considerably less simplified medium-ring bridged macrocycle. Thus, unification of the [3+2]/[4+2] dual cycloaddition strategy, using the staging... 

Isoxazolines 38 and 39 were obtained in different ratios by direct cycloaddition of 4-t-butylbenzonitrile oxide with acids 35 (R = H, path B) and by the intermediate formation of cyclodextrin derivatives 36 and 37 followed by basic hydrolysis and acidification (path A). The reversed regioselectivity as well as an increased rate of the cycloaddition step could be explained through the temporary association of the nitrile oxide with the cyclodextrin to give the inclusion complex 40 <06CEJ8571>. 

Langa et al. [26, 59, 60], while conducting the cycloaddition of N-methylazo-methine ylide with C70 fullerene, proposed a rather similar approach. Theoretical calculations predict an asynchronous mechanism, suggesting that this phenomenon can be explained by considering that, under kinetic control, microwave irradiation will favor the more polar path corresponding to the hardest transition state . 

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