Meta cycloaddition

Making elegant use of the intramolecular arene-olefin meta-cycloaddition reaction, Wender and Howbert have achieved a total synthesis of ( + )-cedrene (575) Irradiation of 569 led to an approximately equal mixture of 570 and 571 which... 

OnBu f. .OnBu ortho meta cycloaddition rate = 2.7 1 12,108, 120... 

For photocycloaddition, to benzene the following conclusions were drawn from this empirical correlation [124], Olefins with poor electron-donor or poor electron-acceptor abilities yield mainly meta adducts with benzene (i.e., if AG > 1.4-1.6 eV, all other olefins yield mainly ortho adducts). Even ethene, which had seemed to behave exceptionally, fits into this correlation provided that it acts as the acceptor. The transition area from ortho to meta cycloaddition (i.e., the AG region where ortho meta = 1 1) is relatively large ( 0.2 eV). This is considered not to be surprising because the AG correlation is based on many different types of olefins. When only AG values for derivatives of 1,3-dioxole and for 1,4-dioxene were used, the transition area was narrowed to 0.03 eV. Not only ethene but also vinylene carbonate now fit into the correlation. According to the ionization potential rule, this compound should give only ortho photocycloaddition with benzene. Mattay s empirical rule predicts mainly meta addition, which is indeed found experimentally. 

A correlation between free enthalpy of electron transfer and mode of the photoreaction was also constructed for addition of alkenes to benzonitrile. Four areas could be differentiated Full electron transfer, leading to substitution, is only observed if AG < 0 eV cycloaddition to the cyano group occurs if 0 < AG < 0.4 eV. All olefins for which AG > 0.4 eV preferentially undergo cycloaddition to the aromatic ring, ortho cycloaddition if AG < 1.7 eV and meta cycloaddition if AG > 1.7 eV. 

Excellent regioselectivity and stereoselectivity has been achieved in each photocycloaddition mode [45 48], Regiochemistry and stereochemistry in the meta process is decided by the orientation of the addends in the exciplex and by stabilization of biradical intermediates having a change transfer (CT) character (6) by the substituents on the arene. Intermolecular meta cycloaddition of arenes with cycloalkenes proceeds with endo selectivity (7) (Scheme 5). In the ortho-process, selectivities can be controlled mainly by the substituents on the reactants. 

Morrison reported that inms-decalin (181) is photochemically inert, but the cis isomer (182) undergoes a singlet-derived, intramolecular meta cycloaddition to give 183 (Scheme 54). Compound 183 efficiently photocycloeliminates to give a carbene-derived product 184 [238],... 

Guo, X.-C. and Chen, Q.-Y. (1999) Photo-induced intramolecular arene-olefin meta-cycloaddition of 5-phenyl-fluorinated-pent-l-enes. Journal of Fluorine Chemistry, 97 (1—2), 149-156. 

A variety of four-membered ring compounds can be obtained with photochemical reactions of aromatic compounds, mainly with the [2 + 2] (ortho) photocycloaddition of alkenes. In the case of aromatic compounds of the benzene type, this reaction is often in competition with the [3 + 2] (meta) cycloaddition, and less frequently with the [4 + 2] (para) cycloaddition (Scheme 5.7) [38-40]. When the aromatic reaction partner is electronically excited, both reactions can occur at the 7t7t singlet state, but only the [2 + 2] addition can also proceed at the %% triplet state. Such competition was also discussed in the context of redox potentials of the reaction partners [17]. Most frequently, it is the electron-active substituents on the aromatic partner and the alkene which direct the reactivity. The [2 + 2] photocycloaddition is strongly favored when electron-withdrawing substituents are present in the substrates. In such a reaction, crotononitrile 34 was added to anisole 33 (Scheme 5.8, reaction 15) [41 ], and only one regioisomer (35) was obtained in good yield. In this transformation, the... 

Three types of cycloaddition products are generally obtained (Sch. 1). While [2+2] (ortho) and [2+3] (meta) cycloaddition are frequently described, the [2+4] (para or photo-Diels-Alder reaction) pathway is rarely observed in benzene ring systems. With naphthalene systems however, the para cycloaddition occurs more frequently [6,8]. The photo-Diels-Alder reaction and other photocyclization reactions are also observed with anthracene derivatives and higher condensed aromatic compounds. However, these reaction are not treated in this chapter since they are caused by the particular photophysical and photochemical properties of these compounds [6,9]. 

At the singlet excited state, ortho and meta photocycloadditions are often competitive processes and physicochemical investigations were carried out to rationalize the modes of cycloaddition of arenes with alkenes. In the context of the study of photochemical electron transfer reactions, it has been proposed that the difference of the redox potentials of the reaction partners might play an important role in this competition [10]. Such a discussion involves the intervention of an exciplex as intermediate. The Rehm-Weller equation [11] was used to quantify the relationship. When an electron transfer process is strongly endergonic (AG>1.5eV), the meta cycloaddition should be favored. When such a process is less endergonic (1 < AG< 1.5 eY), the ortho addition dominate [12]. This means that the... 

The competition of ortho and meta photocycloaddition is much more expressed when the mesomeric effects of the substituents are weak [30,31]. A more precise analysis of the products revealed that ortho and even para side products are formed in minor amounts in cases were normally the meta cycloaddition should be observed as dominant reaction [32]. Bichro-mophroric substrates carrying electron donor substituents on the benzene ring and any electron active groups on the alkene moiety range in this category [15,31,33]. 

Recently, an attempt was made to induce chirality in a meta cycloaddition via complexation with cyclodextrins (Sch. 13) [48]. 1/1 inclusion complexes of 72 and P-cyclodextrin can be synthesized and irradiated at 2 = 300nm. Two regioisomers 73a and 73b are isolated with different enantiomeric excesses. The results can be explained by interactions of different intensity with the chiral environment at the transition state U. In the case of pathway (a) leading to 73a the interaction with the cyclodextrin is more expressed then for pathway (b) leading to 73b. Thus, the formation of 73a occurs with higher enantioselectivity. 

Among the variety of terpenes which were synthesized with an intramolecular meta photocycloaddition as key step, triquinane derivatives were particularly well studied. Two isomers of these compounds are readily accessible via intramolecular meta cycloaddition in position 1,3 (Sch. 9). The following cyclopropanation reaction of intermediate O controls which of the angular or linear isomers is formed (Sch. 17) [67]. As this step is almost always unselective, both isomers are concomitantly formed. However, one of the isomers can be obtained predominantly via an additional photochemical equilibration step (compare Sch. 11). The triquinane frame is obtained by rupture of the distant C-C bond of the cyclopropane in connection to the 10-membered ring moiety. 

H-silphiperfol-5-ene 93 (R = 11, R2 = Me) [70], subergorgic acid 94 [71], crinipellin B 95 (formal synthesis) [72], (—)-retigeranic acid 96 (formal asymmetric synthesis) [73] were synthesized via intramolecular meta cycloaddition as key step (Sch. 18). In the same way, linear triquinane... 

Propellane derivatives are available via intermolecular meta cycloaddition. Compounds 106 [81,82] and modhephene 107 [81] were obtained using this type of photocycloaddition (Sch. 21). Isoiridomyrmecin 108 [83] and decarboxyquadrone 109 [82] can be synthesized via the same photochemical key step. 

Fig. 8.9 Correlation diagram for the meta cycloaddition of ethylene to benzene...

While the orbital symmetry analysis of the arene-alkene cycloadditions addresses their allowedness , it does not specify a sequence for bond formation. It was recognized, however, that these cycloadditions could proceed stepwise and that in the specific case of the meta cycloaddition, three temporally distinct pathways are possible (Scheme 2) (a) a fully concerted path (A) where all bonds are formed simulta-... 

Interactions leading to para cycloaddition (S -i- ethylene LUMO) are only weakly stabUized. Para cycloadditions are also disfavored by the distance-determined (2.79 A) poor overlrq> between interacting orbitals of the arene with those of the alkene. From this analysis it is predicted that an ortho mode of cycloaddition will be favored for an arene AS"" transition while ortho but preferentially meta cycloaddition will be stabilized in the SA " transition. In addition to symmetry considerations, the effectiveness of the... 

In the case of donor-substituted arenes, this FMO analysis indicates that meta cycloaddition is favored over the ortho mode due to the preferential stabilization of the SA"" transition (Scheme 4). This mode selectivity is indeed observed in numerous cycloadditions involving simple alkenes and alkoxy- or alkyl-substituted arenes.However, as the difference in energy between interacting orbitals is increased due to substituent effects, charge transfer becomes more important. In such cases, both ortho and meta modes of cycloaddition are possible but the former is usually preferred on the basis of its better orbital overlap. 

In 1987, Comelisse and coworkers reported a semi-empirical calculation for the meta cycloaddition of benzene with ethylene, which impressively consolidates many experimental aspects of this reaction and flts well with the Mattay analysis. This calculation, performed at the CNDO/S and MNDO levels, supports an exciplex mechanism with charge polarization, in accord with Mattay s treatment and a related mechanism developed earlier in the Comelisse laboratories. According to this mechanism (equa-... 

From another viewpoint, the value of the arene-alkene meta cycloaddition arises from its capacity to produce a cycloadduct (66 equation 14) with three new rings and up to six new stereocenters, an impressive feat even when compared with the highly regarded Diels-Alder cycloaddition. Moreover, the cycloadduct can be used in the synthesis of a variety of commonly encountei structural types including cyclopentanes, cycloheptanes, bicyclo[3.2.1]octanes and bicyclo[3.3.0]octanes. While fr uently overlooked in some discussions of reaction classification, the overall processes leading to cycloheptanes, bi-cyclo[3.2.1]octanes and bicyclo[3.3.0]octanes are clearly classifiable as [5C + 2C], [3C + 2C] and [3C + 2C] cycloadditions, respectively. Examples of these types will be given in the following section. 

With the above synthetic considerations as a backdrop, the use of the arene-alkene cycloaddition in complex molecule total synthesis can now be examined. The emphasis here will be on the meta cycloaddition process since it has received the most study. It will become apparent, however, that even this reaction has received relatively little attention in synthesis in spite of its enormous potential. This situation is likely to change riqiidly as recent theoretical and synthetic advances are assimilated. 

The first example of the triplication of the arene- ene meta cycloaddition in complex molecule synthesis was the total synthesis of the sesquiterpene cedrene (82 Scheme 8). This taiget was selected for... 

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