Cycloadditions Diels-Alder regiochemistry

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

Because the fluorine substituents both inductively and hyperconjugatively withdraw electron density from the C(2)-C(3) tt bond, the LUMO is located there, and Diels-Alder reactions take place exclusively with this bond [25] 1,1 -Difluoro allene and fluoroallene reaet readily with a large selection of cyclic and acyclic dienes, and acyclic dienes, [2+2] cycloadditions compete with the Diels-Alder processes As shown in the example in equation 79, a significantly different regiochemistry is observed for the [2+4] cycloaddition compared with the [2+2]... 

An interpretation based on frontier molecular orbital theory of the regiochemistry of Diels Alder and 1,3-dipolar cycloaddition reactions of the triazepine 3 is available.343 2,4,6-Trimethyl-benzonitrile oxide, for example, yields initially the adduct 6.344... 

Diels-Alder reaction of the furan derivative 148 with homochiral bicyclic enone 149 is the key step [56] in the total synthesis of the diterpenes jatropho-lone A and B, 151 and 152, respectively, isolated from Jatropha gossypiifolia L [57], Initial efforts to carry out the cycloaddition between 148 and 149 under thermal or Lewis-acid conditions failed due to diene instability. Application of 5kbar of pressure to a neat 1 1 mixture of diene and dienophile afforded crystalline 150 with the desired regiochemistry (Scheme 5.23). Subsequent aromatization, introduction of the methylene group, oxidation and methylation afforded (-l-)-jatropholones 151 and 152. 

The aqueous aza-Diels-Alder reaction of an aldehyde and an amine hydrochloride with a diene is catalyzed by lanthanide(III) trifluoromethane sulfonates (Ln(OTf)3, triflates [24]). Some examples are reported in Schemes 6.12 and 6.13. With respect to uncatalyzed reactions, the lanthanide catalyst allows milder reaction conditions, increases the reaction yield and does not affect the diaster-eoselectivity of the reaction, but influences the regiochemistry as in the cycloaddition of 25 with 1,3-dimethyl-1,3-butadiene (Schemes 6.10 and 6.12). These results have been applied [24b-d] to the synthesis of azasugars (Scheme 6.14). 

Ab initio calculations of the ionic Diels-Alder reactions of tiiazoloisoquinolinium and tetramethoxycarbonylquinohzinium ions with electron-rich dienophiles have been reported.215 The 2++ 4-cycloadditions of arenediazonium ions with (T)-penta-l,3-diene, 2,3-dimethylbutadicnc, and ( )-2-methylpenta-l,3-diene produce dihydropyr-idazines and pyridazinium salts.216 The similarity approach has been applied to predict successfiilly the preferred regiochemistry of various types of pericyclic reaction including polar and semi-polar Diels-Alder and 2 + 2-cycloadditions.217... 

The Diels-Alder [4 + 2] cycloaddition of the homochiral dienophile 2-((S)-l-phenylethyl)-l,2-thiazolin-3-one-(S)-l-oxide (535) with 1.1 equiv. of 1-dimethylamino-l-azabutadiene (534) in acetonitrile at 70 °C proceeded with regioselectivity and with greater than 98% diastereoselectivity to give the adduct (536) in 85% yield (Equation (48)) <89TL306i>. In this reaction the regiochemistry is controlled by the acrylate substructure while the sulfinyl group inductively activates the C=C double bond. 

Dienamines are well documented, synthetically useful Diels-Alder dienes2, 78-87. The main features of their reactions with dienophiles are high reactivity and the fact that the amino moiety controls the regiochemistry of the cycloaddition. For example, the reaction of an electron-deficient dienophile with 149 leads to the selective formation of cycloadduct 150, which on elimination of amine gives cyclohexadiene 151 (equation... 

Regiochemistry and stereochemistry When both components of a cycloaddition reaction are unsymmetrically substituted, two regioisomeric cycloadducts are possible. In the case of Diels-Alder reactions, these are shown in the reactions of both C-1 and C-2 substituted dienes and monosubstituted dienophiles. Isomeric adducts can be referred as ortho, meta and para in reference to similar disubstitution isomers of benzene. 

Diradical intermediates may occur in other types of cycloadditions and cycloreversions. Kinetic data for the thermal transformation of ci5,ci5-l,5-cyclooctadiene to butadiene and 4-vinylcyclohexene are consistent with a diradical intermediate the same intermediate may be involved in the reaction of butadiene leading to [2 + 2] adducts and to the Diels-Alder product 4-vinylcyclohexene. - That a Diels-Alder product may arise from a stepwise path is not as unimaginable today as may have been the case just a few years ago. In more elaborate contexts as well, regiochemistry may be successfully rationalized through estimations of the relative stabilities of diradical intermediates. ... 

Dienophiles substituted with appropriate heteroatoms may offer a number of advantages such as (1) provide dienophilic equivalents of C-—C and moieties which do not undergo [4 + 2] cycloadditions to 1,3-dienes because of low (e.g. isolated alkenes, alkynes, allenes) or different reactivities (e.g. ketenes) (2) enhance or invert the regiochemistry of the Diels-Alder process (3) permit facile removal of the activating and/or regiocontrolling group after cycloaddition with or without introduction of further functionalities. The use of nitroalkenes as dienophiles demonstrates these issues most strikingly. 

A route to partially hydrogenated phenanthrenes relies on the Diels-Alder reaction of a benzyne to an annulated furan, e.g. (501) - (503) (Scheme 117). However, regiochemistry raises its ugly head when both the furan and the benzyne are nonsymmetrically substituted (Scheme 118). Hence, the [4 + 2] cycloaddition of 3-methylbenzyne with 2>substituted furans (504) gave the anti and syn adducts (506)... 

In the intramolecular Diels-Alder reaction, two rings are formed in one step. Notable advantages of intramolecular cycloadditions include (1) entropy assistance (2) well-defined regiochemistry, and (3) greater control of endo- versus exo- selectivity. 

Diels-Alder reactions. Unusual regiochemistry of the cycloaddition can be attained as a result of reorganization of the reactants by complexation and capsule formation. 

The Stereoselectivity of 1,3-Dipolar Cycloadditions. The exo or endo stereochemistry of 1,3-dipolar cycloadditions is not as straightforward as it is for Diels-Alder reactions. Stereoselectivity, more often than not, is low, as shown by the nitrone reactions that we saw on p. 335 when we were looking only at regiochemistry. We now see that the major regioisomer 6.344 from the reaction of CVV-diphcnylnitronc with methyl acrylate is a mixture of exo and endo isomers, exo- and endo-6.344. Similarly, the only regioisomer 6.346 from the reaction of A-benzyl-C-ethylnitrone with methyl crotonate is a mixture of exo-6.346 and endo-6.346. In both cases, the reaction is a little in favour of the exo product.867... 

Table 2-II lists a number of representative imino Diels-Alder cycloadditions using acyclic IV-acylimines and Ai-acyliminium dienophiles. In general, cycloadditions using C.iV-diacylimino systems (entries 1-10) and unsymmetrical dienes show good regioselectivity. The adducts from these reactions have the regiochemistry one would predict based on Scheme 2-1...

Mechanistic studies in this area are essentially nonexistent. Recently, the regiochemistry of some [4 + 2] cycloadditions of thioaldehydes has been rationalized based on FMO theory.2 It is difficult to generalize the resulting stereochemistry of this type of Diels-Alder reaction since systematic studies are lacking and since many structurally diverse kinds of thiocarbonyl dienophiles have been used as 277 components. 

These thiocarbonyl compounds were not isolated but were trapped as formed by 1,3-dienes to afford good yields of Diels-Alder adducts (Scheme 5-VIII). 1,3-Dimethylbutadiene gave only a single regioisomer (>98%), having the orientation shown. This regiochemistry is in line with that found previously in cycloadditions of some cyanothioformamides with unsymmetrical dienes (vide infra). 

Since its discovery over sixty years ago [1] the Diels-Alder reaction has lost none of its attraction. [2, 3] It enables, in a one-step inter- or intramolecular reaction, the rapid preparation of cyclic compounds having a six-membered ring. During the course of the [4 -I- 2] cycloaddition four new stereocenters can be introduced directly, and their stereo-control is a topic of major interest in modem synthetic chemistry. [4-6] In addition, in intermolecular reactions, the relative positions of the reaction partners (regiochemistry) must be taken into account. If a concerted reaction is assumed, both a cis addition (suprafacial mode) and a preferred endo orientation (Alder rules) can be expected. But how can the absolute configuration of the desired product be controlled There are three basic possibilities the use of a chirally modified diene, a chirally modified dienophile, or a chiral catalyst. Although the first successes resulted from the attractive, hut difficult, catalytic route, [4b, 7] the majority of the investigators are concerned with the stoichiometric... 

As alluded to above, no detailed studies of the mechanism of the imino Diels-Alder reaction have been reported to date. However, it has been suggested that [4 + 2] cycloadditions of most C=N, N=N, C=0 and N=0 dienophiles are HOMOdiene-LUMOdienopwie controlled. Whether, in fact, these reactions are concerted pericyclic processes has yet to be firmly established. In any case, a simple dipolar mechanistic model (Scheme 2-1) can often be used to qualitatively predict the regiochemistry of imino dienophile cyclizations with unsymmetrical dienes, which usually proceed with high selectivity. This model may, in fact, be indicative... 

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