Endo and exo isomers

Furan and maleic anhydride undergo the Diels-Alder reaction to form the tricycHc 1 1 adduct, 7-oxabicyclo [2.2.1]hept-5-ene-2,3-dicarboxyHc anhydride (4) in exceUent yield. Other strong dienophiles also add to furan (88). Although both endo and exo isomers are formed initially, the former rapidly isomerize to the latter in solution, even at room temperature. The existence of a charge-transfer complex in the system has been demonstrated (89,90). 

Dicyclopentadiene exists ia two stereoisomeric forms, the endo and exo isomers. Commercial DCPD, 3a,4,7,7a-tetrahydro-4,7-methano-lH-iadene, is predominandy the endo isomer (exo endo 6 953 by capillary gas chromatography). The dimer is the form ia which CPD is sold commercially. 

A Diels-Alder type [4+2] cycloadditions of 4,5-dihydropyridazine, prepared in situ from its trimer, with 2-methyl- and 2,3-dimethyl-1,3-butadienes (65, R = H, Me R = Me) afforded a complex reaction mixture, from which 6-methyl- and 6,7-dimethyl-3,4,4n,5-tetrahydro-8//-pyrido[l,2-ftjpyridazines (66, R = H, Me R =Me) could be isolated (97CEJ1588). With 1,3-butadiene (65, R = R =H) only a mixture of endo and exo isomers 67 and 68 (R = R =H) was obtained. 

It has been more difficult to obtain the exo isomer in the above described reaction. Application of the TiCl2-TADDOLate complex induced fair exo selectivity and up to 60% ee. This was improved by the application of succinimide as an auxiliary for the alkene. This approach has been the only entry to a highly exo selective reaction and up to 72% ee of the exo isomer was obtained. In the Pd(BF4)2-BI-NAP-catalyzed reaction which gave mixtures of the endo and exo isomers, high ee of up to 93% was in a single case obtained for the minor exo isomer. In one case it was also observed that a Zn(OTf)2-BOX complex induced some exo selectivity and up to 82% ee of the exo isomer. 

Concerted cycloaddition reactions provide the most powerful way to stereospecific creations of new chiral centers in organic molecules. In a manner similar to the Diels-Alder reaction, a pair of diastereoisomers, the endo and exo isomers, can be formed (Eq. 8.45). The endo selectivity in the Diels-Alder arises from secondary 7I-orbital interactions, but this interaction is small in 1,3-dipolar cycloaddition. If alkenes, or 1,3-dipoles, contain a chiral center(s), the approach toward one of the faces of the alkene or the 1,3-dipole can be discriminated. Such selectivity is defined as diastereomeric excess (de). 

The Diels-Alder reaction of cyclopentadiene with methyl acrylate in methanol was studied by Berson et al. [72] under conventional conditions, and shown to give a mixture of the endo and exo isomers 48 and 49 (Scheme 4.26). 

Deshayes described the cydoaddition of 1-amino-1,3-butadienes 63 with ethyl acrylate (34) under the action of microwave irradiation in a monomode reactor with temperature control [59]. Irradiation for 30 min at 70 °C in the absence of solvent afforded a 60 40 ratio of an inseparable mixture of the endo and exo isomers in 90% yield. Classical heating under the same conditions did not affect the selectivity but the yield was lower (Scheme 9.17). 

Photochemical [2+2]cycloaddition between benzo[b]furan and 3-cyano-2-alkoxy-pyridines in benzene has been reported to follow a very interesting mechanism supported also by Frontier-MO calculations using the PM3 Hamiltonian. It is believed that the singlet excited state of the pyridine and the ground state benzofuran react to form a [2+2] adduct and is followed by ring opening to the cyclooctatriene, which cyclizes to the secondary endo- and exo-isomers shown below <00CC1201>. 

In sharp contrast, a vinylallene bearing two methyl groups at the allenic termi-nusl is treated with [RhCl(PPh3)3] to give ( 4-vinylallene)rhodium(I) complexes as an isolable mixture of endo and exo isomers. The endo isomer is found to isomerize thermally to the exo isomer (Scheme 16.39) [39, 40],... 

As an inversion of enantioselectivity was observed experimentally for 4-(dimethylamino)styrene, (64% R ee) as compared to styrene (64% S ee), we have recalculated the relative thermodynamic stabilities of endo and exo isomers for each step of the catalytic cycle using this second substrate. These calculations allow us to verify the quality of our findings by checking if an inversion in the relative stabilities of the endo and the exo-ri3-silyl-allyl intermediates (with the endo being more stable than the exo) is observed with 4-(dimethylamino)styrene. Using 4-(dimethylamino)styrene as the substrate, the calculated relative stabilities of the intermediates in the Chalk-Harrod mechanism are shown as parenthetic values in Figure 15. 

Taguchi and coworkers175 studied the Lewis acid catalyzed asymmetric Diels-Alder reactions of chiral 2-fluoroacrylic acid derivatives with isoprene and cyclopentadiene. When a chiral l,3-oxazolidin-2-one and diethylaluminum chloride were used as the chiral auxiliary and the Lewis acid catalyst, respectively, a de of 90% was observed for the reaction with isoprene. The reaction with cyclopentadiene afforded a 1 1 mixture of endo and exo isomers with de values of 95% and 96%, respectively. The endo/exo selectivity was improved by using 8-phenylmenthol as the chiral auxiliary. Thus, the reaction... 

Taguchi and colleagues189 studied the reactions of axially chiral maleimide and anilide derivatives 298 and 300 with cyclopentadiene (equation 83). The reaction of 298 with cyclopentadiene, catalyzed by diethylaluminum chloride, proceeded quantitatively with almost complete endo and diastereofacial selectivities to give 299 and 301, respectively. The reaction of 300 with cyclopentadiene was catalyzed by iodine and proceeded via a cationic iodocyclization intermediate. The reaction afforded a mixture of endo and exo isomers in a ratio of endo/exo = 97/3, the endo isomer being obtained with 97% de. 

If one of the substituents R1 or R2 is hydrogen, then the interconversion of the endo-and exo-isomers (101 and 103) is accompanied by an irreversible transformation into l//-2-benzazepines 104 (equation 36). Otherwise (i.e. when R1, R2 / H) the rearrangement of compounds 101 is slower and leads to formation of 5//-2-benzazepine system 102 (equation 35)52. 

But the trimethylsilyloxycyclohexadienes (51 a,b) reacted with the chloro ester 1-Me only under more drastic conditions to give in moderate yield about equal amounts of the regioisomeric cycloadducts 52 and 53, each as a mixture of endo-and exo-isomers (Scheme 13) [281. Upon treatment with acid or acidic work-up of the reaction mixture, compounds 52 and 53 were converted to the tricyclic keto esters 54a and 54b in 25 and 28% yield, respectively (cf. Sect. 4.4). 

The potential activation of different Lewis acid catalysts and their load effect when used in combination with this solvent were explored, in order to determine the improvement of rates and selectivity to the endo and exo isomers. The list of Lewis acid catalysts included Li(OTf), Li(NTf2), Znl2, AICI3, BF3, HOTf, HNTf2, Ce(0Tf)4 5H20, Y(OTf)3, Sc(OTf)3, Sc(NTf2) and a blank without any Lewis acid. The reaction conditions were as follows 2.2 mmol of cyclopentadiene + 2.0 mmol of dienophile + 0.2 mol% of catalyst in 2 mL [hmim][BF4]. When no catalyst was added, the two ketones (R =Me-C=0 R2 = R3 = H and Ri=Et-C=0 R2 = R3 = H) showed modest activity ( 50% in 1 h) with endojexo selectivity = 85/15. Whereas acrolein showed modest activity (59% conversion in 2 h), methacrolein and crotonaldehyde were inert without a Lewis acid catalyst. Acrylonitrile and methyl acrylate underwent low conversions in 1 h (16-17%) whereas, N-phenylmaleimide, maleic anhydride and 2-methyl-1,4-benzoquinone showed complete reaction in 5 min with high endo isomer yields. 

As for intermolecular 1,3-dipolar cycloadditions, the endo- and exo-isomers of each of the regioisomers can be formed in intramolecular reactions. In most cases, the exo-isomer is favored for steric reasons. 

Hydrogenolysis of cyclic orthoesters with diborane (a method using lithium aluminum hydride-aluminum chloride had been described for 1,2-orthoesters37) has been shown to be a route to cyclic acetals38 thus, a mixture of the endo and exo isomers of methyl 3,4-0-(ethoxy-ethylidene)-/3-L-arabinopyranoside led to methyl endo-3,4-0-ethy]i-dene-/3-L-arabinopyranoside (yield 66%). 

In drawing endo and exo isomers, it is best to represent the actual spatial relationships of the atoms as closely as possible. The cyclohexane ring is shown here in the boat form (Section 12-3 A) because it is held in this configuration by the methylene group that bridges the 1,4 positions. If you do not see this, we strongly advise that you construct models. 

The initial data concerning the formation of endo and exo isomers in the synthesis of azirenoimidazoles were given in [89] endo and exo isomers (85A and 85B, respectively) were obtained in the reaction of trans-2-phQny -3-benzoylaziridine 18 with ammonia and benzaldehyde 84 and separated by fractional crystallization (Scheme 1.24). Data concerning separating these isomers were also given in a series of subsequent works [90, 92, 95, 105]. 

However, for exo isomer of 134 instead of the expected trans-2,3-dihydro-2,3,5-triphenylpyrazine 140B, formation of the cis isomer 140A upon irradiation is observed as well. Padwa and Clough [89] explained this by the existence of an equilibrium mixture of the isomeric enediimines 141A and 141B with predominance of isomer 141 A. But the formation of identical reaction products from endo and exo isomers of 134, in our opinion, is more easily explained by... 

Temperature variations of 1H- and 13C-NMR spectra of allyl and pentadienyl compounds of the alkali metals have given information about barriers to rotation about the C—C bonds. The endo and exo isomers of the allyl anions [Eq. (1)] are formed stereospecifically at low temperatures from Z-and E-alkenes, respectively (75,76). 

Ibata was the first to show that the masked carbonyl ylide embedded within the isomiinchnone framework would readily undergo 1,3-dipolar cycloaddition with various dipolarophiles [34], The isolable isomiinchnone 4 was observed to react with dimethyl fumarate to produce cycloadduct 7 which possesses the 7-oxa-2-azabicyclo[2.2.1]heptane skeleton. When the reaction of 1 was carried out using catalytic amounts of Cu(acac)2 in the presence of various dipolarophiles, smooth dipolar cycloaddition was observed to occur giving mixtures of endo and exo isomers. In most cases, the exo isomers were favored. All of Ibata s isomiinchnone cycloadditions contain aromatic substituent groups, presumably selected to facilitate dipole formation. The synthetic utility of the cycloaddition reaction is diminished, however, because of the low reactivity of the aromatic substituents toward further manipulation. 

Cubanes are partially decychzedto tricyclooctadienes when allowed to react with catalytic quantities of [RhCl(LL)]2 complexes (LL = cod, nbd). Monosubstituted cubanes form two products, as shown in equation (13). Homocubanes (equation 14) react similarly. If methyloxyphosphahomocubane is decomposed, two isomeric products are obtained (equation 15). Endo- and exo isomers are obtained from the catalytic isomerization of 9,10-dimethoxycarbonyl bishomocubane (equation 16). Sundry palladium(II) complexes, AgNOs, or PdCl2 form significant quantities of (2). 

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