Exo- product

Under the usual conditions their ratio is kinetically controlled. Alder and Stein already discerned that there usually exists a preference for formation of the endo isomer (formulated as a tendency of maximum accumulation of unsaturation, the Alder-Stein rule). Indeed, there are only very few examples of Diels-Alder reactions where the exo isomer is the major product. The interactions underlying this behaviour have been subject of intensive research. Since the reactions leadirig to endo and exo product share the same initial state, the differences between the respective transition-state energies fully account for the observed selectivity. These differences are typically in the range of 10-15 kJ per mole. ... 

The regioselectivity benefits from the increased polarisation of the alkene moiety, reflected in the increased difference in the orbital coefficients on carbon 1 and 2. The increase in endo-exo selectivity is a result of an increased secondary orbital interaction that can be attributed to the increased orbital coefficient on the carbonyl carbon ". Also increased dipolar interactions, as a result of an increased polarisation, will contribute. Interestingly, Yamamoto has demonstrated that by usirg a very bulky catalyst the endo-pathway can be blocked and an excess of exo product can be obtained The increased di as tereo facial selectivity has been attributed to a more compact transition state for the catalysed reaction as a result of more efficient primary and secondary orbital interactions as well as conformational changes in the complexed dienophile" . Calculations show that, with the polarisation of the dienophile, the extent of asynchronicity in the activated complex increases . Some authors even report a zwitteriorric character of the activated complex of the Lewis-acid catalysed reaction " . Currently, Lewis-acid catalysis of Diels-Alder reactions is everyday practice in synthetic organic chemistry. 

The reaction between 2.4 and 2.5 yields four products two enantiomeric endo products and two enantiomeric exo products. In this section the effect of the solvent, the Lewis-acid and the substituents on the endo-exo selectivity are described. Chapter 3 will mainly focus on aspects dealing with the enantioselectivity of the reaction. 

Endo-exo product mixtures were isolated using the following procedure. A solution of cyclopentadiene (concentration 2-10" M in water and 0.4 M in oiganic solvents) and the dienophile (concentration 1-5 mM) in the appropriate solvent, eventually containing a 0.01 M concentration of catalyst, was stirred at 25 C until the UV-absorption of the dienophile had disappeared. The reaction mixture (diluted with water in the case of the organic solvents) was extracted with ether. The ether layer was washed with water and dried over sodium sulfate. After the evaporation of the ether the... 

The Diels-Alder reaction provides us with a tool to probe its local reaction environment in the form of its endo-exo product ratio. Actually, even a solvent polarity parameter has been based on endo-exo ratios of Diels-Alder reactions of methyl acrylate with cyclopentadiene (see also section 1.2.3). Analogously we have determined the endo-exo ratio of the reaction between 5.1c and 5.2 in surfactant solution and in a mimber of different organic and acpieous media. These ratios are obtained from the H-NMR of the product mixtures, as has been described in Chapter 2. The results are summarised in Table 5.3, and clearly point towards a water-like environment for the Diels-Alder reaction in the presence of micelles, which is in line with literature observations. 

Table 5.3. Endo-exo product ratios of the Diels-Alder reaction of 5.1c with 5.2 in surfactant solution compared to water and organic solvents.

Based on the above-mentioned stereochemistry of the allylation reactions, nucleophiles have been classified into Nu (overall retention group) and Nu (overall inversion group) by the following experiments with the cyclic exo- and ent/n-acetales 12 and 13[25], No Pd-catalyzed reaction takes place with the exo-allylic acetate 12, because attack of Pd(0) from the rear side to form Tr-allyl-palladium is sterically difficult. On the other hand, smooth 7r-allylpalladium complex formation should take place with the endo-sWyWc acetate 13. The Nu -type nucleophiles must attack the 7r-allylic ligand from the endo side 14, namely tram to the exo-oriented Pd, but this is difficult. On the other hand, the attack of the Nu -type nucleophiles is directed to the Pd. and subsequent reductive elimination affords the exo products 15. Thus the allylation reaction of 13 takes place with the Nu nucleophiles (PhZnCl, formate, indenide anion) and no reaction with Nu nucleophiles (malonate. secondary amines, LiP(S)Ph2, cyclopentadienide anion). 

There are probably several factors which contribute to determining the endo exo ratio in any specific case. These include steric effects, dipole-dipole interactions, and London dispersion forces. MO interpretations emphasize secondary orbital interactions between the It orbitals on the dienophile substituent(s) and the developing 7t bond between C-2 and C-3 of the diene. There are quite a few exceptions to the Alder rule, and in most cases the preference for the endo isomer is relatively modest. For example, whereas cyclopentadiene reacts with methyl acrylate in decalin solution to give mainly the endo adduct (75%), the ratio is solvent-sensitive and ranges up to 90% endo in methanol. When a methyl substituent is added to the dienophile (methyl methacrylate), the exo product predominates. ... 

The high enantioselectivity of the exo product opens up a new and readily accessible route to an enantioselective synthesis of interesting isoquinoline alkaloids (Scheme 6.15) [35]. The tricyclic isoxazolidine exo-15b was obtained from the 1,3-dipolar cydoaddition reaction as the pure exo isomer and with 58% ee [34]. As shown in Scheme 6.15 the exo product from the 1,3-dipolar cydoaddition was converted into 17 in two steps without racemization at the chiral center. In addition to the illustrated synthesis, the 6,7-dimethoxy-derived isoxazolidine exo-15b is a very useful precursor for the synthesis of naturally occurring isoquinoline alkaloids [36-40]. 

The Diels-Alder reaction of a diene with a substituted olefinic dienophile, e.g. 2, 4, 8, or 12, can go through two geometrically different transition states. With a diene that bears a substituent as a stereochemical marker (any substituent other than hydrogen deuterium will suffice ) at C-1 (e.g. 11a) or substituents at C-1 and C-4 (e.g. 5, 6, 7), the two different transition states lead to diastereomeric products, which differ in the relative configuration at the stereogenic centers connected by the newly formed cr-bonds. The respective transition state as well as the resulting product is termed with the prefix endo or exo. For example, when cyclopentadiene 5 is treated with acrylic acid 15, the cw fo-product 16 and the exo-product 17 can be formed. Formation of the cw fo-product 16 is kinetically favored by secondary orbital interactions (endo rule or Alder rule) Under kinetically controlled conditions it is the major product, and the thermodynamically more stable cxo-product 17 is formed in minor amounts only. 

The use of catalysts for a Diels-Alder reaction is often not necessary, since in many cases the product is obtained in high yield in a reasonable reaction time. In order to increase the regioselectivity and stereoselectivity (e.g. to obtain a particular endo- or exo-product), Lewis acids as catalysts (e.g. TiCU, AICI3, BF3-etherate) have been successfully employed." The usefulness of strong Lewis acids as catalysts may however be limited, because they may also catalyze polymerization reactions of the reactants. Chiral Lewis acid catalysts are used for catalytic enantioselective Diels-Alder reactions. ... 

A typlciil regioselecdvity and endo/exo selecdvity has been reported in the Diels-Alder reacdon of 2-W-acylamino -l,3-diene v/ith nitroalkenes fEq 8 21) Thus, exo products are predominandy formed, which is generiil for the Diels-Alder reacdon of nitroalkenes v/ith sterically hmdered dienes... 

Another stereochemical feature of the Diels-Alder reaction is that the diene and dienophile partners orient so that the endo product, rather than the alternative exo product, is formed. The words endo and exo are used to indicate relative stereochemistry when referring to bicyclic structures like substituted norbornanes (Section 4.9). A substituent on one bridge is said to be exo if it is anti (trans) to the larger of the other two bridges and is said to be endo if it is syn (cis) to the larger of the other two bridges. 

The thieno unit of thienothiepin 1 reacts with iV-phenylmaleimide at 150 C to give the Diels-Alder exo-product 2, with the loss of sulfur.71 Furanothiepin 3 (X = S) and its corresponding 5-oxide or 5,5-dioxide react readily with the same dienophile at room temperature, but in different ways. While the parent compound 3 and its oxide (X = S, SO) form the cycloadduct 4 with loss of sulfur, the dioxide gives a stable Diels-Alder adduct 5 (mixture of endojexo-isomers) which, upon heating above 100 C, loses sulfur dioxide to provide the sulfur-free adduct.70... 

A stereoelectronic requirement in radical addition to carbon-carbon double bonds first became apparent from studies on radical cyelization and the reverse (Fragmentation) reactions.54 56 It provides a rationalization for the preferential formation of the less thermodynamically stable exo-product (i.e. head addition) from the cyelization of to-alkcny] radicals (16 - Scheme 1.5). s 57 G4... 

The micellar effect on the endo/exo diastereoselectivity of the reaction has also been investigated. The endo/exo ratio of the reaction of cyclopentadiene with methyl acrylate is affected little (compared to water) by the use of SDS and CTAB [73b], while a large enhancement was observed in SDS solution when n-butyl acrylate was the dienophile used [74]. The ratio of endo/exo products in the reaction of 1 with 113c is not affected by CTAB, SDS and C12E7 [72a]. 

However, the homochiral 2- -(/ )-(-)-a-[(2-naphthyl)ethylamino]-4-phenyl-l-thiabuta-l,3-diene reacts with dienophiles when activated by acetyl chloride to give the exo product, exemplified by the cyclopenta[fc]thiopyran derivative (24) <96TL123>. 

The stereospecificity is of course correct all trans diene producing ais substituents and ais dienophile producing endo approach (12) is too much. The exo approach is much easier (13). 

The stereoselectivity of some Diels-Alder reactions was also strongly affected in water.26 At low concentrations, in which both components were completely dissolved, the reaction of cyclopentadiene with butenone gave a 21.4 1 ratio of endo/exo products when they were stirred at 0.15 M concentration in water, compared to only a 3.85 1 ratio in excess cyclopentadiene and an 8.5 1 ratio with ethanol as the solvent. Aqueous detergent solution had no effect on the product ratio. The stereochemical changes were explained by the need to minimize the transition-state surface area in water solution, thus favoring the more compact endo stereochemistry. The results are also consistent with the effect of polar media on the ratio.27... 

Since the rearrangement afforded endo product from endo zwitterion and exo product from exo zwitterion, the rearrangement follows the slither mechanism. 

Extrapolation of the data to zero time suggests that the endo acetates (65) and (67) are produced in amounts as great as or greater than the exo isomer. Solvolysis studies of the bicyclo[3.1.0]hex-2-en-6-yl cation reveal that nucleophilic capture occurs preferentially from the exo side to give (66) rather than (67). Similarly, solvolysis of cation (63) leads to exo product (64) in at least a 90% yield. Photolysis of benzene in deuteriophosphoric acid results in (68), in which all the deuterium is incorporated into the 6-endo position ... 

Slee and LeGoff performed further investigations on the reaction of dimethyl acetylenedicarboxylate 4-20 with an excess of furan 4-21, as first described by Diels and Alder (Scheme 4.5) [la]. At 100 °C, 4-24 and 4-25 were not produced (as proposed), but rather 4-22 and 4-23, since at elevated temperature an equilibrium takes place and the primarily formed 4-24 and 4-25 isomerize to give a 6 1-mixture of the exo-endo and the exo-exo products 4-22 and 4-23, respectively. However, at lower temperature, in the primarily formed [4+2] cycloadduct the double bond substituted with the two carbomethoxy group acts as the dienophile to give the two products 4-24 and 4-25 in a 3 1 ratio with 96% yield within five weeks, as has been shown by Diels and Olsen [la,lc]. For a differentiation of these two types of adducts, Paquette and coworkers [7] used a domino and pincer product . The Cram group [8] described one of the first examples of a reaction of a tethered bisfuran 4-26 with dimethyl acetylenedicarboxylate 4-20a to give 4-27. 

Finally, Parker and coworkers [101] were able to use this approach for the total synthesis of SNF4435C (6/1-190) (Scheme 6/1.51). The Pd-catalyzed reaction of 6/1-191 and 6/1-195 gave a 4 l-mixture of 6/1-190 and its endo-diastereomer 6/1-199 in 53% yield. In this transformation, the tetraene 6/1-196 can be assumed as intermediate, which theoretically could undergo an 8jt/6jt electrocyclization to give the endo-products via conformation 6/1-197 and the exo-products via conformation 6/1-198. However, only the two endo-products 6/1-190 and its diastereomer 6/1-199 are found, and not 6/1-200, which is consistent with the most likely nonenzymahc formation of 6/1-190 and its diastereomer in Nature from their co-metabolite spectabilin. 

A typical regioselectivity and endo/exo selectivity has been reported in the Diels-Alder reaction of 2-(/V-acylamino)- 1,3-diene with nitroalkenes (Eq. 8.27).43 Thus, exo products are predominantly formed, which is general for the Diels-Alder reaction of nitroalkenes with sterically hindered dienes. 

GuoetaLhavereported Diels-Alder reaction of differently substituted2-acetyl-[l, 2,3] diazaphospholes, 6 with cyclopentadiene and obtained both endo and exo cycloadducts in moderate yields depending on the reaction conditions (Scheme 28). By quenching the room temperature reaction after only 5 min, endo product 89 was obtained exclusively in 65-75% yields, while prolongation of reaction time to 3 days led to the isolation of only exo product 90 in 50-75% yields [19]. 

Entry Cpd. R,R X Product11 Relative rates (endo/exo ) Product Relative rates (endo/exo ) ... 

Ionization of either the exo (XXVI) or the endo (XXVII) derivative leads to substitution products with the exo configuration. The endo compounds solvolyze slowly, about like cyclohexyl derivatives, while the exo derivatives solvolyze as much as 350 times faster, indicating participation by neighboring carbon. Furthermore, optically active exo starting material gives racemic exo product. All of these results are consistent with the formation of the symmetrical ion XXVIII, in which carbon atoms 1 and 2 are indistinguishable.287 288 But the ion XXVIII... 

Other aromatic heterocycles undergo Patemo-Btichi reaction with carbonyl compounds, although these reactions have seldom been applied to organic synthesis. For example, thiophene reacts cleanly with benzaldehyde to afford a single exo product in 63% yield87. Pyrroles also react with aldehydes and ketones however, as a result of the lability of the presumed initial cycloadducts, the only products isolated, even with the rigorous exclusion of acid, are the 3-hydroxyalkylpyrroles 200 (equation 7)89. 

Cyclization has also been observed for those cases in which allyl radicals are stabilized by additional substituents. Radicals 9, which carry an ester group at one allyl terminus, cyclize readily in a 5-exo fashion to furnish products 10 in good yield. No 6-exo product was found in this instance (equation 7)45. 

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