Internal Diels-Alder reaction

Intramolecular versions of the Diels-Alder reaction are well known, and this is a powerful method for the synthesis of mono- and polycyclic compounds.There are many examples and variations. One interesting internal Diels-Alder reaction links the diene and dienophile by a C—O—SiR2—or a C—O—SiR2—O—C linkage. Internal cyclization to give a bicyclic product is followed by cleavage of the O-Si unit to give a monocyclic alcohol. 

Dougherty159) reported in 1968 that the peak at m/e = 300 in the mass spectrum of hexahelicene (C26H16) is due to the ion of coronene (C24H12+), formed by an internal Diels-Alder reaction, followed by a fragmentation yielding ethylene. Indeed, traces of coronene were detected on heating hexahelicene at 485 °C for 2 h in an evacuated tube. 

A further formal total synthesis95 of aspidospermine is provided by a new preparation of Stork s tricyclic amido-ketone (152). The hydrolulolidine system in (152) was neatly constructed by cheletropic expulsion of sulphur dioxide from the amide-sulphone (153), followed by an internal Diels-Alder reaction. 

Grieco and co-workers also showed that iminium salts such as 123, formed by reaction of an amine and formaldehyde (sec. 4.4) reacted with cyclopentadiene in aqueous media to give a near-quantitative yield of the Diels-Alder adduct. An internal Diels-Alder reaction was also possible (sec. 11.8). Treatment of an aqueous solution of 124 with formaldehyde at 50°C gave a 98% yield of indolizidine 125. 

In addition to the problems concerning reactivity and the nature of the tether, at least two different regio-isomers are possible for internal Diels-Alder reactions (210 and 211 from 209), depending on the orientation of the alkene as it approaches the diene. If the tether is short, only 211 is possible, but with longer tethers 210 can be a side product or even the major product. An example taken from Thomas studies on the synthesis of cytochalasin is an intramolecular Diels-Alder reaction of 212 that gave a 27 5% mixture of 213 and 214.20 ... 

Table 11.11. cis-trans Selectivity in Internal Diels-Alder Reactions of Trienyl Ketones... 

The search of the key-step in a synthesis is, rather often, a fundamental step. When it has been found, one may say that a general plan of the synthesis has been found. This search has been done in a very simple way in the SAS program this program simply deleted one or several bonds in the target, suggesting ideas of synthesis. For example, in the case of ellipticine (13), it suggested several internal Diels-Alder reactions. Solutions similar to 14 and 16 have been subsequently and independently found experimentally by others groups of researchers (Scheme 14). 

Alternatively, authors have repeatedly invoked the internal pressure of water as an explanation of the rate enhancements of Diels-Alder reactions in this solvent ". They were probably inspired by the well known large effects of the external pressure " on rates of cycloadditions. However, the internal pressure of water is very low and offers no valid explanation for its effect on the Diels-Alder reaction. The internal pressure is defined as the energy required to bring about an infinitesimal change in the volume of the solvents at constant temperature pi = (r)E / Due to the open and... 

Mechanistic studies have tried to unravel the origin of the special effect of water. Some authors erroneously have held aggregation phenomena responsible for the observed acceleration, whereas others have hinted at effects due to the internal pressure. However, detailed studies have identified two other effects that govern the rate of Diels-Alder reactions in water. 

Note that for 4.42, in which no intramolecular base catalysis is possible, the elimination side reaction is not observed. This result supports the mechanism suggested in Scheme 4.13. Moreover, at pH 2, where both amine groups of 4.44 are protonated, UV-vis measurements indicate that the elimination reaction is significantly retarded as compared to neutral conditions, where protonation is less extensive. Interestingy, addition of copper(II)nitrate also suppresses the elimination reaction to a significant extent. Unfortunately, elimination is still faster than the Diels-Alder reaction on the internal double bond of 4.44. 

Palladium catalyzed cycloisomerizations of 6-cn-l-ynes lead most readily to five-membered rings. Palladium binds exclusively to terminal C = C triple bonds in the presence of internal ones and induces cyclizations with high chemoselectivity. Synthetically useful bis-exocyclic 1,3-dienes have been obtained in high yields, which can, for example, be applied in Diels-Alder reactions (B.M. Trost, 1989). 

Catalysis of Diels-Alder reaction by zeolites is predominantly physical rather than chemical in nature [19]. The reactants are concentrated internally in cavities... 

An example of a cyclophane-type cavity is the azacyclophane CP66 supra-molecular system which provides a lipophilic cavity with an internal width of approximately 6.5 A, as well as positive charges which accelerate and increase the selectivity of the process. The Diels-Alder reaction of cyclopentadiene with diethylfumarate at 20 °C in 10% and 50 To dioxane-water is accelerated by the presence of CP66 by 2.9 and 1.5 times, respectively [65c] (Equation 4.12). 

Water s internal pressure acts on the volume of activation (AV ) of a reaction in the same way as an externally applied pressure does. Thus, the internal pressure of water influences the rates of nonpolar reactions in water in the same direction as external pressures. Nonpolar reactions with a negative volume of activation will thus be accelerated by the internal pressure of water, whereas nonpolar reactions with a positive volume of activation will be slowed by the internal pressure. For example, at 20° C the rate of Diels-Alder reaction between cyclopentadiene and butenone, which is known to have a negative volume of activation, in a 4.86 M LiCl solution is about twice as that of the reaction in water alone (Eq. 1.1).4... 

A challenge of a different kind was encountered in the internal vinylation of various vinyl triflates and bromides as depicted in Eq. (11.13) [27]. The electron-rich structures obtained from the reactions were of interest for further use in Diels-Alder reactions, but the risk of degrading the products in the hot reaction medium posed a problem and a prudent choice of energy input was imperative. It turned out that single-mode microwave heating for 5 min at the very low power of 5 W was sufficient to yield 64% of the product with excellent regioselectivity. Measurements with a fluor-optic probe revealed an unexpectedly high temperature of 76 °C [27]. 

The observation that the transition state volumes in many Diels-Alder reactions are product-like, has been regarded as an indication of a concerted mechanism. In order to test this hypothesis and to gain further insight into the often more complex mechanism of Diels-Alder reactions, the effect of pressure on competing [4 + 2] and [2 + 2] or [4 + 4] cycloadditions has been investigated. In competitive reactions the difference between the activation volumes, and hence the transition state volumes, is derived directly from the pressure dependence of the product ratio, [4 + 2]/[2 + 2]p = [4 + 2]/[2 + 2]p=i exp —< AF (p — 1)/RT. All [2 + 2] or [4 + 4] cycloadditions listed in Tables 3 and 4 doubtlessly occur in two steps via diradical intermediates and can therefore be used as internal standards of activation volumes expected for stepwise processes. Thus, a relatively simple measurement of the pressure dependence of the product ratio can give important information about the mechanism of Diels-Alder reactions. 

On heating, dihydrooxazines (548) undergo the known [4 +2]-cycloreversion to give the previously unknown conjugated en-imines CH2=C(C02Me)CH=N—E as intermediates. The latter can be trapped in a Diels—Alder reaction at the terminal or internal electron-rich double bond. 

Limonene, one of the most prominent natural monoterpenes (cf Section VII), represents a particular derivative of 4-vinylcyclohexene since it has been studied with respect to the pronounced energy dependence of its fragmentation behaviour (Scheme 7). Counterintuitively, and in contrast to 4-vinylcyclohexene, the radical cations of limonene (27) do not undergo the retro-Diels-Alder reaction if the internal energy of the ions is low. As... 

While many observations are well understood, e.g. those dealing with the reaction rate or with the selectivity, there are some factors which cannot be generalized. Many transformations of particular reactants or under unusual reaction conditions led to unexpected results. There are often singular explanations for such reactions but no overall concept. For instance, computations on Diels-Alder transition structures and thermodynamics of retro-Diels-Alder reactions confirmed that the activation volume of these [4 + 2]-cycloadditions is negative80. This result, pointing to the compact character of the transition structure, is used to explain the dependence of reactivity and selectivity on internal as well as external pressure81-83. These effects are only observed at relatively high external pressures (Table 5). 

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