Diels-Alder reaction, with pyrroles

The discovery of the structure of 7-azabicyclo[2.2.2]heptene isolated from the Ecuadorian poison frog, Epipedobates tricolor [39], has caused a rebirth of investigation of Diels-Alder reactions with pyrrole as a diene [40]. Subsequently, a large number of 7-azabicyclo[2.2.1]-heptane and 7-azabicyclo[2.2.1]hept-2-ene derivatives have been synthesized and protected by patents [41]. We have... 

Alkynes substituted with one or two trifluoromethyl groups are also highly reactive dienophiles [9] Indeed, hexafluoro-2-butyne is used increasingly as a definitive acetylenic dienophile in "difficult Diels-Alder reactions. It was used, for example, to prepare novel inside-outside bicycloalkanes via its reaction with cir,trnns -l,3-undecadiene [74] (equation 67) and to do a tandem Diels-Alder reaction with a l,l-bis(pyrrole)methane [75] (equation 68) Indeed, its reactions with pyrrole derivatives and furan have been used in the syntheses of 3,4-bis(tri-fluoromethyl)pyrrole [76, 77] (equation 69) and ],4-bis(trifluoromethyl)benzene-2,3-oxide [78] (equation 70), respectively. 

It has been known that aromatic heterocycles such as furan, thiophene, and pyrrole undergo Diels-Alder reactions despite their aromaticity and hence expected inertness. Furans have been especially used efficiently as dienes due to their electron-rich properties. Thiophenes and pyrroles are less reactive as dienes than furans. But pyrroles with A-elecIron-withdrawing substituents are efficient dienes. There exists a limited number of examples of five-membered, aromatic heterocycles acting as dienophiles in Diels-Alder reactions. Some nitro heteroaromatics serve as dienophiles in the Diels-Alder reactions. Heating a mixture of l-(phenylsulfonyl)-3-nitropyrrole and isoprene at 175 °C followed by oxidation results in the formation of indoles (see Eq. 8.22).35a A-Tosyl-3-nitroindole undergoes high-yielding Diels-Alder reactions with... 

Although pyrroles do not generally participate in Diels-Alder reactions with olefinic dienophiles, the very reactive hexafluoro-Dewar benzene with pyrrole gives the 1 1 and 1 2 adducts, 27 and 28, both of which probably have all-ea o stereochemistry. Some other 7-azabicyclo-heptene derivatives have been obtained via cycloaddition reactions of 7-azaquadricyclanes (see Section II, F). 

The furo[3,4- ]pyrroles 132, 133 <2002TL6983>, thieno[2,3-f]furan 134, <1996JOC6166>, and furo[2,3-f]pyrrole 135 <1995T193>, which are mostly less stable than the benzo-fused analogues, were trapped by Diels-Alder reactions with dienophiles followed by elimination of water to give the corresponding indoles 136-139, 140, 141, and benzothiephenes 142, 143, and 144 with good to excellent yields (Scheme 13). 

Pyrroles, indoles and benzo[ft]thiophene act as good dienophiles in inverse electron demand Diels-Alder reactions with 1,2-diazines, 1,2,4-triazines and sy/n/n-tetrazines. This is examplified by the formation of compounds (189) in excellent yields on interaction of indoles and benzo[c]thiophene with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate (87JOC4610 90JOC3257). There are also many examples of such intramolecular reactions, e.g. (190 — 191). 

The Diels-Alder reaction of pyrrole-3-carboxyhc esters with TV-methyl- and N-phenyl-maleimides yield exclusively endo adducts.243 The Diels-Alder reaction of... 

In contrast to the conventional Diels-Alder reaction with free pyrroles, which requires specialized functionalization on both the pyrrole and dienophile, the [2+3] dipolar cycloadditions described herein allow the use of simple alkenes (i.e., bearing at least one electron-withdrawing group) and pyrroles containing no electron-withdrawing groups. Use of... 

If pyrrole would do a similar thermodynamically controlled exo Diels-Alder reaction with a vinyl pyridine, a short route to the interesting analgesic epibatidine could be imagined, with just a simple reduction of the remaining alkene left to do. The reaction looks promising as the pyridine makes the dienophile electron-deficient and pyrrole is an electron-rich diene . 

Since perfluoroalkyl-substituted olefins and alkynes possess low-lying frontier orbitals, [4 + 2] cycloaddition reactions to oxazoles and thiazoles without strongly electron-donating substituents are unfavorable. On the other hand, five-membered heteroaromatic compounds possessing an electron-rich diene substructure, like furans, thiophenes, and pyrroles, should be able to add perfluoroalkyl-substituted olefins as well as alkynes in a normal Diels-Alder process. A reaction sequence consisting of a Diels-Alder reaction with perfluoroalkyl-substituted alkynes as dienophile, and a subsequent retro-Diels-Alder process of the cycloadduct initially formed, represents a preparatively valuable method for regioselective introduction of perfluoroalkyl groups into five-membered heteroaromatic systems. 

The uncoordinated 3-vinylpyrrole complexes (e.g., 1133) resemble an electron-rich diene and, as such, undergo a facile Diels-Alder reaction with electron-deficient alkenes and alkynes under mild conditions, for example T-phenylmaleimide 1134 to generate, after decomplexation and oxidation, a highly functionalized indole 1135 in ca. 60% overall isolated yield (from pyrrole) (Scheme 221) <1996JA7117>. 

Oxazoles represent the most widely recognized heteroaromatic azadiene capable of [4 + 2] cycloaddition reactions. The course of the oxazole Diels-Alder reaction and the facility with which it proceeds are dependent upon the dienophile structure (alkene, alkyne), the oxazole and dienophile substitution, and the reaction conditions. Alkene dienophiles provide pyridine products derived from fragmentation of the [4 + 2] cycloadducts which subsequently aromatize through a variety of reaction pathways to provide the substituted pyridines (Scheme 14). In comparison, alkyne dienophiles provide substituted fiirans that arise from the retro Diels-Alder reaction with loss of R CN from the initial [4 + 2] cycloadduct (Scheme 15,206 Representative applications of the [4 + 2] cycloaddition reactions of oxazoles are summarized in Table 14. Selected examples of additional five-membered heteroaromatic azadienes participatiitg in [4 + 2] cycloaddition reactions have been detailed and include the Diels-Alder reactions of thiazoles, - 1,3,4-oxadiazoles, isoxazoles, pyrroles and imidazoles. ... 

Masked o-benzoquinones (one CO group is acetal- or acylal-protected) as active dienes in Diels-Alder reactions with dienophiles (among them thiophene and pyrrole derivatives) 02ACR856. 

There are a number of examples of substituted pyrroles participating as 4tt components of all-carbon Diels-Alder reactions.63 However, their reported participation as a 1- or 2-azadiene system in [4 + 2] cycloadditions are limited to selected pyrroles.64,65 Pentachloro-2//-pyrrole has been shown to participate in inverse electron demand Diels-Alder reactions with electron-rich dienophiles exclusively in the form of the 2-azadiene system, pentachloro-S/Z-pyrrole,64 and one example of an intramolecular Diels-Alder reaction of a substituted, in situ generated 3//-pyrrole has been described (Chapter 9, Section 2).65... 

Adducts with the 1,4-epiiminonaphthalene skeleton may be prepared by the Diels-Alder reaction between pyrroles and benzynes.460... 

This bond order deviation from an ideal transition state structure to an example of cyclopropene added to a benzo-fused heterocycle may now be applied. Before we exEunine bond order deviation from an ideal transition state, we can take a look at the sums of rings bond order in the transition state structures. To simplify this picture, we will focus only on exo transition state structures between cyclopropene and benzo[c]heterocycles. Previously, we mentioned that the Diels-Alder reaction with benzo[c]heterocycles as dienes is a HOMO controlled diene reaction, therefore, an electron rich (higher sum of bond order) transition state structure should be energetically preferred. If this is the case, the order of reactivity should be benzo[c]furan, benzo[c]thiophene, and then benzo[c]pyrrole, which is exactly the same as determined on the basis FMO energy change (Table 23). 

The ring enlargement of pyrroles providing 3-chloropyridines has already been described (see p 93). Oxazoles react as masked 2-azadienes with alkenes yielding pyridine derivatives of various types (see p 131). With enamines and ynamines, diazines and triazines undergo Diels-Alder reactions with inverse electron demand (see p 441). This leads to pyridines (e.g. 201) by the enamine cycloaddition of the 1,2,4-triazine, as shown below ... 

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