The IntramolecularDiels–Alder Reaction

Abstract

The Diels–Alder reaction is one of the most useful reactions available to the synthetic organic chemist. It is thus surprising that the intramolecular version, in which both diene and dienophile are part of the same molecule, remained virtually unexplored for many years. Early examples were often the result of unexpected observations, and the many advantages of this reaction were recognized and put to use in the synthesis of complex polycyclic molecules only recently. In the intramolecular Diels–Alder reaction, two rings are formed in one step. In addition to the six‐membered ring formed by the [4 + 2]cycloaddition, the product contains a second ring, the size of which depends on the length of the chain connecting diene and dienophile. Of the two possible regiochemical modes of addition, that leading to the fused product usually predominates to the virtual exclusion of the bridged product. The Diels–Alder reaction proceeds through a highly ordered transition state that is reflected in large negative activation entropies. In the intramolecular version, some of the ordering has been accomplished in advance by making the two reacting functionalities part of the same molecule. This results in less negative activation entropies and increased reaction rates under often surprisingly mild conditions. On the other hand, by using forcing conditions one can sometimes carry out intramolecular Diels–Alder additions that would be doomed to failure in the intermolecular version. Lower reaction temperatures, together with the constraints imposed by the connecting chain, often result in pronounced regio‐ and stereoselectivity. Side reactions such as dimerization or polymerization can be avoided by using high dilution or low pressures in the gas phase. Examples where the bimolecular Diels–Alder reaction interferes with the intramolecular cyclization are rare. All of these features suggest that the intramolecular Diels–Alder reaction should be considered for any synthesis of a molecule containing a six‐membered ring fused to a second ring, especially if that ring is five‐ or six‐membered. Such a synthetic scheme may be made convergent by building up the diene and dienophile portions separately and connecting them just prior to the actual cyclization. Another potential use of the intramolecular Diels–Alder reaction that has not received much attention to date is as a supplement to the intermolecular Diels–Alder reaction in cases where the latter is unsuccessful or gives the wrong regio‐ or stereochemistry. By judicious choice of the connecting chain, the reaction may be made to proceed with the desired selectivity; this is followed by cleavage of the chain and conversion of the two ends to the desired functionalities. Once the feasibility of employing the intramolecular Diels–Alder reaction has been recognized, the main challenge often becomes the preparation of the substrate. A discussion of that aspect is beyond the scope of this chapter; however, by scanning the tables for the particular diene, dienophile, and chain one is interested in, and then referring to the original literature, it will often be possible to obtain some indications on how to proceed. An attempt has been made to cover the literature of the thermal intramolecular Diels–Alder reaction as completely as possible up to and including the year 1981. Many of the papers that appeared in 1982 and some from 1983 have also been included. More recent references are given in an addendum at the end of the tabular survey.

A highly efficient and general method for the preparation of (Z)-allylic bromides derived from Morita-Baylis-Hillman adducts

“…These multifunctional compounds can be prepared from α-methylene-β-hydroxyesters 2, which are easily obtained by the well-recognized Morita-BaylisHillman reaction. [14][15][16][17] Typically, the method of choice for the direct conversion of adduct 2 to the corresponding (Z)-allylic bromide 1 relies on the combination of 48% HBr and conc. H 2 SO 4 in CH 2 Cl 2 at low temperature.…”

2-Aminobenzimidazole Organocatalyzed Asymmetric Amination of Cyclic 1,3-Dicarbonyl Compounds

“…First, the search for the appropriate catalyst to carry out this reaction was tackled using ethyl 2-oxocyclopentanecarboxylate (1a) and di-tert-butylazodicarboxylate (2a) as model substrates (Table 1) and different trans-cyclohexanediamine benzimidazole derivatives I-VIII (Table 1, entries [1][2][3][4][5][6][7][8]. The more basic catalysts I-IV afforded the corresponding amination product 3aa in high conversions and enantioselectivities ( Table 1, entries 1-4), reaching up to 90% ee in the case of dimethylamino derivative II ( Table 1, entry 2).…”

“…Among them, the asymmetric electrophilic amination of prochiral carbonyl compounds employing diazocarboxylates as nitrogen source is a simple and straightforward method since the latter reagents are bench-stable and readily available. 2 Particularly interesting is the catalytic asymmetric α-amination of prochiral 1,3-dicarbonyl compounds, since the highly functionalized resulting structures can be further transformed and elaborated. [1][2][3] In this regard, several strategies have recently been developed to accomplish this transformation.…”

“…2 Particularly interesting is the catalytic asymmetric α-amination of prochiral 1,3-dicarbonyl compounds, since the highly functionalized resulting structures can be further transformed and elaborated. [1][2][3] In this regard, several strategies have recently been developed to accomplish this transformation. 3 Thus, since the pioneer work of Jørgensen and co-workers using a copper(II)-box catalytic system 4 different methods, not only metal-catalyzed, 5 but also employing organocatalysts [6][7][8] have been reported.…”

Studies on the transannular Diels–Alder reaction of 15-membered macrocyclic trienes containing a trans-trans diene. Part II: Evidence for unsymmetrical transition states in the formation of A.B.C.[6.6.7] tricyclic products

“…Noncatalyzed thermal reactions in sealed tubes (re$ 25) A clean Pyrex tube (20 cm long, exterior diameter 9 mm, interior diameter 5 mm; quartz was used for reactions with low boiling point solvents at T >250°C) was washed with ammonium hydroxyde, rinsed with distilled water, and oven and flame dried. The macrocyclic triene was addedL4 and the tube was sealed under vacuum.…”