Five-membered heterocycles heterocyclic construction

As shown in Scheme 2, two heteroatom-carbon bonds are constructed in such a way that one component provides both heteroatoms for the resultant heterocycle. By variation of X and Z entry is readily obtained into thiazoles, oxazoles, imidazoles, etc. and by the use of the appropriate oxidation level in the carbonyl-containing component, further oxidized derivatives of these ring systems result. These processes are analogous to those utilized in the formation of five-membered heterocycles containing one heteroatom, involving cyclocondensation utilizing enols, enamines, etc. 

Table 2 illustrates 1,3-dipoles with a double bond and with internal octet stabilization, commonly referred to as the propargyl-allenyl anion type. These are all reactive dipoles and a large number of five-membered heterocycles can be constructed from these readily available dipoles, especially when the dipolarophile is varied to include heterocumulenes, etc. 

The 1,3-dipolar molecules are isoelectronic with the allyl anion and have four electrons in a n system encompassing the 1,3-dipole. Some typical 1,3-dipolar species are shown in Scheme 11.4. It should be noted that all have one or more resonance structures showing the characteristic 1,3-dipole. The dipolarophiles are typically alkenes or alkynes, but all that is essential is a tc bond. The reactivity of dipolarophiles depends both on the substituents present on the n bond and on the nature of the 1,3-dipole involved in the reaction. Because of the wide range of structures that can serve either as a 1,3-dipole or as a dipolarophile, the 1,3-dipolar cycloaddition is a very useful reaction for the construction of five-membered heterocyclic rings. 

Huisgen has reported in 1963 about a systematic treatment of the 1,3-dipolar cycloaddition reaction as a general principle for the construction of five-membered heterocycles. This reaction is the addition of a 1,3-dipolar species 1 to a multiple bond, e. g. a double bond 2 the resulting product is a heterocyclic compound 3. The 1,3-dipolar species can consist of carbon, nitrogen and oxygen atoms (seldom sulfur) in various combinations, and has four non-dienic r-electrons. The 1,3-dipolar cycloaddition is thus An +2n cycloaddition reaction, as is the Diels-Alder reaction. 

The [3 + 2]-cycloaddition reactions of allenes with 1,3-dipoles are useful for the construction of a variety of five-membered heterocycles with a high degree of regio- and stereochemical control [67]. Generally, the dipolar cycloaddition reactions are concerted and synchronous processes with a relatively early transition state. The stereoselectivities and regiochemistries are accounted for by the FMO theory The reaction pathway is favored when maximal HOMO-LUMO overlap is achieved. 

Both target compounds discussed in this review, kelsoene (1) and preussin (2), provide a fascinating playground for synthetic organic chemists. The construction of the cyclobutane in kelsoene limits the number of methods and invites the application of photochemical reactions as key steps. Indeed, three out of five completed syntheses are based on an intermolecular enone [2+2]-photocycloaddition and one—our own—is based on an intramolecular Cu-catalyzed [2+2]-photocycloaddition. A unique approach is based on a homo-Favorskii rearrangement as the key step. Contrary to that, the pyrrolidine core of preussin offers a plentitude of synthetic alternatives which is reflected by the large number of syntheses completed to date. The photochemical pathway to preussin has remained unique as it is the only route which does not retrosynthetically disconnect the five-membered heterocycle. The photochemical key step is employed for a stereo- and regioselective carbo-hydroxylation of a dihydropyrrole precursor. 

Since their introduction by Huisgen (see <1995H(40)1> and references therein), the 1,3-dipolar cycloaddition remains the single most powerful method for the construction of five-membered heterocycles. Literature examples of this approach in an inter- and intramolecular fashion for the assembly of nonconjugated examples of bicyclic 5-5 heterocycles with l 2-heteroatom orientation are common. Heterocycles with either [1,2,4], [1,2,5], or [1,2,6] heteroatom locants (204, 205, and 206, respectively) can be assembled utilizing this approach. The stereoelectronic aspects of the various cycloaddition strategies are not discussed here. 

Burger et al. have largely studied the synthetic utility of 1,3-diazadienes 314 as useful edducts for the construction of five-membered heterocycles... 

The transition metal catalyzed synthesis of five membered heterocycles, particularly of condensed ring systems, has attracted considerable attention. The ease of the formation of five membered rings has been utilised both in intramolecular ring closure processes, and in the combination of two (three) fragments through the formation of a carbon-carbon and a carbon-heteroatom bond. This chapter is dedicated to examples, where the construction of the five membered heterocycle is achieved in a transition metal catalysed step. 

The palladium based catalyst systems were also effective in the construction of carbon-nitrogen bonds on benzannulated five membered heterocycles. The 4-chloroindole derivative shown in 6.78. was coupled with piperazine in excellent yield, using a ferrocene based ligand.109 The analogous 5-bromo-benzimidazole derivative gave similar results (6.79.),110... 

The carbo- and hetero-Diels-Alder reactions are excellent for the construction of six-membered ring systems and are probably the most commonly applied cycloaddition. The 1,3-dipolar cycloaddition complements the Diels-Alder reaction in a number of ways. 1,3-Dipolar cycloadditions are more efficient for the introduction of heteroatoms and are the preferred method for the stereocontrolled construction of five-membered heterocycles (1-4). The asymmetric reactions of 1,3-dipoles has been reviewed extensively by us in 1998 (5), and recently, Karlsson and Hogberg reviewed the progress in the area from 1997 and until now (6). Asymmetric metal-catalyzed 1,3-dipolar cycloadditions have also been separately reviewed by us (7-9). Other recent reviews on special topics in asymmetric 1,3-dipolar cycloadditions have appeared. These include reactions of nitrones (10), reactions of cyclic nitrones (11), the progress in 1996-1997 (12), 1,3-dipolar cycloadditions with chiral allyl alcohol derivatives (13) and others (14,15). 

Well-defined substitution patterns in the target molecules can be constructed by a combination of fluorine-free or fluoro-substituted (1,3 ee) components with fluorine-free and fluoro-substituted (1,2 nn) compounds. A representative example for the introduction of fluorine and fluoro-substituted groups into five-membered heterocycles via both educts is the reaction of fluoro-substituted chalcones and pentafluorophenyl hydrazine (88JIC773). 

The concept of the 1,3-dipolar cycloaddition is especially valuable for the construction of five-membered heterocyclic systems, substituted by... 

As 1,/2-alkenes, 1,6-derivatives are used very frequently leading to five-membered heterocycles, while the use of 1,7-derivatives, which produce six-mem-bered heterocycles, is very rare. The reactions of 1,6-dienes, -enynes, and -diynes are classified into three groups (a) cycloisomerization, (b) tandem addition— cyclization, and (c) cycloaddition, such as the Pau-son—Khand reaction, cyclotrimerization, and the Diels—Alder reaction (Scheme 15).97 In these reactions five-membered heterocycles are constructed upon the carbon—carbon bond-forming processes. 

The hetero-cycloaddition of C—C unsaturated bonds with C=0 and C=N bonds constructs heterocycles through concerted formation of both a carbon—carbon and a carbon—heteroatom bond.177 The hetero-Pau-son—Khand reaction using CO, alkyne, carbonyl group is a typical hetero-[2 + 2 + 1]-cycloaddition, giving five-membered heterocycles. Hetero-Diels— Alder reaction, that is, hetero-[4 + 2]-addition, produces six-membered heterocycles. 

There are two different basic methods for obtaining the five-membered heterocycles. In the first approach, the ring is constructed directly from aliphatic compounds the other and less common approach makes use of congener rings or other heterocyclic systems as starting materials. All the syntheses reported for the tellurophene system have been based on the first principle. 

The chemistry of the trimethylenemethanepaUadium (TMM) intermediate 42 has been developed as a synthetically useful methodology. Its formal [3 + 2] cycloadditions to electron-deficient and some nonactivated aUcenes have been a significant advance in ring construction methodology, as has been demonstrated by facile preparations of cyclopentanes, five-membered heterocycles, and many applications in natural products total synthesis. " " ... 

Herein we deal with cycloaddition reactions of inter- as well as intramolecular carbonyl ylides towards the construction of functionalized five-membered heterocycles and oxa-bridged carbocyclic and heterocycUc sys-... 

---