Synthesis 2 + 2 cycloreversion

Cycloaddition involves the combination of two molecules in such a way that a new ring is formed. The principles of conservation of orbital symmetry also apply to concerted cycloaddition reactions and to the reverse, concerted fragmentation of one molecule into two or more smaller components (cycloreversion). The most important cycloaddition reaction from the point of view of synthesis is the Diels-Alder reaction. This reaction has been the object of extensive theoretical and mechanistic study, as well as synthetic application. The Diels-Alder reaction is the addition of an alkene to a diene to form a cyclohexene. It is called a [47t + 27c]-cycloaddition reaction because four tc electrons from the diene and the two n electrons from the alkene (which is called the dienophile) are directly involved in the bonding change. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with describing the reaction as a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, that of ethylene with butadiene ... 

The Boger pyridine synthesis involves the reaction of triazine 1 with activated alkene 2 in a hetero-Diels-Alder fashion. The intermediate bicyclic species 3 is unstable and a facile cycloreversion takes place due to the loss of nitrogen gas to afford the appropriately substituted pyridine derivative 4. 

An interesting perspective for synthesis is offered by the reaction sequence cycloaddition/cycloreversion. It often does not lead to the initial reactants, but to a different pair of dipole and dipolarophile instead ... 

Triazine (38) is ideal for inverse electron-demand Diels-Alder cycloadditions, for example, with azulene to give a l,4-bis(CF3)phthalazine (89CB711). A rare example of the synthesis of a five-membered heterocycle originating from [4 + 1] cycloaddition followed by [4 + 2] cycloreversion was reported using (38). The intermediate tetraazanorbomadienimine (39) is highly strained and eliminates N2 [82AG(E)284]. 

The retro Diels-Alder reaction usually requires high temperatures in order to surmount the high activation barrier of the cycloreversion. Moreover, the strategy of retro Diels-Alder reaction is used in organic synthesis to mask a diene fragment or to protect a double bond [47]. Some examples are illustrated in Scheme 1.11. 

A [2 + 2] photoaddition-cycloreversion was applied to the enantioselective synthesis of the natural product byssocMamic add (Figure 6.11). Desymmetrization of a meso-cyclopentene dimethyl ester with PLE in pH 7 buffer-acetone (5 1) provided a monoacid, one of the photopartners. It is noteworthy that both enantiomers of this natural product were synthesized from the same monoacid [58]. 

In yet another approach towards the synthesis of cyclocarbons by cycloreversion, Adamson and Rees [71] prepared the 1,2,3-triazole-fused dehydroannulenes 42 - 44, as mixtures of regioisomers in ca. 30 % overall yield, by oxidative Hay coupling of the protected 4,5-diethynyl-l,2,3-triazole 41 (Scheme 7). No investigations have yet been reported on the thermal or mass spectrometric [3-1-2] cycloreversions of 42-44, with loss of the triazole moieties and ultimate formation of the cyclocarbons Cis, C24, and C30, respectively. 

The state of research on the two classes of acetylenic compounds described in this article, the cyclo[ ]carbons and tetraethynylethene derivatives, differs drastically. The synthesis of bulk quantities of a cyclocarbon remains a fascinating challenge in view of the expected instability of these compounds. These compounds would represent a fourth allotropic form of carbon, in addition to diamond, graphite, and the fullerenes. The full spectral characterization of macroscopic quantities of cyclo-C should provide a unique experimental calibration for the power of theoretical predictions dealing with the electronic and structural properties of conjugated n-chromophores of substantial size and number of heavy atoms. We believe that access to bulk cyclocarbon quantities will eventually be accomplished by controlled thermal or photochemical cycloreversion reactions of structurally defined, stable precursor molecules similar to those described in this review. 

Photolytic [4+2] cycloreversion of a disilabicyclo[2.2.2]octadiene precursor is considered to be a general method for the synthesis of disilenes of varying stability. Several examples of this method have been reported (Eq. 9).27-31 First used in reactions producing an unstable disilene, Me2 Si=SiMe2,27 this method is also successful for synthesizing the marginally stable -Bu2Si=Si(t-Bu)2,28 However, it has not yet been applied to the synthesis of disilenes that are fully stable at room temperature, probably because the appropriate precursors are inaccessible. 

Scheme 5 a Flavin-H-phosphonate and formacetal-linked thymine dimer phospho-ramidite used for the synthesis of the flavin and dimer containing DNA-strands 7-12. b Representation of a reduced flavin- and formacetal-linked cyclobutane pyrimidine dimer containing DNA strand, which upon irradiation (hv) and electron transfer (ET) performs a cycloreversion (CR) of the dimer unit, c Depiction of the investigated oligonucleotides... 

Goti, Brandi and coworkers developed an effective synthesis of (-)-rosmarinecine (4-357) via a domino cycloreversion-intramolecular nitrone cycloaddition of 4-355, which led to 4-356 (Scheme 4.79) [125]. 

Furthermore, oxazoles of type 9-82 bearing a secondary amino functionality can be converted into pyrrolo[3,4-b]pyridines 9-86 by reaction with appropriate acid chlorides 9-83 in a triple domino process consisting of amide formation/hetero Diels-Alder reaction and retro-Michael cycloreversion via 9-84 and 9-85 (Scheme 9.17). The pyrrolo[3,4-fc]pyridines can be obtained in even higher yields when the whole sequence is carried out as a four-component synthesis in toluene. Here, 1.5 equiv. NH4C1 must be added for the formation of the now intermediate oxazoles [56b]. 

A similar transformation occurs as a critical step in the total synthesis of (+)-estrone by a Diels-Alder cycloaddition-cycloreversion pathway (Eq. 80).227 It is worth noting that in this reaction the conjugated double bond is stereoselectively reduced while both an isolated double bond and a ketone carbonyl are preserved. 

In a total synthesis of coriandrin 68, the isocoumarin unit is generated by the thermal rearrangement of an indenone epoxide 67, the first application of a cycloreversion route to isocoumarin synthesis (Scheme 46) <00TL3677>. 

Using the unsymmetrically substituted acetylene Me3SiC=CPh, the kinetically favored substituted complex 8a is formed initially, cycloreversion of which gives the symmetrically substituted and thermodynamically more stable product 8b. Due to steric reasons, the other conceivable symmetric product 8c is not formed [9]. Such metallacycles are typically very stable compounds and are frequently used in organic synthesis, as shown by the detailed investigations of Negishi and Takahashi [lm], Bis(trimethylsilyl)acetylene complexes are a new and synthetically useful alternative. 

If the cycloaddition and cycloreversion steps occurred under the same conditions, an equilibrium would establish and a mixture of reactant and product olefins be obtained, which is a severe limitation to its synthetic use. In many cases, however, the two steps can very well be separated, with the cycloreversion under totally different conditions often showing pronounced regioselectivity, e.g. for thermodynamic reasons (product vs. reactant stability), and this type of olefin metathesis has been successfully applied to organic synthesis. In fact, this aspect of the synthetic application of four-membered ring compounds has recently aroused considerable attention, as it leads the way to their transformation into other useful intermediates. For example aza[18]annulene (371) could be synthesized utilizing a sequence of [2 + 2] cycloaddition and cycloreversion. (369), one of the dimers obtained from cyclooctatetraene upon heating to 100 °C, was transformed by carbethoxycarbene addition to two tetracyclic carboxylates, which subsequently lead to the isomeric azides (368) and (370). Upon direct photolysis of these, (371) was obtained in 25 and 28% yield, respectively 127). Aza[14]annulene could be synthesized in a similar fashion I28). 

Other general principles applicable to the synthesis of heterocycles refer to cycloreversions (either pericyclic and cheletropic or 1,3-dipolar), valence-bond isomerisations and retro-annulations leading to enamines. 

Nowadays, solid-phase synthesis has been used as a powerful tool in organic chemistry, especially to prepare small molecule libraries. New linkers to obtain different functionalities after cleavage have been developed. There are different linkers strategies (Fig. 3.2), for example traceless linkers, multifunctional linkers, safety catch linkers, fragmentation/ cycloreversion cleavage linkers, cyclization cleavage linkers, which are useful methods for combinatorial solid-phase chemistry. 

The isorniinchnone cyclization/isocyanate cycloreversion process for substituted furan synthesis has been well studied, as exemplified by the conversion of 104 to 106 (Scheme 19.19). In a solid-phase adaptation of this transformation, two groups independently utilized this reaction to estabhsh a traceless self-cleaving method for the synthesis of substituted furans [176, 177]. Further investigation of the thermal requirements of this cycloreversion led to its application in the split-pool synthesis of a small library of amides [178]. 

These examples already prove that the potential of such reactions for the synthesis of stable fuUerene derivatives is restricted due to the facile cycloreversion to the starting materials. Nevertheless, cycloreversion can also be useful. Reversibility of dimefhylanthracene addition was utilized for the selective synthesis of Ti -symme-trical hexakisadducts (see Chapter 10) [12]. In another example, a dendritic polyamidoamine-addend was reversibly attached to via an anthracene anchor (Figure 4.1) [14, 15]. The dendrofullerene, which is soluble in polar solvents, can be obtained in 70% yield and the retro-Diels-Alder reaction at 45 °C proceeds with a conversion rate of more than 90%. 

In 1984, a facile synthesis of pyrrolo[3,4-/7]indole (5) as a stable indole-2,3-quinodimethane analogue using an intramolecular azide-alkene cycloaddition-cycloreversion strategy was reported (Scheme 9.2) (3). Treatment of bromo compound 3 with NaNs in aqueous tetrahydrofuran (THF) produced the triazoline 4 via an intramolecular 1,3-dipolar cycloaddition of an intermediate azide. Treatment of the triazoline 4 with p-toluenesulfonic acid (p-TSA) effected 1,3-dipolar cycloreversion of 4 to give pyrroloindole 5 in 82% yield along with diethyl diazomalonate. 

The first synthesis of the parent compound of the benzo[4,5]thieno[2,3-f]pyrrole ring system 387 <2003T1477> and its derivatives was accomplished using the same synthetic sequence (Scheme 42). Starting with 2-methyl-benzo[ ]thiophene-3-carbaldehyde 388, an intermediate 389 was obtained. Treatment of bromo compound 389 with sodium azide in ethanol led to the stable triazoline 390. 1,3-Dipolar cycloreversion of 390 was induced by a catalytic amount of />-TsOH to give the parent 2//-benzo[4,5]thieno[2,3-c]pyrrole 387. Alternatively, direct treatment of bromo compound 389 with excess ammonia furnished 387 in one step. Compound 387 was treated with di-/-butyl dicarbonate and 4-dimethylaminopyridine (DMAP) to give iV-BOC derivative 391. Reaction of 389 with... 

A great deal is already known about the pyrolysis of pinenes," which constitutes a perfect case for the study of cyclobutane cycloreversion reactions. In practice, this avenue was first explored with the hope of obtaining products with commercial value.99 Unfortunately, the application of these reactions to organic synthesis is somewhat restricted, because complex product mixtures cause complications. For the sake of clarity Table 6100 110 outlines only the cycloreversion products and their straightforward secondary derivatives nevertheless, it demonstrates some of the synthetic uses of these thermal cleavage reactions. 

Despite the fact that the outcome of cycloreversion reactions of cyclobutane derivatives is usually unpredictable, there have been ample examples that demonstrate the usefulness of these reactions synthetically. Some of these reactions are summarized in Table 7.111-158 Indeed, a practical synthesis of methyl buta-2,3-dienoatc by this cycloreversion strategy has been recorded in a detailed format.111... 

The reverse process is also useful in synthesis. The active components of the cycloreversion reaction are the two a bonds which will be broken and any systems to which both a bonds are allylic (i.e., at least one of m, n is an even number greater than 2). The stereochemistry of the reaction may also be specified in terms of the stereochemical mode of reaction of the active components of the reaction. 

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