Diels-Alder reactions of alkynes

Recent studies have explored and detailed the utility of the intramolecular Diels-Alder reactions of alkyne 1,2,4-triazines [Eq. (32) and Table 10-X].99... 

Since the initial work of Chardonnens and others, few examples of syntheses of [l,2-a]IF derivatives exist outside of patent literature. Shi et al. recently reported [l,2-a]IFs 48a,b and [2,l-c]IFs 49a,b (Scheme 10) [46]. Diels-Alder reaction of alkynes 45a,b, readily available from fluorenones 44a,b, provided regioisomeric mixtures of diols 46a,b and 47a,b. Subsequent acid-catalyzed Friedel-Crafts condensation gives 48 and 49. The two derivatives of both regioisomers showed quantum yields in solution of 60% and showed good thermal stability, with decomposition occurring at temperatures greater than 330 °C. 

The primary and secondary products of photolysis of common diazirines are collected in Table 4. According to the table secondary reactions include not only isomerization of alkenes and hydrogen elimination to alkynes, but also a retro-Diels-Alder reaction of vibrationally excited cyclohexene, as well as obvious radical reactions in the case of excited propene. 

For the microwave-assisted experiments, both solvents were replaced by 1,2-dichlorobenzene, as it couples very effectively with microwaves (loss-tangent (tan 5) at 20 °C 1,2-dichlorobenzene 0.280 as compared to 0.101 for chlorobenzene). Diels-Alder reactions of 3-methoxy or 3-phenyl pyrazinones with DMAD were performed at a pre-selected maximum temperature of 200 °C, whereas the intramolecular reaction of alkyne tethered pyrazinone required a higher temperature (220 °C). The yields obtained under microwave irradiation are comparable with those obtained under conventional conditions, while for the dihydrofuropyridinone the yield was improved from... 

Diels-Alder reactions of cyclopentadienones with alkynes... 

The tricyclic compound 20-C, a potential intermediate for alkaloid synthesis, has been prepared by an intramolecular Diels-Alder reaction of the ketone obtained by deprotection and oxidation of 20-B. Compound 20-B was prepared from 20-A using alkyne-ethene metathesis chemistry. Show the mechanistic steps involved in conversion of 20-A to 20-B. 

It is not quite clear which step takes place first - the Co-catalyzed [2+2+1] cycloaddition of the outer alkyne moiety, or the Diels-Alder reaction of the diene with the inner alkyne to form a 1,4-cyclohexadiene, which then undergoes a Pauson-Khand reaction with the remaining alkyne. Recently, it has been shown that a domino reaction can also be performed using 1 mol of a 1,7-diphenyl-1,6-diyne 6/4-20 and a 1,3-diene 6/4-21 in the presence of Co/C at 150 °C under 30 atm CO, to give the polycyclic compounds 6/4-22 as sole product (Scheme 6/4.7) [282]. 

In work reminiscent of earlier studies by van der Plas <89T803, 89T5611>, Dehaen and co-workers illustrated how the electron deficient pyrimidine ring can be exploited in the intramolecular inverse electron demand Diels-Alder reactions of pyrimidine-tethered alkynes 102 <00SL625>. Under thermal conditions, pyridines 103 were produced in modest to excellent yields. 

Murakami and colleagues132 studied the Diels-Alder reactions of vinylallenes with alkynes catalyzed by a rhodium complex. When a vinylallene lacking substituents at the vinylic terminus was reacted with a terminal alkyne, 1,3,5-trisubstituted benzenes were obtained, the reaction between vinylallene 197 and 1-hexyne (198) being a representative example (equation 55). The reaction was proposed to proceed via a rhodacycle which afforded the primary Diels-Alder adduct via reductive elimination. Aromatization via isomerization of the exocyclic double bond led to the isolation of 199. 

The cobalt mediated homo Diels-Alder reaction of norbomadiene (560) with phenyl acetylene (568a), affording a phenyl substituted deltacyclene, demonstrated the potential of low-valent cobalt complexes as catalysts332. Lautens and coworkers327 extended the scope of this reaction and were able to synthesize a wide range of substituted deltacyclenes from alkynes 568 (equation 164, Table 33). The low-valent cobalt or cobalt(O) species to be used was prepared in situ by reduction of Co(acac)3 with Et2AlCl. Monosubstituted... 

The inverse-electron-demand Diels-Alder reaction of 3,6-dichloro[l,2,4,5]tetrazine with alkenes and alkynes provides the synthesis of highly functionalized pyridazines. ° Also, the 4 + 2-cycloaddition reactions of the parent [l,2,4,5]tetrazine with donor-substituted alkynes, alkenes, donor-substituted and unsubstituted cycloalkenes, ketene acetals, and aminals have been investigated. ... 

Diels-Alder reactions with alkynes as dienophiles have been known for a long time. Iminoboranes, however, will more readily cyclodimerize than react with dienes, and even the cyclodimers are generally superior to dienes in the competition for excess iminoborane. Among many attempts, therefore, only two reactions with iminoboranes as dienophiles have been successful, and in both of them the diene is cyclo-pentadiene [Eq. (55)] (9, 14). 

Enyne 112a having a boron moiety on the alkyne gives vinyl boron 113a [Eq. (6.83)], whose carbon-boron bond can be converted to a carbon-carbon bond. Enyne metathesis followed by Diels-Alder reaction of the resulting diene with DMAD gives tricyclic compound 114 [Eq. (6.84)]. ... 

Inverse electron demand Diels-Alder reactions of 1,2,4,5-tetrazines with alkynes produce pyridazines directly with the elimination of nitrogen and retention of the substituents on the acetylene thus, tributylstannylacetylenes give pyridazines with a 4-tributylstannyl substituent (Scheme 24). 

A synthesis of the furanoeremophilane ( )-ligularone has been accomplished via the intramolecular Diels-Alder reaction of an oxazole with an alkynic dienophile (81JA4611). The lactone (359) was treated with lithium methylisocyanide to yield the oxazole (360). Oxidation of alcohol to aldehyde and reaction of this unstable aldehyde with lithiopropyne gave a 55 45 mixture of diastereomeric alcohols (361). Oxidation of the mixture gave a single alkynic ketone (362) which when refluxed in ethylbenzene afforded the desired furanosesquiterpene (363 Scheme 78). 

Pyridazines and their partially saturated analogs have been prepared on insoluble supports by Diels-Alder reaction of electron-rich alkenes or alkynes with 1,2,4,5-tetrazines (Entries 1-3, Table 15.27). The mechanism of this reaction is outlined in Figure 15.15. An additional approach, also based on the Diels-Alder reaction, is the cycloaddition of azo compounds to 1,3-dienes (Entries 4 and 5, Table 15.27). The resulting tetrahydropyridazines (Entry 4) have been used as constrained 3-strand mimetics for the discovery of new protease inhibitors [323], An example of the N-alkylation of hexahydropyridazines on solid phase is given in Section 10.3. 

Alkynes are poor dienophiles in the Diels- Alder reaction decomposition occurs by an attempted thermal intramolecular Diels-Alder reaction of dienynes at 160 °C. In contrast, the Ni-catalysed [4+2] cycloaddition of the dienyne 50 proceeded smoothly at room temperature using tri(hexafluoro)isopropyl phosphite to give 51, which was converted to the yohimbine skeleton 52 [15]. The same reaction is catalysed by RhCl(Ph3P)3 in trifluoroethanol [16]. Intramolecular Diels-Alder reactions of the 6,8-dieneyne 53 and the 1,3,8-triene 55, efficiently catalysed by [Rh(dppe)(CH2CH2)2]SbF6 at room temperature, gave 54 and 56 [17],... 

Recently we have developed a more general approach to molecules exemplified by III. Thus the Diels-Alder cycloaddition of alkyne II and ct-pyrone, followed by aromatization by loss of carbon dioxide, led to the isolation of III (72%) (5). Alkyne II was obtained in high yields, in two steps from dichloroacetylene and triethylphosphite via Arbuzov-type reactions (5). Since the intermediate chloroalkyne phosphonate I was isolable (90%), phosphorus nucleophiles other than triethylphosphite could be used to give unsymmetrical alkyne diphosphoryl species. We have demonstrated this approach by the reaction of I with PhaPOEt and PhP(OEt)2 (5). 

The reaction with DPA may be viewed as 1.3-dipolar cycloaddition of the alkyne with the C=Fe=CO moiety of the intermediate formed by loss of one CO group. The DMB-reaction may be considered as Diels-Alder reaction of the cyclic C=C bond. 

Diels-Alder reactions of 1 with a variety of alkynes provides a route to various substituted o-di-f-butylbenzenes. 

Although obtained only in low yields upon troublesome chromatography of product mixtures that contained much polymeric material, the tricyclic benzofuran and benzothiophene lactones (61) were shown to be isolable products from attempted Diels-Alder reactions on the allene ester precursors shown in Equation (32) <85JCS(Pl)747>. Although it was noted in the case of the two thiophenes that the tricyclics appeared to be forming from a precursor (presumably a dihydro form) on the chromatographic column, it was not possible to convert the crude suspected cycloaddition adducts directly into the aromatics by dehydrogenation with DDQ. Complex mixtures were obtained instead. It is possible that the actual dienophiles in these Diels-Alder reactions are alkynes. In a related study, the bis-lactone (62) was also obtained (Equation (33)) <86H(24)88l>. 

Drawn from these examples it is apparent that controlling the chemose-lectivity in inter-intermolecular Heck-Diels-Alder reactions of two different alkenes can be tedious if the alkenes show comparable reactivities. Nevertheless, the stepwise approach was realized in several other cases. In a synthesis of a derivative of cephalostatin 1 containing a central benzene instead of the pyrazine ring, Winterfeldt et al. linked two steroidal systems by a Heck coupling and subsequently performed high pressure Diels-Alder reactions of the conjugated diene with electron-deficient alkynes [34], Another example, reported by Hayashi et al., involves a selective Heck reaction of a bromoglu-cal with ethylene or acrylic acid derivatives followed by cycloadditions with maleic anhydride or N-phenylmaleimide [35]. 

This group has used the same reaction conditions with diynes 182 and cyclic dienes like cyclopentadiene to form tetracyclic enone 183 which was transformed into triquinane 184 by means of an oxidative cleavage of the double bond. When phenyl groups at the alkyne terminus were substituted by H or Me they observed a competitive [2 + 2 + 1]/[2+ 2 + 2] process, with the participation of two diyne molecules giving compounds 185 (Scheme 54) [171]. No mechanistic hypothesis appears in this work but the formation of a norbornene derivative by means of the Diels-Alder reaction of cyclopentadiene and the diyne that would react with the other triple bond of the diyne seems attractive in this case. 

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