4-Phenyl-1,2,4-triazoline-3,5-dione cycloadditions

An example of a /zctcro-Diels-Alder reaction in SC-CO2 is the cycloaddition of anthracene with 4-phenyl-1,2,4-triazoline-3,5-dione, carried out at 40 °C and at a pressures between 75 and 216 bar [86]. The rate constant increases with decreasing pressure and the highest reactivity was observed at the critical pressure. The value of the rate constant at the critical pressure was higher than that observed in liquid CHCI3 and MeCN at the same temperature. At higher pressures, the rate is slower than that in the polar solvents, which reflects the apolar nature of SC-CO2 as a solvent. 

Dipolar cycloaddition of pyrido[2,l-A][l,3]thiazinium betaine 507 (R = Me) with 1-diethylamino-l-propyne afforded cycloadduct 508, from which quinolizin-4-one 509 formed by a rapid cheletropic extrusion of COS (Scheme 53) <1995T6651>. 1,4-Dipolar cycloaddition of 507 and 4-phenyl-l,2,4-triazoline-3,5-dione yielded 511 (via 510) <1995H(41)1631> and 512 <1995T6651>. 

The (diphenylmethylene)aminocyclobutenecarboxylates 109 obtained by rearrangement of the DMPA-H adducts of 1-Me, 2-Me, contain a 2-azadiene unit and a cyclobutene moiety. Indeed, the parent compound 109 a reacted with 4-phenyl-l,2,4-triazoline-3,5-dione (PTAD, [80]) at room temperature in a [4-1-2] cycloaddition mode to yield the tricyclic tetraazaundecene 132 in almost quantitative yield (Scheme 44) [8]. As substituted cyclobutenes, compounds 109 should be capable of opening up to the corresponding butadienes [1, 2b, 811. When compounds 109 were subjected to flash vacuum pyrolysis, the dihydro-isoquinolines 135 were obtained, presumably via the expected ring-opened intermediates 133, which subsequently underwent bn electrocyclization followed by a 1,5-shift, as is common for other 3-aza-l,3,5-hexatrienes [82]. 

The following types of dipolarophiles have been used successfully to synthesize five-membered heterocycles containing three heteroatoms by [3 + 2]-cycloaddition of thiocarbonyl ylides azo compounds, nitroso compounds, sulfur dioxide, and Al-sulfiny-lamines. As was reported by Huisgen and co-workers (91), azodicarboxylates were noted to be superior dipolarophiles in reactions with thiocarbonyl ylides. Differently substituted l,3,4-thiadiazolidine-3,4-dicarboxylates of type 132 have been prepared using aromatic and aliphatic thioketone (5)-methylides (172). Bicyclic products (133) were also obtained using A-phenyl l,2,4-triazoline-3,5-dione (173,174). 

We were not able to obtain any cycloadduct from unactivated 2-azadienes 139 and esters of acetylenedicarboxylic acid. However, we found that 139 did cycloadd to typical electron-poor dienophiles such as esters of azodicarboxylic acid and tetracyanoethylene (Scheme 62). Thus, diethyl and diisopropyl azodicarboxylates underwent a concerted [4 + 2] cycloaddition with 139 to afford in a stereoselective manner triazines 278 in 85-90% yield (86CC1179). The minor reaction-rate variations observed with the solvent polarity excluded zwitterionic intermediates on the other hand, AS was calculated to be 48.1 cal K 1 mol-1 in CC14, a value which is in the range of a concerted [4 + 2] cycloaddition. Azadienes 139 again reacted at room temperature with the cyclic azo derivative 4-phenyl-1,2,4-triazoline-3,5-dione, leading stereoselectively to bicyclic derivatives 279... 

Cycloadditions to 3H-azepines appear to be limited to the two examples illustrated in Scheme 14 in which the azepine behaves as the electron-rich 27r-component (78AP786), and to the [4+2]7r adduct (159 R = AT-phthalimido) formed by the electron-rich dimethoxy-3/Z-azepine (69) and l-phenyl-l,3,5-triazoline-2,4-dione (73CC67). 

Substituted l,2,4-triazoline-3,5-diones are excellent dienophiles which react rapidly at room temperature with oxepins, but particularly with the arene oxide valence tautomer. A similar [4+2] cycloaddition reaction between the episulfide tautomer of thiepin (44) and 4-phenyl-l,2,4-triazoline-3,5-dione has been reported (74AG(E)736>. Benzene episulfide (the valence tautomer of thiepin 44) was generated in situ by thermal decomposition of the diepisulfide (151) at 20 °C and trapped as a cycloadduct at the same temperature (equation 34). A 1,3-dipolar cycloaddition reaction between thiepin (152) and diazomethane has been reported (56CB2608). Two possible cycloadduct products are shown since the final structure has not been unequivocally established (equation 35). 

Dipolar cycloaddition of anhydro pyrido[2,l-b][l,3]thiazinium hydroxides (128) with aryl isocyanates and dimethyl acetylenedicarboxylate gave pyrido[l,2]pyrimidines (129) and quinolizine-l,2-dicarboxylates (130), respectively (76CB3668). 1,4-Dipolar cycloaddition of pyrido[2,l-h][l,3]thi-azinium betaine (131, R = Me) with 1-diethylamino-l-propyne afforded cycloadduct 132, from which quinolizin-4-one 133 formed by a rapid cheletropic extrusion of carbonyl sulfide (93TL5405 95T6651). 1,4-Dipolar cycloaddition of anhydro 4-hydroxyl-2-oxo-6,7,8,9-tetrahydro-2//-pyrido-[2,l-b][l,3]thiazinium hydroxides (131) and 4-phenyl-l,2,4-triazoline-3,5-dione yielded 135 via 134 [94H(39)219 95H(41)1631] and 136 (95T6651). 

A 1,4-dipolar cycloaddition between tetrahydropyrido[l,2-a]pyrimidi-none 114 (R = Me) and 4-methyl-l, 2,4-triazoline-3,5-dione 666gave stable adduct 667 in acetonitrile or in acetic acid at room temperature for 1 hour (Scheme 44) (85CB4567). When ethyl cyanoformate was used as dienophile in boiling toluene for 20 hours, ethyl 3-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[ 1,2-a]pyrimidine-2-carboxylate 669 was obtained (86CB1445). Pyrido[l,2-a]pyrimidine-2-carboxylate 669 was formed from the initial adduct 668 by elimination of phenyl isocyanate. Reaction of tetrahydropyr-ido[l,2-a]pyrimidinone 114 (R = Me) with l-(diethylamino)-l-propyne in... 

There are numerous approaches to fused pyridazines using 4-phenyl-l,2,4-triazoline-3,5-dione (PTAD) in [4 + 2] cycloadditions. With this strategy a great number of heterocyclic compounds can be obtained, including some pyridazino[4,5-c]pyridazine derivatives. The conciseness does not... 

Some hetero double bond systems have been shown to enter [3 + 2] cycloaddition reactions with the mesoionic 1,3-dithiolones. Thus, the mesoionic 1,3-dithiolones (2) react with formaldehyde, prepared in situ by depolymerization of paraformaldehyde, with regiospecific formation of the 2-oxa-6,7-dithiabicyclo[2.2.1]heptanone derivatives (131). The corresponding reaction of (2) with the N=N double bond of dimethyl azodicarboxylate proceeds via cycloaddition yielding (132), and a similar reaction takes place between (2) and 4-phenyl-l,2,4-triazoline-3,5-dione (78CB3171). 

The mechanism of this type of reaction has received some attention. ° It has been suggested that these reactions are pericyclic processes, and since N°=N dienophiles have lower lying LUMOs than C=—C compounds, diey are more reactive. Cyclic N—N species have an even lower LUMO energy. However, a recent investigation of the cycloadditions of 4-phenyl-1,2,4-triazoline-3,S-dione (vide infra) indicates that in at least some cases the Diels-Alder reactions involve discrete intermediates. It would appear that a range of mechanisms may be available to azo dienophiles. 

There have been only a few reports of reactions of this type including cycloaddition of dienes 157 with the powerful dienophile 4-phenyl-l,2,4-triazoline-3,5-dione <1996J(P1)2297> and stereoselective cycloaddition of the chiral nitrone 158 with a variety of dipolarophiles <2000JOC7000>. A rare example of intramolecular hetero-Diels-Alder reaction involving a 4-methylene-l,3-oxathiolan-5-one 3 -oxide is provided by the cycloaddition reaction of 159 to give 160 (Equation 42) <1998EJ02733>. 

A [2 + 2] cycloaddition occurred on reaction of 4-phenyl-4//-l, 2,4-triazoline-3,5-dione with vinylcyclopropane (1) or 2-oxabicyclo[3.1.0]hex-3-ene (3). The yields of products 2 and 4 were excellent, and the cycloadduct 4 was formed as a single (cw-a t/-< w)-isomer. Formation of both adducts is, in fact, noteworthy since 4-phenyl-4//-l,2,4-triazoline-3,5-dione (PTAD) reacts in different ways with other alkenes, and 2-oxabicyclo[3.1.0]hex-3-ene undergoes [(2 + 2J + 2J cycloadditions with maleic anhydride and tetracyanoethene. " ... 

Formal [27t + 2ff + 2homo-homo-Diels-Alder) reactions include the cycloaddition of 4-phenyl-l,2-4-triazoline-3,5-dione to benzvalene (7), which served as the key step in the Katz prismane synthesis, and TCNE to 2-exo-methyl-endb-tricyclo[3.2.1.0 ]oct-6-ene (55). ... 

Cycloadditions of dienophiles with homotetraenes are also known. 1,2-Homohep-tafulvene (6-methylenebicyclo[5.1.0]octa-2,4-diene, 20) reacted with 4-phenyl-1,2,4-triazoline-3,5-dione to afford both an [8 + 2] cycloadduct 21 and a Diels-Alder product 22. 

Whereas methylenecyclopropanes only react with highly electron-deficient dienophiles in a [ 2n + 2fT) + 2n] fashion, alkenylidenecyclopropanes 1 readily undergo this cycloaddition type. A number of comprehensive and elaborate investigations with various alkenylidenecyclopropanes and 4-phenyl-l,2,4-triazoline-3,5-dione indicate that these reactions are concerted and proceed via [( 2j+,25+ 2 J -I-, 2 J transition states, involving the terminal double bond in an eight-electron Mobius aromatic transition structure 4. 

Cycloaddition of l,2,4-triazoline-3,5-dione or its 4-phenyl analog to penta-2,4-dienoic acid first affords the cycloadduct 33. This, upon hydrogenation to 34 and alkaline hydrolysis, gives hexahydropyridazine-3-carboxylic... 

The primary adducts, cyclohexadiene derivatives, formed by [4+2] cycloaddition of thiophene dioxides with dienophiles, may further undergo [4+2] cycloaddition with the dienophiles. Thus, the adducts 84 of 3,4-di-ferf-butylthiophene dioxide 83 with maleic anhydride and AT-phenylmaleimide further react with these dienophiles to give excellent yields of bis-adducts, which are composed of the endo-endo and endo-exo isomers, 85a and 85b (Scheme 49) [160]. A similar reaction was also observed with 3,4-dichlorothiophene 1,1-dioxide with N-butyl- and A-p-nitrophenylmaleimides (Scheme 50) [133]. The reaction of highly congested thiophene dioxides 87 with 4-phenyl-1,2,4-triazoline-3,5-dione provides a unique pyridazine synthesis since the bis-adducts 88 are converted into the corresponding pyridazines 89 in one pot and in good yields by treatment with KOH in methanol (Scheme 51) [174]. 

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