Cycloadditions azodicarboxylate

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

The other main source of various pyridopyridazines from pyridines are the [4 + 2] cycloaddition reactions, already mentioned (Section 2.15.8.3), between vinylpyridines and azodicarboxylic esters (79T2027, 79KGS639) or triazolidinediones e.g. 78KGS651). 2-Vinyl-pyridines gave reduced pyrido[3,2-c]pyridazines (370), 4-vinylpyridines gave [3,4-c] analogues, whilst 2-methyl-5-vinylpyridine furnishes a mixture of the [2,3-c] and [4,3-c] compounds. Yields are low, however, and these remain curiosities for practical synthetic purposes. 

Cycloaddition reactions of aziridines with a wide assortment of dipolarophiles have been studied. The reaction of dialkyl azodicarboxylates with the cf5-aziridine (27) is stereospecific... 

Treatment of 6-arylidenehydrazino-3-alkyl-5-nitrouracils 510 with etha-nolic KOH caused a benzylic acid type of rearrangement to give 511, which were alkylated to give 512, whose cyclization with diethyl azodicar-boxylate gave (80H1295) 513 by intramolecular cycloaddition through valence isomerization and then aromatization with diethyl azodicarboxylate (Scheme 107). 

A novel type of heterocyclisation reaction involving the dipolar cycloaddition of jV,A-dialkylamino substituted thioisomunchnones and azodicarboxylates giving 1,2,4-triazine derivatives has been reported. The cycloadduct 26 is initially formed from the isomunchnone 24 and the azodicarboxylate 25, it then undergoes a selective fragmentation to give the 1,2,4-triazine 27 <99TL8675>. 

The reactivity of compound 113 toward reactive linear and cyclic dienophiles was reported in a study directed to find a model systems for the proposed [4+2] cycloaddition in the biosynthesis of the natural products brevianamides, paraherquamides, and marcfortines. With DMAD and diethyl azodicarboxylate the formation of 114 and 115 was almost quantitative after 48 h at 80 °C (Cbz = Carbobenzyloxygroup). When relatively unreactive dienophiles such as cyclopentene and cyclohexene were used, harsh reaction conditions and/or a Lewis acid catalyst are necessary for the formation of 116a and 116b (Scheme 16). In contrast, the analogous intramolecular reaction carried out on compound 117 takes place within a few hours at room temperature, even in the absence of a Lewis acid catalyst, to give 118 in 42% yield (Scheme 16) <2000T6345>. 

Table 5.8 summarizes the glycals that had been converted into 2-aminoglycosides so far. In general, photolytic ds/trans isomerization of trans-azodicarboxylates is necessary to accomplish good yields of the initial cycloadducts [335-337]. However, bis-trichloroethyl azodicarboxylate also reacts under thermal conditions and also gives a more reactive cycloaddition product [338,339]. 

The [4 + 2]cycloaddition of 4,5-dicyano-l,3,2-diazaphospholes and acetylenes yields 1,2-azaphos-pholes (Chapter 3.15). Azodicarboxylic esters (R = Et, Pr ) give a 1,1-addition accompanied by a dimerization of the product (Scheme 32) [Pg.799]

A similar 1,3-dipolar cycloaddition occurs with diethyl azodicarboxylate, and the intermediate 1,3-cycloadduct was isolated. Amidines (101) and halogenoacetonitriles (XCHjCN) yield 4-amino-1,3-diazolium salts (102) directly. These salts (102) could not be transformed into the corresponding meso-ionic heterocycles (98) with base ... 

Stoodley developed an asymmetric synthesis of (5A)-2,3,4,5-tetrahydropyridazine-3-carboxylic acid (see Section 8.01.6.4). The ring construction was achieved via cycloaddition of dienes 295 bearing a tetraacetyl /3-D-glucopyranosyl moiety for chiral induction with azodicarboxylates (Equation 73) <1999J(P1)2591>. 

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). 

Avalos and co-workers (220-228) extensively investigated the 1,3-dipolar cycloaddition chemistry of 2-aminothioisomiinchnones with both acetylenic and olefinic dipolarophiles. For example, sugar derivatives of the mesoionic imi-dazo[2,l-Z7]thiazolium-3-olate system react regioselectively with a variety of acetylenic dipolarophiles [DMAD, diethyl azodicarboxylate (DEAD), methyl propiolate, ethyl phenylpropiolate] to give the corresponding imidazo[l,2-a]pyr-idin-4-ones (e.g., 323) following sulfur extrusion from the not isolable cycloadducts (220). Similarly, these thioisomtinchnones react with diethyl azodicarboxylate and arylisocyanates in the expected fashion (221), and also with aryl aldehydes to form episulfides (222). 

A novel type of heterocyclization involving the [3+2] cycloaddition of IVA -dialkylanuno-substituted thioisomtinchnones 1 with azodicarboxylate 2 gives rise to 1,2,4-triazine derivatives 3 after a selective fragmentation pathway of the transient cycloadducts <99TL8675>. 

Cycloaddition of azodicarboxylates to 2-vinylpyridine in the presence of a biocatalyst (Saccharomyces cerevisiae) proceeded in a highly selective fashion to afford only pyrido[3,2-r ]pyridazine derivatives 259 in >80% yield compared to that found in the literature when the reaction was carried out in an organic medium to give a mixture of 259 in <20% yield and its isomer pyrido[l,2-r ]triazine derivatives 260 <1979T2027, 1993BCJ2429>. Similarly, 1,2,3,4-tetrahydropyrido[3,4-r ]pyridazine-l,2-dicarboxylate 261 was obtained under the same reaction conditions in >60% yield by using 4-vinylpyridine. 

Hydrogenated derivatives of this system have been prepared from acyclic enyne precursors (Scheme 75) by ringclosing metathesis, followed by [4-1-2] cycloaddition of the resulting diene with diethyl azodicarboxylate <2003S2017>. 

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... 

No cycloaddition has been found to occur in the reaction of several indolizines with tetracyanoethylene, substitution occurring instead in the 1- and 3-positions (78JHC1471). Similar products have been formed in the reactions of 2-methylindolizine with nitroethane, yielding (86) (79JPS321), and of indolizines with dialkyl azodicarboxylates, which gave a mixture of (87) and (88) (80TL3673, 79H(12)787>. 

A similar 1,3-dipolar cycloaddition occurs with diethyl azodicarboxylate, and the intermediate 1,3-cycloadduct was isolated.60... 

---