Diazomethane 1,2,4-triazolines

The interaction of diazomethane with 1-azirines was the first example of a 1,3-dipolar cycloaddition with this ring system (64JOC3049, 68JOC4316). 1,3-Dipolar addition produces the triazoline adduct (87). This material can exist in equilibrium with its valence tautomer (88), and allylic azides (89) and (90) can be produced from these triazolines by ring cleavage. 

Certain facts in the urazole series can also be interpreted in this way. Urazole (17) itself reacts with diazomethane quickly to yield 4-methyl-3-methoxy-l,2,4-triazolin-5-onc (18), which is more slowly converted to l,4-dimethyl-3-methoxy-l,2,4-triazolin-5-one (19). 1-Phenylurazolc gives 4-methyI-3-mcthoxy-l-plicnyl-l,2,4-triazolin-5-one (20) however, 4-phenylurazole yields the 1,2-dimethyl derivative (21). In the case of 4-methylurazole both O- and A"-methylation... 

C=C double bonds which are neither strained nor activated by an EWG or EDG react slowly with azides. The reaction may take weeks or even months. The use of high temperatures is restricted as 1,2,3-triazolines are thermally unstable. In such cases, the imine-diazoalkane reaction is a suitable alternative. This method is a versatile route for the preparation of 1,5-substituted triazolines, especially 1,5-diaryltriazolines (848), from the reaction of a SchifTs base and diazomethane under mild conditions <93JHCl 191>. A wide range of substituents can be incorporated from readily available imines. 

Carrie and co-workers studied the cycloaddition of oxime esters derived from methyl cyanoacetate and malonate esters 82 (Scheme 8.20) with diazomethane and some monosubstituted derivatives. Thermally labile 1,2,3-triazolines 83 were obtained when tosyloxy- and benzoyloxyimines were used (141), while methyl acetoxyimino-cyanoacetate (82, X = CN, Y = C02Me, = Ac) gave products derived from both a 1,2,3- and a 1,2,4-triazoline, depending on the stmcture of the diazo compound (142). Not unexpectedly, diazomethane reacted with the corresponding imino-malononitrile (82, X = Y = CN) system at the nitrile function rather than at the C=N bond (143). 

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). 

Olefinic double bonds substituted with one or more electron-withdrawing groups show significant dipolarophilic activity in cycloaddition reactions with organic azides,43,276-278 similar to the electron-rich double bonds of enamines and enol ethers the reactivity is less pronounced in azide additions compared to that observed in diazomethane reactions.7 The first triazolines reported resulted by the action of aryl azides on benzoquinones.1,279-281 As a rule, stereospecific cis additions occur,32 which are usually unidirectional except in the case of methacrylic derivatives67 and certain alkenes bearing... 

Diazoalkanes, like azides, are 1,3-dipoles of the propargyl-allenyl type (Scheme 87)15 and their reaction with imines provides a route for building the triazoline framework from the C—N—N and C—N fragments. Although diazomethane addition to the carbon-carbon double bond was achieved by von Pechmann in 1898,325 its reaction toward the carbon-nitrogen double bond was investigated only 50 years later. 

The first attempt to add diazomethane to a Schiff base was made by Meerwein,326 and the first successful addition was observed by Mustafa.327 Anils bearing nitro groups on the phenyl rings gave a cyclic adduct to which a 1,2,4-triazoline structure was assigned.327 A later reexamination of the reaction established the correct orientation of addition, and the products of the reaction of diazomethane with Schiff bases were assigned a A2-l,2,3-... 

The diazomethane-imine addition can be interpreted in terms of the FMO theory.51 Calculations on diazoalkanes and benzylideneanilines lead to two orbital interactions, a HOMOdiazoalkane-LUMOimine and a LUMOdiazoalkane-HOMOiminc, but regardless of which one is the favored interaction, the coefficients of the atomic orbitals of the bonding atoms favor the formation of a 1,2,3- and not a 1,2,4-triazoline.338 And indeed, the 1,2,4-triazolines proposed by Mustafa327 have never been observed. 

Alkylaluminum halides have been investigated as catalysts in the benzalaniline-diazomethane addition.342 Reaction occurs at — 78°C in the presence of diethylaluminum chloride to yield the triazoline adduct diethyl-aluminum iodide, however, leads only to an aziridine. 

The diazoacetonitrile-imine reaction may be considered complimentary to azide addition to cinnamonitriles because in the latter case only triazoline thermolysis products result.284 The reversed order of reactivity of the diazoacetonitrile to that of diazomethane implies an electrophilic attack on the imine and is explained in terms of a LUMOdi MC lonit[ile-HOMOin,int controlled interaction. Thus electron-rich enamines, which do not react with diazoalkanes, may be expected to react with electron-poor diazo compounds. 

Diazomethane addition to arylidenearyloxyanilines in dioxane-water330 fails to give triazoline adducts in the majority of cases.346 Where good yields of products are reported,346 the reaction appears to be facilitated by the ortho substituents on the C-phenyl group331 the failure of the reaction in other cases appears to arise from the electron-releasing mesomeric effect of the 4-phenoxy substituent on the AT-phenyl ring (Scheme 91). 

Both diazomethane and diazoethane add to these Schiff bases to give the 1,5- and 1,4,5-substituted triazolines, respectively (Scheme 92).347 348 A nitro group in the para position on the diphenyl sulfone ring assists addition, but has no effect on the sulfide compounds. Also, few... 

The cycloaddition of diazomethane to SchifT bases from heterocyclic aldehydes and anilines provides a useful route to heterocyclic substituted triazolines. Unlike olefins bearing heterocyclic substituents, the heterocyclic imines can be obtained readily by reaction of the appropriate aldehyde and amine thus the diazomethane-imine addition has greater scope than the olefin-azide reaction. NMR spectroscopic studies of the orientation of addition are in accord with previously reported mechanistic considerations (see, e.g., Scheme 93).329 In addition to the influence of the N-aryl group, the electron-withdrawing power of the heterocyclic substituent on the Schiff-base carbon also has a substantial effect on imine reactivity, in the order 2-quinolyl 2-, 3-, or 4-pyridyl > phenyl > 2-thienyl as 2-furyl.329... 

Schiff bases, derived from 2-(2,3-dihydropyran)carboxaldehyde and anilines, add diazomethane to give triazoline adducts in yields ranging from 45 to 66%.349... 

A triazoline adduct is also reported from the Schiff base formed from a peptide-bearing carbazoloquinone and diazomethane (Scheme 94).350... 

Reaction of diazomethane with 2-furylidene-4-aminodiphenyl sulfones347 and 2-furylidene-4-carbethoxyanilines351 yields the respective 5-(2-furyl)-substituted triazolines, which in some cases have been reported to have bactericidal activity at concentrations of 10 -lO-5 M.347... 

Nitrobenzylidene-2-aminothiazoles undergo addition to diazomethane to yield l-(2-thiazolyl)triazolines in moderate yields the 2-hydroxybenzylidene compound fails to react (Scheme 95).353 The prolonged reaction period could be shortened and the yields highly improved if dioxane-water were used as the reaction medium.182,329... 

The O-alkyl oximes of dialkyl mesoxalates have also been investigated361,362 the triazoline adducts undergo rapid decomposition at 20°C, at which reaction was performed, and give the required aziridines in 60-80% yields. Because of the presence of an ether substituent on the nitrogen, the oximes require two weeks for completion of reaction. O-Methyl ethers of acetoxime and biacetyl oxime do not react at all with diazomethane even after 3 months in ether at 20°C.361... 

When electron-withdrawing groups are present on both the carbon and nitrogen atoms of the oxime, triazoline adducts ranging in yield from 23 to 89% are obtained by reaction with diazomethane or diazoethane (Scheme 102) the aziridines formed from these triazolines are found to show unusual configurational stability.363,364... 

The reaction of the O-tosyloxime of dimethyl mesoxalate with diazomethane at 0 to — 5°C in methylene chloride-ether for 1 hr gives a quantitative yield of the triazoline361 however, at 20°C the triazoline cannot... 

The possibility of cycloaddition of diazomethane to the imine bond in azirines has been investigated365,366,366 the products comprise a mixture of isomeric allyl azides, and it is possible that bicyclic triazolines are intermediates in this reaction (Scheme 103).366... 

The crystal structures of 1-(4-methyl-l-pyrazolin-3-yl)-5,5-bis(trifluo-romethyl)-AM,2,3-triazoline, the 2 1 cycloadduct of diazomethane and 4-methyl-l,l-bis(trifluoromethyl)-2-aza-l,3-butadiene,359 387 1,4-... 

Triazolines resulting from diazomethane addition to the carbon-nitrogen double bond in oximes decompose rapidly even at 20°C to give N-alkoxyaziridines.361,362... 

Logothetis first reported that azirine (24a) reacts with diazomethane to produce the allyl azide (163).68 This reaction is postulated to proceed by a 1,3-dipolar cycloaddition to form the triazoline (162) which then undergoes a valence tautomerization to the allyl azide (163). 

Similarly to the reaction with diazomethane, [3 + 2] cycloaddition of alkyl azides to C70 affords three constitutionally isomeric adducts (87, 88, and ( )-89) 46.226,227 Thermal elimination of N2 from the fullerene-fused triazolines showed a preference for the formation of 6-5 open azahomofullerene structures (types 90 and ( )-91) as compared to the 6-6 closed aziridine isomers corresponding to 92 and 93 (Scheme 1.9).226,227... 

Dipolarophiles with electronegative heteroatoms such as carbonyl groups, imines and cyano groups also show an orientation in agreement with frontier orbital theory. Because heterodienophiles all have low-energy LUMOs, their reactions will usually be dipole-HO-controlled. The reaction of diazomethane with an imine giving the triazoline 6.240 and the final step in the formation of an ozonide... 

The perfluorinated six-membered azomethine imine and diazomethane react at temperatures as low as -80°C to form the aziridine together with the [3 + 2] cycloadduct, which stabilizes on elimination of HF to give the annulated 1,2,3-triazoline [77JFC(10)553] (Scheme 75). 

In the absence of NH and potential OH, 4-phenyl-l,2,4-triazoline-3,5-dione (76) is converted into the unusual quaternary compound (77) on treatment with diphenyl-diazomethane (Scheme 24) (65G33). Note that (77) is a triazolidinium zwitterion with both charges accommodated on the nucleus, hence distinct from mesoionic compounds (40). 

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