Azides, ethoxycarbonyl

From amino- and alkoxybutenones and benzonitrile iV-oxide as well as from acetyl- and ethoxycarbonyl-iV-phenylnitrilamines and p-methoxyphenyl azide, the corresponding functional isoxazoles, pyrazoles, and tiiazoles were obtained (83DIS 83ZOR2281 92SC2902). 

Ethyl 3-azido-l-methyl-177-indole-2-carboxylate 361 is prepared in 70% yield by diazotization of amine 360 followed by substitution of the created diazonium group with sodium azide. In cycloadditions with nitrile anions, azide 361 forms triazole intermediates 362. However, under the reaction conditions, cyclocondensation of the amino and ethoxycarbonyl groups in 362 results in formation of an additional ring. This domino process provides efficiently 4/7-indolo[2,3-i ]l,2,3-triazolo[l,5- ]pyrimidines 363 in 70-80% yield (Scheme 57) <2006TL2187>. 

The reagents and methods employed for coupling in solid-phase synthesis are the same as for synthesis in solution, but a few are excluded because they are unsuitable. The mixed-anhydride method (see Section 2.6) and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (see Section 2.15) are not used because there is no way to eliminate aminolysis at the wrong carbonyl of the anhydride. Acyl azides (see Section 2.13) are too laborious to make and too slow to react. The preparation of acyl chlorides (see Section 2.14) is too complicated for their routine use this may be rectified, however, by the availability of triphosgene (see Section 7.13). That leaves the following choices, bearing in mind that a two to three times molar excess of protected amino acid is always employed. 

In general, acyl azides are too unstable to survive at the temperatures required for addition to acetylenes, although benzoyl azide adds readily to ynamines in toluene. Ethoxycarbonyl azide also gives triazoles in good yield with ynamines. The azide adds to propargylic alcohols in boiling ethanol, and to acetylene at 100° under pressure. Addition to phenylacetylene and to electron-deficient acetylenes has been carried out at 130°. Oxazoles are also formed at this temperature by competing thermal decomposition of the azide, and addition of ethoxycarbonylnitrene to the acetylenes. The triazole obtained from phenylacetylene is 2-ethoxycarbonyl-4-phenyltriazole the two 1-ethoxycarbonyltriazoles can be isolated if the addition is carried out at 50° over several weeks. Since the IH- to -triazole isomerization takes place readily in these systems, a IH-structure cannot be assumed for a triazole formed by addition of these azides. 

The reaction is most effective with azides bearing electron-withdrawing groups, such as nitrophenyl, toluene-p-sulfonyl, and ethoxy carbonyl. Sulfonyl azide adducts give iV-unsubstituted triazoles, the substituent being lost on aromatization. The triazole which is isolated as a minor product of the reaction of 1,1-dimethoxyethylene with ethoxycarbonyl azide has been assigned a 2/7-triazole structure it is likely that other ethoxycarbonyltriazoles formed by this route also have 2H-structures. 

Addition of iodine azide to 1-ethoxycarbonyl-l/f-azepine is regioselective and in the presence of sodium azide yields a 10 1 mixture of the c/s-4,5- and cis-2,3-diazides. The cis stereochemistry of the adducts is adduced to have arisen by initial trans addition of IN3, substitution of iodide by azide, and then conversion to the cis isomers via the azanor-caradiene valence tautomer (72JOC890). 

On the other hand, 7-azabenzonorbornadiene bearing a tert-but-oxycarbonyl substituent in the 7-position, in spite of the bulky 7-substituent, exhibits exo selectivity in the addition of ethoxycarbonyl azide.129 Benzenesulfonyl and tosyl azides, however, give rise to a complex mixture from which no products could be characterized.129 The phenyl azide adduct has been obtained in 88% yield, but the stereochemistry is not known.1498 An orbital model for the effect of the 7-substituent, as a through-space interaction between the substituent and the syn double bond, has been suggested,150 and generalizations that may help to predict the syn-anti selectivity in these compounds have been developed.99,149,150... 

Azide addition to open-chain vinyl ethers results in different thermolysis products, depending on the azide and the enol ether employed. In Scheme 180, when R = benzoyl or ethoxycarbonyl, R2 = OR1 and R3 = H, imino ethers are obtained by alkoxyl migration along with minor amounts of azir-idine.269 525 However, when R = Ph and the carbons are fully substituted, the imine (108) is obtained apparently from the reversibility of the imine-diazo compound addition (Section IV,B,2) (Scheme 181).270... 

Oxazolines are the principal products in the addition of acyl azides to vinyl ethers or to ketene acetals (Scheme 182).269,440 Ethoxycarbonyl azide reacts... 

Reduction of an azide functionality at C-3 of azetidin-2-one 355 followed by acylation afforded 3-amidoazetidin-2-one 356 (Scheme 50). O-Debenzylation, followed by treatment with the Jones reagent, afforded a m-3,4-disubsti-tuted azetidin-2-one 357, which is a precursor of the antibiotic loracarbef <2001TL4519>. The reduction of an ethoxycarbonyl group and an acetoxy group at C-3 to a hydroxyl group has been accomplished by sodium borohydride (Equation 134) <2001T10155>. 

The base-catalyzed condensation of a-azido esters and ketones with aromatic aldehydes has recently been developed as a new vinyl azide synthesis.42,43 The yields range from moderate to excellent in some cases. The thermal decomposition of ethyl a-azidocinnamate (87) in xylene gives only 2-ethoxycarbonylindole (88).44 The unstable 2-ethoxycarbonyl-3-phenyl-l-azirine could be detected if the thermolysis was carried out at a lower temperature. This fact indicates that the 1-azirine is probably an intermediate leading to the indole, although the intermediacy of the vinyl nitrene could not be established. This result is similar to that observed by Isomura et al. on the pyrolysis of terminal vinyl azides.27,28... 

Fig. 14.45. Transformation of an a-phosphonylcarboxylic acid ester (B) via the related carboxylic acid azide F and its Curtius degradation in ethanol to furnish an ethoxycarbonyl-protected a-aminophosphonic acid ester E. The N- and 0-bound protective groups of the latter compounds are cleaved off under acidic conditions. In this manner a-aminophosphonic acids are synthesized. They are interesting analogs of the biologically important a-amino carboxylic acids.

Norbomene adds to photolytically produced ethoxycarbonylnitrene specifically at the exo face the same aziridine is produced in the thermal addition of ethoxycarbonyl azide, but via the triazoline rather than the nitrene, with much imine by-product. There can be problems of selectivity and rearrangements when one reacts ethoxycarbonylnitrene with more complex substrates, e.g. alkenic steroids. Ethoxycarbonylnitrene via a-elimination) adds to vinyl chlorides to give 2-chloroaziridines, which can be rearranged thermally to yield 2-chloroallyl carbamates. This nitrene also adds to enamines, giving an array of rearranged products. A modem discussion of the reactivities of ethoxycarbonylnitrene (electrophilic) in comparison with phthalimidonitrene (nucleophilic) towards alkenes of different electronic properties has tqipeared. ... 

Dimethyl-5-ethoxycarbonyl-E16c, 122 (En-azid/Ringschl.) Pyrido[3,4-d pyridazin 1,4-Diethoxy-E9c, 68 (Cl - OR) Pyrido[2,3-d(pyrimidin 1 -Butyl-4-hydroxy-2-oxo-l,2-dihydro- E9c, 97 (2-NH R — 3-COOH—py + Urea)... 

Ethoxycarbonyl nitrene is readily formed by thermolysis or photolysis of cthoxycarbonyl azide (ethyl azidoformate), as well as by the base-induced a-elimination of (4-nitrophenylsulfonyloxy)-carbamate9 13> 158> 159. 

A mixture of 27.0 g (0.23 mol) of ethoxycarbonyl azide and 29 g of ( )-1 -phenyl-1 -propene is added dropwisc to 110 g of ( )-1-phenyl-1-propene at 150-160 °C. Heating and stirring are continued until N, evolution ceases (5 h). Distillation in vacuo gives a mixture of trans- and cis-3, bp 91 100 C/0.3 Torr, in 94 6 ratio, as estimated by GC analysis and comparison with authentic samples. Several fractional distillations afford almost pure tran.v-aziridinc. 

The addition of ethoxycarbonyl nitrene, generated by photolysis of ethoxycarbonyl azide or by a-elimination of 4-methylphenylsulfonyl carbamate, to conjugated dienes gave aziridines by 1,2-addition and dihydrooxazoles by rearrangement of the aziridines, generally with low overall yield18. 

The reaction of ethoxycarbonyl nitrene, generated by decomposition of the azide or by the a-elimination method, with enamines gave mixtures of aminimides and a-amino ketone derivatives30.. V-Methoxycarbonyl. A -cyano and N-sulfonyl azides reacted with 1,2-31 and 1,4-dihy-dropyridines32 to afford directly the corresponding aziridines 9 and 10. The configuration of the aziridine 10, relative to the R substituent, was not determined. 

By reaction of ethoxycarbonyl azide with norbomene, norbornadiene, benzonorbornadiene, and substituted derivatives the ew-4,5-dihydro-l,2,3-triazoles were isolated42,48-52 and successively converted to exo-aziridines either thermally, in methanol49, or photochemically, e.g., II42,52. 

A similar sequence was performed by using ethoxycarbonyl azide to prepare the A-unsubstitut-ed and the A-benzoyl aziridine 17. From the latter, the dihydrooxazole precursor 18 of the cis-hydroxyamine was quantitatively obtained53. 

Oxabicyclo[2.2.1]hept-5-cn-2-one derivatives (ketals, cyanohydrins) were prepared in an optically pure form, hence optically pure -functionalized amines can be prepared via the diastereoselective cycloaddition of organic azides. Such transformations have been described for ethoxycarbonyl azide and /ert-butoxycarbonyl azide54, 5. For example 3-amino-3-deoxy-a-altropyranoside hydrochloride 20 was prepared from the dibenzyl acetal 19ss. 

The cycloaddition of ethoxycarbonyl azide to racemic O-acetyl cyanohydrin 21 was performed either at 40 °C in acetone or at room temperature and without solvent in the presence of a metal salt (zinc(II) acetate, nickel chloride or copper(I) cyanide) as catalyst54. The required dihydro-triazole 22 (isolated from the 2 1 mixture of regioisomers) was directly converted to the jS-acetoxy amine via migration of the endo-acetoxy group. The Ivans relationship of the hydrogen atoms at C-5 and C-6 was deduced from ll NMR. 

Better yields, but lower enantiomeric excesses, were obtained by an alternative method, the cycloaddition of ethoxycarbonyl azide, followed by irradiation to give the aziridine64. Interestingly, the opposite configuration at the stereogenic center was formed by the two methods. The enantiomeric excess of the product was determined by ketalization with (2/, 3/ )-2,3-butanediol and GC or l3C-NMR analyses of the reaction mixture. The choice of the chiral auxiliary is crucial unfortunately, the enamine derived from //ww-2,5-dimethyl pyrrolidine does not react with either the nitrene or the azide. 

---