Use of Aryl Azides

McMahan, S.A., and Burgess, R.R. (1994) Use of aryl azide cross-linkers to investigate protein-protein interactions An optimization of important conditions as applied to Escherichia coli RNA polymerase and localization of a tr70-a cross-link to the C-terminal region of a. Biochemistry 33, 12092-12099. 

More convenient is the use of aryl azides which are readily converted into isocyanates upon heating in nonreactive solvents via the loss of nitrogen. The latter method is useful for the synthesis of isocyanates with additional substituents which could not be prepared with phosgene (20). 

The Siindberg indole synthesis using aromadc azides as precursors of nitrenes has been used in synthesis of various indoles. Somekmds of aryl azides are readily prepared by S Ar reacdon of aromadc nitro compounds v/ilh an azide ion. For example, 2,4,6-trinitrotoliiene (TNT can be converted into 2-aryl-4,6-dinitroindole, as shovmin Eq. 10.60. ... 

The thermolysis of aryl azides in alcoholic solution has been used to prepare 2-alkoxy-37f-azepines. Thermolysis of 3-azidophenyl methyl ketone in methanol in a sealed ampule furnishes a mixture of the 6-acetyl- (36a) and 4-acetyl-2-methoxy-3//-azepine (37a) in superior yields to those obtained in the corresponding photolytic reaction.78 Other 3-substituted azides behave similarly, with a preference for the 6-substituted isomers 36, as is observed for azide photolyses in amine solutions. 

Nucleophilic displacement of the butoxy group in 2-butoxy-3//-azepine (1) by the use of excess secondary amine is preferred by some workers64 to the photolysis or thermolysis of aryl azides, or the deoxygenation of nitro- or nitrosoarenes in amine solution, as a preparative route to Ar,Ar-dialkyl-3//-azcpin-2-amines, e.g. 2,... 

The most interesting TV-coupling reaction of this subsection is that with azide ions, which has been known since the end of the last century. This reaction is frequently used for the preparation of aryl azides. Two examples can be found in Organic Syntheses (Smith and Boyer, 1963 Mendenhall and Smith, 1973). As Scheme 6-20... 

The synthesis and mechanism of formation of a triazene from an arenediazonium ion and an amine with one or two aliphatic substituents (see Scheme 13-1, R = alkyl, R = H or alkyl) will be discussed in Section 13.2. Here we will briefly mention Dimroth s method (1903, 1905 a) for synthesis of wholly aliphatic triazenes (Scheme 13-6, R and R = alkyl). Dimroth obtained these by the action of Grignard reagents on alkyl azides followed by isolation via copper(i) salts. The Grignard method can also be applied for the synthesis of triazenes with an aromatic substituent by using an aryl azide. 

Other iron-imido complexes have also been reported. Holland and coworkers reported the synthesis of the imidoiron(III) complex [L FeNAd] [40, 41]. This imidoiron(III) complex has not been isolated and was found to convert to a purple high-spin iron(III) complex. It has an S = 3/2 ground state from EPR measurement. Based on the results of QM/MM computations, [L EeNAd] is a three-coordinated complex with an Fe-N distance of 1.68 A and has a nearly linear Fe=N-C unit with Fe-N-C angle of 174.1°. Chirik and coworkers made use of liable ligands to prepare iron-imido complexes by treatment of C PDI)-Fe(N2)2 ( PDI = (2,6- Pr2CgH3N = CMe)2C5H3N) with a series of aryl azides [47]. 

Of the following amine-reactive and photoreactive crosslinkers, the overwhelming majority use an aryl azide group as the photosensitive functional group. Only a few use alternative photoreactive chemistries, particularly perfluorinated aryl azide, benzophenone, or diazo compounds. For general background information on photoreactive crosslinkers, see Das and Fox (1979), Kiehm and Ji (1977), Vanin and Ji (1981), and Brunner (1993). 

The most frequent synthetic approaches, summarized in Scheme 4, are towards the primary photophores. The preparation of aryl azide derivatives follows the typical retro-synthetic pathway in the majority of the reported cases (Scheme 4 A), and, practically, diazotation is the most commonly used procedure [24 - 29]. In the case of diazirines only one major synthetic sequence is repeated ammonolysis of oximes followed by dehydrogenation (Scheme 4B) [30-32]. There are various ways of preparing diazo- or diazocarbonyl-compounds most frequently the Forster and Bamford-Stevens reactions (Scheme 4C) are employed [33-37]. 

The nature of the intermediate involved in the thermolysis and photolysis of aryl azides in solution under the much less extreme conditions employed for the synthesis of 3H-azepines is still an open question. Notwithstanding, the method has been used extensively for the synthesis of 2-amino-3H-azepines. In addition, and despite early disappointments, the method is now applicable to the synthesis of benzazepines from naphthyl azides and that of pyridoazepines from quinolyl and isoquinolyl azides <82JCS(Pl)43l, 79AG(E)900). 

Alkyl and aryl azides are prepared by the nucleophilic displacement by azide ion on halide, sulfate, phenyldiazonium, hydroxyl, nitrate, iodoxy, alkoxy, and tosylate groups [6]. Sodium azide is the most useful and practical reagent. The use of silver azide is not necessary in most cases. Some examples from the literature [8-33] employing these methods are shown in Table I. 

The photochemistry of aryl azides is quite complex, suggesting that the nitrene 14 may not be the only reactive intermediate and that insertion reactions may not be the only route to form photoconjugates.Although aryl nitrenes are much less susceptible to rearrangements than acyl nitrenes, they may still occur and lead to the formation of reactive intermediates such as azepines, which may go on to react with nucleophiles.[911 141 Addition of nitrenes to double bonds will generate azirines, while dimerization will produce azobenzenesJ11 Aryl azides are stable to most of the procedures used in the course of peptide synthesis except for reduction reactions. Non-photochemical reduction of aryl azides to the primary amines by thiols has been reported by Staros et al.[15]... 

Triazolines obtained by the addition of aryl azides to enamines are generally isolable and a considerable number of triazoline compounds have been prepared in this way (Scheme 45.)208,209 Although usually nitrophenyl azide is used, because electron-withdrawing groups on the azide facilitate addition,28,42 diethylaminophenyl azide also works satisfactorily (Scheme 46).209... 

The consistently low yields in the cycloaddition of aryl azides to certain enamines have been attributed to an unfavorable equilibrium between cycloaddition and cycloreversion reactions.232 The reversibility of the cycloaddition has been demonstrated on the basis of spectroscopic (Section III) and chemical evidence (Scheme 55). The conditions for cycloaddition and cycloreversion have been examined, using MO calculations.72... 

Aryl azides which were introduced as photoaffinity reagents by Fleet et al. (1969) are now the most commonly used photoactivatable reagents. By early 1976 there were almost one hundred examples of their use (Bayley and Knowles, 1977) and today it would be impracticable to list a complete bibliography. The ease of synthesis of aryl azides, and not their other desirable properties, is probably responsible for their great popularity. 

The relative ease of synthesis of aryl azides has contributed greatly to their popularity as photoactivatable reagents. Two methods are generally used... 

Scheme 2 Preparation and examples of aryl azides, (a) Three possible routes for the conversion of an aryl amine into its aryl azide (i) via diazotization [44], (ii) by the use of triflyl azide [45], and (iii) with sulfonyl azides 15 (R = imidazole [46] or R = benzotriazole [55]). (b) Examples of substituted aryl azides...

Recently Liu and coworkers used (porphyrin)iron(III) chloride complex 96 to promote 1,5-hydrogen transfer/SHi reactions of aryl azides 95, which provided indolines or tetrahydroquinolines 97 in 72-82% yield (Fig. 24) [148]. The reaction starts probably with the formation of iron nitrenoids 95A from 95. These diradicaloids undergo a 1,5- or 1,6-hydrogen transfer from the benzylic position of the ortho-side chain. The resulting benzylic radicals 95B react subsequently with the iron(IV) amide unit in an Sni reaction, which liberates the products 97 and regenerates the catalyst. /V,/V-Dialkyl-w// o-azidobenzamides reacted similarly in 63-83% yield. For hydroxy- or methoxy-substituted indolines 97 (R2=OH or OMe) elimination of water or methanol occurred from the initial products 97 under the reaction conditions giving indoles 98 in 74—78% yield. 

Some recent examples of the use of this cycloaddition include reaction of aryl azides with (i) enamine 271 to give diaminodihydrotriazol 272, which on deamination produces... 

In two papers, Miller and co-workers (45,46) have extended their intramolecular ring B cyclization strategy (47) to the use of aryl nitrenes in the synthesis of pyridocarbazoles. Thus, in the first paper, isoquinoline azide 39 was heated at 180-200°C to aiford ellipticine (1) as the minor product (20%) (Scheme 7). The major product was the isomeric pyrido[3,4-a]carbazole 40 (60%). This result is consistent with the relative nucleophilicities of C-6 and C-8 of isoquinoline. The isomeric azido isoquinoline 41 exhibited comparable re-gioselectivity in the cyclization of the corresponding nitrene to yield isoellipticine (27) as the minor product (Scheme 7). 

The reaction of aryl azides with alkenes in the presence of aluminum trichloride gave different products depending on the structure and the geometry of the alkene, the reaction proceeds via the intermediacy of an aziridine 8 complexed with the Lewis acid. Thus aziridines 9 were cleanly obtained from cycloheptene and (Z)-cyclooctene, however, from cyclopentene and cyclohexene a mixture of allylic amines 10 and /5-chloro amines 11 was produced86- 87. The use of 4-chlorophenyl azide in the reaction with cyclohexene gave only a tar. 

Rates of reduction for the series of aryl azides studied are summarized in Table 3.8. It is evident that, for 3- and 4-substituents, the expected pattern of reactivity was observed, with electron-withdrawing substituents (Br, Cl and NO2) resulting in a much faster rate of reduction than for unsubstituted phenyl azide, which was in turn reduced more rapidly than those aryl azides bearing an electron-donating methoxy substituent. In order to obtain some quantitative measure of the contribution of these substituents to reaction rates, the results were modelled using the Hammett relationship [114], and the linear nature of the plot of log k against Hammett constant ([Pg.157]

Chemiluminescence has been used to measure the relative yields of excited ketones formed from self reaction of alkoxyl and alkylperoxyl radical pairs . In the photochemistry of aryl azides a dehydroazepine is detected by time resolved infra red spectroscopy and flash photolysis at room temperature . Singlet and triplet nitrenes and dehydroazepenes have also been detected in the photochemistry of 3- and 4-nitrophenyl azides . Picosecond and nanosecond laser photolysis of p-nitrophenyl acetate in aqueous media produces a triplet state of the -nitrobenzylanion and CO2 after cleavage of the rnr triplet. Absorption, emission, and reaction kinetics of dimethylsilylene produced by flash photolyses of dodecamethylcycloherasilane is another interesting study 2,... 

Brauer have concluded that most of the previously reported red emission does not come from this molecule. Delayed fluorescence has been observed in the deactivation of highly excited triplet states (Skvortsov and Alfimov cf. McGimpsey and Scaiano). The photolysis of aryl azides, long used as a source of arylnitrenes, has been shown also to produce a transient dehydroazepine (Shields et al. Liang and Schuster). 

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