Azepines from azides

Another synthesis of azepines from azides involved the photolysis or thermolysis of aryl azides in the presence of nucleophiles. The photolysis of phenyl azide in diethylamine yielded (34%) 2-diethylamino-3/f-azepine (311) °. In the same manner 2-substituted azepines were obtained from phenyl azide and liquid ammonia, aniline and hydrogen sulphide . 

Much of the work on deoxygenation of aromatic nitro and nitroso compounds by tervalent phosphorus reagents has been reviewed.3 Triethyl phosphite has been used frequently, but diethyl methylphosphonite was found to be superior for the deoxygenation of nitro compounds.3,263 The isolation of azepines from such reactions (Scheme 42) indicated the initial formation of arylnitrenes. However, a marked influence of the nucleophile upon the direction of the apparent migration of the nitrene—away or toward an ortho substituent—was noted (Scheme 42).264 Evidence that the same intermediates are involved in the azepine forming reactions from phenyl azides and nitro-benzenes was obtained by a careful examination of the azepines formed from meta-substituted derivatives (Scheme 43). The ratios of the azepines 216 and... 

The consensus of opinion on the formation of azepines from aryl azides suggests that an intermediate singlet nitrene is in equilibrium with a didehydroazepine, which itself may be in equilibrium with a azepinocarbene. This has received further support form the investigations of Murata and co-workers, who have isolated both the azomethine ylide 1 and the... 

Interestingly, prolonged (60 h) thermolysis of tosyl azide in propionic anhydride in the presence of dimethyl terephthalate produces a moderate yield of dimethyl 1-tosyl-l 7/-azepine-2,5-dicar-boxylate (18) free from the usual accompanying anilide or sulfonamide byproducts.159... 

In contrast to the acyl- and sulfonylnitrenes described in this section, arylnitrenes produced thermally or photolytically from aryl azides, including those bearing strongly electron-withdrawing substituents (e.g., CN, N02, CF3), fail to promote ring expansion of arenes to 1H-azepines, although intermolecular substitution of electron-rich substrates, e.g. mesitylene and A.TV-dimethylaniline, have been noted.167... 

Pioneering studies have shown that the yield of iV-phenyl-3//-azepin-2-amine (32, R = Ph) from the thermolysis of phenyl azide in aniline increases as the ratio of azide to aniline decreases, and in dilute solution with an azide to aniline ratio of 1 200 a 54% yield of the 3//-azepine can be achieved.34 The reaction is successful with other arylamines, but the procedure is of limited preparative value as large volumes of amine are required and only moderate yields of 3H-azepines are obtained. 

Likewise, thermolysis of 4-azidophenyl methyl ketone in methanol yields 5-acetyl-2-methoxy-3//-azepine (60%), compared to only an 8% yield from the photolytic reaction.78 119 The thermolysis of phenyl azide in refluxing cyclohexanol yields no 3H-azepine, only diphenyl-diazene (10%) and aniline (30%).74 In contrast, thermolysis of methyl 2-azidobenzoate in cyclohexanol furnishes a mixture of methyl 2-(cyclohexyloxy)-3//-azepine-3-carboxylate (20 % bp 127°C/0.1 Torr) and methyl 2-aminobenzoate (60%). Thermolysis of the azido ester in methanol under nitrogen in an autoclave at 150 C yields a 7 10 mixture (by 1HNMR spectroscopy) of the amino ester and methyl 2-methoxy-3//-azepine-3-carboxylate, which proved to be difficult to separate, and much tar.74 The acidic medium179 is probably responsible for the failure of methyl 2-azidoberjzoate to yield a 3//-azepine when thermolyzed in 3-methoxyphenol aniline (40%) is the major product.74... 

Photolysis of aryl azides in amine solution, with a tertiary amine as cosolvent to promote stabilization of the singlet nitrene, has met with some success. For example, the yield of 2-piperidino-3 W-azepme. obtained by the photolysis of phenyl azide in piperidine, is increased from 35 to 58% in the presence of A A /V. /V -tetramethylethylenediamine (TMLDA).180 Also, an improved yield (36 to 60 %) of A,(V-diethyl-3W-azepin-2-amine (38, R = Et) can be obtained by irradiating phenyl azide in triethylamine, rather than in dicthylaminc, solution.181 Photolysis (or thermolysis) of phenyl azide in TMEDA produces, in each case, 38 (R = Et) in 40% yield.181 In contrast, irradiation of phenyl azide in aniline with trimethylamine as cosolvent furnishes jV-phenyl-377-azepin-2-amine (32, R = Ph) in only low yield (2%).35... 

There is evidence from a detailed study of the photolyses of 2-alkyl-substituted aryl azides 40 in diethylamine that A3,7V-diethyl-1 //-azepin-2-amines are formed as oxygen-sensitive, meta-stablc intermediates that can give rise to a variety of byproducts, including 5-acyl- A%V-diethyl-pyridin-2-amines and 6-alkyl-7-(diethylamino)-2//-azepin-2-ones 11 however, formation of these oxidation products can be avoided by refluxing the photolysate mixture with methanol prior to exposure to oxygen, in which case practicable yields of the /V,/V-diethyl-3W-azepin-2-amines 41 result. 

Base-catalyzed loss of hydrogen fluoride from the initially formed //../V-diethylG-ltrifluoro-methyl)-3//-azepin-2-amine (66) to give iV,ALdiethyl-3-(difluoromethylene)-3//-azepin-2-amine (67) occurs on photolysis of 2-(trifluoromethyl)phenyl azide (65) in diethylamine.10... 

Attempts to effect ring expansion of methyl 2-azidobenzoate in the presence of other nucleophiles have failed. Thus, photolysis in tetrahydrofuran solution saturated with hydrogen sulfide, or with ammonia, produced methyl 2-aminobenzoate in 54 and 37 % yield, respectively, as the sole identifiable product.197 Photolysis of phenyl azide in ethanolic phenol gave 2-phenoxy-3//-azepine in poor yield (8 %).203,204 2-Mesityl-3//-azepine (10 %) is the surprising, and only tentatively explained, product from the photolysis of phenyl azide in mcsitylene in the presence of trifluoroacetic acid.179... 

The structure of the tar, formed in many azide decompositions, consists of polyazepine units,103 and arises by attack of arylamine, formed from triplet arylnitrene, on the azepine precursor 30 to give the l//-azcpin-2-amine 31, which acts as a nucleophile towards more azepine precursor to yield ultimately the polyazepine 95. 

Iodine azide, generated in situ from an excess of sodium azide and iodine monochloride in acetonitrile, adds to ethyl l//-azepine-l-carboxylate at the C4 — C5 and C2 —C3 positions to yield a 10 1 mixture of the rw-diazidodihydro-l//-azepines 1 and 2, respectively.278 The as stereochemistry of the products is thought to be the result of initial trans addition of the iodine azide followed by an SN2 azido-deiodination. The diazides were isolated and their stereochemistry determined by conversion to their bis-l,3-dipolar cycloadducts with dimethyl acetylene-dicarboxylate. 

Substituted adducts similar to 50 have been obtained from the reactions carried out in chlorobenzene and in toluene 19>. Whereas methanesulphonyl azide does not thermolyze appreciably below 120 °C, when a solution of CH3SO2N3 in benzene was heated at 80 °C for 100 hr, 47 (ca. 0.5%) could be detected by thin layer chromatography but no 49 38>. Almost all the azide remained undecomposed. Similarly, very small, amounts of 47 were observed, together with much tar and undecomposed azide, on photolysis of CH3SO2N3 in benzene at room temperature or at 80 °C 10). This confirms that azepine formation is the kinetically controlled process, while the anilides are the products of thermodynamic control. 

Some related cyclic scaffolds, such as the azepines, were obtained by Ugi-4CR/ RCM combinations (Fig. 5a) [61], and fused benzodiazepine/triazole frameworks were derived from sequential Ugi-4CR/alkyne-azide dipolar cycloaddition (Fig. 5b) [62]. Both are considered as interesting (3-tum mimics. Similarly, bicyclic systems featuring fused DKP rings (Fig. 5c) have been reported to mimic the ten-membered pseudo-cycle of type 1 (3-tums [63, 64]. 

In our hands,photolysis of ort/to-cyanophenyl azide in the presence of diethylamine gives 5//-azepine trapping products, 13c and 14c (Scheme 3). Variation of the solvent led to subtle variation in the product distribution. The solvent effect on the relative rates of cyclization towards and away from the cyano group is small, but finite. The compositions of the mixtures formed under different reaction conditions are shown in Table 5. 

Despite patient and exhaustive effort by many researchers, all attempts to isolate or trap a benzazirine intermediate (214) have so far failed, and unequivocal evidence for their participation in either the photolytic or thermal decomposition of aryl azides is still awaited. Evidence in favor of the proposed reaction pathway (Scheme 22) comes from the work of Sundberg and coworkers, who succeeded in identifying 3-alkyl-2-diethylamino-lff-azepines as oxygen-sensitive, metastable intermediates in the photolysis of o-alkylphenyl azides in diethylamine (72JA513). Later studies on the flash photolysis of aryl azides in dialkylamine solution provided kinetic data which not only confirmed the Iff- to 3/f-azepine tautomer-ism, but also strongly supported the involvement of a benzazirine intermediate (74JA7491). 

Chapman and coworkers (79RTC334) from studies on the low temperature photolysis of phenyl azide in an argon matrix at 8 K produced convincing IR spectroscopic evidence for the formation of l-aza-l,2,4,6-cycloheptatetraene (217), rather than a benzazirine intermediate. In fact, these workers have reinterpreted the formation of 2-alkylamino-3ff-azepines on the basis of amine addition to the cumulated system (217) rather than the benzazirine. 

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). 

Photogenerated nitrenes can undergo cycloaddition with alkenes intermolecular reaction leads to aziridine products (5.38), and intramolecular reaction in vinyl azides gives azirines (5.39). The bicyclic azirine from phenyl azide has not been isolated, but it is the intermediate that best accounts for the formation of a substituted azepine when this azide is irradiated in the presence of a secondary amine (5.401. 

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