LH-Azepines

Prepared similarly were methyl 3-methyl-lH-azepine-l-carboxylate (40% bp 62-65 C/0.15-0.25 Torr) and methyl 3,6-ilimethyl-l -azepine-l-carhoxylate (49% bp 80-85 C/O.t Torr) from 1-methyl-1,4-dihy-drobenzene and 1,4-dimethyl-1,4-dihydrobenzene, respectively. 

More surprising, in view of its poor electrophilic character, is that phcnylnitrene, generated by deoxygenation of nitroso benzene with triethyl phosphite in a mixture of benzene and 2,2,2-trifluoroethanol, yields 1-phenyl-1//-azepine (26), a rare example of a stable 1-aryl-lH-azepine.170... 

CN hexahydro-1-methy 1-4-phenyl-lH-azepine-4-carboxylie acid ethyl ester citrate (1 1)... 

C17H21CIN2O4 59639-73-5) see Vincamine (135-cis)-13-ethyl-7,ll,12,13,16,17-hexahydro-3-methoxy-6//-cycIopenta[a]phenanthren-17-oI acetate ( 22112 03 2911-81-1) see Levonorgestrel 3-ethylhexahydro-3-(3-methoxyphenyl)-lH-azepine (C15H23NO 27180-90-1) see Meptazinol... 

Conformational analysis of hexahydro-lH-azepin-2-one (caprolactam) confirms that it, like other five- to eight-membered lactams, has the cis conformation. The 1SN NMR shift for the seven-membered lactam in CHCI3 appears at 259.7 p.p.m. (upfield from HNO3) (76JA5082). Solvent shifts for the 1SN resonance of caprolactam have been determined (78MI51601). In TFA/(15N-H) is 92.5 0.5 Hz. 

If the lH-azepine bears a ring substituent then a mixture of two isomeric 2-azabicyclohep-tadienes, (38) and (39), is possible, corresponding to the two allowed electrocyclic processes indicated in Scheme 1 (paths a and b, respectively). In fact, the ratio of the two isomers varies with the position of the substituent. For example, the 3-methylazepine (37 R = 3-Me) affords a 1 1 mixture of the 4- and 7-methyl-2-azabicycloheptadienes, whereas the 4-methylazepine (37 R = 4-Me) yields the 5- and 6-methyl derivatives in the ratio of 1.5 1 (B-69MI5600). 

Recently, a new reactivity index has been proposed (80H(14)1717> which predicts accurately the site selectivity of photocyclization of substituted cycloheptatrienes to their bicyclic valence tautomers. Unfortunately, application of the method to substituted lH-azepines is far less successful. For example, for 2-methyl-l-methoxycarbonyl-lH-azepine (37 R = 2-Me) AGrs values for C-2—C-5 and C-4—C-7 cyclization are calculated as 0.093 and 0.040 kJ mol-1, respectively, i.e. predicting the 1-methyl isomer (39) as the major product. Experimentally, however, the reverse is true, the yields being 93.5% for 3-methyl (38 R = Me) and 6.5% for 1-methyl (39 R = Me). The corresponding photoinduced valence isomerizations of 1-benzazepines to 3,4-benz-2-azabicyclo[3.2.0]hepta-3,6-dienes (38a) have been recorded (80JOC462). These isomerizations have also been achieved thermally in the presence of silver ion (80TL3403). 

Reduction of 1-ethoxycarbonyl-l/f-azepine with lithium aluminum hydride in ether at -15 °C yields the thermally unstable 1-(hydroxymethyl) derivative in boiling ether further reduction occurs to N-methyl- lH-azepine, which subsequently dimerizes to the [6+6]ir adduct (see Section 5.16.3.2.3) (B-69MI51600). Surprisingly, the action of phenyllithium on 1 -ethoxycarbonyl-l//-azepine produced the carbinol (2 R CPlhOH, R2 = H), thermal decomposition of which led to the first characterization of 3//-azepine (73CB1033). 

Benzenium ions (199 X = acyl) on treatment with p-TSA in toluene undergo intramolecular O-alkylation to give the oxazolines (201 X=acyl Scheme 18, path b), rather than ring expansion to the lH-azepine as mentioned earlier for the N-tosyl derivative (Scheme 18, path a). However, these oxazolines are thermally labile and on heating at 180 °C rearrange in high yields (84-93%) to 1-acyl-1//-azepines (200 X = ArCO or Ac) <81AG(E)699>. 

The 1,3-dipolar cycloadducts (266) from cyclobutenes with oxazolium 5-oxides (265) (miinchnones) (80JHC1593) extrude carbon dioxide to yield 4,5-dihydro-lH-azepines as illustrated in Scheme 36. 

PREPARATION OF 2-PR0PYL-1-AZACYCL0HEPTANE FROM CYCLOHEXANONE OXIME (lH-AzepIne, hexahydro-2-propy1-. (t))... 

Annular prototropy is not of great importance for small heterocycles. However, it should be mentioned that 1-azirine (2) is much more stable than its antiaromatic 2-isomer (3). By analogy, antiaromaticity is certainly a key factor determing instability of lH-azepines which have never been observed. Thus, demethoxycarbonylation of methyl-3,6-di-r-butylazepine-l-carboxylate (46) by DBU gives a mixture of the corresponding 2H-, 3H-, and 4//-azepines in the approximate ratio 13 56 1 (Scheme 9) (94JCS(P1)1753). The distribution of the azepine isomers is proportional to their relative thermal stabilities as they interconvert via allowed 1,5-hydrogen shifts. 

H-Azepine derivatives form a diene complex with tricarbonyliron, leaving uncomplexed the third of the double bonds. If the 3-position is substituted, two different such complexes are possible, and are in equilibrium, as seen in the XH NMR spectrum. An ester group in the 1-position of the complex can be removed by hydrolysis, to give an NH compound which, in contrast to the free lH-azepine, is stable. The 1-position can then be derivatized in the manner usual for amines (Scheme 22). The same tricarbonyliron complex can, by virtue of the uncomplexed 2,3-double bond, serve as the dienophile with 1,2,4,5-tetrazines. The uncomplexed N-ethoxycarbonylazepine also adds the tetrazine, but to the 5,6-double... 

The polyene character of azepines, particularly 1//-azepines, is apparent not only in the ease with which they dimerize (Section 5.16.3.3) but also in their propensity towards cycloaddition with a variety of reagents. The behavior of lH-azepines in these mainly concerted electrocyclic cycloadditions is somewhat unique in that they display both diene and dienophilic character, and that they can, and do, function as the 2ir, 4iror 677 component. 

Diels-Alder [4 + 2]vr cycloadditions of 1 -alkoxycarbonyl-lH-azepines are successful with all but the weakest dienophiles (e.g. maleic anhydride). Early work showed that with tetracyanoethylene (TCNE) cycloaddition at C-2—C-5 takes place readily in benzene solution at room temperature to yield adducts (140) (69JOC2888, 70JHC1249). The structure of the TCNE adduct with 5-bromo-l-ethoxycarbonyl-l//-azepine has been confirmed by X-ray studies (67JCS(BM12). 

H-Azepin-2-one, 4-allyloxytetrahydro-Claisen rearrangement, 7, 508 lH-Azepin-2-one, hexahydro-conformation analysis, 7, 499 mass spectra, 7, 501... 

Tolazamide. Tolazimide (l-(hexahydio-lH-azepin-l-yl)-3-(p-tolysulfonyl)urea), mol wt 311.40, is a white to off-white crystalline powder, odorless or having a slight odor, mp 170—173°C, with a pKa of —3.6 at 25°C and 5.68 at 37.5°C. It is very slightly soluble in water, freely soluble in chloroform, soluble in acetone, and slightly soluble in alcohol. The trade name is Tolinase. 

Nl - 1(2H)-PHTHALAZINONE, 4-C C4-CHL0R0PHENYL)METHYl)-2-(HEXAHYDR0-l-METHYL-lH-AZEPIN-4-YL)-, HYOROCHLORIOE... 

---