Azepine ester

Azepine esters (39) undergo a number of 1,4-additions of nucleophiles as shown in Scheme 6 <90JHC107>. With citric acid the hydroxy derivative (40) is obtained which can be converted to the ketone (41) on oxidation with PDC, and on gel chromatography with methanol the adduct (42) was formed in quantitative yield. Addition of TMS-CN to (39) in the presence of palladium(II) acetate yielded the nitrile (43). 

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 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 1/f-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... 

Azepine-1-carboxylic acid, methyl ester, tricarbonyliron complex X-ray, 7, 494 <70JCS(B)1783) 4//-Azepine-2-carboxylic acid, 6,7-diphenyl-, methyl ester... 

H-Azepine-3-carboxylic acid, 2-methoxy-, methyl ester... 

C NMR, 7, 498 (79TH51600) 2H-Azepine-4-carboxylic acid, 7-(4-bromophenyl)-3-methoxy-2-oxo-6-phenyl-X-ray, 7, 494 <79H(12)1423> 3H-A2epine-4-carboxylic acid, 6-acetyl-2-ethoxy-3-oxo-7-phenyl-, ethyl ester H NMR, 7, 503 <81H(16)363) 3H-Azepine-4-carboxylic acid, 2,6-diethoxy-3-oxo-7-phenyl-, ethyl ester H NMR, 7, 503 <81H(16)363) 3H-Azepine-4-carboxylic acid, 2-ethoxy-3-oxo-6,7-diphenyl-, ethyl ester HNMR, 7, 503 <81H(16)363) 3H-Azepine-4-carboxylic acid, 2-ethoxy-3-oxo-7-phenyl-, ethyl ester... 

IH-Azepine 1-oxide, 1-methyl- C NMR, 7, 498 <770MR<9)333) 2H-Azepine-2-selenone, hexahydro-l-methyl- C NMR, 7, 498 <79AJC567> 3H-Azepine-2,3,5,7-tetracarboxylic acid, 4,6-diphenyl-, tetramethyl ester X-ray, 7, 494 <72CB982) 3H-Azepine-2,4,6,7-tetracarboxylic acid, 3,5-diphenyl-, tetramethyl ester X-ray, 7, 494 <72CB982>... 

H-Azepine-2-thione, hexahydro-1 -methyl- C NMR, 7, 498 <79AJC567> 4H-Azepine-2,6,7-tricarboxylic acid, trimethyl ester AG 7, 499 (72JA2770)... 

H-Dibenz[6/]azepine, 10,1 l-dihydro-5-niethyl- C NMR, 7, 498 <74JCS(P2)1648) 5H-Dibenz[r c]azepine H NMR, 7, 497 <81LA240) 6H-Dibenz[c,e]azepine, 6-allyl-5,7-dihydro- CNMR, 7, 498 <79JPS890) 5H-Dibenz[6,/]azepine-5-carboxylic acid, 10,11-dihydro-, ethyl ester C NMR, 7, 498 <74JCS(P2)1648)... 

H-Azepine, 2,6,7-tri(methoxycarbonyl)-ring inversion, 7, 499 Azepine-1-carboxylic acid tricarbonylruthenium complexes, 7, 523 1 H-Azepine-2,3-dicarboxylic acid, 4,7-dihydro-6-phenyl-diethyl ester synthesis, 7, 539-540 1 H-Azepine-3,6-dicarboxylic acid... 

Chemical Name a -Cyclohexyl-3-thiopheneacetic acid 2-(hexahydro-1 H-azepin-1 -yDethyl ester... 

Chemical Name 6-(((Hexahydro-1 H-azepin-1-yOmethylene] amino) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0l heptane-2-carboxylic acid (2,2-dimethyl-1-oxopropoxy)methyl ester... 

Recently, a one-pot conversion of 2-methoxy-2,3-dihydro-3,6-alkanooxepins to imidazoazepine derivatives by treatment with glycine methyl ester was reported. In the heptano series a symmetrical azepine triester was isolated as a byproduct.206... 

There are very few examples of naturally occurring, fully unsaturated azepines.100 Surprisingly, in view of the relative stabilities of the azepine tautomers (vide supra), the 2/7-azepine, chal-ciporone (24) and the related propanoate ester, norchalciporyl propanoate (25), are the pungent components of the peppery mushroom, Chalciporus piperatus,40... 

Dehydrocyanation of diethyl 4-cyano-2,7-dimethyl-4,5-dihydro-1 //-azepine-3,6-dicarboxylate (3, R = Et) occurs at 315-320 C to directly yield the 3//-azepine 4.29 The corresponding dimethyl ester, however, on pyrolysis at 262C yields the 4//-azepine 2, which on further heating in sand at 360 °C rearranges to the 3//-isomer 5. 

The metalloporphyrin-catalyzed decomposition of ethyl azidoformate in the presence of an arene has been investigated but with little success in improving the yields of the 1 //-azepines.151 The nickel and copper complexes had no effect, whereas the cobalt-tetraphenylporphyrin complex accelerated the decomposition rate of the azido ester but produced more A-arylurethane rather than 1//-azepine. 

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... 

Alkoxy-3//-azepines 87 by Photolysis of Esters and Amides of 2-Azidobenzoic Acid in Alcohol/THF Solution General Procedure 74... 

The 3//-azepines obtained by cycloaddition of azirines to cyclopentadienones (see Section 3.1.1.1.2.) are thought to arise from the initially formed 2/7-azepines by [1,5]-H suprafacial sigmatropic shifts.31-108 In contrast, 1/Z-azepine 9 results from the thermal rearrangement of the nonisolable 2//-azepine-2-carboxylate 8.13 Presumably, the 1 //-azepine is stabilized, relative to the 3//-isomer, by intramolecular hydrogen bonding between the NH and the adjacent ester group. 

Likewise, synthetic 2//-azepines isomerize to 3//-azepines in refluxing chloroform (2-3 h) or in tert-butyl methyl ether at room temperature.291 The isomers can be readily separated by chromatography on silica gel, as the more basic 2//-azepines30 have lower Rf values. In contrast, 7-butyl-2//-azepin-2-acetic acid (11), obtained by heating the tert-butyl ester 10 with iodotrimethylsilane, is stabilized by intramolecular hydrogen bonding and shows no tendency to rearrange to the 3//-isomer.291... 

The Methylene Blue sensitized photoaddition of singlet oxygen to ethyl l//-azepine-l-car-boxylate was reported originally to yield only a C2-C5 adduct 269 however, a reinvestigation with the methyl ester, and using tetraphenylporphine as a sensitizer, revealed that in addition to adduct 46 the [6 + 2] cycloadduct 47 is also produced.270... 

Addition of the alkyne diester to 3-phenylcyclopent[c]azepine (1) is simpler and yields the 2 1 adduct 9 via addition of a second equivalent of the ester to the initially formed 1,4-dipole.272... 

Irradiation of complex 6 in the presence of ethyl acrylate provides the [6 + 2] 7t-adduct 9 as the single enrfo-diastereomer,276 which may also be obtained by heating a mixture of methyl l//-azepine-l-carboxylate with the ester in the presence of a catalytic amount of tricarbonyl(>]6-naphthalene)chromium(O).277... 

Saponification of the a,/ -unsaturated ester 59, prepared by a Reforma tsky reaction on 8-chloro-5-methyl-5//-dibenz[/>,/]azepin-10(ll//)-one, is accompanied by migration of the exocyclic C —C double bond to form the 5W-dibenz[/>,/]azepine 60.72... 

In contrast to 6-azidobenzo[/)]thiophene, which yields only benzo[i]thiophen-6-amine (9 %) and JVh,Ar(1-diethylbenzo[/)]thiopheiie-6,7-diamine (25 % bp 175-177 C/0.7 Torr), 6-azido-2,3-dibromobcnzojhjthiophene (1 a, R = R2 = Br) on irradiation in diethylamine in the presence of pyrene, a triplet nitrene quenching agent, yields a mixture of 2,3-dibromo-./V6,./V6-diethyl-benzo[5]thiophene-6,7-diamine (2a, R1 = R2 = Br 13%) and the 8W-thieno[2,3-r]azepine 3a.14<1 Likewise, methyl 6-azidobenzo[6]thiophene-2-carboxylate (lb, R1 = C02Me R2 = H) yields the thienoazepine ester 3b.147... 

Benzene-1,2-diamines condense with fi-oxo esters in refluxing xylene to give l//-l,5-benzodi-azepin-2(37/)-ones 19. Selected examples are given.268-271... 

CN a-cyclohexyl-3-thiopheneacetic acid 2-(hexahydro-l//-azepin-l-yl)ethyl ester citrate (1 1)... 

C15HHCI2NO 92428-58-5) see Clomipramine 3-chloro-10,ll-dihydro-5H-dibenz[i4/]azepine-5-carb-oxylic acid 3-(dimethylamino)propyl ester (C20H23CIN2O2 94758-20-0) see Clomipramine... 

C20H27NO4 58115-88-1) see Butorphanol hexahy dro-1 -methyMH-azepin-4-one (C7H13NO 1859-33-2) see Azelastine (3S-trflns)-hexahydro-2-phenyl-l /-pyrroloLl,2-c]imid-azoIe-3-carboxylic acid methyl ester (C14H1KN2O2) see Troglitazone hexahydro-l-(2-propenyl)<4i/-azepin-4-one (CyHi NO) see Talipcxole... 

The same group has developed another synthetically useful photochemically induced domino transformation. Irradiation of the enaminecarbaldehydes 5-40a or 5-40b in the presence of acrylic acid ester 5-41a or acrylonitrile 5-41b afforded the quinolizidines 5-45a and 5-45b as well as the pyrido[l,2-a]azepines 5-45c and 5-45d, respectively, with high stereoselectivity [14]. Only very small amounts of the corresponding diastereomers 5-46a-d were detected. 

Stereochemistry also plays an important role in the recently disclosed 3,4-dihydropyrimidinethione analogs [32]. Racemic dihydropyrimidine derivative (32) is reported to inhibit activation by the TRPA1 agonist HH-dibenzo[fc,e]azepine-10-carboxylic acid methyl ester (16) with an IC50 value of 128 nM for human TRPA1 in HEK293 cells. 

Lysine and its derivatives are used for the preparation of e-caprolactams. From L-Lys or its ester, (5)-3-aminohexahydro-2//-azepin-2-one is prepared (43JCS39 57JCS4830 78S614 79JOC4841 80TL2443). 

The 7-azaquadricyclane (77), like its precursor (12), shows evidence in the NMR spectrum of restricted rotation about the N-CO bond. All the 7-heteroquadricyclanes, 76-79, are thermolabile, and they rearrange very readily to the corresponding azepines (80) or oxepin (81). (In another instance the 7-oxabicyclo[4.1.0] valence-bond tautomer was obtained instead. ) In appropriate conditions the addition of acetylenic esters (methyl propiolate and dimethyl acetylene-dicarboxylate) competes successfully with the isomerization and gives the ca o-tricyclic adducts 82 or 83. " °... 

The second way of making medazepam consists of the initial reduction of the carbonyl group by lithium aluminum hydride into 7-chloro-5-phenyl-2,3-dihydro-17f-l,4-benzodi-azepin-2-one (5.1.1)—the first intermediate product in the synthesis of diazepam—which is synthesized by the cyclocondensation of 2-amino-5-chlorobenzophenone with glycine ethyl ester into 7-chloro-2,3-dihydro-5-phenyl-17/-l,4-benzodiazepine (5.1.41), and the subsequent methylation of the secondary amine nitrogen atom of the resulting product by methyliodide, using sodium hydride as a base [41,42]. 

---