3-Benzazepine derivative

UV irradiation of the naphthalen-l,4-imines 104 and 105 promotes their isomerization to 3-benzazepine derivatives 139 and 140. Although no direct evidence was obtained to confirm the formation of azaquad-ricyclanes (138) as intermediates (see Section II,F), the extra strain associated with structure 138 and the extra benzenoid stabilization of the products 139 and 140 make it understandable that the thermal rearrangement of 138 should occur faster than that of 76 or 78. Analogous photochemical transformations are those of compound 106 to trimethyl 3-benzazepin-l,3,5-tricarboxylate, and of 1,4-epoxynaphthalenes to benzoxepin derivatives. ... 

Reactions of a 2-benzazepin-l-one derivative involving a spiroannelation procedure from 76 to afford the spiro-cyclic 3-benzazepine derivative 83 via 77-82 have been reported (Scheme 9) <2005H(65)1359>, while other chiral substituted 2-benzazepines have been prepared from D-glucose via furo[3,2-f][2]benzazepine derivatives <2005S2307>. 

An interesting series of 3-benzazepine derivatives (including 355) have been reported to be potent and selective (over 5-HT2a and 5-HT2b receptors) 5-HT2q receptor agonists, of potential use for the treatment of obesity <2005BML1467>. 

The intramolecular Heck reaction (type d cyclization) has been used to access 3-benzazepine derivatives from o-bromobenzyl substituted /3-amino ester precursors in excellent yields. A key feature though was the use of microwave irradiation in the poly(ethylene glycol), PEG3400, as the solvent <2007EJ0201>. 

Kurihara T, Yamada A, Kawase M, Motohashi N, Sakagami H, Molnar J (2004) Relationship between electronic structure and cytotoxic activity of dopamine and 3-benzazepine derivatives. In Vivo 18 443-448... 

Kawase, M. Unusual ring expansion observed during the Dakin-West reaction of tetrahydroisoquinoline-1-carboxylic acids using trifluoroacetic anhydride an expedient synthesis of 3-benzazepine derivatives bearing a trifluoromethyl group. J. Chem. Soc., Chem. Commun. 1992,1076-1077. 

Remy, D.C., Britcher, S.F., King, S.W., Anderson, P.S., Hunt, C.A., et al. (1983) Synthesis and receptor binding studies relevant to the neuroleptic activities of some l-methyl-4-pipeiidylcnc-9-substi-tuted-pyrrolo[2,l-i>][3]benzazepine derivatives. J. Med Chem. 26 974-980. 

Kawase, M. et at., Use of the triflamide group for Friedel-Crafts acylation of Af-(P-phenethyl)amino acids to 3-benzazepine derivatives, Heterocycles, 45, 1121, 1997. 

Continuing his studies on the metallation of tetrahydro-2-benzazepine formamidines, Meyers has now shown that the previously unsuccessful deprotonation of 1-alkyl derivatives can be achieved with sec-butyllithium at -40 °C <96H(42)475>. In this way 1,1-dialkylated derivatives are now accessible. The preparation of 3//-benzazepines by chemical oxidation of 2,5- and 2,3-dihydro-l/f-l-benzazepines has been reported <96T4423>. 3Af-Diazepines are also formed by rearrangement of the 5//-tautomers which had been previously reported to be the products of electrochemical oxidation of 2,5-dihydro-lAf-l-benzazepine <95T9611>. The synthesis and radical trapping activities of a number of benzazepine derived nitrones have been reported <96T6519, 96JBC3097>. 

This catalytic system has been applied to the synthesis of the core of complex antibiotic tetrapetalones. Hong and coworkers have successfully established the W-acyliminium ion cyclization in the preparation of 1-benzazepine derivatives. A combination of FeCls (0.5 equiv) and TMSCl (2 equiv) was selected as an optimized condition for such stereoselective cyclization (Scheme 35) [45]. 

Dynamic thermodynamic resolution in a lithiation substitution reaction sequence was used to provide access to the amino ester 48 which could then be converted, via 49 and 50, into the chiral substituted 1-benzazepine derivative 51 <06OL2667>. 

The 4-phenyl and 4-phenyl-2-oxo analogues of (6, n = 3 R1 = R2 = Me) have been reported to exhibit sedative properties [13]. Several carboxamides (7) with a 4-phenyl group have been claimed to be useful as tranquillizers [ 14]. A variety of central effects of the 1-substituted 5-phenyl derivatives (8) has been studied [10]. The 2-(substituted aminomethyl)tetrahydro-l-benzazepine and octahydropyrazino[ l,2-c]-l-benzazepine derivatives have no pharmacological activity on the CNS [15]. 1-Substituted tetrahydro-l-benzazepines having an aminoalkyl group at position 3 are claimed to potentiate the activity of 5-hydroxytryptophan [16]. 

The earliest synthetic method for 1-benzazepine derivatives was a ring closure of -substituted anilines by C-N bond formation. Cyclization of 4-(2-aminophenyl butanoic acid and the corresponding butyl chloride gave the lactam (1, R1 = R2 = H) [1] and the 2-deoxo analogue [93], respectively. Thermal cyclization of (41, R1 = R2 = Me R3 = OH) gives 2,5-dioxo-benzazepines (38, R1 = R2 = Me R3 = R4 = R5 = H) [94]. Treatment of analogous esters with sodium hydride gives the derivatives of (38) [9, 95],... 

A number of 1-benzazepine derivatives show a variety of biological activities. Among them, of particular interest are central depressant (12) [ 21 ], cardiotonic (16) [27], antiarrhythmic (17,18) [30, 36] and ACE-inhibitory (23,26) [52, 55] benzazepines. However none of them has yet reached the goal. The most promising agents are (28) [54, 57] and (30) [64], both ACE inhibitors are now undergoing clinical evaluation. 

A photochemical synthesis of isoquinoline and benzazepine derivatives in good preparative yields is shown in Scheme 23 [127, 128]. Upon electron-transfer-sensitized irradiation, the primary aminoethyl and aminopropyl stil-... 

The photolysis of donor-acceptor systems provides unique synthetic opportunities. Direct irradiation of the donor-acceptor systems, such as systems containing arene and amine components, leads to intramolecular electron transfer, that is, to amine cation-radical and arene anion-radical moieties. After generation, these moieties undergo cyclization reactions providing efficient synthetic routes to fV-heterocycles with a variety of ring sizes. Thus, direct irradiation of secondary amino-ethyl and aminopropyl stilbenes leads to benzazepines in improved yields (Hintz et al. 1996). As known, benzazepines are used in medicine as antidepressants. Scheme 7.44 illustrates ion-radical cyclization with the formation of benzazepine derivative (65% yield). 

The synthesis of thieno[3,2-c]benzazepine derivative 106b has been reported by Friedel-Crafts intramolecular cyclization of isocyanates 105 (Equation (15) (2002S355)). Noteworthy, lactam 106b is formed in 51% yield, while dione 106a can not be obtained due to the electron-withdrawing effect of the carbonyl group. 

Benzazepine derivatives (261) are formed in the reaction of 1-acetyl-3-piperidinoindole (259) with DMAD and methyl propiolate (Scheme 41). A similar reaction has been observed in the case of 2-ethoxyindole, on treatment with DMAD. ... 

Chemical Class Benzazepine derivative cholinesterase inhibitor... 

Irradiation of enamines (249) results in processes related to reduction and cyclization reactions with the participation of the enamine /3-carbon atom (82JOC482). A benzazepine derivative (250) was isolated as one of the products. Enamines (251) interact with aldehydes in a smooth reaction and give diazepines [84CPB3274 91KFZ(11)16]. Benzodiazepine derivatives can be obtained in a similar fashion (95KGS336). 

Enzymatic reactions now have a sound place in contemporary synthetic methodology. Illustrative of this, lipase-catalyzed transesterification of the racemic alcohol 65 has been used effectively to produce (6)-(+)-66 (LipaseQL, 0-5 °C, 4 h 47% yield >99% ee), plus the (R)-(—)-acetoxy derivative 67 (Equation 8). The 1-benzazepine derivative 66 was then converted to a chiral precursor required for the synthesis of the nonpeptide vasopressin V2 receptor agonist, OPC-51803 <2002H(58)635>. The synthesis of a 1-benzazepine-based antagonist (OPC-41061) at this receptor has also been reported <2002H(56)123>. 

A conceptually neat ruthenium-mediated isomerization and ring-closing metathesis was used in the synthesis of the l/f-2-benzazepine derivative 210 in moderate yield from 207 via 208 and 209 (Scheme 27) <2003SL1859>. 

The Pd-catalyzed reaction of 211 with allyltributyltin to give 212, followed by N-alkylation to 213, afforded the 1-benzazepine derivative 214 in high yield on Ru-catalyzed ring-closing metathesis with Grubbs I catalyst 159 (Scheme 28) <2005JOC1545>. 

The conformationally restricted 17/-2-benzazepine derivative 353, which is a dual inhibitor of acetylcholinesterase (ICso=14nM) and the serotonin transporter (IC5o = 6nM), is a potential agent for the treatment of Alzheimer s disease <2003BMC4389>. 

A library of di- and trisubstituted 5-amino-l 77-1-benzazepine derivatives was assembled through attachment of a preformed 1-benzazepine unit to an aminomethylated polystyrene resin. The initial solution phase synthesis of the 1-benzazepine moiety was based on an intramolecular Dieckmann cyclization (type d) followed by a ketone to primary amino group transformation via reduction ( NaBH3CN) of an imine intermediate <2007JC0487>. 

A Beckmann rearrangement-reduction sequence has been used to access a number of substituted H- 1-benzazepine derivatives, with the required substituted a-tetralone precursors being prepared by a xanthate-based free radical cyclization process <2006BMC6165>. 

Classical ring closures (of the FriedelCrafts, Dieckmann, etc., types) can be applied to benzazepine synthesis <1974AHC(17)45>. Particularly useful are approaches to benzazepines based on transition metal-catalyzed cyclizations , as illustrated by the synthesis of 1-benzazepine derivative 149 in high yield by Ru-catalyzed ring-closing metathesis with Grubbs I catalyst (Scheme 87) <2005JOC1545>. 

A benzazepine derivative of homopipecolic acid 53 was formed by the reaction of an A-magnesioaryl amine with a magnesium carbenoid formed from 1-chloroalkyl p-tolyl sulfoxide 51. The intermediate 52 was trapped with ethyl chloroformate to yield the benzoazepine in good yield. In contrast, the corresponding azepine derivative was formed in only 4% yield <07TL7829>. 

The xanthate transfer process provides a simple and uniquely powerful route to a-tetralones, another family of important aromatic derivatives [69-71]. a-Tetralones are starting materials for the synthesis of a host of medicinally important compoimds. They are precursors to naphthalenes, naphthols, naphthylamines, and ring expansion through the Beckmann rearrangement provides access to benzazepine derivatives. The two examples in Scheme 34 illustrate, on one hand, the possibility of preparing a tetralone with a carbohydrate-derived appendage [69] and, on the other, the synthesis of a substituted naphthol 59 by aromatisation of tetralone 58 through acid... 

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