Synthesis azepine derivative

Indolones and isoindolones have been utilised in the synthesis of fused azepine derivatives. In the one reaction, rearrangement of the alkynes 18 to 2-benzazepine-l,5-diones 19 in the presence of Lewis acids has been reported <96XL393>. Xhe yields vary from moderate to very good. Xricyclic azepines 20 are obtained by the reaction of the 4-[2 -(p-toluenesulfonyloxy)ethyl]-2-oxindole with imines <96JHC209>. 

Among the valence-bond isomerisations leading to heterocyclic systems, the synthesis of derivatives of azepine (22) and oxepin (28) have been specially successful (Scheme 6.13) [32]. 

A free radical cyclization of oxime ethers tethered to an aldehyde has been used in the synthesis of azepine derivatives . For example, oxime ether 389 is cyclized to azepine 390 by reaction with Sml2 in HMPA and f-BuOH at —78°C (equation 170) . Similar free radical cyclization of oxime ethers can be carried out also in the presence of Bu3SnH/AIBN in benzene . Oxime 0-methyl ether 391 underwent thermal cyclization in refluxing o-dichlorobenzene (ODCB) leading to the mixture of two products 392 and 393 in ratio 69 31 in overall yield of 91% (equation 171) °. Rearrangement of oxime 0-tosylates in the presence of piperidine also leads to azepine ring formation . ... 

A dominant feature of the type c ring-construction approach to azepine systems has been ruthenium-catalyzed ringclosing metathesis reactions. Examples include the synthesis of the azepine derivative 157 from 156 using either the Grubbs type I catalyst 159 or type II 160. The diene precursor 156 was prepared in turn from 154 via 155, as shown in Scheme 21. Hydrogenation of the C-C double bond in 157 afforded the azepane 158 <2005SL631>. 

The formation of amidines from lactim ethers and amines proceeds readily with high yields,8, >18,21,70-70 e.g., in the synthesis of imidazo-[l,2-6]azepine derivatives reported by Stolle et al.77 (Scheme 9), and in the preparation of the pyrimido[l,2-a]-azepine derivative (Scheme 10).70... 

A combination of ruthenium-mediated isomerisation and ring closing metathesis has been applied to the synthesis of the benz[c]azepine derivative 21 in moderate yield from 20 via 18 and 19 <03SL1859>. 

In the first part of the section on the pyrimido[l,2-a]azepines, the chemistry of 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (8) (generally called diazabicyclo[5.4.0] undec-7-ene, or DBU) is treated in a separate subsection, since DBU has proved to be a useful reagent in synthetic organic chemistry and an important catalyst in the synthesis of macromolecules. Since the appearance of two early reviews (72S591 75MI5), the applications of DBU have rapidly increased because of its favorable nonnucleophilic, yet strongly basic, properties. It can therefore be applied for the preparation of even relatively sensitive molecules. Following this, the synthesis, reactions, physicochemical properties, and briefly the applications of further pyrimido[l,2-a]azepine derivatives are discussed. The treatment of the chemistry of the other pyrimidoazepines (2-5 and 7) follows an essentially identical pattern to that for the pyrimido[l,2-a]azepines. 

Photocyclisation - A wide variety of ring-forming reactions has again been reported. Irradiation of azepine derivative (16) results in 4-n-electrocyclisation to a mixture of the corresponding exo and endo cyclobutenes.6-Ti-Electrocyclisa-tion has been employed in a scaled-up synthesis (>300g) of 6-aza-l,10-phenan-throic anhydride (18) from the stilbazole (17). f-Azobenzene, incorporated into water-swollen acid-form Nafion fluorocarbon membranes, exists as the proto-nated form (19) and exhibits ambient temperature fluorescence, previously... 

The synthetic power of Ru-catalysed ring closing metathesis reactions has continued to be realized, for example, in the synthesis of the azepine derivative 4 from 3, which was prepared in turn from 1 via 2. Reduction of 4 afforded the azepane 1 <05SL631>. 

An asymmetric route to the fused azepine derivatives 44 has been reported by Pedrosa et al. <05EJO2449>. The power of ruthenium-catalysed ring closing metathesis is further demonstrated in this synthesis, involving conversion of 43 to 44 (e.g. with R = H, R = CH3 82% yield, 92% de). Compounds of type 44 could then be readily converted into the reduced azepin-3-ol derivatives 47 via 45 and 46. 

Synthesis by Other Cyclizations. The epimeric amines (49) have been made by means of a novel S 2 reaction of the corresponding 2-bromo-6-amino-cyclohexanone derivative. Double Michael addition of (+)-a-methylbenzyl-amine to cyclo-octa-2,7-dienone derivatives forms the basis of a synthesis of the enantiomeric forms of adaline (50). Intramolecular Friedel-Crafts alkylation has been used in the synthesis of derivatives of the 2,6-methanobenz-azepine, 2,6-methano-3-benzazocine, 2,6-methano-3-benzazonine, and... 

An elegant and efficient synthesis of 6,11-dihydro-ll-ethyl-57/-dibenz[6,c]azepine derivatives 53 has been described which involves a BFs-catalysed aromatic amino-Claisen rearrangement of 51a-d to 52a-d followed by an intramolecular alkene Friedel-Crafts alkylation (acid catalysed) to access the 7-membered ring in 53 in high yield. With the amino-Claisen rearrangement of 51e, an inseparable mixture of 54e and 54e was obtained, since in this case both ortho positions in 56 are free for the rearrangement <04SL2721>. 

MJ Plunkett, JA Ellman. Solid-phase synthesis of structurally diverse 1,4-benzodi-azepine derivatives using the Stille coupling reaction. J Am Chem Soc 117 3306-3307, 1995. 

The Diels-Alder reaction of benzynes offers a route to the synthesis of fused azepine derivatives. Thus it is possible to convert the furan (15) into the fused system (16) in approximately 50% yield by reaction with LiTMP in THF at -78 °C... 

In a new synthesis of azepines, it has been shown that 2/f-pyrones react with 2-aminocinnamates to form 2,3-dihydro-l/f-azepine derivatives <89HCA457> in a reaction which has potential for the synthesis of a number of polycyclic azepines (Scheme 26). 

NBS is used as a reagent for phenylselenyl activation in a route to aziridines and oxazolidin-2-ones. The synthesis of 5-bromoisoquinoline and 5-bromo-8-nitroisoquinoline has been achieved using NBS. 3-Bromo-A-methylpyrrole can be obtained from A-methylpyrrole by the use of NBS and a catalytic amount of PBrs. A new synthetic route to indoloquinones has appeared in which 2-methoxy-2//-azepine derivatives react with NBS to form 3//-azepines. Convenient methods for the bromination of 3,5-diarylisoxazoles and for the synthesis of... 

Starting material for the synthesis of varenicline is o-bromofluorobenzene, which reacts (via benzyne) with cyclopentadiene in a Diels-Alder reaction. Oxidative ring-opening and reductive amination provides a N-benzylbenz-azepine derivative. After N-protection with trifluoroacetic anhydride, nitration with a mixture of nitric andtrifluoromethanesulfonic acids, reduction, and condensation with glyoxal, hydrolysis of the trifluoroacetamide as a final step provides the active compound in good overall yield. [568, 569]... 

Organocatalysts were also reported in the synthesis of azepines. In this way, a-ketoamides 8 were reacted with a,p unsaturated aldehydes 9 and a prolinol catalyst 11 to form oxobridged azepine derivatives 10 with good stereocontrol. 

There continues to be strong interest in the synthesis of seven-membered heterocyclic compounds containing one. two. or three of the heteroatoms N, O, or S and in applications of these heterocyclic compounds in medicinal chemistry. Reviews published include strategies for the synthesis of benzopyrrolo[l,2-(j]azepines (13T9357) and the application of [l,7]electro-cyclization reactions for the preparation of azepine derivatives (13CHE152). 

Other methods exploited for the synthesis of azepine derivatives included ring-closing metathesis (13CEJ16746), alkylation of a primary amine with a 1,6-dihalohexane (13ARK240), and hydroamination of aminohexenes (13JA7235). 

Cephalotaxines are important alkaloids having antileukemic properties and some of the members of the family are under clinical trial phases for further development. The family of natural products has inspired the synthesis of natural product-like molecules. Riva and coworkers [41] have developed a quick access to the tricyclic core skeleton of cephalotaxines based on a clever combination of Ugi-4-C with two postcondensation palladium-catalyzed transformations carried out in a one-pot manner. Thus, the Ugi-4-C product on palladium-catalyzed amination followed by a second catalyzed intramolecular Heck cyclization under MW assistance of the resulting vinyl pyrrolidine derivative 42 led access to the tricyclic azepine derivative 43 (Scheme 6). It is interesting to note that tire major product of the Heck cyclization was the desired 7-exo isomer. 

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