Azepinone derivatives

Other -substituted and reduced 2-azepinone derivatives 22 can also be accessed in high yields (Table 3) by ring closing metathesis on the precursors 21 using Grubbs II catalyst 18. A variety of IV-heteroaryl substitutent groups were tolerated in this reaction <06TL3295>. 

Condensation of cyclic enaminoamides (246) with dimethyl acetylene-dicarboxylate gives 2-azepinone derivatives (247) (85AJC1847). Similarly, immonium salts (248) when treated with bases give enamines, which subsequently react with dimethyl acetylenedicarboxylate or unsaturated ketones and give azepines (81AP787). The reaction of primary enaminonitriles with dimethyl acetylenedicarboxylate proceeds in a similar fashion (84CPB2596). Another route to azepines has been described (95JHC57) (Scheme 51). 

In connection with studies on structure-property relationships with dermal penetration enhancers, substituted azepinone derivatives (e.g., 74, R = Me and 75, R = Me) were made by Kim et al. from the 3-aminoazepanone 71 via 72 and 73 using standard functional group manipulations (Scheme 8) <2001MI183>. 

The /V-acylaminals 136 can serve as substrates for the formation of fused azepinone derivatives on treatment with a catalytic amount of TiCh, although the reaction is sensitive to the nature of the R group. Thus, 138 was obtained from 136 (R = CH2OAc), but with R = Me in 136, the 6,6-fused system 137 resulted (Scheme 18) <1999TL7939>. 

Another type b cyclization route to substituted tetrahydroazepines involved a new and potentially versatile TBSOTf-mediated attack (using excess TBSOTf in DCM) on an acyclic A-formamido precursor further functional group modifications then provided access to an azepinol and azepinone derivative <2007SL497>. 

Indole-fused, or indole-benzo-fused azepinone derivatives have attracted synthetic attention and examples include the preparation of 85 in 84% yield from 84 by intramolecular Heck coupling [01SL848], as well as the preparation of paullone 87 (a CDK inhibitor) by cyclisation of 86 under basic conditions borylation/Suzuki coupling technology was used to access 86 [02JOC1199]. Acid-catalysed cyclisation with polyphosphoric acid was used to prepare the racemic reduced azepino[4,5-6]indoles 92a,b from the precursors 91, which were obtained in turn from CDl-mediated coupling of 88 and 89, followed by reduction of the amide with lithium aluminium hydride [01H1455]. 

In 1996, the same group 87) reported further work on the synthesis of indole analogues of the cephalotaxine ring system (Scheme 52). The key intermediate in this ring-expansion approach, bromoiminium ion 300, was prepared in three steps from tryptamine and the chloro diester 298 via enamine 299. On treatment with several bases, the iminium ion 300 underwent rearrangement, presumably via the intermediate alkoxide 301, to give the azepinone derivative 302, which was reduced with sodium borohydride to a mixture of isomeric alcohols 303. The alcohols 303 underwent rapid intramolecular cyclization when treated with a 95% solution of sulfuric acid to yield pentacyclic ketone 304. 

Oh and Reddy succeeded in developing Rh-catalyzed intramolecular benzannu-lation by use of o-alkynylbenzaldehydes 71, which have a pendent nitrile group, leading to isoquinoline derivatives 72 (Scheme 15.29). Interestingly, the substrate having no gem diester on the tether gave benzo[c]azepinone derivatives exclusively but not isoquinoline frameworks [41],... 

When the 1-position is substituted, 3- and 5-aminopyrazoles react at the C-4 carbon atom, the reactivity of which is enhanced by the amino group. Thus pyrazolo[3,4-Z ]pyridines (545) are obtained either by the Skraup synthesis or from 1,3-diifunctional compounds. Here also aminopyrazolinones have been used instead of aminopyrazoles to prepare (545 R = OH). If 1,4-ketoesters (succinic acid derivatives) are used instead of /3-ketoesters, pyrazolo[3,4-Z ]azepinones (546) are obtained. 

The oxazolo[3,4-a]azepinones 4, in which 5 7 ring fusion imparts considerable planarity and hence antiaromatic character on the ring system, undergo spontaneous dimerization.153 The mode of dimerization appears to depend on the nature and position of substituents. The unsubstituted system and the 9-chloro derivative 4 (R1 = Cl R2 = H) produce the exo.anti-dimers, e.g. 5, upon spray-vacuum pyrolysis at 300 C, whereas the 7-/ert-butyl, 7-bromo, 7-methyl, and 7,9-dichloro (4, R1 = R2 = Cl) compounds yield the exo,syn-dimcrs, e.g. 6. 

Reduction of the 5A/-2-benzazepin-5-one 5, prepared by base-catalyzed (triethylamine) dehydrobromination of4-bromo-8-chloro-l-(2-chlorophenyl)-3//-2-benzazepin-5(4//)-one, with lithium aluminum hydride at — 78 C yields a mixture of the 5//-azepin-5-ol 6 and the dihydrobenz-azepinone 7.78 Attempts to prepare the 5-bromo derivative from the alcohol 6 failed. 

A further variant of Method B is the conversion of the readily available aryl(2-methyl-aminoaryl)methanols 16 into the chloroacelyl derivatives 17, followed by oxidation to Ihe benzophenones 18 with chromium(VI) oxide. The products are transformed into benzodi-azepinones by treatment with sodium iodide and ammonium carbonate (Method D). Selected... 

Regioselective Beckmann rearrangements were used as key steps in the synthesis of phosphonoalkyl azepinones (Scheme 36) [43b] and in a formal total synthesis of the protein kinase C inhibitor balanol (Scheme 37) the optically active azide 197 derived from cyclohexadiene mono-oxide was converted into ketone 198 in several steps. After preparation of the oxime tosylates 199 (2.3 1 mixture), a Lewis acid mediated regioselective Beckmann rearrangement gave the lactams 200 and 201 in 66% and 9% yield, respectively. Lactam 201 underwent a 3-e im-ination to give additional 200, which served as a key intermediate in a balanol precursor synthesis (Scheme 37) [43 cj. 

In the case of the related starting material 95, bearing a chlorovinyl fragment in the side chain, the expected azepinone 96 was accompanied by a new rearranged quinolizine derivative 97 that was generated from allylic transposition of the side chain to C-12b, as shown in Scheme 8 <1996TL5701>. 

Rearrangement reactions have provided access to some interesting azepinone or azepine dione systems. Curtius rearrangement followed by a [3,3] sigmatropic reaction on intermediate carbonyl azides gave azepin-2-one derivatives, for example 2, in fair to moderate yield. The precursor intermediates for this sequence were made, in turn, by treatment of 2-siloxysubstituted 2-alkenylcyclopropanecarboxylic acids (for example, 1) (Scheme 1) with diphenylphosphorazidate and triethylamine <00SL725>. 

A possible mechanism for the observed transformation includes the sequence outlined in Scheme 2.327 (i) propargyl (A) - allene (B) tautomerization, (ii) 8jt-cyclization (C), (iii) N-0 cleavage (diradical D), (iv) diradical recombination (cyclopropanone derivative E), and (v) one or two step cyclizations of the azadienyl cyclopropanone into azepinone F. The occurrence of cyclopropanones (type E), as intermediates, is supported by the formation, in some cases, of isoindoles (type I) (789) as minor products (Scheme 2.327) (139, 850, 851). 

Further elaborations on the dipeptide-azepinone theme present in 29 and 32 have been described. Benzodiazepine 33 was transformed through SAR studies to the more potent a-substituted analog 34 and the potent carboxamide 35 (IC50 = 1.2 nM), which demonstrated 22% bioavailability in rats, but poor brain levels (plasma and brain AUC = 2.9 vs. 0.17 (iM h, respectively) [94,95]. Potent homoaldol 36 (Ap IC50 = 0.06 nM) and related benzodiazepine derivatives have been reported [96]. Caprolactam 37 (Ap IC50 = 17 nM) resulted from modification... 

N-Isopropyl-iV-methyl derivatives (1287) afforded a mixture of 1H-azepinones (1288 and 1289) and 1284 (87CC140). 

Several azepine ring constructions have been reported using palladium catalyzed C-C bond formation. Palladium catalyzed cyclizations of substituted tryptamine derivatives 73 lead to benzo[d]pyrrolo[l,2-a]azepinones 74 (Equation (8) (2000JMC1050)). 

Reaction of the radical derived from substituted 2-bromo indole 78 leads in moderate (37%) yield to benzo[d]pyrrolo[l,2- ]azepinone 79 along with 32% of the reduction product 80. The process occurs via radical addition to the benzene ring followed by rearomatization (Equation (9) (2000TL4209)). 

A general route to azepinones is by intramolecular cyclization of e-aminohexanoic acids or their derivatives (80TL2443). For caprolactam, however, yields are low and superior preparative methods are available (70MI51600, B-75MI51601). Surprisingly few methods are known for the synthesis of C-substituted caprolactams. A useful summary of existing... 

Preparative routes to 5/7-dibenz[6,e]azepine-6,11 -diones (morphanthridinediones) are based mainly on the cyclization of 2-aminobenzophenone-2 -carboxylic acids and their derivatives (55LA(594)89). Studies on a-aminodiphenyImethane-2 -carboxylic acid reveal that cyclization to 5,11 -dibenz[6,e ]azepinone (188) is much slower at room temperature than the cyclizations of the analogous 2-aminobiphenyl-2 -carboxylic acid and the 2 -aminobiphenylacetic acid (189), which at room temperature cyclize spontaneously to phenanthridone and dibenz[f>,d]azepin-6-one (190) respectively (61JOC1329). The hydrogen bromide-induced cyclization of dinitriles (Scheme 16) is adaptable to the synthesis of 2-amino-7-bromo-3//-azepines and 5H-dibenz[c,e]azepin-7-ones (67JOC3325). Apparently, for unsymmetrical dinitriles cyclization is such as always to give the azepine with the bromo substituent attached to the carbon of the a,j8-unsaturated nitrile as exemplified in Scheme 16. 

Components 2 5 and 1 2 were first detected in wort, which was heated above 140 °C. Beer, produced by this process, possessed a bitter aftertaste. Compound 3. was recently identified as a reactive intermediate, which decomposed very soon even by storage at -20 °C. On heating L-proline and monosaccharides at 150 °C for 1.5 h all compounds increased ten to fiftyfold and 2,3-dihydro-1H-pyrrolizines and di- and tetrahydro-1H-azepines were characterized as major components. On roasting L-proline and monosaccharides (or sucrose) pyrrolidines and azepinones predominate among the Maillard products. These compounds were also formed by heating pyrrolidine and glucose at 100 "C. Azepinones and certain pyrrolin-derivatives possess extreme bitter taste and thresholds of 5 - 10 ppm ( 3, 5 ). ... 

---