Pyrrolo azepines

Likewise, aryllithiums generated by lithium-iodine exchange undergo intramolecular cyclization to give pyrrolo-azepine 72. The best results were obtained when Weinreb (R = Me, = OMe) or morpholine amides were used as internal electrophiles, resulting in 66 and 70% yields, respectively (Equation (7) (2005T331D). 

The azepino-indole (600 E = COjMe) is produced by thermolysis of methyl 2-azidodiphenylmethane4 -carboxylate, N3C6H4CH2C6H4C02Me. Treatment of the pyrrolo-azepine (601) with benzoylmethylenetriphenyl-phosphorane, PhCOCH=PPh3, yields the bridged compound (602) by successive Michael addition and intramolecular Wittig reaction The imidazo-azepine (604) is formed from (603) by ring-expansion with diazomethane.Addition of dimethyl acetylenedicarboxylate to the cyclo-... 

Guzzo PR, Surman MD, Grabowski Jr JF, Freeman EE (2011) Azinone-substituted azepino[B] indole and pyrido-pyrrolo-azepine Mch-1 antagonists, methods of making, and use thereof. US2011003793... 

The cyclopentazepine systems are often1-5 referred to as 4-aza-, 5-aza-, and 6-azaazulene, respectively. Confusingly, the cyclopent[a]azepine 8a, which is more correctly known as 1ff-pyrrolo[l,2-a]azepine, has been referred to as 4-azaazulene6 and as 3a-azaazulene.7 Only the carbonyl derivative 8b of this nonconjugated system is included in this section since it can be represented as the fully conjugated, aromatic, dipolar structure 9.6... 

The H and 13CNMR spectra of various cyclopentazepines have been recorded (Tables 1 and 2), as has the HNMR spectrum of 7V,7V-dimethylcyclopent[e]azepin-l-amine.68 A detailed analysis of geminal and long-range 13C-H coupling constants for cyclopent[c]azepine is also available.87 The HNMR spectra of 9//-pyrrolo[l,2-a]azepin-9-one (8b) and its fully delocalized cation have been recorded in various solvents.7... 

Pyrrolo[l,2-a]azepin-9-one (12), which in acid solution exists as the cation 13, is prepared by thermal cyclization of ( , )-4-(dimethylaniino)buta-l,3-dienyl pyrrol-2-yl ketone (ll)7. 

Pyrrolo[l,2-a]azepin-5-one (11), prepared by cyclization of methyl 5-(pyrrol-2-yl)penta-2,4-dienoate (10) with sodium hydride in toluene, in trifluoroacetic acid solution forms the diatropic 5-hydroxypyrrolo[1,2-a]azepinium ion 12.216 6-Methyl-5//-pyrrolo[l,2-tf]azepin-5-one(mp41 -43 C), formed in low yield (20%) by the action of [(ethoxycarbonyl)methylene]triphenylphos-phorane on 4-(pyrrol-2-yl)but-3-en-2-one, behaves similarly. 

A diatropic cation 15 is also noted in strong acid solution for 7//-pyrrolo[l,2-a]azepin-7-one (14), prepared by dehydrogenation of its 5,6-dihydro derivative 13.217 It is presumed that the deep-red solution produced on treating 7-methylene-7//-pyrrolo[l,2- azepine (16), prepared from the ketone 13 as indicated, with strong acid is indicative of the formation of 7-methylpyrrolo[l,2-a]azepinium cation 17 however, the salt could not be isolated nor a satisfactory HNMR spectrum obtained.217... 

Also. 77/-pyrrolo[l,2-fl]azepin-7-ones, e.g. 22, available by the thermal rearrangement of 1-azaspiro[4.5]dcca-l,3,6,9-tetraen-8-ones 21, in trifluoroacetic acid form the deep-blue 7-hy-droxypyrrolo[l,2-tf]azepinium cations, e.g. 23.219 In hot 48 % hydrobromic acid, however, the spiro compound 21 is re-formed. 

Thermolysis of the 3-acyl-3/f-azepine 32 in Decalin at 250°C also gives the phenacylpyridine but in much reduced yield (6%). In a similar manner, 4-chloro-yV,/V-diethyl-3-phenacylpyridin-2-amine (53 % bp 160 C/0.18 Torr) is produced by the photolysis or thermolysis of 3-benzoyl-5-chloro-Ar,Ar-diethyl-3/f-azepin-2-amine.246 However, if the 3ff-azepine bears a secondary amine residue at the 2-position, e.g. 36, then photolysis or thermolysis yields a pyrrolo[2,3-/>]pyridine by intramolecular cyclization of the 3-phenacylpyridin-2-amine intermediate. 

Bis(bromomethyl)-5//-dibenz[/), / ]azepines, e.g. 12, prepared by free-radical bromination of the 10,11-dimethyl compound with yV-bromosuccinimide, on treatment with a primary alkyl-amine followed by alkaline hydrolysis, yield l,2,3,8-tetrahydrodibenzo[. /]pyrrolo[3,4-<7]-azepines, e.g. 13, which possess useful pharmacological properties.91,163... 

Related work described the synthesis of pyrrolo[3,2-c] azepines (eg. 25) as 5-HT2 antagonists and their antiplatelet aggregation activity . 

In an investigation of the intramolecular Schmidt reaction of alkyl azides for the synthesis of benzo-fused l-azabicyclo[m.n.O]alkanes, the perhydrobenzo[/]pyrrolo[l,2-a] azepine 29 was prepared in 72% yield . 

Ring expansion of 4J5>6,7-tetrahydro-4-indolone oximes also underpinned the synthesis of the 3//-azeto[l,2-a]pyrrolo[3,2-c]azepin-8-ones 30 (eg. R = H, Me) in good yield <00H(53)557>. 

Similarly, according to Scheme 2.211 d, the INAC reaction of TV -ally 1-carbohydrate nitrone (472) gave the pyrrolo 1,2-a azepine derivative (473) (Scheme 2.228) (723). 

As in the case of the formation of an azepine (Scheme 43), Pro afforded a pyrrolo[l,2-fl]azepine 88, and pipecolinic acid afforded a pyrido[l,2-a]aze-pine 89 (80JHC1593). 

The special case of the fusion of a five-membered ring to the benzoheteropine ring occurs when the pyrrole or indole N1 and C2 atoms serve as fusion sites (Figure 2). The resultant benzopyrrolo[l,2-fl]azepines differ by the position of the fused benzo ring and are listed in the order of benzo[c]pyrrolo[l,2-fl]- (7), benzo[d]pyrrolo[l,2-fl]- (8), benzo[e]pyrrolo[l,2-fl]- (9) and benzo[/]pyrrolo[l,2-fl]-(10) azepines, respectively. 

Construction of the azepine ring by C-C bond formation. The Heck-type cyclization of amides 11, easily available by amide bond coupling (EDCI, DMAP) between the corresponding indolo- and pyrrolo-[2,3- 7]p)uidine-carboxylic acids and 2-iodobenzylamine, is effective in the presence of Pd(OAc)2/PPh3 catalyst and silver carbonate base and leads to excellent yields of the corresponding azepinones 12 (Equation (1) (2005TL8177)). 

Suitable amide derivatives of pyrrole- and indole-2-caroxylic acids 13 result in good yields of 5,6-dihydrobenzo[c]pyrrolo[3,2-e]azepin-4(3F7)-one 14a and its indole analog 14c (Equation (2) (2005TL8177)). 

Intramolecular electrophilic reactions of substituted pyrrole-2-carboxylic acids or their amides lead to benzo[d]pyrrolo[l,2-a]azepinones. Acid 70 in this fashion undergoes Fiiedel-Crafts cyclization to furnish fused azepine 71 in good yield (Equation (6) (2000JOC2479)). 

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)). 

Dipolar cycloaddition is another route to benzopyrrolo[l,2-a]azepines by pyrrole ring formation. The azomethine ylide derived from imine 88 and difluorocarbene adds to DMAD to produce dimethyl 3-fluoro-9H-dibenzo[c,/]-pyrrolo[l,2-fl]azepine-l,2-dicarboxylate 89 in 20% yield (Equation (12)... 

Dieckmann cyclizations of diesters of type (210) are catalyzed by potassium f-butoxide in toluene, sodium in xylene, or sodium hydride in DMF, and produce 1-benzazepinones in good yields. The method is also applicable to the synthesis of azepines fused to other heterocycles, e.g. pyrrolo[2,3-6]azepin-4-ones (211) (81H(16)399). 

Pyrrolo[ 1,2- ]azepines occurs in a number of natural products and compounds of biological interest. The pyrroloalkyl epoxide (149) is cyclized to the alcohol (150) (85% yield) by Ti(OPri)3Cl (87JOC819). The allylsilyl substituted iV-acylimium salts (151) cyclize to (152) (92H(34)37). 

Little work has been done with simple pyrimidines. 4,6-Dimethyl- and 2,4,6-trimethylpyrimidine in acetonitrile with DMAD gave low yields of 1 2 molar adducts, originally considered336 to be pyrimido[l,2-[Pg.383]

Unlike oxazoles, benzoxazoles do not undergo Diels-Alder reactions with DMAD. Benzoxazole itself, without solvent, gives pyrido[2,l-6]-benzoxazole (15), the earlier477 5a//-isomer structure being discarded 478 because of the 13C NMR spectrum of the compound. 2-Methylbenzox-azole in acetonitrile gave on one occasion479 the azepine 16 and, on another,480 a compound that is almost certainly cyclobuta[4,5]pyrrolo-[2,1 -6]benzoxazole (17).337,481... 

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