Reactions tetracycles

The assumption of these conjugated double bonds makes possible a tetracyclic nucleus which accords with the suggestion previously made by the authors that these alkaloids might be structurally related to the diterpenes. It may also be noted that one of the nitric acid oxidation products of pseudaconitine has been recorded as unexpectedly giving a pyrrole reaction on destructive distillation. ... 

The 2,7-naphthyridine system 53 (Scheme 8.4.18) was combined with 2,4-dinitrochlorobenzene and 2-amino glycerol for in situ reaction of the resulting Zincke salt. The resulting naphthyridinium 54 was trapped by Bradsher cycloaddition with (Z)-vinyl ether 55, providing tetracycle 56 (X-ray) upon internal addition of one of the diastereotopic hydroxymethyl groups to the resulting iminium. This approach was also extended to the use of chiral 2,7-naphthyridinium salts, prepared via the analogous Zincke process. ... 

A synthetic approach to the same tetracyclic y-carboline nucleus (235) is the consecutive Fischer indole and Bischler-Napieralski ring closure of o-acetamidoacetophenone methylphenyUiydrazone (234). The Bischler-Napieralski reaction has also been used in the synthesis of 3,4-benz-j8-carbolines (236) and 3,4-benz-3-carbolines, e.g. 237... 

Cycloaddition reactions of o-benzoquinones with formation of bi- and tetracyclic systems including 2,3-dihydrobenzo[d]dioxine fragment 96SL1143. 

Reaction of 2-(A -allylamino)-3-formyl-4//-pyrido[l, 2-u]pyrimidin-4-ones 219 in EtOH with HONH2 HCI yielded ( )-oximes 220 at 0°C and 221 (R = PhCH2) under reflux. Heating 220 (R = H) in a boiling solvent afforded cw-fused tetracyclic cycloadducts 221 (R = H). In an aprotic solvent (e.g., benzene or MeCN) the main a>fused cycloadducts 221 (R = H) were accompanied by a mixture of trauA-fused cycloadducts 222, A -oxides 223 and tetracyclic isoxazoline 224 (96T887). The basicity of the 2-allylamino moiety of compounds 219 affected the rate of the conversion. Cycloadditions were also investigated in dioxane and BuOH. 

Reaction of 2-[A -(2-alkenyl)amino]-3-formyl-4/f-pyrido[l, 2-n]pyrimidin-4-ones 235 with HONH2 HCl under both acidic and basic conditions (in the absence or in the presence of NEts) gave tetracyclic derivatives 236 in good yields. Higher yields were achieved in the presence of NEts (96T887). 

Intramolecular cycloadditions of 4/f-pyrido[l,2-n]pyrimidin-4-ones 235 (R = H, Me Ph) and MeNHOH HCl gave tetracyclic isoxazolo derivatives 237. In the case of 235 (R = Me) a minor epimer 238 was also isolated (00JCR(S)414). Similar reaction of 235 (R = H, Me, Ph) and sarcosine ethyl ester HCl afforded an isomeric mixture of epimeric tetracyclic pyrrolo derivatives 239 and 240. In the reaction of 235 (R = H) and PhCHjNHCHjCOOEt only one product 241 was obtained. 

Reaction of 2-[A -(rra -crotyl)-A -benzylamino]-3-formyl-4/f-pyrido[l,2-n]pyrimidin-4-one (269) with chiral primary amines 270 and 271 gave mixtures of diastereoisomers of tetracyclic compounds 273 and tricyclic 275 (96T131]]). The chiral centers in 272 and 274 did not provide any stereocontrol for the formation of diastereomers 273 and 275, respectively. 

CuCl/THF followed by catalytic hydrogenation to give the pyrroloquinoline 134. Nitration of the later gave the 9-nitro derivative 135. Reduction of 135 followed by reaction with ethyl trifluoroacetoacetate gave 136 that upon cyclization gave the tetracyclic compound 137 (98JMC623) (Scheme 26). 

Formylation of the V-allyl indole derivatives 311 (obtained by allylation of the indole 310) afforded l-allyl-7-formyl-indole 312. Subsequent condensation of 7-formyl indole derivatives 312 with ethyl acetate in presence of sodium ethoxide gave 313 (89S322). Reaction of 312 with N-methylhydroxylamine hydrochloride afforded the cycloadduct, tetracyclic... 

The aniline derivative 332, prepared from 2-fluoro-6-nitrotoluene, was transformed through successive reactions as shown in Scheme 60 to give the functionalized indole 333. It was then reduced with LiAlH4 to the dimethylaminopropyl derivative which was quaternized with Mel to the trimethyl ammonium salt 334. Subsequent cyclization and functionalization afforded the pyrroloquinoline 335. The latter could be transformed to the tetracyclic acid 336 (90JHC2151). (Scheme 60)... 

Reaction of 4-cyano-3-imino-2,3,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyr-imidin-l-one 169 with 2-chloroethyl isocyanate at ambient temperature and under reflux gave N-acylated 170 and tetracyclic derivative 171, respectively (95MI1). Similar reaction of 3-amino-4-cyano-2,4a5,6,7,8-hexahydro-l// pyrido[l,2-c]pyrimidin-1-ones 172 afforded tricyclic compounds 173. 

Amino-6,6n,7,8,910-hexahydropyrido[2,l-c][l,4]benzoxazine was reacted with ethyl 4,4,4-trifluoroacetoacetate in boiling benzene for 12-16 h, then the reaction mixture was concentrated in vacuo and the residue was treated with cone. H2SO4 at 100°C to give tetracyclic 11-trifluoromethyl-l,2,3,4,4a,5,8,9-octahydropyrido[l, 2 4,5][l,4]oxazino[3,2-a]quinolin-9-one in 30% yield (OlMIPl). 

This reaction also represents an example of the intramolecular Heck reaction, a variant that has gained some importance in recent years. Another instructive example of the potential of this reaction for the construction of ring systems has been reported by de Meijere and coworkers, taking advantage of a sequence of four consecutive intramolecular Heck reactions. The bromodiene-yne 18 reacts in a sequence of domino reactions within 3 d at 80 °C under Heck conditions to give the tetracyclic product 19 in 74% yield ... 

The reaction of relatively simple starting materials, coumarin 40, piperidone 37 and ammonium acetate, leads in a single step to the complex bridged tetracyclic compound 44. The reaction can be rationalized by assuming formation of the iminc 38 from reaction of 37, with ammonia. Conjugate addition of the eneamine-like tautomer 39 to the excellent Michael acceptor 40 will... 

The total synthesis of ( )-estrone [( )-1 ] by Vollhardt et al. is a novel extension of transition metal mediated alkyne cyclotrimeriza-tion technology. This remarkable total synthesis is achieved in only five steps from 2-methylcyclopentenone (19) in an overall yield of 22%. The most striking maneuver in this synthesis is, of course, the construction of tetracycle 13 from the comparatively simple diyne 16 by combining cobalt-mediated and ort/io-quinodimethane cycloaddition reactions. This achievement bodes well for future applications of this chemistry to the total synthesis of other natural products. 

During the course of an elegant synthesis of the multifunctional FR-900482 molecule [( )-43, Scheme 9], the Danishefsky group accomplished the assembly of tetracycle 42 using an intramolecular Heck arylation as a key step.24 In the crucial C-C bond forming reaction, exposure of aryl iodide 41 to a catalytic amount of tetra-kis(triphenylphosphine)palladium(o) and triethylamine in acetonitrile at 80 °C effects the desired Heck arylation, affording 42 in an excellent yield of 93 %. The impressive success of this cyclization reaction is noteworthy in view of the potentially sensitive functionality contained within 41. 

In the event, macrocyclic bis(thiolactones) perform admirably in the macrocycle-to-bicycle bridging reaction (see Scheme 5).17 For example, the eis-fused tetracycle 25 can be produced, in 80%... 

The addition of carbene to a 3-(halopropyl)-5//-dibenz[7>./]azepine 5 (X = Cl, Br) in a Simmons—Smith reaction is more complex and results in a mixture of the tetracycle 6 (6%), its cyclopropano derivative 7 (48 %), the 5-allyl derivative 8 and the (cyclopropyl)methyl compound 9, the latter two products in a combined yield of 12%.31... 

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