Synthesis of isoquinolines. XI. Dibenzo[c,f]-1-azabicyclo[3.3.1]nonanes and 4-phenyl-1,2,3,4-tetrahydroisoquinolines

Bobbitt, James M.; Shibuya, S.

doi:10.1021/jo00829a074

Cited by 18 publications

(10 citation statements)

References 2 publications

(2 reference statements)

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“…After complete addition, the mixture was stirred at Ϫ100°C for 4 h and was quenched with satd. aqueous NH 4 Cl. The mixture was stirred at room temperature until all pre-cipitate had dissolved.…”

Section: Tert-butyl 3-bromo-2-({[(1s)-1-(methoxycarbonyl)-2-methylpromentioning

confidence: 99%

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Double Cyclization of Bis(α‐hetarylmethyl)amino Esters to Optically Active Bridged N‐Heterocycles of HIV‐Inhibiting Activity

et al. 2004

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Section: Tert-butyl 3-bromo-2-({[(1s)-1-(methoxycarbonyl)-2-methylpromentioning

confidence: 99%

“…[2,3] Such compounds as well as thieno analogues were synthesized by acid-catalyzed double cyclization of α-(dibenzylamino)aldehydes, acetals, [1,2,4,5] ketones [6,7] or N,Ndibenzyl-2-propynylamines. [8] Alternatively, suitably functionalized isoquinolines can undergo electrophilic cyclization to 1-azadibenzo[c,f]bicyclo [3.3.1]nonanes.…”

Section: Introductionmentioning

confidence: 99%

Double Cyclization of Bis(α‐hetarylmethyl)amino Esters to Optically Active Bridged N‐Heterocycles of HIV‐Inhibiting Activity

et al. 2004

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“…2,3 Several synthetic methods have been reported for this class of condensed heterocycles and related heterocyclic analogues. Thus acid catalyzed double-cyclization of αdibenzylaminoaldehydes, acetals 2,[4][5][6] or ketones 7,8 afford 8 (X = CH=CH, R = H, alkyl or aryl) with a hydrogen atom, an alkyl or an aryl substituent at position 5. In this synthesis the first cyclization represents a hydroxyalkylation and gives intermediate 2-benzyl-4-hydroxy or 4alkoxy-2-benzyl-tetrahydroisoquinolines that subsequently cyclize by intramolecular Friedel-Crafts like alkylation.…”

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confidence: 99%

New β-Carboline Derivatives by Double-Cyclization of Chiral α-Heteroarylmethylamino Esters

Faltz¹,

Liebscher²

1998

Synlett

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Dialkylation of amino esters 2 with o-bromobromomethylheteroaromatics 1 and double-cyclization of the resulting N,N-disubstituted esters 3 via bromo-lithium exchange to tetrahydropyridine rings gives access to dicondensed 5-hydroxy-1-azabicyclo[3.3.1]nonanes 4, mostly ß-carboline derivatives. The synthesis is highly stereoselective affording optically active products.Dibenzo[c,f]-1-azabicyclo[3.3.1]nonanes 8 (X = CH=CH) have gained interest as antihistaminic compounds 1 and as starting materials for the synthesis of Amaryllidaceae alkaloids. 2,3 Several synthetic methods have been reported for this class of condensed heterocycles and related heterocyclic analogues. Thus acid catalyzed double-cyclization of α-dibenzylaminoaldehydes, acetals 2, 4-6 or ketones 7,8 afford 8 (X = CH=CH, R = H, alkyl or aryl) with a hydrogen atom, an alkyl or an aryl substituent at position 5. In this synthesis the first cyclization represents a hydroxyalkylation and gives intermediate 2-benzyl-4-hydroxy or 4-alkoxy-2-benzyl-tetrahydroisoquinolines that subsequently cyclize by intramolecular Friedel-Crafts like alkylation. Likewise 2-benzyltetrahydroisoquinolines with hydroxy, acyloxy or methoxy groups in position 4 give dibenzo[c,f]-1-azabicyclo[3.3.1]nonanes 8 upon treatment with acids. 4,9,10 These last two methods were also used in the thieno series. 11 5-Methyl-dibenzo[c,f]-1-azabicyclo[3.3.1]nonanes 8 (X = CH=CH, R = Me) were obtained by double-cyclization of N,Ndibenzyl-2-propinylamine in the presence of triflic acid. 12 Finally, acid treatment of oxygenated dihydro-2-benzylisoquinolines 9, 13 or reaction of 4-aryl-tetrahydroisoquinolines with formaldehyde / formic acid gave access to 8 (X = CH=CH). 14 An asymmetric synthesis of the dibenzo[c,f]-1-azabicyclo[3.3.1]nonane 8 (X = CH=CH) or related heterocyclic analogues 8 (X = N, S, O) skeleton has not been reported so far. One optically active member in this series was obtained by resolution of the corresponding racemate. 2 We report now the first synthesis of optically active [c,f]-dicondensed 1-azabicyclo[3.3.1]nonane 4 giving access to 5-hydroxy substituted compounds. Again a double-cyclization strategy was pursued. But unlike in the known syntheses using Friedel-Crafts methodology an activation of the aromatic ring by bromo-lithium exchange was employed now. Esters of natural amino acids 2 were dialkylated with obromo-bromomethyl hetarenes 1. 15 The resulting N,N-dialkylaminoesters 3 gave the 1-azabicyclo[3.3.1]nonane 4 in a straightforward manner after treatment with n-BuLi or t-BuLi. Double cyclization most probably proceeds by prior bromo-lithium exchange followed by attack of the ester moiety by the o-lithiated carbons of both heterocyclic substituents. 16 In a similar manner monocyclization has been reported before with N-monosubstituted amino esters 6 giving rise to the formation of condensed dihydropyridin-3-ones 7. 17 Compound 4e as a member of asymmetrically condensed 1-azabicyclo[3.3.1]nonanes 4 (X 1 ≠ X 2 ) could be obtained from the corresponding N-skatyl-N-thie...

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“…In independent work which appeared concurrently with publication of the cherylline isolation and structure deter mination, Bobbitt demonstrated a facile synthetic method for some phenolic 4-phenyltetrahydroisoquinolines (34) . The acid catalyzed cyclization of a substituted benzylaminoacetal, as shown by the example(XXIX), was followed by coupling with a phenol.…”

Section: Nchmentioning

confidence: 99%

Synthetic and biosynthetic approaches to cherylline and related compounds

Shaffer

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Synthesis of isoquinolines. XI. Dibenzo[c,f]-1-azabicyclo[3.3.1]nonanes and 4-phenyl-1,2,3,4-tetrahydroisoquinolines

Abstract: Notes 1181 Synthesis of Isoquinolines. XI. Dibenzo [c,/]-l-azabicyclo [3.3.1 jnonanes and 4-PhenyI-l,2,3,4-tetrahydroisoquinoIines1

Cited by 18 publications

References 2 publications

Double Cyclization of Bis(α‐hetarylmethyl)amino Esters to Optically Active Bridged N‐Heterocycles of HIV‐Inhibiting Activity

Double Cyclization of Bis(α‐hetarylmethyl)amino Esters to Optically Active Bridged N‐Heterocycles of HIV‐Inhibiting Activity

New β-Carboline Derivatives by Double-Cyclization of Chiral α-Heteroarylmethylamino Esters

Synthetic and biosynthetic approaches to cherylline and related compounds

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