Stereocontrolled synthesis of 2-aryl tetralones. Application in the synthesis of B/C hexahydrobenzo[c]phenanthridine alkaloids

Hexahydrobenzo[c]phenanthridines possessing a B/C cis ring junction have been synthesized in a stereoselective way starting from chiral non-racemic 2-aryl-tetralones prepared by asymmetric alkylation of (+)-(S,S)-pseudoephedrine based arylacetamide enolates with appropriately functionalized 2-aryl-1-iodoethane electrophiles. Subsequent transformations (intramolecular Friedel–Crafts acylation, stereocontrolled reductive amination and Pictet–Spengler cyclization) yielded the target heterocycles in good overall yields and in excellent stereoselectivities.     

An expeditious synthesis of hexahydrobenzo[f]isochromenes and of hexahydrobenzo[f]isoquinoline via iodine-catalyzed Prins and aza-Prins cyclization

Homoallylic alcohols (primary, secondary, or tertiary containing an endocyclic or an exocyclic double bond) react with equimolar amounts of aldehydes (aliphatic or aromatic) and ketones (aliphatic) in the presence of 5 mol % of iodine. This Prins cyclization was used in the preparation of hexahydrobenzo[f]isochromenes and of a 4-hydroxy-tetrahydropyran, in 54-81% yield. The procedure is also efficient for an aza-Prins cyclization of a homoallylic sulfonamide and benzaldehyde, producing a hexahydrobenzo[f]isoquinoline.     

“Golden” Cascade Cyclization to Benzo[c]-Phenanthridines

Herein, we describe a gold-catalyzed cascade cyclization of Boc-protected benzylamines bearing two tethered alkyne moieties in a domino reaction initiated by a 6-endo-dig cyclization. The reaction was screened intensively, and the scope was explored, resulting in nine new Boc-protected dihydrobenzo[c]phenanthridines with yields of up to 98 %; even a π-extension and two bidirectional approaches were successful. Furthermore, thermal cleavage of the Boc group and subsequent oxidation gave substituted benzo[c]phenanthridines in up to quantitative yields. Two bidirectional approaches under the optimized conditions were successful, and the resulting π-extended molecules were tested as organic semiconductors in organic thin-film transistors.     

Synthesis and physicochemical characterization of novel 6-aminopyrido[3,4-c][1,9]phenanthrolines as aza-analogs of benzo[c]phenanthridines

Based on the 6-aminobenzo[c]phenanthridines, a compound class showing noteworthy antitumor activity, an efficient one-step synthesis consisting of a base-catalyzed condensation of 2 equiv of 4-methylpyridine-3-carbonitrile and various aldehydes causing twofold ring closure is described. The obtained 6-amino-11,12-dihydropyrido[3,4-c][1,9]phenanthrolines could be aromatized with Pd/C at high temperatures to form 6-aminopyrido[3,4-c][1,9]phenanthrolines. All compounds were systematically characterized regarding both lipophilicity and solubility and a high cytotoxic potential was evaluated in preliminary in vitro studies. Compared to formerly described 6-aminobenzo[c]phenanthridines our newly developed phenanthrolines turned out to possess improved drugability, due to significantly increased water-solubility and decreased lipophilicity.     

Synthesis of enantiomerically pure inherently chiral calix[4]arenes using the meta-substitution strategy

A meta-substituted aminocalix[4]arene 4 immobilized in the cone conformation was prepared via mercuration of the starting tetra-propoxy derivative, followed by nitrosation and reduction reactions. Acylation of the amino group by chiral amino acid residues ((S)-N-trifluoroacetyl-Ala or (S)-N-trifluoroacetyl-Phe) allowed for the preparation of diastereomeric amides that were separated by preparative TLC on silica gel. Subsequent cyclization under Bischler-Napieralski reaction conditions yielded calixarenes 7b and 7c bearing an oxazole moiety in the meta position instead of the expected upper rim-bridged compounds. The reaction sequence represents a straightforward approach towards enantiomerically pure inherently chiral calix[4]arene derivatives (without HPLC separation steps). The absolute configuration of the enantiomers were confirmed by single crystal structure determination (X-ray).     

Synthesis of 5,6-dihydrobenz[c]acridines: a comparative study

5,6-Dihydrobenz[c]acridines were synthesized by the reaction of 1-chloro-3,4-dihydro-2-naphthaldehyde with aromatic amines under three different conditions:

a.

Thermolysis of 1-chlorovinyl-(N-aryl)imines prepared from 1-chloro-3,4-dihydro-2-naphthaldehyde.

b.

Acid catalyzed cyclization of 1-(N-aryl)amino-3,4-dihydro-2-naphthaldehydes.

c.

Thermolysis of N-arylenaminoimine hydrochlorides derived from 1-chloro-3,4-dihydro-2-naphthaldehyde in DMF medium.

All the three approaches exclusively yielded only 5,6-dihydrobenz[c]acridines and not the isomeric 7,8-dihydrobenzo[k]phenanthridines.The structures of these products have been unambiguously established by detailed NMR spectral study and by independent synthesis as well as by single crystal XRD study.     

Pd-catalyzed assembly of phenanthridines from aryl ketone O-acetyloximes and arynes through C–H bond activation

Pd-catalyzed annulation of aryne and aryl ketone O-acetyloxime via C–H bond activation was realized. Through the C–H bond activation/insertion/cyclization/elimination reaction sequence, phenanthridines are successfully constructed, providing an attractive strategy to approach substituted heterocycle without preactivation of starting materials.     

New approach for the synthesis of 3H-pyrrolo[2,3-c]isoquinoline derivatives

Synthesis of new 2,3-diaryl-3H-pyrrolo[2,3-c]isoquinoline derivatives has been elaborated starting from isoquinoline-3-amine. Buchwald–Hartwig arylation and subsequent iodination in position 4 afforded 3-arylamino-4-iodoisoquinolines. These compounds were subjected to Sonogashira cross-coupling reactions with some selected acetylenes, and the resulting coupled products underwent cyclization in the presence of tetrabutylammonium fluoride to give title derivatives.     

Studies on Quinazolines. Part III. Synthesis of Some Fused-Ring Cationic and Mesoionic Derivatives of the 1,3-Thiazolo[3,2-c]quinazoline Ring System

4-Allylthio-2-arylquinazolines 4a–c undergo cyclization by action of bromine to furnish 5-aryl-3-bromomethyl-2,3-dihydrothiazolo[3,2-c]quinazolin-4-ium bromide 5a–c. Compounds 5a–c undergo ring opening by action of water under acid catalysis to afford the corresponding dibromide derivatives 6a–c. Bromination of 3-allyl-2-aryl-4(3H)quinazolinethiones 7a–c leads to 5-aryl-2-bromomethyl-2,3-dihydrothiazolo[3,2-c]quinazolin-4-ium bromides 8a–c. However, 5-aryl-1,3-thiazolo[3,2-c]quinazolinium-3-olate 10a–c were prepared by the cyclodehydration of the corresponding thioglycolic acids 9a–c with Ac₂O.     

Synthesis of thio- and furan-fused heterocycles: furopyranone,furopyrrolone, and thienopyrrolone derivatives

We report herein the synthesis of a novel class of compounds, ethyl 4-oxo-4H-furo[3,2-c]pyran-6-yl carbonate, (7E)-7-[(dimethylamino)methylene]-4H-furo[3,2-c]pyran-4,6(7H)-dione, 5-oxo-N-phenyl-2,5-dihydro-4H-furo[3,2-b]pyrrole-4-carboxamide, and 5-oxo-N-phenyl-5,6-dihydro-4H-thieno[3,2-b]pyrrole-4-carboxamide starting from the corresponding acid derivatives. Intramolecular cyclization in the presence of thionyl chloride formed the target fused ring systems. Additional transformation was seen in the cyclization of furan-fused heterocycle. A mechanism was proposed based on experimental and computational findings.     

Synthesis of substituted 6H-benzo[c]chromenes: a palladium promoted ring closure of diazonium tetrafluoroborates

A highly efficient palladium-catalysed phenyl diazonium tetrafluoroborate participation of C–H activation ring closure protocol has been developed. A series of 6H-benzo[c]chromenes have been synthesized by intramolecular cyclization of ortho diazonium salts tetrafluoroborate of benzyloxyphenyl (Method A), or phenoxymethyl phenyl (Method B). The transformation allows the synthesis of 6H-benzo[c]chromenes with a wide variety of functional groups and substitution patterns from simple and easily accessible precursors.     

(Z)-Ethyl 2-phenyl-1-(2-vinylphenyl)vinylcarbamates. Part 1: Synthesis and preliminary studies on their divergent transformation into benzo[c]phenanthridines and 2-phenyl-1,4-naphthoquinones

Treatment of N-carbethoxy-1-benzylideneisoquinolines with LDA gives N-ethoxycarbonyl-1-amino-1-(2-vinylphenyl)-2-phenylethylenes, which can easily be transformed into N-carbethoxy-1-amino-2-phenylnaphthalenes. Bischler-Napieralski reaction of these latter compounds affords the corresponding benzo[c]phenanthridines, while their hydrolysis and subsequent oxidation constitutes a novel route to 2-phenyl-1,4-naphthoquinones.     

Enantioselective imine Michael reaction for the preparation of the (8′R,8a′S)-8,8a′-dimethyl-1′,3′,4′,7′,8′,8a′-hexahydrospiro[1,3-dioxolane-2,2′(6′H)naphthalen]-6′-one building block. A formal synthesis of (+)-valencenol

The enantioselective Michael addition of a chiral imine of 4-protected 2-methylcyclohexane-1,4-dione to phenyl crotonate led after cyclization to the corresponding bicyclic lactam. Reductive cleavage of the chiral moiety followed by saponification gave the corresponding keto-acid, which was cyclized to afford a lactone. Belleau–Fujimoto reaction of the lactone then led to the title building block (diastereoselectivity 96:4, e.e. >98%) in 11% overall yield from the starting dione. (8R,8aS)-(+)-8,8a-Dimethyl-3,4,6,7,8,8a-hexahydronaphthalen-2(1H)-one was obtained after reduction of the carbonyl group, acetylation, and reductive cleavage–deprotection (52% overall yield), representing a formal synthesis of (+)-valencenol.     

Synthesis of furo[2,3-c]-2,7-naphthyridine derivatives via domino heterocyclization reaction

2-Amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles were found to react with substituted oxiranes yielding 5,6-diamino-8-dialkylamino-1,2-dihydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitriles. The oxirane ring was shown to be opened selectively from the unsubstituted side and further cyclization occurred with participation of 3-CN, but not 5-CN of the starting pyridines. The furonaphthyridines obtained were converted into 2-dialkylamino-5-methyl-9,10-dihydro-4H-furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyridine-1-carbonitriles and 2-dialkylamino-5,6,9,10-tetrahydro-4H-spiro{furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyridine-5,1′-cyclohexane}-1-carbonitriles by treatment with acetic anhydride and cyclohexanone, respectively. The structure of prepared compounds was confirmed unambiguously by X-ray crystallographic study.     

Glabralides A – C,three novel meroterpenoids from Sarcandra glabra

Glabralides A–C (1–3), three novel meroterpenoids including two unprecedented skeletons were isolated from the whole plants of Sarcandra glabra. Glabralide A (1) represented a unique skeleton of the chalcone-coupled monoterpenoid, bearing a bicyclo [2.2.2] octene core unit with five chiral centers. The structures were established by spectroscopic methods, including 2D NMR experiments, and the absolute configurations were determined using circular dichroic (CD) spectra. The plausible biogenetic pathway for 1 suggested that α-phellandrene was conjugated with chalcone by Diels-Alder cyclization, and for 3 implied that α-phellandrene and o-hydroxy phenylacetate cyclized by an uncommon radical addition and cationic cyclization.     

A facile synthesis of 3-aryl pyroglutamic acid. Facile synthesis of baclofen and chlorpheg

A facile synthesis of 3-aryl pyroglutamic acids via stepwise [3+2] annulation and desulfonated hydrolysis is reported. Base-induced coupling/cyclization reactions of α-sulfonylacetamide with various β-functional groups of (Z)-2-bromoacrylates yielded three contiguous chiral centers on the polysubstituted pyroglutamates system with trans-trans orientation in a one-pot synthesis. This facile strategy was used to synthesize amino acid derivatives baclofen and chlorpheg.     

Cationic and mesoionic 1,3‐thiazolo‐[3,2‐c]quinazoline derivatives

4‐Allylthio‐2‐arylquinazolines 4a–c undergo cyclization by action of bromine to furnish 5‐aryl‐3‐bromomethyl‐2,3‐dihydrothiazolo[3,2‐c]quinazolin‐4‐ium bromides 5a–c . Compounds 5a–c undergo ring opening by action of water under acid catalysis to afford the corresponding dibromide derivatives 6a–c . Bromination of 3‐allyl‐2‐aryl‐4(3H)quinazolinethiones 7a–c leads to 5‐aryl‐2‐bromomethyl‐2,3‐dihydrothiazolo[3,2‐c]quinazolin‐4‐ium bromides 8a–c . However, anhydro‐3‐hydroxy‐5‐aryl‐1,3‐thiazolo[3,2‐c]quinazolin‐4‐ium hydroxide 10a–c were prepared by the cyclodehydration of the corresponding thioglycolic acids 9a–c with Ac₂O. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:576–580, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10148     

N-Aryl indole-derived C–N bond axially chiral phosphine ligands: synthesis and application in palladium-catalyzed asymmetric allylic alkylation

N-Aryl indole-derived C–N bond axially chiral phosphine ligands 2a–c were obtained by DDQ oxidation of N-aryl indoline-derived phosphine oxide followed by silane reduction. Resolution of C–N bond atropisomers was achieved by chiral HPLC. The investigation of the rotation barrier for the C–N bond axial stability of phosphines and the determination of the absolute configuration of 2c are described. Finally, the ability of the chiral ligand 2c was demonstrated in a palladium-catalyzed asymmetric allylic alkylation (up to 99% ee).     

Synthesis of (+)-(1S,2R) and (−)-(1R,2S)-2-aminocyclobutane-1-carboxylic acids

(+)-(1S,2R) and (−)-(1R,2S)-2-aminocyclobutane-1-carboxylic acids have been prepared in >97% ee and in 33% and 20% overall yields starting from a single, chiral, bicyclic compound perceived as a chiral uracil equivalent. Construction of the cyclobutane ring is achieved via a [2+2] photocycloaddition reaction of this chiral precursor with ethylene.     

Stereochemistry of the Diels–Alder reaction at high pressure: diastereo- and enantioselective [4+2]cycloaddition of buta-1,3-diene to glyoxylic acid derivatives catalysed by (salen) chromium(III) complexes

High-pressure [4+2]cycloadditions of buta-1,3-diene 1 to chiral 2a–c and achiral 7a–c glyoxylates, in the presence of (salen) chromium(III) complexes 5 and 6, were studied. The influence of such chiral Lewis acids on diastereoselectivity or enantioselectivity of the cycloaddition was investigated; a moderate asymmetric induction for both diastereo- and enantioselective variants of the cycloaddition was observed (up to 58% de and up to 71% ee, respectively).