Intramolecular Friedel-Crafts Cyclization Research Articles

Stereochemistry of N-Acyl-5H-dibenzo[b,d]azepin-7(6H)-ones.

The stereochemical properties of N-acyl-5H-dibenzo[b,d]azepin-7(6H)-ones (2a-c), which inhibit potassium channels in T cells, were examined by freezing their conformational change due to 4-methyl substitution. N-Acyl-5H-dibenzo[b,d]azepin-7(6H)-ones exist as pairs of enantiomers [(a1R, a2R), (a1S, a2S)], and each atropisomer is separable at room temperature. An alternate procedure for preparing 5H-dibenzo[b,d]azepin-7(6H)-ones involves the intramolecular Friedel-Crafts cyclization of N-benzyloxycarbonylated biaryl amino acids. Consequently, the N-benzyloxy group was removed during the cyclization reaction to produce 5H-dibenzo[b,d]azepin-7(6H)-ones suitable for the subsequent N-acylation reaction.

A Tandem Prins/Friedel‐Crafts Cyclization Strategy for the Stereoselective Synthesis of Hexahydro‐2H‐benzo[g]chromenes

AbstractA tandem Prins/Friedel‐Crafts cascade strategy has been developed for the synthesis of hexahydro‐2H‐benzo[g]chromene derivatives. Under action of equimolecular amount of BF3 etherate, δ,ϵ‐unsaturated alcohols and arylacetaldehydes are coupled to form oxocarbenium ion intermediates, which are captured by the alkene moiety through a favored six‐membered transition state. The Prins‐cyclization resultant tertiary carbenium ions undergo consecutive intramolecular Friedel–Crafts cyclization to create the tricyclic products. This process enables a tandem formation of three new chemical bonds in one single operation with high yields and stereoselectivity in most cases. When cyclic substituents are involved, a variety of spiro derivatives could also be synthesized successfully, which further proved the robustness of this methodology.

Facile and innovative catalytic protocol for intramolecular Friedel-Crafts cyclization of Morita-Baylis-Hillman adducts: Synergistic combination of chiral (salen)chromium(III)/BF3·OEt2 catalysis.

The chiral (salen)Cr(III)/BF3·OEt2 catalytic combination was found to be an effective catalyst for intramolecular Friedel–Crafts cyclization of electron-deficient Morita–Baylis–Hillman adducts. In presence of mild reaction conditions the chiral (salen)Cr(III)/BF3·OEt2 complex affords 2-substituted-1H-indenes from unique substrates of Morita–Baylis–Hillman adducts via an easy operating practical procedure.

Thiopyrylium Scaffolds from the Lewis/Brønsted-Acid-Promoted Cyclization of Thioethers.

A series of acene- or heteroacene-fused thiopyrylium salts was synthesized from diarylthioethers that contain formyl groups via an intramolecular Friedel-Crafts cyclization. The reaction, promoted by a Lewis or Brønsted acid, afforded the new thiopyrylium salts in good yield. Kinetic investigations and density functional theory calculations were used to explore the mechanism of the reaction. The electronic structures of the thiopyrylium salts were examined by UV-vis absorption spectroscopy, which afforded insight into the electronic transitions within these molecules.

Synthesis and Properties of Thiophene-Fused Thiopyrylium Salts.

A new family of thiophene-fused thiopyrylium salts has been synthesized via Lewis-acid-induced Rieche formylation, followed by an intramolecular Friedel-Crafts cyclization of a series of diarylthioethers. Moreover, in the case of diarylthioethers that bear formyl groups, Lewis-acid-promoted intramolecular cyclizations afforded novel thiophene-fused bisthiopyrylium salts in good yield. The electronic structures of the new compounds were determined experimentally by NMR and UV-vis absorption spectroscopy and theoretically investigated by density functional theory calculations. The results of our examinations revealed effective conjugation of the π-electrons over the entire linearly fused heteroacene framework.

Total Synthesis of the Plant Growth Promoter Auxofuran Featuring a Gold(I) Catalyzed Furan Formation.

A concise synthesis of auxofuran (1) was developed. Starting with a Sonogashira cross-coupling reaction, enynol (10) was prepared. A gold(I) catalyzed cycloisomerization led to disubstituted furan 12. Via an intramolecular Friedel-Crafts cyclization, a dihydrobenzofuranone was obtained. Functional group manipulations, including benzylic oxidation, led to the target molecule.

Synthesis of 4-Vinyl-1,2,3,4-tetrahydroisoquinoline from N-Tethered Benzyl-Alkenol Catalyzed by Indium(III) Chloride: Formal Synthesis of (±)-Isocyclocelabenzine

An intramolecular Friedel–Crafts cyclization reaction catalyzed by indium(III) chloride for the formation of 4-vinyl-1,2,3,4-tetrahydroisoquinoline from N-tethered benzyl-alkenol in good yields has been described. The reaction is highly regioselective and generates an exocyclic vinyl functionality in the piperidine ring. The reaction is compatible with a wide range of functional groups. The strategy is demonstrated for the formal synthesis of (±)-isocyclocelabenzine alkaloid.

Enantioselective Formal Total Synthesis of (-)-Quinagolide.

The enantioselective formal total synthesis of (-)-quinagolide has been accomplished in a linear sequence of 8 purification steps from pyridine. The key steps are (a) organocatalyzed Diels-Alder reaction for fixing all three stereocenters on piperidine ring; (b) protecting group enabled deoxygenation of isoquinuclidine skeleton under Birch reduction condition; (c) Lewis acid (TiCl4) catalyzed intramolecular Friedel-Crafts cyclization of dicarboxylic acid; and (d) one-pot diastereoselective ketone reduction-intramolecular cyclization to form oxazolidinone which enables trans-geometry installation. During the course of the synthesis, an interesting reductive cleavage of the C-N bond in the electron-deficient isoquinuclidine skeleton under the Birch reduction conditions has been observed. This is the first synthetic effort to access the core skeleton of (-)-quinagolide.

B(C <sub>6</sub>F>sub>5) <sub>3</sub>-Catalyzed C(Sp <sup>3</sup>)-F Bond Activation With/Without the Cooperation of HFIP: Synthesis of Spirobiindanes, Monofluoroalkenes, and Indane Derivatives

The activation of C(sp3)-F bond in saturated fluorocarbons, especially for aliphatic gem-difluoroalkanes, remains challenging and less reported. Herein, we describe the selective activation of inert C(sp3)-F bonds catalyzed by B(C6F5)3. In hexafluoro-2-propanol (HFIP), chemically robust aliphatic gem-difluorides are converted in high yields to the corresponding substituted 2,2',3,3'-tetrahydro-1,1'-spirobiindenes via a B(C6F5)3-catalyzed intramolecular cascade Friedel-Crafts cyclization, whereby a silicon-based trapping reagent is not required. However, in the absence of a hydrogen-bonding donor solvent such as HFIP, the aliphatic gem-difluorides preferentially engage in a defluorination/elimination process that provides monofluorinated alkenes in good yields. In addition, a series of substituted 1-alkyl-2,3-dihydro-1H-indenes was obtained in high yield from the B(C6F5)3-catalyzed defluorinative cyclization of aliphatic secondary monofluorides in HFIP. The protocol could inspire the development of a new class of main-group Lewis acids-catalyzed C(sp3)-F bond activation in general unactivated fluorocarbons.

Total Synthesis of (−)‐Daphenylline

AbstractA concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (−)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO4)2‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (−)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.

Total Synthesis of (−)‐Daphenylline

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (-)-daphenylline has been accomplished. The synthesis was started from (S)-carvone and proceeded via a stereoselective Mg(ClO4 )2 -catalyzed intramolecular amide addition cyclization, an intramolecular Diels-Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel-Crafts cyclization. The total synthesis of (-)-daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.

Acid-catalyzed chirality-transferring intramolecular Friedel-Crafts cyclization of α-hydroxy-α-alkenylsilanes.

Acid-catalyzed intramolecular Friedel-Crafts cyclization of optically active α-hydroxy-α-alkenylsilanes possessing a benzene ring (>99% ee) with TMSOTf as a Lewis acid gave enantio-enriched tetrahydronaphthalenes (up to 98% ee). The silyl group attached to the chiral carbon played a crucial role in the chirality transfer.

Construction of polycyclic bridged indene derivatives by a tandem 1,3-rearrangement/intramolecular Friedel-Crafts cyclization of propargyl acetates.

An unprecedented Lewis acid-catalyzed cascade 1,3-rearrangement/Friedel-Crafts cyclization of propargyl acetates is developed for the construction of polycyclic bridged indene derivatives in moderate to good yields. This practical procedure features mild conditions, broad substrate scope, and easy operation.

Synthesis of new thioxanthenes by organocatalytic intramolecular Friedel–Crafts reaction

An efficient organocatalytic route has been developed to synthesize novel substituted thioxanthenes (2a–2v) starting from diaryl thioether alcohols (1a–1v) using the intramolecular Friedel–Crafts reaction. The starting materials were obtained in two stages via a coupling reaction followed by the Grignard reaction. In this study, we tried for the first time to use some organic Brønsted acids as organocatalysts (3a–3h) in the intramolecular Friedel–Crafts cyclization reaction of thioether alcohols. The synthesis of original substituted thioxanthenes was achieved within 15 minutes by using N-triflylphosphoramide (3h) with quantitative yields in THF at room temperature.

A Total Synthesis of (-)-Hamigeran B and (-)-4-Bromohamigeran B.

A concise synthesis of (-)-hamigeran B and (-)-4-bromohamigeran B is presented. The key reactions include a Suzuki coupling of enol triflate 15 with arylboronic ester for efficient synthesis of the densely 1,2,3-trisubstituted cyclopentene 23, a coordination-controlled intramolecular Friedel-Crafts cyclization of free phenol 13 for highly regioselective construction of tricyclic core 12, and a LiOH/O2-promoted hydrolysis and concomitant aerobic oxidation of 31 for atom- and step-economic accessing of diketone 32. The application of these key transformations allowed for a rapid and efficient synthesis of (-)-hamigeran B and (-)-4-bromohamigeran B in 13 steps from the readily available chiral material 18.

Convenient synthesis of 12-methyl[1]benzoxepino[3,4-b]quinolin-13(6H)-ones

In this work, a construction of 12-methyl[1]benzoxepino[3,4-b]quinolin-13(6H)-ones, structurally intriguing hybrid molecules consisting of fused 4-methylquinoline and 1-benzoxepin-5-one units, has been successfully achieved via a two-step procedure, involving the onepot synthesis of 2-(aryloxymethyl)-4-methylquinoline-3-carboxylic acids followed by their intramolecular Friedel–Crafts cyclization reaction. Our synthetic protocol described here could be attractive as it is simple, easy to handle and does not involve the use of expensive reagents or catalysts.

The first synthesis of biatriosporin D

Biatriosporin D was synthesized in six steps from 3,5-dimethoxyphenol. The key step was an intramolecular Friedel-Crafts cyclization of an acyl imidazolide to form an ortho-quinone.

A concise, efficient and versatile synthesis of amino-substituted benzo[b]pyrimido[5,4-f]azepines: synthesis and spectroscopic characterization, together with the molecular and supramolecular structures of three products and one intermediate.

A concise, efficient and versatile synthesis of amino-substituted benzo[b]pyrimido[5,4-f]azepines is described: starting from a 5-allyl-4,6-dichloropyrimidine, the synthesis involves base-catalysed aminolysis followed by intramolecular Friedel-Crafts cyclization. Four new amino-substituted benzo[b]pyrimido[5,4-f]azepines are reported, and all the products and reaction intermediates have been fully characterized by IR, 1H and 13C NMR spectroscopy and mass spectrometry, and the molecular and supramolecular structures of three products and one intermediate have been determined. In each of N,2,6,11-tetramethyl-N-phenyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepin-4-amine, C22H24N5, (III), 4-(1H-benzo[d]imidazol-1-yl)-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, which crystallizes as a 0.374-hydrate, C21H19N5·0.374H2O, (VIIIa), and 6,7,9,11-tetramethyl-4-(5-methyl-1H-benzo[d]imidazol-1-yl)-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, C24H25N5, (VIIIc), the azepine ring adopts a boat conformation, but with a different configuration at the stereogenic centre in (VIIIc), as compared with (III) and (VIIIa). In the intermediate 5-allyl-6-(1H-benzo[d]imidazol-1-yl)-N-methyl-N-(4-methylphenyl)pyrimidin-4-amine, C22N21N5, (VIIb), the immediate precursor of 4-(1H-benzo[d]imidazol-1-yl)-6,8,11-trimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, (VIIIb), the allyl group is disordered over two sets of atomic sites having occupancies of 0.688 (5) and 0.312 (5). The molecules of (III) are linked into chains by a C-H...π(pyrimidine) hydrogen bond, and those of (VIIb) are linked into complex sheets by three hydrogen bonds, one of the C-H...N type and two of C-H...π(arene) type. The molecules of the organic component in (VIIIa) are linked into a chain of rings by two C-H...π(arene) hydrogen bonds, and these chains are linked into sheets by the water components; a single weak C-H...N hydrogen bond links molecules of (VIIIc) into centrosymmetric R22(10) dimers. Comparisons are made with some related compounds.

An unexpected thermal-ring-rearrangement of benzochromenes to inden-3-yl-naphthols with pTsOH.

Described here is the first report of an unexpected thermal-ring rearrangement (TRR) of benzochromenes to indene derivatives promoted by pTsOH. This cascade ring-rearrangement proceeds through the protonation of benzochromenes by an acid catalyst followed by ring-opening and ring-closure by an intramolecular Friedel-Crafts cyclization to provide a new bicyclic framework, inden-3-yl-naphthols bearing a quaternary center, which also exhibited atropisomerism. Regioselectivity, broad substrate scope, high yields, solvent-free conditions and atom economy are the additional high points of this ring-rearrangement.

Total synthesis of natural spiro-trisindole enantiomers similisines A, B and their stereoisomers

The first total synthesis of similisines A and B, a pair of unprecedented polybrominated spiro-trisindole enantiomers isolated from Laurencia similis, and their all stereoisomers had been accomplished in 6 steps from the known 5,6-dibromoindole. The described synthesis avoided any protecting-group manipulations, and the key all-carbon spirocenters were constructed via an intramolecular Friedel-Crafts cyclization. In addition, the rotamers of similisines and cytotoxic and NO production inhibitory activities of synthetic compounds were also discussed.