A synthesis of 3-phenyl-1,2,3,4-tetrahydroisoquinoline and 2-phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine via Pummerer-type cyclization: enhancing effect of boron trifluoride diethyl etherate on the cyclization

A synthesis of 6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline (14a) and 7,8-dimethoxy-2-phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine (14b) was achieved via the cyclization of N-(3,4-dimethoxyphenyl)methyl-1-phenyl-2-(phenylsulfinyl)ethylformamide (6a) and N-2-(3,4-dimethoxyphenyl)ethyl-1-phenyl-2-(phenylsulfinyl)-ethylformamide (6b) using the Pummerer reaction as a key step, respectively. The Pummerer reaction of 6a,b under usual conditions using trifluoroacetic anhydride yielded the vinyl sulfides (8a, b), non-cyclized products, as a major product. The cyclization proceeded when boron trifluoride diethyl etherate was used as an additive reagent, thus giving rise to the corresponding cyclized products (7a) and (7b) in moderate yields. We propose that the enhancing effect of the Lewis acid on the cyclization may be attributable to the involvement of a dicationic intermediate, sulfonium-carbenium dication (23).     

Super acid-induced Pummerer-type cyclization reaction: improvement in the synthesis of chiral 1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines

Improved synthesis of four stereoisomeric chiral 1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines (1a, b, ent-1a, b) was achieved via the super acid-induced cyclization of chiral N-[1-methyl-2-(phenylsulfinyl)ethyl]-N-(1-phenylethyl)formamides (4a, b, ent-4a, b) using the Pummerer-type cyclization reaction as a key step. The cyclization leading to the isoquinoline ring proceeded in a quantitative manner when trifluoromethane sulfonic acid (TFSA) was used as the super acid, although Friedel-Crafts-type alkylation of 4-phenylsulfanyl TIQ derivatives (5) with benzene used as the solvent accompanied cyclization to yield the 4-phenyl-TIQs (7). The byproduct (7) was exclusively formed when a large excess amount of TFSA was used.     

A new cyclization to fused pyrazoles tunable for pericyclic or pseudopericyclic route: an experimental and theoretical study

2-Pyrazinyl (2) and 3-pyridazinylketone arylhydrazones (6) and their benzologues undergo a ring closure reaction to yield pyrazolo[3,4- b]pyrazines (4) and pyrazolo[4,3- c]pyridazines (7), respectively, in acceptable to good yields. The reaction was found to be accelerated by using acidic or basic conditions. Quantum chemical calculations suggest the key step of the mechanism to be a direct cyclization; analysis of aromaticity based on computed magnetic properties revealed its medium-dependent pericyclic or pseudopericyclic character. The cyclization reaction has also been extended for the synthesis of related ring systems ( 9, 12, 14).     

A study of vinyl radical cyclization using N-alkenyl-7-bromo-substituted hexahydroindolinones

A new method for the synthesis of the octahydropyrrolo[3,2,1-ij]quinoline ring system that possesses the characteristic skeleton of the aspidosperma family of alkaloids has been developed. The method utilizes an intramolecular Diels-Alder reaction of an amido-substituted furan across a tethered indole pi-bond. To apply this strategy to the synthesis of the indole alkaloid spegazzinidine, it was necessary to address the problem of assembling the final D-ring of the pentacyclic skeleton. Radical cyclization of a model N-allyl-7-bromo-3a-methylhexahydroindolinone system was found to preferentially lead to the 6-endo-trig cyclization product, with the best yield being obtained under high dilution conditions. The six-membered cyclized product is generated through two reaction pathways: (a) 6-endo-trig ring closure and (b) rearrangement of an intermediate methylene-cyclopentyl radical obtained by 5-exo-trig cyclization. A number of related 7-bromo-substituted hexahydroindolinones containing tethered olefinic groups were prepared and found to undergo efficient cyclization under both radical and palladium-mediated reaction conditions. Vinyl radical cyclization with several N-butenyl-substituted systems afforded a mixture of 6-exo and 7-endo cyclization products. A protocol to introduce an ethyl substituent into the C20-position of the aspidospermidine skeleton was also developed.     

Electrophilic chemistry of thia-PAHs: stable carbocations (NMR and DFT), S-alkylated onium salts, model electrophilic substitutions (nitration and bromination), and mutagenicity assay

First examples of stable carbocations are reported from several classes of thia-PAHs with four fused rings, namely, benzo[b]naphtho[2,1-d]thiophene (1) and its 3-methoxy derivative (2), phenanthro[4,3-b]thiophene (3) and its 7-methoxy (4), 10-methoxy (5), and 9-methoxy (6) derivatives, phenanthro[3,4-b]thiophene (7) and its 7-methoxy (8) and 9-methoxy (9) derivatives, and 3-methoxybenzo[b]naphtha[1,2-d]thiophene (11). In several cases, the resulting carbocations were also studied by GIAO-DFT. Charge delocalization modes in the resulting carbocations were probed. A series of S-alkylated onium tetrafluoroborates, namely, 1Me+, 1Et+, 2Et+, and 7Me+ (from 1, 2, and 7), 10Me+ and 10Et+ (from benzo[b]naphtha[1,2-d]thiophene 10), 12Me+ and 12Et+ (from phenanthro[3,2-b][1]benzothiophene 12), 13Me+ (from 3-methoxyphenanthro[3,2-b]benzothiophene 13), 14Me+ (from phenanthro[4,3-b][1]benzothiophene 14), and 15Me+ (from 3-methoxyphenanthro[4,3-b][1]benzothiophene 15), were synthesized. PAH-sulfonium salts 1Me+, 1Et+, 10Me+, 10Et+, 12Me+, and 14Me+ proved to be efficient akylating agents toward model nitrogen nucleophile receptors (imidazole and azaindole). Facile transalkylation to model nucleophiles (including guanine) is also supported by favorable reaction energies computed by DFT. Ring opening energies in thia-PAH-epoxides from 1, 3, and 7 and charge delocalization modes in the resulting carbocations were also evaluated. The four-ring-fused thia-PAHs 1, 2, 3, 4, 5, 7, 8, and 11 are effectively nitrated under extremely mild conditions. Nitration regioselectivity corresponds closely to protonation under stable ion conditions. Bromination of 4 and 6 is also reported. Comparative mutagenicity assays (Ames test) were performed on 1 versus 1NO2, 5 versus 5NO2, and 11 versus 11NO2. Compound 5NO2 was found to be a potent direct acting mutagen.     

Reactions of Aromatic S‐ and O‐Enynes with Two Methyl Substituents on the Olefinic Unit Assisted by a Ruthenium Complex: Tandem Cyclization and Product Selectivity

Ruthenium‐assisted cyclizations of two enynes, HC≡CCH(OH)(C₆H₄)X? CH₂CH?CMe₂ (X=S ( 1a ), O ( 1b )), each of which contains two terminal methyl substituents on the olefinic parts, are explored. The reaction of 1a in CH₂Cl₂ gives the vinylidene complex 2a from the first cyclization and two side products, 3a and the carbene complex 4a with a benzothiophene ligand. The same reaction in the presence of HBF₄ affords 4a exclusively. Air oxidation of 4a in the presence of Et₃N readily gives an aldehyde product. In MeOH, tandem cyclizations of 1a generate a mixture of the benzothiochromene compound 10a and the carbene complex 7a also with a benzothiochromene ligand. First, cyclization of 1b likewise proceeds in CH₂Cl₂ to give 2b . Tandem cyclization of 1b in MeOH yields comparable products 10b and 7b with benzochromene moieties, yet with no other side product. The reaction of [Ru]Cl with HC≡CCH(OH)(C₆H₄)S? CH₂CH?CH₂ ( 1c ), which contains no methyl substituent in the olefinic part, in MeOH gives the carbene complex 15c with an unsubstituted thiochromene by means of a C? S bond formation. Structures of 3a and 15c are confirmed by X‐ray diffraction analysis. The presence of methyl groups of enynes 1a and 1b promotes sequential cyclization reactions that involve C? C bond formation through carbocationic species.     

Proposed mechanism for the reaction catalyzed by a diterpene cyclase,aphidicolan-16beta-ol synthase: experimental results on biomimetic cyclization and examination of the cyclization pathway by ab initio calculations

To examine the mechanism of the cyclization reaction catalyzed by aphidicolan-16beta-ol synthase (ACS), which is a key enzyme in the biosynthesis of diterpene aphidicolin, a specific inhibitor of DNA polymerase alpha, skeletal rearrangement of 2a and biomimetic cyclization of 4b were employed. The structures of the reaction products, which reflect penultimate cation intermediates, allowed us to propose a detailed reaction pathway for the Lewis acid-catalyzed cyclizations and rearrangements. Isolation of these products in an aphidicolin-producing fungus led us to speculate that the mechanism of the ACS-catalyzed cyclization reaction is the same as that of a nonenzymatic reaction. Ab initio calculations of the acid-catalyzed reaction intermediates and the transition states indicate that the overall reaction catalyzed by ACS is an exothermic process though the reaction proceeds via an energetically disfavored secondary cation-like transition state. In conjunction with the solvent effect in the acid-catalyzed reactions, this indicates that the actual role of ACS is to provide a template which enforces conformations of the intermediate cations leading to the productive cyclization although it has been believed that the cation-pi interaction between cation intermediates and aromatic amino acid residues in the active site is important for the enzymatic catalysis. This study provided important information on the role of various cationic species, especially secondary cation-like structures, in both nonenzymatic and enzymatic reactions.     

Thermal C1-C5 diradical cyclization of enediynes

Computational studies at the BLYP/6-31G(d) level (supplemented by BCCD(T)/cc-pVDZ calculations) suggest that in aryl-substituted 1,2-diethynylbenzenes, steric effects disfavor the thermal C1-C6 diradical cyclization reaction (Bergman) and electronic effects favor the regiovariant C1-C5 cyclization to the extent that the C1-C5 process should become an important reaction pathway in the thermolyses of such compounds. Experimentally, thermolyses of 1,2-bis(2,4,6-trichlorophenylethynyl)benzene, a particularly favorable case, yields only products derived from C1-C5 cyclization [specifically, 1-(2,4,6-trichlorobenzylidene)-2-(2,4,6-trichlorophenyl)-1H-indene and its hydrogenation product 3-(2,4,6-trichlorobenzyl)-2-(2,4,6-trichlorophenyl)-1H-indene], and even for the parent hydrocarbon 1,2-bis(phenylethynyl)benzene, the formation of C1-C5 cyclization products is competitive with the major Bergman reaction. Although some C1-C5 cyclization products are probably formed by transfer hydrogenation from 1,4-cyclohexadiene (commonly included in such reactions), thermolyses in the absence of 1,4-CHD as well as deuterium labeling studies confirm the existence of direct C1-C5 diradical cyclizations for diaryl-substituted enediynes.     

Photoreaction of 2-halo-N-pyridinylbenzamide: intramolecular cyclization mechanism of phenyl radical assisted with n-complexation of chlorine radical

The photochemical behavior of 2-halo-N-pyridinylbenzamide (1-4 in Chart 1) was studied. The photoreaction of 2-chloro-N-pyridinylbenzamides 1a, 2a, 3a, and 4 afforded photocyclized products, benzo[c]naphthyridinones (6-9 and 16), in high yield, whereas the bromo analogues 1b, 2b, and 3b produced extensively photoreduced products, N-pyridinylbenzamides (1c, 10, and 11), with minor photocyclized product. Since the photocyclization reaction of 2-chloro-N-pyridinylbenzamide is retarded by the presence of oxygen and sensitized by the presence of a triplet sensitizer, acetone or acetophenone, a triplet state of the chloro analogue is involved in the reaction. Since several radical intermediates, particularly n-complexes of chlorine radical, are identified in the laser flash photolysis of 2-chloro-N-pyridinylbenzamide, an intramolecular cyclization mechanism of phenyl radical assisted with n-complexation of chlorine radical for the cyclization reaction is proposed: the triplet state (78 kcal/mol) of the chloro analogue (1a), which is populated by the excitation of 1a undergoes a homolytic cleavage of the C-Cl bond to give phenyl and chlorine radicals; while chlorine radical holds the neighbor pyridinyl ring with its n-complexation, the intramolecular arylation of the phenyl radical with the pyridinyl ring proceeds to produce a conjugated 2,3-dihydropyridinyl radical and then the conjugated radical aromatizes to afford a cyclized product, benzo[c]naphthyridinone by ejecting a hydrogen. The photoreduction product can be formed by hydrogen atom abstraction of the phenyl sigma radical from the environment.     

多氟芳烃的亲核反应II: 一氯五氟苯的亲核环化

本文报道一氯五氟苯与双官能团亲核试剂反应制备环化产物的研究结果, 发现应用NaH-DMF体系制备醇钠, 有利于亲核反应的顺利进行, 环化产物产率有较大幅度提高.     

Extending Pummerer reaction chemistry. Application to the oxidative cyclization of indole derivatives

Treatment of 2-(phenylsulfinyl)indoles bearing a pendant nucleophile at C(3) with Tf(2)O/lutidine triggers a Pummerer-like cyclization to furnish 3,3-spirocyclic-2-(phenylthio)indolenine products, which can, in turn, be hydrolyzed to 3,3-spirocyclic oxindoles. [reaction: see text]     

"Dimers" and "trimers" of tetrahydroindenes and hexahydroazulenes, respectively generated from [2-(1-cycloalkenyl)ethynyl]carbene complexes (M = W, Cr) by cascade cyclization/cycloaddition reactions

A cascade of cyclization/cycloaddition reactions was triggered by addition of protic oxygen nucleophiles ROH 2 (RO = CH3CO2, PhCO2, PhO) to [2-(1-cyclohexenyl)ethynyl]carbene complexes 1b and 1c (M=W, Cr, respectively), affording highly strained "dimers" 11/11' and "trimers" 12 of the carbene ligand. The first reaction step involved the formation of 1-metalla1,3,5-hexatrienes 7, which readily gave tetrahydroindenes 8 by pi cyclization and extrusion of the metal unit. "Dimers" 11/11' were generated from tetrahydroindenes 8 by a highly exo selective [4+2] cycloaddition of compounds 1b and 1c to afford 1-metalla-1,3,5-hexatriene intermediates 9, and a spontaneous pi cyclization of the latter compounds involving the disengagement of the metal unit. Propenylidene cyclohexenes 13/13' were formed in "ene"-type side reactions to the pi cyclization of 1-metalla-1,3,5-hexatrienes 7, by loss of the metal unit. "Dimers" 11 were transformed into "trimers" 12 by a [4+2] cycloaddition and subsequent pi-cyclization of the resulting 1-metalla-1,3,5-hexatriene system. The course of the reaction was elucidated by means of model reactions with (2-phenylethynyl)carbene complex 14, in which 1-metalla-1,3,5-hexatriene intermediates 16 and 17 were isolated and characterized. Alkynyl benzene derivatives 19 were obtained by an unprecedented ring-expansion of a cyclopentadiene unit of "dimers" 11a and 11c, involving the insertion of a carbene carbon atom of compound 14 into a C=C bond. A reaction cascade leading to "dimers" 24/24' could also be triggered by treatment of compounds 2 with [2-(1-cycloheptenyl)ethynyl]carbene tungsten complex 1d.     

Highly enantioselective reductive cyclization of acetylenic aldehydes via rhodium catalyzed asymmetric hydrogenation

Catalytic hydrogenation of acetylenic aldehydes 1a-12a using chirally modified cationic rhodium catalysts enables highly enantioselective reductive cyclization to afford cyclic allylic alcohols 1b-12b. Using an achiral hydrogenation catalyst, the chiral racemic acetylenic aldehydes 13a-15a engage in highly syn-diastereoselective reductive cyclizations to afford cyclic allylic alcohols 13b-15b. Ozonolysis of cyclization products 7b and 9b allows access to optically enriched alpha-hydroxy ketones 7c and 9c. Reductive cyclization of enyne 7a under a deuterium atmosphere provides the monodeuterated product deuterio-7b, consistent with a catalytic mechanism involving alkyne-carbonyl oxidative coupling followed by hydrogenolytic cleavage of the resulting oxametallacycle. These hydrogen-mediated transformations represent the first examples of the enantioselective reductive cyclization of acetylenic aldehydes.     

OCO and NCO chelated derivatives of heavier group 15 elements. Study on possibility of cyclization reaction via intramolecular ether bond cleavage

A set of four pincer ligands, either the OCO type ligands L(1-3) [2,6-(ROCH(2))(2)C(6)H(3)](-), where R = Me (L(1)), mesityl (L(2)), t-Bu (L(3)) or novel NCO ligand [2-(Me(2)NCH(2))-6-(t-BuOCH(2))C(6)H(3)](-) was studied. The reaction of L(4)Li with PCl(3) resulted in isolation of [2-(OCH(2))-6-(Me(2)NCH(2))C(6)H(3)]PCl (1) as a result of intramolecular ether bond cleavage and elimination of t-BuCl. The conversion between the organolithium compounds L(1,2,4)Li and AsCl(3) led to the desired chlorides, i.e. (L(1))(2)AsCl (2), L(2)AsCl(2) (3), L(4)AsCl(2) (5), but an analogous reaction using the L(3)Li compound gave [2-(OCH(2))-6-(t-BuOCH(2))C(6)H(3)]AsCl (4) as a result of intramolecular cyclization. The organoantimony chloride L(3)SbCl(2) was shown to undergo very slow cyclization in CDCl(3) again via elimination of t-BuCl giving [2-(OCH(2))-6-(t-BuOCH(2))C(6)H(3)]SbCl (6) and it was demonstrated that this reaction may be accelerated by preparation of L(3)Sb(Cl)(OTf) (7) with more Lewis acidic central atom. On the contrary, both antimony derivatives of the NCO ligand L(4), not only the chloride L(4)SbCl(2) (8) but also the ionic pair containing highly Lewis acidic cation [L(4)SbCl](+)[CB(11)H(12)](-) (9), are stable without any indication for etheral bond cleavage. The situation is rather similar in the case of organobismuth derivatives of L(4), which allowed isolation of compounds L(4)BiCl(2) (10), L(4)Bi(Cl)(OTf) (11) and [L(4)BiCl](+)[CB(11)H(12)](-) (12). All studied compounds were characterized by the help of (1)H and (13)C NMR spectroscopy, ESI mass spectrometry, elemental analysis and (except 1) by single-crystal X-ray diffraction.     

Novel phosphine-catalyzed zipper cyclization of aliphatic diyne-dione and yne-dione systems

[reaction: see text] An unexpected tri-n-butylphosphine-catalyzed zipper cyclization of diyne[bond]diones (1a-d) or yne-diones (1e and 1f) is described. Bicyclic ketones (2a, 2b, 2c, 2e, and 2f) with five- or six-membered rings fused to the five-membered ring were obtained from both aliphatic diyne-diones (1a-c) and yne-diones (1e and 1f) having tetra- or pentamethylene spacers. The bicyclic products (2) were produced with high diastereoselectivity.     

Remarkable control of radical cyclization processes of cyclic enyne: total syntheses of (+/-)-methyl gummiferolate, (+/-)-methyl 7beta-hydroxykaurenoate, and (+/-)-methyl 7-oxokaurenoate and formal synthesis of (+/-)-gibberellin a(12) from a common synthetic precursor.

Total syntheses of (+/-)-methyl gummiferolate (13b), (+/-)-methyl 7beta-hydroxykaurenoate (14b), and (+/-)-methyl 7-oxokaurenoate (14d) and a formal synthesis of (+/-)-gibberellin A(12) (15) have been accomplished through the common synthetic precursor, (3aR,7aR)-3,3-dimethyl-7a-(2-propynyl)-3a,4,7,7a-tetrahydroisobenzofuranone (16). The homoallyl-homoallyl radical rearrangement reaction of the monocyclic enyne 25, derived from 16 in two steps, afforded the bicyclo[2.2.2]octane compound 26, which was converted to (+/-)-methyl gummiferolate (13b). In contrast, the radical cyclization of the bicyclic enyne 16 gave the tricyclic lactone 19, leading to (+/-)-methyl 7beta-hydroxykaurenoate (14b) and (+/-)-methyl 7-oxokaurenoate (14d). Transformation of 14d into lactone 20 was carried out in a single step under bromination conditions. This constitutes a formal total synthesis of gibberellin A(12) (15).     

Electrophilic-induced cyclization reaction of hexahydroindolinone derivatives and its application toward the synthesis of (+/-)-erysotramidine

A convenient synthesis of variously substituted octahydroindolo[7a,1a]-isoquinolinones has been achieved by an acid-induced cyclization of hexahydroindolinones bearing tethered phenethyl groups. The formation of a single lactam diastereomer is the result of the stereoelectronic preference for axial attack by the aromatic ring onto the initially formed N-acyliminium ion from the least hindered side. Additional experiments showed that a variety of hexahydroindolinones containing tethered pi-bonds undergo a related acid-induced cyclization reaction. Treatment of the 3-methylbut-3-enyl-substituted hexahydroindolinone with acid furnished a 3:1 mixture of isomeric octahydropyrido[2,1-i]indolinones in near-quantitative yield. Interestingly, cyclization of the closely related 1-(3-methoxybut-3-enyl)-substituted hexahydroindolin-one afforded a pyrrolo[3,2,1-ij]quinolinone as the exclusive product. With this system, initial protonation takes place on the more nucleophilic enol ether pi-bond and the resulting carbonium ion undergoes a subsequent cyclization with the enamido pi-bond to give the observed product. The electrophilic promoted cyclizations were extended to include the related hexahydro[1]pyrindinone and 1H-quinolinone systems. An NBS-promoted intramolecular electrophilic aromatic substitution reaction of 1-[2-(3,4-dimethoxyphenyl)ethyl]-1,4,5,6-tetrahydroindolinone was used to assemble the tetracyclic core of the erythrinone skeleton. The resulting cyclized product was transformed into (+/-)-erysotramidine in three additional steps.     

Synthesis and reactions of 3-carboxytropolone. Conversion to heterocycle-fused troponoid compounds

The haloform reaction of 3-acetyltropolone ( 1 ) afforded 3-carboxytropolone ( 2 ) which was treated with diazomethane to give 2-methoxy-3-methoxycarbonyltropone (3a) and 2-methoxy-7-methoxycarbonyltropone (3b). The tropolone 2 reacted with hydrazine to afford 2-hydrazino-3-hydrazinocarbonyltropone ( 10 ) or 2-hydrazinotropone ( 11 ), depending on the reaction time. The reaction of 2 with phenylhydrazine produced 3-hydroxy-1-phenyl-1,8-dihydrocycloheptapyrazol-8-one (14). The treatment of 2-methoxy-3-methoxycarbonyltropone (3a) with hydrazine or phenylhydrazine gave cyclization products 12 and 15 , respectively. The reaction of 2-methoxy-7-methoxycarbonyltropone (3b) with hydrazine, phenylhydrazine, or methylhydrazine gave 2-hydrazino- ( 13 ), 2-(2-phenylhydrazino)- ( 16 ), and 2-(2-methylhydrazino)-7-methoxycarbonyltropone ( 17 ), respectively.     

Morita-Baylis-Hillman reaction and cyclization of 1-(p-toluenesulfonyl)-1,3-butadiene with aldimines

[reaction: see text] Aldimines 2 underwent Morita-Baylis-Hillman reaction with 1-(p-toluenesulfonyl)-1,3-butadiene (3) in the presence of 3-hydroxyquinuclidine (HQD) to afford adducts 4. The E-isomers of the products cyclized to the corresponding functionalized piperidines 8 under base-catalyzed conditions. Simultaneous equilibration of (E)-4 and (Z)-4 was effected by photoisomerization to improve the efficiency of the cyclization.