Facile synthesis of 2-substituted 1,2-dihydro-1-naphthols and 2-substituted 1-naphthols

[reaction: see text] The palladium-catalyzed ring opening of dimethoxy oxabenzonorbornadiene with aryl or vinyl halides occurred under very mild conditions to give substituted 1,2-dihydronaphthols that were oxidized with IBX to furnish substituted naphthols in excellent overall yields.     

Oxidative coupling of 2-substituted 1,2-dihydro-1-naphthols using Jones reagent: a simple entry into 3,3′-disubstituted 1,1′-binaphthyl-4,4′-diols

2-Substituted 1,2-dihydro-1-naphthols underwent regioselective oxidative dimerization, when treated with Jones reagent, to furnish 3,3′-disubstituted 1,1′-binaphthyl-4,4′-diols. A series of symmetrical binaphthols were prepared and it was shown that the coupling reaction proceeds via the sequential oxidation of 2-substituted 1,2-dihydro-1-naphthols to 2-substituted 1-naphthols, which oxidatively dehydrodimerized.     

Cyclopentene Synthesis from 1,3-Dienes via Base-Induced Ring Contraction of 3,6-Dihydro-2H-thiopyrans: Studies on Diastereoselection and Mechanism

An investigation of the scope and mechanism of a new synthesis of cyclopentenes from 3,6-dihydro-2H-thiopyrans is described. Alkyl halides substituted with an electron-withdrawing group in the alpha-position were reacted with sodium thiosulfate, yielding the corresponding Bunte salts, which could be transformed to reactive thiocarbonyl compounds by elimination of the elements of bisulfite with mild base treatment. In situ trapping by 1,3-dienes afforded in good yields a variety of 3,6-dihydro-2H-thiopyrans substituted with electron-withdrawing groups at the 2-position. Exposure of these cycloadducts to strong base at low temperature effected a novel ring contraction, affording 2-(methylthio)-3-cyclopentenes after quenching with methyl iodide. The level of diastereoselectivity exhibited during the generation of these cyclopentenes was found to be dependent on the nature of the electron-withdrawing group at the 2-position of the dihydrothiopyran as well as the substitution pattern originally present in the diene component. In some cases, reducing the temperature during the ring contraction resulted in the isolation of good yields of vinyl cyclopropanes of high isomeric purity. With one substrate, highly diastereoselective rearrangement of a vinyl cyclopropane to a cyclopentene was unambiguously demonstrated, suggesting that this might be a key feature of the overall ring contraction mechanism.     

Synthesis of 3-substituted 4-aroylisoquinolines via Pd-catalyzed carbonylative cyclization of 2-(1-alkynyl)benzaldimines

A number of 3-substituted 4-aroylisoquinolines have been prepared in good yields by treating N-tert-butyl-2-(1-alkynyl)benzaldimines with aryl halides in the presence of CO and a palladium catalyst. Synthetically the methodology provides a simple and convenient route to isoquinolines containing an aryl, alkyl, or vinylic group at C-3 and an aroyl group at C-4 of the isoquinoline ring. The reaction is believed to proceed via cyclization of the alkyne containing a proximate nucleophilic center promoted by an acylpalladium complex.     

Highly efficient synthesis of 1,2-disubstituted acetylenes derivatives from the cross-coupling reactions of 1-bromoalkynes with organoalane reagents

A Highly efficient route for the synthesis of 1,2-disubstituted acetylene derivatives has been developed by palladium catalyzed cross-couplings of alkynyl halides with (hetero)aryl aluminium reagents under mild conditions. This has given corresponding cross-coupling products good to excellent isolated yields of up to 99%. The aryls bearing electron-donating or electron-withdrawing groups in either alkynylhalides or arylaluminum substrates gave cross-coupling products good yields. This process was simple and easily performed, which provides an efficient method for the synthesis of 1,2-disubstituted acetylenes derivatives. On the basis of the experimental results, a possible catalytic cycle has been proposed.     

A lactam-derived vinyl boronate as a stable and crystalline reagent for the synthesis of 2-substituted piperidines by Pd-catalyzed coupling reactions

A δ-valerolactam-derived vinyl triflate has been converted into the corresponding vinyl boronate by Pd-catalyzed coupling with bis(pinacolato)diboron, which results in an umpolung. This boronate efficiently couples under Pd catalysis with aryl and heteroaryl bromides to give the corresponding 2-substituted piperidines in excellent yields.     

CuI-catalyzed suzuki-miyaura and sonogashira cross-coupling reactions using DABCO as ligand

In the presence of TBAB, CuI-catalyzed Suzuki-Miyaura cross-coupling of vinyl halides and aryl halides with arylboronic acids was conducted smoothly to afford the corresponding diarylethenes and polyaryls in moderate to good yields using DABCO (1,4-diazabicyclo[2.2.2]octane) as the ligand. We also found that the inexpensive CuI/DABCO catalytic system was effective for Sonogashira cross-couplings of aryl halides and vinyl halides. A variety of aryl halides and vinyl halides including activated aryl chlorides underwent the coupling with terminal alkynes in moderate to excellent yields.     

Ring opening of aziridines with ortho-bromophenyl metal reagents: synthesis of 2-substituted indolines

Stabilized ortho-bromo phenyllithium reagents, generated via lithium-halogen exchange of aryl iodides, undergo regioselective ring opening of mono-substituted N-Boc, N-Cbz, and N-tosyl-protected aziridines in good to excellent yields. The resulting ortho-bromo phenethylamines can be cyclized under transition-metal-catalyzed conditions to give 2-substituted chiral, non-racemic indolines in good yields.     

Suzuki-Miyaura cross-coupling reactions of halo derivatives of 4H-pyrido[1,2-a]pyrimidin-4-ones

The palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of halo derivatives of 4H-pyrido[1,2-a]pyrimidin-4-one with (het)arylboronic acids allow easy access to (het)aryl and vinyl derivatives of this bicycle in good to excellent yields, even from chloro derivatives. The sequence of reactivity of the halogen in the different positions of the ring system was also investigated. 6-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one could be prepared by thermal cyclization of isopropylidene (6-phenylpyrid-2-ylamino)methylenemalonate, together with a small amount of 7-phenyl-1,4-dihydro-1,8-naphthyridin-4-one.     

Synthesis of 4-substituted chlorophthalazines, dihydrobenzoazepinediones, 2-pyrazolylbenzoic acid, and 2-pyrazolylbenzohydrazide via 3-substituted 3-hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, N,N-dimethylaminophthalimide (8a) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones 9b, 9i-9am. Many of these hydroxyisoindolinones are converted to chlorophthalazines 1b-1v via reaction with hydrazine, followed by chlorination with POCl(3). We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to N,N-dimethylaminophthalimide (8a) provided dihydrobenzoazepinediones 15a-15c via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids 16a-16d and 2-pyrazolyl benzohydrazides 17a-17g rather than the expected alkynyl phthalazinones.     

Assembly of conjugated enynes and substituted indoles via CuI/amino acid-catalyzed coupling of 1-alkynes with vinyl iodides and 2-bromotrifluoroacetanilides

Cross-coupling of 1-alkynes with vinyl iodides occurs at 80 degrees C in dioxane catalyzed by CuI/N,N-dimethylglycine to afford conjugated enynes in good to excellent yields. Heating a mixture of 2-bromotrifluoroacetanilide, 1-alkyne, 2 mol % of CuI, 6 mol % of L-proline, and K(2)CO(3) in DMF at 80 degrees C leads to the formation of the corresponding indole. This conversion involves a CuI/L-proline-catalyzed coupling between aryl bromide and the 1-alkyne followed by a CuI-mediated cyclization process. An ortho-substituent effect directed by NHCOCF3 enables the reaction to proceed under these mild conditions. Both aryl acetylenes and O-protected propargyl alcohol can be applied, leading to 5-, 6-, or 7-substituted 2-aryl and protected 2-hydroxymethyl indoles in good yields. With simple aliphatic alkynes, however, lower yields were observed.     

Methyltrioxorhenium-catalyzed aerobic oxidative coupling of 2-naphthols to binaphthols

A variety of 2-naphthols have been selectively oxidized to their corresponding 1,1′-bi-2-naphthols in excellent yields with molecular oxygen using methyltrioxorhenium as catalyst.     

Catalytic asymmetric coupling of 2-naphthols by chiral tridentate oxovanadium (IV) complexes

A series of chiral oxovanadium(IV) complexes derived from tridentate N-3,5-substituted and N-3,4-benzo- and N-5,6-benzo-salicylidene-alpha-amino acids can serve as efficient catalysts for the enantioselective oxidative couplings of various 3-, 6-, and 7-substituted 2-naphthols under O(2). The best scenario involves the use of a vanadyl complex arising from 2-hydroxy-1-naphthaldehyde and valine (or phenylalanine) in CCl(4), leading to BINOLs in good yields (75-100%) and with enantioselectivities of up to 68%.     

Catalytic asymmetric oxidative couplings of 2-naphthols by tridentate N-ketopinidene-based vanadyl dicarboxylates

[reaction: see text] A series of oxovanadium(IV) complexes derived from tridentate N-ketopinidene-alpha-amino acids were synthesized. They serve as efficient catalysts for the enantioselective oxidative couplings of various 3-, 6-, or 7-substituted 2-naphthols. The best scenario involves the use of a vanadyl complex arising from L-tert-leucine in CCl4. The asymmetric couplings of 2-naphthols can be conducted smoothly at 40-45 degrees C under a stream of gaseous oxygen, leading to 2,2'-dihydroxy-1,1'-binaphthyls in good yields (61-99%) and with enantioselectivities of up to 87%.     

Palladium-catalyzed heteroannulation leading to heterocyclic structures with two heteroatoms: a highly regio- and stereoselective synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzoxazines and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines.

A highly convenient method has been developed for the synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzoxazines 9 and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines 34-38 through palladium-copper-catalyzed reactions. Aryl halides 7 reacted with 2-[N-alkyl(benzyl)-N-prop-2'-ynyl]aminophenyl tosylate 6 in the presence of (PPh3)2PdCl2 (3 mol %), CuI(5 mol %) in triethylamine at room temperature to yield 2-[N-alkyl(benzyl)-N-(3-aryl-prop-2'-ynyl)]-aminophenyl tosylates 8 in extremely good yields (72-96%). The latter could then be cyclized with KOH in ethanol-water to Z-9 in a highly regio- and stereoselective manner. Similarly, palladium-copper-catalyzed reaction of 2-(prop-2'-ynyloxy)aniline (21) with aryl iodides 7 led to 22-26 which after tosylation and cyclization with cuprous iodide in CH3CN in the presence of K2CO3 and Bu4-NBr led to the (Z)-3-alkyl(aryl)idene-4-tosyl 3,4-dihydro-2H-1,4-benzoxazines 34-38 in good overall yields. The Z-stereochemistry of the products was established from 1H NMR spectra, 3JCH values (between vinylic proton and methylenic carbon of the heterocyclic ring), NOE experiments, and X-ray analysis. The method was also found to be suitable for the synthesis of bis(benzoxazinylated) derivatives 17, 39, and 2-alkyl-3,4-dihydro-2H-1,4-benzoxazines 18. Our method for the synthesis of 3,4-dihydro-2H-1,4-benzoxazines is highly efficacious, using easily available starting materials under very mild conditions. Also the synthesis of some novel 5-substituted uracil derivatives 40 and 41 containing the benzoxazinyl moiety and of potential biological interest is being reported.     

An improved palladium-catalyzed conversion of aryl and vinyl triflates to bromides and chlorides

A facile Pd-catalyzed conversion of aryl and vinyl triflates to aryl and vinyl halides (bromides and chlorides) is described. This method allows convenient access to a variety of aryl, heteroaryl, and vinyl halides in good to excellent yields and with greatly simplified conditions relative to our previous report.     

Substituent directed regioselective synthesis of 2-oxonicotonic acids and methyl nicotinates

An innovative synthesis of aryl tethered 1,2-dihydro-2-oxopyridine-3-carboxylic acids has been developed through nucleophile induced ring transformation of methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylates using either cyanamide or arylamidine in excellent yields. Further, the reaction of methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylates with formamidine acetate under analogous reaction conditions did not follow the same course of reaction and produced methyl nicotinate, regioselectively, in good yield. Decarboxylation of a 6-aryl-4-methylsulfanyl-1,2-dihydro-2-oxopyridine-3-carboxylic acid has been achieved by heating in PPA. The 4-methylsulfanyl substituent in 3 has also been oxidized to the corresponding methylsulfonyl group with m-chloroperbenzoic acid.     

Palladium-phosphine complex catalyzed cross-coupling reaction of 1-methyl-2-pyrrolyl-magnesium bromide and -zinc chloride with organic halides

1-Methyl-2-pyrrolyl-magnesium bromide and -zinc chloride, which were prepared from 1-methyl-2-pyrrolyllithium with MgBr₂ and ZnCl₂ respectively, reacted with aryl- and heteroaromatic halides to give the corresponding 2-substituted pyrroles in good to excellent yields in the presence of palladium-phosphine complexes as catalysts.     

Lithiation of 1-chloromethylbenzotriazole: generation and elaboration of benzotriazolyloxiranes

1-Benzotriazolylchloromethyllithium generated from 1-chloromethylbenzotriazole (1) and LDA reacts with enolizable and nonenolizable ketones to give benzotriazolyloxiranes 2a-g in good yields. The oxiranyllithiums 4a-d generated from 2a-d and n-BuLi at -78 degrees C were trapped by a variety of electrophiles to give oxiranyl derivatives 5a-j in good to excellent yields. Lewis-acid-promoted nucleophilic ring opening of benzotriazolyloxiranes 2a,f,g with allyltrimethylsilane gave the corresponding 1,7-octadien-4-ols 6a-c in 68-75% yield. Hydrolysis of alpha-acylbenzotriazolyloxiranes 5g,h provided 3-hydroxy-1,2-diones 7a and 7b in 73 and 86% yield, respectively.     

Oxidations with IBX: benzyl halides to carbonyl compounds, and the one-pot conversion of olefins to 1,2-diketones

A variety of benzyl halides were converted to the corresponding aldehydes/ketones in respectable yields by IBX in DMSO at 65 °C. The bromohydrin reaction of olefins using NBS-H₂O in DMSO can be nicely adapted to IBX-mediated oxidation of benzyl halides in such a way that olefins are converted to the corresponding 1,2-diketones in good isolated yields in one-pot.