Synthesis of C-4 substituted nicotine derivatives via an N-acylpyridinium salt of (S)-nicotine

[reaction: see text] A variety of novel nicotine derivatives were prepared from (S)-nicotine via a two-step sequence. Addition of a cuprate reagent to an N-acylpyridinium salt of nicotine, followed by aromatization with elemental sulfur, afforded C-4 substituted nicotines in moderate to high yield. Using this method, 4-(dimethylphenylsilyl)nicotine was prepared and oxidized to afford (S)-4-hydroxynicotine.     

Methodology for regioselective synthesis of substituted pyridines via intramolecular oximino malonate hetero Diels-Alder reactions

[structure] Various substituted pyridines can be prepared regioselectively by a sequence involving an intramolecular thermal or high-pressure Diels-Alder cycloaddition of an oximino malonate dienophile tethered to a dienic carboxylic acid, followed by mild aromatization of the resulting cycloadduct with cesium carbonate in DMF at room temperature.     

Convenient route to enantiopure aryl cyclopentanes via Diels-Alder reaction of asymmetric dienes. Total synthesis of (+)-herbertene and (+)-cuparene

A general route for the synthesis of highly substituted aryl cyclopentanes has been developed involving Diels-Alder reaction of asymmetric dienes prepared from (+)-camphoric acid followed by aromatization of the resulting cyclohexene derivatives. Employing this protocol enantiospecific synthesis of (+)-herbertene and (+)-cuparene has been accomplished.     

A visible-light-mediated oxidative cn bond formation/aromatization cascade: photocatalytic preparation of N-arylindoles

Just add light and air: Structurally diverse N-arylindoles can be prepared from readily prepared o-styryl anilines through visible-light photocatalysis. The reaction, which is conducted open to air, is mediated by [Ru(bpz)(3) ](PF(6) )(2) (bpz=2,2'-bipyrazine) and involves both C?N bond formation and aromatization. Using suitably substituted substrates, a 1,2-carbon shift can be also incorporated into this cascade reaction.     

Asymmetric Brønsted Acid‐Catalyzed Nazarov Cyclization of Acyclic α‐Alkoxy Dienones

A Brønsted acid‐catalyzed asymmetric Nazarov cyclization of acyclic α‐alkoxy dienones has been developed. The reaction offers access to chiral cyclopentenones in a highly enantioselective manner. The reaction is complementary to our previously reported Brønsted acid‐catalyzed electrocyclization reactions, which provided differently substituted optically active cyclopentenones with a fused tetrahydropyrane ring in good yields and with excellent enantioselectivities.     

Total Synthesis of Ileabethoxazole,Pseudopteroxazole, and seco‐Pseudopteroxazole

The total syntheses of ileabethoxazole, pseudopteroxazole, and seco‐pseudopteroxazole, three antituberculosis diterpenoids that had been isolated from Pseudopterogorgia elisabethae, were accomplished in a collective fashion. A cascade alkyne carbopalladation/Stille reaction was exploited to construct a triene precursor with suitable geometry. A fully substituted arene was then assembled through a key 6π electrocyclization/aromatization sequence, and served as an advanced common intermediate. Two radical cyclizations led to the formation of the five‐ and six‐membered rings of ileabethoxazole and pseudopteroxazole, respectively, with the desired stereochemistry, and a straightforward side‐chain elongation delivered seco‐pseudopteroxazole.     

Synthesis of 7-substituted benzolactam-V8s and their selectivity for protein kinase C isozymes

[reaction: see text] Condensation of L-valine benzyl ester toluenesulfonic acid salt with a substituted cyclohexadione followed by aromatization with the assistance of NBS provides an N-aryl L-valine benzyl ester. This intermediate is converted into 7-substituted benzolactam-V8s using an asymmetric Strecker reaction as the key step. The target molecules show a different pattern of isozyme selectivity relative to the 8-substituted benzolactam-V8s.     

Total Synthesis of Ileabethoxazole,Pseudopteroxazole, and seco‐Pseudopteroxazole

The total syntheses of ileabethoxazole, pseudopteroxazole, and seco‐pseudopteroxazole, three antituberculosis diterpenoids that had been isolated from Pseudopterogorgia elisabethae, were accomplished in a collective fashion. A cascade alkyne carbopalladation/Stille reaction was exploited to construct a triene precursor with suitable geometry. A fully substituted arene was then assembled through a key 6π electrocyclization/aromatization sequence, and served as an advanced common intermediate. Two radical cyclizations led to the formation of the five‐ and six‐membered rings of ileabethoxazole and pseudopteroxazole, respectively, with the desired stereochemistry, and a straightforward side‐chain elongation delivered seco‐pseudopteroxazole.     

Studies in chlorin chemistry. II. A versatile synthesis of dihydrodipyrrins

[reaction: see text] Dihydrodipyrrins are key building blocks for the synthesis of hydroporphyrins, many of which have important biological activity. The title compounds were prepared in stereo- and regioselective fashion by a three-step sequence consisting of (1) Pd(0)-catalyzed coupling-cyclization of 2-iodopyrroles with gamma-alkynoic acids to afford enelactones of the desired substitution pattern, (2) methylenation at the lactone carbonyl group employing the Petasis reagent, and (3) in situ enol-ether hydrolysis and amination of the resultant 1,4-diketone to close the pyrroline ring (nine examples). Yields for each step were generally high, although in substrates not blocked by geminal substitution aromatization to a dipyrromethane is a competing side reaction.     

Electrochemical [4+2] Annulation‐Rearrangement‐Aromatization of Styrenes: Synthesis of Naphthalene Derivatives

We report the first electrochemical strategy to synthesize functionalized naphthalene derivatives through [4+2] annulation—rearrangement–aromatization from styrenes under mild conditions. The electrolysis does not require metals, oxidants and high valence substrates, indicating the atom and step‐economy ideals. The dehydrodimer produced through [4+2] cycloaddition of 4‐methoxy α‐methyl styrene is isolated and proved to be the key intermediate for the following oxydehydrogenation to form carbon cation, which undergoes rearrangement–aromatization to afford the final products. This reaction represents a powerful access to construct multi‐substituted naphthalene blocks in a single step.     

An unprecedented stereoselective [2+2] cycloreversion of cyclobutanones

A one-pot metathetic ring opening of substituted bicyclo[3.2.0]heptenones to linear polyene ketones is described. The reaction proceeds with conservation of the endocyclic (Z)-double bond. Exo-substituted vinylcyclobutanones result in (4Z,6E)-configured trienones, while endo-substituted phenyl derivatives generate (4Z,6Z)-configured dienones.     

Iodine-Mediated One-Pot Synthesis of 1,4,5-Substituted Pyrazoles from MBH Acetates via Allyl Hydrazone Intermediate

Herein, we report the regioselective one-pot synthesis of 1,4,5-trisubstituted pyrazoles by reacting Morita-Baylis-Hillman (MBH) acetates derived from aryl aldehydes with alkyl or aryl hydrazines in the presence of iodine under aerobic conditions. The reaction proceeds through sequential S_N2′ nucleophilic substitution of substituted hydrazine onto the MBH acetate, I₂-catalyzed oxidation of the allylic hydrazine to allylic hydrazone, heating-induced intramolecular aza-Michael reaction and cyclization, and oxidative aromatization. The key intermediate, the s-trans allyl hydrazones were isolated in good yields by performing the reactions at room temperature. However, the allyl hydrazones prepared from the MBH acetates of aliphatic aldehydes did not furnish the pyrazole owing to the absence of an activated methylene group in the substrate. The synthetic applications of the pyrazoles in Ugi reactions, decarboxylative halogenation, Pd-catalyzed benzoylation of the N-aryl ring, and metal-free tetrazole synthesis has been demonstrated.     

Nickel-catalyzed cycloaddition of unsaturated hydrocarbons and carbonyl compounds

A mild and general route for preparing pyrans and dienones from carbonyls and diynes is described. Ni imidazolylidene complexes were used to mediate cyclizations between diynes and aldehydes. The reaction of an enyne and an aldehyde afforded a mixture of cyclized products. In addition, a spiropyran was prepared from the cycloaddition of a diyne and cyclohexanone. [reaction: see text]     

Direct Catalytic Asymmetric Doubly Vinylogous Michael Addition of α,β‐Unsaturated γ‐Butyrolactams to Dienones

An asymmetric doubly vinylogous Michael addition (DVMA) of α,β‐unsaturated γ‐butyrolactams to sterically congested β‐substituted cyclic dienones with high site‐, diastereo‐, and enantioselectivity has been achieved. An unprecedented DVMA/vinylogous Michael addition/isomerization cascade reaction affords chiral fused tricyclic γ‐lactams with four newly formed stereocenters.     

Facile intramolecular Diels–Alder reaction of 4-(o-propargyloxy)styrylcoumarins leading to highly fluorescent coumarin-containing polycyclic compounds

The 4-(o-propargyloxy)styrylcoumarins are prepared by the condensation of O-propargylated salicylaldehyde with substituted coumarin-4-acetic acids. The intramolecular Diels–Alder reaction of 4-(o-propargyloxy)styrylcoumarins, without any catalyst gives fused-ring coumarins. The reaction in boiling nitrobenzene leads to aromatization of the initial Diels–Alder adduct and these aromatized products are highly fluorescent.     

General synthetic approach towards annelated 3a,6-epoxyisoindoles by tandem acylation/IMDAF reaction of furylazaheterocycles. Scope and limitations

An efficient and versatile one-pot synthesis of 3,6a-epoxyisoindoles annelated with oxazine, oxazole, thiazine, thiazole, pyrimidine fragments and with their benzoannelated analogues is presented. The method is based on tandem N-acylation/intramolecular cycloaddition (the intramolecular Diels–Alder reaction of furan, IMDAF) reaction between α,β-unsaturated acid anhydrides and α-furyl substituted azaheterocycles. The latter can be easily prepared by condensation of diverse furfurals and 1,2- or 1,3-N,X-binucleophiles (aminoalcohols, aminothiols, diamines). The observed IMDAF reaction is stereoselective: exo-adducts are formed exclusively with large prevalence of one of the diastereoisomers. In most cases, the condensation/N-acylation/IMDAF reaction sequence may be carried out via a one-pot domino protocol. The scope and limitations of the proposed approach are thoroughly investigated. The obtained Diels–Alder adducts are attractive and useful substrates for further transformations. Fused isoindoles can be prepared from them in one-step by aromatization of the 7-oxabicyclo[2.2.1]heptene ring. Other transformations, including halogenation, ring cleavage, and Wagner–Meerwein skeletal rearrangement, are also demonstrated. The spatial structures of the obtained compounds have been established by X-ray diffraction analyses.     

A Modular Synthesis of Substituted Cycloparaphenylenes

Herein, we report a modular synthesis providing access to substituted cycloparaphenylenes (CPPs) of different sizes. A key synthon introducing two geminal ester units was efficiently prepared by [2+2+2] cycloaddition. This building block can be conveniently converted to macrocyclic precursors controlling the ring size of the final CPP. Efficient reductive aromatization through single-electron transfer provided the substituted nanohoops in a straightforward manner. The tBu ester substitution pattern enables a tube-like arrangement in the solid-state governed by van der Waals interactions that exhibits one of the tightest packings of CPPs in tube direction, thus opening new avenues in the crystal design of CPPs.     

Gold-catalyzed double migration-benzannulation cascade toward naphthalenes

A novel gold(I)-catalyzed cycloisomerization of propargylic esters leading to unsymmetrically substituted naphthalenes has been developed. This cascade reaction involves an unprecedented tandem sequence of 1,3- and 1,2-migration of two different migrating groups. It is believed that this transformation likely proceeds via the formation of 1,3-diene intermediate or its precursor, which upon cyclization and aromatization steps transforms into the naphthalene core.     

Synthesis of Phenyl‐Substituted Conduritol B and Its Mechanism of Formation

The phenyl‐substituted conduritol B 8 was prepared in racemic form in a five‐step sequence starting from 2‐phenyl‐1,4‐benzoquinone ( 10 ) (Scheme 1). The reaction mechanism of the key step 12b → 13 is discussed (Scheme 2).     

Synthesis of a novel pyrrolo-[3,2-c]quinoline N-oxide by aza-Baylis-Hillman adduct of o-nitrobenzaldehyde

A new and high yielding approach for the synthesis of a novel pyrrolo-[3,2-c]quinoline N-oxide is described. The key step consisted in the palladium-catalyzed reductive cyclization of an uncommon 3-ketopyrrole derivative of o-nitrobenzaldehyde, obtained in a straightforward manner through an aza-Baylis-Hillman/ring closing metathesis/aromatization reaction. A deoxygenation reaction of this novel pyrrolo-[3,2-c]quinoline N-oxide afforded a new substituted pyrrolo-[3,2-c]quinoline analogue.