Asymmetric Diels-Alder reactions with a chiral spirodione, (6S, 7S, 10R)-7-Isopropyl-10-methyl-1-oxaspiro[5.5]undec-3-ene-2,5-dione

The synthesis of the title spirodione, a new class of auxiliary based chiral synthon, using (−)-menthone having a unique carbon-carbon bond is described. Diels-Alder reactions were carried out with variety of dienes using the title auxiliary as a chiral dienophile in the presence of diethyl aluminium chloride as Lewis acid catalyst to afford the cycloadduct with good diastereoselectivity. The configurations of the chiral synthon and cycloadducts were determined by X-ray crystallography. Methodology for detachment of the chiral auxiliary from the cycloadducts has been developed.     

Chromone-3-carboxaldehydes in Diels-Alder reactions with indole-o-quinodimethane. Synthesis of tetrahydrochromeno[2,3-b]carbazoles

An efficient route to a new class of indole derivatives, tetrahydrochromeno[2,3-b]carbazoles, has been developed. The cycloaddition reactions of chromone-3-carboxaldehydes with indole-o-quinodimethane gave a diastereomeric mixture of Diels-Alder cycloadducts in good yields after in situ deformylation.     

Synthesis of Delta(1)-1,2-diazetines via a Diels-Alder cycloaddition approach

[reaction: see text] A novel method for the synthesis of Delta(1)-1,2-diazetines is presented. Diels-Alder cycloaddition of dienophile 4 with five dienes afforded cycloadducts in good to excellent yields. Four of the obtained cycloadducts were converted to the corresponding diazetines.     

Intramolecular Diels-Alder reactions of optically active allenic ketones: chirality transfer in the preparation of substituted oxa-bridged octalones

The intramolecular Diels-Alder reaction of allenic ketones containing a furyl unit (IMDAF) to generate oxatricyclic systems in good yields is described. The alkene dienophiles 1ab give poor yields of the cycloadducts 2ab, presumably due to the facile retro Diels-Alder reaction. However, the analogous allenic dienophile 7 afforded the desired cycloadduct 8 in 91% yield on treatment with dimethylaluminum chloride. When the allene bears an alkyl substituent on the terminal carbon, complete diastereoselectivity is seen in the IMDAF, e.g. cyclization of 14 gave only the cycloadduct 15 in 80% yield presumably due to greater steric hindrance in the transition state II as compared to that in I. Finally we report complete chirality transfer of the stereochemistry of an allene to the carbon framework of the oxatricyclic system. Thus, the optically active allenic ketone 20 afforded only the desired cycloadduct 21 with the correct absolute stereochemistry needed for the synthesis of the arisugacin class of natural products.     

Useful dual Diels-Alder behavior of 2-azetidinone-tethered aryl imines as azadienophiles or azadienes: a beta-lactam-based stereocontrolled access to optically pure highly functionalized indolizidine systems

Imines derived from 4-oxoazetidine-2-carbaldehydes have been found to be versatile Diels-Alder reagents in that they exhibit two reactivity patterns. 2-Azetidinone-tethered imines undergo diastereoselective reaction with Danishefsky's diene in the presence of different Lewis acids. The effect of the amount of catalyst on the conversion rate as well as on the product ratio has been studied. Under standard reaction conditions, indium(III) chloride and zinc(II) iodide provided the best yields, and indium(III) triflate the highest diastereoselectivity in the Lewis acid promoted aza-Diels-Alder cycloaddition. Treatment of the aforementioned imines with cyclopentadiene, 2,3-dimethyl-1,3-butadiene or 3,4-dihydro-2 H-pyran led to cycloadducts arising from inverse electron-demand condensation involving the beta-lactam-tethered aryl imine as the heterodiene component. In addition, the first methodology for preparing indolizidines from beta-lactams has been developed. This process involves amide bond cleavage of the beta-lactam ring in the aza-Diels-Alder cycloadducts with concomitant cyclization. Full chirality transfer occurs when the reaction is performed with an enantiomerically pure substrate.     

Mono and double polar [4 + 2(+)] Diels-Alder cycloaddition of acylium ions with O-heterodienes

Gas-phase reactions of acylium ions with alpha,beta-unsaturated carbonyl compounds were investigated using pentaquadrupole multiple-stage mass spectrometry. With acrolein and metacrolein, CH(3)-C(+)(double bond)O, CH(2)(double bond)CH-C(+)(double bond)O, C(6)H(5)-C(+)(double bond)O, and (CH(3))(2)N-C(+)(double bond)O react to variable extents by mono and double polar [4 + 2(+)] Diels-Alder cycloaddition. With ethyl vinyl ketone, CH(3)-C(+)(double bond)O reacts exclusively by proton transfer and C(6)H(5)-C(+)(double bond)O forms only the mono cycloadduct whereas CH(2)(double bond)CH-C(+)(double bond)O and (CH(3))(2)N-C(+)(double bond)O reacts to great extents by mono and double cycloaddition. The positively charged acylium ions are activated O-heterodienophiles, and mono cycloaddition occurs readily across their C(+)(double bond)O bonds to form resonance-stabilized 1,3-dioxinylium ions which, upon collisional activation, dissociate predominantly by retro-addition. The mono cycloadducts are also dienophiles activated by resonance-stabilized and chemically inert 1,3-dioxonium ion groups, hence they undergo a second cycloaddition across their polarized C(double bond)C ring double bonds. (18)O labeling and characteristic dissociations displayed by the double cycloadducts indicate the site and regioselectivity of double cycloaddition, which are corroborated by Becke3LYP/6-311++G(d,p) calculations. Most double cycloadducts dissociate by the loss of a RCO(2)COR(1) molecule and by a pathway that reforms the acylium ion directly. The double cycloadduct of the thioacylium ion (CH(3))(2)N-C(+)(double bond)S with acrolein dissociates to (CH(3))(2)N-C(+)(double bond)O in a sulfur-by-oxygen replacement process intermediated by the cyclic monoadduct. The double cycloaddition can be viewed as a charge-remote type of polar [4 + 2(+)] Diels-Alder cycloaddition reaction.     

Intramolecular Diels-Alder reactions using alpha-methylene lactones as dienophile

Several dienals were prepared and reacted in the presence of zinc metal with ethyl 2-bromomethylacrylate to provide in a Reformatsky-like reaction alpha-methylene lactones carrying a dienyl side chain. Thermolysis of these compounds (11, 21, 29, and 37) gave in an intramolecular Diels-Alder reaction the corresponding tricyclic cycloadducts (51, 52, 53, and 54). The cycloadditions took place with good diastereoselectivity and yields. The stereochemistry of the major isomer is in accordance with an endo transition state for cycloadducts 51, 52, and 54. In one instance (compound 58), the structure was supported by X-ray crystallography. In contrast to the other substrates, the nonatriene 29 cyclized to the exo product 53exo. The stereochemical situation could also be proven by NOESY NMR. However, the intramolecular Diels-Alder reaction did not work with furan as dienophile (compound 41) and substrate 50 featuring a densely functionalized tether connecting diene and alpha-methylene lactone.     

A novel and facile stereocontrolled synthetic method for polyhydro-quinolines and pyridopyridazines via a diene-transmissive Diels-Alder reaction involving inverse electron-demand hetero Diels-Alder cycloaddition of cross-conjugated azatrienes

Cross-conjugated azatrienes bearing an electron-withdrawing sulfonyl or benzoyl group on the nitrogen atom underwent, on heating or in the presence of a Lewis acid (TMSOTf), an initial inverse electron-demand hetero Diels-Alder reaction with electron-rich dienophiles (vinyl ether, vinyl thioether, and allenyl ether) to produce 1:1 cycloadducts with high endo selectivity. The initial cycloadducts thus obtained underwent a second Diels-Alder reaction stereoselectively on the newly formed diene unit with electron-deficient dienophiles to give the crossed bis-cycloadducts, octahydroquinolines, with high diastereo-π-facial selectivity. The N-sulfonylazatrienes tethering an ortho-cinnamyloxyphenyl dienophile at the triene terminal underwent an initial intramolecular hetero Diels-Alder reaction of the inverse electron-demand type. The subsequent second Diels-Alder reaction of the formed mono-cycloadducts completed the diene-transmissive hetero Diels-Alder protocol to give benzopyrano[3,4-c]quinolines in a highly stereoselective manner.     

Synthesis of cyclic dienamide using ruthenium-catalyzed ring-closing metathesis of ene-ynamide

Ring-closing metathesis of ene-ynamide, which has alkene and ynamide moieties in a molecule, using a second-generation ruthenium carbene complex produced nitrogen-containing heterocycles, which have a dienamide moiety, in high yields. Diels-Alder reaction of the cyclized product with dienophile proceeded smoothly to give an indole or quinoline derivative in high yield.     

Diastereoselective intermolecular ene reactions: synthesis of 4,5,6,7-tetrahydro-1H-benzo[d]imidazoles

The Diels-Alder cycloadducts of 4-vinylimidazoles and N-phenylmaleimide are shown to undergo facile intermolecular ene reactions. Overall the reaction of three simple molecules (a diene, a dienophile and an enophile) in a two-step process gives 4,5,6,7-tetrahydro-1H-benzo[d]imidazoles with high yields, high atom economy and diastereocontrol of up to 5 new stereocentres.     

Gold(I)‐Catalyzed Dearomative [2+2]‐Cycloaddition of Indoles with Activated Allenes: A Combined Experimental–Computational Study

The gold‐catalyzed synthesis of methylidene 2,3‐cyclobutane‐indoles is documented through a combined experimental/computational investigation. Besides optimizing the racemic synthesis of the tricyclic indole compounds, the enantioselective variant is presented to its full extent. In particular, the scope of the reaction encompasses both aryloxyallenes and allenamides as electrophilic partners providing high yields and excellent stereochemical controls in the desired cycloadducts. The computational (DFT) investigation has fully elucidated the reaction mechanism providing clear evidence for a two‐step reaction. Two parallel reaction pathways explain the regioisomeric products obtained under kinetic and thermodynamic conditions. In both cases, the dearomative C?C bond‐forming event turned out to be the rate‐determining step.     

Siloxacyclopentenes as dienophile-linked directing groups in intramolecular Diels-Alder reactions

The synthesis and intramolecular Diels-Alder reactions of trienes 5 and 6 with a siloxacyclopentene-constrained dienophile are described. These reactions provide the primary cycloadducts 7 and 8 with high diastereoselectivity. These cycloadducts possess trans-relationships between the ring fusion proton and the adjacent C(1) alkoxy group and can be further elaborated to alcohols 9 and 11 (via protiodesilylation) or to 10 and 12 (via Fleming-Tamao oxidation) depending on the substitutent R.     

A Facile and Efficient Synthesis of Thieno[2,3-c]furans and Furo[3,4-b]indoles via a Pummerer-Induced Cyclization Reaction

The alpha-thiocarbocation generated from the Pummerer reaction of an o-heteroaroyl-substituted sulfoxide is intercepted by the adjacent keto group to produce an alpha-thio-substituted heteroaromatic isobenzofuran. In the presence of a suitable dienophile, the reactive o-xylylene undergoes a Diels-Alder cycloaddition followed by an acid-catalyzed ring-opening and aromatization to give heteroaromatic naphthalene derivatives. This one-pot procedure occurs smoothly with electron-deficient dienophiles. The tandem Pummerer cyclization-cycloaddition sequence also occurs intramolecularly using unactivated alkenyl tethers of variable length. With acetylenic dienophiles, the primary cycloadducts undergo in situ ring-opening to produce hydroxynaphthalene derivatives. In the absence of a dienophile, it was possible to prepare 4-(ethylthio)-6-phenylthieno[2,3-c]furan and 1-ethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole. Various synthetic approaches were used for the preparation of the requisite thiophene- and indole-derived sulfoxide precursors. The facility of the tandem Pummerer-Diels-Alder reaction was very dependent on the experimental conditions used to promote the reaction. The best results were achieved by employing a mixture of acetic anhydride and toluene which contained a catalytic quantity of p-toluenesulfonic acid. The presence of the acid effectively drives the reaction in the desired direction by preventing formation of the acetoxy sulfide, which corresponds to the normal Pummerer product.     

Stereoselective aza Diels-Alder reaction on solid phase: a facile synthesis of hexahydrocinnoline derivatives

As part of our continuing studies of polymer-supported pericyclic reactions for preparing biologically interesting heterocyclic compounds, we have introduced a traceless solid-phase synthesis of hexahydrocinnolines. We developed a method in which mild reaction conditions can be used for the hetero-Diels-Alder reactions on a polymeric support. The dienoic 3-vinyl-2-cyclohexenol attached to a Wang resin through an ether linkage undergoes [4 + 2] cycloaddition reaction with several azadienophiles. The highly stereoselective Diels-Alder reaction showed preferential formation of a single cycloadduct resulting from an anti attack of the dienophile on the polymer-bound diene. Trifluoroacetic acid-mediated cleavage of the polymer-bound cycloadducts yields fused nonaromatic hexahydrocinnolines in moderate yields in three steps.     

Total synthesis of (±)-cycloclavine and (±)-5-epi-cycloclavine

Novel routes to the naturally occurring indole alkaloid cycloclavine and its unnatural C(5)-epimer are described. Key features include the rapid construction of the heterocyclic core segments by two Diels-Alder reactions. An indole annulation was accomplished by a late-stage intramolecular Diels-Alder furan cycloaddition, and a methylenecyclopropane dienophile was used for a stereoselective intramolecular [4 + 2] cycloaddition to give the cyclopropa[c]indoline building block present in cycloclavine.     

Zur protonenkatalysierten elektrophilen substitution von 2,3-dimethylindol mit arylaldehyden: C6-regioselektivität am indol-gerüst

The proton catalyzed reaction of 2,3-dimethylindole ( 1 ) with several arylaldehydes 2 yields the 6,6′bisindolylarylmethanes 5 regioselectively. No mechanistic information about the predominant attack of the aldehydes on the indole nucleus is obtained, because the reaction proceeds too fast to control. The electron-rich aldehydes, 2,4,6-trimethoxybenzaldehyde and indole-3-carbaldehyde, yield exclusively the 6,6′,6″-trisin-dolylmethane 9 . The constitutions of all isolated methanes were elucidated by 400 MHz ¹H-nmr spectroscopy.     

Intermolecular Diels-Alder reactions of brominated masked o-benzoquinones with electron-deficient dienophiles. A detour method to synthesize bicyclo[2.2.2]octenones from 2-methoxyphenols

Intermolecular Diels-Alder reactions of masked o-benzoquinones, i.e., 6,6-dimethoxy-2,4-cyclohexadienones 5-7 and 21-24 generated from 2-methoxyphenols 1-3 and 17-20, respectively, with electron-deficient dienophiles leading to highly functionalized bicyclo[2.2.2]octenones are described. The masked o-benzoquinones (MOBs) 5-7 underwent Diels-Alder cycloadditions with methyl acrylate, methyl methacrylate, and methyl vinyl ketone to provide bicyclo[2.2.2]octenones 13a-c to 15a-c (direct method) in low to moderate yields with the concomitant formation of considerable amounts of dimers 9-11. To retard dimerization and to improve the yields of the requisite bicyclo[2.2.2]octenones, a detour method comprised of sequential bromination of 2-methoxyphenols 1-4, oxidation and Diels-Alder reaction, and debromination has been developed. The oxidation of bromophenols 17-20 produced MOBs 21-24 which are stable enough to be isolated. The MOBs 21-24 underwent cycloaddition with electron-deficient dienophiles in a very efficient manner to afford the corresponding cycloadducts 25a-c to 28a-c in good to high yields without self-dimerization. When the cycloadducts 25a-c to 28a-c were treated with either Bu(3)SnH/AIBN or tributylammonium formate-palladium reagent, the corresponding debrominated products 13a-cto 16a-c were obtained in high to excellent yields. In general, the cycloadducts 13a-c to 15a-c were obtained in 20-40% higher yields via the detour method than those via the direct method. In both routes, the Diels-Alder reactions proceeded in a highly regio- and stereoselective manner to furnish a single cycloadduct in each case.     

Hetero Diels-Alder reactions of 1-amino-3-siloxy-1,3-butadienes under strictly thermal conditions

The hetero Diels-Alder reaction of 1-amino-3-siloxy-1,3-butadiene (1a) with a range of unactivated aldehydes proceeds readily under remarkably mild conditions: at room temperature and in the absence of Lewis acid catalysts. The cycloadducts are formed in good yields and can be converted directly to the corresponding dihydro-4-pyrones using acetyl chloride. Ketones and imines are also reactive in hetero Diels-Alder reactions with this diene.     

Pd-NHC catalyzed Suzuki–Miyaura couplings on 3-bromo-9H-pyrido[2,3-b]indole-6-sulfonamide

A series of novel α-carboline derivatives such as 3-aryl-9H-pyrido[2,3-b]indole-6-sulfonamides have been synthesized from the readily available low-cost raw material, benzotriazole which is subjected to nucleophilic aromatic substitution with 5-bromo-2-chloropyridine followed by sequential steps of cyclization, sulfonation, amidation, and finally Suzuki–Miyaura coupling reactions. The C–C bond formation between 3-bromo-9H-pyrido[2.3-b]indole-6-sulfonamide and various boronic acids was achieved with more accessible palladium pre-catalyst, Pd-PEPPSI-IPr via Suzuki coupling under microwave condition in a short reaction time with excellent yields.     

Thiocyanation of indoles

Treatment of indole, 2-phenylindole, 2-methylindole, and ethyl indole-2-carboxylate with thiocyanogen in acetic acid at 0° afforded the corresponding 3-thiocyanatoindoles in quantitative yields, whereas similar treatment of 3-methyl-2-phenylindoles and 2,3-diphenylindoles gave the corresponding 6-thiocyanatoindoles in high yields.