High Endo Selectivity Research Articles

Halogen bond catalysis of the [4+2] cycloaddition reaction of 2-alkenylindoles: catalytic modes and stereoselectivity.

Halogen bond donor catalysts have been widely used in organic reactions because they are environmentally friendly, inexpensive and recyclable. The [4+2] cycloaddition reaction is a key reaction in organic synthesis because of its ease of use, fast speed, and wide range of applications. In this work, halogen bond catalysis in the [4+2] cycloaddition reaction between 2-alkenylindoles was investigated based on DFT calculations. There are two modes of I⋯π halogen bond catalysis: either on the ethenyl of 2-alkenylindole (mode A) or on the five-membered ring of 2-alkenylindole (mode B). Both modes involve two steps: the formation of carbon-carbon bonds and the formation of six-membered rings. Gibbs free energy barriers were determined to investigate the stereoselectivity of the endo pathway and exo pathway. For mode A, the exo products were more easily generated when the substituent R = H, and the N-H⋯π interaction promoted high endo selectivity in the case of the substituent R = Ph. For mode B, an increasing proportion of endo products can be obtained in the order of catalyst I2, IBr and ICl. The π⋯π interaction of the substituent R = Ph promotes the [4+2] cycloaddition reaction, which is consistent with the experimental observation that R = Ph has a higher yield than R = H. The study of different catalytic modes and stereoselectivity would provide new ideas for the further study of the [4+2] cycloaddition reaction.

Iodine‐Catalyzed Diels‐Alder Reactions

AbstractThe Diels‐Alder cycloaddition is the most popular pericyclic reaction with numerous applications in synthesis and catalysis. We now demonstrate that we can perform this reaction under mild and metal‐free conditions relying on molecular iodine as the catalyst. Cycloadditions with cyclohexadiene, cyclopentadiene, or isoprene with various dienophiles can be performed typically within minutes in moderate to good yields and high endo selectivity. The mechanistic studies including kinetic and DFT investigations clearly indicate a halogen‐bond activation and rule out other modes of activation. Furthermore, iodine performs equally well as typical metallic Lewis acids like AlCl3, SnCl4, or TiCl4.

Selectivity control in inverse electron demand Diels–Alder reaction of o-Quinone methides catalyzed by chiral N,N′-Dioxide–Sc(III) complex

The reaction mechanism and origin of asymmetric induction in inverse electron demand Diels-Alder (IEDDA) reaction of ortho-quinone methide (o-QM) and fulvene mediated by chiral N,N'-dioxide–Sc(III) catalyst were rationalized using B3LYP-D3(BJ) functional with def2-TZVP basis set. The uncatalyzed IEDDA reaction was concerted but highly asynchronous with activation barriers of 29.8∼31.8 kcal mol−1. Good linear relationship between the Hammett substituent constant (σP) of o-QM and the activation barrier (ΔG≠) of DA reaction was discovered. The secondary orbital interaction (SOI) between the conjugated diene of o-QM and fulvene moiety stabilized the endo-transition state, contributing to high endo-selectivity. The catalytic asymmetric IEDDA reaction occurred via a stepwise mechanism, including the construction of Cβ−C4 bond, followed by the formation of Cα−O1 bond. The bulky substituents (i.e., adamantyl or triphenylmethyl) in amide moiety of ligand furnished sufficient steric shielding for re-face of diene, inducing the attack of fulvene from si-face in endo-pathway. The substituent at exocyclic methylene of the unsymmetrical fulvene was crucial for the adjustment of E/Z selectivity. The steric repulsion between cyclohexyl group in fulvene and aromatic ring in o-QM raised the destabilizing strain energy (ΔEstrain) at the transition state in Z-configuration, contributing to the predominant E-product.

ChemInform Abstract: Chiral Ferrocenyl P,S‐Ligands for Highly Efficient Copper‐Catalyzed Asymmetric [3 + 2] Cycloaddition of Azomethine Ylides

Abstractwith various electron‐deficient olefins giving pyrrole‐type cycloadducts in high endo‐selectivities and excellent enantioselectivities

From nitrobenzenes to substituted tetrahydroquinolines in a single step by a domino reduction/imine formation/aza-diels-alder reaction.

The three-component reaction between a nitrobenzene, an aldehyde, and a dienophile in the presence of iron powder as a reductant and montmorillonite K10 as a catalyst in aqueous citric acid delivers the products of an aza-Diels-Alder (Povarov) reaction with high endo-selectivity and yields up to 99%.

Chiral ferrocenyl P,S-ligands for highly efficient copper-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides

A series of chiral ferrocenyl P,S-ligands based on benzimidazole and imidazole backbones have been prepared from Ugi's amine through a three-step transformation. These ligands were successfully employed in the Cu-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides with various electron-deficient olefins, giving the corresponding cycloadducts in high endo-selectivities and excellent enantioselectivities (up to 99% ee).

Catalytic Synthesis of Pyrano- and Furoquinolines Using Nano Silica Chromic Acid at Room Temperature

Nano silica chromic acid (nano-SCA) is found to catalyze efficiently the three component-coupling reactions of aldehydes, amines, and cyclic enol ethers such as 3,4-dihydro-2H-pyran and 2,3-dihydrofuran under mild conditions to afford the corresponding pyrano- and furanoquinolines in excellent yields with high endoselectivity. Interestingly, 2,3-dihydrofuran afforded selectively endoproducts under the similar reaction conditions. Heterogeneous reaction conditions, easy procedure, short reaction time, and high yields are some important advantages of this method.

A Biomimetic Approach to C-nor-D-homo-Steroids

A biomimetic three-step transformation of classical "6-6-6-5"-steroids into their C-nor-D-homo-counterparts gives an easy and fast access to this highly important substructure of natural products, as it is found in cyclopamine, and nakiterpiosin. A novel reagent combination allows for the rearrangement even of 17-keto steroids with high endoselectivity. In several examples the broadness of this strategy is outlined.

ChemInform Abstract: A Stereoselective Synthesis of 2,6-Dideoxy-6,6,6-trifluoro-arabino-hexoses via an Asymmetric Diels-Alder Strategy.

The enantioselective syntheses of each enantiomer of ethyl 2,6-dideoxy-6,6,6-trifluoro-β-arabino-hexopyranoside (3) and of 2,6-dideoxy-6,6,6-trifluoro-arabino-hexose (4) are described. The key step in the approach is the inverse electron demand Lewis acid catalysed Diels–Alder reaction of the heterodiene (E)-1,1,1-trifluoro-4-[(1R)-1- phenylethoxy]but-3-en-2-one (5) and either ethyl vinyl ether (7a) or benzyl vinyl ether (7b). The titanium(IV) chloride catalysed cycloadditions at low temperature displayed high endo-selectivity and modest diastereofacial selectivity. Hydroboration of the mixture of the cis-cycloadducts (8a) afforded the separable diastereoisomers (9a) and (10a). Hydrogenolysis of (9a) gave ethyl 2,6-dideoxy-6,6,6-trifluoro-β-L-arabino-hexopyranoside (+)-(3), and of (10a) gave the corresponding D-glycoside (−)-(3). Similarly, hydroboration of the cis-cycloadducts (8b) gave the protected benzyl glycosides (9b) and (10b). Hydrogenolysis of each gave 2,6-dideoxy-6,6,6-trifluoro-L-arabino-hexopyranose (−)-(4) and the corresponding D-sugar (+)-(4) respectively. The absolute configurations of fluorinated carbohydrates (+)- and (−)-(3) were determined by comparison of their molar rotations with those of the parent glycosides. These assignments were confirmed by an X-ray crystallographic structure determination of the glycoside (9a).

ChemInform Abstract: Bisoxazoline and Bioxazoline Chiral Ligands Bearing 4-Diphenylmethyl Shielding Substituents. Diels-Alder Reaction of Cyclopentadiene with 3-Acryloyl-2-oxazolidinone Catalyzed by the Aqua Nickel(II) Complex.

Enantiopure 2-amino-3,3-diphenyl-1-propanol has been synthesized by the hidantoin route starting from diphenylacetaldehyde, followed by subsequent functional group transformations and optical resolution by a chiral HPLC. This amino alcohol can be converted into two new chiral ligands: 4,4′-bis(diphenylmethyl)-2,2′-bioxazoline and 2,2′-isopropylidenebis(4-diphenylmethyloxazoline), and further to complexes with copper(II) trifluoromethanesulfonate and nickel(II) perchlorate hexahydrate. The nickel(II) aqua complex derived from the bisoxazoline effectively catalyzes the Diels-Alder reactions of cyclopentadiene with 3-acryloyl-2-oxazolidinone in high endo-selectivities and moderate enantioselectivities through a square planar transition structure.

Samarium Triflate as Mild and Efficient Catalyst for Aza-Diels–Alder Reaction: A Facile Synthesis of cis-Fused Pyrano- and Furanoquinolines

Three-component coupling reactions of aldehydes, amines, and cyclic enol ethers have been carried out in the presence of samarium triflate to afford the corresponding pyrano and furanoquinolines in excellent yields with high endo-selectivity. The reaction conditions are mild and amenable to scale-up.

Theoretical Study of the Cycloaddition Reaction of a Tungsten-Containing Carbonyl Ylide

The [3+2] cycloaddition reaction of a tungsten-containing carbonyl ylide with methyl vinyl ether and the insertion reactions of the nonstabilized carbene complex intermediates produced have been investigated through the use of B3LYP density functional theory. The [3+2] cycloaddition reaction of the tungsten-containing carbonyl ylide has been proven to proceed concertedly, reversibly, and with high endo selectivity. The intermolecular Si-H insertion reactions of the carbene complex intermediates have been proven to be favored over the intramolecular C-H insertion, in good agreement with experimental results. Moreover, the kinetic endo/exo ratio of the [3+2] cycloaddition reaction has been shown to determine the endo/exo selectivity of the Si-H insertion products. In addition, secondary orbital interactions involving the benzene ring and the carbonyl ligand on the metal center have turned out to strongly influence the high endo selectivity of the [3+2] cycloaddition reaction with methyl vinyl ether.

Practical Synthesis and Highly Diastereoselective Diels−Alder Reactions of 1-Alkylthio-3-silyloxybutadienes

An efficient acid-catalyzed method for the synthesis of vinylogous thioesters was developed. 1-Alkylthio-3-silyloxybutadienes were then produced in high yields from the corresponding vinylogous thioesters. These dienes were highly reactive in Diels-Alder reactions, affording the cycloadducts in high endo selectivity under mild conditions.

Mechanistic Insights on the Cycloisomerization of Polyunsaturated Precursors Catalyzed by Platinum and Gold Complexes

Organometallic chemistry provides powerful tools for the stereocontrolled synthesis of heterocycles and carbocycles. The electrophilic transition metals Pt(II) and Au(I, III) are efficient catalysts in these transitions and promote a variety of organic transformations of unsaturated precursors. These reactions produce functionalized cyclic and acyclic scaffolds for the synthesis of natural and non-natural products efficiently, under mild conditions, and with excellent chemoselectivity. Because these transformations are strongly substrate-dependent, they are versatile and may yield diverse molecular scaffolds. Therefore, synthetic chemists need a mechanistic interpretation to optimize this reaction process and design a new generation of catalysts. However, so far, no intermediate species has been isolated or characterized, so the formulated mechanistic hypotheses have been primarily based on labeling studies or trapping reactions. Recently, theoretical DFT studies have become a useful tool in our research, giving us insights into the key intermediates and into a variety of plausible reaction pathways. In this Account, we present a comprehensive mechanistic overview of transformations promoted by Pt and Au in a non-nucleophilic medium based on quantum-mechanical studies. The calculations are consistent with the experimental observations and provide fundamental insights into the versatility of these reaction processes. The reactivity of these metals results from their peculiar Lewis acid properties: the alkynophilic character of these soft metals and the pi-acid activation of unsaturated groups promotes the intra- or intermolecular attack of a nucleophile. 1,n-Enynes (n = 3-8) are particularly important precursors, and their transformation may yield a variety of cycloadducts depending on the molecular structure. However, the calculations suggest that these different cyclizations would have closely related reaction mechanisms, and we propose a unified mechanistic picture. The intramolecular nucleophilic attack of the double bond on the activated alkyne takes place by an endo-dig or exo-dig pathway to afford a cyclopropyl-metallocarbenoid. Through divergent routes, the cyclopropyl intermediate formed by exo-cyclopropanation could yield the metathesis adduct or bicyclic compounds. The endo-cyclization may be followed by a [1,2]-migration of the propargyl moiety to the internal acetylenic position to afford bicyclic [n.1.0] derivatives. This reaction mechanism is applicable for functional groups ranging from H to carboxylate propargyl substituents (Rautenstrauch reaction). In intramolecular reactions in which a shorter enyne bears a propargyl ester or in intermolecular reactions of an ester with an alkene, the ester preferentially attacks the activated alkyne because of enthalpic (ring strain) and entropic effects. Our calculations can predict the correct stereochemical outcome, which may aid the rational design of further stereoselective syntheses. The alkynes activated by electrophilic species can also react with other nucleophiles, such as aromatic rings. The calculations account for the high endo-selectivity observed and suggest that this transformation takes place through a Friedel-Crafts-type alkenylation mechanism, where the endo-dig cyclization promoted by PtCl(2) may involve a cyclopropylmetallacarbene as intermediate before the formation of the expected Wheland-type intermediate. These comparisons of the computational approach with experiment demonstrate the value of theory in the development of a solid mechanistic understanding of these reaction processes.

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.

A diene-transmissive Diels–Alder reaction involving inverse electron-demand hetero-Diels–Alder cycloaddition of cross-conjugated azatrienes

The initial inverse electron-demand hetero-Diels–Alder reaction of N-sulfonyldivinylmethanimine with electron-rich dienophiles (ethyl vinyl ether and ethyl vinyl sulfide) affords [4+2] cycloadducts with high endo selectivity. The monocycloadducts then undergo a second Diels–Alder reaction on the newly formed diene unit with electron-deficient dienophiles (tetracyanoethylene, 4-phenyl-1,2,4-triazoline-3,5-dione, and N-phenylmaleimide) to give highly stereoselectively the crossed biscycloadducts, hexa- and octahydroquinolines, and octahydropyridopyridazines.

Oxazaborolidinone-Catalyzed Enantioselective Diels−Alder Reaction of Acyclic α,β-Unsaturated Ketones

allo-Threonine-derived O-acyl-B-phenyl-oxazaborolidinones are demonstrated to be powerful and highly enantioselective Lewis acid catalysts for the Diels-Alder reaction of simple acyclic enone dienophiles, expanding the scope of ketone dienophiles and dienes. With 10 to 20 mol % of catalyst, the Diels-Alder adducts are obtained in 76-98% ee with high endo-selectivity. The catalyst exhibits high activity for the reaction with the less reactive beta-substituted dienophiles and the less reactive 1,3-cycohexadiene and 1,3-butadiene derivatives. The application of the catalysts to the Diels-Alder reaction of furan is also described.

Catalytic enantioselective Diels–Alder reactions of furans and 1,1,1-trifluoroethyl acrylate

Catalytic enantioselective Diels–Alder reactions of furans and 1,1,1-trifluoroethyl acrylate in the presence of oxazaborolidium catalysts 2 or 3 provide 7-oxabicyclo[2.2.1]hept-5-enes with high endo-selectivity and excellent enantioselectivity.

A Diels–Alder Approach to (−)‐Ovalicin

A fascinating aspect of the Diels–Alder reaction is its endo selectivity. This endo preference is much less pronounced in intermolecular cases compared with the intramolecular and transannular Diels–Alder (IMDA and TADA) reactions. Nevertheless, high endo selectivity is observed in the Diels– Alder additions of (E)-1-O-substituted dienes catalyzed by Lewis acids that lead to cis-1,6-disubstituted cyclohexene systems of type I (Scheme 1). Compounds of type I could be

Utility of a chiral 1,3-dioxane template in stereoselective intramolecular Diels–Alder reactions

The ethylidene acetal of d-erythrose was used as a template for stereoselective IMDA reactions: high endo selectivity and yields in favor of the cis product were observed with 1,3,9-trienes, resulting from a boat transition state. For natural product synthesis, the reaction was successfully applied to a diene with terminal Z-olefin.