Heterocycloaddition Reaction Research Articles

Unveiling the impact of the light-source and steric factors on [2+2] heterocycloaddition reactions.

Information gained from in-depth mechanistic investigations can be used to control the selectivity of reactions, leading to the expansion of the generality of synthetic processes and the discovery of new reactivity. Here, we investigate the mechanism of light-driven [2+2] heterocycloadditions (Paternò-Büchi reactions) between indoles and ketones to develop insight into these processes. Using ground-state UV-Vis absorption and transient absorption spectroscopy (TAS), together with DFT calculations, we found that the reactions can proceed via an exciplex or electron-donor-acceptor (EDA) complex, which are key intermediates in determining the stereoselectivity of the reactions. We used this discovery to control the diastereoselectivity of the reactions, gaining access to previously inaccessible diastereoisomeric variants. When moving from 370 to 456 nm irradiation, the EDA complex is increasingly favoured, and the diastereomeric ratio (d.r.) of the product moves from >99:<1 to 47:53. In contrast, switching from methyl to ipropyl substitution favours the exciplex intermediate, reversing the d.r. from 89:11 to 16:84. Our study shows how light and steric parameters can be rationally used to control the diastereoselectivity of photoreactions, creating mechanistic pathways to previously inaccessible stereochemical variants.

Unveiling the impact of the light-source and steric factors on [2+2] heterocycloaddition reactions.

Information gained from in-depth mechanistic investigations can be used to control the selectivity of reactions, leading to the expansion of the generality of synthetic processes and the discovery of new reactivity. Here, we investigate the mechanism of light-driven [2+2] heterocycloadditions (Paternò-Büchi reactions) between indoles and ketones to develop insight into these processes. Using ground-state UV-Vis absorption and transient absorption spectroscopy (TAS), together with DFT calculations, we found that the reactions can proceed via an exciplex or electron-donor-acceptor (EDA) complex, which are key intermediates in determining the stereoselectivity of the reactions. We used this discovery to control the diastereoselectivity of the reactions, gaining access to previously inaccessible diastereoisomeric variants. When moving from 370 to 456 nm irradiation, the EDA complex is increasingly favoured, and the diastereomeric ratio (d.r.) of the product moves from >99:<1 to 47:53. In contrast, switching from methyl to ipropyl substitution favours the exciplex intermediate, reversing the d.r. from 89:11 to 16:84. Our study shows how light and steric parameters can be rationally used to control the diastereoselectivity of photoreactions, creating mechanistic pathways to previously inaccessible stereochemical variants.

Organocatalytic atroposelective heterocycloaddition to access axially chiral 2-arylquinolines

Axially chiral heterobiaryls play a vital role in asymmetric synthesis and drug discovery. However, there are few reports on the synthesis of atropisomeric heterobiaryls compared with axially chiral biaryls. Thus, the rapid enantioselective construction of optically active heterobiaryls and their analogues remains an attractive challenge. Here, we report a concise chiral amine-catalyzed atroposelective heterocycloaddition reaction of alkynes with ortho-aminoarylaldehydes, and obtain a new class of axially chiral 2-arylquinoline skeletons with high yields and excellent enantioselectivities. In addition, the axially chiral 2-arylquinoline framework with different substituents is expected to be widely used in enantioselective synthesis.

A highly enantioselective [4+2] cycloaddition involving aldehydes and β,γ-unsaturated-α-keto esters

A stereoselective inverse electron demand oxo-Diels-Alder reaction involving electron poor dienes (γ-aryl-β,γ-unsaturated-α-keto ester) and electron rich dienophiles has been studied. These cycloaddition reactions are extremely useful for the construction of O-, N-, S-centered heterocyclic compounds, which are routinely used in both synthetic organic and medicinal chemistry. The [4+2] hetero cycloaddition reactions involving various aldehydes and β,γ-unsaturated-α-keto esters were carried out in which three different types of substituted proline catalysts were examined. For these reactions, high selectivities (enantiomeric excess 93–98%) were obtained using catalyst 3. Due to the bulkiness of catalyst 3, compared to the other catalysts tested, it is more efficient at catalyzing these type reactions.

Regioselective Synthesis of Benzo[h][1,6]‐naphthyridines and Chromenopyrazinones through Alkyne Cyclization

A regioselective approach to the synthesis of benzo[h][1,6]‐naphthyridine and chromenopyrazinone derivatives was developed. The synthetic route to benzo[h][1,6]‐naphthyridines involves the N‐propargylation of aromatic aminobenzaldehydes, followed by reaction with propargylamine in the presence of DBU (1,8‐diazabicyclo[5.4.0]undec‐7‐ene). For the synthesis of chromenopyrazine and chromenopyrazinone derivatives, the acetonitrile group was introduced to salicylaldehyde derivatives, and a DBU‐promoted cyclization reaction between aldehydes and propargylamine gave the chromenopyrazines. The intramolecular heterocycloaddition reaction between the triple bond and the azadiene, which is formed as an intermediate, gave the desired structures.

New method for in situ generation of enolate-iminium 1,4-dipoles for [4 + 2] and [4 + 1] dipolar heterocycloaddition reactions

Thermolysis ofN-(diphenylenamino)pyrrolediones proceeds with formation of dihydropyrazolone 1,4-dipoles. [4 + 4] Homodimerizations and a series of [4 + 2] and [4 + 1] cycloadditions of these species with various dipolarophiles were investigated.

Intermolecular and regioselective access to polysubstituted benzo- and dihydrobenzo[c]azepine derivatives: modulating the reactivity of group 6 non-heteroatom-stabilized alkynyl carbene complexes.

We highlight the versatility of non-heteroatom-stabilized tungsten-carbene complexes 3 synthesized in situ, which have been used in a modular approach to access 2-benzazepinium isolable intermediates 5. By employing very mild conditions, benzazepinium derivatives 5 have been obtained in high yield from simple compounds, such as acetylides 2, Fischer-type alkoxycarbenes 1, and phenylimines 4. The process, involving a formal [4+3] heterocycloaddition, occurs in a totally regioselective manner, which differs from the approach previously observed in similar procedures for other carbene analogues. This work, which involves three components, reveals a control of the reactivity of non-heteroatom-stabilized carbene complexes 3 ([4+3] vs. [2+2]-heterocycloaddition reactions) depending on the acetylide substitution pattern. The influence of the substitution pattern in the behavior of the complexes has been computationally analyzed and rationalized. Finally, elaboration of the 2-benzazepinium intermediates allows access to 3H-benzo[c]azepines 6 and 3H-1,2-dihydrobenzo[c]azepines 7-9 with high control of the substitution of the nine positions of the heterocycle.

Preparation and biological evaluation of novel leucomycin analogs derived from nitroso Diels–Alder reactions

A series of 10,13-disubstituted 16-membered macrolides was synthesized using nitroso Diels-Alder reactions of leucomycin A7. Despite the extensive constituent functionalities in leucomycin, the hetero cycloaddition reactions proceeded in a highly regio- and stereoselective fashion. Subsequent chemical modifications of the nitroso cycloadducts, including N-O bond reduction, were also conducted. Most leucomycin derivatives retained antibiotic profiles similar to leucomycin A7, and, in contrast to leucomycin itself, several exhibited moderate antiproliferative and cytotoxic activity.

Tuning the Reactivity and Chemoselectivity of Electron‐Poor Pyrroles as Dienophiles in Cycloadditions with Electron‐Rich Dienes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Tuning the reactivity and chemoselectivity of electron-poor pyrroles as dienophiles in cycloadditions with electron-rich dienes

Activation by Lewis acid catalysis and high pressure allows pyrrole derivatives to react with electron-rich dienes in normal electron demand [4+2] cycloadditions, provided that the aromatic ring is substituted by at least two electron-withdrawing groups. The dienophilic behavior of the heterocycle is expressed through the involvement of either the aromatic carbon–carbon double bond in an all-carbon process or the carbonyl moiety of the substituent in a heterocycloaddition reaction. In this regard, the nature of the heterocyclic substituents is shown to have a dramatic influence and to direct both the reactivity and the chemoselectivity of the cycloaddition.

Studies on Organophosphorus Compounds. Part 132. A Novel Route to 3‐(O,O‐Diethylphosphoryl)‐2,3‐dihydrofurans via Rhodium‐Catalyzed Heterocycloaddition Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Novel Route to 3‐(O,O‐Diethylphosphoryl)‐2,3‐dihydrofurans via Rhodium‐Catalyzed Heterocycloaddition Reaction#

A series of 3‐phosphoryl‐2,3‐dihydrofurans are efficiently synthesized by the reaction of diethyl 1‐diazo‐2‐oxo‐alkylphosphonates with alkyl vinyl ethers in good yields. 2,3‐Dihydrofurans bearing phosphoryl and trifluoromethyl moieties are also prepared in a similar manner. #Studies on Organophosphorus Compounds, Part 132. For Part 131, see D. Gong, L. Zhang and C. Yuan, Synthetic Commun. 2004, 34 (18).

Graphical Abstracts

Synth. Commun. 2004, 34, 3251 A Novel Route to 3‐(O,O‐Diethylphosphoryl)‐2,3‐Dihydrofurans via Rhodium‐catalyzed Heterocycloaddition Reaction Denghuang Gong, Ling Zhang, and Chengye Yuan Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China A series of 3‐phosphoryl‐2,3‐dihydrofurans are efficiently synthesized by the reaction of diethyl 1‐diazo‐2‐oxo‐alkylphosphonates with alkyl vinyl ethers in good yields.

Organopalladium Complex Promoted Asymmetric Cycloaddition Reactions Involving 3,4-Dimethyl-1-phenylphosphole 1-Sulfide as the Heterocyclic Diene

3,4-Dimethyl-1-phenylphosphole 1-sulfide (DMPPS) reacted as a heterocyclic diene in the asymmetric Diels−Alder reaction with diphenylvinylphosphine in the presence of an organopalladium(II) complex derived from the enantiomerically pure ortho-metalated (R)-(1-(dimethylamino)ethyl)naphthalene. The cycloaddition reaction proceeded at room temperature via an intramolecular mechanism in which the cyclic diene and the dienophile were coordinated simultaneously on the chiral palladium template. The (RP)-exo cycloadduct was obtained with high stereoselectivity as a P−S bidentate chelate on the palladium template. When DMPPS was treated with the heterodienophile thiobenzophenone at 50 °C in the presence of the organopalladium(II) complex, the corresponding heterocycloaddition reaction proceeded to generate the expected cycloadduct as a rigid S−S bidentate chelate on the palladium template. However, the cyclic adduct was obtained as a racemic mixture. The low stereoselectivity in the heterocycloaddition reaction is attributed to the kinetic instability of S→Pd coordination bonds in the intermediate template complex. Both the P−S and S−S cycloadducts could be liberated from the corresponding template complexes by treatment of the template complexes with aqueous potassium cyanide.

Cycloaddition reaction of 2-azadienes derived from beta-amino acids with electron-rich and electron-deficient alkenes and carbonyl compounds. Synthesis of pyridine and 1,3-oxazine derivatives.

Functionalized keto-enamines 6 were obtained by nucleophilic addition of enol ethers to the imine moiety of 2-azadienes derived from dehydroaspartic esters 4. Reactions of 2-azadiene 4c containing three electron-withdrawing substituents (CO(2)R) with enol ethers 5 in the presence of lithium perchlorate led to the formation of tetrahydropyridine derivatives 7 in a regio- and stereoselective fashion. 2H-[1,3]-oxazines 10 and pyridine derivatives 12 and 13 were obtained by heterocycloaddition reactions of electron-poor azadienes 4d-g containing two electron-withdrawing substituents (4-O(2)N-C(6)H(4), CO(2)R) in positions 1 and 4 with carbonyl derivatives (ethyl glyoxalate 9a and diethyl ketomalonate 9b) and the electron-deficient olefin tetracyanoethylene 11.

Lewis Acid Catalysed [4+2] Heterocycloadditions between Ketone Enol Ethers and β-Ethylenic α-Oxo Esters

The [4+2] heterocycloaddition reaction between (E)-γ-substituted β-unsaturated α-oxo esters 1a−d and cyclic and acyclic ketone enol ethers 2a−l afforded heteroadducts 3−5 in high yields when either [Eu(fod)3] or SnCl4 were used as the catalyst. With methyl (E)-benzylidenepyruvate (1a), the two catalytic modes displayed divergent stereoselectivities. In the case of the heterocycloaddition of silyl enol ether 2h, X-ray investigations established the relative configurations of the bicyclic adducts 3h and 5h, each obtained as the major isomer with [Eu(fod)3] and with SnCl4, respectively. These assignments provided valuable information concerning the concerted vs. nonconcerted mechanism of these acid-catalysed reactions. With methyl (E)-tert-butoxymethylenepyruvate (1d), the scope of the reaction proved to be restricted to alkyl enol ethers as the dienophiles. In this case, the stereochemical process followed a different pathway, exemplified by the X-ray structure of the adduct 4q, obtained with total stereoselectivity from 1d and 1-methoxycyclohexene (2f) when SnCl4 was the catalyst.

Organopalladium Complex Promoted Asymmetric Hetero Diels−Alder Reactions between a Thiocarbonyl Dienophile and a Phospha-Substituted Cyclic Diene

The asymmetric [4 + 2] hetero cycloaddition reaction between methyl cyanodithioformate and 1-phenyl-3,4-dimethylphosphole has been achieved stereoselectively by use of the organopalladium(II) complex derived from (S)-N,N-dimethyl-1-(1-naphthylamine) as the chiral reaction template to produce the corresponding (+)-exo-syn-methylthio-substituted phosphanorbornene P−S bidentate chelate. The generation of the chelating cycloadduct involved an intramolecular cycloaddition mechanism in which both the cyclic diene and the hetero dienophile were coordinated simultaneously to the chiral palladium template during the course of the cycloaddition reaction.

X-ray crystallographic proof of regioselectivity in a nitrosobenzene cycloaddition, and development of a novel in situ heterocycloaddition trap for use during decomplexation of tricarbonyliron diene complexes in hippeastrine synthesis

The heterocycloaddition reaction between nitrosobenzene and 2-methylcyclohexa-1,3-diene preferentially affords the regioisomer with the N–Ph group next to the methyl substituent, and this product has been characterised by X-ray crystallography. As a model study for a tricarbonyliron mediated route to the alkaloid hippeastrine, a 2-methyl-6-phenylcyclohexadiene analogue has been prepared from tricarbonyl(η 5-3-methylcyclohexadienyl)iron(1+) hexafluorophosphate(1−) and has been examined in the heterocycloaddition reaction. A novel in situ heterocycloaddition trapping procedure has been developed based on this chemistry. Tricarbonyl(η 4-2-methyl-6-phenylcyclohexadiene)iron(0) can be converted directly into the cycloadduct in this way by reaction with trimethylamine N-oxide in the presence of nitrosobenzene.

ChemInform Abstract: Novel Heterocycloaddition Reaction of Glycals.

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Novel Heterocycloaddition Reaction of Glycals

Diacyl thione species 1 has been generated and reacted in situ with both pyranoid and furanoid glycals to form novel [4 + 2] cycloadducts. Factors such as protecting groups and configuration of substituents in the glycals along with medium effects were varied to discover influences on face selectivity and reactivity. A qualitative correlation of reactivity with the HOMO−LUMO gap between the glycal (HOMO) and the heterodienic species (LUMO) is observed. In one example, the isolation of byproducts suggests that the cycloaddition may in fact be stepwise.