Straightforward hetero Diels-Alder reactions of nitroso dienophiles by microreactor technology

The hetero Diels-Alder reactions of 2-nitrosotoluene and some representative acylnitrosodienophiles with a selected set of 1,3-dienes were studied under microflow conditions. The main assets of the technology, that is, an accurate control of the reaction parameters and continuous operating, led to an increased efficiency of this reaction.     

[4+2] Cycloaddition of 1-phosphono-1,3-butadiene with azo- and nitroso-heterodienophiles

Under microwave activation, diethyl 1-phosphono-1,3-butadiene (1) reacted with t-butyl azodicarboxylate (2) and o-nitrosotoluene (5) to furnish quantitatively [4+2] cycloadducts, 3-phosphono-3,6-dihydro-1,2-pyridazine (3) and 6-phosphono-3,6-dihydro-1,2-oxazine (6), respectively. Selective oxidation and/or reduction of 6 led to functionalized δ-aminophosphonic derivatives in cyclic (7, 8) and aliphatic series (9, 10). Intermediate 10 may be cyclized into 2-phosphono-2,5-dihydro-1-pyrrole (12).     

Exploring structural effects of levoglucosenone derived chiral auxiliaries in asymmetric Diels-Alder cycloadditions

New chiral auxiliaries derived from levoglucosenone were developed in a simple and efficient way and evaluated as chiral inductors in asymmetric Diels-Alder reactions between the corresponding acrylate derivatives and cyclopentadiene. The results showed an important influence of the absolute configuration of the C(2) center of the auxiliary on the level of stereoinduction obtained.     

Single and double asymmetric induction in Diels-Alder cycloadditions with chiral acylnitroso dienophiles

Diels-Alder reaction of the achiral 1-silyloxybutadiene 1a with the chiral acyinitroso dienophile 2a gave cycloadduct 4 in high diastereomeric excess (d.e. > 98 %), a result which is undoubtedly due to the C-2 symmetrical chiral dimethylpyrrolidine inductor. Excellent d.e. was also observed when the (R)-prolinol dienophile 2d was reacted with the chiral diene 1b (d.e. = 96 %), whereas cycloaddition of the (S) enantiomer 2e with 1b gave only poor asymmetric induction (d.e. = 4 %). These two latter examples nicely illustrate the influence of “matched pair” (1b/2d) versus “mismatched pair” (1b/2e) upon double asymmetric induction. All herein reported Diels-Alder cycloadditions were regiospecific.     

Computational evaluation of asymmetric Diels-Alder reactions of vinylboranes with chiral dienes

The asymmetric Diels-Alder reactions of dichlorovinylborane and vinyl-9-BBN with two chiral dienes have been studied theoretically. Calculations suggest high reactivity and regio- and stereoselectivity could be achieved in these processes giving the anti para endo product. This class of reactions represents a potential stereoselective approach to a variety of chiral carbocycles.     

Synthesis of P-chiral phosphines via chiral metal template promoted asymmetric furan Diels-Alder reaction

The organoplatinum complex containing ortho-metalated (S)-(1-(dimethylamino)ethyl)-naphthalene as the chiral auxiliary has been used to promote the asymmetric [4+2] Diels-Alder reaction between phenyldivinylphosphine and 2-diphenylphosphinofuran. The reaction was complete in 6 days at room temperature, with the formation of four isomeric diphosphino-substituted oxanorbornene metal complexes in the ratio of 4:2:2:1. Only the exo-cycloaddition products were formed. The formation of stereogenic carbon centers within the oxanorbornene skeleton are highly stereoselective, with all four cycloadducts adopting the same absolute configurations. However, the stereocontrol at the external phosphorus stereogenic center is less efficient (S_p:R_p = 2:1 for the template cycloadducts). The chiral naphthylamine auxiliary could be removed chemoselectively by treatment with concentrated hydrochloric acid, and further ligand liberation of the dichloro complexes with aqueous cyanide gave the diphosphino-substituted oxanorbornene ligands. Hydrogenation of the double bonds in the cycloadduct stabilizes the phosphorus stereogenic center of the free diphosphine ligand which otherwise undergoes inversion of absolute configuration.     

One catalyst for two distinct reactions: sequential asymmetric hetero Diels-Alder reaction and diethylzinc addition

This paper describes the successful development of a series of chiral zinc catalysts containing (R)-3,3′-Br₂-BINOL ligand and various diimine activators for enantioselective HDA reaction of Danishefsky's diene with aldehydes through a combinatorial approach, affording the corresponding 2,3-dihydro-4H-pyran-4-one derivatives in excellent yields and enantioselectivities. The application of this type of catalysts was also extended to the diethylzinc addition to the benzaldehyde, affording the corresponding secondary alcohol with up to 94.5% ee under optimized conditions. On the basis of these facts, the integration of two distinct enantioselective reactions, HDA and diethylzinc addition reactions, has been realized in one-pot with the promotion of a single chiral zinc catalyst in a sequential manner. The impact of diimine additive on the catalytic system of HDA reaction was also investigated by probing the nonlinear effect of reaction system. The positive nonlinear effect exhibited in the catalytic system could be attributed to the poor solubility of the heterochiral zinc species. On the basis of various experimental findings disclosed in this research, a possible mechanism for the asymmetric induction in the 3,3′-Br₂-BINOL/Zn/diimine catalyzed enantioselective HDA reaction of Danishefsky's diene with aldehydes was outlined.     

Stereoselective intramolecular hetero Diels-Alder reactions of 1-oxa-1,3-butadienes: synthesis of novel annelated pyrrolo[1,2-a]indoles

Novel classes of pyrano-1,3-dioxane-, pyranopyrimidine- and pyranopyrazole-fused pyrrolo[1,2-a]indoles are synthesised via stereoselective intramolecular 1-oxa-1,3-butadiene hetero Diels-Alder reactions.     

Microwave-assisted organocatalytic multicomponent Knoevenagel/hetero Diels-Alder reaction for the synthesis of 2,3-dihydropyran[2,3-c]pyrazoles

A rapid protocol for the multicomponent microwave-assisted organocatalytic domino Knoevenagel/hetero Diels-Alder reaction (DKHDA) has been developed for the synthesis of 2,3-dihydropyran[2,3-c]pyrazoles. The reported procedure could be used for the fast generation of novel substituted 2,3-dihydropyran[2,3-c]pyrazoles with potential anti-tuberculosis activity.     

Diastereoselectivity-switchable and regiospecific hetero Diels-Alder reaction of N-sulfinylper(poly)fluoroalkanesulfinamides with dienes

N-Sulfinylper(poly)fluoroalkanesulfinamides reacted readily with dienes in methylene chloride at −78 °C to give the corresponding cycloadducts with complete regioselectivities and good diastereoselectivities. The diastereoselectivity of the reaction was switchable to the opposite under the catalysis of Lewis acids such as TiCl₄ and SnCl₄.     

Preparation of a chiral azadiene for the synthesis of 5-aza analogues of angucyclinones

We have developed an efficient synthesis of both enantiomers of a key azadiene for the preparation of 5-aza analogues of angucyclinones through a hetero Diels-Alder reaction. These dienes were efficiently prepared via a 4-step procedure from known and readily available chiral diketoesters.     

Computer-assisted design of asymmetric 1,3-dipolar cycloadditions between dimethylvinylborane and chiral nitrones

This report describes a theoretical study of the 1,3-dipolar cycloadditions between dimethylvinylborane and different chiral nitrones, aimed at identifying the requisite structural features to achieve high levels of selectivity. Excellent regioselectivities towards the formation of the 5-borylisoxazolidines are computed in all cases due to the presence of a strong secondary orbital interaction between the boron of the vinylborane and the oxygen of the nitrones. While these transition structures show [3+3] character, 4-boryl regioisomeric structures have classical [3+2] character with weak carbon-boron secondary orbital interactions. Endo transition structures leading to the favoured products adopt chair-like conformations only, unlike their exo counterparts, which exhibit either boat or twist-boat structures. Placing a stereocentre adjacent to the nitrone nitrogen appears to be an effective strategy to stereodiscriminate the anti and syn approaches of the dipolarophile.     

Novel phosphonated bicyclic frameworks from Diels-Alder reaction as chelating agents of di- and trivalent metal cations

The synthesis of novel [4+2] cycloadducts by Diels-Alder (DA) reaction between diethyl 1-phosphono-1,3-butadiene and cyclic CC and NN dienophiles, such as maleimide and 1,2,4-triazole-3,5-dione derivatives, is described. These phosphonated bicyclic frameworks feature a cage shape enabling metal chelation. Indeed, stable complexes were formed in solution with M²⁺ and M³⁺ metal cations, as evidenced by HRMS in the ESI mode (electrospray ionization). L₁:M (one ligand-one metal) and L₂:M (two ligands-one metal) complexes were identified depending on the nature of the cation.     

A hetero Diels-Alder approach to the synthesis of the first angucyclinone and angucycline 5-aza-analogues

The synthesis of two new heterodienes and their regioselective [4+2]cycloaddition reactions with several bromo-naphthoquinones allowed us to prepare the first angucyclinone and angucycline 5-aza-analogues.     

A theoretical investigation into chiral phosphoric acid-catalyzed asymmetric Friedel-Crafts reactions of nitroolefins and 4,7-dihydroindoles: reactivity and enantioselectivity

This article mainly focused on high level Density Functional Theory (DFT) studies on the chiral phosphoric acid-catalyzed Friedel-Crafts reactions between 4,7-dihydroindoles and nitroolefins. Firstly, the reactivities of 4,7-dihydroindole and indole in the chiral phosphoric acid-catalyzed Friedel-Crafts reactions with nitroolefin have been compared. The higher reactivity of 4,7-dihydroindole could be attributed to its higher HOMO energy as well as its more suitable trajectory to attack the nitroolefin in the transition state. Secondly, the origin of the enantioselectivity of the chiral phosphoric acid-catalyzed Friedel-Crafts reaction of 4,7-dihydroindole with nitroolefin has been studied using complete models on PBE1PBE/[6-311+G(d,p), 6-31G(d,p)] level. When (S)-1b was used as the catalyst, the enantioselectivity of the reaction is entirely controlled by the steric effect between the catalyst and the substrate. Whereas for catalyst (S)-1c the enantioselectivity is determined by the solvent effect.     

Stereoselective intramolecular hetero Diels-Alder reactions of 1-oxa-1,3-butadienes: a novel approach for the synthesis of complex annulated uracils

The intramolecular hetero Diels-Alder reactions of 1-oxa-1,3-butadienes 4, obtained from salicylaldehyde 1 via O-allylation followed by Knoevenagel condensation with barbituric acids 3 in the presence of hydrochloric acid as catalyst, affords the tetracyclic uracil derivatives 5 and 6 in a stereoselective manner and high overall yields.     

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.     

Chiral bis(2-oxazolinyl)xanthene (xabox)/transition-metal complexes catalyzed 1,3-dipolar cycloaddition reactions and Diels-Alder reactions

A series of chiral 4,5-bis(2-oxazolinyl)-(2,7-di-tert-butyl-9,9-dimethyl)-9H-xanthenes (xabox) and their transition-metal complexes were synthesized. The X-ray analysis of xabox-RhCl₃ complex shows a unique facial type structure. Xabox-Bn-Mn(II) and xabox-Bn-Mg(II) complexes were found to be efficient catalysts in nitrone 1,3-dipolar cycloaddition (1,3-D.C.) reaction resulting in good to excellent enantioselectivities ranging from 96:4 to >99:1of endo/exo ratio and 91-96% ee for the endo adduct. The correlation between enantiomeric excess of the ligand and the product in the nitrone 1,3-D.C. reaction shows a clear linear relationship, which suggests xabox-metal catalyst worked as a single molecular catalyst. In addition, xabox-i-Pr-Mn(II) complex was also found to be an active catalyst for Diels-Alder (D-A) reaction of acryloyloxazolidinone and cyclopentadiene affording the corresponding cycloadduct in quantitative yield along with 82% ee and 98:2 endo/exo ratio.     

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.     

Asymmetric synthesis of a chiral arsinophosphine via a metal template promoted asymmetric Diels-Alder reaction between diphenylvinylphosphine and 2-furyldiphenylarsine

The asymmetric Diels-Alder reaction between 2-furyldiphenylarsine and diphenylvinylphosphine was achieved stereospecifically by utilizing an organoplatinum reaction promoter containing the ortho-metalated (R)-(1-(dimethylamino) ethyl)-naphthalene as the chiral auxiliary. The optically pure (+)-As-P heterobidentate cycloadduct could be liberated from the template product by successive treatment with concentrated hydrochloric acid and aqueous potassium cyanide.