Palladium- and copper-catalyzed synthesis of medium- and large-sized ring-fused dihydroazaphenanthrenes and 1,4-benzodiazepine-2,5-diones. control of reaction pathway by metal-switching

Methods for the synthesis of dihydroazaphenanthrene fused to macrocycles (2) and medium-ring heterocycles (4), as well as 1,4-benzodiazepine-2,5-diones (5), are developed. A distinctly different catalytic property of palladium and copper catalysts was uncovered that leads to the development of a divergent synthesis of two different heterocyclic scaffolds from the same starting materials, simply by metal-switching. Thus, starting from linear amide 3, palladium acetate triggers a domino intramolecular N-arylation/C-H activation/aryl-aryl bond-forming process to provide 4, while copper iodide promotes only the intramolecular N-arylation reaction leading to 5. In combination with the Ugi multicomponent reaction (Ugi-4CR) for the preparation of the linear amides, a two-step synthesis of either the 5,6-dihydro-8H-5,7a-diazacyclohepta[jk]phenanthrene-4,7-dione (4) or 1,4-benzodiazepine-2,5-diones (5), by appropriate choice of metal catalyst, is subsequently developed from very simple starting materials.     

Diels-Alder Reactions of 6,9-Dipropyl-1, 4-Dioxaspiro[4.5]Deca-6, 8-Diene-2, 10-Dione with Substituted Alkenes. An Entry to Bicyclo[2.2.2]Oct-5-Ene-2, 3-Diones and 1, 3-Cyclohexadienes

The cycloadditions of the title compound, 1, a masked 3, 6-dipropyl-o-benzoquinone to various disubstituted (diethyl maleate, diethyl fumarate, trans- and cis-stilbene, and cycloheptene) and monosubstituted alkenes (methyl acrylate, methyl vinyl ketone, styrene, ethyl vinyl ether, and 1-hexene) have been studied; the yields of the Diels-Alder adducts, 2, are generally high (> 75%) except for stilbenes. These adducts are effectively transformed into the corresponding bicyclo[2.2.2]oct-5-ene-2, 3-diones, 3, whose stereochemistries are determined from the ring current effect of the respective quinoxalines, 4, on the chemical shifts of the vinyl and the methine protons and/or the lanthanide (Eu(fod)₃) induced shift on the pertinent protons of 3. It is interesting to note that the quinoxaline ring current makes the vinyl protons down-field shifted by 0.15–0.27 ppm whereas the methine protons (R³=H) syn to the quinoxaline moiety up-field shifted by 0.18–0.39 ppm as compared to the chemical shifts of the corresponding protons in 3. The transformations of α-diketones 3 into the corresponding 1, 3-cyclohexadienes, 5, by irradition with a Hanovia medium pressure lamp through a uranium glass filter are almost quantitative. The present study provides facile and effective methods for the preparation of bicyclo[2.2.2]oct-5-ene-2, 3-diones and 1, 3-cyclohexadienes from catechols via masked o-benzoquinones.     

Synthesis of 1,4-benzodiazepine-3,5-diones

Even though benzodiazepines have a strong position in medicinal chemistry, very few synthetic routes to 1H-1,4-benzodiazepine-3,5(2H,4H)-diones have ever been published and the claimed products have often been poorly characterized. Through the present work several 1H-1,4-benzodiazepine-3,5(2H,4H)-diones have become available from N-carbamoylmethylanthranilic acids. The required ring closures were achieved only when the amino groups of the starting materials were substituted with electron withdrawing groups such as acetyl, alkyloxycarbonyl, or nitroso. During the synthetic work a novel ring contraction rearrangement from a 1-nitroso-1H-1,4-benzodiazepine-3,5(2H,4H)-dione to a 3H-quinazoline-4-one was observed. The proposed mechanism involves elimination of HNO followed by a proton-mediated loss of CO. The 1-nitrosated 1,4-benzodiazepinediones could be separately denitrosated to the corresponding amino compounds.     

3-nitrocoumarins as dienophiles in the Diels-Alder reaction in water. An approach to the synthesis of nitrotetrahydrobenzo[c]chromenones and dihydrodibenzo[b,d]furans

The [4 + 2] cycloadditions of 3-nitrocoumarin (1a), 6-chloro-3-nitrocoumarin (1b), and 6-, 7-, and 8-hydroxy-3-nitrocoumarins (1c, 5, and 6) with (E)-piperylene (7), isoprene (8), 2,3-dimethyl-1,3-butadiene (9), 2-methoxy-1,3-butadiene (10), 2,3-dimethoxy-1,3-butadiene (11), and cyclopentadiene (12) were investigated in aqueous medium, in organic solvent and under solventless conditions. The reactions performed in water occurred in heterogeneous phase but were faster than those executed in toluene or dichloroethane (DCE). 1a-c, 5, and 6 behaved as 2pi components in the Diels-Alder cycloadditions with 7-10 and 12, and exo adducts were preferentially or exclusively produced. Surprisingly 1a, behaved as a 4pi component in the cycloaddition in water with 11 and 4-substituted 3-nitrochromanones 20 and 21 were isolated. The cycloadditions of hydroxy-3-nitrocoumarins 1c, 5, and 6 with 1,3-diene 9 did not work in water or in organic solvent, but did work under solventless conditions. Nitrotetrahydrobenzo[c]chromenones 13-16, 24, and 25, originating from the normal electron-demand Diels-Alder reactions, were converted into dihydrodibenzo[b,d]furans 27-31 in water, via one-pot Nef-cyclodehydration reactions.     

Recent developments in the enantioselective synthesis of polyfunctionalized pyran and chromene derivatives

Recent developments in the synthesis of 4H- and 2H-pyrans as well as structurally related chromene derivatives that have enabled the enantioselective synthesis of these scaffolds have been surveyed. The role of chiral catalysts in orienting initial reactions of active methylenes, methines and methyl ketones, to unsaturated ketones and nitriles in multi-component reactions or Friedel–Craft alkylations of phenols is discussed to show their involvement in transition states leading to end products. Chromene synthesis via [4+2] cycloadditions, [3+3] and [4+2] annulations as well as ring opening and recyclization leading to high enantio- and diasteroselectivity is also demonstrated. The enantioselectivity in such catalytic asymmetric reactions despite starting with non-chiral starting materials is discussed. On the other hand, in surveying ring opening and recyclization, the starting materials are chiral and the chiral center was not part of the reaction leading to the final product.     

Racemic and asymmetric Diels-Alder reactions of 1-(2-oxazolidinon-3-yl)-3-siloxy-1,3-butadienes

Achiral and chiral 1-(2-oxazolidinon-3-yl)-3-siloxy-1,3-butadienes were prepared from readily available starting materials. Although more stable than the parent 1-amino-3-siloxy dienes, the 1-(2-oxazolidinon-3-yl)-3-siloxy-1,3-butadienes are still very reactive in Diels-Alder reactions, somewhat more than 1,3-dialkoxy-1, 3-butadienes (e.g., Danishefsky's diene). The cycloadditions of the achiral and chiral dienes with several different dienophiles were examined. The reactions proceeded in good yield, with modest to high endo selectivity. The chiral dienes exhibited excellent facial selectivity in cycloadditions with alpha-substituted acroleins, maleic anhydride and N-phenylmaleimide. Upon reduction and hydrolysis of the cycloadducts, substituted cyclohexenones were obtained with ee's ranging from 22% to >98%.     

Diels-alder cycloadditions of 1,3,4,-oxadiazin-6-ones with electron rich pi systems

A study of the cycloaddition behavior of several 2,5-disubstituted 1,3,4-oxadiazin-6-ones with electron rich pi bonds has been carried out. $\text{trans}$-1-Propenylpyrrolidine was found to react with the oxadiazinone ring system to give rise to a ring opened diazatrienyl substituted carboxylic acid. Further heating of the acid results in decarboxylation, hydrolysis, cyclization and pyrrolidine elimination to produce a disubstituted pyrazole. Reaction with the trisubstituted enamine 1 - ( 2 - methyl-propenyl) pyrrolidine, was also studied in some detail. The cycloadditions encountered can be rationalized as proceeding by an initial Diels-Alder reaction followed by cheletropic extrusion of nitrogen to produce a ketoketene intermediate. The fate of the ketene is markedly dependent upon the overall pattern of substitution. Some of the products formed can be explained in terms of a competitive migration of the pyrrolidino group to the ketene and benzoyl groups. With one system the major cycloadduct is derived from the Diels-Alder reaction of a transient azaketene tautomer formed by an electrocyclic opening of the oxadiazinone ring.     

General synthetic entry to linearly-fused dihydrobenzocyclobutene-1,2-diones and benzocyclobutene-1,2-diones via annulation of 1,2-bis(methylene)carbocycles with 3-chloro-3-cyclobutene-1,2-dione

The tandem Diels-Alder/dehydrochlorination reaction of semisquaric chloride (1) with the 1,2-bis(methylene)cycloalkanes 2a-c and 1,2-bis(methylene)-4-cyclohexene (9) affords the linearly-fused cycloalkanodihydrobenzocyclobutene-1,2-diones 3a-c and 3,4,7,8-tetrahydrocyclobuta[b]-naphthalene-1,2-dione (10), respectively. On treatment with MnO2, 3a-c are dehydrogenated to the respective carbocycle-fused benzocyclobutene-1,2-diones 4a-c in good yields. 3a and 3b react with bromine to give the addition products 5a,b, which, on treatment with silver trifluoroacetate, afford the benzocyclobutene-1,2-diones 4a,b. For preparative purposes, the sequence 3-->5-->4 can be performed advantageously as a "one-pot procedure". Double-condensation reactions of 4a,b with alpha,alpha'-biscyano-o-xylene and o-phenylenediamine afford the pentacyclic biphenylenes 7a,b and the cyclobutahetarenes 8a,b, respectively. These cyclobutenediones suggest themselves as building blocks for the construction of extended linearly-fused polycyclic compounds with novel ring sequences. o-Quinodimethanes 12a-g generated in situ by the thermal decomposition of the respective 1,4-dihydro-2,3-benzoxathiin-3-oxides (sultines) 11a-g react with semisquaric chloride (1) to afford the 3,8-dihydronaphtho[b]cyclobutene-1,2-diones 13a-g. These, on dehydrogenation with bromine and/or MnO2, furnish the naphtho[b]cyclobutene-1,2-diones 14a-g in fair to good yields. As described for 4a,b the naphtho[b]cyclobutene-1,2-diones 14a-c are condensed with alpha,alpha'-biscyano-o-xylene and o-phenylenediamine to furnish the pentacyclic biphenylenes 15a-c and the pentacyclic cyclobutahetarenes 16a-c.     

Molecular Design by Cycloaddition Reactions. VII. Facile Thermal Isomerization in the Reaction of Isopyrazole with Diphenylcyclopropenone

Combination of the diazadiene system with three carbon dienophile in the Diels-Alder reaction would provide a synthesis of seven-membered diazaheterocycles. The reaction of 3,6-disubstituted-1,2,4,5-tetrazines with cyclopropene provides a useful route to 2,5-disubstituted-3,4-diazanorcaradienes and 5H-1, 2-diazepines.² However, in the extensive literature on the Diels-Alder reaction, there are only a few examples of cycloadditions with the azadienes as the 4e components.³

We have examined the reaction of isopyrazole with diphenylcyclo-propenone in the hope of obtaining a convenient synthetic route to the medium-size unsaturated heterocycles. Recently, the reactions of the 4,4-disubstituted isopyrazoles have been indicated to react only with cyclobutadiene⁴ and 4-phenyl-1,2,4-triazoline-3,5-dione as one of the most potent dienophiles.⁵     

Diels-Alder cycloadditions of 3-phenylamino-5-bromo-2-pyrone for the synthesis of constrained α-amino acid derivatives

3-Phenylamino-5-bromo-2-pyrone undergoes facile Diels-Alder cycloadditions with various electron deficient dienophiles to afford an array of functionally rich and stereochemically defined cycloadducts in good to excellent isolated yields. Due to the electron donacity of the amine group, it only proceeds in normal electron demand D-A cycloadditions. Subsequent ring openings with NaOMe provided constrained α-amino acid derivatives.     

An experimental and computational investigation of the Diels-Alder cycloadditions of halogen-substituted 2(H)-pyran-2-ones

[reaction: see text] Diels-Alder reactions of 3- and 5-halo-subsituted 2(H)-pyran-2-ones with both electron-rich and electron-deficient dienophiles afford stable and readily isolable bridged bicyclic lactone cycloadducts. These cycloadditions proceed with excellent regioselectivity and very good stereoselectivity. In contrast, Diels-Alder reactions of 4-halo-subsituted 2(H)-pyran-2-ones afford cycloadducts which are very prone to loss of bridging CO(2) and the subsequent formation of barrelenes ([2.2.2]cyclooctenes). Furthermore, these cycloadditions proceed with only moderate regio- and stereoselectivity. For both series of the 3- and 5-halo-subsituted 2(H)-pyran-2-ones and 4-halo-subsituted 2(H)-pyran-2-ones, the reactivity patterns do not significantly change between the halogens. The regio- and stereochemical preferences of the cycloadditions of halo-substituted 2(H)-pyran-2-ones are investigated computationally. Calculations were carried out on the transition states leading to the four possible regio- and stereoisomeric cycloadducts by using density functional theory (B3LYP/6-31G). These studies allow prediction of the regio- and stereoselectivity in these reactions which are broadly in line with experimental observations.     

Studies on the biosynthesis of paraherquamide A and VM99955. A theoretical study of intramolecular Diels-Alder cycloaddition

Intramolecular Diels-Alder reactions of 2-azadiene models have been studied quantum chemically at the B3LYP/6-31G level in order to elucidate the stereochemical features of the cyclization step involved in the biosynthesis of paraherquamide A and VM99955. These cycloadditions take place through concerted transition states associated with [4 + 2] processes. Analysis of the energies along the competitive paths reveals that while the cycloadditions of the oxindoles present a large anti selectivity, the indoles show a low syn selectivity for the formation of the C20 stereogenic center that is larger for the reduced tertiary amide form. The presence of the C14 methyl of the beta-methylproline ring produces a low hindrance along the reaction coordinate for the syn approach of the isoprene framework, in agreement with the low facial selectivity found experimentally. An analysis of the electrophilicity and activation parameters for experimental models of the inter- and intramolecular Diels-Alder reactions reveals several significant factors controlling these biosynthetic cyclizations. The results are in reasonable agreement with the available experimental data.     

Tandem Intramolecular Benzyne-Furan Cycloadditions. Total Synthesis of Vineomycinone B(2) Methyl Ester

We have exploited tandem intramolecular benzyne-furan cycloadditions employing three different benzyne precursors to generate substituted bisoxabenzonorbornadienes in a single operation. The regiochemical outcomes in these Diels-Alder reactions were effectively controlled by using disposable silicon tethers to link the reacting benzyne and furan moieties. Two different methods for converting the intermediate bisoxabenzonorbornadienes to substituted anthrarufins were developed. The first tactic entails the initial cleavage of the silicon tethers followed by regioselective ring opening of the oxabicycloheptadienes and oxidation of the central ring giving the target anthrarufin, whereas the second features the regioselective ring opening of the oxabicycloheptadienes followed by protiodesilylation and oxidation. When the starting furans bear carbohydrate substitutents, this new methodology enables the rapid assembly of the glycosyl-substituted aromatic cores of complex C-aryl glycoside antibiotics from simple starting materials. The utility of this novel approach to anthrarufins and C-aryl glycosides is exemplified in a triply convergent synthesis of vineomycinone B₂ methyl ester.     

Comments on the ring-opening polymerization of morpholine-2,5-dione derivatives by various metal catalysts and characterization of the products formed in the reactions involving R2SnX2, where X = OPr(i) and NMe2 and R = Bu(n), Ph and p-Me2NC6H4

(3S,6S)-3-Isopropyl-6-methyl-morpholine-2,5-dione (1), and (3S,6S)-3,6-dimethyl-morpholine-2,5-dione (2), do not enter into ring-opening polymerization reactions with metal catalyst precursors commonly employed for lactides, and with Sn(II) octanoate, only low molecular weight oligomers are obtained. Reactions with R2SnX2 compounds, where R = Ph, Bu(n) and p-Me2NC6H4 and X = OPr(i) or NMe2, reveal that ring-opening of the morpholine-2,5-diones does occur, but that polymerization is terminated by the formation of kinetically-inert products such as {Ph2Sn[mu,eta(3)-OCH(Me)CONCH(Pr(i))COOPr(i)]}2 (3), and {[Bu(n))2Sn[mu,eta(3)-OCH(Me)CONCH(Me)CONMe2]}2 (4), with elimination of HX. Ph3SnOPr(i) is seen to react reversibly with morpholine-2,5-diones in toluene-d8 by 1H NMR spectroscopy while (Bu(n))3SnNMe2 reacts by ring opening to give (Bu(n))3SnOCH(Me)C(O)NHCHMeC(O)NMe2. The new organotin compounds have been characterized by 1H, 13C{1H} and 118Sn NMR spectroscopy and compounds 1, 2, 3 and 4 by single crystal X-ray crystallography.     

Type 2 intramolecular N-acylnitroso Diels-Alder reaction: scope and application to the synthesis of medium ring lactams

Heteroatom variants of the type 2 intramolecular Diels-Alder reaction provide an efficient method for the preparation of bridged bicyclic heterocycles. The type 2 variant of the intramolecular N-acylnitroso Diels-Alder reaction is an effective method for the synthesis of bridged bicyclic oxazinolactams. Structural studies of the cycloadducts have allowed for quantification of the deformations of the bridgehead functionalities and provided a strategy for the stereoselective synthesis of substituted seven- and eight-membered ring lactams. Diastereoselective cycloadditions followed by cleavage of the oxazine ring afford azepin-2-ones or azocin-2-ones.     

Synthesis and structure of 1,4-diaryl-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydroquinoline-2,5-diones

Condensation of 5-arylidene-2,2-dimefhyl-1,3-dioxane-4,6-diones with 5,5-dimethyl-3-arylamino-2-cyclohexanones yields 1,4-diaryl-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydroquinoline-2,5-diones. The compounds have been characterized from their IR, UV, and PMR spectra. It has been established that the N-phenyl ring, which projects from the plane of the octahydroquinolinedione ring, has a shielding effect on the magnetic field of the protons at the 7- and 8-positions of the ring in the molecules of the compounds synthesized.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1227–1232, September, 1993.     

Photochromic fluorescent indol-3-yl-substituted maleimides

New hetarylethenes, 3-(indol-3-yl)-4-thienyl(but-1-en-1-yl)-substituted pyrrole-2,5-diones containing coumarin or fluorene substituents on the pyrrole nitrogen atom, were synthesized by reactions of furan-2,5-diones with 9H-fluoren-2-amine and 6-amino-2H-chromen-2-one. Acyclic maleimide isomers showed fluorescence with quantum yields of 0.002 to 0.072. Their irradiation with UV light generates non-fluorescing cyclic isomer. The reverse ring opening occurs in the excited state.     

Computational and experimental investigation of the Diels-Alder cycloadditions of 4-chloro-2(H)-pyran-2-one

4-Chloro-2(H)-pyran-2-one undergoes thermal Diels-Alder cycloaddition with electron-deficient dienophiles to afford, without any significant selectivity, 6-endo- and 5-endo-substituted bicyclic lactone cycloadducts. In contrast to 3- and 5-bromo-2(H)-pyran-2-one, 4-chloro-2(H)-pyran-2-one does not undergo thermal cycloadditions with electron-rich dienophiles. The regio- and stereochemical preferences of the cycloadditions of 4-chloro-2(H)-pyran-2-one and other related 2(H)-pyran-2-ones are investigated computationally. Calculations were carried out on the transition states leading to the four possible regio- and stereoisomeric cycloadducts using density functional theory (B3LYP/6-31G). These studies allow prediction of the regio- and stereoselectivity in these reactions which are in line with experimental observations.     

Syntheses of strychnine, norfluorocurarine, dehydrodesacetylretuline, and valparicine enabled by intramolecular cycloadditions of Zincke aldehydes

A full account of the development of the base-mediated intramolecular Diels-Alder cycloadditions of tryptamine-derived Zincke aldehydes is described. This important complexity-generating transformation provides the tetracyclic core of many indole monoterpene alkaloids in only three steps from commercially available starting materials and played a key role in short syntheses of norfluorocurarine (five steps), dehydrodesacetylretuline (six steps), valparicine (seven steps), and strychnine (six steps). Reasonable mechanistic possibilities for this reaction, a surprisingly facile dimerization of the products, and an unexpected cycloreversion to regenerate Zincke aldehydes under specific conditions are also discussed.     

Diels-Alder reactions between dienamides and quinones: stereochemistry of the cycloadditions and cytotoxic activity of the adducts

Tetrahydronaphthoquinones and tetrahydroanthraquinones bearing an amido group have been prepared by Diels-Alder reactions between (E)-1-(N-carbobenzyloxyamino)-1,3-butadiene (2) or (E)-1-(N-benzoyl-N-benzylamino)-1,3-butadiene (5) and benzoquinone or 5-substituted naphthoquinones. The stereochemistry of the cycloadditions was investigated. A high regioselectivity was observed in the reaction of the diene carbamate 2 with 5-methoxy and 5-acetoxy naphthoquinones. This latter gave the unexpected 1,8-regioisomer 3d. The cycloadditions of the dienamide 5 with naphthoquinones 1 (R = OH, OMe, OAc) are regiospecific. Assignment of the structure of the tetrahydroanthraquinone 6b is in good agreement with the known directing effect of the 5-hydroxy group of juglone 1b in analogous Diels-Alder reactions. With 5-methoxy and 5-acetoxy naphthoquinones, the opposite regiochemistry observed is consistent with the electron-donating influence of the methoxy or acetoxy group, making the C-3 carbon atom more electron deficient. Aromatization of the adducts 6b and 7c was accompanied by an unusual elimination of the amido moiety. Thus, 1-hydroxy and 1-methoxy anthraquinones were obtained. Reactions of the dienes 2 and 5 with benzoquinone gave the tetrahydronaphthoquinones 9 and 10 with an endo stereospecificity. Oxidation of 9 by activated manganese dioxide gave the naphthoquinone 11. These compounds were submitted to in vitro cytotoxic assays towards murine L 1210 leukemia cells and clonogenic human tumor cell line MDA-MB 231. The naphthoquinone derivatives 9, 10 and 11 had significant activities with IC50 less than or equal to 0.4 microgram/ml towards these two tumor cell systems.