Pteridines. Part CXIX.

A variety of pyrimidine precursors 12 – 25 were converted into a series of new 7‐hydroxylumazines (=7‐hydroxypteridine‐2,4(1H,3H)‐diones) 26 – 35 which functioned as starting materials for the transformation into the corresponding 7‐chlorolumazines 36 – 45 . Subsequent reaction with hydrazine led to the 7‐hydrazinolumazines 46 – 55 which gave on nitrosation the 7‐azidolumazines 1 and 56 – 64 . These compounds were subjected to short heating in xylene whereby 1 and 56 – 61 showed a new pteridine–purine interconversion in forming a new type of 1,3‐disubstituted or 3‐substituted xanthin‐8‐amine‐derived nitrilium ylides (2,3,6,7‐tetrahydro‐N‐methylidyne‐2,6‐dioxo‐1H‐purin‐8‐aminium ylides) 11 and 65 – 70 . The presence of an additional 6‐alkyl substituent in the 7‐azidolumazines 63 and 64 or of an unsubstituted N(3) position in 62 caused further rearrangement to xanthine‐9‐carbonitriles 71 – 73 . Prolonged heating of 7‐azido‐1,3‐dimethyllumazine ( 1 ) also afforded theophylline‐9‐carbonitrile (=1,2,3,6‐tetrahydro‐1,3‐dimethyl‐2,6‐dioxo‐9H‐purine‐9‐carbonitrile; 5 ). The nitrilium ylide function was established by NMR and UV spectra as well as by elemental analyses. Confirmation of the nitrilium ylide structures was suggested by the result of the heating of 1,3‐dimethyl‐N‐methylidynexanthin‐8‐aminium ylide 11 in EtOH or of 1 in pentan‐1‐ol leading to 8‐aminotheophylline (=8‐amino‐3,7‐dihydro‐1,3‐dimethyl‐1H‐purin‐2,6‐dione; 74 ).     

The Astounding Chemistry of a 2‐Amino‐1,2‐dihydroisoquinoline Derivative

The cycloadducts of isoquinolinium N‐phenyl imide 2 with C=C bonds are derivatives of 2‐amino‐1,2‐dihydroisoquinoline. Their N^β‐vinylphenylhydrazine system is amenable to an acid‐catalyzed [3,3]‐sigmatropic shift; the formation of pentacyclic aminals is exemplified by 6 → 8 . The dimethyl maleate adduct 11 , C₂₁H₂₀N₂O₄, is exceptional by being converted on treatment with acid to bright‐yellow crystals, C₂₄H₂₂N₂O₆ (additional C₃H₂O₂). X‐Ray crystal‐structure analysis and NMR spectra reveal structure 13 , and mechanistic studies indicated an initial β‐elimination at the N−N bond of 11 to yield 18 ; this step is followed by a retro‐Mannich‐type cleavage that gives methyl isoquinoline‐1‐acetate ( 14 ) and methyl 2‐(phenylimino)acetate ( 15 ), according to the sequence C₂₁H₂₀N₂O₄ ( 11 )→ 18 →C₁₂H₁₁NO₂ ( 14 )+C₉H₉NO₂ ( 15 ). In the second act of the drama, electrophilic attack by 15 ‐H⁺ on the ene‐hydrazine group of a second molecule of 11 furnishes 13 by a polystep intramolecular redox reaction. All rate constants must be fine‐tuned in this reaction cascade to give 13 in yields of up to 78% with an overall stoichiometry: 2 C₂₁H₂₀N₂O₄ ( 11 )→C₂₄H₂₂N₂O₆ ( 13 )+C₁₂H₁₁NO₂ ( 14 )+aniline. Interception and model experiments confirmed the above pathway. A by‐product, C₃₃H₃₁N₃O₆ ( 62 ), arises from an acid‐catalyzed dimerization of 11 and subsequent elimination of 15 .     

Triphenylphosphine Mediated Efficient Synthesis of 4-Substituted-1-methyl-2,5-dioxo-3-imidazolines

Summary.  Stable crystalline phosphorus ylides are obtained in excellent yields from the 1:1:1 addition reaction between 1-methylparabanic acid (1-methylimidazoline-2,4,5-trione) and dialkyl acetylenedicarboxylates in the presence of triphenylphosphine. These ylides exist in solution as a mixture of two geometric isomers. This is due to the restricted rotation around the carbon–carbon partial double bond resulting from conjugation of the ylide moiety with the adjacent carbonyl group. These ylides undergo smooth intramolecular Wittig reaction followed by an electrocyclic ring opening to produce dialkyl (E)-2-(1-methyl-2,5-dioxo-3-imidazolin-4-yl)-but-2-enedioates in good yields. Corresponding author. E-mail: isayavar@yahoo.com Received March 26, 2002; accepted (revised) April 24, 2002     

Anomalous Stereochemistry in the Wittig Reaction Induced by Nucleophilic Groups in the Phosphonium Ylide

Abstract

Reaction of ylides from 3–9 with benzaldehyde show that carboxylate and oxido functionalities proximate to the ylide center promote anomalously high E stereoselectivity in alkene formation. Through the use of α-deuterated ylides 12–14, an internal “trans-selective Wittig” mechanism was ruled out as a principal source of exaggerated E alkene production.     

Regioselectivity of the 1,3-dipolar cycloaddition of fluorinated fluoren-9-iminium ylides to heteroelement-containing dipolarophiles: Experimental and quantum-chemical study

N-Substituted 9H-fluoren-9-imines react with difluorocarbene to give the corresponding iminium ylides whose further transformations in the absence of active dipolarophiles depend on the substituent at the nitrogen atom and reaction conditions. N-Ethyl-, N-benzyl-, and N-(2-phenylethyl)-9H-fluoren-9-imines are thus converted in low yield into the formal cyclodimerization products and/or 9H-fluorene-9-carboxamides. N-Methyl-substituted fluoreniminium ylide readily adds at the C=N bond of initial N-(9H-fluoren-9-ylidene)-methanamine with formation of spiro-fused imidazolidine derivative; in the presence of fluorenone, acetaldehyde, or benzaldehyde, addition at the C=O group of the dipolarophile occurs to give the corresponding oxazolidine derivatives. The regioselectivity of the cycloaddition of iminium ylides having a fluorene fragment at a double carbon-heteroelement bond can be described by quantum-chemical calculations in terms of the density functional theory (DFT; local hard and soft acids and bases concept): the cycloaddition leads preferentially to the 2,2-difluoro-substituted adduct.     

Cu(OTf)2-promoted efficient synthetic route towards glycospiro-pyrrolo[2,1-a]isoquinolines

A simple, convenient and efficient protocol for the construction of an array of glycospiro-pyrroloisoquinolines using isoquinolinium ylide and a carbohydrate-derived exocyclic olefin in the presence of Cu(OTf)₂–Et₃N catalytic system is described. Isoquinoline and alkylbromoacetates/2-bromoacetophenones were employed to generate the azomethine ylides in the presence of Et₃N in refluxing toluene and subsequent exposure to the olefin led to the desired isoquinoline derivatives.     

Photochemische Reaktionen. 117. Mitteilung [1] Zur Photochemie von 5,6-Epoxydienen und konjugierten 5,6-Epoxytrienen

Photochemistry of 5,6-Epoxydienes and of Conjugated 5,6-Epoxytrienes On singulet excitation (δ = 254 nm) the 5,6-epoxydiene 6 and the conjugated 5,6-epoxytrienes 7 and 8 exclusively give products arising from cleavage of the C, C-bond of the oxirane (cf. 6 → 9 , 10 , 11 ; 7 → (E)- 15 , 16 , 17 ; 8 → 18 (A+B) , 19 (A+B) , 20 , 21 ). The dihydrofuran compounds 11 and (E/Z)- 15 are formed by cyclization of a ketonium-ylide a and d , respectively. Photolysis of a gives the carbene b which yields the cyclopropene 9 , whereas d forms photochemically the carbenes f and g which yield the methano compounds 16 and 17 . The isomeric cyclopropene derivatives 20 and 21 are products of the intermediates h and i , respectively, which are formed by photolysis of the ylide e . The cyclopropene 21 isomerizes by intramolecular cycloadditions to 18 (A+B) and 19 (A+B) . - On triplet excitation (λ?LD nm; 280 nm; acetone) 6 undergoes cleavage of the C(5), O-bond and isomerizes to 12 and 14 . However, 7 is converted by cleavage of the C, C-bond of the oxirane to yield 15 . On treatment with BF₃O(C₂H₅)₂ 6 gives 14 , whereas 7 yields 22 , and 8 forms 23 and 24 .     

Electrochemical reductions of substituted pyridinium 2-pyridylcarbonylmethylides,their Pt(II) complexes,and substituted n-(2-pyridylcarbonyl)methylpyridinium perchlorates

The title pyridinium salts and pyridinium ylide-platinum(II) complexes have been reduced through a one-electron process at more positive potentials by 0.3 $\text{\$}\text{?}$0.6 V than the corresponding ylides. Both the reduced pyridinium salts and Pt(II)-ylide complexes reacted with dioxygen, followed by elimination of the N-methylene and ylide protons to form pyridinium ylides and Pt(II)-pyridinium ylide complexes containing the three-coordinate ylide carbon atom, respectively.     

Synthesis of New Stable Phosphorus Ylides and 1,4‐Diionic Organophosphorus Compound from a Reaction between Hexamethyl Phosphorous Triamide and Dimethyl Acetylenedicarboxylate in the Presence of CH‐Acids

A simple and efficient one‐pot three‐component reaction between hexamethyl phosphorous triamide and dimethyl acetylenedicarboxylate (DMAD) in the presence of CH‐acids, such as acetylacetone, 1,3‐indandione, dibenzoylmethane, anthrone, and N,N‐dimethylbarbituric acid, has been studied. In all cases, new and stable phosphorus ylides are obtained in excellent yields. These stable ylides exist in solution as a mixture of two geometrical isomers as a result of restricted rotation around the carbon–carbon partial double bond, resulting from conjugation of the ylide moiety with the adjacent carbonyl group. From the reaction of N,N‐dimethylbarbituric acid with DMAD in the presence of hexamethyl phosphorous triamide, a 1,4‐diionic organophosphorus compound is obtained. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 24:84–89, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21067     

Competitive Formation of Ylide and Carbene Intermediates from 1π,π*-Excited α,β-Unsaturated γ,δ-Epoxyketones

Laser flash photolyses (λ = 265mm) of the γ,λ-epoxyenones 1–3, 7 and 8 , the α,β-unsaturated γ,δ-epoxy ester 6 , and the epoxytriene 9 at ambient temperature produced short-lived transients with broad absorption maxima in the visible region, which are identified as carbonyl ylides. Comparison of the rather long-wavelength absorption maxima with the results of standard PPP SCF SCI calculations suggests that some degree of twisting is present in all the ylides studied. The lifetimes of the order of hundreds of ns of these intermediates and Stern-Volmer analysis of the trapping of the carbonyl ylide derived from 2 with CH₃COOH provide conclusive evidence that the carbene products are not formed via the carbonyl-ylide intermediate (Scheme 3).     

In situ generated stabilized phosphorus ylides mediated a mild and efficient method for the preparation of some new sterically congested electron-poor N-vinylated heterocycles

Protonation of the highly reactive 1:1 intermediate produced in the reaction between triphenylphosphine and an acetylenic ester by a N-H acid (4-phenylphthalazin-1(2 H)-one, 5,5-diphenylimidazolidine-2,4-dione) leads to the formation of a vinyltriphenylphosphonium salt. The cation of the salt undergoes an addition reaction with the counter anion in CH₂Cl₂ at room temperature to yield the corresponding stabilized phosphorus ylide. Elimination of triphenylphosphine from the stabilized phosphorus ylides leads to the formation of corresponding electron-poor N-vinylated heterocycles in moderate to high yields (67–95%). The reaction is completely regio- and stereoselective.     

The crystal and molecular structure of pentafluoropropionylbenzoylmethylene triphenylphosphorane

The crystals of pentafluoropropionylbenzoylmethylene triphenylphosphorane that bears two strongly electron-withdrawing groups in alkylidene moiety are monoclinic and its space group is C2/c, with a = 11.271(3)Å, b = 18.253(6)Å, c =23.938(7)Å, β = 91.09(2)°, z = 8. The X-ray diffraction intensity data were collected on a four-circle diffractometer. The structure has been solved by direct method and refined by block-diagonal least-squares method. The final R- index was 0.075 for 3146 independent observed reflexions. In this paper the structure of this ylide is compared with that of corresponding arsonium ylide previously reported. Both ylidic skeleton structures are planar with sp² hybridization. The bond length of P-C(1) is 1.748 (5)Å with bond order. 1.60 while the bond order of As-C(1) in the corresponding arsonium ylide is 1.46, indicating that the phosphonium ylide has a greater contribution of “ylene” structure to the overall structure. As a result the phosphonium ylide should be less reactive than the corresponding arsonium ylide. In both ylides, (he major delocalized canonical forms of negative charge are shown to be 3.     

Carbenoid Reactions of Dimethyl Diazomalonate with Aromatic Thioketones and 1,3-Thiazole-5(4H)-thiones

Dimethyl diazomalonate ( 4 ) and thiobenzophenone ( 2a ) do not react in toluene even after warming to 50°. After addition of catalytic amounts of Rh₂(OAc)₄, a smooth reaction under N₂ evolution afforded a mixture of thiiranedicarboxylate 5 and (diphenylmethylidene)malonate 6 (Scheme 2). A reaction mechanism via an intermediate ‘thiocarbonyl ylide’ 7 , formed by the addition of the carbenoid species 8 to the S-atom of 2a , is plausible. Similar reactions were carried out with 9H-xanthene-9-thione ( 2b ), 9H-thioxanthene-9-thione ( 2c , Scheme 4), and 1,3-thiazole-5(4H)-thione 18 (Scheme 6). In the cases of 2b and 2c , spirocyclic 1,3-dithiolanetetracarboxylates 14a and 14b , respectively, were obtained as the third product. Reaction mechanisms for their formation are proposed in Scheme 5: S-transfer from intermediate thiirane 12 to the carbenoid species yielded thioxomalonate 15 which underwent a 1,3-dipolar cycloaddition with ‘thiocarbonyl ylide’ 16 . An alternative is the formation of ‘thiocarbonyl ylide’ 17 via carbene addition to 15 , followed by 1,3-dipolar cycloaddition with 2b and 2c , respectively.     

Sulfur Ylide Promoted Synthesis of N‐Protected Aziridines: A Combined Experimental and Computational Approach

A range of N‐protected aziridines [N‐Tosyl (N‐Ts), N‐2‐trimethylsilylethanesulfonamide (N‐SES), N‐tert‐butoxycarbonylamido (N‐Boc), and N‐o‐nitrobenzenesulfonamide (oNs)] were prepared in moderate to good yield and with high enantiomeric excess of both isomers starting from N‐protected imines, using a sulfonium salt derived from Eliel’s oxathiane. The diastereoselectivities of the reactions are influenced by the imine N‐protecting group, the imine substituent, and the sulfide structure. An unusual cis selectivity was observed in the formation of N‐tosyl‐2‐phenyl‐3‐tert‐butylaziridine and N‐o‐trimethylsilylethanesulfonamide‐2‐phenyl‐3‐tert‐butylaziridine, which was explained by using computational models. The analysis suggests that betaine formation in the case of N‐tosyl‐tert‐butylaldimine aziridination using oxathiane benzyl sulfonium ylide 1 ′ is reversible and that the selectivity is determined at the rotation step, which is unusual for semistabilized ylide aziridination. We have shown herein that the steric bulk of an imine substituent, in combination with a sterically demanding sulfonium ylide, can also affect the reversibility of the reaction. This is the first example of this sort involving aziridinations using semistabilized ylides.     

A new synthesis of imidazo[1,2-a]pyridine and imidazo[2,1-a]isoquinoline derivatives

A new synthesis of imidazo[1,2-a]pyridine and imidazo[2,1-a]isoquinoline derivatives 4 and 8 , respectively by 1,5-dipolar cyclization reactions of stabilized pyridinium N-ylides 3a-e or isoquinolinium N-ylide 7 is described. The starting N-ylides 3a-e and 7 are prepared by the reaction of the corresponding pyridinium salts 1a-e or isoquinolinium salts 6 with N-bis(methylthio)methylene-p-toluenesulfonamide (2) .     

An Efficient Enantioselective Synthesis of (—)-Serricorole

The cigarette beetle pheromone (–)-serricorole ( 1 ) has been synthesized in 23% overall yield by an eight-step sequence starting from N-propionylsultam 3 . The synthesis features asymmetric anti- and syn-aldolizations 3 → 4 and 8 → 9 , a non-destructive N-acylsultam cleavage with lithiated ethylphenylsulfone ( 10 → 12 ), and the smooth, Ti-mediated cyclization of β-acyloxy-ketone 2 to dihydropyranone 14 .     

Phosphonium Ylides Stabilized with Cyano Group and 5-Acylamino-4-phenyl-2-thiazolyl Residue

Available ylide reagent Ph₃P = C(CN)C(S)NH₂ readily enters cyclocondensation with N-(chlorophenacyl)benzamide and its analogs. By this route were prepared new stabilized phosphonium ylides containing cyano group and the corresponding 5-acylamino-4-phenyl-2-thiazolyl fragment. All these compounds even under standard conditions are dephosphorylated under the action of hydrogen chloride in acetic acid to form 5-acylamino-4-phenyl-2-cyanomethylthiazoles in high yields. Their structure was proved by spectroscopic studies and independent synthesis.     

Oligosaccharides Related to Tumor-Associated Antigens. Part I. Synthesis of the propyl glycoside of the trisaccharide α-L-Fucp-(1 → 2)-β-D-Galp-(1 → 3)-β-D-GalpNAc,component of a tumor antigen recognized by the antibody MBr1

The synthesis of the trisaccharide α-L -Fucp-(1 → 2)-β-D -Galp-(1 → 3)-β-D -GalpNAc-1-OPr ( 2 ) is described. The N-acetylgalactosamine 6 was obtained from 4 by an intramolecular displacement of a (trifluoromethyl)sulfonyloxy by a pivaloyloxy group with its concomitant migration from position 3 to position 4 (Scheme 1). The galactosyl donor 9 was obtained from 7 via 8 by regioselective opening of the orthoester function with AcOH/pyridine followed by treatment with CCl₃CN and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Scheme 2). Glycosylation of 6 with 9 in the presence of BF₃ · OEt₂ gave the disaccharide 10 . Selective deprotection of 10 at O? C(2′) followed by glycosylation with 12 and by standard deprotection afforded the title trisaccharide 2 (Scheme 3). Preliminary biological testing showed that 2 is able to inhibit the binding of the monoclonal antibody MBrl to the target tumor cells MCF7 in a dose-dependent manner.     

An Efficient One-Pot Synthesis of 2,3-Dialkyl-1,1-Diethyl-1-(Acetylamino)-3-(1,1,1-Triphenylphosphanilidene)-1,1,2,3-Propanetetracarboxylates and Their Temperature-Dependent NMR Spectra

Abstract

Stable crystalline phosphorus ylides of 1,1-diethyl 2,3-dimethyl 1-(acetylamino)-3-(1,1,1-triphenylphosphanilidine)-1,1,2,3-propanetetracarboxylates were obtained in excellent yields from the 1:1:1 addition reaction between triphenylphosphine and dialkyl acetylenedicarboxylates in the presence of diethyl acetamidomalonate as a CH-acid. These stable ylides exist in solution as a mixture of two geometrical isomers (E and Z) as a result of restricted rotation around the carbon–carbon partial double bond resulting from conjugation of the ylide moiety with the adjacent carbonyl group on the nuclear magnetic resonance (NMR) time scale at ambient temperature. The dynamic effects in the ylide moieties were investigated by ¹H NMR spectra.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Cucurbit[7]uril complexations of bis(isoquinolinium)alkane dications in aqueous solution

The 1:1 and 2:1 host–guest complexation of a series of 1,n-bis(isoquinolinium)alkane dications (Iq(CH₂)_nIq²⁺, n = 2, 4, 5, 6, 8, 9, 10 and 12, and Iq(p-xylene)Iq²⁺) by cucurbit[7]uril (CB[7]) in aqueous solution has been investigated by ¹H NMR spectroscopy and ESI mass spectrometry. The site of binding of the first CB[7] is dependent on the nature of the central linker group, with encapsulation of the p-xylene group or the polymethylene chain when n = 6–10.With shorter (n = 2–5) or longer (n = 12) chains, the first CB[7] binds over an isoquinolinium group. With a second CB[7], the binding of the central group is abandoned in favour of the CB[7] hosts encapsulating the two cationic isoquinolinium termini. The 1:1 and 2:1 host–guest stability constants are related to modes of binding and the nature of the central linkers, and are compared with dicationic guests bearing different terminal groups.