Bredereck's Reagent Research Articles

Discovery of highly functionalized scaffolds: Pyrroloimidazolediones as P2X7 receptor antagonists

A broad range of pyrroloimidazolediones, new highly functionalized bicyclic heterocycles, was obtained by a cycloaddition reaction between l-pyroglutamide derivatives and Bredereck's reagent. Methanolysis of subsequent pyrroloimidazolediones provided antagonists of P2X7 receptor, with retention of initial stereoconfiguration, with potential applications in the treatment of inflammatory and neurological diseases. We have thus developed a new synthesis of lactamic nitrogen free enaminones which is currently the easiest method cited in the literature to access these compounds.

New Approach for the Construction of the Coumarin Frame and Application in the Total Synthesis of Natural Products

AbstractA new synthetic approach is described for building the coumarin scaffold through the Lewis acid‐promoted cyclization of novel aryl 3‐(dimethylamino)prop‐2‐enoates 2a–2f. The latter precursors were prepared via aminomethylenation of the corresponding aryl acetates 4a–4f with the Bredereck reagent. This approach was used for the synthesis of biologically active natural compounds 1a–1f, through a three‐step procedure starting from the corresponding phenols.

A convenient approach to the canthin‐4‐one ring system: Total synthesis of the alkaloids tuboflavine and norisotuboflavine

Abstract magnified imageCanthin‐4‐one, as well as 5‐ and 6‐alkylcanthin‐4‐ones are readily available through reaction of 1‐acyl‐β‐carbolines with Bredereck's reagent or dimethylacetamide acetals in anhydrous DMF. The intermediate enaminoketones readily undergo cyclization to the canthin‐4‐ones. The alkaloids tuboflavine and norisotuboflavine were prepared following this methodology. J. Heterocyclic Chem., (2009).

Synthesis, spectral, electrochemical and photovoltaic properties of novel heteroleptic polypyridyl ruthenium(II) donor-antenna dyes

A series of new heteroleptic Ru(II)(4,4′-dicarboxylic acid-2,2′-bipyridine)(bipyridyl donor-antenna ligand)(NCS)2 complexes carrying different donor-antenna moieties was designed, synthesised and characterised. A general synthetic procedure was used for the covalent attachment of the donor-antenna units 1,3-di(2-thienyl)benzo[c]-thiophene (DTBT), trans-stilbene (tS) and 4-{2-[2-(2-methoxyethoxy)ethoxy]-ethoxy}-N,N-diphenylbenzenamine (TPA-EO) to 2,2′-bipyridine. First, a Vilsmeier-Haack reaction was applied to get the respective aldehyde-functionalised donor-antenna compounds which secondly reacted with 4,4′-bis(triphenylphosphonium-methyl)-2,2′-bipyridyl chloride under Wittig conditions to give the desired bipyridyl donor-antenna molecules. To create a dimethylamino (NMe2) substituted donor-antenna compound a reaction between 4,4′-dimethyl-2,2′-bipyridine and Bredereck's reagent was carried out. The final Ru(II) complexes referred to as Ru-DTBT-NCS, Ru-tS-NCS, Ru-TPA-EO-NCS and Ru-NMe2-NCS were obtained via one-pot reactions, starting from dichloro(p-cymene)ruthenium(II) dimer. The bipyridyl donor-antenna molecules as well as the complexes were fully characterised and their optical and electrochemical properties were studied in detail. Preliminary tests of the novel Ru(II)bis(bipyridyl)(NCS)2 dyes in solid-state dye-sensitized solar cells under AM1.5G conditions (100 mW cm−2) yielded short-circuit current densities of 1.06, 2.15, 3.42 and 4.03 mA cm−2, open-circuit voltages of 625, 635, 685 and 735 mV and fill factors of about 45% corresponding to overall efficiencies of 0.31, 0.58, 0.99 and 1.37% for Ru-DTBT-NCS, Ru-NMe2-NCS, Ru-tS-NCS and Ru-TPA-EO-NCS, respectively.

A new synthesis of pyrrolo[3,2- b]quinolines by a tandem electrocyclization–oxidation process

A new synthesis of pyrrolo[3,2- b]quinolines is described. Condensation of anilines with dimethyl 4-oxopyrrolidine-1,3-dicarboxylate yields enaminoesters, which upon reaction with Bredereck's reagent produce the title compounds. A possible reaction mechanism is briefly discussed.

Studies in iridoid synthesis. Chemoselective transformations of cis-1,2,4,6-tetrahydrophthalic anhydride

In the course of synthetic studies towards the development of diastereoselective routes to secoiridoid aglycones, cis-1,2,4,6-tetrahydrophthalic anhydride was transformed into the corresponding lactone cis-3a,4,7,7a-tetrahydro-3H-isobenzofuran-1-one, which served as a key precursor for a variety of chemoselective synthetic manipulations. Unsuccessful formylation of an ester intermediate resulted in a (E/Z) mixture of vinyl alcohols which were protected as acetates and as a single p-methoxybenzyl (PMB) ether (E) isomer. Dihydroxylation of the cyclohexene motif using OsO(4) led to the unexpected deprotection of the PMB ether. On the other hand, successful formylation of a suitably silyl protected lactonised intermediate was achieved using tert-butoxybis(dimethylamino)methane, or Bredereck's reagent. Tetrabutylammonium fluoride (TBAF) deprotection of a methoxyethoxymethyl (MEM)-ether intermediate serendipitously afforded an approximately 1 : 1 mixture of pyrano-pyranones, which are products of a seldom encountered intramolecular Michael addition, using an oxygen donor, to the terminus of an alpha,beta-unsaturated system, followed by beta-elimination of the MEM moiety.

New Synthetic Path to 2,2‘-Bipyridine-5,5‘-dicarbaldehyde and Its Use in the [3+3] Cyclocondensation with trans-1,2-Diaminocyclohexane

2,2'-Bipyridine-5,5'-dicarbaldehyde has been prepared in two steps by enamination of 5,5'-dimethyl-2,2'-bipyridine with Bredereck's reagent, and subsequent oxidative cleavage of the enamine groups with sodium periodate. On condensation of this dialdehyde with enantiomerically pure trans-1,2-diaminocyclohexane, the macrocyclic [3+3] hexa Schiff base has been obtained in excellent yield. Its reduction has given large macrocyclic hexaamine having three bipyridine units incorporated into the macrocycle structure.

Synthesis of Dihydrooxepin Models Related to the Antitumor Antibiotic MPC1001

4-Hydroxy-L-proline was converted into the tetrahydrooxepino[4,3-b]pyrrole ring system characteristic of the potent antitumor agent MPC1001. Key steps were regioselective formation of a vinylogous amide by use of Bredereck's reagent and acid-induced cyclization of an alcohol onto the carbon-carbon double bond of that amide by addition-elimination to generate the seven-membered oxacyclic subunit.

Synthesis and Transformation of N,N-Dimethylaminomethylidene Derivatives of Indolylglycines and Some Other Dipeptides

Indolyl glycinates (3, 7, and 11) were transformed with t-butoxybis(dimethylamino)methane (Bredereck's reagent) into 3-[(dimethylamino)methylidene]-2,3-dihydropyrazino[1,2-a]indole-1,4-dione (4), 3-(dimethylamino)-2-[(1H-indol-3-ylcarbonyl)amino]propenoate (8), and 2-(1-methyl-1H-indol-2-yl)-1,3-oxazol-5(4H)-one derivative (12). Dipeptides (16a-c) were transformed with Bredereck's reagent into the hydantoin (imidazolidine-2,4-dione) derivatives (17a-c).

First Total Synthesis of the 2,7‐Naphthyridine Alkaloids Lophocladine A and B

The one-pot reaction of 4-benzylpyridine-3-carbonitrile with Bredereck's reagent and subsequent treatment with either glacial acetic acid and sulfuric acid or ammonium acetate provided the new bioactive naphthyridine alkaloids lophocladine A and B, respectively.

Towards new camptothecins. Part 3: Synthesis of 5-methoxycarbonyl camptothecin

The synthesis of two camptothecin analogs substituted by a carbonyl function on position 5 of cycle C was realized. New conditions were studied to obtain the E-lactone ring of these heterocycles. These compounds were obtained from the reaction of Bredereck's reagent with indolizines derived from pyroglutamic acid. This yielded dimethylaminovinyl groups whose oxidation by NaIO 4 yielded ketones. The indolizinones obtained were reacted in Friedlander condition, to give the scaffold of the desired camptothecins.

Towards new camptothecins. Part 2: Synthesis of the ABCD ring scaffold substituted by a carboxyl group in the 5-position

In the context of formation of camptothecins substituted by a carbonyl function on position 5 of cycle C, synthesis of a new keto tetrahydroindolizine was realized. This compound was obtained from the reaction of Bredereck's reagent with an indolizine derived from pyroglutamic acid. That yielded a dimethylaminovinyl group whose NaIO 4 oxidation gave a ketone. The indolizinone obtained was reacted in Friedlander condition to give the ABCD ring scaffold of camptothecins substituted by a methoxycarbonyl group on the 5-position. It was also shown that, if it is desired, a 5-carboxamide group does not need to be introduced at the beginning of the synthesis sequence.

Bredereck's Reagent Revisited: Latent Anionic Ring‐Opening Polymerization and Transesterification Reactions

AbstractThe ring‐opening polymerization of lactide with commercially available Bredereck‐type reagents in the presence or absence of alcohol initiators was carried out affording polylactide with controlled molecular weight and narrow polydispersities. An anionic mechanism involving heterolytic cleavage to alkoxides is proposed, where these reagents function as latent anionic initiators for the ring‐opening polymerization of lactide.

Novel B-ring modified allocolchicinoids of the NCME series: design, synthesis, antimicrotubule activity and cytotoxicity

Two new series of allocolchicinoids mimicking the structure of (−)-N-acetylcolchinol O-methyl ether (2, NCME) were synthesized and evaluated for their abilities to inhibit tubulin assembly. Possible antitumor properties resulting thereof were evaluated in vitro on the human MCF-7 breast cancer cell line. The first series of NCME-derivatives was brought about by extending the seven membered B-ring to novel semisynthetic variations with a nitrogen containing eight-membered B-ring similar, for example, to the artificial, potent steganacin aza-analogue 3. In the second series the seven-membered B-ring of NCME (2) was modified by annulation with a heterocyclic ring system. The racemic ketone 7a serving as key precursor involved in the syntheses of all the target NCME variants 9–13 and 15, 16 was easily transformed into the eight-membered B-ring lactams 9 and 10 via a Beckmann rearrangement of the corresponding E-oxime 8. The tetrazole annulated congener 11 was prepared via azidotrimethylsilane-mediated Schmidt rearrangement. Treatment of educt 7a with Bredereck's reagent led to the enamino ketone 14, which was easily converted into the pyrazole- or pyrimidine-annulated allocolchicinoids 15 and 16. Remarkably, all the allocolchicinoids 9–13 with an azocin-B-ring affected the tubulin/microtubule equilibrium only moderately. In contrast, the novel heterocycle annulated seven membered B-ring variants 15 and 16 proved to be highly potent tubulin-inhibitory, antimitotic agents. Interaction with tubulin occured at concentrations similar to those observed for colchicine (1) or the lead NCME (2). In all cases the antiproliferative effects correlated roughly with the inhibition of tubulin assembly.

Asymmetric synthesis of α-amino acids from α,β-( Z)-didehydroamino acid derivatives with 1,2,3,6-tetrahydropyrazin-2-one structure

Chiral ( Z)-α,β-didehydroamino acid (DDAA) derivatives 14, 15 and 16 are obtained from a new chiral iminic cyclic glycine template with 1,2,3,6-tetrahydropyrazin-2-one structure 10 by condensation with carbonyl compounds, Eschenmoser's salt and Bredereck's reagent, respectively. The didehydroalanine derivative 15 and the enaminone 16 can give DDAA derivatives 14 using Heck olefination and vinylic nucleophilic substitution. These DDAA derivatives 14 and 15 undergo diastereoselective cyclopropanation, 1,3-dipolar and Diels–Alder cycloaddition reactions giving, after hydrolysis, the corresponding cyclic and bicyclic α-amino acids.

A new germanium-based linker for solid phase synthesis of aromatics: synthesis of a pyrazole library

An efficient synthesis of chlorogermane linker 12 is described. Economic introduction of germanium into this linker is accomplished by insertion of dichlorogermylene [from germanium(IV) chloride] into the homobenzylic C-Cl bond of 4-(2-chloroethyl)phenol 1. Using linker 12, transmetalation with lithiated 4-acetophenone, 3-acetophenone, and 4-(4'methoxy)biphenyl followed by Mitsunobu-type coupling to Argogel gives functionalized resins 14, 16, and 18, respectively. Treatment of resin 18 with TFA, ICl, Br2, or NCS effects clean ipso-degermylation releasing biphenyls 19-22, respectively. Resins 14 and 16 are employed for the parallel synthesis of a library of pyrazoles by enaminone formation (using Bredereck's reagent), condensative ring-closure (using a series of monosubstituted hydrazines), and cleavage (using TFA and Br2). Analysis of this library reveals the influence of the hydrazine substituent on both the regioselectivity of ring-closure and the propensity for electrophilic substitution at the 4-position of the pyrazoles during ipso-degermylative cleavage.

The synthesis of some unsaturated 4-substituted-g-lactones

The synthesis of conjugated and nonconjugated unsaturated 4-substituted lactones of type 1 and 2 are described. The type 1 lactone was prepared by a two step procedure employing Bredereck's reagent. The type 2 lactone was synthesised by combining the Claisen-Ireland rearrangement and selenolactonisation.

Stereoselective Amination of 5-Substituted γ-Lactones and γ-Lactams – A Convenient Route for the Preparation of 5-Substituted (3S,5S)-3-Acetylaminotetrahydrofuran-2-ones and (3S,5S)-3-Acetylaminopyrrolidin-2-ones

5-Substituted (S)-tetrahydrofuran-2-ones (1a,b) and (S)-pyrrolidin-2-ones (1c,d) were transformed in three steps, by treatment with tert-butoxybis(dimethylamino)methane (Bredereck's reagent), followed by nitrosation and stereoselective catalytic hydrogenation, into the corresponding 5-substituted (3S,5S)-3-acetylaminotetrahydrofuran-2-ones (4a,b) and (3S,5S)-3-acetylaminopyrrolidin-2-ones (4c,d).

Synthesis of 3-Methyl and 7-Methyl Regio Isomers of Medorinone

Reaction of 3-aminocrotononitrile (2) with methyl methacrylate (3) and methyl 2-propynolate (9) led to the formation of 1,4,5,6-tetrahydro-2,5-dimethyl-6-oxo-3-pyridinecarbonitrile (4) and 1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrile (10), respectively. Condensation of 4 with Bredereck's reagent [bis(dimethylamino)-tert-butoxymethane], and that of 6-methoxy-2-methyl-3-pyridinecarbonitrile (12) with N,N-dimethylacetamide dimethyl acetal gave the corresponding enamines 5 and 13 which in turn were cyclized with hydrogen bromide to bromonaphthyridinones 6 and 14, respectively

A facile and novel synthesis of 1,6‐naphthyridin‐2(1H)‐ones

AbstractA new and convenient procedure for the synthesis of 1,6‐naphthyridin‐2(1H)‐ones and their derivatives is described. In the first scheme 5‐acetyl‐6‐[2‐(dimethylamino)ethenyl]‐1,2‐dihydro‐2‐oxo‐3‐pyridinecarbonitrile (4) obtained by the reaction of N,N‐dimethylformamide dimethyl acetal with 5‐acetyl‐1,2‐dihydro‐6‐methyl‐2‐oxo‐3‐pyridinecarbonitrile (3) was cyclized to 1,2‐dihydro‐5‐methyl‐2‐oxo‐1,6‐naphthyridine‐3‐carbonitrile (5) by the action of ammonium acetate. Thermal decarboxylation of acid 7 obtained from the hydrolysis of nitrile 5 led to a mixture of 5‐methyl‐1,6‐naphthyridin‐2(1H)‐one (8) and its dimer 9. Hydrazide 11 obtained from nitrile 5 in two steps was converted to 3‐amino‐5‐methyl‐1,6‐naphthyridin‐2(1H)‐one (12) by the Curtius rearrangement. The amino group of 12 was readily replaced by treatment with aqueous sodium hydroxide to yield 3‐hydroxy‐5‐methyl‐1,6‐naphthyridin‐2(1H)‐one (13). In the second scheme, Michael reaction of enamines of type 20 with methyl propiolate, followed by ring closure gave 5‐acyl(aroyl)‐6‐methyl‐2(1H)‐pyridinones (21) which in turn were treated with Bredereck's reagent to produce 5‐acyl(aroyl)‐6‐[2‐(dimethylamino)ethenyl]‐2(1H)‐pyridinones (22). Treatment of 22 with ammonium acetate led to the formation of 1,6‐naphthyridin‐2(1H)‐ones 23.