Efficient and regioselective chromium(0)-catalyzed reaction of 2-substituted furans with diazo compounds: stereoselective synthesis of (2E,4Z)-2-aryl-hexadienedioic acid diesters

Pentacarbonyl(η²-cis-cyclooctene)chromium(0) (1) catalyzes efficiently reactions of diazo compounds with electron-rich furans. The reaction of 2-methoxyfuran (2) with alkyl α-diazoarylacetate (3a-g) furnishes the (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g) in excellent yields. These reactions are highly regioselective. The cyclopropanation intermediates formed from 1 and diazo compounds 3a-g always arise from a carbene addition to the less substituted CC bond of 2. The resulting cyclopropanation product undergoes a ring opening reaction to form the corresponding (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g). The pentacarbonylchromium(0)-catalyzed reactions of 2-alkylfuran (5a-b) with ethyl α-diazophenylacetate (3a) and 9-diazo-9H-fluorene (3h) produce the 1(E),3(E)-butadienes (6a-d) in very good yields.     

Synthesis of ‘thianthrene dimer’ by the coupling reaction of stannylthianthrenes in the presence of copper catalysts

The coupling reaction of 1-tributylstannylthianthrene (5) and 2-tributylstannylthianthrene (7) in the presence of copper catalysts at rt afforded the thianthrene dimer 1,1′-bithianthrene (3), 2,2′-bithianthrene (8), and 1,2′-dithianthrene (9) in high yields. Also we obtained thianthrene oxide dimer (R,R) (S,S)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (12) and (R,S) (S,R)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (13) from 1-tributylstannyl-10-S-monoxythianthrene (10) under the same reaction condition. The final structural conformation of 3, 8, 9, and 12 was performed by X-ray crystallographic analysis. Further, the solvent effects in the coupling reactions were also examined.     

Heck reaction with 3-fluoro-3-buten-2-one

3-Fluoro-3-buten-2-one (2) is readily prepared from 1-fluoro-1-chloro-2-methoxy-2-methylcyclopropane (1) in 82% yield by heating the cyclopropane in aqueous quinoline solution. Ketone 2 reacts with aryl iodides (3) in a Heck reaction catalyzed by Pd(OAc)₂ to give Z-3-fluorobenzalacetones (4) in 36-86% yield.     

Imino Diels-Alder reaction of boronates. Preparation and characterization of new 3,4-dihydroquinoline and 1,2,3,6-tetrahydropyridine derivatives

The preparation of 3,4-dihydroquinolines (2a-d and 3a,b,d), as well as 1,2,3,6-tetrahydropyridines (4a-e) by imino Diels-Alder reaction of boronates (1a-e) with 2,3-dimethylbutadiene is reported. Boronates (1a-d) containing substituents meta and para relative to the imino fragment lead to diastereomeric mixtures of 4-methyl-4-ethenyl-3,4-dihydroquinolines (2, 3) and tetrahydropyridines (4). In contrast, the presence of an electron withdrawing substituent at the para position (1e), favors the iminodienophile behavior giving 4,5-dimethyl-1,2,3,6-tetrahydropyridine (4e) as the main product. The results show that boronates derived from Schiff bases are electron deficient species which can act either as dienophiles or dienes in the reaction with 2,3-dimethylbutadiene to give 3,4-dihydroquinolines and 1,2,3,6-tetrahydropyridines. All products were characterized by NMR and X-ray diffraction analysis of 2b, 2d, 3d and 4c allowed to assign the relative configuration of the newly formed stereogenic centers.     

Diastereoselective schenck ene reaction of singlet oxygen with chiral allylic alcohols; access to enantiomerically enriched 1,2,4-trioxanes

A series of antimalarial chiral 1,2,4-trioxanes (1-8) were synthesised in high enantiomeric purities. Enantioselective addition of R₂Zn reagent to 3-methyl-2-butenal catalysed by (+)-MIB or (−)-MIB yielded both the enantiomers of the chiral allylic alcohols 9-11 (90-98% ee), which were subjected to diastereoselective photooxygenation in the presence of tetraphenylporphine (TPP) to obtain (R,R)-threo- or (S,S)-threo-β-hydroperoxy alcohols (12-14). Reaction of β-hydroperoxy alcohols (12-14) with different cyclic ketones produced optically active trioxanes 1-8.     

The cyclopalladation reaction of 2-phenylaniline revisited

2-Phenylaniline reacted with Pd(OAc)₂ in toluene at room temperature for 24 h in a one-to-one molar ratio and with the system PdCl₂, NaCl and NaOAc in a 1 (2-phenylaniline):1 (PdCl₂):2 (NaCl):1 (NaOAc) molar ratio in methanol at room temperature for one week to give the dinuclear cyclopalladated compounds (μ-X)₂[Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)C₆H₄}]₂ [1a (X = OAc) and 1b (X = Cl)] in high yield. Moreover, the reaction between 2-phenylaniline and Pd(OAc)₂ in one-to-one molar ratio in acid acetic at 60 °C for 4 h, followed by a metathesis reaction with LiBr, allowed isolation of the dinuclear cyclopalladated compound (μ-Br)₂[Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)C₆H₄}]₂ (1c) in moderate yield. A parallel treatment, but using monodeuterated acetic acid (DOAc) as solvent in the cyclopalladation reaction, allowed isolation of a mixture of compounds 1c, 1c_d1 [Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)C₆H₄](μ-Br)₂[Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)-3-d-C₆H₃] and 1c_d2 (μ-Br)₂[Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)-3-d-C₆H₃}]₂ in moderate yield and with a deuterium content of ca. 60%. 1a and 1b reacted with pyridine and PPh₃ affording the mononuclear cyclopalladated compounds [Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)C₆H₄}(X)(L)] [2a (X = OAc, L = py), 2b (X = Cl, L = py), 3a (X = OAc, L = PPh₃) and 3b (X = Cl, L = PPh₃)] in a yield from moderate to high. Furthermore, 1a reacted with Na(acac) · H₂O to give the mononuclear cyclopalladated compound 4 [Pd{κ²-N2′,C1-2-(2′-NH₂C₆H₄)C₆H₄}(acac)] in moderate yield. ¹H NMR studies in CDCl₃ solution of 2a, 2b, 3a, 3b and 4 showed that 2a and 3a presented an intramolecular hydrogen bond between the acetato ligand and the amino group, and were involved in a dynamic equilibrium with water present in the CDCl₃ solvent; and that the enantiomeric molecules of 2b and 4 were in a fast exchange at room temperature, while they were in a slow exchange for 2a, 3a and 3b. The X-ray crystal structures of 3b and 4 were determined. 3b crystallized in the triclinic space group with a = 9.9170(10), b = 10.4750(10), c = 12.0890(10) Å, α = 98.610(10)°, β = 94.034(10)° and γ = 99.000(10)° and 4 in the monoclinic space group P2₁/a with a = 11.5900(10), b = 11.2730(10), c = 12.2150(10) Å, α = 90°, β = 107.6560(10)° and γ = 90°.     

Fluoropropenoates as dienophiles in the Diels-Alder reaction

Several fluorinated alkenes were prepared from known ethyl (R)-2-fluoro-4,5-dihydroxyisopropylidine-2-pentenoate (1). The fluoroalkenoates were tested as dienophiles with several dienes and showed cycloaddition only with the very reactive diene, 1,3-diphenylisobenzofuran (5). Fluorobutenolide 2 reacted with 5 to produce the endo-syn adduct 9 in a highly stereoselective manner.     

Total synthesis of suaveoline and norsuaveoline via intramolecular oxazole-olefin Diels-Alder reaction

Total synthesis of two Rauwolfia alkaloids, suaveoline (1) and norsuaveoline (2), has been achieved through a highly stereoselective route starting from l-tryptophan methyl ester (9) and exploiting the intramolecular Diels-Alder reaction of the oxazole-olefin 16.     

The reaction of 2-fluoroalkyl-1-iodoethylenes with arylamines: a facile method for the synthesis of fluoroalkylated quinolines and enaminoketones

The reaction of 2-fluoroalkyl-1-iodoethylenes with arylamines (1) and the subsequent acid promoted transformation of the products were described. In the presence of ZnCl₂ and triethylamine, 1 reacted readily with various p-substituted anilines in HMPA under a vacuum of 60-70 mmHg to give the corresponding enaminoaldehydes (2) as a mixture of E- and Z-isomers. Cyclization of 2, without further purification in refluxing toluene, catalyzed by strong acids such as p-toluene sulfonic acid and trifluoromethanesulfonic acid gave 2-fluoroalkylquinolines (3) in good yields, while fluoroalkylated enaminoketones (4) were obtained predominantly when 2 was treated with acids in aqueous THF solution. A possible mechanism was proposed for the formation of 3 and 4.     

Synthesis and characterization of polybinaphthalene incorporating chiral (R) or (S)-1,1′-binaphthalene and oxadiazole units by Heck reaction

Chiral conjugated polymers P-1 and P-2 were synthesized by the polymerization of (R)-3,3′-diiodo-2,2′-bisbutoxy-1,1′-binaphthalene ((R)-M-1) and (S)-3,3′-diiodo-2,2′-bisbutoxy-1,1′-binaphthalene ((S)-M-1) with 2,5-bis(4-vinylphenyl)-1,3,4-oxadiazole (M-2) under Pd-catalyzed Heck coupling reaction, respectively. Both monomers and polymers were analysed by NMR, MS, FT-IR, UV, DSC-TG, fluorescent spectroscopy, GPC and CD spectra. The chiral conjugated polymers exhibit strong Cotton effect in their circular dichroism (CD) spectra indicating a high rigidity of polymer backbone. CD spectra of polymers P-1 and P-2 are almost identical and have opposite signs for their position. These polymers have strong blue fluorescence.     

Formation of chiral tertiary homoallylic alcohols via Evans aldol reaction or enzymatic resolution and their influence on the Sharpless asymmetric dihydroxylation

Enantioenriched tertiary homoallylic alcohol derivatives (S)-2c and (S)-2a were obtained via Evans aldol methodology and enzymatic resolution of racemic tertiary acetate 2e, respectively. In order to study asymmetric 1,3-induction of the stereogenic center present in 2, congener (R)-2a as well as its O-protected derivatives (R)-2b-d were submitted to Sharpless asymmetric dihydroxylation to yield the diastereomeric 1,2,4-triol derivatives (2R,4R)- and (2S,4R)-3a-d, revealing that neither the substrate nor the Sharpless catalyst exert any stereocontrol. Similar observations were made for the less bulky alkynyl-substituted derivative 12b. However, by using a directed dihydroxylation, the anti product (2R,4R)-3a was favored.     

Stereochemistry of the reaction of cis,trans,cis-2,4,6,8-tetraisocyanato-2,4,6,8-tetramethylcyclotetrasiloxane with triphenylsilanol and 1,1,3,3-tetraphenyldisiloxane-1,3-diol

All-cis-2,4,6,8-tetramethyl-2,4,6,8-tetrakis(triphenylsiloxy)cyclotetrasiloxane (4) and syn-1,3,9,11-tetramethyl-5,5,7,7,13,13,15,15-octaphenyltricyclo[9.5.1.1^3,9]octasiloxane (5) were synthesized by the reaction of cis,trans,cis-[MeSi(NCO)O]₄ (1) with Ph₃SiOH (2) and [Ph₂Si(OH)]₂O (3), respectively, in the presence of pyridine for the sake of investigating the synthesis of ladder polysilsesquioxanes with perfect siloxane frameworks. Their stereostructures were confirmed by nuclear magnetic resonance spectra and X-ray crystallography, which revealed that 4 and 5 did not retain the stereostructure of the precursor 1. This result was caused by the racemization of 1 with pyridine, and a subsequent nucleophilic substitution reaction of 1 with 2 or 3, including inversion and retention of the configuration at the silicon atoms.     

Synthesis of 2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-ones by the domino Michael addition retro-ene reaction of 2-alkoxyiminoimidazolidines and acetylene carboxylates

2-Alkoxyiminoimidazolidines 2-3 react with acetylene dicarboxylates and ethyl phenylpropiolate to give 8-alkoxy-imidazo[1,2-a]pyrimidin-5(3H)-ones C, which subsequently undergo a sterically induced multihetero-retro-ene fragmentation to give imidazo[1,2-a]pyrimidin-5(1H)-ones 4-7 together with formaldehyde or benzaldehyde. On the other hand, a similar reaction of 2-3 with ethyl propiolate gives corresponding 8-alkoxy-imidazo[1,2-a]pyrimidin-5(3H)-ones 8-10. The unsubstituted imidazo[1,2-a]pyrimidin-5(1H)-one 11 can be prepared by retro-ene reaction of 9 upon prolonged heating in refluxing ethanol. A direct synthetic approach to 1-formyl-7-phenyl-imidazo[1,2-a]pyrimidine-5(1H)-one 14 is reported using DMF/sulfonyl chloride as a new Vilsmeier-type N-formylating reagent.     

An efficient synthesis of chiral isoquinuclidines by Diels-Alder reaction using Lewis acid catalyst

The Diels-Alder reaction of 1,2-dihydropyridine derivatives (1-phenoxycarbonyl-1,2-dihydropyridine 1 or 1-methoxycarbonyl-1,2-dihydropyridine 4) with N-acryloyl (1S)-2,10-camphorsultam (1S)-2 {or N-acryloyl (1R)-2,10-camphorsultam (1R)-2} in the presence of Lewis acid, such as titanium tetrachloride, zirconium tetrachloride, and hafnium tetrachloride afforded the endo-cycloaddition product, 2-azabicyclo[2.2.2]octane derivatives in good yields with excellent diastereoselectivity. The absolute stereochemistry assignment of the endo-cycloaddition product (1S)-5a starting from N-acryloyl (1S)-2,10-camphorsultam (1S)-2 has been established to be (1S,4R,7S) and the reaction mechanism was proposed.     

An efficient glycosylation reaction for the synthesis of asialo GM2 analogues

We investigated the coupling reaction of glycosyl donors N-trichloroethoxycarbonyl-galactosamine-O-trichloroacetimidate (2a) and N-p-nitrobenzyloxycarbonyl-galactosamine-O-trichloroacetimidate (2b) with the 4′-OH of lactose derivatives (3a-d) to synthesize key intermediates of asialo GM2 analogues, and found that the glycosylation yield with 2a was 90% or more in all investigated cases.     

New reaction of ethenetetracarbonitrile with N-arylisoindolines

N-Arylisoindolines 1a-i react with ethenetetracarbonitrile 2 in aerated benzene by formation of [3-(2-aryl-3-dicyanomethylene-2,3-dihydro-1H-isoindol-1-ylidene)-2-aryl-2,3-dihydro-1H-isoindol-1-ylidene]propanedinitriles 8a-i (20-36%), N-aryl-3-dicyanomethylene-isoindol-2-ones 9a-i (15-21%) and N-arylphthalimides 10a-i (4-9%) as well as 1,1,2,2-tetracyanoethane 11 (35-55%). The structure of 8d has been unambiguously confirmed by a single crystal X-ray structure analysis. A rationale for the formation of products 8-11 is presented.     

Solid-state and solution photocycloadditions of 4-acyloxy-2-pyrones with maleimide

Solid-state photosensitized reactions of 4-acyloxy-2-pyrones (1b,c) with maleimide (2) afforded endo-endo double-[4+2] cycloadducts (3b,c) with high stereoselectivity. Sensitized photoreactions of 1a-d with 2 in solution gave exo-endo double-[4+2] cycloadducts (4a-d). 2-Pyrones 1a-d were photolyzed to give carboxylic acids (5a-d) via their valence isomerization in the solid state and in solution. Such kinds of photoreaction of the 4-acyloxy-2-pyrones were dramatically different from regio- and stereoselective [2+2] cycloadditions of 4-alkyloxy-2-pyrones. The photoreaction mechanisms of 1 with 2 and 1 itself were analyzed by powder X-ray diffraction analysis and MO calculations.     

An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

Oxazolidinone cross-alkylation during Evans’ asymmetric alkylation reaction

Starting from Evans’ imidazolidin-2-one (1) two compounds were obtained by trans-N-acylation: the expected one 3 with S,R configuration and a second compound 5, that is, related to 3 by the loss of a CH(CH₃)CO fragment. The stereochemistry of 3 was established by NMR spectroscopy, mainly NOE experiments, as expected, the new center has an S configuration, the compound being thus S,R. The structure of compound 5 was determined by X-ray crystallography. A mechanism of formation of 5 was proposed.     

Surprising 1,7-cyclization of vinyl carbonyl ylides generated from reaction of indanetrione with vinyl diazo compounds

Reactions of tricarbonyl compounds with vinyl diazo compounds 2 were carried out. Reaction of 1,2,3-indanetrione with 2a,b,c gave the spiroindan-1,3-dione-2,2′-benzodihydrooxepin 7a,b,c, but not normal products oxirane and dihydrofuran derivatives expected from intermediate vinyl carbonyl ylides 4. Formation of 7 requires isomerization of vinyl carbonyl ylides 4 bearing a (Z)-cyanostyryl group to unstable (E)-form 5 and subsequent cyclization to oxepin 6 followed by a 1,5-hydrogen shift. However, reaction of 2 with six-membered cyclic tricarbonyl compounds 1,2,3-trioxo-2,3-dihydrophenalene 11 and dimethylalloxane 13 gave the dioxole 12 and the dihydrofuran 14, respectively, typical products expected from vinyl carbonyl ylides.