Search

An experimental and theoretical study of an efficient one-pot three-components cycloaddition reaction leading to pentacyclic dispiropyrrolizidin/pyrrolidinoxindoles endowed by four contiguous stereogenic centres with moderate to good yields was reported.

An efficient diastereoselective route is developed to get access to novel spiropyrrolo[1,2

International audience; In a sustained search for novel α-amylase inhibitors for the treatment of type 2 diabetes mellitus (T2DM), we report herein the synthesis of a series of nineteen novel rhodanine-fused spiro[pyrrolidine-2,3’-oxindoles]. They were obtained by one-pot three component [3+2] cycloaddition of stabilized azomethine ylides, generated in situ by condensation of glycine methyl ester and the cyclic ketones 1H-indole-2,3-dione (isatin), with (Z)-5-arylidine-2-thioxothiazolidin-4-ones. The highlight of this protocol is the efficient high-yield construction of structurally diverse rhodanine-fused spiro[pyrrolidine-2,3'-oxindoles] scaffolds, including four contiguous stereocenters, along with excellent regio- and diastereoselectivities. The stereochemistry of all compounds was confirmed by NMR and corroborated by an X-ray diffraction study performed on one derivative. All cycloadducts were evaluated in vitro for their α-amylase inhibitory activity and showed good α-amylase inhibition with IC50 values ranging between 1.49± 0.10 and 3.06± 0.17µM, with respect to the control drug acarbose (IC50= 1.56µM). Structural activity relationships (SARs) were also established for all synthesized compounds and the binding interactions of the most active spiropyrrolidine derivatives were modelled by means of molecular in silico docking studies. The most potent compounds 5g, 5k, 5s and 5l were further screened in vivo for their hypoglycemic activity in alloxan-induced diabetic rats, showing a reduction of the blood glucose level. Therefore, these spiropyrrolidine derivatives may be considered as promising candidates for the development of new classes of antidiabetic drugs.

A series of diverse heterocycles containing spirooxindole, isoxazoline/triazole, and isoxazole rings has been synthesized via an efficient three-component reaction of (E)-2-(1-propargyl-2-oxoindoline-3-ylidene)acetophenones 1, arylnitrile oxides 2, and arylazides 3 using Cu(I) as catalyst. The regiochemistry and stereochemistry of cycloadducts 4a and 5a have been confirmed by X-ray diffraction studies. The heterocycles were screened against Gram-positive and Gram-negative bacteria and fungi. Several compounds exhibit moderate to excellent activities comparable to those of established standard drugs.

In the quest for new heterocyclic scaffolds exhibiting potentially biological activities for medicinal chemistry, a multicomponent 1,3-dipolar cycloaddition reaction of tetrahydroisoquinolinium N-ylides, generated in situ from cyclic diketones and isoquinoline, and (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones has been developed. This route provides workable access to dispiropyrrolo[2,1-a]isoquinoline-fused pyrrolidine-2,5-diones bearing two adjacent spiro-carbons. An unprecedented regioselectivity was observed in this 1,3-dipolar cycloaddition, leading to the construction of a novel dispirooxindole skeleton. The structure and relative stereochemistry of the spiranic adducts have been confirmed by three X-ray diffraction studies. To reinforce the observed regio- and stereoselectivity of the [3+2] cycloaddition, calculations using the DFT approach at the B3LYP/6-31G(d,p) level were carried out. It was found that this reaction affords the kinetic products.

This work describes an efficient α-phosphorylation of a wide variety of N-aryl tertiary amines under mild conditions. It consists of a simple combination of amines (electron donors) with N-ethoxy-2-methylpyridinium tetrafluoroborate (electron acceptor) in the presence of P(V)–H compounds under visible light irradiation. Physical organic investigations support the formation of an electron-donor–acceptor complex (amine/pyridinium ion) as a key intermediate.

In the quest for new heterocyclic scaffolds exhibiting potentially biological activities for medicinal chemistry, a multicomponent 1,3-dipolar cycloaddition reaction of tetrahydroisoquinolinium

The 1,3-dipolar cycloaddition reaction of (E,E)-1,3-bis(arylidene)indan-2-one with diarylnitrilimines, generated in situ via dehydrohalogenation of the corresponding hydrazonoyl chlorides , affords predominantly monospiropyrazolines and as a mixture of diastereoisomers. Also dispiropyrazolines are formed in moderate yields. The structure and stereochemistry of cycloadducts were confirmed by 1H and 13C-NMR spectroscopy, elemental analyses data, and single-crystal X-ray diffraction studies of and .

Non-stabilized azomethine ylides, generated in situ from isatin derivatives and l -proline, have been reacted with (E,E)-1,3-bis(arylidene)indan-2-ones as dipolarophiles in a 1,3-dipolar cycloaddition reaction. Novel functionalized dispiroheterocyclic compounds were obtained with low diastereoselectivity and the regiochemical outcome of the cycloaddition reaction was confirmed by single crystal X-ray analysis. The compounds were investigated by in vitro screening against Mycobacterium tuberculosis (MIC) using the agar dilution method and displayed good activities.

A series of spiro[pyrrolidin-2,3′-oxindoles] has been synthesized by exo-selective 1,3-dipolar cycloaddition reaction of a stabilized azomethine ylide, generated in situ by thermal [1,5]-prototropy, across various (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones. The stereochemistry of these N-heterocycles has been confirmed using an X-ray diffraction study. To rationalize the observed regio- and stereoselectivity, DFT calculations at the B3LYP/6-31G(d,p) level were employed. It was found that this reaction preferentially affords the kinetic product. The compounds have been screened for their in vitro antibacterial, antifungal, antimalarial and antitubercular activities. Several compounds exhibited good activities comparable to those of established standard drugs.

In an on-going effort to develop novel anti-tubercular agents, a series of original dispiropyrrolothiazole derivatives have been synthesized by three-component 1,3-dipolar cycloaddition of (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones, 1,3-thiazolane-4-carboxylic acid and cyclic diketones. The stereochemistry of the spiranic adducts has been confirmed by an X-ray diffraction analysis. Theoretical calculations have been carried out using DFT approach at the B3LYP/6-31G(d,p) level allowing an explanation for the observed regio- and stereoselectivity. The newly synthesized compounds were screened in vitro against Mycobacterium tuberculosis H37Rv and the most active compounds were tested for cytotoxicity studies. Some compounds exhibited significant activity, in particular dispiropyrrolothiazole derivatives 15c and 15f emerged as the most promising antitubercular agents.

Microwave-assisted 1,3-dipolar cycloaddition of (E,E)-1,3-bisarylidenetetral-2-ones with nitrilimines, generated in situ by dehydrohalogenation of the corresponding hydrazonoyl chlorides, affords a series of spiropyrazolines in good to excellent yields. The presence of a second exocyclic CC bond also allows the preparation of dispiropyrazolines. The cycloaddition proceeds with high chemo-, regio- and diastereoselectivity. The structure of the spiranic adducts has been established on the basis of their spectroscopic data and elemental analyses. The stereochemistry of these N-heterocycles has been confirmed by two X-ray diffraction studies. The luminescence properties and fluorescence quantum yields of these heterocyclic compounds have been investigated revealing that some of them are fluorescent in solution.

Non-stabilized azomethine ylides, generated in situ from isatin (II) or quinone (VI) and L-proline (III), are reacted with bis(arylidene)indan-2-ones (I) as dipolarophiles in a 1,3-dipolar cycloaddition.

Microwave-assisted 1,3-dipolar cycloaddition of (E,E)-1,3-bisarylidenetetral-2-ones with nitrilimines, generated in situ by dehydrohalogenation of the corresponding hydrazonoyl chlorides, affords a series of spiropyrazolines in good to excellent yields. The presence of a second exocyclic CC bond also allows the preparation of dispiropyrazolines. The cycloaddition proceeds with high chemo-, regio- and diastereoselectivity. The structure of the spiranic adducts has been established on the basis of their spectroscopic data and elemental analyses. The stereochemistry of these N-heterocycles has been confirmed by two X-ray diffraction studies. The luminescence properties and fluorescence quantum yields of these heterocyclic compounds have been investigated revealing that some of them are fluorescent in solution.

A series of original spiropyrrolizidine derivatives has been prepared by a one-pot three-component [3 + 2] cycloaddition reaction of (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones, l-proline, and the cyclic ketones 1H-indole-2,3-dione (isatin), indenoquinoxaline-11-one and acenaphthenequinone. We disclose an unprecedented isomerization of some spiroadducts leading to a new family of spirooxindolepyrrolizidines. Furthermore, these cycloadducts underwent retro-1,3-dipolar cycloaddition yielding unexpected regioisomers. Upon treatment of the dipolarophiles with in situ generated azomethine ylides from l-proline or acenaphthenequinone, formation of spiroadducts and unusual polycyclic fused piperazines through a stepwise [3 + 3] cycloaddition pathway is observed. The stereochemistry of these N-heterocycles has been confirmed by several X-ray diffraction studies. Some of these compounds exhibit extensive hydrogen bonding in the crystalline state. To enlighten the observed regio- and stereoselectivity of the [3...

International audience; The novel 1D coordination polymer (CP) [{Cu(mu(2)-Br)(2)Cu}(mu-L2)(2)] CP2 has been obtained by reaction of the tetrakisthioether p-MeSC6H4SCH2SC6H4SMe-p (L2) with CuBr in a 1: 2 metal-to ligand ratio. In contrast to the previously described CP [{Cu(mu(2)-Br)(2)Cu}(mu-L1)(2)] CP1 obtained by reaction of the tetrakisthioether p-MeOC6H4SCH2SC6H4OMe-p (L1) with CuBr, the two independent extended 1D ribbons contain bent Cu(mu(2)-Br)(2)Cu units of the butterfly-type with short Cu center dot center dot center dot Cu separations of 2.679(1) and 2.613(1) angstrom. In contrast to the common planar rhomboid Cu(mu(2)-Br)(2)Cu cluster, this butterfly-shaped geometry of the core is without precedent. A luminescent material of composition [(Cu4I4)(mu-L2)](n) CP3 is formed by reaction of L2 with CuI in a 1: 4 ratio. The two-dimensional CP of stoichiometry [Hg2Br4(L2)](n) CP4 results from treatment of HgBr2 with this tetradentate thioether L2. The structure is of the adduct type with two crystallographically different covalently bound HgBr2 bars assembled in the first step into the chains through the weak Hg-S interactions involving one Hg atom and two S atoms. The chains thus constructed are further brought together through a supplementary Hg1-S1 inter-chain interactions leading to the 2D layered structure. Consequently the Hg1 atom may be considered as pentacoordinated, while the second Hg2 atom has a formal coordination number of 4. The nature of bonding in these CPs has been studied by the Quantum Theory of Atoms in Molecules (QT-AIM) approach allowing a clear classification of metal-ligand bonds and detection of pi-pi stacking interactions. (C) 2016 Elsevier B.V. All rights reserved.

With the aim to develop new potent antitubercular agents, a series of novel dispirooxindolopyrrolidines and dispirooxindolopyrrolothiazoles have been synthesized via a three-component 1,3-dipolar cycloaddition of (Z)-3-arylidenebenzofuran-2-ones, substituted isatin derivatives and α-aminoacids. The stereochemistry of the spiroadducts has been confirmed by an X-ray diffraction analysis. All the target heterocycles were evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain and the most active compounds were subjected to cytotoxicity studies against (RAW 264.7) cell lines. Among them, twelve compounds showed potent anti-tubercular activity with MIC ranging from 1.56 to 6.25 μg/mL. In particular dispirooxindolopyrrolothiazole derivatives 5c and 5f were found to be the most active (MIC of 1.56 μg/mL) with a good safety profile (27.53% and 20.74% at 50 μM, respectively). This is the first report demonstrating the benzofuranone oxindole hybrids as potential antimycobacterial agents.

The substitution of the aryl group at trans position with respect to the N atom in the imine part of 4,4-dihalogeno-1,1-aryl-2-aza­buta-1,3-dienes [Ar2C=N—C(H)=CX 2] by a CN group allows to get an almost perfectly planar mol­ecule., The title compound, C12H10Br2N2O2, represents an example of a planar π-con­jugated 2-aza­butadiene mol­ecule, which is both an inter­esting starting material for further organic transformations and a potential ligand in organometallic coordination chemistry. Its metric mol­ecular parameters are typical for the family of 2-aza­buta-1,3-dienes not substituted at the (CH) 3-position. In the crystal, the almost planar (r.m.s. deviation = 0.0658 Å) aza­diene mol­ecules form one-dimensional double-wide ribbons through inter­molecular halogen bonds (C—Br⋯O and C—Br⋯Br—C), which then stack in a slipped manner through weak C—H⋯Br and π–π inter­actions to generate a three-dimensional network.

Synthesis of a series of novel fused pyrazolines and pyrazoles has been accomplished in good yields by regio- and diastereoselective 1,3-dipolar cycloaddition of enamines of indan-1-one 1a-c towards C-aryl-N-phenylnitrilimines 2d- f. The structure of the cycloadducts was elucidated by 1D and 2D NMR studies.

A series of original spiropyrrolizidine derivatives has been prepared by a one-pot three-component [3 + 2] cycloaddition reaction of (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones, l-proline, and the cyclic ketones 1H-indole-2,3-dione (isatin), indenoquinoxaline-11-one and acenaphthenequinone. We disclose an unprecedented isomerization of some spiroadducts leading to a new family of spirooxindolepyrrolizidines. Furthermore, these cycloadducts underwent retro-1,3-dipolar cycloaddition yielding unexpected regioisomers. Upon treatment of the dipolarophiles with in situ generated azomethine ylides from l-proline or acenaphthenequinone, formation of spiroadducts and unusual polycyclic fused piperazines through a stepwise [3 + 3] cycloaddition pathway is observed. The stereochemistry of these N-heterocycles has been confirmed by several X-ray diffraction studies. Some of these compounds exhibit extensive hydrogen bonding in the crystalline state. To enlighten the observed regio- and stereoselectivity of the [3 + 2] cycloaddition, calculations using the DFT approach at the B3LYP/6-31G(d,p) level were carried out. It was found that this reaction is under kinetic control.

Novel dispiropyrrolothiazole derivatives (IV) and (VI) are synthesized under mild reaction conditions in a complete regio- and stereoselective manner using three-component 1,3-dipolar cycloaddition reactions of cyclic diketones (I) or (V) with thiazolanecarboxylic acid (II) and arylidenepyrolidinedione (III) The dispiropyrrolothiazole derivatives (IVf) and (IVg) are found to exhibit significant antimycobacterial activity and emerge as the most promising antitubercular agents.

With the aim to develop new potent antitubercular agents, a series of novel dispirooxindolopyrrolidines and dispirooxindolopyrrolothiazoles have been synthesized via a three-component 1,3-dipolar cycloaddition of (Z)-3-arylidenebenzofuran-2-ones, substituted isatin derivatives and α-aminoacids. The stereochemistry of the spiroadducts has been confirmed by an X-ray diffraction analysis. All the target heterocycles were evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain and the most active compounds were subjected to cytotoxicity studies against (RAW 264.7) cell lines. Among them, twelve compounds showed potent anti-tubercular activity with MIC ranging from 1.56 to 6.25 μg/mL. In particular dispirooxindolopyrrolothiazole derivatives 5c and 5f were found to be the most active (MIC of 1.56 μg/mL) with a good safety profile (27.53% and 20.74% at 50 μM, respectively). This is the first report demonstrating the benzofuranone oxindole hybrids as potential antimycobacterial agents.

1,3-dipolar cycloaddition of (E)-arylidene-(2H)-indanones 1 (Ar = Ph, p-MeC6H4, p-MeOC6H4, p-ClC6H4) and (E)-2-arylidene-(2H)-tetralones 2 (Ar = Ph, p-MeC6H4, p-MeOC6H4, p-ClC6H4) to N-metalated azomethine ylides 3 generated from methyl N-arylideneglycinate in the presence of silver acetate produces in good yields novel spiro[3,5-(diaryl)-2-carbomethoxypyrrolidine-4:2’-indanones] 4 and spiro[3,5-(diaryl)-2-carbomethoxypyrrolidine-4:2’-tetral-1-ones] 5. The cycloaddition proceeds in regio- and stereoselective manner (100%) at room temperature to afford respectively the syn-endo cycloadducts 4 and 5 via metallo-azomethine ylides. The regio- and stereochemistry of the spiranic adducts has been established on the basis of spectroscopic data and elemental analyses, corroborated by single-crystal X-ray crystallographic analysis of the heterocycles 4cd, 4bb and 5bd. The endo-pyrrolidines 4 were brominated by N-bromosuccinimide to give finally the dehydrobrominated 3,4-dihydro-2H-pyrrole derivatives 6. The spiro-adducts 4 and their corresponding oxidation products 6 are fluorescent in solution.

International audience

Some 4-substituted arylnitrile oxides and (Z)-3-arylidene-2(3H)-benzo-furanones undergo 1,3-dipolar cycloaddition reactions to give exclusively spirodihydroisoxazoles. These spiroadducts have be opened to the corresponding ethyl 3,4-diaryl-5-(orthohydroxyphenyl)-4,5-dihydroisoxazoline-5-carboxylates by the action of concentrated hydrochloric acid at reflux in ethanol.

A new elemane-type sesquiterpene has been isolated from the roots of Periploca laevigata and its structure clucidated by chemical and spectroscopic methods. Periploca laevigata, a species wide spread in the mediterraneen Sahara, have been indicated as a traditional plant medicine useful in the treatment of diabetes in Tunisia