Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 42
Filter
1.
J Org Chem ; 87(11): 7464-7473, 2022 06 03.
Article in English | MEDLINE | ID: mdl-35574806

ABSTRACT

α-Isocyanoacetamide derivatives were first converted to oxazolines under newly developed conditions. These oxazolines were used as precursors of α-isocyanoacrylamides, which could lead to various 2-arylated imidazolones. In addition, it was shown that both oxazolines and their precursors could efficiently lead to imidazolones unsubstituted at C2 in a very rapid, one-pot transformation, thus paving the way toward unprecedented routes to imidazolones, having a good tolerance to different substitution patterns.


Subject(s)
Aldehydes , Cyanides , Imidazoles
2.
Chemistry ; 27(56): 13897-13898, 2021 Oct 07.
Article in English | MEDLINE | ID: mdl-34590752

ABSTRACT

Invited for the cover of this issue are Jean-François Brière, Cédric Schneider, Guillaume Journot and co-workers from the COBRA laboratory and Oril Industrie (Normandy, France). The image shows the progression from questioning how to easily and regioselectively introduce halogen atoms to amino acids to the discovery of a catalytic functional-group-directed C-H halogenation of phenylalanine derivatives. Read the full text of the article at 10.1002/chem.202102411.


Subject(s)
Amines , Palladium , Catalysis , Halogenation , Humans , Phenylalanine
3.
Chemistry ; 27(56): 13961-13965, 2021 Oct 07.
Article in English | MEDLINE | ID: mdl-34403169

ABSTRACT

An efficient primary-amine-directed, palladium-catalyzed C-H halogenation (X=I, Br, Cl) of phenylalanine derivatives is reported on a range of quaternary amino acid (AA) derivatives thanks to suitable conditions employing trifluoroacetic acid as additive. The extension of this original native functionality-directed ortho-selective halogenation was even demonstrated with the more challenging native phenylalanine as tertiary AA.


Subject(s)
Amines , Palladium , Catalysis , Halogenation , Phenylalanine
4.
J Org Chem ; 86(2): 1769-1778, 2021 01 15.
Article in English | MEDLINE | ID: mdl-33406843

ABSTRACT

A computational study on the base-assisted orthogonal C-H arylation of azoles with halides is reported. Although concerted metalation-deprotonation (CMD) is favored under acetate assistance at the C5 site that displays the best balance of nucleophilic and acidic character, the most acidic C2 site may be selectively targeted under carbonate assistance by taking advantage of a carbanionic-type (or non-concerted) metalation-deprotonation mechanism (nCMD). For the latter, several experimental probes including base, ligand, and solvent effects have been collected in favor of an outer-sphere deprotonation process after the formation of a [(Ln)(N1-heteroaryl)PdArX] complex. However, no computational analysis of this fundamental elementary step has been so far provided. We have carried out a series of density functional theory (DFT) calculations that delineate the structural and energetic aspects of the nCMD pathway. Starting with the oxa(thia)zole-4-carboxylates selected in our group to engineer the competitive C2 vs C5 arylation in azoles, we show that the energy barrier of the C2 anion generation is lying unexpectedly lower than the prior heterocycle coordination to Pd that is eventually identified as the rate-determining step. These calculations provide satisfactory explanations for the experimental observations of the divergence between nCMD and CMD reactivity, and notably a lower barrier at the C2 site for the nCMD process. On the other hand, the nCMD process is ineffective at the C5 site. Evaluation of various azoles reveals that the nCMD mechanism at C2 is viable from the most acidic (benzo)oxazoles to moderately acidic (benzo)thiazoles, as well as weakly acidic imidazoles. In all cases, in accordance with previously reported experimental data in orthogonal direct C-H arylation of azoles, the nCMD route is found energetically competitive to the CMD one at C5 for all azoles, except for imidazole which needs stronger basic conditions than simple carbonate assistance. Additionally, the acetate ligand, which is the base of choice for CMD, was found inefficient for nCMD and the comparative performance of acetate vs carbonate to assist CMD in the azole series reveals also considerable changes from electronically close but environmentally divergent C5-H vs C2-H bonds.

5.
J Org Chem ; 84(16): 10535-10545, 2019 08 16.
Article in English | MEDLINE | ID: mdl-31319666

ABSTRACT

A regioselective Pd-catalyzed domino carbopalladation/decarboxylative allylic alkynylation of ortho-iodoallenamides with alkynyl carboxylic acids was studied. This domino process, based on the consecutive formation of C(sp2)-C(sp2) and C(sp3)-C(sp) bonds, was originally achieved for the design of a novel library of prop-2-ynyl isoquinolinones and then extended to indoles. Finally, a general three-step one-pot strategy involving in situ generation of allenamide, π-allyl-Pd complex formation, and decarboxylative allylic alkynylation was subsequently set up.

6.
Org Biomol Chem ; 16(4): 526-530, 2018 01 24.
Article in English | MEDLINE | ID: mdl-29292462

ABSTRACT

Herein, palladium-catalyzed Miyaura borylation of 4-bromo-2,4'-bithiazoles followed by Suzuki-Miyaura cross-coupling reaction (named the MBSC process) with (hetero)aryl- and alkenyl halides is reported. This methodology offers rapid access to various 2',4-disubstituted 2,4'-bithiazole features including naturally-occurring 4-alkenylated and 4-pyridinylated 2,4'-bithiazoles. To prove its application, a concise approach for the synthesis of a heterocyclic cluster of the thiopeptide d-series antibiotic GE2270 is reported through a late-stage MBSC strategy.


Subject(s)
Hydrocarbons, Halogenated/chemistry , Thiazoles/chemical synthesis , Catalysis , Chemistry Techniques, Synthetic/methods , Palladium/chemistry , Peptides, Cyclic/chemistry , Stereoisomerism , Thiazoles/chemistry
7.
Beilstein J Org Chem ; 13: 1407-1412, 2017.
Article in English | MEDLINE | ID: mdl-28781706

ABSTRACT

A straightforward enantiomerically pure synthesis of the heterocyclic core of the D-series GE2270 is reported. The synthetic strategy combines the Hantzsch thiazole's building condensation with a cross-coupling reaction including direct C-H hetarylation to build and connect step-by-step thiazolyl moieties to the 5-bromopicolinate as readily available starting material.

8.
Chemistry ; 22(16): 5520-4, 2016 Apr 11.
Article in English | MEDLINE | ID: mdl-26960963

ABSTRACT

The first one-pot synthesis of N-substituted 2-H-4-benzylidene imidazolones and their subsequent palladium-catalyzed and copper-assisted direct C2-H arylation and alkenylation with aryl- and alkenylhalides are described. This innovative synthesis is step-economical, azide-free, high yielding, highly flexible in the introduction of a variety of electronically different groups, and can be operated on large-scale. Moreover, the method allows direct access to C2-arylated or alkenylated imidazolone-based green fluorescent protein (GFP) and Kaede protein fluorophores, including ortho-hydroxylated models.


Subject(s)
Benzylidene Compounds/chemistry , Green Fluorescent Proteins/chemistry , Green Fluorescent Proteins/chemical synthesis , Imidazoles/chemistry , Catalysis , Copper/chemistry , Molecular Structure , Palladium/chemistry
9.
Org Biomol Chem ; 14(13): 3459-68, 2016 Apr 07.
Article in English | MEDLINE | ID: mdl-26967763

ABSTRACT

The construction and subsequent orthogonal functionalization of a hitherto unknown oxazolo[5',4':4,5]pyrano[2,3-b]pyridine are reported. A palladium-catalyzed direct C-H bond functionalization methodology was used to build the tricyclic scaffold as well as to achieve the subsequent C-H bond functionalization at the C-2 position of the oxazole unit with various (hetero)aryl iodides. Remarkably, selective C-H construction and functionalization procedures preserve the chorine atom on the pyridine moiety offering a late-stage substitution site to progress drug design.

10.
Org Biomol Chem ; 14(1): 353-7, 2016 Jan 07.
Article in English | MEDLINE | ID: mdl-26603641

ABSTRACT

Copper-catalyzed direct C-H fluoroalkenylation of heterocycles using various gem-bromofluoroalkenes as electrophiles is reported. This efficient method offers step-economical, low-cost and stereocontrolled access to relevant heteroarylated monofluoroalkenes. The synthesis of fluorinated analogues of biomolecules and therapeutic agents for the treatment of Duchenne muscular dystrophy as application is reported.


Subject(s)
Alkenes/chemistry , Copper/chemistry , Heterocyclic Compounds/chemistry , Hydrocarbons, Fluorinated/chemical synthesis , Catalysis , Hydrocarbons, Fluorinated/chemistry , Molecular Structure
11.
J Org Chem ; 80(11): 5919-27, 2015 Jun 05.
Article in English | MEDLINE | ID: mdl-25938169

ABSTRACT

A straightforward method for direct decarboxylative arylation of 1- and 3-carboxy isoquinaldic acid N-oxides with aryl iodides is reported. The reaction proceeded selectively at the carboxy function site to exclusively give the corresponding C-1 or C-3 arylated product. This methodology tolerates various aryl iodides substituted by electronically different groups. Combined with subsequent Reissert-Henze chlorination and SNAr amination, the decarboxylative arylation provides an efficient access to 1,3-functionalized isoquinoline-based antitumor agent.


Subject(s)
Cyclic N-Oxides/chemistry , Isoquinolines/chemical synthesis , Halogenation , Iodides/chemistry , Isoquinolines/chemistry , Molecular Structure
12.
Chemistry ; 20(46): 15000-4, 2014 Nov 10.
Article in English | MEDLINE | ID: mdl-25303004

ABSTRACT

Pd/Cu-catalyzed decarboxylative/direct C-H alkenylations of heteroarenes with α-fluoroacrylic acid is reported. This method offers step-economical and stereocontrolled access to valuable heteroarylated monofluoroalkenes as both Z and E isomers, which are known to be useful in the synthesis of fluorinated biomolecules.

13.
Chemistry ; 20(13): 3610-5, 2014 Mar 24.
Article in English | MEDLINE | ID: mdl-24573742

ABSTRACT

Decarboxylative cross-coupling reactions of substituted 2-carboxyazine N-oxides, with a variety of (hetero)aryl halides, by bimetallic Pd(0)/Cu(I) and Pd(0)/Ag(I) catalysis are reported. Two possible pathways, a conventional bimetallic-catalyzed decarboxylative arylation, as well as a protodecarboxylative/direct C-H arylation sequence have been considered. These methods provide the first general decarboxylative arylation methodology for the 2-carboxyazine series.

14.
Sci Rep ; 13(1): 3609, 2023 Mar 03.
Article in English | MEDLINE | ID: mdl-36869125

ABSTRACT

We recently proposed a new approach for the real-time monitoring of particle therapy treatments with the goal of achieving high sensitivities on the particle range measurement already at limited counting statistics. This method extends the Prompt Gamma (PG) timing technique to obtain the PG vertex distribution from the exclusive measurement of particle Time-Of-Flight (TOF). It was previously shown, through Monte Carlo simulation, that an original data reconstruction algorithm (Prompt Gamma Time Imaging) allows to combine the response of multiple detectors placed around the target. The sensitivity of this technique depends on both the system time resolution and the beam intensity. At reduced intensities (Single Proton Regime-SPR), a millimetric proton range sensitivity can be achieved, provided the overall PG plus proton TOF can be measured with a 235 ps (FWHM) time resolution. At nominal beam intensities, a sensitivity of a few mm can still be obtained by increasing the number of incident protons included in the monitoring procedure. In this work we focus on the experimental feasibility of PGTI in SPR through the development of a multi-channel, Cherenkov-based PG detector with a targeted time resolution of 235 ps (FWHM): the TOF Imaging ARrAy (TIARA). Since PG emission is a rare phenomenon, TIARA design is led by the concomitant optimisation of its detection efficiency and Signal to Noise Ratio (SNR). The PG module that we developed is composed of a small PbF[Formula: see text] crystal coupled to a silicon photoMultiplier to provide the time stamp of the PG. This module is currently read in time coincidence with a diamond-based beam monitor placed upstream the target/patient to measure the proton time of arrival. TIARA will be eventually composed of 30 identical modules uniformly arranged around the target. The absence of a collimation system and the use of Cherenkov radiators are both crucial to increase the detection efficiency and the SNR, respectively. A first prototype of the TIARA block detector was tested with 63 MeV protons delivered from a cyclotron: a time resolution of 276 ps (FWHM) was obtained, resulting in a proton range sensitivity of 4 mm at 2[Formula: see text] with the acquisition of only 600 PGs. A second prototype was also evaluated with 148 MeV protons delivered from a synchro-cyclotron obtaining a time resolution below 167 ps (FWHM) for the gamma detector. Moreover, using two identical PG modules, it was shown that a uniform sensitivity on the PG profiles would be achievable by combining the response of gamma detectors uniformly distributed around the target. This work provides the experimental proof-of-concept for the development of a high sensitivity detector that can be used to monitor particle therapy treatments and potentially act in real-time if the irradiation does not comply to treatment plan.

15.
Bioorg Med Chem Lett ; 22(13): 4377-85, 2012 Jul 01.
Article in English | MEDLINE | ID: mdl-22632936

ABSTRACT

Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.


Subject(s)
Adenine/analogs & derivatives , Morpholines/chemistry , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Purines/chemistry , Adenine/chemistry , Adenine/pharmacokinetics , Adenine/toxicity , Administration, Oral , Animals , Apoptosis/drug effects , Binding Sites , Crystallography, X-Ray , G2 Phase Cell Cycle Checkpoints/drug effects , HCT116 Cells , Humans , M Phase Cell Cycle Checkpoints/drug effects , Mice , Molecular Conformation , Morpholines/pharmacokinetics , Morpholines/toxicity , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/toxicity , Protein Serine-Threonine Kinases/metabolism , Structure-Activity Relationship
16.
Org Lett ; 24(44): 8164-8169, 2022 11 11.
Article in English | MEDLINE | ID: mdl-36315966

ABSTRACT

Herein, we present a regioselective Pd-catalyzed C-H [4 + 2] benzannulation of N-unprotected 3-arylindoles with external readily available 1,3-dienes via an original sequence involving a Pd-catalyzed domino carbopalladation of 1,3-dienes/direct C2-H allylation of an indole ring followed by an oxidation or reduction step. Depending on the nature of the solvent, DCE or CH3CN, two consecutive approaches, oxidative or reductive, have been validated and applied to the design of a novel library of C6-alkyl or (E)-C6-styryl-benzo[c]carbazoles in moderate to good yields.


Subject(s)
Carbazoles , Palladium , Molecular Structure , Polyenes , Oxidation-Reduction
17.
Chemistry ; 17(51): 14450-63, 2011 Dec 16.
Article in English | MEDLINE | ID: mdl-22095625

ABSTRACT

Both base-assisted non-concerted metallation-deprotonation (nCMD) and concerted metallation-deprotonation (CMD) have been identified as two potent operating mechanisms in palladium-catalysed direct C-H coupling of oxazole and thiazole-4-carboxylate esters with halides through base- and solvent-effect experiments. Novel C2- and C5-selective CMD direct arylation procedures in oxazole- and thiazole-4-carboxylate series were then designed by controlling the balance between electronic and steric factors. Notably, charge interactions between the palladium catalyst and substrate were identified as a parameter for controlling selectivity and reducing the impact of steric factors in the CMD reaction.


Subject(s)
Carboxylic Acids/chemical synthesis , Oxazoles/chemical synthesis , Thiazoles/chemical synthesis , Carboxylic Acids/chemistry , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure , Oxazoles/chemistry , Palladium , Solvents , Thiazoles/chemistry
18.
Org Biomol Chem ; 9(18): 6215-8, 2011 Sep 21.
Article in English | MEDLINE | ID: mdl-21796283

ABSTRACT

Sequential palladium-catalysed direct (het)arylation of oxazole-4-carboxylates is achieved to give rapid access to DPO and POPOP (di)carboxylate-analogs. Three novel DPO- and POPOP-type sensors with unusual Stokes shifts and high quantum yields are discovered.


Subject(s)
Carboxylic Acids/chemistry , Oxazoles/chemistry , Palladium/chemistry , Catalysis
19.
Beilstein J Org Chem ; 7: 1584-601, 2011.
Article in English | MEDLINE | ID: mdl-22238536

ABSTRACT

Catalytic direct (hetero)arylation of (hetero)arenes is an attractive alternative to traditional Kumada, Stille, Negishi and Suzuki-Miyaura cross-coupling reactions, notably as it avoids the prior preparation and isolation of (hetero)arylmetals. Developments of this methodology in the oxazole series are reviewed in this article. Methodologies, selectivity, mechanism and future aspects are presented.

20.
Org Lett ; 23(8): 3130-3135, 2021 04 16.
Article in English | MEDLINE | ID: mdl-33765389

ABSTRACT

Herein, we present a regioselective Cu-catalyzed oxidative allylic C(sp3)-H arylation by radical relay using a broad range of heteroaryl boronic acids with inexpensive and readily available unactivated terminal and internal olefins. This C(sp2)-C(sp3) allyl coupling has the advantage of using cheap, abundant, and nontoxic Cu2O without the need to use prefunctionalized alkenes, thus offering an alternative method to allylic arylation reactions that employ more traditional coupling partners with preinstalled leaving groups (LGs) at the allylic position.

SELECTION OF CITATIONS
SEARCH DETAIL