Recent advances in direct C-H arylation: Methodology, selectivity and mechanism in oxazole series.

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.

Deprotonative magnesation and cadmation of [1,2,3]triazolo[1,5-a]pyridines.

[1,2,3]Triazolo[1,5-a]pyridine and 3-substituted derivatives were regioselectively metalated at the 7 position using either Bu3MgLi or (TMP)3CdLi, the former at -10 degrees C and the latter at room temperature. The lithium arylmagnesates (R = H, Me, Ph) proved to react with iodine (34-75%) or 3,4,5-trimethoxybenzaldehyde (32-51%). Attempts to obtain the cross-coupling products using 2-bromopyridine under palladium catalysis failed, a result attributed to the low stability of these compounds. The corresponding lithium arylzincates reacted in 17-60% yield under the same reaction conditions. The lithium arylcadmates were either trapped with iodine (38-76%, R = H, Me, Ph, CN, 2-thienyl) or involved in palladium-catalyzed cross-coupling reactions with 2-bromopyridine (26-67%, R = H, Me, Ph). For R = 2-pyridyl, 3-(6-iodo-2-pyridyl)-[1,2,3]triazolo[1,5-a]pyridine was isolated in 73% yield. (TMP)3CdLi also proved suitable for the clean dideprotonation of two substrates (R = H, 2-thienyl), a result demonstrated by quenching with iodine (66-75%).

First Synthesis of Caerulomycin C.

The first synthesis of caerulomycin C (1), an antibiotic produced by Streptomyces caeruleus, is reported. This molecule, which exhibits a 2,3,4,6-tetrasubstituted pyridine structure, was prepared from 3,4-dimethoxypyridine in a five-step sequence. The methodology involves metalation, transmetalation, aromatic cross-coupling, and halogen migration reactions.

Ortho-directed functionalization of arenes using magnesate bases.

Ortho-directed functionalisation of arenes using lithium alkylmagnesate bases were achieved, demonstrating the potential use of arylmagnesates as suitable arylanions, without a further transmetallation step, for challenging functionalizations such as fluorination, hydroxylation, arylation, vinylation and alkylation through epoxide ring-opening.

Synthesis of pyrazine alcaloids from Botryllus leachi. Diazines 43.

[reaction: see text] Regioselective metalation of pyrazines and cross-coupling reactions provides an easy access to botryllazines A and B and to an isomer of botryllazine A with good yields from chloropyrazine.

Deprotonation of benzoxazole and oxazole using lithium magnesates.

The first deprotonations of oxazole and benzoxazole using lithium magnesates are described. The reactions occurred in tetrahydrofuran at room temperature using 1/3 equiv of lithium tributylmagnesate. As 2-lithiooxazole and 2-lithiobenzoxazole, lithium tri(2-oxazolyl)magnesate and lithium tri(2-benzoxazolyl)magnesate very rapidly and completely isomerized to the more stable 2-(isocyano)enolate and 2-(isocyano)phenolate type structures, respectively, a result shown by NMR analysis. The isolation of 2-substituted oxazoles and benzoxazoles in medium to good yields after electrophilic trapping was interpreted in two ways: (1) the equilibration between the open and closed structures is faster than the trapping of the open isomers, and the closed isomers are more reactive than the open ones, or (2) the open isomers react with electrophiles in a intramolecular Passerini type reaction. The nonreactivity of the 2-(isocyano)enolate type structure toward anisaldehyde in the absence of lithium bromide makes the intramolecular Passerini type reaction more plausible.

Solid-phase syntheses of 6-arylpyridazin-3(2H)-ones.

The 3-chloropyridazine moiety was immobilized on a Wang resin, using two different methodologies. The first of these involved direct nucleophilic substitution of 3,6-dichloropyridazine with the alcoholate of Wang resin. The experimental conditions were optimized. The second method involved a Mitsunobu reaction between the Wang resin and 6-chloropyridazin-3-ol during which a problem of regioselectivity was observed. The so-obtained chloropyridazine-containing resins were subsequently reacted with various arylboronic acids under Suzuki conditions. Acid cleavage yielded 6-arylpyridazin-3(2H)-ones with high chemical purity.

Metallation of pyridines and quinolines in the presence of a remote carboxylate group. New syntheses of heterocyclic quinones.

2-(3- and 2-Pyridylcarbonyl)benzoic acids (2,3), 2-(2-pyridylcarbonyl)thiophene-3-carboxylic acid (6), 2-(3-quinolylcarbonyl)benzoic acid (10), and most of the corresponding esters (compounds 1,7 and 9 ) are readily synthesized and involved in a deprotonation-condensation sequence. Biologically active aza-anthraquinones such as benzo[g]isoquinoline-5,10-dione (2-azaanthraquinone, 4 ) and benzo[g]quinoline-5,10-dione (1-azaanthraquinone, 5) are prepared using the strategy. Extension to other heterocyclic quinones such as thieno[3,2-g]quinoline-4,9-dione (8) and benzo[j]phenanthridine-7,12-dione (11) is also investigated.

Synthesis and deprotonation of 2-(pyridyl)phenols and 2-(pyridyl)anilines.

2-(2- and 3-Pyridyl)anilines (1, 2), 2,2-dimethyl-N-[2-(2- and 3-pyridyl)phenyl]propanamides (3, 4), and 2-, 3- and 4-(2-methoxyphenyl)pyridines (7-9) are readily synthesized using cross-coupling reactions. Whereas the amines 1, 2 undergo side reactions, the corresponding amides 3, 4 are deprotonated with lithium 2,2,6,6-tetramethylpiperidide (LTMP): the compound 3 at C6' under in situ quenching, and the compound 4 at C4'. When the ether 7 is subjected to the same reagent, lithiation occurs at C6'.

First synthesis of caerulomycin B. A new synthesis of caerulomycin C.

Caerulomycins produced by Streptomyces caeruleus are bipyridinic molecules endowed with antibiotic properties. The first synthesis of caerulomycin B (1) as well as a new synthesis of caerulomycin C (2) are reported. Starting from 3-hydroxypyridine, the same methodology was used to prepare both compounds 1 and 2. Efficiently controlled reactions such as metalation to allow the synthesis of 2,6-diiodo-3,4-dialkoxypyridines, which are key intermediates, and further halogen-lithium exchange and cross-coupling to reach the targets molecules 1 and 2 have been developed.

Synthesis and deprotonation of 2-(halophenyl)pyridines and 1-(halophenyl)isoquinolines.

The ability of the 2-pyridyl and 1-isoquinolyl groups to direct metalation was studied in the benzene series. For this purpose, 2-(halophenyl)pyridines and 1-(halophenyl)isoquinolines were prepared. Interestingly, nucleophilic addition reactions on the azine ring were not observed under kinetic control using butyllithium, and the substrates were cleanly deprotonated on the benzene ring: the azine ring acidifies the adjacent hydrogen H2' (N-H2' interaction through space and/or inductive electron-withdrawing effect) and probably favors the approach of butyllithium (chelation). Under thermodynamic conditions using lithium dialkylamides, the presence of the azine group makes the lithio derivative at C2' more stable (chelation and/or inductive electron-withdrawing effect). This was evidenced in two ways: (1) syntheses of 2-halophenyllithiums (F, Cl, Br) substituted at C6 by a 2-pyridyl or 1-isoquinolyl group without elimination of lithium halide and (2) iodine migration from C2' to C4' when treating 2-(3-halo-2-iodophenyl)pyridines or 1-(3-fluoro-2-iodophenyl)isoquinoline with LTMP. Comparisons between the 2-pyridyl and fluoro units showed the latter was the stronger directing group for deprotonation.

Cross-coupling reactions of phenylmagnesium halides with fluoroazines and fluorodiazines.

The first nickel-catalyzed cross-coupling reactions between fluoroarenes and aryl organometallics using commercially available ligands are described. The nickel-catalyzed cross-coupling reactions between aryl Grignard reagents and fluoroazines and -diazines occurred in THF at room temperature using commercially available 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, or 1,1'-bis(diphenylphosphino)ferrocene as ligand. Various fluoro substrates such as pyridines, diazines (pyrazine, pyridazine), benzodiazines (quinoxaline), and quinolines were successfully involved in the reaction with phenylmagnesium halides (phenylmagnesium chloride, 2-methoxyphenylmagnesium bromide, and 4-methoxyphenylmagnesium bromide). The conditions used also allowed the cross-coupling of 4-fluorotoluene with arylmagnesium reagents.

Lithiation of functionalized fluoroquinolines: synthesis of dihalo-2-phenylquinoline-4-carboxamides and in vitro evaluation as NK-3 receptor ligands for medical imaging studies.

Fluoroiodo-2-phenylquinoline-4-carboxamides, analogues of NK-3 antagonist SB 223412, were synthesized and evaluated as NK-3 ligands with the aim of developing radioligands suitable for both Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) studies. The key step utilizes metalation directed by the fluorine atom for iodination of the quinoline ring.