Palladium-mediated Coupling Research Articles

A Practical and Efficient Process for the Preparation of Tazarotene

We describe an efficient process for the preparation of tazarotene starting from 4,4-dimethyl-6-bromothiochromane S-oxide (9), 2-methyl-3-butyn-2-ol (10), and 6-chloronicotinic acid ethyl ester (8). Our synthetic pathway compares favorably over the previously reported procedures since tazarotene was prepared straightforwardly using cheap reagents and without the employment of hazardous organometallic compounds. The process is based on the use of sulfoxide 9 as key starting material. The C-15 framework of the target was built up by means of two different approaches based on a palladium-mediated coupling reaction. The molecular structure of compound has been confirmed by X-ray crystallography.

Synthesis and in vitro examination of [ 124I]-, [ 125I]- and [ 131I]-2-(4-iodophenylamino) pyrido[2,3- d]pyrimidin-7-one radiolabeled Abl kinase inhibitors

The pyridopyrimidinones are a potent class of inhibitors of c-Abl kinase and Bcr–Abl kinase, the causative fusion protein in chronic myelogenous leukemia and Src family kinases. A novel method for routine, high-yield no-carrier-added synthesis of [ 124I]-, [ 125I]- and [ 131I]-6-(2,6-dichlorophenyl)-2-(4-iodophenylamino)-8-methyl-8 H-pyrido[2,3- d]pyrimidin-7-one has been developed. The 4′-trimethylstannyl- or 4′-tri- n-butylstannyl-pyridopyrimidinone precursors were prepared from the aryl bromide via a palladium-mediated coupling with hexaalkylditin (dioxane/microwave irradiation/10 min at 160°C). The radioiodination of 4′-stannylpyridopyrimidinones was found to optimally occur via an iododestannylation with Na 124I, Na 125I or Na 131I in the presence of an oxidant [30% H 2O 2/HOAc (1:3)/10 min] in 79–87% radiochemical yield with >99% radiochemical purity. The total radiosynthesis time was 30 min. The 4-iodophenylpyridopyrimidinone 2 inhibited recombinant Abl kinase activity with an IC 50 of 2.0 nM. Cell proliferation of K562 and A431 cells was inhibited with an IC 50 of 2.0 and 20 nM, respectively. Rapid cellular uptake and equilibrium were observed within 10–15 min using [ 131I]-4-iodophenylpyridopyrimidinone 6c in K562 and A431 cells and demonstrated a 2.8-fold uptake selectivity for the Bcr–Abl-expressing K562 cells at 60 min. These results suggest that pyridopyrimidinone radiotracers may be useful in imaging Abl-, Bcr–Abl- or Src-expressing malignancies.

Stereoselective Synthesis of Multisubstituted Alkenes via Conformationally Labile Alkenyllithium Species

Stereoselective synthesis of tri- and tetrasubstituted alkenylsilanes has been realized by the selective intramolecular silicon migration in the rapidly equilibrating alkenyllithium species. Subsequent copper- and palladium-mediated coupling with allyl and aryl halides provides tri- and tetrasubstituted alkenes possessing all different carbon-substituents with complete stereoselectivity. [structure: see text]

Synthesis of 3,5-difunctionalized 1-methyl-1H-pyrazolo[3,4- b]pyridines involving palladium-mediated coupling reactions

Indirect iodination of 2-chloro-nicotinonitrile gave 2-chloro-5-iodonicotinonitrile, which was cyclized with methylhydrazine to lead to 3-amino-5-iodopyrazolo[3,4- b]pyridine. Position 3 was then protected by pivaloyl group and the resulting 5-iodo-3-pivaloylaminopyrazolo[3,4- b]pyridine was engaged in palladium-promoted coupling reactions with various reagents to give 3-pivaloylamino-5-substituted compounds. Deprotection and iododediazoniation followed by cross-coupling reactions in position 3 afforded novel unsymmetrical 3,5-disubstituted pyrazolo[3,4- b]pyridine species.

Combinatorial synthesis of substituted biaryls and heterocyclic arylamines.

In this paper, we report very general conditions that enable palladium-mediated coupling reactions on the solid support. A wide variety of biaryls and arylamines (including pyrimidines) have been synthesized using this protocol. The chemistry facilitates a combinatorial approach to the production of large numbers of medicinally relevant heterocyclic structures.

A Novel Palladium‐Catalyzed Coupling of Thiol Esters with 1‐Alkynes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Studies Towards the Total Synthesis of Cycloaraneosene and Ophiobolin M: A General Strategy for the Construction of the 5—8 Bicyclic Ring System.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Novel Palladium-CatalyzedCoupling of Thiol Esters with 1-Alkynes

A new method for synthesizing α,β-acetylenic ketones by palladium-mediated coupling of thiol esters with 1-alkynes is described. The reaction could be applied to coupling of thiol esters bearing various functional groups, such as aromatic bromides, and ketones, with functionalized terminal acetylenes.

Transition Metal Complexes in Organic Synthesis, Part 69.Total Synthesis of theAmaryllidaceaeAlkaloids Anhydrolycorinone and Hippadine Using Iron- and Palladium-Mediated Coupling Reactions

A novel synthesis of the Amaryllidaceae alkaloids anhydrolycorinone and hippadine has been developed using an iron-mediated oxidative alkylamine cyclization and an intramolecular palladium-mediated biaryl coupling as the key steps.

New and versatile syntheses of 3-alkyl- and 3-aryl-1,2,4-benzotriazine 1,4-dioxides: preparation of the bioreductive cytotoxins SR 4895 and SR 4941

Palladium-mediated coupling of 3-chloro-1,2,4-benzotriazine 1-oxide with a variety of stannanes in the presence of Pd(PPh 3) 4 gives 3-alkyl derivatives in good yields. Suzuki reaction of the 3-chloro compound with phenylboronic acids gives 3-aryl-1,2,4-benzotriazine 1-oxides. Oxidation of 1-oxides with trifluoroperacetic acid gives the 1,4-dioxides. This method provides a better route to the potential anti-cancer agents SR 4895 and SR 4941.

A general approach toward the synthesis of C-nucleoside pyrazolo[1,5-a]-1,3,5-triazines and their 3',5'-bisphosphate C-nucleotide analogues as the first reported in vivo stable P2Y(1)-receptor antagonists.

In our effort to identify potent purinergic P2Y(1) receptor antagonists as potent platelet aggregation inhibitors with enhanced metabolic stability, we developed an efficient route for the large-scale preparation of 2'-deoxy-C-nucleosides of pyrazolo[1,5-a]-1,3,5-triazine. The key strategic elements of this novel synthetic approach involved the following: (i) the use of a novel activating group, the N-methyl-N-phenylamino group, which was easily generated in high yield by treatment of the pyrazolo[1,5-a]-1,3,5-triazin-4-one (5) with phosphorus oxychloride and dimethylaniline under high pressure, (ii) a regio- and stereospecific palladium-mediated coupling reaction of the readily available unprotected glycal 1,4-anhydro-2-deoxy-D-erythro-pent-1-enitol (4b) and the 8-iodo derivative (16), and (iii) the stereoselective reduction of the ketone group of the furanosyl ring followed by the subsequent displacement of the N-methyl-N-phenylamino group upon treatment with methylamine. The beta configuration at the anomeric C-1' position of the glycal moieties was perfectly retained throughout this conversion. This procedure afforded 8-(2'-deoxy-beta-D-ribofuranosyl)-2-methyl-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (21) and 8-(2'-deoxy-beta-D-xylofuranosyl)-2-methyl-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (24) with an overall yield of 50% and 39%, respectively. Finally, the conversion of nucleosides 21 and 24 to the pyrazolotriazine C-nucleotides 3',5'-bisphosphate 2 and 3',5'-cyclophosphate 26 is also described herein and represents the first reported nucleotide derivatives within the pyrazolo[1,5-a]-1,3,5-triazine series. Preliminary biological testing has shown that compound 2 strongly inhibits ADP-induced human platelet aggregation and shape change and possesses significant efficacies 30 min after injection in rat, highlighting a strong P2Y(1)-receptor antagonist activity in vitro combined with a prolonged duration of action in vivo.

Catalytic Cross‐Coupling Reactions Mediated by Palladium/Nucleophilic Carbene Systems.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Studies Towards the Total Synthesis of Cycloaraneosene and Ophiobolin M: A General Strategy for the Construction of the 5−8 Bicyclic Ring System

The synthesis of the core unit of cycloaraneosene and ophiobolin M has been investigated, following a general strategy applicable to both 5−8 bicyclic systems. The synthetic strategy includes a ring-closing metathesis reaction to generate the central eight-membered ring as well as a palladium-mediated coupling of a Grignard reagent to introduce the exocyclic side-chain. The stereochemistry of the ring junction is also discussed and moderate diastereoselectivity has been achieved. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Catalytic cross-coupling reactions mediated by palladium/nucleophilic carbene systems

In this mini-review, we present a summary of our recent work in the field of palladium-catalyzed cross-coupling reactions, with emphasis on the use of nucleophilic N-heterocyclic carbenes (NHC) as ancillary ligand. The palladium-mediated coupling reactions investigated include the Suzuki–Miyaura, Kumada–Tamao–Corriu, Heck, Sonogashira, Stille, Hiyama and aryl amination reactions.

Solid-phase synthesis of 2,3,5-trisubstituted indoles.

2,3,5-Trisubstituted indoles are synthesized in three steps starting from resin-bound aniline 2. R1 is introduced by a palladium-mediated coupling of the aryl iodide with terminal alkynes followed by intramolecular cyclization to form the indole core. Acylation at C-3 with an acid chloride in the presence of AlCl(3) catalyst introduces R2. The indole C-5 position is then diversified either by Sonagashira or Suzuki couplings with the aryl bromide. Finally, indole N-1 can be modified by post-cleavage methylation. [reaction: see text]

Expanding the diversity of purine libraries

In recent years, there has been a resurgence of interest in the synthesis of purine derivatives due to the discovery of purine-derived ligands for a variety of nucleotide dependent enzymes. The majority of chemistry has focused on substitution of the purine core structure by alkylation at N9 and nucleophilic–aromatic substitution reactions at C2 and C6. Here we report the syntheses of aryl, N-aryl, O-aryl substituted purine libraries by the palladium-mediated coupling of boronic acids, anilines or phenols at the C2 position, and copper(II)-mediated N-arylation with boronic acids at the N9 position. The chemistry described here greatly expands our ability to introduce different functionality and create new purine scaffolds.

Enantioselective approach to 3-substituted prolines

Enantioselective synthesis of 3-substituted prolines was achieved starting from commercially available 3-hydroxy-( S)-2-proline. Palladium-mediated couplings were used to introduce a variety of groups at C3 using the corresponding enol triflate derived from N-trityl 3-oxo-( S)-2-proline methyl ester. Cleavage of the trityl residue and hydrogenation provided final products with good to modest diastereoselectivity.

The synthesis and tubulin binding activity of thiophene-based analogues of combretastatin A-4

A number of analogues of combretastatin A-4 ( 1), containing a thiophene ring interposed between the two phenyl groups, have been prepared. The synthesis of these compounds employed a combination of palladium-mediated coupling and iodocyclization techniques. The thiophene compounds 11, 14, 18, and 19 also represent non-benzofused analogues of some recently described tubulin binding benzo[ b]thiophenes 3– 5. The most active thiophene compounds identified in this study were 11, 14, and 18. Overall they are less active than 1 but exhibit comparable activity to the most active of the benzo[ b]thiophenes 3– 5. A structure–activity relationship of these compounds is considered.

Convenient Route to Both Enantiomerically Pure Forms of trans-4,5-Dihydroxy-2-cyclopenten-1-one: Efficient Synthesis of the Neocarzinostatin Chromophore Core

Abstract An enantioselective synthesis of an epoxybicyclo[7.3.0]dodecenediyne core system of the neocarzinostatin chromophore has been achieved via intramolecular acetylide addition and palladium-mediated coupling of iodocyclopentene 5 with alkyne 6. The key cyclopentene moiety, trans-4,5-dihydroxy-2-cyclopenten-1-one 7, was conveniently prepared in both enantiomerically pure forms via enzymatic desymmetrization of meso-3,4,5-trans,trans-trihydroxycyclopentene derivatives.

A novel palladium-mediated coupling approach to 2,3-disubstituted benzo(b)thiophenes and its application to the synthesis of tubulin binding agents.

[structure: see text]. Flexible, convergent access to 2,3-disubstituted benzo[b]thiophenes has been developed. The most concise approach involves sequential coupling of o-bromoiodobenzenes with benzylmercaptan and zinc acetylides to give benzyl o-ethynylphenyl sulfides which react with iodine to give 3-iodobenzo[b]thiophenes in a 5-endo-dig iodocyclization. These iodides can be further elaborated using palladium-mediated coupling and/or metalation techniques. This method has been applied to the synthesis of some novel tubulin binding agents.