Iodide-catalyzed reductions: development of a synthesis of phenylacetic acids.

A new convenient and scalable synthesis of phenylacetic acids has been developed via the iodide catalyzed reduction of mandelic acids. The procedure relies on in situ generation of hydroiodic acid from catalytic sodium iodide, employing phosphorus acid as the stoichiometric reductant.

A highly efficient palladium/copper cocatalytic system for direct arylation of heteroarenes: an unexpected effect of Cu(Xantphos)I.

Heteroarenes are important structural moieties in many chemical industry fields. A highly efficient Pd/Cu-catalyzed C-H arylation method for a range of heterocycles has been discovered. It was found that the key to the success of this transformation is a combination of a palladium catalyst and a well-defined copper cocatalyst. The efficiency and low loadings of catalyst (0.25 mol %) and cocatalyst (1 mol %) together with the mild reaction conditions demonstrate this method to be practically useful and mechanistically interesting.

Palladium-catalyzed chemoselective monoarylation of hydrazides for the synthesis of [1,2,4]triazolo[4,3-a]pyridines.

An efficient and convenient method for the synthesis of [1,2,4]triazolo[4,3-a]pyridines was exemplified by the synthesis of 20 analogues bearing a variety of substituents at the 3-position. The methodology involves a palladium-catalyzed addition of hydrazides to 2-chloropyridine, which occurs chemoselectively at the terminal nitrogen atom of the hydrazide, followed by dehydration in acetic acid under microwave irradiation.

Practical synthesis of a p38 MAP kinase inhibitor.

p38 MAP kinase inhibitors have attracted considerable interest as potential agents for the treatment of inflammatory diseases. Herein, we describe a concise and efficient synthesis of inhibitor 1 that is based on a phthalazine scaffold. Highlights of our approach include a practical synthesis of a 1,6-disubstituted phthalazine building block 24 as well as the one-pot formation of boronic acid 27. Significant synthetic work to understand the reactivity principles of the intermediates helped in selection of the final synthetic route. Subsequent optimization of the individual steps of the final sequence led to a practical synthesis of 1.

Pd-catalyzed deoxygenation of mandelate esters.

A new approach to the synthesis of phenylacetic acids and esters has been developed via the palladium-catalyzed deoxygenation of mandelate esters.

Selective ortho methylation of nitroheteroaryls by vicarious nucleophilic substitution.

An efficient and scalable three-step one-pot approach to 6-methyl-5-nitroisoquinoline (1) from inexpensive 5-nitroisoquinoline, utilizing the vicarious nucleophilic substitution (VNS) as a key step, is described. The optimized reaction conditions can be applied to a limited number of other aromatic and heteroaromatic nitro compounds. Attempts to understand the observed selectivity in the VNS step led to the discovery of two new reaction pathways under VNS conditions, one leading to an isoxazole and the other resulting in the formal cyclopropanation of an aromatic nitro compound.

A mild, one-pot synthesis of 4-quinolones via sequential Pd-catalyzed amidation and base-promoted cyclization.

A mild, one-pot synthesis of 4-quinolones is described. Under the optimal conditions, a variety of 2-substituted 4-quinolones were synthesized via sequential palladium-catalyzed amidation of 2'-bromoacetophenones followed by base-promoted intramolecular cyclization.

Practical synthesis of a vanilloid receptor-1 antagonist.

Small molecule TRPV1 antagonists have been a recent focus in the search for pain treatment agents. We herein describe a practical and scalable synthesis of AMG 628 (1), a bis-substituted pyrimidine derivative that was identified as a highly efficacious agent, suitable for clinical development. Highlights of our approach include a practical route to a substituted benzothiazole, a scalable synthesis of an enantiopure piperazine fragment, and identification of conditions for selective coupling reactions on 2,6-dichloropyrimidine, to access the active pharmaceutical ingredient in high purity and overall yield.

Stereoselective synthesis of a MCHr1 antagonist.

Melanin-concentrating hormone (MCH) is implicated in the feeding behavior in mammals affording a potential target to control overeating in people. Compound 1 (AMG 076) has been identified as a potent MCHr1 antagonist for the treatment of obesity. A synthesis suitable for the large-scale preparation of this lead candidate was developed to support preclinical studies. A Robinson annulation of benzylpiperidone and resolution of the desired enone from a mixture of the diastereomers afforded key intermediate 6 after a stereoselective hydrogenation. Subsequent Fischer indole synthesis with hydrazine 5 then provided the advanced intermediate, indole 2. Two complementary reductive amination strategies employing either aldehyde 3 or lactol 4 led to the synthesis of title compound 1.

New catalysts for Suzuki-Miyaura coupling reactions of heteroatom-substituted heteroaryl chlorides.

The new air-stable PdCl2[PR2(Ph-R')]2 complexes, readily prepared from commercial reagents, exhibit unique efficiency as catalysts for the Suzuki-Miyaura coupling reactions of a variety of heteroatom-substituted heteroaryl chlorides with a diverse range of aryl/heteroaryl boronic acids. The coupling reactions catalyzed by the new complexes exhibit high product yields (88-99%) and high catalyst turnover numbers (up to 10,000 TON).

New air-stable catalysts for general and efficient suzuki-miyaura cross-coupling reactions of heteroaryl chlorides.

[reaction: see text] New air-stable PdCl(2){P(t)Bu(2)(p-R-Ph)}(2) (R = H, NMe(2), CF(3),) complexes represent simple, general, and efficient catalysts for the Suzuki-Miyaura cross-coupling reactions of aryl halides including five-membered heteroaryl halides and heteroatom-substituted six-membered heteroaryl chlorides with a diverse range of arylboronic acids. High product yields (89-99% isolated yields) and turn-over-numbers (10,000 TON) are observed.

Efficient synthesis of a GABA A alpha2,3-selective allosteric modulator via a sequential Pd-catalyzed cross-coupling approach.

A practical synthesis of 2-[3-(4-fluoro-3-pyridin-3-yl-phenyl)-imidazo[1,2-a]pyrimidin-7-yl]-propan-2-ol (1), an oral GABA(A) alpha(2/3)-selective agonist, is described. The five-step process, which afforded 1 in 40% overall yield, included imidazopyrimidine 2 and pyridine boronic acid 4 as key fragments. The synthesis is highlighted by consecutive Pd-catalyzed coupling steps to assemble the final free base 1 in high yield and regioselectivity. A novel method for Pd removal in the final step is also described.

Palladium-catalyzed regioselective arylation of imidazo[1,2-a]pyrimidine.

Imidazo[1,2-a]pyrimidine can be arylated at the 3-position with aryl bromides in the presence of base and a catalytic amount of palladium. This provides an efficient one-step synthesis of 3-arylimidazo[1,2-a]pyrimidines from the unsubstituted heterocycle. [reaction: see text]

A practical synthesis for the core structure of a family of selective prostaglandin D2 receptor antagonists.

A convergent synthesis was developed for the production of the core structure of prostaglandin D(2) receptor antagonists for the treatment of allergic rhinitis. The key steps in this synthesis were a highly diastereoselective alkylation of (+)-nopinone, a chemo- and stereoselective reduction of an oxime to an amine, and a well-controlled reduction of an aminoalkyne to a (Z)-olefin.

An improved protocol for the preparation of 3-pyridyl- and some arylboronic acids.

3-Pyridylboronic acid was prepared in high yield and bulk quantity from 3-bromopyridine via a protocol of lithium-halogen exchange and "in situ quench". This technique was further studied and evaluated on other aryl halides in the preparation of arylboronic acids.

Mechanistic Study of the Jacobsen Asymmetric Epoxidation of Indene.

The asymmetric epoxidation of indene using aqueous NaOCl, catalyzed by Jacobsen's chiral manganese salen complex, provides indene oxide in 90% yield and 85-88% enantioselectivity. The axial ligand, 4-(3-phenylpropyl)pyridine N-oxide (P(3)NO), increases the rate of epoxidation without affecting enantioselectivity and also stabilizes the catalyst. These two effects afford a reduction in catalyst loading to <1%. The turnover-limiting step in the catalytic cycle has been determined to be the oxidation of the manganese catalyst, based on reaction orders of 0 in indene and 1 in catalyst and also based on the dependence of the rate on the hypochlorite concentration. In the presence of the ligand P(3)NO, this rate-limiting oxidation occurs in the organic phase with HOCl as oxidant, as shown by the dependence of the rate on the NaOH concentration. P(3)NO assists the transport of HOCl to the organic layer as demonstrated by titration studies and by measuring the rates of oxidation of a redox indicator, diphenylbenzidine. On the other hand, stirring speed studies indicate that, in the absence of the ligand, oxidation occurs at the interface. Thus, the axial ligand plays at least two roles in the epoxidation of indene: it stabilizes the catalyst, presumably by ligation, and it increases the epoxidation reaction rate by drawing the active oxidant, HOCl, into the organic layer.