A Nitrogen-Assisted One-Pot Heteroaryl Ketone Synthesis from Carboxylic Acids and Heteroaryl Halides.

A practical and highly effective one-pot synthesis of versatile heteroaryl ketones directly from carboxylic acids and heteroaryl halides under mild conditions is reported. This method does not require derivatization of carboxylic acids (preparation of acid chlorides, Weinreb amides, etc.) or the use of any additives/catalysts. A wide substrate scope of carboxylic acids with high functional group tolerance has also been demonstrated. The results reveal that the presence of an α-nitrogen on the halide substrate greatly improves the desired ketone formation.

[Complex regional pain syndrome in a patient with acute drug poisoning: a case report].

We report a case with transition to complex regional pain syndrome (CRPS) caused by nerve injury associated with crush syndrome. The diagnosis was delayed because of coma due to acute drug poisoning. A 44-year-old man had attempted suicide by taking massive amounts of psychotropic drugs 2 days earlier and was transported to our hospital by ambulance. His arms had been compressed due to the prolonged (2 days) consciousness disturbance, and he experienced non-traumatic crush syndrome and rhabdomyolysis. Acute renal failure was prevented with massive infusion and hemofiltration. However, he experienced muscle and nerve injury at the compressed area, which presumably led to CRPS. In cases of suspected crush syndrome associated with acute drug poisoning, it is also important to recognize the possibility of developing CRPS.

Double Reformatsky reaction: divergent synthesis of δ-hydroxy-ß-ketoesters.

The double Reformatsky reaction, tandem addition of two molecules of zinc alkanoate to a carbonyl compound, and its synthetic application to a series of δ-hydroxy-ß-ketoesters has been developed. The key to accelerate the double Reformatsky reaction is considered to be a complex-induced proximity effect of the in situ generated zinc alkoxide coordinated with the pyridyl group of the substrate or bidentate amines. A noteworthy feature of the reaction system is its high tolerance of functional groups due to the moderate nucleophilicity of organozinc reagents and the mild reaction conditions. Moreover, spectroscopic and crystallographic analyses of the zinc complex of the double Reformatsky product support the proposed mechanism of reaction site discrimination for ketones, aldehydes, nitriles, carboxylic acid anhydrides, and esters.

Enantioseparation of benzazoles and benzanilides on polysaccharide-based chiral columns.

The chiral recognition ability of the polysaccharide-based chiral columns (Chiralpak AD-RH, Chiralpak AS-RJ, Chiralpak IC, Chiralcel OD-RH, and Chiralcel OJ-RH) for the benzazoles and the benzanilides was evaluated under reversed phase conditions. The columns showed the high chiral recognition ability for a wide range of benzazoles and benzanilides. Twenty-one racemates were used for the evaluation, and 20 racemates were completely separated on at least one of the columns. In particular, AS-RH and OJ-RH showed the high chiral recognition ability for the benzazoles, and the AD-RH, IC, and OJ-RH were effective for the benzanilides.

Practical synthesis of a neuropeptide Y antagonist via stereoselective addition to a ketene.

[Reaction: see text]. The synthesis of neuropeptide Y antagonist 1, currently under clinical investigation for the treatment of obesity, is described. The convergent synthesis from trans-spirolactone carboxylic acid intermediate 2a and aminopyrazole 3 is predicated on a stereoselective route to the former. The coupling reaction of ethyl 4-oxocyclohexanecarboxylate (10a) with lithiated isonicotinamide 11 was investigated in detail, but even optimized conditions only provided a 45:55 ratio of trans:cis isomers (12a:12b). While selective crystallization schemes were developed to isolate the thermodynamically less stable trans isomer 2a, improved stereocontrol was subsequentially achieved by the application of ketene chemistry. The ketene formation and quench was investigated under a variety of conditions aimed at maximizing the trans:cis ratio. Reacting a mixture of carboxylic acids 2a and 2b with POCl3 in THF, followed by concomitant addition of tert-butyl alcohol in the presence of TMEDA at 35 degrees C provided a 4:1 ratio of trans:cis tert-butyl esters (18a:18b) via in situ ketene formation. Ester hydrolysis, followed by selective crystallization of undesired 2b as the HCl salt, led to isolation of 2a in 47% overall yield. Aminopyrazole intermediate 3 was synthesized via the condensation reaction of 2-fluorophenylhydrazine hydrochloride (4a) with acrylonitrile derivative 5 in 65-70% yield. Coupling of advanced intermediates 2a and 3b via activation with thionyl chloride gave a 92% yield of 1.

Convergent synthesis of the E'FGH ring fragment of ciguatoxin 1B via an acetylene cobalt complex strategy.

A convergent synthesis of the E'FGH ring fragment 28 of ciguatoxin 1B, a principal toxin causing widespread seafood poisonings "ciguatera", has been accomplished through (i) coupling between the E' ring-acetylide 9 and the H ring-aldehyde 20, (ii) stereoselective F ring cyclization via an acetylene cobalt complex, (iii) conversion to a carbonyl function under high-pressure hydrogenation, and (iv) reductive hydroxyketone cyclization to construct the G ring. In the (1)H NMR analysis of 28 at room temperature, a considerable broadening phenomenon was observed due to the slow conformational changes of the FG ring, as reported for natural ciguatoxin 1B. When measured in pyridine at -20 degrees C, the spectra of 28 exhibited a 3.5:1 mixture of two conformational isomers (UP and DOWN conformers).