Bi(NO3)3‐catalyzed ring expansion of five‐membered ring 1,4‐diketones in the presence of primary amines leads to eight‐membered ring lactams. When applied to starting materials with a tetrahydrothiophene or pyrrolidine moiety, tetrahydro‐2H‐1,4‐thiazocin‐3‐ones and hexahydro‐1,4‐diazocin‐2‐ones are obtained as representatives of these very rare heterocyclic systems. In the case of tetrahydrofuran derivatives, other reaction conditions are required and yields of tetrahydro‐2H‐1,4‐oxazocin‐3‐ones are very low.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Oxo esters with pyrrolidine and tetrahydrofuran rings were converted into optically active isobenzofuran and isoindole derivatives. The key step of the sequence was a copper-catalyzed asymmetric Michael reaction with methyl vinyl ketone and enamines prepared from the oxo esters and L-valine diethylamide. The chiral auxiliary was cleaved from the products during workup and 1,5-diketones with a quaternary stereocenter are obtained with 97-99% ee. Subsequent annulation reactions were achieved in two steps via the intermediate aldol products.The isoindole moiety is a common structural motif in heterocyclic compounds, 1 and one of the privileged structures in medicinal chemistry. 2 In contrast, isobenzofurans are less frequently reported. 3 Prominent examples of pharmaceutically active isoindoles are the antidepressant tandospirone, 4 the hypoglycemic mitiglinide (diabetes), 5 and the antiviral tecovirimat (ST-246) ( Figure 1). 6 Examples for pharmaceutically active isobenzofurans are the topoisomerase II-inhibitor etoposide 7 and the thrombolytic SCH 530348, 8 an analogue of the natural product himbacine. 9A couple of years ago we reported on the asymmetric synthesis of optically active octahydroisoquinolone 2 from enamine 1 (Scheme 1). 10 The key step of this reaction was a copper-catalyzed Michael reaction with methyl vinyl ketone (MVK) using L-valine diethylamide as chiral auxiliary. 11 Since then, compound 2 bearing a quaternary stereocenter 12 has continuously been used by us 13 and others 14 as a valuable chiral building block for the synthesis of various heterocyclic compounds, mainly in a medicinal chemistry context. For this reason, we decided to prepare also compound 3a with a pyrrolidine ring instead of the piperidine moiety as well as its tetrahydrofuran congener 3b. In order to obtain both products 3a and 3b in optically pure form, the enamines 4 derived from L-valine diethylamide were chosen as the starting materials in the copper-catalyzed Michael reaction with MVK.The starting material 5a was mentioned before as a byproduct, 15 but never isolated and characterized. We prepared it in a one-pot protocol by conjugate addition of NBoc-GlyOMe (7) 16 to methyl acrylate followed by Dieckmann condensation (90% yield). Tetrahydrofuran derivative 5b was reported before and prepared accordingly. 17 In order to develop suitable tools for enantiomeric analyses, racemic products were prepared prior to asymmetric Michael reactions. Therefore, b-oxo esters 5a and 5b were converted, with MVK and catalytic amounts of FeCl 3 ·6H 2 O, 18 into the racemic 1,5-diketones 6a and 6b in 84% and 87% yield, respectively (Scheme 2). While the product rac-6b gave sufficient baseline resolution in GLC on a chiral phase, pyrrolidine derivative rac-6a did not. For this reason we were seeking for a suitable derivative for GLC analysis and found that the trifluoroacetamide 6c fulfilled these requirements. The compound rac-6c was

The NaH-mediated N-methylbenzimidazole formation starting from carbonitriles and N-methyl-1,2-phenylenediamine is reported to be a procedure compatible with acid-labile acetal protective groups within the starting materials. Products were further converted in Suzuki, Sonogashira, Heck and Buchwald-Hartwig reactions.

Benzimidazole derivatives R 0200Synthesis of 1-Methylbenzimidazoles from Carbonitriles. -The NaH-mediated N-methylbenzimidazole formation starting from N-methyl-1,2-phenylenediamine and nitriles is compatible with acid-labile protecting groups. Product (V) is submitted to

A New Synthesis of Sulfur-, Nitrogen-and Oxygen-Containing Eight-Membered Ring Lactams. -Bi-catalyzed ring expansion of phenylcarbonylmethyl-substituted tetrahydrothiophenones or pyrrolidinones (I) with aliphatic amines provides access towards eight-membered ring lactams (III) in moderate yields. The analogous reaction of tetrahydrofuranones proceeds under different conditions and gives only low yield of product lactam (V). -(PFLANTZ, R.; SLUITER, J.; KRICKA, M.; SAAK, W.; HOENKE, C.; CHRISTOFFERS*, J.; Eur.