The Nazarov cyclization 1 is an efficient process for the construction of cyclopentenone rings from simple acyclic precursors. One of the variants 2 of the Nazarov reaction that we recently described is the cascade isomerization-cyclization-trapping process shown in Scheme 1. Addition of propargyllithium 1 to morpholino enamide 2 led to propargyl vinyl ketone 3. Exposure of 3 to dry activated silica gel that had been thoroughly mixed with 1.2 equiv of cyclohexylamine gave α-aminocyclopentenone 4 in 65% yield. Amine-promoted isomerization of 3 led to an allenyl vinyl ketone that underwent cyclization in the presence of the weakly acidic silica gel. Trapping of the intermediate carbocation by the amine, followed by tautomerization and double bond migration led to the observed product.We hypothesized that the process of Scheme 1 could be carried out with the camphor-derived chiral auxiliary 3 that we developed in place of the propargylic methoxyl. Addition of propargyllithium 5 to morpholino enamide 2 led to ketone 6 (86% yield; Scheme 2) in a highly stereoselective reaction (ca. 50/1 in all cases). 4 Vigorous agitation of 6 for 45 min with dry activated Florisil (ca. 6 g/mmol ketone) that had been treated with 10 equiv of phenethylamine gave amino ketone 9 in 67% yield from 6 as a single diastereomer. The reaction also took place in the presence of silica gel, alumina (neutral, acidic or basic) and in solution, but the yield was lower (40-53%). Thorough agitation of the reaction mixture was critical.The interrupted Nazarov reaction has been developed primarily by West and coworkers, as a cascade process for the formation of one or more carbon-carbon 5a-d or carbon-heteroatom 5e-f bonds subsequent to cyclization. To the best of our knowledge, the present work represents the first example of an asymmetric interrupted Nazarov cyclization process. Table 1 summarizes the results of a series of examples utilizing ketones 6, 10 and 11 and a series of primary, secondary, cyclic and acyclic amines. Yields of aminocyclopentenones varied from 55% to 75%. In none of the reactions was any hydrolytic cleavage of the chiral auxiliary observed, testifying to the mildness of the reaction conditions, β-Phenylcinnamate-derived ketone 12 was not a suitable substrate for the reaction, and led in all cases to complex mixtures of intensely colored decomposition products.The absolute stereochemistry of the aminocyclopentenone products was determined in the case of 20 through X-ray crystallographic analysis of the derived picrate salt (Figure 1). 6 The absolute configuration of the ring carbon atoms was determined to be 4R, 5S. The absolute stereochemistry of all other products was assigned by analogy to 20.The success of the bimolecular asymmetric interrupted Nazarov cyclizations prompted us to investigate an intramolecular reaction. The amine nucleophile could be located at either the NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript β or the β enone carbon atom through a suitable tether. For our first example w...

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Key indicators: single-crystal X-ray study; T = 293 K; mean (C-C) = 0.002 Å; R factor = 0.041; wR factor = 0.132; data-to-parameter ratio = 17.3.The title compound (systematic name: pyrido[4,3-e]thieno-[2,3-c]pyridazine), C 9 H 5 N 3 S, consists of three fused heterocyclic rings. The molecule is planar and the N N bond length of 1.302 (2) Å is in good agreement with values observed in similar compounds. The molecules showstacking interactions, forming molecular stacks along the b axis with interplanar distances of 3.39 (2) and 3.49 (2) Å . The C-H groups of the thiophene ring are involved in C-HÁ Á ÁN interactions, joining molecules into two-dimensional sheets parallel to (011). ExperimentalCrystal data C 9 H 5 N 3 S M r = 187.22 Triclinic, P1 a = 6.8340 (18) Å b = 7.656 (2) Å c = 8.847 (2) Å = 104.172 (3) = 101.376 (4) = 107.042 (5) V = 410.63 (18) Å 3 Z = 2 Mo K radiation = 0.34 mm À1