R. Bunce, Nicholas R. Cain, J. G. Cooper
Jan 1, 2013
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Influential Citations
5
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Journal
Organic Preparations and Procedures International
Abstract
Two recent projects described approaches to 1,1-dimethyl-1,2,3,4-tetrahydronaphthalenes1 and 4,4-dimethyl-1,2,3,4-tetrahydroisoquinolines2 using acid-promoted Friedel-Crafts cyclizations. Both of these ring systems are of interest to us for the synthesis of structures with potential biological activity. The current work explores a further use of this strategy for the synthesis of tetrahydroquinolines bearing gem-dimethyl substituents at C4. Such tetrahydroquinolines have shown activity as peroxisome proliferator activated receptor agonists and, thus, have potential in the treatment of type-2 diabetes.3–5 Several experiments using FeCl3·6H2O in dichloromethane,2,6,7 AlCl3 in benzene, and Amberlyst-15 R © in benzene1 were performed on the parent substrate 4a to identify the best protocol for the ring closure. In the current series, cyclization was complicated by the relatively facile loss of the alcohol side-chain to give the N-aryl-p-toluenesulfonamides 6. This side-chain degradation resulted in slightly lower yields of tetrahydroquinolines relative to our previously reported tetrahydroisoquinolines.2 Indeed, it was found that the optimum reagent for cyclization was dependent on both the nature and location of the substituent group on the aromatic ring. The required tetrahydroquinoline precursors were prepared in three steps from substituted anilines using a strategy that overlaps with a previous synthesis of 4-aminoquinolines reported by Johnson and co-workers.8 Conjugate addition of anilines 1 to methyl acrylate gave the 3-anilinopropionate esters 2 in 61–72% yields. Tosylation at nitrogen then afforded sulfonamides 3 in 79–90%, and Grignard addition with methylmagnesium iodide furnished the requisite precursors 4 in 60–90% yields (see Scheme 1). Based upon our recent success using FeCl3·6H2O for the synthesis of tetrahydroisoquinolines from tertiary alcohols,2 we first examined this mild Lewis acid (Method A) for the current tetrahydroquinoline cyclizations. The optimized conditions using FeCl3·6H2O employed 2.0 equiv of the Lewis acid in chloroform at 60◦C for 2–6 h and gave yields up to 78% with 12–28% loss of the alcohol side chain (see Table 1). As expected,2