New Method for the Preparation of 2-Aryl- and 2-Heteroarylcyclohexanones. Synthesis of 6,7,8,9-Tetrahydro-5H-1,3-dioxolo[4,5-b]carbazole

Abstract

2-Aryl-and 2-heteroarylcyclohexanones were prepared through 1,4-addition of lithiated species to 1-nitro-1-cyclohexene followed by Nef reaction in good yields. As a synthetic application of this method, 6,7,8,9-tetrahydro-5H-1,3-dioxolo[4,5-b]carbazole was synthesized.The chemical literature describes many processes for the synthesis of 2-arylcyclohexanones, 1-22 an interesting class of compounds that can be used as intermediates for the preparation of products with biological activity. 14,23-31 In general, the great majority involves variations of two methods: the first, developed by Newman-Farbman 2 and the second, developed by Wildman-Wildman. 7,30 Alternatively, other synthetic methods were most recently developed, employing titanium tetrachloride, 16 trifluoromethanesulphonic acid, 17,19 alkyl aluminium, 18 aryl-bismuth, 14 and palladium reagents. 31,32 However, some of these reactions have limitations when performed in substrates containing sensitive groups, which are in addition difficult to obtain. Additionally, we have not found mention of the preparation of 2-heteroarylcyclohexanones employing these methods.Based on the results obtained in the addition of organolithium species to 1-nitro-1-cyclohexene, 33 and recent reports of 1,4-conjugate addition under Reformatsky conditions with 1-nitrocyclohexene 34 (2), we conceived an alternative method to access this class of compounds, using the classical Nef reaction in an additional step to produce them. In this paper, we demonstrate a significant number of 1,4-addition of aryl-and heteroaryl-lithiated species to 1-nitrocyclohexene (2), as part of a main objective to obtain the appropriate 2-aryl-or 2-heteroaryl-cyclohexanones 4a−g (Scheme 1).In all cases, the aryl and heteroaryl-lithiated species were generated via well known procedures described in the literature. 35 These intermediates were added to 1-nitro-1-cyclohexene (2) to afford a range of 1-nitro-2-aryl and 1-nitro-2-heteroarylcyclohexanes derivatives 3a−g in good yields (Table). The compound 3-lithium-anisole (1b) was shown to provide a low yield of compound 3b able Yields of 1-Nitro-2-aryl-cyclohexanes 3a−g and 2-Aryl-cylohexanones 4 a−g ntry Compound a−g Aryl-or Heteroaryl-Yield of 3 (%) Yield of 4 (%) a 72 95 b 32 46 c 97 98 d 92 98 e 96 93 f 100 88 g 89 98 Scheme 1 Downloaded by: WEST VIRGINIA UNIVERSITY. Copyrighted material.

2-Aryl-2-nitroacetates as Central Precursors to Aryl Nitromethanes, α-Ketoesters, and α-Amino Acids

“…Notably, application of conventional Nef conditions 25–28 to the 2-aryl-2-nitroacetates did not provide the expected α-ketoesters. Specifically, deprotonation with aqueous NaOH in THF at rt followed by acidification with 5 M HCl yielded only starting material and some decarboxylated byproduct as a result of ester hydrolysis.…”

“…Specifically, deprotonation with aqueous NaOH in THF at rt followed by acidification with 5 M HCl yielded only starting material and some decarboxylated byproduct as a result of ester hydrolysis. 25 An amidine base was also ineffective. 27 Futhermore, exposure of the aryl nitroaceates to 30% H 2 O 2 in the presence of aqueous K 2 CO 3 in MeOH at rt gave only a 20% conversion by 1 H NMR to the α-ketoester after 24 h. 28 …”

Modular construction of α-furanyl ketones via semi-pinacol rearrangement-mediated ring expansion

“…6 Despite several achievements in the synthesis of α-furanyl acyclic ketones, 7 reports on α-furanyl cyclic ketones are rare. Apart from the well-developed α-furanyl cyclopentanones and cyclohexanones, 8 only very few examples involving medium-ring and macrocyclic ketones have been reported so far (Scheme 1c). 9…”