Rearrangements of Substituted 3-Aza-1,2,5-hexatrienes. 3. The Scope and Versatility of an Extremely Mild 3-Aza-Cope Reaction

Abstract

An investigation of the [3,3]-sigmatropic reaction of substituted 3-aza-1,2,5-hexatrienes to give 4-pentenenitriles is presented. This reaction has been found to occur under a wide variety of reactions conditions (10 are reported) starting from readily available N-allylamides. In contrast to other 3-aza-Cope reactions, this process occurs at room temperature, under essentially neutral conditions, allowing for the facile preparation of substituted nitrile products in moderate to excellent yields. The scope and versatility of this reaction are demonstrated by its use on a wide variety of substrates, including nitrogen- and oxygen-substituted amides. The rearrangements of cis- and trans-4-tert-butyl-N-allylcyclohexanecarboxamides 16a and 16b are reported and were found to give a ratio of axial to equatorial (A:E) products consistent with A:E ratios found for other related sigmatropic reactions. The stereochemical requirements for this reaction appear to be similar to other [3,3]-rearrangements even though the transition state for this rearrangement is most likely neither boat nor chairlike.

Amide Formation Using In Situ Activation of Carboxylic Acids with [Et2NSF2]BF4

“…provided the crude product, which was isolated by flash chromatography (ethyl acetate/hexane, 50:50) to give the desired product (164 mg, 94 %) as a white solid. Spectral data of 11 were identical with those previously reported 25…”

Multiple pathways in the synthesis of new annelated analogues of 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (emivirine)

“…18 Compounds 25 and 26 were desulfurized with chloroacetic acid (Scheme 10). In this way 6-(1-phenylbut-3-enyl)-1H-pyrimidine-2,4-dione (27) was obtained in 50% overall yield from 21. During the desulfurization under acidic conditions, the double bond of 26 was concomitantly protonated leading to an intramolecular attack on either C5 of the uracil or on the ortho position of the phenyl ring.…”

“…2-Phenylpent-4-enenitrile (21) was synthesized from N-allyl-1-phenylacetamide by a 3-aza-Cope reaction in 81% yield. 27 5-Methyl-2-phenylhex-4-enenitrile (22) was obtained in 74% yield from phenylacetonitrile using the modified procedure of Wallingford et al 11 for obtaining 8. The corresponding β-keto esters 23 and 24 were obtained in a Blaise reaction in quantitative yields.…”

Transition Metal-Catalyzed Decarboxylative Allylation and Benzylation Reactions

“…After kinetic N -allylation, [3,3]-sigmatropic rearrangement is expected to occur to afford the branched product; related rearrangements are known to take place rapidly at room temperature. 93 Such regioselectivity could also be explained via competing inner-sphere and outer-sphere allylation mechanisms as discussed for enolate intermediates (Section 4.4.1). With this mechanism in mind, the less stabilized α,α-dialkyl anions would be prone to react via an inner-sphere mechanism giving the branched product, while the benzylically stabilized anion could prefer to react via an outer-sphere mechanism.…”