Type 2 Intramolecular N-Acylnitroso Diels−Alder Reaction:  Scope and Application to the Synthesis of Medium Ring Lactams

Abstract

Heteroatom variants of the type 2 intramolecular Diels-Alder reaction provide an efficient method for the preparation of bridged bicyclic heterocycles. The type 2 variant of the intramolecular N-acylnitroso Diels-Alder reaction is an effective method for the synthesis of bridged bicyclic oxazinolactams. Structural studies of the cycloadducts have allowed for quantification of the deformations of the bridgehead functionalities and provided a strategy for the stereoselective synthesis of substituted seven- and eight-membered ring lactams. Diastereoselective cycloadditions followed by cleavage of the oxazine ring afford azepin-2-ones or azocin-2-ones.

Type 2 Intramolecular N-Acylazo Diels−Alder Reaction: Regio- and Stereoselective Synthesis of Bridgehead Bicyclic 1,2-Diazines

“…The double bond distances for bridgehead olefins 11 and 15 are 1.3339(15) Å and 1.3327(16) Å respectively, and are within error of the value for cyclohexene (1.335 (3) Å). 5 Analysis of the amide linkage of 11 and 15 show significant differences in torsional deformation. For bridgehead lactam 11 the torsional distortion is τ = 0.745(10)° and for 15 τ = 17.56(13)° respectively.…”

“…In the presence of 3 mol% Li 2 CuCl 4 , the coupling reaction of iodoester 3 8 with chloroprene Grignard (5) 9 afforded ester 6. 5 This synthetic sequence was subsequently applied to the synthesis of diene ester 7 5 from commercially available ethyl 5-bromovalerate (2) in 66% overall yield. The acylation reaction of ester 6 or 7 with phenyl hydrazine and Al(CH 3 ) 3 10 afforded hydrazides 8 and 9 in 75% yield and 84% yield, respectively (Scheme 2).…”

“…Based on previous studies 5 with N-acylnitroso dienophiles, we anticipated that π-facial selectivity of the T2IMDA reaction with N-acylazo dienophiles would be influenced by the introduction of substituents on the tether at α-position of Diels-Alder precursor. To evaluate the π-facial selectivity in cycloaddition precursors that incorporate substituents at α-position, two derivatives were synthesized (Scheme 9).…”

“…To evaluate the π-facial selectivity in cycloaddition precursors that incorporate substituents at α-position, two derivatives were synthesized (Scheme 9). The synthesis of the α-benzylated esters 20 5 and 22 was achieved by deprotonation of ester 6 or 7 with LDA, followed by alkylation with benzyl bromide to afford the α-substituted ester derivative 20 5 in 65% yield and ester 22 in 74% yield. Coupling reaction of ester 20 or 22 with phenylhydrazine and Al(CH 3 ) 3 provided hydrazide 21 and 23 in 76% yield and 85% yield, respectively.…”

“…More recently, the heteroatom variants of the T2IMDA reaction with N-acylimine and N-acylnitroso dienophiles was employed for the synthesis of bridgehead bicyclic lactams and oxazinolactams (Scheme 1, eq 1,2). [3][4][5] As part of our ongoing interest in the synthesis of nitrogen-containing heterocyclic ring systems, we report T2IMDA reaction with N-acylazo dienophiles (Scheme 1, eq 3).…”