Sequential Five‐Component Construction of the Cyclopenta[e][1,3]oxazine Skeleton using Stable 2‐Azetine Derivatives

Abstract

Dedicated to Professor Julius Rebek, Jr. on the occasion of his 65th birthday Small-ring heterocycles are of prominent importance because of their potential as bioactive compounds and synthetic building blocks. Whilst the chemistry of three-membered nitrogen heterocycles has been widely reported, studies on their four-membered counterparts have focused primarily on 2-azetidinones and, to a much lesser extent, azetidine rings. [1] The 2-azetine system 1,2-dihydroazete, which has a strained cyclic enamine ring, is particularly elusive. [2] Most 2-azetine compounds undergo spontaneous electrocyclic ring opening to afford their 1-azadiene analogues; as such, there are few examples of stable 2-azetines in the literature and those reported require electron-withdrawing substituents, for example, carbonyl, carboxyl, sulfonyl, or nitro groups, attached to the nitrogen atom. [3,4] As a consequence, the chemistry of 2azetines remains largely unexplored, and has been predominantly focused on their potential as a precursor to azadienes. Moreover, there are no general synthetic routes to 2azetines. [5] Although, the [2+2] cycloaddition of alkynes and imines appears to be a convenient route to this type of heterocyclic framework, only a few specific examples have been reported; in these cases, electron-rich alkynes, as ynamines, [6] alkynyl selenides, [7] or alkynyl sulphides, [8] are able to form the expected 2-azetine skeleton, which is not isolated but rapidly opens to the azadiene system. The [2+2] cycloaddition of electron-poor alkynes and imines has only previously been suggested as an intermediate in the cyclization reaction between an alkynyl(ethoxy)carbene of tungsten and imine fluorenones to afford pyrroline derivatives. [9] As part of our interest in Fischer-type metal carbenes, we have recently considered more-electrophilic metal carbenes, the so-called non-heteroatom-stabilized carbenes. [10] These compounds are particularly useful in organic synthesis, and our preliminary results have revealed significant differences in the reactivity of both heteroatom- [11] and non-heteroatomstabilized systems.Herein, we report the [2+2] cycloaddition reaction of alkynyl-substituted (pentacarbonyl)chromium or -tungsten carbene complexes with imines as a suitable procedure for accessing stable 2-azetine derivatives. Moreover, the conjugation of the resulting azetine unit with the metal carbene allows for a facile synthesis of novel cyclopenta[e]-[1,3]oxazines involving treatment with alkynes. This threecomponent process (azetine, alkyne, and CO ligand) features cleavage of the azetine C3 À C4 bond, rather than the expected N À C4 bond, and the formation of three C À C bonds and one CÀO bond (Scheme 1).Stable, easy-to-handle methoxycarbenes 1 are used as in situ precursors of alkynylcarbenes 3 using the methoxyacetylide 2 exchange reaction ( Table 1). The resultant solution of 3 in tetrahydrofuran was treated at À80 8C with 1.3-5.0 equivalents of imine 4 (see the Supporting Information) and the mixture was allowed to warm to 0 8C....

TiCl4‐Mediated [2+2] Cycloaddition for Synthesis of Isolable CF3‐Substituted 2‐Azetines

“…The trimethoxyphenyl group and the 2‐azetine ring are nearly perpendicular (dihedral angle=73.15°), indicating weak π‐conjugation between the aryl group and the N‐heterocyclic system. The C2−C3 distance is that of the C=C double bond, whereas the corresponding bond in azetinylcarbene complex I (Figure 1b) is elongated (1.481 Å) due to the adjacent carbene‐Cr unit [8] . The metric parameters of 3 a are comparable with those of azetinecarboxylic acid II [9] …”

“…Figure 2a shows an ORTEP drawing of 3 a . The 2‐azeting ring is almost planar, and the nitrogen atom is slightly pyramidalized [Σ(angles)=347.8°], which is slightly different from I [8] and II [9] (Figure 1b). The trimethoxyphenyl group and the 2‐azetine ring are nearly perpendicular (dihedral angle=73.15°), indicating weak π‐conjugation between the aryl group and the N‐heterocyclic system.…”

“…The molecular structure of 2‐azetines, on the other hand, has been discussed based on limited examples: Barluenga et al . reported the structure of azetinylcarbene compound I , [8] and Didier and co‐workers succeeded in the isolation and characterization of II as a unique cyclic amino acid (Figure 1b) [9] …”

Fischer Carbene Complexes: A Glance at Two Decades of Research on Higher‐Order Cycloaddition Reactions

“…The main characteristics of these low‐valent metal complexes is their electrophilic nature and remarkable instability [47,159,161] . Although the main applications of such complexes in organic synthesis are currently related to alkene and enyne metathesis, great interest exists in exploring a broader scope due to their unique reactivity [162–167] …”