Base-Mediated Generation of Ketenimines from Ynamides: Direct Access to Azetidinimines by an Imino Staudinger Synthesis

: Ynamides were used as precursors for the in situ generation of highly reactive ketenimines which could be trapped with imines in a [2+2] cycloaddition. This imino Staudinger synthesis led to a variety of imino-analogs of β -lactams, namely azetidinimines (20 examples), that could be further functionalized through a broad range of transformations.

For our part, we have shown that using strongly basic conditions 3 an unprecedented nucleophilic addition of various heteroarenes at the β position could take place. 4Moreover, depending on the substitution pattern of the nitrogen atom, the same basic conditions could lead to an α nucleophilic addition, albeit with the loss of the electron-withdrawing group (EWG).In this latter case, base activation would trigger the cleavage of the EWG, leading to an amide that will eventually evolve towards ketenimine 3. 4,5 In order to further expand the potential of this highly reactive intermediate (3), we sought to trap it in a [2+2] cycloaddition. 6By analogy with the well-established Staudinger synthesis of βlactams, 7 and based on the pioneering studies by Ghosez 8 and Regitz, 9 we envisioned that the N-phenylethenimine 3a generated in situ from ynamide 1a would be sufficiently electrophilic to react with imine 4 to ultimately give azetidinimine 5 (Scheme 2). 10 From our previous experience, an unsubstituted N,N-Boc-aryl-ynamide would be the best precursor for the generation of the ketenimine and we assumed an electron-rich nitrogen atom in the imine would favor the desired cycloaddition.

Scheme 2. In situ Generation of an Ethenimine and Trapping with an Imine
However, direct application of our previously disclosed reaction conditions 4 i.e., 1.0 equiv. of ynamide, 1.0 equiv. of t-BuONa as base, DMF as solvent, with molecular sieves at room temperature proved totally ineffective, even after prolonged reaction time (Table 1, entry 1).We reasoned that the cycloaddition process required thermal activation and thus, while traditional heating (entry 2) was unsuccessful, switching to microwave conditions 11 allowed the reaction to take place (entry 3).By replacing the sodium salt by potassium (entry 4) or lithium (entry 5) t-butanolate the desired azetidinimine 5aa could be isolated with 46% and 47% yield, respectively.Doubling the amount of both the ynamide and the base (X = 2) had little effect (entry 6) unless the temperature was raised to 100 °C (entry 7) which allowed 5aa to be isolated in 50% yield.This 50% threshold could be overcome by using silica gel as the additive instead of molecular sieves (entry 8, 54%).These optimized conditions were then applied to pchlorobenzaldehyde-derived imine 4b which led to the isolation of 64% of azetidinimine 5ab (entry 9).Improved formation of the latter was attempted by using a catalytic amount of a Lewis acid as the additive (entry 10, 50%) or as a co-additive (entry 11, 52%) but to no avail.
[c] An X-ray structure was obtained, see Supporting Information for details. 12 [d] 10 mol% of ZnOTf2 was used as the additive instead of silica gel.
Strongly electron-enriched 3,4,5-trimethoxylated imine 4f reacted smoothly with 1a to give 5af in 54% yield (entry 6) while dianisyl imine 4g led to 5ag in 40% yield (entry 7).In order to allow further functionalization, p-bromo-and p-iodobenzaldehydederived imines (4h and 4i) were subjected to the reaction conditions and the desired adducts were obtained in 63% and 61% yields, respectively (entries 8,9).Imine 4j bearing a methoxycarboxylate was then used, leading to an overall 30% yield of cycloaddition adduct 5a, most of which had been transesterified to the corresponding t-butoxycarboxylate 5aj' during the course of the reaction (entry 10).While various substitution patterns on the imine partner were well tolerated, this was not the case for the ketenimine precursor.Indeed, a series of ynamides was evaluated for which no cycloaddition took place (Table 2, topright b).These include: sulfonamides (GP = tosyl, mesyl and pnosyl) and N-alkyl (R = benzyl or allyl) as well as C-substituted (R' = phenyl, n-butyl and triisopropylsilyl) derivatives.The reaction did take place, however, when functionalized aryl groups such as para halo-(Cl, Br and I), trifluoromethyl-and methoxy-phenyl were incorporated on the ynamide partner (1b-f).All of these reacted with both imines 4a and 4b (entries11-20) providing yields of cycloadducts ranging from 10-36% with imine 4a (entries  11, 13, 15, 17 and 19) to 29-40% with imine 4b (entries 12, 14,  16, 18 and 20).Compared with ynamide 1a, yields were systematically lower and this can be attributed to a variety of factors difficult to unambiguously pinpoint since the substitution of this aryl presumably has an influence on both the generation of the active ketenimine and its subsequent stability and reactivity.
Having a wide panel of azetidinimines at our disposal we then turned our attention to their use for further functionalization.Satisfyingly, this unusual four-membered ring proved to be quite tolerant to a broad range of reaction conditions, obviating the necessity of extensive optimization.First, Suzuki coupling was used as a typical Pd-catalyzed cross-coupling reaction.Thus, an additional p-methoxyphenyl moiety could be added with excellent yields on both the C-aryl (6) or iminoaryl (7) part of the scaffold, using either bromo-(5ah & 5ca) or iodo-azetidinimines (5ai & 5da) (Scheme 3).

Scheme 3. Ynamides: Inherent Polarization vs Acid and Base Activations
A strong Lewis acid such as boron tribromide (Scheme 4, Eq. 1) could be employed, without any noticeable degradation of the amidine ring, to selectively cleave the methyl group of 5ab to give phenolic azetidinimine 8.The latter could in turn be alkylated with t-butyl bromoacetate to give 9 in 78% yield.Finally, treatment of carboxylate 5aj' (Eq.2) with a strong acid such as trifluoroacetic acid or a strong reducing agent such as lithium aluminum hydride gave respectively carboxylic acid 10 (96%) and primary alcohol 11 (82%), leaving the four-member ring untouched.Benzyl alcohol 11 could furthermore be transformed into the corresponding chloride 12 in 70% yield, using methanesulfonyl chloride.

Scheme 4. Further Functionalization around the Azetidinimine Ring
In conclusion, we have taken advantage a specific mode of activation of ynamides under basic conditions to generate Narylethenimines from Boc-aryl-ynamides and react them with imines in a [2+2] cycloaddition.This reaction further ascertains the intermediacy of the ketenimine intermediate and paves the way for other types of cycloadditions.Moreover, the azetidinimines resulting from this imino Staudinger synthesis can undergo a broad array of chemical transformations that leave the 4-membered amidine ring intact.This work should allow for further exploration around this particular heterocyclic scaffold which can be viewed as an imino-analog of monocyclic β-lactams. 13Studies in these directions are currently ongoing in our laboratory and will be reported in due course.

Entry for the Table of Contents
Under strong basic conditions ynamides gave highly reactive ketenimines which could be trapped with imines in a [2+2] cycloaddition.This imino Staudinger synthesis led to a variety of imino-analogs of β-lactams, namely azetidinimines (20 examples), that could be further functionalized through a broad range of transformations.Dr E. Romero, Dr C. Minard, Dr M. Benchekroun, Dr S. Ventre, Dr P. Retailleau, Dr R. H. Dodd,* Dr K. Cariou*