Preparation and in situ use of unstable N-alkyl -diazo--butyrolactams in Rh-catalyzed X-H insertion reactions

N-Alkyl -diazo--butyrolactams previously found to be unstable and undergo unproductive dimerization to bis-hydrazones, were successfully converted immediately to various X-H insertion products with alcohols, aromatic amines and thiols via an in situ Rh-catalyzed reaction. With aliphatic amines or unreactive, sterically hindered anilines, the reaction tends to yield enamine adducts. Introduction Earlier this year, we described the first synthesis and subsequent transformations of a rare type of cyclic -diazocarbonyl compounds, namely, -diazo--butyrolactams [1]. In particular, N-aryl -diazo--butyrolactams 1 were efficiently transformed into pyrrolinones 2 on treatment with AgOTf (1 mol%) and into -alkoxy derivatives 3 via Rh2(OAc)4-catalyzed O-H insertion reaction with various alcohols. In contrast, N-alkyl -diazo--butyrolactams 4 did not enter these reactions typical of -diazocarbonyl compounds as they rapidly dimerized to give bishydrazones 5 (Fig. 1). The instability of N-alkyl -diazo--butyrolactams 4 compared to their Naryl counterparts 1 is most likely related to the reduced electron-withdrawing character of the lactam carbonyl group in the former compared to the latter. This assumption is further supported by the fact that o-substituted N-aryl derivatives 1 (in which conjugation of the aromatic ring with the lone pair of the lactam nitrogen atom is reduced due to sterically forced loss of co-planarity between the aromatic ring and the aminocarbonyl moiety) are as unstable as the N-alkyl derivatives 4 [1].


Introduction
Earlier this year, we described the first synthesis and subsequent transformations of a rare type of cyclic -diazocarbonyl compounds, namely, -diazo--butyrolactams [1]. In particular, N-aryl -diazo--butyrolactams 1 were efficiently transformed into pyrrolinones 2 on treatment with AgOTf (1 mol%) and into -alkoxy derivatives 3 via Rh2(OAc)4-catalyzed O-H insertion reaction with various alcohols. In contrast, N-alkyl -diazo--butyrolactams 4 did not enter these reactions typical of -diazocarbonyl compounds as they rapidly dimerized to give bishydrazones 5 (Fig. 1). The instability of N-alkyl -diazo--butyrolactams 4 compared to their Naryl counterparts 1 is most likely related to the reduced electron-withdrawing character of the lactam carbonyl group in the former compared to the latter. This assumption is further supported by the fact that o-substituted N-aryl derivatives 1 (in which conjugation of the aromatic ring with the lone pair of the lactam nitrogen atom is reduced due to sterically forced loss of co-planarity between the aromatic ring and the aminocarbonyl moiety) are as unstable as the N-alkyl

Results and discussion
Three N-alkyl -ethoxalyl -lactams 6a-c prepared by oxalylation of the respective -lactams as decribed previously [1] underwent a rapid diazo transfer reaction via the conventional protocol [4][5] employing 4-nitrobenzenesulfonyl azide and DBU. Quick filtering through a plug of alumina (in lieu of silica gel which decomposed diazo compounds 4a-c), addition of an alcohol, a thiol or an aromatic amine along with a Rh II catalyst resulted in a rapid insertion reaction and the isolation of the desired -substituted -lactams 7a-o in modest yields (Scheme 1). It should be noted that, after some experimentation, reactions with alcohols and thiols were found to be efficiently catalyzed by 1 mol% of Rh2(OAc)4 and to go to completion within 30 min; for aromatic amines, this catalyst proved inefficient and was replaced with 0.5 mol% of Rh2(esp)2.
Attempted change of the catalyst to Rh2(esp)2 in the reactions with alcohols and thiols (which earlier gave us a marked improvement of the product yield in NH-insertion reactions [2]) resulted in no notable improvement in this case.
The only attempt to employ an aliphatic amine, cyclopropylamine (which would presumably be less reactive in the Rh II -catalyzed insertion reaction [2]) resulted in the formation of a sole identifiable productenamine 8a isolated from a complex mixture of unidentified by-products chromatographically. The formation of 8a (also observed previously, along with the expected, 3 saturated coupling product in the Rh II -catalyzed reaction of cyclopropylamine with N-phenyl diazo 2-pyrrolidone [2]) can be rationalized, as proposed previously [2], either by oxidation of diazo lactam 6c to a respective ketone (a process described in the literature for other diazocarbonyl compounds [6]), followed by nucleophilic attack of cyclopropylamine.
Alternatively, the formation of the enamine product could be envisaged via the reaction of the amine with bis-hydrazone 5 which would form if the N-H insertion pathway was not sufficiently rapid. Both assumptions are in line with the formation of similar enamine coupling product 8b we observed with 2,6-dimethylaniline. With this unreactive, sterically hindered aromatic amine, 6c is likely to undergo either the unwanted N2O oxidation or dimerize to bis-hydrazone 5,

Conclusion
We demonstrated that the scope of -diazo--butyrolactams capable of undergoing Rh IIcatalyzed X-H insertions reactions with alcohols, thiols and aromatic amines can be extended to 5 unstable N-alkyl derivatives for which rapid, unproductive dimerization was previously observed. This was achieved through the immediate addition of the X-H insertion partner and a Rh II catalyst to the solution the diazo compound. The reactions are rapid albeit moderately yielding. Despite the latter drawback, the range of 1,3-disubstituted 2-pyrrolidones attainable via the intermediate formation of -diazo--butyrolactams has been substantially expanded thereby making this approach more useful for potential medicinal chemistry exploration of these disubstituted -lactams.

Supporting information
Supporting Information File 1 General experimental information, synthetic procedures, analytical data and NMR spectra for the reported compounds.