Rapid Access to α‐Alkoxy and α‐Amino Acid Derivatives through Safe Continuous‐Flow Generation of Diazoesters

Abstract

Despite the wide synthetic potential of diazo compounds (XÀH insertion, ylide formation, cyclopropanation, cycloaddition etc.), [1] concerns over the hazards associated with their preparation, isolation, and use have hindered their full exploitation in both academic and industrial laboratories. A few diazo compounds are commercially available (e.g. ethyl and butyl diazoacetate, TMS-diazomethane and diazodimedone), [2] but safe and convenient access to a wider range of useful functionalized diazo species is still desirable.[3] Diazo transfer can be used to access a-diazocarbonyls, but this only partially addresses the safety concerns associated with the diazo species, as the use of equally hazardous azidebased diazo-transfer reagents is still required.[4] Ideally, it would be beneficial if the diazo species could be generated and consumed in situ so that handling of the hazardous diazo compound is avoided altogether.Recent work by Ley, [5] Jamison, [6] Kappe, [7] and others [4,[8][9][10] has shown that highly reactive diazo and azido compounds can be used in lab-scale continuous-flow reactors to achieve a number of very useful synthetic transformations, and indeed work from our own laboratory has shown that ethyl diazoacetate can be used in-flow to access b-keto esters.[11] We therefore wondered if it was possible to actually generate a-diazocarbonyl compounds under flow conditions and then use these materials directly in further synthetic manipulations, thus minimizing exposure to any potentially hazardous material. In effect, could we develop a continuous-flow diazo generator and then demonstrate its use to prepare a range of useful a-alkoxy (3 a-i) and aamino acid (4 a-i) derivatives through O À H and N À H insertion (Scheme 1)?At the outset we were aware that in order to provide an acceptable solution to the problem, we needed to identify a way to access the diazo compounds of interest (2 a-i) from starting materials that showed an acceptable safety profile, that is, the precursor molecules and reagents should be safer to prepare and handle than the diazocarbonyl compounds being produced. Of the methods available for the generation of a-diazocarbonyl compounds, we were particularly attracted to the Bamford-Stevens reaction as it uses readily accessible arylsulfonylhydrazones (e.g., 1 a-i) as starting materials, with the corresponding diazocarbonyls being generated upon exposure to relatively weak base at moderate reaction temperatures. [12][13][14] Thermal stability studies (DSC and TGA) were conducted on the tosylhydrazone 1 b and its corresponding methyl diazoester 2 b [15,16] in order to determine if a safe window of operation could be identified for the continuous-flow process (see the Supporting Information). The results clearly show that the rate of initial mass loss from diazoester 2 b peaks at 125 8C, which corresponds to a significant exotherm. In comparison tosylhydrazone 1 b has a rate of mass loss which peaks at 221 8C, indicating that it is substantially more thermally stable.[15] We therefore co...

Ethyl diazoacetate synthesis in flow

“…Bartrum et al [18] published a flow synthesis of numerous diazo esters starting from the corresponding arylsulfonylhydrazones, where the diazo moiety was installed through elimination of the sulfone substituent. Additionally, Ley et al [19] recently prepared a range of α-hydroxy acids in flow starting from the corresponding amino acids, involving diazotization of the amine to the diazonium salt in a biphasic system.…”

Alkyl Halide‐Free Heteroatom Alkylation and Epoxidation Facilitated by a Recyclable Polymer‐Supported Oxidant for the In‐Flow Preparation of Diazo Compounds

“…In order to address this problem, we, and others, have shown that diazo compounds can be generated safely under continuous flow chemistry conditions,5 thus limiting the exposure and hence hazards previously associated with these reactive compounds. In our previous work we have shown that in‐flow base treatment of sulfonyl hydrazones gives ready access to diazo compounds, and we have shown that these can be used directly in a variety of synthetically useful transformations 6,7. Although this represented a significant improvement of existing methods for in‐flow generation of diazo compounds such as the use nitrosamine precursors,8–10 or sulfonyl azides,11 the production of stoichiometric quantities of 4‐toluenesulfinate as waste results in overall poor atom economy, and further work was required to address this shortcoming.…”

The Generation of Diazo Compounds in Continuous‐Flow

“…Interestingly, longer‐chain aliphatic or branched aliphatic diazo esters were obtained only in moderate yield. In a subsequent batch transformation, Hayes, Moody and co‐workers described the rhodium(II) catalyzed O−H and N−H insertion reactions of these diazo esters (Scheme ) . In a further report, Moody, Hayes and co‐workers extended this protocol to rhodium, and copper catalyzed insertion reactions with thiols, sulfinates and phosphonates …”

“…In as ubsequent batch transformation, Hayes, Moody and co-workers describedt he rhodium(II) catalyzed OÀHa nd NÀHi nsertion reactions of these diazo esters (Scheme 10). [37] In af urtherr eport, Moody,H ayes and co-work-Scheme8.Iterativecoupling of diazo compounds with boronic acids.…”