Synthesis of Acyl Phosphoramidates Employing a Modified Staudinger Reaction

A flow chemistry process for the generation and use of acylketene precursors through extrusion of nitrogen gas is reported. Key to the development of a suitable continuous protocol is the balance of reaction concentration against pressure in the flow reactor. The resulting process enables access to intercepted acylketene scaffolds using volatile amine nucleophiles and has been demonstrated on the gram scale. Thermal gravimetric analysis was used to guide the temperature set point of the reactor coils for a variety of acyl ketene precursors. The simultaneous generation and reaction of two reactive intermediates (both derived from nitrogen extrusion) is demonstrated.

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“…IR (neat) ν max 2356, 2173, 2132, 1684, 1595, 1446, 1315, 1234, 1182, 984, 678 cm –1 . Data consistent with literature …”

Section: Methodssupporting

confidence: 90%

Continuous Flow Generation of Acylketene Intermediates via Nitrogen Extrusion

et al. 2022

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“…Eventually, the optimal condition for the formation of 4 b was established by the application of NaHMDS as a base at room temperature (Table 1, entry 18). Additional control experiments using weaker bases such as triethylamine [14b] gave an increased amount of by‐product 3 a .…”

Section: Resultsmentioning

confidence: 99%

Chemodivergent Staudinger Reactions of Secondary Phosphine Oxides and Application to the Total Synthesis of LL–D05139β Potassium Salt

Luo,

Xu,

Wang

et al. 2023

Angew Chem Int Ed

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Unprecedented Staudinger reaction modes of secondary phosphine oxides (SPO) and organic azides are herein disclosed. By the application of various additives, selective nitrogen atom exclusion from the azide group has been achieved. Chlorotrimethylsilane mediates a stereoretentive Staudinger reaction with a 2‐N exclusion which provides a valuable method for the synthesis of phosphinic amides and can be considered complementary to the stereoinvertive Atherton‐Todd reaction. Alternatively, a 1‐N exclusion pathway is promoted by acetic acid to provide the corresponding diazo compound. The effectiveness of this protocol has been further demonstrated by the total synthesis of the diazo‐containing natural product LL‐D05139β, which was prepared as a potassium salt for the first time in 6 steps and 26.5% overall yield.

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“…88 The modified Staudinger reaction using H-phosphonates (dialkyl phosphites) is shown in Scheme 37. 89 The reaction of DPPA with H-phosphonates 217 and chlorotrimethylsilane afforded (diphenylphosphoryl)phosphoramidates 218 (Scheme 37a). Staudinger reaction of DPPA with several H-phosphonates (DDPO.…”

Section: Staudinger Reactionmentioning

confidence: 99%

“…The modified Staudinger reaction using H -phosphonates (dialkyl phosphites) is shown in Scheme 37. 89 The reaction of DPPA with H -phosphonates 217 and chlorotrimethylsilane afforded (diphenylphosphoryl)phosphoramidates 218 (Scheme 37a). Acyl azides, prepared from carboxylic acids by the action of DPPA and triethylamine, were treated with H -phosphonates 217 in the presence of chlorotrimethylsilane to give acyl phosphoramidates 221 in a single step.…”

Section: Staudinger Reactionmentioning

confidence: 99%