Batch and Continuous‐Flow One‐Pot Processes using Amine Diazotization to Produce Silylated Diazo Reagents

Abstract

An ovel synthesis of trimethylsilyldiazomethane (TMSCHN 2 )b yd iazotization of trimethylsilylmethylamine (TMSCH 2 NH 2 )i sr eported using batch and continuous flow synthesis.T he latter affords ad aily production of 275 g (2.4 mol) of TMSCHN 2 .O ther silylated methylamines were also successfully reacted under the developed reaction conditions to furnish various silicon-bearing diazomethane reagents.T he applicability of the process is highlighted by disclosure of batch and continuous flowone-pot esterification and 1,3-dipolar cycloaddition processes.F urthermore,t he high-yielding esterification of carboxylic acids with silylated and substituted methylamines in continuous flowi sd isclosed. Finally,w ork-up and purification procedures are reported for the preparation of a2 -MeTHF solution of TMSCHN 2 ,w hich can be used in rhodium-catalyzed methylenation and homologation reactions.

An Immobilized‐Dirhodium Hollow‐Fiber Flow Reactor for Scalable and Sustainable C−H Functionalization in Continuous Flow

“…Thus,such reactive compounds are ideally not stored in large quantities on site,a nd just-in-time syntheses are preferred. [17][18][19][20][21][22][23][24][25][26][27] Thep rice of the soluble dirhodium catalysts (Rh 2 L 4 ,L= ligand) is another barrier for industrial applications.R hodium is av ery expensive noble metal and the cost for the synthesis of these ligands for the catalysts also cannot be ignored. To recycle the homogenous dirhodium catalysts, additional separation steps are required and the catalytic activities are often not maintained after recovery and recycle.…”

“…Several studies have recently reported expanding the utilization of diazo compounds in flow; however, the subsequent diazo-consuming reactions were conducted in abatch reactor with homogenous catalyst. [17][18][19][20][21] Relatively few reports have tried to increase the TONo fd irhodium catalysts for CÀHf unctionalization by immobilization of the catalysts. [29][30][31][32][33] These studies have mainly focused on the catalytic performance of the immobilized catalyst with diazo compounds.T ot he best of our knowledge,n oo ne has resolved all the challenges stated above to date;herein, we introduce ascalable flow process for CÀHf unctionalization with dirhodium catalysts by developing cascade reactions employing microfluidic flow reactor systems.Scheme 1describes the overall cascade reaction in aflow system for selective C À Hf unctionalization.…”

Chemoselective Synthesis of Amines from Ammonium Hydroxide and Hydroxylamine in Continuous Flow

“…Recently, we delineated the synthesis of trimethylsilylmethylammonium chloride from trimethylsilylmethyl chloride and ammonium hydroxide in a continuous flow process (Scheme 1). 6 Continuous-flow technologies enable rapid reactions with excellent heat transfer, facilitate the manipulation of gas, and often decrease the formation of byproducts. 7−10 Herein, we report a general amination procedure in flow, applicable to various electrophiles (alkyl halides and epoxides) with ammonia and hydroxylamine.…”

“…We first investigated the amination of phenethyl bromide with ammonia under the previously developed reaction conditions. 6 Low yields were obtained with the formation of the secondary ammonium salt (resulting from the double addition of ammonia to the bromide) as the major byproduct (Table 1, entry 1). When the concentration of the bromide was decreased to 0.25 M (thus increasing the number of equiv of ammonium hydroxide from 28 to 56 equiv) with a 30 min residence time, the yield increased to 74% (entry 2).…”

Systematic Evaluation of 1,2-Migratory Aptitude in Alkylidene Carbenes

“…29 However, after a range of preliminary experiments involving TMS 13 CH2X (X = Cl, Br, I) we pursued an alternative route based on amine diazotization. 30 The requisite 13 C-labelled amine (11) was prepared via a multistep chromatography-free sequence, starting from 13 CH3OH (7), Scheme 3. With the amine 11 in hand, we utilized Lebel's diazotization procedure, and after careful re-optimization for 13 C-labelled synthesis 31 prepared a large stock solution of [ 13 C]-TMSDAM (12, 0.6M in 2-Me-THF; dried over molecular sieves).…”