Continuous synthesis and transformation of diazomethane

—Diazomethane is the simplest diazo compound with high reactivity and is an exceptionally versatile C 1 -building block. However, diazomethane’s application is greatly limited due to its special properties such as highly toxic, carcinogenic, inflammable and explosive. The application of the one-pot reaction and emerging continuous flow technology in the field of hazardous chemicals enable the generated diazomethane to be directly consumed and transformed, effectively ensuring the safety of the reaction process and providing the possibility for its mass production and use. According to the different precursors of diazomethane, the applications of diazomethane in continuous synthesis and in situ transformation in laboratory and industry are systematically summarized.


Introduction
As the simplest diazo compound, Diazomethane (CH 2 N 2 ) has high reactivity and can be used in various transformations with only nitrogen by-products (Fig.1). [1][2][3] But safe production of diazomethane is difficult due to its high carcinogenicity, extreme instability and high volatility, requiring specific safety precautions and dedicated equipments even in very small-scale preparations. [4] In addition, the reaction releases equivalent amounts of nitrogen, resulting in a significant increase in pressure under mass production conditions, increasing the risk of the process and greatly limiting its use in laboratory and industrial production. [5][6][7] As a result, people are working to develop a variety of methods to use CH 2 N 2 in safe and controllable conditions. One-pot reaction has been developed to realize the continuous generation and transformation of CH 2 N 2 . In addition, the emerging continuous flow technology has been widely used in the total synthesis of natural products and drug intermediates synthesis due to its good mass and heat transfer effect and accurate parameter control, which can ensure the safe and efficient reaction of dangerous CH 2 N 2 under continuous flow conditions. [8][9] Based on two commonly used precursors N-Methyl-Nnitrosourea (MNU) and N-Methyl-N-nitrosotoluene-4sulphonamide (Diazald), the continuous synthesis and transformation of CH 2 N 2 in recent ten years were summarized.

Preparation of CH2N2 using MNU
MNU can be alkylated to CH 2 N 2 at lower temperatures and can be readily prepared in one step from the inexpensive and harmless N-Methylurea, making it well suited for continuous processes (Fig.2). [10]

One pot-two phases method
In 2019, Shulishov used a one-pot method with a biphasic solvent system to realize the continuous generation and direct participation of CH 2 N 2 in the cyclopropanylation reaction of spiro [2.4]hepta-4,6-diene (SHD) (Fig.3). [11] CH 2 N 2 generated by MNU under alkali action continuously diffused to organic phase from water phase, and cyclopropane products were prepared under Pd(II) catalysis.

Continuous flow process
In 2011, Rossi reported the preparation of CH 2 N 2 from MNU in Corning GEN1 microflow reactor at a production scale of 19 mol/d. [12] The mixed solution after the reaction was directly channeled into the ethanol solution of benzoic acid, and the final yield of methyl benzoate reached 75% (Fig.4).

Fig.4 Continuous production of diazomethane using MNU
In 2016, Garbarino used a tube-in-flask reactor for the semi-intermittent synthesis of α-chlorone with a maximum yield of 96% (Fig.5). [13] CH 2 N 2 synthesized in two steps from N-Methylurea diffused into conical flask through hydrophobic Teflon AF-2400 membrane to react with anhydride to produce α-diazoketone. Then the αchloroketone was synthesized by adding hydrochloric acid in batches. In 2017, Lehmann used two LL-phase separators to develop a two-step process of preparing CH 2 N 2 with N-Methylurea at a scale of 4.9 g/h (Fig.6). [14] After the reaction, the mixed solution was passed into the LLphase separator to remove the impurities in the water phase. Finally, the organic solution of CH 2 N 2 was directly passed into aryl formic acid to obtain the corresponding aryl methyl ester, with the yield above to 98%. Fig.6 Process for the preparation of CH 2 N 2 using two LL-phase separators In 2020, Hong used the extraction column instead of available LL-phase separator to achieve continuous preparation of CH 2 N 2 from N-Methylure, and finally sent it to the reactor for freezing and dehydrating (Fig.7). [15] The solution can undergo methylation reaction with carboxylic acid and Arndt-Eistert reaction with anhydride to prepare α-diazoketone. Fig.7 Process for the preparation of CH 2 N 2 using extraction column.

Preparation of CH2N2 using Diazald
Diazald can be synthesized from p-toluene sulfonyl chloride through the amidation and nitrosation. It is stable at room temperature and reacts with a base to form CH 2 N 2 under mild conditions, which has become the most widely used precursor (Fig.8). [16] Fig.8 Synthesis of diazomethane using Diazald

One pot-two phases method
In 2012, Morandi proposed a reaction model for the cyclopropanation of olefin catalyzed by FeTPPCl via CH 2 N 2 preparation and direct participation in a twophase system (Fig.9). [17] The water phase contained alkali and Diazald analogizes, in which the generated CH 2 N 2 continuously diffused to the organic phase to form a metal-carbene intermediate with the catalyst, which was continuously captured by the surrounding substrate for reaction.

Continuous flow process
In 2010, Hong injected Diazald and alkali into the upper chamber of the reactor (a) from the feeding port to generate CH 2 N 2 , and the excess reaction liquid flowed into the lower reaction center (b) from the overflow port to continue the reaction. [18] Meanwhile, nitrogen gas was injected to bring the produced CH 2 N 2 out as a gas (Fig.10). In 2011, He used the microreactor technology to synthesize CH 2 N 2 at a rate of 22.3 mol/d, and proposed a reasonable transesterification and ester hydrolysis side reaction mechanism for subsequent methylation reaction (Fig.11). [19] Finally, the side reaction was completely inhibited by respectively using dimethyl sulfoxide as the solvent of the precursor and methanol as the solvent of carboxylic acid. The yield could reach 100%.
In 2019, Yang studied the methylation of benzoic acid from the perspective of chemical reaction and engineering on this basis. It was found that the water content in the system was the key factor affecting the yield, which was assumed to be due to the rapid decomposition of CH 2 N 2 in water. [20] In 2020, Duan used this process to investigate the potential mechanism of the influence of different alcohol solvents on methylation of benzoic acid, further demonstrating the existence of transesterification. [21]  for the continuous generation, separation and consumption of anhydrous CH 2 N 2 (Fig.12). [22] CH 2 N 2 was produced by the reaction of Diazald and potassium hydroxide in the bottom channel and diffused through the membrane to react with the substrate in the upper channel to obtain the corresponding product with the yield of more than 80%. In 2013, Zhang built a simple CH 2 N 2 generating and reacting device which had good applicability to 16 kinds of acids (Fig.13). [23] CH 2 N 2 gas prepared from Diazald was continuously spilt from the small hole in the upper part of the sealed inner tube, and then dissolved in acid solution of conical flask for methylation reaction.

Fig.13 A simple Diazomethane generating and reacting device
In 2010, Koolman used the tube-in-tube reactor to study Pd-catalyzed cyclopropanation of arylcyclopropyl borate compounds (a), [24] and for the first time synthesized several novel multifunctional arylcyclopropyl borate compounds in 45~72% yield (Fig.14). In 2013, Mastronardi developed a continuous process for the preparation of anhydrous CH 2 N 2 at a rate of 35 mmol/d using this reactor. [25] CH 2 N 2 prepared from Diazald diffused through the membrane to the outer tube for methylations of various nucleophiles, [2+3] cycloadditions and cyclopropanations of alkenes (b).
In 2014, Pinho used a tube-in-tube reactor to synthesize chiral α-haloketone with a yield of 87% at a flow rate of 1.25 mmol/h. [26] The Arndt-Eistert reaction between CH 2 N 2 and activated amino acids in the outer cavity yielded α-diazoketone (c), which was finally halogenated in batches to obtain α-halokeone. In the same year, the team achieved the synthesis of β-amino acids from α-diazoketone with 34~54% yield. [27] Fig.14 Reaction of diazomethane in the tube-in-tube reactor In 2014, McKee used CH 2 N 2 gas to directly participate in the cyclopropanation of 7oxabenzonorbornadienes, and synthesized a series of cyclopropanes with good yields (Fig.15). [28] CH 2 N 2 was directly co-distilled with nitrogen when sodium hydroxide aqueous solution was dropped into diethyl ether solution of Diazald, and the gas mixture was directly passed into the reaction bottle containing catalyst and substrates. In 2016, Carlson investigated the reaction effect of 7-Oxabicyclic substrates with bulky C1 or C2 groups, and the yield was good to excellent. [29] In addition, the cyclopropanation of 2,3-diazodicyclic olefin was reported for the first time with yields exceeding 90% (Fig.16). In 2016, Dallinger applied the tube-in-flask reactor to produce CH 2 N 2 from Diazald with a final production scale of 3.9 mg/min. [30] Then Methyl esterification of carboxylic acids (a), synthesis of α-haloketone (b), synthesis of pyrazole (c) and Pd-catalyzed cyclopropanation (d) were performed with yields above 71% (Fig.17). In 2019, Wernik developed a continuous stirred tank reactor (CSTR) tandem tubular reactor for three-step synthesis of chiral α-chloroketone at a rate of 1.54 g/h (Fig.18). [31] CH 2 N 2 prepared from Diazald in the first CH 2 N 2 generator diffused through the membrane to the first CSTR and reacted with activated amino acids to obtain α-diazoketone. To further increase the yield, a similar second device was set up and then α-haloketone was synthesized by halogenation in batches. Fig.18 Synthesis of α-chloroketone in the CSTR cascade In 2021, Sheeran developed a translational flow reactor (PFR) that achieved the production of CH 2 N 2 at a rate of 0.44 mol/h (Fig.19). [32] After the reaction, the mixed solution passed through a GL-phase separator equipped with a selectively permeable hydrophilic membrane to obtain CH 2 N 2 gas. After the absorption of gas, the organic solvent directly passed into the subsequent reactor for methylation reaction and Pdcatalyzed cyclopropanation, with the yield of > 99%. Fig.19 Synthesis of diazomethane in PFR reactor and downstream process

Conclusion
CH 2 N 2 is widely regarded as a useful reagent that can promote various chemical transformations especially methylation and cyclopropanation. It has important applications in pharmaceutical synthesis and fine chemical industry. However, the toxicity, instability and inflammability of CH 2 N 2 greatly increase the difficulty of production and limit its application in industry. In this paper, the applications in the continuous synthesis and transformation of CH 2 N 2 in the past decade are summarized, and the continuous processes involving methylation, cyclopropanylation and Arndt-Eistert reaction at laboratory and industrial scales are described. However, the current processes only focus on verifying the feasibility of classical transformation of CH 2 N 2 , and there are few studies on new reactions and large production scale. Therefore, the development of new process routes and experimental devices for efficient large-scale synthesis and use of CH 2 N 2 under the premise of ensuring safe production will be the focus of future research.