FINE CHEMICALS

SIMON T. R. MÜLLER1, AURÉLIEN MURAT2, PAUL HELLIER2, THOMAS WIRTH1* *Corresponding author 1. School of Chemistry, Cardiff University, Park Place, Main Building, Cardiff CF10 3AT, United Kingdom 2. Institut de Recherche Pierre Fabre, 81603 Gaillac, France

Thomas Wirth

Safe handling of diazo reagents through inline analytics and flow chemistry

KEYWORDS: Diazo compounds, flow chemistry, microreactor, inline analytics, ReactIR.

Through the use of flow chemistry in multistep processes, dangerous but synthetically useful diazo Abstract reagents can be made accessible for large scale applications. The generation, isolation and use of diazo compounds can be performed continuously, therefore never accumulating large quantities of highly energetic material. The use of inline analytics via infrared spectroscopy is key in developing these processes.

INTRODUCTION Another major advantage of continuous fl ow chemistry is continuous information. Rapid optimization of reactions Synthetic chemists thrive to develop and use the most can be easily achieved within microreactors and smaller effi cient ways to assemble complex molecules. For this quantities of expensive reagents are required for optimization purpose, some functional groups stand out in their ability than in typical batch optimizations. It is therefore the perfect to be used fl exibly and selectively for target synthesis. One platform for inline analytic techniques (11). However, the high of the most versatile functional groups is the diazo group, frequencies of potentially different reaction conditions that a highly reactive carbene precursor. Their reactivity stems can be performed within a microreactor have to be met from the formation of metal carbenes using catalysis which by rapid analytics with in-depth information. Inline infrared undergo a broad range of reactions under high chemo-, spectroscopy meets these criteria for many reactions and regio-, and stereocontrol. Examples include stereoselective has been used to detect dangerous residues (12) as well as in cyclopropanation (1), C-H insertion(2) and ring expansion kinetic studies (13). reactions (3). Diazo compounds have been used in the synthesis of natural products such as (+)-Salvileucalin B (4), The outset of this work is to understand how continuous (+)-Lithospermic Acid (5), and (-)-Serotobenine (6). Although fl ow and inline analytics in fl ow can help in handling highly diazo reagents are well studied academically, they are rarely reactive diazo reagents safely and in high effi ciencies. used industrially due to their energetic properties (7).

Continuous fl ow chemistry is one of the most promising ACCESS TO UNSTABILIZED DIAZO REAGENTS IN FLOW techniques for the safe use of hazardous and explosive reagents (8). Exothermal reactions and unstable compounds Most commonly employed diazo reagents are acceptor, can be problematic in batch reactors because the heat transfer acceptor/acceptor or donor/acceptor substituted depends on the surface-to-volume ratio of the reactor used. carbene precursors, due to the relative stability of the When scaling up a reaction from the round bottom fl ask in the lab diazo functionality as well as the enhanced reactivity to production scale, the volume of the reactor increases more of the metal carbene. However, in 2009 Barluenga rapidly than the surface. Therefore, the heat exchange becomes and coworkers found that unstabilized diazo reagents less and less effi cient. Continuous fl ow reactors, however, have such as phenyldiazomethane can react in a reductive a much higher surface-to-volume ratio and are therefore very carbon-carbon bond forming reaction under metal-free effective at heat removal from exothermal reactions. Further, conditions with boronic acids (14). The group of Ley recently continuous processing allows limiting the quantities of hazardous developed a highly effi cient and adaptable fl ow protocol materials formed at any time. Consequently, there are several for the formation and the direct use of unstabilized diazo useful protocols for using dangerous reagents (9) and highly reagents in sp2-sp3 cross-coupling reactions (15) as well as in exothermal reactions in fl ow (10). cyclopropanations (16).

74 Chimica Oggi - Chemistry Today - vol. 33(5) September/October 2015 Problems with unstabilized diazo reagents lie in the reagents. The batch protocol of making these reagents is quite preparation and isolation of these reagents. The most popular slow and requires column chromatography as purification way of making unstabilized diazo compounds so far is the in method. Furthermore, it was unclear if the batch protocol situ decomposition of tosyl hydrazones (17), a reaction with was safe for larger scale operations. We therefore studied the low atom efficiency. Ley and coworkers investigated the development of a more efficient continuous flow protocol oxidation of hydrazones using activated manganese dioxide using inline infrared spectroscopy (18). in flow cartridges to make diazo reagents and subsequently use them without isolation in next reactions (Scheme 1). Diazo compounds in general are often described as highly energetic reagents. To understand the dynamics of the risks associated with diazo compounds, risk class assessment of the reaction shown in Scheme 3 was performed. Differential scanning calorimetry (DSC) was applied on compounds 7 and 8.

Scheme 1. Use of a MnO2 cartridge for diazo formation. BPR: back pressure regulator. Scheme 3. Diazo transfer reaction on methyl phenylacetate 6

The first step of the reaction was optimized by quenching Diazo transfer reagent p-acetamidobenzene sulfonyl azide 7 the diazo compound with acetic acid. Using inline infrared and diazo reagent 8 are both highly energetic with ΔH values -1 -1 analysis, it was found that 10 mmol of MnO2 can oxidize of -331kJ mol and -151kJ mol respectively. Diazo reagent 8 hydrazone 1 for 40 minutes to promote the formation of 2 has a low on-set temperature of 77°C which translates into a mmol of clean diazo reagent 2. safe operation temperature TD24 of just 6°C. Using C80 Calvet- type calorimetry on the reaction mixture it was found that the The coupling products accessible with this method are diazo transfer has to be classified into the highest risk class for highly flexible, demonstrating a broad scope of reaction chemical reactions defined by Stoesselet al. (19). products. Interestingly, multiple double bonds are tolerated and even vinyl diazo reagents can be used in good yields. The kinetics of the diazo transfer reaction in Scheme 3 was The formation of the diazo reagent as well as the coupling determined using inline infrared analysis. For this purpose, starting reaction was performed at room temperature. material 6 and 7 as well as diazo product 8 were calibrated to obtain quantitative data. At 25°C the reaction is complete Because of the mild reaction conditions, it was possible to within 6 hours (> 90% diazo product 8 formed). Although this investigate the kinetics and the mechanism of this cross coupling is a relatively inefficient protocol, the reaction temperature reaction. The reaction was found to be of first order with respect is actually still too high for an easy and safe scale up. The of diazo compound 2. When the substrates are tuned well, the challenge was therefore: could continuous flow chemistry reaction of diazo reagent 2 with boronic acid 3 (k1) is significantly provide a safer and more efficient protocol at the same time? faster than the protodeboronation (k2) to form product 4. Because of that, it is possible to intercept the boronic acid intermediate by Using a continuous set-up with online infrared analysis, we addition of hydrogen peroxide to make benzhydrol 5 (Scheme 2). screened different temperatures (25°C, 40°C, 50°C, and 60°C) and different reaction times (9 min, 17 min, 26 min) in a 3x4 matrix in one day. Figure 1 shows the reaction rate in dependence of the temperature.

Scheme 2. Kinetic studies on cross-coupling reaction of unstabilized diazo compound 2.

Figure 1. Flow reaction rates of diazo transfer reaction in dependence of temperature. DONOR/ACCEPTOR CARBENE CHEMISTRY IN FLOW

One of the most interesting groups of diazo reagents is the class At 25°C batch and flow reaction behave similarly (not of aryl diazoacetates. They give access to donor/acceptor shown). As the reaction rate of the diazo transfer is relatively carbene derivatives, which are highly selective carbene slow, mass transfer in batch mixing is sufficiently efficient.

Chimica Oggi - Chemistry Today - vol. 33(5) September/October 2015 75 When temperatures are increased however, the reaction rate Having established an understanding of diazo formation, can be significantly increased in flow. At °C,60 89% yield can extraction as well as subsequent use of the diazo be obtained within just 26 minutes. This would take around 6 reagents, a multistep system was envisioned. The hours in batch at 25°C. This type of process intensification is multistep set-up is shown in Figure 3. Diazo formation in only possible in flow as conducting the diazo transfer at 60 °C the first reaction coil is followed by the addition of an in batch would be too dangerous. aqueous sodium nitrite quench (1M) and the addition of the extraction solvent n-hexane. The reaction With the results in hand, reaction order and activation energy mixture passes a glass mixer and is then separated into were determined. The diazo transfer on methyl phenylacetate organic and aqueous layer with the use of a liquid/ is a second order reaction. The activation energy of this liquid membrane separating system (FLLEX). The organic -1 -1 reaction is low at EA=56kJ mol K . layer containing the pure diazo species is then pumped into the next coil reactor where carbene reactions are After having established a good understanding of the performed using rhodium catalysis. A broad range of formation of diazo phenylacetates, a way of isolation reactions are accessible, e.g. O-H insertion with high and use of these reagents was studied. For this purpose, yields, cyclopropanations, N-H insertions, S-H insertions a new separation protocol using hydrophobic solvents and carbamate insertions. The system is stable and such as n-hexane or n-heptane was developed. This new can provide multiple gram quantities of material within protocol selectively extracts diazo phenylacetates as several hours of running time. It can further be used for long as their ester chain is n≥3 carbons long with no need combinatorial synthesis by switching the reaction partner of column purification. The solvent ratios have to be well of the diazo compound in the last reactor coil. tuned with a 1 M aqueous sodium nitrite solution being the aqueous solvent. The ratio of n-heptane to aqueous

NaNO2 solution is 11 to 15 volumes per gram of starting ester. The purity of the diazo compound in the organic layer was confirmed by HPLC and inline IR technique

(Figure 2). The partition coefficient KD was determined to be 35.9 by quantitative comparison of the HPLC spectra of the two layers.

Figure 3. Multistep process for formation and use of diazo phenylacetates.

CONCLUSIONS AND OUTLOOK

Diazo reagents are ubiquitously used compounds in academic research. Their thermal properties have limited the use of these powerful reagents on industrial scale so far. Herein, it was discussed how continuous flow chemistry could potentially help overcoming the scarcity of industrial use of diazo reagents. Online monitoring techniques such as infrared analysis provide data rapidly for reaction optimization. Liquid/liquid in-line separation can help to purify diazo reagents to perform multistep reactions so that a batch type diazo isolation is never required. One of the most interesting challenges in the near future will be to scale these systems up to produce kilogram quantities Figure 2. Infrared (above) and HPLC (bottom) spectra of extracted of materials without the need of handling large diazo allyl diazo phenylacetate. quantities at any given time.

Studies on the use of diazo phenylacetates were performed in a continuous flow set-up with inline infrared analysis. REFERENCES AND NOTES Again, the online monitoring provided valuable data on the decomposition reactions showing that a broad range of 1. Lindsay V. N. G., Nicolas C., et al., J. Am. Chem. Soc., 133(23), carbene reactivity is accessible with this set-up. 8972-8981 (2011).

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