Continuous Flow Synthesis and Purification of

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International Edition: DOI: 10.1002/anie.201608444 German Edition: DOI: 10.1002/ange.201608444

Continuous Flow Synthesis

Continuous Flow Synthesis and Purification of Aryldiazomethanes through Hydrazone Fragmentation ric Lvesque, Simon T. Laporte, and Andr B. Charette* Abstract: Electron-rich diazo compounds, such as aryldiazomethanes, are powerful reagents for the synthesis of complex structures, but the risks associated with their toxicity and instability often limit their use. Flow chemistry techniques make these issues avoidable, as the hazardous intermediate can be used as it is produced, avoiding accumulation and handling. Unfortunately, the produced stream is often contaminated with other reagents and by-products, making it incompatible with many applications, especially in catalysis. Herein is reported a metal-free continuous flow method for the production of aryldiazomethane solutions in a non-coordinating solvent from easily prepared, bench-stable sulfonylhydrazones. All by-products are removed by an in-line aqueous wash, leaving a clean, base-free diazo stream. Three successful sensitive metal-catalyzed transformations demonstrated the value of the method.

Diazo compounds are versatile intermediates in organic synthesis. Driven by the release of dinitrogen, this unique structure gives access to highly reactive carbenes,[1] carbenoids[2] or carbocations.[3] However, the toxicity and instability inherent to these compounds usually discourage the exploitation of their chemical potential, especially on large scale applications.[4] Continuous flow chemistry can circumvent these risks.[5] Flow systems allow reagent mixing and product isolation with minimal operator intervention, reducing the risk of exposure. Furthermore, simultaneous reagent production and consumption enables scale-up without increasing the maximum reagent accumulation. Larger quantities can be accessed by increasing the tubings internal diameter or by running reactors in parallel.[6] The development of continuous-flow methods for the safe handling of hazardous intermediates is relevant to the pharmaceutical industry, as safety is the main driver for implementation of continuous flow processing.[7] Electron-rich diazo compounds, such as alkyl- or aryldiazomethanes, are of particular interest because of their inherent nucleophilicity and basicity, allowing alkylations[3] and homologations[8] under mild conditions. However, these same properties increase their Lewis or Brønsted acid sensitivity, complicating their synthesis, storage and use.[9] A straightforward approach for the continuous flow generation of aryldiazomethanes was recently reported by Ley and co-workers.[10] The reagents are obtained by running a CH2Cl2 solution of free hydrazone and diisopropylethyl[*] . Lvesque, S. T. Laporte, Prof. A. B. Charette Department of Chemistry, Universit de Montral P.O. Box 6128 Stn Downtown, Montreal, Quebec, H3C 3J7 (Canada) E-mail: [email protected]

Scheme 1. Alternate approaches for the continuous synthesis of aryldiazomethanes: hydrazone oxidation by metal oxides[10] and sulfonylhydrazone fragmentation (this work).

To be compatible with the most stringent catalytic applications, aryldiazomethanes must be base- and contaminant-free and dissolved in a non-coordinating solvent.[15] Continuous flow production of such solutions requires removal of the base and the sulfinate byproduct from the stream. Several methods have previously been employed to purify specific classes of diazo reagents in flow systems, such as SiO2-filled scavenger columns (R1C(N2)CO2R2),[16] AF2400 tube-in-tube reactors (CH2N2 and CF3CHN2)[17] and membrane-based phase separation (CH2N2 and HC(N2)CO2Et).[18] An aqueous wash followed by a phase separation was deemed the most suitable approach for the preparation of aryldiazomethanes, as it is compatible with most substrates and allows unlimited continuous flow. The system design for such a reaction–purification sequence includes base and sulfonylhydrazone feeds meeting

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amine through a column packed with an excess of solid manganese dioxide. Unfortunately, the resulting diazo solutions still contain a superstoichiometric amount of base, which is incompatible with catalytic systems involving base-sensitive transition metals. Furthermore, the solid oxidizer needs to be conditioned before use and gets reduced and contaminated as the reaction proceeds, requiring interruption of production for column repacking or regeneration. The free hydrazones used as starting materials are also problematic due to their tendency to self-condense into azines,[11] especially when derived from aldehydes. The base-mediated fragmentation of sulfonylhydrazones is an alternative, metal-free approach to aryldiazomethane synthesis. These innocuous,[12] solid and bench-stable[13] compounds readily form via condensation of a sulfonylhydrazide with the corresponding aldehyde and are purified by simple precipitation. Under heat, their conjugate base undergoes sulfinate anion elimination, generating the diazo functional group (Scheme 1).[14]

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Communications before entering a heated reactor. The reactors output is then cooled before addition of an aqueous stream. After sufficient biphasic extraction, the mixture runs through a Zaiput phase separator, leaving all the reaction byproducts behind in the aqueous phase. The cleaned reactive organic phase is then added to the reaction mixture intended to consume the diazo reagent (Figure 1). In order for such a system to operate

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unsatisfactory, but tetramethylguanidine (TMG)[20] turned out to have the perfect combination of a high pKb[21] and a hydrophilic conjugate acid (entry 5). At this point, the only remaining issue was the insolubility of the neutral sulfonylhydrazone precursor in CH2Cl2 before addition of base. Fortunately, it was discovered that one to five equivalents of water-soluble formamide ensured the complete dissolution of most sulfonylhydrazones in CH2Cl2 without negatively impairing the product yield or purity (entry 6). The reaction conditions were then suitable to be tested in the flow reactor (Figure 2). While conditions imitating the

Figure 1. Flow setup concept and expected solution compositions.

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properly, chemicals must be chosen or designed to satisfy its associated constraints. Namely, all reagents and byproducts must be soluble at all times to avoid clogging, and everything but the desired aryldiazomethane must be transferred into the aqueous layer upon extraction. Since the most common reagents for aryldiazomethane preparation do not satisfy Figure 2. Final flow setup to generate and purify aryldiazomethanes. those constraints, a de novo approach had to be designed. At first, the optimal sulfonyl Table 1: Optimization of the sulfonylhydrazone fragmentation into phenyldiazomethane and subsesubstituent was selected. The 4- quent purification. tolylsulfonylhydrazones commonly used for batch synthesis[14] fragment very slowly at temperatures compatible with the sensitive aryldiazomethanes (Table 1, entry 1). Sterically congested sulfonylhydrazones Exp. Solvent(s) R Base Wash Yield Major byhave been reported to undergo Entry type 2 a[a] product(s) [19] elimination more readily, a pro[b] batch MeOH/toluene 4-Tolyl LiOMe H2O 7% 1 cess probably accelerated by steric 1 [b] batch MeOH/toluene Mes LiOMe H2O 47 % BnOMe[c] decompression. The mesityl (Mes) 2[b] 3 batch MeOH/toluene Trip LiOMe H2O 48 % Trip, SO2Li group (entry 2) was optimal, as the 4[d] batch CH2Cl2 Mes LiOiPr H2O 35 % 1 equally efficient triisopropylphenyl 5[d] batch CH2Cl2 Mes TMG H2O 55 % 1 + TMG[e] [f ] (Trip) yielded a water-insoluble sul- 6[d] batch HCONH2/CH2Cl2 Mes TMG H2O 60 % 1 + TMG[e] finate (TripSO2Li, entry 3). 7[g] flow HCONH2/CH2Cl2[f ] Mes TMG H2O 63 % 1 + TMG[e] [h] [f ] flow HCONH2/CH2Cl2 Mes TMG H2O 79 % TMG[e] The typically used alkoxide/ 8 [h] [f ] 9 flow HCONH /CH Cl Mes TMG NH Cl/H O 78 % NH3[i] 2 2 2 4 2 alcohol base and solvent system [h] [f ] flow HCONH2/CH2Cl2 Mes TMG NH5CO3/H2O 79 % none[j] proved problematic. Alcohols can 10[k] 11 batch HCONH2/CH2Cl2[f ] Mes TMG NH5CO3/H2O 75 % none[j] react with diazo reagents (entry 2), 1 and alkali salts tend to be poorly [a] Titrated with BzOH or AcOH and corresponding ester quantified by H-NMR using 1,3,58C, 30 min, 1.0 equiv base. [c] From trimethoxybenzene or triphenylmethane as internal standard. [b] 55 soluble in organic media (entry 4). benzylation of MeOH by phenyldiazomethane. [d] 40 8C, 30 min, 1.0 equiv base. [e] Up to 15 % TMG. Dichloromethane was chosen as [f] 1.0 equiv of formamide. [g] Unoptimized flow conditions (50 8C, 20 min, 1.0 equiv base). [h] Optia non Lewis-basic solvent. mized flow conditions (65 8C, 6 min, 2.0 equiv base). [i] Ammonium benzoate observed after titration Common organic bases, such as [j] No impurity > 3 %, no TMG. [k] Sealed tube heated to 65 8C for 12 min, 2 equiv base, 2 aqueous triethylamine and DBU, were washes. www.angewandte.org

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Communications batch reaction gave a similar result (entry 7), the higher temperature and short reaction time made possible in the pressurized flow reactor increased the yield to a satisfactory 79 % (entry 8). The only major impurity still present in the diazo stream was the excess base. Several mild aqueous proton sources were then tested (entries 9 and 10), and ammonium bicarbonate yielded a clean, uncontaminated aryldiazomethane stream (entry 10). The batch procedure using these optimal parameters resulted in a similar diazo yield, but heating time had to be doubled to achieve complete conversion. Diazo-consuming reactions often use slow addition rates that are usually achieved via syringe pump.[1, 2] To accommodate this constraint, the system was tested at different concentrations and flow rates, adjusting the reactor volume to keep the reaction time constant. Aryldiazomethanes can be produced at rates between 1.0 to 10.0 mmol h 1 [22] and at concentrations between 0.50 m and 0.25 m [23] without significant variations in the yield or purity. The methodology was shown to be quite general (Scheme 2), giving excellent yields of electron-poor aryldiazomethanes (2 b–2 i and 2 s–2 t) and acceptable yields of their highly reactive electron-rich counterparts (2 j–2 n).[24] Diaryldiazomethanes (2 u–2 w) could also be accessed, as well as heterocyclic diazo compounds (2 o–2 p), showcasing the excellent chemoselectivity of the method. For 2 a and 2 l, reagents were pumped continuously for 1 h, producing, respectively 7.1 mmol (71 %) and 6.5 mmol (65 %) No precautions were taken to exclude water and oxygen from the solvents and reagents, as these did not increase the yield and purity of the streams. However, if the diazos intended use involves an air- and water-sensitive reagent system, the stream can be passed through a column packed

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with a 1:1 mixture of dried Celite and 4  molecular sieves with no loss of yield.[25] To investigate the produced aryldiazomethanes applicability to metal-catalyzed reactions, three reagent systems known for their sensitivity to Lewis-basic contaminants were selected. In all cases, the output stream from the flow apparatus was added directly to a stirred reaction mixture. First, the scandium-catalyzed cyclic ketone ring expansion developed by Kingsbury and co-workers was reported to fail when the diazo nucleophile solution is not of high purity.[26] This semipinacol rearrangement was successfully performed with 4 different continuously produced diazo compounds in good yields (Scheme 3). Second, the copper-catalyzed epoxidation of aldehydes reported by Aggarwal and co-workers[1a] involves a typically

Scheme 3. Sc(OTf)3-catalyzed ring expansion of cycloheptanone. 0.23 mmol scale, 0.35 m diazo, 333 mL min 1. [a] Reaction run at 78 8C.

Scheme 2. Flow synthesis of aryldiazomethanes: Scope study using various aldehydes and ketones. Yields are calculated from the isolated ester after titration with benzoic acid. [a] 1 to 5 equiv formamide added in sulfonylhydrazone (1) solution. [b] Sulfonylhydrazone (1) premixed with TMG before injection. [c] Reactor temperature = 65 8C. [d] Reactor temperature = 75 8C. [e] Target concentration: 0.50 m, 0.24 mmol scale [f] Target concentration: 0.25 m, 0.12 mmol scale. [g] Target concentration : 0.25 m, 0.25 mmol scale. [h] Target concentration : 0.50 m, 10.0 mmol scale.  2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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problems usually requiring extensively purified reagents. We are hopeful that this technology will allow a more widespread exploitation of diazo reagents chemical potential.

Experimental Section

Scheme 4. Cu(acac)2-catalyzed epoxidation of 4-NO2-benzaldehyde. 0.28 mmol scale, 0.18 m diazo, 66 mL min 1.

water-sensitive copper carbene and a sulphur ylide as intermediates and requires a very slow addition of the diazo reagent. Nonetheless, the selected aromatic aldehyde underwent smooth epoxidation with 4 different diazo partners (Scheme 4). Finally, the catalytic Simmons–Smith cyclopropanation previously developed in our group[2a] requires the formation of a notoriously Lewis-base sensitive zinc carbenoid.[27] The protected allylic alcohol substrate still underwent cyclopropanation in moderate to excellent yields (Scheme 5).

Typical procedure for the synthesis of mesitylsulfonylhydrazones from aldehydes: Mesitylsulfonylhydrazide (1.00 equiv) was suspended in EtOH in a 20-mL vial open to air and aldehyde (1.01 equiv) was added at once, followed by AcOH (0.005 equiv). Heterogeneous mixture was kept under strong agitation for 90 min. Excess hexanes were added and the resulting off-white solid was recovered by filtration (washing with hexanes). Typical procedure for the continuous flow synthesis and purification of aryldiazomethanes: Stream 1 (1.0 m 1 a, 1.0 m formamide in CH2Cl2, 1.0 equiv, 166 mL min 1) and stream 2 (2.0 m tetramethylguanidine in CH2Cl2, 2.0 equiv, 166 mL min 1) meet in a “T” connector, run through a 2.0 mL coiled tube reactor heated at 65 8C and a 0.25 mL room temperature cooling loop. Stream 3 (1.0 m NH4HCO3/ H2O, 1.00 mL min 1) is added via a second “T” connector. Biphasic stream runs in a 0.25 mL loop to a Zaiput phase separator (PTFE membrane with 1.0 mm pores). Zaiput back pressure regulators are set at 3 atm. Organic stream (333 mL min 1, approx. 0.4 m phenyldiazomethane in DCM) is added directly to the target reaction mixture. Caution! Diazo compounds are presumed to be highly toxic and potentially explosive. Acetic acid should be used to neutralize any spilled or unwanted material. No diazo accumulation was observed in any part of the system after prolonged use. Acetic acid was added upon quenching the catalytic reactions as a precaution, but in all reported examples the diazo was already consumed.

Acknowledgements This work was supported by the Natural Science and Engineering Research Council of Canada (NSERC) under the CREATE Training Program in Continuous Flow Science, the Canada Foundation for Innovation, the Canada Research Chair Program, the FRQNT Centre in Green Chemistry and Catalysis and Universit de Montral. E.L. is grateful to NSERC and Universit de Montral for postgraduate scholarships.

Conflict of interest The authors declare no conflict of interest. Scheme 5. ZnI2-catalyzed cyclopropanation of MOM-protected cinnamyl alcohol. 0.14 mmol scale, 0.35 m diazo, 166 mL min 1.

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In summary, a safe and efficient method for the ondemand production of clean, uncontaminated reactive aryldiazomethane solutions was developed. The sulfonylhydrazone precursors are safe, bench-stable solids easily prepared from the corresponding aldehydes or ketones. The diazo streams concentration and flow rate can be modulated to suit the subsequent reaction. Three typically sensitive reactions were performed on multiple aryldiazomethanes to demonstrate the applicability of this method on real synthetic www.angewandte.org

Keywords: continuous flow · cyclopropanation · diazo compounds · hydrazones · ring expansion

[1] a) V. K. Aggarwal, H. Abdel-Rahman, L. Fan, R. V. H. Jones, M. C. H. Standen, Chem. Eur. J. 1996, 2, 1024; b) X. Creary, J. Hinckley, C. Kraft, M. Genereux, J. Org. Chem. 2011, 76, 2062. [2] a) . Lvesque, S. R. Goudreau, A. B. Charette, Org. Lett. 2014, 16, 1490; b) S. R. Goudreau, A. B. Charette, J. Am. Chem. Soc. 2009, 131, 15633; c) S. H. Goh, L. E. Closs, G. L. Closs, J. Org. Chem. 1969, 34, 25.

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[15] a) S.-F. Zhu, Y. Cai, H.-X. Mao, J.-H. Xie, Q.-L. Zhou, Nat. Chem. 2010, 2, 546; b) M. P. Doyle, V. Bagheri, N. K. Harn, Tetrahedron Lett. 1988, 29, 5119. [16] a) H. E. Bartrum, D. C. Blakemore, C. J. Moody, C. J. Hayes, Chem. Eur. J. 2011, 17, 9586; b) H. E. Bartrum, D. C. Blakemore, C. J. Moody, C. J. Hayes, Tetrahedron 2013, 69, 2276. [17] a) F. Mastronardi, B. Gutmann, C. O. Kappe, Org. Lett. 2013, 15, 5590; b) B. Pieber, C. O. Kappe, Org. Lett. 2016, 18, 1076. [18] a) R. A. Maurya, C. P. Park, J. H. Lee, D.-P. Kim, Angew. Chem. Int. Ed. 2011, 50, 5952; Angew. Chem. 2011, 123, 6074; b) R. A. Maurya, K.-I. Min, D.-P. Kim, Green Chem. 2014, 16, 116. [19] C. C. Dudman, C. B. Reese, Synthesis 1982, 419. [20] T. L. Holton, H. Schechter, J. Org. Chem. 1995, 60, 4725. [21] T. Rodima, I. Kaljurand, A. Pihl, V. Memets, I. Leito, I. A. Koppel, J. Org. Chem. 2002, 67, 1873. [22] Higher or lower rates graze the operating limits of the Zaiput phase separator but could probably be attained by more adapted setups. [23] Numbers suppose a 100 % diazo yield. Multiply by the yield in Scheme 2 to obtain the rates and concentration for a specific substrate. Lower concentrations are also possible. [24] For comparison, the free hydrazone oxidation method reported in Ref. [10] yields 70 % of 2 a, 74 % of 2 b, 48 % of 2 e, 87 % of 2 g and 43 % of 2 l. [25] See Supporting Information. [26] See Supporting Information from D. C. Moebius, J. S. Kingsbury, J. Am. Chem. Soc. 2009, 131, 878. [27] H. Lebel, J.-F. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev. 2003, 103, 977.

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[3] S. E. Metobo, H. Jin, M. Tsiang, C. U. Kim, Bioorg. Med. Chem. Lett. 2006, 16, 3985. [4] P. A. Bray, R. K. Sokas, J. Occup. Environ. Med. 2015, 57, e15. [5] a) B. Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2015, 54, 6688; Angew. Chem. 2015, 127, 6788; b) B. J. Deadman, S. G. Collins, A. R. Maguire, Chem. Eur. J. 2015, 21, 2298; c) Example with MOM-Cl: A. K. Singh, D.-H. Ko, N. K. Vishwakarma, S. Jang, K.-I. Min, D.-P. Kim, Nat. Commun. 2016, 7, 10741; d) Example with isonitriles: S. Sharma, R. A. Maurya, K.-I. Min, G.-Y. Jeong, D.-P. Kim, Angew. Chem. Int. Ed. 2013, 52, 7564; Angew. Chem. 2013, 125, 7712. [6] Y. Su, K. Kuijpers, V. Hessel, T. Nol, React. Chem. Eng. 2016, 1, 73. [7] T. Nol, Y. Su, V. Hessel, in Organometallic Flow Chemistry (Ed.: T. Nol), Springer International Publishing, Cham, 2015, pp. 1 – 41. [8] N. R. Candeias, R. Paterna, P. M. P. Gois, Chem. Rev. 2016, 116, 2937. [9] T. Bug, M. Hartnagel, C. Schlierf, H. Mayr, Chem. Eur. J. 2003, 9, 4068. [10] a) D. N. Tran, C. Battilocchio, S.-B. Lou, J. M. Hawkins, S. V. Ley, Chem. Sci. 2015, 6, 1120; b) N. M. Roda, D. N. Tran, C. Battilocchio, R. Labes, R. J. Ingham, J. M. Hawkins, S. V. Ley, Org. Biomol. Chem. 2015, 13, 2550; c) C. Battilocchio, F. Feist, A. Hafner, M. Simon, D. N. Tran, D. M. Allwood, D. C. Blakemore, S. V. Ley, Nat. Chem. 2016, 8, 360. [11] M. E. Furrow, A. G. Myers, J. Am. Chem. Soc. 2004, 126, 5436. [12] See Supporting Information for DSC-TGA analysis. [13] Samples were kept at room temperature under air for months with no observable chemical change. The sulfonylhydrazone formation was even used as a mean of aldehyde purification/ storage: J. Jiricny, D. M. Orere, C. B. Reese, Synthesis 1978, 919. [14] a) W. R. Bamford, T. S. Stevens, J. Chem. Soc. 1952, 4735; b) R. K. Bartlett, T. S. Stevens, J. Chem. Soc. C 1967, 1964; c) X. Creary, Org. Synth. 1986, 64, 207.

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Communications Continuous Flow Synthesis . Lvesque, S. T. Laporte, A. B. Charette*

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Continuous Flow Synthesis and Purification of Aryldiazomethanes through Hydrazone Fragmentation

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Minimizing risks: A continuous flow method for the production of clean aryldiazomethane solutions was developed. The reagents are generated by the fragmentation of easily prepared, benchstable mesitylsulfonylhydrazones and

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purified by an in-line aqueous wash. A wide array of electron-rich and electronpoor aryldiazomethanes was prepared. The quality of the produced streams is demonstrated by their use in three metalcatalyzed reactions.

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